RU2002100354A - Ditiepino [6,5-b] pyridines, compositions containing these compounds, and methods for their preparation - Google Patents

Claims (63)

1. The compound of formula I

or a pharmaceutically acceptable salt thereof, where (a) R ₁ , R ₂ , R ₃ , R ₄ and R _{5 are} independently selected from the group consisting of H, OH, halogen, cyano, NO ₂ , alkyl, C _1-8 alkoxy, C _1-8 alkylsulfonyl, C _1-4 carbalkoxy group, C _1-8 alkylthio group, difluoromethoxy group, difluoromethylthio group, trifluoromethyl and oxadiazole (formed by R ₁ and R ₂₎ ; (b) R _{7 is} selected from the group consisting of H, C _1-5 straight or branched chain alkyl, aryl, 3-piperidyl, N-substituted 3-piperidyl, N-substituted 2-pyrrolidinylmethylene and substituted alkyl, wherein said N- substituted 3-piperidyl and said N-substituted 2-pyrrolidinylmethylene can be substituted with straight or branched chain C _1-8 alkyl, and said substituted alkyl can be substituted with C _1-8 alkoxy, C _2-8 alkanoyloxy, phenylacetyloxy , benzoyloxy group, hydroxy group, halogen, p-tosyloxy group, mesyloxy group th, amino group, carboalkoxy group or NR′R ″, where (i) R ′ and R ″ are independently selected from the group consisting of H, C _1-8 straight or branched chain alkyl, C _3-7 cycloalkyl, phenyl, benzyl and phenethyl, or (ii) R 'and R''together form a heterocyclic ring selected from the group consisting of piperidino, pyrrolidino, morpholino, thiomorpholino, piperazino, 2-thieno, 3-thieno rings and N-substituted derivative of said heterocyclic rings, said N-substituted derivative substituted with H, C _1-8 alkyl, straight or branched chain alkyl, benzyl, benzhydryl, p Neil and / or substituted phenyl (substituted with NO _2, halogen, C _1-8 alkyl, straight or branched chain C _1-8 vlkoksigruppoy and / or trifluoromethyl); (c) R _{7 is} selected from the group consisting of H, an amino group, an alkyl, aryl, trifluoromethyl, alkoxymethyl, 2-thieno group and 3-thieno group; (d) R _{8 is} attached to a bis-sulfone ring via a single or double bond and is selected from the group consisting of H, alkyl hydroxy, alkenyl, amino, phenyl, benzyl, straight or branched chain C _1-8 alkyl, trifluoromethyl, alkoxymethyl, C _3-7 cycloalkyl, substituted benzyl, formyl, acetyl, tert-butoxycarbonyl, propionyl, substituted alkyl and P ″ СН CH ₂ C = O, where (i) said substituted benzyl is substituted with halogen, trifluoromethyl, C _1-8 alkyl with straight and / or branched chain or C _1-8 alkoxy groups, (ii) said substituted alkyl is substituted by amino groups oh, a dialkylamino group, a C _1-8 alkoxy group, a hydroxy group and / or halogen, and (iii) R ″ ″ represents an amino group, a dialkylamino group, a C _1-8 alkoxy group, a hydroxy group or a halogen; and (f) m, n and their sum each takes integer values from 0 to 4. 2. The compound according to claim 1, where R ₆ represents - (CH ₂ ) ₂ N (CH ₃ ) CH ₂ PH. 3. The compound according to claim 1, where R ₆ is methyl. 4. The compound according to claim 3, where R ₄ represents CF ₃ , R ₅ represents F, R ₇ represents methyl, R ₈ represents methylene, m = 0 and n = 1. 5. The compound according to claim 3 where R ₄ represents CF ₃ , R ₅ represents F, R ₇ represents methyl, R ₈ represents an alkyl hydroxy group, m = 0 and n = 1. 6. The compound according to claim 1, where R ₇ represents methyl. 7. The compound according to claim 6, where R ₆ is - (CH ₂ ) ₂ N (CH ₃ ) CH ₂ PH. 8. The compound according to claim 6, where R ₄ represents CF ₃ and R ₅ represents F. 9. The compound according to claim 6, where R ₅ represents Cl. 10. The compound according to claim 6, where R ₁ represents F, and R ₅ represents Cl. 11. The compound according to claim 1, which is 1,1-,4,4-tetraoxide 2- [methyl (phenylmethyl) amino] ethyl ester 9- (2-chloro-6-fluorophenyl) -2,3,6,9 -tetrahydro-7-methyl-5H-1,4-dithiepino [6,5-b] pyridine-8-carboxylic acid. 12. The compound according to claim 1, which is 1,1,4,4-tetraoxide 2- [methyl (2-thienylmethyl) amino] ethyl ester 2,3,6,9-tetrahydro-7-methyl-9- ( 3,4,5-trifluorophenyl) -5H-1,4-dithiepine [6,5-b] pyridine-8-carboxylic acid. 13. The compound according to claim 1, which is 1,1,4,4-tetraoxide 2- [methyl (phenylmethyl) amino] ethyl ester 9- [2-fluoro-6- (trifluoromethyl) phenyl] -2,3, 6,9-tetrahydro-7-methyl-5H-1,4-dithiepino [6,5-b] pyridine-8-carboxylic acid. 14. The compound according to claim 1, which is 1,1-,4,4-tetraoxide 2- [methyl (phenylmethyl) amino] ethyl ester 9- (2-chloro-6-fluorophenyl) -2,3,6,9 -tetrahydro-7-methyl-5H-1,4-dithiepino [6,5-b] pyridine-8-carboxylic acid (9R). 15. The compound according to claim 1, which is a 1,1-,4,4-tetraoxide 2- [methyl (phenylmethyl) amino] ethyl ester 9- (2-chloro-6-fluorophenyl) -2,3,6,9 -tetrahydro-7-methyl-5H-1,4-dithiepino [6,5-b] pyridine-8-carboxylic acid (9S). 16. The compound according to claim 1, which is 1,1-,4,4-tetraoxide 2- [methyl (phenylmethyl) amino] ethyl ester 9- (2-chloro-6-hydroxyphenyl) -2,3,6,9 -tetrahydro-7-methyl-5H-1,4-dithiepino [6,5-b] pyridine-8-carboxylic acid. 17. The compound according to claim 1, which is 1,1-,4,4-tetraoxide 2- [methyl (phenylmethyl) amino] ethyl ester 9- (2-chlorophenyl) -2,3,6,9-tetrahydro-7 methyl 5H-1,4-dithiepino [6,5-b] pyridine-8-carboxylic acid. 18. The compound according to claim 1, which is 1,1,4,4-tetraoxide 2- [methyl (phenylmethyl) amino] ethyl ester 9- [2-fluoro-3- (trifluoromethyl) phenyl] -2,3, 6,9-tetrahydro-7-methyl-5H-1,4-dithiepino [6,5-b] pyridine-8-carboxylic acid. 19. The compound according to claim 1, which is 1,1,4,4-tetraoxide 2- [methyl (phenylmethyl) amino] ethyl ester 2,3,6,9-tetrahydro-7-methyl-9- (3- nitrophenyl) -5H-1,4-dithiepino [6,5-b] pyridine-8-carboxylic acid. 20. The compound according to claim 1, which is 1,1,4,4-tetraoxide 2- [methyl (phenylmethyl) amino] ethyl ether 2,3,6,9-tetrahydro-7-methyl-9- (3, 4,5-trifluorophenyl) -5H-1,4-dithiepino [6,5-b] pyridine-8-carboxylic acid. 21. The compound of claim 1, which is 9- (2-chloro-6-fluorophenyl) -2,3,6,9-tetrahydro-7-methyl-5H- methyl ester 1,1,4,4-tetraoxide 1,4-ditiepino [6,5-b] pyridine-8-carboxylic acid. 22. The compound according to claim 1, which is a 1,1-,4,4-tetraoxide methyl ester 9- (2-chloro-5-nitrophenyl) -2,3,6,9-tetrahydro-7-methyl-5H- 1,4-ditiepino [6,5-b] pyridine-8-carboxylic acid. 23. The compound according to claim 1, which is 1,1,4,4-tetraoxide methyl ester 2,3,6,9-tetrahydro-7-methyl-9- (pentafluorophenyl) -5H-1,4-ditiepino [ 6,5-b] pyridine-8-carboxylic acid. 24. The compound of claim 1, which is 9- (2,6-difluorophenyl) -2,3,6,9-tetrahydro-7-methyl-5H-1 methyl ester 1,1,4,4-tetraoxide, 4-dithiepino [6,5-b] pyridine-8-carboxylic acid. 25. The compound according to claim 1, which is a 1,1-,4,4-tetraoxide methyl ester 9- (2-chlorophenyl) -2,3,6,9-tetrahydro-7-methyl-5H-1,4- dithiepino [6,5-b] pyridine-8-carboxylic acid. 26. The compound according to claim 1, which is a 9- (2-fluorophenyl) -2,3,6,9-tetrahydro-7-methyl-5H-1,4- methyl ester 1,1,4,4-tetraoxide dithiepino [6,5-b] pyridine-8-carboxylic acid. 27. The compound according to claim 1, which is 9- [2-fluoro-3- (trifluoromethyl) phenyl] -2,3,6,9-tetrahydro-7-methyl methyl ester 1,1,4,4-tetraoxide -5H-1,4-dithiepino [6,5-b] pyridine-8-carboxylic acid. 28. The compound according to claim 1, which is 9- (2,3-difluorophenyl) -2,3,6,9-tetrahydro-7-methyl-5H-1 methyl ester 1,1,4,4-tetraoxide, 4-dithiepino [6,5-b] pyridine-8-carboxylic acid. 29. The compound according to claim 1, which is 1,1,4,4-tetraoxide methyl ester 2,3,6,9-tetrahydro-7-methyl-9- (2-nitrophenyl) -5H-1,4- dithiepino [6,5-b] pyridine-8-carboxylic acid. 30. The compound according to claim 1, which is 9- [2-fluoro-3- (trifluoromethyl) phenyl] -2,3,6,9-tetrahydro-7-methyl methyl ester 1,1,4,4-tetraoxide -3-methylene-5H-1,4-dithiepino [6,5-b] pyridine-8-carboxylic acid. 31. The compound according to claim 1, which is 1,1-,4,4-tetraoxide 2- [methyl (phenylmethyl) amino] ethyl ester 9- [2-fluoro-3- (trifluoromethyl) phenyl] -2,3, 6,9-tetrahydro-7-methyl-3-methylene-5H-1,4-dithiepino [6,5-b] pyridine-8-carboxylic acid. 32. The compound according to claim 1, which is 1,1- [2-fluoro-3- (trifluoromethyl) phenyl] -2,3,6,9-tetrahydro-3- (1,1,4,4-tetraoxide methyl ester hydroxymethyl) -7-methyl-5H-1,4-dithiepino [6,5-b] pyridine-8-carboxylic acid. 33. The compound according to claim 1, which is 1,1-,4,4-tetraoxide 2- [methyl (phenylmethyl) amino] ethyl ester 9- [2-fluoro-3- (trifluoromethyl) phenyl] -2,3, 6,9-tetrahydro-3- (hydroxymethyl) -7-methyl-5H-1,4-dithiepino [6,5-b] pyridine-8-carboxylic acid. 34. The compound according to claim 1, which is 1,1,4,4-tetraoxide 2- (methyl (phenylmethyl) amino] ethyl ester 2,3,6,9-tetrahydro-3- (hydroxymethyl) -7-methyl -9- (3-nitrophenyl) -5H-1,4-dithiepino [6,5-b] pyridine-8-carboxylic acid. 35. The compound according to claim 1, which is 1,1,5,5-tetraoxide 2- [methyl (phenylmethyl) amino] ethyl ester 3,4,7,10-tetrahydro-8-methyl-10- (3- nitrophenyl) -2H, 6H-1,5-dithiocino [3,2-b] pyridine-9-carboxylic acid. 36. The compound according to claim 1, which is 1,1-,5,5-tetraoxide 2- [methyl (phenylmethyl) amino] ethyl ester 10- [2-fluoro-6- (trifluoromethyl) phenyl] -3,4, 7,10-tetrahydro-8-methyl-2H, 6H-1,5-dithiocino [3,2-b] pyridine-9-carboxylic acid. 37. The compound according to claim 1, which is 1,1,5,5-tetraoxide 2- [methyl (phenylmethyl) amino] ethyl ester 3,4,7,10-tetrahydro-8-methyl-10- (pentafluorophenyl) -2H, 6H-1,5-dithiocino [3,2-b] pyridine-9-carboxylic acid. 38. The compound according to claim 1, which is 1,1-,5,5-tetraoxide 2- [methyl (phenylmethyl) amino] ethyl ester 10- [2-fluoro-3- (trifluoromethyl) phenyl] -3,4, 7,10-tetrahydro-8-methyl-2H, 6H-1,5-dithiocino [3,2-b] pyridine-9-carboxylic acid. 39. The compound according to claim 1, which is 1,1-,5,5-tetraoxide 2- [methyl (phenylmethyl) amino] ethyl ester 10- (2-chlorophenyl) -3,4,7,10-tetrahydro-8 -methyl-2H, 6H-1,5-dithiocino [3,2-b] pyridine-9-carboxylic acid. 40. The compound according to claim 1, which is a 1,1,5,5-tetraoxide 2- [methyl (phenylmethyl) amino] ethyl ester 3,4,7,10-tetrahydro-8-methyl-10- (2- nitrophenyl) -2H, 6H-1,5-dithiocino [3,2-b] pyridine-9-carboxylic acid. 41. The compound according to claim 1, which is a 1,1-, 3,3-tetraoxide 2- [methyl (phenylmethyl) amino] ethyl ester 8- [2-fluoro-3- (trifluoromethyl) phenyl] -5,8- dihydro-6-methyl-4H-1,3-dithiino [5,4-b] pyridine-7-carboxylic acid. 42. The compound according to claim 1, which is a 1,1-, 3, 3-tetraoxide of 2- [methyl (phenylmethyl) amino] ethyl ester of 8- (2-chlorophenyl) -5,8-dihydro-6-methyl-4H -1,3-dithiino [5,4-b] pyridine-7-carboxylic acid. 43. The compound of formula (II)

or a pharmaceutically acceptable salt thereof, where (a) R ₁ , R ₂ , R ₃ , R ₄ and R _{5 are} independently selected from the group consisting of H, OH, halogen, cyano, NO ₂ , alkyl, C _1-8 alkoxy, C _1-8 alkylsulfonyl, C _1-4 carbalkoxy group, C _1-8 alkylthio group, difluoromethoxy group, difluoromethylthio group, trifluoromethyl and oxadiazole (formed by R ₁ and R ₂ ); (b) R _{7 is} selected from the group consisting of H, an amino group, an alkyl, aryl, trifluoromethyl, alkoxymethyl, 2-thieno group and 3-thieno group; (c) R _{8 is} connected to a bis-sulfone ring via a single or double bond and is selected from the group consisting of H, an alkyl hydroxy group, alkenyl, an amino group, phenyl, benzyl, C _1-8 straight or branched chain alkyl, trifluoromethyl, alkoxymethyl, C _3-7 cycloalkyl, substituted benzyl, formyl, acetyl, tert-butoxycarbonyl, propionyl, substituted alkyl and R ″ ″ CH ₂ C = O, where (i) said substituted benzyl is substituted with halogen, trifluoromethyl, C _1-8 alkyl with a straight and / or branched chain or a C _1-8 alkoxy group, (ii) said substituted alkyl is substituted with an amino group, di an alkylamino group, a C _1-8 alkoxy group, a hydroxy group and / or a halogen, and (iii) R ″ ″ represents an amino group, a dialkylamino group, a C _1-8 alkoxy group, a hydroxy group or a halogen; (d) R _{9 is} selected from -alkyl-OH, an alkylamino group, a lactone, a cyclic carbonate, an alkyl-substituted cyclic carbonate, an aryl-substituted cyclic carbonate, aryl-C (O) OR ', -alkyl-aryl-C (O) OR ', -alkyl-OS (O) R', -alkyl-C (O) R ', -alkyl-C (O) OR', -alkyl-N (R ") C (O) R ', and -alkyl —N (R ″) C (O) OR ′, where R ′ and R ″ are independently selected from the group consisting of hydrogen, amino, alkyl, aryl, aryl-fused cycloalkyl and heterocyclyl, wherein the amino group, alkyl, aryl, aryl -condensed cycloalkyl and heterocyclyl are optionally substituted with halogen, cyano, NO ₂ , lactone, amino group, alkyl amino, aryl-substituted alkylamino, amido group, carbamate, carbamoyl, cyclic carbonate, alkyl, halogen-substituted alkyl, arylalkyl, alkoxy, heterocyclyl and / or aryl (wherein aryl is optionally substituted by OH, halogen, cyano, NO _2, alkyl , an amino group, a dimethylamino group, an alkoxy group, an alkylsulfonyl group, a C _1-4 carboalkoxy group, an alkylthio group, an alkylthio group and / or trifluoromethyl); (e) m, n and their sum each takes integer values from 0 to 4; (f) p = 0-4. 44. The compound according to item 43, where R ₉ represents aryl-alkyl-OC (O) R '. 45. The compound according to item 43, where R ₉ represents-alkyl-N (R ") C (O) R '. 46. The compound according to item 45, which is: 1,1,4,4-tetraoxide 2 - [[(1,1-dimethylethoxy) carbonyl] amino] ethyl ester 9- (2-chloro-6-fluorophenyl) - 2,3,6,9-tetrahydro-7-methyl-5H-1,4-dithiepino [6,5-b] pyridine-8-carboxylic acid. 47. The compound according to item 43, where R ₉ represents-alkyl-OS (O) R '. 48. The compound according to clause 47, which is 1,1,4,4-tetraoxide 2 - [[(1,2,3,4-tetrahydro-2-naphthalenyl) carbonyl] oxy] ethyl ester 9- (2- chloro-6-fluorophenyl) -2,3,6,9-tetrahydro-7-methyl-5H- [1,4] ditiepino [6,5-b] pyridine-8-carboxylic acid. 49. The compound according to item 47, which is a 1,1,4,4-tetraoxide 2 - [(cycloheptylcarbonyl) oxy] ethyl ester 9- (2-chloro-6-fluorophenyl) -2,3,6,9- tetrahydro-7-methyl-5H- [1,4] dithiepino [6,5-b] pyridine-8-carboxylic acid. 50. The compound according to item 47, which is 1,1,4,4-tetraoxide 2 - [[(4- (1-methylethoxy) benzoyl] oxy] ethyl ester 9- (2-chloro-6-fluorophenyl) - 2,3,6,9-tetrahydro-7-methyl-5H- [1,4] ditiepino [6,5-b] pyridine-8-carboxylic acid. 51. The compound of claim 47, which is 1,1- (2,3-dichlorophenyl) -2,3,6,9 ethyl ether 1,1,4,4-tetraoxide 2- (2-methyl-1-oxopropoxy) ethyl ester -tetrahydro-7-methyl-5H- [1,4] dithiepino [6,5-b] pyridine-8-carboxylic acid. 52. The compound of claim 47, which is 1,1,5,5-tetraoxide 2 - [[4- (1-methyl-ethoxy) benzoyl] oxy] ethyl ester 10- (2-chloro-6-fluorophenyl) -3,4,7,10-tetrahydro-8-methyl-2H, 6H- [1,5] dithiocino [3,2-b] pyridine-9-carboxylic acid. 53. A pharmaceutical composition comprising a compound according to claim 1 or 43 and a pharmaceutically acceptable carrier. 54. A method of treating a subject suffering from a disorder, the attenuation of which is mediated by a decrease in the intake of calcium ions in the cells contributing to the disorder, comprising administering to the subject a therapeutically effective dose of a pharmaceutical composition according to claim 53. 55. The method of inhibition in a subject with an initial stage of the disorder, the weakening of which is mediated by a decrease in the intake of calcium ions in the cells contributing to the disorder, comprising administering to the subject a prophylactically effective dose of the pharmaceutical composition according to claim 53. 56. The method according to item 54 or 55, where the disorder is selected from the group comprising hypersensitivity, allergies, asthma, bronchospasm, dysmenorrhea, esophagospasm, glaucoma, premature birth, urinary tract disorders, disorders of the gastrointestinal tract motor function and cardiovascular disorders. 57. The method of claim 56, wherein the disorder is asthma. 58. The method of claim 56, wherein the cardiovascular disorder is selected from the group consisting of hypertension, coronary artery disease, angina pectoris, congestive heart failure, myocardial infarction, and stroke. 59. An apparatus for administering to a subject a pharmaceutical composition according to claim 53, comprising a container with a pharmaceutical composition, wherein the container is equipped with means for delivering to the subject a therapeutic and / or prophylactic dose of the pharmaceutical composition. 60. A method of obtaining a compound according to claim 1

where m, n and their sum each represents an integer from 1 to 4, comprising the following steps: (a) reacting a compound of formula 1a with a compound of formula 1b

to obtain the compounds of formula 1C

(b) reacting a compound of formula 1c with m-chloroperoxybenzoic acid to form a compound of formula 1d

(c) reacting a compound of formula 1d with compounds of formulas 1e and 1f

with the formation of the compounds according to claim 1. 61. The method of claim 60, wherein R _{8 of the} compound of formula I is a methylene group derived from a methylol group using a dehydration agent. 62. A method of obtaining a compound according to item 43

which includes the following steps: (a) reacting a compound of formula 3a ’with formic acid to form a compound of formula 3b’

(b) reacting a compound of formula 3b with R ₉ Br or R ₉ Cl to form a compound according to claim 43. 63. The method of claim 62, wherein R ₇ is methyl.