PYRROLE AND PYRAZOLE DAAO INHIBITORS

• US 20110092559A1
• Filed: 12/10/2010
• Published: 04/21/2011
• Est. Priority Date: 12/29/2003
• Status: Abandoned Application

• Current Assignee: Sunovion Pharmaceuticals Inc. (Sumitomo Chemical Company Limited)
• Original Assignee: Sunovion Pharmaceuticals Inc. (Sumitomo Chemical Company Limited)
• Inventors: CHYTIL, Milan, HOPKINS, Seth, HEFFERNAN, Michele, FANG, Q. Kevin
• Application Number:
  US12/965,175
• Publication Number:
  US 20110092559A1
• Time in Patent Office: Days
• US Class Current: 514/407
• CPC Class Codes: A61P 21/00 Drugs for disorders of the muscular or neuromuscular system
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/02 for peripheral neuropathies
• CPC Class Codes: A61P 25/04 Centrally acting analgesics, e.g. opioids
• CPC Class Codes: A61P 25/14 for treating abnormal movements, e.g. chorea, dyskinesia
• CPC Class Codes: A61P 25/16 Anti-Parkinson drugs
• CPC Class Codes: A61P 25/18 Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
• CPC Class Codes: A61P 25/28 for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07D 207/34 with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
• CPC Class Codes: C07D 209/42 Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
• CPC Class Codes: C07D 209/44 Iso-indoles; Hydrogenated iso-indoles
• CPC Class Codes: C07D 231/14 with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
• CPC Class Codes: C07D 231/16 Halogen atoms or nitro radicals
• CPC Class Codes: C07D 231/54 condensed with carbocyclic rings or ring systems
• CPC Class Codes: C07D 231/56 Benzopyrazoles; Hydrogenated benzopyrazoles
• CPC Class Codes: C07D 491/04 Ortho-condensed systems

Abstract

Methods for increasing D-Serine concentration and reducing concentration of the toxic products of D-Serine oxidation, for enhancing learning, memory and/or cognition, or for treating schizophrenia, Alzheimer'"'"'s disease, ataxia or neuropathic pain, or preventing loss in neuronal function characteristic of neurodegenerative diseases involve administering to a subject in need of treatment a therapeutically effective amount of a compound of formula I, or a pharmaceutically acceptable salt or solvate thereof:

wherein

• • R¹ and R² are independently selected from hydrogen, halo, nitro, alkyl, acyl, alkylaryl, and XYR⁵;
  • or R¹ and R², taken together, form a 5, 6, 7 or 8-membered substituted or unsubstituted carbocyclic or heterocyclic group;
  • X and Y are independently selected from O, S, NH, and (CR⁶R⁷)_n;
  • R³ is hydrogen, alkyl or M⁺;
  • M is aluminum, calcium, lithium, magnesium, potassium, sodium, zinc ion or a mixture thereof;
  • Z is N or CR⁴;
  • R⁴ is from selected from hydrogen, halo, nitro, alkyl, alkylaryl, and XYR⁵;
  • R⁵ is selected from aryl, substituted aryl, heteroaryl and substituted heteroaryl;
  • R⁶ and R⁷ are independently selected from hydrogen and alkyl;
  • n is an integer from 1 to 6;
  • at least one of R¹, R² and R⁴ is other than hydrogen; and
  • at least one of X and Y is (CR⁶R⁷)_n.
    D-serine or cycloserine may be coadministered along with the compound of formula I.

Claims

1-42. -42. (canceled)

43. A method for increasing the concentration of D-serine and/or decreasing the concentration of toxic products of D-serine oxidation by DAAO in a mammal, the method comprising administering to a subject a therapeutically effective amount of a compound of formula IA or a pharmaceutically acceptable salt thereof:

47. A method according to claim 43, wherein R³ is hydrogen.

51. A method according to claim 43, wherein n is 1 or 2.

55. A method according to claim 43, wherein X and Y are (CR⁶R⁷)_n and n is 1.

59. A method according to claim 43, wherein R⁶ and R⁷ are hydrogen.

63. A method according to claim 43, wherein R^1a is hydrogen and R^2a is XYR⁵.

44. A method for treating schizophrenia, for treating or preventing loss of memory and/or cognition associated with Alzheimer'"'"'s disease, for treating ataxia, or for preventing loss of neuronal function characteristic of neurodegenerative diseases, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula IA, or a pharmaceutically acceptable salt thereof:

48. A method according to claim 44, wherein R³ is hydrogen.

52. A method according to claim 44, wherein n is 1 or 2.

56. A method according to claim 44, wherein X and Y are (CR⁶R⁷)_n and n is 1.

60. A method according to claim 44, wherein R⁶ and R⁷ are hydrogen.

64. A method according to claim 44, wherein R^1a is hydrogen and R^2a is XYR⁵.

45. A method for enhancing learning, memory and/or cognition, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula IA, or a pharmaceutically acceptable salt thereof:

49. A method according to claim 45, wherein R³ is hydrogen.

53. A method according to claim 45, wherein n is 1 or 2.

57. A method according to claim 45, wherein X and Y are (CR⁶R⁷)_n and n is 1.

61. A method according to claim 45, wherein R⁶ and R⁷ are hydrogen.

65. A method according to claim 45, wherein R^1a is hydrogen and R^2a is XYR⁵.

46. A method for treating neuropathic pain, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula IA, or a pharmaceutically acceptable salt thereof:

50. A method according to claim 46, wherein R³ is hydrogen.

54. A method according to claim 46, wherein n is 1 or 2.

58. A method according to claim 46, wherein X and Y are (CR⁶R⁷)_n and n is 1.

62. A method according to claim 46, wherein R⁶ and R⁷ are hydrogen.

66. A method according to claim 46, wherein R^1a is hydrogen and R^2a is XYR⁵.

67. A method for

(a) increasing the concentration of D-serine and/or decreasing the concentration of toxic products of D-serine oxidation by DAAO in a mammal;

(b) treating schizophrenia;

(c) treating or preventing loss of memory and/or cognition associated with Alzheimer'"'"'s disease;

(d) treating ataxia;

(e) preventing loss of neuronal function characteristic of neurodegenerative diseases;

(f) enhancing learning, memory and/or cognition;

or

(g) treating neuropathic pain,

the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound selected from;