Heterocyclic ester and amide hair growth compositions and uses

Abstract

This invention relates to pharmaceutical compositions and methods for treating alopecia and promoting hair growth using heterocyclic esters or amides.

We claim:  
     
         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 ester or amide.  
     
     
         2 . The method of    claim 1   , wherein the heterocyclic ester or amide is non-immunosuppressive.  
     
     
         3 . The method Of    claim 1   , wherein the heterocyclic ester or amide has an affinity for an FKBP-type immunophilin.  
     
     
         4 . The method of    claim 3   , wherein the FKBP-type immunophilin if FKBP-12.  
     
     
         5 . The method of    claim 1   , wherein the heterocyclic ester or amide is a compound of formula I  
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt, ester, or solvate thereof, wherein: 
 A and B, together with the nitrogen and carbon atoms to which they are respectively attacked, 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 1 , N, NH, or NR 1 heteroatom;  
 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 C 2 -C 6  straight or branched chain alkenyl, which 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 9  cycloalkyl, 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 9  cycloalkyl, C 9 -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 the 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 5-6 members; and wherein the heterocyclic ring contains 1-6 heteroatom(s) independently selected from the group consisting of O, N, and S.  
 
     
     
         6 . The method of    claim 5   , 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.  
     
     
         7 . The method of    claim 5   , wherein the one or more additional heteroatom(s) in the 5-7 membered saturated or unsaturated heterocyclic ring is NH or NR 1 .  
     
     
         8 . The method of    claim 1   , wherein the heterocyclic ester or amide is a compound of formula II  
       
         
           
           
               
               
           
         
       
       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 1 ;  
 R 1  is C 1 -C 5  straight or branched chain alkyl or C 2 -C 5  straight or branched chain alkenyl, which is substituted with one or more substituent(s) independently selected from the group consisting of (Ar 1 ) n  and C 1 -C 6  straight or branched chain alkyl or C 2 -C 6  straight or branched chain alkenyl substituted with (Ar 1 ) n ;  
 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 1 -C 8  cycloalkyl, C 5 -C 7  cycloalkenyl or Ar 1 ; and  
 Ar 1  is an alicyclic or aromatic, mono-, bi- or tricyclic, carbo- or heterocyclic ring, wherein the 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 5-6 members; and wherein the heterocyclic ring contains 1-6 heteroatom(s) independently selected from the group consisting of O, N, and S.  
 
     
     
         9 . The method of    claim 8   , 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 2  is selected from the group consisting of 1,1-dimethylpropyl, cyclohexyl, and tert-butyl.    
     
     
         10 . The method of    claim 9   , wherein: 
 S is CH    C is NH; and    R 1  is 3-phenylpropyl.    
     
     
         11 . The method of    claim 9   , wherein: 
 B is S; and    C is CH 2 .    
     
     
         12 . The method of    claim 8   , 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; 
 3-(3-pyridyl)-1-propyl (2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-(4-thiazolidine) carboxylate; and    pharmaceutically acceptable salts, esters, and solvates thereof.    
     
     
         13 . The method of    claim 1   , wherein the heterocyclic ester or amide is a compound of formula III  
       
         
           
           
               
               
           
         
       
       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 1 ;  
 R 1  is C 1 -C 5  straight or branched chain alkyl or C 2 -C 5  straight or branched chain alkenyl, which is substituted with one or more substituent(s) independently selected from the group consisting of (AR 1 ) n  and C 1 -C 6  straight or branched chain alkyl or C 2 -C 6  straight or branched chain alkenyl substituted with (Ar 1 ) n ;  
 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 1 ; and  
 Ar 1 is an alicyclic or aromatic, mono-, bi- or tricyclic, carbo- or heterocyclic ring, wherein the 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 1 -C 4  alkenyloxy, phenoxy, benzyloxy, and amino; wherein the individual ring size is 5-6 members; and wherein the heterocyclic ring contains 1-6 heteroatom(s) independently selected from the group consisting of O, N, and S.  
 
     
     
         14 . The method of    claim 13   , 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 1,1-dimethylpropyl, cyclohexyl, tert-butyl, phenyl, and 3,4,5- trimethoxyphenyl.    
     
     
         15 . The compound of    claim 14   , wherein: 
 C is NH; and    R 2  is 1,1-dimethylpropyl or phenyl.    
     
     
         16 . The method of    claim 1   , wherein the heterocyclic ester or amide is a compound of formula IV  
       
         
           
           
               
               
           
         
       
       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 V, one or more heteroatom(s) independently selected from the group consisting of O, S, SO, SO 2 , N, NH, and NR;  
 R 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 l wherein R 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, C 1 -C 4  alkoxy, C 2 -C 4  alkenyloxy; phenoxy, benzyloxy, thioalkyl, alkylthio, sulfhydryl, amino, alkylamirnno, aminoalkyl, aminocarboxyl and Ar 4 ;  
 Ar 3  and Ar 4  are independenrly 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 5    above.  
 
     
     
         17 . A pharmaceutical composition which comprises: 
 (i) an effective amount of a heterocyclic ester or amide for treating alopecia or promoting hair growth in an animal; and    (ii) a pharmaceutically acceptable carrier.    
     
     
         18 . The pharmaceutical composition of    claim 17   , wherein the heterocyclic ester or amide is non-immunosuppressive.  
     
     
         19 . The pharmaceutical composition of    claim 17   , wherein the heterocyclic ester or amide has an affinity for an FKBP-type immunophilin.  
     
     
         20 . The pharmaceutical composition of    claim 19   , wherein the FKBP-type immunophilin is FKBP-12.  
     
     
         21 . The pharmaceutical composition of    claim 17   , wherein the heterocyclic ester or amide is a compound of formula I  
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt, ester or solvate 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, one or more additional O, S, SO, SO 2 , N, NH, or NR 1  heteroatom;  
 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 C 2 -C 6  straight or branched chain alkenyl, which 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 1 -C 6  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 1 -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 1 -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 the 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 5-6 members; and wherein the heterocyclic ring contains 1-6 heteroatom(s) independently selected from the group consisting of O, N, and S.  
 
     
     
         22 . The pharmaceutical composition of    claim 21   , wherein the mono- or bicyclic, carbo- or heterocyclic ring is selected from the group consisting of napthyl, indolyl, furyl, thiazolyl, thienyl, pyridyl, quinolinyl, isoquinolinyl, fluorenyl, and phenyl.  
     
     
         23 . The pharmaceutical composition of    claim 21   , wherein the one or more additional heteroatom(s) in the 5-7 membered saturated or unsaturated heterocyclic ring is NH or NR 1 .  
     
     
         24 . The pharmaceutical composition of    claim 17   , wherein the heterocyclic ester or amide is a compound of formula II  
       
         
           
           
               
               
           
         
       
       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 1 ;  
 R 1  is C 1 -C 6  straight or branched chain alkyl or C 2 -C 6  straight or branched chain alkenyl, which is substituted with one or more substituent(s) independently selected from the group consisting of (Ar 1 ) n  and C 1 -C 6  straight or branched chain alkyl or C 2 -C 6  straight or branched chain alkenyl substituted with (Ar 1 ) n ;  
 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 9  cycloalkyl, C 5 -C 7  cycloalkenyl, or Ar 1 ; and  
 Ar 1  is a an alicyclic or aromatic, mono, bi- or tricyclic, carbo- or heterocyclic ring, wherein the ring is either unsubstituted or substituted with one or more substituent(s) independently selected from the group consisting or 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 1 -C 5  alkenyloxy, phenoxy, benzyloxy, and amino, wherein the individual ring is 5-6 members; and wherein the heterocyclic ring contains 1-6 heteroatom(s) independently selected from the group consisting of O, N, and S.  
 
     
     
         25 . The pharmaceutical composition of    claim 24   , wherein: 
 A is OF 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 2  is selected from the group consisting of 1,1-dimethylpropyl, cyclohexyl, and tert-butyl.    
     
     
         26 . The pharmaceutical composition of    claim 25   , wherein: 
 B is CH 2 ;    C is NH; and    R 1  is 3-phenylpropyl.    
     
     
         27 . The pharmaceutical composition of    claim 25   , wherein: 
 B is S; and    C is CH 2 .    
     
     
         28 . The pharmaceutical composition of    claim 24   , 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    pharmaceutically acceptable salts, esters, and solvates thereof.    
     
     
         29 . The pharmaceutical composition of    claim 17   , wherein the heterocyclic ester or amide is a compound of formula III  
       
         
           
           
               
               
           
         
       
       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 1 ;  
 R 1  is C 1 -C 5  straight or branched chain alkyl or C 2 -C 5  straight or branched chain alkenyl, which is substituted with one or more substituent(s) independently selected from the group consisting of (Ar 1 ) n  and C 1 -C 6  straight or branched chain alkenyl or C 2 -C 6  straight or branched chain alkenyl substituted with (Ar 1 ) n ;  
 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 9  cycloalkyl, C 5 -C 7  cycloalkenyl, or Ar 1 ; and  
 Ar 1 is an alicyclic or aromatic, mono-, bi- or tricyclic, carbo- or heterocyclic ring, wherein the 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 5-6 members; and wherein the heterocyclic ring contains 1-6 heteroatom(s) independently selected from the group consisting of O, N, and S.  
 
     
     
         30 . The pharmaceutical composition of    claim 29   , wherein: 
 A is C;    B is CH 3 ;    C is S, O or NH;    D is CH 2 ;    R, is selected the group consisting of 3-phenylpropyl and (3,4,5-trimethoxy)phenylpropyl; and    R 2  is selected from the group consisting of 1,1-dimethylpropyl, cyclohexyl, tert-butyl, phenyl, and 3,4,5-trimethoxyphenyl.    
     
     
         31 . The compound of    claim 30   , wherein: 
 C is NH; and    R 2  is 1,1-dimethylpropyl or phenyl.    
     
     
         32 . The pharmaceutical composition of    claim 17   , wherein the heterocyclic ester or amide is a compound of formula IV  
       
         
           
           
               
               
           
         
       
       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;  
 R is either C 1 -C 9  straight or branched chain alkyl, C 1 -C 9  straight or branched chain alkenyl, C 1 -C 9  cycloalkyl, C 5 -C 7  cycloalkenyl, or Ar 3 , wherein R is 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 5  straight or branched chain alkenyl, C 1 -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 21    above.