Antagonists of MCP-1 function and methods of use thereof

• US 6,677,365 B2
• Filed: 03/25/2002
• Issued: 01/13/2004
• Est. Priority Date: 04/03/2001
• Status: Expired due to Fees

• Current Assignee: Telik, Inc. (MabVax Therapeutics Holdings, Inc.), Sanwa Kagaku Kenkyusho Company Limited (Suzuken Company Limited)
• Original Assignee: Telik, Inc. (MabVax Therapeutics Holdings, Inc.), Sanwa Kagaku Kenkyusho Company Limited (Suzuken Company Limited)
• Inventors: Laborde, Edgardo, Robinson, Louise, Anuskiewicz, Steven E., Villar, Hugo O., Peterson, Brian T., Meng, Fanying, Jomori, Takahito, Matsushima, Kouji, Matsumoto, Yukiharu, Inagaki, Hideaki, Kakigami, Takuji, Yokochi, Shoji, Ishiwata, Yoshiro
• Primary Examiner(s): Dentz, Bernard
• Application Number:
  US10/106,881
• Publication Number:
  US 20030092728A1
• Time in Patent Office: 659 Days
• Field of Search: 548/180, 548/217, 548/304.4, 548/361.1, 546/114, 546/115, 546/118, 546/120, 514/405, 514/394, 514/367, 514/379, 514/301, 514/302, 514/303
• US Class Current: 514/379
• CPC Class Codes: A61P 1/00 Drugs for disorders of the alimentary tract or the digestive system
• CPC Class Codes: A61P 1/18 for pancreatic disorders, e.g. pancreatic enzymes
• 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 19/02 for joint disorders, e.g. arthritis, arthrosis
• 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 37/02 Immunomodulators
• 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 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 209/08 with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to carbon atoms of the hetero ring
• CPC Class Codes: C07D 235/06 with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
• CPC Class Codes: C07D 249/18 Benzotriazoles
• CPC Class Codes: C07D 263/56 with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
• CPC Class Codes: C07D 307/79 with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
• CPC Class Codes: C07D 317/68 Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
• 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
• CPC Class Codes: C07D 417/12 : linked by a chain containing hetero atoms as chain links

Abstract

Chemical compounds which are antagonists of Monocyte Chemoattractant Protein-1 (MCP-1) function, pharmaceutical compositions comprising these compounds, methods of treatment employing these compounds and compositions, and processes for preparing these compounds. The compounds are useful in the prevention or treatment of chronic or acute inflammatory or autoimmune diseases, especially those associated with aberrant lymphocyte or monocyte accumulation such as arthritis, asthma, atherosclerosis, diabetic nephropathy, inflammatory bowel disease, Crohn'"'"'s disease, multiple sclerosis, nephritis, pancreatitis, pulmonary fibrosis, psoriasis, restenosis, and transplant rejection.

Claims

1. A compound of Formula IIa or Formula IIIa:

where;

in Formula IIa;

W is N, X is selected from C—

R⁶ and N, and Y is selected from CR⁶R⁷, N—

R⁷, O, or S, provided that one and only one of X and Y comprises a non-carbon ring atom,

in Formula IIIa;

W is selected from CR⁶R⁷, N—

R⁷, O, or S, X is selected from C—

R₆ and N, and Y is N, provided that one and only of W and X comprises a non-carbon ring atom,

Z is N or C—

R⁸;

each R¹, R², R⁶, and R⁸ is independently, hydrogen, optionally substituted lower alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkyl(lower alkyl), optionally substitute heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aryl(lower alkyl), halo(lower alkyl), —

CF₃, halogen, nitro, —

CN, —

OR⁹, —

SR⁹—

, —

NR⁹R¹⁰, —

NR⁹(carboxy(lower alkyl)), —

C(═

O)R⁹, —

C(═

O)OR⁹, —

C(═

O)NR⁹R¹⁰, —

OC(═

O)R⁹, —

SO₂R⁹, —

OSO₂R⁹, —

SO₂NR⁹R¹⁰, —

NR⁹SO₂R¹⁰ or —

NR⁹C(═

O)R¹⁰, wherein R⁹ and R¹⁰ are independently, hydrogen, optionally substituted lower alkyl, lower alkyl-N(C_1-2 alkyl)₂, lower alkyl(optionally substituted heterocycloalkyl), alkenyl, alkynyl, optionally substituted cycloalkyl, cycloalkyl(lower alkyl), optionally substituted heterocycloalkyl(lower alkyl), aryl(lower alkyl), optionally substituted aryl, optionally substituted heteroaryl, heteroaryl(lower alkyl), or R⁹ and R¹⁰ together are —

(CH₂)_4-6-optionally interrupted by one O, S, NH, N-(aryl), N-(aryl(lower alkyl)), N-(carboxy(lower alkyl)) or N-(optionally substituted C_1-2 alkyl) group,

R³ and R⁴ are, independently, hydrogen, lower alkyl optionally substituted lower alkyl, optionally substituted aryl, or optionally substituted aryl(lower alkyl), or, together, are —

(CH₂)_2-4—

;

each R⁷ is hydrogen, optionally substituted lower alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkyl(lower alkyl), optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aryl(lower alkyl), —

C(═

O)R⁹, —

C(═

O)OR⁹, —

C(═

O)NR⁹R¹⁰, —

SO₂R⁹, or —

SO₂NR⁹R¹⁰, where R⁹ and R¹⁰ are independently, hydrogen, optionally substituted lower alkyl, lower alkyl-N(C_1-2 alkyl)₂, lower alkyl(optionally substituted heterocycloalkyl), alkenyl, alkynyl, optionally substituted cycloalkyl, cycloalkyl(lower alkyl), optionally substituted heterocycloalkyl(lower alkyl), aryl(lower alkyl), optionally substituted aryl, optionally substituted heteroaryl, heteroaryl(lower alkyl), or R⁹ and R¹⁰ together are optionally interrupted by one O, S, NH, N-(aryl), N-(aryl(lower alkyl)), N-(carboxy(lower alkyl)) or N-(optionally substituted C_1-2 alkyl) group,

R¹³ is hydrogen, optionally substituted lower alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkyl(lower alkyl), heterocycloalkyl, optionally substituted aryl, optionally substituted aryl(lower alkyl), optionally substituted heteroaryl, optionally substituted heteroaryl(lower alkyl), halo(lower alkyl), —

CF₃, halogen, nitro, —

CN, —

OR¹⁵, —

SR¹⁵, —

NR¹⁵R¹⁶, —

C(═

O)R¹⁵, —

C(═

O)OR¹⁵, —

C(═

O)NR¹⁵R¹⁶, —

OC(═

O)R¹⁵, —

SO₂R¹⁵, —

SO₂NR¹⁵R¹⁶, —

NR¹⁵SO₂R¹⁶ or —

NR¹⁵C(═

O)R¹⁶, wherein R¹⁵ and R¹⁶ are independently, hydrogen, optionally substituted lower alkyl, alkenyl, alkynyl, —

CF₃, halo(lower alkyl, cycloalkyl, optionally substituted heterocycloalkyl, cycloalkyl(lower alkyl), optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heteroaryl(lower alkyl) or, together, are —

(CH₂)_4-6-optionally interrupted by one O, S, NH or N—

(C_1-2 alkyl) group,

each R¹⁴ is independently selected from optionally substituted lower alkyl, optionally substituted aryl, optionally substituted heteroaryl, hydroxy, halogen, —

CF₃, —

OR¹⁷, —

NR¹⁷R¹⁸, —

C(═

O)R¹⁷, —

C(═

O)OR¹⁷, —

O(CH₂)_mC(═

O)OR¹⁷, wherein m is an integer of 1 to 4, or —

C(═

O)NR¹⁷R¹⁸, where R¹⁷ and R¹⁸ are independently, hydrogen, lower alkyl, alkenyl, alkynyl, —

CF₃, optionally substituted heterocycloalkyl, cycloalkyl, cycloalkyl(lower alkyl), optionally substituted aryl, heteroaryl, heteroaryl(lower alkyl) or, together, are —

(CH₂)_4-6—

, optionally interrupted by one O, S, NH or N—

(C_1-2 alkyl) group, and

where n is an integer of 0 to 4,

or a pharmaceutically acceptable salt thereof, as a single stereoisomer or mixture of stereoisomers.

2. The compound of claim 1 that is a compound of Formula IIa or a pharmaceutically acceptable salt thereof, as a single stereoisomer or mixture of stereoisomers.

3. The compound of claim 1 that is a compound of Formula IIIa or a pharmaceutically acceptable salt thereof, as a single stereoisomer or mixture of stereoisomers.

4. The compound of claim 1, where X is CR⁶, where R⁶ is hydrogen, lower alkyl, or optionally substituted aryl.

5. The compound of claim 2, where W is N, X is CR⁶, where R⁶ is hydrogen, lower alkyl, or optionally substituted aryl, and Y is O.

6. The compound of claim 5, where Z is C—

H.

7. The compound of claim 3, where W is O, X is CR⁶, where R⁶ hydrogen, lower alkyl, or optionally substituted aryl, and Y is N.

8. The compound of claim 7, where Z is C—

H.

9. The compound of claim 1, where W is N, X is CR⁶, where R⁶ is hydrogen, lower alkyl, or optionally substituted aryl, Y is N—

R⁷, where R⁷ is hydrogen, lower alkyl, substituted lower alkyl, or optionally substituted aryl(lower alkyl), and Z is C—

H.

10. The compound of claim 3, where W is N—

R⁷, where R⁷ is hydrogen, lower alkyl, substituted lower alkyl, or optionally substituted aryl(lower alkyl), X is CR⁶, where R⁶ is hydrogen, lower alkyl, or optionally substituted aryl, Y is N, and Z is C—

H.

11. The compound of claim 1, where R¹ and R² are independently selected from hydrogen, lower alkyl, halogen, optionally lower alkyl substituted heterocycloalkyl, —

OR⁹, —

SR⁹, or —

NR⁹R¹⁰, where R⁹ and R¹⁰ are hydrogen, lower alkyl or optionally substituted aryl.

12. The compound of claim 1, where R¹³ is alkynyl, optionally substituted aryl, optionally substituted heteroaryl, halogen, —

CF₃, —

CN, —

OR¹⁵, —

C(═

O)R¹⁵, —

C(═

O)N)OR¹⁵, or —

C(═

O)NR¹⁵R¹⁶, where R¹⁵ and R¹⁶ are independently, hydrogen, lower alkyl, halo(lower alkyl), optionally substituted aryl, optionally substituted heteroaryl, heteroaryl(lower alkyl), or R¹⁵ and R¹⁶ together are —

(CH₂)_4-6—

, optionally interrupted by one O, S, NH or N—

(C_1-2 alkyl) group.

13. The compound of claim 1, where each R¹⁴ is independently selected from halogen, —

CF₃, —

OR¹⁷, —

C(═

O)OR¹⁷, —

O(CH₂)_mC(═

O)OR¹⁷, where m is an integer of 1 to 4, or —

C(═

O)NR¹⁷R¹⁸, where R¹⁷ and R¹⁸ are independently, hydrogen, lower alkyl, optionally substituted heteroaryl, or heteroaryl(lower alkyl), or R¹⁷ and R¹⁸ together are —

(CH₂)_4-6—

, optionally interrupted by one O, S, NH or N—

(C_1-2 alkyl) group.

14. The compound of claim 1, where R¹ is hydrogen, optionally substituted lower alkyl, cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aryl(lower alkyl), halogen, —

OR⁹, —

NR⁹[carboxy(lower alkyl)], —

C(═

O)OR⁹, —

C(═

O)NR⁹R¹⁰, —

SO₂NR⁹R¹⁰, or —

NR⁹C(═

O)R¹⁰, where R⁹ and R¹⁰ are independently, hydrogen, optionally substituted lower alkyl, lower alkyl-N(C_1-2 alkyl)₂, lower alkyl(optionally substituted heterocycloalkyl), optionally substituted cycloalkyl, cycloalkyl(lower alkyl), optionally substituted aryl, optionally substituted heteroaryl, heteroaryl(lower alkyl), or R⁹ and R¹⁰ together are —

(CH₂)_4-6-optionally interrupted by one O, S, NH, N-(aryl), N-(aryl(lower alkyl)), N-(carboxy(lower alkyl)) or N-(optionally substituted C_1-2 alkyl) group.

15. The compound of claim 1, where R₂ is hydrogen, optionally substituted lower alkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aryl(lower alkyl), halo(lower alkyl), halogen, —

OR⁹, —

NR⁹R¹⁰, —

C(═

O)OR⁹, or —

C(═

O)NR⁹R¹⁰, where R⁹ and R¹⁰ are independently, hydrogen, optionally substituted lower alkyl, lower alkyl-N(C_1-2 alkyl)₂, lower alkyl(optionally substituted heterocycloalkyl), optionally substituted cycloalkyl, cycloalkyl(lower alkyl), optionally substituted aryl, optionally substituted heteroaryl, heteroaryl(lower alkyl), or R⁹ and R¹⁰ together are —

(CH₂)_4-6-optionally interrupted by one O, S, NH, N-(aryl), N-[aryl(lower alkyl)], N-(carboxy(lower alkyl)) or N-(optionally substituted C_1-2 alkyl) group.

16. The compound of claim 1, where R³ and R⁴ are independently, hydrogen or lower alkyl.

17. The compound of claim 1, where R⁶ and R⁷ are independently hydrogen, optionally substituted lower alkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aryl(lower alkyl), —

C(═

O)R⁹, —

C(═

O)OR⁹, —

C(═

O)NR⁹R¹⁰, —

SO₂R⁹, or —

SO₂NR⁹R¹⁰, where R⁹ and R¹⁰ are independently, hydrogen, optionally substituted lower alkyl, lower alkyl-N(C_1-2 alkyl)₂, alkenyl, alkynyl, optionally substituted cycloalkyl, cycloalkyl(lower alkyl), optionally substituted aryl, heteroaryl, or heteroaryl(lower alkyl).

18. The compound of claim 1, where R⁸ is hydrogen, optionally substituted lower alkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aryl(lower alkyl), halo(lower alkyl), —

CF₃, halogen, —

OR⁹, NR⁹R¹⁰, —

C(═

O)R⁹, —

C(═

O)OR⁹, —

C(═

O)NR⁹R¹⁰ —

OC(═

O)R⁹, —

SO₂R<sup>9, —

SO</sup>₂NR⁹R¹⁰, —

NR⁹SO₂R¹⁰ or —

NR⁹C(═

O)R¹⁰, wherein R⁹ and R¹⁰ are independently, hydrogen, optionally substituted lower alkyl, lower alkyl-N(C_1-2 alkyl)₂, optionally substituted cycloalkyl, cycloalkyl(lower alkyl), optionally substituted aryl, heteroaryl, heteroaryl(lower alkyl), or R⁹ and R¹⁰ together are —

(CH₂)_4-6-optionally interrupted by one O, S, NH, N-(aryl), N-(aryl(lower alkyl)), N-(carboxy(lower alkyl)), or N-(optionally substituted C_1-2 alkyl) group.

19. The compound of claim 1, where R¹, R², and R⁸ are optionally substituted lower alkyl, cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aryl(lower alkyl), halogen, —

OR⁹, —

NR⁹[carboxy(lower alkyl)], —

C(═

O)OR⁹, —

C(═

O)NR⁹R¹⁰, —

SO₂NR⁹R¹⁰, or —

NR⁹C(═

O)R¹⁰, where R⁹ and R¹⁰ independently, hydrogen, lower alkyl, or R⁹ and R¹⁰ together are —

(CH₂)_4-6-optionally interrupted by one O, S, NH, N-(aryl), N-(aryl(lower alkyl)), N-(carboxy(lower alkyl)) or N-(optionally substituted C_1-2 alkyl) group.

20. The compound of claim 1, where R¹³ is hydrogen, optionally substituted lower alkyl, alkenyl, alkynyl, heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heteroaryl(lower alkyl), halo(lower alkyl), —

CF₃, halogen, nitro, —

CN, —

OR¹⁵, —

SR¹⁵, —

NR¹⁵R¹⁶, —

C(═

O)R¹⁵, —

C(═

O)OR¹⁵, —

C(═

O)NR¹⁵R¹⁶, or —

NR¹⁵C(═

O)R¹⁶, where R¹⁵ and R¹⁶ are independently, hydrogen, optionally substituted lower alkyl, alkenyl, cycloalkyl, or halo(lower alkyl).

21. The compound of claim 1, where each R¹⁴ is independently selected from optionally substituted lower alkyl, optionally substituted aryl, optionally substituted heteroaryl, hydroxy, halogen, —

CF₃, —

OR¹⁷ —

NR¹⁷R¹⁸, —

C(═

O)R¹⁷,—

C(═

O)OR¹⁷, —

O(CH₂)_mC(═

O)OR¹⁷, where m is an integer of 1 to 4, and —

C(═

O)NR¹⁷R¹⁸, where R¹⁷ and R¹⁸ are, independently, hydrogen, low alkyl, alkenyl, or optionally substituted aryl.

22. The compound of claim 1 that is selected from;

benzoxazol-5-yl-N-{[(3,4-dichlorophenyl)amino]carbonyl}carboxamide;

benzoxazol-5-yl-N-{[(4-chlorophenyl)amino]carbonyl}carboxamide;

benzoxazol-5-yl-N-{[(3-chlorophenyl)amino]carbonyl}carboxamide;

benzoxazol-5-yl-N-{[(3-bromophenyl)amino]carbonyl}carboxamide;

benzoxazol-5-yl-N-({[4-(trifluoromethyl)phenyl]amino}carbonyl)carboxamide;

benzoxazol-5-yl-N-{[(3-iodophenyl)amino]carbonyl}carboxamide;

benzoxazol-5-yl-N-({[3-(trifluoromethyl)phenyl]amino}carbonyl)carboxamide;

benzoxazol-5-yl-N-{[(4-fluorophenyl)aamino]carbonyl}carboxamide;

benzoxazol-6-yl-N-{[(3,4-dichlorophenyl)amino]carbonyl}carboxamide;

benzoxazol-6-yl-N-{[(4-chlorophenyl) amino]carboxy}carboxamide;

benzoxazol-6-yl-N-({[4-(trifluoromethyl)phenyl]amino}carbonyl)carboxamide;

benzoxazol-6-yl-N-{[(3-chlorophenyl)amino]carboxyl}carboxamide;

benzoxazol-6-yl-N-({[3-(trifluoromethoxy)phenyl]amino}carbonyl)carboxamide;

benzoxazol-6-yl-N-{[(3-cyanophenyl)amino]carbonyl}carboxamide;

benzoxazol-6-yl-N-{[(3-bromophenyl)amino]carbonyl}carboxamide;

methyl 3-{[(benzoxazol-6-ylcarbonylamino)carbonyl]amino}benzoate;

4-{[(benzozazol-6-ylccarbonylamino)carbonyl]amino}-2-clorobenzoic acid;

phenylmethyl 2-(4-{[(benzoxazol-6-ylcarbonylamino)carbonyl]amino}-2-chlorophenoxy)acetate;

4-{[(benzoxazol-6-ylcarbonyl]amino}benzoic acid;

5-{[(benzoxazol-6-ylcarbonylamino)carbonyl]amino}-2-chlorobenzoic acid;

N-{[(3,4-dichlorophenyl)amino]carbonyl}(1-methylbenzimidazol-5-yl)carboxamide;

and the pharmaceutically acceptable salts thereof, as single stereoisomers or mixtures of stereoisomers.

23. A pharmaceutical composition comprising:

(a) a therapeutically effective amount of a compound of claim 1; and

(b) a pharmaceutically acceptable excipient.

24. The pharmaceutical composition of claim 23, further comprising an anti-inflammatory drug, cytokine, or immunomodulator.

25. A method of treating an allergic, inflammatory, or autoimmune disorder or disease, comprising administering a therapeutically effective amount of a compound of claim 1 to a mammal in need of such treatment.

26. The method of claim 25 wherein the compound is administered in combination with an anti-inflammatory drug, cytokine, or immunomodulator.

27. The method of claim 25 wherein the allergic, inflammatory, or autoimmune disorder or disease is selected from the group consisting of asthma, atherosclerosis, glomerulonephritis, pancreatitis, restenosis, rheumatoid arthritis, diabetic nephropathy, pulmonary fibrosis, inflammatory bowel disease, Crohn'"'"'s disease, and transplant rejection.

28. The method of claim 25 where the allergic, inflammatory, or autoimmune disorder or disease is asthma.

29. The method of claim 25 where the allergic, inflammatory, or autoimmune disorder or disease is atherosclerosis.

30. The method of claim 25 where the allergic, inflammatory, or autoimmune disorder or disease is glomerulonephritis.

31. The method of claim 25 where the allergic, inflammatory, or autoimmune disorder or disease is pancreatitis.

32. The method of claim 25 where the allergic, inflammatory, or autoimmune disorder or disease is restenosis.

33. The method of claim 25 where the allergic, inflammatory, or autoimmune disorder or disease is rheumatoid arthritis.

34. The method of claim 25 where the allergic, inflammatory, or autoimmune disorder or disease is diabetic nephropathy.

35. The method of claim 25 where the allergic, inflammatory, or autoimmune disorder or disease is pulmonary fibrosis.

36. The method of claim 25 where the allergic, inflammatory, or autoimmune disorder or disease is inflammatory bowel disease.

37. The method of claim 25 where the allergic, inflammatory, or autoimmune disorder or disease is Crohn'"'"'s disease.

38. The method of claim 25 where the allergic, inflammatory, or autoimmune disorder or disease is transplant rejection.

39. The method of claim 25 wherein the allergic, inflammatory, or auto immune disorder or disease is associated with lymphocyte and/or monocyte accumulation.

40. A method of inhibiting leukocyte migration, comprising administering a therapeutically effective amount of a compound of claim 1 to a mammal in need of such treatment.