Alkynyl containing hydroxamic acid compounds as matrix metalloproteinase/TACE inhibitors

Abstract

Compounds of the formula: useful in the treatment of arthritis, tumor metastasis, tissue ulceration, abnormal wound healing, periodontal disease, bone disease, diabetes (insulin resistance) and HIV infection.

1 . A compound of formula  
       
         
           
           
               
               
           
         
       
       wherein: 
 R 1  is hydrogen, aryl, heteroaryl, alkyl of 1-8 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, cycloalkyl of 3-6 carbon atoms, or —C 4 -C 8 -cycloheteroalkyl;  
 R 2  and R 3  are each, independently, hydrogen, alkyl of 1-6 carbon atoms, —CN, or —CCH;  
 R 7  is hydrogen, aryl, aralkyl, heteroaryl, heteroaralkyl, alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 1-6 carbon atoms, cycloalkyl of 3-6 carbon atoms, —C(O)—R 1 , —SO 2 —R 1 , —C(O)—NHR 1 , —C(O)—NR 5 R 6 , —C(O)R 1 NR 5 R 6 , —C(O)—OR 1 , or —C(NH)—NH 2 ;  
 R 5  and R 6  are each independently, hydrogen, alkyl of 1-6 carbon atoms, cycloalkyl of 3-6 carbon atoms, aryl, aralkyl, heteroaryl, heteroaralkyl or —C 4 -C 8 -cycloheteroalkyl;  
 R 8  and R 9 , together with the carbon atom or atoms to which they are attached, form a —C 4 -C 8 -cycloheteroalkyl ring which is  
                     
  wherein K is O, S or NR 7  and R 7  is as defined hereinabove;  
 R 10  and R 11  are each, independently, hydrogen, aryl heteroaryl, cycloalkyl of 3-6 carbon atoms, —C 4 -C 8 -cycloheteroalkyl, alkyl of 1-18 carbon atoms, alkenyl of 2-18 carbon atoms, or alkynyl of 2-18 carbon atoms;  
 R 12  is hydrogen, aryl, heteroaryl, cycloalkyl of 3-6 carbon atoms, —C 4 -C 8 -cycloheteroalkyl, or alkyl of 1-6 carbon atoms;  
 A is O, S, SO, SO 2 , NR 7 , or CH 2 ;  
 X is O, S, SO, SO 2 , NR 7 , or CH 2 ;  
 Y is aryl or heteroaryl, with the proviso that A and X are not bonded to adjacent atoms of Y; and  
 n is 0-2; or a pharmaceutically acceptable salt thereof.  
 
     
     
         2 . The compound of  claim 1  wherein Y is phenyl, pyridyl, thienyl, furanyl, imidazolyl triazolyl, thiadiazolyl.  
     
     
         3 . (Canceled).  
     
     
         4 . A method of inhibiting pathological changes mediated by TNF-α converting enzyme (TACE) in a mammal in need thereof which comprises administering to said mammal a therapeutically effective amount of a compound having the formula  
       
         
           
           
               
               
           
         
       
       wherein: 
 R 1  is hydrogen, aryl, heteroaryl, alkyl of 1-8 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, cycloalkyl of 3-6 carbon atoms, or —C 4 -C 8 -cycloheteroalkyl;  
 R 2  and R 3  are each, independently, hydrogen, alkyl of 1-6 carbon atoms, —CN, or —CCH;  
 R 7  is hydrogen, aryl, aralkyl, heteroaryl, heteroaralkyl, alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 1-6 carbon atoms, cycloalkyl of 3-6 carbon atoms, —C(O)—R 1 , —SO 2 —R 1 , —C(O)—NHR 1 , —C(O)—NR 5 R 6 , —C(O)R 1 NR 5 R 6 , —C(O)—OR 1 , or —C(NH)—NH 2 ;  
 R 5  and R 6  are each, independently, hydrogen, alkyl of 1-6 carbon atoms, cycloalkyl of 3-6 carbon atoms, aryl, aralkyl, heteroaryl, heteroaralkyl or —C 4 -C 8 -cycloheteroalkyl;  
 R 8  and R 9 , together with the carbon atom or atoms to which they are attached, form a —C 4 -C 8 -cycloheteroalkyl ring which is  
                     
  wherein K is O, S or NR 7  and R 7  is as defined hereinabove;  
 R 10  and R 11  are each, independently, hydrogen, aryl heteroaryl, cycloalkyl of 3-6 carbon atoms, —C 4 -C 8 -cycloheteroalkyl, alkyl of 1-18 carbon atoms, alkenyl of 2-18 carbon atoms, or alkynyl of 2-18 carbon atoms;  
 R 12  is hydrogen, aryl heteroaryl, cycloalkyl of 3-6 carbon atoms, —C 4 -C 8 -cycloheteroalkyl, or alkyl of 1-6 carbon atoms;  
 A is O, S, SO, SO 2 , NR 7 , or CH 2 ;  
 X is O, S, SO, SO 2 , NR 7 , or CH 2 ;  
 Y is aryl or heteroaryl, with the proviso that A and X are not bonded to adjacent atoms of Y; and  
 n is 0-2; or a pharmaceutically acceptable salt thereof.  
 
     
     
         5 . The method of  claim 4  wherein the condition treated is rheumatoid arthritis, graft rejection, cachexia, inflammation, fever, insulin resistance, septic shock, congestive heart failure, inflammatory disease of the central nervous system, inflammatory bowel disease or HIV infection.  
     
     
         6 . A pharmaceutical composition comprising a compound having the formula  
       
         
           
           
               
               
           
         
       
       wherein: 
 R 1  is hydrogen, aryl, heteroaryl, alkyl of 1-8 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, cycloalkyl of 3-6 carbon atoms, or —C 4 -C 8 -cycloheteroalkyl;  
 R 2  and R 3  are each, independently, hydrogen, alkyl of 1-6 carbon atoms, —CN, or —CCH;  
 R 7  is hydrogen, aryl, aralkyl, heteroaryl, heteroaralkyl, alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 1-6 carbon atoms, cycloalkyl of 3-6 carbon atoms, —C(O)—R 1 , —SO 2 —R 1 , —C(O)—NHR 1 , —C(O)—NR 5 R 6 , —C(O)R 1 NR 5 R 6 , —C(O)—OR 1 , or —C(NH)—NH 2 ;  
 R 5  and R 6  are each, independently, hydrogen, alkyl of 1-6 carbon atoms, cycloalkyl of 3-6 carbon atoms, aryl, aralkyl, heteroaryl, heteroaralkyl or —C 4 -C 8 —cycloheteroalkyl;  
 R 8  and R 9 , together with the carbon atom or atoms, to which they are attached, form a —C 4 -C 8 -cycloheteroalkyl ring which is  
                     
  wherein K is O, S or NR 7  and R 7  is as defined hereinabove;  
 R 10  and R 11  are each, independently, hydrogen, aryl heteroaryl, cycloalkyl of 3-6 carbon atoms, —C 4 -C 8 -cycloheteroalkyl, alkyl of 1-18 carbon atoms, alkenyl of 2-18 carbon atoms, or alkynyl of 2-18 carbon atoms;  
 R 12  is hydrogen, aryl heteroaryl, cycloalkyl of 3-6 carbon atoms, —C 4 -C 8 -cycloheteroalkyl, or alkyl of 1-6 carbon atoms;  
 A is O, S, SO, SO 2 , NR 7 , or CH 2 ;  
 X is O, S, SO, SO 2 , NR 7 , or CH 2 ;  
 Y is aryl or heteroaryl, with the proviso that A and X are not bonded to adjacent atoms of Y; and  
 n is 0-2; or a pharmaceutically acceptable salt thereof.  
 
     
     
         7 . The compound of  claim 2  wherein the cycloheteroalkyl ring formed by R 8  and R 9  is selected from the group consisting of piperidine, piperazine, morpholine, tetrahydropyran, tetrahydrofuran and pyrrolidine.  
     
     
         8 . The compound of  claim 7  wherein K is NR 7 .