METHOD OF TREATING HAIR LOSS USING SULFONYL THYROMIMETIC COMPOUNDS

Abstract: A method of treating hair loss comprising administering a composition comprising a cardiac-sparing compound characterized by structure (I) and pharmaceutically acceptable salts, hydrates, and biohydrolyzable amides, esters, and imides thereof, wherein: R1 is -(CH2)n(CHNR7R8)mC(O)R9; n is an integer from 1 to 3; m is an integer from 0 to 1; R3 and R5 are each, independently, selected from the group consisting of chlorine, bromine, iodine, and -CH3, R7 and R8 are each, independently, selected from the group consisting of hydrogen and C1-C4 alkyl; R9 is selected from the group consisting of hydroxy, C1-C4 alkoxy, and -NR7R8; R31 is selected from the group consisting of hydrogen, chlorine, bromine, iodine, C1-C4 alkyl, C4-C6 cycloalkyl, C1-C4 haloalkyl, C4-C6 halocycloalkyl, and -CH(R10)Ar; Ar is selected from the group consisting of 5-hydroxypyrid-2-yl, 6-hydroxypyrid-3-yl, 6-hydroxypyridazin-3-yl, 6-methoxypyridazin-3-yl N-oxide, and 6-hydroxypyridazin-3-yl N-oxide; R10 is selected from the group consisting of hydrogen and C1-C4 alkyl; and R41 is selected from the group consisting of hydroxy and C1-C4 alkoxy.

Description: METHOD OF TREATING HAIR LOSS USING SULFONYL THYROMIMETIC COMPOUNDS 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 in the art, hair growth occurs by a cycle of activity which involves alternating penods of growth and rest. This cycle is often divided into three mam stages which are known as anagen, catagen, and telogen. Anagen is the growth phase of the cycle and may be characterized by penetration of the hair follicle deep into the dermis with rapid proliferation of cells which are differentiating to form hair. The next phase is catagen, which is a transitional stage marked by the cessation of cell division, and during which the hair follicle regresses through the dermis and hair growth is ceased. The next phase, telogen, is often characterized as the resting stage during which the regressed follicle contains a germ with tightly packed dermal papilla cells. At telogen, the initiation of a new anagen phase is caused by rapid cell proliferation in the germ, expansion of the dermal papilla, and elaboration of basement membrane components. 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 fϊnasteπde (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 thyroxine ("T4") converts to thyronme ("T3") in human skin by deiodmase I, a selenoprotem. Selenium deficiency causes a decrease m T3 levels due to a decrease in 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 ., Berman, "Peripheral Effects of L-Thyroxme on Hair Growth and Coloration in Cattle", Journal of Endocrinology, Vol. 20, pp. 282 - 292 (1960); and Gunaratnam, "The Effects of Thyroxme on Hair Growth in the Dog", J Small Antm Pract , Vol. 27, pp. 17 - 29 (1986). Furthermore, T3 and T4 have been the subject of several patent publications relating to treatment of hair loss. See, e.g , Fischer et al., DE 1,617,477, published January 8, 1970; Mortimer, GB 2,138.286, published October 24, 1984; and Lmdenbaum, WO 96/25943, assigned to Life Medical Sciences, Inc., published August 29, 1996. Unfortunately, however, administration of T3 and / or T4 to treat hair loss is not practicable because these thyroid hormones are also known to induce significant cardiotoxicity See, e.g.. Walker et al.. U.S Patent No 5,284,971, assigned to Syntex, issued February 8, 1994 and Emmett et al., U.S. Patent No. 5,061,798, assigned to Smith Kline & French Laboratories, issued October 29, 1991. Surprisingly, however, the present inventors have discovered compounds 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 compounds 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 compounds descπbed for use m the methods and compositions herein are cardiac-spaπng 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 comprising administering a cardiac-sparmg 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 in the present method have the structure: and pharmaceutically acceptable salts, hydrates, and biohydrolyzable amides, esters, and imides thereof, wherein R 1; R 3 , R 5 , R 3 ,, and R 41 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-spaπng The preferred compounds useful in the method of the present invention are therefore, as defined herein below, cardiac-sparmg Publications and patents are referred to throughout this disclosure. All references cited herein are hereby incorporated by reference. All percentages, ratios, and proportions used herein are by weight unless otherwise specified. In the description of the invention various embodiments and/or individual features are disclosed. As will be apparent to the ordinarily skilled practitioner all combinations of such embodiments and features are possible and can result in preferred executions of the invention. As used herein, wherein any variable, moiety, group, or the like occurs more than one time in any variable or structure, its definition at each occurrence is independent of its definition at every other occurrence 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 in the art. Preferred cationic salts include the alkali metal salts (such as, for example, sodium and potassium), alkaline earth metal salts (such as, for example, magnesium and calcium), and organic salts. Preferred aniomc salts include the hahdes (such as, for example, chloride salts) Such acceptable salts must, when administered, be appropπate for mammalian use As used herein, "alkoxy" is an oxygen radical having an alkyl substituent. Examples of alkoxy radicals include -O-methyl and -O-ethyl. As used herein, "alkyl" is a saturated, straight or branched chain monovalent hydrocarbon radical Unless otherwise specified, alkyls have from 1 to about 4 carbon atoms (Ci - C 4 ) Preferred alkyls include, for example, methyl, ethyl, propyl, zso-propyl, tert-butyl, w-butyl, .sec-butyl, and zso-butyl. 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 imides" are imides 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, "carbocychc ring", "carbocycle", or the like is a hydrocarbon πng radical Carbocychc rings are monocyclic or are fused, bridged, or spiro polycychc rings. Unless otherwise specified, monocyclic rings contain from 3 to about 9 atoms, preferably from about 4 to about 7 atoms, and most preferably 5 or 6 atoms Polycychc πngs contain from about 7 to about 17 atoms, preferably from about 7 to about 14 atoms, and most preferably 9 or 10 atoms. Carbocychc πngs (carbocycles) may be substituted or unsubstituted. As used herein, "cycloalkyl" is a saturated carbocychc πng radical having from four to six carbon atoms, such as cyclopentyl and cyclohexyl Optionally, the cycloalkyl may be substituted with one or more alkyl groups As used herein, "haloalkyl" is an alkyl moiety substituted at one or more positions with a halogen radical. As used herein, "halocycloalkyl" an cycloalkyl moiety substituted at one or more positions with a halogen radical. As used herein "halogen" refers to chlorine, bromine, iodine, and fluoπne, preferably chloπne, bromine, and iodine, more preferably chlorine and iodine, and most preferably iodine. 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 Methods of the Present Invention The present invention relates to methods of treating hair loss comprising administering a composition compπsing a compound having the structure- and pharmaceutically acceptable salts, hydrates, and biohydrolyzable amides, esters, and imides thereof, wherein: (a) R, is -(CH 2 ) n (CHNR 7 R 8 ) m C(0)R 9 ; (b) n is an integer from 1 to 3; (c) m is an integer from 0 to 1 , (d) R 3 and R 5 are each, independently, selected from the group consisting of chloπne, bromine, iodine, and -CH 3 ; (e) R 7 and R 8 are each, independently, selected from the group consisting of hydrogen and Ci - C alkyl; (f) R 9 is selected from the group consisting of hydroxy, d - C 4 alkoxy, and -NR 7 R 8 ; (g) R 3 ι is selected from the group consisting of hydrogen, chloπne, bromine, iodine, Ci - C 4 alkyl, C 4 - C 6 cycloalkyl, C, - C 4 haloalkyl, C 4 - C 6 halocycloalkyl, and - CH(R 10 )Ar; (h) Ar is selected from the group consisting of 5-hydroxypyπd-2-yl, 6-hydroxypyπd-3- yl, 6-hydroxypyπdazιn-3-yl, 6-methoxypyndazιn-3-yl N-oxide, and 6- hydroxypyπdazιn-3-yl N-oxide; (i) Rio is selected from the group consisting of hydrogen and - C 4 alkyl; and (j) R 4 ι is selected from the group consisting of hydroxy and C] - C alkoxy. The compounds useful in the method herein are further described m Walker et al., U.S. Patent No. 5,284,971, assigned to Syntex, Inc , issued February 8, 1994 However, for convenience, the compounds are more fully described herein below. The R ! Moietv The R, moiety is -(CH 2 ) n (CHNR-R 8 ) m C(0)R 9 . The integer n is from 1 to 3. Preferably, n is 1 or 2. The integer m is either 0 or 1. R7 and R 8 are each, independently, selected from hydrogen and C] - C 4 alkyl. Preferably, R 7 and R 8 are each hydrogen R 9 is selected from hydroxy, - C 4 alkyl, and -NR R 8 . As stated above, R 7 and R 8 are preferably each hydrogen Preferably, Rj is an alkanoic or 2-ammoalkanoιc acid radical derived from acetic acid, propionic acid, or 2-ammopropιonιc acid, or the methyl or ethyl ester thereof. As used herein, the term "alkanoic acid radical" refers to a monovalent carboxyhc acid radical formed by removal of a hydrogen from the co-carbon of an acid having from two to four carbon atoms, e.g , acetyl (-CH 2 COOH), propionyl (-CH 2 CH 2 COOH), and butyryl (-CH 2 CH 2 CH 2 COOH). As used herein, "ammoalkanoic acid radical" refers to a monovalent alkanoic acid radical having an ammo or mono- or dialkylammo substituent on the -carbon, e g , 2-ammopropιonyl (- CH 2 CH(NH 2 )COOH). The R 3 and Rs Moieties R 3 and R 5 are each, independently, selected from chlorine, bromine, iodine, and -CH 3 (a methyl radical). Preferably, R 3 and R 5 are each, independently, selected from iodine and bromine. Most preferably R 3 and R 5 are either both bromine or both iodine. The R J Moietv R 31 is selected from hydrogen, chlorine, bromine, iodine, C] - C 4 alkyl, C 4 - C 6 cycloalkyl, Q - C haloalkyl, C 4 - C 6 halocycloalkyl, and -CH(R 10 )Ar. Ar is selected from 5-hydroxypyπd-2-yl, 6-hydroxypyπd-3-yl, 6-hydroxypyπdazm-3-yl, 6-methoxypyπdazm-3-yl N-oxide, and 6-hydroxypyπdazιn-3-yl N-oxide. Preferably Ar is selected from 6-hydroxypyπd-3-yl, 6-hydroxypyπdazm-3-yl, 6-methoxypyndazm-3-yl N-oxide, and 6-hydroxypyπdazm-3-yl N-oxide Rio is selected from hydrogen and C] - C 4 alkyl Preferably, R 3! is selected from iodine, .so-propyl, cyclopentyl, cyclohexyl, and - CH(R 10 )Ar The R4 Moietv R 4! is selected from hydroxy and C, - C 4 alkoxy, preferably hydroxy. A preferred alkoxy for R 41 is methoxy. Preferred Compounds Useful in the Present Invention Preferred compounds useful m the methods and compositions of the present invention are: (a) 3,5-dιbromo-4-(4-hydroxy-3-ιodophenylsulfonyl)phenylacetιc acid; (b) 3,5-dιbromo-4-(3-ιodo-4-methoxyphenylsulfonyl)phenylacetιc acid; (c) 3,5-dιbromo-4-(4-hydroxy-3-(6-methoxypyπdazιn-3- ylmethyl)phenylsulfonyl)phenylacetιc acid; (d) 3 ,5 -dιbromo-4-(3 -cyclohexyl -4-hydroxyphenylsulfonyl)phenylacetιc acid; (e) 3 ,5 -dιbromo-4-(3 -cyclohexyl-4-methoxyphenylsulfonyl)phenylacetιc acid; (f) 3,5-dιbromo-4-(3-cyclopentyl-4-hydroxyphenylsulfonyl)phenylacetιc acid; (g) 3-(3,5-dιbromo-4-(4-hydroxy-3-zso-propylphenylsulfonyl)phenyl)propιonιc acid; (h) 2-amιno-3-(3,5-dιbromo-4-(4-hydroxy-3-z5θ-propylphenylsulfonyl)phenyl)propιonιc acid; (i) 3,5-dιbromo-4-(4-hydroxy-(6-hydroxypyπdazιn-3- ylmethyl)phenylsulfonyl)phenylacetιc acid; (j) 3,5-dιbromo-4-(4-hydroxy-3-.5O-propylphenylsulfonyl)phenylacetιc acid; and (k) 3 ,5-dιbromo-4-(3 -wo-propyl)-4-methoxyphenylsulfonyl)phenylacetιc acid. Of these, the most preferred compounds for use m the present invention are 3,5- dιbromo-4-(3-cyclohexyl-4-hydroxyphenylsulfonyl)phenylacetιc acid and 3,5-dιbromo-4-(3- cyclohexyl-4-methoxyphenylsulfonyl)phenylacetιc acid. Analytical Methods The present invention relates to methods of treating hair loss by admmisteπng a compound having a structure as described herein. Preferably, the compound utilized in the present invention will be cardiac-sparing 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 in vehicle daily for 28 of those days as described below. Prior to initiation of the assay, each rat is allowed to acclimate to standard environmental conditions for 5 days. Each rat receives food (standard rat chow diet) and water ad libitum 5 days prior to initiation of the assay as well as to termination of the study. The vehicle is 91 :9 (v:v) propylene glycohethanol. The test compound is prepared at a concentration of 500 μg/mL in the vehicle. Each rat is weighed on day 1 of the assay. Dosage calculations are then performed: each rat will be administered daily a dosing solution of vehicle or test compound m 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 dosing solution for both groups. Body weights are taken for each rat on days 3, 5, 8, 10, 12, 15, 17, 19, 22, 24, 26, and 29 prior to dosing for that day; for each rat, the dosmg solutions are recalculated and administered accordingly upon change m body weight. Treatment occurs once daily m 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 πght auπcles and left and πght ventπcles. Immediately thereafter, any excess tissue is trimmed away, the heart is lightly blotted on a paper towel until no more blood is visibly left behind on the paper towel, and the heart is weighed. The heart weight is divided by the body weight after euthanization for each rat to give the heart/body ratio. The heart/body ratios for each rat in the vehicle control group are added together and divided by 6 (i.e., the total number of rats 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-sparmg. Preferably, C is less than 1.2, more preferably less than 1.15, and most preferably less than 1.1. In accordance with this method, T3 and T4 are not cardiac-spaπng. Telogen Conversion Assay: The Telogen Conversion Assay measures the potential of a test compound to convert mice in the resting stage of the hair growth cycle ("telogen"), to the growth stage of the hair growth cycle ("anagen"). Without intending to be limited by theory, there are three pπncipal phases of the hair growth cycle: anagen, catagen, and telogen. It is believed that there is a longer telogen peπod in C3H mice (Harlan Sprague Dawley, Inc., Indianapolis, IN) from approximately 40 days of age until about 75 days of age, when hair growth is synchronized. It is believed that after 75 days of age, hair growth is no longer synchronized Wherein about 40 day-old mice with dark fur (brown or black) are used in hair growth experiments, melanogenesis occurs along with hair (fur) growth wherein 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 skin. While each treatment is being applied to the mouse topically, a visual grade of from 0 to 4 will be given to the skin 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 skin progresses from white to bluish-black. Following this method, cyclosporm A typically receives a grade of 4 by day 19. Table 2 Method of Making The compounds used in 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 prepaπng the compounds are known, made by known methods, or are commercially available as a starting material. It is recognized that the ordinarily 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 in standard texts such as J. March, Advanced Organic Chemistry. John Wiley & Sons (1992). The ordinarily skilled artisan will readily appreciate that certain reactions are best carried out when other functionalities are masked or protected in the compound, thus increasing the yield of the reaction and / or avoiding any undesirable side reactions. Often, the 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 mateπals, 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 in the present invention are described m the art. Accordingly, the ordinarily skilled artisan will be able to prepare the compounds described herein. For further guidance, the syntheses of the present compounds are described in Walker et al, U.S. Patent No. 5,284,971, assigned to Syntex, Inc., issued February 8, 1994. 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 earner. The compounds herein may be used for the treatment of such conditions as treating hair loss in mammals, including arresting and / or reversing hair loss and promoting hair growth. Such conditions may manifest themselves m, for example, alopecia, including male pattern baldness and female pattern baldness. Preferably the compounds of the present invention are, as defined herein, cardiac- spanng. Preferably, in the methods of the present invention, the compounds are formulated into pharmaceutical or cosmetic compositions for use m treatment or prophylaxis of conditions such as the foregoing. Standard pharmaceutical formulation techniques are used, such as those disclosed in Remington's Pharmaceutical Sciences. Mack Publishing Company, Easton, PA. (1990). Typically, from about 5 mg to about 3000 mg, more preferably from about 5 mg to about 1000 mg, more preferably from about 10 mg to about 100 mg, of a compound having a structure as described herein is administered per day for systemic administration. It is understood that these dosage ranges are by way of example only, and that daily administration can be adjusted depending on various factors. The specific dosage of the compound to be administered, as well as the duration of treatment, and whether the treatment is topical or systemic are interdependent. The dosage and treatment regimen will also depend upon such factors as the specific compound used, the treatment indication, the efficacy of the compound, the personal attributes of the subject (such as, for example, weight, age, sex, and medical condition of the subject), compliance with the treatment regimen, and the presence and severity of any side effects of the treatment. According to the present invention, the subject compounds are co-admmistered with a pharmaceutically-acceptable or cosmetically-acceptable carrier (herein collectively described as "carrier") The term "carrier", as used herein, means one or more compatible solid or liquid filler diluents or encapsulating substances which are suitable for administration to a mammal The term "compatible", as used herein, means that the components of the composition are capable of being commingled with a compound of the present invention, and with each other, m a manner such that there is no interaction which would substantially reduce the efficacy of the composition under ordinary use situations Carπers 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 preferred with topical being most preferred. Depending upon the particular route of administration desired, a variety of carπers 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 carrier employed in conjunction with the compound is sufficient to provide a practical quantity of material for administration per unit dose of the compound. Techniques and compositions for making dosage forms useful m 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 earners or components thereof are sugars, such as lactose, glucose and sucrose; starches, such as corn starch and potato starch; cellulose and its denvatives, such as sodium carboxymefhyl cellulose, ethyl cellulose, and methyl cellulose; powdered tragacanth; malt; gelatin; talc; solid lubncants, 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, glyceπne, sorbitol, manmtol, 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, isotomc salme; and phosphate buffer solutions The choice of a carrier to be used m 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, isotomc salme, and pyrogen- free water. Prefened earners for parenteral administration include propylene glycol, ethyl oleate, pynolidone, ethanol, and sesame oil Preferably, the earner, in compositions for parenteral administration, comprises at least about 90% by weight of the total composition Various oral dosage forms can be used, including such solid forms as tablets, capsules, granules and bulk powders These oral forms comprise a safe and effective amount, usually at least about 5%, and preferably from about 25% to about 50%, of a compound used in 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- mducing 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 carπers suitable for the preparation of unit dosage forms for oral administration are well-known in the art. Tablets typically comprise conventional pharmaceutically-compatible adjuvants as inert diluents, such as calcium carbonate, sodium carbonate, manmtol, lactose and cellulose; binders such as starch, gelatin and sucrose; dismtegrants such as starch, algmic acid and croscarmelose; lubricants such as magnesium stearate, steaπc acid and talc. Ghdants such as silicon dioxide can be used to improve flow characteristics of the powder mixture. Coloπng agents, such as the FD&C dyes, can be added for appearance. Sweeteners and flavoring agents, such as aspartame, sacchaπn, menthol, peppermint, and fruit flavors, are useful adjuvants for chewable tablets. Capsules (including time release and sustained release formulations) typically compnse 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 cπtical 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 earners 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, flavonng 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, polyvmylacetate 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 compnse one or more of soluble filler substances such as sucrose, sorbitol and manmtol; and binders such as acacia, microcrystallme cellulose, carboxymethyl cellulose and hydroxypropyl methyl cellulose. Ghdants, lubricants, sweeteners, colorants, antioxidants and flavoring agents disclosed above may also be included. The compounds of the present invention may also be topically administered. The earner of the topical composition preferably aids penetration of the present compounds into the skm to reach the environment of the hair follicle. Topical compositions of the present invention may be m any form including, for example, solutions, oils, creams, ointments, gels, lotions, shampoos, leave-on and rmse-out hair conditioners, milks, cleansers, moisturizers, sprays, sk patches, and the like. Topical compositions containing the active compound can be admixed with a variety of earner materials well known in the art, such as, for example, water, alcohols, aloe vera gel, allantom, glyceπne, vitamin A and E oils, mineral oil, propylene glycol, PPG-2 mynstyl propionate, and the like. Other materials suitable for use in topical carriers include, for example, emollients, solvents, humectants, thickeners and powders. Examples of each of these types of mateπals, which can be used singly or as mixtures of one or more mateπals, are as follows: Emollients, such as stearyl alcohol, glyceryl monoπcinoleate, glyceryl monostearate, propane- 1,2-dιol, butane-l,3-dιol, mink oil, cetyl alcohol, zso-propyl isostearate, steaπc acid, iso- butyl palmitate, isocetyl stearate, oleyl alcohol, isopropyl laurate, hexyl laurate, decyl oleate, octadecan-2-ol, isocetyl alcohol, cetyl palmitate, dimethylpolysiloxane, dι-«-butyl sebacate, isopropyl mynstate, zso-propyl palmitate, zso-propyl stearate, butyl stearate, polyethylene glycol, tnethylene glycol, lanolin, sesame oil, coconut oil, arachis oil, castor oil, acetylated lanolm alcohols, petroleum, mineral oil, butyl mynstate, lsosteanc acid, palmitic acid, isopropyl lmoleate, lauryl lactate, mynstyl lactate. decyl oleate, and mynstyl mynstate; propellants, such as propane, butane, z o-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- pyrrolιdone-5-carboxylate, soluble collagen, dibutyl phthalate, and gelatin; and powders, such as chalk, talc, fullers earth, kaolm, starch, gums, colloidal silicon dioxide, sodium polyacrylate, terra alkyl ammonium smectites, tπalkyl aryl ammonium smectites, chemically modified magnesium aluminium silicate, organically modified montmoπllonite clay, hydrated aluminium silicate, fumed silica, carboxyvmyl polymer, sodium carboxymethyl cellulose, and ethylene glycol monostearate. The compounds used m the present invention may also be administered in the form of hposome delivery systems, such as small unilamellar vesicles, large umlamellar vesicles, and multilamellar vesicles. Liposomes can be formed from a vaπety of phosphohpids, such as cholesterol, stearylamme or phosphatidylchohnes A preferred formulation for topical delivery of the present compounds utilizes liposomes such as described in Dowton et al.. "Influence of Liposomal Composition on Topical Delivery of Encapsulated Cyclosponn A: I. An in vitro Study Using Hairless Mouse Skin", S TP Pharma Sciences, Vol. 3, pp. 404 - 407 (1993); Wallach and Phi ppot. "New Type of Lipid Vesicle: Novasome ® ", Liposome Technology, Vol. 1, pp. 141 - 156 (1993); Wallach. U.S. Patent No. 4,911,928, assigned to Micro-Pak, Inc., issued March 27, 1990; and Werner et al.. U.S. Patent No. 5,834,014, assigned to The University of Michigan and Micro-Pak, Inc., issued November 10, 1998 (with respect to Werner et al., with a compound as described herein administered in lieu of, or in addition to, mmoxidil). The compounds of the present invention may also be administered by iontophoresis. See, e.g.. internet site www.unιpr.ιt a a dιpfarm erasmus/erasml4.html; Banga et al.. "Hydrogel-based Iontotherapeutic Delivery Devices for Transdermal Delivery of Peptide/Protem Drugs", Pharm Res , Vol. 10 (5), pp. 697-702 (1993), Ferry. "Theoretical Model of Iontophoresis Utilized m Transdermal Drug Delivery", Pharmaceutical Ada Helvetiae, Vol 70, pp. 279-287 (1995), Gangarosa et al.. "Modern Iontophoresis for Local Drug Delivery", Int J Pharm, Vol. 123, pp. 159-171 (1995), Green et al . "lontophoretic Delivery of a Series of Tπpeptides Across the Skm in vitro", Pharm Res , Vol 8, pp. 1 121-1127 (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 in Transdermal Iontophoresis", Pharm Res , Vol 14 (1), pp. 63-66 (1997); Santi et al.. "Reverse Iontophoresis - Parameters Determining Electroosmotic Flow: I. pH and Ionic Strength", J Control Release, Vol 38, pp. 159-165 (1996); Santi et al.. "Reverse Iontophoresis - Parameters Determining Electroosmotic Flow. π. Electrode Chamber Formulation", J Control Release, Vol. 42, pp. 29-36 (1996); Rao et al.. "Reverse Iontophoresis: Nonmvasive Glucose Momtonng 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 in the present invention may also optionally compnse 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-hmitmg examples of other hair growth stimulants which may be used in the compositions herein, including both systemic and topical compositions, include, for example, benzalkonium chlonde, benzethomum chlonde, phenol, estradiol, diphenhydramme hydrochloπde, chlorpheniramme maleate, chlorophylhn derivatives, cholesterol, salicylic acid, cysteme, methionme, red pepper tincture, benzyl mcotmate, D,L - menthol, peppermint oil, calcium pantothenate, panthenol, castor oil, hmokitiol, prednisolone, resorcmol, monosacchandes and estenfied monosacchandes, chemical activators of protein kmase C enzymes, glycosammoglycan chain cellular uptake inhibitors, inhibitors of glycosidase activity, glycosarmnoglycanase inhibitors, esters of pyroglutamic acid, hexosacchaπc acids or acylated hexosacchanc acids, aryl-substituted ethylenes, N-acylated ammo acids, and, of course, mmoxidil or fmasteπde. The most preferred activity enhancers are mmoxidil and fmasteride, 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-hydroxypropιonιc acid, 2-hydroxyoctanoιc acid, propan-1-ol, 1,4-dιoxane, tetrahydrofuran, butan-l,4-dιol, propylene glycol dipelargonate, polyoxypropylene 15 stearyl ether, octyl alcohol, POE ester of oleyl alcohol, oleyl alcohol, lauryl alcohol, dioctyl adipate, dicapryl adipate, di-isopropyl adipate, di-isopropyl sebacate, dibutyl sebacate, diethyl sebacate, dimethyl sebacate, dioctyl sebacate, dibutyl suberate, dioctyl azelate, dibenzyl sebacate, dibutyl phthalate, dibutyl azelate, ethyl mynstate, dimethyl azelate, butyl mynstate, dibutyl succmate, didecyl phthalate, decyl oleate, ethyl caproate, ethyl sahcylate, zso-propyl palmitate, ethyl laurate, 2-ethyl-hexyl pelargonate, zso-propyl isostearate, butyl laurate, benzyl benzoate, butyl benzoate, hexyl laurate, ethyl caprate, ethyl caprylate, butyl stearate, benzyl sahcylate, 2- hydroxypropanoic acid, 2-hyroxyoctanoιc acid, dimethyl sulphoxide, N,N-dιmethyl acetamide, N,N-dιmethyl formamide, 2-pyrrolιdone, l-methyl-2-pyrrohdone, 5-methyl-2-pyrrohdone, 1,5- dιmethyl-2-pynohdone, l-ethyl-2-pynolιdone, phosphme oxides, sugar esters, telrahydrofurfural alcohol, urea, dιethyl-m-toluamιde, and, l-dodecylazacyloheptan-2-one. In all of the foregoing, of course, the compounds used m 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, anestmg 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 suffering from male pattern baldness is treated by a method of this invention. Specifically, for 6 weeks, the above composition is daily administered topically to the subject. Example B A composition for topical administration is made according to the method of Dowton et al., "Influence of Liposomal Composition on Topical Delivery of Encapsulated Cyclosporm A: I. An in vitro Study Using Hairless Mouse Skm", S.T.P. Pharma Sciences. Vol. 3, pp. 404 - 407 (1993), using 3,5-dιbromo-4-(3-cyclohexyl-4-methoxyphenylsulfonyl)phenylacetιc acid in lieu of cyclosporm A and using the Novasome 1 for the non-ionic liposomal formulation. A human male subject suffering from male pattern baldness is treated each day with the above composition. Specifically, for 6 weeks, the above composition is administered topically to the subject. Example C A shampoo is made, comprising 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: Ri is -(CH 2 )n(CHNR 7 R 8 ) m C(O)R 9 ; n is an integer from 1 to 3; m is an integer from 0 to 1 ; R 3 and R 5 are each, independently, selected from the group consisting of chlorine, bromine, iodine, and -CH 3 ; R and Re are each, independently, selected from the group consisting of hydrogen and Ci - C 4 alkyl; Rg is selected from the group consisting of hydroxy, Ci - C 4 alkoxy, and - NR 7 R 8 ; R 31 is selected from the group consisting of hydrogen, chlorine, bromine, iodine, Ci - C 4 alkyl, C 4 - C & cycloalkyl, Ci - C 4 haloalkyl, C - C halocycloalkyl, and -CH(Rιo)Ar; Ar is selected from the group consisting of 5-hydroxypyrid-2-yl, 6- hydroxypyrid-3-yl, 6-hydroxypyridazin-3-yl, 6-methoxypyridazin-3-yl N-oxide, and 6-hydroxypyridazin-3-yl N-oxide; R 10 is selected from the group consisting of hydrogen and Ci - C alkyl; and R 41 is selected from the group consisting of hydroxy and Ci - C 4 alkoxy. 2. A method according to Claim 1 wherein: Ri is -(CH 2 ) n (CH 2 NH 2 ) rn C(0)R 9 ; n is an integer from 1 to 2; R 3 and R are each, independently, selected from the group consisting of chlorine, bromine, and iodine; R 9 is selected from the group consisting of hydroxy, Ci - C alkoxy, and NH 2 ; R 31 is selected from the group consisting of hydrogen, chlorine, bromine, iodine, C-i - C alkyl, C 4 - Cβ cycloalkyl, and -CH 2 Ar; and Ar is selected from the group consisting of 6-hydroxypyrid-3-yl, 6- hydroxypyridazin-3-yl, 6-methoxypyridazin-3-yl N-oxide, and 6-hydroxypyridazin- 3-yl N-oxide. 3. A method according to any of the preceding claims wherein: R 1 is selected from the group consisting of an alkanoic radical derived from an acid and an 2-aminoalkanoic acid radical derived from the acid, wherein the acid selected from the group consisting of acetic acid, propionic acid, 2- aminopropionic acid, and methyl- and ethyl- esters thereof; R 3 and R 5 are the same, and are selected from the group consisting of bromine and iodine; and R 31 is selected from the group consisting of iodine, isopropyl, cyclopentyl, cyclohexyl, and -CH 2 Ar; and R -i is selected from the group consisting of hydroxy, methoxy, and ethoxy. 4. A method according to any of the preceding claims wherein the compound is selected from the group consisting of: 3,5-dibromo-4-(4-hydroxy-3-iodophenylsulfonyl)phenylacetic acid; 3,5-dibromo-4-(3-iodo-4-methoxyphenylsulfonyl)phenylacetic acid; 3,5-dibromo-4-(4-hydroxy-3-(6-methoxypyridazin-3- ylmethyl)phenylsulfonyl)phenylacetic acid; 3,5-dibromo-4-(3-cyclohexyl-4-hydroxyphenylsulfonyl)phenylacetic acid; 3,5-dibromo-4-(3-cyclohexyl-4-methoxyphenylsulfonyl)phenylacetic acid; 3,5-dibromo-4-(3-cyclopentyl-4-hydroxyphenylsulfonyl)phenylacetic acid; 3-(3,5-dibromo-4-(4-hydroxy-3-/ ' so-propylphenylsulfonyl)phenyl)propionic acid; 2-amino-3-(3,5-dibromo-4-(4-hydroxy-3-/ ' so- propylphenylsulfonyl)phenyl)propionic acid; 3,5-dibromo-4-(4-hydroxy-(6-hydroxypyridazin-3- ylmethyl)phenylsulfonyl)phenylacetic acid; 3,5-dibromo-4-(4-hydroxy-3- so-propylphenylsulfonyl)phenylacetic acid; and 3,5-dibromo-4-(3-/so-propyl)-4-methoxyphenylsulfonyl)phenylacetic acid. 5. A method according to any of the preceding claims wherein the compound is selected from the group consisting of: 3,5-dibromo-4-(3-cyclohexyl-4-hydroxyphenylsulfonyl)phenylacetic acid; and 3,5-dibromo-4-(3-cyclohexyl-4-methoxyphenylsulfonyl)phenylacetic acid. 6. A method according to any of the preceding claims wherein the administration is topical. 7. A method according to any of claims 1 , 2, 3, 4, and 5 wherein the administration is oral. 8. A method according to any of claims 1 , 2, 3, 4, 5, and 6 wherein the composition further comprises minoxidil.

Inventors: YOUNGQUIST ROBERT SCOTT, ZHANG LILLY LI-XIN, YOUNGQUIST, ROBERT, SCOTT, ZHANG, LILLY, LI-XIN
Applicants: UNIV TEXAS SOUTHWESTERN MEDICA, YOUNGQUIST ROBERT SCOTT, ZHANG LILLY LI XIN, THE UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CENTER, YOUNGQUIST, ROBERT, SCOTT, ZHANG, LILLY, LI-XIN
Application year: 2000
Main classification: A61K7
IPC codes: A61K8, A61K31, A61P17, A61Q5, A61Q7