MXPA01012492A - Method of treating hair loss. - Google Patents

Abstract

The present disclosure describes methods for treating hair loss in mammals, including arresting and/or reversing hair loss and promoting hair growth. The methods comprise administering a cardiac-sparing coumpound having a structure as described herein and a pharmaceutically-acceptable carrier.

Description

METHOD FOR TREATING CAPILLARY LOSS FIELD OF THE INVENTION < » The present invention relates to methods for treating hair loss in mammals including to stop and / or reverse hair loss and promote 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 reenters 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 dermal papillae cells 4 »tightly packed. In the telogen, the start of a new anagen phase 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, by promoting or prolonging 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 concerns of |? Safety 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 T3 levels is strongly associated with hair loss. Consistent with this observation, hair growth is a reported side effect of the administration of T4. See, for example, Berman's "Peripheral Effets of L-Thyroxine on Hair Growth and Coloration in" Cattle, "Journal of Endocrinology, Vol. 20, p. 282-292 (1960); and Gunaratnam, 5"The Effets 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 10 96/25943, assigned to Life Medical Sciences, Inc., published August 29, 1996. Unfortunately, however, the administration of T3 and / or T4 to treat hair loss is not practicable because these thyroid hormones they are also known to induce significant cardiotoxicity. See, for example, Walker et al., U.S. Patent. No. 5,284,971, assigned to Syntex, 15 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, however, the inventors of the present have discovered compounds that strongly initiate hair growth without inducing cytotoxicity. Consistent with this finding, but without pretending to be limited to 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 do not interact at all. , with selective hormone receptors for 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 loss of hair, including for stopping and / or reversing hair loss and promoting hair growth.

BRIEF DESCRIPTION OF THE INVENTION The present invention relates to methods for treating capillary loss consisting in administering a compound that the inventors have found to be particularly useful for the treatment of capillary loss in mammals, including for stopping and reversing hair loss and for Promote hair growth. The compounds used in the present method have the structure: and pharmaceutically acceptable salts, hydrates and biohydrolyzable amides, esters thereof, wherein Ri, R2, R3, R4, R5, R6, Ri8, R-I9, and are as defined herein.

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to methods for using compounds and compositions that are particularly useful for treating hair loss in mammals, including for stopping and / or reversing hair loss and 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 do not affect cardiac activity. Preferred compounds useful in the method of the present invention, therefore, as defined herein, do not affect cardiac activity. Publications and patents are referred to throughout this description. All references cited herein are incorporated herein by reference. 15 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 can 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.

DEFINITIONS AND USE OF TERMS The following is a list of definitions for terms used here: »As used herein," alkanoyl "is an alkyl substituted with oxo 5 (C = O). 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, "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 very preferably still from 1 to 15 about 4 carbon atoms. Preferred alkyls include, for example, methyl, ethyl, proopyl, iso-propyl and butyl. As used herein, "aryl" is an aromatic ring radical that is either carbocyclic or heterocyclic. Preferred aryl groups include, for example, phenyl, benzyl, tolole, xylyl, cumenyl, naphthyl, biphenyl, thienyl, furyl, 20 pyrrolyl, pyridinyl, pyrazinyl, thiazolyl, pyrimidinyl, quinolinyl, triazolyl, tetrazolyl, benzothiazolyl, benzofuryl, indolyl, indenyl, azulenyl, fluorenyl, anthracenyl, oxazolyl, isoxazolyl, isotriazolyl, imidazolyl, pyrazolyl, oxadiazolyl, indolicinyl, indolyl, soindolyl, purinyl, quinolicinyl, quinolinyl, isoquinolinyl, cynolinyl and the like. Aryls 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. Arylalkyls can be substituted or unsubstituted. As used herein, "biohydrolyzable amides" are amides of the compounds used in the present invention that do not interfere with the activity of the compound, or that are easily converted in vivo by a mammalian subject 10 to produce an active compound. As used herein, "biohydrolyzable esters" are esters of the compounds used in the present invention that do not interfere with the activity of the compound, or that are readily converted in vivo by a mammalian subject to produce an active compound. As used herein, "biohydrolyzable imides" are imides of the compounds used in the present invention that do not interfere with activity 1 of the compound, or that are easily converted in vivo by a mammalian subject to produce an active compound. 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, 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, "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 the p 10 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, "salt" is a cationic salt formed in Any acidic group (eg, carboxyl) or an anionic salt formed by any basic group (eg, 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. The anionic salts 20 include the halides (such as, for example, chloride salts). Said acceptable salts, when administered, should be appropriate for use in mammals.

Methods of the present invention The present invention relates to methods for treating capillary loss consisting of administering a composition comprising a compound t having the structure: and pharmaceutically acceptable biohydrolyzable salts and hydrates and amides, esters, and prodrugs thereof, wherein: (a) X is selected from oxygen, sulfur and CH2; (b) R1 and R2 are each independently selected from hydrogen, halogen, hydroxy, trifluoromethyl, C 1 -C 2 alkyl, C 1 -C 2 alkenyl and C 1 -C 4 alkoxy; (C) R3 is selected from hydrogen, alkyl, aryl, and arylalkyl; (d) R4 is selected from the group consisting of hydrogen,} halogen, C 1 -C 4 alkyl, C 1 -C 4 alkenyl, hydroxy and C 1 -C 4 alkoxy. (e) R5 is selected from hydrogen, halogen, hydroxy, alkyl, C1-C4 alkenyl, C1-C4 alkoxy, cycloalkyl, aryl and arylalkyl; 20 (f) R6 is selected from alkyl, aryl, -CH2CH (NH2) CO2H, -CH2CH (OH) CO2H, -CH2CR7R8NR9R? Or, -YC (0) Rn, - (CH2) n-OH, -CH2C (R12 ) (NH2) CO2R13, -CH2CH (COOH) (NH) C (O) (CH2) mC (O) NH (CH2) nR20, and -CH2CR12R12C (O) OR13; (g) R is selected from hydrogen and C1-C4 alkyl; (h) Re is selected from hydrogen and -C (O) Rn; (i) Rg and R-io are each independently selected from hydrogen, C 1 -C 4 alkyl, and C 1 -C 4 alkanoyl; 5 (j) Y is selected from a bond and C1-C4 alkyl; (k) Rn is selected from hydroxy, C1-C4 alkoxy, NR-14R15, C1-C4 alkyl, C1-C4 alkenyl and C1-C4 alkynyl; (I) R 2 is alkynyl of d-Cß; (m) R 3 is selected from C-pCß alkyl, cycloalkyl, and arylalkyl; EMI10.0 (n) R14 is selected from hydrogen and C1-C4 alkyl; (o) R-15 is selected from hydrogen, C 1 -C 4 alkyl and C 1 -C 4 alkanoyl; (p) R18 and R-19 are each independently selected from hydrogen, CI-CT alkyl, C-i-Cß alkenyl, hydroxy and halogen; 15 (q) m is an integer from 2 to 4; (r) n is an integer from 1 to 4; and β (s) R2o is an unsaturated, unsaturated, five or six membered monocyclic heterocycle containing one to two nitrogen atoms as the only heteroatoms. The X X portion is selected from oxygen (-O-), sulfur (-S-), and -CH2-, Preferably, X is selected from oxygen -CH2-. Most preferably X is »oxygen.

The Ri and R? Ri and R 2 are each independently selected from hydrogen, halogen, hydroxy, trifluoromethyl, C 1 -C 7 alkyl, C 1 -C 2 alkenyl, and C 4 -C 4 alkoxy. Preferably Ri and R2 are each independently selected from hydrogen, halogen, trifluoromethyl and CrC6 alkyl. Most preferably, R 1 and R 2 are each independently selected from halogen, trifluoromethyl and C 1 -C 2 alkyl. Most preferably, R1 and R2 are each independently selected from halogen and C-t-Cß alkyl. The preferred halogens are chlorine and iodine. The portion R3 R3 is selected from hydrogen, alkyl, aryl and arylalkyl.

Preferably, R3 is selected from hydrogen, alkyl, and arylalkyl. Preferred alkyls for R3 are methyl and ethyl. A preferred arylalkyl for R3 is benzyl.

The R 4 R 4 portion is selected from the group consisting of hydrogen, halogen, C 4 alkyl, C 1 -C 4 alkenyl, hydroxy and C 1 -C 4 alkoxy. Preferably, f R4 is selected from hydrogen and halogen (most preferably iodine). Very preferably R4 is hydrogen.

The Rg R5 portion is selected from hydrogen, halogen, hydroxy, alkyl, C 1 -C 4 alkenyl, C 1 -C 4 alkoxy, cycloalkyl, aryl and arylalkyl. Preferably, R5 is selected from hydrogen, halogen (particularly iodo), aryl, cycloalkyl, aryl and arylalkyl. Most preferably R5 is selected from hydrogen, alkyl, cycloalkyl, aryl and arylalkyl. Most preferably still, R5 is selected from alkyl, cycloalkyl, aryl and arylalkyl. Most preferably, R5 is selected from alkyl and arylalkyl (a preferred arylalkyl is benzyl). The R a and R 19 portions R 18 and R 19 are each independently selected from hydrogen, CrC 6 alkyl, C C β alkenyl, hydroxy and halogen. Preferably, R-is and R19 are each independently selected from 20 hydrogen and C 1 -C 2 alkyl. Most preferably, R-? 8 and R-19 are each hydrogen.

Re R6 portion is selected from alkyl, aryl, -CH2CH (NH2) CO2H, -CH2CH (OH) CO2H -CH2CR7R8NRgR? Or, -YC (O) Rn, -CH2) n-OH, CH2C (R? 2) (NH2) CO2R? 3, CH2CH (COOH) (NH) C (O) (CH2) mC (O) NH (CH2) nR20, and -CH2CR? 2R? 2C (O) OR? 3 . Preferably R6 is selected from -CH2CH (NH2) CO2H, -CH2CH (OH) CO2H, -CH2CR7R8NR9R? 0l -YC (OR) Rn, -CH2C (R? 2) (NH2) CO2R? 3, -CH2CH (COOH) NH ) C (O) (CH2) mC (O) NH (CH2) nR20, and - CH2CR? 2R? 2C (O) OR? 3. R is a substituent on -CH2CR R8NR9R? Or. R7 is selected from hydrogen and C1-C4 alkyl. R8 is a substituent on -CH2CR7R8NR R? O. R8 is selected from hydrogen and -C (O) Rn. Preferably R8 is hydrogen. R9 and R10 are substituents on -CH2CR R8NRgR? O and CH2CR7R8NRgR? O. Rg and R10 are each independently selected from hydrogen, C1-C4 alkyl and C1-C4 alkanoyl (alkyl substituted with oxo). Preferably, Rg and R10 are each independently selected from hydrogen and C1-C4 alkyl. And it is a substituent in -YC (O) Rn. Y is selected from a bond and C1-C4 alkyl. Where Y is a bond, in C (O) Rn of -YC (O) Rn is directly linked covalently through a single bond to the respective phenyl ring of the compound. R11 is selected from hydroxy, C1-C4 alkoxy, -NR14R15, C1-C4 alkyl, C1-C4 alkenyl, and CrC4 alkynyl. Preferably, Rn is selected from hydroxy, C1-C4 alkoxy and -NR Ris- Most preferably, Rn is selected from hydroxy and C1-C4 alkoxy. R12 is a substituent on -CH2C (R? 2) (NH2) CO2R? 3 and -CH2CR? 2R? 2C (O) OR? 3. R12 is C? -C6 alkyl. R13 is a substituent on -CH2CR? 2R? 2C (O) OR? 3 and -CH2C (R? 2) (NH2) CO2Ri3- R13 is selected from C-Cß alkyl, cycloalkyl and arylalkyl. Preferably, R 3 is C 6 C alkyl. R14 and R15 are each (optionally) substituents on Rn. R 14 is selected from hydrogen and C 1 -C 4 alkyl, preferably methyl ethyl. R15 P 10 is selected from hydrogen, C 1 -C 4 alkyl and C 1 -C 4 alkanoyl (alkyl substituted with oxo (C = O)). Preferably, R15 is selected from hydrogen and C1-C4 alkyl. The integers m and n are CH2CH (COOH) (NH) C (O) (CH2) mC (O) NH (CH2) nR20. The integer m is 2a 4, Preferably 2, the integer n is from 1 to 4, preferably 1. R or is also from -CH2CH (COOH) (NH) C (O) (CH2) mC (O) NH (CH2) NR20. R20 is a heterocyclic (01, five or six membered monocyclic unsubstituted, containing one to two, preferably one, nitrogen atoms as the only heteroatoms.) Non-limiting examples of preferred heterocycles are pyrolyl, 20 pyrazolyl, imidazolyl, pyridyl, pyridazinyl, pyrimidinyl and pyrazinyl, most preferably imidazolyl, most preferably 5-imidazolyl. Preferred compounds useful in the method of the present invention are reported in Yokovama et al. "Synthesis and Structure - Active Relationships of Oxamic Acid and Acetic Acid Derivatives Related to L- Thyronine", Journal of Medicinal Chemistry, Vol. 38, pp. 695 -707 (1995). These compounds are further described in Table 1 below: < t TABLE 1 F 10 Other preferred compounds useful in the methods of the present invention are those described in Li et al. WO 99/00353, assigned to Karo Bio, published January 7, 1999. Particularly preferred among those compounds have the structure: wherein R5 is selected from CrC6 alkyl and C3-C7 cycloalkyl; R1 and R2 are each independently selected from hydrogen, halogen and CrC6 alkyl, wherein at least one of Ri and R2 is not hydrogen; and Rn »is selected from the group consisting of hydroxy and C1-C4 alkoxy. Preferred compounds of this structure are presented in Table 2 below: TABLE 2 Other preferred compounds used in the methods of the present invention are described in Kun et al .. WO 97/46228, assigned to Octamer, Inc., published December 11, 1997. Particularly preferred among these have the structure: Wherein R3 is selected from methyl and ethyl; R4 is selected from hydrogen and iodine; R5 is selected from hydrogen, iodine and alkyl; R 8 and R 19 are each independently selected from hydrogen and CrCβ alkyl; X is selected from oxygen, sulfur and CH2; and R1 and R2 are each independently selected from hydrogen, halogen and C1-C4 alkyl. Other preferred compounds useful in the methods of the present invention are those described in Kun et al., WO 99/20263, assigned to Octamer, Inc., published April 29, 1999. Other Preferred Compounds Useful in the Methods of the Present 10 invention are those described in Feinberq et al .. US patent Do not. 4,711, 855, assigned to Ciba Corning Diagnostics Corp., issued December 8, 1987. Particularly preferred among these compounds have the structure: where m is an integer from 2 to 4; n is an integer from 1 to 4; and R20 is an unsaturated, unsaturated, five or six membered monocyclic heterocycle having one to two nitrogen atoms as the only heteroatoms. Examples of these heterocycles include, but are not limited to, pyrrolyl, pyrazolyl, imidazolyl, pyridyl, pyridazinyl, pyrimidinyl and pyrazinyl, most preferably imidazolyl, most preferably 5-imidazolyl.

Other preferred compounds useful in the methods of the present invention are those described in Wechter et al., U.S. Pat. No. 3,449,419, assigned to The Upjohn Co., issued June 10, 1969. Particularly preferred among these compounds have the structure: wherein R 3 is selected from hydrogen and C 1 -C 4 alkyl; R is selected from hydrogen and iodine; R5 is selected from hydrogen, iodo and C1-C4 alkyl; Rie and Rig are each independently selected from hydrogen and CrC 4 alkyl; R1 and R2 are each independently halogen; Y is selected from a bond and C1-C3 alkyl; R11 is NR14R15; and R and R15 are each independently selected from hydrogen and C C alkyl. Other preferred compounds useful in the methods of the present invention are those described in Kummer et al., U.S. Pat. No. 3,930,017, issued December 30, 1975. Particularly preferred among these compounds have the structure: 20 wherein R4 is selected from hydrogen and iodine; R1 and R2 are each independently selected from hydrogen and iodine; each R 2 is independently CrC 6 alkyl; and R13 is selected from CrC6 alkyl, cycloalkyl and arylalkyl. Other preferred compounds useful in the methods of the present invention are those described in Ellis et al., U.S. Pat. No. 4,766,121, assigned to Smith Kline & French Laboratories Ltd, issued August 23, 1988. Particularly preferred among these compounds have the structure: and X is selected from oxygen, sulfur, and CH2; R1 and R2 are each independently selected from hydrogen, halogen and CrC alkyl; Re is selected from -CH2CR7R8NR9R? 0 and -YC (O) Rn; R 6 is aryl; and R? it is selected from hydrogen and C1-C4 alkyl. Preferably, X is oxygen; R7 is hydrogen; R6 is -CH2CR7R8NRgR? 0; R8 is -C (O) Rn; Rn is hydroxy; and / or Rg is C 1 -C 4 alkyl and R 10 is hydrogen. Also preferably, R6 is -YC (0) Rn; And Y is CrC alkyl; and / or R1 and R2 are each independently halogen. Particularly preferred groups for Rie are selected from 4-hydroxyphenyl, 5-hydroxy-2-pyridyl, 6-oxo-3 (1 H) pyridyl; and 6-oxo-3 (1 H) pyridazinyl.

Other preferred compounds useful in the methods of the present invention are those described in Leeson et al .. "Selective Thyromimetics, Cardiac-Sparing Thyroid Hormone Analogues Containing 3'-Arilmethi! Substituents"; Journal of Medicinal Chemistry, Vol. 32, pp 320-336 (1989). Particularly preferred among these compounds are those shown in Table 3 below: TABLE 3 ^^^ ¡¡^^ ^ jk. twenty . ^ A? .. AS Analytical Methods The present invention relates to methods for treating hair loss by administering a compound having a structure as described herein. 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 methods well known in the art (but with the term "not affecting cardiac activity" can be used, 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, e.g., Gomberq-Maitland et al .. "Thyroid hormone and Cardiovascular Diesase", American Heart Journal, Vol. 135 (2), p. 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., 15"Thyroid Hormone Therapy and Cardiovascular Disease", Progress in Cardiovascular Diseases, Vol. 37 (4), p. 329-336 (1996). This increases the weight of the heart in relation to the whole body weight. The cardiotoxicity test given hereinafter is used to test compounds for potentially adverse cardiac effects by measuring their effect on heart-to-body weight ratio. Two groups each of six male Sprague Dawley rats (Harían 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 the vehicle or test compound in a vehicle daily for 28 of those ^ days as described below. 5 Before starting the test, each rat was allowed to acclimate to standard environmental conditions for 5 days. Each rat received food (standard feed 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 The test is prepared at a concentration of 500 μm / ml in the vehicle. 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, 15 respectively) to 500 μl of dose solution per kg of rat. For rats in the test compound, this corresponds to a dose of 250 μg of test compound 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, 20 8, 10, 12, 15, 17, 19, 22, 24, 26 and 29 before dosing for that day; for each 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 of such Fw way injection sites are rotated in this area. 5 On day 30 in the morning, the rats of each group are slaughtered with CO2 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 f 10 carefully in the sternum with small scissors, so that the heart and lungs are exposed. With small scissors and forceps, the vessels connected to the heart are cut from 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 thoracic artery and vein 15 internal and any other small connections. The heart is immediately collected intact, including the left and right atria and the left and right P 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. 20 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 heart / body ratios for each rat in the vehicle control vehicle are added together and divided by 6 (ie, 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 test compound group). 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 1.15, and most preferably still less than 1.1. According to this method, T3 and T4 do not affect the cardiac cavity.

Telogen conversion test: 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 hair growth cycle ("anagen"). Without pretending to be limited to the 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 is no longer synchronized. Where mice approximately 40 days old with dark fur (brown or black) are used in growth experiments of ».iL .m, i?» L > 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 4 »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 according to the present invention is administered to the test composition group. The duration of the test is at least 19 days with 15 days of treatment (where the days of treatment occur from Monday to F 10 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. 15 will easily understand that these concentrations can be modified.

TABLE 4 twenty ** The vehicle is 60% ethanol, 20% propylene glycol and 20% dimethyl isosorbide (commercially available from Sigma Chemical Co., St. Louis, MO). # Mice are treated topically from Monday to Friday on their lower back (tail base to lower rib). A pipette and tip are used to deliver 400 μl to the back of each mouse. The application of 400 μl is done slowly while moving the mouse hair to allow the application to reach the skin. Although each treatment is being applied to the mouse via the topical route, a visual grade of 0 to 4 will be given to the color of the skin in the area of application 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. 15 TABLE 5 twenty i AITAT? ? Manufacturing Methods The compounds of the present invention are prepared according to 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 perform standard manipulations of organic compounds without further instructions. Examples of such manipulations are É 10 describe in standard texts such as J. March, Advanced Orqanic 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 15 undesirable side reactions. Often, the person skilled in the art uses protection groups to achieve said 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 of these manipulations can be found, for example, T. 20 Greene, Protectinq Groups in Orqanic synthesis, John Wiley & Sons, 1981. The compounds of the present invention may have one or more quintal 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 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. Thus, 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 synthesis of the compounds useful in the present invention is described in the art. Accordingly, one skilled in the art will be able to prepare the compounds described herein. For further guidance, the synthesis of various compounds of the present invention are described, for example, in Ellis et al, US Pat. No. 4,910,305, assigned to Smith Kline & French Laboratories, issued March 20, 1990; Ellis et al., Patent of E.U.A. No, 4,826,876, assigned to Smith Kline & French Laboratories, issued May 2, 1939; Ellis et al., Smíth Kline & French Laboratories patent of E.U.A. No. 4,766,121, ^ Ak ?? s ^ *? L assigned to Smith Kline & French Laboratories, issued on August 23, 1988; Emmet et al., Patent of E.U.A. No. 5,061, 798, assigned to Smith Kline & French Laboratories, issued on October 29, 1991; Blank et al., Patent of E.U.A. No. 3,149,153, assigned to Smith Kline & French Laboratories, issued on September 15, 1964; Blank et al., Patent of E.U.A. No. 3,287,396, assigned to Smith Kline & French Laboratories, issued on November 22, 1966; Leeson et al., Assigned to Smith Kline & French Laboratories, published on July 23, 1986; Stearns. WO 90/07330, assigned to The Regents of the University of California, published July 12, 1990; Yu et al., Patent of E.U.A. No. P 10 4,363,815 issued December 14, 1982; Kummer et al. patent of E.U.A. No. 3,930,017, issued December 30, 1975; Kummer et al .. patent of E.U.A. No. 4,110,470, issued August 29, 1978; Wechter et al., Patent of E.U.A. No. 3,449,419, assigned to The Upjohn Compay, issued June 10, 1969; Feinberq. patent of E.U.A. DO NOT. 4,711, 855, assigned to Ciba 15 Corning Diagnostics Corp., issued December 8, 1987; Kun et al., WO 97/46228, assigned to Octamer, Inc., published December 11, 1997; Li et al. WO 99/00353, assigned to Karo Bio, published on January 7, 1999; and Leeson et al., "Selective Thryromimetis, Cardiac-Sparing Thyroid Hormone Analogues Containing 3'-Aryl methyl Substituents"; Journal of Medicinal Chemistry, Vol. 32, 20 pp. 320-336 (1989). The following non-limiting examples provide additional guidance for making the compounds used in the present method. j ^ - ^ * a3Ffc ^ fc EXAMPLE 1 To a suspension of bis- (3-isopropyl-4-methoxyphenyl) iodine tetrafluoroborate (prepared by the method of Yokoyama et al. "Synthesis and Structure - Activity Relationships of Oxamic Acid and Acetic Acid Derivatives Related to L-Thyronine"; Journal of Medicinal Chemistry, Vol. 38, pp. 695-707 (1995)), and copper-bronze (6.1 g) in dichloromethane (150 ml), is added to a solution of 3,5-dibromo-4-hydroxybenzoate. methyl (15 g) and triethylamine (5.4 g) in dichloromethane (100 ml) dropwise at room temperature. The mixture is stirred overnight and filtered through celite. After concentration, the resulting residue is passed through a short silica gel column. The pure fractions are combined and concentrated to dryness. The residue is crystallized from methanol to give methyl 3,5-dlbromo -4- (4'-methoxy-3'-isopropylphenoxy) -benzoate. The above ester (6.5) is hydrolyzed by treatment with 1 M aqueous NaOH (60 ml) and methanol (150 ml) to give 3,5-dibromo-4- (4'-methoxy-3'isopropylphenoxy) benzoic acid. The benzoic acid (2 g) is demethylated with boron tribromide (1 M, 26 ml) in dichloromethane at 0 ° C. The mixture is stirred overnight at room temperature before being quenched with a water / ice mixture. The layers are separated and the water layer is extracted with dichloromethane. The combined organic extracts are dried, filtered and concentrated. The resulting residue is recycled to give 3,5-dibromo-4- (4-hydroxy-3-isopropylphenoxy) benzoic acid.

EXAMPLE 2 Bromine (35.2 g) is added dropwise to a suspension of methyl 4-hydroxy-phenylacetate (16.6 g) in water (500 ml). After a day of stirring, the mixture is divided between water and ethyl acetate. The organic layer is washed with aqueous sodium thiosulfate, dried, filtered and concentrated. The residue is recrystallized from methanol to give methyl 3,5-dibromo-4-hydroxyphenylacetate. The above phenol (5 g) is coupled to bis (3-isopropyl-4-methoxyphenyl) iodine tretrafluorate (9.5 g) as described in Example 1. Purification by column chromatography and recrystallization from methanol gives 3- 5-Dibromo-4- (4-methoxy-3-isopropyl-phenoxy) -methyl methacrylate. The above ester (2.4 g) is demethylated with boron tribromide. The crude product is recrystallized from dichloromethane and light petroleum ether to give 3-5-dibromo-4- (4'-hydroxy-3'-isopropylphenoxy) phenylacetic acid.

EXAMPLE 3 Methyl 3,5-dichloro-4-hydroxybenzoate (10 g) is coupled with bis- (3-isopropyl-4-methoxyphenyl) iodine tretrafluoroborate (35 g) using the method described in Example 1. Purification by chromatography on column followed by recrystallization from methanol gives methyl 3-5-dichloro-4- (4-methoxy-3-10 isopropylphenoxy) benzoate. The above methoxy compound (100 mg) is demethylated and hydrolyzed using the method described in Example 1 to give 3,5-dichloro-4- (4-hydroxy-3-isopropylphenoxy) benzoic acid. aiBM EXAMPLE 4 Methyl 3,5-dichloro-4- (4-methoxy-3-isopropylphenoxy) benzoate (see Example 3) (3.0 g) is treated with a 1 M solution of diisobutylaluminum hydride (DIBAL) in tetrahydrofuran (32.5 ml) at 0 ° C and then it is warmed to 10 room temperature and stirred overnight. The reaction mixture is poured into a 1M ice-cold HCl solution and extracted with ethyl acetate three times. The organic layer is washed (brine), dried, filtered and concentrated to dryness to give 3,5-dichloro-4- (4-methoxy-3-isopropylphenoxy) alcohol. The above alcohol (200 mg) is demethylated using the method described in Example 1 to give 3,5-dichloro-4- (4-hydroxy-3-isopropylphenoxy) benzyl alcohol. * - -"""" to-"**- **" * * - -. • * aA * -Aaa EXAMPLE 5 Methyl 3-5-diiodo-4- (4'-ethoxyphenoxy) benzoate is synthesized using the general methodology of Borrows et al., "The Synthesis of Thyroxine and Related Substances." Par I. The Preparation of Tyrosine and Some of its Derivatives , and a New Route to Thyroxine ", Journal of the Chemical Society, 10 Supp. Issue No. 1, S185 - S190 (1949).

EXAMPLE 6 3-5-diiodo-4- (4-methoxyphenoxy) benzoic acid is synthesized using the general methodology of Borrows et al. "The Syntheses of Thyroxine and Related Substances, Part I. The Preparation of Tyrosine and Some of its Derivatives, and 20 a New Route to Thyroxine ", Journal of the Chemical Society, Supp. Issue No. 1, S185 - S190 (1949).

Jt - J "» * ^ - »^ * - - v - - - * - - ......, ^ Af- EXAMPLE 7 3,3 ', 5-triiodothyroacetic acid is commercially available from Sigma Chemical Co., St. Louis, MO.

EXAMPLE 8 3,3 ', 5-triiodotropypropionic acid is commercially available 15 from Sigma Chemical Co., St. Louis, MO.

EXAMPLE 9 9a. 2-isopropyl anisole: potassium hydroxide (5.6 g) is added to 13.4 ml of acetone followed by 2-isopropylphenol (13.6 g). After the potassium hydroxide is dissolved, methyl iodide (14.2 g) is added. The reaction gets At reflux for approximately 16 hours. Then 150 ml of water are added. This reaction is extracted 3 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 magnesium sulfate, the organic solution 20 dried over MgSO4, filtered and concentrated under reduced pressure. The material is fractionally distilled under reduced pressure to give 9a. 9b. Bis (3-isopropyl-4-methoxyphenyl) vodonium tetrafluoroborate: Acetic anhydride (7 ml) is cooled to -15 ° C in a dry ice / acetone bath. Fuming nitric acid (5.4 ml) is added dropwise. Iodine (2.5 g) is added in one piece followed by dropwise addition of 4.7 ml of trifluoroacetic acid. After 20 minutes, the reaction is removed from the bath and stirred at room temperature for 30 minutes. After the iodine has dissolved, the reaction is sprayed to remove nitrogen oxides and then concentrated under vacuum. The material is then taken up in 15 ml of acetic anhydride and cooled to -10 ° C. To this cooled solution is added dropwise a solution of 2-isopropyl anisole 9a; 7.43 g) in 35 ml of acetic anhydride and 5 ml of trifluoroacetic acid. The reaction is allowed to stand in a refrigerator for p about 16 hours. After allowing the reaction to return to room temperature for 3 hours, the reaction is concentrated under high vacuum. The residue is taken up in 25 ml of methanol, 25 ml of 10% sodium bisulfite and 2M sodium tetrafluoroborate. The mixture is stirred vigorously for 30 minutes and the supernatant is decanted. To the residue, 200 ml of hexane 15 are added and stirred for an additional 30 minutes. At this time, the solid is collected, washed with hexane and dried under vacuum to give 9b. 9c. 2 ', 6'-D-IVdo-3-isopropyl-4-methoxy-4'-nitrildiphenyl ether: Bis (3-isopropyl-4-methoxyphenyl) iodonium tetrafluoroborate (9b); 1 g) is weighed, taken up in 3 ml of dichloromethane and 0.17 g of copper-bonce are added. The mixture 20 is cooled in ice water. A solution of 2,6-diiodo-4-nitrilphenol (0.48 g) and triethylamine (0.28 g) in 3 ml of dichloromethane is added dropwise. The reaction is placed in the dark and stirred for 5 days. At this time, the reaction , ..- ¿L, a ¿.ta «* aa --- 3¡áaÉ -» - a «'^ i t. »Iat &AAsMjí? filter through celite and concentrate under reduced pressure. Purification of the product by chromatography on silica gel gives 9c. 9d. Ether 2 ', 6'-divodo-3-¡soprop¡l-4-methoxy-4'-nitrildifeníl¡co: ether 2', 6'-w diiodo-3-isopropyl-4-methoxy-4'-nitrildifeníl¡ co (9c; 280 mg) is dissolved in 4 ml of dichloromethane and cooled in a dry ice / acetone bath. To this solution is added 1.6 ml of boron tribromide (1 M in dichloromethane) dropwise. The reaction is stirred overnight and allowed to react at room temperature. At this time, the reaction is poured into 10 ml of ice and water. To this mixture is added 10 ml of ethyl acetate. The organic layer is separated and the aqueous phase is extracted twice with 10 ml of ethyl acetate. The organic layers are combined, washed with saturated sodium chloride, dried over magnesium sulfate and concentrated under reduced pressure. Purification of the product by chromatography on silica gel gives 9d. 9e. 3,5-d-prodo-4- (4'-hydroxy-3'-isopropylphenoxy) benzoic acid: to ether February 15 ', 6'-diiodo-3-isopropyl-4-methoxy-4'-nitrildifenilíco (9d, 95 mg) 1 ml of sodium hydroxide is added 3 N. The sample is boiled and becomes homogeneous. At this time, the reaction is cooled and neutralized with 1 N HCl. A precipitate is formed and filtered and washed with hexane to give 9e.

Use of the compounds of the present invention The methods of the present invention are carried out by administering to a mammal (preferably a human) a compound having a structure as described herein and, preferably, 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 to stop and reverse hair loss and to promote hair growth. Such conditions may manifest themselves, for example, in alopecia, including male pattern baldness and female pattern baldness. 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, 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 by 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 if the treatment is topical or systemic they are independent. 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). , 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 "carrier", 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 that substantially reduces the effectiveness of the composition under of ordinary use. Of course, the vehicles should be of sufficiently high purity and sufficiently low toxicity to make them suitable for administration to the animal, preferably mammal (most preferably human) 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 in any of a variety of forms, suitable (for example) for oral, rectal, topical, nasal, ocular or parenteral administration. Of these, the Topical and / or oral administration are especially preferred, topical 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 employed in conjunction with the compound is 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 * 15 references: Modern Pharmaceutics, chapters 9 and 10, Banker & Rhodes, eds. (1979); Lieberman et al., Pharmaceutical Dosaqe Forms: Tablets (1981); and 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 20 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, pyrrolidone, ethanol, and sesame oil. Preferably, the vehicle, in compositions for parenteral administration comprises at least about 90% by weight of the total composition. Various forms of oral doses may 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 about 5%, preferably from about 25% to about 50% of a compound used in the present invention. Tablets can be compressed, crushed tablets, enteric-coated, sugar-coated, film-coated tablets or • multiple form, containing binders, lubricants, diluents, disintegrating agents, coloring agents, flavoring agents, flow 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, which contain solvents, preservatives, emulsifying agents, suspending agents. , diluents, sweeteners, fusion agents, coloring agents and suitable flavoring agents. Suitable carriers for the preparation of unit dosage forms for oral administration are well known in the art. The tablets 15 typically comprise conventional pharmaceutically compatible adjuvants 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 20 talcum 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 considerations Secondary sources such as flavor, 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, f. 10 tinctures, 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 sucrose, sorbitol and water. For a suspension, typical suspending agents include methylcellulose, 15 sodium carboxymethyl cellulose, 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 20 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 may be in any form including, for example, solutions, oils, creams, ointments, gels, shampoos, hair rinse and rinse-off conditioners, milks, cleansers, humectants, sprays, patches for the skin 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, oils of vitamin A and E, oil mineral, propylene glycol, PPG-2 myristylpropionate and the like. Fáw 'Other materials suitable for use in topical vehicles 5 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, glycosyl glyceryl monoricinoleate, glyceryl monostearate, propane-1, 3- diol, butane-1,3-diol, mink oil, cetyl alcohol, / 'so-propiolysostearate, stearic acid, / so-butyl palmitate, Acetoacetate, oleyl alcohol, / so-propyl laurate, hexyl laurate, decyl olate, octadecan-2-lo, isocetyl alcohol, cetyl palmitate, dimethyl polysiloxane, di-n-butyl sebacate, so-propyl myristate, iso-propyl palmitate, iso-propyl stearate , 15 butyl stearate, polyethylene glycol, triethylene glycol, glycol, lanolin, sesame oil, coconut oil, arachis oil, castor oil, acetylated lanolin P 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 20 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 clay, talc, Fullers earth, kaolin, starch, colloidal silicon dioxide gums, sodium polyacrylate, Tetralkylammonium smectites, trialkylammonium smectites, chemically modified magnesium aluminum silicate, organically modified montmorillonite clay, hydrated aluminum silicate, 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 15 uses liposomes such as those described in Dowton et al., "Influence of Liposomal Composition on Topical Delivery of Encapsulated Cyclosporin A: I. An in vitro Study Usíng Hairless Mouse Skin", S. T.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. 20 patent of E.U.A. No. 4,911,928, assigned to Mícro-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 in lieu of, or in addition to, minoxidil). 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; Banga et al .. "Hydrogel-based lontotherapeutic Deliver Devices for Transdermal Delivery of Peptide / Protein Drugs", Pharm, Res., Vol. 10 (5), pp. 697-702 (1993); Ferry. "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", 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. 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", 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. Control, Reléase, 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 .. e-a_¿_ «, *. , -. J,. «». -. . * UiU AA "Reverse lontophoresis: Noninvasive Glucose Monitoring in vivo in Humans", 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. WgF 725-730 (1994); and Vol pato 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 10 molecules that can function in different ways to increase the 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 hair growth stimulants that can be used in the compositions herein, including systemic and topical compositions, include, for example, benzalkonium chloride, benzethonium chloride, phenol, estradiol, diphenhydramine hydrochloride, maleate of chlorpheniramine, chlorophyllin derivatives, cholesterol, salicylic acid, cysteine, methionine, pepper red tincture, benzyl nicotinate, D, L-menthol, peppermint oil, calcium pantothenate, panthenol, castor oil, hinocitol, prednisolone , resorcinol, monosaccharides and esterified monosaccharides, chemical activators of protein kinase C enzymes, inhibitors of glycosaminoglycan chain cellular uptake, activity inhibitors of JÍ A? Mlßl? M * IA *? Ab¡t A. . .. .. . : • - > . -,. - - SA *, .. M- «I glycosidase, glycosaminoglycanase inhibitors, esters of pyroglutamic acid, 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, pentane-2,4-diol, acetone, POE methyl ether (2), 2- ^ IO hydroxypropionic acid, 2-hydroxyoctanoic acid, propan-1-ol, 1, 4-dioxane, tetrahydrofuran, butan-1,4-diol, propylene glycol dipelargonate, polyoxypropylene stearyl ether 15, octyl alcohol, POE ester oleyl alcohol, oleyl alcohol, lauryl alcohol, dioctyladipate, dicapriladipate, di-isopropyladipate, diisopropylsebacate , dibutylsebacate, diethylsebacate, dimethylsebacate, dioctylsebacate, dibutyl sulphate, dioctyl silica, dibenzyl stearate, dibutyl phthalate, dibutyl silica, ethyl myristate, dimethylazelate, butyl myristate, dibutyl succinate, didecyl phthalate, decyl oleate, ethylcaproate, ethylsalicylate, / so-propyl palmitate, etillaurate or, 2-ethyl-hexylpelargonate, / so-propyl isostearate, butyl laurate, benzylbenzoate, butylbenzoate, hexillaurate, ethylcaprate, ethylcaprylate, butyl stearate, benzylsalicylate, 2-hydroxypropanoic acid, 2-hydroxyoctanoic acid, methylsulfoxide, N, N-dimethyl acetamide , N, N-dimethyl formamide, 2-pyrrolidone, 1-methyl-2-pyrrolidone, 5-methyl-2-pyrrolidone, 1,5-dimethyl-2-pyrrolidone, ji iMtta -? - iiatd -to J,. . . J. i ».J,. . to " , . jAjB ^ fctaáÉ 1-ethyl-2-pyrrolidone, phosphine oxides, sugar esters, tetrahydrofurfuryl alcohol, urea, diethyl-m-toluamide, and, 1-dodecylazacylheptan-2-one. In all of the foregoing, of course, the compounds used in the present methods may be administered alone or as mixtures, and the compositions may further include additional drugs or excipients as appropriate for the indication. The present invention also 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 relating to methods of application of the compound and / or composition, preferably with the benefit of treating hair loss in mammals.

EXAMPLES OF ADMINISTRATION OF THE COMPOSITION The following examples do not limit the invention, but provide guidance to one 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. f EXAMPLE A A composition is made for topical administration comprising: 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. fifteen EXAMPLE B A composition for topical administration is made according to the method of Dowton et al., "Influence of Lipid Composition on Topical 20 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 who suffers from male pattern baldness is treated every day with the previous composition. Specifically, for 6 weeks, the above composition is administered topically to the ^ subject.

EXAMPLE C A shampoo is made comprising: • 10 fifteen twenty 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.

Claims (9)

NOVELTY OF THE INVENTION CLAIMS

1. A method for treating capillary loss consisting of administering to a mammal a composition comprising a compound having the structure: and pharmaceutically acceptable salts, hydrates and amides, esters and biohydrolyzable esters thereof, wherein: X is selected from oxygen, sulfur and CH2;

R1 and R2 are each independently selected from hydrogen, 15 halogen, hydroxy, trifluoromethyl, C 1 -C 2 alkyl, C 1 alkenyl and alkoxy

CrC4; R3 is selected from hydrogen, alkyl, aryl, and arylalkyl; R 4 is selected from the group consisting of hydrogen, halogen, C 1 -C 4 alkyl, alkenyl

C? -C4, hydroxy and C1-C4 alkoxy; R5 is selected from hydrogen, halogen, hydroxy, alkyl, C1-C4 alkenyl, C4 alkoxy, cycloalkyl, aryl and arylalkyl;

R6 is selected from alkyl, aryl, -CH2CH (NH2) CO2H, -CH2CH (0H) CO2H, -CH2CR7R8NR9R? Or, -YC (0) Rn, - (CH2) n-OH, -CH2C (R12) (NH2 ) CO2Ri3, - CH2CH (COOH) (NH) C (O) (CH2) mC (O) NH (CH2) nR2o, and -CH2CR12R12C (O) OR? 3; R7 is selected from hydrogen and C-? -C alkyl; Rs is selected from hydrogen and -C (O) Rn; Rg and R-io are each independently selected from hydrogen, C 1 -C 4 alkyl, and C 1 -C 4 alkanoyl; Y is selected from a bond and C1-C4 alkyl; R n is selected from hydroxy, C 1 -C 4 alkoxy, NR 14 R 15, C 1 -C 4 alkyl, C 1 -C 4 alkenyl and C 1 -C 4 alkynyl; R12 is C1-C6 alkynyl; R13 is selected from CrC6 alkyl, cycloalkyl, and arylalkyl; Ru is selected from hydrogen and C 1 -C 4 alkyl; R15 is selected from hydrogen, dC alkyl, and C1-C4 alkanoyl; R-? 8 and R19 are each independently selected from hydrogen, C 1 -C 7 alkyl, CrC 6 alkenyl, hydroxy and halogen; m is an integer from 2 to 4; n is an integer from 1 to 4; and R20 is an unsubstituted, unsaturated, five or six membered monocyclic F10 heterocycle containing one to two nitrogen atoms as the sole heteroatoms. 2. A method according to claim 1, further characterized in that the compound is characterized by the structure: wherein R1 and R2 are each independently selected from hydrogen, halogen and C6-C6 alkyl; Re is selected from -CH2CR7R8NR9R10 and -YC (O) R ??; R16 is aryl; and R17 is selected from the group consisting of hydrogen, and C1-C4 alkyl. _fe4JJM3jfc? ai-t-tt ---- ~ j - «- > -. 3. A method according to any of the preceding claims, further characterized in that Re is -YC (O) Rn. 4. A method according to any of the preceding claims, further characterized in that Ri and R2 are each independently halogen. 5. A method according to claim 1, further characterized in that the compound is characterized by the structure: wherein Ri and R2 are each independently selected from the group consisting of hydrogen and iodine.

6. A method according to claim 1, 15 further characterized in that the compound is characterized by the structure:

7. A method according to claim 6, further characterized in that m is 3 and n is 2.

8. A method according to claim 1, further characterized in that the compound is characterized by the structure: »-. I. - :. > : .. & * A ** &! ¡A »i¿.í'¿ -. ^ Rm 5 where R 5 is selected from the group consisting of C 1 -C 7 alkyl and C 3 -C cycloalkyl; R1 and R2 are each independently selected from hydrogen, halogen and CI-CT alkyl, with the proviso that at one point one of R1 and R2 is not hydrogen; and R-n is selected from the group consisting of C1-C4 alkoxy.

9. A method according to any of the preceding claims, further characterized in that the administration is topical.