IE922386A1 - Indoles - 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

INDOLES This invention relates to indole derivatives which have steroid 5 os-reductase inhibitory activity.

More particularly this invention relates to indoles, their preparation and their use as testosterone-5 csreductase inhibitors.

The androgen class of steroidal hormones, which includes testosterone, is responsible for the difference in the physical characteristics of males and females. Of all the organs that produce androgens, the testes produce these hormones in the greatest amounts. Over-production of these hormones in the body results in many undesirable physical manifestations and disease states, e.g. acne vulgaris, alopecia, seborrhoea, female hirsutism, benign prostatic hypertrophy and male pattern baldness.

The principal androgen secreted by the testes is testosterone and it is the primary androgen present in male plasma. The principal mediator of androgenic activity in certain organs such as the prostate and sebaceous gland are the 5a-reduced androgens.

Testosterone is therefore the prohormone of 5ctdihydrotestosterone which is formed locally in the above organs by the action of testosterone-5 cc-reductase. The presence of elevated levels of dihydrotestosterone in many disease states has therefore focussed attention on the synthesis of testosterone 5os-reductase inhibitors.

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

EP-A-0458207 discloses certain indole derivatives which have testosterone 5a-reductase inhibitory activity. -2The present invention provides compounds of the formula:- R1° ....(I) and pharmaceutically acceptable salts thereof, wherein Y is C^-Cg alkylene optionally substituted by Ci-Cg alkyl; R is H, OH, halo, Cj-C^ alkyl or C^-C,, alkoxy; R1, R2, R3 and R4 are each independently selected from H, Cj-C4 alkyl, C^-C,, alkoxy, OH, halo and CF3; one of R6, R7 and R8 R14 I -OCH-Aryl and the remainder, each independently Cj-04 alkoxy, halo is a group of the formula:R14 I or -CHO-Aryl, together with R5 and R9, are selected from H, (^-04 alkyl, and halo (Cj-C4) alkyl; -3R10 is COOH, COOR11 or CONR12R13; R11 is a biolabile ester-forming group; R12 and R13 are each independently selected from H and Cj-^ alkyl; R14 is H, Cj-C6 alkyl, C3-C7 cycloalkyl or aryl; and aryl, used in the definitions of R6, R7, R® and R14, means phenyl optionally substituted by Cj-Cg alkyl, Cj-C6 alkoxy, C2-C6 alkenyl, OH, halo, CF3, halofCj-Cg alkyl), nitro, amino, C2-C6 alkanamido, C2-C6 alkanoyl or phenyl.

In a further aspect of the present invention Y is Cj-Cg alkylene optionally substituted by Ci-Cg alkyl; R is H, OH, halo, Cj-C4 alkyl or Cj-C.^ alkoxy; R1, R2, R3 and R4 are each independently selected from H, Cj-C4 alkyl, Cj-C4 alkoxy, OH, halo and CF3; one of R6, R7 and R® R14 is a group of the formula :R14 I -OCH-Aryl or -CHO-Aryl, and the remainder, together with R5 and R9, are each independently selected from H, Cj-C4 alkyl, Cj-C4 alkoxy, halo and halo(Cj-CJ alkyl; R10 is COOH, COOR11 or CONR12R13; -4R11 is a biolabile ester-forming group; R12 and R13 are each independently selected from H and CL-C4 alkyl; R14 is H, Cj-C6 alkyl, C3-C7 cycloalkyl or aryl; and aryl, used in the definitions of R6, R7, R8 and R14, means phenyl optionally substituted by Cj-Cg alkyl, Cj-C6 alkoxy, C2-C6 alkenyl, OH, halo, CF3, haloiCi-Cg alkyl), nitro, amino, C2-C6 alkanamido, C2-C6 alkanoyl or phenyl: with the provisos i) when R7 is 1-(4-(2-methylpropyl)phenyl) ethoxy, R, R1, R2, R3, R4, R5, R6, R8 and R9 are all H and Y is -(CH2)3-, that R10 is not COOH when the compound of the formula (I) is in the racemic form; ii) when R7 is 1-(4-(2-methylpropy 1) phenyl)propoxy or 2,2-dimethyl-l-(4-(2methylpropy 1) phenyl) propoxy, R, R1, R2, R3, R4, R5, R6, R8 and R9 are all H and Y is -(CH2)3-, that R10 is not COOH or COOC2H5 when the compound of the formula (I) is in the racemic form; iii) when R6 is 1-(3-(2-methylpropy1)phenyl)ethoxy, R, R1, Rz, R3, R4, R5, R7, R8 and R9 are all H and Y is -(CH2)3-, that R10 is not COOH or COOC2H5 when the compound of the formula (I) is in the racemic form; -5iv) when R7 is 1-(4-(2-methylpropyl)phenyl)ethoxy, R5 and R6 are both methyl, R, R1, R2, R3, R4, R8 and R9 are all H and Y is — (CH2)3—, that R10 is not COOH or COOC2H5 when the compound of the formula (I) is in the racemic form; v) when R7 is bis(4-(2-methylpropyl)phenyl)methoxy, R, R1, R2, R3, R4, R5, R6, R8 and R9 are all H and Y is -(CH2)3-, that R10 is not COOH ; vi) when R6 is bis(4-(2-methylpropyl)phenyl)methoxy, R, R1, R2, R3, R4, R5, R7, R8 and R9 are all H and Y is -(CH2)3-, that R10 is not COOH; and vii) when R6 is 4-(2-methylpropyl)phenoxymethyl or 3-(2-methylpropyl)phenoxymethyl, R, R1, R2, R3, R4, R5, R7, R8 and R9 are all H and Y is -(CH2)3—, that R10 is not COOH or COOC2H5.

Alkyl, haloalkyl, alkenyl and alkoxy groups containing three or more carbon atoms and alkanamido and alkanoyl groups containing four or more carbon atoms may be straight- or branched-chain.

The term halo means fluoro, chloro, bromo or iodo.

The term biolabile ester-forming group is well understood in medicinal chemistry as meaning a group which forms an ester which can be readily cleaved in vivo to liberate the corresponding acid of the formula (I) wherein R10 is COOH. A number of such ester groups are well-known, for example in the penicillin area or in the case of the angiotensin-converting enzyme (ACE) inhibitor antihypertensive agents. -6Esters of the formula (I) wherein R1® is CO2(C^-Cg alkyl) are steroid 5a-reductase inhibitors per se but, in general, where R10 is COOR11 such compounds are useful as pro-drugs to provide compounds of the formula (I) wherein R10 is COOH in vivo following oral administration. Such esters are also useful as intermediates for the preparation of compounds of the formula (I) wherein R10 is COOH.

The suitability of any particular ester-forming group for this purpose can be assessed by conventional in vitro or in vivo enzyme hydrolysis studies.

Examples of suitable biolabile ester-forming groups are alkyl (e.g. Cj-Cg alkyl), alkanoyloxyalkyl (including alkyl, cycloalkyl or aryl substituted derivatives thereof), arylcarbonyloxyalkyl (including aryl substituted derivatives thereof), aryl, arylalkyl, indanyl and haloalkyl: wherein alkanoyl groups have from 2 to 8 carbon atoms and alkyl groups have from 1 to 8 carbon atoms, all of which may be straight- or branchedchain, and aryl means phenyl or naphthyl, both of which may be optionally substituted by C1~C4 alkyl, C1~C4 alkoxy or halo.

In addition to C^C^ alkyl, specific examples of other biolabile ester-forming groups are benzyl, 1-(2,2diethylbutyryloxy)ethyl, 2-ethylpropionyloxymethyl, 1-(2ethylpropionyloxy)ethyl, 1-(2,4-dimethylbenzoyloxy)ethyl, cc-benzoyloxybenzyl, 1-(benzoyloxy) ethyl, 2-methyl-lpropionyloxy-l-propyl, 2,4,6-trimethylbenzoyloxymethyl, 1-(2,4,6-trimethylbenzoyloxy)ethyl, pivaloyloxymethyl, phenethyl, phenpropyl, 2,2,2-trifluoroethyl, 1- or 2naphthyl, 2,4-dimethylphenyl, 4-t-butylphenyl and 5indanyl.

The pharmaceutically acceptable salts of the compounds of the formula (I) are the acid addition and the base salts thereof. -7Suitable acid addition salts are formed from acids which form non-toxic salts and examples are the hydrochloride, hydrobromide, hydroiodide, sulphate, bisulphate, phosphate, hydrogen phosphate, acetate, maleate, fumarate, lactate, tartrate, citrate, gluconate, benzoate, methanesulphonate, benzenesulphonate and ptoluenesulphonate salts.

Suitable base salts are formed from bases which form non-toxic salts and examples are the aluminium, calcium, lithium, magnesium, potassium, sodium, zinc and diethanolamine salts.

For a review on suitable salts see Berge et al, J. Pharm. Sci., 66, 1-19 (1977).

In the above definitions relating to the present invention: Preferably Y is C^-Cg alkylene.

More preferably Y is methylene, propylene, butylene or pentylene.

Most preferably Y is propylene.

Preferably R is H or C1~C^ alkyl.

More preferably R is H or methyl.

Most preferably R is H. 3 4 Preferably R , R , R and R are each H.

Preferably one of R6, R7 and R8 is a group of the formula: R14 R14 I I -OCH-Aryl or -CHO-Aryl, and the remainder, together with R5 and R9, are each independently selected from H and Cj-04 alkyl. -8More preferably R7 is a group of the formula :R14 R14 I I -OCH-Aryl or -CHO-Aryl, and R5, R6, R8 and R9 are each independently selected from H and Cj-C^ alkyl.

Most preferably R7 is a group of the formula :R14 I -OCH-Aryl, and R5, R6, R8 and R9 are each H.

Preferably R10 is COOH or COOR11.

Most preferably R10 is COOH.

Preferably R11 is Cj-Cg alkyl.

Most preferably R11 is ethyl.

Preferably R14 is H, C!-C4 alkyl, C4-C6 cycloalkyl or phenyl substituted by Cj-C4 alkyl.

More preferably R14 is H, methyl, n-propyl, cyclopentyl or 4-(n-propyl)phenyl.

Most preferably R14 is methyl.

Preferably aryl means phenyl optionally substituted by from 1 to 3 substituents, more preferably means phenyl optionally substituted by 1 or 2 substituents and most preferably means phenyl optionally substituted by one substituent.

In a preferred aspect of the present invention aryl, means phenyl optionally substituted by Cj-Cg alkyl or halo, more preferably means phenyl optionally substituted by methyl, ethyl, n-propyl, isobutyl or chloro, yet more preferably means phenyl, 4-methylphenyl, 4-ethylphenyl, 4-(n-propyl)phenyl, 4-isobutylphenyl or 3,4-dichlorophenyl and most preferably means 4isobutylphenyl. -9A compound of the formula (I) may contain one or more asymmetric carbon atoms and/or one or more alkenyl groups and may therefore exist in two or more stereoisomeric forms. The present invention includes both the individual stereoisomers of the compounds of the formula (I) together with mixtures thereof. Separation of diastereoisomers or cis and trans isomers may be achieved by conventional techniques, e.g. by fractional crystallisation, chromatography or H.P.L.C. of a stereoisomeric mixture of a compound of the formula (I) or a suitable salt or derivative thereof. An individual enantiomer of a compound of the formula (I) may also be prepared from a corresponding optically pure intermediate or by resolution, such as by H.P.L.C. of a racemate using a suitable chiral support or by fractional crystallisation of the diastereoisomeric salts formed by reaction of a racemate with a suitable optically active acid or base.

A preferred group of compounds of the formula (I) is where one of R6, R7 and R6 is a group of the formula:(Cf c6 alkyl) and the remainder, together with Y, R, R1, R2, R3, R4, R5, R9, R10, R11, R12, R13 and aryl are as previously defined for a compound of the formula (I).

!E 922386 -10Particularly preferred embodiments of the compounds of the formula (I) are (R,S)—4—(3—[4—(1—[4-(2-Methylpropyl)phenyl]ethoxy)benzoyl]indol-l-yl)butanoic acid, (S)-4-(3-[4-(l-[4-(2-MethyIpropy1) phenyl]ethoxy)benzoyl]indol-l-yl)butanoic acid, (R,S)-4-(2-Methyl-3-[4-(l-[4-(2-methylpropyl)phenyl]ethoxy)benzoyl]indol-l-yl)butanoic acid and (S)-4-(2-Methy1-3-[4-(1-[4-(2-methylpropyl)phenyl]ethoxy)benzoyl]indol-l-yl)butanoic acid: and the pharmaceutically acceptable salts thereof.

The compounds of formula (I) provided by the invention may be prepared by the following methods:1) The compounds of the formula (I) wherein R10 is COOH and Y, R and R1 to R9 are as previously defined for a compound of the formula (I) may be prepared by cleavage of an ester of the formula:- ....(11) wherein R15 is a suitable ester-forming group and Y, R and R1 to R9 are as previously defined for a compound of the formula (I) . -11A plethora of suitable ester-forming groups that may be cleaved to provide the corresponding carboxylic acid are known to the skilled man, see, e.g., T.W. Greene and P.G. Wuts, Protective Groups in Organic Synthesis, Wiley-Interscience (2nd edition, 1991).

Where R15 is an ester-forming group that may be removed by hydrolysis, e.g. C^-Cg alkyl or an alternative biolabile ester-forming group as previously defined (i.e. a compound of the formula (I) wherein R10 is COOR11) , the hydrolysis may be carried out under acidic or basic conditions, e.g. 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 an ester of the formula (II) is treated with an aqueous solution of a suitable base, e.g. sodium or potassium hydroxide, and in the presence of a suitable organic co-solvent, e.g. tetrahydrofuran or a Cj-C4 alkanol such as methanol. The hydrolysis is typically carried out at from room temperature to the reflux temperature and preferably is carried out at room temperature. The product is obtained as a base salt which may be converted to the carboxylic acid by acidification in the work-up procedure.

Where R15 is an ester-forming group that may be removed by reduction, e.g. benzyl, the reduction may be carried out by catalytic hydrogenation using, e.g., palladium-on-charcoal, as the catalyst. -122) The compounds of the formula (I) wherein R10 is COOH and Y, R and R1 to R9 are as previously defined for a compound of the formula (I) may be prepared by hydrolysis of a compound of the formula (I) wherein R10 is CONR1ZR13 and Y, R, R1 to R9, R1Z and R13 are as previously defined for a compound of the formula (I) · The hydrolysis may be carried out under acidic or basic conditions, e.g. using an aqueous solution of either a suitable mineral acid, e.q. hydrochloric or sulphuric acid, or a suitable inorqanic base, e.q. sodium or potassium hydroxide, at from room temperature to the reflux temperature. When basic hydrolysis conditions are used the product is obtained as a base salt which may be converted to the carboxylic acid by acidification in the work-up procedure. 3) The compounds of the formula (I) wherein R10 is COOH and Y, R and R1 to R9 are as previously defined for a compound of the formula (I) may be prepared by hydrolysis of a compound of the formula:- -13wherein Y, R and R1 to R9 are as previously defined for a compound of the formula (I) and R16 is H or CjC4 alkyl.

The hydrolysis may be carried out under acidic or basic conditions, e.g. using an aqueous solution of either a suitable acid, e.g. hydrochloric or acetic acid, or a suitable inorganic base, e.g. sodium or potassium hydroxide, at from room temperature to the reflux temperature. When basic hydrolysis conditions are used the product is obtained as a base salt which may be converted to the carboxylic acid by acidification in the work-up procedure. 4) The compounds of the formula (I) wherein R10 is COOH and Y, R and R1 to R9 are as previously defined for a compound of the formula (I) may be prepared by hydrolysis of a compound of the formula:- CN (IV) -14wherein Y, R and R1 to R9 are as previously defined for a compound of the formula (I).

The hydrolysis may be carried out under acidic or basic conditions, e.g. using an aqueous solution of either a suitable acid, e.g. hydrochloric or sulphuric acid, or a suitable inorganic base, e.g. sodium or potassium hydroxide, at from room temperature to the reflux temperature. When basic conditions are used hydrogen peroxide may optionally be present and also the product is obtained as a base salt which may be converted to the carboxylic acid by acidification in the work-up procedure.

) The compounds of the formula (I) wherein R10 is COOH and Y, R and R1 to R9 are as previously defined for a compound of the formula (I) may be prepared by acidic hydrolysis of a compound of the formula:- (V) -15IE 922386 wherein Y, R and R1 to R7 * 9 are as previously defined for a compound of the formula (I) and R17 and R18 taken together represent ethylene, said ethylene group being optionally substituted by phenyl or Cj-C^ alkyl (preferably methyl) . Preferably R17 and R18 taken together represent -CH2C (CH3) 2-.

The hydrolysis may be carried out using an aqueous solution of a suitable acid such as hydrochloric acid at from room temperature to the reflux temperature. 6) The compounds of the formula (I) wherein R10 is CONH2 and Y, R and R1 to R9 are as previously defined for a compound of the formula (I) may be prepared by partial hydrolysis of a compound of the formula (IV) wherein Y, R and R1 to R9 are as previously defined for a compound of the formula (I). The hydrolysis may be carried out using concentrated sulphuric acid at from 0°C to room temperature. 7) The compounds of the formula (I) wherein R10 is COOR11 * * * and Y, R, R1 to R9 and R11 are as previously defined for a compound of the formula (I) may be prepared by esterification of a compound of the formula (I) wherein R10 is COOH and Y, R and R1 to R9 are as previously defined for a compound of the formula (I) with an alcohol of the formula R^OH wherein R11 is as previously defined for this method. -16The reaction may be carried out under classical esterification conditions such as by using an excess of the alcohol and with acid catalysis, e.g. by sulphuric acid or p-toluenesulphonic acid, at from room temperature to the reflux temperature. The water generated during the reaction may be removed by azeotropic distillation or by the use of a dehydrating agent or a molecular sieve.

The esterification may also be carried out by reacting the acid with the alcohol in the presence of a dehydrating agent, e.g. dicyclohexylcarbodiimide or diethylazodicarboxylate/ triphenylphosphine (see 0. Mitsunobu, Synthesis, 1981, 1).

Alternatively the esterification may be carried out by first forming an activated ester or imidazolide derivative of the carboxylic acid, followed by reaction of the activated ester or imidazolide in situ with the alcohol of the formula RnOH. An activated ester may be formed by reacting the carboxylic acid with 1-hydroxybenzotriazole in the presence of a suitable dehydrating agent, e.g. 1-(3Ν,Ν-dimethylaminopropyl)-3-ethylcarbodiimide, and in a suitable solvent, e.g. dichloromethane, at room temperature. An imidazolide may be formed by reacting the carboxylic acid with 1,1'carbonyldiimidazole in a suitable solvent, e.g. dichloromethane, at room temperature. 8) The compounds of the formula (I) wherein R10 is COOR11 wherein Y, R, R1 to R8 9 and R11 are as previously defined for a compound of the formula (I) may be prepared by reaction of a compound of the formula:IE 922386 ....(VI) wherein Y, R and R1 to R9 are as previously defined for a compound of the formula (I) and Z1 is a suitable leaving group, e.g. chloro or bromo, with an alcohol of the formula RnOH wherein R11 is as previously defined for this method.

The reaction may be carried out in the presence of an acid acceptor, e.g. pyridine, and in a suitable solvent, e.g. dichloromethane, at from 0°C to room temperature. 9) The compounds of the formula (I) wherein R10 is COOR11 wherein Y, R, R1 to R9 and R11 are as previously defined for a compound of the formula (I) may be prepared by reaction of a base salt of a compound of the formula (I) wherein R10 is COOH and Y, R and R1 to R9 are as previously defined for a compound of the formula (I) (i.e. a carboxylate base salt) with a compound of the formula RnZz wherein R11 is as previously defined for a compound of the formula (I) and Zz is a suitable leaving group, e.g. halo, preferably bromo or iodo, or p-toluenesulphonyloxy. -18Preferred base salts of the compounds of the formula (I) for use in this method are the sodium and potassium salts. The reaction may be carried out in a suitable solvent, e.g. dimethylformamide or tetrahydrofuran, at from room temperature to the reflux temperature.

) The compounds of the formula (I) wherein R10 is CONR12R13 and Y, R, R1 to R9, R12 and R13 are as previously defined for a compound of the formula (I) may be prepared by reaction of a compound of the formula (I) wherein R10 is COOH and Y, R and R1 to R9 are as previously defined for a compound of the formula (I) with an amine of the formula R12R13NH wherein R12 and R13 are as previously defined for this method in the presence of a dehydrating agent, e.g. dicyclohexylcarbodiimide. The reaction may be carried out in a suitable organic solvent, e.g. dichloromethane, at 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, followed by reaction of the activated ester or imidazolide in situ with the amine of the formula R12R13NH. Suitable procedures for the formation of an activated ester or imidazolide are described in method (7). 11) The compounds of the formula (I) wherein R10 is CONR12R13 and Y, R, R1 to R9, R12 and R13 are as previously defined for a compound of the formula (I) may be prepared by reaction of a compound of the formula (VI) wherein Y, R, R1 to R9 and Z1 are as previously defined for a compound of the formula -19(VI) with an amine of the formula R1ZR13NH wherein R1Z and R13 are as previously defined for this method.

The reaction may be carried out in the presence of an acid acceptor, e.g. pyridine, and in a suitable solvent, e.g. dichloromethane, at from 0°C to room temperature. 12) The compounds of the formula (I) wherein R10 is CONR1ZR13 and Y, R, R1 to R9, R12 and R13 are as previously defined for a compound of the formula (I) may be prepared by reaction of a compound of the formula (II) wherein R15 is a suitable ester-forming group, e.g. C^-Cg alkyl or an alternative biolabile ester-forming group as previously defined (i.e. a compound of the formula (I) wherein R10 is COOR11) , or p-nitrophenyl, and Y, R and R1 to R9 are as previously defined for a compound of the formula (I) with an amine of the formula R1ZR13NH wherein R12 and R13 are as previously defined for this method. The reaction may be carried out in a suitable solvent, e.g. a C!-C4 alkanol, at from room temperature to the reflux temperature. The reaction is usually carried using an excess of the amine and in a sealed reaction vessel (e.g. a bomb). 13) The compounds of the formula (I) wherein R10 is COOH or CONR1ZR13 and Y, R, R1 to R9, R1Z and R13 are as previously defined for a compound of the formula (I) may be prepared by acidic hydrolysis of a compound of the formula:IE 922386 wherein Y, R and R1 to R9 are as previously defined for this method, R19 and R20 are either each Cj-04 alkyl or when taken together represent C2-C3 alkylene, said alkylene group being optionally substituted by C4-C4 alkyl, and R21 is -OH, -OR22 wherein R22 is a suitable ester-forming group that may be removed by hydrolysis, e.g. Cj-Cg alkyl or an alternative biolabile ester-forming group as previously defined, or NR12R13 wherein R12 and R13 are as previously defined for this method. The hydrolysis may be carried out using a suitable acid, e.g. hydrochloric acid or p-toluenesulphonic acid, in the presence of water. -21'eS«3«S A compound of the formula (VII) may be prepared by first forming the corresponding ketal of a compound of the formula (VIII) wherein R and R1 to R9 are as previously defined for this method by reacting with the corresponding alcohol under acidic conditions, e.g. see T.W. Greene and P.G. Wuts, Protective Groups in Organic Synthesis, Wiley-Interscience (2nd edition, 1991) , followed by N-alkylation of the ketal by a similar procedure to that described in method (14) for alkylation of a compound of the formula (VIII). 14) All the compounds of the formula (I) wherein Y, R and R1 to R10 are as previously defined for a compound of the formula (I) may be prepared by alkylation of a base salt (i.e. the N-deprotonated form) of a compound of the formula :- (VIII) -22wherein R and R1 to R9 are as previously defined for a compound of the formula (I) , with a compound of the formula Z3-Y-COORn or Z3-Y-CONR12R13 or with a base salt of a compound of the formula Z3-Y-COOH, as appropriate, wherein Y, R11, R12 and R13 are as previously defined for a compound of the formula (I) and Z3 is a leaving group, e.g. halo, preferably chloro, bromo or iodo, methanesulphonyloxy or ptoluenesulphonyloxy. The preferred base salts of the compounds of the formula Z3-Y-COOH are the alkali metal and alkaline earth metal salts, e.g. the sodium and potassium salts.

The preferred base salts of the compounds of the formula (VIII) are the alkali metal salts, e.g. the sodium and potassium salts.

The reaction may be performed by initial deprotonation of a compound of the formula (VIII) with a suitable base, e.g. sodium hydride, followed by reaction of the resulting anion with a compound of the formula Z3-Y-COORn, Z3-Y-CONR12R13 or a base salt of a compound of the formula Z3-Y-COOH, as required. The reaction may be carried out in a suitable solvent, e.g. Ν,Ν-dimethylformamide or tetrahydrofuran, at from 0°C to the reflux temperature and preferably at about room temperature. The reaction may also be carried out using potassium carbonate as the base and in 2butanone or acetone as the solvent at about the reflux temperature of the solvent.

Alternatively the reaction may be carried out under phase transfer conditions where a suitable base is sodium or potassium hydroxide. -23Where a compound of the formula (I) wherein R10 is COOH is required the product is obtained as a base salt which may be converted to the carboxylic acid by acidification in the work-up procedure.

) All the compounds of the formula (I) wherein Y, R and R1 to R10 are as previously defined for a compound of the formula (I) may be prepared by acylation of an indole of the formula :- ....(IX) or, where R is OH, a base salt thereof, or of a base salt of an indole of the formula :- -24wherein Y, R and R1 to R4 are as previously defined for a compound of the formula (I) and R23 is either OR11 or is NR1ZR13 wherein Ru, R12 and R13 are as previously defined for a compound of the formula (I), with a compound of the formula:- wherein R5 to R9 are as previously defined for this method and Z4 is a leaving group, e.g. halo, preferably chloro, and in the presence of a Lewis acid where R is not OH and optionally in the presence of a Lewis acid where R is OH. Suitable Lewis acids include aluminium chloride and diethylaluminium chloride.

The reaction may be carried out in a suitable solvent, e.g. toluene, at from room temperature to the reflux temperature.

The preferred base salts of the indoles of the formula (X) are the alkali metal and alkaline earth metal salts, e.g. the sodium and potassium salts. -25Where a compound of the formula (I) wherein R10 is COOH is required the product is obtained as a base salt which may be converted to the carboxylic acid by acidification in the work-up procedure.

Where a compound of the formula (I) wherein R is OH is required the compounds of the formula (IX) and (X) must be in the form of an enolate salt. Accordingly an indole of the formula (IX) where R is OH or a base salt of an indole of the formula (X) where R is OH should first be treated with one equivalent of a suitable base, e.g. calcium hydroxide, to form an enolate salt which may then be acylated with a compound of the formula (XI), optionally in the presence of a Lewis acid. Incorporation of an acidification step in the workup procedure affords a compound of the formula (I) wherein R is OH. 16) The compounds of the formula (I) wherein R10 is COOH and Y, R and R1 to R9 are as previously defined for a compound of the formula (I) may be prepared by oxidative cleavage of a compound of the formula:- (XII) -26wherein Z5 is -CH=CH2, alkyl) , -CH^fCjC4 alkyl) 2 or -C^CH and Y, R and R1 to R9 are as previously defined for this method.

The reaction may be carried out by ozonolysis or by treatment with aqueous potassium permanganate solution. 17) The compounds of the formula (I) wherein R10 is COOH and Y, R and R1 to R9 are as previously defined for a compound of the formula (I) may be prepared by oxidation of a compound of the formula :- ch2oh ....(XIII) wherein Y, R and R1 to R9 are as previously defined for a compound of the formula (I). A suitable oxidising agent for this purpose is chromium trioxide in pyridine. 18 18) The compounds of the formula (I) wherein R10 is COOH and Y, R and R1 to R9 are as previously defined for a compound of the formula (I) may be prepared by oxidation of a compound of the formula:IE 922386 co2h ....(XV) or a base salt thereof, wherein R24 is H or OH and Y, R and R1 to R9 are as previously defined for a compound of the formula (I). A suitable oxidising agent for this purpose is chromium trioxide-pyridine complex.

The oxidation may alternatively be carried out on a compound of the formula (XV) wherein R24 is H using 2,3-dichloro-5,6—dicyano—1,4-benzoquinone (DDQ) as the oxidising agent. -28The oxidation may alternatively be carried out on a 24 . compound of the formula (XV) wherein R is OH using manganese dioxide as the oxidising agent or under the conditions of the Swern oxidation reaction.

The starting materials of the formula (XIV) or (XV) wherein R24 is H may be prepared by reacting the corresponding lH-indole-l-magnesium halide derivative with a corresponding benzyl halide of the formula:- ....(XVI) wherein R5 to R9 are as previously defined for this method and Z6 is halo, preferably chloro or bromo, followed by N-alkylation of the indole by a similar procedure to that described in method (14).

A starting material of the formula (XIV) or (XV) wherein R24 is OH may be prepared by reacting the corresponding ΙΗ-indole-l-magnesium halide derivative with a corresponding benzaldehyde of the formula: - ....(XVII) -29wherein R5 to R9 are as previously defined for this method. 19) The compounds of the formula (I) wherein one of R6, R7 and R8 is a group of the formula :R14 I -OCH-Aryl and the remainder, together with Y, R, R1 to R5, R9, R10, R14 and aryl are as previously defined for a compound of the formula (I), may be prepared by reaction of a compound of the formula:- ....(XVIII) or a base salt thereof, wherein one of R25, R26 and R27 is OH and the remainder of R25, R26 and R27 are as previously defined in this method for the remainder of R6, R7 and R8, and Y, R, R1 to R5, R9 and R10 are as previously defined for this method, with a compound of the formula:R147 I Z'-CH-Aryl ....(XIX) -30wherein R14 and aryl are as previously defined for this method and Z7 is a suitable leaving group, e.g. halo, preferably chloro, bromo or iodo, methanesulphonyloxy or p-toluenesulphonyloxy.

The preferred base salts of the compounds of the formula (XVIII) are the sodium and potassium salts.

The reaction is preferably carried out using a base salt of a compound of the formula (XVIII) (i.e. a phenoxide) which may be generated in situ from the corresponding phenol of the formula (XVIII) using a suitable base, e.g. sodium or potassium hydroxide or sodium hydride, and in a suitable solvent, e.g. ethanol or Ν,Ν-dimethylformamide, at from 0°C to the reflux temperature. The reaction may 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.

) The compounds of the formula (I) wherein R10 is COOR11 or CONR1ZR13 and Y, R, R1 to R9, Rn, R12, R13, R14 and aryl are as defined for method (19) may be prepared by reaction of a compound of the formula (XVIII) wherein R10 is COOR11 or CONR1ZR13, as appropriate, wherein R11, R12, R13 and Y, R, R1 to R5 and R9 are as previously defined for this method and R20 * * * * 25 * to R27 are as previously defined for a compound of the formula (XVIII) in method (19), with a compound of the formula :R14 I HO-CH-Aryl ....(XX) wherein R14 and aryl are as previously defined for this method, in the presence of a suitable dehydrating agent, e.g. diethylazodicarboxylate/ -31triphenylphosphine. The reaction may be carried out in a suitable solvent, e.g. tetrahydrofuran, at from room temperature to the reflux temperature. 21) The compounds of the formula (I) wherein one of R6, R7 and R8 is a group of the formula:R14 I -CHO-Aryl, and the remainder, together with Y, R, R1 to R5, R9, R10, R14 and aryl1· are as previously defined for a compound of the formula (I), may be prepared by reaction of a compound of the formula:- ....(XXI) or a base salt thereof, wherein one of R28, R29 and R30 is a group of the formula: R14 I 8 -CH-Z8 -32and the remainder are as previously defined in this method for the remainder of R6, R7 and R8, Y, R, R1 to R5, R9, R10 and R14 are as previously defined for this method and ZB is as defined for Z7 in method (19) , with a base salt of a compound of the formula:Aryl-OH ....(XXII) wherein aryl” is as previously defined for this method.

A base salt of a compound of the formula (XXII) (i.e. a phenoxide) may be generated in situ from the corresponding phenol of the formula (XXII) using a suitable base, e.g. sodium or potassium hydroxide or sodium hydride, and in a suitable solvent, e.g. ethanol or Ν,Ν-dimethylformamide, at from 0°C to the reflux temperature. The reaction may also be carried by reacting a phenol of the formula (XXII) with a compound of the formula (XXI) in the presence of potassium carbonate and in a suitable solvent, e.g. 2-butanone, at up to, and preferably at, the reflux temperature of the solvent. 22) The compounds of the formula (I) wherein R10 is COOR11 or CONR1ZR13 and Y, R, R1 to R9, R11, R1Z, R13, R14 and aryl are as defined for method (21) may be prepared by reaction of a compound of the formula:IE 922386 ....(XXIII) wherein one of R31, R32 and R33 is a group of the formula: R14 I -CH-OH and the remainder are as previously defined in this method for the remainder of R6, R7 and R8, and Y, R, R1 to R5, R9, R10 and R14 are as previously defined for this method, with a compound of the formula (XXII) wherein aryl is as previously defined for this method, in the presence of a suitable dehydrating agent, e.g. diethylazodicarboxylate/ triphenylphosphine. The reaction may be carried out in a suitable solvent, e.g. tetrahydrofuran, at from room temperature to the reflux temperature. -34All of the above reactions and the preparations of novel starting materials used in the preceding methods are conventional and appropriate reagents and reaction conditions for their performance or preparation as well as procedures for isolating the desired products will be well known to those skilled in the art with reference to literature precedents and the Examples and Preparations hereto.

A pharmaceutically acceptable salt of a compound of the formula (I) may be readily prepared by mixing together solutions of a compound of the formula (I) and the desired acid or base, as appropriate. The salt may precipitate from solution and be collected by filtration or is recovered by evaporation of the solvent.

The compounds of the formula (I) are steroid 5osreductase inhibitors and they are therefore useful in the curative or prophylactic treatment of diseases or conditions such as acne vulgaris, alopecia, seborrhoea, female hirsutism, benign prostatic hypertrophy and male pattern baldness.

Certain compounds of the formula (I) are also useful in the treatment of human prostate adenocarcinomas.

The compounds of the formula (I) may be tested in vitro for steroid 5oe-reductase inhibitory activity using prostate tissue from rats or humans. -35The compounds of the formula (I) may be tested for potency in inhibiting rat steroid 5a-reductase using ventral prostate tissue from male rats. In determining inhibitory potency against rat prostatic 5Of-reductase the following procedure was employed:Rat prostates were minced into small pieces. The tissue was homogenised in Buffer A (20mM sodium phosphate, pH 6.5, buffer containing 0.32M sucrose and ImM dithiothreitol) with a Brinkman Polytron (Kinematica GmBH, Luzern), and then homogenised with a motor driven (lOOOrpm) Potter Elvehjem (teflon-toglass) homogeniser. Prostate particles were obtained by centrifugation at 105,000G for 60 minutes. The pellet was washed in 4 volumes of Buffer A and recentrifuged at 105,000G. The resulting pellet was dispersed in Buffer A (1ml per g of prostate tissue originally used) with a motor driven Potter Elvehjem homogeniser as described above. The particulate suspension was stored as lml samples at -70°C.

The following components, dissolved in Buffer B (40mM sodium phosphate buffer, pH 6.5), were added to a test tube: 500μ1 of [3H]-testosterone (lgCi, lnmol; Du Pont, NEN Research Products, Stevenage, U.K.), ΙΟΟμΙ of 0.5mM NADPH, a compound of the formula (I) dissolved in 5μ1 of dimethyl sulphoxide, and Buffer B to give a final reaction volume of lml. The mixture was warmed to 37°C and the reaction started by addition of an aliguot of prostate particulate suspension. The reaction mixture was incubated at 37°C for 30 minutes and then quenched by addition with vigorous mixing of -362ml of ethyl acetate containing 2C^g each of testosterone and 5a-dihydrotestosterone as carriers. The aqueous and organic layers were separated by centrifugation at 2000G for 10 minutes. The organic layer was transferred to a second test tube and evaporated to dryness under nitrogen. The residue was dissolved in 50-80μ1 of absolute ethanol and spotted onto a silica gel 60 F254 TLC plate (E. Merck, Darmstadt, Germany) and developed in chloroform:acetone (185:15).

The radiochemical content in the bands of the substrate (testosterone) and the product (5adihydrotestosterone) was determined with a RITA Radio TLC Analyser (Raytest Instruments Ltd., Sheffield, U.K.). The percent of recovered radiolabel converted to 5 ce-dihydrotestosterone was calculated and used to determine enzyme activity.

All incubations were conducted .so that no more than 15% of substrate (testosterone) was converted to product.

The experimentally obtained data for a range of inhibitor concentrations was computer fitted to a sigmoidal dose-response curve and concentrations of compound giving 50% inhibition of 5 a-reductase activity (IC50's) were calculated using a SIGFIT program (De Lean, A., Munson, P.J. and Rodbard, D., American Journal of Physiology, 235. E97 (1978)).

The compounds of the formula (I) may be tested for potency in inhibiting human steroid 5 «-reductase using tissue from hyperplastic human prostates. In determining inhibitory potency against human prostatic 5«-reductase the following procedure was employed:IE 922386 -37Frozen human prostate tissue was pulverised in liquid nitrogen using a steel mortar and pestle.

The powdered tissue was homogenised in 4 volumes of Buffer A (20mM sodium phosphate, pH 6.5, containing 0.32M sucrose, ImM dithiothreitol and 50μΜ NADPH) with an Ultra-Turrax (Janke and Kunkel GmBH & Co., Staufen i.BR., Germany). The homogenate was centrifuged at 500G for 5 minutes, to remove large particles of tissue, and the supernatant was then centrifuged at 100,000G for 1 hour. The resulting pellet was dispersed in Buffer A (1ml per g of prostate tissue originally used) with the UltraTurrax homogeniser. This particulate preparation was then filtered through 2 layers of cheesecloth and the filtrate was stored as 1ml samples at -70°C.

The following components, dissolved in Buffer B (20mM citrate phosphate buffer, pH 5.2), were added to a test tube: 500μ1 of [3H]-testosterone (ΙμΟϊ, lnmol; Du Pont, NEN Research Products, Stevenage, U.K.), ΙΟΟμΙ of NADPH regeneration system (5mM NADPH, 50mM glucose 6-phosphate, 5 units/ml glucose 6-phosphate dehydrogenase), a compound of the formula (I) dissolved in 5μ1 of dimethyl sulphoxide, and Buffer B to give a final reaction volume of 1ml. The mixture was warmed to 37°C and the reaction started by addition of an aliquot of prostate particulate suspension. The reaction mixture was incubated at 37°C for 30 minutes and then quenched by addition with vigorous mixing of 2ml of ethyl acetate containing 20μg each of testosterone and 5adihydrotestosterone as carriers. The aqueous and organic layers were separated by centrifugation at 2000G for 10 minutes. The organic layer was -38transferred to a second test tube and evaporated to dryness under nitrogen. The residue was dissolved in 50—80μ1 of absolute ethanol and spotted onto a silica gel 60 F254 TLC plate (E. Merck, Darmstadt, Germany) and developed in chloroform:acetone (185:15).

The radiochemical content in the bands of the substrate (testosterone) and the product (5cedihydrotestosterone) was determined with a RITA Radio TLC Analyser (Raytest Instruments Ltd., Sheffield, U.K.). The percent of recovered radiolabel converted to 5a-dihydrotestosterone was calculated and used to determine enzyme activity.

All incubations were conducted so that no more than 15% of substrate (testosterone) was converted to product.

The experimentally obtained data for a range of inhibitor concentrations was computer fitted to a sigmoidal dose-response curve and concentrations of compound giving 50% inhibition of 5 ce-reductase activity (IC^'s) were calculated using a SIGFIT program (De Lean, A., Munson, P.J. and Rodbard, D., American Journal of Physiology, 235. E97 (1978)).

The compounds of the formula (I) may be tested for potency in inhibiting steroid 5 ce-reductase activity in human prostate adenocarcinomas using cell lines DU145 and HPC36M. In determining inhibitory potency against 5α-reductase the following procedure was employed:IE 922386 -39Human prostate adenocarcinoma cell lines were grown in Dulbecco's Modified Eagles medium (DMEM) containing 5% serum. The cells were recovered from the medium by centrifugation, washed in serum free DMEM and suspended at 5-10 χ 106 cells/ml. in serum free medium.

The following components were added to a test tube: ΙΟμΙ of [3H]-testosterone (Ιμϋΐ, 20 pmol) dissolved in ethanol (Du Pont, NEN Research Products, Stevenage, U.K.) and 5μ1 of an ethanol solution of a compound of the formula (I). The ethanol was evaporated under nitrogen and the testosterone and the compound redissolved in 0.25ml of serum free medium containing 0.25μιηο1 NADPH. The mixture was warmed to 37°C and the reaction started by addition of 0.25ml of cell suspension (1.2-2.5 χ 106 cells). The reaction mixture was incubated at 37°C for 2 hours and then quenched by addiction with vigorous mixing of 1.5ml of ethyl acetate containing 20μg each of testosterone and 5a-dihydrotestosterone as carriers. The aqueous and organic layers were separated by centrifugation at 2000G for 10 minutes. The organic layer, containing testosterone and its metabolites, was transferred to a second test tube and evaporated to dryness under nitrogen. The residue was dissolved in 50-80μ1 of absolute ethanol, spotted onto a silica gel 60 F254 TLC plate (E. Merck, Darmstadt, Germany) and developed in dichloromethane:acetone (185:15). -40The radiochemical content in the bands of the substrate (testosterone) and the product (5 adihydrotestosterone) was determined with a RITA Radio TLC Analyser (Raytest Instruments Ltd., Sheffield, U.K.). The percentage of recovered radiolabel converted to 5 α-dihydrotestosterone was calculated and used to determine enzyme activity.

All incubations were conducted so that no more than 15% of substrate (testosterone) was converted to product.

The experimentally obtained data for a range of inhibitor concentrations was computer fitted to a sigmoidal dose-response curve and concentrations of compound giving 50% inhibition of 5o-reductase activity (IC50's) were calculated using a SIGFIT program (De Lean, A., Munson, P.J. and Rodbard D., American Journal of Physiology, 235. E97 (1978)).

For human use, the compounds of the formula (I) can be administered alone, but will generally be administered in admixture with a pharmaceutical carrier selected with regard to the intended route of administration and standard pharmaceutical practice. For example, they can be administered orally in the form of tablets containing such excipients as starch or lactose, or in capsules or ovules either alone or in admixture with excipients, or in the form of elixirs, solutions or suspensions containing flavouring or colouring agents. They can be injected parenterally, for example, intravenously, intramuscularly or subcutaneously.

For parenteral administration, they are best used in the form of a sterile aqueous solution which may contain other substances, for example, enough salts or glucose to make the solution isotonic with blood. -41For oral and parenteral administration to human patients, the daily dosage level of the compounds of the formula (I) will be from 0.01 to 20 mg/kg (in single or divided doses) and preferably will be from 0.1 to lOmg/kg except for the treatment of human prostate adenocarcinomas where doses of up to 20mg/kg may be used. Thus tablets or capsules of the compounds will contain from lmg to 0.5g of active compound for administration singly or two or more at a time, as appropriate. The physician in any event will determine the actual dosage which will be most suitable for an individual patient and it will vary with the age, weight and response of the particular patient. The above dosages are exemplary of the average case; there can, of course, be individual instances where higher or lower dosage ranges are merited, and such are within the scope of this invention.

Alternatively, the compounds of the formula (I) can be administered in the form of a suppository or pessary, or they may be applied topically in the form of a lotion, solution, cream, ointment or dusting powder. For example, they can be incorporated into a cream consisting of an aqueous emulsion of polyethylene glycols or liquid paraffin; or they can be incorporated, at a concentration between 1 and 10%, into an ointment consisting of a white wax or white soft paraffin base together with such stabilizers and preservatives as may be required. -42The compounds of the formula (I) may also be administered together with an «-antagonist (e.g. prazosin or doxazosin), an antiandrogen (e.g. flutamide) or an aromatase inhibitor (e.g. atamestane), particularly for the curative or prophylactic treatment of benign prostatic hypertrophy.

Thus the invention further provides :i) a pharmaceutical composition comprising a compound of the formula (I), or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable diluent or carrier; ii) a compound of the formula (I), or a pharmaceutically acceptable salt or composition thereof, for use as a medicament; iii) the use of a compound of the formula (I), or of a pharmaceutically acceptable salt or composition thereof, for the manufacture of a medicament for inhibiting a steroid 5areductase; iv) the use of a compound of the formula (I), or of a pharmaceutically acceptable salt or composition thereof, for the manufacture of a medicament for the curative or prophylactic treatment of acne vulgaris, alopecia, seborrhoea, female hirsutism, benign prostatic hypertrophy, male pattern baldness or a human prostate adenocarcinoma; -43v) a method of treatment of a human to inhibit a steroid 5a-reductase which comprises treating said human with an effective amount of a compound of the formula (I) or with a pharmaceutically acceptable salt or composition thereof; vi) a method of treatment of a human to cure or prevent acne vulgaris, alopecia, seborrhoea, female hirsutism, benign prostatic hypertrophy, male pattern baldness or a human prostate adenocarcinoma which comprises treating said human with an effective amount of a compound of the formula (I) or with a pharmaceutically acceptable salt or composition thereof; and vii) novel intermediates of the formulae (IV), (VIII) and base salts thereof, (XIII), (XIV), (XV) and base salts thereof, (XVIII) and base salts thereof, (XXI) and base salts thereof, (XXI) and base salts thereof and (XXIII).

The following Examples illustrate the preparation of the compounds of the formula (I):IE 922386 —44 — EXAMPLE 1 (R,S)-4-(3-i4-(l-r 4-(2-Methylpropyl)phenyl1 ethoxy)benzovllindol-l-yl)butanoic acid aq.NaOH,THF,CH 30H t A solution of (R,S)-4-(3-[4-(l-[4-(2methylpropyl)phenyl]ethoxy)benzoyl]indol-l-yl)butanoic acid ethyl ester (3.8g) (see Example 21) in tetrahydrofuran (THF) (35ml) and methanol (35ml) was treated with 2N sodium hydroxide solution (35ml). After stirring at room temperature for 2 hours the mixture was -45cautiously concentrated in vacuo to a volume of about 50ml then cooled in an ice-bath and acidified with 2N hydrochloric acid solution. The acid phase was extracted with ethyl acetate (100ml), the organic extract dried (sodium sulphate) and concentrated in vacuo to provide the title compound as a white foam, (3.27g), m.p. 57°C. Found: C,77.00; H, 6.88; N,2.90; C31H33NO4 requires: C,76.93; H,6.88; N,2.99%.

^-NMR (CDC13) : δ= 0.95(d,6H), 1.70(d,3H), 1.90(m,lH), 2.25(m,2H), 2.40(t,2H), 2.49(d,2H), 4.30(t,2H), 5.50(q,lH), 6.95(d,2H), 7.15(d,2H), 7.27-7.45(m,5H), 7.59(s,lH), 7.79(d,2H), 8.45(m,lH) ppm.

EXAMPLES 2 to 20 The following compounds of the general formula :co2h or base salts thereof, were prepared by hydrolysis of the corresponding ethyl esters (see Examples 22 to 38, 42 and 43) by similar methods to that used in Example 1. •° χ o z ω II to O ω Q co or z. x 0.90 (t,3H), 0.95(t,3H), 1.25-1.65(m,4H), 1.70- 1 10 CD X 'E ci CD X CM e[ o CM CM X e[ ci CM X CN ci 10 CM X CM_ uT CO cm’ 4.20(1,2H), 5.15(m,1H), X CM XJ Lfi l< X CM xi o’ CD co 7.20-7.40(m,5H), 7.50 (s,1H), 7.70(d,2H), 8.30(m,1H) ppm. Found: C.71.86; H.5.93; co χ Ο όο CM X CM «0 ..9 II CO O ω o to or z X X co X3 10 N X co +-» cf X ll* -Ω Μ-» o’ o CM 1 O oo x— o C) N ό N CO X CM_ o’ 10 CM X CM o’ CO N X col ql L_~ -Ω X CM xi o o l< X σ ci 10 10 X CM o’ CO r-2 X CM xi o CM r-2 X xi ci CO X CN_ xi 10 N r-2 7.70(d,2H), 8.00(s,1H), E ex ex X £ 10 CM CO to o oL O Vi >, to CZ < T“ CO CM Z σ> Η O X => 2 cr o S? CD CM z + N co 10 + E CD N T ' Q- O E cn cn X X o o cn ) X cn ff o X o x o o CD or X X m or X X or X X 1 1 co > X X o o ( 1 X ό 111 z CM co Optical Rotation/ Analysis/NMR Found: C,73.30; H.5.66; N.3.06; C27H25NO4.H2O requires: C,72.78; H.6.11; N,3.14%. 1H-NMR (d6-DMSO): δ = 1.95(m,2H), 2.20(t,2H), 2.25(s,3H), 4.25(t,2H), 5.10(s,2H), 7.10(d,2H), 7.15-7.35(m,6H), 7.60 (d,1H), 7.78(d,2H), 8.00(s,1H), 8.20(m,1H) ppm.10 II CO v- tO 1X3 I o X CO x Λ4 £ 5Ξ CM 'T. Oco' w to X> f-. j X -ng ί5.ϊ® n S X J Zinocoino7:oc g ¢0 ® cr cq ' If) CM CM O CM - cn q_ LL Ζ Ο 2 Z J· T-2 CM Tt r< 2-hJ CL Z/UJ 427 (M+) I T- V m.p. CO 1 or co X o o / o X O d co ) y X / o-/ o / co or x X co or X X Dd X X > 1 co CM X o 1 1 CO CM X o X ό LU Z in Έ: B or ο ζ 8 ” ~ ro 5- *— Ο < II CO o ω Q 1 co 2- or z 1 X -sx I 04 Ό Έin y? to . -r-: X-^ to - o’in σ> co o «-' 2.30(s,6H), 2.35(t,2H), 2.45(d,2H), 4.15(t,2H), X OJ τ ci to to LE v— cr in to in 1 in l< x 04 o 1— l< 7.40(m,6H), 8.30(m,1H) E CL CL Found: C,76.83; H.6.95; ox o co . . 04 8* o oo cr oo Φ CO o x ..7 ro E o l—» tD ·*—* O Cb oj g CL O [a]25 -68.4’ (c = 1 D in methanol) II LO n o Q O Cb Σ z 1 X X co •Q O Ο- Χ to τί in CD o X 04 e[ in 04 oj x o co τ— X OJ T3 of 04 X rj o CN 4.30(t,2H), 5.50(q,1H), X O4_ V in i— l< x 04. τί in co to 7.27-7.45(m,5H), 7.59 (s,1H), 7.79(d,2H), 8.45(m,1H) ppm. to co 04 z‘ Λ O co . o o + Ν Ε In CO ο. Ο 1 Ε t- «0 «0 2 X O a <0 CO / X X / o- o CO γ 4 X ) b- X t / _ Cb o X Q o / X o o / cn CO or X o X co m Cb X o X X X co I «0 > oi I ci X o o 1 1 X LLI ό z co CD Optical Rotation/ Analysis/NMR CO T'-' — 5 In 5.Ϊ S -r σ7 Ο-π ω - to T„ 2? - ω§οο°:ώσ in X '« °’..§5 -σ oo join S--S-SciS--S- E I Zominoooc ο°ί -10)00^010)’’to. ll 2 Ο O / ό ν ώ s’ q. • - O £2 ii -c ¢0 m1 . _ τ ^Tin J -Ocn ω m J o r- Z 2 ·«- m !p - β . in in °° SO ° ω 5? & ™ S *3.23 ^E£SiS . E =j Z 0 in in co in c 0 S’00- -r ° ° °> E a- U. Ζ 2 Z cn 'i tfl£s a m/z 498 (M+1)* 1 4o E 1 1 or « I o CJ / X / o—ς x(_/ Xs CO O 5 I P 0 / co X X X m or X X X co X o X > CO X o f co CM X 0 f X 6 LU 2 CN co c g c— rt o oc g CL O OC z w (Λ >> rt c < Found: C.69.96; H.5.95; -o o- CO ώ °θ 2 cv '5 z“ cr .. 1. tO OJ T d CV rah- CM · ZOO II —-—co O -q «25· to T3 -— '-'Z DC Z o o z cv τί in' co ci □? ^E o' co z t— σ uT in in Z cv «i cT r- v· Z CV o r-' z CV τί cT o ri ζΓ CV τά o' co ri Z? CV E^ o' CV ri z CV TO. in co ri ζΓ τ— o' •V; ri Z V”’ e[ ci CV CO z o' σ> ri E CL CL Found: C,63.33; H.5.09; || co co z* co cn •S’ z O it 1° is °,o grt S.2 Z =j fc σ o2? -o CV h- cv z in co II CO cn o Q O DC 2 Z 1 z z CV E^ o' CV ci z' C5 z CV (o' CV z CV C2 •v ci z CV o CD co z' ^r uT co in Z co E^ o in ri 1 O CV ri z CV in r— ri X siS if in ri E CL CL Z E^ if co co N E oo + co σ> v + V 2 ci E p 1 CO Z / O-( « Z o o o /=^ DC m z o y_/ z , o-< o o / / / CD oc Z z «Λ OC Z z DC Z z 1 CM z o cm z o 1 χ ό LU Z LO V“ Isolated as the sodium salt o TO O CT TO O Q. O cr 2 z To to >, to c < Found: C,76.59; H.7.52; II 0 CM **7o z CM 0 in 0 TO ^z” CM cm - co z 0 co CM d z’ co co to r- d io S? ω to Ε 0 cn 0 11 00 'Τώ O Q O cr 2 z 1 z t 0 co x— z in £ tJ- tO z CO_ d st ™ xt if in -Mcn xt 1-' CM 5.40(q,1H), 6.95(d,2H), 7.10(d,2H), 7.24-7.40 (m,5H), 7.55(s,1H), 7.75(d,2H), 8.35(m,1H) E CL Q. Found: C.76.69; H.6.87; < 0 z CO X 0 co 0 to cn CM Z~ in to to z‘ CO l·-· to l·- d co ω co -0 0 co . d 11 in M 'To IO 0 Q V O 0 cd in cr 2 z I ±3 z CM aT co CM Z CM e[ 0 CM CM 2.50(m,2H), 4.28(t,2H), z CM XJ o' ό co TO to r-i Z Z v-_ CM στί to 0 TO 0 in r>-’ z CM xf CO in td ΣΕ TO E[ m xt rd 7.55(s,1H), 7.80(d,2H), E CL CL z e[ 0 xt co σ ω L_ CM z cr ω OJ Z + ♦ -ΰ E 00 cn Tt + 0 t- xt V —’ Q. O 1 E • 1 CO CO X X 0 0 co X 0— • 0 y_ J _) cr X 0 ό co \ X 0 / ) — 0 cr z z in cr z z DC z z 1 m· 1 «0 CM CM > z z 0 0 1 X 0 00 cn LLJ Z -56EXAMPLE 21 (R,S)-4-(3— Γ 4-(1-Γ4 —f 2-Methylpropyl)phenyl1 ethoxy)benzoyl]indol-l-yl)butanoic acid ethyl ester A suspension of sodium hydride (60% dispersion in oil, 716mg) in dry dimethylformamide (DMF) (15ml) at 0°C and under a nitrogen atmosphere was treated dropwise with a solution of 4-(3-[4-hydroxybenzoyl]indol-l-yl)butanoic acid ethyl ester (see Preparation 1) (5.24g) in dimethylformamide (30ml). After stirring for one hour at room temperature a solution of ce-methyl-4-(2-methylpropyl) benzyl bromide (see Preparation 23) (3.95g) in dimethylformamide (5ml) was added to the mixture at 0°C. The resultant mixture was stirred overnight at room temperature. The reaction was partitioned between IN hydrochloric acid solution (100ml) and ethyl acetate (200ml). The separated organic layer was washed -57successively with IN sodium hydroxide solution (100ml), saturated aqueous brine (100ml) and then water (100ml). The organic layer was dried (MgSO4) and concentrated in vacuo to provide a yellow oil. Column chromatography (silica, 4.1 hexane/ethyl acetate) provided, after evaporation of the appropriate fractions, the title compound, (3.8g). Found: C,77.47; H,7.29; N,2.74; C33H37NO4 requires: C,77.63; H,7.48; N,2.73%.

^-NMR (CDC13) : δ = 0.91(d,6H), 1.35(t,3H), 1.70(d,3H), 1.90(m,lH), 2.20(m,2H), 2.31(m,2H), 2.49(d,2H), 4.13(q,2H), 4.25(t,2H), 4.50(q,lH), 6.95(d,2H), 7.15(d,2H), 7.277.45(m,5H), 7.55(s,lH), 7.88(d,2H), 8.45(m,lH) ppm.

EXAMPLES 22 to 32 The following compounds of the general formula:- CO2CH2CH3 were prepared by alkylation of the corresponding phenol derivatives (see Preparations 1, 3 and 4) with the corresponding alkyl bromides (see, e.g., Preparations 20 to 26) by similar methods to that used in Example 21.

Optical Rotation/ Analysis/NMR o' m t? -o- in m in o~X o r- r- 11 X - ™ μ· - x~ *o . . ιηΧΞ· Qoi- . . in . o “ ΟΟωζ Xh-ί -σ o cm 2^-^-ΕΕχσΕυτΕ Ξ ~· *ο4 * Ζιηοιηιη^οιηιηιοοο Ο °ί X J-OWCOr^T-r-pCN u_ZOX ςτ- ο χ-' cm ο- 'Φ ιη γ-' Ή co Ξ- Si'S ΐ? <ο co S J' ό 2/ Ε ZSixi'T-.CMCnCMU'CO Q^jcM^ttiDr^^co — x X J X X X £ X Qi co * °ί °ί - °Ί ;> -—-33. E cr ^3^^3^ Zc/oirfc/crfc/oLr/ d 'CMh-COv-cOCM-ttH. Q_ i’d-dcM'dlrit^t^l^ CL N E 526 (Μ+1)+ 484 (M+1)+ m.p. CC) I f*- or ο X ο χ° \) ο / « X 0 ( ) co )-' X / 0—( 0 / co or X X in or X X or X X σ> X ο 1 1 CO CM X 0 1 X ό LU Z CM CM CO CM Optical Rotation/ Analysis/NMR in fp co σ X ^τ-' τ' <4 · · <4 CM & X oZ /¾ -* p: § άί ιή ? x- S OO CT-t ο τη 2: r- 9· in 2 1H-NMR (CDCI3): δ = 1.20(t,3H), 1.65(d,3H), 2.20(m,2H), 2.30(m,2H), 2.35 (s,3H), 4.10(q,2H), 4.20(t,2H), 5.39(q,1H), 6.95(d,2H), 7.15(d,2H), 7.27-7.45(m,5H), 7.55 (s,1H), 7.75(d,2H), 8.35(m,1H) ppm. m/z 456 (M+1)+ CD ί co 2 Ν’ A-o Ep I 1 x n X o / CJ X 0 • ^3 p o / Δ) <*> )-' I / 0—ς o / co X X X to X T X X X X 1 co CN X o 1 co CN X 0 1 x ό LU Z ^r CM in CN Optical Rotation/ Analysis/NMR . - OO 00 - - - . oo -γ-' ~r X CD . . CM 11 x CM CM CM x § z co ( ε .1= - λ; ω o m co zj ο _”o τ- co cm g -τ- § S ?S 2 T3 g nO) O E 0Ϊ Γγ E ; X CO Zinincoodcjinoc q °i Ss. ’cncocov-T-T-ioco^ llZOO - 0v-'(\Firisssa1H-NMR (CDCI3): δ = 1.20(t,3H), 2.20(q,2H), 2.40(t,2H), 4.20(q,2H), 4.40(t,2H), 5.10(s,2H), 7.00(d,2H), 7.20- 7.55(m,7H), 7.60(s,2H), 7.80(d,2H), 8.40(d,1H) PPm. m/z 484 (M+1)+ + 2 + £ 2 4o E 1 I h- cd '.....C........i3IIa co Cd X X Cd X X Cd X X co CM X o 1 I x ό LLI Z co CM r- CM Optical Rotation/ Analysis/NMR1H-NMR (CDCI3): δ = 0.95(d,6H), 1.20(t,3H), 1.65(d,3H), 1.85(m,1H), 2.10(m,2H), 2.25(t,2H), 2.30(s,6H), 2.45(d,2H), 4.10(q,2H), 4.15(t,2H), 5.35(q,1H), 6.60(d,2H), 7.05-7.40(m,8H), 8.35(m,1H) ppm. .X -x; —o x 11 X ™x H ° - ««?e io '— O cxj <£> 2: ° Q T- . CJ co 00 i X X X r- X £ co Zr ej ™ ™ ™ 2 *£, ,ω, 2- X 5- Z in ίο ο oo o n ο E • CO CO CO -Ϊ- CO CM r CO Ε- ο Έ cj Tt cb (< JEr-i ex m/z 540 (M+1)* T— + o 2 co iE E 1 t N. Cb <0 I o X / o—ς « )—' x / o-( o / CJ X o X* \ ) \_/\ o / to cb co X o X cb co X o X Cb X X > t co CM X o 1 1 x ό LU Z co CJ co 04 Optical Rotation/ Analysis/NMR1H-NMR (CDCI3): δ = 0.90(d,6H), 1.20(t,3H), 1.60(d,3H), 1.80(m,1H), 2.45(d,2H), 4.20(q,2H), 4.85(s,2H), 5.40(q,1H), 6.95(d,2H), 7.10(d,2H), 7.25-7.35(m,5H), 7.55 (s,1H). 7.75(d,2H), 8.40(m,1H) ppm.1H-NMR (CDCI3): δ = 1.25(t,3H), 1.65(d,3H), 2.20(m,2H), 2.35(t,2H), 4.15(q,2H), 4.30(t,2H), 5.35(q,1H), 6.95(d,2H), 7.25-7.50(m,6H), 7.60(s,1H), 7.80(d,2H), 8.35(m,1H) ppm. m/z co + 525 (M+1)+ 4o Ε o 1 I N. X 0 X 0 X / O-/ \_) CJ )-' X / 0—\ 0 / δ δ ο / co X X X tn X X X X X X >- CN X 0 ( co CN X 0 t x ό LU Z 30 co Optical Rotation/ Analysis/NMR11 χ 2 ^z S ^Z XJ TS E E § ™ 00 O -.S-. ~ ^t° ™ Z 1 1 1 to 1 cr oo . F ™ --. cm ‘f- cm ;> x- 32 d S S S £ S- zinw’-tnoinooo c • cn cm p cm χ— σ> χ- xf r-~ q_ F d x-‘ -Scm xt xt rd rd rd cl m/z 552 (M+1)* 4d E z. 1 cr m X o o / co cr z cr z cr z 1 X ό LU Z CM TO -64EXAMPLE 33 (S)-4-(3-Γ 4-(1-Γ4-(2-Methvlpropyl)phenyl1 ethoxy)benzoyl1indol-l-yT)butanoic acid ethyl ester A solution of 4-(3-[4-hydroxybenzoyl]indol-l-yl)butanoic acid ethyl ester (see Preparation 1) (500mg), (R)-l-(4-[2-methylpropyl]phenyl)ethanol (see Preparation 17) (256mg) and triphenylphosphine (410mg) in THF (20ml) was treated with diethylazodicarboxylate (DEAD) (0.27ml) and the mixture stirred at room temperature overnight. Evaporation of the reaction mixture onto silica gel (5g) followed by flash chromatography (silica, 3:1 hexane/ ethyl acetate) gave, after evaporation of the appropriate fractions, the desired compound as a pale yellow gum, (413mg) , m/z = 511 (M+) . -65H.P.L.C. (Cyclobond DMP column eluting with 1:1 1% triethylammonium acetate, pH4.1/CH3CN at 0.7ml/min.) rt= 86.09 min. (100%). lH-NMR (CDC13) : 6= 0.95(d,6H), 1.25(t,3H), 1.70(d,3H), 1.85(m,lH), 2.20(m,2H), 2.30(t,2H), 2.45(d,2H), 4.10(q,2H), 4.25(t,2H), 5.40(q,lH), 6.95(d,2H), 7.15(d,2H) 7.25-7.40(m,5H), 7.55(s,lH), 7.75(d,2H), 8.35(m,lH) ppm.

The title compound may also be prepared by resolution of the product of Example 21 using chiral HPLC (Chiralpak AD column, eluant = 9:1 hexane/ethanol, flow rate = 12ml/min.). The first eluted compound was (R)-4(3-[4-(1—[4-(2-methylpropyl)phenyl]ethoxy)benzoyl]indoll-yl) butanoic acid ethyl ester, rt = 24min. , [a]25 D +52.1° (c=2 in dichloromethane), and the second eluted compound was the title compound, rt = 27min., [a] 25 - 53.8° (c=2 in dichloromethane).

EXAMPLES 34 to 37 The following compounds of the general formula:- co2ch2ch3 were prepared by condensation of the corresponding phenols or alcohols (see Preparations 1, 2 and 27) with the corresponding phenols or alcohols (see, e.g. Preparations 17 and 18) by similar methods to that used in Example 33.

See Example 33 also.

X 5 ζ Ο _i οί X δ = 0.95 1.60 (m,2H), 1.65(d,3H), 2.20 (m,2H), 2.30(t,2H), 2.50 (m,2H), 4.10(q,2H), 4.28 (t,2H), 5.35(q,1H), 6.80 (d,2H), 7.05(d,2H), 7.30- 7.45 (m,3H), 7.50(d,2H), 7.58 (s,1H), 7.80(d,2H), 8.40(m,1H) ppm. o CN II to m o Ω O X 2 z 1 X (t,3H), 1.69(d,3H), 2.20 (m,2H), 2.25(s,3H), 2.35- 2.50 (m,2H), 4.15(q,2H), 4.30 (t,2H), 5.40(q,1H), 6.80 (d,2H), 7.05 (d,2H), 7.35-7.50 (m,3H), X X E Cl CL co ο Ω Ο X Ζ 1 X X co cP CN 5? 7.50(d,2H), 7.60 ( 7.85(d,2H), 8.45(r + Ν 00 σ> Ε σ> Tt Ω. Ο I 1 Ε o X co o X o / < ) Η- J / o 1 to X o to \ T λ -5 >— o co X X X to X X X X X X 1 co 1 co >- X υ o 1 X ό (Ο N- ω ζ co CO — 68 — EXAMPLE 38 4-(3-r4-Benzyloxvbenzoyllindol-l-vl)butanoic acid ethvl ester A cooled (0°C) suspension of sodium hydride (3.40g of a 55% dispersion in mineral oil) in dimethylformamide (50ml) was treated with a solution of 3-(4benzyloxybenzoyl)indole (see Preparation 5) (20.Og) in dimethylformamide (100ml). The resultant orange suspension was allowed to stir for 1 hour at 20°C. The mixture was cooled to 0°C and ethyl 4-bromobutyrate (11.0ml) was added. The mixture was stirred for 2 hours at room temperature, cooled to 0°C and treated with IN aqueous hydrochloric acid (100ml) and ethyl acetate (200ml). The organic layer was separated and washed with water (100ml), IN aqueous hydrochloric acid (100ml), -69saturated aqueous sodium bicarbonate (100ml) and brine (100ml). Evaporation of the ethyl acetate gave an orange gum which was purified by flash chromatography (silica, eluant = 3:1 hexane/ethyl acetate then 2:1 hexane/ethyl acetate) to give, after combination and evaporation of the appropriate fractions, the title compound (16.5g), m.p. 83°C.

JH-NMR (CDC13) : 6= 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,lH), 7.85(d,2H), 8.40(m,lH) ppm.

EXAMPLES 39 to 43 The following compounds of the general formula:- CO2CH2CH3 were prepared by similar methods to that used in Example 38 using the corresponding indoles (see Preparations 5 to 8) and the corresponding ethyl bromoalkanoates as the starting materials.

Analysis/NMR Found: C,73.65; H.6.34; N.2.94; C29H29NO4.H2O requires: C,73.55; H.6.60; N,2.96%. 1H-NMR (CDCI3): δ = 1.30(t,3H), 2.30 (m,1H), 2.45(t,2H), 2.65(s,3H), 4.20 (q,2H), 4.25(t,2H), 5.15(S,2H), 7.05 (d,2H), 7.10-7.45 (m,9H), 7.80(d,2H) ppm.1H-NMR (CDCI3): 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(m,1H) ppm. m/z . + b- X 4o ELx 1 K. or 0 0 c 0 / c / <0 or X rt X 0 m or X rt X 0 tr rt X 0 X 1 rt CM X 0 ( 1 rt CM X 0 1 X ό LlJ Z cn co 40 Analysis/NMR1H-NMR (CDCI3): δ = 1.30(t,3H), 4.25 (q,2H), 4.85(s,2H), 5.20(s,2H), 7.05 (d,2H), 7.25-7.50 (m,4H), 7.60(s,1H), 7.85(d,2H) ppm. Not characterised. m/z 414 (M+1)* « 4o E^ 1 i K Dd P 0 / co X 0 CO / - O X / O-ζ O / co Dd X X in Cd X X Cd X X > « CM X 0 1 1 in X 0 1 x ό LU Z CM Analysis/NMR £ £ 10 - . - — °oor’, τς?ς?τ -τ-Π: ιι ™ Em J cm F OTOT3CM^C?N/COU?Tt oFtr/^^1·0 - E 00 O co x'F, F F Ή-|d ΌΌ ZXcmoooooo'o C 'TOpCMincococoinco F d-S CM Cxi Xt CO |d |d rd Q. Z/LU 498 (M+1)* 4d E·^ 1 r- DC « X o « 1 X / o—ς \_) X / O-/ o / ¢0 cr X to DC X DC X > 1 M· CM X o 1 X ό UJ z 43 -73The following Preparations illustrate the preparation of certain starting materials used in the previous Examples :PREPARATION 1 4-(3-r4-Hydroxybenzoyllindol-l-vl)butanoic acid ethvl ester H2,w% Pd/C, T CH3CO2C2H5 A solution of 4-(3-[4-benzyloxybenzoyl]indol-1yl)butanoic acid ethyl ester (see Example 38) (13.4g) in ethyl acetate (300ml) was hydrogenated at 4.15 χ 105 Pa (60 psi) in the presence of 10% palladium-on-charcoal (3g) at room temperature for 4 hours. The catalyst was removed by filtration of the reaction through a -74cellulose-based filter aid and the filtrate was concentrated in vacuo to a pale pink solid. Trituration with cold diethyl ether gave a white powder, (8.24g). Found: C,71.78; H,6.02; N,3.98; C21H21NO4 requires: C,71.44; H,6.04; N,3.94%.

^-NMR (CDC13) : 6= 1.25(t,3H), 2.22(m,2H), 2.35(m,2H), 4.15(q,2H), 4.30(t,2H), 6.95(d,2H), 7.32-7.45(m,3H), 7.65(S,1H), 7.70(d,2H), 8.47(m,lH) ppm.

PREPARATIONS 2 to 4 The following compounds of the general formula:- OH were prepared by hydrogenation of the corresponding benzyl ethers (see Examples 39 to 41) by similar methods to that used in Preparation 1. -s ox CO cSx _;X E CL OO S X CL X co CM t τ CO Ό cv - . z E uT c ω o X σχ E rxc\i - t U0 « Q_ in ο o §; rt co rt X ex CM cv co cv E, o' 2? E~ ^-x co -X ^x -X CO 3H), -7.3E (m,1l in χ Γ- £ CN o cv co cf'T ri 3H) (t,2 co CO 't—J* co -»-T τ** θ o ' f\j ΣΕ o m —' CM CO z J O cv in . rt o . · 1,6.16; I s; C,72 ci η·' I r. CV . ii rSr &o co m cv cv M- GO .E in CV 1- 00 V χ χ ' cv cv GO I ω . ω °°. -o • •S'V TO TO OC 30; quit Spin o O co ' co O o in cv '«in o o cv £ Q N I S Q QCOS h* ”f O - 'T. - O O z oo .. z IMR ( (t,2H) (s,br (t,1H) — X X DC co ^X X Ct cv χ. « -rj co 2 -S X3 co c < §1 z m ο σ Z o in Z o in O a Li- O ' xr co cv •T CV CO k 5- cv ’ cd in r s + + N ° V 't V E 1 oo X co 2 • cv X co S 4o 1 E CO CD OC X HO X co tf) or X CH X co oc CH X X 1 co ( co > X X X o o o 1 1 1 ep. 0. CV ro rt -76PREPARATION 5 3—(4-Benzyloxybenzovl)-lH-indole A mechanically stirred solution of indole (30.Og) in sodium dried diethyl ether (450ml) was treated dropwise with methylmagnesium iodide (85ml of 3.0M solution in diethyl ether). After stirring for one hour at 20°C 4-benzyloxybenzoyl chloride (see Preparation 10) (67.3g) was added. Stirring was continued for two hours at 20°C and then IN hydrochloric acid (250ml) added to the mixture and the reaction was allowed to stand overnight. The resulting precipitate was filtered off and triturated with hot ethyl acetate (3 x 100ml) to give the desired compound as a pale pink solid, (40.9g). Found: C,80.67; H,5.33; N,4.25; C22H17NO2 requires: C,80.70; H,5.23; N, 4.28%.

^-NMR (d6-DMSO): 6= 5.20(s,2H), 7.15(d,2H), 7.20(m,2H), 7.30-7.50(m,6H), 7.80(d,2H), 7.90(s,lH), 8.23(d,lH), 11.95(s,br,IH) ppm. -77PREPARATIONS 6 to 8 The following indoles of the general formula:- were prepared from the corresponding ΙΗ-indoles and the corresponding acid chlorides (see Preparations 9 to 11) using similar methods to that used in Preparation 5.

Analysis/NMR Found: C,78.45; H.8.31; N.3.90; C23H19NO2 requires: C,78.60; H.8.32; N,3.98%. 1H-NMR (d6-DMSO): δ = 2.40 (s,3H), 5.20(s,2H), 6.957.45(m,11H), 7.65(d,2H), 12.00(s,br,1H) ppm. r-* -Si Z 04 co £ 11 ο E q q co cn co .. pl co in a -r in Oxs Ρ E 2 j (/} T1 a co So> Q •iSt'P co X O Ο Z -i x X x>_ • · - * «.co Ε X - Ziinoo o S Α τ 9 Ά oj it. OX J 2Lcd r- m/z 1 m i-' in 2 co A-O E ( in hcn σ> τ— V— h- X 9 CM X o o 0 CM X o p co X X co X o in X X co X o X co X o X Prep. No. CO r- ie 922386 Analysis/NMR Found: C.81.18; H.6.56; N.3.52; C27H27NO2 requires: C.81.58; H. 6.85; N.3.52%. 1H-NMR (CDCI3): 5 = 0.95(d,6H), I. 70(d,3H), 1.90(m,1H), 2.50(d,2H), 5.40(q,1H), 6.95(d,2H), 7.15(d,2H), 7.30-7.45(m,5H), 7.65(m,1H), 7.80 (d,2H), 8.35(m,1H), 8.80(s,br,1H) ppm. m/z I 4o E x. 1 r*. Cb « X 0 X / 0—/ V X / 0—( 0 / X m ob X Ob X Prep. No. co -80PREPARATION 9 4-Benzyloxy-2,3-dimethvlbenzovl chloride (d) ’’ (COCI)2,DMF,CH2CI2 COCI -81(a) 4-Bromo-2,3-dimethylphenol A solution of 2,3-dimethylphenol (40.Og) in acetic acid (300ml) was cooled to 10°C and treated with a solution of bromine (16.9ml) in acetic acid (100ml). After stirring for 30 minutes saturated aqueous sodium metabisulphite solution (300ml) was added.

The mixture was extracted with dichloromethane, the organic layer dried (MgSO4) , filtered and evaporated to provide the product as a waxy solid, (64.7g).

^-NMR (CDC13) : δ= 2.15(s,3H), 2.25(s,3H), 4.00(s,br,1H), 6.60(d,lH), 7.15(d,lH) ppm.

Crystallisation of the product from hexane gave an analytical sample. Found: C,48.00; H,4.40; C8H9BrO requires: C,47.78; H,4.51%. (b) l-Benzyloxv-4-bromo-2,3-diroethylbenzene A mixture of the product of part (a) (45.Og), benzyl bromide (28.30g), potassium carbonate (38.60g) and potassium iodide (300mg) in acetone (500ml) was heated at reflux overnight. The reaction was cooled, filtered and evaporated to give an oil which was dissolved in diethyl ether and washed with 2N aqueous sodium hydroxide solution. Evaporation of the organic layer gave an oil which was chromatographed (silica, 4:1 hexane/ethyl acetate) to give the desired product, (51.86g). Found: C,62.64; H,5.31; C51H15BrO requires: C,61.85; H, 5.19* ^-NMR (CDC13) : 6= 2.30(s,3H), 2.40(s,3H), 5.00(s,2H), 6.60(d,lH), 7.30-7.50(m,6H) ppm. -82(c) 4-Benzyloxy-2,3-dimethylbenzoic acid A solution of the product of part (b) (33.8g) in tetrahydrofuran (THF) (500ml) at -78°C was treated with n-butyllithium (48.4ml of a 2.5M solution in hexane). After stirring for 30 minutes at -78°C an excess of finely powdered solid carbon dioxide was added and the reaction allowed to warm to room temperature. The THF was removed in vacuo and the residue partitioned between ethyl acetate and 2N hydrochloric acid. The organic layer was washed with brine, dried (MgSO4) and then evaporated to a pink solid. Recrystallisation from ethyl acetate gave the desired compound, (18.8g), m.p. 164-166°C. Found: C,74.87; H,6.21; C16H16O3 requires: C,74.98; H,6.29%. 1H-NMR (CDC13) : 6= 2.10(s,3H), 2.40(s,3H), 5.10(s,2H), 6.95(d,lH), 7.30-7.50(m,5H), 7.60(d,lH) ppm. (d) 4-Benzvloxv-2,3-dimethylbenzoyl chloride The product of part (c) (2.0g) was suspended in dichloromethane (10ml) and treated with oxalyl chloride (1.3ml) and dimethylformamide (DMF) (2 drops). After stirring overnight the homogeneous solution was evaporated to give a white solid which was azeotroped three times with toluene to give the title compound as a white powder (2.24g). This material was used immediately. -83PREPARATION 10 4-Benzyloxvbenzoyl chloride The title compound was prepared using a similar method to that described in Preparation 9(d) except using 4-benzyloxybenzoic acid as the starting material. The material obtained was used immediately.

PREPARATION 11 4-(1-Γ4-Isobutvlphenvnethoxy)benzoyl chloride The title compound was prepared using a similar method to that described in Preparation 9(d) except using 4—(1—[4—isobutylphenyl]ethoxy)benzoic acid (see Preparation 28(b)) as the starting material. The product obtained was used immediately. -84PREPARATION 12 1-(4-n-Propylphenvl)butan-l-ol A solution of 4-n-propylbenzaldehyde (7.4g) in diethyl ether (60ml) was cooled to 0°C and treated with a 2.0M solution of n-propylmagnesium chloride in diethyl ether (27.5ml). The reaction was stirred overnight, diluted with diethyl ether and quenched with saturated aqueous ammonium chloride solution. The organic layer was separated, washed with saturated aqueous ammonium chloride solution and dried (MgSO4) . The organic layer was filtered and evaporated to give a colourless oil which was purified by chromatography (silica, 4:1 hexane/ethyl acetate) to provide, after evaporation of the appropriate fractions, the desired product, (4.06g), m/z = 192 (M+) .

^-NMR (CDC13) : 6= 1.00(m,6H), 1.20-1.40 (m, 2H) , 1.70(q,2H), 1.75-1.90(m,3H), 2.60(t,2H), 4.60(m,lH), 7.10(d,2H), 7.30(d,2H) ppm.

PREPARATION 13 1-f 4-Ethylphenyl)ethanol A solution of 4-ethylacetophenone (10.0g) in methanol (50ml) at 0°C was treated portionwise with sodium borohydride (3.83g). After stirring overnight at 20°C the reaction was partitioned between IN hydrochloric acid and ethyl acetate. The organic layer was washed with IN hydrochloric acid, dried (MgSO4) and evaporated to give a clear oil (9.9g). This was purified by flash chromatography (silica, 3:1 hexane/ethyl acetate) to give, after evaporation of the appropriate fractions, the desired compound, (8.9g), m/z = 150(M+).

^-NMR (CDC13) : 6= 1.25(t,3H), 1.55(d,3H), 2.65(q,2H), 4.90(q,lH), 7.20(d,2H), 7.35(d,2H) ppm.

,E922386 -85PREPARATION 14 4-n-Propylbenzyl alcohol A solution of 4-n-propylbromobenzene (10g) in THF (100ml) at -78°C was treated with n-butyllithium (35ml of a 1.6M solution in hexane). After stirring for 15 minutes at this temperature paraformaldehyde (1.6g) was added and stirring continued for a further one hour. The reaction mixture was partitioned between diethyl ether and water, the organic layer was dried (MgSO4) and evaporated to an oil. Flash chromatography (silica, 3:1 hexane/ethyl acetate) gave, after evaporation of the appropriate fractions, the desired product as a colourless oil, (2.7g).

PREPARATION 15 (R.S)-1-(4-Γ2-Methylpropyllphenyl)ethanol A solution of 4-isobutyrylacetophenone (10.Og) in methanol (50ml) was cooled to 0°C and treated portionwise with sodium borohydride (3.23g). After stirring overnight at room temperature the reaction was quenched with IN hydrochloric acid (50ml) and ethyl acetate (100ml) added. The organic layer was separated, dried (MgSO4) and evaporated to give the title compound as a clear oil, (10.02g), m/z = 178(M+). Found: C,79.69; H,9.90; C12H10O.l/7 H20 requires: C,79.68; H,10.19%.

^-NMR (CDC13) : 6= 0.90(d,6H), 1.50(d,3H), 1.85(m,lH), 2.50(d,2H), 4.85(q,lH), 7.15(d,2H), 7.30(d,2H) ppm.

PREPARATION 16 1-(3,4-Dichlorophenyl)ethanol The title compound was prepared using a similar method to that described in Preparation 15 except using 3,4-dichloroacetophenone as the starting material, m/z = 190 (M+) .

^-NMR (CDC13) : 6= 1.45(d,3H), 2.25 (s, br, IH) , 4.85(q,lH), 7.20(d,lH), 7.40(d,lH), 7.45(s,lH) ppm. -86PREPARATION 17 (R)-1-(4-Γ 2-Methylpropyllphenyl)ethanol (a) Ethanoic acid (R,S)-1-(4-Γ2-methylpropyl1 phenyl)ethyl ester A solution of the product of Preparation 15 (5.0g) in dichloromethane (40ml) at 0°C was treated with dry pyridine (2.5ml) followed by distilled acetyl chloride (2.2ml). After stirring overnight at room temperature the reaction mixture was filtered, silica (lOg) added to the filtrate and the mixture evaporated to dryness. Column chromatography (silica, 12:1 hexane/ethyl acetate) gave, after evaporation of the appropriate fractions, the desired compound as a clear oil, (2.3g).

^-NMR (CDC13) : δ= 0.90(d,6H), 1.55(d,3H), 1.85(m,lH), 2.05(s,3H), 2.45(d,2H), 5.85(q,lH), 7.15(d,2H), 7.25(d,2H) ppm. (b) (R)-1-(4-Γ2-Methylpropyllphenyl)ethanol A suspension of the product of part (a) (3.0g) in pH7 phosphate buffer (100ml) was treated with SAM II lipase (trade mark) (Fluka Chemicals Limited) (50mg) and the mixture stirred vigorously for 2 days at room temperature. The mixture was extracted with ethyl acetate (100ml), the combined organic layers dried (MgSO4) and evaporated. Column chromatography (silica, 9:1 hexane/ethyl acetate) first gave, after combination and evaporation of the appropriate fractions, ethanoic acid (S)-1-(4-[2-methylpropyl]phenylethyl ester, (1.47g). Further elution gave the title compound as a clear oil which crystallised to provide white needles, (1.04g), m.p. 37-38°C, [a]0 + 32.3° (c = 2.7 in methanol).

^-NMR (CDC13) : 6= 0.90(d,6H), 1.50(d,3H), 1.85(m,lH), 2.50(d,2H), 4.85(q,lH), 7.15(d,2H), 7.30(d,2H) ppm. -87PREPARATION 18 (S)-1-(4-Γ2-Methvlpropvl1 phenyl)ethanol Ethanoic acid (S)-1-(4-[2-methylpropyl]phenylethyl ester (see Preparation 17(b)) (1.2g) was treated with a IN solution of sodium hydroxide in absolute ethanol (20ml). After stirring overnight at room temperature the solvent was evaporated and the residue chromatographed (silica, 4:1 hexane/ethyl acetate) to give the title compound as a clear oil, (0.59g), m.p. 34°C, [a]D - 32.7° (c = 2.7 in methanol).

JH-NMR (CDC13) : 6= 0.90(d,6H), 1.50(d,3H), 1.85(m,lH) 2.50(d,2H), 4.85(q,lH), 7.15(d,2H), 7.30(d,2H) ppm.

PREPARATION 19 g-Cyclopentyl-4-n-propylbenzyl alcohol A solution of 4-n-propylbenzaldehyde (2.0g) in diethyl ether (20ml) was cooled to 0°C and treated with a solution of cyclopentylmagnesium chloride (7.4ml of a 2.0M solution in diethyl ether). After stirring at room temperature overnight the mixture was treated with saturated aqueous ammonium chloride solution. The organic layer was separated, dried (MgSO4) and evaporated to provide a yellow oil. Flash chromatography (silica, initial elution with 4:1 hexane/ethyl acetate and then with 3:1 hexane/ethyl acetate) gave, after combination and evaporation of the appropriate fractions, the desired compound as a clear oil, (400mg), m/z = 218(M+).

*H-NMR (CDC13) : δ= 1.00(t,3H), 1.00-1.60 (m, 10H) , 2.25(sextet,1H), 2.60(m,2H), 4.40(d,2H), 7.30(d,2H), 7.40(d,2H) ppm. —88 — PREPARATIONS 20 to 26 The following alkyl bromides were prepared by dissolving the corresponding alcohol (see Preparations 12 to 16 and 19) in dichloromethane and cooling the solution in an ice-bath whilst saturating with dry hydrogen bromide. After stirring the mixture for a short period the reaction was evaporated in vacuo to provide the desired alkyl bromide which was used directly without characterisation.

Preparation No. Alkyl bromide 20 1-Bromo-l-(4-n-propylphenyl)butane. 21 a-Methyl-4-ethylbenzyl bromide. 22 4-n-Propylbenzyl bromide. 23 a-Methyl-4-(2-methylpropyl)benzyl bromide. 24 a-Methyl-3,4-dichlorobenzyl bromide. 25 a-Cyclopentyl-4-n-propylbenzyl bromide. 261 a- (4—n—Propylphenyl) -4-n-propylbenzyl bromide.

For starting material see EP-A-291245. -89PREPARATION 27 4—(3 — Γ4—(1-Hvdroxyethyl)benzoyllindol-l-yl)butanoic acid ethyl ester (a) ▼ (c) y IE 922386 -90a) 3 — f-4 — Γ1— ft-Butyldimethvlsilyloxy) ethyl 1 benzoyl)indole The title compound was prepared by a similar method to that used in Preparation 5 using indole and 4-(1[t-butyldimethylsilyloxy) ethyl)benzoyl chloride as the starting materials, m/z = 380 (M+l)+. Found: C,72.79; H,7.73; N,3.76; C23H29NO2Si requires: C,72.78; H,7.70; N,3.69%.

^-NMR (CDC13) : 6= 0.00(s,3H), 0.40(s,3H), 0.95(s,9H), 1.45(d,3H), 4.95(q,lH), 7.30-7.50(m,5H), 7.70(m,lH), 7.80(d,2H), 8.40(m,lH), 9.20(s,br,1H) ppm. b) 4-f 3-Γ 4-f1-Γ t-Butyldimethylsilvloxvlethyl)benzoyl)indol-l-yl)butanoic acid ethyl ester A solution of the product of part (a) (1.70g) in dimethylformamide (20ml) was treated with sodium hydride (215mg of a 60% dispersion in mineral oil). After stirring for 1 hour at room temperature ethyl 4-bromobutyrate (0.7ml) was added and stirring was continued for 2 hours. The reaction mixture was diluted with ethyl acetate (50ml) and washed successively with 2N aqueous hydrochloric acid and saturated brine. The organic layer was dried (MgSO4) and gave a yellow gum on evaporation of the solvent. Flash chromatography of this gum (silica, 3:1 hexane/ethyl acetate) followed by collection and evaporation of the appropriate fractions gave the title compound as a clear gum (2.20g), m/z = 494 (M+l)+.

^-NMR (CDC13) : 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,lH), 7.20-7.40(m,5H), 7.60(s,lH), 7.80(d,2H), 8.35(m,lH) ppm. -91(c) 4-(3-(4-(1-Hydroxyethyl)benzoyl1indol-l-yl)butanoic acid ethyl ester The product of part (b) was dissolved in tetrahydrofuran (100ml) and treated with tetra-nbutylammonium fluoride (4.92g) and stirred for 1 hour. The reaction mixture was diluted with ethyl acetate (100ml) and washed with 2N aqueous hydrochloric acid and saturated brine. The organic layer was dried (MgSO4) , filtered and evaporated to a brown gum. Flash chromatography (silica, 98:2 dichloromethane/methanol) gave, after collection and evaporation of the appropriate fractions, the title compound (0.92g) as a clear gum, m/z = 380 (M+l)+.

^-NMR (CDC13) : 6= 1.20(t,3H), 1.70(d,3H), 2.00(s,br,IH), 2.20-2.40(m,4H), 4.10(q,2H), 4.30(t,2H), 5.00(q,lH), 7.20-7.60(m,6H), 7.80(d,2H), 8.35(m,lH) ppm.

PREPARATION 28 (S)-4-(3-Γ4-(1-Γ4-(2-Methylpropyl)phenyl1 ethoxy)benzoyllindol-l-yl)butanoic acid (a) (R,S)-4-(1-( 4-(2-Methylpropyl)phenyl1 ethoxy)benzoic acid ethyl ester Ethyl p-hydroxybenzoate (5.16g) was dissolved in acetone (50ml) and treated with anhydrous potassium carbonate (4.40g), tetra-n-butylammonium bromide (0.44g) and (R,S)-o-methyl-4-(2-methylpropyl)benzyl bromide (see Preparation 23) (7.7g). The resultant slurry was stirred overnight at room temperature and filtered. The filtrate was evaporated to give the title compound (13.5g) which was used directly without characterisation. -92(b) (R,S)-4-(l-f4-f 2-Methylpropyl)phenyl)ethoxy)benzoic acid The product of part (a) (13.5g) was dissolved in 95% aqueous ethanol (108ml), treated with 2N aqueous sodium hydroxide (32ml) and heated at 60-70°C for 90 minutes. The solvent was evaporated and water (30ml) added. The mixture was treated with 2N aqueous hydrochloric acid (50ml) and then extracted with ethyl acetate. The combined organic layers were washed with saturated brine and dried (MgSO4) . Removal of the ethyl acetate solvent gave the title compound as a white solid. Trituration with nhexane gave a fine white powder (6.7g).

^-NMR (CDC13) : 6= 0.95(d,6H), 1.70(d,3H), 1.88(m,lH), 2.51(d,2H), 5.40(q,lH), 6.95(d,2H), 7.17(d,2H), 7.30(d,2H), 8.00(d,2H) ppm. (c) (S)-4-(1-Γ4-(2-Methylpropyl)phenyl)ethoxy)benzoic acid, (+)-ephedrine salt The product of part (b) (lOg) was dissolved in 95% aqueous ethanol (60ml) and water (60ml) and treated with (+)-ephedrine hemihydrate (5.84g). The mixture was heated under reflux until complete solution was achieved. The reaction was allowed to stand at room temperature overnight. The resulting precipitate was removed by filtration and dried to provide the title compound (5.20g). [a]20 -21.9° (c=l in methanol).

D -93 — ^-NMR (CDC13) : δ= 0.90(d,6H), 1.10(d,3H), 1.70(d,3H), 1.85(m,lH), 2.45(s,3H), 3.15(m,lH), 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 the product showed it to contain a 95:5 ratio of the (S):(R) enantiomers. (d) (S)-4-(1-Γ4-(2-Methylpropyl)phenyl)ethoxy)benzoic acid The product of part (c) (4.63g) was treated with IN aqueous hydrochloric acid and the resultant slurry stirred for 90 minutes. The resultant precipitate was filtered off and washed with IN aqueous hydrochloric acid then water. The product was dried in vacuo at 50°C to give the desired compound as a colourless solid, (2.94g), m.p. 128-131°C. [a]20 D -51.5° (c=l in methanol).

Found: C,76.76; H,7.30; Ν,Ο.ΟΟ; C19H22O3 requires: C,76.48; H,7.43; N,0.00%.

^-NMR (CDC13) : δ= 0.95(d,6H), 1.70(d,3H), 1.88(m,lH), 2.51(d,2H), 5.40(q,lH), 6.95(d,2H), 7.17(d,2H), 7.30(d,2H), 8.00(d,2H) ppm. (e) (S)-4-(1-Γ4-(2-Methylpropyl)phenvl1 ethoxy)benzoyl chloride The product of part (d) (2g) was dissolved in dichloromethane (10ml) and treated with pyridine (0.60ml) followed by oxalyl chloride (0.64ml). The mixture was stirred for 3 hours at room temperature, one drop of dimethylformamide was added and the mixture stirred overnight. The solvent was removed by evaporation and dry toluene (40ml) added. The resultant precipitate was removed by filtration and -94the filtrate containing the title compound was evaporated to a volume of 10ml and used directly in the next step without characterisation. (f) (S)-3-(4-ri-(4-r2-Methvlpropyl1phenvl)ethoxy1 benzoyl)indole Indole (715mg) was dissolved in toluene (5ml) and treated with methylmagnesium iodide (2.0ml of a 3M solution in diethyl ether). The resultant yellow solution was stirred for 10 minutes and a solution of (S)-4-(1-[4-(2-methylpropyl)phenyl]ethoxy)benzoyl chloride in toluene (10ml) (the product of part (e)) was added. The mixture was stirred at room temperature for 1 hour and then a saturated solution of aqueous ammonium chloride (50ml) was added with vigorous stirring. The mixture was extracted with ethyl acetate (30ml, 40ml and 15ml) and the combined organic layers were dried (MgSO4) , filtered and evaporated to give a brown gum.. Flash chromatography (silica, 3:1 hexane/ethyl acetate initially, followed by 1:1 hexane/ethyl acetate) gave, after evaporation of the appropriate fractions, the title compound as a beige solid (1.05g), m.p. 150-152°C. Found: C,81.69; H,6.83; N,3.58; C27H27NO2 requires: C,81.58; H,6.85; N,3.52%.

^-NMR (CDC13) : 6= 1.00(d,6H), 1.75(d,3H), 1.95(m,lH), 2.55(d,2H), 5.45(q,lH), 7.05(d,2H), 7.25(d,2H) 7.39-7.54(m,4H), 7.70(m,lH), 7.85(d,2H), 8.45(m,lH), 9.10(s,br,IH) ppm. -95(g) f S) -4-f 3-Γ4-(1-f4-(2-Methvlpropvl)phenvllethoxy)benzovllindol-l-yl)butanoic acid ethyl ester A solution of the product of part (f) (500mg) in 2butanone (5ml) was treated with anhydrous potassium carbonate (695mg) and ethyl 4-bromobutyrate (0.23ml). The mixture was heated under reflux overnight, cooled, filtered and the filtrate evaporated to a yellow gum. Flash chromatography (silica, 3:1 hexane/ethyl acetate) gave, after collection and evaporation of the appropriate fractions, the title compound (451mg).

This product had identical mass spectroscopy, H.P.L.C. and ^-NMR characteristics to the compound of Example 33. (h) (S)-4-(3-r4-(l-r4-(2-Methvlpropvl)phenyl)ethoxy)benzoyl1indol-l-yl)butanoic acid A solution of the product of part (g) (108mg) in 95% aqueous ethanol (2ml) was treated with six drops of 2N aqueous sodium hydroxide. The mixture was stirred for 90 minutes then water (3ml) was added followed by 2N aqueous hydrochloric acid until the mixture reached pHl. The mixture was extracted with dichloromethane (3 x 10ml) and the combined organic layers were evaporated to give the title compound as a colourless foam (62mg).

This product had identical mass spectroscopy, optical rotation and ^-NMR characteristics to the compound of Example 9. -96Pharmacoloqical activity A selection of compounds of the formula (I) was tested in vitro for steroid 5α-reductase inhibitory activity using ventral prostate tissue from male rats according to the procedure outlined on pages 34 to 36 of the specification. The results are presented in Table 1.

Table 1 Example No. ICS0(nM) 1 2.19 2 1.2 3 2.3 4 56 5 6.9 6 3.6 7 361 8 0.67 9 1.15 10 JO. 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 lOOnM 34 47% inhibition at lOOOnM -97Toxicity The compound of Example 1 was administered orally to mice up to dose of lOOOmg/kg and the animal showed normal appearance and behaviour throughout the duration of the study.

Claims (16)

1. A compound of the formula:- or a pharmaceutically acceptable salt thereof, wherein Y is Cj-Cg alkylene optionally substituted by Cj-Cg alkyl; R is H, OH, halo, Cj-C 4 alkyl or Cj-04 alkoxy; R 1 , R 2 , R 3 and R 4 are each independently selected from H, Cj-04 alkyl, Cj-^ alkoxy, OH, halo and CF 3 ; one of R 6 , R 7 * * and R R 14 I -OCH-Aryl and the remainder, each independently Cj-C 4 alkoxy, halo 8 is a group of the formula :R 14 I or -CHO-Aryl, together with R 5 and R 8 9 , are selected from H, alkyl, and halo(C 1 -C 4 ) alkyl; IE 922386 99R 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 alkyl; R 14 is H, Cj-Cg alkyl, C 3 -C 7 cycloalkyl or aryl; and aryl·', used in the definitions of R 6 , R 7 , R 8 and R 14 , means phenyl optionally substituted by Cj-Cg alkyl, Cj-Cg alkoxy, C 2 -C 6 alkenyl, OH, halo, CF 3 , halo (Cj-Cg alkyl), nitro, amino, C 2 -C 6 alkanamido, C 2 -C 6 alkanoyl or phenyl.

2. A compound as claimed in claim 1 wherein Y is Cj-Cg alkylene optionally substituted by q-Cg alkyl; R is H, OH, halo, Ci~C 4 alkyl or C!-C 4 alkoxy; R 1 , R 2 , R 3 and R 4 are each independently selected from H, Cj-C 4 alkyl, C 1 -C 4 alkoxy, OH, halo and CF 3 ; one of R 6 , R 7 and R 8 is a group of the formula:R 14 R 14 I I -OCH-Aryl or -CHO-Aryl, and the remainder, together with R 5 and R 9 , are each independently selected from H, Cj-C,, alkyl, Cj—C 4 alkoxy, halo and halo(Cj-C 4 )alkyl; R 10 is COOH, COOR 11 or CONR 1Z R 13 ; -100R 11 is a biolabile ester-forming group; R 12 and R 13 are each independently selected from H and Cj-^ alkyl; R 14 is H, Ci-Cg alkyl, C 3 -C 7 cycloalkyl or aryl; and aryl, used in the definitions of R 6 , R 7 , R 8 and R 14 , means phenyl optionally substituted by Ci-Cg alkyl, Cj-Cg alkoxy, C 2 -C 6 alkenyl, OH, halo, CF 3 , halo(Cj-C 6 alkyl), nitro, amino, C 2 -C 6 alkanamido, C 2 -C 6 alkanoyl or phenyl: with the provisos i) when R 7 is 1-(4-(2-methylpropyl)phenyl) ethoxy, R, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 8 and R 9 are all H and Y is -(CH 2 ) 3 -, that R 10 is not COOH when the .compound of the formula (I) is in the racemic form; ii) when R 7 is 1-(4-(2-methylpropyl)phenyl)propoxy or 2,2-dimethyl-l-(4-(2methylpropyl)phenyl)propoxy, R, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 8 and R 9 are all H and Y is -(CH2)3-, that R 10 is not COOH or COOC2H 5 when the compound of the formula (I) is in the racemic form; iii) when R 6 is 1-(3-(2-methylpropyl) phenyl)ethoxy, R, R 1 , R 2 , R 3 , R 4 , R 5 , R 7 , R 8 and R 9 are all H and Y is -(CH2)3-, that R 10 is not COOH or COOC2H 5 when the compound of the formula (I) is in the racemic form; -101iv) when R 7 is 1-(4-(2-methylpropyl)phenyl)ethoxy, R 5 and R 6 are both methyl, R, R 1 , R 2 , R 3 , R 4 , R 8 and R 9 are all H and Y is - (CH 2 ) 3 -, that R 10 is not COOH or COOC 2 H 5 when the compound of the formula (I) is in the racemic form; v) when R 7 is bis(4-(2-methylpropyl)phenyl)methoxy, R, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 8 and R 9 are all H and Y is -(CH 2 ) 3 -, that R 10 is not COOH; vi) when R 6 is bis(4-(2-methylpropyl)phenyl)methoxy, R, 'r 1 , R 2 , R 3 , R 4 , R 5 , R 7 , R 8 and R 9 are all H and Y is -(CH 2 ) 3 -, that R 10 is not COOH; and vii) when R 6 is 4-(2-methylpropyl)phenoxymethyl or 3-(2-methylpropyl)phenoxymethyl, R, R 1 , R 2 , R 3 , R 4 , R 5 , R 7 , R 8 and R 9 are all H and Y is - (CH2)3-, that R 10 is not COOH or COOC2H 5 .

3. A compound as claimed in claim 1 or 2 wherein R 10 is COOH or COOR 11 .

4. A compound as claimed in any preceding claim wherein R 11 is Cj-Cg alkyl.

5. A compound as claimed in any preceding claim wherein R 10 is COOH.

6. A compound as claimed in any preceding claim wherein Y is Cj-Cg alkylene; R is H or Cj-C 4 alkyl; R 1 , R 2 , R 3 and R 4 are each H; one of R 6 , R 7 and R 8 is a group of the formula:IE 922386 — 102 — R 14 R 14 f I -OCH-Aryl or -CHO-Aryl, and the remainder, together with R 5 and R 9 , are each independently selected from H and Cj-C^ alkyl; R 14 is H, CJ-C4 alkyl, C 4 -C 6 cycloalkyl or phenyl substituted by C],-C 4 alkyl; and aryl, when used in the definitions of R 6 , R 7 and R 8 , means phenyl optionally substituted by from 1 to 3 substituents each independently selected from Cj-Cg alkyl and halo.

7. A compound as claimed in claim 6 wherein Y is methylene, propylene, butylene or pentylene; R is H or methyl; R 7 is a group of the formula :R 14 R 14 I I -OCH-Aryl or - -CHO-Aryl, and R 5 , R 6 , R 8 and R 9 are each independently selected from H and C 1 -C 4 alkyl; R 14 is H, methyl, n-propyl, cyclopentyl or 4-(n-propyl)phenyl; and aryl means phenyl optionally substituted by 1 or 2 substituents each independently selected from methyl, ethyl, n-propyl, isobutyl and chloro.

8. A compound as claimed in claim 7 wherein Y is propylene; R is H; R 7 is a group of the formula :R 14 I -OCH-Aryl, and R 5 , R 6 , R 8 and R 9 are each H; — 103 — R 14 is methyl; and aryl·' means phenyl, 4-methylphenyl, 4-ethylphenyl, 4-(n-propyl)phenyl, 4-isobutylphenyl or 3,4dichlorophenyl.

9. A compound as claimed in claim 8 wherein aryl means 4-isobutylphenyl.

10. A compound as claimed in claim 1 or 2 wherein one of R 6 , R 7 and R 8 is a group of the formula:(Ci C 6 alkyl)>. ,,h -o/sl· Aryl and the remainder, together with 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.

11. (R,S)—4—(3-[4-(1-[4-(2-Methylpropyl)phenyl]ethoxy)benzoyl]indol-l-yl)butanoic acid, (S)-4-(3-(4-(1-[4-(2-Methylpropyl)phenyl]ethoxy)benzoyl]indol-l-yl)butanoic acid, (R,S)-4-(2-Methyl-3-[4-(1-(4-(2-methylpropyl) phenyl]ethoxy)benzoyl]indol-l-yl)butanoic acid or (S)-4-(2-Methyl-3-[4-(l-[4-(2-methylpropyl)phenyl]ethoxy)benzoyl]indol-l-yl)butanoic acid: or a pharmaceutically acceptable salt thereof. -10412. A pharmaceutical composition comprising a compound of the formula (I), or a pharmaceutically acceptable salt thereof, as claimed in any one of the preceding claims, together with a pharmaceutically acceptable diluent or carrier.

12. 13. A compound of the formula (I), or a pharmaceutically acceptable salt or composition thereof, as claimed in any one of claims 1 to 11 and 12 respectively, for use as a medicament.

13. 14. The use of a compound of the formula (I), or of a pharmaceutically acceptable salt or composition thereof, as claimed in any one of claims 1 to 11 and 12 respectively, for the manufacture of a medicament for inhibiting a steroid Sot-reductase.

14. 15. The use of a compound of the formula (I), or of a pharmaceutically acceptable salt or composition thereof, as claimed in any one of claims 1 to 11 and 12 respectively, for the manufacture of a medicament for the curative or prophylactic treatment of acne vulgaris, alopecia, seborrhoea, female hirsutism, benign prostatic hypertrophy or male pattern baldness.

15.

16. The use of a compound of the formula (I), or of a pharmaceutically acceptable salt or composition thereof, as claimed in any one of claims 1 to 11 and 12 respectively, for the manufacture of a medicament for the curative or prophylactic treatment of a human prostate adenocarcinoma.