R-isomers of nonnucleoside inhibitors

Abstract

Novel chiral derivitaves of non-nucleoside inhibitors (NNI), particularly R-isomers of halopyridyl and thiazoyl thiourea compounds are provided as potent inhibitors of reverse transcriptase (RT), and particularly of retroviral RT, most particularly HIV RT. The stereospecific compounds and compositions of the invention inhibit replication of retrovirus, particularly human immunodeficiency virus-1 (HIV-1) and drug resistant strains.

We claim:  
     
         1 . A compound of formula I:  
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof,  
       where 
 X is S or O;  
 R 1  is a carbocyclic or hetereocyclic ring;  
 R 2  is a carbocyclic ring; and  
 R 3 R 3  is aryl, heteroaryl, alkyl, phenyl, naphthyl, carbocyclic or heterocyclic ring, or halo.  
 
     
     
         2 . The compound of  claim 1 , wherein R 1  is a 5 or 6 membered heterocyclic ring.  
     
     
         3 . The compound of  claim 1 , wherein R 1  is a N-containing heterocyclic ring.  
     
     
         4 . The compound of  claim 1 , wherein R 1  is a S-containing heterocyclic ring.  
     
     
         5 . The compound of  claim 1 , wherein R 1  is an unsaturated carbocyclic or heterocyclic ring.  
     
     
         6 . The compound of  claim 1 , wherein R 1  is, phenyl, pyridyl, pyrimidinyl, pyridazinyl, thiazolyl, isothiazolyl, tetrazolyl, napthal, imidazolyl, pyrrole, cyclohexenyl, napthal, indolyl, thienyl, piperazinyl, morpholyl, furyl, adamantyl, or piperonyl.  
     
     
         7 . The compound of  claim 1 , wherein R 1  is pyridyl.  
     
     
         8 . The compound of  claim 1 , wherein R 1  is halopyridyl.  
     
     
         9 . The compound of  claim 1 , wherein R 1  is thiazolyl.  
     
     
         10 . The compound of  claim 1 , wherein R 1  is halothiazolyl.  
     
     
         11 . The compound of  claim 1 , wherein R 2  is a five or six-membered, saturated or unsaturated ring.  
     
     
         12 . The compound of  claim 1 , wherein R 2  is phenyl, cyclohexyl, cyclohexenyl, or cyclopentyl.  
     
     
         13 . The compound of  claim 1 , wherein R 2  is phenyl.  
     
     
         14 . The compound of  claim 1 , wherein R 2  is cyclohexyl.  
     
     
         15 . The compound of  claim 1 , wherein R 3  is halo.  
     
     
         16 . The compound of  claim 1 , wherein R 3  is CH 3 , CH 3  CH 2 , or CH (CH 3 ) 2 .  
     
     
         17 . The compound of  claim 1 , wherein R 3  is phenyl or naphthyl.  
     
     
         18 . The compound of  claim 1 , wherein R 3  is a carbocyclic or heterocyclic ring.  
     
     
         19 . The compound of  claim 1 , wherein R 3  is a carbocyclic or heterocyclic ring, saturated or unsaturated, and optionally substituted with one or more electron withdrawing groups.  
     
     
         20 . The compound of  claim 1 , wherein R 3  is one of the following:  
       
         
           
           
               
               
           
         
       
     
     
         21 . The compound of  claim 1 , wherein R 3  is CH 3 .  
     
     
         22 . A compound selected from: 
 N-[1-(1-(1R)-cyclohexylethyl)]-N-[2-(5-bromopyridyl)] thiourea (PHI-509 R );    N-[1-(1-(1S)-N-[1-(1-(1R)-cyclohexylethyl)]-N-[2-(5-chloropyridyl)]thiourea (PHI-510 R );    N-[1-(1R)-(1-α-methylbenzyl]-N′-[2-(5-bromopyridyl)]thiourea (PHI-511 R );    N-[1-(1-(1R)-α-methylbenzyl]-N′-[2-(5-chloropyridiyl)]thiourea (PHI-512 R );    N-[1-(1-(1R)-cyclohexyl)ethyl]-N′-[2-(thiazolyl)]thiourea (PHI-513 R ); and    a pharmaceutically acceptable salt or ester thereof.    
     
     
         23 . A method for inhibiting the activity of retroviral reverse transcriptase, comprising contacting the retrovirus with a compound of  claim 1 .  
     
     
         24 . A method for inhibiting replication of a retrovirus, comprising contacting the retrovirus with a compound of  claim 1 .  
     
     
         25 . A method for treating a subject suffering from retrovviral infection, comprising administering to the subject an effective anti-retroviral amount of a compound of  claim 1 .  
     
     
         26 . The method of  claim 25 , wherein said retrovirus is human immunodeficiency virus (HIV).  
     
     
         27 . The method of  claim 26 , wherein said retrovirus is HIV-1.  
     
     
         28 . The method of  claim 26 , wheren said retrovirus is an NNI-resistant HIV strain.  
     
     
         29 . A composition comprising a compound of  claim 1  and a pharmaceutically acceptable carrier.  
     
     
         30 . The composition of  claim 29 , wherein at least 50% of the compound of  claim 1  is the R-isomer of the compound.  
     
     
         31 . A method for inhibiting replication of a retrovirus comprising administering a composition consisting essentially of the R-isomer of a compound of  claim 1.