Small molecule sulfonamide hair growth compositions and uses

Abstract

This invention relates to pharmaceutical compositions and methods for treating alopecia and promoting hair growth using small molecule sulfonamides.

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 small molecule sulfonamide.  
     
     
         2 . The method of    claim 1   , wherein the small molecule sulfonamide has an affinity for an FKBP-type immunophilin.  
     
     
         3 . The method of    claim 2   , wherein the FKBP-type immunophilin is FKBP-12.  
     
     
         4 . The method of    claim 1   , wherein the small molecule sulfonamide is immunosuppressive.  
     
     
         5 . The method of    claim 1   , wherein the small molecule sulfonamide is non-immunosuppressive.  
     
     
         6 . The method of    claim 1   , wherein the small molecule sulfonamide is a compound of formula I  
                   
       or a pharmaceutically acceptable salt thereof, wherein: 
 A is CH 2 , O, NH, or N—(C 1 -C 4  alkyl);  
 B and D are independently Ar, hydrogen, 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 unsubstituted or substituted with C 5 -C 7  cycloalkyl, C 5 -C 7  cycloalkenyl or Ar, and wherein one or two carbon atom(s) of said alkyl or alkenyl may be substituted with one or two heteroatom(s) independently selected from the group consisting of O, S, SO, and SO 2  in chemically reasonable substitution patterns, or  
                 
 
 wherein  
 Q is hydrogen, C 1 -C 6  straight or branched chain alkyl, or C 2 -C 6  straight or branched chain alkenyl; and  
 T is Ar or C 5 -C 7  cycloalkyl substituted at positions 3 and 4 with one or more substituent(s) independently selected from the group consisting of hydrogen, hydroxy, O—(C 1 -C 4  alkyl), O—(C 2 -C 4  alkenyl), and carbonyl;  
 provided that both B and D are not hydrogen;  
 Ar is selected from the group consisting of phenyl, 1-napthyl, 2-naphthyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, monocyclic and bicyclic heterocyclic ring systems with individual ring sizes being 5 or 6 which contain in either or both rings a total of 1-4 heteroatoms independently selected from the group consisting of O, N, and S; wherein Ar contains 1-3 substituent(s) independently selected from the group consisting of hydrogen, halo, hydroxy, nitro, trifluoromethyl, trifluoromethoxy, C 1 -C 6  straight or branched chain alkyl, C 2 -C 6  straight or branched chain alkenyl, O—(C 1 -C 4  straight or branched chain alkyl), O—(C 2 -C 4  straight or branched chain alkenyl), O-benzyl,-O-phenyl, 1,2-methylenedioxy, amino, carboxyl, and phenyl;  
 E is C 1 -C 6  straight or branched chain alkyl, C 2 -C 6  straight or branched chain alkenyl, C 5 -C 7  cycloalkyl, C 5 -C 7  cycloalkenyl substituted with C 1 -C 4  straight or branched chain alkyl or C 2 -C 4  straight or branched chain alkenyl, (C 2 -C 4  alkyl or C 2 -C 4  alkenyl) —Ar, or Ar;  
 J is hydrogen, C 1  or C 2  alkyl, or benzyl; K is C 1 -C 4  straight or branched chain alkyl, benzyl, or cyclohexylmethyl; or J and K are taken together to form a 5-7 membered heterocyclic ring which is substituted with O, S, SO, or SO 2 ;  
 n is 0 to 3; and  
 the stereochemistry at carbon positions 1 and 2 is R or S.  
 
     
     
         7 . The method of    claim 6   , wherein J and K are taken together and the compound is represented by formula II  
                   
       or a pharmaceutically acceptable salt thereof, wherein: 
 n is 1 or 2; and  
 m is 0 or 1.  
 
     
     
         8 . The method of    claim 6   , wherein: 
 B is selected from the group consisting of hydrogen, benzyl, 2-phenylethyl and 3-phenylpropyl;    D is selected from the group consisting of phenyl, 3-phenylpropyl, 3-phenoxyphenyl and 4-phenoxyphenyl; and    E is selected from the group consisting of phenyl, 4-methylphenyl, 4-methoxyphenyl, 2-thienyl, 2,4,6-triisopropylphenyl, 4-fluorophenyl, 3-methoxyphenyl, 2-methoxyphenyl, 3,5-dimethoxyphenyl, 3,4,5-trimethoxyphenyl, methyl, 1-naphthyl, 8-quinolyl, 1-(5-N,N-dimethylamino)-naphthyl, 4-iodophenyl, 2,4,6-trimethylphenyl, benzyl, 4-nitrophenyl, 2-nitrophenyl, 4-chlorophenyl, and E-styrenyl.    
     
     
         9 . The method of    claim 1   , wherein the small molecule sulfonamide is a compound of formula III  
                   
       or a pharmaceutically acceptable salt thereof, wherein: 
 B and D are independently Ar, hydrogen, 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 unsubstituted or substituted with C 5 -C 7  cycloalkyl, C 5 -C 7  cycloalkenyl or Ar, and wherein one or two carbon atom(s) of said alkyl or alkenyl may be substituted with one or two heteroatom(s) independently selected from the group consisting of O, S, SO, and SO 2  in chemically reasonable substitution patterns, or  
                 
 
 wherein  
 Q is hydrogen, C 1 -C 6  straight or branched chain alkyl, or C 2 -C 6  straight or branched chain alkenyl; and  
 T is Ar or C 5 -C 7  cycloalkyl substituted at positions 3 and 4 with one or more substituent(s) independently selected from the group consisting of hydrogen, hydroxy, O—(C 1 -C 4  alkyl), O—(C 2 -C 4  alkenyl), and carbonyl;  
 provided that both B and D are not hydrogen;  
 Ar is selected from the group consisting of phenyl, 1-napthyl, 2-naphthyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, monocyclic and bicyclic heterocyclic ring systems with individual ring sizes being 5 or 6 which contain in either or both rings a total of 1-4 heteroatoms independently selected from the group consisting of O, N, and S; wherein Ar contains 1-3 substituent(s) independently selected from the group consisting of hydrogen, halo, hydroxy, nitro, trifluoromethyl, trifluoromethoxy, C 1 -C 6  straight or branched chain alkyl C 2 -C 6  straight or branched chain alkenyl, O—(C 1 -C 4  straight or branched chain alkyl), O—(C 2 -C 4  straight or branched chain alkenyl), O-benzyl, O-phenyl, 1,2-methylenedioxy, amino, carboxyl, and phenyl;  
 E is C 1 -C 6  straight or branched chain alkyl, C 2 -C 6  straight or branched chain alkenyl, C 5 -C 7  cycloalkyl, C 5 -C 7  cycloalkenyl substituted with C 1 -C 4  straight or branched chain alkyl or C 2 -C 4  straight or branched chain alkenyl, (C 2 -C 4  alkyl or C 2 -C 4  alkenyl) —Ar, or Ar; and  
 m is 0 to 3.  
 
     
     
         10 . The method of    claim 1   , wherein the small molecule sulfonamide is a compound of formula IV  
                   
       or a pharmaceutically acceptable salt thereof, wherein: 
 B and D are independently Ar, hydrogen, 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 unsubstituted or substituted with C 5 -C 7  cycloalkyl, C 5 -C 7  cycloalkenyl, or Ar, and wherein one or two carbon atom(s) of said alkyl or alkenyl may be substituted with one or two heteroatom(s) independently selected from the group consisting of O, S, SO, and SO 2  in chemically reasonable substitution patterns, or  
                 
 
 wherein  
 Q is hydrogen, C 1 -C 6  straight or branched chain alkyl, or C 2 -C 6  straight or branched chain alkenyl; and  
 T is Ar or C 5 -C 7  cycloalkyl substituted at positions 3 and 4 with one or more substituent(s) independently selected from the group consisting of hydrogen, hydroxy, O—(C 1 -C 4  alkyl), O—(C 2 -C 4  alkenyl) and carbonyl;  
 provided that both B and D are not hydrogen;  
 Ar is selected from the group consisting of phenyl, 1-napthyl, 2-naphthyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, monocyclic and bicyclic heterocyclic ring systems with individual ring sizes being 5 or 6 which contain in either or both rings a total of 1-4 heteroatoms independently selected from the group consisting of O, N, and S; wherein Ar contains 1-3 substituent(s) independently selected from the group consisting of hydrogen, halo, hydroxy, nitro, trifluoromethyl, trifluoromethoxy, C 1 -C 6  straight or branched chain alkyl, C 2 -C 6  straight or branched chain alkenyl, O—(C 1 -C 4  straight or branched chain alkyl), O—(C 2 -C 4  straight or branched chain alkenyl), O-benzyl, O-phenyl, 1,2-methylenedioxy, amino, carboxyl, and phenyl;  
 E is C 1 -C 6  straight or branched chain alkyl, C 2 -C 6  straight or branched chain alkenyl, C 5 -C 7  cycloalkyl, C 5 -C 7  cycloalkenyl substituted with C 1 -C 4  straight or branched chain alkyl or C 2 -C 4  straight or branched chain alkenyl, (C 2 -C 4  alkyl or C 2 -C 4  alkenyl) —Ar, or Ar; and  
 m is 0 to 3.  
 
     
     
         11 . The method of    claim 1   , wherein the small molecule sulfonamide is a compound of formula V  
                   
       or a pharmaceutically acceptable salt, ester, or solvate thereof, wherein: 
 V is C, N, or S;  
 J and K, 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) 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  cycloakyl, C 5 -C 7  cycloalkenyl, or Ar 1 , wherein R is either unsubstituted of 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, alkylamino, aminoalkyl, aminocarboxyl, and Ar 2 ;  
 Ar 1  and Ar 2  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;  
 A, B, D, E, and n are as defined in    claim 6    above.  
 
     
     
         12 . A pharmaceutical composition which comprises: 
 (i) an effective amount of a small molecule sulfonamide for treating alopecia or promoting hair growth in an animal; and    (ii) a pharmaceutically acceptable carrier.    
     
     
         13 . The pharmaceutical composition of    claim 12   , wherein the small molecule sulfonamide has an affinity for an FKBP-type immunophilin.  
     
     
         14 . The pharmaceutical composition of    claim 13   , wherein the FKBP-type immunophilin is FKBP-12.  
     
     
         15 . The pharmaceutical composition of    claim 12   , wherein the small molecule sulfonamide is immunosuppressive.  
     
     
         16 . The pharmaceutical composition of    claim 12   , wherein the small molecule sulfonamide is non-immunosuppressive.  
     
     
         17 . The pharmaceutical composition of    claim 12   , wherein the small molecule sulfonamide is a compound of formula I  
                   
       or a pharmaceutically acceptable salt thereof, wherein: 
 A is CH 2 , O, NH, or N—(C 1 -C 4  alkyl)  
 B and D are independently Ar, hydrogen, 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 unsubstituted or substituted with C 5 -C 7  cycloalkyl, C 5 -C 7  cycloalkenyl or Ar, and wherein one or two carbon atom(s) of said alkyl or alkenyl may be substituted with one or two heteroatom(s) independently selected from the group consisting of O, S, SO, and SO 2  in chemically reasonable substitution patterns, or  
                 
 
 wherein  
 Q is hydrogen, C 1 -C 6  straight or branched chain alkyl, or C 2 -C 6  straight or branched chain alkenyl; and  
 T is Ar or C 5 -C 7  cycloalkyl substituted at positions 3 and 4 with one or more substituent(s) independently selected from the group consisting of hydrogen, hydroxy, O—(C 1 -C 4  alkyl), O—(C 2 -C 4  alkenyl), and carbonyl;  
 provided that both B and D are not hydrogen;  
 Ar is selected from the group consisting of phenyl, 1-napthyl, 2-naphthyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, monocyclic and bicyclic heterocyclic ring systems with individual ring sizes being 5 or 6 which contain in either or both rings a total of 1-4 heteroatoms independently selected from the group consisting of O, N, and S; wherein Ar contains 1-3 substituent(s) independently selected from the group consisting of hydrogen, halo, hydroxy, nitro, trifluoromethyl, trifluoromethoxy, C 1 -C 6  straight or branched chain alkyl, C 2 -C 6  straight or branched chain alkenyl, O—(C 1 -C 4  straight or branched chain alkyl), O—(C 2 -C 4  straight or branched chain alkenyl), O-benzyl, O-phenyl, 1,2-methylenedioxy, amino, carboxyl, and phenyl;  
 E is C 1 -C 6  straight or branched chain alkyl, C 2 -C 6  straight or branched chain alkenyl, C 5 -C 7  cycloalkyl, C 5 -C 7  cycloalkenyl substituted with C 1 -C 4  straight or branched chain alkyl or C 2 -C 4  straight or branched chain alkenyl, (C 2 -C 4  alkyl or C 2 -C 4  alkenyl) —Ar, or Ar;  
 J is hydrogen, C 1  or C 2  alkyl, or benzyl; K is C 1 -C 4  straight or branched chain alkyl, benzyl, or cyclohexylmethyl; or J and K are taken together to form a 5-7 membered heterocyclic ring which is substituted with O, S, SO, or SO 2 ;  
 n is 0 to 3; and  
 the stereochemistry at carbon positions 1 and 2 is R or S.  
 
     
     
         18 . The pharmaceutical composition of    claim 17   , wherein J and K are taken together and the compound is represented by formula II  
                   
       wherein: 
 is n is 1 or 2; and  
 m is 0 or 1.  
 
     
     
         19 . The pharmaceutical comnposition of    claim 16   , wherein: 
 B is selected from the group consisting of hydrogen, benzyl, 2-phenylethyl and 3-phenylpropyl;    D is selected from the group consisting of phenyl, 3-phenylpropyl, 3-phenoxyphenyl and 4-phenoxyphenyl; and    E is selected from the group consisting of phenyl, 4-methylphenyl, 4-methoxyphenyl, 2-thienyl, 2,4,6-triisopropylphenyl, 4-fluorophenyl, 3-methoxyphenyl, 2-methoxyphenyl, 3,5-dimethoxyphenyl, 3,4,5-trimethoxyphenyl, methyl, 1-naphthyl, 8-quinolyl, 1-(5-N,N-dimethylamino)-naphthyl, 4-iodophenyl, 2,4,6-trimethylphenyl, benzyl, 4-nitrophenyl, 2-nitrophenyl, 4-chlorophenyl, and E-styrenyl.    
     
     
         20 . The pharmaceutical composition of    claim 12   , wherein the small molecule sulfonamide is a compound of formula III  
                   
       or a pharmaceutically acceptable salt thereof, wherein: 
 B and D are independently Ar, hydrogen, 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 unsubstituted or substituted with C 5 -C 7  cycloalkyl, C 5 -C 7  cycloalkenyl or Ar, and wherein one or two carbon atom(s) of said alkyl or alkenyl may be substituted with one or two hete-roatom(s) independently selected from the group consisting of O, S, SO, and SO 2  in chemically reasonable substitution patterns, or  
                 
 
 wherein  
 Q is hydrogen, C 1 -C 6  straight or branched chain alkyl, or C 2 -C 6  straight or branched chain alkenyl; and  
 T is Ar or C 5 -C 7  cycloalkyl substituted at positions 3 and 4 with one or more substituent(s) independently selected from the group consisting of hydrogen, hydroxy, O—(C 1 -C 4  alkyl), O—(C 2 -C 4  alkenyl), and carbonyl;  
 provided that both B and D are not hydrogen;  
 Ar is selected from the group consisting of phenyl, 1-napthyl, 2-naphthyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, monocyclic and bicyclic heterocyclic ring systems with individual ring sizes being 5 or 6 which contain in either or both rings a total of 1-4 heteroatoms independently selected from the group consisting of O, N, and S; wherein Ar contains 1-3 substituent(s) independently selected from the group consisting of hydrogen, halo, hydroxy, nitro, trifluoromethyl, trifluoromethoxy, C l -C 6  straight or branched chain alkyl, C 2 -C 6  straight or branched chain alkenyl, O—(C 1 -C 4  straight or branched chain alkyl), O—(C 2 -C 4  straight or branched chain alkenyl), O-benzyl, O-phenyl, 1,2-methylenedioxy, amino, carboxyl, and phenyl;  
 E is C 1 -C 6  straight or branched chain alkyl, C 2 -C 6  straight or branched chain alkenyl, C 5 -C 7  cycloalkyl, C 5 -C 7  cycloalkenyl substituted with C 1 -C 4  straight or branched chain alkyl or C 2 -C 4  straight or branched chain alkenyl, (C 2 -C 4  alkyl or C 2 -C 4  alkenyl) —Ar, or Ar; and  
 m is 0 to 3.  
 
     
     
         21 . The pharmaceutical composition of    claim 12   , wherein the small molecule sulfonamide is a compound of formula IV  
                   
       or a pharmaceutically acceptable salt thereof, wherein: 
 B and D are independently Ar, hydrogen, 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 unsubstituted or substituted with C 5 -C 7  cycloalkyl, C 5 -C 7  cycloalkenyl, or Ar, and wherein one or two carbon atom(s) of said alkyl or alkenyl may be substituted with one or two heteroatom(s) independently selected from the group consisting of O, S, SO, and SO 2  in chemically reasonable substitution patterns, or  
                 
 
 wherein  
 Q is hydrogen, C 1 -C 6  straight or branched chain alkyl, or C 2 -C 6  straight or branched chain alkenyl; and  
 T is Ar or C 5 -C 7  cycloalkyl substituted at positions 3 and 4 with one or more substituent(s) independently selected from the group consisting of hydrogen, hydroxy, O—(C 1 -C 4  alkyl) O—(C 2 -C 4  alkenyl) and carbonyl;  
 provided that both B and D are not hydrogen;  
 Ar is selected from the group consisting of phenyl, 1-napthyl, 2-naphthyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, monocyclic and bicyclic heterocyclic ring systems with individual ring sizes being 5 or 6 which contain in either or both rings a total of 1-4 heteroatoms independently selected from the group consisting of O, N, and S; wherein Ar contains 1-3 substituent(s) independently selected from the group consisting of hydrogen, halo, hydroxy, nitro, trifluoromethyl, trifluoromethoxy, C 1 -C 6  straight or branched chain alkyl, C 2 -C 6  straight or branched chain alkenyl, O—(C 1 -C 4  straight or branched chain alkyl), O—(C 2 -C 4  straight or branched chain alkenyl), O-benzyl, O-phenyl, 1,2-methylenedioxy, amino, carboxyl, and phenyl;  
 E is C 1 -C 6  straight or branched chain alkyl, C 2 -C 6  straight or branched chain alkenyl, C 5 -C 7  cycloalkyl, C 5 -C 7  cycloalkenyl substituted with C 1 -C 4  straight or branched chain alkyl or C 2 -C 4  straight or branched chain alkenyl, (C 2 -C 4  alkyl or C 2 -C 4  alkenyl) —Ar, or Ar; and  
 m is 0 to 3.  
 
     
     
         22 . The pharmaceutical composition of    claim 12   , wherein the small molecule sulfonamide is a compound of formula V  
                   
       or a pharmaceutically acceptable salt, ester, or solvate thereof, wherein: 
 V is C, N, or S;  
 J and K, 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) selected from the group consisting of O, S, SO, SO 2 , N, NH, and NR;  
 R is either C-C 9  straight or branched chain alkyl, C 2 -C 9  straight or branched chain alkenyl, C 3 -C 9  cycloakyl, C 5 -C 7  cycloalkenyl, or Ar 1 , wherein R is either unsubstituted of 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, alkylamino, aminoalkyl, aminocarboxyl, and Ar 2 ;  
 Ar 1  and Ar 2  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;  
 A, B, D, E, and n are as defined in    claim 17    above.