Heterocyclic compounds and their uses

Abstract

Providing a novel therapeutic agent for central nervous system diseases. 【Solution means】 Formula (I): TIFF2026082788000162.tif32170 (In the formula, R 1 , R 2 are each independently -O - , -OR 4 , or -NR 4Na R 4Nb , R 3 represents hydrogen or alkyl, and R 4 , R 4Na , and R 4Nb each independently represent hydrogen, or alkyl, alkenyl, alkadienyl, or alkynyl which may have 1 to 3 substituents. The alkyl represented by the R 4 , R 4Na , and R 4Nb may have a structure in which some methylene groups (-CH2-) are replaced by -O-, -S-, -CO-, -NH-, -SiR sia R sib -, or -(CO)O-. When both R 1 and R 2 represent -OR 4 , R 1 and R 2 may be the same or different. When both R 1 and R 2 represent -NR 4Na R 4Nb , R 1 and R 2 may be the same or different.) A compound or a salt thereof represented by.

Description

[Technical Field]

[0001] This disclosure relates to specific heterocyclic compounds and their uses. [Background technology]

[0002] 7-[4-(4-benzo[b]thiophen-4-ylpiperazine-1-yl)butoxy]-1H-quinoline-2-one (hereinafter also called brexpiprazole) or its salts have dopamine D2 receptor partial agonist activity and serotonin 5-HT 2A It has receptor antagonist activity and adrenergic α1 receptor antagonist activity. In addition, brexpiprazole or its salts have serotonin reuptake inhibitory activity (or serotonin reuptake inhibitory activity) in addition to these activities, and are known to have a broad therapeutic spectrum for central nervous system disorders (especially schizophrenia) (see, for example, Patent Documents 1 and 2).

[0003] One approach to drug design in the pharmaceutical field involves developing drugs that improve the properties of known drug molecules by chemically transforming or modifying some of their functional groups (for example, to enhance efficacy or slow down metabolism in the body).

[0004] It is highly desirable that similar drug development efforts for brexpiprazole lead to the discovery of novel compounds with improved properties, thereby providing new treatment options for central nervous system diseases. [Prior art documents] [Patent Documents]

[0005] [Patent Document 1] Japanese Patent Publication No. 2006-316052 [Patent Document 2] International Publication No. 2013 / 035892 [Overview of the project] [Problems to be Solved by the Invention]

[0006] One of the problems to be solved in the present disclosure is to provide a novel therapeutic agent for central nervous system diseases. [Means for Solving the Problems]

[0007] As a result of intensive research, the present inventors have found that the following formula (I):

[0008] [Chemical Formula] has succeeded in developing a novel heterocyclic compound and its salts represented by the formula, and has found that it can be a novel therapeutic agent for new central nervous system diseases.

[0009] The present disclosure includes, for example, the subject matter described in the following items.

[0010] Item 1. Formula (I): [Chemical Formula] (In the formula, R 1 , R 2 each independently represents -O - , -OR 4 , or -NR 4Na R 4Nb , R 3 represents hydrogen or alkyl, R 4 , R 4Na , and R 4Nb each independently represents hydrogen, or alkyl, alkenyl, alkadienyl, or alkynyl which may have 1 to 3 substituents, and the alkyl represented by R 4 , R 4Na , and R 4Nb may have a structure in which some of the methylene groups (-CH2-) are replaced by -O-, -S-, -CO-, -NH-, -SiR sia R sib -, or -(CO)O-, When R 1 and R 2 both represent -OR 4 in the formula, R 1 and R 2 may be the same or different, when R 1 and R 2 both represent -NR 4Na R 4Nb in the formula, R 1 and R 2 may be the same or different.) A compound represented by the formula or a salt thereof. Item 2. When R 1 represents -O - and R 2 represents -OR 4 , or -NR 4Na R 4Nb in the formula (R 4 , R 4Na , and R 4Nb are the same as defined above), The compound or a salt thereof according to Item 1. Item 3. Formula (I):

Chemical formula

Table 1A

Table 1B

[0011] The compound represented by formula (I) has a structure in which a specific nitrogen atom of brexpiprazole is chemically modified. The compound represented by formula (I) can be converted to brexpiprazole under physiological conditions after administration to a living organism.

[0012] The compounds represented by formula (I) include (1) compounds with relatively low cytotoxicity. Furthermore, the compounds represented by formula (I) include (2) compounds that are highly stable and easy to handle. Also, the compounds represented by formula (I) include (3) compounds that are absorbed relatively quickly subcutaneously. Furthermore, the compounds represented by formula (I) include (4) compounds that are rapidly converted to brexpiprazole in the body. Also, the compounds represented by formula (I) include (5) compounds suitable for injection, particularly subcutaneous injection. And (6) compounds suitable for sustained-release injections, particularly subcutaneous injections, that maintain blood brexpiprazole concentrations for 1 week to 4 weeks or more. [Brief explanation of the drawing]

[0013] [Figure 1] The plasma drug concentration profile (dosage: 1.25 mg / kg) after subcutaneous administration of the pharmaceutical composition of Example A to rats is shown (N=3, mean ± standard deviation). [Figure 2]The plasma drug concentration profile (dosage: 31.3 mg / kg) after subcutaneous administration of the pharmaceutical composition of Example D (aqueous suspension of compound 1) to rats is shown (N=3, mean ± standard deviation). [Figure 3] The plasma drug concentration profile (dosage: 33.2 mg / kg) after subcutaneous administration of the pharmaceutical composition of Example E (aqueous suspension of zinc salt of compound 1) to rats is shown (N=3, mean ± standard deviation). [Figure 4] The plasma drug concentration profile (dosage: 31.3 mg / kg) after subcutaneous administration of the pharmaceutical composition of Example F (Liquid crystal / lipid gel formulation of compound 1) to rats is shown (N=3, mean ± standard deviation). [Figure 5] The plasma drug concentration profile (dosage: 33.2 mg / kg) after subcutaneous administration of the pharmaceutical composition of Example G (Zinc salt liquid crystal / lipid gel formulation of compound 1) to rats is shown (N=3, mean ± standard deviation). [Figure 6] The results of polarized light microscopy observation of the microspheres from manufacturing example I are shown. [Figure 7] The results of polarized light microscopy observation of the microspheres from manufacturing example J are shown. [Figure 8] The results of polarized light microscopy observation of microspheres from manufacturing example K are shown. [Figure 9] The plasma drug concentration profile (dosage: 31.3 mg / kg) after subcutaneous administration of the pharmaceutical composition of Example H (microsphere formulation of compound 1 (RG505, API ratio 1.5 times)) to rats is shown (N=5 up to day 14, N=3 from day 21 onwards, mean ± standard deviation). [Figure 10] The plasma drug concentration profile (dosage: 31.3 mg / kg) after subcutaneous administration of the pharmaceutical composition of Example J (microsphere formulation of compound 1 (RG504, API ratio 2 times)) to rats is shown (N=5 up to day 14, N=3 from day 21 onwards, mean ± standard deviation). [Figure 11]The plasma drug concentration profile (dosage: 31.3 mg / kg) after subcutaneous administration of the pharmaceutical composition of Example K (microsphere formulation of compound 1 (RG503, API ratio 1.5 times)) to rats is shown (N=5 up to day 14, N=3 from day 21 onwards, mean ± standard deviation). [Figure 12] The plasma drug concentration profile (dosage: 31.3 mg / kg) after subcutaneous administration of the pharmaceutical composition of Example L (microsphere formulation of compound 1 (RG503, API ratio 2 times)) to rats is shown (N=3, mean ± standard deviation). [Figure 13] The plasma drug concentration profile (dosage: 29.8 mg / kg) after subcutaneous administration of the pharmaceutical composition of Example P (aqueous suspension of compound 3) to rats is shown (N=5, mean ± standard deviation). [Figure 14] The plasma drug concentration profile (dosage: 35.5 mg / kg) after subcutaneous administration of the pharmaceutical composition of Example Q (aqueous suspension of compound 10) to rats is shown (N=3, mean ± standard deviation). [Figure 15] The plasma drug concentration profile (dosage: 34.7 mg / kg) after subcutaneous administration of the pharmaceutical composition of Example R (aqueous suspension of compound 12) to rats is shown (N=3, mean ± standard deviation). [Figure 16] The plasma drug concentration profile (dosage: 36.3 mg / kg) after subcutaneous administration of the pharmaceutical composition of Example S (aqueous suspension of compound 13) to rats is shown (N=3, mean ± standard deviation). [Figure 17] The plasma drug concentration profile (dosage: 37.1 mg / kg) after subcutaneous administration of the pharmaceutical composition of Example T (aqueous suspension of compound 44 of Example) to rats is shown (N=3, mean ± standard deviation). [Figure 18] The plasma drug concentration profile (dosage: 36.3 mg / kg) after subcutaneous administration of the pharmaceutical composition of Example U (aqueous suspension of compound 92) to rats is shown (N=3, mean ± standard deviation). [Figure 19]The plasma drug concentration profile (dosage: 37.1 mg / kg) after subcutaneous administration of the pharmaceutical composition of Example V (aqueous suspension of compound 121 of Example) to rats is shown (N=3, mean ± standard deviation). [Modes for carrying out the invention]

[0014] The embodiments included in this disclosure will be described in further detail below. This disclosure preferably includes, but is not limited to, certain novel heterocyclic compounds and their salts (in particular, pharmaceutically acceptable salts), as well as pharmaceutical compositions containing them as active ingredients, and their uses. This disclosure includes everything disclosed herein and recognizable to those skilled in the art.

[0015] Certain novel heterocyclic compounds included in this disclosure are of formula (I):

[0016] [ka] (In the formula, R 1 , R 2 Each is independent of -O - , -OR 4 , or -NR 4Na R 4Nb Show, R 3 This represents hydrogen or alkyl, R 4 , R 4Na , and R 4Nb Each independently represents hydrogen, or an alkyl, alkenyl, alkadienyl, or alkynyl which may have 1 to 3 substituents, and the R 4 , R 4Na , and R 4Nb The alkyl group shown has some methylene groups (-CH2-) that are -O-, -S-, -CO-, -NH-, -SiR sia R sib - or -(CO)O- may be replaced by a structure, R sia and R sib These are the same or different hydrogen atoms or C 1-6 It shows alkyl, The R 1 and R 2 Both are -OR 4 When indicating R, 1 and R 2 They may be the same or different. The R 1 and R 2 Both are -NR 4Na R 4Nb When indicating R, 1 and R 2 They may be the same or different. It is a heterocyclic compound represented by . Note that R sia and R sib These are the same or different hydrogen atoms or C 1-6 It indicates an alkyl group.

[0017] In this specification, the compound represented by formula (I) is also referred to as "compound (I)". In this specification, examples of "alkenils" include 1-18 (1, 2, 3, 4, 5, 6 A linear or branched alkenyl (C) having 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, or 18 carbon atoms. 1-18 Alkenil) is one example, C 1-12 Alkenyl is more preferably mentioned, C 1-8 Alkenyl, or C 1-6 Alkenyls are even more preferred. Furthermore, alkenyls include both cis and trans stereoisomers based on the carbon-carbon double bond. In this specification, an example of an "alkadinyl" is a linear or branched alkadinyl (C) having 1 to 18 (1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, or 18) carbon atoms. 1-18 Alkadinyl) is one example, C 1-12 Alkadienyl is more preferably listed as C 1-8 Alkadienyl, or C 1-6Alkadienyls are even more preferred. Furthermore, alkadienyls encompass both cis and trans stereoisomers based on carbon-carbon double bonds. That is, they encompass any of the following structures, in the order of carbon-carbon double bonds from the terminal end of the alkadienyl: (cis, cis), (cis, trans), (trans, cis), or (trans, trans). In this specification, an example of "alkynyl" is a linear or branched alkynyl (C) having 1 to 18 (1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, or 18) carbon atoms. 1-18 Alkinyl) is one example, C 1-12 Alkinyl is more preferably mentioned, C 1-8 Alkinyl, or C 1-6 Alkinyl is even more preferably mentioned. Also, R 4 , R 4Na , or R 4Nb When represents an alkenyl, alkadienyl, or alkynyl, the alkenyl may have one or more (e.g., 1 to 3, preferably 1) substituent groups, the alkadienyl may have one or more (e.g., 1 to 3, preferably 1) substituent groups, and the alkynyl may have one or more (e.g., 1 to 3, preferably 1) substituent groups. Examples of these substituents include halogens, hydroxyls, lower alkyls, and lower alkoxys.

[0018] In this specification, an example of "alkyl" is a linear or branched alkyl (C) having 1 to 24 (1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, or 24) carbon atoms. 1-24 Examples include alkyl, C 1-18 Alkyl is more preferably mentioned, C 1-16 Alkyl, C 1-12 Alkyl, C 1-8 Alkyl, or C 1-6Alkyls are even more preferred. More specifically, examples include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, isohexyl, 3-methylpentyl, heptyl, octyl, nonyl, decyl, tetradecyl, and the like. In this specification, R 4 , R 4Na , and R 4Nb The alkyl group shown is one in which some of the methylene groups (-CH2-) are -O-, -S-, -CO-, -NH-, -SiR sia R sib This includes structures that have been replaced by - or -(CO)O-. sia and R sib These are the same or different hydrogen atoms or C 1-6 It indicates an alkyl group. In other words, in this specification, R 4 , R 4Na , and R 4Nb The alkyl group indicated by includes alkyl groups having the alternative structure and alkyl groups not having the alternative structure. 4 , R 4Na , and R 4Nb Alkyls other than those indicated by are alkyls that do not have the aforementioned alternative structure, unless otherwise specified. In the alkyl having the alternative structure, the number of methylene groups to be replaced depends on the number of carbon atoms in the alkyl before replacement, but is preferably 1 to 8 (1, 2, 3, 4, 5, 6, 7, or 8), more preferably 1 to 6, and even more preferably 1 to 5 or 1 to 4.

[0019] R 1 and R 2 Both are -OR 4 is or, R 1 ga-O - R 2 ga-OR 4 Or NR 4Na R 4Nb It is preferable that this be the case.

[0020] R 3If it exhibits an alkyl group, it is particularly preferably a lower alkyl group, and more specifically C 1-4 Alkyl is preferred, and methyl or ethyl is more preferred.

[0021] In this specification, the term "lower" used for substituents having a carbon chain means a substituent with 1 to 6 carbon atoms (1, 2, 3, 4, 5, or 6).

[0022] R 4 , R 4Na , or R 4Nb If it indicates an alkyl group, then specifically C 1-24 Alkyl is preferred, C 1-18 Alkyl is more preferred. Furthermore, as described above, the alkyl is the alternative structure (some methylene groups (-CH2-) are -O-, -S-, -CO-, -NH-, -SiR sia R sib It may have a structure substituted with - or -(CO)O-. Also, as described above, the number of methylene groups to be substituted depends on the number of carbon atoms of the alkyl before substitution, but is preferably 1 to 8 (1, 2, 3, 4, 5, 6, 7, or 8), more preferably 1 to 6, and even more preferably 1 to 5 or 1 to 4. 1 , R 2 Each of these independently demonstrates -OR 4 or -NR 4Na R 4Nb In this case, the oxygen atom side (in other words, -OR 4 or -NR 4Na R 4Nb If the phosphorus atom to which the -(CO)O- is bonded is indicated by *, then the -(CO)O- may be either *-(CO)O- or *-O(CO)-. Also, if multiple methylene groups are substituted, the structure after each substitution (i.e., -O-, -S-, -CO-, -NH-, -SiR sia R sib -, or -(CO)O-), may be the same or different.

[0023] For example, -(CH2)2-O-(CH2)2-O-CH3 is an example of a group in which two methylene groups are replaced by -O- in -(CH2)6-CH3. Also, for example, -CH2-(CO)O-CH2-CH3 is an example of a group in which one methylene group is replaced by *-(CO)O- in -(CH2)3-CH3. Also, for example, -(CH2)3-O(CO)-CH3 is an example of a group in which one methylene group is replaced by *-O(CO)- in -(CH2)4-CH3.

[0024] Also, R 4 , R 4Na , or R 4Nb If the alkyl group is alkyl, the alkyl group may have one or more (e.g., 1 to 3) substituent groups. These substituents may be bonded to the carbon atom of the alkyl group, or to the nitrogen atom of the -NH- group that has been replaced by a methylene group, or to the methylene group in the methyl group at the end of the alkyl group. -CH 2 - If the underlined part of H is replaced, then a substituent is bonded to one side of the replacement structure in place of hydrogen (i.e., the substituent is particularly R C1 Expressed as -OR C1 , -SR C1 ,-CO-R C1 , -NH-R C1 , -SiR sia R sib -R C1 , or -(CO)OR C1 , or -O(CO)-R C1 It exists in the structure of [the structure].

[0025] Examples of substituents bonded to the carbon atom of an alkyl group include halogens, hydroxyls, alkyls (preferably lower alkyls), alkoxys (preferably lower alkoxys), cycloalkyls, carboxyls, alkylaminocarbonyls (preferably lower alkylaminocarbonyls), optionally substituted phenyls or benzyls, optionally substituted heterocyclic groups (groups having a structure in which one hydrogen atom bonded to an atom constituting the heterocyclic group has been removed from an optionally substituted heterocyclic group).

[0026] In this specification, examples of "halogen" include fluorine, chlorine, bromine, or iodine (F, Cl, Br, I), with fluorine, chlorine, or bromine being preferred.

[0027] In this specification, "alkylene" refers to linear or branched alkylenes having 1 to 20 carbon atoms. Examples of alkylene groups include methylene, ethylene, trimethylene, tetramethylene, hexamethylene, heptamethylene, octamethylene, nonamethylene, decamethylene, undecamethylene, dodecamethylene, 1-methylethylene, 2-ethyltrimethylene, 1-methylheptamethylene, 2-methylheptamethylene, 1-butylhexamethylene, 2-methyl-5-ethylheptamethylene, 2,3,6-trimethylheptamethylene, and 6-ethyldecamethylene.

[0028] In this specification, an example of "alkoxy" is a linear or branched alkoxy (C) having 1 to 6 carbon atoms. 1-6 Examples include alkoxys, specifically methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy, isopentyloxy, neopentyloxy, hexyloxy, isohexyloxy, and 3-methylpentyloxy.

[0029] In this specification, an example of "cycloalkyl" is a cyclic alkyl (C) having 3 to 7 (3, 4, 5, 6, or 7) carbon atoms. 3-7 Examples include cycloalkyl groups, specifically cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl. A cycloalkyl group is a group having a structure in which one hydrogen atom has been removed from the carbon atom constituting the cycloalkyl group.

[0030] In this specification, examples of "heterocyclic groups" include saturated or unsaturated monocyclic or polycyclic heterocyclic groups containing 1 to 5 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur as ring constituent atoms, and include saturated or unsaturated 3 to 15-membered, preferably 5 to 10-membered monocyclic, bicyclic, or tricyclic heterocyclic groups. Specifically, examples include furan, tetrahydropyran, tetrahydrofuran, 1,3-dioxane, 1,4-dioxane, pyrrole, imidazole, pyrazole, pyridine, pyrimidine, pyrazine, pyridazine, pyrrolidine, imidazolidine, thiophene, piperidine, piperazine, oxazole, isoxazole, oxadiazole, morpholine, indole, indazole, benzimidazole, quinoline, and the like. A heterocyclic group is a group having a structure in which one hydrogen atom bonded to an atom constituting the heterocyclic group has been removed.

[0031] In this specification, examples of "lower alkylaminocarbonyl groups" include methylaminocarbonyl groups, dimethylaminocarbonyl groups, ethylaminocarbonyl groups, propylaminocarbonyl groups, isopropylaminocarbonyl groups, and the like.

[0032] Examples of substituents in optionally substituted hephenyl or benzyl, or in optionally substituted heterocyclic groups, include R 4 Examples include the same substituents that may be present when exhibiting alkylity. Also, halogens, hydroxyls, or halogens, hydroxyls, oxo, or C 1-6 C may be substituted with alkoxy. 1-6C may be substituted with alkyl, halogen, hydroxyl, or oxo atoms. 1-6 Alkoxy compounds are also preferred. Furthermore, examples of the number of substituents in the optionally substituted hephenyl or benzyl group, or in the optionally substituted heterocyclic group, include 1, 2, or 3.

[0033] Furthermore, among compound (I), R 1 However, -O - Show, R 2 However, -OR 4 or -NR 4Na R 4Nb Show, R 3 However, those exhibiting hydrogen or methyl are preferred. In this case, R 4 or -NR 4Na R 4Nb It is more preferable that the base is one of the following, for example. (R 4 :Suitable example 1) R 4 R 4a1 , R 4a2 , or R 4a3 This indicates. R 4a1 teeth, -C n H 2n+1 , -C n H 2n-1 , -C n H 2n-3 , -C n H 2n -OH, -C n H 2n-2 -OH(the relevant -C n H 2n-2 - Preferably, it has one carbon-carbon double bond, or -C n H 2n-4 -OH, (the said -C n H 2n-4 - It is more preferable that the element contains two carbon-carbon double bonds or one carbon-carbon triple bond. (In the above formula, n represents 1 to 24. n is not limited, but may be, for example, 1 to 18, 1 to 12, 1 to 10, or 1 to 6. However, -C n H 2n-1 So n is 2 or greater, -C n H 2n-3 So n is 2 or greater, -C n H 2n-2 -n is 2 or greater, -C n H 2n-4 -Therefore, n is 2 or greater. This indicates. R 4a2 teeth, -CHX 1 X 2 -C n-1 H 2n-2 -CHX 1 X 2 -C n-1 H 2n-4 -CHX 1 X 2 (Such-C) n-1 H 2n-4 - Preferably, it has one carbon-carbon double bond, or -C n-1 H 2n-6 -CHX 1 X 2 , (the said-C n-1 H 2n-6 - It is more preferable that the element contains two carbon-carbon double bonds or one carbon-carbon triple bond. (In the above formula, n represents 2 to 24. n is not limited, but may be, for example, 2 to 18, 2 to 12, 2 to 10, or 2 to 6. However, -C n-1 H 2n-6 - Then n is 3 or greater.

[0034] X 1 and X 2 These elements, either identically or differently, represent a hydrogen atom or a halogen (F, Cl, Br, or I). However, it is preferable that at least one of them represents a halogen. This indicates. R 4a3 teeth, -C nH 2n -R 4-1 , -C n-1 H 2n-2 -CHR 4-1a R 4-1b , -C n H 2n-2 -R 4-1 , or -C n H 2n-4 -R 4-1 , (In the above formula, n represents 1 to 24. n is not limited, but may be, for example, 1 to 18, 1 to 12, 1 to 10, or 1 to 6. However, -C n H 2n-2 -n is 2 or greater, -C n H 2n-4 - Then n is 2 or greater. R 4-1 C 1-6 Alkoxy, -O-phenyl, or C 1-6 This represents a heterocyclic group which may be substituted with an alkyl or halogen. 4-1a and R 4-1b , are the same or different, -C 1-3 Alkylene-C 1-3 It indicates an alkoxy, or is the same or different, -CO-OC 1-3 Alkyl, or -CH2-CO-OC 1-3 (Indicates alkyl.) This is shown. The same applies below. Note, R 4-1 When the group is the aforementioned heterocyclic group, there are no particular limitations, but the following groups are preferred, for example. [ka] (R 4 :Suitable example 2) R 4 R 4b Show, R 4b teeth -(C p H 2p -O) q -C r H 2r -R 4-2, -(C p H 2p -O) q -C r H 2r-2 -R 4-2 , -(C p H 2p-2 -O) q -C r H 2r -R 4-2 , or -(C p H 2p-2 -O) q -C r H 2r-2 -R 4-2 , (In the above equations, p represents 1 to 4, q represents 1 to 4, and r represents 1 to 4. However, C p H 2p-2 So p is 2 or greater, C r H 2r-2 Then r is 2 or greater. When q is between 2 and 4, the 2 to 4 repeating structures that indicate the number of repetitions indicated by q may be the same or different. 4-2 is a hydrogen atom, a hydroxyl group, or "C 1-6 Alkyl, C 1-6 Alkoxy, -C 1-3 Alkylene-C 1-3 (This indicates a cycloalkyl group, phenyl, benzyl, or heterocyclic group that may be substituted with 1 to 3 substituents selected from alkoxy and nitro groups.) The same applies to the following. (R 4 :Suitable example 3) R 4 is -C α H 2α -CO-OR COO Or -C α H 2α -CO-O-CH2-R COO (α represents a range from 1 to 10) -R COO This consists of a hydrogen atom and 1 to 3 carbon atoms. 1-6 C may be substituted with alkoxy. 1-6 Alkyl or C 1-6 Alkoxy, or C1-6 Alkyl, C 1-6 Alkoxy, -C 1-3 Alkylene-C 1-3 This represents a cycloalkyl, phenyl, benzyl, or heterocyclic group, which may be substituted with 1 to 3 substituents selected from alkoxy and nitro groups. The same applies to the following. R 4 Preferably, -C α H 2α -CO-OR COO This indicates. -R COO Preferably, hydrogen atoms or 1 to 3 carbon atoms. 1-6 C may be substituted with alkoxy. 1-6 It indicates an alkyl group. (R 4 :Suitable example 4) R 4 is -C β H 2β -O-CO-R OCO (β represents values ​​from 1 to 10) -R OCO R 4a1 , R 4b , or -C α H 2α -CO-OR COO Show or -C α H 2α -CO-NH-R COO , -C α H 2α -NH-CO-R COO , or -C α H 2α -NH-CO-OR COO To show, Alternatively, C 1-6 Alkyl, C 1-6 Alkoxy, -C 1-3 Alkylene-C 1-3 This represents a cycloalkyl, phenyl, benzyl, or heterocyclic group, which may be substituted with 1 to 3 substituents selected from alkoxy and nitro groups. The same applies to the following. (R 4 :Suitable example 5) R 4 However, -C γ H2γ -O-CO-OR OCOO (γ represents values ​​from 1 to 10) -R OCOO is a hydrogen atom, R 4a1 , R 4b , or -C α H 2α -CO-OR COO To show, Alternatively, C 1-6 Alkyl, C 1-6 Alkoxy, -C 1-3 Alkylene-C 1-3 a The group represents a cycloalkyl, phenyl, benzyl, or heterocyclic group, which may be substituted with 1 to 3 substituents selected from lucoxy and nitro. The same applies to the following. (NR 4Na R 4Nb : Preferred example i) R 4Na and R 4Nb These are 1 to 3 C's, which are identical or different. 1-6 C may be substituted with alkoxy. 1-6 It indicates an alkyl group. (NR 4Na R 4Nb : Preferred example ii) R 4Na It is a hydrogen atom, R 4Nb This is 1 to 3 C 1-6 C may be substituted with alkoxy. 1-6 Indicates alkyl, or -C α H 2α -CO-OR COO , or -C α H 2α -CO-NH-R COO This indicates. The symbols used in the descriptions of each of the above preferred examples may be the same or different. For example, -R COO This is explained in Preferred Example 3 above, and is also described in Preferred Examples 4 and 5, and the -R in Preferred Examples 3 to 5 COO These may be the same or different within the scope of the above description. Also, R 1 and R 2 However, R 1ga-O - R 2 ga-OR 4 Or NR 4Na R 4Nb When R 2 A preferred example is shown in the table below. In this table, R 2 The phosphorus atom bond side is indicated by an asterisk (*). Note that if optical isomers exist in the structural formula in this table, both isomers are included. [Table 1C] TIFF2026082788000019.tif250170TIFF2026082788000020.tif249170TIFF202 6082788000021.tif238170TIFF2026082788000022.tif254170TIFF2026082788 000023.tif241170TIFF2026082788000024.tif237170TIFF2026082788000025. tif250170TIFF2026082788000026.tif244170TIFF2026082788000027.tif90170

[0035] In a more preferred form, compound (I) is given by the following formula (II):

[0036] [ka] (In the formula, R 3 and R 4 This is a compound represented by formula (II) as described above. In this specification, among compound (I), the compound represented by formula (II) is also referred to as "compound (II)". Compound (II) is a compound in which R is represented by formula (I) above. 1 ga-O - R 2 ga-OR 4 It is a compound having the following structure.

[0037] A preferred form of compound (II) is described below. However, the description above also includes a description of compound (II), and compound (II) is not limited to the description below. R 4 Specifically, this refers to hydrogen or C which may have 1 to 3 substituents. 1-18 Alkyl compounds are examples.

[0038] Each of these substituents is independently a halogen, hydroxyl, lower alkoxy, and -O-(CH2) n -OR 5 -O(CO)-(CH2) n -OR 5a ,-(CO)OR 6 ,-( CO)NR 7 R 8 ,-O(CO)R 9 , -O(CO)OR 10 , -O(CO)-(CR 11 R 12 ) n -(CO)OR 13 , C 3-7 This represents a cycloalkyl group or a heterocyclic group which may have substituents. Here, R 5 , R 5a , R 6 , R 9 , R 10 , and R 13 German Standing upright, hydrogen atom, C 1-16 Alkyl, possibly substituted heterocyclic group, or C 3-7 It exhibits cycloalkyl properties. Also, R 7 and R 8 R independently represents a hydrogen atom, or a lower alkyl group in which one or two carbon atoms may be replaced by oxygen or nitrogen atoms, 7 and R 8 They may be joined together to form a ring. Also, R 11 and R 12 R is independent and 11 If there are multiple instances, each is independent, R 12 If multiple exist, each is independently a hydrogen atom, C 1-16Alkyl, or C 3-7 Showing cycloalkyl Also, n represents an integer from 1 to 10 (1, 2, 3, 4, 5, 6, 7, 8, 9, or 10). Furthermore, the statement that "a carbon atom may be replaced by an oxygen atom or a nitrogen atom" in the context of alkyl groups is equivalent to saying that "a methylene group (-CH2-) may be replaced by -O- or -NH-" in the context of alkyl groups. Furthermore, although not particularly limited, examples of heterocyclic groups that may have substituents include the aforementioned R 4-1 C 1-6 The groups described are heterocyclic groups that may be substituted with alkyl or halogen groups. Furthermore, although not particularly limited, R 7 and R 8 If they are joined to form a ring, -NR 7 R 8 For example, as mentioned above, R 4-1 C 1-6 Among the groups described as heterocyclic groups that may be substituted with alkyl or halogen atoms, one example is a group having a structure in which one hydrogen atom bonded to the nitrogen atom has been removed. R 4 More preferably, hydrogen or C which may have one substituent. 1-8 Alkyl compounds are examples. Each substituent can independently be hydroxyl, lower alkoxy, or -O-(CH2) n -OR 5 -O(CO)-(CH2) n -OR 5a ,-(CO )OR 6 ,-O(CO)R 9 , -O(CO)OR 10 , -O(CO)-A-(CO)OR 13 , or two C 1-6 This shows a morpholinyl which may have an alkyl group. Here, R 5 , R 5a , R 6 , R 9 , R 10 , and R 13 These are, independently, hydrogen atoms, C1-16 Alki A heterocyclic group which may have substituents, or C 3-7 It represents a cycloalkyl group. Also, A is C 1-6 This represents alkylene. n is the same as above. R 4 More preferably, hydrogen or C which may have one substituent. 1-8 Alkyl compounds are examples. Each of these substituents is independently hydroxy, C 1-6 Alkoxy, -O-(CH2) n -OR 5 -O(CO)-(CH2) n -OR 5a ,-(CO)OR 6 , -O(CO )R 9 , -O(CO)-A-(CO)OR 13 , or two C 1-6 This shows a heterocyclic group which may have an alkyl group. Here, R 5 C 1-6 Alkyl, R 5a C 1-6 Alkyl, R 6 C 1-6 Alkyl, R 9 C 1-16 Alkyl, R 13 is C 1-6 Alki Lu, or C 1-6 This indicates a pyridyl which may have an alkyl group. Also, A is C 1-6 This represents alkylene. n is the same as above.

[0039] R 4 Also, hydrogen, or -(AY) m -R 14 One example is C. 1-18 It represents alkylene. Also, Y represents a bond, -O-, -(CO)O-, -(CO)NH-. Also, R 14 is hydrogen, halogen, C 1-18 This indicates alkyl, hydroxy, cycloalkyl, or heterocyclic groups. Also, m represents an integer from 0 to 5 (0, 1, 2, 3, 4, or 5).1 , R 2 Each of these independently demonstrates -OR 4 In this case, the oxygen atom side (in other words, -OR 4 If the phosphorus atom to which the bond is attached is indicated by *, then the -(CO)O- may be either *-(CO)O- or *-O(CO)-, and the -(CO)NH- may be either *-(CO)NH- or *-NH(CO)-. More specific preferred examples of compound (I) are shown in the table below. [Table 1D] TIFF2026082788000030.tif215170TIFF2026082788000031.tif212170TIFF2026082788000032.tif221170TIFF2026082788000033.tif215170TIFF2026082788000034.tif214170TIFF2026082788000035.tif254170TIFF2026082788000036.tif209170TIFF2026082788000037.tif216170TIFF2026082788000038.tif217170TIFF2026082788000039.tif218170TIFF2026082788000040.tif214170TIFF2026082788000041.tif216170TIFF2026082788000042.tif216170TIFF2026082788000043.tif244170TIFF2026082788000044.tif248170TIFF2026082788000045.tif245170TIFF2026082788000046.tif208170TIFF2026082788000047.tif209170TIFF2026082788000048.tif198170TIFF2026082788000049.tif194170TIFF2026082788000050.tif253170TIFF2026082788000051.tif202170TIFF2026082788000052.tif228170TIFF2026082788000053.tif227170TIFF2026082788000054.tif195170TIFF2026082788000055.tif195170TIFF2026082788000056.tif205170TIFF2026082788000057.tif212170TIFF2026082788000058.tif245170TIFF2026082788000059.tif232170TIFF2026082788000060.tif226170TIFF2026082788000061.tif236170TIFF2026082788000062.tif223170TIFF2026082788000063.tif223170TIFF2026082788000064.tif248170TIFF2026 082788000065.tif250170TIFF2026082788000066.tif231170TIFF2026082788000067.tif18 5170TIFF2026082788000068.tif234170TIFF2026082788000069.tif213170TIFF202608278 8000070.tif214170TIFF2026082788000071.tif221170TIFF2026082788000072.tif114170.

[0040] In one embodiment, diseases that may be prevented and / or treated by compound (I) or its salts include, for example, the following central nervous system disorders: schizophrenia, treatment-resistant, intractable or chronic schizophrenia, ataxic affective disorder, psychotic disorders, mood disorders, bipolar disorder, mania, depression, endogenous depression, major depression, melancholy and treatment-resistant depression, dysthymic disorder, cyclothymic disorder, anxiety disorders, somatoform disorders, factitious disorders, dissociative disorders, sexual disorders, eating disorders, Sleep disorders, adjustment disorders, substance-related disorders, anhedonia, delirium, Alzheimer's disease, Parkinson's disease, cognitive impairment, cognitive impairment associated with neurodegenerative diseases, cognitive impairment caused by neurodegenerative diseases, cognitive impairment in schizophrenia, cognitive impairment resulting from treatment-resistant, intractable or chronic schizophrenia, vomiting, motion sickness, obesity, migraines, pain, intellectual disability, autism spectrum disorder, Tourette's syndrome, tic disorder, attention deficit hyperactivity disorder, conduct disorder, Down syndrome, impulsivity associated with dementia, and borderline personality disorder.

[0041] [General manufacturing method] Compound (I) can be produced, for example, by the general methods shown below, but is not limited to these.

[0042] The raw material compounds may be commercially available or synthesized according to known or equivalent methods.

[0043] The solvents, acids, bases, protecting groups, and leaving groups used as appropriate in the preparation of compound (I) are not particularly limited as long as they are those commonly used in the field of organic synthesis chemistry.

[0044] In the preparation of compound (I), the product can be used in subsequent reactions as a reaction solution or as a crude product, but it can also be isolated from the reaction mixture according to conventional methods and can be easily purified by conventional separation methods. Conventional separation methods include, for example, filtration, extraction, concentration, distillation, crystallization, recrystallization, reprecipitation, distillation, chromatography, and optical resolution.

[0045] In the production of compound (I), when alkylation reactions, hydrolysis reactions, amination reactions, esterification reactions, amidation reactions, etherification reactions, oxidation reactions, reduction reactions, etc., these reactions can be carried out according to known methods.

[0046] These commonly used reagents and methods include, for example, Organic Functional Group Preparations. It is mentioned in PREPARATIONS, 2nd edition, published by ACADEMIC PRESS, INC. in 1989; Comprehensive Organic Transformations, published by VCH Publishers Inc. in 1989; and in "Greene's Protective Groups in Organic Synthesis" (4th edition, 2006) by PGM Wuts and T.W. Greene, published by John Wiley & Sons in New York in 1991, among others.

[0047] In the general method for producing compound (I), the starting compound, intermediate compound, and compound (I) may be in the form of a salt, and the target compound obtained in each reaction may also form a salt. If each compound is a free compound, it can be converted to the target salt by known methods, and if the compound is a salt, it can be converted to its free form or another target salt by known methods.

[0048] The method for producing compound (II) will be described below in particular. The method for producing compound (II) is a specific example of the method for producing compound (I). Those skilled in the art will understand that compound (I) can be produced by performing similar operations based on this specific example. Furthermore, those skilled in the art will also understand that compound (I) can be produced based on the production methods described in the examples and methods known in the art or methods readily conceivable from known methods.

[0049] Compound (II) can be produced, for example, by the production method shown below. The production method shown below is illustrative and not limited to these. In the following reaction equation, each starting compound may form a salt, provided that it does not inhibit the reaction, and such salts are those exemplified as salts of compound (II).

[0050] Unless otherwise specified, commercially available raw material compounds may be used, or those manufactured according to known or equivalent methods may be used. The solvents, acids, bases, protecting groups, and leaving groups used as appropriate in the preparation of compound (II) are not particularly limited as long as they are those commonly used in the field of organic synthesis chemistry.

[0051] In the preparation of compound (II), the product can be used in the next reaction as a reaction solution or as a crude product, but it can also be isolated from the reaction mixture according to conventional methods and can be easily purified by conventional separation methods. Conventional separation methods include, for example, filtration, extraction, concentration, distillation, crystallization, recrystallization, reprecipitation, distillation, chromatography, and optical resolution.

[0052] More specifically, compound (II) can be synthesized, for example, using methods classified into steps A and B below.

[0053] Step A: Phosphate coupling reaction [ka]

[0054] In the above formula, LG represents a leaving group, and R 15 R represents an alkyl group which may have 1 to 3 substituents, and in which some carbon atoms of the alkyl group may be replaced by -O- and / or -(CO)O-. The other symbols are the same as above. 15 The alkyl group indicated by is as described above. 4 The explanation regarding R applies directly. 4 and R 15 These may be the same or different, and are preferably different. 15 This more preferably represents a linear or branched alkyl group that may be substituted.

[0055] Compound (II-1) can be obtained by reacting compound (1) with compound (2) in an inert solvent, in the presence or absence of a base depending on the reaction conditions (Step A-1). Compound (1) is brexpiprazole.

[0056] Compound (1) can be produced according to the method described in Patent Document 1 (Japanese Patent Publication No. 2006-316052) and can be used in free form or salt form. Examples of salt forms of compound (1) include inorganic acid salts such as hydrochloride, sulfate, phosphate, hydrobromide, hydroiodide, and nitrate; organic acid salts such as formate, propionate, oxalate, carbonate, picrate, methanesulfonate, ethanesulfonate, p-toluenesulfonate, acetate, citrate, tartrate, malonate, succinate, maleate, fumarate, malate, and lactate; and amino acid salts such as aspartate and glutamate.

[0057] Examples of leaving groups include halogen atoms (e.g., chlorine, bromine, iodine), alkyl sulfonyloxy groups (e.g., methyl sulfonyloxy, ethyl sulfonyloxy, trifluoromethyl sulfonyloxy), and aryl sulfonyloxy groups (e.g., benzene sulfonyloxy, p-toluene sulfonyloxy, 2,4,6-trimethylbenzene sulfonyloxy, 2-nitrobenzene sulfonyloxy, 4-nitrobenzene sulfonyloxy). Examples of inert solvents include water; alcoholic solvents such as MeOH, EtOH, isopropanol, n-butanol, trifluoroethanol, and ethylene glycol; ketone solvents such as acetone and methyl ethyl ketone; etheric solvents such as THF, dioxane, Et2O, diisopropyl ether, cyclopentyl methyl ether, and diglyme; esteric solvents such as AcOMe and AcOEt; aprotic polar solvents such as MeCN, DMF, and DMSO; hydrocarbon solvents such as n-pentane, n-hexane, n-heptane, and cyclohexane; halogenated hydrocarbon solvents such as chloroform, DCE, and DCM; or other organic solvents; or mixed solvents thereof. Preferably, halogenated hydrocarbon solvents, such as DCM, or aprotic polar solvents, such as MeCN, are used.

[0058] As bases, a wide range of known inorganic and organic bases can be used. Examples of inorganic bases include alkali metals (e.g., sodium, potassium, etc.), alkali metal bicarbonates (e.g., lithium bicarbonate, sodium bicarbonate, potassium bicarbonate, etc.), alkali metal hydroxides (e.g., LiOH, NaOH, KOH, etc.), alkali metal carbonates (e.g., Li2CO3, Na2CO3, K2CO3, Cs2CO3, etc.), alkali metal lower alkoxides (e.g., sodium methoxide, sodium ethoxide, etc.), and alkali metal hydrides (e.g., NaH, KH, etc.). Examples of organic bases include trialkylamines (e.g., trimethylamine, TEA, DIPEA, etc.), pyridine, quinoline, piperidine, imidazole, picoline, dimethylaminopyridine, dimethylaniline, N-methylmorpholine, DBN, DABCO, DBU, etc. Furthermore, if these bases are liquids, they can also be used as solvents. These bases can be used individually or in mixtures of two or more. The amount of base used is typically 0.1 to 10 moles, preferably 0.1 to 5 moles, per mole of compound (1).

[0059] The reaction conditions are not particularly limited, and the reaction usually proceeds under cooling, room temperature, or heating. This can be done. Preferably, the reaction is carried out at a temperature of room temperature to 100°C for 30 minutes to 350 hours, more preferably 1 hour to 200 hours, and most preferably 1 to 48 hours. Compound (II) can be obtained by reacting compound (II-1) in an inert solvent under acidic or basic conditions, or with an alkali metal halide, although the reaction conditions are not particularly limited (Step A-2). Examples of inert solvents include water; alcoholic solvents such as MeOH, EtOH, isopropanol, n-butanol, trifluoroethanol, and ethylene glycol; ketone solvents such as acetone and methyl ethyl ketone; etheric solvents such as THF, dioxane, Et2O, diisopropyl ether, cyclopentyl methyl ether, and diglyme; esteric solvents such as AcOMe and AcOEt; aprotic polar solvents such as MeCN, DMF, and DMSO; hydrocarbon solvents such as n-pentane, n-hexane, n-heptane, and cyclohexane; halogenated hydrocarbon solvents such as chloroform, DCE, and DCM; other organic solvents; or mixed solvents thereof. Preferably, halogenated hydrocarbon solvents, such as DCM; aprotic polar solvents, such as MeCN; or ketone solvents, such as acetone.

[0060] As bases, a wide range of known inorganic and organic bases can be used. Examples of inorganic bases include alkali metals (e.g., sodium, potassium, etc.), alkali metal bicarbonates (e.g., lithium bicarbonate, sodium bicarbonate, potassium bicarbonate, etc.), alkali metal hydroxides (e.g., LiOH, NaOH, KOH, etc.), alkali metal carbonates (e.g., Li2CO3, Na2CO3, K2CO3, Cs2CO3, etc.), alkali metal lower alkoxides (e.g., sodium methoxide, sodium ethoxide, etc.), and alkali metal hydrides (e.g., NaH, KH, etc.). Examples of organic bases include trialkylamines (e.g., trimethylamine, TEA, DIPEA, etc.), pyridine, quinoline, piperidine, imidazole, picoline, dimethylaminopyridine, dimethylaniline, N-methylmorpholine, DBN, DABCO, DBU, etc. Furthermore, if these bases are liquids, they can also be used as solvents. These bases can be used individually or in mixtures of two or more. The amount of base used is typically 0.1 to 10 moles, preferably 0.1 to 5 moles, per mole of compound (II-1). Examples of acids include inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid, hydrobromic acid, and phosphoric acid; and organic acids such as acetic acid, trifluoroacetic acid, oxalic acid, phthalic acid, fumaric acid, tartaric acid, maleic acid, citric acid, succinic acid, methanesulfonic acid, p-toluenesulfonic acid, and 10-camphorsulfonic acid. Two or more of these may be mixed in appropriate proportions. The amount of acid used is usually 1 molar equivalent to an excess amount relative to compound (II-1). Examples of alkali metal halides include LiI, NaI, and KI. The amount of alkali metal halide used is usually 1 molar equivalent to an excess amount relative to compound (II-1).

[0061] The reaction conditions are not particularly limited, and the reaction can usually proceed under cooling, room temperature, or heating. Preferably, the reaction is carried out at a temperature of room temperature to 100°C for 0.5 to 350 hours.

[0062] Step B: Protection-Deprotection [ka]

[0063] (In the formula, PG indicates a protecting group for the hydroxyl group, -OR 16 is an alkoxy group or -O - (The symbols indicate the same as above, and other symbols are the same as above.) Compound (1) may be converted to the form of compound (3) by protecting it with an appropriate protecting group (Step B-1), and after carrying out the above phosphate coupling reaction (Step A), the protecting group may be deprotected (Step B-2) to synthesize the final product, compound (II) (Step B). Note that when carrying out Step A, it may be stopped at Step A-1 (that is, compound (3) is reacted with compound (2) to produce the compound (-OR) corresponding to (II-1). 16 You may obtain a compound (4)) that exhibits an alkoxy group, or you may then perform Step A-2 to obtain a compound (-OR) corresponding to the above (II). 16 ga-O - A compound (4) exhibiting the following characteristics may be obtained.

[0064] Step B-1: Protective reaction Examples of the hydroxyl group protecting groups (-OPG) mentioned above are not particularly limited as long as they are protecting groups used in the field of organic synthesis chemistry, but for example, ethers (e.g., methyl, methoxymethyl, benzyloxymethyl, methoxyethoxymethyl, 2-(trimethylsilyl)ethoxymethyl, methylthiomethyl, tetrahydropyranyl, phenacyl, cyclopropylmethyl, allyl, prenyl, propargyl, t-butyl, benzyl, 4-(dimethylamino)carbonylbenzyl, 4-methylsulfinylbenzyl, 9-anthrylmethyl, 4-picolyl); silyl ethers (e.g., trimethylsilyl, t-butyldimethylsilyl, t-butyldiph Examples of preferred protecting groups include phenylsilyl, triisopropylsilyl; esters (e.g., formates, acetates, revlinates, pivaloates, benzoates, 9-fluorenecarboxylate); carbonates (e.g., methyl, t-butyl, isopropyl, allyl, 4-methylsulfinylbenzyl, 2,2,2-trichloroethyl, vinyl, benzyl); arylcarbamates (e.g., phenylcarbamate); phosphinates (e.g., dimethylphosphonyl, dimethylphosphonotiol); sulfonates (e.g., methanesulfonate, trifluoromethanesulfonate, toluenesulfonate, benzylsulfonate), etc. Ethers are a preferred example of a protecting group.

[0065] For example, this protective reaction can yield compound (3) by dissolving compound (1) in an inert solvent in the presence of a base.

[0066] As the base, for example, known inorganic bases can be used. Examples of inorganic bases include alkali metals (e.g., sodium, potassium, etc.), alkali metal bicarbonates (e.g., lithium bicarbonate, sodium bicarbonate, potassium bicarbonate, etc.), alkali metal hydroxides (e.g., LiOH, NaOH, KOH, etc.), alkali metal carbonates (e.g., Li2CO3, Na2CO3, K2CO3, Cs2CO3, etc.), alkali metal lower alkoxides (e.g., sodium methoxide, sodium ethoxide, etc.), alkali metal hydrides (e.g., NaH, KH, etc.), and silver carbonate. The amount of base used is usually 1 molar equivalent to an excess amount relative to compound (1). Examples of inert solvents include water; alcoholic solvents such as MeOH, EtOH, isopropanol, n-butanol, trifluoroethanol, and ethylene glycol; ketone solvents such as acetone and methyl ethyl ketone; etheric solvents such as THF, dioxane, Et2O, diisopropyl ether, cyclopentyl methyl ether, and diglyme; esteric solvents such as AcOMe and AcOEt; aprotic polar solvents such as MeCN, DMF, and DMSO; hydrocarbon solvents such as n-pentane, n-hexane, n-heptane, and cyclohexane; halogenated hydrocarbon solvents such as chloroform, DCE, and DCM; other organic solvents; or mixed solvents thereof. Two or more of these may be mixed in appropriate proportions. Preferably, etheric solvents, such as cyclopentyl methyl ether, are used.

[0067] The reaction temperature is typically -80 to 150°C. The reaction time is typically 0.1 to 200 hours.

[0068] Step B-2: Deprotection reaction The deprotection reaction of compound (4) can be carried out using a known reaction depending on the type of protecting group. For example, this deprotection reaction can be performed to deprotect compound (4) in an inert solvent or without a solvent, in the presence or absence of an acid, to obtain compound (II).

[0069] Examples of acids include inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid, hydrobromic acid, and phosphoric acid; and organic acids such as acetic acid, trifluoroacetic acid, oxalic acid, phthalic acid, fumaric acid, tartaric acid, maleic acid, citric acid, succinic acid, methanesulfonic acid, p-toluenesulfonic acid, and 10-camphorsulfonic acid. Two or more of these may be mixed in appropriate proportions. The amount of acid used is usually 1 molar equivalent to an excess amount relative to the intermediate (4). Examples of inert solvents include water; alcoholic solvents such as MeOH, EtOH, isopropanol, n-butanol, trifluoroethanol, and ethylene glycol; ketone solvents such as acetone and methyl ethyl ketone; etheric solvents such as THF, dioxane, Et2O, diisopropyl ether, cyclopentyl methyl ether, and diglyme; esteric solvents such as AcOMe and AcOEt; aprotic polar solvents such as MeCN, DMF, and DMSO; hydrocarbon solvents such as n-pentane, n-hexane, n-heptane, and cyclohexane; halogenated hydrocarbon solvents such as chloroform, DCE, and DCM; other organic solvents; or mixed solvents thereof. Two or more of these may be mixed in appropriate proportions.

[0070] The reaction temperature is typically -80 to 150°C. The reaction time is typically 0.1 to 200 hours. Furthermore, in compound (II), R 4 Compound (II) can also be synthesized by substitution or condensation reactions using a compound in which the atom is a hydrogen atom (represented as compound (5) in the formula below). Examples are shown below.

[0071] Step C-1: Substitution reaction [ka] In the above formula, LG represents a leaving group, and R 4 The same applies as above (except for the hydrogen atom).

[0072] Compound (5) is reacted in an inert solvent, or without a solvent, in the presence or absence of a base depending on the reaction conditions, R 4Compound (II) may be obtained by reacting it with -LG (Step C-1: Substitution reaction).

[0073] Examples of leaving groups include halogen atoms (e.g., chlorine, bromine, iodine), alkyl sulfonyloxy groups (e.g., methyl sulfonyloxy, ethyl sulfonyloxy, trifluoromethyl sulfonyloxy), and aryl sulfonyloxy groups (e.g., benzene sulfonyloxy, p-toluene sulfonyloxy, 2,4,6-trimethylbenzene sulfonyloxy, 2-nitrobenzene sulfonyloxy, 4-nitrobenzene sulfonyloxy).

[0074] Examples of inert solvents include water; alcoholic solvents such as MeOH, EtOH, isopropanol, n-butanol, trifluoroethanol, and ethylene glycol; ketone solvents such as acetone and methyl ethyl ketone; etheric solvents such as THF, dioxane, Et2O, diisopropyl ether, cyclopentyl methyl ether, and diglyme; esteric solvents such as AcOMe and AcOEt; aprotic polar solvents such as MeCN, DMF, and DMSO; hydrocarbon solvents such as n-pentane, n-hexane, n-heptane, and cyclohexane; halogenated hydrocarbon solvents such as chloroform, DCE, and DCM; or other organic solvents; or mixed solvents thereof. Preferably, aprotic polar solvents, such as MeCN, or ketone solvents, such as acetone, or mixed solvents of these with water are used.

[0075] As bases, a wide range of known inorganic and organic bases can be used. Examples of inorganic bases include alkali metals (e.g., sodium, potassium, etc.), alkali metal bicarbonates (e.g., lithium bicarbonate, sodium bicarbonate, potassium bicarbonate, etc.), alkali metal hydroxides (e.g., LiOH, NaOH, KOH, etc.), alkali metal carbonates (e.g., Li2CO3, Na2CO3, K2CO3, Cs2CO3, etc.), alkali metal lower alkoxides (e.g., sodium methoxide, sodium ethoxide, etc.), and alkali metal hydrides (e.g., NaH, KH, etc.). Examples of organic bases include trialkylamines (e.g., trimethylamine, TEA, DIPEA, etc.), pyridine, quinoline, piperidine, imidazole, picoline, dimethylaminopyridine, dimethylaniline, N-methylmorpholine, DBN, DABCO, DBU, etc. Furthermore, if these bases are liquids, they can also be used as solvents. These bases can be used individually or in mixtures of two or more.

[0076] The amount of base used is usually 1 molar equivalent to an excess amount per mole of compound (5) being reacted.

[0077] The reaction conditions are not particularly limited, and the reaction temperature is usually between -80°C and 150°C. The reaction time is usually between 0.1 hours and 200 hours.

[0078] Process C-2, C-2': Condensation reaction [ka] In the above formula, R 4 The same applies as above (except for the hydrogen atom).

[0079] For example, compound (5) is reacted in an inert solvent, or without a solvent, in the presence or absence of a base depending on the reaction conditions, with alcohol (R 4 Compound (II) can be obtained by reacting it with OH) in the presence of a condensing agent (Step C-2: Condensation reaction). Alternatively, instead of the alcohol, an amine (HNR) can be used. 4Na R 4NbBy using R, 1 ga-O - R 2 NR 4Na R 4Nb Compound (II') can also be obtained (step C-2': condensation reaction).

[0080] Examples of inert solvents include water; alcoholic solvents such as MeOH, EtOH, isopropanol, n-butanol, trifluoroethanol, and ethylene glycol; ketone solvents such as acetone and methyl ethyl ketone; etheric solvents such as THF, dioxane, Et2O, diisopropyl ether, cyclopentyl methyl ether, and diglyme; esteric solvents such as AcOMe and AcOEt; aprotic polar solvents such as MeCN, DMF, and DMSO; hydrocarbon solvents such as n-pentane, n-hexane, n-heptane, and cyclohexane; halogenated hydrocarbon solvents such as chloroform, DCE, and DCM; or other organic solvents; or mixed solvents thereof. Preferably, halogenated hydrocarbon solvents, such as DCM; aprotic polar solvents, such as MeCN and DMF; or ketone solvents, such as acetone; or mixed solvents of these with water.

[0081] As bases, a wide range of known inorganic and organic bases can be used. Examples of inorganic bases include alkali metals (e.g., sodium, potassium, etc.), alkali metal bicarbonates (e.g., lithium bicarbonate, sodium bicarbonate, potassium bicarbonate, etc.), alkali metal hydroxides (e.g., LiOH, NaOH, KOH, etc.), alkali metal carbonates (e.g., Li2CO3, Na2CO3, K2CO3, Cs2CO3, etc.), alkali metal lower alkoxides (e.g., sodium methoxide, sodium ethoxide, etc.), and alkali metal hydrides (e.g., NaH, KH, etc.). Examples of organic bases include trialkylamines (e.g., trimethylamine, TEA, DIPEA, etc.), pyridine, quinoline, piperidine, imidazole, picoline, dimethylaminopyridine, dimethylaniline, N-methylmorpholine, DBN, DABCO, DBU, etc. Furthermore, if these bases are liquids, they can also be used as solvents. These bases can be used individually or in mixtures of two or more.

[0082] The amount of base used is usually 1 molar equivalent to an excess amount per mole of compound (5) being reacted.

[0083] As a condensing agent, a wide range of known condensing agents can be used. For example, 3-ethyl-1-(3-dimethylaminopropyl)carbodiimide (WSC) or its HCl salt; 1-[bis(di [methylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-Oxide hexafluorophosphate (HATU); 1-(chloro-1-pyrrolidinylmethylene)pyrrolidinium hexafluorophosphate; N-cyclohexyl-N'-morpholinoethylcarbodiimide; N-cyclohexyl-N'-(4-diethylaminocyclohexyl)carbodiimide; N,N'-diethylcarbodiimide; N,N'-diisopropylcarbodiimide; N,N'-carbonylbis(2-methylimidazole); pentamethyleneketene-N-cyclohexylumine ;Diphenylketene-N-cyclohexylhymine;Ethoxyacetylene;1-alkoxy-1-chloroethylene;Trialkyl phosphite;Ethyl polyphosphate;Isopropyl polyphosphate;Phosphoryl oxychloride (phosphoryl chloride);Phosphorus trichloride;Phosphoryl azide diphenyl;Thionyl chloride;Oxaryl chloride;Alkyl haloidates such as ethyl chloroformate and isopropyl chloroformate;Triphenylphosphine;2-ethyl-7-hydroxybenzisoxazolium salt;2-ethyl-5- Examples include (m-sulfophenyl)isoxazolium hydroxide intramolecular salt; benzotriazole-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate; 1-(p-chlorobenzenesulfonyloxy)-6-chloro-1H-benzotriazole; and so-called Vilsmeyer reagents prepared by the reaction of DMF with thionyl chloride, phosgene, trichloromethyl chloroformate, phosphorus oxychloride, etc.

[0084] The reaction conditions are not particularly limited, and the reaction temperature is usually between -80°C and 150°C. The reaction time is usually between 0.1 hours and 200 hours. Furthermore, each compound (II) can also be synthesized by acylation reaction using compound (5). This acylation reaction can be considered a form of the C-1 (substitution reaction) described above. An example is shown below.

[0085] Step C-3: Acylation reaction [ka] In the above formula, R 17 , R 18This may include, for example, alkyl groups having 1 to 3 substituents (e.g., C 1-18 It is preferable that it is an alkyl group. 17 , R 18 They may be the same or different.

[0086] For example, compound (II) can be obtained by reacting compound (5) with an acylating agent such as a carboxylic acid anhydride in an inert solvent or without a solvent, in the presence of a base depending on the reaction conditions (Step C-3: Acylation reaction).

[0087] Examples of inert solvents include water; alcoholic solvents such as MeOH, EtOH, isopropanol, n-butanol, trifluoroethanol, and ethylene glycol; ketone solvents such as acetone and methyl ethyl ketone; etheric solvents such as THF, dioxane, Et2O, diisopropyl ether, cyclopentyl methyl ether, and diglyme; esteric solvents such as AcOMe and AcOEt; aprotic polar solvents such as MeCN, DMF, and DMSO; hydrocarbon solvents such as n-pentane, n-hexane, n-heptane, and cyclohexane; halogenated hydrocarbon solvents such as chloroform, DCE, and DCM; or other organic solvents; or mixed solvents thereof. Preferably, halogenated hydrocarbon solvents, such as DCM; aprotic polar solvents, such as MeCN and DMF; or ketone solvents, such as acetone.

[0088] As bases, a wide range of known inorganic and organic bases can be used. Examples of inorganic bases include alkali metals (e.g., sodium, potassium, etc.), alkali metal bicarbonates (e.g., lithium bicarbonate, sodium bicarbonate, potassium bicarbonate, etc.), alkali metal hydroxides (e.g., LiOH, NaOH, KOH, etc.), alkali metal carbonates (e.g., Li2CO3, Na2CO3, K2CO3, Cs2CO3, etc.), alkali metal lower alkoxides (e.g., sodium methoxide, sodium ethoxide, etc.), and alkali metal hydrides (e.g., NaH, KH, etc.). Examples of organic bases include trialkylamines (e.g., trimethylamine, TEA, DIPEA, etc.), pyridine, quinoline, piperidine, imidazole, picoline, dimethylaminopyridine, dimethylaniline, N-methylmorpholine, DBN, DABCO, DBU, etc. Furthermore, if these bases are liquids, they can also be used as solvents. These bases can be used individually or in mixtures of two or more.

[0089] The amount of base used is usually 1 molar equivalent to an excess amount per mole of compound (5) being reacted.

[0090] The reaction conditions are not particularly limited, and the reaction temperature is usually between -80°C and 150°C. The reaction time is usually between 0.1 hours and 200 hours.

[0091] In this specification, compound (I), the starting compound, and the intermediate compound may also be used in the form of chemically acceptable geometric isomers, stereoisomers, optical isomers, and tautomers. The various isomers can be separated by general optical resolution methods or produced from the corresponding optically active starting compound.

[0092] In this specification, compound (I), the starting compound, and the intermediate compound may also be in the form of a salt, and the target compound obtained in each reaction may also form a salt. If the compound obtained in each reaction is a free compound, it can be converted to the target salt by known methods, and if the compound is a salt, it can be converted to its free form or another target salt by known methods. Examples of such salts are listed below. As for the salt, a pharmaceutically acceptable salt is preferred, for example, a metal salt (e.g., alkali metal salt, Preferred examples include alkaline earth metal salts, zinc salts, etc. Also preferred are acid addition salts or base addition salts. Examples of acids in acid addition salts include inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, sulfuric acid, and phosphoric acid; organic acids such as formic acid, propionic acid, oxalic acid, carbonic acid, picric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, acetic acid, citric acid, tartaric acid, malonic acid, succinic acid, maleic acid, fumaric acid, malic acid, and lactic acid; and amino acids such as aspartic acid and glutamic acid. Examples of bases in base addition salts include metals such as alkali metals (e.g., sodium, potassium, etc.) and alkaline earth metals (e.g., calcium, magnesium, etc.); inorganic bases such as alkali metal carbonates (e.g., lithium carbonate, potassium carbonate, sodium carbonate, cesium carbonate, etc.), alkali metal bicarbonates (e.g., lithium bicarbonate, sodium bicarbonate, potassium bicarbonate, etc.), and alkali metal hydroxides (e.g., lithium hydroxide, sodium hydroxide, potassium hydroxide, calcium hydroxide, cesium hydroxide, etc.); and organic bases such as methylamine, diethylamine, trimethylamine, triethylamine, N-ethyldiisopropylamine, ethanolamine, diethanolamine, triethanolamine, ethylenediamine, tris(hydroxymethyl)methylamine, dicyclohexylamine, N,N'-dibenzylethylenediamine, guanidine, pyridine, quinoline, piperidine, imidazole, dimethylaminopyridine, dimethylaniline, picoline, choline, N-methylmorpholine, DBN, DBU, DABCO; amino acids such as lysine and arginine; and ammonia.

[0093] Compound (I) or its salts may also be used in the form of various solvates (especially hydrates). Furthermore, compound (I) or its salts may be used in the form of crystalline polymorphs. Compound (I) or its salts may also be used in the form of pharmaceutically acceptable cocrystals or cocrystalline salts. Here, a cocrystal or cocrystalline salt refers to a crystalline substance composed of two or more distinct solids at room temperature, each possessing different physical properties (e.g., structure, melting point, heat of fusion, etc.). Cocrystals and cocrystalline salts can be produced by applying known cocrystallization methods.

[0094] Compound (I) includes compounds in which any one or more atoms of formula (I) are replaced with one or more isotopic atoms. Examples of isotopic atoms include deuterium ( 2 H), tritium ( 3 H), 13 C, 15 N, 18 Examples include O. Compound (I) also includes compounds labeled with various radioactive or non-radioactive isotopes.

[0095] Compound (I) can be used in combination with various therapeutic or prophylactic agents for diseases that can be treated by compound (I). Such combination may be administered simultaneously, or separately, consecutively, or at desired time intervals. The simultaneously administered formulation may be a combination formulation or individually formulated formulations.

[0096] Next, we will describe pharmaceutical preparations (hereinafter also referred to as "pharmaceutical compositions") that contain compound (I) as an active ingredient.

[0097] The above-mentioned pharmaceutical formulation is a formulation of compound (I) in the form of a conventional pharmaceutical formulation, and is prepared using compound (I) or a salt thereof and a pharmaceutically acceptable carrier. Examples of such carriers include commonly used fillers, bulking agents, binders, humectants, disintegrants, surfactants, lubricants, suspending agents, solubilizers, isotonic agents, solvents, and other diluents or excipients.

[0098] Such pharmaceutical preparations can be selected from various forms depending on the therapeutic purpose, and examples include tablets, pills, powders, liquids, suspensions, emulsions, granules, capsules, suppositories, injections, nasal sprays, and inhalants, with injections being particularly preferred. Injectable preparations include intramuscular injections and subcutaneous injections, with subcutaneous injections being particularly preferred.

[0099] A wide range of known carriers can be used when forming tablets, such as excipients including lactose, sucrose, sodium chloride, glucose, urea, starch, calcium carbonate, kaolin, and crystalline cellulose; binders including water, ethanol, propanol, simple syrup, glucose solution, starch solution, gelatin solution, carboxymethylcellulose, shellac, methylcellulose, potassium phosphate, and polyvinylpyrrolidone; and dried starch, sodium alginate, agar powder, laminaran powder, and sodium bicarbonate. Examples of additives include: disintegrants such as calcium carbonate, polyoxyethylene sorbitan fatty acid esters, sodium lauryl sulfate, monoglyceride stearate, starch, and lactose; disintegration inhibitors such as sucrose, stearin, cocoa butter, and hydrogenated oil; absorption enhancers such as quaternary ammonium bases and sodium lauryl sulfate; humectants such as glycerin and starch; adsorbents such as starch, lactose, kaolin, bentonite, and colloidal silicic acid; and lubricants such as refined talc, stearate, boric acid powder, and polyethylene glycol.

[0100] Furthermore, the tablets may be coated with a standard tablet shell as needed, such as sugar-coated tablets, gelatin-coated tablets, enteric-coated tablets, film-coated tablets, or double-layered tablets.

[0101] A wide range of known carriers can be used when forming the product into pill form, such as excipients including glucose, lactose, starch, cocoa butter, hydrogenated vegetable oil, kaolin, and talc; binders including gum arabic powder, tragacanth powder, gelatin, and ethanol; and disintegrants including laminaran and agar.

[0102] A wide range of known carriers can be used when forming the suppository, including polyethylene glycol, cocoa butter, higher alcohols, esters of higher alcohols, gelatin, and semi-synthetic glycerides.

[0103] When prepared as an injectable preparation, the liquid, emulsion, and suspension preparations are preferably sterilized and isotonic with blood. Diluents widely known and used in forming these liquid, emulsion, and suspension preparations can be water, ethanol, propylene glycol, ethoxylated isostearyl alcohol, polyoxylated isostearyl alcohol, polyoxyethylene sorbitan fatty acid esters, etc. In this case, a sufficient amount of sodium chloride, glucose, amino acids, or glycerin to prepare an isotonic solution may be included in the pharmaceutical preparation, as well as conventional solubilizers, buffers, analgesics, etc., and, if necessary, preservatives, stabilizers, antioxidants, solubilizers, and pH adjusters. It may contain other pharmaceuticals or ingredients.

[0104] Brexpiprazole is known to be useful in alleviating symptoms of Alzheimer's disease accompanied by severe agitation, destructiveness, and violent behavior. Since rapid-release injectable antipsychotics are known to be useful as symptomatic treatments for acute patients with severe agitation, destructiveness, and violent behavior in schizophrenia and other conditions, an injectable brexpiprazole that rapidly releases into the bloodstream is expected to be useful as a symptomatic treatment for acute patients with agitation in schizophrenia and Alzheimer's disease. A pharmaceutical composition containing compound (1), designed in a preferred injectable form according to medical needs, is expected to deliver a rapidly effective therapeutic dose of brexpiprazole into the patient's bloodstream in a short time (e.g., several hours) when administered subcutaneously or intramuscularly, thereby enabling rapid onset of action in acute applications such as agitation. Examples of preferred injectable forms for such acute-phase injections include, as necessary, appropriate isotonic agents, buffers, pH adjusters, solubilizers, etc. In addition, an injectable preparation may be obtained by dissolving compound (1) in water for injection, a biocompatible organic solvent, or a mixture of water for injection and a biocompatible organic solvent. The solubilizing agents include polysorbate 80, polysorbate 60, polyoxyethylene hydrogenated castor oil 60, poloxamer, β-cyclodextrin, and sulfobutyl ether-β-sulfobutyl ether. Clodextrin is one example. Examples of isotonic agents include alkali metal chlorides such as sodium chloride and potassium chloride; sugar alcohols such as mannitol, sorbitol, xylitol, and maltitol; sugars such as glucose, trehalose, and maltose; and glycerin. The composition may not contain an isotonic agent, but if it does, the concentration of the isotonic agent in the composition is preferably such that the osmotic pressure of the solution of the composition is isotonic. Depending on the type of isotonic agent, for example, in the case of alkali metal chlorides, it is preferably 0.5 to 20 mg / mL, more preferably 2 to 10 mg / mL, and in the case of sugar alcohols and sugars, it is preferably 10 mg / mL to 200 mg / mL, more preferably 20 to 100 mg / mL. Examples of buffering agents include phosphates such as sodium phosphate, sodium dihydrogen phosphate, monosodium hydrogen phosphate, disodium hydrogen phosphate, potassium phosphate, potassium dihydrogen phosphate, and dipotassium hydrogen phosphate; borates such as sodium borate and potassium borate; citrates such as sodium citrate and disodium citrate; acetates such as sodium acetate and potassium acetate; carbonates such as sodium carbonate and sodium bicarbonate; trishydroxymethylaminomethane (Tris), etc. The concentration of the buffering agent in the composition is, for example, 0.01 to 5.0 mg / mL, preferably 0.1 to 2 mg / mL.

[0105] The pH adjuster may be either an acidic or basic pH adjuster. Examples of acidic pH adjusters include hydrochloric acid, phosphoric acid, acetic acid, and citric acid. Examples of basic pH adjusters include sodium hydroxide, potassium hydroxide, calcium carbonate, magnesium oxide, and magnesium hydroxide. The pH adjuster is usually added in an appropriate amount depending on the desired pH of the composition. Examples of biocompatible organic solvents include those that are miscible with water, such as alcohols like ethanol, propanol, isopropanol, propylene glycol, and glycerin, as well as dimethyl sulfoxide, N-methyl-2-pyrrolidone, polyethylene glycol 300, or polyethylene glycol 400. In the treatment of agitation associated with schizophrenia, depression, and Alzheimer's disease, treatment is often carried out with once-daily tablets. However, in cases of medication refusal or agitation, taking tablets can be difficult. In such cases, a sustained-release injectable preparation (preferably dermal) administered every one to several days may be used. Subcutaneous or intramuscular administration of a sustained-release injectable formulation is considered a useful preparation because it ensures reliable drug delivery and offers convenience. A pharmaceutical composition containing compound (1), designed in a preferred injectable form to meet medical needs, can be administered subcutaneously or intramuscularly, allowing for the sustained delivery of a therapeutically effective dose of brexpiprazole into the patient's bloodstream for a relatively short period (1 to several days), even in patients who have difficulty taking tablets, thus enabling the onset of drug effects over 1 to several days. In the treatment of schizophrenia, sustained-release injectable formulations are useful for improving the therapeutic and preventive effects in patients with poor medication adherence. Generally, for a drug to exert its therapeutic effect, it is desirable for the blood drug concentration to rapidly reach the therapeutic level and then be maintained at a constant level. Representative sustained-release injectable formulations for schizophrenia include aripiprazole and paliperidone palmitate (trade names: Abilify sustained-release suspension for intramuscular injection and Xeplion suspension for intramuscular injection). However, these drugs are poorly soluble and dissolution after administration is slow, so oral medications are often used in combination or the injection interval is shortened to compensate for the blood drug concentration at the start of treatment. A pharmaceutical composition containing compound (1), designed in a preferred injectable form to meet medical needs, can be administered subcutaneously or intramuscularly to rapidly and continuously deliver a therapeutically effective amount of brexpiprazole into the patient's bloodstream for a relatively short period (1 to 4 weeks or more), even in patients who are not expected to achieve sufficient therapeutic or preventive effects due to poor medication adherence. This is expected to improve the therapeutic or preventive effects in such patients.

[0106] Examples of preferred injectable formulations for sustained delivery of brexpiprazole over 1 to several days or 1 to 4 weeks or more include compound (1), suspending agent, and dispersion medium. Examples of pharmaceutical compositions include those containing and in the form of a suspension. The concentration of compound (1) in the composition is not particularly limited as long as it is an effective concentration according to the intended use of the composition. The concentration of compound (1) in the composition is, for example, 50 mg / mL or more, preferably 100 mg / mL or more, more preferably 150 mg / mL or more, in terms of brexpiprazole equivalent, Preferably, the concentration is 200 mg / mL or 250 mg / mL or higher. The upper limit is not particularly limited, but examples include 1000 mg / mL or less, 750 mg / mL or less, or 500 mg / mL or less. For example, it can be used in the range of 50 to 1000 mg / mL. The suspending agent contained in the composition is not particularly limited, as long as it is pharmaceutically acceptable and can achieve a predetermined viscosity. Examples of suspending agents include carboxymethylcellulose and its salts; polyoxyethylene-polyoxypropylene block copolymer such as poloxamer. Examples include rimers; polyethylene glycol (also known as "macrogol"), etc. Examples of carboxymethylcellulose salts include metal salts such as alkali metal salts and ammonium salts. Specifically, examples include sodium carboxymethylcellulose, potassium carboxymethylcellulose, lithium carboxymethylcellulose, ammonium carboxymethylcellulose, and mixtures thereof. In one embodiment, the suspending agent preferably contains carboxymethylcellulose and / or its sodium salt, and particularly preferably contains sodium carboxymethylcellulose. One type of suspending agent It may be used alone or in combination of two or more types. The concentration of the suspending agent in the composition is For example, 0.1 mg / mL or more, preferably 0.2 mg / mL or more, and more preferably 0.5 mg / mL or more. The concentration of the suspending agent in the composition is, for example, 100 mg / mL or less, preferably 50 mg / mL or less. More preferably, the concentration is 25 mg / mL or less. The concentration of the suspending agent in the composition is, for example, 0.1 to 50 mg / mL.

[0107] The dispersion medium included in the composition is not particularly limited, as long as it is pharmaceutically acceptable and capable of dispersing the active ingredient. The dispersion medium may be a single type or a combination of two or more types. The dispersion medium preferably contains at least water. Examples of such dispersion mediums include water, physiological saline, and solvents containing water and a biocompatible organic solvent. In preferred embodiments, the dispersion medium is water, and it is particularly preferable to use purified water, sterile purified water, or water for injection. The composition may contain further optional additives. Such additives are not particularly limited as long as they are pharmaceutically acceptable, and include, for example, the isotonic agents, buffers, pH adjusters, etc. The additives may be used individually or in combination of two or more. The average particle size of the suspended compound (1) is, for example, 0.1 to 30 μm, preferably 0.5 to 20 μm. Yes, such a range is preferable in that it allows the effect to last for a long time. On the other hand, if you want to obtain a high blood drug concentration immediately after administration, the average particle size of the suspended compound (1) should be, for example, 500 nm or less. Preferably, the particle size is 50 to 500 nm. The average particle size is determined by laser diffraction scattering. The average particle diameter is measured. For measuring the average particle diameter using laser diffraction scattering, for example, the SALD-3100 or SALD-2300 (manufacturer: Shimadzu Corporation) can be used. As a method for preparing the above composition, it is preferable to use a wet grinding method. Wet grinding methods include wet ball milling, high pressure homogenization, and high shear homogenization. A bead mill (e.g., a Dino mill) is preferred. In addition to the grinding method described above, other low and high energy mills (e.g., roller mills) can also be used. Other preparation methods include controlled crystallization.

[0108] In one embodiment, the composition is produced by a method comprising, for example, step 1 of mixing compound (1), a suspending agent, and a dispersion medium; step 2 of bead milling the suspension obtained by the mixing; and step 3 of removing beads from the suspension obtained by bead milling. This is possible. In step 1, the mixing order of each component is not particularly limited. One embodiment In this process, step 1 is a step of mixing components other than the active ingredient to obtain a vehicle solution, and the The process consists of mixing the vehicle solution and the active ingredient. In step 2, the bead mill The method is not particularly limited. In one embodiment, step 2 is to add beads to the suspension This is a process of stirring. Examples of bead materials include zirconia, alumina, and glass. The diameter of the beads is, for example, 0.1 to 5 mm, preferably 0.2 to 3 mm. The average particle size of the compound (1) particles obtained by the bead mill can be appropriately adjusted by the size of the beads, the rotation speed (peripheral speed) during grinding, the grinding time, etc. In step 3, The method for removing the beads is not particularly limited. In one embodiment, step 3 is performed more than the beads This step involves recovering the composition using a small-pore needle (e.g., 22G or less), a pipette, or a mesh filter (e.g., 80μm mesh). Another example of a preferred form of injectable formulation for sustained delivery of brexpiprazole over 1 to several days or 1 to 4 weeks or more is a low-viscosity precursor formulation comprising a mixture of compound (1), a plurality of liquid crystal-forming lipids or gel-forming lipids, and at least one biocompatible organic solvent, which forms, or can form, at least one liquid crystal phase structure or lipid gel upon contact with an aqueous fluid in vivo. The precursor formulation typically does not contain a significant amount of water before administration and is a low-viscosity liquid or suspension obtained by dissolving a plurality of liquid crystal-forming lipids or gel-forming lipids in a biocompatible organic solvent. The pre-liquid crystal-forming lipids or gel-forming lipids are certain amphiphilic components, preferably a combination of at least one diacylglycerol and at least one phosphatidylcholine. By dissolving the pre-liquid crystal-forming lipids or gel-forming lipids in at least one biocompatible organic solvent, a low-viscosity solution can be prepared, and by including compound (1) in a dissolved or suspended state in these solutions, a preferred low-viscosity liquid or suspension precursor formulation can be prepared. Such precursor formulations, upon contact with aqueous fluids in the body after administration, form a liquid crystal phase structure or a high-viscosity lipid gel. Generally, the aqueous fluid is a body fluid, particularly extravascular fluid, extracellular / interstitial fluid, or plasma, and the precursor formulation forms a liquid crystal phase structure or a high-viscosity lipid gel upon contact with such fluid (e.g., in vivo fluid).

[0109] A precursor formulation, which is a low-viscosity liquid or suspension, refers to a liquid or suspension that can be easily administered to a subject, particularly a mixture that can be easily administered by a device consisting of a standard syringe and needle. In a particularly preferred embodiment, the precursor formulation in which compound (1) is dissolved, or the medium before compound (1) is suspended, should be a mixture that can pass through a standard sterile filtration membrane such as a 0.22 μm syringe filter. A typical range of preferred viscosity is, for example, 0.1 to 5000 mPa·s at 20°C, preferably 1 to 1000 mPa·s, and more preferably 1 to 500 mPa·s. The viscosity described above is measured using a rotary rheometer at a shear rate in the range of 9000 to 10000 (1 / s) under conditions of 20°C. Examples of rotary rheometers include the Discovery Hybrid Rheometer-2 (DHR-2) or the Discovery Hybrid Rheometer-3 (DHR-3) (manufacturer: TA Instruments). The aforementioned precursor formulation may form a liquid crystal structure called a lyotropic liquid crystal when the amphiphilic compound (multiple types of liquid crystal-forming lipids or gel-forming lipids) is exposed to an aqueous fluid after administration to the body. Examples of such liquid crystal structures include hexagonal structures where cylindrical aggregates form a hexagonal crystal system, lamellar structures, inverted hexagonal structures where water is incorporated into the cylinder and the lipophilic portion is directed outward, cubic structures where spherical micelles form a cubic crystal in a continuous water (or oil) phase, and bicontinuous cubic structures where lipid bilayers form a three-dimensionally connected curved surface. The inventors have discovered that by administering a precursor formulation and then forming the aforementioned liquid crystal or lipid gel, the release of compound (1) after administration is controlled, and the released compound (1) is converted to brexpiprazole in vivo, thereby enabling the sustained delivery of brexpiprazole.

[0110] Furthermore, by injecting the precursor formulation into water and observing the formation of a solid, it is possible to confirm whether a gel or liquid crystal is formed. Whether a liquid crystal is formed can be confirmed by analyzing the obtained solid using small-angle X-ray scattering (SAXS). In addition, if a liquid crystal is formed and a gel is formed... It is also possible that it is in a liquid crystal gel state. Diacylglycerol has two nonpolar "tail" groups, which may be identical or different, may have the same or different number of carbon atoms, and may be independently saturated or unsaturated. Furthermore, either 1,3-diacylglycerol or 1,2-diacylglycerol can be used. Examples of nonpolar groups include C6-C32 alkyl and C6-C32 alkenyl groups, which typically exist as esters of long-chain carboxylic acids. These are often described in reference to the number of carbon atoms and the number of unsaturated atoms in the carbon chain. Therefore, CX:Z represents a hydrocarbon chain with X carbon atoms and Z unsaturated atoms. Examples include, in particular, the caproyl (C6:0) group, capryloyl (C8:0) group, capryl (C10:0) group, lauroyl (C12:0) group, myristoyl (C14:0) group, palmitoyl (C16:0) group, phytanoyl (C16:0) group, palmitreoyl (C16:1) group, stearoyl (C18:0) group, oleoyl (C18:1) group, elidoyl (C18:1) group, linoleoyl (C18:2) group, linolenoyl (C18:3) group, arachidonoyl (C20:4) group, behenoyl (C22:0) group, and lignoceroyl (C24:9) group. Therefore, typical nonpolar chains are based on fatty acids of natural ester lipids, including caproic acid, caprylic acid, capric acid, lauric acid, myristic acid, palmitic acid, phytanic acid, palmitolic acid, stearic acid, oleic acid, elaidic acid, linoleic acid, linolenic acid, arachidonic acid, behenic acid, or lignoceric acid, or their corresponding alcohols. Preferred nonpolar chains are palmitic acid, stearic acid, oleic acid, and linoleic acid, with oleic acid being particularly preferred. While there are no particular limitations on the diacylglycerol, for example, diacylglycerols having the same or different nonpolar chains as described above are preferred, and among these, glycerol dioleate (GDO) is particularly preferred. Diacylglycerol can be used alone or in combination of two or more types. Phosphatidylcholine (PC) is a glycerophospholipid in which choline is ester-bonded to a phosphate group as the hydrophilic part, and two fatty acids are ester-bonded to the glycerol backbone as the hydrophobic part. Phosphatidylcholine is a general term for phospholipids that make up a structure. Due to the numerous combinations of fatty acids, there are multiple phospholipids belonging to phosphatidylcholine. Suitable sources of phospholipids include eggs, hearts (e.g., bovine hearts), brains, livers (e.g., bovine livers), and plant sources including soybeans. A single PC or a mixture of multiple PCs derived from such material sources may be used, but soybean PC (SPC) or egg-derived PC or mixtures thereof are preferred, and essentially pure SPC (high-purity SPC) is most preferred. As the liquid crystal forming lipid or gel forming lipid, it is preferable to use a combination of at least one diacylglycerol and at least one phosphatidylcholine. In particular, it is preferable to use a combination of one or more of the diacylglycerols specifically described above and one or more of the phosphatidylcholines specifically described above. Particularly preferred combinations of liquid crystal-forming lipids or gel-forming lipids are GDO and PC, and especially GDO and soy PC and / or egg PC.

[0111] Examples of biocompatible organic solvents include those that are miscible with water, and typical solvents include at least one solvent selected from alcohols, ketones, esters (including lactones), ethers, amides, and sulfoxides. Alcohols are particularly preferred and form a preferred solvent group. Examples of preferred alcohols include ethanol, isopropanol, propylene glycol, glycerin, and glycerol formal, with ethanol being the most preferred. An example of a ketone is acetone. Examples of esters include n-methylpyrrolidone (NMP) and 2-pyrrolidone. Examples include don and propylene carbonate. Suitable ethers include diethyl ether, glycofurol, diethylene glycol monoethyl ether, dimethyl isobarbide, and polyethylene glycol. Suitable esters include ethyl acetate and isopropyl acetate, and dimethyl sulfide is a suitable sulfide solvent. Suitable amides and sulfoxides include dimethylacetamide (DMA) and dimethyl sulfoxide (DMSO), respectively. Biocompatible organic solvents can be used individually or in combination of two or more. A preferred combination of low-viscosity precursor formulations containing a mixture of multiple liquid crystal-forming lipids or gel-forming lipids and at least one biocompatible organic solvent is a combination of SPC, GDO, and ethanol, and a combination of SPC, GDO, ethanol, and DMSO is also preferred. A preferred low-viscosity precursor formulation is prepared by dissolving or suspending compound (1) in a solution containing multiple liquid crystal-forming lipids or gel-forming lipids and at least one biocompatible organic solvent. Another example of a preferred form of injectable formulation for a sustained-release injectable formulation that delivers brexpiprazole continuously over 1 to several days or 1 to 4 weeks or more is a microsphere containing compound (1) as the active ingredient. Here, microspheres generally refer to spherical formulations with a particle size of several μm to several tens of μm, which may have irregularities on their surface. The microspheres of this disclosure typically include a carrier such as a base polymer (e.g., a biodegradable polymer). The average particle size of the microspheres in this disclosure is preferably 5 to 150 μm, more preferably 10 to 120 μm, even more preferably 20 to 100 μm, and more preferably 30 to 85 μm, in order to obtain the desired release control characteristics of compound (I). Furthermore, if it is necessary to increase the absorption rate to obtain the desired release control characteristics, the average particle size can be reduced, and if it is necessary to decrease the absorption rate, the average particle size can be increased. To obtain the desired release control characteristics of compound (I) and the desired blood drug concentration profile of brexpiprazole, the encapsulation rate of compound (1) in the microspheres of this disclosure is preferably 80% or higher. To improve the encapsulation rate, the amount of active ingredient added to the batch formulation can also be increased.

[0112] In the microspheres of this disclosure, from the viewpoint of obtaining desired release control characteristics of compound (I) and desired blood drug concentration profiles of brexpiprazole, the content of compound (I) is preferably 10-50% by weight, more preferably 20-45% by weight, and even more preferably 30-40% by weight. The microspheres of this disclosure preferably contain a biodegradable polymer as the base polymer. The biodegradable polymer used in this disclosure can be any polymer that is gradually degraded in vivo to obtain the desired sustained-release performance, such as polylactic acid, polyglycolic acid, lactic acid-glycolic acid copolymer (poly(lactic-co-glycolic acid): PLGA), and polycithin. Examples include homopolymers and copolymers thereof such as acids, polymalic acid, lactic acid-aspartic acid copolymer, lactic acid-hydroxycaproic acid copolymer, glycolic acid-hydroxycaproic acid copolymer, polypropiolactone, polybutyrolactone, polyvalerolactone, polycaprolactone, polytrimethylene carbonate, polyp-dioxanone, poly-α-cyanoacrylate, polyβ-hydroxybutyric acid, polytrimethylene oxalate, polyorthoester, polyorthocarbonate, polyethylene carbonate, polyγ-benzyl-L-glutamic acid, poly-L-alanine, polyalginic acid, polycarbonate, polyesteramide, polyamino acids, polyalkylene alkylate, polyethylene glycol, and polyurethane. Among these, polylactic acid and lactic acid-glycolic acid copolymer are preferred. These biodegradable polymers may be used individually or as a mixture of two or more. When using polylactic acid or lactic acid-glycolic acid copolymer, the molecular weight can be appropriately selected from a wide range, but is usually around 2000 to 200000, preferably 4000 to 10 The values ​​are approximately 0000, and in the finer part, approximately 10000 to 70000. Here, the molecular weight mentioned above refers to the weight-average molecular weight of polystyrene, measured by gel permeation chromatography (GPC) using polystyrene as the reference material. Furthermore, in lactic acid-glycolic acid copolymers, lactic acid:glycolic acid (lactide:glycolide) The ratio is not particularly limited and can be appropriately selected from a wide range, but it is usually around 99:1 to 1:99 in terms of the number of molecules, preferably around 85:15 to 50:50. The polylactic acid may be poly-D-lactic acid, poly-L-lactic acid, or poly-DL-lactic acid, with poly-DL-lactic acid being preferred. The lactic acid-glycolic acid copolymer may be D-lactic acid-glycolic acid copolymer, L-lactic acid-glycolic acid copolymer, or DL-lactic acid-glycolic acid copolymer, with DL-lactic acid-glycolic acid copolymer being preferred. Polylactic acid or lactic acid-glycolic acid copolymers can be produced by known methods, or commercially available products (e.g., Resomer, Lactel (manufactured by Evonik)) can be used. The microspheres may contain, in addition to the biodegradable polymer, a non-degradable, biocompatible polymer. Furthermore, the microspheres of this disclosure may contain any additives such as emulsifiers.

[0113] The microspheres of this disclosure can be manufactured using the above-described components by methods known in the pharmaceutical field. From the viewpoint of obtaining microspheres with excellent sustained-release performance, fluidity during filling, and permeability to syringes during administration, it is preferable to manufacture the microspheres of this disclosure by including a step of dissolving or suspending compound (I) or a salt thereof and a biodegradable polymer in an organic solvent, emulsifying them in the presence or absence of an emulsifier, and then removing the organic solvent. Furthermore, steps known in the pharmaceutical field (e.g., a filtration step, a granulation step) may also be included. The method for manufacturing microspheres according to this disclosure is described in more detail below. The method for producing microspheres according to the present disclosure includes the steps of: obtaining a solution or suspension containing compound (I) and a biodegradable polymer in an organic solvent; mixing the obtained solution or suspension with water and emulsifying it in the presence or absence of an emulsifier to obtain an emulsion; and removing the organic solvent from the obtained emulsion. First, compound (I) and the biodegradable polymer are dissolved or suspended in an organic solvent to obtain a homogeneous solution or suspension. Compound (I) may be dissolved in the organic solvent or suspended. The biodegradable polymer is preferably dissolved in the organic solvent. The organic solvents used in the production of microspheres according to this disclosure are not particularly limited as long as they can dissolve the biodegradable polymer, but examples include halogenated hydrocarbons such as chloroform, dichloroethane, trichloroethane, dichloromethane, and carbon tetrachloride; ethers such as ethyl ether and isopropyl ether; fatty acid esters such as ethyl acetate and butyl acetate; aromatic hydrocarbons such as benzene, toluene, and xylene; alcohols such as ethanol, methanol, isopropanol, and benzyl alcohol; nitriles such as acetonitrile; amides such as dimethylformamide; and water-miscible or water-immiscible organic solvents such as acetone. These organic solvents may be used individually or in mixtures of two or more. Among these, water-immiscible organic solvents, particularly dichloromethane, are preferred. Furthermore, an acid or base can be added to these organic solvents. Examples of acids include hydrochloric acid, phosphoric acid, acetic acid, citric acid, formic acid, gluconic acid, lactic acid, oxalic acid, tartaric acid, and oleic acid, but acetic acid is particularly preferred.

[0114] The ratio of compound (I) or its salt to the organic solvent is typically about 0.01 to 30 parts by weight, preferably about 0.1 to 20 parts by weight, and more preferably about 1 to 10 parts by weight of compound (I) or its salt per 100 parts by weight of the organic solvent. The ratio of biodegradable polymer to organic solvent is typically about 0.01 to 30 parts by weight, preferably about 0.1 to 20 parts by weight, and more preferably about 1 to 10 parts by weight of biodegradable polymer per 100 parts by weight of the organic solvent. Next, the obtained organic solvent solution or suspension (compound (I), biodegradable polymer and organic The solvent is emulsified. That is, the resulting organic solvent solution is mixed with water (so-called outer phase) to obtain an O / W type emulsion in which the organic solvent solution is uniformly dispersed in water, or the resulting organic solvent suspension is mixed with water (so-called outer phase) to obtain an S( A solid-oil-water emulsion is obtained. The water used is not particularly limited, but it is preferably that which is acceptable in the field of pharmaceutical formulations, such as purified water or water for injection. The ratio of organic solvent solution or suspension to water is determined by the desired particle size of the O / W or S / O / W emulsion. While not particularly limited as long as the desired solution is obtained, the amount of organic solvent solution or suspension is usually about 0.001 to 0.2 parts by volume, preferably about 0.005 to 0.1 parts by volume, and more preferably about 0.01 to 0.05 parts by volume, per 1 part by volume of water. In this disclosure, whether a water-miscible or water-immiscible organic solvent is used, an emulsifier may be used. When a water-miscible organic solvent is used, it is preferable to use an emulsifier. The emulsifier used in this disclosure is an O / W type or S / O / W type emulsion, preferably Any material capable of forming a stable O / W or S / O / W emulsion is acceptable, for example. Examples include anionic surfactants such as sodium oleate, sodium stearate, and sodium lauryl sulfate; nonionic surfactants such as polyoxyethylene sorbitan fatty acid esters and polyoxyethylene castor oil derivatives; and polyvinylpyrrolidone, polyvinyl alcohol, carboxymethylcellulose, lecithin, gelatin, and hyaluronic acid. These emulsifiers may be used individually or in combination of two or more.

[0115] The emulsifier should be added to the aqueous phase before emulsification. The amount of emulsifier used is not particularly limited and can be selected from a wide range, but the concentration of the emulsifier in the aqueous solution is, for example, about 0.0001 to 20% by weight, preferably about 0.001 to 10% by weight. The concentration is, more preferably, about 0.001 to 5% by weight. The method for preparing the O / W type or S / O / W type emulsion is not particularly limited, and the above organic solvent solution Alternatively, a method may be used in which a suspension (containing compound (I) or its salt, a biodegradable polymer, and an organic solvent) is dispersed in water as droplets or micelles of an appropriate size. As an example of this preparation method, a mixture of the above solution or suspension and water is stirred at an appropriate rotational speed using a homogenizer or the like to finely atomize the solution or suspension in water to form an O / W type or S / O / W type emulsion. A method of atomizing the solution or suspension to form an O / W type or S / O / W type emulsion by passing a mixture of the above solution or suspension and water at a constant speed through a filter having fine through-pores such as a ceramic filter, One possible method is to pass the above solution or suspension through a filter at a constant speed to atomize it, and then mix it with water. If necessary, emulsion formation may be carried out in multiple steps. Furthermore, the desired particle size can be obtained by adjusting the stirring force during emulsion formation. In other words, increasing the stirring force during emulsion formation can reduce the particle size. By removing the organic solvent from the obtained O / W or S / O / W emulsion, An aqueous suspension of crossfairs is obtained. The removal of organic solvents is carried out using commonly used methods. These methods include heating while stirring with a propeller-type stirrer or magnetic stirrer, gradually reducing the pressure, or desorption while adjusting the vacuum level using a rotary evaporator. The microsphere suspension thus obtained may be washed to remove free compound (I) adhering to the surface of the microspheres by adding an appropriate solution or solvent as needed. Suitable washing solutions and solvents include alkaline solutions such as ethanol and 1N sodium hydroxide solution. The following steps are taken: After separating the microspheres by centrifugation or filtration, the free compounds (I), emulsifiers, etc. adhering to the surface of the microspheres are washed several times with distilled water, and if necessary, with an appropriate solution or solvent. Suitable washing solutions and solvents include ethanol and Examples include alkaline solutions such as 1N sodium hydroxide solution. If necessary, after dispensing, heat. By reducing the pressure, the desorption of water and solvent from the microspheres can be more complete. Alternatively, the washed microspheres can be resuspended in water, either in the presence or absence of sugars, sugar alcohols, or other additives, and then freeze-dried to obtain microsphere powder. The freeze-drying conditions are not particularly limited as long as the microspheres can be dried.

[0116] Furthermore, the dried microspheres may be sieved through a sieve as needed to obtain microspheres having the desired average particle size. The microspheres of this disclosure, and in particular the microspheres obtained by the above manufacturing method, have excellent sustained-release properties. The microspheres of this disclosure can release compound (I) or a salt thereof in a therapeutic dose for a period of at least one week, more preferably two, three, or four weeks, and even more preferably six weeks or more. The above effects are particularly evident when the microspheres of this disclosure are provided as an aqueous suspension for injection in water for injection. The microspheres of this disclosure obtained by the above manufacturing method typically have a spherical shape. The spherical shape of the microspheres of this disclosure provides good fluidity during filling in manufacturing and good syringe passage (needle penetration) during administration, and also reduces irritation at the injection site when administered as an intramuscular or subcutaneous injection. The microspheres of this disclosure can be administered to a patient, for example, as an aqueous suspension injection comprising microspheres containing compound (I), a vehicle therefor, and water for injection. Alternatively, in another form, the microspheres of this disclosure can be administered to a patient, for example, as an oily suspension injection comprising microspheres containing compound (I), a vehicle therefor if necessary, and an oil. The oil here is preferably, for example, a triglyceride (particularly a medium-chain triglyceride). The microsphere content of the suspension injection of this disclosure is not particularly limited as long as the microspheres are dispersed in the injection, but is usually about 5 to 50% by weight, preferably about 10 to 40% by weight, and more preferably about 10 to 30% by weight. Examples of vehicles used in this disclosure include the aforementioned suspending agents, isotonic agents, buffering agents, pH adjusters, and the like.

[0117] In this specification, "therapeutically effective dose" refers to an amount that is effective in providing therapeutic benefits, such as symptom relief, when administered to humans or non-humans. The specific dose of a substance administered to obtain therapeutic benefits will, of course, be determined by specific circumstances, such as the specific substance administered, the route of administration, the disease being treated, and the individual being treated. For example, a pharmaceutical preparation may contain compound (I) or a salt thereof in an amount of 1 to 70% by weight, calculated as compound (I).

[0118] For example, in subcutaneous or intramuscular administration, a daily dose that can yield satisfactory results is on the order of approximately 0.001 to 1.5 mg / kg. The daily dose prescribed for subcutaneous or intramuscular administration is in the range of approximately 0.1 mg to 500 mg, more preferably 0.1 to 100 mg, and may be preferably administered once a day or in 2 to 4 divided doses. Accordingly, the unit dosage form for subcutaneous or intramuscular administration may contain, for example, approximately 0.1 mg to 500 mg of compound (I) or its salt, together with a pharmaceutically acceptable diluent or carrier. The upper or lower limit of this range (0.1 mg to 500 mg) may be, for example, 0.2, 0.5, 1, 2, 3, 5, 10, 20, 50, 100, 200, 300, or 400 mg. For example, the range is preferably 0.2 to 100 mg or 0.5 to 50 mg, and more preferably 0.5 to 10 mg.

[0119] In this specification, "pharmaceutically acceptable" means a compound, a composition containing such compound, or a dosage form thereof, within a range that has a reasonable benefit / risk ratio suitable for application to humans or animals, without causing excessive toxicity, irritation, allergic reactions, etc.

[0120] While not particularly limited, pharmaceutical preparations containing compound (I) or its salt are preferably, for example, injectable preparations. Examples of injectable preparations include intramuscular injection preparations and subcutaneous injection preparations, with subcutaneous injection preparations being particularly preferred.

[0121] In this specification, the term "comprising" includes both "consisting essentially of" and "consisting of." Furthermore, this disclosure encompasses all combinations of the constituent elements described herein.

[0122] Furthermore, the various characteristics (properties, structure, function, etc.) described in each embodiment of this disclosure above may be combined in any way to identify the subject matter covered by this disclosure. In other words, this disclosure covers all subject matter consisting of any combination of the combinable characteristics described herein. [Examples]

[0123] The embodiments of this disclosure will be described in more detail below with examples, but the embodiments of this disclosure are not limited to the examples below.

[0124] In this specification, the following abbreviations may be used. REX: Reference example number EX: Example Number STR: Structural formula Data: Physical property data (NMR1: Dimethyl sulfoxide-d6) 1 δ(ppm) in H-NMR; NMR2: in CDCl3 1 δ(ppm) in H-NMR; NMR3: CD3OD 1 δ(ppm) in H-NMR; NMR4: CD3CO2D 1 δ (ppm) in H-NMR, or MS: mass spectrum) Furthermore, the following abbreviations may be used for compound names and reagent names.

[0125] [Table 1E]

[0126] In the following examples, "room temperature" typically refers to a temperature range of approximately 10°C to 35°C. The ratios shown in the mixed solvents are... Unless otherwise specified, the values ​​indicated are volume ratios. Unless otherwise specified, the percentages indicated are weight percentages.

[0127] 1H-NMR (proton nuclear magnetic resonance spectroscopy) is a Fourier transform type NMR (Bruker AVANCE III 400 (400MHz), Bruker AVANCE NEO 400 (400MHz), and Bruker AVANCE III HD (500MHz)). ) was measured using one of the following methods.

[0128] Example 1 (EX1) 7-(4-(benzo[b]thiophen-4-ylpiperazine-1-yl)butoxy)-1H-quinoline-2-ol A mixture of 3.0 g of nitrate, 30 mL of MeCN, and 90 mL of DCM was mixed with 2.074 g of NaI, 1.913 g of K2CO3, and 3.58 g of di-tert-butyl (chloromethyl) phosphate, and stirred at room temperature. 3 days Then, di-tert-butyl (chloromethyl) phosphate (1.790 g) and NaI (1.037 g) were added. The mixture was then stirred. After another 4 days, water was added to the reaction mixture and stirred, the organic layer was extracted, and the mixture was concentrated under reduced pressure. This was dissolved in DCM (90 mL), then TFA (5.33 mL) was added and the mixture was stirred at room temperature for 3 hours. 1N NaOH aqueous solution (138 mL) was added to the reaction mixture and the mixture was stirred for 20 minutes. The aqueous layer was separated from the reaction mixture. The mixture was washed with DCM and Et2O. AcOH (3.96 mL) was added to the aqueous layer and the mixture was stirred at room temperature for 1 hour. The precipitated solid was filtered to obtain the crude product. This crude product was purified by reverse-phase silica gel column chromatography (0.1% AcOH MeCN / 0.1% AcOH H2O), concentrated under reduced pressure, and (4-(benzo[b]thiophen-4-yl)-1-((4-((2-oxo-1,2-dihydroquinoline-7-yl)oxy)butyl)piperazine-1-ium-1-yl)methylhydrogenphosphate (1.71 g). NMR1; 1.77-1.89(2H, m), 1.89-2.01(2H, m), 3.37-3.86(11H, m), 4.10(2H, t, J=6.3Hz), 5.11(2H, d, J=9.0Hz), 6.29(1H, d, J=9.4Hz), 6.80(1H, dd, J=2.4, 8.7Hz), 6.95-7.05(2H, m), 7.31(1H, dd, J=7.9, 7.9Hz), 7.51(1H, d, J=5.5Hz), 7.54(1H, d, J=8.7Hz), 7.71(1H, d, J=8.1Hz), 7.76(1H, d, J=5.5Hz), 7.79(1H, d, J=9.5Hz), 11.93(1H, br).

[0129] Example 2 (EX2) Under a nitrogen atmosphere, (4-(benzo[b]thiophen-4-yl)-1-(4-(((2-(tert-butoxy)quinoli (Ixyl)butyl)piperazine-1-ium-1-yl)methyl tert-butylphospho A mixture of 15.7 g of phosphate, 42.3 mL of AcOH, and 14.1 mL of TFA was stirred at 40°C for 1.5 hours. The reaction mixture was cooled to below 10°C, AcONa (19.6 g) in a water (170 mL) / MeCN (70.7 mL) solution was added, and the mixture was washed with water (30 mL). The mixture was stirred at room temperature for 1 hour, then water (71 mL) was added and the mixture was stirred at 0°C for 1 hour. The precipitated crystals were separated into solid and liquid phases, and washed with water (71 mL) and MeCN / water (1:4, 71 mL). , air-dried at 40℃ for 12 hours, (4-(benzo[b]thiophen-4-yl)-1-((4-((2-oxo-1,2-dihydroquinoline-7-yl)oxy)butyl)piperazine-1-ium-1-yl)methylhydrate Rogen phosphate (13.81 g) was obtained. NMR1; 1.75-1.90(2H, m), 1.90-2.00(2H, m), 3.40-3.85(11H, m), 4.09(2H, t, J=6.4Hz), 5.11(2H, d, J=9.2Hz), 6.29(1H, d, J=9.6Hz), 6.80(1H, dd, J=2.4Hz, 8.8Hz), 6.95-7.05(2H, m), 7.31(1H, dd, J=7.9Hz, 7.9Hz), 7.51(1H, d, J=5.6Hz), 7.54(1H, d, J=8.8Hz), 7.71(1H, d, J=8.0Hz), 7.76(1H, d, J=5.6Hz), 7.79(1H, d, J=9.6Hz), 11.93(1H, br).

[0130] Example 3 (EX3) Dissolve di-tert-butyl (chloromethyl) phosphate (1.82 g) in MeCN / DCM (1 / 1) (60 mL), add 7-((4-(4-(benzo[b]thiophen-4-yl)piperazin-1-yl)butoxy)-2-(tert-butoxy)quinoline (2.2 g), purge with nitrogen, cover with aluminum foil to protect from light, and incubate overnight at 40°C. The mixture was stirred. The reaction mixture was concentrated under reduced pressure to remove most of the DCM, AcOEt / MeOH(9 / 1) and 10% Na2S2O3 aqueous solution were added and extracted. The organic layer was separated and concentrated under reduced pressure. AcOH (30 mL) was added to the residue and stirred at 40°C for 2 hours. After concentrating the reaction mixture under reduced pressure, the torn Egg was added and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (DCM / MeOH) to obtain 4-(benzo[b]thiophen-4-yl)-1-(((diethoxyphosphoryl)oxy)methyl (Lu)-1-(4-((2-oxo-1,2-dihydroquinoline-7-yl)oxy)butyl)piperazine-1-Iu Iodide (3.1 g) was obtained. Acetone (120 mL) and NaI (2.55 g) were added to it, and the mixture was stirred overnight at 60°C. After returning to room temperature, the liquid was removed, and water (50 mL) and AcOH (2.5 mL) were added to the residue. It was added under ice cooling. Water (80 mL) was added and stirred at room temperature for 8 hours. The precipitate was filtered and water was removed. The solution was washed with [method]. After drying under reduced pressure, it was purified by silica gel column chromatography (DCM / MeOH). After crystallization with MeCN / water, the solution was filtered and washed with water. The resulting solid was dried under reduced pressure to obtain (4-(benzo[b]thiophen-4-yl)-1-(4-((2-oxo-1,2-dihydroquinoline-7-yl)oxy)butyl)piperazine-1-ium-1-yl)methyl ethyl phosphate (1.1 g). I obtained it. NMR1; 1.13(3H, t, J=7.1Hz), 1.78-1.89(2H, m), 1.89-2.01(2H, m), 3.38-3.49(4H, m), 3.53-3.66(4H, m), 3.70-3.82(4H, m), 4.10(2H, t, J=6.1Hz), 5.09(2H, d, J=9.1Hz), 6.30(1H, d, J=9.4Hz), 6.82(1H, dd, J=2.4Hz, 8.7Hz), 6.89(1H, d, J=2.3Hz), 7.01(1H, d, J=7.4Hz), 7.32(1H, t, J=7.8Hz), 7.51(1H, d, J=5.5Hz), 7.56(1H, d, J=8.7Hz), 7.71(1H, d, J=8.0Hz), 7.77(1H, d, J=5.6Hz), 7.80(1H, d, J=9.1Hz), 11.69(1H, s).

[0131] Example 4 (EX4) (4-(benzo[b]thiophen-4-yl)-1-(4-((2-(tert-butoxy)quinoline-7-yl)oxy (11.1 g) butylpiperazine-1-ium-1-yl)methyl tert-butylphosphate MeCN (44 mL) and water (44 mL) were added and stirred at 45°C, then water (22 mL) was added. After confirming the disappearance of the starting material, NaHCO3 (1.1 g) was added and concentrated under reduced pressure, and extracted with 10% MeOH / DCM (100 mL). The resulting organic layer was concentrated, and the crude product was purified by silica gel column chromatography (DCM / MeOH) to obtain (4-(benzo[b]thiophene-4-yl)-1-(4-((2-oxo-1,2-dihydroquinoline-7- 8.7 g of yl(oxy)butyl)piperazine-1-ium-1-yl)methyl tert-butyl phosphate was obtained. NMR3;1.47(9H, s), 1.95-2.04(2H, m), 2.05-2.15(2H, m), 3.40-3.60(4H, m), 3.65-3.70(2H, m), 3.70-3.80(2H, m), 3.85-3.95(2H, m), 4.20(2H, t, J=6.0Hz), 5.16(2H, d, J=8.0Hz), 6.44(1H, d, J= 9.6Hz), 6.88-6.92(2H, m), 7.03(1H, dd, J=0.4, 7.6Hz), 7.29(1H, t, J=8.0Hz), 7.49(1H, dd, J=0.8, 5.6Hz), 7.55-7.58(2H, m), 7.64(1H, d, J=8.0Hz), 7.87(1H, d, J=7.6Hz).

[0132] Example 5 (EX5) (4-(benzo[b]thiophen-4-yl)-1-(4-((2-oxo-1,2-dihydroquinoline-7-yl)oxy)butyl)piperazine-1-ium-1-yl)methylhydrogenphosphate (300 mg) Add isopropyl alcohol (10 mL), water (2 mL), and WSC·HCl (317 mg) at room temperature. The mixture was stirred at 70°C for 10 hours. The reaction solution was concentrated, water was added, and it was extracted with DCM / MeOH(9 / 1). The organic layer was concentrated, and the residue was purified by silica gel column chromatography (DCM / MeOH). (4-(benzo[b]thiophen-4-yl)-1-(4-((2-oxo-1,2-dihydroquinoline-7-yl) (44) Oxy)butyl)piperazine-1-ium-1-yl)methylisopropyl phosphate (44 mg was obtained. NMR1; 1.14(6H, d, J=6.2Hz), 1.78-1.89(2H, m), 1.89-2.01(2H, m), 3.41-3.49(4H, m), 3.53-3.66(4H, m), 3.66-3.82(2H, m), 4.10(2H, t, J=6.1Hz), 4.25-4.34 (1H, m), 5.08(2H, d, J=7.2Hz), 6.30(1H, dd, J=2.0Hz, 9.4Hz), 6.82(1H, dd, J=2.4Hz, 8.7Hz), 6.90(1H, d, J=2.3Hz), 7.01(1H, d, J=7.4Hz), 7.32(1H, t, J= 7.8Hz), 7.51(1H, d, J=5.5Hz), 7.56(1H, d, J=8.7Hz), 7.71(1H, d, J=8.0Hz), 7.77(1H, d, J=5.6Hz), 7.80(1H, d, J=9.1Hz), 11.69(1H, s).

[0133] Example 6 (EX6) (4-(benzo[b]thiophen-4-yl)-1-(4-((2-oxo-1,2-dihydroquinoline-7-yl)oxy)butyl)piperazine-1-ium-1-yl)methylhydrogenphosphate (300 mg) Add 1,3-propanediol (10 mL), water (2 mL), and WSC·HCl (212 mg) at room temperature. The mixture was stirred at 40°C. After 30 minutes, the temperature was raised to 50°C, and after another 30 minutes, it was raised to 60°C. After another 2 hours, it was returned to room temperature, azeotropic analysis was performed using AcOEt, and the residue was subjected to silica gel column chromatography. Purified with (DCM / MeOH). Dispersed and washed with AcOEt, and insoluble matter was filtered off. Dried under reduced pressure, (4-( Benzo[b]thiophen-4-yl)-1-(4-((2-oxo-1,2-dihydroquinoline-7-yl)oxy) Butyl)piperazine-1-ium-1-yl)methyl (3-hydroxypropyl)phosphate (200 mg) was obtained. NMR 1; 1.57-1.68 (2H, m), 1.78-1.89 (2H, m), 1.89-2.01 (2H, m), 3.40-3.52 (6H, m), 3.53-3.66 (4H, m), 3.70-3.82 (4H, m), 4.10 (2H, t, J=6.1Hz), 4.70 (1H, t, J=5.6Hz), 5.10(2H, d, J=9.0Hz), 6.30(1H, d, J=9.4Hz), 6.82(1H, dd, J=2.4Hz, 8.7Hz), 6.89(1H, d, J=2.3Hz), 7.01(1H, d, J=7.4Hz), 7.32(1H, t, J=7.8Hz), 7.51(1H, d, J=5.5Hz), 7.56(1H, d, J=8.7Hz), 7.71(1H, d, J=8.0Hz), 7.77(1H, d, J=5.6Hz), 7.81(1H, d, J=9.4Hz), 11.67(1H, s).

[0134] Example 7 (EX7) (4-(benzo[b]thiophen-4-yl)-1-(4-((2-oxo-1,2-dihydroquinoline-7-yl)oxy)butyl)piperazine-1-ium-1-yl)methylhydrogenphosphate (500 mg) Diethylene glycol monomethyl ether (10.00 mL), water (2 mL), and WSC·HCl (353 mg) were added at room temperature and stirred at 40°C. After 3 hours, WSC·HCl (176 mg) was added. The mixture was stirred at 40°C for 3 hours. Water was added to the reaction mixture and extracted with DCM / MeOH(9 / 1). The organic layer was concentrated. The residue was purified by silica gel column chromatography (DCM / MeOH), and (4-(benzo[b] Thiofen-4-yl)-1-(4-((2-oxo-1,2-dihydroquinoline-7-yl)oxy)butyl) Perazin-1-ium-1-yl)methyl(2-(2-methoxyethoxy)ethyl) phosphate (188 mg) was obtained. NMR1; 1.78-1.89(2H, m), 1.89-2.01(2H, m), 3.21(3H, s), 3.40-3.48(6H, m), 3.42-3.49(4H, m), 3.53-3.68(4H, m), 3.70-3.85(4H, m), 4.10(2H, t, J=5.2Hz), 5.09(2H, d, J=9.0Hz), 6.30(1H, d, J=9.4Hz), 6.82(1H, dd, J=2.4Hz, 8.7Hz), 6.89(1H, d, J=2.3Hz), 7.01(1H, d, J=7.3Hz), 7.32(1H, t, J=7.8Hz), 7.51(1H, d, J=5.5Hz), 7.56(1H, d, J=8.7Hz), 7.71(1H, d, J=8.0Hz), 7.77(1H, d, J=5.6Hz), 7.80(1H, d, J=9.1Hz), 11.67(1H, s).

[0135] Example 8 (EX8) (4-(benzo[b]thiophen-4-yl)-1-(4-((2-oxo-1,2-dihydroquinoline-7-yl)oxy)butyl)piperazine-1-ium-1-yl)methylhydrogenphosphate (500 mg) To the reaction mixture, add acetone / water (9 / 1) (10 mL), ethyl glycolate (3 mL), and WSC·HCl (529 mg) at room temperature, stir at 40°C for 5 hours, and stir overnight at room temperature. Add DCM / MeOH(9 / 1) to the reaction mixture. Water was added, and the precipitate was filtered off. The organic layer of the filtrate was concentrated and purified together with the precipitate by silica gel column chromatography (DCM / MeOH) to obtain (4-(benzo[b]thiophen-4-yl)-1-(4-((2-oxo-1,2-dihydroquinoline-7-yl)oxy)butyl)piperazine-1-ium-1-yl)methyl (2-ethoxy-2-oxoethyl) phosphate (16 mg). NMR1; 1.18(3H, t, J=7.1Hz), 1.78-1.89(2H, m), 1.89-2.01(2H, m), 3.42-3.49(4H, m), 3.51-3.68(4H, m), 3.70-3.82(2H, m), 4.10(2H, J=9.6Hz), 4.06-4.15 (2H, m), 4.35 (2H, d, J=9.6Hz), 5.12(2H, d, J=8.8Hz), 6.30(1H, dd, J=1.8Hz, 9.4Hz), 6.83(1H, dd, J=2.4Hz, 8.7Hz), 6.87(1H, d, J=2.3Hz), 7.01(1H, d, J=7.5Hz), 7.33(1H, t, J=7.8Hz), 7.52(1H, d, J=5.5Hz), 7.57(1H, d, J=9.0Hz), 7.72(1H, d, J=8.0Hz), 7.77(1H, d, J=5.6Hz), 7.81(1H, d, J=9.1Hz), 11.65(1H, s).

[0136] Example 9 (EX9) (4-(benzo[b]thiophen-4-yl)-1-(4-((2-oxo-1,2-dihydroquinoline-7-yl)oxy)butyl)piperazine-1-ium-1-yl)methylhydrogenphosphate (1.0 g) is suspended in a mixture of ethylene glycol (10 mL) and water (1 mL), and WSC·HCl (1.06 g) is added. The mixture was added and stirred at 45°C for 5 hours. Acetone and AcOEt were added to the reaction mixture and concentrated under reduced pressure three times. The water was removed by azeotrope. The concentrated solution was then purified by medium-pressure liquid chromatography (DCM / MeOH). It was made. The obtained product was mixed with water and a DCM-MeOH = 4:1 solvent, stirred, and extracted. The organic layer was then extracted. The oil was concentrated under reduced pressure, acetone was added to the resulting oil, and the mixture was stirred overnight at room temperature. The precipitated solid was filtered and air-dried, and then (4-(benzo[b]thiophen-4-yl)-1-(4-((2-oxo-1,2-dihydroxyl Norin-7-yl)oxy)butyl)piperazine-1-ium-1-yl)methyl (2-hydroxyeth (L) Phosphate (71 mg) was obtained. NMR1; 1.78-1.88 (2H, m), 1.90-1.99 (2H, m), 3.42-3.48 (2H, m), 3.49-3.55 (2H, m), 3.56-3.68 (4H, m), 3.72-3.80 (4H, m), 4.10 (2H, t, J = 6.0Hz), 5.11 (2H, d, J = 9.5Hz), 6.30 (1H, dd, J = 9.5Hz, 1.8Hz), 6.83 (1H, dd, J = 8.6Hz, 2.4Hz), 6.88 (1H, d, J = 2.4Hz), 7.00 (1H, d, J = 7.4Hz), 7.32 (1H, t, J = 7.9Hz), 7.51 (1H, d, J = 5.5Hz), 7.56 (1H, d, J = 8.7Hz), 7.71 (1H, d, J = 8.1Hz), 7.77 (1H, d, J = 5.5Hz), 7.80 (1H, d, J = 9.4Hz), 11.7 (1H, s).

[0137] Example 10 (EX10) (4-(benzo[b]thiophen-4-yl)-1-(4-((2-oxo-1,2-dihydroquinoline-7-yl)oxy)butyl)piperazine-1-ium-1-yl)methylhydrogenphosphate (1.0 g) is suspended in a mixture of 1,4-butanediol (20 mL) and water (4 mL), and WSC·HCl (1.06 g) is added. The mixture was added and stirred at 60°C for 5 hours. Acetone and AcOEt were added to the reaction mixture and concentrated under reduced pressure three times. The water was removed by azeotrope. The concentrated solution was purified twice by medium-pressure liquid chromatography. (1st time: silica gel, 2nd time: amino silica gel, eluate: DCM / MeOH) The obtained amorphous material was suspended in water (5 mL) and dissolved with acetone. After standing overnight at room temperature, the precipitated crystals were filtered off and air-dried overnight at 25°C. (4-(benzo[b]thiophen-4-yl)-1-(4-((2-oxo-1,2-dihydroquinoline-7-yl)oxy)butyl)piperazine-1-ium-1-yl)methyl (4-hydroxybutyl) phosphate (438 mg) was obtained. NMR1; 1.39-1.49 (2H, m), 1.50-1.58 (2H, m), 1.78-1.88 (2H, m), 1.89-1.99 (2H, m), 3.37-3.42 (2H, m), 3.42-3.48 (2H, m), 3.53-3.67 (4H, m), 3.68-3.80 (4H, m), 4.10 (2H, t, J = 6.1Hz), 4.43 (1H, t, J = 5.2Hz), 5.09 (2H, d, J = 9.1Hz), 6.30 (1H, d, J = 9.4Hz), 6.82 (1H, dd, J = 8.6Hz, 2.4Hz), 6.89 (1H, d, J = 2.4Hz), 7.01 (1H, d, J = 7.6Hz), 7.32 (1H, t, J = 7.9Hz), 7.51 (1H, d, J = 5.6Hz), 7.56 (1H, d, J = 8.7Hz), 7.71 (1H, d, J = 8.0Hz), 7.76 (1H, d, J = 5.5Hz), 7.80 (1H, d, J = 9.5Hz), 11.7 (1H, s).

[0138] Example 11 (EX11) (4-(benzo[b]thiophen-4-yl)-1-(4-((2-oxo-1,2-dihydroquinoline-7-yl)oxy)butyl)piperazine-1-ium-1-yl)methylhydrogen phosphate (1.0 g) and 1,8-octanediol (3 g) were suspended in a mixed solvent of acetone (8 mL) and water (2 mL), and WSC·HCl (0.71 g) was added. The mixture was stirred at 50°C for 3 hours. Acetone and AcOEt were added to the reaction mixture, and the mixture was concentrated three times under reduced pressure to remove water azeotropically. The concentrate was purified twice by medium-pressure liquid chromatography (1st time using silica gel, 2nd time using amino silica gel, eluent·DCM / MeOH). The obtained amorphous material was suspended in water (5 mL) and dissolved with acetone. After standing overnight at room temperature, the precipitated crystals were filtered off and air-dried overnight at 25°C to obtain (4-(benzo[b]thiophen-4-yl)-1-(4-((2-oxo-1,2-dihydroquinoline-7-yl)oxy)butyl)piperazine-1-ium-1-yl)methyl (8-hydroxyoctyl)phosphate (176 mg). NMR1; 1.18-1.29 (8H, m),1.33-1.42 (2H, m), 1.45-1.52 (2H, m), 1.78-1.87 (2H, m), 1.88-1.98 (2H, m), 3.42-3.50 (4H, m), 3.53-3.80 (8H, m), 4.10 (2H, t, J = 6.1Hz), 4.34 (1H, t, J = 5.2Hz), 5.00 (2H, d, J = 9.0Hz), 6.30 (1H, dd, J = 9.4Hz, 1.4Hz), 6.81 (1H, dd, J = 8.6Hz, 2.4Hz), 6.89 (1H, d, J = 2.4Hz), 7.01 (1H, d, J = 7.4 Hz), 7.32 (1H, t, J = 7.8Hz), 7.51 (1H, dd, J = 5.6Hz, 0.4Hz), 7.56 (1H, d, J = 8.7Hz), 7.71 (1H, d, J = 8.1Hz), 7.76 (1H, d, J = 5.5Hz), 7.80 (1H, d, J = 9.5Hz), 11.7 (1H, s).

[0139] Example 12 (EX12) (4-(benzo[b]thiophen-4-yl)-1-(4-((2-oxo-1,2-dihydroquinoline-7-yl)oxy)butyl)piperazine-1-ium-1-yl)methylhydrogenphosphate (1.0 g) was suspended in a mixture of 2-methoxyethanol (20 mL) and water (2 mL), and WSC·HCl (1.06 g) was added. The mixture was stirred at 60°C for 3 hours. Acetone and AcOEt were added to the reaction mixture and concentrated under reduced pressure three times. The water was then removed using an azeotrope. The concentrated solution was then purified twice using medium-pressure liquid chromatography. (1st time silica gel, 2nd time amino silica gel, eluate: DCM / MeOH) The obtained amorphous material was suspended in water (5 mL) and dissolved with acetone. After standing overnight at room temperature, the precipitated crystals were filtered off and air-dried overnight at 25°C, and then (4-(benzo[b]thiophene 320 mg of (n-4-yl)-1-(4-((2-oxo-1,2-dihydroquinoline-7-yl)oxy)butyl)piperazine-1-ium-1-yl)methyl (2-methoxyethyl) phosphate was obtained. NMR1; 1.79-1.88 (2H, m), 1.89-1.98 (2H, m), 3.24 (3H, s), 3.40-3.48 (4H, m), 3.55-3.67 (4H, m), 4.10 (2H, t, J = 6.1Hz), 5.09 (2H, d, J = 9.0Hz), 6.30 (1H, d, J = 9.5Hz), 6.82 (1H, dd, J = 8.7Hz, 2.4Hz), 6.89 (1H, d, J = 2.4Hz), 7.01 (1H, d, J = 7.4Hz), 7.32 (1H, t, J = 7.8Hz), 7.51 (1H, d, J = 5.5Hz), 7.56 (1H, d, J = 8.7Hz), 7.71 (1H, d, J = 8.0Hz), 7.77 (1H, d, J = 5.5Hz), 7.80 (1H, d, J = 9.5Hz), 11.7 (1H, s).

[0140] Example 13 (EX13) (4-(benzo[b]thiophen-4-yl)-1-(4-((2-oxo-1,2-dihydroquinoline-7-yl)oxy)butyl)piperazine-1-ium-1-yl)methylhydrogenphosphate (1.0 g) is mixed with ethylene glycol monoisopropyl ether (20 mL) and water (2 mL). The mixture was suspended, and WSC·HCl (0.71 g) was added and stirred at 50°C for 7 hours. Acetone and AcOEt were added to the reaction mixture, and the mixture was concentrated under reduced pressure three times to remove water azeotropically. The concentrated solution was then subjected to medium-pressure liquid chromatography. The sample was purified twice using a Raffy filter. (1st time: silica gel, 2nd time: amino silica gel, eluate: DCM / MeOH) The obtained amorphous material was suspended in water (5 mL) and dissolved with acetone (15 mL). After standing at room temperature for 5 days, the precipitated crystals were filtered off and air-dried overnight at 25°C, and then (4-(benzo[b]thiophen-4-yl)-1-(4-((2-oxo-1,2-dihydroquinoline-7-yl)oxy)butyl) Piperazine-1-ium-1-yl)methyl (2-isopropoxyethyl)phosphate (290 mg) was obtained. NMR1; 1.06 (6H, d, J = 6.1Hz), 1.78-1.88 (2H, m), 1.89-2.00 (2H, m), 3.42-3.48 (4H, m), 3.49-3.68 (4H, m), 3.72-3.81 (4H, m), 4.10 (2H, t, J = 6.0Hz), 5.10 (2H, d, J = 9.1Hz), 6.30 (1H, dd, J = 9.4Hz, 1.4Hz), 6.82 (1H, dd, J = 8.6Hz, 2.4Hz), 6.89 (1H, d, J = 2.4Hz), 7.01 (1H, d, J = 7.4Hz), 7.32 (1H, t, J = 7.9Hz), 7.51 (1H, d, J = 5.5Hz), 7.56 (1H, d, J = 8.7Hz), 7.71 (1H, d, J = 8.0Hz), 7.77 (1H, d, J = 5.5Hz), 7.80 (1H, d, J = 9.5Hz), 11.7 (1H, s).

[0141] Example 14 (EX14) (4-(benzo[b]thiophen-4-yl)-1-(4-((2-oxo-1,2-dihydroquinoline-7-yl)oxy)butyl)piperazine-1-ium-1-yl)methyl (2-bromoethyl) phosphate (300 To a solution of (mg) THF (12 mL), morpholine (1.2 mL) was added at room temperature and the mixture was stirred at 40°C for 5 hours. The reaction mixture was concentrated, and the residue was analyzed by silica gel column chromatography (DCM / MeOH). It was purified. After dissolving it in MeCN / H2O (1 / 1), MeCN was added. The precipitate was filtered off and treated with MeCN. Washed. Dry at room temperature. (4-(benzo[b]thiophen-4-yl)-1-(4-((2-oxo-1,2-dihydroquinoline-7-yl)oxy)butyl)piperazine-1-ium-1-yl)methyl (2-morpho Linoethyl phosphate (164 mg) was obtained. NMR1; 1.78-1.89(2H, m), 1.89-2.01(2H, m), 2.34-2.41(4H, m), 2.46 (2H, t, J=6.1Hz), 3.42-3.49(4H, m), 3.50-3.68(8H, m), 3.71-3.85(4H, m), 4.10(2H, t, J=6.1Hz), 5.10(2H, d, J=9.1Hz), 6.30(1H, d, J=9.4Hz), 6.82(1H, dd, J=2.4, 8.7Hz), 6.89(1H, d, J=2.3Hz), 7.01(1H, d, J=7.4Hz), 7.32(1H, t, J=7.8Hz), 7.51(1H, d, J=5.5Hz), 7.56(1H, d, J=8.7Hz), 7.71(1H, d, J=8.0Hz), 7.77(1H, d, J=5.6Hz), 7.80(1H, d, J=9.1Hz), 11.68(1H, s).

[0142] Example 15 (EX15) (4-(benzo[b]thiophen-4-yl)-1-(4-((2-oxo-1,2-dihydroquinoline-7-yl)oxy)butyl)piperazine-1-ium-1-yl)methyl (3-hydroxypropyl)phospho Pyridine (4 mL) and anhydrous acetate (2 mL) were added to (200 mg) at room temperature, and the mixture was stirred overnight. The reaction mixture was concentrated and azeotropically analyzed with toluene. The residue was then subjected to silica gel column chromatography. The product was purified using (DCM / MeOH). EtOH / H2O(1 / 1) was added, and the mixture was dispersed and washed at 40°C. Insoluble matter was filtered off. Washed with water and dried at room temperature, 3-acetoxypropyl ((4-(benzo[b]thiophen-4-yl)-1-(4-((2-oxo-1,2-dihydroquinoline-7-yl)oxy)butyl)piperazine-1- Ium-1-yl(methyl)phosphate (126 mg) was obtained. NMR3; 1.92-2.05(7H, m), 2.04-2.16(2H, m), 3.45-3.56(4H, m), 3.64-3.73 (2H, m), 3.74-3.83(2H, m), 3.86-3.93(2H, m), 4.01(2H, q, J=6.2Hz), 4.15-4.25(4H, m), 4.52-4.65(4H, m), 5.20(2H, d, J=8.1Hz), 6.44(1H, d, J=9.4Hz), 6.89(1H, d, J=2.4Hz), 6.92(1H, dd, J=2.4, 8.7Hz), 7.05(1H, d, J=7.7Hz), 7.30(1H, t, J=7.9Hz), 7.49(1H, dd, J=0.8, 5.6Hz), 7.57(1H, d, J=5.2Hz), 7.59(1H, d, J=2.0Hz), 7.65(1H, d, J=8.1Hz), 7.88(1H, d, J=9.4Hz).

[0143] Example 16 (EX16) (4-(benzo[b]thiophen-4-yl)-1-(4-((2-oxo-1,2-dihydroquinoline-7-yl)oxy)butyl)piperazine-1-ium-1-yl)methylhydrogenphosphate (632 mg) Chloromethyl hexanoate (494 mg) was added to a mixture of acetone (6 mL), water (2 mL), and DIPEA (0.524 mL) under stirring, and then stirred under reflux. After 8 hours, it was cooled to room temperature and the mixture was then... Next, acetone (2 mL) was added and the mixture was stirred. The precipitated solid was filtered off. Acetone / water (3:1), then The crude product was obtained by washing with acetone. Silica gel column chromatography (DCM / MeOH) It was purified using acetone (3 mL) and water (1 mL), and the precipitated solid was filtered off. Wash and dry (4-(benzo[b]thiophen-4-yl)-1-(4-((2-oxo-1,2-dihydrox Norin-7-yl)oxy)butyl)piperazine-1-ium-1-yl)methyl((hexanoyl oxy 269 ​​mg of methyl phosphate was obtained. NMR1; 0.79(3H, t, J=6.9Hz), 1.12-1.27(4H, m), 1.42-1.53(2H, m), 1.78-1.89(2H, m), 1.89-2.01(2H, m), 2.30(2H, t, J=7.5Hz), 3.40-3.52(4H, m), 3.52-3.70(4H, m), 3.70-3.82(2H, m), 4.09(2H, t, J=6.0Hz), 5.09(2H, d, J=8.9Hz), 5.42(2H, d, J=12.7Hz), 6.30(1H, dd, J=1.9Hz, 9.4Hz), 6.82(1H, dd, J=2.4Hz, 8.6Hz), 6.86(1H, d, J=2.3Hz), 7.01(1H, d, J=7.4Hz), 7.32(1H, dd, J=7.9Hz, 7.9Hz), 7.52(1H, dd, J=0.6Hz, 5.5Hz), 7.56(1H, d, J=8.6Hz), 7.72(1H, d, J=8.1Hz), 7.77(1H, d, J=5.5Hz), 7.81(1H, d, J=9.4Hz), 11.64(1H, s).

[0144] Example 17 (EX17) (4-(benzo[b]thiophen-4-yl)-1-(4-((2-oxo-1,2-dihydroquinoline-7-yl)oxy)butyl)piperazine-1-ium-1-yl)methylhydrogenphosphate (630 mg) A mixture of acetone (6 mL), water (3 mL), and DIPEA (0.522 mL) is stirred, and chloromethyl chloride is added. After adding decanoate (220 mg), the mixture was stirred under reflux. After 1 hour, chloromethyldecanoate was added. Alcohol (220 mg) was added. After another hour, chloromethyldecanoate (220 mg) was added. After stirring for another 2 hours, acetone (3 mL) was added. After another 3 hours, DIPEA (0.348 mg) was added. After 1 hour, chloromethyldecanoate (220 mg) was added. Eth (220 mg) was added. After another 1.5 hours, heating was stopped and the mixture was allowed to return to room temperature and stirred overnight. After stirring under reflux for 2 hours, the mixture was allowed to return to room temperature and stirred for another hour. After adding acetone (3 mL), precipitation The solid was filtered off. It was washed with acetone / water (3:1), then with acetone, to obtain a crude product. Add 5 mL of ceton and 1 mL of water, and stir under reflux for 30 minutes. After cooling to room temperature, remove the precipitated solid. Filter, wash with acetone / water (3:1), then with acetone, and dry (4-(benzo[b]thioffin). En-4-yl)-1-(4-((2-oxo-1,2-dihydroquinoline-7-yl)oxy)butyl)piperazi 370 mg of methyl((decanoyloxy)methyl)phosphate was obtained. NMR1; 0.82(3H, t, J=6.9Hz), 1.11-1.26(12H, m), 1.41-1.51(2H, m), 1.78-1.89(2H, m), 1.89-2.01(2H, m), 2.30(2H, t, J=7.5Hz), 3.42-3.50(4H, m), 3.53-3.69(4H, m), 3.71-3.82(2H, m), 4.09(2H, t, J=6.0Hz), 5.09(2H, d, J=8.9Hz), 5.42(2H, d, J=12.8Hz), 6.30(1H, dd, J=1.8Hz, 9.5Hz), 6.82(1H, dd, J=2.4Hz, 8.6Hz), 6.85(1H, d, J=2.3Hz), 7.01(1H, d, J=7.4Hz), 7.32(1H, dd, J=7.9Hz, 7.9Hz), 7.52(1H, dd, J=0.42Hz, 5.5Hz), 7.56(1H, d, J=8.6Hz), 7.71(1H, d, J=8.1Hz), 7.77(1H, d, J=5.5Hz), 7.80(1H, d, J=9.5Hz), 11.63(1H, s).

[0145] Example 18 (EX18) (4-(benzo[b]thiophen-4-yl)-1-(4-((2-oxo-1,2-dihydroquinoline-7-yl)oxy)butyl)piperazine-1-ium-1-yl)methylhydrogenphosphate (632 mg) Chloromethyl cyclohexanecarboxylate (530 mg) was added to a mixture of acetone (6 mL), water (2 mL), and DIPEA (0.524 mL) under stirring, and the mixture was stirred under reflux. After 8 hours, it was cooled to room temperature, and then acetone (2 mL) was added and stirred. The precipitated solid was filtered off and acetone / Washed with water (3:1), then with acetone, to obtain a crude product. Purified by silica gel column chromatography (DCM / MeOH). Acetone (3 mL) and water (1 mL) were added, and the precipitated solid was filtered off. Washed with acetone and dried to obtain (4-(benzo[b]thiophen-4-yl)-1-(4-((2-oxo-1,2- Dihydroquinoline-7-yl)oxy)butyl)piperazine-1-ium-1-yl)methyl(((cyclohexanecarbonyl)oxy)methyl)phosphate (392 mg) was obtained. NMR1; 1.05-1.39(5H, m), 1.46-1.55(1H, m), 1.56-1.66(2H, m), 1.75-1.89(4H, m), 1.89-2.00(2H, m), 2.23-2.34(1H, m), 3.40-3.50(4H, m), 3.52-3.70(4H, m), 3.70-3.82(2H, m), 4.09(2H, t, J=6.0Hz), 5.10(2H, d, J=9.1Hz), 5.42(2H, d, J=12.5Hz), 6.30(1H, dd, J=1.8Hz, 9.4Hz), 6.82(1H, dd, J=2.4Hz, 8.6Hz), 6.86(1H, d, J=2.4Hz), 7.01(1H, d, J=7.4Hz), 7.32(1H, dd, J=7.9Hz, 7.9Hz), 7.52(1H, dd, J=0.4Hz, 5.6Hz), 7.56(1H, d, J=8.7Hz), 7.72(1H, d, J=8.1Hz), 7.77(1H, d, J=5.5Hz), 7.81(1H, d, J=9.5Hz), 11.65(1H, s).

[0146] Example 19 (EX19) (4-(benzo[b]thiophen-4-yl)-1-(4-((2-oxo-1,2-dihydroquinoline-7-yl)oxy)butyl)piperazine-1-ium-1-yl)methylhydrogenphosphate (632 mg) A mixture of acetone (6 mL), water (2 mL), and DIPEA (0.524 mL) is stirred, and chloromethyl chloride is added. After adding cyclohexyl carbonate (578 mg), the mixture was stirred under reflux. After 8 hours, it was left to room temperature. The mixture was cooled, then acetone (2 mL) was added and the mixture was stirred. The precipitated solid was filtered off and washed with acetone / water (3:1), then with acetone, to obtain the crude product. Silica gel column chromatography The solution was purified with (DCM / MeOH). Acetone (3 mL) and water (1 mL) were added, and the precipitated solid was filtered off. The solution was washed with acetone and dried to obtain (4-(benzo[b]thiophen-4-yl)-1-(4-((2-oxo-1,2- Dihydroquinoline-7-yl)oxy)butyl)piperazine-1-ium-1-yl)methyl ((((cyclohexyloxy)carbonyl)oxy)methyl)phosphate (296 mg) was obtained. NMR1; 1.04-1.17(1H, m), 1.18-1.37(4H, m), 1.37-1.47(1H, m), 1.52-1.63(2H, m), 1.75-1.89(4H, m), 1.89-2.00(2H, m), 3.42-3.50(4H, m), 3.53-3.70(4H, m), 3.70-3.81(2H, m), 4.09(2H, t, J=6.0Hz), 4.47-4.55(1H, m), 5.09(2H, d, J=8.5Hz), 5.43(2H, d, J=13.3Hz), 6.30(1H, dd, J=1.9Hz, 9.5Hz), 6.83(1H, dd, J=2.4Hz, 8.6Hz), 6.85(1H, d, J =2.3Hz), 7.00(1H, d, J=7.4Hz), 7.32(1H, dd, J=7.8Hz, 7.8Hz), 7.52(1H, dd, J=0.4Hz, 5.6Hz), 7.56(1H, d, J=8.6Hz), 7.72(1H, d, J=8.0Hz), 7.77(1H, d, J=5.5Hz), 7.81(1H, d, J=9.5Hz), 11.63(1H, s).

[0147] Example 20 (EX20) To a solution of 7-(4-(4-(benzo[b]thiophen-4-yl)piperazin-1-yl)butoxy)-2-(tert-butoxy)quinoline (500 mg) in MeCN / DCM (30 mL) (1 / 2), NaI (306 mg), K2CO3 (282 mg), and dibutyl(chloromethyl) phosphate (528 mg) were added, the mixture was purged with nitrogen, covered with aluminum foil to protect it from light, and stirred overnight at 40°C. Add dibutyl(chloromethyl)phosphate (132 mg) and NaI (77 mg), and incubate at 40°C for 8 minutes. Stirred for a while. DCM and sat. aq. NaHCO3 were added and extracted with DCM. The organic layer was concentrated, and MeCN (10 mL), water (5 mL), and AcOH (0.5 mL) were added to the residue. The mixture was stirred overnight at room temperature. AcOEt / MeOH = 9 / 1 and water were added to the reaction system and extracted. The organic layer was concentrated, and the residue was subjected to silica gel column chromatography. The solution was purified using (DCM / MeOH) to obtain 4-(benzo[b]thiophen-4-yl)-1-(((dibutoxyphosphoryl)oxy)methyl)-1-(4-((2-oxo-1,2-dihydroquinoline-7-yl)oxy)butyl)piperazine-1-ium iodide (545 mg). NMR2; 0.92(6H, t, J=7.4Hz), 1.33-1.46(4H, m), 1.64-1.75(4H, m),1.94-2.04(2H, m) 2.13-2.25(2H m), 3.41-3.60(4H m), 3.85-4.18(8H, m), 4.20(4H, q, J=6.6Hz, 14.0Hz), 5.75(2H, d, J=8.7Hz), 6.42(1H, d, J=9.4Hz), 6.71(1H, dd, J=2.3Hz, 8.6Hz), 6.92(1H, d, J=7.4Hz), 7.12(1H, d, J=2.2Hz), 7.19(1H, t, J=7.9Hz), 7.30(1H, d, J=8.7Hz), 7.35-7.42(2H, m), 7.56(1H, s), 7.58(1H, d, J=2.2Hz), 11.04(1H, s).

[0148] Reference Example 1 (REX1) Under a nitrogen atmosphere, 7-(4-(benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy)-1H-quinoline-2-one (15.0 g) and silver carbonate (20.0 g) were suspended in CPME (300 mL) in a 500 mL round-bottom flask. 2-bromo-2-methylpropane (7.84 mL) was added, and the mixture was stirred at 90°C for 9 hours under light-shielding conditions. Insoluble matter was filtered using Celite and washed with AcOEt (150 mL). Under reduced pressure Remove the solvent by distillation, add MeCN (180 mL) to the residue and stir, then separate the precipitated crystals into solid and liquid and add to MeCN (60 mL). After washing, dry with a fan at 40°C. 7-(4-(4-(benzo[b]thiophene-4-yl)piperazine-1-yl) Butoxy)-2-(tert-butoxy)quinoline (16.0 g) was obtained. NMR2;1.69(9H, s), 1.75-1.83(2H, m), 1.89-1.96(2H, m), 2.55(2H, t, J=7.6Hz), 2.73(4H, m), 3.2(4H, m), 4.15(2H, t, J=6.4Hz), 6.64(1H, d, J=7.6Hz), 6.89(1H, d, J=7.6Hz), 6.99(1H, dd, J=8.8Hz, J=2.4Hz), 7.15(1H, d, J=2.4Hz), 7.27(1H, t, J=7.6Hz), 7.38-7.43(2H, m), 7.53-7.56(2H, m), 7.82 (1H, d, J=8.4Hz).

[0149] Reference Example 2 (REX2) Under a nitrogen atmosphere, 7-(4-(4-(benzo[b]thiophen-4-yl)piperazin-1-yl)butoxy)-2-(tert-butoxy)quinoline (16 g), NaI (9.8 g), and K2CO3 were added to a 1000 mL round-bottom flask. (9.0 g) is suspended in MeCN (240 mL), and di-tert-butyl (chloromethyl) phosphate is added. Add 16.9 g of MeCN and stir at 25-40°C for 2 days. Then, add 240 mL of water and stir at 45°C for 1 hour, after which most of the MeCN was removed under reduced pressure. The obtained crystals were cooled to 0°C, separated into solid and liquid, washed with MeCN / water (1:4, 80 mL), and vacuum dried at 40°C for 16 hours. The obtained crystals (19 g) were placed in a 1 L flask, AcOEt (300 mL) and TEA (1 mL) were added, and the mixture was stirred for 30 minutes. After liquid separation, the mixture was washed with AcOEt (150 mL) and vacuum-dried at 30°C for 5 hours to obtain (4-(benzo[b]thiophen-4-yl)-1-(4-((2-(tert-butoxy)quinoline-7-yl)oxy)butyl)piperazine-1-ium-1-yl)methyl tert-butyl phosphate (15.73 g). NMR3;1.47(9H, s), 1.66(9H, s), 1.95-2.05(2H, m), 2.10-2.20(2H, m), 3.40-3.60(4H, m), 3.65-3.70(2H, m), 3.70-3.80(2H, m), 3.85-3.95(2H, m), 4.24(2H, t, J=5.6Hz), 5.15(2H, d, J=8.0Hz), 6.65(2H, d, J=8.8Hz), 7.00(1H, dd, J=8.8Hz, J=0.8Hz), 7.03(1H, dd, J=8. 8Hz, J=2.4Hz), 7.18(1H, d, J=2.4Hz), 7.26(1H, t, J=8.0Hz), 7.49(1H, dd, J=5.6Hz, J=0.8Hz), 7.57-7.65(3H, m), 7.92(1H, d, J=8.8Hz).

[0150] Reference Example 3 (REX3) NaH (55% oily) (151 mg) is suspended in THF (10 mL), and 7-(4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy)-1H-quinoline-2-one (500 mg) is added, and chloromethyl ester is added. Xanoate (570 mg) was added dropwise, and the mixture was stirred at 50°C for 2 hours. After cooling to 0°C, the chloride solution was added. Quenched with an aqueous ammonium compound solution. Extracted with AcOEt and dried with Na2SO4. This was then processed in the middle. Purified by compressed silica gel column chromatography, (7-(4-(4-(benzo[b]thiophen-4-yl)piperazine-1-yl)butoxy)-2-oxoquinoline-1(2H)-yl)methylhexanoate (217 mg) was obtained. NMR2; 0.85(3H, t, J=6.8Hz), 1.25-1.33(4H, m), 1.58-1.69 (2H, m), 1.70-1.85(2H, m), 1.85-1.95(m, 2H), 2.36(2H, t, J=7.5 Hz), 2.54(2H, t, J=7.4Hz), 2.67-2.78(4H, m), 3.15-3.25(4H, m), 4.08(2H, t, J=6.2Hz), 6.34(2H, brs), 6.52(1H, d, J=9.5Hz), 6.84(1H, dd, J=2.2Hz, 8.6Hz), 6.84-6.92(2H, m), 7.27(1H, dd, J=7.8Hz, 7.8Hz), 7.37-7.43(2H, m), 7.45(1H, d, J=8.6Hz), 7.55(1H, d, J=8.1Hz), 7.62(1H, d, J=9.5Hz).

[0151] Reference Example 4 (REX4) 7-(4-(4-(benzo[b]thiophen-4-yl)piperazine-1-yl)butoxy)quinoline-2(1H)-one (4.0 g) was dissolved in DCM (120 mL), and then, under stirring at room temperature, a solution of iodomethylpiperidine-1-carboxylate (2.98 g) in DCM (10 mL) was added and the mixture was stirred at room temperature for 2 hours. After standing overnight, the mixture was filtered, washed with DCM, and dried to obtain the crude product. This crude product was recrystallized from DCM / DMF (3 / 2) (140 mL). 4-(benzo[b]thiophen-4-yl)-1-(4-((2-oxo-1,2-dihydro Quinoline-7-yl)oxy)butyl)-1-(((piperidine-1-carbonyl)oxy)methyl)piperazine-1-ium iodide (4.06 g) was obtained. NMR1; 1.32-1.63(6H, m), 1.80-2.04(4H, m), 3.25-3.40(2H, m), 3.40-3.58(6H, m), 3.58-3.88(6H, m), 4.10(2H, t, J=5.6Hz), 5.55(2H, s), 6.32(1H, dd, J=1.4Hz, 9.5Hz), 6.74-6.95(2H, m), 7.04(1H, d, J=7.6Hz), 7.34(1H, dd, J=7.8Hz, 7.8Hz), 7.54(1H, d, J=5.5Hz), 7.59(1H, d, J=9.4Hz), 7.73(1H, d, J=8.1Hz), 7.79(1H, d, J=5.5Hz), 7.82(1H, d, J=9.5Hz), 11.64(1H, s).

[0152] Reference Example 5 (REX5) Similar to Reference Example 4, 4-(benzo[b]thiophen-4-yl)-1-(4-((2-oxo-1,2-dihydro Quinoline-7-yl)oxy)butyl)-1-((propionyloxy)methyl)piperazine-1-ium I obtained iodide. NMR1; 1.07(3H, t, J=7.4Hz), 1.71-2.00(4H, m), 2.56(2H, q, J=7.4Hz), 3.47-3.52(4H, m), 3.63-3.71(2H, m), 3.71-3.86(4H, m), 4.10(2H, t, J=5.6Hz), 5.55(2H, s), 6.32(1H, dd, J=1.5Hz, 9.4Hz), 6.77-6.87(2H, m), 7.03(1H, d, J=7.6Hz), 7.34(1H, dd, J=7.9Hz, 7.9Hz), 7.53(1H, d, J=5.6Hz), 7.59(1H, d, =8.5Hz), 7.73(1H, d, J=8.0Hz), 7.78(1H, d, J=5.5Hz), 7.82(1H, d, J=9.5Hz), 11.65(1H, s).

[0153] Reference example 6 (REX6) 4-(benzo[b]thiophen-4-yl)-1-((hexanoyloxy)methyl)-1-(4-((2-oxo-1,2-dihydroquinoline-7-yl)oxy)butyl)piperazine-1-ium iodide was obtained in the same manner as in Reference Example 4. NMR1; 0.83(3H, t, J=6.9Hz), 1.13-1.31(4H, m), 1.46-1.58(2H, m), 1.80-2.02(4H, m), 2.44-2.55(2H, m), 3.48-3.54(4H, m), 3.64-3.88(6H, m), 4.10(2H, t, J=5.5Hz), 5.57(2H, s), 6.29-6.37(1H, m), 6.80-6.88(2H, m), 7.05(1H, d, J= 7.5Hz), 7.35(1H, dd, J=7.9Hz, 7.9Hz), 7.54(1H, d, J=5.5Hz), 7.60(1H, d, =9.4Hz), 7.74(1H, d, J=8.1Hz), 7.79(1H, d, J=5.5Hz), 7.84(1H, d, J=9.5Hz), 11.65(1H, s).

[0154] Reference Example 7 (REX7) 4-(benzo[b]thiophen-4-yl)-1-((((hexyloxy)carbonyl)oxy)methyl)-1-(4-((2-oxo-1,2-dihydroquinoline-7-yl)oxy)butyl)piperazine-1-ium iodide was obtained in the same manner as in Reference Example 4. NMR1; 0.85(3H, t, J=6.9Hz), 1.17-1.37(6H, m), 1.50-1.67(2H, m), 1.77-2.03(4H, m), 3.40-3.56(4H, m), 3.63-3.90(6H, m), 4.09(2H, t, J=5.7Hz), 4.18(2H, t, J=6.7Hz), 5.61(2H, s), 6.31(1H, dd, J=1.8Hz, 9.5Hz), 6.76-6.85(2H, m), 7.03(1H, d, J=7.4Hz), 7.34(1H, dd, J=7.9Hz, 7.9Hz), 7.54(1H, dd, J=0.4Hz, 5.5Hz), 7.58(1H, d, J=8.8Hz), 7.73(1H, d, J=8.1Hz), 7.79(1H, d, J=5.5Hz), 7.82(1H, d, J=9.5Hz), 11.63(1H, s).

[0155] The structural formulas of the reference example compounds (Reference Examples 1-7) and example compounds (Examples 1-20) obtained by the method described above are shown in the table below.

[0156] [Table 2A] TIFF2026082788000080.tif77170

[0157] [Table 2B] TIFF2026082788000082.tif192170TIFF2026082788000083.tif205170TIFF2026082788000084.tif230170TIFF2026082788000085.tif154170In addition, each compound related to the examples other than those listed above was also synthesized and investigated.The numbering, structural formula, manufacturing method, and NMR analysis data for these are listed below in a table.For convenience, the numbering for each example is "EX N". (N is an integer between 1 and 161.) "EX N" may also be written as "Example N," etc. Furthermore, the compounds used in the synthesis of each example are listed below as Reference Examples 8-67, including their numbering, structural formula, manufacturing method, and NMR analysis data. For convenience, each Reference Example is numbered "REX M" (where M is an integer from 8 to 67). "REX M" may also be written as "Reference Example M," etc. [Table 3A] TIFF2026082788000087.tif254170TIFF2026082788000088.tif254170TIFF2026082788000089.tif254170TIFF2026082788000090.tif254170TIFF2026082788000091.tif254170TIFF2026082788000092.tif254170TIFF2026082788000093.tif254170TIFF2026082788000094.tif254170TIFF2026082788000095.tif254170TIFF2026082788000096.tif254170TIFF2026082788000097.tif254170TIFF2026082788000098.tif254170TIFF2026082788000099.tif254170TIFF2026082788000100.tif254170TIFF2026082788000101.tif254170TIFF2026082788000102.tif254170TIFF2026082788000103.tif254170TIFF2026082788000104.tif254170TIFF2026082788000105.tif254170TIFF2026082788000106.tif254170TIFF2026082788000107.tif254170TIFF2026082788000108.tif254170TIFF2026082788000109.tif254170TIFF2026082788000110.tif254170TIFF2026082788000111.tif254170TIFF2026082788000112.tif254170TIFF2026082788000113.tif254170TIFF2026082788000114.tif254170TIFF2026082788000115.tif254170TIFF2026082788000116.tif254170TIFF2026082788000117.tif254170TIFF2026082788000118.tif254170TIFF2026082788000119.tif254170TIFF2026082788000120.tif254170TIFF2026082788000121.tif254170. [Table 3B] TIFF2026082788000123.tif254170TIFF2026082788000124.tif254170TIFF20260827880 00125.tif254170TIFF2026082788000126.tif254170TIFF2026082788000127.tif254170 TIFF2026082788000128.tif254170TIFF2026082788000129.tif254170TIFF20260827880 00130.tif254170TIFF2026082788000131.tif254170TIFF2026082788000132.tif254170

[0158] Each of the obtained compounds was used in the following test examples. The compounds in Reference Examples 3 and 4 are the compounds described in Examples 58 and 706 of Patent Document 2 (International Publication No. 2013 / 035892), respectively.

[0159] Cytotoxicity study using HL-60 cells (1)Cell culture HL-60 cell line (Human acute promyelocytic leukemia) containing 20% ​​Fetal Bovine Serum (FBS) Maintenance culture was performed using RPMI1640 at 37°C in the presence of 95% air / 5% CO2. Prior to evaluation, the cells were pre-cultured for approximately 72 hours in the presence of 10 nM Phorbol 12-myristate 13-acetate (PMA) to induce differentiation into macrophage-like cells.

[0160] (2) Treatment with evaluation compound The evaluation compounds were dissolved in DMSO to prepare a 30 mmol / L solution (or suspension). Each DMSO solution was diluted 100-fold with RPMI1640 containing 2% FBS (final compound concentration: 300 μmol / L) to prepare the treatment solution. The culture supernatant of differentiated HL-60 cells was removed, and each treatment solution was added. After incubation for approximately 24 hours, cytotoxicity was evaluated. Three reference compounds that showed irritation when administered subcutaneously to dogs were used as positive control compounds, and risperidone, which is commercially available as a subcutaneous injection formulation, was used as a negative control compound.

[0161] (3) Cytotoxicity assessment Commercial kit (Cytotoxicity LDH Assay Kit-WST, Dojindo) and plate reader (TECAN) Using an infinite M1000, lactate dehydrogenase (LDH) activity was measured in treatment solutions to which cells had been exposed for approximately 24 hours. Using the obtained measurements, the cytotoxicity (%) of each evaluation compound treatment group was calculated and used as a comparative value, with the untreated group set to 0% and the cell lysis buffer treatment group set to 100%. The test was performed as a triplicate, with 3 wells for each group, and the mean value was adopted. The test was considered valid if clear cytotoxicity was observed in the positive control compound treatment group and almost no cytotoxicity was observed in the negative control compound treatment group.

[0162] (4) Test results (discussion) The table below shows the test results for cytotoxicity (%).

[0163] [Table 4] TIFF2026082788000134.tif251170TIFF2026082788000135.tif214170

[0164] All of the example compounds in the table above exhibited cytotoxicity equivalent to or less than that of the negative control, risperidone. Furthermore, Reference Example 4 compound (REX 4), a quaternary ammonium compound, was positively controlled. It showed stronger cytotoxicity than the reference example compound (REX 3) set as the reference. The example compound was shown to have lower cytotoxicity than the reference example compound 4.

[0165] Confirmation test for conversion to brexpiprazole The conversion of the evaluation compound to brexpiprazole in the buffer (i.e., the stability of the evaluation compound) was evaluated.

[0166] Example 1: The compound was diluted with acetonitrile / water (1:1, v / v) to a concentration of 10 mmol / L. It was dissolved and then further diluted to 100 μmol / L with acetonitrile / water (1:1, v / v) before use.

[0167] Furthermore, the other example compounds and Reference Examples 5-7 compounds, with the exception of the compounds described below, were each dissolved in DMSO to a concentration of 10 mmol / L, and then further diluted with acetonitrile to 100 μmol / L before use. Examples 52, 95, 96, 117, 130 (EX 52, EX 95, EX 96, EX 117, EX 130) For the compound, dissolve it in acetonitrile / water (8:2, v / v) at a concentration of 10 mmol / L, and then... Furthermore, it was diluted to 100 μmol / L with acetonitrile before use. For compound 97 (EX 97), acetonitrile / water (8:2, v / v) was used. Dissolve in 0 mmol / L, then dilute to 100 μmol / L with acetonitrile / water (8:2, v / v). It was used after being diluted. For the compounds in Examples 15 and 116 (EX 15, EX 116), they were dissolved in DMSO at a concentration of 1 mmol / L and then further diluted with acetonitrile to a concentration of 100 μmol / L before use.

[0168] These evaluation compound solutions were prepared immediately before use.

[0169] The reaction was carried out by preparing the reaction solution so that the final concentrations of each component were as follows. The test was also performed using duplicate samples.

[0170] Composition Final concentration Tris-HCl buffer (pH 7.5) 50 mmol / L Magnesium chloride 5 mmol / L Evaluation compound solution 1 μmol / L

[0171] For compounds 1-8, 10-19, 26-27, 37, 50, 87-89, 91, 116, 121, 123, 150, and 151 (EX1-8, 10-19, 26-27, 37, 50, 87-89, 91, 116, 121, 123, 150, and 151), and compounds 5-7 (REX5-7), the reaction solution without the evaluation compound (198 μl) was pre-incubated at 37°C for 3 minutes, then the evaluation compound solution (2 μl) was added and stirred, followed by incubation at 37°C. The reaction was initiated. At 0 or 60 minutes after the start of the reaction, a reaction stop solution (1000 μl) consisting of acetonitrile / isopropanol (4:1, v / v) containing an internal standard substance was added and stirred to stop the reaction. However, the 0-minute reaction sample (198 μl) was prepared by adding the evaluation compound (2 μl) after adding the reaction stop solution (1000 μl). The sample after reaction stoppage was used as the measurement sample. Same composition. Calibration curve samples were prepared (final concentrations of the evaluation compound and brexpiprazole: 0.01, 0.1, and 1 μmol / L, however, for the evaluation compound only, the 0-minute reaction sample was also used as a 1 μmol / L calibration curve sample). Examples 24-25, 28-29, 32-36, 40-49, 51-60, 62-64, 66-77, 80-86, 90, 92-111, 113, 115, 117-120, 122, 124-130, 132-147, 152-160 Compound (EX24-25, 28-29, 32-36, 40-49, 51-60, 62-64, 66 For samples ~77, 80~86, 90, 92~111, 113, 115, 117~120, 122, 124~130, 132~147, and 152~160, a reaction solution (148.5 μL) without the evaluation compound was pre-incubated at 37°C for 3 minutes, then the evaluation compound solution (1.5 μL) was added and stirred before starting the reaction at 37°C. The reaction was stopped at 0 minutes or 60 minutes after the start of the reaction by adding a reaction stop solution (600 μL) consisting of acetonitrile / isopropanol (4:1, v / v) containing an internal standard and stirring. However, the 0-minute reaction sample (148.5 μL) was prepared by adding the evaluation compound (1.5 μL) after adding the reaction stop solution (600 μL). The post-stop sample was used as the measurement sample. Calibration curve samples of the same composition were prepared (final concentrations of the evaluation compound and brexpiprazole: 0.01, 0.1, 1 μmol / L; however, for the evaluation compound only, the 0-minute reaction sample was also used as a 1 μmol / L calibration curve sample).

[0172] For compounds 1-8, 10-19, 26-27, 37, 50, 87-89, 91, 116, 121, 123, 150, and 151 (EX1-8, 10-19, 26-27, 37, 50, 87-89, 91, 116, 121, 123, 150, and 151), and compounds 5-7 (REX5-7), the obtained measurement samples and calibration curve samples were centrifuged. The supernatant is diluted as needed with a mixture of acetonitrile / isopropanol (4:1, v / v) and analyzed using a liquid chromatography-tandem mass spectrometer (HPLC: Shimadzu Prominence UFLC system). The compounds, brexpiprazole, and internal label were evaluated by injection into a TEM (MS: SCIEX API4000). We measured the quasi-substance. Examples 24-25, 28-29, 32-36, 40-49, 51-60, 62-64, 66-77, 80-86, 90, 92-111, 113, 115, 117-120, 122, 124-130, 132-147, 152-160 Compound (EX24-25, 28-29, 32-36, 40-49, 51-60, 62-64, 66-77, 80-86, 90, 92-111, 113, For samples 115, 117-120, 122, 124-130, 132-147, and 152-160, the obtained measurement samples and calibration curve samples were centrifuged, and the supernatant was diluted as appropriate with a mixture of ultrapure water and acetonitrile / isopropanol (4:1, v / v) to a ratio of 20% ultrapure water. The measurement samples were then injected into a liquid chromatograph-tandem mass spectrometer (HPLC: Shimadzu Prominence UFLC system, MS: SCIEX Triple Quad 4500) to measure the evaluation compound, brexpiprazole, and internal standard. Ionization was performed using electrospray ionization with a cation detection method, employing a selective reaction detection method using the set precursor and product ions. The internal standard substance used was the deuterized form of brexpiprazole (Brexpiprazole-d8). The residual amounts of the evaluation compound and the amount of brexpiprazole produced in the 0-minute and 60-minute reaction samples were calculated.

[0173] The difference in the amount of the evaluation compound remaining in the 0-minute reaction sample and the 60-minute reaction sample was taken, and the decrease in the 60-minute reaction sample was calculated. Based on this change in the evaluation compound, the stability of the evaluation compound in the buffer was evaluated.

[0174] The conversion of brexpiprazole to brexpiprazole in the 60-minute reaction sample was evaluated based on the amount of brexpiprazole produced in the 60-minute reaction sample. If brexpiprazole was detected in the 0-minute reaction sample, the difference between the amount of brexpiprazole produced in the 0-minute reaction sample and the 60-minute reaction sample was taken, and the increase in the 60-minute reaction sample was calculated. The stability of the evaluation compound in the buffer was evaluated based on this change in brexpiprazole.

[0175] The test results are shown in the table below. The decrease in concentration of the evaluated compound (μmol / L) and the brexpiprazole production concentration (μmol / L) were tested using duplicates, and the average value was adopted.

[0176] [Table 5] TIFF2026082788000137.tif251170TIFF2026082788000138.tif251170TIFF2026082788000139.tif181170

[0177] [Consideration] The compound used in the example is a quaternary ammonium compound, the same as the control compounds (Reference Examples 5, 6, and 7), but it is stable in the buffer and does not convert to brexpiprazole. On the other hand, the control compounds clearly decompose to brexpiprazole. This indicates that the compound used in the example in this application is stable for formulation and has the potential to be handled stably as a prodrug of brexpiprazole.

[0178] Example 1: Preparation of a pharmaceutical composition of the compound - 1 (Example A) (1.25 mg / mL Solution formulation of compound 1 in Example 1) The compound from Example 1 was dissolved at a concentration of 1.25 mg / mL in phosphate-buffered saline (pH 7.4) containing 10% dimethyl sulfoxide and 0.09% polysorbate 80. (Example B) (0.5 mg / mL Solution formulation of compound 1 from Example 1) Approximately 80% of the final prepared volume of sterile water for injection is weighed out, and D-mannitol and monosodium phosphate monohydrate are added. The mixture was added and stirred to dissolve it. Compound 1 of Example was then added and stirred to disperse it. A 1 M sodium hydroxide solution was gradually added to dissolve Compound 1 of Example, and the pH was adjusted to 8.0. After adding the necessary amount of sterile water for injection to reach the final volume, the mixture was aseptically filtered through a filtration filter (0.2 μm, PVDF membrane). The composition per 1 mL is shown in the table below. [Table 6] (Example C) (5.0 mg / mL Compound 1 solution formulation) Approximately 80% of the final prepared volume of sterile water for injection is weighed out, and D-mannitol and monosodium phosphate monohydrate are added. The mixture was added and stirred to dissolve it. Compound 1 of Example was then added and stirred to disperse it. A 1M sodium hydroxide solution was gradually added to dissolve Compound 1 of Example, and the pH was adjusted to 8.9. After adding the necessary amount of sterile water for injection to reach the final volume, the mixture was aseptically filtered through a filtration filter (0.2 μm, PVDF membrane). The composition per 1 mL is shown in the table below. [Table 7]

[0179] Evaluation of the pharmaceutical composition of Example A The pharmaceutical composition of Example A (1.25 mg / mL solution formulation of Compound 1 of Example A) was administered subcutaneously to male rats, and the plasma concentrations of Compound 1 of Example A and brexpiprazole were measured. Male rats were purchased from Nippon SLC Co., Ltd. at 7 weeks of age and used in the experiment after preliminary rearing. The rearing environment was as follows: Feeding and water intake: no restrictions, 3 rats per cage, temperature: 23±2℃, humidity: 60±10%, lighting time: 7:00-19:00. Rats under isoflurane anesthesia were administered subcutaneously to the back using a plastic syringe. The dose was 1.25 mg / kg. Approximately 0.3 mL of blood was collected from the jugular vein at 5, 10, 20, 30, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, and 8 hours after administration. The blood was quickly heparinized and cooled with ice, and the plasma was separated by centrifugation. The compound concentration was quantified by LC-MS. Figure 1 shows the plasma drug concentration profile after subcutaneous administration of the pharmaceutical composition of Example A (1.25 mg / mL solution formulation of Compound 1 of Example 1). Since Compound 1 of Example 1 and brexpiprazole were detected in the plasma 5 minutes after administration, it is considered that Compound 1 of Example 1 rapidly reaches the blood and systemic area from the subcutaneous tissue, and brexpiprazole is rapidly generated in the blood. Furthermore, since the peak plasma concentration of brexpiprazole was reached 1 hour after subcutaneous administration, a rapid exertion of pharmacological effects can be expected. Therefore, the solution pharmaceutical composition containing Compound 1 of Example 1 is expected to rapidly generate brexpiprazole in the body after subcutaneous administration, and the generated brexpiprazole will exert its pharmacological effects, for example, in the acute phase of schizophrenia and Alzheimer's disease. This pharmaceutical composition is expected to be useful as a treatment for alleviating the symptoms of agitation in patients.

[0180] Preparation of pharmaceutical composition of compound 1 - 2 (Example D) (150 mg / g aqueous suspension formulation of compound 1) Dissolve the following components in sterile water for injection to achieve the concentrations of sodium carboxymethylcellulose (CMC-Na) (1.0% (w / w)), sodium chloride (0.9% (w / w)), and sodium dihydrogen phosphate monohydrate (0.074% (w / w)), and adjust the pH to 6.8 with sodium hydroxide. The prepared aqueous solution was aseptically filtered in a clean bench using a filtration filter (0.2 μm, PES membrane). The compound from Example 1 was added to this aqueous solution to the indicated concentration (150 mg / g) to prepare a primary aqueous suspension. To this primary aqueous suspension, an autoclaved magnetic stirrer and 1 g of autoclaved 1.0 mm diameter zirconia beads were added. After adding the ingredients and sealing the container, the mixture was stirred for 21 hours under 5°C conditions, then wet-ground to create a secondary aqueous suspension. A mixture was prepared. Using a sterile pipette, only the secondary aqueous suspension was collected from the zirconia bead mixture. The particle size distribution of this secondary aqueous suspension was measured using a laser diffraction particle size analyzer SALD-3100 (Shimadzu Corporation). After 1 minute of ultrasonic irradiation using the built-in device, the measurement was performed with a refractive index of 2.00 - 0.20i, and the average particle size was found to be 1.9 μm.

[0181] Evaluation of the pharmaceutical composition of Example D The pharmaceutical composition of Example D (aqueous suspension of the compound from Example 1 at 150 mg / g) was administered subcutaneously to male rats, and the plasma concentrations of the compound from Example 1 and brexpiprazole were measured. Male rats were purchased from SLC Japan Co., Ltd. at 7 weeks of age and used in experiments after preliminary rearing. The rearing environment was as follows: Feeding and water intake: No restrictions, Number of individuals per cage: 3, Temperature: 23±2℃, Humidity: 60±10%, Lighting time: 7:00-19:00. The drug was administered subcutaneously to the back of rats under isoflurane anesthesia using a plastic syringe. The dose was adjusted to 25 mg / kg in terms of brexpiprazole equivalent. Approximately 0.5 mL of blood was collected on the hour, day 1, day 3, day 6, day 9, and day 14. The blood was immediately heparinized and cooled with ice, and the plasma was separated by centrifugation. The compound concentration was quantified by LC-MS. Example D Figure 2 shows the plasma drug concentration profile after subcutaneous administration of the pharmaceutical composition (150 mg / g aqueous suspension formulation of the compound in Example 1) to male rats. When the pharmaceutical composition of Example D was administered subcutaneously, two hours after administration, the compound of Example 1 and brek were observed. Spiprazole was detected. Plasma brexpiprazole concentrations were elevated from 2 hours to 24 hours after administration. The value remained almost constant during the interval, but decreased rapidly from the third day onward. Therefore, the compound of Example 1 The aqueous suspension injection of the substance is expected to exert its pharmacological effect by maintaining plasma brexpiprazole levels for approximately one day after subcutaneous administration. Therefore, the pharmaceutical composition in which the compound from Example 1 is suspended in injection water rapidly generates brexpiprazole in the body after subcutaneous administration, maintains a nearly constant plasma brexpiprazole level for one day after administration, and exerts the pharmacological effect of brexpiprazole. Because it is expected to exert its therapeutic effect, it is convenient for daily use subcutaneous administration to patients with schizophrenia, depression, or agitation in Alzheimer's disease who tend to refuse medication. It is expected to be a useful pharmaceutical composition as an injectable agent.

[0182] Example 1: Preparation of a Compound Pharmaceutical Composition - 3 (Example E) (159 mg / g aqueous suspension formulation of zinc salt compound from Example 1) Dissolve the following components in sterile water for injection to achieve the concentrations of sodium carboxymethylcellulose (CMC-Na) (1.0% (w / w)), D-mannitol (4.5% (w / w)), and sodium dihydrogen phosphate monohydrate (0.074% (w / w)), and adjust the pH to 6.0 with sodium hydroxide. The aqueous solution was aseptically filtered in a clean bench using a filtration filter (0.2 μm, PES membrane) to prepare a suspension medium. 757 mg of the zinc salt of the Example 1 compound and 3873 mg of the suspension medium were weighed out and mixed. The average particle size of the resulting suspension particles was 3.9 μm. The average particle size was measured using a laser diffraction particle size distribution analyzer, SALD-3100 (Shimadzu Corporation). After 1 minute of ultrasonic irradiation using the built-in device, measurements were taken with a refractive index of 2.00 -0.20i. .

[0183] Evaluation of the pharmaceutical composition of Example E The pharmaceutical composition of Example E (159 mg / g aqueous suspension of the zinc salt compound of Example 1) was applied to male rats. The drugs were administered, and the plasma concentrations of the Example 1 compound and brexpiprazole were measured. Male rats were purchased from SLC Japan Co., Ltd. at 7 weeks of age and used in experiments after preliminary rearing. The rearing environment was as follows: Feeding and water intake: No restrictions, Number of individuals per cage: 3, Temperature: 23±2℃, Humidity: 60±10%, Lighting time: 7:00-19:00. Rats under isoflurane anesthesia were administered subcutaneously via glass syringe to the back. The dose was adjusted to 25 mg / kg in terms of brexpiprazole equivalent. Approximately 0.5 mL of blood was collected at 2 hours, 1 day, 3 days, 6 days, 9 days, 14 days, 21 days, and 28 days after administration. The blood was rapidly heparified. The plasma was treated with ionization and ice cooling, separated by centrifugation, and the compound concentration was quantified by LC-MS. The pharmaceutical composition of Example E (159 mg / g aqueous suspension of zinc salt compound from Example 1) was administered subcutaneously to male rats. Figure 3 shows the changes in plasma drug concentration after administration. When the pharmaceutical composition of Example E was administered subcutaneously, two hours after administration, the compound of Example 1 and brek were observed. Spiprazole was detected, and the maximum plasma drug concentration was reached in 24 hours. Compared to Example D, the plasma drug concentrations at 2 hours and 24 hours were suppressed, confirming the sustained-release effect of zinc salt. A constant plasma drug concentration was maintained from day 3 to 14 days prior. Therefore, Example 1 Aqueous suspension injection of a zinc salt compound is expected to exert its pharmacological effect by maintaining brexpiprazole in plasma for 1 to 14 days after subcutaneous administration. Therefore, the pharmaceutical composition in which the zinc salt compound is suspended in injection water in Example 1 is expected to rapidly generate brexpiprazole in the body after subcutaneous administration, maintain brexpiprazole in plasma for several days or more after administration, and exert the pharmacological effect of brexpiprazole. This makes it a highly convenient daily-use formulation for patients with schizophrenia, depression, and agitation in Alzheimer's disease who tend to refuse medication. Therefore, it is expected to be a useful pharmaceutical composition as a subcutaneous injection for weekly use.

[0184] Preparation of a pharmaceutical composition of compound 1 - 4 (Example F) (150 mg / g Liquid crystal / lipid gel formulation of compound from Example 1) Soybean lecithin (soybean phosphatidylcholine; SPC (Lipoid, LIPOID S 100)) and glycerol dioleate (glycerol dioleate; GDO (Merck, Isomeric Mix 1,2 / 1,3-GDO)) were added to ethanol, and the mixture was heated at 40-50°C to dissolve. This solution was filtered through a 0.2 μm disc filter, and the compound from Example 1 was added to the filtrate and volute. The mixture was mixed and homogenized with kus. The composition of the resulting formulation is shown in the table below. [Table 8] (Example G) (159 mg / g Liquid crystal / lipid gel formulation of the zinc salt compound from Example 1) Soybean lecithin (soybean phosphatidylcholine; SPC (Lipoid, LIPOID S 100)) and glycerol dioleate (glycerol dioleate; GDO (Merck, Isomeric Mix 1,2 / 1,3-GDO)) were added to a mixture of DMSO and ethanol and heated to 40-50°C to dissolve. This solution was filtered through a 0.2 μm disc filter, and the zinc salt of the compound from Example 1 was added to the filtrate and mixed by vortex mixing to homogenize it. The composition of the obtained formulation is shown in the table below. [Table 9]

[0185] Evaluation of the pharmaceutical compositions of Examples F and G Viscosity measurement Measurements using a Discovery Hybrid Rheometer (DHR)-2 (manufacturer: TA Instruments) showed that the viscosity of formulation F at a shear rate of 9000-10000 (1 / s) was 402 mPa. It was s. The conditions for the viscosity measurement are as follows: • Shear rate within the measurement range: 0.1 → 10000 (1 / s) • Measurement temperature: 20℃ • Use a 20 mm flat plate. ·Gap:50 μm(40 mm Flat Plate)

[0186] Plasma drug concentration profile The pharmaceutical compositions (formulations) of Examples F and G were administered subcutaneously to male rats, and the plasma concentrations of the compound from Example 1 and brexpiprazole were measured. Male rats were purchased from SLC Japan Co., Ltd. at 7 weeks of age and used in experiments after preliminary rearing. The rearing environment was as follows: Feeding and water intake: No restrictions, Number of individuals per cage: 3, Temperature: 23±2℃, Humidity: 60±10%, Lighting time: 7:00-19:00. Rats under isoflurane anesthesia were administered subcutaneously via glass syringe to the back. The dose was adjusted to 25 mg / kg in terms of brexpiprazole equivalent. Approximately 0.5 mL of blood was collected at 2 hours, 1 day, 3 days, 6 days, 9 days, 14 days, 21 days, and 28 days after administration. The blood was rapidly heparified. The plasma was treated with ionization and ice cooling, separated by centrifugation, and the compound concentration was quantified by LC-MS. Figures 4 and 5 show the plasma drug concentration profiles after subcutaneous administration of the pharmaceutical compositions F and G to male rats, respectively. In Example F, relatively high plasma brexpiprazole concentrations were maintained in the early post-administration period, and even 14 days after administration, relatively high concentrations of brexpiprazole were detected in the plasma, indicating that plasma brexpiprazole concentrations were maintained for more than 14 days. Compared to the aqueous suspension in Example D, the plasma drug concentration was suppressed even further, confirming the sustained-release effect of the liquid crystal / lipid gel formulation.

[0187] In Example G, relatively high plasma brexpiprazole concentrations were maintained in the early post-administration period, and even 21 days after administration, relatively high concentrations of brexpiprazole were detected in the plasma, indicating that plasma brexpiprazole concentrations were maintained for more than 21 days. Compared to the aqueous suspension of zinc salt in Example E, plasma drug concentrations were suppressed even further, confirming the sustained-release effect of the liquid crystal / lipid gel formulation. From these results, it was considered that the release of the Example 1 compound from the formulation can be controlled by an appropriate combination of a sustained-release base and a metal salt, and that the Example 1 compound is converted to brexpiprazole in vivo, making it possible to maintain blood exposure to brexpiprazole at a level that exerts a therapeutic effect for 14 to 21 days or more. Example 1: A pharmaceutical composition that forms a liquid crystal / lipid gel of the compound or its salt is compared in the early post-administration period. Because it maintains a high blood brexpiprazole concentration, it eliminates the need for concomitant use of oral medications or shortening of injection intervals to compensate for the initial blood drug concentration of the sustained-release injectable formulation. Therefore, it is expected to be a useful pharmaceutical composition for preventing relapses in conditions such as schizophrenia.

[0188] Example 1: Preparation of a pharmaceutical composition of the compound - 5 (Examples H, I, J, K, L, M, N, O) (300-400 mg / g) Example 1 Compound Microwave (Rossfair) For each composition shown in the table below, the compound from Example 1 and the biodegradable polymer poly(lactide-co-glyco Resomer RG505, Resomer RG504, Resomer RG503, Resomer RG502, Resomer RG752H, or Lactel 85:15 Poly (DL-lactide-co-glycolide), Ester Terminated (PLGE) Inherent Viscosity Range (IV): 0.76-0.85 dL / g (all Resomer and Lactel are Evonik) are mixed with dichloromethane (Fujifilm Wako Pure Chemical Industries) and vinegar. The oil phase was prepared by dissolving with acid (Fujifilm Wako Pure Chemical Industries). Polyvinyl alcohol 40-88 ( A 0.5% solution of Merck was dissolved in purified water to prepare the aqueous phase (continuous phase). Using a TK Robomix (Primix) equipped with a homomixer, the aqueous phase was rotated at a speed of 2000-3000 rpm. The oil phase was added dropwise while homogenizing. Then the aqueous phase was stirred with a stirrer at 200-500 rpm. Microspheres were prepared by drying in liquid for 5 hours while stirring, and the microspheres after drying in liquid were prepared. Rothspheres were observed using a polarizing microscope. If necessary, additional washing methods were performed after drying in liquid, including the addition of alkalis such as 99.5% ethanol or 1N sodium hydroxide solution. After drying in liquid, the microspheres were filtered by aspiration using a filter with a 20 μm nylon mesh filter, and the aqueous phase was removed. Approximately 1 / 5 the volume of purified water used for the aqueous phase was flowed over the microspheres filtered on the filter to thoroughly wash away the PVA, and the microspheres were recovered. The recovered microspheres were placed in a Falcon tube and stored in a freezer at -20°C or below. The material was brought into storage and frozen, then freeze-dried using a Lyostar-3 (SP Scientific) freeze-dryer to recover the powder microspheres. The molar ratio of lactic acid and glycolic acid, characteristics, weight-average molecular weight, and Inherent Viscosity Range (dL / g) of each PLGA used are as follows. Resomer RG505 lactide:glycolide 50:50, ester terminated, Mw 54,000-69,000, Resomer RG504 lactide:glycolide 50:50, ester terminated, Mw 38,000-54,000, 0.45-0.60 Resomer RG503 lactide:glycolide 50:50, ester terminated, Mw 24,000-38,000, 0.32-0.44 Resomer RG502 lactide:glycolide 50:50, ester terminated, Mw 7,000-17,000, 0.16-0.24 Resomer RG752H lactide:glycolide 75:25, acid terminated, Mw 4,000-15,000, 0.14-0.22 Lactel 85:15 PLGE IV 0.76-0.85 lactide:glycolide 85:15, ester terminated, unknown, 0.76-0.85 [Table 10]

[0189] Evaluation of pharmaceutical compositions of Example H to O Polarized light microscopy observation The microspheres of Examples I, J, and K after drying in liquid were observed using a polarizing microscope. The results are shown in Figure 6. These are shown in 7 and 8. In all cases, the formation of microspheres was confirmed.

[0190] Measurement of average particle diameter The obtained microspheres were suspended in a 0.5% carboxymethylcellulose sodium solution and analyzed by laser diffraction and scattering using a laser diffraction particle size distribution analyzer SALD-3100 (Shimadzu Corporation). The particle size was measured. Purified water was used as the solvent during measurement, and either a batch cell or a circulating cell was used. In the case of a batch cell, the stirring speed was set to maximum, and in the case of a circulating cell, the circulation speed was set to 5. The formulation is added dropwise to purified water until the optimal concentration is reached, and the average particle size is measured with a refractive index of 2.00 - 0.20i. The particle size was measured. The results are shown in the table below. The average particle size was 50-85 μm, and the average particle size of the manufactured sample was suitable for maintaining blood concentration for more than one month. [Table 11] Drug encapsulation rate Dissolve 20 mg of the obtained microspheres in 10 mL of dimethyl sulfoxide / acetic acid (4 / 1) solution. Then, using a test solution prepared by diluting 1 mL of the dissolution 10-fold with acetonitrile, the myctomy was performed by HPLC. The drug encapsulation rate within the crossfair was measured. The encapsulation rate of each prepared manufacturing example was measured by HPLC. The results are shown in the table below. As shown in the table below, the encapsulation rate of Examples H~O was 80% or higher. [Table 12]

number

[0191] Plasma drug concentration profile For administration to animals, the microsphere powders of Examples H, J, K, and L were diluted to 300 mg / mL. Medium-chain triglyceride (MCT, obtained from CRODA, used as a solvent) was added to prepare the MCT suspensions of Examples H, J, K, and L. These suspensions were administered subcutaneously to male rats. The drugs were administered, and the plasma concentrations of Example Compound 1 and brexpiprazole were measured. Male rats were purchased from SLC Japan Co., Ltd. at 7 weeks of age and used in experiments after preliminary rearing. The rearing environment was as follows: Feeding and water intake: No restrictions, Number of individuals per cage: 2-3, Temperature: 23±2℃, Humidity: 60±10%, Lighting time: 7:00-19:00. Rats under isoflurane anesthesia were administered subcutaneously to the back using a glass syringe. The dosage for each formulation was adjusted to 25 mg / kg in terms of brexpiprazole equivalent. 0.5 mL of blood was collected from the jugular vein at time points after administration. The timing of blood collection was as follows: for Example H, 2 hours, 1, 3, 6, 9, 14, 21, and 28 days after administration; and for Examples J, K, and L, 2 hours, 1, 3, 7, 10, 14, 21, 28, 35, 42, and 56 days after administration. Blood was collected immediately after collection. The sample was quickly heparinized and cooled with ice. Plasma was separated by centrifugation, and the concentrations of the example compound and brexpiprazole were measured by LC-MS. Figures 9, 10, 11, and 12 show the plasma drug concentration profiles after subcutaneous administration of the pharmaceutical compositions of Examples H, J, K, and L to male rats. In all cases, in addition to an increase in blood concentration immediately after administration, sustained blood brexpiprazole concentrations for more than one month were confirmed. From these results, it was considered that by preparing microspheres containing the compound of Example 1 using an appropriate biodegradable polymer, the release of the compound of Example 1 from the formulation can be controlled, and the conversion of the compound of Example 1 to brexpiprazole in vivo makes it possible to maintain blood exposure to brexpiprazole at a level that exerts a therapeutic effect for more than one month. Example 1: The pharmaceutical composition of microspheres of the compound showed relatively high blood bleed levels in the early post-administration period. Because it maintains spiprazole concentration, it eliminates the need for concomitant use of oral medications or shortening of injection intervals to compensate for the initial blood drug concentration of the sustained-release injectable formulation. Therefore, it is expected to be a useful pharmaceutical composition for preventing relapses in conditions such as schizophrenia.

[0192] Example 3: Preparation of a compound pharmaceutical composition (Example P) These components are dissolved in sterile water for injection to achieve the following concentrations: sodium carboxymethylcellulose (CMC-Na) (1.23% (w / v)), sucrose (5.75% (w / v)), sodium dihydrogen phosphate monohydrate (0.12% (w / v)), and anhydrous citrate (0.16% (w / v)), and sodium hydroxide. The pH was adjusted to 5.0 by adding an appropriate amount of um to prepare the suspension medium. 712 mg of um 3288 mg of the compound from Example 3 was added to a suspension medium and mixed to prepare a primary suspension. 4 g of 2 mm diameter zirconia beads were added to the primary suspension, and the compound from Example 3 was ground into particles by stirring with a stirrer (grinding time: 8 hours). The zirconia beads were removed using a sterile pipette. Aqueous suspension formulations of the compound in Example 3 were prepared.

[0193] Example 10 Preparation of Compound Pharmaceutical Composition (Example Q) Sodium carboxymethylcellulose (CMC-Na) (0.796% (w / v)), sodium chloride These components were dissolved in sterile water for injection to achieve concentrations of (0.716% (w / v)) and sodium dihydrogen phosphate monohydrate (0.055% (w / v)), and the pH was adjusted to 6.0 by adding an appropriate amount of sodium hydroxide to prepare a suspension medium. 816 mg of the Example 10 compound was added to 3184 mg of the suspension medium and mixed and stirred to prepare a primary suspension. 4 g of 2 mm diameter zirconia beads were added to the primary suspension, and the particles of the Example 10 compound were pulverized by stirring with a stirrer. (Time: 80 minutes). Remove the zirconia beads using a sterile pipette and extract the compound from Example 10. An aqueous suspension formulation was prepared.

[0194] Example 12: Preparation of a compound pharmaceutical composition (Example R) Sodium carboxymethylcellulose (CMC-Na) (0.813% (w / v)), sodium chloride These components were dissolved in sterile water for injection to achieve concentrations of (0.732% (w / v)) and sodium dihydrogen phosphate monohydrate (0.056% (w / v)), and the pH was adjusted to 6.0 by adding an appropriate amount of sodium hydroxide to prepare a suspension medium. 748 mg of the Example 12 compound was added to 3252 mg of the suspension medium and mixed and stirred to prepare a primary suspension. 4 g of 2 mm diameter zirconia beads were added to the primary suspension, and the particles of the Example 12 compound were pulverized by stirring with a stirrer. Grinding time: 2 hours. Using a sterile pipette, the zirconia beads were removed to prepare an aqueous suspension formulation of the compound from Example 12.

[0195] Example 13: Preparation of a compound pharmaceutical composition (Example S) Sodium carboxymethylcellulose (CMC-Na) (0.805% (w / v)), sodium chloride These components were dissolved in sterile water for injection to achieve concentrations of (0.725% (w / v)) and sodium dihydrogen phosphate monohydrate (0.056% (w / v)), and the pH was adjusted to 6.0 by adding an appropriate amount of sodium hydroxide to prepare a suspension medium. 780 mg of the Example 13 compound was added to 3220 mg of the suspension medium and mixed and stirred to prepare a primary suspension. 4 g of 2 mm diameter zirconia beads were added to the primary suspension, and the particles of the Example 13 compound were pulverized by stirring with a stirrer. Grinding time: 3 hours. Using a sterile pipette, the zirconia beads were removed to prepare an aqueous suspension formulation of the compound from Example 13.

[0196] Example 44 Preparation of Compound Pharmaceutical Composition (Example T) Sodium carboxymethylcellulose (CMC-Na) (0.791% (w / v)), sodium chloride These components were dissolved in sterile water for injection to achieve concentrations of (0.712% (w / v)) and sodium dihydrogen phosphate monohydrate (0.055% (w / v)), and the pH was adjusted to 6.0 by adding an appropriate amount of sodium hydroxide to prepare a suspension medium. 836 mg of Example 44 compound was added to 3164 mg of the suspension medium. A primary suspension was prepared by adding it to the turbidity medium and mixing and stirring. A 2 mm diameter zirconium was added to the primary suspension. Add 4 g of Nea Beads and pulverize the particles of the Example 44 compound by stirring with a stirrer. Grinding time: 4 hours. Using a sterile pipette, the zirconia beads were removed to prepare an aqueous suspension formulation of the compound from Example 44.

[0197] Example 92 Preparation of a Compound Pharmaceutical Composition (Example U) A suspension medium was prepared by dissolving sodium carboxymethylcellulose (CMC-Na) (0.803% (w / v)), sodium chloride (0.723% (w / v)), and sodium dihydrogen phosphate monohydrate (0.055% (w / v)) in sterile water for injection to achieve the following concentrations, and adjusting the pH to 6.0 by adding an appropriate amount of sodium hydroxide. 788 mg of the Example 92 compound was added to 3152 mg of the suspension medium and mixed and stirred to prepare a primary suspension. 4 g of 2 mm diameter zirconia beads were added to the primary suspension, and the particles of the Example 92 compound were pulverized by stirring with a stirrer (pulverization time 24 hours). The zirconia beads were removed using a sterile pipette to prepare an aqueous suspension formulation of the Example 92 compound.

[0198] Example 121 Preparation of a compound pharmaceutical composition (Example V) Hydroxypropylcellulose (HPC) (4.02% (w / v)), Glycerin ( These components were dissolved in sterile water for injection to achieve concentrations of 2.01% (w / v) and histidine (0.06% (w / v)), and the pH was adjusted to 7.0 by adding an appropriate amount of hydrochloric acid to prepare a suspension medium. 784 mg of the Example 121 compound was added to 3216 mg of the suspension medium and mixed and stirred to prepare a primary suspension. A 0.5 mm diameter diaphragm was added to the primary suspension. Four g of zirconia beads were added, and the particles of the compound from Example 121 were ground by stirring with a stirrer (ground for 24 hours). The zirconia beads were removed using a sterile pipette, and an aqueous suspension formulation of the compound from Example 121 was prepared.

[0199] Evaluation of pharmaceutical compositions of Examples P to V Measurement of average particle diameter The obtained aqueous suspension formulation was analyzed using a laser diffraction particle size distribution analyzer, SALD-3100 (Shimadzu Corporation). Using this method, the particle size was measured by laser diffraction and scattering at a refractive index setting of 2.00 - 0.20i. The results are shown in the table below. [Table 13]

[0200] Plasma drug concentration profile Aqueous suspensions of the example PVs were administered subcutaneously to male rats, and the plasma concentrations of each example compound and brexpiprazole were measured. Male rats were purchased from SLC Japan Co., Ltd. at 7 weeks of age and used in experiments after preliminary rearing. The rearing environment was as follows: Feeding and water intake: No restrictions, Number of individuals per cage: 3. Temperature: 23±2℃, Humidity: 60±10%, Lighting time: 7:00-19:00. Rats under isoflurane anesthesia were administered subcutaneously to the back using either a plastic or glass syringe. The dosage for both formulations was adjusted to 25 mg / kg in brexpiprazole equivalent. 0.5 mL of blood was collected from the jugular vein at time points after administration. Blood was collected at 2 hours, 1 day, 3 days, 6 days, 9 days, 14 days, 21 days, and 28 days after administration. After blood collection... The samples were promptly treated with heparin and cooled with ice. To suppress hydrolysis in the samples, a phosphatase inhibitor cocktail (Nacalai Tesque) was added to the blood samples of individuals administered with Example PU to a final concentration of 1%, and 2-thenoyltrifluoroacetone (TTFA) was added to the blood samples of individuals administered with Example V to a final concentration of 10 mM. The plasma was separated by centrifugation to obtain the respective compound samples from each example. The concentrations of the substance and brexpiprazole were measured by LC-MS. The results are presented as the mean ± standard deviation of 3-5 cases. Figures 13, 14, 15, 16, 17, 18, and 19 show the plasma drug concentration profiles after subcutaneous administration of the pharmaceutical compositions of Examples P, Q, R, S, T, U, and V to male rats. In all cases, compared to the pharmaceutical composition of Example D (aqueous suspension of compound 1), the bruxpips were even more pronounced. Significantly sustained brexpiprazole concentration, with blood brexpiprazole concentration lasting for 2 weeks or more to 4 weeks or more. The persistence of the effect was confirmed. These results suggest that by performing an appropriate structural modification on the compound in Example 1, the release of the Example compound from the formulation can be controlled, and the Example compound is converted to brexpiprazole in vivo, resulting in exposure to brexpiprazole in the blood for more than 2 weeks to more than 4 weeks. It is believed that this will allow the therapeutic effect to be maintained at a level that persists over time, and it is expected to be a useful pharmaceutical composition for preventing relapses of conditions such as schizophrenia.

[0201] Canine irritation test method Male Beagle dogs were purchased from Kitayama Labes Co., Ltd. at 5-7 months of age and used in experiments after a preliminary rearing period. The rearing environment was as follows: Feeding: 250 g of solid feed once a day; Water supply: Unrestricted. Number of individuals per cage: 1, Temperature: 21-25℃, Humidity: 50-70%, Lighting time: 7:00-19:00 Dogs anesthetized by intravenous administration of 25 mg / kg thiopental sodium were given the test product using a plastic syringe, positioned on the back, and administered at a dose of 10 mg / kg per product. The drug was administered as shown. After 14 days of observation following administration, the dogs were anesthetized by intravenous administration of 25 mg / kg thiamylal sodium and euthanized by exsanguination, and skin samples were collected from the administration site. The collected tissue was subjected to 10% neutral pH testing. The specimens were fixed with buffered formalin, and hematoxylin-eosin stained specimens were prepared for histopathological examination.

[0202] Results and Discussion For several example compounds, external observation of the injection site and histopathological examination during the observation period confirmed that the changes at the injection site were physiological reactions to foreign substances and that the irritation level was within an acceptable range.

Claims

1. Equation (I): 【Chemistry 1】 (In the formula, R １ , R ２ Each is independent of the other, -O － , -OR ４ , or -NR ４Ｎａ R ４Ｎｂ Show, R ３ This represents hydrogen or alkyl, R ４ 、R ４Ｎａ 、and R ４Ｎｂ each independently represents hydrogen, or alkyl, alkenyl, alkadienyl, or alkynyl which may have 1 to 3 substituents, and the alkyl represented by said R ４ 、R ４Ｎａ 、and R ４Ｎｂ may have a structure in which some of the methylene groups (—CH ２ —) are replaced by —O—, —S—, —CO—, —NH—, —SiR ｓｉａ R ｓｉｂ —, or —(CO)O—, and R ｓｉａ and R ｓｉｂ are the same or different and each represents a hydrogen atom or C １－６ alkyl. The R １ and R ２ Both are - OR ４ When indicating R, １ and R ２ They may be the same or different. The R １ and R ２ Both -NR ４Ｎａ R ４Ｎｂ When indicating R, １ and R ２ They may be the same or different. A compound or salt thereof, represented by the formula.

2. R １ ga-O － R ２ ga- OR ４ , or -NR ４Ｎａ R ４Ｎｂ (Note) ４ , R ４Ｎａ , and R ４Ｎｂ (The same as above.) The compound or salt thereof according to claim 1.

3. Equation (I): 【Chemistry 2】 (In the formula, R １ ga-O － R ２ ga- OR ４ , or -NR ４Ｎａ R ４Ｎｂ Show, R ３ is hydrogen or C １－６ It shows alkyl, R ４ This represents hydrogen, or one of the following (0-1) to (5): -NR ４Ｎａ R ４Ｎｂ This indicates either (i) or (ii) below. (0-1): Halogen, Hydroxyl, C １－６ Alkyl and C １－６ C may have 1 to 3 substituents selected from alkoxys. １－１８ Alkenil, (0-2): Halogen, Hydroxyl, C １－６ Alkyl and C １－６ C may have 1 to 3 substituents selected from alkoxys. １－１８ Alkadienil, (0-3): Halogen, Hydroxyl, C １－６ Alkyl and C １－６ C may have 1 to 3 substituents selected from alkoxys. １－１８ Alkinil, (1-1): R ４ａ１ Show, R ４ａ１ teeth, -C ｎ H ２ｎ＋１ 、 -C ｎ H ２ｎ－１ 、 -C ｎ H ２ｎ－３ 、 -C ｎ H ２ｎ -OH、 -C ｎ H ２ｎ－２ -OH, or -C ｎ H ２ｎ－４ This indicates -OH. (In the above equations, n represents 1 to 24. However, -C) ｎ H ２ｎ－１ So n is 2 or greater, -C ｎ H ２ｎ－３ So n is 2 or greater, -C ｎ H ２ｎ－２ - Then n is 2 or greater, -C ｎ H ２ｎ－４ (Then n is 2 or greater.) (1-2): R ４ａ２ Show, R ４ａ２ teeth, -CHX １ X ２ -C ｎ－１ H ２ｎ－２ -CHX １ X ２ -C ｎ－１ H ２ｎ－４ -CHX １ X ２ or -C ｎ－１ H ２ｎ－６ -CHX １ X ２ are shown. (In the above equations, n ranges from 2 to 24. However, -C) ｎ－１ H ２ｎ－４ - Then n is 3 or greater, -C ｎ－１ H ２ｎ－６ - Then n is 3 or greater. X １ and X ２ These represent, either identically or distinctly, a hydrogen atom or a halogen (F, Cl, Br, or I). However, X １ and X ２ At least one of them is a halogen. (1-3): R ４ａ３ Show, R ４ａ３ teeth, -C ｎ H ２ｎ -R ４－１ 、-C ｎ－１ H ２ｎ－２ -CHR ４－１ａ R ４－１ｂ 、 -C ｎ H ２ｎ－２ -R ４－１ , or -C ｎ H ２ｎ－４ -R ４－１ This indicates , (In the above equations, n represents 1 to 24. However, -C) ｎ H ２ｎ－２ - Then n is 2 or greater, -C ｎ H ２ｎ－４ - Then n is 2 or greater. ４－１ C １－６ Alkoxy, -O-phenyl, or C １－６ R indicates a heterocyclic group which may be substituted with an alkyl or halogen. ４－１ａ and R ４－１ｂ , are the same or different, -C １－３ Alkylene-C １－３ It indicates an alkoxy, or is identical or different, -CO-O-C １－３ Alkyl, or -CH ２ -CO-O-C １－３ (Indicates alkyl.) (2): R ４ｂ Show, R ４ｂ teeth, -(C ｐ H ２ｐ -O) ｑ -C ｒ H ２ｒ -R ４－２ 、 -(C ｐ H ２ｐ -O) ｑ -C ｒ H ２ｒ－２ -R ４－２ 、 - (C ｐ H ２ｐ－２ -O) ｑ -C ｒ H ２ｒ -R ４－２ , or - (C ｐ H ２ｐ－２ -O) ｑ -C ｒ H ２ｒ－２ -R ４－２ This indicates , (In the above equations, p represents 1 to 4, q represents 1 to 4, and r represents 1 to 4. However, C ｐ H ２ｐ－２ So p is 2 or greater, C ｒ H ２ｒ－２ Then r is 2 or greater. When q is between 2 and 4, the 2 to 4 repeating structures that indicate the number of repetitions indicated by q may be the same or different. ４－２ is a hydrogen atom, hydroxyl, or C １－６ Alkyl, C １－６ Alkoxy, -C １－３ Alkylene-C １－３ (This represents a cycloalkyl group, phenyl, benzyl, or heterocyclic group, which may be substituted with one to three substituents selected from alkoxy and nitro groups.) (3): -C α H ２α -CO-O-R ＣＯＯ Or -C α H ２α -CO-O-CH ２ -R ＣＯＯ (α represents 1 to 10) -R ＣＯＯ This consists of a hydrogen atom and 1 to 3 carbon atoms. １－６ C may be substituted with an alkoxy group. １－６ Alkyl or C １－６ Alkoxy, or C １－６ Alkyl, C １－６ Alkoxy, -C １－３ Alkylene-C １－３ The group represents a cycloalkyl group, phenyl group, benzyl group, or heterocyclic group, which may be substituted with one to three substituents selected from alkoxy and nitro groups. (4): -C β H ２β -O-CO-R ＯＣＯ (β represents 1 to 10) -R ＯＣＯ R ４ａ１ , R ４ｂ , or -C α H ２α -CO-O-R ＣＯＯ To indicate, or -C α H ２α -CO-NH-R ＣＯＯ , -C α H ２α -NH-CO-R ＣＯＯ , or -C α H ２α -NH-CO-OR ＣＯＯ To indicate, (-R ＣＯＯ (The same applies as above.) Alternatively, C １－６ Alkyl, C １－６ Alkoxy, -C １－３ Alkylene-C １－３ The group represents a cycloalkyl group, phenyl group, benzyl group, or heterocyclic group, which may be substituted with one to three substituents selected from alkoxy and nitro groups. (5): -C γ H ２γ -O-CO-O-R ＯＣＯＯ (γ represents 1 to 10) -R ＯＣＯＯ is a hydrogen atom, R ４ａ１ , R ４ｂ , or -C α H ２α -CO-O-R ＣＯＯ To indicate, (-R ＣＯＯ (The same applies as above.) Alternatively, C １－６ Alkyl, C １－６ Alkoxy, -C １－３ Alkylene-C １－３ The group represents a cycloalkyl group, phenyl group, benzyl group, or heterocyclic group, which may be substituted with one to three substituents selected from alkoxy and nitro groups. (i): R ４Ｎａ and R ４Ｎｂ These are 1 to 3 C's, which may be the same or different. １－６ C may be substituted with an alkoxy group. １－６ It indicates an alkyl group. (ii): R ４Ｎａ It is a hydrogen atom, R ４Ｎｂ This is 1 to 3 C １－６ C may be substituted with an alkoxy group. １－６ Indicates alkyl, or -C α H ２α -CO-O-R ＣＯＯ , or -C α H ２α -CO-NH-R ＣＯＯ This indicates (-R ＣＯＯ (The same as above) A compound or salt thereof, represented by the formula.

4. The compound or salt thereof according to any one of claims 1 to 3, wherein the heterocyclic group is a group having a structure in which one hydrogen atom bonded to an atom constituting the heterocyclic group has been removed from a heterocyclic group selected from furan, tetrahydropyran, tetrahydrofuran, 1,3-dioxane, 1,4-dioxane, pyrrole, imidazole, pyrazole, pyridine, pyrimidine, pyrazine, pyridazine, pyrrolidine, imidazolidine, thiophene, piperidine, piperazine, oxazole, isoxazole, oxadiazole, morpholine, indole, indazole, benzimidazole, and quinoline.

5. -OR ４ However, the R of the oxygen atom in question ４ The opposite side is indicated by * (* - OR ４ ) When this happens, the base is one of the bases listed in the table below, Table 1A -NR ４Ｎａ R ４Ｎｂ However, the R of the nitrogen atom in question ４Ｎａ R ４Ｎｂ The opposite side is indicated by * (*-NR) ４Ｎａ R ４Ｎｂ ) When this happens, the base is one of the bases listed in the table below, Table 1B The compound or salt thereof according to claim 1 or 2.

6. Formula (II): 【Transformation 3】 (In the formula, R ３ is hydrogen or C １－６ It shows alkyl R ４ C may have hydrogen or one to three substituents. １－１８ It shows alkyl, Each of these substituents is independently a halogen, hydroxyl, or C １－６ Alkoxy, -O-(CH ２ ) ｎ -OR ５ , -O(CO)-(CH ２ ) ｎ -OR ５a , - (CO) OR ６ , - (CO) NR ７ R ８ , -O(CO)R ９ , -O(CO)OR １０ , -O(CO)(CR １１ R １２ ) ｎ (CO)OR １３ , C ３－７ It represents a cycloalkyl group or a heterocyclic group which may have substituents, R ５ , R ５a , R ６ , R ９ , R １０ , and R １３ These are, independently, hydrogen atoms, C １－１６ a Lukil, or C ３－７ It shows cycloalkyl, R ７ and R ８ C may independently contain a hydrogen atom, or one or two methylene groups may be replaced by oxygen or nitrogen atoms. １－６ It indicates alkyl, R ７ and R ８ They may be joined together to form a ring, R １１ and R １２ R is independent and １１ If multiple exist, each is independent, R １２ If multiple exist, each is independently a hydrogen atom or C １－１６ (This indicates an alkyl group, where n is an integer between 1 and 10.) A compound or salt thereof, represented by the formula.

7. R ４ However, hydrogen, or -(A-Y) ｍ -R １４ Show, A is C １－１８ Showing alkylene, Y represents a bond, -O-, -(CO)O-, -O(CO)O-, or -(CO)NH-, R １４ is hydrogen, C １－１８ Represents an alkyl, hydroxy, cycloalkyl, or heterocyclic group. m represents an integer between 0 and 5. The compound or salt thereof according to claim 6.

8. R ４ However, C may have hydrogen or one substituent. １－８ It shows alkyl, Each of these substituents is independently hydroxy, C １－６ Alkoxy, -O-(CH ２ ) ｎ -OR ５ , -O(CO)-(CH ２ ) ｎ -OR ５a , - (CO) OR ６ , -O(CO ) R ９ , -O(CO)OR １０ , -O(CO)-A-(CO)OR １３ , or two C 1 －6 It represents a morpholinyl which may have an alkyl group, and n is an integer from 1 to 10. Here, R ５ , R ５a , R ６ , R ９ , R １０ , and R １３ These are, independently, hydrogen atoms, C １－１６ Alkyl, possibly substituted heterocyclic group, or C ３－７ It indicates a cycloalkyl group, where A is C １－６ Showing alkylene, The compound or salt thereof according to claim 6.

9. R ４ However, C may have hydrogen or one substituent. １－８ It shows alkyl, Each of these substituents is independently hydroxy, C １－６ Alkoxy, -O-(CH ２ ) ｎ -OR ５ , -O(CO)-(CH ２ ) ｎ -OR ５a , - (CO) OR ６ , -O(CO ) R ９ , -O(CO)-A-(CO)OR １３ , or one or two C 1－6 It represents a heterocyclic group which may have an alkyl group, and n represents an integer from 1 to 10. Here, R ５ C 1－６ Alkyl, R ５a C １－６ Alkyl, R ６ C １－６ Alkyl, R ９ C １－１６ Alkyl, R １３ is C 1－６ Alkyl, or C １－６ Al A indicates a pyridyl that may have kill, and A is C １－６ Showing alkylene, The compound or salt thereof according to claim 6.

10. A pharmaceutical composition comprising a compound or salt thereof according to any one of claims 1 to 9, and a pharmaceutically acceptable carrier.

11. The pharmaceutical composition according to claim 10, comprising a compound or salt thereof according to any one of claims 1 to 9, a suspending agent, and a dispersion medium, in the form of a suspension.

12. The pharmaceutical composition according to claim 11, wherein the average particle size of the particles in the suspension is 0.5 to 30 μm. thing.

13. The pharmaceutical composition according to claim 11, wherein the average particle size of the particles in the suspension is 50 to 500 nm.

14. The suspending agent is carboxymethylcellulose or a salt thereof. The pharmaceutical composition according to any one of claims 11 to 13, wherein the dispersed liquid is a liquid containing water for injection.

15. a) A compound or salt thereof according to any one of claims 1 to 9, b) Multiple types of liquid crystal forming lipids or gel forming lipids, c) Biocompatible organic solvents and A pharmaceutical composition comprising a viscous mixture, A pharmaceutical composition that is a precursor formulation used to form a liquid crystal phase structure or a lipid gel when brought into contact with an aqueous fluid in a living organism.

16. b) Multiple liquid crystal forming lipids or gel forming lipids b-1) at least one diacylglyceride The pharmaceutical composition according to claim 15, comprising (b) a roll and (b) at least one phosphatidylcholine.

17. a) A compound or salt thereof according to any one of claims 1 to 9, b-1) at least one type of diacylglycerol, and b-2) at least one type of phosphatidylcholine, c) Biocompatible organic solvents and A pharmaceutical composition containing a viscous mixture.

18. A microsphere containing the compound or salt thereof described in any one of claims 1 to 9 as an active ingredient.

19. The microsphere according to claim 18, comprising a compound according to any one of claims 1 to 9 and a biodegradable polymer.

20. The biodegradable polymer is selected from the group consisting of polylactic acid and lactic acid-glycol copolymers. The microsphere according to claim 19, wherein at least one type.

21. The microsphere according to any one of claims 18 to 20, wherein the average particle size is 5 to 150 μm.

22. A pharmaceutical composition containing the microspheres described in any one of claims 18 to 21 in a suspended state.

23. A pharmaceutical composition containing the microspheres described in any one of claims 18 to 21 in a suspended state in oil.

24. The pharmaceutical composition according to claim 23, wherein the oil is a medium-chain fatty acid triglyceride.

25. A pharmaceutical composition according to any one of claims 10 to 17 or 22 to 24, which is used for intramuscular or subcutaneous administration.

26. A pharmaceutical composition according to any one of claims 10 to 17 or 22 to 25, for the prevention and / or treatment of central nervous system diseases.

27. Central nervous system disorders include schizophrenia, treatment-resistant, refractory or chronic schizophrenia, staxic affective disorder, psychotic disorders, mood disorders, bipolar disorder, mania, depression, endogenous depression, major depression, melancholy and treatment-resistant depression, dysthymic disorder, cyclothymic disorder, anxiety disorders, and somatoform disorders. The pharmaceutical composition according to claim 26, which is a central nervous system disorder selected from the group consisting of sexual disorders, factitious disorder, dissociative disorder, sexual disorders, eating disorders, sleep disorders, adjustment disorders, substance-related disorders, anhedonia, delirium, Alzheimer's disease, Parkinson's disease, cognitive impairment, cognitive impairment associated with neurodegenerative diseases, cognitive impairment caused by neurodegenerative diseases, cognitive impairment of schizophrenia, cognitive impairment caused by treatment-resistant, intractable or chronic schizophrenia, vomiting, motion sickness, obesity, migraine, pain, intellectual disability, autism spectrum disorder, Tourette's syndrome, tic disorder, attention deficit hyperactivity disorder, conduct disorder, Down syndrome, impulsive symptoms associated with dementia, and borderline personality disorder.

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