Biclycloheteroaryl Compounds as P2x7 Modulators and Uses Thereof

• US 20100298285A1
• Filed: 03/16/2007
• Published: 11/25/2010
• Est. Priority Date: 03/16/2006
• Status: Abandoned Application

• Current Assignee: Renovis, Inc. (Evotec SE)
• Original Assignee: Renovis, Inc. (Evotec SE)
• Inventors: Wang, Zhan, Cao, Yeyu, Kaub, Carl, Kincaid, John, Kelly, Michael G., Gowlugari, Sumithra, Fang, Yunfeng, He, Jianhua
• Application Number:
  US12/225,275
• Publication Number:
  US 20100298285A1
• Time in Patent Office: Days
• US Class Current: 514/210.18
• CPC Class Codes: A61P 13/00 Drugs for disorders of the urinary system
• CPC Class Codes: A61P 17/06 Antipsoriatics
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/06 Antimigraine agents
• 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 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 3/00 Drugs for disorders of the metabolism of the blood or the extracellular fluid A61P7/00
• CPC Class Codes: A61P 3/04 Anorexiants; Antiobesity agents
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 37/00 Drugs for immunological or allergic disorders
• 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 217/04 with hydrocarbon or substituted hydrocarbon radicals attached to the ring nitrogen atom
• CPC Class Codes: C07D 217/06 with the ring nitrogen atom acylated by carboxylic or carbonic acids, or with sulfur or nitrogen analogues thereof, e.g. carbamates
• CPC Class Codes: C07D 217/08 with a hetero atom directly attached to the ring nitrogen atom
• CPC Class Codes: C07D 401/06 linked by a carbon chain containing only aliphatic carbon atoms
• CPC Class Codes: C07D 401/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 403/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 405/06 linked by a carbon chain containing only aliphatic carbon atoms
• CPC Class Codes: C07D 405/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 409/06 : linked by a carbon chain containing only aliphatic carbon atoms
• CPC Class Codes: C07D 409/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 409/14 : containing three or more hetero rings
• CPC Class Codes: C07D 413/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 413/14 : containing three or more hetero rings
• CPC Class Codes: C07D 417/06 : linked by a carbon chain containing only aliphatic carbon atoms
• CPC Class Codes: C07D 417/12 : linked by a chain containing hetero atoms as chain links

Abstract

Bicycloheteroaryl compounds are disclosed that have a formula represented by the following: The compounds may be prepared as pharmaceutical compositions, and may be used for the prevention and treatment of a variety of conditions in mammals including humans, including by way of non-limiting example, pain, inflammation, traumatic injury, and others.

Claims

1. A bicycloheteroaryl compound having a formula:

2. A compound according to claim 1 wherein A is CH₂.

4. A compound according to claim 1 wherein each of B and Y is CH₂;

and the dotted bond is a single bond.

12. A compound according to claim 1 wherein R¹ is selected from a 5-13 membered aryl and heteroaryl, unsubstituted or substituted with one or more substituents independently selected from halo, hydroxyl, amino, cyano, sulfo, sulfanyl, sulfinyl, amido, carboxy, carbalkoxy, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, and sulfonamide.

16. A compound according to claim 1 wherein R¹ is substituted or unsubstituted phenyl, pyridyl, substituted or unsubstituted quinoline, substituted or unsubstituted benzodioxole, substituted or unsubstituted benzodioxane, substituted or unsubstituted benzofuran, substituted or unsubstituted benzothiophene, and substituted or unsubstituted benzodioxepine.

23. A compound according to claim 1 wherein the compound is according to formula V, VI or VII

29. A compound according to claim 1 wherein the compound is according to formula VIII, IX or X:

34. A compound according to claim 1 wherein L¹ is a CO or SO₂ and R³ is alkyl, or substituted alkyl.

35. A compound according to claim 1 wherein L¹ is a CO or SO₂ and R³ is methyl, ethyl, propyl, iso-propyl, t-butyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxy iso-propyl, or hydroxy t-butyl.

36. A compound according to claim 1 wherein L¹ is a CO or SO₂ and R³ is cyclopropylmethyl, cyclopropylethyl, cyclopropylpropyl, cyclobutylmethyl, cyclobutylethyl, cyclobutylpropyl, cyclopentylmethyl, cyclopentylethyl, cyclopentylpropyl, cyclohexylmethyl, cyclohexylethyl, cyclohexylpropyl, cycloheptylmethyl, cycloheptylethyl, cycloheptylpropyl, phenylmethyl, phenethyl, or phenylpropyl, which can be optionally substituted with alkyl or hydroxy.

37. A compound according to claim 1 wherein L¹ is a CO or SO₂ and R³ is substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted bicycloaryl, and substituted or unsubstituted bicycloheteroaryl.

38. A compound according to claim 1 wherein L¹ is a CO or SO₂ and R³ is substituted or unsubstituted cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, phenyl, naphthyl, pyridyl, pyrrolidinyl, benzopyranyl, benzodioxanyl, or benzofuranyl.

39. A compound according to claim 1 wherein L¹ is a CO or SO₂ and R³ is phenyl substituted with one or more substituents independently selected from halo, hydroxyl, amino, cyano, sulfo, sulfanyl, sulfinyl-amido, carboxy, ester, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, and sulfonamide.

40. A compound according to claim 1 wherein L¹ is a CO or SO₂ and R³ is benzyl substituted with one or more substituents independently selected from halo, hydroxyl, amino, cyano, sulfo, sulfanyl, sulfinyl-amido, carboxy, ester, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, and sulfonamide.

41. A compound according to claim 1 wherein the group -L₁-R³ is selected from

42. A compound according to claim 1 wherein the group -L₁-R³ is selected from

43. A compound according to claim 1 wherein the group -L₁-R³ is selected from

46. A compound according to claim 1 wherein the compound is according to formula XIa, XIb, XIc, XId, XIe, XIf, XIg, XIh, or XIj:

47. A compound according to claim 1 wherein the compound is according to formula XIIa, XIIb, or XIc:

48. A compound according to claim 47 wherein R^2d is methyl, i-Pr or hydroxymethyl.

50. A compound according to claim 1 wherein the compound is according to formula XIIIa, XIIIb, XIIIc, XIIId, or XIIIe:

54. A compound according to any one of claims 29, 46, 47 and 50, wherein m is 1 or 2;

and each R^4a is independently selected from Me, Et, Ph, Cl, F, Br, CN, OH, OMe, OEt, OPh, COPh, CF₃, CHF₂, OCF₃, i-Pr, i-Bu, t-Bu, SMe, CH═

CH—

CO₂H, SOMe, SO₂Me, SO₃H, SO₃Me, and pyridyl.

59. A compound according to any one of claims 1, 23 and 29, wherein each of W and Z is independently CH.

63. A compound according to any one of claims 29, 46, 47 and 50, wherein R⁵ is H, Me, cyclopropyl, Cl, F, or CF₃.

64. A compound according to claim 1 wherein the compound is selected from compounds listed in Table 1.

65. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a pharmaceutically effective amount of a compound of claim 1.

66. The pharmaceutical composition of claim 65, wherein the carrier is a parenteral, oral or topical carrier.

69. A method for preventing, treating or ameliorating in a mammal a disease or condition that is causally related to the aberrant activity of the P2X₇ receptor in vivo, which comprises administering to the mammal an effective disease-treating or condition-treating amount of a compound according to claim 1, or a pharmaceutical composition according to claim 65.

74. A method for preventing, treating or ameliorating in a mammal a disease or condition selected from:

pain including acute, inflammatory and neuropathic pain, chronic pain, dental pain and headache including migraine, cluster headache and tension headache, Parkinson'"'"'s disease, multiple sclerosis;

diseases and disorders which are mediated by or result in neuroinflammation, traumatic brain injury and encephalitis;

centrally-mediated neuropsychiatric diseases and disorders, depression mania, bipolar disease, anxiety, schizophrenia, eating disorders, sleep disorders and cognition disorders;

epilepsy and seizure disorders;

prostate, bladder and bowel dysfunction, urinary incontinence, urinary hesitancy, rectal hypersensitivity, fecal incontinence, benign prostatic hypertrophy and inflammatory bowel disease;

respiratory and airway disease and disorders, allergic rhinitis, asthma and reactive airway disease and chronic obstructive pulmonary disease;

diseases and disorders which are mediated by or result in inflammation, arthritis, rheumatoid arthritis and osteoarthritis, myocardial infarction, various autoimmune diseases and disorders, uveitis and atherosclerosis;

itch/pruritus, psoriasis;

obesity;

lipid disorders;

cancer;

blood pressure;

spinal cord injury; and

renal disorders which comprises administering to the mammal an effective disease-treating or condition-treating amount of a compound according to claim 1, or a pharmaceutical composition of claim 65.

3. (canceled)

5. (canceled)

6. (canceled)

7. (canceled)

8. (canceled)

9. (canceled)

10. (canceled)

11. (canceled)

13. (canceled)

14. (canceled)

15. (canceled)

17. (canceled)

18. (canceled)

19. (canceled)

20. (canceled)

21. (canceled)

22. (canceled)

24. (canceled)

25. (canceled)

26. (canceled)

27. (canceled)

28. (canceled)

30. (canceled)

31. (canceled)

32. (canceled)

33. (canceled)

44. (canceled)

45. (canceled)

49. (canceled)

51. (canceled)

52. (canceled)

53. (canceled)

55. (canceled)

56. (canceled)

57. (canceled)

58. (canceled)

60. (canceled)

61. (canceled)

62. (canceled)

67. (canceled)

68. (canceled)

70. (canceled)

71. (canceled)

72. (canceled)

73. (canceled)

75. (canceled)

76. (canceled)

77. (canceled)

78. (canceled)

79. (canceled)

80. (canceled)

81. (canceled)

82. (canceled)

83. (canceled)

84. (canceled)

85. (canceled)