CN1068816A

CN1068816A - indole derivatives

Info

Publication number: CN1068816A
Application number: CN92108675A
Authority: CN
Inventors: J·布拉格; K·库珀; P·L·施帕戈
Original assignee: Pfizer Inc
Current assignee: Pfizer Inc
Priority date: 1991-07-24
Filing date: 1992-07-24
Publication date: 1993-02-10
Also published as: MX9204342A; CA2112678A1; PT100718A; WO1993002051A1; NO940237D0; BR9206306A; AU2327192A; SK8494A3; JPH06509336A; NZ243687A; NO940237L; JPH06511483A; ZA925546B; FI940311A; EP0598750A1; AU655662B2; AU2327092A; TW223060B; IL102545A0; HU9400199D0

Abstract

The invention provides formula (I) compound and pharmaceutically useful salt thereof, and the pharmaceutical composition that contains these compounds, the preparation method and its usage of these compounds.Y, R and R in the formula (I) ¹-R ¹⁰Such as in the specification sheets definition.

Description

Indole derivatives

The present invention relates to have the active indole derivatives of inhibition steroid class 5.

More specifically, the present invention relates to Benzazole compounds, their preparation and as the application of testosterone-5 inhibitor.

Male hormone class steroid hormone comprises testosterone, and it causes male and female difference on physical trait.Produce in the organ of male hormone at all, testis produces the amount maximum of this parahormone.Excessive in vivo this parahormone of generation can cause many bad health phenomenon and morbid states, as acne vulgaris, alopecia, seborrheic dermatitis, female hirsutism, benign prostatauxe and male pattern baldness.

Main male hormone by testicular secretion is a testosterone, and it is the main male hormone that is present in the male blood plasma.In some organ such as prostate gland and sebiferous gland, the active main medium of male hormone is 5 α-reductive male hormone.Therefore, testosterone is the prohormone of 5 α-dihydrotestosterone, and the latter is by forming in the above-mentioned organ of acting on of testosterone 5.Therefore, the existence of high-caliber dihydrotestosterone has made and attention has focused on synthesizing of testosterone 5 inhibitor in the numerous disease state.

The prostate cancer that testosterone 5 inhibitor also can be used for treating the people.

EP-A-0458207 discloses some indole derivatives, and they have the activity that suppresses the testosterone 5.

The invention provides following formula: compound and pharmaceutically useful salt thereof:

Wherein, Y is by C ₁-C ₆The C that alkyl replaces arbitrarily ₁-C ₆Alkylidene group;

R is H, OH, halogen, C ₁-C ₄Alkyl or C ₁-C ₄Alkoxyl group;

R ¹, R ², R ³And R ⁴Be selected from H, C independently of one another ₁-C ₄Alkyl, C ₁-C ₄Alkoxyl group, OH, halogen and CF ₃;

R ⁶, R ⁷And R ⁸One of be the group of following formula:

Remaining and R ⁵And R ⁹Be selected from H, C independently of one another ₁-C ₄Alkyl, C ₁-C ₄Alkoxyl group, halogen and halo (C ₁-C ₄) alkyl;

R ¹⁰Be COOH, COOR ¹¹Or CONR ¹²R ¹³;

R ¹¹It is biolabile one-tenth ester group;

R ¹²And R ¹³Be selected from H and C independently of one another ₁-C ₄Alkyl;

R ¹⁴Be H, C ₁-C ₆Alkyl, C ₃-C ₇Cycloalkyl or aryl;

At R ⁶, R ⁷, R ⁸And R ¹⁴Definition in used " aryl " be meant by C ₁-C ₆Alkyl, C ₁-C ₆Alkoxyl group, C ₂-C ₆Alkenyl, OH, halogen, CF ₃, halo (C ₁-C ₆Alkyl), nitro, amino, C ₂-C ₆Alkanoyl amido, C ₂-C ₆The phenyl that alkanoyl or phenyl replace arbitrarily.

Of the present invention further aspect,

Y is by C ₁-C ₆The C that alkyl replaces arbitrarily ₁-C ₆Alkylidene group;

R is H, OH, halogen, C ₁-C ₄Alkyl or C ₁-C ₄Alkoxyl group;

R ⁶, R ⁷And R ⁸One of be the group of following formula:

R ¹⁰Be COOH, COOR ¹¹Or CONR ¹²R ¹³;

R ¹¹It is biolabile one-tenth ester group;

R ¹⁴Be H, C ₁-C ₆Alkyl, C ₃-C ₇Cycloalkyl or aryl;

At R ⁶, R ⁷, R ⁸And R ¹⁴Definition in used " aryl " be meant by C ₁-C ₆Alkyl, C ₁-C ₆Alkoxyl group, C ₂-C ₆Alkenyl, OH, halogen, CF ₃, halo (C ₁-C ₆Alkyl), nitro, amino, C ₂-C ₆Alkanoyl amido, C ₂-C ₆The phenyl that alkanoyl or phenyl replace arbitrarily,

Its condition is:

ⅰ) work as R ⁷Be the 1-(4-(2-methyl-propyl) phenyl) oxyethyl group, R, R ¹, R ², R ³, R ⁴, R ⁵, R ⁶, R ⁸And R ⁹Be H, Y is-(CH ₂) ₃-, when the formula I compound is racemic form, R ¹⁰Not COOH;

ⅱ) work as R ⁷Be the 1-(4-(2-methyl-propyl) phenyl) propoxy-or 2,2-dimethyl-1-(4-(2-methyl-propyl) phenyl) propoxy-, R, R ¹, R ², R ³, R ⁴, R ⁵, R ⁶, R ⁸And R ⁹Be H, Y is-(CH ₂) ₃-, when the formula I compound is racemic form, R ¹⁰Not COOH or COOC ₂H ₅;

ⅲ) work as R ⁶Be the 1-(3-(2-methyl-propyl) phenyl) oxyethyl group, R, R ¹, R ², R ³, R ⁴, R ⁵, R ⁷, R ⁸And R ⁹Be H, Y is-(CH ₂) ₃-, when the formula I compound is racemic form, R ¹⁰Not COOH or COOC ₂H ₅;

ⅳ) work as R ⁷Be the 1-(4-(2-methyl-propyl) phenyl) oxyethyl group, R ⁵And R ⁶Be methyl, R, R ¹, R ², R ³, R ⁴, R ⁸And R ⁹Be H, Y is-(CH ₂) ₃-, when the formula I compound is racemic form, R ¹⁰Not COOH or COOC ₂H ₅;

ⅴ) work as R ⁷Be two (4-(2-methyl-propyl) phenyl) methoxyl group, R, R ¹, R ², R ³, R ⁴, R ⁵, R ⁶, R ⁸And R ⁹Be H, Y is-(CH ₂) ₃-time, R ¹⁰Not COOH;

ⅵ) work as R ⁶Be two (4-(2-methyl-propyl) phenyl) methoxyl group, R, R ¹, R ², R ³, R ⁴, R ⁵, R ⁷, R ⁸And R ⁹Be H, Y is-(CH ₂) ₃-time, R ¹⁰Not COOH; And

ⅶ) work as R ⁶Be the 4-(2-methyl-propyl) phenoxymethyl or 3-(2-methyl-propyl) phenoxymethyl, R, R ¹, R ², R ³, R ⁴, R ⁵, R ⁷, R ⁸And R ⁹Be H, Y is-(CH ₂) ₃-time, R ¹⁰Not COOH or COOC ₂H ₅

The alkanoyl amido and the alkanoyl that contain alkyl, haloalkyl, alkenyl and the alkoxyl group of three or more carbon atom and contain four or a plurality of carbon atoms can be straight or brancheds.

Term " halogen " is meant fluorine, chlorine, bromine or iodine.

The meaning of term " biolabile one-tenth ester group " in pharmaceutical chemistry is for forming the group of ester, and this ester is easy to cracking in vivo and discharges R ¹⁰Corresponding acid for the formula I of COOH.Many these class ester groups are known, for example, and in the penicillin field or in the situation of angiotensin converting enzyme (ACE) inhibitor hypotensive agent.

R ¹⁰Be CO ₂(C ₁-C ₆The ester of formula I alkyl) itself is a steroid class 5 inhibitor, still, works as R usually ¹⁰Be COOR ¹¹The time, this compounds is used as prodrug so that R is provided in vivo after oral ¹⁰Formula I compound for COOH.These esters also can be used as preparation R ¹⁰Intermediate for the formula I compound of COOH.

Can be by assess the suitability of any specific one-tenth ester group enzymic hydrolysis research of external or intravital routine to this application.

The example of suitable biolabile one-tenth ester group has: alkyl is (as C ₁-C ₆Alkyl), alkanoyloxy alkyl (comprising the derivative that its alkyl, cycloalkyl or aryl replace), aryl-carbonyl oxygen alkyl (comprising the derivative that its aryl replaces), aryl, aralkyl, 2; 3-indanyl and haloalkyl: wherein alkanoyl has 2 to 8 carbon atoms; alkyl has 1 to 8 carbon atom; they can be straight or brancheds; aryl is a phenyl or naphthyl, and the two can be by C ₁-C ₄Alkyl, C ₁-C ₄Alkoxy or halogen at random replaces.

Except C ₁-C ₆Alkyl, the specific examples of other biolabile one-tenth ester group has: benzyl, 1-(2,2-diethyl butyryl acyloxy) ethyl, 2-ethyl propionyloxy methyl, 1-(2-ethyl propionyloxy) ethyl, 1-(2,4-dimethyl benzene methanoyl) ethyl, α-benzoyloxy benzyl, the 1-(benzoyloxy) ethyl, 2-methyl isophthalic acid-propionyloxy-1-propyl group, 2,4,6-Three methyl Benzene methanoyl methyl, 1-(2,4,6-Three methyl Benzene methanoyl) ethyl, oxy acid methyl neopentyl, styroyl, hydrocinnamyl, 2,2, the 2-trifluoroethyl, 1-or 2-naphthyl, 2, the 4-3,5-dimethylphenyl, 4-tert-butyl-phenyl and 2,3-indane-5-base.

The pharmaceutically useful salt of formula I compound is its acid salt and alkali salt thereof.

Suitable acid salt is to be formed by the acid that can form non-toxic salt, and example has: hydrochloride, hydrobromate, hydriodate, vitriol, hydrosulfate, phosphoric acid salt, hydrophosphate, acetate, maleate, fumarate, lactic acid salt, tartrate, Citrate trianion, gluconate, benzoate, mesylate, benzene sulfonate and tosilate.

Suitable alkali salt is to be formed by the alkali that can form non-toxic salt, and example has: aluminium, calcium, lithium, magnesium, potassium, sodium, zinc and diethanolamine salt.

About the summary of suitable salt referring to people such as Berge, J.Pharm.Sci., 66,1-19(1977).

In the above-mentioned definition relevant with the present invention:

Preferably, Y is C ₁-C ₆Alkylidene group.

More preferably, Y is methylene radical, propylidene, butylidene or pentylidene.

Most preferably, Y is a propylidene.

Preferably, R is H or C ₁-C ₄Alkyl.

More preferably, R is H or methyl.

Most preferably, R is H.

Preferably, R ¹, R ², R ³And R ⁴H respectively does for oneself.

Preferably, R ⁶, R ⁷And R ⁸One of be the group of following formula:

Remaining and R ⁵And R ⁹Be selected from H and C independently of one another ₁-C ₄Alkyl.

More preferably, R ⁷Group for following formula:

R ⁵, R ⁶, R ⁸And R ⁹Be selected from H and C independently of one another ₁-C ₄Alkyl.

Most preferably, R ⁷Be the following formula group:

R ⁵, R ⁶, R ⁸And R ⁹H respectively does for oneself.

Preferably, R ¹⁰Be COOH or COOR ¹¹

Most preferably, R ¹⁰Be COOH.

Preferably, R ¹¹Be C ₁-C ₆Alkyl.

Most preferably, R ¹¹Be ethyl.

Preferably, R ¹⁴Be H, C ₁-C ₄Alkyl, C ₄-C ₆Cycloalkyl or by C ₁-C ₄The phenyl that alkyl replaces.

More preferably, R ¹⁴Be H, methyl, n-propyl, cyclopentyl or 4-n-propyl phenyl.

Most preferably, R ¹⁴Be methyl.

Preferably, " aryl " is meant the phenyl that is replaced arbitrarily by 1 to 3 substituting group, more preferably, is meant the phenyl that is replaced arbitrarily by 1 or 2 substituting group, most preferably, is meant the phenyl that is replaced arbitrarily by a substituting group.

Of the present invention preferred aspect, " aryl " is meant by C ₁-C ₆The phenyl that alkyl or halogen replace arbitrarily, more preferably, be meant the phenyl that is replaced arbitrarily by methyl, ethyl, n-propyl, isobutyl-or chlorine, more preferably, also be meant phenyl, 4-aminomethyl phenyl, 4-ethylphenyl, 4-n-propyl phenyl, 4-isobutyl phenenyl or 3, the 4-dichlorophenyl most preferably, is meant the 4-isobutyl phenenyl.

The formula I compound can contain one or more unsymmetrical carbons and/or one or more alkenyl, and therefore, it can exist by two or more stereoisomer forms.The present invention includes one steric isomer of formula I compound and composition thereof.The separation of diastereomer or cis-trans-isomer can be undertaken by ordinary method, for example, carries out fractional crystallization, chromatography or HPLC chromatography by the stereomeric mixture to formula I compound or its suitable salt or derivative.The one enantiomorph of formula I compound also can be prepared by the pure intermediate of corresponding optically-active, or obtain by splitting, as with suitable chiral support by racemic modification is carried out the HPLC chromatography, or obtain by the fractional crystallization of diastereomeric salt, this diastereomeric salt is to form by racemic modification and suitable optically-active acid or alkali reaction.

In preferred one group of formula I compound, R ⁶, R ⁷And R ⁸One of be the following formula group:

Remaining and Y, R, R ¹, R ², R ³, R ⁴, R ⁵, R ⁹, R ¹⁰, R ¹¹, R ¹², R ¹³" aryl " as above defines in the face of the formula I compound.

Particularly preferred formula I examples for compounds is:

(R, S)-4-(3-(4-(1-(4-(2-methyl-propyl) phenyl) oxyethyl group) benzoyl) indoles-1-yl) butyric acid,

(S)-and 4-(3-(4-(1-(4-(2-methyl-propyl) phenyl) oxyethyl group) benzoyl) indoles-1-yl) butyric acid,

(R, S)-4-(2-methyl-3-(4-(1-(4-(2-methyl-propyl) phenyl) oxyethyl group) benzoyl) indoles-1-yl) butyric acid and

(S)-and 4-(2-methyl-3-(4-(1-(4-(2-methyl-propyl) phenyl) oxyethyl group) benzoyl) indoles-1-yl) butyric acid,

And pharmaceutically useful salt.

Formula I compound provided by the invention can prepare by following method:

1) formula I compound (R wherein ¹⁰Be COOH, Y, R and R ¹～R ⁹As the front formula I compound is defined) can prepare by the cracking of following formula ester,

R wherein ¹⁵Be suitable one-tenth ester group, Y, R and R ¹～R ⁹As the front formula I compound is defined.

Many suitable one-tenth ester group that can cleaved generation corresponding carboxylic acid is that the technician is known, referring to, as " protecting group in the organic synthesis " of T.W.Greene and P.G.Wuts, Wiley-Interscience(the 2nd edition, 1991).

Work as R ¹⁵For the one-tenth ester group that can remove by hydrolysis, as C ₁-C ₆Alkyl or (R during as the defined selective biolabile one-tenth ester group in front ¹⁰Be COOR ¹¹The formula I compound), hydrolysis can be carried out under acidity or alkaline condition, for example, with the aqueous solution of suitable mineral acid or suitable mineral alkali.Hydrolysis is preferably carried out under alkaline condition.

In a typical method, with the ester of formula II at suitable organic cosolvent such as tetrahydrofuran (THF) or C ₁-C ₄Under the existence of alkanol such as methyl alcohol, handle with the aqueous solution of suitable alkali such as sodium hydroxide or potassium hydroxide.Usually, hydrolysis is carried out to reflux temperature in room temperature, preferably at room temperature carries out.The product that obtains is an alkali salt, can by acidifying alkali salt be converted into carboxylic acid in post-processing step.

Work as R ¹⁵During for the one-tenth ester group that can remove by reduction such as benzyl, reduction can be by with carrying out for catalyst hydrogenation as palladium/charcoal.

2) formula I compound (R wherein ¹⁰Be COOH, Y, R and R ¹～R ⁹As the front formula I compound is defined) can be by hydrolysis R wherein ¹⁰Be CONR ¹²R ¹³, Y, R, R ¹～R ⁹, R ¹²And R ¹³As the front the defined formula I compound of formula I compound is prepared.

Hydrolysis, is carried out under acidity or alkaline condition to reflux temperature in room temperature, for example, and with suitable mineral acid example hydrochloric acid or sulfuric acid or the suitable mineral alkali such as the aqueous solution of sodium hydroxide or potassium hydroxide.When using the alkaline hydrolysis condition, the product that obtains is an alkali salt, can by acidifying alkali salt be converted into carboxylic acid in post-processing step.

3) formula I compound (R ¹⁰Be COOH, Y, R and R ¹～R ⁹As the front formula I compound is defined) can prepare by the hydrolysis of following formula: compound.

Wherein Y, R and R ¹～R ⁹The formula I compound is defined R as the front ¹⁶Be H or C ₁-C ₄Alkyl.

Hydrolysis, is carried out under acidity or alkaline condition to reflux temperature in room temperature, for example, and with suitable sour example hydrochloric acid or acetic acid or the suitable mineral alkali such as the aqueous solution of sodium hydroxide or potassium hydroxide.When using the alkaline hydrolysis condition, the product that obtains is an alkali salt, can by acidifying alkali salt be converted into carboxylic acid in post-processing step.

4) formula I compound (R wherein ¹⁰Be COOH, Y, R and R ¹～R ⁹As the front formula I compound is defined) can prepare by the hydrolysis of following formula: compound,

Wherein Y, R and R ¹～R ⁹As the front formula I compound is defined.

Hydrolysis, is carried out under acidity or alkaline condition to reflux temperature in room temperature, for example, and with suitable sour example hydrochloric acid or sulfuric acid or the suitable mineral alkali such as the aqueous solution of sodium hydroxide or potassium hydroxide.When using the alkaline hydrolysis condition, at random can have hydrogen peroxide, and the product that obtains can be converted into carboxylic acid by acidifying with alkali salt also for alkali salt in post-processing step.

5) formula I compound (R wherein ¹⁰Be COOH, Y, R and R ¹～R ⁹As the front formula I compound is defined) can prepare by the acidic hydrolysis of following formula: compound,

Wherein Y, R and R ¹～R ⁹The formula I compound is defined R as the front ¹⁷And R ¹⁸Represent ethylidene together, said ethylidene can by phenyl or

C ₁-C ₄Alkyl (preferable methyl) replaces arbitrarily.Preferably, R ¹⁷And R ¹⁸Representative-CH together ₂C(CH ₃) ₂-.

Hydrolysis can be carried out to reflux temperature in room temperature with the aqueous solution of suitable sour example hydrochloric acid.

6) formula I compound (R wherein ¹⁰Be CONH ₂, Y, R and R ¹～R ⁹As the front formula I compound is defined) can pass through formula IV compound (wherein Y, R and R ¹～R ⁹As the front formula I compound is defined) partial hydrolysis prepare.Hydrolysis can be carried out to room temperature at 0 ℃ with the vitriol oil.

7) formula I compound (R wherein ¹⁰Be COOR ¹¹, Y, R, R ¹～R ⁹And R ¹¹As the front formula I compound is defined) can through type R ¹¹The alcohol of OH (R wherein ¹¹As the front this method is defined) with formula I compound (R wherein ¹⁰Be COOH, Y, R and R ¹～R ⁹As the front formula I compound is defined) carry out esterification and prepare.

This reaction can be carried out under the enzymatic synthesis condition of classics, as also using acid catalysis with excessive alcohol, for example with sulfuric acid or tosic acid, carries out to reflux temperature in room temperature.The water that produces in the reaction process can be removed by component distillation, or by using dewatering agent or molecular sieve to remove.

Esterification also can react in the presence of dewatering agent with alcohol by acid and carry out, and dewatering agent is just like dicyclohexylcarbodiimide or diethyl azodiformate/triphenylphosphine (referring to O.Mitsunobu, Synthesis.1981,1).

Perhaps, esterification can followingly be carried out, and promptly at first forms the active ester or the acyl imdazole derivatives of carboxylic acid, then makes active ester or acyl imidazoles and formula R ¹¹OH alcohol situ reaction.Active ester can be by carboxylic acid and I-hydroxybenzotriazole at suitable dewatering agent such as 1-(3-N, the N-dimethylaminopropyl)-existence of 3-ethyl carbodiimide under, in suitable solvent such as methylene dichloride, at room temperature react and form.The acyl imidazoles can by carboxylic acid and 1,1 '-carbonyl dimidazoles at room temperature reacts in suitable solvent such as methylene dichloride and forms.

8) formula I compound (R wherein ¹⁰Be COOR ¹¹, Y, R, R ¹～R ⁹And R ¹¹As the front formula I compound is defined) can be by following formula: compound and formula R ¹¹The alcohol of OH (R wherein ¹¹As the front this method is defined) reaction be prepared,

Wherein, Y, R and R ¹～R ⁹The formula I compound is defined Z as the front ¹For suitable leavings group, as chlorine or bromine.

This is reflected under the existence of acid acceptor such as pyridine, in suitable solvent such as methylene dichloride, carries out to room temperature at 0 ℃.

9) formula I compound (R wherein ¹⁰Be COOR ¹¹, Y, R, R ¹～R ⁹And R ¹¹As the front formula I compound is defined) can pass through formula I compound (R wherein ¹⁰Be COOH, Y, R and R ¹～R ⁹As the front formula I compound is defined) alkali salt (being the carboxylate salt alkali salt) and formula R ¹¹Z ²Compound (R wherein ¹¹The formula I compound is defined Z as the front ²For suitable leavings group,, preferred bromine or iodine, or tolysulfonyl oxygen base as halogen) reaction prepares.

The alkali salt that preferably is used for the formula I compound of this method is sodium salt and sylvite.This is reflected in suitable solvent such as dimethyl formamide or the tetrahydrofuran (THF), carries out to reflux temperature in room temperature.

10) formula I compound (R wherein ¹⁰Be CONR ¹²R ¹³, Y, R, R ¹～R ⁹, R ¹²And R ¹³As the front formula I compound is defined) can pass through formula I compound (R wherein ¹⁰Be COOH, Y, R and R ¹～R ⁹As the front formula I compound is defined) and formula R ¹²R ¹³The amine of NH (R wherein ¹²And R ¹³As the front this method is defined) in the presence of dewatering agent such as dicyclohexylcarbodiimide, react and prepare.This reaction can be carried out to reflux temperature in room temperature in appropriate organic solvent such as methylene dichloride.

Perhaps, this reaction can followingly be carried out, and promptly at first forms the active ester or the acyl imdazole derivatives of carboxylic acid, then makes active ester or ester imidazoles and formula R ¹²R ¹³The amine situ reaction of NH.The suitable method that is used for preparing active ester or acyl imidazoles is described in method (7).

11) formula I compound (R wherein ¹⁰Be CONR ¹²R ¹³, Y, R, R ¹～R ⁹, R ¹²And R ¹³As the front formula I compound is defined) can pass through formula VI compound (wherein Y, R, R ¹～R ⁹And Z ¹As the front formula VI compound is defined) and formula R ¹²R ¹³The amine of NH (R wherein ¹²And R ¹³As the front this method is defined) reaction prepare.This reaction can in suitable solvent such as methylene dichloride, be carried out to room temperature at 0 ℃ in the presence of acid acceptor such as pyridine.

12) formula I compound (R wherein ¹⁰Be CONR ¹²R ¹³, Y, R, R ¹～R ⁹, R ¹²And R ¹³As the front formula I compound is defined) can pass through formula II compound and formula R ¹²R ¹³The amine of NH (R wherein ¹²And R ¹³As the front this method is defined) reaction prepare, in formula II, R ¹⁵Be suitable one-tenth ester group such as C ₁-C ₆Alkyl or selective biolabile as defined above one-tenth ester group (is R ¹⁰Be COOR ¹¹The formula I compound), or p-nitrophenyl, Y, R and R ¹～R ⁹As the front formula I compound is defined.This reaction can be at suitable solvent such as C ₁-C ₄In the alkanol, to reflux temperature, carry out in room temperature.This reaction is carried out with excessive amine and in closed reactor (as bullet) usually.

13) formula I compound (R wherein ¹⁰Be COOH or CONR ¹²R ¹³, Y, R, R ¹～R ⁹, R ¹²And R ¹³As the front formula I compound is defined) can prepare by the acidic hydrolysis of following formula: compound,

Wherein Y, R and R ¹～R ⁹This method is defined R as the front ¹⁹And R ²⁰C respectively does for oneself ₁-C ₄Alkyl, or represent C together ₂-C ₃Alkylidene group, described alkylidene group can be by C ₁-C ₄Alkyl replaces arbitrarily, R ²¹For-OH ,-OR ²²(R wherein ²²Be the suitable one-tenth ester group that to remove by hydrolysis, as C ₁-C ₆Alkyl or selective biolabile as defined above one-tenth ester group) or NR ¹²R ¹³(R wherein ¹²And R ¹³As the front this method is defined).Hydrolysis can be carried out in the presence of water with suitable sour example hydrochloric acid or tosic acid.

Formula (VII) compound is prepared as follows, i.e. through type (VIII) compound (wherein R and R ¹～R ⁹As the front this method is defined) react under acidic conditions with corresponding alcohol; (for example at first form corresponding ketal; referring to T.W.Greene and P.G.Wuts " protecting group in the organic synthesis "; Wiley-Interscience(the 2nd edition; 1991)); then according to the similar method of alkylating method described in the method (14) to formula (VIII) compound, with this ketal N-alkylation.

14) all formula I compound (wherein Y, R and R ¹～R ¹⁰As the front formula I compound is defined) can pass through following formula: compound (wherein R and R ¹～R ⁹As the front formula I compound is defined) alkali salt (being N-deprotonation form) and formula Z ³-Y-COOR ¹¹Or Z ³-Y-CONR ¹²R ¹³Compound or with formula Z ³The alkylating of the alkali salt of-Y-COOH compound (if suitable) prepares, wherein Y, R ¹¹, R ¹²And R ¹³The formula I compound is defined Z as the front ³Be leavings group, for example, halogen, preferred chlorine, bromine or iodine, mesyloxy or tolysulfonyl oxygen base.Preferred formula Z ³The alkali salt of-Y-COOH compound is basic metal and alkaline earth salt.For example, sodium and sylvite.The alkali salt of preferred formula (VIII) compound is an an alkali metal salt, for example, and sodium and sylvite.

This reaction is following to be carried out: make the deprotonation of formula (VIII) compound elder generation with suitable alkali such as sodium hydride, then with gained negatively charged ion and formula Z ³-Y-COOR ¹¹, Z ³-Y-CONR ¹²R ¹³Compound or with formula Z ³The alkali salt of-Y-COOH compound (if needs) reaction.Reaction can be at suitable solvent such as N, in dinethylformamide or the tetrahydrofuran (THF), at 0 ℃ to reflux temperature and preferably under about room temperature, carry out.Reaction also can in 2-butanone or acetone solvent, be carried out under the reflux temperature of about solvent with salt of wormwood as alkali.

Perhaps, this reaction can be carried out under condition of phase transition, and wherein suitable alkali is sodium hydroxide or potassium hydroxide.

As needs R ¹⁰During for the formula I compound of COOH, the product that obtains is an alkali salt, can by acidifying alkali salt be converted into carboxylic acid in post-processing step.

15) all formula I compounds (wherein Y, R and R ¹～R ¹⁰As the front formula I compound is defined) preparation can pass through the following formula indoles

Or when R is OH, its alkali salt, or the alkali salt of following formula indoles

Wherein Y, R and R ¹～R ⁴The formula I compound is defined R as the front ²³Be OR ¹¹Or NR ¹²R ¹³, R wherein ¹¹, R ¹²And R ¹³As the front formula I compound is defined,

Carry out acylation reaction with following formula: compound and carry out,

R wherein ⁵～R ⁹This method is defined Z as the front ⁴Be leavings group, halogen for example, preferred chlorine, and acylation reaction is carried out in the presence of Lewis acid when R is not OH, and acylation reaction can randomly be carried out in the presence of Lewis acid when R is OH.Suitable Lewis acid comprises aluminum chloride and diethylaluminum chloride.

This reaction can be carried out to reflux temperature in room temperature in suitable solvent such as toluene.

The alkali salt of preferred formula (X) indoles is basic metal and alkaline earth salt, for example sodium and sylvite.

When needing R to be the formula I compound of OH, formula (IX) and (X) compound are necessary for the enolate form.Therefore; wherein R be formula (IX) indoles of OH or wherein R be that the alkali salt of formula (X) indoles of OH should be handled with monovalent suitable alkali such as calcium hydroxide earlier; form enolate, then randomly in the presence of Lewis acid with this enolate usefulness formula (XI) compound acylation.In post-processing step, introduce acidification step and obtain then wherein that R is the formula I compound of OH.

16) formula I compound (R wherein ¹⁰Be COOH, Y, R and R ¹～R ⁹As the front formula I compound is defined) can prepare by the oxicracking of following formula: compound,

Z wherein ⁵Be-CH=CH ₂,-CH=CH(C ₁-C ₄Alkyl) ,-CH=C(C ₁-C ₄Alkyl) ₂Or-C ≡ CH, Y, R and R ¹～R ⁹As the front this method is defined.

This reaction can be carried out by the ozone decomposition or by handling with potassium permanganate solution.

17) formula I compound (R wherein ¹⁰Be COOH, Y, R and R ¹～R ⁹As the front formula I compound is defined) can prepare by the oxidation of following formula: compound,

Wherein Y, R and R ¹～R ⁹As the front formula I compound is defined.The suitable oxygenant that is used for this purpose is chromium trioxide/pyridine.

18) formula I compound (R wherein ¹⁰Be COOH, Y, R and R ¹～R ⁹As the front formula I compound is defined) can prepare by the oxidation of following formula: compound or its alkali salt,

R wherein ²⁴Be H or OH, Y, R and R ¹～R ⁹As the front formula I compound is defined.The suitable oxygenant that is used for this purpose is chromium trioxide-pyridine complex.

This oxidizing reaction also can be with 2,3-two chloro-5, and 6-dicyano-1,4-benzoquinones (DDQ) is made oxygenant, to R ²⁴For formula (X V) compound of H carries out.

This oxidizing reaction also can be made oxygenant or under the Swern oxidation reaction condition, to R with Manganse Dioxide ²⁴For formula (X V) compound of OH carries out.

R ²⁴For the formula (X IV) of H or the preparation of (X V) starting raw material are following carrying out, promptly by of the benzyl halide reaction of corresponding 1H-indoles-1-magnesium halide derivative with corresponding following formula,

R wherein ⁵～R ⁹This method is defined Z as the front ⁶Be halogen, preferred chlorine or bromine is then according to carrying out the N-alkylated reaction of indoles with the similar method of method described in the method (14).

R ²⁴For the preparation of the formula (X IV) of OH or (X V) starting raw material is to be undertaken by the corresponding 1H-indoles-1-magnesium halide derivative and the phenyl aldehyde reaction of corresponding following formula,

R wherein ⁵～R ⁹As the front this method is defined.

19) formula I compound (R wherein ⁶, R ⁷And R ⁸One of be the following formula group: -aryl, remaining and Y, R, R ¹～R ⁵, R ⁹, R ¹⁰, R ¹⁴" aryl " defines the formula I compound as the front) can react and prepare by following formula (X VIII) compound or its alkali salt and following formula (X IX) compound,

R wherein ²⁵, R ²⁶And R ²⁷One of be OH, R ²⁵, R ²⁶And R ²⁷Surplus person such as the front in the method to R ⁶, R ⁷And R ⁸Surplus person define Y, R, R ¹～R ⁵, R ⁹And R ¹⁰As the front this method is defined,

R wherein ¹⁴" aryl " defines this method as the front, Z ⁷Be suitable leavings group, halogen for example, preferred chlorine, bromine or iodine, mesyloxy or tolysulfonyl oxygen base.

The alkali salt of preferred formula (X VIII) compound is sodium and sylvite.

This reaction is preferably carried out with the alkali salt (being phenates) of formula (X VIII) compound, with suitable alkali such as sodium hydroxide or potassium hydroxide or sodium hydride, at suitable solvent such as ethanol or N, in the dinethylformamide, at 0 ℃ to reflux temperature, by the phenol of corresponding formula (X VIII) alkali salt of production (X VIII) compound on the spot.This reaction also can in 2-butanone or acetone solvent, be carried out under the reflux temperature of about solvent with salt of wormwood as alkali.

20) formula I compound (R wherein ¹⁰Be COOR ¹¹Or CONR ¹²R ¹³, Y, R, R ¹～R ⁹, R ¹¹, R ¹², R ¹³, R ¹⁴" aryl " such as the front to method (19) definition) can through type (X VIII) compound (R wherein ¹⁰Be COOR ¹¹Or CONR ¹²R ¹³(if suitable), R ¹¹, R ¹², R ¹³With Y, R, R ¹～R ⁵And R ⁹This method is defined R as the front ²⁵～R ²⁷As in the previous methods (19) formula (X VIII) compound being defined) in the presence of suitable dewatering agent such as diethyl azodiformate/triphenylphosphine, react and prepare with following formula: compound, this reaction can be in suitable solvent such as tetrahydrofuran (THF), carry out to reflux temperature in room temperature

R wherein ¹⁴" aryl " defines this method as the front.

21) formula I compound (R wherein ⁶, R ⁷And R ⁸One of be the following formula group: -aryl, remaining and Y, R, R ¹～R ⁵, R ⁹, R ¹⁰, R ¹⁴" aryl " defines the formula I compound as the front) can react by the alkali salt of following formula (X XI) compound or its alkali salt and following formula (X XII) compound and prepare,

R wherein ²⁸, R ²⁹And R ³⁰One of be the following formula group:

, surplus person such as front are in the method to R ⁶, R ⁷And R ⁸Surplus person define Y, R, R ¹～R ⁵, R ⁹, R ¹⁰And R ¹⁴This method is defined Z as the front ⁸As in method (19) to Z ⁷Define,

Aryl-OH(X XII)

Wherein " aryl " defines this method as the front.

The alkali salt (being phenates) of formula (X XII) compound can be with suitable alkali such as sodium hydroxide or potassium hydroxide or sodium hydride, at suitable solvent such as ethanol or N, in the dinethylformamide, 0 ℃ to reflux temperature, generate on the spot by the phenol of corresponding formula (X XII).This reaction also can in the presence of the salt of wormwood in suitable solvent such as 2-butanone, up to and preferably under the reflux temperature at solvent, the phenol of through type (X XII) and formula (X XI) compound react and carry out.

22) formula I compound (R wherein ¹⁰Be COOR ¹¹Or CONR ¹²R ¹³, Y, R, R ¹～R ⁹, R ¹¹, R ¹², R ¹³, R ¹⁴" aryl " such as the front to method (21) definition) can in the presence of suitable dewatering agent such as diethyl azodiformate/triphenylphosphine, react by following formula: compound and formula (X XII) compound (wherein " aryl " defines this method as the front) and prepare

R wherein ³¹, R ³²And R ³³One of be the following formula group:

, surplus person such as front are in the method to R ⁶, R ⁷And R ⁸After the person define Y, R, R ¹～R ⁵, R ⁹, R ¹⁰And R ¹⁴As the front this method is defined.This reaction can be carried out to reflux temperature in room temperature in suitable solvent such as tetrahydrofuran (THF).

Be used for all reactions of aforesaid method and the preparation of new starting raw material and all use always, its operation or prepare required suitable reagent with reaction conditions and be used to separate the method for required product with reference to formerly embodiment and the preparation example of document and this paper are well known to those skilled in the art.

The pharmaceutically useful salt of formula I compound can mix and be prepared at an easy rate by the solution with formula I compound solution and required acid or alkali (if suitable).Salt can be precipitated out and be filtered collection or pass through evaporating solvent and reclaim in solution.

The formula I compound is a steroid class 5 inhibitor, and therefore, they can be used for treatment or preventing disease or morbid state, as acne vulgaris, alopecia, seborrheic dermatitis, female hirsutism, benign prostatauxe and male pattern baldness.

Some formula I compound also can be used for treating people's prostate cancer.

Prostata tissue with rat or people can be in the inhibition activity of vitro test formula I compound to steroid class 5.

The ability that suppresses the steroid class 5 of rat with the ventral prostate tested tissue formula I compound of male rat.In the inhibition ability of mensuration, use following method to the 5 of rat prostate:

Rat prostate is cut into small shreds.With Brinkman Polytron(Kinematica GmBH, Luzern) make this be organized in buffer A (20mM sodium phosphate, the damping fluid of pH 6.5, wherein contain 0.32M sucrose and 1mM dithiothreitol (DTT)) middle homogenize, use electronic (1000 rpm) Potter Elvehjem(teflon-glass then) the homogenizer homogenize.Centrifugal (105,000G) obtained the prostate gland granule in 60 minutes.With this particle in 4 times of volume buffer A, wash and centrifugal (105,000G).Make the particle suspension (prostata tissue 1ml damping fluid of the initial usefulness of every gram) in buffer A that obtains with above-mentioned electronic Potter Elvehjem homogenizer.This particle suspension liquid is stored under-70 ℃ with the 1ml sample.

With following component add make in the test tube its be dissolved in buffer B (the 40mM sodium phosphate buffer, pH6.5): 500 μ l ( ³H)-testosterone (1 μ Ci, 1 nmol; Du Pont, NEN Research Products, Stevenage, U.K.), 100 μ l, 0.5 mM NADPH is dissolved in formula I compound and buffer B in the 5 μ l methyl-sulphoxides, and obtaining the end reaction volume is 1ml.This mixture is warmed to 37 ℃, makes the reaction beginning by the prostate gland particle suspension liquid that adds aliquots containig.Reaction mixture is incubated 30 minutes down at 37 ℃, by acutely mixing reaction is stopped then, wherein contain each 20 μ g of testosterone and 5 α-dihydrotestosterone in the ethyl acetate as carrier with the 2ml ethyl acetate that adds.Centrifugal (2000G) separated water layer and organic layer in 10 minutes.Transfer to organic layer in second test tube and under nitrogen atmosphere, be evaporated to dried.Resistates is dissolved in the 50-80 μ l dehydrated alcohol, and (E.Merck, Darmstadt is Germany) and at chloroform: launch in the acetone (185: 15) on silica gel 60 F254 TLC plates with its point sample.

Radiological chemistry content in substrate (testosterone) and product (5 α-dihydrotestosterone) bands of a spectrum is that (Raytest Instruments Ltd., Sheffield U.K.) measure with RITA Radio TLC analyser.Calculating is converted into the radiolabeled percentage ratio of the recovery of 5 α-dihydrotestosterone, and determines enzymic activity with it.Carry out all insulation reaction, be converted into product so that be no more than 15% substrate (testosterone).

Make a series of inhibitor concentration data adaptings of obtaining of experiment in S shape dose-response curve with computer, with SIGFIT program (De Lean, A., Munson, P.J. and Rodbard, D., American Journal of Physiology, 235, E97(1978)) calculate and provide the compound concentration (IC that suppresses 50%5 'alpha ' reductase activities ₅₀).

The ability that suppresses people's steroid class 5 with outgrowth people's prostata tissue test formula I compound.In the inhibition ability of mensuration, use following method to people's prostatic 5:

In liquid nitrogen, use steel mortar and pestle that refrigerated people's prostata tissue is ground.With Ultra-Turrax(Janke and Kunkel GmBH ﹠amp; Co., Staufen i.BR. is Germany) with the homogenize in the buffer A (20 mM sodium phosphates, pH6.5 contain 0.32M sucrose, 1mM dithiothreitol (DTT) and 50 μ M NADPH) of 4 times of volumes of this powdered tissue.With this homogenate centrifugal (500G) 5 minutes to remove the macrobead tissue, then with supernatant liquor centrifugal (100,000G) 1 hour.With the Ultra-Turrax homogenizer with the particles dispersed (prostata tissue 1ml damping fluid of the initial usefulness of every gram) in buffer A that obtains.Then this granules preparation thing is filtered by 2 layers of cheese cloth, filtrate is stored under-70 ℃ with the 1ml sample.

To make it be dissolved in buffer B (20 mM Citrate trianion phosphate buffered saline buffers, pH 5.2) in the following component adding test tube: 500 μ l ( ³H)-testosterone (1 μ Ci, 1 nmol; Du Pont, NEN Research Products, Stevenage, U.K.), 100 μ l NADPH regeneration systems (5 mM NADPH, 50 mM glucose 6-phosphoric acid ester, 5 units of every milliliter of glucose 6-phosphate dehydrogenase), be dissolved in formula I compound and buffer B in the 5 μ l methyl-sulphoxides, obtaining the end reaction volume is 1ml.This mixture is warmed to 37 ℃, makes the reaction beginning by the prostate gland particle suspension liquid that adds aliquots containig.Reaction mixture is incubated 30 minutes down at 37 ℃, by acutely mixing with the 2ml ethyl acetate that adds reaction is stopped then, wherein each 20 μ g of testosterone that contains in the ethyl acetate and 5 α-dihydrotestosterone are as carrier.Centrifugal (2000G) made water layer separate with organic layer in 10 minutes.Transfer to organic layer in second test tube and under nitrogen atmosphere, be evaporated to dried.Resistates is dissolved in the 50-80 μ l dehydrated alcohol, and (E.Merck, Darmstadt is Germany) and at chloroform: launch in the propyl alcohol (185: 15) on silica gel 60 F254 TLC plates with its point sample.

Radiological chemistry content in substrate (testosterone) and product (5 α-dihydrotestosterone) bands of a spectrum is that (Raytest Instruments Ltd., Sheffield U.K.) measure with RITA Radio TLC analyser.Calculating is converted into the radiolabeled percentage ratio of the recovery of 5 α-dihydrotestosterone, and it determines enzymic activity.Carry out all insulation reaction and be converted into product so that be no more than 15% substrate (testosterone).

With the active ability of steroid class 5 in clone DU 145 and HPC 36M test formula I compound inhibition people's the prostate cancer.In the inhibition ability of measuring 5, use following method:

People's prostate cancer cell line is grown in containing the Dulbecco ' s Modified Eagles substratum (DMEM) of 5% serum.In the DMEM that does not contain serum, wash from wherein reclaiming cell by centrifugal, and with it with 5-10 * 10 ⁶The concentration of individual cell/ml is suspended in the substratum that does not contain serum.

Following component is added in the test tube: be dissolved in 10 μ l in the ethanol ( ³H)-testosterone (1 μ Ci, and 20pmol) (Du Pont, NEN Research Products, Stevenage, U.K.) and the ethanolic soln of 5 μ l formula I compounds.Ethanol evaporation under nitrogen atmosphere is dissolved in 0.25 ml that contains 0.25 μ mol NADPH again with testosterone and compound and does not contain in the substratum of serum.Mixture is warmed to 37 ℃, by adding 0.25ml cell suspending liquid (1.2-2.5 * 10 ⁶Individual cell) begins reaction.Reaction mixture is 37 ℃ of down insulations 2 hours, then by with 1.5 ml that add, the violent mixing of ethyl acetate stops reaction, wherein contains each 20 μ g of testosterone and 5 α-dihydrotestosterone in the ethyl acetate as carrier.Centrifugal (2000G) made water layer separate with organic layer in 10 minutes.The organic layer that will contain testosterone and meta-bolites thereof is transferred in second test tube, is evaporated to dried under nitrogen atmosphere.Resistates is dissolved in the 50-80 μ l dehydrated alcohol, and (E.Merck, Darmstadt is Germany) and at methylene dichloride: launch in the acetone (185: 15) on silica gel 60 F254 TLC plates with its point sample.

Radiological chemistry content in substrate (testosterone) and product (5 α-dihydrotestosterone) bands of a spectrum is that (Raytest Instruments Ltd., Sheffield U.K.) measure with RITA Radio TLC analyser.Calculating is converted into the radiolabeled percentage ratio of the recovery of 5 α-dihydrotestosterone, and determines enzymic activity with it.Carry out all insulation reaction and be converted into product so that be no more than 15% substrate (testosterone).

For people's application, the formula I compound can be individually dosed, but normally mix administration with pharmaceutical carrier, and the selection of pharmaceutical carrier is to determine according to specified route of administration and general pharmacy practice.For example, the formula I compound can contain the tablet form just like the vehicle of starch or lactose, or with separately or capsule or the ovulum form made with mixed with excipients, or elixir, solution or form of suspension oral administration to contain seasonings or tinting material.The formula I compound can pass through drug administration by injection by parenteral, for example, and by vein, intramuscular or subcutaneous injection.For parenterai administration, preferably use the aseptic aqueous solution form, wherein contain other material such as enough salt or glucose so that solution and blood etc. ooze.

For giving the oral and parenterai administration of patient, the per daily dose of formula I compound is 0.01 to 20mg/kg(to take as single dose or fractionated dose), preferred 0.1 to 10mg/kg, when having only treatment people's prostate cancer, can use the nearly dosage of 20mg/kg.Therefore, the tablet of compound or capsule will contain 1mg to 0.5g active compound, be applicable to single administration or some the time at twice or repeatedly (if suitable words) administration.Under any circumstance all should be suitable for the actual dose of given patient by doctor's decision most, this dosage will change along with concrete patient's age, body weight and reaction.Above-mentioned dosage is typical average case; Certainly, can exist and have the higher of using value or than the individual cases of low dosage scope, such dosage range is all within the scope of the invention.

In addition, the formula I compound can suppository or vaginal suppository form administration, perhaps uses so that washing lotion solution, missible oil, ointment or powder type are local.For example, the formula I compound can be added in the missible oil of forming by the aqueous emulsion of polyoxyethylene glycol or whiteruss; Or the formula I compound is added in the ointment with 1～10% concentration, this ointment is by Chinese wax or paraffinum molle alba base and stablizer and preservatives are formed as required.

The formula I compound also can be with alpha antagonist (as Prazosin Huo Kui Evil piperazine), androgen antagonist agent (as Sch-13521) or aromatization enzyme inhibitor (as atamestane) administration, especially for the treatment or the prevention of benign prostatauxe.

Therefore, the present invention further provides:

ⅰ) a kind of pharmaceutical composition, it comprises formula I compound or its pharmaceutically useful salt and acceptable diluents or carrier;

ⅱ) as formula I compound or its pharmaceutically useful salt or its composition of medicine;

ⅲ) formula I compound or its pharmaceutically useful salt or its composition application in producing the medicine that suppresses steroid class 5;

ⅳ) formula I compound or its pharmaceutically useful salt or its composition application in producing medicine, described medicine can be used for treating or preventing acne vulgaris, alopecia, seborrheic dermatitis, female hirsutism, benign prostatauxe, male pattern baldness or people's prostate cancer.

ⅴ) a kind of needs are suppressed the people's of steroid class 5 methods of treatment, this method comprises formula I compound or its pharmaceutically useful salt or its composition of taking significant quantity to said people;

ⅵ) a kind of people's of the prostate cancer to needs treatments or prevention acne vulgaris, alopecia, seborrheic dermatitis, female hirsutism, benign prostatauxe, male pattern baldness or people methods of treatment, this method comprises formula I compound or its pharmaceutically useful salt or its composition of taking significant quantity to said people; And

ⅶ) new intermediate (IV), (VIII) and alkali salt thereof, (X III), (X IV), (X V) and alkali salt thereof, (X VIII) and alkali salt thereof, (X XI) and alkali salt thereof, (X XI) and alkali salt thereof and (XX III).

The preparation of the following example explanation formula I compound.

Embodiment 1

(R, S)-4-(3-(4-(1-(4-(2-methyl-propyl) phenyl) oxyethyl group) benzoyl) indoles-1-yl) butyric acid

Will (R, S)-4-(3-(4-(1-(4-(2-methyl-propyl) phenyl) oxyethyl group) benzoyl) indoles-1-yl) ethyl butyrate (3.8g) (seeing embodiment 21) tetrahydrofuran (THF) (THF) (35ml) and methyl alcohol (35ml) solution with 2N sodium hydroxide solution (35ml) processing.After at room temperature stirring 2 hours, with mixture carefully vacuum concentration in ice bath, cool off then and with the acidifying of 2N hydrochloric acid soln to about 50ml volume.Ethyl acetate (100ml) extraction is used in acid mutually, uses the dried over sodium sulfate organic extract liquid, and vacuum concentration obtains title compound (3.27g), is white foam shape thing, m.p.57 ℃.

Experimental value: C, 77.00; H, 6.88; N, 2.90;

C ₃₁H ₃₃NO ₄Calculated value: C, 76.93; H, 6.88; N, 2.99%.

¹H-NMR（CDCl ₃）：δ＝0.95（d，6H），1.70（d，3H），1.90（m，1H），2.25（m，2H），2.40（t，2H），2.49（d，2H），4.30（t，2H），5.50（q，1H），6.95（d，2H），7.15（d，2H），7.27-7.45（m，5H），7.59（s，1H），7.79（d，2H），8.45（m，1H）ppm.

Embodiment 2～20

Following general formula compound or its alkali salt are to prepare with being similar to the hydrolysis by corresponding ethyl ester (seeing embodiment 22～38,42 and 43) of method therefor among the embodiment 1.

Embodiment 21

(R, S)-4-(3-(4-(1-(4-(2-methyl-propyl) phenyl) oxyethyl group) benzoyl) indoles-1-yl) ethyl butyrate

Under 0 ℃ and nitrogen atmosphere; dimethyl formamide (30ml) solution of sodium hydride (60% oil dispersion, anhydrous dimethyl formamide 716mg) (DMF) (15ml) suspension with 4-(3-(4-hydroxy benzoyl) indoles-1-yl) ethyl butyrate (5.24g) (seeing preparation example 1) dripped handle.After 1 hour, under 0 ℃, in mixture, add Alpha-Methyl-4-(2-methyl-propyl in stirring at room) dimethyl formamide (5ml) solution of bromotoluene (3.95g) (seeing preparation example 23).The mixture that obtains at room temperature stirred spend the night.Reaction mixture is distributed between 1N hydrochloric acid soln (100ml) and ethyl acetate (200ml).The organic layer of telling is used 1N sodium hydroxide solution (100ml), saturated brine (100ml) and water (100ml) washing successively.With organic layer drying (MgSO ₄) and vacuum concentration, obtain yellow oil.Use column chromatography (silica gel, 4: 1 hexane/ethyl acetate) and purify, after suitable wash-out is partly evaporated, obtain title compound (3.8g).

Measured value: C, 77.47; H, 7.29; N, 2.74;

C ₃₃H ₃₇NO ₄Calculated value: C, 77.63; H, 7.48; N, 2.73%.

¹H-NMR（CDCl ₃）：δ＝0.91（d，6H），1.35（t，3H），1.70（d，3H），1.90（m，1H），2.20（m，2H），2.31（m，2H），2.49（d，2H），4.13（q，2H），4.25（t，2H），4.50（q，1H），6.95（d，2H），7.15（d，2H），7.27-7.45（m，5H），7.55（s，1H），7.88（d，2H），8.45（m，1H）ppm.

Embodiment 22～32

Following general formula compound is that method therefor prepares by the alkylated reaction of corresponding phenol derivatives (seeing preparation example 1,3 and 4) with corresponding alkyl bromide (seeing for example preparation example 20～26) among the embodiment 21 with being similar to.

Embodiment 33

(S)-and 4-(3-(4-(1-(4-(2-methyl-propyl) phenyl) oxyethyl group) benzoyl) indoles-1-yl) ethyl butyrate

With 4-(3-(4-hydroxy benzoyl) indoles-1-yl) ethyl butyrate (500mg) (seeing preparation example 1), (R)-1-(4-(2-methyl-propyl) phenyl) THF(20ml of ethanol (256mg) (seeing preparation example 17) and triphenylphosphine (410mg)) solution (0.27ml) handles with diethyl azodiformate (DEAD), and mixture at room temperature stirs and spends the night.Reaction mixture is evaporated on the silica gel (5g), then passes through flash column chromatography (silica gel, 3: 1 hexane/ethyl acetate), after suitable wash-out is partly evaporated, obtain required compound (413mg), be light yellow gluey thing, m/z=511(M ⁺).HPLC(Cyclobond DMP post is with 1: 1 1% triethylamine acetate, pH 4.1/CH ₃CN was with 0.7ml/ minute flow velocity wash-out) rt=86.09 minute (100%).

¹H-NMR（CDCl ₃）：δ＝0.95（d，6H），1.25（t，3H），1.70（d，3H），1.85（m，1H），2.20（m，2H），2.30（t，2H），2.45（d，2H），4.10（q，2H），4.25（t，2H），5.40（q，1H），6.95（d，2H），7.15（d，2H），7.25-7.40（m，5H），7.55（s，1H），7.75（d，2H），8.35（m，1H）ppm.

Also can use chirality HPLC(Chiralpak AD post, eluent=9: 1 hexane/ethanol, flow velocity=12ml/ minute) prepare title compound by the product that splits embodiment 21.First eluted compound is (R)-4-(3-(4-(1-(4-(2-methyl-propyl) phenyl) oxyethyl group) benzoyl) indoles-1-yl) ethyl butyrate, rt=24 minute, (α) ²⁵ _D+ 52.1 ° (c=2, methylene dichloride), second eluted compound is title compound, rt=27 minute, (α) ²⁵ _D-53.8 ° (c=2, methylene dichloride).

Embodiment 34～37

Following general formula compound is to prepare with being similar to the condensation reaction by corresponding phenolic or alcohols (seeing preparation example 1,2 and 27) and corresponding phenolic or alcohols (seeing preparation example 17 and 18) of method therefor among the embodiment 33.

Embodiment 38

4-(3-(4-benzyloxy benzoyl) indoles-1-yl) ethyl butyrate

With dimethyl formamide (50ml) suspension of refrigerative (0 ℃) sodium hydride (3.40g55% mineral oil dispersion) with 3-(4-benzyloxy benzoyl) dimethyl formamide (100ml) solution-treated of indoles (20.0g) (seeing preparation example 5).The orange suspension that obtains was stirred 1 hour down at 20 ℃.Mixture is cooled to 0 ℃, adds 4-bromo ethyl butyrate (11.0ml).Mixture at room temperature stirred 2 hours, was cooled to 0 ℃, handled with 1N aqueous hydrochloric acid (100ml) and ethyl acetate (200ml).Tell organic layer, water (100ml), 1N aqueous hydrochloric acid (100ml), saturated sodium bicarbonate aqueous solution (100ml) and salt solution (100ml) washing.The evaporation of acetic acid ethyl ester obtains a kind of orange jelly, and it is passed through flash chromatography (silica gel, eluent=3: 1 hexane/ethyl acetate is 2: 1 hexane/ethyl acetate then) purify, merges suitable wash-out partly and after evaporating, obtain title compound (16.5g), m.p.83 ℃.

¹H-NMR（CDCl ₃）：δ＝1.20（t，3H），2.20（q，2H），2.35（t，2H），4.15（q，2H），4.29（t，2H），5.20（s，2H），7.10（d，2H），7.30-7.47（m，8H），7.62（s，1H），7.85（d，2H），8.40（m，1H）ppm.

Embodiment 39～43

Following general formula compound is by being similar to method therefor among the embodiment 38, preparing as starting raw material with corresponding indoles (seeing preparation example 5～8) and corresponding bromo paraffinic acid ethyl ester.

Following preparation example explanation is used for the preparation of some starting raw material of front embodiment:

Preparation example 1

4-(3-(4-hydroxy benzoyl) indoles-1-yl) ethyl butyrate

With 4-(3-(4-benzyloxy benzoyl) indoles-1-yl) ethyl acetate (300ml) solution of ethyl butyrate (13.4g) (seeing embodiment 38), 4.15 * 10 ⁵Pa(60 psi) under the pressure, in the presence of 10% palladium/charcoal (3g), hydrogenation is 4 hours under room temperature.By cellulose filter aid reaction mixture is filtered, remove catalyzer,, obtain the lightpink solid the filtrate vacuum concentration.With the cold diethyl ether development, obtain white powder (8.24g).

Measured value: C, 71.78; H, 6.02; N, 3.98;

C ₂₁H ₂₁NO ₄Calculated value: C, 71.44; H, 6.04; N, 3.94%.

¹H-NMR（CDCl ₃）：δ＝1.25（t，3H），2.22（m，2H），2.35（m，2H），4.15（q，2H），4.30（t，2H），6.95（d，2H），7.32-7.45（m，3H），7.65（s，1H），7.70（d，2H），8.47（m，1H）ppm.

Preparation example 2～4

Following general formula compound is to prepare with being similar to the hydrogenation of method used in the preparation example 1 by corresponding benzyl oxide (seeing embodiment 39～41).

Preparation example 5

3-(4-benzyloxy benzoyl)-the 1H-indoles

Under mechanical stirring, dripping with iodate methyl magnesium (85ml, 3.0M diethyl ether solution) through dry ether (450ml) solution of crossing of sodium of indoles (30.0g) handled.After stirring 1 hour under 20 ℃, add 4-benzyloxy Benzoyl chloride (67.3g) (seeing preparation example 10).Continue down to stir 2 hours at 20 ℃, in mixture, add 1N hydrochloric acid (250ml) then, reactant is placed spent the night.The precipitation of generation is told in filtration, and (3 * 100ml) developments obtain required compound (40.9g), are the lightpink solid with hot ethyl acetate.

Measured value: C, 80.67; H, 5.33; N, 4.25;

C ₂₂H ₁₇NO ₂Calculated value: C, 80.70; H, 5.23; N, 4.28%.

¹H-NMR（d ₆-DMSO）：δ＝5.20（s，2H），7.15（d，2H），7.20（m，2H），7.30-7.50（m，6H），7.80（d，2H），7.90（s，1H），8.23（d，1H），11.95（s，br，1H）ppm.

Preparation example 6～8

The indoles of following general formula is to be prepared by corresponding 1H-indoles and corresponding acyl chlorides (seeing preparation example 9～11) with being similar to method used in the preparation example 5.

Preparation example 9

4-benzyloxy-2, the 3-dimethyl benzoyl chloride

(a) the 4-bromo-2, the 3-xylenol

With 2, acetate (300ml) solution of 3-xylenol (40.0g) is cooled to 10 ℃, with acetate (100ml) solution-treated of bromine (16.9ml).Stir after 30 minutes, add the sodium metabisulfite aqueous solution (300ml).The mixture dichloromethane extraction is with organic layer drying (MgSO ₄), filter and evaporation, obtain product (64.7g), be waxy solid.

¹H-NMR（CDCl ₃）：δ＝2.15（s，3H），2.25（s，3H），4.00（s，br，1H），6.60（d，1H），7.15（d，1H）ppm.

The product crystallization obtains analytic sample above making in hexane.

Measured value: C, 48.00; H, 4.40;

C ₈H ₉BrO calculated value: C, 47.78; H, 4.51%.

(b) 1-benzyloxy-4-bromo-2, the 3-dimethyl benzene

Product (45.0g), bromotoluene (28.30g), salt of wormwood (38.60g) and potassiumiodide (300mg) the mixture heating up backflow in acetone (500ml) of step (a) is spent the night.With the reactant cooling, filter and evaporation, obtain an oily matter, it is dissolved in the ether also washs with the 2N aqueous sodium hydroxide washes.The evaporation organic layer obtains an oily matter, purifies through chromatography (silica gel, 4: 1 hexane/ethyl acetate), obtains required product (51.86g).

Measured value: C, 62.64; H, 5.31;

C ₁₅H ₁₅BrO calculated value: C, 61.85; H, 5.19%.

¹H-NMR（CDCl ₃）：δ＝2.30（s，3H），2.40（s，3H），5.00（s，2H），6.60（d，1H），7.30-7.50（m，6H）ppm.

(c) 4-benzyloxy-2

At-78 ℃, with (500ml) solution n-Butyl Lithium (48.4ml, the 2.5M hexane solution) processing of tetrahydrofuran (THF) (THF) of step (b) product (33.8g)., add excessive finely powdered solidified carbon dioxide, and reactant is warmed to room temperature after 30 minutes-78 ℃ of stirrings.Vacuum is removed THF, and resistates distributes between ethyl acetate and 2N hydrochloric acid.Organic layer salt water washing, dry (MgSO ₄), evaporation obtains pink solid then.Through re-crystallizing in ethyl acetate, obtain required compound (18.8g), m.p.164-166 ℃.

Measured value: C, 74.87; H, 6.21;

C ₁₆H ₁₆O ₃Calculated value: C, 74.98; H, 6.29%.

¹H-NMR（CDCl ₃）：δ＝2.10（s，3H），2.40（s，3H），5.10（s，2H），6.95（d，1H），7.30-7.50（m，5H），7.60（d，1H）ppm.

(d) 4-benzyloxy-2, the 3-dimethyl benzoyl chloride

Step (c) product (2.0g) is suspended in the methylene dichloride (10ml) also with oxalyl chloride (1.3ml) and dimethyl formamide (DMF) (2) processing.After stirring is spent the night,, obtain a white solid, make itself and methylbenzene azeotropic three times, obtain title compound (2.24g), be white powder the evaporation of this homogeneous phase solution.This material is directly used.

Preparation example 10

4-benzyloxy Benzoyl chloride

This title compound is with being similar to preparation example 9(d) described in method prepare, just make starting raw material with 4-benzyloxy phenylformic acid.Resulting material is directly used.

Preparation example 11

4-(1-(4-isobutyl phenenyl) oxyethyl group) Benzoyl chloride

This title compound is with being similar to preparation example 9(d) described in method prepare, just with 4-(1-(4-isobutyl phenenyl) oxyethyl group) phenylformic acid (seeing preparation example 28(b)) be starting raw material.Resulting product is directly used.

Preparation example 12

1-(4-n-propyl phenyl) fourth-1-alcohol

Ether (60ml) solution of 4-n-propylbenzene formaldehyde (7.4g) is cooled to 0 ℃, with ether (27.5ml) solution-treated of 2.0M chlorination n-propyl magnesium.The reactant stirring is spent the night,, reaction is stopped with saturated aqueous ammonium chloride with the ether dilution.Separate organic layer, with the saturated aqueous ammonium chloride washing, dry (MgSO ₄).Organic layer is filtered and evaporation, obtain a kind of colorless oil, it is passed through chromatography (silica gel, 4: 1 hexane/ethyl acetate) purifying, after suitable wash-out is partly evaporated, obtain required product (4.06g), m/z=192(M ⁺).

¹H-NMR（CDCl ₃）：δ＝1.00（m，6H），1.20-1.40（m，2H），1.70（q，2H），1.75-1.90（m，3H），2.60（t，2H），4.60（m，1H），7.10（d，2H），7.30（d，2H）ppm.

Preparation example 13

The 1-(4-ethylphenyl) ethanol

At 0 ℃, methyl alcohol (50ml) solution of 4-ethylbenzene ethyl ketone (10.0g) is handled with sodium borohydride (3.83g) in batches.After 20 ℃ stirring is spent the night down, reactant is distributed between 1N hydrochloric acid and ethyl acetate.Organic layer 1N salt acid elution, dry (MgSO ₄) and evaporation, obtain a transparent oily matter (9.9g).This oily matter with flash chromatography (silica gel, 3: 1 hexane/ethyl acetate) purifying, after suitable wash-out partly evaporated, is obtained required compound (8.9g), m/z=150(M ⁺).

¹H-NMR（CDCl ₃）：δ＝1.25（t，3H），1.55（d，3H），2.65（q，2H），4.90（q，1H），7.20（d，2H），7.35（d，2H）ppm.

Preparation example 14

4-n-propylbenzene methyl alcohol

At-78 ℃, with the THF(100ml of 4-n-propyl bromobenzene (10g)) solution n-Butyl Lithium (35ml, 1.6M hexane solution) processing.After stirring 15 minutes under this temperature, add Paraformaldehyde 96 (1.6g), continue again to stir 1 hour.Reaction mixture is distributed, with organic layer drying (MgSO between ether and water ₄) and evaporation, get an oily matter.With flash chromatography (silica gel, 3: 1 hexane/ethyl acetate) purifying, after suitable wash-out partly evaporated, obtain required product (2.7g), be colorless oil.

Preparation example 15

(R, S)-1-(4-(2-methyl-propyl) phenyl) ethanol

Methyl alcohol (50ml) solution of 4-isobutyryl methyl phenyl ketone (10.0g) is cooled to 0 ℃, and (3.23g) handles in batches with sodium borohydride.After stirred overnight at room temperature, add 1N hydrochloric acid (50ml) and ethyl acetate (100ml) reaction is stopped.With organic layer separation, dry (MgSO ₄) and evaporation, obtain title compound (10.02g), be transparent oily matter, m/z=178(M ⁺).

Measured value: C, 79.69; H, 9.90;

C ₁₂H ₁₈O.1/7 H ₂O calculated value: C, 79.68; H, 10.19%.

¹H-NMR（CDCl ₃）：δ＝0.90（d，6H），1.50（d，3H），1.85（m，1H），2.50（d，2H），4.85（q，1H），7.15（d，2H），7.30（d，2H）ppm.

Preparation example 16

1-(3, the 4-dichlorophenyl) ethanol

This title compound is to prepare with being similar to the method described in the preparation example 15, and just with 3, the 4-dichloroacetophenone is made starting raw material.m/z＝190（M ⁺）。

¹H-NMR（CDCl ₃）：δ＝1.45（d，3H），2.25（s，br，1H），4.85（q，1H），7.20（d，1H），7.40（d，1H），7.45（s，1H）ppm.

Preparation example 17

(R)-and 1-(4-(2-methyl-propyl) phenyl) ethanol

(a) acetate (R, S)-1-(4-(2-methyl-propyl) phenyl)-ethyl ester

Use anhydrous pyridine (2.5ml) and distilled Acetyl Chloride 98Min. (2.2ml) to handle successively at methylene dichloride (40ml) solution of 0 ℃ of product (5.0g) with preparation example 15.After stirred overnight at room temperature, mixture is filtered, (10g) is added in the filtrate with silica gel, and mixture is evaporated to dried.With column chromatography (silica gel, 12: 1 hexane/ethyl acetate) purifying, after suitable wash-out partly evaporated, obtain required compound (2.3g), be a transparent oily matter.

¹H-NMR（CDCl ₃）：δ＝0.90（d，6H），1.55（d，3H），1.85（m，1H），2.05（s，3H），2.45（d，2H），5.85（q，1H），7.15（d，2H），7.25（d，2H）ppm.

(b) (R)-and 1-(4-(2-methyl-propyl) phenyl) ethanol

The product (3.0g) of step (a) suspension in pH 7 phosphate buffered saline buffers (100ml) (50mg) is handled with SAM II lipase (trade mark) (Fluka Chemicals Limited), and mixture is vigorous stirring 2 days at room temperature.This mixture is extracted with ethyl acetate (100ml), with the organic phase drying (MgSO that merges ₄) and evaporation.With column chromatography (silica gel, 9: 1 hexane/ethyl acetate) purifying, after suitable wash-out partly merged and evaporating, at first obtain acetate (S)-1-(4-(2-methyl-propyl) phenyl chlorocarbonate (1.47g).Further wash-out obtains title compound, is a transparent oily matter, makes its crystallization, obtains white needles thing (1.04g), and m.p.37-38 ℃, (α) _D+ 32.3 ° (c=2.7, methyl alcohol).

Preparation example 18

(S)-and 1-(4-(2-methyl-propyl) phenyl) ethanol

With acetate (S)-1-(4-(2-methyl-propyl) phenyl chlorocarbonate (1.2g) (seeing preparation example 17(b)) with dehydrated alcohol (20ml) solution-treated of 1N sodium hydroxide.After stirred overnight at room temperature, steaming desolventizes, and resistates obtains title compound (0.59g) with chromatography (silica gel, 4: 1 hexane/ethyl acetate) purifying, is a transparent oily matter, and m.p.34 ℃, (α) _D-32.7 ° (c=2.7, methyl alcohol).

¹H-NMR（CDCl ₃）：δ＝0.90（d，6H），1.50（d，3H），1.85（m，1H）2.50（d，2H），4.85（q，1H），7.15（d，2H），7.30（d，2H）ppm.

Preparation example 19

α-cyclopentyl-4-n-propylbenzene methyl alcohol

Ether (20ml) solution of 4-n-propylbenzene formaldehyde (2.0g) is cooled to 0 ℃, handles with chlorination cyclopentyl magnesium solution (7.4ml, 2.0M diethyl ether solution).After stirred overnight at room temperature, mixture is handled with saturated aqueous ammonium chloride.Separate organic layer, dry (MgSO ₄) and evaporation, obtain yellow oil.With flash chromatography (silica gel begins then to use 3: 1 hexane/ethyl acetate wash-outs with 4: 1 hexane/ethyl acetate wash-outs) purifying, suitable wash-out is partly merged the back evaporation, obtain required compound (400mg), be a transparent oily matter, m/z=218(M ⁺).

¹H-NMR(CDCl ₃): δ=1.00(t, 3H), 1.00-1.60(m, 10H), the 2.25(sextet, 1H), 2.60(m, 2H), 4.40(d, 2H), 7.30(d, 2H), 7.40(d, 2H) ppm.

Preparation example 20～26

Being prepared as follows of following alkyl bromide carried out, and is about to corresponding alcohol (seeing preparation example 12～16 and 19) and is dissolved in the methylene dichloride, and this solution is cooled off in ice bath, makes this solution saturated with anhydrous hydrogen bromide simultaneously.After mixture stirred the short period of time, with reaction mixture vacuum-evaporation, obtain required alkyl bromide, it is directly used and need not be identified.

Starting raw material is seen EP-A-291245.

Preparation example 27

4-(3-(4-(1-hydroxyethyl) benzoyl) ethyl butyrate indoles-1-yl)

(a) indoles benzoyl 3-(4-(1-(t-butyldimethylsilyloxy base) ethyl))

This title compound is by being similar to method used in the preparation example 5 with indoles and 4-(1-(t-butyldimethylsilyloxy base) ethyl) Benzoyl chloride prepares as starting raw material, m/z=380(M+1) ⁺

Measured value: C, 72.79; H, 7.73; N, 3.76;

C ₂₃H ₂₉NO ₂Si calculated value: C, 72.78; H, 7.70; N, 3.69%.

¹H-NMR（CDCl ₃）：δ＝0.00（s，3H），0.40（s，3H），0.95（s，9H），1.45（d，3H），4.95（q，1H），7.30-7.50（m，5H），7.70（m，1H），7.80（d，2H），8.40（m，1H），9.20（s，br，1H）ppm.

(b) ethyl butyrate indoles-1-yl benzoyl 4-(3-(4-(1-(t-butyldimethylsilyloxy base) ethyl)))

Dimethyl formamide (20ml) solution of the product (1.70g) of step (a) is handled with sodium hydride (215mg, 60% mineral oil dispersion).After at room temperature stirring 1 hour, add 4-bromo ethyl butyrate (0.7ml), continue to stir 2 hours.Reaction mixture is with ethyl acetate (50ml) dilution, successively with 2N aqueous hydrochloric acid and saturated brine washing.With organic layer drying (MgSO ₄) and steam and to desolventize, obtain yellow jelly.This jelly with flash chromatography (silica gel, 3: 1 hexane/ethyl acetate) purifying, after suitable wash-out partly collected and evaporating, is obtained title compound (2.20g), be pure jelly, m/z=494(M+1) ⁺

¹H-NMR（CDCl ₃）：δ＝0.00（s，6H），0.90（s，9H），1.20（t，3H），1.50（d，3H），2.20-2.40（m，4H），4.10（q，2H），4.30（t，2H），5.00（q，1H），7.20-7.40（m，5H），7.60（s，1H），7.80（d，2H），8.35（m，1H）ppm.

(c) ethyl butyrate indoles-1-yl 4-(3-(4-(1-hydroxyethyl) benzoyl))

The product of step (b) is dissolved in the tetrahydrofuran (THF) (100ml), and handles, stirred 1 hour with fluoridizing tetra-n-butyl ammonium (4.92g).Reaction mixture is with ethyl acetate (100ml) dilution, with 2N aqueous hydrochloric acid and saturated brine washing.With organic layer drying (MgSO ₄), filter and evaporation, obtain brown jelly.With flash chromatography (silica gel, 98: 2 methylene chloride) purifying, after suitable wash-out partly collected and evaporating, obtain title compound (0.92g), be pure jelly, m/z=380(M+1) ⁺

¹H-NMR（CDCl ₃）：δ＝1.20（t，3H），1.70（d，3H），2.00（s，br，1H），2.20-2.40（m，4H），4.10（q，2H），4.30（t，2H），5.00（q，1H），7.20-7.60（m，6H），7.80（d，2H），8.35（m，1H）ppm.

Preparation example 28

(S)-and 4-(3-(4-(1-(4-(2-methyl-propyl) phenyl) oxyethyl group) benzoyl) indoles-1-yl) butyric acid

(a) (R, S)-4-(1-(4-(2-methyl-propyl) phenyl) oxyethyl group) ethyl benzoate

Ethyl p-hydroxybenzoate (5.16g) is dissolved in the acetone (50ml), and handle with Anhydrous potassium carbonate (4.40g), bromination tetra-n-butyl ammonium (0.44g) and (R, S)-Alpha-Methyl-4-(2-methyl-propyl) bromotoluene (7.7g) (seeing preparation example 23).The soup compound that obtains at room temperature stirs and spends the night and filter.With the filtrate evaporation, obtain title compound (13.5g), it is directly used and need not be identified.

(b) (R, S)-4-(1-(4-(2-methyl-propyl) phenyl) oxyethyl group) phenylformic acid

The product (13.5g) of step (a) is dissolved in 95% aqueous ethanol (108ml), handles, 60-70 ℃ of heating 90 minutes with 2N aqueous sodium hydroxide solution (32ml).Evaporating solvent adds entry.Mixture is handled with 2N aqueous hydrochloric acid (50ml), uses ethyl acetate extraction then.The organic phase that merges is washed with saturated brine and dry (MgSO ₄).Remove ethyl acetate solvent, obtain title compound, be white solid.Obtain meticulous white powder (6.7g) with the normal hexane development.

¹H-NMR（CDCl ₃）：δ＝0.95（d，6H），1.70（d，3H），1.88（m，1H），2.51（d，2H），5.40（q，1H），6.95（d，2H），7.17（d，2H），7.30（d，2H），8.00（d，2H）ppm.

(c) (S)-and 4-(1-(4-(2-methyl-propyl) phenyl) oxyethyl group) phenylformic acid (+)-ephedrine salt

The product (10g) of step (b) is dissolved in 95% aqueous ethanol (60ml) and the water (60ml), handles with (+) ephedrine semihydrate (5.84g).Mixture heating up is refluxed up to forming solution completely.Reaction mixture is at room temperature placed and is spent the night.The precipitation that filtered and recycled produces is also dry, obtains title compound (5.20g).(α) ²⁰ _D-21.9 ° (c=1, methyl alcohol).

¹H-NMR（CDCl ₃）：δ＝0.90（d，6H），1.10（d，3H），1.70（d，3H），1.85（m，1H），2.45（s，3H），3.15（m，1H），5.45（m，2H），6.88（d，2H），7.10（d，2H），7.30（m，7H），7.90（m，2H）ppm.

To the chirality HPLC analysis revealed of this product, its (S): (R) ratio of enantiomorph is 95: 5.

(d) (S)-and 4-(1-(4-(2-methyl-propyl) phenyl) oxyethyl group) phenylformic acid

The product (4.63g) of step (c) is handled with the 1N aqueous hydrochloric acid, the soup compound that obtains was stirred 90 minutes.The precipitation that filtering separation produced is used 1N aqueous hydrochloric acid and water washing successively.Product 50 ℃ of following vacuum-dryings, is obtained required compound (2.94g), be colorless solid, m.p.128-131 ℃.(α) ²⁰ _D-51.5 ° (c=1, methyl alcohol).

Measured value: C, 76.76; H, 7.30; N, 0.00;

C ₁₉H ₂₂O ₃Calculated value: C, 76.48; H, 7.43; N, 0.00%.

(e) (S)-and 4-(1-(4-(2-methyl-propyl) phenyl) oxyethyl group) Benzoyl chloride

The product (2g) of step (d) is dissolved in the methylene dichloride (10ml), uses pyridine (0.60ml) and oxalyl chloride (0.64ml) to handle successively.Mixture at room temperature stirred 3 hours, added 1 dimethyl formamide and mixture stirred to spend the night.Steaming desolventizes and adds dry toluene (40ml).Remove by filter the gained precipitation, the filtrate that will contain title compound is evaporated to the 10ml volume, and is directly used in next step, need not identify.

(f) (S)-and 3-(4-(1-(4-(2-methyl-propyl) phenyl) oxyethyl group) benzoyl) indoles

Indoles (715mg) is dissolved in the toluene (5ml) also with iodate methyl magnesium (2.0ml, 3M diethyl ether solution) processing.The yellow solution that obtains was stirred 10 minutes, adds (S)-4-(1-(4-(2-methyl-propyl) phenyl) oxyethyl group) toluene (10ml) solution of Benzoyl chloride (product of step (e)).Mixture at room temperature stirred 1 hour, added saturated aqueous ammonium chloride (50ml) then under the vigorous stirring.Mixture is with ethyl acetate (30ml, 40ml and 15ml) extraction, with the organic phase drying (MgSO that merges ₄), filter and evaporation, obtain brown jelly.It is used flash chromatography (silica gel earlier with 3: 1 hexane/ethyl acetate, is used 1: 1 hexane/ethyl acetate wash-out then) purifying, after suitable wash-out is partly evaporated, obtain title compound (1.05g), be beige solid.m.p.150-152℃。

Measured value: C, 81.69; H, 6.83; N, 3.58;

C ₂₇H ₂₇NO ₂Calculated value: C, 81.58; H, 6.85; N, 3.52%.

¹H-NMR（CDCl ₃）：δ＝1.00（d，6H），1.75（d，3H），1.95（m，1H），2.55（d，2H），5.45（q，1H），7.05（d，2H），7.25（d，2H），7.39-7.54（m，4H），7.70（m，1H），7.85（d，2H），8.45（m，1H），9.10（s，br，1H）ppm.

(g) (S)-and 4-(3-(4-(1-(4-(2-methyl-propyl) phenyl) oxyethyl group) benzoyl) indoles-1-yl) ethyl butyrate

With 2-butanone (5ml) solution of the product (500mg) of step (f) with Anhydrous potassium carbonate (695mg) and 4-bromo ethyl butyrate (0.23ml) processing.The mixture heating up backflow is spent the night, and cooling, filtration, evaporated filtrate obtain yellow jelly.It is used flash chromatography (silica gel, 3: 1 hexane/ethyl acetate) purifying, after suitable wash-out is partly evaporated, obtain title compound (451mg).

This product has identical mass spectrum with embodiment 33 compounds, HPLC reaches ¹The H-NMR feature.

(h) (S)-and 4-(3-(4-(1-(4-(2-methyl-propyl) phenyl) oxyethyl group) benzoyl) indoles-1-yl) butyric acid

95% aqueous ethanol (2ml) solution of the product (108mg) of step (g) is handled with 6 2N aqueous sodium hydroxide solutions.Mixture was stirred 90 minutes, add entry (3ml) then, then add the 2N aqueous hydrochloric acid and reach pH1 up to mixture.(3 * 10ml) extraction mixtures, the organic phase evaporation with merging obtains title compound (62mg), is colourless foam shape thing with methylene dichloride.

This product and the compound of embodiment 9 have identical mass spectrum, specific rotation and ¹The H-NMR feature.

Pharmacologically active

According to the method for being narrated on this specification sheets 28-31 page or leaf, be organized in the inhibition activity of the selected formula I compound of vitro test to steroid class 5 with the male rat ventral prostate.The results are shown in the table 1.

Toxicity

Give mouse oral the compound of embodiment 1, dosage as many as 1000mg/kg, in whole research process, animal shows normal appearance and behavior.

Claims

1, the method for preparing following formula: compound or its pharmaceutically useful salt,

R is H, OH, halogen, C ₁-C ₄Alkyl or C ₁-C ₄Alkoxyl group;

R ¹, R ², R ³And R ⁴Be selected from H, C independently of one another ₁-C ₄Alkyl,

C ₁-C ₄Alkoxyl group, OH, halogen and CF ₃

R ⁶, R ⁷And R ⁸One of be the group of following formula:

Remaining and R ⁵And R ⁹Be selected from H, C independently of one another ₁-C ₄Alkyl,

C ₁-C ₄Alkoxyl group, halogen and halo (C ₁-C ₄) alkyl;

R ¹⁰Be COOH, COOR ¹¹Or CONR ¹²R ¹³

R ¹¹It is biolabile one-tenth ester group;

R ¹⁴Be H, C ₁-C ₆Alkyl, C ₃-C ₇Cycloalkyl or aryl;

This method comprises,

(a) be preparation formula I compound (R wherein ¹⁰Be COOH, Y, R and R ¹～R ⁹As the front formula I compound is defined), with the cracking of following formula ester:

R wherein ¹⁵Be can be cleaved to generate R ¹⁰Be COOH, Y, R and R ¹～R ⁹As the one-tenth ester group of front to the defined formula I compound of formula I compound,

(b) be preparation formula I compound (R wherein ¹⁰Be COOH, Y, R and R ¹～R ⁹As the front formula I compound is defined), make formula I compound (R wherein ¹⁰Be CONR ¹²R ¹³, Y, R, R ¹～R ⁹, R ¹²And R ¹³As the front formula I compound is defined) carry out acidity or alkaline hydrolysis;

(c) be preparation formula I compound (R wherein ¹⁰Be COOH, Y, R and R ¹～R ⁹As the front formula I compound is defined), make following formula: compound carry out acidity or alkaline hydrolysis:

Wherein Y, R and R ¹～R ⁹As the front formula I compound is defined;

(d) be preparation formula I compound (R wherein ¹⁰Be COOR ¹¹, Y, R and R ¹～R ⁹And R ¹¹As the front formula I compound is defined), make formula I compound (R wherein ¹⁰Be COOH, Y, R and R ¹～R ⁹As the front formula I compound is defined) and formula R ¹¹OH alcohol (R wherein ¹¹As the front formula I compound is defined) carry out esterification;

(e) be preparation formula I compound (wherein Y, R and R ¹～R ¹⁰As the front formula I compound is defined), make alkali salt (the wherein R and the R of following formula: compound ¹～R ⁹As the front formula I compound is defined) and formula Z ³-Y-COOR ¹¹Or Z ³-Y-CONR ¹²R ¹³Compound or with formula Z ³The alkali salt of-Y-COOH compound (wherein Y, R ¹¹, R ¹²And R ¹³The formula I compound is defined Z as the front ³Be leavings group) carry out alkylated reaction;

(f) be preparation formula I compound (R wherein ¹⁰Be COOH, Y, R and R ¹～R ⁹As the front formula I compound is defined), make following formula: compound carry out oxidizing reaction,

Wherein Y, R and R ¹～R ⁹As the front formula I compound is defined;

(g) be preparation formula I compound (R wherein ¹⁰Be COOH, Y, R and R ¹～R ⁹As the front formula I compound is defined), make formula (XIV) compound or formula (XV) compound or its alkali salt carry out oxidizing reaction,

R wherein ²⁴Be H or OH, Y, R and R ¹～R ⁹As the front formula I compound is defined;

(h) be preparation formula I compound (R wherein ⁶, R ⁷And R ⁸One of be the following formula group:

R ⁶, R ⁷And R ⁸In surplus person and Y, R, R ¹～R ⁵, R ⁹, R ¹⁰, R ¹⁴" aryl " defines the formula I compound as the front), make the reaction of formula (XVIII) compound or its alkali salt and formula (XIX) compound,

Wherein in formula (XVIII), R ²⁵, R ²⁶And R ²⁷One of be OH, R ²⁵, R ²⁶And R ²⁷Surplus person such as the front to the R of formula I compound ⁶, R ⁷And R ⁸After the person define Y, R, R ¹～R ⁵, R ⁹And R ¹⁰As the front formula I compound is defined, in formula (XIX), R ¹⁴" aryl " defines the formula I compound as the front, Z ⁷It is leavings group;

(i) be preparation formula I compound (R wherein ¹⁰Be COOR ¹¹Or CONR ¹²R ¹³, R ⁶, R ⁷And R ⁸One of be the following formula group:

R ⁶, R ⁷And R ⁸After person and Y, R, R ¹～R ⁵, R ⁹, R ¹¹, R ¹², R ¹³, R ¹⁴" aryl " defines the formula I compound as the front), formula (XVIII) compound and formula (XX) compound are reacted in the presence of dewatering agent,

Wherein in formula (XV III), R ¹⁰Be COOR ¹¹Or CONR ¹²R ¹³, Y, R, R ¹～R ⁵, R ⁹, R ¹¹, R ¹²And R ¹³As the definition of front to the formula I compound, R ²⁵, R ²⁶And R ²⁷Such as in claim 1 (h) definition; In formula (XX), R ¹⁴" aryl " defines the formula I compound as the front;

(j) be preparation formula I compound (R wherein ⁶, R ⁷, R ⁸One of be the following formula group

R ⁶, R ⁷And R ⁸After person and Y, R, R ¹～R ⁵, R ⁹, R ¹⁰, R ¹⁴" aryl " defines the formula I compound as the front), make the alkali salt reaction of formula (X XI) compound or its alkali salt and formula (X XI) compound,

Aryl-OH (X XII)

R in formula (X XI) wherein ²⁸, R ²⁹And R ³⁰One of be the following formula group:

R ²⁸, R ²⁹And R ³⁰Surplus person such as the front to the R of formula I compound ⁶, R ⁷And R ⁸After the person define Y, R, R ¹～R ⁵, R ⁹, R ¹⁰And R ¹⁴The formula I compound is defined Z as the front ⁸Be leavings group, " aryl " defines the formula I compound as the front in formula (X XII); Or

(k) be preparation formula I compound (R wherein ¹⁰Be COOR ¹¹Or CONR ¹²R ¹³, R ⁶, R ⁷And R ⁸One of be the following formula group

R ⁶, R ⁷And R ⁸Surplus person and Y, R, R ¹～R ⁵, R ⁹, R ¹¹, R ¹², R ¹³, R ¹⁴" aryl " defines the formula I compound as the front), formula (XX III) compound and formula (X XII) compound are reacted in the presence of dewatering agent,

R in formula (XX III) wherein ³¹, R ³²And R ³³One of be the following formula group:

Surplus person such as front are to the R of formula I compound ⁶, R ⁷And R ⁸After the person define R ¹⁰Be COOR ¹¹Or CONR ¹²R ¹³, Y, R, R ¹～R ⁵, R ⁹, R ¹¹, R ¹², R ¹³And R ¹⁴As the front formula I compound is defined; " aryl " defines the formula I compound as the front in formula (X XII);

After arbitrary method in above-mentioned (a)-(k) method, all can randomly follow the formula I product is converted into its pharmaceutically useful salt.

2, according to the process of claim 1 wherein

R is H, OH, halogen, C ₁-C ₄Alkyl or C ₁-C ₄Alkoxyl group;

R ⁶, R ⁷And R ⁸One of be the following formula group:

Surplus person and R ⁵And R ⁹Be selected from H, C independently of one another ₁-C ₄Alkyl, C ₁-C ₄Alkoxyl group, halogen and halo (C ₁-C ₄) alkyl;

R ¹⁰Be COOH, COOR ¹¹Or CONR ¹²R ¹³;

R ¹¹It is biolabile one-tenth ester group;

R ¹⁴Be H, C ₁-C ₆Alkyl, C ₃-C ₇Cycloalkyl or aryl;

Its condition is:

ⅳ) work as R ⁷Be the 1-(4-(2-methyl-propyl) phenyl) oxyethyl group, R ⁵And R ⁶Be methyl, R, R ¹, R ², R ³, R ⁴, R ⁸And R ⁹Being H, Y is-(CH ₂) ₃-, when the formula I compound is racemic form, R ¹⁰Not COOH or COOC ₂H ₅;

3, according to claim 1(a) or 2 method, wherein cracking is to be undertaken by the acidity or the alkaline hydrolysis of formula II compound.

4, according to claim 1(a), 2 or 3 method, wherein R ¹⁵Be C ₁-C ₆Alkyl.

5, according to the method for claim 3 or 4, wherein cracking is undertaken by alkaline hydrolysis under aqueous conditions with sodium hydroxide or potassium hydroxide.

6, according to claim 1(e) or 2 method, the alkali salt of its Chinese style (VIII) compound is sodium or sylvite.

7, according to claim 1(e), 2 or 6 method, wherein Z ³Be halogen, C ₁-C ₄Alkane sulfonyl oxy or C ₁-C ₄The benzene sulfonamide acyloxy.

8, according to the method for claim 7, Z wherein ³It is bromine.

9, according to claim 1(h) or 2 method, wherein use the alkali salt of formula (X VIII) compound.

10, according to the method for claim 9, wherein alkali salt is sodium or sylvite.

11, according to claim 1(h), 2,9 or 10 method, wherein Z ⁷Be halogen, C ₁-C ₄Alkane sulfonyl oxy or C ₁-C ₄The benzene sulfonamide acyloxy.

12, according to the method for claim 11, Z wherein ⁷It is bromine.

13, according to claim 1(i), 1(k) or 2 method, wherein used dewatering agent is the mixture of diethyl azodiformate and triphenylphosphine.

14, according to claim 1(j) or 2 method, wherein Z ⁸Be halogen, C ₁-C ₄Alkane sulfonyl oxy or C ₁-C ₄The benzene sulfonamide acyloxy.

15, according to method any in the claim 1～14, wherein R ¹⁰Be COOH or COOR ¹¹

16, according to the method for claim 15, R wherein ¹¹Be C ₁-C ₆Alkyl.

17, according to any one or 14 method, wherein R in the claim 1～12 ¹⁰Be COOH.

18, according to method any in the claim 1～17, wherein

Y is C ₁-C ₆Alkylidene group;

R is H or C ₁-C ₄Alkyl;

R ¹, R ², R ³And R ⁴H respectively does for oneself;

R ⁶, R ⁷And R ⁸One of be the following formula group:

Remaining and R ⁵And R ⁹Be selected from H and C independently of one another ₁-C ₄Alkyl;

R ¹⁴Be H, C ₁-C ₄Alkyl, C ₄-C ₆Cycloalkyl or by C ₁-C ₄The phenyl that alkyl replaces; And

At R ⁶, R ⁷And R ⁸Definition in used " aryl " be meant by 1～3 and be selected from C independently of one another ₁-C ₆The phenyl that the substituting group of alkyl and halogen replaces arbitrarily.

19, according to the method for claim 18, wherein

Y is methylene radical, propylidene, butylidene or pentylidene;

R is H or methyl;

R ⁷Be the following formula group:

R ⁵, R ⁶, R ⁸And R ⁹Be selected from H and C independently of one another ₁-C ₄Alkyl;

R ¹⁴Be H, methyl, n-propyl, cyclopentyl or 4-n-propyl phenyl; And

" aryl " is meant by 1 or 2 any phenyl that replaces of substituting group that is selected from methyl, ethyl, n-propyl, isobutyl-and chlorine independently of one another.

20, according to method any in claim 1～13 or 15～17, wherein

Y is a propylidene;

R is H;

R ¹, R ², R ³And R ⁴H respectively does for oneself;

R ⁷Be the following formula group:

R ⁵, R ⁶, R ⁸And R ⁹H respectively does for oneself;

R ¹⁴It is methyl; And

" aryl " is meant phenyl, 4-aminomethyl phenyl, 4-ethylphenyl, 4-n-propyl phenyl, 4-isobutyl phenenyl or 3,4-dichlorophenyl.

21, according to method any in the claim 1～20, wherein " aryl " is meant the 4-isobutyl phenenyl.

22, according to the method for claim 1 or 2, it is used to prepare formula I compound, wherein R ⁶, R ⁷And R ⁸One of be the following formula group:

Remaining and Y, R, R ¹, R ², R ³, R ⁴, R ⁵, R ⁹, R ¹⁰, R ¹¹, R ¹², R ¹³" aryl " is as claim 1 or 2 definition.

23, according to the part method of claim 1 or 2, it is used to prepare following compounds or its pharmaceutically useful salt:

(R, S)-4-(2-methyl-3-(4-(1-(4-(2-methyl-propyl) phenyl) oxyethyl group) benzoyl) indoles-1-yl) butyric acid, or

(S)-and 4-(2-methyl-3-(4-(1-(4-(2-methyl-propyl) phenyl) oxyethyl group) benzoyl) indoles-1-yl) butyric acid.

24, the method for pharmaceutical compositions, this method comprise the formula I compound of the preparation of the either party's method by claim 1～23 or its pharmaceutically useful salt and acceptable diluents or carrier are mixed.