Oxytocin antagonist administration regimens to promote embryo implantation and prevent miscarriage

Abstract

This provides a method for treating patients undergoing embryo transfer therapy. [Solution] The present invention provides compositions and methods for using oxytocin antagonists, particularly substituted pyrrolidine-3-one oxime derivatives, in the treatment of subjects undergoing embryo transfer therapy. The compositions and methods of the present invention can be used to administer oxytocin antagonists, particularly (3Z,5S)-5-(hydroxymethyl)-1-[(2'-methyl-1,1'-biphenyl-4-yl)carbonyl]pyrrolidine-3-one O-methyloxime, to subjects, for example, to improve endometrial receptivity after in vitro fertilization (IVF) and intracytoplasmic sperm injection (ICSI) embryo transfer procedures and to reduce the likelihood of embryo implantation failure and miscarriage.

Description

[Technical Field]

[0001] The present invention relates to a composition and method for administering an oxytocin antagonist to subjects undergoing embryo transfer therapy in order to enhance endometrial receptivity and reduce the likelihood of embryo implantation failure. [Background technology]

[0002] Despite recent advances in assisted reproductive technologies, even more advanced treatments such as in vitro fertilization (IVF) and subsequent embryo transfer (IVF / ET) remain relatively ineffective overall, resulting in an average live birth rate of approximately 30% per treatment cycle (Andersen et al., Human Reproduction 24:1267-1287 (2009)). Furthermore, embryo implantation success rates tend to decrease with age. Many current treatment strategies to improve embryo transfer success in patients undergoing embryo transfer therapy have focused on suppressing uterine contractions before embryo transfer. Such therapies include the administration of β-adrenergic receptor agonists and non-steroidal anti-inflammatory drugs (NSAIDS), which have not been shown to provide sufficient clinical benefit (Bernabeu et al., Human Reproduction 21:364-368 (2006), Moon et al., Fertility and Sterility 82:816-820 (2004), and Tsirigotis et al., Human Reproduction 15:10 (2000)). For example, there is still a need for therapeutic procedures and administration regimens that may be used to promote successful embryo implantation by increasing endometrial receptivity at embryo transfer in patients undergoing assisted reproductive technology procedures. [Overview of the project]

[0003] The present invention provides a method for administering an oxytocin antagonist to a subject undergoing embryo transfer therapy, for example, to enhance endometrial receptivity at embryo implantation and reduce the likelihood of embryo implantation failure and miscarriage. In some embodiments of the present invention, the oxytocin antagonist is an inhibitor of the oxytocin receptor. Examples of oxytocin antagonists that can be used in conjunction with the compositions and methods described herein include substituted pyrrolidine-3-one oxime derivatives such as (3Z,5S)-5-(hydroxymethyl)-1-[(2'-methyl-1,1'-biphenyl-4-yl)carbonyl]pyrrolidine-3-one O-methyloxime. Further examples of oxytocin antagonists that can be used in conjunction with the compositions and methods described herein include epersiban, letosiban, barsiban, and atosiban, as well as their derivatives and variants. Using the compositions and methods described herein, oxytocin antagonists as described herein may be administered to subjects before, concurrently with, or after embryo transfer to improve endometrial receptivity and reduce the likelihood of embryo implantation failure. Oxytocin antagonists may be administered to subjects in single doses or multiple doses, such as doses of varying strengths or repeated doses of the same strength. For example, oxytocin antagonists may be administered to subjects undergoing embryo transfer in single high doses or multiple low-intensity doses to achieve a maximum plasma concentration of the oxytocin antagonist (e.g., about 1 μM to about 20 μM, such as compounds represented by formula (I) or (II) as described herein). According to the methods of the present invention, oxytocin receptor antagonists, such as those described herein, may be administered to subjects before, concurrently with, or after intrauterine transfer of one or more embryos produced in vitro by in vitro fertilization (IVF) or intracytoplasmic sperm injection (ICSI) procedures. One or more embryos may be produced, for example, by fertilization of an egg from a subject undergoing embryo transfer, or they may originate from a donor who has not undergone embryo transfer.

[0004] In a first embodiment, the present invention relates to a compound represented by formula (I), [ka] (I) Alternatively, the present invention provides a method for treating subjects undergoing embryo transfer therapy by administering a therapeutically effective amount of an oxytocin antagonist, such as its geometric isomers, enantiomers, diastereomers, racemic mixtures, or salts, to the target. In the formula, n is an integer between 1 and 3. R 1 It is selected from the group consisting of hydrogen and C1-C6 alkyl groups, R 2 Hydrogen, C1-C6 alkyl, C1-C6 alkylaryl, heteroaryl, C1-C6 alkylheteroaryl, C2-C6 alkenyl, C2-C6 alkenylaryl, C2-C6 alkenylheteroaryl, C2-C6 alkynyl, C2-C6 alkynylaryl, C2-C6 alkynylheteroaryl, C3-C6 cycloalkyl, heterocycloalkyl, C1-C6 alkylcycloalkyl, C1-C6 alkylheterocycloalkyl, C1-C6 alkylcarboxy, acyl, C1-C6 alkylacyl, C1-C6 alkyl Selected from the group consisting of siloxy, C1-C6 alkylalkoxy, alkoxycarbonyl, C1-C6 alkylalkoxycarbonyl, aminocarbonyl, C1-C6 alkylaminocarbonyl, C1-C6 alkylacylamino, C1-C6 alkylureido, amino, C1-C6 alkylamino, sulfonyloxy, C1-C6 alkylsulfonyloxy, sulfonyl, C1-C6 alkylsulfonyl, sulfinyl, C1-C6 alkylsulfinyl, C1-C6 alkylsulfanyl, and C1-C6 alkylsulfonylamino, R 3 It is selected from the group consisting of aryls and heteroaryls, X is oxygen and NR 4 Selected from the group consisting of, R 4 R is selected from the group consisting of hydrogen, C1-C6 alkyl, C1-C6 alkylaryl, C1-C6 alkylheteroaryl, aryl, and heteroaryl. 2 and R 4Together with the nitrogen to which they are attached, they can form a 5- to 8-membered saturated or unsaturated heterocycloalkyl ring.

[0005] In another aspect, the present invention features the use of an oxytocin antagonist such as a compound represented by formula (I) in the method described in the foregoing aspects of the present invention.

[0006] In some embodiments, the oxytocin antagonist is administered to a subject before transplanting one or more embryos (e.g., one, two, three, or more embryos) into the uterus of the subject. In some embodiments, the administration reduces the likelihood of implantation failure.

[0007] In another aspect, the present invention provides a method of treating a subject undergoing embryo transfer therapy by transplanting one or more embryos (e.g., one, two, three, or more embryos) into the uterus of the subject, wherein the subject has been previously administered a therapeutically effective amount of an oxytocin antagonist such as a compound represented by formula (I),

Chemical Formula

[0008] In another aspect, the present invention is characterized by the use of an oxytocin antagonist, such as a compound represented by formula (I), in the method described in the aforementioned aspect of the present invention.

[0009] In some embodiments, administration of oxytocin antagonists reduces the likelihood of embryo implantation failure.

[0010] In a further embodiment, the present invention is a. Compounds represented by formula (I), [ka] (I) Or administering a therapeutically effective dose of an oxytocin antagonist, such as its geometric isomer, enantiomer, diastereomer, racemic mixture, or salt, to the target. In the formula, n is an integer between 1 and 3. R 1 It is selected from the group consisting of hydrogen and C1-C6 alkyl groups, R 2 Hydrogen, C1-C6 alkyl, C1-C6 alkylaryl, heteroaryl, C1-C6 alkylheteroaryl, C2-C6 alkenyl, C2-C6 alkenylaryl, C2-C6 alkenylheteroaryl, C2-C6 alkynyl, C2-C6 alkynylaryl, C2-C6 alkynylheteroaryl, C3-C6 cycloalkyl, heterocycloalkyl, C1-C6 alkylcycloalkyl, C1-C6 alkylheterocycloalkyl, C1-C6 alkylcarboxy, acyl, C1-C6 alkylacyl, C1-C6 alkyl Selected from the group consisting of siloxy, C1-C6 alkylalkoxy, alkoxycarbonyl, C1-C6 alkylalkoxycarbonyl, aminocarbonyl, C1-C6 alkylaminocarbonyl, C1-C6 alkylacylamino, C1-C6 alkylureido, amino, C1-C6 alkylamino, sulfonyloxy, C1-C6 alkylsulfonyloxy, sulfonyl, C1-C6 alkylsulfonyl, sulfinyl, C1-C6 alkylsulfinyl, C1-C6 alkylsulfanyl, and C1-C6 alkylsulfonylamino, R 3 It is selected from the group consisting of aryls and heteroaryls, X is oxygen and NR 4 Selected from the group consisting of, R 4R is selected from the group consisting of hydrogen, C1-C6 alkyl, C1-C6 alkylaryl, C1-C6 alkylheteroaryl, aryl, and heteroaryl. 2 and R 4 They can form a 5-8 member saturated or unsaturated heterocycloalkyl ring together with the nitrogen to which they are bound, when administered. b. A method is provided for treating a subject undergoing embryo transfer therapy by transferring one or more embryos (e.g., one, two, three, or more embryos) into the subject's uterus after administration of an oxytocin antagonist.

[0011] In another aspect, the present invention is characterized by the use of an oxytocin antagonist, such as a compound represented by formula (I), in the method described in the aforementioned aspect of the present invention.

[0012] In some embodiments, administration reduces the likelihood of embryo implantation failure.

[0013] In some embodiments of the above aspects of the present invention, the oxytocin antagonist is administered to the subject about 1 hour to about 24 hours before the transfer of one or more embryos to the subject. In some embodiments, the oxytocin antagonist is administered to the subject about 1 hour to about 12 hours before the transfer of one or more embryos to the subject. In some embodiments, the oxytocin antagonist is administered to the subject about 12 hours to about 24 hours before the transfer of one or more embryos to the subject.

[0014] In some embodiments of the above aspects of the present invention, the oxytocin antagonist is administered to the subject about 1 to 10 hours before the transfer of one or more embryos to the subject. In some embodiments, the oxytocin antagonist is administered to the subject about 1 to 9 hours before the transfer of one or more embryos to the subject. In some embodiments, the oxytocin antagonist is administered to the subject about 1 to 8 hours before the transfer of one or more embryos to the subject. In some embodiments, the oxytocin antagonist is administered to the subject about 1 to 7 hours before the transfer of one or more embryos to the subject. In some embodiments, the oxytocin antagonist is administered to the subject about 1 to 6 hours before the transfer of one or more embryos to the subject. In some embodiments, the oxytocin antagonist is administered to the subject about 1 to 5 hours before the transfer of one or more embryos to the subject. In some embodiments, the oxytocin antagonist is administered to the subject about 1 to 4 hours before the transfer of one or more embryos to the subject.

[0015] In some embodiments of the above aspects of the present invention, the oxytocin antagonist is administered to the subject about 2 to 6 hours before the transfer of one or more embryos to the subject. In some embodiments, the oxytocin antagonist is administered to the subject about 3 to 5 hours before the transfer of one or more embryos to the subject. In some embodiments, the oxytocin antagonist is administered to the subject about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, or 24 hours or more before the transfer of one or more embryos to the subject.

[0016] In some embodiments of any of the above aspects of the present invention, an oxytocin antagonist is administered to the subject about four hours before the transfer of one or more embryos into the subject.

[0017] In some embodiments of any of the above aspects of the present invention, an oxytocin antagonist is administered to the subject before embryo transfer in a single dose.

[0018] In some embodiments of any of the above aspects of the present invention, an oxytocin antagonist is administered to the subject before embryo transfer (i.e., before the transfer of one or more embryos into the subject's uterus) in multiple doses, such as 1 to 20 doses, at intervals of 12, 24, 36, 48, 60, 72, 84, 96, 108, 120, 132, 144, 156, 168 hours, or longer, for example, before embryo transfer. In some embodiments, oxytocin antagonists are administered to subjects before embryo transfer in doses of 1 to 20 times every 24 hours, such as once, twice, three times, four times, five times, six times, seven times, eight times, nine times, ten times, eleven times, twelve times, thirteen times, fourteen times, fifteen times, sixteen times, seventeen times, eighteen times, nine times, ten times, eleven times, twelve times, thirteen times, fourteen times, fifteen times, sixteen times, seventeen times, eighteen times, nineteen times, twenty times, and so on. In some embodiments, oxytocin antagonists are administered to subjects in doses of more than 20 times every 24 hours before embryo transfer.

[0019] For example, in some embodiments, the oxytocin antagonist is administered to the subject in 1 to 10 doses, for example, every 12 hours, 24 hours, 36 hours, 48 ​​hours, 60 hours, 72 hours, 84 hours, 96 hours, 108 hours, 120 hours, 132 hours, 144 hours, 156 hours, 168 hours, or longer, prior to embryo transfer. In some embodiments, the oxytocin antagonist is administered to the subject in 1 to 10 doses every 24 hours prior to embryo transfer, such as once every 24 hours, twice every 24 hours, three times every 24 hours, four times every 24 hours, five times every 24 hours, six times every 24 hours, seven times every 24 hours, eight times every 24 hours, nine times every 24 hours, or ten times every 24 hours.

[0020] In some embodiments, the oxytocin antagonist is administered to the subject in 1 to 5 doses, for example, every 12 hours, 24 hours, 36 hours, 48 ​​hours, 60 hours, 72 hours, 84 hours, 96 hours, 108 hours, 120 hours, 132 hours, 144 hours, 156 hours, 168 hours, or longer, prior to embryo transfer. In some embodiments, the oxytocin antagonist is administered to the subject in 10 to 20 doses, for example, every 12 hours, 24 hours, 36 hours, 48 ​​hours, 60 hours, 72 hours, 84 hours, 96 hours, 108 hours, 120 hours, 132 hours, 144 hours, 156 hours, 168 hours, or longer, prior to embryo transfer. In some embodiments, oxytocin antagonists are administered to subjects in 10 to 15 doses, for example, every 12, 24, 36, 48, 60, 72, 84, 96, 108, 120, 132, 144, 156, 168 hours, or longer intervals prior to embryo transfer.

[0021] In some embodiments, an oxytocin antagonist is administered to the subject in doses of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 144, 156, 168 hours, or more, for example, every 12, 24, 36, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 times, or more, every 12, 24, 36, 36, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 times, or more, before embryo transfer.

[0022] In some embodiments, the oxytocin antagonist is administered to the subject before embryo transfer in up to seven doses every 24 hours (e.g., doses 1, 2, 3, 4, 5, 6, or 7), such as up to seven doses of compound (II) every 24 hours. In some embodiments, the oxytocin antagonist is administered to the subject before embryo transfer in one dose every 24 hours, such as one dose every 24 hours, such as one dose every 24 hours, such as one dose every 24 hours, such as two doses In some embodiments, the oxytocin antagonist is administered to the subject in five doses every 24 hours prior to embryo transfer, such as five doses every 24 hours of compound (II) below. In some embodiments, the oxytocin antagonist is administered to the subject in six doses every 24 hours prior to embryo transfer, such as six doses every 24 hours of compound (II) below. In some embodiments, the oxytocin antagonist is administered to the subject in seven doses every 24 hours prior to embryo transfer, such as seven doses every 24 hours of compound (II) below.

[0023] Multiple doses may be administered, for example, starting approximately 1 hour to 14 days or more before embryo transfer. In some embodiments, multiple doses are administered starting approximately 1 hour to 7 days or more before embryo transfer. In some embodiments, multiple doses may be administered starting approximately 1 day to 14 days before embryo transfer. In some embodiments, multiple doses may be administered starting approximately 3 days to 11 days before embryo transfer. In some embodiments, multiple doses may be administered starting approximately 1 day to 7 days before embryo transfer. In some embodiments, multiple doses may be administered starting approximately 2 days to 5 days before embryo transfer. In some embodiments, multiple doses may be administered starting approximately 3 days to 4 days before embryo transfer. For example, in some embodiments, oxytocin antagonists may be started and administered approximately 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 24 hours, 36 hours, 48 ​​hours, 60 hours, 72 hours, 84 hours, 96 hours, 108 hours, 120 hours, 132 hours, 144 hours, 156 hours, 168 hours, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, 21 days, 22 days, 23 days, 24 days, 25 days, 26 days, 27 days, 28 days, 29 days, 30 days, or more before embryo transfer to the subject.

[0024] In some embodiments, multiple doses are administered starting approximately two days before embryo transfer.

[0025] In some embodiments, multiple doses are administered starting approximately three days before embryo transfer.

[0026] In some embodiments, multiple doses are administered starting approximately four days before embryo transfer.

[0027] In some embodiments, multiple doses are administered starting approximately 5 days before embryo transfer.

[0028] In some embodiments, multiple doses are administered starting approximately 6 days before embryo transfer.

[0029] In some embodiments, multiple doses are administered starting approximately 7 days before embryo transfer.

[0030] In some embodiments, the multi-dose regimen concludes on the day of embryo transfer to the subject. In some embodiments, the multi-dose regimen concludes with a final dose of oxytocin antagonist administered concurrently with (e.g., within 60 minutes) the transfer of one or more embryos to the subject.

[0031] In some embodiments of the above aspects of the present invention, multiple doses continue after embryo transfer. For example, an oxytocin antagonist may be administered to the subject in one or more additional doses simultaneously with embryo transfer. In some embodiments, the oxytocin antagonist is administered approximately 1 hour to approximately 1 week, or longer, after the transfer of one or more embryos to the subject (e.g., approximately 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 24 hours, 36 hours, 48 ​​hours, 60 hours, 72 hours, 84 hours, 96 hours, 108 hours, 120 hours, 132 hours). The patient is administered one or more additional doses after embryo transfer (e.g., multiple regular doses), such as one or more additional doses administered within 144 hours, 156 hours, 168 hours, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, 21 days, 22 days, 23 days, 24 days, 25 days, 26 days, 27 days, 28 days, 29 days, 30 days or longer.

[0032] For example, in some embodiments, the oxytocin antagonist is administered to the subject in one or more additional doses approximately 1 hour to 24 hours after the transfer of one or more embryos to the subject. In some embodiments, the oxytocin antagonist is administered to the subject in one or more additional doses approximately 1 hour to 12 hours after the transfer of one or more embryos to the subject. In some embodiments, the oxytocin antagonist is administered to the subject in one or more additional doses approximately 12 hours to 24 hours after the transfer of one or more embryos to the subject. In some embodiments, the oxytocin antagonist is administered to the subject in one or more additional doses approximately 1 hour to 10 hours after the transfer of one or more embryos to the subject. In some embodiments, the oxytocin antagonist is administered to the subject in one or more additional doses approximately 1 hour to 9 hours after the transfer of one or more embryos to the subject. In some embodiments, the oxytocin antagonist is administered to the subject in one or more additional doses approximately 1 hour to 8 hours after the transfer of one or more embryos to the subject. In some embodiments, the oxytocin antagonist is administered to the subject in one or more additional doses approximately 1 to 7 hours after the transfer of one or more embryos to the subject. In some embodiments, the oxytocin antagonist is administered to the subject in one or more additional doses approximately 1 to 6 hours after the transfer of one or more embryos to the subject. In some embodiments, the oxytocin antagonist is administered to the subject in one or more additional doses approximately 1 to 5 hours after the transfer of one or more embryos to the subject. In some embodiments, the oxytocin antagonist is administered to the subject in one or more additional doses approximately 1 to 4 hours after the transfer of one or more embryos to the subject. In some embodiments, the oxytocin antagonist is administered to the subject in one or more additional doses approximately 2 to 6 hours after the transfer of one or more embryos to the subject. In some embodiments, the oxytocin antagonist is administered to the subject in one or more additional doses approximately 3 to 5 hours after the transfer of one or more embryos to the subject.

[0033] In some embodiments, an oxytocin antagonist is administered to the subject in one or more additional doses, starting at approximately 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 24 hours, 36 hours, 48 ​​hours, 60 hours, 72 hours, 84 hours, 96 hours, 108 hours, 120 hours, 132 hours, 144 hours, 156 hours, 168 hours, or longer after implantation of one or more embryos into the subject.

[0034] In some embodiments, oxytocin antagonists are administered to subjects in multiple additional doses after embryo transfer, for example, every 12 hours, 24 hours, 36 hours, 48 ​​hours, 60 hours, 72 hours, 84 hours, 96 hours, 108 hours, 120 hours, 132 hours, 144 hours, 156 hours, 168 hours, or longer, such as 1 to 20 additional doses. In some embodiments, oxytocin antagonists are further administered to subjects after embryo transfer in doses of 1 to 20 times every 24 hours, such as once, twice, three times, four times, five times, six times, seven times, eight times, nine times, ten times, eleven times, twelve times, thirteen times, fourteen times, fifteen times, sixteen times, seventeen times, eighteen times, and twenty times every 24 hours. In some embodiments, oxytocin antagonists are further administered to subjects after embryo transfer in doses of more than 20 times every 24 hours.

[0035] For example, in some embodiments, the oxytocin antagonist is administered to the subject in 1 to 10 additional doses, for example, every 12 hours, 24 hours, 36 hours, 48 ​​hours, 60 hours, 72 hours, 84 hours, 96 hours, 108 hours, 120 hours, 132 hours, 144 hours, 156 hours, 168 hours, or longer intervals after embryo transfer. In some embodiments, the oxytocin antagonist is further administered to the subject after embryo transfer in 1 to 10 doses every 24 hours, such as once every 24 hours, twice every 24 hours, three times every 24 hours, four times every 24 hours, five times every 24 hours, six times every 24 hours, seven times every 24 hours, eight times every 24 hours, nine times every 24 hours, or ten times every 24 hours.

[0036] In some embodiments, the oxytocin antagonist is administered to the subject in 1 to 5 additional doses, for example, every 12, 24, 36, 48, 60, 72, 84, 96, 108, 120, 132, 144, 156, 168 hours, or longer, after embryo transfer. In some embodiments, the oxytocin antagonist is administered to the subject in 10 to 20 additional doses, for example, every 12, 24, 36, 48, 60, 72, 84, 96, 108, 120, 132, 144, 156, 168 hours, or longer, after embryo transfer. In some embodiments, oxytocin antagonists are administered to subjects in 10 to 15 additional doses, for example, every 12, 24, 36, 48, 60, 72, 84, 96, 108, 120, 132, 144, 156, 168 hours, or longer intervals after embryo transfer.

[0037] In some embodiments, oxytocin antagonists are administered to subjects in additional doses, for example, every 12, 24, 36, 48, 60, 72, 84, 96, 108, 120, 132, 144, 156, 168 hours, or longer, after embryo transfer, for 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 times, or more.

[0038] In some embodiments, the oxytocin antagonist is administered to the subject after embryo transfer in up to seven additional doses every 24 hours (e.g., doses 1, 2, 3, 4, 5, 6, or 7), such as up to seven doses of compound (II) every 24 hours. In some embodiments, the oxytocin antagonist is administered to the subject after embryo transfer in one dose every 24 hours, such as one additional dose every 24 hours of compound (II). In some embodiments, the oxytocin antagonist is administered to the subject after embryo transfer in two doses every 24 hours, such as two additional doses every 24 hours of compound (II). In some embodiments, the oxytocin antagonist is administered to the subject after embryo transfer in three doses every 24 hours, such as three additional doses every 24 hours of compound (II). In some embodiments, the oxytocin antagonist is administered to the subject in four doses every 24 hours after embryo transfer, such as four additional doses of compound (II) every 24 hours. In some embodiments, the oxytocin antagonist is administered to the subject in five doses every 24 hours after embryo transfer, such as five additional doses of compound (II) every 24 hours. In some embodiments, the oxytocin antagonist is administered to the subject in six doses every 24 hours after embryo transfer, such as six additional doses of compound (II) every 24 hours. In some embodiments, the oxytocin antagonist is administered to the subject in seven doses every 24 hours after embryo transfer, such as seven additional doses of compound (II) every 24 hours.

[0039] If one or more additional doses of oxytocin antagonist are administered to the subject after embryo transfer, the administration of oxytocin antagonist may be terminated, for example, within approximately 1 hour to 14 days after embryo transfer, or even later. For example, oxytocin antagonist administration may be terminated within approximately 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 24 hours, 36 hours, 48 ​​hours, 60 hours, 72 hours, 84 hours, 96 hours, 108 hours, 120 hours, 132 hours, 144 hours, 156 hours, 168 hours, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, 21 days, 22 days, 23 days, 24 days, 25 days, 26 days, 27 days, 28 days, 29 days, or 30 days after embryo transfer, or at any time thereafter.

[0040] Therefore, in some embodiments, the oxytocin antagonist is administered to subjects in an additional daily dose approximately 1 to 14 days after embryo transfer. In some embodiments, the additional daily dose is administered to subjects approximately 3 to 11 days after embryo transfer. In some embodiments, the additional daily dose is administered to subjects for 7 days after embryo transfer.

[0041] In another embodiment, the present invention relates to a compound represented by formula (I), [ka] (I) Alternatively, the present invention provides a method for treating subjects undergoing embryo transfer therapy by administering a therapeutically effective amount of an oxytocin antagonist, such as its geometric isomers, enantiomers, diastereomers, racemic mixtures, or salts, to the target. In the formula, n is an integer between 1 and 3. R 1 It is selected from the group consisting of hydrogen and C1-C6 alkyl groups, R 2Hydrogen, C1-C6 alkyl, C1-C6 alkylaryl, heteroaryl, C1-C6 alkylheteroaryl, C2-C6 alkenyl, C2-C6 alkenylaryl, C2-C6 alkenylheteroaryl, C2-C6 alkynyl, C2-C6 alkynylaryl, C2-C6 alkynylheteroaryl, C3-C6 cycloalkyl, heterocycloalkyl, C1-C6 alkylcycloalkyl, C1-C6 alkylheterocycloalkyl, C1-C6 alkylcarboxy, acyl, C1-C6 alkylacyl, C1-C6 alkyl Selected from the group consisting of siloxy, C1-C6 alkylalkoxy, alkoxycarbonyl, C1-C6 alkylalkoxycarbonyl, aminocarbonyl, C1-C6 alkylaminocarbonyl, C1-C6 alkylacylamino, C1-C6 alkylureido, amino, C1-C6 alkylamino, sulfonyloxy, C1-C6 alkylsulfonyloxy, sulfonyl, C1-C6 alkylsulfonyl, sulfinyl, C1-C6 alkylsulfinyl, C1-C6 alkylsulfanyl, and C1-C6 alkylsulfonylamino, R 3 It is selected from the group consisting of aryls and heteroaryls, X is oxygen and NR 4 Selected from the group consisting of, R 4 R is selected from the group consisting of hydrogen, C1-C6 alkyl, C1-C6 alkylaryl, C1-C6 alkylheteroaryl, aryl, and heteroaryl. 2 and R 4 Together with the nitrogen atoms to which they are bonded, they can form a 5-8 member saturated or unsaturated heterocycloalkyl ring. Oxytocin antagonists are administered concurrently with the implantation of one or more embryos (e.g., one, two, three, or more embryos) into the target uterus.

[0042] In another aspect, the present invention is characterized by the use of an oxytocin antagonist, such as a compound represented by formula (I), in the method described in the aforementioned aspect of the present invention.

[0043] In some embodiments, administration reduces the likelihood of embryo implantation failure.

[0044] In another aspect, the present invention provides a method for treating a subject undergoing embryo transfer therapy by implanting one or more embryos (e.g., one, two, three, or more embryos) into the subject's uterus, wherein the subject is a compound represented by formula (I), [ka] (I) Alternatively, a therapeutically effective dose of an oxytocin antagonist, such as its geometric isomer, enantiomer, diastereomer, racemic mixture, or salt, is administered simultaneously. In the formula, n is an integer between 1 and 3. R 1 It is selected from the group consisting of hydrogen and C1-C6 alkyl groups, R 2 Hydrogen, C1-C6 alkyl, C1-C6 alkylaryl, heteroaryl, C1-C6 alkylheteroaryl, C2-C6 alkenyl, C2-C6 alkenylaryl, C2-C6 alkenylheteroaryl, C2-C6 alkynyl, C2-C6 alkynylaryl, C2-C6 alkynylheteroaryl, C3-C6 cycloalkyl, heterocycloalkyl, C1-C6 alkylcycloalkyl, C1-C6 alkylheterocycloalkyl, C1-C6 alkylcarboxy, acyl, C1-C6 alkylacyl, C1-C6 alkyl Selected from the group consisting of siloxy, C1-C6 alkylalkoxy, alkoxycarbonyl, C1-C6 alkylalkoxycarbonyl, aminocarbonyl, C1-C6 alkylaminocarbonyl, C1-C6 alkylacylamino, C1-C6 alkylureido, amino, C1-C6 alkylamino, sulfonyloxy, C1-C6 alkylsulfonyloxy, sulfonyl, C1-C6 alkylsulfonyl, sulfinyl, C1-C6 alkylsulfinyl, C1-C6 alkylsulfanyl, and C1-C6 alkylsulfonylamino, R 3 It is selected from the group consisting of aryls and heteroaryls, X is oxygen and NR 4 Selected from the group consisting of, R 4 R is selected from the group consisting of hydrogen, C1-C6 alkyl, C1-C6 alkylaryl, C1-C6 alkylheteroaryl, aryl, and heteroaryl. 2 and R 4 These can form a 5- to 8-membered saturated or unsaturated heterocycloalkyl ring together with the nitrogen atoms to which they are bonded.

[0045] In another aspect, the present invention is characterized by the use of an oxytocin antagonist, such as a compound represented by formula (I), in the method described in the aforementioned aspect of the present invention.

[0046] In some embodiments, administration of oxytocin antagonists reduces the likelihood of embryo implantation failure.

[0047] In a further embodiment, the present invention is a. Compounds represented by formula (I), [ka] (I) or administering a therapeutically effective amount of an oxytocin antagonist, such as its geometric isomer, enantiomer, diastereomer, racemic mixture, or salt, In the formula, n is an integer between 1 and 3. R 1 It is selected from the group consisting of hydrogen and C1-C6 alkyl groups, R 2Hydrogen, C1-C6 alkyl, C1-C6 alkylaryl, heteroaryl, C1-C6 alkylheteroaryl, C2-C6 alkenyl, C2-C6 alkenylaryl, C2-C6 alkenylheteroaryl, C2-C6 alkynyl, C2-C6 alkynylaryl, C2-C6 alkynylheteroaryl, C3-C6 cycloalkyl, heterocycloalkyl, C1-C6 alkylcycloalkyl, C1-C6 alkylheterocycloalkyl, C1-C6 alkylcarboxy, acyl, C1-C6 alkylacyl, C1-C6 alkyl Selected from the group consisting of siloxy, C1-C6 alkylalkoxy, alkoxycarbonyl, C1-C6 alkylalkoxycarbonyl, aminocarbonyl, C1-C6 alkylaminocarbonyl, C1-C6 alkylacylamino, C1-C6 alkylureido, amino, C1-C6 alkylamino, sulfonyloxy, C1-C6 alkylsulfonyloxy, sulfonyl, C1-C6 alkylsulfonyl, sulfinyl, C1-C6 alkylsulfinyl, C1-C6 alkylsulfanyl, and C1-C6 alkylsulfonylamino, R 3 It is selected from the group consisting of aryls and heteroaryls, X is oxygen and NR 4 Selected from the group consisting of, R 4 R is selected from the group consisting of hydrogen, C1-C6 alkyl, C1-C6 alkylaryl, C1-C6 alkylheteroaryl, aryl, and heteroaryl. 2 and R 4 They can form a 5-8 member saturated or unsaturated heterocycloalkyl ring together with the nitrogen to which they are bound, when administered. b. A method is provided for treating a subject undergoing embryo transfer therapy by simultaneously administering an oxytocin antagonist and transferring one or more embryos (e.g., one, two, three, or more embryos) into the subject's uterus.

[0048] In another aspect, the present invention is characterized by the use of an oxytocin antagonist, such as a compound represented by formula (I), in the method described in the aforementioned aspect of the present invention.

[0049] In some embodiments, administration reduces the likelihood of embryo implantation failure.

[0050] In some embodiments, oxytocin antagonists are administered to subjects simultaneously with a single-dose embryo transfer.

[0051] In some embodiments, oxytocin antagonists are administered to subjects in multiple doses, starting during embryo transfer (e.g., multiple regular doses) and continuing after embryo transfer, such as 1 to 20 doses, starting during embryo transfer and continuing after embryo transfer, for example, every 12, 24, 36, 48, 60, 72, 84, 96, 108, 120, 132, 144, 156, 168 hours, or longer. For example, in some embodiments, an oxytocin antagonist is administered to the subject in 1 to 10 additional doses, starting during embryo transfer and continuing after embryo transfer, for example, every 12, 24, 36, 48, 60, 72, 84, 96, 108, 120, 132, 144, 156, 168 hours, or longer, after embryo transfer. In some embodiments, the oxytocin antagonist is administered to the subject in 1 to 5 additional doses, starting during embryo transfer and continuing after embryo transfer, for example, every 12, 24, 36, 48, 60, 72, 84, 96, 108, 120, 132, 144, 156, 168 hours, or longer, after embryo transfer. In some embodiments, the oxytocin antagonist is administered to the subject in 10 to 20 additional doses, starting during embryo transfer and continuing after embryo transfer, for example, every 12, 24, 36, 48, 60, 72, 84, 96, 108, 120, 132, 144, 156, 168 hours, or longer, after embryo transfer. In some embodiments, oxytocin antagonists are administered to subjects in 10 to 15 additional doses, starting during embryo transfer and continuing after embryo transfer, for example, every 12, 24, 36, 48, 60, 72, 84, 96, 108, 120, 132, 144, 156, 168 hours, or longer, after embryo transfer.In some embodiments, the oxytocin antagonist is administered to the subject in doses of 1, 2, 3, 4, 5, 6, or more times, for example, every 12, 24, 36, 48, 60, 72, 84, 96, 108, 120, 132, 144, 156, 168 hours, or longer, after embryo transfer. In some embodiments, the oxytocin antagonist is administered to the subject in doses of up to 7 times every 24 hours (e.g., 1, 2, 3, 4, 5, 6, or 7 doses), such as up to 7 doses of compound (II) every 24 hours.

[0052] For example, in some embodiments, the oxytocin antagonist is first administered to the subject simultaneously with the transfer of one or more embryos into the subject's uterus, and then the oxytocin antagonist is administered to the subject in one or more additional doses approximately 1 hour to 24 hours after the transfer of one or more embryos into the subject. For example, in some embodiments, the oxytocin antagonist is administered to the subject in one or more additional doses approximately 1 hour to 12 hours after the transfer of one or more embryos into the subject. In some embodiments, the oxytocin antagonist is administered to the subject in one or more additional doses approximately 12 hours to 24 hours after the transfer of one or more embryos into the subject. In some embodiments, the oxytocin antagonist is administered to the subject in one or more additional doses approximately 1 hour to 10 hours after the transfer of one or more embryos into the subject. In some embodiments, the oxytocin antagonist is administered to the subject in one or more additional doses approximately 1 hour to 9 hours after the transfer of one or more embryos into the subject. In some embodiments, the oxytocin antagonist is administered to the subject in one or more additional doses approximately 1 to 8 hours after the transfer of one or more embryos to the subject. In some embodiments, the oxytocin antagonist is administered to the subject in one or more additional doses approximately 1 to 7 hours after the transfer of one or more embryos to the subject. In some embodiments, the oxytocin antagonist is administered to the subject in one or more additional doses approximately 1 to 6 hours after the transfer of one or more embryos to the subject. In some embodiments, the oxytocin antagonist is administered to the subject in one or more additional doses approximately 1 to 5 hours after the transfer of one or more embryos to the subject. In some embodiments, the oxytocin antagonist is administered to the subject in one or more additional doses approximately 1 to 4 hours after the transfer of one or more embryos to the subject. In some embodiments, the oxytocin antagonist is administered to the subject in one or more additional doses approximately 2 to 6 hours after the transfer of one or more embryos to the subject. In some embodiments, an oxytocin antagonist is administered to the subject in one or more additional doses approximately 3 to 5 hours after the implantation of one or more embryos into the subject.

[0053] In some embodiments, the oxytocin antagonist is first administered to the subject simultaneously with the implantation of one or more embryos into the subject's uterus, and then the oxytocin antagonist is administered to the subject in one or more additional doses, starting at approximately 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 24 hours, 36 hours, 48 ​​hours, 60 hours, 72 hours, 84 hours, 96 hours, 108 hours, 120 hours, 132 hours, 144 hours, 156 hours, 168 hours, or longer after the implantation of one or more embryos into the subject.

[0054] In some embodiments, the oxytocin antagonist is first administered to the subject simultaneously with the transfer of one or more embryos into the subject's uterus, and then the oxytocin antagonist is administered to the subject in multiple additional doses after embryo transfer, such as 1 to 20 additional doses, every 12, 24, 36, 48, 60, 72, 84, 96, 108, 120, 132, 144, 156, 168 hours, or longer. In some embodiments, oxytocin antagonists are further administered to subjects after embryo transfer in doses of 1 to 20 times every 24 hours, such as once, twice, three times, four times, five times, six times, seven times, eight times, nine times, ten times, eleven times, twelve times, thirteen times, fourteen times, fifteen times, sixteen times, seventeen times, eighteen times, and twenty times every 24 hours. In some embodiments, oxytocin antagonists are further administered to subjects after embryo transfer in doses of more than 20 times every 24 hours.

[0055] For example, in some embodiments, the oxytocin antagonist is first administered to the subject at the same time as the implantation of one or more embryos into the subject's uterus, and the compound is then administered to the subject in 1 to 10 additional doses, for example, every 12, 24, 36, 48, 60, 72, 84, 96, 108, 120, 132, 144, 156, 168 hours, or longer, after embryo transfer. In some embodiments, oxytocin antagonists are further administered to subjects after embryo transfer in doses of 1 to 10 times every 24 hours, such as once every 24 hours, twice every 24 hours, three times every 24 hours, four times every 24 hours, five times every 24 hours, six times every 24 hours, seven times every 24 hours, eight times every 24 hours, nine times every 24 hours, and ten times every 24 hours.

[0056] For example, in some embodiments, the oxytocin antagonist is first administered to the subject at the same time as the implantation of one or more embryos into the subject's uterus, and the oxytocin antagonist is then administered to the subject in 1 to 5 additional doses, for example, every 12, 24, 36, 48, 60, 72, 84, 96, 108, 120, 132, 144, 156, 168 hours, or longer, after embryo transfer. In some embodiments, the oxytocin antagonist is administered to the subject in 10 to 20 additional doses, for example, every 12 hours, 24 hours, 36 hours, 48 ​​hours, 60 hours, 72 hours, 84 hours, 96 hours, 108 hours, 120 hours, 132 hours, 144 hours, 156 hours, 168 hours, or longer, after embryo transfer. In some embodiments, the oxytocin antagonist is administered to the subject in 10 to 15 additional doses, for example, every 12 hours, 24 hours, 36 hours, 48 ​​hours, 60 hours, 72 hours, 84 hours, 96 hours, 108 hours, 120 hours, 132 hours, 144 hours, 156 hours, 168 hours, or longer, after embryo transfer.

[0057] In some embodiments, the oxytocin antagonist is first administered to the subject at the same time as the implantation of one or more embryos into the subject's uterus, and the compound is subsequently administered to the subject in additional doses, for example, every 12, 24, 36, 48, 60, 72, 84, 96, 108, 120, 132, 144, 156, 168 hours, or longer, for 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 times, or more, after embryo transfer.

[0058] In some embodiments, the oxytocin antagonist is first administered to the subject simultaneously with the transfer of one or more embryos into the subject's uterus, and the oxytocin antagonist is then administered to the subject after embryo transfer in up to seven additional doses every 24 hours (e.g., doses 1, 2, 3, 4, 5, 6, or 7), such as up to seven doses of compound (II) every 24 hours. In some embodiments, the oxytocin antagonist is administered to the subject after embryo transfer in one dose every 24 hours, such as one additional dose every 24 hours of compound (II). In some embodiments, the oxytocin antagonist is administered to the subject after embryo transfer in two doses every 24 hours, such as two additional doses every 24 hours of compound (II). In some embodiments, the oxytocin antagonist is administered to the subject after embryo transfer in three doses every 24 hours, such as three additional doses every 24 hours of compound (II). In some embodiments, the oxytocin antagonist is administered to the subject in four doses every 24 hours after embryo transfer, such as four additional doses of compound (II) every 24 hours. In some embodiments, the oxytocin antagonist is administered to the subject in five doses every 24 hours after embryo transfer, such as five additional doses of compound (II) every 24 hours. In some embodiments, the oxytocin antagonist is administered to the subject in six doses every 24 hours after embryo transfer, such as six additional doses of compound (II) every 24 hours. In some embodiments, the oxytocin antagonist is administered to the subject in seven doses every 24 hours after embryo transfer, such as seven additional doses of compound (II) every 24 hours.

[0059] If one or more additional doses of oxytocin antagonist are administered to the subject after embryo transfer, the administration of oxytocin antagonist may be terminated, for example, within approximately 1 hour to 14 days after embryo transfer, or even later. For example, oxytocin antagonist administration may be terminated within approximately 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 24 hours, 36 hours, 48 ​​hours, 60 hours, 72 hours, 84 hours, 96 hours, 108 hours, 120 hours, 132 hours, 144 hours, 156 hours, 168 hours, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, 21 days, 22 days, 23 days, 24 days, 25 days, 26 days, 27 days, 28 days, 29 days, or 30 days after embryo transfer, or at any time thereafter.

[0060] Therefore, in some embodiments, the oxytocin antagonist is first administered to the subject simultaneously with the transfer of one or more embryos into the subject's uterus, and the oxytocin antagonist is then administered to the subject in an additional daily dose for approximately 1 to 14 days post-embryo transfer. In some embodiments, the additional daily dose is administered to the subject for approximately 3 to 11 days post-embryo transfer. In some embodiments, the additional daily dose is administered to the subject for 7 days post-embryo transfer.

[0061] In another embodiment, the present invention relates to a compound represented by formula (I), [ka] (I) Alternatively, the present invention provides a method for treating subjects undergoing embryo transfer therapy by administering a therapeutically effective amount of an oxytocin antagonist, such as its geometric isomers, enantiomers, diastereomers, racemic mixtures, or salts, to the target. In the formula, n is an integer between 1 and 3. R 1 It is selected from the group consisting of hydrogen and C1-C6 alkyl groups, R 2Hydrogen, C1-C6 alkyl, C1-C6 alkylaryl, heteroaryl, C1-C6 alkylheteroaryl, C2-C6 alkenyl, C2-C6 alkenylaryl, C2-C6 alkenylheteroaryl, C2-C6 alkynyl, C2-C6 alkynylaryl, C2-C6 alkynylheteroaryl, C3-C6 cycloalkyl, heterocycloalkyl, C1-C6 alkylcycloalkyl, C1-C6 alkylheterocycloalkyl, C1-C6 alkylcarboxy, acyl, C1-C6 alkylacyl, C1-C6 alkyl Selected from the group consisting of siloxy, C1-C6 alkylalkoxy, alkoxycarbonyl, C1-C6 alkylalkoxycarbonyl, aminocarbonyl, C1-C6 alkylaminocarbonyl, C1-C6 alkylacylamino, C1-C6 alkylureido, amino, C1-C6 alkylamino, sulfonyloxy, C1-C6 alkylsulfonyloxy, sulfonyl, C1-C6 alkylsulfonyl, sulfinyl, C1-C6 alkylsulfinyl, C1-C6 alkylsulfanyl, and C1-C6 alkylsulfonylamino, R 3 It is selected from the group consisting of aryls and heteroaryls, X is oxygen and NR 4 Selected from the group consisting of, R 4 R is selected from the group consisting of hydrogen, C1-C6 alkyl, C1-C6 alkylaryl, C1-C6 alkylheteroaryl, aryl, and heteroaryl. 2 and R 4 Together with the nitrogen atoms to which they are bonded, they can form a 5-8 member saturated or unsaturated heterocycloalkyl ring. Oxytocin antagonists are administered to the subject after the implantation of one or more embryos (e.g., one, two, three, or more embryos) into the subject's uterus.

[0062] In another aspect, the present invention is characterized by the use of an oxytocin antagonist, such as a compound represented by formula (I), in the method described in the aforementioned aspect of the present invention.

[0063] In some embodiments, administration reduces the likelihood of embryo implantation failure.

[0064] In another aspect, the present invention provides a method for treating a subject undergoing embryo transfer therapy by implanting one or more embryos (e.g., one, two, three, or more embryos) into the subject's uterus, the subject then being treated with a compound represented by formula (I), [ka] (I) Alternatively, a therapeutically effective dose of an oxytocin antagonist, such as its geometric isomer, enantiomer, diastereomer, racemic mixture, or salt, is administered. In the formula, n is an integer between 1 and 3. R 1 It is selected from the group consisting of hydrogen and C1-C6 alkyl groups, R 2 Hydrogen, C1-C6 alkyl, C1-C6 alkylaryl, heteroaryl, C1-C6 alkylheteroaryl, C2-C6 alkenyl, C2-C6 alkenylaryl, C2-C6 alkenylheteroaryl, C2-C6 alkynyl, C2-C6 alkynylaryl, C2-C6 alkynylheteroaryl, C3-C6 cycloalkyl, heterocycloalkyl, C1-C6 alkylcycloalkyl, C1-C6 alkylheterocycloalkyl, C1-C6 alkylcarboxy, acyl, C1-C6 alkylacyl, C1-C6 alkyl Selected from the group consisting of siloxy, C1-C6 alkylalkoxy, alkoxycarbonyl, C1-C6 alkylalkoxycarbonyl, aminocarbonyl, C1-C6 alkylaminocarbonyl, C1-C6 alkylacylamino, C1-C6 alkylureido, amino, C1-C6 alkylamino, sulfonyloxy, C1-C6 alkylsulfonyloxy, sulfonyl, C1-C6 alkylsulfonyl, sulfinyl, C1-C6 alkylsulfinyl, C1-C6 alkylsulfanyl, and C1-C6 alkylsulfonylamino, R 3 It is selected from the group consisting of aryls and heteroaryls, X is oxygen and NR 4 Selected from the group consisting of, R 4 R is selected from the group consisting of hydrogen, C1-C6 alkyl, C1-C6 alkylaryl, C1-C6 alkylheteroaryl, aryl, and heteroaryl. 2 and R 4 These can form a 5- to 8-membered saturated or unsaturated heterocycloalkyl ring together with the nitrogen atoms to which they are bonded.

[0065] In another aspect, the present invention is characterized by the use of an oxytocin antagonist, such as a compound represented by formula (I), in the method described in the aforementioned aspect of the present invention.

[0066] In some embodiments, administration of oxytocin antagonists reduces the likelihood of embryo implantation failure.

[0067] In another embodiment, the present invention is a. Compounds represented by formula (I), [ka] (I) Or administering a therapeutically effective dose of an oxytocin antagonist, such as its geometric isomer, enantiomer, diastereomer, racemic mixture, or salt, to the target. In the formula, n is an integer between 1 and 3. R 1 It is selected from the group consisting of hydrogen and C1-C6 alkyl groups, R 2Hydrogen, C1-C6 alkyl, C1-C6 alkylaryl, heteroaryl, C1-C6 alkylheteroaryl, C2-C6 alkenyl, C2-C6 alkenylaryl, C2-C6 alkenylheteroaryl, C2-C6 alkynyl, C2-C6 alkynylaryl, C2-C6 alkynylheteroaryl, C3-C6 cycloalkyl, heterocycloalkyl, C1-C6 alkylcycloalkyl, C1-C6 alkylheterocycloalkyl, C1-C6 alkylcarboxy, acyl, C1-C6 alkylacyl, C1-C6 alkyl Selected from the group consisting of siloxy, C1-C6 alkylalkoxy, alkoxycarbonyl, C1-C6 alkylalkoxycarbonyl, aminocarbonyl, C1-C6 alkylaminocarbonyl, C1-C6 alkylacylamino, C1-C6 alkylureido, amino, C1-C6 alkylamino, sulfonyloxy, C1-C6 alkylsulfonyloxy, sulfonyl, C1-C6 alkylsulfonyl, sulfinyl, C1-C6 alkylsulfinyl, C1-C6 alkylsulfanyl, and C1-C6 alkylsulfonylamino, R 3 It is selected from the group consisting of aryls and heteroaryls, X is oxygen and NR 4 Selected from the group consisting of, R 4 R is selected from the group consisting of hydrogen, C1-C6 alkyl, C1-C6 alkylaryl, C1-C6 alkylheteroaryl, aryl, and heteroaryl. 2 and R 4 They can form a 5-8 member saturated or unsaturated heterocycloalkyl ring together with the nitrogen to which they are bound, when administered. b. A method is provided for treating a subject undergoing embryo transfer therapy by transferring one or more embryos (e.g., one, two, three, or more embryos) into the subject's uterus before administering an oxytocin antagonist.

[0068] In another aspect, the present invention is characterized by the use of an oxytocin antagonist, such as a compound represented by formula (I), in the method described in the aforementioned aspect of the present invention.

[0069] In some embodiments, administration reduces the likelihood of embryo implantation failure.

[0070] In some embodiments, the oxytocin antagonist is administered to the subject approximately 1 to 24 hours after the transfer of one or more embryos to the subject. For example, in some embodiments, the oxytocin antagonist is administered to the subject approximately 1 to 12 hours after the transfer of one or more embryos to the subject. In some embodiments, the oxytocin antagonist is administered to the subject approximately 12 to 24 hours after the transfer of one or more embryos to the subject. In some embodiments, the oxytocin antagonist is administered to the subject approximately 1 to 10 hours after the transfer of one or more embryos to the subject. In some embodiments, the oxytocin antagonist is administered to the subject approximately 1 to 9 hours after the transfer of one or more embryos to the subject. In some embodiments, the oxytocin antagonist is administered to the subject approximately 1 to 8 hours after the transfer of one or more embryos to the subject. In some embodiments, the oxytocin antagonist is administered to the subject approximately 1 to 7 hours after the transfer of one or more embryos to the subject. In some embodiments, the oxytocin antagonist is administered to the subject approximately 1 to 6 hours after the transfer of one or more embryos to the subject. In some embodiments, the oxytocin antagonist is administered to the subject approximately 1 to 5 hours after the transfer of one or more embryos to the subject. In some embodiments, the oxytocin antagonist is administered to the subject approximately 1 to 4 hours after the transfer of one or more embryos to the subject. In some embodiments, the oxytocin antagonist is administered to the subject approximately 2 to 6 hours after the transfer of one or more embryos to the subject. In some embodiments, the oxytocin antagonist is administered to the subject approximately 3 to 5 hours after the transfer of one or more embryos to the subject.

[0071] For example, in some embodiments, the oxytocin antagonist is administered to the subject approximately 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours, 18 hours, 19 hours, 20 hours, 21 hours, 22 hours, 23 hours, 24 hours, 36 hours, 48 ​​hours, 60 hours, 72 hours, 84 hours, 96 hours, 108 hours, 120 hours, 132 hours, 144 hours, 156 hours, 168 hours, or longer after implantation of one or more embryos into the subject.

[0072] In some embodiments, oxytocin antagonists are administered to subjects after a single-dose embryo transfer.

[0073] In some embodiments, oxytocin antagonists are administered to subjects in multiple doses after embryo transfer, such as in multiple regular doses. In some embodiments, oxytocin antagonists are administered to subjects in 1 to 20 doses after embryo transfer, for example, every 12 hours, 24 hours, 36 hours, 48 ​​hours, 60 hours, 72 hours, 84 hours, 96 hours, 108 hours, 120 hours, 132 hours, 144 hours, 156 hours, 168 hours, or longer. In some embodiments, oxytocin antagonists are administered to subjects after embryo transfer in doses of 1 to 20 times every 24 hours, such as once, twice, three times, four times, five times, six times, seven times, eight times, nine times, ten times, eleven times, twelve times, thirteen times, fourteen times, fifteen times, sixteen times, seventeen times, eighteen times, nine times, ten times, eleven times, twelve times, thirteen times, fourteen times, fifteen times, sixteen times, seventeen times, eighteen times, nineteen times, twenty times, and so on. In some embodiments, oxytocin antagonists are administered to subjects after embryo transfer in doses of more than 20 times every 24 hours.

[0074] For example, in some embodiments, the oxytocin antagonist is administered to the subject in 1 to 10 doses every 24 hours, such as every 12 hours, every 24 hours, every 36 hours, every 48 hours, every 60 hours, every 72 hours, every 84 hours, every 96 hours, every 108 hours, every 120 hours, every 132 hours, every 144 hours, every 156 hours, every 168 hours, or longer intervals after embryo transfer. In some embodiments, the oxytocin antagonist is administered to the subject in 1 to 10 doses every 24 hours after embryo transfer, such as once every 24 hours, twice every 24 hours, three times every 24 hours, four times every 24 hours, five times every 24 hours, six times every 24 hours, seven times every 24 hours, eight times every 24 hours, nine times every 24 hours, or ten times every 24 hours.

[0075] In some embodiments, the oxytocin antagonist is administered to the subject in 1 to 5 doses, for example, every 12 hours, 24 hours, 36 hours, 48 ​​hours, 60 hours, 72 hours, 84 hours, 96 hours, 108 hours, 120 hours, 132 hours, 144 hours, 156 hours, 168 hours, or longer intervals after embryo transfer. In some embodiments, the oxytocin antagonist is administered to the subject in 10 to 20 doses, for example, every 12 hours, 24 hours, 36 hours, 48 ​​hours, 60 hours, 72 hours, 84 hours, 96 hours, 108 hours, 120 hours, 132 hours, 144 hours, 156 hours, 168 hours, or longer intervals after embryo transfer. In some embodiments, oxytocin antagonists are administered to subjects in 10 to 15 doses, for example, every 12, 24, 36, 48, 60, 72, 84, 96, 108, 120, 132, 144, 156, 168 hours, or longer intervals after embryo transfer.

[0076] In some embodiments, the oxytocin antagonist is administered to the subject in 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 144, 156, 168-hour doses, or more, for example, every 12, 24, 36, 48, 48, 60, 72, 84, 96, 108, 120, 132, 144, 156, 168 hours, or longer, after embryo transfer.

[0077] In some embodiments, the oxytocin antagonist is administered to the subject after embryo transfer in up to seven doses every 24 hours (e.g., doses 1, 2, 3, 4, 5, 6, or 7), such as up to seven doses of compound (II) every 24 hours. In some embodiments, the oxytocin antagonist is administered to the subject after embryo transfer in one dose every 24 hours, such as one dose every 24 hours, such as one dose every 24 hours, such as one dose every 24 hours, such as two doses In some embodiments, the oxytocin antagonist is administered to the subject after embryo transfer in five doses every 24 hours, such as five doses every 24 hours of compound (II) below. In some embodiments, the oxytocin antagonist is administered to the subject after embryo transfer in six doses every 24 hours, such as six doses every 24 hours of compound (II) below. In some embodiments, the oxytocin antagonist is administered to the subject after embryo transfer in seven doses every 24 hours, such as seven doses every 24 hours of compound (II) below.

[0078] If oxytocin antagonists are administered in multiple doses after embryo transfer, administration of oxytocin antagonists may be discontinued, for example, within approximately 1 hour to 14 days after embryo transfer, or even later. For example, oxytocin antagonist administration may be terminated within approximately 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 24 hours, 36 hours, 48 ​​hours, 60 hours, 72 hours, 84 hours, 96 hours, 108 hours, 120 hours, 132 hours, 144 hours, 156 hours, 168 hours, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, 21 days, 22 days, 23 days, 24 days, 25 days, 26 days, 27 days, 28 days, 29 days, or 30 days after embryo transfer, or at any time thereafter.

[0079] Therefore, in some embodiments, the oxytocin antagonist is administered to subjects at a daily dose for approximately 1 to 14 days after embryo transfer. In some embodiments, the daily dose is administered to subjects for approximately 3 to 11 days after embryo transfer. In some embodiments, the daily dose is administered to subjects for 7 days after embryo transfer.

[0080] In some embodiments, administration of an oxytocin antagonist to a subject reduces the likelihood of the subject having a miscarriage. For example, administration of an oxytocin antagonist may reduce the likelihood of the subject having a miscarriage after the embryo transfer process, for example, during a gestational period of at least about 24 weeks, so that the subject gives birth to a live baby (e.g., a living human infant).

[0081] In some embodiments, the oxytocin antagonist is administered to the subject in an amount sufficient to achieve a plasma concentration of the oxytocin antagonist in the subject at 1 μM to about 20 μM. In some embodiments, the oxytocin antagonist is a compound represented by formula (I) (e.g., a compound represented by formula (II) herein), and is administered to the subject so that the subject exhibits a plasma concentration of the compound at about 1 μM to about 20 μM at the time of embryo transfer to the subject's uterus. For example, in some embodiments, the compound is administered to the subject in an amount sufficient to achieve a plasma concentration of the compound in the subject at about 5 μM to about 19 μM, 10 μM to about 18 μM, 14 μM to about 17 μM, 15 μM to about 16 μM, 1 μM to about 19 μM, 2 μM to about 18 μM, 3 μM to about 17 μM, 4 μM to about 16 μM, 5 μM to about 15 μM, or higher (e.g., at the time of embryo transfer). In some embodiments, plasma concentrations, such as the maximum plasma concentration achieved from a single dose of the compound, are achieved within approximately 1 to 3 hours (e.g., approximately 1 hour, 1.1 hours, 1.2 hours, 1.3 hours, 1.4 hours, 1.5 hours, 1.6 hours, 1.7 hours, 1.8 hours, 1.9 hours, 2 hours, 2.1 hours, 2.2 hours, 2.3 hours, 2.4 hours, 2.5 hours, 2.6 hours, 2.7 hours, 2.8 hours, 2.9 hours, or 3 hours) of administration of the compound to the subject.

[0082] In some embodiments, one to three embryos are implanted in the target. In some embodiments, one to two embryos are implanted in the target. For example, in some embodiments, one embryo is implanted in the target. In some embodiments, two embryos are implanted in the target. In some embodiments, three embryos are implanted in the target.

[0083] In some embodiments, the subject has previously undergone one or more cycles (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more) of unsuccessful embryo transfer therapy, such as in vitro fertilization-embryo transfer (IVF-ET) or intracytoplasmic sperm injection-embryo transfer (ICSI-ET). In some embodiments, the subject has not previously undergone embryo transfer therapy.

[0084] In some embodiments, the subject is a mammal, and one or more embryos are mammalian embryos. For example, in some embodiments, the mammal is a human, and one or more mammalian embryos are human embryos.

[0085] In some embodiments, one or more embryos are produced in vitro by in vitro fertilization (IVF), such as by IVF of one or more eggs derived from the subject. In some embodiments, one or more embryos are produced in vitro by intracytoplasmic sperm injection (ICSI), such as by ICSI of one or more eggs derived from the subject.

[0086] In some embodiments, one or more oocytes are derived from one or more oocytes (1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more oocytes) isolated from the subject. In some embodiments, one or more oocytes contain 1 to 4 oocytes (mature oocytes). For example, in some embodiments, one or more oocytes contain 1 mature oocyte. In some embodiments, one or more oocytes contain 2 mature oocytes. In some embodiments, one or more oocytes contain 3 mature oocytes. In some embodiments, one or more oocytes contain 4 mature oocytes.

[0087] In some embodiments, one or more oocytes are isolated directly from the subject.

[0088] In some embodiments, one or more oocytes or eggs are isolated from the subject approximately 1 to 7 days before implantation into one or more embryos. In some embodiments, one or more oocytes or eggs are isolated from the subject approximately 2 to 6 days before implantation into one or more embryos. In some embodiments, one or more oocytes or eggs are isolated from the subject approximately 3 to 5 days before implantation into one or more embryos. In some embodiments, one or more oocytes or eggs are isolated from the subject approximately 3 days before implantation into one or more embryos. In some embodiments, one or more oocytes or eggs are isolated from the subject approximately 4 days before implantation into one or more embryos. In some embodiments, one or more oocytes or eggs are isolated from the subject approximately 5 days before implantation into one or more embryos.

[0089] In some embodiments, a gonadotropin-releasing hormone (GnRH) antagonist is administered to the subject before isolation of one or more oocytes (e.g., including one or more mature oocytes) or eggs from the subject. In some embodiments, human chorionic gonadotropin (hCG) is administered to the subject before isolation of one or more oocytes or eggs from the subject. For example, hCG may be administered to the subject in a single dose. In some embodiments, hCG may be administered to the subject in multiple doses. hCG may be administered to the subject intravenously, such as by intravenous injection.

[0090] In some embodiments, progesterone is administered to the subject after the isolation of one or more oocytes or eggs from the subject. Progesterone may be administered intravaginally in doses of approximately 300 mg to approximately 600 mg (e.g., approximately 300 mg, 310 mg, 315 mg, 320 mg, 325 mg, 330 mg, 335 mg, 340 mg, 345 mg, 350 mg, 355 mg, 360 mg, 365 mg, 370 mg, 375 mg, 380 mg, 385 mg, 390 mg, 395 mg, 400 mg, 405 mg, 410 mg, 415 mg, 420 mg, 425 mg, 430 mg, 435 mg, 440 mg, 445 mg) It may be administered in doses of mg, 450 mg, 455 mg, 460 mg, 465 mg, 470 mg, 475 mg, 480 mg, 485 mg, 490 mg, 495 mg, 500 mg, 505 mg, 510 mg, 515 mg, 520 mg, 525 mg, 530 mg, 535 mg, 540 mg, 545 mg, 550 mg, 555 mg, 560 mg, 565 mg, 570 mg, 575 mg, 580 mg, 585 mg, 590 mg, 595 mg, 600 mg or more. In some embodiments, 300 mg of progesterone per dose is administered to the subject after the isolation of one or more oocytes or eggs from the subject. In some embodiments, 600 mg of progesterone per dose is administered to the subject after the isolation of one or more oocytes or eggs from the subject. In some embodiments, progesterone is administered to the subject daily, preferably starting within about 24 hours of the isolation of one or more oocytes or eggs from the subject (e.g., within about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, or 24 hours) and continuing for about 6 weeks or more after the transfer of one or more embryos to the subject (e.g., about 6 weeks, about 7 weeks, about 8 weeks, about 9 weeks, about 10 weeks, or longer).

[0091] In some embodiments, one or more embryos are newly implanted into the target uterus (i.e., implanted into the target uterus during the same menstrual cycle as the isolation of one or more oocytes or eggs from the target). For example, one or more embryos may be implanted into the target uterus approximately 1 to 7 days after the isolation of one or more oocytes or eggs from the target in preparation for IVF or ICSI (e.g., approximately 3 to 5 days, such as approximately 3, 4, or 5 days).

[0092] In some embodiments, one or more embryos are frozen and thawed before being implanted into a target.

[0093] In some embodiments, each of the one or more embryos contains 6 to 8 blastomeres immediately before implantation into a target. The blastomeres may be approximately equal in size when evaluated by visual microscopy before implantation into a target. In some embodiments, the one or more embryos include embryos having the morphology of a morula. In some embodiments, the one or more embryos include embryos having the morphology of a blastula (e.g., a mammalian blastocyst).

[0094] In some embodiments, the oxytocin antagonist is (3Z,5S)-5-(hydroxymethyl)-1-[(2'-methyl-1,1'-biphenyl-4-yl)carbonyl]pyrrolidine-3-one O-methyloxime, represented by formula (II). [ka] (II)

[0095] In some embodiments, the compound represented by formula (II) (i.e., (3Z,5S)-5-(hydroxymethyl)-1-[(2'-methyl-1,1'-biphenyl-4-yl)carbonyl]pyrrolidine-3-one O-methyloxime) is substantially pure. For example, in some embodiments, the compound represented by formula (II) has a purity of at least 85%, such as 85% to 99.9% or higher (e.g., 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.1%, 99.2%, 99.3%, 99.4%, 99.5%, 99.6%, 99.7%, 99.8%, 99.9%, or higher). The purity of the compound represented by formula (II) can be evaluated using chromatographic methods such as nuclear magnetic resonance (NMR) techniques and / or high-performance liquid chromatography (HPLC) procedures, which are well known in the art and described herein, such as those techniques described in U.S. Patent No. 9,670,155, the disclosure of which is incorporated herein by reference in whole.

[0096] In some embodiments, the compound represented by formula (II) is substantially pure with respect to the diastereomer of the compound and other by-products that may be formed during the synthesis of the compound. For example, in some embodiments, the compound represented by formula (II) has a purity of at least 85%, such as 85% to 99.9% or higher (e.g., 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.1%, 99.2%, 99.3%, 99.4%, 99.5%, 99.6%, 99.7%, 99.8%, 99.9%, or higher), with respect to the diastereomer of the compound and other by-products that may be formed during the synthesis of the compound, such as the by-product formed during the synthesis of the compound as described in U.S. Patent No. 9,670,155. The purity of the compound represented by formula (II) can be evaluated using chromatographic methods such as NMR techniques and / or HPLC procedures, which are well known in the art and described herein, such as those techniques described in U.S. Patent No. 9,670,155.

[0097] In some embodiments, the compound represented by formula (II) is substantially pure with respect to its (3E) diastereomer, (3E,5S)-5-(hydroxymethyl)-1-[(2'-methyl-1,1'-biphenyl-4-yl)carbonyl]pyrrolidine-3-one O-methyloxime. For example, in some embodiments, the compound represented by formula (II) has a purity of at least 85%, such as 85% to 99.9% or higher with respect to (3E,5S)-5-(hydroxymethyl)-1-[(2'-methyl-1,1'-biphenyl-4-yl)carbonyl]pyrrolidine-3-one O-methyloxime (e.g., 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.1%, 99.2%, 99.3%, 99.4%, 99.5%, 99.6%, 99.7%, 99.8%, 99.9%, or higher). For example, compound (II) may be administered in the form of a composition containing less than 15% of the (3E) diastereomer (e.g., tablets such as dispersible tablets, capsules, gel caps, powders, liquid solutions, or liquid suspensions). For example, compound (II) may be administered in the form of a composition containing less than 14%, less than 13%, less than 12%, less than 11%, less than 10%, less than 9%, less than 8%, less than 7%, less than 6%, less than 5%, less than 4%, less than 3%, less than 2%, less than 1%, less than 0.1%, less than 0.01%, less than 0.001%, or less of the (3E) diastereomer (e.g., tablets such as dispersible tablets, capsules, gel caps, powders, liquid solutions, or liquid suspensions). The purity of the compound represented by formula (II) may be evaluated using chromatographic methods such as NMR techniques and / or HPLC procedures, which are well known in the art and described herein, such as those techniques described in U.S. Patent No. 9,670,155.

[0098] In some embodiments, the compound is in a crystalline state. In some embodiments, the compound exhibits characteristic X-ray powder diffraction peaks at approximately 7.05°2θ, 13.13°2θ, and 23.34°2θ. For example, the compound may exhibit characteristic X-ray powder diffraction peaks at approximately 7.05°2θ, 12.25°2θ, 13.13°2θ, 16.54°2θ, 18.00°2θ, 21.84°2θ, and 23.34°2θ. In some embodiments, the compound exhibits characteristic X-ray powder diffraction peaks as shown in Table 1 below. Table 1. Characteristic X-ray powder diffraction (XRPD) peaks of the crystalline form of compound (II). [Table 1]

[0099] In some embodiments, the compound is administered orally to the subject. In some embodiments, the compound is administered intravenously to the subject. For example, the compound may be administered to the subject in the form of a tablet, capsule, gel cap, powder, liquid solution, or liquid suspension. In some embodiments, the compound is administered to the subject in the form of a tablet, such as a dispersible tablet. A dispersible tablet may have, for example, one or more of the following components: a. Approximately 1-20% by weight of calcium silicate, b. Approximately 0.1-20% by weight of PVP30K, c. Approximately 0.01-5% by weight of poloxamer 188, d. Approximately 0.5-20% by weight of croscarmellose sodium e. Approximately 1-90% by weight of microcrystalline cellulose 112, f. Approximately 1-90% by weight of lactose monohydrate. g. Approximately 0.01-0.5% by weight of sodium saccharin, and h. Approximately 0.1-10% by weight of glycerol dibehenate. For example, a dispersible tablet may have the following composition: a. Approximately 5% by weight of calcium silicate, b. Approximately 1% by weight of PVP30K, c. Approximately 2% by weight of poloxamer 188, d. Approximately 5% by weight of croscarmellose sodium, e. Approximately 1.5% by weight of microcrystalline cellulose 112, f. Approximately 47.8% by weight of lactose monohydrate. g. Approximately 0.2% by weight of sodium saccharin, and h. Approximately 4% by weight of glycerol dibehenate.

[0100] In some embodiments, the compound is present in approximately 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 105 mg, 110 mg, 115 mg, 120 mg, 125 mg, 130 mg, 135 mg, 140 mg, 145 mg, 150 mg, 155 mg, 1 The compound is administered to the subject in unit dosage forms containing approximately 25 mg to approximately 250 mg of the compound, such as unit dosage forms containing 60 mg, 165 mg, 170 mg, 175 mg, 180 mg, 185 mg, 190 mg, 195 mg, 200 mg, 205 mg, 210 mg, 215 mg, 220 mg, 225 mg, 230 mg, 235 mg, 240 mg, 245 mg, 250 mg, or more of the compound. In some embodiments, the compound is administered to the subject in unit dosage forms containing approximately 25 mg to approximately 75 mg of the compound, such as unit dosage forms containing approximately 50 mg of the compound. In some embodiments, the compound is administered to the subject in unit dosage forms containing approximately 175 mg to approximately 225 mg of the compound, such as unit dosage forms containing approximately 200 mg of the compound.

[0101] In some embodiments, subjects are administered approximately 50 mg to 950 mg of the compound per dose. For example, subjects are administered approximately 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 105 mg, 110 mg, 115 mg, 120 mg, 125 mg, 130 mg, 135 mg, 140 mg, 145 mg, 150 mg, 155 mg, 160 mg, 165 mg, 170 mg, 175 mg per dose. mg, 180mg, 185mg, 190mg, 195mg, 200mg, 205mg, 210mg, 215mg, 220mg, 225mg, 230mg, 235mg, 240 mg, 245mg, 250mg, 255mg, 260mg, 265mg, 270mg, 275mg, 280mg, 285mg, 290mg, 295mg, 300mg, 305m g, 310mg, 315mg, 320mg, 325mg, 330mg, 335mg, 340mg, 345mg, 350mg, 355mg, 360mg, 365mg, 370m g, 375mg, 380mg, 385mg, 390mg, 400mg, 405mg, 410mg, 415mg, 420mg, 425mg, 430mg, 435mg, 440mg , 445mg, 450mg, 455mg, 460mg, 465mg, 470mg, 475mg, 480mg, 485mg, 490mg, 500mg, 505mg, 510mg , 515mg, 520mg, 525mg, 530mg, 535mg, 540mg, 545mg, 555mg, 560mg, 565mg, 570mg, 575mg, 580mg,585mg, 590mg, 595mg, 600mg, 605mg, 610mg, 615mg, 620mg, 625mg, 630mg, 635mg, 640mg, 645mg, 655mg, 660mg, 665mg, 670mg, 675mg, 680mg, 685mg, 690mg, 695mg, 700mg, 705mg, 710mg, 715mg, 720mg, 725mg, 730mg, 735mg, 740mg, 745mg, 750mg, 755mg, 760mg, 765mg, 770mg, 775mg, 780 mg, 785 mg, 790 mg, 795 mg, 800 mg, 805 mg, 810 mg, 815 mg, 820 mg, 825 mg, 830 mg, 835 mg, 840 mg, 845 mg, 850 mg, 855 mg, 860 mg, 865 mg, 870 mg, 875 mg, 880 mg, 885 mg, 890 mg, 895 mg, 900 mg, 905 mg, 910 mg, 915 mg, 920 mg, 925 mg, 930 mg, 935 mg, 940 mg, 945 mg, 950 mg, or more of the compound may be administered.

[0102] In some embodiments, subjects are administered approximately 50 mg to 150 mg of a compound per dose, such as 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 105 mg, 110 mg, 115 mg, 120 mg, 125 mg, 130 mg, 135 mg, 140 mg, 145 mg, or 150 mg of the compound per dose. In some embodiments, subjects are administered approximately 100 mg of the compound per dose.

[0103] In some embodiments, subjects are administered approximately 250 mg to 350 mg of the compound per dose, such as approximately 255 mg, 255 mg, 260 mg, 265 mg, 270 mg, 275 mg, 280 mg, 285 mg, 290 mg, 295 mg, 300 mg, 305 mg, 310 mg, 315 mg, 320 mg, 325 mg, 330 mg, 335 mg, 340 mg, 345 mg, or 350 mg of the compound per dose. In some embodiments, subjects are administered approximately 300 mg of the compound per dose.

[0104] In some embodiments, subjects are administered approximately 850 mg to 950 mg of a compound per dose, such as 850 mg, 855 mg, 860 mg, 865 mg, 870 mg, 875 mg, 880 mg, 885 mg, 890 mg, 895 mg, 900 mg, 905 mg, 910 mg, 915 mg, 920 mg, 925 mg, 930 mg, 935 mg, 940 mg, 945 mg, or 950 mg of the compound per dose. In some embodiments, subjects are administered approximately 900 mg of the compound per dose.

[0105] Administration of oxytocin antagonists causes a reduction in uterine contractility. In some embodiments, subjects exhibit a reduction in the frequency of uterine contractions after administration of oxytocin antagonists, such as a reduction of about 1% to about 20% (e.g., about 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, or more) compared to the subject's measured uterine contraction frequency recorded before oxytocin antagonist administration.

[0106] In some embodiments, subjects exhibit a serum progesterone (P4) concentration of less than approximately 320 nM prior to the transfer of one or more embryos into the subjects. For example, subjects may exhibit a serum P4 concentration of approximately 200 nM to approximately 300 nM (e.g., serum P4 concentrations of approximately 200 nM, 205 nM, 210 nM, 215 nM, 220 nM, 225 nM, 230 nM, 235 nM, 240 nM, 245 nM, 250 nM, 255 nM, 260 nM, 265 nM, 270 nM, 275 nM, 280 nM, 285 nM, 290 nM, 295 nM, or 300 nM) prior to the transfer of one or more embryos into the subjects. In some embodiments, subjects are determined to exhibit a serum P4 concentration of less than 320 nM within 24 hours prior to the transfer of one or more embryos to the subjects (for example, within 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours, 18 hours, 19 hours, 20 hours, 21 hours, 22 hours, 23 hours, or 24 hours prior to the transfer of one or more embryos to the subjects).

[0107] In some embodiments, the subjects are determined to exhibit a serum P4 concentration of approximately 200 nM to approximately 300 nM within 24 hours prior to the transfer of one or more embryos to the subjects (for example, within 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours, 18 hours, 19 hours, 20 hours, 21 hours, 22 hours, 23 hours, or 24 hours prior to the transfer of one or more embryos to the subjects).

[0108] In some embodiments, subjects exhibit a serum P4 concentration of less than approximately 2.0 ng / ml prior to the transfer of one or more embryos into the subject. In some embodiments, subjects are determined to exhibit a serum P4 concentration of less than approximately 2.0 ng / ml about 1 to 7 days before the transfer of one or more embryos into the subject.

[0109] In some embodiments, subjects have been determined to have a serum P4 concentration of less than approximately 2.0 ng / ml within 24 hours of or immediately before the isolation of one or more oocytes or eggs from subjects undergoing IVF-ET or ICSI-ET, or approximately one day before the transfer of one or more embryos to the subject.

[0110] In some embodiments, subjects have been determined to have a serum P4 concentration of less than 2.0 ng / ml within 24 hours of or immediately before the isolation of one or more oocytes or eggs from subjects undergoing IVF-ET or ICSI-ET, or approximately two days before the transfer of one or more embryos to the subject.

[0111] In some embodiments, subjects have been determined to have a serum P4 concentration of less than approximately 2.0 ng / ml within 24 hours of or immediately before the isolation of one or more oocytes or eggs from subjects undergoing IVF-ET or ICSI-ET, or approximately 3 days before the transfer of one or more embryos to the subject.

[0112] In some embodiments, subjects have been determined to have a serum P4 concentration of less than approximately 2.0 ng / ml within 24 hours of or immediately before the isolation of one or more oocytes or eggs from subjects undergoing IVF-ET or ICSI-ET, or approximately 4 days before the transfer of one or more embryos to the subject.

[0113] In some embodiments, subjects were determined to have a serum P4 concentration of less than approximately 2.0 ng / ml within 24 hours of or immediately before the isolation of one or more oocytes or eggs from subjects undergoing IVF-ET or ICSI-ET, or approximately 5 days before the transfer of one or more embryos to the subject.

[0114] In some embodiments, subjects have been determined to have a serum P4 concentration of less than approximately 2.0 ng / ml within 24 hours of or immediately before the isolation of one or more oocytes or eggs from subjects undergoing IVF-ET or ICSI-ET, or approximately 6 days before the transfer of one or more embryos to the subject.

[0115] In some embodiments, subjects have been determined to have a serum P4 concentration of less than approximately 2.0 ng / ml within 24 hours of or immediately before the isolation of one or more oocytes or eggs from subjects undergoing IVF-ET or ICSI-ET, or approximately 7 days before the transfer of one or more embryos to the subject.

[0116] In some embodiments, subjects are determined to exhibit a serum P4 concentration of less than 2.0 ng / ml within approximately one hour of hCG administration, such as approximately one hour or less before hCG administration.

[0117] In some embodiments, subjects exhibit a serum P4 concentration of less than approximately 1.5 ng / ml prior to the transfer of one or more embryos into the subject. In some embodiments, subjects are determined to exhibit a serum P4 concentration of less than approximately 1.5 ng / ml about 1 to 7 days before, for example, the transfer of one or more embryos into the subject.

[0118] In some embodiments, subjects have been determined to have a serum P4 concentration of less than 1.5 ng / ml within 24 hours of or immediately before the isolation of one or more oocytes or eggs from subjects undergoing IVF-ET or ICSI-ET, or approximately one day before the transfer of one or more embryos to the subject.

[0119] In some embodiments, subjects have been determined to have a serum P4 concentration of less than 1.5 ng / ml within 24 hours of or immediately before the isolation of one or more oocytes or eggs from subjects undergoing IVF-ET or ICSI-ET, or approximately two days before the transfer of one or more embryos to the subject.

[0120] In some embodiments, subjects have been determined to have a serum P4 concentration of less than 1.5 ng / ml within 24 hours of or immediately before the isolation of one or more oocytes or eggs from subjects undergoing IVF-ET or ICSI-ET, or approximately 3 days before the transfer of one or more embryos to the subject.

[0121] In some embodiments, subjects have been determined to have a serum P4 concentration of less than 1.5 ng / ml within 24 hours of or immediately before the isolation of one or more oocytes or eggs from subjects undergoing IVF-ET or ICSI-ET, or approximately 4 days before the transfer of one or more embryos to the subject.

[0122] In some embodiments, subjects have been determined to have a serum P4 concentration of less than 1.5 ng / ml within 24 hours of or immediately before the isolation of one or more oocytes or eggs from subjects undergoing IVF-ET or ICSI-ET, or approximately 5 days before the transfer of one or more embryos to the subject.

[0123] In some embodiments, subjects were determined to have a serum P4 concentration of less than 1.5 ng / ml within 24 hours of or immediately before the isolation of one or more oocytes or eggs from subjects undergoing IVF-ET or ICSI-ET, or approximately 6 days before the transfer of one or more embryos to the subject.

[0124] In some embodiments, subjects have been determined to have a serum P4 concentration of less than 1.5 ng / ml within 24 hours of or immediately before the isolation of one or more oocytes or eggs from subjects undergoing IVF-ET or ICSI-ET, or approximately 7 days before the transfer of one or more embryos to the subject.

[0125] In some embodiments, subjects are determined to exhibit a serum P4 concentration of less than 1.5 ng / ml within approximately one hour of hCG administration, such as approximately one hour or less before hCG administration.

[0126] In some embodiments, serum P4 concentration is assessed immediately after isolation of a sample (e.g., blood serum sample) from the subject. In some embodiments, the sample (e.g., blood serum sample) is collected from the subject and stored or preserved before progesterone analysis. In some embodiments, (i) the sample is collected from the subject, and (ii) the determination of the progesterone concentration in the sample is performed immediately before isolation of one or more oocytes or eggs from the subject, such as a subject undergoing IVF-ET or ICSI-ET. For example, in some embodiments, the sample is collected from the subject, and serum P4 concentration is assessed about 1 to 7 days before the transfer of one or more embryos to the subject. In some embodiments, the sample is collected from the subject, and serum P4 concentration is assessed about 3 days before the transfer of one or more embryos to the subject. In some embodiments, the sample is collected from the subject, and serum P4 concentration is assessed about 4 days before the transfer of one or more embryos to the subject. In some embodiments, the sample is collected from the subject, and serum P4 concentration is assessed about 5 days before the transfer of one or more embryos to the subject. In some embodiments, the sample is taken from the subject, and the serum P4 concentration is evaluated within approximately one hour of administering hCG to the subject, for example, within approximately 60 minutes, 55 minutes, 50 minutes, 45 minutes, 40 minutes, 35 minutes, 30 minutes, 25 minutes, 20 minutes, 15 minutes, 10 minutes, 5 minutes before or less than administering hCG to the subject, in preparation for the retrieval of oocytes or eggs.

[0127] In some embodiments, the subject exhibits increased expression of endometrial and / or myometrial prostaglandin E2 (PGE2) after administration of an oxytocin antagonist, as evaluated, for example, by mass spectrometry and / or spectroscopic techniques described herein or known in the art. In some embodiments, the subject exhibits increased expression of endometrial and / or myometrial prostaglandin F2α (PGF2α) after administration of an oxytocin antagonist, as evaluated, for example, by mass spectrometry and / or spectroscopic techniques described herein or known in the art. In some embodiments, the subject exhibits increased concentration of, for example, phosphatidyl insolitol-4,5-bisphosphate (PIP2), and / or diacylglycerol (DAG), inositol-1,4,5-trisphosphate (IP3), and / or Ca25, such as in the sarcoplasmic reticulum. 2+ Intracellular calcium (Ca) released from the store 2+ Reduced endometrial and / or myometrial PGF2α signaling after administration of an oxytocin antagonist is assessed by detecting a decrease in the concentration of one or more secondary messengers involved in PGF2α signaling, such as [DAG], [IP3], and / or [Ca]. For example, the subjects include, for example, endometrial and / or myometrial [DAG], [IP3], and / or [Ca]. 2+ As is evident from the reduction of [ ], this may result in a transient increase in endometrial and / or myometrial PGF2α expression, followed by a decrease in PGF2α signaling in these tissues.

[0128] In some embodiments, the subjects maintain pregnancy for approximately 14 days after the transfer of one or more embryos to the subjects, such as during the following periods: 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 3 weeks, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36 weeks or longer. In some embodiments, the subjects maintain a pregnancy for at least 6 weeks after the transfer of one or more embryos to the subjects, such as during weeks 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, or longer. In some embodiments, the subject maintains pregnancy for at least 10 weeks after the transfer of one or more embryos into the subject and / or after the retrieval of one or more oocytes or eggs from the subject, such as during weeks 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, or longer.

[0129] In some embodiments, pregnancy is assessed by a blood pregnancy test, such as by detecting the presence and / or amount of hCG in a blood sample isolated from the subject. In some embodiments, pregnancy is assessed by detecting an intrauterine embryonic heartbeat, for example, at about six weeks or longer after the transfer of one or more embryos to the subject and / or after the retrieval of one or more oocytes or eggs from the subject (e.g., at about six weeks, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, sixteen, seventeen, eighteen, nineteen, twenty

[0130] In some embodiments, subjects maintain pregnancy and give birth to live offspring after administration of an oxytocin antagonist. For example, in some embodiments, subjects maintain pregnancy and give birth to live offspring at a gestational age of at least approximately 24 weeks, such as at approximately 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36 weeks, or longer.

[0131] In another embodiment, the present invention relates to the accompanying documentation and a compound represented by formula (I), [ka] (I) The kit provides an oxytocin antagonist, such as its geometric isomers, enantiomers, diastereomers, racemic mixtures, or salts. In the formula, n is an integer between 1 and 3. R 1 It is selected from the group consisting of hydrogen and C1-C6 alkyl groups, R 2Hydrogen, C1-C6 alkyl, C1-C6 alkylaryl, heteroaryl, C1-C6 alkylheteroaryl, C2-C6 alkenyl, C2-C6 alkenylaryl, C2-C6 alkenylheteroaryl, C2-C6 alkynyl, C2-C6 alkynylaryl, C2-C6 alkynylheteroaryl, C3-C6 cycloalkyl, heterocycloalkyl, C1-C6 alkylcycloalkyl, C1-C6 alkylheterocycloalkyl, C1-C6 alkylcarboxy, acyl, C1-C6 alkylacyl, C1-C6 alkyl Selected from the group consisting of siloxy, C1-C6 alkylalkoxy, alkoxycarbonyl, C1-C6 alkylalkoxycarbonyl, aminocarbonyl, C1-C6 alkylaminocarbonyl, C1-C6 alkylacylamino, C1-C6 alkylureido, amino, C1-C6 alkylamino, sulfonyloxy, C1-C6 alkylsulfonyloxy, sulfonyl, C1-C6 alkylsulfonyl, sulfinyl, C1-C6 alkylsulfinyl, C1-C6 alkylsulfanyl, and C1-C6 alkylsulfonylamino, R 3 It is selected from the group consisting of aryls and heteroaryls, X is oxygen and NR 4 Selected from the group consisting of, R 4 R is selected from the group consisting of hydrogen, C1-C6 alkyl, C1-C6 alkylaryl, C1-C6 alkylheteroaryl, aryl, and heteroaryl. 2 and R 4 Together with the nitrogen atoms to which they are bonded, they can form a 5-8 member saturated or unsaturated heterocycloalkyl ring. The accompanying instructions direct the user of the kit to carry out any of the methods described above in the embodiments and models of the present invention. In some embodiments, the oxytocin antagonist is a compound represented by formula (II). [ka] (II)

[0132] In some embodiments, the compound represented by formula (II) (i.e., (3Z,5S)-5-(hydroxymethyl)-1-[(2'-methyl-1,1'-biphenyl-4-yl)carbonyl]pyrrolidine-3-one O-methyloxime) is substantially pure. For example, in some embodiments, the compound represented by formula (II) has a purity of at least 85%, such as 85% to 99.9% or higher (e.g., 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.1%, 99.2%, 99.3%, 99.4%, 99.5%, 99.6%, 99.7%, 99.8%, 99.9%, or higher). The purity of the compound represented by formula (II) can be evaluated using chromatographic methods such as NMR techniques and / or HPLC procedures, which are well known in the art and described herein, such as those techniques described in U.S. Patent No. 9,670,155, the disclosure of which is incorporated herein by reference in whole.

[0133] In some embodiments, the compound represented by formula (II) is substantially pure with respect to the diastereomer of the compound and other by-products that may be formed during the synthesis of the compound. For example, in some embodiments, the compound represented by formula (II) has a purity of at least 85%, such as 85% to 99.9% or higher (e.g., 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.1%, 99.2%, 99.3%, 99.4%, 99.5%, 99.6%, 99.7%, 99.8%, 99.9%, or higher), with respect to the diastereomer of the compound and other by-products that may be formed during the synthesis of the compound, such as the by-product formed during the synthesis of the compound as described in U.S. Patent No. 9,670,155. The purity of the compound represented by formula (II) can be evaluated using chromatographic methods such as NMR techniques and / or HPLC procedures, which are well known in the art and described herein, such as those techniques described in U.S. Patent No. 9,670,155.

[0134] In some embodiments, the compound represented by formula (II) is substantially pure with respect to its (3E) diastereomer, (3E,5S)-5-(hydroxymethyl)-1-[(2'-methyl-1,1'-biphenyl-4-yl)carbonyl]pyrrolidine-3-one O-methyloxime. For example, in some embodiments, the compound represented by formula (II) has a purity of at least 85%, such as 85% to 99.9% or higher with respect to (3E,5S)-5-(hydroxymethyl)-1-[(2'-methyl-1,1'-biphenyl-4-yl)carbonyl]pyrrolidine-3-one O-methyloxime (e.g., 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.1%, 99.2%, 99.3%, 99.4%, 99.5%, 99.6%, 99.7%, 99.8%, 99.9%, or higher). For example, compound (II) may be administered in the form of a composition containing less than 15% of the (3E) diastereomer (e.g., tablets such as dispersible tablets, capsules, gel caps, powders, liquid solutions, or liquid suspensions). For example, compound (II) may be administered in the form of a composition containing less than 14%, less than 13%, less than 12%, less than 11%, less than 10%, less than 9%, less than 8%, less than 7%, less than 6%, less than 5%, less than 4%, less than 3%, less than 2%, less than 1%, less than 0.1%, less than 0.01%, less than 0.001%, or less of the (3E) diastereomer (e.g., tablets such as dispersible tablets, capsules, gel caps, powders, liquid solutions, or liquid suspensions). The purity of the compound represented by formula (II) may be evaluated using chromatographic methods such as NMR techniques and / or HPLC procedures, which are well known in the art and described herein, such as those techniques described in U.S. Patent No. 9,670,155.

[0135] In some embodiments, the compound is formulated for oral administration to a subject and may be in the form of, for example, tablets, capsules, gel caps, powders, liquid solutions, or liquid suspensions. In some embodiments, the compound is formulated as tablets, such as dispersible tablets. The compound is available in doses of approximately 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 105 mg, 110 mg, 115 mg, 120 mg, 125 mg, 130 mg, 135 mg, 140 mg, 145 mg, 150 mg, 155 mg, 160 mg, 1 The compound may be formulated in unit dosage forms containing approximately 25 mg to approximately 250 mg of the compound, such as unit dosage forms containing 65 mg, 170 mg, 175 mg, 180 mg, 185 mg, 190 mg, 195 mg, 200 mg, 205 mg, 210 mg, 215 mg, 220 mg, 225 mg, 230 mg, 235 mg, 240 mg, 245 mg, 250 mg, or more of the compound. In some embodiments, the compound is formulated in unit dosage forms containing approximately 25 mg to approximately 75 mg of the compound, such as unit dosage forms containing approximately 50 mg of the compound. In some embodiments, the compound is formulated in unit dosage forms containing approximately 175 mg to approximately 225 mg of the compound, such as unit dosage forms containing approximately 200 mg of the compound.

[0136] In some embodiments, the oxytocin antagonist is epersiban, or a salt, derivative, variant, crystalline form, or formulation thereof, for example, a salt, derivative, variant, crystalline form, or formulation described in U.S. Patents 7,514,437, 8,367,673, 8,541,579, 7,550,462, 7,919,492, 8,202,864, 8,742,099, 9,408,851, 8,716,286, or 8,815,856, the respective disclosures of which are incorporated herein by reference in whole.

[0137] In some embodiments, the oxytocin antagonist is letsiban, or a salt, derivative, variant, crystalline form, or formulation thereof, for example, a salt, derivative, variant, crystalline form, or formulation described in U.S. Patents 7,514,437, 8,367,673, 8,541,579, 8,071,594, 8,357,685, 8,937,179, or 9,452,169, the respective disclosures of which are incorporated herein by reference in whole.

[0138] In some embodiments, the oxytocin antagonist is barsiban, or a salt, derivative, variant, crystalline form, or formulation thereof, such as salts, derivatives, variants, crystalline forms, or formulations described in, for example, U.S. Patents 6,143,722, 7,091,314, 7,816,489, or 9,579,305, or International Publication 2017 / 060339, the respective disclosures of which are incorporated herein by reference in whole.

[0139] In some embodiments, the oxytocin antagonist is atosiban, or a salt, derivative, variant, crystalline form, or formulation thereof, such as the salts, derivatives, variants, crystalline forms, or formulations described in U.S. Patent No. 4,504,469 or No. 4,402,942, the respective disclosures of which are incorporated herein by reference in whole.

[0140] In another embodiment, the present invention is characterized by a method for treating a subject undergoing embryo transfer therapy, wherein the concentration of P4 in a sample isolated from the subject is a. Compare the concentration of P4 with the P4 reference level, b. If the concentration of P4 in a sample isolated from the subject is below the P4 reference level, the subject is administered a therapeutically effective dose of oxytocin antagonist, which is used to determine this. One or more embryos are implanted into the target uterus.

[0141] In another embodiment, the present invention is a. Determine the concentration of P4 in the sample isolated from the subject, b. Compare the concentration of P4 to the P4 reference level, c. A method of treating subjects undergoing embryo transfer therapy, characterized by administering a therapeutically effective dose of oxytocin antagonist to a subject if the concentration of P4 in a sample isolated from the subject is below the P4 reference level. One or more embryos are implanted into the target uterus.

[0142] In another aspect, the present invention is characterized by the use of an oxytocin antagonist in a method for treating a subject undergoing embryo transfer therapy, wherein the concentration of P4 in a sample isolated from the subject has been determined, and the method is a. Compare the concentration of P4 with the P4 reference level, b. If the concentration of P4 in a sample isolated from the subject is below the P4 reference level, administer a therapeutically effective dose of oxytocin antagonist to the subject, One or more embryos are implanted into the target uterus.

[0143] In another aspect, the present invention is characterized by the use of an oxytocin antagonist in a method for treating a subject undergoing embryo transfer therapy, the method being: a. Determine the concentration of P4 in the sample isolated from the subject, b. Compare the concentration of P4 to the P4 reference level, c. If the concentration of P4 in a sample isolated from the subject is below the P4 reference level, administer a therapeutically effective dose of oxytocin antagonist to the subject, One or more embryos are implanted into the target uterus.

[0144] In some embodiments, a subject is identified as having a concentration of P4 in a sample isolated from the subject that is lower than the P4 reference level. Thus, in some embodiments, the method includes comparing the concentration of P4 in a sample isolated from the subject to the P4 reference level, determining that the concentration of P4 in the sample isolated from the subject is lower than the P4 reference level, and administering a therapeutically effective dose of oxytocin antagonist to the subject.

[0145] In some embodiments, the method includes the step of informing the subject that it has been identified as having a concentration of P4 in a sample isolated from the subject that is lower than the P4 reference level.

[0146] In another embodiment, the present invention is characterized by a method for treating a subject undergoing embryo transfer therapy, wherein the concentration of P4 in a sample isolated from the subject is a. Compare the concentration of P4 with the P4 reference level, b. If the concentration of P4 in the sample isolated from the subject is below the P4 reference level, administer a therapeutically effective dose of oxytocin antagonist to the subject. c. This is determined by transferring one or more embryos into the target uterus.

[0147] In another embodiment, the present invention is a. Determine the concentration of P4 in the sample isolated from the subject, b. Compare the concentration of P4 to the P4 reference level, c. If the concentration of P4 in the sample isolated from the subject is below the P4 reference level, administer a therapeutically effective dose of oxytocin antagonist to the subject. d. A method characterized by the implantation of one or more embryos into the target uterus, thereby treating the subject undergoing embryo transfer.

[0148] In another aspect, the present invention is characterized by the use of an oxytocin antagonist in a method for treating a subject undergoing embryo transfer therapy, wherein the concentration of P4 in a sample isolated from the subject has been determined, and the method is a. Compare the concentration of P4 with the P4 reference level, b. If the concentration of P4 in the sample isolated from the subject is below the P4 reference level, administer a therapeutically effective dose of oxytocin antagonist to the subject. c. Including the transfer of one or more embryos into the target uterus.

[0149] In another aspect, the present invention is characterized by the use of an oxytocin antagonist in a method for treating a subject undergoing embryo transfer therapy, the method being: a. Determine the concentration of P4 in the sample isolated from the subject, b. Compare the concentration of P4 to the P4 reference level, c. If the concentration of P4 in the sample isolated from the subject is below the P4 reference level, administer a therapeutically effective dose of oxytocin antagonist to the subject. d. Including the transfer of one or more embryos into the target uterus.

[0150] In some embodiments, a subject is identified as having a concentration of P4 in a sample isolated from the subject that is lower than the P4 reference level. Thus, in some embodiments, the method includes comparing the concentration of P4 in a sample isolated from the subject to the P4 reference level, determining that the concentration of P4 in a sample isolated from the subject is lower than the P4 reference level, administering a therapeutically effective dose of oxytocin antagonist to the subject, and implanting one or more embryos into the subject's uterus.

[0151] In some embodiments, the method includes the step of informing the subject that it has been identified as having a concentration of P4 in a sample isolated from the subject that is lower than the P4 reference level.

[0152] In another embodiment, the present invention features a method for determining whether a subject undergoing embryo transfer therapy is likely to benefit from oxytocin antagonist therapy, wherein the concentration of P4 in a sample isolated from the subject is determined, and the method comprises comparing the concentration of P4 to a P4 reference level, and identifying the subject as likely to benefit from oxytocin antagonist therapy before, concurrently with, and / or after the transfer of one or more embryos to the subject if the reduced concentration of P4 in the sample isolated from the subject relative to the P4 reference level.

[0153] In another embodiment, the present invention features a method for determining whether a subject undergoing embryo transfer therapy is likely to benefit from oxytocin antagonist therapy, the method comprising determining the concentration of P4 in a sample isolated from the subject and comparing the concentration of P4 to a P4 reference level, wherein a reduced concentration of P4 in the sample isolated from the subject relative to the P4 reference level identifies the subject as likely to benefit from oxytocin antagonist therapy before, concurrently with, and / or after the transfer of one or more embryos to the subject.

[0154] In another embodiment, the present invention features a method for collecting data to determine whether a subject undergoing embryo transfer therapy is likely to benefit from oxytocin antagonist therapy, wherein the concentration of P4 in a sample isolated from the subject is determined, and the method comprises comparing the concentration of P4 to a P4 reference level, and identifying a subject as likely to benefit from oxytocin antagonist therapy before, concurrently with, and / or after the transfer of one or more embryos to the subject if the reduced concentration of P4 in the sample isolated from the subject relative to the P4 reference level.

[0155] In another embodiment, the present invention features a method for collecting data to determine whether a subject undergoing embryo transfer therapy is likely to benefit from oxytocin antagonist therapy, the method comprising determining the concentration of P4 in a sample isolated from the subject and comparing the concentration of P4 to a P4 reference level, wherein a reduced concentration of P4 in a sample isolated from the subject relative to the P4 reference level identifies the subject as likely to benefit from oxytocin antagonist therapy before, concurrently with, and / or after the transfer of one or more embryos to the subject.

[0156] In another embodiment, the present invention features a probe for specifically detecting P4 in the manufacture of a kit for use in a method for determining whether a subject undergoing embryo transfer therapy is likely to benefit from oxytocin antagonist therapy, wherein the concentration of P4 in a sample isolated from the subject is determined, and the method comprises comparing the concentration of P4 to a P4 reference level, and identifying a subject as likely to benefit from oxytocin antagonist therapy before, concurrently with, and / or after the transfer of one or more embryos to the subject if the reduced concentration of P4 in the sample isolated from the subject is relative to the P4 reference level.

[0157] In another aspect, the present invention features a probe for specifically detecting P4 in the manufacture of a kit for use in a method for determining whether a subject undergoing embryo transfer therapy is likely to benefit from oxytocin antagonist therapy, the method comprising determining the concentration of P4 in a sample isolated from the subject and comparing the concentration of P4 to a P4 reference level, and identifying the subject as likely to benefit from oxytocin antagonist therapy before, concurrently with, and / or after the transfer of one or more embryos to the subject if the reduced concentration of P4 in the sample isolated from the subject relative to the P4 reference level.

[0158] In another embodiment, the present invention features a method for determining whether a subject undergoing embryo transfer therapy is likely to exhibit enhanced endometrial receptivity in response to oxytocin antagonist therapy, wherein the concentration of P4 in a sample isolated from the subject is determined, and the method comprises comparing the concentration of P4 to a P4 reference level, wherein a reduced concentration of P4 in a sample isolated from the subject relative to the P4 reference level identifies the subject as likely to exhibit enhanced endometrial receptivity in response to oxytocin antagonist therapy before, at, and / or after the transfer of one or more embryos to the subject.

[0159] In another embodiment, the present invention features a method for determining whether a subject undergoing embryo transfer therapy is likely to exhibit enhanced endometrial receptivity in response to oxytocin antagonist therapy, the method comprising determining the concentration of P4 in a sample isolated from the subject and comparing the concentration of P4 to a P4 reference level, wherein a reduced concentration of P4 in a sample isolated from the subject relative to the P4 reference level identifies the subject as likely to exhibit enhanced endometrial receptivity in response to oxytocin antagonist therapy before, concurrently with, and / or after the transfer of one or more embryos to the subject.

[0160] In another embodiment, the present invention features a method for collecting data to determine whether a subject undergoing embryo transfer therapy is likely to exhibit enhanced endometrial receptivity in response to oxytocin antagonist therapy, wherein the concentration of P4 in a sample isolated from the subject is determined, and the method comprises comparing the concentration of P4 to a P4 reference level, wherein a reduced concentration of P4 in a sample isolated from the subject relative to the P4 reference level identifies the subject as likely to exhibit enhanced endometrial receptivity in response to oxytocin antagonist therapy before, concurrently with, and / or after the transfer of one or more embryos to the subject.

[0161] In another embodiment, the present invention features a method for collecting data to determine whether a subject undergoing embryo transfer therapy is likely to exhibit enhanced endometrial receptivity in response to oxytocin antagonist therapy, the method comprising determining the concentration of P4 in a sample isolated from the subject and comparing the concentration of P4 to a P4 reference level, wherein a reduced concentration of P4 in a sample isolated from the subject relative to the P4 reference level identifies the subject as likely to exhibit enhanced endometrial receptivity in response to oxytocin antagonist therapy before, concurrently with, and / or after the transfer of one or more embryos to the subject.

[0162] In another embodiment, the present invention relates to the manufacture of a kit for use in a method for determining whether a subject undergoing embryo transfer therapy is likely to exhibit enhanced endometrial receptivity in response to oxytocin antagonist therapy, characterized by a probe for specifically detecting progesterone, wherein the concentration of P4 in a sample isolated from the subject is determined, and the method comprises comparing the concentration of P4 to a P4 reference level, wherein a reduced concentration of P4 in a sample isolated from the subject relative to the P4 reference level identifies the subject as likely to exhibit enhanced endometrial receptivity in response to oxytocin antagonist therapy before, concurrently with, and / or after the transfer of one or more embryos to the subject.

[0163] In another embodiment, the present invention relates to the manufacture of a kit for use in a method for determining whether a subject undergoing embryo transfer therapy is likely to exhibit enhanced endometrial receptivity in response to oxytocin antagonist therapy, characterized by a probe for specifically detecting progesterone, the method comprising determining the concentration of P4 in a sample isolated from the subject and comparing the concentration of P4 to a P4 reference level, wherein a reduced concentration of P4 in a sample isolated from the subject relative to the P4 reference level identifies the subject as likely to exhibit enhanced endometrial receptivity in response to oxytocin antagonist therapy before, concurrently with, and / or after the transfer of one or more embryos to the subject.

[0164] In some embodiments of the aforementioned twelve aspects of the present invention, the subject is identified as having a concentration of P4 in a sample isolated from the subject that is lower than the P4 reference level.

[0165] In some embodiments, the method includes a step of informing the subject that the subject has been identified as having a concentration of P4 in a sample isolated from the subject that is below the P4 reference level. Thus, in some embodiments, the method includes a step of informing the subject that the subject has been identified as potentially benefiting from oxytocin antagonist therapy. In some embodiments, the method includes a step of informing the subject that the subject has been identified as potentially exhibiting enhanced endometrial receptivity in response to oxytocin antagonist therapy.

[0166] In some embodiments, the method includes administering a therapeutically effective dose of oxytocin antagonist to a subject if a reduced concentration of P4 is detected in a sample isolated from the subject relative to a P4 reference level. Thus, in some embodiments, the method includes comparing the concentration of P4 to a P4 reference level, determining that the concentration of P4 in a sample isolated from the subject is lower than the P4 reference level, identifying that the subject is likely to benefit from oxytocin antagonist treatment and / or that the subject is likely to exhibit enhanced endometrial receptivity in response to oxytocin antagonist treatment, and administering a therapeutically effective dose of oxytocin antagonist to the subject.

[0167] In some embodiments of any of the above aspects of the present invention, administration of an oxytocin antagonist reduces the likelihood of embryo implantation failure in the subject.

[0168] In some embodiments of any of the above aspects of the present invention, an oxytocin antagonist is administered to the subject before the implantation of one or more embryos into the subject's uterus.

[0169] In some embodiments of the above aspects of the present invention, the oxytocin antagonist is administered to the subject about 1 hour to about 24 hours before the transfer of one or more embryos to the subject. In some embodiments, the oxytocin antagonist is administered to the subject about 1 hour to about 12 hours before the transfer of one or more embryos to the subject. In some embodiments, the oxytocin antagonist is administered to the subject about 12 hours to about 24 hours before the transfer of one or more embryos to the subject.

[0170] In some embodiments of the above aspects of the present invention, the oxytocin antagonist is administered to the subject about 1 to 10 hours before the transfer of one or more embryos to the subject. In some embodiments, the oxytocin antagonist is administered to the subject about 1 to 9 hours before the transfer of one or more embryos to the subject. In some embodiments, the oxytocin antagonist is administered to the subject about 1 to 8 hours before the transfer of one or more embryos to the subject. In some embodiments, the oxytocin antagonist is administered to the subject about 1 to 7 hours before the transfer of one or more embryos to the subject. In some embodiments, the oxytocin antagonist is administered to the subject about 1 to 6 hours before the transfer of one or more embryos to the subject. In some embodiments, the oxytocin antagonist is administered to the subject about 1 to 5 hours before the transfer of one or more embryos to the subject. In some embodiments, the oxytocin antagonist is administered to the subject about 1 to 4 hours before the transfer of one or more embryos to the subject.

[0171] In some embodiments of the above aspects of the present invention, the oxytocin antagonist is administered to the subject about 2 to 6 hours before the transfer of one or more embryos to the subject. In some embodiments, the oxytocin antagonist is administered to the subject about 3 to 5 hours before the transfer of one or more embryos to the subject. In some embodiments, the oxytocin antagonist is administered to the subject about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, or 24 hours or more before the transfer of one or more embryos to the subject.

[0172] In some embodiments of any of the above aspects of the present invention, an oxytocin antagonist is administered to the subject about four hours before the transfer of one or more embryos into the subject.

[0173] In some embodiments of any of the above aspects of the present invention, an oxytocin antagonist is administered to the subject before embryo transfer in a single dose.

[0174] In some embodiments of any of the above aspects of the present invention, an oxytocin antagonist is administered to the subject before embryo transfer (i.e., before the transfer of one or more embryos into the subject's uterus) in multiple doses, such as 1 to 20 doses, at intervals of 12, 24, 36, 48, 60, 72, 84, 96, 108, 120, 132, 144, 156, 168 hours, or longer, for example, before embryo transfer. In some embodiments, oxytocin antagonists are administered to subjects before embryo transfer in doses of 1 to 20 times every 24 hours, such as once, twice, three times, four times, five times, six times, seven times, eight times, nine times, ten times, eleven times, twelve times, thirteen times, fourteen times, fifteen times, sixteen times, seventeen times, eighteen times, nine times, ten times, eleven times, twelve times, thirteen times, fourteen times, fifteen times, sixteen times, seventeen times, eighteen times, nineteen times, twenty times, and so on. In some embodiments, oxytocin antagonists are administered to subjects in doses of more than 20 times every 24 hours before embryo transfer.

[0175] For example, in some embodiments, the oxytocin antagonist is administered to the subject in 1 to 10 doses, for example, every 12 hours, 24 hours, 36 hours, 48 ​​hours, 60 hours, 72 hours, 84 hours, 96 hours, 108 hours, 120 hours, 132 hours, 144 hours, 156 hours, 168 hours, or longer, prior to embryo transfer. In some embodiments, the oxytocin antagonist is administered to the subject in 1 to 10 doses every 24 hours prior to embryo transfer, such as once every 24 hours, twice every 24 hours, three times every 24 hours, four times every 24 hours, five times every 24 hours, six times every 24 hours, seven times every 24 hours, eight times every 24 hours, nine times every 24 hours, or ten times every 24 hours.

[0176] In some embodiments, the oxytocin antagonist is administered to the subject in 1 to 5 doses, for example, every 12 hours, 24 hours, 36 hours, 48 ​​hours, 60 hours, 72 hours, 84 hours, 96 hours, 108 hours, 120 hours, 132 hours, 144 hours, 156 hours, 168 hours, or longer, prior to embryo transfer. In some embodiments, the oxytocin antagonist is administered to the subject in 10 to 20 doses, for example, every 12 hours, 24 hours, 36 hours, 48 ​​hours, 60 hours, 72 hours, 84 hours, 96 hours, 108 hours, 120 hours, 132 hours, 144 hours, 156 hours, 168 hours, or longer, prior to embryo transfer. In some embodiments, oxytocin antagonists are administered to subjects in 10 to 15 doses, for example, every 12, 24, 36, 48, 60, 72, 84, 96, 108, 120, 132, 144, 156, 168 hours, or longer intervals prior to embryo transfer.

[0177] In some embodiments, an oxytocin antagonist is administered to the subject in doses of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 144, 156, 168 hours, or more, for example, every 12, 24, 36, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 times, or more, every 12, 24, 36, 36, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 times, or more, before embryo transfer.

[0178] In some embodiments, the oxytocin antagonist is administered to the subject before embryo transfer in up to seven doses every 24 hours (e.g., doses 1, 2, 3, 4, 5, 6, or 7), such as up to seven doses of compound (II) every 24 hours. In some embodiments, the oxytocin antagonist is administered to the subject before embryo transfer in one dose every 24 hours, such as one dose of compound (II) every 24 hours. In some embodiments, the oxytocin antagonist is administered to the subject before embryo transfer in two doses every 24 hours, such as two doses of compound (II) every 24 hours. In some embodiments, the oxytocin antagonist is administered to the subject before embryo transfer in three doses every 24 hours, such as three doses of compound (II) every 24 hours. In some embodiments, the oxytocin antagonist is administered to the subject before embryo transfer in four doses every 24 hours, such as four doses of compound (II) every 24 hours. In some embodiments, the oxytocin antagonist is administered to the subject in five doses every 24 hours prior to embryo transfer, such as five doses of compound (II) every 24 hours. In some embodiments, the oxytocin antagonist is administered to the subject in six doses every 24 hours prior to embryo transfer, such as six doses of compound (II) every 24 hours. In some embodiments, the oxytocin antagonist is administered to the subject in seven doses every 24 hours prior to embryo transfer, such as seven doses of compound (II) every 24 hours.

[0179] Multiple doses may be administered, for example, starting approximately 1 hour to 14 days or more before embryo transfer. In some embodiments, multiple doses are administered starting approximately 1 hour to 7 days or more before embryo transfer. In some embodiments, multiple doses may be administered starting approximately 1 day to 14 days before embryo transfer. In some embodiments, multiple doses may be administered starting approximately 3 days to 11 days before embryo transfer. In some embodiments, multiple doses may be administered starting approximately 1 day to 7 days before embryo transfer. In some embodiments, multiple doses may be administered starting approximately 2 days to 5 days before embryo transfer. In some embodiments, multiple doses may be administered starting approximately 3 days to 4 days before embryo transfer. For example, in some embodiments, oxytocin antagonists may be started and administered approximately 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 24 hours, 36 hours, 48 ​​hours, 60 hours, 72 hours, 84 hours, 96 hours, 108 hours, 120 hours, 132 hours, 144 hours, 156 hours, 168 hours, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, 21 days, 22 days, 23 days, 24 days, 25 days, 26 days, 27 days, 28 days, 29 days, 30 days, or more before embryo transfer to the subject.

[0180] In some embodiments, multiple doses are administered starting approximately two days before embryo transfer.

[0181] In some embodiments, multiple doses are administered starting approximately three days before embryo transfer.

[0182] In some embodiments, multiple doses are administered starting approximately four days before embryo transfer.

[0183] In some embodiments, multiple doses are administered starting approximately 5 days before embryo transfer.

[0184] In some embodiments, multiple doses are administered starting approximately 6 days before embryo transfer.

[0185] In some embodiments, multiple doses are administered starting approximately 7 days before embryo transfer.

[0186] In some embodiments, the multi-dose regimen concludes on the day of embryo transfer to the subject. In some embodiments, the multi-dose regimen concludes with a final dose of oxytocin antagonist administered concurrently with (e.g., within 60 minutes) the transfer of one or more embryos to the subject.

[0187] In some embodiments of the above aspects of the present invention, multiple doses continue after embryo transfer. For example, an oxytocin antagonist may be administered to the subject in one or more additional doses simultaneously with embryo transfer. In some embodiments, the oxytocin antagonist is administered approximately 1 hour to approximately 1 week, or longer, after the transfer of one or more embryos to the subject (e.g., approximately 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 24 hours, 36 hours, 48 ​​hours, 60 hours, 72 hours, 84 hours, 96 hours, 108 hours, 120 hours, 132 hours). The patient is administered one or more additional doses after embryo transfer (e.g., multiple regular doses), such as one or more additional doses administered within 144 hours, 156 hours, 168 hours, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, 21 days, 22 days, 23 days, 24 days, 25 days, 26 days, 27 days, 28 days, 29 days, 30 days or longer.

[0188] For example, in some embodiments, the oxytocin antagonist is administered to the subject in one or more additional doses approximately 1 hour to 24 hours after the transfer of one or more embryos to the subject. In some embodiments, the oxytocin antagonist is administered to the subject in one or more additional doses approximately 1 hour to 12 hours after the transfer of one or more embryos to the subject. In some embodiments, the oxytocin antagonist is administered to the subject in one or more additional doses approximately 12 hours to 24 hours after the transfer of one or more embryos to the subject. In some embodiments, the oxytocin antagonist is administered to the subject in one or more additional doses approximately 1 hour to 10 hours after the transfer of one or more embryos to the subject. In some embodiments, the oxytocin antagonist is administered to the subject in one or more additional doses approximately 1 hour to 9 hours after the transfer of one or more embryos to the subject. In some embodiments, the oxytocin antagonist is administered to the subject in one or more additional doses approximately 1 hour to 8 hours after the transfer of one or more embryos to the subject. In some embodiments, the oxytocin antagonist is administered to the subject in one or more additional doses approximately 1 to 7 hours after the transfer of one or more embryos to the subject. In some embodiments, the oxytocin antagonist is administered to the subject in one or more additional doses approximately 1 to 6 hours after the transfer of one or more embryos to the subject. In some embodiments, the oxytocin antagonist is administered to the subject in one or more additional doses approximately 1 to 5 hours after the transfer of one or more embryos to the subject. In some embodiments, the oxytocin antagonist is administered to the subject in one or more additional doses approximately 1 to 4 hours after the transfer of one or more embryos to the subject. In some embodiments, the oxytocin antagonist is administered to the subject in one or more additional doses approximately 2 to 6 hours after the transfer of one or more embryos to the subject. In some embodiments, the oxytocin antagonist is administered to the subject in one or more additional doses approximately 3 to 5 hours after the transfer of one or more embryos to the subject.

[0189] In some embodiments, an oxytocin antagonist is administered to the subject in one or more additional doses, starting at approximately 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 24 hours, 36 hours, 48 ​​hours, 60 hours, 72 hours, 84 hours, 96 hours, 108 hours, 120 hours, 132 hours, 144 hours, 156 hours, 168 hours, or longer after implantation of one or more embryos into the subject.

[0190] In some embodiments, oxytocin antagonists are administered to subjects in multiple additional doses after embryo transfer, for example, every 12 hours, 24 hours, 36 hours, 48 ​​hours, 60 hours, 72 hours, 84 hours, 96 hours, 108 hours, 120 hours, 132 hours, 144 hours, 156 hours, 168 hours, or longer, such as 1 to 20 additional doses. In some embodiments, oxytocin antagonists are further administered to subjects after embryo transfer in doses of 1 to 20 times every 24 hours, such as once, twice, three times, four times, five times, six times, seven times, eight times, nine times, ten times, eleven times, twelve times, thirteen times, fourteen times, fifteen times, sixteen times, seventeen times, eighteen times, and twenty times every 24 hours. In some embodiments, oxytocin antagonists are further administered to subjects after embryo transfer in doses of more than 20 times every 24 hours.

[0191] For example, in some embodiments, the oxytocin antagonist is administered to the subject at additional doses of 1 to 10 times, for example, every 12 hours, every 24 hours, every 36 hours, every 48 hours, every 60 hours, every 72 hours, every 84 hours, every 96 hours, every 108 hours, every 120 hours, every 132 hours, every 144 hours, every 156 hours, every 168 hours, or longer after embryo transfer. In some embodiments, the oxytocin antagonist is further administered to the subject at doses of 1 to 10 times per 24 hours, such as 1 dose per 24 hours, 2 doses per 24 hours, 3 doses per 24 hours, 4 doses per 24 hours, 5 doses per 24 hours, 6 doses per 24 hours, 7 doses per 24 hours, 8 doses per 24 hours, 9 doses per 24 hours, 10 doses per 24 hours, etc. after embryo transfer.

[0192] In some embodiments, the oxytocin antagonist is administered to the subject at additional doses of 1 to 5 times, for example, every 12 hours, every 24 hours, every 36 hours, every 48 hours, every 60 hours, every 72 hours, every 84 hours, every 96 hours, every 108 hours, every 120 hours, every 132 hours, every 144 hours, every 156 hours, every 168 hours, or longer after embryo transfer. In some embodiments, the oxytocin antagonist is administered to the subject at additional doses of 10 to 20 times, for example, every 12 hours, every 24 hours, every 36 hours, every 48 hours, every 60 hours, every 72 hours, every 84 hours, every 96 hours, every 108 hours, every 120 hours, every 132 hours, every 144 hours, every 156 hours, every 168 hours, or longer after embryo transfer. In some embodiments, the oxytocin antagonist is administered to the subject at additional doses of 10 to 15 times, for example, every 12 hours, every 24 hours, every 36 hours, every 48 hours, every 60 hours, every 72 hours, every 84 hours, every 96 hours, every 108 hours, every 120 hours, every 132 hours, every 144 hours, every 156 hours, every 168 hours, or longer after embryo transfer.

[0193] In some embodiments, oxytocin antagonists are administered to subjects in additional doses, for example, every 12, 24, 36, 48, 60, 72, 84, 96, 108, 120, 132, 144, 156, 168 hours, or longer, after embryo transfer, for 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 times, or more.

[0194] In some embodiments, the oxytocin antagonist is administered to the subject after embryo transfer in up to seven additional doses every 24 hours (e.g., doses 1, 2, 3, 4, 5, 6, or 7), such as up to seven doses of compound (II) every 24 hours. In some embodiments, the oxytocin antagonist is administered to the subject after embryo transfer in one dose every 24 hours, such as one additional dose of compound (II) every 24 hours. In some embodiments, the oxytocin antagonist is administered to the subject after embryo transfer in two doses every 24 hours, such as two additional doses of compound (II) every 24 hours. In some embodiments, the oxytocin antagonist is administered to the subject after embryo transfer in three doses every 24 hours, such as three additional doses of compound (II) every 24 hours. In some embodiments, the oxytocin antagonist is administered to the subject after embryo transfer in four doses every 24 hours, such as four additional doses of compound (II) every 24 hours. In some embodiments, the oxytocin antagonist is administered to the subject in five doses every 24 hours after embryo transfer, such as five additional doses of compound (II) every 24 hours. In some embodiments, the oxytocin antagonist is administered to the subject in six doses every 24 hours after embryo transfer, such as six additional doses of compound (II) every 24 hours. In some embodiments, the oxytocin antagonist is administered to the subject in seven doses every 24 hours after embryo transfer, such as seven additional doses of compound (II) every 24 hours.

[0195] When an additional dose of an oxytocin antagonist is administered to a subject after embryo transfer, the administration of the oxytocin antagonist may end, for example, within about 1 hour to about 14 days, or more, after embryo transfer. For example, the administration of the oxytocin antagonist may end at about 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 24 hours, 36 hours, 48 hours, 60 hours, 72 hours, 84 hours, 96 hours, 108 hours, 120 hours, 132 hours, 144 hours, 156 hours, 168 hours, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, 21 days, 22 days, 23 days, 24 days, 25 days, 26 days, 27 days, 28 days, 29 days, 30 days, or more, after embryo transfer.

[0196] Thus, in some embodiments, the oxytocin antagonist is administered to the subject in an additional daily dose for about 1 day to about 14 days after embryo transfer. In some embodiments, the additional daily dose is administered to the subject for about 3 days to about 11 days after embryo transfer. In some embodiments, the additional daily dose is administered to the subject for 7 days after embryo transfer.

[0197] In some embodiments of any of the above aspects of the present invention, the oxytocin antagonist is administered to the subject simultaneously with the transfer of one or more embryos into the uterus of the subject.

[0198] In some embodiments, the oxytocin antagonist is administered to the subject simultaneously with a single-dose embryo transfer.

[0199] In some embodiments, oxytocin antagonists are administered to subjects in multiple doses, starting during embryo transfer (e.g., multiple regular doses) and continuing after embryo transfer, such as 1 to 20 doses, starting during embryo transfer and continuing after embryo transfer, for example, every 12, 24, 36, 48, 60, 72, 84, 96, 108, 120, 132, 144, 156, 168 hours, or longer. For example, in some embodiments, an oxytocin antagonist is administered to the subject in 1 to 10 additional doses, starting during embryo transfer and continuing after embryo transfer, for example, every 12, 24, 36, 48, 60, 72, 84, 96, 108, 120, 132, 144, 156, 168 hours, or longer, after embryo transfer. In some embodiments, the oxytocin antagonist is administered to the subject in 1 to 5 additional doses, starting during embryo transfer and continuing after embryo transfer, for example, every 12, 24, 36, 48, 60, 72, 84, 96, 108, 120, 132, 144, 156, 168 hours, or longer, after embryo transfer. In some embodiments, the oxytocin antagonist is administered to the subject in 10 to 20 additional doses, starting during embryo transfer and continuing after embryo transfer, for example, every 12, 24, 36, 48, 60, 72, 84, 96, 108, 120, 132, 144, 156, 168 hours, or longer, after embryo transfer. In some embodiments, oxytocin antagonists are administered to subjects in 10 to 15 additional doses, starting during embryo transfer and continuing after embryo transfer, for example, every 12, 24, 36, 48, 60, 72, 84, 96, 108, 120, 132, 144, 156, 168 hours, or longer, after embryo transfer.In some embodiments, the oxytocin antagonist is administered to the subject in doses of 1, 2, 3, 4, 5, 6, or more times, for example, every 12, 24, 36, 48, 60, 72, 84, 96, 108, 120, 132, 144, 156, 168 hours, or longer, after embryo transfer. In some embodiments, the oxytocin antagonist is administered to the subject in doses of up to 7 times every 24 hours (e.g., 1, 2, 3, 4, 5, 6, or 7 doses), such as up to 7 doses of compound (II) x 100 mg every 24 hours, starting during embryo transfer and continuing after embryo transfer.

[0200] For example, in some embodiments, the oxytocin antagonist is first administered to the subject simultaneously with the transfer of one or more embryos into the subject's uterus, and then the oxytocin antagonist is administered to the subject in one or more additional doses approximately 1 hour to 24 hours after the transfer of one or more embryos into the subject. For example, in some embodiments, the oxytocin antagonist is administered to the subject in one or more additional doses approximately 1 hour to 12 hours after the transfer of one or more embryos into the subject. In some embodiments, the oxytocin antagonist is administered to the subject in one or more additional doses approximately 12 hours to 24 hours after the transfer of one or more embryos into the subject. In some embodiments, the oxytocin antagonist is administered to the subject in one or more additional doses approximately 1 hour to 10 hours after the transfer of one or more embryos into the subject. In some embodiments, the oxytocin antagonist is administered to the subject in one or more additional doses approximately 1 hour to 9 hours after the transfer of one or more embryos into the subject. In some embodiments, the oxytocin antagonist is administered to the subject in one or more additional doses approximately 1 to 8 hours after the transfer of one or more embryos to the subject. In some embodiments, the oxytocin antagonist is administered to the subject in one or more additional doses approximately 1 to 7 hours after the transfer of one or more embryos to the subject. In some embodiments, the oxytocin antagonist is administered to the subject in one or more additional doses approximately 1 to 6 hours after the transfer of one or more embryos to the subject. In some embodiments, the oxytocin antagonist is administered to the subject in one or more additional doses approximately 1 to 5 hours after the transfer of one or more embryos to the subject. In some embodiments, the oxytocin antagonist is administered to the subject in one or more additional doses approximately 1 to 4 hours after the transfer of one or more embryos to the subject. In some embodiments, the oxytocin antagonist is administered to the subject in one or more additional doses approximately 2 to 6 hours after the transfer of one or more embryos to the subject. In some embodiments, an oxytocin antagonist is administered to the subject in one or more additional doses approximately 3 to 5 hours after the implantation of one or more embryos into the subject.

[0201] In some embodiments, the oxytocin antagonist is first administered to the subject simultaneously with the implantation of one or more embryos into the subject's uterus, and then the oxytocin antagonist is administered to the subject in one or more additional doses, starting at approximately 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 24 hours, 36 hours, 48 ​​hours, 60 hours, 72 hours, 84 hours, 96 hours, 108 hours, 120 hours, 132 hours, 144 hours, 156 hours, 168 hours, or longer after the implantation of one or more embryos into the subject.

[0202] In some embodiments, the oxytocin antagonist is first administered to the subject simultaneously with the transfer of one or more embryos into the subject's uterus, and then the oxytocin antagonist is administered to the subject in multiple additional doses after embryo transfer, such as 1 to 20 additional doses, every 12, 24, 36, 48, 60, 72, 84, 96, 108, 120, 132, 144, 156, 168 hours, or longer. In some embodiments, oxytocin antagonists are further administered to subjects after embryo transfer in doses of 1 to 20 times every 24 hours, such as once, twice, three times, four times, five times, six times, seven times, eight times, nine times, ten times, eleven times, twelve times, thirteen times, fourteen times, fifteen times, sixteen times, seventeen times, eighteen times, and twenty times every 24 hours. In some embodiments, oxytocin antagonists are further administered to subjects after embryo transfer in doses of more than 20 times every 24 hours.

[0203] For example, in some embodiments, the oxytocin antagonist is first administered to the subject at the same time as the implantation of one or more embryos into the subject's uterus, and the oxytocin antagonist is then administered to the subject in 1 to 10 additional doses, for example, every 12, 24, 36, 48, 60, 72, 84, 96, 108, 120, 132, 144, 156, 168 hours, or longer, after embryo transfer. In some embodiments, oxytocin antagonists are further administered to subjects after embryo transfer in doses of 1 to 10 times every 24 hours, such as once every 24 hours, twice every 24 hours, three times every 24 hours, four times every 24 hours, five times every 24 hours, six times every 24 hours, seven times every 24 hours, eight times every 24 hours, nine times every 24 hours, and ten times every 24 hours.

[0204] For example, in some embodiments, the oxytocin antagonist is first administered to the subject at the same time as the implantation of one or more embryos into the subject's uterus, and the oxytocin antagonist is then administered to the subject in 1 to 5 additional doses, for example, every 12, 24, 36, 48, 60, 72, 84, 96, 108, 120, 132, 144, 156, 168 hours, or longer, after embryo transfer. In some embodiments, the oxytocin antagonist is administered to the subject in 10 to 20 additional doses, for example, every 12 hours, 24 hours, 36 hours, 48 ​​hours, 60 hours, 72 hours, 84 hours, 96 hours, 108 hours, 120 hours, 132 hours, 144 hours, 156 hours, 168 hours, or longer, after embryo transfer. In some embodiments, the oxytocin antagonist is administered to the subject in 10 to 15 additional doses, for example, every 12 hours, 24 hours, 36 hours, 48 ​​hours, 60 hours, 72 hours, 84 hours, 96 hours, 108 hours, 120 hours, 132 hours, 144 hours, 156 hours, 168 hours, or longer, after embryo transfer.

[0205] In some embodiments, the oxytocin antagonist is first administered to the subject at the same time as the implantation of one or more embryos into the subject's uterus, and the oxytocin antagonist is subsequently administered to the subject in additional doses of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 or more times, for example, every 12, 24, 36, 48, 48, 60, 72, 84, 96, 108, 120, 132, 144, 156, 168 hours, or longer, after embryo transfer.

[0206] In some embodiments, the oxytocin antagonist is first administered to the subject simultaneously with the transfer of one or more embryos into the subject's uterus, and the oxytocin antagonist is then administered to the subject after embryo transfer in up to seven additional doses every 24 hours (e.g., doses 1, 2, 3, 4, 5, 6, or 7), such as up to seven doses of compound (II) every 24 hours. In some embodiments, the oxytocin antagonist is administered to the subject after embryo transfer in one dose every 24 hours, such as one additional dose of compound (II) every 24 hours. In some embodiments, the oxytocin antagonist is administered to the subject after embryo transfer in two doses every 24 hours, such as two additional doses of compound (II) every 24 hours. In some embodiments, the oxytocin antagonist is administered to the subject after embryo transfer in three doses every 24 hours, such as three additional doses of compound (II) every 24 hours. In some embodiments, the oxytocin antagonist is administered to the subject in four doses every 24 hours after embryo transfer, such as four additional doses of compound (II) every 24 hours. In some embodiments, the oxytocin antagonist is administered to the subject in five doses every 24 hours after embryo transfer, such as five additional doses of compound (II) every 24 hours. In some embodiments, the oxytocin antagonist is administered to the subject in six doses every 24 hours after embryo transfer, such as six additional doses of compound (II) every 24 hours. In some embodiments, the oxytocin antagonist is administered to the subject in seven doses every 24 hours after embryo transfer, such as seven additional doses of compound (II) every 24 hours.

[0207] If one or more additional doses of oxytocin antagonist are administered to the subject after embryo transfer, the administration of oxytocin antagonist may be terminated, for example, within approximately 1 hour to 14 days after embryo transfer, or even later. For example, oxytocin antagonist administration may be terminated within approximately 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 24 hours, 36 hours, 48 ​​hours, 60 hours, 72 hours, 84 hours, 96 hours, 108 hours, 120 hours, 132 hours, 144 hours, 156 hours, 168 hours, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, 21 days, 22 days, 23 days, 24 days, 25 days, 26 days, 27 days, 28 days, 29 days, or 30 days after embryo transfer, or at any time thereafter.

[0208] Therefore, in some embodiments, the oxytocin antagonist is first administered to the subject simultaneously with the transfer of one or more embryos into the subject's uterus, and the oxytocin antagonist is then administered to the subject in an additional daily dose for approximately 1 to 14 days post-embryo transfer. In some embodiments, the additional daily dose is administered to the subject for approximately 3 to 11 days post-embryo transfer. In some embodiments, the additional daily dose is administered to the subject for 7 days post-embryo transfer.

[0209] In some embodiments of any of the above aspects of the present invention, an oxytocin antagonist is administered to the subject after the implantation of one or more embryos into the subject's uterus.

[0210] In some embodiments, the oxytocin antagonist is administered to the subject approximately 1 to 24 hours after the transfer of one or more embryos to the subject. For example, in some embodiments, the oxytocin antagonist is administered to the subject approximately 1 to 12 hours after the transfer of one or more embryos to the subject. In some embodiments, the oxytocin antagonist is administered to the subject approximately 12 to 24 hours after the transfer of one or more embryos to the subject. In some embodiments, the oxytocin antagonist is administered to the subject approximately 1 to 10 hours after the transfer of one or more embryos to the subject. In some embodiments, the oxytocin antagonist is administered to the subject approximately 1 to 9 hours after the transfer of one or more embryos to the subject. In some embodiments, the oxytocin antagonist is administered to the subject approximately 1 to 8 hours after the transfer of one or more embryos to the subject. In some embodiments, the oxytocin antagonist is administered to the subject approximately 1 to 7 hours after the transfer of one or more embryos to the subject. In some embodiments, the oxytocin antagonist is administered to the subject approximately 1 to 6 hours after the transfer of one or more embryos to the subject. In some embodiments, the oxytocin antagonist is administered to the subject approximately 1 to 5 hours after the transfer of one or more embryos to the subject. In some embodiments, the oxytocin antagonist is administered to the subject approximately 1 to 4 hours after the transfer of one or more embryos to the subject. In some embodiments, the oxytocin antagonist is administered to the subject approximately 2 to 6 hours after the transfer of one or more embryos to the subject. In some embodiments, the oxytocin antagonist is administered to the subject approximately 3 to 5 hours after the transfer of one or more embryos to the subject.

[0211] For example, in some embodiments, the oxytocin antagonist is administered to the subject approximately 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours, 18 hours, 19 hours, 20 hours, 21 hours, 22 hours, 23 hours, 24 hours, 36 hours, 48 ​​hours, 60 hours, 72 hours, 84 hours, 96 hours, 108 hours, 120 hours, 132 hours, 144 hours, 156 hours, 168 hours, or longer after implantation of one or more embryos into the subject.

[0212] In some embodiments, oxytocin antagonists are administered to subjects after a single-dose embryo transfer.

[0213] In some embodiments, oxytocin antagonists are administered to subjects in multiple doses after embryo transfer, such as in multiple regular doses. In some embodiments, oxytocin antagonists are administered to subjects in 1 to 20 doses after embryo transfer, for example, every 12 hours, 24 hours, 36 hours, 48 ​​hours, 60 hours, 72 hours, 84 hours, 96 hours, 108 hours, 120 hours, 132 hours, 144 hours, 156 hours, 168 hours, or longer. In some embodiments, oxytocin antagonists are administered to subjects after embryo transfer in doses of 1 to 20 times every 24 hours, such as once, twice, three times, four times, five times, six times, seven times, eight times, nine times, ten times, eleven times, twelve times, thirteen times, fourteen times, fifteen times, sixteen times, seventeen times, eighteen times, nine times, ten times, eleven times, twelve times, thirteen times, fourteen times, fifteen times, sixteen times, seventeen times, eighteen times, nineteen times, twenty times, and so on. In some embodiments, oxytocin antagonists are administered to subjects after embryo transfer in doses of more than 20 times every 24 hours.

[0214] For example, in some embodiments, the oxytocin antagonist is administered to the subject in 1 to 10 doses every 24 hours, such as every 12 hours, every 24 hours, every 36 hours, every 48 hours, every 60 hours, every 72 hours, every 84 hours, every 96 hours, every 108 hours, every 120 hours, every 132 hours, every 144 hours, every 156 hours, every 168 hours, or longer intervals after embryo transfer. In some embodiments, the oxytocin antagonist is administered to the subject in 1 to 10 doses every 24 hours after embryo transfer, such as once every 24 hours, twice every 24 hours, three times every 24 hours, four times every 24 hours, five times every 24 hours, six times every 24 hours, seven times every 24 hours, eight times every 24 hours, nine times every 24 hours, or ten times every 24 hours.

[0215] In some embodiments, the oxytocin antagonist is administered to the subject in 1 to 5 doses, for example, every 12 hours, 24 hours, 36 hours, 48 ​​hours, 60 hours, 72 hours, 84 hours, 96 hours, 108 hours, 120 hours, 132 hours, 144 hours, 156 hours, 168 hours, or longer intervals after embryo transfer. In some embodiments, the oxytocin antagonist is administered to the subject in 10 to 20 doses, for example, every 12 hours, 24 hours, 36 hours, 48 ​​hours, 60 hours, 72 hours, 84 hours, 96 hours, 108 hours, 120 hours, 132 hours, 144 hours, 156 hours, 168 hours, or longer intervals after embryo transfer. In some embodiments, oxytocin antagonists are administered to subjects in 10 to 15 doses, for example, every 12, 24, 36, 48, 60, 72, 84, 96, 108, 120, 132, 144, 156, 168 hours, or longer intervals after embryo transfer.

[0216] In some embodiments, the oxytocin antagonist is administered to the subject, for example, every 12 hours, every 24 hours, every 36 hours, every 48 hours, every 60 hours, every 72 hours, every 84 hours, every 96 hours, every 108 hours, every 120 hours, every 132 hours, every 144 hours, every 156 hours, every 168 hours, or longer after embryo transfer, at 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 doses, or more.

[0217] In some embodiments, the oxytocin antagonist is administered to the subject after embryo transfer at a maximum of 7 doses (e.g., 1, 2, 3, 4, 5, 6, or 7 doses) every 24 hours, such as a dose of up to 7 x 100 mg every 24 hours of compound (II). In some embodiments, the oxytocin antagonist is administered to the subject after embryo transfer at a dose of once every 24 hours, such as a dose of once every 24 hours of compound (II). In some embodiments, the oxytocin antagonist is administered to the subject after embryo transfer at a dose of twice every 24 hours, such as a dose of twice every 24 hours of compound (II). In some embodiments, the oxytocin antagonist is administered to the subject after embryo transfer at a dose of three times every 24 hours, such as a dose of three times every 24 hours of compound (II). In some embodiments, the oxytocin antagonist is administered to the subject after embryo transfer at a dose of four times every 24 hours, such as a dose of four times every 24 hours of compound (II). In some embodiments, the oxytocin antagonist is administered to the subject after embryo transfer at a dose of five times every 24 hours, such as a dose of five times every 24 hours of compound (II). In some embodiments, the oxytocin antagonist is administered to the subject after embryo transfer at a dose of six times every 24 hours, such as a dose of six times every 24 hours of compound (II). In some embodiments, the oxytocin antagonist is administered to the subject after embryo transfer at a dose of seven times every 24 hours, such as a dose of seven times every 24 hours of compound (II).

[0218] If oxytocin antagonists are administered in multiple doses after embryo transfer, administration of oxytocin antagonists may be discontinued, for example, within approximately 1 hour to 14 days after embryo transfer, or even later. For example, oxytocin antagonist administration may be terminated within approximately 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 24 hours, 36 hours, 48 ​​hours, 60 hours, 72 hours, 84 hours, 96 hours, 108 hours, 120 hours, 132 hours, 144 hours, 156 hours, 168 hours, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, 21 days, 22 days, 23 days, 24 days, 25 days, 26 days, 27 days, 28 days, 29 days, or 30 days after embryo transfer, or at any time thereafter.

[0219] Therefore, in some embodiments, the oxytocin antagonist is administered to subjects at a daily dose for approximately 1 to 14 days after embryo transfer. In some embodiments, the daily dose is administered to subjects for approximately 3 to 11 days after embryo transfer. In some embodiments, the daily dose is administered to subjects for 7 days after embryo transfer.

[0220] In some embodiments of any of the above aspects of the present invention, administration of an oxytocin antagonist to a subject reduces the likelihood that the subject will have a miscarriage after the transfer of one or more embryos into the subject.

[0221] In some embodiments, the sample is a blood sample.

[0222] In some embodiments, embryo transfer therapy includes the transfer of one or two embryos to a subject. In some embodiments, embryo transfer therapy includes the transfer of one embryo to a subject. In some embodiments, embryo transfer therapy includes the transfer of two embryos to a subject.

[0223] In some embodiments, the subject is a mammal, and one or more embryos are mammalian embryos. In some embodiments, the mammal is a human, and one or more embryos are human embryos.

[0224] In some embodiments, one or more embryos are produced in vitro by IVF, such as by IVF of one or more eggs derived from the subject.

[0225] In some embodiments, one or more embryos are produced in vitro by ICSI, such as by ICSI into one or more eggs derived from the subject.

[0226] In some embodiments, one or more oocytes are derived from one or more oocytes isolated from the subject. In some embodiments, one or more oocytes are isolated from the subject about 1 to 7 days before the transfer of one or more embryos to the subject. In some embodiments, one or more oocytes are isolated from the subject about 2 days before the transfer of one or more embryos to the subject. In some embodiments, one or more oocytes are isolated from the subject about 3 days before the transfer of one or more embryos to the subject. In some embodiments, one or more oocytes are isolated from the subject about 4 days before the transfer of one or more embryos to the subject. In some embodiments, one or more oocytes are isolated from the subject about 5 days before the transfer of one or more embryos to the subject.

[0227] In some embodiments, one or more oocytes contain 1 to 4 mature oocytes (i.e., 1 to 4 eggs).

[0228] In some embodiments, a GnRH antagonist is administered to the subject prior to the isolation of one or more oocytes from the subject (e.g., one or more mature oocytes).

[0229] In some embodiments, hCG is administered to a subject prior to the isolation of one or more oocytes (e.g., one or more mature oocytes) from the subject, for example by a single intravenous injection, to induce final follicular maturation.

[0230] In some embodiments, progesterone is administered to the subject after the isolation of one or more oocytes from the subject. Progesterone may be administered intravaginally. In some embodiments, the subject is administered approximately 300 mg to 600 mg of progesterone per dose. In some embodiments, progesterone is administered to the subject daily, starting approximately 24 hours after the isolation of one or more oocytes from the subject and continuing for approximately 6 weeks or more after the transfer of one or more embryos to the subject.

[0231] In some embodiments, one or more oocytes are isolated directly from the subject. In some embodiments, one or more oocytes are isolated from the subject about 1 to 7 days before the transfer of one or more embryos to the subject. In some embodiments, one or more oocytes are isolated from the subject about 2 days before the transfer of one or more embryos to the subject. In some embodiments, one or more oocytes are isolated from the subject about 3 days before the transfer of one or more embryos to the subject. In some embodiments, one or more oocytes are isolated from the subject about 4 days before the transfer of one or more embryos to the subject. In some embodiments, one or more oocytes are isolated from the subject about 5 days before the transfer of one or more embryos to the subject.

[0232] In some embodiments, a GnRH antagonist is administered to the subject prior to the isolation of one or more oocytes from the subject, such as by a single intravenous injection.

[0233] In some embodiments, hCG is administered to a subject prior to the isolation of one or more oocytes from the subject, for example, by a single intravenous injection, in order to induce final follicular maturation.

[0234] In some embodiments, progesterone is administered to the subject after the isolation of one or more oocytes from the subject. Progesterone may be administered intravaginally. In some embodiments, the subject is administered approximately 300 mg to 600 mg of progesterone per dose. In some embodiments, progesterone is administered to the subject daily, starting approximately 24 hours after the isolation of one or more oocytes from the subject and continuing for approximately 6 weeks or more after the transfer of one or more embryos to the subject.

[0235] In some embodiments, one or more embryos are isolated from the subject and implanted into the subject during the same menstrual cycle.

[0236] In some embodiments, one or more embryos are isolated from the subject and implanted into the subject during the same menstrual cycle.

[0237] In some embodiments, one or more embryos are frozen and thawed before being implanted into a target.

[0238] In some embodiments, each of the one or more embryos contains 6 to 8 blastomeres immediately before implantation into a target. The blastomeres may be approximately equal in size when evaluated by visual microscopy before implantation into a target. In some embodiments, the one or more embryos include embryos having the morphology of a morula. In some embodiments, the one or more embryos include embryos having the morphology of a blastula (e.g., a mammalian blastocyst).

[0239] In some embodiments, the oxytocin antagonist is a compound represented by formula (I), [ka] (I) or its geometric isomers, enantiomers, diastereomers, racemates, or salts, In the formula, n is an integer between 1 and 3. R 1 It is selected from the group consisting of hydrogen and C1-C6 alkyl groups, R 2Hydrogen, C1-C6 alkyl, C1-C6 alkylaryl, heteroaryl, C1-C6 alkylheteroaryl, C2-C6 alkenyl, C2-C6 alkenylaryl, C2-C6 alkenylheteroaryl, C2-C6 alkynyl, C2-C6 alkynylaryl, C2-C6 alkynylheteroaryl, C3-C6 cycloalkyl, heterocycloalkyl, C1-C6 alkylcycloalkyl, C1-C6 alkylheterocycloalkyl, C1-C6 alkylcarboxy, acyl, C1-C6 alkylacyl, C1-C6 alkyl Selected from the group consisting of siloxy, C1-C6 alkylalkoxy, alkoxycarbonyl, C1-C6 alkylalkoxycarbonyl, aminocarbonyl, C1-C6 alkylaminocarbonyl, C1-C6 alkylacylamino, C1-C6 alkylureido, amino, C1-C6 alkylamino, sulfonyloxy, C1-C6 alkylsulfonyloxy, sulfonyl, C1-C6 alkylsulfonyl, sulfinyl, C1-C6 alkylsulfinyl, C1-C6 alkylsulfanyl, and C1-C6 alkylsulfonylamino, R 3 It is selected from the group consisting of aryls and heteroaryls, X is oxygen and NR 4 Selected from the group consisting of, R 4 R is selected from the group consisting of hydrogen, C1-C6 alkyl, C1-C6 alkylaryl, C1-C6 alkylheteroaryl, aryl, and heteroaryl. 2 and R 4 These can form a 5- to 8-membered saturated or unsaturated heterocycloalkyl ring together with the nitrogen atoms to which they are bonded.

[0240] In some embodiments, the compound is (3Z,5S)-5-(hydroxymethyl)-1-[(2'-methyl-1,1'-biphenyl-4-yl)carbonyl]pyrrolidine-3-one O-methyloxime, represented by formula (II). [ka] (II)

[0241] In some embodiments, the compound represented by formula (II) (i.e., (3Z,5S)-5-(hydroxymethyl)-1-[(2'-methyl-1,1'-biphenyl-4-yl)carbonyl]pyrrolidine-3-one O-methyloxime) is substantially pure. For example, in some embodiments, the compound represented by formula (II) has a purity of at least 85%, such as 85% to 99.9% or higher (e.g., 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.1%, 99.2%, 99.3%, 99.4%, 99.5%, 99.6%, 99.7%, 99.8%, 99.9%, or higher). The purity of the compound represented by formula (II) can be evaluated using chromatographic methods such as NMR techniques and / or HPLC procedures, which are well known in the art and described herein, such as those techniques described in U.S. Patent No. 9,670,155, the disclosure of which is incorporated herein by reference in whole.

[0242] In some embodiments, the compound represented by formula (II) is substantially pure with respect to the diastereomer of the compound and other by-products that may be formed during the synthesis of the compound. For example, in some embodiments, the compound represented by formula (II) has a purity of at least 85%, such as 85% to 99.9% or higher (e.g., 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.1%, 99.2%, 99.3%, 99.4%, 99.5%, 99.6%, 99.7%, 99.8%, 99.9%, or higher), with respect to the diastereomer of the compound and other by-products that may be formed during the synthesis of the compound, such as the by-product formed during the synthesis of the compound as described in U.S. Patent No. 9,670,155. The purity of the compound represented by formula (II) can be evaluated using chromatographic methods such as NMR techniques and / or HPLC procedures, which are well known in the art and described herein, such as those techniques described in U.S. Patent No. 9,670,155.

[0243] In some embodiments, the compound represented by formula (II) is substantially pure with respect to its (3E) diastereomer, (3E,5S)-5-(hydroxymethyl)-1-[(2'-methyl-1,1'-biphenyl-4-yl)carbonyl]pyrrolidine-3-one O-methyloxime. For example, in some embodiments, the compound represented by formula (II) has a purity of at least 85%, such as 85% to 99.9% or higher with respect to (3E,5S)-5-(hydroxymethyl)-1-[(2'-methyl-1,1'-biphenyl-4-yl)carbonyl]pyrrolidine-3-one O-methyloxime (e.g., 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.1%, 99.2%, 99.3%, 99.4%, 99.5%, 99.6%, 99.7%, 99.8%, 99.9%, or higher). For example, compound (II) may be administered in the form of a composition containing less than 15% of the (3E) diastereomer (e.g., tablets such as dispersible tablets, capsules, gel caps, powders, liquid solutions, or liquid suspensions). For example, compound (II) may be administered in the form of a composition containing less than 14%, less than 13%, less than 12%, less than 11%, less than 10%, less than 9%, less than 8%, less than 7%, less than 6%, less than 5%, less than 4%, less than 3%, less than 2%, less than 1%, less than 0.1%, less than 0.01%, less than 0.001%, or less of the (3E) diastereomer (e.g., tablets such as dispersible tablets, capsules, gel caps, powders, liquid solutions, or liquid suspensions). The purity of the compound represented by formula (II) may be evaluated using chromatographic methods such as NMR techniques and / or HPLC procedures, which are well known in the art and described herein, such as those techniques described in U.S. Patent No. 9,670,155.

[0244] In some embodiments, the compound is in a crystalline state. In some embodiments, the compound exhibits characteristic X-ray powder diffraction peaks at approximately 7.05°2θ, 13.13°2θ, and 23.34°2θ. For example, the compound may exhibit characteristic X-ray powder diffraction peaks at approximately 7.05°2θ, 12.25°2θ, 13.13°2θ, 16.54°2θ, 18.00°2θ, 21.84°2θ, and 23.34°2θ. In some embodiments, the compound exhibits characteristic X-ray powder diffraction peaks as shown in Table 1 above.

[0245] In some embodiments, the compound is administered orally to the subject. In some embodiments, the compound is administered intravenously to the subject. For example, the compound may be administered to the subject in the form of a tablet, capsule, gel cap, powder, liquid solution, or liquid suspension. In some embodiments, the compound is administered to the subject in the form of a tablet, such as a dispersible tablet. A dispersible tablet may have, for example, one or more of the following components: a. Approximately 1-20% by weight of calcium silicate, b. Approximately 0.1-20% by weight of PVP30K, c. Approximately 0.01-5% by weight of poloxamer 188, d. Approximately 0.5-20% by weight of croscarmellose sodium e. Approximately 1-90% by weight of microcrystalline cellulose 112, f. Approximately 1-90% by weight of lactose monohydrate. g. Approximately 0.01-0.5% by weight of sodium saccharin, and h. Approximately 0.1-10% by weight of glycerol dibehenate. For example, a dispersible tablet may have the following composition: a. Approximately 5% by weight of calcium silicate, b. Approximately 1% by weight of PVP30K, c. Approximately 2% by weight of poloxamer 188, d. Approximately 5% by weight of croscarmellose sodium, e. Approximately 1.5% by weight of microcrystalline cellulose 112, f. Approximately 47.8% by weight of lactose monohydrate. g. Approximately 0.2% by weight of sodium saccharin, and h. Approximately 4% by weight of glycerol dibehenate.

[0246] In some embodiments, the compound is present in approximately 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 105 mg, 110 mg, 115 mg, 120 mg, 125 mg, 130 mg, 135 mg, 140 mg, 145 mg, 150 mg, 155 mg, 1 The compound is administered to the subject in unit dosage forms containing approximately 25 mg to approximately 250 mg of the compound, such as unit dosage forms containing 60 mg, 165 mg, 170 mg, 175 mg, 180 mg, 185 mg, 190 mg, 195 mg, 200 mg, 205 mg, 210 mg, 215 mg, 220 mg, 225 mg, 230 mg, 235 mg, 240 mg, 245 mg, 250 mg, or more of the compound. In some embodiments, the compound is administered to the subject in unit dosage forms containing approximately 25 mg to approximately 75 mg of the compound, such as unit dosage forms containing approximately 50 mg of the compound. In some embodiments, the compound is administered to the subject in unit dosage forms containing approximately 175 mg to approximately 225 mg of the compound, such as unit dosage forms containing approximately 200 mg of the compound.

[0247] In some embodiments, subjects are administered approximately 50 mg to 950 mg of the compound per dose. For example, subjects may be administered approximately 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 105 mg, 110 mg, 115 mg, 120 mg, 125 mg, 130 mg, 135 mg, 140 mg, 145 mg, 150 mg, 155 mg, 160 mg, 165 mg, 170 mg, 175 mg, 180 mg, 185 mg, 190 mg, 195 mg, 200 mg, 205 mg, 210 mg, 215 mg, 220 mg, 225 mg, 230 mg, 235 mg, 240 mg per dose. 245mg, 250mg, 255mg, 260mg, 265mg, 270mg, 275mg, 280mg, 285mg, 290mg, 295mg, 300mg, 305mg, 310mg, 315mg, 320mg, 325mg, 330mg, 335mg, 340mg , 345mg, 350mg, 355mg, 360mg, 365mg, 370mg, 375mg, 380mg, 385mg, 390mg, 400mg, 405mg, 410mg, 415mg, 420mg, 425mg, 430mg, 435mg, 440mg, 445m g, 450mg, 455mg, 460mg, 465mg, 470mg, 475mg, 480mg, 485mg, 490mg, 500mg, 505mg, 510mg, 515mg, 520mg, 525mg, 530mg, 535mg, 540mg, 545mg, 555 mg, 560mg, 565mg, 570mg, 575mg, 580mg, 585mg, 590mg, 595mg, 600mg, 605mg, 610mg, 615mg, 620mg, 625mg, 630mg, 635mg, 640mg, 645mg, 655mg, 66 0mg, 665mg, 670mg, 675mg, 680mg, 685mg, 690mg, 695mg, 700mg, 705mg, 710mg, 715mg, 720mg, 725mg, 730mg, 735mg, 740mg, 745mg, 750mg, 755mg, 7 60mg, 765mg, 770mg, 775mg, 780mg, 785mg, 790mg, 795mg, 800mg, 805mg, 810mg, 815mg, 820mg, 825mg, 830mg, 835mg, 840mg, 845mg, 850mg, 855mg,860 mg, 865 mg, 870 mg, 875 mg, 880 mg, 885 mg, 890 mg, 895 mg, 900 mg, 905 mg, 910 mg, 915 mg, 920 mg, 925 mg, 930 mg, 935 mg, 940 mg, 945 mg, 950 mg, or higher doses of the compound may be administered.

[0248] In some embodiments, subjects are administered approximately 50 mg to 150 mg of a compound per dose, such as 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 105 mg, 110 mg, 115 mg, 120 mg, 125 mg, 130 mg, 135 mg, 140 mg, 145 mg, or 150 mg of the compound per dose. In some embodiments, subjects are administered approximately 100 mg of the compound per dose.

[0249] In some embodiments, subjects are administered approximately 250 mg to 350 mg of the compound per dose, such as approximately 255 mg, 255 mg, 260 mg, 265 mg, 270 mg, 275 mg, 280 mg, 285 mg, 290 mg, 295 mg, 300 mg, 305 mg, 310 mg, 315 mg, 320 mg, 325 mg, 330 mg, 335 mg, 340 mg, 345 mg, or 350 mg of the compound per dose. In some embodiments, subjects are administered approximately 300 mg of the compound per dose.

[0250] In some embodiments, subjects are administered approximately 850 mg to 950 mg of a compound per dose, such as 850 mg, 855 mg, 860 mg, 865 mg, 870 mg, 875 mg, 880 mg, 885 mg, 890 mg, 895 mg, 900 mg, 905 mg, 910 mg, 915 mg, 920 mg, 925 mg, 930 mg, 935 mg, 940 mg, 945 mg, or 950 mg of the compound per dose. In some embodiments, subjects are administered approximately 900 mg of the compound per dose.

[0251] In some embodiments, the oxytocin antagonist is epersiban, or a salt, derivative, variant, crystalline form, or formulation thereof, for example, a salt, derivative, variant, crystalline form, or formulation described in U.S. Patents 7,514,437, 8,367,673, 8,541,579, 7,550,462, 7,919,492, 8,202,864, 8,742,099, 9,408,851, 8,716,286, or 8,815,856, the respective disclosures of which are incorporated herein by reference in whole.

[0252] In some embodiments, the oxytocin antagonist is letsiban, or a salt, derivative, variant, crystalline form, or formulation thereof, for example, a salt, derivative, variant, crystalline form, or formulation described in U.S. Patents 7,514,437, 8,367,673, 8,541,579, 8,071,594, 8,357,685, 8,937,179, or 9,452,169, the respective disclosures of which are incorporated herein by reference in whole.

[0253] In some embodiments, the oxytocin antagonist is barsiban, or a salt, derivative, variant, crystalline form, or formulation thereof, such as salts, derivatives, variants, crystalline forms, or formulations described in, for example, U.S. Patents 6,143,722, 7,091,314, 7,816,489, or 9,579,305, or International Publication 2017 / 060339, the respective disclosures of which are incorporated herein by reference in whole.

[0254] In some embodiments, the oxytocin antagonist is atosiban, or a salt, derivative, variant, crystalline form, or formulation thereof, such as the salts, derivatives, variants, crystalline forms, or formulations described in U.S. Patent No. 4,504,469 or No. 4,402,942, the respective disclosures of which are incorporated herein by reference in whole.

[0255] In some embodiments, oxytocin antagonists are administered orally.

[0256] In some embodiments, oxytocin antagonists are administered parenterally.

[0257] In some embodiments, oxytocin antagonists are administered intravenously.

[0258] In some embodiments, the P4 reference level is approximately 1.0 ng / ml to approximately 2.0 ng / ml. For example, the P4 reference level may be, among other things, 1.0 ng / ml, 1.1 ng / ml, 1.2 ng / ml, 1.3 ng / ml, 1.4 ng / ml, 1.5 ng / ml, 1.6 ng / ml, 1.7 ng / ml, 1.8 mg / ml, 1.9 ng / ml, or 2.0 ng / ml. In some embodiments, the P4 reference level is 1.5 ng / ml.

[0259] In some embodiments, the sample is isolated from the subject approximately 1 to 7 days before the transfer of one or more embryos into the subject. For example, in some embodiments, the sample is isolated from the subject approximately 2 days before the transfer of one or more embryos into the subject. In some embodiments, the sample is isolated from the subject approximately 3 days before the transfer of one or more embryos into the subject. In some embodiments, the sample is isolated from the subject approximately 4 days before the transfer of one or more embryos into the subject. In some embodiments, the sample is isolated from the subject approximately 5 days before the transfer of one or more embryos into the subject.

[0260] In some embodiments, the sample is administered to the subject up to 24 hours before the isolation of one or more oocytes from the subject (e.g., including one or more mature oocytes) (e.g., about 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours, 18 hours, 19 hours, 20 hours, 21 hours, 22 hours, 23 hours, or 24 hours before). In some embodiments, the sample is isolated from the subject immediately before the isolation of one or more oocytes from the subject.

[0261] In some embodiments, the sample is administered to the subject up to 24 hours before the isolation of one or more oocytes from the subject (e.g., about 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours, 18 hours, 19 hours, 20 hours, 21 hours, 22 hours, 23 hours, or 24 hours before). In some embodiments, the sample is isolated from the subject immediately before the isolation of one or more oocytes from the subject.

[0262] In some embodiments, the sample is isolated from the subject within approximately one hour after administration of hCG.

[0263] In some embodiments, the P4 reference level is approximately 200 nM to approximately 400 nM. In some embodiments, the P4 reference level is 320 nM. In some embodiments, the sample is isolated from the subject up to 24 hours before the transfer of one or more embryos to the subject, such as 1 to 24 hours before embryo transfer, 1 to 12 hours before embryo transfer, 1 to 8 hours before embryo transfer, 1 to 4 hours before embryo transfer, or immediately before embryo transfer to 1 hour before embryo transfer. In some embodiments, the sample is isolated from the subject immediately before the transfer of one or more embryos to the subject (i.e., up to 60 minutes before the scheduled transfer of one or more embryos to the subject).

[0264] In some embodiments, the subject exhibits increased expression of endometrial and / or myometrial PGE2 after administration of an oxytocin antagonist, as evaluated, for example, by mass spectrometry and / or spectroscopic techniques described herein or known in the art. In some embodiments, the subject exhibits increased expression of endometrial and / or myometrial PGF2α after administration of an oxytocin antagonist, as evaluated, for example, by mass spectrometry and / or spectroscopic techniques described herein or known in the art. In some embodiments, the subject exhibits increased concentration of PIP2, and / or Ca2+, such as DAG, IP3, and / or sarcoplasmic reticulum. 2+ intracellular (Ca) released from the store 2+ Reduced endometrial and / or myometrial PGF2α signaling after administration of an oxytocin antagonist is assessed by detecting a decrease in the concentration of one or more secondary messengers involved in PGF2α signaling, such as [DAG], [IP3], and / or [Ca]. For example, the subjects include, for example, endometrial and / or myometrial [DAG], [IP3], and / or [Ca]. 2+ As is evident from the reduction of [ ], this may result in a transient increase in endometrial and / or myometrial PGF2α expression, followed by a decrease in PGF2α signaling in these tissues.

[0265] In some embodiments, the subjects maintain pregnancy for approximately 14 days after the transfer of one or more embryos to the subjects, such as during the following periods: 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 3 weeks, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36 weeks or longer. In some embodiments, the subjects maintain a pregnancy for at least 6 weeks after the transfer of one or more embryos to the subjects, such as during weeks 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, or longer. In some embodiments, the subject maintains pregnancy for at least 10 weeks after the transfer of one or more embryos into the subject and / or after the retrieval of one or more oocytes or eggs from the subject, such as during weeks 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, or longer.

[0266] In some embodiments, pregnancy is assessed by a blood pregnancy test, such as by detecting the presence and / or amount of hCG in a blood sample isolated from the subject. In some embodiments, pregnancy is assessed by detecting an intrauterine embryonic heartbeat, for example, at about six weeks or longer after the transfer of one or more embryos to the subject and / or after the retrieval of one or more oocytes or eggs from the subject (e.g., at about six weeks, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, sixteen, seventeen, eighteen, nineteen, twenty

[0267] In some embodiments, subjects maintain pregnancy and give birth to live offspring after administration of an oxytocin antagonist. For example, in some embodiments, subjects maintain pregnancy and give birth to live offspring at a gestational age of at least approximately 24 weeks, such as at approximately 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36 weeks, or longer.

[0268] In another embodiment, the present invention provides a kit comprising a document and an oxytocin antagonist, the document instructing the user of the kit to carry out any of the aforementioned embodiments and models of the present invention. In some embodiments of this embodiment, the oxytocin antagonist is a compound represented by formula (I), [ka] (I) or its geometric isomers, enantiomers, diastereomers, racemates, or salts, In the formula, n is an integer between 1 and 3. R 1 It is selected from the group consisting of hydrogen and C1-C6 alkyl groups, R 2 is selected from the group consisting of hydrogen, C1-C6 alkyl, C1-C6 alkylaryl, heteroaryl, C1-C6 alkylheteroaryl, C2-C6 alkenyl, C2-C6 alkenylaryl, C2-C6 alkenylheteroaryl, C2-C6 alkynyl, C2-C6 alkynylaryl, C2-C6 alkynylheteroaryl, C3-C6 cycloalkyl, heterocycloalkyl, C1-C6 alkylcycloalkyl, C1-C6 alkylheterocycloalkyl, C1-C6 alkylcarboxy, acyl, C1-C6 alkylacyl, C1-C6 alkylacyloxy, C1-C6 alkylalkoxy, alkoxycarbonyl, C1-C6 alkylalkoxycarbonyl, aminocarbonyl, C1-C6 alkylaminocarbonyl, C1-C6 alkylacylamino, C1-C6 alkylureido, amino, C1-C6 alkylamino, sulfonyloxy, C1-C6 alkylsulfonyloxy, sulfonyl, C1-C6 alkylsulfonyl, sulfinyl, C1-C6 alkylsulfinyl, C1-C6 alkylsulfanyl, and C1-C6 alkylsulfonylamino, R 3 is selected from the group consisting of aryl and heteroaryl, X is selected from the group consisting of oxygen and NR 4 and R 4 is selected from the group consisting of hydrogen, C1-C6 alkyl, C1-C6 alkylaryl, C1-C6 alkylheteroaryl, aryl, and heteroaryl, R 2 and R 4 together with the nitrogen to which they are attached can form a 5- to 8-membered saturated or unsaturated heterocycloalkyl ring, In some embodiments, the compound is represented by formula (II).

Chemical formula

[0269] In some embodiments, the compound represented by formula (II) (i.e., (3Z,5S)-5-(hydroxymethyl)-1-[(2'-methyl-1,1'-biphenyl-4-yl)carbonyl]pyrrolidine-3-one O-methyloxime) is substantially pure. For example, in some embodiments, the compound represented by formula (II) has a purity of at least 85%, such as 85% to 99.9% or higher (e.g., 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.1%, 99.2%, 99.3%, 99.4%, 99.5%, 99.6%, 99.7%, 99.8%, 99.9%, or higher). The purity of the compound represented by formula (II) can be evaluated using chromatographic methods such as NMR techniques and / or HPLC procedures, which are well known in the art and described herein, such as those techniques described in U.S. Patent No. 9,670,155, the disclosure of which is incorporated herein by reference in whole.

[0270] In some embodiments, the compound represented by formula (II) is substantially pure with respect to the diastereomer of the compound and other by-products that may be formed during the synthesis of the compound. For example, in some embodiments, the compound represented by formula (II) has a purity of at least 85%, such as 85% to 99.9% or higher (e.g., 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.1%, 99.2%, 99.3%, 99.4%, 99.5%, 99.6%, 99.7%, 99.8%, 99.9%, or higher), with respect to the diastereomer of the compound and other by-products that may be formed during the synthesis of the compound, such as the by-product formed during the synthesis of the compound as described in U.S. Patent No. 9,670,155. The purity of the compound represented by formula (II) can be evaluated using chromatographic methods such as NMR techniques and / or HPLC procedures, which are well known in the art and described herein, such as those techniques described in U.S. Patent No. 9,670,155.

[0271] In some embodiments, the compound represented by formula (II) is substantially pure with respect to its (3E) diastereomer, (3E,5S)-5-(hydroxymethyl)-1-[(2'-methyl-1,1'-biphenyl-4-yl)carbonyl]pyrrolidine-3-one O-methyloxime. For example, in some embodiments, the compound represented by formula (II) has a purity of at least 85%, such as 85% to 99.9% or higher with respect to (3E,5S)-5-(hydroxymethyl)-1-[(2'-methyl-1,1'-biphenyl-4-yl)carbonyl]pyrrolidine-3-one O-methyloxime (e.g., 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.1%, 99.2%, 99.3%, 99.4%, 99.5%, 99.6%, 99.7%, 99.8%, 99.9%, or higher). For example, compound (II) may be administered in the form of a composition containing less than 15% of the (3E) diastereomer (e.g., tablets such as dispersible tablets, capsules, gel caps, powders, liquid solutions, or liquid suspensions). For example, compound (II) may be administered in the form of a composition containing less than 14%, less than 13%, less than 12%, less than 11%, less than 10%, less than 9%, less than 8%, less than 7%, less than 6%, less than 5%, less than 4%, less than 3%, less than 2%, less than 1%, less than 0.1%, less than 0.01%, less than 0.001%, or less of the (3E) diastereomer (e.g., tablets such as dispersible tablets, capsules, gel caps, powders, liquid solutions, or liquid suspensions). The purity of the compound represented by formula (II) may be evaluated using chromatographic methods such as NMR techniques and / or HPLC procedures, which are well known in the art and described herein, such as those techniques described in U.S. Patent No. 9,670,155.

[0272] In some embodiments, the oxytocin antagonist is epersiban, or a salt, derivative, variant, crystalline form, or formulation thereof, for example, a salt, derivative, variant, crystalline form, or formulation described in U.S. Patents 7,514,437, 8,367,673, 8,541,579, 7,550,462, 7,919,492, 8,202,864, 8,742,099, 9,408,851, 8,716,286, or 8,815,856, the respective disclosures of which are incorporated herein by reference in whole.

[0273] In some embodiments, the oxytocin antagonist is letsiban, or a salt, derivative, variant, crystalline form, or formulation thereof, for example, a salt, derivative, variant, crystalline form, or formulation described in U.S. Patents 7,514,437, 8,367,673, 8,541,579, 8,071,594, 8,357,685, 8,937,179, or 9,452,169, the respective disclosures of which are incorporated herein by reference in whole.

[0274] In some embodiments, the oxytocin antagonist is barsiban, or a salt, derivative, variant, crystalline form, or formulation thereof, such as salts, derivatives, variants, crystalline forms, or formulations described in, for example, U.S. Patents 6,143,722, 7,091,314, 7,816,489, or 9,579,305, or International Publication 2017 / 060339, the respective disclosures of which are incorporated herein by reference in whole.

[0275] In some embodiments, the oxytocin antagonist is atosiban, or a salt, derivative, variant, crystalline form, or formulation thereof, such as the salts, derivatives, variants, crystalline forms, or formulations described in U.S. Patent No. 4,504,469 or No. 4,402,942, the respective disclosures of which are incorporated herein by reference in whole.

[0276] In some embodiments of any of the above aspects of the present invention, the subjects are human female subjects, such as human female subjects aged 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, or 44 years old, or human female subjects up to 44 years old, such as human female subjects from 18 to 44 years old. In some embodiments of any of the above aspects of the present invention, the subjects are human female subjects, such as human female subjects aged 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, or 42 years old, or human female subjects up to 42 years old, such as human female subjects aged 18 to 42 years old. In some embodiments of any of the above aspects of the present invention, the subjects are human female subjects, such as human female subjects aged 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, or 36 years old, or human female subjects up to 36 years old, such as human female subjects from 18 to 36 years old.

[0277] definition As used herein, the term "about" refers to a value that is within 10% above or below the value stated. For example, the phrase "about 50 mg" refers to a value between 45 mg and 55 mg, and including those values.

[0278] As used herein, the term "affinity" refers to the strength of the binding interaction between two molecules, such as a ligand and a receptor. iWhen used herein, "Ki" is intended to refer to the suppression constant of an antagonist with respect to a particular molecule of interest and is expressed as molar concentration (M). The Ki value for an antagonist-target interaction can be determined, for example, using methods established in the art. Methods that can be used to determine the Ki of an antagonist with respect to a molecular target include, for example, competitive binding experiments such as the competitive radioligand binding assay described in U.S. Patent No. 9,670,155, the disclosure of which is incorporated herein by reference in its entirety. d When used herein, "refers to the dissociation rate constant (k) of two molecules, for example. d The association rate constant (k) of the two molecules a It is intended to refer to the dissociation constant that can be obtained from the ratio to ), and is expressed as molar concentration (M). K for receptor-ligand interaction d The value can be determined, for example, using methods established in the art. Methods that can be used to determine the Kd of receptor-ligand interactions include, for example, surface plasmon resonance using biosensor systems such as the BIACORE® system.

[0279] As used herein, the term “assisted reproductive technology” or “ART” refers to a fertility treatment in which one or more female gametes (oocytes) and male gametes (spermocytes) are manipulated outside the body to facilitate oocyte fertilization and the formation of a zygote or embryo. The zygote or embryo is then implanted into the uterus of a female subject, for example, using compositions and methods described herein. Exemplary assisted reproductive technology procedures include in vitro fertilization (IVF) and intracytoplasmic sperm injection (ICSI) techniques described herein and known in the art.

[0280] Where used herein, the term “benefit” in the context of a subject undergoing embryo transfer therapy means any clinical improvement in the subject’s condition or ability to successfully implant and develop an embryo. Illustrative benefits in this context include, but are not limited to, increased endometrial receptivity and prevention of miscarriage in the subject after the transfer of one or more embryos. A subject may be determined to benefit from oxytocin antagonist treatment as described herein by observing enhanced endometrial receptivity in the subject (e.g., assessed by detecting a decrease in prostaglandin F2α (PGF2α) signaling as described herein) and / or by assessing the subject’s ability to maintain pregnancy for at least 14 days, 6 weeks, 10 weeks, or longer, and / or by detecting the subject’s ability to deliver a live birth at least 24 weeks after the transfer of one or more embryos. Additionally or alternatively, a subject may be determined to benefit from the oxytocin antagonist treatment described herein by monitoring the subject for miscarriage after the transfer of one or more embryos into the subject and observing that the subject has not miscarried.

[0281] As used herein, the term “simultaneously with” in the context of the administration of therapeutic agents, such as oxytocin antagonists, as described herein, during embryo transfer therapy describes a process in which the therapeutic agent is administered to the subject substantially simultaneously with the transfer of one or more embryos into the subject’s uterus. For example, if the therapeutic agent is administered to the subject within one hour (e.g., 60, 55, 50, 45, 40, 35, 30, 25, 20, 15, 10, 5 minutes, or less), the therapeutic agent is considered to be administered to the subject simultaneously with the transfer of one or more embryos.

[0282] As used herein, the term “controlled ovarian hyperstimulation” refers to a procedure in which ovulation is induced in a subject, such as a human subject, prior to the retrieval of oocytes or eggs for use in embryogenesis, for example, by in vitro fertilization (IVF) or intracytoplasmic sperm injection (ICSI). A controlled ovarian hyperstimulation procedure may include the administration of human chorionic gonadotropin (hCG) and / or gonadotropin-releasing hormone (GnRH) antagonists to a subject to promote follicular maturation. Controlled ovarian hyperstimulation methods are known in the art and are described, for example, in U.S. Patents 7,405,197 and 7,815,912, the respective disclosures of which are incorporated herein by reference as they relate to methods for inducing follicular maturation and ovulation in conjunction with assisted reproductive technologies.

[0283] As used herein, the terms “crystalline” or “crystalline form” mean having a physical state that is a regular three-dimensional arrangement of atoms, ions, molecules, or molecular assemblies. A crystalline form has a lattice arrangement of constituent elements called asymmetric units, which are arranged according to clearly defined symmetry and form a repeating unit cell in three dimensions. In contrast, the terms “amorphous” or “amorphous form” refer to an unorganized (disorderly) structure. The physical state of a therapeutic compound may be determined by exemplary techniques such as X-ray diffraction, polarized light microscopy, thermogravimetric analysis, and / or differential scanning calorimetry.

[0284] As used herein, the term “derived from” in the context of cells derived from a subject means cells such as mammalian oocytes that are isolated from the subject or obtained from the expansion, division, maturation, or manipulation of one or more cells isolated from the subject (e.g., in vitro expansion, division, maturation, or manipulation). For example, an oocyte is “derived from” the subject or oocyte as described herein, such as an oocyte isolated from the subject about 1 to 7 days before the subject undergoes embryo transfer (e.g., an oocyte isolated from the subject about 3 to 5 days before the subject undergoes embryo transfer).

[0285] As used herein, the term “dispersible tablet” means a tablet that may disintegrate rapidly in water and is to be swallowed by a subject, or that disintegrates rapidly in water and is subsequently swallowed by a subject, such as a subject undergoing embryo transfer therapy as described herein.

[0286] As used herein, the term “dose” means the amount of a therapeutic agent, such as an oxytocin antagonist described herein, administered to a subject for the treatment of a disorder or condition, such as to enhance endometrial receptivity and promote successful embryo implantation in the context of assisted reproductive technology. The therapeutic agents described herein may be administered in single doses or multiple doses. In each case, the therapeutic agent may be administered using one or more unit dosage forms of the therapeutic agent. For example, a single dose of 100 mg of the therapeutic agent may be administered, for example, using two 50 mg unit dosage forms of the therapeutic agent. Similarly, a single dose of 300 mg of the therapeutic agent may be administered, among other things, using, for example, six 50 mg unit dosage forms of the therapeutic agent or two 50 mg unit dosage forms of the therapeutic agent and one 200 mg unit dosage form of the therapeutic agent. Similarly, a single dose of 900 mg of the therapeutic agent may be administered, in particular, using, for example, six 50 mg units of the therapeutic agent and three 200 g units of the therapeutic agent, or ten 50 mg units of the therapeutic agent and two 200 mg units of the therapeutic agent.

[0287] As used herein, the term “embryo” refers to a multicellular post-conjugation derivative of a fertilized egg. An embryo may contain two or more blastomeres. For example, embryos for use with the compositions and methods of the present invention may contain six to eight blastomeres. Embryos may be produced in vitro by in vitro fertilization (IVF) of an egg, for example, an egg isolated from a subject or donor undergoing embryo transfer therapy, or an egg that can be produced by the maturation of an oocyte isolated from a subject or donor undergoing embryo transfer therapy. Embryos may be produced in vitro by intracytoplasmic sperm injection (ICSI) of an egg, for example, an egg isolated from a subject or donor undergoing embryo transfer therapy, or an egg that can be produced by the maturation of an oocyte isolated from a subject or donor undergoing embryo transfer therapy. Embryos may have various multicellular morphologies resulting from oocyte fertilization and subsequent mitosis of the zygote. For example, an embryo may have the morula morphology, typically formed about 3 to 4 days after oocyte fertilization, and containing two or more cells (e.g., 2 to 16 cells, e.g., 6 to 8 cells) packed adjacently in a spherical arrangement. An embryo may also have the blastula morphology (e.g., mammalian or trophectoderm), typically formed about 5 to 7 days after oocyte fertilization, and is characterized by a spherical morphology that includes an inner cell mass and an outer layer of cells (e.g., mammalian trophoblast or trophoblast) surrounding a fluid-filled cavity (e.g., mammalian blastocoel).A blastocyst contains, for example, approximately 20 to 300 cells (for example, approximately 20 cells, 25 cells, 30 cells, 35 cells, 40 cells, 45 cells, 50 cells, 55 cells, 60 cells, 65 cells, 70 cells, 75 cells, 80 cells, 85 cells, 90 cells, 95 cells, 100 cells, 105 cells, 110 cells, 115 cells, 120 cells, 125 cells, 130 cells, 135 cells, 140 cells, 145 cells, 150 cells, 15 This may include 5 cells, 160 cells, 165 cells, 170 cells, 175 cells, 180 cells, 185 cells, 190 cells, 195 cells, 200 cells, 205 cells, 210 cells, 215 cells, 220 cells, 225 cells, 230 cells, 235 cells, 240 cells, 255 cells, 265 cells, 270 cells, 275 cells, 280 cells, 285 cells, 290 cells, 295 cells, or 300 cells) or more.

[0288] As used herein, the term “embryo transfer therapy” refers to a procedure in which one or more embryos are administered into the uterus of a subject, such as a mammalian subject (e.g., a human subject), to facilitate the implantation of one or more embryos into the endometrium of the subject. Embryos may be produced in vitro, for example, by in vitro fertilization (IVF) or intracytoplasmic sperm injection (ICSI), and optionally, one or more oocytes derived from the subject (e.g., one or more oocytes obtained from the maturation of one or more oocytes isolated from the subject) or one or more oocytes derived from a donor (e.g., one or more oocytes obtained from the maturation of one or more oocytes isolated from a donor) may be used. Embryos may be newly transferred to the subject by intrauterine embryo transfer within about 1 to 7 days, such as within about 3 to 5 days of oocyte retrieval from the subject or donor, using one or more embryos produced by fertilization. Embryo transfer is considered “fresh” if ovarian hyperstimulation and oocyte / oocyte retrieval from the subject occur during the same menstrual cycle as the embryo transfer to the subject. Alternatively, embryos can be cryopreserved for long-term storage and then thawed before embryo transfer. This process is referred to herein as frozen embryo transfer (FET).

[0289] As used herein, the term “endogenous” refers to a molecule (e.g., polypeptide, nucleic acid, or cofactor) that is naturally found in a particular organism (e.g., a human) or in a particular location within an organism (e.g., an organ, tissue, or cell such as a human cell).

[0290] As used herein, the term "endometrial receptivity" refers to the ability of the uterus to provide optimal conditions that promote proper implantation and development of embryos such as embryos produced in vitro by in vitro fertilization of an egg (e.g., an egg obtained directly from a subject undergoing an embryo transfer procedure or by maturation of one or more oocytes obtained from a subject undergoing an embryo transfer procedure, or an egg obtained directly from a donor not undergoing an embryo transfer procedure or by maturation of one or more oocytes obtained from a donor not undergoing an embryo transfer procedure) or intracytoplasmic sperm injection into the same. Endometrial receptivity can be enhanced (i.e., increased) using the compositions and methods described herein, for example, by administration of an oxytocin antagonist to a subject undergoing embryo transfer therapy before, at the same time as, and / or after transfer of one or more embryos to the subject. Enhanced endometrial receptivity can be clinically manifested in one or more ways. For example, a subject exhibiting enhanced endometrial receptivity (e.g., in response to treatment with an oxytocin antagonist before, at the same time as, and / or after transfer of one or more embryos to the subject) may exhibit reduced prostaglandin F2α (PGF2α) signaling in the endometrium and / or endometrial tissue of the subject. For example, the subject may have intracellular calcium (Ca 2+ released from stores such as diacylglycerol (DAG), inositol-1,4,5-trisphosphate (IP3), and / or the sarcoplasmic reticulum. 2+If a subject shows reduced concentrations of one or more secondary messengers involved in PGF2α signaling, such as ), the subject may be determined to exhibit enhanced endometrial receptivity in response to oxytocin antagonist administration. For example, a subject may be determined to exhibit enhanced endometrial receptivity in response to oxytocin antagonist treatment, as described herein, by detecting a decrease in the concentration of one or more of the aforementioned secondary messengers in tissue, cell, or blood samples isolated from the subject's endometrium and / or myometrium by 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 100%, 200%, 300%, 400%, 500%, or more compared to a measurement of secondary messengers prior to oxytocin antagonist administration. Enhanced endometrial receptivity in subjects undergoing embryo transfer therapy can also be observed by assessing the subject's ability to maintain pregnancy over the period following embryo transfer to the subject's uterus. For example, subjects exhibiting enhanced endometrial receptivity in response to oxytocin antagonist therapy may maintain pregnancy for at least 14 days after the transfer of one or more embryos to the subject, when assessed by blood pregnancy tests, such as by detecting the presence and / or amount of human chorionic gonadotropin (hCG) in a blood sample isolated from the subject using hCG tests known in the art and / or described herein. Subjects exhibiting enhanced endometrial receptivity in response to oxytocin antagonist therapy may maintain pregnancy for at least six weeks, such as 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, or 40 weeks, after the transfer of one or more embryos into a subject and / or after the retrieval of one or more oocytes or eggs from a subject, as assessed by detecting intrauterine embryonic heartbeats.Subjects exhibiting enhanced endometrial receptivity in response to oxytocin antagonist therapy may, for example, give birth to a live baby at 24 weeks of gestation, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, or 40 weeks of gestation.

[0291] As used herein, the term “exogenous” refers to a molecule (e.g., polypeptide, nucleic acid, or cofactor) that is not naturally found in a particular organism (e.g., a human) or in a particular location within an organism (e.g., an organ, tissue, or cell such as a human cell). Exogenous substances include those supplied to an organism or a culture extracted from an organism from an external source.

[0292] As used herein, the term “preterm labor” describes how far along a particular pregnancy is, measured from the first day of the last menstrual cycle to the present day for a pregnant woman. As used herein, the term “delivery” (sometimes called birth) refers to the expulsion of the fetus and placenta from the uterus for a pregnant woman. In a normal pregnancy, labor can occur at approximately 40 weeks of gestation. As used herein, “preterm labor” refers to a situation in which labor begins three weeks before the end of pregnancy, which is usually around 40 weeks. That is, preterm labor can occur at any stage before, for example, 38 weeks of gestation. Preterm labor usually leads to the onset of labor or labor-related physiological changes in a pregnant woman if left untreated. Preterm labor may or may not be associated with vaginal bleeding or rupture of the uterine membrane. Preterm labor is sometimes called premature labor. Avoiding preterm labor in a subject can extend gestational age, thus avoiding premature birth and consequently reducing the risk of neonatal death and morbidity.

[0293] As used herein, the terms “gonadotropin-releasing hormone antagonist” or “GnRH antagonist” refer to compounds that can inhibit gonadotropin-releasing hormone receptors such as inhibiting the release of one or more gonadotropins (such as follicle-stimulating hormone and luteinization). Examples of GnRH antagonists include 2-phenylethylpyrimidine-2,4(1H,3H)-dione derivatives, such as those described in U.S. Patents 7,056,927, 7,176,211, or 7,419,983, the respective disclosures of which are incorporated herein by reference in their entirety. Exemplary GnRH antagonists include, among others, ellagolix, relgolix, ASP-1707, and SKI2670.

[0294] As used herein, the term "IC 50 "The effectiveness of a reference agonist or the constitutive activity of a biological target can be measured, for example, by a competitive ligand binding assay or Ca 2+ This refers to the concentration of a substance (antagonist) that reduces the concentration of oxytocin antagonists by 50% when measured in cell-based functional assays such as recruitment assays. 50 An example of Ca that can be used to determine 2+ The recruitment assays include fluorescence imaging assays, such as those described in U.S. Patent No. 9,670,155, the disclosures thereof which are incorporated herein by reference in their entirety.

[0295] As used herein, the term “in vitro fertilization” (IVF) refers to the process by which an egg, such as a human egg, is brought into contact with one or more spermatids outside the body to facilitate fertilization and zygote formation. The egg may originate from a subject, such as a human subject undergoing embryo transfer therapy. For example, an egg can be obtained from the maturation of one or more oocytes isolated from a subject, for example, about 1 to 7 days before the transfer of one or more embryos to the subject (for example, about 3 to 5 days before embryo transfer to the subject). The egg may also be retrieved directly from a subject, for example, by transvaginal oocyte retrieval procedures known in the art. Alternatively, the egg may originate from or be isolated from a donor.

[0296] As used herein, the term “intracytoplasmic sperm injection” (ICSI) refers to the process by which spermatids are directly injected into an egg, such as a human egg, to facilitate fertilization and zygote formation. Spermatatids may be injected into an egg, for example, by penetrating the egg cell membrane with a microinjector to deliver the spermatids directly into the cytoplasm of the egg. ICSI procedures useful in combination with the compositions and methods described herein are known in the art and are described, for example, in particular, in International Publication No. 2013 / 158658, International Publication No. 2008 / 051620, and International Publication No. 2000 / 009674, the disclosures of which are incorporated herein by reference as they relate to compositions and methods for performing intracytoplasmic sperm injection.

[0297] As used herein, the term “miscarriage” refers to the spontaneous termination of a pregnancy at a stage in which the embryo or fetus cannot survive independently of the mother. For example, in human subjects, a fetus or embryo may not survive independently of the mother at a gestational age of less than approximately 20 weeks (e.g., a gestational age of approximately 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 weeks).

[0298] As used herein, the term “oral bioavailability” refers to the proportion of a compound administered to a target organism, such as a mammal (e.g., human), that reaches the systemic circulation of the organism and is neither sequestered in non-target organs nor excreted without being absorbed into the gastrointestinal tract. This term refers to the plasma concentration incorporated over time and is usually expressed as a percentage of the orally administered dose.

[0299] As used herein, the terms “oocyte” and “mature oocyte” refer to the germ cells or gametes of a mature haploid female. In the context of assisted reproductive technologies as described herein, oocytes may be produced in vitro by the maturation of one or more oocytes isolated from a subject undergoing embryo transfer therapy. Oocytes may also be isolated directly from a subject by transvaginal oocyte retrieval methods described herein or known in the art.

[0300] As used herein, the terms “oxytocin antagonist” or “OT antagonist” refer to compounds that can inhibit oxytocin receptors such as suppressing the activity of one or more downstream signaling molecules in the oxytocin signaling cascade. Oxytocin antagonists for use with the compositions and methods described herein include pyrrolidine-3-one oxime derivatives, such as those described in U.S. Patent No. 7,115,754, the disclosure of which is incorporated herein by reference in whole. For example, an oxytocin antagonist is (3Z,5S)-5-(hydroxymethyl)-1-[(2'-methyl-1,1'-biphenyl-4-yl)carbonyl]pyrrolidine-3-one O-methyl oxime, as described in U.S. Patent No. 9,670,155, the disclosure of which is incorporated herein by reference in whole. Further examples of oxytocin antagonists include, among others, atosiban, letosiban, barsiban, and epelisiban, as well as their derivatives. For example, oxytocin antagonists that can be used in conjunction with the compositions and methods described herein include epelisiban, as well as salts, derivatives, variants, crystalline forms, and formulations thereof, such as the salts, derivatives, variants, crystalline forms, or formulations described in U.S. Patents No. 7,514,437, 8,367,673, 8,541,579, 7,550,462, 7,919,492, 8,202,864, 8,742,099, 9,408,851, 8,716,286, or 8,815,856, the disclosures of each of which are incorporated herein by reference in whole.Further oxytocin antagonists that may be used in conjunction with the compositions and methods described herein include letosiban, as well as salts, derivatives, variants, crystalline forms, and formulations thereof, such as the salts, derivatives, variants, crystalline forms, or formulations described in U.S. Patents No. 7,514,437, 8,367,673, 8,541,579, 8,071,594, 8,357,685, 8,937,179, or 9,452,169, the disclosures of which are incorporated herein by reference in their entirety. Oxytocin antagonists useful in conjunction with the compositions and methods described herein include barsiban, as well as salts, derivatives, variants, crystalline forms, and formulations thereof, for example, salts, derivatives, variants, crystalline forms, or formulations described in U.S. Patent No. 6,143,722, No. 7,091,314, No. 7,816,489, or No. 9,579,305, or International Publication No. 2017 / 060339, the disclosures of which are incorporated herein by reference in their entirety. Oxytocin antagonists useful in conjunction with the compositions and methods described herein include barsiban, as well as salts, derivatives, variants, crystalline forms, and formulations thereof, for example, salts, derivatives, variants, crystalline forms, or formulations described in U.S. Patent No. 4,504,469 or No. 4,402,942, the disclosures of which are incorporated herein by reference in their entirety.

[0301] As used herein, the term “pharmaceutical composition” means a mixture containing therapeutic compounds, such as oxytocin antagonists described herein, administered to a mammalian subject, such as a human, to prevent, treat, or control a particular disease or condition that is affecting or may affect, such as reducing the likelihood of implantation failure in a subject undergoing embryo transfer.

[0302] As used herein, the term “pharmaceutically acceptable” means a compound, material, composition, and / or dosage form suitable for contact with the tissue of a subject, such as that of a mammal (e.g., human), without excessive toxicity, irritation, allergic response, and other problematic complications, in proportion to a reasonable benefit-to-risk ratio.

[0303] As used herein, the term “probe” refers to a drug, such as an antibody, that specifically binds to an analyte of interest and can detect its presence. Examples of probes for use in the detection of progesterone include monoclonal antibodies described herein and known in the art, such as those manufactured and released under ATCC accession number HB8886 as described in U.S. Patent No. 4,720,455, the disclosures of which are incorporated herein by reference in their entirety.

[0304] As used herein, the terms “prostaglandin F2α signaling” or “PGF2α signaling” refer to an endogenous signaling cascade in which PGF2α enhances the intracellular activity of the PGF2α receptor to produce one or more biological responses. PGF2α signaling is G q PGF2α-mediated stimulation of the PGF2α receptor (FP), a G protein-coupled receptor, leads to the activation of proteins, which in turn lead to phospholipase C (PLC), phosphatidylinositol 3-kinase (PI3K), and extracellular signal-regulated kinases (ERK) 1 and 2. PGF2α signaling involves an increase in the concentration of phosphatidylinosolitol-4,5-bisphosphate (PIP2), and / or the release of intracellular calcium (Ca2+) from Ca2+ stores such as the sarcoplasmic reticulum. 2+This can be detected by observing a decrease in the concentration of one or more secondary messengers involved in PGF2α signaling, such as ). The PGF2α signaling cascade is described in detail, for example, Xu et al., Reproduction 149:139-146 (2015), and its disclosure is incorporated herein by reference as it relates to the proteins and messengers involved in PGF2α signaling.

[0305] As used herein, the terms “progesterone reference level” and “P4 reference level” refer to the concentration of progesterone present in a mammalian subject (e.g., a human subject undergoing embryo transfer) or less, in a sample isolated from the mammalian subject (e.g., a serum sample), indicating that the subject is likely to benefit from an oxytocin antagonist at the same time as and / or after the transfer of one or more embryos into the subject's uterus. As described herein, the P4 reference level may have different values ​​depending on when the patient’s serum progesterone level is assessed. For example, a P4 reference level of approximately 320 nM may be used in conjunction with the compositions and methods described herein, when compared to the concentration of P4 present in the serum of a human subject on the day of embryo transfer. In another example, a P4 reference level of approximately 1.5 ng / ml may be used in conjunction with the compositions and methods described herein, when compared to the concentration of P4 present in the serum of a human subject on the day of oocyte or oocyte retrieval from the subject.

[0306] As used herein, the term “sample” means a specimen isolated from a subject (e.g., blood, blood components (e.g., serum or plasma), urine, saliva, amniotic fluid, cerebrospinal fluid, tissue (e.g., placental tissue or skin tissue), pancreatic juice, chorionic villi specimens, and / or cells).

[0307] As used herein, the expressions “specifically bind” and “bind” refer to a binding reaction that determines, for example, the presence of a particular protein in a heterogeneous population of proteins and other biological molecules recognized by a specific ligand. A ligand that specifically binds to a protein (e.g., a protein, peptide, or small molecule) is, for example, less than 100 nM of K. D It then binds to the protein. For example, ligands that specifically bind to a protein have a maximum K content of 100 nM (e.g., 1 pM to 100 nM). D Ligands that do not exhibit specific binding to a protein or its domain may have a K content greater than 100 nM (e.g., greater than 200 nM, 300 nM, 400 nM, 500 nM, 600 nM, 700 nM, 800 nM, 900 nM, 1 μM, 100 μM, 500 μM, or 1 mM) to that particular protein or its domain. D This may be the case. Various assay formats can be used to determine the affinity of a ligand to a specific protein. For example, solid-phase ELISA assays are routinely used to identify ligands that specifically bind to target proteins. For a description of assay formats and conditions that may be used to determine the binding of a specific protein, see, for example, Harlow & Lane, Antibodies, A Laboratory Manual, Cold Spring Harbor Press, New York (1988) and Harlow & Lane, Using Antibodies, A Laboratory Manual, Cold Spring Harbor Press, New York (1999).

[0308] As used herein, the terms “subject” and “patient” are interchangeable and refer to an organism receiving treatment for a specific disease or condition described herein. Examples of subjects and patients include mammals such as humans receiving treatment for a disease or condition, such as before, during, or after embryo transfer therapy for a sex hormone-dependent disease, in order to reduce the likelihood of implantation failure.

[0309] As used herein, the term “substantially pure” means, for example, a compound that is well known in the art and has a purity of at least 85% when evaluated using nuclear magnetic resonance (NMR) and / or high-performance liquid chromatography (HPLC) techniques described herein.

[0310] When used in this specification, the term "t 最大 "The time elapsed since administration of the compound to the target subject at which the compound exhibits its maximum concentration in the target subject's blood (e.g., serum or plasma) is the term used.

[0311] Compounds, salt forms, crystalline polymorphs, therapeutic agents, or other compositions described herein may be referred to as having graphical data "substantially shown" in the figures. Such data may include, but are not limited to, powder X-ray diffractograms, NMR spectra, differential scanning calorimetry curves, and thermogravimetric analysis curves. As is known in the art, such graphical data may provide additional technical information for further defining compounds, salt forms, crystalline polymorphs, therapeutic agents, or other compositions. As will be understood by those skilled in the art, the graphical representation of such data may be affected by slight variations in peak relative intensity and peak position due to factors such as variations in instrument response and variations in sample concentration and purity. Nevertheless, it will be easy for those skilled in the art to compare the graphical data in the figures herein with graphical data generated for compounds, salt forms, crystalline polymorphs, therapeutic agents, or other compositions to determine whether the two sets of graphical data characterize the same substance or two different substances. For example, the crystalline forms of (3Z,5S)-5-(hydroxymethyl)-1-[(2'-methyl-1,1'-biphenyl-4-yl)carbonyl]pyrrolidine-3-one O-methyloxime as referred herein as those characterized by graphic data "substantially shown" in the figures will therefore be understood to include any crystalline forms of (3Z,5S)-5-(hydroxymethyl)-1-[(2'-methyl-1,1'-biphenyl-4-yl)carbonyl]pyrrolidine-3-one O-methyloxime as characterized by graphic data, having one or more smaller variations, e.g., any one or more variations known to those skilled in the art as described above.

[0312] Where used herein, the terms “to treat” or “to treat” in the context of subjects undergoing embryo transfer therapy mean, for example, treatment with the administration of an oxytocin antagonist for the purpose of increasing endometrial receptivity, thereby reducing the likelihood of embryo implantation failure and promoting pregnancy in the subject. Subjects requiring treatment include female mammalian subjects, such as human female subjects, who are undergoing embryo transfer therapy, such as subjects undergoing oocyte or egg retrieval followed by in vitro fertilization or intracytoplasmic sperm injection, and subsequent embryo transfer. Subjects requiring treatment also include female mammalian subjects, such as human female subjects, who are undergoing embryo transfer therapy using embryos produced in vitro by in vitro fertilization or intracytoplasmic sperm injection of one or more eggs derived from a donor (e.g., isolated directly from the donor by transvaginal oocyte retrieval or by maturation of one or more oocytes obtained directly from the donor). Subjects may undergo fresh embryo transfer or frozen embryo transfer, and may transfer, for example, one, two, three, or more embryos according to the methods described herein. The subjects include those who have previously undergone successful or unsuccessful embryo transfer, and who have previously undergone one or more cycles (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more cycles) of unsuccessful embryo transfer therapy. If a subject exhibits endometrial receptivity after administration of the therapeutic agent, the subject may be considered to have been treated, for example, by administration of an oxytocin antagonist as described herein.Endometrial receptivity occurs approximately 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, and 21 days after the transfer of one or more embryos to a target and / or after the retrieval of one or more oocytes or eggs from the target. A variety of clinical symptoms may be observed, including a reduction in prostaglandin F2α (PGF2α) signaling after administration of an oxytocin antagonist, successful implantation of the embryo into the subject's endometrium, and the subject's ability to achieve and maintain pregnancy after lung transplantation, during weeks 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, or beyond. Pregnancy may be assessed using methods described herein or known in the art, such as by detecting and / or quantifying human chorionic gonadotropin (hCG) in blood samples isolated from the subject, and / or by detecting intrauterine embryonic heartbeats.

[0313] As used herein, the term “unit dosage form” refers to a single composition containing a therapeutic agent, such as an oxytocin antagonist, as described herein, formulated in a manner appropriate for administration to a subject, such as a subject undergoing embryo transfer therapy as described herein. Unit dosage forms include solid and liquid formulations such as tablets (e.g., dispersible tablets), capsules, gel caps, powders, liquid solutions, and liquid suspensions. A subject may receive a single dose of the therapeutic agent by administering one or more unit dosage forms. For example, a single dose of 100 mg of the therapeutic agent may be administered using two 50 mg unit dosage forms of the therapeutic agent.

[0314] As used herein, the term “acyl” refers to the chemical moiety-C(O)R in which R is a C1-C6 alkyl, aryl, heteroaryl, C1-C6 alkylaryl, or C1-C6 alkylheteroaryl.

[0315] As used herein, the term “acylamino” refers to the chemical moiety -NRC(O)R' in which R and R' are independently hydrogen, C1-C6-alkyl, aryl, heteroaryl, C1-C6-alkylaryl, or C1-C6-alkylheteroaryl.

[0316] As used herein, the term “acyloxy” refers to the chemical part -OC(O)R where R is a C1-C6 alkyl, aryl, heteroaryl, C1-C6 alkylaryl, or C1-C6 alkylheteroaryl.

[0317] As used herein, the term “alkoxy” refers to the chemical part-OR where R is a C1-C6 alkyl, aryl, heteroaryl, C1-C6 alkylaryl, or C1-C6 alkylheteroaryl group. Exemplary alkoxy groups include methoxy, ethoxy, and phenoxy.

[0318] As used herein, the term “alkoxycarbonyl” refers to the chemical moiety-C(O)OR in which R is hydrogen, C1-C6 alkyl, aryl, heteroaryl, C1-C6 alkylaryl, or C1-C6 alkylheteroaryl.

[0319] As used herein, the term “amino” means that each of R and R' is independently a hydrogen atom, a C1-C6 alkyl atom, an aryl atom, a heteroaryl atom, a C1-C6 alkylaryl atom, a C1-C6 alkylheteroaryl atom, a cycloalkyl atom, or a heterocycloalkyl atom, or that R and R' together with the nitrogen atom to which they are bonded can optionally form a 3- to 8-membered heterocycloalkyl ring - NRR'.

[0320] As used herein, the term "aminocarbonyl" refers to the chemical moiety -C(O)NRR' in which R and R' are independently hydrogen, C1-C6 alkyl, aryl, heteroaryl, C1-C6 alkylaryl, or C1-C6 alkylheteroaryl.

[0321] As used herein, the term "aryl" refers to an unsaturated aromatic carbocyclic group of 6 to 14 carbon atoms having a monocycle (e.g., optionally substituted phenyl) or a plurality of fused rings (e.g., optionally substituted naphthyl). Exemplary aryl groups include phenyl, naphthyl, and phenantrenyl. As used herein, the term "aryl" includes substituted aryl substituents such as aryl moieties containing C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, C1-C6 alkylaryl, C1-C6 alkylheteroaryl, C1-C6 alkylcycloalkyl, C1-C6 alkylheterocycloalkyl, amino, ammonium, acyl, acyloxy, acylamino, aminocarbonyl, alkoxycarbonyl, ureido, carbamate, aryl, heteroaryl, sulfinyl, sulfonyl, alkoxy, sulfanyl, halogen, carboxy, trihalomethyl, cyano, hydroxy, mercapto, or nitro substituents. Examples of exemplary substituted aryl groups include biphenyls and substituted biphenyl substituents.

[0322] As used herein, the term "C1-C6 alkyl" refers to any branched alkyl moiety having 1 to 6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, tert-pentyl, and hexyl.

[0323] As used herein, the term "C2-C6 alkenyl" refers to any branched alkenyl moiety having 2 to 6 carbon atoms, such as vinyl, allyl, 1-propenyl, isopropenyl, 1-butenyl, 2-butenyl, and 2-methylallyl.

[0324] As used herein, the term "C2-C6 alkynyl" refers to any branched alkynyl moiety having 2 to 6 carbon atoms, such as ethynyl and 2-propynyl.

[0325] As used herein, the term "carboxyl" means the chemical part -C(O)OH, as well as its ionized form, -C(O)O - , and the salt thereof.

[0326] As used herein, the term "cycloalkyl" refers to monocyclic cycloalkyl groups having, for example, 3 to 8 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.

[0327] As used herein, the term "halogen" refers to a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom.

[0328] As used herein, the term “heteroaryl” refers to a monocyclic heteroaromatic or a bicyclic or tricyclic fused heteroaromatic group. Exemplary heteroaryl groups include optionally substituted pyridyl, pyrrolyl, furyl, thienyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, 1,3,4-triazinyl, 1,2,3-triazinyl, benzofuryl, [2,3-dihydro]benzofuryl, isobenzofuryl, benzothienyl, benzotriazolyl, isobenzothienyl Examples include ru, indolyl, isoindolyl, 3H-indolyl, benzimidazolyl, imidazo[1,2-a]pyridyl, benzothiazolyl, benzoxazolyl, quinolidinyl, quinazolinyl, phthalazinyl, quinoxalinyl, cinnolinyl, naphthilidinyl, pyrido[3,4-b]pyridyl, pyrido[3,2-b]pyridyl, pyrido[4,3-b]pyridyl, quinolyl, isoquinolyl, tetrazolyl, 5,6,7,8-tetrahydroquinolyl, 5,6,7,8-tetrahydroisoquinolyl, purinyl, pteridinyl, carbazolyl, xanthenyl, and benzoquinolyl.

[0329] As used herein, the term "heterocycloalkyl" refers to a 3- to 8-membered heterocycloalkyl group having one or more heteroatoms, such as a nitrogen atom, an oxygen atom, or a sulfur atom, and optionally one or more oxo groups. Examples of heterocycloalkyl substituents include pyrrolidinyl, piperidinyl, oxopiperidinyl, morpholinyl, piperazinyl, 1-methylpiperazinyl, oxopiperazinyl, thiomorpholinyl, azepanyl, diazepanyl, oxazepanyl, thiazepanyl, dioxothiazepanyl, azokanyl, tetrahydrofuranil, and tetrahydropyranil.

[0330] As used herein, the term "sulfanyl" refers to the chemical moiety-SR in which R is a C1-C6 alkyl, aryl, heteroaryl, C1-C6 alkylaryl, or C1-C6 alkylheteroaryl group. Examples of sulfanyl groups include methylsulfanyl and ethylsulfanyl.

[0331] As used herein, the term "sulfinyl" refers to the chemical moiety -S(O)-R in which R is a C1-C6 alkyl, aryl, heteroaryl, C1-C6 alkylaryl, or C1-C6 alkylheteroaryl, which is substituted with one or more halogens such as hydrogen, a C1-C6 alkyl, or a -SO-CF3 substituent.

[0332] As used herein, the term "sulfonyl" refers to the chemical moiety -SO2-R in which R is substituted with one or more halogens such as hydrogen, aryl, heteroaryl, C1-C6 alkyl, C1-C6 alkylaryl, or C1-C6 alkyl heteroaryl.

[0333] As used herein, the term “sulfonylamino” refers to the chemical moiety -NRSO2-R' in which R and R' are independently hydrogen, C1-C6 alkyl, aryl, heteroaryl, C1-C6 alkylaryl, or C1-C6 alkylheteroaryl.

[0334] As used herein, the term "sulfonyloxy" refers to the chemical moiety -OSO2-R in which R is a C1-C6 alkyl, aryl, heteroaryl, C1-C6 alkylaryl, or C1-C6 alkyl heteroaryl, substituted with one or more halogens such as hydrogen, a C1-C6 alkyl, or a -OSO2-CF3 substituent.

[0335] As used herein, the term “ureid” means the chemical part -NRC(O)NR'R'', where each of R' and R'' independently is a hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkylaryl, C1-C6 alkylheteroaryl, C2-C6 alkenylaryl, C2-C6 alkenylheteroaryl, C2-C6 alkynylaryl, C2-C6 alkynylheteroaryl, C1-C6 alkylcycloalkyl, or C1-C6 alkylheterocycloalkyl, or R' and R'' together with the nitrogen atom to which they are bonded can optionally form a 3- to 8-membered heterocycloalkyl ring.

[0336] Unless specifically limited by the definition of each substituent, the aforementioned chemical parts such as the "alkyl," "alkenyl," "alkynyl," "aryl," and "heteroaryl" groups may be optionally substituted with 1 to 5 substituents selected from the group consisting of, for example, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, C1-C6 alkylaryl, C1-C6 alkylheteroaryl, C1-C6 alkylcycloalkyl, C1-C6-alkylheterocycloalkyl, amino, ammonium, acyl, acyloxy, acylamino, aminocarbonyl, alkoxycarbonyl, ureido, carbamate, aryl, heteroaryl, sulfinyl, sulfonyl, alkoxy, sulfanyl, halogen, carboxy, trihalomethyl, cyano, hydroxy, mercapto, nitro, and the like. The substitutions include substituents formed by ring closure, such as when adjacent substituents undergo ring closure, including ring closure of adjacent functional group substituents, to form lactams, lactones, cyclic anhydrides, acetals, hemiacetals, thioacetals, aminals, and heminaminals, and for example, provide protecting groups. [Brief explanation of the drawing]

[0337] [Figure 1] This graph shows the calculated plasma concentrations of compound (II) after administration to human subjects at doses of 100 mg (third curve from the top), 300 mg (second curve from the top), and 900 mg (first curve from the top), three days after oocytes were collected from subjects in preparation for embryo transfer therapy. These pharmacokinetic profiles are in contrast to the calculated plasma concentrations of atosiban in human subjects after administration of atosiban three days after oocyte collection in preparation for embryo transfer therapy (first curve from the bottom). The indicated doses of compound (II) were administered orally to human subjects. Atosiban was administered intravenously to human subjects as a 6.75 mg bolus infusion, followed by infusions of 18 mg / hour over 0-1 hours, and then 6 mg / hour over 1-3 hours. [Figure 2]Figure 1 is an enlarged view of the calculated pharmacokinetic profile. For clarity, the x-axis is limited to values ​​2.9 to 3.5 days after oocyte retrieval. [Figure 3] This chart shows the number of human subjects who gave birth to a live baby (black circles) and those who did not (white circles) at the end of pregnancy after treatment with placebo (left column) or 100 mg, 300 mg, or 900 mg of compound (II) (first, second, and third columns on the right, respectively) approximately 4 hours before embryo transfer, as described in Example 1 below. The number of subjects who gave birth to a live baby and those who did not are plotted against the pre-treatment serum progesterone concentration of each subject on the day of embryo transfer, and shown in nM units on the y axis. The horizontal lines passing through each column represent the first (25th percentile), second (median), and second (75th percentile) quartiles of the serum progesterone concentration before administration on the day of embryo transfer among all subjects. [Figure 4] This graph shows the percentage of human subjects who tested positive for pregnancy 10 weeks after oocyte retrieval (black bars) and subjects who gave birth to a live offspring at least 24 weeks (gray bars) in the study described in Example 1. The proportion of subjects exhibiting these characteristics is plotted as a function of the quartiles of pre-treatment serum progesterone concentration, shown on the x-axis, as measured on the day of embryo transfer. [Figure 5] This graph shows the percentage of human subjects who tested positive for pregnancy 10 weeks after oocyte retrieval (black bars) and subjects who gave birth to a live baby at least 24 weeks (gray bars) in the study described in Example 1. The percentages plotted in Figure 5 exclude data from subjects who exhibited pre-treatment serum progesterone levels on the day of embryo transfer within the top quartile of this criterion. [Modes for carrying out the invention]

[0338] The present invention features compositions and methods for use in combination with assisted reproductive technologies. For example, the compositions and methods described herein may be used to treat subjects undergoing embryo transfer therapy by administering an oxytocin antagonist to the subject to enhance endometrial receptivity and reduce the likelihood of embryo implantation failure. The compositions and methods described herein can similarly reduce the likelihood of miscarriage in subjects undergoing embryo transfer therapy. Using the methods described herein, an oxytocin antagonist may be administered to a subject before, during, and / or after the transfer of one or more embryos into the subject's uterus to promote successful embryo transfer and maintained pregnancy. The oxytocin antagonist may be administered in single doses or multiple doses, such as doses of varying intensities or repeated doses of the same intensity. For example, an oxytocin antagonist may be administered in a single high dose or multiple low-intensity doses to achieve the maximum plasma concentration of the oxytocin antagonist. An oxytocin antagonist useful in combination with the compositions and methods described herein is a pyrrolidine-3-one oxime compound represented by formula (I). [ka] (I) or including its geometric isomers, enantiomers, diastereomers, racemic mixtures, or salts, In the formula, n is an integer between 1 and 3. R 1 It is selected from the group consisting of hydrogen and C1-C6 alkyl groups, R 2Hydrogen, C1-C6 alkyl, C1-C6 alkylaryl, heteroaryl, C1-C6 alkylheteroaryl, C2-C6 alkenyl, C2-C6 alkenylaryl, C2-C6 alkenylheteroaryl, C2-C6 alkynyl, C2-C6 alkynylaryl, C2-C6 alkynylheteroaryl, C3-C6 cycloalkyl, heterocycloalkyl, C1-C6 alkylcycloalkyl, C1-C6 alkylheterocycloalkyl, C1-C6 alkylcarboxy, acyl, C1-C6 alkylacyl, C1-C6 alkyl Selected from the group consisting of siloxy, C1-C6 alkylalkoxy, alkoxycarbonyl, C1-C6 alkylalkoxycarbonyl, aminocarbonyl, C1-C6 alkylaminocarbonyl, C1-C6 alkylacylamino, C1-C6 alkylureido, amino, C1-C6 alkylamino, sulfonyloxy, C1-C6 alkylsulfonyloxy, sulfonyl, C1-C6 alkylsulfonyl, sulfinyl, C1-C6 alkylsulfinyl, C1-C6 alkylsulfanyl, and C1-C6 alkylsulfonylamino, R 3 It is selected from the group consisting of aryls and heteroaryls, X is oxygen and NR 4 Selected from the group consisting of, R 4 R is selected from the group consisting of hydrogen, C1-C6 alkyl, C1-C6 alkylaryl, C1-C6 alkylheteroaryl, aryl, and heteroaryl. 2 and R 4 These, together with the nitrogen to which they are bonded, can form a 5- to 8-membered saturated or unsaturated heterocycloalkyl ring. Compounds of this genus are described, for example, in U.S. Patent No. 7,115,754, the disclosure of which is incorporated herein by reference in its entirety. For example, oxytocin antagonists that can be used in conjunction with the compositions and methods described herein include (3Z,5S)-5-(hydroxymethyl)-1-[(2'-methyl-1,1'-biphenyl-4-yl)carbonyl]pyrrolidine-3-one O-methyloxime, represented by compound (II) below. [ka] (II)

[0339] Using the methods described herein, an oxytocin antagonist such as compound (I) or compound (II) can be administered to a mammalian subject (e.g., a female human subject) to promote enhanced endometrial receptivity, reduce the likelihood of embryo implantation failure, and / or prevent miscarriage in the subject after the transfer of one or more embryos into the subject's uterus. According to the methods described herein, a compound of formula (I), such as compound (II), may be administered to the subject before, concurrently with, and / or after the transfer of one or more embryos into the subject's uterus to achieve, for example, a serum concentration of the compound of about 1 μM to about 20 μM.

[0340] Further oxytocin antagonists that may be used in conjunction with the compositions and methods described herein include, among others, eperiban, letosiban, barsiban, and atosiban, as well as their derivatives and variants. For example, oxytocin antagonists that may be used in conjunction with the compositions and methods described herein include eperiban, as well as its salts, derivatives, variants, crystalline forms, and formulations thereof, such as the salts, derivatives, variants, crystalline forms, or formulations described in U.S. Patents No. 7,514,437, No. 8,367,673, No. 8,541,579, No. 7,550,462, No. 7,919,492, No. 8,202,864, No. 8,742,099, No. 9,408,851, No. 8,716,286, or No. 8,815,856, the disclosures of each of which are incorporated herein by reference in whole. Further oxytocin antagonists that may be used in conjunction with the compositions and methods described herein include letosiban, as well as salts, derivatives, variants, crystalline forms, and formulations thereof, such as the salts, derivatives, variants, crystalline forms, or formulations described in U.S. Patents No. 7,514,437, 8,367,673, 8,541,579, 8,071,594, 8,357,685, 8,937,179, or 9,452,169, the disclosures of which are incorporated herein by reference in their entirety. Oxytocin antagonists useful in conjunction with the compositions and methods described herein include barsiban, as well as salts, derivatives, variants, crystalline forms, and formulations thereof, for example, salts, derivatives, variants, crystalline forms, or formulations described in U.S. Patents 6,143,722, 7,091,314, 7,816,489, or 9,579,305, or International Publication 2017 / 060339, the disclosures of which are incorporated herein by reference in their entirety.Oxytocin antagonists useful in conjunction with the compositions and methods described herein include, but are not limited to, atosiban, as well as salts, derivatives, variants, crystalline forms, and formulations thereof, e.g., salts, derivatives, variants, crystalline forms, or formulations described herein, e.g., U.S. Patent No. 4,504,469 or No. 4,402,942, the disclosures of which, in whole, are incorporated herein by reference. Using the methods herein, one of the aforementioned oxytocin antagonists can be administered to a subject, such as a mammalian subject (e.g., a female human subject), to reduce the likelihood of embryo implantation failure. According to the methods herein, one of the aforementioned oxytocin antagonists can be administered to a subject before, concurrently with, and / or after the transfer of one or more embryos into the subject's uterus, in order to promote enhanced endometrial receptivity, reduce the likelihood of embryo implantation failure, and / or prevent miscarriage in the subject after the transfer of one or more embryos into the subject's uterus.

[0341] The subjects may have previously undergone one or more successful or unsuccessful embryo transfer procedures. Alternatively, the subjects may not have undergone any previous embryo transfer cycles. According to the methods herein, one or more embryos ultimately implanted in the subject can be obtained, for example, by in vitro fertilization (IFV) or intracytoplasmic sperm injection (ICSI) of oocytes isolated from or derived from the subject or a donor. If the oocytes are isolated from or derived from the subject, they may be isolated directly from the subject or produced in vitro by inducing the maturation of one or more oocytes isolated from the subject. The oocytes or oocytes may be isolated from the subject, for example, about 1 to 7 days before embryo transfer. In some embodiments, the oocytes or oocytes are isolated from the subject about 2 to 5 days before embryo transfer (e.g., 2, 3, 4, or 5 days before embryo transfer). Following fertilization of an egg by contact with one or more spermatids, the zygote subsequently formed may be matured in vitro to produce an embryo such as a morula or blastula (e.g., a mammalian blastocyst), and then implanted in the uterus of the subject for implantation into the endometrium. Embryo transfer that may be carried out using the methods herein includes fresh embryo transfer in which an egg or oocyte to be used for embryogenesis is recovered from the subject, and the subsequent embryo is transferred to the subject during the same menstrual cycle. Alternatively, the embryo may be produced prior to transfer to the subject and cryopreserved for long-term storage.

[0342] The present invention further features a dosing regimen that may be applied to subjects undergoing lung transplant therapy with an oxytocin antagonist such as a compound of formula (I) or formula (II), or another oxytocin antagonist described herein, such as epersiban, letosiban, barsiban, or atosiban, or their salts, derivatives, variants, crystalline forms, or formulations. Using the methods described herein, an oxytocin antagonist such as one of the aforementioned drugs may be administered to a subject before, during, or after embryo transfer to enhance endometrial receptivity, promote successful embryo implantation, and / or prevent the occurrence of miscarriage in the subject.

[0343] For example, a compound of formula (I) or formula (II) may be administered to a subject several hours before embryo transfer, such as about 1 to 24 hours before the transfer of one or more embryos into the subject's uterus, for example, in a single dose of about 100 mg, 300 mg, or 900 mg, or in multiple doses of lower intensity, such as repeated doses of about 100 mg each. In some embodiments, the compound is administered to the subject about 1 to 12 hours before embryo transfer, such as about 4 hours before embryo transfer. Using the method herein, an oxytocin antagonist such as a compound of formula (I) or formula (II) may be administered to a subject simultaneously with the transfer of one or more embryos into the subject's uterus, such as within 60 minutes after embryo transfer, for example, in a single dose of about 100 mg, 300 mg, or 900 mg, or in multiple doses of lower intensity, such as repeated doses of about 100 mg each. Additionally or alternatively, oxytocin antagonists may be administered to subjects after embryo transfer, such as approximately 1 to 24 hours after embryo transfer. For example, oxytocin antagonists may be administered to subjects in single doses of approximately 100 mg, 300 mg, or 900 mg, or in lower-intensity multiple doses, for example, in repeated doses of approximately 100 mg each, after embryo transfer. In dosing regimens in which oxytocin antagonists are administered in multiple doses, the compound (e.g., compound (I) or compound (II)) may be administered in multiple doses per day, such as once to seven times per day. Dosage may be terminated, for example, on the day of embryo transfer to the subject, or may be continued after embryo transfer.

[0344] The following section provides a description of various oxytocin antagonists useful in conjunction with the compositions and methods provided by the present invention to promote enhanced endometrial receptivity, reduce the likelihood of embryo implantation failure, and / or prevent miscarriage in subjects undergoing assisted reproductive treatment, as well as a description of administration regimens that may guide the administration of oxytocin antagonists to subjects.

[0345] (3Z,5S)-5-(hydroxymethyl)-1-[(2'-methyl-1,1'-biphenyl-4-yl)carbonyl]pyrrolidin-3-one O-methyloxime (compound II) Compounds of formula (I), such as (3Z,5S)-5-(hydroxymethyl)-1-[(2'-methyl-1,1'-biphenyl-4-yl)carbonyl]pyrrolidine-3-one O-methyloxime, represented by formula (II) above, are non-peptide oxytocin antagonists that can be used to enhance endometrial receptivity, promote successful embryo implantation, and reduce the likelihood of miscarriage in subjects undergoing or who have undergone embryo transfer therapy. In particular, compound (II) inhibits the human oxytocin receptor at 52 nM K i This suppresses Ca in cultured HEK293EBNA cells. 2+ Mobilization of 81nM IC 50 It is an orally active oxytocin antagonist that can inhibit the vasopressin VIa receptor. Furthermore, compound (II) inhibits the vasopressin VIa receptor with 120 nM K i Because it inhibits oxytocin receptors more selectively than vasopressin VIA receptors, compound (II) exhibits oral bioavailability of 42-100%, and therefore has a serum half-life of 11-12 hours and a thrombolytic activity of approximately 1-4 hours. 最大 Furthermore, it exhibits various desirable pharmacokinetic properties. In addition, compound (II) is safely tolerable in human subjects, for example, at doses up to 1500 mg. The aforementioned biochemical properties of compound (II), as well as methods for its synthesis and purification, are described in detail, for example, in U.S. Patent No. 9,670,155, the disclosure of which is incorporated herein by reference in its entirety.

[0346] Synthesis of compound (II) An exemplary procedure for the synthesis of compound (II) is shown in Scheme 1 below. Scheme 1. Exemplary synthesis of compound (II) [ka]

[0347] Purity of compound (II) In some embodiments, the compound represented by formula (II) (i.e., (3Z,5S)-5-(hydroxymethyl)-1-[(2'-methyl-1,1'-biphenyl-4-yl)carbonyl]pyrrolidine-3-one O-methyloxime) is substantially pure. For example, in some embodiments, the compound represented by formula (II) has a purity of at least 85%, such as 85% to 99.9% or higher (e.g., 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.1%, 99.2%, 99.3%, 99.4%, 99.5%, 99.6%, 99.7%, 99.8%, 99.9%, or higher). The purity of the compound represented by formula (II) can be evaluated using chromatographic methods such as NMR techniques and / or HPLC procedures, which are well known in the art and described herein, such as those techniques described in U.S. Patent No. 9,670,155, the disclosure of which is incorporated herein by reference in whole.

[0348] In some embodiments, the compound represented by formula (II) is substantially pure with respect to the diastereomer of the compound and other by-products that may be formed during the synthesis of the compound. For example, in some embodiments, the compound represented by formula (II) has a purity of at least 85%, such as 85% to 99.9% or higher (e.g., 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.1%, 99.2%, 99.3%, 99.4%, 99.5%, 99.6%, 99.7%, 99.8%, 99.9%, or higher), with respect to the diastereomer of the compound and other by-products that may be formed during the synthesis of the compound, such as the by-product formed during the synthesis of the compound as described in U.S. Patent No. 9,670,155. The purity of the compound represented by formula (II) can be evaluated using chromatographic methods such as NMR techniques and / or HPLC procedures, which are well known in the art and described herein, such as those techniques described in U.S. Patent No. 9,670,155.

[0349] In some embodiments, the compound represented by formula (II) is substantially pure with respect to its (3E) diastereomer, (3E,5S)-5-(hydroxymethyl)-1-[(2'-methyl-1,1'-biphenyl-4-yl)carbonyl]pyrrolidine-3-one O-methyloxime. For example, in some embodiments, the compound represented by formula (II) has a purity of at least 85%, such as 85% to 99.9% or higher with respect to (3E,5S)-5-(hydroxymethyl)-1-[(2'-methyl-1,1'-biphenyl-4-yl)carbonyl]pyrrolidine-3-one O-methyloxime (e.g., 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.1%, 99.2%, 99.3%, 99.4%, 99.5%, 99.6%, 99.7%, 99.8%, 99.9%, or higher). For example, compound (II) may be administered in the form of a composition containing less than 15% of the (3E) diastereomer (e.g., tablets such as dispersible tablets, capsules, gel caps, powders, liquid solutions, or liquid suspensions). For example, compound (II) may be administered in the form of a composition containing less than 14%, less than 13%, less than 12%, less than 11%, less than 10%, less than 9%, less than 8%, less than 7%, less than 6%, less than 5%, less than 4%, less than 3%, less than 2%, less than 1%, less than 0.1%, less than 0.01%, less than 0.001%, or less of the (3E) diastereomer (e.g., tablets such as dispersible tablets, capsules, gel caps, powders, liquid solutions, or liquid suspensions). The purity of the compound represented by formula (II) may be evaluated using chromatographic methods such as NMR techniques and / or HPLC procedures, which are well known in the art and described herein, such as those techniques described in U.S. Patent No. 9,670,155.

[0350] therapeutic activity This invention is partly based on the finding that compounds of formula (I), such as compound (II), can promote successful endometrial implantation of implanted embryos and prolong pregnancy in human female subjects not treated with the compound. Specifically, compound (II) has been found to reduce the risk of embryo implantation failure in clinical trials conducted in human subjects who have previously undergone ovarian hyperstimulation and oocyte retrieval. Compounds of formula (I), such as compound (II), have been found to increase the rate of successful embryo implantation, as assessed by various metrics. These indications have been found to include increased rates of positive pregnancy tests at 14 days, 6 weeks, and 10 weeks after embryo transfer and / or oocyte retrieval, as well as increased live birth rates at least 24 weeks of gestation.

[0351] Surprisingly, oxytocin antagonists such as the compounds of formulas (I) and (II), as well as other oxytocin antagonists described herein, are particularly effective in subjects that do not exhibit elevated serum progesterone (P4) concentrations. For example, as described in detail in Example 1 below, compound (II) was found to improve the successful embryo transfer rate (e.g., as assessed by the above-described metrics) in a dose-dependent manner. This dose-dependent response was found to be particularly strong in subjects exhibiting pretreatment serum P4 concentrations of less than 320 nM, such as approximately 200 nM to approximately 300 nM. The aforementioned P4 concentrations were measured on the day of transfer of one or more embryos to the subjects. These elevated P4 levels indicate elevated P4 concentrations on the day of oocyte or oocyte retrieval from subjects with P4 concentrations of 1.0 ng / ml to 2.0 ng / ml (e.g., 1.0 ng / ml, 1.1 ng / ml, 1.2 ng / ml, 1.3 ng / ml, 1.4 ng / ml, 1.5 ng / ml, 1.6 ng / ml, 1.7 ng / ml, 1.8 ng / ml, 1.9 ng / ml, or 2.0 ng / ml P4 concentration, and especially 1.5 ng / ml). Therefore, it has been found that the tendency of a subject to benefit from treatment with an oxytocin antagonist such as the compound of formula (I) or formula (II), or another oxytocin antagonist described herein such as epersiban, letosiban, barsiban, atosiban, or their salts, derivatives, variants, crystalline forms, or formulations, can be determined based on the subject's pre-treatment serum P4 levels.

[0352] Using the compositions and methods described herein, those skilled in the art can assess the likelihood of a subject benefiting from oxytocin antagonist treatment (e.g., experiencing enhanced (i.e., increased) endometrial receptivity in response to such treatment) before determining the patient's serum P4 concentration by determining the subject's serum P4 concentration before treatment with an oxytocin antagonist. If a subject exhibits a serum P4 concentration below a reference level, such as less than 320 nM on the day of embryo transfer (e.g., up to 24 hours before scheduled embryo transfer, such as immediately before scheduled embryo transfer), or less than 1.5 ng / ml on the day of oocyte or oocyte retrieval (e.g., 1 to 7 days before embryo transfer in patients undergoing an IVF-ET procedure, such as 3 to 5 days before embryo transfer in patients undergoing an IVF-ET procedure), the subject may be administered an oxytocin antagonist, for example, before, concurrently with, and / or after, the transfer of one or more embryos to the subject. If a subject exhibits a serum P4 concentration above the normal level, such as a serum P4 concentration of more than 320 nM on the day of embryo transfer (e.g., up to 24 hours before the scheduled embryo transfer, such as immediately before the scheduled embryo transfer), or a serum P4 concentration above 1.5 ng / ml on the day of oocyte or oocyte retrieval (e.g., 1 to 7 days before embryo transfer for patients undergoing an IVF-ET procedure, such as 3 to 5 days before embryo transfer for patients undergoing an IVF-ET procedure), a physician in the art may determine that the subject will not be administered an oxytocin antagonist and / or that the subject's oocyte or oocyte retrieval or embryo transfer schedule will be changed until the subject's serum P4 concentration falls below the normal P4 level.

[0353] Furthermore, without being limited by mechanism, oxytocin antagonists such as the compounds of formulas (I) and (II), as well as other oxytocin antagonists described herein, may promote transient overexpression of prostaglandin F2α (PGF2α) and prostaglandin E2 (PGE2), and subsequently suppress the propagation of PGF2α signaling. Attenuation of PGF2α signaling may occur, for example, by desensitization of the PGF2α receptor in response to an initial flare of PGF2α secretion. This pattern of (i) transiently increased expression of PGF2α, followed by (ii) reduction of PGF2α signaling induced by oxytocin antagonists such as the compounds of formulas (I) and (II), as well as other oxytocin antagonists described herein, can then enhance endometrial receptivity to one or more exogenous embryos, thereby promoting endometrial transfer and reducing the likelihood of embryo transfer failure. In particular, P4 is a negative regulator of PGF2α expression, and oxytocin antagonists such as the compounds of formulas (I) and (II), especially other oxytocin antagonists described herein, may have a particularly strong therapeutic effect on subjects who do not exhibit elevated pre-treatment serum P4 concentrations. Such subjects include those who do not exhibit a pre-treatment serum P4 concentration of 320 nM or higher on the day of embryo transfer and / or a pre-treatment serum P4 concentration of 1.5 ng / ml or higher on the day of oocyte or oocyte retrieval, as described in Examples 1 and 2 below.

[0354] The aforementioned findings form an important basis for the oxytocin antagonist administration regimens described herein. To optimally enhance endometrial receptivity to one or more implanted embryos, compounds of formulas (I) and (II), as well as further oxytocin antagonists described herein and known in the art, such as epersiban, letosiban, barsiban, and atosiban, or their salts, derivatives, variants, crystalline forms, or formulations, may be administered to subjects to saturate oxytocin receptors and achieve complete (i.e., 100%) inhibition of the receptors at embryo transfer. This can be achieved, for example, by administering to subjects undergoing embryo transfer therapy, such as compounds of formula (I) or (II), or another oxytocin antagonist described herein or known in the art, such as epersiban, letosiban, barsiban, and atosiban, or their salts, derivatives, variants, crystalline forms, or formulations, so that the maximum plasma concentration of the compound is reached at embryo transfer.

[0355] For example, the compound of formula (I) or (II) may be administered to a subject approximately 1 to 24 hours before embryo transfer, such as approximately 1 to 8 hours before embryo transfer, in order to achieve the maximum plasma concentration of the compound at the time of embryo transfer. In some embodiments, it has been found that oral administration of various doses of compound (II) results in a peak plasma concentration of the compound approximately 1 to 4 hours after administration of the compound; therefore, the compound is administered approximately 4 hours before embryo transfer. The compound of formula (I) or (II) may be administered before, during, and / or after embryo transfer to enhance endometrial receptivity and promote successful embryo implantation, as described below, for example.

[0356] The following sections further describe additional oxytocin antagonists that may be used in conjunction with the compositions and methods of the present invention, as well as administration schedules for administering oxytocin antagonists to subjects undergoing embryo transfer therapy, and methods for evaluating whether a subject is likely to benefit from oxytocin antagonist treatment based on their pre-treatment progesterone levels.

[0357] Oxytocin antagonist administration regimen Compounds of formula (I) or (II), or other oxytocin antagonists described herein, may be administered to subjects (e.g., human subjects) before, during, or after embryo transfer therapy to promote endometrial receptivity and successful embryo implantation, and to reduce the likelihood of miscarriage. In each case, compounds of formula (I) or (II), or other oxytocin antagonists described herein, may be administered to subjects before, during, and / or after embryo transfer to saturate oxytocin receptors and achieve receptor inhibition (e.g., 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% inhibition).

[0358] Administration to be started before embryo transfer therapy Compounds of formula (I) or (II), or other oxytocin antagonists described herein, such as epersiban, letosiban, barsiban, or atosiban, or their salts, derivatives, variants, crystalline forms, or formulations, may be administered to a subject before embryo transfer, such as about 1 hour to about 24 hours before the transfer of one or more embryos to the subject. In some embodiments, the compound is administered to the subject to achieve the maximum plasma concentration of the compound at the time of embryo transfer. For example, in some embodiments, the compound is administered to the subject about 1 hour to about 8 hours before embryo transfer, such as about 4 hours before embryo transfer.

[0359] Compounds of formula (I) or (II) may be administered to subjects undergoing embryo transfer therapy in single doses, such as a single dose of approximately 100 mg, 300 mg, or 900 mg of the compound, or in multiple doses. When multiple doses of the compound are administered, the compound may be administered in multiple repeated doses of the same strength (e.g., consecutive doses of approximately 100 mg, 300 mg, or 900 mg of the compound) or in multiple doses of varying strengths (e.g., one or more doses of approximately 100 mg of the compound, followed by one or more doses of approximately 300 mg of the compound and / or one or more doses of approximately 900 mg of the compound; one or more doses of approximately 300 mg of the compound, followed by one or more doses of approximately 100 mg of the compound and / or one or more doses of approximately 900 mg of the compound; or one or more doses of approximately 900 mg of the compound, followed by one or more doses of approximately 100 mg of the compound and / or one or more doses of approximately 300 mg of the compound). When multiple doses are administered, the compound may be administered in lower doses, such as approximately 100 mg or 300 mg. In some embodiments, higher multiple doses, such as approximately 900 mg of the compound, may be administered to the subject prior to embryo transfer therapy.

[0360] Compounds of formula (I) or (II) may be administered to a subject in a single or multiple dose before embryo transfer. For example, in preparation for embryo transfer, a subject may be administered 1 to 20 doses, for example, every 12 hours, 24 hours, 36 hours, 48 ​​hours, 60 hours, 72 hours, 84 hours, 96 hours, 108 hours, 120 hours, 132 hours, 144 hours, 156 hours, 168 hours, or longer, before embryo transfer. In some embodiments, the compound may be administered to a subject before embryo transfer in up to 7 doses every 24 hours (e.g., 1, 2, 3, 4, 5, 6, or 7 doses), such as up to 7 doses of compound (II) every 24 hours. Multiple doses may be initiated and administered at various points before embryo transfer, such as approximately 1 to 7 hours or more before embryo transfer. For example, in some cases, multiple doses are administered starting approximately 1 to 7 days before embryo transfer. Additionally or alternatively, compounds of formula (I) or formula (II) may be administered to subjects for up to 2, 3, 4 weeks, or longer in preparation for embryo transfer therapy. Administration of the compound to a subject may start, for example, on the day of oocyte or oocyte retrieval from the subject, which may occur approximately 1 to 7 days before embryo transfer, such as approximately 2 to 5 days before embryo transfer. Subjects may be administered low-dose, high-intensity doses (e.g., one or more doses of compounds of formula (I) or (II) at approximately 300 mg or 900 mg per dose). Additionally or alternatively, subjects may be administered higher-dose, low-intensity doses (e.g., two or more doses of compounds of formula (I) or (II) at approximately 100 mg).

[0361] If a subject is administered multiple doses of an oxytocin antagonist in preparation for embryo transfer, the multiple doses may be terminated, for example, on the day of embryo transfer to the subject. In some embodiments, the multiple doses terminate with a final dose of the compound administered concurrently with (e.g., within 60 minutes) the transfer of one or more embryos to the subject. Alternatively, multiple doses of compound (I) or (II) may continue after embryo transfer. For example, the compound may be administered to the subject in one or more additional doses after embryo transfer, for example, in multiple repeated doses or doses of varying intensities. The compound may be administered to the subject in one or more additional doses after the implantation of one or more embryos into the subject, for example, within about 1 hour to about 1 week, or longer (for example, within about 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 24 hours, 36 hours, 48 ​​hours, 60 hours, 72 hours, 84 hours, 96 hours, 108 hours, 120 hours, 132 hours, 144 hours, 156 hours, 168 hours, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, 21 days, 22 days, 23 days, 24 days, 25 days, 26 days, 27 days, 28 days, 29 days, 30 days or longer). If multiple doses of compound (I) or compound (II) are administered to a subject after embryo transfer, the subject may, for example, receive additional doses periodically. Compound (I) or compound (II) may be administered to a subject after embryo transfer therapy in 1 to 20 additional doses, for example, daily, weekly, monthly, or more frequently. For example, the compound may be administered to a subject after embryo transfer in up to 7 doses every 24 hours (e.g., 1, 2, 3, 4, 5, 6, or 7 doses), such as up to 7 doses of compound (II) at 100 mg every 24 hours.

[0362] Initiation of administration during embryo transfer therapy Compounds of formula (I) or (II), or other oxytocin antagonists described herein, such as epersiban, letosiban, barsiban, or atosiban, or their salts, derivatives, variants, crystalline forms, or formulations, may be administered to the subject during embryo transfer, such as within approximately 60 minutes or less of the time of embryo transfer to the subject's uterus. In such cases, the compound may be administered to the subject in a single dose, such as a single dose of approximately 100 mg, 300 mg, or 900 mg of compound (I) or (II), or in multiple doses. A single dose of the compound may be administered, for example, at the start of the embryo transfer procedure. For example, compound (I) or (II) may be administered to the subject when an embryo delivery device, such as a catheter containing one or more embryos to be transferred to the subject, enters the subject's vaginal canal. Additionally or alternatively, the compound may be administered to the subject at the same time that the embryo delivery device enters the subject's uterus beyond the cervix. The compound may be administered to the subject upon the elimination of one or more embryos to be transferred from the embryo delivery device and / or upon the removal of the embryo delivery device from the subject's uterus or vaginal canal. In some embodiments, multiple doses of the compound may be administered during the embryo transfer process. The compound of formula (I) or (II) may be administered continuously throughout the entire embryo transfer process, for example, by continuous intravenous administration.

[0363] If multiple doses of compound (I) or compound (II) are initiated and administered to a subject during the embryo transfer process, the multiple doses may consist of multiple repeated doses (e.g., consecutive doses of approximately 100 mg, 300 mg, or 900 mg of the compound) or multiple doses of varying intensities (e.g., one or more doses of approximately 100 mg of the compound, followed by one or more doses of approximately 300 mg of the compound and / or one or more doses of approximately 900 mg of the compound; one or more doses of approximately 300 mg of the compound, followed by one or more doses of approximately 100 mg of the compound and / or one or more doses of approximately 900 mg of the compound; or one or more doses of approximately 900 mg of the compound, followed by one or more doses of approximately 100 mg of the compound and / or one or more doses of approximately 300 mg of the compound). When multiple doses are administered, the compound may be administered in lower doses, such as multiple doses of approximately 100 mg or 300 mg. In some embodiments, higher doses, such as approximately 900 mg of the compound, may be administered to the target individual.

[0364] Administration of oxytocin antagonists initiated during embryo transfer (e.g., within 60 minutes of embryo transfer) may be continued after embryo transfer. For example, the compound may be administered to the subject in one or more additional doses after embryo transfer, for example, in multiple repeated doses or doses of varying strengths. The compound may be administered to the subject in one or more additional doses after the implantation of one or more embryos into the subject, for example, within about 1 hour to about 1 week, or longer (for example, within about 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 24 hours, 36 hours, 48 ​​hours, 60 hours, 72 hours, 84 hours, 96 hours, 108 hours, 120 hours, 132 hours, 144 hours, 156 hours, 168 hours, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, 21 days, 22 days, 23 days, 24 days, 25 days, 26 days, 27 days, 28 days, 29 days, 30 days or longer). If multiple doses of compound (I) or compound (II) are administered to a subject after embryo transfer, the subject may, for example, receive additional doses periodically. Compound (I) or compound (II) may be administered to a subject after embryo transfer therapy in 1 to 20 additional doses, for example, daily, weekly, monthly, or more frequently. For example, the compound may be administered to a subject after embryo transfer in up to 7 doses every 24 hours (e.g., 1, 2, 3, 4, 5, 6, or 7 doses), such as up to 7 doses of compound (II) at 100 mg every 24 hours.

[0365] Initiation of administration after embryo transfer therapy Administration of an oxytocin antagonist (for example, a compound of formula (I) or (II), or another oxytocin antagonist described herein, such as epersiban, letosiban, barsiban, or atosiban, or their salts, derivatives, variants, crystalline forms, or formulations) may be initiated after the completion of the embryo transfer process. For example, the compound of formula (I) or (II) may be administered to a subject after embryo transfer in single or multiple doses, such as in multiple repeated doses (e.g., consecutive doses of approximately 100 mg, 300 mg, or 900 mg of the compound) or in multiple doses of varying intensities (e.g., one or more doses of approximately 100 mg of the compound, followed by one or more doses of approximately 300 mg of the compound and / or one or more doses of approximately 900 mg of the compound; one or more doses of approximately 300 mg of the compound, followed by one or more doses of approximately 100 mg of the compound and / or one or more doses of approximately 900 mg of the compound; or one or more doses of approximately 900 mg of the compound, followed by one or more doses of approximately 100 mg of the compound and / or one or more doses of approximately 300 mg of the compound). When multiple doses are administered, the compound may be administered in lower doses, such as multiple doses of approximately 100 mg or 300 mg. In some embodiments, higher doses, such as approximately 900 mg of the compound, may be administered to subjects after embryo transfer therapy.

[0366] The compound may be administered to the subject in one or more doses after the implantation of one or more embryos into the subject, for example, within about 1 hour to about 1 week, or longer (for example, within about 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 24 hours, 36 hours, 48 ​​hours, 60 hours, 72 hours, 84 hours, 96 hours, 108 hours, 120 hours, 132 hours, 144 hours, 156 hours, 168 hours, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, 21 days, 22 days, 23 days, 24 days, 25 days, 26 days, 27 days, 28 days, 29 days, 30 days or longer). If multiple doses of compound (I) or compound (II) are administered to a subject after embryo transfer, the subject may, for example, receive the doses regularly. Compound (I) or compound (II) may be administered to a subject after embryo transfer therapy in doses of 1 to 20 times over a period of, for example, 1 day, 1 week, 1 month, or longer. For example, the compound may be administered to a subject after embryo transfer in doses of up to 7 times every 24 hours (e.g., 1, 2, 3, 4, 5, 6, or 7 doses), such as up to 7 doses of compound (II) at 100 mg every 24 hours.

[0367] Further oxytocin antagonists In addition to the compounds of formulas (I) and (II), oxytocin antagonists that can be used in combination with the compositions and methods described herein include epersiban, letosiban, barsiban, and atosiban, as well as their salts, derivatives, variants, crystalline forms, and formulations. The following section provides a description of these agents, as well as synthetic methods for the preparation of these oxytocin antagonists.

[0368] Epersiban Oxytocin antagonists useful in conjunction with the compositions and methods described herein include epersiban ((3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-1-[(1R)-1-(2,6-dimethyl-3-pyridinyl)-2-(4-morpholinyl)-2-oxoethyl]-6-[(1S)-1-methylpropyl]-2,5-piperazinedione), as well as salts, derivatives, variants, crystalline forms, and formulations thereof. For example, salts, derivatives, variants, crystalline forms, or formulations described in U.S. Patents No. 7,514,437, 8,367,673, 8,541,579, 7,550,462, 7,919,492, 8,202,864, 8,742,099, 9,408,851, 8,716,286, or 8,815,856, each disclosure of which is incorporated herein by reference in whole. Epersiban is schematically represented by the following structural formula (III). [ka] (III)

[0369] An exemplary method for preparing epersiban is described, for example, in U.S. Patent No. 8,742,099, and is shown in Scheme 2 below. Scheme 2. Exemplary method for the synthesis of epersiban. [ka] (wherein X represents oxygen or sulfur.) It should be understood that the aforementioned compounds can be synthesized by alternative methods, for example, by replacing one of the amide bond-forming agents shown in the scheme above with another amide bond-forming agent described herein or known in the art.

[0370] Retosiban Oxytocin antagonists useful in conjunction with the compositions and methods described herein include letosiban ((3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-1-[(1R)-1-(2)-methyl-1,3-oxazole-4-yl)-2-(4-morpholinyl)-2-oxoethyl]-6-[(1S)-1-methylpropyl]-2,5-piperazinedione), as well as salts, derivatives, Variants, crystalline forms, and formulations thereof include, for example, salts, derivatives, variants, crystalline forms, or formulations described in U.S. Patents No. 7,514,437, 8,367,673, 8,541,579, 8,071,594, 8,357,685, 8,937,179, or 9,452,169, the disclosures of which are incorporated herein by reference in whole. Letosiban is schematically represented by the following structural formula (IV). [ka] (IV)

[0371] An exemplary method for preparing letosiban is described, for example, in U.S. Patent No. 8,937,139, and is shown in Scheme 3 below. Scheme 3. Exemplary method for the synthesis of letsiban [ka] It should be understood that the aforementioned compounds may be synthesized by alternative methods, for example, by replacing one of the amide bond-forming agents shown in the scheme described above with another amide bond-forming agent described herein or known in the art.

[0372] Barsiban Oxytocin antagonists useful in conjunction with the compositions and methods described herein include barsiban, as well as salts, derivatives, variants, crystalline forms, and formulations thereof, such as salts, derivatives, variants, crystalline forms, or formulations described in U.S. Patents 6,143,722, 7,091,314, 7,816,489, or 9,579,305, or International Publication 2017 / 060339, the disclosures of which are incorporated herein by reference in their entirety. Barsiban is schematically represented by the following structural formula (V). [ka] (V)

[0373] Exemplary methods for preparing barsiban are described, for example, in International Publication No. 2017 / 060339, and may include solid-phase peptide synthesis, as well as liquid-phase cyclization by, for example, thioetherification. It should be understood that the aforementioned compounds may be synthesized by alternative methods, for example, by replacing one of the amide bond-forming agents shown in International Publication No. 2017 / 060339 with another amide bond-forming agent described herein or known in the art.

[0374] Atosiban Oxytocin antagonists useful in conjunction with the compositions and methods described herein include atosiban, as well as salts, derivatives, variants, crystalline forms, and formulations thereof, such as the salts, derivatives, variants, crystalline forms, or formulations described in U.S. Patent No. 4,504,469 or No. 4,402,942, the disclosures of which are incorporated herein by reference in whole. Atosiban is schematically represented by the following structural formula (VI). [ka] (VI)

[0375] Exemplary methods for preparing atosiban are described, for example, in U.S. Patents 4,504,469 and 4,402,942, and may include solid-phase peptide synthesis and, for example, liquid-phase cyclization by disulfide bond formation. It should be understood that the aforementioned compounds may be synthesized by alternative methods, for example, by replacing one of the amide bond-forming agents shown in U.S. Patents 4,504,469 or 4,402,942 with another amide bond-forming agent described herein or known in the art.

[0376] Methods for evaluating serum progesterone levels Using the compositions and methods described herein, those skilled in the art can assess the likelihood that a subject undergoing embryo transfer therapy (e.g., a human subject) may benefit from oxytocin antagonist treatment by comparing the subject's serum progesterone concentration to a progesterone reference level. For example, a physician in the art may draw a sample from a subject undergoing embryo transfer therapy at one of several time points during the assisted reproductive technology process. Comparing the subject's serum progesterone concentration to a suitable progesterone reference level, a determination that the subject exhibits a reduced serum progesterone concentration compared to the progesterone reference level indicates that the subject is particularly well-suited to and likely to benefit from treatment with an oxytocin antagonist, such as a compound of formula (I) or (II), or another oxytocin antagonist described herein, such as epersiban, letosiban, barsiban, or atosiban, before, concurrently with, and / or after the transfer of one or more embryos to the subject.

[0377] For example, if the subject is using autogenous gametes for in vitro embryo production, the sample may be taken from the subject on the day of oocyte or oocyte retrieval. In such cases, the progesterone reference level may be between 1.0 ng / ml and 2.0 ng / ml, such as 1.0 ng / ml, 1.1 ng / ml, 1.2 ng / ml, 1.3 ng / ml, 1.4 ng / ml, 1.5 ng / ml, 1.6 ng / ml, 1.7 ng / ml, 1.8 ng / ml, 1.9 ng / ml, or 2.0 ng / ml. In such cases, the progesterone reference level may be, for example, 1.5 ng / ml. The physician may then compare the progesterone concentration in the sample isolated from the subject (e.g., serum sample) to the progesterone reference level. A determination that a subject exhibits reduced serum progesterone levels compared to normal levels indicates that the subject is particularly well-suited for and likely to benefit from oxytocin antagonist treatment (e.g., likely to exhibit enhanced endometrial receptivity in response to treatment).

[0378] Additionally or alternatively, in the case of subjects using their own gametes for in vitro embryo production, a sample may be taken from the subject on the day of the embryo transfer procedure (e.g., after oocyte or oocyte retrieval in the case of subjects using their own gametes for in vitro embryo production). In such cases, the progesterone reference level may be 200 nM to 300 nM or higher, such as 320 nM. The physician may then compare the progesterone concentration in a sample isolated from the subject (e.g., a serum sample) to the progesterone reference level. A determination that a subject exhibits a serum progesterone concentration reduced compared to the progesterone reference level indicates that the subject is particularly well-suited for and likely to benefit from treatment with an oxytocin antagonist (e.g., likely to exhibit enhanced endometrial receptivity in response to treatment).

[0379] Methods for quantifying the concentration of progesterone in a sample isolated from a subject (e.g., a serum sample) are known in the art and include, for example, competitive enzyme-linked immunosorbent assays (ELISAs) as described in U.S. Patent No. 9,201,077, the disclosure of which is incorporated herein by reference in whole. Antibodies that can specifically bind to progesterone and can be used in combination with progesterone detection assays include those manufactured and released by ATCC acceptance number HB8886 as described in U.S. Patent No. 4,720,455, the disclosure of which is incorporated herein by reference in whole.

[0380] Follicle maturation and retrieval of follicular cells / oocytes In conjunction with the compositions and methods described herein, various methods may be used to induce follicular maturation and retrieve oocytes (e.g., mature oocytes). In some embodiments, oocytes are isolated from a subject about 1 to 7 days before the transfer of one or more embryos into the subject, such as about 2 to 5 days before embryo transfer. The oocytes isolated from the subject may contain mature oocytes, such as 1 to 4 mature oocytes that are ready for fertilization upon contact with one or more spermatids. Oocytes may be isolated from subjects undergoing embryo transfer therapy, such as family donors.

[0381] Subjects undergoing embryo transfer therapy, or donors, may be prepared for oocyte or oocyte retrieval by controlled ovarian hyperstimulation, for example, according to methods described herein or known in the art. For example, to prevent premature increases in serum luteinizing hormone (LH) levels, subjects or donors may be administered a GnRH antagonist. Additionally or alternatively, final follicular maturation may be achieved by administering hCG to subjects or donors prior to the isolation of one or more oocytes. For example, hCG may be administered to subjects in single or multiple doses, for example, by intravenous injection according to procedures known in the art.

[0382] In some embodiments, a corpus luteum support is provided to the subject or donor after the retrieval of oocytes or oocytes. This can be done, for example, by administering progesterone to the subject or donor after the retrieval procedure. For example, progesterone may be administered intravaginally to the subject or donor in doses of approximately 300 mg to approximately 600 mg. Progesterone may be administered to the subject in single or multiple doses. For example, progesterone may be administered to the subject at regular intervals, starting within approximately 24 hours of the isolation of one or more oocytes or oocytes, such as within 12 hours of retrieval, and continuing for approximately 6 weeks or more after the transfer of one or more embryos to the subject.

[0383] Embryo quality and condition Embryos for use in combination with the compositions and methods described herein include, for example, those in the morula or blastula stage of embryonic development. For example, embryos that can be implanted into a subject as described herein include those containing 6 to 8 blastomeres immediately before implantation into a subject of one or more embryos. The blastomeres may be approximately equal in size when evaluated by visual microscopy before implantation into a subject of one or more embryos.

[0384] Embryos for use in combination with the compositions and methods described herein include, for example, those formed by IVF or ICSI methods known in the art. In some embodiments, the embryos are newly implanted into the uterus of a subject, for example, about 1 to about 7 days (e.g., about 2 to about 5 days) after isolation of one or more oocytes or eggs from the subject for IVF or ICSI. In some embodiments, one or more embryos are thawed and frozen before implantation into the subject and cryopreserved for long-term storage. Methods for cryopreserving embryos are known in the art and are described, for example, in International Publication No. 1991 / 003935 and International Publication No. 2010 / 011766, and the disclosures of each of them are incorporated herein by reference as they relate to compositions and procedures for cryopreservation.

[0385] Methods for assessing pregnancy Techniques for assessing pregnancy for use in combination with the compositions and methods described herein include qualitative and quantitative evaluation of a sample isolated from a subject, such as a blood or urine sample. Methods for assessing pregnancy include detecting the presence and / or amount of hCG in a sample isolated from a subject. This can be achieved using conventional receptor-ligand binding assays known in the art, such as through the use of a competitive radioligand binding assay described in U.S. Patent No. 4,094,963 for the detection of hCG, the disclosure of which is incorporated herein by reference as it relates to a method for detecting hCG in a subject sample for assessing pregnancy. Additionally or alternatively, a test specimen may be used to determine the hCG concentration, for example, as described in U.S. Patent No. 7,989,217, the disclosure of which is incorporated herein by reference as it relates to a method for detecting hCG in a subject sample for assessing pregnancy. A urine sample isolated from a subject may be further analyzed to determine pregnancy, for example, as described in U.S. Patent No. 4,315,908, the disclosure of which is incorporated herein by reference as it relates to a method for detecting hCG in a subject sample for assessing pregnancy.

[0386] Additionally or alternatively, pregnancy may be assessed by detecting intrauterine heartbeats, such as the embryonic heartbeat, or by developing the fetus after successful embryonic implantation. Compositions and methods for detecting embryonic and fetal heartbeats are known in the art and are described, for example, in U.S. Patent Nos. 3,780,725 and 4,437,467, each of which disclosures are incorporated herein by reference as they relate to methods for detecting heartbeats for assessing the pregnancy in question.

[0387] For example, as described herein, after embryo transfer, a subject may be subjected to one or more pregnancy tests using, for example, one or more of the procedures described above. A subject may be tested for pregnancy at one or more points after embryo transfer therapy, such as about 14 days, about 6 weeks, about 10 weeks, or longer, after embryo transfer and / or oocyte retrieval.

[0388] Pharmaceutical composition Oxytocin antagonists for use with the compositions and methods of the present invention can be formulated into pharmaceutically acceptable compositions for administration to subjects such as female human subjects in a biocompatible form suitable for in vivo administration. A pharmaceutically acceptable composition comprising an oxytocin antagonist (e.g., a compound of formula (I) or (II) above) may further comprise a suitable diluent, carrier, or excipient. The oxytocin antagonist may be administered to the subject, for example, by oral or intravenous injection. Under normal storage and use conditions, the pharmaceutically acceptable composition may contain preservatives, for example, to prevent microbial growth. Conventional procedures and components for the selection and preparation of suitable formulations are described, for example, in Remington: The Science and Practice of Pharmacy (2012, 22nd ed.) and The United States Pharmacopeia: The National Formulary (2015, USP 38 NF 33), and the disclosures of each thereof are incorporated herein by reference as they relate to pharmaceutically acceptable formulations of the pharmaceutically acceptable compositions.

[0389] In some embodiments, compound (II) is administered to a subject in crystalline form according to the method described herein. For example, compound (II) may be administered to a subject undergoing embryo transfer therapy in a crystalline system exhibiting characteristic X-ray powder diffraction peaks at approximately 7.05°2θ, 13.13°2θ, and 23.34°2θ. For example, the compound may exhibit characteristic X-ray powder diffraction peaks at approximately 7.05°2θ, 12.25°2θ, 13.13°2θ, 16.54°2θ, 18.00°2θ, 21.84°2θ, and 23.34°2θ. In some embodiments, the compound exhibits characteristic X-ray powder diffraction peaks as shown in Table 1 below.

[0390] Compound used In another aspect, the present invention provides a compound of formula (I) or (II), or another oxytocin antagonist described herein, such as epersiban, letsiban, barsiban, or atosiban, or their salts, derivatives, variants, crystalline forms, or formulations, for use in the treatment of a subject undergoing embryo transfer therapy, wherein the compound is administered to the subject before the transfer of one or more embryos into the subject's uterus, and the administration reduces the likelihood of embryo implantation failure.

[0391] medicine In a further embodiment, the present invention provides, in the preparation of a drug for the treatment of a subject undergoing embryo transfer therapy, a compound of formula (I) or (II), or another oxytocin antagonist described herein, such as epersiban, letosiban, barsiban, or atosiban, or their salts, derivatives, variants, crystalline forms, or formulations, the drug being administered to the subject before the transfer of one or more embryos into the subject's uterus, the administration of which reduces the likelihood of embryo implantation failure. Table 1. Characteristic X-ray powder diffraction (XRPD) peaks of the crystalline form of compound (II). [Table 2]

[0392] The aforementioned crystalline form has been shown to exhibit enhanced stability against aqueous media and physical stress, as described in detail, for example, in U.S. Patent Publication No. 2016 / 0002160, the disclosure of which is incorporated by reference in its entirety.

[0393] Compounds of formula (I) or (II) can be administered by various routes, such as orally or intravenously. When formulated for oral administration, the compound may be administered in the form of a tablet, capsule, gel cap, powder, liquid solution, or liquid suspension. In some embodiments, the compound is administered to the target in the form of a tablet, such as a dispersible tablet. A dispersible tablet may have, for example, one or more, or all of the following components: a. Approximately 1-20% by weight of calcium silicate, b. Approximately 0.1-20% by weight of PVP30K, c. Approximately 0.01-5% by weight of poloxamer 188, d. Approximately 0.5-20% by weight of croscarmellose sodium e. Approximately 1-90% by weight of microcrystalline cellulose 112, f. Approximately 1-90% by weight of lactose monohydrate. g. Approximately 0.01-0.5% by weight of sodium saccharin, and h. Approximately 0.1-10% by weight of glycerol dibehenate. For example, a dispersible tablet may have the following composition: a. Approximately 5% by weight of calcium silicate, b. Approximately 1% by weight of PVP30K, c. Approximately 2% by weight of poloxamer 188, d. Approximately 5% by weight of croscarmellose sodium, e. Approximately 1.5% by weight of microcrystalline cellulose 112, f. Approximately 47.8% by weight of lactose monohydrate. g. Approximately 0.2% by weight of sodium saccharin, and h. Approximately 4% by weight of glycerol dibehenate.

[0394] The aforementioned formulations of compound (II) have been shown to exhibit rapid absorption kinetics upon administration to subjects, as described in detail, for example, in U.S. Patent Publication No. 2015 / 0164859, the disclosure of which is incorporated herein by reference in its entirety.

[0395] Pharmaceutical compositions of compound (I) or (II) may include sterile aqueous solutions, dispersions, or powders, for example, those for the immediate preparation of sterile solutions or dispersions. In all cases, the form can be sterilized using techniques known in the art and can be fluidized to the extent that it can be easily administered to subjects requiring treatment. [Examples]

[0396] The following examples are provided to those skilled in the art to explain how the compositions and methods described herein may be used, prepared, and evaluated, and are intended purely as examples of the present invention and not to limit the scope of what the inventors consider to be their own invention.

[0397] Example 1. Oral administration of compound (II) promotes successful embryo implantation and prolongs pregnancy in subjects undergoing embryo transfer therapy. material and method In a randomized, double-blind, parallel-group phase 2 clinical study investigating the efficacy of compound (II) in enhancing endometrial receptivity and promoting successful embryo transfer in humans, the compound was orally administered at varying doses to subjects undergoing embryo transfer therapy. A total of 247 women were selected for treatment based on various selection criteria. Of these, 244 completed the study. The study was open to healthy female volunteers aged 18–36 years who had previously undergone up to one IVF or ICSI cycle that resulted in a negative pregnancy test, as assessed by hCG detection, despite the transfer of at least one good quality embryo, defined as having 6–8 blastomeres of uniform size and shape on embryo transfer day, non-granular oocyte cytoplasm, no multinucleation, and up to 10% fragmentation. Subjects included in the study had at least one functional ovary, were able to communicate with researchers and research staff, and adhere to the requirements of the study protocol. A demographic summary of the subjects included in the study is shown in Table 2 below. Data are presented in the form of mean (standard deviation). Table 2. Demographic summary of the subjects included in the study. [Table 3]

[0398] Participants in the study underwent an initial screening period that began up to 12 weeks prior to the date of oocyte retrieval from each participant. During this 12-week period, participants underwent physical and gynecological examinations in preparation for oocyte retrieval. This analysis included recording of participants' vital signs, hematological and biochemical analysis of blood samples taken from participants, urine analysis, and a comprehensive review of each participant's medical history.

[0399] At the end of the screening period, subjects received controlled ovarian hyperstimulation with GnRH antagonists to prevent premature increases in serum LH levels. Concurrent prior treatment with oral contraceptives before controlled ovarian hyperstimulation was permitted but not required. Final follicular maturati...

Claims

1. A method for treating a subject undergoing embryo transfer therapy, wherein the method involves administering a therapeutically effective amount of a compound represented by formula (I) to the subject. 【Chemistry 1】 (I) or administering its geometric isomers, enantiomers, diastereomers, racemic mixtures, or salts, In the formula, n is an integer between 1 and 3. R １ is hydrogen and C １ ~C ６ Selected from the group consisting of alkyl groups, R ２ is hydrogen, C １ -C ６ alkyl, C １ -C ６ alkylaryl, heteroaryl, C １ -C ６ alkylheteroaryl, C ２ -C ６ alkenyl, C ２ -C ６ alkenylaryl, C ２ -C ６ alkenylheteroaryl, C ２ -C[[ID=X]] ６ alkynyl, C ２ -C ６ alkynylaryl, C ２ -C ６ alkynylheteroaryl, C ３ -C ６ cycloalkyl, heterocycloalkyl, C １ -C ６ alkylcycloalkyl, C １ -C ６ alkylheterocycloalkyl, C １ -C<X ６ alkylcarboxy, acyl, C １ -C ６ alkylacyl, C １ -C ６ alkylacyloxy, C １ -C ６ alkylalkoxy, alkoxycarbonyl, C １ -C ６ alkylalkoxycarbonyl, aminocarbonyl, C １ -C ６ alkylaminocarbonyl, C １ -C ６ alkylacylamino, C １ -C ６ alkylureido, amino, C １ -C ６ alkylamino, sulfonyloxy, C １ -C ６ alkylsulfonyloxy, sulfonyl, C １ -C ６ alkylsulfonyl, sulfinyl, C １ ~C ６ Alkyl sulfinyl, C １ ~C ６ Alkyl sulfanyl, and C １ ~C ６ Selected from the group consisting of alkylsulfonylaminos, R ３ It is selected from the group consisting of aryls and heteroaryls, X is oxygen and NR ４ Selected from the group consisting of, R ４ is hydrogen, C １ ~C ６ Alkyl, C １ ~C ６ Alkylaryl, C １ ~C ６ Selected from the group consisting of alkylheteroaryl, aryl, and heteroaryl, R ２ and R ４ Together with the nitrogen atoms to which they are bonded, they can form a 5- to 8-membered saturated or unsaturated heterocycloalkyl ring. The compound is administered to the subject before the transfer of one or more embryos into the subject's uterus, and the administration reduces the possibility of embryo implantation failure.

2. A method for treating a subject undergoing embryo transfer therapy, the method comprising transferring one or more embryos into the uterus of the subject, wherein the subject is a compound represented by formula (I) in a therapeutically effective amount. 【Chemistry 2】 (I) Alternatively, the patient may have been previously administered a geometric isomer, enantiomer, diastereomer, racemic mixture, or salt thereof. In the formula, n is an integer between 1 and 3. R １ is hydrogen and C １ ~C ６ Selected from the group consisting of alkyl groups, R ２ is hydrogen, C １ -C ６ alkyl, C １ -C ６ alkylaryl, heteroaryl, C １ -C ６ alkylheteroaryl, C ２ -C ６ alkenyl, C ２ -C ６ alkenylaryl, C ２ -C ６ alkenylheteroaryl, C ２ -C ６ alkynyl, C<已存在的标签编号>-C<已存在的标签编号>alkynylaryl, C<已存在于原文的标签编号>-C<已存在于原文的标签编号>alkynylheteroaryl, C<已存在于原文的标签编号>-C<已存在于原文的标签编号>cycloalkyl, heterocycloalkyl, C<已存在于原文的标签编号>-C<已存在于原文的标签编号>alkylcycloalkyl, C<已存在于原文的标签编号>-C<已存在于原文的标签编号>alkylheterocycloalkyl, C<已存在于原文的标签编号>-C<已存在于原文的标签编号>alkylcarboxy, acyl, C<已存在于原文的标签编号>-C<已存在于原文的标签编号>alkylacyl, C<已存在于原文的标签编号>-C<已存在于原文的标签编号>alkylacyloxy, C<已存在于原文的标签编号>-C<已存在于原文的标签编号>alkylalkoxy, alkoxycarbonyl, C<已存在于原文的标签编号>-C<已存在于原文的标签编号> alkylalkoxycarbonyl, aminocarbonyl, C<已存在于原文的标签编号> -C<已存在于原文的标签编号> alkylaminocarbonyl, C<已存在于原文的标签编号> -C<已存在于原文的标签编号> alkylacylamino, C<已存在于原文的标签编号> -C<已存在于原文的标签编号> alkylureido, amino, C<已存在于原文的标签编号> -C<已存在于原文的标签编号> alkylamino, sulfonyloxy, C<已存在于原文的标签编号> -C<已存在于原文的标签编号> alkylsulfonyloxy, sulfonyl, C<已存在于原文的标签编号> -C ６ alkylsulfonyl, sulfinyl, C １ ~C ６ Alkyl sulfinyl, C １ ~C ６ Alkyl sulfanyl, and C １ ~C ６ Selected from the group consisting of alkylsulfonylaminos, R ３ It is selected from the group consisting of aryls and heteroaryls, X is oxygen and NR ４ Selected from the group consisting of, R ４ is hydrogen, C １ ~C ６ Alkyl, C １ ~C ６ Alkylaryl, C １ ~C ６ Selected from the group consisting of alkylheteroaryl, aryl, and heteroaryl, R ２ and R ４ Together with the nitrogen atoms to which they are bonded, they can form a 5- to 8-membered saturated or unsaturated heterocycloalkyl ring. The administration of the aforementioned compound is a method for reducing the possibility of embryo implantation failure.

3. A method for treating a subject undergoing embryo transfer therapy, wherein the method is a. A therapeutically effective amount of the compound represented by formula (I) to the subject, 【Transformation 3】 (I) or administering its geometric isomers, enantiomers, diastereomers, racemic mixtures, or salts, In the formula, n is an integer between 1 and 3. R １ is hydrogen and C １ ~C ６ Selected from the group consisting of alkyl groups, R ２ is hydrogen, C １ ~C ６ Alkyl, C １ ~C ６ Alkylaryl, heteroaryl, C １ ~C ６ Alkyl heteroaryl, C ２ ~C ６ Alkenil, C ２ ~C ６ Alkenylaryl, C ２ ~C ６ Alkenyl heteroaryl, C ２ ~C ６ Alkinyl, C ２ ~C ６ Alkynylaryl, C ２ ~C ６ Alkinyl heteroaryl, C ３ ~C ６ Cycloalkyl, heterocycloalkyl, C １ ~C ６ Alkylcycloalkyl, C １ ~C ６ Alkyl heterocycloalkyl, C １ ~C ６ Alkylcarboxy, acyl, C １ ~C ６ Alkylacyl, C １ ~C ６ Alkylacyloxy, C １ ~C ６ Alkylalkoxy, alkoxycarbonyl, C １ ~C ６ Alkylalkoxycarbonyl, aminocarbonyl, C １ ~C ６ Alkylaminocarbonyl, C １ ~C ６ Alkyl acylamino, C １ ~C ６ Alkyl ureido, amino, C １ ~C ６ Alkylamino, sulfonyloxy, C １ ~C ６ Alkyl sulfonyl oxy, sulfonyl, C １ ~C ６ Alkylsulfonyl, sulfinyl, C １ ~C ６ Alkyl sulfinyl, C １ ~C ６ Alkyl sulfanyl, and C １ ~C ６ Selected from the group consisting of alkylsulfonylaminos, R ３ It is selected from the group consisting of aryls and heteroaryls, X is oxygen and NR ４ Selected from the group consisting of, R ４ is hydrogen, C １ ~C ６ Alkyl, C １ ~C ６ Alkylaryl, C １ ~C ６ Selected from the group consisting of alkylheteroaryl, aryl, and heteroaryl, R ２ and R ４ They can form a 5-8 member saturated or unsaturated heterocycloalkyl ring together with the nitrogen to which they are bound, when administered, b. The procedure involves implanting one or more embryos into the target uterus after administering the compound, The aforementioned administration is a method to reduce the possibility of embryo implantation failure.

4. The method according to any one of claims 1 to 3, wherein the compound is administered to the subject about 1 hour to about 24 hours before the transfer of one or more embryos to the subject.

5. The method according to claim 4, wherein the compound is administered to the subject about 1 to 8 hours before the transfer of one or more embryos to the subject.

6. The method according to claim 5, wherein the compound is administered to the subject about 3 to 5 hours before the transfer of one or more embryos to the subject.

7. The method according to claim 6, wherein the compound is administered to the subject about four hours before the transfer of one or more embryos to the subject.

8. The method according to any one of claims 1 to 7, wherein the compound is administered to the subject in a single dose.

9. The method according to any one of claims 1 to 7, wherein the compound is administered to the subject in multiple doses.

10. The method according to claim 9, wherein the compound is administered to the subject in doses of 1 to 20 times per day prior to the transfer of one or more embryos to the subject.

11. The method according to claim 10, wherein the compound is administered to the subject in doses of 1 to 7 times per day prior to the transfer of one or more embryos to the subject.

12. The method according to any one of claims 9 to 11, wherein the compound is administered to the subject daily for about 1 to about 14 days prior to the transfer of one or more embryos to the subject.

13. The method according to claim 12, wherein the compound is administered to the subject daily for about 3 to 11 days prior to the transfer of one or more embryos to the subject.

14. The method according to claim 13, wherein the compound is administered to the subject daily for seven days prior to the transfer of one or more embryos to the subject.

15. The method according to any one of claims 9 to 14, wherein the compound is further administered to the subject at the same time as the transfer of one or more embryos to the subject.

16. The method according to any one of claims 9 to 15, wherein the compound is further administered to the subject after the transfer of one or more embryos to the subject.

17. The method according to claim 16, wherein the compound is further administered to the subject about 1 hour to about 24 hours after the transfer of one or more embryos to the subject.

18. The method according to claim 16 or 17, wherein the compound is further administered to the subject in doses of 1 to 20 times per day after the transfer of one or more embryos to the subject.

19. The method according to claim 18, wherein the compound is further administered to the subject in doses of 1 to 7 times per day after the transfer of one or more embryos to the subject.

20. The method according to any one of claims 16 to 19, wherein the compound is further administered to the subject daily for about 1 to about 14 days after the transfer of one or more embryos to the subject.

21. The method according to claim 20, wherein the compound is further administered to the subject daily for about 3 to 11 days after the transfer of one or more embryos to the subject.

22. The method according to claim 21, wherein the compound is further administered to the subject daily for seven days after the transfer of one or more embryos to the subject.

23. A method for treating a subject undergoing embryo transfer therapy, wherein the method involves administering a therapeutically effective amount of a compound represented by formula (I) to the subject. 【Chemistry 4】 (I) or administering its geometric isomers, enantiomers, diastereomers, racemic mixtures, or salts, In the formula, n is an integer between 1 and 3. R １ is hydrogen and C １ ~C ６ Selected from the group consisting of alkyl groups, R ２ is hydrogen, C １ ~C ６ Alkyl, C １ ~C ６ Alkylaryl, heteroaryl, C １ ~C ６ Alkyl heteroaryl, C ２ ~C ６ Alkenil, C ２ ~C ６ Alkenylaryl, C ２ ~C ６ Alkenyl heteroaryl, C ２ ~C ６ Alkinyl, C ２ ~C ６ Alkynylaryl, C ２ ~C ６ Alkinyl heteroaryl, C ３ ~C ６ Cycloalkyl, heterocycloalkyl, C １ ~C ６ Alkylcycloalkyl, C １ ~C ６ Alkyl heterocycloalkyl, C １ ~C ６ Alkylcarboxy, acyl, C １ ~C ６ Alkylacyl, C １ ~C ６ Alkylacyloxy, C １ ~C ６ Alkylalkoxy, alkoxycarbonyl, C １ ~C ６ Alkylalkoxycarbonyl, aminocarbonyl, C １ ~C ６ Alkylaminocarbonyl, C １ ~C ６ Alkyl acylamino, C １ ~C ６ Alkyl ureido, amino, C １ ~C ６ Alkylamino, sulfonyloxy, C １ ~C ６ Alkyl sulfonyl oxy, sulfonyl, C １ ~C ６ Alkylsulfonyl, sulfinyl, C １ ~C ６ Alkyl sulfinyl, C １ ~C ６ Alkyl sulfanyl, and C １ ~C ６ Selected from the group consisting of alkylsulfonylaminos, R ３ It is selected from the group consisting of aryls and heteroaryls, X is oxygen and NR ４ Selected from the group consisting of, R ４ is hydrogen, C １ ~C ６ Alkyl, C １ ~C ６ Alkylaryl, C １ ~C ６ Selected from the group consisting of alkylheteroaryl, aryl, and heteroaryl, R ２ and R ４ Together with the nitrogen atoms to which they are bonded, they can form a 5- to 8-membered saturated or unsaturated heterocycloalkyl ring. The compound is administered to the subject simultaneously with the implantation of one or more embryos into the subject's uterus, and the administration reduces the possibility of embryo implantation failure.

24. A method for treating a subject undergoing embryo transfer therapy, the method comprising transferring one or more embryos into the uterus of the subject, wherein the subject is a compound represented by formula (I) in a therapeutically effective amount. 【Transformation 5】 (I) or the administration of its geometric isomers, enantiomers, diastereomers, racemates, or salts simultaneously, In the formula, n is an integer between 1 and 3. R １ is hydrogen and C １ ~C ６ Selected from the group consisting of alkyl groups, R ２ is hydrogen, C １ ~C ６ Alkyl, C １ ~C ６ Alkylaryl, heteroaryl, C １ ~C ６ Alkyl heteroaryl, C ２ ~C ６ Alkenil, C ２ ~C ６ Alkenylaryl, C ２ ~C ６ Alkenyl heteroaryl, C ２ ~C ６ Alkinyl, C ２ ~C ６ Alkynylaryl, C ２ ~C ６ Alkinyl heteroaryl, C ３ ~C ６ Cycloalkyl, heterocycloalkyl, C １ ~C ６ Alkylcycloalkyl, C １ ~C ６ Alkyl heterocycloalkyl, C １ ~C ６ Alkylcarboxy, acyl, C １ ~C ６ Alkylacyl, C １ ~C ６ Alkylacyloxy, C １ ~C ６ Alkylalkoxy, alkoxycarbonyl, C １ ~C ６ Alkylalkoxycarbonyl, aminocarbonyl, C １ ~C ６ Alkylaminocarbonyl, C １ ~C ６ Alkyl acylamino, C １ ~C ６ Alkyl ureido, amino, C １ ~C ６ Alkylamino, sulfonyloxy, C １ ~C ６ Alkyl sulfonyl oxy, sulfonyl, C １ ~C ６ Alkylsulfonyl, sulfinyl, C １ ~C ６ Alkyl sulfinyl, C １ ~C ６ Alkyl sulfanyl, and C １ ~C ６ Selected from the group consisting of alkylsulfonylaminos, R ３ It is selected from the group consisting of aryls and heteroaryls, X is oxygen and NR ４ Selected from the group consisting of, R ４ is hydrogen, C １ ~C ６ Alkyl, C １ ~C ６ Alkylaryl, C １ ~C ６ Selected from the group consisting of alkylheteroaryl, aryl, and heteroaryl, R ２ and R ４ Together with the nitrogen atoms to which they are bonded, they can form a 5- to 8-membered saturated or unsaturated heterocycloalkyl ring. The administration of the aforementioned compound is a method for reducing the possibility of embryo implantation failure.

25. A method for treating a subject undergoing embryo transfer therapy, wherein the method is a. A therapeutically effective amount of the compound represented by formula (I) to the subject, 【Transformation 6】 (I) or administering its geometric isomers, enantiomers, diastereomers, racemic mixtures, or salts, In the formula, n is an integer between 1 and 3. R １ is hydrogen and C １ ~C ６ Selected from the group consisting of alkyl groups, R ２ is hydrogen, C １ ~C ６ Alkyl, C １ ~C ６ Alkylaryl, heteroaryl, C １ ~C ６ Alkyl heteroaryl, C ２ ~C ６ Alkenil, C ２ ~C ６ Alkenylaryl, C ２ ~C ６ Alkenyl heteroaryl, C ２ ~C ６ Alkinyl, C ２ ~C ６ Alkynylaryl, C ２ ~C ６ Alkinyl heteroaryl, C ３ ~C ６ Cycloalkyl, heterocycloalkyl, C １ ~C ６ Alkylcycloalkyl, C １ ~C ６ Alkyl heterocycloalkyl, C １ ~C ６ Alkylcarboxy, acyl, C １ ~C ６ Alkylacyl, C １ ~C ６ Alkylacyloxy, C １ ~C ６ Alkylalkoxy, alkoxycarbonyl, C １ ~C ６ Alkylalkoxycarbonyl, aminocarbonyl, C １ ~C ６ Alkylaminocarbonyl, C １ ~C ６ Alkyl acylamino, C １ ~C ６ Alkyl ureido, amino, C １ ~C ６ Alkylamino, sulfonyloxy, C １ ~C ６ Alkyl sulfonyl oxy, sulfonyl, C １ ~C ６ Alkylsulfonyl, sulfinyl, C １ ~C ６ Alkyl sulfinyl, C １ ~C ６ Alkyl sulfanyl, and C １ ~C ６ Selected from the group consisting of alkylsulfonylaminos, R ３ It is selected from the group consisting of aryls and heteroaryls, X is oxygen and NR ４ Selected from the group consisting of, R ４ is hydrogen, C １ ~C ６ Alkyl, C １ ~C ６ Alkylaryl, C １ ~C ６ Selected from the group consisting of alkylheteroaryl, aryl, and heteroaryl, R ２ and R ４ They can form a 5-8 member saturated or unsaturated heterocycloalkyl ring together with the nitrogen to which they are bound, when administered, b. The procedure comprises administering the compound and simultaneously implanting one or more embryos into the target uterus, The aforementioned administration is a method to reduce the possibility of embryo implantation failure.

26. The method according to any one of claims 23 to 25, wherein the compound is administered to the subject in a single dose.

27. The method according to any one of claims 23 to 25, wherein the compound is administered to the subject in multiple doses.

28. A method for treating a subject undergoing embryo transfer therapy, wherein the method involves administering a therapeutically effective amount of a compound represented by formula (I) to the subject. 【Transformation 7】 (I) or administering its geometric isomers, enantiomers, diastereomers, racemic mixtures, or salts, In the formula, n is an integer between 1 and 3. R １ is hydrogen and C １ ~C ６ Selected from the group consisting of alkyl groups, R ２ is hydrogen, C １ ~C ６ Alkyl, C １ ~C ６ Alkylaryl, heteroaryl, C １ ~C ６ Alkyl heteroaryl, C ２ ~C ６ Alkenil, C ２ ~C ６ Alkenylaryl, C ２ ~C ６ Alkenyl heteroaryl, C ２ ~C ６ Alkinyl, C ２ ~C ６ Alkynylaryl, C ２ ~C ６ Alkinyl heteroaryl, C ３ ~C ６ Cycloalkyl, heterocycloalkyl, C １ ~C ６ Alkylcycloalkyl, C １ ~C ６ Alkyl heterocycloalkyl, C １ ~C ６ Alkylcarboxy, acyl, C １ ~C ６ Alkylacyl, C １ ~C ６ Alkylacyloxy, C １ ~C ６ Alkylalkoxy, alkoxycarbonyl, C １ ~C ６ Alkylalkoxycarbonyl, aminocarbonyl, C １ ~C ６ Alkylaminocarbonyl, C １ ~C ６ Alkyl acylamino, C １ ~C ６ Alkyl ureido, amino, C １ ~C ６ Alkylamino, sulfonyloxy, C １ ~C ６ Alkyl sulfonyl oxy, sulfonyl, C １ ~C ６ Alkylsulfonyl, sulfinyl, C １ ~C ６ Alkyl sulfinyl, C １ ~C ６ Alkyl sulfanyl, and C １ ~C ６ Selected from the group consisting of alkylsulfonylaminos, R ３ It is selected from the group consisting of aryls and heteroaryls, X is oxygen and NR ４ Selected from the group consisting of, R ４ is hydrogen, C １ ~C ６ Alkyl, C １ ~C ６ Alkylaryl, C １ ~C ６ Selected from the group consisting of alkylheteroaryl, aryl, and heteroaryl, R ２ and R ４ Together with the nitrogen atoms to which they are bonded, they can form a 5- to 8-membered saturated or unsaturated heterocycloalkyl ring. The compound is administered to the subject after the transfer of one or more embryos into the subject's uterus, and the administration reduces the possibility of embryo implantation failure.

29. A method for treating a subject undergoing embryo transfer therapy, the method comprising transferring one or more embryos into the uterus of the subject, wherein the subject subsequently receives a therapeutically effective amount of a compound represented by formula (I). 【Transformation 8】 (I) or administering its geometric isomers, enantiomers, diastereomers, racemic mixtures, or salts, In the formula, n is an integer between 1 and 3. R １ is hydrogen and C １ ~C ６ Selected from the group consisting of alkyl groups, R ２ is hydrogen, C １ ~C ６ Alkyl, C １ ~C ６ Alkylaryl, heteroaryl, C １ ~C ６ Alkyl heteroaryl, C ２ ~C ６ Alkenil, C ２ ~C ６ Alkenylaryl, C ２ ~C ６ Alkenyl heteroaryl, C ２ ~C ６ Alkinyl, C ２ ~C ６ Alkynylaryl, C ２ ~C ６ Alkinyl heteroaryl, C ３ ~C ６ Cycloalkyl, heterocycloalkyl, C １ ~C ６ Alkylcycloalkyl, C １ ~C ６ Alkyl heterocycloalkyl, C １ ~C ６ Alkylcarboxy, acyl, C １ ~C ６ Alkylacyl, C １ ~C ６ Alkylacyloxy, C １ ~C ６ Alkylalkoxy, alkoxycarbonyl, C １ ~C ６ Alkylalkoxycarbonyl, aminocarbonyl, C １ ~C ６ Alkylaminocarbonyl, C １ ~C ６ Alkyl acylamino, C １ ~C ６ Alkyl ureido, amino, C １ ~C ６ Alkylamino, sulfonyloxy, C １ ~C ６ Alkyl sulfonyl oxy, sulfonyl, C １ ~C ６ Alkylsulfonyl, sulfinyl, C １ ~C ６ Alkyl sulfinyl, C １ ~C ６ Alkyl sulfanyl, and C １ ~C ６ Selected from the group consisting of alkylsulfonylaminos, R ３ It is selected from the group consisting of aryls and heteroaryls, X is oxygen and NR ４ Selected from the group consisting of, R ４ is hydrogen, C １ ~C ６ Alkyl, C １ ~C ６ Alkylaryl, C １ ~C ６ Selected from the group consisting of alkylheteroaryl, aryl, and heteroaryl, R ２ and R ４ Together with the nitrogen atoms to which they are bonded, they can form a 5- to 8-membered saturated or unsaturated heterocycloalkyl ring. The administration of the aforementioned compound is a method for reducing the possibility of embryo implantation failure.

30. A method for treating a subject undergoing embryo transfer therapy, wherein the method is a. A therapeutically effective amount of the compound represented by formula (I) to the subject, 【Chemistry 9】 (I) or administering its geometric isomers, enantiomers, diastereomers, racemic mixtures, or salts, In the formula, n is an integer between 1 and 3. R １ is hydrogen and C １ ~C ６ Selected from the group consisting of alkyl groups, R ２ is hydrogen, C １ ~C ６ Alkyl, C １ ~C ６ Alkylaryl, heteroaryl, C １ ~C ６ Alkyl heteroaryl, C ２ ~C ６ Alkenil, C ２ ~C ６ Alkenylaryl, C ２ ~C ６ Alkenyl heteroaryl, C ２ ~C ６ Alkinyl, C ２ ~C ６ Alkynylaryl, C ２ ~C ６ Alkinyl heteroaryl, C ３ ~C ６ Cycloalkyl, heterocycloalkyl, C １ ~C ６ Alkylcycloalkyl, C １ ~C ６ Alkyl heterocycloalkyl, C １ ~C ６ Alkylcarboxy, acyl, C １ ~C ６ Alkylacyl, C １ ~C ６ Alkylacyloxy, C １ ~C ６ Alkylalkoxy, alkoxycarbonyl, C １ ~C ６ Alkylalkoxycarbonyl, aminocarbonyl, C １ ~C ６ Alkylaminocarbonyl, C １ ~C ６ Alkyl acylamino, C １ ~C ６ Alkyl ureido, amino, C １ ~C ６ Alkylamino, sulfonyloxy, C １ ~C ６ Alkyl sulfonyl oxy, sulfonyl, C １ ~C ６ Alkylsulfonyl, sulfinyl, C １ ~C ６ Alkyl sulfinyl, C １ ~C ６ Alkyl sulfanyl, and C １ ~C ６ Selected from the group consisting of alkylsulfonylaminos, R ３ It is selected from the group consisting of aryls and heteroaryls, X is oxygen and NR ４ Selected from the group consisting of, R ４ is hydrogen, C １ ~C ６ Alkyl, C １ ~C ６ Alkylaryl, C １ ~C ６ Selected from the group consisting of alkylheteroaryl, aryl, and heteroaryl, R ２ and R ４ They can form a 5-8 member saturated or unsaturated heterocycloalkyl ring together with the nitrogen to which they are bound, when administered, b. The procedure involves implanting one or more embryos into the target uterus before administering the compound, The aforementioned administration is a method to reduce the possibility of embryo implantation failure.

31. The method according to any one of claims 28 to 30, wherein the compound is administered to the subject about 1 hour to about 24 hours after the transfer of one or more embryos to the subject.

32. The method according to any one of claims 28 to 31, wherein the compound is administered to the subject in a single dose.

33. The method according to any one of claims 28 to 31, wherein the compound is administered to the subject in multiple doses.

34. The method according to claim 33, wherein the compound is administered to the subject in doses of 1 to 20 times per day after the transfer of one or more embryos to the subject.

35. The method according to claim 34, wherein the compound is administered to the subject in a dose of 1 to 7 times per day after the transfer of one or more embryos to the subject.

36. The method according to any one of claims 33 to 35, wherein the compound is administered to the subject daily for about 1 to 14 days after the transfer of one or more embryos to the subject.

37. The method according to claim 36, wherein the compound is administered to the subject daily for about 3 to 11 days after the transfer of one or more embryos to the subject.

38. The method according to claim 37, wherein the compound is administered to the subject daily for seven days after the transfer of one or more embryos to the subject.

39. The method according to any one of claims 33 to 38, wherein the compound is further administered to the subject at the same time as the transfer of one or more embryos to the subject.

40. The method according to any one of claims 33 to 39, wherein the compound is further administered to the subject before the transfer of one or more embryos to the subject.

41. The method according to claim 40, wherein the compound is further administered to the subject about 1 hour to about 24 hours before the transfer of one or more embryos to the subject.

42. The method according to claim 41, wherein the compound is further administered to the subject about 1 to 8 hours before the transfer of one or more embryos to the subject.

43. The method according to claim 42, wherein the compound is further administered to the subject about 3 to 5 hours before the transfer of one or more embryos to the subject.

44. The method according to claim 43, wherein the compound is further administered to the subject about four hours before the transfer of one or more embryos to the subject.

45. The method according to any one of claims 40 to 44, wherein the compound is further administered to the subject in doses of 1 to 20 times per day prior to the transfer of one or more embryos to the subject.

46. The method according to claim 45, wherein the compound is further administered to the subject in doses of 1 to 7 times per day prior to the transfer of one or more embryos to the subject.

47. The method according to any one of claims 40 to 46, wherein the compound is further administered to the subject daily about 1 to 14 days before the transfer of one or more embryos to the subject.

48. The method according to claim 47, wherein the compound is further administered to the subject daily for about 3 to about 11 days prior to the transfer of one or more embryos to the subject.

49. The method according to claim 48, wherein the compound is further administered to the subject daily for seven days prior to the transfer of one or more embryos to the subject.

50. The method according to any one of claims 1 to 49, wherein the administration of the compound reduces the likelihood of the subject miscarrying after the transfer of one or more embryos.

51. The method according to any one of claims 1 to 50, wherein the compound is administered to the subject in an amount sufficient to achieve a plasma concentration of the compound in the subject of about 1 μM to about 20 μM.

52. The method according to claim 51, wherein the plasma concentration is achieved within approximately 1 to 3 hours after administration of the compound to the subject.

53. The method according to any one of claims 1 to 52, wherein one or two embryos are implanted into the subject.

54. The method according to claim 53, wherein one embryo is implanted into the subject.

55. The method according to claim 53, wherein two embryos are implanted into the subject.

56. The method according to any one of claims 1 to 55, wherein the subject is a mammal and the one or more embryos are mammalian embryos.

57. The method according to claim 56, wherein the mammal is a human, and the embryo of one or more mammals is a human embryo.

58. The method according to any one of claims 1 to 57, wherein one or more embryos are produced in vitro by in vitro fertilization (IVF).

59. The method according to claim 58, wherein one or more embryos are produced in vitro by IVF of one or more oocytes derived from the subject.

60. The method according to any one of claims 1 to 57, wherein one or more embryos are produced in vitro by intracytoplasmic sperm injection (ICSI).

61. The method according to claim 60, wherein the one or more embryos are produced in vitro by ICSI of one or more oocytes derived from the subject.

62. The method according to claim 59 or 61, wherein the one or more eggs are derived from one or more oocytes isolated from the subject.

63. The method according to claim 62, wherein one or more oocytes are isolated from the subject about one to seven days before the transfer of one or more embryos to the subject.

64. The method according to claim 63, wherein one or more oocytes are isolated from the subject about two days before the transfer of one or more embryos to the subject.

65. The method according to claim 63, wherein one or more oocytes are isolated from the subject about three days before the transfer of one or more embryos to the subject.

66. The method according to claim 63, wherein one or more oocytes are isolated from the subject about four days before the transfer of one or more embryos to the subject.

67. The method according to claim 63, wherein one or more oocytes are isolated from the subject about five days before the transfer of one or more embryos to the subject.

68. The method according to any one of claims 62 to 67, wherein the one or more oocytes comprises one to four mature oocytes.

69. The method according to any one of claims 62 to 68, wherein a gonadotropin-releasing hormone (GnRH) antagonist is administered to the subject before the isolation of one or more oocytes from the subject.

70. The method according to any one of claims 62 to 69, wherein human chorionic gonadotropin (hCG) is administered to the subject before the isolation of one or more oocytes from the subject.

71. The method according to claim 70, wherein the hCG is administered to the subject by a single intravenous injection.

72. The method according to any one of claims 62 to 71, wherein progesterone is administered to the subject after isolation of one or more oocytes from the subject.

73. The method according to claim 72, wherein the progesterone is administered intravaginally.

74. The method according to claim 72 or 73, wherein approximately 300 mg to approximately 600 mg of progesterone per dose is administered to the subject.

75. The method according to any one of claims 72 to 74, wherein the progesterone is administered to the subject daily, preferably starting within about 24 hours of the isolation of one or more oocytes from the subject and continuing for about 6 weeks or more after the transfer of one or more embryos to the subject.

76. The method according to claim 59 or 61, wherein one or more eggs are directly isolated from the subject.

77. The method according to claim 76, wherein one or more oocytes are isolated from the subject about one to seven days before the transfer of one or more embryos to the subject.

78. The method according to claim 77, wherein one or more oocytes are isolated from the subject approximately two days before the transfer of one or more embryos to the subject.

79. The method according to claim 77, wherein one or more oocytes are isolated from the subject approximately three days before the transfer of one or more embryos to the subject.

80. The method according to claim 77, wherein one or more oocytes are isolated from the subject about four days before the transfer of one or more embryos to the subject.

81. The method according to claim 77, wherein one or more oocytes are isolated from the subject about five days before the transfer of one or more embryos to the subject.

82. The method according to any one of claims 76 to 81, wherein a GnRH antagonist is administered to the subject before the isolation of one or more oocytes from the subject.

83. The method according to any one of claims 76 to 82, wherein hCG is administered to the subject before the isolation of one or more eggs from the subject.

84. The method according to claim 83, wherein the hCG is administered to the subject by a single intravenous injection.

85. The method according to any one of claims 76 to 84, wherein progesterone is administered to the subject after the isolation of one or more eggs from the subject.

86. The method according to claim 85, wherein the progesterone is administered intravaginally.

87. The method according to claim 85 or 86, wherein approximately 300 mg to approximately 600 mg of progesterone per dose is administered to the subject.

88. The method according to any one of claims 85 to 87, wherein the progesterone is administered to the subject daily, preferably starting within about 24 hours of the isolation of one or more oocytes from the subject and continuing for about 6 weeks or more after the transfer of one or more embryos to the subject.

89. The method according to any one of claims 62 to 75, wherein the one or more embryos are implanted into the subject during the same menstrual cycle as the isolation of the one or more oocytes from the subject.

90. The method according to any one of claims 76 to 88, wherein the one or more embryos are implanted into the subject during the same menstrual cycle as the isolation of the one or more eggs from the subject.

91. The method according to any one of claims 1 to 62, 68 to 76, and 82 to 88, wherein one or more embryos are frozen and thawed before the transfer of one or more embryos to the target.

92. The method according to any one of claims 1 to 91, wherein each of the one or more embryos contains 6 to 8 blastomeres immediately before the transfer of the one or more embryos to the target.

93. The method according to claim 92, wherein the blastomeres are substantially equal in size when evaluated by visual microscopy.

94. The method according to any one of claims 1 to 93, wherein the compound is represented by formula (II). 【Chemistry 10】 (II)

95. The method according to claim 94, wherein the compound is in a crystalline state.

96. The method according to claim 95, wherein the compound exhibits characteristic X-ray powder diffraction peaks at approximately 7.05°²θ, approximately 13.13°²θ, and approximately 23.34°²θ.

97. The method according to any one of claims 1 to 96, wherein the compound is administered orally to the subject.

98. The method according to claim 97, wherein the compound is administered to the subject in the form of a tablet, capsule, gel cap, powder, liquid solution, or liquid suspension.

99. The method according to claim 98, wherein the compound is administered to the subject in the form of a tablet.

100. The method according to claim 99, wherein the tablet is a dispersible tablet.

101. The aforementioned dispersible tablet, a. Approximately 1-20% by weight of calcium silicate, b. Approximately 0.1 to 20% by weight of PVP30K, c. Approximately 0.01 to 5% by weight of poloxamer 188, d. Approximately 0.5 to 20% by weight of croscarmellose sodium, e. Approximately 1-90% by weight of microcrystalline cellulose 112, f. Approximately 1-90% by weight of lactose monohydrate. g. Approximately 0.01 to 0.5% by weight of sodium saccharin, and h. The method according to claim 100, comprising about 0.1 to 10% by weight of glycerol dibehenate.

102. The aforementioned dispersible tablet, a. Approximately 5% by weight of calcium silicate, b. Approximately 1% by weight of PVP30K, c. Approximately 2% by weight of poloxamer 188, d. Approximately 5% by weight of croscarmellose sodium, e. Approximately 1.5% by weight of microcrystalline cellulose 112, f. Approximately 47.8% by weight of lactose monohydrate, g. Approximately 0.2% by weight of sodium saccharin, and h. The method according to claim 101, comprising approximately 4% by weight of glycerol dibehenate.

103. The method according to any one of claims 97 to 102, wherein the compound is administered to the subject in a unit dosage form containing about 50 mg of the compound.

104. The method according to any one of claims 97 to 102, wherein the compound is administered to the subject in a unit dosage form containing about 200 mg of the compound.

105. The method according to any one of claims 1 to 104, wherein approximately 50 mg to approximately 950 mg of the compound per dose is administered to the subject.

106. The method according to claim 105, wherein approximately 50 mg to approximately 150 mg of the compound per dose is administered to the subject.

107. The method according to claim 106, wherein approximately 100 mg of the compound per dose is administered to the subject.

108. The method according to claim 105, wherein approximately 250 mg to approximately 350 mg of the compound per dose is administered to the subject.

109. The method according to claim 108, wherein approximately 300 mg of the compound per dose is administered to the subject.

110. The method according to claim 105, wherein approximately 850 mg to approximately 950 mg of the compound per dose is administered to the subject.

111. The method according to claim 110, wherein approximately 900 mg of the compound per dose is administered to the subject.

112. The method according to any one of claims 1 to 97, wherein the compound is administered intravenously to the subject.

113. The method according to any one of claims 1 to 112, wherein the subject exhibits a reduction in the frequency of uterine contractions after administration of the compound to the subject.

114. The method according to claim 113, wherein the reduction is about 1% to about 20% of the measured frequency of uterine contractions of the subject recorded before administration of the compound to the subject.

115. The method according to any one of claims 1 to 114, wherein the subject is determined to have a serum progesterone (P4) concentration of less than 320 nM prior to the transfer of one or more embryos to the subject, and optionally, the subject is determined to have a serum P4 concentration of less than approximately 320 nM within 24 hours prior to the transfer of one or more embryos to the subject.

116. The method according to claim 115, wherein the subject is determined to exhibit a serum P4 concentration of 200 nM to 300 nM prior to the transfer of one or more embryos to the subject, and optionally, the subject is determined to exhibit a serum P4 concentration of approximately 200 nM to approximately 300 nM within 24 hours prior to the transfer of one or more embryos to the subject.

117. The method according to any one of claims 1 to 114, wherein the subject is determined to have a serum P4 concentration of less than 2.0 ng / ml prior to the transfer of one or more embryos to the subject, and optionally, the subject is determined to have a serum P4 concentration of less than 2.0 ng / ml approximately 1 to 7 days before the transfer of one or more embryos to the subject.

118. The method according to claim 117, wherein the subject is determined to have a serum P4 concentration of less than 2.0 ng / ml approximately two days before the transfer of one or more embryos to the subject.

119. The method according to claim 117, wherein the subject is determined to have a serum P4 concentration of less than 2.0 ng / ml approximately three days before the transfer of one or more embryos to the subject.

120. The method according to claim 117, wherein the subject is determined to have a serum P4 concentration of less than 2.0 ng / ml approximately four days before the transfer of one or more embryos to the subject.

121. The method according to claim 117, wherein the subject is determined to have a serum P4 concentration of less than 2.0 ng / ml approximately 5 days before the transfer of one or more embryos to the subject.

122. The method according to any one of claims 117 to 121, wherein the subject is determined to exhibit the serum P4 concentration immediately before the isolation of one or more oocytes or eggs from the subject.

123. The method according to claim 122, wherein it is determined that the subject exhibits the serum P4 concentration within approximately one hour after administration of hCG to the subject.

124. The method according to claim 117, wherein the subject is determined to have a serum P4 concentration of less than 1.5 ng / ml prior to the transfer of one or more embryos to the subject, and optionally, the subject is determined to have a serum P4 concentration of less than 1.5 ng / ml approximately 1 to 7 days before the transfer of one or more embryos to the subject.

125. The method according to claim 124, wherein the subject is determined to have a serum P4 concentration of less than 1.5 ng / ml approximately two days before the transfer of one or more embryos to the subject.

126. The method according to claim 124, wherein the subject is determined to have a serum P4 concentration of less than 1.5 ng / ml approximately three days before the transfer of one or more embryos to the subject.

127. The method according to claim 124, wherein the subject is determined to have a serum P4 concentration of less than 1.5 ng / ml approximately four days before the transfer of one or more embryos to the subject.

128. The method according to claim 124, wherein the subject is determined to have a serum P4 concentration of less than 1.5 ng / ml approximately 5 days before the transfer of one or more embryos to the subject.

129. The method according to any one of claims 124 to 128, wherein the subject is determined to exhibit the serum P4 concentration immediately before the isolation of one or more oocytes or eggs from the subject.

130. The method according to claim 129, wherein it is determined that the subject exhibits the serum P4 concentration within approximately one hour after administration of hCG to the subject.

131. The method according to any one of claims 1 to 130, wherein the subject exhibits an increase in the expression of endometrial prostaglandin F2α (PGF2α) after administration of the compound to the subject.

132. The method according to any one of claims 1 to 131, wherein the subject exhibits a reduction in PGF2α signaling after administration of the compound to the subject.

133. The method according to any one of claims 1 to 132, wherein the subject exhibits an increase in the expression of endometrial prostaglandin E2 (PGE2) after administration of the compound to the subject.

134. The method according to any one of claims 1 to 133, wherein the subject maintains pregnancy for at least about 14 days after the transfer of one or more embryos to the subject.

135. The method according to claim 134, wherein the subject maintains a pregnancy for at least about six weeks after the transfer of one or more embryos to the subject.

136. The method according to claim 135, wherein the subject maintains pregnancy for at least about 10 weeks after the retrieval of one or more embryos or eggs from the subject.

137. The method according to any one of claims 134 to 136, wherein pregnancy is evaluated by a blood pregnancy test.

138. The method according to claim 137, wherein the blood pregnancy test includes detecting hCG in a blood sample isolated from the subject.

139. The method according to claim 135 or 136, wherein pregnancy is assessed by detecting an intrauterine embryonic heartbeat.

140. The method according to any one of claims 1 to 139, wherein the subject maintains pregnancy and gives birth to a live child after administration of the compound to the subject.

141. The method according to claim 140, wherein the subject exhibits the birth of the offspring during a gestation period of at least approximately 24 weeks.

142. A kit containing an accompanying document and a compound represented by formula (I), 【Chemistry 11】 (I) or including its geometric isomers, enantiomers, diastereomers, racemic mixtures, or salts, In the formula, n is an integer between 1 and 3. R １ is hydrogen and C １ ~C ６ Selected from the group consisting of alkyl groups, R ２ is hydrogen, C １ ~C ６ Alkyl, C １ ~C ６ Alkylaryl, heteroaryl, C １ ~C ６ Alkyl heteroaryl, C ２ ~C ６ Alkenil, C ２ ~C ６ Alkenylaryl, C ２ ~C ６ Alkenyl heteroaryl, C ２ ~C ６ Alkinyl, C ２ ~C ６ Alkynylaryl, C ２ ~C ６ Alkinyl heteroaryl, C ３ ~C ６ Cycloalkyl, heterocycloalkyl, C １ ~C ６ Alkylcycloalkyl, C １ ~C ６ Alkyl heterocycloalkyl, C １ ~C ６ Alkylcarboxy, acyl, C １ ~C ６ Alkylacyl, C １ ~C ６ Alkylacyloxy, C １ ~C ６ Alkylalkoxy, alkoxycarbonyl, C １ ~C ６ Alkylalkoxycarbonyl, aminocarbonyl, C １ ~C ６ Alkylaminocarbonyl, C １ ~C ６ Alkyl acylamino, C １ ~C ６ Alkyl ureido, amino, C １ ~C ６ Alkylamino, sulfonyloxy, C １ ~C ６ Alkyl sulfonyl oxy, sulfonyl, C １ ~C ６ Alkylsulfonyl, sulfinyl, C １ ~C ６ Alkyl sulfinyl, C １ ~C ６ Alkyl sulfanyl, and C １ ~C ６ Selected from the group consisting of alkylsulfonylaminos, R ３ It is selected from the group consisting of aryls and heteroaryls, X is oxygen and NR ４ Selected from the group consisting of, R ４ is hydrogen, C １ ~C ６ Alkyl, C １ ~C ６ Alkylaryl, C １ ~C ６ Selected from the group consisting of alkylheteroaryl, aryl, and heteroaryl, R ２ and R ４ Together with the nitrogen atoms to which they are bonded, they can form a 5- to 8-membered saturated or unsaturated heterocycloalkyl ring. A kit wherein the accompanying documentation instructs the user of the kit to perform the method described in any one of claims 1 to 141.

143. The kit according to claim 142, wherein the compound is represented by formula (II). 【Chemistry 12】 (II)

144. The kit according to claim 142 or 143, wherein the compound is formulated for oral administration to the subject.

145. The kit according to claim 144, wherein the compound is formulated as a tablet, capsule, gel cap, powder, liquid solution, or liquid suspension.

146. The kit according to claim 145, wherein the compound is formulated as a tablet.

147. The kit according to claim 146, wherein the tablet is a powder tablet.

148. The kit according to any one of claims 142 to 147, wherein the compound is formulated in a unit dosage form containing about 50 mg of the compound.

149. The kit according to any one of claims 142 to 147, wherein the compound is formulated in a unit dosage form containing about 200 mg of the compound.

150. A method for treating a subject undergoing embryo transfer therapy, wherein the concentration of P4 in a sample isolated from the subject is determined, and the method is a. Comparing the concentration of P4 with the P4 reference level, b. If the concentration of P4 in the sample isolated from the subject is below the P4 reference level, administer a therapeutically effective dose of oxytocin antagonist to the subject, A method comprising implanting one or more embryos into the target uterus.

151. A method for treating a subject undergoing embryo transfer therapy, wherein the concentration of P4 in a sample isolated from the subject is determined, and the method is a. Comparing the concentration of P4 with the P4 reference level, b. If the concentration of P4 in the sample isolated from the subject is below the P4 reference level, administer a therapeutically effective dose of oxytocin antagonist to the subject, c. A method comprising implanting one or more embryos into the uterus of the subject.

152. A method for determining whether a subject undergoing embryo transfer therapy is likely to benefit from oxytocin antagonist therapy, wherein the concentration of P4 in a sample isolated from the subject is determined, the method comprising comparing the concentration of P4 to a P4 reference level, and identifying that the reduced concentration of P4 in the sample isolated from the subject relative to the P4 reference level indicates that the subject is likely to benefit from oxytocin antagonist therapy before, concurrently with, and / or after the transfer of one or more embryos to the subject.

153. A method for determining whether a subject undergoing embryo transfer therapy is likely to exhibit enhanced endometrial receptivity in response to oxytocin antagonist therapy, wherein the concentration of P4 in a sample isolated from the subject is determined, and the method comprises comparing the concentration of P4 to a P4 reference level, and identifying that the reduced concentration of P4 in the sample isolated from the subject relative to the P4 reference level indicates that the subject is likely to exhibit enhanced endometrial receptivity in response to oxytocin antagonist therapy before, simultaneously with, and / or after the transfer of one or more embryos to the subject.

154. The method according to claim 152 or 153, wherein if a reduced concentration of P4 is detected in the sample isolated from the subject relative to the P4 reference level, the method further comprises administering a therapeutically effective amount of oxytocin antagonist to the subject.

155. The method according to any one of claims 150, 151, and 154, wherein the administration reduces the possibility of embryo implantation failure.

156. The method according to any one of claims 150, 151, 154, and 155, wherein the oxytocin antagonist is administered to the subject before the transfer of one or more embryos into the subject's uterus.

157. The method according to claim 156, wherein the oxytocin antagonist is administered to the subject about 1 hour to about 24 hours before the transfer of one or more embryos to the subject.

158. The method according to claim 157, wherein the oxytocin antagonist is administered to the subject about 1 hour to about 8 hours before the transfer of one or more embryos to the subject.

159. The method according to claim 158, wherein the oxytocin antagonist is administered to the subject about 3 to 5 hours before the transfer of one or more embryos to the subject.

160. The method according to claim 159, wherein the oxytocin antagonist is administered to the subject about four hours before the transfer of one or more embryos to the subject.

161. The method according to any one of claims 156 to 160, wherein the oxytocin antagonist is administered to the subject in a single dose.

162. The method according to any one of claims 156 to 160, wherein the oxytocin antagonist is administered to the subject in multiple doses.

163. The method according to claim 162, wherein the oxytocin antagonist is administered to the subject in a dose of 1 to 20 times per day prior to the transfer of one or more embryos to the subject.

164. The method according to claim 163, wherein the oxytocin antagonist is administered to the subject in a dose of 1 to 7 times per day prior to the transfer of one or more embryos to the subject.

165. The method according to any one of claims 162 to 164, wherein the oxytocin antagonist is administered to the subject daily for about 1 to about 14 days prior to the transfer of one or more embryos to the subject.

166. The method according to claim 165, wherein the oxytocin antagonist is administered to the subject daily for about 3 to 11 days prior to the transfer of one or more embryos to the subject.

167. The method according to claim 166, wherein the oxytocin antagonist is administered to the subject daily for about seven days prior to the transfer of one or more embryos to the subject.

168. The method according to any one of claims 162 to 167, wherein the oxytocin antagonist is further administered to the subject at the same time as the transfer of one or more embryos to the subject.

169. The method according to any one of claims 162 to 168, wherein the oxytocin antagonist is further administered to the subject after the transfer of one or more embryos to the subject.

170. The method according to claim 168, wherein the oxytocin antagonist is further administered to the subject about 1 hour to about 24 hours after the transfer of one or more embryos to the subject.

171. The method according to claim 169 or 170, wherein the oxytocin antagonist is further administered to the subject in doses of 1 to 20 times per day after the transfer of one or more embryos to the subject.

172. The method according to claim 171, wherein the oxytocin antagonist is further administered to the subject in doses of 1 to 7 times per day after the transfer of one or more embryos to the subject.

173. The method according to any one of claims 170 to 172, wherein the oxytocin antagonist is further administered to the subject daily for about 1 to about 14 days after the transfer of one or more embryos to the subject.

174. The method according to claim 173, wherein the oxytocin antagonist is further administered to the subject daily for about 3 to 11 days after the transfer of one or more embryos to the subject.

175. The method according to claim 174, wherein the oxytocin antagonist is further administered to the subject daily for about seven days after the transfer of one or more embryos to the subject.

176. The method according to any one of claims 150, 151, 154, and 155, wherein the oxytocin antagonist is administered to the subject at the same time as the transfer of one or more embryos to the subject.

177. The method according to claim 176, wherein the oxytocin antagonist is administered to the subject in a single dose.

178. The method according to claim 176, wherein the oxytocin antagonist is administered to the subject in multiple doses.

179. The method according to any one of claims 150, 151, 154, and 155, wherein the oxytocin antagonist is administered to the subject after the transfer of one or more embryos to the subject.

180. The method according to claim 179, wherein the oxytocin antagonist is administered to the subject about 1 hour to about 24 hours after the transfer of one or more embryos to the subject.

181. The method according to claim 179 or 180, wherein the oxytocin antagonist is administered to the subject in a single dose.

182. The method according to claim 179 or 180, wherein the oxytocin antagonist is administered to the subject in multiple doses.

183. The method according to claim 182, wherein the oxytocin antagonist is administered to the subject in a dose of 1 to 20 times per day after the transfer of one or more embryos to the subject.

184. The method according to claim 183, wherein the oxytocin antagonist is administered to the subject in a dose of 1 to 7 times per day after the transfer of one or more embryos to the subject.

185. The method according to any one of claims 182 to 184, wherein the oxytocin antagonist is administered to the subject daily for about 1 to about 14 days after the transfer of one or more embryos to the subject.

186. The method according to claim 185, wherein the oxytocin antagonist is administered to the subject daily for about 3 to 11 days after the transfer of one or more embryos to the subject.

187. The method according to claim 186, wherein the oxytocin antagonist is administered to the subject daily for about seven days after the transfer of one or more embryos to the subject.

188. The method according to any one of claims 182 to 187, wherein the oxytocin antagonist is further administered to the subject at the same time as the transfer of one or more embryos to the subject.

189. The method according to any one of claims 182 to 188, wherein the oxytocin antagonist is further administered to the subject before the transfer of the one or more embryos to the subject.

190. The method according to claim 189, wherein the oxytocin antagonist is further administered to the subject about 1 hour to about 24 hours before the transfer of one or more embryos to the subject.

191. The method according to claim 190, wherein the oxytocin antagonist is further administered to the subject about 1 to 8 hours before the transfer of one or more embryos to the subject.

192. The method according to claim 191, wherein the oxytocin antagonist is further administered to the subject about 3 to 5 hours before the transfer of one or more embryos to the subject.

193. The method according to claim 192, wherein the oxytocin antagonist is further administered to the subject about four hours before the transfer of one or more embryos to the subject.

194. The method according to any one of claims 189 to 193, wherein the oxytocin antagonist is further administered to the subject in doses of 1 to 20 times per day prior to the transfer of one or more embryos to the subject.

195. The method according to claim 194, wherein the oxytocin antagonist is further administered to the subject in doses of 1 to 7 times per day prior to the transfer of one or more embryos to the subject.

196. The method according to any one of claims 183 to 195, wherein the oxytocin antagonist is further administered to the subject daily for about 1 to about 14 days prior to the transfer of one or more embryos to the subject.

197. The method according to claim 196, wherein the oxytocin antagonist is further administered to the subject daily for about 3 to about 11 days prior to the transfer of one or more embryos to the subject.

198. The method according to claim 197, wherein the oxytocin antagonist is further administered to the subject daily for about seven days prior to the transfer of one or more embryos to the subject.

199. The method according to any one of claims 150 to 198, wherein the sample isolated from the subject is a blood sample.

200. The method according to any one of claims 150, 151, and 154-199, wherein the administration of the oxytocin antagonist reduces the likelihood of the subject miscarrying after the transfer of one or more embryos.

201. The method according to any one of claims 150 to 200, wherein the embryo transfer therapy includes the transfer of one to two embryos to the subject.

202. The method according to claim 201, wherein one embryo is implanted into the subject.

203. The method according to claim 201, wherein two embryos are implanted into the subject.

204. The method according to any one of claims 150 to 203, wherein the subject is a mammal and the one or more embryos are mammalian embryos.

205. The method according to claim 204, wherein the mammal is a human, and the embryo of one or more mammals is a human embryo.

206. The method according to any one of claims 150 to 205, wherein one or more embryos are produced in vitro by IVF.

207. The method according to claim 206, wherein one or more embryos are produced in vitro by IVF of one or more oocytes derived from the subject.

208. The method according to any one of claims 150 to 205, wherein one or more embryos are produced in vitro by ICSI.

209. The method according to claim 208, wherein the one or more embryos are produced in vitro by ICSI of one or more oocytes derived from the subject.

210. The method according to claim 207 or 209, wherein the one or more eggs are derived from one or more oocytes isolated from the subject.

211. The method according to claim 210, wherein one or more oocytes are isolated from the subject about one to seven days before the transfer of one or more embryos to the subject.

212. The method according to claim 211, wherein one or more oocytes are isolated from the subject about two days before the transfer of one or more embryos to the subject.

213. The method according to claim 211, wherein one or more oocytes are isolated from the subject about three days before the transfer of one or more embryos to the subject.

214. The method according to claim 211, wherein one or more oocytes are isolated from the subject about four days before the transfer of one or more embryos to the subject.

215. The method according to claim 211, wherein one or more oocytes are isolated from the subject about five days before the transfer of one or more embryos to the subject.

216. The method according to any one of claims 210 to 215, wherein the one or more oocytes comprises one to four mature oocytes.

217. The method according to any one of claims 210 to 216, wherein a GnRH antagonist is administered to the subject before the isolation of one or more oocytes from the subject.

218. The method according to any one of claims 210 to 217, wherein hCG is administered to the subject before the isolation of one or more oocytes from the subject.

219. The method according to claim 218, wherein the hCG is administered to the subject by a single intravenous injection.

220. The method according to any one of claims 210 to 219, wherein progesterone is administered to the subject after isolation of one or more oocytes from the subject.

221. The method according to claim 220, wherein the progesterone is administered vaginally.

222. The method according to claim 220 or 221, wherein approximately 300 mg to approximately 600 mg of progesterone per dose is administered to the subject.

223. The method according to any one of claims 220 to 222, wherein the progesterone is administered to the subject daily, preferably starting within about 24 hours of the isolation of one or more oocytes from the subject and continuing for about 6 weeks or more after the transfer of one or more embryos to the subject.

224. The method according to claim 207 or 209, wherein one or more eggs are directly isolated from the subject.

225. The method according to claim 224, wherein one or more oocytes are isolated from the subject about one to seven days before the transfer of one or more embryos to the subject.

226. The method according to claim 225, wherein one or more oocytes are isolated from the subject about two days before the transfer of one or more embryos to the subject.

227. The method according to claim 225, wherein one or more oocytes are isolated from the subject about three days before the transfer of one or more embryos to the subject.

228. The method according to claim 225, wherein one or more oocytes are isolated from the subject about four days before the transfer of one or more embryos to the subject.

229. The method according to claim 225, wherein one or more oocytes are isolated from the subject about five days before the transfer of one or more embryos to the subject.

230. The method according to any one of claims 224 to 229, wherein a gonadotropin-releasing hormone (GnRH) antagonist is administered to the subject before the isolation of one or more oocytes from the subject.

231. The method according to any one of claims 224 to 230, wherein human chorionic gonadotropin (hCG) is administered to the subject before the isolation of one or more oocytes from the subject.

232. The method according to claim 231, wherein the hCG is administered to the subject by a single intravenous injection.

233. The method according to any one of claims 224 to 232, wherein progesterone is administered to the subject after the isolation of one or more eggs from the subject.

234. The method according to claim 233, wherein the progesterone is administered intravaginally.

235. The method according to claim 233 or 234, wherein approximately 300 mg to approximately 600 mg of progesterone per dose is administered to the subject.

236. The method according to any one of claims 233 to 235, wherein the progesterone is administered to the subject daily, preferably starting within about 24 hours of the isolation of one or more eggs from the subject and continuing for about 6 weeks or more after the transfer of one or more embryos to the subject.

237. The method according to any one of claims 210 to 223, wherein the one or more embryos are implanted into the subject during the same menstrual cycle as the isolation of the one or more oocytes from the subject.

238. The method according to any one of claims 224 to 236, wherein the one or more embryos are implanted into the subject during the same menstrual cycle as the isolation of the one or more eggs from the subject.

239. The method according to any one of claims 150 to 238, wherein one or more embryos are frozen and thawed before the transfer of one or more embryos to the target.

240. The method according to any one of claims 150 to 239, wherein each of the one or more embryos contains 6 to 8 blastomeres immediately before the transfer of the one or more embryos to the target.

241. The method according to claim 240, wherein the blastomeres are substantially equal in size when evaluated by visual microscopy.

242. The oxytocin antagonist is a compound represented by formula (I), 【Chemistry 13】 (I) or its geometric isomers, enantiomers, diastereomers, racemates, or salts, In the formula, n is an integer between 1 and 3. R １ is hydrogen and C １ ~C ６ Selected from the group consisting of alkyl groups, R ２ is hydrogen, C １ ~C ６ Alkyl, C １ ~C ６ Alkylaryl, heteroaryl, C １ ~C ６ Alkyl heteroaryl, C ２ ~C ６ Alkenil, C ２ ~C ６ Alkenylaryl, C ２ ~C ６ Alkenyl heteroaryl, C ２ ~C ６ Alkinyl, C ２ ~C ６ Alkynylaryl, C ２ ~C ６ Alkinyl heteroaryl, C ３ ~C ６ Cycloalkyl, heterocycloalkyl, C １ ~C ６ Alkylcycloalkyl, C １ ~C ６ Alkyl heterocycloalkyl, C １ ~C ６ Alkylcarboxy, acyl, C １ ~C ６ Alkylacyl, C １ ~C ６ Alkylacyloxy, C １ ~C ６ Alkylalkoxy, alkoxycarbonyl, C １ ~C ６ Alkylalkoxycarbonyl, aminocarbonyl, C １ ~C ６ Alkylaminocarbonyl, C １ ~C ６ Alkyl acylamino, C １ ~C ６ Alkyl ureido, amino, C １ ~C ６ Alkylamino, sulfonyloxy, C １ ~C ６ Alkyl sulfonyl oxy, sulfonyl, C １ ~C ６ Alkylsulfonyl, sulfinyl, C １ ~C ６ Alkyl sulfinyl, C １ ~C ６ Alkyl sulfanyl, and C １ ~C ６ Selected from the group consisting of alkylsulfonylaminos, R ３ It is selected from the group consisting of aryls and heteroaryls, X is oxygen and NR ４ Selected from the group consisting of, R ４ is hydrogen, C １ ~C ６ Alkyl, C １ ~C ６ Alkylaryl, C １ ~C ６ Selected from the group consisting of alkylheteroaryl, aryl, and heteroaryl, R ２ and R ４ The method according to any one of claims 150 to 241, wherein the atoms, together with the nitrogen to which they are bonded, can form a 5- to 8-membered saturated or unsaturated heterocycloalkyl ring.

243. The method according to claim 242, wherein the oxytocin antagonist is a compound represented by formula (II). 【Chemistry 14】 (II)

244. The method according to claim 243, wherein the compound is in a crystalline state.

245. The method according to claim 244, wherein the compound exhibits characteristic X-ray powder diffraction peaks at approximately 7.05°²θ, approximately 13.13°²θ, and approximately 23.34°²θ.

246. The method according to any one of claims 242 to 245, wherein the compound is administered orally to the subject.

247. The method according to claim 246, wherein the compound is administered to the subject in the form of a tablet, capsule, gel cap, powder, liquid solution, or liquid suspension.

248. The method according to claim 247, wherein the compound is administered to the subject in the form of a tablet.

249. The method according to claim 248, wherein the tablet is a dispersible tablet.

250. The aforementioned dispersible tablet, a. Approximately 1-20% by weight of calcium silicate, b. Approximately 0.1 to 20% by weight of PVP30K, c. Approximately 0.01 to 5% by weight of poloxamer 188, d. Approximately 0.5 to 20% by weight of croscarmellose sodium, e. Approximately 1-90% by weight of microcrystalline cellulose 112, f. Approximately 1-90% by weight of lactose monohydrate. g. Approximately 0.01 to 0.5% by weight of sodium saccharin, and h. The method according to claim 249, comprising about 0.1 to 10% by weight of glycerol dibehenate.

251. The aforementioned dispersible tablet, a. Approximately 5% by weight of calcium silicate, b. Approximately 1% by weight of PVP30K, c. Approximately 2% by weight of poloxamer 188, d. Approximately 5% by weight of croscarmellose sodium, e. Approximately 1.5% by weight of microcrystalline cellulose 112, f. Approximately 47.8% by weight of lactose monohydrate, g. Approximately 0.2% by weight of sodium saccharin, and h. The method according to claim 250, comprising approximately 4% by weight of glycerol dibehenate.

252. The method according to any one of claims 246 to 251, wherein the compound is administered to the subject in a unit dosage form containing about 50 mg of the compound.

253. The method according to any one of claims 246 to 251, wherein the compound is administered to the subject in a unit dosage form containing about 200 mg of the compound.

254. The method according to any one of claims 242 to 253, wherein approximately 50 mg to approximately 950 mg of the compound per dose is administered to the subject.

255. The method according to claim 254, wherein approximately 50 mg to approximately 150 mg of the compound per dose is administered to the subject.

256. The method according to claim 255, wherein approximately 100 mg of the compound per dose is administered to the subject.

257. The method according to claim 254, wherein approximately 250 mg to approximately 350 mg of the compound per dose is administered to the subject.

258. The method according to claim 257, wherein approximately 300 mg of the compound per dose is administered to the subject.

259. The method according to claim 254, wherein approximately 850 mg to approximately 950 mg of the compound per dose is administered to the subject.

260. The method according to claim 259, wherein approximately 900 mg of the compound per dose is administered to the subject.

261. The method according to claim 242 or 243, wherein the compound is administered intravenously to the subject.

262. The method according to any one of claims 150 to 241, wherein the oxytocin antagonist is epersiban.

263. The method according to any one of claims 150 to 241, wherein the oxytocin antagonist is letsiban.

264. The method according to any one of claims 150 to 241, wherein the oxytocin antagonist is atosiban.

265. The method according to any one of claims 150 to 241, wherein the oxytocin antagonist is valsivan.

266. The method according to any one of claims 262 to 265, wherein the oxytocin antagonist is orally administered to the subject.

267. The method according to any one of claims 262 to 265, wherein the oxytocin antagonist is administered intravenously to the subject.

268. The method according to any one of claims 150 to 267, wherein the P4 reference level is approximately 1.0 ng / ml to approximately 2.0 ng / ml.

269. The method according to claim 268, wherein the P4 reference level is 1.5 ng / ml.

270. The method according to claim 268 or 269, wherein the sample is isolated from the subject about 1 to 7 days before the transfer of one or more embryos to the subject.

271. The method according to claim 270, wherein the sample is isolated from the subject about two days before the transfer of one or more embryos to the subject.

272. The method according to claim 270, wherein the sample is isolated from the subject about three days before the transfer of one or more embryos to the subject.

273. The method according to claim 270, wherein the sample is isolated from the subject about four days before the transfer of one or more embryos to the subject.

274. The method according to claim 270, wherein the sample is isolated from the subject about five days before the transfer of one or more embryos to the subject.

275. The method according to any one of claims 268 to 274, wherein the sample is isolated from the subject up to 24 hours before the isolation of one or more oocytes from the subject.

276. The method according to claim 275, wherein the sample is isolated from the subject immediately before the isolation of one or more oocytes from the subject.

277. The method according to any one of claims 268 to 274, wherein the sample is isolated from the subject up to 24 hours before the isolation of one or more oocytes from the subject.

278. The method according to claim 277, wherein the sample is isolated from the subject immediately before the isolation of one or more eggs from the subject.

279. The method according to any one of claims 275 to 278, wherein the sample is isolated from the subject within approximately one hour after administering hCG to the subject.

280. The method according to any one of claims 150 to 267, wherein the P4 reference level is approximately 200 nM to approximately 400 nM.

281. The method according to claim 280, wherein the P4 reference level is 320 nM.

282. The method according to claim 280 or 281, wherein the sample is isolated from the subject up to 24 hours before the transfer of one or more embryos to the subject.

283. The method according to claim 282, wherein the sample is isolated from the subject immediately before the transfer of one or more embryos to the subject.

284. The method according to any one of claims 150, 151, and 154 to 283, wherein the subject exhibits an increase in endometrial PGF2α expression after administration of the oxytocin antagonist to the subject.

285. The method according to any one of claims 150, 151, and 154 to 284, wherein the subject exhibits a reduction in PGF2α signaling after administration of the oxytocin antagonist to the subject.

286. The method according to any one of claims 150, 151, and 154 to 285, wherein the subject exhibits increased expression of PGE2 after administration of the oxytocin antagonist to the subject.

287. The method according to any one of claims 150, 151, and 154-286, wherein the subject maintains pregnancy for at least about 14 days after the transfer of one or more embryos to the subject.

288. The method according to claim 287, wherein the subject maintains a pregnancy for at least about six weeks after the transfer of one or more embryos to the subject.

289. The method according to claim 288, wherein the subject maintains pregnancy for at least about 10 weeks after the retrieval of one or more embryos or eggs from the subject.

290. The method according to any one of claims 287 to 289, wherein pregnancy is evaluated by a blood pregnancy test.

291. The method according to claim 290, wherein the blood pregnancy test includes detecting hCG in a blood sample isolated from the subject.

292. The method according to claim 288 or 289, wherein pregnancy is assessed by detecting an intrauterine embryonic heartbeat.

293. The method according to any one of claims 150, 151, and 154 to 292, wherein the subject maintains pregnancy and gives birth to a live child after administration of the compound to the subject.

294. The method according to claim 293, wherein the subject exhibits the birth of the offspring during a gestation period of at least approximately 24 weeks.

295. A kit comprising an instruction leaflet and an oxytocin antagonist, wherein the instruction leaflet instructs the user of the kit to perform the method according to any one of claims 150 to 294.

296. The oxytocin antagonist is a compound represented by formula (I), 【Chemistry 15】 (I) or its geometric isomers, enantiomers, diastereomers, racemates, or salts, In the formula, n is an integer between 1 and 3. R １ is hydrogen and C １ ~C ６ Selected from the group consisting of alkyl groups, R ２ is hydrogen, C １ ~C ６ Alkyl, C １ ~C ６ Alkylaryl, heteroaryl, C １ ~C ６ Alkyl heteroaryl, C ２ ~C ６ Alkenil, C ２ ~C ６ Alkenylaryl, C ２ ~C ６ Alkenyl heteroaryl, C ２ ~C ６ Alkinyl, C ２ ~C ６ Alkynylaryl, C ２ ~C ６ Alkinyl heteroaryl, C ３ ~C ６ Cycloalkyl, heterocycloalkyl, C １ ~C ６ Alkylcycloalkyl, C １ ~C ６ Alkyl heterocycloalkyl, C １ ~C ６ Alkylcarboxy, acyl, C １ ~C ６ Alkylacyl, C １ ~C ６ Alkylacyloxy, C １ ~C ６ Alkylalkoxy, alkoxycarbonyl, C １ ~C ６ Alkylalkoxycarbonyl, aminocarbonyl, C １ ~C ６ Alkylaminocarbonyl, C １ ~C ６ Alkyl acylamino, C １ ~C ６ Alkyl ureido, amino, C １ ~C ６ Alkylamino, sulfonyloxy, C １ ~C ６ Alkyl sulfonyl oxy, sulfonyl, C １ ~C ６ Alkylsulfonyl, sulfinyl, C １ ~C ６ Alkyl sulfinyl, C １ ~C ６ Alkyl sulfanyl, and C １ ~C ６ Selected from the group consisting of alkylsulfonylaminos, R ３ It is selected from the group consisting of aryls and heteroaryls, X is oxygen and NR ４ Selected from the group consisting of, R ４ is hydrogen, C １ ~C ６ Alkyl, C １ ~C ６ Alkylaryl, C １ ~C ６ Selected from the group consisting of alkylheteroaryl, aryl, and heteroaryl, R ２ and R ４ The kit according to claim 295, wherein the atoms, together with the nitrogen atoms to which they are bound, can form a 5- to 8-membered saturated or unsaturated heterocycloalkyl ring.

297. The kit according to claim 296, wherein the compound is represented by formula (II). 【Chemistry 16】 (II)

298. The kit according to claim 295, wherein the oxytocin antagonist is epersiban.

299. The kit according to claim 295, wherein the oxytocin antagonist is letsiban.

300. The kit according to claim 295, wherein the oxytocin antagonist is valsivan.

301. The kit according to claim 295, wherein the oxytocin antagonist is atosiban.

302. A method for treating a subject undergoing embryo transfer therapy, the method comprising administering to the subject a therapeutically effective amount of a compound represented by formula (II), 【Chemistry 17】 (II) The compound is administered to the subject 3 to 5 hours before implanting one or more embryos into the subject's uterus, wherein the administration of the compound reduces the possibility of embryo implantation failure.

303. The method according to claim 302, wherein the compound is administered to the subject about four hours before the transfer of one or more embryos into the subject's uterus.

304. The method according to claim 302, wherein the one or more embryos are produced in vitro by IVF or ICSI using one or more oocytes isolated from the subject, and the subject is determined to have a serum P4 concentration of less than 1.5 ng / ml up to 24 hours prior to the isolation of the one or more oocytes from the subject.

305. The method according to claim 304, wherein one or more oocytes are isolated from the subject about three to five days before the transfer of one or more embryos to the subject.

306. The method according to claim 305, wherein the compound is administered to the subject in a total amount of 100 mg, 300 mg, or 900 mg prior to the transfer of one or more embryos into the subject's uterus.

307. A method for treating a subject undergoing embryo transfer therapy, wherein the concentration of P4 in a blood sample isolated from the subject is determined, and the method is a. Comparing the concentration of P4 with the P4 reference level, b. If the concentration of P4 in the sample isolated from the subject is below the P4 reference level, administer a therapeutically effective dose of oxytocin antagonist to the subject, A method comprising: implanting one or more embryos into the uterus of the subject; producing the one or more embryos in vitro by IVF or ICSI using one or more oocytes isolated from the subject; having a P4 reference level of 1.5 ng / ml; and being isolated from the subject up to 24 hours prior to the isolation of the one or more oocytes from the subject.

308. The method according to claim 307, wherein one or more oocytes are isolated from the subject about three to five days before the transfer of one or more embryos to the subject.

309. A method for determining whether a subject undergoing embryo transfer therapy is likely to benefit from oxytocin antagonist therapy, wherein the concentration of P4 in a blood sample isolated from the subject is determined, the method comprising comparing the concentration of P4 to a P4 reference level, the reduced concentration of P4 in the sample isolated from the subject relative to the P4 reference level identifies that the subject is likely to benefit from oxytocin antagonist therapy before, concurrently with, and / or after the transfer of one or more embryos to the subject, the one or more embryos being produced in vitro by IVF or ICSI using one or more oocytes isolated from the subject, the P4 reference level being 1.5 ng / ml, and the sample being isolated from the subject up to 24 hours prior to the isolation of the one or more oocytes from the subject.

310. The method according to claim 307 or 309, wherein the oxytocin antagonist is a compound represented by formula (II). [Chemistry 18] (II)

311. The method according to claim 307 or 309, wherein the oxytocin antagonist is selected from the group consisting of epersiban, letosiban, barsiban, and atosiban.

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