(Substituted)acyl dipeptidyl inhibitors of the ICE/ced-3 family of cysteine proteases

Abstract

This invention is directed to novel (substituted)acyl dipeptidyl ICE/ced-3 family inhibitor compounds. The invention is also directed to pharmaceutical compositions containing these compounds, as well as the use of such compositions in the treatment of patients suffering inflammatory, autoimmune and neurodegenerative diseases, for the prevention of ischemic injury, and for the preservation of organs that are to undergo a transplantation procedure.

We claim:  
     
         1 . A compound of the following formula:  
       
         
           
           
               
               
           
         
         Formula I  
         wherein:  
         n is 0, 1 or 2;  
         X is CH 2 , C═O, O, S or NH;  
         A is a natural or unnatural amino acid of Formula IIa-i:  
         
           
             
             
                 
                 
             
           
         
         B is a hydrogen atom, a deuterium atom, C 1-10  straight chain or branched alkyl, cycloalkyl, phenyl, substituted phenyl, naphthyl, substituted naphthyl, 2-benzoxazolyl, substituted 2-oxazolyl, (CH 2 ) m cycloalkyl, (CH 2 ) m phenyl, (CH 2 ) m (substituted phenyl), (CH 2 ) m (1 or 2-naphthyl), (CH 2 ) m heteroaryl, halomethyl, CO 2 R 13 , CONR 14 R 15 , CH 2 ZR 16 , CH 2 OCO(aryl), CH 2 OCO(heteroaryl), or CH 2 OPO(R 17 )R 18 , where Z is an oxygen or a sulfur atom, or B is a group of the Formula IIIa-c:  
         
           
             
             
                 
                 
             
           
         
         R 1  is phenyl, substituted phenyl, naphthyl, substituted naphthyl, heteroaryl, or substituted heteroaryl;  
         R 2  is hydrogen, alkyl, cycloalkyl, phenyl, substituted phenyl, (CH 2 ) m NH 2 , (CH 2 ) m NHCOR 10 , (CH 2 ) m N(C═NH)NH 2 , (CH 2 ) p CO 2 R 3 , (CH 2 ) p OR 11 , (CH 2 ) p SR 12 , (CH 2 ) m cycloalkyl, (CH 2 ) m phenyl, (CH 2 ) m (substituted phenyl), (CH 2 ) m (1 or 2-naphthyl), or (CH 2 )heteroaryl, wherein heteroaryl includes (but is not limited to) pyridyl, thienyl, furyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, pyrazinyl, pyrimidyl, triazinyl, tetrazolyl, and indolyl;  
         R 3  is hydrogen, alkyl, cycloalkyl, (cycloalkyl)alkyl, phenylalkyl, or substituted phenylalkyl;  
         and wherein  
         R 4  is alkyl, cycloalkyl, phenyl, substituted phenyl, (CH 2 ) m NH 2 , (CH 2 ) m NHCOR 10 , (CH 2 ) m N(C═NH)NH 2 , (CH 2 ) p CO 2 R 3 , (CH 2 ) p OR 11 , (CH 2 ) p SR 2 , (CH 2 ) m cycloalkyl, (CH 2 ) m phenyl, (CH 2 ) m (substituted phenyl), (CH 2 ) m (1 or 2-naphthyl), or (CH 2 ) m heteroaryl, wherein heteroaryl includes (but is not limited to) pyridyl, thienyl, furyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, pyrazinyl, pyrimidyl, triazinyl, tetrazolyl, and indolyl;  
         R 4a  is hydrogen, or methyl, or R 4  and R 41  taken together are —(CH 2 ) d — where d is an interger from 2 to 6;  
         R 5  is phenyl, substituted phenyl, (CH 2 ) p phenyl, (CH 2 ) p (substituted phenyl), cycloalkyl, or benzofused cycloalkyl;  
         R 6  is hydrogen, alkyl, cycloalkyl, phenyl, substituted phenyl, (CH 2 ) m cycloalkyl, (CH 2 ) m phenyl, (CH 2 ) m (substituted phenyl), or (CH 2 ) m (1 or 2-naphthyl);  
         R 7  is hydrogen, fluorine, oxo, alkyl, cycloalkyl, phenyl, substituted phenyl, naphthyl, (CH 2 ) m cycloalkyl, (CH 2 ) m phenyl, (CH 2 ) m (substituted phenyl), (CH 2 ) m (1 or 2-naphthyl), OR 11 , SR 12 , or NHCOR 10 ;  
         R 8  is hydrogen, oxo, alkyl, cycloalkyl, phenyl, substituted phenyl, naphthyl, (CH 2 ) m cycloalkyl, (CH 2 ) m phenyl, (CH 2 ) m (substituted phenyl), or (CH 2 ) m (1 or 2-naphthyl);  
         R 9  is alkyl, cycloalkyl, (CH 2 ) m cycloalkyl, (CH 2 ) m phenyl, (CH 2 ) m (substituted phenyl), (CH 2 ) m (1 or 2-naphthyl), or COR 10 ;  
         R 10  is hydrogen, alkyl, cycloalkyl, phenyl, substituted phenyl, naphthyl, (CH 2 ) m cycloalkyl, (CH 2 ) m phenyl, (CH 2 ) m (substituted phenyl), (CH 2 ) m (1 or 2-naphthyl), OR 13 , or N 14 R 15 ;  
         R 11  is hydrogen, alkyl, cycloalkyl, phenyl, substituted phenyl, naphthyl, (CH 2 ) m cycloalkyl, (CH 2 ) m phenyl, (CH 2 ) m (substituted phenyl), or (CH 2 ) m (1 or 2-naphthyl);  
         R 12  is alkyl, cycloalkyl, phenyl, substituted phenyl, naphthyl, (CH 2 ) m cycloalkyl, (CH 2 ) m phenyl, (CH 2 ) m (substituted phenyl), or (CH 2 ) m (1 or 2-naphthyl);  
         R 13  is alkyl, cycloalkyl, (CH 2 ) m cycloalkyl, (CH 2 ) m phenyl, (CH 2 ) m (substituted phenyl), or (CH 2 ) m (1 or 2-naphthyl);  
         R 14  is hydrogen, alkyl, cycloalkyl, phenyl, substituted phenyl, naphthyl, substituted naphthyl, (CH 2 ) m cycloalkyl, (CH 2 ) m phenyl, (CH 2 ) m (substituted phenyl), or (CH 2 ) m (1 or 2-naphthyl);  
         R 15  is hydrogen or alkyl; or  
         R 14  and R 15  taken together form a five, six or seven membered carbocyclic or heterocyclic ring, such as morpholine or N-substituted piperazine;  
         R 16  is phenyl, substituted phenyl, naphthyl, substituted naphthyl, heteroaryl, (CH 2 ) m phenyl, (CH 2 ) m (substituted phenyl), (CH 2 ) m (1 or 2-naphthyl), or (CH 2 ) m heteroaryl;  
         R 17  and R 18  are independently alkyl, cycloalkyl, phenyl, substituted phenyl, naphthyl, or phenylalkyl, substituted phenylalkyl, or (cycloalkyl)alkyl;  
         R 19  and R 20  are independently hydrogen, alkyl, phenyl, substituted phenyl, (CH 2 ) m phenyl, or (CH 2 ) m (substituted phenyl), or R 19  and R 20  taken together are —(CH═CH) 2 —;  
         R 21  is hydrogen, alkyl, phenyl, substituted phenyl, (CH 2 ) m phenyl, (CH 2 ) m (substituted phenyl);  
         R 22 , R 23  and R 24  are independently hydrogen or alkyl;  
         Y 1  is CH 2 , (CH 2 ) 2 , (CH 2 ) 3 , or S;  
         Y 2  is O or NR 24 ;  
         Y 3  is CH 2 , O, or NR 24 ;  
         a is 0 or 1 and b is 1 or 2, provided that when a is 1 then b is 1;  
         c is 1 or 2, provided that when c is 1 then a is 0 and b is 1;  
         m is 1, 2, 3 or 4; and  
         p is 1 or 2;  
         or a pharmaceutically acceptable salt thereof.  
       
     
     
         2 . The compound of  claim 1  where X is oxygen.  
     
     
         3 . The compound of  claim 1  where X is sulfur.  
     
     
         4 . The compound of  claim 1  where X is NH.  
     
     
         5 . The compound of  claim 1  where X is CH 2 .  
     
     
         6 . The compound of  claim 1  where X is C═O.  
     
     
         7 . The compound of  claim 1  wherein A is  
       
         
           
           
               
               
           
         
       
     
     
         8 . The compound of  claim 7  wherein 
 R 4  is lower alkyl, cycloalkyl, phenyl, substituted phenyl, (CH 2 ) n NH 2 , (CH 2 ) m OR 10 , (CH 2 ) m SR 11 , (CH 2 ) n cycloalkyl, (CH 2 ) n phenyl, (CH 2 ) n (substituted phenyl), or (CH 2 ) n (1 or 2-naphthyl); and  
 R 4a  is hydrogen.  
 
     
     
         9 . The compound of  claim 1  wherein A is  
       
         
           
           
               
               
           
         
       
     
     
         10 . The compound of  claim 9  wherein R 5  is phenyl, substituted phenyl, (CH 2 ) m phenyl, (CH 2 ) m (substituted phenyl), cycloalkyl, or 2-indanyl.  
     
     
         11 . The compound of  claim 1  wherein A is  
       
         
           
           
               
               
           
         
       
     
     
         12 . The compound of  claim 11  wherein R 7  is hydrogen, fluorine, cycloalkyl, phenyl, substituted phenyl, naphthyl, (CH 2 ) n cycloalkyl, (CH 2 ) n phenyl, (CH 2 ) n (substituted phenyl), (CH 2 ) n (1 or 2-naphthyl), OR 10 , or SR 11 .  
     
     
         13 . The compound of  claim 1  wherein A is  
       
         
           
           
               
               
           
         
       
     
     
         14 . The compound of  claim 13  wherein 
 R 8  is hydrogen, oxo, cycloalkyl, phenyl, substituted phenyl, or naphthyl; and  
 Y 1  is CH 2 , (CH 2 ) 2 , (CH 2 ) 3 , or S.  
 
     
     
         15 . The compound of  claim 1  wherein A is  
       
         
           
           
               
               
           
         
       
     
     
         16 . The compound of  claim 15  wherein a is 0.  
     
     
         17 . The compound of  claim 1  wherein 
 B is hydrogen, 2-benzoxazolyl, substituted 2-oxazolyl, CH 2 ZR 15 , CH 2 OCO(aryl), or CH 2 OPO(R 16 )R 17 ; and  
 Z is O or S.  
 
     
     
         18 . The compound of  claim 1  wherein B is  
       
         
           
           
               
               
           
         
       
     
     
         19 . The compound of  claim 18  wherein R 19  and R 20  are independently hydrogen, alkyl, or phenyl, or wherein R 19  and R 20  taken together are —(CH═CH) 2 —.  
     
     
         20 . The compound of  claim 1  wherein 
 X is O or NH;  
 n is 0 or 1;  
 R 1  is substituted phenyl, naphthyl, or substituted naphthyl;  
 R 2  is hydrogen, lower alkyl, (CH 2 ) p CO 2 R 3 , (CH 2 ) m (substituted phenyl), (CH 2 ) m (1- or 2-naphthyl), or (CH 2 ) m tetrazolyl; and  
 R 3  is hydrogen or lower alkyl.  
 
     
     
         21 . The compound of  claim 20  wherein R 1  is 1-naphthyl.  
     
     
         22 . The compound of  claim 20  wherein R 1  is 2naphthyl.  
     
     
         23 . The compound of  claim 20  wherein R 1  is substituted naphthyl.  
     
     
         24 . The compound of  claim 23  wherein substituted naphthyl is 2-carboxy-1-naphthyl.  
     
     
         25 . The compound of  claim 20  wherein R 1  is substituted phenyl.  
     
     
         26 . The compound of  claim 25  wherein substituted phenyl is 2-substituted phenyl.  
     
     
         27 . The compound of  claim 26  wherein 2-substituted phenyl is (2-phenyl)phenyl.  
     
     
         28 . The compound of  claim 20  wherein A is alanine, valine, leucine cyclohexylalanine, phenylgycine or t-butylglycine.  
     
     
         29 . The compound of  claim 28  wherein R 1  is 1-naphthyl.  
     
     
         30 . The compound of  claim 28  wherein R 1  is 2-naphthyl.  
     
     
         31 . The compound of  claim 28  wherein R 1  is substituted naphthyl.  
     
     
         32 . The compound of  claim 31  wherein substituted naphthyl is 2-carboxy-1-naphthyl.  
     
     
         33 . The compound of  claim 28  wherein R 1  is 2-substituted phenyl.  
     
     
         34 . The compound of  claim 33  wherein 2-substituted phenyl is (2-phenyl)phenyl.  
     
     
         35 . The compound of  claim 20  wherein R 2  is (CH 2 ) 2 CO 2 R 3  and n is 0.  
     
     
         36 . A pharmaceutical composition comprising a compound of  claim 1  in combination with a pharmaceutically acceptable carrier.  
     
     
         37 . A method for treating an autoimmune disease, comprising administering an effective amount of the pharmaceutical composition of  claim 36  to a patient in need thereof.  
     
     
         38 . A method of treating an inflammatory disease, comprising administering an effective amount of the pharmaceutical composition of  claim 36  to a patient in need thereof.  
     
     
         39 . A method of treating a neurodegenerative disease, comprising administering an effective amount of the pharmaceutical composition of  claim 36  to a patient in need thereof.  
     
     
         40 . A method of preventing ischemic injury to a patient suffering from a disease associated with ischemic injury, comprising administering an effective amount of the pharmaceutical composition of  claim 36  to a patient in need thereof.  
     
     
         41 . A method for expanding of hematopoietic cell populations or enhancing their survival, comprising contacting the cells with an effective amount of the pharmaceutical composition of  claim 36 .  
     
     
         42 . The method of  claim 41  wherein the cell populations are granulocytes, monocytes, erthrocytes, lymphocytes or platelets for use in cell transfusions.  
     
     
         43 . A method of prolonging the viability of an organ that has been removed from a donor or isolated cells derived from an organ for the purpose of a future transplantation procedure, comprising applying an effective amount of the pharmaceutical composition of  claim 36  to the organ or isolated cells to prolong the viability of the same as compared to untreated organ or isolated cells.  
     
     
         44 . The method of  claim 43  wherein the organ is an intact organ.  
     
     
         45 . The method of  claim 43  wherein the isolated cells are pancreatic islet cells, dopaminergic neurons, blood cells or hematopoietic cells.