CN100475781C - 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

Androgen receptor modifier

Technical field

The present invention relates to the new benzonitrile of a class with and as the application of androgen receptor modifier.Others of the present invention relate to the topical application that these compounds are used to alleviate alopecia and oily skin.

Technical background

Alopecia or deglabration are the FAQs that medical science still will be cured.It is unknown that the physiological mechanism of this alopecia remains.But more known have the individual natural on-off cycles of hair growth of alopecia worry to be changed.

Hair follicle experiences that some relate to vegetative period, the activity cycle of quiescent stage and the phase of coming off.People's scalp comprises 100,000 to 350,000 hair fibres or hair shafts usually, and it carries out various distortion three different stages:

(a) vegetative period (anagen) in, hair follicle (that is, hair root) is penetrated in the corium deeply, simultaneously in the process of accumulated angle albumen (main ingredient of hair), the cell of hair follicle is division and differentiation rapidly.For the people of deglabration is not taken place, continue this vegetative period from 1 year to 5 years;

(b) transitional period (catagen) be masked as stathmokinesis and continue from two thoughtful several weeks and;

(c) quiescent stage (telogen), this time interim, hair keeps high to 12 weeks on scalp, substitutes until the subcutaneous longer new hair follicle growth of looking unfamiliar of its head of a quilt.

For the people, this growth cycle is also asynchronous.Individual interimly in these three periods each the time all have thousands of hair follicles.But, the anagen that most of hair follicles all being in.For healthy young adult, the anagen and the ratio of telogen can be as high as 9: 1.For the individuality of alopecia, this ratio may drop to and be low to moderate 2: 1.

Androgenetic alopecia is by caused to the activation of androgenic heredity susceptibility.It is modal alopecia type.It not only influences male sex's (50%) but also influences women's (30%), mainly is white people (Caucasian origin).As time goes by and along with the increase at age, the diameter and the length of hair shaft all change gradually.Terminal hair is gradually transformed into short, thin, colourless hair.As a result, the male sex begins to notice that its hair becomes more and more thinner and shorter and shorter in its twenty or thirty when year and women during its thirty or forty years and four or five ten years old.For the male sex, most of alopecias betide the front portion and the crown of head.The women is attenuation on whole scalp then.As discussed above, the anagen and the ratio of telogen significantly reduce, thereby make natural on-off cycles of hair growth slack-off.

Minoxidil (a kind of potassium channel openers) can promote natural on-off cycles of hair growth.Minoxidil the U.S. can with

Trade mark obtain by commercial sources.Though the definite mechanism of action of not clear minoxidil has proved the macrocyclic influence of its correct generation well.Minoxidil has promoted hair follicle growth and has increased time anagen that hair follicle being arranged in (anagen of promptly having increased and the ratio of telogen).

Though minoxidil has promoted natural on-off cycles of hair growth,, the beauty treatment of this growth is renderd a service and is but differed greatly.For example, Roenigk has reported the result of the clinical trial that relates to 83 male sex, and they use 3% minoxidil topical application solution, use 19 months.The hair tonic phenomenon has appearred in 55% individuality.But only 20% individuality thinks that this growth is relevant with beauty treatment.( Clin.Res., 33, the 4 phases, 914A, 1985).Tosti has reported among its patient that the acceptable regeneration of beauty treatment has appearred in 18.1% patient.( Dermatologica, 173, the 3 phases, 136-138,1986).Therefore, in this field, need some to make hair loss patient the compound of the acceptable natural on-off cycles of hair growth of cosmetology occur with higher ratio.

General introduction of the present invention

The present invention has found 4-oxo-benzonitrile that a class is new.These compounds with and pharmaceutically useful salt, hydrate and prodrug can represent with following formula:

Wherein:

X ¹Expression halogen or haloalkyl;

X ²Expression CR ³R ⁴R ⁵,-CH=CH ₂, or-C ≡ CH;

R ¹, and R ²Expression independently of one another is selected from hydrogen, halogen, C _1-6The substituting group of alkyl, haloalkyl, hydroxyalkyl, sulfhedryl and sulfane base (thioalkyl);

R ³, R ⁴, and R ⁵Expression independently of one another is selected from hydrogen, halogen, C _1-6Alkyl, haloalkyl, hydroxyl, hydroxyalkyl, sulfhedryl, sulfane base and-NR ⁶R ⁷Substituting group;

N represents 0 or 1 integer;

ALK ¹Expression C _1-8Straight-chain alkyl-sub-, the height to 8 of a wherein said alkylidene group hydrogen atom can randomly be selected from C _1-6Alkyl, haloalkyl, halogen, hydroxyl, hydroxyalkyl, sulfhedryl, sulfane base and-NR ⁶R ⁷Substituting group replace;

R ⁶And R ⁷Represent hydrogen or C independently of one another _1-6Alkyl

Condition is:

1) if n is 0 and X ²Expression-CH=CH ₂Or-C ≡ CH, then R ¹Or R ²In at least one the expression sulfhedryl, hydroxyalkyl or sulfane base;

2) if n is 1 and X ²Expression-CH=CH ₂Or-C ≡ CH, then or R ¹Or R ²In at least one expression be selected from the substituting group of sulfhedryl, hydroxyalkyl and sulfane base, perhaps Alk ¹At least one hydrogen atom substituting group of being selected from hydroxyl, sulfhedryl, hydroxyalkyl and sulfane base replace;

3) if n is 0 and X ²Expression-CR ³R ⁴R ⁵, then or R ¹Or R ²In at least one expression be selected from the substituting group of sulfhedryl, hydroxyalkyl and sulfane base, perhaps R ³, R ⁴, or R ⁵In at least one expression hydroxyl, hydroxyalkyl, sulfhedryl or sulfane base;

4) if n is 1 and X ²Expression-CR ³R ⁴R ⁵, then or: a) R ¹Or R ²In at least one expression be selected from the substituting group of sulfhedryl, hydroxyalkyl and sulfane base, b) R ³, R ⁴, or R ⁵In at least one expression be selected from the substituting group of hydroxyl, hydroxyalkyl, sulfhedryl and sulfane base, perhaps c) Alk ¹At least one hydrogen atom substituting group of being selected from hydroxyl, sulfhedryl, sulfane base and hydroxyalkyl replace.

The compound of formula I is an androgen receptor modifier.This compound has avidity and will cause certain biological action by combining with this receptor androgen receptor.This compound generally can be used as antagonist.In embodiment selected, it can be used as partial agonist, full agonist or tissue selectivity agonist.As androgen receptor modifier, these compounds can be used to treat or mitigation and the relevant situation of the inappropriate activation of androgen receptor.For as for the antagonist, the example of such situation comprises without limitation that acne, sebum secretion are excessive, androgenetic alopecia, hormonal dependent cancer such as prostate cancer and hirsutism.These compounds as partial agonist, full agonist or tissue selectivity agonist can be used for treating osteoporosis, hypogonadism, anaemia or stimulated muscle quality increase (especially in the situation of wasting diseases).

The invention still further relates to can effectively regulate and control the pharmaceutical composition that androgen receptor activatory quantity comprises at least a formula I compound.In another embodiment, the invention still further relates to a kind of goods that comprise the packaged compound that is used for the formula I that retail distributes, subsidiaryly be useful on the suggestion human consumer and how use this compound to alleviate the explanation of the situation relevant with the inappropriate activation of androgen receptor.Another embodiment relates to the compound of formula I as the application of surveying the inappropriate activatory diagnostic reagent of androgen receptor.

In another embodiment, the compound of formula I is used to that the part is induced and/or stimulating hair growth and/or slow down trichomadesis.But described compound also topical application is used for treating the excessive and/or acne of sebum.

Detailed description of the present invention

Title in the presents only is to be used for promoting that the reader looks back it.It should not be considered to and will limit the present invention or claim by any way.

Definition and example

Unless specify in addition, defined implication below the term in the application's (comprising claim) below used has.Except that the expression numeral, odd number and plural number are used interchangeably:

A. " halogen " refers to chlorine, fluorine or bromine atoms.

B. " C ₁-C ₆Alkyl " refer to the branched-chain or straight-chain alkyl that comprises 1 to 6 carbon atom, as methyl, ethyl, just-propyl group, sec.-propyl, just-butyl, isobutyl-, amyl group, hexyl etc.

C. " haloalkyl " refers to the branched-chain or straight-chain alkyl that comprises 1 to 6 carbon atom, and wherein at least one hydrogen atom (is C by the halogen replacement ₁-C ₆Haloalkyl).The example of suitable haloalkyl comprises chloromethyl, difluoromethyl, trifluoromethyl, 1-fluoro-2-chloro-ethyl, 5-fluoro-hexyl, 3-two fluoro-sec.-propyls, 3-chloro-isobutyl-etc.

D. " hydroxyalkyl " refers to the branched-chain or straight-chain alkyl that comprises 1 to 6 carbon atom, and wherein at least one hydrogen atom (is C by the hydroxy functional group replacement ₁-C ₆Hydroxyalkyl).The example of suitable hydroxyalkyl comprises hydroxymethyl, 1,2-dihydroxyl-propyl group, 1-hydroxyl-amyl group, 6-hydroxyl-hexyl, 2-hydroxyl-ethyl etc.

E. " sulfane base " refers to the branched-chain or straight-chain alkyl that comprises 1 to 6 carbon atom, and wherein at least one hydrogen atom (promptly-SH) is replaced by sulfhedryl.The example of suitable sulfane base comprises thiomethyl alcohol, 2-thiol-ethyl, 1,3-two thiols-propyl group, 6-thiol-hexyl, 4-thiol-amyl group etc.

F. " straight-chain alkyl-sub-that comprises 1 to 8 carbon atom " to refer to the alkyl that comprises 1 to 8 carbon atom as the linking group in the molecule (be non-end-CH ₃Functional group).The example of such alkyl comprises-CH ₂-,-CH ₂-(CH ₂) ₄-CH ₂-,-CH ₂-(CH ₂) ₆-CH ₂-,-CH ₂-CH ₂-CH ₂-,-CH ₂-(CH ₂) ₂-CH ₂-etc.

G. " solvate " is the crystallized form that comprises the compound or its salt of one or more recrystallisation solvent molecules, promptly comprises the formula I compound or its salt with molecular form bonded solvent." hydrate " is the solvate that a kind of wherein said solvent is a water.

H. " polymorphic " is the compound or its salt that exists with at least a crystallized form, suc as formula the compound or its salt of I.

I. " male sex hormone " refer to testosterone with and precursor and metabolite and 5-α reductive male sex hormone, include but not limited to dihydrotestosterone.Male sex hormone refers to male sex hormone and the androgenic form of ownership natural, synthetic and that be substituted or modify that derives from testis, suprarenal gland and ovary.

J. " pharmaceutically useful salt " refers to " pharmaceutically useful acid salt " or " pharmaceutically useful base addition salt ", according to the practical structures of said compound.

K. " pharmaceutically useful acid salt " refers to any nontoxic organic or inorganic acid salt of the basic cpd shown in the formula I or its any intermediate.The illustrative example that forms the mineral acid of suitable salt comprises hydrochloric acid, Hydrogen bromide, sulfuric acid and phosphoric acid and acid metal salt such as ortho-phosphoric acid list hydrogen sodium and sal enixum.That the organic acid illustrative example that forms suitable salt comprises is single-, two-and tricarboxylic acid.Such sour illustrative example has for example acetic acid, oxyacetic acid, lactic acid, pyruvic acid, propanedioic acid, succsinic acid, pentanedioic acid, fumaric acid, oxysuccinic acid, tartrate, Citric Acid, xitix, toxilic acid, hydroxymaleic acid, phenylformic acid, hydroxy-benzoic acid, toluylic acid, styracin, Whitfield's ointment, 2-phenoxy benzoic acid, right-toluenesulphonic acids and sulfonic acid class such as methylsulfonic acid and 2-ethylenehydrinsulfonic acid.Such salt can exist with hydrate or substantially anhydrous form.Generally speaking, the acid salt of these compounds is in water and be can dissolved in the various hydrophilic organic solvents.

L. " pharmaceutically useful base addition salt " refers to any nontoxic organic or inorganic base addition salt of the compound shown in the formula I or its any intermediate.The illustrative example that forms the alkali of suitable salt comprises basic metal or alkaline earth metal hydroxides such as sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide or hydrated barta; Ammonia and aliphatic series, alicyclic or aromatics organic amine such as methylamine, dimethylamine, Trimethylamine 99 and picoline.

M. " prodrug " thus refer to and for example can transform the compound that produces the parent compound of following formula by hydrolysis in blood in vivo apace.At T.Higuchi and V.Stella, " as the prodrug (Pro-drugs as Novel DeliverySystems) of newtype drug transfer system; " the 14th volume, A.C.S.Symposium Series, with the bioreversible carrier (Bioreversible Carriers in Drug Design) in the medicinal design, Edward B.Roche chief editor, American Pharmaceutical Association and PergamonPress, in 1987 it is gone through, it here all is introduced into as a reference.

N. " compound of formula I ", " compound of the present invention " and " compound " can exchange in this application and use and should be regarded as synonym.

O. " patient " refer to warm-blooded animal as, for example, cavy, mouse, rat, pallasiomy, cat, rabbit, dog, monkey, chimpanzee, docking macaque (stump tail macques) and people.

P. " treatment " refer to the ability of compounds for reducing, alleviation or the patient disease that slows down (or situation) process or any tissue injury relevant with said disease.

The compound of some formula I will exist with the form of optical isomer.All refer to for the appellation of one of compound shown in the formula I in this application and comprise the optical isomer that it is specific or the mixture (unless clearly getting rid of) of optical isomer.Can separate the fractionation of carrying out by selective crystallization to it then and come specific optical isomer is separated and reclaims with technology well known in the prior art such as chiral stationary phase chromatography method or by forming chirality salt.Perhaps optical isomer that can be specific prepares corresponding isomer as end product as parent material.

In addition, compound of the present invention can also and have acceptable solvent such as the solvation form of water, ethanol etc. exists with the form of solvation not.For purpose of the present invention, it has been generally acknowledged that solvation form and solvation form not are equal to.Compound can also exist with different polymorphic forms and will be understood that claim covers all such forms.

The compound of all formula I all comprises a phenyl ring.In order further the present invention to be illustrated, the numbering system of this ring with and substitute mode as follows:

1 of this phenyl ring is always replaced by above-mentioned cyano group part.4 Sauerstoffatoms that are formed ether moiety replace.As X ¹Shown in, this phenyl ring can also further be replaced by halogen atom or haloalkyl part on 2 or 3.This halogen or haloalkyl part typically are positioned on the 2-position.It more typically is the trifluoroalkyl that is positioned on this phenyl ring 2-position.

As implied above, 4 of this phenyl ring are replaced by a kind of ether moiety, and it all will comprise all the time :-(CR ¹R ²)-(ALK ¹) _n-X ²When existing, AlK ¹Represent a kind of C ₁To C ₈The straight-chain alkyl-sub-part is as methylene radical, ethylidene, propylidene, butylidene, pentylidene, hexylidene, inferior heptyl or octylene.The height to 8 of a this alkylene moiety hydrogen atom can be by a kind of replacement the in the substituting group as defined above.Alk ¹Any single carbon atom can not be substituted, coverlet replaces or two replacements.These carbon atoms can be replaced by identical substituting group or different substituting groups.

Ether moiety-(CR ¹R ²)-(ALK ¹) _n-X ²To be replaced by at least one hydroxyl, sulfhedryl, hydroxyalkyl or sulfane base portion branch.This replacement can (it depends on that still there is not Alk in existence by a kind of the finishing in two kinds of substitute modes ¹).If in this molecule, there is not Alk ¹(being that n is 0), then R ³, R ⁴, or R ⁵In a kind ofly can represent hydroxyl, hydroxyalkyl, sulfhedryl or sulfane base, perhaps R ¹Or R ²In one can represent hydroxyalkyl, sulfhedryl or sulfane base.If Alk ¹There is (being that n is 1), then: a) R ³, R ⁴, R ⁵In one can represent hydroxyl, hydroxyalkyl, sulfhedryl or sulfane base, b) R ¹Or R ²In one can represent hydroxyalkyl, sulfhedryl or sulfane base, perhaps c), Alk ¹A carbon atom can be replaced by hydroxyl, hydroxyalkyl, sulfhedryl or sulfane base.

This requirement that this molecule comprises hydroxyl or sulfhedryl functional group should not regarded as this molecule only is defined as a hydroxyl or sulfhedryl part.If necessary, this ether moiety-(CR ¹R ²)-(ALK ¹) _n-X ²Can consistently comprise a plurality of hydroxyls, hydroxyalkyl, sulfane base and sulfhedryl functional group with above-mentioned substitute mode.

In another optional embodiments of the present invention, for these compounds, X wherein ²Be CR ³R ⁴R ⁵With n be 0; R ¹, R ², R ³, R ⁴, or R ⁵In at least one the expression C ₁-C ₆Alkyl, haloalkyl, sulfane base or hydroxyalkyl (be said ether residue ,-CR ¹R ²-(Alk ¹) _n-X ²Be branched-chain alkyl).In another alternative embodiment, for these compounds, X wherein ²Be CR ³R ⁴R ⁵With n be 1; R ¹, R ², R ³, R ⁴, or R ⁵In at least one the expression C ₁-C ₆Alkyl, haloalkyl, sulfane base or hydroxyalkyl or Alk ¹A hydrogen atom be selected from C ₁-C ₆The substituting group of alkyl, haloalkyl, sulfane base or hydroxyalkyl replace (be said ether residue ,-CR ¹R ²-(Alk ¹) _n-X ²Be branched-chain alkyl).

The more specific embodiment of the present invention relates to wherein:

1) X ¹Be CF ₃And be positioned on the 2-position of said phenyl ring and X ²Be CR ³R ⁴R ⁵, R wherein ³, R ⁴, or R ⁵In one be hydroxyl;

2) X ¹Be on Cl and the 2-position that is positioned at said phenyl ring and X ²Be CR ³R ⁴R ⁵, R wherein ³, R ⁴, or R ⁵In one be hydroxyl;

3) X ¹Be CF ₃And be positioned on the 2-position of said phenyl ring R ¹Be hydrogen and R ²Be C ₁-C ₆Alkyl, n are 1, wherein Alk ¹Be methylene radical, ethylidene, propylidene or butylidene, X ²Be-CR ³R ⁴R ⁵, R wherein ³Be hydrogen or C ₁-C ₆Alkyl, R ⁴Be hydrogen or C ₁-C ₆Alkyl, and R ⁵It is hydroxyl;

4) X ¹Be CF ₃And be positioned on the 2-position of said phenyl ring R ¹Be hydrogen or C ₁-C ₆Alkyl, R ²Be hydrogen, n is 0, and X ²Be CR ³R ⁴R ², R wherein ²Be hydroxyl or hydroxyalkyl, R ⁴Be hydrogen or C ₁-C ₂Alkyl and R ⁵Be hydrogen; Perhaps

5) X ¹Be CF ₃Perhaps Cl and be positioned on the 2-position of said phenyl ring R ¹And R ²Each is hydrogen naturally, and n is 1, wherein Alk ¹Be that (it can be independently selected from hydroxyl, hydroxyalkyl or C by 1 to 3 for methylene radical, ethylidene, propylidene or butylidene ₁-C ₆The substituting group of alkyl replaces) and X ²Be CR ³R ⁴R ⁵, R wherein ³Be hydrogen or hydroxyl, and R ⁴And R ⁵Each is hydrogen or C naturally ₁-C ₆Alkyl

The compound of formula I.

The more specific example of the compound that formula I is included comprises:

I) 4-(2-hydroxyl-1-ethyl-propoxy-)-2-trifluoromethyl-benzonitrile;

Ii) 4-(2-hydroxyl-1-methyl-propoxy-)-2-trifluoromethyl-benzonitrile;

Iii) 4-(3-hydroxyl-1-methyl-butoxy)-2-trifluoromethyl-benzonitrile;

Iv) 4-(2-hydroxyl-6-methyl-heptan oxygen base)-2-trifluoromethyl-benzonitrile;

V) 4-(2-hydroxyl-7-hydroxyl-heptan oxygen base)-2-trifluoromethyl-benzonitrile;

Vi) 4-(2-hydroxyl-octyloxy)-2-trifluoromethyl-benzonitrile;

Vii) 4-(2-hydroxyl-8-hydroxyl-8-methyl-octyloxy)-2-trifluoromethyl-benzonitrile;

Viii) 4-(2-hydroxyl-Xin-7-alkene oxygen base)-2-trifluoromethyl-benzonitrile;

Ix) 4-(2-hydroxyl-Xin-7-alkynyloxy group)-2-trifluoromethyl-benzonitrile;

X) 4-(2-ethyl-3-hydroxyl-butoxy)-2-trifluoromethyl-benzonitrile;

Xi) 4-(3-hydroxyl-butoxy)-2-trifluoromethyl-benzonitrile;

Xii) 4-(3-hydroxyl-own-5-alkene oxygen base)-2-trifluoromethyl-benzonitrile;

Xiii) 4-(3-hydroxyl-own-5-alkynyloxy group)-2-trifluoromethyl-benzonitrile;

Xiv) 4-(3-hydroxy-2-methyl-butoxy)-2-trifluoromethyl-benzonitrile;

Xv) 4-(3-hydroxyl-2-propyl group-butoxy)-2-trifluoromethyl-benzonitrile;

Xvi) 4-(3-hydroxyl-2,2-dimethyl-propoxy-)-2-trifluoromethyl-benzonitrile;

Xvii) 4-(3-hydroxy-3-methyl-butoxy)-2-trifluoromethyl-benzonitrile;

Xviii) 4-(4-hydroxy-3-methyl-pentyloxy)-2-trifluoromethyl-benzonitrile;

Xix) 4-(3-hydroxyl-2,2,4-trimethylammonium-pentyloxy)-2-trifluoromethyl-benzonitrile;

Xx) 4-(2-ethyl-3-hydroxyl-hexyloxy)-2-trifluoromethyl-benzonitrile;

Xxi) 4-[2-(1-hydroxyl-ethyl)-hexyloxy]-2-trifluoromethyl-benzonitrile;

Xxii) 4-(3-hydroxyl-1-methyl-butoxy)-2-trifluoromethyl-benzonitrile;

Xxiii) 4-(3-hydroxyl-1-methyl-2-ethyl-butoxy)-2-trifluoromethyl-benzonitrile

Xxiv) 4-(4-hydroxyl-butoxy)-2-trifluoromethyl-benzonitrile;

Xxv) 4-(6-hydroxyl-heptan oxygen base)-2-trifluoromethyl-benzonitrile;

Xxvi) 4-(4-hydroxyl-heptan oxygen base)-2-trifluoromethyl-benzonitrile;

Xxvii) 4-(4-hydroxyl-1-propyl group-butoxy)-2-trifluoromethyl-benzonitrile;

Xxviii) 4-(4-hydroxyl-1-methyl-pentyloxy)-2-trifluoromethyl-benzonitrile;

Xxix) 4-(5-hydroxyl-pentyloxy)-2-trifluoromethyl-benzonitrile;

Xxx) 4-(5-hydroxyl-hexyloxy)-2-trifluoromethyl-benzonitrile;

Xxxi) 4-(5-hydroxy-3-methyl-pentyloxy)-2-trifluoromethyl-benzonitrile;

Xxxii) 2-chloro-4-(3-hydroxyl-2,2,4-trimethylammonium-pentyloxy)-benzonitrile;

Xxxiii) 2-chloro-4-(4-hydroxyl-butoxy)-benzonitrile;

Xxxiv) 2-chloro-4-(3-hydroxyl-propoxy-)-benzonitrile;

Xxxv) 2-chloro-4-(1-hydroxymethyl-allyloxy)-benzonitrile;

Xxxvi) 2-chloro-4-(1-hydroxymethyl-second alkynyloxy group)-benzonitrile;

Xxxvii) 2-chloro-4-(3-hydroxy-2-methyl-propoxy-)-benzonitrile;

Xxxviii) 2-chloro-4-(5-hydroxyl-pentyloxy)-benzonitrile;

Xxxix) 2-chloro-4-(4-hydroxyl-1-methyl-pentyloxy)-benzonitrile, or;

Xl) 2-chloro-4-(5-hydroxy-3-methyl-pentyloxy)-benzonitrile.

Synthetic

The compound of formula I can be prepared with the currently known methods similar methods that is used to prepare ether with this area.Reader's attention can be put on September 1 nineteen eighty-two disclosed european patent application 58932, and its content of describing such reaction here is introduced into as a reference.Following schema I summarizes a kind of such technology:

Schema I

As described above, one of parent material is the alcohol shown in the structure 1.As required in the end product, R ¹, R ², Alk ¹And X ²Should represent identical substituting group.These alcohol are known in the prior art, and can be buied by known commercial source.Perhaps, it can be as Tetrahedron:Asymmetry, 1991 the 2nd volumes, being prepared like that described in the 569th page.

Another kind of parent material is the 4-fluoro-benzonitrile shown in the structure 2.As required in the end product, X ¹Should represent identical substituting group.These benzonitriles are known in the prior art and can synthesize as described in the Japanese patent application 01097937.

Above-mentioned nucleophilic substitution can as be known in the artly be carried out like that.With the alcohol of structure 1 and excessive slightly alkali, contact as sodium hydride, produce a kind of alcoholate ion.This reaction is at aprotic solvent, as carrying out under about 0C under inert atmosphere (being generally nitrogen) in the tetrahydrofuran (THF).Said alcohol was stirred 5 to 60 minutes with said alkali.

Then, the 4-fluoro-benzonitrile that adds 1 equivalent structure 2 in this reaction medium also stirs time enough so that said alcoholate ion is replaced fluorine from this benzonitrile with this reactant.It generally needs 30 minutes to 24 hours.Usually this reaction allows to be heated to room temperature.

Can reclaim the product of required formula I by extraction, evaporation or other technology well known in the prior art.Then, can randomly come it is carried out purifying with chromatography, recrystallization, distillation or other technology well known in the prior art.

Such just as skilled in the art will be aware of; as discussed above; some methods that are used to prepare this compounds may need specific protective group, for example disturb or keep the integrity of such functional group to prevent that in reaction such functional group produces on the other parts of this molecule.Whether need the type of such protection and protection easily to determine by those skilled in the art, and will be along with the character of for example functional group and selected preparation method's condition and change.Can be referring to for example T.W.Greene, Protective Groups In Organic Synthesis, John Wiley﹠amp; Sons, New York, 1991.

Compounds more of the present invention are tart, thus its can with pharmaceutically useful salt forming cation.Compounds more of the present invention are alkaline, so it can form salt with pharmaceutically useful negatively charged ion.All such salt all in scope of the present invention and its can be prepared with ordinary method, as being prepared by said acidity and alkaline entity being combined (usually with stoichiometric ratio) in the medium of water-based, non-aqueous or partially aqueous with depending on the circumstances.Depend on the circumstances, can by filter, with the non-solvent precipitation filter then, solvent evaporation reclaims these salt, perhaps in the situation of the aqueous solution, can reclaim these salt by lyophilize.According to method well known in the prior art, these compounds can obtain with crystallized form, for example can be by it being dissolved in The suitable solvent (solvent mixture) as obtaining in ethanol, hexane or the water/alcohol mixture.

Medical science and cosmetic application

The compound of formula I is an androgen receptor modifier.It can be used for alleviating and the relevant situation of the inappropriate activation of androgen receptor.Can be used for treatment or alleviate the hormonal dependent cancer such as prostate cancer, prostatic hyperplasia of prostate, acne, hirsutism, sebum are excessive, alopecia, crinosity, sexual prematurity, prostamegaly, manlike and polycystic ovary syndrome as the compound of androgen antagonist.Compound as partial agonist or full agonist can be used for treatment or alleviates male hypogonadism, male sexual dysfunction (impotence, maledysspemtatogenic sterility), abnormality of sexual differentiation (malehermaphroditism), male delayed puberty, male infertility, aplastic anemia, hemolytic anemia, sicklemia, idiopathic thrombocytopenic purpura, myelofibrosis, the kidney anaemia, wasting diseases is (after the operation, malignant tumour, wound, chronic nephropathy, burn or AIDS inductive), alleviate the pain of female sex organs cancer in latter stage, inoperable breast cancer, mastopathy, endometriosis, female sexual disorder, osteoporosis, wound healing and muscle tissue reparation.

In order to show above-mentioned therapeutic property, these compounds need be to be enough to regulate and control androgen receptor activatory quantity by administration.Whether this quantity can be along with severity, the patient of the specified disease/situation of being treated, patient disease/situation, existed other basic morbid state to wait by the specific compound of administration, route of administration and this patient changes.When by the whole body administration, for top listed any disease or situation, the dosage range that described compound shows effect is generally about 0.1mg/kg/ days to about 100mg/kg/ days.May wish every day repeat administration and this administration will change along with the top condition of summarizing.

Compound of the present invention can carry out administration by all means.If it is effective for an oral administration.Said compound can also be by parenteral admin (promptly subcutaneous, intravenously, intramuscular, intraperitoneal or intrathecal drug delivery), rectal administration or topical.

In a typical embodiment, said compound is by topical.For hirsutism, alopecia, acne and sebum are excessive, especially be suitable for topical.Its dosage is variable, but instructs as general, and said compound will be with about 0.01 to 50w/w%, is more typically about 0.1 to 10w/w% quantity and is present in the skin acceptable carrier.This skin preparation will be applied to affected zone 1 to 4 time by every day." skin is acceptable " refers to and a kind ofly can be applicable to skin or hair and make drug diffusion arrive the carrier of site of action.Its more specific specially referring to needs to suppress androgen receptor activatory position.

In another embodiment, said compound is used for alleviating alopecia, especially androgenetic alopecia by topical application.Male sex hormone all has profound influence to hair growth and trichomadesis.In most of body area, as beard and pubis skin place, the vegetative period of male sex hormone by prolonging hair cycle (anagen) and increase hair follicle size come stimulating hair growth.Hair growth on the scalp does not need male sex hormone, and still, paradoxically, male sex hormone but is to have the scalp deglabration (androgenetic alopecia) of individuality of inherited genetic factors necessary, in this case, the anagen and the hair follicle size reduce gradually.Androgenetic alopecia is also very common in the women, and it is usually expressed as alopecia generalisata rather than shows as viewed pattern in the male sex.

Though said compound in most cases is used to alleviate androgenetic alopecia usually, the present invention is not limited to this specific situation.This compound can be used to alleviate the alopecia of any kind.The example of non--androgenetic alopecia comprises alopecia areata, because radiotherapy or alopecia that chemotherapy caused, alopecia cicatrisata, the alopecia relevant etc. with anxiety.The hair that used " alopecia " refers on the scalp among the application partially or completely comes off.

Therefore, said compound can be applied topically to scalp and hair and prevents or alleviate deglabration.Said compound also can be used for inducing or promote hair growth on the scalp by topical application.

In another embodiment of the invention, the compound of formula I by topical application to prevent from not wish to take place the hair growth in the hair growth zone.A kind of such application is to be used for alleviating hirsutism.Hirsutism is the hair excess growth in the zone (being female face) that does not have hair usually.Such unfavorable hair growth in most cases usually betides the women and usually comes across climacteric.The topical of The compounds of this invention will be alleviated this situation, thereby reduce or eliminate this unfavorable or undesirable hair growth.

Said compound also can be reduced sebum by topical application and produce, and more specifically is used to alleviate oily skin.Equally, these compounds also can be used for mitigate acne by topical application.

In another embodiment, these compounds as partial agonist or full agonist can be used for treatment or releasing osteoporosis disease.Being characterized as of osteoporosis owing to the unbalance bone loss that causes between bone resorption (destruction) and the bone forming, it is during since 40 years old and continue to run through people's (Eastell in all one's life with the ratio of annual approximately 1-4%, the treatment of postmenopausal osteoporosis (Treatment of postmenopausal osteoporosis), New Eng.J.Med.338:736,1998).In the U.S., there are 20,000,000 people to suffer from the perceptible vertebral fracture that causes owing to osteoporosis approximately at present.In addition, 250,000 patients that also have an appointment every year are owing to hip fracture takes place in osteoporosis, and its mortality ratio in initial 2 years is 12%-20%, and 30% patient needs family's nurse nursing and many people walking freely again after fracture simultaneously.For postmenopausal women, just after menopause, oestrogen deficiencies makes bone resorption increase, thereby has caused the bone loss in every year about 5% in the vertebra.Therefore, the first-line treatment/prevention of this situation is to suppress bone resorption with diphosphonate, oestrogenic hormon, selective estrogen receptor modulators (SERMs) and thyrocalcitonin.But bone resorption inhibitor is not enough to recover lost the patient's of a large amount of sclerotin sclerotin.After treating 7 years with Allan phosphoric acid salt, the increase of the spinal column B MD that the diphosphonate treatment reaches can reach 11%.In addition, because the speed difference that bone reverses between each position; Reversal speed in the vertebra bone trabecula is than the height in the long bone cortex, so bone resorption inhibitor effectiveness aspect bmd of proximal femur increase and prevention Hip Fracture is relatively poor.Therefore, the bone compound agent (osteoanabolic agents) that increases cortex/periosteum bone formation and long bone sclerotin can satisfy osteoporosis therapy, especially the needs that are not satisfied in the patient's that the hip fracture risk the is high treatment.

Many male sex hormones that studies have shown that are bone syntheticss (osteoanabolic) of the women and the male sex.Show the anabolic steroid material, can increase the sclerotin of postmenopausal women as abolon or Win-14833.Proved fully that in research recently male sex hormone is to the beneficial effect of postmenopausal osteoporosis (people such as Hofbauer with testosterone and oestrogenic hormon Combined Preparation, male sex hormone is to the effect of bone metabolism: latest developments and arguement (Androgen effects on bone metabolism:recent progress and controversies), Eur.J.Endocrinol.140,271-286,1999).Therefore, these compounds that show the formula I of agonist or partial agonist activity can be used for treatment or releasing osteoporosis disease, comprise primary osteoporosis as after old, the menopause and teenager's osteoporosis and secondary osteoporosis, as because the osteoporosis that hyperthyroidism or hypercortisolism (because corticosteroid treatment causes), acromegaly, hypogonadism, anostosi and hypophosphatasemia are caused.Other indication relevant with bone of the treatment correction that can be undertaken by the male sex hormone agonist comprises osteoporotic fracture, the spontaneous bone loss of children, alveolar bone loss, the loss of mandibular bone bone, fracture, osteotomy, periodontitis or prosthese inwardly grow (prosthetic ingrowth).

Can also be used for stimulating being subjected to wasting diseases the patient's who torments as AIDS, carcinemia, burn, ephrosis etc. muscle quality as these compounds of agonist or partial agonist.Suffering from the patient of wound, bedsore and gerontal patient etc. also can be benefited from androgenic anabolism.

Co-administered

In another embodiment of the invention, the compound of formula I can further strengthen its activity with other compound co-administered or possible side effect is minimized.For example, but known potassium channel openers such as minoxidil stimulating hair growth and induce the anagen.The example of other potassium channel openers comprises (3S; 4R)-3; 4-dihydro-4-(2; 3-dihydro-2-methyl-3-oxo pyridazine-6-yl) oxygen base-3-hydroxyl-6-(3-hydroxy phenyl) alkylsulfonyl-2; 2; 3-trimethylammonium-2H-benzo [b] pyrans, diaxozide and the also known energy of the PO1075 Triiodothyronine stimulating hair growth of developing by Leo Pharmaceuticals.Show that also synthetic Triiodothyronine substituent (promptly intending thyroid drug) also can stimulating hair growth.This comparison thyroid drug was carried out description in the former document.Be used to alleviate the discussion of alopecia for this compounds and its, the reader can note european patent application 1262177, and its content here is introduced into as a reference.A kind of special compound of interest is 2-{4-[3-(4-fluoro-benzyl)-4-hydroxyl-phenoxy group]-3,5-dimethyl-phenyl }-2H-[1,2,4] triazine-3, the 5-diketone.Anti--androgenic drug can work by many different mechanism.For example, some compounds block the conversion of testosterone to 5-α-dihydrotestosterone (it is responsible for the biological actions in many tissues).But 5-alpha-reductase inhibitors such as finasteride stimulating hair growth have been shown.Finasteride can by commercial sources with

Trade(brand)name derive from Merck.His chest amine (Glaxo Smithkline) of the example degree of comprising of other 5-alpha-reductase inhibitors.The compound co-administered of this compounds and formula I can be alleviated alopecia.

But the anagen of also having shown the inhibitors of protein kinase C stimulating hair growth and induced.Shown that Calphostin C (it is the protein kinase C selective depressant) is the anagen of can inducing.Also show the anagen that other selectivity inhibitors of protein kinase C such as HEXADECYL PHOSPHOCHOLINE, chlorination palmitoyl-DL-carnitine and Polymyxin B-sulfate USP can being induced.Skin Pharmacol Appl Skin Physiol in May, 2000-August; 13 (3-4): 133-42.Any such inhibitors of protein kinase C can be alleviated alopecia with the compound co-administered of formula I.

Immunophilin belongs to cytoplasmic protein family.Its part comprises S-Neoral, FK 506 and rapamycin.It derives from fungi and is developed mainly due to its potent protein immunization inhibition.S-Neoral and albumen---cyclophilin combines, and FK506 and rapamycin conjugated protein with FK (FKBP) combine.Shown that these compounds can stimulating hair growth and induce the anagen.Any such immunophilin part can be alleviated alopecia with the compound co-administered of formula I.

Used co-administered refers to the dosage regimen that promotes patient's hair growth the compound of formula I and the second kind of anti--alopecia agent administration together that has the different mechanisms of action usually among the application.It comprises that administration simultaneously, the different time in a day carry out administration or even do not carrying out administration on the same day.These compounds can or can be integrated in a kind of unitary agent by independent administration.Below the technology that is used to prepare such preparation is described.

Preparation

If necessary, said compound can be by directly administration under the situation of not using any carrier.But,, generally it is formulated in the pharmaceutical carrier for the facilitation administration.Equally, it the most typically is prepared in skin usefulness or the cosmetic carrier.In this application, term " skin carrier " and " beauty treatment " carrier can exchange use.It relates to the preparation that is designed to directly deliver medicine on skin or the hair.

Pharmaceutical composition and cosmetic compositions can be prepared with technology well known in the prior art.Usually the said compound of significant quantity and the pharmaceutically acceptable/usefulness of can improving looks carrier is admixed together.

For oral administration, said compound can be prepared to solid or liquid preparation such as capsule, pill, tablet, lozenge, melt, pulvis, suspension or emulsion.Solid unit dosage form can be to comprise the coventional type gelatine capsule of for example tensio-active agent, lubricant and inert filler such as lactose, sucrose and W-Gum or it can be a sustained release preparation.

In another embodiment, can in conjunction with tackiness agent such as gum arabic, W-Gum or gelatin, disintegrating agent such as yam starch or alginic acid and lubricant such as stearic acid or Magnesium Stearate the compound of formula I be become tablet with conventional tablet matrix such as lactose, sucrose and W-Gum.Liquid preparation is prepared by said activeconstituents is dissolved in water-based or the non-aqueous acceptable solvent, and as be known in the art such, it can also comprise suspensoid, sweeting agent, correctives and sanitas.

For parenteral admin, said compound dissolution can be carried out administration in the acceptable pharmaceutical carrier of physiology and with its form with solution or suspension.The illustrative example of suitable pharmaceutical carrier has the oil in water, salt solution, glucose solution, fructose soln, ethanol or animal, plant or synthetic source.As be known in the art such, this pharmaceutical carrier can also comprise sanitas, buffer reagent etc.When said compound during by intrathecal drug delivery, as be known in the art like that, it can also be dissolved in the celiolymph.

Compound of the present invention generally will be by topical.So as used herein, the part refers to said compound (with optional carrier) is directly applied on skin and/or the hair.Topical composition of the present invention can be the form of any other preparation commonly used in solution, lotion, ointment, emulsifiable paste, ointment, liposome, sprays, gel, foam, roller (roller sticks) or the dermatology.

Therefore, another embodiment relates to beauty treatment or pharmaceutical composition, particularly dermatological compositions, and it comprises the compound of at least a top formula I.Such dermatological compositions will comprise 0.001% to 10%w/w% said compound and with its blended skin acceptable carrier, and more typically comprise 0.1 to 5w/w% said compound.This based composition is employed 1 to 4 time common every day.For the discussion that how to prepare such preparation, but reader's main reference Remington ' s Pharmaceutical Science, the 17th edition, MackPublishing Co., Easton, PA.

Composition of the present invention can also be made up of the solid preparation of forming cleaning soap or cleaning rod.These compositions can be prepared with ordinary method.

Said compound can also be applied to hair with the form of the form of water-based, alcohol or water-based-alcohol solution or emulsifiable paste, gel, emulsion or mousse or the form that also comprises the pressurised aerosol composition of propelling agent.Composition of the present invention can also be a hair care composition, and particularly shampoo, hair setting lotion, processing lotion, typing emulsifiable paste or gel, dyeing composition, the lotion that is used to prevent trichomadesis or gel etc.The quantity of various components is quantity commonly used in the institute consideration field in the dermatological compositions of the present invention.

The medical science and the cosmetic compositions that comprise The compounds of this invention distribute (promptly making article) with packaged to be used for retail usually.Usually come such article are labelled and packed in the mode that is used to instruct the patient how to use this product.Such guidance will comprise time length, administration time table of the situation of being treated, treatment etc.

As be known in the art like that, the compound of formula I can also be mixed with any inert support and uses it in the laboratory test to measure the concentration of said compound in patient's serum, urine etc.Said compound can also be used as research tool.

Though invention has been described to have used its specific embodiment, but should be understood that, it can also carry out other variation, and the application covers any modification of the present invention, usage or accommodation, they follow principle of the present invention usually, and comprise known in the technical field of the invention or in the conventional practice scope, take place with the departing from of the disclosure of invention.Come the present invention is further described with the following examples and biological data.Should not think this openly is to limit the invention by any way.

Embodiment 1

(1S, 2S)-4-(2-hydroxyl-1-methyl-propoxy-)-2-trifluoromethyl-benzonitrile

With NaH (0.20g 4.14mmol) is suspended among the anhydrous THF of 15ml, then to wherein add (2S, 3S)-(+)-2,3-butyleneglycol (0.32g, 3.45mmol are arranged in the anhydrous THF of 5ml).This mixture was stirred 10 minutes down at 0 ℃, then to wherein adding 4-fluoro-2-trifluoromethyl-benzonitrile.This reaction mixture under nitrogen atmosphere, was stirred 1 hour down at 0 ℃.Then, in stink cupboard, at room temperature restir is 2 hours with this mixture.Should react with the extinguishing of 25ml distilled water, with ethyl acetate (3 * 20ml) extractions.Product is carried out purifying with column chromatography, use hexane: ethyl acetate=5: 1 to 1: 1 obtains pure product as eluent.

(M+1 is for C for MS:260.0 ₁₂H ₁₂F ₃NO ₂) LCMS:C-18 post (50%H ₂O/50%CH ₃CN), retention time: 1.81 minutes

Embodiment 2-27

With the general operation of embodiment 1, replace relevant parent material, the described compound of preparation Table I.Chromatography is on Foxy 200 fraction collectors, (all use 50: 50 water in all embodiment: acetonitrile is as eluting solvent with preparation Biotage SiliconGe l post, but except the embodiment 8,16,17,26, it uses 25: 75 water: the mixture of acetonitrile) carry out.Mass spectrum in the Table I writes down with Hewlett Packard mass spectrograph.

Embodiment 28

2-chloro-4-(4-hydroxyl-1-methyl-pentyloxy)-benzonitrile

To 2, (28mg 0.240mmol) adds excessive butanols potassium to the 5-hexylene glycol in the solution in tetrahydrofuran (THF).With this mixture simple agitation, to wherein add 2-chloro-4-fluoro-benzonitrile (37mg, 0.240mmol).This mixture was at room temperature stirred 72 hours.Carry out purifying with anti-phase high pressure chromatography, with a kind of solvent gradient elution (0.1% formic acid in 15% 0.1% formic acid/water/CH ₃CN to 100%0.1% formic acid/water), obtain 28.4mg 2-chloro-4-(4-hydroxyl-1-methyl-pentyloxy)-benzonitrile. ¹H NMR(CDCl ₃)δ7.50(d，1H)，6.95(m，1H)，6.79(br d，1H)，4.43(m，1H)，3.79(m，1H)，1.89-1.40(m，4H)，1.30(d，3H)，1.17(d，3H)；MS m/z 253。

Embodiment 29

2-chloro-4-(3-hydroxyl-propoxy-)-benzonitrile

To 1, ammediol (320mg, add in 4.2mmol) sodium (21mg, 0.92mmol).This mixture at room temperature stirred 10 minutes and to wherein add 2-chloro-4-fluoro-benzonitrile (156mg, 1.0mmol).This reaction is heated to 105 ℃ of heating 24 hours.This reaction is cooled to room temperature, and dilute with water is also used Et ₂O (3x) extracts.With organic solution drying (MgSO ₄), filter, concentrate.Resistates is carried out purifying with anti-phase high pressure chromatogram, with a kind of solvent gradient elution (0.1% formic acid in 15% 0.1% formic acid/water/CH ₃CN to 100%0.1% formic acid/water), obtain 107mg 2-chloro-4-(3-hydroxyl-propoxy-)-benzonitrile. ¹H NMR(CDCl ₃)δ7.54(d，1H)，7.00(m，1H)，6.85(dd，1H)，4.15(t，2H)，3.83(t，2H)，2.04(m，2H)。

Embodiment 30

2-chloro-4-(4-hydroxyl-butoxy)-benzonitrile

According to embodiment 29 described operations, make 1, (1mL, 10mmol) (159mg 1.0mmol) at room temperature reacts 24 hours to the 4-butyleneglycol with 2-chloro-4-fluoro-benzonitrile.Carry out purifying with anti-phase high pressure chromatography, with a kind of solvent gradient elution (0.1% formic acid in 15% 0.1% formic acid/water/CH ₃CN to 100%0.1% formic acid/water), obtain 10mg 2-chloro-4-(4-hydroxyl-butoxy)-benzonitrile. ¹H NMR(CDCl ₃)δ7.54(d，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)；MS226.1(M+1)。

Embodiment 31

2-chloro-4-(1-hydroxymethyl-allyloxy)-benzonitrile

Steps A: 1-(tert-butyl-dimethyl-siloxy-)-Ding-3-alkene-2-alcohol

To being positioned at CH ₂Cl ₂(+/-) (25mL)-3-butene-1, the 2-glycol (500mg, 5.67mmol) add in the solution imidazoles (444mg, 6.53mmol).With this solution be cooled to 0 ℃ and to wherein add tert-butyl dimetylsilyl chlorine (1.0M is arranged in THF, 6.24mL, 6.24mmol).This is reflected at 0 ℃ stirred 15 minutes down, at room temperature stirred 1 hour 30 minutes.With this mixture NH ₄The dilution of the Cl aqueous solution is also used CH ₂Cl ₂(3x) extract.With organic solution salt water washing, dry (MgSO ₄), filter, concentrate.With this resistates with in press chromatogram to carry out purifying, with a kind of solvent gradient elution (EtOAc to 100%EtOAc in 5% the hexane), obtain 827.5mg 1-(tert-butyl-dimethyl-siloxy-)-Ding-3-alkene-2-alcohol. ¹H NMR(CDCl ₃)δ5.81(m，1H)，5.34(d，1H)，5.19(d，1H)，4.17(m，1H)，3.66(dd，1H)，3.45(dd，1H)，0.90(s，9H)，0.08(s，6H)；MSm/z 202。

Step B:4-[1-(tert-butyl-dimethyl-siloxy-methyl)-allyloxy]-2- The chloro-benzonitrile

Under-78 ℃, to 1-(tert-butyl-dimethyl-siloxy-)-Ding-3-alkene-2-alcohol (1.102g, 5.45mmol) add in the solution in THF (26mL) uncle-butanols potassium (1.0M is arranged in THF, 5.99mL, 5.99mmol).With this solution stirring 15 minutes and under-78 ℃ to wherein add 2-chloro-4-fluoro-benzonitrile (847mg, 5.45mmol).Should react and at room temperature stir 24 hours, the water extinguishing also extracts with EtOAc (3x).Organic solution water and salt solution are washed dry (MgSO ₄), filter, concentrate, obtain 1.67g 4-[1-(tert-butyl-dimethyl-silane oxygen ylmethyl)-allyloxy]-2-chloro-benzonitrile and 4-[2-(tert-butyl-dimethyl-silicon alkoxyl group)-Ding-3-alkene oxygen base]-1: 1 mixture of 2-chloro-benzonitrile. ¹HNMR(CDCl ₃)δ7.55(m，2H)，7.02(m，2H)，5.91-5.78(m，2H)，5.42-5.22(m，4H)，4.75(m，1H)，4.51(m，1H)，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

Embodiment 31 upward, step B regional isomer intermixture (1.67g, 4.95mmol) add in the solution in THF (15mL) fluoridize the tert-butyl ammonium (1.0M is arranged in THF, 5.44mL, 5.44mmol).Should react and at room temperature stir 15 minutes, use NH ₄The Cl aqueous solution dilutes and extracts with EtOAc (3x).With organic solution salt water washing, dry (MgSO ₄), filter, concentrate.With resistates with in press chromatogram purification, with a kind of solvent gradient elution (hexane to 100% is arranged in the EtOAc of hexane, 70 minutes), obtain 112mg 2-chloro-4-(1-hydroxymethyl-allyloxy)-benzonitrile. ¹H NMR(CDCl ₃)δ7.55(d，1H)，7.04(d，1H)，6.89(dd，1H)，5.85-5.76(m，1H)，5.38(m，2H)，4.80(m，1H)，3.80(m，2H)。

Embodiment 31A

Present embodiment further illustrate (1S, 4S)-4-(4-hydroxyl-1-methyl pentyloxy)-2-trifluoromethyl-benzonitrile, the preparation of the product of embodiment 23.

NaH (60%, be arranged in mineral oil) is suspended in the anhydrous THF of 100ml, with its stirring and at N ₂Down it is cooled to 0 ℃, stirred 10 minutes, then to wherein adding (2S, 5S)-(+)-2,5-hexylene glycol (12.g is arranged in the anhydrous THF of 120ml).In 30 minutes, by dropping funnel to wherein dripping said glycol, this mixture was stirred 60 minutes down at 0 ℃, at room temperature stirred then 30 minutes, it is cooled to 0 ℃ again, then in 30 minutes, to wherein adding 4-fluoro-2-(trifluoromethyl) benzonitrile (20g is arranged in the anhydrous THF of 80ml).Then, this is reflected at 0 ℃ to the room temperature at N ₂Stir under (9 o'clock 11 o'clock-next day of the morning).With TLC (Hex: ethyl acetate=1: 1) and LC/MS this reaction is monitored.

Purifying: (hexane: ethyl acetate=3: 1), carry out purifying with column chromatography, use hexane: ethyl acetate=5: 1 to 1: 1 obtains the pure product of the required product of 22g as eluent in the 80ml mixed solvent with this dissolving crude product.

Embodiment 32

The compound of formula I has avidity to androgen receptor.The acceptor of having chosen has proved this avidity of selected compounds.Following specification sheets to how carrying out said test is described.

CBA be on the hAR extract that baculovirus/Sf9 produces substances that has or do not exist different concns and fixed concentration as tracer agent ³The H-dihydrotestosterone ( ³H-DHT) carry out under the situation.This in conjunction with test method be before described scheme (people such as Liao S., J.Steroid Biochem.20:11-171984) modification.Briefly, the compound that concentration is reduced gradually exist the hAR extract (people such as Chang, P.N.A.S. the 89th volume, 5546-5950 page or leaf, 1992), hydroxylapatite and 1nM ³Cultivated 1 hour down at 4 ℃ under the situation of H-DHT.Subsequently, described association reaction thing washing three times is excessive unconjugated to remove fully ³H-DHT.There is mensuration hAR bonded under the situation of compound ³H-DHT level (promptly=competition in conjunction with) also compares its level that combines (=maximum combined) when not having competitor.Compound is expressed as half repressed compound concentration of maximum combined to the avidity of hAR.Below Table II the result that obtains with selected compound is provided (data of being reported are averages of test of many times as follows)

Table II

The average of twice test of a

The average of three tests of b

The average of four tests of c

Embodiment 33

Measured the ability of said compound antagonism male sex hormone in the described below full test cell line to the effect of androgen receptor.

The experimental technique of AR antagonist test cell line

Clone: MDA-MB453-MMTV clones 54-19.This clone is the clone (a kind of people's breast cancer tumor clone of expressing androgen receptor) with stable transfection of MDA-MB453 cell background.At first, the MMTV minimal promoter that will comprise ARE is cloned into the front of Photinus pyralis LUC reporter gene.Then, this cascade is cloned among the transfection carrier pUV120puro.Come the MDA-MB-453 cell is carried out transfection with electroporation.Select the stable cell lines of tolerance tetracycline.

Cell culture medium and reagent:

Substratum: DMEM (high sugar, Gibco cat#:11960-044), 10%FBS and 1%L-glutamine

Plate substratum: DMEM (not containing phenol red), the HyClone serum that 10% charcoal is handled, 1%L-glutamine

Test medium: DMEM (not containing phenol red), HyClone serum, 1%L-glutamine and 1% penicillin/streptomycin that 1% charcoal is handled

3X luciferase damping fluid: 2% beta-mercaptoethanol, 0.6%ATP, 0.0135% is arranged in the fluorescein of molten born of the same parents' damping fluid

Test method:

1. cell is maintained in the substratum, when it reaches the fusion of 80-90% with these cellular segregation

2. for some compounds are tested, these cells are coated with in the plate substratum that is plated to the 100ul/ hole in the opaque 96 porocyte culture plates with the density of 10,000 cells/well, with its under 37 ℃ in the cell cultures thermostat container overnight incubation

3. carefully remove the plate substratum, then to wherein adding the test medium of heating in advance in the 80ul/ hole,, to wherein adding test compound (final concentration is 1000nM, 200nM, 40nM, 8nM, 1.6nM and 0.32nM) it was cultivated 30 minutes down at 37 ℃ with the quantity in 10ul/ hole

4. the quantity with the 10ul/ hole adds freshly prepd DHT (final concentration is 100pM) in each hole, and it is cultivated 17 hours (spending the night) down at 37 ℃

With the quantity in 50ul/ hole to wherein adding 3X luciferase damping fluid, it was at room temperature cultivated 5 minutes, then it is counted on luxmeter

To compare with background, not have inducing multiple to be normalized to 100% form and experimental result being expressed as the form that test compound suppresses per-cent of 100pM DHT under the test compound situation.

Its result is as described in the following Table III.These results are the average (test number (TN) is shown in footnote) of following test of many times.N.D. represent that this compound tests.

Table III

The average of twice test of a

The average of three tests of b

The average of four tests of c

Embodiment 34

The androgenetic alopecia animal model

As described above, alopecia is the problem that the ten minutes effort always of a kind of medical science will solve.The same with any lysis, developed some animal models and made scientist to screen some compounds that has certain effect.Think that these compounds that show efficient in these animal models can further be chosen and study.Up to now, two kinds of different animal models for alopecia, have been set up.First kind is conversion test telogen, and it uses female C3H/HeN mouse.Second kind of model uses the docking macaque, and it is the monkey that suffers from androgenetic alopecia.

This conversion test telogen measured compound with the active period that changes into growth cycle of hair stationary phase (" telogen ") of mouse growth cycle of hair (" anagen ") may.This test has utilized the fur (being hair) of big C3H/HeN mouse of 7-week to be positioned at the fact of telogen.Continue to about 75 days this period greatly always.In this test, the hair in the selected zone of mouse is shaved off, it is contacted with substances or contrast, and the difference (the inducing anagen of being) of measurement hair growth speed.The anagen first kind of sign be in the preparation of chromogenesis calmness owing to hair follicle in melanophore begin the skin color that synthesis of melanin causes and deepen.This model has many advantages.It comprises that the rapid utilizability of female CH3HeN mouse, the ability that can screen chemical compound lot rapidly and such animal are easy to raise and handle.

The main drawback of this model is that it does not have androgen-dependent.Though the definite reason of still not clear people's alopecia has proved well that male sex hormone induced disappearing of hair follicle in the scalp.This postpubertal disappearing property variation is the major cause of male pattern alopecia (i.e. " androgenetic alopecia ").As described above, the masculinity and femininity of this phenomenon inherited character that betides alopecia hereditary.For the more detailed discussion of male sex hormone for the effect of people's scalp, the reader mainly can be referring to Trueb, RM, and the molecule mechanism of androgenetic alopecia (Molecular Mechanisms of Androgenic Alopecia), Exp. Gerontology, 2002,27:981-990.

The investigator is seeking its hair growth other animal similar to people's growth pattern.It makes the researchist search out the docking macaque.These primates also suffer from androgenetic alopecia.The nearly all postpubertal macaque of two kinds of sexes all can form alopecia.Similar to the development of people's male pattern alopecia, male sex hormone also is the necessary triggering factor of macaque alopecia.At about identical age (4 years old), when the testosterone serum level of male animal significantly raise, the hair of anterior scalp began attenuation.Though the rising of jenny testosterone is approximately 1/10th of male level, the incidence of alopecia and take place not have difference between the age between the male and female docking macaque.The topical application antiandrogen has overturn male and this alopecia (Pan jenny, people such as HJ, in prostate gland PC3 cell to as the RU58841 of antiandrogen and in the bareheaded scalp of docking macaque to its assessment of carrying out as the effect of the anti-alopecia agent in part (Evaluation of RU58841 as an anti-androgen in prostate PC3 cellsand a topical anti-alopecia agent in the bald scalp of stumptailed macaques). Endocrine1998; 9:39-43).

Though this model has remarkable improvement with comparing as conversion test telogen of people's alopecia model, it also has many shortcomings of putting into practice the aspect.Macaque is very expensive, and is rare relatively, raises the labour intensity height of keeping, and the wash-out phase between test is long.Therefore, for the screening chemical compound lot, macaque is not a kind of model with practicality.

Have been found that male C3H/HeN mouse can be used for said conversion test telogen when the androgenic test compound of antagonism is assessed.Therefore, this model relates to the modification that existing conversion test telogen is carried out.Use big male C3H/HeN mouse of about 7 weeks.Similar to its jenny, these animals are also very consistent in telogen.But, in case by being shaved hair, in these male mices the inherent male sex hormone that occurs suppressed hair follicle to the anagen conversion.Anti--androgenic drug will be blocked this androgenic effect, and will be therefore similar to its female sex partner, the anagen that its hair follicle will being converted into.

Embodiment 34A

With the above-mentioned conversion test of having carried out changing telogen to embodiment 23 described compounds, (1S, 4S)-4-(4-hydroxyl-1-methyl-pentyloxy)-2-trifluoromethyl-benzonitrile further tests.This test can be carried out with following mode.

These research use 6 to 7 all big male C3H/HeN mouse (Charles RiverLaboratories, Raleigh, NC).Before beginning to study, prune the fur in mouse back zone.This research only selects to use the mouse with pink colour skin (vision sign of telogen).

Test compound is dissolved in the matrix of being made up of propylene glycol (30%) and ethanol (70%), and making its concentration is 0.2%w/v, 0.5%w/v, 1%w/v or 3%w/v.With relevant dose with 20 μ l/cm ²Volume be applied topically to mouse in the test group (7-10 mouse) and carried out the dorsal area of pruning.The 3rd treated animal is only accepted matrix, with it in contrast.Use twice every day, handled for 4 weeks.

Every other day the hair growth sign in the zone of having carried out handling is observed and marked.Come hair growth response to assess by writing down the fate of each animal when showing the hair growth sign for the first time in processed zone.The anagen first kind of sign deepen for the skin color that begins synthesis of melanin owing to the melanophore in the hair follicle in producing the preparation of coloured hair and cause.Mouse was observed 35 days or more of a specified duration.Following figure I has represented to show in treatment group and the control group per-cent of the mouse of hair growth sign.When testing under the concentration 1%, the compound of embodiment 23 has produced a large amount of hair growths anagen of inducing by the irritant test animal.The hair growth speed of 5% test group does not surpass the matrix control group.

Embodiment 34B

With the above-mentioned product that has carried out conversion test telogen of change to embodiment 27,2-chloro-4-(3-hydroxyl-2,2,4-trimethylammonium-pentyloxy)-benzonitrile is further tested.This test is to use the mode identical with the mode of embodiment 37A, carries out under the experimental concentration of 3%w/v.The hair growth speed of test group does not surpass the matrix control group.

Embodiment 35

Suppress the animal model that sebum produces

People such as Luderschmidt have described the animal model whether a kind of test compound can regulate and control sebum secretion.Arch.Derm.Res.258，185-191(1977)。This model uses male Syrian hamster, and its ear comprises sebiferous gland.With this model prepared compound above selected is screened.

Carry out the sebum inhibition test with following mode.With 9 to 10 weeks big male Syrian hamsters be incorporated in the laboratory environment and before using it for this research, make it adapt to for 2 weeks.Each group comprises 5 animals and parallel matrix and the positive control of carrying out.Before administration, with each compound dissolution of 30mg in 1mL Universal solvent (in ethanol/propylene glycol (70/30%v/v) to the final concentration of 3w/v%.

With these animal twice ground topicals every day, administration is 5 days weekly, 4 weeks of administration.Each dosage comprises contrast of 25 microlitre matrix or medicine.With the outside of belly of this dose application in animal auris dextra and left ear.All animals were all put to death in about 18-24 hour after the administration the last time.Collect auris dextra and it is carried out the sebum analysis by each animal.

With following mode these ears are prepared it is carried out the HPLC analysis.Just the tip biopsy perforation of getting a 8mm above the phenotypic marker in the anatomy " V " of ear is with the sample area stdn.Peel off this perforation.Keep the back side that outside of belly examination of living tissue surface (wherein said local dose is applied directly to areas containing sebaceous glands) is used to test and discard the biopsy perforation.

With these tissue samples N ₂Brush and it is analyzed being stored under the nitrogen under-80 ℃ until carrying out HPLC.Except that these ear samples, also the aliquots containig (250ul at least) with each medicine and matrix is stored under-80 ℃ to carry out the HPLC analysis.

HPLC analyzes and carries out with the tissue sample extract.These tissue samples are contacted with 3ml solvent (4: 1 mixtures of pure isooctane and Virahol).With this mixture jolting 15 minutes and with its store overnight at room temperature under the situation of lucifuge.In second day morning, in this sample, add 1 ml water and with its jolting 15 minutes.Then, with these samples under about 1500rpm centrifugal 15 minutes.This organic phase of 2ml (top layer) is transferred in the vial, under 37 ℃ under nitrogen dry about 1 hour, then with about 48 hours of its lyophilize.Then, these samples are taken out from lyophilizer and with each bottle with (trimethylpentane/tetrahydrofuran (THF) (99: the 1) reorganization of 600 μ l solvent orange 2 As.Then, these samples are closed the lid again and with its vortex 5 minutes.

Then, 200 each sample of μ l are transferred in the 200 μ l HPLC bottles that carried out mark in advance with 200 μ L glass inserts.These HPLC bottles are put in the pallet of Agilent 1100series HPLC device automatic sampler.This Agilent 1100HPLC system is made up of homothermic automatic sampler, quaternary pump, column oven and A/D interface module.With Agilent ChemStation software all assemblies are controlled.With Agilent column oven device with the temperature maintenance of Waters Spherisorb S3W 4.6 * 100mm analytical column at 30 ℃.Give the programming of HPLC automatic sampler in operational process, sample temperature is maintained 20 ℃.

Each sample of 10uL is expelled in the post in triplicate.Carry out solvent gradient elution with two kinds of solvents.Solvent orange 2 A is the mixture of trimethylpentane and tetrahydrofuran (THF) (99: 1).Solvent B is an ethyl acetate.Used gradient is as described in the following table:

Time (min)	Solvent orange 2 A (%)	Solvent B (%)	Flow velocity (mL/min)
				0	99	1	2
2	96	4	2
				6	60	40	2
7	5	95	2
				10	5	95	2
10.1	99	1	2

Sedex 75 Evaporative Light Scattering Detector (ELSD) operate N down at 45 ℃ with 5 increment ₂Pressure is maintained at 3.1 crust.To deliver in the Agilent A/D interface module with the simulating signal that this device obtains, it is converted to a kind of numeral output there.This conversion is that the setting point with the 10000mAU/ volt is that carry out on the basis, and data rate is set at 10Hz (0.03min).Then, the numeral output of gained is delivered in the Agilent ChemStation software so that its peak area is carried out integration.

The result that HPLC analyzes is as described in the following Table I V.These results report with the form of comparing the reduction of cholesteryl ester (CE) and wax ester (WE) generation with the matrix contrast.

The 1st row and the 2nd are listed as with structure and embodiment number compound are determined.The influence that compound reduces sebum component (CE and WE) has been shown in the 3rd to 5 tabulation.These results are represented as the form of the difference of comparing with the matrix contrast.Positive number is represented measured sebum component, i.e. the generation of cholesteryl ester (CE) and wax ester (WE) reduces.

The 3rd tabulation shows that said compound reduces the ability of cholesteryl ester quantity in the sebum sample.The influence that compound produces wax ester is shown in the 4th tabulation.Wax ester be sebiferous gland the special marking thing and skin any other the layer in immeasurability arrive.Wax ester is the component that content is the highest in the sebum (about 25%).Therefore, reduce wax ester and can make that usually sebum secretion significantly reduces.The 5th row are the summations (and further specify active relative different with it) of result shown in the 3rd and 4 row.As shown in Table IV, the androgen modulators of formula I has significantly reduced the generation of cholesteryl ester and wax ester.

Claims (15)

1. the hydrate of the compound of formula I, described compound or pharmaceutically useful salt,

Wherein:

X ¹Expression halogen or halo C ₁-C ₆Alkyl;

X ²Expression-CR ³R ⁴R ⁵

R ¹And R ²Represent hydrogen or C independently of one another _1-6Alkyl;

R ³, R ⁴, and R ⁵Represent hydrogen, C independently of one another _1-6Alkyl or hydroxyl;

N represents 0 or 1;

ALK ¹Expression C _1-8Straight-chain alkyl-sub-, the height to 8 of a wherein said alkylidene group hydrogen atom can be randomly by C _1-6Alkyl replaces;

Condition is:

1) if n is 0, R then ³, R ⁴, or R ⁵In at least one the expression hydroxyl;

2) if n is 1, then: a) R ³, R ⁴, or R ⁵In at least one the expression hydroxyl; Perhaps b) Alk ¹At least one hydrogen atom replaced by hydroxyl.

2. compound as claimed in claim 1, wherein n is 0 and R ¹, R ², R ³, R ⁴, R ⁵In at least one the expression C _1-6Alkyl.

3. compound as claimed in claim 1, wherein n is 1, and Alk ¹At least one hydrogen atom by C _1-6Alkyl replaces, perhaps R ¹, R ², R ³, R ⁴, R ⁵In one the expression C _1-6Alkyl.

4. as claim 1,2 or 3 described compound, wherein X ¹Be CF ₃And be positioned on the 2-position of this phenyl ring.

5. as claim 1,2 or 3 described compound, wherein R ³, R ⁴, or R ⁵In at least one is a hydroxyl.

6. compound as claimed in claim 5, wherein R ³, R ⁴, or R ⁵In at least one is a methyl.

7. compound as claimed in claim 1, wherein said compound is selected from:

(1S, 2S)-4-(2-hydroxyl-1-methyl-propoxy-)-2-trifluoromethyl-benzonitrile;

(1R, 2R)-4-(2-hydroxyl-1-methyl-propoxy-)-2-trifluoromethyl-benzonitrile;

4-(2-hydroxyl-1-methyl-propoxy-)-2-trifluoromethyl-benzonitrile;

4-(2-hydroxyl-6-methyl-heptan oxygen base)-2-trifluoromethyl-benzonitrile;

4-(2-hydroxyl-octyloxy)-2-trifluoromethyl-benzonitrile;

4-(2-hydroxyl-Xin-7-alkene oxygen base)-2-trifluoromethyl-benzonitrile;

4-(3-hydroxyl-butoxy)-2-trifluoromethyl-benzonitrile;

(3S)-4-(3-hydroxyl-butoxy)-2-trifluoromethyl-benzonitrile;

4-(the 3-hydroxyl-oneself-5-alkene oxygen base)-2-trifluoromethyl-benzonitrile;

4-(3-hydroxy-2-methyl-butoxy)-2-trifluoromethyl-benzonitrile;

4-(3-hydroxyl-2,2-dimethyl-propoxy-)-2-trifluoromethyl-benzonitrile;

4-(3-hydroxy-3-methyl-butoxy)-2-trifluoromethyl-benzonitrile;

4-(3-hydroxyl-2,2,4-trimethylammonium-pentyloxy)-2-trifluoromethyl-benzonitrile;

4-(2-ethyl-3-hydroxyl-hexyloxy)-2-trifluoromethyl-benzonitrile;

4-[2-(1-hydroxyl-ethyl)-hexyloxy]-2-trifluoromethyl-benzonitrile;

(1S, 3S)-4-(3-hydroxyl-1-methyl-butoxy)-2-trifluoromethyl-benzonitrile;

(1R, 3R)-4-(3-hydroxyl-1-methyl-butoxy)-2-trifluoromethyl-benzonitrile;

4-(4-hydroxyl-butoxy)-2-trifluoromethyl-benzonitrile;

4-(4-hydroxyl-butoxy)-2-trifluoromethyl-benzonitrile;

4-(4-hydroxyl-heptan oxygen base)-2-trifluoromethyl-benzonitrile;

4-(4-hydroxyl-1-propyl group-butoxy)-2-trifluoromethyl-benzonitrile;

4-(4-hydroxyl-1-methyl-pentyloxy)-2-trifluoromethyl-benzonitrile;

(1S, 4S)-4-(4-hydroxyl-1-methyl-pentyloxy)-2-trifluoromethyl-benzonitrile;

4-(5-hydroxyl-pentyloxy)-2-trifluoromethyl-benzonitrile;

4-(5-hydroxyl-hexyloxy)-2-trifluoromethyl-benzonitrile;

4-(5-hydroxy-3-methyl-pentyloxy)-2-trifluoromethyl-benzonitrile;

2-chloro-4-(3-hydroxyl-2,2,4-trimethylammonium-pentyloxy)-benzonitrile;

2-chloro-4-(4-hydroxyl-butoxy)-benzonitrile;

2-chloro-4-(3-hydroxyl-propoxy-)-benzonitrile;

2-chloro-4-(1-hydroxymethyl-allyloxy)-benzonitrile; With

2-chloro-4-(4-hydroxyl-1-methyl-pentyloxy)-benzonitrile.

8. according to the compound of claim 7, be selected from 4-(2-hydroxyl-Xin-7-alkene oxygen base)-2-trifluoromethyl-benzonitrile, 4-(3-hydroxyl-own-5-alkene oxygen base)-2-trifluoromethyl-benzonitrile and 2-chloro-4-(1-hydroxymethyl-allyloxy)-benzonitrile.

9. according to the compound of claim 7, its be (1S, 4S)-4-(4-hydroxyl-1-methyl-pentyloxy)-2-trifluoromethyl-benzonitrile or its pharmaceutically useful salt.

10. as the application of any described compound among the claim 1-9 as medicine.

11. as the application of any described compound among the claim 1-9 in the activatory medicine of preparation regulation and control androgen receptor.

12. as any described compound is used for androgenetic alopecia in preparation among the claim 1-9, sebum is excessive or the application of the topical drug of acne.

13. comprise pharmaceutical composition as any described compound among the claim 1-9 and one or more pharmaceutically useful vehicle.

14. comprise as any described compound among the claim 1-9 and one or more and be suitable for the topical pharmaceutical formulation of the pharmaceutically acceptable vehicle of dermal application.

15. comprise the packaged medicine that retail distributes that is used for as any described compound among the claim 1-9, comprising explanation suggestion human consumer how to use this compound to alleviate the situation that is selected from acne, alopecia and oily skin.