Inhibitors of melanocyte tyrosinase as topical skin lighteners

Abstract

Methods and formulations are provided to reduce pigmentation in skin, using an array of compounds selected from benzimidazoles, phenylthioureas, phenyltiols, phenylamines, bi- and multicyclic phenols, thiopheneamines, and benzothiamides. The compounds preferably inhibit pigment systhesis in melanocytes through the tyrosinase pathway. The methods can be used for lightening skin, and for treating uneven skin complexions which result from hyperpigmentation-related medical conditions such as melasma, age spots, freckles, ochronosis, and lentigo. The compounds can be used medically or cosmetically.

What is claimed is:  
     
         1 . A method of inhibiting or preventing pigment production in a mammal comprising administering to the mammal an effective amount of a compound defined by structure (I), or a pharmaceutically acceptable salt or ester thereof:  
       
         
           
           
               
               
           
         
       
       wherein: 
 a. R 1  is H or a valence for bonding;  
 b. R 2  is S, or SH;  
 c. one of the dotted lines (- - -) represents a bond;  
 d. R 4 , R 5 , R 6 , and R 7  are independently CR 8 , or N;  
 e. R 3  is (i) substituted or unsubstituted alkyl, alkenyl, aryl, or heterocycle, (ii) —C 1-5  alkoxy, (iii) —OH, (iv) hydrogen, (v) —NR 9 R 10 , (vi) C(O)-C 1-3  alkyl, (vii) —(CH 2 ) 1-5 C(O)NR 9 R 10 , or (viii) a valence for bonding;  
 f. R 8  is (i) hydrogen, (ii) halogen, (iii) NO 2 , (iv) —CN, (v) —OR 10 , (vi) —NHSO 2 -Cl 1-3 alkyl, (vii) —NHCO-C 1-5  alkyl, (viii) oxime, (ix) hydrazine, (x) —NR 9 R 10 , (xi) HSO 2 , (xii) HSO 3 , (xiii) thio-C 1-5  alkyl, (xiv) C 1-5  acyloxy, (xv) H 2 PO 3 , (xvi) thiol, (xvii) —COOR 9 , (xviii) C 1-5  alkynyl, or (xix) —C 1-5  alkyl, —C 1-5  alkenyl, aryl, heteroaryl, or heterocycle, optionally substituted with one or more of —OH, —SH, C(O)H, COOR 9 , C 1-5  acyloxy, halogen, NR 9 R 10 , C 1-5  thioether, or C 1-5  alkoxy;  
 g. R 9  is hydrogen or C 1-3  alkyl;  
 h. R 10  is hydrogen, or C 1-5  alkyl optionally substituted with —OH;  
 i. R″ is C or CH;  
 j. when R″ is C: 
 i. R′ is CR 8 , C(R 8 ) 2 , N or NH, and forms a bond with R″;  
 ii. 1 or 2 of R 5  and R 6  are N or COR 10  other than COH, the remainder of R 4 , R 5 , R 6 , and R 7  being CH; and  
 
 k. when R″ is CH, R′ is CH 3  or NH 2 .  
 
     
     
         2 . The method of  claim 1  wherein R″ is CH, R 4 , R 5 , R 6 , and R 7  are independently selected from CR 8 , R is OR 9 , and 2 or 3 of R 4 , R 5 , R 6 , and R 7  are CH.  
     
     
         3 . The method of  claim 1  wherein R″ is CH, R′ is NH 2  and R 4 , R 5 , and R 7  are CH, and R 6  is COH.  
     
     
         4 . The method of  claim 1  wherein R″ is C, R′ is NH or N, and 
 a) R 5  is COCH 3 , and R 4 , R 6 , and R 7  are CH;  
 b) R 6  is COCH 3 , and R 4 , R 5 , and R 7  are CH; or  
 c) R 5  and R 6  are COCH 3 , and R 4  and R 7  are CH.  
 
     
     
         5 . The method of  claim 1  wherein the compound has an IC 50  against mammalian tyrosinase activity of less than or equal to 300 uM, and an IC 50  of cytotoxicity in mammalian melanocytic cells of greater than 500 uM.  
     
     
         6 . The method of  claim 1  wherein the compound has an IC 50  against melanin production in mammalian melanocytic cells of less than or equal to 300 uM, and an IC 50  of cytotoxicity in mammalian melanocytic cells of greater than 500 uM.  
     
     
         7 . The method of  claim 1  wherein the compound absorbs ultraviolet radiation.  
     
     
         8 . The method of  claim 1  wherein the compound is an antioxidant.  
     
     
         9 . The method of  claim 1  wherein the mammal is a human.  
     
     
         10 . The method of  claim 1  wherein the administration is through a topical formulation or an occlusive patch.  
     
     
         11 . The method of  claim 1  wherein the method is for lightening skin pigmentation.  
     
     
         12 . The method of  claim 1  wherein the method is for treating hyperpigmentation-related medical conditions such as melasma, age spots, freckles, ochronosis, postinflammatory hyperpigmentation, and lentigo.  
     
     
         13 . A method of inhibiting or preventing pigment production in a mammal comprising administering to the mammal an effective amount of a compound defined by structure (II), or a pharmaceutically acceptable salt or ester thereof:  
       
         
           
           
               
               
           
         
       
       wherein: 
 a) R 1  is H;  
 b) R 2  is selenium;  
 c) R″ is C or CH;  
 d) when R″ is C, R′ is C(R 8 ) 2  or NR 3 , and forms a bond with R″;  
 e) when R″ is CH, R′ is CH 3  or NH 2 ;  
 f) R 4 , R 5 , R 6 , and R 7  are independently CR 8 , or N;  
 g) R 3  is (i) substituted or unsubstituted alkyl, alkenyl, aryl, or heterocycle, (ii) —C 1-5  alkoxy, (iii) —OH, (iv) hydrogen, (v) C(O)-C 1-3  alkyl, or (vi) —(CH 2 ) 1-5 C(O)NR 9 R 10 ;  
 h) R 8  is (i) hydrogen, (ii) halogen, (iii) NO 2 , (iv) —CN, (v) —OR 10 , (vi) —NHSO 2 -C 1-3 alkyl, (vii) —NHCO-C 1-5  alkyl, (viii) oxime, (ix) hydrazine, (x) —NR 9 R 10 , (xi) HSO 2 , (xii) HSO 3 , (xiii) thio-C 1-5  alkyl, (xiv) C 1-5  acyloxy, (xv) H 2 PO 3 , (xvi) thiol, (xvii) —COOR 9 , (xviii) C 1-5  alkynyl, or (xix) —C 1-5  alkyl, —C 1-5  alkenyl, aryl, heteroaryl, or heterocycle, optionally substituted with one or more of —OH, —SH, C(O)H, COOR 9 , C 1-5  acyloxy, halogen, NR 9 R 10 , C 1-5  thioether, or C 1-5  alkoxy;  
 i) R 9  is hydrogen or C 1-3  alkyl; and  
 j) R 10  is hydrogen, or C 1-5  alkyl optionally substituted with —OH.  
 
     
     
         14 . The method of  claim 13  wherein R″ is C or CH, R 4 , R 5 , R 6 , and R 7  are independently selected from CR 8 , R 8  is (i) hydrogen, (ii) halogen, (iii) —OR 9 , (iv) —OH, (v) —NR 9 R 9 , (vi) thiol, or (vii) —C 1-3  alkyl or alkenyl optionally substituted with one or more of —OH, —SH, halogen, or NH 2 , 2 or 3 of R 4 , R 5 , R 6 , and R 7  are CH, and R′ is NR 3 .  
     
     
         15 . The method of  claim 13  wherein R″ is C, R′ is NH, and R 4 , R 5 , R 6 , and R 7  are CH.  
     
     
         16 . The method of  claim 13  wherein the compound has an IC 50  against mammalian tyrosinase activity of less than or equal to 300 uM, and an IC 50  of cytotoxicity in mammalian melanocytic cells of greater than 500 uM.  
     
     
         17 . The method of  claim 13  wherein the compound has an IC 50  against melanin production in mammalian melanocytic cells of less than or equal to 300 uM, and an IC 50  of cytotoxicity in mammalian melanocytic cells of greater than 500 uM.  
     
     
         18 . The method of  claim 13  wherein the compound absorbs ultraviolet radiation.  
     
     
         19 . The method of  claim 13  wherein the compound is an antioxidant.  
     
     
         20 . The method of  claim 13  wherein the mammal is a human.  
     
     
         21 . The method of  claim 13  wherein the administration is through a topical formulation or an occlusive patch.  
     
     
         22 . The method of  claim 13  wherein the method is for lightening skin pigmentation.  
     
     
         23 . The method of  claim 13  wherein the method is for treating hyperpigmentation-related medical conditions such as melasma, age spots, freckles, ochronosis, postinflammatory hyperpigmentation, and lentigo.  
     
     
         24 . A method of inhibiting or preventing pigment production in a mammal comprising administering to the mammal an effective amount of a compound defined by structure (III), or a pharmaceutically acceptable salt or ester thereof:  
       
         
           
           
               
               
           
         
       
       wherein: 
 a) R 1  is (CH 2 ) n SR 7 , (CH 2 ) n NHR 7 , or OR 7 ;  
 b) n is 0, 1, 2, or 3,  
 c) R 2 , R 3 , R 4 , R 5  and R 6  are independently selected from (i) hydrogen, (ii) halogen, (iii) NO 2 , (iv) —CN, (v) —OR 10 , (vi) —NHSO 2 -C 1-3 alkyl, (vii) —NHCO-C 1-5  alkyl, (viii) oxime, (ix) hydrazine, (x) —NR 9 R 10 , (xi) HSO 2 , (xii) HSO 3 , (xiii) thio-C 1-5  alkyl, (xiv) C 1-5  acyloxy, (xv) H 2 PO 3 , (xvi) thiol, (xvii) —COOR 9 , (xviii) C 1-5  alkynyl, or (xix) —C 1-5  alkyl, —C 1-5  alkenyl, aryl, heteroaryl, or heterocycle, optionally substituted with one or more of —OH, —SH, C(O)H, COOR 9 , C 1-5  acyloxy, halogen, NR 9 R 10 , C 1-5  thioether, or C 1-5  alkoxy;  
 d) alternatively, R 3  and R 4 , or R 4  and R 5 , combine to form a fused ring-structure which is cycloalkyl, aryl, or heterocyclic selected from phenyl, cyclopentyl, cyclohexyl, pyrrole, furan, thiophene, pyrazole, pyridine, —X—(CH 2 ) n —X— wherein n′ is 1 and X is nitrogen, sulfur, or oxygen, and —(CH) n XH— wherein n″ is 2 and X is as defined above;  
 e) R 7  is (i) substituted or unsubstituted alkyl, alkenyl, aryl, or heterocycle, (ii) —C 1-5  alkoxy, (iii) hydrogen, (iv) C(O)-C 1-3  alkyl, or (v) —(CH 2 ) m C(O)NR 9 R 10 ;  
 f) R 9  is hydrogen or C 1-3  alkyl;  
 g) R 10  is hydrogen, or C 1-5  alkyl optionally substituted with —OH;  
 h) m is 1, 2, 3, 4, or 5; and  
 i) provided that when R 1  is OR 7 , R 3  and R 4 , or R 4  and R 5 , combine to form a fused ring-structure which is cycloalkyl, aryl, or heterocyclic selected from phenyl, cyclopentyl, cyclohexyl, pyrrole, furan, thiophene, pyrazole, pyridine, —X—(CH 2 ) n′ —X— wherein n′ is 1 and X is nitrogen, sulfur, or oxygen, and —(CH) n″ XH— wherein n″ is 2 and X is as defined above.  
 
     
     
         25 . The method of  claim 24  wherein R 1  is (CH 2 ) n SR 7 , and R 7  is hydrogen, C 1-5  alkyl optionally substituted with —OH, or C(O)C 1-3  alkyl.  
     
     
         26 . The method of  claim 24  wherein R 1  is (CH 2 ) n SR 7 , and R 7  is hydrogen, C 1-5  alkyl optionally substituted with —OH, or C(O)C 1-3  alkyl, R 4 , is —NHCO-C 1-3  alkyl; and R 2 , R 3 , R 5  and R 6  are CH.  
     
     
         27 . The method of  claim 24  wherein R 1  is (CH 2 ) n SR 7 , and 
 a) n is 0, R 7  is hydrogen, R 4  is —NHCO-CH 3 , and R 2 , R 3 , R 5  and R 6  are hydrogen and, or  
 b) n is 0, R 7  is C(O)C 1-3  alkyl, R 4  is —NHCO-CH 3 , and R 2 , R 3 , R 5  and R 6  are hydrogen.  
 
     
     
         28 . The method of  claim 24  wherein the compound has an IC 50  against mammalian tyrosinase activity of less than or equal to 300 uM, and an IC 50  of cytotoxicity in mammalian melanocytic cells of greater than 500 uM.  
     
     
         29 . The method of  claim 24  wherein the compound has an IC 50  against melanin production in mammalian melanocytic cells of less than or equal to 300 uM, and an IC 50  of cytotoxicity in mammalian melanocytic cells of greater than 500 uM.  
     
     
         30 . The method of  claim 24  wherein the compound absorbs ultraviolet radiation.  
     
     
         31 . The method of  claim 24  wherein the compound is an antioxidant.  
     
     
         32 . The method of  claim 24  wherein the mammal is a human.  
     
     
         33 . The method of  claim 24  wherein the administration is through a topical formulation or an occlusive patch.  
     
     
         34 . The method of  claim 24  wherein the method is for lightening skin pigmentation.  
     
     
         35 . The method of  claim 24  wherein the method is for treating hyperpigmentation-related medical conditions such as melasma, age spots, freckles, ochronosis, postinflammatory hyperpigmentation, and lentigo.  
     
     
         36 . A method of inhibiting or preventing pigment production in a mammal comprising administering to the mammal an effective amount of a compound defined by structure (IV) or (V), or a pharmaceutically acceptable salt or ester thereof:  
       
         
           
           
               
               
           
         
       
       wherein: 
 a) R 1 , R 2 , and R 3  are independently (i) substituted or unsubstituted alkyl, alkenyl, aryl, or heterocycle, (ii) hydrogen, (iii) C(O)-C 1-3  alkyl, or (iv) —(CH 2 ) 1-5 C(O)NR 9 R 10 ;  
 b) R 9  is hydrogen or C 1-3  alkyl;  
 c) R 10  is hydrogen, or C 1-5  alkyl optionally substituted with —OH;  
 d) Y and Y′ are independently sulfur or oxygen;  
 e) X is oxygen, sulfur, or nitrogen; and  
 f) R 4  is C 1-5  alkyl, optionally substituted by —OH, or NR 9 R 9 .  
 
     
     
         37 . The method of  claim 36  wherein the compound is defined by structure (IV), R 1  is hydrogen, and R 2  and R 3  are C 1-5  alkyl optionally substituted with —OH.  
     
     
         38 . The method of  claim 36  wherein the compound is defined by structure (IV), Y is sulfur, Y′ is oxygen, R 1  and R 2  are hydrogen, and R 3  is methyl.  
     
     
         39 . The method of  claim 36  wherein the compound is defined by structure (V) and: 
 a) X is sulfur, R 1  is hydrogen, R 2  is C 1-5  alkyl optionally substituted with —OH; and R 4  is unsubstituted (CH 2 ) 1-5 ; or  
 b) X is sulfur, R 1  is hydrogen, R 2  is hydrogen or C 1-3  alkyl, and R 4  is unsubstituted (CH 2 ) 1-3 .  
 
     
     
         40 . The method of  claim 36  wherein the compound is defined by structure (V), X is sulfur, R 4  is ethylene and R 1  and R 2  are hydrogen.  
     
     
         41 . The method of  claim 36  wherein the compound has an IC 50  against mammalian tyrosinase activity of less than or equal to 300 uM, and an IC 50  of cytotoxicity in mammalian melanocytic cells of greater than 500 uM.  
     
     
         42 . The method of  claim 36  wherein the compound has an IC 50  against melanin production in mammalian melanocytic cells of less than or equal to 300 uM, and an IC 50  of cytotoxicity in mammalian melanocytic cells of greater than 500 uM.  
     
     
         43 . The method of  claim 36  wherein the compound absorbs ultraviolet radiation.  
     
     
         44 . The method of  claim 36  wherein the compound is an antioxidant.  
     
     
         45 . The method of  claim 36  wherein the mammal is a human.  
     
     
         46 . The method of  claim 36  wherein the administration is through a topical formulation or an occlusive patch.  
     
     
         47 . The method of  claim 36  wherein the method is for lightening skin pigmentation.  
     
     
         48 . The method of  claim 36  wherein the method is for treating hyperpigmentation-related medical conditions such as melasma, age spots, freckles, ochronosis, postinflammatory hyperpigmentation, and lentigo.  
     
     
         49 . A method of inhibiting or preventing enzymatic browning of fruit or vegatables comprising administering any one of the compounds of claims  1 ,  13 ,  24 , and  36 .  
     
     
         50 . A method of inhibiting tyrosine hydroxylase comprising administering any one of the compounds of claims  1 ,  13 ,  24 , and  36 .