IP Library › Patent Application 12297596

Patent Application

App. No. 12/297,596

ISOXAZOLE DERIVATIVES AS CALCIUM CHANNEL BLOCKERS

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Patent No.: US None
App. No.: 12/297,596

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Abstract

Methods and compounds effective in ameliorating conditions characterized by unwanted calcium channel activity, particularly unwanted N-type or T-type calcium channel activity are disclosed. Specifically, a series of isoxazole containing compounds are disclosed of the general formula (1) where Z is N or CHNR 3 and (Ar 1 ) 2 CR 4 is optionally substituted benzhydryl.

Claims (152)

1 . A method to treat a condition modulated by calcium ion channel activity, which method comprises administering to a subject in need of such treatment an amount of the compound of formula (1) effective to ameliorate said condition, wherein said compound is of the formula:

or a pharmaceutically acceptable salt or conjugate thereof

wherein Z is N or CHNR 3 ;

X 1 is an optionally substituted alkylene (1-8C), alkenylene (2-8C), alkynylene (2-8C), heteroalkylene (2-8C), heteroalkenylene (2-8C), or heteroalkynylene (2-8C);

X is an optionally substituted alkylene (1-2C);

each Ar 1 and Ar 2 is independently an aromatic or heteroaromatic ring and is optionally substituted;

each R 1 is independently ═O, halo, CN, OR′, SR′, SOR′, SO 2 R′, NR′ 2 , NR′(CO)R′, or NR′SO 2 R′, wherein each R′ is independently H or an optionally substituted group selected from alkyl (1-6C), alkenyl (2-8C), alkynyl (2-8C), heteroalkyl (2-8C), heteroalkenyl (2-8C), heteroalkynyl (2-8C), heteroaryl (5-12C), and aryl (6-10C); or R 1 may be an optionally substituted group selected from alkyl (1-8C), alkenyl (2-8C), alkynyl (2-8C), heteroalkyl (2-8C), heteroalkenyl (2-8C), heteroalkynyl (2-8C), aryl (6-1° C.), heteroaryl (5-12C), O-aryl (6-1° C.), O-heteroaryl (5-12C) and C6-C12-aryl-C1-C8-alkyl;

R is H, halo, CN, NO 2 , CF 3 , COOR′, CONR 12 , OR′, SR′, SOR′, SO 2 R′, NR 12 , NR′(CO)R′, or NR′SO 2 R′, wherein each R′ is independently H or an optionally substituted group selected from alkyl (1-6C), alkenyl (2-8C), alkynyl (2-8C), heteroalkyl (2-8C), heteroalkenyl (2-8C), heteroalkynyl (2-8C), heteroaryl (5-12C), and aryl (6-10C); or R 2 may be an optionally substituted group selected from alkyl (1-8C), alkenyl (2-8C), alkynyl (2-8C), heteroalkyl (2-8C), heteroalkenyl (2-8C), heteroalkynyl (2-8C), aryl (6-10C), heteroaryl (5-12C), O-aryl (6-10C), O-heteroaryl (5-12C) and C6-C12-aryl-C1-C8-alkyl;

R 3 is H, or an optionally substituted group selected from alkyl (1-8C), alkenyl (2-8C) and alkynyl (2-8C);

R 4 is H, OH, alkyl (1-4C), alkenyl (2-4C), OR′, C(O)R, CN, or Arl, wherein each R is optionally substituted alkyl (1-4C);

n is 0 or 1;

m is 0-4, and

wherein the optional substituents for each Ar 1 and Ar 2 are independently selected from the group consisting of halo, CN, NO 2 , CF 3 , COOR′, CONR 12 , OR′, SR′, SOR′, SO 2 R′, NR 12 , NR′(CO)R′, or NR′SO 2 R′, wherein each R′ is independently H or an optionally substituted group selected from alkyl (1-6C), alkenyl (2-8C), alkynyl (2-8C), heteroalkyl (2-8C), heteroalkenyl (2-8C), heteroalkynyl (2-8C), heteroaryl (5-12C), and aryl (6-10C); or the optional substituent may be an optionally substituted group selected from alkyl (1-8C), alkenyl (2-8C), alkynyl (2-8C), heteroalkyl (2-8C), heteroalkenyl (2-8C), heteroalkynyl (2-8C), aryl (6-1° C.), heteroaryl (5-12C), O-aryl (6-1° C.), O-heteroaryl (5-12C) and C6-C12-aryl-C1-C8-alkyl.

2 . The method of claim 1 wherein said condition is modulated by N-type calcium channel activity.

3 . The method of claim 1 wherein said condition is chronic or acute pain, mood disorders, neurodegenerative disorders, gastrointestinal disorders, genitorurinary disorders, neuroprotection, metabolic disorders, cardiovascular disease, epilepsy, diabetes, prostate cancer, sleep disorders, Parkinson's disease, schizophrenia or male birth control.

4 . The method of claim 3 wherein said condition is chronic or acute pain.

5 . The method of claim 1 , wherein Z is N.

6 . The method of claim 1 , wherein (Ar 1 ) 2 CR 4 is an optionally substituted benzhydryl.

7 . (canceled)

8 . The method of claim 1 , wherein n is 0.

9 . The method of claim 1 , wherein n is 1.

10 . The method of claim 9 wherein X 1 is an optionally substituted alkylene (1-4C), alkenylene (2-4C), alkynylene (2-4C), heteroalkylene (2-4C), heteroalkenylene (2-4C), or heteroalkynylene (2-4C).

11 . The method of claim 10 wherein X 1 is an optionally substituted alkylene (1-4C) or heteroalkylene (2-4C).

12 . The method of claim 11 wherein X 1 is an optionally substituted heteroalkylene containing at least one of NH, O, S, SO, and SO 2 .

13 . The method of claim 12 wherein X 1 is NHCH 2 CO, OCH 2 CO, SCH 2 CO, SOCH 2 CO or SO 2 CH 2 CO.

14 . (canceled)

15 . The method of claim 10 , wherein X 1 is optionally substituted alkylene (1-4C) substituted by ═O.

16 . The method of claim 15 wherein X 1 is CH 2 CO.

17 . The method of claim 1 , wherein X 2 is an optionally substituted alkylene (1-4C) or heteroalkylene (1-4C).

18 . The method of claim 17 wherein X 2 is an optionally substituted alkylene (1-2C)

19 . (canceled)

20 . The method of claim 18 wherein X 2 is substituted by ═O.

21 . The method of claim 18 wherein X 2 is CH 2 or CO.

22 . The method of claim 18 , wherein R 4 is H.

23 . The method of claim 1 , wherein Ar 2 is an optionally substituted phenyl.

24 . (canceled)

25 . The method of claim 1 , wherein the compound is:

(4-benzhydrylpiperazin-1-yl)(3-phenylisoxazol-5-yl)methanone;

5-((4-benzhydrylpiperazin-1-yl)methyl)-3-phenylisoxazole;

(4-benzhydrylpiperazin-1-yl)(3-(2-fluorophenyl)isoxazol-5-yl)methanone;

(4-benzhydrylpiperazin-1-yl)(3-(2-methoxyphenyl)isoxazol-5-yl)methanone;

5-((4-benzhydrylpiperazin-1-yl)methyl)-3-(2-methoxyphenyl)isoxazole;

5-((4-benzhydrylpiperazin-1-yl)methyl)-3-(2-fluorophenyl)isoxazole;

1-(4-((3-(2-fluorophenyl)isoxazol-5-yl)methyl)piperazin-1-yl)-3,3-diphenylpropan-1-one;

1-(4-((3-(2-methoxyphenyl)isoxazol-5-yl)methyl)piperazin-1-yl)-3,3-diphenylpropan-1-one;

3,3-diphenyl-1-(4-((3-phenylisoxazol-5-yl)methyl)piperazin-1-yl)propan-1-one;

5-((4-((2,4-dimethylphenyl)(phenyl)methyl)piperazin-1-yl)methyl)-3-phenylisoxazole;

(4-((2,4-dimethylphenyl)(phenyl)methyl)piperazin-1-yl)(3-(2-fluorophenyl)isoxazol-5-yl)methanone;

5-((4-((2,4-dimethylphenyl)(phenyl)methyl)piperazin-1-yl)methyl)-3-(2-fluorophenyl)isoxazole;

5-((4-((2,4-dimethylphenyl)(phenyl)methyl)piperazin-1-yl)methyl)-3-(2-methoxyphenyl)isoxazole;

5-((4-((2,4-dichlorophenyl)(phenyl)methyl)piperazin-1-yl)methyl)-3-phenylisoxazole;

(4-((2,4-dichlorophenyl)(phenyl)methyl)piperazin-1-yl)(3-(2-fluorophenyl)isoxazol-5-yl)methanone;

5-((4-((2,4-dichlorophenyl)(phenyl)methyl)piperazin-1-yl)methyl)-3-(2-fluorophenyl) isoxazole;

2-(benzhydrylamino)-1-(4-((3-(2-fluorophenyl)isoxazol-5-yl)methyl)piperazin-1-yl)ethanone;

2-(benzhydryloxy)-1-(4-((3-(2-fluorophenyl)isoxazol-5-yl)methyl)piperazin-1-yl)ethanone;

2-(benzhydrylthio)-1-(4-((3-(2-fluorophenyl)isoxazol-5-yl)methyl)piperazin-1-yl)ethanone;

2-(benzhydrylsulfinyl)-1-(4-((3-(2-fluorophenyl)isoxazol-5-yl)methyl)piperazin-1-yl)ethanone;

2-(benzhydrylamino)-1-(4-((3-(2-methoxyphenyl)isoxazol-5-yl)methyl)piperazin-1-yl)ethanone;

2-(benzhydryloxy)-1-(4-((3-(2-methoxyphenyl)isoxazol-5-yl)methyl)piperazin-1-yl)ethanone;

2-(benzhydrylthio)-1-(4-((3-(2-methoxyphenyl)isoxazol-5-yl)methyl)piperazin-1-yl)ethanone;

2-(benzhydrylsulfinyl)-1-(4-((3-(2-methoxyphenyl)isoxazol-5-yl)methyl)piperazin-1-yl)ethanone;

2-(benzhydrylamino)-1-(4-((3-phenylisoxazol-5-yl)methyl)piperazin-1-yl)ethanone;

2-(benzhydryloxy)-1-(4-((3-phenylisoxazol-5-yl)methyl)piperazin-1-yl)ethanone;

2-(benzhydrylthio)-1-(4-((3-phenylisoxazol-5-yl)methyl)piperazin-1-yl)ethanone;

2-(benzhydrylsulfinyl)-1-(4-((3-phenylisoxazol-5-yl)methyl)piperazin-1-yl)ethanone;

2-(benzhydrylamino)-1-(4-(3-(2-methoxyphenyl)isoxazole-5-carbonyl)piperazin-1-yl)ethanone; or

a pharmaceutically acceptable salt of any of these.

26 . The method of claim 17 wherein the compound is:

(4-benzhydrylpiperazin-1-yl)(3-phenylisoxazol-5-yl)methanone;

5-((4-benzhydrylpiperazin-1-yl)methyl)-3-phenylisoxazole;

(4-benzhydrylpiperazin-1-yl)(3-(2-fluorophenyl)isoxazol-5-yl)methanone;

5-((4-benzhydrylpiperazin-1-yl)methyl)-3-(2-methoxyphenyl)isoxazole;

1-(4-((3-(2-fluorophenyl)isoxazol-5-yl)methyl)piperazin-1-yl)-3,3-diphenylpropan-1-one;

1-(4-((3-(2-methoxyphenyl)isoxazol-5-yl)methyl)piperazin-1-yl)-3,3-diphenylpropan-1-one;

5-((4-((2,4-dimethylphenyl)(phenyl)methyl)piperazin-1-yl)methyl)-3-phenylisoxazole;

(4-((2,4-dimethylphenyl)(phenyl)methyl)piperazin-1-yl)(3-(2-fluorophenyl)isoxazol-5-yl)methanone;

or a pharmaceutically acceptable salt of one of these.

27 . A compound of the formula:

or a pharmaceutically acceptable salt or conjugate thereof

wherein Z is N or CHNR 3 ;

X 1 is an optionally substituted alkylene (1-8C), alkenylene (2-8C), alkynylene (2-8C), heteroalkylene (2-8C), heteroalkenylene (2-8C), or heteroalkynylene (2-8C);

X 2 is an optionally substituted alkylene (1-2C);

each Ar 1 and Ar 2 is independently an aromatic or heteroaromatic ring and is optionally substituted;

each R 1 is independently ═O, halo, CN, OR′, SR′, SOR′, SO 2 R′, NR 12 , NR′(CO)R′, or NR′SO 2 R′, wherein each R′ is independently H or an optionally substituted group selected from alkyl (1-6C), alkenyl (2-8C), alkynyl (2-8C), heteroalkyl (2-8C), heteroalkenyl (2-8C), heteroalkynyl (2-8C), heteroaryl (5-12C), and aryl (6-10C); or R 1 may be an optionally substituted group selected from alkyl (1-8C), alkenyl (2-8C), alkynyl (2-8C), heteroalkyl (2-8C), heteroalkenyl (2-8C), heteroalkynyl (2-8C), aryl (6-1° C.), heteroaryl (5-12C), O-aryl (6-1° C.), O-heteroaryl (5-12C) and C6-C12-aryl-C1-C8-alkyl;

R 2 is H, halo, CN, NO 2 , CF 3 , COOR′, CONR 12 , OR′, SR′, SOR′, SO 2 R′, NR 12 , NR′(CO)R′, or NR′SO 2 R′, wherein each R 1 is independently H or an optionally substituted group selected from alkyl (1-6C), alkenyl (2-8C), alkynyl (2-8C), heteroalkyl (2-8C), heteroalkenyl (2-8C), heteroalkynyl (2-8C), heteroaryl (5-12C), and aryl (6-10C); or R 2 may be an optionally substituted group selected from alkyl (1-8C), alkenyl (2-8C), alkynyl (2-8C), heteroalkyl (2-8C), heteroalkenyl (2-8C), heteroalkynyl (2-8C), aryl (6-1° C.), heteroaryl (5-12C), O-aryl (6-1° C.), O-heteroaryl (5-12C) and C6-C12-aryl-C1-C8-alkyl;

R 3 is H, or an optionally substituted group selected from alkyl (1-8C), alkenyl (2-8C) and alkynyl (2-8C);

R 4 is H, OH, alkyl (1-4C), alkenyl (2-4C), OR′, C(O)R, CN, or Ar 1 , wherein each R is optionally substituted alkyl (1-4C);

n is 1;

m is 0-4, and

wherein the optional substituents for each Ar 1 and Ar 2 are independently selected from the group consisting of halo, CN, NO 2 , CF 3 , COOR′, CONR 12 , OR′, SR′, SOR′, SO 2 R′, NR 12 , NR′(CO)R′, or NR′SO 2 R′, wherein each R′ is independently H or an optionally substituted group selected from alkyl (1-6C), alkenyl (2-8C), alkynyl (2-8C), heteroalkyl (2-8C), heteroalkenyl (2-8C), heteroalkynyl (2-8C), heteroaryl (5-12C), and aryl (6-10C); or the optional substituent may be an optionally substituted group selected from alkyl (1-8C), alkenyl (2-8C), alkynyl (2-8C), heteroalkyl (2-8C), heteroalkenyl (2-8C), heteroalkynyl (2-8C), aryl (6-1° C.), heteroaryl (5-12C), O-aryl (6-10C), O-heteroaryl (5-12C) and C6-C12-aryl-C1-C8-alkyl.

28 . The compound of claim 27 wherein Z is N.

29 . The compound of claim 27 wherein (Ar 1 ) 2 CR 4 is an optionally substituted benzhydryl.

30 . (canceled)

31 . The compound of claim 27 wherein n is 0.

32 . (canceled)

33 . The compound of claim 27 , wherein X 1 is an optionally substituted alkylene (1-4C), alkenylene (2-4C), alkynylene (2-4C), heteroalkylene (2-4C), heteroalkenylene (2-4C), or heteroalkynylene (2-4C).

34 . The compound of claim 33 wherein X 1 is an optionally substituted alkylene (1-4C) or heteroalkylene (2-4C).

35 . The compound of claim 34 wherein X 1 is an optionally substituted heteroalkylene containing at least one of NH, O, S, SO, and SO 2 .

36 . The compound of claim 35 wherein X 1 is NHCH 2 CO, OCH 2 CO, SCH 2 CO, SOCH 2 CO or SO 2 CH 2 CO.

37 . (canceled)

38 . The compound of claim 27 , wherein X 1 is an optionally substituted alkylene (1-4C) substituted by ═O.

39 . The compound of claim 38 wherein X 1 is CH 2 CO.

40 . The compound of claim 27 wherein X 2 is an optionally substituted alkylene (1-4C) or heteroalkylene (1-4C).

41 . The compound of claim 40 , wherein X 2 is an optionally substituted alkylene (1-2C)

42 . The compound of claim 41 , wherein X 2 is unsubstituted.

43 . The compound of claim 41 , wherein X 2 is substituted by ═O.

44 . The compound of claim 41 , wherein X 2 is CH 2 or CO.

45 . The compound of claim 41 , wherein R 4 is H.

46 . The compound of claim 27 , wherein Ar 2 is an optionally substituted phenyl.

47 . The compound of claim 45 wherein Ar 2 is an unsubstituted phenyl.

48 . The compound of claim 27 wherein the compound is: