MXPA01012496A - Biaryl compounds. - Google Patents

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

BIARLIO COMPOUNDS FIELD OF THE INVENTION * 5 The present invention relates to methods for treating capillary loss in mammals including to arrest and / or reverse hair loss and promotion of hair growth.

BACKGROUND OF THE INVENTION 10 * Hair loss is a problem that 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. Said capillary loss is accompanied by loss of new growth 15 of hair that causes partial or complete baldness. As is well known in the art, hair growth occurs through a cycle of activity and involves alternating periods of growth and rest. This cycle is often divided into three main stages known as anagen, catagen and telogen. Anagen is the growth phase of the cycle and 20 can be characterized by penetration of the hair follicle deep into the dermis with rapid proliferation of cells that are differentiated to form hair. The next phase is catagen, which is a transition stage marked by the cessation of cell division, and during which the hair follicle re-enters > .., -, i- > .i., to * -ia¿ _. _. through the dermis and hair growth ceases. The next phase, telogen, is often characterized as the resting stage by which the follicle that has re-entered contains a germ with tightly packed papillary dermal cells. In the telogen, the start of a new phase of anagen 5 is caused by rapid proliferation of cells in the germ, expansion of the dermal papillae and development of components of the basement membrane. Where hair growth ceases, most of the sharp follicles lie in anagen and the anagen is not involved, thus causing the onset of complete or partial baldness. There have been many attempts in the literature to induce * hair regrowth, for example, through the promotion or prolongation of anagen. Currently, there are two drugs approved by the Food and Drug Administration of the United States for the treatment of male pattern baldness: topical minoxidil (marketed as Rogaine® by 15 Pharmacia & Upjohn), and oral finasteride (marketed as Propecia® Merck &Co., Inc.). However, for several reasons including safety concerns and / or lack of effectiveness, the search for effective hair growth inducers is ongoing. Interestingly, it is known that the known thyroid hormone 20 as thyroxine ("T4") is converted to thyronine ("T3") in human skin by deiodinase I, a selenoprotein. Selenium deficiency causes a decrease in T3 levels due to the reduction in deiodinase I activity; This reduction in levels of T3 is strongly associated with the faith-. a a > & 2 & JL * A¿?, ^ «Hair loss. Consistent with this observation, hair growth is a reported side effect of the administration of T4. See, for example, Berman "Peripheral Effects of L-Thyroxine on Hair Growth and Coloration in Cattle," Journal of Endocrinology, Vol. 20, pp. 282-292 (1960); and Gunaratnam. "The Effects of thyroxine on Hair Growth in the Dog", J. Small Anim. Pract, Vol. 27, pp. 17-29 (1986). In addition, T3 and T4 have been the subject of several patent publications related to the treatment of hair loss. See, for example, Fischer et al. DE 1, 617,477, published January 8, 1970; Mortimer. GB 2,138,286, published October 24, 1984; and Lindenbaum. WO 96/25943, assigned to Life Medical Sciences, Inc., published on August 29, 1996. Unfortunately, however, the administration of T3 and / or T4 to treat hair loss is not practicable because these thyroid hormones are also they are known to induce significant cardiotoxicity. See, for example, Walker et al., U.S. Patent. No. 5,284,971, assigned to Syntex, issued February 8, 1994 and Emmett et al., Patent of E.U.A. No. 5,061, 798, assigned to Smith Kline &; French Laboratories, issued October 29, 1991. Surprisingly, the inventors of the present have discovered compounds that strongly initiate hair growth without inducing cytotoxicity. Consistent with this finding, but not intending to be limited to theory, the inventors hereby have surprisingly discovered that the preferred compounds of the present invention interact strongly with hair-selective thyroid hormone receptors but interact less strongly, or do not interact at all, with receptors-selective hormones for the hair. These unique properties, of course, are not shared with T3 and / or T4. Accordingly, the compounds and compositions of the present invention are useful for hair loss, including for stopping and / or reversing hair loss and promoting hair growth.

BRIEF DESCRIPTION OF THE INVENTION The present invention relates to compounds and compositions that are particularly useful for the treatment of hair loss in mammals, including for stopping and / or reversing hair loss and for promoting hair growth. The compounds of the present invention have the structure: and pharmaceutically acceptable salts, hydrates and biohydrolyzable amides, esters and imides thereof, wherein R f R2, R3, P, R5, Re, Re ', R7, Re, Rg, R10. And, X. R11 and R12 are as defined here.

" DETAILED DESCRIPTION OF THE INVENTION The present invention relates to compounds and compositions that are particularly useful for treating hair loss in mammals, including for stopping and / or reversing hair loss and for promoting hair growth. In addition to discovering that the compounds of the present invention are useful for the treatment of hair loss, the present inventors have also surprisingly discovered that the preferred compounds of the present invention do not affect cardiac activity. Publications and patents are referred to throughout this description. All references cited herein are incorporated herein by reference. All percentages and ratios and proportions used here are by weight unless otherwise specified. In the description of the invention, various modalities and / or individual aspects are described. As will be apparent to one skilled in the art, all combinations of such embodiments and aspects are possible and may result in preferred embodiments of the invention. As used here, where any variable, portion, group or similar occurs more than once in any variable or structure, its definition in each occurrence is independent of its definition in each other occurrence.

M tl A d t ^ fa ^ *. & , - Definitions and use of terms The following is a list of definitions for terms used here: As used herein, "salt" is a cationic salt formed in any acid group (eg, carboxyl) or an anionic salt formed by any group basic (for example, amino). Many of these 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. Anionic salts include halides (such as, for example, chloride salts). Said acceptable salts, when administered, should be appropriate for use in mammals. As used herein, "alkenyl" is an unsubstituted or substituted hydrocarbon chain radical having from 2 to 15 carbon atoms; preferably from 2 to about 10 carbon atoms; most preferably from 2 to about 8 carbon atoms; and most preferably from 2 to about 6 carbon atoms. The alkenyls have at least one olefinic double bond. Non-limiting examples of alkenyls include vinyl, alkyl 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 can be substituted or unsubstituted.

- As used herein, "aryloxy" is an oxygen radical having an aryl substituent. An aryloxy radical can 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; very preferably from 1 to about 6 carbon atoms; and most preferably still from 1 to about 4 carbon atoms. Preferred alkyls include, for example, methyl, ethyl, proopyl, isopropyl and butyl. As used herein, "alkylene" refers to an alkyl, alkenyl or alkynyl that is a diradical. For example, "methylene" is -CH2 .. Alkylene can be substituted or unsubstituted. As used herein, "alkynyl" is an unsubstituted or unsubstituted hydrocarbon chain radical having from 2 to 15 carbon atoms; preferably from 2 to about 10 carbon atoms; most preferably from 2 to about 8 carbon atoms; and most preferably still from about 2 to about 6 carbon atoms. Alkynyl have a triple bond. As used herein, "aryl" is an aromatic ring radical that 20 is either carbocyclic or heterocyclic. Preferred aryl groups include, for example, phenyl, benzyl, tolyl, xylyl, cumenyl, naphthyl, biphenyl, thienyl, furyl, pyrrolyl, pyridinyl, pyrazinyl, thiazolyl, pyrimidinyl, quinolinyl, triazolyl, tetrazolyl, benzothiazolyl, benzofuryl, indolyl, indenyl. , azulenyl, fluorenyl, anthracenyl, '-aiJfejte ^ a ^ * Mfc!: a ^ »afe < -t. »J .i.JMií¿-i? . ~? **, oxazolyl, idoxazolyl, isotriazolyl, imidazolyl, pyrazolyl, oxadiazolyl, indolicinyl, indolyl, isoindolyl, purinyl, quinolicinyl, quinolinyl, isoquinolinyl, cinolinyl and the like. Aryls can 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. The arylalkenyls can 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. Arylalkyl groups include benzyl, phenylethyl and phenylpropyl. Arylalkyl can be substituted or unsubstituted. As used herein, "biohydrolyzable amides" are amides of the compounds of the present invention that do not interfere with the activity of the compound, or that are easily converted in vivo by a mammalian subject to produce an active compound. As used herein, "biohydrolyzable esters" are esters of the compounds of the present invention that do not interfere with the activity of the compound, or that are easily converted in vivo by a mammalian subject to produce an active compound. As used herein, "biohydrolyzable imides" are imides of the compounds of the present invention that do not interfere with the activity of the compound, or that are easily converted in vivo by a mammalian subject to produce an active compound.

- As used herein, "cyclic ring", "carbocycle", or the like is a hydrocarbon ring radical. The carbocyclic rings are monocyclic or are fused, bridged or polycyclic spiro rings. Unless otherwise specified, the noncyclic rings contain from 3 to 9 atoms, preferably from about 4 to about 7 atoms, and most preferably 5 or 6 atoms. The polycyclic rings contain from about 7 to about 17 atoms, preferably from about 7 to about 14 atoms, and most preferably 9 or 10 atoms. The carbocyclic rings (carbocycles) can be substituted or unsubstituted. As used herein, "cycloalkyl" is a saturated carbocyclic or heterocyclic ring radical. Preferred cycloalkyl groups include, for example, cyclobutyl, cyclopentyl and cyclohexyl. The cycloalkyls can be substituted or unsubstituted. As used herein, "cycloalkenyl" is an unsaturated carbocyclic or heterocyclic ring radical having at least one double bond. The cycloalkenyls can be substituted or unsubstituted. As used herein, preferred "halogens" (or "halos" or the like) are bromine, chlorine, iodine and fluorine, most preferably, bromine and iodine, most preferably still bromine and chlorine, and most preferably chlorine. As used herein "heteroalkenyl" is an alkenyl radical composed of carbon atoms and one or more heteroatoms wherein the heteroatoms are selected from the group consisting of oxygen, sulfur, * - §% i - nitrogen and phosphorus, most preferably oxygen, sulfur and nitrogen. The heteroalkenyls can be substituted or unsubstituted. As used herein "heteroalkyl" is an alkyl radical • composed of carbon atoms and one or more heteroatoms where the 5 heteroatoms are selected from the group consisting of oxygen, sulfur, nitrogen and phosphorus, most preferably oxygen, sulfur and nitrogen. Heteroalkyls can be substituted or unsubstituted. As used herein, "heteroalkynyl" is an alkynyl radical composed of carbon atoms and one or more heteroatoms wherein the heteroatoms are selected from the group consisting of oxygen, sulfur, nitrogen and phosphorus, most preferably oxygen, sulfur and nitrogen. Heteroalkynyls can be substituted or unsubstituted. As used herein, "heteroaryl" is an aryl radical composed of carbon atoms and one or more heteroatoms wherein the heteroatoms are 15 are selected from the group consisting of oxygen, sulfur, nitrogen and phosphorus, most preferably oxygen, sulfur and nitrogen. The heteroaryls can be substituted or unsubstituted. As used herein, "heteroarylalkenyl" is an arylalkenyl radical wherein the aryl group and / or the alkenyl group is composed of 20 carbon atoms and one or more heteroatoms wherein the heteroatoms are selected from the group consisting of oxygen, sulfur , nitrogen and phosphorus, most preferably oxygen, sulfur and nitrogen. The heteroalkenyls can be substituted or unsubstituted.

As used herein, "heteroarylalkyl" is an arylalkyl radical wherein the aryl group and / or the alkyl group is composed of carbon atoms and one or more heteroatoms wherein the heteroatoms are selected from the group consisting of oxygen, sulfur, nitrogen and phosphorus, most preferably oxygen, sulfur and nitrogen. The heteroarylalkyl can be substituted or unsubstituted. As used herein, "heterocyclic ring", "heterocycle", or the like is a ring radical composed 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 phosphorus, most preferably oxygen, sulfur and nitrogen. The heterocycles are monocyclic or are polycyclic rings fused, bridged or spiro. Unless otherwise specified, the monocycles contain from 3 to about 9 atoms, preferably from about 4 to about 7 atoms, and most preferably 5 or 6 atoms. The polyclysters contain from about 7 to about 17 atoms, preferably from about 7 to about 14 atoms, and most preferably 9 or 10 atoms. Heterocyclic rings (heterocycles) can be substituted or unsubstituted. As used herein, "heterocycloalkyl" is a cycloalkyl having at least one heteroatom in the ring. The heterocycloalkyls can be substituted or unsubstituted.

- As used herein, "heterocycloalkenyl" is a cycloalkenyl having at least one heteroatom in the ring. The heterocycloalkyls can be substituted or unsubstituted. • As used herein, a "lower" portion (eg, "lower 5" alkyl) is a portion having from 1 to about 6, preferably from 1 to about 4, carbon atoms. 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 show biological activity, preferably wherein the biological activity is disrupting and / or reversing hair loss or promoting hair growth, at the site (s) of activity in a mammalian subject, without adverse side effects (such as toxicity, irritation or allergic response), proportional to a reasonable risk / benefit ratio when used in the manner of this invention. As used herein, unless otherwise specified, the term "substituted" in reference to a group, portion or the like, means having one or more substituent groups each selected independently of hydrogen, alkyl, alkenyl, alkoxy , hydroxy, nitro, alkylamino, cyano, halogen, thiol, aryl, cycloalkyl, heteroaryl, heterocycloalkyl (eg, piperidinyl, morpholinyl, pyrrolidinyl), imino, hydroxyalkyl, aryloxy and arylalkyl, preferably hydrogen, alkyl, alkenyl, alkoxy, hydroxy, nitro, amino, alkylamino, halogen, thiol and aryloxy, most preferably hydrogen, alkyl, alkenyl, alkoxy, hydroxy, nitro, amino, alkylamino and halogen, most preferably still 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 amides, esters and bioamides thereof, wherein: (a) Ri, R2, R5, R7 and Rio are each independently selected from the group consisting of hydrogen, halogen, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl and heteroalkynyl; (b) R is selected from the group consisting of halogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, ayl, arylalkyl, heteroalkyl, heteroalkenyl, heteroalkynyl, heterocycloalkyl, heterocycloalkenyl, heteroaryl, heteroarylalkyl and heteroarylalkenyl; wherein when R2 is hydrogen Y is -CH2CHK- ?, X is selected from the group consisting of -NZ- and -, i > _Lt fa, < -., -.

NH-, and R? 2 is CrC4 alkyl wherein Ki is selected from hydrogen and CrC4 alkyl and Z is C-? -C alkyl, then R4 is not arylalkyl; (c) Ra and Rg are each independently selected from the group consisting of hydrogen, halogen, alkyl, alkenyl, alkynyl, 5-cycloalkyl, cycloalkenyl, aryl, arylalkyl, heteroalkyl, heteroalkenyl, heteroalkynyl, heterocycloalkyl, heterocycloalkenyl, heteroaryl, heteroarylalkyl and heteroarylalkenyl; wherein at least one of Rβ and Rg is not hydrogen; (d) R3 is selected from the group consisting of hydrogen, allyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, arylalkyl, heteroalkyl, heteroalkenyl, heteroalkynyl, heterocycloalkyl, heterocycloalkenyl, heteroaryl, heteroarylalkyl and heteroarylalkenyl; (e) Re and Re 'are each, independently, selected from the group consisting of hydrogen, halogen, hydroxy, amino, nitro, cyano, carboxy, Thiol, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl and heteroalkynyl; where R6 and Re '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 -O; 0 (h) Rn is selected from the group consisting of bond and -C (O) -; where when Y is bond and X is -O- then Rn is -C (O) -; (i) R-? 2 is selected from the group consisting of alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, t & i. ... to.? a ^ i cycloalkieryl, heterocycloalkyl, heterocycloalkenyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, and heteroarylalkenyl; or wherein when R-n is bond, then R-? 2 and Z can be optionally linked together to form a cycle selected from the group consisting of cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl and heteroaryl; wherein when R 2 is heteroalkyl, heteroalkenyl, heteroalkynyl, heterocycloalkyl, heterocycloalkenyl, heteroaryl, heteroarylalkyl or heteroarylalkenyl, then an R 2 heteroatom is not directly covalently linked to R n; wherein when Y is a bond, X is -O-, and Rn is -C (O) - then R-? 2 is not alkyl; and (j) Z is selected from the group consisting of alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, and heteroalkynyl; or where when Rn is a bond, then R? 2 and Z can optionally be linked together to form a cycle selected from the group consisting of cycloalkyl, 15-cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, and heteroaryl. The compounds of the present invention are biphenyl compounds bonded through a carbon atom which is substituted with substituents R6 and Rß'- The remaining substituents, as well as R6 and R '' are described in detail below. 20 The substitutes R ?. R ?. Rg. R? v Rin Substituents Ri, R2 > R5, R7 and R10 each substitute one of the phenyl rings of the structure shown here. R-i, R2, R5, R7 and R10 are each independently selected from hydrogen, halogen, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl and heteroalkynyl. R-i, R2. R5, R7 and R10 are preferably each ^^ ^ independently, selected from hydrogen, halogen, alkyl, alkenyl, Heteroalkyl and heteroalkenyl. R1 f R2, R5, R7 and R10 are more preferably each independently selected from hydrogen, halogen and lower alkyl. Most preferably R1, R2 > R5, R7 and R10 are each hydrogen.

The substitute R? * 10 The substituent R 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 -CH2CHK1, X is selected from the group consisting of -NZ- and -15 NH-, and R? 2 is C-1-C4 alkyl, wherein K1 is selected from hydrogen and alkyl of dC and Z is d-C4 alkyl, wherein R is not arylalkyl. R 4 is preferably selected from halogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroalkyl, heteroalkenyl, heteroalkynyl, heterocycloalkyl, heterocycloalkenyl, heteroaryl, Heteroarylalkyl and heteroarylalkenyl. R is most preferably selected from halogen, alkyl, alkenyl, heteroalkyl and heteroalkenyl. R is most preferably selected from halogen, alkyl, alkenyl and heteroalkyl. R 4 is very preferably still selected from halogen and lower alkyl. Most of the preferred halogens of R are chlorine, bromine and iodine, preferably chlorine and iodine, and most preferably iodine. The most preferred lower alkyls for R are methyl, ethyl, / 'so-propyl and te / butyl, preferably methyl, / so-propyl and ^^^ te / t-butyl, very preferably / 'so-propyl or ferf-butyl. Most preferably R 5 is lower alkyl, particularly / so-propyl and fe / t-butyl.

The Substituents Rg and Rg Substituents Rβ and Rg 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 Rβ and Rg are not hydrogen. Preferably, each of Rβ and Rg are not hydrogen. R8 and Rg are preferably each independently, 15 selected from halogen, alkyl, alkenyl, heteroalkyl and heteroalkenyl. Rβ and R9 are preferably each independently, selected from halogen, alkyl, alkenyl and heteroalkyl. Rβ and Rg are most preferably independently, selected from halogen and lower alkyl. The most preferred halogens for Rβ and R9 are chlorine and bromine, preferably chlorine.

The most preferred lower alkyls for Rβ and Rg are methyl, ethyl, / 'so-propyl and fer-butyl, preferably methyl / ε-propyl and fer-butyl, most preferably methyl and / or propyl. Most preferably Rß and Rg are each, * - *. ¿- independently, selected from lower alkyl and halogen, particularly methyl and chloro, respectively.

The substitutent Rj 5 R3 replaces the oxygen portion of the biphenyl structure as shown above. R3 is selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, arylalkyl, heteroalkyl, heteroalkenyl, heteroalkynyl, heterocycloalkyl, heterocycloalkenyl, I »heteroaryl, heteroarylalkyl and heteroarylalkenyl. Preferably, R3 is 10 selected from hydrogen, alkyl, alkenyl, cycloalkyl, aryl, arylalkyl, heteroalkyl, heteroalkenyl, heterocycloalkyl, heteroaryl and heteroarylalkyl. Most preferably, R3 is selected from hydrogen, alkyl, alkenyl, aryl, arylalkyl, heteroalkyl, heteroaryl and heteroarylalkyl. Most preferably still R3 is selected from hydrogen, alkyl, alkenyl, arylalkyl (preferably 15 benzyl), heteroalkyl and heteroarylalkyl. Most preferably still, 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 Re V RR 'Rβ and Rβ' are each, independently, selected from hydrogen, halogen, hydroxy, amino, nitro, cyano, carboxy, thiol, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl and heteroalkenyl; or where Rß and Rß 'are, together oxo or thioxo. Preferably, R6 and R '' are each independently, selected from hydrogen, halogen, hydroxy, amino, thiol, alkyl and heteroalkyl; or where Rß and Rß 'are, together, oxo. Very • preferably, R6 and Rß 'are each independently, selected from Hydrogen, halogen, hydroxy, amino and lower alkyl; or where Rß and Rß 'are, together, oxo. Most preferably Rβ and Rβ 'are each independently, selected from hydrogen, halogen, hydroxy and lower alkyl (most preferably C 1 -C 3 alkyl); or where Rß and Rß 'are, together, oxo. Most preferably still Rß and Rß 'are each independently, selected 10 of hydrogen and hydroxy; or where Rß and Rß 'are, together, oxo. Most preferably, R6 and R 'are each hydrogen.

- The substitutent Y is selected from a bond, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl and heteroalkynyl. Where Y is a link, X is directly linked to the phenyl ring having R, Rβ, Rg, and RioY is preferably selected from a bond, alkyl, alkenyl, heteroalkyl and heteroalkenyl. More preferably, Y is selected from a bond and lower alkyl. Most preferably, Y is a link.

Substituent X 10 X is selected from -NZ-, -NH-, and -O-. Z is substituted on the nitrogen of -NZ- and is selected from alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl and heteroalkynyl; or wherein Rn is a bond, then R-? 2 and Z can be optionally linked 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? 2 and Z are joined together to form a selected cycle of ^ cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl and heteroaryl. Most preferably, Z is lower alkyl, or R 2 and Z are joined together to form a cycle selected from cycloalkyl, cycloalkenyl, Heterocycloalkyl, heterocycloalkenyl, aryl and heteroaryl. Most preferably, Z is C 1 -C 3 alkyl, particularly methyl, or R 12 and Z are joined together to form a cycle selected from cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl and heteroaryl. l.s tr.A n í -.i-- i,. . Faith -. S 4 Preferably, X is selected from -NH- and -NZ-. Most preferably, X is -NH-, -N (CH3) -, or -NZ- wherein R-? 2 and Z are joined together to form a cycle selected from the group consisting of cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl and heteroaryl. Where R12 is linked to Z to form a ring, the ring is preferably selected from cycloalkyl, heterocycloalkyl, aryl and heteroaryl, most preferably cycloalkyl, heterocycloalkyl and aryl, most preferably still cycloalkyl and heterocycloalkyl, most preferably still heterocycloalkyl. In addition to the optional substituents described above, the cycle may also optionally have one or more oxo substituents (i.e., double-linked oxygen). Non-limiting examples of these cycles include piperidinyl, norpholinyl, piperazinyl, pyrrolidinyl, idolinyl, succinimidyl and hydantoinyl.

The substitutent Rii Rn is selected from a bond and -C with the proviso that Y is a bond and X is -O- then Rn is -C (O) -. Where Rn is a bond, R12 is directly linked to X and the compound is an amine (where X is - NZ- or -NH-) or an ether (where X is -O- and Y is not a bond) . Although both Linkage as -C (O) - are both highly preferred for Rn, most preferably Rn is -C (O) -.

- The substitute Ri? R-? 2 is selected from alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, • heterocycloalkenyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl and Heteroarylalkenyl; or wherein when Rn is a bond, then R? 2 and Z may optionally be together to form a selected cycle comprising the group consisting of cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl and heteroaryl; wherein when R 12 is heteroalkyl, heteroalkenyl, heteroalkynyl, heterocycloalkyl, * 10 heterocycloalkenyl, heteroaryl, heteroarylalkyl or heteroarylalkenyl, then an heteroatom of R-? 2 is not directly covalently linked to Rn. Therefore the carbamates and ureas in the bond of -Y-X-R11-R12 are not contemplated within the present invention. For example, wherein R-? 2 is heteroalkyl, is not, for example, -0-CH2-CH3, but could be, for example, -CH2-O-CH3. Further, where Y is a bond, X is -O-, and Rn is -C (O) - then R12 is not alkyl. Preferably R12 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. Most 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. Most 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, R12 is a lower alkyl, or is bonded to Z to form a cycle selected from cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, and heteroaryl. The most preferred alkyls for R 2 are flp 10 methyl, ethyl, n-propyl, / so-propyl, n-butyl, ferf-butyl and n-pentyl, particularly methyl, n-propyl, / so-propyl, n- butyl and ferf-butyl. Where R-? 2 is bonded to Z to form a ring, the ring is preferably selected from cycloalkyl, heterocycloalkyl, aryl and heteroaryl, most preferably cycloalkyl, heterocycloalkyl and aryl, very Preferably still cycloalkyl and heterocycloalkyl, and most preferably still heterocycloalkyl. In addition to the optional substituents described above, the cycle may also optionally have one or more oxo substituents (ie, double bound oxygen). Non-limiting examples of these cycles include piperidinyl, morpholinyl, piperazinyl, Pyrrolidinyl, indolinyl, succinimidyl and hydantoinyl. Preferred compounds of the present invention are set forth in the following tables: TABLE 1 Preferred compounds of the present invention • In the following preferred compounds, R6 and R 'are each 5 hydrogen: - * t ti .- .. * "Ü-JiJ» -, < - ** M: * - 1"1» "' l? < .4 -. -áit-! Ae? & - TABLE 2 Preferred Compounds of the Present Invention In the following preferred compounds, Rβ and Rβ 'are, together oxo: 20 * t Í.M 20 «ai- vt -i -.- i ¡tuse-t,.;. J-- < a_iltaj _.-.,. J-AjSJa, -t - t - _fc -a ^ s-jt-t-taa TABLE 3 Preferred compounds of the present invention # In the following preferred compounds, R6 is hydrogen and R6 'is 5-hydroxy: S i i - t, 1 - &4"i i twenty Analytical Methods The present invention relates to compounds and methods for 15 treat hair loss. Preferably, the compound used in the present invention will not affect cardiac activity. Compounds (test compounds) can be tested for their ability to induce anagen and their lack of cardiotoxicity (which does not affect cardiac activity) using the following methods. Alternatively, other well-known methods can be used in the 20 technique (but with the term "that does not affect cardiac activity" being defined according to the method described below).

- Cardiotoxicity test: The cardiotoxicity test measures the potential of a test compound to adversely affect the cardiovascular system. As the • hormone (T3) damages the cardiovascular system, the heart enlarges. See, 5 e.g., Gomberq-Maitland et al .. "Thyroid hormone and Cardiovascular Diesase", American Heart Journal, Vol. 135 (2), pp. 187-196 (1998); Klein and Ojamaa, "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 ™? O Cardiovascular Diseases, Vol. 37 (4), pp. 329-336 (1996). This increases the Weight of the heart in relation to the whole weight of the body. The cardiotoxicity test given here below is used to test compounds for potentially adverse cardiac effects by measuring their effect on the heart-to-body weight ratio. 15 Two groups each of six male Sprague Dawley rats (Harran Sprague Dawley, Inc., Indianapolis, IN) (each weighing approximately 220 grams to 235 grams) were used. The first group is a vehicle control group and the second group is a group of test compound. The duration of the test is 30 days, with the treatment of 20 vehicle or test compound in a vehicle daily for 28 of those days as described below. Before beginning the test, each rat was allowed to acclimate to standard environmental conditions for 5 days. Each rat received food (standard increase diet for rat) and water ad libitum 5 days before starting the test as well as finishing the study. The vehicle is 91: 9 (v: v) propylene glycol: ethanol. The compound of ^^ Test is prepared at a concentration of 500 μm / ml in the vehicle. 5 Each rat is weighed on day 1 of the test. The dose calculations are then made: to each rat a vehicle dose solution or vehicle test compound will be administered daily (depending on whether the rat is in the vehicle control group or in the test compound group, respectively) to 500 μl of dose solution per kg of rat. For rats in the ío test compound, this corresponds to a dose of 250 μg of compound test per kg of rat. Day 2 is the first day of treatment with the dosing 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 before dosing for that day; for each 15 rat, the dosing solutions are recalculated and administered according to them to change the body weight. The treatment occurs once a day in the morning on days 2 to 29, inclusive, for each rat in each group. For each treatment the dose solution is administered subcutaneously between the shoulders of the rat in such a way that the injection sites are rotated in this area. On day 30 in the morning, the rats of each group are slaughtered with C02 from dry ice. Each rat is started immediately for a total body weight.

- The hearts of each rat are removed in the following manner. An incision is made to expose the abdominal cavity. The rib cage is cut carefully in the sternum with small scissors, in such a way that they remain # exposed the heart and lungs. With small scissors and forceps, the vessels 5 connected to the heart are cut to the heart. These vessels include the caudal vena cava, the left cranial vena cava (pulmonary trunk), the right cranial vena cava, the thoracic aorta, the right subclavian artery, the internal thoracic artery and vein, and any other small connections. The heart is immediately collected intact, including the left and right atria and the 10 left and right ventricles. Immediately afterwards, any excess tissue is cut, the heart is left to dry on paper towel until no more blood is visible on the paper towel and the heart is weighed. The weight of the heart is divided by the weight of the body after sacrifice for each rat to give the heart / body relationship. The relationships 15 heart / body for each rat in the vehicle control vehicle are added together and divided by 6 (i.e., the total number of rats in 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 the group of 20 test compound). The C index is calculated by dividing RT by RV. As defined herein, wherein C is less than 1.3, the test compound does not affect cardiac activity. Preferably, C is less than 1.2, most preferably less than -15, and most preferably still less than 1.1. According to this method, T3 and T4 do not affect the cardiac cavity.

^^ Telogen conversion test: 5 The telogen conversion test measures the potential of a test compound to convert mice into the resting stage of the hair growth cycle ("telogen"), to the growth stage of the cycle of growth. hair growth ("anagen"). Without pretending to be limited to theory, there are three main phases of the hair growth cycle: anagen, catagen and telogen. It is believed that there is a longer telogen period in C3H mice (Harran Sprague Dawley, Inc., Indianapolis, IN) from about 40 days of age to about 75 days of age, when hair growth is synchronized. It is believed that after 75 days of age, hair growth 15 is no longer synchronized. Where mice approximately 40 days old with dark fur (brown or black) are used in growth experiments of? hair, melanogenesis occurs along with hair growth (hair) where the topical application of hair growth inductors are evaluated. The telogen composition test here below is used to select 20 compounds for potential hair growth by measuring melanogenesis. Three groups of 44-day-old C3H mice are used: a vehicle control group, and a group of test compound, wherein a compound of conformance is administered to the test composition group. «> I i - with the present invention. The duration of the test is at least 19 days with 15 days of treatment (where the days of treatment occur from Monday to Friday). Day 1 is the first day of treatment. Most studies will end on day 19, but some may be carried out until day 24 if the melanogenesis response looks positive, but occurs slowly. A typical study design is shown in Table 4 below. Typical dose concentrations are set forth in Table 4, however, those skilled in the art will readily understand that such concentrations can be modified. * 10 TABLE 4 ** The vehicle is 60% ethanol, 20% propylene glycol and 20% dimethylisosorbide (commercially available from Sigma Chemical Co., St. Louis, MO). 20 The mice are treated topically from Monday to Friday on their lower back (base of the tail at the lower rib). A pipette and tip are used to deliver 400 μl to the back of each mouse. The 400 μl application is made & -C «ll» -8., ¡. ^ .rj, jf ?? i ?, í .r _. -.___ »_-__, ___ .., slowly 'while moving the mouse's hair to allow the application to reach the skin. Although each treatment is being applied to the mouse via # Topical, a visual grade of 0 to 4 will be given to the color of the skin in the application area of each animal. Since a mouse converts from telogen to anagen, its skin color will become more bluish black. As indicated in Table 5, grades 0 to 4 represent the following visual observations as the skin progresses from white to bluish black. 10 TABLE 5 fifteen Manufacturing Methods The compounds of the present invention are prepared in accordance 20 with methods that are well known to those skilled in the art. The starting materials used in the preparation of the compounds of the invention are known, are made by known methods or are commercially available as a starting material.

"It is recognized that one skilled in the art of organic chemistry can easily carry out standard manipulations of organic compounds without additional instructions, examples of such manipulations are described in standard texts such as J. March, Advanced Qrqanic. 5 Chemistrv. John Wiley & Sons, 1992. The person skilled in the art will readily appreciate that certain reactions are best carried out when other functionalities are covered or protected in the compound, thus increasing the reaction and / or avoiding any undesirable side reactions. Often, the person skilled in the art uses Protection groups to achieve such increased yields or to avoid unwanted reactions. These reactions are found in the literature and are also within the reach of the person skilled in the art. Examples of many such manipulations can be found, for example, T. Greene, Protectinq Groups in Orqanic svnthesis. John Wíley & Sons, 1981. The compounds of the present invention may have one or more chiral centers. As a result, an optical isomer, including diastereomers and enantiomers, can be selectively prepared on others, for example by chiral starting materials, catalysts or solvents, or both stereoisomers or both optical isomers can be prepared, including 20 diastereomers and enantiomers at the same time (a racemic mixture). Since the compounds of the present invention can exist as racemic mixtures, mixtures of optical isomers, including distereomers and enantiomers, or stereoisomers can be separated using known methods, such as by the use of, for example, chiral salts and chiral chromatography. Furthermore, it is recognized that an optical isomer, including a diastereomer and enantiomer, or a stereoisomer, may have favorable properties over the others. In this way, when the invention is described and claimed, when a racemic mixture is described, it is clearly contemplated that both optical isomers, including diastereomers and enantiomers, or a stereoisomers substantially free of the others, are described and claimed as well. The compounds of the present invention can be prepared using a variety of methods known to those skilled in the art. Non-limiting general preparations include the following. The compounds of the invention can be prepared, after the removal of temporary protective groups, by condensation (for example, acylation or alkylation) a compound of the structure: wherein R 1 t R 2, R 3, R 4, R 5, R b, R b ', R 7, R b, R g, R 10, Y, and X are as defined above and are in an appropriately protected form if necessary (see, for example. T. Greene, Protectinq Groups in Orqanic Svnthesis.'John Wiley & Sons, 1981), with a reactive derivative of a structure: .R12 HO '(ip? Q ^ Ri2 (IV) Wherein R12 is defined herein above and is an appropriately protected form if necessary and Q is halogen, preferably bromine or iodine, and most preferably iodine. The reactive derivatives of structure II include activated esters such as 1-hydroxybenzotriazole esters and similar active esters known to those skilled in the art. 15 and include mixed anhydrides with organic or inorganic acids such as hydrochloric acid, other halogen acids and sulfonic acids as well as similar acids known to those skilled in the art. In addition, the reactive derivatives of structure II include symmetrical anhydrides of structure II. Activated derivatives of structure III include trifluoromethanesulfonic esters 20 and other activated derivatives known to those skilled in the art. The compounds of structure IV are generally reactive, suitable 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 known to those skilled in the art. Many appropriately activated derivatives of the formulas II, III or IV are commercially available and others can be prepared by methods known to those skilled in the art. A The non-limiting example of condensations of this type is given in Example IV, further on. In addition, appropriately protected compounds resulting from the condensation of a compound of structure I with a compound of structure II, III or IV can be further modified to give additional compounds of the invention after the removal of protecting groups. 10 temporary. Such modifications include, but are not limited to the reduction of an amide, to an amine as described in Example 5 to give a secondary or tertiary amine and alkylation of an amine as described in Example 9. In addition, the compounds of the present invention wherein Rβ and R6 'are together oxo, can be reduced to give additional compounds of the invention after removal of any temporary protection groups by functionally reducing the ketone to an alcohol functionality giving a benzhydrol in which, for example, Rβ is hydroxy and Rß 'is hydrogen. A non-limiting example of this reaction is given in Example 5. The reduction Further addition of this type of compound, in an appropriately protected form is necessary, it is then possible to give a compound of the present invention wherein both, R6 and R6 'are hydrogen. Non-limiting examples of this reaction are provided in Examples 2, 6 and 8. It is also possible to oxidize the i? ? a i__L * & &, & X compounds wherein Rβ is hydroxy and Rβ 'is hydrogen to compounds of the invention wherein Rβ and Rβ' are together oxo using an oxidizing agent, for example pyridinium dichromate in an inert solvent (eg, dichloromethane) at a reduced temperature , for example 0 ° C. Compounds of structure I can also be prepared from compounds of structure V (see below) where P is, for example, nitro or cyano. Compounds of structure V are prepared by activation of an aromatic acid of structure VI by alkylation of an anisole of structure VII using Friedel-Crafs conditions familiar to those skilled in the art. The compounds of structures V. and IV are commercially available or can be prepared by means known in the art. A non-limiting example of this alkylation reaction is set forth in Example 3.

"Compounds of formula V can be converted to compounds of structure I by further transformation For example, where P is nitro, the resulting compound of structure V can be converted to a compound of • Structure I by reduction to the amine using standard chemical reaction conditions such as hydrogen and palladium on carbon as in Example 3. Where P is cyano, the compound of structure V can be converted to a compound of structure I by reduction to an alkylated amine using conditions known to those skilled in the art.

The compounds of the present invention can also be prepared using aromatic halides of structure VIII and benzaldehyde derivatives of structure IX. The compounds of structures VIII and IX 20 are commercially available or can be prepared by means well known in the art. A non-limiting example of the preparation of a compound of structure VIII is provided in Example 1. Derivatives of structures IX can be prepared from aromatic halides as described in Examples 1, 7 and 10. The aromatic halogenide of the Structure VIII is converted to the aryl lithium using a lithium-halogen exchange reaction as described in Examples 1, 7 and 10 and reacted with the derivative ^^ of structure IX, to give a compound of the present invention in which Rβ is hydroxy and Rβ 'is hydrogen. For further guidance, the following provides non-limiting examples that illustrate more specifically to make various compounds of the present invention. As used herein, the following abbreviations are used: EXAMPLE 1 1a. 4-bromo-3,5-d? Met? Ln? Trobenzene: 2 ', 6'-d? Met? L-4-n? Trotenol (3 g) is added to 50 ml of dichloromethane followed by the addition of 3.6 ml of pyridine. The solution is cooled to 0 ° C and 3.6 ml of trifluoromethanesulfonic 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 of 1 N hydrochloric acid, twice with 25 ml of water, twice with 25 ml of 1 N hydroxide, twice with 25 ml of water, dried with magnesium sulfate and Concentrate under reduced pressure. The remaining residue is dissolved in 40 ml of DMF followed by the 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 of water and 60 ml of ethyl acetate are added and stirred. The mixture is filtered and the organic layer is separated and dried with magnesium sulfate. The organic layer is concentrated under high vacuum and the remaining residue is reabsorbed to silica gel using dichloromethane. The preabsorbed residue is purified by chromatography on silica gel (hexane: ethyl acetate) and crystallization from hexanes. 1 B. 4-bromo-3,5-dimethylaniline: A solution of 4-bromo-3,5-dimethyl-nitrobenzene (1a, 0.6 g) is dissolved in 10 ml of ethyl acetate and 80 mg of 10% palladium is added carbon. The reaction is hydrogenated and then filtered through celite and concentrated under reduced pressure to give 1b. 15 1c. ? / - r4-bromo-3,5-dimethylphenrolpyrrolidine: 4-bromo-3,5-dimethylaniline (1b, 0.88 g) is dissolved in 2 ml of ethanol and 0.75 ml of 1,4-diiodobutane are 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 brine. After drying over sodium sulfate, filtering and concentrating under reduced pressure, it is purified by chromatography on silica gel (hexane: ethyl acetate) to give 1c. ^ fAj-tt "-. i. a?» »__« _, _ t, .___ «. _., _, t. t 4.. r ?. ** &. .. -.« . ^ -á-fetA "1 d. ? -r4-carboxaldehyde-3,5-dimethylphenyl-pyrrolidine:? - [4-Bromo-3,5-dimethylphenyljpyrrolidine (1c, 0.44 g) is dissolved in 10 ml of THF and cooled to -78 ° C under a nitrogen atmosphere. To this solution is added 2.0 ml of tert-butyllithium (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 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 separatory funnel with 15 ml of ether and 15 ml of water and the aqueous layer is acidified with 1 N HCl. The organic layer is isolated and extracted 5 times with brine and the organic layer is dried over Sodium sulfate and concentrated under reduced pressure. Purification by chromatography on silica gel (hexane: ethyl acetate) gives 1d. 1e 2- / so-propylanisole: Potassium hydroxide (5.6 g) is added to 13.4 ml of acetone followed by 2- / so-propylphenol (13.6 g). After it dissolves After the potassium hydroxide, methyl iodide (14.2 g) is added. The reaction is refluxed overnight. 150 ml of water are added. This reaction is extracted 3 l times with 100 ml of diethyl ether. The organic layer is extracted twice with 100 ml of 10% sodium hydroxide in water, once with 100 ml of water and once with 100 ml of saturated ammonium chloride. After drying over The magnesium sulfate is added, the organic solution is dried over magnesium sulfate, filtered and concentrated under reduced pressure. The material is fractionally distilled under reduced pressure to give 1e. 1f. 4-bromo-2- / so-propylanisole: Potassium bromide (6.3 g) is suspended in 80 ml of 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 of dichloromethane. At this time, 3-chloroperoxybenzoic acid (9.2 g) 5 in 100 ml of dichloromethane is added. Then 2- / so-propylanisole (1e; 4 g) is added dropwise and the reaction is stirred for a further 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 an aqueous solution of sodium bicarbonate, 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) gives 1f. 1q. ? / - f3.5-dimethyl-4- (3 '- / so-propyl-4'-methoxy-benzylhydroxy) phenanthyrrolidia: 4-bromo-2- / so-propiianisole (1f; 0.6 g ) is dissolved in 15 ml of THF and cooled to -78 ° C under an atmosphere of nitrogenous. To this solution 3.4 are added 15 ml of fer-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? / - [4- carboxaldehyde-3,5-dimethylphenyl] pyrrolidine (1d, 0.53 g) is added. The reaction is stirred for 1 hour and then the cooling bath is removed and stirred for 20 2 additional hours. The reaction is transferred to a separatory funnel with 15 ml of ether and 15 ml of water and the aqueous layer is acidified with 1N HCl. The organic layer is isolated and extracted 5 times with brine, then dried over a-á-s? i? -hfffr ^ ¿> The sodium sulfate is concentrated and concentrated under reduced pressure. Purification by chromatography on silica gel (hexa no: ethyl acetate) gives 1 g.

Wr EXAMPLE 2 2. ? / - f3.5-dimethyl-4- (3 '- / so-propyl-4'-methoxy-benzyl) phenypyrrolidine:? / - [3,5-dimethyl-4- (3, - / 'so-propyl-4'-methoxybenzylhydroxy) phenyl] pyrrolidine (1 g, 0.4 g) is dissolved in 10 ml of 9% acetic acid in ethanol and 50 mg of palladium is added 15 to 10% on carbon. The reaction is hydrogenated, then filtered through celite and concentrated under reduced pressure to give 2. l Mfc- ... fc¿__i__a ____ B_tfe -iaak_-.

EXAMPLE 3 3a. 2,6-Dichloro-4-nitrobenzoic acid: 2,6-dichloro-4-nitrotoluene (3 g) is dissolved in 12.5 ml of pyridine followed by the addition of 12.8 ml of water. The mixture is heated to 90 ° C and potassium permanganate (14.1 g) is added for 1 hour. The mixture is then refluxed for 1 hour and then filtered hot. The filtrate is extracted once with 50 ml of chloroform. The aqueous layer is acidified with 6N hydrochloric acid and extracted twice with 50 ml of chloroform. After drying over magnesium sulfate, the organic solution is filtered and concentrated under reduced pressure to give 3a. 3b. 2,6-dichloro-4-nitro-3 '- / so-propyl-4'-methoxy-benzophenone: 2,6-dichloro-4-nitrobenzoic acid (3a, 0.4 g) is dissolved in 5 ml of thionyl chloride and reflux for 1 hour. The thionyl chloride is then distilled off under reduced pressure and the remaining residue is dissolved in 300 μl of dichloromethane. To this solution, 150 μl of trifluoromethanesulfonic acid and 2- / so-propylanisole (1e, 0.17 g) is added and reacted for 5 hours. Dichloromethane is üY: ü. . r. 'And, ri -.-: ^. stir afterwards under reduced pressure and the remaining residue is dissolved in 20 ml of ethyl acetate. The organic solution is extracted twice with 20 ml of brine solution. The organic layer is concentrated under reduced pressure and purified by chromatography on silica gel (hexane: ethyl acetate) to give 3b. 3c. 2,6-dichloro-4-amino-3 '- /' so-propyl-4'-methoxy-benzophenone: 2,6-dichloro-4-nitro-3, - / so-propyl-4'-methoxy-benzophenone (3b, 144 mg) is dissolved in a mixture containing 10 ml of ethanol and 10 ml of ethyl acetate. To this mixture, 19.2 mg of 10% palladium on carbon are added. The reaction Hydrogenated, then filtered through celite and concentrated under reduced pressure to give 3c.

EXAMPLE 4 3c 20 4. 2,6-dichloro-4-butyrylamido-3 '- / so-propyl-4'-methoxybenzophenone: Pyridine (91 μl) and butyric anhydride (184 μl) are added to 2,6-dichloro-4- amino-3'- / so-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 of ethyl acetate. The organic solution is extracted once with 20 ml of saturated sodium bicarbonate, once with 20 ml of hydrochloric acid ^ .. p 0.1 N, concentrated under reduced pressure and purified by chromatography on silica gel (9: 1 hexane: ethyl acetate) to give 4.

EXAMPLE 5 EL? / - f3,5-dichloro-4- (3 '- /' so-propyl-4'-methoxybenzylhydroxy) phenan-15-butylamine: 2,6-dichloro-4-butyrylamido-3 '- / so- Propyl-4'-methoxybenzophenone (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 of 15% sodium hydroxide and then 15 ml of water. The precipitate that forms is filtered and the precipitate is washed with THF and ethyl acetate. The filtrate is concentrated under reduced pressure and the product is purified by chromatography on silica gel (hexane: methylene chloride) to give 5. -t -4 r% 4 -k-j > -a &-i. ,. .--. fc - a., .- - EXAMPLE 6 5 6 6.? / - r3.5-d.methyl-4- (3 '- / so-propyl-4'-methoxy-benzyl) phenyl-1-butyl-amine: N- [3,5-dichloro-4- (3 '- / so-propyl-4, -methoxybenzylhydroxy) phenyl] butylamine (5; 0.6 g) is dissolved in 12 ml of 9% acetic acid in ethanol and 75 mg of 10 palladium at 10% on carbon. 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: dichloromethane) to give 6.

EXAMPLE 7 20 7a. N-r4-bromo-3,5-d-methylphenylmorpholine: 4-bromo-3,5-dimethyl-aniline (1 b, 0.72 g) is dissolved in 2 ml of ethanol and 0.95 ml of di (2-iodoethyl) ether is added. The sample is refluxed overnight. In this »« < to 4, & ~ hJ te i - »* moment,« e under reduced pressure. The sample is taken up in ethyl acetate and extracted with 0.1 N sodium hydroxide, water and brine. After drying over sodium sulfate, filtering and concentrating under reduced pressure, the mixture T ^ is purified by chromatography on silica gel (hexane: ethyl acetate) to give 7a. 7b. ? / - [3,5-d.methyl-4- (3 '- / so-propyl-4'-methoxy-benzylhydroxy) phenylmorpholine:? / - [3,5-dimethyl-4- (3, - / so-propyl-4'-methoxybenzylhydroxy) phenyl] morpholine (7b) is prepared analogously to the preparation described above for AV¬ EXAMPLE 8 8. ? / - r3,5-dimethyl-4- (3 '- / so-propyl-4'-methoxybenzyl) phennomorpholine: N- 20 [3,5-dimethyl-4- (3' - / so-propyl- 4'-methoxybenzylhydroxy) phenyl] morpholine: (7b, 0.3 g) is dissolved in 10 ml of 9% acetic acid in ethanol and 45 mg of 10% palladium on carbon is added. The reaction is hydrogenated (approximately 16 hours), and:, Aj-teA ^ -ja ^ - * a ^ fa- > . The mixture is then filtered through celite and concentrated under reduced pressure to give 8.

EXAMPLE 9 9. ? / - methylene -? / - f3,5-dimethyl-4- (3 '- / so-propyl-4'-methoxybenzyl) phenin-butylamine:? - [3,5-dimethyl-4- (3, - / so-propyl-4, -methoxybenzyl) phenyl] butylamine: (6), 0.1 g, is dissolved in 1 ml of THF. To this solution is added 50 mg of sodium borohydride. The resulting suspension is added at 0 ° C to a solution of 0.24 ml of 15 3.0 M sulfuric acid, 0.086 ml of 37% aqueous formaldehyde solution and 1 ml of THF. The reaction is stirred for 2 hours and then it is drained in 3 ml of 1 N sodium hydroxide. The aqueous layer is extracted twice with diethyl ether and the organic layers are combined and washed with brine. The organic layer is filtered and the filtrate is concentrated under reduced pressure and the product is purified by 20 chromatography on silica gel (hexane: dichloromethane) to give 9.

-MattÉ-JÉt-ai EXAMPLE 10 10a 10b 10c. ? / - f3,5-diemthyl-4- (3'-benzyl-4'-methoxybenzylhydroxy) phenan-pyrrolidine: A / - [3, -dimethyl-4- (3'-benzyl-4 -'- methoxybenzylhydroxy) phenyl] pyrrolidine (10c) is prepared analogously to A / - [3,5-d.methyl-4- (3 '- /' so-propyl-4'-methoxybenzylhydroxy) -phenyl-pyrrolidine (1g), substituting 2 - / so-propylphenol by benzylphenol.

Use of the compounds of the present invention In accordance with 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 carrier.

The compounds of the present invention can be used for the treatment of conditions such as hair loss in mammals, including interruption and / or reversal of hair loss and promotion of hair growth. Such conditions may manifest themselves, for example, in 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 may include stimulation of nail growth, treatment of skin conditions, prevention of hair discoloration, obesity, cholesterol reduction, treatment of thyroid disorders and treatment of osteoporosis. Preferably, the compounds of the present invention, as defined herein, do not affect cardiac activity. Preferably, in the methods of the present invention, the compounds are formulated in pharmaceutical or cosmetic compositions for use in the treatment or prophylaxis of conditions such as the foregoing. Standard pharmaceutical formulation techniques are used, such as those described in Reminqton's Pharmaceutical Sciences. Mack Publishing Company, 20 Easton, PA. (1990). Typically, from about 5 mg to about 3000 mg, most preferably from about 5 mg to about 1000 mg, most preferably still from about 10 mg to about 100 mg of a compound having a structure as defined herein is administered per day for systemic administration. It is understood that these dose ranges are by way of example only, and that daily administration can be adjusted depending on several factors. The specific dose of the compound can be administered, as well as the duration of treatment and whether the treatment is topical or systemic are interdependent. The dose and treatment regimen will also depend on factors such as the specific compound used, indication of treatment, efficacy of the compound, personal attributes of the subject (such as, for example, weight, age, sex and medical condition of the subject). , 10 compliance with the treatment regimen, and the presence and severity of any side effects of the treatment. In accordance with the present invention, the compounds of the present invention are co-administered with a pharmaceutically acceptable or cosmetically acceptable carrier (here collectively described as "carrier"). The term "vehicle", as used herein, means one or more compatible solid or liquid filler diluents or encapsulating substances that are ? suitable for administration to a mammal. The term "compatible", as used herein, means that the components of the composition are capable of being combined with a compound of the present invention, and with each other, in a manner such that there is no interaction substantially reducing the Effectiveness of the composition under ordinary use situations. Of course, the vehicles should be of sufficiently high purity and sufficiently low toxicity to make them suitable for administration to the animal, preferably la.i j »» a t iiti. » > . . » ,, ..,. -,. • ___, _._. «_, .. n r. - t - * tt-. , - -. ,.: -? -t? JiftiSSSíilt ^ mammal (most preferably human) that is being treated. The vehicle itself may be inert or may possess pharmaceutical benefits and / or own cosmetics. The compositions of the present invention can be 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 preferred with topical administration being the most preferred. Depending on the particular route of administration desired, a variety of vehicles well known in the art can be used. These include fillers, diluents, hydrotropes, surface active agents and solid or liquid encapsulating substances. Optional pharmaceutically active or cosmetically active materials may be included that do not substantially interfere with the activity of the compound of the present invention. The amount of vehicle used together with the compound is 15 sufficient to provide a practical amount of material to be administered per unit dose of the compound. The 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 Dosaqe Forms: Tablets (1981); Y 20 Ansel. Introduction to Pharmaceutical Dosaqe Forms. 2nd Ed .. (1976). Some examples of substances that can serve as vehicles 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; jelly; talcum powder; 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 theobroma oil; polyols such as polyethylene glycol, glycerin, sorbitol, mannitol and polyethylene glycol; alginic acid; emulsifiers, such as TWEENS; wetting agents such sodium lauryl sulfate; coloring agents; flavoring agents; tabletting agents, stabilizers; antioxidants; conservatives; pyrogen-free water, isotonic saline; and phosphate pH regulating solutions. The choice of a vehicle to be used in conjunction with the compound herein is typically determined by the manner in which the compound is administered. In particular, the vehicles for systemic administration include sugars, starches, cellulose and its derivatives, malt, gelatin, talc, calcium sulfate, vegetable oils, synthetic oils, polyols, alginic acid, pH-regulating solutions of phosphate, emulsifiers, saline solution isotonic and pyrogen-free water. Preferred carriers for parenteral administration include propylene glycol, ethyl oleate, pyrollidone, ethanol, and sesame oil. Preferably, the vehicle, in compositions for parenteral administration comprises at least about 90% by weight of the total composition. fe-1- »*" * - Various forms of oral doses can be used, including solid forms such as tablets, capsules, granules and bulk powders.These oral forms comprise a safe and effective amount, usually at least? w of about 5%, preferably from about 25% to about 50% of a compound used in the present invention Tablets can be compressed, tablet crushed, enteric coated, sugar coated, film coated or compressed in multiple form, containing binders, lubricants, diluents, disintegrating agents, coloring agents, flavoring agents, flux-inducing agents and suitable melting agents.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 solvent is, preservatives, emulsifying agents, suspending agents, 15 suitable diluents, sweeteners, fusion agents, coloring agents and flavoring agents. Suitable carriers for the preparation of unit dosage forms for oral administration are well known in the art. The tablets typically comprise pharmaceutically compatible adjuvants 20 conventional such as inert diluents, such as calcium carbonate, sodium carbonate, mannitol, lactose and cellulose; binders such as starch, gelatin and sucrose; disintegrants such as starch, alginic acid and croscarmellose; lubricants such as magnesium stearate, stearic acid and talc. Sliding agents such as silicon dioxide can be used to improve the flow characteristics of the powder mixture. Coloring agents, such as FD &C dyes can be added for appearance. Sweeteners and flavoring agents such as aspartame, saccharin, menthol, mint and fruit flavors are useful adjuvants for chewable tablets. Capsules (including time release and sustained release formulations) typically comprise one or more solid diluents described above. The selection of vehicle components depends on secondary considerations such as taste, cost and storage stability, which are not critical for the purposes of the present invention, and which can be easily made by one skilled in the art. Orally administered compositions also include liquid solutions, emulsions, suspensions, powders, granules, elixirs, dyes, syrups and the like. Suitable carriers for preparing such compositions are well known in the art. Typical vehicle components for syrups, elixirs, emulsions and suspensions include ethanol, glycerol, propylene glycol, polyethylene glycol, liquid sacorosa, sorbitol and water. For a suspension, typical suspending agents include methylcellulose, sodium carboxymethylcellulose, AVICEL RC-591, tragacanth and sodium alginate; Typical wetting agents include lecithin and polysorbate 80; and typical preservatives include methylparaben and sodium benzoate. The peroral liquid compositions may also contain one or more components such as sweeteners, flavoring agents and colorants described above. Said compositions may also be coated by conventional methods, typically with pH or time dependent coatings, such that the compound herein is released into the gastrointestinal tract in the vicinity of the desired topical application, or several times to extend the desired action. Said dosage forms typically include, but are not limited to, one or more of cellulose acetate phthalate, polyvinylacetate phthalate, hydroxypropylmethylcellulose phthalate, ethylcellulose, Eudragit coatings, waxes and lacquer. Other compositions useful for achieving systemic assortment of the present compounds include sublingual, buccal and nasal dosage forms. Said compositions typically comprise one or more of the soluble filler substances such as sucrose, sorbitol and mannitol; and binders such as acacia, microcrystalline cellulose, carboxymethylcellulose and hydroxypropylmethylcellulose. The sliders, lubricants, sweeteners, colorants, antioxidants and flavors described above can also be included. The compounds of the present invention can also be administered topically. The vehicle of the topical composition preferably aids in the penetration of the present compounds into the skin to reach the environment of the hair follicle. The topical compositions of the present invention can be in any form including, for example, solutions, oils, creams, ointments, gels, shampoos, ''. I '' i non-rinsing and rinseable hair conditioners, milks, cleansers, moisturizers, sprays, skin patches and the like. Topical compositions containing the active compound can be mixed with a variety of carrier materials well known in the art, such as, for example, water, alcohols, aloe vera gel, allantoin, glycerin, vitamin A and E oils, mineral oil, propylene glycol, PPG-2 myristyl propionate and the like. Other materials suitable for use in topical vehicles include, for example, emollients, solvents, humectants, thickeners and powders. Examples of each of these types of materials may be used individually or as mixtures of one or more materials in the following manner: Emollients, such as stearyl alcohol, glyceryl monoricinoleate, glyceryl monostearate, propane-1,3-diol, butane -1, 3-diol, mink oil, cetyl alcohol, / so-propiolisostearate, stearic acid, / so-butyl palmitate, isocetyl stearate, oleyl alcohol, / so-propyl laurate, hexyl laurate, decyl oleate, octadecan-2-lo , isocetyl alcohol, cetylpalmitate, dimethylpolysiloxane, di-n-butylsebacate, iso-propylmyristate, iso-propylpalmitate, iso-propyl stearate, butyl stearate, polyethylene glycol, triethylene glycol, glycol, lanolin, sesame oil, coconut oil, arachis oil, olive oil, castor, acetylated lanolin alcohols, petroleum, mineral oil, butyl myristate, stearic acid, palmitic acid, / so-propyl linoleate, lauryl-lactate, myristyl-lactate, decyl oleate, and myristyl myristate; propellants, such as propane, butane, / so-butane, ether -. a,. *. * n. *! ^^ ¡¡^ ^ ^ ^^ dimethyl, -carbon dioxide and nitrous oxide; solvents, such as ethyl alcohol, methylene chloride, / 'so-propanol, castor oil, ethylene glycol monoethyl ether, diethylene glycol monobutyl ether, diethylene glycol monoethyl ether, methylsulfoxide, dimethylformamide, tetrahydrofuran; humectants such as glycerin, sorbitol, sodium 2-pyrrolidone-5-carboxylate, soluble collagen, dibutyl phthalate and gelatin; and powders, such as chalk, talc, Fullers earth, kaolin, starch, colloidal silicon dioxide gums, sodium polyacrylate, tetralkylammonium smectites, trialkylammonium smectites, chemically modified magnesium aluminum silicate, organically modified montmorillonite clay, silicate aluminum hydratate, fumed silica, carboxyvinyl polymer, sodium carboxymethylcellulose and ethylene glycol monostearate. The compounds used in the present invention can also be administered in the form of liposome assortment systems, such as small unilamellar vesicles, large unilamellar vesicles and multilamellar vesicles. Liposomes can be formed from a variety of phospholipids, such as cholesterol, stearylamine or phosphatidylcholines. A preferred formulation for topical administration of the present compounds utilizes liposomes such as those described in Dowton et al., "Influence of Liposomal Compositon on Topical Delivery of Encapsulated Cyclosporin A: I. An In Vitro Study Using Hairless Mouse Skin", S .7.P. Pharma Sciences, Vol. 3, pp. 404-407 (1993); Wallach and Philippot. "New Type of Lipid Vesicle: Novasome®", Liposome Technology. Vol. 1, pp. 141-156 (1993); Wallach, patent of'E.U.A. No. 4,911,928, assigned to Micro-Pak, Inc., issued March 27, 1990; and Weiner 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 Weiner et al., With a compound as described herein administered instead of or in addition to , monoxidil). The compounds of the present invention can also be administered by iontophoresis. See, for example, the website www.unipr.it/arpa/dipfarm/erasmus/erasm14.html; Banqa et al. "Hydrogel-based Lontotherapeutic Delivery Devices for Transdermal Delivery of Peptide / Protein Drugs", Pharm, Res., Vol. 10 (5), pp. 697-702 (1993); Ferrv. "Theorical Model of lontophoresis Utilized in Transdermal Drug Delivery", Pharmaceutical Acta Helvetiae, Vol. 70, pp. 279-287 (1995); Ganqarosa et al. "Modern lontophoresis 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 Skin in vitro", 15 Pharm. Res., Vol. 8, pp. 1121-1127 (1991); Jadoul et al. "Quantification and Localization of Fertanyl and TRH Delivered by Lontophoresis in the Skin", Int. J. -W Pharm., Vol. 120, pp. 221-8 (1995); O'Brien et al .. "An Updated Review of its Antiviral Activity, Pharmacokinetic Properties and Therapeutic Efficacy", Drugs, Vol. 37, pp. 233-309 (1989); Parrv et al .. "Acyclovir Biovailability in Human Skin", 20 J., Invest. Dermatol., Vol. 98 (6), pp. 856-63 (1992); Santi et al .. "Drug Reservoir Composition and Transport of Calcitonin Salmon in Transdermal lontophofesis", Pharm, Res., Vol 14 (1), pp. 63-66 (1997); Santi et al .. "Reverse lontophoresis - Parameters Determining Electroosmotic Flow: I. pH and lonic Strength", J. ?? 4? 'jtir &r? -á & tí-kk. tJ, Control, Relay, Vol., 38, pp. 159-165 (1996); Santi et al .. "Reverse lontophoresis - Parameters Determining Electroosmotic Flow: II Electrode Chamber Formulation", J. Control Reléase, Vol. 42, pp. 29-36 (1996); Rao et al ..? w "Reverse lontophoresis: Noninvasive Glucose Monitoring in vivo in Humans", 5 Pharm. Res., Vol. 12 (12), pp. 1869-1873 (1995); Thvsman et al .. "Human Calcitonin Delivery in Rats by lontophoresis", J. Pharm. Pharmacol., Vol. 46, pp. 725-730 (1994); and Volpato et al., "lontophoresis Enhances the Transport of Acyclovir through Nude Mouse Skin 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 that can work in different ways to increase the hair growth effects of a compound of the present invention. 15 Particular classes of activity enhancers include other hair growth stimulants and penetration enhancers. m Non-limiting examples of hair growth stimulants that can be used in the compositions herein, including systemic and topical compositions, include, for example, 20 benzalkonium, benzethonium chloride, phenol, estradiol, diphenhydramine hydrochloride, chlorpheniramine maleate, chlorophyllin derivatives, cholesterol, salicylic acid, cysteine, methionine, pepper red tincture, benzyl nicotinate, D, L-menthol, oil mint, calcium pantothenate, panthenol, oil Castor, hinocitol, prednisolone, resorcinol, esterified monosaccharides and monosaccharides, chemical activators of protein kinase C enzymes, inhibitors of glycosaminoglycan chain cell uptake, inhibitors of glycosidase activity, glycosaminoglycanase inhibitors, pyroglutamic acid esters, hexosaccharides or acetylated hexosaccharide acids; substituted aryl ethylenes, N-acetylated amino acids, and, of course, monoxidil or finasteride. The most preferred activity enhancers are minoxidil and finasteride, most preferably minoxidil. Non-limiting examples of penetration enhancers that can be used in the compositions herein include, for example, 2-methyl propan-2-ol, ethyl-2-hydroxypropanoate, hexan-2,5-diol, ethyl ether of POE ( 2), di (2-hydroxypropyl) ether, pentan-2,4-diol, acetone, POE methyl ether (2), 2-hydroxypropionic acid, 2-hydroxyoctanoic acid, propan-1-lo, 1,4-dioxane , tetrahydrofuran, butan-1,4-diol, propylene glycol dipelargonate, polyoxypropylene stearyl ether 15, octyl alcohol, POE ester of oleyl alcohol, oleyl alcohol, lauryl alcohol, dioctyladipate, dicapriladipate, di-isopropyladipate, di-isopropylsebacate, dibutylsebacate, diethylsebacate, dimethylsebacate, dioctylsebacate, dibutyl sulphate, dioctyl silica, dibenzyl stearate, dibutyl phthalate, dibutyl diacelate, ethyl myristate, dimethylacetate, butyl myristate, dibutyl succinate, didecyl phthalate, decyl oleate, ethylcaproate, ethylsalicylate, / so-propyl palmitate, etillaurate, 2-ethylhexylpelargonate, / so-propyl isostearate, butyl laurate, benzylbenzoate, butylbenzoate, hexylurate, ethylcaprate, ethylcaprylate, butyl stearate, benzylsalicylate, 2-hydroxypropanoic acid, 2- * - hydroxyoctanoic acid, methylsulfoxide, NN-dimethyl acetamide, N, N-dimethyl formamide, 2-pyrrolidone, 1-methyl-2-pyrrolidone, 5-methyl-2-pyrrolidone, 1,5-dimethyl-2-pyrrolidone, 1-ethyl-2-pyrrolidone, phosphine oxides, sugar esters, tetrahydrofurfural alcohol, urea, diethyl-m-toluamide, and, 1-dodecylazacylheptan-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 can further include additional drugs or excipients as appropriate for the indication. The present invention further relates to equipment comprising a compound and / or composition of the present invention and information and / or instructions by words, images and / or the like, that the use of the equipment will provide treatment for hair loss in mammals (particularly humans) including, for example, interruption and / or reversal of hair loss and / or promotion of hair growth. In addition or alternatively, the kit may comprise a compound and / or composition of the present invention and information and / or instructions concerning methods of application of the compound and / or composition, preferably with the benefit of treating hair loss in mammals.

? ^ A ^^ j ^ - ^ my I - is &SY EXAMPLES OF ADMINISTRATION OF THE COMPOSITION The following examples do not limit the invention, but provide a guide for the person skilled in the art to carry out the methods of the present invention. In each example, a compound other than that mentioned may be substituted in the example by another having a structure as described herein with similar results.

EXAMPLE A A composition for topical administration is made comprising: fifteen m 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 administered topically daily to the subject.

** TO . at -J 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 place of cyclosporin A and using Novasome 1 for the nonionic liposomal formulation. A male human subject suffering from pattern baldness ^ 10 Male is treated every day with the previous composition. Specifically, for 6 weeks, the above composition is administered topically to the subject.

EXAMPLE C 15 A shampoo is made comprising: twenty k ^., k fc * »* -! ^^ 10 A human 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. m l ..

Claims (10)

1. NOVELTY OF THE INVENTION CLAIMS 1. - A compound characterized by the structure: and pharmaceutically acceptable salts, hydrates and amides, biohydrolyzable esters and imides thereof, wherein: Rt, R 2, R 5, R 7 and R 10 are each independently selected from the group consisting of hydrogen, halogen, alkyl, alkenyl, alkynyl, heteroalkyl , heteroalkenyl and heteroalkynyl; R 4 is selected from the group consisting of halogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, ayl, arylalkyl, heteroalkyl, heteroalkenyl, heteroalkynyl, heterocycloalkyl, heterocycloalkenyl, heteroaryl, heteroarylalkyl and heteroarylalkenyl; wherein when R2 is hydrogen Y is -CH2CHK1, X is selected from the group consisting of -NZ- and -NH-, and R-? 2 is C -C alkyl wherein K-? is selected from hydrogen and C 4 alkyl and Z is C 1 -C alkyl, then R 4 is not arylalkyl; R8 and R9 are each The compounds are 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 Rs and R9 is not hydrogen; R3 is selected from the group consisting of hydrogen, allyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, arylalkyl, heteroalkyl, heteroalkenyl, heteroalkynyl, heterocycloalkyl, heterocycloalkenyl, heteroaryl, heteroarylalkyl and heteroarylalkenyl; R6 and R 'are each, independently, selected from the group consisting of W 10 hydrogen, halogen, hydroxy, amino, nitro, cyano, carboxy, thiol, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl and heteroalkynyl; wherein Rβ and Rβ 'are, together oxo or 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 15 group consisting of bond and -C (O) -; where 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; or where when Rn is Binding, then R12 and Z can be optionally linked together to form a cycle selected from the group consisting of cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl and heteroaryl; wherein when R 12 is heteroalkyl, heteroalkenyl, heteroalkynyl, heterocycloalkyl, heterocycloalkenyl, heteroaryl, heteroarylalkyl or heteroaplalkenyl, then a heteroatom of R-? 2 is not directly covalently linked to R-M; where when Y is a link, X is -O-, and P ^ R-n is -C (O) - then R? 2 is not alkyl; and Z is selected from the group that 5 consists of alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, and heteroalkynyl; or wherein when R-n is a bond, then R-? 2 and Z can be optionally linked 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, further characterized because Y is a bond and because each of Rβ and Rg is not hydrogen. 3. A compound according to any of the preceding claims, further characterized in that X is selected from 15 group consisting of -NH- and -NZ-. 4. A compound according to any of the preceding claims, further characterized in that *. Rß and Rg are each one independently selected from the group consisting of halogen, alkyl, alkenyl and heteroalkyl, and because R3 is selected from the group 20 consists of hydrogen and lower alkyl. 5. A compound according to any of the preceding claims, further characterized in that Rβ and Rβ 'are each independently selected from the group consisting of hydrogen, halogen, "hydroxy and lower alkyl, with the proviso that R6 and R6 'are oxygen together. 6. - A compound in accordance with any of the previous claims, further characterized in that R12 is selected from 5 group consisting of alkyl, heteroaryl, arylalkyl and heteroarylalkyl, with the condition that when Rn is a bond, then R12 and Z are optionally linked together to form a cycle selected from the group consisting of cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl and heteroaryl. 7 - A compound in accordance with any of the previous claims, further characterized in that Ri, R2, R5, R7 and R10 they are each hydrogen. 8. - A compound in accordance with any of the previous claims, further characterized in that X is -NZ- and Z is C 1 -C 3 alkyl, with the proviso that when R n is a bond, then R 2 and Z are linked 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 of 20 according to any of the preceding claims and a vehicle. 10 -. 10 - A method to treat capillary loss consisting of administer to a mammal a composition as claimed in the claim 9. The present invention describes novel compounds and compositions that are useful for treating hair loss in mammals, including for stopping and / or reversing hair loss and stimulating hair growth; the compounds have a biphenyl structure, as described in formula (I) and preferably do not affect cardiac activity, and pharmaceutically acceptable salts, hydrates and biohydrolyzable amides, esters and imides thereof, wherein R 1 f R 2, R 3, R 4, R 5, R b, R e, R 7, R s, R 9, R 10, Y, X, R11, and R12 are as defined herein. P01 / 1947F