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(12) United States Patent (10) Patent No.: US 8,563,754 B2 Orlow Et Al

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(12) United States Patent (10) Patent No.: US 8,563,754 B2 Orlow Et Al US008563754B2 (12) United States Patent (10) Patent No.: US 8,563,754 B2 Orlow et al. (45) Date of Patent: Oct. 22, 2013 (54) COMPOUNDS, COMPOSITIONS AND FOREIGN PATENT DOCUMENTS METHODS FOR PREVENTING SKIN JP 2004-352658 * 12/2004 DARKENING WO 99.09011 2, 1999 WO 9964O25 12/1999 (75) Inventors: Seth J. Orlow, New York, NY (US); Li WO OO62742 10, 2000 Ni Komatsu, Clarksville, MD (US) WO 01.01131 1, 2001 WO O2098347 12/2002 WO 2007110415 10/2007 (73) Assignee: New York University, New York, NY WO WO2O11,068595 * 6, 2011 (US) OTHER PUBLICATIONS (*) Notice: Subject to any disclaimer, the term of this Silverman et al., “The Organic Chemistry of Drug Design and Drug patent is extended or adjusted under 35 Action” Published 1992 by Academic Press, pp. 352-397.* U.S.C. 154(b) by 320 days. Vippagunta et al., “Crystalline Solids' Advanved Drug Delivery Reviews (2001) vol. 48 pp. 3-26.* Jain et al., “Polymorphism in Pharmacy” Indian Drugs (1986) vol. 23 (21) Appl. No.: 13/015,882 No. 6 pp. 315-329.* Braga et al., “Making Crystals from Crystals: a green route to crystal (22) Filed: Jan. 28, 2011 engineering and polymorphism” Chemcomm (2005) pp. 3635 3645.* (65) Prior Publication Data Lieberman et al., “Pharmaceutical Dosage Forms: Tablets' published 1990 by Marcel Dekker, Inc., pp. 462-472.* US 2011 FO190229 A1 Aug. 4, 2011 English machine translation of JP2004-352658, published Dec. 6. 2004. Suzuki et al., “Cancer Preventive Agents. Part5. Anti-tumor-Promot ing Effects of Coumarins and Related Compounds on Epstein-Barr Related U.S. Application Data Virus Activation and Two-stage Mouse Skin Carcinogenesis' Phar maceutical Biology (2006) vol. 44 No. 3, pp. 178-182.* (60) Provisional application No. 61/299.335, filed on Jan. Gia et al., “4'-Methyl Derivatives of 5-MOP and 5-MOA: Synthesis, 28, 2010. Photoreactivity, and Photobiological Activity” Journal of Medicinal Chemistry (1996) vol. 39 pp. 4489-4496.* (51) Int. Cl. Bundgard, H., “Design of Prodrugs”, pp. 7-9, 21-24. Elsevier, A6 IK3I/37 (2006.01) Amsterdam 1985. Niemiec et al., Pharm. Res. 12:1184-88 (1995). (Abstract). C07D 309/38 (2006.01) Remington's Pharmaceutical Sciences, 17th Ed., Mack Publishing (52) U.S. C. Company, Easton, PA, 1990 (supra). CPC ...................................... A6 IK3I/37 (2013.01) Pharmaceutical Dosage Forms and Drug Delivery Systems, 6th Ed., USPC ........................................... 549/387: 514/455 Williams & Wilkins (1995). (58) Field of Classification Search McCutcheon's Detergents and Emulsifiers, North American Edition, None pp. 317-324 (1986), published by Allured Publishing Corporation. See application file for complete search history. T.W. Greene and P.G.M. Wuts, “Protectingi Groups in Organic Syn thesis.” Second Edition, Wiley, New York, 1991. (56) References Cited (Continued) U.S. PATENT DOCUMENTS Primary Examiner — Eric S Olson (74) Attorney, Agent, or Firm — Klauber & Jackson LLC 3,155,591 A 11, 1964 Hilfer 3,755,560 A 8, 1973 Dickert et al. (57) ABSTRACT 3,929,678 A 12/1975 Laughlin et al. 3,959,461 A 5/1976 Bailey et al. A method for preventing hyperpigmented skin, undesired 4,139,619 A 2/1979 Chidsey, III pigmentation disorder of skin, or undesired darkening of skin 4,387,090 A 6/1983 Bolich, Jr. using coumarin compounds, the use of such compounds, and 4.421,769 A 12/1983 Dixon et al. compositions and formulations thereof are disclosed. In a 4,684,635 A 8, 1987 Orentreich et al. particular embodiment, the coumarin compounds are 4,822,596 A 4, 1989 Callingham et al. 4,904,463 A 2f1990 Johnson et al. selected from robustic acid methyl ether, Scandenin, and cou 5,011,681 A 4, 1991 Ciotti et al. mophos. The compounds may be prepared as additives to 5,073,371 A 12/1991 Turner et al. pharmaceutical and cosmetic compositions, and in personal 5,073.372 A 12/1991 Turner et al. care products Such as antiperspirants. In a particular embodi 5, 120,532 A 6, 1992 Wells et al. ment extends to an antiperspirant product containing a skin 5,132,740 A 7, 1992 Okamoto et al. 5,151,209 A 9, 1992 McCall et al. darkening inhibitory amount of a compound of the invention. 5,151,210 A 9, 1992 Steuri et al. Also, the present skin darkening compounds may be prepared 5,214,028 A 5, 1993 Tomita et al. in combination with each other. The compounds, composi 5,389,611 A 2f1995 Tomita et al. tions and formulations of the invention may be used for the 5,580,549 A 12/1996 Fukuda et al. 5,691.380 A 11/1997 Mason et al. prevention of the onset or progression of conditions charac 5,968,528 A 10, 1999 Deckner et al. terized by unwanted skin darkening, including those that may 6,123,959 A 9, 2000 Jones et al. be causally related to aberrant melanogenesis activity includ 6.255,324 B1* 7/2001 Heindel et al. ................ 514,314 ing, by way of non-limiting example, hyperpigmentation and 2006/0269494 A1* 11/2006 Gupta ...... ... 424.70.1 others. 2012/0196926 A1* 8, 2012 Orlow ...... ... 514,452 2012fO220545 A1 8, 2012 Orlow et al. .................... 514/27 15 Claims, 4 Drawing Sheets US 8,563,754 B2 Page 2 (56) References Cited McCutcheon's, Detergents & Emulsifiers, North American Edition OTHER PUBLICATIONS (1979), M.C. Publishing Co. Orlow, 1998, in The Pigmentary System: Physiology and Fox, Charles, “An Introduction to Multiple Emulsions.” Cosmetics & Pathophysiology 97, Oxford University Press, New York, Nordlund Toiletries, vol. 101, Nov. 1986, pp. 101-102. et al., eds. Fox, C.F. “Cosmetics and Toiletries.” Nov. 1986, Vo. 191, pp. 101 112. * cited by examiner U.S. Patent Oct. 22, 2013 Sheet 1 of 4 US 8,563,754 B2 . S. y Y Š Šy c EQE3.803 ; S. Elsie U.S. Patent Oct. 22, 2013 Sheet 2 of 4 US 8,563,754 B2 s s & 3 3 3 s 8 gx -0. Coulos Calda U.S. Patent Oct. 22, 2013 Sheet 3 of 4 US 8,563,754 B2 s | c c e s 8 S3 d s s |OJuO3 JO % uueeW U.S. Patent Oct. 22, 2013 Sheet 4 of 4 US 8,563,754 B2 / co c s 3 8 s s oluoso Jo 9 uueeN US 8,563,754 B2 1. 2 COMPOUNDS, COMPOSITIONS AND stances work by either bleaching existing pigment or prevent METHODS FOR PREVENTING SKIN ing new pigment synthesis by inhibiting the activity of tyro DARKENING sinase, the principal rate limiting enzyme in the production of melanin. U.S. Pat. No. 6,123.959, for example, describes the RELATED APPLICATION 5 use of aqueous compositions comprising liposomes and at least one competitive inhibitor of an enzyme involved in The present application claims the benefit under 35 U.S.C. melanin synthesis. U.S. Pat. No. 5,132.740 describes the use S119 of U.S. Provisional Application Ser. No. 61/299,335 of certain resorcinol derivatives as skin lightening agents. filed Jan. 28, 2010. The content of said provisional applica WO 99/64025 describes compositions for skin lightening tion is hereby incorporated by reference in its entirety. 10 which contain tyrosinase inhibiting extracts from dicotyle donous plant species indigenous to Canada. U.S. Pat. No. GOVERNMENT RIGHTS 5,580,549 describes an external preparation for skin lighten ing comprising 2-hydroxybenzoic acid derivatives and salts This invention was made in part with government Support thereofas inhibitors of tyrosinase. WO99/09011 describes an under Grant No. AR41880 awarded by the National Institute 15 agent for inhibiting skin erythema and/or skin pigmentation, of Health. Accordingly, the United States Government has containing at least one carboStyril derivative and salts thereof. certain rights in the invention. U.S. Pat. Nos. 5,214,028 and 5,389,611, describe lactoferrin FIELD OF THE INVENTION hydrolyzates for use as tyrosinase inhibitory agents. 2O In WOO2 98347. Manga describes methods for identifying The present invention relates to the identification of par compounds that alter melanogenesis in melanogenic cells, ticular coumarin compounds that can prevent the darkening more particularly, compounds that inhibit or enhance P pro of skin. This invention further relates to compositions and tein function. This method is based, in part, on the observation formulations containing Such compounds, products contain that P protein function is required for proper cellular local ing Such compounds as an additive, and to methods for pre 25 ization of tyrosinase and other melanosomal proteins, and is venting darkening or hyperpigmentation of skin, comprising required for both full tyrosinase activity and melanogenesis in administering an effective amount of the compounds and/or melanogenic cell types. of formulations containing or comprising the compounds. As Orlow et al. describe screens for identifying compounds described herein, the formulations include cosmetic products that inhibit or increase melanogenesis in melanogenic cells. and related personal care products, and would contain an 30 See WO 01 1131. These studies were based upon the discov effective amount of a compound of the invention therewithin. ery that some compounds that inhibit melanogenesis do so by It is to be understood that such compounds may be used either causing a mislocalization of tyrosinase, the key enzyme in alone or in combination with other compounds having the activity set forth herein. melanin synthesis. Also, WO 2007/110415 is directed to the 35 preparation of particular diacetyl trimers, and their use in BACKGROUND OF THE INVENTION compositions for cosmetic or therapeutic use, for decreasing melanin synthesis and concentration, for the lightening of Several publications and patent documents are referenced skin. in this application in order to more fully describe the state of The above disclosures are predicated on a method of action the art to which this disclosure pertains.
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