Inhibition of melanogenesis by chemically modified curcumins

Abstract

The present invention provides a method of treating a subject afflicted with hyperpigmentation or of lightening the skin tone of a subject comprising administering to the subject an amount of a compound having the structure: or a salt or ester thereof, so as to thereby treat the subject or lighten the skin tone of the subject.

What is claimed is: 
     
         1 . A method of treating a subject afflicted with hyperpigmentation comprising administering to the subject an amount of a compound having the structure: 
       
         
           
           
               
               
           
         
       
       wherein bond α and β are each, independently, present or absent;
 X is CR 5  or N; Y is CR 10  or N; 
 R 1  is —SR 12 , —SO 2 R 13 , —COR 14 , —CSR 14 , —C(—NR 12 ) R 4 , —C(—NH)R 14 , —SOR 12 , —POR 12 , —P(═O)(OR 12 )(OR 13 ), or —P(OR 12 ).(OR 13 ),
 wherein R 12  is C 1-10  alkyl, C 2-10  alkenyl, C 2-10  alkynyl, aryl, heteroaryl, or heterocyclyl; 
 R 13  is H, C 1-10  alkyl, C 2-10  alkenyl, C 2-10  alkynyl, aryl, heteroaryl, or heterocyclyl; 
 R 14  is C 2-10  alkyl, C 2-10  alkenyl, C 2-10  alkynyl, heteroaryl, heterocyclyl, methoxy, —OR 15 , or —NR 16 R 17 ,
 wherein 
 R 15  is H, C 3-10  alkyl, C 2-10  alkenyl, C 2-10  alkynyl; 
 R 16  and R 17  are each, independently, H, C 1-10  alkyl, C 2-10  alkenyl, C 2-10  alkynyl, aryl, heteroaryl, or heterocyclyl; 
 
 
 R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , and R 11  are each independently, H, halogen, —NO 2 , —CN, —NR 28 R 29 , —NHR 28 R 29   + , —SR 28 , —SO 2 R 28 , —OR 28 , —CO 2 R 28 , CF 3 , C 1-10  alkyl, C 2-10  alkenyl, C 2-10  alkynyl, aryl, heteroaryl, or heterocyclyl;
 wherein R 28  and R 29  are each, H, CF 3 , C 1-10  alkyl, C 2-10  alkenyl, C 2-10  alkynyl, or —C(═O)-heterocyclyl; and 
 
 
       wherein each occurrence of alkyl, alkenyl, or alkynyl is branched or unbranched, unsubstituted or substituted, 
       or a salt or ester thereof, so as to thereby treat the subject. 
     
     
         2 . The method of  claim 1 , wherein the compound reduces melanin synthesis in the subject. 
     
     
         3 . The method of  claim 1 , wherein the compound inhibits melanogenesis in the subject. 
     
     
         4 . The method of  claim 1 , wherein the compound inhibits tyrosinase activity in the subject. 
     
     
         5 . The method of  claim 1 , wherein the compound lightens the skin tone of the subject relative to the subject's natural skin tone. 
     
     
         6 . A method of lightening the skin tone of a subject comprising administering to the subject an amount of a compound having the structure: 
       
         
           
           
               
               
           
         
       
       wherein bond α and β are each, independently, present or absent;
 X is CR 5  or N; Y is CR 10  or N; 
 R 1  is —SR 12 , —SO 2 R 13 , —COR 14 , —CSR 14 , —C(—NR 12 ) R 14 , —C(NH) R 14 , —SOR 12 , —POR 12 , —P(═O)(OR 12 )(OR 13 ), or —P(OR 12 ).(OR 13 ),
 wherein R 12  is C 1-10  alkyl, C 2-10  alkenyl, C 2-10  alkynyl, aryl, heteroaryl, or heterocyclyl; 
 R 13  is H, C 1-10  alkyl, C 2-10  alkenyl, C 2-10  alkynyl, aryl, heteroaryl, or heterocyclyl; 
 R 14  is C 2-10  alkyl, C 2-10  alkenyl, C 2-10  alkynyl, heteroaryl, heterocyclyl, methoxy, —OR 15 , or —NR 16 R 17  wherein 
 R 15  is H, C 3-10  alkyl, C 2-10  alkenyl, C 2-10  alkynyl; 
 R 16  and R 17  are each, independently, H, C 1-10  alkyl, C 2-10  alkenyl, C 2-10 alkynyl, aryl, heteroaryl, or heterocyclyl; 
 
 R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , and R 11  are each independently, H, halogen, —NO 2 , —CN, —NR 28 R 29   + , —NHR 28 R 29   + , —SR 28 , —SO 2 R 28 , —OR 28 , —CO 2 R 28 , CF 3 , C 1-10  alkyl, C 2-10  alkenyl, C 2-10  alkynyl, aryl, heteroaryl, or heterocyclyl;
 wherein R 28  and R 29  are each, H, CF 3 , C 1-10  alkyl, C 2-10  alkenyl, C 2-10  alkynyl, or —C(—)-heterocyclyl; and 
 
 
       wherein each occurrence of alkyl, alkenyl, or alkynyl is branched or unbranched, unsubstituted or substituted, or a salt or ester thereof, so as to thereby lighten the skin tone of the subject. 
     
     
         7 . The method of  claim 6 , wherein the compound reduces melanin synthesis in the subject. 
     
     
         8 . The method of  claim 6 , wherein the compound inhibits melanogenesis in the subject. 
     
     
         9 . The method of  claim 6 , wherein the compound inhibits tyrosinase activity in the subject. 
     
     
         10 . The method of  claim 6 , wherein the compound lightens the skin tone of the subject relative to the subject's natural skin tone. 
     
     
         11 . The compound of  claim 1  or  6 , wherein a and 3 are each present. 
     
     
         12 . The compound of  claim 1  or  6 , wherein a and R are each absent. 
     
     
         13 . The method of any one of  claims 1 - 11 , wherein the compound has the structure: 
       
         
           
           
               
               
           
         
         R 3 , R 4 , R 8  and R 9  are each independently, H, halogen, —NO 2 , —CN, —NR 28 R 29 , —NHR 28 R 29   + , —SR 28 , —SO 2 R 28 , —OR 28 , —CO 2 R 28 , CF 3 , C 1-10  alkyl, C 2-10  alkenyl, C 2-10  alkynyl, aryl, heteroaryl, or heterocyclyl;
 wherein R 28  and R 29  are each, H, CF 3 , C 1-10  alkyl, C 2-10  alkenyl, C 2-10  alkynyl, or —C(═O)-heterocyclyl; and 
 
         R 14  is methoxy, —OR 15 , or —NR 16 R 17 ,
 wherein R 15  is H, C 3-10  alkyl, C 2-10  alkenyl, C 2-10  alkynyl; and 
 R 16  and R 17  are each, independently, H, C 1-10  alkyl, C 2-10  alkenyl, C 2-10 alkynyl, aryl, heteroaryl, or heterocyclyl; 
 
       
       wherein each occurrence of alkyl, alkenyl, or alkynyl is branched or unbranched, unsubstituted or substituted, or a salt or ester thereof. 
     
     
         14 . The method of any one of  claims 1 - 10  or  12 , wherein the compound has the structure: 
       
         
           
           
               
               
           
         
         R 3 , R 4 , R 8  and R 9  are each independently, H, halogen, —NO 2 , —CN, —NR 28 R 29 , —NHR 28 R 29   + , —SR 28 , —SO 2 R 28 , —OR 28 , —CO 2 R 2 , CF 3 , C 1-10  alkyl, C 2-10  alkenyl, C 2-10  alkynyl, aryl, heteroaryl, or heterocyclyl;
 wherein R 28  and R 29  are each, H, CF 3 , C 1-10  alkyl, C 2-10  alkenyl, C 2-10  alkynyl, or —C(═O)-heterocyclyl; and 
 
         R 14  is methoxy, —OR 15 , or —NR 16 R 17 ,
 wherein R 15  is H, C 3-10  alkyl, C 2-10  alkenyl, C 2-10  alkynyl; and 
 R 16  and R 17  are each, independently, H, C 1-10  alkyl, C 2-10  alkenyl, C 2-10  alkynyl, aryl, heteroaryl, or heterocyclyl; 
 
       
       wherein each occurrence of alkyl, alkenyl, or alkynyl is branched or unbranched, unsubstituted or substituted, or a salt or ester thereof. 
     
     
         15 . The method of  claim 13  or  14 , wherein R 14  is methoxy or —NR 16 R 17 , wherein R 16  and R 17  are each, independently, aryl or heteroaryl. 
     
     
         16 . The method of  claim 13  or  14 , wherein R 3 , R 4 , R 8  and R 9  are each independently, H or —OR 28 , wherein R 28  is H or C 1-10  alkyl. 
     
     
         17 . The method of  claim 13  or  14 , wherein R 3 , R 4 , R 8  and R 9  are each —OR 28 , wherein each R 28  is, independently, H or C 1-10  alkyl. 
     
     
         18 . The method of  claim 13  or  14 , wherein R 3 , R 4 , R 8 , and R 9  are each, independently, H, —OCH 3 , or —OH; and R 14  is methoxy or —N(CH 3 ) 2 . 
     
     
         19 . The method of any one of  claims 1 - 11 , wherein the compound has the structure: 
       
         
           
           
               
               
           
         
       
       or a salt thereof. 
     
     
         20 . The method of any one of  claims 1 - 10  or  12 , wherein the compound has the structure: 
       
         
           
           
               
               
           
         
       
       or a salt thereof. 
     
     
         21 . The method of any one of  claims 1 - 20 , wherein the compound is administered topically to the subject. 
     
     
         22 . A method of inhibiting melanogenesis for reducing skin melanin levels in a subject comprising administering to the subject an amount of a compound having the structure: 
       
         
           
           
               
               
           
         
       
       wherein bond α and β are each, independently, present or absent;
 X is CR 5  or N; Y is CR 10  or N; 
 R 1  is —SR 12 , —SO 2 R 13 , —COR 14 , —CSR 14 , —C(—NR 12 )R 14 , —C(—NH)R 14 , —SOR 12 , —POR 12 , —P(═O)(OR 12 )(OR 13 ), or —P(OR 12 ).(OR 13 ),
 wherein R 12  is C 1-10  alkyl, C 2-10  alkenyl, C 2-10  alkynyl, aryl, heteroaryl, or heterocyclyl; 
 R 13  is H, C 1-10  alkyl, C 2-10  alkenyl, C 2-10  alkynyl, aryl, heteroaryl, or heterocyclyl; 
 R 14  is C 2-10  alkyl, C 2-10  alkenyl, C 2-10  alkynyl, heteroaryl, heterocyclyl, methoxy, —OR 15 , or —NR 16 R 17  wherein 
 R 15  is H, C 3-10  alkyl, C 2-10  alkenyl, C 2-10  alkynyl; 
 R 16  and R 17  are each, independently, H, C 1-10  alkyl, C 2-10  alkenyl, C 2-10  alkynyl, aryl, heteroaryl, or heterocyclyl; 
 
 R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , and R 11  are each independently, H, halogen, —NO 2 , —CN, —NR 28 R 29 , —NHR 28 R 29   + , —SR 28 , —SO 2 R 28 , —OR 28 , —CO 2 R 28 , CF 3 , C 1-10  alkyl, C 2-10  alkenyl, C 2-10  alkynyl, aryl, heteroaryl, or heterocyclyl;
 wherein R 28  and R 29  are each, H, CF 3 , C 1-10  alkyl, C 2-10  alkenyl, C 2-10  alkynyl, or —C(═O)-heterocyclyl; and 
 
 
       wherein each occurrence of alkyl, alkenyl, or alkynyl is branched or unbranched, unsubstituted or substituted, or a salt or ester thereof, so as to thereby inhibit melanogenesis for reducing skin melanin levels in the subject.