Quaternary salt CCR2 antagonists

1. A compound which is a quaternary ammonium salt, the cation having Formula (I)

or pharmaceutically acceptable forms of said compound thereof, wherein

A is carbonyl, thiocarbonyl or sulfonyl;

X is a bond —or —CH═CH—;

R 1 is selected from

(1). aryl optionally substituted by one or more lower alkyl, —(CH 2 ) n —CF 3 , lower alkoxy, alkoxycarbonyl, cyano, halogen or phenyl optionally substituted by lower alkyl, —(CH 2 ) n —CF3, lower alkoxy, alkoxycarbonyl, cyano or halogen; or

(2). C 5 -C 15 cycloalkyl optionally substituted by one or more lower alkyl, —(CH 2 ) n —CF 3 , lower alkoxy, aryl, halogen-substituted aryl, alkoxycarbonyl, cyano or halogen;

n is 0, 1, 2, 3, or 4;

Y is a bond or —CH 2 —;

X 2 is —(CH 2 ) m — wherein m is 1 or 2;

R 2 is —N + (R4R 5 )—ZR 3 ;

Z is —(CH 2 ) p — wherein p is 0, 1 or 2;

R 3 is selected from

(1). aryl optionally substituted by one or more lower alkyl, —(CH 2 ) n —CF 3 , lower alkoxy, aryl, halogen-substituted aryl, alkoxycarbonyl, cyano or halogen;

(2). C 5 -C 15 cycloalkyl optionally substituted with one or more lower alkyl, —(CH 2 ) n —CF 3 , lower alkoxy, aryl, halogen-substituted aryl, alkoxycarbonyl, cyano or halogen; or

(3). heterocyclyl optionally substituted with one or more lower alkyl, —(CH 2 ) n —CF 3 , lower alkoxy, aryl, halogen-substituted aryl, alkoxycarbonyl, cyano or halogen; wherein, when heterocyclyl is attached via a carbon atom ring member and a heteroatom ring member is adjacent to said carbon atom, then p is 1 or 2;

R 4 and R 5 are each individually lower alkyl or lower alkenyl; or

alternatively, R 4 and R 5 combine with the nitrogen atom of Formula (I) to form a heterocyclyl ring of 5 to 9 total ring atoms optionally containing one of an oxygen or sulfur ring atom, wherein the heterocyclyl ring nitrogen atom is substituted with one of lower alkyl or lower alkenyl to form a quaternary salt, and wherein —ZR 3 is absent and the heterocyclyl ring is optionally substituted with aryl optionally substituted with one or more lower alkyl, —(CH 2 ) n —CF 3 , lower alkoxy, aryl, halogen-substituted aryl, alkoxycarbonyl, cyano or halogen, said heterocyclyl for ring R 3 being tetrahydropyran, tetrahydrofuran, tetrahydrothiophene, tetrahydrothiopyran, pyrrolidine, morpholine, thiomorpholine, piperidine, thiophene or piperazine.

2. The compound of claim 1 , wherein A is carbonyl; X is a bond; R 1 is selected from aryl substituted by one or more lower alkyl or halogen, and C 5 -C 15 cycloalkyl optionally substituted by one or more halogen, Y is a bond; X 2 is —CH 2 —; R 2 is —N + (R 4 R 5 )—R 3 ; R 3 is selected from C 5 -C 15 cycloalkyl or heterocyclyl and R 4 and R 5 are each individually lower alkyl.

3. The compound of claim 1 , wherein A is carbonyl, X is a bond, R 1 is aryl optionally substituted by one or more halogen, Y is a bond, X 2 is —CH 2 —, R 2 is —N + (R 4 R 5 )—R 3 , R 3 is heterocyclyl and R 4 and R 5 are each individually lower alkyl.

4. The compound of claim 1 , wherein A is carbonyl.

5. The compound of claim 1 , wherein R 1 is selected from

(1). aryl optionally substituted by one or more lower alkyl, —(CH 2 ) n —CF 3 , lower alkoxy, cyano, halogen or phenyl optionally substituted by lower alkyl, —(CH 2 ) n ——CF 3 , lower alkoxy, cyano or halogen; and

(2). C 5 -C 15 cycloalkyl optionally substituted by one or more lower alkyl, —(CH 2 ) n —CF 3 , lower alkoxy, cyano or halogen.

6. The compound of claim 1 , wherein n is 0.

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

8. The compound of claim 1 , wherein R 3 is C 5 -C 15 cycloalkyl or heterocyclyl;

wherein, when heterocyclyl is attached via a carbon atom ring member and a heteroatom ring member is adjacent to said carbon atom, then p is 1.

9. The compound of claim 1 , wherein R 4 and R 5 are each individually lower alkyl or lower allyl.

10. The compound of claim 1 , wherein R 4 and R 5 combine with the nitrogen atom of Formula (I) to form a heterocyclyl ring of 5 to 9 total ring atoms optionally containing one of an oxygen or sulfur ring atom, wherein the heterocyclyl ring nitrogen atom is substituted with lower alkyl to form a quaternary salt, and wherein —ZR 3 is absent and the heterocyclyl ring is optionally substituted with one or more lower alkyl, —(CH 2 ) n —CF 3 , lower alkoxy, cyano or halogen.

11. The compound of claim 1 , wherein R 4 and R 5 combine with the nitrogen atom of Formula (I) to form a heterocyclyl ring of 5 to 9 total ring atoms optionally containing one of an oxygen or sulfur ring atom, wherein the heterocyclyl ring nitrogen atom is substituted with lower alkyl to form a quaternary salt, and wherein —ZR 3 is absent and the heterocyclyl ring is optionally substituted with aryl optionally substituted with lower alkoxy.

12. A compound which is a quaternary ammonium salt, or pharmaceutically acceptable forms thereof, the cation of said compound selected from

13. A composition comprising an effective amount of the compound of claim 1 and a pharmaceutically acceptable carrier.

14. The composition of claim 13 selected from a topically applied composition, an intranasally applied composition or an ocularly applied composition.

15. A process for preparing the composition of claim 13 comprising the step of admixing said compound with a pharmaceutically acceptable carrier.

16. A method for treating CCR2 mediated inflammation in a subject in need thereof comprising administering to the subject an effective amount of the compound of claim 1 or pharmaceutically acceptable form of said compound.

17. The method of claim 16 wherein the effective amount is from about 0.001 mg/kg/day to about 300 mg/kg/day.

18. The method of claim 16 , wherein the CCR2 mediated inflammation is associated with elevated MCP-1 expression or MCP-1 over expression, or is an inflammatory condition that accompanies syndromes, disorders or diseases associated with elevated MCP-1 expression or MCP-1 overexpression.

19. The method of claim 16 , wherein the CCR2 mediated inflammation is associated with ophthalmic disorders, atherosclerosis, rheumatoid arthritis, psoriasis, psoriatic arthritis, atopic dermatitis, multiple sclerosis, Crohn's Disease, ulcerative colitis, nephritis, organ allograft rejection, fibroid lung, renal insufficiency, diabetes and diabetic complications, diabetic nephropathy, diabetic retinopathy, diabetic retinitis, diabetic microangiopathy, tuberculosis, chronic obstructive pulmonary disease, sarcoidosis, invasive staphyloccocia, inflammation after cataract surgery, allergic rhinitis, allergic conjunctivitis, chronic utricaria, asthma, periodontal diseases, diastolic cardiomyopathies, cardiac infarction, myocarditis, chronic heart failure, angiostenosis, restenosis, reperfusion disorders, glomerulonephritis, solid tumors and cancers, chronic lymphocytic leukemia, chronic myelocytic leukemia, multiple myeloma, malignant myeloma or Hodgkin's disease.

20. The method of claim 16 , wherein the method comprises treating CCR2 mediated inflammation associated with ophthalmic disorders, rheumatoid arthritis, psoriasis, psoriatic arthritis, atopic dermatitis, chronic obstructive pulmonary disease, allergic rhinitis, asthma, or periodontal diseases in a subject in need thereof by administering to the subject an effective amount of said compound or pharmaceutically acceptable form of said compound.

21. The method of claim 20 , wherein the ophthalmic disorder is selected from uveitis or allergic conjunctivitis and the periodontal disease is selected from periodontitis and gingivitis.

22. The method of claim 21 , wherein uveitis is acute, recurring or chronic uveitis.

23. The method of claim 21 , wherein uveitis is anterior uveitis, intermediate uveitis, posterior uveitis or panuveitis.

24. The method of claim 16 , wherein the method comprises treating CCR2 mediated inflammation associated with acute uveitis, recurring uveitis, chronic uveitis, allergic conjunctivitis, rheumatoid arthritis, psoriasis, psoriatic arthritis, atopic dermatitis, chronic obstructive pulmonary disease, allergic rhinitis, asthma, periodontitis or gingivitis in a subject in need thereof by administering to the subject an effective amount of said compound or pharmaceutically acceptable form of said compound.

25. The method of claim 16 , wherein the method comprises treating a CCR2 mediated inflammation in a subject in need thereof by administering to the subject an effective amount of said compound or pharmaceutically acceptable form of said compound in a combination therapy with one or more anti-inflammatory agents, anti-infective agents or immunosuppressive agents.

26. The compound according to claim 1 wherein the cation of Formula (I) is:

27. The method of claim 16 wherein the CCR2 mediated inflammation is associated with rhinitis, uveitis, asthma, periodontitis, or gingivitis.

28. The method according to claim 16 wherein the cation of Formula (I) is

29. The method according to claim 16 wherein the CCR2 mediated inflammation is associated with periodontitis or gingivitis.

30. The method of claim 19 wherein the ophthalmic disorder is uveitis, the asthma is allergic asthma, the periodontal disease is periodontitis or gingivitis and the solid tumor and cancers are carcinomas of the bladder, breast, cervix, colon, lung, prostate or stomach.

31. The method of claim 20 wherein the asthma is allergic asthma.

32. The method of claim 24 wherein the asthma is allergic asthma.

33. The method of claim 16 wherein the CCR2 mediated inflammation is associated with ophthalmic disorder, asthma, periodontal disease, or allergic rhinitis.

34. The method according to claim 33 wherein the periodontal disease is gingivitis or periodontitis and the ophthalmic disorder is uveitis.

35. The method according to claim 27 wherein rhinitis is allergic rhinitis.