Small molecule inhibitors of rotamase enzyme activity

Abstract

This invention relates to neurotrophic compounds having an affinity for FKBP-type immunophilins, their preparation and use as inhibitors of the enzyme activity associated with immunophilin proteins, and particularly inhibitors of peptidyl-prolyl isomerase or rotamase enzyme activity.

1 . A non-immunosuppressive neurotrophic compound of the formula: 
       
         
           
           
               
               
           
         
         where R 1  is a C 1 -C 9  straight or branched chain alkyl or alkenyl group optionally substituted with C 3 -C 8  cycloalkyl, C 3  or C 5  cycloalkyl, C 5 -C 7  cycloalkenyl, or Ar 1 , where said alkyl, alkenyl, cycloalkyl or cycloalkenyl groups may be optionally substituted with C 1 -C 4  alkyl, C 1 -C 4  alkenyl, or hydroxy, and where Ar 1  is selected from the group consisting of 1-naphthyl, 2-naphthyl, 2-indolyl, 3-indolyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-, 3-, or 4-pyridyl, or phenyl, having one to three substituents which are independently selected from the group consisting of hydrogen, halo, hydroxyl, nitro, trifluoromethyl, C 1 -C 6  straight or branched alkyl or alkenyl, C 1 -C 4  alkoxy or C 1 -C 4  alkenyloxy, phenoxy, benzyloxy, and amino; 
         X is selected from the group consisting of oxygen and sulfur; 
         Y is oxygen or NR 2 , where R 2  is hydrogen or C 1 -C 6  alkyl; and 
         Z is a C 2 -C 6  straight or branched chain alkyl or alkenyl, wherein the alkyl chain is substituted in one or more positions with Ar 1  as defined above, C 3 -C 8  cycloalkyl, cycloalkyl connected by a C 1 -C 6  straight or unbranched alkyl or alkenyl chain, or Ar 2  where Ar 2  is selected from the group consisting of 2-indolyl, 3-indolyl, 2-furyl, 3-furyl, 2-thiazolyl, 2-thienyl, 3-thienyl, 2-, 3-, or 4-pyridyl, or phenyl, having one to three substituents which are independently selected from the group consisting of hydrogen, halo, hydroxyl, nitro, trifluoromethyl, C 1 -C 6  straight or branched alkyl or alkenyl, C 1 -C 4  alkoxy or C 1 -C 4  alkenyloxy, phenoxy, benzyloxy, and amino; 
         Z may also be the fragment: 
       
       
         
           
           
               
               
           
         
         where R 3  is selected from the group consisting of straight or branched alkyl C 1 -C 8  optionally substituted with C 3 -C 8  cycloalkyl, or Ar 1  as defined above; 
         X 2  is O or NR 5 , where R 5  is selected from the group consisting of hydrogen, C 1 -C 6  straight or branched alkyl and alkenyl; 
         R 4  is selected from the group consisting of phenyl, benzyl, C 1 -C 5  straight or branched alkyl or alkenyl, and C 1 -C 5  straight or branched alkyl or alkenyl substituted with phenyl; or pharmaceutically acceptable salts or hydrates thereof.