MXPA06008439A - Androgen receptor modulators - Google Patents

Abstract

The present invention is directed to a new class of 4-oxo-benzonitriles, their use as androgen modulators, and to their use in the treatment of alopecia.

Description

MODULATORS OF ANDRÓGENOS RECEPTORS FIELD OF THE INVENTION The present invention relates to a new class of benzonitriles and their use as modulators of androgen receptors. Other aspects of the invention relate to the topical use of these compounds to alleviate alopecia and oily skin.

BACKGROUND OF THE INVENTION Alopecia, or baldness, is a common problem that medical science has not yet cured. The physiological mechanism by which hair loss occurs is unknown. However, it is known that hair growth is altered in individuals suffering from alopecia. Hair follicles experience activity cycles that involve periods of growth, rest and fall. The human scalp typically contains from 100,000 to 350,000 hair fibers or stems, which undergo metamorphosis in three distinct stages: (a) during the growth phase (anagen), the follicle (ie the hair root) penetrates deep into the dermis so that the cells of the follicle divide rapidly and differentiate in the process of synthesis of keratin, the predominant component of hair. In humans without baldness, this phase of growth lasts from one to five years; (b) the transition phase (catagen) is marked by the cessation of mitosis and lasts from two to several weeks, and; (c) the rest phase (telogen), where the hair stays on the scalp for up to 12 weeks, until it is displaced by the new follicular growth of the lower scalp.

In humans, this growth cycle is not synchronized. An individual will have thousands of follicles in each of these three phases. However, most hair follicles will be in the anagen phase. In healthy young adults, the ratio between anagen and telogen can be as high as 9 to 1. In individuals with alopecia, this ratio can be reduced to a value as low as 2: 1. Androgenic alopecia arises from the activation of an inherited sensitivity to androgenic hormones. It is the most common type of alopecia. It affects both men (50%) and women (30%), mainly of Caucasian origin. Gradual changes in the diameter and length of the capillary stem are experienced over time and with increasing age. The terminal hair gradually turns into short, fine, colorless and hairy hair. As a result, men in their 20s and women in their 30s and 40s begin to notice that their hair becomes thinner and shorter. In men, most of the hair loss occurs on the front and on the crown of the head. Women experience a fineness all over their scalp. As discussed above, the relationship between anagen and telogen is significantly reduced, resulting in less capillary growth. Minoxidil, a potassium channel opener, promotes hair growth. Minoxidil is available in the market in the United States under the trade name ROGAINE®. Although the exact mechanism of action of minoxidil is unknown, its impact on the hair growth cycle is well documented. Minoxidil promotes the growth of the hair follicle and increases the period of time during which the hair follicle is in the anagen phase (ie, increases the relationship between anagen and telogen). Although minoxidil promotes hair growth, the cosmetic efficacy of this growth can vary considerably. For example, Roenigk reported the results of a clinical trial that included 83 men who used a topical solution of 3% minoxidil over a period of 19 months. Hair growth occurred in 55% of the subjects. However, only 20% of the subjects considered growth to be cosmetically relevant (Clin Res., 33, No. 4, 914A, 1985). Tosti reported cosmetically acceptable re-growth in 18.1% of his subjects. (Dermatological, 173, No. 3,136-138,1986). Thus, the technique still requires compounds that have the ability to produce higher rates of cosmetically acceptable capillary growth in patients with alopecia.

SUMMARY OF THE INVENTION In accordance with the present invention, a new class of 4-oxo-benzonitriles has been discovered. These compounds and their pharmaceutically acceptable salts, hydrates and prodrugs thereof can be represented by the following formula: wherein: X1 is represented by halogen or haloalkyl; X2 is represented by -CR3R4R5, -CH = CH2 or -C = CH; each of R and R2 is independently represented by a substituent selected from the group consisting of hydrogen, halogen, C 1-6 alkyl, haloalkyl, hydroxyalkyl, thiol and thioalkyl; each of R3, R4 and R5 is independently represented by a substituent selected from the group consisting of hydrogen, halogen, C1-6 alkyl, haloalkyl, hydroxy, hydroxyalkyl, thiol, thioalkyl and -NR6R7; n is represented by the integer 0 or 1; ALK1 is represented by a C-rβ linear alkylene group, in which up to 8 hydrogen atoms of the alkylene group can be optionally replaced by a substituent selected from the group consisting of d-β alkyl, haloalkyl, halogen, hydroxy, hydroxyalkyl, thiol, thioalkyl and -NR6R7; each of R6 and R7 are independently represented by hydrogen or C6 alkyl with the proviso that: 1) if n is 0 and X2 is represented by -CH = CH2 or -C = CH, then at least one of R1 or R2 it is represented by thiol, hydroxyalkyl or thioalkyl; 2) if n is 1 and X2 is represented by -CH = CH2 or -C = CH, then in the alternative, at least one of R1 or R2 is represented by a substituent selected from the group consisting of thiol, hydroxyalkyl and thioalkyl or at least one hydrogen atom of Alk1 is replaced with a substituent selected from the group consisting of hydroxy, thiol, hydroxyalkyl and thioalkyl; 3) if n is 0 and X2 is represented by -CR3R4R 5, then, in the alternative, at least one of R1 or R2 is represented by a substituent selected from the group consisting of thiol, hydroxyalkyl and thioalkyl or at least one of R3 , R4 or R5 is represented by hydroxy, hydroxyalkyl, thiol or thioalkyl; 4) if n is 1 and X2 is represented by -CR3R4R 5, then alternatively: a) at least one of R1 or R2 is represented by a substituent selected from the group consisting of thiol, hydroxyalkyl and thioalkyl, b) at least one of R3, R4 or R5 is represented by a substituent selected from the group consisting of hydroxy, hydroxyalkyl, thiol and thioalkyl or c) at least one hydrogen atom of Alk1 is replaced with a substituent selected from the group consisting of hydroxy, thiol, thioalkyl and hydroxyalkyl. The compounds of Formula I are modulators of androgen receptors.

The compounds have affinity for the androgen receptor and will cause a biological effect by binding to the receptor. Typically, the compounds will act as antagonists. In the selected embodiments they will act as partial agonists, total agonists or selective tissue agonists. As modulators of androgen receptors, the compounds can be used to treat or alleviate conditions associated with inappropriate activation of the androgen receptor. Examples of such conditions for antagonists include, but are not limited to, acne, excess sebum secretion, androgenic alopecia, hormone-dependent cancers such as prostate cancer and hirsutism. Compounds that are partial agonists, total agonists or selective tissue agonists can be used to treat osteoporosis, hypogonadism, anemia or to stimulate the increase of muscle mass, especially in debilitating diseases. The invention also relates to pharmaceutical compositions containing at least one of the compounds of Formula I, in an amount effective to modulate the activation of the androgen receptor. In a further embodiment, the invention relates to an article of manufacture containing a compound of Formula I, packaged for retail distribution, together with instructions advising the consumer on how to use the compound to alleviate a condition associated with activation. inappropriate androgen receptor. A further embodiment relates to the use of a compound of Formula I as a diagnostic agent to detect inappropriate activation of the androgen receptor.

In a further embodiment, the compounds of Formula I are used topically to induce and / or stimulate hair growth and / or to slow hair loss. The compounds can also be used topically in the treatment of excess sebum and / or acne.

DETAILED DESCRIPTION OF THE INVENTION The headings in this document are only used to facilitate their analysis by the reader. They should not be construed as limiting the invention or the claims in any way.

Definitions and Illustration As used throughout this application, including the claims, the following terms have the meanings defined below, unless otherwise specifically indicated. The plural and the singular must be treated indistinctly, different from the indication of the number: a. "halogen" refers to a chlorine, fluorine or bromine atom. b. "C6 alkyl" refers to a straight or branched chain alkyl group containing from 1 to 6 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, / 7-butyl, isobutyl, pentyl, hexyl, etc. . c. "haloalkyl" refers to a straight or branched chain alkyl group containing from 1 to 6 carbon atoms, wherein at least one hydrogen atom is replaced with a halogen (i.e. haloalkyl Ci-Ce). Examples of suitable haloalkyls include chloromethyl, difluoromethyl, trifluoromethyl, 1-fluoro-2-chloro-ethyl, 5-fluoro-hexyl, 3-difluoro-isopropyl, 3-chloro-isobutyl, etc. d. "hydroxyalkyl" refers to a straight or branched chain alkyl group containing from 1 to 6 carbon atoms where at least one hydrogen atom is replaced with a hydroxy function (ie hydroxyalkyl CrC6). Examples of suitable hydroxyalkyls include hydroxymethyl, 1,2-dihydroxy-propyl, 1-hydroxy-pentyl, 6-hydroxy-hexyl, 2-hydroxy-ethyl, etc. and. "thioalkyl" refers to a straight or branched chain alkyl group containing from 1 to 6 carbon atoms where at least one hydrogen atom is replaced with a sulfhydryl group (i.e. -SH). Examples of suitable thioalkyls include methylmercaptan, 2-thiol-ethyl, 1,3-dithiol-propyl, 6-thiol-hexyl, 4-thiol-pentyl, etc. F. "linear alkylene group containing from 1 to 8 carbon atoms" refers to an alkyl group containing from 1 to 8 carbon atoms which serves as a linker group in the molecule (ie, non-terminal -CH3 function). Examples of such alkyl groups include -CH2-, -CH2- (CH2) 4 -CH2-, -CH2- (CH2) 6 -CH2-, -CH2-CH2-CH2-, -CH2- (CH2) 2 -CH2 -, etc. g. "solvate" is a crystalline form of a compound or salt thereof, which contains one or more solvent molecules of crystallization, ie, a compound of Formula I or a salt thereof, which contains the combined solvent in the molecular form. A "hydrate" is a solvate in which the solvent is water. h. "Polymorph" is a compound or salt thereof, such as the compound of Formula I or a salt thereof, which is produced in at least one crystalline form. i. "androgens" refers to testosterone and its particular precursors and metabolites, and to reduced 5-alpha androgens, including but not limited to dihydrotestosterone. Androgens refers to androgens of the testes, adrenal gland and ovaries, as well as to all forms of natural, synthetic and substituted or modified androgens. j. "pharmaceutically acceptable salts" is intended to refer to "pharmaceutically acceptable acid addition salts" or "pharmaceutically acceptable base addition salts" depending on the actual structure of the compound. k. "Pharmaceutically acceptable acid addition salts" is intended to be applied to any addition salt of non-toxic organic or inorganic acids of the base compounds represented by Formula I or any of their intermediates. Illustrative inorganic acids which form suitable salts include hydrochloric, hydrobromic, sulfuric and phosphoric acid and acid metal salts such as sodium monohydrogen orthophosphate and potassium hydrogen sulfate. Illustrative organic acids, which form suitable salts include the mono-, di- and tricarboxylic acids. Illustrative of such acids are for example, acetic, glycolic, lactic, pyruvic, malonic, succinic, glutaric, fumaric, malic, tartaric, citric, ascorbic, maleic, hydroxymaleic, benzoic, hydroxy-benzoic, phenylacetic, cinnamic, salicyclic , 2-phenoxybenzoic acid, p-toluenesulfonic acid and sulfonic acids such as methanesulfonic acid and 2-hydroxyethanesulfonic acid. Such salts may exist in hydrated or substantially anhydrous form. In general, the acid addition salts of these compounds are soluble in water and in various organic hydrophilic solvents. I. "Pharmaceutically acceptable basic addition salts" is intended to be applied to any non-toxic organic or inorganic basic addition salt of the compounds represented by Formula I, or any of their intermediates. Illustrative bases which form suitable salts include alkali metal or alkaline earth metal hydroxides such as sodium, potassium, calcium, magnesium or barium hydroxides.; ammonia, and aliphatic, alicyclic or aromatic organic amines such as methylamine, dimethylamine, trimethylamine and picoline. m. "prodrug" refers to compounds that are readily transformed in vivo to produce the parent compound of the above formulas, for example, by hydrolysis in blood. A thorough analysis is provided in T. Higuchi and V. Stella, "Pro-drugs as Novel Delivery Systems", Vol. 14 of A.C.S. Symposium Series and in Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987, both incorporated herein by reference. n. "compound of Formula I", "compounds of the invention" and "compounds" are used interchangeably throughout the application and should be treated as synonyms. or. "patient" refers to warm-blooded animals such as, for example, guinea pigs, mice, rats, gerbils, cats, rabbits, dogs, monkeys, chimpanzees, stump macaques and humans. p. "treating" refers to the ability of the compounds to dissipate, alleviate or slow down the progress of the disease (or condition) of the patient or of any tissue injury associated with the disease. Some of the compounds of Formula I will exist in the form of optical isomers. Any reference in this application to one of the compounds represented by Formula I is intended to encompass a specific optical isomer or a mixture of optical isomers (unless expressly excluded). The specific optical isomers can be separated and recovered by techniques known in the art such as chromatography on chiral stationary phases or resolution by chiral salt formation and subsequent separation by selective crystallization. Alternatively, the use of a specific optical isomer as the starting material will produce the corresponding isomer in the form of the final product.

In addition, the compounds of the present invention can exist in unsolvated form as well as in solvated form with pharmaceutically acceptable solvents such as water, ethanol and the like. In general, solvated forms are considered equivalent to unsolvated forms for the purposes of the present invention. A compound may also exist in different polymorphic forms and the claims should be construed as covering all of these forms. All compounds of formula I contain a phenyl ring. To further illustrate the invention, the numbering system of this ring and its substitution pattern are shown below: The 1-position of this phenyl ring will always be replaced with a cyano residue as represented above. Position 4 will be replaced with an oxygen atom that forms an ether residue. The phenyl ring will be further substituted, as represented by X1, in the 2 or 3 position with a halogen atom or with a haloalkyl radical. Typically, this halogen or haloalkyl moiety will be in the 2-position. More typically, it will be trifluoroalkyl, which is in the 2-position of the phenyl ring. As indicated above, the 4-position of the phenyl ring is replaced with an ether residue, which always includes: - (CR1R2) - (ALK1) n-X2. ALK1, when present, represents a linear alkylene moiety of chain Ci to Ce, such as methylene, ethylene, propylene, butylene, pentylene, hexylene, heptylene or octylene. Up to 8 hydrogen atoms of this alkylene moiety can be replaced with one of the substituents defined above. Any individual carbon atom of Alk1 may be unsubstituted, monosubstituted or disubstituted. These carbon atoms can be substituted with the same substituent or with different substituents. The ether - (CR1R2) - (ALK1) n -X2 moiety will be substituted with at least one hydroxy, thiol, hydroxyalkyl or thioalkyl moiety. This can be done by one of two alternative substitution patterns (depending on the presence or absence of Alk1). If Alk1 is not present in the molecule (ie, n is 0), then one of R3, R4 or R5 can be represented by hydroxy, hydroxyalkyl, thiol or thioalkyl, or one of R1 or R2 can be represented by hydroxyalkyl, thiol or thioalkyl . If Alk1 is present (ie, n is 1), then alternatively: a) one of R3, R4 or R5 may be represented by hydroxy, hydroxyalkyl, thiol or thioalkyl, b) one of R1 or R2 may be represented by hydroxyalkyl , thiol or thioalkyl, or c), one of the carbon atoms of Alkl may be substituted with hydroxy, hydroxyalkyl, thiol or thioalkyl. This requirement that the molecule contain a hydroxy or thiol function should not be construed as limiting the molecule to a single hydroxy or thiol moiety. If desired, the ether moiety - (CR1R2) - (ALK1) n -X2 may contain multiple hydroxy, hydroxyalkyl, thioalkyl and thiol functions consistent with the substitution pattern described above. In another optional embodiment of the invention, for compounds wherein X2 is CR3R4R5 and n is 0; at least one of R1, R2, R3, R4 or R5 is represented by C6 alkyl, haloalkyl, thioalkyl or hydroxyalkyl (ie the ether residue -CR1R2- (Alk1) n-X2, is branched alkyl). In a further optional embodiment, for the compounds wherein X2 is CR3R4R5 and n is 1; at least one of R1, R2, R3, R4 or R5 is represented by CrC6 alkyl, haloalkyl, thioalkyl or hydroxyalkyl or alternatively a hydrogen atom of Alk1 is replaced with a substituent selected from the group consisting of C? -C6 alkyl, haloalkyl, thioalkyl or hydroxyalkyl (i.e., the ether moiety -CR1R2- (Alk1) n-X2, is branched alkyl). The more specific embodiments of the invention relate to compounds of Formula I wherein: 1) X1 is CF3 and is at the 2-position of the phenyl ring and X2 is CR3R4R5, where one of R3, R4 or R5 is hydroxy; 2) X1 is Cl and is at position 2 of the phenyl ring and X2 is CR3R4R5, where one of R3, R4 or R5 is hydroxy; 3) X1 is CF3 and is in the 2-position of the phenyl ring, R1 is hydrogen and R2 is CrC6 alkyl, n is 1 where Alk1 is methylene, ethylene, propylene or butylenes, X2 is -CR3R4R5, where R3 is hydrogen or alkyl C? -C6, R4 is hydrogen or C1-C6 alkyl and R5 is hydroxy; 4) X1 is CF3 and is in the 2-position of the phenyl ring, R is hydrogen or Ci-Cß alkyl, R2 is hydrogen, n is 0 and X2 is CR3R4R 5, where R3 is hydroxy or hydroxylalkyl, R4 is hydrogen or alkyl C Cß and R5 is hydrogen; or 5) X1 is CF3 or Cl and is in the 2-position of the phenyl ring, each of R1 and R2 is hydrogen, n is 1 where Alk1 is methylene, ethylene, propylene or butylene, which is substituted with 1 to 3 substituents independently selected from hydroxy, hydroxyalkyl or C-? -C6 alkyl and X2 is CR3R4R5, where R3 is hydrogen or hydroxy and each of R4 and R5 are hydrogen or C-? -C6 alkyl. More specific examples of compounds encompassed by Formula I include: i) 4- (2-hydroxy-1-ethyl-propoxy) -2-trifluoromethyl-benzonitrile; ii) 4- (2-hydroxy-1-methyl-propoxy) -2-trifluoromethyl-benzonitrile; iii) 4- (3-hydroxy-1-methy1-butoxy) -2-trifluoromethyl-benzonitrile; V) 4- (2-hydroxy-6-methyl-heptyloxy) -2-trifluoromethyl-benzonitrile; v) 4- (2-hydroxy-7-hydroxy-heptyloxy) -2-trifluoromethyl-benzonitrile; vi) 4- (2-hydroxy-octyloxy) -2-trifluoromethyl-benzonitrile; vii) 4- (2-hydroxy-8-hydroxy-8-methyl-octyloxy) -2-trifluoromethyl-benzonitrile; viii) 4- (2-hydroxy-oct-7-enyloxy) -2-trifluoromethyl-benzonitrile; X) 4- (2-hydroxy-oct-7-phenyl) -2-trifluoromethyl-benzonitrile; x) 4- (2-ethyl-3-Hydroxy-butoxy) -2-trifluoromethyl-benzonitrile; xi) 4- (3-hydroxy-butoxy) -2-trifluoromethyl-benzonitrile; x!) 4- (3-hydroxy-hex-5-en-loxy) -2-trifluoromethyl-benzonitrile; xiii) 4- (3-hydroxy-hex-5-ynyloxy) -2-trifluoromethyl-benzonitrile; xiv) 4- (3-hydroxy-2-methyl-butoxy) -2-trifluoromethyl-benzonitrile; xv) 4- (3-hydroxy-2-propyl-butoxy) -2-trifluoromethyl-benzonitrile; xvi) 4- (3-hydroxy-2,2-dimethyl-propoxy) -2-trifluoromethyl-benzonitrile; xvii) 4- (3-hydroxy-3-methy1-butoxy) -2-trifluoromethyl-benzonitrile; xviii) 4- (4-hydroxy-3-methy1-pentoxy) -2-trifluoromethyl-benzonitrile; xix) 4- (3-hydroxy-2,2,4-triamethyl-pentyloxy) -2-trifluoromethyl-benzonitrile; xx) 4- (2-ethyl-3-hydroxy-hexyloxy) -2-trifluoromethyl-benzonitrile; xxi) 4- [2- (1-hydroxy-ethyl) -hexyloxy] -2-trifluoromethyl-benzonitrile; xxii) 4- (3-hydroxy-1-methyl-butoxy) -2-trifluoromethyl-benzonitrile; xxiii) 4- (3-hydroxy-1-methyl-2-ethyl-butoxy) -2-trifluoromethyl-benzonitrile; xxiv) 4- (4-hydroxy-butoxy) -2-trifluoromethyl-benzonitrile; xxv) 4- (6-hydroxy-heptoxy) -2-trifluoromethyl-benzonitrile; xxvi) 4- (4-Hydroxy-heptyloxy) -2-trifluoromethyl-benzonitrile; xxvii) 4- (4-hydroxy-1-propyl-butoxy) -2-trifluoromethyl-benzonitrile; xxviii) 4- (4-hydroxy-1-methyl-pentyloxy) -2-trifluoromethyl-benzonitrile; xxix) 4- (5-hydroxy-pentyloxy) -2-trifluoromethyl-benzonitrile; xxx) 4- (5-hydroxy-hexyloxy) -2-trifluoromethyl-benzonitrile; xxxi) 4- (5-hydroxy-3-methyl-pentyloxy) -2-trifluoromethyl-benzonitrile; xxxii) 2-chloro-4- (3-hydroxy-2,2,4-triamethyl-pentyloxy) -benzonitrile; xxxiii) 2-chloro-4- (4-hydroxy-butoxy) -benzonitrile; xxxiv) 2-chloro-4- (3-hydroxy-propoxy) -benzonitrile; xxxv) 2-chloro-4- (1-hydroxymethyl-allyloxy) -benzonitrile; xxxvi) 2-chloro-4- (1-hydroxymethyl-acetyleneoxy) -benzonitrile; xxxv) 2-chloro-4- (3-hydroxy-2-methyl-propoxy) -benzontromethyl; xxxviii) 2-chloro-4- (5-hydroxy-pexytyloxy) -benzontromile; xxxix) 2-chloro-4- (4-hydroxy-1-methyl-pent-loxy) -benzontromile; or xl) 2-chloro-4- (5-hydroxy-3-methyl-pentyloxy) -benzonitrile.

Synthesis The compounds of Formula I can be prepared using procedures analogous to those known in the art for the preparation of ethers. The reader's attention is directed to European Patent Application Number 58932, published on September 1, 1982, the contents of which are incorporated herein by reference for a description of such reactions. The following Scheme I provides an overview of one such technique: SCHEME I H Nucleophilic substitution NaH / 0 ° CenTHF As depicted above, one of the starting materials is an alcohol as represented by structure 1. R1, R2, Alk1 and X2 must be represented by the same substituent as is desired in the final product. These alcohols are known in the art and can be purchased from known commercial sources. Alternatively, they can be prepared as described in Tetrahedron: Asymmetry, 1991 Vol. 2, page 569. The other starting material is a 4-fluoro-benzonitrile as represented by structure 2. X1 must be represented by the same substituent as you want in the final product. These benzonitriles are known in the art and can be synthesized as described in Japanese Patent Application Number 01097937. The nucleophilic substitution depicted above can be performed as is known in the art. The alcohol of structure 1 is contacted with a slight excess of a base, such as sodium hydride, to produce an alkoxide ion. The reaction is carried out in an aprotic solvent, such as tetrahydrofuran, in an inert atmosphere (typically nitrogen) at a temperature of about 0 ° C. The alcohol is stirred with the base for a period of time ranging from 5 to 60 minutes. Then, an equivalent of the 4-fluoro-benzonitrile of structure 2 is added to the reaction medium and the reactants are stirred for a sufficient period of time to allow the alkoxide ion to displace the fluorine of the benzonitrile. This typically takes 30 minutes to 24 hours. Typically, the reaction e is allowed to warm to room temperature. The desired product of Formula I can be recovered by extraction, evaporation or other techniques known in the art. Then, it can optionally be purified by chromatography, recrystallization, distillation or other techniques known in the art.

As will be appreciated by those skilled in the art, some of the methods useful for the preparation of such compounds, as discussed above, may require the protection of a particular functionality, for example, to prevent interference by such functionality in reactions in others. sites within the molecule or to preserve the integrity of such functionality. The need for, and the type of, such protection is readily determined by a person skilled in the art, and will vary depending on, for example, the nature of the functionality and the conditions of the selected preparation process. See, for example, T.W. Greene, Protective Groups ¡n Organic Svnthesis. John Wiley and Sons, New York, 1991. Some of the compounds of this invention are acidic and form salts with a pharmaceutically acceptable cation. Some of the compounds of this invention are basic and form salts with pharmaceutically acceptable anions. All these salts are within the scope of this invention and can be prepared by conventional methods such as combining the acidic and basic entities, usually in a stoichiometric ratio, in an aqueous, non-aqueous or partially aqueous medium, as appropriate. The salts are recovered by filtration, by precipitation with a non-solvent followed by filtration, by evaporation of the solvent or, in the case of aqueous solutions, by lyophilization, as appropriate. The compounds are obtained in crystalline form according to procedures known in the art, such as by dissolution in an appropriate solvent (s) such as ethanol, hexanes or water / ethanol mixtures.

Medical and Cosmetic Uses The compounds of Formula I are modulators of androgen receptors.

They can be used to alleviate conditions associated with the inappropriate activation of the androgen receptor. Compounds that act as androgen antagonists can be used to treat or alleviate hormone-dependent cancers such as prostate carcinomas, benign prostatic hyperplasia, acne, hirsutism, excess sebum, alopecia, hypertrichosis, precocious puberty, prostatomegaly, virilization and polycystic ovary syndrome. Compounds that act as partial agonists, or total agonists, can be used to treat or alleviate male hypogonadism, male sexual dysfunction (impotence, male disespermatatogenic sterility), abnormal sexual differentiation (male hermaphroditism), delayed male puberty, male infertility, aplastic anemia , hemolytic anemia, sickle cell anemia, idiopathic thrombocytopenic purpura, myelofibrosis, renal anemia, debilitating diseases (post-operative, malignant tumor, trauma, chronic kidney disease, burns or AIDS-induced), elimination of pain in terminal genital carcinoma female, non-operable breast cancer, mastopathy, endometriosis, female sexual dysfunction, osteoporosis, wound healing and repair of muscle tissue. In order to show the therapeutic properties described above, the compounds need to be administered in an amount sufficient to modulate the activation of androgen receptors. This amount may vary depending on the particular disease / condition being treated, the severity of the disease / condition of the patient, the patient, the particular compound to be administered, the route of administration and the presence of other underlying disease states in the patient, etc. When administered systemically, the compounds typically exhibit their effect in a dosage range of about 0.1 mg / kg / day to about 100 mg / kg / day for any of the diseases or conditions indicated above. Repeated daily administration may be desired and this will vary according to the conditions indicated above. The compounds of the present invention can be administered by various routes. They are effective if they are administered orally. The compounds can also be administered parenterally (i.e., subcutaneously, intravenously, intramuscularly, intraperitoneally or intrathecally), rectally or topically. In a typical embodiment, the compounds are administered topically. Topical administration is especially appropriate for hirsutism, alopecia, acne and excess sebum. The dose will vary, but as a general guideline, the compound will be present in a dermatologically acceptable vehicle in an amount of from about 0.01 to 50% w / w and more typically from about 0.1 to 10% w / w. The dermatological preparation will be applied to the affected area from 1 to 4 times a day. "Dermatologically acceptable" refers to a vehicle that can be applied to the skin or hair, and which will allow the drug to spread to the site of action. More specifically, it refers to the site where the inhibition of the activation of an androgen receptor is desired. In a further embodiment, the compounds are used topically to alleviate alopecia, especially androgenic alopecia. Androgens have a great effect on both hair growth and hair loss. In most parts of the body, such as the beard and pubic skin, androgens stimulate hair growth by prolonging the growth phase of the capillary cycle (anagen) and increasing follicular size. Hair growth in the scalp does not require androgens but, paradoxically, androgens are necessary for baldness in the scalp in genetically predisposed individuals (androgenic alopecia) where there is a progressive decrease in the duration of anagen and in the size of the hair follicle . Androgenic alopecia is also common in women where it usually occurs in the form of diffuse capillary loss rather than showing the pattern observed in men. Although the compounds will be used more typically to alleviate androgenic alopecia, the invention is not limited to this specific condition. The compounds can be used to alleviate any type of alopecia. Examples of non-androgenic alopecia include alopecia areata, alopecia due to radiotherapy or chemotherapy, scar alopecia, stress related alopecia, etc. As used in this application, "alopecia" refers to the partial or complete loss of hair on the scalp. In this way, the compounds can be applied topically on the scalp and on the hair to prevent or alleviate baldness. In addition, the compound can be applied topically to induce or promote the growth of hair on the scalp. In a further embodiment of the invention, a compound of Formula I is applied topically in order to prevent hair growth in areas where such hair growth is not desired. One of these uses will be to relieve hirsutism. Hirsutism is excessive hair growth in areas that typically do not have hair (that is, on a woman's face). Such inappropriate hair growth occurs most commonly in women and is frequently observed at menopause. Topical administration of the compounds will alleviate this condition leading to a reduction or elimination of this inappropriate or unwanted hair growth. The compounds can also be used topically to decrease sebum production and more specifically to relieve oily skin. Also, the compounds can be used topically to relieve acne. In a further embodiment, compounds that act as partial agonists, or total agonists, can be used to treat or alleviate osteoporosis. Osteoporosis is characterized by the loss of bone mass, resulting in an imbalance between bone resorption (destruction) and bone formation, which begins in the fourth decade and continues throughout life at a rate of approximately 1- 4% per year (Eastell, Treatment of postmenopausal osteoporosis, New Eng., J. Med. 338: 736, 1998). In the United States, there are currently approximately 20 million people with detectable fractures of the vertebrae due to osteoporosis. further, there are approximately 250,000 hip fractures a year due to osteoporosis, associated with a mortality rate of 12% -20% in the first two years, while 30% of patients require healthcare at home after the fracture and many never become completely ambulatory again. In postmenopausal women, the lack of estrogen leads to increased bone resorption, causing bone loss in the vertebrae of about 5% per year, immediately after menopause. In this way, the first line of treatment / prevention of this condition is the inhibition of bone resorption by bisphosphonates, estrogens, selective modulators of estrogen receptors (SERM) and calcitonin. However, inhibitors of bone resorption are not sufficient to restore bone mass for patients who have already lost a significant amount of bone. The increase in spinal BMD achieved by bisphosphonate therapy can reach 11% after 7 years of treatment with alendronate. In addition, as the bone turnover rate differs from one site to another; It is higher in the trabecular bone of the vertebrae than in the cortex of the long bones, inhibitors of bone resorption are less effective in increasing BMP of the hip and in the prevention of hip fractures. Therefore, osteoanabolic agents, which increase the formation of cortical / periosteal bone and bone mass in long bones, will address an unmet need in the treatment of osteoporosis especially for patients with a high risk of hip fractures. Several studies show that androgens are osteoanabolic in women and men. It has been shown that anabolic steroids, such as nandrolone decanoate or stanozolol, increase bone mass in postmenopausal women. The beneficial effects of androgens on bone in post-menopausal osteoporosis have been well documented in recent studies using the combined administration of testosterone and estrogens (Hofbauer, et al., Androgen effects on bone metabolism: recent progress and controversies, Eur. J. Endocrinol, 140, 271-286, 1999). In this manner, compounds of Formula I that exhibit agonist or partial agonist activity can be used to treat or alleviate osteoporosis, including primary osteoporosis such as senile, postmenopausal and juvenile osteoporosis, as well as secondary osteoporosis, such as osteoporosis due to hyperthyroidism or Cushing's syndrome (due to corticosteroid treatment), acromegaly, hypogonadism, dysosteogenesis, and hypophosphatasemia. Other indications related to reformable bones for treatment from androgen agonists include osteoporotic fracture, loss of dioptase bone mass in childhood, alveolar bone loss, mandibular bone loss, bone fracture, osteotomy, periodontitis or bone growth in prostheses. Compounds that act as agonists or partial agonists can also be used to stimulate muscle mass in patients suffering from debilitating diseases, such as AIDS, cancerous cachexia, burns, kidney disease, etc. Patients suffering from trauma, decubitus ulcer, age, etc. They can also benefit from the anabolic effects of androgens.

Co-administration In a further embodiment of the invention, the compounds of Formula I can be co-administered with other compounds to improve their activity, or to minimize potential side effects. For example, it is known that potassium channel openers, such as minoxidil, stimulate capillary growth and induce anagen. Examples of other potassium channel openers include (3S, 4R) -3,4-dihydro-4- (2,3-dihydro-2-methyl-3-oxopyridazin-6-yl) oxy-3 -hydroxy-6- (3-hydroxyphenyl) sulfonyl-2,2,3-trimethyl-2-benzo [b] pyran, diaxozide and PO 1075 which is being developed by Leo Pharmaceuticals. It is also known that thyroid hormone stimulates hair growth. It has also been shown that synthetic replacements of thyroid hormone (ie, thyromimetics) stimulate hair growth. Such thyromimetics have been described previously in the literature. The reader's attention is directed to European Patent Application Number 1262177, the contents of which are incorporated herein by reference, for an analysis of such compounds and for their use to alleviate alopecia. A particular compound of interest is 2-. { 4- [3- (4-fluoro-benzyl) -4-hydroxy-phenoxy] -3,5-dimethyl-phenyl) -2H- [1, 2,4] triazine-3,5-dione. Anti-androgens can function through several different mechanisms. For example, some compounds block the conversion of testosterone to 5-a-dihydrotestosterone, which is responsible for the biological effect in many tissues. It has been shown that 5-alpha-reductase inhibitors, such as finasteride, stimulate hair growth. Finasteride is available commercially from Merck under the trade name Propecia®. Examples of other 5-a-reductase inhibitors include dutasteride (Glaxo Smithkline). Such compounds may be coadministered with the compounds of Formula I to alleviate alopecia. It has also been shown that inhibitors of protein kinase C stimulate capillary growth and induce anagen. It has been shown that calfostin C, which is a selective inhibitor of protein kinase C, induces the anagen phase. It has also been shown that other selective inhibitors of protein kinase C, such as hexadecylphosphocholine, palmitoyl-DL-carnitine chloride and polymyxin B sulfate induce anagen. Skin Pharmacol Appl Skin Physiol 2000 May-August; 13 (3-4): 133-42. Any protein kinase C inhibitor can be coadministered with a compound of Formula I to alleviate alopecia. Immunophilins are a family of cytoplasmic proteins. Its ligands include cyclosporin, FK506 and rapamycin. They are derived from fungi and were developed mainly because of their potent immunosuppressive properties. Cyclosporin binds to the protein, cyclophilin, while FK506 and rapamycin bind to the FK binding protein (FKBP). It has been shown that all these compounds stimulate capillary growth and induce anagen. Any immunophilin ligand of that type can be co-administered with a compound of Formula I to alleviate alopecia.

As used in this application, co-administered refers to administering a compound of Formula I with a second anti-alopecia agent, which typically has a different mechanism of action, using a dosage regimen that promotes capillary growth in the patient. This can refer to simultaneous dosing, dosing in different periods of time during a single day or even dosing on different days. The compounds can be administered separately or can be combined in a single formulation. The techniques for preparing such formulations are described below.

Formulations If desired, the compounds can be administered directly without any vehicle. However, to facilitate administration, they will typically be formulated in pharmaceutical vehicles. Likewise, they will typically be formulated in dermatological or cosmetic vehicles. In this application, the terms "dermatological vehicle" and "cosmetic vehicle" are used interchangeably. They refer to formulations designed to be administered directly to the skin or hair. The pharmaceutical and cosmetic compositions can be manufactured using techniques known in the art. Typically, an effective amount of a compound will be mixed with a pharmaceutical / cosmetically acceptable vehicle. For oral administration, the compounds can be formulated into solid or liquid preparations such as capsules, pills, tablets, dragees, melts, powders, suspensions or emulsions. The solid unit dosage forms can be conventional gelatin-type capsules containing, for example, surfactants, lubricants and inert fillers such as lactose, sucrose and corn starch or can be sustained release preparations. In another embodiment, the compounds of Formula I can be compressed with conventional tablet bases such as lactose, sucrose and corn starch together with binders, such as gum arabic, corn starch or gelatin, disintegrating agents such as potato starch or alginic acid. and a lubricant such as stearic acid or magnesium stearate. Liquid preparations are prepared by dissolving the active ingredient in an aqueous or non-aqueous pharmaceutically acceptable solvent, which may also contain suspending agents, sweetening agents, flavoring agents and preservatives as is known in the art. For parenteral administration, the compounds can be dissolved in a physiologically acceptable pharmaceutical carrier and can be administered in the form of a solution or a suspension. Illustrative examples of suitable pharmaceutical carriers are water, saline, dextrose solutions, fructose solutions, ethanol or animal, vegetable or synthetic origin oils. Pharmaceutical vehicles may also contain preservatives, buffers, etc., as is known in the art. When the compounds are administered intrathecally, they can also be dissolved in cerebrospinal fluid as is known in the art. The compounds of this invention will typically be administered topically. As used herein, topic refers to the application of the compounds (and optional vehicle) directly on the skin and / or hair. The topical composition according to the present invention may be in the form of solutions, lotions, ointments, creams, ointments, liposomes, sprays, gels, foams, ball dispenser, or any other formulation normally used in dermatology. Thus, a further embodiment relates to cosmetic or pharmaceutical compositions, in particular dermatological compositions, comprising at least one of the compounds corresponding to Formula I above. Such dermatological compositions will contain from 0.001% to 10% w / w of the compounds mixed with a dermatologically acceptable vehicle, and more typically, from 0.1 to 5% w / w of the compounds. Such compositions will typically be applied 1 to 4 times a day. The reader's attention is directed to Remington's Pharmaceutical Science. 17th edition, Mack Publishing Co., Easton, PA for an analysis on how to prepare such formulations. The compositions according to the invention can also consist of solid preparations constituting cleaning soaps or tablets. These compositions are prepared according to conventional procedures. The compounds can also be used for the hair in the form of aqueous, alcoholic or aqueous-alcoholic solutions, or in the form of creams, gels, emulsions or foams, or alternatively in the form of aerosol compositions which also comprise a pressurized propellant. The composition according to the invention can also be a hair care composition, and in particular a shampoo, a hair fixation lotion, a treatment lotion, a styling cream or gel, a dye composition, a lotion or gel to prevent hair loss, etc. The amounts of the various constituents in the dermatological compositions according to the invention are those conventionally used in the fields considered. The medicinal and cosmetic compositions containing the compounds of the invention will typically be packaged for retail distribution (i.e., an article of manufacture). Such items will be labeled and packaged so that they instruct the patient how to use the product. Such instructions will include the condition to be treated, the duration of the treatment, the dosage program, etc. The compounds of Formula I can also be mixed with any inert carrier and can be used in laboratory tests in order to determine the concentration of the compounds in the serum, urine, etc., of the patient as is known in the art. The compounds can also be used as a research tool. Although the invention has been described with respect to specific embodiments thereof, it will be understood that further modifications may be made and that this application is intended to cover any variation, use or adaptation of the invention by following, in general, the principles of the invention and including the variations of the present description that come with known or conventional practice within the technique of the invention. The following examples and biological data are presented in order to further illustrate the invention. This description should not be construed as limiting the invention in any way.

EXAMPLE 1 (1S, 2S) -4- (2-Hydroxy-1-methyl-propoxy) -2-trifluoromethyl-benzonitrile NaH (0.20 g, 4.14 mmol) was suspended in 15 ml of dry THF and then (2S, 3S) - (+) - 2,3-butanediol (0.32 g, 3.45 mmol) was added. , in 5 ml of dry THF). This mixture was stirred at 0 ° C for 10 minutes, followed by the addition of 4-fluoro-2-trifluoromethyl-benzonitrile. The reaction mixture was stirred, at 0 ° C for 1 hour, under a nitrogen atmosphere. Then, the mixture was stirred for a further 2 hours, at room temperature, in a vessel. The reaction was quenched with 25 ml of distilled water and extracted with ethyl acetate (3 x 20 ml). The product was purified by column chromatography, using hexane: ethyl acetate = from 5: 1 to 1: 1 as eluent, yielding the pure product. MS: 260.0 (M + 1 for Ci2H12F3N02). EMCL: column C-18 (50% H2O / 50% CH3CN), Retention time: 1.81 min EXAMPLES 2-27 Using the general procedure of Example 1, but substituting the relevant starting materials, prepare the compounds described in Table I. Chromatography was performed on a Foxy 200 fraction collector, using a prepared Biotage Silicon Gel column ( Water: Methylnitrile was used as elution solvent, 50:50, in all the examples except 8, 16, 17 and 26, in which a 25:75 mixture of water: methylnitrile was used). The mass spectrum of Table I was recorded with a Hewlett Packard mass spectrometer.

EXAMPLE 28 2-Chloro-4- (4-hydroxy-1-methyl-pentyloxy) -benzonitrile To a solution of 2,5-hexanediol (28 mg, 0.240 mmol) in tetrahydrofuran was added an excess of potassium butoxide. The mixture was stirred briefly and 2-chloro-4-fluoro-benzonitrile (37 mg, 0.240 mmol) was added. The mixture was stirred at room temperature for 72 hours. Purification by reverse phase high pressure chromatography eluting with a solvent gradient (15% 0.1% formic acid / CH3CN in 0.1% formic acid / water at 100% 0.1% formic acid / water) provided 28.4 mg of 2-chloro-4- (4-hydroxy-1-methyl-pentyloxy) -benzonitrile. 1 H NMR (CDCl 3) d 7.50 (d, 1 H), 6.95 (m, 1 H), 6.79 (da, 1 H), 4.43 (m, 1 H), 3.79 (m, 1 H), 1, 89-1, 40 (m, 4H), 1, 30 (d, 3H), 1, 17 (d, 3H); MS m / z 253, EXAMPLE 29 2-Chloro-4- (3-hydroxy-propoxy) -benzonitrile To 1, 3-propanediol (320 mg, 4.2 mmol) was added sodium (21 mg, 0.92 mmol). The mixture was stirred at room temperature for 10 minutes and 2-chloro-4-fluoro-benzonitrile (156 mg, 1.0 mmol) was added. The reaction was heated at 105 ° C for 24 hours. The reaction was cooled to room temperature, diluted with water and extracted with E 2 O (3 x). The organic solution was dried (MgSO4), filtered and concentrated. The residue was purified by high pressure reverse phase chromatography eluting with a solvent gradient (15% 0.1% formic acid / CH3CN in 0.1% formic acid / water at 100% formic acid 0.1 % / water), yielding 107 mg of 2-chloro-4- (3-hydroxy-propoxy) -benzonitrile. 1 H NMR (CDCl 3) d 7.54 (d, 1 H), 7.00 (m, 1 H), 6.85 (dd, 1 H), 4.15 (t, 2 H), 3.83 (t , 2H), 2.04 (m, 2H).

EXAMPLE 30 2-Chloro-4- (4-hydroxy-butoxy) -benzonitrile Following the procedure described for Example 29, 1,4-butanediol (1 mL, 10 mmol) was reacted with 2-chloro-4-fluoro- benzonitrile (159 mg, 1.0 mmol) for 24 hours at room temperature. Purification by high pressure reverse phase chromatography eluting with a solvent gradient (15% 0.1% formic acid / CHsCN in 0.1% formic acid / water at 100% 0.1% formic acid / water) provided 10 mg of 2-chloro-4- (4-hydroxy-butoxy) -benzonitrile. 1 H NMR (CDCl 3) d 7.54 (d, 1 H), 6.98 (d, 1 H), 6.83 (dd, 1 H), 4.03 (t, 2 H), 3.71 (t, 2H), 1.90 (m, 2H), 1.72 (m, 2H); EM 226.1 (M + 1).

EXAMPLE 31 2-Chloro-4- (1-hydroxymethyl-allyloxy) -benzonitrile Step A: 1- (ferc-Butyl-dimethyl-silanyloxy) -but-3-en-2-ol To a solution of (+/-) - 3-butene-1,2-diol (500 mg, 5.67 mmol) in CH 2 Cl 2 (25 mL) was added imidazole (444 mg, 6.53 mmol). The solution was cooled to 0 ° C and ε-butyldimethylsilyl chloride (1) was added., 0 M in THF, 6.24 ml, 6.24 mmol). The reaction was stirred at 0 ° C for 15 minutes and at room temperature for 1 hour and 30 minutes. The mixture was diluted with aqueous NH 4 Cl and extracted with CH 2 Cl 2 (3 x). The organic solution was washed with brine, dried (MgSO4), filtered and concentrated. The residue was purified by medium pressure chromatography eluting with a solvent gradient (5% EtOAc in hexanes to 100% EtOAc), yielding 827.5 mg of 1- (tert-butyl-dimethyl-silanyloxy) -but-3-. en-2-ol. 1 H NMR (CDCl 3) d 5.81 (m, 1 H), 5.34 (d, 1 H), 5.19 (d, 1 H), 4.17 (m, 1 H), 3.66 (dd, 1H), 3.45 (dd, 1 H), 0.90 (s, 9H), 0.08 (s, 6H); MS m / z 202. Step B: 4-f1- (C-Butyl-dimethyl-silayloxymethyl) -alyloxy-1-2-chloro-benzonitrile acid To a solution of 1- (tert-butyl-dimethyl-silanyloxy) -but -3-en-2-ol (1.102 g, 5.45 mmol) in THF (26 mL) at -78 ° C was added potassium tert-butoxide (1.0 M in THF, 5.99 mL, 5.99 mmol). The solution was stirred for 15 minutes and 2-chloro-4-fluoro-benzonitrile (847 mg, 5.45 mmol) was added at -78 ° C. The reaction was stirred at room temperature for 24 hours, quenched with water and extracted with EtOAc (3 x). The organic solution was washed with water and brine, dried (MgSO4), filtered and concentrated to give 1.67 g of a 1: 1 mixture of 4- [1- (tert-butyl-dimethyl-silylanyloxymethyl) -alloyloxy] -2-chloro-benzonyltriand 4- [2- (tert-butyl-dimethyl-silanyloxy) -but-3-enyloxy] -2-chloro-benzonitrile. 1 H NMR (CDCl 3) d 7.55 (m, 2H), 7.02 (m, 2H), 5.91-5.78 (m, 2H), 5.42-5.22 (m, 4H), 4.75 (m, 1 H), 4.51 (m, 1 H), 3.90 (m, 2H), 3.79 (m, 2H), 0.89 (s, 9H), 0.87. (s, 9H), 0.07 (s, 6H), 0.04 (s, 6H). Step C: 2-Chloro-4- (1-hydroxymethyl-allyloxy) -benzonitrile To a solution of the above regioisomer mixture, Example 31, Step B, (1.67 g, 4.95 mmol) in THF (15 ml ) was added ferricbutylammonium fluoride (1.0 M in THF, 5.44 ml, 5.44 mmol). The reaction was stirred at room temperature for 15 minutes, diluted with aqueous NH 4 Cl and extracted with EtOAc (3 x). The organic solution was washed with brine, dried (MgSO4), filtered and concentrated. The residue was purified by medium pressure chromatography eluting with a solvent gradient (from hexanes to 100% EtOAc in hexanes for 70 minutes), yielding 112 mg of 2-chloro-4- (1-hydroxymethylalyloxy) -benzonitrile. 1 H NMR (CDCl 3) d 7.55 (d, 1 H), 7.04 (d, 1 H), 6.89 (dd, 1 H), 5.85-5.76 (m, 1 H), 5, 38 (m, 2H), 4.80 (m, 1H), 3.80 (m, 2H).

EXAMPLE 31 A This example further illustrates the preparation of (1S, 4S) -4- (4-hydroxy-1-methylpentyloxy) -2-trifluoromethyl-benzonitrile, the product of Example 23. NaH was suspended (60% in mineral oil) in 100 ml of dry THF, stirred and cooled to 0 ° C under N2 for 10 min before (2S, 5S) - (+) - 2,5-hexanediol (12 g) was added. in 120 ml of dry THF). The diol was added dropwise through an addition funnel for 30 min, this mixture was stirred at 0 ° C for 60 min and then at RT for 30 min and cooled again to 0 ° C before the addition was carried out. -fluoro-2- (trifluoromethyl) benzonitrile (20 g in 80 ml of dry THF) for 30 min. Then, the reaction was stirred at 0 ° C to RT in an atmosphere of N2 (11 a.m.-9 a.m. the next day). The reaction was monitored by TLC (Hex: Ethyl acetate = 1: 1) and LC / MS. Purification: The crude product was dissolved in 80 ml of a solvent mixture (hexane: ethyl acetate = 3: 1), column purification using hexane: ethyl acetate = from 5: 1 to 1: 1 as eluent, yielding 22 g of the desired pure product.

EXAMPLE 32 The compounds of Formula I have affinity for the androgen receptor.

This affinity has been demonstrated for the compounds selected using the human receptor. The description shown below describes how the test was performed. Competitive binding analysis was performed on baculoviruses / hAR extracts generated by Sf9 in the presence or absence of different concentrations of test agent and a fixed concentration of 3H-dihydrotestosterone (3H-DHT) as indicator. This binding assay procedure is a modification of a protocol previously described (Liao S. et al., J. Steroid Biochem.20: 11-17, 1984). Briefly, concentrations are progressively incubated in decreases of compounds in the presence of hAR extract (Chang et al., PNAS Vol. 89, pp. 5546-5950, 1992), hydroxylapatite and 1 nM 3H-DHT for one hour at 4 ° C. . Subsequently, the binding reactions are washed three times to completely remove the excess unbound 3H-DHT. The levels of hAR bound to 3H-DHT are determined in the presence of the compounds (= that is, competitive binding) and are compared with the levels of binding when the competitor is not present (= that is, maximum binding). The binding affinity of the compound for hAR is expressed as the concentration of the compound to which half of the maximum binding is inhibited. Table II below shows the results that were obtained for the selected compounds (the presented data is the average of multiple trials as shown below).

TABLE II a - average of two trials b - average of three trials c - average of four trials EXAMPLE 33 The ability of the compounds to antagonize the effects of androgens on the androgen receptor was determined in a whole cell assay as described just below.

Experimental procedure for the assay of AR antagonist cells Cell line: Clone 54-19 MDA-MB453-MMTV. This cell line is a stable transfected cell line with the background MDA-MB453 cell (a human breast tumor cell line that expresses the androgen receptor). A minimal MMTV promoter containing ARE was first cloned in front of a firefly luciferase reporter gene. Then, the cascade was cloned into transfection vector pUV120puro. The electroporation procedure was used to transfect the MDA-MB-453 cell. The stable cell line resistant to puromycin was selected.

Reagents and cell culture media: Culture medium: DMEM (high glucose level, Gibco catalog number: 11960-044), 10% FBS and 1% L-glutamine.

Culture medium in plates: DMEM (without phenol red): 10% carbon treated with HyClone serum, 1% L-glutamine. Test medium: DMEM (without red phenol), 1% charcoal treated with HyClone serum, 1% L-glutamine and 1% penicillin / streptomycin 3X Luciferase buffer: 2% beta-mercaptoethanol, 0.6% ATP %, 0.0135% urucine in cell lysis buffer Test procedure: 1. The cells are maintained in culture medium, the cells divide when they reach a confluence of 80-90%. 2. To assay the compounds, place 10,000 cells / well in 96-cell opaque culture plates in 100 μl / well of culture medium in plates, culture overnight at 37 ° C in cell culture incubator 3. Carefully remove. the plate culture medium, then add 80 μl / well of the pre-heated test medium, add 10 μl / well of the test compound (final concentration at 1000 nM, 200 nM, 40 nM, 8 nM, 1.6 nM and 0.32 nM), incubate at 37 ° C for 30 minutes. 4. Add 10 μl / well of freshly prepared DHT (final concentration at 100 pM) to each well, incubate at 37 ° C for 17 hours (overnight). 5. Add 50 μl / well of 3X luciferase buffer, and incubate at room temperature for 5 minutes, then count in a Luminometer. The induction multiplied with respect to the background level by 100 pM DHT in the absence of the test compounds is standardized as 100% and the experimental result is expressed as percent inhibition by testing the compounds. The results are described below in Table III. The results are indicated as the average of multiple trials described below (the numbers of trials are indicated in the footnote). N.D. indicates that the compound was not tested.

TABLE a - average of two trials b - average of three trials c - average of four trials EXAMPLE 34 Animal Model for Androgenic Alopecia As described above, alopecia is a problem to which medical science has devoted considerable resources. As with any disease process, animal models have been developed to allow scientists to investigate their potential relative efficacy in compounds. Those compounds that show the highest efficacy in these animal models are considered for further studies in humans. To date, two different animal models have been developed for alopecia. The first is the telogen conversion assay, which uses female C3H / HeN mice. The second model uses rabones macaques, which are monkeys suffering from androgenic alopecia. The telogen conversion assay measures the potential of a compound to convert the resting stage of the capillary growth cycle ("telogen") into the active stage of the capillary growth cycle ("anagen") in mice. This assay takes advantage of the fact that the coat (i.e., hair) of 7-week-old C3H / HeN mice is in the telogen phase. This phase continues until approximately 75 days of age. In this test, the selected areas of the mice are shaved, contacted with a test agent, or a control, and the difference in hair growth rate (ie, induction of the anagen phase) is measured. . The first sign of anagen is the darkening of the skin color according to the melanocytes of the follicles begin to synthesize melanin, in preparation for the production of pigmented hair. This model has many advantages. This includes the easy availability of CH3H mice in female, the ability to investigate large numbers of compounds quickly and the ease of housing and handling such animals. The main disadvantage of this model is its lack of androgenic dependence. Although the exact cause of human baldness is unknown, it has been well documented that androgens induce a regression of the hair follicles in the scalp. This post-adolescent regressive change is a fundamental cause of the male pattern baldness (ie, "androgenic alopecia"). This phenomenon appears in men and women who have inherited the genetic trait of alopecia, as previously mentioned. For a more detailed discussion of the effects of androgens on the human scalp, readers' attention is directed to Trueb, RM, Molecular Mechanisms of Androgenic Alopecia, Exp. Gerontology, 2002, 27: 981-990. The researchers looked for other animals whose capillary growth was similar to that of humans. This led the researchers to the rhesus macaques. These primates also suffer from androgenic alopecia. Essentially all post-adolescent macaques, of both sexes, show the development of baldness. As the development of male pattern baldness in humans, androgens are an indispensable triggering factor in the baldness of macaques. The thinning of the capillaries of the frontal scalp begins to appear around the same age (4 years) when serum testosterone levels begin to rise drastically in male animals. Although the elevation of testosterone in females is approximately one tenth of the level of the males, there is no difference in the incidence and age of onset of baldness between the male and female macaques rabones. Topical application of anti-androgens has reversed this baldness in animals of both sexes (Pan, HJ et al., Evaluation of RU58841 as an anti-androgen in prostate PC3 cells and a topical anti-alopecia agent in the bald scalp of stump tailed macaques Endocrine 1998; 9: 39-43). Although this model is a significant improvement over the telogen conversion assay as a model for human baldness, it suffers from a number of practical disadvantages. Macaques are expensive, relatively infrequent, an intensive task is required to maintain them and require long periods of washing between trials. In this way, the macaque is not a practical model for investigating a large number of compounds. It has been found that male C3H / HeN mice can be used in the telogen conversion assay, when testing anti-androgen test compounds. In this way, the model refers to a modification of the existing telogen conversion assay. Male C3H / HeN mice are used at approximately 7 weeks of age. These animals are also uniformly in the telogen phase, just like their female counterparts. However, once shaved, the androgens inherently present in these male mice inhibit the conversion of the hair follicles to the anagen phase. An anti-androgen will block this androgenic effect and the follicles will be converted to the anagen phase, in the same way as their female counterparts.

Example 34A The compound described in Example 23, (1S, 4S) -4- (4-hydroxy-1-methyl-pentyloxy) -2-trifluoromethyl-benzonitrile was subjected to another test using the modified telogen conversion test, described previously. The test was carried out in the following manner. Male C3H / HeN mice, 6 to 7 weeks of age (Charles River Laboratories, Raleigh, NC) were used for the study. The hair was cut from the dorsal region of the mice before the start of the study. Only mice with pink skin, a visual indication of the telogen phase, were selected for inclusion in the study. The test compound was dissolved in a vehicle consisting of propylene glycol (30%) and ethanol (70%) to achieve a concentration of 0.2% w / v, 0.5% w / v, 1% w / v 3 % p / v. The relevant dose was applied topically to the cut dorsal region of the mice in a test group (7-10 mice) in a volume of 20 μl / cm2. A third group of animals received only the vehicle to serve as control. The treatments were applied twice a day for 4 weeks. The treatment area was observed and graduated every two days for capillary growth signals. The capillary growth response was quantified by recording, for each animal, the day on which said capillary growth signals appeared for the first time on the treated area. The first sign of the anagen was the darkening of the skin color according to the melanocytes of the follicles beginning to synthesize melanin in the preparation for the production of pigmented hair. The mice were observed for 35 days or more. The percentage of mice showing capillary growth signals in the treatment group and in the control group is shown graphically below in Figure I. The compound of Example 23, when tested at a concentration of 1%, produced a growth of substantial hair by stimulating the induction of the anagen phase in the test animals. The capillary growth rate of the 5% test group did not exceed that of the control vehicle group. 3% Bca ple 23 1% Example 23 0.5% Example 23 0.2% B ample 23 Vehicle Control Example 34 B The product of Example 27, 2-chloro-4- (3-hydroxy-2,2,4-trimethyl-pentyloxy) -benzonitrile, was subjected to the modified telogen conversion test, described above. The test was performed in the same manner as in Example 37 A, at a test concentration of 3% w / v. The capillary growth rate of the test group did not exceed that of the control vehicle.

Example 35 Animal Model for the Inhibition of Sebum Production Luderschmidt et al. describe an animal model for testing whether the compounds are capable of modulating the secretion of sebum. Arch. Derm. Res. 258, 185-191 (1977). This model uses male Sirius hamsters, whose ears contain sebaceous glands. The selected compounds produced above were investigated in this model. The test for sebum inhibition was carried out in the following manner. Male Syrian hamsters from 9 to 10 weeks of age were introduced into the laboratory medium and acclimated for 2 weeks before use in the study. Each group consisted of 5 animals and were processed in parallel with vehicle and positive controls. Before administration, 30 mg of each compound was dissolved in 1 ml of Universal solvent (ethanol / propylene glycol (70/30% v / v) to achieve a final concentration of 3% w / v. The animals were dosed topically twice per day, five days a week, for 4 weeks Each dose consisted of 25 microliters of control vehicle or drug.The dose was applied to the ventral surfaces of the right and left ears.All animals were slaughtered approximately 18-24 hours after the last dose, the right ears were collected from each animal and used for tallow analysis, the ears were prepared for HPLC analysis as follows, an 8 mm distal biopsy was taken., just above the anatomical mark "V" of the ear to normalize the area of the samples. The punch moved away. The surface of the ventral biopsy (the area in which the topical dose was applied directly to the sebaceous glands) was retained for the test and the dorsal surface of the biopsy was discarded. N2 gas was injected into tissue samples and stored at -80 ° C in a nitrogen atmosphere until HPLC analysis. In addition to the ear samples, an aliquot of each drug and vehicle (at least 250 μl) was also stored at -80 ° C for inclusion in the HPLC analysis. The HPLC analysis was performed on an extract of the tissue sample. The tissue samples were contacted with 3 ml of solvent (a 4: 1 mixture of 2,2,4-trimethylpentane and isopropyl alcohol). The mixture was stirred for 15 minutes and stored overnight at room temperature, protected from light. The next morning, 1 milliliter of water was added to the sample and stirred for 15 minutes. Then, the mixture was centrifuged at about 1500 rpm for 15 min. Two ml of the organic phase (upper layer) was transferred to a glass vial, dried at 37 ° C, under a nitrogen atmosphere, for about 1 hour and then lyophilized for about 48 hours. The samples were then removed from the lyophilizer and each vial was reconstituted with 600 μl of solvent A (trimethylpentane / tetrahydrofuran (99: 1)), then the samples were again covered and vortexed for 5 minutes, then 200 were transferred. μl of each sample to a 200 μl HPLC vial pre-labeled with 200 μl glass inserts HPLC vials were placed in the automatic sampling tray for the Agilent 1100 series HPLC unit. Agilent 1100 consisted of an automatic sampler with thermostat, a quaternary pump, a column heater and an A / D interface module.All components were controlled by Agilent ChemStation software.An analytical column of 4.6 x 100 mm was maintained Waters Spherisorb S3W at 30 ° C using the Agilent column heating unit The HPLC automatic sampler was programmed to maintain the temperature of the sample at 20 ° C during the execution. n 10 μl of each sample in triplicate in the column. Two solvents were used for the solvent gradient. Solvent A was a mixture of trimethylpentane and tetrahydrofuran (99: 1). Solvent B was ethyl acetate. The gradient used is described in the table below: The Sedex 75 Evaporative Light Dispersion Detector (ELSD) was operated at 45 ° C with a gain of 5 and the pressure of N2 was maintained at 3.1 bar (310 kPa). An analog signal obtained by the instrument was sent to the Agilent A / D interface module where it was converted into a digital output. The conversion was based on a target point of 10000 mAU / volt and the data rate was set at 10 Hz (0.03 min). Afterwards, the resulting digital output was introduced into the Agilent ChemStation software for the integration of the peak area. The results of the HPLC analysis are presented below in Table IV. The results are presented as the reduction of the production of cholesterol ester (CE) and wax ester (WE), when compared to the control vehicle. of Example. Columns 3 to 5 show the effect of the compounds on the reduction of tallow components (CE and WE). The results are expressed as the difference with respect to the control vehicle. A positive number reflects a decrease in measured sebum production, ie, cholesterol ester (CE) or wax ester (WE). Column 3 shows the ability of the compounds to reduce the amount of cholesterol ester in the tallow sample. Column 4 shows the effect of the compound on the generation of wax ester. Wax esters are specific markers of the sebaceous glands and are not detectably detectable in any other layer of the skin. The wax ester is the main component of tallow (approximately 25%). In this way, the reduction of the wax ester typically leads to significant reductions in sebum secretion. Column 5 is the sum of the results expressed in columns 3 and 4 (and is included to better elucidate the relative differences in activity). As shown in Table IV, the androgen modulators of Formula I significantly decrease the production of cholesterol ester and wax ester.

Claims (14)

1. A compound of formula: Or a prodrug of said compound, a hydrate of said compound or a pharmaceutically acceptable salt of said compound, wherein: X1 is represented by halogen or haloalkyl; X2 is represented by -CR3R4R5, -CH = CH2 or -C = CH; each of R1 and R2 is independently represented by a substituent selected from the group consisting of hydrogen, halogen, C6 alkyl, haloalkyl, hydroxyalkyl, thiol and thioalkyl; each of R3, R4 and R5 is independently represented by a substituent selected from the group consisting of hydrogen, halogen, C6-6 alkyl, haloalkyl, hydroxy, hydroxyalkyl, thiol, thioalkyl and -NR6R7; Q n is represented by the integer 0 or 1; ALK1 is represented by a linear Crβ alkylene group, in which up to 8 hydrogen atoms of the alkylene group can be optionally replaced by a substituent selected from the group consisting of C 1-6 alkyl, haloalkyl, halogen, hydroxy, hydroxyalkyl, thiol, thioalkyl and -NR6R7; 5 each of R6 and R7 is independently represented by hydrogen or C-? -6 alkyl with the proviso that: 1) if n is O and X2 is represented by -CH = CH2 or -C = CH, then at least one of R1 or R2 is represented by thiol, hydroxyalkyl or thioalkyl; 2) if n is 1 and X2 is represented by -CH = CH2 or -C = CH, then alternatively, at least one of R1 or R2 is represented by a substituent selected from the group consisting of thiol, hydroxyalkyl and thioalkyl or minus one hydrogen atom of Alk1 is replaced with a substituent selected from the group consisting of hydroxy, thiol, hydroxyalkyl and thioalkyl; 3) if n is 0 and X2 is represented by -CR3R4R 5, then, alternatively, at least one of R1 or R2 is represented by a substituent selected from the group consisting of thiol, hydroxyalkyl and thioalkyl or at least one of R3, R 4 or R 5 is represented by hydroxy, hydroxyalkyl, thiol or thioalkyl; 4) if n is 1 and X2 is represented by -CR3R4R 5, then alternatively: a) at least one of R or R2 is represented by a substituent selected from the group consisting of thiol, hydroxyalkyl and thioalkyl, b) at least one of R3, R4 or R5 is represented by a substituent selected from the group consisting of hydroxy, hydroxyalkyl, thiol and thioalkyl or c) at least one hydrogen atom of Alk1 is replaced with a substituent selected from the group consisting of hydroxy, thiol, thioalkyl and hydroxyalkyl.

2. A compound according to claim 1, wherein n is 0 and at least one of R, R 2, R 3, R 4, R 5 is represented by C 1 -6 alkyl, haloalkyl, hydroxyalkyl and thioalkyl.

3. A compound according to claim 1, wherein n is one, and at least one hydrogen atom of Alk1 has been replaced with a substituent selected from the group consisting of C-? 6 alkyl, haloalkyl, hydroxyalkyl and thioalkyl, or one of R1, R2, R3, R4, R5 is represented by C1-6 alkyl, haloalkyl, hydroxyalkyl, and thioalkyl.

4. A compound according to claim 1, 2 or 3 wherein X 1 is CF 3 and located at the 2-position of the phenyl ring.

5. A compound according to claim 1, 2, 3 or 4 wherein X 2 is CR 3 R 4 R 5, wherein at least one of R 3, R 4 or R 5 is hydroxy or hydroxyalkyl.

6. A compound according to claim 5, wherein at least one of R3, R4 or R5 is methyl.

7. A compound according to claim 1 wherein said compound is selected from the group consisting of: (1S, 2S) -4- (2-hydroxy-1-methyl-propoxy) -2-trifluoromethyl-benzonitrile; (1R, 2z?) -4- (2-hydroxy-1-methyl-propoxy) -2-trifluoromethyl-benzonitrile; 4- (2-hydroxy-1-methyl-propoxy) -2-trifluoromethyl-benzonitrile; 4- (2-hydroxy-6-methyl-heptyloxl) -2-trifluoromethyl-benzonitrile; 4- (2-hydroxy-octyloxy) -2-trifluoromethyl-benzonitrile; 4- (2-hydroxy-oct-7-enyloxy) -2-trifluoromethyl-benzonitrile; 4- (3-hydroxy-butoxy) -2-trifluoromethyl-benzonitrile; (3S) -4- (3-hydroxy-butoxy) -2-trifluoromethyl-benzonitrile; 4- (3-hydroxy-hex-5-enyloxy) -2-trifluoromethyl-benzonitrile; 4- (3-hydroxy-2-methyl-butoxy) -2-trifluoromethyl-benzonitrile; 4- (3-hydroxy-2,2-dimethyl-propoxy) -2-trifluoromethyl-benzonitrile; 4- (3-hydroxy-3-methyl-butoxy) -2-trifluoromethyl-benzonitrile; 4- (3-hydroxy-2,2,4-trimethyl-pentyloxy) -2-trifluoromethyl-benzonitrile; 4- (2-ethyl-3-hydroxy-hexyloxy) -2-trifluoromethyl-benzonitrile; 4- [2- (1-hydroxy-ethyl) -hexyloxy] -2-trifluoromethyl-benzonitrile; (1S, 3S) -4- (3-hydroxy-1-methyl-butoxy) -2-trifluoromethyl-benzonitrile; (1 R, 3R) -4- (3-hydroxy-1-methyl-butoxy) -2-trifluoromethyl-benzonitrile; 4- (4-hydroxy-butoxy) -2-trifluoromethyl-benzonitrile; 4- (4-hydroxy-butoxy) -2-trifluoromethyl-benzonitrile; 4- (4-hydroxy-heptyloxy) -2-trifluoromethyl-benzonitrile; 4- (4-hydroxy-1-propyl-butoxyl) -2-trifluoromethyl-benzonitrile; 4- (4-hydroxy-1-methyl-pentyloxy) -2-trifluoromethyl-benzonitrile; (1?, 4r?) -4- (4-hydroxy-1-methyl-pentyloxy) -2-trifluoromethyl-benzonitrile; (1S, 4S) -4- (4-hydroxy-1-methyl-pentyloxy) -2-trifluoromethyl-benzonitrile; 4- (5-hydroxy-pentyloxy) -2-trifluoromethyl-benzonitrile; 4- (5-hydroxy-hexyloxy) -2-trifluoromethyl-benzonitrile; 4- (5-hydroxy-3-methyl-pentyloxy) -2-trifluoromethyl-benzonitrile; 2-chloro-4- (3-hydroxy-2,2,4-trimethyl-pentyloxy) -benzonitrile; 2-chloro-4- (4-hydroxy-butoxy) -benzonitrile; 2-chloro-4- (3-hydroxy-propoxy) -benzonitrile; 2-chloro-4- (1-hydroxymethyl-alloxy) -benzonitrile; 2-chloro-4- (3-hydroxy-2-methyl-propoxy) -benzonitrile; 2-chloro-4- (5-hydroxy-pentyloxy) -benzonitrile; 2-chloro-4- (4-hydroxy-1-methyl-pentyloxy) -benzonitrile, and; 2-Chloro-4- (5-hydroxy-3-methyl-pentyloxy) -benzonitrile.

8. (1S, 4S) -4- (4-Hydroxy-1-methyl-pentyloxy) -2-trifluoromethyl-benzonitrile, or a pharmaceutically acceptable salt thereof.

9. Use of a compound according to any one of claims 1-8 as a medicine.

10. Use of a compound according to any one of claims 1-8 in the manufacture of a medicament for modulating the activation of the androgen receptor.

11. Use of a compound according to any one of claims 1-8 in the manufacture of a topical medicament for androgenic alopecia, excess sebum or acne.

12. A pharmaceutical composition comprising a compound according to any one of claims 1-8 in admixture with 1, or more, pharmaceutically acceptable excipients.

13. A topical pharmaceutical formulation comprising a compound according to any one of claims 1-8 in admixture with 1, or more pharmaceutically acceptable excipients suitable for dermal application.

14. An article of manufacture comprising a compound according to any one of claims 1-8 packaged for retail distribution that advises the consumer on how to use the compound to alleviate a condition selected from the group consisting of acne, alopecia, and skin grease.