NZ243687A - 1-(omega-carboxyalkyl)-3-[3 or 4-(1-phenylalkoxy or 1-phenoxyalkyl)benzoyl]indole derivatives having steroid 5alpha-reductase inhibitory activity and medicaments - Google Patents

Description

New Zealand Paient Spedficaiion for Paient Number £43687 24 3 6 87i Priority Date(s): .. .<24*.'71: f.', Complete Specification Filed: JA'.TL*/??,-.. Class: Publication Date: . .?.?.?£P. P.O. Journal, No: ., f&n....

NEW ZEALAND PATENTS ACT, 1953 No.: Date: COMPLETE SPECIFICATION indoles We, PFIZER INC., a corporation organised under the laws of the State of Delaware, United States of America, of 235 East 42nd Street, New York, New York 10017, United States of America, hereby declare the invention for which we pray that a patent may be granted to us, and the method by which it is to be performed, to be particularly described in and by the following statement:- 0|5,'!! -i- (followed by page 1A) 24 3 6 8 7 PLC 553 - Case A -lA- INDOLES This invention relates to indole derivatives which have steroid 5cc-reductase inhibitory activity.

More particularly this invention relates to indoles, their preparation and their use as testosterone-5ce-reductase 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 5a-dihydrotestosterone which is formed locally in the above organs by the action of testosterone-5a-reductase. The presence of elevated levels of dihydrotestosterone in many disease states has therefore focussed attention on the synthesis of testosterone 5 oc-reductase inhibitors.

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

EP-A-0458207 discloses certain indole derivatives which have testosterone 5oc-reductase inhibitory activity. m, 24 3 6 8 7 The present invention provides compounds of the formula:- and pharmaceutically acceptable salts thereof, wherein Y is Cj-Cg alkylene optionally substituted by Cj-Cg alkyl; R is H, OH, halo, (^-04 alkyl or C^-C^ alkoxy; R1, R2, R3 and R4 are each independently selected from H, Cj-C^ alkyl, C1-C4 alkoxy, OH, halo and CF3; 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, <^-04 alkyl, Cj-04 alkoxy, halo and halo (0^04) alkyl; 2A 3 6 8 7 R10 is COOH, COOR11 or CONR12R13; R11 is a biolabile ester-forming group; R12 and R13 are each independently selected from H and C^-C^ alkyl; R14 is H, Cj-Cg alkyl, C3-C7 cycloalkyl or aryl; and "aryl", used in the definitions of R6, R7, R8 and R14, means phenyl optionally substituted by C^—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.

In a further aspect of the present invention Y is Cj-Cg alkylene optionally substituted by C^-Cg alkyl; R is H, OH, halo, Cx-C4 alkyl or Cj^C4 alkoxy; R1, Rz, R3 and R4 are each independently selected from H, Cx-C4 alkyl, Cx-C4 alkoxy, OH, halo and CF3; one of R6, R7 and R8 is a group of the formula:- R H R14 I I -OCH-Aryl or -CHO-Aryl, and the remainder, together with R5 and R9, are each independently selected from H, CJ-C4 alkyl, CY-CA alkoxy, halo and halo (C1-C4) alkyl; R10 is COOH, COOR11 or CONR12R13; 9 4 3 6 —4 — R11 is a biolabile ester-forming group; Rlz and R13 are each independently selected from H and Cj-C^ alkyl; R14 is H, C^Cg alkyl, C3-C7 cycloalkyl or aryl; and "aryl", used in the definitions of R6, R7, R8 and R14, means phenyl optionally substituted by C^-Cg alkyl, C^Cg alkoxy, Cz-C6 alkenyl, OH, halo, CF3, haloCCj-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, Rs, 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-methylpropyl)-phenyl)propoxy or 2,2-dimethyl-l-(4-(2-methylpropyl) 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-methylpropyl)phenyl)-ethoxy, 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 when the compound of the formula (I) is in the racemic form; 9 A 3 6 8 7 -5— iv) 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, Rz, 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 R"*"^ 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. 3 6 Esters of the formula (I) wherein R1^ is C02(C^-Cg alkyl) are steroid 5ce-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. C^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 branched-chain, 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 ^"Cg alkyl, specific examples of other biolabile ester-forming groups are benzyl, l-(2,2-diethylbutyryloxy)ethyl, 2-ethylpropionyloxymethyl, l-(2-ethylpropionyloxy)ethyl, l-(2,4-dimethylbenzoyloxy)ethyl, ct-benzoyloxybenzyl, 1-(benzoyloxy) ethyl, 2-methyl-l-propionyloxy-l-propyl, 2,4,6-trimethylbenzoyloxymethyl, 1-(2,4,6-trimethylbenzoyloxy)ethyl, pivaloyloxymethyl, phenethyl, phenpropyl, 2,2,2-trifluoroethyl, 1- or 2-naphthyl, 2,4-dimethylphenyl, 4-t-butylphenyl and 5-indanyl.

The pharmaceutically acceptable salts of the compounds of the formula (I) are the acid addition and the base salts thereof. 0 A 3 6 8 7 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 £>-toluenesulphonate 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 C1-Cg alkylene.

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

Most preferably Y is propylene.

Preferably R is H or alkyl.

More preferably R is H or methyl.

Most preferably R is H. 12 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-C^ alkyl. 943687 More 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 COOR1 Most preferably R10 is COOH.

Preferably Ru is C^Cg alkyl.

Most preferably R11 is ethyl.

Preferably R14 is H, CX-CA alkyl, C4-C6 cycloalkyl or phenyl substituted by ^-04 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 C1-C6 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 4-isobutylphenyl. 24 3 6 A 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 R8 is a group of the formula 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). 24 3 6 8 7 Particularly preferred embodiments of the compounds of the formula (I) are (R,S)-4-(3-[4-(l-[4-(2-Methylpropyl)phenyl]ethoxy)-benzoyl]indol-l-yl)butanoic acid, (S)-4-(3-[4-(l-[4-(2-Methylpropyl)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-Methyl-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 for.mula:- ....(II) 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). 94 3 6 87' -li- 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 R15 is an ester-forming group that may be removed by hydrolysis, e.g. C1-C6 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-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 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. 94 3 6 8 7 2) 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 CONRlzR13 and Y, R, R1 to R9, R12 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 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:- S\ ^(A CONHNHR16 ....(III) 24 3 6 8 7 wherein Y, R and R1 to R9 are as previously defined for a compound of the formula (I) and R16 is H or C:-C4 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.

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:- ..(IV) 94 3 6 8 7 wherein 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:- -00 24 3 6 8 7 wherein Y, R and R1 to R9 are as previously defined for a compound of the formula (I) and R17 and R10 taken together represent ethylene, said ethylene group being optionally substituted by phenyl or Cj-Qj 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 RnOH wherein R11 is as previously defined for this method. ?43 6 8 7 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).

Alternatively the esterification may be carried out by first forming an activated ester or imidazolide derivative of the carboxylic add, 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. l-(3-N,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 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 compound of the formula:- 94 3 6 87 R* y i 1 coz1 ....(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.

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 RUZ2 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. 2 4 3 6 8 7 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 C0NR1ZR13 and Y, R, R1 to R9, Rlz 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 R*° 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 R1ZR13NH 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 R12R13NH. Suitable procedures for the formation of an activated ester or imidazolide are described in method (7).

The compounds of the formula (I) wherein R10 is C0NR1ZR13 and 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 formula (VI) wherein Y, R, Rl to R9 and Z1 are as previously defined for a compound of the formula 24 3 6 8 7 (VI) 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 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 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 (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 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-C,, 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 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 acidic hydrolysis of a compound of the formula:- •>4 3 6 8 7 B4 r»20/-» r»D19 R9 COR .—(VII) wherein Y, R and R1 to R9 are as previously defined for this method, R19 and Rzo are either each C1-C4 alkyl or when taken together represent C2-C3 alkylene, said alkylene group being optionally substituted by Cj-C^ alkyl, and RZ1 is -OH, -ORzz wherein Rzz 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 NR1ZR13 wherein R1Z 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. 24 3 6 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).

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) 3 6 24 3 6 wherein R and R1 to R9 are as previously defined for a compound of the formula (I) , with a compound of the formula Z3-Y-COORu 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 p-toluenesulphonyloxy. 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. N,N-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 2-butanone or acetone as the solvent at about the reflux temperature of the solvent.

Alternatively the reaction may be carried out under phase transfer conditions where a suitable base is sodium or potassium hydroxide. 24 36 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.

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: N R R1 Y C02H ....(X) 24 3 6 wherein 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 R11, 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. 24 3 6 87 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 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) 24 36 wherein Z5 is -CH=CH2, -CH=CH(C1-C4 alkyl), -CH^CCi-C4 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:- r4 ° r9 ....(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) 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:- # Ik3 6 8 7 r24 r9 or 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-l,4-benzoquinone (DDQ) as the oxidising agent. 94 3687 The 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 lH-indole-l-magnesium halide derivative with a corresponding benzaldehyde of the formula:- ..(XVII) tk 3 6 wherein 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 r4 0 r9 ....(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 R5, 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:- R14 7 I Z -CH-Aryl (XIX) ° a 3 6 8 7' wherein 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 N,N-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 CONRlzR13 and Y, R, R1 to R9, R11, 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 CONR12R13, as appropriate, wherein R11, R12, R13 and Y, R, R1 to R5 and R9 are as previously defined for this method and R25 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/ 94 36 triphenylphosphine. 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 "aryl" are as previously defined for a compound of the formula (I), may be prepared by reaction of a compound of the formula or a base salt thereof, wherein one of R28, R29 and R30 is a group of the formula:- R14 I 8 -CH-Z8 24 3 6 8 7i and 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 Z8 is as defined for Z7 in method (19) , with a base salt of a compound of the formula:- Aryl-OH (XXII) i 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 N,N-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.

The compounds of the formula (I) wherein R10 is COOR11 or CONR12R13 and Y, R, R1 to R9, R11, R12, R13, R14 and "aryl" are as defined for method (21) may be prepared by reaction of a compound of the formula:- 24 3 6 8 7 ....(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. 24 36 All 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 5o-reductase 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 5a-reductase inhibitory activity using prostate tissue from rats or humans. 2 4 3 6 8 7 The compounds of the formula (I) may be tested for potency in inhibiting rat steroid 5ce-reductase using ventral prostate tissue from male rats. In determining inhibitory potency against rat prostatic 5 ce-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-to-glass) homogeniser. Prostate particles were obtained by centrifugation at 105,C)00G 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 (1ml per g of prostate tissue originally used) with a motor driven Potter Elvehjem homogeniser as described above. The particulate suspension was stored as 1ml samples at -70°C.

The following components, dissolved in Buffer B (40mM sodium phosphate buffer, pH 6.5), were added to a test tube: 500/il of [3H]-testosterone (1/zCi, lnmol; Du Pont, NEN Research Products, Stevenage, U.K.), 10Qfj.l of 0.5mM NADPH, a compound of the formula (I) dissolved in 5/xl 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 243687 2ml of ethyl acetate containing 20/iig each of testosterone and 5o-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 50-80pi.l of absolute ethanol and spotted onto a silica gel 60 F254 TLC plate (E. Merck, Darmstadt, Germany) and developed in chloroform:acetone v/v (185:15).

The radiochemical content in the bands of the substrate (testosterone) and the product (5ot-dihydrotestosterone) 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 cs-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 5a-reductase the following procedure was employed:- N.7. office " 8 SEP 1994 received 24 36 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 0.3 2M sucrose, ImM dithiothreitol and 50/iM 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 Ultra-Turrax 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: 500/il of [3H]-testosterone (1/nCi, lnmol; Du Pont, NEN Research Products, Stevenage, U.K.), 100/xl 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 5^1 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 3 0 minutes and then quenched by addition with vigorous mixing of 2ml of ethyl acetate containing 2 0^g each of testosterone and 5 a-dihydrotestosterone as carriers. The aqueous and organic layers were separated by centrifugation at 2000G for 10 minutes. The organic layer was 243687 transferred to a second test tube and evaporated to dryness under nitrogen. The residue was dissolved in 50-80/il of absolute ethanol and spotted onto a silica gel 60 F254 TLC plate (E. Merck, Darmstadt, Germany) and developed in chloroform:acetone v/v (185:15).

The radiochemical content in the bands of the substrate (testosterone) and the product (5 a-dihydrotestosterone) 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 5a-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 5 a-reductase the following procedure was employed:- 243687 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 x 106 cells/ml. in serum free medium.

The following components were added to a test tube: 10/il of [3H]-testosterone (1/iCi, 20 pmol) dissolved in ethanol (Du Pont, NEN Research Products, Stevenage, U.K.) and 5fil 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 0.25/zmol 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 20/tig each of testosterone and 5Cf-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 50-80/il of absolute ethanol, spotted onto a silica gel 60 F254 TLC plate (E. Merck, Darmstadt, Germany) and developed in dichloromethane:acetone v/v (185:15). 2 A 3 6 The radiochemical content in the bands of the substrate (testosterone) and the product (5tt-dihydrotestosterone) was determined with a RITA Radio TLC Analyser (Raytest Instruments Ltd., Sheffield, U.K.). The percentage of recovered radiolabel converted to 5 ot-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)) .

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. 24 3 6 8 7 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 2 0mg/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. 943687 The compounds of the formula (I) may also be administered together with an Cfr-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 5oc-reductase ; 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; 243687 v) 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 and (XXIII).

The following Examples illustrate the preparation of the compounds of the formula (I):- 1<*■' « ... 24 3 6 8 7 -44-EXAMPLE 1 CR.S^-4-C3-r4-fl-r4-(2-Methvlpropvl)phenyl1ethoxy)-benzoyl1indol-l-vl)butanoic acid co2ch2ch3 aq.NaOH,THF,CH 30H C02H A solution of (R,S)-4-(3—[4—(1—[4-(2— methylpropyl)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 (3 5ml). After stirring at room temperature for 2 hours the mixture was 24 3 6 8 7 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), m.p. 57°C. Found: C,77.00; H, 6.88; N,2.90; C31H33N04 requires: C,76.93; H,6.88; N,2.99%. 1H-NMR (CDC13) : 6= 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,1H), 6.95(d,2H), 7.15(d,2H), 7.27-7.45(m,5H), 7.59(s,1H), 7.79(d,2H), 8.45(m,lH) ppm.

EXAMPLES 2 to 20 The following compounds of the general formula:- 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. ?4 3 6 8 7 II co o'2- ■ • o r- co ■B OL 3 o a: TO o Q. o z "w CO c < Q , ■ <s 2. a: —cm X CD ^ T- - E fsr# — £ 0 -S cm o in 01 « ^ . cn in X co X X E E X X CM CM Z o iS r- O ID O CM CD o in o CO CM CM* CM ^ ■ « I c3 E - E o — lo^ CM - o o rr o 05 CM - CO cd -i£- oo co CD in co x" X O CM CO CO X ▼— °9 CNJ Is- h- Tf o O o •b c CO Z O) CM T. if) <D U- *13 O CD -J CM a> O - rg liZO CT Sz It to ^ co St 2 Q ^ CC X ° &<=> Zoo ' ■<- CO X O CM q __r "T ° 6 «? -tf-CO ^ ^1 X T, CM 03 *s o| 8 4 CM -iS TJ -w o o o CO h-" h-" X X ■<-_ CM_ o o in cm in h-* X x T3* cn CD CD C (DO ^ sco a X X ±.

CM_ CM - JL in o in N CN oo -t! E 0O CD in + 10 2 ■o co X o rt X o- \ / or \ CO I o- \ / en IO 01 cd > X o LU Z X o CM X o CO Ex. No.

Y R R5 R6 R7 m.p.

CO m/z Optical Rotation/ Analysis/NMR -(CH2)3 H H H 427 (M+) Found: 0,73.30; H.5.66; N.3.06; C27H25NO4.H2O requires: 0,72.78; H.6.11; N.3.14%. 1H-NMR (de-DMSO): 5 = 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. 1 ■c-I -(CH2)3- H H H 441 (M+) Found: 0,71.86; H.6.16; N.3.00; C28H27N04.iy2H20 requires: 0,71.78; H,6.45; N,2.99%. 1H-NMR (de-DMS0): 5 = 1.55(d,3H), 2.00(m,2H), 2.20(t,2H), 2.25(s,3H), 4.28(t,2H), 5.55(q,1H), 7.05(d,2H), 7.15(d,2H), 7.20-7.35(m,4H), 7.60 (d,1H), 7.70(d,2H), 7.90(s,1H), 8.25(m,1H) ppm.

S3 45s Cj4 o> OO ^4 o Ex. No.

Y R R5 R6 R7 m.p. (X) m/z Optical Rotation/ Analysis/NMR -(CH2)3- H H H 59-61 455 (M+) Found: 0,72.60; H.6.06; N.2.90; C29H29N04.iy2H20 requires: 0,72.18; H.6.11; N,2.90%. 1H-NMR (de-DMSO): 8 = 0.90(t,3H), 1.55(m,2H), 2.00(m,2H), 2.20(t,2H), 2.50(t,2H), 4.25(t,2H), 5.10(s,2H), 7.10(d,2H), 7.20-7.40(m,6H), 7.60 (d,1H), 7.75(d,2H), 8.00(s,1H), 8.20(d,1H) ppm.

I 4> 00 I -(CH2)3- H H H 63-65 482 (M+) Found: 0,61.30; H.4.06; N.2.64; C2eH21Cl2N04.11/2H20 requires: C.61.30; H.4.55; N,2.75%. 1H-NMR (CDCIg): 8 = 2.25(m,2H), 2.45(t,2H), 4.30(t,2H), 5.10(s,2H), 7.05(d,2H), 7.25-7.55(m,6H), 7.60(s,1H), 7.85(d,2H), 8.35(m,1H) ppm.

Os« <y> co 9 4 3 6 C\l ill tz o ro o cc "co o Q.

O Cd in en > CO II oS £ CM-CM-§S"~ □ 2 CNJ m in m o m CM CO <0 T3 —■ -—X C£ CD s s Z o ±§ CNJ ^ CD CD CO CO JlXII^ ' - CD CM ■«-_ CM_ - E ,c£s cr "o £ wo in In o o d 00 CO CO T- Tt ^ t- C\i oi If) N N CL in CD CD X* CO oo CD* r- o" -b c 13 o u_ V? O CD . . CM ffl Z 3 co" cr oo OJ CD o-1' .. ^ o> CD co Q) °° x c6 cm t- r- O O .. ° Hi TO — ^ °VE * cd .e ro co o •■S.SJ3 0£ "5 to _r ~«o Q ,r~ O ^ "-"X cr; cd Z in ' CT> d X ^ °i X E CNL u?S CM CD CM 'in CM CM X CM in in X CM X CM o in 00 CD CM CD o o CD Tj" CD in ^1 c T CM C "IS. & E®-•«—h- x in . • ± ^ r~>- r: m CM . -3" ^od N E in oo ■o CD X o- co X o Cd CO X o- \ / / CD Cd in Cd Dd > X O LU Z C5 X o CO X o <N X o oo X o CD < > Ex. No.

Y R R5 R6 R7 m.p. CC) m/z Optical Rotation/ Analysis/NMR -(CH2)3- H H H _l"3 ^ ch3 484 (M+1)+ Found: C.74.11; H.6.71; N.3.12; C31H33N04.H20 requires: C,74.23; H.7.03; N.2.80%. 1H-NMR (CDCI3): 8 = 0.95 (d,6H), 1.70 (d,3H), 1.90(m,1H), 2.25(m,2H), 2.40 (t,2H), 2.49(d,2H), 4.30(t,2H), 5.50 (q,1H), 6.95(d,2H), 7.15(d,2H), 7.27- 7.45(m,5H), 7.59 (s,1H), 7.79(d,2H), 8.45(m,1H) ppm. 11 -(CH2)3- H H H ch3 jt ' M N°^n x ch3 574 (M+1)+ 1H-NMR (d6-DMSO): 8 = 0.95 (t,6H), 1.50 (m,4H), 2.20(m,2H), 2.35(t,2H), 2.50 (t,4H), 4.20(t,2H), 6.25(s,1H), 7.02 (d,2H), 7.17(d,4H), 7.30-7.40(m,7H), 7.55(s,1H), 7.80 (d,2H), 8.40(m,1H) ppm.

I Ui 0 1 I I I I N> 04 O* OO < > o Ex. No.

Y R R5 R6 R7 m.p.

C C) m/z Optical Rotation/ Analysis/NMR 12 -(CH2)3 CH, H H 498 (M+1)+ Found: C.75.14; H.6.78; N.2.88; C32H35N04.H20 requires: C.74.54; H.7.23; N,2.72%. 1H-NMR (d6-DMSO): 8 = 0.90(d,6H), 1.65(d,3H), 1.85(m,1H), 2.10(m,2H), 2.45(m,4H), 2.60(s,3H), 4.20(t,2H), 5.40(q,1H), 6.90(d,2H), 7.00-7.40(m,8H), 7.40(d,2H) ppm.

I 13 -(CH2)3- H H H Found: C.73.61; H.5.53; N.3.29; C26H24N04.1/2H20 requires: C.73.92; H.5.73; N.3.32%. 1H-NMR (d6-DMSO): 8 = 2.00(m,2H), 2.15(m,2H), 4.05(t,2H), 5.05(s,2H), 6.95(d,2H), 7.15-7.40 (m,8H), 7.55(s,1H), 7.75(d,2H), 8.10(m,1H) ppm. ro CM o> (> o Ex.

No.

Y R R5 Re R7 m.p. CO m/z Optical Rotation/ Analysis/NMR 141 -CH,- H H H 478 (M+) Found: C.69.96; H.5.95; N,2.57; C29H29N04Na requires: C.70.29; H.6.10; N,2.83%. 1H-NMR (d6 0.80(d,6H), 1.69(m,1H), 4.72(s,2H), 7.00(d,2H), 7.20(m,2H), 7.40(m,1 H), 7.90(s,1H), ppm.

;-DMSO): 5 = 1.55(d,3H), 2.35(d,2H), 5.55(q,1H), 7.10(d,2H), 7.30(d,2H), 7.65(d,2H), 8.20(m,1H) i Ui I -{CH2)3- H H H 496 (M+1)+ Found: C.63.33; H.5.09; N.3.13; C27H23N04CI2.H20 requires: C.63.04; H.4.90; N.2.72%, 1H-NMR (CDCI3): 5 = 1.65 (d,3H), 2.20(m,2H), 2.40(t,2H), 4.25(t,2H), 5.35(q,1H), 6.90(d,2H), 7.20-7.50(m,6H), 7.55(s,1H), 7.75(d,2H), 8.35(m,1H) ppm. ro Cj4 o> OO Isolated as the sodium salt. o Ex. No.

Y R R5 R6 R7 m.p.

CO m/z Optical Rotation/ Analysis/NMR 16 -(CH2)3- H H H 524 (M+1)+ 1H-NMR (CDCI3): 5 = 0.90 (t,3H), 1.20-1.65(m,10H), 1.90(m,1H), 2.20(m,2H), 2.35(t,2H), 2.55(t,2H), 4.20(t,2H), 4.90(d,1H), 6.90(d,2H), 7.10(d,2H), 7.25-7.40(m,5H), 7.50(s,1H), 7.70(d,2H), 8.35(m,1H) ppm. 17 -(CH2)5- H H H .512 (M+1)+ 1H-NMR (CDCIg): 5 = 0.90(d,6H), 1.30-1.40(m,2H), 1.60-1.65(m,6H), 1.80-1.90 (m,4H), 2.30(t,2H), 2.42 (d,2H), 4.10(t,2H), 5.35 (q,1H), 6.95(d,2H), 7.10 (d,2H), 7.25-7.40(m,5H), 7.52(s,1H), 7.70(d,2H), 8.30(m,1H) ppm. 1 Ln I 4>-CM a> 24 3 6 8 •° cd £ 2 o Z ? I 8 % c o < CNJ in N-" X~ cd" lo CD h- O "O °o tz Is- §3 ll z OO CNJ O ^ CM in X ~co O oo lo cd ■*d .2 » ^ ^ ® co f-5 ^ cm rr cm O ®Z £ ■ cd o o 00 II X— X ■ CM co <■—s , 7 1 ^ n to ou CNJ o E CNJ a o CD X rr ^ CO z if CD in cd X T3 ■*" "" " ' ! oj cnj _r "o o 1^ in in tj- t— o> cnj cd n XXX cm_ t- cnj_ t>" ^ O O Tt rj; T- CNi uri x >§. t- in w" °? In 00 lo _-c. x - cnj XS . in in p e"^ a. 5n cl h- CO cd x ■* -O CD Z co 5 CD X 1^- S O O in CD CD x" co" N-CD N- O* o a> d II to O Q O 9 X in X X ST X cm_ X cnj cnj cm cm E[ i£i£-"b "g" ~o~ in cd oo co 5" « ™ § - o' lo o' co cm -*fr cd n n n E Q. q. in o co cd cnj* co g; 2> CO •5® o" cnj 03 " Cd X X £ cm cm -r - E E cf "O X ^X co i v- w Z ^ z x ±2 o o cd o in in cm in oo q m;; in w cvi in n h-* h-' o co _n E O cd to cd cd cd oo \ cd x o r-. -<3- CO X o CO X o- co X o CO X o- \ / / \ / CO X o >- x o LU Z CM X o oo X o CD Ex. No.

Y R R5 R6 R7 m.p.

CC) m/z Optical Rotation/ Analysis/NMR -(CH2)3- H H H 442 (M+1)+ ch, ch, 1H-NMR (CDCI3): 5 = 1.65 (d,3H), 2.20(t,2H), 2.25(s,3H), 2.40(t,2H), 4.25(t,2H), 5.35(q,1H), 6.78(d,2H), 7.00(d,2H), 7.30-7.42(m,3H), 7.50(d,2H), 7.57(s,1H), 7.80(d,2H), 8.40(m,1H) ppm.

I Un I ro Osl en co ^4 243687 -56-EXAMPLE 21 (R.S)-4—(3-T4 — CI—T4-(2-Methylpropyl)phenyl1ethoxy)-benzovllindol-l-yl)butanoic acid ethyl ester co2ch2ch3 co2ch2ch3 A suspension of sodium hydride (60% w/w 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) (5.2 4g) in dimethylformamide (30ml). After stirring for one hour at room temperature a solution of cc-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 243687 successively with IN sodium hydroxide solution (100ml), saturated aqueous brine (100ml) and then water (100ml). The organic layer was dried (MgS04) and concentrated in vacuo to provide a yellow oil. Column chromatography (silica, 4*. 1 v/v 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; C33H37N04 requires: C,77.63; H,7.48; N,2.73%. to-NMR (CDC13) : 6= 0 . 91 (d, 6H) , 1.35(t,3H), 1.70(d,3H), 1.90(m,1H), 2.20(m,2H), 2.31(m,2H), 2.49(d,2H), 4.13(q,2H), 4.25(t,2H), 4.50(q,1H), 6.95(d,2H), 7.15(d,2H), 7.27-7.45(m,5H), 7.55(s,lH), 7.88(d,2H), 8.45(m,lH) ppm.

EXAMPLES 2 2 to 3 2 The following compounds of the general formula:- o 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. 7 4 3 6 8 7 c TO O CH in co in in r^- o h-; i£? d O ^ Z <31 0 CO ".h: in ^ S-CNi cfl '(/) '■s ra 5- c o < O O cr a) ro o 13 o Lies t^cnj co O co (N x*!^' Z O X " X to CO - • _£?N-O CD Q d O ^ a: io o •Nf E, o CO in ■ ^ csi i cnj cm X S cnj -,-r Z. CD X ^ o £5 .Si o in cnj cd X CM_ . in' • in Csi -§X m ^ 9 £ CNJ CZ- cn CD X J cnj - ^cr E_ o in o X . in cm c ™ -6 o. ^ o x^5 cm _ Si m ^ iri - & CD CO e ^ oo 11 X to CO CM ^CT in X* £ cH —r -o X x (/> '"CM0 (q in m lo fp; in ~ ■« ■ ^ /"N.I /"Tv r\I ^ ^ rO 82o.^ o _~x cm cd cm cd n CO CO CC Jo « 2 ~ S Zoo ' cm n X j y T"I T cr cf ~o* £.xT m o'aT o' o ur> c c? ^ co cnj ^ n g_ cnj Tt in n n n a.

N E co cnj in + °o + O <0 X o X o- t"- 01 \ \ / / QL C£L CC >- x o LLI Z CM X o cm cm X o co cm Ex. No.

Y R R5 R6 f R7 m.p. C C) m/z Optical Rotation/ Analysis/NMR 24 -(CH2)3- H h H ^^ch3 456 (M+1)+ Found: C.75.87; H.6.35; N.3.06; C29h2gn04 requires: C,76.46; H.6.42; N.3.07%. 1 H-NMR (CDCI3): 5 = 1.25(t,3H), 2.15-2.43(m,4H), 2.45(s,3H), 4.10(q,2H), 4.25(t,2H), 5.15(s,2H), 7.10(d,2H), 7.25-7.45(m,7H), 7.60(s,1H), 7.85(d,2H), 8.40(m,1H) ppm. -(ch2)3- h h H ch3 ^^ch3 469 (M+) 1H-NMR (CDCI3): 5 = 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.

I Ln v£> I iV> cm O) CO ^4 24 3 6 8 71 c ■2* O z q: ~ro o cn to > oo oo CD x~ cn CD CD N- d CO CD .. c\i CO -r~ 0) Z l_ . _ "a O cro a> CD X-Z £- ^ ro - c O < _N E °-o E ■o o §2f® « CD co - CM «- N-O - «■> — o o oo 11 X oo CO -iAif-tn _£> O •<— y.;px aS"-s ».§ 2 m in ' cn co XXx CM CM CN Cti ^ "C3 O m «> ™ o X CM "<3- . ■■ N-n- - o oo J ^linll ~ *• - CM T— CM E -5 en co ^ oo' O O UT O co r- t- v- in oo CM in h-' h-* N-* CL E CL co X O or \ / / CO Cd lO Cd Cd > x o UJ Z CM X o co CM II X X X oo ^ ^ CM_ •_• cr cr co" _£> o c^o O CM CM t- Q oi ^ in O t, X X X 9r CO CM CM SiE w -j-T w to w Is-* r"~" CO CM 1 - CM s *_r -o" E o o o CM -*!■ Tj-•*-' CM Tf S--3."0 o'in'o' cf ° in c° §_ S S N Q. in O O \ / / X o h-CM 24 3 6 87' c ~ Cd B 2 o z * « ro ^ o '■5 to 5- c O < II X to <"! tj o o ^ Q T~ O X o: co ^ S Z in ±2 X X - CNJ e ~ CNJ cn cn CO T3 in co in cn cn cn E o -Q JO, m wo f— co cn rf co XXX to cn ■<-_ to cr cr e 00 S X x) £ X E o o CO T- CN CN in N o h-" ^ in m o co oo " X to CO 3 o q cn Q T-' O - *5 Z in X ■T" o x cn X wo^10 cn CO CN cn o o ti-nI uSX cn _ 2 k! m t X T— e" oo co f SS5 in o o CO CO t- CO T-* CN (6 LO - X i-." X . cn o' t-~ o c: °i £°° Q-h- -s-r^ cl jn e m o co O CO X o- to X o □c: o X o- \ / / CO Cd Qd Cd m X o X o >- x o LU Z CM X o oo cn X o CD cn 24 3 6 8 7 cd c o ro o ~z_ 8 % ""5 ™ Q- c O < II X to ■*—» ■^O O ™ Q "" O ^ —'X Cd <o ^ S 2 o ±3 i X x x - CM T- CN cf TJ, o' O O O OO CNJ Tj- T— T1 't Lf) S □Tx^ix x 00 cm cm cm "D T3 W T3 o'ln'LO lPT cd -st oo cd t— cm co LO LO ^X _: ~r cm E e io — —- r-~ x lo • oo - i nr — loio CNJ _ co II X to _2> in (J cd Q T-" O ^ £ « X cm US' co cm X cm co ^ e in cm ZT LO O cm cm in cp CD X CD <°- ^ e X o t-_ in •S rv LrT in 00 cm X cm_ •g" ° e °° o. r- cl o lPT CD 00 cm Tf m n n oo .N e ■o CO + §1 co X o- co X o Cd CO X o- \ / / CD DC Cd Cd > x O LLI 2 CM X o o co in CM in O CO I o- \ / / CM X o oo # Ex. No.

Y R R5 R6 R7 m.p.

CO m/z Optical Rotation/ Analysis/NMR 32 -(CH2)3- H H H 552 (M+1)+ 1H-NMR (CDCI3): 6 = 0.95(t,3H), 1.20(t,3H), 1.22-1.80(m,10H), 1.90 (m,1H), 2.15(m,2H), 2.25(t,2H), 2.60(t,2H), 4.10(q,2H), 4.20(t,2H), 4.95(d,1H), 6.95(d,2H), 7.10(d,2H), 7.20-7.40(m,5H), 7.50(s,1H), 7.70(d,2H), 8.40(m,1H) ppm. ro 4^ CA o> 243687 -64-EXAMPLE 3 3 (S)-4-(3-(4-(1-f 4-(2-Methylpropyl)phenyl1ethoxy)-benzoyl1indol-l-vl)butanoic acid ethyl ester Her (*) Ph3P, DEAD, THF A solution of 4-(3-[4-hydroxy-benzoyl] indol-l-yl) -butanoic acid ethyl ester (see Preparation 1) (500mg), (R)-1-(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 v/v hexane/ ethyl acetate) gave, after evaporation of the appropriate fractions, the desired compound as a pale yellow gum, (413mg) , m/z = 511 (M+) .

N.Z. P/-TI. - 8 sep 199*» RECEIVED 243687 H.P.L.C. (Cyclobond DMP column eluting with 1:1 v/v 1% by volume triethylammonium acetate in water, pH4.1/CH3CN at 0.7ml/min.) rt= 86.09 min. (100%).

*H-NMR (CDC13) : 6= 0. 95 (d, 6H) , 1.25(t,3H), 1.70(d,3H), 1.85(m,1H), 2.20(m,2H), 2.30(t,2H), 2.45(d,2H), 4.10(q,2H), 4.25(t,2H), 5.40(q,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 v/v hexane/ethanol, flow rate = 12ml/min.). The first eluted compound was (R)-4- (3-[4-(1-[4-(2-methylpropyl)phenyl]ethoxy)benzoyl]indol- l-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.

RECEIVED Ex No Y R R5 R6 R7 m.p. (*C) m/z H.P.L.C./NMR 341 "(CH2)3 H H H 511 (M+) H.P.L.C. (Cyclobond DMP column eluting with 1:1 1% triethylammonium acetate, pH 4.I/CH3CN at 0.7ml/min.) rt = 85.73min. (100%). 1H-NMR (CDCI3): 5 = 0.95(d,6H), 1.25 (t,3H), I.70(d,3H), 1.85(m,1H), 2.20 (m,2H), 2.30(t,2H), 2.45(d,2H), 4.10 (q,2H), 4.25(t,2H), 5.40(q,1H), 6.95 (d,2H), 7.15(d,2H), 7.25-7.40(m,5H), 7.55(s,1H), 7.75 (d,2H), 8.35(m,1H) ppm.

I ON ON I -(CH2)3- CH, H H 525 (M+) H.P.L.C. (Cyclobond DMP column eluting with 1:1 1% triethylammonium acetate, pH 4.I/CH3CN at 0.7ml/min.) rt = 64.52min. (100%). 1H-NMR (CDCI3): 5 = 0.95 (d,6H), 1.30 (t,3H), 1.70 (d,3H), I.85(m,1H), 2.15 (m,2H), 2.40(t,2H), 2.45 (d,2H), 2.60 (s,3H), 4.15 (q,2H), 4.20(t,2H), 5.40 (q,1H), 6.95(d,2H), 7.00-7.40(m,8H), 7.70(d,2H) ppm. 04 o> OO ^4 See Example 33 also. 24 3 6 8 7 m cn o o ii oo CM CM LO CN CO CN O -X Cd o _i CL X Z3T. O co Q cti O o ' CN cd ^ co 0° CD cfT_- co CM H-ii LO^ O CD CO t * c\i . . . m CN X ^ S-o S° r . CO E N- . ' Q- m co in Z X ±m X X CN CN N X -1- CO E X X m ;EEE CNJ CN in oo o in N-' 1^ CO O , ^ in T- o CO II CN CN . CO _ —. o"-5 Q H-m (J CD CN X ~x CN X CN cr """l xj CT--' ;=rm X X m . m •co Cd CN CN X _ ' CM CN Z X CNJ X 2- E o o o in co co CN CD X o m co to g r-' co o zeTzT in CN CN irjow co in co r>-' E Q. CL _N E oo CD -3" CD + Si °-o c? X o \ / Cd CO 3C o Cd Dd Cd > X o ill Z CM X o CD CO X O c- co 243&81 EXAMPLE 38 4-C3-r4-Benzvloxvbenzovl1indol-l-vl)butanoic acid ethvl ester A cooled (0°C) suspension of sodium hydride (3.40g of a 55% w/w dispersion in mineral oil) in dimethylformamide (50ml) was treated with a solution of 3-(4-benzyloxybenzoyl)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), N.z. p/'Itnt orncE - 8 sep 199*1 RECEIVED —■"riTliirr-»-iri¥ni-M^ 24368 saturated 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 v/v hexane/ethyl acetate then 2:1 v/v hexane/ethyl acetate) to give, after combination and evaporation of the appropriate fractions, the title compound (16.5g), m.p. 83°C.

^-NMR (CDC13) : 8= 1. 20 (t, 3H) , 2.20(q,2H), 2.35(t,2H), 4.15(q,2H), 4.29(t,2H), 5.20(s,2H), 7.10(d,2H), 7.30-7.47(m,8H), 7.62(s,1H), 7.85(d,2H), 8.40(m,lH) ppm.

EXAMPLES 39 to 43 The following compounds of the general formula o 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.

N.Z. r/.i'L.T;' OFF - 8 sep 199*» RECE'VLD Ex. No.

Y R R5 R6 r R7 m.p.

(°C) m/z Analysis/NMR 39 -(CH2)3- ch3 H h x,J Found: C,73.65; H.6.34; N.2.94; C29H29N04.H20 requires: C.73.55; H.6.60; N.2.96%. 1H-NMR (CDCI3): 5 = 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. 40 -(CH2)3- H ch3 ch3 470 (M+1)+ 1H-NMR (CDCI3): 8 = 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.

I ~-J 0 1 fO O4 o> Ex. No.

Y R R5 R7 m.p.

(°C) m/z Analysis/NMR 41 -CH,- H H H 414 (M+1)+ 1H-NMR (CDCI3): 5 = 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. 42 -(CH2)£ H H H Not characterised. 1 ro 04 cn 00 Ex. No.

Y R R5 R6 R7 m.p.

(X) m/z Analysis/NMR 43 -(CH2)4- H H H ch3 ^°[^i r ^ ch3 498 (M+1)+ 1H-NMR (CDCI3): 8 = 0.90 (t,3H), 1.18(t,3H), 1.58 (m,2H), 1.65(d,3H), 2.15-2.20 (m,2H), 2.30(t,2H), 2.50 (t,2H), 4.10(q,2H), 4.30 (t,2H), 5.38(q,1H), 6.80 (d,2H), 7.05(d,2H), 7.30-7.45 (m,3H), 7.50(d,2H), 7.55 (s,1H), 7.80(d,2H), 8.40 (m,1H) ppm. ro CnI o> oo *>'- 3 6 7 The following Preparations illustrate the preparation of certain starting materials used in the previous Examples:- PREPARATION 1 4- (3-1" 4-Hvdroxvbenzovl 1 indol-l-vl) butanoic acid ethvl ester H2j10% w/w Pd/c5 ch3co2c2h5 o A solution of 4-(3-[4-benzyloxybenzoyl]indol-l-yl) butanoic acid ethyl ester (see Example 38) (13.4g) in ethyl acetate (300ml) was hydrogenated at 4.15 x 105 Pa (60 psi) in the presence of 10% w/w palladium-on-charcoal (3g) at room temperature for 4 hours. The catalyst was removed by filtration of the reaction through a n.z. PATENT OFFICE - 8 sep 1994 24 3 6 87 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).

Found: C,71.78; H,6.02; N,3.98; C21H21N04 requires: C,71.44; H,6.04; N,3.94%. 1H-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:- o co2ch2ch3 were prepared by hydrogenation of the corresponding benzyl ethers (see Examples 3 9 to 41) by similar methods to that used in Preparation 1.

Prep. No.

Y R R5 R® m.p. rc) m/z Analysis/NMR 2 -(CH2)3- ch3 H H Found: C.72.30; H.6.16; N.3.75; C22H23N04 requires: C.72.31; H.6.34; N,3.83%. 1H-NMR (CDCI3): 5 = 1.30(t,3H), 2.15(m,2H), 2.45(t,2H), 2.65(s,3H), 4.20(q,2H), 4.25(t,2H), 6.60 (s,br,1H), 6.85(d,2H), 7.10(t.1H), 7.20(t,1H), 7.40(d,2H), 7.70(d,2H) ppm. 3 -(CH2)3- h ch3 ch3 380 (M+1)+ 1H-NMR (CDCI3): 5 = 1.25(t,3H), 2.25(s,3H), 2.30(s,3H), 4.10(q,2H), 4.20(t,2H), 6.70(d,1H), 7.15(d, 1H), 7.25-7.45(m,4H), 8.30(m,1H) ppm. 4 -ch2- h h H 324 (M+1)+ 1H-NMR (CDCI3): 8 = 1.20(t,3H), 4.20(q,2H), 4.90(s,2H), 6.95(d,2H), 7.20-7.35(m,3H), 7.55(s,1H), 7.70(d,2H), 8.35(m,1H) ppm. oo ^4 24 3 6 8 7 -76-P-REPARATION 5 3- (4-BenzvloxvbenzovH -lH-iridole A mechanically stirred solution of indole (3 0.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 . 2 5 ; C22H17N02 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,1H) ppm. 24 3 6 8 7 PREPARATIONS 6 to 8 The following indoles of the general formula:- were prepared from the corresponding IH-indoles and the corresponding acid chlorides (see Preparations 9 to 11) using similar methods to that used in Preparation 5. (> o Prep. No.

R R5 R6 R7 m.p.

(*C) m/z Analysis/NMR CH, H H -och2^^ Found: C.78.45; H.8.31; N.3.90; C23H19N02 requires: C.78.60; H.8.32; N.3.98%. 1H-NMR (d6-DMSO): 5 = 2.40 (s,3H), 5.20(s,2H), 6.95-7.45(m,11H), 7.65(d,2H), 12.00(s,br,1H) ppm.

H CH, CH, 195-197 355 (M+) -och2— Found: C.80.73; H.6.06; N.3.97; C24H21NO2 requires: C.81.13; H.5.92; N,3.94%. 1H-NMR (d6-DMSO): 5 = 2.10 (s,3H), 2.15(s,3H), 5.20(s,2H), 6.95(d,1H), 7.15-7.50(m,9H), 7.60(s,1H), 8.15(m,1H), 12.00(s,br,1H) ppm.

I OO I ro CM CD CO ^4 I > o Prep. No.

R R5 R6 R7 m.p. co m/z Analysis/NMR 8 H H H ch3 CHa ^ ch3 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.

I vo I ro 04 o> OO ^4 2 43 6 87 PREPARATION 9 4-Benzvloxv-2.3-dimethvlbenzovl chloride CH3 Br2JCH3COOH (a) (b) (c) 1) n-C4H9U,THF 2) C02 CsHgCHjBr.KaCOa, KI,(CHj)2CO (d) (COCI)2,DMF,CH 2CI2 COCI 243687 (a) 4-Bromo-2.3-dimethvlphenol 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 (MgS04) , filtered and evaporated to provide the product as a waxy solid, (64.7g).

^-NMR (CDC13) : 6= 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-Benzvloxv-4-bromo-2.3-dimethvlbenzene A mixture of the product of par.t (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 v/v 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%. lH-NMR (CDCI3) : 6= 2 . 3 0 (s, 3H) , 2.40(s,3H), .00(s,2H), 6.60(d,1H), 7.30-7.50(m,6H) ppm.

N 7. ' mT OFFICE - 8 sep 1994 RECEIVED 24 3 6 8 7 (c) 4-Benzvloxv-2.3-dimethvlbenzoic acid A solution of the product of part (b) (3 3.8g) 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 (MgS04) 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; C16H1603 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,1H), 7.30-7.50(m,5H), 7.60(d,lH) ppm. (d) 4-Benzvloxv-2.3-dimethvlbenzovl 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. 24 3 6 8 7 -8 3-PREPARATION 10 4-Benzvloxvbenzovl 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-f4-Isobutvlphenvllethoxy)benzoyl chloride The title compound was prepared using a similar method to that described in Preparation 9(d) except using 4-(l-[4-isobutylphenyl]ethoxy)benzoic acid (see Preparation 28(b)) as the starting material. The product obtained was used immediately. -84-PREPARATION 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 (MgS04) . The organic layer was filtered and evaporated to give a colourless oil which was purified by chromatography (silica, 4:1 v/v 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.

A solution of 4-ethylacetophenone (10.Og) 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 (MgS04) and evaporated to give a clear oil (9.9g). This was purified by flash chromatography (silica, 3:1 v/v hexane/ethyl acetate) to give, after evaporation of the appropriate fractions, the desired compound, (8.9g), m/z = 150(M+).

^-NMR (CDCI3) : 6 = 1. 2 5 (t, 3H) , 1.55(d,3H), 2.65(q,2H), 4.90(q,1H) , 7.2 0(d,2H) , 7.35(d,2H) ppm.

PREPARATION 13 1-M-Ethvlphenvl)ethanol 8 sep 1931! I I? 243687 PREPARATION 14 4-n-Propylbenzvl alcohol A solution of 4-n-propylbromobenzene (lOg) 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 (MgS04) and evaporated to an oil. Flash chromatography (silica, 3:1 v/v hexane/ethyl acetate) gave, after evaporation of the appropriate fractions, the desired product as a colourless oil, (2.7g).

PREPARATION 15 fR.S)-1-(4-T2-Methylpropyl1 phenyl)ethanol A solution of 4-isobutyrylacetophenone (10.Og) in methanol (50ml) was cooled to 0°C and treated portionwise with sodium borohydride (3.23g). Af.ter 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 (MgS04) and evaporated to give the title compound as a clear oil, (10.02g), m/z = 178(M+). Found: C,79.69; H, 9 . 90; C12H1bO. 1/7 H20 requires: C,79.68; H,10.19%.

:H-NMR (CDC13) : 8= 0. 90 (d, 6H) , 1.50(d,3H), 1.85(m,lH), 2.50(d,2H), 4.85(q,1H), 7.15(d,2H), 7.30(d,2H) ppm.

PREPARATION 16 1-(3.4-Dichlorophenyl)ethanol The title compound was prepared using a similar method to that described in Preparation 15 except using 3,4-dichloroacetophenone as the starting material. m/z = 190 (M+) .

H-NMR (CDCI3) : 6= 1. 45 (d, 3H) , 2 . 25 (s, br, 1H) , 4 . JbTqrTH)' N.z.. pa 7 . 20(d,1H) , 7.40(d,1H) , 7.45(s,lH) ppm. $1. PAfENT OFFICE .• - 8 sep 1994 RECEiVL'D 243687 -86-PREPARATION 17 (R)-1-(4-f2-Methylpropyl1 phenyl)ethanol a) Ethanoic acid (R.S)—1-(4-r2-methylpropyl1 phenyl)-ethvl 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 (10g) added to the filtrate and the mixture evaporated to dryness. Column chromatography (silica, 12:1 v/v hexane/ethyl acetate) gave, after evaporation of the appropriate fractions, the desired compound as a clear oil, (2.3g).

H-NMR (CDC13) : 6= 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), .25(d,2H) ppm. (b) (R)-1-(4-T2-Methylpropyl1 phenyl)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 (MgS04) and evaporated. Column chromatography (silica, 9:1 v/v 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, (l.04g), m.p. 37-38°C, [cc]0 + 32.3° (c = 2.7 in methanol).

H-NMR (CDCI3) : 5= 0.90(d,6H) , 1.50(d,3H), 1.85(m,lH), . 50 (d, 2H) , 4 . 85 (q , 1H) , 7.15(d,2H), 7.30(d,2H) pwnr? N.Z. PATENT OFFICE - 8 sep 1994 RECEIVED 243687 -87-PREPARATION 18 (S)-1-(4— f 2-Methylpropyl1 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 v/v hexane/ethyl acetate) to give the title compound as a clear oil, (0.59g), m.p. 34°C, [oc]D - 32.7° (c = 2.7 in methanol).

*H-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-Cvclopentvl-4-n-propvlbenzvl 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 (MgS04) and evaporated to provide a yellow oil. Flash chromatography (silica, initial elution with 4:1 v/v hexane/ethyl acetate and then with 3:1 v/v hexane/ethyl acetate) gave, after combination and evaporation of the appropriate fractions, the desired compound as a clear oil, (400mg), m/z = 218 (M+).

^-NMR (CDCI3) : 6= 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. - 8 sep 1991! RECEIVED 1 4 3 6 PREPARATIONS 20 to 2 6 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 1-Bromo-l-(4-n-propylphenyl)butane. 21 a-Methyl-4-ethylbenzy1 bromide. 22 4-n-Propylbenzyl bromide. 23 ce-Methyl-4- (2-methylpropyl) benzyl bromide. 24 Ct-Methyl-3,4-dichlorobenzyl bromide. cc-Cyclopenty 1-4 -n-propy lbenzy 1 bromide. 261 a- (4-n-Propylphenyl)-4-n-propylbenzy1 bromide.

For starting material see EP-A-291245. f 3 6 8 7 -89-PREPARATION 27 4- f 3-r 4- fl-Hvdroxvethvl) benzoyl 1 indol-l-yl') butanoic acid ethvl ester CI0C\^\ OSIMe2tBu CH, (a) N' H .OSIMe,tBu CH, (b) r^\ (CH2)3C02C2H5 CH, OSIMe^Bu (c) OH (CH2)3C02C2H5 CH3 243687 a) 3—(A-r1—(t-Butvldimethvlsilvloxv)ethvll-benzoyl)indole The title compound was prepared by a similar method to that used in Preparation 5 using indole and 4-(l-[t-butyldimethylsilyloxy]ethyl)benzoyl chloride as the starting materials, m/z = 380 (M+l)+. Found: C, 72 . 79 ; H,7.73; N,3.76; C23H29N02Si 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 . 2 0 (s, br, 1H) ppm. b) 4-f 3 — f4-Cl-rt-Butyldimethvlsilvloxvlethvl)-benzoyl1indol-l-vl)butanoic acid ethvl ester A solution of the product of part (a) (1.70g) in dimethylformamide (20ml) was treated with sodium hydride (215mg of a 60% w/w 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 (MgS04) and gave a yellow gum on evaporation of the solvent. Flash chromatography of this gum (silica, 3:1 v/v 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 (CDCI3) : 0 . 00 (s , 6H) , 0.90(s,9H), 1.2 0(t,3H) , 1.50(d, 3H) , 2.20-2.40(m,4H) , 4.10(q,2H), 4.3 0(t,2H) , 5.00 (q,1H) , 7. 20-7.40(m,5H) , 7.60(s,lH), 7.80(d,2H), 8.35(m,lH) ppm. 243687 (c) 4—(3-r4-(1-Hvdroxvethvl)benzoyl1indol-l-vl)butanoic acid ethvl ester The product of part (b) was dissolved in tetrahydrofuran (100ml) and treated with tetra-n-butylammonium 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 (MgS04) , filtered and evaporated to a brown gum. Flash chromatography (silica, 98:2 v/v 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,1H), 2.20-2.40(m,4H), 4.10(q,2H), 4.30(t,2H), 5.00(q,1H), 7.20-7.60(m,6H), 7.80(d,2H), 8.35(m,1H) ppm.

PREPARATION 28 (S)-4-f 3-r 4-(1-r 4-f 2-Methylpropyl)phenyl1ethoxy)-benzoyl1indol-l-vl)butanoic acid (a) CR,S)-4-(1-T4-(2-Methylpropyl)phenyl1ethoxy)benzoic acid ethvl 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) -ce-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 (I3.5g) which was used directly without characterisation.

N.7. fLNf OFFICE - 8 sep 199% FiECD\T-D 243687 (b) f R. S)-4-C1-r 4-(2-Methylpropyl)phenyl1ethoxy)benzoic acid The product of part (a) (13.5g) was dissolved in 95:5 v/v sodium hydroxide (32ml) and heated at 60-70°C for 90 minutes. The solvent was evaporated and water (3 0ml) 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 (MgS04) . Removal of the ethyl acetate solvent gave the title compound as a white solid. Trituration with n-hexane gave a fine white powder (6.7g).

XH-NMR (CDC13) : 6= 0 . 95 (d, 6H) , 1.70(d,3H), 1. 88 (in, 1H) , 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) fs)—4—(1—f 4—(2-Methylpropyl)phenyl1ethoxy)benzoic acid, (+)-ephedrine salt The product of part (b) (lOg) was dissolved in 95:5 v/v ethanolswater (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). ethanol:water (108ml), treated with 2N aqueous d 8 sep 1934 : 4 36 1H-NMR (CDCI3) : 6= 0.90(d, 6H) , 1.10(d,3H), 1 - 70 (d, 3H) , 1.85(m, 1H) , 2.45(s,3H), 3.15(xn,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.

(S)-4-(1-f4—(2-Methylpropyl)phenyl1ethoxy)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. [oc]20 D -51.5° (c=l in methanol).

Found: C,7 6.76; H,7.30; N,0.00; CigH2203 requires: C,76.48; H,7.43; N,0.00%. 1H-NMR (CDCI3) : 5= 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) , 7.3 0(d,2H), 8.00(d,2H) ppm.

(S)-4-(1-f4-(2-Methylpropyl)phenyl!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 243687 the filtrate containing the title compound was evaporated to a volume of 10ml and used directly in the next step without characterisation. (f) (S)—3—f4-n—(4—r 2-Methylpropyl 1 phenyl) -ethoxvlbenzoyl)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-(l-[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 (3 0ml, 40ml and 15ml) and the combined organic layers were dried (MgS04) , filtered and evaporated to give a brown gum.. Flash chromatography (silica, 3:1 v/v hexane/ethyl acetate initially, followed by 1:1 v/v 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; C27H27N02 requires: C,81.58; H,6.85; N,3.52%.

^-NMR (CDC13) : 6= 1. 00 (d, 6H) , 1.75(d,3H), 1.95(m,1H), 2.55(d,2H), 5.45(q,lH), 7.05(d,2H), 7.2 5(d,2H) 7.39-7.54 (m,4H) , 7.70(m,lH), 7.85(d,2H), 8.45(m,lH), 9.10(s,br,1H) ppm. 7 " "_>T OFFICE - 8 sep 1994 243687 (g) (S)—4—f3—f4—fl—f4-(2-Methylpropyl)phenyl1-ethoxy)benzoyl1indol-l-vl)butanoic acid ethvl ester A solution of the product of part (f) (500mg) in 2-butanone (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 v/v 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 *H-NMR characteristics to the compound of Example 33. (h) (S)—4-(3 — T4—(1—T4—(2-Methylpropyl)phenyl!-ethoxy)benzoyl!indol-l-vl)butanoic acid A solution of the product of pg,rt (g) (108mg) in 95:5 v/v ethanol:water (2ml) was treated with six drops of 2N aqueous sodium hydroxide. The mixture was stirred for 9 0 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 *H-NMR characteristics to the compound of Example 9. 24 36 Pharmacoloaical 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 3 4 to 36 of the specification. The results are presented in Table 1.

Table 1 Example No.

IC50(nM) 1 2 .19 2 1.2 3 2.3 4 56 6.9 6 3.6 7 361 8 0.67 9 1.15 .2 11 6.3 12 2.8 13 42 . 5 14 449 16.5 16 2.64 18 207 19 4.76 33 42% inhibition at lOOnM 34 47% inhibition at lOOOnM

Claims (20)

? 4 3 6 -97-Toxicitv 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. 243687 PLC 553 - Case A -98- what Y/WE cuum is:

1. A compound of the formula:- r4 0 d9 or a pharmaceutically acceptable salt thereof, wherein Y is C^Cs alkylene optionally substituted by Ci-Cg alkyl; R is H, OH, halo, alkyl or Cx-C4 alkoxy; R1, R2, R3 and R4 are each independently selected from H, C1-CA alkyl, C^C,, alkoxy, OH, halo and CF3; 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, C^C^ alkyl, C1-C4 alkoxy, halo and halo (Cj—C4) alkyl; 24 3 6 8 7 -99- R10 is COOH, COOR11 or CONR12R13; Ru is a biolabile ester-forming group; R12 and R13 are each independently selected from H and C^^ alkyl; R14 is H, C1-C6 alkyl, C3-C7 cycloalkyl or aryl; and "aryl", used in the definitions of R6, R7, R8 and R14, means phenyl optionally substituted by C1-C6 alkyl, C^Cg alkoxy, C2-C6 alkenyl, OH, halo, CF3, halo(C1-C6 alkyl) , nitro, amino, C2-C6 alkanamido, C2-C6 alkanoyl or phenyl. compound as claimed in claim 1 wherein Y is Cj-Cg alkylene optionally substituted by Cj-Cg alkyl; R is H, OH, halo, C1-C4 alkyl or C1~CA alkoxy; R1, R2, R3 and R4 are each independently selected from H, Cj-C4 alkyl, C1-C4 alkoxy, OH, halo and CF3; 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, alkyl, Cj-C4 alkoxy, halo and halo(C:-C4) alkyl; R10 is COOH, COOR11 or CONR12R13; 24 36 -100- R11 is a biolabile ester-forming group; R12 and R13 are each independently selected from H and alkyl; R14 is H, C^Cg 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-Cg alkoxy, C2-C6 alkenyl, OH, halo, CF3, haloCCj-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, Rz, R3, R4, R5, R6, Ra 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-methylpropyl)-phenyl)propoxy or 2,2-dimethyl-l-(4-(2-methylpropyl) 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-methylpropyl)phenyl)-ethoxy, 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 when the compound of the formula (I) is in the racemic form; 24 3 6 8 -101- iv) 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, R

2, R3, R4, R5, R7, R8 and R9 are all H and Y is -(CH2)3-, that R10 is not COOH or COOCZH5.

3. A compound as claimed in claim 1 or 2 wherein R10 is COOH or COOR11.

4. A compound as claimed in any preceding claim wherein R11 is C^Cg alkyl.

5. A compound as claimed in any preceding claim wherein R10 is COOH.

6. A compound as claimed in any preceding claim wherein Y is Cj—C6 alkylene; R is H or CJ-C4 alkyl; R1, R2, R3 and R4 are each H; one of R6, R7 and R8 is a group of the formula:- 24 3 6 8 -102- R14 R14 f I -OCH-Aryl or -CHO-Aryl, and the remainder, together with R5 and R9, are each independently selected from H and C^C,, alkyl; R14 is H, C^C,, alkyl, C4-C6 cycloalkyl or phenyl substituted by C^^ alkyl; and "aryl", when used in the definitions of R6, R7 and R8, means phenyl optionally substituted by from 1 to 3 substituents each independently selected from C^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; 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; R14 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; R7 is a group of the formula:- R14 I -OCH-Aryl, and R5, R6, R8 and R9 are each H; 243687 -103- R14 is methyl; and "aryl" means phenyl, 4-methylphenyl, 4-ethylphenyl, 4-(n-propyl)phenyl, 4-isobutylphenyl or 3,4-dichlorophenyl.

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 R6, R7 and R8 is a group of the formula:- and the remainder, together with Y, R, R1, R2, R3, R4, R5, R9, R10, R11, R12, R13 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-Methy1-3-[4-(l-[4-(2-methylpropyl)-phenyl]ethoxy)benzoyl]indol-l-yl)butanoic acid or (S)-4-(2-Methy1-3-[4-(1-[4-(2-methylpropyl)phenyl]-ethoxy)benzoyl]indol-l-yl)butanoic acid: or a pharmaceutically acceptable salt thereof. N.Z 243687 -104-

12. 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.

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.

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 5ot-reductase.

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. N.Z. r " '"'FiCE - 8 sep 1994 RECEIVED

16. A compound of the formula R1 Y I CN ....(iv) ....(viii) or a base salt thereof; N.Z . LMT OFFICE - 8 sep uktt RECEIVED 9 4 3 6 8 7 -106- r4 0 r9 l ch2oh .(XIV) i co2h .(XV) or a base salt thereof; -107- 24368 ....(XVIII) or a base salt thereof; wherein Y, R, R1, R2, R3, R4, R5, , R8, R9 and R10 are as defined in claim 1 or 2; R^/is H or OH; one of R25, R26 and Rz/ is OH and the remainder of R: >26 >27 25 R 26 and R27 are as defined in claim 1 or 2 for the remainder of R6, R7 and R8; with the proviso that for a compound of the formula (XVIII), when Y is methylene, R is methyl, R^ is methoxy, R^-, R^, r4, R5 and R9 are each H, R25 and R27 are each bromo and R26 is hydroxy, that R^O is not -COOH. n.z. patf> - 8 sep w rec:- - 108 - 243687

17. A compound of the formula (I) or a pharmaceutically acceptable salt thereof substantially as herein described with reference to any example thereof.

18. A pharmaceutical composition as defined in claim 12 substantially as herein described with reference to any example thereof.

19. The use of a compound of the formula (I) or of a pharmaceutically acceptable salt or composition thereof as claimed in claim 14 or claim 15 substantially as herein described with reference to any example thereof. (i1* * <

20. A compound of formula (IV), (VIII), (XIII), (XIV), 0 v* * < (xv) or (xviii) „ • or a base salt thereof — substantially as herein described with reference to any example thereof. ppi^?-e:R i.MC. By the authorised agents A J PARK & SON Per n.z. patent c< ce - 8 sep 1994 RECTI'1