# US 8,772,252 B2 · Coumarin compounds as melanogenesis modifiers and uses thereof

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- Number: US 8,772,252 B2
- Document ID: US8772252B2
- Status: Granted
- Kind: B2
- Application number: 13/360,619
- Filed: 2012-01-27
- Published: 2012-08-30
- Granted: 2014-07-08
- Earliest claimed: 2011-01-27
- Assignees: New York University
- Applicants: Seth J. Orlow; Li Ni Komatsu
- Inventors: Seth J. Orlow; Li Ni Komatsu
- Web page: https://patentgrep.com/patent/US8772252B2

## CPC

- A61K 31/37: Coumarins, e.g. psoralen
- A61K 8/498: {having 6-membered rings or their condensed derivatives, e.g. coumarin}
- A61K 8/9789: Magnoliopsida [dicotyledons]
- A61K 9/0014: {Skin, i.e. galenical aspects of topical compositions (non-active ingredients are additionally classified in A61K47/00; A61K9/0009, A61K9/0021, A61K9/7015, A61K9/7023 take precedence; cosmetic preparations A61K8/00, A61Q; preparations for wound dressings or bandages A61L26/00)}
- A61K 9/0019: {Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner (non-active ingredients are additionally classified in A61K47/00)}
- A61K 9/06: Ointments; Bases therefor; {Other semi-solid forms, e.g. creams, sticks, gels (composition of ointments, creams or gels A61K47/00)}
- A61K 9/08: Solutions {(composition of solutions A61K47/00)}
- A61K 9/2063: {Proteins, e.g. gelatin}
- A61K 9/4866: {Organic macromolecular compounds}
- A61K 36/48: Fabaceae or Leguminosae (Pea or Legume family); Caesalpiniaceae; Mimosaceae; Papilionaceae
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- A61K 47/20: containing sulfur, e.g. dimethyl sulfoxide [DMSO], docusate, sodium lauryl sulfate or aminosulfonic acids
- A61P 17/00: Drugs for dermatological disorders
- A61Q 19/02: for chemically bleaching or whitening the skin
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61Q: SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS

## Abstract

Provided are coumarin compounds of formula I, for example, robustic acid methyl ether, and the use of such compounds and compositions thereof to modulate (e.g., inhibit) melanogenesis and pigmentation. wherein R3, R4, R5, R6, R7 and R8 are described herein. Also provided are plant extracts containing a compound of formula I, and the use of such a plant extract to modulate (e.g., inhibit) melanogenesis and pigmentation. The compound or plant extract may be prepared as pharmaceutical and cosmetic compositions, and may be used for the prevention and treatment of conditions that are related to aberrant melanogenesis activity.

## Claims

### Claim 1

A method for inhibiting melanogenesis or a method for promoting skin lightening in a mammal in need thereof, comprising administering to the mammal an effective amount of either lonchocarpic acid or a compound of formula I:
wherein
R3 is selected from the group consisting of halo, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, unsubstituted phenyl, 3,4-dihydroxyphenyl, 4-methoxyphenyl, 3,4-dimethoxyphenyl, and substituted or unsubstituted heteroaryl;
R4 is selected from the group consisting of H, halo, hydroxy, alkoxy, alkenyloxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, and substituted or unsubstituted phenyl;
each R5, R6, and R8 is independently selected from the group consisting of H, halo, hydroxy, alkoxy, alkenyloxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, and substituted or unsubstituted phenyl;
R7 is selected from the group consisting of H, halo, hydroxy, alkoxy, alkenyloxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, and heterocycloalkyl; or R7 is —P(═O)(alkoxy)2, or —P(═S)(alkoxy)2; or R6 and R7 or R7 and R8 are joined to form a 5- or 6-membered heterocycloalkyl or heterocycloalkenyl; and the heterocycloalkyl or heterocycloalkenyl is unsubstituted or substituted with one or more groups selected from the group consisting of alkyl, alkenyl, hydroxyalkyl, acyloxyalkyl, hydroxy, and alkoxy; and
provided that the compound is other than robustic acid; or pharmaceutically acceptable salts, solvates, isomers, tautomers, metabolites, analogs, isotopic variants or prodrugs thereof.

### Claim 2 (depends on 1)

The method of claim 1 wherein the compound is of formula I; and R7 is selected from the group consisting of H, substituted or unsubstituted alkyl, and substituted or unsubstituted alkenyl.

### Claim 3 (depends on 1)

The method of claim 1, wherein the compound is of formula I; and R3 is Cl, alkyl, unsubstituted phenyl, 3,4-dihydroxyphenyl, 4-methoxyphenyl, or 3,4-dimethoxyphenyl.

### Claim 4 (depends on 1)

The method of claim 1, wherein the compound is of formula I; and R4 is H, Cl, alkyl, or substituted or unsubstituted phenyl.

### Claim 5 (depends on 1)

The method of claim 1, wherein the compound is of formula I; and R5 is H, Cl, alkyl, hydroxy, or alkoxy.

### Claim 6 (depends on 1)

The method of claim 1, wherein the compound is of formula I; and R6 is H, Cl, alkyl, alkenyl, hydroxy, alkoxy, or alkenyloxy.

### Claim 7 (depends on 1)

The method of claim 1, wherein the compound is of formula I; and R8 is H, Cl, alkyl, alkenyl, hydroxy, alkoxy, or alkenyloxy.

### Claim 8 (depends on 1)

The method of claim 1 wherein the compound is of formula I; each R4, R5, R6 is H; R7 is as in claim 1; and R8 is substituted or unsubstituted alkenyl.

### Claim 9 (depends on 1)

The method of claim 1, wherein R4 is H, Cl, alkyl, hydroxy, alkoxy, or substituted or unsubstituted phenyl.

### Claim 10 (depends on 1)

The method of claim 1, further comprising an additional active agent, and said additional active agent is selected from the group consisting of a pharmacological agent, a skin brightening agent and a skin lightening agent.

### Claim 11 (depends on 1)

A method for altering or restoring pigmentation in mammalian skin, hair, wool or fur comprising administering to the mammalian skin, hair, wool or fur an amount of a composition comprising:
a) an amount, which is effective to alter or restore pigmentation in mammalian skin, hair, wool or fur, of one or more compounds of claim 1; and b) a suitable carrier, wherein the amount of the composition is effective to alter or restore pigmentation in mammalian skin, hair, wool or fur.

### Claim 12 (depends on 11)

The method of claim 11, wherein the compound is a melanogenesis inhibitor.

### Claim 13 (depends on 1)

A method for altering or restoring pigmentation in mammalian hair, wool or fur comprising administering to the mammalian hair, wool or fur an amount, which is effective to alter or restore pigmentation in mammalian hair, wool or fur, of a compound of claim 1 and a cosmetically active agent.

### Claim 14 (depends on 13)

The method of claim 13, wherein the cosmetically active agent is a skin lightening compound.

### Claim 15 (depends on 1)

The method of claim 1 wherein the compound is of formula IIa, or IIb:
or a pharmaceutically acceptable salt, solvate or prodrug thereof, and stereoisomers, tautomers and isotopic variants thereof; and wherein
R3, R4, R5, and R8 are as in claim 1; and
each R6a, R7a, and R7b is independently selected from the group consisting of H, alkyl, hydroxyalkyl, and alkenyl.

### Claim 16 (depends on 1)

The method of claim 1 wherein the compound is of formula IIIa, or IIIb:
or a pharmaceutically acceptable salt, solvate or prodrug thereof, and stereoisomers, tautomers and isotopic variants thereof; and wherein
R3, R4, R5, and R8 are as in claim 1; and
each R6a, R7a and R7b is independently selected from the group consisting of H, alkyl, hydroxyalkyl, and alkenyl.

### Claim 17 (depends on 1)

The method of claim 1 wherein the compound is of formula IV:
or a pharmaceutically acceptable salt, solvate or prodrug thereof, and stereoisomers, tautomers and isotopic variants thereof; and wherein
R3, R4, R5, and R8 are as in claim 1; and
each R6a and R7a is independently selected from the group consisting of H, alkyl, and alkenyl.

### Claim 18 (depends on 1)

The method of claim 1 wherein the compound is of formula Va, or Vb:
or a pharmaceutically acceptable salt, solvate or prodrug thereof, and stereoisomers, tautomers and isotopic variants thereof; and wherein
R3, R5, and R8 are as in claim 1.

### Claim 19 (depends on 1)

The method of claim 1 wherein the compound is of formula VIa, or VIb:
or a pharmaceutically acceptable salt, solvate or prodrug thereof, and stereoisomers, tautomers and isotopic variants thereof; and wherein
R3 and R8 are as in claim 1.

### Claim 20 (depends on 1)

The method of claim 1 wherein the compound is of formula VIIa:
or a pharmaceutically acceptable salt, solvate or prodrug thereof, and stereoisomers, tautomers and isotopic variants thereof; and wherein
R8 is as in claim 1.

### Claim 21 (depends on 1)

The method of claim 1, wherein the compound is robustic acid methyl ether.

### Claim 22 (depends on 1)

The method of claim 1, wherein the compound is lonchocarpic acid.