Arylpiperazinyl compounds

• US 7,153,858 B2
• Filed: 01/30/2004
• Issued: 12/26/2006
• Est. Priority Date: 01/31/2003
• Status: Expired due to Fees

• Current Assignee: EPIX Delaware, Inc. (EPIX Pharmaceuticals, Inc.)
• Original Assignee: EPIX Delaware, Inc. (EPIX Pharmaceuticals, Inc.)
• Inventors: Heifetz, Alexander, Sharadendu, Anurag, Becker, Oren, Noiman, Silvia, Marantz, Yael, Chen, Dongli, Cheruku, Srinivasa Rao, Inbal, Boaz, Bar-Haim, Shay, Dhanoa, Dale S., Mohanty, Pradyumna, Fichman, Merav, Nudelman, Raphael, Shachem, Sharon
• Primary Examiner(s): BERNHARDT, EMILY B
• Application Number:
  US10/768,579
• Publication Number:
  US 20040220192A1
• Time in Patent Office: 1,061 Days
• Field of Search: 544/392, 544/393, 544/394, 544/360
• US Class Current: 514/253.01
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 13/10 of the bladder
• CPC Class Codes: A61P 15/00 Drugs for genital or sexual disorders for disorders of sex hormones A61P5/24; Contraceptives
• CPC Class Codes: A61P 15/10 for impotence
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/04 Centrally acting analgesics, e.g. opioids
• CPC Class Codes: A61P 25/06 Antimigraine agents
• CPC Class Codes: A61P 25/16 Anti-Parkinson drugs
• CPC Class Codes: A61P 25/22 Anxiolytics
• CPC Class Codes: A61P 29/02 without antiinflammatory effect
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 9/00 Drugs for disorders of the cardiovascular system
• CPC Class Codes: A61P 9/08 Vasodilators for multiple indications
• CPC Class Codes: A61P 9/10 for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: C07D 211/96 Sulfur atom
• CPC Class Codes: C07D 213/74 Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
• CPC Class Codes: C07D 239/42 One nitrogen atom nitro radicals C07D239/30
• CPC Class Codes: C07D 295/13 to an acyclic saturated chain
• CPC Class Codes: C07D 401/12 linked by a chain containing hetero atoms as chain links

Abstract

The invention relates to 5-HT receptor agonists or antagonists. Novel arylpiperazinyl sulfonamide compounds represented by Formulae I: and II, and synthesis and uses of those compounds for treating diseases including those mediated directly or indirectly by 5-HT receptors, are disclosed. Such conditions include central nervous system disorders such as generalized anxiety disorder, ADD/ADHD, neural injury, stroke, and migraine. Methods of preparation and novel intermediates and pharmaceutical salts thereof are also included.

Claims

1. A compound having the formula

2. The compound of claim 1, wherein R₂ is selected from the group consisting of lower alkoxy;

amino;

nitro;

NHCO-alkyl;

NHCO-cycloalkyl;

—

N-(alkyl)-CO-alkyl; and

—

NHSO₂alkyl.

3. The compound of claim 2, wherein R₂ is nitro, NHCO-alkyl, —

N-(alkyl)-CO-alkyl, or alkylamino; and

R₃ is H.

4. The compound of claim 3, wherein said NHCO-alkyl is NHCO-lower alkyl.

5. The compound of claim 4, wherein said NHCO-lower alkyl is NHCO—

(CH₃), NHCO—

(CH₂CH₃), NHCO—

(CH₂CH₂—

CH₃), or NHCO—

(CH(CH₃)₂.

6. The compound of claim 3, wherein R₂ is in the meta position.

7. The compound of claim 1, wherein said lower alkyl or alkoxy is lower (C₁–

C₄).

8. The compound of claim 1, wherein said cycloalkyl is (C₃–

C₆).

9. The compound of claim 1, wherein R₁ is n-butyl, s-butyl, i-butyl, or cycloalkyl.

10. The compound of claim 1, wherein said cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexylmethyl, or cyclohexylphenyl.

11. The compound of claim 1, wherein m is 0.

12. The compound of claim 1, wherein n is 1 or 4.

13. A pharmaceutical composition comprising the compound of claim 1, and a pharmaceutically-acceptable carrier.

57. The compound of claim 1, wherein p is 0 or 1.

14. 4-Methyl-N-{4-[4-(3-nitro-phenyl)-piperazin-1-yl]-butyl}-benzenesulfonamide;

or pharmaceutically acceptable salts thereof.

15. 4-Methyl-N-{4-[4-(3-nitro-phenyl)-piperazin-1-yl]-butyl}-benzenesulfonamide HCl.

16. N-(3-{4-[4-(Toluene-4-sulfonylamino)-butyl]-piperazin-1-yl}-phenyl)-butyramide;

or pharmaceutically acceptable salts thereof.

17. 2,2-Dimethyl-N-(3-{4-[4-(toluene-4-sulfonylamino)-butyl]-piperazin-1-yl}-phenyl)-propionamide;

or pharmaceutically acceptable salts thereof.

18. N-(3-{4-[4-(Toluene-4-sulfonylamino)-butyl]-piperazin-1-yl}-phenyl)-isobutyramide;

or pharmaceutically acceptable salts thereof.

19. N-{4-[4-(3-Ethanesulfonylamino-phenyl)-piperazin-1-yl]-butyl}-4-methyl-benzenesulfonamide;

or pharmaceutically acceptable salts thereof.

20. 4-Methyl-N-(4-{4-[3-(propane-2-sulfonylamino)-phenyl]-piperazin-1-yl}-butyl)-benzenesulfonamide;

or pharmaceutically acceptable salts thereof.

21. 4-Methyl-N-{4-[4-(3-nitro-phenyl)-piperazin-1-yl]-butyl}-benzenesulfonamide;

or pharmaceutically acceptable salts thereof.

22. N-{4-[4-(2-Methoxy-5-nitro-phenyl)-piperazin-1-yl]-butyl}-4-methyl-benzenesulfonamide;

or pharmaceutically acceptable salts thereof.

23. N-{4-[4-(3-Methoxy-phenyl)-piperazin-1-yl]-butyl}-4-methyl-benzenesulfonamide;

or pharmaceutically acceptable salts thereof.

24. N-{4-[4-(3-Ethanesulfonylamino-phenyl)-piperazin-1-yl]-butyl}-4-methyl-benzenesulfonamide;

or pharmaceutically acceptable salts thereof.

25. N-{4-[4-(3-Methanesulfonylamino-phenyl)-piperazin-1-yl]-butyl}-4-methyl-benzenesulfonamide;

or pharmaceutically acceptable salts thereof.

26. N-[4-(4-Biphenyl-3-yl-piperazin-1-yl)-butyl]-4-methyl-benzenesulfonamide;

or pharmaceutically acceptable salts thereof.

27. 4-Methyl-N-[4-(4-phenyl-piperazin-1-yl)-butyl]-benzenesulfonamide;

or pharmaceutically acceptable salts thereof.

28. 1-cyclohexyl-N-(4-(4-(2-methoxyphenyl)piperazin-1-yl)butyl)methanesulfonamide;

or pharmaceutically acceptable salts thereof.

29. N-(3-{4-[4-(Toluene-4-sulfonylamino)-butyl]-piperazin-1-yl}-phenyl)-propionamide;

or pharmaceutically acceptable salts thereof.

30. (3-{4-[1-(4-Fluoro-benzenesulfonyl)-piperidin-4-ylmethyl]-piperazin-1-yl}-phenyl)-dimethyl-amine;

or pharmaceutically acceptable salts thereof.

31. 1-cyclohexyl-N-(4-(4-(3-(dimethylamino)phenyl)piperazin-1-yl)butyl)methanesulfonamide;

or pharmaceutically acceptable salts thereof.

32. N-(3-{4-[1-(4-Fluoro-benzenesulfonyl)-piperidin-4-ylmethyl]-piperazin-1-yl}-phenyl)-acetamide;

or pharmaceutically acceptable salts thereof.

33. N-(3-{4-[4-(4-Fluoro-benzenesulfonylamino)-butyl]-piperazin-1-yl}-phenyl)-acetamide;

or pharmaceutically acceptable salts thereof.

34. 1-(2-Methoxy-phenyl)-4-[1-(toluene-4-sulfonyl)-piperidin-3-ylmethyl]-piperazine;

or pharmaceutically acceptable salts thereof.

35. A compound having the formula

36. The compound of claim 35, wherein said NHCO-lower alkyl is NHCO—

(CH₃), NHCO—

(CH₂CH₃), NHCO—

(CH₂CH₂—

CH₃), or NHCO—

(CH(CH₃)₂.

37. The compound of claim 35, wherein R₂ is in the meta position.

38. The compound of claim 35, wherein said lower alkyl or alkoxy is lower C₁–

C₄).

39. The compound of claim 35, wherein said cycloalkyl is (C₃–

C₆).

40. The compound of claim 35, wherein R₁ is n-butyl, s-butyl, i-butyl, or cycloalkyl.

41. The compound of claim 40, wherein said cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexylmethyl, or cyclohexylphenyl.

42. The compound of claim 35, wherein m is 0.

43. The compound of claim 35, wherein n is 1 or 4.

44. The compound of claim 35, wherein p is 0 or 1.

56. A pharmaceutical composition comprising the compound of claim 35, and a pharmaceutically-acceptable carrier.

45. Cyclopropanecarboxylic acid (3-{4-[4-(toluene-4-sulfonylamino)-butyl]-piperazin-1-yl}-phenyl)-amide;

or pharmaceutically acceptable salts.

46. N-(3-{4-[4-(Toluene-4-sulfonylamino)-butyl]-piperazin-1-yl}-phenyl)-acetamide;

or pharmaceutically acceptable salts thereof.

47. N-{3-[4-(4-Cyclohexylmethanesulfonylamino-butyl)-piperazin-1-yl]-phenyl}-acetamide;

or pharmaceutically acceptable salts thereof.

48. N-{3-[4-(1-Cyclohexylmethanesulfonyl-piperidin-4-ylmethyl)-piperazin-1-yl]-phenyl}-acetamide;

or pharmaceutically acceptable salts thereof.

49. Cyclopropanecarboxylic acid {3-[4-(4-cyclohexylmethanesulfonylamino-butyl)-piperazin-1-yl]-phenyl}-amide;

or pharmaceutically acceptable salts thereof.

50. N-(3-{4-[1-(Propane-2-sulfonyl)-piperidin-4-ylmethyl]-piperazin-1-yl}-phenyl)-acetamide;

or pharmaceutically acceptable salts thereof.

51. N-(3-{4-[4-(Propane-2-sulfonylamino)-butyl]-piperazin-1-yl}-phenyl)-acetamide;

or pharmaceutically acceptable salts thereof.

52. N-{3-[4-(4-Cyclohexanesulfonylamino-butyl)-piperazin-1-yl]-phenyl}-acetamide;

or pharmaceutically acceptable salts thereof.

53. N-(3-{4-[4-(Cyclohexylmethanesulfonyl-methyl-amino)-butyl]-piperazin-1-yl}-phenyl)-acetamide;

or pharmaceutically acceptable salts thereof.

54. N-(3-{4-[4-(2-Methyl-propane-1-sulfonylamino)-butyl]-piperazin-1-yl}-phenyl)-acetamide;

or pharmaceutically acceptable salts thereof.

55. N-[3-(4-{4-[Methyl-(2-methyl-propane-1-sulfonyl)-amino]-butyl}-piperazin-1-yl)-phenyl]-acetamide;

or pharmaceutically acceptable salts thereof.