IE922387A1

IE922387A1 - Indoles

Info

Publication number: IE922387A1
Application number: IE238792A
Authority: IE
Inventors: Julian Blagg; Kelvin Cooper; Peter Lionel Spargo
Original assignee: Pfizer Ltd
Priority date: 1991-07-24
Filing date: 1992-07-23
Publication date: 1993-01-27
Also published as: NZ243687A; PT100718A; EP0598750A1; ZA925546B; BR9206306A; CZ13694A3; AU655662B2; FI940311A0; HU9400199D0; NO940237L; TW223060B; JPH06509336A; ZA925547B; AU2327192A; EP0598754A1; PT100717A; CN1068817A; CN1068816A; NO940237D0; CA2112689A1

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 α-reductase inhibitory activity.

More particularly this invention relates to indoles, their preparation and their use as testosterone-5 areductase 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 5ce-reduced androgens.

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

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

EP-A-0458207 discloses certain indole derivatives which have testosterone 5α-reductase inhibitory activity. -2The present invention provides compounds of the formula: - ....(I) and pharmaceutically acceptable salts thereof, wherein X is 0, NH, N(Cl-C4 alkyl), C^-Q, alkylene, C2-C4 alkenylene or C2-C4 alkynylene, said alkylene, alkenylene and alkynylene groups being optionally substituted by C1-C4 alkyl or aryl; Y is Cj-Cg alkylene optionally substituted by Cj-Cg alkyl; R is H, OH, halo, Cj-C4 alkyl or Cj-C4 alkoxy; R1, R2, R3 and R4 are each independently selected from H, C!-C4 alkyl, Cj-C^ alkoxy, OH, halo and CF3; one of R6, R7 and R8 is Cy-Cyg alkyl or a group of the formula -ZfCj-C^ alkyl), -Z(aryl) or -Z(C3-C7 cycloalkyl), said alkyl group being optionally interrupted by O, S(0)q, NH or N(Cjc6 alkyl), and said alkyl group and the alkyl group of said -ZCCj-Cjg alkyl) group being optionally substituted by Cj-C^ alkoxy, aryl, C3-C7 cycloalkyl or a group of the formula -Z(aryl), and the remainder of R6, R7 and R8 and R5 and R9 are each independently selected from H, Cj-C4 alkyl, C^-C^ alkoxy, halo and halo(C1-C4 alkyl); —3R10 is COOH, COOR11 or C0NR12R13; R11 is a biolabile ester-forming group; R12 and R13 are each independently selected from H and Cr-CA alkyl; Z is 0, S(0)q, NH or NfCj-Cg alkyl); q is Ο, 1 or 2; and aryl, used in the definitions of X, R6, R7 and R8, means phenyl optionally substituted by Cj-Cg alkyl, Cj-Cg alkoxy, C2-C6 alkenyl, OH, halo, CF3, halo^-Cg alkyl) , nitro, amino, C2-C6 alkanamido, C2-C6 alkanoyl or phenyl.

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. -4Esters of the formula (I) wherein R10 is -CO2(C1-C6 alkyl) are steroid 5ct-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 Cl-CA alkyl, Cj-C,, alkoxy or halo.

In addition to Cj-Cg 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, ce-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. —5 — Suitable 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 X is 0, NH, Cj-C4 alkylene or C2-C4 alkenylene.

More preferably X is 0, NH, methylene, ethylene or ethenylene.

Most preferably X is methylene.

Preferably Y is C^-Cg alkylene.

Most preferably Y is propylene.

Preferably R is H or Cj-C4 alkyl.

Most preferably R is H.

Preferably R1, Rz, R3 and R4 are each H. -6Preferably one of R6, R7 and R8 is -OiCj-Cjg alkyl), the alkyl of said -OfCj-Cjg alkyl) group being optionally substituted by aryl, and the remainder of R6, R7 and R8 and R5 and R9 are each H.

More preferably one of R6, R7 and R8 is -OCH2(aryl) or —OCH(Cj-C4 alkyl) (aryl) and the remainder of R6, R7 and R8 and R5 and R9 are each H.

Most preferably R7 is -OCH(CH3) (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-C6 alkyl.

Most preferably R11 is ethyl.

Preferably Z is 0.

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, C^Cg alkoxy, halo, CF3, nitro or phenyl and more preferably means phenyl optionally substituted by npropyl, isobutyl, methoxy, chloro, CF3, nitro or phenyl. Yet more preferably aryl means phenyl, 4-(npropyl)phenyl, 4-isobutylphenyl, 4-methoxyphenyl, 2,4dichlorophenyl, 3,4-dichlorophenyl, 4trifluoromethylphenyl, 4-nitrophenyl or 4-phenylphenyl and most preferably means 4-isobutylphenyl. -7A 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.

Particularly preferred embodiments of the compounds of the formula (I) are (R,S)-4-(3-(4-(1—[4—(2-methylpropy1)pheny1]ethoxy) phenylethanoyl]indol-l-yl)butanoic acid and (S)-4-(3-[4-(l-[4-(2-methylpropyl) phenyl]ethoxy) phenylethanoyl]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 X, 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:IE 922387 Y, R and R1 to R9 are as previously defined for a compound of the formula (I).

A 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 R14 is an ester-forming group that may be removed by hydrolysis, e.g. Cj-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. -9tetrahydrofuran or a Cj-C^ 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 R14 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. 2) The compounds of the formula (I) wherein R10 is COOH and X, 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 X, 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.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 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 X, 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:IE 922387 — 10 — wherein X, Y, R and R1 to R9 are as previously defined for a compound of the formula (I) and R15 is H or Cj-C,, 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. -114) The compounds of the formula (I) wherein R10 is COOH and X, 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:- ....(IV) wherein X, 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. -125) The compounds of the formula (I) wherein R10 is COOH and X, 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:- wherein X, Y, R and R1 to R9 are as previously defined for a compound of the formula (I) and R16 and R17 taken together represent ethylene, said ethylene group being optionally substituted by phenyl or Cj-C^ alkyl (preferably methyl) . Preferably R16 and R17 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. -136) The compounds of the formula (I) wherein R10 is CONH2 and X, 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 X, Y, R and Rl 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 X, 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 X, Y, R and R1 to R9 are as previously defined for a compound of the formula (I) with an alcohol of the formula RnOH wherein R11 is as previously defined for this method.

The 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). -14Alternatively 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-(3N,N-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.

The compounds of the formula (I) wherein R10 is COOR11 wherein X, Y, R, R1 to RTh 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:8) 8) coz1 -15wherein X, 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 O°C to room temperature. 9) The compounds of the formula (I) wherein R10 is COOR11 wherein X, 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 X, 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 RnZ2 wherein R11 is as previously defined for a compound of the formula (I) and Z2 is a suitable leaving group, e.g. halo, preferably bromo or iodo, or p-toluenesulphonyloxy. Preferred 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 X, 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 X, Y, R and R1 to — 16 — R9 are as previously defined for a compound of the formula (I) , with an amine of the formula R12R13NH wherein R1Z 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 R1ZR13NH. 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 CONR1ZR13 and X, Y, R, R1 to R9, B12 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 X, Y, R, R1 to R9 and Z1 are as previously defined for a compound of the formula (VI) , with an amine of the formula R12R13NH 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 X, Y, R, R1 to R9, R1Z and R13 are as previously defined for a compound of the formula (I) may be prepared by reaction of a compound of the -17formula (II) wherein R14 is a suitable ester-forming group, e.g. Cj-C6 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 X, 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.

The reaction may be carried out in a suitable solvent, e.g. a Cj-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.

The compounds of the formula (I) wherein R10 is COOH or CONR12R13, X is Cj-C4 alkylene, C2-C4 alkenylene or C2-C4 alkynylene, said alkylene, alkenylene and alkynylene groups being optionally substituted by CjC4 alkyl or aryl, and Y, R, R1 to R9, R12 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:13) 13) R1 Y -18wherein X, Y, R and R1 to R9 are as previously defined for this method, R14 * * * 18 and R19 are either each Cj-C4 alkyl or when taken together represent C2-C3 alkylene, said alkylene group being optionally substituted by Cj-C^ alkyl, and R20 is OH, OR21 wherein R21 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.

A compound of the formula (VII) may be prepared by first forming the corresponding ketal of a compound of the formula (VIII) wherein X, 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, Protective Groups in Organic Synthesis, Wiley-Interscience (1981), followed by N-alkylation of the ketal by a similar procedure to that described in method (14) for alkylation of compounds of the formula (VIII). 14) All the compounds of the formula (I) wherein X, 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:Έ922387 wherein X, R and R1 to R9 are as previously defined for a compound of the formula (I) , with a compound of the formula Z3-Y-COOR22, Z3-Y-CONR12R13 or a base salt of a compound of the formula Z3-Y-COOH, as appropriate, wherein Y, R12 and R13 are as previously defined for a compound of the formula (I), Z3 is a leaving group, e.g. halo, preferably chloro, bromo or iodo, methanesulphonyloxy or ptoluenesulphonyloxy, and R22 is a biolabile esterforming group as previously defined for R11. 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.

IE 922387 -20The reaction may be performed by initial deprotonation of the compound of the formula (VIII) with a suitable base, e.g. sodium hydride, followed by reaction of the resulting anion with the compound of the formula Z3-Y-COOR22, Z3-Y-CONR12R13 or a base salt of the compound of the formula Z3-Y-COOH, as required. The reaction may be carried out in a suitable solvent, e.g. N,N-dimethyIformamide 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 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.

Where 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.

) The compounds of the formula (I) wherein X is Cjalkylene, C2-C4 alkenylene or C2-C4 alkynylene, said alkylene, alkenylene and alkynylene groups being optionally substituted by Cj-^ alkyl or aryl, and 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:IE 922387 ....(IX) or, where R or of a base is OH, a salt of base salt an indole thereof, of the formula:- wherein Y, R and R1 to R4 are as previously defined for a compound of the formula (I) and R23 is either OR24 wherein R24 is a biolabile ester-forming group as previously defined for R11, or is NR12R13 wherein R12 and R13 are as previously defined for a compound of the formula (I), with a compound of the formula:»9 (XI) -22wherein X and 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.

Where 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 formulae (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 the compound of the formula (I) wherein R is OH. -2316) The compounds of the formula (I) wherein R10 is COOH, X is 0, NH, N(C1-C4 alkyl) or Cj-C4 alkylene, said alkylene group being optionally substituted by C1-C4 alkyl or aryl, 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:- Z5 wherein Z5 is -CH=CH2, -CH=CH(C1-C4 alkyl), -CH=C(C1-C4 alkyl) z or -C=CH and X, 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 X is 0, R10 is either COOR11 or CONR1ZR13 and Y, R, R1 to R9, R11, R1Z and R13 are as previously defined for a compound of the formula (I), may be prepared by esterification of a compound of the formula:IE 922387 CO(OR11 orNR12R13) wherein Y, R, R1 to R4, previously defined for the formula :Ru, R12 and R13 are as this method, with a phenol of wherein R5 to R9 are as previously defined for this method. A similar esterification procedure to any one of those described in method (7) may be used. -2518) The compounds of the formula (I) wherein X, Y, R and R1 to R10 are as defined for a compound of the formula (I) in method (17) may be prepared by reaction of a compound of the formula:- CO(OR11 or NR12R13) wherein Y, R, R1 to R4, R11, R12 and R13 are as previously defined for this method and Z6 is a leaving group, e.g. chloro or bromo, with a phenol of the formula (XIV) wherein R5 to R9 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. 19) The compounds of the formula (I) wherein X is NH or N(C1-C4 alkyl), R10 is either COOR11 or CONR1ZR13 and Y, R, R1 to R9, R11, 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 (XIII) or an activated ester or imidazolide thereof, wherein Y, R, R1 to R4, R11, R12 and R13 are as previously defined for this method, with an amine of the formula: IE 922387 wherein R24 is H or Cj-Cj alkyl and R5 to R9 are as previously defined for this method.

The reaction may be carried out in the presence of a suitable dehydrating agent, e.g. dicyclohexylcarbodiimide, and 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. Suitable procedures for the formation of an activated ester or imidazolide are described in method (7) . -2720) The compounds of the formula (I) wherein X, Y, R and R1 to R10 are as defined for a compound of the formula (I) in method (19) may be prepared by reaction of a compound of the formula (XV) wherein Y, R, R1 to R4, R11, R12 and R13 are as previously defined for this method and Z6 is as previously defined for a compound of the formula (XV), with an amine of the formula (XVI) wherein R5 to R9 and R24 are as previously defined for an amine of the formula (XVI). 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. 21) The compounds of the formula (I) wherein X is NH or N(Cj-C4 alkyl), R10 is COOH or CONR12R13 and Y, R, R1 to R9, R12 and R13 are as defined for a compound of the formula (I), may be prepared by reaction of a compound of the formula :- ... (XVII) CO(OH orNR12R13) or a base salt thereof -28wherein Y, R, R1 to R4, R12 and R13 are as previously defined for this method and R25 is a suitable esterforming group, e.g. Cj-C4 alkyl or p-nitrophenyl, with an amine of the formula (XVI) wherein R5 to R9 are as previously defined for this method and R24 is as previously defined for a compound of the formula (XVI).

The reaction may be carried out in a suitable solvent, e.g. a Cj-C4 alkanol, at from room temperature to the reflux temperature. 22) The compounds of the formula (I) wherein R10 is COOH and X, 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:- wherein X, 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. -2923) The compounds of the formula (I) wherein X is C2-C4 alkylene optionally substituted by Cj-C^ alkyl or aryl, and Y, R and R1 to R10 are as previously defined for a compound of the formula (I), may be prepared by reduction of a compound of the formula (I) wherein X is C2-C4 alkenylene or C2-C4 alkynylene, said alkenylene or alkynylene group being optionally substituted by Cj-C4 alkyl or aryl, and Y, R and R1 to R10 are as previously defined for a compound of the formula (I).

The reduction may be carried out using hydrogen in the presence of a suitable catalyst, e.g. palladiumon-charcoal, and in a suitable solvent, e.g. ethanol or ethyl acetate, at from room temperature to the reflux temperature and at a pressure of from one to five atmospheres (1.01 χ 105 to 5.07 x 10s Pa). 24) The compounds of the formula (X) wherein one of R6, R7 and RB is a group of the formula -Z(Cj-C15 alkyl) or -Z(C3-C7 cycloalkyl), the alkyl of said -ZiCj-Cjj alkyl) group being optionally substituted by Cj-Cjq alkoxy, aryl, C3-C7 cycloalkyl or a group of the formula -Z(aryl), Z is 0, S, NH or NiCj-Cg alkyl) and the remainder of R6, R7 and R8, R5, R9, X, Y, R, R1 to R4, R10 and aryl are as previously defined for a compound of the formula (I), may be prepared by reaction of a compound of the formula:IE 922387 -30R R X—( V-R2» ....(XIX) or a base salt thereof, wherein one of R27, R28 and R29 is a group of the formula -Z7-H wherein Z7 is 0, S, NH or N(C1-C6 alkyl) and the remainder of R27, R28 and R29 are as previously defined for this method for the remainder of R6, R7 and R8, R26 and R30 are as previously defined for this method for R5 and R9 and X, Y, R, R1 to R4 and R10 are as previously defined for this method, with a compound of the formula R31Z8 wherein R31 is Cj-C^ alkyl or C3-C7 cycloalkyl, as appropriate, said alkyl group being optionally substituted by Cj-C10 alkoxy, aryl, C3-C7 cycloalkyl or a group of the formula -Z(aryl), wherein aryl and Z are as previously defined for this method, and Z8 is a suitable leaving group, e.g. halo, preferably chloro, bromo or iodo, methanesulphonyloxy or p-toluenesulphonyloxy. -31The preferred base salts of the compounds of the formula (XIX) are the sodium and potassium salts.

Where Z7 is 0 or S the reaction is preferably carried out using a base salt (i.e. a phenoxide or thiophenoxide base salt) of a compound of the formula (XIX) which may be generated in situ from the corresponding phenol or thiophenol of the formula (XIX) using a suitable base, e.g. sodium or potassium hydroxide or sodium hydride, and in a suitable solvent, e.g. ethanol or Ν,Νdimethylformamide, at from 0°C to the reflux temperature.

Where Z7 is NH or NfCj-Cg alkyl) a compound of the formula (XIX) may be reacted with a compound of the formula R31Z8 in the presence of an additional acid acceptor, e.g. pyridine, and in a suitable organic solvent, e.g. dichloromethane.

) The compounds of the formula (I) wherein R10 is COOR11 or CONR12R13, one of R6, R7 and R8 is a group of the formula -0((^-^ alkyl), -O(aryl) or -O(C3-C7 cycloalkyl) , the alkyl of said -OfCj-C^ alkyl) group being optionally substituted by ci“ cio alkoxy, aryl, C3-C7 cycloalkyl or a group of the formula -Z(aryl), and the remainder of R6, R7 and R8, R5, R9, X, Y, Z, R, R1 to R4, R11, R12, R13 and aryl are as previously defined for a compound of the formula (I), may be prepared by reaction of a compound of the formula (XIX) wherein one of R27, R28 and R29 is OH and the remainder of R27, R28 and R29 and R26 and R30 are as previously defined for a compound of the formula (XIX) in method (24) and X, Y, R, R1 to R4 and R10 are as previously defined for this method, with a compound of the formula R32OH wherein R32 is Cj-Cjg alkyl, aryl or C3-C7 cycloalkyl, as appropriate, -32said alkyl group being optionally substituted by C7C10 alkoxy, aryl, C3-C7 cycloalkyl or a group of the formula -Z(aryl), wherein aryl and Z are 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. 26) The compounds of the formula (I) wherein X is CH(Ci~ C4 alkyl) , R10 is COOR11 or CONR12R13 and Y, R, R1 to R9, R11, R12 and R13 are as previously defined for a compound of the formula (I), may be prepared by alkylation of a base salt of a compound of the formula (I) wherein X is CH2 and Y, R and R1 to R13 are as previously defined for this method, with a compound of the formula (Cj-C4 alkyl) Z9 wherein Z9 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 (I) for use in this method are the sodium and potassium salts.

The reaction may be carried out by first reacting a compound of the formula (I) wherein X is CH2 with a suitable base, e.g. sodium hydride, and in a suitable solvent, e.g. Ν,Ν-dimethylformamide, at from 0°C to room temperature, followed by in situ alkylation of the base salt formed with a compound of the formula (Cj-C4 alkyl) Z9. -33All 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 5areductase 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 5α-reductase inhibitory activity using prostate tissue from rats or humans.

The compounds of the formula (I) may be tested for potency in inhibiting rat steroid 5o-reductase using ventral prostate tissue from male rats. In determining inhibitory potency against rat prostatic 5α-reductase the following procedure was employed:IE 922387 -34Rat 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 lmM dithiothreitol) with a Brinkman Polytron (Kinematica, Luzern, GmBH), and then homogenised with a motor driven (lOOOrpm) Potter Elvehjem (teflon-to-glass) 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,OOOG. The resulting pellet was dispersed in Buffer A (lml 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 (Ιμϋΐ, 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 aliquot of prostate particulate suspension.. The reaction mixture was incubated at 37 °C for 3 0 minutes and then quenched by addition with vigorous mixing of 2ml of ethyl acetate containing 20μ% each of testosterone and 5 adihydrotestosterone 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). -35The radiochemical content in the bands of the substrate (testosterone) and the product (5otdihydrotestosterone) was determined with a RITA Radio TLC Analyser (Raytest Instruments Ltd., Sheffield, U.K.). The percent of recovered radiolabel converted to 5oc-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 5ce-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 5ce-reductase using tissue from hyperplastic human prostates. In determining inhibitory potency against human prostatic 5α-reductase the following procedure was employed: Frozen 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 -36pellet 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 (Ιμϋΐ, 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 5ctdihydrotestosterone 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). -37The 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 5ce-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 5a-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 steroid 5a-reductase activity in human prostate adenocarcinomas using cell lines DU145 and HPC36M. In determining inhibitory potency against 5o-reductase the following procedure was employed:Human 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. -38The following components were added to a test tube: 10μ1 of [3H]-testosterone (1/iCi, 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 x 106 cells). The reaction mixture was incubated at 37°C for 2 hours and then quenched by addition with vigorous mixing of 1.5ml of ethyl acetate containing 20μg each of testosterone and 5oe-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).

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 percentage of recovered radiolabel converted to 5ce-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. -39The 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.

For 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 -40any 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.

The 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; -41ii) 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; v) a method of treatment of a human to inhibit a steroid 5α-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 (II) (with the proviso that R14 is not as defined for R11) , (IV), (VIII) or a base salt thereof and (XIX) or a base salt thereof. -42The following Examples illustrate the preparation of the compounds of the formula (I):I ILLUSTRATIVE METHOD 1 (R,S)-4-(3-Γ4-(1-Γ 4-(2-Methylpropyl)phenvl)ethoxy)benzoyl)indol-l-yl)butanoic acid A solution of (R,S)-4-(3-[4-(l-[4-(2methylpropyl)phenyl]ethoxy)benzoyl]indol-l-yl)butanoic acid ethyl ester (3.8g) 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 cautiously 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).

EXAMPLES 1 to 18 The following compounds of the general formula:- (CH2)3COOH or base salts thereof, were prepared by hydrolysis of the corresponding ethyl esters (see Examples 19 to 36) by similar methods to that used in illustrative Method 1. -43ω ω ro c < CM CM CO ν° φ u- C0 Ξ ΝCTcm CM CO 10 X 0)0( CD CO ϋθ .. .. Ζ co tg°o § 3= £ ο a1'-LL ο ο ιοΞ « ρ ° -Ε11 ιη LO f'-. Ο ~ ω χ Ω TD α> m 53 ·ν £ ?ξ X -σ X CM ΐ^ > ιη ιο cm ο £ Tj- C- CL . . CL ΙΙΐχφ· CM CM CM ·,--L « cnι · in co oo CM •T X co t CM Ο ί) m o o O CO CO CO 7 CM CM in h- co CO M CM cn O Oo X O CO co I in o ι< X OO .. z T5 ® n o S LL O <+ cn in x' cn co t-’ 1^O w s? 2 <0 •5 cr cv ω -το Τ CM CM CM 11 O to 'g o ω x Ω '“'CM O' 2 X Z CM X E X CM §5 cn co JE - o X CM CO co —'χ in Eo co X CM in o CM CM xt C~E CL CL Analysis/NMR X o ο x 2- . CM J1 CM CN Ο p Z w · - c\i ω A ± ON- .. ^to -L Q mq 11 o . pp co O in to T Lp- in 4. θ x 9 X X - - O jX ω t- o to OX · on v N; S cn in τ t S Ω ~L°> & g- 4 O ·«,£ N- c g S.2g Σι~^Ε Ε X A Z cn in ο o o & σ<\ . -CN CN xr ll O 2 ζ Λ 3-xt r- 00 Found: C.78.11; H.7.23; N.2.99; C33H37NO4 requires: C.77.47; H. 7.29; N.2.74%. 1H-NMR (de-DMS0): 0.90 (m,6H), I. 30-2.00(m,7H), 2.20(m,2H), 2.35(t,2H), 2.49(t,2H), 4.00(s,2H), 4.10(t,2H), 5.00(m,1H), 6.80(d,2H), 7.10-7.40 (m,9H), 7.75(s,1H), 8.40(m,1H) ppm. m/z co Τ' ♦ ™ + 4o E 1 1 r-. X δ δ σ> X o ο \ x* (/ o / X CN X o CN X o Example No. co N Od co co ro c < Dd jn CL E ro . x . LLI -45ο I CM O CM £ 11 O 60 00 χΗ o ω x '—'CM Dd 2 X Z CM X E X CM m c τΤ E Qϊ°ι E‘ 3co CM O cm r-2 't -+^-00 -ZX X ·+ X ™ E o o cT τ- cn co -+' to bb- + m X o o in cn CM co co -+ x' cn Φ i— CTo^ Φ ID *— bO CM iz UO co o in <7 “4 co Ο τ dzJb^S ζχφ o S<°ll Ο O co bco cn -+ CM X o co ο I CM CM CM £, II IO 60 O O ω x CM Q ®s Ό X '-CM Dd Ξ X Z CM x e' X CM T? σ> X to - 22 X ° CM to OO b^ CM_ in χ in cn E CL CL O CO b~’ E in ιή o cm cm -+ Tf' b 03 -46- X X X - CM T“ • «“ . - CM .80 co’ CD CO o XS . E, .71 co co o X XJ in CM cj o r=> ό CM in CM CM in ς?- z’ CM ii°· ™ z‘ CD CM ω Oi X 5.32; CD O c/j II to CD o . xj, H 77 o oj co 5Γ CM co M· O c/j φ II LO o Έ co . ω χ· ο cj °? Db “T Φ o ~ ω “O X =J o S-Z ω • ¢/3 X cr • ω X **-** • alysis/NM : C,68.37; ω 00 £ σ> cd LD O 2 z · - Q 'ts XZ, Db cm m x cE'T in o in - -S oj τ o in CM OO τ' 1— : C,65.06; φ S< CM *00 θ CM Sz O J- Q co TO^ ob CJ «ί CM m χ ο ο x O oj E CL Ο- Χ c < XJ c -» CM CM ,_ X U Z X X xi-Tcm in in ii o ppm. Ό C CO Γ** xs 2 z X CM *£,ίγ in ό ci o LL r- IO CM O X r- CM CM -ίΕΈ i< OO l·-’ o LL fs't O X » X e[ 4.2 7.2 oo + N CO £ b-1 '—' ci o 1 £ CM o z \ o \ 1 2 N. / \ Ob > o \ 6 > o \ CM cm X X X o o φ CL E to X ό z N- 00 UJ OC 5 z 7/5 (Λ >» Found: C,74.76; H.5.84; N.3.17; w ω Z0 cr Φ V- o CM X o z IA CM X K. CM o C,74.30; H.6.00; N,3.21%. in o cm II to O ω Q 1 CD OC z X X CM v/ in o X cm if CM CM X CM £ 4.30(t,2H), 5.05 (s,2H), 6.95(d,2H), ί 7.20-7.40(m,7H), 7.60(d,1H), 8.20(d,1H), 8.60(s,1H) ppm. co r- C,70.11; H,7.19; N,3.03%. X co_ o CD o II X E* X CM E[ cf CM CM X co e[ cf Ο- ι o CM 2.35(t,2H), 4.05(s,2H), 4.20( 4.25(t,2H), 6.80(d,2H), 7.20- X to ° c oo E Ο- Χ m .£ o •^r r-‘ 8.40(m,1H) pp TO £Z < N ♦ oo co + E CM rt ci O E β < r // co X o CM X o CM r- oc X o ό X o \ o k CM CM X X X O o Φ Cl E TO X No. σ> o LU X 2 z ~ui ω >> CO t= < A- 03 ^10 CO 'T CM CM E Z cm‘ οχ ii o - - So to CM χ χ χ in czi AA^ ™ -r ω o A. O’ 2, F «§.§ sS°S° ^2« 9.S·»^.» “S'2 S'.5»-* ό 210 3> τ tn E w £l ” ZCMOOO o s10- -j- c Ο N oq ll Ο I r £m s s Found: C.72.38; H.5.38; N.3.29; C26H24NO5 requires: C.72.54; H.5.62; N.3.25%. 1H-NMR (de-DMSO): δ = 2.15 (m,2H), 2.25(t,2H), 4.20 (t,2H), 5.00(s,2H), 6.90 (d,2H), 7.10(d,2H), 7.20-7.40(m,8H), 7.95(s,1H), 8.10(m,1H) ppm. JM E co + 430 (M+) I 4o E IT) co m m x— x— CD b00 CO x— x— X P o / P o \ X NH 1 o Example No. - CM DC 2 z To to >. to c < Found: C.74.11; H.6.62; N.5.61; AT co xt 1- O to’ ω '|sA CT r\i 2 co v TO Ql Z Z.AT co Ftb co O X o 00 o 11 (O O ω S Q to TJ, DC 2 z 1 X (d,6H), 1.55(d,3H), 1.75 (m,1H), 2.10(m,2H), 2.20 (t,2H), X ssfT liSrL E_ TO Ο O to x- CO CM O xt co r-~ co xx X X CM x-_ CM x- 2, £oF Ο O TO Io xt CM O hcm to rT t-T 8.15(s,br,1H) ppm. Found: C,76.07; H.5.60; N.3.18; CM TO CO b~ d co 0) •S= 3 o'er CD φ x- O Z Z„TO o TO CM O X II to o co Q to Ό DC 2 Z 1 X X CM e[ CO CM CM X CM e[ o CM X o Sg 7.84(d,2H), 8.35 (d,1H), 8.78(s,1H) ppm. F O CM TO X CM e[ o TO xt 7.12(d,2H), 7.20-7. N cn Τ' cn Τ' E $2 TO xt F ci 1 CO r~- 1 m co CD co TO TO E • co X CO o X ( r- DC co X y_ Λ o o / > / X o To' ll c I X co X z O F. φ CL TO ° TO Xt x Z V— nr- UJ Analysis/NMR Found: C,73.85; H.7.04; N.2.53; co CN Ν’ r- O in Φ L_ 3 σ o Φ o'*- CN co O CN ro Z ό -τ’oo « CO CO O X o oo o II MO o ω Ω 1 co 2, X Z 1 X I (d,6H), 1.44(d,3H), 1.65 (septet,1H), 1.94(m,2H), 2.12(t,2H), 2.35(d,2H), 2.80(t,2H), 3.06(t,2H), 4.18(t,2H), 5.35(q,1 H), 6.75(d,2H), 7.00-7.30 (m,8H), X ρ LO co CO X P cn 00 X TO c\f iq r-‘ ppm. N. 2.54; res: f O. -L X X 'r« cr Ή- ίΗ O CN 6.75(d,2H), 7.15(d,2H), 7.28- 7.40(m,3H), 7.45(d,2H), 7.58(d,2H), 7.77(s,1H), 8.40(m,1H) ppm. I Found: C,67.00; H,5.24; ω · CN O z CN X n + to O ζ n / * u. r- tt> v- CM X o o Z/LU Tf co LO + T— + o τ- ΙΟ + τ— + m.p. p - 1 Ci X ο O X/ ro UL o / /- < c ) „ 4- CO 5-< λ /KO / o / X CN ^CN X p CN X o Ω. t (0 X LU ό z LO co Isolated as the sodium salt. -51X ζ To ω _>x ro c < ο to CM Ζ io co Χ* <Ζ) . Φ ι_ θ' 3 Ν σ-co φ CM Ο . χ-' χ**» A Ν °θ CO CO ‘Q.

·* X ΟΟ .. .. Ζ σ> σ § X £> ο LL Ο Ο τ X CM co -σ Ό Ο in o CO CM CL co N CO c CL II X CM X c CO in X CO ο- a' e[ (O o up co CM ο’ co t o CM CO N Q in A 00 X CM ε Ζ ο Τ 04 CM χ I X CM ό ω ο CM Ν co ο χ— A Α A JM E h- ♦ o rX / CM X o Ν CO CM ζ' CM CM a x‘ X co o in co o II LO X co E CL CL X x IF cm cm zx X Ε E 0-^5 A in co Φ CL E ro . x . LU ω A> U. CD co S™ co Q.CO CM X V CO A^x o O ... Z C*5 σ § X <£ o u_ Ο O 'To in O Q O '-'X QJ co Ξ -σ in o cm N CO CM CM N co in co σ N co xxx sx x CM CM X CM σ E~ ο o in ο χ— in o in CO CM CM CM o co x— F CM N in A A to X / co X o X o co -52ILLUSTRATIVE METHOD 2 (R, S) —4 — (3 - f 4 - f1-Γ4-(2-Methvlpropy1)phenyl1ethoxy)benzoyl1indol-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 (5.24g) in dimethylformamide (30ml). After stirring for one hour at room temperature a solution of «-methyl-4-(2-methylpropyl)benzyl bromide (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 successively 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). -53EXAMPLES 19 to 30 The following compounds of the general formula :- // \ R7 (CH2)3CO2CH2CH3 were prepared by alkylation of the corresponding phenol derivatives (see Preparation 4 and Example 37) with the corresponding alkyl bromides (see, e.g., Preparations 11 to 13) by similar methods to that used in illustrative Method 2.

- - X CD X X5fX £ -- F ΪΜ F ^- xt tO X TO X CM t5 o JClfi TOOC? s-J^rs CM z' N- o o TO TO CM CM xt rT cn ’ CM τΓ Γ'*- ---EE AT CD l·- TO 11 X X ZXog±z CM CXJ CM xf o CD o II X X X ,F CM_ CM. ω- nalysis/NMR -Q- CT Ό h* ο f-> (VN to Ό ν — cn CM r 5 ~ ; 2 s £ TC X x CC to ™ F °i 00 5 Ε ω cto d: C,79.00; H, in Φ . .!= xo 3 CT TO φ CO CM O Z z ·- n CD CO o Q O DC TO TO CM τ' CM E FS-O TO C° °®A »SE E CL CL X E < Z o* o cf to* in F c -j£?CM Z TO* to o to TO 1 TO CM x— CM χ— - o m CO n 1 T CM x— x— CD xt ΣΞ ▼“ v’ CM xt TO Γ-.' F LL O X -L CM xt to 00 + JM CD CM E CM TO TO TO ο. O I Ε — 1 • co / λ X V CO O X_/ // > / / /= (/ T // // <0 )-' r*. X / / DC o / \ o / CM CM X X X O o Φ CL Ε (0 ό cn o X z CM LLI - - - m _._r X XX T X CM X CM CM l~ co 1 co -*-T m CM in in CM CM T r-' XX XX in CD o X in iff χ~ co in cm in £cm . ° χ χ X o Q. II CM CM CM IJ CO CTO to CO — ri73 T DC 2 co in Τζ'ιη co Q CD CM μ oo E '''co σ —, ι ~r in o in “ CO CO ζΞ TO CM - Z 7n o Q O . CM CM CO iC cx . (CDC v-' cm co r- _E_ ^Z^Z. - ,-zxo ω X X X X X X =FX X 'T co c OC 2 E OT-S TO T- E e’ oc CO CM Jiq t- -M- co e‘s'wf e‘e'-S < z in if o in in z o o in m in J » X CM v- o cm in in ’Φ T co X CO CM Ο Ο T-T cm T in T 77 + JM rt Τ' o T— + E CM in rt in 4d 1 E • co X o o / o 4 ) /— / // S V-L // s. DC o / T / CM CM X X X o o Φ CL E · TO ° X— CM x z LU CM CM -56Dd Z Ίο co ro CZ < CM τ— co ..

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X CM 60 J-Lo _”CO Ο 8r ie’ Ζ o X Λ CM X CM CO in cn +2 X x CM-CM co o m τ- CM ·+ X x CO- CM co cr cTin co ι-; co +X P jE CL CO τ' CM o b00 X +- X £2 in co cn co co r-2 X co in CM X CM cT +CM CM +' bX II CM co Z-b O _£? CO O CM Q . 9x £ Z co 1 CM X · - CM XXX CM- CM- TCTTO co’ „ σ o 2 cn co 2Ξ- CD bE CL CL XXX cm cn TΎ E in in ο o co co to +; +-’ in r-2 co CM ω 22 -57(Λ ω CO c < JM £ CL ω CL £ co . X . LU Ss St tn i X ί j c cn 1 co TJ 60 ’ ®' O CM u. o : o LO CM X o LO CM X cn in CM X CM ίΤ> ιό CM CM n- r-Z X II CM to c£Xo _p 8j o Ζ o X^· •Τ' CM o v χιιφ CM -1- CM CM CM SSS-o ° ° O CM. CO !£ cn co CO S x x x x x CM in ΐ Eo in £.32 o o n- in rZ rZ E CL CL co’ co CM Z* to CM in x’ in cn co co O X) c o LL CM nco co O w ω L_ 'O cr x Q) 0^ *- l~ * co θ CM Sz O a: x„in CM O X M- + cm ;> in ECM X co CM X X CM cn •4—» , Γ 0 in eg cm in n· rZ II to Ω O DC Z I X X X X X CM CM CM_ T^sSS^32 ο _ Ο <3 eg cn co cm cd rZ E CL CL X spX X X CM CM CO M£^32^ ,§j= ο ο φ 0 0 cMT-T-in·^cm n- in rZ co / x Db 2 Z ω >, ro c < τ x § CM CM . — co IE 8«»’”· . Ο E ε II O -1- Ϊ 10 S 2 CM - Tt CX Ei0 « rr 2 2 CM CO * o”vi Si-5X f £7 CC £ 2 Em cm oo Z in ο o in ~z • CM CM CM oo - ? T-’ CM Tt CD iS 10 S in , 2. CM C55 3E Z? c zj ° . . £ I . . £- 05 . - CX coN. ο^ΙχΧ^^Ε^ 2 Ο x 2.X 2.X 3= ί$Ή b- . ω c cm c t\ . j· y X'$ E 04-5^ ^cM°n-hQSSS co σO Οω^^ ^· φ co q j· ω s co b- o .-5 . 002 ~χίχ5^ί5ί x> -co wc w b SSSiS E X 2 Z ii co i\ c\fin in ο o q £ l\. 'CMCOCOOt-CMt-S; 11 Ο T rE-c\jc0 4ifibb JM E 1 1 4ϋ E 1 ) r- Db CM CO X o CM X o CM X o X o o 1 « X CO o J o / X CM X o CM CM X o Example No. b- CM 1 28 X ζ ^/5 w >, ro c <1H-NMR (CDCI3): δ = 1.25(t,3H), 1.60(d,3H), 2.15(m,2H), 2.25(t,2H), 4.00(s,2H), 4.15(q,2H), 4.21 (t,2H), 5.30(q,1H), 6.80(q,2H), 7.15(q,2H), 7.25-7.40(m,3H), 7.50(d,2H), 7.60(d,2H), 7.77(s,1H), 8.40(m,1H) ppm. Ή-NMR (CDCI3): δ = 1.24(t,3H), 1.65(d,3H), 2.18(m,2H), 2.30(t,2H), 4.00(s,2H), 4.11(q,2H), 4.19(t,2H), 5.31(q,1H), 6.85(d,2H), 7.20(d,2H), 7.28-7.60(m,12H), 7.75(s,1H), 8.40(m,1H) ppm. JN E 00 + co A-o' E 1 • X co P o / o 4 o / X CM X o CN X o Example No. CD CN o co -60EXAMPLE 31 4—(3 — Γ2—(4 — Γ1-(4-r2-Methvlpropyllphenyl) ethoxy1phenvl)propanoyllindol-l-vl)butanoic acid ethyl ester (racemate) (CH2)3CO2CH2CH3 (CH2)3CO2CH2CH3 A solution of (R,S)-4-[3-(4-[l-(4-[2methylpropyl]phenyl)ethoxy]phenylethanoyl)indol-1yljbutanoic acid ethyl ester (see Example 19) (522mg) in DMF (5ml) was treated with sodium hydride (60% dispersion in oil, 43mg) and stirred at room temperature for 10 minutes. Methyl iodide (62μ1) was added and stirring was continued for 16 hours at room temperature. The mixture was diluted with ethyl acetate (30ml) and washed with IN hydrochloric acid solution (30ml) and water (30ml). The organic layer was dried (MgSO4) and evaporated to give a yellow oil which was purified by flash chromatography (silica, 3:1 hexane/ethyl acetate) to give, after evaporation of the appropriate fractions, the title compound as a yellow oil (247mg). -61^-NMR (CDC13) : δ= 0.90(d,6H), 1.30(t,3H), 1.50(d,2H), 1.55(d,3H), 1.80(m,lH), 2.15(m,2H), 2.24(m,2H), 2.40(m,2H), 4.10(m,4H), 4.38(q,lH), 5.20(q,lH), 6.78(d,2H), 7.05(d,2H), 7.10-7.40(m,7H), 7.62(d,lH), 8.40(10,111) ppm.

EXAMPLE 32 (R.S)-4-(3-ΓΝ-(4-ί1-f4-Γ2-Methylpropyl1 phenyl) ethoxvlphenyl)carbamoyl)indol-l-vl)butanoic acid ethyl ester CO2CH2CH3 -62A solution of 4-(3-[N-(4-hydroxyphenyl)carbamoyl]indol-l-yl)butanoic acid ethyl ester (see Preparation 2) (220mg) in DMF (5ml) was treated with sodium hydride (60% dispersion in oil, 26mg). After stirring for 30 minutes a solution of a-methyl-4-(2-methylpropyl)benzyl bromide (see Preparation 12) (174mg) in DMF (2ml) was added and stirring continued for 45 minutes. The mixture was diluted with ethyl acetate (30ml) and washed successively with 2N hydrochloric acid solution (50ml), water (5 x 30ml) and saturated brine (2 x 30ml).

The organic layer was dried (MgSO4) and evaporated to give a yellow oil (265mg). Flash chromatography (silica, 3:1 hexane/ethyl acetate) gave, after evaporation of the appropriate fractions, the title compound as a gum which crystallised from diethyl ether, (193mg), m.p. 101-103°C. Found: C,75.56; H,6.97; N,5.39; C33H38N2O4 requires: C,75.30; H,7.28; N,5.32%.

^-NMR (CDC13) : 6= 0.90(d,6H), 1.25(t,3H), 1.60(d,3H), 1.81(m,lH), 2.15(m,2H), 2.30(t,2H), 2.45(d,2H), 4.10(q,2H), 4.20(t,2H), 5.25(q,lH), 6.85(d,2H), 7.10(d,2H), 7.25-7.50(m,7H), 7.55(s,lH), 7.75(s,lH), 8.00(m,lH) ppm.

,E 922387 -63EXAMPLE 33 4-(3-fN-(4-Benzvloxyphenyl)carbamoyl)indol-lyl) butanoic acid ethyl ester co2ch2ch3 -64A solution of 3-(N-[4-benzyloxyphenyl]carbamoyl)-1Hindole (see Preparation 3) (4.0g) in DMF (60ml) was added to a suspension of sodium hydride (60% dispersion in oil, 5l5mg) in DMF (20ml). After stirring for 30 minutes at 20°C a solution of ethyl 4-bromobutyrate (2.52g) in DMF (20ml) was added. After stirring for 30 minutes at 20°C the DMF was removed in vacuo. The resultant off-white solid was triturated with ethyl acetate and filtered.

The filtrate was absorbed onto silica gel and chromatographed (silica, 1:1 ethyl acetate/hexane) to give, after evaporation of the appropriate fractions, the desired product, (850mg), m.p. 124-126°C. Found: C,73.91; H,6.38; N,6.14; C28H28N2O4 requires: C,73.66; H,6.18; N,6.13%.

^-NMR (CDC13) : 6= 1.20(t,3H), 2.15(m,2H), 2.25(t,2H), 4.10(q,2H), 4.20(t,2H), 5.04(s,2H), 6.95(d,2H), 7.257.50(m,8H), 7.55(d,2H), 7.65(s,lH), 7.75(s,lH), 8.05(m,lH) ppm.

EXAMPLES 34 to 36 The following compounds of the general formula:- / % (CH2)3CO2CH2CH3 were prepared by similar methods to that used in Example 33 using the corresponding ΙΗ-indoles (see Preparations 4 to 6) and ethyl 4-bromobutyrate as the starting materials.

Example No. X m.p. (°C) m/z Analysis/NMR 34 0 96- 97 Found: C,73.07; H,5.87; N,3.03; C,oHo7NOc requires: C, 7 3.34; H,5:94; N,3.05%. ^-NMR (CDC13) : δ = 1.30 (t,3H), 2.25(m,2H), 2.40 (t,2H), 4.20(q,2H), 4.35 (t,2H), 5.10(s,2H), 7.05 (d,2H), 7.20(d,2H), 7.307.50(m,8H), 8.00(s,lH), 8.30(m,lH) ppm. 35 CH=CH (trans) 83- 84 468 (M+l)+ Found: C,77.00; H,6.11; N,3.01; C28H25NO4 requires: C,77.06; H,6.25; N,3.00%. ^-NMR (CDC13) : δ= 1.28 (t,3H), 2.30 (m,2H), 2.40(m,2H), 4.20 (m,2H), 4.35(m,2H), 5.15 (s,2H), 7.02(d,2H), 7.28-7.55 (m,9H), 7.65(d,2H), 7.84 (d,lH), 7.94 (S,1H), 8.55(m,lH) ppm.

Example No. X m.p. (°C) m/z Analysis/NMR 361 ch2 Found: C,76.22; H,6.29; N,2.98; C29H29NO4 requires: C, 76.46; H,6.42; N,3.07%. lH-NMR (CDC13) : 5= 1.30 (t,3H), 2.20(m,2H), 2.35 (t,2H), 4.10(s,2H), 4.15 (q,2H), 4.25(t,2H), 5.05 (S,2H), 6.95(d,2H), 7.257.45(m,10H), 7.8O(S,1H), 8.45(m,lH) ppm.

The reaction mixture work-up was to add IN hydrochloric acid solution and extract the mixture with ethyl acetate. The organic layer was washed with brine and then water, dried and concentrated in vacuo to provide the required product. The chromatographic work-up used in Example 33 was hence unnecessary. — 67 — EXAMPLE 37 4-(3-Γ 3-(4-Benzyloxyphenyl)propanoyllindol-lyl) butanoic acid ethyl ester co2ch2ch3 -68A solution of (E)-4-(3-[3-(4-benzyloxyphenyl)propenoyl]indol-l-yl)butanoic acid ethyl ester (see Example 35) (lg) in ethyl acetate (25ml) was hydrogenated in the presence of 10% palladium-on-charcoal (250mg) at 4.15 x 10s Pa for 4.5 hours. The reaction was filtered through a cellulose-based filter aid and the filtrate concentrated in vacuo. The residual oil was chromatographed (silica, 40% ethyl acetate/hexane) to first provide, after combination and evaporation of the appropriate fractions, the title compound, (580mg), m.p. 123-5°C, rn/ζ = 442 (M+l)+. Found: C,75.89; H,6.20; N,3.17; C28H27NO4 requires: C,76.17; H,6.16; N,3.17%.

^-NMR (dg-DMSO): δ= 2.00 (quintet, 2H) , 2.25(t,2H), 2.90(t,2H), 3.12(t,2H), 4.25(t,2H), 5.05(s,2H), 6.90(d,2H), 7.20—7.48(m,9H), 7.60(d,lH), 8.20(d,lH), 8.40(s,lH), 12.25(s,br,IH) ppm.

Further elution provided, after combination and evaporation of the appropriate fractions, 4-(3-[3-(4hydroxyphenyl)propanoyl]indol-l-yl)butanoic acid ethyl ester, (240mg).

^-NMR (CDC13) : δ= 1.25(t,3H), 2.14 (quintet, 2H) , 2.28(t,2H), 3.02(m,2H), 3.12(m,2H), 4.02-4.26(m,4H), 5.62(S,1H), 6.75(d,2H), 7.10(d,2H), 7.22-7.40(m,3H), 7.54(S,1H), 8.40(m,lH) ppm. -69The following Preparations illustrate the preparation of certain starting materials used in the previous Examples:ILLUSTRATIVE METHOD 3 4-(3—Γ4—Hydroxybenzoyl1indol-l-yl)butanoic acid ethyl ester A solution of 4 —(3-[4-benzyloxybenzoyl]indol-lyl) butanoic acid ethyl ester (13.4g) in ethyl acetate (300ml) was hydrogenated at 4.15 x 105 Pa 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 cellulose-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).

PREPARATIONS 1 and 2 The following compounds of the general formula:- (CH2)3CO2CH2CH3 were prepared by hydrogenation of the corresponding benzyl ethers (see Examples 33 and 36) by similar methods to that used in illustrative Method 3.

Prep. No. X m.p. (°C) m/z Analysis/NMR 1 CHZ 366 (M+l)+ ^-NMR (CDC13) : δ = 1.25(t,3H), 2.20(m,2H), 2.35(t,2H), 4.10(s,2H), 4.15(q,2H), 4.25(t,2H), 6.80(d,2H), 7.20(d,2H), 7.25-7.45(m,3H), 7.75(S,1H), 8.40(m,lH) ppm. 21 NH 193- 196 Found: C,68.88; H,5.98; N,7.40; C2iH22N2O4 requires: C,68.83; H,6.05; N,7.64%. ^-NMR (d6-DMSO) : 6 = 1.05(t,3H), 2.00(m,2H), 2.15(t,2H), 3.90(q,2H), 4.05(t,2H), 6.60(d,2H), 7.10(m,2H), 7.25(d,lH), 7.30(d,2H), 7.75(s,lH), 8.05(d,lH), 8.45(s,lH), 8.55(s,lH) ppm.

Hydrogenation carried out at 40°C. —71— PREPARATION 3 3-(N-f 4-Benzyloxyphenyllcarbamoyl)-lH-indole ^X___^C00H A stirred solution of lH-indole-3-carboxylic acid (6.0g) in dichloromethane (100ml) was treated with 1hydroxybenzotriazole hydrate (5.0g) and l-(3-N,Ndimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (14.2g) followed by triethylamine (21ml) and 4-benzyloxyaniline hydrochloride (9.65g). The mixture was stirred at room temperature for 2 hours, diluted with dichloromethane and washed successively with water (2 x 100ml), 2N hydrochloric acid (4 x 100ml) and saturated aqueous brine (2 x 50ml). The organic layer was dried (Na2SO4), filtered and evaporated. During the evaporation the desired product crystallised as a white solid and was collected by filtration (5.89g). The mother liquors were evaporated to a pale brown oil and chromatographed (silica, 1:1 ethyl acetate/hexane) to give a further crop of the desired product, (995mg), m.p. 211-214°C.

Found: C,77.55; H,5.51; N,8.26; C22H18N2O2 requires: C,77.18; H,5.30; N,8.18%.

^-NMR (d6-DMSO) : 6= 5.05(S,2H), 6.95(d,2H), 7.10(m,2H), 7.25-7.45(m,6H), 7.60(d,2H), 8.10(s,lH), 8.15(d,lH), 9.60(s,lH), 11.70(s,br,lH) ppm. -72 — PREPARATION 4 lH-Indole-3-carboxylic acid 4-benzyloxvphenyl ester A suspension of lH-indole-3-carboxylic acid (lOg) in dichloromethane (250ml) was cooled to 0°C and treated with oxalyl chloride (8.9ml) and dimethylformamide (DMF) (5 drops). After stirring for one hour the clear solution was evaporated and azeotroped three times with dichloromethane to give the acid chloride as a brown crystalline solid. -73To a solution of 4-benzyloxyphenol (12.40g) in dichloromethane (200ml) was added pyridine (7.5ml) followed by a solution of the acid chloride prepared above in dichloromethane (200ml). After stirring overnight the mixture was evaporated and partitioned between ethyl acetate (100ml) and 2N hydrochloric acid (50ml). The separated organic layer was washed with 2N hydrochloric acid (2 x 50ml) and then saturated brine (2 x 50ml). The organic layer was dried (MgSO4) , evaporated and the residue crystallised from dichloromethane to give the title compound as a white solid, (19.57g), m.p. 188189°C.

Found: C,77.07; H,4.77; N,4.05; C22H17NO3 requires: C,76.95; H,4.99; N,4.08%.

^-NMR (CDC13) : δ = 4.90(s,2H), 6.85(d,2H), 7.00(d,2H), 7.05-7.40(m,8H), 7.90(s,lH), 8.00(m,lH), 11.00(s,br,IH) ppm.

ILLUSTRATIVE METHOD 4 3-(4-Benzyloxybenzovl)-lH-indoIe 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 (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). -74PREPARATIONS 5 and 6 The following indoles of the general formula:- were prepared from ΙΗ-indole and the corresponding acid chlorides (see Preparations 7 and 8) using similar methods to that used in illustrative Method 4.

Prep. No. X m.p. (°C) m/z Analysis/NMR 5 ch2 341 (M+) ^-NMR (d6-DMSO) : δ = 4.00(s,2H), 5.00(s,2H), 6.90(d,2H), 7.107.40(m,10H), 8.10(d,lH), 8.45(s,lH), 12.00(s,br,IH) ppm. 6 CH=CH (trans) 354 (M+l)+ NMR (d6-DMSO) : δ = 5.15(s,2H), 7.007.80(m,14H), 8.30(d,lH), 8.65(d,lH) ppm. -76I ILLUSTRATIVE METHOD 5 4-Benzyloxy-2,3-dimethvlbenzovl chloride 4-Benzyloxy-2,3-dimethylbenzoic acid (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).

PREPARATION 7 4-Benzyloxyphenacyl chloride The title compound was prepared using a similar method to that described in illustrative Method 5 except using 4-benzyloxyphenylacetic acid as the starting material. The material obtained was used immediately.

PREPARATION 8 (E)-3-(4-Benzvloxvphenvl)propenoyl chloride The title compound was prepared using a similar method to that described in illustrative Method 5 except using (E)-3-(4-benzyloxyphenyl)propenoic acid as the starting material. The material obtained was used immediately.

PREPARATION 9 1-(4-n-Propylphenyl)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+) . —77 — ^-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 10 (R.S)-1-(4-f2-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; C12H18O.l/7 H20 requires: C,79.68; H,10.19%.

}H-NMR (CDC13) : δ= 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.

PREPARATIONS 11 to 13 The following alkyl bromides were prepared by dissolving the corresponding alcohol (see, e.g., Preparations 9 and 10) 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 11 1-Bromo-l-(4-n-propylphenyl)butane. 12 Οί-Methy 1-4 - (2-methylpropyl) benzyl bromide. 131 ct- (4-n-Propylphenyl) -4-n-propylbenzyl bromide.

For starting material see EP-A-291245. -78Pharroacological activity A selection of compounds of the formula (I) was tested in vitro for steroid 5ce-reductase inhibitory activity using ventral prostate tissue from male rats according to the procedure outlined on pages 33 to 35 of the specification. The results obtained are presented in Table 1.

Table 1 Example No. IC50(nM) 1 42.6 2 321 3 300 4 39.7 5 1000 6 1000 7 300 8 1780 9 316 10 1400 11 1260 12 64 13 147 14 186 15 276 16 140 17 39.2 18 191 In addition, the compound of Example 36 was tested in vitro for steroid 5a-reductase inhibitory activity using tissue from hyperplastic human prostates by the procedure outlined on pages 35 to 37 of the specification. An IC50 value of 89.7nM was obtained for this compound.

Claims

1. A compound of the formula :- .(I) or a pharmaceutically acceptable salt thereof, wherein X is 0, NH, N(C 1 -C 4 alkyl), Cj-C 4 alkylene, C 2 -C 4 alkenylene or C 2 -C 4 alkynylene, said alkyl'ene, alkenylene and alkynylene groups being optionally substituted by Cj-C 4 alkyl or aryl; Y is Cj-Cg alkylene optionally substituted fo y c i“ c 6 alkyl; R is H, OH, halo, ρ-0 4 alkyl or Cj-C 4 alkoxy; R 1 , R 2 , R 3 and R 4 are each independently selected from Η, ρ-0 4 alkyl, C 7 -C 4 alkoxy, OH, halo and CF 3 ; one of R 6 , R 7 and R 8 is Cj-Cjg alkyl or a group of the formula -ZfCyCjg alkyl), -Z(aryl) or -Z(C 3 -C 7 cycloalkyl), said alkyl group being optionally interrupted by 0, S(0) q , NH or NfCj-Cg alkyl), and said alkyl group and the alkyl group of said -Ζ(ρ-Ο 15 alkyl) group being optionally substituted by alkoxy, aryl, C 3 -C 7 cycloalkyl or a group of the formula -80-Z(aryl), and the remainder of R 6 , R 7 and R 8 and R 5 and R 9 are each independently selected from H, Cj-C 4 alkyl, Cj-C 4 alkoxy, halo and haloiCj-C,, 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 Cj-C 4 alkyl; Z is O, S(0) q , NH or N(C X -C 6 alkyl); q is Ο, 1 or 2; and aryl, used in the definitions of X, R 6 , R 7 and R B , means phenyl optionally substituted by Cj-C 6 alkyl, Cj-Cg alkoxy, C 2 -C 5 alkenyl, OH, halo, CF 3 , haloiCy-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 X is O, NH, ^-Ο 4 alkylene or C 2 C 4 alkenylene; Y is Cj-Cg alkylene; R is H or Ci~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 -OCCj-Cjg alkyl), the alkyl of said -O(Cj-C 15 alkyl) group being optionally substituted by aryl, and the remainder of R 6 , R 7 and R 8 and R 5 and R 9 are each H; R 10 is COOH or COOR 11 ; and aryl means phenyl optionally substituted by from 1 to

3. Substituents each independently selected from Cj-Cg alkyl, Cj-Cg alkoxy, halo, CF 3 , nitro and phenyl. -813. A compound as claimed in claim 2 wherein X is 0, NH, methylene, ethylene or ethenylene; Y is propylene; R is H; one of R 6 , R 7 and R 8 is -0CH z (aryl) or —OCH(Cj-C 4 alkyl)(aryl) and the remainder of R 6 , R 7 and R 8 and R 5 and R 9 are each H; and R 10 is COOH or COOfC^Cg alkyl).

4. A compound as claimed in claim 3 wherein X is methylene; R 7 is -OCH(CH 3 ) (aryl) and R 5 , R 6 , R 8 and R 9 are each H; R 10 is COOH or COOC 2 H 5 ; and aryl means phenyl optionally substituted by 1 or 2 substituents each independently selected from n-propyl, isobutyl, methoxy, chloro, CF 3 , nitro or phenyl.

5. A compound as claimed in claim 4 wherein R 10 is COOH and aryl means phenyl, 4-(n-propyl)phenyl, 4-isobutylphenyl, 4methoxyphenyl, 2,4-dichlorophenyl, 3,4dichlorophenyl, 4-trifluoromethylphenyl, 4-nitrophenyl or 4-phenylpheny1.

6. A compound as claimed in claim 5 wherein aryl means 4-isobutylphenyl.

7. (R,S)-4—(3-(4-(1-(4-(2-Methylpropyl) phenyl]ethoxy)phenylethanoyl]indol-l-yl)butanoic acid or (S)-4-(3-(4-(1-[4-(2-Methylpropyl)phenyl]ethoxy)phenylethanoyl]indol-l-yl)butanoic acid: or a pharmaceutically acceptable salt thereof. -828. 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.

8. 9. A compound of the formula (I), or a pharmaceutically acceptable salt or composition thereof, as claimed in any one of claims 1 to 7 and 8 respectively, for use as a medicament.

9. 10. 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 7 and 8 respectively, for the manufacture of a medicament for inhibiting a steroid 5a-reductase.

10. 11. 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 7 and 8 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.

11. 12. 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 7 and 8 respectively, for the manufacture of a medicament for the curative or prophylactic treatment of a human prostate adenocarcinoma. -8313. A compound of the formula:- or a base salt thereof; or or a base salt thereof: wherein X, Y, R and R 1 to R 10 are as defined in claim 1, R 14 is an ester-forming group that may be cleaved to provide a compound of the formula (I) wherein R 10 is COOH with the proviso that R 14 is not as defined for R 11 in claim l, one of R 27 , R 28 and R 29 is a group of the formula -Z 7 -H wherein Z 7 is 0, S, NH or N(Cj-Cg alkyl) and the remainder of R 27 , R 28 and R 29 are as defined in claim 1 for the remainder of R 6 , R 7 and R 8 , and R 26 and R 30 are as defined in claim l for R s and R 9 .

12. 14. A compound of the formula (I) given and defined in claim 1 or a pharmaceutically acceptable salt thereof, which is specifically hereinbefore mentioned, other than a compound as claimed in claim 7.

13. 15. A process for the preparation of a compound of the formula (I) given and defined in claim 1 or a pharmaceutically acceptable salt thereof, substantially as hereinbefore described with particular reference to the accompanying Illustrative Methods, Examples and Preparations. •Ε 922387

14. 16. A compound of the formula (I) given and defined in claim 1 or a pharmaceutically acceptable salt thereof, whenever prepared by a process claimed in claim 15.

15. 17. A pharmaceutical composition according to claim 8, substantially as hereinbefore described.

16. 18. Use according to claim 9, substantially as hereinbefore described.

17. 19. Use according to any one of claims 10-12, substantially as hereinbefore described.

18. 20. A compound of any one of the formulae (II), (IV), (VIII) or a base salt thereof or (XIX) or a base salt thereof given and defined in claim 13, which is specifically hereinbefore mentioned.