Series of Skin Whitening (Lightening) Compounds

Patent metadata

Field	Value
Publication number	US-2017275224-A1
Application number	US-201715620395-A
Country	US
Kind code	A1
Filing date	Jun 12, 2017
Priority date	Jul 21, 2008
Publication date	Sep 28, 2017
Grant date	—

Abstract

The present invention is directed to inhibitors of tyrosinase, pharmaceutical compositions comprising such tyrosinase inhibitors, and methods of making and using the same. Specifically, included in the present invention are compositions of matter comprised of at least one 2,4-dihydroxybenzene analog, which inhibit the activity of tyrosinase and which inhibit the overproduction of melanin.

First claim

1 - 32 : (canceled)

33 . A compound of Formula IV:

wherein represents double or single bond;
R 1 is selected from the group consisting of H, or C 1 -C 10 alkyl;
R 4 is selected from the group consisting of ═H, OH or O; and
R 5 is a selected from the group consisting of an aromatic, heteroaromatic or heterocyclic ring selected from the group consisting of phenyl, biphenyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-furanyl, 3-furanyl or 2-tetrahydrofuranyl; wherein R 5 is substituted with 1 to 3 moieties (R′, R″, R′″) independently selected from the group consisting of a C1-C10 alkyl group, a C1-C10 alkoxy group or a hydroxyl group;
with the following provisos:
proviso 1: when R 1 ═R 4 ═H; R 5 cannot be 1′-(2,4-dimethoxy-3-methyl)phenyl;
proviso 2: when R 1 ═R 4 ═H; R 5 cannot be 1′-(2,4-dihydroxy)phenyl; 1′-(2,4-dialkoxy)phenyl; 1′-(2,4-dialkenoxy)phenyl or 1′-(2,4-dibenzyloxy)phenyl;
proviso 3: R 5 cannot be 1′-(4-hydroxy)phenyl;
proviso 4: when R 1 ═R 4 ═H; R 5 cannot be 1′-(2,4-di(CO)R 1 , wherein R 1 is a (C 1 -C 20 )-alkyl group;
proviso 5: when R 1 ═R 4 ═H and R 5 cannot be a 1′-(2,4-disubstituted)phenyl; wherein said substituents are selected from —OR 2 and —OR 3 , wherein R 2 and R 3 are independently selected from the group consisting of H or a (C 1 -C 20 )-alkyl; and
proviso 6: when R 1 ═H and R 4 ═OH; R 5 cannot be 1′-(3,4-dihydroxy)phenyl; 1′-(3,4-dimethoxy)phenyl; 1′-(2-hydroxy)phenyl; 1′-(2-methoxy)phenyl; 1′-(4-methoxy)phenyl; phenyl; 1′-(3-methoxy,4-hydroxy)phenyl.

34 . The compound of claim 33 , wherein R 1 ═R 4 ═H and R 5 is selected from 1′-(3′,5′-dimethoxy)phenyl; 1′-(3′,5′-dihydroxy)phenyl; 1-(2′,4′,6-trimethoxyphenyl); R 1 =Me, R 4 ═OH, and R 5 is 1′-(2′,4′-dihydroxy)phenyl; R 1 =Me, R 4 ═O, and R 5 is 1′-(2′,4′-dihydroxy)phenyl; and R 1 ═R 4 ═H, R 5 —CH 2 CH 2 OH.

35 . The compound of claim 33 selected from the group consisting of 4-(3-(3,5-dimethoxyphenyl)propyl)benzene-1,3-diol (28), 4-(3-(3,5-dimethoxyphenyl)-1-hydroxypropyl)benzene-1,3-diol (29), 4-(3-(3,5-dihydroxyphenyl)propyl)benzene-1,3-diol (30), 4-(3-(2,4,6-trimethoxyphenyl)propyl)benzene-1,3-diol (31), 4-(3-(2,4-dihydroxyphenyl)propyl)-2-methylbenzene-1,3-diol (32), 4-(3-(2,4-dihydroxy-3-methylphenyl)-3-(2,4-dihydroxyphenyl)propane-1-one (33), 4-(5-hydroxypentyl)benzene-1,3-diol (34).

36 . A composition of matter comprising the compound of claim 33 .

37 . The composition of matter of claim 36 , wherein the compound is selected from the group consisting of compounds 4-(3-(3,5-dimethoxyphenyl)propyl)benzene-1,3-diol (28), 4-(3-(3,5-dimethoxyphenyl)-1-hydroxypropyl)benzene-1,3-diol (29), 4-(3-(3,5-dihydroxyphenyl)propyl)benzene-1,3-diol (30), 4-(3-(2,4,6-trimethoxyphenyl)propyl)benzene-1,3-diol (31), 4-(3-(2,4-dihydroxyphenyl)propyl)-2-methylbenzene-1,3-diol (32), 4-(3-(2,4-dihydroxy-3-methylphenyl)-3-(2,4-dihydroxyphenyl)propane-1-one (33), 4-(5-hydroxypentyl)benzene-1,3-diol (34) or a pharmaceutically acceptable salt thereof.

38 . A method for inhibiting the activity of tyrosinase comprising administering to a patient in need thereof a composition comprising the compound of claim 33 .

39 . The method of claim 38 , wherein the method for inhibiting the activity of tyrosinase comprising administering to a patient in need thereof a composition comprising one or more of a compound selected from the group consisting of 4-(3-(3,5-dimethoxyphenyl)propyl)benzene-1,3-diol (28), 4-(3-(3,5-dimethoxyphenyl)-1-hydroxypropyl)benzene-1,3-diol (29), 4-(3-(3,5-dihydroxyphenyl)propyl)benzene-1,3-diol (30), 4-(3-(2,4,6-trimethoxyphenyl)propyl)benzene-1,3-diol (31), 4-(3-(2,4-dihydroxyphenyl)propyl)-2-methylbenzene-1,3-diol (32), 4-(3-(2,4-dihydroxy-3-methylphenyl)-3-(2,4-dihydroxyphenyl)propane-1-one (33), 4-(5-hydroxypentyl)benzene-1,3-diol (34).

40 . A method for inhibiting the production of melanin comprising administering to a subject in need thereof a composition comprising one or more of the compound of claim 33 .

41 . The method of claim 40 , wherein the method for inhibiting the production of melanin comprising administering to a subject in need thereof a composition comprising one or more of a compound selected from the group consisting of 4-(3-(3,5-dimethoxyphenyl)propyl)benzene-1,3-diol (28), 4-(3-(3,5-dimethoxyphenyl)-1-hydroxypropyl)benzene-1,3-diol (29), 4-(3-(3,5-dihydroxyphenyl)propyl)benzene-1,3-diol (30), 4-(3-(2,4,6-trimethoxyphenyl)propyl)benzene-1,3-diol (31), 4-(3-(2,4-dihydroxyphenyl)propyl)-2-methylbenzene-1,3-diol (32), 4-(3-(2,4-dihydroxy-3-methylphenyl)-3-(2,4-dihydroxyphenyl)propane-1-one (33), 4-(5-hydroxypentyl)benzene-1,3-diol (34).

42 . A method for preventing and treating diseases and conditions related to the overproduction or uneven distribution of melanin comprising administering to a subject in need thereof an effective amount of a composition comprising one or more of the compound of claim 33 .

43 . The method of claim 42 , wherein the method for preventing and treating diseases and conditions related to the overproduction or uneven distribution of melanin comprising administering to a subject in need thereof an effective amount of a composition comprising one or more compounds selected from the group consisting of 4-(3-(3,5-dimethoxyphenyl)propyl)benzene-1,3-diol (28), 4-(3-(3,5-dimethoxyphenyl)-1-hydroxypropyl)benzene-1,3-diol (29), 4-(3-(3,5-dihydroxyphenyl)propyl)benzene-1,3-diol (30), 4-(3-(2,4,6-trimethoxyphenyl)propyl)benzene-1,3-diol (31), 4-(3-(2,4-dihydroxyphenyl)propyl)-2-methylbenzene-1,3-diol (32), 4-(3-(2,4-dihydroxy-3-methylphenyl)-3-(2,4-dihydroxyphenyl)propane-1-one (33), 4-(5-hydroxypentyl)benzene-1,3-diol (34).

44 . The method of claim 43 , wherein said diseases and conditions are selected from the group consisting of suntan, hyper pigmentation spots caused by skin aging, melasma, liver diseases, thermal burns and topical wounds, skin pigmentation due to inflammatory conditions caused by fungal, microbial and viral infections, vitilago, carcinoma, melanoma, as well as other mammalian skin conditions.

45 . A method for whitening or lightening skin comprising administering to a subject in need thereof a composition comprising one or more of the compound of claim 33 .

46 . The method of claim 45 , wherein the method for whitening or lightening skin comprising administering to a subject in need thereof a composition comprising one or more of a compound selected from the group consisting of 4-(3-(3,5-dimethoxyphenyl)propyl)benzene-1,3-diol (28), 4-(3-(3,5-dimethoxyphenyl)-1-hydroxypropyl)benzene-1,3-diol (29), 4-(3-(3,5-dihydroxyphenyl)propyl)benzene-1,3-diol (30), 4-(3-(2,4,6-trimethoxyphenyl)propyl)benzene-1,3-diol (31), 4-(3-(2,4-dihydroxyphenyl)propyl)-2-methylbenzene-1,3-diol (32), 4-(3-(2,4-dihydroxy-3-methylphenyl)-3-(2,4-dihydroxyphenyl)propane-1-one (33), 4-(5-hydroxypentyl)benzene-1,3-diol (34).

47 . A method for inhibit the browning and color changes in fruits, vegetables, juices and other food products comprising administering a 2,4-dihydroxybenzene derivatives selected from the group consisting of 4-(3-(3,5-dimethoxyphenyl)propyl)benzene-1,3-diol (28), 4-(3-(3,5-dimethoxyphenyl)-1-hydroxypropyl)benzene-1,3-diol (29), 4-(3-(3,5-dihydroxyphenyl)propyl)benzene-1,3-diol (30), 4-(3-(2,4,6-trimethoxyphenyl)propyl)benzene-1,3-diol (31), 4-(3-(2,4-dihydroxyphenyl)propyl)-2-methylbenzene-1,3-diol (32), 4-(3-(2,4-dihydroxy-3-methylphenyl)-3-(2,4-dihydroxyphenyl)propane-1-

Assignees

• Unigen Inc

Inventors

• Nandy Sandip K
• Liu Jiyun
• Nesterov Alexandre Mikhailovitch
• Hertel Carmen
• Papmapiya Abeysinghe Arrachchigae

Classifications

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P31/04

  Antibacterial agents · CPC title

• A61P31/00

  Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics · CPC title

• A61P29/00

  Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID] · CPC title

• A61P35/00

  Antineoplastic agents · CPC title