Quaternary salt CCR2 antagonists

• US 7,799,824 B2
• Filed: 06/22/2005
• Issued: 09/21/2010
• Est. Priority Date: 06/25/2004
• Status: Active Grant

• Current Assignee: Johnson & Johnson Consumer Inc. (Johnson & Johnson)
• Original Assignee: OraPharma, Inc. (Bausch Health Cos., Inc.)
• Inventors: Wachter, Michael, Lagu, Bharat
• Primary Examiner(s): Andres; Janet L.
• Assistant Examiner(s): COVINGTON, RAYMOND K
• Application Number:
  US11/159,018
• Publication Number:
  US 20060293379A1
• Time in Patent Office: 1,917 Days
• Field of Search: 549/9, 549/12, 549/60, 549/355, 549/424, 546/173, 546/196, 546/202, 546/205, 546/333, 546/337, 564/15, 564/16, 564/180, 548/338.1, 548/517, 540/593, 544/145, 544/149, 544/379, 544/393, 514/431, 514/510, 514/116, 514/119, 514/255, 514/320, 514/331, 514/357, 514/396, 514/422, 514/438, 514/450, 514/459, 514/617
• US Class Current: 514/431
• 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 11/02 Nasal agents, e.g. decongestants
• CPC Class Codes: A61P 11/06 Antiasthmatics
• CPC Class Codes: A61P 11/08 Bronchodilators
• CPC Class Codes: A61P 13/12 of the kidneys
• CPC Class Codes: A61P 17/04 Antipruritics
• CPC Class Codes: A61P 17/06 Antipsoriatics
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 25/28 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 27/12 for cataracts
• 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 31/04 Antibacterial agents
• CPC Class Codes: A61P 31/06 for tuberculosis
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 35/02 specific for leukemia
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 9/04 Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
• 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: C07C 233/80 : with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by a carbon atom of a six-membered aromatic ring
• CPC Class Codes: C07C 2601/08 : the ring being saturated
• CPC Class Codes: C07C 2601/14 : The ring being saturated
• CPC Class Codes: C07C 2602/42 : the bicyclo ring system containing seven 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 235/24 : 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 in position 2
• CPC Class Codes: C07D 295/135 : with the ring nitrogen atoms and the substituent nitrogen atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
• CPC Class Codes: C07D 307/14 : Radicals substituted by nitrogen atoms not forming part of a nitro radical
• CPC Class Codes: C07D 307/22 : Nitrogen atoms not forming part of a nitro radical
• CPC Class Codes: C07D 307/52 : Radicals substituted by nitrogen atoms not forming part of a nitro radical
• CPC Class Codes: C07D 307/56 : 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 307/84 : Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
• CPC Class Codes: C07D 309/04 : with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
• CPC Class Codes: C07D 309/14 : Nitrogen atoms not forming part of a nitro radical
• CPC Class Codes: C07D 311/58 : other than with oxygen or sulphur atoms in position 2 or 4
• CPC Class Codes: C07D 311/92 : Naphthopyrans; Hydrogenated naphthopyrans
• CPC Class Codes: C07D 313/08 : condensed with one six-membered ring
• CPC Class Codes: C07D 333/36 : Nitrogen atoms
• CPC Class Codes: C07D 333/70 : attached in position 2
• CPC Class Codes: C07D 335/02 : not condensed with other rings
• CPC Class Codes: C07D 405/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 407/12 : 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

Quaternary salt compounds of Formula (I)

or pharmaceutically acceptable forms thereof, which are CCR2 antagonists and are useful in preventing, treating or ameliorating CCR2 mediated inflammatory syndromes, disorders or diseases in a subject in need thereof.

Claims

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

2. The compound of claim 1, wherein A is carbonyl;

X is a bond;

R₁ is selected from aryl substituted by one or more lower alkyl or halogen, and C₅-C₁₅ cycloalkyl optionally substituted by one or more halogen, Y is a bond;

X₂ is —

CH₂—

;

R₂ is —

N⁺(R₄R₅)—

R₃;

R₃ is selected from C₅-C₁₅ cycloalkyl or heterocyclyl and R₄ and R₅ are each individually lower alkyl.

3. The compound of claim 1, wherein A is carbonyl, X is a bond, R₁ is aryl optionally substituted by one or more halogen, Y is a bond, X₂ is —

CH₂—

, R₂ is —

N⁺(R₄R₅)—

R₃, R₃ is heterocyclyl and R₄ and R₅ are each individually lower alkyl.

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

5. The compound of claim 1, wherein R₁ is selected from

(1). aryl optionally substituted by one or more lower alkyl, —

(CH₂)_n—

CF₃, lower alkoxy, cyano, halogen or phenyl optionally substituted by lower alkyl, —

(CH₂)_n—

—

CF₃, lower alkoxy, cyano or halogen; and

(2). C₅-C₁₅ cycloalkyl optionally substituted by one or more lower alkyl, —

(CH₂)_n—

CF₃, 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 R₃ is C₅-C₁₅ 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 R₄ and R₅ are each individually lower alkyl or lower allyl.

10. The compound of claim 1, wherein R₄ and R₅ 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 —

ZR₃ is absent and the heterocyclyl ring is optionally substituted with one or more lower alkyl, —

(CH₂)_n—

CF₃, lower alkoxy, cyano or halogen.

11. The compound of claim 1, wherein R₄ and R₅ 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 —

ZR₃ is absent and the heterocyclyl ring is optionally substituted with aryl optionally substituted with lower alkoxy.

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.

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