Skin Lightening Compositions

• US 20110171149A1
• Filed: 01/04/2011
• Published: 07/14/2011
• Est. Priority Date: 01/06/2010
• Status: Active Grant

• Current Assignee: ELC Management LLC (The Estee Lauder Companies Inc.)
• Original Assignee: ELC Management LLC (The Estee Lauder Companies Inc.)
• Inventors: Yoshida, Masaki, Ando, Hideya, Matsui, Mary S., Niki, Yoko, Ichihashi, Masamitsu, Yarosh, Daniel B.
• Granted Patent: US 8,722,026 B2
• Time in Patent Office: Days
• US Class Current: 424/62
• CPC Class Codes: A61K 2800/782 Enzyme inhibitors; Enzyme antagonists
• CPC Class Codes: A61K 8/49 containing heterocyclic compounds
• CPC Class Codes: A61K 8/4946 Imidazoles or their condensed derivatives, e.g. benzimidazoles
• CPC Class Codes: A61P 17/00 Drugs for dermatological disorders
• CPC Class Codes: A61P 17/16 Emollients or protectives, e.g. against radiation
• CPC Class Codes: A61Q 17/04 Topical preparations for affording protection against sunlight or other radiation; Topical sun tanning preparations
• CPC Class Codes: A61Q 19/02 for chemically bleaching or whitening the skin

Abstract

Compositions and methods for lightening and/or depigmenting skin are provided, the compositions comprising compounds having the structure:

or having the structure:

as defined herein.

Claims

1. A topically applicable composition for lightening or depigmenting skin, comprising a skin lightening or depigmenting effective amount of at least one compound represented by the structural formula:

2. The composition of claim 1, comprising a compound of the formula (I), wherein R₁ and R₂ are the same or different and are each selected from the group consisting of hydrogen, alkyl, and alkoxy, whether or not halogen-substituted, R₆ is selected from the group consisting of hydrogen, methyl, and ethyl, and R₃, R₄, and R₅ are the same or different and are each selected from the group consisting of hydrogen, alkyl and alkoxy, whether or not substituted by halogen.

3. The composition of claim 1, comprising a compound of the formula (I), wherein R₁ and R₂ are the same or different and are each selected from the group consisting of hydrogen, methyl, methyl substituted by halogen, methoxy, and methoxy substituted by halogen, R₆ is hydrogen, R₃, R₄, and R₅ are the same or different and are each selected from the group consisting of hydrogen, methyl, ethyl, propyl, methoxy, ethoxy, propoxy, methoxymethoxy, ethoxyethoxy, propoxypropoxy, methoxyethoxy, ethoxymethoxy, methoxypropoxy, propoxymethoxy, ethoxypropoxy, propoxyethoxy, whether or not substituted by halogen.

4. The composition of claim 1, comprising a compound of the formula (I) selected from the group consisting of compounds wherein R₁ and R₂ are each hydrogen or methoxy, R3 and R₅ are methyl and R₄ is methoxy;

in which R₁, R₂, R₅ and R₆ are hydrogen, R₃ is methyl and R₄ is propoxymethoxy;

in which R₁, R₂, R₃, R₄, R₅ and R₆ all are hydrogen;

in which R₁, R₂, R₅ and R₆ all are hydrogen, R₃ is methyl and R₄ is ethoxy substituted by halogen; and

, in which R₁ and R₂ are hydrogen or methoxy substituted by halogen, R₆ is hydrogen, R₃ is hydrogen and R₄ and R₅ are methoxy.

5. The composition of claim 1, wherein the compound of the formula (I) is selected from the group consisting of omeprazole, 5- or 6-methoxy-2-{[(4-methoxy-3,5-dimethylpyridin-2-yl)methyl]sulfinyl}-1H-benzimidazole;

esomeprazole, S-5-methoxy-2-{(4-methoxy-3,5 dimethylpyridin-2-yl)methylsufinyl]-3H-benzoimidazole;

lansoprazole, 2-{[3-methyl-4-(2,2,2-trifluoroethoxy)pyridin-2-yl]methylsulfinyl-1H-benzo(d)imidazole;

pantoprazole, RS-6-(difluoromethoxy))-2-[(3,4-dimethoxypyridin-2-yl)methylsulfinyl]-1H-benzo(d)imidazole; and

rabeprazole (pariprazole), 2-([4-(3-methoxypropoxy)-3-methylpyridin-2-yl]methylsulfinyl)-1H-benzo(d)imidazole, leminoprazole, 2-((o-(isobutylmethylamino)benzyl)sulfinyl)benzimidazole;

timoprazole, 2-(pyridine-2-ylmethylsulfinyl)-1H-benzimidazole; and

sulfides and sodium salts thereof.

6. The composition of claim 1, wherein the compound of the formula (I) is 5- or 6-methoxy-2-{[(4-methoxy-3,5-dimethylpyridin-2-yl)methyl]sulfinyl}-1H-benzimidazole, or a derivative thereof.

7. The composition of claim 1, comprising a compound of the formula (II), wherein R₂ is methyl or ethyl;

R₃ is —

NH₂, —

NHC₂H₅, —

CH₂CN, —

CH₃, —

CH₂OH or —

CH₂N═

C;

R4 is —

OCH₂Ar, —

NHCH₂Ar, —

CH═

CH—

(CH₂)_n Ar or —

CH₂CH₂(CH₂)_nAr wherein n is zero or one and Ar is as defined hereinabove; and

R₅ is hydrogen, fluoro, chloro or methyl.

8. The composition of claim 1, comprising a compound of the formula (II), wherein R₄ is at the 8-position and is selected from phenylmethoxy, phenylethyl, 3-phenyl-1-propenyl, phenylethenyl, benzylamino, 3-thienylmethoxy and 3-thienylmethanamino;

R₂ is methyl;

R₃ is amino, cyanomethyl or methyl; and

R₅ is hydrogen or methyl at the 7-position.

9. The composition of claim 1, wherein the compound of the formula (II) is selected from the group consisting of SCH 28080, 3-(cyanomethyl)-2-methyl-8-phenylmethoxy-imidazo[1,2-a]pyridine;

and SCH 32651, 3-amino-2-methyl-8-phenylmethoxyimidazo[1,2-a]pyrazine.

10. The composition of claim 1, comprising an anhydrous composition, an aqueous-based solution, suspension, dispersion, lotion, serum, essence, emulsion, milk, cream, gel, paste, ointment, spray, stick, mousse, aerosol or microcapsules.

11. The composition of claim 1, further comprising at least one cosmetic or dermatological additive or adjuvant.

12. A method of lightening or depigmenting the skin, comprising topically applying to skin in need of such treatment a topically applicable composition for lightening or depigmenting skin, comprising a safe and effective skin-lightening or depigmenting amount of at least one compound represented by the structural formula:

13. The method of claim 12, wherein the composition comprises a compound of the formula (I), wherein R₁ and R₂ are the same or different and are each selected from the group consisting of hydrogen, alkyl, and alkoxy, whether or not halogen-substituted, R₆ is selected from the group consisting of hydrogen, methyl, and ethyl, and R₃, R₄, and R₅ are the same or different and are each selected from the group consisting of hydrogen, alkyl and alkoxy, whether or not substituted by halogen.

14. The method of claim 12, wherein the composition comprises a compound of the formula (I), wherein R₁ and R₂ are the same or different and are each selected from the group consisting of hydrogen, methyl, methyl substituted by halogen, methoxy, and methoxy substituted by halogen, R₆ is hydrogen, R₃, R₄, and R₅ are the same or different and are each selected from the group consisting of hydrogen, methyl, ethyl, propyl, methoxy, ethoxy, propoxy, methoxymethoxy, ethoxyethoxy, propoxypropoxy, methoxyethoxy, ethoxymethoxy, methoxypropoxy, propoxymethoxy, ethoxypropoxy, propoxyethoxy, whether or not substituted by halogen.

15. The method of claim 12, wherein the composition comprises a compound of the formula (I) selected from the group consisting of compounds wherein R₁ and R₂ are each hydrogen or methoxy, R3 and R₅ are methyl and R₄ is methoxy;

in which R₁, R₂, R₅ and R₆ are hydrogen, R₃ is methyl and R₄ is propoxymethoxy;

in which R₁, R₂, R₃, R₄, R₅ and R₆ all are hydrogen;

in which R₁, R₂, R₅ and R₆ all are hydrogen, R₃ is methyl and R₄ is ethoxy substituted by halogen; and

, in which R₁ and R₂ are hydrogen or methoxy substituted by halogen, R₆ is hydrogen, R₃ is hydrogen and R₄ and R₅ are methoxy.

16. The method of claim 12, wherein the composition comprises a compound of the formula (I) selected from the group consisting of omeprazole, 5- or 6-methoxy-2-{[(4-methoxy-3,5-dimethylpyridin-2-yl)methyl]sulfinyl}-1H-benzimidazole;

esomeprazole, S-5-methoxy-2-{(4-methoxy-3,5 dimethylpyridin-2-yl)methylsufinyl]-3H-benzoimidazole;

lansoprazole, 2-{[3-methyl-4-(2,2,2-trifluoroethoxy)pyridin-2-yl]methylsulfinyl-1H-benzo(d)imidazole;

pantoprazole, RS-6-(difluoromethoxy))-2-[(3,4-dimethoxypyridin-2-yl)methylsulfinyl]-1H-benzo(d)imidazole; and

rabeprazole (pariprazole), 2-([4-(3-methoxypropoxy)-3-methylpyridin-2-yl]methylsulfinyl)-1H-benzo(d)imidazole, leminoprazole, 2-((o-(isobutylmethylamino)benzyl)sulfinyl)benzimidazole;

timoprazole, 2-(pyridine-2-ylmethylsulfinyl)-1H-benzimidazole; and

sulfides and sodium salts thereof.

17. The method of claim 16, wherein the composition comprises a compound of the formula (I) which is 5- or 6-methoxy-2-{[(4-methoxy-3,5-dimethylpyridin-2-yl)methyl]sulfinyl}-1H-benzimidazole, or a derivative thereof.

18. The method of claim 12, wherein the composition comprises a compound of the formula (II), wherein R₂ is methyl or ethyl;

R₃ is —

NH₂, —

NHC₂H₅, —

CH₂CN, —

CH₃, —

CH₂OH or —

CH₂N═

C;

R4 is —

OCH₂Ar, —

NHCH₂Ar, —

CH═

CH—

(CH₂)_n Ar or —

CH₂CH₂(CH₂)_nAr wherein n is zero or one and Ar is as defined hereinabove; and

R₅ is hydrogen, fluoro, chloro or methyl.

19. The method of claim 12, wherein the composition comprises a compound of the formula (II), wherein R₄ is at the 8-position and is selected from phenylmethoxy, phenylethyl, 3-phenyl-1-propenyl, phenylethenyl, benzylamino, 3-thienylmethoxy and 3-thienylmethanamino;

R₂ is methyl;

R₃ is amino, cyanomethyl or methyl; and

R₅ is hydrogen or methyl at the 7-position.

20. The method of claim 12, wherein the composition comprises a compound of the formula (II) which is selected from the group consisting of SCH 28080, 3-(cyanomethyl)-2-methyl-8-phenylmethoxy-imidazo[1,2-a]pyridine;

and SCH 32651, 3-amino-2-methyl-8-phenylmethoxyimidazo[1,2-a]pyrazine.

21. A method of screening compounds for efficacy in modulating melanin synthesis, the method comprising (a) selecting a compound to be tested that alters cellular or cell organelle pH;

(b) incubating melanocytes or melanoma cells with the test compound at various concentrations and with a positive control compound; and

(c) determining the melanin content of the cells.

22. A method of screening compounds for efficacy in modulating melanin synthesis, the method comprising (a) selecting a compound to be tested that alters cellular or cell organelle pH;

(b) incubating melanocytes or melanoma cells with the test compound at various concentrations and with a positive control compound;

(c) incubating the melanocytes or melanoma cells with a weak base;

(d) incubating the cells with a labelled antibody to the weak base; and

(e) assessing the change in pH.