UA82286C2 - 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

Description of the invention

The presented invention relates to a new class of benzonitriles and their use as androgen receptor 2 modulators. Other aspects of the invention relate to the topical application of these compounds to alleviate alopecia and oily skin.

Alopecia, or baldness, is a common problem that medical science has not cured. The physiological mechanism that causes hair loss is unknown. However, it is known that hair growth changes in people suffering from alopecia. 70 Hair follicles undergo cyclical activity that includes periods of growth, rest, and shedding. The human scalp typically contains between 100,000 and 350,000 hairs, which undergo transformation in three distinct stages: (a) during the growth (anagen) phase, the follicle (ie, the root of the hair) penetrates deep into the dermis with rapid cell division of the follicle and differentiation in the process of synthesis keratin, the dominant component of hair. In 12 people who do not go bald, this growth phase is completed within one to five years; (6) the intermediate phase (catagen) is marked by the arrest of mitosis and is completed in two to seven weeks, and; (c) the resting phase (telogen), in which the hair remains on the scalp for up to 12 weeks before being replaced by a new follicle growing from below.

In humans, this growth cycle is not synchronized. A person has thousands of follicles in each of these three phases. However, 20 most hair follicles are in the analog phase. In healthy young adults, the anogen to telogen ratio can be as high as 9 to 1. In individuals with alopecia, this ratio can decrease to less than 2:1.

Androgenetic alopecia occurs as a result of activation of inherited sensitivity to androgenic hormones.

It is the most common type of alopecia. It affects both men (5090) and women (30905), initially people of 25 Caucasian race. Over time and with increasing age, gradual changes occur in the diameter and length of the hair shaft. Long hair gradually turns into short, thin, colorless hair. As a result, 20-year-old men and 30-40-year-old women begin to notice that their hair is becoming thinner and shorter. . In men, the greatest loss of hair occurs on the forehead and crown of the head. Women observe hair thinning all over the scalp. As described above, the ratio of anagen to telogen is significantly reduced, which ik o, 30 leads to less hair growth. with

Minoxidil, a potassium channel opener, promotes hair growth. Minoxidil is commercially available in the United States under the trade name ROSAIME. While the exact mechanism of action of minoxidil is unknown, its effect on the hair growth cycle is well documented. Minoxidil promotes the growth of hair follicles and urine increases the time during which hair follicles are in the anagen phase (ie, increases the ratio of 35 anagen to telogen). co

Along with the fact that minoxidil promotes hair growth, the cosmetic effectiveness of this growth can be very broad. For example, Roenigk described the results of a clinical trial involving 83 men who used a topical solution of 395 minoxidil for 19 months. Hair growth occurred in 55,905 subjects. "

However, only 2,095 subjects considered the growth to be cosmetically appropriate. ISIip. Kev., 33, Mo. 4, 914A, 70 1985). Tosti reported cosmetically acceptable growth in 18,195 of his subjects. (Oegtaiiodisa, 173, Mo. 3, Z p. 136-138, 1986) Thus, there is a need for compounds capable of inducing a high rate of cosmetically acceptable hair growth in patients with alopecia.

In accordance with the presented invention, a new class of 4-oxobenzonitriles was discovered. These compounds and their pharmaceutically acceptable salts, hydrates and their prodrugs can be represented by the following formula: in M ko XX Ukh ko so (42) z o--(С882А---Ф(А КК) -х2

F); " in which:

X! is halogen or haloalkyl; 60 X? represents -СВЗВ"В, "SNASN" or -С-- СН;

In Her B2 is each, independently, a substituent selected from the group consisting of hydrogen, halogen, C 1-6 alkyl, haloalkyl, hydroxyalkyl, thiol, and thioalkyl;

C, 2, and BZ are each, independently, a substituent selected from the group consisting of hydrogen, halogen, C..6 alkyl, 65 haloalkyl, hydroxy, hydroxyalkyl, thiol, thioalkyl, and -me 98 7; n is an integer 0 or 1;

AK" is a C. 8 linear alkylene group in which up to 8 hydrogen atoms of the alkylene group can be replaced by a substituent selected from the group consisting of C 3.6 alkyl, haloalkyl, halogen, hydroxy, hydroxyalkyl, thiol, thioalkyl and -"MEV 7; 25 B is each, independently, hydrogen or C. in alkyl, provided that: 1) if ps bi x: represents -SNASN" or -C--CH, then at least one of B or c? represents is thiol, hydroxyalkyl or thioalkyl; 70 2) if pe 1 ih? is -CH-CH" or -C-- CH, while alternatively, at least one of B or c" is a substituent selected from the group which contains thiol, hydroxyalkyl and thioalkyl, or at least one hydrogen atom

Ah! substituted with a substituent selected from the group consisting of hydroxy, thiol, hydroxyalkyl and thioalkyl; 3) if n is 0 and X? is -CB ZB", while alternatively, at least one of B or B? is a substituent selected from the group consisting of thiol, hydroxyalkyl | thioalkyl, or at least one of 23, B or B 75 is hydroxy, hydroxyalkyl, thiol, or thioalkyl; 4) if n is 1 and X2 represents -CB ZE", while the alternative: a) at least one of KB" or BK? is a substituent selected from the group consisting of thiol, hydroxyalkyl and thialkyl, b) at least one of 23, c or b is a substituent selected from the group containing hydroxy, hydroxyalkyl, thiol and thioalkyl, or c) at least one hydrogen atom Aik! is replaced by a substituent selected from the group containing hydroxy, thiol, 20 thioalkyl, and hydroxyalkyl.

Compounds of the formula | are androgen receptor modulators. The compounds have an affinity for the androgen receptor and their biological action will be due to receptor binding. Typically, compounds will act as antagonists. In selected embodiments, they will act as partial agonists, full agonists, or tissue-selective agonists. As modulators of the androgen receptor, the compounds can be used in the treatment or alleviation of conditions associated with inappropriate activation of the androgen receptor. Examples of such conditions for antagonists include, but are not limited to, acne, excessive sebum secretion, androgenic alopecia, hormone-dependent cancers such as prostate cancer, and hirsutism. These compounds, which are partial agonists, full agonists or tissue-selective agonists, can be used in the treatment of osteoporosis, hypogonadism, anemia or to stimulate the increase of muscle mass, especially in wasting diseases. ee 30 The invention also relates to pharmaceutical compositions containing at least one of the compounds of formula I, in an amount effective for modulating the activation of the androgen receptor. In a further embodiment, the invention relates to a product of manufacture containing a compound of formula I, packaged for retail sale, in combination with instructions for the purchaser how to use the compound to alleviate a condition associated with Gα inappropriate activation of the androgen receptor. An additional embodiment relates to the use of the compound

From formula I, as a diagnostic agent for detecting inappropriate activation of the androgen receptor. co

In a further embodiment, compounds of formula I are used topically to induce and/or stimulate hair growth and/or to slow down hair loss. Tau compounds can also be used topically in the treatment of excessive sebum secretion and/or acne. "

Headings in this document are used only for the reader's convenience. They should not be construed as limiting the invention or the claims in any way. c) s As used in this application, including the claims, the following terms have the meaning of" defined below, unless specifically indicated otherwise. Plural and singular should be interpreted as equivalent values, other than the specified number: a. "halogen" refers to a chlorine, fluorine or bromine atom. in. "C4-C6 alkyl" refers to a branched or unbranched alkyl group containing from 1 to 6 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, pentyl, hexyl, etc. 1. with "haloalkyl" refers to a branched or unbranched alkyl group containing from 1 to 6 carbon atoms in which at least one hydrogen atom is replaced by a halogen (ie, C1-C6 haloalkyl). Examples of suitable haloalkyls are chloromethyl, difluoromethyl, trifluoromethyl, 1-fluoro-2-chloroethyl, 5-fluorohexyl, 50 3-difluoroisopropyl, 3-chloroisobutyl, etc. and. "hydroxyalkyl" refers to a branched or unbranched alkyl group containing from 1 to 6 m carbon atoms in which at least one hydrogen atom is replaced by a hydroxy group (ie, C 1 -C 4 hydroxyalkyl).

Examples of suitable hydroxyalkyls are hydroxymethyl, 1,2-dihydroxypropyl, 1-hydroxypentyl, b-hydroxyhexyl, 2-hydroxyethyl, etc. 99 e. "thioalkyl" refers to a branched or unbranched alkyl group containing from 1 to 6 atoms

GF! carbon, at least one hydrogen atom is replaced by a sulfhydryl group (ie, -ZH). Examples of suitable thioalkyls are methylmercaptan, 2-thioethyl, 1,3-dithiopropyl, b-thiolhexyl, 4-tulpentyl, etc. to her the expression "linear alkylene group containing from 1 to 8 carbon atoms" refers to an alkyl group containing from 1 to 8 carbon atoms that is a fragment of a linking group within the molecule (ie, not a 60 terminal -CH3 group). Examples of such alkyl groups are -СНо-, -СНО-"(СНо)-СНоео-, -СНо-(СНао)в-СН", -бн.-сСн.-СнНо-, -СНо-(СНо)»-СнНа -, etc. e. "solvate" is a crystalline form of a compound or its salt containing one or more molecules of a crystallization solvent, i.e., a compound of formula I! or its salt and solvent combined in molecular form. A "hydrate" is a solvate in which water is the solvent. because the term "polymorph" is a compound or its salt, such as a compound of the formula | or its salt which occurs

at least in one crystalline form. and. "androgen" refers to testosterone | its precursors and metabolites, and 3-alpha-reducing androgens, including, but not limited to, dihydrotestosterone. Androgen refers to androgens from the testes, adrenal glands, and ovaries, as well as all forms of natural, synthetic, and substituted or modified androgens. )|. "Pharmaceutically acceptable salts" refers to either "Pharmaceutically acceptable acid addition salts" or "Pharmaceutically acceptable base addition salts" depending on the actual structure of the compound.

"Pharmaceutically acceptable acid addition salts" is used for any non-toxic organic or inorganic acid addition salt of the basic compounds represented by formula I! or any intermediate 7/0 compounds thereof. Illustrative inorganic acids that form suitable salts are hydrochloric, hydrobromic, sulfuric and phosphoric acids and acidic metal salts such as sodium monohydrophosphate and potassium hydrosulfate.

Illustrative organic acids which form suitable salts are mono-, di- and tricarboxylic acids.

Illustrative examples of such acids are, for example, acetic, glycolic, lactic, pyruvic, malonic, succinic, glutaric, fumaric, malic, tartaric, citric, ascorbic, maleic, hydroxymaleic, /5 benzoic, hydroxy-benzoic, phenylacetic, cinnamic, salicylic, 2-phenoxybenzoic, p-toluenesulfonic acid and sulfonic acids such as methanesulfonic acid and 2-hydroxyethanesulfonic acid. Such salts may exist in either hydrated or essentially anhydrous form. In general, acid addition salts of these compounds are solutions in water and various hydrophilic organic solvents.

I. "Pharmaceutically acceptable base addition salts" is used for any non-toxic organic or inorganic base addition salt of compounds represented by formula I or any of their intermediate compounds, illustrative bases that form suitable salts are alkali metal hydroxides | alkaline earth metals, such as hydroxides of sodium, potassium, calcium, magnesium or barium; ammonium and aliphatic, alicyclic or aromatic organic amines such as methylamine, dimethylamine, trimethylamine and picoline. i.e. "prodrug form" refers to a compound that is rapidly transformed simultaneously with the formation of the main compound of the above-mentioned formulas, for example, by hydrolysis in the blood. The discussion of these forms is given in T.

Nidispi and M. eeyMya, "Rgo-dgydz az Mome! Oeiiimegu Zuvietv, MoiI.14 oi She A.S.5. Butrozvisht Zegiyev, and in (8)

Viohemegvirie Saigtiege ip YuOgyd YuOezidp, ed. Edulaga V. Kospe, Ategisap RPpagtaseciisa| Avzzosiaiop apa Regdatop

Rgezv, 1987, both of which are incorporated herein by reference. p. "compounds of formula I", "compounds of the invention" and "compounds" are used interchangeably throughout the description and "c" and "c" should be considered synonymous. at. "patient" refers to warm-blooded animals such as, for example, guinea pigs, mice, rats, pygmy gerbils, cats, rabbits, dogs, monkeys, chimpanzees, macaques, and humans. pp. "treatment" refers to the ability of compounds to either reduce, alleviate, or slow the progression of a patient's disease (or condition) or any tissue damage associated with the disease. with

Some compounds of formula I! will exist as optical isomers. Any reference in this application to a compound of formula I is meant to cover either specific optical isomers or a mixture of optical isomers (unless specifically stated otherwise). Specific optical isomers can be separated and isolated using techniques known in the art, such as chromatography on a chiral stationary phase or separation by obtaining a chiral salt followed by separation using selective crystallization. Alternatively, "

Using a specific optically active isomer as a starting material will give the corresponding isomer, with c as the final product.

In addition, the compounds of the present invention may exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol and the like. In general, solvated forms are considered equivalent to unsolvated forms for purposes of the present invention. The compound can also exist in various polymorphic forms and the claims cover all such forms. All compounds of formula I! contain a phenyl ring. For further disclosure of the invention, the numbering system of this ring and its substituents are shown below co

ZE

And Z b to o o 4 ko Position 1 of this phenyl ring will always be occupied by a cyano substituent as shown above. Position 4 will be replaced by an oxygen atom forming an ether substituent. The phenyl ring will also be substituted, as shown by X", in the 2- or 3-position, with a halogen atom or a haloalkyl substituent. Typically, this halogen or haloalkyl substituent will be in the 2-position. More typically, it will be a trifluoroalkyl in the 2-position of the phenyl rings

As stated above, the 4-position of the phenyl ring is a substituted ether substituent, which will always include: -"СЕ22)-(АК 7-Х, AK", when present, represents a C .-Cv linear alkylene substituent such as methylene, ethylene , propylene, butylene, pentylene, hexylene, heptylene, or octylene. Up to 8 hydrogen atoms of this alkylene substituent may be replaced by one of the substituents defined above. Any individual carbon atom of AIK" may be unsubstituted, monosubstituted, or disubstituted. These carbon atoms may be substituted by the same substituent or different substituents.

Ether substitute "SK 22)-(AIK7)4-X? will be substituted by at least one hydroxy, thiol, hydroxyalkyl or thioalkyl. This can be accomplished by one of two alternative methods of substitution (depending on the presence or absence of AK") If AIK' is not present in the molecule (ie n is 0), then one of

KZ, V! or CO may be represented by hydroxy, hydroxyalkyl, thiol or thioalkyl, or one of

B' or B? can be represented by hydroxyalkyl, thiol or thioalkyl, if AIK" is present (ie, n is 1), then alternatively: a) one of KZ, EK" or KE? can be represented by hydroxy, hydroxyalkyl, thiol or thioalkyl, b) one of B! or B? can be represented by hydroxyalkyl, thiol or thioalkyl, or c) one of the carbon atoms of AIK! may be substituted by hydroxy, hydroxyalkyl, thiol or thioalkyl.

The requirement that the molecule contains a hydroxy or thiol group should not be interpreted as limiting the molecule 75 to only one hydroxy or thiol substituent. If desired, the ether substituent "CE '22)-(AK)-X2 can contain several hydroxy, hydroxyalkyl, thioalkyl and thiol functions, which does not contradict the substitution strategy described above.

In the following optional embodiment of the invention, for compounds in which X 2 is CA in ipeo; at least one

With CT, p2, BZ, p" or 5 is C1-C6 alkyl, haloalkyl, thioalkyl, or hydroxyalkyl (that is, the ether residue, -СВ'B2-(AIK").-X7, is a branched alkyl). In an additional optional embodiment, for a compound in which X? is SAZVUV1 n is 1; at least one of B", K7, KZ, KE" or KE? is a C.-Cv alkyl, haloalkyl, thioalkyl, or hydroxyalkyl or alternatively one hydrogen atom of AIK' is replaced by a substituent selected from the group containing C.4-C.alkyl, haloalkyl, thioalkyl or hydroxyalkyl (i.e., an ether residue, - СВ'В2(АиИК)-Х?, where is a branched alkyl).

More specific embodiments of the invention relate to compounds of formula I, in which: o) 1) X! is CE" and located in the 2-position of the phenyl ring and X? is SEZE"R?, in which one of KZ, BC" or BU. is hydroxy; 29 X is SI and located in the 2-position of the phenyl ring and X? is SEZE"B", in which one of VZ, B" or B? is "o hydroxy;

C) X is CE" and located in the 2-position of the phenyl ring, VE! is hydrogen and K2 is C.-Sv alkyl, n is 1, in which Ak! oo is methylene, ethylene, propylene or butylene, X? is -"SEZE"B?, in which Kz is hydrogen or C.-Cv alkyl, BK" is hydrogen or SM

S.-Se is alkyl, and KZ is hydroxy; si 4) X is CE" and located in the 2-position of the phenyl ring, VE! is hydrogen or C.-Cv alkyl, 2 is hydrogen, n is so 0.1 X? is SEZ" B", in which Raz is hydroxy or hydroxyalkyl, K" is hydrogen or C.-Cv alkyl and KE? there is hydrogen; or 5) X is CE" or CI, and is located in the 2-position of the phenyl ring, B and B2 are each hydrogen, n is 1, in which AK is methylene, ethylene, propylene, or butylene, which is substituted with 1-3 substituents, that independently, choose from hydroxy, hydroxyalkyl or C.4-Cv alkyl and X? is SEZV"R?, in which K3 is hydrogen or hydroxy, and K7 and KE? are each "hydrogen or C1-C6 alkyl. More specific examples of compounds covered by formula I are: c i) 4-( 2-hydroxy-1-ethylpropoxy)-2-trifluoromethylbenzonitrile; "» her) 4-(2-hydroxy-1-methylpropoxy)-2-trifluoromethylbenzonitrile; iii) 4-(3-hydroxy-1-methylbutoxy)-2-trifluoromethylbenzonitrile; im) 4-(2-hydroxy-b-methylheptyloxy)-2-trifluoromethylbenzonitrile; (se) M) 4-(2-hydroxy-7-hydroxyheptyloxy)-2-trifluoromethylbenzonitrile; mi) 4-(2-hydroxyoctyloxy)-2-trifluoromethyl benzonitrile; about me). 4-(2-hydroxy-8-hydroxy-8-methyloctyloxy)-2-trifluoromethylbenzonitrile; to mine). 4-(2-hydroxyoct-7-enyloxy)-2-trifluoromethylbenzonitrile; their) 4-(2-hydroxyoct-7-ynyloxy)-2-trifluoromethylbenzonitrile; so x) 4-(2-ethyl-3-hydroxybutoxy)-2-trifluoromethylbenzonitrile;

HI xi) 4-(3-hydroxybutoxy)-2-trifluoromethylbenzonitrile; hii). 4-(3-hydroxyhex-5-enyloxy)-2-trifluoromethylbenzonitrile; hiiii). 4-(3-hydroxyhex-5-ynyloxy)-2-trifluoromethylbenzonitrile; chemical). 4-(3-hydroxy-2-methylbutoxy)-2-trifluoromethylbenzonitrile; khm) 4-(3-hydroxy-2-propylbutoxy)-2-trifluoromethylbenzonitrile;

F) hmm). 4-(3-hydroxy-2,2-dimethylpropoxy)-2-trifluoromethylbenzonitrile; chemicals) 4-(3-hydroxy-3-methylbutoxy)-2-trifluoromethylbenzonitrile; hmmiii). 4-(4-hydroxy-3-methylpentoxy)-2-trifluoromethylbenzonitrile; 60 khih). 4-(3-hydroxy-2,2,4-trimethylpentyloxy)-2-trifluoromethylbenzonitrile; xx). 4-(2-ethyl-3-hydroxyhexyloxy)-2-trifluoromethylbenzonitrile; xxi). 4-12-(1-hydroxyethyl)hexyloxy|-2-trifluoromethylbenzonitrile; xhiii). 4-(3-hydroxy-1-methylbutoxy)-2-trifluoromethylbenzonitrile; hiiiiii). 4-(33-hydroxy-1-methyl-2-ethylbutoxy)-2-trifluoromethylbenzonitrile; 6E ххим). 4-(4-hydroxybutoxy)-2-trifluoromethylbenzonitrile; xhu) 4-(6-hydroxyheptoxy)-2-trifluoromethylbenzonitrile;

hmmm). 4-(4-hydroxyheptyloxy)-2-trifluoromethylbenzonitrile; khmiya). 4-(4-hydroxy-1-propylbutoxy)-2-trifluoromethylbenzonitrile; hmmiii). 4-(4-hydroxy-1-methylpentyloxy)-2-trifluoromethylbenzonitrile; xxx). 4-(5-hydroxypentyloxy)-2-trifluoromethylbenzonitrile; xxx). 4-(5-hydroxyhexyloxy)-2-trifluoromethylbenzonitrile; xxx). 4-(5-hydroxy-3-methylpentyloxy)-2-trifluoromethylbenzonitrile; xxxii) 2-chloro-4-(3-hydroxy-2,2,4-trimethylpentyloxy)benzonitrile; xxxiii). 2-chloro-4-(4-hydroxybutoxy)benzonitrile; 70 xxhim). 2-chloro-4-(3-hydroxypropoxy)benzonitrile; hmm). 2-chloro-4-(1-hydroxymethylallyloxy)benzonitrile; hhhhmi). 2-chloro-4-(1-hydroxymethylacetylenoxy)benzonitrile; Khumiyya). 2-chloro-4-(3-hydroxy-2-methylpropoxy)benzonitrile; khumiiii). 2-chloro-4-(5-hydroxy-pentyloxy)benzonitrile; xxx) 2-chloro-4-(4-hydroxy-1-methylpentyloxy)benzonitrile, or; xi) 2-chloro-4-(5-hydroxy-3-methylpentyloxy)benzonitrile.

Compounds of the formula | can be obtained using methods similar to those known in the field for obtaining ethers. The reader's attention is directed to European Patent Application 58932, published September 1, 1982, the contents of which are incorporated herein by reference for the description of such reactions. Scheme I, below, reveals one of these techniques:

SCHEME

M ry 1r23--- 1U ssh no (sk Kk ) (AK a x: shchi She Nucleophilic substitution sch 1

E Manis vF at 2 (Se)

M xx Khy so s s zv o-(Flag)--(AKS) 2 so

AND

As shown above, one of the starting materials is an alcohol as shown in structure 1. VK, 2, AIk!, and X? must be represented by the same substituents as necessary in the final product. These alcohols are known in the art and can be prepared from known commercial sources. Alternatively, they can be prepared as described in Tegapedagop: Azutteigu, 1991 Moi.2, rade 569. z» Another starting material is 4-fluorobenzonitrile represented by structure 2. X! must be represented by the same by the substituents themselves as required in the final product.These benzonitriles are known in the art and can be synthesized as described in Japanese Patent Application 01097937.

The nucleophilic substitution shown above is carried out as is known from the literature. An alcohol of structure 1 contacts with a small excess of a base, such as sodium hydride, to form 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 approximately 02C. The alcohol is mixed with the base for a time ranging from 5 to 60 minutes. where One equivalent of 4-fluoro-benzonitrile of structure 2 is added to the reaction medium and reagents

Go! 20 are stirred for a period of time sufficient to replace the fluorine of benzonitrile with an alkoxide ion. Typically, this takes from 30 minutes to 24 hours. The reaction is typically carried out by heating to room temperature. m The desired product of formula I can be isolated by extraction, evaporation or other techniques known in the art. It may optionally be purified by chromatography, recrystallization, distillation, or other techniques known in the art. 25 As should be appreciated by one skilled in the art, several methods are useful for preparing compounds such as

GF! described above, may require the protection of individual functional groups, for example, to prevent the influence of such functional groups on reactions elsewhere in the molecule or to preserve the integrity of such functional groups. The necessity and type of such protection will be easily determined by a person skilled in the art and will depend on, for example, the nature of the functional group and the conditions of the selected method of preparation. See, 60 for example, T.M. Sgeepe, Rgoyesiime Ogotsmrz ip Ogdapis Zupipevziv, duopp UMIeu 5 ope, Mem Hogk, 1991.

Certain compounds of the present invention are acids and can form salts with a pharmaceutically acceptable cation. Some compounds of the present invention are basic and form salts with fPharmaceutically acceptable anions.

All such salts fall within the scope of the present invention and can be obtained using conventional methods, such as combining the acidic and basic components, usually in a stoichiometric ratio, in either an aqueous, non-aqueous, or partially aqueous medium, as required. Salts are isolated either by filtration, precipitation with a non-solvent followed by filtration, evaporation of the solvent, or, in the case of aqueous solutions, by lyophilization, depending on the circumstances. The compounds are obtained in crystalline form according to techniques known in the art, such as dissolution in an acceptable solvent(s) such as ethanol, hexanes, or water/ethanol mixtures.

Compounds of the formula | are androgen receptor modulators. They can be used to relieve conditions associated with inappropriate activation of the androgen receptor. The compounds act as androgen antagonists and can be used to treat, or alleviate, hormone-dependent cancers such as prostate carcinoma, benign prostatic hyperplasia, acne, hirsutism, excessive sebum, alopecia, 7/0 Pipertrichosis, precocious puberty, prostamegaly, virilization and polycystic ovary syndrome. Compounds acting as partial agonists or full agonists may be used in the treatment or relief of male hypogonadism, male sexual dysfunction (impotence, male dispermatogenic infertility), abnormal sexual differentiation (male hermaphroditism), delayed male puberty, male infertility, aplastic anemia , hemolytic anemia, sickle cell /5 anemia, idiopathic thrombocytopenic purpura, myelofibrosis, renal anemia, debilitating diseases (post-operative conditions, malignant tumor, trauma, chronic kidney disease, burn or AIDS), pain reduction in terminal carcinoma of the female genitalia, inoperable breast cancer, mastopathy, endometriosis, sexual dysfunction in women, osteoporosis, wound healing and regeneration of muscle tissue.

In order for the therapeutic properties described above to manifest, the compounds must be administered in a quantity of 20 sufficient to modulate the activity of the androgen receptor. This amount may greatly depend on the characteristics of the disease/condition being treated, the complexity of the patient's disease/condition, the patient himself, the compound being administered, the route of administration, and the presence of other diseases in the patient, etc. When administered systemically, the compounds are typically effective at doses in the range of about 0.1 mg/kg/day to about 10 mg/kg/day for any of the diseases or conditions listed above. Repeated administration throughout the day may be desirable and will vary according to the conditions given above.

The compounds of the present invention can be administered by various routes. They are effective if administered orally. The compounds may also be administered parenterally (ie, subcutaneously, intravenously, intramuscularly, intraperitoneally or intrathecally), rectally or topically.

In a typical embodiment, the compounds are administered topically. Local administration is especially suitable for hirsutism, alopecia, acne and excessive secretion of sebum. The dosage will vary, but as usually determined, the compound will be present in a dermatologically acceptable carrier in an amount of from about 0.01 to 5O/vO, and more typically from about 0.1 to 1O/vO. The dermatological formulation will be applied to the affected surface from 1 to 4 times a day. "Dermatologically acceptable" refers to a carrier that can be applied to the skin or hair and that will allow the drug to diffuse into the site of action. More specifically, it refers to the site in which EM is desired to inhibit the action of the androgen receptor. co

In another embodiment, the compounds are used topically to reduce alopecia, particularly androgenetic alopecia. Androgens have a strong effect on both hair growth and hair loss. In most areas of the body, such as the beard and pubic region, androgens stimulate hair growth by prolonging the growth phase of the hair cycle (anagen) and increasing the size of the follicle. Hair growth on the scalp does not require androgens, but, paradoxically, androgens are necessary for hair loss on the scalp in genetically predisposed individuals - c (androgenic alopecia), when there is a progressive decrease in the duration of the anagen phase and the size of hair follicles. Androgenic alopecia is also common in women, where it usually presents as diffuse hair loss compared to the localized hair loss seen in men.

While the compounds are most typically used to alleviate androgenetic 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 are alopecia areata, alopecia due to radiotherapy or chemotherapy, alopecia areata, stress-related alopecia, etc. As used herein, "alopecia" refers to partial or complete loss of hair on the scalp.

Thus, the compounds can be applied topically to the scalp and hair to prevent or alleviate baldness. In addition, the compound can be used topically to induce or co-promote hair growth on the scalp.

Fo In a further embodiment of the invention, the compound of formula I is applied topically to prevent hair growth in areas where such hair growth is undesirable. One such application would be the relief of hirsutism.

Hirsutism is excessive hair growth in places where hair does not normally grow (ie, a woman's face). Such unacceptable hair growth is most common in women and is often observed during menopause.

Topical administration of the compound will alleviate this condition by reducing or eliminating this (F) inappropriate or unwanted hair growth. t The compounds can also be used topically to reduce sebum production and more specifically to moderate oily skin. The compounds can also be used topically to relieve acne breakouts.

In another embodiment, these compounds act as partial agonists or full agonists, and can be used to treat or alleviate osteoporosis. Osteoporosis is characterized by a loss of bone mass, which is a consequence of the imbalance of bone resorption (destruction) and bone formation, which begins in the fourth decade and continues throughout life at a rate of approximately 1-495 per year (Eavieyi, Tgeaitepi oi 65 rositeporiza! ovieorogosis, Mem/ Epd. U. May 338: 736, 1998). In the United States, approximately 20 million people currently experience a spinal fracture due to osteoporosis. In addition, there are approximately 250,000 hip fractures per year due to osteoporosis, associated with 1,295-2,095 deaths in the first two years, while 3,095 patients require nursing home placement after the fracture and many never fully recover after such cases. In postmenopausal women, estrogen deficiency leads to increased bone resorption and, accordingly, spinal bone loss of approximately 595 per year, immediately after menopause. Thus, the primary treatment/prevention of this condition is inhibition of bone resorption using bisphosphonates, estrogens, selective estrogen receptor modulators (SERMs), and calcitonin.

However, bone resorption inhibitors do not sufficiently restore bone mass in patients who already have significant bone loss. The increase in spinal WMO achieved by bisphosphonate treatment can be 1195 7/0 After 7 years of alendronate treatment. In addition, bone turnover varies from site to site, being greatest in the trabecular bone of the spine compared to the cortex of long bones, bone resorption inhibitors are less effective in increasing hip WMO and preventing hip fracture. Therefore, osteoanabolic agents that increase cortical/periosteal bone formation and long bone bone mass will address an unmet need in the treatment of osteoporosis, particularly in patients at high risk of /5 hip fracture.

A number of studies demonstrate that androgens are osteoanabolic in women and men. Anabolic steroids such as nandrolone decanoate or stanozolol have been shown to increase bone mass in postmenopausal women.

The healing effect of androgens on bones in postmenopausal osteoporosis is well documented in recent studies using the joint administration of testosterone and estrogen. 9. Epadoshypoi. 140, 271-286, 1999). Thus, compounds of the formula | exhibiting agonistic or partial agonistic activity may be used in the treatment or alleviation of 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 hypophosphatemia. Other bone-dependent conditions that are corrected with androgen agonist therapy are osteoporotic fracture, childhood idiopathic bone loss, alveolar bone loss, mandibular bone loss, bone fracture, osteotomy, periodontitis, or denture ingrowth.

These compounds, which act as agonists or partial agonists, can also be used to stimulate muscle growth in patients affected by debilitating diseases such as AIDS, cancerous cachexia, burns, kidney disease, etc. Patients suffering from trauma, bedsores, age, etc. may also benefit from the anabolic effects of androgens. with

In the next embodiment of the invention, compounds of the formula | may be administered together with other compounds to further enhance their activity or reduce potential side effects. For example, potassium channel openers such as minoxidil are known to stimulate hair growth and induce anagen. Examples of other potassium channel openers are co (35,4K)-3,4-dihydro-4-(2,3-dihydro-2-methyl-3-oxopyridazin-b-yl)oxy-3-hydroxy-6-( 3-hydroxyphenyl)sulfonyl-2 2,3-trimethyl-2H-benzoyl|p|pyran, diaxoside, and PO 1075, which was developed by I eo Rpaptaseciisaiz. Thyroid hormone is also known as a hair growth stimulant. Synthetic thyroid hormone replacements (ie, thyromimetics) have also been shown to stimulate hair growth. Such thyromimetics were described in the literature 70 years ago. The reader's attention is directed to European Patent Application Mo1262177, the contents of which are incorporated herein by reference, for a discussion of such compounds and their use in alleviating alopecia. One of the particularly interesting compounds is 2-(A4-(3--4-Fluorobenzyl)-4-hydroxyphenoxy|-3,5-dimethylphenyl)-2H-(1,2,4)griazine-3,5-dione. z Antiandrogens can act by a number of different mechanisms. For example, some compounds block the conversion of testosterone into 5-A-dihydrotestosterone, which is responsible for its biological effects in many tissues. 5-alpha reductase inhibitors, such as finasturide, stimulate hair growth. Finasturide is commercially available from Megsk

Go! under the trade name Propecia U. An example of other 5-A-reductase inhibitors is dutasteid (Siaho ZtiyKiipe).

Such compounds can be administered together with compounds of formula I to alleviate alopecia. where Protein kinase C inhibitors have been shown to stimulate hair growth and induce anagen. Calphostin C, which is a selective inhibitor of protein kinase C, induces anagen. Other selective inhibitors of protein kinase C, such as hexadecylphosphocholine, palmitoyl-OH-carnitine chloride, and polymyxin B sulfate, have been shown to induce anagen. ZKip Rpagtaso! Arri 5Kip RPuzioi 2000 Mau-Atsao; 13(3-43: 133-42. Any such inhibitors

Fo protein kinase C can be administered together with compounds of formula I| to relieve alopecia.

Immunophilins are a family of cytoplasmic proteins. their ligands are cyclosporine, EKBOB and rapamycin. they are isolated from fungi and were originally proposed as potent immunosuppressive agents. Cyclosporine binds the protein, cyclophilin, while EC5BOb and rapamycin bind EC-binding protein (ECB). All of these compounds have been shown to stimulate hair growth and induce anagen. Any such immunophiles can be administered together with (F) compounds of formula I to alleviate alopecia. As used herein, co-administration refers to the administration of a compound of formula I with a second agent for the treatment of alopecia, typically having a different mechanism of action, using a dosage regimen that promotes hair growth in the patient. This may involve simultaneous administration, administration at different times within the same day, or even administration on different days. The compounds may be administered individually or may be combined in a single formulation. Methods of obtaining such recipes are described below.

If desired, the compounds can be administered directly without any carrier. However, for ease of administration, they are typically incorporated into pharmaceutical carriers. Also, more typically they are introduced into dermatological or cosmetic carriers. In this application, the terms "dermatological carrier" and "cosmetic" carrier are used interchangeably. They refer to formulations intended for application directly to the skin or hair.

Pharmaceutical and cosmetic compositions can be made using techniques known in the field.

Typically, an effective amount of the compound is mixed with a pharmaceutically/cosmetically acceptable carrier.

For oral administration, the compounds may be formulated into solid or liquid formulations such as capsules, pills, tablets, lozenges, lozenges, powders, suspensions or emulsions. Solid unit dosage forms may be plain gelatin capsules containing, for example, surfactants, lubricating agents, and inert fillers such as lactose, sucrose, and corn starch, or they may be sustained-release formulations.

In another embodiment, compounds of the formula | can be tableted using conventional 70 tablet bases such as lactose, sucrose and corn starch in combination with binding agents such as acacia, corn starch or gelatin, disintegrants such as corn starch or alginic acid, and a lubricating agent such as such as stearic acid or magnesium stearate. Liquid formulations are prepared by dissolving the active ingredient in an aqueous or non-aqueous pharmaceutically acceptable solvent, which may also contain suspending agents, sweeteners, flavors and preservatives, which are known in the art.

For parenteral administration, the compound can be dissolved in a physiologically acceptable pharmaceutical carrier and used either as a solution or as a suspension. Illustrative examples of suitable pharmaceutical carriers are water, saline, dextrose solutions, fructose solutions, ethanol or animal, vegetable or synthetic fats.

The pharmaceutical carrier may also contain preservatives, buffering agents, etc., which are known in the art.

When the compounds are administered intrathecally, they can be diluted in the cerebrospinal fluid, as is known in the art.

The compounds of the present invention are typically applied topically. As used herein, topical refers to the application of the compounds (and optionally the carrier) directly to the skin and/or hair. The topical composition according to the present invention can be in the form of solutions, lotions, balms, creams, ointments, liposomes, sprays, gels, foams or any other formulations regularly used in dermatology.

Thus, the following embodiment relates to cosmetic or pharmaceutical compositions, in particular dermatological compositions, which contain at least one of the compounds corresponding to Formula I, above. Such dermatological compositions will contain from 0.00195 to 1095 v/v95 of the compound in combination with a dermatologically acceptable carrier, and more typically, from 0.1 to 5 v/v90 of the compound. Such compositions will typically be used from 1 to 4 times per day . The reader's attention is drawn to Ketipdiopye Rpaptaseshis! Zsiepse, Edyop 17, Mask

Rybiizpipd So., Easiop, RA for familiarization with how to obtain such recipes. co

Compositions according to the invention can also be part of solid formulations that include cleansing soaps or bars. These compositions are obtained according to conventional methods.

The compounds can also be applied to the hair in the form of water, alcohol or water-alcohol solutions. EM either in the form of creams, gels, emulsions or mousses, or alternatively in the form of aerosol compositions containing a propellant under pressure. The composition according to the invention can also be a composition for hair care and, in particular, a shampoo, a hair fixing lotion, a treatment lotion, a hair modeling cream or gel, a paint, a hair loss prevention lotion or gel, etc. The amounts of the various ingredients in the dermatological compositions according to the invention are conventionally used in these fields. "

Medical and cosmetic preparations containing the compound of the invention are typically packaged for retail sale with (i.e., product). Such products have stickers and are packaged in such a way as to provide the patient with instructions for using the product. Such instructions will include conditions of treatment, duration of treatment, dosage, etc. from the Compound of the formula | can also be mixed with any inert carrier and used in laboratory tests to determine the concentration of compounds in the serum, urine, etc., of a patient, as is known 45. 8 in the art. Compounds can also be used as a research tool. While the invention is described in connection with specific embodiments, it is understood that subsequent modifications are possible and this application is intended to cover any subsequent variations, applications or adaptations to the invention, generally, the principles of the invention and including such deviations from the presented description as will be within the limits of knowledge or common practice in the field to which the invention belongs. The following examples and biological data are presented to further illustrate the invention. This description should not be construed as limiting the invention in any way.

Fo Example 1 (15,25)-4--2-Pdroxy-1-methylpropoxy)-2-trifluoromethylbenzonitrile

ES g on Man, os

GF! (0.20 g, 4.14 mmol) was suspended in 15 ml of dry THF, then (25.35)-()-2 was added, 3-butanediol (0.32g,

C45mmol, in bml of dry THF). This mixture was stirred at 09C for 10 minutes, after which 4-fluoro-2-trifluoromethylbenzonitrile was added. The reaction mixture was stirred at 02C for 1 hour under a nitrogen atmosphere.

The mixture was stirred for another 2 hours, at room temperature, under the lid. The reaction was quenched with 25 ml of 65% distilled water, extracted with ethyl acetate (3x2O0 ml). The product was purified by column chromatography using hexane:ethyl acetate - 5:1 to 1:1 as eluent to give pure product.

MS: 260.0 (MT for С42Н42Рз3МО») РХМС: Column С-18 (5090Н20/5090СНзЗСМ), Retention time. 1.81 min.

Examples 2-27

Using the general procedure of Example 1, but substituting the appropriate starting materials, the compounds described in Table 1 were obtained. Chromatography was performed on a Rochus 200 fraction collector using a Violiade 5 Joseph column (water:methylnitrile was used as eluent, 50:50, in all examples except 8, 16, 17, 26, where a 25:75 water:methylnitrile mixture was used). Mass spectrum in Table | taken on a Nemek RaskKaga mass spectrometer.

Table 1 1K,2K)-4-(2-Hydroxy-

E MS: 280.0 (Ma

With 1-methylpropoxy)-2-

Y f i 1.85 for - her "on riftomethyloenzoni

M obi С12Н2РзиMO») ryl 4-(2-Hydroxy-1-es MS: 260.0 (Ma1

With methylpropoxy)-2- 1.80 g for he riftomethylbenzoni

ROK Cg H12RzichO 5) 4-(2-Hydroxy-b-o) with MS: 316.2. (Ma methylheptyloxy)-2- /1.95

And why is 4-(2-s) so on rifluoromethylbenzone so zotr "vNEzMO")

Hydroxyoctypoxy)-2- MO: 316.2. (Ma p

Ez 1.76 so in riftormethypbenzone for ur put ryl SviNgobz MO") " on 7 (3-Hydroxybutoxy) With other and MS: 260.1. (Ma "z - 2.90 and Ez for riftomethylbenzoni

KAH, fluorine C12NiaEzMO») son ryl ko) (35)-4-(3- coHydroxybutoxy)-2- that MS: 260.1 (Ma ' (sg) all riftomethylbenzoni for z t; and Aryl Ca Ni2PzMO» ) 4 "ZH 4-(3-Hydroxyhex-5-o (td MS: 280.0 (Maenyloxy)-2 2.42 ke e ES , for n riftomethylbenzone in AJ mNiRzMo) teryl b5

4-(3-Hydroxy-2-

I es MS: 274.0 (Ma

Az methylbutoxy)-2- 12 2 then MTU. iy riftomethylbenzoni yalya ti ii NO

And ke | ril 13.4 3MO 2)

M-(3-Hydroxy-2,2-70 and all dimethylpropoxy)-2-rifluoromethylbenzoni lo! oon ryl 4-(3-Hydroxy-3- and in MO: 274.1 (M methylbutoxy)-2- 12 Es i b 2295 pchia riftormethypbenzoni

C3 No ZMO

M. AJ, ryl 131chig 3 2) 4-(3-Hydroxy-2,2,4-rimethyllentyloxy)- with gv |Z Ezs and o

KU. where riftomethylbenzoni

II (in; he ryl 4-(2-Etyp-3- yn so

Hydroxyhexyloxy) - MS: 316.2 (Ma 14 Rzs, n 2. 3.8 for cm and . s

HO riftomethyloenzoni C evaGogzichO») soryl 4-12-(1-Hydroxy-ethyl!-

Y GI Tidr and MS: 318.2 (Ma «

She hexyloxy)-2- 40. | 5 KU. f i | for t and riftomethylbenzoni with ! Water of SivNoog zmo) with on ryl 15,35)-4-(3-Pydroxy" 175 and methylbutosn Mo: 2740 (My so 16 kas, f ШІ in loz for z riftomethylbenzony y UAD ryl | 19754173 2) so ev MS : 2740 (Me!

M 1-methylbutoxy)-2- sho 17 same Fut y 02

In, SA ril | 13Nlaz MO") (F) "(4-Hydroxybutoxy)- MO: 250.0 (M in de 18 | - for the 60th GU tato riftomethylbenzoni Si2 No EzMO") 65 pn Sl p POV

І 4-(4-Hydroxybutoxy)-(4Pydroxybutoxy) MS: 274.0 (Me 19 Pa MB52 for on iffluoromethylbenzoni; coril C by MO) | 4-(4- Hydroxygeltyloxy )- MO: 302.1 (Ma z

TU, - oh for and for yourself and What! riftomethylobenzoni Siv zMO) ryl 4-(4-Hydroxy-1-20 propylbutoxy)-2- MS: 302.1 (Me 1 riftomethylbenzoni 3.16 for

Eu S ryl Si5NivEziMO) 4 o ns 4-(4-Hydroxy-1- o

MS: 288.1 (MA methylpentyloxy)-2-2 and 227 i riftomethylbenzoni Nek MO re)

That 1

IY lu ryl 1m"NivRz MO") with (15.48)3-444-Hydroxy- cm with 1-methylpentyloxy)- s: 281 (Ma s

MO: , I and I 29 (so

M Y x i C14NivEzMO" ; o, p» riftomethylbenzoni ryl « 70 4-(5-Hydroxy- in c MS: 274.0 (MA and pentyloxy)-2-a and E Y 1.54 for

And riftormethypbenzoni ra syziNchaEzichO»)

M a on ryl salts: t GPydroxyhexyloxy)- Mo: 288.0 (MA t 50.25 - 31 la so .

B, riftomethylpbenzoni C aNchaiz MO") (42) in ryl -(5-Hydroxy-3- | ! 25 (dr MS: 288.2 (MA methyllenthyloxy)-2-

F, in more f and Om i

And riftomethylbenzoni ko i ryl sled ZMO") because in the beginning of 65

"Chloro-4-(3-Hydroxy- p MS: 282.1 (Ma1 si ! A- 7 n | 1.70 for 7-rimethylpentyloxy)

Yu o , SNI MO") oenzonitrile 4-(2-Hydroxyoct-7-tho niloxy)-2- 19 Me: 314.1. (Ma in Ez riftomethylbenzoni! for sludge of SvANiva MO

Her to be r 16Ai1vE ziMO 2) on

Example 28 2-Chloro-4-(4-hydroxy-1-methylpentyloxy)benzonitrile

Us. MON with (8) sn, (Se) (ge) with I with I so

M

An excess of potassium butoxide was added to a solution of 2,5-hexanediol (28 mg, 0.240 mmol) in tetrahydrofuran. The mixture was stirred rapidly and 2-chloro-4-fluoro-benzonitrile (37 mg, 0.240 mmol) was added. The mixture was stirred at room temperature for 72 hours. It was purified by reversed-phase high-performance liquid chromatography using a gradient of solvents (1595 0.196 formic acid / SNUSM in :z» 0.190 formic acid / water to 10095 0.195 formic acid / water) as an eluent to obtain 28.4 mg of 2-chloro-4- (4-hydroxy-1-methylpentyloxy)benzonitrile. "H NMR (SOSIv) 5 7.50 (5, 1H), 6.95 (m, 1H), 6.79 (w d, 45. 1H), 4.43 (m, 1H), 3.79 ( m, 1H), 1.89-1.40 (m, 4H), 1.30 (d, ЗН), 1.17 (d, ЗН); MS t/z 253. so Example 29 2-Chlor-4 -(3-hydroxypropoxy)benzonitrile M and TSI so

F SI co

He is 60

To 1,3-propanediol (32mg, 4.2mmol) was added sodium (21mg, 0.92mmol). The mixture was stirred at room temperature for 10 minutes and 2-chloro-4-fluoro-benzonitrile (15mg, 1.0mmol) was added. The reaction was heated to 10592 for 24 hours. The reaction was cooled to room temperature, diluted with water and extracted

ESO (Zh). The organic solution was dried (Mo950O), filtered and concentrated. The residue was purified by reversed-phase high-performance liquid chromatography using a gradient of solvents (1595 0.196 formic acid/CHZSM to 0.195 formic acid/water to 10095 0.195 formic acid/water) as eluent.

receiving 107 mg of 2-chloro-4-(3-hydroxypropoxy)benzonitrile. "H NMR (SOSIv) 5 7.54 (5, 1H), 7.00 (m, 1H), 6.85 (dd, 1H), 4.15 (t, 2H), 3.83 (t, 2H ), 2.04 (m, 2H).

Example 30 2-Chloro-4-(4-hydroxybutoxy)benzonitrile 7rione

SI for

Following the procedure described for Example 29, 1,4-butanediol (1 mL, 10 mmol) was reacted with 75 2-chloro-4-fluorobenzonitrile (159 mg, 1.0 mmol) for 24 hours at room temperature. Purified by reversed-phase high-performance liquid chromatography using a solvent gradient (1595 0.190 formic acid / SNUSM in 0.190 formic acid / water to 10095 0.195 formic acid / water) as eluent to give 1 µg of 2-chloro-4-(4-hydroxybutoxy) benzonitrile. "H NMR (SOSI") 5 7.54 (5, 1H), 6.98 (d, 1H), 6.83 (dd, 1H), 4.03 (t, 2H), 3.71 (t, 2H), 1.90 (m, 2H), 1.72 (m, 2H); MO 226.1 (M.n1).

Example 31 2-Chloro-4-(1-hydroxymethylallyloxy)benzonitrile

Ma. and he school about

SI about

Sn, "so so

Stage A: 1-(tert-Butyl-dimethylsilanyloxy)-but-3-en-2-ol

Imidazole (444 mg, b.5 mmol) was added to a solution of (/-)-3-butene-1,2-diol (500 mg, 5.67 mmol) in CHClCl (25 mL). SM

The solution was cooled to 02C and t-butyldimethylsilyl chloride (1.0M in THF, 6.24ml, 6.24mmol) was added. The reaction was stirred at 02C for 15 minutes and at room temperature for 1 hour and 30 minutes. Mixture 32 was diluted with water emergency! and extracted СНоСі" (Жх). The organic solution was washed with brine, dried with O9 (M95O,)), filtered and concentrated. The residue was purified by means of medium pressure chromatography, using as eluent a gradient of solvents (5906 EOAc in hexanes to 10096 EOAc) to obtain 827.5 mg of 1-(tert-butyl-dimethylsilanyloxy)-but-33-en-2-ol. "H NMR (SOSIv) 5 5.81 (n, 1H), 5.34 (d, 1H), 5.19 (d, 1), « 4.17 (m, 1H), 3.66 (dd, 1H), 3.45 (dd, 1H), 0.90 (s, 9H), 0.08 (s, 6H); MS t/2 202. 40 . . . : . -

Stage B: 4-/1-(tert-Butyldimethylsilanyloxymethyl)allyloxy|-2-chlorobenzonitrile c To a solution of 1-(tert-butyldimethylsilanyloxy)but-3-en-2-ol (1.102g, 545Bmmol) in THF (2bml) at -782C: with" potassium tert-butoxide (1.0M in THF, 5.99ml, 5.99mmol) was added. The solution was stirred for 15 minutes and 2-chloro-4-fluoro-benzonitrile (847 mg, 5.45 mmol) was added at -182C. The reaction was stirred at room temperature

For 24 hours, quenched with water and extracted with EudAs (3x). The organic solution was washed with water and brine, dried (Mo5O), filtered and concentrated to obtain 1.67 g of a mixture of 4-(/1-(tert-butyldimethylsilanyloxymethyl)allyloxy|-2-chlorobenzonitrile and 4-(2-(tert- butyldimethylsilanyloxy)but-3-enyloxy|-2-chlorobenzonitrile. "H NMR (SOCIv) 5 7.55 (w 2H), 7.02 ko (m, 2H), 5.91-5.78 (m, 2H) , 542-522 (m, 4H), 4.75 (m, 1H), 4.51 (m, 1H), 3.90 (m, 2H), 3.79 (m, 2H), 0.89 ( c, 9H), 0.87 (c, 9H), 0.07 (c, 6H), 0.04 (c, 6H). co Stage B: 2-Chloro-4-(1-hydroxymethylallyloxy)benzonitrile

Pr To a solution of the per-regioisomeric mixture described above, Example 31, Stage B, (1.67g, 4.95mmol) in THF (15ml) was added tert-butylammonium fluoride (1.0M in THF, 5.44ml, 5.44mmol). The reaction was stirred at room temperature for 15 minutes, diluted with aqueous MHCl and extracted with EAs (3x). The organic solution was washed with brine, dried (Ma5O), filtered and concentrated. The residue was purified by means of medium pressure chromatography, using as eluent a gradient of solvents (hexanes to 10095 EUAs in o hexanes over 70 minutes), obtaining 112 mg of 2-chloro-4-(1-hydroxymethylallyloxy)benzonitrile. "H NMR (SOSIZ) 5 ko 7.55 (5, 1H), 7.04 (d, 1H), 6.89 (dd, 1H), 5.85-5.76 (m, 1H), 5, 98 (m, 2H), 4.80 (m, 1H), 3.80 (m, 2H).

Example 31A 60 This Example is further illustrated by the preparation of (15,45)-4-(4-hydroxy-1-methylpentyloxy)-2-trifluoromethylbenzonitrile, the product of Example 23.

Mann (6095 in mineral oil) was suspended in 100 ml of dry THF, it was stirred and cooled to 09 under Mo for 1 hr and then (25.55)-(w)-2,5-hexanediol (12 g in 120 ml of dry THF) was added. The diol was added dropwise through the dropping funnel over 30 min, the mixture was stirred at 02 for 20 min, then RT

ЗОхв., cooled to 02С and 4-fluoro-2-(trifluoromethyl)benzonitrile (20 g in vOml of dry THF) was added during

REFERENCE The reaction was stirred at 09C until CT under Mo (11.00-9.00 the next day). The reaction was monitored by TLC (Hex:ethyl acetate - 1:1) and LC/MO.

Purification: The crude product was dissolved in 8Oml of a mixture of solvents (hexane-ethyl acetate - 3/1), purified using a column using hexane:ethyl acetate - 5:1 to 1:1 as eluent, obtaining 22 g of pure desired product.

Example 32

Compounds of the formula | have affinity for the androgen receptor. This affinity is demonstrated for certain compounds using a human receptor. The following is a description of how the study was conducted. 70 Competitive binding analysis was performed in extracts of baculovirus/3i9, which generate PAK (human androgen receptor) in the presence or absence of different concentrations of the test agent and a fixed concentration of ZnH-dihydrotestosterone (ZH-ONT) as an indicator. This binding assay method is a modified protocol previously described (Giao 5., ei. aiYi. U. e(egoid Biospet. 20:11-17 1984). Briefly, gradually decreasing concentrations of compounds are incubated in the presence of NAK extract ( Sapa ei ai. R.M.A.5. 75 Mo1.89, pp. 5546-5950, 19921, hydroxyapatite and 1 nm ZN-ONT for one hour at 4 2 C. Then, the binding reactions were washed three times until complete removal of excess unbound ZN-ONT PAK binding levels of ZN-ONT in the presence of compound (- i.e., competitive binding) were determined and compared to binding levels in the absence of competitor (- i.e., maximal binding) The binding affinity of the compound with

PAC was expressed as the concentration of the compound at which maximum binding is inhibited by half. Table II, below, shows the results obtained for certain compounds (the data shown are the average of a series of tests as shown below) c (8) (Ce) (he) c c

From so - s. and? so ko ko so (42)

F) ko 60 b5

Her table

Example / Linking structure

Mo AR to ISvo (NM) 1 Gz 351 (c) u n o my 2 EzS 201 (c) -i-U : shchi y - ОН o aka (Se) so

From Eze 6b (6) sch

N s y (ge) ki o « s 14 gz 442 (a) what with

M

He so ko ko so 50 (42) is. why 32 (a)

Ar 5 n 6 and 415 (a)

K p. 7" of you 274 (a) same

AKA, t5 iv to 213 (a)

TAY "on

ro

Mts 268 (a)

Kk rrpIDYA e. with a 70 (g) sch 25 | And hear about

IN

11 to, 706 (a) so 30 no U. so and A sch 12 gas 27 (8) cm 35 TU. scha n (ge) 13 i 442 (a) « 40 times - p

From" 14 te on 280 (6)

K i tu so o 15 V 210 (8) t 50 s b so | he and (16 and 6 (in) ki v ton o 17 | not a urologist) yu ;

YAKU, ov ; m bo PD b5

18 t 74 (8) g children

M

19 t 505 (a)

Ko et 10. 20 Ra 243 (a) and on

M

What, the 21st | vov (d) yu and o on 22 v 185 (a)

F obout sch o 23 v-jv 41 (v) and: er | «so so 24 / 632 (in) s i diti ton | s 7 28 Z | / 504 (a) so

K a aa " 26 y 777 (a) 8 :z" ts V 27 ono 53 (c) y 4 i; so o- U, ko 28 sh 49 (a) so KU. he so 50 y z 4) 29 s, 394 (a) rachoch o zo vi 99 (z) y Om 7 di bo b5

And 31 what it is! 156 (a)

And a

And what is 70 and a - the value of two tests b - the value of three tests 15. c- values of four tests

Example 33

The ability of the compounds to antagonize the effect of androgen on the androgen receptor was determined in a whole cell assay as described below.

Experimental procedure of cellular research of AR antagonist

Cell line: MOA-MV453-MMTM clone 54-19. This cell line is a stably transfected cell line with

MOA-MV453 background cells (human breast tumor cell line expressing the androgen receptor).

First, a MMTMU minimal promoter containing ACE was cloned in front of the firefly luciferase reporter gene. Then the cascade was cloned into the pOM120rygo transfection vector. Electroporation was used to transfect MOA-MV-453 cells. A cell line with stable resistance to pyromycin was selected.

Cell culture medium and reagents:

Culture medium: OMEM (high glucose content, Sirso cat Mo11960-044), 1095SET, and 195 I -glutamine.

Tablet medium: OMEM (phenol red free), 1095 charcoal treated with NuSiope serum, 190 o |-glutamine. co

Research medium: OMEM (phenol red free), 195 charcoal treated with NuSiope whey, 195

I-glutamine, and 195 penicillin/streptomycin. and.

Cx luciferase buffer: 295 beta-mercaptoethanol, 0.696 ATP, 0.0135956 luciferin in cell lysis c buffer.

Research methodology: c 1. Cells are maintained in a culture medium, cells are separated when they reach 80-9090 confluence. 2. Test compounds, 10,000 cells/well are placed on opaque 96-well culture plates in 10µl/well medium, the culture is maintained overnight at 372 in a cell culture incubator. 50 Z. Carefully remove the plate medium, then add 8 Ωcl/well of pre-warmed test medium, add 1 Ωcl/well of the test compound (final concentration) 100OnM, 20OnM, "» 4OnM, 8nM, 1.6nM and 0.32nM) , incubate at 372C for 30 minutes." 4. Add 1 µl/well of freshly obtained ONT (final concentration 100 pM) to each well, incubate at 372 for 17 h (overnight). y y no y so 5. Add 5µl/well of 3x luciferase buffer, incubate at room temperature for 5 minutes, then count on a Luminometer. io) The fold induction over the background of 100 pM ONT in the absence of the test compounds was standardized to 10090 and the experimental results were expressed as a percentage of inhibition of the test compounds. o 50 The results are presented below in Table II. The results are expressed as the mean value of several tests, (se) as described below (number of tests is indicated in the footnote). M.O. means that the compound has not been tested. (42)

F) ko 60 b5

Table I! | Example | The structure of AR cells

Mo ISvo (NM) 70 1 Ez and Ah

M

2 С M.0.

U. - Jan

Mshchi - with 13 Ezo 21000 (a); (5)

N y a y so 4 in 21000 (a) c s

M br so 5 pe 5OZ (a) " pav no s " an z pe 662 (a) so Or

Ф НН for 17 gzs 21000 (c) and ANU yu m » u shchi on o y P 21000 (a) bo b5 u on MO and dits on | 274 a)

VU

ЙЙ К е ч ЕС Mo 5 и оон

I 42 ES 289 (a) 20 times 13 | TU. IMO /x - scha cm 25 o 1 4 ES AJ | 794 (a)

M y o Y (se) 30 ra | co

Criminal Code 124 (a) p

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Example 34

Animal model of androgenic alopecia

As described above, alopecia is a problem to which medicine devotes considerable attention. As with any disease, researchers are developing animal models to test compounds to determine their relative effectiveness. Compounds showing the highest efficacy in these animal models are used in subsequent human studies. Two different animal models have been developed to study alopecia. The first is a telogen conversion study using female SZN/Nem mice. The second model uses cynomolgus monkeys, which are monkeys with androgenetic alopecia.

The telogen shift assay measures the activity of a compound to convert the resting stage of the hair growth cycle ("telogen") into the active stage of the hair growth cycle ("anagen") in mice. This study has the advantage that the fur (ie, hair) of 7-week-old SZN/NeM mice is in the telogen phase. This phase continues until approximately 75 days of age.In this study, mice are shaved in specific areas, treated with either a test agent or a control agent, and the difference in the rate of hair growth (ie, induction of the anagen phase) is measured. The first sign of anagen is the darkening of the skin color due to the synthesis of melanin by melanocytes in the follicles, in preparation for the production of pigmented hair. This model has a number of advantages, including the availability of female CHzNemMm mice, suitability for rapid screening of a large number of compounds, and ease of maintenance and manipulation of such animals.

The first advantage of this model is its similarity to androgenetic dependence. While the exact cause of baldness in humans is unknown, it is well known that androgens induce regression of hair follicles on the scalp. This postadolescent regressive change is the fundamental cause of male pattern baldness (ie, androgenetic alopecia). This phenomenon occurs in men and women who have inherited genetic alopecia, as mentioned earlier. For a more detailed introduction to the effect of androgens on the human scalp, the reader's attention is drawn to the publication Tcher, KM, MoiIesciag Mespapiztvoi Apagodepis AIoresia, Ehr

Segopioiodu, 2002, 27:981-990.

The researchers also looked at other animals that had hair growth similar to humans. This led researchers to tailless macaques. These primates also suffer from androgenetic alopecia. Essentially, all post-adolescent macaques, of both sexes, develop baldness. Similar to the development of male pattern baldness in humans, male androgens are a mandatory initiating factor for male pattern baldness in macaques. Thinning of hair on the frontal part of the scalp begins to manifest itself during the same age (4 years) when (8) serum testosterone levels begin to rise dramatically in male animals. Although the increase in testosterone levels in females is about one-tenth that of males, there is no difference between the degree and age of onset of baldness in male and female cynomolgus macaques. Local application of anti-androgens reverses this baldness in animals of both sexes |Rap, N.) ei aiYi, Emaishsayop oi KI58841 az ap apii-apagodep ip rgoviaie RSZ seiYiiv and a Ooris! apii-aIoresia adepi ip (Pe raia zsayir oi zishtr (ayey tasadzez Epdosgipe 1998; 9:39-43). so

Although this model is a significant improvement on the study of telogen conversion, as a model of human baldness, it suffers from a number of practical drawbacks. Macaques are expensive, relatively rare, require considerable attention in care, and require extensive washing before testing. Thus, the macaque is not a practical model for the study of a large number of compounds. co

It has been discovered that male SZN/NeMm mice can be used in telogen conversion studies when anti-androgen compounds are evaluated. Thus, the model involves a modification of existing research on telogen conversion. Male SZN/NeM mice approximately 7 weeks of age are used. These animals are also constantly in the telogen phase, just like their female counterparts. However, once shaved, the androgens present in these male mice inhibit the conversion of hair follicles into the anagen phase. Anti-androgens will block this androgenetic effect and the follicles will turn into anagen, just like their female counterparts.

Example 34A from the compound described in Example 23, (15,45)-4-(4-Hydroxy-1-methylpentyloxy)-2-trifluoromethylbenzonitrile was proposed for further experiments using the modified telogen transformation study described above. Testing was carried out as follows. co In this study, male SZN/NemM mice, aged 6-7 weeks, were used (SNagiez Kimeg and Arogayogiev,

Kaividy, MS) The fur was trimmed with scissors on the backs of the mice before the start of the study. Only mice with pink skin, visually induced telogen phase, were selected for inclusion in the study. of the Test Compound was dissolved in a solvent containing propylene glycol (30905) and ethanol (7095) to give a 5p concentration of either 0.290 v/o, 0.590 v/o, 195 v/o or 395 v/o. The relevant dose was applied locally to the clipped dorsal region of mice in the first group being tested (7-10 mice) in a volume of 20 μl/cm 2. The third group of animals

Fo received only the solvent and was used as a control. Treatment was carried out twice a day for 4 weeks.

The treated area was analyzed and evaluated every subsequent day for signs of hair growth. Hair growth was measured and noted, for each animal, from the day on which the first signs of hair growth appeared on the treated surface. The first sign of anagen was the darkening of skin color due to the start of synthesis (F) of melanin by melanocytes in the follicles, in preparation for the production of pigmented hair. Mice were observed for 35 days or longer. The percentage of mice showing signs of hair growth in both the treated group and the control group is graphically presented below in Fig.1. The compound of Example 23, when tested at a concentration of 195, caused significant hair growth by stimulating the induction of anagen in the test animals.

The rate of hair growth in the 595 test group did not exceed the value of the solvent-treated control group.

Example 348

The product of Example 27, 2-chloro-4-(3-hydroxy-2,2,4-trimethylpentyloxy)benzonitrile, was submitted to testing 65 using the modified telogen conversion assay described above. Testing was carried out in the same way as Example C37A, the test concentration was 395 ppm. Hair growth rate for the tested group,

did not exceed the value of the control group.

Example 35

Animal model of sebum production inhibition

The authors describe an animal model for testing the ability of compounds to modulate sebum secretion. Agsp. Yuegt. Kevz. 258, 185-191 (1977). This model uses male Syrian hamsters whose ears contain sebaceous glands. this study used some of the compounds obtained above.

Sebum inhibition testing was performed as follows. Male Syrian hamsters aged 9-10 weeks were placed in laboratory conditions and acclimatized for 2 weeks before the study. Each group of 7/0 consists of 5 animals and a parallel study with solvent and positive control was performed. Before use, 30 mg of each compound was dissolved in 1 ml of a universal solvent (ethanol/propylene glycol (70/309606/o6) to obtain a final concentration of Zv/o9b5.

The compound was applied topically to the animals twice a day, five days a week, for 4 weeks. Each dose contains 25 microliters of control solvent or active agent. Doses were applied to the ventral surfaces /5 of the right and left ears. All animals were killed approximately 18-24 hours after the last dose. The right ears of each animal were collected and used for sebum analysis.

Ears were subjected to HPLC analysis as follows. One 8 mm distal biopsy puncture was taken, just above the anatomical "M" mark in all to normalize the plane of the specimen. The puncture was pulled out separately. The ventral biopsy surface (the area on which the local dose was directly applied) was kept for testing and the dorsal surface of the biopsy puncture was discarded.

Tissue samples were washed with M" and stored at -802C under nitrogen until HPLC analysis. In addition to each of the ear samples, an aliquot of each active agent and solvent (at least 2500 μl) was also stored at -802C during entry into the HPLC analysis.

HPLC analysis was performed on the tissue sample extract. Fabric samples were brought into contact with 3 ml of solvent (41 F with a mixture of 2,2,4-trimethylpentane and isopropyl alcohol). The mixture was shaken for 15 minutes and stored overnight at room temperature, in a place protected from light. The next morning, 1 milliliter of water was added to the samples and shaken for 15 minutes. The sample was centrifuged at approximately 1500 rpm for 15 minutes. Two ml of the organic phase (upper layer) was transferred to a glass flask, dried at 37 2С, in a nitrogen atmosphere, for about 1 hour, and then lyophilized for about 48 hours. Samples (Ce) were removed from the lyophilizer and each flask was reconstituted with 100 μl of solvent A (trimethylpentane/tetrahydrofuran (99:1). Samples were capped and shaken for 5 minutes. 200 μl of each sample was transferred to a prelabeled 200 μl HPLC cone with 200 μl glass sleeves.

HPLC flasks were placed in the autosampler tray of the Adiepi 1100 series HPLC device. The Adiiepi 1100 HPLC system includes a thermostatic autosampler, a quaternary pump, a column heater, and an A/O interface module. All the villages

Components were monitored using Addiepi Spatbiaop software. Analytical co-column UMaiege ZrPegizogb ZZMU 4.6x100mm was maintained at 302 using an Adiyepi column heater.

The HPLC autosampler was programmed to maintain the sample temperature at 202C throughout the passage through the column. 10 μl of each sample was injected three times into the column. Two solvents were used to create a solvent gradient. Solvent A was a mixture of trimethylpentane and tetrahydrofuran (99:11). Solvent B was also ethyl acetate. The gradient was used as described in the following table: ;" ; in" av 1412 so yuyu kyu yuyu | in its 1 so Bedeh 75 Emarogaime GidnE ZsaKegipda Oei(esiyuog (EI 50) worked at 452 with an increase of 5 and a pressure of Mo 3.1bar in The analog signal received using the device was sent to the software module Adiyepi A/U, where it was converted into a digital conversion was based on 10000mA/volt per point I data rate was 10Hz (0.03min) The resulting digital signal was fed to the Adiyepi Speto5iayop program for peak plane integration

The results of the HPLC analysis are given below in Table IM. The results are given as a reduction in the production of cholesterol ester (CE) and wax ester (ME) compared to the control solvent

Go) Table IM 60 b5

Fo Decrease | 95 Reduction of the amount

Compound Structure

IS

E E

Example 23 m 67 8795 15495 and ser p -v 9 74 9 18 ryklad 15 E no. .sn, A 496 12896

Columns 1 and 2 identify the compound by structure and example number. Columns C -5 show the effect of the compounds on reducing sebum components (SE and M/E). The results are expressed as the difference with the control solvent. A positive value reflects a decrease in the production of measured components of sebum, i.e. cholesterol ester (CE) or wax ester (ME).

Column C shows that the compounds are able to reduce the amount of cholesterol ester in the sebum sample.

Scheme 4 shows the effect of the compound on wax ester generation. Wax esters are specific markers of the sebaceous glands and are largely undetectable in any other layer of the skin. Wax ester is the most important component of sebum (about 2595). Thus, the reduction of the wax ester typically leads to a significant reduction in sebum secretion. In column 5, the summarized results are expressed in columns 3 and 4 (and included to further explain relative differences in activity). As shown in Table IM, the androgen modulators of formula I significantly reduce the production of both cholesterol ester and wax ester. (Te) co

Claims (14)

The formula of the invention p 1. Compound of the formula: s M ze ! ХХО) ге) и зо--(Снна-АК-2 « prodrug form of the mentioned compound, hydrate of the mentioned compound or pharmaceutically acceptable salt of the mentioned (-) с compound, in which: h» X is halogen or haloalkyl; " X? is and 2 are each, independently, a substituent selected from the group consisting of hydrogen, halogen, C 16 alkyl, 395 haloalkyl, hydroxyalkyl, thiol, and thioalkyl ; co C, 2, and B3 are each, independently, a substituent selected from the group consisting of hydrogen, halogen, C-6 alkyl, co haloalkyl, hydroxy, hydroxyalkyl, thiol, thialkyl, and -Mv987 t p represents 0 or 1; AIK' is a C 4.8 linear alkylene group in which up to 8 hydrogen atoms of the alkylene group can be co-substituted with a substituent selected from the group consisting of C 46 alkyl, haloalkyl, halogen, hydroxy, b hydroxyalkyl, thiol, thioalkyl and -MA9B 7; BZ B is each, independently, hydrogen or C. in alkyl; provided that: 1) if n is 0 and X? is -"СНА-СН о or -сСе СН , then at least one of К' or К? is thiol, Ge) hydroxyalkyl or thioalkyl; 2) if n is 1 and X? is -"СН-СН". or -Ce CH , then, alternatively, at least one of K" or VK? is a substituent selected from the group consisting of thiol, hydroxyalkyl, and thialkyl, or at least one hydrogen atom of AK! is replaced by a substituent selected from the group , which contains hydroxy, thiol, hydroxyalkyl, and thioalkyl; 3) if n is 0 and X? represents -CB ZB", then, alternatively, at least one of B or EC? is a substituent selected from the group consisting of thiol, hydroxyalkyl, and thialkyl, or at least one of 23, 27, or 2? is hydroxy, hydroxyalkyl, thiol or thioalkyl; 4) if n is 1 and X2? represents -CB ZB", then, as an alternative: a) at least one of K' or B? is a 65 substituent selected from the group consisting of thiol, hydroxyalkyl and thioalkyl, b) at least one of 23, 7 or b5 represents is a substituent selected from the group containing hydroxy, hydroxyalkyl, thiol and thioalkyl, or c) at least one hydrogen atom AIK! substituted with a substituent selected from the group consisting of hydroxy, thiol, thioalkyl and hydroxyalkyl. 2. The compound according to point 1, in which n is 0 and at least one of KE", B2, KZ, BK", B? is C 46 alkyl, haloalkyl, hydroxyalkyl and thioalkyl. Z. The compound according to item 1, in which n is 1 and at least one hydrogen atom is АЙКк! substituted with a substituent selected from the group consisting of C 1-6 alkyl, haloalkyl, hydroxyalkyl and thioalkyl, or one of 2", 2, 83, 7, Vo is C 1-6 alkyl, haloalkyl, hydroxyalkyl and thioalkyl. 4. The compound according to item 1, 2 or 3, in which Hu is CEz and is located in the 2-position of the phenyl ring. 5. A compound according to item 1, 2, C or 4, in which X? is SEZV"R", in which at least one of KZ, KK? or BO / is hydroxy or hydroxyalkyl. 6. A compound according to claim 5, wherein at least one of C, B" or B" is methyl. 7. The compound according to item 1, wherein said compound is selected from the group consisting of: (15,25)-4-(2-hydroxy-1-methylpropoxy)-2-trifluoromethylbenzonitrile; t (15,25)-4-(2-hydroxy-1-methylpropoxy)-2-trifluoromethylbenzonitrile; 4-(2-hydroxy-1-methylpropoxy)-2-trifluoromethylbenzonitrile; 4-(2-hydroxy-β6-methylheptyloxy)-2-trifluoromethylbenzonitrile; 4-(2-hydroxyoctyloxy)-2-trifluoromethylbenzonitrile; 4-(2-hydroxyoct-7-enyloxy)-2-trifluoromethylbenzonitrile; 20 4-(3-hydroxybutoxy)-2-trifluoromethylbenzonitrile; (35)-4-(3-hydroxybutoxy)-2-trifluoromethylbenzonitrile; 4-(3-hydroxyhex-5-enyloxy)-2-trifluoromethylbenzonitrile; 4-(3-hydroxy-2-methylbutoxy)-2-trifluoromethylbenzonitrile; 4-(3-hydroxy-2, 2-dimethylpropoxy)-2-trifluoromethylbenzonitrile; c 25 4-(3-hydroxy-3-methylbutoxy)-2-trifluoromethylbenzonitrile; Ge) 4-(3-hydroxy-2,2,4-trimethylpentyloxy)-2-trifluoromethylbenzonitrile; 4-(2-ethyl-3-hydroxyhexyloxy)-2-trifluoromethylbenzonitrile; 4-(2-(1-hydroxyethyl)hexyloxy|-2-trifluoromethylbenzonitrile; (15,35)-4-(3-hydroxy-1-methylbutoxy)-2-trifluoromethylbenzonitrile; i-th 3o (1kK,3k)-4 -(3-hydroxy-1-methylbutoxy)-2-trifluoromethylbenzonitrile; c 4-(4-hydroxybutoxy)-2-trifluoromethylbenzonitrile; 4-(4-hydroxybutoxy)-2-trifluoromethylbenzonitrile; c 4-(4-hydroxyheptyloxy)-2 -trifluoromethylbenzonitrile; c 4-(4-hydroxy-1-propylbutoxy)-2-trifluoromethylbenzonitrile; 35 4-(4-hydroxy-1-methylpentyloxy)-2-trifluoromethylbenzonitrile; c (1kK,4kK)-4-(4-hydroxy -1-methylpentyloxy)-2-trifluoromethylbenzonitrile; (15,45)-4-(4-hydroxy-1-methylpentyloxy)-2-trifluoromethylbenzonitrile 4-(5-hydroxypentyloxy)-2-trifluoromethylbenzonitrile; « 4-(5-hydroxyhexyloxy )-2-trifluoromethylbenzonitrile; 70 4-(5-hydroxy-3-methylpentyloxy)-2-trifluoromethylbenzonitrile; in c 2-chloro-4-(3-hydroxy-2,2,4-trimethylpentyloxy)benzonitrile; ; with" 2 -chloro-4-(4-hydroxybutoxy)benzonitrile; 2-chloro-4-(3-hydroxypropoxy)benzonitrile; 2-chloro-4-(1-hydroxymethylallyloxy)benzonitrile; 2-chloro-4-(3-hydro xy-2-methylpropoxy)benzonitrile; so 2-chloro-4-(5-hydroxy-pentyloxy)benzonitrile; Kz 2-chloro-4-(4-hydroxy-1-methylpentyloxy)benzonitrile and 2-chloro-4-(5-hydroxy-3-methylpentyloxy)benzonitrile. o 8. (15,45)-4-(4-hydroxy-1-methylpentyloxy)-2-trifluoromethylbenzonitrile or its pharmaceutically acceptable o 50 salt, 9. Use of the compound according to any of items 1-8 as a medicament. shi 10. Use of the compound according to any of items 1-8 in the production of a medicament for modulating the activity of the androgen receptor. 11. Use of the compound according to any of items 1-4 in the production of a topical medication for the treatment of androgenetic alopecia, excess sebum or acne. F! 12. A pharmaceutical composition containing a compound according to any one of items 1-8 in combination with 1 or more pharmaceutically acceptable excipients. who 13. A topical pharmaceutical formulation comprising a compound according to any one of claims 1-8 in combination with 1 or more pharmaceutically acceptable excipients suitable for dermal application. 60 14. A product containing a compound according to any one of claims 1-8, packaged for retail sale, which has instructions for the purchaser to use the compound to alleviate a condition selected from the group consisting of acne, alopecia and oily skin. b5