8-Quinolinxanthine and 8-isoquinolinxanthine derivatives as PDE 5 inhibitors

Abstract

A compound of formula (I) R 1 is hydrogen or alkyl optionally substituted by hydroxy, alkoxy, or alkylthio, R 2 is hydrogen, alkyl, hydroxyalkyl, alkylcarbonyloxyalkyl, alkoxyalkyl, alkylthioalkyl, alkenyl, cycloalkylalkyl, heterocyclylalkyl, aralkyl in which the aryl ring thereof is optionally fused to a 5-membered heterocyclic group or is optionally substituted by one or more substituents selected from alkoxy, amino, alkylamino, dialkylamino, acylamino, halogen, hydroxy, aminosulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl, alkylsulfonylamino or dialkylaminosulfonylamino, R 3 is hydrogen or alkyl optionally substituted by hydroxy, alkoxy, or alkylthio, R 4 is hydrogen or alkyl, R 5 is a quinolinyl, isoquinolinyl or oxodihydroisoquinolinyl group optionally fused to a 5-membered heterocyclic group and optionally substituted by one or more substituents selected from halogen, cyano, hydroxy, alkyl, hydroxyalkyl, alkoxyalkyl, alkylthioalkyl, alkoxy, alkylthio, alkenyl, alkoxycarbonyl, alkynyl, carboxyl, acyl, a group of formula —N(R 6 )R 7 , aryl optionally substituted by one or more substituents selected from halogen or alkoxy, or heteroaryl having 5 or 6 ring atoms attached through a ring carbon atom to the indicated carbon atom, and R 6 and R 7 are each independently hydrogen or alkyl optionally substituted by hydroxy or alkoxy or one of R 6 and R 7 is hydrogen and the other is acyl, or R 6 and R 7 together with the nitrogen atom to which they are attached denote a 5- or 6-membered heterocyclyl group.

1 - 12 . (canceled)  
     
     
         13 . A method of treating stable, unstable and variant (Prinzmetal) angina, hypertension, pulmonary hypertension, congestive heart failure, atherosclerosis, conditions of reduced blood vessel patency, or peripheral vascular disease comprising administering a therapeutically effective amount of a pharmaceutical composition comprising a compound of formula  
       
         
           
           
               
               
           
         
       
       in free or salt form, wherein 
 R 1  is hydrogen or alkyl optionally substituted by hydroxy, alkoxy, or alkylthio,  
 R 2  is hydrogen, alkyl, hydroxyalkyl, alkylcarbonyloxyalkyl, alkoxyalkyl, alkylthioalkyl, alkenyl, cycloalkylalkyl, heterocyclylalkyl, aralkyl in which the aryl ring thereof is optionally fused to a 5-membered heterocyclic group or is optionally substituted by one or more substituents selected from alkoxy, amino, alkylamino, dialkylamino, acylamino, halogen, hydroxy, aminosulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl, alkylsulfonylamino or dialkylaminosulfonylamino,  
 R 3  is hydrogen or alkyl optionally substituted by hydroxy, alkoxy, or alkylthio,  
 R 4  is hydrogen or alkyl,  
 R 5  is a quinolinyl, isoquinolinyl or oxodihydroisoquinolinyl group optionally fused to a 5-membered heterocyclic group and optionally substituted by one or more substituents selected from halogen, cyano, hydroxy, alkyl, hydroxyalkyl, alkoxyalkyl, alkylthioalkyl, alkoxy, alkylthio, alkenyl, alkoxycarbonyl, alkynyl, carboxyl, acyl, a group of formula —N(R 5 )R 7 , aryl optionally substituted by one or more substituents selected from halogen or alkoxy, or heteroaryl having 5 or 6 ring atoms attached through a ring carbon atom to the indicated carbon atom, and  
 R 6  and R 7  are each independently hydrogen or alkyl optionally substituted by hydroxy or alkoxy or one of R 6  and R 7  is hydrogen and the other is acyl, or R 6  and R 7  together with the nitrogen atom to which they are attached denote a 5- or 6-membered heterocyclyl group.  
 
     
     
         14 . The method of  claim 13  wherein the PDE 5 inhibitor is 3-isobutyl-8-(6-methoxy-isoquinolin-4-ylmethyl)-1-methyl-3,7-dihydro-purine-2,6-dione.  
     
     
         15 . The method of  claim 13  wherein a condition of reduced blood vessel patency is post-percutaneous transluminal coronary angioplasty.