METALLOPROTEIN INHIBITORS

• US 20070117848A1
• Filed: 10/30/2006
• Published: 05/24/2007
• Est. Priority Date: 04/29/2004
• Status: Active Grant

• Current Assignee: University of California San Diego (University of California)
• Original Assignee: University of California San Diego (University of California)
• Inventors: Puerta, David, Lewis, Jana, Cohen, Seth
• Granted Patent: US 7,579,486 B2
• Time in Patent Office: Days
• US Class Current: 514/337
• CPC Class Codes: A61K 31/167 having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
• CPC Class Codes: A61K 31/35 having six-membered rings with one oxygen as the only ring hetero atom
• CPC Class Codes: A61K 31/435 having six-membered rings with one nitrogen as the only ring hetero atom
• 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 31/04 Antibacterial agents
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• 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 213/69 Two or more oxygen atoms
• CPC Class Codes: C07D 309/36 with oxygen atoms directly attached to ring carbon atoms
• CPC Class Codes: C07D 309/40 Oxygen atoms attached in positions 3 and 4, e.g. maltol

Abstract

The present invention relates to metalloprotein inhibitors comprising: a. an organic substituent and at least one zinc binding group (ZBG) covalently attached thereto; or
b. a ZBG substituted by a side chain wherein the ZBG is of formula (I):
wherein X is O or S and each R¹, R², R³, and R⁴ is individually hydrogen or an organic radical. The metalloprotein inhibitors are useful for preventing or treating a pathological disease, condition, or symptom that is associated with pathological metalloprotein activity and/or that is alleviated by inhibition of said activity.

Claims

1. A metalloprotein inhibitor of formula (I):

2. The inhibitor of claim 1 wherein (C₆-C₁₀)aryl is phenyl.

3. The inhibitor of claim 1 wherein t is 1 and w or o is 1.

4. The inhibitor of claim 3 wherein p is 0, s is 0, t is 1, o is 1 and w is 0.

5. The inhibitor of claim 4 wherein p is 0.

6. The inhibitor of claim 1 wherein one of R¹, R², R³ or R⁴ is a substituent of formula (III).

7. The inhibitor of claim 1 wherein formula (I) is:

8. The inhibitor of claim 1 wherein one or two of the substituents of formula (III) are individually biphenylcarbamyl, biphenylcarbamyl(C₁-C₆)alkyl, biphenyl(C₁-C₆)alkylcarbamyl, biphenyl(C₁-C₆)alkylcarbamyl(C₁-C₆)alkyl, 4-phenylbiphenylcarbamyl, 4-phenylbiphenyl(C₁-C₆)alkylcarbamyl, 4-(4-cyanophenyl)benzylcarbamyl, 4-methoxybenzylcarbamyl, phenoxyphenylcarbamyl, (C₆-C₁₀)aryl(C₁-C₆)alkylamino(C₁-C₆)alkyl, biphenyl(C₁-C₆)alkylamino(C₁-C₆)alkyl, (C₆-C₁₀)arylcarbonylamino(C₁-C₆)alkyl, (C₆-C₁₀)aryl(C₁-C₆)alkylcarbonylamino(C₁-C₆)alkyl, biphenyloxy(C₁-C₆)alkylcarbonylamino(C₁-C₆)alkyl, or phenoxyphenylcarbamyl(C₁-C₆)alkyl, wherein the phenyl or aryl group(s) may be optionally substituted with one to four R¹, or a pharmaceutically acceptable salt thereof.

9. The inhibitor of claim 1 wherein the substituent of formula (III) is selected from the group consisting of biphenylmethylcarbamyl, 4-phenylbenzylcarbamyl, 4-(4-phenyphenyl)phenylmethylcarbamyl, 4-phenylphenethylcarbamyl, 4-(4-cyanophenyl)benzylcarbamyl, 4-styrylbenzylcarbamyl, 4-(indol-2-yl)benzylcarbamyl, phenoxyphenylcarbamyl, biphenylcarbamyl, benzylaminomethyl, phenethylaminomethyl, benzoylaminomethyl, benzylcarbonylaminomethyl, phenethylcarbonylaminomethyl, phenylpropylcarbonylaminomethyl, biphenylmethylcarbamylmethyl, phenoxyphenylcarbamylmethyl, biphenylcarbamylmethyl, biphenylyloxyethylcarbonylaminomethyl, and a pharmaceutically acceptable salt thereof.

10. The inhibitor of claim 1 wherein one of R¹, R², or R³ is (C₁-C₃)alkyl.

11. The inhibitor of claim 1 wherein one of R¹, R², or R³ is H.

12. The inhibitor of claim 1 comprising an NR⁴ moiety wherein R⁴ is (C₁-C₃)alkyl, benzyl, t-Boc, (C₃-C₆)cycloalkyl(C₁-C₃)alkyl, or H.

13. The inhibitor of claim 1 wherein a phenyl or aryl group of the substituent of formula (III) is substituted with (C₁-C₆)alkyl, halo, (C₁-C₆)alkoxy, heteroaryl, styryl, phenyl, CN, sulfonamide, amino or NO₂.

17. A composition comprising a compound of claim 1 in combination with a solid or liquid carrier or diluent.

18. A method of inhibiting metalloprotein activity in a mammal in need of therapy for a pathological disease, condition, or symptom associated with metalloprotein activity, which comprises administering an effective amount of a compound of claim 1.

19. A therapeutic method of treating a mammal threatened or afflicted with pathology associated with elevated metalloprotein activity comprising administering to said mammal an effective amount of the compound of claim 1.

20. The method of claim 18 wherein the metalloprotein activity is a matrix metalloproteinase activity.

21. The method of claim 18 wherein the metalloprotein activity is histone deacetylase activity.

22. The method of claim 18 wherein the metalloprotein activity comprises anthrax lethal factor activity.

23. The method of claim 18 wherein the pathological disease is cancer.

24. The method of claim 18 wherein the amount is effective to inhibit inflammation.

25. The method of claim 18 wherein the pathological condition is myocardial infarction.

26. The method of claim 18 wherein the compound is administered orally.

27. The method of claim 18 wherein the compound is administered parenterally.

14. A metalloprotein inhibitor of the formula:

15. The inhibitor of claim 14 wherein R′

is H.

16. The inhibitor of claim 14 wherein R′

is CH₃.