Heterocyclic ketone and thioester compounds and uses

Abstract

This invention relates to neurotrophic, low molecular weight, small molecule heterocyclic ketone and thioester compounds, compositions containing the same, and the use of such compounds for treating neurological disorders, including physically damaged nerves and neurodegenerative diseases.

We claim:  
     
         1 . A neurotrophic, low molecular weight, small molecule heterocyclic ketone or thioester compound.  
     
     
         2 . The compound of  claim 1 , wherein the compound is non-immunosuppressive.  
     
     
         3 . The compound of  claim 1 , wherein the compound has an affinity for an FKBP-type immunophilin.  
     
     
         4 . A pharmaceutical composition comprising: 
 (i) an effective amount of the compound of  claim 1;  and    (ii) a pharmaceutically acceptable carrier.    
     
     
         5 . A method of effecting a neuronal activity in an animal, comprising administering to said animal an effective amount of the compound of  claim 1 .  
     
     
         6 . The method of  claim 5 , 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 a neurological disorder.  
     
     
         7 . The method of  claim 6 , wherein the neurological disorder is selected from the group consisting of peripheral neuropathy caused by physical injury or disease state, traumatic injury to the brain, physical damage to the spinal cord, stroke associated with brain damage, and neurological disorders relating to neurodegeneration.  
     
     
         8 . The method of  claim 7 , wherein the neurological disorder relating to neurodegeneration is selected from the group consisting of Alzheimer's Disease, Huntington's Disease, Parkinson's Disease, and amyotrophic lateral sclerosis.  
     
     
         9 . A compound of formula II:  
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt, ester, or solvate thereof, wherein: 
 n is 1 or 2;  
 X is O or S;  
 Z is selected from the group consisting of CH 2 , CHR 1  and CR 1 R 2 ;  
 R 1 , R 2 , and R 3  are independently selected from the group consisting of C 1 -C 5  straight or branched chain alkyl, C 2 -C 5  straight or branched chain alkenyl, and Ar, wherein said R 1 , R 2 , or R 3  is unsubstituted or substituted with one or more substituents independently selected from the group consisting of halo, trifluoromethyl, nitro, C 1 -C 6  straight or branched chain alkyl, C 2 -C 6  straight or branched chain alkenyl, hydroxy, C 1 -C 4  alkoxy, C 2 -C 4  alkenyloxy, phenoxy, benzyloxy, amino, and Ar;  
 R 4  is selected from the group consisting of C 1 -C 9  straight or branched chain alkyl, C 2 -C 9  straight or branched chain alkenyl, C 3 -C 8  cycloalkyl, C 5 -C 7  cycloalkenyl, and Ar; and  
 Ar is aryl, wherein said Ar is unsubstituted or substituted with halo, trifluoromethyl, hydroxy, nitro, C 1 -C 6  straight or branched chain alkyl, C 2 -C 6  straight or branched chain alkenyl, C 1 -C 4  alkoxy, C 2 -C 4  alkenyloxy, phenoxy, benzyloxy, or amino.  
 
     
     
         10 . The compound of  claim 9 , wherein: 
 n is 1; and    X is O.    
     
     
         11 . The compound of  claim 10 , wherein Z is CH 2 .  
     
     
         12 . The compound of  claim 11 , wherein R 3  is 3-pyridylpropyl and R 4  is 1,1-dimethylpropyl.  
     
     
         13 . The compound of  claim 11 , wherein R 3  is 2-phenylethyl, and R 4  is tert-butyl.  
     
     
         14 . The compound of  claim 11 , wherein R 3  is 3-(4-hydroxyphenyl)propyl and R 4  is 1,1-dimethylpropyl.  
     
     
         15 . The compound of  claim 11 , which is selected from the group consisting of: 
 (2S)-3,3-dimethyl-1-[2-(5-phenylpentanoyl)pyrrolidinyl]pentane-1,2-dione;    (2S)-3,3-dimethyl-1-[2-(5-(3-pyridyl)pyrrolidinyl]pentane-1,2-dione;    (2S)-2-({1-oxo-5-phenyl}pentyl-1-(3,3-dimethyl-1,2-dioxobutyl)pyrrolidine;    (2S)-3,3-dimethyl-1-[2-(5(4-hydroxyphenyl)pentanoyl)pyrrolidinyl]pentane-1,2-dione;    (2S)-2-({1-Oxo-5-phenyl}pentyl-1-(2-Cyclohexyl-1,2-dioxoethyl)pyrrolidine;    2-(1-Oxo-4-phenyl)-butyl-1-(3,3-dimethyl-1,2-dioxobutyl)pyrrolidine;    (2S)-2-[5,5-di(4-Fluorophenyl)pentanoyl]-1-(3,3 dimethyl-1,2-pentanedione)pyrrolidine; and pharmaceutically acceptable salts, esters, or solvates thereof.    
     
     
         16 . The compound of  claim 15  which is (2S)-3,3-dimethyl -1-[2-(5-(3-pyridyl)pyrrolidinyl]pentane-1,2-dione, or a pharmaceutically acceptable salt, ester, or solvate thereof.  
     
     
         17 . The compound of  claim 15  which is 2-(1-Oxo-4-phenyl)-butyl -1-(3,3-dimethyl-1,2-dioxobutyl)pyrrolidine, or a pharmaceutically acceptable salt, ester, or solvate thereof.  
     
     
         18 . The compound of  claim 15  which is (2S)-3,3-dimethyl -1-[2-(5-(4-hydroxyphenyl)pentanoyl)pyrrolidinyl]pentane-1,2-dione, or a pharmaceutically acceptable salt, ester, or solvate thereof.  
     
     
         19 . The compound of  claim 9 , wherein: 
 n is 1; and    X is S.    
     
     
         20 . The compound of  claim 19 , wherein Z is CH 2 .  
     
     
         21 . The compound of  claim 9 , wherein: 
 n is 2; and    X is O.    
     
     
         22 . The compound -of  claim 21 , wherein Z is CH 2 .  
     
     
         23 . The compound of  claim 22 , wherein R 3  is 4-phenylbutyl and R 4  is 1,1-dimethylpropyl.  
     
     
         24 . The compound of  claim 22 , which is selected from the group consisting of: 
 2-({1-Oxo-6-phenyl}-hexyl-1-(2-Cyclohexyl-1,2-dioxoethyl)piperidine;    2-({1-oxo-6-phenyl}-hexyl) (2S)-1-(3,3-dimethyl -1,2-dioxopentyl)piperidine;    3,3-Dimethyl-1-[2-(5-phenylpentanoyl)piperidino]-1,2-pentanedione; and pharmaceutically acceptable salts, esters, or solvates thereof.    
     
     
         25 . The compound of  claim 24  which is 2-({1-oxo-6-phenyl}-hexyl) (2S)-1-(3,3-dimethyl-1,2-diocopentyl)piperidine or a pharmaceutically acceptable salt, ester, or solvate thereof.  
     
     
         26 . The compound of  claim 9 , wherein: 
 n is 2; and    X is S.    
     
     
         27 . The compound of  claim 26 , wherein Z is CH 2 .  
     
     
         28 . The compound of  claim 26 , wherein Z is CHR 1 .  
     
     
         29 . The compound of  claim 28 , which is 2-({1-Oxo-[2-{2′-phenyl}ethyl]-4-phenyl}-butyl-1-(3,3-dimethyl -1,2-dioxobutyl)piperidine.  
     
     
         30 . A pharmaceutical composition comprising: 
 (i) an effective amount of the compound of claim  9 ; and    (ii) a pharmaceutically acceptable carrier.    
     
     
         31 . The pharmaceutical composition of  claim 30 , wherein, in said compound: 
 n is 1; and    X is O.    
     
     
         32 . The pharmaceutical composition of  claim 31 , wherein, in said compound, Z is CH 2 .  
     
     
         33 . The pharmaceutical composition of  claim 32 , wherein R 3  is 3-pyridylpropyl and R 4  is 1,1-dimethylpropyl.  
     
     
         34 . The pharmaceutical composition of  claim 32 , wherein R 3  is 2-phenylethyl, and R 4  is tert-butyl.  
     
     
         35 . The pharmaceutical composition of  claim 32 , wherein R 3  is 3-(4-hydroxyphenyl)propyl and R 4  is 1,1-dimethylpropyl.  
     
     
         36 . The pharmaceutical composition of  claim 32 , wherein said compound is selected from the group consisting of: 
 (2S)-3,3-dimethyl-1-[2-(5-phenylpentanoyl)pyrrolidinyl]pentane-1,2-dione;    (2S)-3,3-dimethyl-1-[2-(5-(3-pyridyl)pyrrolidinyl]pentane-1,2-dione;    (2S)-2-({1-oxo-5-phenyl}pentyl-1-(3,3-dimethyl-1,2-dioxobutyl)pyrrolidine;    (2S)-3,3-dimethyl-1-[2-(5-(4-hydroxyphenyl)pentanoyl)pyrrolidinyl]pentane-1,2-dione;    (2S) -2-({1-Oxo-5-phenyl}pentyl-1-(2-Cyclohexyl-1,2-dioxoethyl)pyrrolidine;    2-(1-Oxo-4-phenyl)-butyl-1-(3,3-dimethyl-1,2-dioxobutyl)pyrrolidine;    (2S)-2-[5,5-di(4-Fluorophenyl)pentanoyl]-1-(3,3 dimethyl-1,2-pentanedione)pyrrolidine; and pharmaceutically acceptable salts, esters, or solvates thereof.    
     
     
         37 . The pharmaceutical composition of  claim 36  wherein said compound is (2S)-3,3-dimethyl-1-[2-(5-(3-pyridyl)pyrrolidinyl]pentane-1,2-dione, or a pharmaceutically acceptable salt, ester, or solvate thereof.  
     
     
         38 . The pharmaceutical composition of  claim 36  wherein said compound is 2-(1-Oxo-4-phenyl)-butyl-1-(3,3-dimethyl-1,2-dioxobutyl)pyrrolidine, or a pharmaceutically acceptable salt, ester, or solvate thereof.  
     
     
         39 . The pharmaceutical composition of  claim 36  wherein said compound is (2S)-3,3-dimethyl-1-[2-(5-(4-hydroxyphenyl)pentanoyl)pyrrolidinyl]pentane-1,2-dione, or a pharmaceutically acceptable salt, ester, or solvate thereof.  
     
     
         40 . The pharmaceutical composition of  claim 30 , wherein, in said compound: 
 n is 1; and    X is S.    
     
     
         41 . The pharmaceutical composition of  claim 40 , wherein, in said compound, Z is CH 2 .  
     
     
         42 . The pharmaceutical composition of  claim 30 , wherein, in said compound: 
 n is 2; and    X is O.    
     
     
         43 . The pharmaceutical composition of  claim 42 , wherein, in said compound, Z is CH 2 .  
     
     
         44 . The pharmaceutical composition of  claim 43 , wherein R 3  is 4-phenylbutyl and R 4  is 1,1-dimethylpropyl.  
     
     
         45 . The pharmaceutical composition of  claim 43 , wherein said compound is selected from the group consisting of: 
 2-({1-Oxo-6-phenyl}-hexyl-1-(2-Cyclohexyl-1,2-dioxoethyl)piperidine;    2-({1-oxo-6-phenyl}-hexyl) (2S)-1-(3,3-dimethyl -1,2-dioxopentyl)piperidine;    3,3-Dimethyl-1-[2-(5-phenylpentanoyl)piperidino]-1,2-pentanedione; and pharmaceutically acceptable salts, esters, or solvates thereof.    
     
     
         46 . The pharmaceutical composition of  claim 45  wherein said compound is 2-({1-oxo-6-phenyl}-hexyl) (2S)-1-(3,3-dimethyl-1,2-dioxopentyl)piperidine.  
     
     
         47 . The pharmaceutical composition of  claim 30 , wherein, in said compound: 
 n is 2; and    X is S.    
     
     
         48 . The pharmaceutical composition of  claim 47 , wherein, in said compound, Z is CH 2 .  
     
     
         49 . The pharmaceutical composition of  claim 47 , wherein, in said compound, Z is CHR 1 .  
     
     
         50 . The pharmaceutical composition of  claim 49 , wherein said compound is 2-({1-Oxo-[2-{2′-phenyl}ethyl]-4-phenyl}-butyl-1-(3,3-dimethyl-1,2-dioxobutyl)piperidine.  
     
     
         51 . A method for effecting a neuronal activity in an animal, comprising administering to the animal an effective amount of the compound of  claim 9 .  
     
     
         52 . The method of  claim 51 , 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.  
     
     
         53 . The method of  claim 52 , wherein the neurological disorder is selected from the group consisting of peripheral neuropathy caused by physical injury or disease state, traumatic injury to the brain, physical damage to the spinal cord, stroke associated with brain damage, and neurological disorder relating to neurodegeneration.  
     
     
         54 . The method of  claim 53 , wherein the neurological disorder relating to neurodegeneration is selected from the group consisting of Alzheimer's Disease, Huntington's Disease, Parkinson's Disease, and amyotrophic lateral sclerosis.  
     
     
         55 . The method of  claim 51 , wherein, in said compound: 
 n is 1; and    X is O.    
     
     
         56 . The method of  claim 55 , wherein, in said compound, Z is CH 2 .  
     
     
         57 . The method of  claim 56 , wherein R 3  is 3-pyridylpropyl and R 4  is 1,1-dimethylpropyl.  
     
     
         58 . The method of  claim 56 , wherein R 3  is 2-phenylethyl, and R 4  is tert-butyl.  
     
     
         59 . The method of  claim 56 , wherein R 3  is 3-(4-hydroxyphenyl)propyl and R 4  is 1,1-dimethylpropyl.  
     
     
         60 . The method of  claim 56 , wherein said compound is selected from the group consisting of: 
 (2S)-3,3-dimethyl-1-[2-(5-phenylpentanoyl)pyrrolidinyl]pentane-1,2-dione;    (2S)-3,3-dimethyl-1-[2-(5-(3-pyridyl)pyrrolidinyl]pentane-1,2-dione;    (2S)-2-({1-oxo-5-phenyl}pentyl-1-(3,3-dimethyl-1,2-dioxobutyl)pyrrolidine;    (2S)-3,3-dimethyl-1-[2-(5-(4-hydroxyphenyl)pentanoyl)pyrrolidinyl]pentane-1,2-dione;    (2S) -2-({1-Oxo-5-phenyl}pentyl-1-(2-Cyclohexyl-1,2-dioxoethyl)pyrrolidine;    2-(1-Oxo-4-phenyl)-butyl-1-(3,3-dimethyl-1,2-dioxobutyl)pyrrolidine;    (2S)-2-[5,5-di(4-Fluorophenyl)pentanoyl]-1-(3,3 dimethyl-1,2-pentanedione)pyrrolidine; and pharmaceutically acceptable salts, esters, or solvates thereof.    
     
     
         61 . The method of  claim 61  wherein said compound is (2S)-3,3-dimethyl-1-[2-(5-(3-pyridyl)pyrrolidinyl]pentane-1,2-dione, or a pharmaceutically acceptable salt, ester, or solvate thereof.  
     
     
         62 . The method of  claim 61  wherein said compound is 2-(1-Oxo-4-phenyl)-butyl-1-(3,3-dimethyl-1,2-dioxobutyl)pyrrolidine, or a pharmaceutically acceptable salt, ester, or solvate thereof.  
     
     
         63 . The method of  claim 61 , wherein said compound is (2S)-3,3-dimethyl-1-[2-(5-(4-hydroxyphenyl)pentanoyl)pyrrolidinyl]pentane-1,2-dione, or a pharmaceutically acceptable salt, ester, or solvate thereof.  
     
     
         64 . The method of  claim 51 , wherein, in said compound: 
 n is 1; and    X is S.    
     
     
         65 . The method of  claim 64 , wherein, in said compound, Z is CH 2 .  
     
     
         66 . The method of  claim 51 , wherein, in said compound: 
 n is 2; and    X is O.    
     
     
         67 . The method of  claim 66 , wherein, in said compound, Z is CH 2 .  
     
     
         68 . The method of  claim 67 , wherein R 3  is 4-phenylbutyl and R 4  is 1,1-dimethylpropyl.  
     
     
         69 . The method of  claim 67 , wherein said compound is selected from the group consisting of: 
 2-({1-Oxo-6-phenyl}-hexyl-1-(2-Cyclohexyl-1,2-dioxoethyl)piperidine;    2-({1-oxo-6-phenyl}-hexyl) (2S)-1-(3,3-dimethyl -1,2-dioxopentyl)piperidine;    3,3-Dimethyl-1-[2-(5-phenylpentanoyl)piperidino]-1,2-pentanedione; and pharmaceutically acceptable salts, esters, or solvates thereof.    
     
     
         70 . The method of  claim 69 , wherein said compound is 2-({1-oxo-6-phenyl}-hexyl) (2S)-1-(3,3-dimethyl-1,2-dioxopentyl)piperidine.  
     
     
         71 . The method of  claim 51 , wherein, in said compound: 
 n is 2; and    X is S.    
     
     
         72 . The method of  claim 71 , wherein, in said compound, Z is CH 2 .  
     
     
         73 . The method of  claim 71 , wherein in said compound, Z is CHR 1 .  
     
     
         74 . The method of  claim 73 , wherein said compound is 2-({1-Oxo-2-{2′-phenyl}ethyl]-4-phenyl}-butyl-1-(3,3-dimethyl-1,2-dioxobutyl)piperidine.  
     
     
         75 . The compound of  claim 1 , wherein the compound has a molecular weight no more than about 800 daltons.  
     
     
         76 . The compound of  claim 1 , wherein the compound has a molecular weight no more than about 500 daltons.  
     
     
         77 . The compound of  claim 1 , wherein the compound has a molecular weight no more than about 330 daltons.  
     
     
         78 . The compound of  claim 1 , wherein the compound exhibits a Chick Dorsal Root Ganglion Neurite Outgrowth Assay ED 50  value of less than about 10 nM.  
     
     
         79 . The compound of  claim 1 , wherein the compound exhibits a Chick Dorsal Root Ganglion Neurite outgrowth Assay ED 50  value Of less than about 1.0 nM.  
     
     
         80 . The compound of  claim 1 , wherein the compound exhibits a Chick Dorsal Root Ganglion Neurite Outgrowth Assay ED 50  value of less than about 0.1 nM.  
     
     
         81 . The compound of  claim 1 , wherein the compound exhibits an MPTP Assay value which is greater than about 20% recovery of TH-stained dopaminergic neurons.  
     
     
         82 . The compound of  claim 1 , wherein the compound exhibits an MPTP Assay value which is greater than about 35% recovery of TH-stained dopaminergic neurons.  
     
     
         83 . The compound of  claim 1 , wherein the compound exhibits an MPTP Assay value which is greater than about 50% recovery of TH-stained dopaminergic neurons.