Heterocyclic esters and amides

Abstract

This invention relates to neurotrophic low molecular weight, small molecule heterocyclic ester and amides having an affinity for FKBP-type immunophilins, and their use as inhibitors of the enzyme activity associated with immunophilin proteins, particularly peptidyl-prolyl isomerase, or rotamase, enzyme activity.

What is claimed is:  
     
         1 . A compound of formula I:  
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, wherein: 
 A and B, together with the nitrogen and carbon atoms to which they are respectively attached, form a 5-7 membered saturated or unsaturated heterocyclic ring containing, in addition to the nitrogen atom, at least one additional O, S, SO, SO 2 , NH or NR 1  heteroatom in any chemically stable oxidation state;  
 X is O or S;  
 Z is O, NH or NR 1 ;  
 W and Y are independently O, S, CH 2  or H 2 ;  
 R 1  is C 1 -C 6  straight or branched chain alkyl or alkenyl, which is substituted in one or more position(s) with (Ar 1 ) n , (Ar 1 ) n  connected by a C 1 -C 6  straight or branched chain alkyl or alkenyl, C 3 -C 8  cycloalkyl, C 3 -C 8  cycloalkyl connected by a C 1 -C 6  straight or branches chain alkyl or alkenyl, Ar 2 , or a combination thereof;  
 n is 1 or 2;  
 R 2  is either C 1 -C 9  straight or branched chain alkyl or alkenyl, C 3 -C 8  cycloalkenyl, C 5 -C 7  cycloalkenyl, or Ar 1 , wherein said alkyl, alkenyl, cycloalkyl or cycloalkenyl is either unsubstituted or substituted in one or more position(s) with C 1 -C 4  straight or branched chain alkyl or alkenyl, hydroxyl, or a combination thereof; and  
 Ar 1  and Ar 2  are independently a mono-, bi- or tricyclic, carbo- or heterocyclic ring, wherein the ring is either unsubstituted or substituted in one to three position(s) with halo, hydroxyl, nitro, trifluoromethyl, C 1 -C 6  straight or branched chain alkyl or alkenyl, C 1 -C 4  alkoxy, C 1 -C 4  alkenyloxy, phenoxy, benzyloxy, amino, or a combination thereof; wherein the individual ring sizes are 5-6 members; and wherein the heterocyclic ring contains 1-6 heteroatom(s) selected from the group consisting of O, N, S, and a combination thereof.  
 
     
     
         2 . The compound of  claim 1 , wherein the mono- or bicyclic, carbo- or heterocyclic ring is selected from the group consisting of naphthyl, indolyl, furyl, thiazolyl, thienyl, pyridyl, quinolinyl, isoquinolinyl, fluorenyl and phenyl.  
     
     
         3 . The compound of  claim 1 , wherein the at least one additional heteroatom in the 5-7 membered saturated or unsaturated heterocyclic ring is NH or NR 1 .  
     
     
         4 . The compound of  claim 1 , wherein the compound has an affinity for FKBP-type immunophilins.  
     
     
         5 . The compound of  claim 4 , wherein the FKBP-type immunophilin is FKBP12.  
     
     
         6 . The compound of  claim 1 , wherein the compound inhibits rotamase enzyme activity.  
     
     
         7 . A pharmaceutical composition comprising a neurotrophically effective amount of the compound of  claim 1  and a pharmaceutically acceptable carrier.  
     
     
         8 . A method of effecting a neuronal activity in an animal, comprising: 
 administering to the animal a neurotrophically effective amount of the compound of  claim 1 .    
     
     
         9 . The method of  claim 8 , wherein the neuronal activity is selected from the group consisting of stimulation or damaged neurons, promotion of neuronal regeneration, prevention of neurodegeneration and treatment of neurological disorder.  
     
     
         10 . The method or  claim 9 , wherein the neurological disorder is selected from the group consisting of peripheral neuropathy caused by physical injury or disease state, physical damage to the brain, physical damage to the spinal cord, stroke associated with brain damage, and neurological disorder relating to neurodegeneration.  
     
     
         11 . The method of  claim 10 , wherein the neurological disorder relating to neurodegeneration is selected from the group consisting of Alzheimer's Disease, Parkinson's Disease, and amyotrophic lateral sclerosis.  
     
     
         12 . A compound of formula II:  
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, wherein: 
 A, B and C are independently CH 2 ,O, S, SO, SO 2 , NH or NH 1 ;  
 R 1  is C 1 -C 5  straight or branched chain a alkenyl, which is substituted in one or more position(s) with (Ar 1 ) n , (Ar 1 ) n  connected by a C 1 -C 6  straight or branched chain alkyl or alkenyl, or a combination thereof;  
 n is 1 or 2;  
 R 2  is either C 1 -C 9  straight or branched chain alkyl or alkenyl, C 3 -C 9  cycloalkyl, C 5 -C 7  cycloalkenyl, or Ar 1 ; and  
 Ar 1  is a mono-, bi- or tricyclic, carbo- or heterocyclic ring, wherein the ring is either unsubstituted or substituted in one to three position(s) with halo, hydroxyl, nitro, trifluoromethyl, C 1 -C 6  straight or branched chain alkyl or alkenyl, C 1 -C 4  alkoxy, C 1 -C 4  alkenyloxy, phenoxy, benzyloxy, amino, or a combination thereof; wherein the individual ring sizes are 5-6 members; and wherein the heterocyclic ring contains 1-6 heteroatom(s) selected from the group consisting of O, N, S, and a combination thereof.  
 
     
     
         13 . The compound of  claim 12 , wherein: 
 A is CH 2 ;    B is CH 2  or S;    C is CH 2  or NH;    R 1  is selected from the group consisting of 3-phenylpropyl and 3-(3-pyridyl)propyl; and    R 1  is selected from the group consisting of 3,3-dimethylpentyl, cyclohexyl, and tert-butyl.    
     
     
         14 . The compound of  claim 13 , wherein: 
 B is CH 2 ;    C is NH; and    R 1 is 3-phenylpropyl.    
     
     
         15 . The compound of  claim 13 , wherein: 
 B is S; and    C is CH 2 .    
     
     
         16 . The compound of  claim 12 , wherein the compound is selected from the group consisting of: 
   3 -phenyl-1-propyl(2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-(4-thiazolidine)carboxylate; and    3-(3-pyridyl)-1-propyl(2S)-1-(3,3-dimethyl-1, 2-dioxopentyl)-2-(4-thiazolidine) carboxylate.    
     
     
         17 . The compound of  claim 12 , wherein the compound has an affinity for FKBP-type immunophilins.  
     
     
         18 . The compound of  claim 17 , wherein the FKBP-type immunophilin is FKBP12.  
     
     
         19 . The compound of  claim 12 , wherein the compound inhibits rotamase enzyme activity.  
     
     
         20 . A pharmaceutical composition comprising a neurotrophically effective amount of the compound of  claim 12  and a pharmaceutically acceptable carrier.  
     
     
         21 . A method of effecting a neuronal activity in an animal, comprising: 
 administering to the animal a neurotrophically effective amount of the compound of  claim 12 .    
     
     
         22 . The method of  claim 21 , wherein the neuronal activity is selected from the group consisting of stimulation of damaged neurons, promotion of neuronal regeneration, prevention of neurodegeneration and treatment of neurological disorder.  
     
     
         23 . The method of  claim 22 , wherein the neurological disorder is selected from the group consisting of peripheral neuropathy caused by physical injury or disease state, physical damage to the brain, physical damage to the spinal cord, stroke associated with brain damage, and neurological disorder relating to neurodegeneration.  
     
     
         24 . The method of  claim 23 , wherein the neurological disorder relating to neurodegeneration is selected from the group consisting of Alzheimer's Disease, Parkinson's Disease, and amyotrophic lateral sclerosis.  
     
     
         25 . A compound of formula III:  
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, wherein: 
 A, B, C and D are independently CH 2 , O, S, SO, SO 2 , NH or NR 1 ;  
 R 1  is C 1 -C 5  straight or branched chain alkyl or alkenyl, which is substituted in one or more position(s) With (Ar 1 ) n , (Ar 1 ) n  connected by a C 1 -C 6  straight or branched chain alkyl or alkenyl, or a combination thereof;  
 n is 1 or 2;  
 R 2  is either C 1 -C 9  straight or branched chain alkyl or alkenyl, C 3 -C 8  cycloalkyl, C 5 -C 7  cycloalkenyl, or Ar 1 ; and  
 Ar 1  is a mono-, bi- or tricyclic, carbo- or heterocyclic ring, wherein the ring is either unsubstituted or substituted in one to three position(s) with halo, hydroxyl, nitro, trifluoromethyl, C 1 -C 6  straight or branched chain alkyl or alkenyl, C 1 -C 4  alkoxy, C 1 -C 4  alkenyloxy, phenoxy, benzyloxy, amino, or a combination thereof; wherein the individual ring sizes are 5-6 members; and wherein the heterocyclic ring contains 1-6 heteroatom(s) selected from the group consisting of O, N, S, and a combination thereof.  
 
     
     
         26 . The compound of  claim 25 , wherein: 
 A is CH 2;      B is CH 2 ;    C is S, O or NH;    D is CH 2 ;    R 1  is selected from the group consisting of 3-phenylpropyl and (3,4,5-trimethoxy) phenylpropyl; and    R 2  is selected from the group consisting of 3,3-dimethylpentyl, cyclohexyl, 3-3-dimethylpropyl, phenyl, and 3,4,5-trimethoxyphenyl.    
     
     
         27 . The compound of  claim 26 , wherein: 
 C is NH; and    R 2  is 3,3-dimethylpropyl or phenyl.    
     
     
         28 . The compound of  claim 25 , wherein the compound has an affinity for FKBP-type immunophilins.  
     
     
         29 . The compound of  claim 28 , wherein the FKBP-type immunophilin is FKBP12.  
     
     
         30 . The compound of  claim 25 , wherein the compound inhibits rotamase enzyme activity.  
     
     
         31 . A pharmaceutical composition comprising a neurotrophically effective amount of the compound of  claim 25  and a pharmaceutically acceptable carrier.  
     
     
         32 . A method of effecting a neuronal activity in an animal, comprising: 
 administering to the animal a neurotrophically effective amount of the compound of  claim 25 .    
     
     
         33 . The method of  claim 32 , wherein the neuronal activity is selected from the group consisting of stimulation of damaged neurons, promotion of neuronal regeneration, prevention of neurodegeneration and treatment of neurological disorder.  
     
     
         34 . The method of  claim 33 , wherein the neurological disorder is selected from the group consisting of peripheral neuropathy caused by physical injury or disease state, physical damage to the brain, physical damage to the spinal cord, stroke associated with brain damage, and neurological disorder relating to neurodegeneration.  
     
     
         35 . The method of  claim 34 , wherein the neurological disorder relating to neurodegeneration is selected from the group consisting of Alzheimer's Disease, Parkinson's Disease, and amyotrophic lateral sclerosis.