Adamantylglycine-based inhibitors of dipeptidyl peptidase IV and methods

Abstract

Compounds are provided having the formula (I) wherein: n is 0, 1 or 2; m is 0, 1 or 2; the sum of n+m less then or equal to 2; the dashed bonds forming a cyclopropyl ring can only be present when Y is CH; X is H or CN; Y is CH, CH 2 , CHF, CF 2 , O, S, SO, or SO 2 ; and A is adamantyl. Further provided are methods of using such compounds for the treatment of diabetes and related diseases, and to pharmaceutical compositions containing such compounds.

1 - 16 . (canceled)  
   
   
       17 . A method for treating or delaying the progression or onset of diabetes, diabetic retinopathy, diabetic neuropathy, diabetic nephropathy, wound healing, insulin resistance, hyperglycemia, hyperinsulinemia, Syndrome X, diabetic complications, elevated blood levels of free fatty acids or glycerol, hyperlipidemia, obesity, hypertriglyceridemia, atherosclerosis or hypertension, which comprises administering to a mammalian species in need of treatment a therapeutically effective amount of a compound of formula (I)  
     
       
         
         
             
             
         
       
       wherein:  
       n is 0, 1 or 2;  
       m is 0, 1 or 2;  
       the sum of n plus m is less then or equal to 2;  
       the dashed bonds forming a cyclopropyl ring when Y is CH;  
       X is hydrogen or CN;  
       Y is CH, CH 2 , CHF, CF 2 , O, S, SO, or SO 2    
       A is adamantyl which can be optionally substituted with from zero to six substituents each independently selected from OR 1 , NR 1 R 2 , alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, bicycloalkyl, bicycloalkylalkyl, alkylthioalkyl, arylalkylthioalkyl, cycloalkenyl, aryl, aralkyl, heteroaryl, heteroarylalkyl, cycloheteroalkyl and cycloheteroalkylalkyl, all optionally substituted through available carbon atoms with 1, 2, 3, 4 or 5 groups selected from hydrogen, halo, alkyl, polyhaloalkyl, alkoxy, haloalkoxy, polyhaloalkoxy, alkoxycarbonyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, polycycloalkyl, heteroarylamino, arylamino, cycloheteroalkyl, cycloheteroalkylalkyl, hydroxy, hydroxyalkyl, nitro, cyano, amino, substituted amino, alkylamino, dialkylamino, thiol, alkylthio, alkylcarbonyl, acyl, alkoxycarbonyl, aminocarbonyl, alkynylaminocarbonyl, alkylaminocarbonyl, alkenylaminocarbonyl, alkylcarbonyloxy, alkylcarbonylamino, arylcarbonylamino, alkylsulfonylamino, alkylaminocarbonylamino, alkoxycarbonylamino, alkylsulfonyl, aminosulfonyl, alkylsulfinyl, sulfonamido and sulfonyl;  
       R 1  and R 2  are each independently selected from hydrogen, alkyl, alkenyl, alkynyl, aryl and heteroaryl;  
       including pharmaceutically acceptable salts thereof, and prodrug esters thereof, and all stereoisomers thereof,  
       with the proviso that the compound of formula (I) is not selected from  
       
         
           
           
               
               
           
         
       
     
   
   
       18 . A method according to  claim 17  further comprising administering, concurrently or sequentially, a therapeutically effective amount of at least one additional therapeutic agent selected from the group consisting of an antidiabetic agent, an anti-obesity agent, a anti-hypertensive agent, an anti-atherosclerotic agent, an agent for inhibiting allograft rejection in transplantation and a lipid-lowering agent.  
   
   
       19 . (canceled)  
   
   
       20 . A method of inhibiting DPP-IV comprising administering a pharmaceutical composition comprising a compound of formula (I)  
     
       
         
         
             
             
         
       
       wherein:  
       n is 0, 1 or 2;  
       m is 0, 1 or 2;  
       the sum of n plus m is less then or equal to 2;  
       the dashed bonds forming a cyclopropyl ring when Y is CH;  
       X is hydrogen or CN;  
       Y is CH, CH 2 , CHF, CF 2 , O, S, SO, or SO 2    
       A is adamantyl which can be optionally substituted with from zero to six substituents each independently selected from OR 1 , NR 1 R 2 , alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, bicycloalkyl, bicycloalkylalkyl, alkylthioalkyl, arylalkylthioalkyl, cycloalkenyl, aryl, aralkyl, heteroaryl, heteroarylalkyl, cycloheteroalkyl and cycloheteroalkylalkyl, all optionally substituted through available carbon atoms with 1, 2, 3, 4 or 5 groups selected from hydrogen, halo, alkyl, polyhaloalkyl, alkoxy, haloalkoxy, polyhaloalkoxy, alkoxycarbonyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, polycycloalkyl, heteroarylamino, arylamino, cycloheteroalkyl, cycloheteroalkylalkyl, hydroxy, hydroxyalkyl, nitro, cyano, amino, substituted amino, alkylamino, dialkylamino, thiol, alkylthio, alkylcarbonyl, acyl, alkoxycarbonyl, aminocarbonyl, alkynylaminocarbonyl, alkylaminocarbonyl, alkenylaminocarbonyl, alkylcarbonyloxy, alkylcarbonylamino, arylcarbonylamino, alkylsulfonylamino, alkylaminocarbonylamino, alkoxycarbonylamino, alkylsulfonyl, aminosulfonyl, alkylsulfinyl, sulfonamido and sulfonyl;  
       R 1  and R 2  are each independently selected from hydrogen, alkyl, alkenyl, alkynyl, aryl and heteroaryl;  
       including pharmaceutically acceptable salts thereof, and prodrug esters thereof, and all stereoisomers thereof,  
       with the proviso that the compound of formula (I) is not selected from  
       
         
           
           
               
               
           
         
       
     
   
   
       21 . The method as defined in  claim 17  wherein the compound of formula (I) is selected from  
     
       
         
         
             
             
         
       
     
   
   
       22 . The method as defined in  claim 17  wherein the compound of formula (I) is selected from  
     
       
         
         
             
             
         
       
     
   
   
       23 . The method as defined in  claim 17  wherein the compound of formula (I) is selected from  
     
       
         
         
             
             
         
       
     
   
   
       24 . The method as defined in  claim 17  wherein the compound of formula (I) is selected from  
     
       
         
         
             
             
         
       
     
   
   
       25 . The method as defined in  claim 18  wherein the compound of formula (I) is selected from