Abstract:
A method of inhibiting hirsutism or alopecia in women comprising administering to a female human in need of treatment an effective amount of a compound having the formula ##STR1## wherein R 1  and R 3  are independently hydrogen, --CH 3 , ##STR2## wherein Ar is optionally substituted phenyl; R 2  is selected from the group consisting of pyrrolidine, hexamethyleneamino, and piperidino; or a pharmaceutically acceptable salt of solvate thereof.

Description:
BACKGROUND OF THE INVENTION 
     Hirsutism (hypertrichosis) is characterized by excessive growth of hair. In women, hirsutism refers specifically to excessive growth of hair in a male pattern and distribution. Clinically, hirsutism in women is seen as a growth of terminal hair on the face (particularly on the upper lip), the chin, chest, back, and lower abdomen (escutcheon). This growth of hair is often seen as unsightly and can be the cause of embarrassment and psychological distress. Hirsutism is a common occurrence at the menopause, but can occur any time after puberty. The etiology of the condition has been linked to over production of androgens by either the ovaries or adrenal glands or both. 
     Hirsutism in women can be treated in a variety of ways. Cosmetic treatment of the condition, including shaving, plucking of hairs, and bleaching, while effective in improving the appearance of the patient, are only palliative and must be constantly re-applied. Glucocortacoid steroids are often effective; however, they have the potential of serious side-effects such as Cushing&#39;s Syndrome. Oral contraceptives can be effective; however, care must be taken because certain progestins used in common oral contraceptive regiments may actually contribute hirsutism because of their androgenic side-effects. Cimetidine and Spironolactone have shown some effectiveness in the treatment of hirsutism; howevers each of these can have unwanted side-effects. Clearly, a more effective and better tolerated agent would be useful. 
     Alopecia (hair loss) can occur in women for a variety of reasons, and includes female pattern alopecia. Female pattern alopecia is characterized by chronic and progressive hair loss often beginning around thirty years of age and accelerating at menopause. The hair loss is usually confined to the central scalp in a diffuse pattern. This loss of hair is cosmetically damaging and often psychologically disturbing to the patient. The etiology of the condition has been linked to an elevated level of androgens and the subsequent response of androgen sensitive hair follicles. Treatment of the condition is primarily cosmetic in nature, e.g., wigs, hair styles which cover the effected area, etc. The drug, Spironolactone, has been used, but does have side-effects. Clearly, an effective treatment for this condition would be useful. 
     SUMMARY OF THE INVENTION 
     This invention provides methods for inhibiting hirsutism or alopecia in women comprising administering to a female human in need of treatment an effective amount of a compound of formula I ##STR3## 
     wherein R 1  and R 3  are independently hydrogen, --CH 3 , ##STR4## wherein Ar is optionally substituted phenyl; 
     R 2  is selected from the group consisting of pyrrolidino, hexamethyleneimino, and piperidino; and pharmaceutically acceptable salts and solvates thereof. 
    
    
     DETAILED DESCRIPTION OF THE INVENTION 
     The current invention concerns the discovery that a select group of 2-phenyl-3-aroylbenzothiophenes (benzothiophenes), those of formula I, are useful for inhibiting alopecia or hirsutism in women. The methods of treatment provided by this invention are practiced by administering to a human in need a dose of a compound of formula I or a pharmaceutically acceptable salt or solvate thereof, that is effective to inhibit alopecia or hirsutism. The term inhibit is defined to include its generally accepted meaning which includes prophylactically treating a human subject to incurring a problem described, and holding in check and/or treating an existing problem. As such, the present method includes both medical therapeutic and/or prophylactic treatment, as appropriate. 
     Raloxifene, a compound of this invention wherein it is the hydrochloride salt of a compound of formula 1, R 1  and R 3  are hydrogen and R 2  is 1-piperidinyl, is a nuclear regulatory molecule. Raloxifene has been shown to bind to the estrogen receptor and was originally thought to be a molecule whose function and pharmacology was that of an anti-estrogen in that it blocked the ability of estrogen to activate uterine tissue and estrogen dependent breast cancers. Indeed, raloxifene does block the action of estrogen in some cells; however in other cell types, raloxifene activates the same genes as estrogen does and displays the same pharmacology, e.g., osteoporosis, hyperlipidemia. As a result, raloxifene has been referred to as an anti-estrogen with mixed agonist-antagonist properties. The unique profile which raloxifene displays and differs from that of estrogen is now thought to be due to the unique activation and/or suppression of various gene functions by the raloxifene-estrogen receptor complex as opposed to the activation and/or suppression of genes by the estrogen-estrogen receptor complex. Therefore, although raloxifene and estrogen utilize and compete for the same receptor, the pharmacological outcome from gene regulation of the two is not easily predicted and is unique to each. 
     Generally, the compound is formulated with common excipients, diluents or carriers, and compressed into tablets, or formulated as elixirs or solutions for convenient oral administration, or administered by the intramuscular or intravenous routes. The compounds can be administered transdermally, and may be formulated as sustained release dosage forms and the like. 
     The compounds used in the methods of the current invention can be made according to established procedures, such as those detailed in U.S. Pat. Nos. 4,133,814, 4,418,068, and 4,380,635 all of which are incorporated by reference herein. In general, the process starts with a benzo[b]thiophene having a 6-hydroxyl group and a 2-(4-hydroxyphenyl) group. The starting compound is protected, acylated, and deprotected to form the formula I compounds. Examples of the preparation of such compounds are provided in the U.S. patents discussed above. Substituted phenyl includes phenyl substituted once or twice with C 1  -C 6  alkyl, C 1  -C 4  alkoxy, hydroxy, nitro, chloro, fluoro, or tri(chloro or fluoro)methyl. 
     The compounds used in the methods of this invention form pharmaceutically acceptable acid and base addition salts with a wide variety of organic and inorganic acids and bases and include the physiologically acceptable salts which are often used in pharmaceutical chemistry. Such salts are also part of this invention. Typical inorganic acids used to form such salts include hydrochloric, hydrobromic, hydroiodic, nitric, sulfuric, phosphoric, hypophosphoric and the like. Salts derived from organic acids, such as aliphatic mono and dicarboxylic acids, phenyl substituted alkanoic acids, hydroxyalkanoic and hydroxyalkandioic acids, aromatic acids, aliphatic and aromatic sulfonic acids, may also be used. Such pharmaceutically acceptable salts thus include acetate, phenylacetate, trifluoroacetate, acrylate, ascorbate, benzoate, chlorobenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, methylbenzoate, o-acetoxybenzoate, naphthalene-2-benzoate, bromide, isobutyrate, phenylbutyrate, β-hydroxybutyrate, butyne-1,4-dioate, hexyne-1,4-dioate, caprate, caprylate, chloride, cinnamate, citrate, formate, fumarate, glycollate, heptanoate, hippurate, lactate, malate, maleate, hydroxymaleate, malonate, mandelate, mesylate, nicotinate, isonicotinate, nitrate, oxalate, phthalate, teraphthalate, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, propiolate, propionate, phenylpropionate, salicylate, sebacate, succinate, suberate, sulfate, bisulfate, pyrosulfate, sulfite, bisulfite, sulfonate, benzene-sulfonate, p-bromophenylsulfonate, chlorobenzenesulfonate, ethanesulfonate, 2-hydroxyethanesulfonate, methanesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, p-toluenesulfonate, xylenesulfonate, tartarate, and the like. A preferred salt is the hydrochloride salt. 
     The pharmaceutically acceptable acid addition salts are typically formed by reacting a compound of formula I with an equimolar or excess amount of acid. The reactants are generally combined in a mutual solvent such as diethyl ether or benzene. The salt normally precipitates out of solution within about one hour to 10 days and can be isolated by filtration or the solvent can be stripped off by conventional means. 
     Bases commonly used for formation of salts include ammonium hydroxide and alkali and alkaline earth metal hydroxides, carbonates, as well as aliphatic and primary, secondary and tertiary amines, aliphatic diamines. Bases especially useful in the preparation of addition salts include ammonium hydroxide, potassium carbonate, methylamine, diethylamine, ethylene diamine and cyclohexylamine. 
     The pharmaceutically acceptable salts generally have enhanced solubility characteristics compared to the compound from which they are derived, and thus are often more amenable to formulation as liquids or emulsions. 
     Pharmaceutical formulations can be prepared by procedures known in the art. For example, the compounds can be formulated with common excipients, diluents, or carriers, and formed into tablets, capsules, suspensions, powders, and the like. Examples of excipients, diluents, and carriers that are suitable for such formulations include the following: fillers and extenders such as starch, sugars, mannitol, and silicic derivatives; binding agents such as carboxymethyl cellulose and other cellulose derivatives, alginates, gelatin, and polyvinyl pyrrolidone; moisturizing agents such as glycerol; disintegrating agents such as calcium carbonate and sodium bicarbonate; agents for retarding dissolution such as paraffin; resorption accelerators such as quaternary ammonium compounds; surface active agents such as cetyl alcohol, glycerol monostearate; adsorptive carriers such as kaolin and bentonite; and lubricants such as talc, calcium and magnesium stearate, and solid polyethyl glycols. 
     The compounds can also be formulated as elixirs or solutions for convenient oral administration or as solutions appropriate for parenteral administration, for instance by intramuscular, subcutaneous or intravenous routes. Additionally, the compounds are well suited to formulation as sustained release dosage forms and the like. The formulations can be so constituted that they release the active ingredient only or preferably in a particular part of the intestinal tract, possibly over a period of time. The coatings, envelopes, and protective matrices may be made, for example, from polymeric substances or waxes. 
     The particular dosage of a compound of formula I required to inhibit alopecia or hirsutism, according to this invention will depend upon the severity of the condition, the route of administration, and related factors that will be decided by the attending physician. Generally, accepted and effective daily doses will be from about 0.1 to about 1000 mg/day, and more typically from about 50 to about 200 mg/day. Such dosages will be administered to a subject in need of treatment from once to about three times each day, or more often as needed to effectively treat the problem. 
     It is usually preferred to administer a compound of formula I in the form of an acid addition salt, as is customary in the administration of pharmaceuticals bearing a basic group, such as the piperidino ring. 
     Formulations 
     In the formulations which follow, &#34;Active ingredient&#34; means a compound of formula I. 
     
         ______________________________________Formulation 1: Gelatin CapsulesHard gelatin capsules are prepared using the following:Ingredient        Quantity (mg/capsule)______________________________________Active ingredient 0.1-1000Starch, NF        0-650Starch flowable powder             0-650Silicone fluid 350 centistokes             0-15______________________________________ 
    
     The ingredients are blended, passed through a No. 45 mesh U.S. sieve, and filled into hard gelatin capsules. 
     Examples of specific capsule formulations of raloxifene that have been made include those shown below: 
     
         ______________________________________Raloxifene capsuleIngredient        Quantity (mg/capsule)______________________________________Formulation 2:Raloxifene        1Starch, NF        112Starch flowable powder             225.3Silicone fluid 350 centistokes             1.7Formulation 3:Raloxifene        5Starch, NF        108Starch flowable powder             225.3Silicone fluid 350 centistokes             1.7Formulation 4:Raloxifene        10Starch, NF        103Starch flowable powder             225.3Silicone fluid 350 centistokes             1.7Formulation 5:Raloxifene        50Starch, NF        150Starch flowable powder             397Silicone fluid 350 centistokes             3.0______________________________________ 
    
     The specific formulations above may be changed in compliance with the reasonable variations provided. 
     A tablet formulation is prepared using the ingredients below: 
     
         ______________________________________Formulation 6: TabletsIngredient       Quantity (mg/tablet)______________________________________Active ingredient            0.1-1000Cellulose, microcrystalline            0-650Silicon dioxide, fumed            0-650Stearate acid    0-15______________________________________ 
    
     The components are blended and compressed to form tablets. 
     Alternatively, tablets each containing 0.1-1000 mg of active ingredient are made up as follows: 
     
         ______________________________________Formulation 7: TabletsIngredient          Quantity (mg/tablet)______________________________________Active ingredient   0.1-1000Starch              45Cellulose, microcrystalline               35Polyvinylpyrrolidone               4(as 10% solution in water)Sodium carboxymethyl cellulose               4.5Magnesium stearate  0.5Talc                1______________________________________ 
    
     The active ingredient, starch, and cellulose are passed through a No. 45 mesh U.S. sieve and mixed thoroughly. The solution of polyvinylpyrrolidone is mixed with the resultant powders which are then passed through a No. 14 mesh U.S. sieve. The granules so produced are dried at 50°-60° C. and passed through a No. 18 mesh U.S. sieve. The sodium carboxymethyl starch, magnesium stearate, and talc, previously passed through a No. 60 U.S. sieve, are then added to the granules which, after mixing, are compressed on a tablet machine to yield tablets. 
     Suspensions each containing 0.1-1000 mg of medicament per 5 mL dose are made as follows: 
     
         ______________________________________Formulation 8: SuspensionsIngredient           Quantity (mg/5 ml)______________________________________Active ingredient    0.1-1000 mgSodium carboxymethyl cellulose                50       mgSyrup                1.25     mgBenzoic acid solution                0.10     mLFlavor               q.v.Color                q.v.Purified water to    5        mL______________________________________ 
    
     The medicament is passed through a No. 45 mesh U.S. sieve and mixed with the sodium carboxymethyl cellulose and syrup to form a smooth paste. The benzoic acid solution, flavor, and color are diluted with some of the water and added, with stirring. Sufficient water is then added to produce the required volume. 
     The following compositions are prepared for topical application: 
     
         ______________________________________Ingredient           Quantity (mg/5 ml)______________________________________Formulation 9Hydroxypropylcellulose                1.5      gActive Ingredient    1.5-30   gIsopropanol qs       100      gFormulation 10Hydroxypropylcellulose                1.5      gEthyl lactate        15.0     gActive Ingredient    1.5-30   gIsopropanol qs       100      gFormulation 11Hydroxypropylcellulose                1.0      gButylated hydroxytoluene                0.02     gActive Ingredient    1.5-25   gEthanol qs           100      gFormulation 12Hydroxypropylcellulose                1.5      gButylated hydroxytoluene                0.01     gC.sub.8 -C.sub.12 fatty acid triglycerides                10.0     gActive Ingredient    1.5-30   gIsopropanol qs       100      g______________________________________ 
    
     Formulations 9-12 take the form of gels, and are intended for the topical treatment of acne. 
     
         ______________________________________Ingredient           Quantity (mg/5 ml)______________________________________Formulation 13Isopropanol          46.0     gActive Ingredient    1.0-15   gC.sub.8 -C.sub.12 fatty acid triglycerides                49.0     gFormulation 14Ethanol              69.0     gEthyl lactate        10.0     gActive Ingredient    1.5-20   gC.sub.8 -C.sub.12 fatty acid triglycerides                30.0     gFormulation 15Isopropanol          47.0     gAcetone              10.0     gEthyl lactate        10.0     gActive Ingredient    1-15     gC.sub.8 -C.sub.12 fatty acid triglycerides                30.0     gFormulation 16Ethanol              95.08    gButylated hydroxytoluene                0.02     gActive Ingredient    1.5-25   g______________________________________ 
    
     Formulations 13, 14, 15, and 16 take the form of lotions. 
     
         ______________________________________Ingredient          Quantity (mg/5 ml)______________________________________Formulation 17White vaseline      50.0     gLiquid paraffin     15.0     gRefined paraffin wax               32.0     gActive Ingredient   1-20     gFormulation 18White vaseline      50.0     gLiquid paraffin     13.0     gRefined paraffin wax               32.0     gActive Ingredient   1-20     g______________________________________ 
    
     Formulations 17 and 18 take the form of sticks. 
     TEST PROCEDURES 
     Hirsutism 
     Three to twenty women suffering from hirsutism are selected. These patients are initially scored for the extent and severity of hirsutism. The clinical evaluation is made by the methods described in the reference &#34;Methods of Skin Research,&#34; John Wiley and Sons, pp 308-318 (1985), and the references cited therein. The patients receive 10-400 mg of an active compound of this invention per day as a single or split dose by oral administration. Alternatively, they apply a 10%, by weight of active ingredient, creme or lotion once or twice a day to the affected areas. The patient continues this protocol for six months. At appropriate intervals, re-evaluation by one of the methods described above would be made. 
     Alopecia 
     Three to twenty women suffering from female pattern alopecia are selected. These patients are initially scored for the extent and severity of the alopecia. This clinical evaluation is made by the methods described in &#34;Methods of Skin Research,&#34; John Wiley and Sons, pp 308-318 (1985) and Habif, T., &#34;Clinical Dermatology,&#34; C. V. Mosby Co., Chapter 23, pp 493-504 (1985); and references therein, herein incorporated by reference. Especially helpful in these evaluations is the &#34;hair pluck&#34; procedure and measurement of anagen to telogen ratio. The patients receive 10-400 mg of an active compound of this invention per day as a single or split dose by oral administration. Alternatively, the patients apply a 5-10% (by weight of a compound of this invention) as a creme, lotion, or shampoo to the affected area, once to twice a day. This protocol continues for six months. At appropriate intervals, re-evaluation by one of the methods described in the above references is made. A positive result is exhibited by an increase in the anagen to telogen ratio or an increase in the number of terminal hairs in the affected scalp region. 
     Utility of the compounds of the invention is illustrated by the positive impact they have on one or more of the symptoms when used in a study as above.