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 - 6 . (canceled)  
   
   
       7 . A pharmaceutical combination 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 throuqh 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  
                     
 and at least one therapeutic agent selected from the group consisting of an antidiabetic agent, an anti-obesity agent, a anti-hypertensive agent, an anti-atherosclerotic agent and a lipid-lowering agent.  
 
   
   
       8 . The pharmaceutical combination as defined in  claim 7  wherein the therapeutic agent is an antidiabetic agent.  
   
   
       9 . The combination as defined in  claim 8  wherein the antidiabetic agent is at least one agent selected from the group consisting of a biguanide, a sulfonyl urea, a glucosidase inhibitor, a PPAR gamma agonist, a PPAR alpha/gamma dual agonist, an aP2 inhibitor, a SGLT2 inhibitor, an insulin sensitizer, a glucagon-like peptide-I (GLP-I), insulin and a meglitinide.  
   
   
       10 . The combination as defined in  claim 9  wherein the antidiabetic agent is at least one agent selected from the group consisting of mefformin, glyburide, glimepiride, glipyride, glipizide, chlorpropamide, gliclazide, acarbose, miglitol, pioglitazone, troglitazone, rosiglitazone, insulin, isaglitazone, repaglinide muraglitazar, peliglitizar and nateglinide.  
   
   
       11 . The combination as defined in  claim 8  wherein the compound is present in a weight ratio to the antidiabetic agent in the range of about 0.01 to about 300:1.  
   
   
       12 . The combination as defined in  claim 7  wherein the anti-obesity agent is at least one agent selected from the group consisting of a beta 3 adrenergic agonist, a lipase inhibitor, a serotonin (and dopamine) reuptake inhibitor, a thyroid receptor beta compound and an anorectic agent.  
   
   
       13 . The combination as defined in  claim 12  wherein the anti-obesity agent is at least one agent selected from the group consisting of orlistat, sibutramine, topiramate, axokine, dexamphetamine, phentermine, phenylpropanolamine and mazindol.  
   
   
       14 . The combination as defined in  claim 7  wherein the lipid lowering agent is at least one agent selected from the group consisting of an MTP inhibitor, cholesterol ester transfer protein, an HMG CoA reductase inhibitor, a squalene synthetase inhibitor, a fibric acid derivative, an upregulator of LDL receptor activity, a lipoxygenase inhibitor, or an ACAT inhibitor.  
   
   
       15 . The combination as defined in  claim 14  wherein the lipid lowering agent is at least one agent selected from the group consisting of pravastatin, lovastatin, simvastatin, atorvastatin, cerivastatin, fluvastatin, nisvastatin, visastatin, fenofibrate, gemfibrozil, clofibrate and avasimibe.  
   
   
       16 . The combination as defined in  claim 14  wherein the compound as defined in claim  1  is present in a weight ratio to the lipid-lowering agent in the range of about 0.01 to about 100:1.  
   
   
       17 - 20 . (canceled)  
   
   
       21 . The pharmaceutical composition as defined in  claim 7  wherein the compound of formula (I) is selected from  
     
       
         
         
             
             
         
       
     
   
   
       22 . The pharmaceutical composition as defined in  claim 7  wherein the compound of formula (I) is selected from  
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
   
   
       23 . The pharmaceutical composition as defined in  claim 7  wherein the compound of formula (I) is selected from  
     
       
         
         
             
             
         
       
     
   
   
       24 . The pharmaceutical composition as defined in  claim 7  wherein the compound of formula (I) is selected from