CA2112689A1 - Indoles - Google Patents

Abstract

The present invention provides compounds of formula (I) and pharmaceutically acceptable salts thereof, wherein Y is C1-C6 alkylene optionally substituted by C1-C6 alkyl; R is H, OH, halo, C1-C4 alkyl or C1-C4 alkoxy; R1, R2, R3 and R4 are each independently selected from H, C1-C4 alkyl, C1-C4 alkoxy, OH, halo and CF3; one of R6, R7 and R8 is a group of formula (a) or (b), and the remainder, together with R5 and R9, are each independently selected from H, C1-C4 alkyl, C1-C4 alkoxy, halo and halo(C1-C4)alkyl; R10 is COOH, COOR11 or CONR12R13; R11 is a biolabile ester-forming group; R12 and R13 are each independently selected from H and C1-C4 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, C1-C6 alkoxy, C2-C6 alkenyl, OH, halo, CF3, halo(C1-C6 alkyl), nitro, amino, C2-C6 alkanamido, C2-C6 alkanoyl or phenyl: together with pharmaceutical compositions containing, processes for the preparation of and uses of, such compounds.

Description

~ 93/02~0 2 1 L 2 ~ 8 3 PCT/EPg~/0162~

INDOLES

This invention relates to indole derivatives whirh have steroid So~reductase inhibitory activity.
More particularly this in~ention relates to indoles, their preparation and their use as testosterone-So~
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 ~ody 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 5o~reduced androqens.
TestGsterone is therefore the prohormone of 5~
dihydrotestoste~one whlch is formed locally in the above organs by the action of testosterone-So~redu~tase. The presence of elevated levels of dihydrotestosterone in many disease states has therefore focussed attention on the synthesis of testosterone So~reductase inhibitors.
Testosterone 5o~reductase inhibitors may also be useful in the treatment of human prostate adenocarcinomas.
EP-A-0458207 discloses certain indole derivatives which have testosterone 5o~reductase inhibitory activity~

W093/U~0 ~ 3 PCT/EP92/01625 The present invention provides compounds of the formula:-R ~ ~ ,J ~ 1, R8 R2~N R ~R7 R1 I R~

and pharmaceutically acceptable salts thereof,wherein Y is Cl-C6 alkylene optionally substituted by Cl-C6 alkyl;

R is H, OH, halo, C1-C4 alkyl or C1-C4 alkoxy;

R1, R2,' R3 and R4 are each independently selected from H, Cl-C4 alkyl, Cl-C4 alkoxy, OH, halo and . , .
~F3;

one of R6, R7 and Ra is a group of the formula:-Rl4 Rl4 -OCH-Aryl or ~CHO~Aryl, and the remainder, together with R5 and R9, are each independently selected from H, Cl-C4 alkyl Cl-C4 alkoxy, halo and halo(Cl-C4)alkyl;

W093J02~ 12 ~ ~ 9 PCT/EP92/01625 R10 is COOH, COOR11 or CoNRl2Rl3i R11 is a biolabile ester-forming group;

R12 and R13 are each independently selected from H and C1-C4 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, 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 C1-C6 alkylene optionally substituted by C1-C6 alkyl;

R is H, OH, halo, C1-C4 alkyl or C1~C4 alkoxy;

R1, R2, R3 and R4 are each independently selected from H, C1-C4 alkyl, Cl-C4 alkoxy, OH, halo and CF3;
.
one of R6, R7 and R~ is a group of the formula:-Rl4 Rl4 -OCH-Aryl or -CHO-Aryl, and the remainder, together with Rs and R9, are ~ach independently selected from H, C1-C4 alkyl, C1-C4 alkoxy, halo and halo(C~-C4)alkyl;

R10 i~ COOH, COOR11 or CoNR12Rl3;

W093/02~0 ')'~ PCT/EP92/01625 R11 is a biolabile ester-forming group;

R12 and R13 are each independently selected from H and C~-C4 alkyl;

R14 is H, C1-C6 alkyl, C3-C7 cycloalkyl or aryl;

and "aryl", used in the definitions of R6, R7, Rs and R14, means phenyl optionally substituted by C~-C6 alkyl, C~-C6 alkoxy, C2-C6 alkenyl, OH, halo, CF3, halo(C1-C6 alkyl), nitro, amino, C2-C6' alkanamido, C2-C6 alkanoyl or phenyl:

with the provisos i) when R7 is l-(4-(2-methylpropyl)-phenyl)ethoxy, R, R1, R , R , R , R , R , R
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 R~ i5 1- (4-(2-methylpropyl3-phenyl)propoxy or 2,2-dimethyl~ 4-(2- :
methylpropyl)phenyl)propoxy, R, R1, R2, R3, R4, Rs, R6, R~ and R9 are all H and Y is - (CH2) 3-, that R10 iæ not COOH or COOC2H5 when the compound of the formula (I) is in the racemic fo~m;
iii) when RÇ is l-(3-(2-methylpropyl~phenyl)-ethoxy, R, R1, ~2, R3, R4 Rs ~ R~ a d R9 are all H and Y is -(CH2)3-, that Rl is not COOH or COOC2Hs wh~n the compound of the formula (I) is in the racemic form ~093/02~0 ~ ~.12 G 3 9 PCT/EP92/01625 iv~ when R7 is 1-(4-(2-methylpropyl)phenyl)-ethoxy, RS and Rs 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 COOC2Hs 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 Rs R6 R8 d 9 are all H and Y is -(CH2) 3-, that ~10 is n~t COOH;
vi) when R6 is bis(4-~2-methylpropyl)phenyl)- ' methoxy R Rl R2 R3 R4 Rs R7 Rs a~d R9 are all H and Y is -(CH2) 3-, that R10 is not COOH; and vii) when R6 is 4-(2-methylpropyl)phenoxyDIethyl or 3-(2-methylpropyl)phenoxymethyl, R, Rl, R2, R3~ R4~ R5, R7, R8 and R9 are all H and Y
iS - (CH2) 3-, that Rl is not COOH or COOC2Hs .

Alkyl, haloalkyl, alkenyl and alkoxy groups containing three or more c~rbon atoms and alkanamido and alkanoyl groups containing four or more carbon atoms may be straight- or branched-chain.
The term "halo" means fluoro, chloro, bromo or iodo.
The term "biolabile ester-forming group~' is well understood in medicinal chemistry as meaning a group which forms an ester which can be readily cleaved in vivo to liberate the corresponding acid of the formula (I) wherein R10 is COOH. A number of such ester groups are well-known, for example in the penicillin area or in the case of the angiotensin-converting enzyme (ACE) inhibitor antihypertensive agents.

~ 9 -6-Esters of the formula (I) wherein Rl0 is CO2(Cl-c6 alkyl) are steroid So~reductase inhibitors per se but, in general, where Rl0 is COORll such compounds are useful as pro-drugs to provide compounds of the formula (I) wherein Rl0 is COOH in vivo following oral administration. Such esters are also useful as intermediates for the preparation of compounds of the formula (I) wherein Rl0 is C~OH.
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. C1-C6 alkyl), alkanoyloxyalkyl (including alkyl, cycloalkyl or aryl substituted derivatives thereof), arylcarbonyloxyalkyl (including aryl substituted derivatives thereof), aryl, arylalkyl, jndanyl and haloalkyl: wllerein alkanoyl groups have from 2 to 8 carbon atoms and alkyl groups have from l 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 Cl-C4 alkyl, Cl-C4 alkoxy or halo.
In addition to Cl-C6 alkyl, specific examples of other biolabile ester-forming groups are benzyl, l-(2,2-diethylbutyryloxy)ethyl, 2-ethylpropionyloxymethyl, l-(2-ethylpropionyloxy)ethyl,-l-t2,4-dimethylbenzoyloxy)ethyl, o~benzoyloxybenzyl, l-(benzoyloxy)ethyl, 2-methyl-l-propionyloxy-l-propyl, 2,4,6-trimethylbenzoyloxymethyl, l-t2,4,6-trimethylbenzoyloxy)ethyl, pivaloyloxymethyl, phenethyl, phenpropyl, 2,2,2-trifluoroethyl, l- 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.

'~093/02050 2 ~ PCT/EP92/01625 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, benzenesulphona~.e and ~-toluenesulphonate salts~
Suitable base salts are formed from bases whieh 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 r J.
Pharm. Sci., 66, l-l9 (1977).
In the above definitions relating to the present invention:

Preferably Y is Cl-C6 alkylene.
Nore prefera~ly Y is methylene, propylene, butylene or pentylene.
Nost preferably Y is propylene.

Preferably R is H or Cl-C4 alkyl.
More preferably R is H or methyl.
- Most preferably R is H.

- Preferably Rl, R2, R3 and R4 are each H.

Prefera~ly one of R6, R7 and R~ is a group of the formula:-Rl4 Rl4 -OCH-Aryl or -CHO-Aryl, and the remainder, together with R~ and R9, are each independently selected from H and C1-C4 alkyl.

W~ 93/02~ 2 ~ 1 u 3 .~ PCT/EP92/0162~

--B--More preferably R7 is a group of the formula:--OCH-Aryl or -CHO-Aryl, and R5, R6, R8 and R9 are each independently selected from H and C~-C4 alkyl.
Most preferably R7 is a group of the formula:- ;
Rl4 - -OCH-Aryl, and Rs, R6, R8 and R9 are each H.

Preferably R10 is COOH or COOR1l.
Most preferably R10 is COOH.

Preferably R11 is C1-C6 alkyl.
Most preferably R11 is ethyl.

Preferably R1~ is H, C1-C4 alkyl, C4-C6 cycloalkyl or phenyl substituted by C1-C4 alkyl.
More preferably R1~ is H, methyl, n-propyl, cyclopentyl or 4-(n-propyl)phenyl.
Most preferably R14 is methyl.

Preferably "aryl" means phenyl optionally substituted by from l to 3 substituents, more preferably means phenyl optionally ~ubstituted by l or 2 substituents and most-pre~erably 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. -~093/02~0 2 1 i ~ ~ 8 9 PCT/EP92/01625 A compound of the formula (I) may oontain one or more asymmetric carbon atoms and/or one or more alk~nyl 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 ~ompound 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 ~y 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 co~pounds of the formula (I) is where one of R6, R7 and R3 is a group of the formula:-C6 alkYI)~lH
o (S Ar~l and the remainder, together wit~ Y, R, R1, R2, R3, R4, Rs,R9, R10, R11, R12, R13 and "aryl" are as previously defined for a compound of the formula (I).

W093/02~0 PCT/EP92/0162 J~ ?/~ -10-Particularly preferred em~odiments of the compounds of the formula (I) are (R,S)-4-(3-[4-(1-[4-(2-Methylpropyl)phenyl]ethoxy~-benzoyl~indol-l yl)butanoic acid, (S)-4-(3-[4-(1-l4-(2-Methylpropyl)phenyl]ethoxy)-benzoyl~indol-l-yl)butanoic acid, (~,S)-4-(2-Methyl-3-t4-(1-[4-(2-mathylproE~yl)-phenyl3ethoxy)benzoyl]indol-1-yl)butanoic acid and (S)-4-(2-Methyl-3-{4-(1-[4-(2-methylpropyl)phenyl~-ethoxy)benzoyl]indol-1-yl)butanoic acid:
and 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 Rl to R9 are as previously defined for a compound of the formula (I) may be prepared by cleavage of an ester of the formula:-R4 0 R~ 8 R2 ~R7 Rl y R6 CoOR15 .... (01) ,:~

wherein R15 is a suitable ester-forming group and Y, R and Rl to R9 are as previously defined for a compound of the formula (I).

~!~O 93/02050 ~ 1 1 2 S ~ 3 Pcr/Ep92/ol62s 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 Synth~sis", Wiley-Interscience (2nd edition, 1991).

Where Rls is an ester-forming group that may be removed by hydrolysis, e.g. Cl-C6 alkyl or an alternative biolabile ester-forming group as previously defined (i.e. a compound of the formula (I) wherein Rl is COORll), 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 C1-C4 alkanol such as methanol.
The hydrolysis is typically carried out at from room temperature to the reflux temperature and preferably is carried out at room temperature. The product is obtained as a base salt which may be converted to the carboxylic acid by acidification in the work-up procedure.

Where Rl5 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.

W093/02~0 2 1 1 ~ S 8 3 PCT/EP92/01625 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 Rl is CoNRl2Rl3 and Y, R, R1 to R9, Rl2 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.gO 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 potassi~m hydroxide, at from room temperature to the reflux temperature. When basic hydrolysis conditions are used the produot is obtained as a base salt which may be converted to the ~arboxylic acid by acidification in the work-up procedure.

3) The compounds of the formula (I) wher~in Rl 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:-~4 0 ~9 R .Ij, ~R7 Rl y RÇ
CONHNHR 16 :~

.~..(111) ~093/02~ 2 :~12 ~ 8 9 PCT/EW2/0l625 wherein Y, R and Rl to R9 are as previously defined for a compound of the formula (I) and R16 is H or Cl-C~ alkyl.

The hydrolysis may be carried out under acidic or basiG 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. ~odium or potassium hydroxide, at from room temperature to the reflux temperature. When basic hydrolysis conditions are used the product is obtained as a base salt which may be converted to the carboxylic acid by acidification in the work-up procedure.

4) The compounds of the formula (I) wherein Rl 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:-R2 ~ r ~ ~ ~ R7 Rl y R6 CN

....(IV) W093/02~0 PCT/EP92/01625 2~ GS9 wherein Y, R and Rl 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 aeid, 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..

5) ~he compounds of the formula (I) wherein R10 is COOH
and Y, R and Rl to R9 are as previously defined for a compound ~f the formula (I3 may be prepared by acidic hydrolysis of a compound of the formula:-R~R8 R1 y R6 ~r ....~

.~093/02~ 2 1 ~ 9 PCT/EP92/01625 wherein Y, R and R1 to R9 are as previously defined for a compound of the formula (I) and R17 and R18 taken together represent ethylene, said ethylene group being optionally substituted by phenyl or C1-C4 alkyl (preferably methyl). Preferably R17 and Rl0 taken together represent -CH2C(CH3) 2- . -The hydrolysis may be carried out using an aqueoussolution of a suitable acid such as hydro~hloric acid at from room temperature to the reflux temperature.

6) The compounds of the formula (I) wherein R1~ 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 0C to room temperature.

7) The compounds of the formula (I) whexein R10 is COOR
and Y, R, R1 to R9 and R11 are as previously defined for a ~ompound of the formula ~I) may be prepared by -esterification of-a compound of the formula (I) - wherein Rl 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 Rl1OH wherein R1l is as previously defined for this method.

W093/02~ PCT/EP92/0162~
fi ~ S3 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 ke 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 o. Mitsunobu, Synthesis, lg81, 1).

Alternatively the esterification may be carried out by first forming an activated ester or imidazolide derivative of the carboxylic acid, followed by reaction of the activated ester or imidazolide in situ with the alcohol of the formula Rl1OH. An activated ester may be formed by reacting the carboxylic acid with l-hydroxybenzotriazo~e in the presence of a suitable dehydrating agent, e.g. 1-~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.

8) The compounds of the formula (I) wherein Rl is COOR
wherein Y, R, Rl to R9 and Rll are as previously defined for a compound of the formula (I) may be prepared by reaction of a compound of the formula:-~u~D93~02050 2 :i 1 2 ~ 3 ~ PCT/EP92/0162S

R~ R~
R2 ~ R R ~ R7 R1 y R~
~oz1 ....(VI) whe~ein Y, R and Rl to R9 are as previously defined for a compound of the form~la (I) and Z1 is a sui~able leaving group, e.g. chloro or bromo, with an alcohol o~ the formula R1lOH wherein R1l is as previously defined for this method.

The reaction may be carried out in the presence of an acid acceptor, e.g. pyr~dine, and in a suitable sol~ent, e.g. dichloromethane, at from OC to room temperature.

9) ,. The compounds~of the formula (I~ wherein Rl is COOR
wherein Y, R, Rl to R9 and R1l 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 Rl is COOH and Y, R and Rl 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 RllZ2 wherein R~1 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.

W093~02~0 PCT/EP92/0162 ~ ,1...v~ 18-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.

10) The compounds of the formula (I) wherein Rl is coN~l2Rl3 and Y, R, R1 to R9, R12 and R13 are as previously defined ~or a compound of the formula (I) may be prepared by reaction of a compound of the formula (I) wherein Rl is COOH and Y, R and R1 to R9 are as previously defined for a compound of the formula (I) with an amine of the formula R12R13NH
wherein R12 and R13 are as previously defined for this method in the presence of a dehydrating agent, e.g.
dicyclohexylcarbodiimide. The reaction may be carried out in a suitable organic solvent, e.g.
dichloromethane, at from room temperature to the reflux temperature.

Alternatively the reaction may be carried out by first forming an activated ester or imidazolide de~ivative of the carboxylic acid, followed by reaction of the activated ester or imidazolide in situ with the amine of the formula Rl2Rl3NH. Suitable procedures for the formation of an activated ester or imidazolide are described in method (7).

ll) The compounds of the formula (I) wherein R10 is coNRl2Rl3 and Y, R, R1 to R9, R12 and R13 are as previously defined for a compound of the formula ~I) may be prepared by reaction of a compound of the formula (VI) wherein Y, R, R1 to R9 and z1 are as previously defined for a compound of the formula ~093~02~ 2 1 1 2 ~ g ~ PCT/EP92/0162~

--19-- . .
(VI) with an amine cf the formula Rl2R13NH wherein R12 and Rl3 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 0C to room temperature. .

12) The compounds of the ~ormula (I) wherein Rl is CoNRl2R13 and Y, R, R1 to R9, R~2 and Rl3 are as previously defined for a compound of the formula tI) may be prepared by reaction of a compound of the formula tII) wherein Rls is a suitable ester-forming group, e.g. C1-C6 alkyl or an alternative biolabile ester-forming group as previously defined (i.e. a compound of the formula (I) wherein Rl is COORll), or p-nitrophenyl, and Y, R and R~ 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 Cl-C4 alkanol, at from room temperature to the reflux temperature. The reaction is usually carried using an excess of the amine and in a sealed reaction vessel (e.g. a bomb).

13) The compounds of the formula (I) wh~r~in R10 is COOH
or CoNR12R13 and Y R Rl to R9 R12 and Rl3 are as previously defined for a compound of the formula ~I) may be prepared by acidic hydrolysis of a compound of the formula:-W093/02~0 PCT/EP92/01625 ~ 8 9 -20-I~R7 CoR21 ..... ~VII) -wherein Y, R and Rl to R9 are as pre~iously defined for this method, Rl9 and R20 are either each Cl-C4 al~yl or when taken together represen~ C2-C3 alkylene, said alkylene group being optionally substituted by Cl-C4 alkyl, and R2l is -OH, -OR22 wherein R22 is a suitable ester-forming group that may be removed by hydrolysis, e~g. C1-C6 alXyl or an alternative biolabile ester-f orming group as pr~viously definPd, or N~l~Rl3 wherein Rl2 and Rl3 are as previously def ined 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.

~'~93/02~ 9 PCT/EP92/01625 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-Inter~cience (2nd edition, l99l), followed ~y N-alkylation of the ketal ~y a similar procedure to that described in method (14) for alkylation of a compound of the formula (VIII).

14) All the compounds of the formula (I) wherein Y, R
and R1 to R10 are as previously defined for a compound of the formula (I~ may be prepared by alkylation of a base salt (i.e. the N-deprotonated form) of a compound of the formula:-R2~a R R~R7 Rl - R6 .. . ..

W093/02~0 PCT/EP92/0162~

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-CooR11 or Z3-Y-coNRl2Rl3 or with a base salt of a compound of the formula Z3-Y-CooH, as aPPrpriate, wherein y, R11, R12 and R13 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 th formula Z3-Y-cooRll~ 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 0C 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.

,, . .. , .. ..... , .. , - ~ --`YD93/02~ 2 1 1 2 ~ g 3 PCT/EP92/01625 Where a compound of the ~ormula (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.

lS) All the compounds of the formula (I) wherein Y, R
and Rl to R1D are as previously defined for a compound of the formula (I) may be prepared ~y acylation of an indole of the formula:-~1 ~r R1 y l oR~3 .. ~.(lx) .
or, where R is OH, a base salt thereof, or of a base salt of an indole of the formula:- -R~

R1 1 :

....tx) W093102~0 J j PCT/EP92/0162 -24- .

wherein Y, R and Rl to R4 are as previously defined for a compound of the formula (I) and R23 is either OR11 or is NRl2R13 wherein Rl1, R12 and R are as previously defined for a compound of the formula (I~, with a co~pound of the formula:-R~R7 wherein Rs to ~9 are as previously defined for thismethod and ~4 is a leaving group, e.g. h~lo, preferably chloro, and in the presence of a Lewis acid where R is not ~H and optionally in the presence of ~ Lewis a~id where R is OH~ Suitable Lewis acids include al~minium 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 pot~ssium salts.

.'-Y~93/02050 ~ 8 3 pcTrEp92/ol62s Where a compound of the formula (I) wh~rein Rl 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 acyla~ed with a compound of the formula (XI), optionally in the presence of a Lewis acid.
Incorporation of an acidification step in the work-up procedure affor~s 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 Rl 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:-R~ `f ! R ~ R7 R1 y R6 Z~

W093/02~0 PCT/EP9~/01625 wherein Z5 is -CH=CH2, -CH=CH(C1-C4 alkyl), -CH-C(Cl-C4 alkyl) 2 or -C=CH and Y, R a~d 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 Rl is COOH
and Y, R and Rl to R9 are as previously defined for a compound of the formula (I) may ~e prepared by oxidation of a compound of the formula:-r~ R7 i .` ....~111) wherein Y, R and R1 ~o R9 are as previously definedfor a compound of th~ formula (I). A suitable oxidising agent for this purpose is chromium trioxide in pyridine.

18) The compounds of the formula (I) wherein Rl is COOH
and Y, R and Rl to R9 are as previously defined for a compound of the formula (I) may be prepared by oxidation of a compound of the formula:-~'~3/02~0 ~112 ~ 8 9 PCT/EP92/01625 R2~7 ....(XIY) or R~ ~ ~ `~
R1 y F,6 ' ....~V) or a base salt thereof, wherein R24 is H or OH and Y, R and R~ to R9 are aspreviously 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.

W093/02~0 ~ 3 ~ PCT/EP92/0162$~

The oxidation may alternatively be carried out on a compound of the formula (XV) wherein R24 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 R2~ is H may be prepared by reacting the corresponding lH-indole-l-magnesium halide derivative with a corresponding benzyl halide of the formula:-R~ ~R~

Z6CH2~R7 Rs R6 ....(XVI) wherein Rs to R9 are as previously defined for thismethod 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:-R~ ~R~

- oHC~R7 ~....(XVII) ~093/02~ 2 i . 2 6 8 9 PCT~EP92/01625 wherein Rs to R9 are as previously defined for this method.

l9) The compounds of the formula ~I) wherein one of R6, R7 and Rs i~ a group of the formula:--OCH-Aryl and the remainder, together with Y, R, R1 to R5, R9, R10, R14 and l'aryl" are as previously defined for a compound of the formula (I), may be prepared by reaction of a compound of the formula:-4 O ~9 ~ ; 1 R1 y R2 F~10 .... (XVIII~ ' or a base salt thereof, ~
.
wherein one of R2~, R26 and R27 is OH and the remainderof R25, R26 and R27 are as previously defined in this method for the remainder of R6, R7 and R~, and Y, R, R1 to Rs, R9 and R1U are as previously defined for this method, with a compound of the formula:-Rl4 Z7-CH-Aryl .... (XIX) W093/02~ 2 i 1 ~ ~j 8 ~ PCT/EP92/016 ~

-30- .
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 0C 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 solv~nt.

20) The compounds of the formula (I) wherein R10 is COOR
or CoNR12R13 and Y, R, R1 to R9, R11, R12, R13, R14 and "aryl" are as defined for method (l9~ may be prepared by reaction of a compound of the formula (XVIII) wherein R10 is COORll or CoNR12R13, as appropriate, wherein Rllt R12, R13 and ~, R, R1 to ~5 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 (l9), with a compound of the formula:- -` Rl4 H0-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/

.~093/02~0 ~ 1 1 2 & ~ 3 PCT/EP92/01625 -3l-triphenylphosphine. The reaction may be carried out in a suitable solvent, e.~. tetrahydrofuran, at from room temperature to the reflux temperature.

2l) The compounds of the formula (I) wherein one of R6, R7 and R9 is a group of the formula:-Rl4 -CHO-Ary l, and the remainder, together with Y, ~, Rl to R5, R9, Rl, Rl4 and "aryl" are as previously defined for a compound of the formula (I), may be prepared by reaction of a compound of the formula:-R~

R2~f ~ R R~R~9 R1 y R28 . .~.. (XXI) , or a base salt thereof, wherein one of R28, R29 and R30 is a group of theformula:--CH-z8 W093/020~0 ~ L.'.,~ 32- PCT~EP92/0162 and the remainder are as previously defined in this method for the remainder of R6, R7 and R8, Y, R, Rl to Rs, R9, Rl and Rl4 are as previously defined for this method and Z3 is as defined for Z7 in method (19), with a base salt of a compound of the formula:-Aryl-OH ....(XXII~

wherein "aryl" is as previ~usly 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 (XXIIj 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 OC to the reflux temperature. The reaction may also be carried by rea ting a phenol of the fo~mula (XXII~
with a csmpound of the formula (XXI) in the presence of potassium carbonate and in a suitabl~ solvent, e.g. 2-butanone, at up to, and preferahly at, the reflux temperature of the solven~.

22) The compounds of the formula ~I~ wherein Rl is COOR
or CoNRI2Rl3 and Y, R, Rl to R9, Rll, Rl2, R13, Rl4 and "aryl" are as defined for method (21) may ke prepared by reaction of a compound of the formula:-.~ 93/02~ . 2 f3 8 3 PCTfEPg2/01625 R2 ~ , r Rl y R31 R1o ~.............................. ..... ......... (~0~111) wherein one of R31, R32 and R33 is a group of the formula:-Rl4 -CH-OH
and the remainder are as previously defined in this method for the remainder of R6~ R7 and R8, and Y, R, Rl to R5, R9, ~1~ and Rl4 are as previously defined for this method, with a co~pound 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.

W093/020s0 PCT/EP92/0162 ,3~

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 tréatment o~ human prostate-adenocarcinomas.

The compounds of the formula (I) may be tested in vitro for steroid 5c~reductase inhibitory activity using prostate tissue from rats or humans.

~`~D93J02~ 2 ~ ~ 9 PCT/EP92/01625 The compounds of the formula (I) may be tested for potency in inhibiting rat steroid 5o~reductase using ventral prostate tissue from male rats. In determining inhibitory potency against rat prostatic 5o~reductase the following procedure was employed:-Rat prostates were ~inced into small pieces. Thetissue was homogenised in Buffer A (20mM sodium phosphate, pH 6.5, buffer containing 0.32M sucrose and lmM dithiothrei~ol) 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 a~ 105,QOOG for 60 minutes. The pellet was washed in 4 volumes of Buffer A and recentrifuged at lOS,OOOG. The resulting pellet was dispersed in Buffer A (lml per g of prostate tissue originally used) with a motor driven Potter Elvehjem homogeniser as described a~ove. The particulate suspension was stored as lml samples at -70C.

The following components, dissolved in Buffer B
(40mM sodium phosphate buffer, pH 6.5), were added to a test tube: 500~l of ~3Hj-testosterone ~l~Ci, - lnmol; Du Pont,-NEN Research Products, Stevenage, U.K.), lOO~l of O.5mM NADPH, a compound of the formula (I) dissolved in 5~l of dimethyl sulphoxide, and Buffer B to give a final reaction volume of lml.
The mixture was warmed to 37C and the reaction started by addition of an aliquot of prostate particulate suspension. The reaction mixture was incubated at 37C for 30 minutes and then quenched by addition with vigorous mixing of W093/02~0 ~ ~ PCT/EP9~J01625 2ml of ethyl acetate containing 20~g each of testosterone and So~dihydrotestosterone as carriers.
The aqueous and organic layers were separated by centrifugation a~ 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 50-80~1 of absolute ethanol and spotted onto a silica gel 60 F254 TLC plate (E.
Nerck, Darmstadt, Germany) and developed in chloroform:acetone (185:15).

The radiochemical content in the bands of the substrate (testosterone) and the product (So~
dihydrotestosterone) was determined with a RITA
Radio TLC Analyser (Raytest Instruments Ltd., Sheffield, U.K.). The percent of recovered radiolabel converted ~o Sc~dihydrotestosterone was calculated and used to determine enzyme activity.
All incubations were conducted so that no more than 15% of su~strate ~testosterone) was converted to product.

The experimentally obtained data for a range of inhibitor concentrations was computer fitted to a sigmoidal dose-response curve and concentrations of compound giving 50% inhibition of 5o~r ductase activity (ICso's) were calculated using a SIGFIT ` ~
program (De Lean, A., Munson, P.J. and Rodbard, D., American Journal of Physiology, 235, E97 (1~78)).

The compounds of the formula (I) may be tested for potency in inhibiting human steroid 5~reductase using tissue from hyperplastic human prostates. In determining inhibitory potency against human prostatic 5o~reductase the following procedure was employed:-~V~093/02 ~ 2 1 i 2 ~ ~ 9 PCT/EP92/01625 Frozen human prostate tissue was pulverised in liquid nitrogen using a steel mortar and pestle.
The powdered tissue was homogenised in 4 volumes of Buffer A (20mM sodium phosphate, pH 6.5, containing 0.32M sucrose, lmM dithiothreitol and 50~M 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 lOo,OOOG for l hour. The resulting pellet was dispersed in Buffer A (lml 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 lml samples at -70C.

The following components, dissolved in Buffer B
(20mM citrate phosphate ~uffer, pH 5.2), were added to a test tube: 500~1 of t3H]-testosterone (l~Ci, lnmol; Du Pont, NEN Research Products, Stevenage, U.K.), lOO~l 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 S~l o~ dimethyl sulphoxide, and Buffer B to give a final reaction volume of lml.
The mixture was warmed to 37C and the reaction started by addition of an aliquot of prostate particulate suspension. The reaction mixture was incubated at 37C for 30 minutes and then quenched by addition with ~igorous mixing of 2ml of ethyl acetate containing 20~g each of testosterone and 5o~
dihydrotestosterone as carriers. The aqueous and organic layers were separated by centrifugation at 2000G for lO minutes. The organic layer was W093/02050 ~ 8 ~ PCT/EP92/01625 transferred to a second te~t tu~e and evaporated to dryness under nitrogen. T~e residue was dissolved in 50-80~1 of absolute ethanol and spotted onto a silica gel 60 F254 TLC plate (E. Merck, Darmstadt, Germany) and developed in chloroform:acetone (185:15).

The radiochemical content in the bands of the substrate (testosterone) and the product (5o~
dihydrotestosterone) was determined with a RITA
Radio TLC Analyser (Raytest Instruments Ltd., Sheffield, U.K.). The percent of recovered radiolabel converted to S~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~reductase activity ~IC50's) were calculated using a SIGFIT
program (De Lean, A., Munson, P.J. and Rodbard~ D., American Journal of Physiology, 235, E~7 (1978)).
:, . . ......... ; ~
The compounds of the formula (I) may ~e tested for potency in inhibiting steroid 5~reductase activity in human prostate adenocarcinomas using cell lines DU145 and HPC36M. In determining inhibitory potency against 5~reductase the following procedure was employed:-~ 93/02~ 2 1 i ~ ~ 8 ~ PCT/EP92/01625 Human prostate adenocarcin~ma 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 S-10 x 106 cells/ml. in serum free medium.

The following components were added to a test tube:
10~1 of [3H~-testosterone (l~Ci, 20 pmol) dissolved in ethanol (Du Pont, NEN Research Products, Stevenage, U.K.) and S~l 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~mol NADPH. The mixture was warmed to 37C 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 37C for 2 hours and then quenched by addition with vigorous mixing of l.Sml of ethyl acetate containing 20~g 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, containing testosterone and its metabolites, was transferred to a second test tube and evaporated to dryness under nitrogen. The residue was dissolved in 50-80~1 of absolute ethanol, spotted onto a siIica gel 60 F254 TLC plate (E. Merck, Darmstadt, Germany) and developed in dichloromethane:acetone (185:15).

W093/02~0 PCT/EP92/01625 ~ _;;v~ ~ 40 The radiochemical content in the bands of the substrate (testosterone) and the product (So~
dihydrotestosterone) was determined with a RITA
Radio TLC Analyser (Raytest Instruments Ltd., - Sheffield, U.K.). The percentage of recovered radiolabel converted to 5o~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 S0% inhibition of 5o~reductase activity (ICso'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 ~lood.

~ 93/02~ 2 1 1 2 & 3 ~ PCT/EP92/01625 For oral and parenteral administration to human patients, the daily dosage level of the compounds of the formula (I) will be from O.Ol to 20 mg/kg (in single or divided doses) and preferably will be from O.l to lOmg/kg except for the treatment of human prostate adenocarcînomas where doses of up to 20mg/kg may be used. Thus tablets or capsules of the compounds will contain from lmg to 0.5g of active compound for administration singly or two or more at a time, as appropri~te. 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 low~r 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 l and 10%, into an ointment consisting of a white wax or white sof~ paraffin base together with such stabilizers and preservatives as may be required.

W093/02~0 PCT/EP92/01625_ ~ J~ 2-The compounds of the formula (I) may also be administered together with an o~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 prostatlc hypertrophy.

Thus the invention further provides:-i) a pharmaceutical composition comprising acompound 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 5 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;

~093/02~0 2 1 i ~ 5 8 9 PCT/EP92/01625 v) a method of treatment of a human to inhibit a steroid 5o~reductase which comprises treating said human with an effective amount of a compound of the formula (I) or with a pharmaceutically acceptable salt or composition thereof;
vi) a method of treatment of a human to cure or prevent acne vulgaris, alopecia, seborrhoea, female hirsutism, benign prostatic hypertrophy, male pattern baldness or a human prostate adenocarcinoma which comprises treating said huma~ with an effective amount of a compound of the formula (I~ or with a pharmaceutically acceptable salt or composition thereof, and vii) novel intermediates of the formulae (IV), (VIII) and base salts thereof, (XIII), (XIV), (XV) and base salts thereof, (XVIII) and base salts thereof, (XXI~ and base salts thereof, (XXI~ and base salts thereof and (XXIII).

The following Examples illustrate the preparation of the compounds of the formula (I):-W093~0Z~0 -` PCT/EP92J016 rR,S)-4-(3-r4-(1-r4-(2-Methvlro~vl~phenyl~ethoxy)~
benzovllindol-1-Yl)butanoic acid Cl ~ o~H3 O2CH2CH~ CH3 ¦ aq.NaOH,THF,CH30H

~ ~ CH3 A solution of ~R,S~-4-~3-t4-(1-[4-(2-methylpropyl)phenyl3ethoxy)benzoyl]indol-1-yl)butanoic acid e~hyl ester (3.8g) (see Example 21) in tetrahydrofuran (THF) (35ml) and methanol (35ml) was treated with 2N sodium hydroxide solution (35ml). After stirring at room temperature for 2 hours the mixture was W093/02050 2 1 ~ 2 ~ 8 9 PCT/EP92/01625 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 (lOOml), the organic extract dried (sodium sulphate) and concentrated in vacuo to provide the title compound as a white foam, (3.27g), m.p. 57C.
Found: C,77.00; H, 6.88; N,2.90; C31H33NO~ requires:
C,76.93; H,6.88; N,2.99%.

lH-NMR (CDCl3): ~ = 0.95(d,6H), 1.70(d,3~), l.90(m,1H), 2.25(m,2H), 2.40(t,2H), 2.49(d,2H), 4.30(t,2H), t 5.50(q,lH), 6.95(d,2H), 7.15(d,2H), 7.27-7.45(m,5H), 7.59(s,lH), 7.79(d,2H), 8.45(m,lH) ppm.

EXAMPLES 2 to 20 The following compounds of the general formula:-~ R7 ,.,...... .... .

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.

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(R.S)-4-(3-14-(1-r4-f2-MethvlPro~vl)phen~llethoxY~-benzovll indol-l-vl~ butanoic acid_ethvl_ester OH
CO2CH2CHs ) N~H,DMF
2~ ~H3 Br~cH3 "o~ ~3 cc)2cH2cH3 CH3 A suspension of sodium hydride ( 60% dispersion in oil, 716mg~ in dry dimethylformamide (DMF) (lSml) at 0C and under a nitrogen atmosphere was treated dropwise with a solution of 4-(3-[4-hydroxybenzoyl]indol-1-yl)butanoic acid ethyl ester (see Preparation 1) (5.24g) in dimet`hylformamide (30ml). After stirring for one hour at room temperature a solution of o~methyl-4-(2-methylpropyl)ben~yl bromide ~see Preparation 23) (3.95g) in dimethylformamide (5ml~ was added to the mixture at 0C. The resultant mixture was stirred overnight at room temperature. The reaction was partitioned be~ween lN hydrochloric acid solution (~OOml) and ethyl acetate (200ml). The separated organic layer was washed ~ J3~
`'YD93J020SO PCT/EP92/01625 successively with lN sodium hydroxide solution (lOOml), saturated aqueous brine (lOOml) and then water (lOOml3. The organic layer was dried (MgSOI) and concentrated in vacuo to provide a yellow oil. Column chromatography (silica, 4.1 hexane/ethyl acetate) provided, after evaporation of the appropriate fractions, the title compound, (3.8g). Found:
C,77.47; H,7.29; N,2.74; C33H3~NO~ requires: C,77.63; H,7.48;
N,2.73%.

lH-NMR (CDCl3): ~ = O.91(d,6H), 1.35(t,3H), 1.70(d,3H), l.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,SH), 7.55(s,lH), 7.88(d,2H), 8.45(m,lH) ppm.

EXAMPLES 22 to 32 The following compounds of the general formula:-R~ R6 r 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) ~y similar methods to that used in Example 21.

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W093/020s0 PCT/EP~2/0162~_ ~ EXAMPLE 33 (S)-4-(3- r 4-(1- r 4 - l 2 -MethylPro~Yl )Phenvll~thoxYL~
benzovllindol-l-yl)butanoic acid ethvl este~

OH ~ CH3 CO2~H2C~b ¦ Ph3P,DEAD, "H
N O ~ H3 ~ CO~CH2C~3 CH3 A solution of 4-(3-[4-hydroxybe~zoyl~indol-1-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 (20~1) was treated with diethylazodicarboxylate (DEAD) (0.27ml) and the mixture stirred at room temperature overnight.
Evaporation of the reaction mixture onto sîlica gel (5g) followed by flash chromatography (silica, 3:1 hexane~
ethyl acetate) gave, after evaporatiQn of the appropriate fractions, the desired compound as a pale yellow gum, (413mg), mlz = 511 (M~).

i26~'~
~~ 93/02~0 - PCT/EP92/01625 H.P.L.C. (Cyclobond DMP ~vlumn eluting with 1:1 1%
triethylammonium acetate, pH4~1/CH3CN at 0.7ml/min.) rt-86.09 min. (100%).

lH-NMR (CDCl3): ~ = 0.95~d,6H), 1.25(t,3H), 1.70(d,3H~, 1.85(m,1H), 2.20(m,2H), 2.30(t,2H), 2.4S(d,~H), 4.10(q,2H), 4.25(t,2H), 5.40(q,1H), 6.95(d,2H), 7.lS(d,2H) 7.25-7.40(m,5H), 7.55(s,lH), 7.75(d,2H), 8.35(m,1H) ppm.

The title compound may also be prepared ~y reso}ution of the product of Example 21 using chiral HPLC
(Chiralpak AD column, eluant = 9:1 hexane/ethanol, flow rate = 12ml/min.). The first eluted compound was ~R)-4-(3-~4-(1-[4-(2-methylpropyl)phenyl]ethoxy)~enzoyl~indol-1-yl)butanoic acid ethyl ester/ rt = 24min., ~a] 25 +52.1 (CC2 in dichloromethane~, and the second eluted compoun~ was the title compound, rt = 27min., s _ 53.8 (c=2 in dichloromethan~).

EXAMPLES 34 to 37 The following compounds of the general formula:-O

R5 ~6 y I

were pxepared 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.

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W093/02~0 PCT/EP92/0162~
h i ~ 8 3 -68-4-(3-~4-Benzvloxybenzoyllindol-1-vl~butanoic acid ethYl ester 3 NaH,DMF
2) Br ~ CO2CH2CH3 o-~

~CO2CH2Ct~3 A cooled (0C~ suspension of sodium hydride (3.40g of a 55~ dispersion in mineral oil) in dimethylformamide (50ml) was treated with a solution of 3 (4-benzyloxybenzoyl~indole (see Preparation 5~ (20.0g) in dimethylformamide (lOOml). The resultant orange suspension was allowed to stir for 1 hour at 20C. The mixture was cooled to 0C and ethyl 4-bromobutyrate (ll.Oml) was added. The mixture was stirred for 2 hours at room temperature, cooled to 0C and treated with lN
aqueous hydrochloric acid ~lOOml) and ethyl acetate (~OOml). The organic layer was separated and washed with water (lOOml), lN aqueous hydrochloric acid (lOOml), -~93/02~0 2 ~ 1 2 5 ~ ~ PCT/EP92/01625 saturated aqueous sodium bicarbonate (lOOml) and brine (lOOml). Evaporatio~ of the ethyl acetate gave an orange gum which was purified by flash chromatography (silica, eluant = 3:1 hexane/ethyl acetate then 2:1 hexane/ethyl acetate) to give, after combination and evaporation of the appropriate fractions, the title compound (16.Sg), m.p. 83C.

IH-NMR (CDCl3): 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,lH), 7.85(d,2H), 8.40(m,lH) ppm.

EXAMPLES_39 to 43 The following compounds of the general formula:-~R7 R5 R~

co2CH2~3 were prepared by similar methods to that used in Example38 using the corresponding indoles ~see Preparations 5 to 8) and the corresponding ethyl bromoalkanoates as the starting materials.

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-~D93/02~0 ~ 7 I ~ 6~9 PCT/EP92/Ot625 . -73-The following Preparation~ illustrate the preparation of certain starting materials used in the previous Examples:-4~(3~ r 4-Hvdroxvbenzoyl~indol-1-Yl)butanoic acid ethvl ester ~o~3 ~CO2CH2CH3 H2,lo% PdlC, CH3C02C2Hs CJ~h ~OH

A solution of 4-(3-t4-benzyloxybenzoyl]indol-1-- 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% palladium-on-charcoal (3g) at room temperature for 4 hours. The catalyst was removed by filtration of the reaction through a W093/02~0 ~.L ~ 2 ~ ~ 3 PCT/EPg2/0162~

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; C21H2lNO4 requires: -C,71.44; H,6.04; N,3.94%.

lH-NMR (CDCl3): ~ = 1.25(t,3H), 2.22(m,2H), 2.35(m,2H), 4.15(q,2H), 4.30(t,2H), 6.95(d,2H), 7032-7.45(m,3H), 7.65(s,lH), 7.70(d,2H), 8.4~(m,lH) ppm.

PREPARATIONS 2_to 4 The following compounds of the general formula:-OH

CO2CH2~ H3 were prepared by hydrogenation of the correspondingbenzyl ethe~s (see Examples 39 to 41) by similar methods to that used in Preparation 1.

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3-(4-BenzyloxYbenzovl)-1H-indole ) CH3~gl1(cH3cH~2o A OCH2 9 H 2) b~cH20{}cocl A mechanically stirred solution of indole (30.0g) in sodium dried diethyl ether (450ml) was treated dropwise with methylmagnesium iodide (85ml of 3.OM solution in diethyl ether). After stirring for one hour at 20C
4-benzyloxybenzoyl chloride (see Preparation 10) (~7.3g) was added. Stirring was continued for two hours at 20C
and then lN hydrochloric acid ~250ml~ added to the mi~ture and the reaction was allowed to stand overnight.
The resulting precipitate was filtered off and triturated with hot ethyl acetate (3 x lOOml~ to giv~ the desired compound as a pale pink solid, (40.9g). Found: C,80.67;
~,5.33; N,4~25; C22H17NO2 requires: C,80.70; H,5.23;
N,4.2~.

lH-NMR (d6-DMSO): ~ = 5.20~s,2H), 7.15(d,2H), 7.20~m,2H), 7.30-7.50(m,6H), 7~80~d,2H), 7.90(s,1H), 8.23~d,1H), 11.95(s,br,1H) ppm.

' ~93/02050 ~ 9 PCT/EP92/01625 PREPARATIQNS 6 to 8 The following indoles of the general formula:-r r ,~

were prepared from the corresponding lH-indoles and the corresponding acid chlorices (see Preparations 9 to ll) using similar methods to that used in Preparation 5.

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w~o 93/02~0 ~ 8 9 ~CT/EP92/01625 ~ -81-(a) 4-Bromo-2 3-dimethylphenol A solution of 2,3-dimethylphenol (40.0g) in acetic acid (300ml) was cooled to 10C and treated with a solution of bromine (16.9ml) in acetic acid (lOOml~.
After stirring for 30 minutes saturated aqueous sodium metabisulphite solution (300ml) was added.
The mixture was extracted with dichloromethane, the organic layer dried (MgSO4), filtered and evaporated to provide the product as a waxy solid, (64.7g)~

lH-NMR (CDCl3): ~ = 2.15(s,3H), 2.25(s,3H), 4.00(s,br,1H), 6.60(d,1H), 7.15(d,1H) ppm.

Crystallisation of the product from hexane gave an analytical sample. Found: c,48.00; H,4.40; C8HgBrO
requires: C,47.78; H,4.51~.

(b) l-Benzyloxy-4-bro~o-2 3-dimethylbenzene A mixture of the product of part (a) (45.0g), benzyl bromide ~28.3Qg), 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 - ~he organic layer gave an oil which was chromatographed (silica, 4:1 hexane/ethyl acetate) to giv~ the desired product, (51.86g). Found:
C,62.64; H,5.31; CslHlsBro requires: C,61.85; H,5.1g%.

lH-NMR lCDCl3): 8 = 2.30(s,3H), 2.40(s,3H), 5.00(s,2H), 6.60(d,1H), 7.30-7~50(m,6H) ppm.

W093/02~ PCT/EPg2/0162 ~ 82-(c) 4-~enzyloxy-2,3-dimethylbenzoic acid A solution of the product of part (b) (33.8g) in tetrahydrofuran (THF) (500ml~ at -78OC was treated with a-butyllithium (48.4ml of a 2.5M solution in hexane). After stirring for 30 minutes at -780C 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. ~ecrystallisation from ethyl acetate gave the desired compound, t18.8g), m.p. 164-166C.
Found: C,74.87; H,6.21; Cl6H1603 requires: c,74.98;
H,6.29%.

H-NMR (CDCl3): ~ = 2.10(s,3H), 2.40(s,3H), 5.10(s,2H), 6.g5(d,lH), 7.30-7.50(m,5H), 7.60(d,lH) ppm.

(d) 4-Benzyloxy-2.3-dimethylbenzoYl chloride The product of part (c) (2.0g) was suspended in dichloromethane (lOml) and treated with oxalyl chloride (1.3ml) and dimethylformamide (DMF) (2 drsps). 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.

W093/02~0 ~l i 2 6 ~ 9 PCT/~P92/~1625 PREPARATION lO
4-Benzvloxybenzoyl 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 ~l 4-(l-r4-Isobutyl~henyl1ethoxy)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.

2~ i2~i8g 1-(4-n-Pro~vlnhenYl)butan-1-ol A solution of 4-n-propylbenzaldehyde (7.4g) in diethyl ether (60ml) was cooled to 0C and treated with a 2.OM 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 separatedl washed with saturated aqueous ammonium chloride solution and dried (MgSO4). The organic layer was filtered and evaporated to give a colourless oil which was purified by chromatography (silica, 4:1 hexane/ethyl acetate) to provide, after evaporation of the appropriate fractions, the desired product, (4.06g), m/z = 192(M+).

1H-NMR (CDCl3): ~ = 1.OO(m,6H), 1.20-1.40(m,2H), 1.70(q,2H), 1.75-l.90(m,3H), 2.60(t,2H), 4.60(m,lH), 7.10(d,2H), 7.30(d,2H) ppm.

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

lH-NMR (CDC13): ~ = 1.25(t,3H), l.55(d,3H), 2.65(q,2H), 4-9otq~lH)~ 7-20(d,2H), 7.35(d,2H) ppm.

W~093/02050 ~ S 8 9 PCT/EP92/01625 -~5-4-n-Pro~vlbenzyl alcohol A solution of 4-n-propylbromobenzene (lOg) in THF
(lOOml) at -78C 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 tMgSO4) and evaporated to an oil. Flash chromatography (silica~ 3:1 hexane/ethyl acetate) gave, after evaporation of the appropriate fractions, the desired product as a colourless oil, (2.7g).

(R,S)-1-(4-r2-Meth~ll~ropvl~phenyl)ethanol A solution of 4-isobutyrylacetophenone (lO.Og) in methanol (50ml~ was cooled to 0C and treated portionwise with sodium borohydride (3.23g). After stirring overnight at room temperature the reaction was quenched with lN hydrochloric acid (50ml) and ethyl acetate (lOOml) added. ~he organic layer was separated, dried (Mg504) and evaporated to give the title compound as a clear oil, (10.02g), m/z = 178(M+). Found: C,79.69;
H,9.90; Cl2HI80.1j7 H20 requires: C,79.68; H~10.19%.

.
lH-NMR (CDCl3): ~ - O.90(d,6H), 1.SO(d,3H~, 1.85(m,lH), 2.50(d,2H), 4.85(q,lH), 7.15(d,2H), 7.30(d,2H) ppm.

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

lH-NMR (CDC13): ~ = 1.45(d,3H), 2.25(s,br,1H), 4.85(q,1H), 7.20(d,1H), 7.40(d,1H~, 7.45(s,1H) ppm.

W093~02050 PCT/EP92/0162 u~ -86-(R)-1-(4-r2-Methvl~ropvll~henvl~ethanol (a) Ethanoic acid fR,S)-1-(4-r2-methylpropyl~phenvl~-ethyl ester A solution of the product of Preparation 15 (5.0g) in dichloromethane (40ml) at OC was treated with dry pyridine (2.5ml) followed by distilled acetyl chloride (2.2ml). After stirring overnight at room temperature the reaction mixture was filtered, silica (lOg) added to the filtrate and the mixture ' evaporated to dryness. Column chromatography (silica, 12:1 hexane/ethyl acetate) gave, after evaporation of the appropriate fractions, the desired compound as a clear oil, (2.3g).

lH-NMR (CDCl3): 8 = O.9O(d,6H), 1O55(d,3H), 1.85(m,1H), 2.05(s,3H), 2.45(d,2H), 5.85(g,1H), 7.15(d,2H), 7.25(d,2H) ppm.

(b) !R~-1-f4-~2-MethvlProDvl1~henyl~ethanol A suspension of the product of part (a~ (3.0g) in pH7 phosphate buffer (lOOml) was treated with SAM II
lipase (trade mark) (Fluka Chemicals Limited) (50mg) and the mixture stirred vigorously f or 2 days at room temperature. The mixture was extracted with -ethyl acetate (lOOml), the combined organic layers dried IMgSO4) and evaporated. Column chromatography (silica, 9:1 hexanelethyl acetate) first gave, after combination and evaporation of the appropriate fractions, ethanoic acid (S)-1-(4-~2-methylpropyl]-phenylethyl ester, (1.47g). Further elution gave the title compound as a clear oil which crystallised to provide white needles, (1.04g), m.p. 37-38C, [~a 32.3 (c = 2.7 in methanol).

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

~W~93~02 ~ ~ PCT/EP92/0162S

PREPARATI~N 18 (S)-l-(4- r 2-MethvlpropylJphenvl)ethanol Ethanoic acid (S)-l-(4-[2-methylpropylJphenylethyl ester (see Preparation 17(b)) (l.2g) was treated with a lN solution of sodium hydroxide in absolute ethanol (20ml). After stirring overnight at room temperature the solvent was evaporated and the residue chromatographed (silica, 4:l hexane/ethyl acetate) to give the title compound as a clear oil, (0.59g), m.p. 34C, [~]D - 32.7 (c = 2.7 in methanol).

lH-NMR (CDCl3): ~ = O.90(d,6H), l.SO(d,3H), l.85(m,lH) 2.50(d,2H), 4.85(q,lH), 7.15(d,2H), 7.30~d,2H) ppm.

PREPARATION l9 o~Cy~lopentyl-4-n-PropYlbenzyl alcohol A s~lution of 4-n-propylbenzaldehyde (2.0g) in diethyl ether ~20ml) was cooled to 0C and treated with a solution of cyclopentylmagnesium chloride (7.4ml of a 2.OM solution in diethyl ether). After stirring at room temperature overnight the mixture was treated with saturated aqueous ammonium chloride solution. The organic layer was separated, dried (MgSO4) and evaporated to-provide a yellow oil. Flash chromatography (silica, initial elution with 4:l hexane/ethyl acetate and then with 3:l hexane/ethyl acetate) gave, after combination and evaporation of the appropriate fractions, the desired compound as a clear oil, (400mg), m/z = 218(M~).

lH-NMR (CDCl3): ~ = 1.OO(t,3H), l.OO-l.60(m,lOH), 2.2S(sextet,lH), 2.60(m,2H), 4.40(d,2H), 7.30(d,2H), 7.40(d,2H) ppm.

W093/02~0 ~ 9 PCT/EP92/01625 PREPARATIONS 20 to 26 The following alkyl bromides were prepared by dissolving the corresponding alcohol (see Preparations 12 to 16 and l9~ 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 u~ed directly without characterisation.

. ~, Preparation I No. Alkyl bromide I _ . _ l-Bromo-l-(4-n-propylphenyl)butane.
I
¦ 2l ~Methyl-4-ethylbenzyl bromide.
22 4-n-Propylbenzyl bromide.
23 o~Methyl-4-~2-methylpropyl)benzyl bromide.
24 o~Methyl-3,4-dichlorobenzyl bromide o~Cyclopentyl-4-n-propylbenzyl bromide.
261 o~(4-n-Propylphenyl)-4-n-propylbenzyl bromide.
For starting material see EP-A-29l245.

wo 93/02050 h ~ L ~ PCI/EP92/0162 --8~--4- ( 3 - ~ 4 - Ll-HYdroxvethvl ~ benzoYl 1 indol-l-yl ) butanoic acid ethyl ester ~lOC
~,1~, OSIMe2tE~u (a) o I~JI~ ,~1 1~1~" OslMe2tBu ~H3 ~(b) o ~ OSlMe2tBu - (CH2)3~:O2c2H5 ~:H3 ~c) OH

~CH2)3~2C2Hs CH3 W093/02~ PCT/EP92/0162~

~ ~ _ L ' V _I S ~ _ g o _ a) 3-~4-LL=l~-Butyldimethylsilyloxy)ethyl]
~nzoyl)indole The title compound was prepared by a similar method to that used in Preparation S using indole and 4- ( 1-[t-butyldimethylsilyloxy]ethyl)benzoyl chloride as the starting materials, m/z = 380 (M+1)~. Found:
C,72.79; H,7.73; N,3.76; C23H29No2Si requires:
C,72.78; H,7.70; N,3.69%.

lH-NMR (CDCl3): ~ = O.OO(s,3H), 0.40(s,3H), 0.95(s,9H), 1.45(d,3H), 4.95(q,1H), 7.30-7.50(m,5H),.
7.70(m,1H~, 7.80(d,2H), 8.40(m,1H), 9~20(s,br,1H) ppm.

b) 4-(3-~4-(1- r t-Butyldimethvlsilyloxy3eth ~enzoYllindol-1-vl)butanoic acid ethyl ester A solution of the product of part (a) (1,70~) in dimethylformamide (20ml) was treated with sodium hydride (215mg of a 60% dispersion in mineral oil).
A~ter stirring for l 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 ~SOml) and washed suc~essively with 2N aqueous hydrochloric acid and saturated brine. The organic layer was dried (MgSO4) and gave a yellow gum on e~aporation of the s~lvent.
Flash chromatography of this gum ~silica, 3:1 hexane/ethyl acetate) followed by collection and evaporation of the appropriate fractions gave the title compound as a clear gum (2.20g), m/z =
494(M+1)~-H-NMR (CDCl3): ~ ~ O.OO(s,6H), O.90(s,~H), 1.20(t, 3H), 1. 50 (d, 3H), 2 . 20-2.40(m,4H), 4.10(q,2H), 4.~0(t,2H), 5.00(q,1H), 7.20-7.40(m,5H), 7.60(s,1H~, 7.80(d,2H), 8.35(m,1H) ppm.

~ 93/02~ 2 1 1 ~ S 8 9 PCT/EP92/01625 (c) 4-(3-r4-(1-Hydroxyethyi)benzoyllindol-l-yl~butanoic acid ethyl ester The product of part (b) was dissolved in tetrahydrofuran (lOOml) and treated with tetra-n-butylammonium fluoride (4.92g) and stirred for 1 hour. The reaction mixture was diluted with ethyl acetate (lOOml) and washed with 2N aqueous hydrochloric acid and saturated brine. The organic layer was dried (MgSO~), filtered and evaporated to a brown gum. Flash chromatography (silica, 98:2 dichloromethane/methanol) gave, after collection and ' evaporation of the appropriate fractions, the title compound (0.92g) as a clear gum, m/z = 380 ~M~

~H-NMR (CDCl3): ~ = 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,lH) ppm.

PRE~RATION 28 (S~-4-(3-r4-(1-14-(2-Methylpropyl)~henyl~ethoxy)-benzoyllindol-~-ylLbutanoic acid (a) (R S)-4-(1-~4-~ ethylpropy~ phenyl~ethoxY)~enzoic acid ethyl ester Ethyl p-hydroxybenzoate (5.16g) was dissolved in acetone (SOml)~and treated with anhydrous potassium carbonate (4.40g), tetra-a-butylammonium bromide (0.44g) and (R,S)-o~methyl-4-(2-methylpropyl)benzyl bromide (see Preparation 23) (7.7g). The resultant slurry was stirred overnight at room temperature and filtered. The filtrate was evaporated to give the title compound (13.5g) which was used directly without chara~terisation. ;

W093/02~0 2 1 1 ~ PCT/EP92/0l625 --g2--,S~-4-(l-t4-(2-MethYlPropyl)~henyllethoxy~benzoic acid The product of part ~a) (13.5g) was dissolved in 95%
aqueous ethanol (108ml), treated with 2N aqueous sodium hydroxide (32ml) and heated at 60-700C for 9o minutes. The solvent was evaporated and water (3Oml) added. The mixture was treated with 2N
aqueous hydrochloric acid (SOml) and then extracted with ethyl acetate. The combined organic layers were washed with saturated brine and dried (MgSO~
Removal of the ethyl acetate solvent gave the title ' compound as a white solid. Trituration with n- :
hexane gave a fi~e white powder (6.7g).

H-NMR (CDCl3): ~ = 0.95(d,6H), 1~70(d,3H), 1.88(m,lH), 2.51(d,2H), 5.40(q,lH), 6.95(d,2H), 7.17(d,2H), 7.30(d,2H), 8.QO(d,2H) ppm.

~c) ~S)-4~ t4-(2-Methylpropyl~phenyllethoxy)benzoic acid, (+)-ephedrine salt The product of part (b) (lQg) was dissolved in 95~
aqueous ethanol (60ml) and water (60ml) and treated with (~)-ephedrine hemihydrate (5.84g). The mixture was heated under reflux until complete solution was achieved. The reaction Wa5 allowed to stand at room temperature overnight. The resulting precipitate was removed by filtration and dried to provide the title compound (5.20g).
[a32o -21.9 (c=1 in methanol).

W093/020S0 2 i 1 2 ~ 8 3 PCT/EP92/01625 IH-NMR (CDCl3): ~ = O.90(d,6H), l.lO(d,3H), 1.70(d,3H), 1.85(m,1H), 2.45(s,3H), 3.15(m,1H), 5.45(m,2H), 6.88(d,2H), 7.10(d,2H), 7.30(m,7H), 7.90(m,2H~ ppm.

Chiral HPLC analysis of the product showed it to contain a 9S:S ratio of the (S):(R) enantiomers.

(d) (S?-4-tl-r4-r2-MethvlProPYl)~henYl3ethoxy!benzoic acid The product of part (c) ~4.63g) was treated with lN
aqueous hydrochloric acid and the resultant slurry stirred for 90 minutes. The resultant precipitate was filtered off and washed with lN aqueous hydrochloric acid then water. The product was dried in vacuo at 50C to give the desired compound as a colourless solid, (2.94g), m.p. 128-131C. ~20 -51.5 (c=1 in me~hanol).
Found: C,7~.76; H,7.30; N,O.OO; ClgH2203 requires:
- C,76.48; H,7.43; N,0.00%.

H-NMR (CDCl3~: ~ = 0.95(d,6H), 1.70(d,3H)~
1.88(m,1H~, 2.51(d,2H~, 5.40(q,1H3, 6.95(d,2H), 7.17(d,2H3, 7.30(d,2H), 8.00(d,2H) ppm.

(e) rS~-4-~1-r4-(2-Methylpropyl)ph~nyl]ethoxy~benzoy~l chloride The product of part (d) ~2g) was dissolved in dichloromethane (lOml) 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 (4Oml) added. The resultant precipitate was removed by filtration and ~`

W093/020~0 PCT/EP92/01625 ~; ~ i S 3 ~ - -94-the f~ltrate containing the title compound was evaporated to a volume of lOml and used directly in the next step without characterisation.

(f) (S)-3-(4-~ 4- r 2-Methvl~ropyl1phenyl)-et~oxy~benzoyl~indole Indole (715mg) was dissolved in toluene (5ml) and treated with methylmagnesium iodide (2.Oml of a 3M
solution in diethyl ether). The resultant yellow solution was stirrPd for 10 minutes and a solution of (S)-4-(1-[4-(2-methylpropyl)phenyl]ethoxy)benzoyl chloride in toluene (lOml) (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 (SOml) was added with vigorous stirring. The mixture was extracted with ethyl acetate (30ml, 40ml and 15ml) and the combined organic layers were dried (MgSO4), filtered and evaporated to give a brown gum. Flash chromatography (silica, 3:1 hexane/ethyl acetate initially, followed by 1:1 hexane/ethyl acetate) gave, after evaporation of the appropriate fractions, the title compound as a beige solid (1.05g), m.p. 150-152C. Found: C,81.69; H,6.83;
N, 3 . 58; C27H27N02 require5: C, 81. 58; H, 6 . 85; N, 3 . 52g6.

lH--NMR (CDCl3): ti = 1 . 00 (d, 6H~, 1 . 75 (d, 3H), 1.95(m,1H), 2.55(d,2H~, 5.45(q,1H), 7.05(d,2H), 7 . 25 (d,2H) 7.39-7.54(m, 4H), 7 . 70 (m,lH), 7. 85 (d, 2H), 8.4S(m,lH), 9.10(s,br,1H) ppm.

wo 93/02~ 1 2 ~ 8 9 PCTJEP92/01625 (g) (~)-4-~3-r4-(~-r4-(2-Methylpropyl)phenyl~-ethoxY)benzoyl3indol-1-yl)butanoic acid ethyl_estver A solution of the product of part (f~ (500mg) in 2-butanone ~Sml) was treated with anhydrous potassium carbonate (695mg) and ethyl 4-bromobutyrate (0.23ml). The mixture was heated under reflux overnight, cooled, filtered and the filtrate evaporated to a yellow gum. Flash chromatography (silica, 3:1 hexane/ethyl acetate) gave, after collection and evaporation of the appropriate fractions, the title compound (451mg).

This product had identical mass spectroscopy, H.P.L.C. and 1H-NMR characteristics to the compound of Example 33.

(h) lS~-4-(3-r4-(1-t4-(2-M~thy~propyl)phenyll-ethoxy)benzoyl~indol-1-vl)butanoic acid A solution of the product of part (g) (108mg) in 95 aqueous ethanol (2ml) was treated with six drops of 2N aqueous sodium hydroxide. The mixture was stirred for 90 minutes then water (3ml) was added followed ~y 2N aqueous hydrochloric acid until the mixture reached pHl. The mixture was extracted with dichloromethane (3 x lOml) 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 lH-NMR characteristics to the compound of Example 9.

W093/02~ PCT/EP92/0162~
~ (, 3 -96-Pharmacoloaical activity A selection of compounds of the formula (~) was tested in vitro for steroid 5o~reductase inhibitory activity using ventral prostate tissue from male rats according to the procedure outlined on pages 34 to 36 of the specification. The results are presented in Table 1.

Table 1 Exa ~le No.

i .. I
47% inhibition at lOOOnM

~D93/02~0 PCT/EP92/01625 ~ vS ~ Toxicitv The compound of Example 1 was admini~tered orally to mice up to dose of lOOOmg/kg and the animal showed normal appearance and behaviour throughout the duration of the study.

Claims (44)

-98-

1. A compound of the formula:- ....(I) or a pharmaceutically acceptable salt thereof, wherein Y is C1-C6 alkylene optionally substituted by C1-C6 alkyl;

R is H, OH, halo, C1-C4 alkyl or C1-C4 alkoxy;

R1, R2, R3 and R4 are each independently selected from H, C1-C4 alkyl, C1-C4 alkoxy, OH, halo and CF3;

one of R6, R7 and R8 is a group of the formula:- or , and the remainder, together with R5 and R9, are each independently selected from H, C1-C4 alkyl, C1-C4 alkoxy, halo and halo(C1-C4)alkyl;

R10 is COOH, COOR11 or CONR12R13;

R11 is a biolabile ester-forming group;

R12 and R13 are each independently selected from H and C1-C4 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, C1-C6 alkoxy, C2-C6 alkenyl, OH, halo, CF3, halo(C1-C6 alkyl), nitro, amino, C2-C6 alkanamido, C2-C6 alkanoyl or phenyl.

2. A compound as claimed in claim 1 wherein Y is C1-C6 alkylene optionally substituted by C1-C6 alkyl;

R is H, OH, halo, C1-C4 alkyl or C1-C4 alkoxy;

R1, R2, R3 and R4 are each independently selected from H, C1-C4 alkyl, C1-C4 alkoxy, OH, halo and CF3;

one of R6, R7 and R8 is a group of the formula:- or , and the remainder, together with R5 and R9, are each independently selected from H, C1-C4 alkyl, C1-C4 alkoxy, halo and halo(C1-C4)alkyl;

R10 is COOH, COOR11 or CONR12R13;

R11 is a biolabile ester-forming group;

R12 and R13 are each independently selected from H and C1-C4 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, C1-C6 alkoxy, C2-C6 alkenyl, OH, halo, CF3, halo(C1-C6 alkyl), nitro, amino, C2-C6 alkanamido, C2-C6 alkanoyl or phenyl:

with the provisos i) when R7 is 1-(4-(2-methylpropyl)-phenyl)ethoxy, R, R1, R2, R3, R4, R5, R6 R8 and R9 are all H and Y is -(CH2)3-, that R10 is not COOH when the compound of the formula (I) is in the racemic form;
ii) when R7 is 1-(4-(2-methylpropyl)-phenyl)propoxy or 2,2-dimethyl-1-(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;

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, R2, R3, R4, R5, R7, R8 and R9 are all H and Y
is -(CH2)3-, that R10 is not COOH or COOC2H5.

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 C1-C6 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 C1-C6 alkylene;
R is H or C1-C4 alkyl;
R1, R2, R3 and R4 are each H;
one of R6, R7 and R8 is a group of the formula:- or , and the remainder, together with R5 and R9, are each independently selected from H and C1-C4 alkyl;

R14 is H, C1-C4 alkyl, C4-C6 cycloalkyl or phenyl substituted by C1-C4 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 C1-C6 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:- or , and R5, R6, R8 and R9 are each independently selected from H and C1-C4 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:-, and R5, R6, R8 and R9 are each H;

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-1-yl)butanois acid, (S)-4-(3-[4-(1-[4-(2-Methylpropyl)phenyl]ethoxy)-benzoyl]indol-1-yl)butanoic acid, (R,S)-4-(2-Methyl-3-[4-(1-[4-(2-methylpropyl)-phenyl]ethoxy)benzoyl]indol-1-yl)butanoic acid or (S)-4-(2-Methyl-3-[4-(1-[4-(2-methylpropyl)phenyl]-ethoxy)benzoyl]indol-1-yl)butanoic acid: or a pharmaceutically acceptable salt thereof.

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 5.alpha.-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.

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

17. A method of treatment of a human to inhibit a steroid 5.alpha.-reductase which comprises treating said human with an effective amount of a compound of the formula (I) or with a pharmaceutically acceptable salt or composition thereof as claimed in any one of claims 1 to 11 and 12 respectively.

18. A method of treatment of a human to cure or prevent acne vulgaris, alopecia, seborrhoea, female hirsutism, benign prostatic hypertrophy, male pattern baldness or a human prostate adenocarcinoma which comprises treating said human with an effective amount of a compound of the formula (I) or with a pharmaceutically acceptable salt or composition thereof as claimed in any one of claims 1 to 11 and 12 respectively.

19. A compound of the formula:- ;
....(IV) ....(VIII) or a base salt thereof;

;
....(XIII) ;
....(XIV) ....(XV) or a base salt thereof;

....(XVIII) or a base salt thereof;
....(XXI) or a base salt thereof; or , ....(XXIII) wherein Y, R, R1, R2, R3, R4, R5, R6, R7, R8, R9 and R10 are as defined in claim 1 or 2; R24 is H or OH; one of R5, R26 and R27 is OH and the remainder of R25, R26 and R27 are as defined in claim 1 or 2 for the remainder of R6, R7 and R8; one of R28, R29 and R30 is a group of the formula:- wherein R14 is as defined in claim 1 or 2 and Z8 is a leaving group, and the remainder of R28, R29 and R30 are as defined in claim 1 or 2 for the remainder of R6 R7 and R8; and one of R31, R32 and R33 is a group of the formula:- wherein R14 is as defined in claim 1 or 2, and the remainder of R31, R32 and R33 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, R2 is methoxy, R1, R3, R4, R5 and R9 are each H, R25 and R27 are each bromo and R26 is hydroxy, that R10 is not -COOH.

20. A compound of the formula (XXI) or a base salt thereof as claimed in claim 19 wherein Z8 is halo, C1-C4 alkanesulphonyloxy or C1-C4 alkylphenylsulphonyloxy.

21. A process for the preparation of a compound of the formula:- ....(I) or a pharmaceutically acceptable salt thereof, wherein Y is C1-C6 alkylene optionally substituted by C1-C6 alkyl;

R is H, OH, halo, C1-C4 alkyl or C1-C4 alkoxy;

R1, R2, R3 and R4 are each independently selected from H, C1-C4 alkyl, C1-C4 alkoxy, OH, halo and CF3;

one of R6, R7 and R8 is a group of the formula:- or , and the remainder, together with R5 and R9, are each independently selected from H, C1-C4 alkyl, C1-C4 alkoxy, halo and halo(C1-C4)alkyl;

R10 is COOH, COOR11 or CONR12R13;

R11 is a biolabile ester-forming group;

R12 and R13 are each independently selected from H and C1-C4 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, C1-C6 alkoxy, C2-C6 alkenyl, OH, halo, CF3, halo(C1-C6 alkyl), nitro, amino, C2-C6 alkanamido, C2-C6 alkanoyl or phenyl, which comprises, (a) for the preparation 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), cleavage of an ester of the formula:- ....(II) wherein R15 is an ester forming group that may be cleaved to provide 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);

(b) for the preparation 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), acidic or basic hydrolysis of a compound 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);

(c) for the preparation 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), acidic or basic 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);

(d) for the preparation of a compound 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), 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 R11OH wherein R11 is as previously defined for a compound of the formula (I);

(e) for the preparation of a compound of the formula (I) wherein Y, R and R1 to R10 are as previously defined for a compound of the formula (I), alkylation of a base salt of a compound of the formula:- ....(VIII) 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-COOR11 or Z3-Y-CONR12R13 or with a base salt of a compound of the formula Z3-Y-COOH, wherein Y, R11, R12 and R13 are as previously defined for a compound of the formula (I) and Z3 is a leaving group;

(f) for the preparation 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), oxidation of a compound of the formula:- , ....(XIII) wherein Y, R and R1 to R9 are as previously defined for a compound of the formula (I);

(g) for the preparation 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), oxidation of a compound of the formula:- , ....(XIV) or ....(XV) or a base salt thereof, wherein R24 is H or OH and Y, R and R1 to R9 are as previously defined for a compound of the formula (I);
(h) for the preparation of a compound of the formula (I) wherein one of R6, R7 and R8 is a group of the formula:- and the remainder of R6, R7 and R8, together with Y, R, R1 to R5, R9, R10, R14 and "aryl" are as previously defined for a compound of the formula (I), reaction of a compound of the formula:- ....(XVIII) or a base salt thereof, wherein one of R2s, R26 and R27 is OH and the remainder of R25, R26 and R27 are as previously defined for the remainder of R6, R7 and R8 for a compound of the formula (I), and Y, R, R1 to R5, R9 and R10 are as previously defined for a compound of the formula (I), with a compound of the formula:- ....(XIX) wherein R14 and "aryl" are as previously defined for a compound of the formula (I) and Z7 is a leaving group;
(i) for the preparation of a compound of the formula (I) wherein R10 is COOR11 or CONR12R13, one of R6, R7 and R8 is a group of the formula:- and the remainder of R6, R7 and R8, together with Y, R, R1 to R5, R9, R11, R12, R13, R14 and "aryl" are as previously defined for a compound of the formula (I), reaction of a compound of the formula (XVIII) wherein R10 is COOR11 or CONR12R13, Y, R, R1 to R5, R9, R11, R12 and R13 as previously defined for a compound of the formula (I) and R25, R26 and R27 are as defined in

claim 21(h), with a compound of the formula:- ....(XX) wherein R14 and "aryl" are as previously defined for a compound of the formula (I), in the presence of a dehydrating agent;

(j) for the preparation of a compound of the formula (I) wherein one of R6, R7 and R8 is a group of the formula:-, and the remainder of R6, R7 and R8, together with Y, R, R1, to R5, R9, R10, R14 and "aryl" are as previously defined for a compound of the formula (I), reaction of a compound of the formula:- ....(XXI) or a base salt thereof, wherein one of R28, R29 and R30 is a group of the formula:- and the remainder of R28, R29 and R30 are as previously defined for the remainder of R6, R7 and R8 for a compound of the formula (I), Y, R, R1 to R5, R9, R10 and R14 are as previously defined for a compound of the formula (I) and Z8 is a leaving group, with a base salt of a compound of the formula:-Aryl-OH ....(XXII) wherein "aryl" is as previously defined for a compound of the formula (I); or (k) for the preparation of a compound of the formula (I) wherein R10 is COOR11 or CONR12R13, one of R6, R7 and R8 is a group of the formula:-, and the remainder of R6, R7 and R8, together with Y, R, R1 to R5, R9, R11, R12, R13, R14 and "aryl" are as previously defined for a compound of the formula (I), reaction of a compound of the formula:- ....(XXIII) wherein one of R31, R32 and R33 is a group of the formula:- and the remainder are as previously defined for the remainder of R6, R7 and R8 for a compound of the formula (I), R10 is COOR11 or CONR12R13 and Y, R, R1 to R5, R9, R11, R12, R13 and R14 are as previously defined for a compound of the formula (I), with a compound of the formula (XXII) wherein "aryl" is as previously defined for a compound of the formula (I), in the presence of a dehydrating agent: any one of said processes (a) to (k) being optionally followed by conversion of the product of the formula (I) to a pharmaceutically acceptable salt thereof.

22. A process as claimed in claim 21 wherein Y is C1-C6 alkylene optionally substituted by C1-C6 alkyl;
R is H, OH, halo, C1-C4 alkyl or C1-C4 alkoxy;
R1, R2, R3 and R4 are each independently selected from H, C1-C4 alkyl, C1-C4 alkoxy, OH, halo and CF3;
one of R6, R7 and R3 is a group of the formula:- or , and the remainder, together with R5 and R9, are each independently selected from H, C1-C4 alkyl, C1-C4 alkoxy, halo and halo(C1-C4)alkyl;
R10 is COOH, COOR11 or CONR12R13;
R11 is a biolabile ester-forming group;
R12 and R13 are each independently selected from H and C1-C4 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, C1-C6 alkoxy, C2-C6 alkenyl, OH, halo, CF3, halo(C1-C6 alkyl), nitro, amino, C2-C6 alkanamido, C2-C6 alkanoyl or phenyl:
with the provisos i) when R7 is 1-(4-(2-methylpropyl)-phenyl)ethoxy, R, R1, R2, R3, R4, R5, R6, R8 and R9 are all H and Y is -(CH2)3-, that R10 is not COOH when the compound of the formula (I) is in the racemic form;
ii) when R7 is 1-(4-(2-methylpropyl)-phenyl)propoxy or 2,2-dimethyl-1-(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 R7 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;
iv) when R7 is 1-(4-(2-methylpropyl)phenyl)-ethoxy, R5 and R6 are both methyl, R, R1, R2, R3, R4, R5 and R9 are all H and Y is -(CH2)3-, that R10 is not COOH or COOC2H5 when the compound of the formula (I) is in the racemic form;
v) when R7 is bis(4-(2-methylpropyl)phenyl)-methoxy, R, R1, R2, R3, R4, R5, R6, R8 and R9 are all H and Y is -(CH2)3-, that R10 is not COOH;

vi) when R6 is bis(4-(2-methylpropyl)phenyl)-methoxy, R, R1, R2, R3, R4, R5, R7, R8 and R9 are all H and Y is -(CH2)3-, that R10 is not COOH; and vii) when R6 is 4-(2-methylpropyl)phenoxymethyl or 3-(2-methylpropyl)phenoxymethyl, R, R1, R2, R3, R4, R5, R7, R8 and R9 are all H and Y
iS -(CH2)3-, that R10 is not COOH or COOC2H5.

23. A process as claimed in claim 21(a) or 22 where the cleavage is carried out by acidic or basic hydrolysis of a compound of the formula (II).

24. A process as claimed in claim 21(a), 22 or 23 wherein R15 is C1-C6 alkyl.

25. A process as claimed in claim 23 or 24 where the cleavage is carried out by basic hydrolysis using sodium or potassium hydroxide under aqueous conditions.

26. A process as claimed in claim 21(e) or 22 where the base salt of a compound of the formula (VIII) is a sodium or potassium salt.

27. A process as claimed in claim 21(e), 22 or 26 wherein Z3 is halo, C1-C4 alkanesulphonyloxy or C1-C4 alkylphenylsulphonyloxy.

28. A process as claimed in claim 27 wherein Z3 is bromo.

29. A process as claimed in claim 21(h) or 22 where a base salt of a compound of the formula (XVIII) is used.

30. A process as claimed in claim 29 where the base salt is a sodium or potassium salt.

31. A process as claimed in çlaim 21(h), 22, 29 or 30 wherein Z7 is halo, C1-C4 alkanesulphonyloxy or C1-C4 alkylphenylsulphonyloxy.

32. A process as claimed in claim 31 wherein Z7 is bromo.

33. A process as claimed in claim 21(i), 21(k) or 22 where the dehydrating agent used is a combination of diethyl azodicarboxylate and triphenylphosphine.

34. A process as claimed in claim 21(j) or 22 wherein Z8 is halo, C1-C4 alkanesulphonyloxy or C1-C4 alkylphenylsulphonyloxy.

35. A process as claimed in any one of claims 21 to 34 wherein R10 is COOH or COOR11.

36. A process as claimed in claim 35 wherein R11 is C1-C6 alkyl.

37. A process as claimed in any one of claims 21 to 32 or 34 wherein Rl0 is COOH.

38. A process as claimed in any one of claims 21 to 37 wherein Y is C1-C6 alkylene;
R is H or C1-C4 alkyl;
R1, R2, R3 and R4 are each H;
one of R6, R7 and R8 is a group of the formula:- or , and the remainder, together with R5 and R9, are each independently selected from H and C1-C4 alkyl;
R14 is H, C1-C4 alkyl, C4-C6 cycloalkyl or phenyl substituted by C1-C4 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 C1-C6 alkyl and halo.

39. A process as claimed in claim 38 wherein Y is methylene, propylene, butylene or pentylene;
R is H or methyl;
R7 is a group of the formula:- or , and R5, R6, R8 and R9 are each independently selected from H and C1-C4 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.

40. A process as claimed in any one of claims 21 to 33 or 35 to 37 wherein Y is propylene;
R is H;
R1, R2, R3 and R4 are each H;
R7 is a group of the formula:- and R5, R6, R8 and R9 are each H;
R14 is methyl; and "aryl" means phenyl, 4-methylphenyl 4-ethylphenyl, 4-(n-propyl)phenyl, 4-isobutylphenyl or 3,4-dichlorophenyl.

41. A process as claimed in any one of claims 21 to 40 wherein "aryl" means 4-isobutylphenyl.

42. A process as claimed in claim 21 or 22 which is used to prepare a compound of the formula (I) 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 21 or 22.

43. A process as claimed in claim 21 or 22, in part, which is used to prepare (R,S)-4-(3-[4-(1-[4-(2-Methylpropyl)phenyl]ethoxy)-benzoyl]indol-1-yl)butanoic acid, (S)-4-(3-[4-(1-[4-(2-Methylpropyl)phenyl]ethoxy)-benzoyl]indol-1-yl)butanoic acid, (R,S) -4-(2-Methyl-3-[4-(1-[4-(2-methylpropyl)-phenyl]ethoxy)benzoyl]indol-1-yl)butanoic acid or (S)-4-(2-Methyl-3-[4-(1-[4-(2-methylpropyl)phenyl]-ethoxy)benzoyl]indol-1-yl)butanoic acid: or a pharmaceutically acceptable salt thereof.

44. A process for the preparation of a pharmaceutical composition which comprises combining a compound of the formula (I), or a pharmaceutically acceptable salt thereof, which has been prepared by a process as claimed in any one of claims 21 to 43, together with a pharmaceutically acceptable diluent or carrier.