WO2001010836A1 - Method of treating hair loss using multivalent ketoamides and amides - Google Patents

Method of treating hair loss using multivalent ketoamides and amides Download PDF

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WO2001010836A1
WO2001010836A1 PCT/US2000/020601 US0020601W WO0110836A1 WO 2001010836 A1 WO2001010836 A1 WO 2001010836A1 US 0020601 W US0020601 W US 0020601W WO 0110836 A1 WO0110836 A1 WO 0110836A1
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aryl
selected
independently
group consisting
heteroaryl
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PCT/US2000/020601
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French (fr)
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Charles Raymond Degenhardt
David Joseph Eickhoff
John Mcmillan Mciver
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The Procter & Gamble Company
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    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61QSPECIFIC USE OF COSMETICS OR SIMILAR TOILET PREPARATIONS
    • A61Q7/00Preparations for affecting hair growth
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K8/00Cosmetics or similar toilet preparations
    • A61K8/18Cosmetics or similar toilet preparations characterised by the composition
    • A61K8/30Cosmetics or similar toilet preparations characterised by the composition containing organic compounds
    • A61K8/40Cosmetics or similar toilet preparations characterised by the composition containing organic compounds containing nitrogen
    • A61K8/44Aminocarboxylic acids or derivatives thereof, e.g. aminocarboxylic acids containing sulfur; Salts; Esters or N-acylated derivatives thereof
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K8/00Cosmetics or similar toilet preparations
    • A61K8/18Cosmetics or similar toilet preparations characterised by the composition
    • A61K8/30Cosmetics or similar toilet preparations characterised by the composition containing organic compounds
    • A61K8/49Cosmetics or similar toilet preparations characterised by the composition containing organic compounds containing heterocyclic compounds
    • A61K8/4906Cosmetics or similar toilet preparations characterised by the composition containing organic compounds containing heterocyclic compounds with one nitrogen as the only hetero atom
    • A61K8/4926Cosmetics or similar toilet preparations characterised by the composition containing organic compounds containing heterocyclic compounds with one nitrogen as the only hetero atom having six membered rings
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K8/00Cosmetics or similar toilet preparations
    • A61K8/18Cosmetics or similar toilet preparations characterised by the composition
    • A61K8/30Cosmetics or similar toilet preparations characterised by the composition containing organic compounds
    • A61K8/49Cosmetics or similar toilet preparations characterised by the composition containing organic compounds containing heterocyclic compounds
    • A61K8/494Cosmetics or similar toilet preparations characterised by the composition containing organic compounds containing heterocyclic compounds with more than one nitrogen as the only hetero atom
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D207/00Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/10Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms, with at the most one to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/16Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D211/00Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D211/60Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals

Abstract

The present disclosure describes methods and compounds useful for treating hair loss in mammals, including arresting and/or reversing hair loss and promoting hair growth. The methods comprise administering a compound having a structure as described herein and a pharmaceutically-acceptable carrier. The compounds herein have the structure: M-L-Q wherein M and Q are each, independently, radicals of struture (I).

Description

METHOD OF TREATING HAIR LOSS USING MULTIVALENT KETOAMIDES AND AMIDES

FIELD OF THE INVENTION

The present invention relates to methods for treating hair loss m mammals, including arresting and / or reversing hair loss and promoting hair growth.

BACKGROUND OF THE INVENTION

Hair loss is a common problem which occurs, for example, through natural processes or is often chemically promoted through the use of certain therapeutic drugs designed to alleviate conditions such as cancer. Often such hair loss is accompanied by lack of hair regrowth which causes partial or full baldness.

As is well-known in the art, hair growth occurs by a cycle of activity which involves alternating periods of growth and rest. This cycle is often divided into three mam stages which are known as anagen, catagen, and telogen. Anagen is the growth phase of the cycle and may be characterized by penetration of the hair follicle deep into the dermis with rapid proliferation of cells which are differentiating to form hair. The next phase is catagen, which is a transitional stage marked by the cessation of cell division, and during which the hair follicle regresses through the dermis and hair growth is ceased. The next phase, telogen, is often characterized as the resting stage during which the regressed follicle contains a germ with tightly packed dermal papilla cells. At telogen, the initiation of a new anagen phase is caused by rapid cell proliferation in the germ, expansion of the dermal papilla, and elaboration of basement membrane components. This cycle is repeated throughout hair growth. Wherein hair growth ceases, most of the hair follicles reside in telogen and anagen is not engaged, thus causing the onset of full or partial baldness.

There have been many attempts m the literature to invoke the regrowth of hair by, for example, the promotion or prolongation of anagen. Currently, there are two drugs approved by the United States Food and Drug Administration for the treatment of male pattern baldness: topical mmoxidil (marketed as Rogaine® by Pharmacia & Upjohn), and oral fmasteπde (marketed as Propecia® by Merck & Co., Inc.).

There are conflicting reports, however, regarding the ability of mmoxidil to grow hair to any significant extent. In fact, early clinical studies investigating decreased blood pressure via the use of mmoxidil did not even mention hypertrichosis (hair growth) as a side effect. See Dormois et al., "Mmoxidil in Severe Hypertension: Value When Conventional Drugs Have Failed", American Heart Journal. Vol. 90, pp. 360 - 368 (1975). Indeed, the manufacturers of mmoxidil have reported only limited hair growth in a portion of patients using mmoxidil. See. e.g.. Physician's Desk Reference®, 49th Ed. (1995), p. 2580. Furthermore, serious side effects of mmoxidil are possible, including vasodilation (which leads to retention of fluid around the heart and increased heart rate), difficulty in breathing, and weight gain. Physician's Desk Reference®, 49th Ed. (1995), p. 2581.

Furthermore, while early indicators show that Propecia® may be more effective than Rogaine®, patients using Propecia® are also experiencing limited hair growth. See The New England Journal of Medicine. Vol. 338, No. 9, February 26, 1998. Furthermore, potential side effects of Propecia® are serious. Propecia® may cause impotence, decreased sexual drive, decreased volume of ejaculate, breast tenderness and enlargement, and hypersensitivity reactions, including lip swelling and skin rash. Furthermore, Propecia® is not indicated for women and children. In fact, women who are pregnant or potentially pregnant should not even handle crushed or broken tablets containing the drug. See Physician's Desk Reference®, 52th Ed. (1998), p. 1737 and The New England Journal of Medicine. Vol. 338, No. 9, February 26, 1998.

Interestingly, the immunosuppressive agents cyclospoπn A and FK506 are known to invoke a prominent hypertπchotic side effect. See Iwabuchi et al., "Effects of Immunosuppressive Peptidyl-Prolyl cis-trans Isomerase (PPIase) Inhibitors, Cyclospoπn A, FK506, Ascomycm, and Rapamycm, on Hair Growth Initiation in Mouse: Immunosuppression is not Required for New Hair Growth", Journal of Dermatological Science, Vol. 9, pp. 64 - 69 (1995); Yamamoto et al., "Hair Growth-Stimulating Effects of Cyclospoπn A and FK506, Potent Immunosuppressants", Journal of Dermatological Science. Vol. 7 (suppl.), pp. S47 - S54 (1994); Yamamoto et al., "Stimulation of Hair Growth by Topical Application of FK506, a Potent Immunosuppressive Agent", Journal of Investigational Dermatology. Vol. 102, pp. 160 - 164 (1994); Jiang et al., "Induction of Anagen m Telogen Mouse Skin by Topical Application of FK506, a Potent Immunosuppressant", Journal of Investigational Dermatology. Vol. 104, pp. 523 - 525 (1995); McElwee et al., "Topical FK506: A Potent Immunotherapy for Alopecia Areata? Studies Using the Dundee Experimental Bald Rat Model", British Journal of Dermatology, Vol. 137, pp. 491 - 497 (1997); Maurer et al., "Hair Growth Modulation by Topical Immunophilm Ligands", American Journal of Pathology, Vol. 150, No. 4, pp. 1433 - 1441 (1997); and Paus et al.. "Hair Growth Control by Immunosuppression", Arch. Dermatol. Res., Vol. 288, pp. 408 - 410 (1996). However, use of these compounds as hair growth actives may not be desirable due to their striking potency as immunosuppressive agents.

FK506 is a complex, macrocychc molecule having the following structure:

Figure imgf000004_0001

Stocks et al., "The Contribution to Binding of the Pyranoside Substituents in the Excised Binding Domain of FK-506", Bioorgamc & Medicinal Chemistry Letters. Vol.. 4, No. 12, pp. 1457 - 1460 (1994). Analogs closely resembling this complex macrocycle have been disclosed as having hair growth properties in the form of, for example, alopecia areata and / or male pattern baldness. See, e.g., Kawai et al., U.S. Patent No. 5,541,193, assigned to Abbott Laboratories, issued July 30,1996; Asakura et al.. U.S. Patent No. 5,496,564, assigned to Fujisawa Pharmaceutical Co., issued March 5, 1996; Baumann et al.. U.S. Patent No. 5,352,671 assigned to Sandoz Ltd., issued October 4, 1994; and Rupprecht et al., U.S. Patent No. 5,550,233, assigned to Merck & Co., Inc., issued August 27, 1996.

However, excitement related to the hypertrichotic activities of cyclospoπn A and FK506 was historically somewhat quelled by the lack of reports of hypertrichosis by various non- macrocychc immunosuppressive and non-immunosuppressive compounds which are less complex in structure than FK506. Only recently has it been reported that certain non- lmmunosuppressive analogs of FK506 have hypertrichotic potential. See Hamilton et al.. WO 98/55090, assigned to Guilford Pharmaceuticals Inc., published December 10, 1998.

Divalent ketoamide analogs of such FK506 analogs have been reported in, for example, Keenan et al. "Synthesis and Activity of Bivalent FKBP12 Ligands for the Regulated Dimeπzation of Proteins", Bioorgamc & Medicinal Chemistry, Vol. 6, pp. 1309 - 1335 (1998); Holt et al . WO 97/31898, assigned to Ariad Gene Therapeutics, Inc., published September 4, 1997; and Holt et al.. WO 97/31899, assigned to Ariad Gene Therapeutics, Inc., published September 4, 1997. However, there are no reports of utility of these types of compounds for treatment of hair loss.

Surprisingly, the present inventors have discovered a class of divalent amides and ketoamides which arrest and / or reverse hair loss or promote hair growth but do not share the macrocyc c structure of FK506. The present inventors have further discovered that compounds among this class invoke hair growth yet are surprisingly non-immunosuppressive or are nominally immunosuppressive. The minimized and / or absent immunosuppressive activity of these hypertrichotic compounds are distinct advantages as compared to the immunosuppressive compounds cyclospoπn A and FK506.

SUMMARY OF THE INVENTION

The present invention relates to methods for treating hair loss comprising administering compounds which have been found by the present inventors to be particularly useful for treating hair loss in mammals, including arresting and / or reversing hair loss and promoting hair growth. The compounds utilized in the present method have the structure:

M-L-Q

and pharmaceutically acceptable salts, hydrates, and biohydrolyzable amides, esters, and lmides thereof, wherein M and Q are each, independently, radicals of structure I; wherein structure I is:

Figure imgf000005_0001
wherein G, X, Ri, and n are defined herein.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to methods of using compounds and compositions to treat hair loss in mammals, including arresting and / or reversing hair loss and promoting hair growth.

In addition to discovering that the present compounds are useful for treating hair loss, the present inventors have also surprisingly discovered that immunosuppression is not required for hair growth stimulation The present inventors have further discovered compounds that are useful for treating hair loss but are surprisingly non-immunosuppressive. Preferred compounds useful in the methods of the present invention are therefore, as defined herein, non- lmmunosuppressive.

Publications and patents are referred to throughout this disclosure. All references cited herein are hereby incorporated by reference.

All percentages, ratios, and proportions used herein are by weight unless otherwise specified.

In the description of the invention various embodiments and/or individual features are disclosed. As will be apparent to the ordinarily skilled practitioner all combinations of such embodiments and features are possible and can result in preferred executions of the invention.

As used herein, wherein any variable, moiety, group, or the like occurs more than one time in any variable or structure, its definition at each occurrence is independent of its definition at every other occurrence. For example, each X of structure I is independently selected from -0-, -NH-, and -CH2-. Because the definition at each occurrence of X is independent of its definition at every other occurrence, the X of M may be -O- even though the X of Q is -NH-.

Definition and Usage of Terms

The following is a list of definitions for terms used herein:

As used herein "salt" is a catiomc salt formed at any acidic (e g , carboxyl) group, or an anionic salt formed at any basic (e.g , ammo) group. Many such salts are known in the art. Preferred catiomc salts include the alkali metal salts (such as, for example, sodium and potassium), alkaline earth metal salts (such as, for example, magnesium and calcium), and organic salts. Preferred anionic salts include the hahdes (such as, for example, chloride salts). Such acceptable salts must, when administered, be appropriate for mammalian use.

As used herein, "alkenyl" is an unsaturated straight or branched hydrocarbon chain radical. Alkenyls have at least one olefinic double bond. Alkenyls may be substituted or unsubstituted. Unless otherwise specified, alkenyls preferably have from 2 to about 8 carbon atoms (C? - C8); preferably from 2 to about 10 carbon atoms (C2 - C6). Non-hmitmg examples of alkenyls include prop-2-enyl, but-2-enyl, but-3-enyl, 2-methylprop-2-enyl, hex-2-enyl, hex-5- enyl, 2,3-dιmethylbut-2-enyl, and the like.

As used herein, "aliphatic" includes both saturated and unsaturated straight, branched, cyclic (cycloahphatic), or polycychc (cycloahphatic) aliphatic hydrocarbons. Unless otherwise specified, ahphatics have from 1 to about 15 carbon atoms, preferably from 1 to about 10 carbon atoms, more preferably from 1 to about 8 carbon atoms, most preferably from 1 to about 6 carbon atoms. Ahphatics are optionally substituted with one or more moieties selected from the group consisting of hydroxy, alkoxy, acyl, carbamoyl, ammo, alkylamino, dialkylamino, N- acylamino, keto, halo, trihalomethyl, cyano, carboxyl, alkyl, heteroalkyl, aryl, heteroaryl, heterocycloaliphatic, cycloahphatic, and sulfonamido (unless otherwise specified, the alkyl, other aliphatic, alkoxy, and acyl substituent moieties preferably contain from 1 to 8, and m many cases from 1 to 6, contiguous aliphatic carbon atoms). Thus, as used herein, "aliphatic" is thus intended to include alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, and cycloalkynyl moieties.

As used herein, "alkyl" is a saturated straight or branched hydrocarbon chain radical. Alkyls may be substituted or unsubstituted Unless otherwise specified, alkyls preferably have from 1 to about 8 carbon atoms (C* - C8), preferably from 1 to about 6 carbon atoms (C* - C6). Preferred alkyls include, for example, methyl, ethyl, .7-propyl, zso-propyl, butyl, iso-butyl, sec- butyl, tert-butyl, pentyl, iso-pentyl, tert-pentyl, hexyl, iso-hexyl, and the like Suitable substituted alkyls include, for example, fluoromethyl, difluoromethyl, tπfluoromethyl, 2- fluoroethyl, 3-fluoropropyl, hydroxymethyl, 2-hydroxyethyl, 3 -hydroxypropyl, and the like.

As used herein, "alkynyl" is an unsaturated straight or branched hydrocarbon chain radical. Alkynyls have at least one triple bond. Alkynyls may be substituted or unsubstituted. Unless otherwise specified, alkynyls preferably have from 2 to about 8 carbon atoms (C2 - C8); preferably from 2 to about 6 carbon atoms (C2 - C6). Non-hmitmg examples of alkynyls include prop-2-ynyl, but-2-enyl, but-3-ynyl, but-3-ynyl, pent-2-ynyl, 3-methylpent-4-ynyl, hex-2-ynyl, hex-5-ynyl, and the like.

As used herein, the terms "aryl" and "heteroaryl" are used to refer to mono- or polycychc, heterocychc, polycychc, and polyheterocychc unsaturated moieties having from 3 to 14 carbon atoms which may be substituted or unsubstituted Non-hmitmg examples of useful aryl ring groups include, for example, phenyl, halophenyl, alkoxyphenyl, dialkoxyphenyl, trialkoxyphenyl, alkylenedioxyphenyl, napthyl, phenanthryl, anthryl, phenanthro, and the like. Non-limiting examples of heteroaryl rings include 5-membered monocychc ring groups such as thienyl, pyrrolyl, lmidazolyl, pyrazolyl, furyl, isothiazolyl, furazanyl, isoxazolyl, thiazolyl, and the like; 6-membered monocychc groups such as pyridyl, pyrazinyl, pyrimidmyl, pyridazmyl, triazmyl, and the like, and polycychc heterocychc ring groups such as benzo[b]thιenyl, naphtho[2,3-b]thιenyl, thianthrenyl, isobenzofuranyl, chromenyl, xanthenyl, phenoxathienyl, indolizinyl, isoindolyl, indolyl, indazolyl, purmyl, isoquinolyl, qumolyl, phthalazmyl, naphthyridmyl, qumoxahnyl, quinazo nyl, benzothiazole, benzimidazole, tetrahydroqumohne cinnohnyl, pteπdinyl, carbazolyl, beta-carbolmyl, phenanthridmyl, acπdmyl, perimidmyl, phenanthrohnyl, phenazmyl, isothiazolyl, phenothiazmyl, phenoxazmyl, and the like. The aryl and heteroaryl moieties may be substituted with from one to five substituents selected from the group consisting of hydroxy, C- - C8 alkoxy, d - C8 alkyl, acyloxy, carbamoyl, ammo, N- acylammo, mtro, halo, tπhalomethyl, cyano, and carboxy.

As used herein, "biohydrolyzable amides" are amides of the compounds used in the present invention which do not interfere with the activity of the compound, or that are readily converted in vivo by a mammalian subject to yield an active compound.

As used herein, "biohydrolyzable esters" are esters of the compounds used m the present invention which do not interfere with the activity of the compound, or that are readily converted in vivo by a mammalian subject to yield an active compound.

As used herein, "biohydrolyzable lmides" are lmides of the compounds used in the present invention which do not interfere with the activity of the compound, or that are readily converted in vivo by a mammalian subject to yield an active compound.

As used herein, "cycloahphatic" refers to cyclic aliphatic groups preferably having from three to seven (C3 - C7), more preferably three to six (C3 - C6) carbon atoms Suitable cycloahphatics include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and the like. Cycloahphatics may be substituted or unsubstituted.

As used herein, "halo", "halogen", or the like refers to a fluoro, chloro, bromo, or lodo substituent.

As used herein, "heteroahphatic" refers to an aliphatic moiety which contains one or more oxygen, sulfur, or nitrogen atoms, e g , m place of one or more carbon atoms. Heteroahphatics may be substituted or unsubstituted.

As used herein, "heterocycloaliphatic" and "heterocycle" each refer to cyclic aliphatic groups having one or more heteroatoms, and preferably three to seven ring atoms total including, for example, oxetane, tetrahydrofuranyl, tetrahydropyranyl, aziπdme, pyrrohdme, pipeπdine, morphohne, piperazme, and the like. Heterocycloahphatics (heterocycles) may be substituted or unsubstituted.

As used herein, "pharmaceutically acceptable" means suitable for use in a human or other mammal, preferably human.

As used herein, "safe and effective amount of a compound" (or composition, or the like) means an amount that is effective to exhibit biological activity, preferably wherein the biological activity is arresting and / or reversing hair loss or promoting hair growth, at the sιte(s) of activity in a mammalian subject, without undue adverse side effects (such as toxicity, irritation, or allergic response), commensurate with a reasonable benefit / risk ratio when used in the manner of this invention.

As used herein, moieties may be substituted or unsubstituted. Unless otherwise specified, preferred substituents include hydroxy, alkoxy, acyl, carbamoyl, amino, alkylamino, dialkylammo, N-acylammo, keto, halo, trihalomethyl, cyano, carboxyl, alkyl, heteroalkyl, aryl, heteroaryl, heterocycloaliphatic, cycloahphatic, and sulfonamido (unless otherwise specified, the alkyl, other aliphatic, alkoxy, and acyl preferably contain from 1 to about 8, more preferably from 1 to about 6, contiguous aliphatic carbon atoms).

Methods and Compounds of the Present Invention

The present invention relates to methods of treating hair loss comprising administering a composition comprising a compound having the structure:

M-L-Q and pharmaceutically acceptable salts, hydrates, and biohydrolyzable amides, esters, and lmides thereof, wherein M and Q are each, independently, radicals of structure I and wherein L is a linker moiety which covalently links M and Q together. Preferably, M and Q are equivalent. As used herein, structure I is:

Figure imgf000009_0001
wherein:

(a) each G is, independently, selected from nil, aliphatic, heteroahphatic, aryl, heteroaryl, cycloahphatic, heterocycloaliphatic, and

Figure imgf000009_0002

(b) each n is, independently, an integer selected from 1 and 2;

(c) each X is, independently, selected from -0-, -NH-, and -CH2-;

(d) each R] is, independently, selected from aliphatic, heteroahphatic, cycloahphatic, heterocycloaliphatic, aryl, and heteroaryl; (e) each CA is a carbon atom;

(f) each CB is a carbon atom;

(g) each B) and B2 is, independently, selected from hydrogen, aliphatic, heteroahphatic, aryl, and heteroaryl; or wherein each Bi and B2 of the same G are, together, a carbonyl group; and

(h) each R2 is, independently, selected from nil, aliphatic, heteroahphatic, cycloahphatic, heterocycloaliphatic, aryl, and heteroaryl; wherein when G of M is nil, L is covalently attached to CA of M, wherein when G of Q is nil, L is covalently attached to CA of Q; wherein when B* and B2 of M are, together, a carbonyl group and R2 is nil, L is covalently attached to CB of M, and wherein when B* and B2 of Q are, together, a carbonyl group and R2 is nil, L is covalently attached to CB of Q. The Linker L

The present compounds are "divalent" meaning they have two groups, M and Q, which can potentially bind with a receptor binding site. The linker, L, of these compounds covalently connects M to Q. The linker may be any mechanism through which M and Q may be covalently bonded together. The linker may, but need not, participate in binding which a receptor binding site. However, a preferred linker will optimize, e g , physiochemical and / or pharmacokmetic properties of the compound.

Because the linker is a mechanism for covalent bonding, the ordinarily skilled artisan will recognize that the linker may be selected from a broad range of structures. A simple, and preferred, linker is merely a covalent bond which links M to Q, herein referred to as "bond" Another preferred linker is a heteroatom diradical e g , -O- or -N(OH)-. Preferred heteroatom radicals are selected from oxygen (-0-), nitrogen (-NH- or substituted -N-), and sulfur (-S-), more preferably oxygen and nitrogen; and most preferably oxygen. Wherein nitrogen is the linker, it may be substituted (substituted -N-) wherein the preferred substituent is alkyl.

Particularly preferred linkers include ethers, thioethers, amines, amides, ureas, carbamates, sulfonamides, thiocarbamates, esters, thioesters, and ketones.

Other non-hmitmg examples of linkers include radicals such as, for example, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, heteroaryl, heteroarylalkyl, heteroarylalkenyl, and heteroarylalkynyl. These radicals may be substituted or unsubstituted Preferred among these examples are alkyl. alkenyl, heteroalkyl, heteroalkenyl, aryl, arylalkyl, arylalkenyl, heteroaryl, heteroarylalkyl, and heteroarylalkenyl. More preferred among these examples are alkyl, heteroalkyl, aryl, arylalkyl, heteroaryl, and heteroarylalkyl, most preferably aryl. Most preferred among these examples are phenyl, naphthyl, and biphenyl.

In a preferred embodiment of the invention, the linker is a bis-amide linker, a retro bis- amide linker, a polyether urea linker, or a polyether linker. These linkers are descπbed below The "attachment locations" are the points at which M and Q, respectively, are linked to L.

Overall, the most preferred linkers are selected from bond, aryl, alkyl, biaryl ether (i.e., aryl-O-aryl), biaryl methyl (i e , aryl-CH2-aryl), -O-, -S-, and -NH-, more preferably bond, lower alkyl, aryl, biaryl ether, -O-, and-NH-, even more preferably bond, aryl, biaryl ether, and -0-, with the most preferable among these being phenyl, naphthyl, biphenyl, biphenyl ether, biphenyl methyl, methyl, and -0-.

Examples of bis-amide linkers are1

Figure imgf000011_0001
Figure imgf000012_0001
Figure imgf000013_0001

Examples of retro bis-amide linkers are:

Figure imgf000013_0002
Figure imgf000014_0001

An example of a polyether urea linker is:

attachment attachment

Figure imgf000014_0002
location location

Examples of polyether linkers are:

Figure imgf000014_0003
O, ,0. .0

'O' attachment X 'σ attachment location bcation

A preferred sulfonamide linker is shown below:

Figure imgf000015_0001

The G Moiety

The G moiety is present in structure I as described above. Each G is independently selected from nil, aliphatic, heteroahphatic, aryl, heteroaryl, cycloahphatic, heterocycloaliphatic, and

Figure imgf000015_0002

Preferably, each G is independently selected from aliphatic, heteroahphatic, aryl, heteroaryl, cycloahphatic, heterocycloaliphatic, and

Figure imgf000015_0003
wherein each B, and B2 of the same G are, together, a carbonyl group.

More preferably, each G is independently selected from aryl, heteroaryl, cycloahphatic, heterocycloaliphatic, and

Figure imgf000015_0004
wherein each Bj and B2 of the same G are, together, a carbonyl group. Wherein G requires an R2 moiety, each R2 is independently selected from ml, aliphatic, heteroahphatic, cycloahphatic, heterocycloaliphatic, aryl, and heteroaryl. Preferably, each R2 is independently selected from nil, aliphatic, heterocycloaliphatic, aryl, and heteroaryl. More preferably, each R2 is independently selected from nil, aliphatic, aryl, and heteroaryl. Most preferably, each R2 is independently selected from nil, aliphatic (preferably branched alkyl) and aryl.

Wherein G requires B, and / or B2 moieties, each B] and B2 is independently selected from hydrogen, aliphatic, heteroahphatic, aryl, and heteroaryl; or wherein each B* and B2 of the same G are, together, a carbonyl group. Preferably, each Bi and B2 is independently selected from hydrogen and aliphatic (preferably, alkyl); or wherein each Bi and B2 of the same G are, together, a carbonyl group. Most preferably, each B* and B2 is hydrogen or wherein each B- and B2 of same G are, together, a carbonyl group.

Wherein the G moiety of M or Q is nil, then the linker is preferably selected from alkyl, heteroalkyl, aryl, arylalkyl, heteroaryl, and heteroarylalkyl, most preferably aryl. Wherein when G of M is nil, L is covalently attached to CA of M. WTierem when G of Q is nil, L is covalently attached to CA of Q.

Wherein the R2 moiety of M or Q is nil, then the linker is preferably selected from alkyl, heteroalkyl, aryl, arylalkyl, heteroaryl, and heteroarylalkyl, most preferably aryl. Wherein when R2 of a G moiety is nil, then the linker moiety (L) is directly attached to CB of that same G moiety. The Integer n

Each integer n is, independently, and integer selected from 1 and 2. Preferably, at least one integer n is 2. Most preferably, each integer n is 2. The X Moiety

Each X is independently selected from -0-, -NH-, and -CH2-. Preferably, each X is independently selected from -O- and -NH-. More preferably, at least one X is -NH-. Most preferably, each X is -NH-. The RL Moiety

Each Ri moiety is, independently, selected from aliphatic, heteroahphatic, cycloahphatic, heterocycloaliphatic, aryl, and heteroaryl. Most preferably, each R, moiety is aliphatic (preferably alkyl) substituted with at least one of alkyl, heteroalkyl, heterocycle, aryl, and heteroaryl. For example, a preferred R* moiety is:

Figure imgf000017_0001
wherein:

(a) each R4 is selected from the group consisting of hydrogen, alkyl, heteroalkyl, aryl, and heteroaryl;

(b) each R5 is C, - C8 alkyl; and

(c) each R6 is selected from the group consisting of alkyl, heteroalkyl, heterocycle, aryl, and heteroaryl.

Preferably, in this R* moiety, R5 is C, alkyl (preferably methyne) and each of R4 and R6 are alkyl (most preferably, C3 alkyl), wherein each R4 and R6 are preferably independently substituted with aryl (most preferably, substituted or unsubstituted phenyl)

Preferred compounds useful in the methods of the present invention are shown in Table 1 below:

Table 1

Figure imgf000017_0002
Figure imgf000018_0001
Figure imgf000019_0001
Figure imgf000020_0001
Figure imgf000021_0001

Figure imgf000022_0001

In the following compounds, R5 of M is methyne, R4 of M is heteroalkyl substituted with aryl, R6 of M is heteroalkyl substituted with oxo, R5 of Q is methyne, R, of Q is heteroalkyl substituted with aryl, R6 of Q is heteroalkyl substituted with oxo, and L is phenyl:

Table 2

Figure imgf000022_0002

Preferred Compounds of the Present Invention Preferred compounds of the present invention which may be utilized in the present methods have the structure:

M-L-Q and pharmaceutically acceptable salts, hydrates, and biohydrolyzable amides, esters, and imides thereof, wherein M and Q are each, independently, radicals of structure II and wherein L is a linker moiety which covalently links M and Q together; and wherein structure II is:

Figure imgf000023_0001
wherein:

(a) each G is independently selected from nil and

Figure imgf000023_0002

(b) each n is, independently, an integer selected from 1 and 2;

(c) each X is independently selected from -0-, -NH-, and -CH2-;

(d) each R, is, independently, selected from aliphatic, heteroahphatic, cycloahphatic, heterocycloaliphatic, aryl, and heteroaryl;

(e) each CA is a carbon atom;

(f) each CB is a carbon atom;

(g) L is aryl; wherein when G of M is nil, L is covalently attached to CA of M; wherein when G of Q is nil, L is covalently attached to CA of Q; wherein when G of M is:

Figure imgf000023_0003

L is covalently attached to CB of M; and wherein when G of Q is-

Figure imgf000023_0004

L is covalently attached to CB of Q. Other preferred compounds of the present invention which may be utilized m the present methods have the structure:

M-L-Q and pharmaceutically acceptable salts, hydrates, and biohydrolyzable amides, esters, and imides thereof, wherein M and Q are each, independently, radicals of structure III and wherein L is a linker moiety which covalently links M and Q together; wherein structure III is:

Figure imgf000024_0001
wherein:

(a) each G is independently selected from aliphatic, heteroahphatic, aryl, heteroaryl, cycloahphatic, heterocycloaliphatic, and

Figure imgf000024_0002

(b) each n is, independently, an integer selected from 1 and 2;

(c) each X is independently selected from -0-, -NH-, and -CH2-;

(d) each Bt and B2 is, independently, selected from hydrogen, aliphatic, heteroahphatic, aryl, and heteroaryl; or wherein each B* and B2 of the same G are, together, a carbonyl group;

(e) each Rj is, independently, selected from aliphatic, heteroahphatic, cycloahphatic, heterocycloaliphatic, aryl, and heteroaryl;

(f) each R2 is, independently, selected from aliphatic, heteroahphatic, cycloahphatic, heterocycloaliphatic, aryl, and heteroaryl; and

(g) L is selected from bond, -O-, -S-, and -NH-.

Highly preferred compounds wherein M and Q are each structures II or III (each of these are also compounds wherein M and Q are contemplated within structure I) are shown below. In the following compound, G of M is phenyl, G of Q is phenyl, and the linker is -0-'

Figure imgf000025_0001

In the following compound B, and B2 of M are, together, carbonyl, and R2 of M is phenyl, B* and B2 of Q are, together, carbonyl, and R2 of Q is phenyl, and L is -0-:

Figure imgf000025_0002

In the following compound, G of M is nil, G of Q is nil, and L is biphenyl, linked directly to CA of M and CA of Q:

Figure imgf000025_0003

In the following compound Bi and B2 of M are, together, carbonyl, and R2 of M is nil, B* and B2 of Q are, together, carbonyl, R2 of Q is nil, and L is biphenyl, linked directly to CA of M and CA of Q:

Figure imgf000025_0004
In the following compound, G of M is nil, G of Q is nil, and L is naphthyl, linked directly to CA of M and CA of Q:

Figure imgf000026_0001

In the following compound, Bi and B2 of M are, together, carbonyl, and R2 of M is nil, Bi and B2 of Q are, together, carbonyl, R2 of Q is nil, and L is naphthyl, linked directly to CA of M and CA of Q:

Figure imgf000026_0002

Analytical Methods The present invention relates to methods of treating hair loss by administering a compound having a structure as descπbed herein. Of such compounds, the preferred compounds are non-immunosuppressive. Compounds (test compounds) may be tested for their ability to induce anagen and their immunosuppressive activity (or lack thereof) using the following methods. Alternatively, other methods well-known in the art may be used (but with the term "non-immunosuppressive" being defined according to the method disclosed herein below). Telogen Conversion Assay: The Telogen Conversion Assay measures the potential of a test compound to convert mice in the resting stage of the hair growth cycle ("telogen"), to the growth stage of the hair growth cycle ("anagen").

Without intending to be limited by theory, there are three principal phases of the hair growth cycle: anagen, catagen, and telogen. It is believed that there is a longer telogen period in C3H mice (Harlan Sprague Dawley, Inc., Indianapolis, IN) from approximately 40 days of age until about 75 days of age, when hair growth is synchronized. It is believed that after 75 days of age, hair growth is no longer synchronized. Wherein about 40 day-old mice with dark fur (brown or black) are used in hair growth experiments, melanogenesis occurs along with hair (fur) growth wherein a hair growth promoter is applied. The Telogen Conversion Assay herein below is used to screen compounds for potential hair growth by measuring melanogenesis.

Three groups of 44 day-old C3H mice are utilized: a vehicle control group, a positive control group, and a test compound group, wherein the test compound group is administered a compound used in the method of the present invention. The length of the assay is at least 19 days with 15 treatment days (wherein the treatment days occur Mondays through Fridays). Day 1 is the first day of treatment. Most studies will end on Day 19, but a few may be carried out to Day 24 if the melanogenesis response looks positive, but occurs slowly. A typical study design is shown in Table 3 below:

Table 3

Figure imgf000027_0001

**The vehicle is 60% ethanol, 20% propylene glycol, and 20% dimethyl isosorbide (commercially available from Sigma Chemical Co., St. Louis, MO).

The mice are treated topically Monday through Friday on their lower back (base of tail to the lower rib). A pipettor and tip are used to deliver 400 μL to each mouse's back. The 400 μL application is applied slowly while moving hair on the mouse to allow the application to reach the skin. While each treatment is being applied to the mouse topically, a visual grade of from 0 to 4 will be given to the skm color m the application area of each animal. As the mice convert from telogen to anagen their skm color will become more bluish-black. As indicated in Table 4, the grades 0 to 4 represent the following visual observations as the skin progresses from white to bluish-black:

Table 4

Figure imgf000028_0001

Immunosuppression Assay:

The immunosuppression assay herein predicts the immunosuppressive activity of a compound used in the method of the present invention. The assay is performed as follows:

Spleens are excised from euthanized (C02 asphyxiation) adult male C3H mice ranging in age from seven to sixteen weeks old (live mice commercially available from Harlan Sprague Dawley, Inc., Indianapolis, IN). The spleens are placed immediately m cold Hanks Balanced Salt Solution (HBSS, commercially available from Gibco-BRL, Gaithersburg, MD) The spleens are then ground up between frosted glass slides and filtered through a sterile screen to remove tissue debris. The resulting cell suspension is underlayed with an equal volume of Ficoll-Paque Plus (commercially available from Pharmacia Biotech, Piscataway, NJ) and centπfuged at 400 x g for approximately forty minutes at 20 °C in order to collect the splenocytes. The splenocytes are collected from the interface using a disposable pipet and are washed twice with HBSS, followed by centrifugation at 100 x g for ten mm at 20 °C. Splenocytes are resuspended in five to ten mL of cell culture media consisting of phenol red-free RPMI 1640 (culture media commercially available from Gibco-BRL) containing 10% heat- mactivated fetal bovine serum (Gibco-BRL), penicillin (50 U/mL), streptomycin (100 μg/mL), L-glutamme (2 mM), 2-mercaptoethanol (105 M), and N-2-hydroxyethylpιperazιne-N'-2- ethanesulfomc acid (HEPES) (10 mM). The cells are counted and checked for viability using, for example, trypan blue. Splenocytes are resuspended in medium at 106 cells/mL and pipetted into 96 well round bottom plates at 105 cells/well. Splenocytes are activated by addition of 50 μL/well of conconavahn A (final assay concentration = 5 μg/ml) in the presence or absence of a test compound. Test compounds are made up as stock solutions m methyl sulfoxide (DMSO), then diluted m medium and 50 μL/well added, such that the final concentration of DMSO in the assay is below 0.05%. The plates are incubated at 37 °C with 5% C02 for 48 hours. After 48 hours, the cells are pulsed with 1 μCi/well of methyl-3H-thymιdιne (commercially available from Amersham, Buckinghamshire, England) and incubated an additional 24 hours.

After 24 hours, the cells are harvested onto GF/C filter plates (commercially available from Packard, Downers Grove, IL), solubihzed in Microscmt 20 (Packard), and counted on a TopCount microplate scintillation and luminescence plate counter (Packard). Activity is measured as a percentage of control activity in the absence of test compound and plotted versus test compound concentration. The data are fit to a 4-parameter curve fit (Sigmaplot) and IC50 values are calculated. As used herein, test compounds are considered non-immunosuppressive if, by using this method, the ratio of (cyclosporin A IC50/test compound IC50) x 100 is less than or equal to 0.02, i.e., a non-immunosuppressive test compound has < 2% of the immunosuppressive activity of cyclosporin A.

Cell viability is assessed using the MTT (3-[4,5-dιmethyl-thιazoyl-2-yl]2,5-dιphenyl- tetrazohum bromide) dye assay as described by Nelson et al., Journal of Immunology, Vol. 150, No. 6, pp. 2139 - 2147 (1993), with the exception that the assay is carried out in serum-free, phenol red-free RPMI 1640 and the dye is solubihzed in 100 μL/well DMSO and read at an OD of 540 nm with a background correction at 650 nm on a SpectraMax Plus microplate reader (Molecular Devices, Menlo Park, CA).

Multi-Drug Resistance

As disclosed herein, the present compounds are also useful, for example, to increase the antiprohferative activity of a drug and / or prevent and / or treat multi-drug resistance. The present compounds may be assayed for this property as described in U.S. Patent No. 5,744,485, Zelle et al.. assigned to Vertex Pharmaceuticals Inc., issued April 28, 1998, U.S. Patent No. 5,726,184, Zelle et al.. assigned to Vertex Pharmaceuticals Inc., issued March 10, 1998, U.S. Patent No. 5,620,971, Armistead et al., assigned to Vertex Pharmaceuticals Inc., issued April 15, 1997, and U.S. Patent No. 5,543,423, Zelle et al.. assigned to Vertex Pharmaceuticals Inc., issued August 6, 1996.

Methods of Making

The compounds used in the methods of the present invention are prepared according to methods which are well-known to those skilled in the art. The starting materials used m preparing the compounds are known, made by known methods, or are commercially available as a starting material.

It is recognized that the skilled artisan in the art of organic chemistry can readily carry out standard manipulations of organic compounds without further direction. Examples of such manipulations are discussed m standard texts such as J. March, Advanced Organic Chemistry. John Wiley & Sons, 1992.

The skilled artisan will readily appreciate that certain reactions are best carried out when other functionalities are masked or protected in the compound, thus increasing the yield of the reaction and / or avoiding any undesirable side reactions. Often, the skilled artisan utilizes protecting groups to accomplish such increased yields or to avoid the undesired reactions. These reactions are found in the literature and are also well within the scope of the skilled artisan. Examples of many such manipulations can be found in, for example, T. Greene, Protecting Groups in Organic Synthesis. John Wiley & Sons, 1981.

The compounds of the present invention may have one or more chiral center. As a result, one may selectively prepare one optical isomer, including diastereomers and enantiomers, over another, for example by chiral starting materials, catalysts or solvents, or may prepare both stereoisomers or both optical isomers, including diastereomers and enantiomers at once (a racemic mixture). Since the compounds of the invention may exist as racemic mixtures, mixtures of optical isomers, including diastereomers and enantiomers, or stereoisomers may be separated using known methods, such as through the use of, for example, chiral salts and chiral chromatography.

In addition, it is recognized that one optical isomer, including a diastereomer and enantiomer, or a stereoisomer, may have favorable properties over the other. Thus, when disclosing and claiming the invention, when one racemic mixture is disclosed, it is clearly contemplated that both optical isomers, including diastereomers and enantiomers, or stereoisomers substantially free of the other are disclosed and claimed as well.

The syntheses of compounds utilized m methods of the present invention are described in the following references: Keenan et al. "Synthesis and Activity of Bivalent FKBP12 Ligands for the Regulated Dimerization of Proteins", Bioorgamc & Medicinal Chemistry, Vol. 6, pp. 1309 - 1335 (1998); WO 97/31898, Holt et al., assigned to Ariad Gene Therapeutics, published September 4, 1997; and WO 97/31899, Holt et al.. assigned to Ariad Gene Therapeutics, published September 4, 1997.

In addition, the following provides non-hmitmg examples illustrating more specifically the methods of making various compounds of the present invention.

As used herein, the following abbreviations are used:

Figure imgf000031_0002

Example 1

Figure imgf000031_0001
la. (S)-(N-tert-Butoxycarbonyl)pipecolinic acid l,7-diphenyl-4-heptylamide: (S)-(N-tert- Butoxycarbonyl)pιpecohnιc acid (4.66 g, 20.3 mmol) is dissolved in 200 mL of DMF. 1,7- Dιphenyl-4-amιnoheptane (5.44 g, 20.3 mmol) and ι-Pr2EtN (5.25 g, 40.7 mmol) are added followed by PyBOP (10.6 g, 20.3 mmol). The reaction is stirred for 18 hours at room temperature, then poured onto ice-cold 0.1N HCI (800 mL) and extracted with ethyl acetate (800 mL). The layers are separated and the organic layer washed successively with brine (200 mL), saturated NaHC03 solution (400 mL) and brine (200 mL). The organic solution is dried over MgS04, filtered, and concentrated under reduced pressure. Purification of the product by chromatography on silica gel affords the desired amide la. lb. (S)-Pipecolinic acid l,7-diphenyl-4-heptylamide: The amide la (8.74 g, 18.3 mmol) is dissolved in 150 mL of anhydrous dichloromethane. TFA (100 mL) is added dropwise over a 5 minute period. After about 2 hours the mixture is cooled m an ice-bath and saturated K2C03 solution is added until the pH is approximately 8. The mixture is transferred to a separatory funnel containing dichloromethane (200 mL) and water (200 mL) and shaken. The organic layer is separated and washed with water (200 mL) before drying over MgS04. The mixture is filtered and concentrated under reduced pressure to afford the desired amme lb.

Figure imgf000032_0001

2. Bis-4,4'-((S)-N-(phenylcarbonyI)pipecolinic acid l,7-diphenyl-4-heptylamide) ether:

The amine of Example lb (8.43 g, 22.3 mmol), 4,4'-oxybιs(benzoιc acid) (2.5 g, 9.7 mmol; Aldπch Chemical Co., Milwaukee, WI) and ι-Pr2EtN (8.4 mL, 48.4 mmol) are dissolved m 150 mL of anhydrous dichloromethane. The PyBOP (12.6 g, 24.2 mmol) is added m one portion. The reaction is stirred for 6 hours at room temperature, then poured onto ice-cold 0.1N HCI (300 mL) and extracted with dichloromethane (300 mL). The layers are separated and the organic layer washed successively with saturated NaHC03 solution (150 mL) and brine (50 mL). The organic solution is dried over MgS04, filtered, and concentrated under reduced pressure. Purification of the product by chromatography on silica gel affords the desired amide 2.

Figure imgf000033_0001

3. 2,6-Naphthalenedicarbonyl((S)-N-pipecolinic acid l,7-diphenyl-4-heptylamide): The amine of Example lb (8.43 g, 22.3 mmol), 2,6-naphthalenedicarboxyhc acid (2.1 g, 9.7 mmol; Aldnch Chemical Co, Milwaukee, WI) and ι-Pr2EtN (8.4 mL, 48.4 mmol) are dissolved in 200 mL of anhydrous dichloromethane. The PyBOP (12.6 g, 24.2 mmol) is added in one portion. The reaction is stirred for about 22 hours at room temperature, then poured onto ice-cold 0.1N HCI (400 mL) and extracted with dichloromethane (300 mL). The layers are separated and the organic layer washed successively with saturated NaHC03 solution (150 mL) and brine (50 mL). The organic solution is dried over MgS04, filtered, and concentrated under reduced pressure. Purification of the product by chromatography on silica gel affords the desired amide 3.

Example 4

Figure imgf000033_0002

4a

4a. 4,4'-biphenylglyoxylic acid: 4,4'-dιacetylbιphenyl (5 g, 21 mmol, Aldnch Chemical Co., Milwaukee, WI) is dissolved in anhydrous pyπdine (65 mL) at ambient temperature. Selenium dioxide (9.3 g, 83.9 mmol) is added in one portion and the resulting mixture is carefully heated to reflux. After 24 hours at reflux the reaction mixture is cooled to ambient temperature then filtered through a pad of diatomaceous earth, washed with pyπdine, and concentrated under reduced pressure. The residue is slurried in ethyl acetate (100 mL) and 1 N HCI (100 mL) until dissolution is complete. The layers are separated, and the aqueous layer is extracted with ethyl acetate (100 mL). The combined ethyl acetate extracts are dried (MgS04), filtered, and concentrated under vacuum to afford the desired bis-α-ketoacid 4a.

Figure imgf000034_0001
lb 4a

Figure imgf000034_0002

4b. 4,4'-biphenylglyoxyl((S)-N-pipecolic acid l,7-diphenyl-4-heptylamide): Amme lb (7.3 g, 19.3 mmol) is dissolved in anhydrous dichloromethane (75 mL) at ambient temperature. 4,4'- biphenyl-glyoxyhc acid 4a (2.5 g, 8.4 mmol) is added followed by ι-Pr2EtN (7.3 mL, 42 mmol) and PyBOP (10.91 g, 21 mmol) in succession. The reaction solution is stirred at ambient temperature for 18 hours then concentrated under vacuum. The residue is dissolved m ethyl acetate (250 mL) then washed successively with 0.2 N HCI (100 mL), saturated aqueous sodium bicarbonate (50 mL), and brine (50 mL). The organic solution is dried over MgS0 , filtered, and concentrated under reduced pressure. Purification of the product by preparative chromatography affords the desired bis-α-ketoamide 4b. Example 5

Figure imgf000035_0001

5a. 4,4'-(phenylglyoxylic acid) ether: 4-acetylphenyl ether (5 g, 19.2 mmol, Trans World Chemicals, Rockville, MD) is dissolved in anhydrous pyndine (65 mL) at ambient temperature. Selenium dioxide (8.73 g, 78.7 mmol) is added in one portion and the resulting mixture is carefully heated to reflux. After 24 hours at reflux the reaction mixture is cooled to ambient temperature then filtered through a pad of diatomaceous earth, washed with pyndine, and concentrated under reduced pressure. The residue is dissolved in ethyl acetate (250 mL) and extracted successively with 1 N HCI (100 mL), then saturated aqueous sodium bicarbonate (2 x 50 mL). The combined aqueous bicarbonate extracts are acidified with concentrated HCI then extracted with dichloromethane (3 x 50 mL). A precipitate persists throughout the dichloromethane extractions which is removed by filtration, water washed, and dried to afford the desired bis-α-ketoacid 5a.

Figure imgf000035_0002

5b 5b. 4,4'-(phenylglyoxyl) ether((S)-N-pipecolic acid l,7-diphenyl-4-heptylamide). Amine lb (7.3 g, 19.3 mmol) is dissolved in anhydrous dichloromethane (75 mL) at ambient temperature. 4,4'-bιphenyl-glyoxyhc acid 5a (2.63 g, 8.37 mmol) is added followed by ι-Pr2EtN (7.3 mL, 42 mmol), DMF (25 mL), and PyBOP (10.9 g, 21 mmol) in succession. The reaction slurry is stirred at ambient temperature for 5 hours then additional PyBOP (5 g, 9.61 mmol) is added. The slurry is stirred at ambient temperature for another 13 hours then filtered to remove insoluble materials. The filtrate is concentrated under reduced pressure. The residue is dissolved m ethyl acetate (250 mL) then washed successively with a mixture of water (75 mL) and brine (25 mL), 0.2 N HCI (100 mL), saturated aqueous sodium bicarbonate (75 mL), and brine (50 mL). The organic solution is concentrated under reduced pressure. Purification of the product by preparative chromatography affords the desired bis-α-ketoamide 5b.

Use of the Present Compounds

The methods of the present invention is performed by administration of a compound having a structure herein and a pharmaceutically-acceptable carrier.

The compounds herein may be used for the treatment of such conditions as treating hair loss in mammals, including arresting and / or reversing hair loss and promoting hair growth. Such conditions may manifest themselves in, for example, alopecia, including male pattern baldness and female pattern baldness.

WTule certain of the present compounds may exhibit immunosuppressive activity, the preferred compounds of the present invention are, as defined herein, non-immunosuppressive

Furthermore, in addition to treating hair loss, the compounds utilized in the present invention may be used to treat a variety of clinical conditions which include, but are not limited to, multi-drug resistance (particularly for use in cancer chemotherapy), neurological disorders and neurodegenerative diseases, cardiac injury associated with ischemia/reperfusion injury, and treatment of fungal, microbial, viral (especially HIV), malarial or other parasitic diseases or conditions. The present compounds may also be useful as inhibitors of multi-drug transporter proteins to enhance, for example, pharmacokmetics and bioavailabihty. Certain compounds of the present invention may exhibit immunomodulatory properties. These compounds would prove useful in the treatment of organ transplant rejection and various autoimmune diseases which include, but are not limited to, Behcet's disease, Crohn's disease, systemic lupus erythematosus, psoriasis, rheumatoid arthritis, eczema, multiple sclerosis, myasthenia gravis, insulin -dependent diabetes melhtus, and Graves' disease. In addition, the present compounds may have utility for the treatment of certain inflammatory and allergic disease states, including urticaria, allergic contact dermatitis, atopic dermatitis, atopic keratoconjunctivitis, inflammatory bowel disease, and asthma. The present compounds may also be useful in the treatment of cardiac hypertrophy in congestive heart failure.

The present compounds may also be useful in combination with a matrix metalloprotemase inhibitor for treatment of various conditions including, for example, tissue destructive diseases mediated by excessive metalloprotemase activity, cancer, and multi-drug resistance, as well as all of the conditions previously mentioned herein above. Particularly preferred matrix metalloprotemase inhibitors useful in such combination include those described m U.S. Patent No. 5,830,915, Pikul et al, assigned to The Procter & Gamble Co., filed August 26, 1997; U.S. Patent Application Serial No 08/918,317, Natchus et al.. assigned to The Procter & Gamble Co., filed August 26, 1997, U.S. Patent Application Serial No. 08/918,957, Pikul et al_, assigned to The Procter & Gamble Co., filed August 26, 1997; U.S. Patent Application Serial No. 08/918,419, Pikul et al.. assigned to The Procter & Gamble Co., filed August 26, 1997; U.S. Patent Application Serial No. 08/921,953, De et al.. assigned to The Procter & Gamble Co., filed August 28, 1996; and U.S. Patent Application Serial No. 08/918,328, Wang et al.. assigned to The Procter & Gamble Co., filed August 26, 1997.

Preferably, in the methods of the present invention, the compounds are formulated into pharmaceutical compositions for use in treatment or prophylaxis of conditions such as the foregoing Standard pharmaceutical formulation techniques are used, such as those disclosed in Remington's Pharmaceutical Sciences. Mack Publishing Company, Easton, PA. (1990).

Typically, from about 5 mg to about 3000 mg, more preferably from about 5 mg to about 1000 mg, more preferably from about 10 mg to about 100 mg, of a compound having a structure as described herein is administered per day for systemic administration. It is understood that these dosage ranges are by way of example only, and that daily administration can be adjusted depending on various factors. The specific dosage of the compound to be administered, as well as the duration of treatment, and whether the treatment is topical or systemic are interdependent. The dosage and treatment regimen will also depend upon such factors as the specific compound used, the treatment indication, the efficacy of the compound, the personal attributes of the subject (such as, for example, weight, age, sex, and medical condition of the subject), compliance with the treatment regimen, and the presence and severity of any side effects of the treatment. According to the present invention, the subject compounds are co-admmistered with a pharmaceutically-acceptable carrier ("carrier"). The term pharmaceutically-acceptable carrier, as used herein, means one or more compatible solid or liquid filler diluents or encapsulating substances which are suitable for administration to a mammal. The term "compatible", as used herein, means that the components of the composition are capable of being commingled with a compound of the present invention, and with each other, m a manner such that there is no interaction which would substantially reduce the efficacy of the composition under ordinary use situations. Carriers must, of course, be of sufficiently high purity and sufficiently low toxicity to render them suitable for administration to the animal, preferably mammal, being treated. The carrier can itself be inert or it can possess pharmaceutical benefits of its own.

The compositions utilized in this invention may be in any of a variety of forms, suitable (for example) for oral, rectal, topical, nasal, ocular or parenteral administration. Of these, topical or oral administration is especially preferred. Depending upon the particular route of administration desired, a variety of pharmaceutically-acceptable carriers well-known in the art may be used. These include solid or liquid fillers, diluents, hydrotropes, surface-active agents, and encapsulating substances. Optional pharmaceutically-active materials may be included, which do not substantially interfere with the activity of the compound of the present invention. The amount of carrier employed in conjunction with the compound is sufficient to provide a practical quantity of material for administration per unit dose of the compound. Techniques and compositions for making dosage forms useful in the methods of this invention are described in the following references: Modern Pharmaceutics. Chapters 9 and 10, Banker & Rhodes, eds. (1979); Lieberman et al., Pharmaceutical Dosage Forms. Tablets (1981); and Ansel, Introduction to Pharmaceutical Dosage Forms, 2nd Ed., (1976).

Some examples of substances which can serve as pharmaceutically-acceptable carriers or components thereof are sugars, such as lactose, glucose and sucrose; starches, such as com starch and potato starch; cellulose and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose, and methyl cellulose; powdered tragacanth; malt; gelatin; talc; solid lubricants, such as steaπc acid and magnesium stearate; calcium sulfate; vegetable oils, such as peanut oil, cottonseed oil, sesame oil, olive oil, corn oil and oil of theobroma; polyols such as propylene glycol, glycerine, sorbitol, mannitol, and polyethylene glycol; algmic acid; emulsifiers, such as the TWEENS; wetting agents, such sodium lauryl sulfate; coloring agents; flavoring agents; tabletmg agents, stabilizers; antioxidants; preservatives; pyrogen-free water; isotonic saline; and phosphate buffer solutions.

The choice of a pharmaceutically-acceptable carrier to be used m conjunction with the subject compound is basically determined by the way the compound is to be administered.

In particular, pharmaceutically-acceptable carriers for systemic administration include sugars, starches, cellulose and its derivatives, malt, gelatin, talc, calcium sulfate, vegetable oils, synthetic oils, polyols, algmic acid, phosphate buffer solutions, emulsifiers, isotonic saline, and pyrogen-free water. Preferred carriers for parenteral administration include propylene glycol, ethyl oleate, pyrrolidone, ethanol, and sesame oil. Preferably, the pharmaceutically-acceptable earner, in compositions for parenteral administration, comprises at least about 90% by weight of the total composition.

Various oral dosage forms can be used, including such solid forms as tablets, capsules, granules and bulk powders. These oral forms comprise a safe and effective amount, usually at least about 5%, and preferably from about 25% to about 50%, of a compound of the present invention. Tablets can be compressed, tablet triturates, enteric- coated, sugar-coated, film-coated, or multiple-compressed, containing suitable binders, lubricants, diluents, disintegrating agents, coloring agents, flavoring agents, flow-inducing agents, and melting agents. Liquid oral dosage forms include aqueous solutions, emulsions, suspensions, solutions and/or suspensions reconstituted from non-effervescent granules, and effervescent preparations reconstituted from effervescent granules, containing suitable solvents, preservatives, emulsifying agents, suspending agents, diluents, sweeteners, melting agents, coloring agents and flavoring agents.

The pharmaceutically-acceptable carrier suitable for the preparation of unit dosage forms for oral administration are well-known in the art. Tablets typically comprise conventional pharmaceutically-compatible adjuvants as inert diluents, such as calcium carbonate, sodium carbonate, mannitol, lactose and cellulose; binders such as starch, gelatin and sucrose; disintegrants such as starch, algmic acid and croscarmelose; lubricants such as magnesium stearate, steaπc acid and talc. Ghdants such as silicon dioxide can be used to improve flow characteristics of the powder mixture. Coloring agents, such as the FD&C dyes, can be added for appearance. Sweeteners and flavoring agents, such as aspartame, saccharin, menthol, peppermint, and fruit flavors, are useful adjuvants for chewable tablets. Capsules (including time release and sustained release formulations) typically comprise one or more solid diluents disclosed above. The selection of carrier components depends on secondary considerations like taste, cost, and shelf stability, which are not critical for the purposes of the subject invention, and can be readily made by a person skilled in the art.

Orally administered compositions also include liquid solutions, emulsions, suspensions, powders, granules, elixirs, tinctures, syrups, and the like. The pharmaceutically-acceptable earners suitable for preparation of such compositions are well known in the art. Typical components of carriers for syrups, elixirs, emulsions and suspensions include ethanol, glycerol, propylene glycol, polyethylene glycol, liquid sucrose, sorbitol and water. For a suspension, typical suspending agents include methyl cellulose, sodium carboxymethyl cellulose, AVICEL RC-591, tragacanth and sodium alginate; typical wetting agents include lecithin and polysorbate 80; and typical preservatives include methyl paraben and sodium benzoate. Peroral liquid compositions may also contain one or more components such as sweeteners, flavoring agents and colorants disclosed above.

Such compositions may also be coated by conventional methods, typically with pH or time-dependent coatings, such that the subject compound is released in the gastrointestinal tract in the vicinity of the desired topical application, or at various times to extend the desired action. Such dosage forms typically include, but are not limited to, one or more of cellulose acetate phthalate, polyvinylacetate phthalate, hydroxypropyl methyl cellulose phthalate, ethyl cellulose, Eudragit coatings, waxes and shellac.

Other compositions useful for attaining systemic delivery of the subject compounds include sublmgual, buccal and nasal dosage forms. Such compositions typically comprise one or more of soluble filler substances such as sucrose, sorbitol and mannitol; and binders such as acacia, microcrystalhne cellulose, carboxymethyl cellulose and hydroxypropyl methyl cellulose. Ghdants, lubricants, sweeteners, colorants, antioxidants and flavoring agents disclosed above may also be included.

The compounds of the present invention may also be topically administered. The carrier of the topical composition preferably aids penetration of the present compounds into the skm to reach the environment of the hair follicle. Topical compositions of the present invention may be in any form including, for example, solutions, creams, ointments, gels, lotions, shampoos, leave- on and rmse-out hair conditioners, milks, cleansers, moisturizers, sprays, skm patches, and the like.

Topical compositions containing the active compound can be admixed with a variety of carrier materials well known in the art, such as, for example, water, alcohols, aloe vera gel, allantom, glycerine, vitamm A and E oils, mineral oil, propylene glycol, PPG-2 mynstyl propionate, and the like.

Other materials suitable for use in topical carriers include, for example, emollients, solvents, humectants, thickeners and powders Examples of each of these types of materials, which can be used singly or as mixtures of one or more materials, are as follows:

Emollients, such as stearyl alcohol, glyceryl monoπcinoleate, glyceryl monostearate, propane-l,2-dιol, butane-l,3-dιol, mink oil, cetyl alcohol, wo-propyl isostearate, steaπc acid, iso- butyl palmitate, isocetyl stearate, oleyl alcohol, isopropyl laurate, hexyl laurate, decyl oleate, octadecan-2-ol, isocetyl alcohol, cetyl palmitate, dimethylpolysiloxane, dι-«-butyl sebacate, isopropyl myπstate, .so-propyl palmitate, iso-pτopy stearate, butyl stearate, polythylene glycol, tπethylene glycol, lanolin, sesame oil, coconut oil, arachis oil, castor oil, acetylated lanolin alcohols, petroleum, mineral oil, butyl mynstate, lsosteaπc acid, palmitic acid, isopropyl hnoleate, lauryl lactate, mynstyl lactate, decyl oleate, and mynstyl mynstate; propellants, such as propane, butane, jso-butane, dimethyl ether, carbon dioxide, and nitrous oxide; solvents, such as ethyl alcohol, methylene chloride, wo-propanol, castor oil, ethylene glycol monoethyl ether, diethylene glycol monobutyl ether, diethylene glycol monoethyl ether, dimethyl sulphoxide, dimethyl formamide, tetrahydrofuran; humectants, such as glycerin, sorbitol, sodium 2- pyrrohdone-5-carboxylate, soluble collagen, dibutyl phthalate, and gelatin; and powders, such as chalk, talc, fullers earth, kaolin, starch, gums, colloidal silicon dioxide, sodium polyacrylate, tetra alkyl ammonium smectites, tπalkyl aryl ammonium smectites, chemically modified magnesium aluminium silicate, organically modified montmoπllonite clay, hydrated aluminium silicate, fumed silica, carboxyvinyl polymer, sodium carboxymethyl cellulose, and ethylene glycol monostearate.

The compounds used in the present invention may also be administered in the form of hposome delivery systems, such as small unilamellar vesicles, large umlamellar vesicles, and multilamellar vesicles. Liposomes can be formed from a variety of phospholipids, such as cholesterol, stearylamme or phosphatidylchohnes. A preferred formulation for topical delivery of the present compounds utilizes liposomes such as described in Dowton et al., "Influence of Liposomal Composition on Topical Delivery of Encapsulated Cyclosporin A: I. An in vitro Study Using Hairless Mouse Skm", S.T.P Pharma Sciences. Vol. 3, pp. 404 - 407 (1993), Wallach and Phihppot, "New Type of Lipid Vesicle: Novasome®", Liposome Technology, Vol. 1, pp. 141 - 156 (1993), and Wallach. U.S Patent No 4,911,928, assigned to Micro-Pak, Inc., issued March 27, 1990. The compounds utilized m the present invention may also be administered by iontophoresis. See, e.g.. www.unιpr.ιt/a a/dιpfarm erasmus/erasml4.html, Banga et al., "Hydrogel-based Iontotherapeutic Delivery Devices for Transdermal Delivery of Peptide/Protem Drugs", Pharm. Res.. Vol. 10 (5), pp. 697-702 (1993), Ferry L.L., "Theoretical Model of Iontophoresis Utilized in Transdermal Drug Delivery", Pharmaceutical Acta Helvetiae, Vol 70, pp. 279-287 (1995), Gangarosa et al., "Modern Iontophoresis for Local Drug Delivery", Int. J. Pharm, Vol. 123, pp. 159-171 (1995), Green et al., "lontophoretic Delivery of a Series of Tπpeptides Across the Skm in vitro", Pharm Res., Vol 8, pp. 1121-1127 (1991), Jadoul et al., "Quantification and Localization of Fentanyl and TRH Delivered by Iontophoresis in the Skin", Int. J. Pharm.. Vol. 120, pp. 221-8 (1995), O'Brien et al., "An Updated Review of its Antiviral Activity, Pharmacok etic Properties and Therapeutic Efficacy", Drugs, Vol. 37, pp. 233-309 (1989), Parry et al., "Acyclovir Biovailabihty in Human Skin", J. Invest. Dermatol.. Vol. 98 (6), pp. 856-63 (1992), Santi et al., "Drug Reservoir Composition and Transport of Salmon Calcitonin in Transdermal Iontophoresis", Pharm. Res., Vol 14 (1), pp. 63-66 (1997), Santi et al., "Reverse Iontophoresis - Parameters Determining Electroosmotic Flow: I. pH and Ionic Strength", J. Control. Release. Vol. 38, pp. 159-165 (1996), Santi et al., "Reverse Iontophoresis - Parameters Determining Electroosmotic Flow: II. Electrode Chamber Formulation", J. Control. Release, Vol. 42, pp. 29-36 (1996), Rao et al., "Reverse Iontophoresis: Nonmvasive Glucose Monitoring in vivo in Humans", Pharm. Res., Vol. 12 (12), pp. 1869-1873 (1995), Thysman et al., "Human Calcitonin Delivery in Rats by Iontophoresis", J Pharm. Pharmacol.. Vol 46, pp. 725-730 (1994), Volpato et al., "Iontophoresis Enhances the Transport of Acyclovir through Nude Mouse Skin by Electrorepulsion and Electroosmosis", Pharm. Res., Vol. 12 (11), pp. 1623-1627 (1995).

The compositions utilized in the present invention may also optionally comprise an activity enhancer. The activity enhancer can be chosen from a wide variety of molecules which can function in different ways to enhance hair growth effects of a compound of the present invention. Particular classes of activity enhancers include other hair growth stimulants and penetration enhancers.

Additional hair growth stimulants can be chosen from a wide variety of molecules which can function in different ways to enhance the hair growth effects of the compositions and methods of the present invention. These optional other hair growth stimulants, when present, are typically employed in the compositions herein at a level ranging from about 0.01% to about 15%, preferably from about 0.1% to about 10%, most preferably from about 0.5% to about 5% by weight of the composition.

Vasodilators such as potassium channel agonists including, for example, mmoxidil and mmoxidil derivatives such as ammexil and such as those described in U.S. Patent 3,382,247, U.S. Patent 5,756,092, issued May 26, 1998, U.S. Patent 5,772,990, issued June 30, 1998, U.S. Patent 5,760,043, issued June 2, 1998, U.S. Patent 328,914, issued July 12, 1994, U.S. Patent 5,466,694, issued November 14, 1995, 5,438,058, issued August 1, 1995, and U.S. Patent 4,973,474, issued November 27, 1990, (all of which are herein incorporated by reference), and cromakahn and diazoxide can be used as an additional hair growth stimulant in the compositions herein.

One suitable class of additional hair growth stimulant for use herein are antiandrogens. Examples of suitable antiandrogens may include, but are not limited 5-α-reductase inhibitors such as finesteπde and those described in U.S. Patent 5,516,779, issued May 14, 1996 (herein incorporated by reference) and in Nane et al., Cancer Research 58, "Effects of Some Novel Inhibitors of C17,20-Lyase and 5α-Reductase in vitro and in vivo and Their Potential Role in the Treatment of Prostate Cancer," as well as cyproterone acetate, azelaic acid and its derivatives and those compounds described in U.S. Patent 5,480,913, issued January 2, 1996, flutamide, and those described in U.S. Patents 5,411,981, issued May 2, 1995, U.S. Patent5,565,467, issued October 15, 1996 and U.S. Patent 4,910,226, issued March 20, 1990, all of which are herein incorporated by reference.

Another suitable class of optional hair growth stimulants are immunosuppressants or non-immunosuppressants such as 1) cyclosporin and cyclosporin analogs including those described in U.S. Provisional Patent Application No. 60/122,925, Fulmer et al., "Method of Treating Hair Loss Using Non-immunosuppressive Compounds", filed March 5, 1999, herein incorporated by reference, and 2) FK506 analogs such as those described in U.S. Provisional Patent Application No. 60/102,449, Mclver et al., "Heterocychc 2-Substιtuted Ketoamides", filed September 30, 1998, U.S. Provisional Patent Application No. 60/102,448, Mclver et al., "2- Substituted Ketoamides", filed September 30, 1998, U.S. Provisional Patent Application No. 60/102,539, Mclver et al., "2-Substιtuted Heterocychc Sulfonamides", filed September 30, 1998, U.S. Provisional Patent Application No. 60/102,458, Tiesman et al., "Method of Treating Hair Loss Using Ketoamides", filed September 30, 1998, and U.S. Provisional Patent Application No. 60/102,437, Mclver et al., "Method of Treating Hair Loss Using Sulfonamides", filed September 30, 1998, all of which are herein incorporated by reference. Another suitable class of optional hair growth stimulants are antimicrobials such as selenium sulfide, ketoconazole, friclocarbon, tnclosan, zmc pynthione, ifraconazole, asiatic acid, hmokitiol, mipirocm and those described in EPA 0,680,745 (herein incorporated by reference), clinacycm hydrochloπde, benzoyl peroxide, benzyl peroxide and mmocyclm.

Anti-inflammatoπes can also be incorporated into the compositions herein as an optional hair growth stimulant Examples of suitable anti-mflammatones may include glucocorticoids such as hydrocortisone, mometasone furoate and prednisolone, nonsteroidal anti-mflammatones including cyclooxygenase or hpoxygenase inhibitors such as those described in U.S Patent 5,756,092, and benzydamine, salicylic acid, and those compounds described in EPA 0,770,399, published May 2, 1997, WO 94/06434, published March 31, 1994, and FR 2,268,523, published November 21 , 1975, all of which are herein incorporated by reference.

Another suitable class of optional hair growth stimulants are thyroid hormones and derivatives and analogs thereof. Examples of suitable thyroid hormones for use herein may include tniodothyπonine Examples of thyroid hormone analogs which may be suitable for use herein include those described in U.S. Provisional Patent Application No. 60/136,996, Zhang et al., "Method of Treating Hair Loss", filed June 1, 1999, U.S. Provisional Patent Application No. 60/137,024, Zhang et al., "Method of Treating Hair Loss Using Biphenyl Compounds", filed June 1, 1999, U.S. Provisional Patent Application No 60/137,022, Zhang et al , "Method of Treating Hair Loss Using Carboxyl Derivatives", filed June 1, 1999, U.S. Provisional Patent Application No. 60/137,023, Zhang et al., "Method of Treating Hair Loss Using Sulfonyl Thyromimetic Compounds", filed June 1, 1999, U.S. Provisional Patent Application No. 60/137,052, Youngqmst et al, "Biaryl Compounds", filed June 1, 1999, U.S. Provisional Patent Application No 60/137,063, Youngqmst et al., "Sulfur-Bridged Compounds", filed June 1, 1999, and U.S. Provisional Patent Application No. 60/136,958, Youngqmst et al., "Substituted Biaryl Ether Compounds", filed June 1, 1999.

Prostaglandm agonists or antagonists can also be used as optional hair growth stimulants in the compositions herein. Examples of suitable prostaglandms agonists or antagonists include latanoprost and those described in WO 98/33497, Johnstone, published August 6, 1998, WO 95/11003, Stjernschantz, published April 27, 1995, JP 97-100091, Ueno and JP 96-134242, Nakamura.

Another class of optional hair growth stimulants for use herein are retinoids. Suitable retmoids may include isotretinoin, acitretin, and tazarotene. Another class of optional hair growth stimulants for use herein are triterpenes such as, for example, those disclosed in Bradbury et al., U.S. Patent Application Serial No. 09/353,408, "Method for Regulating Hair Growth", filed July 15, 1999 and Bradbury et al., U.S. Patent Application Serial No. 09/353,409, "Compositions Which Contain Triterpenes for Regulating Hair Growth", filed July 15, 1999, each incorporated by reference in their entirety.

Other classes of optional hair growth stimulants for use herein include flavmoids, ascomycm derivatives and analogs, histam e antagonists such as diphenhydramme hydrochlonde, other triterpenes such as oleanolic acid and ursolic acid and those described in U.S. Patent 5,529,769, JP 10017431, WO 95/35103, U.S. Patent 5,468,888, JP 09067253, WO 92/09262, JP 62093215, U.S. Patent 5,631,282, U.S. Patent 5,679,705, JP 08193094, saponms such as those described in EP 0,558,509 to Bonte et al., published September 8, 1993 and WO 97/01346 to Bonte et al, published January 16, 1997 (both of which are herein incorporated by reference in their entirety), proteoglycanase or glycosammoglycanase inhibitors such as those described in U.S. Patents 5,015,470, issued May 14, 1991, U.S. Patent 5,300,284, issued April 5, 1994 and U.S. Patent 5,185,325, issued February 9, 1993 (all of which are herein incorporated m their entirety by reference) estrogen agonists and antagonists, pseudoteπns, cytokme and growth factor promotors, analogs or inhibitors such as interleukinl inhibitors, mterleukm-6 inhibitors, mterleukm-10 promotors, and tumor necrosis factor inhibitors, vitamins such as vitam D analogs and parathyroid hormone antagonists, Vitamin B12 analogs and panthenol, mterfuron agonists and antagonists, hydroxyacids such as those described in U.S. Patent 5,550,158, benzophenones, and hydantom anticonvulsants such as phenytom.

Other additional hair growth stimulants are described in detail in, for example, JP 09- 157,139 to Tsuji et al., published June 17, 1997; EP 0277455 Al to Mirabeau, published August 10, 1988; WO 97/05887 to Cabo Soler et al., published February 20, 1997; WO 92/16186 to Bonte et al., published March 13, 1992; JP 62-93215 to Okazaki et al., published April 28, 1987; U.S. Patent 4,987,150 to Kurono et al., issued January 22, 1991; JP 290811 to Ohba et al., published October 15, 1992; JP 05-286,835 to Tanaka et al., published November 2, 1993, FR 2,723,313 to Greff, published August 2, 1994, U. S. Patent 5,015,470 to Gibson, issued May 14, 1991, U.S. Patent 5,559,092, issued September 24, 1996, U.S. Patent 5,536,751, issued July 16, 1996, U.S. Patent 5,714,515, issued February 3, 1998, EPA 0,319,991, published June 14, 1989, EPA 0,357,630, published October 6, 1988, EPA 0,573,253, published December 8, 1993, JP 61- 260010, published November 18, 1986, U.S. Patent 5,772,990, issued June 30, 1998, U.S. Patent 5,053, 410, issued October 1, 1991, and U.S. Patent 4,761,401, issued August 2, 1988, all of which are herein incorporated by reference.

Non-hmitmg examples of penetration enhancers which may be used in the compositions herein include, for example, 2-methyl propan-2-ol, propan-2-ol, ethyl-2-hydroxypropanoate, hexan-2,5-dιol, POE(2) ethyl ether, dι(2-hydroxypropyl) ether, pentan-2,4-dιol, acetone, POE(2) methyl ether, 2-hydroxypropιonιc acid, 2-hydroxyoctanoιc acid, propan-1-ol, 1,4-dioxane, tetrahydrofuran, butan-l,4-dιol, propylene glycol dipelargonate, polyoxypropylene 15 stearyl ether, octyl alcohol, POE ester of oleyl alcohol, oleyl alcohol, lauryl alcohol, dioctyl adipate, dicapryl adipate, di-isopropyl adipate, di-isopropyl sebacate, dibutyl sebacate, diethyl sebacate, dimethyl sebacate, dioctyl sebacate, dibutyl suberate, dioctyl azelate, dibenzyl sebacate, dibutyl phthalate, dibutyl azelate, ethyl mynstate, dimethyl azelate, butyl mynstate, dibutyl succ ate, didecyl phthalate, decyl oleate, ethyl caproate, ethyl sahcylate, zsø-propyl palmitate, ethyl laurate, 2-ethyl-hexyl pelargonate, zso-propyl isostearate, butyl laurate, benzyl benzoate, butyl benzoate, hexyl laurate, ethyl caprate, ethyl caprylate, butyl stearate, benzyl sahcylate, 2- hydroxypropanoic acid, 2-hyroxyoctanoιc acid, dimethyl sulphoxide, N,N-dιmethyl acetamide, N,N-dιmethyl formamide, 2-pyrrohdone, 1 -methyl-2 -pyrrolidone, 5-methyl-2 -pyrrolidone, 1,5- dimethyl -2 -pyrrolidone, l-ethyl-2 -pyrrolidone, phosphme oxides, sugar esters, tetrahydro furfural alcohol, urea, dιethyl-/;.-toluamιde, and, l-dodecylazacyloheptan-2-one.

In all of the foregoing, of course, the compounds used in the present method can be administered alone or as mixtures, and the compositions may further include additional drugs or excipients as appropriate for the indication

The present invention further relates to kits comprising a compound and / or composition herein and information and / or instructions by words, pictures, and / or the like, that use of the kit will provide treatment for hair loss in mammals (particularly humans) including, for example, arresting and / or reversing hair loss and / or promoting hair growth. In addition or m the alternative, the kit may comprise a compound and / or composition herein and information and / or instructions regarding methods of application of the compound and / or composition, preferably with the benefit of treating hair loss m mammals.

Examples of Composition Administration

The following examples do not limit the invention, but provide guidance to the skilled artisan to perform the methods of the present invention. In each example, a "compound" other than the one mentioned may be substituted in the example by one having a structure as descnbed herein with similar results. Example A A composition for topical administration is made, comprising:

Figure imgf000047_0001

A human male subject suffering from male pattern baldness is treated by a method of this invention. Specifically, for 6 weeks, the above composition is daily administered topically to the subject.

Example B

A composition for topical administration is made according to the method of Dowton et al., "Influence of Liposomal Composition on Topical Delivery of Encapsulated Cyclosporin A- I. An in vitro Study Using Hairless Mouse Skin", S.T.P. Pharma Sciences, Vol. 3, pp. 404 - 407 (1993), using the compound of Example 2 in lieu of cyclosporin A and using the Novasome 1 for the non-ionic liposomal formulation.

A human male subject suffering from male pattern baldness is treated each day with the above composition. Specifically, for 6 weeks, the above composition is administered topically to the subject.

Example C

A shampoo is made, comprising:

Figure imgf000047_0002

Figure imgf000048_0001

A human male subject suffering from male pattern baldness is treated by a method of this invention. Specifically, for 12 weeks, the above shampoo is used daily by the subject.

Claims

What is claimed is:
1. Use, in the manufacture of a composition to treat hair loss, of a compound characterized by the structure:
M-L-Q and pharmaceutically acceptable salts, hydrates, and biohydrolyzable amides, esters, and imides thereof, wherein M and Q are each, independently, radicals of structure I and wherein L is a linker moiety which covalently links M and Q together; wherein structure I is:
Figure imgf000049_0001
wherein:
(a) each G is, independently, selected from the group consisting of nil, aliphatic, heteroahphatic, aryl, heteroaryl, cycloahphatic, heterocycloaliphatic, and
Figure imgf000049_0002
(b) each n is, independently, an integer selected from the group consisting of 1 and 2;
(c) each X is independently selected from the group consisting of -0-, -NH-, and -CH2-;
(d) each R] is, independently, selected from the group consisting of aliphatic, heteroahphatic, cycloahphatic, heterocycloaliphatic, aryl, and heteroaryl;
(e) each CA is a carbon atom;
(f) each Cβ is a carbon atom;
(g) each Bi and B is, independently, selected from the group consisting of hydrogen, aliphatic, heteroahphatic, aryl, and heteroaryl; or wherein each Bi and B of the same G are, together, a carbonyl group; and
(h) each R2 is, independently, selected from the group consisting of nil, aliphatic, heteroahphatic, cycloahphatic, heterocycloaliphatic, aryl, and heteroaryl; wherein when G of M is nil, L is covalently attached to CA of M; wherein when G of Q is nil, L is covalently attached to CA of Q; wherein when B] and B of M are, together, a carbonyl group and R2 is nil, L is covalently attached to CB of M; and wherein when B] and B2 of Q are, together, a carbonyl group and R2 is nil, L is covalently attached to CB of Q.
2. A use according to claim 1 wherein each G is:
Figure imgf000050_0001
and wherein each Bi and B2 of each G are, together, a carbonyl group.
3. A use according to claim 2 wherein M and Q are equivalent.
4. A use according to claim 3 wherein each Ri is:
Figure imgf000050_0002
wherein:
(a) each R is selected from the group consisting of hydrogen, alkyl, heteroalkyl, aryl, and heteroaryl optionally substituted with aryl;
(b) each R5 is - C8 alkyl; and
(c) each R6 is selected from the group consisting of alkyl, heteroalkyl, heterocycle, aryl, and heteroaryl optionally substituted with aryl.
5. A use according to claim 4 wherein each R2 is ml.
6. A use according to claim 1 wherein each G is:
Figure imgf000050_0003
and wherein each Bi and B is, independently, selected from the group consisting of hydrogen, aliphatic, heteroahphatic, aryl, and heteroaryl.
7. A use according to claim 6 wherein each Bi and B2 is hydrogen.
8. A use according to claim 7 wherein M and Q are equivalent.
9. A use according to claim 8 wherein each Ri is:
Figure imgf000051_0001
wherein:
(a) each R4 is selected from the group consisting of hydrogen, alkyl, heteroalkyl, aryl, and heteroaryl optionally substituted with aryl;
(b) each R5 is Ci - Cg alkyl; and
(c) each R6 is selected from the group consisting of alkyl, heteroalkyl, heterocycle, aryl, and heteroaryl optionally substituted with aryl.
10 A use according to claim 1 wherein the composition is administered by a method selected from the group consisting of topically and orally.
11. A compound characterized by the structure:
M-L-Q and pharmaceutically acceptable salts, hydrates, and biohydrolyzable amides, esters, and imides thereof, wherein M and Q are each, independently, radicals of structure II and wherein L is a linker moiety which covalently links M and Q together; and wherein structure II is:
Figure imgf000051_0002
wherein:
(a) each G is independently selected from nil and
Figure imgf000051_0003
(b) each n is, independently, an integer selected from 1 and 2; (c) each X is independently selected from -O-, -NH-, and -CH -;
(d) each Ri is, independently, selected from aliphatic, heteroahphatic, cycloahphatic, heterocycloaliphatic, aryl, and heteroaryl;
(e) each CA IS a carbon atom;
(f) each CB IS a carbon atom;
(g) L is aryl; wherein when G of M is nil, L is covalently attached to CA of M; wherein when G of Q is nil, L is covalently attached to CA of Q; wherein when G of M is:
Figure imgf000052_0001
L is covalently attached to CB of M; and wherein when G of Q is:
Figure imgf000052_0002
L is covalently attached to CB of Q.
12. A compound characterized by the structure:
M-L-Q and pharmaceutically acceptable salts, hydrates, and biohydrolyzable amides, esters, and imides thereof, wherein M and Q are each, independently, radicals of structure III and wherein L is a linker moiety which covalently links M and Q together; wherein structure HI is:
Figure imgf000052_0003
wherein:
(a) each G is independently selected from aliphatic, heteroahphatic, aryl, heteroaryl, cycloahphatic, heterocycloaliphatic, and
Figure imgf000052_0004
(b) each n is, independently, an integer selected from the group consisting of 1 and 2;
(c) each X is independently selected from the group consisting of -0-, -NH-, and -CH2-; (d) each Bi and B is, independently, selected from the group consisting of hydrogen, aliphatic, heteroahphatic, aryl, and heteroaryl; or wherein each Bi and B2 of the same G are, together, a carbonyl group;
(e) each R- is, independently, selected from the group consisting of aliphatic, heteroahphatic, cycloahphatic, heterocycloaliphatic, aryl, and heteroaryl;
(f) each R2 is, independently, selected from the group consisting of aliphatic, heteroahphatic, cycloahphatic, heterocycloaliphatic, aryl, and heteroaryl; and
(g) L is selected from the group consisting of bond, -0-, -S-, and -NH-.
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