EP1194422A1

EP1194422A1 - Biaryl compounds

Info

Publication number: EP1194422A1
Application number: EP00915935A
Authority: EP
Inventors: Robert Scott Youngquist; John Mcmillan Mciver
Original assignee: UT Southwestern Medical Center
Current assignee: UT Southwestern Medical Center
Priority date: 1999-06-01
Filing date: 2000-03-01
Publication date: 2002-04-10
Also published as: MXPA01012496A; JP2003500483A; CA2375674A1; AU3711700A; WO2000073292A1

Abstract

The present disclosure describes novel compounds and compositions which are particularly useful for treating hair loss in mammals, including arresting and/or reversing hair loss and promoting hair growth. The compounds have a biphenyl structure as described in formula (I) and are preferably cardiac-sparing, and pharmaceutically acceptable salts, hydrates and biohydrolyzable amides, esters, and imides thereof, wherein, R1, R2, R3, R4, R5, R6, R6', R7, R8, R9, R10, Y, X, R11, and R12 are defined herein.

Description

BIARYL COMPOUNDS

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 m 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 m the germ, expansion of the dermal papilla, and elaboration of basement membrane components. 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 in 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 Rogame^® by Pharmacia & Upjohn), and oral fmasteπde (marketed as Propecia^® by Merck & Co., Inc.). For several reasons, however, including safety concerns and / or lack of efficacy, the search for efficacious hair growth mducers is ongoing.

Interestingly, it is known that the thyroid hormone known as thyroxme ("T4") converts to thyronme ("T3") in human skin by deiodmase I, a selenoprotem. Selenium deficiency causes a decrease in T3 levels due to a decrease in deiodinase I activity; this reduction in T3 levels is strongly associated with hair loss. Consistent with this observation, hair growth is a reported side effect of administration of T4. See, e g , Berman, "Peripheral Effects of L-Thyroxme on Hair Growth and Coloration in Cattle", Journal of Endocrinology, Vol. 20, pp 282 - 292 (1960); and Gunaratnam, "The Effects of Thyroxme on Hair Growth m the Dog", J Small Anun. Pract., Vol. 27, pp. 17 - 29 (1986). Furthermore, T3 and T4 have been the subject of several patent publications relating to treatment of hair loss See, e.g., Fischer et al., DE 1,617,477, published January 8, 1970; Mortimer. GB 2,138,286, published October 24, 1984; and Lmdenbaum, WO 96/25943, assigned to Life Medical Sciences, Inc., published August 29, 1996

Unfortunately, however, administration of T3 and / or T4 to treat hair loss is not practicable because these thyroid hormones are also known to induce significant cardiotoxicity. See, e.g.. Walker et al., U.S. Patent No. 5,284,971, assigned to Syntex, issued February 8, 1994 and Emmett et al., U.S. Patent No. 5,061,798, assigned to Smith Kline & French Laboratories, issued October 29, 1991. Surprisingly, the present inventors have discovered compounds which strongly initiate hair growth without inducing cardiotoxicity. Consistent with this discovery, but without intending to be limited by theory, the present inventors have surprisingly discovered that the preferred compounds of the present invention interact strongly with hair-selective thyroid hormone receptors but interact less strongly, or not at all, with heart-selective hormone receptors. These unique properties are, of course, not shared with T3 and / or T4. Accordingly, the compounds and compositions herein are useful for treating hair loss, including arresting and / or reversing hair loss and promoting hair growth.

SUMMARY OF THE INVENTION

The present invention relates to compounds and compositions which are particularly useful for treating hair loss m mammals, including arresting and / or reversing hair loss and promoting hair growth.

The compounds of the present invention have the structure:

and pharmaceutically acceptable salts, hydrates, and biohydrolyzable amides, esters, and lmides thereof, wherein R_l5 R₂, R₃, ^, R-, Re, Re', R , Rs, R9, Rio, Y, X, Rπ, and R_u are defined herein

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to compounds and compositions which are particularly useful for treating 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 the preferred compounds of the present invention are cardiac-spaπng.

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 mvention vaπous 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 vaπable, moiety, group, or the like occurs more than one time m any variable or structure, its definition at each occurrence is independent of its definition at every other occurrence.

Definition and Usage of Terms The following is a list of definitions for terms used herein'

As used herein "salt" is a cationic 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 cationic 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 ha des (such as, for example, chloride salts) Such acceptable salts must, when administered, be appropriate for mammalian use.

As used herein, "alkenyl" is an unsubstituted or substituted hydrocarbon chain radical having from 2 to about 15 carbon atoms; preferably from 2 to about 10 carbon atoms; more preferably from 2 to about 8 carbon atoms, and most preferably from about 2 to about 6 carbon atoms. Alkenyls have at least one olefmic double bond. Non-hmitmg examples of alkenyls include vinyl, allyl, and butenyl

As used herein, "alkoxy" is an oxygen radical having an alkyl, alkenyl, or alkynyl, preferably an alkyl or alkenyl, and most preferably an alkyl substituent. Examples of alkoxy radicals include -O-alkyl and -O-alkenyl. An alkoxy radical may be substituted or unsubstituted.

As used herein, "aryloxy" is an oxygen radical having an aryl substituent. An aryloxy radical may be substituted or unsubstituted.

As used herein, "alkyl" is an unsubstituted or substituted saturated hydrocarbon chain radical having from 1 to about 15 carbon atoms; preferably from 1 to about 10 carbon atoms; more preferably from 1 to about 6 carbon atoms; and most preferably from 1 to about 4 carbon atoms. Preferred alkyls include, for example, methyl, ethyl, propyl, ..rø-propyl, and butyl.

As used herein, "alkylene" refers to an alkyl, alkenyl, or alkynyl which is a diradical. For example, "methylene" is -CH2-. Alkylenes may be substituted or unsubstituted.

As used herein, "alkynyl" is an unsubstituted or substituted hydrocarbon chain radical having from 2 to about 15 carbon atoms, preferably from 2 to about 10 carbon atoms; more preferably from 2 to about 8 carbon atoms, and most preferably from about 2 to about 6 carbon atoms. Alkynyls have at least one triple bond.

As used herein, "aryl" is an aromatic ring radical which is either carbocychc or heterocyclic. Preferred aryl groups include, for example, phenyl, benzyl, tolyl, xylyl, cumenyl, napthyl, biphenyl, thienyl, furyl, pyrrolyl, pyridmyl, pyrazmyl, thiazolyl, pyπmidmyl, qumolmyl, triazolyl, tetrazolyl, benzothiazolyl, benzofuryl, indolyl, mdenyl, azulenyl, fluorenyl, anthracenyl, oxazolyl, isoxazolyl, isotπazolyl, lmidazolyl, pyraxolyl, oxadiazolyl, mdohzmyl, indolyl, isoindolyl, puπnyl, qumohzmyl, qumolmyl, lsoqumohnyl, cmnolmyl, and the like. Aryls may be substituted or unsubstituted. As used herein, "arylalkenyl" is an alkenyl radical substituted with an aryl group or an aryl radical substituted with an alkenyl group Arylalkenyls may be substituted or unsubstituted

As used herein, "arylalkyl" is an alkyl radical substituted with an aryl group or an aryl radical substituted with an alkyl group. Preferred arylalkyl groups include benzyl, phenylethyl, and phenylpropyl. Arylalkyls may be substituted or unsubstituted.

As used herein, "biohydrolyzable amides" are amides of the compounds of 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 of 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 of 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, "carbocychc ring", "carbocycle", or the like is a hydrocarbon ring radical. Carbocychc rings are monocyclic or are fused, bridged, or spiro polycychc rings. Unless otherwise specified, monocyclic πngs contain from 3 to about 9 atoms, preferably from about 4 to about 7 atoms, and most preferably 5 or 6 atoms. Polycychc rings contain from about 7 to about 17 atoms, preferably from about 7 to about 14 atoms, and most preferably 9 or 10 atoms. Carbocychc πngs (carbocycles) may be substituted or unsubstituted.

As used herein, "cycloalkyl" is a saturated carbocychc or heterocychc ring radical Preferred cycloalkyl groups include, for example, cyclobutyl, cyclopentyl, and cyclohexyl Cycloalkyls may be substituted or unsubstituted.

As used herein, "cycloalkenyl" is an unsaturated carbocychc or heterocychc πng radical having at least one double bond. Cycloalkenyls may be substituted or unsubstituted.

As used herein, preferred "halogens" (or "halos" or the like) are bromine, chloπne, iodine, and fluoπne, more preferably, bromine, chlorine, and iodine, even more preferably bromine and chloπne, and most preferably chloπne.

As used herein, "heteroalkenyl" is an alkenyl radical comprised of carbon atoms and one or more heteroatoms wherein the heteroatoms are selected from the group consisting of oxygen, sulfur, nitrogen, and phosphorous, more preferably, oxygen, sulfur, and nitrogen. Heteroalkenyls may be substituted or unsubstituted.

As used herein, "heteroalkyl" is an alkyl radical comprised of carbon atoms and one or more heteroatoms wherein the heteroatoms are selected from the group consisting of oxygen, sulfur, nitrogen, and phosphorous, more preferably, oxygen, sulfur, and nitrogen. Heteroalkyls may be substituted or unsubstituted.

As used herein, "heteroalkynyl" is an alkynyl radical comprised of carbon atoms and one or more heteroatoms wherein the heteroatoms are selected from the group consisting of oxygen, sulfur, nitrogen, and phosphorous, more preferably, oxygen, sulfur, and nitrogen. Heteroalkynyls may be substituted or unsubstituted.

As used herein, "heteroaryl" is an aryl radical comprised of carbon atoms and one or more heteroatoms wherein the heteroatoms are selected from the group consisting of oxygen, sulfur, nitrogen, and phosphorous, more preferably, oxygen, sulfur, and nitrogen. Heteroaryls may be substituted or unsubstituted.

As used herein, "heteroarylalkenyl" is an arylalkenyl radical wherein the aryl group and / or the alkenyl group is comprised of carbon atoms and one or more heteroatoms wherein the heteroatoms are selected from the group consisting of oxygen, sulfur, nitrogen, and phosphorous, more preferably, oxygen, sulfur, and nitrogen. Heteroarylalkenyls may be substituted or unsubstituted.

As used herein, "heteroarylalkyl" is an arylalkyl radical wherein the aryl group and / or the alkyl group is compπsed of carbon atoms and one or more heteroatoms wherein the heteroatoms are selected from the group consisting of oxygen, sulfur, nitrogen, and phosphorous, more preferably, oxygen, sulfur, and nitrogen. Heteroarylalkyls may be substituted or unsubstituted.

As used herein, "heterocychc πng", "heterocycle", or the like is a ring radical compπsed of carbon atoms and one or more heteroatoms in the ring wherein the heteroatoms are selected from the group consisting of oxygen, sulfur, nitrogen, and phosphorous, more preferably, oxygen, sulfur, and nitrogen. Heterocycles are monocyclic or are fused, bridged, or spiro polycychc πngs. Unless otherwise specified, monocycles contain from 3 to about 9 atoms, preferably from about 4 to about 7 atoms, and most preferably 5 or 6 atoms. Polycycles contain from about 7 to about 17 atoms, preferably from about 7 to about 14 atoms, and most preferably 9 or 10 atoms. Heterocychc πngs (heterocycles) may be substituted or unsubstituted.

As used herein, "heterocycloalkyl" is a cycloalkyl having at least one heteroatom m the πng. Heterocycloalkyls may be substituted or unsubstituted.

As used herein, "heterocycloalkenyl" is a cycloalkenyl having at least one heteroatom m the πng. Heterocycloalkyls may be substituted or unsubstituted.

As used herein, a "lower" moiety (e g , "lower" alkyl) is moiety having 1 to about 6, preferably 1 to about 4, carbon atoms. 7

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

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 unless otherwise specified, the term "substituted" m reference to a group, moiety, or the like, means having one or more substituent groups each independently selected from hydrogen, alkyl, alkenyl, alkoxy, hydroxy, mtro, ammo, alkylammo, cyano, halo, thiol, aryl, cycloalkyl, heteroaryl, heterocycloalkyl (e g , pipeπdinyl, morpholmyl, pyrrolidmyl), lmino, hydroxyalkyl, aryloxy, and arylalkyl, preferably hydrogen, alkyl, alkenyl, alkoxy, hydroxy, mtro, ammo, alkylammo, halo, thiol, and aryloxy, more preferably hydrogen, alkyl, alkenyl, alkoxy, hydroxy, mtro, ammo, alkylammo, and halo, even more preferably hydrogen, alkyl, and alkoxy, and most preferably alkoxy.

Compounds of the Present Invention The compounds of the present invention have the structure:

and pharmaceutically acceptable salts, hydrates, and biohydrolyzable amides, esters, and lmides thereof, wherein: (a) Ri, R₂, R₅, R₇, and R]₀ are each, independently, selected from the group consisting of hydrogen, halogen, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, and heteroalkynyl,

(b) R₄ is selected from the group consisting of halogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, arylalkyl, heteroalkyl, heteroalkenyl, heteroalkynyl, heterocycloalkyl, heterocycloalkenyl, heteroaryl, heteroarylalkyl, and heteroarylalkenyl; wherein when R is hydrogen, Y is -CH₂CHKι, X is selected from the group consisting of -NZ- and -NH-, and R₁₂ is - C₄ alkyl, wherein K] is selected from hydrogen and C, - C₄ alkyl and Z is Cj - C₄ alkyl, then R, is not arylalkyl;

(c) R₈ and R₉ are each, independently, selected from the group consisting of hydrogen, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, arylalkyl, heteroalkyl, heteroalkenyl, heteroalkynyl, heterocycloalkyl, heterocycloalkenyl, heteroaryl, heteroarylalkyl, and heteroarylalkenyl; wherein at least one of Rg and R₉ is not hydrogen;

(d) R₃ is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, arylalkyl, heteroalkyl, heteroalkenyl, heteroalkynyl, heterocycloalkyl, heterocycloalkenyl, heteroaryl, heteroarylalkyl and heteroarylalkenyl ;

(e) Re and R are each, independently, selected from the group consisting of hydrogen, halogen, hydroxy, ammo, mtro, cyano, carboxy, thiol, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, and heteroalkynyl, or wherein R₆ and R₆' are, together, oxo or thioxo;

(f) Y is selected from the group consisting of bond, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, and heteroalkynyl;

(g) X is selected from the group consisting of -NZ-, -NH- and -0-;

(h) R_π is selected from the group consisting of bond and -C(O)-; wherein when Y is bond and X is -O- then R„ is -C(O)-;

(1) R₁₂ is selected from the group consisting of alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, and heteroarylalkenyl; or wherein when R_u is bond, then R_]2 and Z may be optionally bonded together to form a cycle selected from the group consisting of cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, and heteroaryl; wherein when R₁₂ is heteroalkyl, heteroalkenyl, heteroalkynyl, heterocycloalkyl, heterocycloalkenyl, heteroaryl, heteroarylalkyl, or heteroarylalkenyl, then a heteroatom of R_]2 is not directly covalently bonded to R_π; and wherein when Y is bond, X is -0-, and Rn is -C(O)- then R_] is not alkyl; and (j) Z is selected from the group consisting of alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, and heteroalkynyl; or wherein when R_n is bond, then R₁₂ and Z may be optionally bonded together to form a cycle selected from the group consisting of cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, and heteroaryl.

The present compounds are biphenyl compounds linked through a carbon atom which is substituted with substituents R_f, and RN The remaining substituents, as well as R_<; and R₆' are described in further detail below

The Substituents Ru R , Rs. R₇, and Rio

The substituents R_1; R₂, R₅, R₇, and R₁₀ each substitute on one of the phenyl rings of the structure shown herein. R_l5 R₂, R₅, R₇, and R_]0 are each, independently, selected from hydrogen, halogen, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, and heteroalkynyl.

Ri, R₂, R5, R7, and R₁₀ are preferably each, independently, selected from hydrogen, halogen, alkyl, alkenyl, heteroalkyl, and heteroalkenyl. R,, R₂, R₅, R₇, and Rj₀ are more preferably each, independently, selected from hydrogen, halogen, and lower alkyl Most preferably, Ri, R₂, R₅, R₇, and R₁₀ are each hydrogen.

The Substituent R4

The substituent R₄ is selected from halogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, arylalkyl, heteroalkyl, heteroalkenyl, heteroalkynyl, heterocycloalkyl, heterocycloalkenyl, heteroaryl, heteroarylalkyl, and heteroarylalkenyl; wherein when R₂ is hydrogen, Y is -CH₂CHKι, X is selected from the group consisting of -ΝZ- and -ΝH-, and R_l2 is Ci - C alkyl, wherein Kj is selected from hydrogen and Cj - C₄ alkyl and Z is - C alkyl, then ₄ is not arylalkyl.

R₄ is preferably selected from halogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroalkyl, heteroalkenyl, heteroalkynyl, heterocycloalkyl, heterocycloalkenyl, heteroaryl, heteroarylalkyl, and heteroarylalkenyl. R₄ is more preferably selected from halogen, alkyl, alkenyl, heteroalkyl, and heteroalkenyl. R, is even more preferably selected from halogen, alkyl, alkenyl, and heteroalkyl. ( is most preferably selected from halogen and lower alkyl. The most 10

preferred halogens for R, are chloπne, bromine, and iodine, preferably chlorine and iodine, and most preferably iodine. The most preferred lower alkyls for R₄ are methyl, ethyl, wσ-propyl, and tert-butyl, preferably methyl, .so-propyl, and tert-butyl, more preferably zso-propyl or tert-butyl. Most preferably, R, is lower alkyl, particularly .50-propyl or tert-butyl.

The Substituents R₈ and R₉

R₈ and R₉ are each, independently, selected from hydrogen, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, arylalkyl, heteroalkyl, heteroalkenyl, heteroalkynyl, heterocycloalkyl, heterocycloalkenyl, heteroaryl, heteroarylalkyl, and heteroarylalkenyl; wherein at least one of R₈ and R₉ is not hydrogen Preferably, each of R₈ and R₉ are not hydrogen.

R₈ and R₉ are preferably each, independently, selected from halogen, alkyl, alkenyl, heteroalkyl, and heteroalkenyl. R₈ and R₉ are more preferably each, independently, selected from halogen, alkyl, alkenyl, and heteroalkyl R₈ and R₉ are even more preferably each, independently, selected from halogen and lower alkyl. The most preferred halogens for R₈ and R₉ are chloπne and bromine, preferably chlorine. The most preferred lower alkyls for R₈ and R₉ are methyl, ethyl, zso-propyl, and tert-butyl, preferably methyl, ..SO-propyl, and tert-butyl, more preferably methyl and .50-propyl. Most preferably, R₈ and R₉ are each, independently, selected from lower alkyl and halogen, particularly methyl and chlorine, respectively.

The Substituent R₃

R₃ substitutes on the oxygen moiety of the biphenyl structure as shown above. R₃ is selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, arylalkyl, heteroalkyl, heteroalkenyl, heteroalkynyl, heterocycloalkyl, heterocycloalkenyl, heteroaryl, heteroarylalkyl and heteroarylalkenyl. Preferably, R₃ is selected from hydrogen, alkyl, alkenyl, cycloalkyl, aryl, arylalkyl, heteroalkyl, heteroalkenyl, heterocycloalkyl, heteroaryl, and heteroarylalkyl. More preferably, R₃ is selected from hydrogen, alkyl, alkenyl, aryl, arylalkyl, heteroalkyl, heteroaryl, and heteroarylalkyl. Still more preferably, R₃ is selected from hydrogen, alkyl, alkenyl, arylalkyl (preferably benzyl), heteroalkyl, and heteroarylalkyl. Even more preferably, R₃ is selected from hydrogen, lower alkyl, and lower alkenyl. Most preferably, R₃ is selected from hydrogen and lower alkyl The most preferred lower alkyl for R₃ is methyl.

The Substituents Rή and R '

Re and Re' are each, independently, selected from hydrogen, halogen, hydroxy, ammo, mtro, cyano, carboxy, thiol, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, and 11

heteroalkynyl; or wherein Rg and R₆' are, together, oxo or thioxo. Preferably, R₆ and R ' are each, independently, selected from hydrogen, halogen, hydroxy, ammo, thiol, alkyl, and heteroalkyl; or wherein R and R₆' are, together, oxo. More preferably, Re and R₆' are each, independently, selected from hydrogen, halogen, hydroxy, ammo, and lower alkyl; or wherein Re and Re' are, together, oxo. Still more preferably, R₆ and Re' are each, independently, selected from hydrogen, halogen, hydroxy, and lower alkyl (most preferably Ci - C₃ alkyl); or wherein Re and Re' are, together, oxo Even more preferably, R₆ and R₆' are each, independently, selected from hydrogen and hydroxy, or wherein R₆ and R₆' are, together, oxo. Most preferably, R₆ and Re' are each hydrogen.

The Substituent Y

Y is selected from bond, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, and heteroalkynyl. Wherein Y is bond, X is directly bonded to the phenyl πng beaπng R₇, R₈, R₉, and R₁₀. Y is preferably selected from bond, alkyl, alkenyl, heteroalkyl, and heteroalkenyl. More preferably, Y is selected from bond and lower alkyl. Most preferably, Y is bond.

The Substituent X

X is selected from -NZ-, -NH-, and -0-. Z substitutes on the nitrogen of -NZ- and is selected from alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, and heteroalkynyl; or wherein when Rn is bond, then R₁₂ and Z may be optionally bonded together to form a cycle selected from cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, and heteroaryl. Preferably, Z is selected from alkyl, alkenyl, heteroalkyl, and heteroalkenyl, or R_π and Z are bonded together to form a cycle selected from cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, and heteroaryl. More preferably, Z is lower alkyl, or R₁₂ and Z are bonded together to form a cycle selected from cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, and heteroaryl. Most preferably, Z is - C₃ alkyl, particularly methyl, or R_]2 and Z are bonded together to form a cycle selected from cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, and heteroaryl.

Preferably, X is selected from -NH- and -NZ-. Most preferably, X is -NH-, -N(CH₃)-, or -NZ- wherein R_I2 and Z are bonded together to form a cycle selected from the group consisting of cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, and heteroaryl.

Wherein R_!2 is bonded to Z to form a cycle, the cycle is preferably selected from cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, more preferably from cycloalkyl, heterocycloalkyl, and aryl, even more preferably from cycloalkyl and heterocycloalkyl, and most preferably heterocycloalkyl. In addition to the optional substituents descnbed herein above, the cycle may also optionally bear one or more oxo (i e , doubly bonded oxygen) substituents. Non- limiting examples of these cycles include pipeπdmyl, morpholmyl, piperazmyl, pyrrolidinyl, mdolmyl, succimrmdyl, and hydantomyl.

The Substituent R_π

Rj ) is selected from bond and -C(O)- with the proviso that wherein when Y is bond and X is -O- then Rn is -C(O)-. Wherein R_n is bond, R_!2 is directly bonded to X and the compound is an armne (wherein X is -NZ- or -NH-) or an ether (wherein X is -O- and Y is not bond). While both bond and -C(O)- are both highly preferred for Rj i , most preferably, Rj i is -C(O)-.

The Substituent Rn

R₁₂ is selected from alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, and heteroarylalkenyl; or wherein when Rn is bond, then R₁₂ and Z may be optionally bonded together to form a cycle selected from the group consisting of cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, and heteroaryl; wherein when R_I2 is heteroalkyl, heteroalkenyl, heteroalkynyl, heterocycloalkyl, heterocycloalkenyl, heteroaryl, heteroarylalkyl, or heteroarylalkenyl, then a heteroatom of R_]2 is not directly covalently bonded to Rn. Accordingly, carbamates and ureas at the -Y-X-R_ι Rι₂ linkage are not contemplated withm the present invention. For example, wherein R₁₂ is heteroalkyl, it is not, e g , -0-CH₂- CH₃, but could be, e g , -CH₂-0-CH₃.

Additionally, wherein when Y is bond, X is -0-, and R_π is -C(O)- then R₁₂ is not alkyl.

Preferably, R_]2 is selected from alkyl, alkenyl, heteroalkyl, heteroalkenyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, and heteroarylalkenyl, or is bonded to Z to form a cycle selected from cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, and heteroaryl. More preferably, R_!2 is selected from alkyl, alkenyl, heteroalkyl, heteroalkenyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, and heteroarylalkenyl, or is bonded to Z to form a cycle selected from cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, and heteroaryl. Even more preferably, R₁₂ is selected from alkyl, heteroalkyl, arylalkyl, and heteroarylalkyl, or is bonded to Z to form a cycle selected from cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, and heteroaryl. Most preferably, Rι₂ is lower alkyl, or is bonded to Z to form a cycle selected from cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, and heteroaryl. The most preferred 13

lower alkyls for R₁₂ are methyl, ethyl, «-propyl, .so-propyl, /.-butyl, tert-butyl, and ft-pentyl, particularly methyl, «-propyl, zso-propyl, «-butyl, and tert-butyl.

Wherein R_]2 is bonded to Z to form a cycle, the cycle is preferably selected from cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, more preferably from cycloalkyl, heterocycloalkyl, and aryl, even more preferably from cycloalkyl and heterocycloalkyl, and most preferably heterocycloalkyl In addition to the optional substituents described herein above, the cycle may also optionally bear one or more oxo (i e , doubly bonded oxygen) substituents. Non- limiting examples of these cycles include piperidmyl, morpholmyl, piperazmyl, pyrrolidmyl, mdohnyl, succmimidyl, and hydantoinyl.

Preferred compounds of the present mvention are set forth in the following tables:

Table 1 - Preferred Compounds of the Present Invention In the following preferred compounds, Re and R^' are each hydrogen:

Table 2 - Preferred Compounds of the Present Invention In the following preferred compounds, R₆ and R₆' are, together, oxo:

Table 3 - Preferred Compounds of the Present Invention ing preferred compounds, R₆ is hydrogen and R₆' is hydroxy:

Analytical Methods The present invention relates to compounds and methods for treating hair loss. Preferably, the compound utilized in the present invention will be cardiac-spaπng. Compounds (test compounds) may be tested for their ability to induce anagen and their lack of cardiotoxicity (cardiac-sparmg) using the following methods. Alternatively, other methods well-known in the art may be used (but with the term "cardiac-sparmg" being defined according to the method disclosed herein below).

Cardiotoxicity Assay:

The cardiotoxicity assay measures the potential of a test compound to adversely affect the cardiovascular system As thyroid hormone (T3) damages the cardiovascular system, the heart enlarges. See, e.g., Gomberg-Maitland et al , "Thyroid hormone and Cardiovascular Disease", American Heart Journal, Vol. 135(2), pp. 187-196 (1998); Klem and Oiamaa, "Thyroid Hormone and the Cardiovascular System", Current Opinion in Endocrinology and Diabetes, Vol. 4, pp.341-346 (1997); and Klemperer et al., "Thyroid Hormone Therapy and Cardiovascular Disease", Progress in Cardiovascular Diseases, Vol. 37 (4), pp. 329-336 (1996). 25

This increases the weight of the heart relative to whole body weight The cardiotoxicity assay herein below is used to test compounds for potentially adverse cardiac effects by measuring their effect on the heart-to-body weight ratio.

Two groups each of six male Sprague Dawley rats (Harlan Sprague Dawley, Ine , Indianapolis, IN) (each weighing from approximately 220 grams to 235 grams) are utilized. The first group is a vehicle control group and the second group is a test compound group. The length of the assay is 30 days, with treatment of vehicle or test compound m vehicle daily for 28 of those days as described below

Prior to initiation of the assay, each rat is allowed to acclimate to standard environmental conditions for 5 days. Each rat receives food (standard rat chow diet) and water ad libitum 5 days prior to initiation of the assay as well as to termination of the study

The vehicle is 91 :9 (vv) propylene glycohethanol The test compound is prepared at a concentration of 500 μg/mL in the vehicle.

Each rat is weighed on day 1 of the assay. Dosage calculations are then performed: each rat will be administered daily a dosing solution of vehicle or test compound in vehicle (depending on whether the rat is in the vehicle control group or the test compound group, respectively) at 500 μL of dosmg solution per kg of rat. For rats in the test compound group, this corresponds to a dose of 250 μg of test compound per kg of rat.

Day 2 is the first day of treatment with dosmg solution for both groups Body weights are taken for each rat on days 3, 5, 8, 10, 12, 15, 17, 19, 22, 24, 26, and 29 prior to dosmg for that day; for each rat, the dosmg solutions are recalculated and administered accordingly upon change in body weight.

Treatment occurs once daily in the morning on days 2 through 29, inclusive, for each rat in each group. For each treatment, the dosing solution is administered subcutaneously between the shoulders of the rat such that the injection sites are rotated in this area.

On day 30 in the morning, the rats of each group are euthanized with C0₂ from dry ice. Each rat is immediately weighed for total body weight.

The hearts of each rat are then excised as follows. An incision is made to expose the abdominal cavity. The rib cage is carefully cut at the sternum with small scissors, such that the heart and lungs are exposed. With small scissors and forceps, the vessels connected to the heart are cut away from the heart. These vessels include the caudal vena cava, left cranial vena cava (pulmonary trunk), πght cranial vena cava, thoracic aorta, right subclavian artery, internal thoracic artery and vein, and any other small attachments. The heart is then immediately taken out intact, including the left and πght auricles and left and right ventπcles. ]-rnmedιately 26

thereafter, any excess tissue is trimmed away, the heart is lightly blotted on a paper towel until no more blood is visibly left behind on the paper towel, and the heart is weighed

The heart weight is divided by the body weight after euthanization for each rat to give the heart/body ratio. The heart/body ratios for each rat in the vehicle control group are added together and divided by 6 (i e , the total number of rats m the group) to give RV (ratio for vehicle control group). Similarly, the heart/body ratios for each rat in the test compound group are added together and divided by 6 to give RT (ratio for test compound group).

The index C is then calculated by dividing RT by RV. As defined herein, where C is less than 1.3, the test compound is cardiac-sparmg. Preferably, C is less than 1.2, more preferably less than 1.15, and most preferably less than 1 1. In accordance with this method, T3 and T4 are not cardiac-sparme.

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 pπncipal phases of the hair growth cycle: anagen, catagen, and telogen. It is believed that there is a longer telogen period m 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 the topical application of hair growth mducers are evaluated. 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 and a test compound group, wherein the test compound group is administered a compound according to 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 earned out to Day 24 if the melanogenesis response looks positive, but occurs slowly. A typical study design is shown in Table 4 below. Typical dosage concentrations are set forth in Table 4, however the ordinarily skilled artisan will readily understand that such concentrations may be modified.

Table 4 27

**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 in the application area of each animal. As a mouse converts from telogen to anagen, its skin color will become more bluish-black. As indicated in Table 5, the grades 0 to 4 represent the following visual observations as the skm progresses from white to bluish-black.

Table 5

Methods of Making The compounds of the present invention are prepared according to methods which are well-known to those ordinarily skilled m the art. The starting materials used m prepanng the 28

compounds of the invention are known, made by known methods, or are commercially available as a starting material

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

The ordinarily 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 ordinarily 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 withm the scope of the ordinarily 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 compounds of the present invention may be prepared using a vaπety of procedures known to those ordmanly skilled m the art. Non-limiting general preparations include the following.

The compounds of the invention can be prepared, after removal of temporary protection groups, by condensing (e.g , acylatmg or alkylatmg) a compound of the structure:

wherein R_ls R₂, R₃, R- , R„ Re, Re', R7, R₈, R9, Rio, Y, and X are defined herein above and are m an appropπately protected form if necessary (see, e.g., T. Greene, Protecting Groups in Organic Synthesis, John Wiley & Sons, 1981), with a reactive derivative of a structure.

. R 12

HO^' (in)

or

.R 12 (IN)

wherein R₁₂ is defined herein above and is in an appropriately protected form if necessary and Q is a halogen, preferably bromine or iodine, and most preferably iodine. Reactive derivatives of structure II include activated esters such as 1 -hydroxybenzotπazole esters and similar active esters known to those ordinarily skilled m the art and includes mixed anhydndes with organic or inorganic acids such as hydrochloric acid, other halo-acids and sulfonic acids as well as similar acids known to those ordinarily skilled m the art. Additionally, reactive deπvatives of structure II include symmetπcal anhydrides of the acids of structure II. Activated deπvatives of structure HI include tπfluoromethane sulfonyl esters and other activated derivatives known to those ordmanly skilled in the art. Compounds of structure IV are generally appropnately reactive without further modification; however, it may be necessary to convert a less reactive halogen to a more reactive halogen such as bromine or iodine as is known by those ordmanly skilled in the art. Many appropnately activated denvatives of formulas π, HI, or IV are commercially available and others can be prepared by methods known to those ordmanly skilled in the art. A non-limiting example of condensations of this type is given m Example 4, below.

Additionally, appropriately protected compounds resulting from the condensation of a compound of stucture I with a compound of structure II, III or IV may be further modified to afford additional compounds of the invention after removal of temporary protection groups. These modifications include, but are not limited to, reduction of an amide to an amme as described in Example 5 to afford a secondary or tertiary amme and alkylation of an amine as described in Example 9.

Furthermore, compounds of the present invention wherein R₆ and R₆' are together oxo, may be reduced to afford additional compounds of the invention after removal of any temporary protecting groups by reduction of the ketone functionality to an alcohol functionality affording a benzhydrol in which, for example, R is hydroxy and Re' is hydrogen A non-limitmg example of this reaction is given in Example 5. Additional reduction of this type of compound, m an appropriately protected form if necessary, is then possible to afford a compound of the present invention wherein both Re, and R₆' are hydrogen. Non-limiting examples of this reaction are provided in Examples 2, 6, and 8. One may also oxidize compounds wherein Re is hydroxy and Re' is hydrogen to compounds of the invention wherein R^ and R₆' are together oxo using an oxidizing agent, for example pyπdinium dichromate in an inert solvent (e g , dichloromethane) at a reduced temperature, for example 0 °C.

Compounds of the structure I may also be prepared from compounds of structure V (see below) wherein P is, for example, mtro or cyano. Compounds of structure V are prepared by activation of an aromatic acid of the structure VI by alkylation of an anisole of structure VII using Fπedel-Crafts conditions familiar to those ordinarily skilled in the art. Compounds of the structures V and IN are commercially available or may be prepared by means well known in the art. A non-limitmg example of this alkylation reaction is set forth m Example 3.

31

Compounds of the structure V may be converted to compounds of structure I by further transformation. For example, wherein P is mtro, the resulting compound of structure V may be converted into a compound of structure I by reduction to the amme using standard chemical reaction conditions such as hydrogen and palladium on carbon as in Example 3. Wherein P is cyano, the compound of structure V may be converted a compound of structure I by reduction to an alkylated amme using conditions known to those ordinarily skilled in the art.

Compounds of the present invention can also be prepared using aromatic hahdes of structure VH and benzaldehyde deπvatives of the structure LX. Compounds of the structures VHJ and LX are commercially available or may be prepared by means well known in the art. A non-limiting of the preparation of a compound of structure VUI is provided in Example 1. 32

Derivatives of the structure LX may be prepared from aromatic hahdes as described in Examples 1, 7 and 10. The aromatic hahde of the structure VHI is converted to the aryl lithium using a hthium-halogen exchange reaction as described m Examples 1, 7 and 10 and reacted with the derivative of structure LX to afford a compound of the present invention which either Re is hydroxy and R₆' is hydrogen.

For even further guidance, the following provides non-limiting examples illustrating more specifically the methods of making various compounds of the present invention.

As used herein, the following abbreviations are used:

Example 1

33

la. 4-bromo-3,5-dimethyl-nitrobenzene: 2',6'-dιmethyl-4-nιtrophenol (3 g) is added to 50 mL dichloromethane followed by addition of 3.6 mL pyπdme. The solution is cooled to 0 °C and 3.6 mL tπfluoromethanesulfonic anhydride is added dropwise over 20 minutes. The reaction is mixed for about 2.5 hours at 0 °C Water (25 mL) is added to quench the reaction. The organic layer is extracted twice with 25 mL IN hydrochloric acid, twice with 25 mL water, twice with 25 mL IN sodium hydroxide, twice with 25 mL water, dried with magnesium sulfate, and concentrated under reduced pressure. The remaining residue is dissolved in 40 mL of DMF followed by addition of lithium bromide (4.7 g). The mixture is refluxed for 17 hours at 150 °C. The mixture is concentrated under high vacuum. To this residue, 60 mL water and 60 mL ethyl acetate is added and stirred. This mixture is filtered and the organic layer is separated and dned with magnesium sulfate. The organic layer is concentrated under high vacuum and the remaining residue presorbed to silica gel using dichloromethane. The presorbed residue is then 34

purified by chromatography on silica gel (hexane. ethyl acetate) and crystallization from hexanes to afford la

lb. 4-bromo-3,5-dimethylaniline: A solution of 4-bromo-3,5-dιmethyl-nιtrobenzene (la; 0.6 g) is dissolved in 10 mL of ethyl acetate and 80 mg of 10% palladium on carbon is added. The reaction is hydrogenated and then filtered through Cehte and concentrated under reduced pressure to afford lb

lc. 7V-[4-bromo-3,5-dimethylphenyl]pyrrolidine: 4-bromo-3,5-dιmethylanalme (lb; 0.88 g) is dissolved m 2 mL ethanol and 0.75 mL 1 ,4-dnodobutane is added. The sample is refluxed overnight. At this time, it is concentrated under reduced pressure The sample is taken up in ethyl acetate and extracted with 0.1 N sodium hydroxide, water, and brme After drying over sodium sulfate, filtering and concentration under reduced pressure, it is purified by chromatography on silica gel (hexane:ethyl acetate) to afford lc.

Id. N-[4-carboxaldehyde-3,5-dimethylphenyl]pyrrolidine: N-[4-bromo-3,5- dιmethylphenyl]pyrrolιdme (lc; 0.44 g) is dissolved in 10 mL THF and cooled to -78 °C under a nitrogen atmosphere. To this solution is added 2.0 mL tert-butyl lithium (1.7 M in pentane) and the reaction is stirred for 10 minutes. At this time, it is removed from the cooling bath and allowed to stir for 10 minutes. It is then cooled to -78 °C and 0.27 mL DMF is added. After 10 minutes, the cooling bath is removed and the reaction is stirred for an additional 2 hours. The reaction is transferred to a separately funnel with 15 mL ether and 15 mL water and the aqueous layer is acidified with 1 Ν HC1. The organic layer is isolated and extracted 5 times with brme and the organic layer is dried over sodium sulfate and concentrated under reduced pressure. Purification by chromatography on silica gel (hexane:ethyl acetate) affords Id.

le. 2-isø-propyl anisole: Potassium hydroxide (5.6 g) is added to 13.4 mL acetone followed by 2-zso-propylphenol (13.6 g). After the potassium hydroxide is dissolved, methyl iodide (14.2 g) is added. The reaction is refluxed overnight. 150 mL of water is added. This reaction is extracted 3 times with 100 mL diethyl ether. The organic layer is extracted twice with 100 mL 10% sodium hydroxide in water, once with 100 mL water, and once with 100 mL saturated ammonium chloπde. After drying over magnesium sulfate, the organic solution is dried over magnesium sulfate, filtered and concentrated under reduced pressure. The material is fractionally distilled under reduced pressure to afford le. If. 4-bromo-2- so-propyl anisole: Potassium bromide (6 3 g), is suspended in 80 mL dichloromethane and the reaction is cooled to 0 °C under nitrogen. To this mixture is added 18- crown-6 (0.7 g) dissolved in 20 mL dichloromethane. At this time, 3-chloroperoxybenzoιc acid (9.2 g) in 100 mL dichloromethane is added Then, 2-z-fo-propyl anisole (le; 4 g) is added dropwise and the reaction stirs for an additional 3 hours at 0 °C under nitrogen At this time, the reaction is poured into 300 mL of ice water and stirred for 30 minutes. The organic layer is isolated and washed with a saturated sodium hydrogen carbonate solution, then water and the organic layer is dried over magnesium sulfate and concentrated under reduced pressure. Purification by chromatography on silica gel (hexane:ethyl acetate) affords If.

Ig. -V-[3,5-dimethyl-4-(3'-ι^;so-propyI-4'-methoxybenzyIhydroxy)phenyl]pyrrolidine: 4- bromo-2-z5o-propyl anisole (If, 0.6 g) is dissolved in 15 mL THF and cooled to -78 °C under a nitrogen atmosphere. To this solution is added 3.4 mL tert-butyl lithium (1.7 M in pentane) and the reaction is stirred for 10 minutes. At this time, the mixture is removed from the cooling bath and allowed to stir for 10 minutes. It is then cooled to -78 °C and N-[4-carboxaldehyde-3,5- dιmethylphenyl]pyrrolιdme (Id; 0.53 g) is added. The reaction is stirred for 1 hour then the cooling bath is removed and stirred for an additional 2 hours The reaction is transferred to a separatory funnel with 15 mL ether and 15 mL water and the aqueous layer is acidified with 1 Ν HCl. The organic layer is isolated and extracted 5 times with brme, then dried over sodium sulfate and concentrated under reduced pressure Purification by chromatography on silica gel (hexane:ethyl acetate) affords lg.

36

Example 2

2. N-[3,5-dimethyl-4-(3'- so-propyI-4'-methoxybenzyl)phenyl]pyrrolidine: N-[3,5- dιmethyl-4-(3'-z-ro-propyl-4'-methoxybenzylhydroxy)phenyl]pyrrolιdme (lg; 0.4 g) is dissolved in 10 mL of 9% acetic acid in ethanol and 50 mg of 10% palladium on carbon is added. The reaction is hydrogenated, then filtered through Celite and concentrated under reduced pressure to afford 2.

Example 3

le

3a. 2,6-dichloro-4-nitrobenzoic acid: 2,6-dιchloro-4-mtrotoluene (3 g) is dissolved in 12.5 mL pyridme followed by addition of 12.8 mL water. The mixture is warmed to 90 °C and potassium permanganate (14.1 g) is added over 1 hour. The mixture is then refluxed for 1 hour and then filtered hot. The filtrate is extracted once with 50 mL chloroform. The aqueous layer is acidified with 6Ν hydrochloric acid and extracted twice with 50 mL chloroform. After drying over magnesium sulfate, the organic solution is filtered, and concentrated under reduced pressure to afford 3a.

3b. 2,6-dichloro-4-nitro-3'- so-propyI-4'-methoxy-benzophenone: 2,6-dιchloro-4- mtrobenzoic acid (3a, 0.4 g) is dissolved in 5 mL thionyl chloride and refluxed for 1 hour. The thionyl chloride is then distilled away under reduced pressure and the remaining residue dissolved 300 μL dichloromethane. To this solution, 150 μL tπfluoromethanesulfonic acid and 2-z.sO-propyl anisole (le; 0.17 g) is added and reacted for 5 hours. The dichloromethane is then removed under reduced pressure and the remaining residue dissolved in 20 mL ethyl acetate. The organic solution is extracted twice with 20 mL brine solution. The organic layer is concentrated under reduced pressure and purified by chromatography on silica gel (hexane:ethyl acetate) to afford 3b.

3c. 2,6-dichloro-4-amino-3'- so-propyl-4'-methoxy-benzophenone: 2,6-dιchloro-4-mtro-3 '- wo-propyl-4'-methoxy-benzophenone (3b; 144 mg) is dissolved in a mixture containing 10 mL ethanol and 10 mL ethyl acetate. To this mixture, 19.2 mg of 10% palladium on carbon is added. The reaction is hydrogenated, then filtered through Celite and concentrated under reduced pressure to afford 3c.

Example 4

3c 4

4. 2,6-dichloro-4-butyryl amido-3'-.sø-propyl-4'-methoxy-benzophenone: Pyridme (91 μL) and butyric anhydride (184 μL) are added to 2,6-dιchloro-4-amιno-3'-zso-propyl-4'-methoxy- benzophenone (3c; 130 mg) and the reaction is stirred overnight. The reaction mixture is concentrated under reduced pressure and the residue is taken up in 20 mL ethyl acetate. The organic solution is extracted once with 20 mL saturated sodium bicarbonate, once with 20 mL 38

0.1 N hydrochloric acid, concentrated under reduced pressure and purified by chromatography on silica gel (9: 1 hexane:ethyl acetate) to afford 4.

Example 5

4 5

5. N-[3,5-dichloro-4-(3'- so-propyl-4'-methoxybenzylhydroxy)phenyl]butylamine: 2,6- dichloro-4-butyryl amιdo-3'-wo-propyl-4'-methoxy-benzophenone (4; 0.53 g) is dissolved in THF (10 mL) and added dropwise to a mixture of lithium aluminum hydride (0.33 g) in THF (20 mL) under nitrogen and allowed to react overnight. The reaction is cooled in an ice bath and water (2 mL) is added dropwise followed by 2 mL 15% sodium hydroxide then 15 mL water. The precipitate that is formed is filtered off and the precipitate is washed with THF and ethyl acetate. The filtrate is concentrated under reduced pressure and the product is punfied by chromatography on silica gel (hexanes:methylene chloride) to afford 5.

5 6

6. N-[3,5-dimethyI-4-(3'-ιso-propyl-4'-methoxybenzyl)phenyl]butylamine: N-[3,5-dιchloro- 4-(3'-z50-propyl-4'-methoxybenzylhydroxy)phenyl]butylamme (5; 0.6 g) is dissolved m 12 mL of 9% acetic acid in ethanol and 75 mg of 10% palladium on carbon is added. The reaction is hydrogenated. The reaction is filtered through Celite and concentrated under reduced pressure and the product is purified by chromatography on silica gel (hexanes:dιchloromethane) to afford 6.

Example 7

7a. N-[4-bromo-3,5-dimethylphenyl]morpholine: 4-bromo-3,5-dιmethylanalme (lb; 0.72 g) is dissolved m 2 mL ethanol and 0.95 mL dι(2-ιodoethyl)ether is added. The sample is refluxed overnight. At this time, it is concentrated under reduced pressure. The sample is taken up in ethyl acetate and extracted with 0.1 Ν sodium hydroxide, water, and bnne. After drying over sodium sulfate, filtenng, and concentrating under reduced pressure, the mixture is purified by chromatography on silica gel (hexane:ethyl acetate) to afford 7a. 40

7b. N-[3,5-dimethyl-4-(3'- so-propyl-4'-methoxybenzylhydroxy)phenyI]morpholine: N-

[3,5-dimethyl-4-(3'-z50-propyl-4'-methoxybenzylhydroxy)phenyl]morpholme (7b) is prepared analogously to the preparation described above for N-[3,5-dιmethyl-4-(3'-z5O-propyl-4'- methoxybenzylhydroxy)phenyl]pyrrolιdιne (lg)

Example 8

8. N-[3,5-dimethyl-4-(3'- s->-propyl-4'-methoxybenzyl)phenyl]morpholine: N-[3,5- dιmethyl-4-(3'-z5θ-propyl-4'-methoxybenzylhydroxy)phenyl]moφholme (7b, 0.3 g) is dissolved m 10 mL of 9% acetic acid in ethanol and 45 mg of 10% palladium on carbon is added. The reaction is hydrogenated (about 16 hours), then filtered through Celite and concentrated under reduced pressure to afford 8.

9. N-methyl-N-[3,5-dimethyl-4-(3'- s->-propyl-4'-methoxybenzyl)phenyI]butylamine: N-

[3,5-dimethyl-4-(3'-z5o-propyl-4'-methoxybenzyl)phenyl]butylamme (6), 0.1 g, is dissolved in 1 mL THF. To this solution is added 50 mg sodium borohydnde The resulting slurry is added to a 0 °C solution of 0.24 mL 3 0 M sulfuric acid, 0.086 mL 37% aqueous solution of formaldehyde and 1 mL THF. The reaction is stirred for 2 hours and then poured into 3 mL IN sodium hydroxide. The aqueous layer is extracted twice with diethyl ether and the organic layers are combined and washed with bnne. The organic layer is filtered and the filtrate is concentrated under reduced pressure and the product is purified by chromatography on silica gel (hexanes: dichloromethane) to afford 9.

10a 10b

10c. V-[3,5-dimethyl-4-(3'-benzyl-4'-methoxybenzylhydroxy)phenyl]pyrrolidine: N-[3,5- dιmethyl-4-(3'-benzyl-4'-methoxybenzylhydroxy)phenyl]pyrrolιdme (10c) is prepared analogously to N-[3,5-dιmethyl-4-(3 '-z50-propyl-4'-methoxybenzylhydroxy)phenyl]pyrrohdme (lg), by substituting 2-benzylphenol for 2-zso-propylphenol.

Use of the Present Compounds

According to the methods of the present invention, a compound having a structure as described herein is administered, most preferably with a pharmaceutically-acceptable or cosmetically-acceptable earner.

The compounds of the present invention 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.

In addition, the compounds of the present invention may be useful for weight control, including the treatment and / or prevention of obesity. Other uses for the compounds of the present invention include stimulation of nail growth, treatment of skm conditions, prevention of 43

hair discoloration, obesity, cholesterol lowering, treatment of thyroid disorders, and treatment of osteoporosis

Preferably the compounds of the present invention are, as defined herein, cardiac- sparmg.

Preferably, the compounds are formulated into pharmaceutical or cosmetic 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 or cosmetically-acceptable carrier (herein collectively described as "carrier"). The term "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, in 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 (most preferably human), being treated. The carrier can itself be inert or it can possess pharmaceutical and / or cosmetic benefits of its own.

The compositions of 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 and / or oral administration are especially prefeπed with topical being most prefeπed. Depending upon the particular route of administration desired, a variety of earners well-known m the art may be used These include solid or liquid fillers, diluents, hydrotropes, surface-active agents, and encapsulating substances. Optional pharmaceutically-active or cosmetically-active materials may be included which do not substantially interfere with the activity of the compound of the present invention The amount of caπier 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, 2^nd Ed , (1976).

Some examples of substances which can serve as carriers or components thereof are sugars, such as lactose, glucose and sucrose; starches, such as corn 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 stearic 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; algimc acid, emulsifiers, such as the TWEENS; wetting agents, such sodium lauryl sulfate; coloring agents; flavoring agents; tabletmg agents, stabilizers; antioxidants; preservatives; pyrogen-free water; isotomc salme; and phosphate buffer solutions.

The choice of a carrier to be used conjunction with the subject compound is typically determined by the way the compound is to be administered

In particular, carriers for systemic administration include sugars, starches, cellulose and its derivatives, malt, gelatin, talc, calcium sulfate, vegetable oils, synthetic oils, polyols, algimc acid, phosphate buffer solutions, emulsifiers, isotomc salme, and pyrogen- free water. Prefeπed earners for parenteral administration include propylene glycol, ethyl oleate, pyπolidone, ethanol, and sesame oil. Preferably, the caπier, 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 used m 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- 45

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 carriers 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, manmtol, lactose and cellulose; binders such as starch, gelatin and sucrose; dismtegrants such as starch, algimc acid and croscarmelose; lubricants such as magnesium stearate, stearic acid and talc. Ghdants such as silicon dioxide can be used to improve flow characteristics of the powder mixture. Colonng 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 earner components depends on secondary considerations like taste, cost, and shelf stability, which are not critical for the puφoses of the subject invention, and can be readily made by a person ordinarily skilled in the art.

Orally administered compositions also include liquid solutions, emulsions, suspensions, powders, granules, elixirs, tinctures, syrups, and the like. The carriers suitable for preparation of such compositions are well known m 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 carboxymefhyl cellulose, AVICEL RC-591, tragacanth and sodium algmate; 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 m 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. 46

Other compositions useful for attaining systemic delivery of the subject compounds include sublingual. buccal and nasal dosage forms. Such compositions typically comprise one or more of soluble filler substances such as sucrose, sorbitol and manmtol; and binders such as acacia, microcrystallme 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 sk to reach the environment of the hair follicle Topical compositions of the present invention may be in any form including, for example, solutions, oils, 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 earner materials well known in the art, such as, for example, water, alcohols, aloe vera gel, allantoin, glyceπne, vitamin A and E oils, mineral oil, propylene glycol, PPG-2 myπstyl propionate, and the like.

Other materials suitable for use in topical earners 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 monoπcmoleate, glyceryl monostearate, propane-l,2-dιol, butane-l,3-dιol, mmk oil, cetyl alcohol, zλo-propyl isostearate, stearic acid, iso- butyl palmitate, isocetyl stearate, oleyl alcohol, zsø-propyl laurate, hexyl laurate, decyl oleate, octadecan-2-ol, isocetyl alcohol, cetyl palmitate, dimethylpolysiloxane, dι-«-butyl sebacate, iso- propyl mynstate, zso-propyl palmitate, zs -propyl stearate, butyl stearate, polyethylene glycol, tnethylene glycol, lanolm, sesame oil, coconut oil, arachis oil, castor oil, acetylated lanolm alcohols, petroleum, mineral oil, butyl mynstate, lsosteaπc acid, palmitic acid, zso-propyl lmoleate, lauryl lactate, myπstyl lactate, decyl oleate, and myπstyl mynstate; propellants, such as propane, butane, zso-butane, dimethyl ether, carbon dioxide, and nitrous oxide; solvents, such as ethyl alcohol, methylene chloride, zso-propanol, castor oil, ethylene glycol monoethyl ether, diethylene glycol monobutyl ether, diethylene glycol monoethyl ether, methylsulfoxide, dimethyl formamide, tetrahydrofuran; humectants, such as glycerin, sorbitol, sodium 2- pyπolιdone-5-carboxylate, soluble collagen, dibutyl phthalate, and gelatin; and powders, such as chalk, talc, fullers earth, kaolin, starch, gums, colloidal silicon dioxide, sodium polyacrylate, terra alkyl ammonium smectites, tπalkyl aryl ammonium smectites, chemically modified 47

magnesium aluminium silicate, organically modified montmoπllonite clay, hydrated aluminium silicate, fumed silica, carboxyvinyl polymer, sodium carboxymethyl cellulose, and ethylene glycol monostearate.

The compounds used m the present mvention may also be administered in the form of liposome delivery systems, such as small umlamellar vesicles, large unilamellar vesicles, and multilamellar vesicles. Liposomes can be formed from a variety of phospholipids, such as cholesterol, stearylamme or phosphatidylcholmes. A prefeπed 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 Cyclospoπn A: I. An in vitro Study Using Hairless Mouse Skm", S TP 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); Wallach, U.S. Patent No. 4,911,928, assigned to Micro-Pak, Inc., issued March 27, 1990; and Werner et al.. U.S. Patent No. 5,834,014, assigned to The University of Michigan and Micro-Pak, Inc., issued November 10, 1998 (with respect to Werner et al., with a compound as described herein administered in lieu of, or in addition to, mmoxidil).

The compounds of the present invention may also be administered by iontophoresis. See, e.g., internet site www.unιpr.ιi aφa/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. "Theoretical Model of Iontophoresis Utilized in Transdermal Drug Delivery", Pharmaceutical Ada 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 Tripeptides 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 m the Skm", Int. J. Pharm., Vol. 120, pp. 221-8 (1995); O'Brien et al.. "An Updated Review of its Antiviral Activity, Pharmacokmetic Properties and Therapeutic Efficacy", Drugs, Vol. 37, pp. 233-309 (1989); Parry et al„ "Acyclovir Biovailabihty in Human Skm", J. Invest. Dermatol, Vol. 98 (6), pp. 856-63 (1992); Santi et al., "Drug Reservoir Composition and Transport of Salmon Calcitonm 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: U. Electrode Chamber Formulation", J. Control. Release, Vol. 42, pp. 29-36 (1996); Rao et al., "Reverse Iontophoresis: Nonmvasive Glucose Momtoπng in vivo in Humans", Pharm Res., Vol. 12 (12), pp. 1869-1873 (1995); Thvsman et 48

aJL, "Human Calcitonm Delivery in Rats by Iontophoresis", J Pharm Pharmacol , Vol 46, pp. 725-730 (1994), and Volpato et al . "Iontophoresis Enhances the Transport of Acyclovir through Nude Mouse Skm by Electrorepulsion and Electroosmosis", Pharm Res , Vol. 12 (11), pp. 1623-1627 (1995)

The compositions used 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 m 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.

Non-limiting examples of other hair growth stimulants which may be used m the compositions herein, including both systemic and topical compositions, include, for example, benzalkonium chloride, benzethonium chloride, phenol, estradiol, diphenhydramine hydrochloπde, chloφhemramme maleate, chlorophyllm derivatives, cholesterol, salicylic acid, cysteme, mefhionme, red pepper tincture, benzyl mcotmate, D,L - menthol, peppermint oil, calcium pantothenate, panthenol, castor oil, hinokitiol, predmsolone, resorcmol, monosaccharides and esteπfied monosacchandes, chemical activators of protein kmase C enzymes, glycosammoglycan chain cellular uptake inhibitors, inhibitors of glycosidase activity, glycosammoglycanase inhibitors, esters of pyroglutamic acid, hexosacchaπc acids or acylated hexosacchaπc acids, aryl-substituted ethylenes, N-acylated ammo acids, and, of course, mmoxidil or fmasteπde. The most prefeπed activity enhancers are mmoxidil and finasteπde, most preferably mmoxidil.

Non-limitmg 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-dιoxane, 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 succinate, didecyl phthalate, decyl oleate, ethyl caproate, ethyl sahcylate, z-rø-propyl palmitate, ethyl laurate, 2-ethyl-hexyl pelargonate, z-o-propyl isostearate, butyl laurate, benzyl benzoate, butyl benzoate, hexyl laurate, ethyl caprate, ethyl caprylate, butyl stearate, benzyl sahcylate, 2- hydroxypropanoic acid, 2-hyroxyoctanoιc acid, methylsulfoxide, N,N-dιmethyl acetamide, N,N- 49

dimethyl formamide, 2-pyπohdone, 1 -methyl-2 -pyπolidone, 5-methyl-2 -pyπolidone, 1,5- dimethyl -2 -pyrrolidone, l-ethyl-2-pyπohdone, phosph e oxides, sugar esters, tetrahydrofurfural alcohol, urea, diethyl-zzz-toluamide, and, l-dodecylazacyloheptan-2-one.

In all of the foregoing, of course, the compounds used in the present methods 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 of the present invention 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, aπestmg and / or reversing hair loss and / or promoting hair growth. In addition or in the alternative, the kit may comprise a compound and / or composition of the present invention and information and / or instructions regarding methods of application of the compound and / or composition, preferably with the benefit of treating hair loss in mammals.

Examples of Composition Administration The following examples do not limit the invention, but provide guidance to the ordinarily 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 another having a structure as descnbed herein with similar results.

Example A A composition for topical administration is made, comprising:

A human male subject suffeπng 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 Cyclosponn A: I. An in vitro Study Using Hairless Mouse Skm", S T P Pharma Sciences, Vol. 3, pp. 404 - 407 (1993), using the compound of Example 2 in lieu of cyclosponn 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.

51

Example C

A shampoo is made, comprising:

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

Claims

52What is claimed is:

1. A compound characterized by the structure:

and pharmaceutically acceptable salts, hydrates, and biohydrolyzable amides, esters, and imides thereof, wherein:

Ri. R2, Rδ_> R7. and R10 are each, independently, selected from the group consisting of hydrogen, halogen, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, and heteroalkynyl;

R₄ is selected from the group consisting of halogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, arylalkyl, heteroalkyl, heteroalkenyl, heteroalkynyl, heterocycloalkyl, heterocycloalkenyl, heteroaryl, heteroarylalkyl, and heteroarylalkenyl; with the proviso that when R₂ is hydrogen, Y is -CH₂CHK₁, X is selected from the group consisting of -NZ- and -NH-, and R1₂ is Ci - C₄ alkyl, wherein K₁ is selected from hydrogen and Ci - C alkyl and Z is Ci - C₄ alkyl, then R₄ is not arylalkyl;

R₈ and R₉ are each, independently, selected from the group consisting of hydrogen, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, arylalkyl, heteroalkyl, heteroalkenyl, heteroalkynyl, heterocycloalkyl, heterocycloalkenyl, heteroaryl, heteroarylalkyl, and heteroarylalkenyl; with the proviso that at least one of Rs and Rg is not hydrogen; 53

R₃ is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, arylalkyl, heteroalkyl, heteroalkenyl, heteroalkynyl, heterocycloalkyl, heterocycloalkenyl, heteroaryl, heteroarylalkyl and heteroarylalkenyl;

R₆ and R₆' are each, independently, selected from the group consisting of hydrogen, halogen, hydroxy, amino, nitro, cyano, carboxy, thiol, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, and heteroalkynyl; and with the proviso that optionally Rε and R₆' together are selected from the group consisting of oxo and thioxo;

Y is selected from the group consisting of bond, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, and heteroalkynyl;

X is selected from the group consisting of -NZ-, -NH- and -O-;

Rn is selected from the group consisting of bond and -C(O)-; with the proviso that when Y is bond and X is -O- then Rn is -C(O)-;

R-₁2 is selected from the group consisting of alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, and heteroarylalkenyl; with the provisos that: when Rn is bond, then R-ι₂ and Z are optionally bonded together to form a cycle selected from the group consisting of cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, and heteroaryl; when R-ι₂ is heteroalkyl, heteroalkenyl, heteroalkynyl, heterocycloalkyl, heterocycloalkenyl, heteroaryl, heteroarylalkyl, or heteroarylalkenyl, then a heteroatom of R-ι₂ is not directly covalently bonded to R1₁; and when Y is bond, X is -O-, and Rn is -C(O)-, then R₁₂ is not alkyl; and

Z is selected from the group consisting of alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, and heteroalkynyl; with the proviso that when Rn is bond, then R₁₂ and Z are optionally bonded together to form a cycle selected from the group consisting of cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, and heteroaryl.

2. A compound according to claim 1 wherein Y is bond; and wherein each of R₈ and R₉ is not hydrogen. 54

3. A compound according to any of the preceding claims wherein X is selected from the group consisting of -NH- and -NZ-.

4. A compound according to any of the preceding claims wherein R₄, R₈, and Rg are each, independently, selected from the group consisting of halogen, alkyl, alkenyl, and heteroalkyl; and wherein R₃ is selected from the group consisting of hydrogen and lower alkyl.

5. A compound according to any of the preceding claims wherein R₆ and RQ are each, independently, selected from the group consisting of hydrogen, halogen, hydroxy, and lower alkyl; with the proviso that optionally Re and Re' together are oxo.

6. A compound according to any of the preceding claims wherein R-ι₂ is selected from the group consisting of alkyl, heteroalkyl, arylalkyl, and heteroarylalkyl; with the proviso that when Rn is bond, then R₁₂ and Z are optionally bonded together to form a cycle selected from the group consisting of cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, and heteroaryl.

7. A compound according to any of the preceding claims wherein R-i, R₂, R₅, R₇, and R₁₀ are each hydrogen.

8. A compound according to any of the preceding claims wherein X is -NZ- and Z is Ci - C₃ alkyl; with the proviso that when Rn is bond, then R₁₂ and Z are bonded together to form a cycle selected from the group consisting of cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, and heteroaryl.

9. A composition characterized by a compound according to any of the preceding claims and a carrier. 55

10. A method of treating hair loss comprising administering to a mammal a composition according to Claim 9.