SK8494A3 - Endoles, method of their manufacturing and pharmaceutical preparations on their base - Google Patents

Abstract

The present invention provides compounds of formula (I) and pharmaceutically acceptable salts thereof, wherein Y is C1-C6 alkylene optionally substituted by C1-C6 alkyl; R is H, OH, halo, C1-C4 alkyl or C1-C4 alkoxy; R<1>, R<2>, R<3> and R<4> are each independently selected from H, C1-C4 alkyl, C1-C4 alkoxy, OH, halo and CF3; one of R<6>, R<7> and R<8> is a group of formula (a) or (b), and the remainder, together with R<5> and R<9>, are each independently selected from H, C1-C4 alkyl, C1-C4 alkoxy, halo and halo(C1-C4)alkyl; R<10> is COOH, COOR<11> or CONR<12>R<13>; R<11> is a biolabile ester-forming group; R<12> and R<13> are each independently selected from H and C1-C4 alkyl; R<14> is H, C1-C6 alkyl, C3-C7 cycloalkyl or aryl; and ''aryl'', used in the definitions of R<6>, R<7>, R<8> and R<14>, means phenyl optionally substituted by C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl, OH, halo, CF3, halo(C1-C6 alkyl), nitro, amino, C2-C6 alkanamido, C2-C6 alkanoyl or phenyl: together with pharmaceutical compositions containing, processes for the preparation of and uses of, such compounds.

Description

The invention relates to indole derivatives which exhibit a steroid 5α-reductase inhibitory effect. In particular, the invention relates to certain indole derivatives as such, to a process for their preparation, to pharmaceutical preparations based thereon, and to the use of these compounds as testosterone-5α-reductase inhibitors.

BACKGROUND OF THE INVENTION

The class of androgens that belong to steroid hormones, including testosterone, is responsible for the differences in physical characteristics between men and women. Of all the organs that produce androgens, they are the eggs where most of these hormones are produced. Overproduction of these hormones in the body results in many undesirable physical manifestations and disease states such as acne vulgaris, alopecia, seborrhoea, female hirsutism, benign hypertrophy

- male prostate and baldness.

Testosterone is the most important androgen secreted by the eggs and is the major androgen present in the plasma of men. The major mediators of androgen activity in certain organs, such as the prostate gland and the adipose gland, are 5? -Reduced androgens. Thus, testosterone is the prohormone of 5α-dihydrotestosterone, which is produced locally in these organs by the action of testosterone 5α-reductase. The presence of elevated dihydrotestosterone levels in many disease states has therefore caused attention to be focused on the synthesis of testosterone 5α-reductase inhibitors.

Testosterone 5α-reductase inhibitors may also be useful in the treatment of human prostate adenocarcinomas.

Patent application EP-A-0458207 discloses certain indole derivatives that exhibit testosterone 5α-reductase inhibitory activity.

SUMMARY OF THE INVENTION

The present invention provides indole compounds of formula I

R ¹⁰ (I) and pharmaceutically acceptable salts thereof, wherein

Y is (C 1 -C 6) alkylene optionally substituted with (C 1 -C 6) alkyl;

R is hydrogen, hydroxy, halogen, C 1 -C 4 alkyl or C 1 -C 4 alkoxy;

r! R R, R ^ _and R ^ are each independently hydrogen, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, hydroxy, halogen or trifluoromethyl;

One of the symbols

R ⁶ , R ⁷ and R ⁸ represent a group formula

R ¹⁴ R ¹⁴

I I

-OCH-aryl or -CHO-aryl and each of the remaining R, R and R as well as R ⁵ and R ⁹ are each independently hydrogen, C 1 -C 4 alkyl, C 1 -C 4 alkoxy a carbon atom, a halogen atom or a haloalkyl group having 1 to 4 carbon atoms;

R ¹⁰ represents a carboxy group or a group of the formula COOR ¹¹ or CONR ¹² R ¹³ ;

R ¹¹ represents a biolabile ester-forming group;

R ¹² and R ¹³ are each independently hydrogen or C 1 -C 4 alkyl;

R ( ¹⁴⁾ is hydrogen, (C1-C6) -alkyl, (C3-C7) -cycloalkyl or aryl; ar 7 Q 14 aryl or aryl in the definitions of R, R, R and R are phenyl optionally substituted with C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 2 -C 6 alkenyl, hydroxy a halogen atom, a trifluoromethyl group, a haloalkyl group having 1 to 6 carbon atoms, a nitro group, an amino group, an alkanoyl group having 2 to 6 carbon atoms, an alkanoyl group having 2 to 6 carbon atoms or a phenyl group.

In another aspect, the present invention provides compounds as defined above, wherein

Y is (C 1 -C 6) alkylene optionally substituted with (C 1 -C 6) alkyl;

R is hydrogen, hydroxy, halogen, C 1 -C 4 alkyl or C 1 -C 4 alkoxy;

R ¹ , R ² , R ³ and R ⁴ are each independently hydrogen, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, hydroxy, halogen or trifluoromethyl;

One of the symbols

R ⁸ , R ⁷ and R ⁸ represent a group of the general formula

R ¹⁴ R

II

-OCH-aryl or -CHO-aryl and each of the other R @ 6, R @ ⁷ and R @ ⁸ as well as R @ ⁸ and R @ ⁸ independently represent hydrogen, C1 -C4 alkyl, C1 -C4 alkyl; up to 4 carbon atoms, a halogen atom or a haloalkyl group having 1 to 4 carbon atoms;

R ¹⁰ represents a carboxy group or a group of the formula COOR ³³ or CONR ³² R ³³ ;

R ¹¹ represents a biolabile ester-forming group;

R ¹² and R ¹³ are each independently hydrogen or C 1 -C 4 alkyl;

R ( ¹⁴⁾ is hydrogen, (C1-C6) -alkyl, (C3-C7) -cycloalkyl or aryl; and aryl or aryl in the definitions of R ⁶ , R ⁷ , R ⁸ and R ¹⁴ is phenyl optionally substituted with C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 2 -C 6 alkenyl, hydroxy , halogen, trifluoromethyl, haloalkyl of 1 to 6 carbon atoms, nitro, amino, alkanoyl of 2 to 6 carbon atoms, alkanoyl of 2 to 6 carbon atoms or phenyl, provided that:

(i) when R ⁷ is 1- (4- (2-methylpropyl) phenyl) ethoxy, all R, R ¹ , R ² , R ³ , R ⁴ , R 5, R ⁸ , R ⁸ and R ⁹ are hydrogen; and Y represents a group of the formula - (O) 3-, does not represent a R ¹⁰ carboxy group when the compound of formula I is in racemic form;

(ii) when R ⁷ is 1- (4- (2-methylpropyl) phenyl) propoxy or 2,2-dimethyl-1- (4- (2-methylpropyl) phenyl) propoxy, all R, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁸ and R ⁹ are hydrogen and Y is - (CH ₂ ) 3 -, not R ^{18 is} carboxy or ethoxycarbonyl when the compound of formula I is in racemic form;

iii) when R ⁶ is 1- (3- (2-methylpropyl) phenyl) ethoxy, all R, R 6, R ² , R ³ , R ⁴ , R 6, R ⁷ , R ⁸ and R ⁹ are hydrogen atoms and Y is - (CH ₂ ) ₃ -, R ^{10 is not} carboxy or ethoxycarbonyl when the compound of formula I is in racemic form;

(iv) when R ⁷ is 1- (4- (2-methylpropyl) phenyl) ethoxy, each of R 1 and R ⁶ is methyl, all R ¹ , R ¹ , R ² , R ³ , R ⁴ ,

R® and R ⁹ are H, and Y is a group of formula ~ · - (CH ₂₎ 3 ', R ¹⁰ does not represent carboxy or etoxykarbonylskupinu, as long as the compound of formula I in racemic form;

(v) when R ⁷ is bis (4- (2-methylpropyl) phenyl) methoxy, all R, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁸ and R ⁹ are hydrogen; and Y is - (CH ₂ ) ₃ -, R ^{10 is not} carboxy;

vi) when R ⁶ is bis (4- (2-methylpropyl) phenyl) methoxy, all R, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁷ , R ⁸ and R ⁹ are hydrogen; and Y is - (CH ₂ ) ₃ -, R ^{10 is not} carboxy; ^and vii) when R ⁶ is 4- (2-methylpropyl) phenoxymethyl or 3- (2-methylpropyl) phenoxymethyl, all of R ¹ , R ¹ , R ² , R ³ , R ⁴ , R ⁵ ,

Q Q

R, R and R are hydrogen and Y is - (CH ₂ ) ₃ -, R ^{10 is not} carboxy or ethoxycarbonyl.

Alkyl, haloalkyl, alkenyl and alkoxy groups having 3 or more carbon atoms and the alkano amido and alkanoyl groups having 4 or more carbon atoms may be straight or branched.

The term halogen refers to fluorine, chlorine, bromine or iodine.

The term biolabile ester-forming group is well established in medical chemistry and refers to an ester-forming group that can be readily cleaved in vivo to give the corresponding acid of formula I, i. a compound wherein R ¹⁰ is carboxy. A number of such ester groups are well known, for example in the field of penicillin chemistry or in the case of antihypertensive agents based on angiotensin converting enzyme (ACE) inhibitors.

Esters of formula I, i. compounds wherein R ¹⁰ is C 1 -C 6 alkoxycarbonyl are steroid 5α-reductase inhibitors but generally when R ¹⁰ is COOR ¹¹ , these compounds are useful as prodrugs providing, in vivo, oral administration of a compound of formula I, wherein R ¹⁰ is carboxy. Such esters are also useful as intermediates for the preparation of compounds of formula I wherein R ¹⁰ is carboxy.

The suitability of any particular ester-forming group for this purpose can be determined based on conventional enzymatic hydrolysis studies in vitro or in vivo.

Examples of suitable biolabile ester-forming groups include alkyl groups (e.g., C 1 -C 6 alkyl), alkanoyloxyalkyl (including alkyl-, cycloalkyl- or aryl-substituted-derivatives thereof), arylcarbonyloxyalkyl-groups (including their aryl-substituted-alkyls), arryls indanyl and haloalkyl, wherein the alkanoyl group contains 2 to 8 carbon atoms and the alkyl group contains 1 to 8 carbon atoms and, where possible, all these are straight or branched and the term aryl or aryl means both phenyl or naphthyl which are both optionally substituted with C 1 -C 4 alkyl, C 1 -C 4 alkoxy or halogen.

In addition to C 1 -C 6 alkyl, specific examples of other biolabile ester-forming groups include, benzyl, 1- (2,2-diethylbutyryloxy) ethyl, 2-ethylpropionyloxymethyl, 1- (2-ethylpropionyloxy) ethyl, 1- (2, 2-ethylpropionyloxy) ethyl. 4-dimethylbenzoyloxy) ethyl, α-benzoyloxybenzyl, 1- (benzoyloxy) ethyl, 2-methyl-1-propionyloxy-1-propyl 1,2,4,6-trimethylbenzoyloxymethyl, 1- (2,4,6-trimethylbenzoyloxy) ethyl , pivaloyloxymethyl, phenethyl, fenpropyl,

2,2,2-trifluoroethyl, 1- or 2-naphthyl, 2,4-dimethylphenyl, 4-tert-butylphenyl and 5-indanyl.

Pharmaceutically acceptable salts of the compounds of formula I include acid addition salts and base salts thereof.

Suitable acid addition salts are derived from acids which provide non-toxic salts. Examples of such salts include hydrochlorides, hydrobromides, hydroiodides, sulfates, hydrogensulfates, phosphates, hydrogenphosphates, acetates, maleates, fumarates, lactates, tartrates, citrates, gluconates, benzoates, methanesulfonates, benzenesulfonates and p-toluenesulfonates.

Suitable base salts are derived from bases which provide non-toxic salts. Examples of such salts include aluminum, calcium, lithium, magnesium, potassium, sodium, zinc and diethanolamine salts.

A review of suitable salts is given, for example, in Berge et al., J. Pharm. Sci., 66, 1-19 (1977).

In the above definitions of individual symbols, priority is given to the following meanings:

Preferably Y is C 1 -C 6 alkylene, preferably methylene, propylene, butylene or pentylene, and most preferably propylene.

R is preferably hydrogen or C1-C4alkyl, preferably hydrogen or methyl, and most preferably hydrogen.

Of the symbols R ¹ , R ² , R ³ and R ⁴ preferably all represent hydrogen atoms.

One of R ⁶ , R ⁷ and R ⁸ preferably represents a group of the formula

R ¹⁴ R

-OCH-aryl or -CHO-aryl and each of the remaining R ⁶ , R ⁷ and R ⁸ , as well as R and R, independently represents a hydrogen atom or a C 1 -C 4 alkyl group.

’> 7

Still more preferred is the case where R is a group of formula

R ¹⁴ R ¹⁴

I I

-OCH-aryl or -CHO-aryl and each of R ⁵ , R ⁶ , R ⁸ and R ⁹ independently represents a hydrogen atom or a C 1 -C 4 alkyl group.

Most preferably, R ⁷ is a group of the formula

R ¹⁴

I

-OCH-aryl and each of R ⁵ , R ⁶ , R ⁸ and R ⁹ represents a hydrogen atom.

Preferably, R ^1U is carboxyl group of the formula COOR ^11, most preferably carboxyl.

Preferably R ¹¹ is C 1 -C 6 alkyl, most preferably ethyl.

R ¹⁴ is preferably hydrogen, C 1 -C 4 alkyl, C 4 -C 6 cycloalkyl or C 1 -C 4 -alkyl substituted phenyl. Preferably R ( ⁴⁾ is hydrogen, methyl, n-propyl, cyclopentyl or 4- (n-propyl) phenyl. Most preferably, R ^{14 is} methyl.

The term aryl or aryl preferably denotes a phenyl group which is optionally substituted with 1 to 3 substituents, preferably a phenyl group which is optionally substituted with 1 to 2 substituents, and most preferably a phenyl group which is optionally substituted with 1 substituent.

In a preferred embodiment of the present invention, aryl or aryl is phenyl optionally substituted by C 1-6 alkyl or halogen and more preferably phenyl optionally substituted by methyl, ethyl, n-propyl, isobutyl or chlorine, especially then phenyl, 4-methylphenyl, 4-ethylphenyl, 4- (n-propyl) phenyl, 4-isobutylphenyl or 3,4-dichlorophenyl, and most preferably 4-isobutylphenyl.

The compound of formula I may contain: one or more asymmetric carbon atoms and / or one or more alkenyl groups and therefore may exist in two or more stereoisomeric forms. The present invention includes both the individual stereoisomers of the compounds of formula (I) and mixtures thereof. Separation of diastereoisomers or cis- or transisomers may be accomplished by conventional procedures, for example, fractional crystallization, chromatography or HPLC (high performance liquid chromatography), which is applied to a compound of formula I or a suitable salt or derivative thereof. The individual enantiomer of the compound of formula (I) may also be prepared from the corresponding optically pure intermediate or by resolution, such as by HPLC, racemate, using a suitable chiral carrier, or by fractional crystallization of diastereomeric salts formed in racemate reactions with a suitable optically active acid or base.

A preferred group of compounds of formula (I) are those in which one of R ⁶ , R ⁷ and R ⁸ represents a group of formula

7 g and the rest of R, R and R, and also Y, R, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁹ , R ¹⁰ , R ¹¹ , R ¹² and R ¹³ and aryl are as defined above for formula I.

Preferred particular compounds of formula I include (R, S) -4- (3- [4- (1- [4- (2-methylpropyl) phenyl] ethoxy) benzoyl] indol-1-yl) butanoic acid, (S) -4- (3- [4- (1- [4- (2-methylpropyl) phenyl] ethoxy) benzoyl] indol-1-yl) butanoic acid, (R, S) -4- (2-methyl) -3- [4- (1- [4- (2-methylpropyl) phenyl] ethoxy) benzoyl] indol-1-yl) butanoic acid and (S) -4- (2-methyl-3- [4- (1) - [4- (2-methylpropyl) phenyl] ethoxy) benzoyl] indol-1-yl) butanoic acid and pharmaceutically acceptable salts thereof.

The compounds of the formula I according to the invention can be prepared by the following processes:

1) Compounds of formula I wherein R ¹⁰ is

Q is carboxy and Y, R and R to R are as defined above for formula I, may be prepared by cleaving the ester of formula II

wherein R ¹⁵ represents a suitable ester-forming group and

Y, R, and R ¹ to R ⁹ are as defined above for Formula I.

Those skilled in the art are aware of the large number of suitable ester-forming groups which can be cleaved to give the corresponding carboxylic acid (see, for example, T. W. Greene and P. G. Wuts, Protective Groups in Organic Synthesis, Wiley-Interscience (2nd edition, 1991)).

When R ¹⁵ is an ester-forming group which can be cleaved by hydrolysis, for example a C 1 -C 6 alkyl group or an alternative biolabile ester-forming group as defined above (i.e., a compound of formula I wherein R ¹⁰ is COOR ¹¹ ), the hydrolysis may be carried out under acidic or basic conditions, for example using an aqueous solution of either a suitable mineral acid or a suitable inorganic base. Preferably, the hydrolysis is carried out under basic conditions.

In a typical procedure of this type, the ester of formula (II) is treated with an aqueous solution of a suitable base such as sodium hydroxide or potassium hydroxide in the presence of a suitable organic cosolvent such as tetrahydrofuran or a C 1 -C 4 alkanol such as methanol. The hydrolysis is generally carried out at a temperature from room temperature to the reflux temperature, and preferably at room temperature. The product is obtained in the form of a salt with a base, and this salt can be converted to the carboxylic acid by acidification during work-up of the reaction mixture.

When R is an ester-forming group which can be separated by reduction, for example benzyl, the reduction can be carried out by catalytic hydrogenation using, for example, palladium on activated carbon as a catalyst.

2) Compounds of formula (I) wherein they are carboxy and Y, R and R and R are as defined above for formula (I) may be prepared by hydrolyzing a compound of formula (I) wherein R ¹⁰ is CONR ¹² R ¹³ and Y, R, R ¹ to R ⁹ , R ¹² a

O have the meaning given above for formula I.

The hydrolysis may be carried out under acidic or basic conditions, for example using an aqueous solution of either a suitable mineral acid, for example hydrochloric or sulfuric acid, or a suitable inorganic base, for example sodium hydroxide or potassium hydroxide, at a temperature ranging from room temperature to room temperature. backflow. When hydrolysis is carried out under basic conditions, the product is obtained in the form of a salt with a base, and this salt can be converted to the carboxylic acid by acidification during processing of the reaction mixture.

3) Compounds of formula I wherein R ¹⁰ is carboxy and Y, R and R to R are as defined above for formula I may be prepared by hydrolyzing a compound of formula III

wherein Y, R and R ¹ to R ⁹ are as defined above for a compound of formula I and R ¹⁶ is hydrogen or C 1 -C 4 alkyl.

The hydrolysis may be carried out under acidic or basic conditions, for example using an aqueous solution of either a suitable acid, for example hydrochloric acid or acetic acid, or a suitable inorganic base, for example sodium hydroxide or potassium hydroxide, at a temperature ranging from room temperature to reflux. .

When hydrolysis is carried out under basic conditions, the product is obtained in the form of a salt with a base, and this salt can be converted to the carboxylic acid by acidification during processing of the reaction mixture.

4) Compounds of formula I wherein R ¹⁰ is carboxy and Y, R and R ¹ to R ⁹ are as defined above for formula I may be prepared by hydrolyzing a compound of formula IV

CN

Wherein Y, R and R to R are as defined above for Formula I.

The hydrolysis may be carried out under acidic or basic conditions, for example using an aqueous solution of either a suitable mineral acid, for example hydrochloric or sulfuric acid, or a suitable inorganic base, for example sodium hydroxide or potassium hydroxide, at a temperature ranging from room temperature to reflux. flow.

If the hydrolysis is carried out under basic conditions, optionally hydrogen peroxide may be present in the reaction mixture and, moreover, the product is obtained in the form of a salt with a base. This salt can be converted to the carboxylic acid by acidification during processing of the reaction mixture.

5) Compounds of formula I wherein R ¹⁰ is carboxy and Y, R and R ¹ to R ⁹ are as defined above for formula I can be prepared by hydrolyzing a compound of formula V under acidic conditions

(IN)

Q wherein Y, R and R and R are as defined above for Ί 7 1 Q of formula I and R and R together represent an ethylene group, which ethylene group is optionally substituted with phenyl or C 1 -C 4 alkyl (preferably methyl) . Preferably R @ ⁷

Ί O and R taken together represent a group of the general formula (CH2) 2 ~ *

This hydrolysis may be carried out using an aqueous solution of a suitable acid, such as hydrochloric acid, at a temperature ranging from room temperature to reflux.

6) Compounds of formula I wherein R is CONH ₂ and Y, R and R ¹ to R ⁹ are as defined above for formula I may be prepared by partially hydrolyzing a compound of formula IV wherein Y , R 1 and R ¹ to R ⁹ are as defined above for formula (I).

This hydrolysis can be carried out using concentrated sulfuric acid at a temperature ranging from 0 ° C to room temperature.

7) Compounds of formula I wherein R ¹⁰ is COOR ¹¹ and Y, R, R ¹ to R ⁹ and R ¹¹ are as defined above for formula I may be prepared by esterifying a compound of formula I wherein R is COOH and Y, R and ^R1 to ^R9 are as previously defined for formula I, an alcohol of the formula R ¹¹ OH wherein R ¹¹ is as previously defined for this method.

This reaction can be carried out under conventional esterification conditions, such as using an excess of alcohol and acid catalysis, for example with sulfuric acid or p-toluenesulfonic acid, at a temperature ranging from room temperature to reflux. The water formed during the reaction can be removed by azeotropic distillation or by means of a dehydrating agent or molecular sieve.

This esterification can also be carried out by reacting the acid with an alcohol in the presence of a dehydrating agent such as dicyclohexylcarbodiimide or a mixture of diethyl azodicarboxylate and triphenylphosphine (see 0. Mitsunobu, Synthesis, 1981, 1).

Alternatively, this esterification can be carried out by first forming an activated ester or imidazolide derivative of the carboxylic acid and then reacting the resulting activated ester or imidazolide in situ with an alcohol of the formula R 2 OH. The activated ester may be prepared by reacting a carboxylic acid with 1-hydroxybenzotriazole in the presence of a suitable dehydrating agent, for example 1- (3-N, N-dimethylaminopropyl) -3-ethylcarbodiimide, and in a suitable solvent, for example dichloromethane, at room temperature. The imidazolide may be prepared by reacting a carboxylic acid with 1,1'-carbonyldiimidazole in a suitable solvent, for example dichloromethane, at room temperature.

8) Compounds of formula I wherein R ^{1 (} R 6 is COOR ¹¹ and Y, R, R ¹ to R ^{8 9} and R ¹¹ are as defined above for formula I) may be prepared by forming a compound of the formula of formula VI

Y Coz ¹ (VI)

Y, R and R ¹ to R ⁹ are as defined above for formula I and Z ¹ is a suitable leaving group, for example chlorine or bromine, reacted with an alcohol of formula R ^1: OH, where R ¹¹ is as defined above this procedure.

This reaction may be carried out in the presence of an acid binder (acid acceptor), for example pyridine, and in a suitable solvent, for example dichloromethane, at a temperature of from 0 ° C to room temperature.

9) Compounds of formula I wherein R ¹⁰ is COOrU and Y, R, R 4 to R ⁹ and R ¹¹ are as defined above for formula I may be prepared by treating a salt of a compound of formula I with with a base wherein R ¹⁰ is carboxy and Y, R and R ¹ to R ⁹ are as defined above for formula I (i.e., the carboxylate salt of the base) is reacted with a compound of formula R 2 wherein R ¹¹ is as defined above I and Z ² represent a suitable leaving group, for example halogen, preferably bromine or iodine, or p-toluenesulfonyloxy.

Preferred salts of the compounds of formula (I)

Bases for this process include sodium and potassium salts. The reaction may be carried out in a suitable solvent, for example dimethylformamide or tetrahydrofuran, at a temperature ranging from room temperature to reflux.

10) The compounds of formula I, wherein R ¹⁰ is a group of the formula CONR ² R ^2, and Y, R, R and R ^9, iniq

R @ 1 and R @ 2 are as defined above for formula (I), and can be prepared by reacting a compound of formula (I) wherein R @ 1 is carboxy and Y, R and R @ 2 are as defined above for formula (I). with an amine of the formula R ¹² R ¹³ NH, wherein R ¹² and R ¹³ are as defined above in the present process, in the presence of a dehydrating agent, for example dicyclohexylcarbodiimide.

This reaction may be carried out in a suitable organic solvent, for example dichloromethane, at a temperature ranging from room temperature to the reflux temperature.

Alternatively, the reaction may be carried out by first forming an activated ester or imidazolide derivative of the carboxylic acid and then reacting the activated ester or imidazolide in situ with an amine of formula R ¹² R ¹³ NH. Suitable processes for producing the activated ester or imidazolide are described in Method 7.

11) Compounds of formula I wherein R ¹⁰ is CONR ¹² R ¹³ and Y, R, R ¹ to R ¹¹

R, R, and R- ^LJ are as defined above for Formula I, may be prepared by providing a compound of the formula VI wherein Y, R, R ¹ to R ⁹ and Z ¹ are as defined above for Formula VI, is reacted with an amine of formula R ¹² R ¹³ NH, where R ¹ and R 1 are as defined above for this process.

This reaction may be carried out in the presence of an acid acceptor, for example pyridine, and in a suitable organic solvent, for example dichloromethane, at a temperature ranging from 0 ° C to room temperature.

12) Zlúčen.i; .y of formula I, wherein R ¹⁰ is a group of formula CONR ¹² R ^13, and Y, R, R ¹ -C

R ⁹ , R ¹² and R ¹³ are as defined above for formula I, may be prepared by the preparation of a compound of formula II wherein R is a suitable ester-forming group, for example a C 1 -C 6 alkyl group or an alternative biolabile ester-forming group radical, as defined above (i.e. compounds of the formula I, wherein R ¹⁰ is COOR ¹¹⁾ or p-nitrophenyl, and Y, R, and R and R are as previously defined for formula I, with an amine of the formula R12R13NH wherein R ^ ² and R · ¹ · ³ have the meaning given above in this process.

This reaction may be carried out in a suitable solvent, for example a C 1 -C 4 alkanol, at a temperature ranging from room temperature to reflux. The reaction is usually carried out using an excess of amine in a sealed reaction vessel, for example a bomb autoclave.

13) The compounds of formula I, wherein R ¹⁰ is carboxy or a group of formula CONR ^3-2 R ^13, and Y, R, R ¹ to R ^9, R ¹² and R ¹³ are as defined for formula I, may be prepared by hydrolyzing the compound of formula VII under acidic conditions

(VII) wherein Y, R and R ¹ to R ⁹ are as defined above for this process, each of R and R is either C 1 -C 4 alkyl or both together represent C 2 -C 3 alkylene, wherein: the alkylene group is optionally substituted with a C 1 -C 4 alkyl group and R is a hydroxy group or a 9-OR 9 -OR group wherein R is a suitable ester-forming group which can be cleaved by hydrolysis, for example a C 1 -C 6 alkyl group or an alternative biolabile ester-forming group as previously defined, or a group of formula NR 12 _r 13, _r 12 _ar 13 _{So is} the previously defined for this method.

This hydrolysis can be carried out using a suitable acid, for example hydrochloric acid or p-toluenesulfonic acid, in the presence of water.

The compound of formula (VII) may be prepared by first preparing a ketal of a compound of formula (VIII), wherein R and R to R are as defined above, by reaction with the corresponding alcohol under acidic conditions (see, e.g., TW Greene and PG Wuts, Protective Groups in Organic Synthesis, Wiley-Interscience (2nd Edition, 1991)), then N-alkylation of this ketal is performed in a similar manner to that described in Procedure 14 for alkylating a compound of Formula VIII.

14) All compounds of formula I wherein Y, R and R ¹ to R ³ · ⁹ are as defined above for formula I may be prepared by alkylating a salt with a base (i.e., N-deprotonated form) of a compound of formula of formula VIII

Wherein R and R to R are as defined above for Formula I, a compound of formula Z ³ -Y-COOR 11 ^: or Z ³ -Y-CONR ¹² R ^13, or a salt of a compound of formula Z ³ -Y-COOH with a base, according to which, if required, wherein Y, R ^11, R ¹² and R ¹³ are as previously defined for a compound of

0 and I represent a leaving group, for example halogen, preferably chlorine, bromine or iodine, methanesulfonyloxy or p-toluenesulfonyloxy.

Preferred base salts of the compounds of formula Z ³ -Y-COOH are alkali metal and alkaline earth metal salts, for example sodium and potassium salts. Preferred base salts of compounds of formula VIII are alkali metal salts such as sodium and potassium salts.

The reaction may be carried out by first deprotonating a compound of formula VIII with a suitable base, for example sodium hydride, and then reacting the resulting anion with a compound of formula Z ³ -Y-COOR ³ · ³ · or Z ³ -Y-CONR ''^'2 R ^3, or a salt of a compound of the formula Z ³ -Y-COOH with a base, according to which, where necessary. The reaction may be carried out in a suitable solvent, for example N, N-dimethylformamide or tetrahydrofuran, at a temperature ranging from 0 ° C to reflux temperature and preferably at room temperature. The reaction can also be carried out using potassium carbonate as the base and in 2-butanone or acetone as the solvent at about the reflux temperature of the solvent.

Alternatively, the reaction may be carried out under phase transfer conditions using sodium or potassium hydroxide as a suitable base.

When a compound of formula I wherein R is carboxy is desired, the product is obtained in the form of a salt with a base and this salt is converted to the carboxylic acid by acidification during work up of the reaction mixture.

15)

All compounds of formula I wherein Y, R and R ¹ to R ¹⁰ are as defined above for formula I may be prepared by acylating an indole of formula IX

or when R is hydroxy, a base salt thereof or an indole base salt of formula X

(X) wherein Y, R and R ¹ to R ⁴ are as defined above for o 3, and R is OR ¹¹ or NR ¹² R ¹³ , wherein R ¹¹ , R ¹² and R ¹³ are as defined above for a compound of formula I, a compound of formula XI

c _ q. wherein R and R are as described above for this process and Z ⁴ is a leaving group such as halogen, preferably chlorine and in the presence of a Lewis acid when R is not hydroxy and optionally in the presence of a Lewis acid when R is hydroxy.

Suitable Lewis acids include aluminum chloride and diethylaluminum chloride. This reaction may be carried out in a suitable solvent, for example toluene, at a temperature ranging from room temperature to the reflux temperature.

Preferred base salts of the indoles of formula X are alkali metal and alkaline earth metal salts, for example sodium and potassium salts.

When a compound of formula (I) wherein R ¹⁰ is carboxy is desired, the product is obtained in the form of a salt with a base and this salt is converted to the carboxylic acid by acidification during work up of the reaction mixture.

In order to obtain the compound of formula I, wherein R is hydroxy, the compounds of formula IX and X must be in the form of an enolate salt. In this case, an indole of formula IX, wherein R is hydroxy, or an indole salt of formula X, wherein R is hydroxy, is first reacted with a base with one equivalent of a suitable base, for example calcium hydroxide, to prepare the enolate salt, which is still acylated with a compound of formula XI, optionally in the presence of a Lewis acid. When an acidification step is introduced into the working up of the reaction mixture, a compound of formula (I) wherein R is hydroxy is obtained.

16)

Compounds of formula I wherein. R ^{3 -O} is carboxy and Y, R and R ¹ -R ⁹ are as defined above for formula I, may be prepared by oxidatively cleaving a compound of formula XII

(XII) wherein Z ⁵ represents a group of the formula -CH = CH ₂ , -CH = CH-alkyl, wherein the alkyl contains 1 to 4 carbon atoms, -CH = C- (alkyl) 2, wherein each alkyl contains 1 to 4 atoms or -CH 2 and Y, R and R ¹ to R ⁹ are as defined above in this process.

in this case, the reaction may be carried out by ozonolysis or by treatment with an aqueous solution of potassium permanganate.

17)

Compounds of formula I wherein R ¹⁰ is carboxy and Y, R and R ¹ to R ⁹ are as defined above for formula I may be prepared by oxidizing a compound of formula XIII

uses

(18) wherein Y, R and R ¹ to R ⁹ are as defined above for Formula I.

As a suitable oxidizing agent in this process, chromium trioxide in pyridine is used.

Compounds of formula I wherein R ¹⁰ is carboxy and Y, R and R ¹ to R ⁹ are as defined above for formula I may be prepared by oxidizing a compound of formula XIV or XV

CH ₂ OH (XIV)

or a salt thereof with a base, wherein R ²⁴ represents a hydrogen atom or a hydroxy group and Y, R and R 6 to R ⁹ have the meaning given above in the general formula I.

As a suitable oxidizing agent for this purpose, chromium trioxide-pyridine complex can be used.

Alternatively, the oxidation may be carried out in a compound of formula XV wherein R ²⁴ is hydrogen using 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) as the oxidizing agent.

Alternatively, the oxidation can be carried out in a compound of formula XV, wherein R ²⁴ is hydroxy, using manganese dioxide as the oxidizing agent, or under conditions of a Swern oxidation reaction.

The starting materials of the formulas XIV or XV, wherein R ²⁴ represents a hydrogen atom, can be obtained by reacting the corresponding 1H-indole-1-magnesium halide derivatives with the corresponding benzyl halide of the formula XVI

(XVI) wherein R ⁵ to R ⁹ are as defined above in this process and Z ⁶ is halogen, preferably chlorine or bromine, then N-alkylation of the indole is carried out in a similar manner to that described in Procedure 14.

The starting materials of formula XIV or XV, wherein R ²⁴ is hydroxy, may be obtained by reacting the corresponding 1H-indole-1-magnesium halide derivative with the corresponding benzaldehyde of formula XVII

(XVII) wherein R ⁵ to R ⁹ are as defined above in this process.

19)

Compounds of formula I wherein one of R ⁶ , R ⁷ and R ⁸ represents a group of the formula

R ¹⁴

I

-OCH-aryl and each of the remaining R ⁶ , R ⁷ and R ^{8 as} well as each of Y, R, R ¹ to R ⁵ , R ⁹ , R ¹⁰ , R ¹⁴ and aryl have the meanings given above for formula I may be prepared by the compound of formula XVIII

(XVIII) or a salt thereof with a base, wherein one of R ²⁵ , R ²⁶ n 7 and R is hydroxy and each of the remaining R ² , R ² , and R ²⁷ is as defined above for the rest of the symbols R ⁶ , R ⁷ and R ⁸ ; and Y, R, R ¹ to R ⁵ , R ⁹ and R ¹⁰ are as defined above in this process, reacted with a compound of formula XIX

R ¹⁴ ₇ I

Z-CH-aryl (XIX) wherein R ¹⁴ and aryl are as defined above in this process and Z represents a suitable leaving group, for example halogen, preferably chlorine, bromine or iodine, methanesulfonyloxy or p-toluenesulfonyloxy.

Preferred base salts of compounds of formula XVIII are sodium and potassium salts.

The reaction is preferably carried out using a salt of a compound of formula XVIII with a base (i.e., phenoxide), which may be formed in situ from the corresponding phenol of formula XVIII using a suitable base such as sodium or potassium hydroxide or sodium hydride in a suitable solvent such as ethanol or Ν, Ν-dimethylformamide, at a temperature from 0 ° C to the reflux temperature. The reaction can also be carried out using potassium carbonate as the base and in 2-butanone or acetone as the solvent at about the reflux temperature of the solvent.

20) Compounds of formula I wherein R ¹⁰ is COOR ¹¹ or CONR ¹² R ¹³ and Y, R, R ¹ to R ⁹ , R ¹¹ , R ¹² , R ¹³ , R ¹⁴ and aryl have

21) as described for the process 19 can be prepared by reacting a compound of formula XVIII, wherein R ¹⁰ is a group of formula COOR ¹¹ or CONR ¹² R ^13, according to which, if required, wherein R ^11, R ¹² , R ¹³ , Y, R, R ¹ to R ⁵ and R ⁹ are as defined above for this process, and R ² to R ²⁷ are as defined above for a compound of formula XVIII in process 19, reacted with a compound of formula XX

R ¹⁴

I

HO-CH-aryl (XX) wherein R ¹⁴ and aryl are as defined above in this process, in the presence of a suitable dehydrating agent, for example a mixture of diethyl azodicarboxylate and triphenylphosphine. The reaction may be carried out in a suitable solvent, for example tetrahydrofuran, at a temperature ranging from room temperature to the reflux temperature.

Compounds of formula (I) wherein one of the symbols

R ⁶ , R ⁷ and R ⁸ represent a group of the general formula

R ¹⁴

I

-CHO-aryl and each of the remaining R ⁶ , R ⁷ and R ^{8 as} well as each of Y, R, R ¹ to R ⁵ , R ⁹ , R ¹⁰ , R ¹⁴ and aryl have the meanings given above for formula I , can be prepared by the compound of formula XXI (XXI)

or a base salt thereof, wherein one of R ²⁸ , r ²⁹

O and R are a group of formula

R ^{14 1} CH ~ Z 8 ° and each of the remaining radicals R ^28, R ²⁹ and R ⁸⁰ is as defined for this method defined in the remaining radicals R ^6, R ⁷ and R ^8; and Y, R, R ¹ to R ⁵ , R ⁹ , R ¹⁰ and R ¹⁴ are as defined above for this process and Z ⁸ is as defined above for Z ⁷ in process 19, reacted with a base salt of a compound of formula XXII with a base aryl-OH (XXII) wherein aryl has the meaning given above in this process.

The base (i.e., phenoxide) salt of a compound of formula XXII may be formed in situ from the corresponding phenol of formula XXII using a suitable base, for example sodium or potassium hydroxide or sodium hydride in a suitable solvent, for example ethanol or Ν, Ν-dimethylformamide. , at a temperature of from 0 ° C to the reflux temperature. The reaction may also be carried out by reacting the phenol of formula XXII with a compound of formula XXI in the presence of potassium carbonate and in a suitable solvent, for example 2-butanone, at a temperature up to the reflux temperature of the solvent, preferably at this temperature.

22) The compounds of formula I, wherein R ¹⁰ is a group of formula COOR ¹¹ or CONR ¹³ R -'- ^2, and Y, R, R ¹ to R ^9, R ^11, R ^12, R ^13, R ¹⁴ and aryl are as as described in Process 21 above, can be prepared by reacting a compound of Formula XXIII

(XXIII) wherein one of R ³¹ , R ³² and R ³³ represents a group of the general formula

R ¹⁴

I

-CH-OH and each of the remaining R ³¹ , R ³² and R ³³ is as defined above for the remaining R ⁶ , R ⁷ and R ⁸ ; and Y, R, R ¹ to R ⁵ , R ⁹ , R ¹⁰ and R ¹⁴ are as defined hereinbefore, reacted with a compound of formula XXII, wherein aryl is as defined above, in the presence of a suitable dehydrating agent , for example, mixtures of diethyl azodicarboxylate and triphenylphosphine.

This reaction may be carried out in a suitable solvent, for example tetrahydrofuran, at a temperature ranging from room temperature to reflux.

All of the above reactions and methods for preparing the novel starting materials described in the above procedures are conventional, and those skilled in the art are familiar with the appropriate reagents and reaction conditions for carrying them out and for isolating the desired products, considering that there are a number of precedents in the literature. In addition, all of these aspects are illustrated in the following examples and preparative procedures.

........ Pharmacy = utt4. _; Suitable salts of the compounds of formula (I) may be readily prepared by mixing together a solution of a compound of formula (I) and the desired acid or base. The salt may precipitate out of solution and be filtered or isolated by evaporation of the solvent.

The compounds of Formula I are steroid 5α-reductase inhibitors and are therefore useful in the curative and prophylactic treatment of diseases or conditions such as acne vulgaris, alopecia, seborrhoea, female hirsutism, benign prostate hypertrophy, and male-type baldness.

Some of the compounds of Formula I are also useful in the treatment of human prostate adenocarcinoma.

Compounds of formula (I) may be tested in vitro for steroid 5α-reductase inhibitory activity using rat or human prostate tissue.

Thus, compounds of Formula I may be tested for activity in inhibiting rat steroid 5α-reductase using tissue from the ventral portion of the male prostate prostate. The following procedure is used to determine the inhibitory activity against prostatic 5α-reductase in rats:

Prostate rats are ground into small pieces. The tissue is homogenized in buffer A (20 mM sodium phosphate, pH 6.5; buffer contains 0.32M sucrose and 1 mM dithiothreitol) using a Brinkman Polytron (Kinematica GmBH, Lucerne, Switzerland) and then homogenized using a Potter Elvehjem motor homogenizer. (teflon-to-glass speed 1000 ^min-1). Prostate particles are obtained by centrifugation at 105,000 x G for 60 minutes.

The pellet is washed with four volumes of buffer A and then centrifuged again at 105,000 x G. The resulting pellet is dispersed in buffer A (1 ml per gram of prostate tissue originally used) using a Potter Elvehjem motor homogenizer as described above. The particle suspension is stored as 1 ml samples at -70 ° C.

The following components, dissolved in Buffer B (40 mM sodium phosphate, pH 6.5), are placed in a test tube: 500 μΐ [ ³ H] -testosterone (1 μθί, 1 nmol); Du Pont, NEN Research, Products, Stevenage, UK 100 μΐ of 0.5 mM NADPH, a compound of formula I, dissolved in 5 μΐ of dimethyl sulfoxide, the volume of the resulting mixture being made up to a total reaction volume of 1 ml with Buffer B. The mixture is warmed to 37 ° C and the reaction is opened by adding an aliquot of the prostate particle suspension. The reaction mixture is incubated at 37 ° C for 30 minutes and then quenched with vigorous stirring by the addition of 2 ml of ethyl acetate containing 20 µg of testosterone and 20 µg of 5α-dihydrotestosterone as carriers. The aqueous layer was separated from the organic layer by centrifugation at 2000 x G for 10 minutes. The organic layer was transferred to a second tube and evaporated to dryness under a nitrogen atmosphere.

Dissolve the residue in 50 to 80 μΐ absolute ethanol and spot on silica gel thin-layer plates (60 F254, E. Merck, Darmstadt, Germany), developing with a 185: 15 mixture of chloroform and acetone.

The radiochemical content of substrate bands (testosterone) and product (5α-dihydrotestosterone) was determined using a RITA Radio TLC Analyzer (Raytest Instruments Ltd., Sheffield, UK). The percentage of radiolabelled testosterone converted to 5α-dihydrotestosterone is calculated and used to characterize the activity of the enzyme. All incubations are performed so that no more than 15% of the substrate (testosterone) is converted to the product.

Experimental data for a range of inhibitor concentrations are computed into a sigma curve and using the SIGFIT program (De Lean, A., Munson, PJ, and Rodbard, D., American Journal of Physiology, 235, E97 (1978)). calculates the concentration of compound giving 50% inhibition (IC ₅₀ ) of 5α-reductase activity.

Compounds of formula I may also be tested for activity in inhibiting human steroid 5α-reductase using hyperplastic human prostate tissue. The following procedure may be used to test inhibitory activity against human prostatic 5α-reductase:

The frozen human prostate tissue is pulverized in liquid nitrogen using a steel mortar and pestle. The pulverulent tissue is homogenized in 4 volumes of buffer A [20 mM sodium phosphate, pH 6.5 containing sucrose (0.32M), dithiothreitol (1 mM) and NADPH (50 µM) J using an Ultra-Turrax ( Janke and Kunkel GmBH & Co., Staufen i.BR., Germany). The homogenate is centrifuged at 500 x G for 5 minutes to remove large tissue particles and the supernatant is then centrifuged at 100,000 x G for 1 hour.

The resulting pellet was dispersed in Buffer A (1 ml per gram of originally used prostate tissue) using an Ultra-Turrax homogenizer. The particulate preparation is then filtered through 2 layers of gauze and the filtrate is stored as one ml samples at -70 ° C.

The following components, dissolved in Buffer B (20 mM citrate and phosphate buffer, pH 5.2), are placed in a test tube: 500 μΐ of [ ³ H] -testosterone (1 μθί, 1 nmol; Du Pont, NEN Research, Products, Stevenage) , United Kingdom), 100 μΐ of NADPH regeneration system (5 mM NADPH, 50 mM glucose 6-phosphate, 5 U / ml glucose 6-phosphate dehydrogenase) and a compound of formula I dissolved in 5 μΐ dimethylsufoxide, the volume of the resulting mixture with buffer B make up to a total reaction volume of 1 ml. The mixture is warmed to 37 ° C and the reaction is opened by adding an aliquot of the prostate particle suspension. The reaction mixture is incubated at 37 ° C for 30 minutes and then quenched with vigorous stirring by the addition of 2 ml of ethyl acetate containing 20 µg of testosterone and 20 µg of 5α-dihydrotestosterone as carriers. The aqueous layer was separated from the organic layer by centrifugation at 2000 x G for 10 minutes. The organic layer was transferred to a second tube and evaporated to dryness under a nitrogen atmosphere. Dissolve the residue in 50 to 80 μΐ absolute ethanol and spot on silica gel thin-layer plates (60 F254, E. Merck, Darmstadt, Germany), developing with a 185: 15 mixture of chloroform and acetone.

The radiochemical content of substrate strips (testosterone) and product (5α-dihydrotestosterone) was determined using a RITA Radio TLC Analyzer (Raytest Instruments Ltd., Sheffield, UK). The percentage of radiolabeled testosterone converted to 5α-dihydrotestosterone is calculated and used to characterize the enzyme activity. All incubations are performed so that no more than 15% of the substrate (testosterone) is converted to the product.

Experimental data for a range of inhibitor concentrations are computed into a sigma curve and using the SIGFIT program (De Lean, A., Munson, PJ, and Rodbard, D., American Journal of Physiology, 235, E97 (1978)). calculates the concentration of compound giving 50% inhibition (IC ₅₀ ) activity. 5a-reductase.

Compounds of formula I may also be tested for activity in inhibiting steroid 5α-reductase activity in human prostate adenocarcinoma using DU145 and HPC36M cell lines. The following procedure is used to determine 5α-reductase inhibitory activity:

Human prostate adenocarcinoma cell lines are grown in Dulbecco's Modified Eagles Medium (DMEM) containing 5% serum. Cells are harvested from the medium by centrifugation, washed with serum-free DMEM and suspended to a concentration of 5 to 10 x 10 ⁶ cells per milliliter in serum-free medium.

The following ingredients are placed in the test tube: 10 μΐ of [ ³ H] -testosterone (1 μθΐ, 20 pmol) dissolved in ethanol (Du Pont, NEN Research, Products, Stevenage, UK) and 5 μΐ of an ethanolic solution of the compound of formula I. Evaporate under nitrogen and testosterone and dissolve the compound again in 0.25 ml of serum free medium containing 0.25 μιηοΐ of NADPH. The mixture is warmed to 37 ° C and the reaction is opened by the addition of 0.25 ml of cell suspension (1.2 to 2.5 x 10 ⁶ cells). The reaction mixture is incubated at 37 ° C for 2 hours and then quenched with vigorous stirring by the addition of 1.5 ml of ethyl acetate containing 20 µ9 of testosterone and 20 µg of 5α-dihydrotestosterone as carriers. The aqueous layer was separated from t

The organic layer was centrifuged at 2000 x G for 10 minutes. The organic layer containing testosterone and its metabolites was transferred to a second tube and evaporated to dryness under a nitrogen atmosphere. Dissolve the residue in 50 to 80 μΐ absolute ethanol and spot on silica gel thin-layer plates (60 F254, E. Merck, Darmstadt, Germany), developing with a 185: 15 mixture of chloroform and acetone. .......................

The radiochemical content of substrate bands (testosterone) and product (5α-dihydrotestosterone) was determined using a RITA Radio TLC Analyzer (Raytest Instruments Ltd., Sheffield, UK). Calculate the percentage of recovered radiolabel converted to testosterone 5.alpha.-dihydrotestosterone was calculated and used to characte aturisation ¹ enzyme activity. All incubations are performed so that no more than 15% of the substrate * (testosterone) is converted to the product.

Experimental data for a range of inhibitor concentrations are computed into a sigma curve and using the SIGFIT program (De Lean, A., Munson, PJ, and Rodbard, D., American Journal of Physiology, 235, E97 (1978)). calculates the concentration of compound giving 50% inhibition (IC ₅₀ ) of 5α-reductase activity.

For human administration, the compounds of formula (I) may be administered alone, but are usually administered in admixture with pharmaceutical carriers which are chosen having regard to the intended route of administration and standard pharmaceutical practice. For example, administration can be by the oral route in the form of tablets containing excipients such as starch or lactose, or in the form of capsules or ovules, either with or without excipients. For oral administration, elixirs, solutions or suspensions containing flavoring or coloring agents may also be used. Injection may be performed parenterally, for example intravenously, intramuscularly or subcutaneously. For parenteral administration, it is most advantageous to use the compounds of formula I in the form of sterile aqueous solutions which optionally contain other substances, for example, sufficient salts or glucose to adjust the isotonicity of the blood solution.

The daily dose of the compounds of formula I when administered orally or parenterally to human patients will be in the range of 0.01 to 20 mg / kg (in single or multiple doses), preferably in the range of 0.1 to 10 mg / kg, except for the treatment of human prostate adenocarcinoma where doses up to 20 mg / kg may be used. Thus, tablets or capsules based on the compounds of formula I, intended to be administered one, two or more, will contain from 1 mg to 0.5 g of active compound, as appropriate. In any case, the physician will determine the actual dosage best suited to the particular patient. This amount will vary depending on the age, weight and response of the particular patient. The above dosage is given by way of example and applies on average.

In particular cases, it is naturally possible to use higher or lower dosages, and such dosages are within the scope of the invention.

Alternatively, the compounds of formula I may be administered in the form of lace or pessaries, or may be administered topically in the form of lotions, solutions, creams, ointments or dusting powders. For example, they can be introduced into a cream consisting of an aqueous emulsion of polyethylene glycols or liquid paraffin, or an ointment (in this case used in a concentration of 1 to 10%), which consists of a base formed by white wax or white soft paraffin. and stabilizer and preservative additives, as appropriate.

The compounds of formula I may also be administered in conjunction with an α-antagonist (e.g., prasosine or doxasosine), an anti-androgen (e.g., flutamide) or an aromatase inhibitor (e.g., atamestane), particularly in the curative or prophylactic treatment of benign prostatic hypertrophy.

The subject of the invention is therefore:

i) a pharmaceutical composition comprising a compound of formula I or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable diluent or carrier;

ii) a compound of Formula I, or a pharmaceutically acceptable salt thereof, or a composition thereof, for use as a medicament;

iii) use of a compound of formula I or a pharmaceutically acceptable salt or preparation thereof, in the manufacture of a medicament for inhibiting steroid 5α-reductase;

iv) use of a compound of formula I or a pharmaceutically acceptable salt or preparation thereof for the manufacture of a medicament for the curative or prophylactic treatment of acne vulgaris, alopecia, seborrhoea, female hirsutism, benign prostate hypertrophy, male-type baldness or human prostate adenocarcinoma;

v) a method of treating a human to inhibit the steroid 5α-reductase comprising administering to the patient an effective amount of a compound of Formula I, or a pharmaceutically acceptable salt or preparation thereof;

vi) a method of treating a human to treat or prevent acne vulgaris, alopecia, seborrhoea, female hirsutism, benign prostatic hypertrophy, male-type baldness or adenocarcinoma of the human prostate, comprising administering to a human patient an effective amount of a compound of the formula And (vii) new intermediates of formulas (V) and (VIII) and their salts with bases, novel intermediates of formulas (XIII, XIV and XV) and their salts with bases, novel intermediates of formula (XVIII) and their salts with bases, novel intermediates of formula XXI and their salts with bases and novel intermediates of formula XXIII.

The preparation of the compounds of formula I is illustrated in more detail in the following examples.

Examples of the invention

Example 1 (R, S) -4- (3- [4- (1- [4- (2-methylpropyl) phenyl] ethoxy) benzoyl] indol-1-yl) butanoic acid

ABOUT

water. NaOH, THF, CH ₃ OH

T

To a solution of (R, S) -4- (3- [4- (1- [4- (2-methylpropyl) phenyl] ethoxy) benzoyl] indol-1-yl) butanoic acid ethyl ester (3.8 g) (see Example 21) in tetrahydrofuran (THF) (35 mL) and methanol (35 mL) was treated with 2N sodium hydroxide solution (35 mL). The mixture was stirred at room temperature for 2 hours and then carefully concentrated in vacuo to approximately 50 mL. The mixture was then cooled in an ice bath and acidified with 2N hydrochloric acid solution. The acid phase was extracted with ethyl acetate (100 mL) and the organic extract was dried over sodium sulfate and concentrated in vacuo. The title compound is obtained as a white foam (3.27 g), m.p.

Analysis for C ₃₁ H ₃₃ NO ₄

Calcd. C, 76.93; H, 6.88; N, 2.99

Found: C, 77.00; H, 6.88; N, 2.90% ¹ H-NMR (CDC1 _3): S = 0.95 (d, 6H), 70 (d, 3H), 90 (m, lH);

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.

Examples 2 to 20

The following compounds of formula

ABOUT

₂ h or their base salts are prepared by hydrolyzing the corresponding ethyl esters (see Examples 22-38, 42 and 43) or by similar methods to those used in Example 1.

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4-9

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Λ • Η ο C7 21 J-> £ Ο 2 C \ 0 r-i • Ή CC J-: C Q <ίθ Ο Found: C, 75.14; Η.6,78; Ν.2,88; C ₃₂ H ₃₅ NO _X .H ₂ O calc. : C.74,54; Η.7,23; Ν.2,72%. Δ-NMR (d ₆ -DMSO): δ = 0.90 (d, 6H), 1.65 (d, 3H), 1.85 (m, 1H), 2.10 (m, 2H), 2, 45 (m, 4H) ₁ 2.60 (s, 3H). 4.20 (t, 2H), 5.40 (q, 1H), 6.90 (d, 2H), 7,007,40 (m, 8H) ₁ 7.40 (d, 2H). - O £ II CO r. ¹ _ -r- .—. ^x nE ^ -Xc 'T -f. - <_> ^c - tv. p ^x On co In <- Z ° in! x x ° £ £ cm> Q cm o ·. co XX. mm ⁰⁰ X KU -o OO .. 0 c3 -T- xx „.. · X at cm - <n_ en ... cm 5 t of 7o c 2 ~ 8 - X 0 in m co in c-à- θ ⁰ . ⁰ . ^p . and X> X nr ω X with c. Z / LU + eo T o X ΤΓ X «~~~ Ρ • 0 l CL ' C5 X o C-> l Delta - l T. \ _J o o X I u I ⁰ 0 / ο X x Zr ιπ X x x oL n T o X > - > <n Cm X ω 1 1 n CM x ω ‘‘ Cu> υ cm WHAT x-

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Compound isolated as sodium salt

\ m • Μ • r-4 o Ό i-5 ~ C 2 P 2: X Ľ - -> H í ¹ cc o. c O Λ o CD _.- d X n; — Cm cm f X X e ^ 2 2 2 2 2 S S- ^{c c c} l l l g g V V V V. cm tt e 0 ° - - - - ° 3 --- CM_X £ Τ ol ol ol C J J T T Z CM CM CM 'TX _- 2 _ <E -C - ~ ~ o_ Γγ, ίΣ, Coίοιηοοώοιη »co σ> co cm σ> _ cm_ in_ co_ ~ Ž, t ~ CM ~ -M- CO * D ~~ hl CO ~ H-NMR _(CDCl3): δ = 0.90 (d, 6H), 1,30- 1:40 (m, 2H), 1.60- 1.65 (m, 6H), 1.80-1.90 ( m, 4H), 2.30 (t, 2H). 2.42 (d, 2H), 4.10 (t, 2H), 5.35 (q, 1H), 6.95 (d, 2H), 7.10 (d, 2H), 7.25-7 40 (m, 1H), 7.52 (s, 1H), 7.70 (d, 2H), 8.30 (m, 1H) ppm. 2 / UJ ♦ * T CM X ΙΩ - ♦ CM S S P u • 0 4-> - 1 1 R (Z about X O in_/ about / WHAT X u cn / x / o < \ _) x / o --- R about / CD x x x it QL x Article x x > I <T> CM X o ΜΊ CM ABOUT P · cu> υ WHAT r-

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--- 54 -

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Example 21

(R, S) -4- (3- [4- (1- (4- (2-Methyl-propyl) -phenyl] -ethoxy) -benzoyl) -indol-1-yl) -butyric acid ethyl ester

To a suspension of sodium hydride (60% dispersion in oil, 716 mg) in dry dimethylformamide (DMF) (15 mL) was added dropwise a solution of ethyl 4- (3- [4-hydroxybenzoyl] indol-1-yl) butanoic acid ethyl ester (see see below). Preparation 1) (5.24 g) in dimethylformamide (30 mL). After stirring at room temperature for 1 hour, a solution of α-methyl-4- (2-methylpropyl) benzyl bromide (see Preparation 23) (3.95 g) in dimethylformamide (5 mL) was added at 0 ° C. The resulting mixture was stirred overnight at room temperature and then partitioned between 1N hydrochloric acid solution (100 mL) and ethyl acetate (200 mL). The separated organic layer was washed successively with 1N sodium hydroxide solution (100 mL), saturated aqueous sodium chloride solution (100 mL), and then water (100 mL). The organic layer was dried (MgSO 4) and concentrated in vacuo to a yellow oil. Column chromatography (silica, 4: 1 hexane / ethyl acetate) and evaporation of the solvents from the appropriate fractions gave the title compound (3.8 g).

Analysis for C ₃₃ H ₃₇ NO ₄

Calcd. C, 77.63; H, 7.48; N, 2.73 Found: C, 77.47; H, 7.29; N, 2.74% ^! 1 H-NMR (CDCl ₃ ): δ = 0.91 (d, 6H), 1.35 (t, 3H), 1.70 (d, 3H), 1.90 (m, 1H), 4 _f 25 ( t, 2H), 7.45 (m, 5H);

2.20 (m, 2H);

4.50 (q, H),

7.55 (s, 1H).

2.31 (m, 2H)

6.95 (d, 2H)

7.88 (d, 2H)

2 _r 49 (d, 2H), 4.13 (q, 2H), 7.15 (d, 2H), 7.278 _r 45 (m, 1H) ppm.

Examples 22 to 32

Compounds of the following general formula

were prepared by alkylating the corresponding phenol derivatives (see Preparations 1, 3 and 4) with the corresponding alkyl bromides (see, for example, Preparations 20-26) by a similar procedure to that used in Example 21.

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Example 33

(S) -4- (3- [4- (1- [4- (2-Methyl-propyl) -phenyl] -ethoxy) -benzoyl) -indol-1-yl) -butyric acid ethyl ester

Ph ₃ P, DEAD, THF

Solution of 4- (3- [4-hydroxybenzoyl] indol-yl) butanoic acid ethyl ester (see Preparation 1) (500 mg), (R) -1- (4- [2-methylpropyl] phenyl) ethanol (see Preparation 17) ( 256 mg) and triphenylphosphine (410 mg) in tetrahydrofuran (20 ml) were treated with diethyl azodicarboxylate (DEAD) (0.27 ml) and the mixture was stirred overnight at room temperature. The reaction mixture was evaporated on silica gel (5 g) and then subjected to flash chromatography (silica, hexane / ethyl acetate 3: 1). Evaporation of the solvents from the appropriate fractions gave the title compound as a pale yellow resin (413 mg), m / z = 51% (m / z).

HPLC (Cyclobond DMP column, eluting with 1% triethylammonium acetate pH 4.1 and 1: 1 acetonitrile at a flow rate of 0.7 mL / min) rt = 86.09 min (100%).

1 H-NMR (CDCl ₃ ): δ = 0.95 (d, 6H), 1.25 (t, 3H), 1.70 (d, 3H), 1.85 (m, 1H), 2.20 (m, 1H) 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), _F 7 75 (d, 2H), 8.35 (m, lH) ppm.

The title compound can also be prepared by cleaving the product of Example 21 by chiral HPLC (Chiralpot AD column, eluting with hexane: ethanol 9: 1, flow rate 12 ml / min). (R) -4- (3- [4- (1- [4- (2-methylpropyl) phenyl] ethoxy) benzoyl] indol-1-yl) butanoic acid ethyl ester was eluted first, rt = 24 min, [a] ²⁵ D + 52.1 ° (c = 2, dichloromethane). Secondly, the title compound elutes, rt = 27 min, [α] ²⁵ D - 53.8 (c = 2, in dichloromethane).

Examples 34 to 3 7

The following compounds of formula

co ₂ ch ₂ ch ₃ are prepared by condensation of the corresponding phenols or alcohols (see Preparations 1, 2 and 27) with the corresponding phenols or alcohols (see for example Preparations 17 and 18) by a similar procedure to that used in Example 33.

HPLC / NMR 1 • H Ό C C O n: ft O V -i 3 ΟΉ -P tn '<c 0 (D4J ε o ONO 1) CC a s E ά -h 3 P 0 -H .CD-Z C X í — — »CC CC CC O O O O O O t t t t t 3 3:::: P rH • H P P O Ή -p ε x CM_ 15 and 'T (M X CM θ ’co_ cm" X CM £ X CM_ uo 'CM M ^- X CM CT 0 5.40 (q, 1 H), 6.95 (d, 2 H), X CO E, 0 M_- N * LO CM b- I CM V and b- ~ 7.55 (s, 1H); 7.75 (d, 2H). 8.35 (m, IH) ppm. || 1 • H P P Ό -P Ή C n M? 0 · \ (d, 6H), 1.30 (t, 3H), 1.70 (d, 3H). 1.85 (π, 1Η), 2.15 (m, 2H), g with δ, -tCM T xf CM. Are you m M-CT ™ X mT CM_ _ ° Cm 42- 5.40 (q, 1 H), 6.95 (d, 2 H), 7.00- 7.40 (m, 8H); 7.70 (d, 2H) ppm. 3? H ¾> bO O. . t "* r> s g E O CO - o 10 2 11 · _ X x CO m CM_ X CO m cd_ 0 0 CM_ cm " X e [in co_ X CO τί o r-_ nc ^- -p 0 o -h rH Ή PC 0 W'CO 0 oppo opp 0 ε φ <υ NOOO CO CO φ co ε C.-HP CO 7—1 O Ή P Ό C -, m ho X4 <d ε 4CO O ΉΡ PP> C 2h SP XQOK S • H 11 2? O bO c O c = ° ⁰ E 8 CM - CD -> CD '; II - x About CC · WHAT e A c ω r — i ε O ~ about Γ " T " \ N m E S b CM im 2> • +> 0 • 0 P 1 n WHAT x x 0 0 r> n x 0 - 0- 0 • T · \\ ») about_ y_ / Z 7 bw CĹ As- 0 / o 0 / 0 Article x - _L m oL x X r> QL x T ABOUT 1 1 WHAT > - CN X CM -L · 0 and 0 P CU ; ύ l ΤΓ CO m CO

see also example -55

The HPLC / NMR it CD. o ~ II <jO <n O Q ω CĹ S z 1 X about CD * X WHAT about CXI x WHAT (m, 2H), 1.65 (d, 3H), 2.20 (m, 2H), 2.30 (t, 2H), 2.50 CO CM ΤΓ x CM ABOUT ΤΓ X CM FROM o ° CO 1 J S σ £ in g CD _ ιη * ·. x Z Ί0 7.45 (m, 3H); 7.50 (d, 2H); 7.58 (s, 1 H), 7.80 (d, 2 H), 8.40 (m, 1 H) ppm. o CM 11 WHAT n O Q O X Z> z 1 ľT (1.31-1), 1.69 (d, 3H), 2.20 1 m <n_x CM Pk CT T CD CD. ’From <Z> M CD —C. ™, X CM CM T CM O äS- 4.30 (t, 2H); 5.40 (q, 1H); 6.80 (d, 2H), 7.05 (d, 2H), 7.35-7.50 (m, 3H), 7.50 (d, 2H), 7.60 (s, 1H), 7.85 (d, 2H); 8.45 (m, 1H) ppm. ♦ N CO CD T “+ CD j CD 5 E 't T -P about 1 • 0 4J Γ9 ABOUT ABOUT x about / / - j / with ) N- / about m X C r>  X b X ABOUT λ ABOUT 0 x LL j un - DĹ X -i- DĹ x T ΓΊ n > rw x o about 1 • P CD r- pole > u WHAT WHAT

Example 38

4- (3- [4-Benzyloxybenzoyl] indol-1-yl) butanoic acid ethyl ester

1) NaH, DMF

2) Br CO ₂ CH ₂ CH ₃

IN

To a cooled (0 ° C) suspension of sodium hydride (55% dispersion in mineral oil, 3.40 g) in dimethylformamide (DMF) (50 mL) was added a solution of 3- (4-benzyloxybenzoyl) indole (see Preparation 5) (20, 0 g) in dimethylformamide (100 mL). The resulting orange suspension was stirred at 20 ° C for 1 hour and then cooled to 0 ° C and ethyl 4-bromobutyrate (11.0 mL) was added. The resulting mixture was stirred at room temperature for 2 hours and then cooled to 0 ° C and partitioned between 1N aqueous hydrochloric acid solution (100 mL) and ethyl acetate (200 mL). The separated organic layer was washed successively with water (100 mL), 1N aqueous hydrochloric acid (100 mL), saturated aqueous sodium bicarbonate (100 mL), and brine (100 mL). The ethyl acetate was evaporated and the orange resin obtained was purified by flash column chromatography (silica, eluting first with hexane / ethyl acetate 3: 1 and then with hexane / ethyl acetate 2: 1). Evaporation of the solvents from the appropriate fractions gave the title compound (16.5 g), m.p. 83 ° C.

H-NMR (CDC1 _3): delta = 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), 7.307.47 (m, 8H), 7.62 (s, 1H), 7.85 (d, 2H) , 8.40 (m, 1H) ppm.

Examples 39 to 43

The following compounds of formula

The co ₂ ch ₂ ch ₃ were prepared by similar procedures to those used in Example 38 using the corresponding indoles (see Preparation 5-8) and the corresponding ethyl bromoalkanoates as starting materials.

Analysis / NMR about • WHAT what Q. to * Z 2Γ * Z co T χ <N ° ί in Z vo - ° in cm in Z C CD 8 CO * O CO_ CD_ g. c <I b CM CM CM - O E CL SO m (j TH T CM VO Z • - <T · <D 5 ľ W S Ό n co_> Q cd z o o o o o o o r-l CM Ou CM _J_ CO M CM 1 - Ί - CO Z * J? Z er- -r- CM * -M- ”uo b- ~ r- ~ ¹ H-NMR (CDCl ₃ ): δ = 1.25 (t, 3H), 2.20 (m, 1H), 2.25 (s, 3H), 2.30 (s, 3H), 4.10 (q, 2H), 4.20 (t, 2H), 5.15 (s, 2H), 6.80 (d, 1H), 7.27-7.55 (m, 10H), 8.40 (s) m, 1H) ppm. m / z T ♦ o T r- -½ M- jg -u u • 0 4> 1 » R FROM p about / P about / o Z T <n Z o krt Z FROM cn of o FROM n Z O from > i r *> T »“ T o and n CM Z o 1 --l · cu> u CD CO o ΤΓ

Analysis / NMR T * t- ° CX (í m m o j £ £ 3 3 3 <<<<<.... Cl OV V V V V V V V V V V V V V V ⁰⁰ ) o-rC -S d z The compound is not characterized ΙΊΠ / Ζ ♦ Ξ + ^- • • +> U • 0 -P - · 1 1 h * cr ABOUT about / ef ABOUT X / about--( (/ about )-----' x / about--( about / CD X T x 10 X I x X ΞΣ x > - 1 CM X ω 1 IN) CM X o P · CU> u xr OJ tt

! Analysis / NMR SA. ° 8 ^ ΐχχΧ x5 • ^ τΟΓΟοω ^ χίΛο □ 0 Ό CM 7. - o \ Q “ ¹⁰ . £ ^Νω 0 ° o <° _Χ —'Τ, ^ ΜΧΧΐιηΙΧ fT -r-. p * O4_ OJ - -T CM_ 04 S x <x * W x Z x o x c x o x cm m co_ co_ co_ in co £. £ CM * oj ”Ά CO ^- O-“ Γ- 'b? CL m / z ♦ ⁰⁰ T Oi X ^ r (p + »O • 0 -P - » BQI n X o x / Q --- < „W X / Q --- < ABOUT / d: X io CĹ x] and: □ Z > - 1 CM X o 1 p · cu> □ co ΤΓ

The following Preparations illustrate the preparation of certain starting materials used in the previous examples.

Preparation 1

4- (3- [4-Hydroxybenzoyl] indol-1-yl) butanoic acid ethyl ester

A solution of 4- (3- [4-benzyloxybenzoyl] indol-1-yl) butanoic acid ethyl ester (see Example 38) (13.4 g) in ethyl acetate (300 mL) was hydrogenated at 4.15 x 10 ⁵ Pa in the presence of 10 ml. % palladium on activated carbon (3 g) at room temperature? 4 hours. The catalyst is filtered from the reaction mixture by filtration through a cellulose filter aid

- 75 and concentrate the filtrate to a light pink solid under reduced pressure. Trituration with cold diethyl ether gave a white powder (8.24 g).

Analysis for ^C 21 ^H 21 ^NO 4

Calcd. C, 71.44; H, 6.04; N, 3.94

Found: C, 71.78; H, 6.02; N, 3.98% H-NMR (CDC1 _3): delta = l, 25 (t, 3H), 2.22 (m, 2H), 2.35 (m, 2H), _r 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 2 to 4

The following compounds of formula

were prepared by hydrogenation of the corresponding benzyl ethers (see Examples 39 to 41) by similar procedures to those used in Preparation 1.

θ '· co X X f. X WHAT J_ CM X X CL X WHAT CM cn Ό CM -. from E. uo ľn r CM - c *. * - Q_ σί 0 X uo X. X d- E 0 co. g- 'd WHAT* ^ X a CM <D g -E- CM __T ^T_ with. CM XO Ό- '—'T .. ^ο . in t b- WHAT X CST M O OJ C X.-o - T CO X ° is what CO X- - . m T — CO S b E CO -r- χ-b- X X O X 0 10 * WHAT X * CM J- * χ * CM CO Z 'r 0 CM X b- uo ..Tr ABOUT - * CM i X WHAT X Γ “-_ CM _ cm - in- , CM b - CO 't - ¾ 7.0 CD ” II to 1 š CO to CM II X CD ¹ cm xr to -. - 11 x x CM CM to X> ô 00 ® O cr b- γζ Ό o CZ s O 84 CO> 1 r> 0 uo ⁰ 0 cd X incl 7o x o. Dream of O x oT Q oj'Xo- ' q TT b- Q CO b- <0 1 · -r ABOUT O XX O XX N '> 1 O O ·· Z . X X -Q T CM X co T —X x IV CM v- i-1 • r> N Σ s / iš with E <u t from U) O O Z 0 CD Z O UO rH Cm 05 _z 1 t? CD CM »CO t-r - • γ. GO.UO. ž O CM CD b- r oj s X “<- b * N 0 T X m / I co X CO S CM -τΟΟ from> J u 1 1 1 n it CCL _L · ABOUT Ziz <n it X X ABOUT j r> CL ' CH ^from x 1 <n n CM CM cm > - X x LL 0 0 0 1 Prep. no. CM WHAT xr

Preparation 5

3- (4-benzyloxy-benzoyl) -lH-indole

To a mechanically stirred solution of indole (30.0 g) in sodium-dried diethyl ether (450 mL) was added dropwise a solution of methylmagnesium iodide (85 mL of a 3.0 M solution in diethyl ether). The mixture was stirred at 20 ° C for 1 hour and then 4-benzyloxybenzoyl chloride (see Preparation 10) (67.3 g) was added. Stirring at 20 ° C was continued for 2 hours and then 1N hydrochloric acid (250 ml) was added and the reaction mixture was allowed to stand overnight. The resulting precipitate was filtered off and triturated with hot ethyl acetate (3 x 100 mL). The desired compound was obtained as a light pink solid (40.9 g).

Analysis for ^C 22 ^H 17 ^NO 2 Calculated: C, 80.70; H, 5.23; N, 4.28 Found: C, 80.67; H, 5.33; N, 4.25% 1 H-NMR (d _with -DMSO): δ = 5.20 (s, 2H), 7.15 (d, 2H), 7.20 (m, 2H),

7.30-7.50 (m, 6H), 7.80 (0.2-), 7.90 (s, 1H), 8.23 (d 1H),

11.95 (s, or, 1H)

Preparation of 6 to 8 Indoles of the following general formula

are prepared from the corresponding ind-indoles and the corresponding acid chlorides (see Preparation 9-11) using methods similar to those used in Preparation 5.

and Analysis / NMR ABOUT .. about CO O ΜΓ 2 <About CM * CO_ Q *. C> CD CXJ CO X. CD - o '- X · O 'X in ~ 1 - 9 ^^ x * «X O O Z in -r- -R . and CM M E X n —r co í x «L ^ cï gďx * b-05 O X.? 2 05 j Z ^ _- ^M (Λ CT> cb * °° O £ X oq ¹⁰ 15-x CD * X mm T- -r c c · ω =? -S q. ( b * QdirZcïX S c <-r ^{10 10} X - T N - CJ-i oz oz oz ľ ľ z z z z £ £ £ X X X X X U U U U U U U U U S ^UO - -X 05 CD X from OX r sSto s r- 2 / LU T WHAT ^- WHAT ID X U • 0 4J T ιό b ~ O) 05 T ”T“ hX T CM X o o Tf \ 04 X o o X ' n x o V) x χ n “T o x n x o lll Q. CD, CL> O WHAT

Ρί s z -. (OJ — — 1 <6 G CM what what H-NMR (CDCl): δ = 0.95 (d, 6H), 1.70 (d, 3H), 1, ΘΟζπΊ, ΙΗ), _2/50 (d, 2H) ₁ 5.40 (q, 1H), 6.95 (d, 2H), 7.15 (d, 2H). _7.30-7/45 (m, 5 H) ₁ 7.65 (m, 1H), 7.80 (d, 2H), 8.35 (m, 1H), 8.80 (s, br, 1H) ppm. Nalez.:C,81,18; H, 6.56; N, it. WHAT ABOUT . " > u CM O x b. CM X b. CM O H, 6.85; N, 3.52% pq E J u • 0 4J - 1 about x o-- n X O in o> x / o --- ) about / <D x -U - m CĹ x Article x Prep. no. WHAT

Preparation 9

4-Benzyloxy-2,3-dimethylbenzoyl chloride

Br ₂ , CH ₃ COOH (a) (c)

CgHjCH3BjjK ^ CO.j, Kl.fCHJjCO (b)

T

1) n C ₄ H ₉ Li, THF

2) CO ₃

(a) 4-bromo-2,3-dimethylphenol

A solution of 2,3-dimethylphenol (40.0 g) in acetic acid (300 mL) was cooled to 10 ° C and treated with a solution of bromine (16.9 mL) in acetic acid (100 mL). After stirring for 30 minutes, a saturated aqueous sodium metabisulfite solution (300 mL) was added to the mixture. The mixture was extracted with dichloromethane and the organic layer was dried over magnesium sulfate, filtered and evaporated. Obtained as a waxy solid (64.7 g).

¹ H-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.

Recrystallization of this product from hexane gave an analytical sample.

Analysis for C ₉ H ₉ BrO

Calcd. C, 47.78; H, 4.51 Found :. C, 48.00; H, 4.40% (b) 1-benzyloxy-4-bromo-2,3-dimethylbenzene

A mixture of (a) (45.0 g), benzyl bromide (28.30 g), potassium carbonate (38.60 g) and potassium iodide (300 mg) in acetone (500 mL) was refluxed overnight. . The reaction mixture was cooled, filtered and evaporated to an oil which was dissolved in diethyl ether. The resulting solution was washed with 2N aqueous sodium hydroxide solution and then the organic layer was evaporated to an oil which was chromatographed on silica gel using hexane / ethyl acetate (4: 1) as eluent. The desired product was obtained (51.86 g).

Analysis for C ₅₁ H ₁₅ BrO

Calcd. C, 61.85; H, 5.19 Found: C, 62.64; H, ^{5.31%; H-NMR} (CDC1 _3): δ = 2.30 (s, 3H), 2.40) s, 3H), 5.00 (s, 2H), b, b0 (d, 1H), 7.30-7.50 (m, 6H) ppm.

(c) 4-benzyloxy-2,3-dimethylbenzoic acid

To a solution of the product of (b) (33.8 g) in tetrahydrofuran (THF) (500 mL) at -78 ° C was added n-butyllithium (48.4 mL of a 2.5 M solution in hexane). The mixture was stirred at -78 ° C for 30 minutes, excess solid carbon dioxide was added as a fine powder, and the reaction was allowed to warm to room temperature. The tetrahydrofuran was evaporated under reduced pressure and the residue was partitioned between ethyl acetate and 2N hydrochloric acid solution. The organic layer was washed with brine, dried over magnesium sulfate and then evaporated to a pink solid. Recrystallization from ethyl acetate gave the title compound (18.8 g), mp 164-166 ° C.

Analysis for ^C 16 ^H ₁₆ O ₃ Calculated: C, 74.98; H, 6.29 Found: C, 74.87; H, 6.21% ¹ H-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-2,3-dimethylbenzoyl chloride

The product of (c) (2.0 g) was suspended in dichloromethane (10 mL) and oxalyl chloride (1.3 mL) and dimethylformamide (DMF) were added (two drops). The mixture was stirred overnight and the resulting homogeneous solution was evaporated. The resulting white solid was azeotroped with toluene 3 times to give the title compound as a white powder (2.24 g). In this state the substance is used immediately.

Preparation 10

4-benzyloxybenzoyl

The title compound was prepared in a manner analogous to Preparation 9 (d) except that 4-benzyloxybenzoic acid was used as the starting material. The obtained compounds were used immediately for the next reaction.

Preparation 11

4- (1- [4-isobutylphenyl] ethoxy) benzoyl chloride

The title compound was prepared in a similar manner to that described in Preparation 9 (d) except that 4- (1- (4-isobutylphenyl) ethoxy) benzoic acid was used as the starting material (see Preparation 28 (b)). The obtained substance was used immediately for the next reaction.

Preparation 12

1- (4-n-propyl-phenyl) butan-l-ol

A solution of 4-n-propylbenzaldehyde (7.4 g) in diethyl ether (60 mL) was cooled to 0 ° C and then treated with a 2.0 M solution of n-propylmagnesium chloride in diethyl ether (27.5 mL). The reaction mixture was stirred overnight, then diluted with diethyl ether and quenched with saturated aqueous ammonium chloride solution. The organic layer was separated, washed with a saturated aqueous ammonium chloride solution, and dried over magnesium sulfate. The organic layer was filtered and evaporated. A colorless oil is obtained which is purified by chromatography on silica gel with hexane / ethyl acetate

4: 1 as eluent. Evaporation of the solvents from the appropriate fractions gave the desired product (4.06 g), m / z = 192 (M ⁺ ).

¹ H-NMR (CDC1 _3): δ = l, 00 (m, 6H), 1.20-1.40 (m, 2H), 70 (q, 2H), 75-L, 90 ( m, 3H), 2.60 (t, 2H), 4.60 (m, 1H), 7.10 (d, 2H), 7.30 (d, 2H) ppm.

Preparation 13 1- (4-ethylphenyl) ethanol

To a solution of 4-ethylacetophenone (10.0 g) in methanol (50 mL) at 0 ° C was added portionwise sodium borohydride (3.83 g). The mixture was stirred overnight at 20 ° C and then partitioned between 1N hydrochloric acid and ethyl acetate. The organic layer was washed with 1N hydrochloric acid, dried over magnesium sulfate and evaporated to a clear oil (9.9 g). The oil was purified by flash chromatography (silica gel, 3: 1 hexane / ethyl acetate). The appropriate fractions were combined and evaporated to give the desired compound (8.9 g), m / z = 150 (M ⁺ ).

¹ H-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 14

4-n-propylbenzylalkohol

To a solution of 4-n-propyl bromobenzene (10 g) in tetrahydrofuran (100 mL) at -78 ° C was added n-butyllithium (35 mL of a 1.6 M solution in hexane). The reaction mixture was stirred at this temperature for 15 minutes, then paraformaldehyde (1.6 g) was added and stirring was continued for another hour. The reaction mixture was partitioned between diethyl ether and water, and the organic layer was dried over magnesium sulfate and evaporated to an oil. The oil was subjected to flash chromatography (silica, eluting with hexane / ethyl acetate 3: 1). The appropriate fractions were combined and evaporated to give the desired product as a colorless oil (2.7 g).

Preparation 15 (R, S) -1- (4- [2-methylpropyl] phenyl) ethanol

A solution of 4-isobutyrylacetophenone (10.0 g) in methanol (50 mL) was cooled to 0 ° C and then sodium borohydride (3.23 g) was added portionwise. The mixture was stirred overnight at room temperature and then quenched by the addition of 1N hydrochloric acid solution (50 mL). Ethyl acetate (100 mL) was added and the organic layer was separated, dried over magnesium sulfate and evaporated. Obtained the title compound as a clear oil (10.02 g), m / z = 178 (M ⁺ ).

Analysis for ^C 18 ^H I 2 ° ^{'1/7 H} 2 ° Calculated: C, 79.68; H, 10.19 Found: C, 79.69; H, 9.90% ¹ H-NMR (CDC1 _3): 8 = 0.90 (d, 6H), 50 (d, 3H), 85 (m, IH), 2.50 (d, 2H), 4.85 (q, 1H), 7.15 (d, 2H), 7.30 (d, 2H) ppm.

Preparation 16 1- (3,4-Dichlorophenyl) ethanol

The title compound was prepared in a similar manner to that described in Preparation 15, except that 3,4-dichloroacetophenone was used as the starting material. m / z = 190 (M &lt; ^{+ &gt;} ).

¹ H-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 17 (R) -1- (4- [2-Methylpropyl] phenyl) ethanol (a) (R, S) -1- (4- [2-methylpropyl] phenyl) ethanoic acid ester

To a solution of the product of Preparation 15 (5.0 g) in dichloromethane (40 mL) at 0 ° C was added dry pyridine (2.5 mL) followed by distilled acetyl chloride (2.2 mL). The reaction mixture was stirred overnight at room temperature and then filtered and silica gel (10 g) was added to the filtrate and the mixture was evaporated to dryness. The residue was subjected to column chromatography on silica gel (hexane / ethyl acetate 12: 1). The appropriate fractions were combined and the solvents were evaporated. The title compound was obtained as a clear oil (2.3 g).

¹ H-NMR (CDC1 ₃₎ 6 = :, 0.90 (d, 6H), 55 (d, 3H), 85 (m, IH), 2.05 (s, 3H), 2, 45 (d, 2H), 5.85 (q, 1H), 7.15 (d, 2H), 7.25 (d, 2H) ppm.

(b) (R) -1- (4- [2-methylpropyl] phenyl) ethanol

A suspension of the product of (a) (3.0 g) in pH 7 phosphate buffer (100 mL) was mixed with SAM II lipase (Trademark of Fluka Chemicals Limited) (50 mg) and stirred vigorously. diii at room temperature. The mixture was extracted with ethyl acetate (100 mL) and the combined organic layers were dried (MgSO 4) and evaporated. The residue was subjected to column chromatography on silica gel (hexane / ethyl acetate 9: 1). Combine the appropriate fractions and concentrate to give (S) -1- (4- [2-methylpropyl] phenylethyl ethanoate (1.47 g). The title compound is eluted as a second product to give a clear oil after workup. Crystallization to give white needles (1.04 g), mp 37-38 ° C, [α] _D + 32.3 ° (c = 2.7 in methanol).

¹ H-NMR (CDC1 _3): δ = 0.90 (d, 6H), 50 (d, 3H), 85 (m, IH), 2.50 (d, 2H), 4.85 (q, 1H), 7.15 (d, 2H), 7.30 (d, 2H) ppm.

Preparation 18 (S) -1- (4- [2-methylpropyl] phenyl) ethanol

Ethanoic acid (S) -1- (4- [2-methylpropyl] phenylethyl ester (see Preparation 17 (b)) (1.2 g) was treated with a 1N solution of sodium hydroxide in absolute ethanol (20 mL). The residue was chromatographed on silica gel (hexane / ethyl acetate 4: 1) to give the title compound as a clear oil (0.59 g), m.p. mp 34 ° C, [α] _D - 32.7 ° (c = 2.7 in methanol).

^X H-NMR (CDC1 _3): δ = 0.90 (d, 6H), 50 (d, 3H), 85 (m, IH), 2.50 (d, 2H), 4.85 (q, 1H), 7.15 (d, 2H), 7.30 (d, 2H) ppm.

Preparation 19 α-Cyclopentyl-4-n-propylbenzyl Alcohol A solution of 4-n-propylbenzaldehyde (2.0 g) in diethyl ether (20 mL) was cooled to 0 ° C and then cyclopentylmagnesium chloride solution (7.4 mL 2) was added. 0M solution in diethyl ether). The mixture was stirred at room temperature overnight and then saturated aqueous ammonium chloride solution was added. The organic layer was separated, dried over magnesium sulfate and evaporated to a yellow oil. The oil was purified by flash chromatography on silica gel, eluting first with 4: 1 hexane: ethyl acetate, then with 3: 1 hexane: ethyl acetate. The appropriate fractions were combined and evaporated. The desired compound was obtained as a clear oil (400 mg, m / z = 218 (M ⁺ )).

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

Preparations 20 to 26

The following alkyl bromides are obtained by dissolving the corresponding alcohol (see Preparations 12-16 and 19) in dichloromethane and saturating the resulting solution with dry hydrogen bromide while cooling in an ice bath. The reaction mixture was stirred for a short time and then evaporated under reduced pressure. The obtained alkyl bromides were directly used for further reactions without characterization.

Preparation no. bromide 20 1-bromo-l- (4-n-propylphenyl) butane 21 a-methyl-4-ethylbenzyl bromide 22 4-n-propylbenzylbromid 23 a-methyl-4- (2-methylpropyl) benzyl bromide 24 a-methyl-3,4-dichlorobenzyl bromide 25 α-cyclopentyl-4-n-propylbenzylbromid 26 a- (4-n-propylphenyl) -4-n-propylbenzylbromid

The starting material is described in EP-A-291245

Preparation 27

4- (3- [4- (1-hydroxyethyl) benzoyl] indol-1-yl) butanoic acid ethyl ester

(A)

Y

(C)

T

a) 3- (4- [1- (t-butyldimethylsilyloxy) ethyl] benzoyl) indole

The title compound was prepared in a similar manner to that used in Preparation 5 from indole and 4- (1- (tert-butyldimethylsilyloxy) ethyl) benzoyl chloride as starting material, m / z = 380 (M + 1) ⁺ .

Analysis for C ₂₃ H ₂ gNO ₂ Si Calcd: C, 72.78; H, 7.70; N, 3.69

Found: C, 72.79; H, 7.73; N, 3.76% ¹ H-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) 4- (3- [4- (1- (t-ButyldimethylsilyloxyJetyl) benzoyl] indol-1-yl) butanoic acid ethyl ester

To a solution of the product of part a) (1.70 g) in dimethylformamide (20 mL) was added sodium hydride (215 mg 60% dispersion in mineral oil). The mixture was stirred at room temperature for 1 hour, then ethyl 4-bromobutyrate (0.7 ml) was added and stirring was continued for 2 hours. The reaction mixture was diluted with ethyl acetate (50 mL) and washed successively with 2N aqueous hydrochloric acid solution and saturated sodium chloride solution. The organic layer was dried (MgSO4) and the solvent was evaporated. The yellow resin obtained is subjected to flash chromatography on silica gel using a 3: 1 mixture of hexane and ethyl acetate. The appropriate fractions were combined and evaporated. The title compound was obtained as a clear resin (2.20 g), m / z = 494 (M + 1) ⁺ .

¹ H-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) 4- (3- [4- (1- (1-Hydroxyethyl) benzoyl] indol-1-yl) butanoic acid ethyl ester

The product from b) was dissolved in tetrahydrofuran (100 mL) and tetra-n-butylammonium fluoride (4.92 g) was added to the solution, followed by stirring for 1 hour. The reaction mixture was then diluted with ethyl acetate (100 mL) and washed with 2N aqueous hydrochloric acid and saturated sodium chloride solution. The organic layer was dried over magnesium sulfate, filtered, and evaporated to a brown resin. The resin was purified by flash chromatography on silica gel (dichloromethane / methanol 98: 2). The appropriate eluate fractions were combined and evaporated. There was thus obtained the title compound (0.92 g) as a clear resin, m / z = 380 (M + 1) ⁺ .

¹ H-NMR (CDC1 _3): δ = l, 20 (t, 3H), 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 28 (S) -4- (3- (4- (1- (4- (2-methylpropyl) phenyl) ethoxy) benzoyl] indol-1-yl) butanoic acid (a) (R, S) -4- ( 1- [4- (2-methylpropyl) phenyl] ethoxy) benzoic acid

Ethyl p-hydroxybenzoate (5.16 g) was dissolved in acetone (50 mL) and anhydrous potassium carbonate (4.40 g, tetra-n-butylammonium bromide (0.44 g) and (R, S) was added. .alpha.-methyl-4- (2-methylpropyl) benzyl bromide (see Preparation 23) (7.7 g) The resulting suspension was stirred overnight at room temperature and then filtered, and the filtrate was evaporated to give the title compound. (13.5 g) which was directly used without characterization.

(b) (R, S) -4- (1- [4- (2-Methylpropyl) phenyl] ethoxy) benzoic acid

The product from (a) (13.5 g) was dissolved in 95% aqueous ethanol (108 mL), 2N aqueous sodium hydroxide (32 mL) was added and the mixture was heated at 60-70 ° C for 90 min. . The solvent was evaporated and water (30 ml) was added. To the mixture was added 2N aqueous hydrochloric acid (50 mL), and the resulting mixture was extracted with ethyl acetate.

The combined organic layers were washed with saturated sodium chloride solution and dried over magnesium sulfate. After evaporation of the solvent, i. ethyl acetate, to afford the title compound as a white solid. Trituration with n-hexane gave a fine white powder (6.7 g).

¹ H-NMR (CDC1 _3): δ = 0.95 (d, 6H), 70 (d, 3H), 88 (m, IH), 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) -4- (1- [4- (2-methylpropyl) phenyl] ethoxy) benzoic acid (+) - ephedrine salt,

The product from (b) (10 g) was dissolved in 95% aqueous ethanol (60 mL) and water (60 mL), and (+) - ephedrine carbohydrate (5.84 g) was added. The mixture is refluxed until complete dissolution of the solid is achieved. The reaction mixture was allowed to stand overnight at room temperature. The resulting precipitate was filtered off and dried. There was thus obtained the title compound (5.20 g).

[α] ²⁰ _D - 21.9 ° (c = 1 in methanol) ¹ H-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.

Chiral HPLC analysis of this product showed the product to contain 95: 5 enantiomers (S) and (R).

(d) (S) -4- (1- [4- (2-methylpropyl) phenyl] ethoxy) benzoic acid

The product from (c) (4.63 g) was treated with 1N aqueous hydrochloric acid and the resulting suspension was stirred for 90 minutes. The resulting precipitate was filtered off and washed with 1N aqueous hydrochloric acid and then with water. The product was dried under vacuum at 50 ° C to give the title compound as a colorless solid (2.94 g), mp 128-131 ° C.

[α] ²⁰ _D - 51.5 ° (c = 1 in methanol)

Analysis for ^C 19 ^H 22 ° 3 Calculated: C, 76.48; H, 7.43; N, 0.00 Found:? G, 76.76; H, 7.30; N, ^{0.00%; H-NMR} (CDC1 _3): δ = 0.95 (d, 6H), 70) d, 3H), 88 (m, IH), 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.

(e) (S) -4- (1- [4- (2-methylpropyl) phenyl] ethoxy) benzoyl chloride

The product of (d) (2 g) was dissolved in dichloromethane (10 mL) and pyridine (0.60 mL) was added followed by oxalyl chloride (0.64 mL). The mixture was stirred at room temperature for 3 hours, 1 drop of dimethylformamide was added, and the mixture was stirred overnight. The solvent was evaporated and dry toluene (40 mL) was added. The resulting precipitate was filtered off and the filtrate containing the desired compound was evaporated to a volume of 10 ml. In this state, the title compound is used without characterization for the next reaction.

(f) (S) -3- (4- [1- [4- [2-methylpropyl) phenyl] ethoxy) benzoyl) indole

Indole (715 mg) was dissolved in toluene (5 mL) and methyl magnesium iodide (2.0 mL of a 3M solution in diethyl ether) was added. The resulting yellow solution was stirred for 10 minutes and then a solution of (S) -4- (1- [4- (2-methylpropyl) phenyl] ethoxy) benzoyl chloride in toluene (10 mL) was added (product from (e)). ). The mixture was stirred at room temperature for 1 hour and then saturated aqueous ammonium chloride solution (50 mL) was added with vigorous stirring. The mixture was extracted with ethyl acetate (30 mL, 40 mL, 15 mL) and the combined organic layers were dried over magnesium sulfate, filtered and evaporated to a brown resin. The resin residue was flash chromatographed on silica gel using hexane: ethyl acetate (3: 1) and then hexane: ethyl acetate (1: 1) as the eluent. The appropriate fractions were collected and the solvents were evaporated to give the title compound as a beige solid (1.05 g), mp 150-152 ° C.

Analysis for P27H27NO2

Calcd .: C, 81, 58; H, 6.85; N, 3.52 Found: C, 81.69; H, 6.83; N, 3.58% H-NMR (CDC1 _3): δ = l, 00 (d, 6H), 75 (d, 3H), 95 (m, IH), 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, 1 H) ppm.

(g) (S) -4- (3- [4- (1- [4- (2-Methylpropyl) phenyl] ethoxy) benzoyl] indol-lyl) butanoic acid ethyl ester

A solution of (f) (500 mg) in 2-butanone (5 mL) was treated with anhydrous potassium carbonate (695 mg) and ethyl 4-bromobutyrate (0.23 mL). The mixture was refluxed overnight and then cooled and filtered. The filtrate was evaporated to a yellow resin and this was chromatographed on flash silica gel using hexane / ethyl acetate (3: 1) as eluent. The appropriate fractions were combined and evaporated to give the title compound (4 □ 1 mg).

This product has the same characteristics in mass spectroscopy, HPLC, and ¹ H-NMR as the compound of Example 33.

(h) (S) -4- (3- [4- (1- [4- (2-methylpropyl) phenyl] ethoxy) benzoyl] indol-1-yl) butanoic acid

A solution of the product from (g) (108 mg) in 95% aqueous ethanol (2 ml was mixed with 6 drops of 2N aqueous sodium hydroxide solution. The mixture was stirred for 90 minutes and then water (3 ml) and such an amount were added. 2N aqueous hydrochloric acid was added to adjust its pH to 1. The mixture was extracted with dichloromethane (3 x 10 mL) and the combined organic layers were evaporated to give the title compound as a colorless foam (62 mg).

This product has the same characteristics in mass spectroscopy, optical rotation assay and 1 H-NMR as the compound of Example 9.

Pharmacological efficacy

Certain selected compounds of Formula I have been tested in vitro for steroid 5α-reductase inhibitory activity using tissue from the ventral portion of male prostate rats as described above. The results are shown in Table 1.

Table 1

Example number IC ₅₀ o (nM) 1 2.19 2 l, ² 3 2.3 4 56 5 6.9 6 3.6 7 361  .-. vr 8 0.67 .. .... ¢ ..-.-. _g 1.15 10 30.2 11 6.3 12 2.8 13 42.5 14 449 15 16.5 16 2.64 18 207 19 4/76 33 42% inhibition at 100nM 34 47% inhibition at 100nM

toxicity

The compound of Example 1 was orally administered to mice at up to 1000 mg / kg and the animals maintained their normal appearance and behavior throughout the duration of the study.

ÍV Ά - 9y

Claims (43)

1. General indoles R ⁸ R ⁷ (I) and pharmaceutically acceptable salts thereof, wherein: is an alkylene group optionally substituted by an alkyl group having 1 to 6 carbon atoms; 1 to 6 carbon atoms, R is hydrogen, hydroxy, halogen, C 1 -C 4 alkyl or C 1 -C 4 alkoxy; R ¹ , R ² , R ³ and R ⁴ are each independently hydrogen, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, hydroxy, halogen or trifluoromethyl; one of the symbols £ 70 R, R, and R 0 are a group of formula R ¹⁴ R 1I -OCH-aryl or -CHO-aryl and each of the remaining R, R and R as well as R ⁵ and R ⁹ are each independently hydrogen, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, halogen or C 1 -C 4 haloalkyl; R ¹⁰ represents a carboxy group or a group of the formula COOR ³ · ³ · or CONR 4 R ³ · ³ ; R ¹¹ represents a biolabile ester-forming group; R ¹² and R ¹³ are each independently hydrogen or C 1 -C 4 alkyl; R ( ¹⁴⁾ is hydrogen, (C1-C6) -alkyl, (C3-C7) -cycloalkyl or aryl; and aryl or aryl in the definitions of R ⁶ , R ⁷ , R ⁸ and R ¹⁴ is phenyl optionally substituted with C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 2 -C 6 alkenyl, hydroxy a halogen atom, a trifluoromethyl group, a haloalkyl group having 1 to 6 carbon atoms, a nitro group, an amino group, an alkanoyl group having 2 to 6 carbon atoms, an alkanoyl group having 2 to 6 carbon atoms or a phenyl group. The indoles of claim 1, wherein Y is (C 1 -C 6) alkylene optionally substituted with (C 1 -C 6) alkyl; R is hydrogen, hydroxy, halogen, C 1 -C 4 alkyl or C 1 -C 4 alkoxy; 101 R ¹ , R ² , R ³ and R ⁴ are each independently hydrogen, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, hydroxy, halogen or trifluoromethyl; One of the symbols R ⁶ , R ⁷ and R ⁸ represent a group of the general formula R ¹⁴ R ¹⁴ ........ '..... I. - ..... I ... -OCH-aryl or -CHO-aryl and each of the remaining R ⁶ , R ⁷ and R ⁸ , as well as R ⁵ and R ^9, each independently represent a hydrogen atom, a C 1 -C 4 alkyl group, a C 1 -C 4 alkoxy group C 4, halogen or C 1 -C 4 haloalkyl; R ¹⁰ is carboxy or a group of formula COOR ¹¹ or -CONR-, NRCO- ^1-2 · ³ R ^3; R ¹¹ represents a biolabile ester-forming group; R ¹² and R ¹³ are each independently hydrogen or C 1 -C 4 alkyl; R ( ¹⁴⁾ is hydrogen, (C1-C6) -alkyl, (C3-C7) -cycloalkyl or aryl; and aryl or aryl in the definitions of R ⁶ , R ⁷ , R ⁸ and R ¹⁴ is phenyl optionally substituted with C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 2 -C 6 alkenyl, hydroxy halogen, trifluoromethyl, halogen 102 with these (i) (ii) (iii) (iv) C 1 -C 6 alkyl, nitro, amino, C 2 -C 6 alkanamide, C 2 -C 6 alkanoyl or phenyl, subject to: when R is 1- (4- (2-methylpropyl) phenyl) ethoxy, all R, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁸ and R ⁹ are hydrogen and Y is a group of formula - (CH ₂ ) ₃ -, R ¹⁰ does not represent a carboxy group when the compound of formula I is in racemic form; when R ⁷ is 1- (4- (2-methylpropyl) phenyl) propoxy or 2,2-dimethyl-1- (4- (2-methylpropyl) phenyl) propoxy, all R, R ³ , R ² , R ^3, R ^4, R®, R ^6, R ⁸ and R ⁹ are hydrogen and Y is - (CH _{2) 3} -, R does not represent carboxy or etoxykarbonylskupinu ^iU, when the compound of formula I in racemic form; when R ⁶ is 1- (3- (2-methylpropyl) phenyl) ethoxy, all R, R ¹ , R ² , R ³ , R ⁴ , R * 7 Q Q R ³ , R, R ^c and R ³ are hydrogen and Y is - (CH ₂ ) ₃ -, R ^{10 is not} carboxy or ethoxycarbonyl when the compound of formula I is in racemic form; * 7 when R is 1- (4- (2-methylpropyl) phenyl) ethoxy, each of R ⁵ and R ⁶ is methyl, all R, R ¹ , R ² , R ³ , R ⁴ , Q Q R and R are hydrogen and Y is - (CH ₂ ) ₃ -, R ^{10 is not} carbo 103 is xyloxy or ethoxycarbonyl when the compound of formula I is in racemic form; (v) when R ⁷ is bis (4- (2-methylpropyl) phenyl) methoxy, all R, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁸ and R ⁹ are hydrogen; and Y is - (CH 2) ^- , R ^{10 is not} carboxy; vi) when R ⁶ is bis (4- (2-methylpropyl) phenyl) methoxy, all R, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁷ , R ⁸ and R ⁹ are hydrogen; and Y is - (CH ₂ ) ₃ -, R ^{10 is not} carboxy; ^and vii) when R ⁶ is 4- (2-methylpropyl) phenoxymethyl or 3- (2-methylpropyl) phenoxymethyl, all of R ¹ , R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁷ , R ⁸ and R ⁹ is hydrogen and Y is - (CH ₂ ) ₃ -, not R ³ · ^{O is} carboxy or ethoxycarbonyl. Indoles according to claim 1 or 2, wherein R ¹⁰ represents a carboxy group or a group of the formula COOR ¹¹ . The indoles according to any one of the preceding claims, wherein R ¹¹ is C 1 -C 6 alkyl. The indoles of any of the preceding claims, wherein R ¹⁰ is carboxy. Indoles according to any one of the preceding claims, wherein 104 Y represents an alkylene group having 1 to 6 carbon atoms; r is hydrogen or (C 1 -C 4) alkyl; each of the symbols R ¹ , R ² , R ³ and R ⁴ represent a hydrogen atom; One of the symbols R ⁶ , R ⁷ and R ⁸ represent a group of the general formula R ¹⁴ R ¹⁴ I I -OCH-aryl or -CHO-aryl and each of the remaining R ⁶ , R ⁷ and R ⁸ , as well as R ⁵ and R ^9, independently represents a hydrogen atom or a C 1 -C 4 alkyl group; R ( ¹⁴⁾ is hydrogen, (C1-C4) alkyl, (C4-C6) cycloalkyl or (C1-C4) -phenyl; and aryl when used in the definitions of R ⁶ , R ^7, and R ⁶ Q R 1 is phenyl, which is optionally substituted with one to three substituents independently selected from the group consisting of C 1 -C 6 alkyl and halogen. The indoles of claim 6, wherein Y represents a methylene, propylene, butylene or pentylene group; • i- *: - 105 - R is hydrogen or methyl; R ⁷ R ¹⁴ R ¹⁴ 11 is -OCH-aryl or -CHO-aryl and each of R ⁵ , R ⁸ , R ⁸ and R ^{9 is} independently hydrogen or C 1 -C 4 alkyl; R ¹⁴ is hydrogen, methyl, n-propyl, cyclopentyl or 4- (n-propyl) phenyl; and aryl, is phenyl, which is optionally Y substituted with one to two substituents independently selected from the group consisting of methyl, ethyl, n-propyl, isobutyl and chloro. The indoles of claim 7, wherein represents a propylene group; R represents a hydrogen atom; R ⁷ a group of formula ^R14-aryl-OCH and each of R ⁵ , R ⁸ , R ⁸ and R ⁹ represents a hydrogen atom; R ¹⁴ is methyl; 106 aryl, is phenyl, 4-methylphenyl, 4-ethylphenyl, 4- (n-propyl) phenyl, 4-isobutylphenyl or 3,4-dichlorophenyl. The indoles of claim 8, wherein aryl is 4-isobutylphenyl. The indoles according to claim 1 or 2, wherein one of R ⁶ , R ⁷ and R ⁸ is a group of the formula and the rest of R ⁶ , R ⁷ and R ^8, and further Y, R, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁹ , R ¹⁰ , R ¹¹ , R ¹² , R ¹³ and aryl are as defined in claim 1 or 2. A compound selected from the group consisting of (R, S) -4- (3- (4- (1- (4- (2-methylpropyl) phenyl) ethoxy) benzoyl] indol-1-yl) butanoic acid, (S ) -4- (3- [4- (1- (4- (2-methylpropyl) phenyl) ethoxy) benzoyl] indol-1-yl) butanoic acid, (R, S) -4- (2-methyl- 3- [4- (1- (4- (2-methylpropyl) phenyl] ethoxy) benzoylindol-1-yl) butanoic acid and (S) -4- (2-methyl-3- [4- (1- ( 4- (2-Methylpropyl) phenyl (ethoxy) benzoyl] indol-1-yl) butanoic acid; 107 and pharmaceutically acceptable salts thereof. A pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, as claimed in any preceding claim, together with a pharmaceutically acceptable diluent or carrier therefor. A compound of formula I, or a pharmaceutically acceptable salt thereof, or a composition thereof, according to any one of claims 1 to 11 and 12 for use as a medicament. Use of a compound of formula I or a pharmaceutically acceptable salt or preparation thereof, according to any one of claims 1 to 11 and 12 for the manufacture of a medicament for inhibiting steroid 5α-reductase. Use of a compound of formula I or a pharmaceutically acceptable salt or preparation thereof according to any one of claims 1 to 11 and 12 for the manufacture of a medicament for the curative or prophylactic treatment of acne vulgaris, alopecia, seborrhoea, female hirsutism, benign prostatic hypertrophy or baldness. male type. Use of a compound of formula I or a pharmaceutically acceptable salt or preparation thereof, according to any one of claims 1 to 11 and 12 for the manufacture of a medicament for the curative or prophylactic treatment of human prostate adenocarcinoma. 17. A method of treating a human to inhibit steroid 5α-reductase, comprising administering to the patient an effective amount of a compound of Formula I, or a pharmaceutically acceptable salt or preparation thereof, according to any one of claims 1 to 11 and 12. - 108 - A method of treating a human to treat or prevent acne vulgaris, alopecia, seborrhoea, female hirsutism, benign prostatic hypertrophy, male-type baldness or adenocarcinoma of the human prostate, comprising administering to a human patient an effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof, or a preparation thereof, according to any one of claims 1 to 11 and 12a Compounds of formula IV CN (IV); compounds of formula VIII (VIII) or salts thereof with bases; compounds of formula XIII (XIII); 109 (XIV); of XIV (X) _CO2 H or its salts; compounds of formula XVIII (XVIII) or salts thereof with bases; compounds of formula XXI (XXI) 110 or a salt thereof with a base; and compounds of formula XXIII (XXIII) wherein Y, R, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ and R ¹⁰ are as defined in claim 1 or 2 ; R ²⁴ is hydrogen or hydroxy; one of R ²⁵ , R ²⁶ and R ²⁷ is hydroxy and the remaining R ²⁵ , R ²⁶ and R ²⁷ are as defined in claim 1 or 2 for the remaining R ⁶ , R ⁷ and R ⁸ ; one of R ²⁸ , R ²⁹ and R ³⁰ represents a group of the general formula R ^{14 1} 8 CH-Z ¹⁴ wherein R ° is as defined in claim 1 or 2, and Z ⁸ is a leaving group and the other groups R ^28, R ²⁹ and R ³⁰ are as defined in claim 1 or 2 for the other groups R ⁶ . R ⁷ and R ⁸ ; one of R ³¹ , R ³² and R ³³ represents a group of the general formula R ¹⁴ CH-OH 111 wherein R ¹⁴ is as defined in claim 1 or 2 and the remaining R ³¹ , R ³² and R ³³ are as defined in claim 1 or r 7 Q 2 for the remaining R 0, R 3 and R 3, provided that in the compound of formula XVIII, where Y is methylene, R is methyl, R ² is methoxy, each of R ¹ , R ³ , R ⁴ , R ⁵ and R ⁹ represents a hydrogen atom, each of R ²⁵ and R ^2; R @ ² is bromine and R @ ² is hydroxy, R @ ^{10 is not} carboxy. Compounds of formula (XXI) or salts thereof with bases according to claim 19, wherein Z ⁸ is halogen, C 1 -C 4 alkanesulfonyloxy or C 1 -C 4 alkylphenylsulfonyloxy. 21) A process for the preparation of compounds of formula I R ¹⁰ and pharmaceutically acceptable salts thereof, wherein Y is (C 1 -C 6) alkylene optionally substituted with (C 1 -C 6) alkyl; R is hydrogen, hydroxy, halogen, C 1 -C 4 alkyl, or C 1 -C 4 alkoxy; R ¹ , R ² , R ² and R ⁴ are each independently hydrogen, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, hydroxy, halogen or trifluoromethyl; One of the symbols R ⁶ , R ⁷ and R ⁸ represent a group of the general formula R ¹⁴ R YOCH-aryl or -CHO-aryl and each of the remaining R ⁶ , R ⁷ and R ⁸ , as well as from CQ, R and R are each independently hydrogen, C 1 -C 4 alkyl, C 1 -C 4 alkoxy C 4, halogen or C 1 -C 4 haloalkyl; R ¹⁰ represents a carboxy group or a group of the formula COOR ¹¹ or CONR ¹² R ¹³ ; 1 Ί R. represents a biolabile ester-forming group; R ¹² and R ¹³ are each independently hydrogen or C 1 -C 4 alkyl; R ( ¹⁴⁾ is hydrogen, (C1-C6) -alkyl, (C3-C7) -cycloalkyl or aryl; and arvl or aryl in the definitions of R ⁶ , R ⁷ , R ⁸ and R ¹⁴ is phenyl which is optionally - 113 substituted with C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 2 -C 6 alkenyl, hydroxy, halogen, trifluoromethyl, haloC 1-6 alkyl, nitro, amino, alkanamidino (C až-C alk) alkanoyl or phenyl group, characterized in that: (a) for the preparation of compounds of formula I wherein R ¹⁰ is carboxy and Y, R and R ¹ to R ⁹ are as defined above for formula I, the ester of formula II is cleaved. Kde A wherein R represents a suitable cleavable ester-forming group and Y, R and R ¹ to R ⁹ are as defined above for formula I; b) for the preparation of compounds of formula I wherein R ¹⁰ is carboxy and Y, R and R ¹ to R ⁹ are as defined above for formula I, the compound of formula I wherein R ¹⁰ is a group is hydrolyzed under acidic or basic conditions CONR ¹² R ¹³ and Y, R, 114 R ^{@ 1} to R ^{@ 9} , R ^{@ 12} and R @ ¹³ are as defined above for formula I; (c) for the preparation of compounds of formula I wherein R ¹⁰ is carboxy and Y, R and R ¹ to R ⁹ are as defined above for formula I, the compound of formula IV is hydrolyzed under acidic or basic conditions CN (IV) where Y, R ^{@ 1} and R ^{@ 1} - R ^{@ 9} are as defined above for formula I; d) for the preparation of compounds of formula I wherein R ¹⁰ is COOR ¹¹ and Y, R, R ¹ to R ⁹ and R ¹¹ are as defined above for formula I, the compound of formula I wherein R ¹⁰ is esterified represents a carboxy group and Y, R and R ^ to R ⁹ are as defined above for formula (I), an alcohol of formula (IIqh), wherein R ¹¹ is as defined above for formula (I); (e) for the production of compounds of formula I, where Ί 1 Π Y, R, and R to R are as defined above for the general formula I is alkylated with a base salt of a compound of formula VIII 115 (VIII) wherein R and R ¹ to R ⁹ are as defined above for formula I, a compound of formula Z ³ -Y-COOR ¹¹ or Z ³ -Y-CONR ¹² R ¹³ or with a base salt of a compound of formula Z ³ -Y-COOH, wherein Y, R ¹¹ , R ¹² and R ¹³ are as defined above for the compound of Formula I and Z ³ is a leaving group; f) for the preparation of compounds of formula I wherein R ¹⁰ is carboxy and Y, R and R ¹ to R ⁹ are as defined above for formula I, the compound of formula XIII is oxidized CH ₂ OH (xiii). Wherein Y, R and R and R are as defined above for Formula I; g) for the preparation of compounds of formula I wherein R ¹⁰ is carboxy and Y, R and R ¹ to R ⁹ are as defined above for formula I, the compound of formula XIV or XV (XIV) is oxidized CO ₂ H (XV) or a salt thereof with a base, wherein R ²⁴ represents a hydrogen atom or a hydroxyl group; Q and Y, R and R 1 are as defined above for formula I; h) for the preparation of compounds of the formula I, wherein one of R ⁶ , R ⁷ and R ⁸ represents a group of the formula - 117 R ¹⁴ -OCH-aryl and each of the remaining R ⁶ , R ⁷ and R ^{8 as} well as each of Y, R, R ¹ to R ⁸ , R ⁹ , R ¹⁰ , R ¹⁴ and aryl has the meaning given above in the general formula I, a compound of formula XVIII (XVIII) wherein one of R ²⁵ , R ²⁸ and R ²⁷ is hydroxy and each of the remaining R ²⁵ , R ²⁶ and R ²⁷ are as defined above for the remaining R, R and R in the general formula I; and Y, R, R ¹ to R ⁵ , R ⁹ and R ¹⁰ are as defined above for a compound of formula I, or a salt thereof with a base, is reacted with a compound of formula XIX R ¹⁴ ₇ I Z'-CH-aryl (XIX) wherein R ¹⁴ and aryl are as defined above for the compound of formula I for this and Z ⁷ represents a leaving group; · R » 118 (i) for the preparation of compounds of the formula I, in which R ¹⁰ represents a group of the formula COOR ³³ or CONR ³² R ³³ and one of R ⁶ , R ⁷ and R ⁸ represents a group of the formula R ¹⁴ I Aryl-OCH And each of the remaining R, R, and R, as well as each of Y, R, R ¹ to R ⁵ , R ⁹ , R ¹¹ , R ¹² , R ¹³ , R ¹⁴ and aryl has the meanings given above in general formula I, a compound of formula XVIII, wherein R ¹⁰ is a group of formula COOR ¹¹ or CONR ¹² R ^13, Y, R, R ¹ to R 5, R ^9, R ¹ · ^ · R ³ · ² and R ^13, are as defined above for formula (I) and R ²⁵ , R ²⁶ and R ²⁷ are as defined above in part of claim 21 (h), reacted with a compound of formula XX R ¹⁴ I HO-CH-aryl (XX) wherein R ¹⁴ and aryl are as defined for formula I above in the presence of a dehydrating agent; j) for the preparation of compounds of the formula I, wherein one of R ⁶ , R ⁷ and R ⁸ represents a group of the formula R ¹⁴ CHO-aryl And each of the remaining R, R, and R ° as well as each of Y, R, R ³ to R ³ , R ⁹ , R ³⁰ , R ³⁴ and aryl is as defined above for formula I, is a compound of formula XXI wherein one of R ²⁸ , R ²⁹ and R ³⁰ is a group of formula R ^{14 f} 8 -CH-Z ⁸ and each of the remaining R ²⁸ , R ^29, and R ³⁰ is as defined above for the remaining R ⁶ , R ⁷ and R ⁸ for the compound of formula I, Y, R, R ¹ to R ⁵ , R ⁹ , R ¹⁰ and R ¹⁴ are as defined above for formula I and Z ⁸ is a leaving group, or a salt thereof with a base, reacted with a salt of a compound of formula XXII with an aryl-OH (XXII) base wherein aryl is above for Formula I; a) the preparation of compounds of formula I, wherein Rpredstavuje a group of the formula -COOR ^ · ^ · or CONR ^1-2 R · '· ³ one of R ^e, R ⁷ and R ⁸ is a group of 120 formula R ¹⁴ I -CHO-aryl and each of the remaining R ⁶ , R ⁷ and R ^8, and also each of Y, R, R ¹ to R ⁵ , R ⁹ , R ¹¹ , R ¹² , R ¹³ , R ¹⁴ and aryl have as defined above for the general formula I, the compound of the general formula XXIII and 0 r ^ R ³³ R ² ^ 1 1 1 ^X R R ⁵ Γ I ^X R ³² (XXIII) R ¹ Y R ³¹ Ŕ ¹⁰ where one of the symbols R ³¹ / R ³² a R ³³ is a group of the general formula R ¹⁴ I -CH-OH and each of the remaining R ³¹ , R ³² and R ³³ is as defined above for the remaining R 0, R 1 and R 0 of the compound of formula I, R ¹⁰ is COOR ¹¹ or CONR ¹² R ¹³ and Y, R, R ¹ to R ⁵ , R ⁹ , R ¹¹ , R ¹² , R ¹³ and R ¹⁴ are as defined above for a compound of formula I reacted with a compound of formula XXII, wherein aryl is as defined above a compound of formula I in the presence of a dehydrating agent; wherein any one of process variants a) to k) optionally followed by conversion of the product of formula I to a pharmaceutically acceptable salt thereof. 121 22. The method of claim 21, wherein: Y is (C 1 -C 6) alkylene optionally substituted with (C 1 -C 6) alkyl; R is hydrogen, hydroxy, halogen, C 1 -C 4 alkyl or C 1 -C 4 alkoxy; R ¹ , R ² , R ³ and R ⁴ are each independently hydrogen, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, hydroxy, halogen or trifluoromethyl; One of the symbols R ⁶ , R ⁷ and R ⁸ represent a group of the general formula R ¹⁴ R II -OCH-aryl or -CHO-aryl and each of the remaining R ⁶ , R ⁷ and R ⁸ , as well as CQ ^J symbols R and R 'are each independently H, C 1 -C 4 alkyl, C 1 -C 4 alkyl, halogen or C 1 -C 4 alkyl; R ¹⁰ represents a carboxy group or a group of the formula COOR ¹³ · or CONR ^3-2 R ³ · ³ ; R ¹¹ represents a biolabile ester-forming group; Ί P Ί Ί R and R are each independently hydrogen or (C 1 -C 4) alkyl; 122 R ( ¹⁴⁾ is hydrogen, (C1-C6) -alkyl, (C3-C7) -cycloalkyl or aryl; and aryl or aryl in the definitions of R ⁶ , R ⁷ , R ⁸ and R ¹⁴ is phenyl optionally substituted with C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 2 -C 6 alkenyl, hydroxy , halogen, trifluoromethyl, haloalkyl of 1 to 6 carbon atoms, nitro, amino, C 2 -C 6 alkanoylamino, C 2 -C 6 alkanoyl or phenyl, with the following reservations: (i) when R ⁷ is 1- (4- (2-methylpropyl) phenyl) ethoxy, all R, R ¹ , R ² , R ³ , R ⁴ , r ⁵ , r ⁶ , r ⁸ and R ⁹ are hydrogen; and Y represents a group of the formula - (CH ₂ ) ₃ -, and does not represent R ¹⁰ carboxy when the compound of formula I is in racemic form; (ii) when R ⁷ is 1- (4- (2-methylpropyl) phenyl) propoxy or 2,2-dimethyl-1- (4- (2-methylpropyl) phenyl) propoxy, all R, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁸ and R ⁹ are hydrogen and Y is - (CH ₂ ) ₃ -, R ^{18 is not} carboxy or ethoxycarbonyl when the compound of formula I is in racemic form; iii) when R ⁶ is 1- (3- (2-methylpropyl) phenyl) ethoxy, all R, R ¹ , R ² , R ³ , R ⁴ ; ί ts ts; · »·. iv) IN) vi) R ^5, R ^7, R ⁸ and R ⁹ are hydrogen and Y is - _{(CH2) 3} ~, R is not a carboxy group and ^X0 etoxykarbonylskupinu, when the compound of formula I in racemic form; when R ⁷ is 1- (4- (2-methylpropyl) phenyl) ethoxy, each of R and R is methyl, all R, R ^X , R ² , R ³ , R ⁴ , R ⁸ and R ⁹ are hydrogen atoms and Y is - (CH ₂ ) ₃ -, R ^{10 is not} carboxy or ethoxycarbonyl when the compound of formula I is in racemic form; when R ⁷ is bis (4- (2-methylpropyl) phenyl) methoxy, all R, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁸ and R ⁹ are hydrogen and Y is - (CH ₂ ) ₃ -, R ^{10 is not} carboxy; when R ⁶ is bis (4- (2-methylpropyl) phenyl) methoxy, all R, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁷ , R ⁸ and R ⁹ are hydrogen and Y is - (CH ₂ ) ₃ -, R ^{10 is not} carboxy; ^and when R ⁶ is 4- (2-methylpropyl) phenoxymethyl or 3- (2-methylpropyl) phenoxymethyl, all the symbols R, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁷ , R ⁸ and R ⁹ are hydrogen atoms and Y is - (CH ₂ ) ₃ -, R ^{10 is not} carboxy or ethoxycarbonyl. vii) 124 A process according to claim 21 (a) or 22, characterized in that the cleavage is carried out by acidic or basic hydrolysis of a compound of formula II. A process according to claim 21 (a), 22 or 23, characterized in that R ¹⁵ is C 1 -C 6 alkyl. 25. A process according to claim 23 or 24, wherein the cleavage is carried out by basic hydrolysis using sodium or potassium hydroxide in the presence of water. 26. A process according to claim 21 or 22, wherein the salts of the compound of formula (VIII) are sodium or potassium. A process according to claim 21 e), 22 or 26, characterized in that Z ³ is halogen, C 1 -C 4 alkanesulfonyloxy or alkylphenylsulfonyloxy. C 1-4 alkyl. 28. The method of claim 27, characterized in that Z ³ is bromo. A process according to claim 21 h) or 22, wherein a base salt of a compound of formula XVIII is used. 30. The method of claim 29, wherein the salt of the compound is a sodium or potassium salt. 31. The method of claim 21, 22, 29 or 30, wherein Z is halo 125 gene, C 1 -C 4 alkanesulfonyloxy or C 1 -C 4 alkylphenylsulfonyloxy. 32. The method of claim 31, characterized in characterized in that Z ⁷ is bromo. Process according to claim 21 i), 21 k) or 22, characterized in that the dehydrating agent is used in combination with diethyl azodicarboxylate and triphenylphosphine. 34. A process according to claim 21 or 22, wherein Z &lt; 0 &gt; is halogen, C1 -C4 alkanesulfonyloxy or C1 -C4 alkylphenylsulfonyloxy. Process according to any one of claims 21 to 34, characterized in that R ¹⁰ represents a carboxy group or a group of the formula COOR ¹¹ . 36. The method of claim 35, characterized in characterized in that R ¹¹ is C 1 -C 6 alkyl. The process according to any one of claims 21 to 32 or 34, wherein R ¹⁰ is carboxy. A method according to any one of claims 21 to 37, characterized in that Y represents an alkylene group having 1 to 6 carbon atoms; R is hydrogen or (C 1 -C 4) alkyl; 126 each of the symbols R ¹ , R ² , R ³ and R ⁴ represent a hydrogen atom; One of the symbols R ⁶ , R ⁷ and R ⁸ represent a group of the general formula R ¹⁴ R ¹⁴ I I -OCH-aryl or -CHO-aryl and each of the remaining R ⁶ , R ⁷ and R ⁸ , as well as R 8 and R ^9, independently represents a hydrogen atom or a C 1 -C 4 alkyl group; R ( ¹⁴⁾ is hydrogen, (C1-C4) alkyl, (C4-C6) cycloalkyl or (C1-C4) -phenyl; and aryl, when used in the definitions of R, R and R ⁸ , is a phenyl group optionally substituted with one to three substituents independently selected from the group consisting of C 1 -C 6 alkyl and halogen. 39. The method of claim 38, wherein: .... Y represents a methylene, propylene, butylene or pentylene group; R is hydrogen or methyl; R is a radical of formula 127 R ¹⁴ R ¹⁴ I -OCH-aryl or -CHO-aryl and each of R ⁵ , R ⁶ , R ⁸ and R ⁹ independently represents a hydrogen atom or a C 1 -C 4 alkyl group; R ¹⁴ is hydrogen, methyl, n-propyl, cyclopentyl or 4- (n-propyl) phenyl; and aryl is phenyl, which is optionally substituted with one to two substituents independently selected from methyl, ethyl, n-propyl, isobutyl and chloro. The method of any one of claims 21 to 33 or 35 to 37, characterized in that Y represents a propylene group; R represents a hydrogen atom; each of the symbols R ¹ , R ² , R ³ and R ⁴ represent a hydrogen atom; R ⁷ represents a group of the general formula R ¹⁴ I -OCH-aryl and each of R ⁵ , R ⁶ , R ⁸ and R ⁹ represents a hydrogen atom; R ¹⁴ is methyl; 128 aryl, is phenyl, 4-methylphenyl, 4-ethylphenyl, 4- (n-propyl) phenyl, 4-isobutylphenyl or 3,4-dichlorophenyl. . A process according to any one of claims 21 to 40, wherein aryl is 4-isobutylphenyl. Process according to claims 21 or 22, characterized in that a compound of formula (I) is prepared wherein one of R, R 'and R represents a group of formula (C 1 -C ₆ alkyl) > ---- O ( ^s ) Aryl and the remainder of R ⁸ , R ⁷ and R ^8, and also Y, R, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁹ , R ¹⁰ , R ¹¹ , R ¹² , R ¹³ and aryl are as defined in claim 21 or 22. ' 43. The method of claim 21 or 22, wherein a compound selected from the group consisting of (R, S) -4- (3- [4- (1- [4- (2-methylpropyl) phenyl) ethoxy) benzoyl] is prepared. (S) -4- (3- [4- (1- [4- (2-methylpropyl) phenyl] ethoxy) benzoyl] indol-1-yl) butanoic acid, (R, indol-1-yl) butanoic acid, S) -4- (2-methyl-3- [4- (1- [4- (2-methylpropyl) phenyl] ethoxy) benzoyl] indol-1-yl) butanoic acid and 129 (S) -4- (2-methyl-3- [4- (1- (4- (2-methylpropyl) phenyl) benzoyl] indol-1-yl) butanoic acid and pharmaceutically acceptable salts thereof. A process for the manufacture of a pharmaceutical composition comprising mixing a compound of formula (I) or a pharmaceutical composition thereof (iv) produced by a process according to any one of claims 21 and a pharmaceutically acceptable diluent or carrier.