Topical lightening composition and uses thereof
View Patent ↗The disclosure relates to novel topical lightening compositions a skin depigmenting agent and a vehicle. There is provided a topical lightening composition comprising a substituted-4-oxobutanoic acid, ester, or amide tyrosinase inhibitor, and a vehicle. The depigmenting agents of this disclosure can be used as such or as a pharmaceutically acceptable salt including conventional non-toxic salts which include a metal salt or an alkaline earth metal salt, an ammonium salt, or an organic base salt. The depigmenting agents of this disclosure can be incorporated into any cosmetically-, dermatologically-, or cosmeticatically-acceptable vehicle or carrier normally used for topical application. The compositions and methods of the disclosure are effective to lighten skin, hair, lips, and/or nails.
1. A topical skin lightening composition, comprising a substituted-4-oxobutanoic acid, ester, or amide skin depigmenting agent of Formula I:
wherein, where Z is a sulfur atom or a group NR N , wherein R N is selected from H, alkyl of 1 to 6 carbons, or cycloalkyl of 3 to 6 carbons,
G is an aryl of 6 to 10 carbons optionally substituted with R 3 -R 4 ;
R 3 represents, independently at each occurrence, a bond without R 3 or one of the following: (i) an aliphatic C 1 -C 20 hydrocarbon radical; (ii) a C 1 -C 20 aromatic hydrocarbon radical; or (iii) a C 1 -C 20 heteroaryl radical;
R 4 is selected independently at each occurrence from hydrogen; —F; —Cl; —Br; —I; —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; —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 ; —(C═O)—R; —PR 2 ; —O—P(═O)(OR) 2 ; —P(═O)(OR) 2 ; ═O; ═S; ═NR; an aliphatic C 1 -C 20 hydrocarbon radical; a C 1 -C 20 aromatic hydrocarbon radical; or a C 1 -C 20 heteroaryl radical;
R 1 and R 2 are each selected from: H, alkyl of 1 to 6 carbons, or cycloalkyl of 3 to 6 carbons;
X is oxygen or nitrogen;
Y is H, alkyl of 1 to 6 carbons; alkoxyalkyl of 2 to 12 carbons; or G substituted with R 3 -R 4 ;
Q is alkyl of 1 to 10 carbons, cycloalkyl of 3 to 6 carbons, alkylaryl the alkyl of which has 1 to 6 carbons and said aryl has 6 to 10 carbons, or optionally substituted with R 3 -R 4 ;
n is 0, 1, or 2, with the proviso that when Z is NR N , n will be zero; and
a cosmetically, dermatologically or pharmaceutically acceptable vehicle.
2. A topical skin lightening composition according to claim 1 , wherein Z is NR N .
3. A topical skin lightening composition according to claim 2 , wherein R N is selected from the group consisting of methyl, ethyl, propyl, and butyl.
4. A topical skin lightening composition according to claim 2 , wherein R N is methyl.
5. A topical skin lightening composition comprising a skin depigmenting agent of Formula II:
wherein G is aryl of 6 carbons optionally substituted with alkyl of 1 to 4 carbons, halogen or alkoxy of 2 to 4 carbons; Q is aryl optionally substituted with halogen, arylalkyl said alkyl of 1 to 6 carbons and said aryl optionally substituted with halogen, or cycloalkyl said alkyl from 3 to 6 carbons; X is oxygen or nitrogen; Y is H, alkyl of 1 to 6 carbons, or an alkoxyalkyl of 2 to 12 carbons; and R 1 and R 2 are each selected from H, alkyl of 1 to 6 carbons, or cycloalkyl of 3 to 6 carbons; and
a cosmetically, dermatologically or pharmaceutically acceptable vehicle.
6. A topical skin lightening composition comprising a skin depigmenting agent of Formula III:
wherein G is aryl of 6 carbons optionally substituted with alkyl of 1 to 4 carbons, halogen or alkoxy of 2 to 4 carbons; R N is selected from H, alkyl of 1 to 6 carbons, or cycloalkyl of 3 to 6 carbons, Q is aryl optionally substituted with halogen, arylalkyl said alkyl of 1 to 6 carbons and said aryl optionally substituted with halogen, arylheteroalkyl, or cycloalkyl said alkyl from 3 to 6 carbons; X is oxygen or nitrogen; Y is H, alkyl of 1 to 6 carbons, or an alkoxyalkyl of 2 to 12 carbons; and R 1 and R 2 are each selected from H, alkyl of 1 to 6 carbons, or cycloalkyl of 3 to 6 carbons; and
a cosmetically, dermatologically or pharmaceutically acceptable vehicle.
7. The composition of claim 1 , wherein said skin depigmenting agent is present in an amount of about 0.0001% to about 20% by weight.
8. The composition of claim 1 , wherein said skin depigmenting agent is present in an amount of 0.001% to about 5% by weight.
9. The composition of claim 1 , wherein said skin depigmenting agent is present in an amount of about 0.01% to about 2.5% by weight.
10. The composition of claim 1 , wherein the skin depigmenting agent is present in an amount effective to lighten skin.
11. The composition of claim 1 , wherein said composition has a pH ranging from about 1 to about 8.
12. The composition of claim 11 , wherein said composition has a pH ranging from about 2 to about 7.
13. The composition of claim 11 , wherein said composition has a pH ranging from about 3.5 to about 5.5.
14. The composition of claim 1 , wherein said composition is in a product form of a cream, a lotion, an ointment, an emulsion, a gel, a foam, a mousse, a pomade, a solid, a powder, a spray, a liquid dispersion, a mask, a patch, or a towelette.
15. A topical skin lightening composition of claim 1 , comprising a skin depigmenting agent selected from the group consisting of:
2-(4′-chlorophenylthio)-4-(4′-t-butylphenyl)-4-oxobutanoic acid;
2-(4′-chlorophenylthio)-4-(4′-methylphenyl)-4-oxobutanoic acid;
2-(4′-chlorophenylthio)-4-(4′-ethoxyphenyl)-4-oxobutanoic acid;
2-(4′-phenylthio)-4-(4′-t-butylphenyl)-4-oxobutanoic acid;
2-(4′-cyclohexylthio)-4-(4′-chlorophenyl)-4-oxobutanoic acid;
2-(4′-cyclohexylthio)-4-(4′-t-butylphenyl)-4-oxobutanoic acid;
2-(4′-chlorophenylmethylthio)-4-(4′-chlorophenyl)-4-oxobutanoic acid;
2-(4′-chlorophenylmethylthio)-4-(4′-ethoxyphenyl)-4-oxobutanoic acid;
2-(2-furanylmethylamino)-4-(4′-methylphenyl)-4-oxobutanoic acid;
2-(3-pyridylmethylamino)-4-(4′-methoxyphenyl)-4-oxobutanoic acid; and
2-(benzylamino)-4-(4′-methylphenyl)-4-oxobutanoic acid,
and combinations thereof, and
a cosmetically, dermatologically or pharmaceutically acceptable vehicle.
16. The composition according to claim 15 , wherein the skin depigmenting agent is 2-(4′-chlorophenylmethylthio)-4-(4′-chlorophenyl)-4-oxobutanoic acid.
17. The composition of claim 15 , wherein said skin depigmenting agent is present in an amount of about 0.0001% to about 20% by weight.
18. The composition of claim 15 , wherein the skin depigmenting agent is present in an amount effective to lighten skin.
19. The composition of claim 15 , wherein said composition has a pH ranging from about 1 to about 8.
20. The composition of claim 15 , wherein said composition is in a product form of a cream, a lotion, an ointment, an emulsion, a gel, a foam, a mousse, a pomade, a solid, a powder, a spray, a liquid dispersion, a mask, a patch, or a towelette.
21. A method comprising topically applying the composition of claim 1 to a keratinous surface in need of lightening.
22. A method according to claim 21 , wherein said keratinous surface is skin, scalp, hair, or nails.
23. A method according to claim 21 , wherein the composition is topically applied to treat a skin condition selected from the group consisting of freckles, age spots, dark spots, hyperpigmentation, post-inflammatory pigmentation, discoloration, yellowing, melasma, dark circles under the eyes, and any combinations thereof.
24. A method comprising topically applying the composition of claim 5 to a keratinous surface in need of lightening.
25. A method according to claim 23 , wherein said keratinous surface is skin, scalp, hair, or nails.
26. A method according to claim 24 , wherein the composition is topically applied to treat a skin condition selected from the group consisting of freckles, age spots, dark spots, hyperpigmentation, post-inflammatory pigmentation, discoloration, yellowing, melasma, dark circles under the eyes, and any combinations thereof.
27. A method comprising topically applying the composition of claim 15 to a keratinous surface in need of lightening.
28. A method according to claim 27 , said keratinous surface is skin, scalp, hair, or nails.
29. A method according to claim 27 , wherein the composition is topically applied to treat a skin condition selected from the group consisting of freckles, age spots, dark spots, hyperpigmentation, post-inflammatory pigmentation, discoloration, yellowing, melasma, dark circles under the eyes, and any combinations thereof.
30. A method of reducing pigmentation in a mammal, comprising administering to the mammal an effective amount of a compound as claimed in claim 1 or a pharmaceutically acceptable salt of ester thereof.
31. A method of inhibiting tyrosinase, comprising administering an effective amount of a compound as claimed in claim 1 or a pharmaceutically acceptable salt of ester thereof.