Benzamide, heteroarylamide and reverse amides

• US 20030186981A1
• Filed: 11/12/2002
• Published: 10/02/2003
• Est. Priority Date: 11/12/2001
• Status: Active Grant

• Current Assignee: ZOETIS LLC (Zoetis Incorporated)
• Original Assignee: Pfizer Inc.
• Inventors: Subramanyam, Chakrapani, Duplantier, Allen J.
• Granted Patent: US 7,214,677 B2
• Time in Patent Office: Days
• US Class Current: 514/242
• CPC Class Codes: A61P 1/02 Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
• CPC Class Codes: A61P 1/04 for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 11/06 Antiasthmatics
• CPC Class Codes: A61P 13/12 of the kidneys
• CPC Class Codes: A61P 17/02 for treating wounds, ulcers, burns, scars, keloids, or the like
• CPC Class Codes: A61P 17/06 Antipsoriatics
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 19/06 Antigout agents, e.g. antihyperuricemic or uricosuric agents
• CPC Class Codes: A61P 19/10 for osteoporosis
• CPC Class Codes: A61P 21/04 for myasthenia gravis
• 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 25/06 Antimigraine agents
• 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 25/24 Antidepressants
• 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 27/02 Ophthalmic agents
• 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 3/10 : for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 31/00 : Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
• CPC Class Codes: A61P 31/04 : Antibacterial agents
• CPC Class Codes: A61P 31/18 : for HIV
• CPC Class Codes: A61P 33/06 : Antimalarials
• CPC Class Codes: A61P 35/00 : Antineoplastic agents
• CPC Class Codes: A61P 35/04 : specific for metastasis
• CPC Class Codes: A61P 37/04 : Immunostimulants
• CPC Class Codes: A61P 37/06 : Immunosuppressants, e.g. drugs for graft rejection
• CPC Class Codes: A61P 37/08 : Antiallergic agents antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14
• CPC Class Codes: A61P 43/00 : Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 7/00 : Drugs for disorders of the blood or the extracellular fluid
• CPC Class Codes: A61P 7/02 : Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
• CPC Class Codes: A61P 9/00 : Drugs for disorders of the cardiovascular system
• CPC Class Codes: A61P 9/04 : Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
• 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 211/76 : attached in position 2 or 6
• CPC Class Codes: C07D 213/64 : attached in position 2 or 6
• CPC Class Codes: C07D 241/08 : with oxygen atoms directly attached to ring carbon atoms
• CPC Class Codes: C07D 249/12 : Oxygen or sulfur atoms
• CPC Class Codes: C07D 263/24 : with hydrocarbon radicals, substituted by oxygen atoms, attached to other ring carbon atoms
• CPC Class Codes: C07D 279/16 : condensed with one six-membered ring
• CPC Class Codes: C07D 405/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 409/12 : linked by a chain containing hetero atoms as chain links

Abstract

The present invention relates to novel to P2X₇ inhibitors of formula I

and to processes for their preparation, intermediates useful in their preparation, pharmaceutical compositions containing them, and their use in therapy. The active compounds of the present invention are potent inhibitors of P2X₇ and as such are useful in the treatment of inflammation, osteoarthritis, rheumatoid arthritis, cancer, reperfusion or ischemia in stroke or heart attack, autoimmune diseases and other disorders.

Claims

1. A compound of the formula

2. A compound according to claim 1 wherein X, Y and Z are ═

(CR⁶)—

, ═

(CR⁷)—

, and ═

(CR⁸)—

respectively.

3. A compound according to claim 1 wherein X, Y and Z are ═

(CR⁶)—

, ═

(CR⁷)—

, and ═

(CR⁸)—

, respectively; and

each of R⁶, R⁷, and R⁸ is hydrogen.

4. A compound according to claim 1 wherein X, Y and Z are ═

N—

, ═

(CR⁷)—

, and ═

(CR⁸)—

respectively.

5. A compound according to claim 1 wherein X, Y and Z are ═

(CR⁶)—

, ═

N—

, and ═

(CR⁸)—

respectively.

6. A compound according to claim 1 wherein X, Y and Z are ═

(CR⁶)—

, ═

(CR⁷)—

, and ═

N—

respectively.

7. A compound according to claim 1 wherein X, Y and Z are ═

N—

, ═

(CR⁷)—

, and ═

N—

respectively.

8. A compound according to claim 1 wherein X, Y and Z are ═

(CR⁶)—

, ═

N—

, and ═

N—

respectively.

9. A compound according to claim 3, wherein A is —

(C═

O)NH—

.

10. A compound according to claim 3, wherein A is —

NH(C═

O)—

.

11. A compound according to claim 9, wherein R³ is (C₄-C₁₀)alkyl.

12. A compound according to claim 9, wherein R³ is (C₄-C₁₀)alkyl substituted with one to three substituents independently selected from halo, hydroxy, —

CN, (C₁-C₄)alkyl, (C₁-C₄)alkoxy, —

CF₃, CF₃O—

, (C₁-C₄)alkyl-S—

, (C₁-C₄)alkyl-(S═

O)—

, (C₁-C₄)alkyl-(SO₂)—

, (C₁-C₄)alkyl-O—

(C═

O)—

, formyl, and (C₁-C₄)alkyl-(C═

O)—

.

13. A compound according to claim 9, wherein R³ is (C₃-C₁₂)cycloalkyl-(CR¹¹R¹²)_s—

wherein R¹¹ and R¹² are each independently hydrogen or (C₁-C₄)alkyl.

14. A compound according to claim 9, wherein R³ is (C₃-C₁₂)cycloalkyl-(CR¹¹R¹²)_s—

wherein at least one of R¹¹ and R¹² is other than hydrogen or (C₁-C₄)alkyl.

15. A compound according to claim 9, wherein R³ is (C₃-C₁₂)cycloalkyl-(CR¹¹R¹²)_s—

;

optionally substituted by one to three substituents independently selected from the group consisting of hydrogen, halo, hydroxy, —

CN, (C₁-C₄)alkyl, (C₁-C₄)alkoxy, oxo, —

CO₂-(C₁-C₄)alkyl, formyl, (C₁-C₄)alkyl-(C═

O)—

.

16. A compound according to claim 9, wherein R³ is (C₃-C₁₂)cycloalkyl-(CR¹¹R¹²)_s—

optionally substituted by one to three substituents independently selected from the group consisting of hydrogen, halo, hydroxy, —

CN, (C₁-C₄)alkyl and (C₁-C₄)alkoxy.

17. A compound according to claim 9, wherein R³ is (C₃-C₁₂)cycloalkyl-(CR¹¹R¹²)_s—

optionally substituted by at least one substituent selected from the group consisting of (C₆-C₁₀)aryl, (C₃-C₈)cycloalkyl, (C₁-C₁₀)heteroaryl, (C₁-C₁₀)heterocyclyl, (C₆-C₁₀)aryl-O—

, (C₃-C₈)cycloalkyl-O—

, (C₁-C₁₀)heteroaryl-O— and

(C₁-C₁₀)heterocyclyl-O—

;

wherein each of the aforesaid (C₆-C₁₀)aryl, (C₃-C₈)cycloalkyl, (C₁-C₁₀)heteroaryl and (C₁-C₁₀)heterocyclyl anywhere on said (C₃-C₁₂)cycloalkyl-(CR¹¹R¹²)_s—

substituents may optionally be substituted by one to three moieties per ring, independently selected from the group consisting of halo, hydroxy, —

CN, (C₁-C₄)alkyl, (C₁-C₄)alkoxy, —

CF₃, CF₃O—

, (C₁-C₄)alkyl-S—

, (C₁-C₄)alkyl-(S═

O)—

, (C₁-C₄)alkyl-(SO₂)—

, —

CO₂-(C₀-C₄)alkyl, formyl, and (C₁-C₄)alkyl-(C═

O)—

.

18. A compound according to claim 9, wherein R³ is (C₃-C₁₂)cycloalkyl-(CR¹¹R¹²)_s—

optionally substituted by at least one spiro substituent selected from the group consisting of (C₆-C₁₀)aryl, (C₃-C₈)cycloalkyl, (C₁-C₁₀)heteroaryl, (C₁-C₁₀)heterocyclyl, (C₆-C₁₀)aryl-O—

, (C₃-C₈)cycloalkyl-O—

, (C₁-C₁₀)heteroaryl-O— and

(C₁-C₁₀)heterocyclyl-O—

;

wherein each of the aforesaid (C₆-C₁₀)aryl, (C₃-C₈)cycloalkyl, (C₁-C₁₀)heteroaryl and (C₁-C₁₀)heterocyclyl spiro substituent on said (C₃-C₁₂)cycloalkyl-(CR¹¹R¹²)_s—

may optionally be substituted by one to three moieties per ring, independently selected from the group consisting of halo, hydroxy, —

CN, (C₁-C₄)alkyl, (C₁-C₄)alkoxy, —

CF₃, CF₃O—

, (C₁-C₄)alkyl-S—

, (C₁-C₄)alkyl-(S═

O)—

, (C₁-C₄)alkyl-(SO₂)—

, —

CO₂-(C₁-C₄)alkyl, formyl, and (C₁-C₄)alkyl-(C═

O)—

.

19. A compound according to claim 9, wherein R³ is (C₆-C₁₀)aryl-(CR¹¹R¹²)_q—

(CH₂)—

;

wherein R¹¹ and R¹² are each independently hydrogen or (C₁-C₄)alkyl.

20. A compound according to claim 9, wherein R³ is (C₆-C₁₀)aryl-(CR¹¹R¹²)_q—

(CH₂)—

;

wherein R¹¹ and R¹² are each independently selected from the group consisting of hydrogen and (C₁-C₄)alkyl and wherein each of R¹¹ and R¹² of the CR¹¹R¹² directly attached to group A are hydrogen; and

wherein said (C₆-C₁₀)aryl of said (C₆-C₁₀)aryl-(CR¹¹R¹²)_q—

(CH₂)—

group member is substituted by one to three substituents independently selected from the group consisting of hydrogen, halo, hydroxy, —

CN, (C₁-C₄)alkyl, (C₁-C₄)alkoxy, oxo, (C₁-C₄)alkyl-O—

(C═

O)—

, formyl, benzyloxy and (C₁-C₄)alkyl-(C═

O)—

.

21. A compound according to claim 9, wherein R³ is (C₆-C₁₀)aryl-(CR¹¹R¹²)_q—

(CH₂)—

;

wherein R¹¹ and R¹² are each independently selected from the group consisting of hydrogen and (C₁-C₄)alkyl; and

wherein said (C₆-C₁₀)aryl of said (C₆-C₁₀)aryl-(CR¹¹R¹R²)_q—

(CH₂)—

group member is substituted by one to three substituents independently selected from the group consisting of hydrogen, halo, —

CN, (C₁-C₄)alkyl, benzyloxy and (C₁-C₄)alkoxy.

22. A compound according to claim 9, wherein R³ is (C₆-C₁₀)aryl-(CR¹R¹²)_q—

(CH₂)—

;

wherein R¹¹ and R¹² are each independently selected from the group consisting of hydrogen and (C₁-C₄)alkyl; and

wherein said (C₆-C₁₀)aryl of said (C₆-C₁₀)aryl-(CR¹¹R¹²)_q—

(CH₂)—

group member is substituted by at least one substituent selected from the group consisting of (C₆-C₁₀)aryl, (C₃-C₈)cycloalkyl, (C₁-C₁₀)heteroaryl, (C₁-C₁₀)heterocyclyl, (C₆-C₁₀)aryl-O—

, (C₃-C₈)cycloalkyl-O—

, (C₁-C₁₀)heteroaryl-O— and

(C₁-C₁₀)heterocyclyl-O—

;

wherein each of the aforesaid (C₆-C₁₀)aryl, (C₃-C₈)cycloalkyl, (C₁-C₁₀)heteroaryl and (C₁-C₁₀)heterocyclyl substituents may optionally be substituted by one to three moieties per ring, independently selected from the group consisting of halo, hydroxy, —

CN, (C₁-C₄)alkyl, (C₁-C₄)alkoxy, —

CF₃, CF₃O—

, (C₁-C₄)alkyl-S—

, (C₁-C₄)alkyl-(S═

O)—

, (C₁-C₄)alkyl-(SO₂)—

, (C₁-C₄)alkyl-O—

(C═

O)—

, formyl, benzyloxy and (C₁-C₄)alkyl-(C═

O)—

.

23. A compound according to claim 9, wherein R³ is (C₁-C₁₀)heteroaryl-(CR¹¹R¹²)_s—

optionally substituted on any carbon atom able to support an additional substituent by one to three substituents per ring independently selected from the group consisting of halo, hydroxy, —

CN, (C₁-C₄)alkyl, (C₁-C₄)alkoxy, (C₁-C₄)alkyl-O—

(C═

O)—

, formyl, and (C₁-C₄)alkyl-(C═

O)—

.

24. A compound according to claim 9, wherein R³ is (C₁-C₁₀)heteroaryl-(CR¹¹R¹²)_s—

optionally substituted on any carbon atom able to support an additional substituent by one to three substituents per ring independently selected from the group consisting of halo, —

CN, (C₁-C₄)alkyl, (C₁-C₄)alkoxy, formyl, and (C₁-C₄)alkyl-(C═

O)—

.

25. A compound according to claim 9, wherein R³ is (C₁-C₁₀)heteroaryl-(CR¹¹R¹²)_s—

optionally substituted on at least one carbon atom able to support an additional substituent by a substituent selected from the group consisting of (C₆-C₁₀)aryl, (C₃-C₈)cycloalkyl, (C₁-C₁₀)heteroaryl, (C₁-C₁₀)heterocyclyl, (C₆-C₁₀)aryl-O—

, (C₃-C₈)cycloalkyl-O—

, (C₁-C₁₀)heteroaryl-O— and

(C₁-C₁₀)heterocyclyl-O—

;

wherein the aforesaid (C₆-C₁₀)aryl, (C₃-C₈)cycloalkyl, (C₁-C₁₀)heteroaryl, (C₁-C₁₀)heterocyclyl, (C₆-C₁₀)aryl-O—

, (C₃-C₈)cycloalkyl-O—

, (C₁-C₁₀)heteroaryl-O— and

(C₁-C₁₀)heterocyclyl-O—

substituents may optionally be substituted on any ring carbon atom by one to three moieties per ring, independently selected from the group consisting of halo, hydroxy, —

CN, (C₁-C₄)alkyl, (C₁-C₄)alkoxy, —

CF₃, CF₃O—

, (C₁-C₄)alkyl-S-, (C₁-C₄)alkyl-(S═

O)—

, (C₁-C₄)alkyl-(SO₂)-, (C₁-C₄)alkyl-O—

(C═

O)—

, formyl, and (C₁-C₄)alkyl-(C═

O)—

.

26. A compound according to claim 9, wherein R³ is (C₁-C₁₀)heterocyclyl-(CR¹¹R¹²)_s—

optionally substituted on any carbon atom able to support an additional substituent by one to three substituents per ring independently selected from the group consisting of halo, hydroxy, —

CN, (C₁-C₄)alkyl, (C₁-C₄)alkoxy, oxo, (C₁-C₄)alkyl-O—

(C═

O)—

, formyl, and (C₁-C₄)alkyl-(C═

O)—

.

27. A compound according to claim 9, wherein R³ is (C₁-C₁₀)heterocyclyl-(CR¹¹R¹²)_s—

optionally substituted on any carbon atom able to support an additional substituent by one to three substituents per ring independently selected from the group consisting of halo, —

CN, (C₁-C₄)alkyl, (C₁-C₄)alkoxy, oxo, formyl, and (C₁-C₄)alkyl-(C═

O)—

.

28. A compound according to claim 9, wherein R³ is (C₁-C₁₀)heterocyclyl-(CR¹¹R¹²)_s—

optionally substituted on at least one carbon atom able to support an additional substituent by a substituent selected from the group consisting of (C₆-C₁₀)aryl, (C₃-C₈)cycloalkyl, (C₁-C₁₀)heteroaryl, (C₁-C₁₀)heterocyclyl, (C₆-C₁₀)aryl-O—

, (C₃-C₈)cycloalkyl-O—

, (C₁-C₁₀)heteroaryl-o— and

(C₁-C₁₀)heterocyclyl-O—

;

wherein the aforesaid (C₆-C₁₀)aryl, (C₃-C₈)cycloalkyl, (C₁-C₁₀)heteroaryl, (C₁-C₁₀)heterocyclyl, (C₁-C₁₀)aryl-O—

, (C₃-C₈)cycloalkyl-O—

, (C₁-C₁₀)heteroaryl-O— and

(C₁-C₁₀)heterocyclyl-O—

substituents may optionally be substituted on any ring carbon atom by one to three moieties per ring, independently selected from the group consisting of halo, hydroxy, —

CN, (C₁-C₄)alkyl, (C₁-C₄)alkoxy, —

CF₃, CF₃O—

, (C₁-C₄)alkyl-S—

, (C₁-C₄)alkyl-(S═

O)—

, (C₁-C₄)alkyl-(SO₂)—

, (C₁-C₄)alkyl-O—

(C═

O)—

, formyl, and (C₁-C₄)alkyl-(C═

O)—

.

29. A compound according to claim 9, wherein R³ is (C₁-C₁₀)heterocyclyl-(CR¹¹R¹²)_s—

optionally substituted on at least one carbon atom able to support an additional substituent by a spiro substituent selected from the group consisting of (C₆-C₁₀)aryl, (C₃-C₈)cycloalkyl, (C₁-C₁₀)heteroaryl, (C₁-C₁₀)heterocyclyl, (C₆-C₁₀)aryl-O—

, (C₃-C₈)cycloalkyl-O—

, (C₁-C₁₀)heteroaryl-O— and

(C₁-C₁₀)heterocyclyl-O—

;

wherein the aforesaid (C₆-C₁₀)aryl, (C₃-C₈)cycloalkyl, (C₁-C₁₀)heteroaryl, (C₁-C₁₀)heterocyclyl, (C₆-C₁₀)aryl-O—

, (C₃-C₈)cycloalkyl-O—

, (C₁-C₁₀)heteroaryl-O— and

(C₁-C₁₀)heterocyclyl-O—

spiro substituents may optionally be substituted on any ring carbon atom by one to three moieties per ring, independently selected from the group consisting of halo, hydroxy, —

CN, (C₁-C₄)alkyl, (C₁-C₄)alkoxy, —

CF₃, CF₃O—

, (C₁-C₄)alkyl-S—

, (C₁-C₄)alkyl-(S═

O)—

, (C₁-C₄)alkyl-(SO₂)—

, (C₁-C₄)alkyl-O—

(C═

O)—

, formyl, and (C₁-C₄)alkyl-(C═

O)—

.

30. A compound according to claim 3, wherein R² is chloro or bromo.

31. A compound according to claim 3, wherein R² is chloro.

32. A compound according to claim 3, wherein R² is (C₁-C₄)alkyl or —

CN.

33. A compound according to claim 3, wherein R² is hydroxy.

34. A compound according to claim 1, wherein R⁷ is other than hydrogen.

35. A compound according to claim 3, wherein R¹ is optionally substituted (C₁-C₁₀)heterocyclyl selected from the group consisting of

36. A compound according to claim 3, wherein R¹ is optionally substituted (C₁-C₁₀)heterocyclyl selected from the group consisting of

37. A compound according to claim 3, wherein R¹ is optionally substituted (C₁-C₁₀)heterocyclyl selected from the group consisting of

38. A compound according to claim 3, wherein R¹ is optionally substituted (C₁-C₁₀)heterocyclyl selected from the group consisting of

39. A compound according to claim 3, wherein R¹ is optionally substituted (C₁-C₁₀)heterocyclyl selected from the group consisting of

40. A compound according to claim 3, wherein R¹ is optionally substituted (C₁-C₁₀)heterocyclyl selected from the group consisting of

41. A compound according to claim 3, wherein R¹ is optionally substituted (C₁-C₁₀)heterocyclyl selected from the group consisting of

42. A compound according to claim 3, wherein R¹ is optionally substituted (C₁-C₁₀)heterocyclyl selected from the group consisting of

43. A compound according to claim 3, wherein R¹ is optionally substituted (C₁-C₁₀)heterocyclyl selected from the group consisting of

44. A compound according to claim 3, wherein R¹ is optionally substituted (C₁-C₁₀)heterocyclyl selected from the group consisting of

45. A compound according to claim 3, wherein R¹ is selected from the group

46. A compound according to claim 3, wherein R¹ is

47. A compound according to claim 1, wherein said compound of formula I has the formula

48. A compound according to claim 1 wherein said compound of formula I has the formula

49. A compound according to claim 1 wherein said compound of formula I has the formula

50. A compound according to claim 1, wherein said compound is selected from the group consisting of:

2-Chloro-N-[2-(2-chloro-phenyl)-ethyl]-5-(3,5-dioxo-4,5-dihydro-3H-[1,2,4]triazin-2-yl)-benzamide;

2-Chloro-5-(3,5-dioxo-4,5-dihydro-3H-[1,2,4]triazin-2-yl)-N-[2-(2-fluoro-phenyl)-ethyl]-benzamide;

2-Chloro-5-(3,5-dioxo-4,5-dihydro-3H-[1,2,4]triazin-2-yl)-N-(2,2-diphenyl-ethyl)-benzamide;

N-[2-(2-Chloro-phenyl)-ethyl]-5-(3,5-dioxo-4,5-dihydro-3H-[1,2,4]triazin-2-yl)-2-methyl-benzamide;

N-[2-(2-Benzyloxy-phenyl)-ethyl]-2-chloro-5-(3,5-dioxo-4,5-dihydro-3H-[1,2,4]triazin-2-yl)-benzamide;

2-Chloro-5-(3,5-dioxo-4,5-dihydro-3H-[1,2,4]triazin-2-yl)-N-(1-phenyl-cyclohexylmethyl)-benzamide;

2-Chloro-5-(3,5-dioxo-4,5-dihydro-3H-[1,2,4]triazin-2-yl)-N-(1-p-tolyl-cyclohexylmethyl)-benzamide;

2-Chloro-N-[2-(2-chloro-phenyl)-ethyl]-5-(4-methy1-3,5-dioxo-4,5-dihydro-3H-[1,2,4]triazin-2-yl)-benzamide;

2-Chloro-5-(3,5-dioxo-4,5-dihydro-3H-[1,2,4]triazin-2-yl)-N-[2-(2-trifluoromethyl-phenyl)-ethyl]-benzamide; and

2-Chloro-N-[2-(2-chloro-phenyl)-ethyl]-5-(3-oxo-2,3-dihydro-benzo[1,4]thiazin-4-yl)-benzamide.

51. A method for treating a P2X₇ mediated disease in a mammal in need thereof, which comprises administering to said mammal an effective amount of a compound according to claim 1.

52. A method for treating a condition selected from the group consisting of arthritis inflammatory bowel disease, Crohn'"'"'s disease, emphysema, acute respiratory distress syndrome, adult respiratory distress syndrome, asthma, chronic obstructive pulmonary disease, chronic pulmonary inflammatory disease, silicosis, pulmonary sarcoidosis, allergic reactions, allergic contact hypersensitivity, eczema, contact dermatitis, psoriasis, sunburn, cancer, tissue ulceration, restenosis, periodontal disease, epidermolysis bullosa, osteoporosis, bone resorption disease, loosening of artificial joint implants, atherosclerosis, aortic aneurysm, congestive heart failure, myocardial infarction, stroke, cerebral ischemia, head trauma, neurotrauma, spinal cord injury, neuro-degenerative disorders, Alzheimer'"'"'s disease, Parkinson'"'"'s disease, migraine, depression, peripheral neuropathy, pain, cerebral amyloid angiopathy, nootropic or cognition enhancement, amyotrophic lateral sclerosis, multiple sclerosis, ocular angiogenesis, corneal injury, macular degeneration, corneal scarring, scleritis, abnormal wound healing, burns, autoimmune disorders, Huntington'"'"'s disease, diabetes, AIDS, cachexia, sepsis, septic shock, endotoxic shock, conjunctivitis shock, gram negative sepsis, toxic shock syndrome, cerebral malaria, cardiac and renal reperfusion injury, thrombosis, glomerularonephritis, graft vs. host reaction, allograft rejection, organ transplant toxicity, ulcerative colitis, and muscle degeneration, in a mammal, including a human, comprising administering to said mammal an amount of a compound according to claim 1, effective in treating such a condition.

53. A pharmaceutical composition for the treatment of a P2X₇ mediated disease in a mammal which comprises an effective amount of a compound according to claim 1 and a pharmaceutically acceptable carrier.

54. A pharmaceutical composition for the treatment of a condition selected from the group consisting of arthritis, inflammatory bowel disease, Crohn'"'"'s disease, emphysema, acute respiratory distress syndrome, adult respiratory distress syndrome, asthma, chronic obstructive pulmonary disease, chronic pulmonary inflammatory disease, silicosis, pulmonary sarcoidosis, allergic reactions, allergic contact hypersensitivity, eczema, contact dermatitis, psoriasis, sunburn, cancer, tissue ulceration, restenosis, periodontal disease, epidermolysis bullosa, osteoporosis, bone resorption disease, loosening of artificial joint implants, atherosclerosis, aortic aneurysm, congestive heart failure, myocardial infarction, stroke, cerebral ischemia, head trauma, neurotrauma, spinal cord injury, neuro-degenerative disorders, Alzheimer'"'"'s disease, Parkinson'"'"'s disease, migraine, depression, peripheral neuropathy, pain, cerebral amyloid angiopathy, nootropic or cognition enhancement, amyotrophic lateral sclerosis, multiple sclerosis, ocular angiogenesis, corneal injury, macular degeneration, corneal scarring, scleritis, abnormal wound healing, burns, autoimmune disorders, Huntington'"'"'s disease, diabetes, AIDS, cachexia, sepsis, septic shock, endotoxic shock, conjunctivitis shock, gram negative sepsis, toxic shock syndrome, cerebral malaria, cardiac and renal reperfusion injury, thrombosis, glomerularonephritis, graft vs. host reaction, allograft rejection, organ transplant toxicity, ulcerative colitis, and muscle degeneration in a mammal, including a human, comprising an amount of a compound according to claim 1, effective in treating such a condition and a pharmaceutically acceptable carrier.

55. A compound of the formula

56. A compound of the formula