Melanin production inhibitor

Abstract

Disclosed is a melanin production inhibitor which has an excellent inhibitory activity on the production of melanin and is highly safe. The melanin production inhibitor is represented by general formula (1) (excluding clotrimazole) and/or a pharmacologically acceptable salt thereof. In the formula, A1, A2 and A3 are independently selected from a hydrogen atom, an aryl group which may have a substituent, and an aromatic heterocyclic group which may have a substituent. At least one of A1, A2 and A3 is selected from the aryl group and the aromatic heterocyclic group, the total number of carbon atoms contained in A1, A2 and A3 is 6 to 50 and, when at least two of A1, A2 and A3 represent the aryl groups or the aromatic heterocyclic groups, the adjacent two aryl or aromatic heterocyclic groups may be bound to each other via an alkyl chain or an alkenyl chain to form a ring; m represents an integer of 0 to 2; X represents a hetero atom, a hydrogen atom, or a carbon atom; R1 and R2 are independently selected from a hydrogen atom and an oxo group. When one of R1 and R2 is an oxo group, the other is not presen. R3 is selected from a hydrogen atom, and a C 1-8 hydrocarbon group in which one or some of hydrogen atoms or carbon atoms may be substituted by a hetero atom or hetero atoms. The number of R3's present in the compound corresponds to X and, when two or more R3's are present, the R3's are independently present and the adjacent two R3's may be bound to each other to form, together with X, a ring, and the terminal of R3 may be bound to a carbon atom to which A1, A2 and A3 are bound, thereby forming a ring.

What is claimed is: 
     
         1 . A melanin production inhibitor, comprising a compound represented by the following general formula (1), excluding clotrimazole, and/or a pharmacologically acceptable salt thereof: 
       
         
           
           
               
               
           
         
         where A1, A2, and A3 are each independently selected from a hydrogen atom, an aryl group which may have a substituent, and an aromatic heterocyclic group which may have a substituent, provided that at least one of A1, A2, and A3 is selected from the aryl group and the aromatic heterocyclic group, and a total number of carbon atoms included in A1, A2, and A3 is 6 to 50;
 when two or more of A1, A2, and A3 each represent the aryl or the aromatic heterocyclic groups, the adjacent two aryl groups or aromatic heterocyclic groups may be bound to each other via an alkyl chain or an alkenyl chain to further form a ring; 
 m represents an integer of 0 to 2; 
 X represents a hetero atom, a hydrogen atom, or a carbon atom; 
 R1 and R2 are each independently selected from a hydrogen atom and oxo, provided that, when one of R1 and R2 represents the oxo, the other is absent; 
 R3 is selected from a hydrogen atom, and a hydrocarbon group having 1 to 8 carbon atoms, in which part of hydrogen atoms or carbon atoms may be substituted by a hetero atom, and a number of R3's corresponds to X; 
 provided that, when two or more R3's are present, the R3's are each independent of each other, and when two or more R3's are present, the adjacent two R3's may be bound to each other to form a ring together with X; and 
 a terminal of R3 may be bound to a carbon atom to which A1, A2, and A3 are bound, thereby forming a ring. 
 
       
     
     
         2 . The melanin production inhibitor according to  claim 1 , wherein X represents a hetero atom or a carbon atom. 
     
     
         3 . The melanin production inhibitor according to  claim 2 , wherein the aryl group is selected from the group consisting of phenyl, biphenyl, and naphthyl, and the aromatic heterocyclic group is selected from the group consisting of pyridyl and quinolyl. 
     
     
         4 . The melanin production inhibitor according to  claim 2 , wherein X represents a nitrogen atom, an oxygen atom, or a carbon atom. 
     
     
         5 . The melanin production inhibitor according to  claim 2 , wherein m represents 0. 
     
     
         6 . The melanin production inhibitor according to  claim 2 , wherein —X—R3 represents a group represented by the following general formula (2): 
       
         
           
           
               
               
           
         
         where X1 represents a carbon atom or a nitrogen atom; 
         R4 and R5 are bound to each other to form, together with X1, a heterocyclic ring or hydrocarbon ring which has 2 to 8 carbon atoms and may have a substituent; and 
         R6 represents a hydrogen atom, provided that R6 is absent when X1 represents a carbon atom and the heterocyclic ring or hydrocarbon ring represents an aromatic ring, and when X1 represents a nitrogen atom. 
       
     
     
         7 . The melanin production inhibitor according to  claim 2 , wherein —X—R3 represents a group represented by the following general formula (3): 
       
         
           
           
               
               
           
         
         where X1 represents a carbon atom or a nitrogen atom; 
         R7 represents a hydrocarbon ring group which has 3 to 8 carbon atoms and may have a substituent; and 
         R8 represents a hydrogen atom, and a number of R8's corresponds to X1. 
       
     
     
         8 . The melanin production inhibitor according to  claim 2 , wherein —X—R3 represents a group represented by the following general formula (4): 
       
         
           
           
               
               
           
         
         where X2 represents a nitrogen atom or an oxygen atom; 
         n represents an integer of 0 to 5; 
         Y is selected from hydroxyl, amino, and an alkyloxy having 1 to 6 carbon atoms; 
         R9 is selected from a hydrogen atom, hydroxyl, and a hydroxyalkyl having 1 to 6 carbon atoms when X2 represents a nitrogen atom, and R9 is absent when X2 represents an oxygen atom; and 
         R10, R11, and R12 are each independently selected from a hydrogen atom, hydroxyl, oxo, and a hydroxyalkyl having 1 to 5 carbon atoms, provided that, when one of R10 and R11 represents the oxo, the other is absent. 
       
     
     
         9 . The melanin production inhibitor according to  claim 6 , wherein the compound represented by the general formula (1) comprises a compound represented by the following general formula (5): 
       
         
           
           
               
               
           
         
         where A4, A5, and A6 are each independently selected fromphenyl and pyridyl which may be substituted by methyl, methoxy, or hydroxyl; and 
         R13 and R14 are bound to each other to form, together with a nitrogen atom represented by N, a saturated heterocyclic ring which has 4 or 5 carbon atoms and may be substituted by hydroxyl or oxo. 
       
     
     
         10 . The melanin production inhibitor according to  claim 8 , wherein the compound represented by the general formula (1) comprises a compound represented by the following general formula (6): 
       
         
           
           
               
               
           
         
         where A4, A5, and A6 are each independently selected fromphenyl and pyridyl each of which may be substituted by methyl, methoxy, or hydroxyl; 
         X2 represents a nitrogen atom or an oxygen atom; 
         Y1 represents hydroxyl or amino; 
         R15 is selected from a hydrogen atom, hydroxyl, and a hydroxyalkyl having 1 to 3 carbon atoms when X2 represents a nitrogen atom, and R15 is absent when X2 represents an oxygen atom; and 
         R16 is selected from a hydrogen atom, hydroxyl, and a hydroxyalkyl having 1 to 3 carbon atoms. 
       
     
     
         11 . The melanin production inhibitor according to  claim 9 , wherein the compound represented by the general formula (5) is selected from 1-triphenylmethylpiperidine (Compound 5) and 1-triphenylmethylpyrrolidine (Compound 6). 
       
         
           
           
               
               
           
         
       
     
     
         12 . The melanin production inhibitor according to  claim 10 , wherein the compound represented by the general formula (6) is selected from the group consisting of 2-(triphenylmethyloxy)ethanol (Compound 2), 2-(triphenylmethylamino) ethanol (Compound 3), and 2-(triphenylmethyloxy)ethylamine (Compound 4). 
       
         
           
           
               
               
           
         
       
     
     
         13 . The melanin production inhibitor according to  claim 1 , wherein the compound represented by the general formula (1) is selected from the group consisting of triphenylmethylamine, triphenylmethanol, triphenylmethane, and aminodiphenylmethane. 
       
         
           
           
               
               
           
         
       
     
     
         14 . The melanin production inhibitor according to  claim 1 , wherein the compound represented by the general formula (1) is free of an imidazole skeleton. 
     
     
         15 . The melanin production inhibitor according to  claim 1 , wherein the melanin production inhibitor has MIC 80  10 times or more that of clotrimazole. 
     
     
         16 . The melanin production inhibitor according to  claim 1 , wherein the melanin production inhibitor is free of an effect of inhibiting expression of tyrosinase protein at a minimum effective dose for melanin production inhibition. 
     
     
         17 . An external preparation for skin for melanin production inhibition, comprising the melanin production inhibitor according to  claim 1 . 
     
     
         18 . The external preparation for skin according to  claim 17 , comprising the melanin production inhibitor in an amount of 0.001 w/w % to 10 w/w % with respect to a total amount of the external preparation for skin. 
     
     
         19 . The external preparation for skin according to  claim 17 , wherein the external preparation for skin is a cosmetic.