Arylsubstituted piperazines useful in the treatment of benign prostatic hyperplasia

Abstract

This invention relates to a series of arylsubstituted piperazines, of Formula I pharmaceutical compositions containing them and intermediates used in their manufacture. The compounds of the invention selectively inhibit binding to the α-1a adrenergic receptor, a receptor which has been implicated in benign prostatic hyperplasia. As such the compounds are potentially useful in the treatment of this and other disease.

What is claimed is:  
     
         1 . A compound of Formula I  
       
         
           
           
               
               
           
         
       
       wherein: 
 A is (CH 2 ) n  where n is 1-6;  
 R 1  is C 1-6 alkyl, phenyl, 
 substituted phenyl 
 where the phenyl substituents are independently selected from one or more of the group consisting of C 1-5 alkyl, C 1-5 alkoxy and halogen, phenylC 1-5 alkyl, or  
 
 substituted phenylC 1-5 alkyl 
 where the phenyl substituents are independently selected from one or more of the group consisting of C 1-5 alkyl, C 1-5 alkoxy and halogen;  
 
 
 R 2  is hydrogen, C 1-5 alkyl, C 1-5 alkenyl, C 1-5  alkynyl, phenylC 1-5 alkyl, 
 or substituted phenylC 1-5 alkyl  
 where the phenyl substituents are independently selected from one or more of the group consisting of C 1-5 alkyl, C 1-5 alkoxy and halogen;  
 
 E is  
                     
 where:  
 m is 1-5;  
 R 3  is hydrogen. C 1-6 alkyl or oxygen, 
 where if R 3  is oxygen, the hashed line represents a bond and if R 3  is C 1-6 alkyl the hashed line is absent;  
 
 R 4  oxygen, hydrogen, C 1-5 alkyl, formyl, carboxy, 
 C 1-5 alkylcarbonyl, C 1-5 alkoxycarbonyl, phenylC 1-5 alkoxy,  
 substituted phenylC 1-5 alkoxy 
 where the phenyl substituents are independently selected from one or more of the group consisting of C 1-5 alkyl, C 1-5 alkoxy and halogen, amido, and  
 
 substituted amido 
 where the nitrogen substituents are independently selected from one or more of the group consisting or hydrogen, C 1-5 alkyl, C 1-5 alkoxy and hydroxy, 
 where if R 4  is oxygen, the hashed line represents a bond and if R 4  is any other substituent, the hashed line is absent;  
 
 
 
 R 5  is hydrogen, C 1-5 alkyl or taken together with R 6  to form a cyclohexane, cyclopentane or cyclopropane ring;  
 R 6  is hydrogen, C 1-5 alkyl or taken together with R 5  to form a cyclohexane, cyclopentane or cyclopropane ring;  
 and pharmaceutically acceptable salts thereof.  
 
     
     
         2 . The compounds of  claim 1  where R 1  is C 1-6 alkyl, n is 2-4, and R 2  is hydrogen or C 1-6 alkyl, C 1-6 alkenyl.  
     
     
         3 . The compounds of  claim 2   
       
         
           
           
               
               
           
         
       
     
     
         4 . The compounds of  claim 2  where R 3  is oxygen and R 4  is hydrogen, C 1-5 alkoxycarbonyl, or oxygen.  
     
     
         5 . The compounds of  claim 4  where R 4  is hydrogen and E is  
       
         
           
           
               
               
           
         
       
     
     
         6 . The compounds of  claim 7  where m is 2 to 5.  
     
     
         7 . A compound and pharmaceutically acceptable salts thereof selected from the group consisting of N-[ethyl-2-(2-iso-propyloxyphenyl)piperazin-4-yl)]-[1′-(2-oxy-piperdinyl)]acetamidemide, N-[ethyl-2-(2-iso-propyloxyphenyl)piperazin-4-yl)]-N-methyl-[1′-(2-oxy-piperdinyl)]acetamidemide, and N-[propyl-3-(2-iso-propyloxyphenyl)piperazin-4-yl)]-[1′-(2-oxy-piperdinyl)]acetamidemide.  
     
     
         8 . A compound N-[ethyl-2-(2-iso-propyloxyphenyl)piperazin-4-yl)]-[1′-(2-oxy-piperdinyl)]acetamidemide and pharmaceutically acceptable salts thereof.  
     
     
         9 . A pharmaceutical composition comprising a compound according to  claim 1  and a pharmaceutically acceptable carrier or diluent.  
     
     
         10 . A pharmaceutical composition comprising a compound according to  claim 6  and a pharmaceutically acceptable carrier or diluent.  
     
     
         11 . A pharmaceutical composition comprising a compound according to  claim 8  and a pharmaceutically acceptable carrier or diluent.  
     
     
         12 . A method of treating a disease mediated by the α-1 a  adrenergic receptor comprising administering a compound of  claim 1  to a patient at an effective dose.  
     
     
         13 . A method of treating a disease mediated by the α-1 a  adrenergic receptor comprising administering a composition of  claim 6  to a patient at an effective dose.  
     
     
         14 . A method of treating a disease mediated by the α-1 a  adrenergic receptor comprising administering a composition of  claim 8  to a patient at an effective dose.  
     
     
         15 . The method of claim  18  where the compound is administered orally and an effective dose is 0.01-100 mg/kg daily.  
     
     
         21 . The method of  claim 15  where the dose is 0.05-1.0 mg/kg daily.  
     
     
         22 . A method of treating benign prostatic hyperplasia comprising administering an effective dose of a compound of Formula I.  
     
     
         23 . A compound of Formula II  
       
         
           
           
               
               
           
         
       
       wherein: 
 A is (CH 2 ) n  where n is 1-6;  
 R 1  is C 2-6 alkyl, phenyl, 
 substituted phenyl 
 where the phenyl substituents are independently selected from one or more of the group consisting of C 1-5 alkyl, C 1-5 alkoxy and halogen, phenylC 1-5 alkyl, or  
 
 substituted phenylC 1-5 alkyl 
 where the phenyl substituents are independently selected from one or more of the group consisting of C 1-5 alkyl, C 1-5 alkoxy and halogen;  
 
 
 R 7  is hydrogen, BOC or CBZ.  
 
     
     
         24 . The compounds of  claim 23  where n is 2-4 and R 1  is C 2-6 alkyl.  
     
     
         25 . The compounds of  claim 25  where R 7  is hydrogen.  
     
     
         26 . A compound selected from the group consisting of 1-(2-aminoethyl)-4-(2-2-iso-propyloxyphenyl)piperazine, 1-(3-aminopropyl)4-(2-2-iso-propyloxyphenyl)piperazine, and 1-(4-aminobutyl)-4-(2-2-iso-propyloxyphenyl)piperazine.  
     
     
         27 . A compound 1-(2-aminoethyl)-4-(2-2-iso-propyloxyphenyl)piperazine.  
     
     
         28 . A compound of Formula III  
       
         
           
           
               
               
           
         
       
       wherein: 
 m is 1-5.  
 
     
     
         29 . The compounds of  claim 28  where m is 2-5.  
     
     
         30 . A compound, 1-t-butoxycarbonylmethyl-2-piperidone.