Small molecule inhibitors of rotamase enzyme activity

Abstract

This invention relates to neurotrophic N-glyoxylprolyl ester 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.

What is claimed is:  
     
         1 . A 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 9  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-napthyl, 2-napthyl, 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, alkyl or alkenyl, C 1 -C 4  alkoxy or C 1 -C 4  alkenyloxy, phenoxy, benzyloxy, and amino;  
 X is oxygen, sulfur, methylene (CH 2 ), or H 2 ;  
 Y is oxygen or NR 2 , where R 2  is hydrogen or C 1 -C 6  alkyl; and  
 Z is a C2-C6 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 1  is selected from the group consisting of straight or branched alkyl C 1 -C 9  optionally substituted with C 3 -C 9  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.  
 
     
     
         2 . The neurotrophic compound of  claim 1 , which has an affinity for FKBP-type immunophilins.  
     
     
         3 . The neurotrophic compound of  claim 2 , where the FKBP-type immunophilin is FKBP-12.  
     
     
         4 . The neurotrophic compound of  claim 1 , capable of inhibiting rotamase activity.  
     
     
         5 . The neurotrophic compound of  claim 1 , where Z and R 1  are lipophilic groups.  
     
     
         6 . The neurotrophic compound according to  claim 1  that is selected from the group consisting of 
 3-phenyl-1-propyl (2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate,  
 3-phenyl-1-prop-2-(E)-enyl (2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate,  
 3-(3,4,5-trimethoxyphenyl)-1-propyl (2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate,  
 3-(3,4,5-trimethoxyphenyl)-1-prop-2-(E)-enyl (2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate,  
 3-(4,5-dichlorophenyl)-1-propyl (2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate,  
 3-(4,5-dichlorophenyl)-1-prop-2-(E)-enyl (2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate,  
 3-(4,5-methylenedioxyphenyl)-1-propyl (2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate,  
 3-(4,5-methylenedioxyphenyl)-1-prop-2-(E)-enyl (2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate,  
 3-cyclohexyl-1-propyl (2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate,  
 3-cyclohexyl-1-prop-2-(E)-enyl (2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate,  
 (1R)-1,3-diphenyl-1-propyl (2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate,  
 (1R)-1,3-diphenyl-1-prop-2-(E)-enyl (2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate,  
 (1R)-1-cyclohexyl-3-phenyl-1-propyl (2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate,  
 (1R)-1-cyclohexyl-3-phenyl-1-prop-2-(E)-enyl (2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate,  
 (1R)-1-(4,5-dichlorophenyl)-3-phenyl-1-propyl (2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate,  
 3-phenyl-1-propyl (2S)-1-(1,2-dioxo-2-cyclohexyl) ethyl-2-pyrrolidinecarboxylate,  
 3-phenyl-1-propyl (2S)-1-(1,2-dioxo-4-cyclohexyl) ethyl-2-pyrrolidinecarboxylate,  
 3-phenyl-1-propyl (2S)-1-(1,2-dioxo-2-[2-furanyl])ethyl-2-pyrrolidinecarboxylate,  
 3-phenyl-1-propyl (2S)-1-(1,2-dioxo-2-[2-thienyl])ethyl-2-pyrrolidinecarboxylate,  
 3-phenyl-1-propyl (2S)-1-(1,2-dioxo-2-[2-thiazolyl])ethyl-2-pyrrolidinecarboxylate,  
 3-phenyl-1-propyl (2S)-1-(1,2-dioxo-2-phenyl) ethyl-2-pyrrolidinecarboxylate,  
 1,7-diphenyl-4-heptyl (2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate,  
 3-Phenyl-1-propyl (2S)-1-(3,3-dimethyl-1,2-dioxo-4-hydroxybutyl)-2-pyrrolidinecarboxylate,  
 3-phenyl-1-propyl (2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate,  
 1-[1-(3,3-dimethyl-1,2-dioxopentyl)-L-proline]-L-phenylalanine ethyl ester,  
 1-[1-(3,3-dimethyl-1,2-dioxopentyl)-L-proline]-L-leucine ethyl ester,  
 1-[1-(3,3-dimethyl-1,2-dioxopentyl)-L-proline]-L-phenylglycine ethyl ester,  
 1-[1-(3,3-dimethyl-1,2-dioxopentyl)-L-proline]-L-phenylalanine ethyl ester,  
 1-[1-(3,3-dimethyl-1,2-dioxopentyl)-L-proline]-L-phenylalanine benzyl ester, and  
 1-[1-(3,3-dimethyl-1,2-dioxopentyl)-L-proline]-L-isoleucine ethyl ester.  
 
     
     
         7 . A pharmaceutical composition comprising a neurotrophically effective amount of the compound of  claim 1  and a pharmaceutically acceptable carrier.  
     
     
         8 . A method of stimulating growth of damaged peripheral nerves, which comprises: 
 administering to damaged peripheral nerves the neurotrophic compound of  claim 1  in sufficient amounts to stimulate the growth of said nerves.    
     
     
         9 . A 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-napthyl, 2-napthyl, 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 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; or pharmaceutically acceptable salts or hydrates thereof.  
 
     
     
         10 . The neurotrophic compound of  claim 9 , wherein R 1  is selected from the group consisting of C 1 -C 9  straight or branched chain alkyl, 2-cyclohexyl, 4-cyclohexyl, 2-furanyl, 2-thienyl, 2-thiazolyl, and 4-hydroxybutyl.  
     
     
         11 . The neurotrophic compound of  claim 9  having an affinity for FKBP-type immunophilins.  
     
     
         12 . The neurotrophic compounds of  claim 11 , where the FKBP-type immunophilin is FKBP-12.  
     
     
         13 . The neurotrophic compound of  claim 9 , capable of inhibiting rotamase activity.  
     
     
         14 . The neurotrophic compound of  claim 9 , where Z and R 1  are liphophilic groups.  
     
     
         15 . A pharmaceutical composition comprising a neurotrophically effective amount of the compound of  claim 9  and a pharmaceutically acceptable carrier.  
     
     
         16 . A neurotrophic compound of the formula:  
       
         
           
           
               
               
           
         
       
       where 
 Z is the fragment:  
                     
 where  
 R 1  is selected from the group consisting of straight or branched alkyl C 1 -C 9  optionally substituted with C 3 -C 9  cycloalkyl, or Ar 1  as defined above, and unsubstituted Ar 1 ;  
 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.  
 
     
     
         17 . The neurotrophic compound of  claim 16 , having an affinity for FKBP-type immunophilins.  
     
     
         18 . The neurotrophic compound of  claim 17 , wherein the FKBP-type immunophilin is FKBP-12.  
     
     
         19 . The neurotrophic compound of  claim 16 , capable of inhibiting rotamase activity.  
     
     
         20 . The neurotrophic compound of  claim 16 , where Z′ is a lipophilic group.  
     
     
         21 . A pharmaceutical composition comprising a neurotrophically effective amount of the compound of  claim 16  and a pharmaceutically acceptable carrier.  
     
     
         22 . A neurotrophic compound having an affinity for FKBP-type immunophilins wherein the immunophilin exhibits rotamase activity and the neurotrophic compound inhibits the rotamase activity of the immunophilin.  
     
     
         23 . The neurotrophic compound of  claim 22 , wherein the FKBP-type immunophilin is FKBP-12.  
     
     
         24 . A method of treating a neurological disorder in an animal comprising administering a therapeutically effective amount of a compound having an affinity for FKBP-type immunophilins wherein the immunophilin exhibits rotamase activity and the neurotrophic compound inhibits the rotamase activity of the immunophilin.  
     
     
         25 . The method of  claim 24 , wherein the FKBP-type immunophilin is FKBP-12.  
     
     
         26 . The method of  claim 24 , wherein the neurological disorder is selected from the group consisting of peripheral neuropathies, and neurological pathologies related to neurodegeneration.  
     
     
         27 . The method of  claim 24 , wherein the neurological disorder is Alzheimer's disease.  
     
     
         28 . The method of  claim 24 , wherein the neurological disorder is Parkinson's disease.  
     
     
         29 . The method of  claim 24 , wherein the neurological disorder is amyotrophic lateral sclerosis.  
     
     
         30 . A method of promoting neuronal regeneration and growth in mammals, comprising administering to a subject an effective amount of a neurotrophic compound having an affinity for FKBP-type immunophilins wherein the immunophilin exhibits rotamase activity and the neurotrophic compound inhibits the rotamase activity of the immunophilin.  
     
     
         31 . The method of  claim 30 , wherein the FKBP-type immunophilin is FKBP-12.  
     
     
         32 . A method of preventing neurodegeneration in an animal comprising administering an effective amount of a compound having an affinity for FKBP-type immunophilins wherein the immunophilin exhibits rotamase activity and the neurotrophic compound inhibits the rotamase activity of the immunophilin.  
     
     
         33 . The method of  claim 32 , wherein the FKBP-type immunophilin is FKBP-12.  
     
     
         34 . A neurotrophic N-glyoxyl prolyl ester compound of the formula:  
       
         
           
           
               
               
           
         
       
       where 
 R 1  is a C 1 -C 5  straight or branched chain alkyl or alkenyl group optionally substituted with C 3  to C 6  cycloalkyl, or Ar 1 , where Ar 1  is selected from the group consisting of 2-furyl, 2-thienyl, or phenyl;  
 X is selected from the group consisting of oxygen and sulfur;  
 Y is oxygen; and  
 Z is a 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 1 -C 6  cycloalkyl, Ar 2  where Ar 2  is selected from the group consisting of 2-, 3-, or 4-pyridyl, or phenyl, having one to three substituents which are independently selected from the group consisting of hydrogen and C 1 -C 4  alkoxy.  
 
     
     
         35 . The neurotrophic N-glyoxyl prolyl ester compound of  claim 34 , where Z and R 1  are lipophilic groups.  
     
     
         36 . The neurotrophic N-glyoxyl prolyl ester compound according to  claim 34  that is selected from the group consisting of: 
 3-(2,5-dimethoxyphenyl)-1-propyl (2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate,  
 3-(2,5-dimethoxyphenyl)-1-prop-2-(E)-enyl (2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate,  
 2-(3,4,5-trimethoxyphenyl)-1-ethyl (2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate,  
 3-(3-Pyridyl)-1-propyl (2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate,  
 3-(2-Pyridyl)-1-propyl (2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate,  
 3-(4-Pyridyl)-1-propyl (2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate,  
 3-phenyl-1-propyl (2S)-1-(2-tert-butyl-1,2-dioxoethyl)-2-pyrrolidinecarboxylate,  
 3-phenyl-1-propyl (2S)-1-(2-cyclohexylethyl-1,2-dioxoethyl)-2-pyrrolidinecarboxylate,  
 3-(3-pyridyl)-1-propyl (2S)-1-(2-cyclohexylethyl-1,2-dioxoethyl)-2-pyrrolidinecarboxylate,  
 3-(3-pyridyl)-1-propyl (2S)-1-(2-tert-butyl-1,2-dioxoethyl)-2-pyrrolidinecarboxylate,  
 3,3-diphenyl-1-propyl (2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate,  
 3-(3-pyridyl)-1-propyl (2S)-1-(2-cyclohexyl-1,2-dioxoethyl)-2-pyrrolidinecarboxylate,  
 3-(3-Pyridyl)-1-propyl (2S)-N-([2-thienyl]glyoxyl)pyrrolidinecarboxylate,  
 3,3-Diphenyl-1-propyl (2S)-1-(3,3-dimethyl-1,2-dioxobutyl)-2-pyrrolidinecarboxylate,  
 3,3-Diphenyl-1-propyl (2S)-1-cyclohexylglyoxyl-2-pyrrolidinecarboxylate,  
 3,3-Diphenyl-1-propyl (2S)-1-(2-thienyl)glyoxyl-2-pyrrolidinecarboxylate.  
 
     
     
         37 . A pharmaceutical composition comprising a neurotrophically effective amount of the N-glyoxyl prolyl ester compound of  claim 34  and a pharmaceutically acceptable carrier.  
     
     
         38 . A method of stimulating growth of damaged peripheral nerves, which comprises: 
 administering to damaged peripheral nerves the neurotrophic N-glyoxyl prolyl ester compound of  claim 34  in sufficient amounts to stimulate the growth of said nerves.    
     
     
         39 . A method of treating a neurological disorder selected from the group consisting of peripheral neuropathies, and neurological pathologies related to neurodegeneration in an animal which comprises administering a therapeutically effective amount of a neurotrophic N-glyoxyl prolyl ester compound having an affinity for FKBP-type immunophilins wherein the immunophilin exhibits rotamase activity and the neurotrophic N-glyoxyl prolyl ester compound inhibits the rotamase activity of the immunophilin.  
     
     
         40 . The method of  claim 39 , wherein the FKBP-type immunophilin is FKBP-12.  
     
     
         41 . The method of  claim 39 , wherein the neurological disorder is Alzheimer's disease.  
     
     
         42 . The method of  claim 39 , wherein the neurological disorder is Parkinson's disease.  
     
     
         43 . The method of  claim 39 , wherein the neurological disorder is amyotrophic lateral sclerosis.