Tyrosinase inhibitors

Abstract

The compositions and methods of described herein comprise novel ingredients effective to reduce unwanted pigmentation, such as skin discoloration, freckles, age spots, liver spots, sun damage, tans, pigmented acne marks, scars, pigmented birthmarks, hyperpigmentation, post-inflammatory hyperpigmentation, post-injury hyperpigmentation, melasma, cholasma, after-burn scar, nail stain, yellowing of skin, dark circles under eyes, and the like. The composition may include additional ingredients accordingly for a colored cosmetic, moisturizer, cleanser, toner, and the like.

1 . A cosmetic composition for improving the aesthetic appearance of human skin comprising a cosmetically acceptable vehicle, and an effective amount of a compound according to formula I(a): 
       
         
           
           
               
               
           
         
       
       wherein,
 R 1  and R 2  are independently selected from hydrogen, aliphatic C 1 -C 12  hydrocarbon radicals; aromatic C 1 -C 12  hydrocarbon radicals; aliphatic C 1 -C 12  heterocycles, aromatic C 1 -C 12  heterocycles, or combinations thereof; each of the foregoing optionally containing from 1-8 heteroatoms selected from halogen, O, N, and S and being optionally substituted with one or more groups R, and wherein R 1  and R 2  may together form a three- to six-membered ring, with the proviso that one of R 1  and R 2  are not hydrogen; 
 R 3  and R 4  are independently selected from hydrogen, aliphatic C 1 -C 12  hydrocarbon radicals; aromatic C 1 -C 12  hydrocarbon radicals; aliphatic C 1 -C 12  heterocycles, aromatic C 1 -C 12  heterocycles, or combinations thereof; each of the foregoing optionally containing from 1-8 heteroatoms selected from halogen, O, N, and S and being optionally substituted with one or more groups R, and wherein R 3  and R 4  may together form a three- to six-membered heterocyclic ring, with the proviso that one of R 3  and R 4  are not hydrogen; 
 R is selected, independently at each occurrence, from hydrogen, —F; —Cl; —Br; —I; ═O, —OH, —OR*; —NH 2 ; —NHR*; —N(R*) 2 ; —N(R*) 3 ; —N(R*)—OH; —N(—O)(R*) 2 ; —O—N(R*) 2 ; —N(R*)—O—R*; —N(R*)—N(R*) 2 ; —C═N—R*; —N═C(R*) 2 ; —C═N—N(R*) 2 ; —C(═NR*)—N(R*) 2 ; —SH; —SR*; —CN; —NC; —(C═O)—R*; —CHO; —CO 2 H; —CO 2   − ; —CO 2 R*; —(C═O)—S—R*; —O—(C═O)—H; —O—(C═O)—R*; —S—(C═O)—R*; —(C═O)—NH 2 ; —(C═O)—N(R*) 2 ; —(C═O)—NHNH 2 ; —O—(C═O)—NHNH 2 ; —(C═S)—NH 2 ; —(C═S)—N(R*) 2 ; —N(R*)—CHO; —N(R*)—(C═O)—R*; —(C═NR)—O—R*; —O—(C═NR*)—R*, —SCN; —NCS; —NSO; —SSR*; —N(R*)—C(═O)—N(R*) 2 ; —N(R*)—C(═S)—N(R*) 2 ; —SO 2 —R*; —O—S(═O) 2 —R*; —S(═O) 2 —OR*; —N(R*)—SO 2 —R*; —SO 2 —N(R*) 2 ; —O—SO 3 ; —O—S(═O) 2 —OR*; —O—S(═O)—OR*; —O—S(═O)—R*; —S(═O)—OR*; —S(═O)—R*; —NO; —NO 2 ; —NO 3 ; —O—NO; —O—NO 2 ; —N 3 ; —N 2 —R*; —N(C 2 H 4 ); —Si(R*) 3 ; —CF 3 ; —O—CF 3 ; —PR* 2 ; —O—P(═O)(OR*) 2 ; —P(═O)(OR*) 2 ; C 1 -C 8  perfluoroalkyl; an aliphatic C 1 -C 8  hydrocarbon radical; a C 1 -C 8  aromatic hydrocarbon radical; or a C 1 -C 8  heteroaryl radical; 
 where R* is independently at each occurrence hydrogen or a straight chained, branched, or cyclic C 1 -C 20  hydrocarbon radical, which may be saturated, partially saturated, or aromatic, each of which may be optionally substituted with one or more groups R, or optionally substituted with 1-6 heteroatoms selected from nitrogen, oxygen, sulfur, or halogen; 
 and cosmetically acceptable salts thereof. 
 
     
     
         2 . (canceled) 
     
     
         3 . The composition according to  claim 1 , wherein the compound has a structure according to Formula I(b): 
       
         
           
           
               
               
           
         
       
       where ring “A” is a five or six-membered optionally aromatic ring, ω 1  is C or N; and ω 2 -ω 6  are independently selected from —N—, —NH—, —NR*—, —NL 1 -, —O—, —S—, —CH—, —CR—, —CR*—, —CL 1 -, and in the case where ring “A” is a five membered ring, ω 4  is a bond (i.e., it is absent); and wherein ω 2  or ω 6  may also be a group —NL 1 - or —CL 1 -, where L 1  is a linking moiety that forms a linkage between ring A and R 2 , where L 1  is group —X a —(CH 2 ) n —(CH═CH) m —X b —(CH 2 ) n —(CH═CH) m —X c —, where X a , X b , and X c  are independently a bond (i.e., absent), —O—, —S—, —NH—, —NR*— and “n” and “m” are independently at each occurrence integers from 0-2, with the proviso that L 1  comprises no more than four atoms in the direct chain between rings A and R 2 . 
     
     
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         5 . The composition according to  claim 3 , wherein ω 4  is a bond (i.e., it is absent), such that ring “A” is a five membered selected from the group consisting of: 
       
         
           
           
               
               
           
         
       
       wherein ε 1 , ε 2 , and ε 3 , are independently selected from N, NH, NR*, S, and O; with the proviso that where the point of attachment is ε 1 , ε 2 , or ε 3 , then that position represents N; and wherein carbon atoms which are not the point of attachment may be optionally substituted with a group R; and wherein the dashed circles indicate that each ring may comprise zero, one, or two double bonds. 
     
     
         6 . The composition according to  claim 5 , wherein ring “A” is a ring Q, having the form: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       wherein any available site on the ring “A” may be optionally substituted with a group R. 
     
     
         7 . The composition according to  claim 6 , wherein ring “A” is: 
       
         
           
           
               
               
           
         
       
       where R is independently at each occurrence hydrogen or lower alkyl. 
     
     
         8 . The composition according to  claim 7 , wherein ring “A” is: 
       
         
           
           
               
               
           
         
       
       where R is independently at each occurrence hydrogen or lower alkyl. 
     
     
         9 . The composition according to  claim 3 , wherein ring “A” is a six membered aromatic ring Ω, where Ω has the form: 
       
         
           
           
               
               
           
         
       
       R 5 -R 9  are independently selected from hydrogen, R, or L 1 ; and wherein any two adjacent groups R 5 -R 9  may together form a five or six membered fused ring with ring “A,” each optionally comprising from 1 to 6 heteroatoms selected from oxygen, nitrogen, sulfur, and halogen. 
     
     
         10 . (canceled) 
     
     
         11 . (canceled) 
     
     
         12 . (canceled) 
     
     
         13 . (canceled) 
     
     
         14 . The composition according to  claim 1 , wherein R 3  is hydrogen or lower alkyl; and R 4  is a group of the form: 
       
         
           
           
               
               
           
         
       
       where “z” is an integer from 1-4; and
 ring “B” is a five or six-membered ring, ε 1  is C or N; and ε 2 -ε 6  are independently selected from —N—, —NH—, —NR*—, —O—, —S—, —CH—, —CR—, —CR*—, and in the case where ring “A” is a five membered ring, ε 4  is a bond (i.e., it is absent); and wherein ε 2  or ε 6  may also be a group —NL 1 - or —CL 1 -, where L 1  is a linking moiety that forms a linkage between ring “B” and R 3 , where L 1  is group —X a —(CH 2 ) n —(CH═CH) m —X b —(CH 2 ) n —(CH═CH) m —X c —, where X a , X b , and X c  are independently a bond (i.e., absent), —O—, —S—, —NH—, —NR*— and “n” and “m” are independently at each occurrence integers from 0-2, with the proviso that L 1  comprises no more than four atoms in the direct chain between ring “A” and R 3 . 
 
     
     
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         19 . (canceled) 
     
     
         20 . (canceled) 
     
     
         21 . (canceled) 
     
     
         22 . (canceled) 
     
     
         23 . A cosmetic composition according to  claim 1 , wherein said compound is selected from the group consisting of: 
       
         
           
           
               
               
           
         
       
       and cosmetically acceptable salts thereof. 
     
     
         24 . A cosmetic composition for improving the aesthetic appearance of human skin comprising a cosmetically acceptable vehicle, and an effective amount of a compound according to formula II(a): 
       
         
           
           
               
               
           
         
       
       wherein,
 R 1  is selected from hydrogen, aliphatic C 1 -C 12  hydrocarbon radicals; aromatic C 1 -C 12  hydrocarbon radicals; aliphatic C 1 -C 12  heterocycles, aromatic C 1 -C 12  heterocycles, or combinations thereof; each of the foregoing optionally containing from 1-8 heteroatoms selected from halogen, O, N, and S and being optionally substituted with one or more groups R; 
 R 2  is either a bond (i.e., it is absent) or a methylene group —CH 2 —; 
 R 3  and R 4  are independently selected from hydrogen, aliphatic C 1 -C 12  hydrocarbon radicals; aromatic C 1 -C 12  hydrocarbon radicals; aliphatic C 1 -C 12  heterocycles, aromatic C 1 -C 12  heterocycles, or combinations thereof; each of the foregoing optionally containing from 1-8 heteroatoms selected from halogen, O, N, and S and being optionally substituted with one or more groups R, and wherein R 3  and R 4  may together form a three- to six-membered heterocyclic ring, with the proviso that one of R 3  and R 4  are not hydrogen; 
 R is selected, independently at each occurrence, from hydrogen, —F; —Cl; —Br; —I; ═O, —OH, —OR*; —NH 2 ; —NHR*; —N(R*) 2 ; —N(R*) 3 ; —N(R*)—OH; —N(—O)(R*) 2 ; —O—N(R*) 2 ; —N(R*)—O—R*; —N(R*)—N(R*) 2 ; —C═N—R*; —N═C(R*) 2 ; —C═N—N(R*) 2 ; —C(═NR*)—N(R*) 2 ; —SH; —SR*; —CN; —NC; —(C═O)—R*; —CHO; —CO 2 H; —CO 2   − ; —CO 2 R*; —(C═O)—S—R*; —O—(C═O)—H; —O—(C═O)—R*; —S—(C═O)—R*; —(C═O)—NH 2 ; —(C═O)—N(R*) 2 ; —(C═O)—NHNH 2 ; —O—(C═O)—NHNH 2 ; —(C═S)—NH 2 ; —(C═S)—N(R*) 2 ; —N(R*)—CHO; —N(R*)—(C═O)—R*; —(C═NR)—O—R*; —O—(C═NR*)—R*, —SCN; —NCS; —NSO; —SSR*; —N(R*)—C(═O)—N(R*) 2 ; —N(R*)—C(═S)—N(R*) 2 ; —SO 2 —R*; —O—S(═O) 2 —R*; —S(═O) 2 —OR*; —N(R*)—SO 2 —R*; —SO 2 —N(R*) 2 ; —O—SO 3 ; —O—S(═O) 2 —OR*; —O—S(═O)—OR*; —O—S(═O)—R*; —S(═O)—OR*; —S(═O)—R*; —NO; —NO 2 ; —NO 3 ; —O—NO; —O—NO 2 ; —N 3 ; —N 2 —R*; —N(C 2 H 4 ); —Si(R*) 3 ; —CF 3 ; —O—CF 3 ; —PR* 2 ; —O—P(═O)(OR*) 2 ; —P(═O)(OR*) 2 ; C 1 -C 8  perfluoroalkyl; an aliphatic C 1 -C 8  hydrocarbon radical; a C 1 -C 8  aromatic hydrocarbon radical; or a C 1 -C 8  heteroaryl radical; 
 where R* is independently at each occurrence hydrogen or a straight chained, branched, or cyclic C 1 -C 20  hydrocarbon radical, which may be saturated, partially saturated, or aromatic, each of which may be optionally substituted with one or more groups R, or optionally substituted with 1-6 heteroatoms selected from nitrogen, oxygen, sulfur, or halogen; 
 and cosmetically acceptable salts thereof. 
 
     
     
         25 . (canceled) 
     
     
         26 . The composition according to  claim 24 , wherein R 1  is a ring “Q” or a ring “Ω”. 
     
     
         27 . The composition according to  claim 24 , wherein R 1  is a ring “Ω” having the form: 
       
         
           
           
               
               
           
         
       
       where R 7 -R 11  are independently selected at each occurrence from hydrogen, halogen, hydroxyl, methoxy, amino, lower alkyl, and groups R. 
     
     
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         30 . The composition according to  claim 24 , wherein R 3  is hydrogen or lower alkyl; and R 4  is a group of the form: 
       
         
           
           
               
               
           
         
       
       where “z” is an integer from 1-4; and
 ring “B” is a five or six-membered ring, ε 1  is C or N; and ε 2 -ε 6  are independently selected from —N—, —NH—, —NR*—, —O—, —S—, —CH—, —CR—, —CR*—, and in the case where ring “A” is a five membered ring, ε 4  is a bond (i.e., it is absent); and wherein ε 2  or ε 6  may also be a group —NL 1 - or —CL 1 -, where L 1  is a linking moiety that forms a linkage between ring “B” and R 3 , where L 1  is group —X a —(CH 2 ) n —(CH═CH) m —X b —(CH 2 ) n —(CH═CH) m —X c —, where X a , X b , and X c  are independently a bond (i.e., absent), —O—, —S—, —NH—, —NR*— and “n” and “m” are independently at each occurrence integers from 0-2, with the proviso that L 1  comprises no more than four atoms in the direct chain between ring “A” and R 3 . 
 
     
     
         31 . (canceled) 
     
     
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         33 . The composition according to  claim 30 , wherein “z” is an integer from 1-2, and ring B is a group Ω having the form: 
       
         
           
           
               
               
           
         
       
       where R 7 -R 11  are independently selected at each occurrence from hydrogen, halogen, hydroxyl, methoxy, amino, lower alkyl, and groups R. 
     
     
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         39 . The composition according to  claim 33 , having the following structure: 
       
         
           
           
               
               
           
         
       
       and cosmetically acceptable salts thereof. 
     
     
         40 . The cosmetic composition according to  claim 1 , further comprising a cosmetically acceptable vehicle, and a cosmetic ingredient selected from a film forming polymer, a thickener, a pH adjuster, a preservative, an emulsifier, a gelling agent, an antioxidant, an emollient, a humectant, a fragrance, and a colorant. 
     
     
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         45 . A method for improving the aesthetic appearance of human skin comprising topically applying to an area of the skin in need thereof a composition according to  claim 1 , for a time sufficient to improve the aesthetic appearance of said human skin. 
     
     
         46 . The method according to  claim 45 , wherein said aesthetic improvement of said human skin is selected from the group consisting of:
 (a) treatment, reduction, and/or prevention of fine lines or wrinkles;   (b) reduction of skin pore size;   (c) improvement in skin thickness, plumpness, and/or tautness;   (d) improvement in skin smoothness, suppleness and/or softness;   (e) improvement in skin tone, radiance, and/or clarity;   (f) improvement in procollagen, and/or collagen production;   (g) improvement in maintenance and remodeling of elastin;   (h) improvement in skin texture and/or promotion of retexturization;   (i) improvement in skin barrier repair and/or function;   (j) improvement in appearance of skin contours;   (k) restoration of skin luster and/or brightness;   (l) replenishment of essential nutrients and/or constituents in the skin;   (m) improvement of skin appearance decreased by aging and/or menopause;   (n) improvement in skin moisturization;   (o) increase in skin elasticity and/or resiliency;   (p) treatment, reduction, and/or prevention of skin sagging;   (q) improvement in skin firmness; and   (r) reduction of pigment spots and/or mottled skin; and   (s) improvement of optical properties of skin by light diffraction or reflection.   
     
     
         47 . The method according to  claim 45 , wherein said composition is applied at least once daily for a period of at least four weeks.