Claims for Patent: 7,598,279

Summary for Patent: 7,598,279

Title:	Neurotherapeutic azole compounds
Abstract:	Azole compounds containing carbamoyl group and pharmaceutically useful salts thereof are described. The compounds are effective anticonvulsants which are used in the treatment of disorders of the central nervous system, especially as anxiety, depression, convulsion, epilepsy, migraine, bipolar disorder, drug abuse, smoking, ADHD, obesity, sleep disorder, neuropathic pain, stroke, cognitive impairment, neurodegeneration, stroke and muscle spasm.
Inventor(s):	Yong Moon Choi, Choon-Gil Kim, Han-Ju Yi, Young-Sun Kang, Hyun-Seok Lee
Assignee:	SK Biopharmaceuticals Co Ltd
Application Number:	US11/407,526
Patent Litigation and PTAB cases:	See patent lawsuits and PTAB cases for patent 7,598,279
Patent Claims:	1. An azole compound of the formula: wherein, G is a ring selected from the group consisting of piperonyl, indanyl, naphtyl, phenyl and phenoxy methyl which ring may be substituted with one or more identical or different substituents selected from the group consisting of hydrogen, lower alkyl of 1 to 8 carbon atoms, halogen, alkoxy containing 1 to 8 carbon atoms, thioalkoxy containing 1 to 8 carbon atoms, hydroxy, perfluoroalkyl, phenoxy, phenylalkyloxy of 1 to 8 carbon atoms or phenoxyalkyl of 1 to 8 carbon atoms, wherein the phenyl moiety of phenoxy, phenoxyalkyl and phenylalkyloxy is unsubstituted or substituted with amino, mono- or di-substituted amino with lower alkyl of 1 to 8 carbon atoms, amido, sulfonamido, nitro, carboxyl, or perfluoroalkyl of 1 to 8 carbon atoms; m is an integer from 0 to 6; Y is selected from the group consisting of hydrogen, halogen, and lower alkyl of 1 to 8 carbon atoms; n is an integer from 0 to 6; A is azole group represented by the following structural formula (X-1) or (X-2): wherein, A1 is selected from the group consisting of nitrogen atom and CH; Q is selected from the group consisting of hydrogen, perfluoroalkyl, halogen, amino, mono- or di-substituted alkyl amino with alkyl of 1 to 8 carbon atoms, amido, linear or branched alkyl of 1 to 8 carbon atoms, cycloalkyl of 3 to 8 carbon atoms, arylalkyl, morpholino, piperidino, pyrrolidino, thioalkoxy of 1 to 8 carbon atoms, benzylthio, thienyl, aminoalkyl, hydroxyalkyl, styryl, carboxylic, pyridyl, unsubstituted phenyl and phenyl substituted with one or more identical or different substituents selected from the group consisting of hydrogen, lower alkyl of 1 to 8 carbon atoms, arylalkyl, halogen, alkoxy containing 1 to 8 carbon atoms, phenoxy, amino, mono- or di-substituted amino with alkyl of 1 to 8 carbon atoms, nitro, hydroxy, thioalkoxy, furanyl, sulfonamido, or perfluoroalkyl; R1 and R2 are independently selected from the group consisting of hydrogen, C(═O)NH2, lower alkyl of 1 to 8 carbon atoms, non-substituted or substituted phenyl, and non-substituted or substituted phenylalkyl of 1 to 8 carbon atoms, or taken together with attached nitrogen form a imidazole, piperazine or phenyl piperazine ring or cyclic amine ring represented by the following structural formula (XI): wherein, A2 is selected from the group consisting of nitrogen atom and carbon atom; E and U are independently selected from the group consisting of hydrogen, hydroxy and O-carbamoyl or taken together form oxo; W is selected from a ring consisting of piperonyl, indanyl, naphtyl, tetrazolyl, triazolyl, pyridyl and phenyl which ring may be substituted with one or more identical or different substituents selected from the group consisting of hydrogen, lower alkyl of 1 to 8 carbon atoms, halogen, alkoxy containing 1 to 8 carbon atoms, thioalkoxy containing 1 to 8 carbon atoms, phenoxy, phenylalkyloxy of 1 to 8 carbon atoms, phenyloxyalkyl of 1 to 8 carbon atoms, where the phenyl moiety of phenoxy, phenylalkyloxy and phenoxyalkyl is unsubstituted or substituted with amino, mono- or di-substituted amino with alkyl of 1 to 8 carbon atoms, amido, sulfonamido, nitro, carboxyl, hydroxy, or perfluoroalkyl of 1 to 8 carbon atoms; j is an integer from 0 to 4; and t is an integer from 0 to 4; or a pharmaceutically acceptable salt thereof. 2. The azole of claim 1, wherein said compound has the formula: wherein, X1 is selected from the group consisting of lower alkyl of 1 to 8 carbon atoms, halogen, alkoxy containing 1 to 8 carbon atoms, thioalkoxy containing 1 to 8 carbon atoms, hydroxy, phenoxy, phenylalkyloxy of 1 to 8 carbon atoms, phenoxyalkyl of 1 to 8 carbon atoms wherein the phenyl moiety of phenoxy, phenylalkyloxy and phenoxyalkyl is unsubstituted or substituted with amino, mono- or di-substituted amino with lower alkyl of 1 to 8 carbon atoms, amido, sulfonamido, nitro, carboxyl, or perfluoroalkyl of 1 to 8 carbon atoms; X2 and X3 may be the same with or different from each other and are independently selected from the group consisting of hydrogen, lower alkyl of 1 to 8 carbon atoms, halogen, alkoxy containing 1 to 8 carbon atoms, thioalkoxy containing 1 to 8 carbon atoms, hydroxy, phenoxy, phenylalkyloxy of 1 to 8 carbon atoms, phenoxyalkyl of 1 to 8 carbon atoms wherein the phenyl moiety of phenoxy, phenylalkyloxy and phenoxyalkyl is unsubstituted or substituted with amino, mono- or di-substituted amino with lower alkyl of 1 to 8 carbon atoms, amido, sulfonamido, nitro, carboxyl, or perfluoroalkyl of 1 to 8 carbon atoms; m is an integer from 0 to 6; Y is selected from the group consisting of hydrogen and lower alkyl of 1 to 8 carbon atoms; n is an integer from 0 to 6; A is azole group represented by the following structural formula (X-1) or (X-2): wherein, A1 is selected from the group consisting of nitrogen atom and CH; Q is as above; and R1 and R2 are as above; or a pharmaceutically acceptable salt thereof. 3. The azole of claim 1, wherein said compound has the formula: wherein, X4 and X6 are independently selected from the group consisting of lower alkyl of 1 to 8 carbon atoms, halogen, alkoxy containing 1 to 8 carbon atoms, thioalkoxy containing 1 to 8 carbon atoms, hydroxy, phenoxy, phenylalkyloxy of 1 to 8 carbon atoms, phenoxyalkyl of 1 to 8 carbon atoms wherein the phenyl moiety of phenoxy, phenylalkyloxy and phenoxyalkyl is unsubstituted or substituted with amino, mono- or di-substituted alkyl amino with alkyl of 1 to 8 carbon atoms, amido, sulfonamido, nitro, carboxyl, or perfluoroalkyl of 1 to 8 carbon atoms; X5 and X7 may the same with or different from each other and are independently selected from the group consisting of hydrogen, lower alkyl of 1 to 8 carbon atoms, halogen, alkoxy containing 1 to 8 carbon atoms, thioalkoxy containing 1 to 8 carbon atoms, hydroxy, phenoxy, phenylalkyloxy of 1 to 8 carbon atoms, phenoxyalkyl of 1 to 8 carbon atoms wherein the phenyl moiety of phenoxy, phenylalkyloxy and phenoxyalkyl is unsubstituted or substituted with amino, mono- or di-substituted alkyl amino with alkyl of 1 to 8 carbon atoms, amido, sulfonamido, nitro, carboxyl, or perfluoroalkyl of 1 to 8 carbon atoms; m is an integer from 0 to 6; l is an integer from 1 to 6; A is azole group represented by the following structural formula (X-1) or (X-2): wherein, A1 is selected from the group consisting of nitrogen atom and CH; and Q, R1 and R2 are as above. 4. The azole of claim 1, wherein said compound has the formula: wherein, X8 and X9 are independently selected from the group consisting of hydrogen, lower alkyl of 1 to 8 carbon atoms, halogen, alkoxy containing 1 to 8 carbon atoms, thioalkoxy containing 1 to 8 carbon atoms, hydroxy, phenoxy, phenylalkyloxy, phenoxyalkyl wherein the phenyl moiety of phenoxy, phenylalkyloxy and phenoxyalkyl is unsubstituted or substituted with amino, mono- or di-substituted amino with alkyl of 1 to 8 carbon atoms, amido, sulfonamido, nitro, carboxyl, and perfluoroalkyl of 1 to 8 carbon atoms; m is an integer from 0 to 6; Y is selected from the group consisting of hydrogen and lower alkyl of 1 to 8 carbon atoms; n is an integer from 0 to 6; and A, R1 and R2 are as above. 5. The azole of claim 1, wherein said compound has the formula: wherein, Ph is phenyl, piperonyl, indanyl or naphtyl which maybe substituted with one or more identical or different substituents selected from the group consisting of hydrogen, lower alkyl of 1 to 8 carbon atoms, halogen, alkoxy containing 1 to 8 carbon atoms, thioalkoxy containing 1 to 8 carbon atoms, phenoxy, phenylalkyloxy of 1 to 8 carbon atoms, phenoxyalkyl of 1 to 8 carbon atoms, wherein the phenyl moiety of phenoxy, phenylalkyloxy and phenoxyalkyl is unsubstituted or substituted with amino, mono- or di-substituted amino with alkyl of 1 to 8 carbon atoms, amido, sulfonamido, nitro, carboxyl, hydroxy, or perfluoroalkyl of 1 to 8 carbon atoms; l is an integer from 1 to 6; and A, R1 and R2 are as above. 6. The azole of claim 1, wherein said compound has the formula: wherein, E, U, W, A2, A, G, j and t are as above and l is an integer from 1 to 4; or a pharmaceutically acceptable salt thereof. 7. The azole of claim 1, wherein said compound has the formula: wherein Y is as above; A3, A4 and A5 are independently selected from the group consisting of CH or N, with at least one of A3, A4 and A5 being CH and at least one of the other of A3, A4 and A5 being N; R6 and R7 being selected from the group consisting of hydrogen, halogen, perfluoroalkyl, alkyl of from 1 to 8 carbon atoms, lower alkoxy, thioalkoxy; R3 and R4 are alkyl or hydrogen, or taken together with the attached nitrogen atom forms an imidazole, or phenyl piperazine ring; or y is an integer of from 0 to 4. 8. The azole of claim 7, wherein one of A3, A4 and A5 are CH and the others are N. 9. The azole of claim 8, wherein R6 and R7 are independently hydrogen, halogen or perfluoroalkyl. 10. The azole of claim 9, wherein said compound is carbamic acid 1-(2-chloro-phenyl)-2tetrazol-2-yl-ethyl ester. 11. The azole of claim 10, wherein said compound is carbamic acid (R)-(+)-1-(2-chloro-phenyl)-2-tetrazol-2-yl-ethyl ester substantially free of its (S)enantiomer and said (R)-enantiomer is present to the extent of at least about 95%. 12. The azole of claim 10, wherein said compound is carbamic acid (S)-(−)-1-(2-chloro-phenyl)-2-tetrazol-2-yl-ethyl ester substantially; free of its (R)-enantiomer and said (S)-enantiomer is present to the extent of at least about 95%. 13. The azole of claim 9, wherein said compound is methyl-carbamic acid-1-(2-chloro-phenyl)-2-tetrazol-2-yl-ethyl ester. 14. The azole of claim 13, wherein said compound is methyl-carbamic acid (R)-1-(2-chloro-phenyl)-2-tetrazol-2-yl-ethyl ester substantially free of its (S)-enantiomer and said (R)-enantiomer is present to the extent of at least about 95%. 15. The azole of claim 13, wherein said compound is methyl-carbamic acid (S)-1-(2-chloro-phenyl)-2-tetrazol-2-yl-ethyl ester substantially free of its (R)-enantiomer and said (S)-enantiomer is present to the extent of at least about 95%. 16. The azole of claim 9, wherein said compound is carbamic acid -1-(2,4-dichloro-phenyl)2-tetrazol-2-yl-ethyl ester. 17. The azole of claim 16, wherein said compound is carbamic acid (R)-1-(2,4-dichloro-phenyl)-2-tetrazol-2-yl-ethyl ester substantially free of its (S)-enantiomer and said (R)-enantiomer is present to the extent of at least about 95%. 18. The azole of claim 16, wherein said compound is carbamic acid (S)-1-(2,4-dichloro-phenyl)-2-tetrazol-2-yl-ethyl ester substantially free of its (R)-enantiomer and said (S)-enantiomer is present to the extent of at least about 95%. 19. The azole of claim 9, wherein said compound is carbamic acid 1-(3,4-dichloro-phenyl)-2-tetrazol-2-yl-ethyl ester. 20. The azole of claim 19, wherein said compound is carbamic acid (R)-1-(3,4-dichloro-phenyl)-2-tetrazol-2-yl-ethyl ester substantially free of its (S)-enantiomer and said (R)-enantiomer is present to the extent of at least about 95%. 21. The azole of claim 19, wherein said compound is carbamic acid (S)-1-(3,4-dichloro-phenyl)-2-tetrazol-2-yl-ethyl ester substantially free of its (R)-enantiomer and said (S)-enantiomer is present to the extent of at least about 95%. 22. The azole of claim 9, wherein said compound is carbamic acid-1-(2,6-dichloro-phenyl)-2-tetrazol-2-yl-ethyl ester. 23. The azole of claim 9, wherein said compound is carbamic acid 1-(3,4-dichloro-phenyl)-2-tetrazol-2-yl-propyl ester. 24. The azole of claim 7, wherein one of A3, A4 and A5 is N and the others are CH. 25. The azole of claim 24, wherein R6 and R7 are independently hydrogen, halogen or perfluoroalkyl. 26. The azole of claim 25, wherein said compound is carbamic acid-1-(2-chloro-phenyl)-2-[1,2,3]triazol-2-yl-ethyl ester. 27. The azole in accordance with claim 26 wherein said compound is Carbamic acid (R)-1-(2-chloro-phenyl)-2-[1,2,3]triazol-2-yl-ethyl ester substantially free of its (S)-enantiomer and said (R)-enantiomer is present to the extent of at least about 95%. 28. The azole in accordance with claim 26 wherein said compound is Carbamic acid (S)-1-(2-chloro-phenyl)-2-[1,2,3]triazol-2-yl-ethyl ester substantially free of its (R)-enantiomer and said (S)-enantiomer is present to the extent of at least about 95%. 29. The azole of claim 25, wherein said compound is carbamic acid-1-(2,4-dichloro-phenyl)-2-[1,2,3]triazol-1-yl-ethyl ester. 30. The azole in accordance with claim 29 wherein said compound is Carbamic acid (R)-1-(2,4-dichloro-phenyl)-2-[1,2,3]triazol-2-yl-ethyl ester substantially free of its (S)-enantiomer and said (R)-enantiomer is present to the extent of at least about 95%. 31. The azole in accordance with claim 29 wherein said compound is Carbamic acid (S)-1-(2,4-dichloro-phenyl)-2-[1,2,3]triazol-2-yl-ethyl ester substantially free of its (R)-enantiomer and said (S)-enantiomer is present to the extent of at least about 95%. 32. The azole of claim 25, wherein said compound is carbamic acid 1-(3,4-dichloro-phenyl)-2-[1,2,3]triazol-2-yl-ethyl ester. 33. The azole in accordance with claim 32 wherein said compound is Carbamic acid (R)-1-(3,4-dichloro-phenyl)-2-[1,2,3]triazol-2-yl-ethyl ester substantially free of its (S)-enantiomer and said (R)-enantiomer is present to the extent of at least about 95%. 34. The azole in accordance with claim 32 wherein said compound is Carbamic acid (S)-1-(3,4-dichloro-phenyl)-2-[1,2,3]triazol-2-yl-ethyl ester substantially free of its (R)-enantiomer and said (S)-enantiomer is present to the extent of at least about 95%. 35. The azole of claim 1 wherein said compound has the formula: wherein Y is as above; A3, A4 and A5 are independently selected from the group consisting of CH or N, with at least one of A3, A4 and A5 being CH and at least one of the other of A3, A4 and A5 being N; R6 and R7 being selected from the group consisting of hydrogen, halogen, perfluoroalkyl, alkyl of from 1 to 8 carbon atoms, thioalkoxy; R3 and R4 are alkyl or hydrogen, or taken together with the attached nitrogen atom form an imidazole, or phenyl piperazine ring; y is an integer of from 0 to 4; and p is an integer from 0 to 1. 36. The azole of claim 35, wherein R6 and R7 are independently hydrogen, halogen or perfluoroalkyl. 37. The azole of claim 36, wherein said compound is carbamic acid 2-(3,4-dichloro-phenoxy)-1-tetrazol-2-ylmethyl-ethyl ester. 38. The azole of claim 36, wherein said compound is carbamic acid 2-(2-chloro-phenoxy)-1-tetrazol-2-ylmethyl-ethyl ester. 39. The azole of claim 35, wherein one of A3, A4 and A5 is N and the others are CH. 40. The azole of claim 39, wherein R6 and R7 are independently hydrogen, halogen or perfluoroalkyl. 41. The azole of claim 40, wherein said compound is carbamic acid 2-(2,4-dichloro-phenoxy)-1-[1,2,3]triazol-2-ylmethyl-ethyl ester. 42. The azole of claim 1, wherein said compound is: wherein R8 and R9 taken together with the attached nitrogen atom form a substituent of the formula: wherein E, U and A2 are as above; k and v are an integer from 0 to 1; Z is a phenyl, phenoxy, alkyl or phenylalkyloxy substitued where the phenyl moiety of said substitutent is unsubstituted or substituted with from one to three substituents selected from the group consisting of halogen, alkyl, perfluoroalkyl or alkoxy; A3, A4 and A5 are independently selected from the group consisting of CH or N, with at least one of A3, A4 and A5 being CH and at least one of the other of A3, A4 and A5 being N; Y is a hydrogen, halogen or alkyl; y is an integer of from 0 to 1; R6 and R7 are selected from the group consisting of hydrogen, halogen, perfluoroalkyl, thioalkoxy, alkoxy and alkyl; or a pharmaceutically acceptable salt thereof. 43. The azole of claim 42, wherein one of A3, A4 and A5 are CH and the others are N. 44. The azole of claim 43, wherein R6 and R7 are independently hydrogen, halogen or perfluoroalkyl. 45. The azole of claim 44, wherein said compound is 4-(3,4-dichloro-benzyl)-piperidine-1-carboxylic acid 1-(2,4-dichloro-phenyl)-2-tetrazol-2-yl-ethyl ester. 46. The azole of claim 44, wherein said compound is 4-(3,4-dichloro-benzyl)-piperidine-1-carboxylic acid 1-(3,4-dichloro-phenyl)-2-tetrazol-2-yl-ethyl ester. 47. The azole of claim 44, wherein said compound is 4-(3,5-bis-trifluoromethyl-benzyl)-piperidine-1-carboxylic acid 1-(2-chloro-phenyl)-2-tetrazol-2-yl-ethyl ester. 48. The azole of claim 44, wherein said compound is 3-phenethyl-pyrrolidine-1-carboxylic acid 1-(2,5-dichloro-phenyl)-2-tetrazol-2-yl-ethyl ester. 49. The azole of claim 42, wherein one of A3, A4 and A5 is N and the others are CH. 50. The azole of claim 49, wherein R6 and R7 are independently hydrogen, halogen or perfluoroalkyl. 51. The azole of claim 50, wherein said compound is 4-benzyl-piperidine-1-carboxylic acid-1-(2-chloro-phenyl)-2-[1,2,3]triazol-2-yl-ethyl ester. 52. The azole in accordance with claim 51 wherein said compound is 4-benzyl-piperidine-1-carboxylic acid (R)-1-(2-chloro-phenyl)-2-[1,2,3]triazol-2-yl-ethyl ester substantially free of its (S)-enantiomer and said (R)-enantiomer is present to the extent of at least about 95%. 53. The azole in accordance with claim 51 wherein said compound is 4-benzyl- piperidine-1-carboxylic acid (S)-1-(2-chloro-phenyl)-2-[1,2,3]triazol-2-yl-ethyl ester substantially free of its (R)-enantiomer and said (S)-enantiomer is present to the extent of at least about 95%. 54. The compound of claim 1 having the formula: wherein A1 is as above; R8 and R9 are hydrogen, halogen, lower alkoxy, lower alkyl, hydroxy, trifluromethyl, amino, mono or dilower alkyl amino, nitro or R8 and R9 when substituted on adjacent carbon atoms and when R10 is hydrogen can be taken together to form a cyclolower alkyl, phenyl or heterocyclolower alkyl ring; R10 is lower alkoxy, phenoxy, phenylalkoxy, hydrogen, cycloloweralkyl, halogen, hydroxy, lower alkyl, nitro, trifluoromethyl mono or lower dikalkyl amino or amino; R11 is hydrogen, lower alkyl, phenyl or phenyl lower alkyl wherein the phenyl group can be unsubstituted or mono or disubstituted with a lower alkyl, hydroxy, lower alkoxy, or halo; R12 is hydrogen or lower alkyl or R12 taken together with R11 and their attached nitrogen atom form a 4 to 6 membered heteroarmatic ring containing at most 3 additional hetero nitrogen atoms; R14 is hydrogen, amino carbonyl, or lower alkyl: R13 is hydrogen, lower alkyl, amino, mono or dilower alkylamino hetero aromatic, amino carbonyl or phenyl where the phenyl group can be unsubstituted or mono or disubstituted with a lower alkyl, hydroxy, lower alkoxy, or halo; and 0 and p are integers from 0-1. 55. The compound of claim 54 wherein p is 0 and o is 1. 56. The compound of claim 54 wherein o is 0 and p is 1. 57. The compound of claim 1 wherein said compound has the formula: wherein is a 4 to 6 membered a heterocycloalkyl ring containing at most 1 additional hetero nitrogen atom; A1 is as above; R8 and R9 are hydrogen, halogen, lower alkoxy, lower alkyl, hydroxy, trifluromethyl, amino, mono or dilower alkyl amino, nitro or R8 and R9 when substituted on adjacent carbon atoms and when R10 is hydrogen can be taken together to form a cyclolower alkyl, phenyl or heterocyclolower alkyl ring; R10 is lower alkoxy, phenyoxy, phenylalkoxy, hydrogen, halogen, hydroxy lower alkyl, nitro, trifluoromethyl, mono or lower dikalkyl amino or amino; R14 is hydrogen, amino carbonyl, or lower alkyl; R13 is hydrogen, lower alkyl, amino, mono or dilower alkylamino hetero aromatic, amino carbonyl or phenyl where the phenyl group can be unsubstituted or mono or disubstituted with a lower alkyl, hydroxy, lower alkoxy, or halo; and 0, z and p are integers from 0-1; R16 is phenyl, phenyl carbonyl, a five or six membered hetero aromatic ring containing from 1 to 4 nitro heteroatoms, wherein said phenyl and heteroaromatic rings can be unsubstituted or mono or di-substituted with hydroxy, hydroxy lower alkyl, lower alkoxy, halogen, phenyl or trifloromethyl. 58. The compound of claim 57 wherein o is 0 and p equals 1. 59. The compound of claim 57 wherein p is 0 and o is 0. 60. An azole compound of the formula: wherein A1 is selected from the group consisting of a nitrogen atom and CH; R11 is hydrogen, lower alkyl, amino carbonyl, phenyl or phenyl lower alkyl wherein the phenyl group can be unsubstituted or mono or disubstituted with a lower alkyl, hydroxy, lower alkoxy, halo, cyclo lower alkyl; R12 is hydrogen or lower alkyl; or R12 taken together with R11 and their attached nitrogen atom form a 4 to 6 membered heteroarmatic ring containing at most 3 additional hetero nitrogen atoms; R13 is hydrogen, amino, mono or dilower lower alkylamino hetero aromatic, amino carbonyl or phenyl where the phenyl group can be unsubstituted or mono or disubstituted with a lower alkyl, hydroxy, lower alkoxy, or halo; and R′15 and R′16 when taken together with their attached carbon atoms form a cycloalkyl or phenyl ring which can be unsubstituted or substituted with halo, lower alkyl, lower alkoxy, hydroxy, halogen or trifluoromethyl.