Compositions and uses thereof for treating insomnia

Abstract

Provided are methods and compositions for treating insomnia, comprising administering a composition comprising a compound of formula A or formula I (e.g., anordrin), or a pharma- ceutically acceptable salt or ester thereof. In some embodiments, the compound is anordrin. In some embodiments according to any one of the above methods, the individual is in the perimenopausal stage, has reached menopause, is postmenopausal, or has undergone surgical removal of ovaries. In some embodiments, the individual is a postmenopausal woman.

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to International Application No. PCT / CN2021 / 095700, filed May 25, 2021, the contents of which are incorporated by reference in their entirety for all purposes.

[0002] The present invention relates to methods and compositions for treating insomnia. [Background technology]

[0003] Sleep is essential to health and quality of life. Insomnia is a growing health problem worldwide. Insomnia is a condition characterized by difficulty falling asleep (sleep onset), frequent awakenings during the night (fragmented sleep), early awakenings (early final awakening), and / or waking feeling unrefreshed. In the National Sleep Foundation's (NSF) Sleep in America Poll 2005, 42% of survey respondents reported waking frequently during the night, 22% of adults waking too early and unable to get back to sleep, and 38% reported feeling unrefreshed when they awaken.

[0004] Estrogen is a hormone that regulates human reproductive development and metabolism. For example, women who have undergone oophorectomy and postmenopausal symptoms with reduced blood estrogen levels develop autonomic organ dysfunction or atrophy symptoms. Most notably, these include hot flashes, mood disorders, insomnia, and sleep-disordered breathing. In general, postmenopausal women are less satisfied with their sleep, with as many as 61% of women reporting symptoms of insomnia.

[0005] Treatment with estrogen (estrogen replacement therapy, ERT) or estrogen and progesterone (hormone replacement therapy, HRT) has been found to help relieve menopausal symptoms. However, a recent large U.S. government-funded study, the Women's Health Initiative, was halted due to safety concerns after it was found that taking HRT may put women at risk for cardiovascular disease and dementia. It was also widely recognized that estrogen treatment may cause hormone-induced cancers, such as breast and endometrial cancer.

[0006] The disclosures of all publications, patents, patent applications, and published patent applications mentioned herein are hereby incorporated by reference in their entirety. Summary of the Invention [Means for solving the problem]

[0007] The present application provides a method of treating insomnia in an individual, comprising administering to the individual an effective amount of a composition comprising a compound of formula I described herein (e.g., anordrin), or a pharma- ceutically acceptable salt or ester thereof. In some embodiments, the compound is anordrin.

[0008] The present application, in one aspect, provides a method of treating insomnia in an individual, comprising administering to the individual a compound of formula I [ka] or a pharma- ceutically acceptable salt or ester thereof, 2 Carbon with R 3 Between the carbon [ka] represents a single bond, and R 3 Carbon with R 4 Between the carbon [ka] represents a single bond, and R 2 and R 4 is independently selected from the group consisting of hydrogen, hydroxyl, mercaptan, keto, and C1-C3 alkyl; R 3 is selected from the group consisting of hydrogen, hydroxyl, mercaptan, and C1-C3 alkyl, or R 2 Carbon with R 3 Between the carbon [ka] represents a double bond, and R 3 Carbon with R 4 Between the carbon [ka] represents a single bond, and R 2 is selected from the group consisting of hydrogen, hydroxyl, mercaptan, and C1-C3 alkyl; R 3 does not exist, and R 4 is selected from the group consisting of hydrogen, hydroxyl, mercaptan, keto, and C1-C3 alkyl, or R 2 Carbon with R 3 Between the carbon [ka] represents a single bond, and R 3 Carbon with R 4 Between the carbon [ka] represents a double bond, and R 2 is selected from the group consisting of hydrogen, hydroxyl, mercaptan, keto, and C1-C3 alkyl; R 3 does not exist, and R 4 is selected from the group consisting of hydrogen, hydroxyl, mercaptan, and C1-C3 alkyl; b) R 1 is C1-C3 alkyl, and c) R 5, R 7 , R 8 , R 12 , R 13 and R 14 is independently selected from the group consisting of hydrogen, hydroxyl, mercaptan, keto, and C1-C3 alkyl; d) R 6 is selected from the group consisting of hydrogen, hydroxyl, mercaptan, and C1-C3 alkyl; e) R 9 is hydrogen and -C(=O)R 9a f) R 10 is hydrogen and -C(=O)R 10a g) R 9a and R 10a is independently selected from the group consisting of C1-C6 alkyl and C2-C6 alkenyl, wherein C1-C6 alkyl and C2-C6 alkenyl are optionally substituted with -C(=O)OH; h) R 11 is selected from the group consisting of C1-C3 alkyl. 9 and R 10 is independently hydrogen or -C(=O)CH2CH3. In some embodiments, R 1 and R 11 In some embodiments, one or both of R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 12 , R 13 , and R 14 Any one or more of is hydrogen.

[0009] In some embodiments according to any one of the above methods, the compound is anordrin.

[0010] In some embodiments according to any one of the above methods, the individual is female.

[0011] In some embodiments according to any one of the above methods, the individual is a human.

[0012] In some embodiments of any one of the above methods, the individual is in the perimenopausal stage, has reached menopause, is postmenopausal, or has undergone surgical removal of the ovaries. In some embodiments, the individual is a postmenopausal woman.

[0013] In some embodiments according to any one of the above methods, the individual has low levels of estrogen.

[0014] In some embodiments of any one of the above methods, the individual has a score of at least about 7 on the Athens Insomnia Scale.

[0015] In some embodiments according to any one of the above methods, the individual has a score of at least about 11 on the Pittsburgh sleep quality index (PSQI).

[0016] In some embodiments of any one of the above methods, insomnia is assessed with another sleep disorder questionnaire (SDQ), such as the Epworth Sleeping Scale. In some embodiments, insomnia is assessed with a sleep monitor.

[0017] In some embodiments according to any one of the above methods, the individual is not undergoing or has never undergone hormone therapy.

[0018] In some embodiments according to any one of the above methods, the dose of the compound for each administration is at least about 20 μg in humans, or an equivalent dose in non-human individuals. In some embodiments, the dose of the compound for each administration is at least about 50 μg in humans, or an equivalent dose in non-human individuals. In some embodiments, the dose of the compound for each administration is at least about 100 μg in humans, or an equivalent dose in non-human individuals. In some embodiments, the dose of the compound for each administration is at least about 150 μg in humans, or an equivalent dose in non-human individuals.

[0019] In some embodiments according to any one of the above methods, the dose of compound for each administration is no more than 1 mg in humans, or an equivalent dose in non-human individuals.

[0020] In some embodiments according to any one of the above methods, the dose of the compound for each administration is about 20 μg to about 2 mg in humans, or an equivalent dose in non-human individuals. In some embodiments, the dose of the compound for each administration is about 20 μg to about 200 μg in humans, or an equivalent dose in non-human individuals. In some embodiments, the dose of the compound for each administration is about 400 μg to about 2 mg in humans, or an equivalent dose in non-human individuals.

[0021] In some embodiments according to any one of the above methods, the composition is administered at a frequency of about once every two weeks to about three times a day. In some embodiments, the composition is administered daily. In some embodiments, the composition is administered daily at a dosage of about 20 μg to about 200 μg (e.g., about 50 μg, about 100 μg, or about 150 μg). In some embodiments, the composition is administered weekly. In some embodiments, the composition is administered weekly at a dosage of about 400 μg to about 2 mg.

[0022] In some embodiments according to any one of the above methods, the composition is administered intravenously, intraarterially, intraperitoneally, intravesically, subcutaneously, intrathecally, intrapulmonary, intramuscularly, intratracheally, intraocularly, transdermally, orally, or by inhalation. In some embodiments, the composition is administered orally.

[0023] In some embodiments according to any one of the above methods, the method further comprises administering a second agent.

[0024] In some embodiments according to any one of the above methods, the method further comprises assessing estrogen levels in the individual.

[0025] In some embodiments according to any one of the above methods, the insomnia is chronic insomnia.

[0026] In another aspect of the present application, there is provided a unit dosage form for treating insomnia, comprising: a) a composition comprising a compound of formula I, wherein the amount of the compound ranges from about 20 μg to about 2 mg; and b) a pharma- ceutically acceptable carrier.

[0027] In another aspect of the present application, there is provided the use of a composition comprising an effective amount of a compound of formula I (eg, anordrin) for treating insomnia.

[0028] In another embodiment of the present application, there is provided a composition comprising a compound of formula I (eg, anordrin) for treating insomnia.

[0029] In another aspect of the present application, a kit is provided that includes: a) a composition comprising a compound of formula I; and b) instructions for using the kit to treat insomnia. [Brief description of the drawings]

[0030] [Figure 1] 1 shows an exemplary diagnostic procedure for chronic insomnia.

[0031] [Diagram 2] 1 shows an exemplary table for self-assessment of insomnia using the Athens Insomnia Scale (AIS).

[0032] [Diagram 3] The change in AIS number after treatment with Anordrin is shown.

[0033] [Figure 4] 1 shows various formulas exemplified in this application.

[0034] [Diagram 5] 1 shows that anordrin induces an ATP surge in neuronal cell cultures. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0035] The present application provides methods and compositions for treating insomnia. In some embodiments, the present application provides compositions and methods of using the compositions for treating insomnia in an individual, the compositions comprising a compound of formula A: [ka]

[0036] or a pharma- ceutically acceptable salt or ester thereof, 2 Carbon with R 3 Between the carbon [ka] represents a single bond, and R 3 Carbon with R 4 Between the carbon [ka] represents a single bond, and R 2 and R 4 is independently selected from the group consisting of hydrogen, hydroxyl, mercaptan, keto, and C1-C3 alkyl; R 3is selected from the group consisting of hydrogen, hydroxyl, mercaptan, and C1-C3 alkyl, or R 2 Carbon with R 3 Between the carbon [ka] represents a double bond, and R 3 Carbon with R 4 Between the carbon [ka] represents a single bond, and R 2 is selected from the group consisting of hydrogen, hydroxyl, mercaptan, and C1-C3 alkyl; R 3 does not exist, and R 4 is selected from the group consisting of hydrogen, hydroxyl, mercaptan, keto, and C1-C3 alkyl, or R 2 Carbon with R 3 Between the carbon [ka] represents a single bond, and R 3 Carbon with R 4 Between the carbon [ka] represents a double bond, and R 2 is selected from the group consisting of hydrogen, hydroxyl, mercaptan, keto, and C1-C3 alkyl; R 3 does not exist, and R 4 is selected from the group consisting of hydrogen, hydroxyl, mercaptan, and C1-C3 alkyl; b) R 1 is C1-C3 alkyl, and c) R 5 , R 7 , R 8 , R 12 , R 13 and R 14 is independently selected from the group consisting of hydrogen, hydroxyl, mercaptan, keto, and C1-C3 alkyl; d) R 6is selected from the group consisting of hydrogen, hydroxyl, mercaptan, and C1-C3 alkyl; e) R 9 is hydrogen and -C(=O)R 9a f) R 10 is hydrogen and -C(=O)R 10a g) R 9a and R 10a is independently selected from the group consisting of C1-C6 alkyl and C2-C6 alkenyl, wherein C1-C6 alkyl and C2-C6 alkenyl are optionally substituted with -C(=O)OH; h) R 11 is selected from the group consisting of hydrogen and C1-C3 alkyl. 11 is hydrogen or CH. In some embodiments, R 11 is CH3. In some embodiments, R 11 is hydrogen. In some embodiments, R 9a is -CH2CH3, and / or R 10a is -CH2CH3. In some embodiments, the method comprises administering to the individual anordrin or an analog thereof.

[0037] In some embodiments, the present application provides compositions and methods of use thereof for treating insomnia in an individual, the composition comprising a compound of formula (I): [ka] or a pharma- ceutically acceptable salt or ester thereof, 2 Carbon with R 3 Between the carbon [ka] represents a single bond, and R 3 Carbon with R 4 Between the carbon [ka] represents a single bond, and R 2 and R4 is independently selected from the group consisting of hydrogen, hydroxyl, mercaptan, keto, and C1-C3 alkyl; R 3 is selected from the group consisting of hydrogen, hydroxyl, mercaptan, and C1-C3 alkyl, or R 2 Carbon with R 3 Between the carbon [ka] represents a double bond, and R 3 Carbon with R 4 Between the carbon [ka] represents a single bond, and R 2 is selected from the group consisting of hydrogen, hydroxyl, mercaptan, and C1-C3 alkyl; R 3 does not exist, and R 4 is selected from the group consisting of hydrogen, hydroxyl, mercaptan, keto, and C1-C3 alkyl, or R 2 Carbon with R 3 Between the carbon [ka] represents a single bond, and R 3 Carbon with R 4 Between the carbon [ka] represents a double bond, and R 2 is selected from the group consisting of hydrogen, hydroxyl, mercaptan, keto, and C1-C3 alkyl; R 3 does not exist, and R 4 is selected from the group consisting of hydrogen, hydroxyl, mercaptan, and C1-C3 alkyl; b) R 1 is C1-C3 alkyl, and c) R 5 , R 7 , R 8 , R 12 , R 13 and R14 is independently selected from the group consisting of hydrogen, hydroxyl, mercaptan, keto, and C1-C3 alkyl; d) R 6 is selected from the group consisting of hydrogen, hydroxyl, mercaptan, and C1-C3 alkyl; e) R 9 is hydrogen and -C(=O)R 9a f) R 10 is hydrogen and -C(=O)R 10a g) R 9a and R 10a is independently selected from the group consisting of C1-C6 alkyl and C2-C6 alkenyl, wherein C1-C6 alkyl and C2-C6 alkenyl are optionally substituted with -C(=O)OH; h) R 11 is selected from the group consisting of C1-C3 alkyl. 11 is CH3. In some embodiments, R 9a is -CH2CH3, and / or R 10a is -CH2CH3. In some embodiments, the method comprises administering to the individual anordrin or an analog thereof.

[0038] The present application is based at least in part on the remarkable beneficial effect in the treatment of insomnia in postmenopausal women under the treatment of representative compound anordrin. Anordrin is one of the selective estrogen receptor modulators (SERMs), which are a class of synthetic nonsteroidal drugs with various estrogen agonist and antagonist activities in different tissues. How different SERMs act as estrogen agonists in some tissues and as estrogen antagonists in other tissues has not been clearly established to date. Most of the various SERMs that have been intensively tested do not have any known effect in the treatment of insomnia. See Pinkerton et al.J Steroid Biochem Mol Biol.2014 Jul;142:142-54. The present application shows that 100% of postmenopausal women with insomnia treated with various doses of anordrin showed significant improvement in sleep. See Example 1. Additionally, Anordrin has a good safety profile and can be used for extended periods of time. For at least these reasons, the compositions and methods described herein provide an ideal solution for women who have low estrogen levels and suffer from insomnia.

[0039] definition The term "effective amount" as used herein refers to a sufficient amount of a compound or composition to treat a particular disorder, condition or disease, such as relieving, temporarily relieving, reducing, and / or delaying one or more of the symptoms. With respect to insomnia, in some embodiments, an effective amount includes an amount sufficient to cause a decrease in 1) Athens Insomnia Scale (AIS) score (e.g., a decrease in self-assessed AIS score after treatment compared to before treatment), 2) Pittsburgh Sleep Quality Index (PSQI) score (e.g., a decrease in self-assessed PSQI score after treatment compared to before treatment), 3) the degree of insomnia reflected in other sleep disorder questionnaires (SDQ) (e.g., Epworth Sleep Scale), 4) the Sleep Dysfunction Rating Scale (SDRS) by a sleep monitor, or 5) or prevent insomnia.

[0040] The term "individual" refers to a mammal, including a human. An individual includes, but is not limited to, a human, a cow, a horse, a cat, a dog, a rodent, or a primate. In some embodiments, an individual is a human.

[0041] As used herein, "pharmacologically acceptable" or "pharmacologically compatible" means a substance that is biologically or otherwise undesirable, e.g., a substance may be incorporated into a pharmaceutical composition administered to a patient without causing any significant undesirable biological effects or interacting in a deleterious manner with any of the other components of the composition in which it is contained. A pharma-ceutically acceptable carrier or excipient preferably has met the necessary standards of toxicological and manufacturing testing and / or is included in the Inactive Ingredients Guide prepared by the U.S. Food and Drug Administration.

[0042] An "alkyl" is a straight-chain or branched saturated hydrocarbon. For example, an alkyl group can have 1 to 12 carbon atoms (i.e., C1 to C6). 12 alkyl)) or 1 to 10 carbon atoms (i.e., (C1-C 10The alkyl group may have 1 to 8 carbon atoms (i.e., (C1-C8 alkyl)), or 1 to 6 carbon atoms (i.e., (C1-C6 alkyl)), or 1 to 4 carbon atoms (i.e., (C1-C4 alkyl). Examples of suitable alkyl groups include methyl (Me, -CH3), ethyl (Et, -CH2CH3), 1-propyl (n-Pr, n-propyl, -CH2CH2CH3), 2-propyl (i-Pr, i-propyl, isopropyl, -CH(CH3)2), 1- Butyl (n-Bu, n-butyl, -CH2CH2CH2CH3), 2-methyl-1-propyl (i-Bu, i-butyl, -CH2CH(CH3)2), 2-butyl (s-Bu, s-butyl, -CH(CH3)CH2CH3), 2-methyl-2-propyl (t-Bu, t-butyl, -C(CH3)3), 1-pentyl (n-pentyl, -CH2CH2CH2CH2CH3), 2-pentyl (-CH(CH3)CH2CH2CH3), 3-pentyl (-CH(CH2CH3)2), 2-methyl-2-bu ethyl (-C(CH3)2CH2CH3), 3-methyl-2-butyl (-CH(CH3)CH(CH3)2), 3-methyl-1-butyl (-CH2CH2CH(CH3)2), 2-methyl-1-butyl (-CH2CH(CH3)CH2CH3), 1-hexyl (-CH2CH2CH2CH2CH2CH3), 2-hexyl (-CH(CH3)CH2CH2CH2CH3), 3-hexyl (-CH(CH2CH3)(CH2CH2CH3)), 2-methyl-2-pentyl (-C(CH3)2CH2CH 2CH3), 3-methyl-2-pentyl (-CH(CH3)CH(CH3)CH2CH3), 4-methyl-2-pentyl (-CH(CH3)CH2CH(CH3)2), 3-methyl-3-pentyl (-C(CH3)(CH2CH3)2), 2-methyl-3-pentyl (-CH(CH2CH3)CH(CH3)2), 2,3-dimethyl-2-butyl (-C(CH3)2CH(CH3)2), and 3,3-dimethyl-2-butyl (-CH(CH3)C(CH3)3. x Alkyl refers to an alkyl group having x carbon atoms.

[0043] "Alkenyl" refers to a straight or branched chain hydrocarbon having at least one carbon-carbon double bond. For example, an alkenyl group can be an alkyl group having 2 to 12 carbon atoms (i.e., C2 to C4). 12 alkenyl), or 2 to 10 carbon atoms (i.e., C2 to C 10 alkenyl), or 2 to 8 carbon atoms (i.e., C2-C8 alkenyl), or 2 to 6 carbon atoms (i.e., C2-C6 alkenyl), or 2 to 4 carbon atoms (i.e., C2-C4 alkenyl). Examples of suitable alkenyl groups include, but are not limited to, ethylene or vinyl (-CH=CH2), allyl (-CH2CH=CH2), and 5-hexenyl (-CH2CH2CH2CH2CH=CH2). C x Alkenyl refers to an alkenyl group having x carbon atoms.

[0044] "Hydroxyl" refers to an --OH moiety.

[0045] "Keto" refers to the (=O) moiety.

[0046] "Mercaptan" refers to an -SH moiety.

[0047] The term "optionally substituted" as used throughout this specification means that a group may be unsubstituted or substituted with one or more (e.g., one, two, or three) of the substituents listed for that group. For example, "C1-C6 alkyl optionally substituted with -C(=O)OH" means that the C1-C6 alkyl may be, but need not be, substituted with -C(=O)OH. In one embodiment, an optionally substituted group has one substituent. In one embodiment, an optionally substituted group has two substituents. In one embodiment, an optionally substituted group is unsubstituted.

[0048] It will be understood that aspects and embodiments of the invention described herein include aspects and embodiments that "consist of" and / or "consist essentially of".

[0049] References herein to "about" a value or parameter include (and account for) the variation about that value or parameter itself. For example, a reference to "about X" includes the description of "X."

[0050] As used in this specification and the appended claims, the singular forms "a," "or," and "the" include plural referents unless the content clearly dictates otherwise. It is understood that aspects and variations of the invention described herein include "consisting of" and / or "consisting essentially of" aspects and variations.

[0051] Method of the present application The present application provides a method of treating insomnia (e.g., chronic insomnia) in an individual, comprising administering to the individual an effective amount of a composition comprising a compound of formula A described herein (e.g., anordrin). The present application provides a method of treating insomnia (e.g., chronic insomnia) in an individual, comprising administering to the individual an effective amount of a composition comprising a compound of formula I described herein (e.g., anordrin). In some embodiments, R 9a is -CH2CH3, and / or R 10a is -CH2CH3. In some embodiments, the compound is anordrin. In some embodiments, the individual has reached menopause, is postmenopausal, or has undergone surgical removal of the ovaries. In some embodiments, the dose of the compound for each administration is about 20 μg to about 1 mg (e.g., about 20 μg to about 200 μg or about 400 μg to about 1 mg) in humans, or an equivalent dose for non-human individuals. In some embodiments, the compound is administered for at least about 2 weeks. In some embodiments, the compound is administered daily. In some embodiments, the compound is administered weekly.

[0052] The application, in one aspect, provides a method of treating insomnia (e.g., chronic insomnia) in an individual, comprising administering to the subject an effective amount of a compound of formula A: [ka] or a pharma- ceutically acceptable salt or ester thereof, 2 Carbon with R 3 Between the carbon [ka] represents a single bond, and R 3 Carbon with R 4 Between the carbon [ka] represents a single bond, and R 2 and R 4 is independently selected from the group consisting of hydrogen, hydroxyl, mercaptan, keto, and C1-C3 alkyl; R 3 is selected from the group consisting of hydrogen, hydroxyl, mercaptan, and C1-C3 alkyl, or R 2 Carbon with R 3 Between the carbon [ka] represents a double bond, and R 3 Carbon with R 4 Between the carbon [ka] represents a single bond, and R 2 is selected from the group consisting of hydrogen, hydroxyl, mercaptan, and C1-C3 alkyl; R 3 does not exist, and R 4 is selected from the group consisting of hydrogen, hydroxyl, mercaptan, keto, and C1-C3 alkyl, or R 2 Carbon with R 3 Between the carbon [ka] represents a single bond, and R 3Carbon with R 4 Between the carbon [ka] represents a double bond, R 2 is selected from the group consisting of hydrogen, hydroxyl, mercaptan, keto, and C1-C3 alkyl; R 3 does not exist, and R 4 is selected from the group consisting of hydrogen, hydroxyl, mercaptan, and C1-C3 alkyl; b) R 1 is C1-C3 alkyl, and c) R 5 , R 7 , R 8 , R 12 , R 13 and R 14 is independently selected from the group consisting of hydrogen, hydroxyl, mercaptan, keto, and C1-C3 alkyl; d) R 6 is selected from the group consisting of hydrogen, hydroxyl, mercaptan, and C1-C3 alkyl; e) R 9 is hydrogen and -C(=O)R 9a f) R 10 is hydrogen and -C(=O)R 10a g) R 9a and R 10a is independently selected from the group consisting of C1-C6 alkyl and C2-C6 alkenyl, wherein C1-C6 alkyl and C2-C6 alkenyl are optionally substituted with -C(=O)OH; h) R 11 is selected from the group consisting of hydrogen and C1-C3 alkyl. 9 and R 10 is independently hydrogen or -C(=O)CH2CH3. In some embodiments, R 11 is hydrogen. In some embodiments, R 11 is C1-C3 alkyl. In some embodiments, R 1 and R 11 In some embodiments, one or both of R 1 is -CH3, R 11is hydrogen. In some embodiments, R 1 and R 11 and R are -CH3. 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 11 , R 12 , R 13 , and R 14 Any one or more of R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 12 , R 13 , and R 14 Any one or more of R 9 and R 10 is independently hydrogen or -C(=O)CH2CH3. In some embodiments, R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 11 , R 12 , R 13 , and R 14 Any one or more (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, or 11) of R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 12 , R 13 , and R 14 Any one or more (e.g., 2, 3, 4, 5, 6, 7, 8, 9, or 10) of R 9a is -CH2CH3. In some embodiments, R10ais -CH2CH3. In some embodiments, the compound is anordrin. In some embodiments, the individual is female. In some embodiments, the individual is human. In some embodiments, the individual has reached menopause, is postmenopausal, or has undergone surgical removal of ovaries. In some embodiments, the individual is a postmenopausal woman. In some embodiments, the individual has low levels of estrogen. In some embodiments, the individual has a score of at least about 7 on the Athens Insomnia Scale. In some embodiments, the individual has a score of at least about 11 on the Pittsburgh Sleep Quality Index (PSQI). In some embodiments, the insomnia is assessed by the Epworth Sleep Scale with a sleep monitor or other sleep disorder questionnaire (SDQ), such as the Sleep Dysfunction Rating Scale (SDRS). In some embodiments, the individual is not undergoing or has never undergone hormone therapy. In some embodiments, the insomnia is associated with low levels of estrogen. In some embodiments, the insomnia is associated with peri-menopause, menopause, or post-menopause. In some embodiments, the dose of the compound for each administration is at least about 20 μg in a human (e.g., at least about 50 μg, 100 μg, or 150 μg) or an equivalent dose in a non-human individual. In some embodiments, the dose of the compound for each administration is 2 mg or less in a human, or an equivalent dose in a non-human individual. In some embodiments, the dose of the compound for each administration is about 20 μg to about 2 mg in a human (e.g., about 20 μg to about 200 μg or about 400 μg to about 2 mg) or an equivalent dose in a non-human individual. In some embodiments, the composition is administered at a frequency of about once every two weeks to about three times a day. In some embodiments, the composition is administered daily. In some embodiments, the composition is administered daily at a dose of about 20 μg to about 200 μg. In some embodiments, the composition is administered weekly. In some embodiments, the composition is administered weekly at a dose of about 400 μg to about 2 mg. In some embodiments, the compositions are administered intravenously, intraarterially, intraperitoneally, intravesically, subcutaneously, intrathecally, intrapulmonary, intramuscular, intratracheal, intraocular, transdermally, orally, or by inhalation.In some embodiments, the composition is administered orally.

[0053] The application, in one aspect, provides a method of treating insomnia (e.g., chronic insomnia) in an individual, comprising administering to the individual an effective amount of a compound of formula I: [ka] or a pharma- ceutically acceptable salt or ester thereof, 2 Carbon with R 3 Between the carbon [ka] represents a single bond, and R 3 Carbon with R 4 Between the carbon [ka] represents a single bond, and R 2 and R 4 is independently selected from the group consisting of hydrogen, hydroxyl, mercaptan, keto, and C1-C3 alkyl; R 3 is selected from the group consisting of hydrogen, hydroxyl, mercaptan, and C1-C3 alkyl, or R 2 Carbon with R 3 Between the carbon [ka] represents a double bond, and R 3 Carbon with R 4 Between the carbon [ka] represents a single bond, and R 2 is selected from the group consisting of hydrogen, hydroxyl, mercaptan, and C1-C3 alkyl; R 3 does not exist, and R 4is selected from the group consisting of hydrogen, hydroxyl, mercaptan, keto, and C1-C3 alkyl, or R 2 Carbon with R 3 Between the carbon [ka] represents a single bond, and R 3 Carbon with R 4 Between the carbon [ka] represents a double bond, R 2 is selected from the group consisting of hydrogen, hydroxyl, mercaptan, keto, and C1-C3 alkyl; R 3 does not exist, and R 4 is selected from the group consisting of hydrogen, hydroxyl, mercaptan, and C1-C3 alkyl; b) R 1 is C1-C3 alkyl, and c) R 5 , R 7 , R 8 , R 12 , R 13 and R 14 is independently selected from the group consisting of hydrogen, hydroxyl, mercaptan, keto, and C1-C3 alkyl; d) R 6 is selected from the group consisting of hydrogen, hydroxyl, mercaptan, and C1-C3 alkyl; e) R 9 is hydrogen and -C(=O)R 9a f) R 10 is hydrogen and -C(=O)R 10a g) R 9a and R 10a is independently selected from the group consisting of C1-C6 alkyl and C2-C6 alkenyl, wherein C1-C6 alkyl and C2-C6 alkenyl are optionally substituted with -C(=O)OH; h) R 11 is selected from the group consisting of C1-C3 alkyl. 9 and R 10is independently hydrogen or -C(=O)CH2CH3. In some embodiments, R 1 and R 11 In some embodiments, one or both of R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 12 , R 13 , and R 14 Any one or more of R 9 and R 10 is independently hydrogen or -C(=O)CH2CH3. In some embodiments, R 1 and R 11 In some embodiments, one or both of R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 12 , R 13 , and R 14 Any one or more (e.g., 2, 3, 4, 5, 6, 7, 8, 9, or 10) of R 9a is -CH2CH3. In some embodiments, R 10ais -CH2CH3. In some embodiments, the compound is anordrin. In some embodiments, the individual is female. In some embodiments, the individual is human. In some embodiments, the individual has reached menopause, is postmenopausal, or has undergone surgical removal of ovaries. In some embodiments, the individual is a postmenopausal woman. In some embodiments, the individual has low levels of estrogen. In some embodiments, the individual has a score of at least about 7 on the Athens Insomnia Scale. In some embodiments, the individual has a score of at least about 11 on the Pittsburgh Sleep Quality Index (PSQI). In some embodiments, the insomnia is assessed by the Epworth Sleep Scale with a sleep monitor or other sleep disorder questionnaire (SDQ), such as the Sleep Dysfunction Rating Scale (SDRS). In some embodiments, the individual is not undergoing or has never undergone hormone therapy. In some embodiments, the insomnia is associated with low levels of estrogen. In some embodiments, the insomnia is associated with peri-menopause, menopause, or post-menopause. In some embodiments, the dose of the compound for each administration is at least about 20 μg in a human (e.g., at least about 50 μg, 100 μg, or 150 μg) or an equivalent dose in a non-human individual. In some embodiments, the dose of the compound for each administration is 2 mg or less in a human, or an equivalent dose in a non-human individual. In some embodiments, the dose of the compound for each administration is about 20 μg to about 2 mg in a human (e.g., about 20 μg to about 200 μg or about 400 μg to about 2 mg) or an equivalent dose in a non-human individual. In some embodiments, the composition is administered at a frequency of about once every two weeks to about three times a day. In some embodiments, the composition is administered daily. In some embodiments, the composition is administered daily at a dose of about 20 μg to about 200 μg. In some embodiments, the composition is administered weekly. In some embodiments, the composition is administered weekly at a dose of about 400 μg to about 2 mg. In some embodiments, the compositions are administered intravenously, intraarterially, intraperitoneally, intravesically, subcutaneously, intrathecally, intrapulmonary, intramuscular, intratracheal, intraocular, transdermally, orally, or by inhalation.In some embodiments, the composition is administered orally.

[0054] In some embodiments, a method of treating insomnia (e.g., chronic insomnia) in an individual is provided, comprising administering to the individual an effective amount of a composition comprising a compound of Formula II-A, III-A, or IV-A, or a pharma- ceutically acceptable salt or ester thereof, wherein R 9 is hydrogen and -C(=O)R 9a R 10 is hydrogen and -C(=O)R 10a R 9a and R 10a is independently selected from the group consisting of C1-C6 alkyl and C2-C6 alkenyl; C 1~ C6 alkyl and C2-C6 alkenyl are optionally substituted with -C(=O)OH, R 1 is selected from the group consisting of hydrogen and C1-C3 alkyl; R 11 is selected from the group consisting of C1 to C3 alkyl.

[0055] In some embodiments, the composition comprises a compound of formula II-A-1, III-A-1, or IV-A-1, or a pharma- ceutically acceptable salt or ester thereof. In some embodiments, the composition comprises a compound of formula II-A-1-a, III-A-1-a, or IV-A-1-a. In some embodiments, R 9 and R 10 is independently hydrogen or -C(=O)CH2CH3. In some embodiments, R 9a is -CH2CH3. In some embodiments, R 10a is -CH2CH3. In some embodiments, R 1 and R 11One or both of is -CH3. In some embodiments, the compound is anordrin. In some embodiments, the individual is female. In some embodiments, the individual is human. In some embodiments, the individual has reached menopause, is postmenopausal, or has undergone surgical removal of ovaries. In some embodiments, the individual is a postmenopausal woman. In some embodiments, the individual has abnormal levels of hormones, such as estrogen. In some embodiments, the individual has a score of at least about 7 on the Athens Insomnia Scale. In some embodiments, the individual has a score of at least about 11 on the Pittsburgh Sleep Quality Index (PSQI). In some embodiments, the insomnia is assessed by a sleep monitor with the Epworth Sleep Scale or other sleep disorder questionnaires (SDQ), such as the Sleep Dysfunction Rating Scale (SDRS). In some embodiments, the individual is not or has never undergone hormone therapy. In some embodiments, the insomnia is associated with abnormal levels of estrogen. In some embodiments, the insomnia is associated with peri-menopause, menopause, or post-menopause. In some embodiments, the dose of the compound for each administration is about 20 μg to about 2 mg for humans (e.g., about 20 μg to about 200 μg or about 400 μg to about 2 mg), or an equivalent dose for non-human individuals. In some embodiments, the composition is administered about once every two weeks to about three times a day. In some embodiments, the composition is administered daily. In some embodiments, the composition is administered daily at a dose of about 20 μg to about 200 μg. In some embodiments, the composition is administered weekly. In some embodiments, the composition is administered weekly at a dose of about 400 μg to about 2 mg. In some embodiments, the composition is administered orally.

[0056] In some embodiments, a method of treating insomnia (e.g., chronic insomnia) in an individual is provided, comprising administering to the individual an effective amount of a composition comprising a compound of any one of Formulas II-B, III-B, IV-B, II-C, III-C, and IV-C, or a pharma- ceutically acceptable salt or ester thereof; 2 and R4 is independently selected from the group consisting of hydrogen, hydroxyl, mercaptan, keto, and C1-C3 alkyl; R 3 is selected from the group consisting of hydrogen, hydroxyl, mercaptan, and C1-C3 alkyl, or is absent; b) R 1 is C1-C3 alkyl, and c) R 5 , R 7 , R 8 , R 12 , R 13 and R 14 is independently selected from the group consisting of hydrogen, hydroxyl, mercaptan, keto, and C1-C3 alkyl; d) R 6 is selected from the group consisting of hydrogen, hydroxyl, mercaptan, and C1-C3 alkyl; e) R 9a and R 10a is independently selected from the group consisting of C1-C6 alkyl and C2-C6 alkenyl, wherein the C1-C6 alkyl and C2-C6 alkenyl are optionally substituted with -C(=O)OH; f) R 11 is selected from the group consisting of C1-C3 alkyl. In some embodiments, the composition comprises a compound of formula II-B, III-B, or IV-B, or a pharma- ceutically acceptable salt or ester thereof. In some embodiments, the composition comprises a compound of formula II-C, III-C, or IV-C, or a pharma- ceutically acceptable salt or ester thereof. In some embodiments, the composition comprises a compound of formula II-C-1, III-C-1, or IV-C-1, or a pharma- ceutically acceptable salt or ester thereof. In some embodiments, R 1 and R 11 is independently C alkyl. In some embodiments, R 9 and R 10 is independently hydrogen or -C(=O)CH2CH3. In some embodiments, R 9a is -CH2CH3. In some embodiments, R 10a is -CH2CH3. In some embodiments, R 1 and R 11In some embodiments, one or both of R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 12 , R 13 , and R 14 Any one or more of (such as 2, 3, 4, 5, 6, 7, 8, 9, or 10) are hydrogen. In some embodiments, the compound is anordrin. In some embodiments, the individual is female. In some embodiments, the individual is human. In some embodiments, the individual is menopausal, postmenopausal, or has undergone surgical removal of the ovaries. In some embodiments, the individual is a postmenopausal woman. In some embodiments, the individual has a low level of estrogen. In some embodiments, the individual has a score of at least about 7 on the Athens Insomnia Scale. In some embodiments, the individual has a score of at least about 11 on the Pittsburgh Sleep Quality Index (PSQI). In some embodiments, the insomnia is assessed by a sleep monitor with the Epworth Sleep Scale or other sleep disorder questionnaires (SDQ), such as the Sleep Dysfunction Rating Scale (SDRS). In some embodiments, the individual is not receiving or has never received hormone therapy. In some embodiments, the insomnia is associated with low levels of estrogen. In some embodiments, the insomnia is associated with peri-menopause, menopause, or post-menopause. In some embodiments, the dose of the compound for each administration is about 20 μg to about 2 mg in humans (e.g., about 20 μg to about 200 μg or about 400 μg to about 2 mg), or an equivalent dose for non-human individuals. In some embodiments, the composition is administered at a frequency of about once every two weeks to about three times a day. In some embodiments, the composition is administered daily. In some embodiments, the composition is administered daily at a dosage of about 20 μg to about 200 μg. In some embodiments, the composition is administered weekly. In some embodiments, the composition is administered weekly at a dosage of about 400 μg to about 2 mg. In some embodiments, the composition is administered orally.

[0057] In some embodiments, a method for treating insomnia (e.g., chronic insomnia) in an individual is provided, comprising administering to the individual an effective amount of a composition comprising a compound of formula A as described herein (e.g., anordrin), or a pharmaceutically acceptable salt or ester thereof, wherein the individual is in a perimenopausal stage, has reached menopause, is postmenopausal, or has undergone surgical removal of an ovary. In some embodiments, a method for treating insomnia (e.g., chronic insomnia) in an individual is provided, comprising administering to the individual an effective amount of a composition comprising a compound of formula I as described herein (e.g., anordrin), or a pharmaceutically acceptable salt or ester thereof, wherein the individual is in a perimenopausal stage, has reached menopause, is postmenopausal, or has undergone surgical removal of an ovary. In some embodiments, the individual is selected for treatment based on being in a perimenopausal stage, has reached menopause, is postmenopausal, or has undergone surgical removal of an ovary. In some embodiments, the individual is a postmenopausal woman. In some embodiments, the composition comprises a compound of formula II-A, III-A, or IV-A (II-A-1, III-A-1, or IV-A-1, such as II-A-1-a, III-A-1-a, or IV-A-1-a), or a pharma- ceutically acceptable salt or ester thereof. In some embodiments, the composition comprises a compound of any one of formulas II-B, III-B, IV-B, II-C, III-C, and IV-C, or a pharma- ceutically acceptable salt or ester thereof. In some embodiments, the composition comprises a compound of formula II-B, III-B, or IV-B, or a pharma- ceutically acceptable salt or ester thereof. In some embodiments, the composition comprises a compound of formula II-C, III-C, or IV-C, or a pharma- ceutically acceptable salt or ester thereof. In some embodiments, the composition comprises a compound of formula II-C-1, III-C-1, or IV-C-1, or a pharma- ceutically acceptable salt or ester thereof. In some embodiments, R 9 and R 10is independently hydrogen or -C(=O)CH2CH3. In some embodiments, R 9a is -CH2CH3. In some embodiments, R 10a is -CH2CH3. In some embodiments, R 11 is hydrogen. In some embodiments, R 11 is C1-C3 alkyl. In some embodiments, R 1 and R 11 In some embodiments, one or both of R 1 is -CH3, R 11 is hydrogen. In some embodiments, R 1 and R 11 and R are -CH3. 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 11 , R 12 , R 13 , and R 14 Any one or more (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, or 11) of R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 12 , R 13 , and R 14Any one or more of (such as 2, 3, 4, 5, 6, 7, 8, 9, or 10) are hydrogen. In some embodiments, the compound is anordrin. In some embodiments, the individual is human. In some embodiments, the individual has a low level of estrogen. In some embodiments, the individual has a score of at least about 7 on the Athens Insomnia Scale. In some embodiments, the individual has a score of at least about 11 on the Pittsburgh Sleep Quality Index (PSQI). In some embodiments, the insomnia is assessed by a sleep monitor with the Epworth Sleep Scale or other sleep disorder questionnaire (SDQ), such as the Sleep Dysfunction Rating Scale (SDRS). In some embodiments, the individual is not receiving or has never received hormone therapy. In some embodiments, the insomnia is associated with low levels of estrogen. In some embodiments, the insomnia is associated with peri-menopause, menopause, or post-menopause. In some embodiments, the dose of the compound for each administration is about 20 μg to about 1 mg in humans (e.g., about 20 μg to about 200 μg or about 400 μg to about 2 mg), or an equivalent dose for a non-human individual. In some embodiments, the composition is administered about once every two weeks to about three times a day. In some embodiments, the composition is administered daily. In some embodiments, the composition is administered daily at a dose of about 20 μg to about 200 μg. In some embodiments, the composition is administered weekly. In some embodiments, the composition is administered weekly at a dose of about 400 μg to about 2 mg. In some embodiments, the composition is administered orally.

[0058] In some embodiments, a method of treating insomnia (e.g., chronic insomnia) in an individual is provided, comprising administering to the individual an effective amount of a composition comprising a compound of formula A described herein (e.g., anordrin), or a pharmaceutically acceptable salt or ester thereof, wherein the individual has a low level of hormone (e.g., estrogen). In some embodiments, a method of treating insomnia (e.g., chronic insomnia) in an individual is provided, comprising administering to the individual an effective amount of a composition comprising a compound of formula I described herein (e.g., anordrin), or a pharmaceutically acceptable salt or ester thereof, wherein the individual has a low level of hormone (e.g., estrogen). In some embodiments, the individual has a serum estrogen level (e.g., serum estradiol (E2) level, e.g., average serum estradiol level) of less than 35 pg / mL or 18 pg / mL. In some embodiments, the individual has a serum FSH level of more than 40 IU / L. In some embodiments, the composition comprises a compound of formula II-A, III-A, or IV-A (II-A-1, III-A-1, or IV-A-1, such as II-A-1-a, III-A-1-a, or IV-A-1-a), or a pharma- ceutically acceptable salt or ester thereof. In some embodiments, the composition comprises a compound of any one of formulas II-B, III-B, IV-B, II-C, III-C, and IV-C, or a pharma- ceutically acceptable salt or ester thereof. In some embodiments, the composition comprises a compound of formula II-B, III-B, or IV-B, or a pharma- ceutically acceptable salt or ester thereof. In some embodiments, the composition comprises a compound of formula II-C, III-C, or IV-C, or a pharma- ceutically acceptable salt or ester thereof. In some embodiments, the composition comprises a compound of formula II-C-1, III-C-1, or IV-C-1, or a pharma- ceutically acceptable salt or ester thereof. In some embodiments, R 9 and R 10 is independently hydrogen or -C(=O)CH2CH3. In some embodiments, R 9ais -CH2CH3. In some embodiments, R 10a is -CH2CH3. In some embodiments, R 11 is hydrogen. In some embodiments, R 11 is C1-C3 alkyl. In some embodiments, R 1 and R 11 In some embodiments, one or both of R 1 is -CH3, R 11 is hydrogen. In some embodiments, R 1 and R 11 and R are -CH3. 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 11 , R 12 , R 13 , and R 14 Any one or more (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, or 11) of R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 12 , R 13 , and R 14Any one or more of (such as 2, 3, 4, 5, 6, 7, 8, 9, or 10) are hydrogen. In some embodiments, the compound is anordrin. In some embodiments, the individual is female. In some embodiments, the individual is human. In some embodiments, the individual has reached menopause, is postmenopausal, or has undergone surgical removal of ovaries. In some embodiments, the individual is a postmenopausal woman. In some embodiments, the individual has a score of at least about 7 on the Athens Insomnia Scale. In some embodiments, the individual has a score of at least about 11 on the Pittsburgh Sleep Quality Index (PSQI). In some embodiments, the insomnia is assessed by a sleep monitor with the Epworth Sleep Scale or other sleep disorder questionnaires (SDQ), such as the Sleep Dysfunction Rating Scale (SDRS). In some embodiments, the individual is not or has never undergone hormone therapy. In some embodiments, the insomnia is associated with abnormal levels of estrogen. In some embodiments, the insomnia is associated with peri-menopause, menopause, or post-menopause. In some embodiments, the dose of the compound for each administration is about 20 μg to about 1 mg in humans (e.g., about 20 μg to about 200 μg or about 400 μg to about 2 mg), or an equivalent dose for a non-human individual. In some embodiments, the composition is administered about once every two weeks to about three times a day. In some embodiments, the composition is administered daily. In some embodiments, the composition is administered daily at a dose of about 20 μg to about 200 μg. In some embodiments, the composition is administered weekly. In some embodiments, the composition is administered weekly at a dose of about 400 μg to about 2 mg. In some embodiments, the composition is administered orally.

[0059] In some embodiments, a method of treating insomnia (e.g., chronic insomnia) in a human individual is provided, comprising administering to the human individual an effective amount of a composition comprising a compound of formula A described herein (e.g., anordrin), or a pharmaceutically acceptable salt or ester thereof, wherein the dose of the compound for each administration is about 20 μg to about 2 mg in a human (e.g., about 20 μg to about 200 μg or about 400 μg to about 2 mg). In some embodiments, a method of treating insomnia (e.g., chronic insomnia) in a human individual is provided, comprising administering to the human individual an effective amount of a composition comprising a compound of formula I described herein (e.g., anordrin), or a pharmaceutically acceptable salt or ester thereof, wherein the dose of the compound for each administration is about 20 μg to about 2 mg in a human (e.g., about 20 μg to about 200 μg or about 400 μg to about 2 mg). In some embodiments, the composition is administered daily. In some embodiments, the composition is administered daily at a dosage of about 20 μg to about 200 μg (e.g., about 50 μg, about 100 μg, or about 150 μg). In some embodiments, the composition is administered weekly. In some embodiments, the composition is administered weekly at a dosage of about 400 μg to about 2 mg. In some embodiments, the composition comprises a compound of formula II-A, III-A, or IV-A (II-A-1, III-A-1, or IV-A-1, such as II-A-1-a, III-A-1-a, or IV-A-1-a), or a pharma- ceutically acceptable salt or ester thereof. In some embodiments, the composition comprises a compound of any one of formulas II-B, III-B, IV-B, II-C, III-C, and IV-C, or a pharma- ceutically acceptable salt or ester thereof. In some embodiments, the composition comprises a compound of formula II-B, III-B, or IV-B, or a pharma- ceutically acceptable salt or ester thereof. In some embodiments, the composition comprises a compound of formula II-C, III-C, or IV-C, or a pharma- ceutically acceptable salt or ester thereof. In some embodiments, the composition comprises a compound of formula II-C-1, III-C-1, or IV-C-1, or a pharma- ceutically acceptable salt or ester thereof. In some embodiments, R.9 and R 10 is independently hydrogen or -C(=O)CH2CH3. In some embodiments, R 9a is -CH2CH3. In some embodiments, R 10a is -CH2CH3. In some embodiments, R 11 is hydrogen. In some embodiments, R 11 is C1-C3 alkyl. In some embodiments, R 1 and R 11 In some embodiments, one or both of R 1 is -CH3, R 11 is hydrogen. In some embodiments, R 1 and R 11 and R are -CH3. 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 11 , R 12 , R 13 , and R 14 Any one or more (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, or 11) of R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 12 , R 13 , and R 14Any one or more of (such as 2, 3, 4, 5, 6, 7, 8, 9, or 10) are hydrogen. In some embodiments, the compound is anordrin. In some embodiments, the individual is female. In some embodiments, the individual is human. In some embodiments, the individual has reached menopause, is postmenopausal, or has undergone surgical removal of the ovaries. In some embodiments, the individual is a postmenopausal woman. In some embodiments, the individual has low levels of hormones (such as estrogen). In some embodiments, the individual has a score of at least about 7 on the Athens Insomnia Scale. In some embodiments, the individual has a score of at least about 11 on the Pittsburgh Sleep Quality Index (PSQI). In some embodiments, the insomnia is assessed by a sleep monitor with the Epworth Sleep Scale or other sleep disorder questionnaires (SDQ), such as the Sleep Dysfunction Rating Scale (SDRS). In some embodiments, the individual is not receiving or has never received hormone therapy. In some embodiments, the insomnia is associated with low levels of estrogen. In some embodiments, the insomnia is associated with peri-menopause, menopause, or post-menopause. In some embodiments, the dose of the compound for each administration is about 20 μg to about 2 mg in humans (e.g., about 20 μg to about 200 μg or about 400 μg to about 2 mg). In some embodiments, the composition is administered at a frequency of about once every two weeks to about three times a day. In some embodiments, the composition is administered daily. In some embodiments, the composition is administered daily at a dosage of about 20 μg to about 200 μg. In some embodiments, the composition is administered weekly. In some embodiments, the composition is administered weekly at a dosage of about 400 μg to about 2 mg. In some embodiments, the composition is administered orally.

[0060] In some embodiments, a method of treating insomnia (e.g., chronic insomnia) in a female individual comprises administering to the individual an effective amount of a composition comprising a compound of any one of formulas selected from the group consisting of II-A-1-a, III-A-1-a, IV-A-1-a, II-C, III-C, and IV-C, or a pharma- ceutically acceptable salt or ester thereof; 1 and R 11 and R are both -CH3, and the individual is a) in the perimenopausal stage, has reached menopause, is postmenopausal, or has had surgical removal of the ovaries, or b) has abnormal levels of hormones (e.g., estrogen). 9a is -CH2CH3. In some embodiments, R 10a is -CH2CH3. In some embodiments, R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 12 , R 13 , and R 14Any one or more of (such as 2, 3, 4, 5, 6, 7, 8, 9, or 10) are hydrogen. In some embodiments, the compound is anordrin. In some embodiments, the individual is a human. In some embodiments, the individual is a postmenopausal woman. In some embodiments, the individual has a score of at least about 7 on the Athens Insomnia Scale. In some embodiments, the individual has a score of at least about 11 on the Pittsburgh Sleep Quality Index (PSQI). In some embodiments, the insomnia is assessed by a sleep monitor with the Epworth Sleep Scale or other sleep disorder questionnaire (SDQ), such as the Sleep Dysfunction Rating Scale (SDRS). In some embodiments, the individual is not receiving or has never received hormone therapy. In some embodiments, the insomnia is associated with low levels of estrogen. In some embodiments, the insomnia is associated with peri-menopause, menopause, or post-menopause. In some embodiments, the dose of the compound for each administration is about 20 μg to about 2 mg in humans (e.g., about 20 μg to about 200 μg or about 400 μg to about 2 mg), or an equivalent dose for a non-human individual. In some embodiments, the composition is administered about once every two weeks to about three times a day. In some embodiments, the composition is administered daily. In some embodiments, the composition is administered daily at a dose of about 20 μg to about 200 μg. In some embodiments, the composition is administered weekly. In some embodiments, the composition is administered weekly at a dose of about 400 μg to about 1 mg. In some embodiments, the composition is administered orally.

[0061] In some embodiments, a method of treating insomnia (e.g., chronic insomnia) in an individual includes administering to the individual an effective amount of a composition comprising a compound of any one of formulas selected from the group consisting of II-A-1-a, III-A-1-a, IV-A-1-a, II-C, III-C, and IV-C, or a pharma- ceutically acceptable salt or ester thereof; and R 1 and R 11and the dose of the compound for each administration is about 20 μg to about 1 mg (e.g., about 20 μg to about 200 μg or about 400 μg to about 2 mg) in humans. 9a is -CH2CH3. In some embodiments, R 10a is -CH2CH3. In some embodiments, R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 12 , R 13 , and R 14Any one or more of (e.g., 2, 3, 4, 5, 6, 7, 8, 9, or 10) are hydrogen. In some embodiments, the compound is anordrin. In some embodiments, the composition is administered daily. In some embodiments, the composition is administered daily at a dosage of about 20 μg to about 200 μg (e.g., about 50 μg, about 100 μg, or about 150 μg). In some embodiments, the composition is administered weekly. In some embodiments, the composition is administered weekly at a dosage of about 400 μg to about 2 mg. In some embodiments, the individual is female. In some embodiments, the individual is human. In some embodiments, the individual has reached menopause, is postmenopausal, or has undergone surgical removal of the ovaries. In some embodiments, the individual is a postmenopausal female. In some embodiments, the individual has low levels of hormones (e.g., estrogen). In some embodiments, the individual has a score of at least about 7 on the Athens Insomnia Scale. In some embodiments, the individual has a score of at least about 11 on the Pittsburgh Sleep Quality Index (PSQI). In some embodiments, the insomnia is assessed by a sleep monitor with the Epworth Sleep Scale or other sleep disorder questionnaires (SDQ), such as the Sleep Dysfunction Rating Scale (SDRS). In some embodiments, the individual is not receiving or has never received hormone therapy. In some embodiments, the insomnia is associated with low levels of estrogen. In some embodiments, the insomnia is associated with perimenopause, menopause, or postmenopause. In some embodiments, the composition is administered at a frequency of about once every two weeks to about three times a day. In some embodiments, the composition is administered daily. In some embodiments, the composition is administered daily at a dosage of about 20 μg to about 200 μg. In some embodiments, the composition is administered weekly. In some embodiments, the composition is administered weekly at a dosage of about 400 μg to about 2 mg. In some embodiments, the composition is administered orally.

[0062] In some embodiments, a method of treating insomnia (e.g., chronic insomnia) in a female human individual is provided, comprising administering to the individual an effective amount of a composition comprising anordrin or an analog thereof (such as anordrin), the individual being a) in the perimenopausal stage, reaching menopause, being postmenopausal, or having undergone surgical removal of the ovaries, or b) having low levels of estrogen, and optionally, the dose of anordrin or an analog thereof for each administration is about 20 μg to about 2 mg (e.g., about 20 μg to about 200 μg or about 400 μg to about 2 mg) in humans, or an equivalent dose for non-human individuals. In some embodiments, the composition is administered daily at a dosage of about 20 μg to about 200 μg (e.g., about 50 μg, about 100 μg, or about 150 μg). In some embodiments, the composition is administered weekly. In some embodiments, the composition is administered weekly at a dosage of about 400 μg to about 2 mg. In some embodiments, the individual is a postmenopausal woman. In some embodiments, the individual has a score of at least about 7 on the Athens Insomnia Scale. In some embodiments, the individual has a score of at least about 11 on the Pittsburgh Sleep Quality Index (PSQI). In some embodiments, the insomnia is assessed by a sleep monitor with the Epworth Sleep Scale or other sleep disorder questionnaires (SDQ), such as the Sleep Dysfunction Rating Scale (SDRS). In some embodiments, the individual is not receiving or has never received hormone therapy. In some embodiments, the insomnia is associated with low levels of estrogen. In some embodiments, the insomnia is associated with peri-menopause, menopause, or post-menopause. In some embodiments, the composition is administered at a frequency of about once every two weeks to about three times a day. In some embodiments, the composition is administered daily. In some embodiments, the composition is administered daily at a dosage of about 20 μg to about 200 μg. In some embodiments, the composition is administered weekly. In some embodiments, the composition is administered weekly at a dosage of about 400 μg to about 2 mg. In some embodiments, the composition is administered orally.

[0063] In some embodiments, a method for improving sleep in an individual is provided, comprising administering (e.g., orally administering) to the individual an effective amount of a compound of formula A described herein (e.g., anordrin), or a composition comprising a pharmaceutically acceptable salt or ester thereof. In some embodiments, a method for improving sleep in an individual is provided, comprising administering (e.g., orally administering) to the individual an effective amount of a compound of formula I described herein (e.g., anordrin), or a composition comprising a pharmaceutically acceptable salt or ester thereof. In some embodiments, the individual is a female individual. In some embodiments, the individual is in the perimenopausal stage, has reached menopause, is postmenopausal, or has undergone surgical removal of ovaries. In some embodiments, the individual has low levels of hormones (e.g., estrogen). In some embodiments, improving sleep comprises improving any one or more (e.g., 2, 3, 4, 5, 6, 7, or 8) of the events assessed on the Athens Insomnia Scale (see FIG. 2). For example, events include sleep onset time, nighttime awakening, final awakening earlier than desired, total sleep time, overall sleep quality, daytime well-being, function, and daytime sleepiness. In some embodiments, improvement in these events can be demonstrated by an individual's self-assessment before and after administration of the compound. In some embodiments, the post-administration self-assessment is performed after at least about 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, or 6 weeks of administration of the compound at the frequency and / or doses described herein.

[0064] In some embodiments, a method of reducing the severity of insomnia in an individual is provided, comprising administering (e.g., orally administering) to the individual an effective amount of a compound of formula A described herein (e.g., anordrin), or a composition comprising a pharmaceutically acceptable salt or ester thereof. In some embodiments, a method of reducing the severity of insomnia in an individual is provided, comprising administering (e.g., orally administering) to the individual an effective amount of a compound of formula I described herein (e.g., anordrin), or a composition comprising a pharmaceutically acceptable salt or ester thereof. In some embodiments, the insomnia score is reduced by at least about 10%, 20%, 30%, 40%, 50%, or 60% after treatment at a frequency and dosage for a period of time described herein. In some embodiments, the individual is a female individual. In some embodiments, the individual is in the perimenopausal stage, has reached menopause, is postmenopausal, or has undergone surgical removal of the ovaries. In some embodiments, the individual has low levels of hormones (e.g., estrogen). In some embodiments, improving sleep includes improving any one or more (e.g., 2, 3, 4, 5, 6, 7, or 8) of the events rated on the Athens Insomnia Scale (see FIG. 2). For example, the events include sleep onset time, nighttime awakening, final awakening earlier than desired, total sleep time, overall sleep quality, daytime well-being, functioning, and daytime sleepiness. In some embodiments, improvement of these events can be shown by an individual's self-assessment before and after administration of the compound. In some embodiments, the post-administration self-assessment is performed after at least about 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, or 6 weeks of administration of the compound at the frequency and / or doses described herein.

[0065] In some embodiments, a method is provided for increasing sleep time in an individual, comprising administering (e.g., orally administering) to the individual an effective amount of a compound of formula A described herein (e.g., anordrin), or a composition comprising a pharmaceutically acceptable salt or ester thereof. In some embodiments, a method is provided for decreasing sleep onset time in an individual, comprising administering (e.g., orally administering) to the individual an effective amount of a compound of formula A described herein (e.g., anordrin), or a composition comprising a pharmaceutically acceptable salt or ester thereof. In some embodiments, a method is provided for decreasing nighttime wake time in an individual, comprising administering (e.g., orally administering) to the individual an effective amount of a compound of formula A described herein (e.g., anordrin), or a composition comprising a pharmaceutically acceptable salt or ester thereof. In some embodiments, a method is provided for improving overall sleep quality in an individual, comprising administering (e.g., orally administering) to the individual an effective amount of a compound of formula A described herein (e.g., anordrin), or a composition comprising a pharmaceutically acceptable salt or ester thereof. In some embodiments, a method of improving the quality of life of an individual is provided, the method comprising administering (e.g., orally administering) to the individual an effective amount of a composition comprising a compound of formula A described herein (e.g., anordrin), or a pharmaceutically acceptable salt or ester thereof.

[0066] In some embodiments, a method is provided for increasing sleep time in an individual, comprising administering (e.g., orally administering) to the individual an effective amount of a compound of formula I described herein (e.g., anordrin), or a composition comprising a pharmaceutically acceptable salt or ester thereof. In some embodiments, a method is provided for decreasing sleep onset time in an individual, comprising administering (e.g., orally administering) to the individual an effective amount of a compound of formula I described herein (e.g., anordrin), or a composition comprising a pharmaceutically acceptable salt or ester thereof. In some embodiments, a method is provided for decreasing nighttime wake time in an individual, comprising administering (e.g., orally administering) to the individual an effective amount of a compound of formula I described herein (e.g., anordrin), or a composition comprising a pharmaceutically acceptable salt or ester thereof. In some embodiments, a method is provided for improving overall sleep quality in an individual, comprising administering (e.g., orally administering) to the individual an effective amount of a compound of formula I described herein (e.g., anordrin), or a composition comprising a pharmaceutically acceptable salt or ester thereof. In some embodiments, a method of improving the quality of life of an individual is provided, the method comprising administering (e.g., orally administering) to the individual an effective amount of a composition comprising a compound of formula I described herein (e.g., anordrin), or a pharma- ceutically acceptable salt or ester thereof.

[0067] In some embodiments, a method for treating insomnia (e.g., chronic insomnia) or improving sleep in an individual is provided, comprising administering to the individual an effective amount of a composition comprising a compound of formula A described herein (e.g., anordrin), or a pharmaceutically acceptable salt or ester thereof, for at least about 2 weeks (e.g., at least about 3, 4, 5, 6, 7, or 8 weeks). In some embodiments, a method for treating insomnia (e.g., chronic insomnia) or improving sleep in an individual is provided, comprising administering to the individual an effective amount of a composition comprising a compound of formula I described herein (e.g., anordrin), or a pharmaceutically acceptable salt or ester thereof, for at least about 2 weeks (e.g., at least about 3, 4, 5, 6, 7, or 8 weeks). In some embodiments, the composition is administered for at least about 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 15, or 18 months. In some embodiments, the composition is administered for at least about 1 year, 1.5 years, 2 years, 3 years, 4 years, or 5 years. In some embodiments, the composition is administered daily. In some embodiments, the composition is administered daily at a dosage of about 20 μg to about 200 μg. In some embodiments, the composition is administered weekly. In some embodiments, the composition is administered weekly at a dosage of about 400 μg to about 2 mg.

[0068] In some embodiments according to any of the above methods, the individual has a low level of estrogen. In some embodiments, a low level of hormone (e.g., estrogen) is a hormone (e.g., estrogen) level lower than a control level (e.g., at least about either 18 pg / mL, or 35 pg / mL). In some embodiments, the individual has a serum FSH level higher than about 20, 30, or 40 IU / L. In some embodiments, the individual has a serum estrogen level (e.g., serum estradiol (E2) level, e.g., average serum estradiol level) of about 35 pg / mL or less than 18 pg / mL. In some embodiments, the individual has an endometrium with a thickness of about 7 mm, 6 mm, 5 mm, 4.5 mm, or 4 mm or less.

[0069] In some embodiments, the method further comprises administering a second agent.

[0070] In some embodiments, the method further comprises evaluating hormone (e.g., estrogen) levels in the individual. In some embodiments, the method further comprises selecting the individual for treatment based on hormone levels (e.g., serum estrogen levels). Methods for evaluating estrogen levels are well known in the art. For example, serum estrogen levels can be evaluated by measuring estradiol (E2) in blood.

[0071] Compositions and Compounds The present application provides, in one aspect, compositions and compounds that can be used to treat insomnia in the methods described herein.

[0072] In one embodiment, a compound of formula (A): [ka] or a pharma- ceutically acceptable salt or ester thereof, a)R 2 Carbon with R 3 Between the carbon [ka] represents a single bond, and R 3 Carbon with R 4 Between the carbon [ka] represents a single bond, and R 2 and R 4 is independently selected from the group consisting of hydrogen, hydroxyl, mercaptan, keto, and C1-C3 alkyl; R 3 is selected from the group consisting of hydrogen, hydroxyl, mercaptan, and C1-C3 alkyl; or R 2 Carbon with R 3 Between the carbon [ka] represents a double bond, and R 3 Carbon with R 4 Between the carbon [ka] represents a single bond, and R 2 is selected from the group consisting of hydrogen, hydroxyl, mercaptan, and C1-C3 alkyl; R 3 does not exist, and R 4 is selected from the group consisting of hydrogen, hydroxyl, mercaptan, keto, and C1-C3 alkyl; or R 2 Carbon with R 3 Between the carbon [ka] represents a single bond, and R 3 Carbon with R 4 Between the carbon [ka] represents a double bond, and R 2 is selected from the group consisting of hydrogen, hydroxyl, mercaptan, keto, and C1-C3 alkyl; R 3 does not exist, and R 4 is selected from the group consisting of hydrogen, hydroxyl, mercaptan, and C1-C3 alkyl; b)R 1 is C1-C3 alkyl, c)R 5 , R 7 , R 8 , R 12 , R 13 , and R 14 is independently selected from the group consisting of hydrogen, hydroxyl, mercaptan, keto, and C1-C3 alkyl; d) R 6 is selected from the group consisting of hydrogen, hydroxyl, mercaptan, and C1-C3 alkyl; e)R 9 is hydrogen and -C(=O)R 9a is selected from the group consisting of f)R 10 is hydrogen and -C(=O)R 10a is selected from the group consisting of g)R 9a and R 10a is independently selected from the group consisting of C1-C6 alkyl and C2-C6 alkenyl, wherein C1-C6 alkyl and C2-C6 alkenyl are optionally substituted with -C(=O)OH; h)R 11 is selected from the group consisting of hydrogen and C1-C3 alkyl.

[0073] In one embodiment, a compound of formula (I): [ka] or a pharma- ceutically acceptable salt or ester thereof, a)R 2 Carbon with R 3 Between the carbon [ka] represents a single bond, and R 3 Carbon with R 4 Between the carbon [ka] represents a single bond, and R 2 and R 4 is independently selected from the group consisting of hydrogen, hydroxyl, mercaptan, keto, and C1-C3 alkyl; R 3 is selected from the group consisting of hydrogen, hydroxyl, mercaptan, and C1-C3 alkyl; or R 2 Carbon with R 3 Between the carbon [ka] represents a double bond, and R 3 Carbon with R 4 Between the carbon [ka] represents a single bond, and R 2 is selected from the group consisting of hydrogen, hydroxyl, mercaptan, and C1-C3 alkyl; R 3 does not exist, and R 4 is selected from the group consisting of hydrogen, hydroxyl, mercaptan, keto, and C1-C3 alkyl; or R 2 Carbon with R 3 Between the carbon [ka] represents a single bond, and R 3 Carbon with R 4 Between the carbon [ka] represents a double bond, and R 2 is selected from the group consisting of hydrogen, hydroxyl, mercaptan, keto, and C1-C3 alkyl; R 3 does not exist, and R 4 is selected from the group consisting of hydrogen, hydroxyl, mercaptan, and C1-C3 alkyl; b)R 1 is C1-C3 alkyl, c)R 5 , R 7 , R 8 , R 12 , R 13 , and R 14 is independently selected from the group consisting of hydrogen, hydroxyl, mercaptan, keto, and C1-C3 alkyl; d) R 6 is selected from the group consisting of hydrogen, hydroxyl, mercaptan, and C1-C3 alkyl; e)R 9 is hydrogen and -C(=O)R 9a is selected from the group consisting of f)R 10 is hydrogen and -C(=O)R 10a is selected from the group consisting of g)R 9a and R 10a is independently selected from the group consisting of C1-C6 alkyl and C2-C6 alkenyl, wherein C1-C6 alkyl and C2-C6 alkenyl are optionally substituted with -C(=O)OH; h)R 11 is selected from the group consisting of C1 to C3 alkyl.

[0074] In some embodiments, R 2 Carbon with R 3 Between the carbon [ka] represents a single bond, and R 3 Carbon with R 4 Between the carbon [ka] represents a single bond, and R 2 and R 4 is independently selected from the group consisting of hydrogen, hydroxyl, mercaptan, keto, and C1-C3 alkyl; R 3 is selected from the group consisting of hydrogen, hydroxyl, mercaptan, and C1-C3 alkyl. 2 , R 3 , and R 4 is independently selected from the group consisting of hydrogen, hydroxyl, mercaptan, and C1-C3 alkyl (i.e., methyl, ethyl, n-propyl, or isopropyl). 2 , R 3 , and R 4 is independently selected from the group consisting of hydrogen, hydroxyl, and -CH. In some embodiments, R 2, R 3 , and R 4 is independently selected from the group consisting of hydrogen, hydroxyl, and -CH2CH3. 2 , R 3 , and R 4 Each is hydrogen. In some embodiments, R 2 , R 3 , and R 4 is hydroxyl and each of the others is hydrogen. In some embodiments, R 2 is hydroxyl and R 3 and R 4 Each is hydrogen. In some embodiments, R 3 is hydroxyl and R 2 and R 4 Each is hydrogen. In some embodiments, R 4 is hydroxyl and R 2 and R 3 Each is hydrogen. In some embodiments, R 2 , R 3 , and R 4 is a mercaptan and each of the others is hydrogen. 2 is a mercaptan and R 3 and R 4 Each is hydrogen. In some embodiments, R 3 is a mercaptan and R 2 and R 4 Each is hydrogen. In some embodiments, R 4 is a mercaptan and R 2 and R 3 Each is hydrogen. In some embodiments, R 2 , R 3 , and R 4 is -CH3 and each of the others is hydrogen. 2 , R 3 , and R 4 is -CHCH and the others are each hydrogen. 2 , R 3 , and R 4One of R is C alkyl (i.e., n-propyl or isopropyl) and each of the others is hydrogen. 2 is C1-C3 alkyl (i.e., methyl, ethyl, n-propyl, or isopropyl), and R 3 and R 4 are each hydrogen. In some embodiments, R 3 is C1-C3 alkyl (i.e., methyl, ethyl, n-propyl, or isopropyl), and R 2 and R 4 are each hydrogen. In some embodiments, R 4 is C1-C3 alkyl (i.e., methyl, ethyl, n-propyl, or isopropyl), and R 2 and R 3 are each hydrogen. In some embodiments, R 2 and R 4 In some embodiments, one of R 2 is keto and R 3 and R 4 is selected from the group consisting of hydrogen, hydroxyl, mercaptan, and C1-C3 alkyl (i.e., methyl, ethyl, n-propyl, or isopropyl). 2 is keto and R 3 and R 4 Each is hydrogen. In some embodiments, R 2 is keto and R 3 is hydrogen, and R 4 is hydroxyl. In some embodiments, R 2 is keto and R 3 is hydrogen, and R 4 is a mercaptan. In some embodiments, R 2 is keto and R 3 is hydrogen, and R 4 is C1-C3 alkyl. In some embodiments, R 2 is keto and R 3 is hydrogen, and R 4 is -CH3. In some embodiments, R 4is keto and R 2 and R 3 is selected from the group consisting of hydrogen, hydroxyl, mercaptan, and C1-C3 alkyl (i.e., methyl, ethyl, n-propyl, or isopropyl). 4 is keto and R 2 and R 3 are each hydrogen. In some embodiments, R 4 is keto and R 3 is hydrogen, and R 2 is hydroxyl. In some embodiments, R 4 is keto and R 3 is hydrogen, and R 2 is a mercaptan. In some embodiments, R 4 is keto and R 3 is hydrogen, and R 2 is C1-C3 alkyl. In some embodiments, R 4 is keto and R 3 is hydrogen, and R 2 is -CH3. In some embodiments, R 2 and R 4 In some embodiments, both of R 2 and R 4 Both are keto and R 3 is hydrogen.

[0075] In some embodiments, R 2 Carbon with R 3 Between the carbon [ka] represents a single bond, and R 3 Carbon with R 4 Between the carbon [ka] represents a single bond, and R 2 and R 4is independently selected from the group consisting of hydrogen, hydroxyl, mercaptan, keto, and C1-C3 alkyl; R 3 is selected from the group consisting of hydrogen, hydroxyl, mercaptan, and C1-C3 alkyl. 3 is hydrogen. In some embodiments, R 3 is hydroxyl. In some embodiments, R 3 is a mercaptan. In some embodiments, R 3 is C1-C3 alkyl (i.e., methyl, ethyl, n-propyl, or isopropyl). In some embodiments, R 3 is -CH3.

[0076] In some embodiments, R 2 Carbon with R 3 Between the carbon [ka] represents a double bond, and R 3 Carbon with R 4 Between the carbon [ka] represents a single bond, and R 2 is selected from the group consisting of hydrogen, hydroxyl, mercaptan, and C1-C3 alkyl; R 3 does not exist, and R 4 is selected from the group consisting of hydrogen, hydroxyl, mercaptan, keto, and C1-C3 alkyl. 2 and R 4 is independently selected from the group consisting of hydrogen, hydroxyl, mercaptan, and C1-C3 alkyl (i.e., methyl, ethyl, n-propyl, or isopropyl). 2 and R 4 is independently selected from the group consisting of hydrogen, hydroxyl, and -CH. In some embodiments, R 2 and R 4is independently selected from the group consisting of hydrogen, hydroxyl, and -CH2CH3. 2 and R 4 are each hydrogen. In some embodiments, R 2 is hydroxyl and R 4 is hydrogen. In some embodiments, R 4 is hydroxyl and R 2 is hydrogen. In some embodiments, R 2 is a mercaptan and R 4 is hydrogen. In some embodiments, R 4 is a mercaptan and R 2 is hydrogen. In some embodiments, R 2 is C1-C3 alkyl (i.e., methyl, ethyl, n-propyl, or isopropyl), and R 4 is hydrogen. In some embodiments, R 2 is -CH3, R 4 is hydrogen. In some embodiments, R 4 is C1-C3 alkyl (i.e., methyl, ethyl, n-propyl, or isopropyl), and R 2 is hydrogen. In some embodiments, R 4 is -CH3, R 2 is hydrogen. In some embodiments, R 4 is keto and R 2 is selected from the group consisting of hydrogen, hydroxyl, mercaptan, and C1-C3 alkyl. 4 is keto and R 2 is hydrogen. In some embodiments, R 4 is keto and R 2 is hydroxyl. In some embodiments, R 4 is keto and R 2 is a mercaptan. In some embodiments, R 4 is keto and R 2 is C1-C3 alkyl. In some embodiments, R 4 is keto and R 2is -CH3.

[0077] In some embodiments, R 2 Carbon with R 3 Between the carbon [ka] represents a single bond, and R 3 Carbon with R 4 Between the carbon [ka] represents a double bond, and R 2 is selected from the group consisting of hydrogen, hydroxyl, mercaptan, keto, and C1-C3 alkyl; R 3 does not exist, and R 4 is selected from the group consisting of hydrogen, hydroxyl, mercaptan, and C1-C3 alkyl. 2 and R 4 is independently selected from the group consisting of hydrogen, hydroxyl, mercaptan, and C1-C3 alkyl (i.e., methyl, ethyl, n-propyl, or isopropyl). 2 and R 4 is independently selected from the group consisting of hydrogen, hydroxyl, and -CH. In some embodiments, R 2 and R 4 is independently selected from the group consisting of hydrogen, hydroxyl, and -CH2CH3. 2 and R 4 are each hydrogen. In some embodiments, R 2 is hydroxyl and R 4 is hydrogen. In some embodiments, R 4 is hydroxyl and R 2 is hydrogen. In some embodiments, R 2 is a mercaptan and R 4 is hydrogen. In some embodiments, R 4 is a mercaptan and R 2is hydrogen. In some embodiments, R 2 is C1-C3 alkyl (i.e., methyl, ethyl, n-propyl, or isopropyl), and R 4 is hydrogen. In some embodiments, R 2 is -CH3, R 4 is hydrogen. In some embodiments, R 4 is C1-C3 alkyl (i.e., methyl, ethyl, n-propyl, or isopropyl), and R 2 is hydrogen. In some embodiments, R 4 is -CH3, R 2 is hydrogen. In some embodiments, R 2 is keto and R 4 is selected from the group consisting of hydrogen, hydroxyl, mercaptan, and C1-C3 alkyl. 2 is keto and R 4 is hydrogen. In some embodiments, R 2 is keto and R 4 is hydroxyl. In some embodiments, R 2 is keto and R 4 is a mercaptan. In some embodiments, R 2 is keto and R 4 is C1-C3 alkyl. In some embodiments, R 2 is keto and R 4 is -CH3.

[0078] In some embodiments, R 1 is C1-C3 alkyl. In some embodiments, R 1 is methyl, ethyl, n-propyl, or isopropyl. In some embodiments, R 1 is -CH3. In some embodiments, R 1 is -CH2CH3. In some embodiments, R 1 is -CH2CH2CH3. In some embodiments, R 1 is -CH(CH3)2.

[0079] In some embodiments, R 11 is selected from the group consisting of hydrogen or C1-C3 alkyl. 11 is selected from the group consisting of C1-C3 alkyl. 11 is hydrogen. In some embodiments, R 11 is methyl, ethyl, n-propyl, or isopropyl. In some embodiments, R 11 is hydrogen or -CH. In some embodiments, R 11 is -CH3. In some embodiments, R 11 is -CH2CH3. In some embodiments, R 11 is -CH2CH2CH3. In some embodiments, R 11 is -CH(CH3)2.

[0080] In some embodiments, R 1 is C1-C3 alkyl, R 11 is hydrogen. In some embodiments, R 1 is -CH3, R 11 is hydrogen.

[0081] In some embodiments, R 1 and R 11 is independently selected from the group consisting of C1-C3 alkyl. 1 and R 11 In some embodiments, one or both of R 1 and R 11 Both are -CH3.

[0082] In some embodiments, the compound of formula A is a pharma- ceutically acceptable salt thereof.In some embodiments, the compound of formula (I) is a pharma- ceutically acceptable salt thereof.

[0083] In some embodiments, the compound of formula (I) is a compound of formula (II): [ka] or a pharma- ceutically acceptable salt thereof; In the formula, R 1 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , and R 14 is as defined herein for any embodiment or variation of a compound of formula (I), and R 2 and R 4 is independently selected from the group consisting of hydrogen, hydroxyl, mercaptan, keto, and C1-C3 alkyl; R 3 is selected from the group consisting of hydrogen, hydroxyl, mercaptan, and C1-C3 alkyl.

[0084] In some embodiments, the compound of formula (II) is a compound of formula (II-A): [ka] or a pharma- ceutically acceptable salt thereof; In the formula, R 1 , R 9 , R 10 , and R 11 is as defined herein for any embodiment or variation of a compound of formula (II). In some embodiments, R 1 is -CH3. In some embodiments, R 11 is -CH3.

[0085] In some embodiments, the compound of formula (II-A) is a compound of formula (II-A-1): [ka] or a pharma- ceutically acceptable salt thereof. In the formula, R 9 and R 10is as defined herein for any embodiment or variation of a compound of formula (II). In some embodiments, R 9 is hydrogen. In some embodiments, R 9 is -C(=O)CH2CH3. In some embodiments, R 10 is hydrogen. In some embodiments, R 10 is -C(=O)CH2CH3.

[0086] In some embodiments, the compound of formula (II-A-1) is a compound of formula (II-A-1-a): [ka] or a pharma- ceutically acceptable salt thereof; In the formula, R 9a and R 10a is as defined herein for any embodiment or variation of a compound of formula (II). In some embodiments, R 9a is -CH2CH3. In some embodiments, R 10a is -CH2CH3.

[0087] In some embodiments, the compound of formula (II) is a compound of formula (II-B): [ka] or a pharma- ceutically acceptable salt thereof; In the formula, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 11 , R 12 , R 13 , and R 14 is as defined herein for any embodiment or variation of a compound of formula (II). In some embodiments, R 1 is -CH3. In some embodiments, R 11is -CH3. In some embodiments, R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 12 , R 13 , and R 14 is hydrogen.

[0088] In some embodiments, the compound of formula (II) is a compound of formula (II-C): [ka] or a pharma- ceutically acceptable salt thereof; In the formula, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9a , R 10a , R 11 , R 12 , R 13 , and R 14 is as defined herein for any embodiment or variation of a compound of formula (II). In some embodiments, R 1 is -CH3. In some embodiments, R 11 is -CH3. In some embodiments, R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 12 , R 13 , and R 14 is hydrogen. In some embodiments, R 9a is -CH2CH3. In some embodiments, R 10a is -CH2CH3.

[0089] In some embodiments, the compound of formula (II-C) is a compound of formula (II-C-1): [ka] or a pharma- ceutically acceptable salt thereof; In the formula, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 11 , R 12 , R 13 , and R 14 is as defined herein for any embodiment or variation of a compound of formula (II). In some embodiments, R 1 is -CH3. In some embodiments, R 11 is -CH3. In some embodiments, R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 12 , R 13 , and R 14 is hydrogen.

[0090] In some embodiments, the compound of formula (I) is a compound of formula (III); [ka] or a pharma- ceutically acceptable salt thereof; R 1 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , and R 14 is as defined herein for any embodiment or variation of a compound of formula (I), and R2 is selected from the group consisting of hydrogen, hydroxyl, mercaptan, and C1-C3 alkyl; R 4 is selected from the group consisting of hydrogen, hydroxyl, mercaptan, keto, and C1-C3 alkyl.

[0091] In some embodiments, the compound of formula (III) is a compound of formula (III-A): [ka] or a pharma- ceutically acceptable salt thereof; In the formula, R 1 , R 9 , R 10 , and R 11 is as defined herein for any embodiment or variation of a compound of formula (III). In some embodiments, R 1 is -CH3. In some embodiments, R 11 is -CH3.

[0092] In some embodiments, the compound of formula (III-A) is a compound of formula (III-A-1): [ka] or a pharma- ceutically acceptable salt thereof; In the formula, R 9 and R 10 is as defined herein for any embodiment or variation of a compound of formula (III). In some embodiments, R 9 is hydrogen. In some embodiments, R 9 is -C(=O)CH2CH3. In some embodiments, R 10 is hydrogen. In some embodiments, R 10 is -C(=O)CH2CH3.

[0093] In some embodiments, the compound of formula (III-A-1) is a compound of formula (III-A-1-a): [ka] or a pharma- ceutically acceptable salt thereof; In the formula, R 9a and R 10a is as defined herein for any embodiment or variation of a compound of formula (III). In some embodiments, R 9a is -CH2CH3. In some embodiments, R 10a is -CH2CH3.

[0094] In some embodiments, the compound of formula (III) is a compound of formula (III-B): [ka] or a pharma- ceutically acceptable salt thereof; In the formula, R 1 , R 2 , R 4 , R 5 , R 6 , R 7 , R 8 , R 11 , R 12 , R 13 , and R 14 is as defined herein for any embodiment or variation of a compound of formula (III). In some embodiments, R 1 is -CH3. In some embodiments, R 11 is -CH3. In some embodiments, R 2 , R 4 , R 5 , R 6 , R 7 , R 8 , R 12 , R 13 , and R 14 is hydrogen.

[0095] In some embodiments, the compound of formula (III) is a compound of formula (III-C): [ka] or a pharma- ceutically acceptable salt thereof; In the formula, R 1 , R 2 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9a , R 10a , R 11 , R 12 , R 13 , and R 14 is as defined herein for any embodiment or variation of a compound of formula (III). In some embodiments, R 1 is -CH3. In some embodiments, R 11 is -CH3. In some embodiments, R 2 , R 4 , R 5 , R 6 , R 7 , R 8 , R 12 , R 13 , and R 14 is hydrogen. In some embodiments, R 9a is -CH2CH3. In some embodiments, R 10a is -CH2CH3.

[0096] In some embodiments, the compound of formula (III-C) is a compound of formula (III-C-1): [ka] or a pharma- ceutically acceptable salt thereof; In the formula, R 1 , R 2 , R 4 , R 5 , R 6 , R 7 , R 8 , R 11 , R 12 , R 13 , and R 14 is as defined herein for any embodiment or variation of a compound of formula (III). In some embodiments, R1 is -CH3. In some embodiments, R 11 is -CH3. In some embodiments, R 2 , R 4 , R 5 , R 6 , R 7 , R 8 , R 12 , R 13 , and R 14 is hydrogen.

[0097] In some embodiments, the compound of formula (I) is a compound of formula (IV): [ka] or a pharma- ceutically acceptable salt thereof; In the formula, R 1 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , and R 14 is as defined herein for any embodiment or variation of a compound of formula (I), and R 2 is selected from the group consisting of hydrogen, hydroxyl, mercaptan, keto, and C1-C3 alkyl; R 4 is selected from the group consisting of hydrogen, hydroxyl, mercaptan, and C1-C3 alkyl.

[0098] In some embodiments, the compound of formula (IV) is a compound of formula (IV-A): [ka] or a pharma- ceutically acceptable salt thereof; In the formula, R 1 , R 9 , R 10 , and R 11is as defined herein for any embodiment or variation of a compound of formula (IV). In some embodiments, R 1 is -CH3. In some embodiments, R 11 is -CH3.

[0099] In some embodiments, the compound of formula (IV-A) is a compound of formula (IV-A-1): [ka] or a pharma- ceutically acceptable salt thereof; In the formula, R 9 and R 10 is as defined herein for any embodiment or variation of a compound of formula (IV). In some embodiments, R 9 is hydrogen. In some embodiments, R 9 is -C(=O)CH2CH3. In some embodiments, R 10 is hydrogen. In some embodiments, R 10 is -C(=O)CH2CH3.

[0100] In some embodiments, the compound of formula (IV-A-1) is a compound of formula (IV-A-1-a): [ka] or a pharma- ceutically acceptable salt thereof; In the formula, R 9a and R 10a is as defined herein for any embodiment or variation of a compound of formula (IV). In some embodiments, R 9a is -CH2CH3. In some embodiments, R 10a is -CH2CH3.

[0101] In some embodiments, the compound of formula (IV) is a compound of formula (IV-B): [ka] or a pharma- ceutically acceptable salt thereof; In the formula, R 1 , R 2 , R 4 , R 5 , R 6 , R 7 , R 8 , R 11 , R 12 , R 13 , and R 14 is as defined herein for any embodiment or variation of a compound of formula (IV). In some embodiments, R 1 is -CH3. In some embodiments, R 11 is -CH3. In some embodiments, R 2 , R 4 , R 5 , R 6 , R 7 , R 8 , R 12 , R 13 , and R 14 is hydrogen.

[0102] In some embodiments, the compound of formula (IV) is a compound of formula (IV-C): [ka] or a pharma- ceutically acceptable salt thereof; In the formula, R 1 , R 2 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9a , R 10a , R 11 , R 12 , R 13 , and R 14 is as defined herein for any embodiment or variation of a compound of formula (IV). In some embodiments, R 1 is -CH3. In some embodiments, R 11 is -CH3. In some embodiments, R 2, R 4 , R 5 , R 6 , R 7 , R 8 , R 12 , R 13 , and R 14 is hydrogen. In some embodiments, R 9a is -CH2CH3. In some embodiments, R 10a is -CH2CH3.

[0103] In some embodiments, the compound of formula (IV-C) is a compound of formula (IV-C-1): [ka] or a pharma- ceutically acceptable salt thereof; In the formula, R 1 , R 2 , R 4 , R 5 , R 6 , R 7 , R 8 , R 11 , R 12 , R 13 , and R 14 is as defined herein for any embodiment or variation of a compound of formula (IV). In some embodiments, R 1 is -CH3. In some embodiments, R 11 is -CH3. In some embodiments, R 2 , R 4 , R 5 , R 6 , R 7 , R 8 , R 12 , R 13 , and R 14 is hydrogen.

[0104] In some embodiments, R 5 , R 7 , R 8 , R 12 , R 13 , and R 14is independently selected from the group consisting of hydrogen, hydroxyl, mercaptan, keto, and C1-C3 alkyl; R 6 is selected from the group consisting of hydrogen, hydroxyl, mercaptan, and C1-C3 alkyl. 5 , R 6 , R 7 , R 8 , R 12 , R 13 , and R 14 is independently selected from the group consisting of hydrogen, hydroxyl, mercaptan, and C1-C3 alkyl (i.e., methyl, ethyl, n-propyl, or isopropyl). 5 , R 6 , R 7 , R 8 , R 12 , R 13 , and R 14 is independently selected from the group consisting of hydrogen, hydroxyl, -CH, and -CHCH. 5 , R 6 , R 7 , R 8 , R 12 , R 13 , and R 14 is independently selected from the group consisting of hydrogen, hydroxyl, and -CH. In some embodiments, R 5 , R 6 , R 7 , R 8 , R 12 , R 13 , and R 14 are all hydrogen. In some embodiments, R 5 , R 6 , R 7 , R 8 , R 12 , R 13 , and R 14 In some embodiments, six of R 5 , R 6 , R 7 , R 8 , R 12 , R 13 , and R 14In some embodiments, five of R 5 , R 6 , R 7 , R 8 , R 12 , R 13 , and R 14 In some embodiments, four of R 5 , R 6 , R 7 , R 8 , R 12 , R 13 , and R 14 In some embodiments, three of R 5 , R 6 , R 7 , R 8 , R 12 , R 13 , and R 14 In some embodiments, two of R 5 , R 6 , R 7 , R 8 , R 12 , R 13 , and R 14 In some embodiments, one of R 5 , R 6 , R 7 , R 8 , R 12 , R 13 , and R 14 In some embodiments, three of R 5 , R 6 , R 7 , R 8 , R 12 , R 13 , and R 14 In some embodiments, two of R 5 , R 6 , R 7 , R 8 , R 12 , R 13 , and R 14 In some embodiments, one of R 5 is hydroxyl. In some embodiments, R6 is hydroxyl. In some embodiments, R 7 is hydroxyl. In some embodiments, R 8 is hydroxyl. In some embodiments, R 12 is hydroxyl. In some embodiments, R 13 is hydroxyl. In some embodiments, R 14 is hydroxyl.

[0105] In some embodiments, R 5 , R 6 , R 7 , R 8 , R 12 , R 13 , and R 14 In some embodiments, three of R 5 , R 6 , R 7 , R 8 , R 12 , R 13 , and R 14 In some embodiments, two of R 5 , R 6 , R 7 , R 8 , R 12 , R 13 , and R 14 In some embodiments, one of R 5 is a mercaptan. In some embodiments, R 6 is a mercaptan. In some embodiments, R 7 is a mercaptan. In some embodiments, R 8 is a mercaptan. In some embodiments, R 12 is a mercaptan. In some embodiments, R 13 is a mercaptan. In some embodiments, R 14 is a mercaptan.

[0106] In some embodiments, R 5 , R 7 , R8 , R 12 , R 13 , and R 14 In some embodiments, three of R 5 , R 7 , R 8 , R 12 , R 13 , and R 14 In some embodiments, two of R 5 , R 7 , R 8 , R 12 , R 13 , and R 14 In some embodiments, one of R 5 is keto. In some embodiments, R 7 is keto. In some embodiments, R 8 is keto. In some embodiments, R 12 is keto. In some embodiments, R 13 is keto. In some embodiments, R 14 is keto.

[0107] In some embodiments, R 5 , R 6 , R 7 , R 8 , R 12 , R 13 , and R 14 are all independently C1-C3 alkyl. In some embodiments, R 5 , R 6 , R 7 , R 8 , R 12 , R 13 , and R 14 Six of R are independently C1-C3 alkyl. 5 , R 6 , R 7 , R 8 , R 12 , R 13 , and R 14 Five of are independently C1-C3 alkyl. 5 , R6 , R 7 , R 8 , R 12 , R 13 , and R 14 Four of are independently C1-C3 alkyl. 5 , R 6 , R 7 , R 8 , R 12 , R 13 , and R 14 Three of R are independently C1-C3 alkyl. 5 , R 6 , R 7 , R 8 , R 12 , R 13 , and R 14 Two of are independently C1-C3 alkyl. In some embodiments, R 5 , R 6 , R 7 , R 8 , R 12 , R 13 , and R 14 In some embodiments, one of R 5 is -CH3 or -CH2CH3. In some embodiments, R 6 is -CH3 or -CH2CH3. In some embodiments, R 7 is -CH3 or -CH2CH3. In some embodiments, R 8 is -CH3 or -CH2CH3. In some embodiments, R 12 is -CH3 or -CH2CH3. In some embodiments, R 13 is -CH3 or -CH2CH3. In some embodiments, R 14 is -CH3 or -CH2CH3.

[0108] In some embodiments, R 5 , R 6 , R 7 , R 8 , R 12 , R 13, and R 14 Three of R are hydroxyl and the others are each hydrogen. 5 , R 6 , R 7 , R 8 , R 12 , R 13 , and R 14 Two of R are hydroxyl and the others are each hydrogen. 5 , R 6 , R 7 , R 8 , R 12 , R 13 , and R 14 is hydroxyl and the others are each hydrogen. 5 , R 6 , R 7 , R 8 , R 12 , R 13 , and R 14 Three of R are mercaptans and the others are each hydrogen. 5 , R 6 , R 7 , R 8 , R 12 , R 13 , and R 14 Two of R are mercaptans and the others are each hydrogen. 5 , R 6 , R 7 , R 8 , R 12 , R 13 , and R 14 is a mercaptan and the others are each hydrogen. 5 , R 6 , R 7 , R 8 , R 12 , R 13 , and R 14 Three of R are independently C1-C3 alkyl and the others are each hydrogen. 5 , R 6 , R7 , R 8 , R 12 , R 13 , and R 14 Two of R are independently C1-C3 alkyl and the others are each hydrogen. 5 , R 6 , R 7 , R 8 , R 12 , R 13 , and R 14 One of R is C1-C3 alkyl and the others are each hydrogen. 5 , R 6 , R 7 , R 8 , R 12 , R 13 , and R 14 One of the groups is hydroxyl and R 5 , R 6 , R 7 , R 8 , R 12 , R 13 , and R 14 In some embodiments, one of R is C1-C3 alkyl and the others are each hydrogen. 5 , R 6 , R 7 , R 8 , R 12 , R 13 , and R 14 One of them is a mercaptan, R 5 , R 6 , R 7 , R 8 , R 12 , R 13 , and R 14 One of R is C1-C3 alkyl and the others are hydrogen. 5 , R 6 , R 7 , R 8 , R 12 , R 13 , and R 14 When is C1-C3 alkyl, it is understood that each C1-C3 alkyl is independently methyl, ethyl, n-propyl, or isopropyl.

[0109] In some embodiments, R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 11 , R 12 , R 13 , and R 14 Any one or more of R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 11 , R 12 , R 13 , and R 14 are all hydrogen. In some embodiments, R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 12 , R 13 , and R 14 Any one or more of R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 12 , R 13 , and R 14 are all hydrogen.

[0110] In some embodiments, R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 12 , R 13 , and R 14 is independently in the α or β configuration. In some embodiments, R2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 12 , R 13 , and R 14 are all in the α configuration. In some embodiments, R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 12 , R 13 , and R 14 Nine of the R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 12 , R 13 , and R 14 Eight of R are in the α configuration. 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 12 , R 13 , and R 14 Seven of R are in the α configuration. 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 12 , R 13 , and R 14 In some embodiments, six of R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 12, R 13 , and R 14 In some embodiments, five of R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 12 , R 13 , and R 14 In some embodiments, four of R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 12 , R 13 , and R 14 In some embodiments, three of R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 12 , R 13 , and R 14 In some embodiments, two of R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 12 , R 13 , and R 14 In some embodiments, one of R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 12 , R 13 , and R 14 are all in the β configuration. In some embodiments, R 2 , R 3 , R 4 , R5 , R 6 , R 7 , R 8 , R 12 , R 13 , and R 14 Nine of R are in the β configuration. 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 12 , R 13 , and R 14 Eight of R are in the β configuration. 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 12 , R 13 , and R 14 Seven of R are in the β configuration. 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 12 , R 13 , and R 14 Six of R are in the β configuration. 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 12 , R 13 , and R 14 Five of R are in the β configuration. 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 12 , R 13 , and R 14In some embodiments, four of R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 12 , R 13 , and R 14 In some embodiments, three of R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 12 , R 13 , and R 14 In some embodiments, two of R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 12 , R 13 , and R 14 In some embodiments, one of R 3 and R 6 In some embodiments, both of R 3 is the β configuration, and R 6 is in the α-configuration. In some embodiments, substituents above the plane of the compound are described as being in the β-configuration and may be depicted as a wedge-shaped bond. In some embodiments, substituents below the plane of the compound are described as being in the α-configuration and may be depicted as a dashed bond.

[0111] In some embodiments, R 2 Carbon with R 3 Between the carbon [ka] represents a single bond, and R 2 is selected from the group consisting of hydroxyl, mercaptan, and C1-C3 alkyl; R2 In some embodiments, R 2 In some embodiments, R 2 is the β configuration.

[0112] In some embodiments, R 2 Carbon with R 3 Between the carbon [ka] represents a single bond, and R 3 Carbon with R 4 Between the carbon [ka] represents a single bond, and R 3 is selected from the group consisting of hydrogen, hydroxyl, mercaptan, and C1-C3 alkyl; R 3 In some embodiments, R 3 In some embodiments, R 3 is the β configuration.

[0113] In some embodiments, R 3 Carbon with R 4 Between the carbon [ka] represents a single bond, and R 4 is selected from the group consisting of hydroxyl, mercaptan, and C1-C3 alkyl; R 4 In some embodiments, R 4 In some embodiments, R 4 is the β configuration.

[0114] In some embodiments, R 5 is selected from the group consisting of hydroxyl, mercaptan, and C1-C3 alkyl; R 5In some embodiments, R 5 In some embodiments, R 5 is the β configuration.

[0115] In some embodiments, R 6 is selected from the group consisting of hydrogen, hydroxyl, mercaptan, and C1-C3 alkyl; R 6 In some embodiments, R 6 In some embodiments, R 6 is the β configuration.

[0116] In some embodiments, R 7 is selected from the group consisting of hydroxyl, mercaptan, and C1-C3 alkyl; R 7 In some embodiments, R 7 In some embodiments, R 7 is the β configuration.

[0117] In some embodiments, R 8 is selected from the group consisting of hydroxyl, mercaptan, and C1-C3 alkyl; R 8 In some embodiments, R 8 In some embodiments, R 8 is the β configuration.

[0118] In some embodiments, R 12 is selected from the group consisting of hydroxyl, mercaptan, and C1-C3 alkyl; R 12 In some embodiments, R 12 In some embodiments, R 12 is the β configuration.

[0119] In some embodiments, R 13 is selected from the group consisting of hydroxyl, mercaptan, and C1-C3 alkyl; R13 In some embodiments, R 13 In some embodiments, R 13 is the β configuration.

[0120] In some embodiments, R 14 is selected from the group consisting of hydroxyl, mercaptan, and C1-C3 alkyl; R 14 In some embodiments, R 14 In some embodiments, R 14 is the β configuration.

[0121] In some embodiments, R 9 is hydrogen and -C(=O)R 9a In some embodiments, R 9 is -C(=O)R 9a and R 9a is selected from the group consisting of C1-C6 alkyl and C2-C6 alkenyl, wherein C1-C6 alkyl and C2-C6 alkenyl are optionally substituted with -C(=O)OH.

[0122] In some embodiments, R 9 is hydrogen.

[0123] In some embodiments, R 9 is -C(=O)R 9a where R 9a is a C1-C6 alkyl optionally substituted with -C(=O)OH.

[0124] In some embodiments, R 9 is -C(=O)R 9a and R 9a is an unsubstituted C1-C6 alkyl (i.e., C1 alkyl, C2 alkyl, C3 alkyl, C4 alkyl, C5 alkyl, or C6 alkyl). 9 is -C(=O)R 9a where R 9ais an unsubstituted C1-C3 alkyl (i.e., methyl, ethyl, n-propyl, or isopropyl). 9 is -C(=O)R 9a where R 9a is -CH2CH3. In some embodiments, R 9 is -C(=O)R 9a where R 9a is -CH3.

[0125] In some embodiments, R 9 is -C(=O)R 9a and R 9a is a C1-C6 alkyl (i.e., C1 alkyl, C2 alkyl, C3 alkyl, C4 alkyl, C5 alkyl, or C6 alkyl) substituted with -C(=O)OH. 9 is -C(=O)R 9a and R 9a is a C1-C3 alkyl (i.e., methyl, ethyl, n-propyl, or isopropyl) substituted with -C(=O)OH. In some embodiments, R 9 is -C(=O)R 9a and R 9a is -CHC(=O)OH, -CHCHC(=O)OH, -CH(C(=O)OH)CH, -CHCHCHC(=O)OH, -CHCH(C(=O)OH)CH, -CH(C(=O)OH)CHCH, -CH(CH)CHC(=O)OH, or -C(CH)C(=O)OH. In some embodiments, R 9 is -C(=O)R 9a and R 9a is -CH2CH2C(=O)OH.

[0126] In some embodiments, R 9 is -C(=O)R 9a and R 9a is a C2-C6 alkenyl optionally substituted with -C(=O)OH.

[0127] In some embodiments, R 9 is -C(=O)R 9a and R 9a is an unsubstituted C2-C6 alkenyl (i.e., C2 alkenyl, C3 alkenyl, C4 alkenyl, C5 alkenyl, or C6 alkenyl). 9 is -C(=O)R 9a and R 9a is an unsubstituted C4-C6 alkenyl containing one or two carbon-carbon double bonds (e.g., -CH=CHCH2CH3, -CH=CHCH2CH2CH3, -CH=CHCH2CH2CH2CH3, or -CH=CHCH=CH2). It is understood that the internal alkenyl can have an E or Z configuration. For example, -CH=CHCH2CH3 is [ka] where the wavy line indicates the point of attachment to the remainder of the molecule. 9a is an unsubstituted C4-C5 alkenyl containing one carbon-carbon double bond (e.g., -CH=CHCH2CH3, -CH2CH=CHCH3, -CH2CH2CH=CH2, -CH=CHCH2CH2CH3, -CH2CH=CHCH2CH3, -CH2CH2CH=CHCH3, -CH2CH2CH2CH=CHCH2, or -CH=CHCH(CH3)2). 9a is an unsubstituted C6 alkenyl containing one or two carbon-carbon double bonds (e.g., -CH=CHCH2CH2CH2CH3, -CH2CH=CHCH2CH2CH3, -CH2CH2CH=CHCH2CH3, -CH2CH2CH2CH=CHCH3, -CH2CH2CH2CH2CH=CHCH2, -CH=CHCH2CH(CH3)2, -CH=CHCH=CHCH2CH3, -CH=CHCH2CH=CHCH3, or -CH=CHCH2CH2CH=CH2).

[0128] In some embodiments, R 9 is -C(=O)R 9a and R 9ais a C2-C6 alkenyl (i.e., C2 alkenyl, C3 alkenyl, C4 alkenyl, C5 alkenyl, or C6 alkenyl) substituted with -C(=O)OH. 9 is -C(=O)R 9a and R 9a is a C2-C4 alkenyl (e.g., ethenyl or propenyl) substituted with -C(=O)OH. 9 is -C(=O)R 9a and R 9a is -CH=CHC(=O)OH, -CH=CHCH2C(=O)OH, -CH2CH=CHC(=O)OH, or -CH=C(CH3)C(=O)OH. In some embodiments, R 9 is -C(=O)R 9a and R 9a is -CH=CHC(=O)OH.

[0129] In some embodiments, R 10 is hydrogen and -C(=O)R 10a In some embodiments, R 10 is -C(=O)R 10a and R 10a is selected from the group consisting of C1-C6 alkyl and C2-C6 alkenyl, wherein C1-C6 alkyl and C2-C6 alkenyl are optionally substituted with -C(=O)OH. 10

[0130] In some embodiments, R 10 is hydrogen.

[0131] In some embodiments, R 10 is -C(=O)R 10a and R 10a is a C1-C6 alkyl optionally substituted with -C(=O)OH.

[0132] In some embodiments, R 10 is -C(=O)R 10a and R 10ais an unsubstituted C1-C6 alkyl (i.e., C1 alkyl, C2 alkyl, C3 alkyl, C4 alkyl, C5 alkyl, or C6 alkyl). 10 is -C(=O)R 10a and R 10a is an unsubstituted C1-C3 alkyl (i.e., methyl, ethyl, n-propyl, or isopropyl). 10 is -C(=O)R 10a and R 10a is -CH2CH3. In some embodiments, R 10 is -C(=O)R 10a and R 10a is -CH3.

[0133] In some embodiments, R 10 is -C(=O)R 10a and R 10a is a C1-C6 alkyl (i.e., C1 alkyl, C2 alkyl, C3 alkyl, C4 alkyl, C5 alkyl, or C6 alkyl) substituted with -C(=O)OH. 10 is -C(=O)R 10a and R 10a is a C1-C3 alkyl (i.e., methyl, ethyl, n-propyl, or isopropyl) substituted with -C(=O)OH. In some embodiments, R 10 is -C(=O)R 10a and R 10a is -CHC(=O)OH, -CHCHC(=O)OH, -CH(C(=O)OH)CH, -CHCHCHC(=O)OH, -CHCH(C(=O)OH)CH, -CH(C(=O)OH)CHCH, -CH(CH)CHC(=O)OH, or -C(CH)C(=O)OH. In some embodiments, R 10 is -C(=O)R 10a and R 10a is -CH2CH2C(=O)OH.

[0134] In some embodiments, R10 is -C(=O)R 10a and R 10a is a C2-C6 alkenyl optionally substituted with -C(=O)OH.

[0135] In some embodiments, R 10 is -C(=O)R 10a and R 10a is an unsubstituted C2-C6 alkenyl (i.e., C2 alkenyl, C3 alkenyl, C4 alkenyl, C5 alkenyl, or C6 alkenyl). 10 is -C(=O)R 10a and R 10a is a group consisting of one or two carbon-carbon double bonds (e.g., -CH=CHCH2CH3, -CH=CHCH2CH2CH 3、 In some embodiments, R is an unsubstituted C4-C6 alkenyl containing -CH=CHCH2CH2CH2CH3, or -CH=CHCH=CH2. 10a is an unsubstituted C4-C5 alkenyl containing one carbon-carbon double bond (e.g., -CH=CHCH2CH3, -CH2CH=CHCH3, -CH2CH2CH=CH2, -CH=CHCH2CH2CH3, -CH2CH=CHCH2CH3, -CH2CH2CH=CHCH3, -CH2CH2CH2CH=CHCH2, or -CH=CHCH(CH3)2). 10a is an unsubstituted C6 alkenyl containing one or two carbon-carbon double bonds (e.g., -CH=CHCH2CH2CH2CH3, -CH2CH=CHCH2CH2CH3, -CH2CH2CH=CHCH2CH3, -CH2CH2CH2CH=CHCH3, -CH2CH2CH2CH2CH=CHCH2, -CH=CHCH2CH(CH3)2, -CH=CHCH=CHCH2CH3, -CH=CHCH2CH=CHCH3, or -CH=CHCH2CH2CH=CH2).

[0136] In some embodiments, R 10 is -C(=O)R 10a and R 10ais a C2-C6 alkenyl (i.e., C2 alkenyl, C3 alkenyl, C4 alkenyl, C5 alkenyl, or C6 alkenyl) substituted with -C(=O)OH. 10 is -C(=O)R 10a and R 10a is a C2-C4 alkenyl (e.g., ethenyl or propenyl) substituted with -C(=O)OH. 10 is -C(=O)R 10a and R 10a is -CH=CHC(=O)OH, -CH=CHCH2C(=O)OH, -CH2CH=CHC(=O)OH, or -CH=C(CH3)C(=O)OH. In some embodiments, R 10 is -C(=O)R 10a and R 10a is -CH=CHC(=O)OH.

[0137] In some embodiments, R 9 and R 10 is independently hydrogen or -C(=O)CH2CH3. In some embodiments, R 9 and R 10 Each is hydrogen. In some embodiments, R 9 and R 10 are each -C(=O)CH2CH3. In some embodiments, R 9 is hydrogen, and R 10 is -C(=O)CH2CH3. In some embodiments, R 9 is -C(=O)CH2CH3, and R 10 is hydrogen.

[0138] Arnoldrin 2β,7α-Diethyl-A-nor-5α-androstane-2α,17β-diol (anordiol) was first reported to have antiestrogenic activity. See Bank et al, Proc. Soc. Expt. Biol. Med 111, 595 (1962) and Pincus et al, Steroids, 5, 193, (1965). Li et al. esterified anordiol with propionic acid to synthesize 2α,17α-diethynyl-A-nor-5α-androstane-2β,17β-diol dipropionate (anordrin, ANO) in 1969. Anordrin was marketed as an antifertility drug in China under the brand name AF-53 since 1976. Estrogen is known to cause hormone-induced cancer, and anordrin, as an estrogen receptor antagonist, was subsequently found to inhibit malignant cell growth and treat cancer. See Xu et al, Tumor, 9, 197 (1989); Ma et al, Acta Pharmacol.Sin, 21, 939 (2000); Li et al, US Patent 5001120 (1991).

[0139] In some embodiments, anordrin or an analog thereof is anordrin. [ka]

[0140] insomnia Insomnia is one of the most common symptoms that adults seek medical advice for. Insomnia can be caused by a variety of factors. In some embodiments, the insomnia described in this application is insomnia associated with low estrogen levels. In some embodiments, insomnia is associated with perimenopause, menopause, or postmenopause.

[0141] Insomnia is usually measured using sleep disturbance questionnaires (SDQs) such as the Pittsburgh Sleep Quality Index (PSQI), the Epworth Sleep Scale, or the Athens Insomnia Scale (AIS), or sleep quality monitors to count sleep dysfunction rating scales (SDRS). The AIS is one of the commonly used SEQs, see Figure 1. It is measured by assessing eight factors, the first five of which are related to nighttime sleep and the last three are related to daytime dysfunction. These are rated on a scale of 0 to 3, and sleep is finally evaluated from the cumulative score of all factors and reported as an individual's sleep outcome. Over time, the AIS has been considered to be an effective tool in sleep analysis and has been validated in various countries by testing on local patients. A cutoff score of at least 6 on the AIS is used to establish the diagnosis of insomnia. See Soldatos CR, Dikeos DG, Paparrigopoulos TJ(2002). “The diagnostic validity of the Athens Insomnia Scale”. J Psychosom Res. 55(3):263-7.

[0142] In some embodiments, the insomnia is chronic insomnia.

[0143] In some embodiments, the insomnia is a severe form of insomnia (e.g., the AIS score is at least about 22). In some embodiments, the insomnia is a moderate form of insomnia (e.g., the AIS score is at least about 15). In some embodiments, the AIS score is reduced by at least about 10%, 20%, 30%, 40%, 50%, or 60% after treatment at a frequency and dosage for a period of time described herein.

[0144] In some embodiments, the insomnia is a severe form of insomnia (e.g., a PSQI score of at least about 16). In some embodiments, the insomnia is a moderate form of insomnia (e.g., a PSQI score of at least about 11). In some embodiments, the PSQI score is reduced by at least about 10%, 20%, 30%, 40%, 50%, or 60% after treatment at a frequency and dosage for a period of time described herein.

[0145] Patient population In some embodiments, the individual is a mammal, hi some embodiments, the individual is a human.

[0146] In some embodiments, the individual is female.

[0147] In some embodiments, the individual has a thick endometrium, hi some embodiments, the endometrium is no greater than 6 mm, 5 mm, 4.5 mm, or 4 mm thick.

[0148] In some embodiments, the individual has undergone a hysterectomy.

[0149] In some embodiments, the individual is at least about 35, 40, or 45 years of age. In some embodiments, the individual is from about 45 to about 90 years of age or older.

[0150] In some embodiments, the individual is in the perimenopausal stage (e.g., the individual is still having menstrual periods, but estrogen levels are declining. In some embodiments, the individual has reached menopause. In some embodiments, the individual is in the postmenopausal stage. In some embodiments, it has been at least about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months since the last episode of menstruation.

[0151] In some embodiments, the individual has undergone surgical removal of the ovaries.

[0152] In some embodiments, the individual is not undergoing hormone therapy. In some embodiments, the individual is undergoing hormone therapy.

[0153] In some embodiments, the individual has or previously had cancer, hi some embodiments, the cancer is breast cancer, ovarian cancer, or endometrial cancer.

[0154] In some embodiments, the individual has had a stroke or has previously had a stroke, liver disease, blood clots in the legs or lungs, or unexplained vaginal bleeding.

[0155] In some embodiments, the individual has a severe form of insomnia (e.g., an AIS score of at least about 22). In some embodiments, the individual has a moderate form of insomnia (e.g., an AIS score of at least about 15). In some embodiments, the individual has an AIS score of at least about 6. In some embodiments, the individual has an AIS score of at least about 7. In some embodiments, the individual has an AIS score of at least about 15. In some embodiments, the individual has an AIS score of at least about 22.

[0156] In some embodiments, the individual has a severe form of insomnia (e.g., a PSQI score of at least about 16). In some embodiments, the individual has a moderate form of insomnia (e.g., a PSQI score of at least about 11). In some embodiments, the individual has a PSQI score of at least about 11. In some embodiments, the individual has a PSQI score of at least about 16.

[0157] Dosage and Administration The dosage of the composition comprising the compound of formula A or formula I may vary depending on the specific composition, the nature of the individual, the mode of administration, and the severity of insomnia. In some embodiments, the amount of formula I is sufficient to provide improved sleep in any one of the following conditions selected from the group consisting of: a) sleep onset time, b) nighttime waking time, c) when the final waking is earlier than desired and the degree of early waking, d) total sleep time, e) overall sleep quality, f) daytime well-being, g) daytime functioning (physical and / or mental), and h) daytime sleepiness. In some embodiments, the amount of formula I is sufficient to provide at least about 5%, 10%, 15%, 20%, 30%, 40%, 50%, or 60% reduction in SDQ or SDRS score. In some embodiments, the amount of Formula I is sufficient to result in a reduction in AIS score of at least about 5%, 10%, 15%, 20%, 30%, 40%, 50%, or 60% for at least 1, 2, 3, or 4 weeks. The AIS score can be assessed by an individual, for example, by filling out the table in FIG. 1 before and after treatment.

[0158] In some embodiments, the amount of Formula I is sufficient to induce a surge in extracellular ATP levels among neuronal cells (see, eg, Example 3 and / or FIG. 5).

[0159] In some embodiments, the dose of the compound for each administration is about 1 μg to about 10 mg (e.g., about 10 μg to about 1 mg) in humans, or an equivalent dose for non-human individuals. In some embodiments, the dose of the compound for each administration is at least about 1 μg, 5 μg, 10 μg, 20 μg, 50 μg, 75 μg, 100 μg, 125 μg, 150 μg, 175 μg, 200 μg, 250 μg, 300 μg, 350 μg, 400 μg, 450 μg, or 500 μg in humans, or an equivalent dose for non-human individuals. In some embodiments, the dose of the compound for each administration is about 10 mg, 7.5 mg, 5 mg, 2.5 mg, 2 mg, 1.5 mg, 1 mg, 0.9 mg, 0.8 mg, 0.7 mg, 0.6 mg, 0.5 mg, 0.4 mg, 0.3 mg, or 0.2 mg or less in humans, or an equivalent dose for non-human individuals. In some embodiments, the dose of the compound for each administration is about 20 μg to about 2 mg (e.g., about 20 μg to about 200 μg, or about 400 μg to about 2 mg) in humans, or an equivalent dose for non-human individuals. Equivalent doses for non-human individuals can be calculated based on the guidance provided, for example, in Nair, AB, & Jacob, S. (2016). A simple practice guide for dose conversion between animals and human. Journal of basic and clinical pharmacy, 7(2), 27.

[0160] In some embodiments, the dose of the compound for each administration in a human subject is about 0.01 mg to about 10 mg. In some embodiments, the dose of the compound for each administration in a human subject is about 0.01 mg to about 1 mg (e.g., about 0.05 mg to about 0.5 mg). In some embodiments, the dose of the compound for each administration in a human subject is about 0.5 mg to about 5 mg. In some embodiments, the dose of the compound for each administration in a human subject is at least about 0.01 mg, e.g., at least about 0.02 mg, e.g., at least about 0.05 mg.

[0161] In some embodiments, the dose of the compound for each administration in a human subject is about 0.05 mg. In some embodiments, the dose of the compound for each administration in a human subject is about 0.1 mg, and the dose of the compound for each administration in a human subject is about 0.15 mg.

[0162] In some embodiments, the daily dose of the compound in a human subject is about 0.01 mg to about 10 mg (e.g., about 0.05 mg to about 0.5 mg, e.g., about 0.05 mg to about 0.15 mg). In some embodiments, the weekly dose of the compound in a human subject is about 0.1 mg to about 10 mg (e.g., about 0.25 mg to about 5 mg, e.g., about 0.25 mg to about 1.2 mg).

[0163] In some embodiments, the composition is administered about once, twice, or three times per day. In some embodiments, the composition is administered about once, twice, or three times per week. In some embodiments, the composition is administered about once every two weeks.

[0164] In some embodiments, the composition is administered daily at a dosage of about 20 μg to about 200 μg (e.g., about 50 μg, 100 μg, or 150 μg). In some embodiments, the composition is administered weekly at a dosage of about 400 μg to about 2 mg.

[0165] In some embodiments, the composition is administered to the individual (e.g., at a frequency and / or dose described herein) for at least about 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, or 8 weeks. In some embodiments, the composition is administered to the individual (e.g., at a frequency and / or dose described herein) for at least 2 weeks. In some embodiments, the composition is administered to the individual for at least about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months (e.g., at a frequency and / or dose described herein). In some embodiments, the composition is administered to the individual (e.g., at a frequency and / or dose described herein) for at least about 1 year, 1.5 years, 2 years, 3 years, 4 years, or 5 years.

[0166] The compositions described herein can be administered to an individual (such as a human) via a variety of routes, including, for example, intravenous, intraarterial, intraperitoneal, intrapulmonary, oral, inhalation, intravesical, intramuscular, intratracheal, subcutaneous, intraocular, intrathecal, transmucosal, and transdermal. In some embodiments, the compositions are administered orally.

[0167] Pharmaceutical Compositions Further provided are pharmaceutical compositions comprising a compound of Formula A or Formula I as described herein, or a pharma- ceutically acceptable salt or ester thereof, and one or more pharma- ceutically acceptable carriers, excipients, stabilizers, diluents, and / or other agents known in the art, for use in the methods described herein.

[0168] In some embodiments, a pharmaceutical composition is provided comprising a compound of formula I (such as anordrin) or a pharma- ceutically acceptable salt or ester thereof, and a pharma- ceutically acceptable carrier.

[0169] The pharmaceutical compositions described herein can be formulated as a solution, emulsion, suspension, dispersion, or inclusion complex such as cyclodextrin in a suitable pharmaceutical solvent or carrier, or with a solid carrier by conventional methods known in the art for preparing various dosage forms, as pills, tablets, lozenges, suppositories, sachets, dragees, granules, powders, powders for reconstitution, or capsules. The pharmaceutical compositions of the embodiments can be administered by a suitable delivery route, such as oral, parenteral, rectal, nasal, topical, or ocular, or by inhalation. In some embodiments, the pharmaceutical compositions are formulated for oral administration.

[0170] For oral administration, the pharmaceutical composition may be provided in a solid form, such as a tablet or capsule, or as a solution, emulsion, or suspension. In some embodiments, the pharmaceutical composition is formulated as a tablet, capsule, or pill. Oral tablets may contain the active ingredient(s) mixed with compatible pharma- ceutically acceptable excipients, such as diluents, disintegrants, binders, lubricants, sweeteners, flavorings, colorings, and preservatives. Suitable inert fillers include sodium and calcium carbonate, sodium and calcium phosphate, lactose, starch, sugar, glucose, methylcellulose, magnesium stearate, mannitol, sorbitol, and the like. Exemplary liquid oral excipients include ethanol, glycerol, water, and the like. Starch, polyvinyl-pyrrolidone (PVP), sodium starch glycolate, microcrystalline cellulose, and alginic acid are exemplary disintegrants. Binders may include starch and gelatin. Lubricant, if present, can be magnesium stearate, stearic acid or talc.If desired, tablet can be coated with a material for delaying absorption in the digestive tract, such as glyceryl monostearate or glyceryl distearate, or can be coated with an enteric coating.Oral formulation can be presented as separate units such as capsules, cachets or tablets, each containing a predetermined amount of active ingredient, as powder or granules, as a solution or suspension in aqueous or non-aqueous liquid, or as an oil-in-water or water-in-oil liquid emulsion.Active ingredient can be presented as a bolus, electuary or paste.

[0171] Tablets can be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets can be prepared by compressing the active ingredient in a free-flowing form, such as powder or granules, mixed with optional binders (e.g., povidone, gelatin, hydroxypropylmethylcellulose), lubricants, inert diluents, preservatives, disintegrants (e.g., sodium starch glycolate, cross-linked povidone, cross-linked sodium carboxymethylcellulose), surface active agents or dispersants, in a suitable machine. Molded tablets can be made by molding a mixture of powdered compounds moistened with an inert liquid diluent in a suitable machine. Tablets can be optionally coated or scored, and can be formulated to provide delayed or controlled release of the active ingredient therein, for example, using hydroxypropylmethylcellulose in various proportions, to provide a desired release profile.

[0172] Capsules for oral administration include hard and soft gelatin capsules. To prepare hard gelatin capsules, the active ingredient(s) can be mixed with a solid, semi-solid, or liquid diluent. Soft gelatin capsules can be prepared by mixing the active ingredient with water, oil, such as peanut oil or olive oil, liquid paraffin, a mixture of mono- and diglycerides of short chain fatty acids, polyethylene glycol 400, or propylene glycol. Capsules may also contain gelatin, iron oxide, stearic acid, and titanium dioxide as inactive ingredients.

[0173] The liquid for oral administration can be in the form of suspension, solution, emulsion or syrup, or can be lyophilized or provided as a dry product for reconstitution with water or other suitable vehicle before use.This liquid composition can optionally contain pharma- ceutically acceptable excipients such as suspending agents (e.g., sorbitol, methylcellulose, sodium alginate, gelatin, hydroxyethylcellulose, carboxymethylcellulose, aluminum stearate gel, etc.); non-aqueous vehicles such as oils (e.g., almond oil or coconut oil), propylene glycol, ethyl alcohol, or water; preservatives (e.g., methyl p-hydroxybenzoate or propyl p-hydroxybenzoate or sorbic acid); wetting agents such as lecithin; and, if desired, flavorings or colorings.

[0174] Kits, pharmaceuticals, compositions and unit doses The present application also provides kits, pharmaceuticals, compositions, and unit dosage forms for use in any of the methods described herein.

[0175] The kits of the invention include one or more containers containing a composition (such as a pharmaceutical composition) comprising a compound of Formula A or Formula I as described herein, or a pharma- ceutically acceptable salt or ester thereof (or a unit dosage form and / or an article of manufacture), and further include instructions for use according to any of the methods described herein. The kit may further include instructions for selecting a suitable individual or treatment. The instructions provided in the kits of the invention are typically written instructions on a label or insert (e.g., a paper included in the kit), although machine-readable instructions (e.g., instructions carried on a magnetic or optical memory disk) are also acceptable.

[0176] For example, in some embodiments, the kit includes a) a composition comprising a compound of formula I described herein (e.g., anordrin), or a pharma- ceutically acceptable salt or ester thereof, and b) instructions for administering the composition for the treatment of insomnia. In some embodiments, the kit includes a) a composition comprising anordrin, and b) instructions for administering (e.g., orally administering) the composition for the treatment of insomnia. In some embodiments, the kit further includes a second agent. The composition and the other agent may be in separate containers or in a single container. For example, the kit may include one different composition or two or more compositions, one composition comprising the composition and one composition comprising another agent.

[0177] The kit of the present invention is in suitable packaging. Suitable packaging includes, but is not limited to, vials, bottles, jars, flexible packaging (e.g., sealed Mylar or plastic bags), and the like. The kit may optionally provide additional components, such as buffers and interpretable information. Thus, the present application also provides articles of manufacture that include vials (such as sealed vials), bottles, jars, flexible packaging, and the like.

[0178] The instructions for use of the composition generally include information regarding dosage, dosing schedule, and route of administration for the intended treatment. The container may be a unit dose, bulk package (e.g., multi-dose package), or divided unit dose. For example, a kit may be provided that contains a sufficient dose of a compound (such as anordrin) disclosed herein to provide effective treatment of an individual for any period of about 1, 2, 3, 4, 5, 6, or 7 days, or about 1, 2, 3, 4, 5, or 6 weeks, or about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months, or about 1, 2, 3, 4, 5, or 6 years. The kit may also include a plurality of unit doses of a compound (such as anordrin) of formula I, as well as pharmaceutical compositions and instructions for use, and may be packaged in an amount sufficient for storage and use of the compound in pharmacies, such as hospital pharmacies and compounding pharmacies.

[0179] Also provided are medicaments, compositions, and unit dosage forms useful for the methods described herein. In some embodiments, a medicament (or composition) for use in treating insomnia is provided, comprising a composition comprising a compound of formula I (e.g., anordrin) as described herein, or a pharma- ceutical acceptable salt or ester thereof.

[0180] Exemplary embodiments Embodiment 1. A method of treating insomnia in an individual, comprising administering to the individual an effective amount of a compound of formula I: [ka] or a pharma- ceutically acceptable salt or ester thereof, a)R 2 Carbon with R 3 Between the carbon [ka] represents a single bond, and R 3 Carbon with R 4 Between the carbon [ka] represents a single bond, and R 2 and R 4 is independently selected from the group consisting of hydrogen, hydroxyl, mercaptan, keto, and C1-C3 alkyl; R 3 is selected from the group consisting of hydrogen, hydroxyl, mercaptan, and C1-C3 alkyl; or R 2 Carbon with R 3 Between the carbon [ka] represents a double bond, and R 3 Carbon with R 4 Between the carbon [ka] represents a single bond, and R 2 is selected from the group consisting of hydrogen, hydroxyl, mercaptan, and C1-C3 alkyl; R 3 does not exist and R 4 is selected from the group consisting of hydrogen, hydroxyl, mercaptan, keto, and C1-C3 alkyl; or R 2 Carbon with R 3 Between the carbon [ka] represents a single bond, and R 3 Carbon with R 4 Between the carbon [ka] represents a double bond, and R 2 is selected from the group consisting of hydrogen, hydroxyl, mercaptan, keto, and C1-C3 alkyl; R 3 does not exist and R 4 is selected from the group consisting of hydrogen, hydroxyl, mercaptan, and C1-C3 alkyl; b)R 1 is C1-C3 alkyl, c)R 5 , R 7 , R 8 , R 12 , R 13 , and R 14 is independently selected from the group consisting of hydrogen, hydroxyl, mercaptan, keto, and C1-C3 alkyl; d) R 6 is selected from the group consisting of hydrogen, hydroxyl, mercaptan, and C1-C3 alkyl; e)R 9 is hydrogen and -C(=O)R 9a is selected from the group consisting of f)R 10 is hydrogen and -C(=O)R 10a is selected from the group consisting of g)R 9a and R 10ais independently selected from the group consisting of C1-C6 alkyl and C2-C6 alkenyl, wherein the C1-C6 alkyl and C2-C6 alkenyl are optionally substituted with -C(=O)OH; h)R 11 is selected from the group consisting of hydrogen and C1-C3 alkyl.

[0181] Embodiment 2.R 9 and R 10 is independently hydrogen or -C(=O)CH2CH3.

[0182] Embodiment 3.R 1 and R 11 3. The method of embodiment 1 or embodiment 2, wherein one or both of is -CH3.

[0183] Embodiment 4.R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 12 , R 13 , and R 14 The method of any one of embodiments 1 to 3, wherein any one or more of is hydrogen.

[0184] Embodiment 5. The method of any one of embodiments 1-4, wherein the compound is anordrin.

[0185] Embodiment 6. The method of any one of embodiments 1 to 5, wherein the individual is a female.

[0186] Embodiment 7. The method of any one of embodiments 1 to 6, wherein the individual is a human.

[0187] Embodiment 8. The method of any one of embodiments 1-7, wherein the individual is in the perimenopausal stage, has reached menopause, is postmenopausal, or has undergone surgical removal of the ovaries.

[0188] Embodiment 9. The method of embodiment 8, wherein the individual is a postmenopausal woman.

[0189] Embodiment 10. The method of any one of embodiments 1-9, wherein the individual has an abnormal level of estrogen.

[0190] Embodiment 11. The method of any one of embodiments 1 to 10, wherein the individual has a score of at least about 7 on the Athens Insomnia Scale.

[0191] Embodiment 12. The method of any one of embodiments 1-11, wherein the individual is not undergoing or has never undergone hormone therapy.

[0192] Embodiment 13. The method of any one of embodiments 1-12, wherein said dose of said compound for each administration is at least about 20 μg in a human, or an equivalent dose in a non-human individual.

[0193] Embodiment 14. The method of embodiment 13, wherein said dose of said compound for each administration is at least about 50 μg in a human, or an equivalent dose in a non-human individual.

[0194] Embodiment 15. The method of embodiment 14, wherein said dose of said compound for each administration is at least about 100 μg in a human, or an equivalent dose in a non-human individual.

[0195] Embodiment 16. The method of embodiment 15, wherein said dose of said compound for each administration is at least about 150 μg in a human, or an equivalent dose in a non-human individual.

[0196] Embodiment 17. The method of any one of embodiments 1-16, wherein said dose of said compound for each administration is no more than 2 mg in a human, or an equivalent dose in a non-human individual.

[0197] Embodiment 18. The method of any one of embodiments 1 to 17, wherein the dose of the compound for each administration is from about 20 μg to about 2 mg in a human, or an equivalent dose in a non-human individual.

[0198] Embodiment 19. The method of embodiment 18, wherein said dose of said compound for each administration is from about 20 μg to about 200 μg in a human, or an equivalent dose in a non-human individual.

[0199] Embodiment 20. The method of embodiment 19, wherein said dose of said compound for each administration is from about 400 μg to about 2 mg in a human, or an equivalent dose in a non-human individual.

[0200] Embodiment 21. The method of any one of embodiments 1-20, wherein the composition is administered at a frequency of about once every two weeks to about three times a day.

[0201] Embodiment 22 The method of embodiment 21, wherein the composition is administered daily.

[0202] Embodiment 23. The method of embodiment 22, wherein the composition is administered daily in a dosage of about 20 μg to about 200 μg.

[0203] Embodiment 24 The method of embodiment 21, wherein the composition is administered weekly.

[0204] Embodiment 25. The method of embodiment 24, wherein the composition is administered weekly at a dosage of about 400 μg to about 2 mg.

[0205] Embodiment 26. The method of any one of embodiments 1-25, wherein the composition is administered intravenously, intraarterially, intraperitoneally, intravesically, subcutaneously, intrathecally, intrapulmonary, intramuscularly, intratracheally, intraocularly, transdermally, orally, or by inhalation.

[0206] Embodiment 27 The method of embodiment 26, wherein the composition is administered orally.

[0207] Embodiment 28 The method of any one of embodiments 1 to 27, wherein the method further comprises administering a second agent.

[0208] Embodiment 29. The method of any one of embodiments 1 to 28, further comprising assessing estrogen levels in the individual.

[0209] Embodiment 30. The method of any one of embodiments 1 to 29, wherein the insomnia is chronic insomnia.

[0210] Embodiment 31. A unit dosage form for treating insomnia comprising: a) a composition comprising a compound of formula I, wherein the amount of the compound ranges from about 20 μg to about 2 mg; and b) a pharma- ceutically acceptable carrier.

[0211] Embodiment 32. Use of a composition comprising an effective amount of a compound of formula I (e.g., anordrin) for treating insomnia.

[0212] Embodiment 33. A composition comprising a compound of formula I (e.g., anordrin) for treating insomnia.

[0213] Embodiment 34. A kit comprising: a) a composition comprising a compound of formula I; and b) instructions for using the kit to treat insomnia. EXAMPLES

[0214] The following examples are intended to be purely illustrative of the present invention and therefore should not be construed as limiting the present invention in any way. The following examples and detailed description are offered by way of illustration and not by way of limitation.

[0215] Example 1. Individuals who took Anordrin (less than 1 mg) self-assessed the presence and severity of insomnia before and after they took Anordrin. Specifically, 13 postmenopausal women took Anordrin for approximately 2 weeks to several months. Their sleep quality was assessed with the Athens Insomnia Scale (AIS). See Figure 2. [Table 1]

[0216] As shown in Figure 3 and Table 1, the number of AIS in each patient was significantly reduced after treatment with Anordrin. The average number of AIS was reduced by 63%. The results indicate that Anordrin effectively improved the sleep of these individuals.

[0217] The compound of formula A was also tested and showed efficacy (data not shown).

[0218] Example 2. This Phase II clinical trial will be conducted in three clinical trial centers using a randomized, double-blind, parallel-controlled design. A total of three drug groups will be pre-established: A) 0.05 mg / day dosage group, b) 0.1 mg / day dosage group, and c) 0.15 mg / day dosage group, and a placebo group. The drug intervention period will be 8 weeks, and the drug intervention will be followed up for 4 weeks. The primary efficacy endpoints include vaginal exfoliation cell maturation index and dryness in postmenopausal women. Secondary efficacy endpoints include quality of postmenopausal women, vaginal microecological index, vaginal pH of postmenopausal women, and safety endpoints. The efficacy and safety of different doses of α-Anoldrin tablets will be preliminarily evaluated.

[0219] Medication Regimen Group 1 (0.05 mg dose group): one 0.05 mg α-Anordrin enteric coated tablet is orally administered daily. Group 2 (0.1 mg dose group): one 0.1 mg α-Anordrin enteric coated tablet is orally administered daily. Group 3 (0.15 mg dose group): one 0.15 mg α-Anordrin enteric coated tablet is orally administered daily. Group 4: Placebo group.

[0220] Inclusion criteria To be eligible to enroll in the study, subjects must meet all of the following criteria: 1) 45-80 years of age, after surgery to remove the ovaries or at least 12 months have passed since the last menstrual period;2) Female patients with chronic insomnia and an Athens Insomnia Scale (AIS) index of 7 or more;3) Follicle-stimulating hormone (FSH) serum level is more than 40 U / L, estradiol (E2) is less than 35 pg / mL, and β-hCG is negative;4) Pelvic ultrasound examination reveals that the endometrial thickness is 0.4 cm or less, or the subject has undergone hysterectomy;5) Meet the criteria for diagnosis and treatment of external vaginal atrophy: the results of the vaginal cell maturity index test show that the percentage of upper vaginal cells is 5% or less, and the vaginal pH is more than 5;6) Based on the subject's evaluation, they are able to complete the clinical trial according to the program;7) Voluntarily participate in the clinical study after fully understanding the purpose, content, process, possible benefits and risks of the clinical study, sign the informed consent, and comply with the requirements of the clinical study.

[0221] Endpoints Efficacy endpoints included: a) change in vaginal exfoliation cell maturation index compared to baseline value; b) change in insomnia severity index score compared to baseline value; c) change in vaginal microecological index score compared to baseline value; and d) change in vaginal pH compared to baseline value.

[0222] Safety endpoints included adverse events (including serious adverse events), clinical and ancillary tests, vital signs, and physical examinations.

[0223] Preliminary results Table 2 shows the Athens Insomnia Scale (AIS) index change of three patients after the treatment of Anordrin.As shown, all three patients showed that sleep quality improved significantly after the treatment of Anordrin 0.05mg / day.The results are consistent with those seen in Example 1. [Table 2]

[0224] Example 3. It has been reported that ATP levels in brain regions are stable during wakefulness, but show a surge during the early hours of sleep. This ATP surge shows a significant positive correlation with the intensity of EEG slow wave activity in non-rapid eye movement (NREM) sleep, which is a parameter of sleep depth and homeostatic need for sleep. See Chikahisa et al., Front Neurol. 2011;2:87. In this example, neurons are treated with anordrin and ATP levels are measured to understand whether anordrin treatment induces ATP surge.

[0225] Materials and equipment included cell culture medium, FBS and charcoal-stripped FBS, ATP assay kit (Thermofisher), and rat primary neuronal cells (Wuhan servisebio).

[0226] Primary neuronal cells (2 × 10 6 ) were grown in medium containing 10% FBS in 6-well plates for 24 hours. The medium was then replaced with phenol red-free medium containing 5% charcoal-stripped FBS for 24 hours. 10 nM anordrin or vehicle was added to the medium for 24 hours, and then the cells were harvested. ATP fluorescence density was assayed using an ATP assay kit according to the manufacturer's instructions.

[0227] As shown in FIG. 5, anordrin significantly increased neuronal ATP levels, demonstrating the positive effect of anordrin on sleep regulation.

Claims

1. 1. A composition for use in a method of treating insomnia in an individual, the method comprising administering to the individual the composition, the composition comprising a compound of formula A: 【Chemistry 1】 or a pharma- ceutically acceptable salt or ester thereof, a) R ２ and a carbon having R ３ Between the carbon 【Chemistry 2】 represents a single bond, R ３ and a carbon having R ４ Between the carbon 【Chemistry 3】 represents a single bond, R ２ and R ４ are independently hydrogen, hydroxyl, mercaptan, keto, and C １ ~C ３ alkyl; R ３ is hydrogen, hydroxyl, mercaptan, and C １ ~C ３ alkyl; or R ２ and a carbon having R ３ Between the carbon 【Chemistry 4】 represents a double bond, R ３ and a carbon having R ４ Between the carbon 【Chemistry 5】 represents a single bond, R ２ is hydrogen, hydroxyl, mercaptan, and C １ ~C ３ alkyl; R ３ does not exist, and R ４ is hydrogen, hydroxyl, mercaptan, keto, and C １ ~C ３ alkyl; or R ２ and a carbon having R ３ Between the carbon 【Chemistry 6】 represents a single bond, R ３ and a carbon having R ４ Between the carbon 【Chemistry 7】 represents a double bond, R ２ is hydrogen, hydroxyl, mercaptan, keto, and C １ ~C ３ alkyl; R ３ does not exist, and R ４ is hydrogen, hydroxyl, mercaptan, and C １ ~C ３ is selected from the group consisting of alkyl, b) R １ But, C １ ~C ３ is alkyl, c) R ５ , R ７ , R ８ , R １２ , R １３ , and R １４ are independently hydrogen, hydroxyl, mercaptan, keto, and C １ ~C ３ is selected from the group consisting of alkyl, d) R ６ is hydrogen, hydroxyl, mercaptan, and C １ ~C ３ is selected from the group consisting of alkyl, e) R ９ is hydrogen and -C(=O)R ９ａ is selected from the group consisting of f) R １０ is hydrogen and -C(=O)R １０ａ is selected from the group consisting of g) R ９ａ and R １０ａ is independently １ ~C ６ Alkyl and C ２ ~C ６ alkenyl, １ ~C ６ Alkyl and C ２ ~C ６ The alkenyl is optionally substituted with -C(=O)OH; h) R １１ is hydrogen and C １ ~C ３ The composition is selected from the group consisting of alkyl.

2. R ９ and R １０ are independently hydrogen or -C(=O)CH ２ CH ３ 2. The composition of claim 1 ,

3. R １ and R １１ One or both of ３ The composition of claim 2 ,

4. R ２ , R ３ , R ４ , R ５ , R ６ , R ７ , R ８ , R １２ , R １３ , and R １４ The composition of claim 3, wherein any one or more of is hydrogen.

5. The composition of claim 4, wherein the compound is anordrin.

6. The composition according to any one of claims 1 to 5, wherein the individual is a female.

7. The composition according to any one of claims 1 to 5, wherein the individual is a human.

8. The composition of any one of claims 1 to 5, wherein the individual is in the perimenopausal stage, has reached menopause, is postmenopausal, or has undergone surgical removal of the ovaries.

9. The composition of claim 5 , wherein the individual is a postmenopausal woman.

10. The composition of any one of claims 1 to 5, wherein the individual has low levels of estrogen.

11. The composition of any one of claims 1 to 5, wherein the dose of said compound for each administration is at least about 20 μg in a human, or an equivalent dose in a non-human individual.

12. 12. The composition of claim 11, wherein the dose of the compound for each administration is at least about 50 μg in a human, or an equivalent dose in a non-human individual.

13. 13. The composition of claim 12, wherein the dose of the compound for each administration is at least about 200 μg in a human, or an equivalent dose in a non-human individual.

14. 14. The composition of claim 13, wherein the dose of the compound for each administration is no more than 400 μg in a human, or an equivalent dose in a non-human individual.

15. The composition of any one of claims 1 to 5, wherein the dose of the compound for each administration is no more than 2 mg in humans, or an equivalent dose in non-human individuals.

16. The composition of any one of claims 1 to 5, wherein the dose of the compound for each administration is from about 20 μg to about 2 mg in humans, or an equivalent dose in a non-human individual.

17. 17. The composition of claim 16, wherein the dose of the compound for each administration is from about 50 μg to about 400 μg in a human, or an equivalent dose in a non-human individual.

18. 18. The composition of claim 17, wherein the dose of the compound for each administration is from about 50 μg to about 200 μg in a human, or an equivalent dose in a non-human individual.

19. The composition of any one of claims 1 to 5, wherein the composition is administered at a frequency of about once every two weeks to about three times a day.

20. 20. The composition of claim 19, wherein the composition is administered once daily.

21. 21. The composition of claim 20, wherein the composition is administered once daily at a dosage of about 50 μg to about 300 μg.

22. 20. The composition of claim 19, wherein the composition is administered weekly.

23. 23. The composition of claim 22, wherein the composition is administered weekly at a dosage of about 400 μg to about 2 mg.

24. 6. The composition of any one of claims 1 to 5, wherein the composition is administered intravenously, intraarterially, intraperitoneally, intravesically, subcutaneously, intrathecally, intrapulmonary, intramuscularly, intratracheally, intraocularly, transdermally, orally, or by inhalation.

25. 25. The composition of claim 24, wherein the composition is administered orally.

26. The composition of any one of claims 1 to 5, wherein the method further comprises administering to the individual a second agent.

27. The composition of any one of claims 1 to 5, wherein the method further comprises assessing estrogen levels in the individual.

28. The composition according to any one of claims 1 to 5, wherein the insomnia is chronic insomnia.

29. 1. A unit dosage form for treating insomnia, comprising: a) a compound of formula I 【Chemistry 1】 wherein the amount of the compound ranges from about 20 μg to about 2 mg; and b) a pharma- ceutically acceptable carrier, wherein a) Between the carbon bearing R 2 and the carbon bearing R 3 【Chemistry 2】 represents a single bond, and between the carbon having R 3 and the carbon having R 4 【Chemistry 3】 represents a single bond; R 2 and R 4 are independently selected from the group consisting of hydrogen, hydroxyl, mercaptan, keto, and C 1 -C 3 alkyl; and R 3 is selected from the group consisting of hydrogen, hydroxyl, mercaptan, and C 1 -C 3 alkyl; or Between the carbon bearing R 2 and the carbon bearing R 3 【Chemistry 4】 represents a double bond, and between the carbon having R 3 and the carbon having R 4 【Chemistry 5】 represents a single bond, R 2 is selected from the group consisting of hydrogen, hydroxyl, mercaptan, and C 1 -C 3 alkyl, R 3 is absent, and R 4 is selected from the group consisting of hydrogen, hydroxyl, mercaptan, keto, and C 1 -C 3 alkyl; or Between the carbon bearing R 2 and the carbon bearing R 3 【Chemistry 6】 represents a single bond, and between the carbon having R 3 and the carbon having R 4 【Chemistry 7】 represents a double bond, R 2 is selected from the group consisting of hydrogen, hydroxyl, mercaptan, keto, and C 1 -C 3 alkyl, R 3 is absent, and R 4 is selected from the group consisting of hydrogen, hydroxyl, mercaptan, and C 1 -C 3 alkyl; b) R 1 is C 1 -C 3 alkyl; c) R 5 , R 7 , R 8 , R 12 , R 13 , and R 14 are independently selected from the group consisting of hydrogen, hydroxyl, mercaptan, keto, and C 1 -C 3 alkyl; d) R 6 is selected from the group consisting of hydrogen, hydroxyl, mercaptan, and C 1 -C 3 alkyl; e) R 9 is selected from the group consisting of hydrogen and -C(=O)R 9a ; f) R 10 is selected from the group consisting of hydrogen and -C(=O)R 10a ; g) R 9a and R 10a are independently selected from the group consisting of C 1 -C 6 alkyl and C 2 -C 6 alkenyl, which are optionally substituted with -C(=O)OH; h) The above unit dosage form wherein R 11 is selected from the group consisting of hydrogen and C 1 -C 3 alkyl.

30. 1. A composition for treating insomnia, comprising a compound of formula I: 【Chemistry 1】 where a) Between the carbon bearing R 2 and the carbon bearing R 3 【Chemistry 2】 represents a single bond, and between the carbon having R 3 and the carbon having R 4 【Chemistry 3】 represents a single bond; R 2 and R 4 are independently selected from the group consisting of hydrogen, hydroxyl, mercaptan, keto, and C 1 -C 3 alkyl; and R 3 is selected from the group consisting of hydrogen, hydroxyl, mercaptan, and C 1 -C 3 alkyl; or Between the carbon bearing R 2 and the carbon bearing R 3 【Chemistry 4】 represents a double bond, and between the carbon having R 3 and the carbon having R 4 【Chemistry 5】 represents a single bond, R 2 is selected from the group consisting of hydrogen, hydroxyl, mercaptan, and C 1 -C 3 alkyl, R 3 is absent, and R 4 is selected from the group consisting of hydrogen, hydroxyl, mercaptan, keto, and C 1 -C 3 alkyl; or Between the carbon bearing R 2 and the carbon bearing R 3 【Chemistry 6】 represents a single bond, and between the carbon having R 3 and the carbon having R 4 【Chemistry 7】 represents a double bond, R 2 is selected from the group consisting of hydrogen, hydroxyl, mercaptan, keto, and C 1 -C 3 alkyl, R 3 is absent, and R 4 is selected from the group consisting of hydrogen, hydroxyl, mercaptan, and C 1 -C 3 alkyl; b) R 1 is C 1 -C 3 alkyl; c) R 5 , R 7 , R 8 , R 12 , R 13 , and R 14 are independently selected from the group consisting of hydrogen, hydroxyl, mercaptan, keto, and C 1 -C 3 alkyl; d) R 6 is selected from the group consisting of hydrogen, hydroxyl, mercaptan, and C 1 -C 3 alkyl; e) R 9 is selected from the group consisting of hydrogen and -C(=O)R 9a ; f) R 10 is selected from the group consisting of hydrogen and -C(=O)R 10a ; g) R 9a and R 10a are independently selected from the group consisting of C 1 -C 6 alkyl and C 2 -C 6 alkenyl, which are optionally substituted with -C(=O)OH; h) The above composition wherein R 11 is selected from the group consisting of hydrogen and C 1 -C 3 alkyl.

31. A kit comprising: i) a compound of formula I 【Chemistry 1】 A composition comprising: a) Between the carbon bearing R 2 and the carbon bearing R 3 【Chemistry 2】 represents a single bond, and between the carbon having R 3 and the carbon having R 4 【Chemistry 3】 represents a single bond; R 2 and R 4 are independently selected from the group consisting of hydrogen, hydroxyl, mercaptan, keto, and C 1 -C 3 alkyl; and R 3 is selected from the group consisting of hydrogen, hydroxyl, mercaptan, and C 1 -C 3 alkyl; or Between the carbon bearing R 2 and the carbon bearing R 3 【Chemistry 4】 represents a double bond, and between the carbon having R 3 and the carbon having R 4 【Chemistry 5】 represents a single bond, R 2 is selected from the group consisting of hydrogen, hydroxyl, mercaptan, and C 1 -C 3 alkyl, R 3 is absent, and R 4 is selected from the group consisting of hydrogen, hydroxyl, mercaptan, keto, and C 1 -C 3 alkyl; or Between the carbon bearing R 2 and the carbon bearing R 3 【Chemistry 6】 represents a single bond, and between the carbon having R 3 and the carbon having R 4 【Chemistry 7】 represents a double bond, R 2 is selected from the group consisting of hydrogen, hydroxyl, mercaptan, keto, and C 1 -C 3 alkyl, R 3 is absent, and R 4 is selected from the group consisting of hydrogen, hydroxyl, mercaptan, and C 1 -C 3 alkyl; b) R 1 is C 1 -C 3 alkyl; c) R 5 , R 7 , R 8 , R 12 , R 13 , and R 14 are independently selected from the group consisting of hydrogen, hydroxyl, mercaptan, keto, and C 1 -C 3 alkyl; d) R 6 is selected from the group consisting of hydrogen, hydroxyl, mercaptan, and C 1 -C 3 alkyl; e) R 9 is selected from the group consisting of hydrogen and -C(=O)R 9a ; f) R 10 is selected from the group consisting of hydrogen and -C(=O)R 10a ; g) R 9a and R 10a are independently selected from the group consisting of C 1 -C 6 alkyl and C 2 -C 6 alkenyl, which are optionally substituted with -C(=O)OH; h) said composition, wherein R 11 is selected from the group consisting of hydrogen and C 1 -C 3 alkyl; and ii) said kit, comprising: instructions for using said kit to treat insomnia.

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