Heterocyclic compound and use thereof

Abstract

The present invention provides a novel therapeutic agent for central nervous system diseases. More specifically, the present invention provides a compound represented by formula (I) in which R1 and R2 each independently represent-O-,-OR4, or-NR4NaR4Nb, or a salt of the compound; r3 represents hydrogen or an alkyl group; r4, R4Na and R4Nb each independently represent hydrogen or an alkyl group, an alkenyl group, a diene group or an alkynyl group which may have 1 to 3 substituents, some methylene groups (-CH2-) in the alkyl group represented by R4, R4Na or R4Nb may be replaced by-O-,-S-,-CO-,-NH-,-SiRsiaRsib-or-(CO) O-; if both R1 and R2 represent-OR4, then R1 and R2 may be the same or different; and if both R1 and R2 represent-NR4NaR4Nb, then R1 and R2 may be the same or different.

Description

Technical Field

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

[0002] 7-[4-(4-benzo[b]thiophene-4-yl-piperazin-1-yl)butoxy]-1H-quinoline-2-one (hereinafter “epipipazole”) or its salts have partial agonist activity on dopamine D2 receptors and serotonin 5-HT. 2A It has receptor antagonistic effects and adrenergic α1 receptor antagonistic effects. In addition to these effects, ipilipazole or its salts also have serotonin uptake inhibition (or serotonin reuptake inhibition) and are known to have a broad therapeutic spectrum for central nervous system disorders, particularly schizophrenia (Patent Literature (PTL) 1 and 2).

[0003] In the pharmaceutical field, one approach to drug design is to develop a drug that aims to improve the properties of a known drug molecule (e.g., enhance its therapeutic efficacy or slow its metabolism in the body) by chemically transforming or modifying certain functional groups of that molecule.

[0004] There is great anticipation that the development of this type of drug using epipiperazole will uncover a new compound with improved properties and provide new options for the treatment of central nervous system diseases.

[0005] Citation List

[0006] Patent documents

[0007] PTL 1: JP2006-316052A

[0008] PTL 2: WO2013 / 035892A Summary of the Invention

[0009] Technical issues

[0010] One of the objectives of this disclosure is to provide a novel therapeutic agent for diseases of the central nervous system.

[0011] Solution to the problem

[0012] The inventors have conducted extensive research and successfully developed a novel heterocyclic compound and its salt represented by formula (I):

[0013] They also discovered that this compound could be a novel therapeutic agent for central nervous system diseases.

[0014] This disclosure includes, for example, the subject matter described in the following entries.

[0015] Item 1. A compound or a salt thereof represented by formula (I):

[0016] in

[0017] R 1 and R 2 Each is represented independently -O - -OR 4 or -NR 4Na R 4Nb , R 3 Indicates hydrogen or alkyl. R 4 R 4Na and R 4Nb Each independently represents hydrogen or each optionally has one to three substituents, namely alkyl, alkenyl, dienyl or ynyl, wherein R 4 R 4Na or R 4Nb The alkyl group may have one or more methylene groups (-CH2-) surrounded by -O-, -S-, -CO-, -NH-, or -SiR. sia R sib The structure is replaced by - or -(CO)O-. If R 1 and R 2 Both indicate -OR 4 Then R 1 and R 2 They can be the same or different, and If R 1 and R 2 Both indicate -NR 4Na R 4Nb Then R 1 and R 2 They can be the same or different.

[0018] Item 2. The compound or salt thereof as described in Item 1, wherein R 1 -O - R 2 Indicates -OR 4 or -NR 4Na R 4Nb , where R 4 R 4Na and R 4Nb As defined above.

[0019] Item 3. A compound or a salt thereof represented by formula (I):

[0020] in

[0021] R 1 Indicates -O - , R 2 Indicates -OR 4 or -NR 4Na R 4Nb , R 3 Indicates hydrogen or C 1-6 alkyl, R 4 Represents hydrogen or any of the following (0-1) to (5), -NR 4Na R 4Nb This indicates either (i) or (ii): (0-1): optionally having 1 to 3 ions selected from halogens, hydroxyl groups, C 1-6 Alkyl and C 1-6 C of alkoxy substituent 1-18 alkenyl, (0-2): optionally having 1 to 3 ions selected from halogens, hydroxyl groups, C 1-6 Alkyl and C 1-6 C of alkoxy substituent 1-18 Dieneyl, (0-3): optionally having 1 to 3 ions selected from halogens, hydroxyl groups, C 1-6 Alkyl and C 1-6 C of alkoxy substituent 1-18 alkynyl group, (1-1): R 4a1 , Where R 4a1 express -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 -OH, Where n represents 1 to 24, and the condition is in -C n H 2n-1 In -C, n is 2 or greater; n H 2n-3 In -C, n is 2 or greater; n H2n-2 - where n is 2 or greater; and in -C n H 2n-4 - where n is 2 or greater (1-2): R 4a2 , Where R 4a2 express -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 , in n represents 2 to 24, and the condition is in -C n-1 H 2n-4 -n indicates 3 or greater; in -C n-1 H 2n-5 - In this context, n represents 3 or greater. X 1 and X 2 The same or different and representing hydrogen or halogen (F, Cl, Br or I), condition X 1 or X 2 Either or both of them represent halogens. (1-3): R 4a3 , Where R 4a3 express -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 , in n represents 1 to 24, and the condition is in -C n H2n-2 -n in - indicates 2 or greater; in -C n H 2n-4 - In this context, n represents 2 or greater. R 4-1 C represents 1-6 Alkoxy, -O-phenyl, or optionally C 1-6 Alkyl or halogen-substituted heterocyclic groups, R 4-1a and R 4-1b Same or different and indicates -C 1-3 Alkylene-C 1-3 Alkyl groups, or the same or different ones, and indicating -CO-OC 1-3 Alkyl or -CH2-CO-OC 1-3 alkyl, (2): R 4b , Where R 4b express -(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 , Where p represents 1 to 4, q represents 1 to 4, r represents 1 to 4, and the condition is C. p H 2p-2 In C, p represents 2 or greater. r H 2r-2 In this context, r represents 2 or greater. When q is 2 to 4, the 2 to 4 repeating structures represented by q can be the same or different. R 4-2 It represents hydrogen, hydroxyl, or each optionally having 1 to 3 C atoms selected from C. 1-6 Alkyl, C1-6 Alkoxy, -C 1-3 Alkylene-C 1-3 The alkoxy and nitro substituents are cycloalkyl, phenyl, benzyl, or heterocyclic groups. (3): -C α H 2α -CO-OR COO or -C α H 2α -CO-O-CH2-R COO Where α represents 1 to 10, Where -R COO Represents hydrogen, each optionally bound by 1 to 3 carbon atoms. 1-6 alkoxy-substituted C 1-6 Alkyl or C 1-6 alkoxy groups, or each optionally having 1 to 3 C2 groups. 1-6 Alkyl, C 1-6 Alkoxy, -C 1-3 Alkylene-C 1-3 The alkoxy and nitro substituents are cycloalkyl, phenyl, benzyl, or heterocyclic groups. (4): -C β H 2β -O-CO-R OCO Where β represents 1 to 10, Where -R OCO R represents 4a1 R 4b or -C α H 2α -CO-OR COO ,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 , where -R COO As defined above, or Each may have 1 to 3 selected from C 1-6 Alkyl, C 1-6 Alkoxy, -C 1-3 Alkylene-C 1-3 The alkoxy and nitro substituents are cycloalkyl, phenyl, benzyl, or heterocyclic groups. (5): -C γ H 2γ -O-CO-OR OCOO Where γ represents 1 to 10, Where -R OCOO Represents hydrogen, R 4a1 R 4b or -C α H 2α -CO-OR COO , where -R COO As defined above, or Each may have 1 to 3 selected from C 1-6 Alkyl, C 1-6 Alkoxy, -C 1-3 Alkylene-C 1-3 The alkoxy and nitro substituents are cycloalkyl, phenyl, benzyl, or heterocyclic groups. (i) R 4Na and R 4Nb Same or different, and indicates that it is optionally controlled by 1 to 3 Cs. 1-6 alkoxy-substituted C 1-6 alkyl, (ii) R 4Na Represents hydrogen, and R 4Nb Indicates that it can be arbitrarily divided by 1 to 3 Cs 1-6 alkoxy-substituted C 1-6 Alkyl, or -C α H 2α -CO-OR COO or -C α H 2α -CO-NH-R COO , Where -R COO As defined above.

[0022] Item 4. A compound or a salt thereof according to any one of items 1 to 3, wherein the heterocyclic group has a structure in which hydrogen atoms bonded to constituent atoms of the heterocycle are removed from the heterocycle, the heterocycle being selected from furan, tetrahydropyran, tetrahydrofuran, 1,3-dioxane, etc. Alkane, 1,4-di Alkane, pyrrole, imidazole, pyrazole, pyridine, pyrimidine, pyrazine, pyridazine, pyrrolidine, imidazoline, thiophene, piperidine, piperazine azole, isotonic azole, Diazole, morpholine, indole, indazole, benzimidazole, and quinoline.

[0023] Item 5. A compound or a salt thereof as described in any one of items 1 to 4, wherein -OR 4 This indicates any group listed in the table below, where the asterisk " "" indicates relative to oxygen atom and R 4 The opposite side ( -OR4 ):

[0024] And -NR 4Na R 4Nb This indicates any group listed in the table below, where the asterisk " "" indicates relative to nitrogen atom and R 4Na R 4Nb The opposite side ( -NR 4Na R 4Nb ): .

[0025] Item 6. A pharmaceutical composition comprising a compound or a salt thereof as described in any one of items 1 to 5 and a pharmaceutically acceptable carrier.

[0026] Item 7. A pharmaceutical composition according to Item 6, comprising a compound or a salt thereof according to any one of Items 1 to 5, a suspending agent and a dispersion medium, wherein the pharmaceutical composition is in the form of a suspension.

[0027] Item 8. The pharmaceutical composition according to Item 7, wherein the average particle size of the particles in the suspension is from 0.5 μm to 30 μm.

[0028] Item 9. The pharmaceutical composition according to Item 7, wherein the average particle size of the particles in the suspension is from 50 nm to 500 nm.

[0029] Item 10. A pharmaceutical composition according to any one of items 7 to 9, wherein the suspending agent is carboxymethyl cellulose or a salt thereof, and the dispersion medium is a liquid containing water for injection.

[0030] Item 11. A pharmaceutical composition comprising a viscous mixture of the following substances: a) The compound or its salt described in any of entries 1 to 5. b) Two or more lipids that form liquid crystals or lipids that form gels, and c) Biocompatible organic solvents, The pharmaceutical composition is a prodrug for forming a liquid crystal phase structure or lipid gel by contacting the pharmaceutical composition with an aqueous fluid in vivo.

[0031] Item 12. The pharmaceutical composition according to Item 11, wherein b) the two or more liquid crystal forming lipids or gel forming lipids contain

[0032] b-1) at least one diacylglycerol, and

[0033] b-2) At least one phosphatidylcholine.

[0034] Item 13. A pharmaceutical composition comprising a viscous mixture of the following substances: a) The compound or its salt described in any of entries 1 to 5. b-1) At least one diacylglycerol, b-2) At least one phosphatidylcholine, and c) Biocompatible organic solvents.

[0035] Item 14. A microsphere comprising a compound or a salt thereof as an active ingredient according to any one of items 1 to 5.

[0036] Item 15. The microspheres according to Item 14, comprising the compounds and biodegradable polymers according to any one of Items 1 to 5.

[0037] Item 16. The microspheres according to Item 15, wherein the biodegradable polymer is selected from at least one of polylactic acid and lactic acid-diol copolymers.

[0038] Item 17. Microspheres according to any one of items 14 to 16, having an average particle size of 5 to 150 μm (preferably 30 to 100 μm).

[0039] Item 18. A pharmaceutical composition comprising microspheres as described in any one of Items 14 to 17, and in the form of a suspension.

[0040] Item 19. A pharmaceutical composition comprising microspheres as described in any one of Items 14 to 17, and in the form of an oil suspension.

[0041] Item 20. The pharmaceutical composition according to Item 19, wherein the oil is a medium-chain fatty acid triglyceride.

[0042] Item 21. A pharmaceutical composition according to any one of items 6 to 13 and 18 to 20, for intramuscular or subcutaneous administration.

[0043] Item 22. A pharmaceutical composition according to any one of items 6 to 13 and 18 to 21, for the prevention and / or treatment of diseases of the central nervous system.

[0044] Item 23. According to the pharmaceutical composition described in item 22, the central nervous system disorder is selected from schizophrenia, treatment-resistant, refractory or chronic schizophrenia, schizoaffective disorder, psychotic disorder, mood disorder, bipolar disorder, mania, depression, endogenous depression, major depressive disorder, melancholic and treatment-resistant depression, dysphoric disorder, cyclothymic mood disorder, anxiety disorder, somatic symptom disorder, affective disorder, dissociative disorder, sexual dysfunction, eating disorder, sleep disorder, adjustment disorder, substance-related disorder, loss of interest, 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 caused by treatment-resistant, refractory or chronic schizophrenia, vomiting, motion sickness, obesity, migraine, pain, intellectual disability, autism, Tourette syndrome, tic disorder, attention deficit hyperactivity disorder, conduct disorder, Down syndrome, impulsive symptoms associated with dementia, and borderline personality disorder.

[0045] Item 24. The pharmaceutical composition according to any one of items 6 to 13 and 18 to 23, administered at intervals of 1 day or 2 to 3 days.

[0046] Item 25. The pharmaceutical composition according to any one of items 6 to 13 and 18 to 23, administered at intervals of 2 weeks or longer.

[0047] Item 26. The pharmaceutical composition according to any one of items 6 to 13 and 18 to 23, administered at intervals of 4 weeks or longer.

[0048] Item 27. A pharmaceutical agent for the prevention and / or treatment of diseases of the central nervous system, comprising a compound or a salt thereof as an active ingredient according to any one of items 1 to 5.

[0049] Item 28. According to the medicine described in entry 27, the central nervous system disorder is selected from schizophrenia, treatment-resistant, refractory or chronic schizophrenia, schizoaffective disorder, psychotic disorder, mood disorder, bipolar disorder, mania, depression, endogenous depression, major depressive disorder, melancholic and treatment-resistant depression, dysphoric disorder, cyclothymic mood disorder, anxiety disorder, somatic symptom disorder, affective disorder, dissociative disorder, sexual dysfunction, eating disorder, sleep disorder, adjustment disorder, substance-related disorder, loss of interest, 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 caused by treatment-resistant, refractory or chronic schizophrenia, vomiting, motion sickness, obesity, migraine, pain, intellectual disability, autism, Tourette syndrome, tic disorder, attention deficit hyperactivity disorder, conduct disorder, Down syndrome, impulsive symptoms associated with dementia, and borderline personality disorder.

[0050] Item 29. The use of a compound or its salt as described in any one of items 1 to 5 as a medicine.

[0051] Item 30. A method for preventing and / or treating diseases of the central nervous system, said method comprising administering to a person or animal a compound or a salt thereof as described in any one of Items 1 to 5.

[0052] Item 31. The method according to Item 30, wherein the central nervous system disorder is selected from schizophrenia, treatment-resistant, treatment-intractable or chronic schizophrenia, schizoaffective disorder, psychotic disorder, mood disorder, bipolar disorder, mania, depression, endogenous depression, major depressive disorder, melancholic and treatment-resistant depression, dysphoric disorder, cyclothymic mood disorder, anxiety disorder, somatic symptom disorder, affective disorder, dissociative disorder, sexual dysfunction, eating disorder, sleep disorder, adjustment disorder, substance-related disorder, loss of interest, 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 caused by treatment-resistant, treatment-intractable or chronic schizophrenia, vomiting, motion sickness, obesity, migraine, pain, intellectual disability, autism, Tourette syndrome, tic disorder, attention deficit hyperactivity disorder, conduct disorder, Down syndrome, impulsive symptoms associated with dementia, and borderline personality disorder.

[0053] Item A-1. A compound or a salt thereof represented by formula (I):

[0054] in

[0055] R 1 and R 2 Each is represented independently -O - or -OR 4 , R 3 Indicates hydrogen or alkyl. R 4 Represents hydrogen or an alkyl group optionally having 1 to 3 substituents, wherein R 4 The alkyl group may have some carbon atoms replaced by -O- and / or -(CO)O-, and If R 1 and R 2 Both indicate -OR 4 Then R 4 They can be the same or different.

[0056] Item A-2. The compound or its salt as described in item A-1, wherein

[0057] By R 4 The carbon atom of the terminal methyl group of the alkyl group is replaced by -O- or -(CO)O-. The -O- or -(CO)O- has a substituent R bonded at one end thereto. C1 ,and R C1 It represents hydrogen, lower alkyl, optionally substituted cycloalkyl, or optionally substituted heterocyclic group.

[0058] Item A-3. The compound or its salt according to Item A-1 or A-2, wherein the alkyl substituents optionally having 1 to 3 substituents are

[0059] (i) Substituents attached to the carbon atom of an alkyl group, or

[0060] (ii) A substituent (R) attached to one end of the -O- or -(CO)O- group. C1 ), in The substituent in (i) is a halogen, hydroxyl, lower alkyl, lower alkoxy, cycloalkyl, carboxyl, lower alkylaminocarbonyl, or optionally substituted heterocyclic group, and (ii) substituents (R) C1 () is hydrogen, a lower alkyl group, an optionally substituted cycloalkyl group, or an optionally substituted heterocyclic group.

[0061] Item A-4. A compound or a salt thereof according to any one of items A-1 to A-3, wherein the compound represented by formula (I) is a compound represented by formula (II):

[0062] Where R 3 and R 4 As defined above.

[0063] Item A-5. The compound or salt thereof described in any one of items A-1 through A-4, in R 3 Indicates hydrogen or C 1-6 alkyl, R 4 C represents hydrogen or optionally has 1 to 3 substituents. 1-18 Alkyl, wherein R 4 The alkyl group may have 1 to 5 carbon atoms replaced by -O- and / or -(CO)O-, and If R 1 and R 2 Both indicate -OR 4 Then R 4 They can be the same or different.

[0064] Item A-6. The compound or salt thereof described in any one of items A-1 through A-5, in R 4 C represents hydrogen or optionally has 1 to 3 substituents. 1-18 alkyl, Each of the substituents independently represents hydrogen, halogen, hydroxyl, lower alkoxy, or -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 Cycloalkyl or optionally substituted heterocyclic groups, R 5 R 5a R 6 R 9 R 10 and R 13 Independently representing hydrogen and C 1-16 Alkyl or C 3-7 cycloalkyl, R 7and R 8 Independently representing hydrogen or optionally having one or two carbon atoms replaced by oxygen or nitrogen atoms, R 7 and R 8 They can combine to form rings. R 11 and R 12 Independently representing hydrogen or C 1-16 Alkyl groups, wherein two or more R groups are present 11 Then the two or more R 11 Independently representing hydrogen or C 1-16 Alkyl groups, and if two or more R groups are present 12 Then the two or more R 12 Independently representing hydrogen or C 1-16 alkyl, n represents an integer from 1 to 10 (1, 2, 3, 4, 5, 6, 7, 8, 9, or 10), and If R 1 and R 2 Both indicate -OR 4 Then R 4 They can be the same or different.

[0065] Item A-7. The compound or salt thereof described in any one of items A-1 through A-6, in R 4 Indicates hydrogen or -(AY) m -R 14 , A represents C 1-18 Alkylene Y represents a bond, -O-, -(CO)O-, -O(CO)O-, or -(CO)NH-. R 14 Indicates hydrogen, C 1-18 Alkyl, hydroxyl, cycloalkyl, or heterocyclic groups, and m represents an integer from 0 to 5 (0, 1, 2, 3, 4 or 5).

[0066] Item A-8. A compound or a salt thereof as described in any one of items A-4 to A-6, in R 4 C represents hydrogen or optionally has a substituent. 1-8 alkyl, The substituents independently represent hydroxyl, lower alkoxy, -O-(CH2) n -OR 5 -O(CO)-(CH2) n -OR5a -(CO)OR 6 -O(CO)R 9 -O(CO)OR 10 -O(CO)-A-(CO)OR 13 Or optionally have two Cs 1-6 Alkyl morpholino, n represents an integer from 1 to 10. R 5 R 5a R 6 R 9 R 10 and R 13 Independently representing hydrogen and C 1-16 Alkyl, optionally substituted heterocyclic or C 3-7 cycloalkyl, and A represents C 1-6 Alkylene.

[0067] Item A-9. A compound or a salt thereof as described in any one of items A-4 to A-6, in R 4 C represents hydrogen or optionally has a substituent. 1-8 alkyl, The substituents independently represent hydroxyl, C 1-6 Alkyl group, -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 optionally have two Cs 1-6 alkyl heterocyclic groups, n represents an integer from 1 to 10. R 5 C represents 1-6 alkyl, R 5a C represents 1-6 alkyl, R 6 C represents 1-6 alkyl, R 9 C represents 1-16 alkyl, R 13 C represents 1-6 Alkyl groups or optionally having C 1-6 Alkyl pyridyl, and A represents C1-6 Alkylene.

[0068] Item A-10. A compound or a salt thereof according to any one of items A-4 to A-9, wherein the heterocyclic group has a structure in which hydrogen atoms bonded to constituent atoms of the heterocycle are removed from the heterocycle, the heterocycle being selected from furan, tetrahydropyran, tetrahydrofuran, 1,3-dioxane. Alkane, 1,4-di Alkane, pyrrole, imidazole, pyrazole, pyridine, pyrimidine, pyrazine, pyridazine, pyrrolidine, imidazoline, thiophene, piperidine, piperazine azole, isotonic azole, Diazole, morpholine, indole, indazole, benzimidazole, and quinoline.

[0069] Item A-11. A pharmaceutical composition comprising a compound or a salt thereof described in any one of items A-1 to A-10 and a pharmaceutically acceptable carrier.

[0070] Item A-12. A pharmaceutical composition according to item A-11, comprising a compound or a salt thereof, a suspending agent, and a dispersion medium according to any one of items A-1 to A-10, wherein the pharmaceutical composition is in the form of a suspension.

[0071] Item A-13. The pharmaceutical composition according to Item A-12, wherein the average particle size of the particles in the suspension is from 0.5 μm to 30 μm.

[0072] Item A-14. The pharmaceutical composition according to Item A-12, wherein the average particle size of the particles in the suspension is from 50 nm to 500 nm.

[0073] Item A-15. A pharmaceutical composition according to any one of items A-12 to A-14, wherein the suspending agent is carboxymethyl cellulose or a salt thereof, and the dispersion medium is a liquid containing water for injection.

[0074] Item A-16. A pharmaceutical composition comprising a viscous mixture of the following substances: a) The compound or its salt described in any of entries A-1 to A-10 b) Two or more lipids that form liquid crystals or lipids that form gels, and c) Biocompatible organic solvents, The pharmaceutical composition is a prodrug for forming a liquid crystal phase structure or lipid gel by contacting the pharmaceutical composition with an aqueous fluid in vivo.

[0075] Item A-17. The pharmaceutical composition according to Item A-16, wherein b) the two or more liquid crystal forming lipids or gel forming lipids contain

[0076] b-1) at least one diacylglycerol, and

[0077] b-2) At least one phosphatidylcholine.

[0078] Item A-18. A pharmaceutical composition comprising a viscous mixture of the following substances: a) The compound or its salt described in any of entries A-1 to A-10 b-1) At least one diacylglycerol, b-2) At least one phosphatidylcholine, and c) Biocompatible organic solvents.

[0079] Item A-19. A microsphere comprising a compound or a salt thereof as an active ingredient according to any one of items A-1 to A-10.

[0080] Item A-20. Microspheres according to item A-19, comprising a compound and a biodegradable polymer according to any one of items A-1 to A-10.

[0081] Item A-21. The microspheres according to Item A-20, wherein the biodegradable polymer is selected from at least one of polylactic acid and lactic acid-diol copolymers.

[0082] Item A-22. Microspheres according to any one of items A-19 to A-21, having an average particle size of 5 to 150 μm (preferably 30 to 100 μm).

[0083] Item A-23. A pharmaceutical composition comprising microspheres as described in any one of items A-19 to A-22, and in the form of a suspension.

[0084] Item A-24. A pharmaceutical composition comprising microspheres as described in any one of items A-19 to A-22, and in the form of an oil suspension.

[0085] Item A-25. The pharmaceutical composition according to Item A-24, wherein the oil is a medium-chain fatty acid triglyceride.

[0086] Item A-26. A pharmaceutical composition according to any one of items A-11 to A-18 and A-23 to A-25, for intramuscular or subcutaneous administration.

[0087] Item A-27. A pharmaceutical composition according to any one of items A-11 to A-18 and A-23 to A-26, for the prevention and / or treatment of diseases of the central nervous system.

[0088] Item A-28. A pharmaceutical agent for the prevention and / or treatment of diseases of the central nervous system, comprising a compound or a salt thereof as an active ingredient according to any one of items A-1 to A-10.

[0089] Item A-29. According to the medication described in entry A-28, the central nervous system disorder described therein is selected from schizophrenia, treatment-resistant, refractory or chronic schizophrenia, schizoaffective disorder, psychotic disorder, mood disorder, bipolar disorder, mania, depression, endogenous depression, major depressive disorder, melancholic and treatment-resistant depression, dysphoric disorder, cyclothymic mood disorder, anxiety disorder, somatic symptom disorder, affective disorder, dissociative disorder, sexual dysfunction, eating disorder, sleep disorder, adjustment disorder, substance-related disorder, loss of interest, 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 caused by treatment-resistant, refractory or chronic schizophrenia, vomiting, motion sickness, obesity, migraine, pain, intellectual disability, autism, Tourette syndrome, tic disorder, attention deficit hyperactivity disorder, conduct disorder, Down syndrome, impulsive symptoms associated with dementia, and borderline personality disorder.

[0090] Item A-30. The use of a compound or its salt as described in any of items A-1 through A-10 as a medicine.

[0091] Item A-31. A method for preventing or treating diseases of the central nervous system, the method comprising administering to a person or animal a compound or a salt thereof as described in any one of items A-1 to A-10.

[0092] Item A-32. According to the method described in entry A-31, the central nervous system disorder is selected from schizophrenia, treatment-resistant, refractory or chronic schizophrenia, schizoaffective disorder, psychotic disorder, mood disorder, bipolar disorder, mania, depression, endogenous depression, major depressive disorder, melancholic and treatment-resistant depression, dysphoric disorder, cyclothymic mood disorder, anxiety disorder, somatic symptom disorder, affective disorder, dissociative disorder, sexual dysfunction, eating disorder, sleep disorder, adjustment disorder, substance-related disorder, loss of interest, 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 caused by treatment-resistant, refractory or chronic schizophrenia, vomiting, motion sickness, obesity, migraine, pain, intellectual disability, autism, Tourette syndrome, tic disorder, attention deficit hyperactivity disorder, conduct disorder, Down syndrome, impulsive symptoms associated with dementia, and borderline personality disorder.

[0093] In the above entries, the "heterocycle" of the optionally substituted heterocyclic group is, for example, a saturated or unsaturated monocyclic or polycyclic heterocycle containing 1 to 5 heteroatoms independently selected from nitrogen, oxygen and sulfur as the atoms constituting the ring, and includes, for example, saturated or unsaturated monocyclic, bicyclic or tricyclic heterocycles of 3 to 15 members, preferably 5 to 10 members.

[0094] Specifically, examples of heterocyclic compounds include furan, tetrahydropyran, tetrahydrofuran, and 1,3-dihydropyran. Alkane, 1,4-di Alkane, pyrrole, imidazole, pyrazole, pyridine, pyrimidine, pyrazine, pyridazine, pyrrolidine, imidazoline, thiophene, piperidine, piperazine azole, isotonic azole, Diazoles, morpholines, indoles, indazoles, benzimidazoles, and quinolines. Heterocyclic groups have structures in which hydrogen atoms bonded to constituent atoms of the heterocycle are removed from said heterocycle.

[0095] In the foregoing entries, the substituents of the optionally substituted heterocyclic group include halogen, hydroxyl, optionally halogenated, hydroxyl, oxo, or C. 1-6 alkoxy-substituted C 1-6 Alkyl groups, and C groups optionally substituted with halogens, hydroxyl groups, or oxo groups. 1-6 Alkyl group.

[0096] The number of substituents is, for example, 1, 2 or 3.

[0097] Advantages of the present invention

[0098] The compound represented by formula (I) has a structure in which a specific nitrogen atom of epipiperazole is chemically modified. Upon administration of the compound represented by formula (I) in vivo, the compound is converted to epipiperazole under physiological conditions.

[0099] The compounds represented by formula (I) encompass (1) compounds with relatively low cytotoxicity. The compounds represented by formula (I) encompass (2) highly stable and easily manipulated compounds. The compounds represented by formula (I) encompass (3) compounds with relatively rapid subcutaneous absorption. The compounds represented by formula (I) encompass (4) compounds that are rapidly converted to epipiperazole in vivo. The compounds represented by formula (I) encompass (5) compounds suitable for injection, particularly subcutaneous injection. The compounds represented by formula (I) encompass (6) compounds suitable for long-acting injection, particularly long-acting subcutaneous injection, which maintains epipiperazole concentrations in the blood for 1 to 4 weeks or longer. Attached Figure Description

[0100] Figure 1 The graph shows the change in plasma drug concentration after subcutaneous administration of the drug composition of Example A (dose: 1.25 mg / kg) to rats (N=3, mean ± standard deviation).

[0101] Figure 2 The graph shows the change in plasma drug concentration after subcutaneous administration of the drug composition of Example D (an aqueous suspension of the compound of Example 1) (dose: 31.3 mg / kg) to rats (N=3, mean ± standard deviation).

[0102] Figure 3 The graph shows the change in plasma drug concentration after subcutaneous administration of the drug composition of Example E (an aqueous suspension of the zinc salt of the compound of Example 1) (dose: 33.2 mg / kg) to rats (N=3, mean ± standard deviation).

[0103] Figure 4 The graph shows the change in plasma drug concentration after subcutaneous administration of the pharmaceutical composition of Example F (a liquid crystal / lipogel formulation of the compound of Example 1) (dose: 31.3 mg / kg) to rats (N=3, mean ± standard deviation).

[0104] Figure 5 The graph shows the change in plasma drug concentration after subcutaneous administration of the drug composition of Example G (a liquid crystal / lipid gel formulation of the zinc salt of the compound of Example 1) (dose: 33.2 mg / kg) to rats (N=3, mean ± standard deviation).

[0105] Figure 6 The results of polarized light microscopy observations of the microspheres of Production Example I are shown.

[0106] Figure 7 The results of polarized light microscopy observations of the microspheres of production example J are shown.

[0107] Figure 8 The results of polarized light microscopy observations of the microspheres produced in Example K are shown.

[0108] Figure 9 This is a graph showing the change in plasma drug concentration after subcutaneous administration of the drug composition of Example H (microsphere formulation of the compound of Example 1 (RG 505, 1.5 times the API)) (dose: 31.3 mg / kg) to rats (N=5 up to day 14, N=3 after day 21, mean ± standard deviation).

[0109] Figure 10 This is a graph showing the change in plasma drug concentration after subcutaneous administration of the drug composition of Example J (microsphere formulation of the compound of Example 1 (RG 504, 2 times the API)) (dose: 31.3 mg / kg) to rats (N=5 up to day 14, N=3 after day 21, mean ± standard deviation).

[0110] Figure 11 This is a graph showing the change in plasma drug concentration after subcutaneous administration of the drug composition of Example K (microsphere formulation of the compound of Example 1 (RG 503, 1.5 times the API)) (dose: 31.3 mg / kg) to rats (N=5 up to day 14, N=3 after day 21, mean ± standard deviation).

[0111] Figure 12 The graph shows the change in plasma drug concentration after subcutaneous administration of the drug composition of Example L (microsphere formulation of the compound of Example 1 (RG 503, 2 times the API)) (dose: 31.3 mg / kg) to rats (N=3, mean ± standard deviation).

[0112] Figure 13 The graph shows the change in plasma drug concentration after subcutaneous administration of the drug composition of Example P (an aqueous suspension of the compound of Example 3) (dose: 29.8 mg / kg) to rats (N=5, mean ± standard deviation).

[0113] Figure 14 The graph shows the change in plasma drug concentration after subcutaneous administration of the drug composition of Example Q (an aqueous suspension of the compound of Example 10) (dose: 35.5 mg / kg) to rats (N=3, mean ± standard deviation).

[0114] Figure 15The graph shows the change in plasma drug concentration after subcutaneous administration of the drug composition of Example R (an aqueous suspension of the compound of Example 12) (dose: 34.7 mg / kg) to rats (N=3, mean ± standard deviation).

[0115] Figure 16 The graph shows the change in plasma drug concentration after subcutaneous administration of the drug composition of Example S (an aqueous suspension of the compound of Example 13) (dose: 36.3 mg / kg) to rats (N=3, mean ± standard deviation).

[0116] Figure 17 The graph shows the change in plasma drug concentration after subcutaneous administration of the drug composition of Example T (an aqueous suspension of the compound of Example 44) (dose: 37.1 mg / kg) to rats (N=3, mean ± standard deviation).

[0117] Figure 18 The graph shows the change in plasma drug concentration after subcutaneous administration of the drug composition of Example U (an aqueous suspension of the compound of Example 92) (dose: 36.3 mg / kg) to rats (N=3, mean ± standard deviation).

[0118] Figure 19 The graph shows the change in plasma drug concentration after subcutaneous administration of the drug composition of Example V (an aqueous suspension of the compound of Example 121) (dose: 37.1 mg / kg) to rats (N=3, mean ± standard deviation). Detailed Implementation

[0119] Embodiments falling within the scope of this disclosure are described in more detail below. While this disclosure includes specific novel heterocyclic compounds and their salts (particularly pharmaceutically acceptable salts), pharmaceutical compositions containing said compounds and / or their salts as active ingredients, and their uses, this disclosure is not limited to these. This disclosure covers all matters disclosed in this specification and that may be recognized by those skilled in the art.

[0120] The specific novel heterocyclic compounds falling within the scope of this disclosure are compounds whose heterocycles are represented by formula (I):

[0121] in

[0122] R 1 and R 2 Each is represented independently -O - -OR 4 or -NR 4Na R 4Nb , R 3 Indicates hydrogen or alkyl. R 4 R 4Na and R 4Nb Each independently represents hydrogen or each optionally has one to three substituents: alkyl, alkenyl, dienyl, or ynyl, wherein R 4 R 4Na Or R 4Nb The alkyl group may have one or more methylene groups (-CH2-) surrounded by -O-, -S-, -CO-, -NH-, or -SiR. sia R sib The structure is replaced by - or -(CO)O-. R sia and R sib Same or different and indicating hydrogen or C 1-6 alkyl, If R 1 and R 2 Both indicate -OR 4 Then R 1 and R 2 They can be the same or different. If R 1 and R 2 Both indicate -NR 4Na R 4Nb Then R 1 and R 2 They can be the same or different.

[0123] R sia and R sib Same or different, and indicating hydrogen or C 1-6 alkyl.

[0124] In this specification, the compound represented by formula (I) is also referred to as "compound (I)".

[0125] In this specification, alkenyl is, for example, a straight-chain or branched alkenyl group 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 Alkenyl), more preferably C 1-12 Alkenyl, more preferably C 1-8 alkenyl or C 1-6 Alkenyl. Due to the carbon-carbon double bond, alkenyl groups also include stereoisomers such as cis and trans. In this specification, dienyl is, for example, a straight-chain or branched dienyl group (C1) 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 Dienyl), more preferably C 1-12 diene group, more preferably C1-8 Dieneyl or C 1-6 Dienyl. Due to the carbon-carbon double bond, dienyl also includes stereoisomers such as cis and trans.

[0126] Specifically, dienyl includes dienyl having any of the structures (cis, cis), (cis, trans), (trans, cis), or (trans, trans), the order of which is based on the carbon-carbon double bond located closer to the dienyl end.

[0127] In this specification, the alkynyl group is, for example, a straight-chain or branched alkynyl group 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 (acetylenic group), more preferably C 1-12 Alkyne group, more preferably C 1-8 alkynyl or C 1-6 Alkyne group.

[0128] If R 4 R 4Na or R 4Nb If the expression indicates alkenyl, dienyl, or alkynyl, then the alkenyl group may have one or more (e.g., 1 to 3, preferably 1) substituents (substituent groups), the dienyl group may have one or more (e.g., 1 to 3, preferably 1) substituents (substituent groups), and the alkynyl group may have one or more (e.g., 1 to 3, preferably 1) substituents (substituent groups). Examples of such substituents include halogens, hydroxyl groups, lower alkyl groups, and lower alkoxy groups.

[0129] In this specification, alkyl is, for example, a straight-chain or branched alkyl group 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 Alkyl), more preferably C 1-18 Alkyl, more preferably C 1-16 Alkyl, C 1-12 Alkyl, C 1-8 Alkyl or C 1-6 alkyl.

[0130] More specifically, the alkyl group can be methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, isohexyl, 3-methylpentyl, heptyl, octyl, nonyl, decyl, tetradecyl, etc.

[0131] In this specification, R 4 R 4Na or R 4NbThe alkyl group represented includes one or more methylene groups (-CH2-) in its structure surrounded by -O-, -S-, -CO-, -NH-, -SiR-. sia R sib - or -(CO)O- substituted alkyl group. R sia and R sib Same or different, and indicating hydrogen or C 1-6 alkyl.

[0132] More specifically, in this specification, R 4 R 4Na or R 4Nb The alkyl group represented includes alkyl groups having the above-described substitution structure and alkyl groups without such substitution structure. Unless otherwise specified, it is defined by R. 4 R 4Na or R 4Nb Alkyl groups other than those indicated are alkyl groups without such substitution structures.

[0133] In the alkyl group having the substitution structure, the number of substituted methylene groups depends on the number of carbons in the alkyl group 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.

[0134] Preferably, R 1 and R 2 All are -OR 4 , or R 1 Yes -O - And R 2 Yes - OR 4 or NR 4Na R 4Nb .

[0135] If R 3 It is an alkyl group, with lower alkyl groups being particularly preferred; more specifically, C 1-4 Alkyl groups are preferred, and methyl or ethyl groups are even more preferred.

[0136] In this specification, when used with substituents having a carbon chain, "lower" means that the number of carbon atoms is 1 to 6 (1, 2, 3, 4, 5 or 6).

[0137] If R 4 R 4Na or R 4Nb If it is an alkyl group, then specifically, C 1-24 Alkyl groups are preferred, and C 1-18 Alkyl groups are preferred. As described above, alkyl groups may have substitution structures (where one or more methylene groups (-CH2-) are replaced by -O-, -S-, -CO-, -NH-, -SiR-). sia Rsib - or -(CO)O- replaced structures). As mentioned above, the number of substituted methylene groups depends on the number of carbons in the alkyl group 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. Independently composed of R 1 and R 2 -OR 4 or -NR 4Na R 4Nb In the middle, if the asterisk " "On one side of the oxygen atom (i.e., at -OR)" 4 or -NR 4Na R 4Nb If it combines with one side of a phosphorus atom, then -(CO)O- can be... -(CO)O- or -O(CO)-. If multiple methylene groups are replaced, the resulting structure (i.e., -O-, -S-, -CO-, -NH-, -SiR) is... sia R sib - or -(CO)O-) can be the same or different.

[0138] For example, -(CH2)2-O-(CH2)2-O-CH3 is an example where -O- replaces two methylene groups in -(CH2)6-CH3. As another example, -CH2-(CO)O-CH2-CH3 is... -(CO)O- is an example of replacing one methylene group in -(CH2)3-CH3. As another example, -(CH2)3-O(CO)-CH3 is... An example of -O(CO)- replacing a methylene group in -(CH2)4-CH3.

[0139] If R 4 R 4Na or R 4Nb If the alkyl group is indicated, then the alkyl group may have one or more (e.g., 1 to 3) substituents (substituent groups).

[0140] The substituent is bonded to the carbon atom of the alkyl group or to the nitrogen atom of the -NH- group replacing the methylene group; or if the methylene group at the alkyl terminus is... -CH2- If the underlined portion of H is replaced, then the substituent is bonded to one end of the replaced structure rather than to a hydrogen atom (i.e., if the substituent is specifically represented as "R"). C1 "Then the substituent is in the form of -OR C1 -SR C1 -CO-R C1 -NH-R C1 -SiRsia R sib -R C1 or-(CO)OR C1 or -O(CO)-R C1 (exists in the form of).

[0141] Examples of substituents incorporated into the carbon atom of an alkyl group include halogens, hydroxyl groups, alkyl groups (preferably lower alkyl groups), alkoxy groups (preferably lower alkoxy groups), cycloalkyl groups, carboxyl groups, alkylaminocarbonyl groups (preferably lower alkylaminocarbonyl groups), optionally substituted phenyl or benzyl groups, and optionally substituted heterocyclic groups (groups in which a hydrogen atom of the constituent atom of the optionally substituted heterocyclic group is removed from the heterocycle).

[0142] Examples of halogens in this specification include fluorine, chlorine, bromine, and iodine (F, Cl, Br, and I), wherein fluorine, chlorine, or bromine is preferred.

[0143] In this specification, alkylene is, for example, a straight-chain or branched alkylene having 1 to 20 carbon atoms.

[0144] More specific examples include methylene, ethylene, propylene, butylene, hexylene, heptylene, octylene, decylene, undecylene, dodecylene, 1-methylethylene, 2-ethylpropylene, 1-methylheptylene, 2-methylheptylene, 1-butylhexylene, 2-methyl-5-ethylheptylene, 2,3,6-trimethylheptylene, and 6-ethyldecylene.

[0145] In this specification, alkoxy groups are, for example, straight-chain or branched alkoxy groups having 1 to 6 carbon atoms (C... 1-6 Alkoxy); specific examples include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentoxy, isopentoxy, neopentoxy, hexoxy, isohexoxy, and 3-methylpentoxy.

[0146] In this specification, cycloalkyl is, for example, a cycloalkyl group having 3 to 7 (3, 4, 5, 6 or 7) carbon atoms (C 3-7 (Cycloalkyl); specific examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.

[0147] Cycloalkyl groups have a structure in which hydrogen atoms bonded to the carbon atoms constituting the cycloalkyl group are removed.

[0148] In this specification, "heterocycle" refers to, for example, a saturated or unsaturated monocyclic or polycyclic heterocycle containing 1 to 5 heteroatoms independently selected from nitrogen, oxygen, and sulfur as atoms constituting the ring, and includes, for example, saturated or unsaturated 3 to 15-member (preferably 5 to 10-member) monocyclic, bicyclic, or tricyclic heterocycles.

[0149] Specifically, examples of heterocyclic compounds include furan, tetrahydropyran, tetrahydrofuran, and 1,3-dihydropyran. Alkane, 1,4-di Alkane, pyrrole, imidazole, pyrazole, pyridine, pyrimidine, pyrazine, pyridazine, pyrrolidine, imidazoline, thiophene, piperidine, piperazine azole, isotonic azole, Diazoles, morpholines, indoles, indazoles, benzimidazoles, and quinolines. Heterocyclic groups have structures in which hydrogen atoms bonded to constituent atoms of the heterocycle are removed from said heterocycle.

[0150] Examples of lower alkylaminocarbonyl groups in this specification include methylaminocarbonyl, dimethylaminocarbonyl, ethylaminocarbonyl, propylaminocarbonyl, and isopropylaminocarbonyl.

[0151] The substituents of the optionally substituted phenyl or benzyl or optionally substituted heterocyclic groups can be, for example, with those derived from R. 4 The alkyl group represents the same substituent.

[0152] The substituents also include halogens, hydroxyl groups, optionally halogenated, hydroxyl-substituted, oxo-substituted, or C-substituted groups. 1-6 alkoxy-substituted C 1-6 Alkyl groups and C groups optionally substituted with halogens, hydroxyl groups, or oxo groups 1-6 Alkyl group.

[0153] The number of substituents in the optionally substituted phenyl or benzyl or optionally substituted heterocyclic group is, for example, 1, 2 or 3.

[0154] Among compounds falling within the scope of compound (I), where R 1 -O - R 2 Indicates -OR 4 or -NR 4Na R 4Nb And R 3 Compounds representing hydrogen or methyl are preferred.

[0155] In this case, R is more preferably 4 or -NR 4Na R 4Nb It is, for example, the following groups.

[0156] (R) 4 Preferred embodiment 1)

[0157] R 4 R represents 4a1 R 4a2 or R 4a3 .

[0158] R 4a1 express

[0159] -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 (preferably at -C) n H 2n-2 - containing a single carbon-carbon double bond) or -C n H 2n-4 -OH (more preferably in -C) n H 2n-4 - It has two carbon-carbon double bonds or a single carbon-carbon triple bond) (In the above chemical formula, n represents 1 to 24. n can represent, but is not limited to, 1 to 18, 1 to 12, 1 to 10, or 1 to 6. However, in -C n H 2n-1 In this context, n represents 2 or greater, and in -C n H 2n-3 In this context, n represents 2 or greater, and in -C n H 2n-2 - In this context, n represents 2 or greater, and in -C n H 2n-4 -In this context, n represents 2 or greater.

[0160] R 4a2 express

[0161] -CHX 1 X 2 , -C n-1 H 2n-2 -CHX 1 X 2 , -C n-1 H 2n-4 -CHX 1 X 2 (more preferably in -C) n-1 H 2n-4 - containing a single carbon-carbon double bond) or -C n-1 H 2n-6 -CHX 1 X 2 (more preferably in -C) n-1 H2n-6 - It has two carbon-carbon double bonds or a single carbon-carbon triple bond) (In the above chemical formulas, n represents 2 to 24. n can represent, but is not limited to, 2 to 18, 2 to 12, 2 to 10, or 2 to 6. However, in -C n-1 H 2n-6 -In this context, n represents 3 or greater.

[0162] X 1 and X 2 They may be the same or different and may represent hydrogen or halogen (F, Cl, Br or I). However, at least one of them is preferred to be a halogen.

[0163] R 4a3 express

[0164] -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 , (Where n represents 1 to 24. n can represent, but is not limited to, 1 to 18, 1 to 12, 1 to 10, or 1 to 6. However, in -C n H 2n-2 - In this context, n represents 2 or greater, and in -C n H 2n-4 - In this context, n represents 2 or greater. R 4-1 C represents 1-6 Alkoxy, -O-phenyl, or optionally C 1-6 Alkyl or halogen-substituted heterocyclic groups. R 4-1a and R 4-1b They can be the same or different and are represented by -C 1-3 Alkylene-C 1-3 Alkyl groups, or the same or different ones, and represented as -CO-OC 1-3 Alkyl or -CH2-CO-OC 1-3 Alkyl group). This also applies below.

[0165] If R 4-1 If it is the above heterocyclic group, then R 4-1 Preferred examples include, but are not particularly limited to, the following groups: .

[0166] (R) 4 Preferred embodiment 2)

[0167] R 4 R represents 4b ,and

[0168] R 4b express

[0169] -(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 chemical formulas, p represents 1 to 4, q represents 1 to 4, and r represents 1 to 4. However, in C...) p H 2p-2 p in C represents 2 or greater, and in C r H 2r-2 In this context, r represents 2 or greater. When q is 2 to 4, the number of repetitions represented by q (2 to 4 repeating structures) can be the same or different. R 4-2 Indicates hydrogen, hydroxyl, or "each optionally having 1 to 3 C-12 groups". 1-6 Alkyl, C 1-6 Alkoxy, -C 1-3 Alkylene-C 1-3 "Cycloalkyl, phenyl, benzyl, or heterocyclic groups with alkoxy and nitro substituents." This also applies below.

[0170] (R) 4 Preferred embodiment 3)

[0171] R 4 Indicates -C α H 2α-CO-OR COO or -C α H 2α -CO-O-CH2-R COO (α represents 1 to 10).

[0172] -R COO Represents hydrogen, each optionally bound by 1 to 3 carbon atoms. 1-6 alkoxy-substituted C 1-6 Alkyl or C 1-6 alkoxy groups, or each optionally having 1 to 3 C2 groups. 1-6 Alkyl, C 1-6 Alkoxy, -C 1-3 Alkylene-C 1-3 The alkyl, phenyl, benzyl, or heterocyclic groups are substituents of alkoxy and nitro groups. This also applies below.

[0173] R 4 Preferably, -C α H 2α -CO-OR COO .

[0174] -R COO Preferably, it represents hydrogen or optionally 1 to 3 carbon atoms. 1-6 alkoxy-substituted C 1-6 alkyl.

[0175] (R) 4 (Preferred embodiment 4)

[0176] R 4 Indicates -C β H 2β -O-CO-R OCO (β represents 1 to 10).

[0177] -R OCO R represents 4a1 R 4b or -C α H 2α -CO-OR COO ; 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 ; or each may optionally have 1 to 3 selected from C 1-6 Alkyl, C 1-6 Alkoxy, -C 1-3 Alkylene-C1-3 Alkoxy and nitro substituents are cycloalkyl, phenyl, benzyl, or heterocyclic groups.

[0178] This also applies to the following text.

[0179] (R) 4 (Preferred embodiment 5)

[0180] R 4 Indicates -C γ H 2γ -O-CO-OR OCOO (γ represents 1 to 10).

[0181] -R OCOO Represents hydrogen, R 4a1 R 4b or -C α H 2α -CO-OR COO ; or each may optionally have 1 to 3 selected from C 1-6 Alkyl, C 1-6 Alkoxy, -C 1-3 Alkylene-C 1-3 The alkyl, phenyl, benzyl, or heterocyclic groups are substituents of alkoxy and nitro groups. This also applies below.

[0182] (NR) 4Na R 4Nb Preferred embodiment i)

[0183] R 4Na and R 4Nb Same or different, and indicates that it is optionally controlled by 1 to 3 Cs. 1-6 alkoxy-substituted C 1-6 alkyl.

[0184] (NR) 4Na R 4Nb Preferred embodiment ii)

[0185] R 4Na It represents hydrogen. R 4Nb Indicates that it can be arbitrarily divided by 1 to 3 Cs 1-6 alkoxy-substituted C 1-6 Alkyl; or -C α H 2α -CO-OR COO or -C α H 2α -CO-NH-R COO .

[0186] The letter symbols used in the preferred embodiments may be the same or different. For example, -R is explained in preferred embodiment 3, and also in preferred embodiments 4 and 5.COO Preferred examples 3 to 5: -R COO Within the above range, they can be the same or different.

[0187] Furthermore, the following shows when R 1 Yes -O - And R 2 Yes - OR 4 or NR 4Na R 4Nb At that time, R 2 Relative to R 1 and R 2 Preferred examples. In the table, the asterisk " " indicates R 2 It binds to one side of the phosphorus atom. This disclosure also covers any optical isomers of the structural formulas shown in the table.

[0188] .

[0189] In a more preferred embodiment, compound (I) is a compound represented by formula (II):

[0190] (where R) 3 and R 4 As defined above). In this specification, among compounds falling within the scope of compound (I), the compound represented by formula (II) is also specifically referred to as "compound (II)". Compound (II) has R in formula (I). 1 Yes -O - And R 2 Yes - OR 4 The structure.

[0191] Preferred examples of compound (II) are further described below. However, the above description also includes the description of compound (II), and compound (II) is not limited to the interpretations below.

[0192] Specifically, R4 It can be hydrogen or C24 with 1 to 3 substituents. 1-18 alkyl.

[0193] The substituents independently represent halogens, hydroxyl groups, lower alkoxy groups, 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 Cycloalkyl or optionally substituted heterocyclic groups. R 5 R 5a R 6 R 9 R 10 and R 13 Independently representing hydrogen and C 1-16 Alkyl, optionally substituted heterocyclic or C 3-7 Cycloalkyl. R 7 and R 8 Independently represents hydrogen or, optionally, a lower alkyl group in which one or two carbon atoms are replaced by oxygen or nitrogen atoms. R 7 and R 8 They can combine to form rings. R 11 and R 12 Independently representing hydrogen and C 1-16 Alkyl or C 3-7 cycloalkyl, wherein two or more R are present 11 Then the two or more R 11 Independently representing hydrogen and C 1-16 Alkyl or C 3-7 Cycloalkyl, and if two or more R are present 12 Then the two or more R 12 Independently representing hydrogen and C 1-16 Alkyl or C 3-7 Cycloalkyl. n represents an integer from 1 to 10 (1, 2, 3, 4, 5, 6, 7, 8, 9 or 10).

[0194] For alkyl groups, "optionally having one or two carbon atoms replaced by oxygen or nitrogen atoms" is synonymous with "one or more methylene groups (-CH2-) may be replaced by -O- or –NH".

[0195] Although there are no particular limitations, examples of optionally substituted heterocyclic groups include those described above as R. 4-1 The listed groups are optionally represented by C. 1-6 Alkyl or halogen-substituted heterocyclic groups. There are no particular restrictions, if R... 7 and R 8 The combination forms a ring, then -NR 7 R 8 Instances include those as R 4-1 The listed representations are optionally C 1-6 A heterocyclic group in which an alkyl or halogen-substituted group has a hydrogen atom that is bonded to a nitrogen atom removed from its structure.

[0196] R 4 More preferably, it is hydrogen or optionally C having a substituent. 1-8 alkyl.

[0197] The substituents independently represent hydroxyl, lower alkoxy, -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 optionally have two Cs 1-6 Alkyl morpholino. R 5 R 5a R 6 R 9 R 10 and R 13 Independently representing hydrogen and C 1-16 Alkyl, optionally substituted heterocyclic or C 3-7 Cycloalkyl. A represents C 1-6 Alkylene. n is as defined above.

[0198] R 4 More preferably, it is hydrogen or optionally C having a substituent. 1-8 Alkyl group. The substituents independently represent hydroxyl, C... 1-6 Alkyl group, -O-(CH2) n -OR 5 -O(CO)-(CH2) n -OR 5a -(CO)OR 6 -O(CO)R 9 -O(CO)-A-(CO)OR 13Or optionally have two Cs 1-6 Alkyl heterocyclic group. R 5 C represents 1-6 Alkyl group. R 5a C represents 1-6 Alkyl group. R 6 C represents 1-6 Alkyl group. R 9 C represents 1-16 Alkyl group. R 13 C represents 1-6 Alkyl groups or optionally having C 1-6 pyridyl group of alkyl group. A represents C. 1-6 Alkylene. n is as defined above.

[0199] R 4 It also indicates hydrogen or -(AY). m -R 14 Where A represents C 1-18 Alkylene, Y represents bond, -O-, -(CO)O- or -(CO)NH-, R 14 Indicates hydrogen, halogen, C 1-18 Alkyl, hydroxyl, cycloalkyl or heterocyclic, and m represents an integer from 0 to 5 (0, 1, 2, 3, 4 or 5).

[0200] Independently by R 1 and R 2 -OR 4 In the middle, if the asterisk " "On one side of the oxygen atom (i.e., at -OR)" 4 If the phosphorus atom is bound to one side, then -(CO)O- can be... -(CO)O- or -O(CO)-, and -(CO)NH- can be -(CO)NH- or -NH(CO)-.

[0201] The following shows a more preferred example of a particular compound (I).

[0202]

[0203] In one embodiment, examples of diseases that can be prevented and / or treated with compound (I) or its salts include the following central nervous system disorders: schizophrenia, treatment-resistant, treatment-refractory or chronic schizophrenia, schizoaffective disorder, psychotic disorder, mood disorder, bipolar disorder, mania, depression, endogenous depression, major depressive disorder, melancholic and treatment-resistant depression, dysphoric disorder, cyclothymic mood disorder, anxiety disorder, somatic symptom disorder, affective disorder, dissociative disorder, sexual dysfunction, eating disorder, sleep disorder, and somatic symptom disorder. Response disorders, substance-related disorders, loss of interest, 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 caused by treatment-resistant, treatment-resistant, or chronic schizophrenia, vomiting, motion sickness, obesity, migraine, pain, intellectual disability, autism, Tourette syndrome, tic disorders, attention deficit hyperactivity disorder, conduct disorder, Down syndrome, impulsive symptoms associated with dementia, and borderline personality disorder.

[0204] General preparation method

[0205] Compound (I) can be prepared, for example, according to the general preparation methods described below. However, the methods are not limited to these methods.

[0206] The starting material compounds used can be commercial products or synthesized using known methods or methods equivalent to known methods.

[0207] The solvent, acid, base, protecting group, and leaving group used in the preparation of compound (I) can be any such material commonly used in the field of synthetic organic chemistry.

[0208] In the preparation of compound (I), the product, either in the form of a reaction solution or a crude product, can be used in subsequent reactions, or the product can be separated from the reaction mixture by commonly used methods and readily purified by conventional separation techniques. Examples of conventional separation techniques include filtration, extraction, condensation, evaporation, crystallization, recrystallization, redeposition, distillation, chromatography, and optical resolution.

[0209] In the preparation of compound (I), reactions such as alkylation, hydrolysis, amination, esterification, amidation, etherification, oxidation, and reduction can be carried out according to known methods.

[0210] These various commonly used reagents and methods are described in, for example, *Organic Functional Group Preparations* (2nd edition, Academic Press, Inc., 1989), *Comprehensive Organic Transformations* (VCH Publishers, Inc., 1989, PGM Wuts), and *Greene's Protective Groups in Organic Synthesis* (4th edition, 2006, TW Greene, John Wiley & Sons, New York, 1991).

[0211] In the general preparation method of compound (I), the starting material compound, intermediate compound and compound (I) can be in their salt form; the target compound obtained in each reaction can also be in salt form.

[0212] If these compounds are in free form, they can be converted into the desired salt form using known methods. If the compounds are in salt form, they can be converted into the free form or other desired salt form using known methods.

[0213] A method for preparing compound (II) is specifically described below. The method for preparing compound (II) described below is a specific example of a method for preparing compound (I). Those skilled in the art will understand that compound (I) can be prepared by performing the same operations according to the specific example. Those skilled in the art will also understand that compound (I) can be prepared according to the preparation method described in the examples, methods known in the art, or methods readily conceived from known methods.

[0214] Compound (II) can be prepared, for example, according to the preparation methods described below. The preparation methods described below are merely examples and are not intended to limit the ways in which compound (II) can be prepared. In the reaction formulas below, each starting material compound may form a salt if it does not inhibit the reaction. The salt used can be one of those listed as examples of salts of compound (II).

[0215] For starting material compounds for which no specific preparation method is described, commercially available products may be used, or the starting material compounds may be prepared according to known methods or methods equivalent to known methods. The solvent, acid, base, protecting group, and leaving group used to prepare compound (II) may be any such materials commonly used in the field of synthetic organic chemistry.

[0216] In the preparation of compound (II), the product, either in the form of a reaction solution or a crude product, can be used in subsequent reactions, or the product can be separated from the reaction mixture by commonly used methods and readily purified by conventional separation techniques. Examples of conventional separation techniques include filtration, extraction, condensation, evaporation, crystallization, recrystallization, recrystallization, distillation, chromatography, and optical resolution.

[0217] More specifically, compound (II) can be synthesized, for example, by a method that is divided into steps A and B as described below.

[0218] Step A: Phosphoric acid coupling reaction

[0219] In the above formula, LG represents the leaving group, and R 15 This indicates an alkyl group optionally having 1 to 3 substituents, wherein some carbon atoms of the alkyl group may be replaced by -O- and / or -(CO)O-. Other letter symbols are as defined above. For those derived from R... 15 With respect to the alkyl group represented, for the above R 4 The explanation applies directly. R 4 and R 15 They can be the same or different, and preferably different. R 15 More preferably, it is an optional substituted straight-chain or branched alkyl group.

[0220] Compound (II-1) can be obtained by reacting compound (1) with compound (2) in an inert solvent, with or without a base (depending on the reaction conditions) (step A-1).

[0221] Compound (1) is epipipazole.

[0222] Compound (1) can be prepared according to the method described in PTL 1 (JP2006-316052A) and can be used in free or salt form. Examples of compounds (1) in salt form include inorganic acid salts, such as hydrochlorides, sulfates, phosphates, hydrobroms, hydroiodic acids and nitrates; organic acid salts, such as formates, propionates, oxalates, carbonates, picrates, methanesulfonates, ethanesulfonates, p-toluenesulfonates, acetates, citrates, tartrates, malonates, succinates, maleates, fumarates, malates and lactates; and amino acid salts, such as aspartate and glutamate.

[0223] Examples of leaving groups include halogen atoms (e.g., chlorine, bromine, and iodine), alkyl sulfonyloxy (e.g., methyl sulfonyloxy, ethyl sulfonyloxy, and trifluoromethyl sulfonyloxy), and aryl sulfonyloxy (e.g., benzene sulfonyloxy, p-toluene sulfonyloxy, 2,4,6-trimethylbenzene sulfonyloxy, 2-nitrobenzene sulfonyloxy, and 4-nitrobenzene sulfonyloxy).

[0224] Examples of inert solvents include water; alcohol solvents such as MeOH, EtOH, isopropanol, n-butanol, trifluoroethanol, and ethylene glycol; ketone solvents such as acetone and methyl ethyl ketone; and ether solvents such as THF, diethyl ether, and diethyl ether. Alkanes, Et2O, diisopropyl ether, cyclopentylmethyl ether, and diethylene glycol dimethyl ether; ester 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; haloalkanes solvents, such as chloroform, DCE, and DCM; other organic solvents; and mixtures of these solvents, wherein haloalkanes solvents (e.g., DCM) or aprotic polar solvents (e.g., MeCN) are preferred.

[0225] The base used can be selected, for example, from a variety of known inorganic and organic bases. Examples of inorganic bases include alkali metals (e.g., sodium and potassium), alkali metal bicarbonates (e.g., lithium bicarbonate, sodium bicarbonate, and potassium bicarbonate), alkali metal hydroxides (e.g., LiOH, NaOH, and KOH), alkali metal carbonates (e.g., Li₂CO₃, Na₂CO₃, K₂CO₃, and Cs₂CO₃), alkali metal lower alkoxides (e.g., sodium methoxide and sodium ethoxide), and alkali metal hydrides (e.g., NaH and KH). Examples of organic bases include trialkylamines (e.g., trimethylamine, TEA, and DIPEA), pyridine, quinoline, piperidine, imidazole, methylpyridine, dimethylaminopyridine, dimethylaniline, N-methylmorpholine, DBN, DABCO, and DBU. If these bases are liquids, they can also be used as solvents. These bases can be used alone or in combination of two or more. The amount of base used is typically 0.1 to 10 mol per mole of compound (1), preferably 0.1 to 5 mol.

[0226] The reaction conditions are not particularly limited, and the reaction can generally be carried out under cooling, room temperature, or heating conditions. Preferably, the reaction is carried out at a temperature in the range of room temperature to 100°C for 30 minutes to 350 hours, more preferably 1 hour to 200 hours, and particularly preferably 1 hour 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, but the reaction conditions are not limited (step A-2).

[0227] Examples of inert solvents include water; alcohol solvents such as MeOH, EtOH, isopropanol, n-butanol, trifluoroethanol, and ethylene glycol; ketone solvents such as acetone and methyl ethyl ketone; and ether solvents such as THF, diethyl ether, and diethyl ether. Alkanes, Et2O, diisopropyl ether, cyclopentylmethyl ether, and diethylene glycol dimethyl ether; ester 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; haloalkanes solvents, such as chloroform, DCE, and DCM; other organic solvents; and mixtures of these solvents, wherein haloalkanes solvents (e.g., DCM), aprotic polar solvents (e.g., MeCN), or ketone solvents (e.g., acetone) are preferred.

[0228] The base used can be selected from various known inorganic and organic bases. Examples of inorganic bases include alkali metals (e.g., sodium and potassium), alkali metal bicarbonates (e.g., lithium bicarbonate, sodium bicarbonate, and potassium bicarbonate), alkali metal hydroxides (e.g., LiOH, NaOH, and KOH), alkali metal carbonates (e.g., Li₂CO₃, Na₂CO₃, K₂CO₃, and Cs₂CO₃), alkali metal lower alkoxides (e.g., sodium methoxide and sodium ethoxide), and alkali metal hydrides (e.g., NaH and KH). Examples of organic bases include trialkylamines (e.g., trimethylamine, TEA, and DIPEA), pyridine, quinoline, piperidine, imidazole, methylpyridine, dimethylaminopyridine, dimethylaniline, N-methylmorpholine, DBN, DABCO, and DBU. If these bases are liquids, they can also be used as solvents. These bases can be used alone or in combination of two or more. The amount of base used is typically 0.1 to 10 mol per mole of compound (II-1), preferably 0.1 to 5 mol.

[0229] 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. These acids can be used in combination of two or more in appropriate proportions. The amount of acid used relative to compound (II-1) is typically in the range of 1 molar equivalent to excess. Examples of alkali metal halides include LiI, NaI, and KI. The amount of alkali metal halides used relative to compound (II-1) is typically in the range of 1 molar equivalent to excess.

[0230] There are no restrictions on the reaction conditions, and the reaction can generally be carried out under cooling, room temperature, or heating conditions. Preferably, the reaction is carried out at a temperature in the range of room temperature to 100°C for 0.5 to 350 hours.

[0231] Step B: Protect - Remove Protection

[0232] (In the above formula, PG represents the protecting group of the hydroxyl group, -OR) 16 Indicates alkoxy or -O - Other symbols are as defined above.

[0233] Compound (1) can be protected with a suitable protecting group to form compound (3) (step B-1), and undergo a phosphate coupling reaction (step A), then release the protecting group (step B-2) to synthesize compound (II), which is the final product (step B). In step A, the operation can be performed in step A-1 (i.e., reacting compound (3) with compound (2) to obtain the compound corresponding to compound (II-1) (i.e., where -OR) 16 The process ends after (4) which is an alkoxy compound, or step A-2 may be performed subsequently to obtain a compound corresponding to compound (II) (i.e., where -OR) 16 Yes -O - Compound (4)).

[0234] Step B-1: Protective reaction

[0235] The protecting group (-OPG) of the hydroxyl group can be any hydroxyl protecting group used in synthetic organic chemistry. Examples include ethers (e.g., methyl, methoxymethyl, benzyloxymethyl, methoxyethoxymethyl, 2-(trimethylsilyl)ethoxymethyl, methylthiomethyl, tetrahydropyranyl, benzoylmethyl, cyclopropylmethyl, allyl, isopreneyl, propargyl, tert-butyl, benzyl, 4-(dimethylamino)carbonylbenzyl, 4-methylsulfinylbenzyl, 9-anthraylmethyl, and 4-pyridylmethyl); and silyl ethers (e.g., trimethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl). Protecting groups include: triisopropylsilyl; esters (e.g., formate, acetate, levulinate, neopentanoate, benzoate, and 9-fluorenate); carbonates (e.g., methyl, tert-butyl, isopropyl, allyl, 4-methylsulfinylbenzyl, 2,2,2-trichloroethyl, vinyl, and benzyl); arylcarbamates (e.g., phenylcarbamate); phosphonites (e.g., dimethylphosphonooxy and dimethylthiophosphono); and sulfonates (e.g., methanesulfonate, trifluoromethanesulfonate, toluenesulfonate, and benzylmethylsulfonate). Preferred examples of protecting groups are ethers.

[0236] For example, the protective reaction can be carried out using compound (1) in an inert solvent in the presence of a base to obtain compound (3).

[0237] The base used can be, for example, a known inorganic base. Examples of inorganic bases include alkali metals (e.g., sodium and potassium), alkali metal bicarbonates (e.g., lithium bicarbonate, sodium bicarbonate, and potassium bicarbonate), alkali metal hydroxides (e.g., LiOH, NaOH, and KOH), alkali metal carbonates (e.g., Li₂CO₃, Na₂CO₃, K₂CO₃, and Cs₂CO₃), lower alkali metal alkoxides (e.g., sodium methoxide and sodium ethoxide), alkali metal hydrides (e.g., NaH and KH), and silver carbonate. The amount of base used relative to compound (1) is typically in the range of 1 molar equivalent to excess.

[0238] Examples of inert solvents include water; alcohol solvents such as MeOH, EtOH, isopropanol, n-butanol, trifluoroethanol, and ethylene glycol; ketone solvents such as acetone and methyl ethyl ketone; and ether solvents such as THF, diethyl ether, and diethyl ether. Alkanes, Et₂O, diisopropyl ether, cyclopentylmethyl ether, and diethylene glycol dimethyl ether; ester 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; halocarbon solvents, such as chloroform, DCE, and DCM; other organic solvents; and mixtures of these solvents. These inert solvents may be used in combination of two or more in appropriate proportions. Preferably, the inert solvent is an ether solvent, such as cyclopentylmethyl ether.

[0239] The reaction temperature is typically between -80 and 150°C.

[0240] The reaction time is typically 0.1 to 200 hours.

[0241] Step B-2: Deprotection reaction

[0242] Depending on the type of protecting group, the deprotection reaction of compound (4) can be a known reaction. For example, the deprotection reaction can be carried out by deprotecting compound (4) in an inert solvent or in solvent-free conditions, with or without an acid, to obtain compound (II).

[0243] 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. These acids may be used in combination of two or more in appropriate proportions. The amount of acid used relative to intermediate (4) is typically in the range of 1 molar equivalent to excess.

[0244] Examples of inert solvents include water; alcohol solvents such as MeOH, EtOH, isopropanol, n-butanol, trifluoroethanol, and ethylene glycol; ketone solvents such as acetone and methyl ethyl ketone; and ether solvents such as THF, diethyl ether, and diethyl ether. Alkanes, Et₂O, diisopropyl ether, cyclopentylmethyl ether, and diethylene glycol dimethyl ether; ester 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; haloalkanes solvents, such as chloroform, DCE, and DCM; other organic solvents; and mixtures of these solvents. These inert solvents may be used in combination of two or more in appropriate proportions.

[0245] The reaction temperature is typically between -80 and 150°C.

[0246] The reaction time is typically 0.1 to 200 hours.

[0247] Furthermore, various compounds (II) can also be obtained by using R in compound (II). 4 It is synthesized by substitution or condensation reactions of compounds containing hydrogen atoms (represented by compound (5) in the following formula). An example is described below.

[0248] Step C-1: Substitution reaction

[0249] In the above formula, LG represents the leaving group, and R 4 As defined above (but excluding hydrogen atoms).

[0250] Compound (5) can react with R, depending on the reaction conditions, in an inert solvent or in the absence of a solvent, in the presence or absence of a base. 4 -LG reaction to obtain compound (II) (step C-1: substitution reaction).

[0251] Examples of leaving groups include halogen atoms (e.g., chlorine, bromine, and iodine), alkyl sulfonyloxy (e.g., methyl sulfonyloxy, ethyl sulfonyloxy, and trifluoromethyl sulfonyloxy), and aryl sulfonyloxy (e.g., benzene sulfonyloxy, p-toluene sulfonyloxy, 2,4,6-trimethylbenzene sulfonyloxy, 2-nitrobenzene sulfonyloxy, and 4-nitrobenzene sulfonyloxy).

[0252] Examples of inert solvents include water; alcohol solvents such as MeOH, EtOH, isopropanol, n-butanol, trifluoroethanol, and ethylene glycol; ketone solvents such as acetone and methyl ethyl ketone; and ether solvents such as THF, diethyl ether, and diethyl ether. Alkanes, Et2O, diisopropyl ether, cyclopentylmethyl ether, and diethylene glycol dimethyl ether; ester 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; haloalkanes solvents, such as chloroform, DCE, and DCM; other organic solvents; and mixtures of these solvents, wherein aprotic polar solvents (e.g., MeCN), ketone solvents (e.g., acetone), or any mixture of these solvents are preferred.

[0253] The base used can be selected from various known inorganic and organic bases, for example.

[0254] Examples of inorganic bases include alkali metals (e.g., sodium and potassium), alkali metal bicarbonates (e.g., lithium bicarbonate, sodium bicarbonate, and potassium bicarbonate), alkali metal hydroxides (e.g., LiOH, NaOH, and KOH), alkali metal carbonates (e.g., Li₂CO₃, Na₂CO₃, K₂CO₃, and Cs₂CO₃), alkali metal lower alkoxides (e.g., sodium methoxide and sodium ethoxide), and alkali metal hydrides (e.g., NaH and KH). Examples of organic bases include trialkylamines (e.g., trimethylamine, TEA, and DIPEA), pyridine, quinoline, piperidine, imidazole, methylpyridine, dimethylaminopyridine, dimethylaniline, N-methylmorpholine, DBN, DABCO, and DBU. If these bases are liquids, they can also be used as solvents. These bases can be used alone or in combination of two or more.

[0255] The amount of base used is usually in the range of 1 molar equivalent to excess per mole of the compound to be reacted (5).

[0256] There are no particular restrictions on the reaction conditions. The reaction temperature is typically from -80°C to 150°C. The reaction time is typically from 0.1 hours to 200 hours.

[0257] Steps C-2 and C-2': Condensation reaction

[0258] In the above formula, R 4 As defined above (but excluding hydrogen atoms).

[0259] Compound (5) can react with an alcohol (R) in the presence or absence of a solvent, in the presence or absence of a base, or in the presence of a condensing agent, depending on the reaction conditions. 4 The reaction of OH) yields compound (II) (step C-2: condensation reaction).

[0260] Use amine (HNR) 4Na R 4Nb ) replacing alcohol also produces R in it. 1 Yes -O -And R 2 It is NR 4Na R 4Nb Compound (II') (Step C-2': Condensation reaction).

[0261] Examples of inert solvents include water; alcohol solvents such as MeOH, EtOH, isopropanol, n-butanol, trifluoroethanol, and ethylene glycol; ketone solvents such as acetone and methyl ethyl ketone; and ether solvents such as THF, diethyl ether, and diethyl ether. Alkanes, Et2O, diisopropyl ether, cyclopentylmethyl ether, and diethylene glycol dimethyl ether; ester 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; haloalkanes solvents, such as chloroform, DCE, and DCM; other organic solvents; and mixtures of these solvents, wherein haloalkanes solvents (e.g., DCM), aprotic polar solvents (e.g., MeCN and DMF), ketone solvents (e.g., acetone), or any mixture of these solvents with water are preferred.

[0262] The base used can be selected from a variety of known inorganic and organic bases. Examples of inorganic bases include alkali metals (e.g., sodium and potassium), alkali metal bicarbonates (e.g., lithium bicarbonate, sodium bicarbonate, and potassium bicarbonate), alkali metal hydroxides (e.g., LiOH, NaOH, and KOH), alkali metal carbonates (e.g., Li₂CO₃, Na₂CO₃, K₂CO₃, and Cs₂CO₃), alkali metal lower alkoxides (e.g., sodium methoxide and sodium ethoxide), and alkali metal hydrides (e.g., NaH and KH). Examples of organic bases include trialkylamines (e.g., trimethylamine, TEA, and DIPEA), pyridine, quinoline, piperidine, imidazole, methylpyridine, dimethylaminopyridine, dimethylaniline, N-methylmorpholine, DBN, DABCO, and DBU. If these bases are liquids, they can also be used as solvents. These bases can be used alone or in combination of two or more.

[0263] The amount of base used is usually in the range of 1 molar equivalent to excess per mole of the compound to be reacted (5).

[0264] The condensing agent used can be selected, for example, from a variety of known condensing agents. Examples include 3-ethyl-1-(3-dimethylaminopropyl)carbodiimide (WSC) or its HCl salt, 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU), 1-(chloro-1-pyrrolylmethylene)pyrrolidineonium hexafluorophosphate, N-cyclohexyl-N'-morpholinoethylcarbodiimide, N-cyclohexyl-N'-(4-diethylaminocyclohexyl)carbodiimide, N,N'-diethylcarbodiimide Amines, N,N'-diisopropylcarbodiimide, N,N'-carbonylbis(2-methylimidazolium), pentamethylenone-N-cyclohexylimide, diphenylenone-N-cyclohexylimide, ethoxyacetylene, 1-alkoxy-1-chloroethylene, trialkyl phosphite, ethyl polyphosphate, isopropyl polyphosphate, phosphorus oxychloride (phosphoryl chloride), phosphorus trichloride, diphenylphosphoryl azide, thionyl chloride, oxalyl chloride, alkyl halogenated formates such as ethyl chloroformate and isopropyl chloroformate, triphenylphosphine, 2-ethyl-7-hydroxybenzisyl Azoxylium salt; 2-ethyl-5-(m-sulfonylphenyl)iso Azolium hydroxide inner salts; benzotriazol-1-yloxy-tris(dimethylamino)hexafluorophosphate phosphonium, 1-(p-chlorobenzenesulfonyloxy)-6-chloro-1H-benzotriazine, and Vilsmeier reagents prepared by reacting DMF with thionyl chloride, phosgene, trichloromethyl chloroformate, phosphorus oxychloride, etc.

[0265] There are no particular restrictions on the reaction conditions. The reaction temperature is typically from -80°C to 150°C. The reaction time is typically from 0.1 hours to 200 hours.

[0266] Furthermore, various compounds (II) can also be synthesized by acylation of compound (5). Acylation is one implementation method of C-1 (substitution reaction). An example is described below.

[0267] Step C-3: Acylation reaction

[0268] In the above formula, R 17 and R 18 Preferably, alkyl groups having, for example, 1 to 3 substituents (e.g., C10, C20, C30, C40, C50, C60, C70, C80, C9 ... 1-18 Alkyl group). R 17 and R 18 They can be the same or different.

[0269] For example, compound (5) can be reacted with an acylating agent, such as carboxylic anhydride, in the presence of a base, in an inert solvent or in the absence of a solvent, depending on the reaction conditions, to obtain compound (II) (step C-3: acylation reaction).

[0270] Examples of inert solvents include water; alcohol solvents such as MeOH, EtOH, isopropanol, n-butanol, trifluoroethanol, and ethylene glycol; ketone solvents such as acetone and methyl ethyl ketone; and ether solvents such as THF, diethyl ether, and diethyl ether. Alkanes, Et2O, diisopropyl ether, cyclopentylmethyl ether, and diethylene glycol dimethyl ether; ester 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; haloalkanes solvents, such as chloroform, DCE, and DCM; other organic solvents; and mixtures of these solvents, wherein haloalkanes solvents (e.g., DCM), aprotic polar solvents (e.g., MeCN and DMF), or ketone solvents (e.g., acetone) are preferred.

[0271] The base used can be selected from a variety of known inorganic and organic bases. Examples of inorganic bases include alkali metals (e.g., sodium and potassium), alkali metal bicarbonates (e.g., lithium bicarbonate, sodium bicarbonate, and potassium bicarbonate), alkali metal hydroxides (e.g., LiOH, NaOH, and KOH), alkali metal carbonates (e.g., Li₂CO₃, Na₂CO₃, K₂CO₃, and Cs₂CO₃), alkali metal lower alkoxides (e.g., sodium methoxide and sodium ethoxide), and alkali metal hydrides (e.g., NaH and KH). Examples of organic bases include trialkylamines (e.g., trimethylamine, TEA, and DIPEA), pyridine, quinoline, piperidine, imidazole, methylpyridine, dimethylaminopyridine, dimethylaniline, N-methylmorpholine, DBN, DABCO, and DBU. If these bases are liquids, they can also be used as solvents. These bases can be used alone or in combination of two or more.

[0272] The amount of base used is usually in the range of 1 molar equivalent to excess per mole of the compound to be reacted (5).

[0273] There are no particular restrictions on the reaction conditions. The reaction temperature is typically from -80°C to 150°C. The reaction time is typically from 0.1 hours to 200 hours.

[0274] In this specification, compound (I), starting material compound, and intermediate compound may be used in the form of chemically acceptable geometric isomers, stereoisomers, optical isomers, or tautomers. These isomers may be isolated according to common optical resolution methods or prepared from the corresponding optically active starting material compound.

[0275] In this specification, compound (I), starting material compound, and intermediate compound may be in the form of salts. 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 into a target salt according to known methods. If the compound is a salt, it can be converted into its free form or another target salt according to known methods. Examples of such salts are described below.

[0276] The salt is preferably a pharmaceutically acceptable salt; for example, metal salts (e.g., alkali metal salts, alkaline earth metal salts, and zinc salts) are preferred. Acid addition salts and base addition salts are also preferred. Examples of acids used for 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 used in base addition salts include metals, such as alkali metals (e.g., sodium and potassium) and alkaline earth metals (e.g., calcium and magnesium); inorganic bases, such as alkali metal carbonates (e.g., lithium carbonate, potassium carbonate, sodium carbonate, and cesium carbonate), alkali metal bicarbonates (e.g., lithium bicarbonate, sodium bicarbonate, and potassium bicarbonate), and alkali metal hydroxides (e.g., lithium hydroxide, sodium hydroxide, potassium hydroxide, calcium hydroxide, and cesium hydroxide); organic bases, such as methylamine, diethylamine, trimethylamine, triethylamine, N-ethyldiisopropylamine, ethanolamine, diethanolamine, triethanolamine, ethylenediamine, tri(hydroxymethyl)methylamine, dicyclohexylamine, N,N'-diphenylmethylethylenediamine, guanidine, pyridine, quinoline, piperidine, imidazole, dimethylaminopyridine, dimethylaniline, methylpyridine, choline, N-methylmorpholine, DBN, DBU, and DABCO; amino acids, such as lysine and arginine; and ammonia.

[0277] Compound (I) or its salts may also be used in various solvates (especially hydrates). Compound (I) or its salts may also be used in crystalline polymorphs. Compound (I) or its salts may also be used in pharmaceutically acceptable eutectic or eutectic salt forms.

[0278] Eutectic or eutectic salt refers to a crystalline substance composed of two or more distinct substances that are solid at room temperature, each of which has different physical properties (e.g., structure, melting point, and heat of fusion). Eutectic and eutectic salt can be produced according to known co-crystallization methods.

[0279] Compound (I) includes compounds in which one or more atoms of formula (I) are replaced by one or more isotopic atoms. Examples of isotopic atoms include deuterium (…). 2 H), tritium ( 3 H) 13C 15 N and 18 O. Compound (I) also includes compounds labeled with various radioactive or non-radioactive isotopes.

[0280] Compound (I) can be used in combination with various therapeutic or preventative agents for diseases that can be treated with compound (I). The combined compound (I) and the therapeutic or preventative agent can be administered simultaneously, or they can be administered sequentially or at desired time intervals. Formulations for simultaneous administration of compound (I) and the therapeutic or preventative agent can be combinations of combined drugs or individually formulated preparations.

[0281] The following describes a pharmaceutical preparation containing compound (I) as an active ingredient (hereinafter referred to as the "pharmaceutical composition").

[0282] The pharmaceutical formulation is a formulation of compound (I) in a common pharmaceutical formulation form, and is prepared by using compound (I) or its salts and a pharmaceutically acceptable carrier. Such carriers include commonly used fillers, extenders, binders, humectants, disintegrants, surfactants, lubricants, suspending agents, solubilizers, isotonic agents, diluents such as solvents, and excipients.

[0283] Such pharmaceutical preparations may be selected from various forms according to the therapeutic purpose, such as tablets, pills, powders, liquids, suspensions, emulsions, granules, capsules, suppositories, injections, nasal sprays, and inhalers, with injections being particularly preferred. The injections include those for intramuscular administration and those for subcutaneous administration, with those for subcutaneous administration being particularly preferred.

[0284] The carrier used to form tablets can be selected from a variety of known carriers. Examples include excipients such as lactose, sucrose, sodium chloride, glucose, urea, starch, calcium carbonate, kaolin, and crystalline cellulose; binders such as water, ethanol, propanol, simple syrup, dextran solution, starch solution, gelatin solution, carboxymethyl cellulose, shellac, methyl cellulose, potassium phosphate, and polyvinylpyrrolidone; disintegrants such as dry starch, sodium alginate, agar powder, kelp polysaccharide powder, sodium bicarbonate, calcium carbonate, polyoxyethylene sorbitan fatty acid ester, sodium lauryl sulfate, glyceryl monostearate, starch, and lactose; disintegration inhibitors such as sucrose, stearin, cocoa butter, and hydrogenated oil; absorption promoters such as quaternary ammonium bases and sodium lauryl sulfate; humectants such as glycerin and starch; adsorbents such as starch, lactose, kaolin, bentonite, and colloidal silica; and lubricants such as purified talc, stearates, boric acid powder, and polyethylene glycol.

[0285] In addition, the tablets may optionally be formulated as tablets with common coatings, such as sugar-coated tablets, gelatin-coated tablets, enteric-coated tablets, film-coated tablets, or bilayer or multilayer tablets.

[0286] The carrier used to form the pellet can be selected from a variety of known carriers. Examples include excipients such as glucose, lactose, starch, cocoa butter, hydrogenated vegetable oil, kaolin, and talc; binders such as gum arabic, tragacanth, gelatin, and ethanol; and disintegrants such as laminarin and agar.

[0287] The carrier used to form the suppository can be selected from a variety of known carriers. Examples include polyethylene glycol, cocoa butter, higher alcohols, esters of higher alcohols, gelatin, and semi-synthetic glycerides.

[0288] If the pharmaceutical preparation is prepared in the form of an injection, the liquid, emulsion or suspension is sterilized and preferably isotonic with blood.

[0289] The diluents used to form these liquids, emulsions, or suspensions can be selected from widely used known diluents, such as water, ethanol, propylene glycol, ethoxylated isostearyl alcohol, polyoxyethylene isostearyl alcohol, and polyoxyethylene sorbitol fatty acid esters.

[0290] In this case, the pharmaceutical preparation may contain salts, glucose, amino acids or glycerol sufficient to prepare an isotonic solution, as well as commonly used solubilizers, buffers, pain relievers, etc., and may also contain preservatives, stabilizers, antioxidants, solubilizers, pH adjusters and other drugs if desired.

[0291] Epilippazole is known to be used to relieve symptoms associated with severe agitation, destructiveness, and violent behavior in Alzheimer's disease. Since immediately released injectable antipsychotic drugs are known to be used as therapeutic agents to relieve symptoms in acute-phase patients with severe agitation, destructiveness, and violent behavior in conditions such as schizophrenia, it is anticipated that injectable formulations of epipiperazole that are immediately released into the bloodstream could be used as therapeutic agents to relieve symptoms in acute-phase patients with agitation in both schizophrenia and Alzheimer's disease. Pharmaceutical compositions containing compound (1) and designed, as needed, to be in a preferred injectable form are intended to provide immediate therapeutic effects through subcutaneous or intramuscular administration and by immediately delivering a therapeutically effective amount of epipiperazole into the patient's bloodstream within a short time (e.g., several hours) for use in the acute phase of agitation, etc. Examples of preferred injectable forms for use in the acute phase include injectable formulations 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, wherein appropriate isotonic agents, buffers, pH adjusters, solubilizers, etc., are added as needed.

[0292] Examples of the solubilizers include polysorbate 80, polysorbate 60, polyoxyethylene hardened castor oil 60, poloxamer, β-cyclodextrin, and sulfobutyl ether-β-cyclodextrin.

[0293] 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 glycerol. The composition may be free of isotonic agents. If an isotonic agent is included, the concentration of the isotonic agent in the composition is preferably such that the osmotic pressure of the solution is isotonic. The concentration depends on the type of isotonic agent. For example, in the case of alkali metal chlorides, the concentration is preferably 0.5 to 20 mg / mL, more preferably 2 to 10 mg / mL; in the case of sugar alcohols and sugars, the concentration is preferably 10 mg / mL to 200 mg / mL, more preferably 20 to 100 mg / mL.

[0294] Examples of the buffer include phosphates, such as sodium phosphate, sodium dihydrogen 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; and tris(hydroxymethyl)aminomethane (Tris). The concentration of the buffer in the composition is, for example, from 0.01 to 5.0 mg / mL, preferably from 0.1 to 2 mg / mL.

[0295] The pH adjuster may be an acidic pH adjuster or an alkaline pH adjuster. Examples of acidic pH adjusters include hydrochloric acid, phosphoric acid, acetic acid, and citric acid. Examples of alkaline pH adjusters include sodium hydroxide, potassium hydroxide, calcium carbonate, magnesium oxide, and magnesium hydroxide. The pH adjuster is typically added in an appropriate amount according to the desired pH of the composition.

[0296] Examples of biocompatible organic solvents include organic solvents miscible with water. Examples of such solvents include alcohols such as ethanol, propanol, isopropanol, propylene glycol, and glycerol, as well as dimethyl sulfoxide, N-methyl-2-pyrrolidone, polyethylene glycol 300, and polyethylene glycol 400.

[0297] Agitation associated with schizophrenia, depression, and Alzheimer's disease is typically treated with once-daily tablets. However, in cases involving medication refusal or agitation, tablet administration can be difficult. In such cases, long-acting injectable formulations (preferably subcutaneous) administered daily to every few days are considered useful because drug administration can be reliably performed and are convenient to use. Pharmaceutical compositions containing compound (1) and designed, as needed, preferably in injectable form, are expected to provide efficacy for one to several days, even in patients who have difficulty taking tablets, through subcutaneous or intramuscular administration and by continuously delivering a therapeutically effective amount of epipiperazole into the patient's bloodstream over a relatively short period of time (one to several days).

[0298] In the treatment of schizophrenia, long-acting injectable formulations are a useful dosage form that can improve treatment and prevention in patients with poor medication adherence. Generally, for a drug to exert its therapeutic effect, it is desirable for the blood concentration to reach the therapeutic range immediately and then be maintained at a certain level. Although aripiprazole and palapirone palmitate formulations (trade names: IM ABILIFY long-release aqueous suspension for injection and IM XEPLION aqueous suspension for injection) are used clinically as typical long-acting injectable formulations for schizophrenia, these drugs have poor solubility and dissolve slowly after administration; therefore, it is necessary to use oral medications in combination or shorten the injection interval at the start of treatment to compensate for the blood drug concentration. Pharmaceutical compositions containing compound (1) and designed as a preferred injectable form according to medical needs have been shown to improve treatment and prevention in patients with poor medication adherence by administering subcutaneously or intramuscularly and by continuously delivering a therapeutically effective amount of epipirazole into the patient's bloodstream immediately and over a relatively short period of time (one to four weeks or longer), even in patients who are not expected to have sufficient treatment or prevention effects due to poor medication adherence.

[0299] Examples of preferred injectable forms of long-acting injectable ipilapiazole for continuous delivery for one to several days or one to four weeks or longer include pharmaceutical compositions in suspension form containing compound (1), a suspending agent and a dispersion medium.

[0300] 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 higher based on epipiperazole, preferably 100 mg / mL or higher, more preferably 150 mg / mL or higher, and even more preferably 200 mg / mL or 250 mg / mL or higher. There is no particular upper limit, for example, 1000 mg / mL or lower, 750 mg / mL or lower, or 500 mg / mL or lower. For example, the concentration used can be in the range of 50 to 1000 mg / mL.

[0301] There are no particular limitations on the suspending agent contained in the composition, as long as it is pharmaceutically acceptable and can achieve the desired viscosity. Examples of suspending agents include carboxymethyl cellulose and its salts; polyoxyethylene-polyoxypropylene block copolymers, such as poloxamer; and polyethylene glycol (also known as "polyethylene glycol").

[0302] Examples of salts of carboxymethyl cellulose include metal salts, such as alkali metal salts and ammonium salts. Specific examples include sodium carboxymethyl cellulose, potassium carboxymethyl cellulose, lithium carboxymethyl cellulose, ammonium carboxymethyl cellulose, and mixtures thereof. In one embodiment, the suspending agent preferably contains carboxymethyl cellulose and / or its sodium salt, particularly preferably sodium carboxymethyl cellulose. The suspending agent can be used alone or in combination of two or more. The concentration of the suspending agent in the composition is, for example, 0.1 mg / mL or higher, preferably 0.2 mg / mL or higher, more preferably 0.5 mg / mL or higher. The concentration of the suspending agent in the composition is, for example, 100 mg / mL or lower, preferably 50 mg / mL or lower, more preferably 25 mg / mL or lower. The concentration of the suspending agent in the composition is, for example, from 0.1 to 50 mg / mL.

[0303] The dispersion medium contained in the composition is not particularly limited, as long as it is pharmaceutically acceptable and capable of dispersing the active ingredient. The dispersion medium can be used alone or in combination of two or more different types. The dispersion medium preferably contains at least water. Examples of dispersion media include water, physiological saline, and solvents containing water and the aforementioned biocompatible organic solvents. In a preferred embodiment, the dispersion medium is water, and particularly preferably purified water, sterile purified water, water for injection, etc., are used.

[0304] The composition may further comprise any additives. The additives may be any pharmaceutically acceptable additives, and may be, for example, the isotonic agents, buffers, and pH adjusters described above. The additives may be used alone or in combination of two or more.

[0305] The average particle size of the suspended compound (1) is, for example, 0.1 to 30 μm, preferably 0.5 to 20 μm. These ranges are preferred for maintaining its effect over a long period. On the other hand, in order to obtain a high blood concentration immediately after administration, the average particle size of the suspended compound (1) is preferably, for example, 500 nm or less, more preferably 50 to 500 nm. The average particle size is measured by laser diffraction scattering. To measure the average particle size by laser diffraction scattering, for example, SALD-3100 or SALD-2300 (manufacturer: Shimadzu Corporation) can be used.

[0306] For the preparation method of the composition, a wet milling method is preferably used. The wet milling method is preferably wet ball milling, high-pressure homogenization, high-shear homogenization, bead milling (e.g., Dyno Mill), etc. In addition to these milling methods, other methods may be used, such as low-energy and high-energy milling (e.g., roller milling). Examples of other preparation methods include controlled crystallization.

[0307] In one embodiment, the composition can be prepared by, for example, a method comprising step 1 of mixing compound (1), a suspending agent, and a dispersion medium, step 2 of bead milling the suspension obtained by mixing, and step 3 of removing the beads from the suspension obtained by bead milling. In step 1, there is no particular limitation on the mixing order of each component. In one embodiment, step 1 includes mixing the components other than the active ingredient to obtain a media solution, and mixing the media solution with the active ingredient. In step 2, there is no particular limitation on the bead milling method. In one embodiment, step 2 is the addition of beads to the suspension followed by stirring. Examples of the bead material include zirconium oxide, 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 bead milling can be appropriately adjusted by, for example, adjusting the bead size, the rotational speed (circumferential speed) during milling, and the milling time. In step 3, there is no particular limitation on the method used to remove the beads. In one embodiment, step 3 is the step of collecting the composition using an injection needle (e.g., 22G or smaller), a pipette, or a mesh filter with a pore size smaller than a bead (e.g., an 80 μm mesh filter).

[0308] Another example of a preferred injectable form of a long-acting injectable form of ipilipazole delivered continuously for one to several days or one to four weeks or longer includes a pharmaceutical composition which is a low-viscosity prodrug containing a mixture of compound (1), two or more lipids that form liquid crystals or lipids that form gels, and at least one biocompatible organic solvent, and which forms or is capable of forming at least one liquid crystal phase structure or lipid gel when in vivo in contact with an aqueous fluid.

[0309] The prodrug formulation typically contains no significant amount of water prior to administration and is a low-viscosity liquid or suspension in which two or more liquid crystal-forming lipids or gel-forming lipids are dissolved in a biocompatible organic solvent. The liquid crystal-forming lipids or gel-forming lipids are specific types of amphiphilic components, and the combination of at least one diacylglycerol and at least one phosphatidylcholine is preferred. A low-viscosity solution can be prepared by dissolving the liquid crystal-forming lipids or gel-forming lipids in at least one biocompatible organic solvent, and a prodrug formulation, preferably a low-viscosity liquid or suspension, can be prepared by dissolving or suspending compound (1) in these solutions. Upon administration, this prodrug formulation forms a liquid crystal phase structure or a high-viscosity lipid gel by contacting an aqueous fluid in vivo. Typically, the aqueous fluid is a bodily fluid, particularly extravascular fluid, extracellular / interstitial fluid, or plasma, and the prodrug formulation forms a liquid crystal phase structure or a high-viscosity lipid gel by contacting such fluid (e.g., bodily fluid).

[0310] The prodrug formulation, as a low-viscosity liquid or suspension, represents a liquid or suspension that can be readily administered to a subject, and more specifically, a mixture that can be readily administered using a device consisting of a standard syringe or needle. In a particularly preferred embodiment, the medium preceding the prodrug formulation or suspension of compound (1) should be a mixture that can pass through a standard sterile filter membrane, such as a 0.22 μm syringe filter. A typical range of suitable viscosity at 20°C is 0.1 to 5000 mPa. s, preferably 1 to 1000 mPa s, more preferably 1 to 500 mPa s.

[0311] The above viscosity was measured using a rotational rheometer at a temperature of 20°C and a shear rate in the range of 9000 to 10000 (1 / s). Examples of rotational rheometers include the Discovery Hybrid Rheometer-2 (DHR-2) and the Discovery Hybrid Rheometer-3 (DHR-3) (manufacturer: TA Instruments).

[0312] When the amphiphilic compound (two or more lipids that form liquid crystals or lipids that form gels) is exposed to an aqueous fluid after administration in vivo, the prodrug formulation can form a liquid crystal structure known as a lyotropic liquid crystal. Known examples of such liquid crystal structures include hexagonal structures in which cylindrical aggregates form a hexagonal crystal system, layered structures, inverse hexagonal structures in which water is introduced into the cylinders and the hydrophobic portions are directed outward, cubic structures in which spherical micelles form a cubic system in an aqueous (or oil) continuous phase, and bicontinuous cubic structures in which lipid bilayers are arranged in three dimensions to form curved surfaces. The inventors have discovered that, upon administration of the prodrug formulation in vivo, the liquid crystal or lipid gel forms, thereby controlling the release of compound (1) after administration, and the released compound (1) is converted into epipiperazole in vivo, enabling continuous delivery of epipiperazole.

[0313] The formation of the gel or liquid crystal can be confirmed by injecting the precursor formulation into water and observing the formation of agglomerates. Liquid crystal formation can be confirmed by analyzing the obtained agglomerates using small-angle X-ray scattering (SAXS). In some cases, the liquid crystal can form in a gel state (liquid crystal gel).

[0314] Diacylglycerol has two nonpolar "tail" groups. These two nonpolar groups can be the same or different, can have the same or different numbers of carbon atoms, and can each be independently saturated or unsaturated. Both 1,3-diacylglycerol and 1,2-diacylglycerol can be used. Examples of nonpolar groups include C6-C. 32 Alkyl and C6-C 32 Alkenyl groups are typically found as esters of long-chain carboxylic acids. Their description is usually made by referring to the number of carbon atoms in the carbon chain and the degree of unsaturation. Therefore, CX:Z represents a hydrocarbon chain, where X represents the number of carbon atoms and Z represents the degree of unsaturation. Specifically, examples include hexanoyl (C6:0), octanoyl (C8:0), decanoyl (C10:0), lauroyl (C12:0), myristoyl (C14:0), palmitoyl (C16:0), phytanoyl (C16:0), palmitoleoyl (C16:1), stearoyl (C18:0), oleoyl (C18:1), transoleoyl (C18:1), linoleoyl (C18:2), linolenic acid (C18:3), arachidonic acid (C20:4), behenoyl (C22:0), and creosyl (C24:9).

[0315] Therefore, typical nonpolar chains include hexanoic acid, caprylic acid, capric acid, lauric acid, myristic acid, palmitic acid, phytic acid, palmitoleic acid, stearic acid, oleic acid, transoleic acid, linoleic acid, linolenic acid, arachidonic acid, behenic acid, and lignanic acid, as well as those chains of fatty acids based on natural ester lipids containing alcohols corresponding to these fatty acids. Preferred nonpolar chains include palmitic acid, stearic acid, oleic acid, and linoleic acid, with oleic acid being particularly preferred.

[0316] There are no particular limitations on diacylglycerols, but diacylglycerols having, for example, the same or different nonpolar chains described above are preferred. Among them, glyceryl dioleate (GDO) is particularly preferred.

[0317] The diacylglycerol can be used alone or in combination of two or more.

[0318] Phosphatidylcholine (PC) is a general term for phospholipids having a structure in which choline is a hydrophilic moiety of glycerophospholipids bonded with phosphate esters, while two fatty acids are hydrophobic moieties bonded to the glycerol backbone esters. Due to the wide variety of fatty acid combinations, many phospholipids belong to the phosphatidylcholine family. Examples of preferred phospholipid sources include eggs, hearts (e.g., beef heart), brains, and livers (e.g., beef liver), as well as plant sources including soybeans. Single PCs or mixtures of multiple PCs derived from such material sources can be used. Soybean PC (SPC) or egg-derived PCs or mixtures thereof are preferred, with substantially pure SPCs (high-purity SPCs) being most preferred.

[0319] The lipids used to form liquid crystals or gels are preferably a combination of at least one diacylglycerol and at least one phosphatidylcholine. Specifically, the use of a combination of one or more diacylglycerols and one or more phosphatidylcholine mentioned above is preferred. A particularly preferred combination of the lipids used to form liquid crystals or gels is a combination of GDO and PC, especially a combination of GDO and soybean PC and / or egg PC.

[0320] The biocompatible organic solvent is preferably a water-miscible organic solvent, typically including at least one solvent selected from alcohols, ketones, esters (including lactones), ethers, amides, and sulfoxides. Alcohols are particularly suitable, forming a suitable solvent group. Examples of suitable alcohols include ethanol, isopropanol, propylene glycol, glycerol, and glycerol formaldehyde, with ethanol being the most preferred. Examples of ketones include acetone, n-methylpyrrolidone (NMP), 2-pyrrolidone, and propylene carbonate. Examples of suitable ethers include diethyl ether, tetrahydrofuran polyethylene glycol ether, diethylene glycol monoethyl ether, dimethyl isobarbide, and polyethylene glycol. Examples of suitable esters include ethyl acetate and isopropyl acetate. Dimethyl sulfide is a suitable sulfide solvent. Examples of suitable amides and sulfoxides include dimethylacetamide (DMA) and dimethyl sulfoxide (DMSO), respectively. The biocompatible organic solvent can be used alone or in combination of two or more.

[0321] In a low-viscosity precursor formulation comprising a mixture of two or more liquid crystal-forming lipids or gel-forming lipids and at least one biocompatible organic solvent, a combination of SPC, GDO, and ethanol is preferred, and a combination of SPC, GDO, ethanol, and DMSO is also suitable. The preferred low-viscosity precursor formulation is prepared by dissolving or suspending compound (1) in a solution comprising two or more liquid crystal-forming lipids or gel-forming lipids and at least one biocompatible organic solvent.

[0322] Another example of a preferred injectable form of a long-acting injectable formulation for continuous delivery of ipilipazole for one to several days or one to four weeks or longer includes microspheres containing compound (1) as the active ingredient. Microspheres here generally refer to spherical formulations with particle sizes ranging from about a few micrometers to tens of micrometers and may have an uneven surface. The microspheres of this disclosure typically contain a carrier, such as a base polymer (e.g., a biodegradable polymer).

[0323] To achieve the desired controlled-release performance of compound (I), the average particle size of the microspheres disclosed herein is preferably 5 to 150 μm, more preferably 10 to 120 μm, even more preferably 20 to 100 μm, and even more preferably 30 to 85 μm. To achieve the desired controlled-release performance, the average particle size can be decreased if a faster absorption rate is required, and increased if a slower absorption rate is required.

[0324] To achieve the desired controlled-release properties of compound (I) and the desired changes in epipiperazole blood drug concentration, the inclusion percentage of compound (I) in the microspheres of this disclosure is preferably 80% or higher. To increase the inclusion percentage, the amount of the main drug added to the batch formulation can be increased.

[0325] In the microspheres of this disclosure, from the perspective of obtaining the desired controlled-release performance of compound (I) and the desired change in blood drug concentration of epipiprazole, the content of compound (I) is preferably 10 to 50% by weight, more preferably 20 to 45% by weight, and even more preferably 30 to 40% by weight.

[0326] The microspheres of this disclosure preferably comprise a biodegradable polymer as the base polymer. The biodegradable polymer used in this disclosure can be one that gradually degrades in vivo to achieve the desired sustained-release properties. Examples include homopolymers and copolymers, such as polylactic acid, polyglycolic acid, lactic acid-glycolic acid copolymer (polylactic acid-co-glycolic acid: PLGA), polycitric acid, polymalic acid, lactic acid-aspartic acid copolymer, lactic acid-hydroxyhexanoic acid copolymer, glycolic acid-hydroxyhexanoic acid copolymer, polypropiolactone, polybutyrolactone, polyvalerol, polycaprolactone, polypropylene carbonate, polydioxane, poly(p-dioxane), poly(α-cyanoacrylate), poly(β-hydroxybutyrate), polypropylene oxalate, polyorthoester, polyorthocarbonate, polyethylene carbonate, poly(γ-phenylmethyl-L-glutamic acid), poly(L-alanine), polyalginate, polycarbonate, polyesteramide, polyamino acid, polyalkylene alkylene compounds, polyethylene glycol, and polyurethane. Polylactic acid and lactic acid-glycolic acid copolymers are preferred. These biodegradable polymers can be used alone or in combination of two or more.

[0327] When used, the molecular weight of polylactic acid or lactic acid-glycolic acid copolymer can be suitably selected in a wide range, and is typically from about 2,000 to 200,000, preferably from about 4,000 to 100,000, and more preferably from about 10,000 to 70,000.

[0328] The molecular weight mentioned above refers to the weight-average molecular weight of polystyrene measured by gel permeation chromatography (GPC) using polystyrene as a reference material.

[0329] There are no particular restrictions on the ratio of lactic acid to glycolic acid (lactide: glycolide) in the lactic acid-glycolic acid copolymer, and it can be appropriately selected from a wide range; it is usually about 99:1 to 1:99 in terms of molecular number, and preferably about 85:15 to 50:50 in terms of molecular number.

[0330] The polylactic acid can be poly-D-lactic acid, poly-L-lactic acid, or poly-DL-lactic acid, preferably poly-DL-lactic acid. The lactic acid-glycolic acid copolymer can be D-lactic acid-glycolic acid copolymer, L-lactic acid-glycolic acid copolymer, or DL-lactic acid-glycolic acid copolymer, and preferably DL-lactic acid-glycolic acid copolymer.

[0331] The polylactic acid or lactic acid-glycolic acid copolymer used can be produced by known methods or can be a commercial product (e.g., Resomer and Lactel (produced by Evonik)).

[0332] In addition to the biodegradable polymers described herein, the microspheres of this disclosure may also contain non-degradable biocompatible polymers. The microspheres of this disclosure may also contain any additives, such as emulsifiers.

[0333] The microspheres of this disclosure can be produced using the components listed above, according to methods known in the field of pharmaceutical formulation. From the viewpoint of obtaining microspheres with excellent sustained-release properties, excellent flowability upon filling, and excellent syringe penetration upon administration, the microspheres of this disclosure are preferably prepared by a method comprising the steps of: dissolving or suspending compound (I) or its salt and a biodegradable polymer in an organic solvent, emulsifying the solution or suspension with or without an emulsifier, and then removing the organic solvent. This method may further include steps known in the field of pharmaceutical formulation (e.g., filtration and granulation steps).

[0334] The method for producing the microspheres of this disclosure is described in more detail below.

[0335] The method for preparing microspheres disclosed herein includes the following steps: 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 the mixture with or without an emulsifier to obtain an emulsion; and removing the organic solvent from the obtained emulsion.

[0336] 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 or suspended in the organic solvent. The biodegradable polymer is preferably dissolved in the organic solvent.

[0337] The organic solvent used to produce the microspheres of this disclosure can be any organic solvent capable of dissolving the biodegradable polymer. Examples include halogenated hydrocarbons, such as chloroform, dichloroethane, trichloroethane, dichloromethane, and carbon tetrachloride; ethers, such as diethyl 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; acetone; and other organic solvents that are miscible with or immiscible with water. These organic solvents can be used alone or in combination of two or more. Among them, organic solvents immiscible with water are preferred, and dichloromethane is particularly preferred.

[0338] An acid or base may 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, with acetic acid being particularly preferred.

[0339] The ratio of compound (I) or its salt to organic solvent is generally such that the amount of compound (I) or its salt per 100 parts by weight of organic solvent is about 0.01 to 30 parts by weight, preferably about 0.1 to 20 parts by weight, more preferably about 1 to 10 parts by weight.

[0340] The ratio of biodegradable polymer to organic solvent is typically such that for every 100 parts by weight of organic solvent, the amount of biodegradable polymer is 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.

[0341] Next, the obtained organic solvent solution or suspension (containing compound (I), the biodegradable polymer, and the organic solvent) is emulsified. That is, the obtained organic solvent solution is mixed with water (i.e., the external phase) to obtain an O / W emulsion in which the organic solvent solution is uniformly dispersed in water, or the obtained organic solvent suspension is mixed with water (i.e., the external phase) to obtain an S (solid) / O / W emulsion in which the suspension is uniformly dispersed in water.

[0342] There are no particular restrictions on the water used, but water accepted in the pharmaceutical formulation field, such as purified water and water for injection, is preferred.

[0343] There are no particular restrictions on the ratio of organic solvent solution or suspension to water, as long as an O / W or S / O / W emulsion with the desired particle size is obtained. The ratio typically results in an amount of about 0.001 to 0.2 parts by volume of water, preferably about 0.005 to 0.1 parts by volume, and more preferably about 0.01 to 0.05 parts by volume per volume part.

[0344] In this disclosure, emulsifiers may be used even when using organic solvents that are miscible or immiscible with water. If a water-miscible organic solvent is used, an emulsifier is preferably used. The emulsifiers used in this disclosure can be any emulsifier capable of forming O / W or S / O / W emulsions, preferably stable O / W or S / O / W emulsions. 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, carboxymethyl cellulose, lecithin, gelatin, and hyaluronic acid. These emulsifiers may be used alone or in combination of two or more.

[0345] The emulsifier can be added to the aqueous phase before emulsification.

[0346] There are no particular restrictions on the amount of emulsifier used, and it can be selected from a wide range. 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, and more preferably about 0.001 to 5% by weight.

[0347] There are no particular limitations on the preparation method of the O / W or S / O / W emulsion. The emulsion can be prepared by dispersing the organic solvent solution or suspension (containing compound (I) or its salt, a biodegradable polymer, and an organic solvent) as droplets or micelles of suitable size in water. Examples of preparation methods include: purifying the solution or suspension in water by stirring a mixture of the solution or suspension with water at an appropriate rotational speed in a homogenizer or the like to obtain an O / W or S / O / W emulsion; purifying the solution or suspension by passing a mixture of the solution or suspension with water at a constant rate through a filter with fine perforations, such as a ceramic filter, to obtain an O / W or S / O / W emulsion; and purifying the solution or suspension by passing it at a constant rate through a filter with fine perforations, such as a ceramic filter, and then mixing it with water.

[0348] If necessary, the emulsion formation can be performed in multiple steps.

[0349] The desired particle size can be obtained by adjusting the stirring force during emulsion formation. In other words, the particle size can be reduced by increasing the stirring force during emulsion formation.

[0350] An aqueous suspension of microspheres is obtained by removing the organic solvent from the obtained O / W or S / O / W emulsion.

[0351] The organic solvent can be removed using common methods. For example, the removal can be achieved by heating while stirring with a propeller or magnetic stirrer, by gradually reducing the pressure, or by desorption using a rotary evaporator or similar method with adjusted vacuum.

[0352] The resulting microsphere suspension can be washed, if necessary, with the addition of a suitable solution or solvent to remove free compounds (I) adhering to the microsphere surface. Examples of cleaning solutions and solvents include ethanol and alkaline solutions, such as 1N sodium hydroxide solution. The microspheres separated by centrifugation or filtration are washed several times with distilled water, and, if necessary, with a suitable solution or solvent to remove free compounds (I), emulsifiers, etc., adhering to the microsphere surface. Examples of cleaning solutions and solvents include ethanol and alkaline solutions, such as 1N sodium hydroxide solution. After separation, the microspheres are heated if necessary to more completely desorb water from the microspheres under reduced pressure and to desorb the solvent from the microspheres. The washed microspheres can be resuspended in water in the presence or in the presence of sugars, sugar alcohols, or other additives, and then freeze-dried to obtain microsphere powder. There are no particular limitations on the freeze-drying conditions, as long as the microspheres can be dried.

[0353] Furthermore, the dried microspheres can be sieved as needed to obtain microspheres with the desired average particle size.

[0354] The microspheres of this disclosure, particularly those obtained by the above-described production method, exhibit excellent sustained-release properties. The microspheres of this disclosure can release compound (I) or its salt at a therapeutic dose for at least one week, preferably two, three, or four weeks, more preferably six weeks or longer. The microspheres of this disclosure can exhibit the aforementioned effects, particularly when suspended in water for injection to obtain an aqueous suspension for injection.

[0355] The microspheres of this disclosure obtained by the above preparation method generally have a spherical shape. Due to their spherical shape, the microspheres of this disclosure have excellent flowability during production and good syringe penetration (needle penetration) during application, and cause less irritation at the injection site when administered as an intramuscular or subcutaneous injection.

[0356] The microspheres of this disclosure can be administered to a patient, for example, as an aqueous suspension containing microspheres containing compound (I), a medium thereof, and water for injection. Alternatively, in another embodiment, the microspheres of this disclosure can be administered to a patient, for example, as an oil suspension containing microspheres containing compound (I), optionally a medium thereof, and an oil. For example, triglycerides (especially medium-chain triglycerides) are suitable as the oil used herein.

[0357] There are no particular limitations on the microsphere content in the suspension injection of this disclosure, as long as the microspheres are dispersed in the injection, and it is generally about 5 to 50% by weight, preferably about 10 to 40% by weight, more preferably about 10 to 30% by weight.

[0358] Examples of media used in this disclosure include the aforementioned suspending agents, isotonic agents, buffers, and pH adjusters.

[0359] In this specification, the term "therapeuticly effective amount" refers to the amount that, when administered to humans or non-human animals, effectively provides therapeutic benefit (e.g., symptom relief). Of course, the specific dosage of the substance administered to obtain therapeutic benefit will depend, for example, on the specific circumstances, such as the specific substance to be administered, the route of administration, the pathological condition to be treated, and the individual to be treated. For example, the pharmaceutical preparation may contain 1 to 70% by weight of compound (I) or a salt thereof, based on the amount of compound (I).

[0360] For example, for subcutaneous or intramuscular administration, a satisfactory daily dose can be in the range of about 0.001 to 1.5 mg / kg. The daily dose for subcutaneous or intramuscular administration can range from about 0.1 mg to 500 mg, preferably from 0.1 mg to 100 mg, which can be suitably administered once daily or divided into two to four daily doses. Therefore, a unit dosage form for subcutaneous or intramuscular administration can contain, for example, an amount of compound (I) from about 0.1 mg to 500 mg, or a salt thereof, and a pharmaceutically acceptable diluent or carrier. The upper or lower limit of this range (0.1 mg to 500 mg) can 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, more preferably 0.5 to 10 mg.

[0361] In this specification, the term "pharmaceutical acceptable" means that a compound, a composition comprising the compound, or a dosage form thereof falls within a reasonable benefit / risk ratio and is suitable for use in humans or animals without causing excessive toxicity, irritation, allergic reactions, etc.

[0362] Although there are no particular limitations, pharmaceutical preparations containing compound (I) or its salts are preferably, for example, injectable formulations. These injectable formulations include those for intramuscular administration or those for subcutaneous administration, with those for subcutaneous administration being particularly preferred.

[0363] In this specification, the terms "comprising" and "containing" also include "consistently composed of" and "comprises of". Furthermore, this disclosure covers any combination of the constituent elements described in this specification.

[0364] Furthermore, in describing the subject matter covered by this disclosure, the various features (properties, structures, functions, etc.) described in each embodiment of this disclosure above can be combined in any way. In other words, this disclosure covers all subject matter including all combinations of the composable features described in this specification.

[0365] Example

[0366] The embodiments of this disclosure are described in more detail below with reference to the examples. However, the embodiments of this disclosure are not limited to the following examples.

[0367] The following abbreviations may be used in this article.

[0368] REX: Reference Example Number

[0369] EX: Example number

[0370] STR: structural formula

[0371] Data: Physical property data (NMR1: 1 δ (ppm) in dimethyl sulfoxide-d6 in H-NMR; NMR2: 1 δ (ppm) in CDCl3 in H-NMR; NMR3: 1 δ (ppm) in CD3OD in H-NMR; NMR4: 1 δ (ppm) in CD3CO2D in H-NMR, or MS: mass spectrometry

[0372] In addition, the following abbreviations may be used for compound and reagent names.

[0373] Table 1E

[0374] In the examples described below, "room temperature" is typically between about 10 and 35°C. Unless otherwise stated, the ratios of the mixed solvents are by volume. Unless otherwise stated, the unit "%" indicates a weight percentage.

[0375] 1 H NMR (proton nuclear magnetic resonance spectroscopy) is measured by Fourier transform NMR (Bruker Avance III 400 (400 MHz), Bruker Avance Neo 400 (400 MHz) or Bruker Avance III HD (500 MHz)).

[0376] Example 1 (EX 1)

[0377] To a mixture of 7-(4-(benzo[b]thiophene-4-yl-piperazin-1-yl)butoxy)-1H-quinoline-2-one (3.0 g), MeCN (30 mL), and DCM (90 mL), NaI (2.074 g), K2CO3 (1.913 g), and di-tert-butyl(chloromethyl) phosphate (3.58 g) was added, and the resulting mixture was stirred at room temperature. After three days, di-tert-butyl(chloromethyl) phosphate (1.790 g) and NaI (1.037 g) were added and stirred. After another four days, water was added to the reaction mixture and stirred, the organic layer was extracted, and concentrated under reduced pressure. The resulting product was dissolved in DCM (90 mL), TFA (5.33 mL) was added, and the mixture was stirred at room temperature for 3 hours. 1 N NaOH aqueous solution (138 mL) was added to the reaction mixture and stirred for 20 minutes. The aqueous layer was separated from the reaction mixture and washed with DCM and Et2O. AcOH (3.96 mL) was added to the aqueous layer and stirred at room temperature for 1 hour. The precipitated solid was filtered off to obtain the crude product. The crude product was purified by reversed-phase silica gel column chromatography (0.1% AcOH MeCN / 0.1% AcOH H2O) and concentrated under reduced pressure to give (4-(benzo[b]thiophene-4-yl)-1-((4-((2-oxo-1,2-dihydroquinolin-7-yl)oxy)butyl)piperazin-1-onthiol-1-yl)methylhydrogen phosphate (1.71 g).

[0378] NMR1; 1.77-1.89 (2H, m), 1.89-2.01 (2H, m), 3.37-3.86 (11H, m), 4.10(2H, t, J = 6.3 Hz), 5.11 (2H, d, J = 9.0 Hz), 6.29 (1H, d, J = 9.4 Hz), 6.80(1H, dd, J = 2.4, 8.7 Hz), 6.95-7.05 (2H, m), 7.31 (1H, dd, J = 7.9, 7.9 Hz), 7.51 (1H, d, J = 5.5 Hz), 7.54 (1H, d, J = 8.7 Hz), 7.71 (1H, d, J = 8.1 Hz), 7.76 (1H, d, J = 5.5 Hz), 7.79 (1H, d, J = 9.5 Hz), 11.93 (1H, br).

[0379] Example 2 (EX 2)

[0380] In a nitrogen atmosphere, a mixture of (4-(benzo[b]thiophene-4-yl)-1-(4-(((2-(tert-butoxy)quinoline-7-yl)oxy)butyl)piperazin-1-onthiol-1-yl)methyl tert-butyl phosphate (15.7 g), AcOH (42.3 mL), and TFA (14.1 mL) was stirred at 40 °C for 1.5 h. The reaction mixture was cooled to below 10 °C, and a solution of AcONa (19.6 g) in water (170 mL) / MeCN (70.7 mL) was added. The resulting liquids were washed with water (30 mL) and combined. The resulting mixture was stirred at room temperature for 1 h, and water (71 mL) was added. The mixture was then stirred at 0 °C for 1 h. The precipitated crystals were subjected to solid-liquid separation, and the resulting product was separated with water (71 mL) and MeCN / water (1:4, 71 mL). Washed (mL) and air-dried at 40°C for 12 hours, yielding (4-(benzo[b]thiophene-4-yl)-1-((4-((2-oxo-1,2-dihydroquinolin-7-yl)oxy)butyl)piperazine-1-onthiol-1-yl)methylhydrogen phosphate (13.81 g).

[0381] NMR1; 1.75-1.90 (2H, m), 1.90-2.00 (2H, m), 3.40-3.85 (11H, m), 4.09(2H, t, J = 6.4 Hz), 5.11 (2H, d, J = 9.2 Hz), 6.29 (1H, d, J = 9.6 Hz), 6.80(1H, dd, J = 2.4 Hz, 8.8 Hz), 6.95-7.05 (2H, m), 7.31 (1H, dd, J = 7.9 Hz,7.9 Hz), 7.51 (1H, d, J = 5.6 Hz), 7.54 (1H, d, J = 8.8 Hz), 7.71 (1H, d, J =8.0 Hz), 7.76 (1H, d, J = 5.6 Hz), 7.79 (1H, d, J = 9.6 Hz), 11.93 (1H, br).

[0382] Example 3 (EX 3)

[0383] Di-tert-butyl (chloromethyl) phosphate (1.82 g) was dissolved in MeCN / DCM (1 / 1) (60 mL), and 7-((4-(4-(benzo[b]thiophene-4-yl)piperazin-1-yl)butoxy)-2-(tert-butoxy)quinoline (2.2 g) was added. After purging with nitrogen, the mixture was stirred overnight at 40 °C in the dark with aluminum foil. The reaction mixture was concentrated under reduced pressure to remove most of the DCM, and then extracted by adding AcOEt / MeOH (9 / 1) and a 10% Na2S2O3 aqueous solution. The organic layer was separated and concentrated under reduced pressure. AcOH (30 g) was added to the residue. The mixture was stirred at 40 °C for 2 hours. The reaction mixture was concentrated under reduced pressure, and toluene was added, followed by further concentration under reduced pressure. The residue was purified by silica gel column chromatography (DCM / MeOH) to give 4-(benzo[b]thiophene-4-yl)-1-(((diethoxyphosphoryl)oxy)methyl)-1-(4-(((2-oxo-1,2-dihydroquinolin-7-yl)oxy)butyl)piperazine-1-onium iodide (3.1 g). Acetone (120 mL) and NaI (2.55 g) were added, and the mixture was stirred at 60 °C overnight. The mixture was cooled to room temperature, the liquid was removed, and water (50 mL) and AcOH (2.5 mL) were added to the residue under ice-cooled conditions. Water (80 mL) was added to the residue. The mixture was stirred at room temperature for 8 hours. The precipitate was filtered off and washed with water. After drying under reduced pressure, it was purified by silica gel column chromatography (DCM / MeOH). After crystallization with the addition of MeCN / water, the product was filtered off and washed with water. The resulting solid was dried under reduced pressure to give (4-(benzo[b]thiophene-4-yl)-1-(4-((2-oxo-1,2-dihydroquinolin-7-yl)oxy)butyl)piperazin-1-onthiol-1-yl)methylethyl phosphate (1.1 g).

[0384] NMR1; 1.13 (3H, t, J = 7.1 Hz), 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 = 9.1 Hz), 6.30 (1H, d, J = 9.4 Hz), 6.82 (1H, dd, J =2.4 Hz, 8.7 Hz), 6.89 (1H, d, J = 2.3 Hz), 7.01 (1H, d, J = 7.4 Hz), 7.32(1H, t, J = 7.8 Hz), 7.51 (1H, d, J = 5.5 Hz), 7.56 (1H, d, J = 8.7 Hz), 7.71(1H, d, J = 8.0 Hz), 7.77 (1H, d, J = 5.6 Hz), 7.80 (1H, d, J = 9.1 Hz),11.69 (1H, s).

[0385] Example 4 (EX 4)

[0386] MeCN (44 mL) and water (44 mL) were added to (11.1 g) benzo[b]thiophene-4-yl)-1-(4-((2-(tert-butoxy)quinoline-7-yl)oxy)butyl)piperazin-1-onth-1-yl)methyl tert-butyl phosphate, and the mixture was stirred at 45 °C, followed by the addition of water (22 mL). After confirming the disappearance of the starting material, NaHCO3 (1.1 g) was added, and the mixture was 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 give (8.7 g) benzo[b]thiophene-4-yl)-1-(4-((2-oxo-1,2-dihydroquinoline-7-yl)oxy)butyl)piperazin-1-onth-1-yl)methyl tert-butyl phosphate.

[0387] 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 = 6.0 Hz), 5.16 (2H, d, J = 8.0 Hz), 6.44 (1H, d, J = 9.6 Hz), 6.88-6.92(2H, m), 7.03 (1H, dd, J = 0.4, 7.6 Hz), 7.29 (1H, t, J = 8.0 Hz), 7.49 (1H,dd, J = 0.8, 5.6 Hz), 7.55-7.58 (2H, m), 7.64 (1H, d, J = 8.0 Hz), 7.87 (1H,d, J = 7.6 Hz).

[0388] Example 5 (EX 5)

[0389] At room temperature, isopropanol (10 mL), water (2 mL), and [other components] were added to (4-(benzo[b]thiophene-4-yl)-1-(4-((2-oxo-1,2-dihydroquinolin-7-yl)oxy)butyl)piperazin-1-onthiol-1-yl)methylhydrogen phosphate (300 mg). (317 mg), and the mixture was stirred at 70 °C for 10 hours. The reaction mixture was concentrated, water was added, and the mixture was extracted with DCM / MeOH (9 / 1). The organic layer was concentrated, and the residue was purified by silica gel column chromatography (DCM / MeOH) to give (4-(benzo[b]thiophene-4-yl)-1-(4-((2-oxo-1,2-dihydroquinoline-7-yl)oxy)butyl)piperazin-1-onthiol-1-yl)methylisopropyl phosphate (44 mg).

[0390] NMR1; 1.14 (6H, d, J = 6.2 Hz), 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 6.90 (1H, d, J = 2.3 Hz), 7.01(1H, d, J = 7.4 Hz), 7.32 (1H, t, J = 7.8 Hz), 7.51 (1H, d, J = 5.5 Hz), 7.56 (1H, d, J = 8.7 Hz), 7.71 (1H, d, J = 8.0 Hz), 7.77 (1H, d, J = 5.6 Hz), 7.80(1H, d, J = 9.1 Hz), 11.69 (1H, s).

[0391] Example 6 (EX 6)

[0392] At room temperature, 1,3-propanediol (10 mL), water (2 mL), and [other components] were added to (4-(benzo[b]thiophene-4-yl)-1-(4-((2-oxo-1,2-dihydroquinolin-7-yl)oxy)butyl)piperazin-1-onthiol-1-yl)methylhydrogen phosphate (300 mg). (212 mg) and the mixture was stirred at 40 °C. After 30 minutes, the mixture was heated to 50 °C. After another 30 minutes, the mixture was heated again to 60 °C. After another 2 hours, the mixture was cooled to room temperature and azeotropically treated with AcOEt. The residue was purified by silica gel column chromatography (DCM / MeOH). The resulting product was dispersed and washed with AcOEt, the insoluble solids were filtered off, and then dried under reduced pressure to give (4-(benzo[b]thiophene-4-yl)-1-(4-((2-oxo-1,2-dihydroquinolin-7-yl)oxy)butyl)piperazin-1-onthiol-1-yl)methyl(3-hydroxypropyl)phosphate (200 mg).

[0393] NMR1; 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 = 6.1 Hz), 4.70 (1H, t, J = 5.6 Hz), 5.10 (2H, d, J = 9.0 Hz), 6.30 (1H, d, J = 9.4 Hz), 6.82 (1H, dd, J = 2.4 Hz, 8.7 Hz), 6.89 (1H, d, J = 2.3 Hz), 7.01 (1H, d, J =7.4 Hz), 7.32 (1H, t, J = 7.8 Hz), 7.51 (1H, d, J = 5.5 Hz), 7.56 (1H, d, J =8.7 Hz), 7.71 (1H, d, J = 8.0 Hz), 7.77 (1H, d, J = 5.6 Hz), 7.81 (1H, d, J =9.4 Hz), 11.67 (1H, s).

[0394] Example 7 (EX 7)

[0395] At room temperature, diethylene glycol monomethyl ether (10.00 mL), water (2 mL), and [other components] were added to (4-(benzo[b]thiophene-4-yl)-1-(4-((2-oxo-1,2-dihydroquinolin-7-yl)oxy)butyl)piperazin-1-onthiol-1-yl)methylhydrogen phosphate (500 mg). (353 mg), and the mixture was stirred at 40°C. After 3 hours, add... (176 mg). 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 and the residue was purified by silica gel column chromatography (DCM / MeOH) to give (4-(benzo[b]thiophene-4-yl)-1-(4-((2-oxo-1,2-dihydroquinolin-7-yl)oxy)butyl)piperazin-1-onthiol-1-yl)methyl(2-(2-methoxyethoxy)ethyl)phosphate (188 mg).

[0396] 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 = 5.2 Hz), 5.09 (2H, d, J = 9.0 Hz), 6.30 (1H, d, J = 9.4 Hz), 6.82 (1H,dd, J = 2.4 Hz, 8.7 Hz), 6.89 (1H, d, J = 2.3 Hz), 7.01 (1H, d, J = 7.3 Hz),7.32 (1H, t, J = 7.8 Hz), 7.51 (1H, d, J = 5.5 Hz), 7.56 (1H, d, J = 8.7 Hz), 7.71 (1H, d, J = 8.0 Hz), 7.77 (1H, d, J = 5.6 Hz), 7.80 (1H, d, J = 9.1 Hz),11.67 (1H, s).

[0397] Example 8 (EX 8)

[0398] At room temperature, acetone / water (9 / 1) (10 mL), ethyl glycolate (3 mL), and [other components] were added to (4-(benzo[b]thiophene-4-yl)-1-(4-((2-oxo-1,2-dihydroquinolin-7-yl)oxy)butyl)piperazin-1-onthiol-1-yl)methylhydrogen phosphate (500 mg). (529 mg), and the mixture was stirred at 40°C for 5 hours, then stirred overnight at room temperature. DCM / MeOH (9 / 1) and water were added to the reaction mixture, and the precipitate was filtered off. The organic layer of the filtrate was concentrated and purified by silica gel column chromatography (DCM / MeOH) together with the filtered precipitate obtained above, to give (4-(benzo[b]thiophene-4-yl)-1-(4-((2-oxo-1,2-dihydroquinoline-7-yl)oxy)butyl)piperazin-1-onthiol-1-yl)methyl(2-ethoxy-2-oxoethyl)phosphate (16 mg).

[0399] NMR1; 1.18 (3H, t, J = 7.1 Hz), 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 = 9.6 Hz), 5.12 (2H, d, J = 8.8 Hz), 6.30 (1H, dd, J = 1.8 Hz, 9.4 Hz), 6.83 (1H, dd, J = 2.4 Hz, 8.7 Hz), 6.87(1H, d, J = 2.3 Hz), 7.01 (1H, d, J = 7.5 Hz), 7.33 (1H, t, J = 7.8 Hz), 7.52(1H, d, J = 5.5 Hz), 7.57 (1H, d, J = 9.0 Hz), 7.72 (1H, d, J = 8.0 Hz), 7.77(1H, d, J = 5.6 Hz), 7.81 (1H, d, J = 9.1 Hz), 11.65 (1H, s).

[0400] Example 9 (EX 9)

[0401] (1.0 g) of (4-(benzo[b]thiophene-4-yl)-1-(4-((2-oxo-1,2-dihydroquinolin-7-yl)oxy)butyl)piperazin-1-onthiol-1-yl)methylhydrogen phosphate was suspended in a mixture of ethylene glycol (10 mL) and water (1 mL), and then added to it. (1.06 g), and the mixture was stirred at 45°C for 5 hours. Acetone and AcOEt were added to the reaction mixture, and the mixture was concentrated three times under reduced pressure and water was removed by azeotropic extraction. The concentrated residue was directly purified by medium-pressure liquid chromatography (DCM / MeOH).

[0402] The product was added to a mixture of water and DCM-MeOH (4:1), the mixture was stirred and extracted. The organic layer 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 off and air-dried to give (4-(benzo[b]thiophene-4-yl)-1-(4-((2-oxo-1,2-dihydroquinolin-7-yl)oxy)butyl)piperazin-1-onthiol-1-yl)methyl(2-hydroxyethyl)phosphate (71 mg).

[0403] 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 = 6.0 Hz), 5.11 (2H, d, J = 9.5 Hz), 6.30 (1H, dd, J = 9.5 Hz, 1.8 Hz), 6.83 (1H, dd, J =8.6 Hz, 2.4 Hz), 6.88 (1H, d, J = 2.4 Hz), 7.00 (1H, d, J = 7.4 Hz), 7.32(1H, t, J = 7.9 Hz), 7.51 (1H, d, J = 5.5 Hz), 7.56 (1H, d, J = 8.7 Hz), 7.71(1H, d, J = 8.1 Hz), 7.77 (1H, d, J = 5.5 Hz), 7.80 (1H, d, J = 9.4 Hz), 11.7(1H, s).

[0404] Example 10 (EX 10)

[0405] (1.0 g) of (4-(benzo[b]thiophene-4-yl)-1-(4-((2-oxo-1,2-dihydroquinolin-7-yl)oxy)butyl)piperazin-1-onthiol-1-yl)methylhydrogen phosphate was suspended in a mixture of 1,4-butanediol (20 mL) and water (4 mL), and then added to it. (1.06 g), and the mixture was stirred at 60 °C for 5 hours. Acetone and AcOEt were added to the reaction mixture, and the mixture was concentrated three times under reduced pressure and water was removed by azeotropic extraction. The concentrated residue was purified twice directly by medium-pressure liquid chromatography (first time: silica gel, second time: amino silica gel, eluent: DCM / MeOH).

[0406] The resulting amorphous product was suspended in water (5 mL) and dissolved in acetone. After standing overnight at room temperature, the precipitated crystals were filtered off and air-dried overnight at 25 °C to give (4-(benzo[b]thiophene-4-yl)-1-(4-((2-oxo-1,2-dihydroquinolin-7-yl)oxy)butyl)piperazin-1-onthiol-1-yl)methyl(4-hydroxybutyl)phosphate (438 mg).

[0407] 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 = 6.1 Hz), 4.43 (1H, t, J = 5.2 Hz), 5.09 (2H,d, J = 9.1 Hz), 6.30 (1H, d, J = 9.4 Hz), 6.82 (1H, dd, J = 8.6 Hz, 2.4 Hz),6.89 (1H, d, J = 2.4 Hz), 7.01 (1H, d, J = 7.6 Hz), 7.32 (1H, t, J = 7.9 Hz), 7.51 (1H, d, J = 5.6 Hz), 7.56 (1H, d, J = 8.7 Hz), 7.71 (1H, d, J = 8.0 Hz), 7.76 (1H, d, J = 5.5 Hz), 7.80 (1H, d, J= 9.5 Hz), 11.7 (1H, s).

[0408] Example 11 (EX 11)

[0409] (1.0 g) of (4-(benzo[b]thiophene-4-yl)-1-(4-((2-oxo-1,2-dihydroquinolin-7-yl)oxy)butyl)piperazin-1-onthiol-1-yl)methylhydrogen phosphate and (3 g) of 1,8-octanediol were suspended in a mixed solvent of acetone (8 mL) and water (2 mL). Added to it... (0.71 g), and the mixture was stirred at 50 °C for 3 hours. Acetone and AcOEt were added to the reaction mixture, and the mixture was concentrated under reduced pressure and water was removed by azeotropic extraction three times. The concentrated residue was purified twice directly by medium-pressure liquid chromatography (first: silica gel, second: amino silica gel, eluent: DCM / MeOH). The resulting amorphous product was suspended in water (5 mL) and dissolved in acetone. After standing overnight at room temperature, the precipitated crystals were filtered off and air-dried overnight at 25 °C to give (4-(benzo[b]thiophene-4-yl)-1-(4-((2-oxo-1,2-dihydroquinoline-7-yl)oxy)butyl)piperazin-1-onthiol-1-yl)methyl(8-hydroxyoctyl)phosphate (176 mg).

[0410] 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 = 6.1 Hz), 4.34 (1H, t, J = 5.2 Hz), 5.00 (2H, d, J = 9.0 Hz), 6.30(1H, dd, J = 9.4 Hz, 1.4 Hz), 6.81 (1H, dd, J = 8.6 Hz, 2.4 Hz), 6.89 (1H, d,J = 2.4 Hz), 7.01 (1H, d, J = 7.4 Hz), 7.32 (1H, t, J = 7.8 Hz), 7.51 (1H,dd, J = 5.6 Hz, 0.4 Hz), 7.56 (1H, d, J = 8.7 Hz), 7.71 (1H, d, J = 8.1 Hz), 7.76 (1H, d, J = 5.5 Hz), 7.80 (1H, d, J = 9.5 Hz), 11.7 (1H, s).

[0411] Example 12 (EX 12)

[0412] (1.0 g) of (4-(benzo[b]thiophene-4-yl)-1-(4-((2-oxo-1,2-dihydroquinolin-7-yl)oxy)butyl)piperazin-1-onthiol-1-yl)methylhydrogen phosphate was suspended in a mixture of 2-methoxyethanol (20 mL) and water (2 mL). Add to it... (1.06 g), and the mixture was stirred at 60 °C for 3 hours. Acetone and AcOEt were added to the reaction mixture, and the mixture was concentrated under reduced pressure, and water was removed by azeotropic extraction three times. The concentrated residue was purified twice directly by medium-pressure liquid chromatography (first: silica gel, second: aminosilica gel, eluent: DCM / MeOH).

[0413] The resulting amorphous product was suspended in water (5 mL) and dissolved in acetone. After standing overnight at room temperature, the precipitated crystals were filtered off and air-dried overnight at 25 °C to give (4-(benzo[b]thiophene-4-yl)-1-(4-((2-oxo-1,2-dihydroquinoline-7-yl)oxy)butyl)piperazin-1-onthiol-1-yl)methyl(2-methoxyethyl)phosphate (320 mg).

[0414] 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 = 6.1 Hz), 5.09 (2H, d, J = 9.0Hz), 6.30 (1H, d, J = 9.5 Hz), 6.82 (1H, dd, J = 8.7 Hz, 2.4 Hz), 6.89 (1H,d, J = 2.4 Hz), 7.01 (1H, d, J = 7.4 Hz), 7.32 (1H, t, J = 7.8 Hz), 7.51 (1H,d, J = 5.5 Hz), 7.56 (1H, d, J = 8.7 Hz), 7.71 (1H, d, J = 8.0 Hz), 7.77 (1H,d, J = 5.5 Hz), 7.80 (1H, d, J = 9.5 Hz), 11.7 (1H, s).

[0415] Example 13 (EX 13)

[0416] (1.0 g) of (4-(benzo[b]thiophene-4-yl)-1-(4-((2-oxo-1,2-dihydroquinolin-7-yl)oxy)butyl)piperazin-1-onthiol-1-yl)methylhydrogen phosphate was suspended in a mixed solution of ethylene glycol monoisopropyl ether (20 mL) and water (2 mL). Add to it... (0.71 g), and the mixture was stirred at 50°C for 7 hours. Acetone and AcOEt were added to the reaction mixture, and the mixture was concentrated under reduced pressure, with water removed by azeotropic extraction three times. The concentrated residue was purified twice directly by medium-pressure liquid chromatography (first: silica gel, second: aminosilica gel, eluent: DCM / MeOH).

[0417] The resulting amorphous product was suspended in water (5 mL) and dissolved in acetone (15 mL). After standing at room temperature for 5 days, the precipitated crystals were filtered off and air-dried overnight at 25 °C to give (4-(benzo[b]thiophene-4-yl)-1-(4-((2-oxo-1,2-dihydroquinolin-7-yl)oxy)butyl)piperazine-1-onthiol-1-yl)methyl(2-isopropoxyethyl)phosphate (290 mg).

[0418] NMR1; 1.06 (6H, d, J = 6.1 Hz), 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 = 9.1 Hz), 6.30 (1H, dd, J = 9.4 Hz, 1.4 Hz), 6.82 (1H,dd, J = 8.6 Hz, 2.4 Hz), 6.89 (1H, d, J = 2.4 Hz), 7.01 (1H, d, J = 7.4 Hz),7.32 (1H, t, J = 7.9 Hz), 7.51 (1H, d, J = 5.5 Hz), 7.56 (1H, d, J = 8.7 Hz), 7.71 (1H, d, J = 8.0 Hz), 7.77 (1H, d, J = 5.5 Hz), 7.80 (1H, d, J = 9.5 Hz),11.7 (1H, s).

[0419] Example 14 (EX 14)

[0420] Morpholine (1.2 mL) was added to a solution of (300 mg) 4-(benzo[b]thiophene-4-yl)-1-(4-((2-oxo-1,2-dihydroquinolin-7-yl)oxy)butyl)piperazin-1-onthiol-1-yl)methyl(2-bromoethyl)phosphate (12 mL) in THF at room temperature, and the mixture was stirred at 40 °C for 5 hours. The reaction mixture was concentrated, and the residue was purified by silica gel column chromatography (DCM / MeOH). After dissolving the resulting product in MeCN / H2O (1 / 1), MeCN was added. The precipitate was filtered off and washed with MeCN. The product was dried at room temperature to give (4-(benzo[b]thiophene-4-yl)-1-(4-((2-oxo-1,2-dihydroquinoline-7-yl)oxy)butyl)piperazine-1-on-1-yl)methyl(2-morpholinoethyl)phosphate (164 mg).

[0421] NMR1; 1.78-1.89 (2H, m), 1.89-2.01 (2H, m), 2.34-2.41 (4H, m), 2.46(2H, t, J = 6.1 Hz), 3.42-3.49 (4H, m), 3.50-3.68 (8H, m), 3.71-3.85 (4H, m),4.10 (2H, t, J = 6.1 Hz), 5.10 (2H, d, J = 9.1 Hz), 6.30 (1H, d, J = 9.4 Hz),6.82 (1H, dd, J = 2.4, 8.7 Hz), 6.89 (1H, d, J = 2.3 Hz), 7.01 (1H, d, J =7.4 Hz), 7.32 (1H, t, J = 7.8 Hz), 7.51 (1H, d, J = 5.5 Hz), 7.56 (1H, d, J =8.7 Hz), 7.71 (1H, d, J = 8.0 Hz), 7.77 (1H, d, J = 5.6 Hz), 7.80 (1H, d, J =9.1 Hz), 11.68 (1H, s).

[0422] Example 15 (EX 15)

[0423] Pyridine (4 mL) and acetic anhydride (2 mL) were added to (4-(benzo[b]thiophene-4-yl)-1-(4-(((2-oxo-1,2-dihydroquinoline-7-yl)oxy)butyl)piperazin-1-onth-1-yl)methyl(3-hydroxypropyl)phosphate (200 mg) at room temperature, and the mixture was stirred overnight. The reaction mixture was concentrated and azeotropically reacted with toluene. The residue was purified by silica gel column chromatography (DCM / MeOH). EtOH / H2O (1 / 1) was added to disperse the mixture, and it was washed at 40 °C and the insoluble solids were filtered off. The resulting product was washed with water and dried at room temperature, giving 3-acetoxypropyl((4-(benzo[b]thiophene-4-yl)-1-(4-((2-oxo-1,2-dihydroquinoline-7-yl)oxy)butyl)piperazin-1-onth-1-yl)methyl)phosphate (126 mg).

[0424] 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 = 6.2 Hz), 4.15-4.25 (4H, m), 4.52-4.65 (4H, m), 5.20( 2H, d, J = 8.1 Hz), 6.44 (1H, d,J = 9.4 Hz), 6.89 (1H, d, J = 2.4 Hz), 6.92 (1H, dd, J = 2.4, 8.7 Hz), 7.05(1H, d, J = 7.7 Hz), 7.30 (1H, t, J = 7.9 Hz), 7.49 (1H, dd, J = 0.8, 5.6Hz), 7.57 (1H, d, J = 5.2 Hz), 7.59 (1H, d, J = 2.0 Hz), 7.65 (1H, d, J = 8.1Hz), 7.88 (1H, d, J = 9.4 Hz).

[0425] Example 16 (EX 16)

[0426] Chloromethyl hexanoate (494 mg) was added to a mixture of (4-(benzo[b]thiophene-4-yl)-1-(4-((2-oxo-1,2-dihydroquinoline-7-yl)oxy)butyl)piperazin-1-onthiol-1-yl)methylhydrogen phosphate (632 mg), acetone (6 mL), water (2 mL), and DIPEA (0.524 mL) under stirring, and the mixture was stirred under reflux. After 8 hours, the mixture was cooled to room temperature, and then acetone (2 mL) was added, followed by stirring. The precipitated solid was filtered off. The resulting product was washed with acetone / water (3:1), followed by washing with acetone to obtain a crude product. Purification was performed by silica gel column chromatography (DCM / MeOH). Acetone (3 mL) and water (1 mL) were added, and the precipitated solid was filtered off. The product was washed with acetone and dried to give (4-(benzo[b]thiophene-4-yl)-1-(4-((2-oxo-1,2-dihydroquinolin-7-yl)oxy)butyl)piperazine-1-on-1-yl)methyl((hexanoyloxy)methyl)phosphate (269 mg).

[0427] NMR1; 0.79 (3H, t, J = 6.9 Hz), 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 = 7.5 Hz), 3.40 - 3.52 (4H, m), 3.52 - 3.70 (4H, m), 3.70 - 3.82 (2H, m), 4.09 (2H, t, J = 6.0 Hz), 5.09 (2H, d, J = 8.9 Hz), 5.42 (2H, d, J = 12.7 Hz), 6.30 (1H, dd, J = 1.9 Hz, 9.4 Hz), 6.82 (1H, dd, J = 2.4 Hz, 8.6 Hz), 6.86 (1H, d, J = 2.3 Hz), 7.01 (1H, d, J = 7.4 Hz), 7.32 (1H, dd, J = 7.9 Hz, 7.9 Hz), 7.52 (1H, dd, J = 0.6 Hz, 5.5 Hz), 7.56 (1H, d, J = 8.6 Hz), 7.72 (1H, d, J = 8.1 Hz), 7.77 (1H, d, J = 5.5 Hz), 7.81 (1H, d, J = 9.4 Hz), 11.64 (1H, s).

[0428] Example 17 (EX 17)

[0429] Chloromethyl decanoate (220 mg) was added to a mixture of (4-(benzo[b]thiophene-4-yl)-1-(4-(((2-oxo-1,2-dihydroquinoline-7-yl)oxy)butyl)piperazin-1-onthiol-1-yl)methylhydrophosphate (630 mg), acetone (6 mL), water (3 mL), and DIPEA (0.522 mL), and the mixture was stirred under reflux. After 1 hour, chloromethyl decanoate (220 mg) was added. After another 1 hour, chloromethyl decanoate (220 mg) was added. After another 2 hours of stirring, acetone (3 mL) was added. After another 3 hours, DIPEA (0.348 mL) and chloromethyl decanoate (220 mg) were added. After another 1 hour, chloromethyl decanoate (220 mg) was added. After another 1.5 hours, heating was stopped, the mixture was cooled to room temperature, and stirred for eight nights. After stirring under reflux for 2 hours, the mixture was cooled to room temperature and stirred for an additional hour. The precipitated solid was filtered off after the addition of acetone (3 mL). The resulting product was washed with acetone / water (3:1), followed by washing with acetone to obtain a crude product. Acetone (5 mL) and water (1 mL) were added, and the mixture was stirred under reflux for 30 minutes. After cooling to room temperature, the precipitated solid was filtered off, washed with acetone / water (3:1), followed by washing with acetone and drying to give (4-(benzo[b]thiophene-4-yl)-1-(4-((2-oxo-1,2-dihydroquinoline-7-yl)oxy)butyl)piperazin-1-onthiol-1-yl)methyl((decanoyloxy)methyl)phosphate (370 mg).

[0430] NMR1; 0.82 (3H, t, J = 6.9 Hz), 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 = 7.5 Hz), 3.42 - 3.50 (4H, m), 3.53 - 3.69 (4H, m), 3.71 - 3.82 (2H, m), 4.09 (2H, t, J = 6.0 Hz), 5.09 (2H, d, J = 8.9 Hz), 5.42 (2H, d, J = 12.8 Hz), 6.30 (1H, dd, J = 1.8 Hz, 9.5 Hz), 6.82 (1H, dd, J = 2.4 Hz, 8.6 Hz), 6.85 (1H, d, J = 2.3 Hz), 7.01 (1H, d, J = 7.4 Hz), 7.32 (1H, dd, J = 7.9 Hz, 7.9 Hz), 7.52 (1H, dd, J = 0.42 Hz, 5.5 Hz), 7.56 (1H, d, J = 8.6 Hz), 7.71 (1H, d, J = 8.1 Hz), 7.77 (1H, d, J = 5.5 Hz), 7.80 (1H, d, J = 9.5 Hz), 11.63 (1H, s).

[0431] Example 18 (EX 18)

[0432] A mixture of (4-(benzo[b]thiophene-4-yl)-1-(4-((2-oxo-1,2-dihydroquinoline-7-yl)oxy)butyl)piperazin-1-onthiol-1-yl)methylhydrogen phosphate (632 mg), acetone (6 mL), water (2 mL), and DIPEA (0.524 mL) was added with stirring, and the mixture was stirred under reflux. After 8 hours, the mixture was cooled to room temperature, and then acetone (2 mL) was added, followed by stirring. The precipitated solid was filtered off, and the resulting product was washed with acetone / water (3:1), followed by washing with acetone to obtain the crude product. Purification was performed by silica gel column chromatography (DCM / MeOH). Acetone (3 mL) and water (1 mL) were added, and the precipitated solid was filtered off. The product was washed with acetone and dried to give (4-(benzo[b]thiophene-4-yl)-1-(4-((2-oxo-1,2-dihydroquinolin-7-yl)oxy)butyl)piperazine-1-on-1-yl)methyl(((cyclohexanecarbonyl)oxy)methyl)phosphate (392 mg).

[0433] 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 = 6.0 Hz), 5.10 (2H, d, J =9.1 Hz), 5.42 (2H, d, J = 12.5 Hz), 6.30 (1H, dd, J = 1.8 Hz, 9.4 Hz), 6.82(1H, dd, J = 2.4 Hz, 8.6 Hz), 6.86 (1H, d, J = 2.4 Hz), 7.01 (1H, d, J = 7.4Hz), 7.32 (1H, dd, J = 7.9 Hz, 7.9 Hz), 7.52 (1H, dd, J = 0.4 Hz, 5.6 Hz), 7.56 (1H, d, J = 8.7 Hz), 7.72 (1H, d, J = 8.1 Hz), 7.77 (1H, d, J = 5.5 Hz), 7.81 (1H, d, J = 9.5 Hz), 11.65 (1H, s).

[0434] Example 19 (EX 19)

[0435] Chloromethylcyclohexyl carbonate (578 mg) was added to a mixture of (4-(benzo[b]thiophene-4-yl)-1-(4-((2-oxo-1,2-dihydroquinoline-7-yl)oxy)butyl)piperazin-1-onthiol-1-yl)methylhydrogen phosphate (632 mg), acetone (6 mL), water (2 mL), and DIPEA (0.524 mL), and the mixture was stirred under reflux. After 8 hours, the mixture was cooled to room temperature, and then acetone (2 mL) was added, followed by stirring. The precipitated solid was filtered off and washed with acetone / water (3:1), then washed with acetone again to obtain the crude product. Purification was performed by silica gel column chromatography (DCM / MeOH). Acetone (3 mL) and water (1 mL) were added, and the precipitated solid was filtered off. The product was washed with acetone and dried to give (4-(benzo[b]thiophene-4-yl)-1-(4-((2-oxo-1,2-dihydroquinolin-7-yl)oxy)butyl)piperazine-1-on-1-yl)methyl((((cyclohexyloxy)carbonyl)oxy)methyl)phosphate (296 mg).

[0436] NMR 1; 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 = 6.0 Hz), 4.47 - 4.55 (1H, m), 5.09 (2H, d, J = 8.5 Hz), 5.43 (2H, d, J = 13.3 Hz), 6.30 (1H, dd, J = 1.9 Hz, 9.5 Hz), 6.83 (1H, dd, J = 2.4 Hz, 8.6 Hz), 6.85 (1H, d, J = 2.3 Hz), 7.00 (1H, d, J = 7.4 Hz), 7.32 (1H, dd, J = 7.8 Hz, 7.8 Hz), 7.52 (1H, dd, J = 0.4 Hz, 5.6 Hz), 7.56 (1H, d, J = 8.6 Hz), 7.72 (1H, d, J = 8.0 Hz), 7.77 (1H, d, J = 5.5 Hz), 7.81 (1H, d, J = 9.5 Hz), 11.63 (1H, s).

[0437] Example 20 (EX 20)

[0438] To a solution of 7-(4-(4-(benzo[b]thiophene-4-yl)piperazin-1-yl)butoxy)-2-(tert-butoxy)quinoline (500 mg) in MeCN / DCM (30 mL) (2 / 1), add NaI (306 mg), K2CO3 (282 mg), and dibutyl(chloromethyl) phosphate (528 mg). After purging with nitrogen, stir the mixture overnight at 40 °C protected from light by aluminum foil. Add dibutyl(chloromethyl) phosphate (132 mg) and NaI (77 mg), and stir the mixture at 40 °C for 8 hours. Add DCM and a saturated aqueous solution of NaHCO3, and extract with DCM. Concentrate the organic layer, and add MeCN (10 mL), water (5 mL), and AcOH (0.5 mL) to the residue. Stir the mixture overnight at room temperature. Add AcOEt / MeOH = 9 / 1 and water to the reaction mixture, and extract. The organic layer was concentrated and the residue was purified by silica gel column chromatography (DCM / MeOH) to give 4-(benzo[b]thiophene-4-yl)-1-(((dibutoxyphosphoryl)oxy)methyl)-1-(4-((2-oxo-1,2-dihydroquinoline-7-yl)oxy)butyl)piperazine-1-onium iodide (545 mg).

[0439] NMR2; 0.92 (6H, t, J = 7.4 Hz), 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 = 6.6 Hz, 14.0 Hz), 5.75 (2H, d, J = 8.7 Hz), 6.42 (1H, d, J =9.4 Hz), 6.71 (1H, dd, J = 2.3 Hz, 8.6 Hz), 6.92 (1H, d, J = 7.4 Hz), 7.12(1H, d, J = 2.2 Hz), 7.19 (1H, t, J = 7.9 Hz), 7.30 (1H, d, J = 8.7 Hz), 7.35-7.42 (2H, m), 7.56 (1H, s), 7.58 (1H, d, J = 2.2 Hz), 11.04 (1H, s).

[0440] See Example 1 (REX 1)

[0441] In a 500 mL round-bottom flask under a nitrogen atmosphere, 15.0 g of 7-(4-(benzo[b]thiophene-4-yl-piperazin-1-yl)butoxy)-1H-quinoline-2-one and 20.0 g of silver carbonate were suspended in CPME (300 mL). 7.84 mL of 2-bromo-2-methylpropane was then added, and the mixture was stirred at 90 °C for 9 hours in the dark. The insoluble material was filtered through diatomaceous earth and washed with AcOEt (150 mL). The solvent was evaporated under reduced pressure, and 180 mL of MeCN was added to the residue, and the mixture was stirred. The precipitated crystals were subjected to solid-liquid separation, and the resulting product was washed with 60 mL of MeCN and air-dried at 40 °C to give 16.0 g of 7-(4-(benzo[b]thiophene-4-yl)piperazin-1-yl)butoxy)-2-(tert-butoxy)quinoline.

[0442] NMR2; 1.69 (9H, s), 1.75-1.83 (2H, m), 1.89-1.96 (2H, m), 2.55 (2H, t,J = 7.6 Hz), 2.73 (4H, m), 3.2 (4H, m), 4.15 (2H, t, J = 6.4 Hz), 6.64 (1H,d, J = 7.6 Hz), 6.89 (1H, d, J = 7.6 Hz), 6.99 (1H, dd, J = 8.8 Hz, J = 2.4Hz), 7.15 (1H, d, J = 2.4 Hz), 7.27 (1H, t, J = 7.6 Hz), 7.38-7.43 (2H, m),7.53-7.56 (2H, m), 7.82 (1H, d, J = 8.4 Hz).

[0443] See Example 2 (REX 2)

[0444] In a 1000 mL round-bottom flask under a nitrogen atmosphere, 7-(4-(4-(benzo[b]thiophene-4-yl)piperazin-1-yl)butoxy)-2-(tert-butoxy)quinoline (16 g), NaI (9.8 g), and K₂CO₃ (9.0 g) were suspended in MeCN (240 mL), and di-tert-butyl(chloromethyl) phosphate (16.9 g) was added. The mixture was stirred at 25–40 °C for 2 days. Water (240 mL) was added further, and the mixture was stirred at 45 °C for 1 hour. Subsequently, most of the MeCN was distilled off under reduced pressure. The resulting crystals were cooled to 0 °C, subjected to solid-liquid separation, washed with MeCN / water (1:4, 80 mL), and dried under vacuum at 40 °C for 16 hours. The resulting crystals (19 g) were placed in a 1 L flask, and AcOEt (300 mL) and TEA (1 mL) were added, followed by stirring for 30 minutes. After solid-liquid separation, the product was washed with AcOEt (150 mL) and dried under vacuum at 30 °C for 5 hours to give (4-(benzo[b]thiophene-4-yl)-1-(4-((2-(tert-butoxy)quinolin-7-yl)oxy)butyl)piperazine-1-onth-1-yl)methyl tert-butyl phosphate (15.73 g).

[0445] 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 = 5.6 Hz), 5.15 (2H, d, J = 8.0 Hz), 6.65 (2H, d, J = 8.8Hz), 7.00 (1H, dd, J = 8.8 Hz, J = 0.8 Hz), 7.03 (1H, dd, J = 8.8 Hz, J = 2.4Hz), 7.18 (1H, d, J = 2.4 Hz), 7.26 (1H, t, J = 8.0 Hz), 7.49 (1H, dd, J =5.6 Hz, J = 0.8 Hz), 7.57-7.65 (3H, m), 7.92 (1H, d, J = 8.8 Hz).

[0446] See Example 3 (REX 3)

[0447] 151 mg of 55% NaH in oil was suspended in 10 mL of THF. 500 mg of 7-(4-(4-benzo[b]thiophene-4-yl-piperazin-1-yl)butoxy)-1H-quinoline-2-one was added, followed by dropwise addition of 570 mg of chloromethyl hexanoate. The mixture was stirred at 50 °C for 2 hours. After cooling to 0 °C, the product was quenched with an aqueous solution of ammonium chloride. Extraction was performed using AcOEt, followed by dehydration on Na₂SO₄. The product was purified by medium-pressure silica gel column chromatography to give 217 mg of (7-(4-(4-(benzo[b]thiophene-4-yl)piperazin-1-yl)butoxy)-2-oxoquinoline-1(2H)-yl)methyl hexanoate.

[0448] NMR2; 0.85 (3H, t, J = 6.8 Hz), 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 = 7.4 Hz), 2.67-2.78 (4H, m), 3.15-3.25 (4H, m), 4.08 (2H, t, J = 6.2 Hz), 6.34 (2H, brs), 6.52 (1H, d, J = 9.5 Hz), 6.84 (1H, dd, J = 2.2 Hz, 8.6 Hz), 6.84-6.92 (2H, m), 7.27 (1H, dd, J = 7.8 Hz, 7.8 Hz), 7.37-7.43 (2H, m), 7.45(1H, d, J = 8.6 Hz), 7.55 (1H, d, J = 8.1 Hz), 7.62 (1H, d, J = 9.5 Hz).

[0449] See Example 4 (REX 4)

[0450] 7-(4-(4-(benzo[b]thiophene-4-yl)piperazin-1-yl)butoxy)quinoline-2(1H)-one (4.0 g) was dissolved in DCM (120 mL). Then, a solution of piperidine-1-carboxylic acid iodomethyl ester (2.98 g) in DCM (10 mL) was added at room temperature with stirring, and the mixture was stirred at room temperature for 2 hours. After standing overnight, the resulting product was filtered, washed with DCM, and dried to obtain a crude product. The crude product was recrystallized in DCM / DMF (3 / 2) (140 mL) to give 4-(benzo[b]thiophene-4-yl)-1-(4-((2-oxo-1,2-dihydroquinoline-7-yl)oxy)butyl)-1-(((piperidine-1-carbonyl)oxy)methyl)piperazin-1-onium iodide (4.06 g).

[0451] 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 = 5.6 Hz), 5.55 (2H, s), 6.32(1H, dd, J = 1.4 Hz, 9.5 Hz), 6.74-6.95 (2H, m), 7.04 (1H, d, J = 7.6 Hz), 7.34 (1H, dd, J = 7.8 Hz, 7.8 Hz), 7.54 (1H, d, J = 5.5 Hz), 7.59 (1H, d, J =9.4 Hz), 7.73 (1H, d, J = 8.1 Hz), 7.79 (1H, d, J = 5.5 Hz), 7.82 (1H, d, J =9.5 Hz), 11.64 (1H, s).

[0452] See Example 5 (REX 5)

[0453] 4-(benzo[b]thiophene-4-yl)-1-(4-((2-oxo-1,2-dihydroquinolin-7-yl)oxy)butyl)-1-((propionyloxy)methyl)piperazine-1-onium iodide was obtained in the same manner as in Reference Example 4.

[0454] NMR1; 1.07 (3H, t, J = 7.4 Hz), 1.71-2.00 (4H, m), 2.56 (2H, q, J =7.4 Hz), 3.47-3.52 (4H, m), 3.63-3.71 (2H, m), 3.71-3.86 (4H, m), 4.10 (2H,t, J = 5.6 Hz), 5.55 (2H, s), 6.32 (1H, dd, J = 1.5 Hz, 9.4 Hz), 6.77-6.87(2H, m), 7.03 (1H, d, J = 7.6 Hz), 7.34 (1H, dd, J = 7.9 Hz, 7.9 Hz), 7.53(1H, d, J = 5.6 Hz), 7.59 (1H, d, J = 8.5 Hz), 7.73 (1H, d, J = 8.0 Hz), 7.78(1H, d, J = 5.5 Hz), 7.82 (1H, d, J = 9.5 Hz), 11.65 (1H, s).

[0455] See Example 6 (REX 6)

[0456] 4-(benzo[b]thiophene-4-yl)-1-((hexanoyloxy)methyl)-1-(4-((2-oxo-1,2-dihydroquinoline-7-yl)oxy)butyl)piperazine-1-onium iodide was obtained in the same manner as in Reference Example 4.

[0457] NMR1; 0.83 (3H, t, J = 6.9 Hz), 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 = 5.5 Hz), 5.57 (2H, s), 6.29-6.37 (1H, m), 6.80-6.88 (2H, m),7.05 (1H, d, J = 7.5 Hz), 7.35 (1H, dd, J = 7.9 Hz, 7.9 Hz), 7.54( 1H, d, J =5.5 Hz), 7.60 (1H, d, J = 9.4 Hz), 7.74 (1H, d, J = 8.1 Hz), 7.79 (1H, d, J =5.5 Hz), 7.84 (1H, d, J = 9.5 Hz), 11.65 (1H, s).

[0458] See Example 7 (REX 7)

[0459] 4-(benzo[b]thiophene-4-yl)-1-((((hexyloxy)carbonyl)oxy)methyl)-1-(4-((2-oxo-1,2-dihydroquinoline-7-yl)oxy)butyl)piperazine-1-onium iodide was obtained in the same manner as in Reference Example 4.

[0460] NMR1; 0.85 (3H, t, J = 6.9 Hz), 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 = 6.7 Hz), 5.61 (2H, s), 6.31 (1H, dd, J = 1.8 Hz, 9.5Hz), 6.76-6.85 (2H, m), 7.03 (1H, d, J = 7.4 Hz), 7.34 (1H, dd, J = 7.9 Hz,7.9 Hz), 7.54 (1H, dd, J = 0.4 Hz, 5.5 Hz), 7.58 (1H, d, J = 8.8 Hz), 7.73(1H, d, J = 8.1 Hz), 7.79 (1H, d, J = 5.5 Hz), 7.82 (1H, d, J = 9.5 Hz),11.63 (1H, s).

[0461] The following table shows the structural formulas of the reference example compounds (reference examples 1 to 7) and the example compounds (examples 1 to 20) obtained according to the methods described above.

[0462] Table 2A

[0463] Table 2B

[0464] Compounds from the examples other than those described above were also synthesized and examined. Example numbers, structural formulas, preparation methods, and their NMR analysis data are listed in the table below. For convenience, each example number is referred to as "EX N" (where N is an integer from 1 to 161). "EX N" may also be displayed as "Example N," etc.

[0465] In addition, the compounds used in the synthesis of each embodiment are listed in the table below along with their numbers, structural formulas, preparation methods, and NMR analysis data, as Reference Examples 8 to 67. For convenience, each Reference Example number is referred to as "REX M" (where M is an integer from 8 to 67). "REX M" may also be shown as "Reference Example M", etc.

[0466] Table 3A

[0467] Table 3B

[0468] Each of the obtained compounds was used in each of the following test examples. The compounds in Reference Examples 3 and 4 are the compounds described in Examples 58 and 706 of PTL 2 (WO2013 / 035892) above.

[0469] Cytotoxicity test using HL-60 cells

[0470] (1) Cell culture

[0471] HL-60 cell lines (human acute promyelocytic leukemia cells) were cultured continuously in RPMI 1640 containing 20% ​​fetal bovine serum (FBS) at 37°C and 95% atmospheric / 5% CO2. Prior to evaluation, cells were pre-cultured for approximately 72 hours in the presence of 10 nM phorbol 12-myristate 13-acetate (PMA) to induce macrophage-like differentiation.

[0472] (2) Evaluation of compound treatment

[0473] The evaluation compounds were dissolved in DMSO to obtain 30 mmol / L solutions (or suspensions). Each DMSO solution was diluted 100-fold with RPMI 1640 containing 2% FBS (final compound concentration: 300 μmol / L) to obtain treatment solutions. The culture supernatant of differentiated HL-60 cells was removed, each treatment solution was added, and the cells were incubated for approximately 24 hours before cytotoxicity assessment. The compound from Reference Example 3, which showed irritation when administered subcutaneously to dogs, was used as a positive control, while risperidone, a commercially available subcutaneous injectable formulation, was used as a negative control.

[0474] (3) Cytotoxicity assessment

[0475] Lactate dehydrogenase (LDH) activity was measured in treatment solutions after cells were exposed for approximately 24 hours using a commercially available kit (WST Cytotoxicity LDH Assay Kit, Dojindo Laboratories) and a plate reader (Tecan Infinite M1000). Cytotoxicity (%) was calculated using the obtained measurements as a comparison value for each evaluation compound treatment group, with the untreated group at 0% and the cell lysis buffer-treated group at 100%. The test was performed in triplicate, with each approximation in three wells, and the average value was used as the adoption value. The test was considered feasible when the positive control compound treatment group showed significant cytotoxicity, while the negative control compound treatment group showed almost no cytotoxicity.

[0476] (4) Test Results (Discussion)

[0477] The results below show the cytotoxicity (%) test results.

[0478] Table 4

[0479] The example compounds in the table above all showed cytotoxicity comparable to or lower than that of the negative control (i.e., risperidone). Furthermore, Reference Example 4 compound (REX 4), as a quaternary ammonium compound, showed stronger cytotoxicity than Reference Example 3 compound (REX3), which was set as a positive control. These results indicate that the example compounds have lower cytotoxicity than Reference Example 4 compound.

[0480] Confirmatory study on conversion to epipiperazole

[0481] The conversion of the evaluation compound to epipipeazole in buffer solution was evaluated (i.e., the stability of the evaluation compound).

[0482] The compound of Example 1 was dissolved in acetonitrile / water (1:1, v / v) to 10 mmol / L and further diluted with acetonitrile / water (1:1, v / v) to 100 μmol / L for use.

[0483] In addition to the compounds described below, the other example compounds and the compounds of Reference Examples 5 to 7 were dissolved in DMSO to 10 mmol / L and further diluted with acetonitrile to 100 μmol / L for use.

[0484] The compounds of Examples 52, 95, 96, 117 and 130 (EX 52, EX 95, EX 96, EX 117 and EX 130) were dissolved in acetonitrile / water (8:2, v / v) to 10 mmol / L and further diluted with acetonitrile to 100 μmol / L for use.

[0485] The compound of Example 97 (EX 97) was dissolved in acetonitrile / water (8:2, v / v) to 10 mmol / L and further diluted with acetonitrile / water (8:2, v / v) to 100 μmol / L for use.

[0486] The compounds of Examples 15 and 116 (EX 15 and EX 116) were dissolved in DMSO to 1 mmol / L and further diluted with acetonitrile to 100 μmol / L for use.

[0487] These evaluation compound solutions are prepared during use.

[0488] The reactions were carried out by preparing each reaction solution such that the final concentration of each component was as described below. Tests were performed in duplicate.

[0489] Final concentration

[0490] Tris-hydrochloric acid buffer (pH 7.5) 50 mmol / L

[0491] Magnesium chloride 5 mmol / L

[0492] Evaluation of compound solution 1 μmol / L

[0493] For the compounds of Examples 1 to 8, 10 to 19, 26 to 27, 37, 50, 87 to 89, 91, 116, 121, 123, 150 and 151 (EX 1 to EX 8, EX 10 to EX 19, EX 26 to EX 27, EX 37, EX 50, EX 87 to EX 89, EX 91, EX 116, EX 121, EX 123, EX 150 and EX 151) and the compounds of Reference Examples 5 to 7 (REX 5 to REX 7), a reaction solution (198 μl) without the evaluation compound was preheated at 37°C for 3 minutes, and then a solution of each evaluation compound (2 μl) was added and stirred; then the reaction was started at 37°C. The reaction was terminated at 0 or 60 minutes after initiation by adding 1000 μl of a reaction termination solution consisting of acetonitrile / isopropanol (4:1, v / v) containing an internal standard and stirring. However, the 0-minute reaction sample (198 μl) was prepared by adding the evaluation compound (2 μl) after adding the reaction termination solution (1000 μl). The terminated sample was used as the measurement sample. Calibration curve samples with the same composition were prepared (final concentrations of the evaluation compound and epipiperazole: 0.01, 0.1, and 1 μmol / L, provided that the 0-minute reaction sample was also used as the 1 μmol / L calibration curve sample only for the evaluation compound).

[0494] For compounds of Examples 24 to 25, 28 to 29, 32 to 36, 40 to 49, 51 to 60, 62 to 64, 66 to 77, 80 to 86, 90, 92 to 111, 113, 115, 117 to 120, 122, 124 to 130, 132 to 147 and 152 to 160 (EX 24 to EX25, EX 28 to EX 29, EX 32 to EX 36, EX 40 to EX 49, EX 51 to EX 60, EX 62 to EX 64, EX 66 to EX77, EX 80 to EX 86, EX 90, EX 92 to EX 111, EX 113, EX 115, EX 117 to EX 120, EX 122, EX 124 to EX 130, EX 124 to EX 130, EX 125, EX 12 ...5, EX 122, EX 124 to EX 130 For EX 132 to EX 147 and EX 152 to EX 160, a reaction solution (148.5 μl) without the evaluation compound was preheated at 37 °C for 3 min, followed by the addition of each evaluation compound solution (1.5 μl) and stirring; the reaction was then initiated at 37 °C. The reaction was terminated at 0 or 60 min after initiation by adding a reaction termination 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 termination solution (600 μl). The terminated sample was used as the measurement sample. Calibration curve samples with the same composition were prepared (final concentrations of the evaluation compound and epipiperazole: 0.01, 0.1, and 1 μmol / L, provided that only for the evaluation compound, the 0-minute reaction sample was also used as a 1 μmol / L calibration curve sample).

[0495] For the compounds of Examples 1 to 8, 10 to 19, 26 to 27, 37, 50, 87 to 89, 91, 116, 121, 123, 150, and 151 (EX 1 to EX 8, EX 10 to EX 19, EX 26 to EX 27, EX 37, EX 50, EX 87 to EX 89, EX 91, EX 116, EX 121, EX 123, EX 150, and EX 151) and the compounds of Reference Examples 5 to 7 (REX 5 to REX 7), the obtained measurement samples and calibration curve samples were centrifuged, the supernatant was appropriately diluted with a mixture of acetonitrile / isopropanol (4:1, v / v), and the obtained samples were injected into a liquid chromatography-tandem mass spectrometer (HPLC: Shimadzu Prominence UFLC system, MS: SCIEX API). In 4000, compounds, epipiprazole, and internal standards are measured and evaluated.

[0496] For compounds of Examples 24 to 25, 28 to 29, 32 to 36, 40 to 49, 51 to 60, 62 to 64, 66 to 77, 80 to 86, 90, 92 to 111, 113, 115, 117 to 120, 122, 124 to 130, 132 to 147 and 152 to 160 (EX 24 to EX25, EX 28 to EX 29, EX 32 to EX 36, EX 40 to EX 49, EX 51 to EX 60, EX 62 to EX 64, EX 66 to EX77, EX 80 to EX 86, EX 90, EX 92 to EX 111, EX 113, EX 115, EX 117 to EX 120, EX 122, EX 124 to EX 130, EX 124 to EX 130, EX 125, EX 12 ...5, EX 122, EX 124 to EX 130 For EX 132 to EX 147 and EX 152 to EX 160, the obtained measurement samples and calibration curve samples were centrifuged, and the supernatant was appropriately diluted with a mixture of ultrapure water and acetonitrile / isopropanol (4:1, v / v) (so that the ultrapure water ratio is 20%). The resulting diluted measurement samples were then injected into a liquid chromatography-tandem mass spectrometer (HPLC: Shimadzu Prominence UFLC system, MS: SCIEX Triple Quad 4500) to measure and evaluate the compounds, epipiperazole, and internal standards.

[0497] For ionization, electrospray ionization was performed using positive ion detection, and a selected reaction monitoring method was adopted by setting precursor and product ions. For the internal standard, deuterium of epipiperazole (epipipezazole-d8) was used. The residual amount of the compound and the amount of epipiperazole formed were calculated in samples reacted at 0 minutes and 60 minutes.

[0498] The reduction in the 60-minute reaction sample was calculated using the difference in residual amounts of the evaluation compound between the 0-minute and 60-minute reaction samples. The stability of the evaluation compound in the buffer solution was evaluated based on the change in the amount of the evaluation compound.

[0499] The conversion to epipiperazole in the 60-minute reaction sample was assessed based on the amount of epipiperazole formed in the 60-minute reaction sample. If epipiperazole was detected in the 0-minute reaction sample, the increase in the 60-minute reaction sample was calculated using the difference in the amount of epipiperazole formed between the 0-minute and 60-minute reaction samples. The stability of the evaluation compound in buffer solution was assessed based on the change in epipiperazole amount.

[0500] The results are presented below. The decrease in compound concentration (μmol / L) and the concentration of formed epipiperazole (μmol / L) were determined in duplicate, and the average value was used.

[0501] Table 5

[0502] discuss

[0503] Although the example compounds are the same quaternary ammonium compounds as the control compounds (Reference Examples 5, 6, and 7), the example compounds are stable in buffer solution and do not convert to epipiperazole. In contrast, the control compounds clearly degrade to epipiperazole. These results indicate that the example compounds of this application are stable for pharmaceutical formulations, demonstrating their potential for stable use as prodrugs of epipiperazole.

[0504] Example 1 Preparation of pharmaceutical compositions of the compounds - 1

[0505] Example A: A 1.25 mg / mL solution formulation of the compound from Example 1

[0506] The compound of Example 1 was dissolved at a concentration of 1.25 mg / mL in a phosphate-buffered saline solution (pH: 7.4) containing 10% dimethyl sulfoxide and 0.09% polysorbate 80.

[0507] Example B: 0.5 mg / mL solution formulation of the compound from Example 1

[0508] Weigh approximately 80% of the final dosage volume of water for injection, add D-mannitol and sodium monohydrate of phosphate, and stir to dissolve. Add the compound of Example 1 and stir to disperse. Gradually add 1 M sodium hydroxide solution to dissolve the compound of Example 1 and adjust the pH to 8.0. After adding the remaining water for injection to reach the final dosage, sterilize the mixture by filtering it through a 0.2 μm PVDF membrane. The composition per milliliter is shown below.

[0509] Table 6

[0510] Composition of Example B (a 0.5 mg / mL solution of the compound from Example 1) Based on the conversion of anhydrous substances Example C: A 5.0 mg / mL solution formulation of the compound from Example 1 Weigh approximately 80% of the final dosage volume of water for injection, add D-mannitol and sodium monohydrate of phosphate, and stir to dissolve. Add the compound of Example 1 and stir to disperse. Gradually add 1 M sodium hydroxide solution to dissolve the compound of Example 1 and adjust the pH to 8.0. After adding the remaining water for injection to reach the final dosage, sterilize the mixture by filtering it through a 0.2 μm PVDF membrane. The composition per milliliter is shown below.

[0511] Table 7

[0512] Composition of Example C (5.0 mg / mL solution of the compound from Example 1) Based on the conversion of anhydrous substances Evaluation of the pharmaceutical composition of Example A The pharmaceutical composition of Example A (a 1.25 mg / mL solution of the compound of Example 1) was administered subcutaneously to male rats, and the plasma concentrations of the compound of Example 1 and ipilipazole were measured. The male rats were purchased at 7 weeks of age from JapanSLC, Inc. and used in the experiment after initial rearing. The rearing environment was as follows: Food and water intake: unrestricted; number of animals per cage: 3; temperature: 23±2℃; humidity: 60±10%; light duration: 7:00–19:00.

[0513] Under isoflurane anesthesia, the compound was administered subcutaneously to the back of rats 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, 1, 2, 4, 6, and 8 hours after administration. The blood was immediately heparinized and cooled with ice. Plasma was separated by centrifugation, and the compound concentration was quantified by LC-MS.

[0514] Figure 1 The change in plasma drug concentration following subcutaneous administration of the pharmaceutical composition of Example A (a 1.25 mg / mL solution of the compound of Example 1) is shown. Since the compound of Example 1 and epipiperazole were detected in plasma 5 minutes after administration, it is presumed that the compound of Example 1 immediately reaches the bloodstream and systemic system from the subcutaneous site and immediately forms epipiperazole in the blood. The plasma concentration of epipiperazole reaches its maximum 1 hour after subcutaneous administration. Therefore, immediate pharmacological action is expected. Thus, the pharmaceutical composition containing the compound of Example 1 in solution form is promising for use as a therapeutic agent, for example, as a symptom reliever in patients with agitation in the acute phase of schizophrenia or Alzheimer's dementia, because epipiperazole is immediately formed in the body after subcutaneous administration, and the formed epipiperazole exerts its pharmacological effect.

[0515] Example 1 Preparation of pharmaceutical compositions of the compounds - 2

[0516] Example D: A 150 mg / g aqueous suspension of the compound from Example 1

[0517] Sodium carboxymethyl cellulose (CMC-Na) (1.0% (w / w)), sodium chloride (0.9% (w / w)), and sodium dihydrogen phosphate monohydrate (0.074% (w / w)) were dissolved in water for injection such that the concentrations of these components were as stated. The pH was adjusted to 6.8 with sodium hydroxide, and the resulting aqueous solution was sterilized by filtration through a 0.2 μm, PES membrane in a laminar flow hood. The compound of Example 1 was added to the aqueous solution to the indicated concentration (150 mg / g) to prepare a primary aqueous suspension. A pressure-sterilized magnetic stirrer and 1 g of pressure-sterilized 1.0 mm diameter zirconia beads were added to the primary aqueous suspension, and after sealing the container, the mixture was stirred at 5°C for 21 hours, followed by wet milling to prepare a secondary aqueous suspension. Only the secondary aqueous suspension was collected from the zirconia bead mixture using a sterile pipette. The particle size distribution of the secondary aqueous suspension was measured using a SALD-3100 laser diffraction particle size analyzer (Shimadzu Corporation). The average particle size was measured after one minute of ultrasonic irradiation using the built-in device, by setting the refractive index from 2.00 to 0.20i; the average particle size was 1.9 μm.

[0518] Evaluation of the pharmaceutical composition in Example D

[0519] The pharmaceutical composition of Example D (a 150 mg / g aqueous suspension of the compound of Example 1) was administered subcutaneously to male rats, and the plasma concentrations of the compound of Example 1 and epilapiazole were measured.

[0520] The male rats were purchased from Japan SLC, Inc. at 7 weeks of age and used for experiments after initial rearing. The rearing environment was as follows: food and water intake: unrestricted; number of animals per cage: 3; temperature: 23±2℃; humidity: 60±10%; light time: 7:00-19:00.

[0521] Under isoflurane anesthesia, rats were administered the compound subcutaneously via the back using a plastic syringe. The dose was adjusted to 25 mg / kg of ipilipazole. Approximately 0.5 mL of blood was collected at 2 hours, 1 day, 3 days, 6 days, 9 days, and 14 days post-administration. The blood was immediately heparinized and cooled on ice. Plasma was separated by centrifugation, and compound concentrations were quantified by LC-MS.

[0522] Figure 2The changes in plasma drug concentrations after subcutaneous administration of the pharmaceutical composition of Example D (a 150 mg / g aqueous suspension of the compound of Example 1) to male rats are shown.

[0523] When the pharmaceutical composition of Example D was administered subcutaneously, the compound of Example 1 and epipiperazole were detected 2 hours after administration. The plasma concentration of epipiperazole remained almost constant from 2 to 24 hours after administration, and decreased rapidly from day 3 onwards. Therefore, it is expected that injection of an aqueous suspension of the compound of Example 1 will exert its pharmacological effect by maintaining epipiperazole in plasma for approximately 1 day after subcutaneous administration. Therefore, the pharmaceutical composition obtained by suspending the compound of Example 1 in water for injection is expected to generate epipiperazole in the body immediately after subcutaneous administration, maintaining an almost constant plasma level of epipiperazole for one day after administration, thereby exerting the pharmacological effect of epipiperazole. Therefore, this pharmaceutical composition holds promise as a useful and very convenient pharmaceutical composition for daily use as a subcutaneous injection, for example, for patients with agitation exhibiting a tendency to refuse medication in schizophrenia, depression, and Alzheimer's dementia.

[0524] Example 1 Preparation of pharmaceutical compositions of the compounds - 3

[0525] Example E: A 159 mg / g aqueous suspension of the zinc salt of the compound from Example 1

[0526] Sodium carboxymethyl cellulose (CMC-Na) (1.0% (w / w)), D-mannitol (4.5% (w / w)), and sodium dihydrogen phosphate monohydrate (0.074% (w / w)) were dissolved in water for injection such that the concentrations of these components were as stated. The pH was adjusted to 6.0 with sodium hydroxide, and the resulting aqueous solution was sterilized by filtration through a 0.2 μm PES membrane in a laminar flow hood to prepare a suspension medium. The zinc salt of the compound from Example 1 (757 mg) and the suspension medium (3873 mg) were weighed and mixed. The average particle size of the resulting suspended particles was 3.9 μm. The average particle size was measured using a SALD-3100 laser diffractometer (Shimadzu Corporation) by setting the refractive index to 2.00 to 0.20i after ultrasonic irradiation with the built-in device for one minute.

[0527] Evaluation of the pharmaceutical composition of Example E

[0528] The pharmaceutical composition of Example E (a 159 mg / g aqueous suspension of the zinc salt of the compound of Example 1) was administered subcutaneously to male rats, and the plasma concentrations of the compound of Example 1 and epilapiazole were measured.

[0529] The male rats were purchased from Japan SLC, Inc. at 7 weeks of age and used for experiments after initial rearing. The rearing environment was as follows: food and water intake: unrestricted; number of animals per cage: 3; temperature: 23±2℃; humidity: 60±10%; light time: 7:00-19:00.

[0530] Under isoflurane anesthesia, rats were administered the compound subcutaneously via the back using a glass syringe. The dose was adjusted to 25 mg / kg of epipiperazole. 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 post-administration. The blood was immediately heparinized and cooled with ice. Plasma was separated by centrifugation, and compound concentrations were quantified by LC-MS. Figure 3 The changes in plasma drug concentrations after subcutaneous administration of the pharmaceutical composition of Example E (a 159 mg / g aqueous suspension of the zinc salt of the compound of Example 1) to male rats are shown.

[0531] When the pharmaceutical composition of Example E was administered subcutaneously, the compound of Example 1 and ipilipazole were detected 2 hours after administration, and the plasma drug concentration reached its peak at 24 hours. Compared with Example D, the plasma drug concentration was suppressed at 2 hours and 24 hours, confirming the sustained-release effect of the zinc salt. From day 3 until day 14, the plasma drug concentration remained at a constant level. Therefore, it is expected that the injection of an aqueous suspension of the zinc salt of the compound of Example 1 will exert its pharmacological effect by maintaining ipilipazole in the plasma for 1 to 14 days after subcutaneous administration. Therefore, the pharmaceutical composition obtained by suspending the zinc salt of the compound of Example 1 in water for injection is expected to form ipilipazole in the body immediately after subcutaneous administration, maintain ipilipazole in the plasma for several days or longer after administration, and exert the pharmacological effect of ipilipazole. Therefore, this pharmaceutical composition is expected to be used as a useful and very convenient pharmaceutical composition for daily and weekly use as a subcutaneous injection, for example, for patients with agitation in schizophrenia, depression, and Alzheimer's dementia who show a tendency to refuse medication.

[0532] Example 1 Preparation of pharmaceutical compositions of the compounds - 4

[0533] Example F: 150 mg / g liquid crystal / lipogel formulation of the compound from Example 1

[0534] Soy lecithin (soy phosphatidylcholine (SPC) (LIPOID S 100, Lipoid)) and dioleoylglycerol (GDO) (isomeric mixture 1,2 / 1,3-GDO, Merck) were added to ethanol, and the mixture was heated to dissolve at 40 to 50 °C. The resulting solution was filtered through a 0.2 μm disc filter, and the compound of Example 1 was added to the filtrate. The mixture was then homogenized by vortexing. The composition of the resulting formulation is shown below.

[0535] Table 8

[0536] Composition of Example F (150 mg / g liquid crystal / lipogel formulation of the compound from Example 1) The amount of compound (anhydrous) in Example 1 was 15.0 w / w, and the water content was 2.5 w / w. The amount calculated as epipiperazole was 12.0 w / w.

[0537] Example G: A 159 mg / g liquid crystal / lipid gel formulation of the zinc salt of the compound from Example 1.

[0538] Soy lecithin (soy phosphatidylcholine (SPC) (LIPOID S 100, Lipoid)) and dioleoylglycerol (GDO) (isomer mixture 1,2 / 1,3-GDO, Merck) were added to a mixture of DMSO and ethanol and heated to dissolve at 40 to 50 °C. The resulting 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. The mixture was then homogenized by vortexing. The composition of the resulting formulation is shown below.

[0539] Table 9

[0540] Composition of Example G (159 mg / g liquid crystal / lipid gel formulation of zinc salt of compound from Example 1) The amount of zinc salt (anhydrous) in the compound of Example 1 was 15.9 w / w, and the water content was 0.5 w / w. The amount calculated as epipiperazole was 12.0 w / w.

[0541] Evaluation of the pharmaceutical compositions in Examples F and G

[0542] Viscosity measurement

[0543] When measured using a rheometer (Discovery Mixed Rheometer (DHR)-2, manufacturer: TA Instruments), the viscosity of formulation F is 402 mPa at shear rates of 9000 to 10000 (1 / s). The conditions for viscosity measurement are as follows.

[0544] - Shear rate within the measurement range: 0.1 → 10000 (1 / s)

[0545] - Temperature measured: 20℃

[0546] - Use a 20 mm flat plate

[0547] - Gap: 50 μm (40 mm flat plate)

[0548] Changes in plasma drug concentration

[0549] The pharmaceutical compositions (formulations) of Examples F and G were administered subcutaneously to male rats, and the plasma concentrations of the compound of Example 1 and epilapiazole were measured.

[0550] The male rats were purchased from Japan SLC, Inc. at 7 weeks of age and used for experiments after initial rearing. The rearing environment was as follows: food and water intake: unrestricted; number of animals per cage: 3; temperature: 23±2℃; humidity: 60±10%; light time: 7:00-19:00.

[0551] Under isoflurane anesthesia, rats were administered the compound subcutaneously via the back using a glass syringe. The dose was adjusted to 25 mg / kg of epipiperazole. 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 post-administration. The blood was immediately heparinized and cooled with ice. Plasma was separated by centrifugation, and compound concentrations were quantified by LC-MS. Figure 4 and 5 The changes in plasma drug concentrations after subcutaneous administration of the drug compositions of Examples F and G to male rats are shown, respectively.

[0552] Example F maintained a relatively high plasma concentration of epipiperazole in the initial phase after administration and also showed a relatively high plasma concentration of epipiperazole even 14 days after administration; the plasma concentration of epipiperazole was maintained for 14 days or longer. The plasma drug concentration was even more inhibited compared to the aqueous suspension of Example D, confirming the sustained-release effect of the liquid crystal / lipogel formulation.

[0553] Example G maintained a relatively high plasma concentration of epipiperazole in the initial phase after administration and exhibited a relatively high plasma concentration even 21 days after administration; the plasma concentration of epipiperazole was maintained for 21 days or longer. The plasma drug concentration was even more inhibited compared to the aqueous suspension of the zinc salt in Example E, confirming the sustained-release effect of the liquid crystal / lipogel formulation. These results indicate that the pharmaceutical composition forming the liquid crystal / lipogel of the compound of Example 1 or its salt can control the release of the compound of Example 1 from the formulation by combining a suitable sustained-release base with a metal salt, and that the level of epipiperazole exposure in the blood can be maintained at a level sufficient to exert a therapeutic effect for 14 to 21 days or longer by converting the compound of Example 1 into epipiperazole in vivo. Because this pharmaceutical composition maintains a relatively high blood concentration of epipiperazole in the early phase after administration, blood drug concentrations can be maintained without the need for combined use of oral medications or shorter injection intervals to compensate for blood drug concentrations at the start of treatment with a sustained-release injectable. Therefore, this pharmaceutical composition holds promise for use, for example, as a pharmaceutical composition for the prevention of relapse in conditions such as schizophrenia.

[0554] Example 1 Preparation of pharmaceutical compositions of the compounds - 5

[0555] Examples H, I, J, K, L, M, N, and O: 300-400 mg / g microspheres of the compound from Example 1

[0556] According to the compositions shown in the table below, the compounds of Example 1 and poly(lactide-co-glycolic acid) copolymers (lactic acid-glycolic acid copolymers (PLGA)) as biodegradable polymers (e.g., Resomer RG 505, Resomer RG 504, Resomer RG 503, Resomer RG 502, Resomer RG 752 H or Lactel 85:15 polyester-terminated poly(DL-lactide-co-glycolic acid) (PLGE), intrinsic viscosity range (IV): 0.76-0.85 dL / g (all Resomer and Lactel products are from Evonik)) were dissolved in dichloromethane (FUJIFILM Wako Pure Chemical Corporation) and acetic acid (FUJIFILM Wako Pure Chemical Corporation) to prepare the oil phase. Polyvinyl alcohol 40-88 (Merck) was dissolved in purified water to 0.5% to prepare the aqueous phase (continuous phase). While homogenizing the aqueous phase using a TK Robomix (PRIMIX Corporation) equipped with a homogenizer at 2000 to 3000 rpm, the oil phase was added dropwise. Then, while stirring with a stirrer at 200 to 500 rpm, the aqueous phase was dried in the solution for 5 hours to prepare microspheres, and the dried microspheres were observed under a polarized light microscope. After drying in the solution, additional washing was performed as needed by adding 99.5% ethanol or an alkali such as 1N sodium hydroxide solution. After drying in the solution, the aqueous phase was removed by suction using a filter device with a 20 μm nylon filter screen, and the microspheres were filtered out. Approximately 1 / 5 the volume of purified water used was poured onto the filtered microspheres to thoroughly wash away PVA and collect the microspheres. The microspheres were collected in Falcon tubes and frozen at -20°C or lower, then freeze-dried using a LyoStar 3 freeze dryer (SPScientific) to collect the microsphere powder.

[0557] The following are the molar ratio of lactic acid to glycolic acid, characteristics, weight-average molecular weight, and intrinsic viscosity range (dL / g) for each type of PLGA used.

[0558] Resomer RG 505: Lactide: Glycolide 50:50, ester-terminated, molecular weight 54000-69000

[0559] Resomer RG 504: Lactide: Glycolide 50:50, ester-terminated, molecular weight 38000-54000, 0.45-0.60

[0560] Resomer RG 503: Lactide: Glycolide 50:50, ester-terminated, molecular weight 24000-38000, 0.32-0.44

[0561] Resomer RG 502: Lactide: Glycolide 50:50, ester-terminated, molecular weight 7000-17000, 0.16-0.24

[0562] Resomer RG 752 H: lactide: glycolide 75:25, acid-capped, molecular weight 4000-15000, 0.14-0.22

[0563] Lactel 85:15 PLGE IV 0.76-0.85: lactide: glycolide 85:15, ester-capped, unknown, 0.76-0.85

[0564] Table 10

[0565] Composition of H to O (microspheres of the compound from Example 1) and rotation speed during homogenization process Use an amount that is 5% larger than the indicated amount (for example, 2.0 g in Example H is actually 2.0 × 1.05 = 2.1 g).

[0566] Evaluation of pharmaceutical compositions of examples H to O

[0567] Polarized light microscopy observation

[0568] Microspheres of Examples I, J, and K were observed under a polarizing microscope after drying in liquid. Figure 6 , 7 Figures 8 and 9 show the results. All results confirm the formation of microspheres.

[0569] Measurement of average particle size

[0570] The obtained microspheres were suspended in a 0.5% sodium carboxymethyl cellulose solution, and the particle size was measured using a SALD-3100 laser diffraction particle size analyzer (Shimadzu Corporation) via laser diffraction scattering. Purified water was used as the solvent, and measurements were performed in either a batch or circulating tank. For the batch tank, the stirring speed was set to maximum, and for the circulating tank, the circulation speed was set to 5. The formulation was added dropwise to the purified water to achieve optimal concentration, and the refractive index was set from 2.00 to 0.20i to measure the average particle size. The results are shown in the table below. The average particle size ranged from 50 to 85 µm, and the average particle size in the production example is suitable for maintaining blood concentrations for one month or longer.

[0571] Table 11

[0572] Average particle size of compounds H to O in Examples (microspheres of compound 1)

[0573] Drug content percentage

[0574] The obtained microspheres (20 mg) were dissolved in 10 mL of dimethyl sulfoxide / acetic acid (4 / 1) solution, and the drug content percentage in the microspheres was determined by HPLC using a test solution obtained by diluting 1 mL of the resulting solution 10-fold with acetonitrile. The drug content percentage for each production example was determined by HPLC. The results are shown below. As shown in the table below, the drug content percentage for Examples H to O was 80% or higher.

[0575] Table 12

[0576] Drug content percentage (%) of Examples H to O (microspheres of compounds from Example 1) : :

[0577] Since the microspheres are prepared via a drying step, the denominator (the theoretical concentration of the compound of Example 1 in the microspheres) in the formula for the percentage (%) of the drug contained above essentially represents the concentration of the compound of Example 1 relative to the total amount of the compound of Example 1 and PLGA used.

[0578] Changes in plasma drug concentration

[0579] For animal administration, suspensions of the MCTs in Examples H, J, K, and L were prepared by adding medium-chain triglycerides (MCT, obtained from Croda and used as a solvent) to the microsphere powders of Examples H, J, K, and L to a concentration of 300 mg / mL. These suspensions were administered subcutaneously to male rats, and the plasma concentrations of the compounds of Example 1 and epipiperazole were measured.

[0580] The male rats were purchased from Japan SLC, Inc. at 7 weeks of age and used for experiments after initial rearing. The rearing environment was as follows: food and water intake: unrestricted; number of animals per cage: 2 to 3; temperature: 23±2℃; humidity: 60±10%; light time: 7:00-19:00.

[0581] Under isoflurane anesthesia, rats were administered the drug subcutaneously via the back using a glass syringe. For all formulations, the dose was adjusted to 25 mg / kg of epipiperazole. Following administration, 0.5 mL of blood was collected from the jugular vein at various times. For Example H, blood was collected at 2 hours, 1 day, 3 days, 6 days, 9 days, 14 days, 21 days, and 28 days after administration. For Examples J, K, and L, blood was collected at 2 hours, 1 day, 3 days, 7 days, 10 days, 14 days, 21 days, 28 days, 35 days, 42 days, and 56 days after administration. The collected blood was immediately heparinized and cooled with ice. Plasma was separated by centrifugation, and the concentrations of the compounds and epipiperazole in the examples were determined by LC-MS.

[0582] Figure 9 , 10 Figures 11 and 12 show changes in plasma drug concentrations following subcutaneous administration of the pharmaceutical compositions of Examples H, J, K, and L to male rats. All cases confirmed an immediate increase in blood concentrations after administration, and also confirmed that blood concentrations of epipiperazole were maintained for a month or longer. These results indicate that pharmaceutical compositions of microspheres containing the compounds of Example 1 can control the release of the compounds of Example 1 from the formulation by using suitable biodegradable polymers to prepare microspheres containing the compounds of Example 1, and that the level of epipiperazole exposure in the blood can be maintained at a level sufficient to exert a therapeutic effect for a month or longer by converting the compounds of Example 1 into epipiperazole in vivo. Because this pharmaceutical composition maintains relatively high blood concentrations of epipiperazole in the early stages after administration, blood drug concentrations can be maintained without the need for combined use with oral agents or shorter injection intervals to compensate for blood drug concentrations at the start of treatment with a sustained-release injectable. Therefore, such pharmaceutical compositions hold promise for use, for example, in the prevention of relapse in conditions such as schizophrenia.

[0583] Example 3 Preparation of pharmaceutical compositions of the compounds

[0584] Example P

[0585] Sodium carboxymethyl cellulose (CMC-Na) (1.23% (w / v)), sucrose (5.75% (w / v)), sodium dihydrogen phosphate monohydrate (0.12% (w / v)), and anhydrous citric acid (0.16% (w / v)) were dissolved in water for injection to achieve the concentrations of these components as stated. The pH was adjusted to 5.0 by adding an appropriate amount of sodium hydroxide to prepare a suspension medium. Compound of Example 3 (712 mg) was added to the suspension medium (3288 mg), and the mixture was stirred to prepare a primary suspension. Zirconia beads (4 g) with a diameter of 2 mm were added to the primary suspension, and the particles of Compound of Example 3 were ground by stirring with a stirrer (grinding time: 8 hours). The zirconia beads were removed with a sterile pipette to prepare an aqueous suspension formulation of Compound of Example 3.

[0586] Example 10 Preparation of pharmaceutical compositions of the compounds

[0587] Example Q

[0588] Sodium carboxymethyl cellulose (CMC-Na) (0.796% (w / v)), sodium chloride (0.716% (w / v)), and sodium dihydrogen phosphate monohydrate (0.055% (w / v)) were dissolved in water for injection to achieve the concentrations of these components as stated. The pH was adjusted to 6.0 by adding an appropriate amount of sodium hydroxide to prepare a suspension medium. Compound 10 (816 mg) was added to the suspension medium (3184 mg), and the mixture was stirred to prepare a primary suspension. Zirconia beads (4 g) with a diameter of 2 mm were added to the primary suspension, and the particles of Compound 10 were ground by stirring with a stirrer (grinding time: 80 min). The zirconia beads were removed using a sterile pipette to prepare an aqueous suspension formulation of Compound 10.

[0589] Example 12 Preparation of pharmaceutical compositions of the compounds

[0590] Example R

[0591] Sodium carboxymethyl cellulose (CMC-Na) (0.813% (w / v)), sodium chloride (0.732% (w / v)), and sodium dihydrogen phosphate monohydrate (0.056% (w / v)) were dissolved in water for injection to achieve the concentrations of these components as stated. The pH was adjusted to 6.0 by adding an appropriate amount of sodium hydroxide to prepare a suspension medium. Compound 12 (748 mg) was added to the suspension medium (3252 mg), and the mixture was stirred to prepare a primary suspension. Zirconia beads (4 g) with a diameter of 2 mm were added to the primary suspension, and the particles of Compound 12 were ground by stirring with a stirrer (grinding time: 2 hours). The zirconia beads were removed using a sterile pipette to prepare an aqueous suspension formulation of Compound 12.

[0592] Example 13 Preparation of pharmaceutical compositions of the compounds

[0593] Example S

[0594] Sodium carboxymethyl cellulose (CMC-Na) (0.805% (w / v)), sodium chloride (0.725% (w / v)), and sodium dihydrogen phosphate monohydrate (0.056% (w / v)) were dissolved in water for injection to achieve the concentrations of these components as stated. The pH was adjusted to 6.0 by adding an appropriate amount of sodium hydroxide to prepare a suspension medium. Compound 13 (780 mg) was added to the suspension medium (3220 mg), and the mixture was stirred to prepare a primary suspension. Zirconia beads (4 g) with a diameter of 2 mm were added to the primary suspension, and the particles of compound 13 were ground by stirring with a stirrer (grinding time: 3 hours). The zirconia beads were removed using a sterile pipette to prepare an aqueous suspension formulation of compound 13.

[0595] Example 44 Preparation of pharmaceutical compositions of the compounds

[0596] Example T

[0597] Sodium carboxymethyl cellulose (CMC-Na) (0.791% (w / v)), sodium chloride (0.712% (w / v)), and sodium dihydrogen phosphate monohydrate (0.055% (w / v)) were dissolved in water for injection to achieve the concentrations of these components as stated. The pH was adjusted to 6.0 by adding an appropriate amount of sodium hydroxide to prepare a suspension medium. Compound 44 (836 mg) was added to the suspension medium (3164 mg), and the mixture was stirred to prepare a primary suspension. Zirconia beads (4 g) with a diameter of 2 mm were added to the primary suspension, and the particles of compound 44 were ground by stirring with a stirrer (grinding time: 4 hours). The zirconia beads were removed using a sterile pipette to prepare an aqueous suspension formulation of compound 44.

[0598] Preparation of pharmaceutical compositions of the compounds in Example 92

[0599] Example U

[0600] Sodium carboxymethyl cellulose (CMC-Na) (0.803% (w / v)), sodium chloride (0.723% (w / v)), and sodium dihydrogen phosphate monohydrate (0.055% (w / v)) were dissolved in water for injection to achieve the concentrations of these components as stated. The pH was adjusted to 6.0 by adding an appropriate amount of sodium hydroxide to prepare a suspension medium. Compound of Example 92 (788 mg) was added to the suspension medium (3152 mg), and the mixture was stirred to prepare a primary suspension. Zirconia beads (4 g) with a diameter of 2 mm were added to the primary suspension, and the particles of Compound of Example 92 were ground by stirring with a stirrer (grinding time: 24 hours). The zirconia beads were removed using a sterile pipette to prepare an aqueous suspension formulation of Compound of Example 92.

[0601] Example 121 Preparation of pharmaceutical compositions of the compounds

[0602] Example V

[0603] Hydroxypropyl cellulose (HPC) (4.02% w / v), glycerol (2.01% w / v), and histidine (0.06% w / v) were dissolved in water for injection to achieve the concentrations of these components as stated. The pH was adjusted to 7.0 by adding an appropriate amount of hydrochloric acid to prepare a suspension medium. Compound 121 (784 mg) was added to the suspension medium (3216 mg), and the mixture was stirred to prepare a primary suspension. Zirconia beads (4 g) with a diameter of 0.5 mm were added to the primary suspension, and the particles of compound 121 were ground by stirring with a stirrer (grinding time: 24 hours). The zirconia beads were removed using a sterile pipette to prepare an aqueous suspension formulation of compound 121.

[0604] Evaluation of pharmaceutical compositions of Examples P to V

[0605] Measurement of average particle size

[0606] The particle size of the obtained aqueous suspension was measured by laser diffraction scattering using a SALD-3100 laser diffraction particle size analyzer (Shimadzu Corporation) with the refractive index set from 2.00 to 0.20i. The results are shown below.

[0607] Table 13

[0608] Average particle size of P to V in Examples

[0609] Changes in plasma drug concentration

[0610] The aqueous suspensions of Examples P to V were administered subcutaneously to male rats, and the plasma concentrations of the compounds and epilapiazole of each example were measured.

[0611] The male rats were purchased from Japan SLC, Inc. at 7 weeks of age and used for experiments after initial rearing. The rearing environment was as follows: food and water intake: unrestricted; number of animals per cage: 3; temperature: 23±2℃; humidity: 60±10%; light time: 7:00-19:00.

[0612] Under isoflurane anesthesia, rats were administered the drug subcutaneously via the back using a plastic or glass syringe. For all formulations, the dose was adjusted to 25 mg / kg of epipiperazole. Following administration, 0.5 mL of blood was collected from the jugular vein at various times. Blood was collected at 2 hours, 1 day, 3 days, 6 days, 9 days, 14 days, 21 days, and 28 days post-administration. The collected blood was immediately heparinized and cooled with ice. To inhibit hydrolysis in the samples, 1% of a phosphatase inhibitor mixture (Nacalai Tesque, Inc.) and 10 mM 2-thiophenecarboxylic acid trifluoroacetone (TTFA) were added to blood samples from animals administered Example PU and Example V, respectively. Plasma was separated by centrifugation, and the concentrations of each compound and epipiperazole were determined by LC-MS. Figure 13 , 14 Examples 15, 16, 17, 18, and 19 show changes in plasma drug concentrations after subcutaneous administration of the pharmaceutical compositions of Examples P, Q, R, S, T, U, and V to male rats, with results shown as mean ± standard deviation for 3 to 5 examples. In all cases, compared to the pharmaceutical composition of Example D (an aqueous suspension of the compound of Example 1), the concentration of epipiperazole was maintained in an even more significant manner, and the blood concentration of epipiperazole was maintained for 2 weeks or longer to 4 weeks or longer. These results indicate that appropriate structural conversion of the compound of Example 1 can control the release of the compound from the formulation, and that the conversion of the compound to epipiperazole in vivo can maintain the level of epipiperazole exposure in the blood at a level sufficient to exert a therapeutic effect for 2 weeks or longer to 4 weeks or longer. Therefore, these products hold promise as pharmaceutical compositions that can be used, for example, for the prevention of relapse in conditions such as schizophrenia.

[0613] Dog stimulation studies

[0614] method

[0615] Male Beagles, aged 5-7 months, were purchased from Kitayama Labes Co., Ltd. and used for the experiment after acclimatization. The following conditions were observed: feeding: 250 g solid food once daily; water intake: unlimited; number of animals per cage: 1; temperature: 21-25℃; humidity: 50-70%; light time: 7:00-19:00. Using a plastic syringe, the test formulation was administered subcutaneously at a dose of 10 mg / kg to dogs anesthetized with 25 mg / kg sodium thiopental, changing the position on the back. After administration, the dogs were observed for 14 days, then euthanized by exsanguination under anesthesia with 25 mg / kg sodium thiopental, and tissue was collected from the injection site. The collected tissue was fixed in 10% neutral buffered formalin and stained with hematoxylin and eosin for histopathological examination.

[0616] Results and discussion

[0617] For some compounds, external observation and histopathological examination of the injection site indicate that the changes at the injection site are a physiological response to the foreign body, and the irritation is within acceptable limits.

Claims

1. A compound or a salt thereof represented by formula (I): in R 1 and R 2 Each is represented independently -O - -OR 4 or -NR 4Na R 4Nb , R 3 Indicates hydrogen or alkyl. R 4 R 4Na and R 4Nb Each independently represents hydrogen or each optionally has one to three substituents, namely alkyl, alkenyl, dienyl or ynyl, wherein R 4 R 4Na or R 4Nb The alkyl group may have one or more methylene groups (-CH2-) surrounded by -O-, -S-, -CO-, -NH-, or -SiR. sia R sib The structure is replaced by - or -(CO)O-. R sia and R sib They can be the same or different, and represent hydrogen or C. 1-6 alkyl, If R 1 and R 2 Both indicate -OR 4 Then R 1 and R 2 They can be the same or different, and If R 1 and R 2 Both indicate -NR 4Na R 4Nb Then R 1 and R 2 They can be the same or different.

2. The compound or a salt thereof according to claim 1, wherein... R 1 Indicates -O - , R 2 Indicates -OR 4 or -NR 4Na R 4Nb , where R 4 R 4Na and R 4Nb As defined above.

3. A compound represented by formula (I) or a salt thereof: in R 1 Indicates -O - , R 2 Indicates -OR 4 or -NR 4Na R 4Nb , R 3 Indicates hydrogen or C 1-6 alkyl, R 4 Represents hydrogen or any of the following (0-1) to (5), -NR 4Na R 4Nb This indicates either (i) or (ii): (0-1): optionally having 1 to 3 ions selected from halogens, hydroxyl groups, C 1-6 Alkyl and C 1-6 C of alkoxy substituent 1-18 alkenyl, (0-2): optionally having 1 to 3 ions selected from halogens, hydroxyl groups, C 1-6 Alkyl and C 1-6 C of alkoxy substituent 1-18 Dieneyl, (0-3): optionally having 1 to 3 ions selected from halogens, hydroxyl groups, C 1-6 Alkyl and C 1-6 C of alkoxy substituent 1-18 alkynyl group, (1-1)：R 4a1 ， Where R 4a1 express -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 -OH, Where n represents 1 to 24, and the condition is in -C n H 2n-1 In -C, n is 2 or greater; n H 2n-3 In -C, n is 2 or greater; n H 2n-2 - where n is 2 or greater; and in -C n H 2n-4 - where n is 2 or greater (1-2)：R 4a2 ， Where R 4a2 express -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 , in n represents 2 to 24, and the condition is in -C n-1 H 2n-4 -n indicates 3 or greater; in -C n-1 H 2n-6 - In this context, n represents 3 or greater. X 1 and X 2 The same or different and representing hydrogen or halogen (F, Cl, Br or I), condition X 1 or X 2 Either or both of them represent halogens. (1-3)：R 4a3 ， Where R 4a3 express -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 , in n represents 1 to 24, and the condition is in -C n H 2n-2 -n in - indicates 2 or greater; in -C n H 2n-4 - In this context, n represents 2 or greater. R 4-1 C represents 1-6 Alkoxy, -O-phenyl, or optionally C 1-6 Alkyl or halogen-substituted heterocyclic groups, R 4-1a and R 4-1b Same or different and indicate -C 1-3 Alkylene-C 1-3 Alkyl groups, or the same or different ones, and indicating -CO-OC 1-3 Alkyl or -CH2-CO-OC 1-3 alkyl, (2)：R 4b ， Where R 4b express -(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 , Where p represents 1 to 4, q represents 1 to 4, r represents 1 to 4, and the condition is C. p H 2p-2 In C, p represents 2 or greater. r H 2r-2 In this context, r represents 2 or greater. When q is 2 to 4, the 2 to 4 repeating structures represented by q can be the same or different. R 4-2 It represents hydrogen, hydroxyl, or each optionally having 1 to 3 C atoms selected from C. 1-6 Alkyl, C 1-6 Alkoxy, -C 1-3 Alkylene-C 1-3 The alkoxy and nitro substituents are cycloalkyl, phenyl, benzyl, or heterocyclic groups. (3): -C α H 2α -CO-OR COO or -C α H 2α -CO-O-CH2-R COO Where α represents 1 to 10, Where –R COO Represents hydrogen, each optionally bound by 1 to 3 carbon atoms. 1-6 alkoxy-substituted C 1-6 Alkyl or C 1-6 alkoxy groups, or each optionally having 1 to 3 C2 groups. 1-6 Alkyl, C 1-6 Alkoxy, -C 1-3 Alkylene-C 1-3 The alkoxy and nitro substituents are cycloalkyl, phenyl, benzyl, or heterocyclic groups. (4): -C β H 2β -O-CO-R OCO Where β represents 1 to 10, Where -R OCO R represents 4a1 R 4b or -C α H 2α -CO-OR COO ,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 , where -R COO As defined above, or Each may optionally have 1 to 3 selected from C 1-6 Alkyl, C 1-6 Alkoxy, -C 1-3 Alkylene-C 1-3 The alkoxy and nitro substituents are cycloalkyl, phenyl, benzyl, or heterocyclic groups. (5): -C γ H 2γ -O-CO-OR OCOO Where γ represents 1 to 10, Where -R OCOO Represents hydrogen, R 4a1 R 4b or -C α H 2α -CO-OR COO , where -R COO As defined above, or Each may optionally have 1 to 3 selected from C 1-6 Alkyl, C 1-6 Alkoxy, -C 1-3 Alkylene-C 1-3 The alkoxy and nitro substituents are cycloalkyl, phenyl, benzyl, or heterocyclic groups. (i) R 4Na and R 4Nb Same or different, and indicates that it is optionally controlled by 1 to 3 Cs. 1-6 alkoxy-substituted C 1-6 alkyl, (ii) R 4Na Represents hydrogen, and R 4Nb Indicates that it can be arbitrarily divided by 1 to 3 Cs 1-6 alkoxy-substituted C 1-6 Alkyl, or -C α H 2α -CO-OR COO or -C α H 2α -CO-NH-R COO , Where -R COO As defined above.

4. The compound or a salt thereof according to any one of claims 1 to 3, wherein the heterocyclic group has a structure in which hydrogen atoms bonded to constituent atoms of the heterocycle are removed from the heterocycle, the heterocycle being selected from furan, tetrahydropyran, tetrahydrofuran, 1,3-dihydropyran, and 1,3-dihydropyran. Alkane, 1,4-di Alkane, pyrrole, imidazole, pyrazole, pyridine, pyrimidine, pyrazine, pyridazine, pyrrolidine, imidazoline, thiophene, piperidine, piperazine azole, isotonic azole, Diazole, morpholine, indole, indazole, benzimidazole, and quinoline.

5. The compound or a salt thereof according to claim 1 or 2, wherein -OR 4 This indicates any group listed in the table below, where the asterisk " "" indicates relative to oxygen atom and R 4 The opposite side ( -OR 4 ): And -NR 4Na R 4Nb This indicates any group listed in the table below, where the asterisk " "" indicates relative to nitrogen atom and R 4Na R 4Nb The opposite side ( -NR 4Na R 4Nb ): 。 6. A compound represented by formula (II) or a salt thereof: in R 3 Indicates hydrogen or C 1-6 alkyl, R 4 C represents hydrogen or optionally has 1 to 3 substituents. 1-18 alkyl, The substituents independently represent halogens, hydroxyl groups, and C. 1-6 Alkyl group, -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 Cycloalkyl or optionally substituted heterocyclic groups, R 5 R 5a R 6 R 9 R 10 and R 13 Independently representing hydrogen and C 1-16 Alkyl or C 3-7 cycloalkyl, R 7 and R 8 Independently representing hydrogen or optionally one or two methylene groups replaced by oxygen or nitrogen atoms. 1-6 alkyl, R 7 and R 8 They can combine to form rings. R 11 and R 12 Independently representing hydrogen or C 1-16 Alkyl groups, wherein two or more R groups are present 11 Then the two or more R 11 Independently representing hydrogen or C 1-16 Alkyl groups, and if two or more R groups are present 12 Then the two or more R 12 Independently representing hydrogen or C 1-16 Alkyl, and n represents an integer from 1 to 10.

7. The compound or a salt thereof according to claim 6, in R 4 Indicates hydrogen or -(AY) m -R 14 , A represents C 1-18 Alkylene Y represents -O-, -(CO)O-, -O(CO)O-, or -(CO)NH-. R 14 Indicates hydrogen, C 1-18 Alkyl, hydroxyl, cycloalkyl, or heterocyclic groups, and m represents an integer from 0 to 5.

8. The compound or a salt thereof according to claim 6, in R 4 C represents hydrogen or optionally has a substituent. 1-8 alkyl, The substituents independently represent hydroxyl, C 1-6 Alkyl group, -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 optionally have two Cs 1-6 Alkyl morpholino, n represents an integer from 1 to 10. R 5 R 5a R 6 R 9 R 10 and R 13 Independently representing hydrogen and C 1-16 Alkyl, optionally substituted heterocyclic, or C 3-7 cycloalkyl, and A represents C 1-6 Alkylene.

9. The compound or a salt thereof according to claim 6, in R 4 C represents hydrogen or optionally has a substituent. 1-8 alkyl, The substituents independently represent hydroxyl, C 1-6 Alkyl group, -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 optionally have 1 or 2 Cs 1-6 alkyl heterocyclic groups, n represents an integer from 1 to 10. R 5 C represents 1-6 alkyl, R 5a C represents 1-6 alkyl, R 6 C represents 1-6 alkyl, R 9 C represents 1-16 alkyl, R 13 C represents 1-6 Alkyl groups or optionally having C 1-6 Alkyl pyridyl, and A represents C 1-6 Alkylene.

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

11. The pharmaceutical composition of claim 10, comprising the compound or salt thereof according to any one of claims 1 to 9, a suspending agent and a dispersion medium, wherein the pharmaceutical composition is 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 from 0.5 μm to 30 μm.

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

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

15. A pharmaceutical composition comprising a viscous mixture of the following substances: a) The compound or a salt thereof according to any one of claims 1 to 9, b) Two or more lipids that form liquid crystals or lipids that form gels, and c) Biocompatible organic solvents, The pharmaceutical composition is a prodrug for forming a liquid crystal phase structure or lipid gel by contacting the pharmaceutical composition with an aqueous fluid in vivo.

16. The pharmaceutical composition of claim 15, wherein b) the two or more liquid crystal forming lipids or gel forming lipids contain b-1) at least one diacylglycerol, and b-2) At least one phosphatidylcholine.

17. A pharmaceutical composition comprising a viscous mixture of the following substances: a) The compound or a salt thereof according to any one of claims 1 to 9, b-1) At least one diacylglycerol, b-2) At least one phosphatidylcholine, and c) Biocompatible organic solvents.

18. A microsphere comprising, as an active ingredient, a compound or a salt thereof according to any one of claims 1 to 9.

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

20. The microspheres of claim 19, wherein the biodegradable polymer is selected from at least one of polylactic acid and lactic acid-diol copolymers.

21. The microspheres according to any one of claims 18 to 20, having an average particle size of 5 μm to 150 μm.

22. A pharmaceutical composition comprising microspheres according to any one of claims 18 to 21, and in suspension form.

23. A pharmaceutical composition comprising microspheres according to any one of claims 18 to 21, and in the form of an oil suspension.

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

25. The pharmaceutical composition according to any one of claims 10 to 17 and 22 to 24, for intramuscular or subcutaneous administration.

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

27. The pharmaceutical composition of claim 26, wherein the central nervous system disease is selected from: schizophrenia, treatment-resistant, refractory or chronic schizophrenia, schizoaffective disorder, psychotic disorder, mood disorder, bipolar disorder, mania, depression, endogenous depression, major depressive disorder, melancholic and treatment-resistant depression, dysphoric disorder, cyclothymic mood disorder, anxiety disorder, somatic symptom disorder, affective disorder, dissociative disorder, sexual dysfunction, eating disorder, sleep disorder, adjustment disorder, substance-related disorder, loss of interest, 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 caused by treatment-resistant, refractory or chronic schizophrenia, vomiting, motion sickness, obesity, migraine, pain, intellectual disability, autism, Tourette syndrome, tic disorder, attention deficit hyperactivity disorder, conduct disorder, Down syndrome, impulsive symptoms associated with dementia, and borderline personality disorder.

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