Novel phthalimido arylpiperazines useful in the treatment of benign prostatic hyperplasia

Abstract

This invention relates to a series of heterocyclic substituted 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-1 a adrenergic receptor, a receptor which has been implicated in benign prostatic hyperplasia. As such the compounds are potentially useful in the treatment of this disease.

What is claimed is:  
     
         1 . A compound of Formula I  
       
         
           
           
               
               
           
         
       
       wherein: 
 R 1  is hydrogen, halogen, C 1-5 alkoxy, hydroxyl, or C 1-5 alkyl;  
 R 2  is C 1-6 alkyl, substituted C 1-6 alkyl 
 where the alkyl substituents are independently selected from one or more halogens,  
 
  phenyl,  
  substituted phenyl 
 where the phenyl substituents are independently selected from one or more members of the group consisting of C 1-5 alkyl, C 1-5 alkoxy, and trihaloC 1-5 alkyl,  
 
  phenylC 1-5 alkyl, or  
  substituted phenylC 1-5 alkyl 
 where the phenyl substituents are independently selected from one or more members of the group consisting of C 1-5 alkyl, halogen, C 1-5 alkoxy, and trihaloC 1-5 alkyl;  
 
 R 3  is hydrogen, hydroxy or C 1-5 alkoxy if the hashed line is absent or is oxygen if the hashed line is present;  
 R 4  is hydrogen, C 1-5 alkyl, phenyl 1-5 alkyl or substituted phenylC 1-5 alkyl 
 where the phenyl substitutents are independently selected from one or more members of the group consisting of C 1-5 alkyl, C 1-5 alkoxy, and trihaloC 1-5 alkyl;  
 
 R 5  is hydrogen, halogen, hydroxy, C 1-8 alkyl, substituted C 1-8 alkyl 
 where the alkyl substitutents are independently selected from one or more halogens,  
 
  C 1-5 alkoxy, amino, C 1-5 alkylamino, diC 1-5 alkylamino, C 1-5 alkylcarbonyl, C 1-5 alkoxycarbonyl, nitrile, or nitro;  
 R 6  is hydrogen, halogen, hydroxy, C 1-8 alkyl, substituted C 1-8 alkyl 
 where the alkyl substitutents are independently selected from one or more halogens,  
 
  C 1-5 alkoxy, amino, C 1-5 alkylamino, diC 1-5 alkylamino, C 1-5 alkylcarbonyl, C 1-5 alkoxycarbonyl, or nitro;  
 R 7  is hydrogen, halogen, hydroxy, C 1-8 alkyl, substituted C 1-8 alkyl 
 where the alkyl substitutents are independently selected from one or more halogens,  
 
  C 1-5 alkoxy, amino, C 1-5 alkylamino, diC 1-5 alkylamino, C 1-5 -alkylcarbonyl, C 1-5 alkoxycarbonyl, or nitro;  
 A is nitrogen or carbon;  
 B is nitrogen or carbon;  
 E is nitrogen or carbon;  
 with the proviso that only one of A, B, or E is nitrogen;  
 pharmaceutically acceptable salts thereof; and  
 stereoisomers, racemic mixtures, as well as enantiomers thereof.  
 
     
     
         2 . The compound of  claim 1  wherein 
 R 1  is hydrogen, halogen or hydroxy,  
 R 2  is C 1-6 alkyl, phenyl, substituted phenyl, phenyl C 1-6 alkyl or hydrogen,  
 R 3  is hydroxy or hydrogen,  
 R 4  is hydrogen or C 1-5 alkyl,  
 R 5  is hydrogen, halogen, hydroxy, C 1-8 alkyl, C 1-5 alkoxy, amino, diC 1-5 alkylamino, C 1-5 alkylcarbonyl, or nitrile,  
 R 6  is hydrogen, halogen,hydroxy, C 1-8 -alkyl, C 1-5 alkoxy, amino, diC 1-5 alkylamino, C 1-5 alkylcarbonyl, or nitrile,  
 R 7  is hydrogen, halogen,hydroxy, C 1-8 alkyl, C 1-5 alkoxy, amino, diC 1-5 alkylamino, C 1-5 alkylcarbonyl, or nitrile, and  
 A, B, and E are carbon.  
 
     
     
         3 . The compound of  claim 1  wherein 
 R 1  is hydrogen,  
 R 2  is C 1-6 alkyl, phenyl or substituted phenyl,  
 R 3  is hydroxy or hydrogen,  
 R 4  is hydrogen,  
 R 5  is hydrogen, halogen, hydroxy, C 1-8 alkyl, C 1-5 alkoxy,  
 C 1-5 alkylcarbonyl, or diC 1-5 alkylamino,  
 R 6  is hydrogen, halogen, hydroxy, C 1-8 alkyl, C 1-5 alkoxy,  
 C 1-5 alkylcarbonyl, or diC 1-5 alkylamino,  
 R 7  is hydrogen, halogen, hydroxy, C 1-8 alkyl, C 1-5 alkoxy,  
 C 1-5 alkylcarbonyl, or diC 1-5 alkylamino, and  
 A, B, and E are carbon.  
 
     
     
         4 . The compound of  claim 1  wherein 
 R 1  is hydrogen,  
 R 2  is C 1-8 alkyl, substituted phenyl,  
 R 3  is hydroxy,  
 R 4 is hydrogen,  
 R 5  is hydrogen, halogen, hydroxy, C 1-8 alkyl, C 1-5 alkoxy,  
 C 1-5 alkylcarbonyl, or diC 1-5 alkylamino,  
 R 6  is hydrogen, halogen, hydroxy, C 1-8 alkyl, C 1-5 alkoxy,  
 C 1-5 alkylcarbonyl, or diC 1-5 alkylamino,  
 R 7  is hydrogen, halogen, hydroxy, C 1-8 alkyl, C 1-5 alkoxy,  
 C 1-5 alkylcarbonyl, or diC 1-5 alkylamino, and  
 A, B, and E are carbon.  
 
     
     
         5 . The compound of  claim 1  wherein R 1  is hydrogen, R 2  is isopropyl, R 3  is hydroxy, R 4  is hydrogen, R 5  is 4-dimethylamino, and R 6  and R 7  are hydrogen.  
     
     
         6 . The compound of  claim 1  wherein R 1  is hydrogen, R 2  is isopropyl, R 3  is hydrogen, R 4  is hydrogen, R 5  is 4-methyl, and R 6  and R 7  are hydrogen.  
     
     
         7 . The compound of  claim 1  wherein R 3  is hydroxy and R 5  is amino, C 1-5 alkylamino or diC 1-5 alkylamino.  
     
     
         8 . The compound of  claim 1  selected from the group consisting of 
 2-[4-(fluoro)phenyl]-2,3-dihydro-N-[2-hydroxy-3-[4-[2-(1-methylethoxy)phenyl]-1-piperazinyl]propyl]-1,3-dioxo-1H-isoindole-5-carboxamide;  
 2-[3-fluorophenyl]-2,3-dihydro-N-[2-hydroxy-3-[4-[2-(1-methylethoxy)phenyl]-1-piperazinyl]propyl]-1,3-dioxo-1H-isoindole-5-carboxamide;  
 2-[4-(dimethylamino)phenyl]-2,3-dihydro-N-[2-hydroxy-3-[4-[2-(1-methylethoxy)phenyl]-1-piperazinyl]propyl]-1,3-dioxo-1H-isoindole-5-carboxamide;  
 2-[4-methylphenyl]-2,3-dihydro-N-[2-hydroxy-3-[4-[2-(1-methylethoxy)phenyl]-1-piperazinyl]propyl]-1,3-dioxo-1H-isoindole-5-carboxamide;  
 2-[3,4,5-trimethoxyphenyl]-2,3-dihydro-N-[2-hydroxy-3-[4-[2-(1-methylethoxy)phenyl]-1-piperazinyl]propyl]-1,3-dioxo-1H-isoindole-5-carboxamide;  
 2-[4-chlorophenyl]-2,3-dihydro-N-[2-hydroxy-3-[4-[2-(1-methylethoxy)phenyl]-1-piperazinylpropyl]-1,3-dioxo-1H-isoindole-5-carboxamide;  
 2-[4-hydroxyphenyl]-2,3-dihydro-N-[2-hydroxy-3-[4-[2-(1-methylethoxy)phenyl]-1-piperazinyl]propyl]-1,3-dioxo-1H-isoindole-5-carboxamide;  
 2-[5-methoxyphenyl]-2,3-dihydro-N-[2-hydroxy-3-[4-[2-(1-methylethoxy)phenyl]-1-piperazinyl]propyl]-1,3-dioxo-1H-isoindole-5-carboxamide; and  
 2-[4-ethylphenyl]-2,3-dihydro-N-[2-hydroxy-3-[4-[2-(1-methylethoxy)phenyl]-1-piperazinyl]propyl]-1,3-dioxo-1H-isoindole-5-carboxamide.  
 
     
     
         9 . The compound of  claim 8  wherein the stereochemistry of the chiral carbon is ‘S’.  
     
     
         10 . The compounds of  claim 4  wherein the stereochemistry of the chiral carbon at R 3  is ‘S’.  
     
     
         11 . The compound of  claim 1 , (S)-2-[4-(dimethylamino)phenyl]-2,3-dihydro-N-[2-hydroxy-3-[4-[2-(1-methylethoxy)phenyl]-1-piperazinyl]propyl]-1,3-dioxo-1H-isoindole-5-carboxamide.  
     
     
         12 . The compound of  claim 1  selected from the group consisting of 
 2-[4-(fluoro)phenyl]-2,3-dihydro-N-[3-[4-[2-(1-methylethoxy)phenyl]-1-piperazinyl]propyl]-1,3-dioxo-1H-isoindole-5-carboxamide;  
 2-[3-fluorophenyl]-2,3-dihydro-N-[3-[4-[2-(1-methylethoxy)phenyl]-1-piperazinyl]propyl]-1,3-dioxo-1H-isoindole-5-carboxamide;  
 2-[4-(dimethylamino)phenyl]-2,3-dihydro-N-[3-[4-[2-(1-methylethoxy)phenyl]-1-piperazinyl]propyl]-1,3-dioxo-1H-isoindole-5-carboxamide;  
 2-[4-methylphenyl]-2,3-dihydro-N-[3-[4-[2-(1-methylethoxy)phenyl]-1-piperazinyl]propyl]-1,3-dioxo-1H-isoindole-5-carboxamide;  
 2-[3,4,5-trimethoxyphenyl]-2,3-dihydro-N-[3-[4-[2-(1-methylethoxy)phenyl]-1-piperazinyl]propyl]-1,3-dioxo-1H-isoindole-5-carboxamide;  
 2-[4-chlorophenyl]-2,3-dihydro-N-[3-[4-[2-(1-methylethoxy)phenyl]-1-piperazinyllpropyl]-1,3-dioxo-1H-isoindole-5-carboxamide;  
 2-[4-hydroxyphenyl]-2,3-dihydro-N-[3-[4-[2-(1-methylethoxy)phenyl]-1-piperazinyl]propyl]-1,3-dioxo-1H-isoindole-5-carboxamide;  
 2-[5-methoxyphenyl]-2,3-dihydro-N-[3-[4-[2-(-methylethoxy)phenyl]-1-piperazinyl]propyl]-1,3-dioxo-1H-isoindole-5-carboxamide; and  
 2-[4-ethylphenyl]-2,3-dihydro-N-[3-[4-[2-(1-methylethoxy)phenyl]-1-piperazinyl]propyl]-1,3-dioxo-1H-isoindole-5-carboxamide.  
 
     
     
         13 . A method of treating benign prostatic hyperplasia consisting of administering an effective dose of a compound of Formula I to a mammal.  
     
     
         14 . The method of  claim 13  wherein the effective dose is about 0.1 to about 25.0 mg/kg.  
     
     
         15 . A method of treating diseases associated with the α1 a  adrenergic receptor consisting of administering an effective dose of a compound of Formula I to a mammal.  
     
     
         16 . The method of  claim 15  wherein the effective does is about 0.1 to about 25.0 mg/kg.  
     
     
         17 . A pharmaceutical composition containing an effective dose of a compound of Formula I.  
     
     
         18 . A pharmaceutical composition of  claim 17  wherein the effective dose of a compound of Formula I is about 0.01 to about 25.0 mg/kg.  
     
     
         19 . A pharmaceutical composition of  claim 17  wherein the effective dose of a compound of Formula I is about 0.01 to about 1.0 mg/kg.  
     
     
         20 . A compound of Formula II  
       
         
           
           
               
               
           
         
       
       wherein 
 R 8  is hydrogen, halogen, C 1-5 alkoxy, hydroxyl, or C 1-5 alkyl;  
 R 9  is C 1-6 alkyl, substituted C 1-6 alkyl 
 where the alkyl substituents are independently selected from one or more halogens,  
 
  phenyl,  
  substituted phenyl 
 where the phenyl substituents are independently selected from one or more members of the group consisting of C 1-5 alkyl, C 1-5 alkoxy, and trihaloC 1-5 alkyl,  
 
  phenylC 1-5 alkyl, or  
  substituted phenylC 1-5 alkyl 
 where the phenyl substituents are independently selected from one or more members of the group consisting of C 1-5 alkyl, halogen, C 1-5 alkoxy, and trihaloC 1-5 alkyl;  
 
 R 10  is hydrogen, C 1-5 alkoxycarbonyl, phenylC 1-5 alkoxycarbonyl, or allyloxycarbonyl;  
 R 11  is hydrogen, phenylC 1-5 alkyl, or substituted phenylC 1-5 alkyl; 
 where the phenyl substituents are independently selected from one or more members of the group consisting of C 1-5 alkyl, halogen, C 1-5 alkoxy, and nitro;  
 
 
     
     
         21 . The compound of  claim 20  where R 8  is hydrogen or halogen, R 9  is C 1-6 alkyl, phenyl or substituted phenyl, R 10  is hydrogen or C 1-5 alkoxycarbonyl, and R 11  is hydrogen, phenylC 1-5 alkyl or C 1-5 alkoxy substituted phenylC 1-5 alkyl .  
     
     
         22 . The compound of  claim 20  wherein R 8  is hydrogen, R 9  is isopropyl, R 10  is C 1-5 alkoxycarbonyl, and R 11  is phenylC 1-5 alkyl.  
     
     
         23 . The compound of  claim 20  wherein R 8  is hydrogen, R 9  is isopropyl, R 10  is t-butoxycarbonyl, and R 11  is benzyl.  
     
     
         24 . The compound of  claim 20  wherein R 8  is hydrogen, R 9  is isopropyl, R 10  is hydrogen, and R 11  is benzyl.  
     
     
         25 . The compound of  claim 20  wherein R 8  is hydrogen, R 9  is isopropyl, R 10  is hydrogen, and R 11  is hydrogen.  
     
     
         26 . A compound of Formula III  
       
         
           
           
               
               
           
         
       
       wherein 
 R 10  is C 1-5 alkoxycarbonyl, phenylC 1-5 alkoxycarbonyl, or allyloxycarbonyl;  
 R 11  is phenylC 1-5 -alkyl, or substituted phenylC 1-5 alkyl 
 where the phenyl substituents are independently selected from one or more members of the group consisting of C 1-5 alkyl, halogen, C 1-5 alkoxy, and nitro;  
 
 R 12  is halogen, hydroxyl, mesyl, or tosyl.  
 
     
     
         27 . The compound of  claim 26  wherein R 10  is t-butoxycarbonyl and R 11  is benzyl.  
     
     
         28 . The compound of  claim 26  wherein R 12  is chloro.  
     
     
         29 . Reacting a compound of Formula III  
       
         
           
           
               
               
           
         
       
       wherein 
 R 10  is C 1-5 alkoxycarbonyl, phenylC 1-5 alkoxycarbonyl, or allyloxycarbonyl;  
 R 11  is phenylC 1-5 alkyl, or substituted phenylC 1-5 alkyl 
 where the phenyl substituents are independently selected from one or more members of the group consisting of C 1-5 alkyl, halogen, C 1-5 alkoxy, and nitro;  
 
 R 12  is halogen, mesyl or tosyl.  
 with a piperazine derivative of Formula IV  
                     
 wherein  
 R 8  is hydrogen, halogen, C 1-5 alkoxy, hydroxyl, or Calkyl;  
 R 9  is C 1-6 alkyl, substituted C 1-6 alkyl; 
 where the alkyl substituents are independently selected from one or more halogens,  
 
  phenyl,  
  substituted phenyl 
 where the phenyl substituents are independently selected from one or more members of the group consisting of C 1-5 alkyl, C 1-5 alkoxy, and trihaloC 1-5 alkyl,  
 
  phenylC 1-5 alkyl, or  
  substituted phenylC 1-5 alkyl 
 where the phenyl substituents are independently selected from one or more members of the group consisting of C 1-5 alkyl, halogen, C 1-5 alkoxy, and trihaloC 1-5 alkyl;  
 in the presence of a basic reagent to produce a compound for Formula II  
                     
 wherein  
 
 R 8  is hydrogen, halogen, C 1-5 alkoxy, hydroxyl, or C 1-5 alkyl;  
 R 9  is C 1-6 alkyl, substituted C 1-6 alkyl 
 where the alkyl substituents are independently selected from one or more halogens,  
 
  phenyl,  
  substituted phenyl 
 where the phenyl substituents are independently selected from one or more members of the group consisting of C 1-5 alkyl, C 1-5 alkoxy, and trihaloC 1-5 alkyl,  
 
 phenylC 1-5 alkyl, or  
 substituted phenylC 1-5 alkyl 
 where the phenyl substituents are independently selected from one or more members of the group consisting of C 1-5 alkyl, halogen, C 1-5 alkoxy, and trihaloC 1-5 alkyl;  
 
 R 10  is C 1-5 alkoxycarbony, phenylC 1-5 alkoxycarbonyl, or allyloxycarbonyl;  
 R 11  is phenylC 1-5 alkyl, or substituted phenylC 1-5 alkyl 
 where the phenyl substituents are independently selected from one or more members of the group consisting of C 1-5 alkyl, halogen, C 1-5 alkoxy, and nitro;  
 
 
     
     
         30 . The method of  claim 29  wherein R 8  is hydrogen, R 9  is isopropyl, R 10  is t-butoxycarbonyl, and R 11  is benzyl.  
     
     
         31 . Reacting a compound of Formula II  
       
         
           
           
               
               
           
         
       
       wherein 
 R 8  is hydrogen, halogen, C 1-5 alkoxy, hydroxyl, or C 1-5 alkyl;  
 R 9  is C 1-6 alkyl, substituted C 1-6 alkyl 
 where the alkyl substituents are independently selected from one or more halogens,  
 
  phenyl,  
  substituted phenyl 
 where the phenyl substituents are independently selected from one or more members of the group consisting of C 1-5 alkyl, C 1-5 alkoxy, and trihaloC 1-5 alkyl,  
 
  phenylC 1-5 alkyl, or  
  substituted phenylC 1-5 alkyl 
 where the phenyl substituents are independently selected from one or more members of the group consisting of C 1-5 alkyl, halogen, C 1-5 alkoxy, and trihaloC 1-5 alkyl;  
 
 R 10  is C 1-5 alkoxycarbonyl, phenylC 1-5 alkoxycarbonyl, or allyloxycarbonyl;  
 R 11  is phenylC 1-5 alkyl, or substituted phenylC 1-5 alkyl 
 where the phenyl substituents are independently selected from one or more members of the group consisting of C 1-5 alkyl, halogen, C 1-5 alkoxy, and nitro;  
 with an acidic reagent to give a compound of Formula II  
                     
 wherein  
 
 R 8  is hydrogen, halogen, C 1-5 alkoxy, hydroxyl, or C 1-5 alkyl;  
 R 9  is C 1-6 alkyl, substituted C 1-6 alkyl 
 where the alkyl substituents are independently selected from one or more halogens,  
 
  phenyl,  
  substituted phenyl 
 where the phenyl substituents are independently selected from one or more members of the group consisting of C 1-5 alkyl, C 1-5 alkoxy, and trihaloC 1-5 alkyl,  
 
  phenylC 1-5 alkyl, or  
  substituted phenylC 1-5 alkyl 
 where the phenyl substituents are independently selected from one or more members of the group consisting of C 1-5 alkyl, halogen, C 1-5 alkoxy, and trihaloC 1-5 alkyl;  
 
 R 10  is hydrogen  
 R 11  is phenylC 1-5 alkyl, or substituted phenylC 1-5 alkyl 
 where the phenyl substituents are independently selected from one or more members of the group consisting of C 1-5 alkyl, halogen, C 1-5 alkoxy, and nitro;  
 
 
     
     
         32 . The method of  claim 31  where R 8  is hydrogen, R 9  is isopropyl, R 11  is benzyl.  
     
     
         33 . Reacting a compound of Formula II  
       
         
           
           
               
               
           
         
       
       wherein 
 R 8  is hydrogen, halogen, C 1-5 alkoxy, hydroxyl, or C 1-5 alkyl;  
 R 9  is C 1-6 alkyl, substituted C 1-6 alkyl 
 where the alkyl substituents are independently selected from one or more halogens,  
 
  phenyl,  
  substituted phenyl 
 where the phenyl substituents are independently selected from one or more members of the group consisting of C 1-5 alkyl, C 1-5 alkoxy, and trihaloC 1-5 alkyl,  
 
  phenylC 1-5 alkyl, or  
  substituted phenylC 1-5 alkyl 
 where the phenyl substituents are independently selected from one or more members of the group consisting of C 1-5 alkyl, halogen, C 1-5 alkoxy, and trihaloC 1-5 alkyl;  
 
 R 10  is hydrogen  
 R 11  is phenylC 1-5 alkyl, or substituted phenylc 1-5 alkyl 
 where the phenyl substituents are independently selected from one or more members of the group consisting of C 1-5 alkyl, halogen, C 1-5 alkoxy, and nitro;  
 with a reducing agent to give a compound of Formula II  
                     
 wherein  
 
 R 8  is hydrogen, halogen, C 1-5 alkoxy, hydroxyl, or C 1-5 alkyl;  
 R 9  is C 1-6 alkyl, substituted C 1-6 alkyl 
 where the alkyl substituents are independently selected from one or more halogens,  
 
  phenyl,  
  substituted phenyl 
 where the phenyl substituents are independently selected from one or more members of the group consisting of C 1-5 alkyl, C 1-5 alkoxy, and trihaloC 1-5 alkyl,  
 
  phenylC 1-5 alkyl, or  
  substituted phenylC 1-5 alkyl 
 where the phenyl substituents are independently selected from one or more members of the group consisting of C 1-5 alkyl, halogen, C 1-5 alkoxy, and trihaloC 1-5 alkyl;  
 
 R 10  is hydrogen;  
 R 11  is hydrogen;  
 
     
     
         34 . The method of  claim 33  wherein R 8  is hydrogen and R 9  is isopropyl.  
     
     
         35 . The method of  claim 33  wherein the reducing agent is ammonium formate and Pd/C.  
     
     
         36 . The method of  claim 31  where the acidic reagent is trifluoroacetic acid.  
     
     
         37 . The method of  claim 29  where the basic reagent is potassium hydroxide.