METHOD OF TREATING HAIR LOSS USING DIPHENYLETHER DERIVATIVES

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 compound having a structure of formula (I) as described herein and a pharmaceutically-acceptable carrier.

Description: METHOD OF TREATING HAIR LOSS USING DIPHENYLETHER DERIVATIVES FIELD OF THE INVENTION The present invention relates to methods for treating hair loss in mammals, including arresting and / or reversing hair loss and promoting hair growth BACKGROUND OF THE INVENTION Hair loss is a common problem which occurs, for example, through natural processes or is often chemically promoted through the use of certain therapeutic drugs designed to alleviate conditions such as cancer. Often such hair loss is accompanied by lack of hair regrowth which causes partial or full baldness. As is well-known m the art, hair growth occurs by a cycle of activity which involves alternating periods of growth and rest This cycle is often divided into three mam stages which are known as anagen, catagen, and telogen. Anagen is the growth phase of the cycle and may be characteπzed by penetration of the hair follicle deep into the dermis with rapid proliferation of cells which are differentiating to form hair. The next phase is catagen, which is a transitional stage marked by the cessation of cell division, and during which the hair follicle regresses through the dermis and hair growth is ceased. The next phase, telogen, is often characteπzed as the resting stage during which the regressed follicle contains a germ with tightly packed dermal papilla cells. At telogen, the initiation of a new anagen phase is caused by rapid cell proliferation in the germ, expansion of the dermal papilla, and elaboration of basement membrane components. Wherein hair growth ceases, most of the hair follicles reside m telogen and anagen is not engaged, thus causing the onset of full or partial baldness. There have been many attempts m the literature to invoke the regrowth of hair by, for example, the promotion or prolongation of anagen. Currently, there are two drugs approved by the United States Food and Drug Administration for the treatment of male pattern baldness: topical mmoxidil (marketed as Rogame ® by Pharmacia & Upjohn), and oral finastende (marketed as Propecia ® by Merck & Co., Inc.). For several reasons, however, including safety concerns and / or lack of efficacy, the search for efficacious hair growth mducers is ongoing. Interestingly, it is known that the thyroid hormone known as thyroxme ("T4") converts to thyronme ("T3") in human skm by deiodmase I, a selenoprotem. Selenium deficiency causes a decrease in T3 levels due to a decrease m deiodmase I activity; this reduction in T3 levels is strongly associated with hair loss Consistent with this observation, hair growth is a reported side effect of administration of T4 See, e g . Berman, "Peπpheral 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 Thyroxme on Hair Growth in the Dog", J. Small Amm Pract , Vol. 27, pp. 17 - 29 (1986). Furthermore, T3 and T4 have been the subject of several patent publications relating to treatment of hair loss. See, e.g., Fischer et al.. DE 1,617,477, published January 8, 1970, Mortimer. GB 2,138,286, published October 24, 1984; and Lmdenbaum. WO 96/25943, assigned to Life Medical Sciences, Inc., published August 29, 1996. Unfortunately, however, administration of T3 and / or T4 to treat hair loss is not practicable because these thyroid hormones are also known to induce significant cardiotoxicity. See, e.g , Walker et al., U.S. Patent No. 5,284,971, assigned to Syntex, issued February 8, 1994 and Emmett et al., U.S. Patent No. 5,061,798, assigned to Smith Klme & French Laboratories, issued October 29, 1991. Surprisingly, however, the present inventors have discovered biphenyl derivatives which promote hair growth without inducing cardiotoxicity. Consistent with this discovery, but without intending to be limited by theory, the present inventors have surprisingly discovered that the biphenyl deπvatives useful in the present invention interact strongly with hair-selective thyroid hormone receptors but interact less strongly, or not at all, with heart-selective hormone receptors. These unique properties are, of course, not shared with T3 and / or T4. Accordingly, the biphenyl derivatives descπbed for use in the methods and compositions herein are cardiac-sparmg compounds useful for treating hair loss, including arresting and / or reversing hair loss and promoting hair growth. SUMMARY OF THE INVENTION The present invention relates to methods for treating hair loss compπsmg admmisteπng a cardiac-spaπng compound which has been found by the present inventors to be particularly useful for treating hair loss in mammals, including arresting and / or reversing hair loss and promoting hair growth. The compounds utilized m the present method are biphenyl derivatives having the structure 1 and pharmaceutically acceptable salts, hydrates, and biohydrolyzable amides, esters, and lmides thereof, wherein R, R ls R 2 , R 3 , ^, R 5 , R 6 , R 7 , X, W, and Z are defined herein. DETAILED DESCRIPTION OF THE INVENTION The present invention relates to methods of using compounds and compositions which are particularly useful for treating hair loss m mammals, including arresting and / or reversing hair loss and promoting hair growth. In addition to discovering that the present compounds are useful for treating hair loss, the present inventors have also surprisingly discovered that the preferred compounds are cardiac-sparmg. The preferred compounds useful in the method of the present invention are therefore, as defined herein below, cardiac-spaπng. Publications and patents are referred to throughout this disclosure. All references cited herein are hereby incorporated by reference. All percentages, ratios, and proportions used herein are by weight unless otherwise specified. In the descπption of the invention various embodiments and/or individual features are disclosed. As will be apparent to the ordinarily skilled practitioner all combinations of such embodiments and features are possible and can result in preferred executions of the invention. As used herein, wherein any vaπable, moiety, group, or the like occurs more than one time in any vaπable or structure, its definition at each occurrence is independent of its definition at every other occurrence. Definition and Usage of Terms The following is a list of definitions for terms used herein: As used herein "salt" is a cationic salt formed at any acidic (e g., carboxyl) group, or an aniomc salt formed at any basic (e g , ammo) group. Many such salts are known m the art. Preferred catiomc salts include the alkali metal salts (such as, for example, sodium and potassium), alkaline earth metal salts (such as, for example, magnesium and calcium), and organic salts Preferred anionic salts include the hahdes (such as, for example, chloride salts). Such acceptable salts must, when administered, be appropriate for mammalian use As used herein, "alkyl" is a saturated, straight or branched chain monovalent hydrocarbon radical Unless otherwise specified, alkyls have from 1 to about 10 carbon atoms (Ci - Cio). Preferred alkyls include, for example, methyl, ethyl, propyl, zso-propyl, tert-butyl, n-butyl, sec-butyl, and iso-butyl. As used herein, the term "aryl" is a carbocychc or heterocychc aryl. Carbocychc aryl is optionally substituted phenyl or optionally substituted naphthyl. Heterocychc aryl is optionally substituted phenyl or optionally substituted naphthyl, having at least one heteroatom (N, O, or S) making up the aryl ring. As used herein, the term "aryl-lower alkyl" is aryl substituted by at least one alkyl, lower alkoxy, lower alkanoyloxy, or tπfluoromethyl. As used herein, "biohydrolyzable amides" are amides of the compounds used in the present invention which do not interfere with the activity of the compound, or that are readily converted in vivo by a mammalian subject to yield an active compound. As used herein, "biohydrolyzable esters" are esters of the compounds used in the present invention which do not interfere with the activity of the compound, or that are readily converted in vivo by a mammalian subject to yield an active compound. As used herein, "biohydrolyzable lmides" are lmides of the compounds used in the present invention which do not interfere with the activity of the compound, or that are readily converted in vivo by a mammalian subject to yield an active compound. As used herein "cycloalkyl" refers to a saturated cyclic hydrocarbon radical, preferably C 5 - C 7 cycloalkyl. Most preferably, a cycloalkyl is cyclopentyl or cyclohexyl. As used herein, the term "cycloalkyl-lower alkyl" is cycloalkyl substituted by at least one alkyl, lower alkoxy, lower alkanoyloxy, or tπfluoromethyl. Non-limitmg examples of cycloalkyl-lower alkyl include 1- or 2-(cyclopentyl or cyclohexyl)ethyl; 1-, 2-, or 3- (cyclopentyl) or cyclohexyl)propyl; or 1-, 2-, 3-, or 4-(cyclopentyl or cyclohexyl)butyl. As used herein "halogen", "halo", or the like refers to chlorine, bromine, iodine, and fluoπne, preferably fluoπne and chloπne. As used herein, the term "lower" m connection with organic radicals or compounds defines such with up to and including 7, preferably up to an including 4, and most preferably one or two carbon atoms. The "lower" radical or compound may be straight or branched. As used herein, "pharmaceutically acceptable" means suitable for use in a human or other mammal. As used herein, "safe and effective amount of a compound" (or composition, or the like) means an amount that is effective to exhibit biological activity, preferably wherein the biological activity is arresting and / or reversing hair loss or promoting hair growth, at the sιte(s) of activity m a mammalian subject, without undue adverse side effects (such as toxicity, irritation, or allergic response), commensurate with a reasonable benefit / risk ratio when used in the manner of this invention. Acyl is preferably lower alkanoyl, carbocychc aryl-lower alkanoyl, or carbocychc aroyl. Lower alkanoyl is preferably acetyl, propionyl, butyryl, or pivaloyl. Lower alkyanoyloxy is preferably acetoxy, pivaloyloxy, or propionyloxy. Methods of the Present Invention The present invention relates to methods of treating hair loss compπsmg administering a composition compπsmg a compound having the structure: and pharmaceutically acceptable salts, hydrates, and biohydrolyzable amides, esters, and lmides thereof, wherein: (a) R is selected from the group consisting of hydrogen, hydroxy, esteπfied hydroxy, and etheπfied hydroxy; (b) Rj, R 2 , and R are each, independently, selected from the group consisting of hydrogen, halogen, tπfluoromethyl, and lower alkyl; (c) R 3 is selected from the group consisting of halogen, tπfluoromethyl, lower alkyl, aryl, aryl-lower alkyl, cycloalkyl, cycloalkyl-lower alkyl, and: Rs — C- R 9 I R ιo (d) R 8 is selected from the group consisting of hydrogen, lower alkyl, aryl, cycloalkyl, aryl-lower alkyl, and cycloalkyl-lower alkyl; (e) R 9 is selected from the group consisting of hydroxy and acyloxy; (f) R 10 is selected from the group consisting of hydrogen and lower alkyl, or wherein R 9 and R 10 together represent oxo, (g) W is selected from the group consisting of -O- and -S-; (h) X is selected from the group consisting of -NR 7 , S, and O; (i) R 5 is selected from the group consisting of hydrogen, lower alkyl, and aryl-lower alkyl and R 6 is hydrogen; or wherein R 5 and R 6 are together oxo, provided that X (j) R 7 is selected from the group consisting of hydrogen and lower alkyl; and (k) Z is selected from the group consisting of carboxyl and carboxyl deπvatized as a pharmaceutically acceptable ester or amide. The compounds useful in the method herein are further described in Yokoyama et al., U.S. Patent No. 5,401,772, assigned to Ciba-Geigy Corp., issued March 28, 1995; Yokoyama et al., EP 0,580,550, assigned to Ciba-Geigy Corp., published January 26, 1994; and Yokoyama et al., "Synthesis and Structure-Activity Relationships of Oxamic Acid and Acetic Acid Derivative Related to L-Thyronme", Journal of Medicinal Chemistry, Vol. 38, pp. 695 - 707 (1995). However, for convenience, the compounds are more fully descπbed herein below: The R Moiety The R moiety is selected from hydrogen, hydroxy, esteπfied hydroxy, and etheπfied hydroxy. As used herein "esteπfied hydroxy" refers to acyloxy, e.g., acyloxy deπved from an organic carboxyhc acid. Preferred esteπfied hydroxy include lower alkanoyloxy, aroyloxy, and aryl-lower alkanoyloxy. As used herein, "etheπfied hydroxy" preferably represents lower alkoxy, lower alkenyloxy, C 5 - C 7 cycloalkyloxy, carbocychc aryl-lower alkoxy, tetrahydropyranyloxy, C 5 - C 7 cycloalkyl-lower alkoxy, and the like. More preferably, the R moiety is selected from hydroxy, esteπfied hydroxy, and etheπfied hydroxy Even more preferably, the R moiety is selected from hydroxy, lower alkanoyloxy, lower alkoxy, and tetrahydropyranyloxy. Most preferably, the R moiety is hydroxy Preferably, the R moiety substitutes at the 4' position as shown herein. The Ru R 7 , and R Vtoieties Ri, R 2 , and R 4 are each, independently, selected from hydrogen, halogen, trifluoromethyl and lower alkyl. Preferably, Ri and R 2 are each, independently, selected from halogen, trifluoromethyl, and Ci - C 3 alkyl More preferably, R, and R 2 are each, independently, selected from halogen and Ci - C 3 alkyl Still more preferably, Ri and R 2 are each, independently, selected from chlorine and methyl. Preferably, R, and R 2 are equivalent Most preferably, R) and R 2 are each methyl R 4 is preferably hydrogen. Preferably, Ri substitutes at the 3 position as shown herein. Preferably, R 2 substitutes at the 5 position as shown herein. Preferably, R 4 substitutes at the 5' position as shown herein. The R j jVloietv The R 3 moiety is selected from halogen, trifluoromethyl, lower alkyl, aryl, aryl-lower alkyl, cycloalkyl-lower alkyl, and: R 8 is selected from hydrogen, lower alkyl, aryl, cycloalkyl, aryl-lower alkyl, and cycloalkyl- lower alkyl. R 9 is selected from hydroxy and acyloxy. As used herein, the term "acyloxy" is -O-acyl, wherein acyl is preferably selected from lower alkanoyl, carbocychc aryl-lower alkanoyl, and carbocychc aroyl. Rio is selected from hydrogen and lower alkyl; or wherein R 9 and R 10 together represent oxo (doubly-bonded oxygen). Preferably, the R 3 moiety is selected from lower alkyl, aryl-lower alkyl, cycloalkyl- lower alkyl and More preferably, the R 3 moiety is selected from zso-propyl, benzyl, benzyl substituted with halogen, and tπfluoromethyl. Most preferably, R 3 is .sø-propyl. The R 3 moiety preferably substitutes at the 3 ' position as shown herein. The W Moiety W is selected from -O- and -S- Most preferably, W is -O- The X Moiety X is selected from -NR 7 -, -S-. and -0-. Preferably, X is -NR 7 - or -O- Most preferably, X is -NR 7 -. The R - and R^ Moieties R 5 is selected from hydrogen, lower alkyl, and aryl-lower alkyl. R^ is hydrogen. Alternatively, and most preferably, R 5 and R 6 are, together, an oxo moiety (=O). The R; Moiety R 7 is selected from hydrogen and lower alkyl. Most preferably, R 7 is hydrogen. The Z Moiety Z is selected from carboxyl (-CO 2 H) and carboxyl derivatized as a pharmaceutically acceptable ester or amide. As used herein, a "carboxyl derivatized as a pharmaceutically acceptable ester" represents esteπfied carboxyl, preferably a prodrug ester which is convertible by solvolysis or under physiological conditions to the corresponding free carboxyhc acid. Similarly, a "carboxyl derivatized as a pharmaceutically acceptable amide" represents carboxyl which has been functionahzed as an amide, preferably a prodrug amide which is convertible by solvolysis or under physiological conditions to the corresponding free carboxyhc acid. The amide may be a pπmary amide, i.e , -C(=O)NH 2 . Preferably, Z is selected from carboxyl and carboxyl deπvatized as a pharmaceutically acceptable ester. Most preferably, Z is carboxyl. Preferred carboxyl derivatized as a pharmaceutically acceptable ester include lower alkoxycarbonyl; (ammo, acylammo, mono- or di-lower alkylammo)-lower alkoxycarbonyl; carboxy-lower alkoxycarbonyl, e g., α-carboxy-lower alkoxycarbonyl; lower alkoxycarbonyl- lower alkoxycarbonyl, e.g , α-lower alkoxycarbonyl-lower alkoxycarbonyl; α-(dι-lower alkylamino, ammo, mono-lower alkylammo, morphohno, pipeπdmo, pyrrohdmo, 1 -lower alkyl-pιperazmo)-carbonyl-lower alkoxycarbonyl, carbocychc and heterocychc aryl-lower alkoxycarbonyl, preferably optionally (halo, lower alkyl or lower alkoxy)-substιtuted benzyloxycarbonyl, or pyridylmethoxycarbonyl, 1 -(hydroxy, lower alkanoyloxy or lower alkoxy)-lower alkoxycarbonyl, e g , pivaloyloxymethoxycarbonyl, (hydroxy, lower alkanoyloxy or lower alkoxy)-lower alkoxymethoxycarbonyl, 1 -(lower alkoxycarbonyloxy)- lower alkoxycarbonyl, 5-ιndanyloxycarbonyl, 3-phthahdoxycarbonyl and (lower alkyl, lower alkoxy or halo)-substιtuted 3-phthahdoxycarbonyl, dihydroxypropyloxycarbonyl wherein hydroxy groups are free or are protected in the form of ketals, e g , a lower alkylidene, a benzyhdene or a 5- or 6-membered cycloalkyhdene derivative, preferably (2,2-dιmethyl- 1,3- dιoxolan-4-yl)-methoxycarbonyl Carboxyl derivatized as a pharmaceutically acceptable prodrug ester is most preferably Ci - C 4 alkoxycarbonyl, benzyloxycarbonyl optionally substituted on phenyl by lower alkyl, lower alkoxy, halo or trifluoromethyl, 1-(C 2 - C 4 -alkanoyloxy)-ethoxycarbonyl, (2,2-dιmethyl-l,3-dιoxolan-4-yl)-methoxycarbonyl, 5-mdanyloxycarbonyl, 1-( - C 4 - alkoxycarbonyloxy)-ethoxycarbonyl or 3 -pyridylmethoxycarbonyl Carboxyl derivatized as a pharmaceutically acceptable amide is preferably carbamoyl or N-substituted carbamoyl, preferably lower alkylammo carbamoyl, arylammo carbamoyl, di-lower alkylammo carbamoyl, morpholmo carbamoyl, N-lower alkylpiperazmo carbamoyl, pyrrohdmo carbamoyl, pipeπdmo carbamoyl, (ammo or acylammo)-lower alkylammo carbamoyl or aryl-lower alkylammo carbamoyl Preferred Compounds of the Present Invention Preferred compounds of the present invention include those wherein X is -NR 7 and R 5 and R^ are together oxo Such compounds are represented as An even more preferred compound of this structure is wherein W is -O- Further preferred compounds include those wherein R substitutes at the 4' position, R 3 substitutes at the 3' position, R, substitutes at the 3 position, R 2 substitutes at the 5 position, and R 4 is hydrogen Such compounds are represented as. An even more preferred compound of this structure is wherein W is -O-. Other preferred compounds useful in the present invention are descπbed in Yokoyama et al . "Synthesis and Structure - Activity Relationships of Oxamic Acid and Acetic Acid Derivatives Related to L-Thyronme", Journal of Medicinal Chemistry, Vol. 38, pp. 695 - 707 (1995). These compounds are further descπbed in Table 1 below: Table 1 Analytical Methods The present invention relates to methods of treating hair loss by administering a compound having a structure as described herein. Preferably, the compound utilized m the present invention will be cardiac-spaπng. Compounds (test compounds) may be tested for their ability to induce anagen and their lack of cardiotoxicity (cardiac-sparmg) using the following methods. Alternatively, other methods well-known in the art may be used (but with the term "cardiac-sparmg" being defined according to the method disclosed herein below) Cardiotoxicity Assay: The cardiotoxicity assay measures the potential of a test compound to adversely affect the cardiovascular system. As thyroid hormone (T3) damages the cardiovascular system, the heart enlarges. See, e g.. Gomberg-Maitland et al., "Thyroid hormone and Cardiovascular Disease", American Heart Journal, Vol. 135(2), pp. 187-196 (1998); Klein and Oiamaa, "Thyroid Hormone and the Cardiovascular System", Current Opinion in Endocrinology and Diabetes, Vol. 4, pp.341 -346 (1997); and Klemperer et al., "Thyroid Hormone Therapy and Cardiovascular Disease", Progress in Cardiovascular Diseases, Vol. 37 (4), pp. 329-336 (1996). This increases the weight of the heart relative to whole body weight. The cardiotoxicity assay herein below is used to test compounds for potentially adverse cardiac effects by measuπng their effect on the heart-to-body weight ratio. Two groups each of six male Sprague Dawley rats (Harlan Sprague Dawley, Inc., Indianapolis, IN) (each weighing from approximately 220 grams to 235 grams) are utilized The first group is a vehicle control group and the second group is a test compound group. The length of the assay is 30 days, with treatment of vehicle or test compound m vehicle daily for 28 of those days as descπbed below. Prior to initiation of the assay, each rat is allowed to acclimate to standard environmental conditions for 5 days Each rat receives food (standard rat chow diet) and water ad libitum 5 days prior to initiation of the assay as well as to termination of the study The vehicle is 91:9 (w) propylene glycohethanol The test compound is prepared at a concentration of 500 μg/mL in the vehicle. Each rat is weighed on day 1 of the assay. Dosage calculations are then performed: each rat will be administered daily a dosmg solution of vehicle or test compound in vehicle (depending on whether the rat is in the vehicle control group or the test compound group, respectively) at 500 μL of dosing solution per kg of rat. For rats in the test compound group, this corresponds to a dose of 250 μg of test compound per kg of rat. Day 2 is the first day of treatment with dosmg solution for both groups. Body weights are taken for each rat on days 3, 5, 8, 10, 12, 15, 17, 19, 22, 24, 26, and 29 prior to dosmg for that day; for each rat, the dosmg solutions are recalculated and administered accordingly upon change in body weight. Treatment occurs once daily in the morning on days 2 through 29, inclusive, for each rat in each group. For each treatment, the dosmg solution is administered subcutaneously between the shoulders of the rat such that the injection sites are rotated in this area. On day 30 in the morning, the rats of each group are euthanized with C0 2 from dry ice. Each rat is immediately weighed for total body weight. The hearts of each rat are then excised as follows. An incision is made to expose the abdominal cavity. The πb cage is carefully cut at the sternum with small scissors, such that the heart and lungs are exposed. With small scissors and forceps, the vessels connected to the heart are cut away from the heart. These vessels include the caudal vena cava, left cranial vena cava (pulmonary trunk), right cranial vena cava, thoracic aorta, right subclavian artery, internal thoracic artery and vein, and any other small attachments. The heart is then immediately taken out intact, including the left and right auricles and left and πght ventricles. Immediately thereafter, any excess tissue is tπmmed away, the heart is lightly blotted on a paper towel until no more blood is visibly left behind on the paper towel, and the heart is weighed. The heart weight is divided by the body weight after euthanization for each rat to give the heart body ratio. The heart/body ratios for each rat m the vehicle control group 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 test compound group). The index C is then calculated by dividing RT by RV As defined herein, where C is less than 1.3, the test compound is cardiac-sparing Preferably, C is less than 1.2, more preferably less than 1.15, and most preferably less than 1 1 In accordance with this method, T3 and T4 are not cardiac-sparmg Telogen Conversion Assay The Telogen Conversion Assay measures the potential of a test compound to convert mice m the resting stage of the hair growth cycle ("telogen"), to the growth stage of the hair growth cycle ("anagen"). Without intending to be limited by theory, there are three principal phases of the hair growth cycle- anagen, catagen, and telogen It is believed that there is a longer telogen period in C3H mice (Harlan Sprague Dawley, Inc , Indianapolis, IN) from approximately 40 days of age until about 75 days of age, when hair growth is synchronized. It is believed that after 75 days of age, hair growth is no longer synchronized Wherein about 40 day-old mice with dark fur (brown or black) are used m hair growth experiments, melanogenesis occurs along with hair (fur) growth wherein the topical application of hair growth mducers are evaluated. The Telogen Conversion Assay herein below is used to screen compounds for potential hair growth by measuring melanogenesis. Three groups of 44 day-old C3H mice are utilized- a vehicle control group, a positive control group, and a test compound group, wherein the test compound group is administered a compound used in the method of the present invention The length of the assay is at least 19 days with 15 treatment days (wherein the treatment days occur Mondays through Fridays). Day 1 is the first day of treatment. Most studies will end on Day 19, but a few may be carried out to Day 24 if the melanogenesis response looks positive, but occurs slowly. A typical study design is shown in Table 1 below Typical dosage concentrations are set forth in Table 1, however the skilled artisan will readily understand that such concentrations may be modified. Table 1 **The vehicle is 60% ethanol, 20% propylene glycol, and 20% dimethyl isosorbide (commercially available from Sigma Chemical Co., St. Louis, MO). The mice are treated topically Monday through Friday on their lower back (base of tail to the lower rib). A pipettor and tip are used to deliver 400 μL to each mouse's back. The 400 μL application is applied slowly while moving hair on the mouse to allow the application to reach the skm. While each treatment is being applied to the mouse topically, a visual grade of from 0 to 4 will be given to the skm color in the application area of each animal. As a mouse converts from telogen to anagen, its skin color will become more bluish-black. As indicated in Table 2, the grades 0 to 4 represent the following visual observations as the skm progresses from white to bluish-black. Table 2 Method of Making The compounds used m the methods of the present invention are prepared according to procedures which are well-known to those ordinarily skilled in the art. The starting mateπals used in preparing the compounds are known, made by known methods, or are commercially available as a starting material. It is recognized that the ordmaπly skilled artisan in the art of organic chemistry can readily carry out standard manipulations of organic compounds without further direction. Examples of such manipulations are discussed m standard texts such as J. March, Advanced Organic Chemistry, John Wiley & Sons (1992) The ordinarily skilled artisan will readily appreciate that certain reactions are best carried out when other functionalities are masked or protected in the compound, thus increasing the yield of the reaction and / or avoiding any undesirable side reactions Often, the artisan utilizes protecting groups to accomplish such increased yields or to avoid the undesired reactions. These reactions are found in the literature and are also well within the scope of the skilled artisan Examples of many such manipulations can be found in, for example, T Greene, Protecting Groups in Organic Synthesis. John Wiley & Sons (1981). The compounds of the present invention may have one or more chiral centers. As a result, one may selectively prepare one optical isomer, including diastereomers and enantiomers, over another, for example by chiral starting materials, catalysts or solvents, or may prepare both stereoisomers or both optical isomers, including diastereomers and enantiomers at once (a racemic mixture). Since the compounds of the invention may exist as racemic mixtures, mixtures of optical isomers, including diastereomers and enantiomers, may be separated using known methods, such as through the use of, for example, chiral salts and chiral chromatography. In addition, it is recognized that one optical isomer, including a diastereomer and enantiomer, or a stereoisomer, may have favorable properties over the other. Thus, when disclosing and claiming the invention, when one racemic mixture is disclosed, it is clearly contemplated that both optical isomers, including diastereomers and enantiomers, or stereoisomers substantially free of the other are disclosed and claimed as well. The syntheses of the compounds useful the present invention are descπbed in the art. Accordingly, the ordmaπly skilled artisan will be able to prepare the compounds described herein. For further guidance, the syntheses of the present compounds are described m Yokoyama et al., U.S. Patent No. 5,401,772, assigned to Ciba-Geigy Corp., issued March 28, 1995; Yokoyama et al. EP 0,580,550, assigned to Ciba-Geigy Corp., published January 26, 1994; and Yokoyama et al., "Synthesis and Structure-Activity Relationships of Oxamic Acid and Acetic Acid Deπvative Related to L-Thyronme", Journal of Medicinal Chemistry, Vol. 38, pp. 695 - 707 (1995). For example, the following describes the synthesis of illustrative compounds utilized in the present invention. Example 1 la. 2-isopropyl anisole: Potassium hydroxide (5.6 g) is added to 13.4 mL acetone followed by 2-isopropylphenol (13.6 g). After the potassium hydroxide is dissolved, methyl iodide (14.2 g) is added. The reaction is refluxed for about 16 hours. 150 mL of water is added. This reaction is extracted 3 times with 100 mL diethyl ether. The organic layer is extracted twice with 100 mL 10% sodium hydroxide in water, once with 100 mL water, and once with 100 mL saturated ammonium chloride. After drying over magnesium sulfate, the organic solution is dried over MgS0 4 , filtered, and concentrated under reduced pressure. The material is fractionally distilled under reduced pressure to afford la. lb. Bis(3-isopropyl-4-methoxyphenyl)iodonium 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 lodme (2.5 g) is added in one piece followed by dropwise addition of 4 7 mL 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 sparged to remove nitrogen oxides and then concentrated under vacuum. The material is then taken up in 15 mL acetic anhydride and cooled to -10 °C. To this cooled solution is added dropwise a solution of 2-ιsopropyl anisole (la; 7 43 g) in 35 mL acetic anhydride and 5 mL trifluoroacetic acid. The reaction is allowed to stand in a refrigerator for 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 methanol, 25 mL 10% sodium bisulfite, and 188 mL 2M sodium tetrafluoroborate. The mixture is stirred vigorously for 30 minutes and the supernatant is decanted off. To the residue is added 200 mL hexane and it is stirred for an additional 30 minutes. The solid is collected, washed with hexane, and dπed under vacuum to afford lb. lc. 2',6'-dimethyl-3-isopropyl-4-methoxy-4'-nitrodiphenyl ether: Bιs(3-ιsopropyl-4- methoxyphenyl)ιodomum tetrafluoroborate (lb; 3 g) is weighed and taken up in 1.1 mL dichloromethane and 0.5 g copper bronze is added. The mixture is cooled in an ice water bath. A solution of 2,6-dιmethyl-4-nιtrophenol (0.65 g) and tπethylamine (0.44 g) in 5.2 mL dichloromethane is added dropwise. The reaction is placed m the dark and stirred for 5 days. At this time, the reaction is filtered through cehte and concentrated under reduced pressure. Purification of the product by chromatography on silica gel followed by crystallization from hexane: ethyl acetate affords lc Id. Methyl -V-[3,5-dimethyl-4-(4'-methoxy-3'-isopropylphenoxy)phenyl]oxamate: 2',6'- dιmethyl-3-ιsopropyl-4-methoxy-4'-mtrodιphenyl ether (lc; 0.51 g) is dissolved m 20 mL ethanol and 60 mg of 10% palladium on carbon is added. The reaction is hydrogenated for 3 hours, then filtered through cehte and concentrated under reduced pressure. Dimethyl oxamate (3 g), is added to the residue and the reaction is heated to 120 °C for 4 hours. The reaction mixture is concentrated under reduced pressure and purified by chromatography on silica gel to afford Id. le. V-[3,5-dimethyl-4-(4'-hydroxy-3'-isopropylphenoxy)phenyl]oxamate: Methyl V-[3,5- dιmethyl-4-(4'-methoxy-3'-ιsopropylphenoxy)phenyl]oxamate (Id; 350 mg) is dissolved in 3.5 mL dichloromethane and cooled in a dry ice acetone bath. To this solution is dropwise added 2 mL boron tπbromide (1 M in dichloromethane). The reaction is stirred about 16 hours and is allowed to reach ambient temperature. At this time, the reaction is poured onto 10 mL ice and water. To this mixture is added 10 mL ethyl acetate. The organic layer is separated and the aqueous phase is extracted twice with 10 mL ethyl acetate. The organic layers are combined, dried over magnesium sulfate, and concentrated under reduced pressure. The material is dissolved m 1: 1 acetonιtπle:water and loaded onto a column containing 5 g C 18 -deπvatιzed silica gel and equilibrated with water. The product is eluted using a step gradient, 2 x 15 mL 25:75 acetonιtπle:water, 1 x 15 mL 35:65 acetonιtπle:water, 1 x 15 mL 40:60 acetonitπle: water, 2 x 15 mL 45:55 acetomtπle:water, and 1 x 15 mL 50:50 acetonιtπle:water to afford le. The compound of Example 2 is synthesized as described m Yokoyama et al.. "Synthesis and Structure-Activity Relationships of Oxamic Acid and Acetic Acid Derivative Related to L-Thyronme", Journal of Medicinal Chemistry, Vol. 38, pp. 695 - 707 (1995). The compound of Example 3 is synthesized as descπbed in Yokoyama et al., U.S. Patent No. 5,401,772, assigned to Ciba-Geigy Corp., issued March 28, 1995 Example 4 4a. 2',6'-diiodo-3-isopropyl-4-methoxy-4'-nitrodiphenyl ether: Bιs(3-ιsopropyl-4- methoxyphenyl)ιodomum tetrafluoroborate (prepared as descπbed m Example lb) (3 g) is weighed is taken up m 7.7 mL dichloromethane and 0.5 g copper bronze is added. The mixture is cooled m an ice water bath. A solution of 2,6-dιιodo-4-nιtrophenol (1.53 g) and tπethyl amme (0.43 g) 5 mL dichloromethane is added dropwise. The reaction is placed in the dark and stirred for 5 days. At this time, 25 mL methanol is added to the reaction and is filtered through a plug of silica gel. The silica gel is washed with an additional 5 mL of methanol and the filtrate is concentrated under reduced pressure. Purification of the product by chromatography on silica gel affords 4a. 4b. Methyl V-[3,5-diiodo-4-(4'-methoxy-3'-isopropylphenoxy)phenyl]oxamate: 2',6'- dnodo-S-isopropyM-methoxy^'-nitrodiphenyl ether (4a) (0.62 g) is dissolved in 20 mL ethanol and 2 mL N,N-dιmethylformamιde and 40 mg of 10% palladium on carbon is added. The reaction is hydrogenated for 4 hours, then filtered through cehte and concentrated under reduced pressure. Dimethyl oxamate (3g) is added to the residue and the reaction is heated to 120 °C for 3 hours. The reaction mixture is concentrated under reduced pressure and purified by chromatography on silica gel to afford 4b. 4c. 7V-[3,5-diiodo-4-(4'-hydroxy-3'-isopropylphenoxy)phenyl]oxamate: Methyl N-[3,5- dπodo-4-(4'-methoxy-3'-ιsopropylphenoxy)phenyl]oxamate (4b) (62 mg) is dissolved 1 mL dichloromethane and cooled in a dry ice acetone bath. To this solution is added 0.2 mL boron tπbromide (1 M in dichloromethane). The reaction is stirred for about 16 hours and allowed to reach room temperature. The reaction is poured onto 10 mL ice and water. To this mixture is added 10 mL ethyl acetate. The organic layer is separated and the aqueous phase is extracted a second time with 10 mL ethyl acetate. The organic layers are combined, washed with brme, dried over magnesium sulfate, and concentrated under reduced pressure. Purification of the product by chromatography on silica gel affords 4c. Example 5 5. iV-[3,5-dimethyl-4-(4'-methoxy-3'-isopropylphenoxy)phenyl]oxamate: Methyl -V-[3,5- dιmethyl-4-(4'-methoxy-3'-ιsopropylphenoxy)phenyl]oxamate (prepared as described in Example Id) (750 mg) is dissolved in 12 mL methanol and 2.2 mL 1 N sodium hydroxide is added. The sample is reacted overnight. The mixture is concentrated under reduced pressure. To the mixture is added 25 mL water and 15 mL ethyl acetate, followed by 5 mL 1 N HCl. The mixture is transferred to a separatory funnel and an additional 35 mL ethyl acetate is added. The organic layer is separated and the aqueous phase is extracted once with 15 mL ethyl acetate and once with 10 mL ethyl acetate. The organic layers are combined, washed with 25 mL saturated sodium chloride, and dried over magnesium sulfate. The solution is filtered and concentrated under reduced pressure to afford 5. Use of the Present Compounds The methods of the present invention are performed 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 herein may be used for the treatment of such conditions as treating hair loss m mammals, including arresting and / or reversing hair loss and promoting hair growth. Such conditions may manifest themselves m, for example, alopecia, including male pattern baldness and female pattern baldness. Preferably the compounds of the present invention are, as defined herein, cardiac- spaπng. Preferably, m the methods of the present invention, the compounds are formulated into pharmaceutical or cosmetic compositions for use in treatment or prophylaxis of conditions such as the foregoing. Standard pharmaceutical formulation techniques are used, such as those disclosed in Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, PA. (1990). Typically, from about 5 mg to about 3000 mg, more preferably from about 5 mg to about 1000 mg, more preferably from about 10 mg to about 100 mg, of a compound having a structure as described herein is administered per day for systemic administration. It is understood that these dosage ranges are by way of example only, and that daily administration can be adjusted depending on various factors. The specific dosage of the compound to be administered, as well as the duration of treatment, and whether the treatment is topical or systemic are interdependent. The dosage and treatment regimen will also depend upon such factors as the specific compound used, the treatment indication, the efficacy of the compound, the personal attributes of the subject (such as, for example, weight, age, sex, and medical condition of the subject), compliance with the treatment regimen, and the presence and severity of any side effects of the treatment. According to the present invention, the subject compounds are co-admmistered with a pharmaceutically-acceptable or cosmetically-acceptable earner (herein collectively described as "carrier") The term "carrier", as used herein, means one or more compatible solid or liquid filler diluents or encapsulating substances which are suitable for administration to a mammal The term "compatible", as used herein, means that the components of the composition are capable of being commingled with a compound of the present invention, and with each other, in a manner such that there is no interaction which would substantially reduce the efficacy of the composition under ordinary use situations Carriers must, of course, be of sufficiently high purity and sufficiently low toxicity to render them suitable for administration to the animal, preferably mammal (most preferably human), being treated The carrier can itself be inert or it can possess pharmaceutical and / or cosmetic benefits of its own The compositions of this invention may be in any of a variety of forms, suitable (for example) for oral, rectal, topical, nasal, ocular or parenteral administration. Of these, topical and / or oral administration are especially prefeπed with topical being most prefeπed. Depending upon the particular route of administration desired, a variety of carriers well-known in the art may be used. These include solid or liquid fillers, diluents, hydrotropes, surface-active agents, and encapsulating substances. Optional pharmaceutically-active or cosmetically-active materials may be included which do not substantially interfere with the activity of the compound of the present invention. The amount of earner employed in conjunction with the compound is sufficient to provide a practical quantity of material for administration per unit dose of the compound Techniques and compositions for making dosage forms useful in the methods of this invention are described in the following references: Modern Pharmaceutics, Chapters 9 and 10, Banker & Rhodes, eds. (1979), Lieberman et al., Pharmaceutical Dosage Forms: Tablets (1981); and Ansel, Introduction to Pharmaceutical Dosage Forms, 2 nd Ed., (1976). Some examples of substances which can serve as carriers or components thereof are sugars, such as lactose, glucose and sucrose; starches, such as corn starch and potato starch; cellulose and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose, and methyl cellulose; powdered tragacanth, malt; gelatin; talc; solid lubπcants, such as steaπc acid and magnesium stearate; calcium sulfate; vegetable oils, such as peanut oil, cottonseed oil, sesame oil, olive oil, corn oil and oil of theobroma; polyols such as propylene glycol, glycerine, sorbitol, mannitol, and polyethylene glycol; algmic acid; emulsifiers, such as the TWEENS; wetting agents, such sodium lauryl sulfate, coloring agents, flavoring agents, tabletmg agents, stabilizers, antioxidants, preservatives, pyrogen-free water, isotonic saline; and phosphate buffer solutions The choice of a carrier to be used in conjunction with the subject compound is typically determined by the way the compound is to be administered In particular, earners for systemic administration include sugars, starches, cellulose and its derivatives, malt, gelatin, talc, calcium sulfate, vegetable oils, synthetic oils, polyols, algmic acid, phosphate buffer solutions, emulsifiers, isotonic saline, and pyrogen-free water Preferred earners for parenteral administration include propylene glycol, ethyl oleate, pyπohdone, ethanol, and sesame oil. Preferably, the caπier, in compositions for parenteral administration, comprises at least about 90% by weight of the total composition Various oral dosage forms can be used, including such solid forms as tablets, capsules, granules and bulk powders These oral forms comprise a safe and effective amount, usually at least about 5%, and preferably from about 25% to about 50%, of a compound used m the present invention Tablets can be compressed, tablet triturates, enteric-coated, sugar-coated, film-coated, or multiple-compressed, containing suitable binders, lubricants, diluents, disintegrating agents, coloring agents, flavoring agents, flow-mducmg agents, and melting agents Liquid oral dosage forms include aqueous solutions, emulsions, suspensions, solutions and/or suspensions reconstituted from non- effervescent granules, and effervescent preparations reconstituted from effervescent granules, containing suitable solvents, preservatives, emulsifying agents, suspending agents, diluents, sweeteners, melting agents, coloring agents and flavoring agents. The carriers suitable for the preparation of unit dosage forms for oral administration are well-known m the art. Tablets typically comprise conventional pharmaceutically- compatible adjuvants as inert diluents, such as calcium carbonate, sodium carbonate, mannitol, lactose and cellulose; binders such as starch, gelatin and sucrose; dismtegrants such as starch, algmic acid and croscarmelose; lubπcants such as magnesium stearate, steaπc acid and talc. Ghdants such as silicon dioxide can be used to improve flow characteπstics of the powder mixture. Coloring agents, such as the FD&C dyes, can be added for appearance. Sweeteners and flavoring agents, such as aspartame, saccharin, menthol, peppermint, and fruit flavors, are useful adjuvants for chewable tablets Capsules (including time release and sustained release formulations) typically compπse one or more solid diluents disclosed above. The selection of earner components depends on secondary considerations like taste, cost, and shelf stability, which are not critical for the purposes of the subject invention, and can be readily made by a person skilled in the art. Orally administered compositions also include liquid solutions, emulsions, suspensions, powders, granules, elixirs, tinctures, syrups, and the like. The carriers suitable for preparation of such compositions are well known in the art. Typical components of carriers for syrups, elixirs, emulsions and suspensions include ethanol, glycerol, propylene glycol, polyethylene glycol, liquid sucrose, sorbitol and water. For a suspension, typical suspending agents include methyl cellulose, sodium carboxymethyl cellulose, AVICEL RC- 591, tragacanth and sodium algmate; typical wetting agents include lecithin and polysorbate 80; and typical preservatives include methyl paraben and sodium benzoate. Peroral liquid compositions may also contain one or more components such as sweeteners, flavoring agents and colorants disclosed above. Such compositions may also be coated by conventional methods, typically with pH or time-dependent coatings, such that the subject compound is released in the gastrointestinal tract in the vicinity of the desired topical application, or at various times to extend the desired action. Such dosage forms typically include, but are not limited to, one or more of cellulose acetate phthalate, polyvinylacetate phthalate, hydroxypropyl methyl cellulose phthalate, ethyl cellulose, Eudragit coatings, waxes and shellac. Other compositions useful for attaining systemic delivery of the subject compounds include sublmgual, buccal and nasal dosage forms. Such compositions typically compπse one or more of soluble filler substances such as sucrose, sorbitol and mannitol; and binders such as acacia, microcrystalhne cellulose, carboxymethyl cellulose and hydroxypropyl methyl cellulose. Ghdants, lubricants, sweeteners, colorants, antioxidants and flavonng agents disclosed above may also be included. The compounds of the present invention may also be topically administered. The carrier of the topical composition preferably aids penetration of the present compounds into the skin to reach the environment of the hair follicle. Topical compositions of the present invention may be in any form including, for example, solutions, oils, creams, ointments, gels, lotions, shampoos, leave-on and πnse-out hair conditioners, milks, cleansers, moistuπzers, sprays, sk patches, and the like. Topical compositions containing the active compound can be admixed with a vaπety of carrier mateπals well known in the art, such as, for example, water, alcohols, aloe vera gel, allantom, glyceπne, vitamin A and E oils, mineral oil, propylene glycol, PPG-2 myπstyl propionate, and the like. Other materials suitable for use in topical carriers include, for example, emollients, solvents, humectants, thickeners and powders Examples of each of these types of materials, which can be used singly or as mixtures of one or more materials, are as follows Emollients, such as stearyl alcohol, glyceryl monoπcmoleate, glyceryl monostearate, propane- 1,2-dιol, butane-l,3-dιol, mmk oil, cetyl alcohol, zso-propyl isostearate, steaπc acid, zso-butyl palmitate, isocetyl stearate. oleyl alcohol, isopropyl laurate, hexyl laurate, decyl oleate, octadecan-2-ol, isocetyl alcohol, cetyl palmitate, dimethylpolysiloxane, dι-«-butyl sebacate, zsopropyl myπstate, zso-propyl palmitate, zso-propyl stearate, butyl stearate, polyethylene glycol, friethylene glycol, lanolm, sesame oil, coconut oil, arachis oil, castor oil, acetylated lanolm alcohols, petroleum, mineral oil, butyl myπstate, lsosteaπc acid, palmitic acid, isopropyl hnoleate, lauryl lactate, myπstyl lactate, decyl oleate, and myπstyl myπstate, propellants, such as propane, butane, zso-butane, dimethyl ether, carbon dioxide, and nitrous oxide, solvents, such as ethyl alcohol, methylene chloride, zso-propanol, castor oil, ethylene glycol monoethyl ether, diethylene glycol monobutyl ether, diethylene glycol monoethyl ether, dimethyl sulphoxide, dimethyl formamide, tetrahydrofuran; humectants, such as glycerin, sorbitol, sodium 2-pyrrohdone-5-carboxylate, soluble collagen, dibutyl phthalate, and gelatin; and powders, such as chalk, talc, fullers earth, kaolm, starch, gums, colloidal silicon dioxide, sodium polyacrylate, tetra alkyl ammonium smectites, tπalkyl aryl ammonium smectites, chemically modified magnesium aluminium silicate, organically modified montmoπllomte clay, hydrated aluminium silicate, fumed silica, carboxyvmyl polymer, sodium carboxymethyl cellulose, and ethylene glycol monostearate. The compounds used in the present invention may also be administered in the form of hposome delivery systems, such as small umlamellar vesicles, large umlamellar vesicles, and multilamellar vesicles. Liposomes can be formed from a variety of phosphohpids, such as cholesterol, stearylamme or phosphatidylcholmes A preferred formulation for topical delivery of the present compounds utilizes liposomes such as described m Dowton et al.. "Influence of Liposomal Composition on Topical Delivery of Encapsulated Cyclospoπn A: I. An in vitro Study Using Hairless Mouse Skm", S T.P Pharma Sciences, Vol. 3, pp. 404 - 407 (1993); Wallach and Phihppot. "New Type of Lipid Vesicle: Novasome ® ", Liposome Technology. Vol 1, pp. 141 - 156 (1993), Wallach. U.S. Patent No. 4,911,928, assigned to Micro-Pak, Inc., issued March 27, 1990; and Werner et al . U.S. Patent No. 5,834,014, assigned to The University of Michigan and Micro-Pak, Inc., issued November 10, 1998 (with respect to Werner et al., with a compound as described herein administered m lieu of, or in addition to, mmoxidil). The compounds of the present invention may also be administered by iontophoresis. See, e. . internet site www.unipr.it arpa/dipfarm/erasmus/erasml4.html; Banga et al.. "Hydrogel-based Iontotherapeutic Delivery Devices for Transdermal Delivery of Peptide/Protem Drugs", Pharm Res , Vol 10 (5), pp. 697-702 (1993); Ferry, "Theoretical Model of Iontophoresis Utilized in Transdermal Drug Delivery", Pharmaceutical Ada Helvetiae, Vol 70, pp. 279-287 (1995), Gangarosa et al , "Modern Iontophoresis for Local Drug Delivery", Int. J Pharm, Vol. 123, pp 159-171 (1995), Green et al., "Iontophoretic Delivery of a Series of Tπpeptides Across the Skm in vitro", Pharm Res , Vol 8, pp. 1 Hil l 27 (1991); Jadoul et al., "Quantification and Localization of Fentanyl and TRH Delivered by Iontophoresis in the Skm", Int J Pharm , Vol. 120, pp. 221-8 (1995); O'Brien et al.. "An Updated Review of its Antiviral Activity, Pharmacokmetic Properties and Therapeutic Efficacy", Drugs, Vol. 37, pp. 233-309 (1989), Parry et al.. "Acyclovir Biovailabihty in Human Skm", J Invest Dermatol, Vol. 98 (6), pp. 856-63 (1992); Santi et al.. "Drug Reservoir Composition and Transport of Salmon Calcitonm m Transdermal Iontophoresis", Pharm. Res , Vol 14 (1), pp. 63-66 (1997); Santi et al.. "Reverse Iontophoresis - Parameters Determining Electroosmotic Flow: I. pH and Ionic Strength", J Control. Release, Vol. 38, pp. 159-165 (1996); Santi et al.. "Reverse Iontophoresis - Parameters Determining Electroosmotic Flow: II. Electrode Chamber Formulation", J. Control. Release, Vol. 42, pp. 29-36 (1996); Rao et al.. "Reverse Iontophoresis- Nonmvasive Glucose Monitoring in vivo in Humans", Pharm. Res., Vol. 12 (12), pp. 1869-1873 (1995); Thvsman et al.. "Human Calcitonm Delivery in Rats by Iontophoresis", J. Pharm Pharmacol, Vol. 46, pp. 725-730 (1994); and Volpato et al., "Iontophoresis Enhances the Transport of Acyclovir through Nude Mouse Skm by Electrorepulsion and Electroosmosis", Pharm. Res., Vol. 12 (11), pp. 1623- 1627 (1995). The compositions used m the present invention may also optionally compπse an activity enhancer. The activity enhancer can be chosen from a wide vaπety of molecules which can function in different ways to enhance hair growth effects of a compound of the present invention. Particular classes of activity enhancers include other hair growth stimulants and penetration enhancers. Non-limiting examples of other hair growth stimulants which may be used m the compositions herein, including both systemic and topical compositions, include, for example, benzalkonium chloride, benzethomum chloπde, phenol, estradiol, diphenhydramine hydrochloπde, chlorpheniramme maleate, chlorophyllm deπvatives, cholesterol, salicylic acid, cysteme, methionine, red pepper tincture, benzyl nicotmate, D,L - menthol, peppermint oil, calcium pantothenate, panthenol, castor oil, hmokitiol, prednisolone, resorc ol, monosaccharides and esteπfied monosaccharides, chemical activators of protein k ase C enzymes, glycosammoglycan chain cellular uptake inhibitors, inhibitors of glycosidase activity, glycosammoglycanase inhibitors, esters of pyroglutamic acid, hexosaccharic acids or acylated hexosaccharic acids, aryl-substituted ethylenes, N-acylated ammo acids, and, of course, mmoxidil or fmasteπde The most preferred activity enhancers are mmoxidil and finasteπde, most preferably mmoxidil Non-limiting examples of penetration enhancers which may be used in the compositions herein include, for example, 2-methyl propan-2-ol, propan-2-ol, ethyl-2- hydroxypropanoate, hexan-2,5-dιol, POE(2) ethyl ether, dι(2-hydroxypropyl) ether, pentan- 2,4-dιol, acetone, POE(2) methyl ether, 2-hydroxypropιomc acid, 2-hydroxyoctanoιc acid, propan-1-ol, 1,4-dιoxane, tetrahydrofuran, butan-l,4-dιol, propylene glycol dipelargonate, polyoxypropylene 15 stearyl ether, octyl alcohol, POE ester of oleyl alcohol, oleyl alcohol, lauryl alcohol, dioctyl adipate, dicapryl adipate, di-isopropyl adipate, di-isopropyl sebacate, dibutyl sebacate, diethyl sebacate, dimethyl sebacate, dioctyl sebacate, dibutyl suberate, dioctyl azelate, dibenzyl sebacate, dibutyl phthalate, dibutyl azelate, ethyl myπstate, dimethyl azelate, butyl myπstate, dibutyl succmate, didecyl phthalate, decyl oleate, ethyl caproate, ethyl sahcylate, zso-propyl palmitate, ethyl laurate, 2-ethyl-hexyl pelargonate, zsø-propyl isostearate, butyl laurate, benzyl benzoate, butyl benzoate, hexyl laurate, ethyl caprate, ethyl caprylate, butyl stearate, benzyl sahcylate, 2-hydroxypropanoιc acid, 2-hyroxyoctanoιc acid, dimethyl sulphoxide, N,N-dιmethyl acetamide, N,N-dιmethyl formamide, 2-pyrrolιdone, 1- methyl-2-pyπolιdone, 5-methyl-2-pyrrohdone, 1,5 -dimethyl -2 -pyrrohdone, l-ethyl-2- pyrrohdone, phosphme oxides, sugar esters, tetrahydrofurfural alcohol, urea, diethyl-wz- toluamide, and, 1 -dodecylazacyloheptan-2-one In all of the foregoing, of course, the compounds used in the present methods can be administered alone or as mixtures, and the compositions may further include additional drugs or excipients as appropriate for the indication The present invention further relates to kits comprising a compound and / or composition herein and information and / or instructions by words, pictures, and / or the like, that use of the kit will provide treatment for hair loss in mammals (particularly humans) including, for example, arresting and / or reversing hair loss and / or promoting hair growth In addition or in the alternative, the kit may comprise a compound and / or composition herein and information and / or instructions regarding methods of application of the compound and / or composition, preferably with the benefit of treating hair loss in mammals Examples of Composition Administration The following examples do not limit the invention, but provide guidance to the skilled artisan to perform the methods of the present invention. In each example, a compound other than the one mentioned may be substituted m the example by another having a structure as described herein with similar results. Example A A composition for topical administration is made, comprising: A human male subject suffeπng from male pattern baldness is treated by a method of this invention. Specifically, for 6 weeks, the above composition is daily administered topically to the subject. Example B A composition for topical administration is made according to the method of Dowton et al., "Influence of Liposomal Composition on Topical Delivery of Encapsulated Cyclospoπn A: I. An in vitro Study Using Hairless Mouse Skm", S.T.P. Pharma Sciences. Vol. 3, pp. 404 - 407 (1993), using 3,5-Example 1 in lieu of cyclospoπn A and using the Novasome 1 for the non-ionic liposomal formulation. A human male subject suffeπng from male pattern baldness is treated each day with the above composition. Specifically, for 6 weeks, the above composition is administered topically to the subject. Example C A shampoo is made, compπsmg: 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: What is claimed is: 1. A method of treating hair loss comprising administering a composition comprising a cardiac-sparing compound characterized by the structure: and pharmaceutically acceptable salts, hydrates, and biohydrolyzable amides, esters, and imides thereof, wherein: R is selected from the group consisting of hydrogen, hydroxy, esterified hydroxy, and etherified hydroxy; R-i, R 2 , and R are each, independently, selected from the group consisting of hydrogen, halogen, trifluoromethyl and lower alkyl; R 3 is selected from the group consisting of halogen, trifluoromethyl, lower alkyl, aryl, aryl-lower alkyl, cycloalkyl, cycloalkyl-lower alkyl, and: Re is selected from the group consisting of hydrogen, lower alkyl, aryl, cycloalkyl, aryl-lower alkyl, and cycloalkyl-lower alkyl; Rg is selected from the group consisting of hydroxy and acyloxy; R-io is selected from the group consisting of hydrogen and lower alkyl; with the proviso that Rg and R 10 collectively optionally represent oxo; W is selected from the group consisting of -O- and -S-; X is selected from the group consisting of -NR , S, and O; R 5 is selected from the group consisting of hydrogen, lower alkyl, and aryl-lower alkyl and Re is hydrogen; with the proviso that when X is -NR 7 , R 5 and Re together are optionally oxo; R 7 is selected from the group consisting of hydrogen and lower alkyl; and Z is selected from the group consisting of carboxyl and carboxyl derivatized as a pharmaceutically acceptable ester or amide. 2. A method according to claim 1 wherein X is -NR and R 5 and Re together are oxo. 3. A method according to any of claims 1 and 2 wherein: R substitutes on the 4' position; Ri substitutes on the 3 position; R 2 substitutes on the 5 position; R 3 substitutes on the 3' position; and R 4 substitutes on the 5' position. 4. A method according any of claims 1 and 2 wherein: W is -0-; R is selected from the group consisting of hydroxy, esterified hydroxy, and etherified hydroxy; R is hydrogen; R 3 is selected from the group consisting of lower alkyl, aryl-lower alkyl, cycloalkyl-lower alkyl and Rs C-R 9 I Rl ° and Z is selected from the group consisting of carboxyl and carboxyl derivatized as a pharmaceutically acceptable ester. 5. A method according to claim 4 wherein the compound is characterized by the structure: wherein Ri and R 2 are each, independently, selected from the group consisting of hydrogen, halogen, trifluoromethyl, and Ci - C 3 alkyl. 6. A method according claim 5 wherein R 7 is selected from the group consisting of hydrogen and Ci - C 3 alkyl. 7. A method according to any of claims 5 and 6 wherein R is hydroxy. 8. A method according to any of claims 5, 6, and 7 wherein R 3 is selected from the group consisting of isopropyl, benzyl, benzyl substituted with halogen, and trifluoromethyl. 9. A method according to any of claims 5, 6, 7, and 8 wherein Z is carboxyl. 10. A method according to any of the preceding claims wherein the administration is topical.

Inventors: YOUNGQUIST ROBERT SCOTT, ZHANG LILLY LI-XIN, YOUNGQUIST, ROBERT, SCOTT, ZHANG, LILLY, LI-XIN
Applicants: PROCTER & GAMBLE, YOUNGQUIST ROBERT SCOTT, ZHANG LILLY LI XIN, THE PROCTER & GAMBLE COMPANY, YOUNGQUIST, ROBERT, SCOTT, ZHANG, LILLY, LI-XIN
Application year: 2000
Main classification: A61K7
IPC codes: A61K8, A61K31, A61P17, A61Q5, A61Q7