Dihydropyrimidines and uses thereof

Abstract

This invention is directed to dihydropyrimidines which are selective antagonists for human α 1a receptors. This invention is also related to uses of these compounds for relaxing lower urinary tract tissue, treating benign prostatic hyperplasia and for the treatment of any disease where the antagonism of the α 1a receptor may be useful. The invention further provides a pharmaceutical composition comprising a therapeutically effective amount of the above-defined compounds and a pharmaceutically acceptable carrier.

What is claimed is:  
     
         1 . A compound having the structure:  
       
         
           
           
               
               
           
         
         wherein R 1  is —OCH 3  or OH;  
         wherein R, is —CH 2 OH, —CH 2 OCH 3 , or —COOH;  
         wherein R 1  and R 2  together form a 5-membered lactone ring;  
         wherein R 3  is selected from the group consisting of  
         —(CH 2 ) 3 OH,  
         
           
             
             
                 
                 
             
           
         
         provided that when R 1  is OH, R 3  cannot be  
         
           
             
             
                 
                 
             
           
         
         or a pharmaceutically acceptable salt thereof.  
       
     
     
         2 . The (−) enantiomer of the compound of  claim 1 .  
     
     
         3 . The (+) enantiomer of the compound of  claim 1 .  
     
     
         4 . The compound of  claim 1  having the structure:  
       
         
           
           
               
               
           
         
       
     
     
         5 . The compound of  claim 4  having the structure:  
       
         
           
           
               
               
           
         
       
     
     
         6 . The compound of  claim 4  having the structure:  
       
         
           
           
               
               
           
         
       
     
     
         7 . The compound of  claim 4  having the structure:  
       
         
           
           
               
               
           
         
       
     
     
         8 . The compound of  claim 4  having the structure:  
       
         
           
           
               
               
           
         
       
     
     
         9 . The compound of  claim 4  wherein R3 is selected from the group consisting of  
       
         
           
           
               
               
           
         
       
     
     
         10 . The compound of  claim 1  having the structure:  
       
         
           
           
               
               
           
         
       
     
     
         11 . The compound of  claim 10  having the structure:  
       
         
           
           
               
               
           
         
       
     
     
         12 . The compound of  claim 10  having the structure:  
       
         
           
           
               
               
           
         
       
     
     
         13 . The compound of  claim 10  having the structure:  
       
         
           
           
               
               
           
         
       
     
     
         14 . A compound having the structure:  
       
         
           
           
               
               
           
         
       
     
     
         15 . A pharmaceutical composition comprising a therapeutically effective amount of the compound of  claim 1 ,  6 ,  8 ,  9 ,  12 ,  13  or  14  and a pharmaceutically acceptable carrier.  
     
     
         16 . The pharmaceutical composition of  claim 15 , wherein the therapeutically effective amount is an amount from about 0.01 mg to about 500 mg.  
     
     
         17 . The pharmaceutical composition of  claim 16 , wherein the therapeutically effective amount is an amount from about 0.1 mg to about 60 mg.  
     
     
         18 . The pharmaceutical composition of  claim 17 , wherein the therapeutically effective amount is an amount from about 1 mg to about 30 mg.  
     
     
         19 . The pharmaceutical composition of  claim 15 , wherein the carrier is a liquid and the composition is a solution.  
     
     
         20 . The pharmaceutical composition of  claim 15 , wherein the carrier is a solid and the composition is a tablet.  
     
     
         21 . The pharmaceutical composition of  claim 15 , wherein the carrier is a gel and the composition is a suppository.  
     
     
         22 . A method of treating a subject suffering from benign prostatic hyperplasia which comprises administering to the subject an amount of the compound of  claim 1  or  14  effective to treat benign prostatic hyperplasia.  
     
     
         23 . A method of treating a subject suffering from benign prostatic hyperplasia which comprises administering to the subject an amount of the compound of  claim 1  or  14  in combination with a 5 alpha-reductase inhibitor effective to treat benign prostatic hyperplasia.  
     
     
         24 . The method of  claim 23 , wherein the 5-alpha reductase inhibitor is finasteride.  
     
     
         25 . A method of relaxing lower urinary tract tissue which comprises administering to the subject an amount of the compound of  claim 1  effective to relax lower urinary tract tissue.  
     
     
         26 . The method of  claim 25 , wherein the lower urinary tract tissue is urethral smooth muscle.  
     
     
         27 . A method of inhibiting contraction of prostatic tissue in a subject which comprises administering an amount of a compound according to  claim 1  or  14  effective to, inhibit contraction of prostatic tissue.  
     
     
         28 . A method of treating a disease which is susceptible to treatment by antagonism of the α 1A  receptor which comprises administering to the subject an amount of the compound of  claim 1  or  14  effective to treat the disease.  
     
     
         29 . A pharmaceutical composition comprising a therapeutically effective amount of the compound of  claim 1  or  14  in combination with therapeutically effective amount of finasteride and a pharmaceutically acceptable carrier.  
     
     
         30 . The pharmaceutical composition of  claim 29 , wherein the therapeutically effective amount of the compound is an amount from about 0.01 mg to about 500 mg and the therapeutically effective amount of the finasteride is about 5 mg.  
     
     
         31 . The pharmaceutical composition of  claim 29 , wherein the therapeutically effective amount of the compound is an amount from about 0.1 mg to about 60 mg and the therapeutically effective amount of the finasteride is about 5 mg.  
     
     
         32 . The pharmaceutical composition of  claim 29 , wherein the therapeutically effective amount of the compound is an amount from about 1 mg to about 30 mg and the therapeutically effective amount of the finasteride is about 5 mg.  
     
     
         33 . A process for making a pharmaceutical composition which comprises combining a therapeutically effective amount of a compound of  claim 1  or  14  and a pharmaceutically acceptable carrier.