Small molecule carbamate or urea hair growth compositions and uses

Abstract

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

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 carbamate or urea.  
     
     
         2 . The method of  claim 1 , wherein the small molecule carbamate or urea 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 carbamate or urea is immunosuppressive.  
     
     
         5 . The method of  claim 1 , wherein the small molecule carbamate or urea is non-immunosuppressive.  
     
     
         6 . The method of  claim 1 , wherein the small molecule carbamate or urea is a compound of formula I  
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt, ester, or solvate 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, C 2 -C 6  straight or branched chain alkenyl or alkynyl, C 5 -C 7  cycloalkyl substituted C 1 -C 6  straight or branched chain alkyl or C 3 -C 6  straight or branched chain alkenyl or alkynyl, C 5 -C 7  cycloalkenyl substituted C 1 -C 6  straight or branched chain alkyl or C 3 -C 6  straight or branched chain alkenyl or alkynyl, Ar substituted C 1 -C 6  straight or branched chain alkyl, or Ar substituted C 3 -C 6  straight or branched chain alkenyl or alkynyl; wherein any carbon atom of said alkyl is optionally replaced by a heteroatom selected from the group consisting of O, S, SO, SO 2  and NR, wherein R is selected from the group consisting of hydrogen, C 1 -C 4  straight or branched chain alkyl, C 3 -C 4  straight or branched chain alkenyl or alkynyl, and C 1 -C 4  bridging alkyl wherein a bridge is formed between the nitrogen and a carbon atom of said heteroatom-containing chain to form a ring, and wherein said ring is optionally fused to an Ar group;  
 J is selected from the group consisting of hydrogen, C 1 -C 6  straight or branched chain alkyl, C 3 -C 6  straight or branched chain alkenyl, and —CH 2 Ar; K is selected from the group consisting of C 1 -C 4  straight or branched chain alkyl, —CH 2 Ar, and 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 ;  
 Z is C or S;  
 Y is O or N, provided that 
 when Y is O, then R 1  is a lone pair of electrons and R 2  is selected from the group consisting of Ar, C 3 -C 6  straight or branched chain alkyl, and C 3 -C 6  straight or branched chain alkenyl or alkynyl; and  
 when Y is N, then R 1  and R 2  are independently selected from the group consisting of Ar, C 1 -C 6  straight or branched chain alkyl, and C 3 -C 6  straight or branched chain alkenyl or alkynyl; or R 1  and R 2  are taken together to form a heterocyclic 5-6 membered ring selected from the group consisting of pyrrolidine, imidazolidine, pyrazolidine, piperidine, and piperazine;  
 
 Ar is a carbocyclic aromatic group selected from the group consisting of phenyl, 1-naphthyl, 2-naphthyl, indenyl, azulenyl, fluorenyl, and anthracenyl; or a heterocyclic aromatic group selected from the group consisting of 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyraxolyl, 2-pyrazolinyl, pyrazolidinyl, isoxazolyl, isotriazolyl, 1,2,3-oxadiazolyl, 1,2,3-triazolyl, 1,3,4-thiadiazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, 1,3,5-triazinyl, 1,3,5-trithianyl, indolizinyl, indolyl, isoindolyl, 3H-indolyl, indolinyl, benzo blfuranyl, benzo[b]thio-phenyl, 1H-indazolyl, benzimidazolyl, benzthiazolyl, purinyl, 4H-quinolizinyl, quinolinyl, 1,2,3,4-tetrahydroquinolinyl, isoquinolinyl, 1,2,3,4-tetrahydroisoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 1,8-naphthyridinyl, pteridinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, and phenoxazinyl; wherein Ar is unsubstituted or substituted with one or more substituent(s) independently selected from the group consisting of hydrogen, halogen, hydroxy, nitro, —SO 3 H, trifluoromethyl, trifluoromethoxy, C 1 -C 6  straight or branched chain alkyl, C 2 -C 6  straight or branched chain alkenyl, O-(C 1 -C 6  straight or branched chain alkyl), O-(C 3 -C 4  straight or branched chain alkenyl), O-benzyl, O-phenyl, 1,2-methylenedioxy, —NR 3 R 4 , carboxyl, N-(C 1 -C 5  straight or branched chain alkyl or C 3 -C 5  straight or branched chain alkenyl) carboxamides, N,N-di-(C 1 -C 5  straight or branched chain alkyl or C 3 -C 5  straight or branched chain alkenyl) carboxamides, morpholinyl, piperidinyl, O—X, CH 2 —(CH 2 ) q —X, O—(CH 2 ) q —X, (CH 2 ) q —O—X, and CH═CH—X;  
 R 3  and R 4  are independently selected from the group consisting of C 1 -C 6  straight or branched chain alkyl, C 3 -C 6  straight or branched chain alkenyl, hydrogen, and benzyl; or R 3  and R 4  are taken together to form a 5-6 membered heterocyclic ring;  
 X is selected from the group consisting of 4-methoxyphenyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, pyrazyl, quinolyl, 3,5-dimethylisoxazoyl, isoxazoyl, 2-methylthiazoyl, thiazoyl, 2-thienyl, 3-thienyl, and pyrimidyl;  
 q is 0-2; and  
 n is 0 or 1.  
 
     
     
         7 . The method of  claim 6 , wherein J and K are taken together to form a 5-7 membered ring.  
     
     
         8 . The method of  claim 7 , wherein at least one of said B and D is/are independently represented by the formula —(CH 2 ) r —(X)—(CH 2 ) s —Ar, wherein: 
 r is 1-4;  
 s is 0-1; and  
 each X is independently selected from the group consisting of CH 2 , O, S, SO, SO 2 , and NR, wherein R is selected from the group consisting of hydrogen, C 1 -C 4  straight or branched chain alkyl, C 3 -C 4  straight or branched chain alkenyl or alkynyl, and C 1 -C 4  bridging alkyl wherein a bridge is formed between the nitrogen atom and Ar.  
 
     
     
         9 . The method of  claim 6 , wherein: 
 Ar is selected from the group consisting of phenyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, indolyl, isoindolyl, quinolinyl, isoquinolinyl, 1,2,3,4-tetrahydroiso-quinolinyl, and 1,2,3,4-tetrahydroquinolinyl, wherein said Ar is unsubstituted or substituted with one or more substituent(s) independently selected from the group consisting of hydrogen, hydroxy, nitro, trifluoromethyl, C 1 -C 6  straight or branched chain alkyl, O-(C 1 -C 6  straight or branched chain alkyl), halogen, SO 3 H, and NR 3 R 4 ; and    R 3  and R 4  are independently selected from the group consisting of C 1 -C 6  straight or branched chain alkyl, C 3 -C 6  straight or branched chain alkenyl, hydrogen, and benzyl; or R 3  and R 4  are taken together to form a 5-6 membered heterocyclic ring.    
     
     
         10 . The method of  claim 1 , wherein the small molecule carbamate or urea is a compound of formula II or III  
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt, ester, or solvate thereof, wherein: 
 Y, R 1  and R 2  are as defined in claim  6 ;  
 Ar is as defined in claim  6 ;  
 J is hydrogen, C 1 -C 6  straight or branched chain alkyl, or C 3 -C 6  straight or branched chain alkenyl; and  
 w is 1 or 2.  
 
     
     
         11 . The method of  claim 1 , wherein the small molecule carbamate or urea is a compound of formula IV or V  
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt, ester, or solvate thereof, wherein: 
 Y, R 1 , and R 2  are as defined in claim  6 ;  
 Ar is as defined in claim  6 ;  
 J is hydrogen, C 1 -C 6  straight or branched chain alkyl, or C 3 -C 6  straight or branched chain alkenyl; and  
 w is 1 or 2.  
 
     
     
         12 . The method of  claim 1 , wherein the small molecule carbamate or urea is a compound of formula VI  
       
         
           
           
               
               
           
         
       
       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  cycloalkyl, 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, R 1 , R 2 , Y, Z, and n are as defined in  claim 6  above.  
 
     
     
         13 . A pharmaceutical composition which comprises: 
 (i) an effective amount of a small molecule carbamate or urea for treating alopecia or promoting hair growth in an animal; and    (ii) a pharmaceutically acceptable carrier.    
     
     
         14 . The pharmaceutical composition of  claim 13 , wherein the small molecule carbamate or urea has an affinity for an FKBP-type immunophilin.  
     
     
         15 . The pharmaceutical composition of  claim 14 , wherein the FKBP-type immunophilin is FKBP-12.  
     
     
         16 . The pharmaceutical composition of  claim 13 , wherein the small molecule carbamate or urea is immunosuppressive.  
     
     
         17 . The pharmaceutical composition of  claim 13 , wherein the small molecule carbamate or urea is non-immunosuppressive.  
     
     
         18 . The pharmaceutical composition of  claim 13 , wherein the small molecule carbamate or urea is a compound of formula I  
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt, ester, or solvate 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, C 2 -C 6  straight or branched chain alkenyl or alkynyl, C 5 -C 7  cycloalkyl substituted C 1 -C 6  straight or branched chain alkyl or is C 3 -C 6  straight or branched chain alkenyl or alkynyl, C 5 -C 7  cycloalkenyl substituted C 1 -C 6  straight or branched chain alkyl or C 3 -C 6  straight or branched chain alkenyl or alkynyl, Ar substituted C 1 -C 4  straight or branched chain alkyl, or Ar substituted C 3 -C 6  straight or branched chain alkenyl or alkynyl; wherein any carbon atom of said alkyl is optionally replaces by a heteroatom selected from the group consisting of O, S, SO, SO 2  and NR, wherein R is selected from the group consisting of hydrogen, C 1 -C 4  straight or branched chain alkyl, C 3 -C 4  straight or branched chain alkenyl or alkynyl, and C 1 -C 4  bridging alkyl wherein a bridge is formed between the nitrogen and a carbon atom of said heteroatom-containing chain to form a ring, and wherein said ring is optionally fused to an Ar group;  
 J is selected from the group consisting of hydrogen, C 1 -C 6  straight or branched chain alkyl, C 3 -C 6  straight or branched chain alkenyl, and —CH 2 Ar; K is selected from the group consisting of C 1 -C 4  straight or branched chain alkyl, —CH 2 Ar, and 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 ;  
 Z is O or S;  
 Y is O or N, provided that 
 when Y is O, then R 1  is a lone pair of electrons and R 2  is selected from the group consisting of Ar, C 1 -C 6  straight or branched chain alkyl, and C 3 -C 6  straight or branched chain alkenyl or alkynyl; and  
 when Y is N, then R 1  and R 2  are independently selected from the group consisting of Ar, C 1 -C 6  straight or branched chain alkyl, and C 3 -C 6  straight or branched chain alkenyl or alkynyl; or R 1  and R 2  are taken together to form a heterocyclic 5-6 membered ring selected from the group consisting of pyrrolidine, imidazolidine, pyrazolidine, piperidine, and piperazine;  
 
 Ar is a carbocyclic aromatic group selected from the group consisting of phenyl, 1-naphthyl, 2-naphthyl, indenyl, azulenyl, fluorenyl, and anthracenyl; or a heterocyclic aromatic group selected from the group consisting of 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyraxolyl, 2-pyrazolinyl, pyrazolidinyl, isoxazolyl, isotriazolyl, 1,2,3-oxadiazolyl, 1,2,3-triazolyl, 1,3,4-thiadiazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, 1,3,5-triazinyl, 1,3,5-trithianyl, indolizinyl, indolyl, isoindolyl, 3H-indolyl, indolinyl, benzo[b]furanyl, benzo[b]thio-phenyl, 1H-indazolyl, benzimidazolyl, benzthiazolyl, purinyl, 4H-quinolizinyl, quinolinyl, 1,2,3,4-tetrahydroquinolinyl, isoquinolinyl, 1,2,3,4-tetrahydroisoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 1,8-naphthyridinyl, pteridinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, and phenoxazinyl; wherein Ar is unsubstituted or substituted with one or more substituent(s) independently selected from the group consisting of hydrogen, halogen, hydroxy, nitro, —SO 3 H, trifluoromethyl, trifluoromethoxy, C 1 -C 6  straight or branched chain alkyl, C 2 -C 6  straight or branched chain alkenyl, O-(C 1 -C 6  straight or branched chain alkyl), O-(C 3 -C 4  straight or branched chain alkenyl), O-benzyl, O-phenyl, 1,2-methylenedioxy, —NR 3 R 4 , carboxyl, N-(C 1 -C 5  straight or branched chain alkyl or C 3 -C 5  straight or branched chain alkenyl) carboxamides, N,N-di-(C 1 -C 5  straight or branched chain alkyl or C 3 -C 5  straight or branched chain alkenyl) carboxamides, morpholinyl, piperidinyl, O—X, CH 2 —(CH 2 ) q —X, O—(CH 2 ) q —X, (CH 2 ) q —O—X, and CH═CH—X;  
 R 3  and R 4  are independently selected from the group consisting of C 1 -C 6  straight or branched chain alkyl, C 3 -C 6  straight or branched chain alkenyl, hydrogen, and benzyl; or R 3  and R 4  are taken together to form a 5-6 membered heterocyclic ring;  
 X is selected from the group consisting of 4-methoxyphenyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, pyrazyl, quinolyl, 3,5-dimethylisoxazoyl, isoxazoyl, 2-methylthiazoyl, thiazoyl, 2-thienyl, 3-thienyl, and pyrimidyl;  
 q is 0-2; and  
 n is 0 or 1.  
 
     
     
         19 . The pharmaceutical composition of  claim 18 , wherein J and K are taken together to form a 5-7 membered ring.  
     
     
         20 . The pharmaceutical composition of  claim 19 , wherein at least one of said B and D is/are independently represented by the formula —(CH 2 ) r —(X)—(CH 2 ) s —Ar, wherein: 
 r is 1-4;  
 s is 0-1; and  
 each X is independently selected from the group consisting of CH 2 , O, S, SO, SO 2 , and NR, wherein R is selected from the group consisting of hydrogen, C 1 -C 4  straight or branched chain alkyl, C 3 -C 4  straight or branched chain alkenyl or alkynyl, and C 1 -C 4  bridging alkyl wherein a bridge is formed between the nitrogen atom and Ar.  
 
     
     
         21 . The pharmaceutical composition of  claim 18 , wherein: 
 Ar is selected from the group consisting of phenyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, indolyl, isoindolyl, quinolinyl, isoquinolinyl, 1,2,3,4-tetrahydroiso-quinolinyl, and 1,2,3,4-tetrahydroquinolinyl, wherein said Ar is unsubstituted or substituted with one or more substituent (s) independently selected from the group consisting of hydrogen, hydroxy, nitro, trifluoromethyl, C 1 -C 6  straight or branched chain alkyl, O-(C 1 -C 6  straight or branched chain alkyl), halogen, SO 3 H, and NR 3 R 4 ; and    R 3  and R 4  are independently selected from the group consisting of C 1 -C 6  straight or branched chain alkyl, C 3 -C 6  straight or branched chain alkenyl, hydrogen, and benzyl; or R 3  and R 4  are taken together to form a 5-6 membered heterocyclic ring.    
     
     
         22 . The pharmaceutical composition of  claim 13 , wherein the small molecule carbamate or urea is a compound of formula II or III  
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt, ester, or solvate thereof, wherein: 
 Y, R 1  and R 2  are as defined in claim  18 ;  
 Ar is as defined in claim  18 ;  
 J is hydrogen, C 1 -C 6  straight or branched chain alkyl, or C 3 -C 6  straight or branched chain alkenyl; and  
 w is 1 or 2.  
 
     
     
         23 . The pharmaceutical composition of  claim 13 , wherein the small molecule carbamate or urea is a compound of formula IV or V  
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt, ester, or solvate thereof, wherein: 
 Y, R 1  and R 2  are as defined in claim  18 ;  
 Ar is as defined in claim  18 ;  
 J is hydrogen, C 1 -C 6  straight or branched chain alkyl, or C 3 -C 6  straight or branched chain alkenyl; and  
 w is 1 or 2.  
 
     
     
         24 . The pharmaceutical composition of  claim 13 , wherein the small molecule carbamate or urea is a compound of formula VI  
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt, ester, or solvate thereof, wherein: 
 V is C, N, N. or S;  
 J and K, taken together with V and carbon atom to which they are respectively attached, form a 5-7 membered, saturated or unsaturated heterocyclic ring containing, in addition to a, 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  cycloalkyl, 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, R 1 , R 2 , Y, Z, and n are as defined in  claim 18  above.