Heterocyclic derived metalloprotease inhibitors

Abstract

This invention provides novel heterocyclic derived matrix metalloprotease inhibitors of the formula: and pharmaceutical compositions comprising same, useful for treating disorders ameliorated by antagonizing matrix metalloproteases. This invention also provides therapeutic and prophylactic methods using the instant pharmaceutical compositions.

1 .- 32 . (canceled) 
     
     
         33 . A method of treating a subject having a condition ameliorated by antagonizing matrix metalloproteinase in appropriate cells in the subject, which method comprises administering to the subject a therapeutically effective dose of the compound of Formula 1: 
       
         
           
           
               
               
           
         
       
       wherein
 Ring a is a 6, 7, 8, or 9-membered ring selected from heteroaryl and heterocyclyl, wherein
 X is O or S, 
 E is selected from an sp 2  carbon, 
 
 
       
         
           
           
               
               
           
         
       
       and N, wherein
     R 5  is selected from H, hydroxy, amino, alkoxy, alkylthio, sulfonyl, C 1-10 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, aryl, heteroaryl, and heterocyclyl, and     Q is N or an sp 2  carbon, provided that when E is an sp 2  carbon, Q is N;   
 Ring b is selected from
 aryl; 
 heteroaryl; and 
 heterocyclyl of the formula 
 
 
       
         
           
           
               
               
           
         
       
       wherein
     G 1  and G 2  are independently selected from N, C, and CH; and     D 1  and D 2  are each 1-3 independent members selected from CH, CH 2 , N, S, and O, provided that when G 1  or G 2  is N, D 1  and D 2  are independently selected from CH and C 2 ,   
 R 1  is selected from halo, nitrile, hydroxyl, thiol, amino, alkoxy, alkylthio, sulfonyl, C 1-10 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, carbonyl, and —CHO; 
 R 2  is 0-2 independent members selected from halo, nitrile, hydroxyl, amino, C 1-10 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, alkoxy, alkylthio, sulfonyl, aryl, heteroaryl, heterocyclyl, —C(O)R 3 , —C(O)OR 3 , and —C(O)NR 3 R 4 , wherein
 R 3  and R 4  are independently selected from H, C 1-10 alkyl, aryl, heteroaryl, and heterocyclyl, or 
 R 3  and R 4  together with the N they are attached to form a 3-, 4-, 5-, 6-, or 7-membered heterocyclyl: 
 
 W is selected from a covalent bond, —(CH 2 ) p —O—, —O—(CH 2 ) p —, —S(O) p —, —C(O)—, C 1-3 alkylene, C 2-3 alkenylene, C 2-3 alkynylene, and 5-7 membered aliphatic ring containing one or two nitrogens, wherein
 p is 0, 1, or 2; 
 
 Y is selected from O, S, S(O), S(O) 2 , —SO 2 N(R 6 )—, —N(R 6 )SO 2 —, —N(R 6 )SO 2 N(R 7 )—, N(R 6 )CO—, —N(R 6 )PO(OR 8 )—, —N(SO 2 R 8 )—, —N(COR 8 )—, —N(POOR 8 R 9 )—, —CH(OH)—, 
 
       
         
           
           
               
               
           
         
       
       wherein
   R 6  and R 7  are independently selected from H, C 1-10 alkyl, alkylsulfonyl, arylsulfonyl, alkylcarbonyl, and arylcarbonyl, and   R 8  and R 9  are independently selected from C 1-6 alkyl, aryl, heteroaryl, and heterocyclyl:   
 Z is —CH(R 10 )— or —CH(R 10 )CH(R 11 )—, wherein
 R 10  and R 11  are independently selected from H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, aryl, heteroaryl, and heterocyclyl; 
 
 in is 0, 1, or 2; and 
 n is 0 or 1 with the proviso that when n is 0, E is not N and Y is not O; 
 
       or an optical isomer, enantiomer, diastereomer, racemate, prodrug or pharmaceutically acceptable salt thereof. 
     
     
         34 . A method of preventing a subject having a condition ameliorated by antagonizing matrix metalloproteinase in appropriate cells in the subject, which method comprises administering to the subject a prophylactically effective dose of the compound of  claim 33  either preceding or subsequent to an event anticipated to cause a condition ameliorated by antagonizing matrix metalloproteinase in appropriate cells in the subject. 
     
     
         35 . The method of  claim 33 , wherein the condition is selected from vascular and myocardial tissue morphogenesis, cancer, cardiovascular diseases, inflammatory diseases, acute and chronic CNS disorders, neurovascular disorders, neurodegenerative diseases, demylinating diseases, movement disorders, and associated symptoms or complications thereof. 
     
     
         36 . The method of  claim 33 , wherein the condition is selected from ischemic or hemorrhagic stroke, Parkinson's disease, Alzheimer's disease, cerebral amyloid angiopathy, vascular dementia, headaches, migraine, traumatic brain injury, multiple sclerosis, edema, atherosclerotic plaque rupture, aneurysm, osteoarthritis, rheumatoid arthritis, gastric ulcers, pulmonary hypertension, chronic obstructive pulmonary disease, inflammatory bowel disease, periodontal disease, skin ulcers, liver fibrosis, emphysema, Marfan's syndrome, and associated symptoms or complications thereof. 
     
     
         37 . The method of  claim 33  wherein said compound, or an optical isomer, enantiomer, diastereomer, racemate, prodrug or pharmaceutically acceptable salt thereof, is administered in combination administration with one or more other compounds or therapeutic agents. 
     
     
         38 . The method of  claim 33  wherein the subject is a human. 
     
     
         39 . The method of  claim 33  wherein the therapeutically effective amount of a compound of Formula (I) is in a range of from about 0.001 mg/kg of body weight to about 200 mg/kg of body weight of the subject. 
     
     
         40 . The method of  claim 35  wherein the subject is a human. 
     
     
         41 . The method of  claim 36  wherein the subject is a human. 
     
     
         42 .- 43 . (canceled)