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

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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. The disclosure of 40 that proposes to modulate cellular activity, and that by doing each of these publications and documents is expressly incor So, would function to modify melanin content and thereby, the porated by reference herein. color or hue of the skin. The present invention focuses instead One of the causes of skin darkening is the synthesis of on the darkening that results from a variety of seemingly melanin by cells known as melanocytes. Melanocytes synthe disparate origins, and seeks only to prevent Such darkening, size melanin inside specialized organelles called melano 45 and not to modulate melanogenesis. somes (reviewed in Orlow, 1998, in The Pigmentary System: As described herein, the present invention addresses the Physiology and Pathophysiology 97, Oxford University need for novel agents that are capable of preventing the dark Press, New York, Nordlund et al., eds). Melanosomes are ening phenomenon. Accordingly, the present invention pro formed by the fusion of two types of vesicles. Melanin is a vides compounds for use in skin care and personal care for dark biological pigment (biochrome) found in the skin, hair, 50 mulations, and corresponding methods for preventing feathers, Scales, eyes, and some internal membranes of many hyperpigmented skin, undesired pigmentation disorder of animals that confers protection against ultraviolet radiation. skin, or undesired darkening of skin comprising administer Melanism refers to the deposition of melanin in the tissues of ing Such compounds, or formulations or compositions con living animals, the chemistry of which depends on the taining an effective amount of the inventive compounds. metabolism of the amino acid tyrosine. More specifically, 55 melanins are formed as an end product during metabolism of SUMMARY OF THE INVENTION the amino acid tyrosine. A particular problem that has been noted is the unwanted In a first aspect, the present invention is directed to com darkening of skin. This may result from a variety of causes, pounds that are capable of inhibiting or preventing unwanted including skin conditions such as acne, and the application of 60 skin darkening. Such compounds may be incorporated into certain topical compositions that cause Such darkening as a topical products for personal care, such as anti-perspirants, side-effect. By way of example, such darkening is experi deodorants, perfumes, lotions, and the like, as well as corre enced from the application of certain deodorants or antiper sponding formulations for pharmaceutical use. spirants, or from other topical skin care products or topically Inafurther aspect of the invention, a method for preventing administered medicaments. 65 the hyperpigmentation or undesired darkening of skin com While a variety of substances have been proposed for use as prises administering an effective amount of a compound of regulators of skin pigmentation, almost all of these Sub formula I US 8,563,754 B2 4 In another particular embodiment, with respect to formula I I, the compound is formula VIIb (scandenin): R7 R8

O O O

VIIb

R6 afn R5 R4 10 or a pharmaceutically acceptable salt, Solvate or prodrug thereof, and stereoisomers, tautomers and isotopic vari ants thereof, and wherein R is selected from H, halo, substituted or unsubstituted 15 alkyl, substituted or unsubstituted alkenyl, or substituted or unsubstituted aryl; and substituted or unsubstituted heteroaryl; or a pharmaceutically acceptable salts, Solvates, isomers, tau tomers, metabolites, analogs, isotopic variants or prodrugs R" is selected from H, halo, hydroxy, alkoxy, alkenyloxy, thereof. substituted or unsubstituted alkyl, substituted or unsub Another aspect of this invention relates to the use of a stituted alkenyl, and substituted or unsubstituted phenyl: compound of the invention in a therapeutic method, a phar each R, RandR is independently selected from H, halo, maceutical composition, and the manufacture of Such com hydroxy, alkoxy, alkenyloxy, Substituted or unsubsti position, useful for the prevention of either the onset or the tuted alkyl, substituted or unsubstituted alkenyl, and 25 progression of conditions involving aberrant or unwanted substituted or unsubstituted phenyl: increases in pigmentation or darkening of skin as may be R’ is selected from H, halo, hydroxy, alkoxy, alkenyloxy, attributable to e.g. hyperpigmentation, acne, melasma and substituted or unsubstituted alkyl, substituted or unsub chloasma. This invention also relates to processes for the stituted alkenyl, or heterocycloalkyl; or R is - P(=O) 30 preparation of the compounds of the invention. (alkoxy), or—P(=S)(alkoxy); or In a further aspect, the present invention provides compo RandR or Rand Rare joined to form a 5- or 6-mem sitions, including cosmetic formulations, comprising a com bered heterocycloalkyl or heterocycloalkenyl; and the pound or compounds of the invention, and a Suitable biocom heterocycloalkyl or heterocycloalkenyl is unsubstituted patible or bioinert carrier, excipient or diluent. In this aspect or Substituted with one more groups selected from alkyl, 35 of the invention, the cosmetic or pharmaceutical composition alkenyl, hydroxyalkyl, acyloxyalkyl, hydroxy, and can comprise one or more of the compounds described herein. alkoxy; and Moreover, the compounds of the present invention useful in provided that the cosmetic and pharmaceutical compositions and treatment methods disclosed herein, are all pharmaceutically accept i) when R is H; then R is substituted or unsubstituted 40 able as prepared and used. alkenyl: In a further aspect, the present invention provides personal ii) the compound is other than robustic acid; and care products, such as deodorant and/or anti-perspirant com iii) when each of R. R. R. and R is H; and R is 3-me positions, that include or contain an effective amount of a thylbut-2-enyl; then R is other than Me. compound of the invention, to prevent the skin darkening that 45 is a side-effect of the use of such products. Such a product can In one particular embodiment, with respect to formula I, comprise an antiperspirant and/or a deodorant active, in liq the compound is formula VIIa (robustic acid methyl ether): uid, Solid (particulate) or aerosol form, together with a carrier providing either a solid or a liquid form to the product, and conventional additives, such as gellants, oils, and the like. 50 In a further aspect, the present invention provides compo sitions comprising a combination of a compound of the inven VIIa tion with various compounds or agents that may have a like effect. In this aspect of the invention, the compositions can comprise one or more of the compounds described herein, 55 individually or in combination with each other. Other objects and advantages will become apparent to those skilled in the art from a consideration of the ensuing detailed description, which proceeds with reference to the following illustrative drawings. 60 BRIEF DESCRIPTION OF THE DRAWINGS FIG. 1 is a graph of the results of comparative dose-re sponse testing of compounds of the invention as inhibitors of or a pharmaceutically acceptable salts, Solvates, isomers, tau 65 skin darkening. tomers, metabolites, analogs, isotopic variants or prodrugs FIG. 2 is a graph of the individual dose response testing of thereof. Scandenin, a particular compound of the invention. US 8,563,754 B2 5 6 FIG. 3 is a graph of the individual dose response testing of nocarbonylamino, aminocarbonyloxy, aryl, aryloxy, azido, Robustic acid methyl ether, a particular compound of the carboxyl, cyano, cycloalkyl, Substituted cycloalkyl, halogen, invention. heteroaryl, hydroxyl, keto, nitro, thioalkoxy, substituted thio FIG. 4 is a graph of the individual dose response testing of alkoxy, thioaryloxy, thioketo, thiol, alkyl-S(O)—, aryl-S Coumophos, a particular compound of the invention. 5 (O)—, alkyl-S(O) and aryl-S(O) -. "Alkoxycarbonylamino” refers to the group - NRC(O) DETAILED DESCRIPTION OF THE INVENTION R’ where R is hydrogen, alkyl, aryl or cycloalkyl, and R' is alkyl or cycloalkyl. Definitions Alkyl refers to monovalent saturated alkane radical 10 groups particularly having up to about 11 carbonatoms, more When describing the compounds, pharmaceutical and/or particularly as a lower alkyl, from 1 to 8 carbonatoms and still cosmetic compositions containing Such compounds and more particularly, from 1 to 6 carbonatoms. The hydrocarbon methods of using Such compounds and compositions, the chain may be either straight-chained or branched. This term is following terms have the following meanings unless other exemplified by groups such as methyl, ethyl, n-propyl, iso wise indicated. It should also be understood that any of the 15 propyl. n-butyl, iso-butyl, tert-butyl, n-hexyl, n-octyl, tert moieties defined forth below may be substituted with a vari octyl and the like. The term “lower alkyl refers to alkyl ety of substituents, and that the respective definitions are groups having 1 to 6 carbon atoms. The term “alkyl also intended to include such substituted moieties within their includes “cycloalkyls' as defined below. Scope. “Substituted alkyl includes those groups recited in the As used in this specification and the appended claims, the definition of “substituted herein, and particularly refers to an singular forms “a”, “an', and “the' include plural references alkyl group having 1 or more substituents, for instance from unless the context clearly dictates otherwise. Thus for 1 to 5 substituents, and particularly from 1 to 3 substituents, example, reference to “the method’ includes one or more selected from the group consisting of acyl, acylamino, acy methods, and/or steps of the type described herein and/or loxy, alkoxy, Substituted alkoxy, alkoxycarbonyl, alkoxycar which will become apparent to those persons skilled in the art 25 bonylamino, amino, Substituted amino, aminocarbonyl, ami upon reading this disclosure. nocarbonylamino, aminocarbonyloxy, aryl, aryloxy, azido, “Acyl refers to a group or radical–C(O)R’, where R' carboxyl, cyano, cycloalkyl, Substituted cycloalkyl, halogen, is hydrogen, alkyl, cycloalkyl, cycloheteroalkyl, aryl, aryla hydroxyl, heteroaryl, keto, nitro, thioalkoxy, substituted thio lkyl, heteroalkyl, heteroaryl, heteroarylalkyl as defined alkoxy, thioaryloxy, thioketo, thiol, alkyl-S(O)—, aryl-S herein. Representative examples include, but are not limited 30 (O)—, alkyl-S(O) , and aryl-S(O) -. to, formyl, acetyl, cylcohexylcarbonyl, cyclohexylmethylcar Alkylene' refers to divalent saturated alkene radical bonyl, benzoyl, benzylcarbonyl and the like. groups having 1 to 11 carbonatoms and more particularly 1 to “Acylamino” refers to a group or radical NRC(O)R’, 6 carbon atoms which can be straight-chained or branched. where R is hydrogen, alkyl, cycloalkyl, cycloheteroalkyl, This term is exemplified by groups such as methylene aryl, arylalkyl, heteroalkyl, heteroaryl, heteroarylalkyl and 35 (—CH2—), ethylene (-CHCH ), the propylene isomers R’ is hydrogen, alkyl, alkoxy, cycloalkyl, cycloheteroalkyl, (e.g., —CH2CH2CH2— and —CH(CH)CH2—) and the aryl, arylalkyl, heteroalkyl, heteroaryl or heteroarylalkyl, as like. defined herein. Representative examples include, but are not “Substituted alkylene' includes those groups recited in the limited to, formylamino, acetylamino, cyclohexylcarbony definition of “substituted herein, and particularly refers to an lamino, cyclohexylmethyl-carbonylamino, benzoylamino, 40 alkylene group having 1 or more Substituents, for instance benzylcarbonylamino and the like. from 1 to 5 substituents, and particularly from 1 to 3 substitu Acyloxy” refers to the group or radical —OC(O)R’ ents, selected from the group consisting of acyl, acylamino, where R is hydrogen, alkyl, aryl or cycloalkyl. acyloxy, alkoxy, Substituted alkoxy, alkoxycarbonyl, alkoxy “Substituted alkenyl' includes those groups recited in the carbonylamino, amino, Substituted amino, aminocarbonyl, definition of “substituted herein, and particularly refers to an 45 aminocarbonylamino, aminocarbonyloxy, aryl, aryloxy, alkenyl group having 1 or more Substituents, for instance azido, carboxyl, cyano, halogen, hydroxyl, keto, nitro, thio from 1 to 5 substituents, and particularly from 1 to 3 substitu alkoxy, Substituted thioalkoxy, thioaryloxy, thioketo, thiol, ents, selected from the group consisting of acyl, acylamino, alkyl-S(O)—, aryl-S(O)—, alkyl-S(O) and aryl-S(O) . acyloxy, alkoxy, Substituted alkoxy, alkoxycarbonyl, alkoxy Alkenyl refers to monovalent olefinically unsaturated carbonylamino, amino, Substituted amino, aminocarbonyl, 50 hydrocarbyl groups preferably having 2 to 11 carbon atoms, aminocarbonylamino, aminocarbonyloxy, aryl, aryloxy, particularly, from 2 to 8 carbonatoms, and more particularly, azido, carboxyl, cyano, cycloalkyl, Substituted cycloalkyl, from 2 to 6 carbon atoms, which can be straight-chained or halogen, hydroxyl, keto, nitro, thioalkoxy, Substituted thio branched and having at least 1 and particularly from 1 to 2 alkoxy, thioaryloxy, thioketo, thiol, alkyl-S(O)—, aryl-S sites of olefinic unsaturation. Particular alkenyl groups (O)—, alkyl-S(O) and aryl-S(O) -. 55 include ethenyl (-CH=CH), n-propenyl “Alkoxy” refers to the group -OR where R is alkyl. (—CH-CH=CH-), isopropenyl ( C(CH)—CH), vinyl Particular alkoxy groups include, by way of example, meth and substituted vinyl, and the like. oxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, Alkenylene' refers to divalent olefinically unsaturated sec-butoxy, n-pentoxy, n-hexoxy, 1,2-dimethylbutoxy, and hydrocarbyl groups particularly having up to about 11 carbon the like. 60 atoms and more particularly 2 to 6 carbonatoms which can be “Substituted alkoxy” includes those groups recited in the straight-chained or branched and having at least 1 and par definition of “substituted herein, and particularly refers to an ticularly from 1 to 2 sites of olefinic unsaturation. This term is alkoxy group having 1 or more substituents, for instance from exemplified by groups such as ethenylene (-CH=CH-), 1 to 5 substituents, and particularly from 1 to 3 substituents, the propenylene isomers (e.g., —CH=CHCH2— and selected from the group consisting of acyl, acylamino, acy 65 —C(CH)—CH and —CH=C(CH)—) and the like. loxy, alkoxy, Substituted alkoxy, alkoxycarbonyl, alkoxycar Alkynyl refers to acetylenically or alkynically unsatur bonylamino, amino, Substituted amino, aminocarbonyl, ami ated hydrocarbyl groups particularly having 2 to 11 carbon US 8,563,754 B2 7 8 atoms and more particularly 2 to 6 carbonatoms which can be “Alkylarylamino” refers to a radical-NR'R' where R straight-chained or branched and having at least 1 and par represents an alkyl or cycloalkyl group and R is an aryl as ticularly from 1 to 2 sites of alkynyl unsaturation. Particular defined herein. non-limiting examples of alkynyl groups include acetylenic, “Alkylsulfonyl refers to a radical-S(O).R where R ethynyl ( C=CH), propargyl ( CHC=CH), and the like. is an alkyl or cycloalkyl group as defined herein. Represen “Substituted alkynyl includes those groups recited in the tative examples include, but are not limited to, methylsulfo definition of “substituted herein, and particularly refers to an nyl, ethylsulfonyl, propylsulfonyl, butylsulfonyl and the like. alkynyl group having 1 or more Substituents, for instance “Alkylsulfinyl refers to a radical-S(O)R where R is from 1 to 5 substituents, and particularly from 1 to 3 substitu an alkyl or cycloalkyl group as defined herein. Representative 10 examples include, but are not limited to, methylsulfinyl, eth ents, selected from the group consisting of acyl, acylamino, ylsulfinyl, propylsulfinyl, butylsulfinyl and the like. acyloxy, alkoxy, Substituted alkoxy, alkoxycarbonyl, alkoxy “Alkylthio” refers to a radical–SR where R is an alkyl carbonylamino, amino, Substituted amino, aminocarbonyl, or cycloalkyl group as defined herein that may be optionally aminocarbonylamino, aminocarbonyloxy, aryl, aryloxy, substituted as defined herein. Representative examples azido, carboxyl, cyano, cycloalkyl, Substituted cycloalkyl, 15 include, but are not limited to, methylthio, ethylthio, propy halogen, hydroxyl, keto, nitro, thioalkoxy, Substituted thio lthio, butylthio, and the like. alkoxy, thioaryloxy, thioketo, thiol, alkyl-S(O)—, aryl-S “Amino” refers to the radical —NH. (O)—, alkyl-S(O) - and aryl-S(O) -. “Substituted amino” includes those groups recited in the Alkanoyl or “acyl as used herein refers to the group definition of “substituted herein, and particularly refers to R7 C(O)—, where R is hydrogen or alkyl as defined the group - N(R), where each R is independently above. selected from the group consisting of hydrogen, alkyl, Sub Aryl refers to a monovalent aromatic hydrocarbon group stituted alkyl, alkenyl, Substituted alkenyl, alkynyl, Substi derived by the removal of one hydrogen atom from a single tuted alkynyl, aryl, cycloalkyl, Substituted cycloalkyl, and carbon atom of a parent aromatic ring system. Typical aryl where both R groups are joined to form an alkylene group. groups include, but are not limited to, groups derived from 25 When both R groups are hydrogen, N(R) is an amino aceanthrylene, acenaphthylene, acephenanthrylene, group. anthracene, aZulene, benzene, chrysene, coronene, fluoran “Aminocarbonyl refers to the group –C(O)NR'R'' thene, fluorene, hexacene, hexaphene, hexylene, as-indacene, where each R7 is independently hydrogen, alkyl, aryl and S-indacene, indane, indene, naphthalene, octacene, cycloalkyl, or where the R groups are joined to form an 30 alkylene group. octaphene, octalene, ovalene, penta-2,4-diene, pentacene, “Aminocarbonylamino” refers to the group - NRC(O) pentalene, pentaphene, perylene, phenalene, phenanthrene, NRR where each R is independently hydrogen, alkyl, picene, pleiadene, pyrene, pyranthrene, rubicene, triph aryl or cycloalkyl, or where two R groups are joined to form enylene, trinaphthalene and the like. Particularly, an aryl an alkylene group. group comprises from 6 to 14 carbon atoms. 35 “Aminocarbonyloxy' refers to the group —OC(O) “Substituted Aryl includes those groups recited in the NR'R' where each R is independently hydrogen, alkyl, definition of “substituted herein, and particularly refers to an aryl or cycloalkyl, or where the R groups are joined to forman aryl group that may optionally be substituted with 1 or more alkylene group. substituents, for instance from 1 to 5 substituents, particularly Arylalkyloxy' refers to an —O-arylalkyl radical where 1 to 3 Substituents, selected from the group consisting of acyl, 40 arylalkyl is as defined herein. acylamino, acyloxy, alkenyl, Substituted alkenyl, alkoxy, Sub “Arylamino” means a radical -NHR' where R' repre stituted alkoxy, alkoxycarbonyl, alkyl, Substituted alkyl, sents an aryl group as defined herein. alkynyl. Substituted alkynyl, amino, Substituted amino, ami Aryloxycarbonyl refers to a radical —C(O)—O-aryl nocarbonyl, aminocarbonylamino, aminocarbonyloxy, aryl, where aryl is as defined herein. aryloxy, azido, carboxyl, cyano, cycloalkyl, Substituted 45 “Arylsulfonyl refers to a radical-S(O) R' where R' is cycloalkyl, halogen, hydroxyl. nitro, thioalkoxy, Substituted an aryl or heteroaryl group as defined herein. thioalkoxy, thioaryloxy, thiol, alkyl-S(O)—, aryl-S(O)—, “AZido” refers to the radical N. alkyl-S(O) - and aryl-S(O) . “Bicycloaryl refers to a monovalent aromatic hydrocar “Fused Aryl refers to an aryl having two of its ring carbon bon group derived by the removal of one hydrogenatom from in common with a second aryl ring or with an aliphatic ring. 50 a single carbonatom of a parent bicycloaromatic ring system. Alkaryl” refers to an aryl group, as defined above, substi Typical bicycloaryl groups include, but are not limited to, tuted with one or more alkyl groups, as defined above. groups derived from indane, indene, naphthalene, tetrahy Aralkyl or “arylalkyl refers to an alkyl group, as defined dronaphthalene, and the like. Particularly, an aryl group com above, Substituted with one or more aryl groups, as defined prises from 8 to 11 carbon atoms. above. 55 “Bicycloheteroaryl refers to a monovalent bicyclohet Aryloxy' refers to —O-aryl groups wherein “aryl' is as eroaromatic group derived by the removal of one hydrogen defined above. atom from a single atom of a parent bicycloheteroaromatic “Alkylamino” refers to the group alkyl-NR'R'', wherein ring system. Typical bicycloheteroaryl groups include, but each of R and Rare independently selected from hydro are not limited to, groups derived from benzofuran, benzimi gen and alkyl. 60 dazole, benzindazole, benzdioxane, chromene, chromane, “Arylamino” refers to the group aryl-NR'R'', wherein cinnoline, phthalazine, indole, indoline, indolizine, isoben each of RandR are independently selected from hydro Zofuran, isochromene, isolindole, isoindoline, isoquinoline, gen, aryland heteroaryl. benzothiazole, benzoxazole, naphthyridine, benzoxadiazole, “Alkoxyamino” refers to a radical-N(H)OR where R' pteridine, purine, benzopyran, benzpyrazine, pyridopyrimi represents an alkyl or cycloalkyl group as defined herein. 65 dine, quinazoline, quinoline, quinolizine, quinoxaline, ben Alkoxycarbonyl refers to a radical—C(O)-alkoxy where Zomorphan, tetrahydroisoquinoline, tetrahydroquinoline, alkoxy is as defined herein. and the like. Preferably, the bicycloheteroaryl group is US 8,563,754 B2 10 between 9-11 membered bicycloheteroaryl, with 5-10 mem “Ethenyl refers to substituted or unsubstituted bered heteroaryl being particularly preferred. Particular bicy —(C=C)—. cloheteroaryl groups are those derived from benzothiophene, “Ethylene' refers to substituted or unsubstituted —(C– benzofuran, benzothiazole, indole, quinoline, isoquinoline, benzimidazole, benzoxazole and benzdioxane. “Ethynyl refers to —(C=C)—. “Carbamoyl refers to the radical –C(O)N(R'), where "Halo’ or “halogen refers to fluoro, chloro, bromo and each R" group is independently hydrogen, alkyl, cycloalkyl iodo. Preferred halo groups are either fluoro or chloro. or aryl, as defined herein, which may be optionally substi “Hydroxy” refers to the radical –OH. tuted as defined herein. “Nitro” refers to the radical - NO. “Carboxy” refers to the radical –C(O)OH. 10 “Substituted” refers to a group in which one or more hydro “Carboxyamino” refers to the radical N(H)C(O)OH. gen atoms are each independently replaced with the same or “Cycloalkyl refers to cyclic hydrocarbyl groups having different substituent(s). Typical substituents include, but are from 3 to about 10 carbon atoms and having a single cyclic not limited to X, R, O,-O, OR, SR, S, ring or multiple condensed rings, including fused and bridged —S=NR, CX CF, CN, OCN, SCN, NO, 15 —NO, =N. —N. —S(O).O., —S(O),OH, S(O),R, ring systems, which optionally can be substituted with from 1 OS(O)O, OS(O).R, P(O)(O) = P(O)(OR) to 3 alkyl groups. Such cycloalkyl groups include, by way of (O), OP(O)(OR)(OR7), C(O)R, C(S)R, example, single ring structures such as cyclopropyl, cyclobu C(O)OR, C(O)NR'R'', C(O)O, C(S)OR, tyl, cyclopentyl, cyclooctyl, 1-methylcyclopropyl, 2-methyl NRC(O)NR'R'7, NRC(S)NR'R''7, NRC cyclopentyl, 2-methylcyclooctyl, and the like, and multiple (NR)NR'R'' and C(NR)NR'R'7, where each X is ring structures such as adamantanyl, and the like. independently a halogen; each R', R, R and R are “Substituted cycloalkyl includes those groups recited in independently hydrogen, alkyl, Substituted alkyl, aryl, Substi the definition of “substituted herein, and particularly refers tuted alkyl, arylalkyl, substituted alkyl, cycloalkyl, substi to a cycloalkyl group having 1 or more Substituents, for tuted alkyl, cycloheteroalkyl, substituted cycloheteroalkyl, instance from 1 to 5 substituents, and particularly from 1 to 3 25 heteroalkyl, substituted heteroalkyl, heteroaryl, substituted Substituents, selected from the group consisting of acyl, acy heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, lamino, acyloxy, alkoxy, Substituted alkoxy, alkoxycarbonyl, NR'R'', C(O)R’ or S(O)R’ or optionally Rand alkoxycarbonylamino, amino, Substituted amino, aminocar R" together with the atom to which they are both attached bonyl, aminocarbonylamino, aminocarbonyloxy, aryl, ary form a cycloheteroalkyl or substituted cycloheteroalkyl ring: loxy, azido, carboxyl, cyano, cycloalkyl, Substituted 30 and R' and R are independently hydrogen, alkyl, substi cycloalkyl, halogen, hydroxyl, keto, nitro, thioalkoxy, Substi tuted alkyl, aryl, substituted alkyl, arylalkyl, substituted tuted thioalkoxy, thioaryloxy, thioketo, thiol, alkyl-S(O)—, alkyl, cycloalkyl, substituted alkyl, cycloheteroalkyl, substi aryl-S(O)—, alkyl-S(O)—and aryl-S(O)7. tuted cycloheteroalkyl, heteroalkyl, substituted heteroalkyl, “Cycloalkoxy” refers to the group -OR where R is heteroaryl, substituted heteroaryl, heteroarylalkyl or substi cycloalkyl. Such cycloalkoxy groups include, by way of 35 tuted heteroarylalkyl. example, cyclopentoxy, cyclohexoxy and the like. Examples of representative substituted aryls include the “Cycloalkenyl refers to cyclic hydrocarbyl groups having following from 3 to 10 carbon atoms and having a single cyclic ring or multiple condensed rings, including fused and bridged ring 40 systems and having at least one and particularly from 1 to 2 N N1 N sites of olefinic unsaturation. Such cycloalkenyl groups s 52. -Rs and include, by way of example, single ring structures such as cyclohexenyl, cyclopentenyl, cyclopropenyl, and the like. 2. 2 2. “Substituted cycloalkenyl includes those groups recited 45 in the definition of “substituted herein, and particularly Xa --R52. refers to a cycloalkenyl group having 1 or more Substituents, for instance from 1 to 5 substituents, and particularly from 1 S x to 3 Substituents, selected from the group consisting of acyl, acylamino, acyloxy, alkoxy, Substituted alkoxy, alkoxycarbo 50 nyl, alkoxycarbonylamino, amino, Substituted amino, ami In these formulae one of RandR may behydrogen and nocarbonyl, aminocarbonylamino, aminocarbonyloxy, aryl, at least one of R* and R is each independently selected aryloxy, azido, carboxyl, cyano, cycloalkyl, Substituted from alkyl, alkenyl, alkynyl, cycloheteroalkyl, alkanoyl, cycloalkyl, halogen, hydroxyl, keto, nitro, thioalkoxy, Substi alkoxy, aryloxy, heteroaryloxy, alkylamino, arylamino, het tuted thioalkoxy, thioaryloxy, thioketo, thiol, alkyl-S(O)—, 55 eroarylamino, NR'COR, NRSOR, NRSOR7, aryl-S(O)—, alkyl-S(O) and aryl-S(O), . COOalkyl, COOaryl, CONRRS, CONRORS, NRSR55, “Fused Cycloalkenyl refers to a cycloalkenyl having two SONR'R', S-alkyl, S-alkyl, SOalkyl, SO-alkyl, Saryl, of its ring carbonatoms in common with a second aliphatic or SOaryl, SOaryl; or R and R may be joined to form a aromatic ring and having its olefinic unsaturation located to cyclic ring (saturated or unsaturated) from 5 to 8 atoms, impart aromaticity to the cycloalkenyl ring. 60 optionally containing one or more heteroatoms selected from “Cyanato” refers to the radical OCN. the group N, O or S. R. R. and R are independently “Cyano” refers to the radical —CN. hydrogen, alkyl, alkenyl, alkynyl, perfluoroalkyl, cycloalkyl, “Dialkylamino” means a radical NR'R' where R' cycloheteroalkyl, aryl, substituted aryl, heteroaryl, substi and R' independently represent an alkyl, substituted alkyl, tuted or hetero alkyl or the like. aryl, Substituted aryl, cycloalkyl, Substituted cycloalkyl, 65 “Hetero” when used to describe a compound or a group cycloheteroalkyl, substituted cycloheteroalkyl, heteroaryl, or present on a compound means that one or more carbonatoms Substituted heteroaryl group as defined herein. in the compound or group have been replaced by a nitrogen, US 8,563,754 B2 11 12 oxygen, or Sulfur heteroatom. Hetero may be applied to any of the hydrocarbyl groups described above Such as alkyl, e.g. heteroalkyl, cycloalkyl, e.g. cycloheteroalkyl, aryl, e.g. het Y ye 1y eroaryl, cycloalkenyl, cycloheteroalkenyl, and the like having from 1 to 5, and especially from 1 to 3 heteroatoms. 5 -OOC-El C “Heteroaryl” refers to a monovalent heteroaromatic group derived by the removal of one hydrogen atom from a single atom of a parent heteroaromatic ring system. Typical het y eroaryl groups include, but are not limited to, groups derived from acridine, arsindole, carbazole, B-carboline, chromane, 10 chromene, cinnoline, furan, imidazole, indazole, indole, indoline, indolizine, isobenzofuran, isochromene, isoindole, wherein each X is selected from CR, CRNR, Oand S; isoindoline, isoquinoline, isothiazole, isoxazole, naphthyri and each Y is selected from NR, O and S; and R is dine, oxadiazole, oxazole, perimidine, phenanthridine, independently hydrogen, alkyl, cycloalkyl, cycloheteroalkyl, phenanthroline, phenazine, phthalazine, pteridine, purine, 15 aryl, heteroaryl, heteroalkyl or the like. These cyclohet pyran, pyrazine, pyrazole, pyridazine, pyridine, pyrimidine, eroalkyl rings may be optionally substituted with one or more pyrrole, pyrrolizine, quinazoline, quinoline, quinolizine, qui groups selected from the group consisting of acyl, acylamino, noxaline, tetrazole, thiadiazole, thiazole, thiophene, triazole, acyloxy, alkoxy, Substituted alkoxy, alkoxycarbonyl, alkoxy xanthene, and the like. Preferably, the heteroaryl group is carbonylamino, amino, Substituted amino, aminocarbonyl, between 5-15 membered heteroaryl, with 5-10 membered aminocarbonylamino, aminocarbonyloxy, aryl, aryloxy, heteroaryl being particularly preferred. Particular heteroaryl azido, carboxyl, cyano, cycloalkyl, Substituted cycloalkyl, groups are those derived from thiophene, pyrrole, ben halogen, hydroxyl, keto, nitro, thioalkoxy, Substituted thio Zothiophene, benzofuran, indole, pyridine, quinoline, imida alkoxy, thioaryloxy, thioketo, thiol, alkyl-S(O)—, aryl-S Zole, oxazole and pyrazine. (O)—, alkyl-S(O) and aryl-S(O) . Substituting groups Examples of representative heteroaryls include the follow 25 include carbonyl or thiocarbonyl which provide, for example, 1ng: lactam and urea derivatives. Examples of representative cycloheteroalkenyls include the following: N N N Cy C C C, O 30 Y 1 Y 1 NN OOO C. C. 2 2 2 2 35 ON COC,N N CN N N n N\ Na2 2 / N 40 wherein each X is selected from CR, CRNR, Oand S; and each Y is selected from carbonyl, N, NR, O and S; and M R is independently hydrogen, alkyl, cycloalkyl, cyclohet Y Y eroalkyl, aryl, heteroaryl, heteroalkyl or the like. Examples of representative aryl having hetero atoms con wherein each Y is selected from carbonyl, N, NR, O, and S; 45 taining Substitution include the following: and R is independently hydrogen, alkyl, cycloalkyl, cyclo heteroalkyl, aryl, heteroaryl, heteroalkyl or the like. As used herein, the term “cycloheteroalkyl refers to a stable heterocyclic non-aromatic ring and fused rings con taining one or more heteroatoms independently selected from 50 N, O and S. A fused heterocyclic ring system may include carbocyclic rings and need only include one heterocyclic ring. Examples of heterocyclic rings include, but are not limited to, piperazinyl, homopiperazinyl, piperidinyl and 55 -O). morpholinyl, and are shown in the following illustrative examples: wherein each X is selected from CR, NR, O and S; and each Y is selected from carbonyl, NR, O and S; and R is independently hydrogen, alkyl, cycloalkyl, cycloheteroalkyl, ty ty 60 aryl, heteroaryl, heteroalkyl or the like. “Hetero substituent” refers to a halo, O, S or N atom containing functionality that may be present as an Rina R' 4 - N x 1N group present as Substituents directly on the ring or rings of the compounds of this invention, or that may be present as a OC) -O-O- Substituent in any “substituted aryl and aliphatic groups present in the compounds. US 8,563,754 B2 13 14 Examples of hetero substituents include: As used herein, “mammal’ refers to any member of the -halo, higher vertebrate animals comprising the class Mammalia, NO, NH, NHR, N(R), which includes, but is not limited to, humans. NRCOR, NRSOR, NRSOR, OH, CN, As used herein, the term “melanogenesis inhibitor” is used —COH, to describe a compound or an agent, extract of a natural R OH, O R, COOR, material, or the like, that is known or is identified herein as CONCR), CONROR, possessing the ability to inhibit melanogenesis in a melano - SOH, - R S, SON(R), cyte. S(O)R’, S(O).R As used herein, an “amount effective' shall mean an wherein each R is independently an aryl or aliphatic, 10 optionally with Substitution. Among hetero Substituents con amount Sufficient to cover the region of skin, hair, fur, or wool taining R groups, preference is given to those materials Surface where a change in pigmentation is desired. having aryland alkyl R groups as defined herein. Preferred "Pharmaceutically acceptable” means approved by a regu hetero substituents are those listed above. latory agency of the Federal or a state government or listed in “Dihydroxyphosphoryl refers to the radical —PO(OH). 15 the U.S. Pharmacopoeia or other generally recognized phar “Substituted dihydroxyphosphoryl' includes those groups macopoeia for use in animals, and more particularly in recited in the definition of “substituted herein, and particu humans. larly refers to a dihydroxyphosphoryl radical wherein one or "Pharmaceutically acceptable salt” refers to a salt of a both of the hydroxyl groups are substituted. Suitable substitu compound of the invention that is pharmaceutically accept ents are described in detail below. able and that possesses the desired pharmacological activity Aminohydroxyphosphoryl” refers to the radical —PO of the parent compound. Such salts include: (1) acid addition (OH)NH. salts, formed with inorganic acids such as hydrochloric acid, “Substituted aminohydroxyphosphoryl' includes those hydrobromic acid, Sulfuric acid, nitric acid, phosphoric acid, groups recited in the definition of “substituted herein, and and the like; or formed with organic acids such as acetic acid, particularly refers to an aminohydroxyphosphoryl wherein 25 propionic acid, hexanoic acid, cyclopentanepropionic acid, the amino group is substituted with one or two Substituents. glycolic acid, pyruvic acid, lactic acid, malonic acid, Succinic Suitable substituents are described in detail below. In certain acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric embodiments, the hydroxyl group can also be substituted. acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cin “Thioalkoxy” refers to the group - SR" where R' is namic acid, mandelic acid, methanesulfonic acid, ethane alkyl. 30 Sulfonic acid, 1.2-ethane-disulfonic acid, 2-hydroxyethane “Substituted thioalkoxy” includes those groups recited in sulfonic acid, benzenesulfonic acid, the definition of “substituted” herein, and particularly refers 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, to a thioalkoxy group having 1 or more Substituents, for 4-toluenesulfonic acid, camphorsulfonic acid, 4-methylbicy instance from 1 to 5 substituents, and particularly from 1 to 3 clo2.2.2-oct-2-ene-1-carboxylic acid, glucoheptonic acid, Substituents, selected from the group consisting of acyl, acy 35 lamino, acyloxy, alkoxy, Substituted alkoxy, alkoxycarbonyl, 3-phenylpropionic acid, trimethylacetic acid, tertiary buty alkoxycarbonylamino, amino, Substituted amino, aminocar lacetic acid, lauryl Sulfuric acid, gluconic acid, glutamic acid, bonyl, aminocarbonylamino, aminocarbonyloxy, aryl, ary hydroxynaphthoic acid, Salicylic acid, Stearic acid, muconic loxy, azido, carboxyl, cyano, cycloalkyl, Substituted acid, and the like; or (2) salts formed when an acidic proton cycloalkyl, halogen, hydroxyl, keto, nitro, thioalkoxy, Substi 40 present in the parent compound either is replaced by a metal tuted thioalkoxy, thioaryloxy, thioketo, thiol, alkyl-S(O)—, ion, e.g., an alkali metal ion, an alkaline earth ion, or an aryl-S(O)—, alkyl-S(O) and aryl-S(O), . aluminum ion; or coordinates with an organic base Such as “Sulfanyl refers to the radical HS-. “Substituted sulfa ethanolamine, diethanolamine, triethanolamine, N-methyl nyl refers to a radical such as RS wherein R is any sub glucamine and the like. Salts further include, by way of stituent described herein. 45 example only, Sodium, potassium, calcium, magnesium, "Sulfonyl refers to the divalent radical —S(O)—. “Sub ammonium, tetraalkylammonium, and the like; and when the stituted sulfonyl refers to a radical such as R'—(O)S compound contains a basic functionality, salts of non toxic wherein R' is any substituent described herein. “Aminosul organic or inorganic acids, such as hydrochloride, hydrobro fonyl' or "Sulfonamide” refers to the radical HN(O)S , mide, tartrate, mesylate, acetate, maleate, oxalate and the and “substituted aminosulfonyl” “substituted sulfonamide' 50 like. refers to a radical such as R.N.(O.)S wherein each R is The term “pharmaceutically acceptable cation” refers to a independently any substituent described herein. non toxic, acceptable cationic counter-ion of an acidic func "Sulfone” refers to the group —SO.R. In particular tional group. Such cations are exemplified by Sodium, potas embodiments, R is selected from H. lower alkyl, alkyl, aryl sium, calcium, magnesium, ammonium, tetraalkylammo and heteroaryl. 55 nium cations, and the like. “Thioaryloxy” refers to the group - SR" where R is "Pharmaceutically acceptable vehicle' refers to a diluent, aryl. adjuvant, excipient or carrier with which a compound of the “Thioketo refers to the group —S. invention is administered. “Thiol” refers to the group - SH. “Preventing or “prevention” refers to a reduction in risk of One having ordinary skill in the art of organic synthesis 60 acquiring a disease or disorder (i.e., causing at least one of the will recognize that the maximum number of heteroatoms in a clinical symptoms of the disease not to develop in a subject stable, chemically feasible heterocyclic ring, whether it is not yet exposed to or predisposed to the disease, and not yet aromatic or non aromatic, is determined by the size of the experiencing or displaying symptoms of the disease). ring, the degree of unsaturation and the Valence of the het “Prodrugs’ refers to compounds, including derivatives of eroatoms. In general, a heterocyclic ring may have one to four 65 the compounds of the invention, which have cleavable groups heteroatoms so long as the heteroaromatic ring is chemically and become by Solvolysis or under physiological conditions feasible and stable. the compounds of the invention which are pharmaceutically US 8,563,754 B2 15 16 active in vivo. Such examples include, but are not limited to, compounds may be used for drug and/or Substrate tissue choline ester derivatives and the like, N-alkylmorpholine distribution studies. The radioactive isotopes tritium, i.e. H. esters and the like. and carbon-14, i.e. ''C, are particularly useful for this pur “Solvate” refers to forms of the compound that are associ pose in view of their ease of incorporation and ready means of ated with a solvent, usually by a Solvolysis reaction. Conven detection. Further, compounds may be prepared that are Sub tional Solvents include water, ethanol, acetic acid and the like. stituted with positron emitting isotopes, such as 'C, F, 'O The compounds of the invention may be prepared e.g. in and 'N, and would be useful in Positron Emission Topogra crystalline form and may be solvated or hydrated. Suitable phy (PET) studies for examining substrate receptor occu Solvates include pharmaceutically acceptable Solvates, such pancy. as hydrates, and further include both stoichiometric solvates 10 and non-stoichiometric Solvates. All isotopic variants of the compounds provided herein, “Subject' includes humans. The terms “human, patient’ radioactive or not, are intended to be encompassed within the and “subject' are used interchangeably herein. Scope of the invention. “Therapeutically effective amount’ means the amount of a It is also to be understood that compounds that have the compound that, when administered to a subject for treating a 15 same molecular formula but differ in the nature or sequence disease or a condition, is sufficient to effect such treatment for of bonding of their atoms or the arrangement of their atoms in the disease or condition. The “therapeutically effective space are termed "isomers'. Isomers that differ in the amount can vary depending on the compound, the disease or arrangement of their atoms in space are termed “stereoiso condition and its severity, and the age, weight, etc., of the mers’. subject to be treated. Stereoisomers that are not mirror images of one another are “Treating or “treatment of any disease or disorder refers, termed "diastereomers' and those that are non-Superimpos in one embodiment, to ameliorating the disease or disorder able mirror images of each other are termed “enantiomers’. (i.e., arresting or reducing the development of the disease or When a compound has an asymmetric center, for example, it at least one of the clinical symptoms thereof). In another is bonded to four different groups, a pair of enantiomers is embodiment “treating or “treatment” refers to ameliorating 25 possible. An enantiomer can be characterized by the absolute at least one physical parameter, which may not be discernible configuration of its asymmetric center and is described by the by the subject. In yet another embodiment, “treating” or R- and S-sequencing rules of Cahn and Prelog, or by the “treatment” refers to modulating the disease or disorder, manner in which the molecule rotates the plane of polarized either physically, (e.g., stabilization of a discernible symp light and designated as dextrorotatory or levorotatory (i.e., as tom), physiologically, (e.g., stabilization of a physical param 30 (+) or (-)-isomers respectively). A chiral compound can exist eter), or both. In yet another embodiment, “treating” or “treat as either individual enantiomer or as a mixture thereof. A ment” refers to delaying the onset of the disease or disorder, mixture containing equal proportions of the enantiomers is or even preventing the same. In a still further embodiment, called a “racemic mixture'. “treating or “treatment” refers to administration of the com “Tautomers' refer to compounds that are interchangeable pound or composition of the invention for cosmetic purposes. 35 forms of a particular compound structure, and that vary in the Other derivatives of the compounds of this invention have displacement of hydrogen atoms and electrons. Thus, two activity in both their acid and acid derivative forms, but in the structures may be in equilibrium through the movement of It acid sensitive form often offers advantages of solubility, tis electrons and an atom (usually H). For example, enols and Sue compatibility, or delayed release in the mammalian ketones are tautomers because they are rapidly interconverted organism (see, Bundgard, H., Design of Prodrugs, pp. 7-9, 40 by treatment with either acid or base. Another example of 21-24, Elsevier, Amsterdam 1985). Prodrugs include acid tautomerism is the aci- and nitro-forms of phenylni derivatives well know to practitioners of the art, such as, for tromethane, that are likewise formed by treatment with acid example, esters prepared by reaction of the parent acid with a or base. Suitable alcohol, or amides prepared by reaction of the parent Tautomeric forms may be relevant to the attainment of the acid compound with a substituted or unsubstituted amine, or 45 optimal chemical reactivity and biological activity of a com acid anhydrides, or mixed anhydrides. Simple aliphatic or pound of interest. aromatic esters, amides and anhydrides derived from acidic The compounds of this invention may possess one or more groups pendant on the compounds of this invention are pre asymmetric centers; such compounds can therefore be pro ferred prodrugs. In some cases it is desirable to prepare duced as individual (R)- or (S)-stereoisomers or as mixtures double ester type prodrugs such as (acyloxy)alkyl esters or 50 thereof. Unless indicated otherwise, the description or nam ((alkoxycarbonyl)oxy)alkylesters. Preferred are the C to Cs ing of a particular compound in the specification and claims is alkyl, C-Cs alkenyl, aryl, C7-C. Substituted aryl, and intended to include both individual enantiomers and mix C7-Carylalkyl esters of the compounds of the invention. tures, racemic or otherwise, thereof. The methods for the As used herein, the term “isotopic variant” refers to a determination of stereochemistry and the separation of stere compound that contains unnatural proportions of isotopes at 55 oisomers are well-known in the art. one or more of the atoms that constitute Such compound. For example, an "isotopic variant' of a compound can contain one The Compounds or more non-radioactive isotopes, such as for example, deu terium (H or D), carbon-13 (''C), nitrogen-15 ('N), or the As described herein, the present invention relates to the like. It will be understood that, in a compound where such 60 identification of compounds that prevent or inhibit skin dark isotopic Substitution is made, the following atoms, where ening. This invention also relates to methods for preventing present, may vary, so that for example, any hydrogen may be and/or treating conditions that may include or involve skin “H/D, any carbon may be 'C, or any nitrogen may be 'N, darkening, Such as aberrant pigmentation, including hyper and that the presence and placement of Such atoms may be pigmentation of all etiologies, uneven pigmentation, and the determined within the skill of the art. Likewise, the invention 65 like, using the compounds and compositions of the invention. may include the preparation of isotopic variants with radio This invention further relates to methods for preventing isotopes, in the instance for example, where the resulting hyperpigmented skin, undesired pigmentation disorder of US 8,563,754 B2 17 18 skin, or undesired darkening of skin comprising administer In another embodiment of the invention, the invention pro ing an effective amount of a coumarin compound as defined vides a method for preventing undesired pigmentation disor herein. der of skin comprising administering an effective amount of a In accordance with the present invention, a plurality of compound of formula I. compounds has been identified that are capable of inhibiting 5 In another embodiment of the invention, the invention pro skin darkening. These compounds, which were not previ vides a method for preventing undesired darkening of skin ously identified as possessing Such a capability, are listed comprising administering an effective amount of a compound herein. Accordingly, the present invention is directed to their of formula I. use in inhibiting or preventing darkening in in vitro and in In one embodiment of the invention, with respect to for Vivo applications. With respect to in vitro applications, test 10 mula I, R is selected from H, substituted or unsubstituted tube based and additional cell-based assays may be used to alkyl, and substituted or unsubstituted alkenyl. test the ability of modified versions and/or derivatives of In one embodiment of the invention, with respect to for compounds listed herein to prevent darkening. In vivo appli mula I, R is H, C1, alkyl, or substituted or unsubstituted cations are directed to the administration of at least one of the 15 phenyl. novel inhibitor compounds listed herein to a subject in need In another embodiment of the invention, with respect to thereof to prevent increases in pigmentation levels for pro formula I, R is H, C1, Me, phenyl, 4-hydroxyphenyl, or phylactic, therapeutic and/or cosmetic purposes. 4-methoxyphenyl. One aspect of the invention provides a method for prevent ing hyperpigmented skin, undesired pigmentation disorder of In one embodiment of the invention, with respect to for skin, or undesired darkening of skin comprising administer mula I, R is H, C1, alkyl, or substituted or unsubstituted ing an effective amount of a compound of formula I phenyl. In another embodiment of the invention, with respect to formula I, R is H, Cl, Me, phenyl, or 4-methoxyphenyl. In one embodiment of the invention, with respect to for 25 mula I, R is H, C1, alkyl, hydroxy, or alkoxy. In another embodiment of the invention, with respect to O O O formula I, R is H, Cl, Me, OH, or OMe. In one embodiment of the invention, with respect to for mula I, R is H. Cl, alkyl, alkenyl, hydroxy, alkoxy, or alk R6 an 30 enyloxy. R5 R4 In another embodiment of the invention, with respect to formula I, R is H, C1, OH, OMe, 3-methylbut-2-enyl, or or a pharmaceutically acceptable salt, Solvate or prodrug 3-methylbut-2-enyloxy. thereof, and stereoisomers, tautomers and isotopic vari 35 In one particular embodiment of the invention, with respect ants thereof, and wherein to formula I, R is H, H, or OMe. R is selected from H, halo, substituted or unsubstituted In one embodiment of the invention, with respect to for alkyl, substituted or unsubstituted alkenyl, or substituted mula I, R is H, Cl, alkyl, alkenyl, hydroxy, alkoxy, or alk or unsubstituted aryl; and substituted or unsubstituted enyloxy. heteroaryl; 40 In another embodiment of the invention, with respect to R" is selected from H, halo, hydroxy, alkoxy, alkenyloxy, formula I, R is H, C1, OH, OMe, 3-methylbut-2-enyl, or substituted or unsubstituted alkyl, substituted or unsub 3-methylbut-2-enyloxy. stituted alkenyl, and substituted or unsubstituted phenyl: In one particular embodiment of the invention, with respect each R, RandR is independently selected from H, halo, to formula I, R is H, OH, OMe, or 3-methylbut-2-enyl. hydroxy, alkoxy, alkenyloxy, Substituted or unsubsti 45 In one particular embodiment of the invention, with respect tuted alkyl, substituted or unsubstituted alkenyl, and to formula I, R is H, Me, 3-methylbut-2-enyl, P(=O)(OEt), substituted or unsubstituted phenyl: P(=S)(OEt), or 6-hydroxymethyl-3,4,5-trihydroxypyran R’ is selected from H, halo, hydroxy, alkoxy, alkenyloxy, 2-yl. substituted or unsubstituted alkyl, substituted or unsub In one particular embodiment of the invention, with respect stituted alkenyl, or heterocycloalkyl; or R is - P(=O) 50 to formula I, each R. R. R. R. is H; R is as described for (alkoxy), or—P(=S)(alkoxy); or formula I; and R is substituted or unsubstituted alkenyl. In Rand R7 or R7 and Rare joined to form a 5- or 6-mem another embodiment, R is 3-methylbut-2-enyl; and R7 is bered heterocycloalkyl or heterocycloalkenyl; and the other than Me. heterocycloalkyl or heterocycloalkenyl is unsubstituted In one particular embodiment of the invention, with respect or Substituted with one more groups selected from alkyl, 55 to formula I, each R. R. R. R. is H: R is substituted or alkenyl, hydroxyalkyl, acyloxyalkyl, hydroxy, and unsubstituted alkenyl; and R7 is H. Me, 3-methylbut-2-enyl, alkoxy; and P(=O)(OEt), P(=S)(OEt), or 6-hydroxymethyl-3,4,5-tri provided that hydroxypyran-2-yl. In another embodiment, R is substituted iv) when R is H; then R is substituted or unsubstituted or unsubstituted alkenyl; and R7 is Me. In yet another particu alkenyl: 60 lar embodiment, R is 3-methylbut-2-enyl and R is Me. V) the compound is other than robustic acid; and In one particular embodiment of the invention, with respect vi) when each of R. R. R. and R is H; and R is 3-me to formula I, R. R. R. R7 and R are as described for thylbut-2-enyl; then R is other than Me. formula I; and R is C1. In one embodiment of the invention, the invention provides In one particular embodiment of the invention, with respect a method for preventing hyperpigmented skin comprising 65 to formula I, R. R. R. and Rare as described for formula administering an effective amount of a compound of formula I; and R is Cl; and R7 is H, Me, 3-methylbut-2-enyl, P(=O) I. (OEt), P(=S)(OEt), or 6-hydroxymethyl-3,4,5-trihy US 8,563,754 B2 19 20 droxypyran-2-yl. In another embodiment, R is Me, or P(=S) R is selected from H, halo, hydroxy, alkoxy, alkenyloxy, (OEt). In yet another embodiment, R7 is Me, or P(=S) substituted or unsubstituted alkyl, substituted or unsubsti (OEt). tuted alkenyl, or substituted or unsubstituted phenyl; and In one particular embodiment of the invention, with respect each R', R', R', and R is independently selected from to formula I, the compound is coumophos. H, alkyl, hydroxyalkyl, or alkenyl. In one embodiment of the invention, with respect to for In one embodiment of the invention, with respect to for mula I, R and R are joined to form a 5- or 6-membered mula I, the compound is according to formulae IIIa, IIIb, IIIc heterocycloalkyl or heterocycloalkenyl; and the heterocy or IIId: cloalkyl or heterocycloalkenyl is unsubstituted or substituted with one more groups selected from alkyl, alkenyl, hydroxy 10 alkyl, acyloxyalkyl, hydroxy, and alkoxy. IIIa In one embodiment of the invention, with respect to for R8 mula I, R and R are joined to form a 5- or 6-membered Re O O O heterocycloalkyl or heterocycloalkenyl; and the heterocy 15 cloalkyl or heterocycloalkenyl is unsubstituted or substituted with one more groups selected from alkyl, alkenyl, hydroxy alkyl, acyloxyalkyl, hydroxy, and alkoxy. In one embodiment of the invention, with respect to for mula I, the compound is according to formulae IIa, IIb, IIc, or IIIb. IId:

IIa 25

IIIc

30

IIb

35

III

IIc 40

45

or a pharmaceutically acceptable salt, Solvate or prodrug

IId thereof, and stereoisomers, tautomers and isotopic vari 50 ants thereof, and wherein R. R. and Rare as described for formula I; R is selected fromhalo, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, or substituted or unsub stituted phenyl: 55 R is selected from H, halo, hydroxy, alkoxy, alkenyloxy, substituted or unsubstituted alkyl, substituted or unsubsti tuted alkenyl, or substituted or unsubstituted phenyl; and each R', R'' and R' is independently selected from H, 60 alkyl, hydroxyalkyl, or alkenyl. or a pharmaceutically acceptable salt, Solvate or prodrug In one embodiment of the invention, with respect to for thereof, and stereoisomers, tautomers and isotopic vari mulae IIa, IIc and IIIa-IIId, R' is H or Me. ants thereof, and wherein In one embodiment of the invention, with respect to for R. R. and Rare as described for formula I; mulae IIa, IIe and IIIa-IIId, R' is H or Me. R is selected from halo, substituted or unsubstituted alkyl, 65 In one particular embodiment, each of R'' and R' is Me. substituted or unsubstituted alkenyl, or substituted or unsub In one embodiment of the invention, with respect to for stituted phenyl: mulae IIc, IId, IIIc, or IIId, R is H or Me. US 8,563,754 B2 21 22 In one embodiment of the invention, with respect to for -continued mulae IIc, IId, IIIc, or IIId, R is H, Me, OH, OMe, 3-meth Vb ylbuten-2-yl; or 3-methylbuten-2-yloxy. In one embodiment of the invention, with respect to for mula I, the compound is according to formula IV: 5

IV

10

WC

15

or a pharmaceutically acceptable salt, Solvate or prodrug O thereof, and stereoisomers, tautomers and isotopic vari ants thereof, and wherein Vc R', and Rare as described for formula I; R is selected from halo, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, or substituted or unsub stituted phenyl: R is selected from H, halo, hydroxy, alkoxy, alkenyloxy, 25 substituted or unsubstituted alkyl, substituted or unsubsti tuted alkenyl, or substituted or unsubstituted phenyl; and each R" and R' is independently selected from H, alkyl, or alkenyl. 30 In one embodiment of the invention, with respect to for or a pharmaceutically acceptable salt, Solvate or prodrug mulae I-IV, R is H, Cl, alkyl, hydroxy, alkoxy, or substituted thereof, and stereoisomers, tautomers and isotopic vari or unsubstituted phenyl. ants thereof, and wherein In one embodiment of the invention, with respect to for R. R. and Rare as described for formula I; mulae I-IV, R is H. Me, OH, OMe, or 4-methoxyphenyl. 35 R is selected fromhalo, substituted or unsubstituted alkyl, In one embodiment of the invention, with respect to for substituted or unsubstituted alkenyl, or substituted or unsub mulae I-IV, R is OH or OMe. stituted phenyl: R is selected from H, halo, hydroxy, alkoxy, alkenyloxy, In one embodiment of the invention, with respect to for substituted or unsubstituted alkyl, substituted or unsubsti mulae I-IV, R is H or Me. 40 tuted alkenyl, or substituted or unsubstituted phenyl. In one embodiment of the invention, with respect to for In one embodiment of the invention, with respect to for mulae I-IV, R is H. mulae I-Vd, R is H, C1, alkyl, hydroxy, or alkoxy. In one embodiment of the invention, with respect to for mulae I-IV, R7 is H or Me. In one embodiment of the invention, with respect to for 45 mulae I-Vd, R is H, Cl, Me, OH, or OMe. In one embodiment of the invention, with respect to for In one embodiment of the invention, with respect to for mulae I-IV, R' is H or Me. mulae I-Vd, R is OH or OMe. In one embodiment of the invention, with respect to for In one embodiment of the invention, with respect to for mulae I-IV, each R7 and R7 is H or Me. mulae I-Vd, R is H. Cl, alkyl, alkenyl, hydroxy, alkoxy, or In one embodiment of the invention, with respect to for 50 alkenyloxy. mulae I-IV, each R'' and R' is Me. In one embodiment of the invention, with respect to for In one embodiment of the invention, with respect to for mulae I-Vd, R is H, C1, OH, OMe, 3-methylbut-2-enyl, or mulae I-IV, R is H or Me. 3-methylbut-2-enyloxy. In one embodiment of the invention, with respect to for 55 In one embodiment of the invention, with respect to for mula I, the compound is of formulae Va, Vb, Vc, or Vd: mulae I-Vd, R is H or 3-methylbut-2-enyl. In one embodiment of the invention, with respect to for mulae I-Vd, R is H, C1, alkyl, alkenyl, hydroxy, alkoxy, or Wa alkenyloxy. 60 In one embodiment of the invention, with respect to for mulae I-Vd, R is H, C1, OH, OMe, 3-methylbut-2-enyl, or 3-methylbut-2-enyloxy. In one embodiment of the invention, with respect to for 65 mulae I-Vd, R is 3-methylbut-2-enyl. In one embodiment of the invention, with respect to for mula I, the compound is of formulae VIa, VIb, VIc, or VId: US 8,563,754 B2 24 -continued

VIIb

WIa

10

WIb

15 or a pharmaceutically acceptable salt, Solvate or prodrug thereof, and stereoisomers, tautomers and isotopic vari ants thereof.

WIC In one particular embodiment, with respect to formula I, the compound is formula VIIa (robustic acid methyl ether):

VIIa

25

WId

30 OMe

or a pharmaceutically acceptable salts, Solvates, isomers, tau tomers, metabolites, analogs, isotopic variants or prodrugs 35 thereof. In another particular embodiment, with respect to formula I, the compound is formula VIIb (scandenin):

or a pharmaceutically acceptable salt, Solvate or prodrug 40 VIIb thereof, and stereoisomers, tautomers and isotopic vari ants thereof, and wherein R is selected from halo, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, or substituted or unsubstituted phenyl. 45 In one embodiment of the invention, with respect to for mulae I-VId, R is C1, alkyl, or substituted or unsubstituted phenyl. In one embodiment of the invention, with respect to for 50 mulae I-VId, R is Me, phenyl, 4-hydroxyphenyl, 3,4-dihy droxyphenyl, 4-methoxyphenyl, or 3,4-dimethoxyphenyl. or a pharmaceutically acceptable salt, Solvate, isomer, tau In one embodiment of the invention, with respect to for tomer, metabolite, analog, isotopic variant or prodrug thereof. mula I, the compound is of formulae VIIa, or VIIb: 55 In one particular embodiment, with respect to formula I, the compound is selected from the compounds listed in Table 1.

VIIa In another particular embodiment of the invention, with respect to formula I, the compound is pachyrrhizin, robustic 60 acid methyl ether, or Scandenin In one embodiment of the invention, with respect to for mula I, the compound is robustic acid methyl ether. In one embodiment of the invention, with respect to for 65 mula I, the compound is scandenin. O In one embodiment of the invention, with respect to for mula I, the compound is pachyrrhizin. US 8,563,754 B2 25 26 In one embodiment, with respect to the method of the amount of the combination, wherein the like acting agent is a invention, the method comprises a step of contacting skin pharmacologically active agent. with In a further embodiment of the combination described a) a composition comprising a compound as set forth in any above, a topical formulation is prepared that comprises a of formulae I-VIIb in a sufficient amount to prevent composition for cosmetic or dermatological use, which com hyperpigmented skin, undesired pigmentation disorder position comprises a cosmetically and/or dermatologically of skin, or undesired darkening of skin, and effective amount of the combination stated above, wherein b) an acceptable carrier. the like acting agent is a cosmetically active agent. In other aspect the invention, the invention provides a com The methods and compositions of the present invention 10 contemplate the use of one or more of the compounds listed position for preventing hyperpigmented skin, undesired pig hereinas an active ingredient(s) for various uses. In a particu mentation disorder of skin, or undesired darkening of skin lar embodiment, the active ingredient(s) is combined with an comprising an amount of a compound according to formulae acceptable carrier to form a topical formulation for applica I-VIIb effective to inhibit such conditions. The compositions tion to the skin, for example, for cosmetic and/or therapeutic may be for cosmetic or dermatological use, and may be 15 dermatological uses. Topical formulations may include oint selected from lotions, cremes, gels, sprays, and may include ments, lotions, pastes, creams, gels, drops, suppositories, emollients, perfumes, and the like. sprays, liquids, shampoos, powders and transdermal patches. In one embodiment of the invention, with respect to the Thickeners, diluents, emulsifiers, dispersing aids or binders composition, the composition is selected from skin lotion, may be used as needed. Preferably, one function of the carrier skin softener, skintoner, astringent, lotion, milk lotion, mois is to enhance skin penetration of the active ingredient(s), and ture lotion, nutrient lotion, massage cream, nutrient cream, should be capable of delivering the active ingredient(s) to moisture cream, hand cream, foundation, essence, nutrient melanocytes under in vivo conditions. Suitable carriers are essence, pack, cleansing foam, cleansing lotion, cleansing well known to skilled practitioners, and include liposomes, cream, body lotion, body cleanser, treatment or beauty Solu ethanol, dimethylsulfoxide (DMSO), petroleum jelly (petro tion. 25 latum), mineral oil (liquid petrolatum), water, dimethylfor In yet another aspect the invention, the invention provides mamide, dekaoxyethylene-oleylether, oleic acid, 2-pyrroli a combination to prevent hyperpigmented skin, undesired done and AZone(R) brand penetration enhancer (Upjohn). A pigmentation disorder of skin, or undesired darkening of skin particular composition may be formulated to include an consisting of a compound according to formulae I-VIIb and a active ingredient(s) as described in Table I, with one of 2-pyr like-acting agent. 30 rolidone, oleic acid and/or AZone(R) added to enhance pen In one embodiment of the invention, with respect to the etration, solubilized in a base of water, ethanol, propanol combination, the like acting agent is selected from a cosmetic and/or propylene glycol. ingredient and a pharmacologically active agent. As indicated above, vehicles comprising liposomes may be In one embodiment of the invention, with respect to the used for topical delivery of some of the compositions of the combination, the said pharmacologically active agent is 35 invention. Depending on the composition, and at the discre selected from another melanogenesis inhibitor. tion of a skilled practitioner, Such liposomes may be non In one embodiment of the invention, with respect to the ionic and contain a) glycerol dilaurate (preferably in an method, composition or combination as described above, the amount of between about 5% and about 70% by weight); b) hyperpigmented skin, undesired pigmentation disorder of compounds having the steroid backbone found in cholesterol skin, or undesired darkening of skin is caused by environmen 40 (preferably in an amount of between about 5% and about 45% tal or physiological conditions. by weight); and c) one or more fatty acid ethers having from In one embodiment of the invention, with respect to the about 12 to about 18 carbon atoms preferably in an amount of method, composition or combination as described above, the between about 5% and about 70% by weight collectively), hyperpigmented skin, undesired pigmentation disorder of wherein the constituent compounds of the liposomes are pref skin, or undesired darkening of skin is due to the use of 45 erably in a ratio of about 37.5:12.5:33.3:16.7. For some com personal care products. positions, liposomes comprised of glycerol dilaurate/choles In one embodiment of the invention, with respect to the terol/polyoxyethylene-10-stearyl ether/polyoxyethylene-9- method, composition or combination as described above, the lauryl ether (GDL liposomes) are preferred. Liposomes may hyperpigmented skin, undesired pigmentation disorder of be present in an amount, based upon the total Volume of the skin, or undesired darkening of skin is age spots, freckles, 50 composition, of from about 10 mg/mL to about 100 mg/mL, drug-induced hyperpigmentation, post-inflammatory hyper and more preferably from about 20 mg/mL to about 50 pigmentation as seen in acne, melasma or chloasma. mg/mL. A ratio of about 37.5:12.5:33.3:16.7 may be used to In one embodiment of the invention, with respect to the particular advantage. Suitable liposomes may be prepared in method, composition or combination as described above, the accordance with standard methods commonly used in the art. skin is mammalian skin. 55 The above described composition may be prepared by In one embodiment of the invention, with respect to the combining the desired components in a suitable container and method, composition or combination as described above, the mixing them under ambient conditions in any conventional skin is human skin. high shear mixing means well known in the art for non-ionic A further aspect of the invention extends to a formulation liposome preparations, such as those disclosed in Niemiec et that comprises a combination of a compound with respect to 60 al. (Pharm. Res. 12:1184-88 (1995)), which is incorporated formulae I-VIIb, and a like-acting agent. In a particular by reference herein in its entirety. The presence of such lipo embodiment, the like acting agent is selected from a cosmetic Somes enhances the depigmenting capabilities of some com ingredient and a pharmacologically active agent. positions. In a particular embodiment of the combination just Other formulations may contain, for example, soybean described, a pharmaceutical composition is prepared that is 65 milk or other liquid formulations derived directly from useful to treat a disease for which a melanogenesis inhibitoris legumes or other Suitable plant. Such a formulation may, for indicated, which comprises a therapeutically effective example, contain a large proportion of soybean milk, an US 8,563,754 B2 27 28 emulsifier that maintains the physical stability of the soybean The compounds useful according to the invention that are milk, and, optionally a chelating agent, preservatives, emol basic in nature are capable of forming a wide variety of lients, humectants and/or thickeners or gelling agents. different salts with various inorganic and organic acids. Oil-in-water emulsions, water-in-oil emulsions, solvent Although Such salts must be pharmaceutically acceptable for based formulations and aqueous gels known to those of skill 5 administration to animals, it is often desirable in practice to in the art may also be utilized as vehicles for the delivery of initially isolate a compound of formula I from the reaction the compositions of this invention. mixture as a pharmaceutically unacceptable salt and then Depending on the specific application, the compositions of simply convert the latter back to the free base compound by the present invention may also include other active ingredi treatment with an alkaline reagent and Subsequently convert 10 the latter free base to a pharmaceutically acceptable acid ents, as well as inert or inactive ingredients. In Such alterna addition salt. The acid addition salts of the active base com tive embodiments, the topically active pharmaceutical or cos pounds of this invention are readily prepared by treating the metic composition may be optionally combined with other base compound with a Substantially equivalent amount of the ingredients such as moisturizers, cosmetic adjuvants, Surfac chosen mineral or organic acid in an aqueous solvent medium tants, foaming agents, conditioners, humectants, fragrances, 15 or in a Suitable organic solvent, Such as methanol or ethanol. Viscosifiers, buffering agents, preservatives, Sunscreens and Upon careful evaporation of the solvent, the desired solid salt the like. is readily obtained. The amount of the aforementioned examples of additional Those compounds useful according to the invention that active ingredients for skin treatment (one or more com are acidic in nature are capable of forming base salts with pounds) in the formulations according to the invention may various pharmaceutically acceptable cations. Examples of vary in accordance with the end use of the product and in Such salts include the alkali metal and alkaline earth metal accordance with accepted norms for Such formulations. salts and, particularly, the Sodium and potassium salts. These Exemplary ranges may be from about 0.01 to about 30 wt.%. salts can be prepared by conventional techniques. The chemi particularly from about 0.01 to about 20 wt.%, and more cal bases that are used as reagents to prepare the pharmaceu particularly from about 0.01 to about 5 wt.%, based on the 25 tically acceptable base salts of this invention are those that total weight of the preparation. The foregoing ranges are form non-toxic base salts with the acidic compounds of for presented by way of illustration and not limitation. mula I. Such non-toxic base salts include those derived from In certain aspects, the present invention provides prodrugs Such pharmaceutically acceptable cations as sodium, potas and derivatives of the compounds of the invention. Prodrugs sium, calcium and magnesium, etc. These salts can easily be are derivatives of the compounds of the invention, which have 30 prepared by treating the corresponding acidic compounds metabolically cleavable groups and become by Solvolysis or with an aqueous solution containing the desired pharmaceu under physiological conditions the compounds of the inven tically acceptable cations, and then evaporating the resulting tion, which are pharmaceutically active, in vivo. Such solution to dryness, preferably under reduced pressure. Alter examples include, but are not limited to, choline ester deriva natively, they can also be prepared by mixing lower alkanolic tives and the like, N-alkylmorpholine esters and the like. 35 Solutions of the acidic compounds and the desired alkali Other derivatives of the compounds of this invention have metal alkoxide together, and then evaporating the resulting activity in both their acid and acid derivative forms, but the Solution to dryness, as described above. In either case, sto acid sensitive form often offers advantages of solubility, tis ichiometric quantities of reagents are preferably employed in Sue compatibility, or delayed release in the mammalian order to ensure completeness of reaction and maximum organism (see, Bundgard, H., Design of Prodrugs, pp. 7-9, 40 yields of the desired final products. 21-24, Elsevier, Amsterdam 1985). Prodrugs include acid The compounds useful according to the invention, and their derivatives well know to practitioners of the art, such as, for pharmaceutically acceptable salts, are useful for the preven example, esters prepared by reaction of the parent acid with a tion of disorders of human pigmentation, including Solar and Suitable alcohol, or amides prepared by reaction of the parent simple lentigines (including age/liver spots), melasma/chlo acid compound with a substituted or unsubstituted amine, or 45 asma and postinflammatory hyper-pigmentation. acid anhydrides, or mixed anhydrides. Simple aliphatic or The appropriate dose regimen, the amount of each dose aromatic esters, amides and anhydrides derived from acidic administered, and specific intervals between doses of the groups pendant on the compounds of this invention are pre active compound will depend upon the particular active com ferred prodrugs. In some cases it is desirable to prepare pound employed, the condition of the patient being treated, double ester type prodrugs such as (acyloxy)alkyl esters or 50 and the nature and severity of the disorder or condition being ((alkoxycarbonyl)oxy)alkylesters. Preferred are the C to Cs treated. Preferably, the active compound is administered in an alkyl, C-Cs alkenyl, aryl, C7-C. Substituted aryl, and amount and at an interval that results in the desired treatment C7-Carylalkyl esters of the compounds of the invention. of or improvement in the disorder or condition being treated. The present invention also relates to the cosmetologically Although methods and materials similar or equivalent to and pharmaceutically acceptable acid addition and base salts 55 those described herein can be used in the practice or testing of of any of the aforementioned compounds of formulae I-VIIb. the invention, preferred methods and materials are described The acids which are used to prepare the pharmaceutically below. The materials, methods, and examples are illustrative acceptable acid addition salts of the aforementioned base only and not intended to be limiting. Other features and compounds of this invention are those which form non-toxic advantages of the invention will be apparent from the detailed acid addition salts, i.e., salts containing pharmacologically 60 description, examples, and the claims. acceptable anions, such as the hydrochloride, hydrobromide, Rational Drug Design hydroiodide, nitrate, Sulfate, bisulfate, phosphate, acid phos Compounds identified by the methods of the invention or phate, acetate, lactate, citrate, acid citrate, tartrate, bitartrate, compounds disclosed herein may serve as the basis for Succinate, maleate, fumarate, gluconate, Saccharate, ben molecular modeling techniques for the design of chemical Zoate, methanesulfonate, ethanesulfonate, benzenesulfonate, 65 analogs that are more effective. For example, chemical ana p-toluenesulfonate and pamoate (i.e., 1,1-methylene-bis-(2- logs of any of the compounds listed herein can be created hydroxy-3-naphthoate)) salts. using these or other modeling techniques. Examples of US 8,563,754 B2 29 30 molecular modeling systems are the CHARM (Polygen Cor unpleasant odor resulting from the decomposition of human poration, Waltham, Mass.) and QUANTA (Molecular Simu Sweat by bacteria. Specific compositions prepared for use as lations Inc., San Diego, Calif.) programs. CHARM performs antiperspirants and/or deodorants will include an active the energy minimization and molecular dynamics functions. ingredient that is often known as an “antiperspirant aluminum QUANTA performs the construction, graphic modeling and salt.” As used herein, the term “antiperspirant aluminum salt” analysis of molecular structure, and allows interactive con means any salt or any aluminum complex that has the effect of struction, modification, visualization, and analysis of the reducing or limiting the flow of Sweat. Numerous aluminum behavior of molecules with each other. salts are known in the art, and the following discussion offers For example, compounds of the present invention can fur a non-limiting review. ther be used to design more effective analogs using modeling 10 packages such as Ludi, Insight II, C-Minimizer and Affinity Aluminum salts that may be used include aluminum halo (Molecular Simulations Inc., San Diego, Calif.). A particu hydrates; aluminum zirconium halohydrates; and complexes larly preferred modeling package is MacroModel (Columbia of Zirconium hydroxychloride and aluminum hydroxychlo University, New York, N.Y.). ride with an amino acid, such as those commonly known as The compounds of the present invention can further be 15 “ZAG complexes.” for example, as described in U.S. Pat. No. used as the basis for developing a rational combinatorial 3,792,068, the disclosure of which is incorporated herein by library. Such a library can also be screened to identify more reference in its entirety. effective compounds. While the nature of the combinatorial Specific aluminum salts include aluminum chlorohydrate library is dependent on various factors such as the particular in activated or unactivated form, aluminum chlorohydrex, compound chosen from the preferred compounds of the aluminum chlorohydrex polyethylene glycol complex, alu present invention to form the basis of the library, as well as the minum chlorohydrex propylene glycol complex, aluminum desire to synthesize the library using a resin, it will be recog dichlorohydrate, aluminum dichlorohydrex polyethylene nized that the compounds of the present invention provide glycol complex, aluminum dichlorohydrex propylene glycol requisite data Suitable for combinatorial design programs complex, aluminum sesquichlorohydrate, aluminum ses such as C-QSAR (Molecular Simulations Inc., San Diego, 25 quichlorohydrex polyethylene glycol complex, aluminum Calif.). sesquichlorohydrex propylene glycol complex, and alumi Methods of Inhibiting Skin Darkening num sulfate buffered with sodium aluminum lactate. Also As stated above, the compounds of the invention can be included are aluminum zirconium double salts such as alu used to treat animals or, preferably, humans that have dis minum zirconium octachlorohydrate, aluminum zirconium eases, conditions, or disorders that may be caused at least in 30 pentachlorohydrate, aluminum Zirconium tetrachlorohy part, by the production or overproduction of melanin. Such drate, and aluminum Zirconium trichlorohydrate. diseases, conditions, or disorders include those that can be Complexes of zirconium hydroxychloride and of alumi characterized by discolorations of the skin or hair such as, for num hydroxychloride with an amino acid are generally example, hyperpigmentation caused by inflammation or from known as ZAG when the amino acid is glycine. ZAG com diseases such as melasma, or brown spots such as “cafe au 35 plexes include aluminum zirconium octachlorohydrex gly lait' macules. cine, aluminum zirconium pentachlorohydrex glycine, alu For the purposes of this application, the terms “treatment, minum zirconium tetrachlorohydrex glycine, and aluminum “therapeutic use”, and “medicinal use’ shall refer to any and Zirconium trichlorohydrex glycine complexes. For example, all uses of the compositions of the invention which remedy a aluminum chlorohydrate in activated or unactivated form disease state or one or more symptoms, or otherwise prevent, 40 may be used. hinder, or retard, the progression of disease or one or more The antiperspirant aluminum salts may be present in the other undesirable symptoms in any way whatsoever. compositions of the invention in an amount ranging from The invention further provides methods and pharmaceuti about 0.5% to 25% by weight relative to the total weight of the cal compositions for inhibiting skin darkening comprising the composition. Zinc gluconate may be present in the composi use of the present compounds either alone or in combination 45 tions in an amount ranging from about 0.1% to 10% by with other, like-acting agents. weight, such as from 0.1% to 7% by weight, relative to the Personal Care Products and Applications total weight of the composition. In addition to pharmaceutical uses, and in a particular In order to provide a composition effective for antiperspi embodiment of the invention, the compounds, compositions rant purposes, it is preferred that the aluminum salt is present and methods are intended for use in personal care topical 50 in the composition of the invention in amounts corresponding products that can include the skin darkening inhibitor com to a total aluminum content of up to 3 gram atoms of Al per pounds. Such products include antiperspirant and deodorant kilogram of composition, in particular from 1.0 to 2.0 gram compositions, the preparation and composition of which are atoms Alper kg composition. illustrated in U.S. Pat. No. 7,504,091, the disclosure of which The carrier or carriers in which the antiperspirant alumi is incorporated herein by reference in its entirety. Thus for 55 num salt is dissolved and/or dispersed may be any of the example, a representative antiperspirant includes the active carriers traditionally used for incorporation into antiperspi ingredient, a carrier that may be solid or liquid, and that is rant compositions. Thus, the carrier may be a liquid, a gel, a generally water-immiscible, and other additives such as gel semisolid or a powder. Liquid carriers may be alcohols, gly lants, perfumes, colorants and the like. cols, fats, fatty acid esters, fatty acids, paraffins, liquid poly In a particular aspect, the present invention comprises the 60 mers (such as silicone oil), for example ethyl alcohol, isopro incorporation of the present skin darkening inhibitor com pyl myristate, glycerine, propylene glycol, etc. as well as pounds into personal care products such as deodorants, and mixtures thereof. A gel carrier may be analcohol or another of the preparation of Such products with the skin darkening the above mentioned liquid carriers such as ethyl alcohol inhibitor compounds included therein. Generally, personal containing a cellulose derivative Such as hydroxypropyl cel care products such as antiperspirant and deodorant composi 65 lulose. A semisolid carrier may be a polyglycol, a paraffin (for tions have as their function and objective, to reduce the flow example Vaseline), fats, or any of the above mentioned liquids of Sweat and to mask, absorb, improve and/or reduce the containing a polymer Such as liquid paraffin containing dis US 8,563,754 B2 31 32 solved polyethylene (marketed under the trade name Plasti Non-volatile emollient oils that may be used in the com base). A solid carrier may be talc, starch, kaolin etc. positions include hydrocarbon-based derivatives; mineral Deodorant compositions may be prepared in a variety of oils; fatty alcohols; esters of C-Cs alcohols with C-Cls forms depending upon the particular end use or application, acids; esters of benzoic acid with C-C alcohols and mix Such as for use as cosmetic product. The deodorant compo tures thereof C-C polyols, for example, glycerol, propy sitions may thus be prepared as lotions, creams or fluid gels lene glycol, and Sorbitol; and polyalkylene glycol polymers. distributed as an aerosol spray, in a pump-dispenserbottle, as The emollient oils may be present in the composition in an a roll-on, in the form of thick creams distributed in tubes or a amount ranging from 1% to 50% by weight, for example, grille, in the form of wands (sticks). The compositions thus from 5% to 40% by weight, relative to the total weight of the prepared may include ingredients generally used in products 10 composition. of this type, that are well known to those of skill in the art, The deodorant compositions may further comprise at least Such ingredients however, chosen on the basis that they do not one additional deodorant active agent, for example, bacterio interfere with the aluminum salt and the Zinc gluconate static agents and bactericidal agents such as 2,4,4-trichloro described above. 2'-hydroxydiphenyl ether (Triclosan), 2,4-dichloro-2'-hy The deodorant compositions provided herein may option 15 droxydiphenyl ether, 3',4',5'-trichlorosalicylanilide, 1-(3',4'- ally comprise at least one aqueous phase. They may be for dichlorophenyl)-3-(4-chlorophenyl)urea (Triclocarban), and mulated as aqueous lotions, water-in-oil emulsions, oil-in 3.7.11-trimethyldodeca-2.5,10-trienol (Farnesol); quater water emulsions, or as multiple emulsions such as oil-in nary ammonium salts, for example, cetyltrimethylammo water-in-oil and water-in-oil-in-water triple emulsions. Such nium salts and cetylpyridinium salts; chlorhexidine and salts emulsions are known and described, for example, by C. F. Fox thereof diglyceryl monocaprate, diglyceryl monolaurate, in “Cosmetics and Toiletries, November 1986, Vol. 101, and glyceryl monolaurate; and polyhexamethylene biguanide pages 101-112. salts. The aqueous phase of these compositions generally com At least one suspension agent may be used to improve the prises water and generally at least one water-soluble or water homogeneity of the compositions. Suspension agents include miscible solvent. Water-soluble and water-miscible solvents 25 hydrophobic-modified montmorillonite clays, for example, include short-chain monoalcohols, such as C-C monoalco hydrophobic-modified bentonites and hectorites. Examples hols, for example ethanol and isopropanol; as well as diols include stearalkonium bentonite (CTFA name, product of and polyols, for example, ethylene glycol, 1,2-propylene gly reaction of bentonite and the quaternary ammonium Stear col. 1,3-butylene glycol, hexylene glycol, diethylene glycol, alkonium chloride). Such as the commercial product sold dipropylene glycol, 2-ethoxyethanol, diethylene glycol 30 under the name Tixogel MP 250 by Sud Chemie Rheologi monomethyl ether, triethylene glycol monomethyl ether, and cals, United Catalysts Inc.; and the product disteardimonium sorbitol. For example, propylene glycol and glycerol may be hectorite (CTFA name, product of reaction of hectorite and of used. distearyldimonium chloride) sold under the name Bentone 38 The antiperspirant compositions may optionally be anhy or Bentone Gel by Elementis Specialities. The suspension drous. As used herein, the term “anhydrous” refers to a com 35 agents may be present in an amount ranging from 0.1% to 5% position with a free or added water content of less than 3% by by weight, for example from 0.2% to 2% by weight, relative weight, for example with an added water content of less than to the total weight of the composition. 1% by weight, relative to the total weight of the composition. The compositions may optionally further comprise at least The compositions may optionally comprise at least one one filler, such as an organic powder. Fillers that may be used water-immiscible organic liquid phase. This phase generally 40 in the compositions include organic powders. As used herein, comprises at least one hydrophobic compound that renders the term “organic powder” means any solid that is insoluble in the phase water-immiscible. The water-immiscible organic the medium at room temperature (25°C.). liquid phase is liquid (in the absence of a structuring agent) at Organic powders that may be used in the compositions room temperature (25° C.) The water-immiscible organic include polyamide particles such as those sold under the liquid phase generally comprises an oil or mixture of oils and 45 name Orgasol by Atochem; polyethylene powders; micro comprises at least 80% of compounds with a vapor pressure spheres based on acrylic copolymers, such as those made of not exceeding 4 kPa (30 mmHg) at 25°C. ethylene glycol dimethacrylate/lauryl methacrylate copoly The water-immiscible organic liquid phase may optionally mer, sold by Dow Corning under the name Polytrap; polym comprise at least one volatile or non-volatile, silicone-based ethyl methacrylate microspheres, sold under the name Micro or hydrocarbon-based emollient oil. Suitable emollient oils 50 sphere M-100 by Matsumoto and under the name Covabead include those described in U.S. Pat. Nos. 4,822,596 and LH85 by Wackherr; ethylene-acrylate copolymer powders, 4,904,463, the entire disclosures of which are incorporated for example, those sold under the name Flobeads by Sumi herein by reference. tomo Seika Chemicals; expanded powders such as hollow As is known in the art, Volatile silicones are compounds microspheres and microspheres formed from a terpolymer of that are volatile at room temperature. Volatile silicones 55 vinylidene chloride, of acrylonitrile and of methacrylate and include cyclic and linear Volatile dimethylsiloxane silicones sold under the name Expancel by Kemanord Plast under the with chains comprising from 3 to 9 silicone-based residues. references 551 DE 12 (particle size of about 12 um and Cyclomethicones D4, D5, and D6 may be used. density of 40kg/m),551 DE 20(particle size of about 30 um Correspondingly, non-volatile silicones are compounds and a density of 65 kg/m) and 551 DE 50 (particle size of with a low vapor pressure at room temperature. Non-volatile 60 about 40 um), and the microspheres sold under the name silicones include polyalkylsiloxanes, such as polyalkylsilox Micropearl F 80 ED by Matsumoto; powders of natural anes, for example linear polydimethylsiloxanes and dimethi organic materials such as starch powders, for example, of cones, sold by Dow Corning under the name “Dow Corning corn Starch, wheat starch, and rice starch, which may or may 245 Fluid;' polyalkylarylsiloxanes, such as polymethylphe not be crosslinked, such as the starch powder crosslinked with nylsiloxanes sold by Dow Corning under the name “Dow 65 octenylsuccinate anhydride, sold under the name Dry-Flo by Corning 556 Fluid;' and polyether and siloxane copolymer, National Starch; silicone resin microbeads such as those sold for example, dimethicone copolyols. under the name Tospearl by Toshiba Silicone, for example, US 8,563,754 B2 33 34 Tospearl 240; amino acid powders such as the lauroyllysine The distribution means, which forms a part of the aerosol powder sold under the name Amihope LL-11 by Ajinomoto; device, generally comprises a distribution valve controlled by particles of wax microdispersion, which have mean sizes of a distribution head comprising a nozzle via which the aerosol less than 1 Jum, for example, ranging from 0.02 um to 1 um, composition is vaporized. The container comprising the pres and which comprise a wax or a mixture of waxes, such as the Surized composition may be opaque or transparent. It may be products sold under the name Aquacer by Byk Cera and made of glass, of polymeric material or of metal, optionally Aquacer 520 (mixture of synthetic and natural waxes), coated with a coat of protective varnish. Aquacer 514 and 513 (polyethylene wax), Aquacer 511 Cosmetic Applications (polymer wax), the products sold under the name Jonwax 120 The personal care application of the present invention by Johnson Polymer (mixture of polyethylene wax and par 10 extends to the use of the compounds, compositions and meth affin wax), and under the name Ceraflour 961 by Byk Cera ods of the current invention for cosmetic purposes. Cosmetic (micronized modified polyethylene wax); and mixtures applications for methods of the present invention include the thereof. topical application of compositions containing one or more The compositions may also include adjuvants useful for 15 compounds to prevent the alteration by darkening, of the personal care and cosmetic applications, that are chosen from visual appearance of skin or hair. Occurrences in the skin or waxes, softeners, antioxidants, opacifiers, stabilizers, mois hair of noticeable but undesired pigmentation Such as, from turizers, vitamins, fragrances, bactericides, preserving melanin overproduction, can be prevented using the methods agents, polymers, fragrances, thickeners, propellants, and of the present invention. Suitable formulations for these pur any other ingredient usually used informulations of this type. poses can be prepared by those skilled in the art, and Such As stated above, when the compositions are to be prepared details of preparation are considered within the scope of the in Solid form, a variety of known ingredients are included. For present invention. example, such ingredients include Waxes include animal, Methods of Administration fossil, plant, mineral, and synthetic waxes, for example, bees The compounds of the invention can be administered topi waxes, carnauba wax, candelilla wax, Sugarcane wax, Japan 25 cally, e.g., as patches, ointments, creams, gels, lotions, Solu wax, oZokerites, montan wax, microcrystalline waxes, paraf tions, foams, masks or transdermal administration. fins, silicone waxes, and resins. If in vivo use is contemplated, the composition is prefer The thickeners, which may be nonionic, include modified ably of high purity and substantially free of potentially harm and unmodified guar gums and celluloses, such as hydrox ful contaminants, e.g., at least National Food (NF) grade, ypropyl guar gum and cetylhydroxyethylcellulose, silicas, for 30 generally at least analytical grade, and preferably at least example, Bentone Gel MIO sold by NL Industries, and Vee gum Ultra sold by Polyplastic. pharmaceutical grade. To the extent that a given compound The compositions may optionally further comprise at least must be synthesized prior to use, Such synthesis or Subsequent one other agent for structuring or gelling the water-immis purification shall preferably result in a product that is sub cible organic liquid phase of the composition, such as linear 35 stantially free of any potentially contaminating toxic agents solid fatty alcohols and/or waxes; fatty acids and salts thereof, that may have been used during the synthesis or purification for example, Stearic acid, sodium Stearate, and 12-hydroxyS procedures. tearic acid; dibenzylidene alditols (DBS); lanosterol; N-acy Useful pharmaceutical dosage forms for administration of lamino acid derivatives; di- and tricarboxylic acid derivatives, the present compounds are described below. for example, alkyl-N,N'-dialkylsuccin-amides, e.g., dodecyl 40 The pharmaceutical compositions can be applied directly N,N'-dibutylsuccinamide; elastomeric polyorganosiloxanes to the skin. Alternatively, they can be delivered by various such as those described in PCT Patent Application No. WO transdermal drug delivery systems, such as transdermal 97/44010, the disclosure of which is incorporated herein in its patches as known in the art. For example, for topical admin entirety. istration, the active ingredient can beformulated in a solution, The compositions according may also be pressurized and 45 gel, lotion, ointment, cream, Suspension, foam, mask, paste, may be packaged in an aerosol device. Suitable and exem liniment, powder, tincture, aerosol, patch, or the like in a plary aerosol devices may comprise: (a) a container compris pharmaceutically or cosmetically acceptable form by meth ing a composition as defined above, (b) at least one propel ods well known in the art. The composition can be any of a lant, and (c) a means for distributing the composition. variety of forms common in the pharmaceutical or cosmetic The propellants generally used in products of this type, 50 arts for topical application to animals or humans, including which are well known to those skilled in the art, include, for Solutions, lotions, sprays, creams, ointments, salves, gels, example, dimethyl ether (DME) and volatile hydrocarbons etc., as described below. Preferred agents are those that are Such as n-butane, propane, and isobutane, and mixtures Viscous enough to remain on the treated area, those that do not thereof, optionally with at least one chlorohydrocarbon and/ readily evaporate, and/or those that are easily removed by or fluorohydrocarbon. Examples include the compounds sold 55 rinsing with water, optionally with the aid of soaps, cleansers by Dupont de Nemours under the names Freon(R) and and/or shampoos. Actual methods for preparing topical for Dymel(R), for example, monofluorotrichloromethane, difluo mulations are known or apparent to those skilled in the art, rodichloromethane, tetrafluorodichloroethane and 1,1-dif and are described in detail in Remington's Pharmaceutical luoroethane sold under the trade name Dymel 152 A by Sciences, 1990 (supra); and Pharmaceutical Dosage Forms Dupont. Carbon dioxide, nitrous oxide, nitrogen, and com 60 and Drug Delivery Systems, 6th ed., Williams & Wilkins pressed air may also be used as propellants. (1995). The composition comprising the deodorant active agents In order to enhance the percutaneous absorption of the and the propellants may be in the same compartment or in active ingredients, one or more of a number of agents can be different compartments in the aerosol container. The concen added in the topical formulations including, but not limited to, tration of propellant generally ranges from 5% to 95% by 65 dimethylsulfoxide, dimethylacetamide, dimethylformamide, pressurized weight, for example from 50% to 85% by weight, Surfactants, aZone, alcohol, acetone, propylene glycol and relative to the total weight of the pressurized composition. polyethylene glycol. In addition, physical methods can also US 8,563,754 B2 35 36 be used to enhance transdermal penetration Such as, e.g., by 99.9%, more preferably from about 90% to about 98%, and iontophoresis or sonophoresis. Alternatively, or in addition, most preferably from about 90% to about 95% of the com liposomes may be employed. position. Atopically applied composition of the invention contains a The carrier utilized in the compositions of the invention pharmaceutically effective amount of at least one of the com 5 can be in a wide variety of forms. These include emulsion pounds of the invention as described herein, and those ingre carriers, including, but not limited to, oil-in-water, water-in dients as are necessary for use as a carrier, Such as an emul oil, water-in-oil-in-water, and oil-in-water-in-silicone emul Sion, a cream, an ointment, an ophthalmic ointment, an sions, a cream, anointment, an ophthalmic ointment, an aque ous solution, a lotion oran aerosol. As will be understood by aqueous Solution, a lotion or an aerosol. Non-limiting the skilled artisan, a given component will distribute prima examples of such carriers are described in more detail below rily into either the water or oil/silicone phase, depending on and may be found in International Patent Publication WO the water solubility/dispersibility of the component in the 00/62742, published Oct. 26, 2000, U.S. Pat. No. 5,691,380 to composition. Mason et al., issued on Nov. 25, 1997 and U.S. Pat. No. Emulsions according to the present invention generally 5,968,528 to Deckner et al., issued on Oct. 19, 1999, U.S. Pat. 15 contain a pharmaceutically effective amount of an agent dis No. 4,139,619 to Chidsey, III, issued on Feb. 13, 1979 and closed herein and a lipid or oil. Lipids and oils may be derived U.S. Pat. No. 4,684,635 to Orentreich et al., issued on Aug. 4. from animals, plants, or petroleum and may be natural or 1987 which are incorporated herein by reference. Suitable synthetic (i.e., man-made). Preferred emulsions also contain pharmaceutical carriers are further described in Remington's a humectant. Such as glycerin. Emulsions will preferably Pharmaceutical Sciences, 17th ed., Mack Publishing Com further contain from about 1% to about 10%, more preferably pany, Easton, Pa. (1990) a standard reference text in this field. from about 2% to about 5%, of an emulsifier, based on the The pharmaceutical compositions of the invention may weight of the carrier. Emulsifiers may be nonionic, anionic or also include optional components. Such optional components cationic. Suitable emulsifiers are described in, for example, should be suitable for application to keratinous tissue, that is, U.S. Pat. No. 3,755,560, issued to Dickert, et al. Aug. 28, when incorporated into the composition, they are Suitable for 25 1973: U.S. Pat. No. 4,421,769, issued to Dixon, et al. Dec. 20, use in contact with human keratinous tissue without undue 1983; and McCutcheon's Detergents and Emulsifiers, North toxicity, incompatibility, instability, allergic response, and American Edition, pages 317-324 (1986). the like within the scope of Sound medical judgment. In The emulsion may also contain an anti-foaming agent to addition, Such optional components are useful provided that minimize foaming upon application to the keratinous tissue. they do not unacceptably alter the benefits of the active com 30 Anti-foaming agents include high molecular weight silicones pounds of the invention. The CTFA Cosmetic Ingredient and other materials well known in the art for such use. Handbook, Second Edition (1992) describes a wide variety of Suitable emulsions may have a wide range of viscosities, non-limiting cosmetic and pharmaceutical ingredients com depending on the desired product form. Exemplary low vis monly used in the skin care industry, which are suitable for cosity emulsions, which are preferred, have a viscosity of use in the compositions of the present invention. Examples of 35 about 50 centistokes or less, more preferably about 10 cen these ingredient classes include: abrasives, absorbents, aes tistokes or less, most preferably about 5 centistokes or less. thetic components such as fragrances, pigments, coloringS/ The emulsion may also contain an anti-foaming agent to colorants, essential oils, skin sensates, astringents, etc. (e.g., minimize foaming upon application to the keratinous tissue. clove oil, menthol, camphor, eucalyptus oil, eugenol, menthyl Anti-foaming agents include high molecular weight silicones lactate, witch hazel distillate), anti-acne agents, anti-caking 40 and other materials well known in the art for such use. agents, antifoaming agents, antimicrobial agents (e.g., One type of emulsion is a water-in-silicone emulsion. iodopropylbutylcarbamate), antioxidants, binders, biologi Water-in-silicone emulsions contain a continuous silicone cal additives, buffering agents, bulking agents, chelating phase and a dispersed aqueous phase. Preferred water-in agents, chemical additives, colorants, cosmetic astringents, silicone emulsions of the present invention comprise from cosmetic biocides, denaturants, drug astringents, external 45 about 1% to about 60%, preferably from about 5% to about analgesics, film formers or materials, e.g., polymers, for aid 40%, more preferably from about 10% to about 20%, by ing the film-forming properties and Substantivity of the com weight of a continuous silicone phase. The continuous sili position (e.g., copolymer of eicosene and vinyl pyrrolidone), cone phase exists as an external phase that contains or Sur opacifying agents, pH adjusters, propellants, reducing rounds the discontinuous aqueous phase described hereinaf agents, sequestrants, skin-conditioning agents (e.g., humec 50 ter. tants, including miscellaneous and occlusive), skin soothing The continuous silicone phase may contain a polyorga and/or healing agents (e.g., panthenol and derivatives (e.g., nosiloxane oil. A preferred water-in-silicone emulsion sys ethyl panthenol), aloe Vera, pantothenic acid and its deriva tem is formulated to provide an oxidatively stable vehicle for tives, allantoin, bisabolol, and dipotassium glycyffhizinate), delivery of a pharmaceutically effective amount of an agent skin treating agents, thickeners, and vitamins and derivatives 55 disclosed herein. The continuous silicone phase of these pre thereof. ferred emulsions comprises between about 50% and about In addition to the pharmaceutically effective amount of the 99.9% by weight of organopolysiloxane oil and less than anti-darkening compound or compounds disclosed herein, about 50% by weight of a non-silicone oil. In an especially topical compositions of the present invention also comprise a preferred embodiment, the continuous silicone phase com dermatologically acceptable carrier. The phrase "dermato 60 prises at least about 50%, preferably from about 60% to about logically acceptable carrier, as used herein, means that the 99.9%, more preferably from about 70% to about 99.9%, and carrier is suitable for topical application to the skin, i.e., even more preferably from about 80% to about 99.9%, poly keratinous tissue, has good aesthetic properties, is compatible organosiloxane oil by weight of the continuous silicone with the active agents of the present invention and any other phase, and up to about 50% non-silicone oils, preferably less components, and will not cause any safety or toxicity con 65 about 40%, more preferably less than about 30%, even more cerns. A safe and effective amount of carrier is from about preferably less than about 10%, and most preferably less than 50% to about 99.99%, preferably from about 80% to about about 2%, by weight of the continuous silicone phase. These US 8,563,754 B2 37 38 useful emulsion systems may provide more oxidative stabil Known or conventional emulsifying agents can be used in the ity over extended periods of time than comparable water-in composition, provided that the selected emulsifying agent is oil emulsions containing lower concentrations of the polyor chemically and physically compatible with essential compo ganosiloxane oil. Concentrations of non-silicone oils in the nents of the composition, and provides the desired dispersion continuous silicone phase are minimized or avoided alto 5 characteristics. Suitable emulsifiers include silicone emulsi gether so as to possibly further enhance oxidative stability of fiers, e.g., organically modified organopolysiloxanes, also the active compound of the invention in the compositions. known to those skilled in the art as silicone Surfactants, non Water-in-silicone emulsions of this type are described in U.S. silicon-containing emulsifiers, and mixtures thereof, known Pat. No. 5,691,380 to Mason et al., issued Nov. 25, 1997. by those skilled in the art for use in topical personal care The organopolysiloxane oil for use in the composition may 10 products. be volatile, non-volatile, or a mixture of volatile and non Useful emulsifiers include a wide variety of silicone emul volatile silicones. The term “nonvolatile' as used in this con sifiers. These silicone emulsifiers are typically organically text refers to those silicones that are liquid under ambient modified organopolysiloxanes, also known to those skilled in conditions and have a flash point (under one atmospheric of the art as silicone surfactants. Suitable emulsifiers are pressure) of or greater than about 100°C. The term “volatile' 15 described, for example, in McCutcheons, Detergents and as used in this context refers to all other silicone oils. Suitable Emulsifiers, North American Edition (1986), published by organopolysiloxanes can be selected from a wide variety of Allured Publishing Corporation; U.S. Pat. No. 5,011,681 to silicones spanning a broad range of Volatilities and Viscosi Ciotti et al., issued Apr. 30, 1991; U.S. Pat. No. 4,421,769 to ties. Examples of Suitable organopolysiloxane oils include Dixon et al., issued Dec. 20, 1983; and U.S. Pat. No. 3,755, polyalkylsiloxanes, cyclic polyalkylsiloxanes, and polyalky 560 to Dickert et al., issued Aug. 28, 1973. larylsiloxanes, which are known to those skilled in the art and Other preferred topical carriers include oil-in-water emul commercially available. sions, having a continuous aqueous phase and a hydrophobic, The continuous silicone phase may contain one or more water-insoluble phase (“oil phase') dispersed therein. non-silicone oils. Concentrations of non-silicone oils in the Examples of Suitable carriers comprising oil-in-water emul continuous silicone phase are preferably minimized or 25 sions are described in U.S. Pat. No. 5,073,371 to Turner, D.J. avoided altogether so as to further enhance oxidative stability et al., issued Dec. 17, 1991, and U.S. Pat. No. 5,073,372, to of the pharmaceutically effective agent in the compositions. Turner, D. J. et al., issued Dec. 17, 1991. An especially pre Suitable non-silicone oils have a melting point of about 25°C. ferred oil-in-water emulsion, containing a structuring agent, or less, under about one atmosphere of pressure. Examples of hydrophilic surfactant and water, is described in detail here non-silicone oils Suitable for use in the continuous silicone 30 inafter. phase are those well known in the chemical arts in topical A preferred oil-in-water emulsion comprises a structuring personal care products in the form of water-in-oil emulsions, agent to assist in the formation of a liquid crystalline gel e.g. mineral oil, vegetable oils, synthetic oils, semisynthetic network structure. Without being limited by theory, it is oils, etc. believed that the structuring agent assists in providing rheo Useful topical compositions of the present invention com 35 logical characteristics to the composition which contribute to prise from about 30% to about 90%, more preferably from the stability of the composition. The structuring agent may about 50% to about 85%, and most preferably from about also function as an emulsifier or surfactant. Preferred com 70% to about 80% of a dispersed aqueous phase. In emulsion positions of this invention comprise from about 0.5% to about technology, the term “dispersed phase' is a term well-known 20%, more preferably from about 1% to about 10%, most to one skilled in the art which means that the phase exists as 40 preferably from about 1% to about 5%, by weight of the Small particles or droplets that are suspended in and Sur composition, of a structuring agent. The preferred structuring rounded by a continuous phase. The dispersed phase is also agents of the present invention are selected from the group known as the internal or discontinuous phase. The dispersed consisting of stearic acid, palmitic acid, Stearyl alcohol, cetyl aqueous phase is a dispersion of Small aqueous particles or alcohol, behenyl alcohol, Stearic; acid, palmitic acid, the droplets Suspended in and Surrounded by the continuous sili 45 polyethylene glycol ether of Stearyl alcohol having an aver cone phase described hereinbefore. The aqueous phase can be age of about 1 to about 21 ethylene oxide units, the polyeth water, or a combination of water and one or more water ylene glycol ether of cetyl alcohol having an average of about soluble or dispersible ingredients. Nonlimiting examples of 1 to about 5 ethylene oxide units, and mixtures thereof. Such optional ingredients include thickeners, acids, bases, The preferred oil-in-water emulsions comprise from about salts, chelants, gums, water-soluble or dispersible alcohols 50 0.05% to about 10%, preferably from about 1% to about 6%, and polyols, buffers, preservatives, Sunscreening agents, col and more preferably from about 1% to about 3% of at least orings, and the like. one hydrophilic Surfactant which can disperse the hydropho The topical compositions of the present invention typically bic materials in the water phase (percentages by weight of the comprise from about 25% to about 90%, preferably from topical carrier). The Surfactant, at a minimum, must be hydro about 40% to about 80%, more preferably from about 60% to 55 philic enough to disperse in water. Suitable surfactants about 80%, water in the dispersed aqueous phase by weight of include any of a wide variety of known cationic, anionic, the composition. Zwitterionic, and amphoteric surfactants. See, McCutch The water-in-silicone emulsions of the present invention eons. Detergents and Emulsifiers, North American Edition preferably comprise an emulsifier. In a preferred embodi (1986), published by Allured Publishing Corporation; U.S. ment, the composition contains from about 0.1% to about 60 Pat. No. 5,011,681 to Ciotti et al., issued Apr. 30, 1991; U.S. 10% emulsifier, more preferably from about 0.5% to about Pat. No. 4,421,769 to Dixon et al. issued Dec. 20, 1983; and 7.5%, most preferably from about 1% to about 5%, emulsifier U.S. Pat. No. 3,755,560. The exact surfactant chosen depends by weight of the composition. The emulsifier helps disperse upon the pH of the composition and the other components and Suspend the aqueous phase within the continuous silicone present. Preferred are cationic surfactants, especially dialkyl phase. 65 quaternary ammonium compounds, examples of which are A wide variety of emulsifying agents can be employed described in U.S. Pat. No. 5,151,209 to McCall et al. issued herein to form the preferred water-in-silicone emulsion. Sep. 29, 1992; U.S. Pat. No. 5,151,210 to Steuri et al. issued US 8,563,754 B2 39 40 Sep. 29, 1992; U.S. Pat. No. 5,120,532; U.S. Pat. No. 4,387, about 2% of a thickening agent; and a pharmaceutically effec 090; U.S. Pat. No. 3,155,591; U.S. Pat. No. 3,929,678; U.S. tive amount of an agent described herein. Pat. No. 3,959,461; McCutcheon's, Detergents & Emulsifiers By way of non-limiting example, 1000 g of topical cream (North American edition 1979) M.C. Publishing Co.; and is prepared from the following types and amounts of ingre Schwartz, et al., Surface Active Agents. Their chemistry and dients: a pharmaceutically effective amount of an agent dis Technology, New York: Interscience Publishers, 1949. closed herein, tegacid regular (150 g) (a self-emulsifying Alternatively, other useful cationic emulsifiers include glyceryl monostearate from Goldschmidt Chemical Corpo amino-amides. Nonlimiting examples of these cationic emul ration, New York, N.Y.), polysorbate 80 (50 g), spermaceti sifiers include stearamidopropyl PG-dimonium chloride (100 g), propylene glycol (50 g), methylparaben (1 g), and phosphate, behenamidopropyl PG dimonium chloride, 10 deionized water in sufficient quantity to reach 1000 gm. The Stearamidopropyl ethyldimonium ethosulfate, Stearami tegacid and spermaceti are melted togetherata temperature of dopropyl dimethyl (myristyl acetate) ammonium chloride, 70-80° C. The methylparaben is dissolved in about 500 g of Stearamidopropyl dimethyl cetearyl ammonium tosylate, water and the propylene glycol, polysorbate 80, and 6-amino Stearamidopropyl dimethyl ammonium chloride, Stearami 1.2-dihydro-1-hydroxy-2-imino-4-piperidinopyrimidine dopropyl dimethyl ammonium lactate, and mixtures thereof. 15 free base are added in turn, maintaining a temperature of A wide variety of anionic Surfactants are also useful herein. 75-80°C. The methylparaben mixture is added slowly to the See, e.g., U.S. Pat. No. 3,929.678, to Laughlin et al., issued tegacid and spermacetimelt, with constant stirring. The addi Dec. 30, 1975. In addition, amphoteric and Zwitterionic sur tion is continued for at least 30 minutes with additional stir factants are also useful herein. ring until the temperature has dropped to 40-45° C. Finally, The preferred oil-in-water emulsion comprises from about sufficient water is added to bring the final weight to 1000 g 25% to about 98%, preferably from about 65% to about 95%, and the preparation stirred to maintain homogeneity until more preferably from about 70% to about 90% water by cooled and congealed. weight of the topical carrier. By way of non-limiting example, 1000 g of a topical oint The hydrophobic phase is dispersed in the continuous ment is prepared from the following types and amounts of aqueous phase. The hydrophobic phase may contain water 25 ingredients: a pharmaceutically effective amount of an agent insoluble or partially soluble materials such as are known in disclosed herein, Zinc oxide (50 g), calamine (50 g), liquid the art, including but not limited to the silicones described petrolatum (heavy) (250 g), wool fat (200 g), and enough herein in reference to silicone-in-water emulsions, and other white petrolatum to reach 1000 g. Briefly, the white petrola oils and lipids such as described above in reference to emul tum and wool fat are melted and 100 g of liquid petrolatum sions. 30 added thereto. The pharmaceutically effective amount of an The topical compositions of the Subject invention, includ agent disclosed herein, Zinc oxide, and calamine are added to ing but not limited to lotions and creams, may comprise a the remaining liquid petrolatum and the mixture milled until dermatologically acceptable emollient. Such compositions the powders are finely divided and uniformly dispersed. The preferably contain from about 2% to about 50% of the emol mixture is stirred into the white petrolatum, melted and lient. As used herein, "emollient” refers to a material useful 35 cooled with stirring until the ointment congeals. for the prevention or relief of dryness, as well as for the By way of non-limiting example, 1000 g of an ointment, protection of the skin. A wide variety of suitable emollients e.g., an ophthalmic ointment, containing a pharmaceutically are known and may be used herein. See, e.g., Sagarin, Cos effective amount of an agent disclosed herein is prepared metics, Science and Technology, 2nd Edition, Vol. 1, pp. 3243 from the following types and amounts of ingredients: a phar (1972), which contains numerous examples of materials Suit 40 maceutically effective amount of an agent disclosed herein, able as an emollient. A preferred emollient is glycerin. Glyc light liquid petrolatum (250 g), wool fat (200g), and enough erin is preferably used in an amount of from or about 0.001 to white petrolatum to reach 1000 g. Briefly, the pharmaceuti or about 20%, more preferably from or about 0.01 to or about cally effective amount of an agent disclosed herein is finely 10%, most preferably from or about 0.1 to or about 5%, e.g., divided and added to the light liquid petrolatum. The wool fat 3%. 45 and white petrolatum are melted together, strained, and the Lotions and creams according to the present invention temperature adjusted to 45-50° C. The liquid petrolatum generally comprise a solution carrier system and one or more slurry is added, and the ointment stirred until congealed. emollients. Lotions typically comprise from about 1% to By way of non-limiting example, 1000 ml of an aqueous about 20%, preferably from about 5% to about 10% of emol Solution containing a pharmaceutically effective amount of lient; from about 50% to about 90%, preferably from about 50 an agent disclosed herein is prepared from the following types 60% to about 80% water; and a pharmaceutically effective and amounts of ingredients: a pharmaceutically effective amount of an agent described herein. A cream typically com amount of an agent disclosed herein, polyethylene glycol prises from about 5% to about 50%, preferably from about 4000 (120 g) myristyl-gamma-picolinium chloride (0.2 g), 10% to about 20% of emollient; from about 45% to about polyvinylpyrrolidone (1 g), and enough deionized water to 85%, preferably from about 50% to about 75% water; and a 55 reach 1000 milliliters. Briefly, the ingredients are dissolved in pharmaceutically effective amount of an agent described the water and the resulting solution is sterilized by filtration. herein. By way of non-limiting example, 1000 g oflotion contain Ointments of the present invention may comprise a simple ing a pharmaceutically effective amount of an agent disclosed carrier base of animal or vegetable oils or semi-solid hydro herein is prepared from the following types and amounts of carbons (oleaginous); absorption ointment bases which 60 ingredients: a pharmaceutically effective amount of an agent absorb water to form emulsions; or water soluble carriers, disclosed herein, N-methylpyrolidone (40 g), and enough e.g., a water Soluble solution carrier. Ointments may further propylene glycol to reach 1000 g. comprise a thickening agent, such as described in Sagarin, By way of non-limiting example, an aerosol containing a Cosmetics, Science and Technology, 2nd Edition, Vol. 1, pp. pharmaceutically effective amount of an agent disclosed 72-73 (1972), incorporated herein by reference, and/or an 65 herein is prepared from the following types and amounts of emollient. For example, an ointment may comprise from materials: a pharmaceutically effective amount of an agent about 2% to about 10% of an emollient; from about 0.1% to disclosed herein, absolute alcohol (4.37 g), Dichlorodifluo US 8,563,754 B2 41 42 roethane (1.43 g) and dichlorotetrafluoroethane (5.70 g). tional groups from undergoing undesired reactions. The Briefly, the pharmaceutically effective amount of an agent choice of a Suitable protecting group for a particular func disclosed herein is dissolved in the absolute alcohol and the tional group as well as Suitable conditions for protection and resulting solution filtered to remove particles and lint. This deprotection are well known in the art. For example, numer solution is chilled to about -30°C. Then, to this is added the chilled mixture of dichlorodifluoromethane and dichlorotet ous protecting groups, and their introduction and removal, are rafluoroethane. described in T. W. Greene and P. G. M. Wuts, Protecting Groups in Organic Synthesis, Second Edition, Wiley, New The following additional formulation examples illustrate York, 1991, and references cited therein. representative compositions that may be prepared in accor 10 dance with this invention. The present invention, however, is Example 1 not limited to the following compositions. Formulation 1 Screening of Compounds in Cultured Murine 15 Melanocytes Liquid The Spectrum Collection library consisting of 2000 drug A compound of the invention (125 mg) may be admixed compounds or natural products represents a source for the with Sucrose (1.75 g) and Xanthan gum (4 mg) and the result ant mixture may be blended, passed through a No. 10 mesh identification of compounds useful in the present invention. U.S. sieve, and then mixed with a previously made solution of The library may be screened to identify novel pigmentation microcrystalline cellulose and sodium carboxymethyl cellu inhibitors in cultured murine melanocytes (melan-a). Com lose (11:89, 50 mg) in water. Sodium benzoate (10 mg), pounds are dissolved in dimethylsulfoxide (DMSO) to a final flavor, and color could be diluted with water and added with 25 concentration of 10 mM. Screening is performed with cul stirring. Sufficient water may then be added to produce a total tured melanocytes in 24-well plates followed by melanin Volume of 5 mL. assay (see below). A minimum change of 50% in melanin formation is established as significant for a pigmentation inhibitor. DMSO may be used as a negative control and the Formulation 2 30 widely used depigmenting agent, hydroquinone, may be used as a positive control on every plate. Primary screening is Topical performed at a final concentration of 1 uM and potential Stearyl alcohol (250 g) and a white petrolatum (250 g) may candidates from the primary screening are reconfirmed in be melted at about 75° C. and then a mixture of a compound 35 duplicate at final concentrations of 1 and 5uM. of the invention (50 g) methylparaben (0.25 g), propylpara Melan-a cells are plated at 5x10" cells per well in 1 ml of ben (0.15 g), Sodium lauryl Sulfate (10 g), and propylene culture media in 24-well plates the day before adding the glycol (120 g) dissolved in water (about 370 g) could be library compounds. All compounds are added at the indicated added and the resulting mixture would be stirred until it 40 final concentrations. Cells are harvested after 72 hours of congeals. incubation, and the melanin assay is performed. For further test and mechanism of action studies, the com General Methods of Preparation pounds may be purchased from Sigma, MicroSource or other 45 known Suppliers. The compounds are dissolved in dimethyl The compounds of this invention are generally available sulfoxide (DMSO) to a final concentration of 10 mM, and are and can be purchased from commercial Sources and tested for tested for their effect on melanin synthesis at the indicated their activities. The test compounds which are not commer final concentrations. cially available can be prepared from readily available start 50 ing materials using various general methods and procedures Example 2 known in the art. For example, the compounds may be syn thetically prepared from known starting materials by conven tional laboratory procedures and protocols. Likewise, those Melanin Assay compounds that may be found in existing natural materials 55 may be isolated and/or purified by known procedures, to For the primary and secondary screening, cells were har attain the requisite concentration and content of the active, to vested and dissolved in 200ul of 2N NaOH in 20% DMSO at be efficacious when formulated into compositions in accor 70° C. A 180-ul aliquot of the resulting solution was mea dance with the present invention. Such preparations may also sured for absorbance at 490 nm. be described as formulations or materials that are enriched for 60 A series of structurally related compounds was then tested the particular compound(s) of the invention, and the present in this screen, to identify compounds that inhibit skin dark invention embraces such preparations within its scope. ening. The compounds, their structures, inhibition data Additionally, as will be apparent to those skilled in the art expressed as % of control remaining, are shown in Table 1, with respect to the methods of preparation of the compounds 65 below. In addition, dose-response data as to Scandenin, robus of the invention involving organic synthesis, conventional tic acid methyl ether, and coumophos are also presented in protecting groups may be necessary to prevent certain func FIGS 1-4. US 8,563,754 B2

TABLE 1.

Skin Darkening Inhibition Data

% of control % of control melanin melanin remaining remaining after after treatment treatment (a) ID Name Structure (a) 1 M 5 M 1 PRENYLETIN HO 79 8O

)- ODOCl. O O 2 OBLIQUIN 84 95

O O O

3 DIHYDRO-OBLIQUIN 81 81 O

th O DOCl.O O 4 FRAXIDINMETHYL 1. 87 95 ETHER O O O O

N

5 XANTHYLETIN 99 110

6 IMPERATORIN / N 91 96

O O O

O

2

7 PACHYRREHIZIN 75 71

8 HERNLARIN 84 81 US 8,563,754 B2 45 46 TABLE 1-continued

Skin Darkening Inhibition Data

% of control % of control melanin melanin remaining remaining after after treatinent treatment (c) ID Name Structure (a) 1 M 5 M

ROBUSTIC ACID 69 16 METHYLETHER

10 ROBUSTIC ACID 91 93

11 KUHLMANNIN o1 81 84 O

HO 21

12 SPHONDIN O 89 101

O

O On 13 ISOPIMPINELLIN No 86 95 N

O

O US 8,563,754 B2 47 48 TABLE 1-continued

Skin Darkening Inhibition Data

% of control % of control melanin melanin remaining remaining after after treatment treatment (a) ID Name Structure (a) 1 M 5 M

14 PIMPINELLIN 76 109

15 ISOBERGAPTENE O 86 108 c \

/ O O \

16 SCANDENIN 90 64

17 HYMECROMONE 96 93 METHYLETHER N

No O O

18 BERGAPTENE 1. 1OO 93

19 COUMOPHOS l 81 48 C O N Sns 1 No O O US 8,563,754 B2 49 50 TABLE 1-continued

Skin Darkening Inhibition Data

% of control % of control melanin melanin remaining remaining after after treatinent treatment (c) ID Name Structure (a) 1 M 5 M

METHOXSALEN 120 125

21 NOVOBIOCIN 90 94 SODIUM

i

22 TRIOXSALEN 90 118

23 CITROPTEN 86 97

24 4-METHYLESCULETIN HO 88 1OO

HO

25 ESCULETIN HO 87 88

HO US 8,563,754 B2 51 52 TABLE 1-continued Skin Darkening Inhibition Data

% of control % of control melanin melanin remaining remaining after after treatment treatment (a) Name Structure (a) 1 M 5 M

AESCULIN 70 84

LOMATIN 89 85

SELINIDIN 85 82

PTERYXIN 93 101

DIHYDROSAMIDIN 106 88

MARMESIN N 89 97

HO O O O US 8,563,754 B2 53 54 TABLE 1-continued Skin Darkening Inhibition Data

% of control % of control melanin melanin remaining remaining after after treatment treatment (a) ID Name Structure (a) 1 M 5 M

32 MARMESINACETATE N 77 92

III. I.

N. O O O

34 PEUCEDANIN NO 83 84 / N

O O O

35 LONCHOCARPIC 84 81 ACID

36 DERRUSNIN 81 87

37 4- OH 83 88 METHYLDAPHINETIN HO O O

21

38 SCOPOLETIN 77 83 O N

HO O O

39 FRAXETIN 84 89 O N

HO O O

OH US 8,563,754 B2 55 56 TABLE 1-continued Skin Darkening Inhibition Data % of control % of control melanin melanin remaining remaining after after treatment treatment (a) ID Name Structure (a) 1 M 5 M 40 FELAMIDIN NO 97 88

O O O

As the assay above compares the accumulation of melanin three tissues under each treatment condition are taken out, in cells treated only with carrier (DMSO) versus those treated 2O and one was used for histological studies and the other two are with 1 and 5 uM test compound, it can be seen that com used for the melanin assay. The same protocol is followed pounds 7, 9, 16, 19 and 33 show a robust dose dependent with the MEL-B samples after 13 days treatment and ability to block melanin accumulation, thus leading to the MEL-A after either 13 or 16 days treatments. discovery of these compounds as agents capable of blocking For the histological studies: skin darkening. 25 Procedure 1: the effects of the inventive compounds or extract on melanin synthesis in MEL-A or B are evaluated by light Example 3 microscopy (views from the top surface of the tissue). Procedure 2: the distribution of melanin in the treated MelanoDerm Pigmentation Assay 30 MEL-A or B is accessed by image analysis using Fontana Masson stained histological sections (views from the side of The compounds of the invention may be tested in the Mel the tissue). anoDermTM pigmentation assay, to confirm and demonstrate For the melanin tissues, the melanin content of each indi their activity as inhibitors in a setting that replicates in vivo vidual tissue is determined, and the final data show the aver conditions. MelanoDermTM, made by Mattek Corp., is a 35 age melanin content of 2 tissues treated under identical con viable reconstituted three-dimensional human skin equiva ditions. lent containing normal melanocytes and keratinocytes that While certain of the preferred embodiments of the present are derived from African-American (MEL-B), Asian (MEL invention have been described and specifically exemplified A) or Caucasian (MEL-C) donors. Both MEL-A and MEL-B 40 above, it is not intended that the invention be limited to such tissues are used in the study, and they are maintained in the embodiments. Various modifications may be made thereto NMM-113 medium as recommended by the manufacturer. without departing from the scope and spirit of the present The test compound is dissolved in 30% ethanol: 70% pro invention, as set forth in the following claims. pylene glycol to a final concentration of 1.0 mM (equal to From the foregoing description, Various modifications and 356.6 g/ml), and this is maintained constant and used on all 45 changes in the compositions and methods of this invention samples tested. A 25ul of its aliquot is applied topically to the will occur to those skilled in the art. All such modifications MelanoDermTM tissue (MEL-B) on Days 0, 1, 3, 6, 8 and 10. coming within the scope of the appended claims are intended The MelanoDermTM tissues are fed every other day with 5 ml to be included therein. fresh NMM-113. Prior to each application, the tissues are 50 All publications, including but not limited to patents and washed with 1 ml PBS to remove any residual test compound. patent applications, cited in this specification are herein Tissues are fixed on Days 10 and 13 for microscopic analysis incorporated by reference as if each individual publication and histological evaluation. In addition, duplicate tissues are were specifically and individually indicated to be incorpo frozen on Days 10 and 13 for the melanin assay. rated by reference herein as though fully set forth. Similar experiments may be performed on Asian skin 55 The chemical names of compounds given in this applica equivalent (MEL-A) except: the treatments are applied on tion were generated using various commercially available Days 0, 1, 3, 6, 8, 10 and 13. Tissues are taken out on Days 13 chemical naming software tools including MDL's ISIS Draw and 16 for the various assays. 30% ethanol: 70% propylene AutonomSoftware tool, and were not verified. Particularly, in glycol is used as a negative control and the well-known pig the event of inconsistency, the depicted structure governs. mentation inhibitor, arbutin (at concentration of 3 mg/ml), 60 may be used as a positive control. The experiments are repeated twice on both MEL-A and What is claimed is: MEL-B tissues from different lots to make sure that the 1. A method for preventing the hyperpigmentation or results are reproducible (study 1 or 2). For each experiment, undesired darkening of skin comprising administering to a six tissues are treated with a compound or extract of the 65 subject in need thereof an effective amount of either lon invention, and six were treated with vesicle (30% ethanol: chocarpic acid or a compound of formulae IIIa, IIIb, IIIc or 70% PEG) or arbutin if applicable. For MEL-B, on day 10, IIId: US 8,563,754 B2 57 58

IIIa IV R8 R8

R O O O 5 R O O O R7b R6a 2 R3, I 25as R5 R4 10 R5 R4 IIIb. or a pharmaceutically acceptable salt, Solvate or prodrug thereof, and stereoisomers, tautomers and isotopic vari 15 ants thereof; and wherein R" is selected from H. halo, hydroxy, alkoxy, alkenyloxy, substituted or unsubstituted alkyl, substituted or unsub

IIIc stituted alkenyl, and substituted or unsubstituted phenyl: 2O R is selected from H, halo, hydroxy, alkoxy, alkenyloxy, substituted or unsubstituted alkyl, substituted or unsub stituted alkenyl, and substituted or unsubstituted phenyl: R is selected from halo, substituted or unsubstituted alkyl, 25 substituted or unsubstituted alkenyl, phenyl, 3,4-dihy droxyphenyl, 4-methoxyphenyl, or 3,4-dimethoxyphe O nyl: R is selected from H. halo, hydroxy, alkoxy, alkenyloxy,

III 30 substituted or unsubstituted alkyl, substituted or unsub stituted alkenyl, or substituted or unsubstituted phenyl: and each R" and R' is independently selected from H, alkyl, or alkenyl. 3. A method for preventing the hyperpigmentation or 35 undesired darkening of skin comprising administering to a subject in need thereof an effective amount of either lon chocarpic acid or a compound of formulae Va, Vb, Vc, or Vd:

40 or a pharmaceutically acceptable salt, Solvate or prodrug Wa thereof, and stereoisomers, tautomers and isotopic vari ants thereof, and wherein R is selected from H. halo, hydroxy, alkoxy, alkenyloxy, 45 substituted or unsubstituted alkyl, substituted or unsub stituted alkenyl, and substituted or unsubstituted phenyl: R and R are independently selected from H, halo, hydroxy, alkoxy, alkenyloxy, Substituted or unsubsti Vb tuted alkyl, substituted or unsubstituted alkenyl, and 50 substituted or unsubstituted phenyl: R is selected from halo, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, phenyl, 3,4-dihy droxyphenyl, 4-methoxyphenyl, or 3,4-dimethoxyphe- 55 nyl: R is selected from H, halo, hydroxy, alkoxy, alkenyloxy,

WC substituted or unsubstituted alkyl, substituted or unsub stituted alkenyl, or substituted or unsubstituted phenyl: and 60 each R', R'' and R' is independently selected from H, alkyl, hydroxyalkyl, or alkenyl. 2. A method for preventing the hyperpigmentation or undesired darkening of skin comprising administering to a 65 subject in need thereofan effective amount of a compound of formula IV US 8,563,754 B2 59 60 -continued -continued

WId Vc

10

or a pharmaceutically acceptable salt thereof, and Stereoi or a pharmaceutically acceptable salt thereof, and stereoi Somers, tautomers and isotopic variants thereof, and Somers, tautomers and isotopic variants thereof, and 15 wherein wherein R is selected from halo, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, phenyl, 3,4-dihy R is selected from H. halo, hydroxy, alkoxy, alkenyloxy, droxyphenyl, 4-methoxyphenyl, or 3,4-dimethoxyphe substituted or unsubstituted alkyl, substituted or unsub nyl: stituted alkenyl, and substituted or unsubstituted phenyl: and R is selected from H. halo, hydroxy, alkoxy, alkeny R and R are independently selected from H, halo, loxy, substituted or unsubstituted alkyl, substituted or hydroxy, alkoxy, alkenyloxy, Substituted or unsubsti unsubstituted alkenyl, and substituted or unsubstituted tuted alkyl, substituted or unsubstituted alkenyl, and phenyl. substituted or unsubstituted phenyl: 5. A method for preventing the hyperpigmentation or undesired darkening of skin comprising administering to a R is selected from halo, substituted or unsubstituted alkyl, 25 substituted or unsubstituted alkenyl, phenyl, 3,4-dihy subject in need thereofan effective amount of a compound of droxyphenyl, 4-methoxyphenyl, or 3,4-dimethoxyphe formula VIIa: nyl: VIIa R is selected from H, halo, hydroxy, alkoxy, alkenyloxy, 30 substituted or unsubstituted alkyl, substituted or unsub stituted alkenyl, or substituted or unsubstituted phenyl. 4. A method for preventing the hyperpigmentation or undesired darkening of skin comprising administering to a subject in need thereofan effective amount of a compound of 35 formulae Via, VIb, VIc, or Vid OMe

WIa 40 or a pharmaceutically acceptable salt thereof, and Stereoi Somers, tautomers and isotopic variants thereof, and wherein Rare as in claim 1. 6. The method of claim 1, wherein the compound is robus tic acid methyl ether. 45 7. The method of claim 1, wherein the method comprises a step of contacting skin with a) a composition comprising a compound as defined in

WIb claim 1 in a sufficient amount to prevent the hyperpig mentation or undesired darkening of skin, and 50 b) an acceptable carrier. 8. A composition for preventing the hyperpigmentation or undesired darkening of skin comprising a pharmaceutically acceptable carrier and a pharmaceutically effective amount of a compound as defined in claim 1. 55 9. The composition of claim 7 wherein the carrier is a parenteral carrier, oral or topical carrier. WIC 10. A topical formulation, comprising a composition for cosmetic ordermatological use, said composition comprising a compound as defined in claim 1, and an acceptable carrier; 60 and wherein the cosmetic or dermatological use is associated with the prevention of the hyperpigmentation or undesired darkening of skin. 11. A topical formulation for use in personal care or hygiene which includes a personal care or hygiene promoting 65 agent, and a carrier therefor, wherein said formulation includes a skin darkening inhibitor comprising a compound as defined in claim 1. US 8,563,754 B2 61 62 12. The composition of claim8, wherein the composition is selected from skin lotion, skin softener, skintoner, astringent, lotion, milk lotion, moisture lotion, nutrient lotion, massage cream, nutrient cream, moisture cream, hand cream, founda tion, essence, nutrient essence pack, cleansing foam, cleans ing lotion, cleansing cream, body lotion, body cleanser, deodorant, antiperspirant, treatment or beauty solution. 13. A combination to prevent the hyperpigmentation or undesired darkening of skin consisting of a compound as defined in claim 1 and a like-acting agent. 10 14. The combination of claim 13, wherein said like acting agent is selected from a cosmetic ingredient and a pharmaco logically active agent. 15. The combination of claim 14, wherein said pharmaco logically active agent is selected from another skin darkening 15 inhibitor.