Heterocyclic thioester and ketone hair growth compositions and uses

Abstract

This invention relates to pharmaceutical compositions and methods for treating alopecia and promoting hair growth using heterocyclic thioesters and ketones.

1 . A method for treating alopecia or promoting hair growth in an animal, which comprises administering to said animal an effective amount of a heterocyclic thioester or ketone.  
     
     
         2 . The method of  claim 1 , wherein the heterocyclic thioester or ketone is non-immunosuppressive.  
     
     
         3 . The method of  claim 1 , wherein the heterocyclic thioester or ketone has an affinity for an FKBP-type immunophilin.  
     
     
         4 . The method of  claim 3 , wherein the FKBP-type immunophilin is FKBP-12.  
     
     
         5 - 36 . (Canceled)  
     
     
         37 . A pharmaceutical composition which comprises: 
 (i) an effective amount of a heterocyclic thioester or ketone for treating alopecia or promoting hair growth in an animal; and    (ii) a pharmaceutically acceptable carrier.    
     
     
         38 . The pharmaceutical composition of  claim 37 , wherein the heterocyclic thioester or ketone is non-immunosuppressive.  
     
     
         39 . The pharmaceutical composition of  claim 37 , wherein the heterocyclic thioester or ketone has an affinity for an FKBP-type immunophilin.  
     
     
         40 . The pharmaceutical composition of  claim 39 , wherein the FKBP-type immunophilin is FKBP-12.  
     
     
         41 . The pharmaceutical composition of  claim 37 , wherein the heterocyclic thioester or ketone is a compound of formula I  
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt, ester, or solvate thereof,  
         wherein:  
         A and B, taken 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, one or more additional O, S, SO, SO 2 , N, NH, or NR 2  heteroatom(s);  
         X is either O or S;  
         Z is either S, CH 2 , CHR 1  or CR 1 R 3 ;  
         W and Y are independently O, S, CH 2  or H 2 ;  
         R 1  and R 3  are independently C 1 -C 6  straight or branched chain alkyl or C 2 -C 6  straight or branched chain alkenyl, wherein said alkyl or alkenyl is substituted with one or more substituent(s) independently selected from the group consisting of (Ar 1 ) n , C 1 -C 6  straight or branched chain alkyl or C 2 -C 6  straight or branched chain alkenyl substituted with (Ar 1 ) n , C 3 -C 8  cycloalkyl, C 1 -C 6  straight or branched chain alkyl or C 2 -C 6  straight or branched chain alkenyl substituted with C 3 -C 8  cycloalkyl, and Ar 2 ;  
         n is 1 or 2;  
         R 2  is either 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 or Ar n , wherein said alkyl, alkenyl, cycloalkyl or cycloalkenyl is either unsubstituted or substituted with one or more substituent(s) independently selected from the group consisting of C 1 -C 4  straight or branched chain alkyl, C 2 -C 4  straight or branched chain alkenyl, and hydroxy; and  
         Ar 1  and Ar 2  are independently an alicyclic or aromatic, mono-, bi- or tricyclic, carbo- or heterocyclic ring, wherein said ring is either unsubstituted or substituted with one or more substituent(s) independently selected from the group consisting of halo, hydroxy, nitro, trifluoromethyl, 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, and amino; wherein the individual ring size is 5-8 members; and wherein the heterocyclic ring has 1-6 heteroatom(s) independently selected from the group consisting of O, N, and S.  
       
     
     
         42 . The pharmaceutical composition of  claim 41 , 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.  
     
     
         43 . The pharmaceutical composition of  claim 37 , wherein the heterocyclic thioester or ketone is 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 S, CH 2 , CHR 1 , and CR 1 R 3 ;  
         R 1  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 1 , wherein said alkyl, alkenyl or AR 1  is unsubstituted or substituted with one or more substituent(s) independently selected from the group consisting of halo, 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 1 ;  
         R 2  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 1 ; and  
         Ar 1  is phenyl, benzyl, pyridyl, fluorenyl, thioindolyl or naphthyl, wherein said Ar 1  is unsubstituted or substituted with one or more substituent(s) independently selected from the group consisting of 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, and amino.  
       
     
     
         44 . The pharmaceutical composition of  claim 43 , wherein: 
 n is 1; and    x is O.    
     
     
         45 . The pharmaceutical composition of  claim 44 , wherein Z is CH 2 .  
     
     
         46 . The pharmaceutical composition of  claim 45 , wherein the compound is selected from the group consisting of: 
 (2S)-2-({1 -Oxo-5-phenyl}-pentyl-1-(3,3-dimethyl-1,2-dioxopentyl)pyrrolidine;    3,3-Dimethyl-1-[(2S)-2-(5-(3-pyridyl)pentanoyl)-1-pyrrolidine]-1, 2-pentanedione;    (2S) -2-({1-Oxo-4-phenyl}-butyl-1-(3,3-dimethyl-1,2-dioxobutyl)pyrrolidine;    (2S) -2-({1-Oxo-4-phenyl}-butyl-1-(2-cyclohexyl-1,2-dioxoethyl) pyrrolidine    2-({1-Oxo-4-phenyl}-butyl-1-(3,3-dimethyl-1,2-dioxobutyl) pyrrolidine;    1-{(2S)-2-[5,5-di (4-Fluorophenyl)pentanoyl]-2-pyrrolidine}-3,3-dimethyl-1,2-pentanedione; and    pharmaceutically acceptable salts, esters, and solvates thereof.    
     
     
         47 . The pharmaceutical composition of  claim 44 , wherein Z is S.  
     
     
         48 . The pharmaceutical composition of  claim 47 , wherein the compound is selected from the group consisting of: 
 2-Phenyl-1-ethyl (2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarbothioate;    (3-Thioindolyl)methyl (2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarbothioate;    2-Phenyl-1-ethyl (2S)-1-(2-cyclohexyl-1,2-dioxoethyl)-2-pyrrolidinecarbothioate;    2-Phenyl-1-ethyl (2S)-1-(1-cyclopencyl-1,2-dioxoethyl)-2-pyrrolidinecarbothioate;    3-Phenyl-1-propyl (2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarbothioate;    3-(3-Pyridyl)-1-propyl (2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarbothioate;    3-Phenyl-1-propyl (2S)-1-(2-cyclohexyl-1,2-dioxoethyl)-2-pyrrolidinecarbothioate;    4-Phenyl-1-butyl (2S)-1-(2-cyclohexyl-1,2-dioxoethyl)-2-pyrrolidinecarbothioate;    4-Phenyl-1-butyl (2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarbothioate;    3-(3-Pyridyl)-1-propyl (2S)-1-(2-cyclohexyl-1,2-dioxoethyl)-2-pyrrolidinecarbothioate;    3,3-Diphenyl-1-propyl (2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarbothioate;    3,3-Diphenyl-1-propyl (2S)-1-(2-Cyclohexyl-1,2-dioxoethyl)-2-pyrrolidinecarbothioate;    3-(para-Methoxyphenyl)-1-propyl (2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarbothioate;    3,3-Di(para-Fluoro)phenyl-1-propyl (2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarbothioate;    4,4-Di(para-fluorophenyl)butyl 1-(3,3-dimethyl-2-oxopentanoyl)-2-pyrrolidinecarbothioate;    3-(1-Naphthyl)propyl (2S)-1-(3,3-dimethyl-2-oxopentanoyl)-2-pyrrolidinecarbothioate;    2,2-Diphenylethyl (2S)-1-(3,3-dimethyl-2-oxopentanoyl) tetrahydro-1H-2-pyrrolidinecarbothioate;    3-[4-(Trifluoromethyl)phenyl]propyl (2S)-1-(3,3-dimethyl-2-oxopentanoyl)-2-pyrrolidinecarbothioate;    3-(2-Naphthyl)propyl (2S)-1-(3,3-dimethyl-2-oxopentanoyl)-2-pyrrolidinecarbothioate;    3-(3-Chlorophenyl)propyl (2S)-1-(3,3-dimethyl-2-oxopentanoyl)-2-pyrrolidinecarbothioate;    3-[3-(Trifluoromethyl)phenyl]propyl (2S)-1-(3,3-dimethyl-2-oxopentanoyl)-2-pyrrolidinecarbothioate;    3-(1-Biphenyl)propyl (2S)-1-(3,3-dimethyl-2-oxopentanoyl)-2-pyrrolidinecarbothioate;    3-(2-Fluorophenyl)propyl (2S)-1-(3,3-dimethyl-2-oxopentanoyl)-2-pyrrolidinecarbothioate;    3-(3-Fluorophenyl)propyl (2S)-1-(3,3-dimethyl-2-oxopentanoyl)-2-pyrrolidinecarbothioate;    3-(2-Chlorophenyl)propyl (2S)-1-(3,3-dimethyl-2-oxopentanoyl)-2-pyrrolidinecarbothioate;    3-(3,4-Dimethoxyphenyl)propyl (2S)-1-(3,3-dimethyl-2-oxopentanoyl)-2-pyrrolidinecarbothioate; and    pharmaceutically acceptable salts, esters, and solvates thereof.    
     
     
         49 . The pharmaceutical composition of  claim 48 , wherein the compound is 3,3-Diphenyl-1-propyl (2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarbothioate or a pharmaceutically acceptable salt, ester, or solvate thereof.  
     
     
         50 . The pharmaceutical composition of  claim 48 , wherein the compound is 3-(1-Naphthyl)propyl (2S)-1-3,3-dimethyl-2-oxopentanoyl)-2-pyrrolidinecarbothioate or a pharmaceutically acceptable salt, ester, or solvate thereof.  
     
     
         51 . The pharmaceutical composition of  claim 48 , wherein the compound is 2,2-Diphenylethyl (2S)-1-(3, 3-dimethyl-2-oxopencanoyl) tetrahydro-1H-2-pyrrolidinecarbothioate or a pharmaceutically acceptable salt, ester, or solvate thereof.  
     
     
         52 . The pharmaceutical composition of  claim 48 , wherein the compound is 3-[4-(Trifluoromethyl)phenyl]propyl (2S)-1-(3,3-dimethyl-2-oxopentanoyl)-2-pyrrolidinecarbothioate or a pharmaceutically acceptable salt, ester, or solvate thereof.  
     
     
         53 . The pharmaceutical composition of  claim 48 , wherein the compound is 3-(2-Naphthyl)propyl (2S)-i-(3, 3-dimethyl-2-oxopentanoyl)-2-pyrrolidinecarbothioate or a pharmaceutically acceptable salt, ester, or solvate thereof.  
     
     
         54 . The pharmaceutical composition of  claim 43 , wherein: 
 n is 1, and    x is S.    
     
     
         55 . The pharmaceutical composition of  claim 54 , wherein Z is CH 2 .  
     
     
         56 . The pharmaceutical composition of  claim 54 , wherein Z is S.  
     
     
         57 . The pharmaceutical composition of  claim 43 , wherein: 
 n is 2; and    X is O.    
     
     
         58 . The pharmaceutical composition of  claim 57 , wherein Z is CH 2 .  
     
     
         59 . The pharmaceutical composition of  claim 58 , wherein the compound is selected from the group consisting of: 
 2-({1-Oxo-6-phenyl}-hexyl-1-(2-cyclohexyl-1,2-dioxoethyl ) piperidine;    3,3-Dimethyl-1-[2-(4-phenylpentanoyl)piperidino]-1,2-pentanedione; and    pharmaceutically acceptable salts, esters, and solvates thereof.    
     
     
         60 . The pharmaceutical composition of  claim 57 , wherein Z is S.  
     
     
         61 . The pharmaceutical composition of  claim 60 , wherein the compound is selected from the group consisting of: 
 2-Phenyl-1-ethyl 1-(3,3-dimethyl-1,2-dioxopentyl)-2-piperidinecarbothioate;    2-Phenyl-1-ethyl 1-(2-phenyl-1,2-dioxoethyl)-2-piperidinecarbothioate;    3-Phenyl-1-propyl 1-(3,3-dimethyl-1,2-dioxobutyl)-2-piperidinecarbothioate;    4-Phenyl-1-butyl 1-(1,2-dioxo-3,3-dimethylbutyl)-2-piperidinecarbothioate;    1,5-Diphenyl-3-pentyl 1-(3,3-dimethyl-1,2-dioxopentyl)-2-piperidinecarbothioate;    1,5-Diphenyl-3-mercaptopentyl 1-(3-phenyl-1,2-dioxoethyl)-2-piperidinecarbothioate;    3-(para-Methoxyphenyl)-1-propyl 1-(1,2-dioxo-3,3-dimethylpentyl) piperidine-2-carbothioate;    3-(para-Methoxyphenyl)-1-propyl 1-(2-phenyl-1,2-dioxoethyl) piperidine-2-carbothioate;    3-(1-Naphthyl)-1-propyl 1-(3,3-dimethyl-1,2-dioxopentyl) piperidine-2-carbothioate;    2,2-Diphenylethyl (2S)-1-(3,3-dimethyl-2-oxopentanoyl)-2-piperidinecarbothioate;    3,3-Diphenylpropyl 1-(3,3-dimethyl-2-oxopentanoyl)-2-piperidinecarbothioate;    3-(2-Naphthyl)propyl (2R,S)-1-(3,3-dimethyl-2-oxopentanoyl)-2-piperidinecarbothioate;    4-Phenylbutyl 1-(3,3-dimethyl-2-oxopentanoyl)-2-piperidinecarbothioate;    3-Phenylpropyl 1-(3,3-dimethyl-2-oxopentanoyl)-2-piperidinecarbothioate;    3-(2-Chlorophenyl)propyl 1-(3,3-dimethyl-2-oxopentanoyl)-2-piperidinecarbothioate;    3-(2-Fluorophenyl)propyl 1-(3,3-dimethyl-2-oxopentanoyl)-2-piperidinecarbothioate; and    3-(3-Fluorophenyl)propyl 1-(3,3-dimethyl-2-oxopentanoyl)-2-piperidinecarbothioate; and    pharmaceutically acceptable salts, esters, and solvates thereof.    
     
     
         62 . The pharmaceutical composition of  claim 61 , wherein the compound is 3,3-Diphenylpropyl 1-(3,3-dimethyl-2-oxopentanoyl)-2-piperidinecarbothioate or a pharmaceutically acceptable salt, ester, or solvate thereof.  
     
     
         63 . The pharmaceutical composition of  claim 43 , wherein: 
 n is 2; and    X is S.    
     
     
         64 . The pharmaceutical composition of  claim 63 , wherein Z is CH 2 .  
     
     
         65 . The pharmaceutical composition of  claim 63 , wherein Z is S.  
     
     
         66 . The pharmaceutical composition of  claim 63 , wherein Z is CHR 1 .  
     
     
         67 . The pharmaceutical composition of  claim 66 , wherein the compound is 2-({1-Oxo-[2-{2′-phenyl}ethyl]-4-phenyl}-butyl-1-(3,3-dimethyl-1,2-dioxobutyl)piperidine.  
     
     
         68 . The pharmaceutical composition of  claim 37 , wherein the heterocyclic thioester or ketone is a compound formula III  
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt, ester, or solvate thereof, wherein: A, B, and C are independently CH 2 , O, S, SO, SO 2 , NH or NR 2 ; 
 X is O or S;  
 Z is S, CH 2 , CHR 1 , or CR 1 R 3 ;  
 R 1  and R 3  are independently C 1 -C 6  straight or branched chain alkyl or C 2 -C 6  straight or branched chain alkenyl, wherein said alkyl or alkenyl is substituted with one or more substituent(s) independently selected from the group consisting of (Ar 1 ) n , C 1 -C 6  straight or branched chain alkyl or C 2 -C 6  straight or branched chain alkenyl substituted with (Ar 1 ) n , C 3 -C 8  cycloalkyl, C 1 -C 6  straight or branched chain alkyl or C 2 -C 6  straight or branched chain alkenyl substituted with C 3 -C 8  cycloalkyl, and Ar 2 ;  
 R 2  is either C 1 -C 9  straight or branched chain alkyl or C 2 -C 9  straight or branched chain alkenyl, C 3 -C 8  cycloalkyl, C 5 -C 7  cycloalkenyl or Ar 1 , wherein said alkyl, alkenyl, cycloalkyl or cycloalkenyl is either unsubstituted or substituted with one or more substituent(s) independently selected from the group consisting of C 1 -C 4  straight or branched chain alkyl, C 2 -C 4  straight or branched chain alkenyl, and hydroxy; and  
 Ar 1  and Ar 2  are independently an alicyclic or aromatic, mono-, bi- or tricyclic, carbo- or heterocyclic ring, wherein said ring is either unsubstituted or substituted with one or more substituent(s) independently selected from the group consisting of halo, hydroxy, nitro, trifluoromethyl, 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, and amino; wherein the individual ring size is 5-8 members; and wherein the heterocyclic ring contains 1-6 heteroatom(s) independently selected from the group consisting of O, N, and S.  
 
     
     
         69 . The pharmaceutical composition of  claim 68 , wherein: 
 A is CH 2 ;    B is CH 2  or S;    C is CH 2  or NH;    X is O or S;    Z is S or CH 2 ;    R 1  is 2-phenethyl or 3-phenylpropyl; and    R 2  is 1,1-dimethylpropyl.    
     
     
         70 . The pharmaceutical composition of  claim 37 , wherein the heterocyclic thioester or ketone is a compound is of formula IV  
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt, ester, or solvate thereof, wherein:  
         A, B, C and D are independently CH 2 , O, S, SO, SO 2 , NH, or NR 2 ;  
         X is O or S;  
         Z is S, CH 2 , CHR 1 , or CR 1 R 3 ;  
         R 1  and R 3  are independently C 1 -C 6  straight or branched chain alkyl or C 2 -C 6  straight or branched chain alkenyl, wherein said alkyl or alkenyl is substituted with one or more substituent(s) independently selected from the group consisting of (Ar 1 ) n , C 3 -C 6  straight or branched chain alkyl or C 2 -C 6  straight or branched chain alkenyl substituted with (Ar 1 ) n , C 3 -C 8  cycloalkyl, C 1 -C 6  straight or branched chain alkyl or C 2 -C 6  straight or branched chain alkenyl substituted with C 3 -C 8  cycloalkyl, and Ar 2 ;  
         n is 1 or 2;  
         R 2  is either C 1 -C 9  straight or branched chain alkyl or C 2 -C 9  straight or branched chain alkenyl, C 3 -C 8  cycloalkyl, C 5 -C 7  cycloalkenyl or Ar 1 , wherein said alkyl, alkenyl, cycloalkyl or cycloalkenyl is either unsubstituted or substituted with one or more substituent(s) independently selected from the group consisting of C 1 -C 4  straight or branched chain alkyl, C 2 -C 4  straight or branched chain alkenyl, and hydroxy; and  
         Ar 1  and Ar 2  are independently an alicyclic or aromatic, mono-, bi- or tricyclic, carbo- or heterocyclic ring, wherein said ring is either unsubstituted or substituted with one or more substituent(s) independently selected from the group consisting of halo, hydroxy, nitro, trifluoromethyl, 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, and amino; wherein the individual ring size is 5-8 members; and wherein the heterocyclic ring has 1-6 heteroatom(s) independently selected from the group consisting of O, N, and S.  
       
     
     
         71 . The pharmaceutical composition of  claim 70 , wherein: 
 A is CH 2 ;    B is CH 2 ;    C is S or O;    D is CH 2 ;    X is O;    Z is CH 2  or S;    R 1  is 3-phenylpropyl or 2-phenethyl; and    R 2  is 1,1-dimethylpropyl.    
     
     
         72 . The pharmaceutical composition of  claim 37 , wherein the heterocyclic thioester or ketone is a compound of formula V  
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt, ester, or solvate thereof, wherein:  
         V is C, N or S;  
         A and B, taken together with V and the carbon atom to which they are respectively attached, form a 5-7 membered saturated or unsaturated heterocyclic ring containing, in addition to V, one or more heteroatom(s) independently selected from the group consisting of O, S, SO, SO 2 , N, NH, and NR 4 ;  
         R 4  is either C 1 -C 9  straight or branched chain alkyl, C 2 -C 9  straight or branched chain alkenyl, C 3 -C 9  cycloalkyl, C 5 -C 7  cycloalkenyl, or Ar 3 , wherein R 4  is either unsubstituted or substituted with one or more substituent(s) independently selected from the group consisting of halo, haloalkyl, carbonyl, carboxy, hydroxy, nitro, trifluoromethyl, C 1 -C 6  straight or branched chain alkyl, C 2 -C 6  straight or branched chain alkenyl, Cl-C 4  alkoxy, C 2 -C 4  alkenyloxy, phenoxy, benzyloxy, thioalkyl, alkylthio, sulfhydryl, amino, alkylamino, aminoalkyl, aminocarboxyl, and Ar 4 ;  
         Ar 3  and Ar 4  are independently an alicyclic or aromatic, mono-, bi- or tricyclic, carbo- or heterocyclic ring; wherein the individual ring size is 5-8 members; wherein said heterocyclic ring contains 1-6 heteroatom(s) independently selected from the group consisting of O, N, and S; and  
         R 1 , R 2 , W, X, Y, and Z are as defined in  claim 41  above.