Inhibition of matrix metalloproteases by substituted biaryl oxobutyric acids

Abstract

Matrix metalloprotease inhibiting compounds, pharmaceutical compositions thereof and a method of disease treatment using such compounds are presented. The compounds of the invention have the generalized formulas: wherein r is 0-2, T is selected from and R 40 is a mono- or bi-heterocyclic structure. These compounds are useful for inhibiting matrix metalloproteases and, therefore, combating conditions to which MMP's contribute, such as osteoarthritis, rheumatoid arthritis, septic arthritis, periodontal disease, comeal ulceration, proteinuria, aneurysmal aortic disease, dystrophobic epidermolysis, bullosa, conditions leading to inflammatory responses, osteopenias mediated by MMP activity, tempero mandibularjoint disease, demyelating diseases of the nervous system, tumor metastasis or degenerative cartilage loss following traumatic joint injury, and coronary thrombosis from athrosclerotic plaque rupture. The present invention also provides pharmaceutical compositions and methods for treating such conditions.

1 . Matrix metalloproteinase inhibitors having the general formula:  
     
       
         
         
             
             
         
       
       wherein r is 0-2, T is selected from the group consisting of:  
       
         
           
           
               
               
           
         
       
       and R 40  is selected from the group consisting of  
       
         
           
           
               
               
           
         
       
     
   
   
       2 . A composition having matrix metalloprotease inhibitory activity, comprising a compound of  claim 1  and a pharmaceutically acceptable carrier.  
   
   
       3 . A method of inhibiting matrix metalloprotease activity in a mammal comprising administration of an effective amount of a matrix metalloprotease inhibitor compound of  claim 1  to said mammal.  
   
   
       4 . The method of  claim 3  wherein said mammal is a human.  
   
   
       5 . A method of treating a mammal comprising administering to the mammal a matrix metalloprotease inhibiting amount of a compound according to  claim 1  sufficient to: 
 (a) alleviate the effects of osteoarthritis, rheumatoid arthritis, septic arthritis, periodontal disease, corneal ulceration, proteinuria, aneurysmal aortic disease, dystrophobic epidermolysis, bullosa, conditions leading to inflammatory responses, osteopenias mediated by MMP activity, tempero mandibular joint disease, demyelating diseases of the nervous system;    (b) retard tumor metastasis or degenerative cartilage loss following traumatic joint injury;    (c) reduce coronary thrombosis from arthrosclerotic plaque rupture; or    (d) effect birth control.    
   
   
       6 . The method of  claim 5  wherein the effect is alleviation of osteo arthritis.  
   
   
       7 . The method of  claim 5  wherein the effect is retardation of tumor metastasis.