RU2003101970A - CONDENSED ASEPINE DERIVATIVES AND THEIR USE AS ANTI-DIURETIC AGENTS - Google Patents

Claims (43)

1. The compound corresponding to General formula 1 or 2, or its tautomer or pharmaceutically acceptable salt

where W represents either N or CR ⁴ ; R ¹ -R ⁴ are independently selected from H, F, Cl, Br, alkyl, CF ₃ , phenyl, OH, O-alkyl, NH ₂ , NH-alkyl, N (alkyl) ₂ , NO ₂ and CN, or R ² and R ³ together may represent —CH═CH — CH═CH—; G ¹ represents a bicyclic or tricyclic condensed derivative of azepine selected from general formulas 3-8,

in which A ¹ , A ⁴ , A ⁷ and A ^{10 are} each independently selected from CH ₂ , O and NR ⁵ ; A ² , A ³ , A ⁹ , A ¹¹ , A ¹³ , A ¹⁴ and A ¹⁵ , each independently selected from CH and N; either A ⁵ represents a covalent bond and A ⁶ represents S, or A ⁵ represents N = CH and A ⁶ represents a covalent bond; A ⁸ and A ¹² are each independently selected from NH, N-CH ₃ and S; A ¹⁶ and A ¹⁷ are both CH ₂ or one of A ¹⁶ and A ¹⁷ is CH ₂ and the other is selected from CH (OH), CF ₂ , O, SO _a and NR ⁵ ; R ^{5 is} selected from H, alkyl, CO-alkyl, and (CH ₂ ) _b R ⁶ ; R ^{6 is} selected from phenyl, pyridyl, OH, O-alkyl, NH ₂ , NH-alkyl, N- (alkyl) ₂ , NO ₂ , CO ₂ H and CN; a = 0, 1 or 2; b is 1, 2, 3 or 4; Y represents CH or N; Z represents CH = CH or S; and G ² represents a group selected from general formulas 9-11

in which Ar is selected from phenyl, pyridyl, naphthyl and mono- or polysubstituted phenyl or pyridyl, where the substituents are selected from F, Cl, Br, alkyl, OH, O-alkyl, NH ₂ , NH-alkyl, N (alkyl) ₂ , NO ₂ or CN; D represents a covalent bond or NH; E ¹ and E ² are both H, OMe or F, or one of E ¹ and E ² is OH, O-alkyl, OBn, OPh, OAc, F, Cl, Br, N ₃ , NH ₂ , NHBn or NHAc and the other represents H, or E ¹ and E ² together represent = O, —O (CH ₂ ) _q O— or —S (CH ₂ ) _q S—; F ¹ and F ² represent both H, or together represent = O or = S; L is selected from OH, O-alkyl, NH ₂ , NH-alkyl and NR ⁹ R ¹⁰ ; R ^{7 is} selected from H, alkyl, alkenyl, and COR ⁸ ; R ^{8 is} selected from OH, O-alkyl, NH ₂ , NH-alkyl, N (alkyl) ₂ , pyrrolidinyl and piperidinyl; R ⁹ and R ¹⁰ both represent alkyl, or together represent - (CH ₂ ) _h - or - (CH ₂ ) ₂ O (CH ₂ ) ₂ -; V represents O, N-CN or S; c is 0 or 1; d is 0 or 1; e is 0 or 1; f is 0, 1, 2, 3 or 4; g is 2 or 3; h = 3, 4 or 5, provided that d and e are both not equal to 0. 2. The compound according to claim 1, or a tautomer thereof, or a pharmaceutically acceptable salt, wherein the compound is a compound according to general formula 1. 3. The compound according to claim 2, or its tautomer, or a pharmaceutically acceptable salt, where W is CR ⁴ . 4. The compound according to claim 3, or its tautomer, or a pharmaceutically acceptable salt, where at least one of R ¹ -R ^{4 is} not N. 5. The compound according to claim 4, or its tautomer, or a pharmaceutically acceptable salt, where one of R ¹ -R ⁴ is methyl, F or Cl and the others are all N. 6. The compound according to claim 1, or a tautomer thereof, or a pharmaceutically acceptable salt, wherein the compound is a compound according to general formula 2. 7. The compound according to any preceding paragraph, or its tautomer, or a pharmaceutically acceptable salt, where G ¹ represents a group corresponding to one of the general formulas 3-7. 8. The compound according to claim 7, or its tautomer, or a pharmaceutically acceptable salt, where Y is CH. 9. The compound of claim 8, or a tautomer thereof, or a pharmaceutically acceptable salt, wherein Z is —CH═CH—. 10. The compound of claim 8, or its tautomer, or a pharmaceutically acceptable salt, where Z is S. 11. The compound according to claim 7, or its tautomer, or a pharmaceutically acceptable salt, where Y is N and Z is —CH = CH—. 12. The compound according to any one of claims 7 to 11, or its tautomer, or a pharmaceutically acceptable salt, where G ¹ represents a group corresponding to General formula 3. 13. The compound according to item 12, or its tautomer, or a pharmaceutically acceptable salt, where A ¹ represents CH ₂ and A ² and A ³ both represent CH. 14. A compound according to any one of claims 7-11, or a tautomer thereof, or a pharmaceutically acceptable salt, wherein G ¹ represents a group corresponding to general formula 6. 15. The compound of claim 14, or a tautomer thereof, or a pharmaceutically acceptable salt, wherein A ¹¹ is CH and A ¹² is S. 16. The compound according to any one of claims 1 to 6, or its tautomer, or a pharmaceutically acceptable salt, where G ¹ represents a group corresponding to General formula 8. 17. The compound according to clause 16, or its tautomer, or a pharmaceutically acceptable salt, where A ¹⁷ represents CH ₂ . 18. The compound according to claim 16 or 17, or a tautomer thereof, or a pharmaceutically acceptable salt, wherein A ¹⁶ is CH ₂ . 19. The compound according to any one of the preceding paragraphs, or its tautomer, or a pharmaceutically acceptable salt, where G ² represents a group corresponding to General formula 9. 20. The compound according to claim 19, or its tautomer, or a pharmaceutically acceptable salt, where Ar is mono - or polysubstituted phenyl. 21. The compound according to claim 19 or 20, or a tautomer thereof, or a pharmaceutically acceptable salt, wherein Ar is phenyl substituted with at least two halogen atoms selected from F and Cl. 22. The compound according to any one of paragraphs.19-21, or its tautomer, or a pharmaceutically acceptable salt, where Ar is 2,6-difluorophenyl. 23. The compound according to any one of claims 1 to 18, or its tautomer, or a pharmaceutically acceptable salt, where G ² represents a group corresponding to General formula 10. 24. The compound of claim 23, or a tautomer thereof, or a pharmaceutically acceptable salt, wherein R ⁷ is COR ⁸ . 25. The compound according to paragraph 24, or its tautomer, or a pharmaceutically acceptable salt, where R ⁸ represents N (alkyl) ₂ . 26. The compound according to any one of claims 1 to 18, or a tautomer thereof, or a pharmaceutically acceptable salt, where G ² represents a group corresponding to general formula 11. 27. The compound according to p. 26, or its tautomer, or a pharmaceutically acceptable salt, where F ¹ and F ² together represent = O. 28. The compound according to claim 26 or 27, or a tautomer thereof, or a pharmaceutically acceptable salt, wherein E ¹ and E ² are both H, or one is H and the other is Oalkyl. 29. The compound according to any one of claims 26 to 28, or a tautomer thereof, or a pharmaceutically acceptable salt, wherein one of E ¹ and E ² is H and the other is Alkyl and the stereochemistry at the center of CE ¹ E ² is an R-absolute configuration. 30. The compound according to any one of claims 26-29, or a tautomer thereof, or a pharmaceutically acceptable salt, wherein the stereochemistry adjacent to the nitrogen of the ring is an S-absolute configuration. 31. The compound according to claim 1, or its tautomer, or a pharmaceutically acceptable salt selected from 1- (4- [3- (2-Chloro-6-fluorophenyl) ureidomethyl] -3-methylbenzoyl) -2,3,4,5-tetrahydro-1H-1-benzazepine, 1- (4- [3- (2,6-Difluorophenyl) ureidomethyl] -3-methylbenzoyl) -5- (3-pyridyl) methyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine, 1- (3-Chloro-4- [3- (2-chloro-6-fluorophenyl) ureidomethyl] benzoyl) -5-ethyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine, 4- (3-Chloro-4- [3- (2,6-difluorophenyl) ureidomethyl] benzoyl) -5,6,7,8-tetrahydrothieno [3,2-b] azepine, 1- (3-Chloro-4- (3- (methyloxycarbonyl) propanoylaminomethyl) benzoyl) -2,3,4,5-tetrahydro-1-benzazepine, 1- (2-Methyl-4- (5- (3-pyridylmethyl) -2,3,4,5-tetrahydro-1,5-benzodiazepin-1-ylcarbonyl) benzyl) -3- (methyloxycarbonylmethyl) urea, N, N-Dimethylamide 1- (2-methyl-4- (2,3,4,5-tetrahydro-1-benzazepin-1-ylcarbonyl) benzylcarbamoyl) -L-proline, N, N-Dimethylamide (4R) -4-hydroxy-1- (2-methyl-4- (2,3,4,5-tetrahydro-1-benzazepin-1-ylcarbonyl) benzylcarbamoyl) -L-proline, N, N-Dimethylamide (4R) -1- (3-chloro-4- (2,3,4,5-tetrahydro-1-benzazepin-1-ylcarbonyl) benzylcarbamoyl) -4-methoxy-L-proline, N, N-Dimethylamide (4R) -1- (2-chloro-4- (2,3,4,5-tetrahydro-1-benzazepin-1-ylcarbonyl) benzylcarbamoyl) -4-methoxy-L-proline, N, N-Dimethylamide (4R) -4-benzyloxy-1- (2-methyl-4- (2,3,4,5-tetrahydro-1-benzazepin-1-ylcarbonyl) benzylcarbamoyl) -L-proline, N, N-Dimethylamide (4R) -4-methoxy-1- (2-methyl-4- (2,3,4,5-tetrahydro-1-benzazepin-1-ylcarbonyl) benzylcarbamoyl) -L-proline, N, N-Dimethylamide (4R) -4-methoxy-1- (3-methyl-4- (2,3,4,5-tetrahydro-1-benzazepin-1-ylcarbonyl) benzylcarbamoyl) -L-proline, N, N-Dimethylamide (4R) -1- (2-chloro-4- (5,6,7,8-tetrahydro-4H-thieno [3,2-b] azepin-4-ylcarbonyl) benzylcarbamoyl) -4- methoxy L-proline, N, N-Dimethylamide (4R) -1- (4- (10,11-dihydro-5H-pyrrolo [2,1-c] (1,4) benzodiazepin-10-ylcarbonyl) -2-methylbenzylcarbamoyl) -4- methoxy L-proline, N, N-Dimethylamide (4R) - (1- (2-chloro-4- (10,11-dihydro-5H-pyrrolo [2,1-c] (1,4) benzodiazepin-10-ylcarbonyl) benzylcarbamoyl) - 4-methoxy-L-proline and N, N-Dimethylthioamide (4R) -1- (4- (10,11-dihydro-5H-pyrrolo [2,1-c] (1,4) benzodiazepin-10-ylcarbonyl) -2-methylbenzylcarbamoyl) -4- methoxy L-proline. 32. The compound according to claim 1, or its tautomer, or a pharmaceutically acceptable salt selected from N, N-Dimethylamide 1- (2-methyl-4- (2,3,4,5-tetrahydro-1-benzazepin-1-ylcarbonyl) benzylcarbamoyl) -L-proline and N, N-Dimethylamide (4R) -4-hydroxy-1- (2-methyl-4- (2,3,4,5-tetrahydro-1-benzazepin-1-ylcarbonyl) benzylcarbamoyl) -L-proline. 33. The use of a compound according to any one of claims 1 to 32, or a pharmaceutically acceptable salt thereof, as a component of a pharmaceutical composition. 34. The use of a compound according to any one of claims 1 to 32 or a pharmaceutically acceptable salt thereof as a therapeutic agent for the treatment of nocturnal enuresis, nocturia, polyuria resulting from central diabetes insipidus, urinary incontinence or bleeding disorders. 35. A pharmaceutical composition comprising, as an active ingredient, a compound according to any one of claims 1 to 32. 36. The pharmaceutical composition according to clause 35, which is used to treat polyuria. 37. The pharmaceutical composition according to clause 35, which is used to regulate the function of urinary incontinence. 38. The pharmaceutical composition according to clause 37, which is intended to "delay emptying." 39. The pharmaceutical composition according to clause 35, which is used to treat bleeding disorders. 40. A method of treating nocturnal enuresis, nocturia and diabetes insipidus, comprising administering to a patient in need of such treatment an effective amount of a composition according to claim 35. 41. A method of regulating the function of urinary incontinence, comprising administering to a patient in need of such treatment an effective amount of a composition according to claim 35. 42. The method of regulating the function of urinary incontinence according to paragraph 41, where the treatment leads to a “delayed emptying”. 43. A method of treating bleeding disorders, comprising administering to a patient in need of such treatment an effective amount of a composition according to claim 35.