Selective hydroxamic acid based mmp-12 and mmp-13 inhibitors

Abstract

The present invention provides a compound of formula (I) said compound is inhibitor of MMP-12 and/or MMP-13, and thus can be employed for the treatment of a disorder or disease characterized by abnormal activity of MMP-12 and/or MMP-13. Accordingly, the compound of formula (I) can be used in treatment of disorders or diseases mediated by MMP-12 and/or MMP-13. Finally, the present invention also provides pharmaceutical composition that include the compound of formula (I).

1 . A compound of formula (I) 
       
         
           
           
               
               
           
         
         wherein 
         R 1  is hydrogen, alkyl, alkenyl, alkynyl, aryl-alkyl-, cycloalkyl, or heterocycloalkyl, each of which is optionally substituted by one to three substituents selected from aryl-alkoxy-, hydroxy, alkoxy, HS—, alkyl-S—, alkyl-O—(O)C—, cyano, alkyl-SO 2 —, and aryl; 
         R 2  is H, alkyl, alkenyl, alkynyl, aryloxy-alkyl-, aryl-alkyl-, heteroaryl-alkyl-, or heterocycloalkyl-alkyl, each of which is optionally substituted by one to three substituents selected from HS—, halo, alkoxy, alkyl, and dialkylamino; 
         X is hydrogen, hydroxyl, alkoxy, or halo; 
         Y is R 3 —NH—, wherein R 3  is hydrogen, alkyl, alkyl-C(O)—, or aryl; or 
         Y is alkoxy, alkyl, hydrogen, hydroxyl, alkyl-C(O)—NH—, alkenyl-O—, or aryl-alkoxy-; 
         R 1  and R 2  taken together with the carbon atom and the nitrogen atom to which they are attached, form a 3- to 7-membered ring; 
         or a pharmaceutically acceptable salts thereof; or an optical isomer thereof; or a mixture of optical isomers. 
       
     
     
         2 . The compound of  claim 1 , wherein R 1  is (C 1 -C 7 ) alkyl, (C 1 -C 7 ) alkenyl, (C 1 -C 7 ) alkynyl, or (4- to 7-membered) heterocycloalkyl, each of which is optionally substituted by one to three substituents selected from hydroxy, HS—, (C 1 -C 7 ) alkyl-S—, (C 6 -C 10 ) aryl, or (C 1 -C 7 ) alkyl-O—C(O)—; R 2  is (C 1 -C 7 ) alkyl, (C 1 -C 7 ) alkenyl, (C 6 -C 10 ) aryl-(C 1 -C 7 ) alkyl-, (5- to 9-membered) heteroaryl-(C 1 -C 7 ) alkyl-, and (C 6 -C 10 ) aryloxy-(C 1 -C 7 ) alkyl-; X is hydrogen, hydroxy, or (C 1 -C 7 ) alkoxy; Y is hydrogen, (C 1 -C 7 ) alkyl, (C 1 -C 7 ) alkenyl-O—, H 2 N—, or (C 1 -C 7 ) alkyl-C(O)—NH—; or R 1  and R 2  taken together with the carbon atom and the nitrogen atom to which they are attached, form a 3- to 7-membered ring; or a 
       pharmaceutically acceptable salts thereof; or an optical isomer thereof; or a mixture of optical isomers. 
     
     
         3 . The compound of  claim 2 , wherein R 1  is a (C 1 -C 7 ) alkyl, or (C 1 -C 7 ) alkenyl; R 2  is a (C 1 -C 7 ) alkyl, (C 1 -C 7 ) alkenyl, (C 1 -C 7 ) alkynyl, or (C 6 -C 10 ) aryl-(C 1 -C 7 ) alkyl-; Y is H, H 2 N—, (C 1 -C 4 ) alkoxy, (C 1 -C 4 ) alkyl, or (C 1 -C 4 ) alkyl-NH—; X is H, HO—, or (C 1 -C 4 ) alkoxy; or a pharmaceutically acceptable salts thereof; or an optical isomer thereof; or a mixture of optical isomers. 
     
     
         4 . A compound of formula (II) according to  claim 1 : 
       
         
           
           
               
               
           
         
         wherein 
         R 1  is hydrogen, alkyl, alkenyl, alkynyl, aryl-alkyl-, cycloalkyl, or heterocycloalkyl, each of which is optionally substituted by one to three substituents selected from aryl-alkoxy-, hydroxy, alkoxy, HS—, alkyl-S—, alkyl-O—(O)C—, cyano, alkyl-SO 2 —, and aryl; 
         R 2  is H, alkyl, alkenyl, alkynyl, aryloxy-alkyl-, aryl-alkyl-, heteroaryl-alkyl-, or heterocycloalkyl-alkyl, each of which is optionally substituted by one to three substituents selected from HS—, halo, alkoxy, alkyl, and dialkylamino; 
         X is hydrogen, hydroxyl, alkoxy, or halo; 
         Y is R 3 —NH—, wherein R 3  is hydrogen, alkyl, alkyl-C(O)—, or aryl; or 
         Y is alkoxy, alkyl, hydrogen, hydroxyl, alkyl-C(O)—NH—, alkenyl-O—, or aryl-alkoxy-; 
         R 1  and R 2  taken together with the carbon atom and the nitrogen atom to which they are attached, form a 3- to 7-membered ring; 
         or a pharmaceutically acceptable salts thereof; or an optical isomer thereof; or a mixture of optical isomers. 
       
     
     
         5 . The compound of  claim 4 , wherein R 1  is (C 1 -C 7 ) alkyl, (C 1 -C 7 ) alkenyl, (C 1 -C 7 ) alkynyl, or (4- to 7-membered) heterocycloalkyl, each of which is optionally substituted by one to three substituents selected from hydroxy, HS—, (C 1 -C 7 ) alkyl-S—, (C 6 -C 10 ) aryl, or (C 1 -C 7 ) alkyl-O—C(O)—; R 2  is (C 1 -C 7 ) alkyl, (C 1 -C 7 ) alkenyl, (C 6 -C 10 ) aryl-(C 1 -C 7 ) alkyl-, (5- to 9-membered) heteroaryl-(C 1 -C 7 ) alkyl-, and (C 6 -C 10 ) aryloxy-(C 1 -C 7 ) alkyl-; X is hydrogen, hydroxy, or (C 1 -C 7 ) alkoxy; Y is hydrogen, (C 1 -C 7 ) alkyl, (C 1 -C 7 ) alkenyl-O—, H 2 N—, or (C 1 -C 7 ) alkyl-C(O)—NH—; or R 1  and R 2  taken together with the carbon atom and the nitrogen atom to which they are attached, form a 3- to 7-membered ring; or a pharmaceutically acceptable salts thereof; or an optical isomer thereof; or a mixture of optical isomers. 
     
     
         6 . The compound of  claim 5 , wherein R 1  is a (C 1 -C 7 ) alkyl, or (C 1 -C 7 ) alkenyl; R 2  is a (C 1 -C 7 ) alkyl, (C 1 -C 7 ) alkenyl, (C 1 -C 7 ) alkynyl, or (C 6 -C 10 ) aryl-(C 1 -C 7 ) alkyl-; Y is H, H 2 N—, (C 1 -C 4 ) alkoxy, (C 1 -C 4 ) alkyl, or (C 1 -C 4 ) alkyl-NH—; X is H, HO—, or (C 1 -C 4 ) alkoxy; or a pharmaceutically acceptable salts thereof; or an optical isomer thereof; or a mixture of optical isomers. 
     
     
         7 . A compound of formula (IIA) according to  claim 1   
       
         
           
           
               
               
           
         
         wherein 
         R 1  is alkyl, R 2  is alkyl or aryl-alkyl-, A is aryl-NH—, H 2 N—, Alkyl, hydroxyl, alkoxy, alkyl-C(O)—NH—, alkenyl-O—, or aryl-alkyl-O—, or a pharmaceutically acceptable salts thereof; or an optical isomer thereof; or a mixture of optical isomers. 
       
     
     
         8 . The compound of  claim 7 , wherein R 1  is (C 1 -C 4 ) alkyl, R 2  is (C 1 -C 7 ) alkyl, or (C 6 -C 10 ) aryl-(C 1 -C 7 ) alkyl-, A is (C 1 -C 7 ) alkyl, (C 1 -C 7 ) alkenyl-O—, H 2 N—, or (C 1 -C 7 ) alkyl-C(O)—NH—, or (C 6 -C 10 ) aryl-(C 1 -C 7 ) alkyl-O—; or a pharmaceutically acceptable salts thereof; or an optical isomer thereof; or a mixture of optical isomers. 
     
     
         9 . A compound of formula (III). 
       
         
           
           
               
               
           
         
         wherein 
         Z 1  and Z 2  are independently C or N; 
         R 1  and R 2  are independently hydrogen, alkyl, alkenyl, or alkynyl; 
         R 1  and R 2  taken together with the carbon atom and the nitrogen atom to which they are attached, form a 3- to 7-membered ring; or 
         or a pharmaceutically acceptable salts thereof; or an optical isomer thereof; or a mixture of optical isomers. 
       
     
     
         10 . The compound of  claim 9 , wherein Z 1  is N, Z 2  is C, R 1  and R 2  are independently (C 1 -C 7 ) alkyl, (C 1 -C 7 ) alkenyl, or (C 1 -C 7 ) alkynyl; or R 1  and R 2  taken together with the carbon atom and the nitrogen atom to which they are attached, form a 3- to 7-membered ring; or a pharmaceutically acceptable salts thereof; or an optical isomer thereof; or a mixture of optical isomers. 
     
     
         11 . The compound of  claim 9 , wherein Z 1  is C, Z 2  is N, R 1  and R 2  are independently (C 1 -C 7 ) alkyl, (C 1 -C 7 ) alkenyl, or (C 1 -C 7 ) alkynyl; or R 1  and R 2  taken together with the carbon atom and the nitrogen atom to which they are attached, form a 3- to 7-membered ring; or a pharmaceutically acceptable salts thereof; or an optical isomer thereof; or a mixture of optical isomers. 
     
     
         12 . A method of inhibiting activity of MMP-13 and/or MMP-12 in a subject, comprising administering to the subject a therapeutically effective amount of the compound according to  claim 1 . 
     
     
         13 . A method of treating a disorder or a disease in a subject mediated by MMP-13 and/or MMP-12, wherein the method comprises administering to the subject a therapeutically effective amount of the compound according to  claim 1  or  9 . 
     
     
         14 . The method of  claim 13 , wherein the disorder or the disease is selected from the group consisting of Alport syndrome, asthma, rhinitis, chronic obstructive pulmonary diseases (COPD), arthritis, atherosclerosis, cancer invasion and metastasis, diseases involving tissue destruction, loosening of hip joint replacements, periodontal disease, diseases related to the weakening of the extracellular matrix, heart failure, and aortic aneurysms. 
     
     
         15 . A pharmaceutical composition comprising a therapeutically effective amount of a compound of  claim 1  or  9  and one or more pharmaceutically acceptable carriers. 
     
     
         16 . A pharmaceutical composition comprising a therapeutically effective amount of the compound according to  claim 1  or  9  and one or more therapeutically active agents selected from an antiinflamatory agent and an anitrheumatic agent. 
     
     
         17 - 20 . (canceled)