AU655662B2 - pndoles - Google Patents

Description

I OPI DATE 23/02/93 APPLN. ID 23270/92 AOJP DATE 29/04/93 PCT NUMBER PCT/EP92/01625 l II 111111 1 11111 IAU9223 Ill II270 III AU9223270 ATY (PCT) (51) International Patent Classification 5 International Publication Number: WO 93/02050 C07D 209/12, A61K 31/405 A l (43) International Publication Date: 4 February 1993 (04.02.93) (21) International Application Number: PCT/EP92/01625 (74)Agents: WOOD, David, John et al.; Pfizer Limited, Patents Department, Ramsgate Road, Sandwich, Kent (22) International Filing Date: 20 July 1992 (20.07.92) CT13 9NJ (GB).

Priority data: (81) Designated States: AT, AU, BB, BG, BR, CA, CH, CS, 9115951.7 24 July 1991 (24.07.91) GB DE, DK, ES, FI, GB, HU, JP, KP, KR, LK, LU, MG, MN, MW, NL, NO, PL, RO, RU, SD, SE, US, European patent (AT, BE, CH, DE, DK, ES, FR, GB, GR, (71)Applicant (for GB only): PFIZER LIMITED [GB/GB]; IT, LU, MC, NL, SE), OAPI patent (BF, BJ, CF, CG, Ramsgate Road, Sandwich, Kent CT13 9NJ CI, CM, GA, GN, ML, MR, SN, TD, TG).

(71) Applicant (for all designated States except GB US): PFIZER, INC. [US/US]; 235 East 42nd Street, New York, NY Published 10017 With international search report.

(72) Inventors; and Inventors/Applicants (for US only) BLAGG, Julian [GB/ GB]; c/o Pfizer Central Research, Ramsgate Road, Sandwich, Kent CTI3 9NJ COOPER, Kelvin [GB/GB]; c/o Pfizer Central Research, Eastern Point 6 5 5 6 6 2 Road, Groton, CT 06340 SPARGO, Peter, Lionel [US/US]; c/o Pfizer Central Research, Ramsgate Road, Sandwich, Kent CTI3 9NJ (US).

(54)Title: INDOLES

R

14 -OCH-Aryl

R

14 -CHO-Aryl (57) Abstract The present invention provides compounds of formula and pharmaceutically acceptable salts thereof, wherein Y is

C

1

-C

6 alkylene optionally substituted by CI-C 6 alkyl; R is H, OH, halo, CI-C 4 alkyl or Ci-C 4 alkoxy; R 1

R

2

R

3 and R 4 are each independently selected from H, CI-C 4 alkyl, CI-C 4 alkoxy, OH, halo and CF 3 one of R 6

R

7 and R 8 is a group of formula or and the remainder, together with R 5 and R 9 are each independently selected from H, Ci-C 4 alkyl, Ci-C 4 alkoxy, halo and halo(Ci-C 4 )alkyl; R'o is COOH, COOR I 1 or CONR 12 RI3; R" 1 is a biolabile ester-forming group; R 12 and

R

13 are each independently selected from H and C 1

-C

4 alkyl; R 14 is H, CI-C 6 alkyl, C 3

-C

7 cycloalkyl or aryl; and "aryl", used in the definitions of R 6

R

7

R

8 and R 1 4 means phenyl optionally substituted by C 1 -Cs alkyl, Ci-C 6 alkoxy, C 2

-C

6 alkenyl, OH, halo, CF 3 halo(Ci-C 6 alkyl), nitro, amino, C 2

-C

6 alkanamido, C 2

-C

6 alkanoyl or phenyl: together with pharmaceutical compositions containing, processes for the preparation of and uses of, such compounds.

WO 93/02050 PCT/EP92/01625 -1-

INDOLES

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

More particularly this invention relates to indoles, their preparation and their use as reductase inhibitors.

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

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

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

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

EP-A-0458207 discloses certain indole derivatives which have testosterone 5c-reductase inhibitory activity.

oi WO 9 A'21O50 PCT/EP92/01625 -2- The present invention provides compounds of the formula: R4 R2 N RR/IS R' Y R1) and pharmaceutically acceptable salts thereof, wherein Y is Cl-C 6 alkylene optionally substituted by Cl-C 6 alkyl; R is H, OH, halo, Cl-C 4 alkyl or Cl-C 4 alkoxy;

R

1

R

2

R

3 and R 4 are each independently selected from H, Cl-C 4 alkyl, Cl-C 4 alkoxy, OH, halo and

CF

3 one of R 6

R

7 and RB is a group of the formula: R R -OCH-Aryl or -CHO-Aryl, and the remainder, together with R 5 and R 9 are each independently selected from H, Cl-C 4 alkyl, Cl-C 4 alkoxy, halo and halo (C 1

-C

4 alkyl; WO 93/02050 PCr/EP92/01625 -3-

R"

0 is COOH, C00R 11 or CONR 2

R"

3

R

11 is a biolabile ester-forming group;

R

12 and R 13 are each independently selected from H and C 1

-C

4 alkyl; R 14 is H, Cj-C 6 alkyl, C 3

-C

7 cycloalkyl or aryl; and "aryl", used in the definitions of R 6

R

7 RI and R" 4 means phenyl optionally substituted by Cj-C 6 alkyl, C 1

-C

6 alkoxy, C 2

-C

6 &%".kenyl, OH, halo, CF 3 halo(C 1

-C

6 alkyl) nitro, amino, C 2

-C.

6 alkanamido, C 2

-(C

6 alkanoyl or phenyl.

In a further aspect of the present invention Y is C 1

-C

6 alkylene optionally substituted by

C

1

-C

6 alkyl; R is H, OH, halo, C 1

-C

4 alkyl or C 1

-C

4 alkoxy;

R

1 R 2

R

3 and R 4 are each independently selected from H, C 1

-C

4 alkyl, C 1

-C

4 alkoxy, OH, halo and

CF

3 one of R 6 R 7 and R 8 is a group of the formula: R14 R 14 -OCH-Aryl Or -CHO-Aryl, and the remainder, together with R 5 and R 9 are each independently selected from H, C 1

-C

4 alkyl,

C

1

-C

4 alkoxy, halo and halo (Cl-C 4 alkyl;

R'

0 is COCH, C00R 11 or C0NR 12

R

13 WO 93/02050 PCT/EP92/01625

R

11 is a biolabile ester-forming group;

R

12 and R 1 are each independently selected from H and C 1

-C

4 alkyJ.;

R

14 isH 1 C lyC- 7 cycloalkyl or aryl; and flaryl", used in the def initions of R R,

R

8 and R 14 means phenyl optionally substituted by C 1

-C

6 alkyl, C 1

-C

6 alkoxy,

C

2

-C

6 alkenyl,

OH,

halo, CF 3 halo (C,-C 6 alkyl) nitro, amino, C 2

-C

6 alkanamido,

C

2

-C

6 alkanoyl or phenyl: with the provisos i) when R 7 is :L-(4-(2-methylpropyl)phenyl) ethoxy, R, RI, R 2 R 3 R 4

R

5 R 6

R

8 and R 9 are all H and Y is -(CH 2 3 that is rct COOH when the compound of the formula is in the racemic form; ii) when R 7 is 1- (2-Thethylpropyl) phenyl)propoxy or 2,2-dimethyl-l-(4-(2methylpropyl)phen1yl)propoxy, R, R R 2 1 R R 4, RI, R 6 R' anc6 R 9 are all H and Y is

(CH

2 that R 13 I is not COOH or COOC 2

H

when the compound of the f ormula is in the racemic form; iii) when R 6 is3 1-(3-(2-methylpropyl)phenyl)h ethoxy, R, R 1

R

2 R R RI, R R' and R9 are all H and Y is -(CH 2 3 that R 10 is not COOM or COOC 2

H

5 when the compound of the formula is in the racemic form; WO 93/02050 PCT/EP92/01625 iv) when R is 1-(4-(2-methylpropyl)phenyl)ethoxy, R 5 and R 6 are both methyl, R, R,

R

2

R

3

R

4

R

8 and R 9 are all H and Y is that RIO is not COOH or COOCzHs when the compound of the formula is in the racemic form; v) when R 7 is bis(4-(2-methylpropyl)phenyl)methoxy, R, R 1

R

2

R

3

R

4

R

5 R, R 8 and R 9 are all H and Y is -(CH 2 3 that R 10 is not

COOH;

vi) when R 6 is bis(4-(2-methylpropyl)phenyl)methoxy, R, R 1

R

2

R

3

R

4

R

s

R

7 R' and R 9 are all H and Y is that R

I

O is not COOH; and vii) when R6 is 4-(2-methylpropyl)phenoxymethyl or 3-(2-methylpropyl)phenoxymethyl, R, R 1

R

2

R

3

R

4

R

7

R

8 and R 9 are all H and Y is -(CH 2 3 that R 10 is not COOH or COOC2H

S

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

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

The term "biolabile ester-forming group" is well understood in medicinal chemistry as meaning a group which forms an ester which can be readily cleaved in vivo to liberate the corresponding acid of the formula (I) wherein R1 0 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.

i <f-i, WO 93/02050 PCT/EP92/01625 -6- 10 Esters of the formula wherein R1 is O 2 (C -C 6 alkyl) are steroid 5c-reductase inhibitors per se but, in 10 11 general, where R 0 is COOR such compounds are useful as pro-drugs to provide compounds of the formula wherein

R

0 is COOH jvivo following oral administration. Such esters are also useful as intermediates for the preparation of compounds of the formula wherein R0 is COOH.

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

Examples of suitable biolabile ester-forming groups are alkyl C 1

-C

6 alkyl), alkanoyloxyalkyl (including alkyl, cycloalkyl or aryl substituted derivatives thereof), arylcarbonyloxyalkyl (including aryl substituted derivatives thereof), aryl, arylalkyl, indanyl and haloalkyl: wherein alkanoyl groups have from 2 to 8 carbon atoms and alkyl groups have from 1 to 8 carbon atoms, all of which may be straight- or branchedchain, and aryl means phenyl or naphthyl, both of which may be optionally substituted by C 1 -Cq alkyl, C 1

-C

4 alkoxy or halo.

In addition to C 1

-C

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

The pharmaceutically acceptable salts of the compounds of the formula are the acid addition and the base salts thereof.

r 1 I 260163 i INSTR CODE: 60050 (N:\LIBW108629:EAR 1 of 1 Z' 4 2 k

I

WO 93/02050 PCT/EP92/01625 Suitable acid addition salts are formed from acids which fnrm non-toxic salts and examples are the hydrochloride, hydrobromide, hydroiodide, sulphate, bisulphate, phosphate, hydrogen phosphate, acetate, maleate, fumarate, lactate, tartrate, citrate, gluconate, benzoate, methanesulphonate, benzenesulphonate and ptoluenesulphonate salts.

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

For a review on suitable salts see Berge et al, J.

Pharm. Sci., 66, 1-19 (1977).

In the above definitions relating to the present invention: Preferably Y is C -C 6 alkylene.

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

Most preferably Y is propylene.

Preferably R is H or C 1

-C

4 aikyl.

More preferably R is H or methyl.

Most preferably R is H.

1 2 3 4 Preferably R R R and R are each H.

Preferably one of R 6

R

7 and R 8 is a group of the formula:- R14 R14 I I -OCH-Aryl or -CHO-Aryl, and the remainder, together with R 5 and R 9 are each independently selected from H and Ci-C 4 alkyl.

I

i WO 93/02050 PCT/EP92/01625 -8- More preferably R 7 is a group of the formula:- R14

R

14 I I -OCH-Aryl or -CHO-Aryl, and R 5

R

6

R

8 and R 9 are each independently selected from H and Cl-C 4 alkyl.

Most preferably R 7 is a group of the formula:-

R

1 4

R

-OCH-Aryl, and R 5

R

5

R

8 and R 9 are each H.

Preferably R 10 is COOH or COOR".

Most preferably R 1 0 is COOH.

Preferably R" is Cl-C 6 alkyl.

Most preferably R 1 is ethyl.

Preferably R 14 is H, Cl-C 4 alkyl, C 4

-C

6 cycloalkyl or phenyl substituted by C 1

-C

4 alkyl.

More preferably R 1 4 is H, methyl, n-propyl, cyclopentyl or 4-(n-propyl)phenyl.

Most preferably R 1 is methyl.

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

In a preferred aspect of the present invention "aryl", means phenyl optionally substituted by CI-C 6 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 .ost preferably means 4isobutylphenyl.

i i ma Y is CI-C 6 alkylene optionally substituted by ./2 i C 6 alkyl e

I

WO 93/02050 PCT/EP92/01625 -9- A compound of the formula may contain one or more asymmetric carbon atoms and/or one or more alkenyl groups and may therefore exist in two or more stereoisomeric forms. The present invention includes both the individual stereoisomers of the compounds of the formula together with mixtures thereof. Separation of diasterec'isomers or cis and trans isomers may be achieved by conventional techniques, e.g. by fractional crystallisation, chromatography or H.P.L.C. of a stereoisomeric mixture of a compound of the formula (I) or a suitable salt or derivative thereof. An individual enantiomer of a compound of the formula may also be prepared from a corresponding optically pure intermediate or by resolution, such as by H.P.L.C. of a racemate using a suitable chiral support or by fractional crystallisation of the diastereoisomeric salts formed by reaction of a racemate with a suitable optically active acid or base.

A preferred group of compounds of the formula is where one of R 6

R

7 and R 8 is a group of the formula:- (C C 6 alkyl) 0 (S Aryl and the remainder, together with Y, R, R 1

R

2

R

3

R

4

R

5

R

9

R

10

R

1

R

1 2

R

1 3 and "aryl" are as previously defined for a compound of the formula 1 1 1

I

WO 93/02050 WO 9302050PCr/EP92/01625 Particularly preferred embodiments of the compounds of the formula are (R,S)-4-(3-(4-(l-[4-(2-Methylpropyl)phenyl)ethoxy)benzoyl] indol-l-yl) butanoic acid, (S)-4-(3-L4-(l-(4-(2-Methylpropyl)phenyl~ethoxy)benzoyl] indol-l-yl)butanoic acid, (R,S)-4,-(2-lMethyl-3-[4-(l-(4-(2-methylpropyl)phenyl]ethoxy) benzoyl] indol-l-yl) butanoic acid and -4-(2-Methyl-3-(4-(l-(4-(2-methylpropyl)phenyl..

ethoxy) benzoyl] indol-1-yl) butanoic acid: and the pharmaceutically acceptable salts thereof.

The compounds of formula provided by the invention may be prepared by the following methods:- 1) The compounds of the formula wherein R 10 is COOH and Y, R and R' to R 9 are as previously defined for a compound of the formula may be prepared by cleavage of an ester of the formula:- I0F 1 (11) wherein R1 5 is a suitable ester-forming group and Y, R and R1 to R 9 are as previously defined for a compound of the formula

~EI

I I I or a base salt thereof; WO 93/02050 PCT/EP92/01625 -11- A plethora of suitable ester-forming groups that may be cleaved to provide the corresponding carboxylic acid are known to the skilled man, see, T.W.

Greene and P.G. Wuts, "Protective Groups in Organic Synthesis", Wiley-Interscience (2nd edition, 1991).

Where R 15 is an ester-forming group that may be removed by hydrolysis, e.g. C 1

-C

6 alkyl or an alternative biolabile ester-forming group as previously defined a compound of the formula wherein R 10 is COOR1) 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 C 1

-C

4 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 R 15 is an ester-forming group that may be removed by reduction, e.g. benzyl, the reduction may be carried out by catalytic hydrogenation using, palladium-on-charcoal, as the catalyst.

I

group of the formula:- I WO 93/02050 PCT/EP92/01625 -12- 2) The compounds of the formula wherein R 10 is COOH and Y, R and R 1 to R 9 are as previously defined for a compound of the formula may be prepared by hydrolysis of a compound of the formula wherein Rio is CONR"R 3 and Y, R, R' to R 9

R

12 and R 1 3 are as previously defined for a compound of the formula The hydrolysis may be carried out under acidic or basic conditions, e.g. using an aqueous solution of either a suitable mineral acid, e.g. hydrochloric or sulphuric acid, or a suitable inorganic base, e.g.

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

3) The compounds of the formula wherein R I 0 is COOH and Y, R and R 1 to R 9 are as previously defined for a compound of the formula may be prepared by hydrolysis of a compound of the formula:-

R

4 0

R

9 R R R2 N5"Y R 7 R' Y R 6

CONHNHR

16

(III)

WO 93/02050 PCT/EP92/01625 -13wherein Y, R and R 1 to R 9 are as previously defined for a compound of the formula and R 16 is H or C 1

C

4 alkyl.

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

4) The compounds of the formula wherein R 10 is COOH and Y, R and R 1 to R 9 are as previously defined for a compound of the formula may be prepared by hydrolysis of a compound of the formula:-

R

4 R9

R

2 R Rs R 7

R

1 Y R 6

CN

4. 1 UAJY, ijail a l u a s ,.jvr, v.v uor iun n Is a oloiaDOne ester-Ormning group; KI and

RI

3 are each independently selected from H and CI-C 4 alkyl; RI4 is H, Ci-C 6 alkyl, C 3

-C

7 cycloalkyl or aryl; and "aryl", used in the definitions of R 6

R

7

R

8 and R 1 4 means phenyl optionally substituted by Ci-C 6 alkyl, CI-Cs alkoxy, C 2

-C

6 alkenyl, OH, halo, CFj, halo(Ci-C 6 alkyl), nitro, amino, C 2

-C

6 alkanamido, C 2

-C

6 alkanoyl or phenyl: together with pharmaceutical compositions containing, processes for the preparation of and uses of, such compounds.

ec WO 93/02050 PCT/EP92/01625 -14wherein Y, R and R 1 to R 9 are as previously defined for a compound of the formula The hydrolysis may be carried out under acidic or basic conditions, e.g. using an aqueous solution of either a suitable acid, e.g. hydrochloric or sulphuric acid, or a suitable inorganic base, e.g.

sodium or potassium hydroxide, at from room temperature to the reflux temperature. When basic conditions are used hydrogen peroxide may optionally be present and also the product is obtained as a base salt which may be converted to the carboxylic acid by acidification in the work-up procedure.

The compounds of the formula wherein R 10 is COOH and Y, R and R 1 to R 9 are as previously defined for a compound of the formula may be prepared by acidic hydrolysis of a compound of the formula:-

R

18

R

17 WO 93/02050 PCT/EP92/01625 J wherein Y, R and R 1 to R 9 are as previously defined for a compound of the formula and R 17 and R 18 taken together represent ethylene, said ethylene group being optionally substituted by phenyl or CI-C 4 alkyl (preferably methyl,). Preferably R 1 7 and R 1 8 taken together represent -CH 2

C(CH

3 2 The hydrolysis may be carried out using an aqueous solution of a suitable acid such as hydrochloric acid at from room temperature to the reflux temperature.

6) The compounds of the formula wherein R 1 0 is CONH 2 and Y, R and R 1 to R 9 are as previously defined for a compound of the formula may be prepared by partial hydrolysis of a compound of the formula (IV) wherein Y, R and R I to R 9 are as previously defined for a compound of the formula The hydrolysis may be carried out using concentrated sulphuric acid at from OOC to room temperature.

7) The compounds of the formula wherein Ro is COOR" and Y, R, R 1 to R 9 and R 1 are as previously defined for a compound of the formula may be prepared by esterification of a compound of the formula (I) wherein R 10 is COOH and Y, R and R 1 to R 9 are as S* previously defined for a compound of the formula (I) with an alcohol of the formula R"OH wherein R 11 is as previously defined for this method.

WO 93/02050 PCT/EP92/01625 -16- The reaction may be carrie 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. Ths water generated during the reaction may be removed by azeotropic distillation or by the use of a dehydrating agent or a molecular sieve.

The esterification may also be carried out by reacting the acid with the alcohol in the presence of a dehydrating agent, e.g.

dicyclohexylcarbodiimide or diethylazodicarboxylate/ triphenylphosphine (see O. Mitsunobu, Synthesis, 1981, 1).

Alternatively the esterification may be carried out by first forming an activated ester or imidazolide derivative of the carboxylic acid, followed by reaction of the activated ester or imidazolide in situ with the alcohol of the formula R"OH. An activated ester may be formed by reacting the carboxylic acid with l-hydroxybenzotriazole 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 wherein R e0 is COOR" wherein Y, R, R 1 to R 9 and R' are as previously defined for a compound of the formula may be prepared by reaction of a compound of the formula:-

I

R

1 0 is COOH, COOR 1 or CONR 1 2

R

13 1-

:F

1 1 1 1 WO 93/02050 PCr/EP92/01625 -17-

I

COZ

1 wherein Y, R and R 1 to R 9 are as previously defined for a compound of the formula and Z 1 is a suitable leaving group, e.g. chloro or bromo, with an alcohol of the formula R"OH wherein R" is as previously defined for this method.

The reaction may be carried out in the presence of an acid acceptor, e.g. pyridine, and in a suitable solvent, e.g. dichloromethane, at from OOC to room temperature.

9) The compounds of the formula wherein R 1 0 is COOR" wherein Y, R, R 1 to R 9 and R" are as previously defined for a compound of the formula may be prepared by reaction of a base salt of a compound of the formula wherein R 10 is COOH and Y, R and R 1 to R 9 are as previously defined for a compound of the formula a carboxylate base salt) with a compound of the formula R 1

Z

2 wherein R 1 is as previously defined for a compound of tha formula (I) and Z 2 is a suitable leaving group, e.g. halo, preferably bromo or iodo, or p-toluenesulphonyloxy.

i ii i i id i, S l-L I I WO 93/02050 PCT/EP92/01625 -18- Preferred base salts of the compounds of the formula for use in this method are the sodium and potassium salts. The reaction may be carried out in a suitable solvent, e.g. dimethylformamide or tetrahydrofuran, at from room temperature to the reflux temperature.

The compounds of the formula wherein R 10 is

CONR

2 R" and Y, R, R 1 to R 9

R"

2 and R" are as previously defined for a compound of the formula (I) may be prepared by reaction of a compound of the formula wherein R 1 0 is COOH and Y, R and R 1 to R 9 are as previously defined for a compound of the formula with an amine of the formula R" 2

R"NH

wherein R' 2 and R l3 are as previously defined for this method in the presence of a dehydrating agent, e.g.

dicyclohexylcarbodiimide. The reaction may be carried out in a suitable organic solvent, e.g.

dichloromethane, at from room temperature to the reflux temperature.

Alternatively the reaction may be carried out by first forming an activated ester or imidazolide derivative of the carboxylic acid, followed by reaction of the activated ester or imidazolide in situ with the amine of the formula R 12

R

13 NH. Suitable procedures for the formation of an activated ester or imidazolide are described in method 11) The compounds of the formula wherein R" 1 is

CONR"R

13 and Y, R, R' to R 9

R

1 2 and R 1 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, R 1 to R 9 and Z 1 are as previously defined for a compound of the formula i 3 WO 93/02050 PCT/EP92/01625 -19- (VI) with an amine of the formula R 12

R'

3 NH wherein R 12 and R 13 are as previously defined for this method.

The reaction may be carried out in the presence of an acid acceptor, e.g. pyridine, and in a suitable solvent, e.g. dichloromethane, at from 0°C to room temperature.

12) The compounds of the formula wherein R 10 is

CONR"R

13 and Y, R, R 1 to R 9

R

12 and R 13 are as previously defined for a compound of the formula (I) may be prepared by reaction of a compound of the formula (II) wherein R 15 is a suitable ester-forming group, e.g. C 1

-C

6 alkyl or an alternative biolabile ester-forming group as previously defined a compound of the formula wherein R 1 0 is COOR 1 or p-nitrophenyl, and Y, R and R 1 to R 9 are as previously defined for a compound of the formula (I) with an amine of the formula R 1 2

R

13 NH wherein R 12 and

R

1 3 are as previously defined for this method. The reaction may be carried out in a suitable solvent, e.g. a Ci-C 4 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 a bomb).

13) The compounds of the formula wherein R 10 is COOH or CONRI 2

R

3 and Y, R, R 1 to R 9

R"

2 and R 13 are as previously defined for a compound of the formula (I) may be prepared by acidic hydrolysis of a compound of the formula:i 4 7,7 WO 93/02050 PCr/EP92/01625 1 21

C:OR

wherein Y, R and R 1 to R 9 are as previously def ined f or this method, R 19 and R 20 are either each C 1

-C

4 alkyl or when taken to--;ether represent C 2

-C

3 alkylene, said alkylene group be:6!g optionaly substituted by CI-C 4 alkyl, and R 21 is -OH, -OR 2 wherein R 2 4 is a suitable ester-forming group that may be removed by hydrolysis, e.g. Cj-C 6 alkyl or an alternative biolabile ester-forming group as previously defined, or NR 1

'R

13 wherein R 1 and R 13 are as previously defined for this method. The hydrolysis may be carried out using a suitable acid, e.g. hydrcec1Loric acid or p-toluenesulphonic acid, in the presence of water.

I

I

Sii

J

F

I

WO 93/02050 PCT/EP92/01625 -21- 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 R' to R 9 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 Croups in Organic Synthesis", Wiley-Interscience (2nd edition, 1991), followed by N-alkylation of the ketal by a similar procedure to that described in method (14) for alkylation of a compound of the formula (VIII).

14) All the compounds of the formula wherein Y, R and R 1 to R 1 0 are as previously defined for a compound of the formula may be prepared by alkylation of a base salt the N-deprotonated for.) of a compound of the formula:- R4 R R Re R H R 6

(VIII)

/1 i 1 WO 93/02050 PCT/EP92/01625 -22wherein R and R' to R 9 are as previously defined for a compound of the formula with a compound of the formula Z 3 -Y-COOR" or Z 3

-Y-CONR"R

13 or with a base salt of a compound of the formula Z 3 -Y-COOH, as appropriate, wherein Y, R 1 2 and R' are as previously defined for a compound of the formula (I) and Z 3 is a leaving group, e.g. halo, preferably chloro, bromo or iodo, methanesulphonyloxy or ptoluenesulphonyloxy. The preferred base salts of the compounds of the formula

Z

3 -Y-COOH are the alkali metal and alkaline earth metal salts, e.g. the sodium and potassium salts The preferred base salts of the compounds of the formula (VIII) are the alkali metal salts, e.g. the sodium and potassium salts.

The reaction may be performed by initial deprotonation of a compound of the formula (VIII) with a suitable base, e.g. sodium hydride, followed by reaction of the resulting anion with a compound of the formula Z 3 -Y-CCOR", Z 3

-Y-CONR

2

R

1 3 or a base salt of a compound of the formula Z 3 -Y-COOH, as required. The reaction may be carried out in a suitable solvent, e.g. N,N-dimethylformamide or tetrahydrofuran, at from OOC to the reflux temperature and preferably at about room temperature. The reaction may also be carried out using potassium carbonate as the base and in 2butanone or acetone as the solvent at about the reflux temperature of the solvent.

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

I t i i 1 'e a r i* i i j :B r r; WO 93/02050 PCr/EP92/01625 -23- Where a compound of the formula wherein R 10 is COOH is required the product is obtained as a base salt which may be converted to the carboxylic acid by acidification in the work-up procedure.

All the compounds of the formula wherein Y, R and R 1 to R 10 are as previously defined for a compound of the formula may be prepared by acylation of an indole of the formula:-

(IX)

or, where A is OH, a base salt thereof, or of a base salt of an indole of the formula:-

CO

2

H

-1 WO 93/02050 PCT/EP92/01625 -24wherein Y, R and R 1 to R 4 are as previously defined for a compound of the formula and R 23 is either

OR

1 or is NR" 2

R

3 wherein R 1

R

12 and R 1 3 are as previously defined for a compound of the formula with a compound of the formula:- S iR9

R'

R 7

R

s

R

R

6 (xl) wherein R 5 to R 9 are as previously defined for this method and Z 4 is a leaving group, e.g. halo, preferably chloro, and in the presence of a Lewis acid where R is not OH and optionally in the presence of a Lewis acid where R is OH. Suitable Lewis acids include aluminium chloride and diethylaluminium chloride.

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

The preferred base salts of the indoles of the formula are the alkali metal and alkaline earth metal salts, e.g. the sodium and potassium salts.

i i WO 93/02050 PCT/EP92/01625 T Where a compound of the formula wherein R 10 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 wherein R is OH is required the compounds of the formula (IX) and must be in the form of an enolate salt.

Accordingly an indole of the formula (IX) where R is OH or a base salt of an indole of the formula (X) where R is OH should first be treated with one equivalent of a suitable base, e.g. calcium hydroxide, to form an enolate salt which may then be acylated with a compound of the formula (XI), optionally in the presence of a Lewis acid.

Incorporation of an acidification step in the workup procedure affords a compound of the formula (I) wherein R is OH.

16) The compounds of the formula wherein R 10 is COOH and Y, R and R 1 to R 9 are as previously defined for a compound of the formula may be prepared by oxidative cleavage of a compound of the formula:- R R R

R

8

R

2 ^N R RTY R 7

R

1 Y R 6

(XII)

I V 1 WO 9/0250 PI'/P92/162 WO 93/02050 P(7r/EP92/01625 -26wherein Z 5 is -CH=CH 2 -CH=CH(Cl-C 4 alkyl), -CH=C(CI-

C

4 alkyl) 2 or -C-CH and Y, R and R 1 to R 9 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 wherein R I 0 is COOH and Y, R and R 1 to R 9 are as previously defined for a compound of the formula may be prepared by oxidation of a compound of the formula:-

CH

2

OH

(XIII)

wherein Y, R and R 1 to R 9 are as previously defined for a compound of the formula A suitable oxidising agent for this purpose is chromium trioxide in pyridine.

18) The compounds of the formula wherein R 10 is COOH and Y, R and R 1 to R 9 are as previously defined for a compound of the formula may be prepared by oxidation of a compound of the formula:- WO 93/02050 PC/EP92/01625 -27-

(XIV)

C0 2

H

(Xv) or a base salt thereof, wherein R 24 is H or OH and Y, R and R I to R 9 are as previously defined for a compound of the formula 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 R 24 is H using 2,3-dichloro-5,6-dicyano-l,4-benzoquinone (DDQ) as the oxidising agent.

e r._ WO 93/02050 PCT/EP92/01625 -28- The oxidation may alternatively be carried out on a 24 compound of the formula (XV) wherein R 24 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 R 24 is H may be prepared by reacting the corresponding 1H-indole-l-magnesium halide derivative with a corresponding benzyl halide of the formula:-

Z

6

CH

2 R 7

R

5

R

(XVI)

wherein R 5 to R 9 are as previously defined for this method and Z 6 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 R 24 is OH may be prepared by reacting the corresponding 1H-indole-l-magnesium halide derivative with a corresponding benzaldehyde of the formula:- OHC R

R

5

R

(XVII)

fi I I r WO 93/02050 PCT/EP92/01625 -29wherein R 5 to R 9 are as previously defined for this method.

19) The compounds of the formula wherein one of R 6

R

7 and R 8 is a group of the formula:- R"4 -OCH-Aryl and the remainder, together with Y, R, R 1 to R 5

R

9

R

10

R

1 4 and "aryl" are as previously defined for a compound of the formula may be prepared by reaction of a compound of the formula:-

.R

2 7

(XVIII)

or a base salt thereof, wherein one of R 25

R

2 6 and R 2 7 is OH and the remainder of R 25

R

26 and R 27 are as previously defined in this method for the remainder of R 6

R

7 and R 8 and Y, R, R' to R 5

R

9 and R 10 are as previously defined for this method, with a compound of the formula:-

R

1 4 IH-Aryl Z -CH-Aryl

(XIX)

i I WO 93/02050 PCT/EP92/01625 wherein R 14 and "aryl" are as previously defined for this method and Z 7 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) a phenoxide) which may be generated in situ from the corresponding phenol of the formula (XVIII) using a suitable base, e.g. sodium or potassium hydroxide or sodium hydride, and in a suitable solvent, e.g.

ethanol or N,N-dimethylformamide, at from 0°C to the reflux temperature. The reaction may also be carried out using potassium carbonate as the base and in 2-butanone or acetone as the solvent at about the reflux temperature of the solvent.

The compounds of the formula wherein R 1 0 is COOR" or CONR 2 R and Y, R, R 1 to R, R, R 12

R

13

R

14 and "aryl" are as defined for method (19) may be prepared by reaction of a compound of the formula (XVIII) wherein R' 0 is COOR" or CONR" 2

R

3 as appropriate, wherein R' 1

R

12

R

1 3 and Y, R, R 1 to R and R 9 are as previously defined for this method and

R

25 to R 27 are as previously defined for a compound of Sthe formula (XVIII) in method with a compound of the formula:-

R

14 HO-CH-Aryl

(XX)

wherein R 1 4 and "aryl" are as previously defined for this method, in the presence of a suitable dehydrating agent, e.g. diethylazodicarboxylate/ i i

I

i

I

WO 93/02050 PCT/EP92/01625 -31triphenylphosphine. The reaction may be carried out in a suitable solvent, e.g. tetrahydrofuran, at from room temperature to the reflux temperature.

21) The compounds of the formula wherein one of R 6

R

7 and R 8 is a group of the formula:- R14 -CHO-Aryl, and the remainder, together with Y, R, R 1 to R 5

R

R

10

R

14 and "aryl" are as previously defined for a compound of the formula may be prepared by reaction of a compound of the formula:- R 29

(XXI)

or a base salt thereof, wherein one of R 28

R

29 and R 30 is a group of the formula:-

R

14

-CH-Z

8 WO 93/02050 PCT/EP92/01625 -32and the remainder are as previously defined in this method for the remainder of R 6

R

7 and R 8 Y, R, R 1 to

R

5

R

9

R

1 0 and R 14 are as previously defined for this method and Z 8 is as defined for Z 7 in method (19), with a base salt of a compound of the formula:- Aryl-OH (XXII) wherein "aryl" is as previously defined for this method.

A base salt of a compound of the formula (XXII) a phenoxide) may be generated in situ from the corresponding phenol of the formula (XXII) using a suitable base, e.g. sodium or potassium hydroxide or sodium hydride, and in a suitable solvent, e.g.

ethanol or N,N-dimethylformamide, at from 0 0 C to the reflux temperature. The reaction may also be carried by reacting a phenol of the formula (XXII) with a compound of the formula (XXI) in the presence of potassium carbonate and in a suitable solvent, e.g. 2-butanone, at up to, and preferably at, the reflux temperature of the solvent.

22) The compounds of the formula wherein R 1 0 is COOR" or CONR 2

R

1 3 and Y, R, R 1 to R 9

R

12

R

3

R

14 and "aryl" are as defined for method (21) may be prepared by reaction of a compound of the formula:i -I

LI

il_ PCT/EP92/01625 WO 93/02050

Y

I

R1o

(XXIII)

wherein one of R 31

R

32 and R 33 is a group of the formula:-

R

1 4

-CH-OH

and 'he remainder are as previously defined in this method for the remainder of R 6

R

7 and R 8 and Y, R,

R

1 to R 5

R

9

R

10 and R 14 are as previously defined for this method, with a compound of the formula (XXII) wherein "aryl" is as previously defined for this method, in the presence of a suitable dehydrating agent, e.g. diethylazodicarboxylate/ triphenylphosphine. The reaction may be carried out i'i a suitable solvent, e.g. tetrahydrofuran, at from room temperature to the reflux temperature.

WO 93/02050 PCT/EP92/01625 -34- All of the above reactions and the preparations of novel s.arting materials used in the preceding methods are conventional and appropriate reagents an. reaction conditions for their performance or preparation as well as procedures for isolating the desired products will be well known to those skilled Sin the art with reference to literature precedents and the Exalples and Preparations hereto.

A pharmaceutically acceptable salt of a compound of the formula may be readily prepared by mixing together sclutions 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 are steroid reductase inhibitors and they ara therefore useful in the c, rative or prophylactic treatment of diseases or conditions such as acne vulgaris, alopecia, seborrhoea, female hirautisz, benign prostatic hypertrophy and male pattern baldness.

Certain compounds of the formula are also useful in the treatment of human prostate adenocarcirnoas.

The '.mpounds of the formula may be tested in vitro for steroid Sc-reductase inhibitory activity using prostate tissue from rats or humans.

J

Lid

;J

7'7771 WO 93/02050 PCT/EP92/01625 The compounds of the formula may be tested for potency in inhibiting rat steroid 5c-reductase using ventral prostate tissue from male rats. In determining inhibitory potency against rat prostatic the following procedure was employed:- Rat prostates were minced into small pieces. The tissue was homogenised in Buffer A (20mM sodium i phosphate, pH 6.5, buffer containing 0.32M sucrose and 1mM dithiothreitol) with a Brinkman Polytron (Kinematica GmBH, Luzern), and then homogenised with a motor driven (1000rpm) Potter Elvehje. (teflon-toglass) homogeniser. Prostate particles were obtained by centrifugation at 105,000G for minutes. The pellet was washed in 4 volumes C< Buffer A and recentrifuged at 105,000G. The resulting pellet was dispersed in Buffer A (iml per g of prostate tissue originally used) with a motor driven Potter Elvehjem homogeniser as described above. The particulate suspension was stored as iml samples at -70 0

C.

The following components, dissolved in Buffer B sodium phosphate buffer, pH were added to a test tube: 5001 of [3H]-testosterone (lrCi, Inmol; Du Pont, NEN Research Products, Stevenage, lOil of 0.5mM NADPH, a compound of the formula dissolved in 541 of dimethyl sulphoxide, and Buffer B to give a final reactio volume of lml.

The mixture was warmed to 37°C and the reaction started by addition of an aliquot of prostate particulate suspension, The reaction mixture was incubated at '7°C for 30 minutes and then quenched by addition with vigorous mixing of t 1 1 WO 93/02050 PCT/EP92/01625 -3- 2ml of ethyl acetate containing 20Ag each of testosterone and 5c-dihydrotestosterone as carriers.

The aqueous and organic layers were separated by centrifuation at 2000G for 10 minutes. The organic layer was transferred to a second test tube and evaporated to dryness under nitrogen. The residue was dissolved in 50-80/l 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 dihydrotestostercne) was determined with a RITA Radio TLC Analyser (Raytest Instruments Ltd., Sheffield, The percent of recovered radiolabel converted to 50-dihydrotestosterone was calculated and used to determine enzyme activity.

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

The experimentally obtained data for a range of inhibitor concentrations w4; computer fitted to a sigmoidal dose-response ,rve and concentrations of compound giving 50% inhibition of activity (ICso's) were calculated using a SIGFIT program (De Lean, Munson, P.J. and Rodbard, D., American Journal of Physiology, 235, E97 (1978)).

The compounds of the formula may be tested for potency in inhibiting human steroid using tissue from hyperplastic human prostates. In determining inhibitory potency against human prostatic 5c-reductase the following procedure was employed:i N 1 fe.- i 1 1 1 i 1 WO 93/02050 PCT/EP92/01625 -37- Frozen human prostate ,issue 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, 1mM dithiothreitol and 50gM NADPH) with an Ultra-Turrax (Janke and Kunkel GmBH Co., Staufen i.BR., Germany). The homogenate was centrifuged at 500G for 5 minutes, to remove large particles of tissue, and the supernatant was then centrifuged at 100,000G for 1 hour. The resulting pellet was dispersed in Buffer A (1ml per g of prostate tissue originally used) with the Ultra- Turrax homogeniser. This particulate preparation was then filtered through 2 layers of cheesecloth and the filtrate was stored as 1ml samples at The following components, dissolved in Buffer B citrate phosphate buffer, pH were added to a test tube: 5004 of 3 H]-testosterone (1Ci, Inmol; Du Pont, NEN Research Products, Stevenage, 100l of NADPH regeneration system NADPH, 50mM glucose 6-phosphate, 5 units/ml glucose 6-phosphate dehydrogenase), a compound of the formula dissolved in 5l of dimethyl sulphoxide, and Buffer B to give a final reaction volume of iml.

The mixture was warmed to 370C and the reaction started by addition of an aliquot of prostate particulate suspension. The reaction mixture was incubated at 37 0 C for 30 minutes and then quenched by addition with vigorous mixing of 2ml of ethyl acetate containing 20gg each of testosterone and dihydrotestosterone as carriers. The aqueous and organic layers were separated by centrifugation at 2000G for 10 minutes. The organic layer was WO 93/02050 PCT/EP92/01625 -38transferred 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 Merck, Darmstadt, Germany) and developed in chloroform:acetone (185:15).

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

All incubations were conducted so that no more than 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 activity (IC 50 were calculated using a SIGFIT program (De Lean, Munson, P.J. and Rodbard, D., American Journal of Physiology, 235, E97 (1978)).

The compounds of the formula may be tested for potency in inhibiting steroid 5c-reductase activity in human prostate adenocarcinomas using cell lines DU145 and HPC36M. In determining inhibitory potency against 5c-reductase the following procedure was employed:i WO 93/02050 PCT/EP92/01625 -39- Human prostate adenocarcinoma cell lines were grown in Dulbecco's Modified Eagles medium (DMEM) containing 5% serum. The cells were recovered from the medium by centrifugation, washed in serum free DMEM and suspended at 5-10 x 106 cells/ml. in serum free medium.

The following components were added to a test tube: of 3 H]-testosterone (lCi, 20 pmol) dissolved in ethanol (Du Pont, NEN Research Products, Stevenage, and 5A1 of an ethanol--sfution of a compound of the formula The ethanol was evaporated under nitrogen and the testosterone and the compound redissolved in 0.25ml of serum free medium containing 0.25gmol NADPH. The mixture was warmed to 37 0 C and the reaction started by addition of 0.25ml of cell suspension (1.2-2.5 x 106 cells).

The reaction mixture was incubated at 37°C for 2 hours and then quenched by addition with vigorous mixing of 1.5ml of ethyl acetate containing each of testosterone and 50-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 -801 of absolute ethanol, spotted onto a silica gel 60 F254 TLC plate Merck, Darmstadt, Germany) and developed in dichloromethane:acetone (185:15).

I

s 1 i .i WO 93/02050 PCT/EP92/01625 The radiochemical content in the bands of the substrate (testosterone) and the product dihydrotestosterone) was determined with a RITA Radio TLC Analyser (Raytest Instruments-Ltd.7 Sheffield, The-percentage of recovered radiolabiel converted to 5 o-dihydrotestosterone was calculated and used to determine enzyme activity.

All incubations were conducted so that no more than 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 activity (IC 50 were calculated using a SIGFIT program (De Lean, Munson, P.J. and Rodbard D., American Journal of Physiology, 235, E97 (1978)).

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

For parenteral administration, they are best used in the form of a sterile aqueous solution which may contain other substances, for example, enough salts or glucose to make the solution isotonic with blood.

m i a 1 n- WO 93/02050 PCT/EP92/01625 -41- For oral and parenteral administration to human patients, the daily dosage level of the compounds of the formula will be from 0.01 to 20 mg/kg (in single or divided doses) and preferably will be from 0.1 to lO0mg/kg except for the treatment of human prostate adenocarcinomas where doses of up to may be used. Thus tablets or capsules of the compounds will contain from Img to 0.5g of active compound for administration singly or two or more at a time, as appropriate. The physician in any event will determine the actual dosage which will be most suitable for an individual patient and it will vary with the age, weight and response of the particular patient. The above dosages are exemplary of the average case; there can, of course, be individual instances where higher or lower dosage ranges are merited, and such are within the scope of this invention.

Alternatively, the compounds of the formula can be administered in the form of a suppository or pessary, or they may be applied topically in the form of a lotion, solution, cream, ointment or dusting powder. For example, they can be incorporated into a cream consisting of an aqueous emulsion of polyethylene glycols or liquid paraffin; or they can be incorporated, at a concentration between 1 and 10%, into an ointment consisting of a white wax or white soft paraffin base together with such stabilizers and preservatives as may be required.

i I I i 1 a WO 93/02050 PCT/EP92/01625 -42- The compounds of the formula may also be administered together with an c-antagonist (e.g.

prazosin or doxazosin), an antiandrogen (e.g.

flutamide) or an aromatase inhibitor (e.g.

atamestane), particularly for the curative or prophylactic treatment of benign prostatic hypertrophy.

Thus the invention further provides:i) a pharmaceutical composition comprising a compound of the formula or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable diluent or carrier; ii) a compound of the formula or a pharmaceutically acceptable salt or composition thereof, for use as a medicamet; iii) the use of a compound of the formula or of a pharmaceutically acceptable salt or composition thereof, for the manufacture of a medicament for inhibiting a steroid reductase; iv) the use of a compound of the formula 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; i WO 93/02050 PCT/EP92/01625 -43v) a method of treatment of a human to inhibit a steroid 5c-reductase which comprises treating said human with an effective amount of a compound of the formula or with a pharmaceutically acceptable salt or composition thereof; vi) a method of treatment of a human to cure or prevent acne vulgaris, alopecia, seborrhoea, female hirsutism, benign prostatic hypertrophy, male pattern baldness or a human prostate adenocarcinoma which comprises treating said human with an effective amount of a compound of the formula 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

I

i i 1~ W-l-, WO 93/02050 PCTr/EP92/01625 -44- EXAMPLE 1 4-3-r4- (1-r4- (2-Methylipropyl) henyllethoxv) benzovll indol-l-vl~ butanoic acid -C0 2

CH

2

CH

3 Iaq.NaOH,THF,CH 3 0H

CO

2

H

'CH

3 A solution of methylpropyl)phenyl]ethoxy) benzoyl] indol-1-yl) butanoic acid ethyl ester (3.8g) (see Example 21) in tetrahydrofuran (THF) (35m1) and methanol (35m1) was treated with 2N sodium hydroxide solution (35m1). After stirring at room temperature for 2 hours the mixture was WO 93/02050 PCr/EP92/01625 cautiously __=,-ntrated in vacuo to a volume of about then cooled in an ice-bath cnd acidified with 2N hydrochloric acid solution. The acid phase was extracted with ethyl acetate (lO0ml), the organic extract dried (sodium sulphate) and concentrated in vacuo to provide the title compound as a white foam, (3.27g), m.p. 57 0

C.

Found: C,77.00; H, 6.88; N,2.90; C 3 jH 33 N0 4 requires: C,76.93; H,6.88; N,2.99%.

t H-NMR (CDCl 3 0. 95(d, 6H) 1. 70(d, 3H) 1. 90(m,l1H) 2.25(m,2H), 2.40(t,2H), 2.49(cz,2H), 4.30(t,2H), 5.50(q,H) 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 The following compounds of the general for mula:- 0 R

R

7 IN

R

6 C0 2

H

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.

M.P. 11Optical Rotation/

R

T

7( C) IMlZ Analysis/NMR 498 (M+1) IH-NMR (do-DMSO0): 8 0.90 0.95(t,3H), 1.25-1.65(m,4H), 1.70- 1.90(m,1H), 1.95- 2.10(m,IH), 2.20(m,2H), 2.35(t,2H), 2.50(t,2H), 4.20(t,2H), 5.15(m,1H), 6.90(d,2H), 7.15(d,2H), 7.20-7.40(m,5H), 7.50 7.70(d,2H), 8.30(m,1H) ppm.

4 1-4. 4- -t 4- 4 55

CH

3 I

CH

3 Found: C,71.86; H,5.93; N,2.81; C~gH 2 gN0 4 .1 1

H

2 0 requires: C,72.18; H,6.1 1; N,2.90%.

IH-NMR (d 6 ;-DMSO): 8 1.1 0(t,3H), 1 .45(d,3H), 1 .80-2.00(t,br,4H), 2.50(t,2H), 3.40-4.00 (s,br,ca.1 4.30(t,2H), 5.50(q,1H), 7.00(d 1 2H), 7.20(d,2H), 7.30(t.2H), 7.45(d,2H), 7.60(d,1H), 7.70(d,2H), 8.00(s.1H), 8.25(m,1H) ppm.

~r-

K,

Ex. IM.P. OpticalRoain No. Y R R 5 R 6 MlZ Analysis/NMAR 4 -(CH 2 3 H H H 427 Found: C,73.30; H,5.66; 0 N,3.0,3,, o IC 2 7

H

25 N0 4

.H

2 0 requires: C,.72.78; H,6.1 1; N,3.14%.

CH 3 'H-NMR (d 6 -DMSO): 8 1 .95tm, 1 2.20(t,2 1 2.25(s,3H), 4.25(t,2H), 5.10(s,2H), 7.10(d,2H), 7.15-7.35(m,61-), 7.60 7.78(d,2H), 8.20(rryl H) ___ppmr.

-(CH

2 3 H H H 441 Found: C,71.86-, H,6.16; N%3.00;

CH

3 rC 28

H

27 N0 4 .1%H 2

O

requires: C,'71.78; H,6.45; N. N,2.99%.

N I 1 H-NMR (de-DMASO): 8 CH 3 1.55(d.3H), 2.00(m,2H), 2.20(t.2H), 2.25(s,3H), 4.28(t,21-), 5.55(q,IH), 7.05(d,2H), 7.15(d,2H), 7.20-7.35(m,4H), 7.60 (d,111), 7.70(d,2H), ppm.J M.P. Optical Rotation/ mlZ Analysis/NMVR 455 Found: C,72.60; H,6.06; N,2.90;

C

29

H

2 gN0 4 1 Y21- 2 0 requires: C,72.18; H,6.11; N,2. 9 0%.

IH-NMR (dg-DMSO): 8 0.90(t,3H), I .55(m,2H), 2.O0(m,2H), 2.20(t,2H), 2.50(t,2H), 4.25[t,2H), 5.10(s,2H), 7.1O(d,2H), 7.20-7.40(m,6H), 7.60 7.75(d,2H), 8.00(s,1H), 8.20(d,1H) ppm.

Found: C,61.30; H,4.06; N,2.64;

C

2 61- 21 C1 2

NO

4 1 YAH 2 0O requires: C,61.30; H,4.55; N,2.75%.

11H-NMVR (CDC 3 8 2.25(vv,2H-), 2.45(t,2H), 4.3rJ(t,2H), 5.1 O(s,2H), 7.05(d,21-), 7.25- 7.55(m,6H), 7.85(d,2H), 8.35(m,1 H) PPrI.

(CH

2 3 H IH I H 482 0C >-k \ZZ 1 Xi mopp--7 EX. M.P. Optical Rotation/ No. yR R 5

R

6 R MlZ Analysis/NMVR 8 -(CH 2 3 H CH 3

CH

3 511 Ht--NMVR (do-DMSO): 8 CH 3 O.90(d,6H), 1.65(d,,AH), 1.85(m,1H), 2.15(m,2H),

CH

3 2.30(s,6H), 2.35(t,2H), 01 2.45(d,2H), 4.1 5(t,2H), 5.35(q,1H), 6.60(d,2H), CH 3 7.iO(d,2H), 7.15- 7.40(m,6H), 8.30(m,1H)

A-

9 -(CH 2 3 H H H 48z C,76.83; H,6.95; 2.86; t.

31

H

33 N0 4 requires:

ICH

3 H C,76.99; H,6.88; N,2.90%.

0()CH 3 Optical Rolajion: [a] 2 1 -68.4' (c 1 CH 3 D in methanol) IH-NMR (CDC 3 8= O.95(d,6H), 1.70(d,3H), 1.90(m,1H), 2.25(m,2H), 4.30(t,2H), 5.50(q,1H), 6.95(d,2H), 7.15(d,2H), 7.27-7.45(m,5H), 7.59 8.45(m,1H) ppm.

0

CI

W

U1 m w Ex. Optical Rotation/ No. Y R R 5

R

8 6( C) MlZ Analysis/NMVR H H H 484 Found: C,74.1 1; H,6.7 1;

C

31 H33NO 4 requires:

CH

3 H C,74.23; H,7.03; N,2.80%.

-0 (R)CH 3 'H-NMR (CDC 3 8 0.95 N. 1.70 (d,3H),

CH

3 1.90(m,1H), 2.25(m,2H), 2.40 (t,2H)t 2.49(d,2H), 4.30(t,2H), 5.50 (q,IH), 6.95(d,2H), 7.15(d,2H), 7.27- 7.45(m,5H), 7.59 7.79(d,2H), I 8.45(m,IH) ppm.

11 H H H 574 'H-NMR (d 6 -DMSO): 2.20(m,2H), 2.35(t,2H), 2.50 4.20(t,2H), 6.25(s,1H), 7.02 (d,2H), 7.17(d,4H), 7.30- 7.80 8.40(m,1H) 0

PM

LI

CH

3 'ii Ex. M.P. Optical Rotation/ No. Y IR R6 R1 C T C) MlZ Arialysis/NMR 12 -(CH 2 3

OH

3 H H 498, Found: C,75.14; H,6.78;

CH

3 1

HC

32

H

35 N0 4

.H

2 0 requires: -03 (S CH 3 C,74.54; H,7.23; N,2.72%.

IH-NMR (d6-DMSO): 8

CH

3 O.90(d,6H), 1.65(d,3H), 1.85(m,1H), 2.1O(m,2H), 2.45(m,4H), 2.60(s,3H), 4.20(t,2H), 5.40(q,1 H), 6.90(d,2H), 7.00- 7.40(m,8H), 7.40(d,2H) ppm.

13 -(OH 2 3 H H H Found- 0,73.61; H,5.53; N,3.29; C 26

H

2 4 N0 4 1

AH

2 0 requires: C,73.92; H,5.73; N,3.32%.

IH-NMR (d 6 -DMSO): 8 2.00(m,2H), 2.15(m,2H), 4.05(t,2H), 5.05(s,2H), 6.95(d,2H), 7.15-7.40 7.55(s,1H), 7.75(d,2H), 8.10(m,1H) ppm.

A

s Ift- -11 kw- Ex. M.P. Optical Rotationl No. Y R R 5 IRS C) ml: Analysis/NMR 14' -CH 2 H H H 478 Found: C,69.96; H,5.95; N,2.57;

CH

3

C

2

,H

2

,NO

4 Na requires: 0,70.29; H,6.10; N,2.83%.

0CH 3 'H-NMR (d 6 -DMSO): 8= 0.80(d,6H), I .55(d,3H),

CH

3 1.69(frn,IH-), 2.35(d,2H), 4.72(s,2H), 5.55(q,IH), 7.00(d,2H), 7.10(d,2H), 7.20(m,2H), 7.30(d,2H), 7.40(m,1 7.65(d,2H), 7.90(s, 1H), 8.20(m, 1H)

-(OH

2 3 H H H 496 Found: C,63.33; H,5.09;

CH

3 N,3.13;

C

27

H-

23 N0 4 C1 2

.H-

2 0 C11 requires: C,63.04; H,4.90; 0 CI 1 H-NMR (CDCI 3 85 1.65 2.20(m,2H), 2.40(t,2H), 4.25(t,2H), 5.35(q, 1 6.90(d,2H), 7.20-7.50(m,6H), 7.55(s, 1H), 7.75(d,2H), ppm.

Isolated as the sodium salt.

-J

72 U IhT~ Ex. M.P. Optical Rotation! No. Y R R 5

R

6 R MlZ Analysis/NMVR 16 H H H 524 IH-NMR (CDC 3 8 0.90 1.90(m,IH), 2.20(m,2H), 2.35(t 1 2H), 2.55(t,2H), N.~O 4.20(t,2H), 4.90(d,1H), 0 6.90(d,2H), 7.10(d,2H), 7.25-7.40(m

CH

3 7.50(s,IH), 7.70(d,2H), 8.35(m,IH) ppm.

17 -(CH 2 5 H H H 512 IH-NMR (CDC 3 8 0.90(d,6H), 1.30- 1.40(m,2H), 1.60- 1.65(m,6H), 1.80-1.90

CH

3 2.30(t,2H), 2.42 4.10(t,2H), 5.35 CH3 6.95(d,2H), 7.10

CH

3 7.25-7.40(m,5H), 7.52(s,IH), 7.70(d,2H),

CH

3 8.30(m,IH) ppm.

4

AW

EM.P. Optical Rotation/ No0. Y R R 5

R

6 (C7 mlz Analysis/NMR 18 H H H 498 Found: C,76.59; H,7.52;

CH

3

C

32

H

35 N0 4 1 5(C 2

HS)

2 0 requires: C,76.88; H,7.28; 0CH 3 N,2.73%.

IH-NMR (CDC 3 8 0.90

CH

3 1.64(m,5H), 1.80- 1.95(m,3H), 2.28(t,2H), 2.44(d,2H), 4.15(t,2H), 5.40(q,1H), 6.95(d,2H), 7.10(d,2H), 7.24-7.40 7.55(s,1H), 7.75(d,2H), 8.35(m,1H) 4 ___ppm.

19 -(CH 2 3 H H H 470 Found: C,76.69; H,6.87; N,2.93; C 30

H-

3 IN0 4 requires: C,76.73; H,6.65; 0 N,2.98%.

IH-NMR (CDC 3 8 0.90 CH 3 CH23(,2H), 86(t,2H), 2.50(m,2H), 4.28(t,2H), 250(q,IH), .8(d,2H), 7.00(d,2H), 7.30-d2) 7.45(m,3H), 7.50(d2) 7.80(d,2H), 8.40(m,1H) ppm. .J Ex. m.O. Optical Rotation/ No. Y R R 5 R 6 mlz Analysis/NMR

-(CH

2 3 H H H 442 1 H-NMR (CDC 3 8 1.65 oa 2.20(t,2H), 2.25(s,3H), 2.40(t,2H), 4.25(t,2H), 5.35(q,IH),

CH

3 CH6.78(d,2H), 7.0O(d,2H), CH3 CH37.30-7.42(m ,3H), 7.50(d,2H), 7.57(s,1H), 7.80(d,2H), 8.40(m,1 H) ppm.

WO 93/02050 PCr/EP92/01625 -56- EXAMPLE 21 S)-4 3 -r 4 r4 -(2-Methy lpropvl) ihen ljethoxvbenzovllindol-l-vlbutanoic acid ethyl ester 0 N OH

CO

2

CH

2

CH

3 i) NaH,DMF 2) H 3 Br H3

OH

3 0 OP

HH

N H0 H 3

CO

2

CH

2

CH

3

OH

3 A suspension of sodium hydride (60% dispersion in oil, 716mg) in dry dimethylformamide (DMF) (15m1) at 0 0 C arid 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 dimethylformamide (30m1) After stirring for one hour at room temperature a solution of e -methyl-4- (2-methylpropyl) benzyl bromide (see Preparation 23) (3.95g) in dimethylformamide (5m1) was added to the mixture at 0 0 C. The resultant mixture was stirred overnight at room temperature. The reaction was partitioned between 1N hydrochloric acid solution (lO0ml) and ethyl acetate (200m1). The separated organic layer was washed WO 93/02050 PCr/EP92/01625 -57successively with iN sodium hydroxide solution (lO0mi), saturated aqueous brine (lO0mi) and then water (lO0mi). The organic layer was dried (MgSO 4 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, Found: C,77.47; H,7.29; N,2.74; C 33

H

37 N0 4 requires: C,77.63; H,7.48; N,2.73%.

1 H-NMR (CDCl 3 0. O91(d, 6H) 1.35 1.70 3H) 2.20(m,2H), 2.31(m,2H), 2.49(d,2H), 4.13(q,2H), 4.25(t,2H), 4.50(q,lH), 6.95(d,2H), 7.15(d,2H), 7.27- 7.45(m,5H), 7.55(s,1H), 7.88(d,2H), 8.45(m,lH) ppm.

EXAM~PLES 22 to 32 The following compounds of the general formula:-

CO

2

CH

2

CH

3 were prepared by alkylation of the corresponding phenol derivatives (see Preparations 1, 3 and 4) with the corresponding alkyl bromides (see, Preparations 20 to 26) by similar methods to that used in Example 21.

mm L7' Ex. M.P. Optical Rot ation/ No. Y R R 5 R 6 MlZ Analysis/NMR 22 H H H 526 Found: C,75.54; H,7.65; N,2.60; C 34

H

3 N0 4 .115

CH

3

CH

2

CI

2 requires: C,75.70; H,7.32; N,2.58%.

IH-NMR (CDC 3 8 0.96(t,3H), 0.97(t,3H), 0 1.20(t,3H), 1.40- 1.65(m,4H), 1.80(m,1H),

CH

3 2.05(m, 1H), 2.12-2.25 2.55(t,2H), 4.10(q,2H). 4.20(t,2H), 5.15(m,IH), 6.90(d,2H), 7.15(d,2H), 7.25-7.40 7.70(d,2H), 8.28(m,IH) ppm.

23 -(CH 2 3 H H H 484 'H-NMR (CDC 3 8=

CH

3 1.70(d,3H), 2.10- 2.35(m,4H), 2.65(q,2H), 0 4.10(q,2H), 4.25(t,2H), 0 I 5.39(q,1H), 6.95(d,2H), CH1 3 7.20(d,2H), 7.25- 7.40(m.5H), 7.50(s.1H).

7.75(d,2H), 8.35(m, 1 H) I m w~

I

Ii Ex- M.P. Optical Rotation/ No. Y R R 5

R

6

C

7 C) MlZ Analysis/NMVR 24 -(CH 2 3 H H jH 456 Found: C,75.87; H,6.35; N,3.06;

C

2 ,H2,NO 4 requires: 0 C,76.46; H.6.42; N,3.07%.

CH

3 1 H-NMR (CDCI 3 8 CH3 1.25(t,3H), 2.15- 2.43(m,4H), 2.45(s,3H), 4.1 O(q,2H), 4.25(t,2H), 5.15(s,2H), 7.100d,2H-), 7.25-7.45(m,7H), 7.60(s,1 7.85(d,2H), 8.40(m,1H) ppm.

-(CH

2 3 H H H 469 IH-NMR (CDC1 3 8 1.20(t,3H), 1.65(d.3H), CH 3 2.20(m,2H), 2.30(m,2H), 2.35 4.1O(q,2H), 4.20(t,2H), 5.39(q,1 H), o0 6.95(d,2H), 7.15(d,2H), 7.27-7.45(m,5H), 7.55

CH

3 7.75(d,2H), 8.35(m,IH) ppm.

I

Ex. M.P. Optical Rotation/ No. Y R R 5

R

6 T MlZ AnalysisINMR 26 -(CH 2 3 H H H 484 Found: C,76.99; H,6.88;

C

3 jH 33 N0 4 requires: C,76.97; H,7.00; N,2.98%.

'H-NMR (CDC1 3 8

CH

3 0.95(t,3H), 1.20(t,3H), 1.65(m,2H), 2.15- 2.38(m,4H), 2.60(t,2H), 4.10 4.25(t,2H), 5.1O(s,2H), 7.05(d,2H), 7.1 0-7.45(m,7H), 7.55(s, 1H), 7.80(d,2H), 8.40(m,1 H) ppm.

27 -(CH 2 3 H H H 510 'H-NMR (CDC 3 8 C11 2.40(t,2H), 4.20(q,2H), NC 4.40(t,2H), 5.10(s,2H), 7.O0(d,2H), 7.20- 7.55(m,7H), 7.60(s,2H), C11 7.80(d,2H), 8.40(d,1 H) ppm.

J

-I

ii? Ex. M.P. Optical Rotation/ No. Y R R 5

R

6 7 MlZ Analysis/NMR 28 -(CH2) 3 H CH 3

OH

3 540 IH-NMR (CDC 3 8

CH

3 1.65(d,3H), 1.85(m,IH), 2.1O(m,2H), 2.25(t,2H), 0CH 3 2.30(s,6H), 2.45(d,2H), 0 4.1 0(q,2H), 4.15(t,2H), 5.35(q,1H), 6.60(d2H),

CH

3 7.05-7.40(m,8H), 8.35(m,1H) ppm.

29 -(CH 2 3 H H H 601 IH-NMR (CDC 3 8 C7

CH

3 0.95(t,6H), 1.20(t,3H), I .65(m,4H), 2.20(M,2H), 2.30(t,2H), 2.60(t,4H), 4.10(q,2H), 4.21(t,2H), 6.30(s,2H), 7.05(d,2H), 7.20(d,4H), 7.25-7.40 7.58(s,1H), 7.80(d,2H), 8.40(m,1H) ppm.

CH

3

L

Ex.

No. R R H H

M.P.

-CH

2 mlZ 483

CH

3 0.

CH

3

CH

3 Optical Rotation/ Analysis/NMR 1 H-NMR (CDC1 3 8 O.90(d,6H), I .20(t,3H), 1.60(d,3H), 1.80(m,1H), 2.45(d,2H), 4.20(q,2H), 4.85(s,2H), 5.40(q,1H), 7.25-7.35(m,5H), 7.55 7.75(d,2H), 8.40(m,IH) ppm.

-I I 4 9 I

-(CH

2 3 HI H 525

CH

3

CI

1 H-NMR (CDCI 3 8 I .25(t,3H), 1 .65(d,3H), 2.20(m,2H), 2.35(t,2h), 4.1 5(q,2H), 4.30(t,2H), 5.35(q,1H), 7.25-7.50(m,6H), 7.60(s,IH), 7.80(d,2H), 8.35(mIH) ppm.

w [Ex. R 7 M.P. Optical Rotation/ No._ R Analysis/NMVR 32 -(CH 2 3 H- 552 1 H-NMR (CDC 3 0.95(t,3H), 1.20(t,3H), 1.22-1.80(m,1OH), 1.90 2.15(m,2H), 2.25(t,2H), 2.60(t,2H), 4.10(q,2HI), 4.20(t,2H), 0 4.95(d,1H), 6.951d,21-), 7.l0(d,2H), 7.20-

CH

3 7.40(m.5H), 7.50(s,IH), 7.70(d,2H), 8.40(m,1H) ppm..

-,AN

WO 93/02050 PCT/EP92/01625 -64- EXAMPLE 33 (S--3r-lr-2Mtypov~hnlehx) benzovllindol-1-yl)butanr,.' acid ethyl ester

CH

3

CH

2 C14 3 Ph 3 P, DEAD, THF

CO

2

CH

2

CH

3 A solution of 4-(3-(4-hydroxybelzoyl, indol-1-yl)butanoic acid ethyl ester (see Preparatiois 1) (500mg), (R)-1-(4-t2-methylpropyl)phelyl) ethanol (see Preparation 17) (256mg) and triphenylphosphine (410mg) in THF (?0m1) was treated with diethylazodicarboxylate (DEAD) (0.27m1) and the mixture stirred at room temperature overnight.

Evaporation of the reaction mixture onto silica gel followed by flash chromatography (silica, 3:1 hexane/ ethyl acetate) gave, after evaporation of the appropriate fractions, the desired compound as a pale yellow gum, (413mg) m/z 511 tI~ Ra WO 93/02050 PCT/EP92/O 1625 H.P.L.C. (Cyclobond DMP column eluting with 1:1 1) triethylammonium acetate, pH4.l/CH 3 CN at O.7m1/min.) rt= 86.09 min. (100%).

'H-NMR (CDCl 3 8 0.95(d,6H), l.25(t,3H), 1.70(d,3H), l.85(m,1H), 2.20(m,2H), 2.30(t,2H), 2.45(d,2H), 4.10(q,2H), 4.25(t,2H), 5.40(q,1H), 6.95(d,2H), 7.15(d,2H) 7.25-7.40(m,5H), 7.55(s,lH), 7.75(d,2H), 8.35(m,1H) ppm.

The title compound may also be prepared by resolution of the product of Example 21 using chiral HPLC (Chiralpak AD column, eluant 9:1 hexane/ethanol, flow rate l2ml/min.). The first eluted compound was (3-[4-(1-[4-(2-methylpropyl)phenyl~ethoxy)benzoyl~indol- 1-yl)butanoic acid ethyl ester, rt 24mmn., +52.10 (c=2 in dichloromethane), and the second eluted compound was the title compound, rt 27mmn., l 53.801 (c=2 in dichioromethane).

EXAMPLES 34 to 37 The following cc~npounds of the general formula:- Fl 7

CO

2

CH

2

CH

3 were prepared by condensation of the corresponding phenols or alcohols (see Preparations 1, 2 and 27) withI the corresponding phenols or alcohols (see, e.g.

Preparations 17 and 18) by similar methods to that used in Example 33.

Ex M.P.

No Y R R 5

R

6

C

7 C) mlz H.P.L.C./NMVR 341 -(OH 2 3 H H H 511 H.P.L.C. (Cyclobond DMVP column eluting with 1:1 1% triethylamnmonium acetate, pH H 3 4.1/CH 3 CN at 0.7m1/min.) N CH 3 rt 85.73min. (100%).

I 'H-NMVR (C0013): 8 0.95(d,6H), 1.25

CH

3 1.70(d,3H), 1.85(m,1H), 2.20 2.30(t,2H), 2.45(d,2H), 4 .10 4.25(1,2H), 5.40(q,1H), 6.95 7.15(d,2H), 7.25-7.40(m,5H), 7.55(s,1H), 7.75 1HI-) ppm.

-(OH

2 3

OH

3 H H 525 H.P.L.C. (Cyclobond DMP column eluting with 1:1 1% triethylamnmonium acetate, PH C ~H 41IC 3 CN at 0.7ml/min.)

CH

3 rt =64.52min. (100%).

0 CH 'H-NMVR (00013): 8 0.95 1.30 1.70

CH

3 1.85(m,1H), 2.15 2.40(t,2H), 2.45 2.60 4.15 4.20(t,2H), 5.40 6.95(d,2H), 7.00- 7.70(d,2H) ppm.

0

S.-

C

C

C

0' 0'

C

a.' U' I See Example 33 also.

Mgt Ex.

M.P.

Nn. yR R 5 R6 R 7 CC) MlZ H.P.L.C./NMR H H H 498 IH-NMR (CDC 3 8 0.95 1.20(t,3H), 1.60 0 (m,21i), 1.65(d,3H), 2.20 2.30(t,2H), 2.50 "Y 4.10(q,2H), 4.28 CH 3 CH 3 5.35(q,1H), 6.80 7.05(d,2H), 7.30- 7.45 7.50(d,2H), 7.58 7.80(d,2H), 8.40(m,1H) ppm.

37 -(CH 2 3 H H H 469 'H-NMR (CDC 3 8 1.20 (ml) 1.69(d,3H), 2.20 0 2.25(s,3H), 2.35- 2.50 4.15(q,2H), 'Y 4.30 5.40(q,1 H), C3 CH 3 6.80 7.05 (d,2H),

CH

3 7.35-7.50 (rn,3H), 7.50(d,2H), 7.60 (s,1H), 7.85(d,2H), 8.45(m,1H) ppm.

-4 -4 a1 WO 93/02050 PCT/EP92/01625 -68- EXAMPLE 38 4-(3-f4-Benzvloxvbenzovllindol-l-yl)butanoic acid ethyl ester 1) NaH,DMF 2) Br 'CO 2

CH

2

CH

3

-CO

2

CH

2

CH

3 A cooled (0 0 C) suspension of sodium hydride (3.40g of a 55% dispersion in mineral oil) in dimethylformamide was treated with a solution of 3-(4benzyloxybenzoyl)indole (see Preparation 5) (20.0g) in dimethylformamide (100ml). The resultant orange suspension was allowed to stir for 1 hour at 20qC. The mixture was cooled to 0 C and ethyl 4-bromobutyrate (11.0ml) was added. The mixture was stirred for 2 hours at room temperature, cooled to 0°C and treated with 1N aqueous hydrochloric acid (100ml) and ethyl acetate (200ml). The organic layer was separated and washed with water (100ml), IN aqueous hydrochloric acid (100ml), r I~ _pr ~n~N, WO 93/02050 PC/EP92/01625 -69saturated aqueous sodium bicarbonate (100ml) and brine (100ml). Evaporation of the ethyl acetate gave an orange gum which was purified by flash chromatography (silica, eluant 3:1 hexane/ethyl acetate then 2:1 hexane/ethyl acetate) to give, after combination and evaporation of the appropriate fractions, the title compound (16.5g), m.p. 83 0

C.

'H-NMR (CDCl 3 6= 1.20(t,3H), 2.20(q,2H), 2.35(t,2H), 4.15(q,2H), 4.29(t,2H), 5.20(s,2H), 7.10(d,2H), 7.30- 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:-

CO

2

CH

2

CH

3 were prepared by similar methods to that used in Example 38 using the corresponding indoles (see Preparations 5 to 8) and the corresponding ethyl bromoalkanoates as the starting materials.

No. Y R R 5 R 6 C AimiyisNM 39 -(CH 2 3

CH

3 H H Found: C,73.65; H,6.34; N,2.94; C 2 gH 2 gNO 4

.H

2 0 requires: 0,73.55; H,6.60; N .2.96%.

I 1 H-NMR (CDCI 3 8 1.30(t,3H), 2.30 (m,1H), 2.45(t,2H), 2.65(s,3H), 4.20 4.25(t,2H), 5.15(s,2H), 7.05 (d,2H), 7.10-7.45 (m,9H), 7.80(d,2H) ppm.

-(CH

2 3 H CH 3

CH

3 470 1 H-NMR (CDC1 3 8 1.25(t,3H), 2.20 (m,1H), 2.25(s,3H), 2.30(s,3H), 4.10 4.20(t,2H), I 5.15(s,2H), 6.80 (d,1H), 7.27-7.55 (m,1OH), 8.40(m,1H) ppm.

77~7~]7 Ex. M.P.

No. Y R W Re w(C) MlZ Analysis/NMR 41 -H H H H 414 1 H-NMR (CDC 3 8 1.30(t,3H), 4.25 (q,2H), 4.85(s,2H), 5.20(s,2H), 7.05 7.25-7.50 I 7.60(s,IH), 7.85(d,2H) ppm.

42 -(CH 2 5 H H H Not characterised.

CH

3 0 ~CH 3

CH

3 1 '11, I ~Ik~ Ex. 7M.P.

No. Y R R 5 Re R 7 CC) M/Z Analysis/NMR 43 H H H 498 'H-NMR (CDC 3 8 0.90 1.18(t,3H), 1.58 1.65(d,3H), 2.15-

CH

3 2.20 2.30(t,2H), 2.50 4.1O(q,2H), N 0CH 3 4.30 5.38(q,1H), I 6.80 7.05(d,2H),

CH

3 7.30-7.45 (m,3H), CH3 7.50(d,2H), 7.55 (s,1H), 7.80(d,2H), 8.40 (m,1H) ppm.

i WO 93/02050 PCr/EP92/01625 -73- The following Preparations illustrate the preparation of certain starting materials used in the previous Examples:- PREPARATION 1 4-(3-[4-Hvdroxybenzoyl]indol-l-yl)butanoic acid ethyl ester

H

2 ,10% Pd/C,

CH

3

CO

2

C

2

H

'C0 2

CH

2

CH

3 A solution of 4-(3-[4-benzyloxybenzoyl]indol-lyl)butanoic acid ethyl ester (see Example 38) (13.4g) in ethyl acetate (300ml) was hydrogenated at 4.15 x l05 Pa 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 WO 93/02050 PTE9/12 PCr/EP92/01625 -74cellulose-based filter aid and the filtrate was concentrated in vacuo to a pale pink solid. Trituration with cold diethyl ether gave a white powder, (8.24g).

Found: C,71.78; H,6.02; N,3.98; C21H21NO 4 requires: C,71.44; H,6.04; N,3.94%.

'H-NMR (CDCl 3 8= l.25(t,3H), 2.22(m,2H), 2.35(m,2H), 4.15(q,2H), 4.30(t,2H), 6.95(d,2H), 7.32-7.45(m,3H), 7.65(s,lH), 7.70(d,2H), 8.47(m,lH) ppm.

PREPARATIONS 2 to 4 The following compounds of the general formula:t

I

t C0 2

CH

2

CH

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

'I

i ~li-

U

I

Prep.I No. YR R 5 2 CH3I H'

M.P.

R

6

ICC)

MlZ Analysis/NMR

H

Found: C,72.30; H,6.16; N,3.75;

C

22

H

23 N0 4 requires: C,72.31; H,6 .34; N,3.83%.

'H-NMR (CD013): 8 1.30(t,3H), 2.15(m,2H), 2.45(t,2H), 2.65(s,3H), 4.20(q,2H), 4.25(t,2H), 6.60 (s,br,l1H), 6.85(d,2H), 7.1 7.20(t,l 7.40(d,2H), 7.70(d,2H) ppm.

3 -(tOH 2 3 A OH 3

OH

3 380 IH-NMR (CDCI 3 8 1.25(t,3H), 2.25(s,3H), 2.30(s,3H), 4.1 0(q,2H), 4.20(t,2H), 6.70(d,1 H), 7.1 5(d,1 7.25-7.45(m,4H), 8.30(m,1 H) ppm.

4 -CH 2 H H H -324 IH-NMR (00013): 8 1.20(t,3H), 4.20(q,2H), (M+1 )4 4.90(s,2H), 6.95(d,2H), 7.20-7.35(m,3H), 7.55(s,1 7.70(d,2H), 8.35(m,1 H) ppm.

WO 93/02050 WO 9302050PCr/EP92/01625 -76- PREPARATION 3- (4-Benzvloxvbenzovfl)-1H-indole ~J77 i)CH 3 MgI 1

(CH

3

CH

2 2 0 NH0_Q CC A mechanically stirred solution of indole (30.0g) in sodium dried diethyl ether (450rnl) was treated dropwise with methylm~agnesium iodide (85m1 of 3.OM solution in diethyl ether). After stirring for one i116,ur at 20 0

C

4-benzyloxybenzoyl chloride (see Preparation 10) (67.3g) was added. Stirring was continued for two hours at 20 0

C

and then 1N hydrochloric acid (250m1) added to the mixture and the reaction was allowed to stand overnight.

The resulting precipitate was filtered of f and triturated with hot ethyl acetate (3 x lO0ml) to give the desired compound as a pale pink solid, (40.9g). Found: C,80.67; H,5.33; N,4.25; C 22

HI

7 N0 2 requires: C,80.70; H,5.23; N,4.28%.

'H-NHR (d 6 -DMSO): 8= 5.20(s,2H), 7.15(d,2H), 7.20(m,2H), 7.30-7.50(m,6H), 7.80(d,2H), 7.90(s,lH), 8.23(d,lH), 11.95(s,br,1H) ppm.

Y ji: i I I I I WO 93/02050 PCT/EP92/01625 -77- PREPARATIONS 6 to 8 The following indoles of the general formula:- 0

R

N R R H R were prepared from the corresponding 1H-indoles and the corresponding acid chlorides (see Preparations 9 to 11) using similar methods to that used in Preparation 1A~-u

R

T l Analysis/NMR Found: C,78.45; H,8.31; N,3.90*.

C

23

H

10 N0 2 requires: C,78.60; H,8.32; N,3.98%.

-OCH

2 'H-NMR (do-DMSO): 8 2.40 5.20(s,2H), 6.95- 7.45(m,1 7.65(d,2H), I 2.00(s,br,l1H) ppm.

0 00 4-4. 5-4 4 4. 4

CH

3

CH

3 195- 197 355 (ml -OH/

\Q

Found: C,80.73; H,6.06; N,3.97;

C

24

H

21 N0 2 requires: C,81.13; H,5.92; N,3.94%.

'H-NMR (do-DMSO): 8 2.10 2.15(s,3H), 5.20(s,2H), 6.95(d,1H)g 7.15-7.50(m,9H), 12.00(s,br,IH) ppm.

L J I L I Prep. M.P.

No. R R 5 RO R" c) mlz Analysis/NMR 8 H H H Found: C,81.18; H,6.56; N,3.52;

C

27

H

2 7N0 2 requires: C.81 .58; H.6.85; N,3.52%.

'H-NMR (CDC 3 8 O.95(d,6H),

CH

3 1.70(d.3H) 1.90(m,1H), 2.50(d,2H), CH 5.40(q,1 6.95(d,2H), 7.1 5(d,2H), 0C 3 7.30-7.45(m,5H), 7.65(m,IH), 7.80 I (d 8.35(m 8.80(s,br,1 H)

CH

3 ppm.

0%

I~J

If- I I 7- WO 93/02050 PCI/EP92/01625 PREPARATION 9 4-BenzvloxV-2.3-dimethvlbeflzovl chloride

H

3 HO CH 3 Br 2

,CH

3 COOH *CH 3 'Br

H

3 0 CH 3 C0 2

H

(b)

(C)

)n-C 4

H

9 Li,THF 2) CO 2

C

6 HsCH 2 Br,K2CO 3 KI,(CH 3) 2

CO

H

3 0~ CH 3 'N Br (COCI) 2 ,DMF,CH 2 C1 2 0N Ha CH 3 'N Cod WO 93/02050 WO 9302050PCr/EP92/01625 -81- 4-Bromo-2. 3-dimethviphenol A solution of 2,3-dimethyiphenol (40.0g) in acetic acid (300m1) was cooled to 10 0 C and treated with a solution of bromine (16.9ml) in acetic acid (lO0ml).

After stirring for 30 minutes saturated aqueous sodium metabisulphite solution (300m1) was added.

The mixture was extracted with dichloromethane, the organic layer dried (MgSO 4 f iltered and evaporated to provide the product as a waxy solid, (64.7g).

1 H-NMR (CDCl 3 8= 2.15(s,3H), 2.25(s,3H), 4.00(s,br,1H), 6.60(d,1H), 7.15(d,lH) ppm.

Crystallisation of the product from hexane gave an analytical sample. Found: C,48.00; H,4.40; C8H 9 BrO requires: C,47.78; H,4.51%.

1-Benzvloxv-4-bromo-2 3-dimethvlbenzene A mixture of the product of part (45.0g), benzyl bromide (28.30g), potassium carbonate (38.60g) and potassium iodide (300mg) in acetone (500m1) was heated at ref lux overnigM. The reaction was cooled, filtered and evapo~rated to give an oil which was dissolved in diethyl ether and washed with 2N aqueous sodium hydroxide solution. Evaporation of the organic layer gave an oil which was chromatographed (silica, 4:1 hexanef ethyl acetate) to give the desired product, (51.86g). Found: C,62.64; H,5.31; Cs 1

H

15 Br0 requires: C,61.85; H,5.19%.

'H-NMR (CDCl 3 8= 2.30(s,3H), 2.40(s,3H), 5.00(s,2H), 6.60(d,1H), 7.30-7.50(m,6H) ppm.

WO 93/02050 PCT/EP92/01625 -83- PREPARATION 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 11 4-(1-[4-Isobutvlphenyl1ethoxy)benzovl 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.

I

1 1 i i WO 93/02050 PCT/EP92/01625 -82- 4-Benzvloxv-2,3-dimethvlbenzoic acid A solution of the product of part (33.8g) in tetrahydrofuran (THF) (500ml) at -78 0 C was treated with n-butyllithium (48.4ml of a 2.5M solution in hexane). After stirring for 30 minutes at -78 0 C an excess of finely powdered solid carbon dioxide was added and the reaction allowed to warm to room temperature. The THF was removed in vacuo end the residue partitioned between ethyl acetate and 2N hydrochloric acid. The organic layer was washed with brine, dried (MgSO4) and then evaporated to a pink solid. Recrystallisation from ethyl acetate gave the desired compound, (18.8g), m.p. 164-166 0

C.

Found: C,74.87; H,6.21; C, 1

H

1 6 0 3 requires: C,74.98; H,6.29%.

1 H-NMR (CDC1 3 6= 2.10(s,3H), 2.40(s,3H), 5.10(s,2H), 6.95(d,1H), 7.30-7.50(m,5H), 7.60(d,lH) ppm.

4-Benzvloxv-2.3-dimethvlbenzovl chloride The product of part (2.0g) was suspended in dichloromethane (10ml) and treated with oxalyl chloride (1.3ml) and dimethylformamide (DMF) (2 drops). After stirring overnight the homogeneous solution was evaporated to give a white solid which was azeotroped three times with toluene to give the title compound as a white powder (2.24g). This material was used immediately.

WO 93/02050 PCT/EP92/01625 -84- PREPARATION 12 l-(4-n-Propylphenyl)butan-l-ol A solution of 4-n-propylbenzaldehyde (7.4g) in diethyl ether (60ml) was cooled to 0oc and treated with a solution of n- -p'ylmagnesium chloride in diethyl ether (27.5ml). The reaction was stirred overnight, diluted with diethyl ether and quenched with saturated aqueous ammonium chloride solution. The organic layer was separated, washed with saturated aqueous ammonium chloride solution and dried (MgSO 4 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).

'H-NMR (CDC 3 6= 1.00(m,6H), 1.20-1.40(m,2H), 1.70(q,2H), 1.75-1.90(m,3H), 2.60(t,2H), 4.60(m,1H), 7.10(d,2H), 7.30(d,2H) ppm.

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

IH-NMR (CDC1 3 6= 1.25(t,3H), 1.55(d,3H), 2.65(q,2H), 4.90(q,IH), 7.20(d,2H), 7.35(d,2H) ppm.

L

a 1 1 J~ 11 WO 93/02050 PCT/EP92/01625 PREPARATION 14 4-n-Propylbenzvl alcohol A solution of 4-n-propylbromobenzene (10g) in THF (100ml) at -78°C was treated with n-butyllithium (35ml of a 1.6M solution in hexane). After stirring for 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 (MgSO 4 and evaporated to an oil. Flash chromatography (silica, 3:1 hexane/ethyl acetate) gave, after evaporation of the appropriate fractions, the desired product as a colourless oil, (2.7g).

PREPARATION S) 2-Methvlpropyllphenyl ethanol A solution of 4-isobutyrylacetophenone (10.0g) in methanol (50ml) was cooled to 0 C and treated portionwise with sodium borohydride (3.23g). After stirring overnight at room temperature the reaction was quenched with IN hydrochloric acid (50ml) and ethyl acetate (100ml) added. The organic layer was separated, dried (MgSO 4 and evaporated to give the title compound as a clear oil, (10.02g), m/z 178(M+). Found: C,79.69; H,9.90; C 1 2 HiO 8 .1/7 120 requires: C,79.68; H,10.19%.

IH-NMR (CDC1 3 8= 0.90(d,6H), 1.50(d,3H), 1.85(m,1H), 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 1 H-NMR (CDC1 3 6= 1.45(d,3H), 2.25(s,br,1H), 4.85(q,1H), 7.20(d,lH), 7.40(d,1H), 7.45(s,1H) ppm.

WO 93/02050 PCT/EP92/01625 -86- PREPARATION 17 (R)-1-(4-[2-Methylproovylphenvl)ethanol Ethanoic acid (R,S)-l-(4-r2-methylpropyl1phenyl)ethyl ester A solution of the product of Preparation 15 in dichloromethane (40ml) at 0 C was treated with dry pyridine (2.5ml) followed by distilled acetyl chloride (2.2ml). After stirring overnight at room temperature the reaction mixture was filtered, silica (lOg) added to the filtrate and the mixture evaporated to dryness. Column chromatography (silica, 12:1 hexane/ethyl acetate) gave, after evaporation of the appropriate fractions, the desired compound as a clear oil, (2.3g).

1H-NMR (CDC1 3 6= 0.90(d,6H), 1.55(d,3H), 1.85(m,lH), 2.05(s,3H), 2.45(d,2H), 5.85(q,lH), 7.15(d,2H), 7.25(d,2H) ppm.

(R)-1-(4-r2-Methylpropyl1phenv1)ethanol A suspension of the product of part (3.0g) in pH7 phosphate buffer (100ml) was treated with SAM II lipase (trade mark) (Fluka Chemicals Limited) and the mixture stirred vigorously for 2 days at room temperature. The mixture was extracted with ethyl acetate (100ml), the combined organic layers dried (MgSO 4 and evaporated. Column chromatography (silica, 9:1 hexane/ethyl acetate) first gave, after combination and evaporation of the appropriate fractions, ethanoic acid (S)-l-(4-[2-methylpropyl]phenylethyl ester, (1.47g). Further elution gave the title compound as a clear oil which crystallised to provide white needles, (l.04g), m.p. 37-38 0 C, [a]o 32.30 (c 2.7 in methanol).

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

WO 93/02050 PCT/EP92/01625 -87- PREPARATION 18 (S)-l-(4-r2-Methylpropvllphenvl)ethanol Ethanoic acid (S)-1-(4-[2-methylpropyl]phenylethyl ester (see Preparation 17(b)) (1.2g) was treated with a iN solution of sodium hydroxide in absolute ethanol After stirring overnight at room temperature the solvent was evaporated and the residue chromatographed (silica, 4:1 hexane/ethyl acetate) to give the title compound as a clear oil, (0.59g), m.p. 34 0 C, [ao] 32.70 (c 2.7 in methanol).

H-NMR (CDC1 3 8= 0.90(d,6H), 1.50(d,3H), 1.85(m,H) 2.50(d,2H), 4.85(q,1H), 7.15(d,2H), 7.30(d,2H) ppm.

PREPARATION 19 c-Cyclopentyl-4-n-propvlbenzvl alcohol A solution of 4-n-propylbenzaldehyde (2.0g) in diethyl ether (20ml) was cooled to 0 0 C 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 (MgSO 4 and evaporated to provide a yellow oil. Flash chromatography (silica, initial elution with 4:1 hexane/ethyl acetate and then with 3:1 hexane/ethyl acetate) gave, after combination and evaporation of the appropriate fractions, the desired compound as a clear oil, (400mg), m/z 218(M+).

'H-NMR (CDC13): g=1.00(t,3H), 1.00-1.60(m,10H), 2.25(sextet,1H), 2.60(m,2H), 4.40(d,2H), 7.30(d,2H), 7.40(d,2H) ppm.

r WO 93/02050 PCr/EP92/01625 -88- PREPARATIONS 20 to 26 The following alkyl bromides were prepared by dissolving the corresponding alcohol (see Preparations 12 to 16 and 19) in dichloromethane and cooling the solution in an ice-bath whilst saturating with dry hydrogen bromide. After stirring the mixture for a short po-riod the reaction was evaporated in vacuo to provide the desired alkyl bromide which was used directly without characterisation.

Preparation No. Alkyl bromide ___1-Bromo-l-(4-n-propylphenyl) butane.

21 ar-Methyl-4-ethylbenzyl bromide.

22 4-n-Propylbenzyl bromide.

23 cg--Methyl-4- (2-methylpropyl) benzyl bromide.

24 oe-Methyl-3 ,4-dichlorobenzyl bromide.

c-Cyclopentyl-4-n-propylbenzyl bromide.

26' c-(4-n-Propylpheny -4-n-propylbenzyl ibromide.

For starting material see EP-A-291245.

[1LW III i *4 WO 93102050 PCT/EP92/01625 -89- PREPARATION 27 4- (3-r4- (1-Hvdrctcvethfl ben zovl Iindol-l-vfl)butanoic acid ethyl ester cloG, OSlMe 2 tBu

CH

3 OSlMe 2 tBU

CH

3 a N IOSlMe 2 tBU

(CH

2 3 C0 2

CH

5

CH

3 Iiy

(CH

2 3 00 2

C

2 HS CH 3 7.30-7.50(m,6H) 7.80(d,2H) 7.90(s,1H) 8.23(d,lH) ll.95(s,br,1H) ppm.

WO 93/02050 PCT/EP92/01625 a) 3-(4-rl-(t-Butyrldimithvlsilvloxvlethvlbenzovl I indole The title compound tas prepared by a similar method to that used in Preparation 5 using indole and 4-(1- [t-butyldimethylsilyloxyj ethyl) benzoyl chloride as the starting materials, m/z 380 Found: C,72.79; 11,7.73; N,3.76; C 23

H

29

NO

2 Si requires: C,72.78; H,7.70; N,3.69%.

IH-NMR (CDC1 3 0. 00(s, 3H) 0. 40 3H) 0.95(s,9H), 1.45(d,3H), 4.95(q,lH), 7.30-7.50(m,5H), 7.70(m,1H), 7.80(d,2H), 8.40(m,1H), 9.20(s,br,lH) ppm.

b) 4- (3-r4-(l-rt-Butvldimethvlsilvloxvlethvl)benzovllindol-l-vl)butanoic acid ethyl ester A solution of the product of part (1.70g) in dimethylformamide (20m1) was treated with sodium hydride (2 15mg of a 6Ui; dispersion in mineral oil) After stirring for 1 hour at room temperature ethyl 4-bromobutyrate (O.7m1) was added and stirring was continued for 2 hours. The reaction mixture was diluted with ethyl acetate (50m1) and washed successively with 2N aqueous hydrochloric acid and saturated brine. The organic layer was dried (MgSO 4 and gavt a yellow gum on evaporation of the solvent.

Flash chromatography of this gum (silica, 3:1 hexane/ethyl acetate) followed by collection and evaporation of the appropriate fractions gave the title compound as a clear gum (2.20g), m/z= 494 'H-NMR (CDC1 3 0. 00(s, 6H) 0. 90 9H) l.20(t,3H), l.50(d,3H), 2.20-2.40(m,4H), 4.10(q,2H), 4.30(t,2H), 5.00(q,lH), 7.20-7.40(m,5H), 7.60(s,1H), 7.80(d,2H), 8.35(m,lH) ppm.

I

WO 93/02050 PCT/EP92/01625 -91- 4 r4 -Hdroxveth 1) ben zovl11indo 1- 1- 1) butano ic acid ethyl ester The product of part was dissolved in tetrahydrofuran (lO0mi) and treated with tetra-nbutylammonium fluoride (4.92g) and stirred for 1 hour. The reaction mixture was diluted with ethyl acetate (lO0mi) and~washed with 2N aqueous hydrochloric acid and saturated brine. The organic layer was dried (MgSO 4 filtered and evaporated to a brown gum. Flash chromatography (silica, 98:2 dichioromethane/methanol) gave, after collection and evaporation of the appropriate fractions, the title compound (0.92g) as a clear gum, m/z 380 l1--NMR (CDCl 3 8= l.20(t,3H), l.70(d,3H), 2.20-2.40(m,4H), 4.1O(q,2H), 4.30(t,2H) 5.00(q,H) 7.20-7.60(m,6H) 7.80(d,2H), 8.35(m,1H) ppm.

PREPARATION 28 (1-F4- (2-Methv1propvl) phenvl 1ethoxy)benzovll indol-l-vl) butanoic acid (RS)-4--(1-r4-(2-Methvlp~roipvllphenvllethoxv)benzoic acid ethyl ester Ethyl p-hydroxybenzoate (5.16g) was dissolved in acetone (50m1) and treated with anhydrous potassium carbonate (4.40Og), tetra-n-butylammonium bromide (0.44g) and (R,S)-ce-methyl-4-(2-methylpropyl)benzyI bromide (see Preparation 23) The resultant slurry was stirred overnight at room temperature and filtered. The filtrate was evaporated to give the title compound (13.5g) which was used directly without characterisation.

WO 93/02050 PCT/EP92/01625 -92i (R S) 4- (2-Methvlpropl) phenyl ethoxv)benzoic acid The product of part (13.5g) was dissolved in aqueous ethanol (108ml), treated with 2N aqueous sodium hydroxide (32ml) and heated at 60-70 0 C for minutes. The solvent was evaporated and water added. The mixture was treated with 2N aqueous hydrochloric acid (50ml) and then extracted with ethyl acetate. The combined organic layers were washed with saturated brine and dried (MgSO 4 Removal of the ethyl acetate solvent gave the title compound as a white solid. Trituration with nhexane gave a fine white powder (6.7g).

'H-NMR (CDC1 3 6= 0.95(d,6H), 1.70(d,3H), 1.88(m,lH), 2.51(d,2H), 5.40(q,lH), .6.95(d,2H), 7.17(d,2H), 7.30(d,2H), 8.00(d,2H) ppm.

(S)-4-(1-r4-(2-Methvlpropvl) phenvl ethoxv)benzoic acid. (+)-ephedrine salt The product of part (10g) was dissolved in aqueous ethanol (60ml) and water (60ml) and treated with (+)-ephedrine hemihydrate (5.84g). The mixture was heated under reflux until complete solution was achieved. The reaction was allowed to stand at room temperature overnight. The resulting precipitate was removed by filtration and dried to provide the title compound (5.20g).

-21.9" (c=l in methanol).

O WO 93/02050 PCr/EP92/01625 -93- 'H-NMR (CDCl 3 0. Q90 6H), 1i10(d, 3H), 1.70(d,3H), 1.85(m,lH), 2.45(s,3H), 3.15(m,lH), 5.45(m,2H), 6.88(d,2H), 7.lQ(d,2H), 7.30(m,7H), 7.90(m,2H) ppm.

Chiral HPLC analysis of the product showed it to contain a 95:5 ratio of the enantiomers.

(S)-4-(1-f4-(2-Methylp~ro~vl)Phenyllethoxv)benzoic aLcid I The product of part (4.63g) was treated with 1N aqueous hydrochloric acid and the resultant slurry stirred for 90 minutes. The resultant precipitate was filtered of f and washed with iN aqueous hydrochloric acid then water. The product was dried in vacuo at 500C to give the desired compound as a colourless solid, (2.94g) m.p. 128-131 0 C. (co 20 0 ~51.50 (c=1 in methanol).

Found: C,76.76; H,7.30; N,0.00; C 19

H

22 0 3 requires: C,76.48; H,7.43; N,0.00%.

'H-NMR (CDCl 3 8= 0.95(d,6H), l.70(d,3H), l.88(m,1H), 2.51(d,2H), 5.40(q,lH), 6.95(d,2H), 7.17(d,2H), 7.30(d,2H), 8.00(d,2H) ppm.

(S)-4-(l-r4-(2-Methvlproipvl)iphenvllethoxv)benzovl chloride The product of part (2g) was dissolved in dichioromethane (l0ml) and treated with pyridine (0.60m1) followed by oxalyl chloride (0.64m1). 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 (40m1) added. TheI resultant precipitate was removed by filtration and WO 93/02050 PCT/EP92/01625 -94the filtrate containing the title compound was evaporated to a volume of 10ml and used directly in the next step without characterisation.

(S)-3-(4-rl-(4-r2-Methylpropyl]phenyl)ethoxylbenzovl)indole Indole (715mg) was dissolved in toluene (5ml) and treated with methylmagnesium iodide (2.0ml of a 3M solution in diethyl ether). The resultant yellow solution was stirred for 10 minutes and a solution of (S)-4-(1-(4-(2-methylpropyl)phenyl]ethoxy)benzoyl chloride in toluene (10ml) (the product of part was added. The mixture was stirred at room temperature for 1 hour and then a saturated solution of aqueous ammonium chloride (50ml) was added with vigorous stirring. The mixture was extracted with ethyl acetate (30ml, 40ml and 15ml) and the combined organic layers were dried (MgSO 4 filtered and evaporated to give a brown gum. Flash chromatography (silica, 3:1 hexane/ethyl acetate initially, followed by 1:1 hexane/ethyl acetate) gave, after evaporation of the appropriate fractions, the title compound as a beige solid (1.05g), m.p. 150-152 0 C. Found: C,81.69; H,6.83; N,3.58; C 27

H

27

NO

2 requires: C,81.58; H,6.85; N,3.52%.

'H-NMR (CDC13): 6= 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), 8.45(m,1H), 9.10(s,br,lH) ppm.

1

I

S

WO 93/02050 PCT/EP92/01625 (S)-4-(3-r4-(1-r4-(2-Methvlpropyl) henvllethoxvybenzovllindol-l-yl)butanoic acid ethyl ester A solution of the product of part (500mg) in 2butanone (5ml) was treated with anhydrous potassium carbonate (695mg) and ethyl 4-bromobutyrate (0.23ml). The mixture was heated under reflux overnight, cooled, filtered and the filtrate evaporated to a yellow gum. Flash chromatography (silica, 3:1 hexane/ethyl acetate) gave, after collection and evaporation of the appropriate fractions, the title compound (451mg).

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

(S)-4-(3-r4-(l-r4-(2-Methylpropvl)phenyllethoxv)benzovylindol-l-vl)butanoic acid A solution of the product of part (108mg) in aqueous ethanol (2ml) was treated with six drops of 2N aqueous sodium hydroxide. The mixture was stirred for 90 minutes then water (3ml) was added followed by 2N aqueous hydrochloric acid until the mixture reached pHl. The mixture was extracted with dichloromethane (3 x 10ml) and the combined organic layers were evaporated to give the title compound as a colourless foam (62mg).

This product had identical mass spectroscopy, A optical rotation and 'H-NMR characteristics to the compound of Example 9.

I -m ,u WO 93/02050 PCTIEP92/01625 -96- Pharmacoloaical activity A selection of compounds of the formula was tested in vitro for steroid 5c-reductase inhibitory activity using ventral prostate tissue from male rats according to the procedure outlined on pages 34 to 36 of the specification. The -results are presented in Table 1.

Table 1 Example No. IC 5 0 (nM) 1 2.19 2 1.2 3 2.3 4 56 6.9 6 3.6 7 361 8 0.67 9 1.15 30.2 11 6.3 12 2.8 13 42.5 14 449 16.5 16 2.64 18 207 19 4.76 33 42% inhibition at 100nM 34 47% inhibition at 1000nM i~

P

i WO 93/02050 PCr/EP92/01625 -97- Toxicity The compound of Example 1 was administered orally to mice up to dose of 1000mg/kg and the animal showed normal appearance and behaviour throughout the duration of the study.

Claims (10)

1. A compound of the formula:- (I) or a pharmaceutically acceptable salt thereof, where in Y is Cl-C 6 alkylene optionally substituted by Cl-C 6 alkyl; R is H, OH, halo, C 1 -C 4 alkyl or Cl-C 4 alkoxy; R 1 R 2 R 3 and R 4 are each independently selected from H, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, OH, halo and CF 3 one of R 6 R 7 and Re is a group of the formula: -OCH-Aryl or -CHO-Aryl, and the remainder, together with R 5 and R 9 are each independently selected from H, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, halo and halo (C 1 alkyl; WO 93/02050 PCT/EP92/01625 -99- R 10 is COOH, COOR" or CONR' 2 R'O; R' 1 is a biolabile ester-forming group; R 12 and R 13 are each independently selected from H and C 1 -C 4 alkyl; 1 is H, CI-C 6 alkyl, C 3 -C 7 cycloalkyl or aryl; and "aryl", used in the definitions of R 6 R 7 R' and IR4 means phenyl optionally substituted by Cl-Cs alkyl, C1-C 6 alkoxy, C2-Cs alkenyl, OH, halo, CF 3 halo(C-C6 alkyl) nitro, amino, C 2 -C 6 alkanamido, C 2 -C 6 alkanoyl or phenyl.

2. A compound as claimed in claim 1 wherein Y iz CI-C, alkylene optionally substituted by C1-C 6 alkyl; R is H, OH, halo, Cj-C 4 alkyl or alkoxy; R R R 3 and R 4 are each independently selected from H, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, OH, halo and CF 3 one of R 6 R 7 and R 8 is a group of the f ormula: -OCH-Aryl or -CHO-Aryl, and the remainder, together with R 5 and R 9 are each independently selected from H, CI-C 4 alkyl, C 1 -C 4 alkoxy, halo and halo (C,-C 4 alkyl; R" 0 is COOH, COOR 11 or CONR 12 R'; 2.50(d,2H),

4..85(q,lH),

7.l5(d,2H), 7.30(d,2H) ppm. WO 9302050PCT/EP92/01625 -100- R 11 is a biolabile ester-forming group; R 12 and R 1 3 are each independently selected from H and C 1 -C 4 alkyl; 1' 4 iHC- 6 alkyl, C 3 -C 7 cycloalkyl or ary]; and "aryl", used in the definitions of R R 7 R 8 and R 1 4 means phenyl optionally substituted by Cj-C 6 alkyl, C 1 -C 6 alkoxy, C 2 -C 6 alkenyl, OH, halo, CF 3 halo(Cl-C 6 alkyl) nitro, amino, C 2 -C al~kanamido, C 2 -C 6 alkanoyl or phenyl: with the provisos i) when R 7 is l-(4-(2-methylpropyl)- pheny1) ethoxy, R, R 1 R R Ra and R 9 are all H and Y is -(CH 2 3 that R 10 is not COCH when the compound of the formula is in the racemic form; ii) when R 7 is l-(4-(2-methylpropyl)- phenyl) propoxy or 2, 2-dimethyl-l- (2- methylpropyl)phe-,yl)propoxy, R, Rit p 2 p~ 3 R R R Ra and R 9 are all H and Y is -(CH' 2 3 that R 10 is not COCH or COOC 2 HS when the compound of the formula is in the racemic form; iii) when R 6 is l-(3-(2-methylpropyl)phenyl)- ethoxy, R, R1, R 2 R 4 R 7 R' and R' are all H and Y is -(CH 2 3 that R" 0 is not COOH or COOC 2 H 5 when the compound of the formula is in the racemic form; WO 93/02050 PCr/EP92/0I 625 7 -101- iv) when R 7 is l-(4-(2-methylpropyl)phenyl)- ethoxy, R 5 and R6, are both methyl, R, R 1 R R' iand R' are all H and Y is -(CH 2 3 that R1 0 is not CoOH or COOC 2 H, when the compoun."d of the formula is in the racemic form; v) when R 7 is bis(4-(2-methylpropyl)phenyl)- methoxy, R, R 1 R R R' and R' are all H and Y is (CH 2 3 -1 that R 10 is not COOH; vi) when R 6 is bis(4-(2-methylpropyl)phenyl)- methoxy, R, R 1 ,I R I R R I R 5 1 R R' and R' are all H and Y is (CH 2 3 that R 10 is not COOH; and vii) when R 6 is 4-(2-methylpropyl)phenoxymethyl or 3- (2 -methylpropyl) phenioxymethyl, R, R', R 2 R 7 RI and R 9 are all H and Y is -(CH 2 3 that R 10 is not CC)OH or COOC 2 Hs,. 3. A compound as claimad in claim 1 or 2 wherein R1 0 is COOH or COOR 11 4. A compound as claimed in any preceding claim wherein R 11 is Ct-Cs alkyl. A compound as claimed in any preceding claimn wherein R 10 is COOH. 6. A compound as claimed in any preceding claim wherein Y is Cl-C 6 alkylene; R is H or Cl-C 4 alkyl; R 1 R R 3 and R 4 are each H; one of R, R 7 and R 8 is a group of the formula: WO 93/02050 PCT/EP92/01625 -102- R14 R14 -OCH-Aryl or -CHO-Aryl, and the remainder, together with R 5 and R 9 are each independently selected from H and C)-C 4 alkyl; R 14 is H, Ci-C 4 alkyl, C 4 -C 6 cycloalkyl or phenyl substituted by CI-C 4 alkyl; and "aryl", when used in the definitions of R 6 R 7 and means phenyl optionally substituted by from 1 to 3 substituents each independently selected from Cl-C 6 alkyl and halo. 7. A compound as claimed in claim 6 wherein Y is methylene, propylene, butylene or pentylene; R is H or methyl; R 7 is a group of the formula:- R14 R14 I I -OCH-Aryl or -CHO-Aryl, and R 5 R 6 R 8 and R 9 are each independently selected from H and Cl-C 4 alkyl; R 14 is H, methyl, n-propyl, cyclopentyl or 4-(n-propyl)phenyl; and "aryl" means phenyl optionally substituted by 1 or 2 substituents each independently selected from methyl, ethyl, n-propyl, isobutyl and chlors.

8. A compound as claimed in claim 7 wherein Y is propylene; R is H; R 7 is a group of the formula:- R14 -OCH-Aryl, and R 5 R 6 R 8 and R 9 are each H; (I WO 93/02050 PCT/EP92/01625 -103- R 14 is methyl; and "aryl"' means phenyl, 4-methyiphenyl, 4-ethyiphenyl, 4-(n-propyl)phenyl, 4-isobutyiphenyl or 3,4- dichiorophenyl.

9. A compound as claimed in claim 8 wherein, "aryl" mears 4-isobutylphenyl. A compound as claimed in claim 1 or 2 wherein one of R, R 7 and Re is a group of the f ormula: (C 1 06 alky) '1H -0 (S Aryl and the remainder, together with Y, R, R', R 5 R 9 R 10 R' 1 R1 2 R 13 and "arvl are as def ined in ::iaim 1 or 2. 4 [4 r4 2-Methy lpropy )pheny 1] ethoxy) benzoyl] indol-1-yl) butanoic acid, (S)-4-(3-(4-(l-(4-(2-Methylpropyl)phenyl~ethoxy) benzoyl] indol-1-yl)butanoic acid, (R,S)-4-(2-Methyl-3-(4-(1-(4-(2-methylpropyl)- phenyljethoxy) benzoyl) indol-l-yl)butanoic acid or (S)-4-(2-Methyl-3-(4-(l-(4-(2-methylpropyl)phenyl)- ethoxy)benzoyl)indol-l-yl)butanoic acid: or a pharmaceutically acceptable salt thereof. I I

12. A 3 -(arylmethoxybenzoyl)-indol-1-yl carbonylic and derivative, substantially as hereinbefore described with reference to any one of the Examples.

13. A compound of the formula:- (IV) (VIII) or a base salt thereof; t It [N:\LIBAAIOOZ01:EAR PCT/EP92/01625 WO 93/02050 (XIII) y CH 2 0H (XIN) C0 2 H .fl Q(l~j~) or a base salt thereof; r '04 WO 93/02050 PCT/EP92/01625 (XVIIB) or a base salt thereof; or a base salt thereof; or I I 2 3 4 6 7 i 107 wherein Y, R, R, R 3 R 4 R 5 R 6 R 7 R 8 R 9 and R 1 0 are as defined in claim 1-or 2; R 24 is H or OH; one of R 25 R 26 and R 27 is OH and the remainder of R 25 R 26 and R 27 are as defined in claim 1 or 2 for the remainder of R 6 R 7 and R 8 one of R 28 R 29 and R 3 0 is a j group of the formula:- R 14 I -CH-Z 8 wherein R 1 4 is as defined in claim 1 or 2 and Z 8 is a leaving group, and the remainder o'f R 28 R 29 and R 3 0 are as defined in claim 1 or 2 for the remainder of R 6 R 7 and R 8 and one of R 31 R 32 and R1 3 is a group of I the formula:- f14 R -CH-OH wherein R' 4 is as defined in claim 1 or 2, and the remainder of R 31 R 32 and R 33 are as defined in claim 1 or 2 for the remainder of R 6 R 7 and R 8 with the proviso that for a compound of the formula (XVIII),- when Y is methylene, R is methyl, R 2 is methoxy, R 1 R 3 R 4 R 5 and R 9 are each H, R' and R 27 are each bromo and R 26 is hydroxy, that R1 0 is not I t. I t t -COOH. j 14. A compound of the formula (XXI) or a base salt thereof -as claimed in claim 13 wherein Z 8 is halo, C 1 -C 4 alkanesulphonyloxy or Cl-C S 25 alkylphenylsulphonyloxy. S S C CC *CL 108 A process for the preparation of a compound of the formula: or a pharmaceutically acceptable salt thereof, wherein Y is C 1 -C 6 alkylene optionally substituted by *R is H, OH, halo, C 1 -C 4 alkyl or Cl-C 4 alkoxy; R 2 R 3 and R 4 are each independently selected from H, Cl-C 4 alkyl, Cl-C 4 alkoxy, OH, halo and 10 CF 3 4 4* *4 4 6

44.4 4. 4." 4414, 4 4444 4~ 4 4 44 r*~ 4' C 4 C 4 one of R 6 R 7 and RO is a group of the formula: R 14 R1 -OCH-Aryl or -CHO-Aryl, and the remainder, together with R 5 and R 9 are each independently selected from H, C 1 -C 4 alkyl, CI-C 4 alkoxy, halo and halo (Cl-C 4 alkyl; i WO 93/02050 PCT/EP92/01625 -e- R 1 0 is COOH, COOR 1 or CONR 2 R 13 R 1 is a biolabile ester-forming group; R 12 and R 1 3 are each independently selected from H and C 1 -C 4 alkyl; R 1 4 is H, C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl or aryl; and "aryl", used in the definitions of R 6 R 7 R and R 14 means phenyl optionally substituted by Ci-C 6 alkyl, CI-C 6 alkoxy, C 2 -C 6 alkenyl, OH, halo, CF 3 halo(C-C 6 alkyl), nitro, amino, C 2 -C 6 alkanamido, C 2 -C 6 alkanoyl or phenyl, which comprises, for the preparation of a compound of the formula wherein R' 1 is COOH and Y, R and R 1 to R 9 are as previously defined for a compound of the formula cleavage of an ester of the formula:- R 4 0 R9 R R R2 S 7 R 1 Y R 6 COOR i s (ii) wherein R' 5 is an ester-forming group that may be cleaved to provide a compound of the formula wherein R 10 is COOH and Y, R and R 1 to R 9 are as previously defined for a compound of the formula WO 93/02050 PCT/EP92/0 1625 aw i WO 93/02050- PEP92/01625 for the preparation of a compound of the formula wherein R 10 is COOH and Y, R and R 1 to R 9 are as previously defined for a compound of the formula acidic or basic hydrolysis of a compound of the formula wherein R 10 is CONR"R 1 3 and Y, R, R 1 to R 9 R 12 and R 3 are as previously defined for a compound of the formula for the preparation of a compound of the formula wherein R 10 is COOH and Y, R and R 1 to R 9 are as previously defined for a compound of the formula acidic or basic hydrolysis of a compound of the formula:- R 4 O R 9 R R R2 R 5 Y R R Y R 6 CN (IV) wherein Y, R and R 1 to R 9 are as previously defined for a compound of the formula for the preparation of a compound of the formula wherein R 10 is COOR 1 and Y, R, R 1 to R 9 and R 1 are as previously defined for a compound of the formula esterification of a compound of the formula wherein R 10 is N i I WO 93/02050 PCT/EP92/01625 +2- COOH and Y, R and R 1 to R 9 are as previously defined for a compound of the formula with an alcohol of the formula R"OH wherein R" is as previously defined for a compound of the formula for the preparation of a compound of the formula wherein Y, R and R 1 to R 10 are as previously defined for a compound of the formula alkylation of a base salt of a compound of the formula:- R 4 O R9 R 2 N R s R R 1 H R6 (VIII) wherein R and R 1 to R 9 are as previously defined for a compound of the formula with a compound of the formula Z 3 -Y-COOR 1 or Z 3 -Y-CONR 2 R 13 or with a base salt of a compound of the formula Z 3 -Y-COOH, wherein Y, R 1 R 1 2 and R 13 are as previously defined for a compound of the formula and Z 3 is a leaving group; for the preparation of a compound of the formula wherein R 1 0 is COOH and Y, R and R 1 9 to R 9 are as previously defined for a compound of the formula oxidation of a compound of the formula:- -1 -41 t I WO 93/02050 PCT/EP92/01625 (XIII) wherein Y, R and R 1 to R 9 are as previously defined for a compound of the formula for the preparation of a compound of the formula wherein R 1 0 is COOH and Y, R and R 1 to R 9 are as previously defined for a compound of the formula oxidation of a compound of the formula:- I (X I) or WO 93/02050 PCT/EP92/01625 I CO,2H or a base salt thereof, wherein R 24 is H or OH and Y, R and R 1 to R 9 are as previously defined for a compound of the formula for the preparation of a compound of the formula wherein one of R 6 R 7 and R 8 is a group of the formula:- R14 -OCH-Aryl and the remainder of R 6 R 7 and R', together with Y, R, R 1 to R 5 R 10 R 14 and "aryl" are as previously defined for a compound of the formula reaction of a compound of the formula:- (XVIII) WO 93/02050 PCT/EP92/01625 or a base salt thereof, wherein one of R 25 R 2 6 and R 27 is OH and the remainder of R 25 R 26 and R 27 are as previously defined for the remainder of R 6 R 7 and Re for a compound of the formula and Y, R, R 1 to R 5 R 9 and R 1 0 are as previously defined for a compound of the formula with a compound of the formula:- R 14 Z-CH-Aryl (XIX) wherein R 14 and "aryl" are as previously defined for a compound of the formula and Z 7 is a leaving group; for the preparation of a compound of the formula wherein R 0 is COOR" or CONR 2 R 1 3 one of R 6 R 7 and R B is a group of the formula:- R14 -OCH-Aryl and the remainder of R 6 R 7 and R 8 together with Y, R, R 1 to R 5 R 9 R 11 R 12 R 3 R 1 4 and "aryl" are as previously defined for a compound of the formula reaction of a compound of the formula (XVIII) wherein R 10 is COOR" or CONR 2 R 1 3 Y, R, R to R 5 R 9 R 1 2 and R 1 3 are as previously defined for a compound of the formula and R 25 R 26 and R 27 are as defined in claim 21(h), with a compound of the formula:- R14 HO-CH-Aryl (XX) wherein R 14 and "aryl" are as previously defined for a compound of the formula in the presence of a dehydrating agent; i l 4 WO 93/02050 PCT/EP92/01625 for the preparation of a compount the formula wherein one of R 6 R' ?d R 8 is a group of the formula:- R14 -CHO-Aryl, and the remainder of R 6 R 7 and R 8 together with Y, R, R' to R 5 R 9 R 10 R 1 4 and "aryl" are as previously defined for a compound of the fcrmula reaction of a compound of the formula:- R1 0 (XX) or a base salt thereof, wherein one of R 28 R 29 and R 30 is a group of the formula:- R14 -CH-Z 8 and the remainder of R 2 8 R 29 and R 3 0 are as previously defined for the remainder of R 6 R 7 and R 8 for a compound of the formula Y, R, R 1 to R 5 R 9 R 0 and R 1 4 are as previously defined for a compound of the formula and Zo is a leaving group, aith a base salt of a compound of the formula:- WO 93/02050 PCr/EP92/01625 Aryl-OH (XXII) wh~e,,in "aryl" is as previously defined for a coimpound of the formula or for the preparation of a compound of the f ormnula wherein R" 0 is COOR 1 or CQNR 2 R 3 one of R 6 R 7 ,and R 8 is a group of the formula: and the remainder of R 6 R 7 and R 8 together with Y, R, R' to R 12 R" nd of the formula reaction of a compound of tformula:- -io-r, dene foacmpud RRIN R R5 1 1 ,R~adR 4 aea II 117 with a compound of the formula (XXII) wherein "aryl"' is as previously defined for a compound of the fbrmu:La in'the presence of a I dehydrating agent: any one of said processes to being optionally followed by conversnion of the product of the formula'(I) to I a pharmaceutically acceptable salt thereof. 4, A process as claimed in claim 15 wherein Y is C 1 -'C 6 ajlkylene optionally substituted by. c 1 -C 6 alkyl; R is H, OH, halo, CrC 4 alkyl or C 1 -C 4 alkoxy; R, 2 R 3 and R 4 are each indepe'ndently se1ctcK' from H, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, OH, halo anc' CF 3 -one of 'R R and R 8 i a group o~f the formula:- -OCH-Aryl or -CHO-Aryl, and the remainder,, together with R 5 and R 9 are each independently selected from H, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, halo and halo (Cl-C 4 )alkyl; 111 20 is COOH, COOR" or CONR 2 R" 3 is a biolabile ester-forming group; R. R 1 2 and R 1 3 are each indeper, dently selected from H and CrC 4 alkyl; R 1 4 is H, CI-C 6 alkyl, C 3 -C 7 cycloalkyl or axVl;' C4 g 118 and "aryl", used in the definitions of R 6 R, Re and R' 4 means phenyl optionally substituted by CI-C6 alkyl, C 1 -C 6 alkoxy, C 2 -C 6 alkenyl, -OH, halo, CF 3 halo (CI-C 6 alkyl) nitro, amino, C 2 -C6 alkanaw 1 ido, C 2 -Qs dlkanoyl or phenyl: with the provisos ri) when R 7 is l-(4-(2-methylpropyl)- c1phenyl) ethoxy, R, R 1 R 2 R 3 R 4 R 5 R 6 Re and R 9 are all H and Y is -C 2 3 that 2.1 is not COOH when the compound of the formula is in the racemic form; i) when R 7 is l-(4-(2-methylpropyl)- phenyl)propoxy or 2,2-dimethyl-l-(4-(2- methylpropyl)phenyl)propoxy, R, R 2 R, R 6 Re and R 9 are all H and Y is (CH 2 3 that R'D is not COOH or COOC 2 H, when the compound of the for'.ula is in the racemic form; iii) when R 6 is l-(3-(2-methylpropyl)phenyl)- ethoxy, R, R R R Re -and R' are all H and Y is (CH 2 3 -1 that R' 0 is not COOH or C00C 2 H 5 when the compound of the formula is in the. .:acemic form; )iv) when R 7 is 1- (4 hylpropyl) phenyl) ethoxy, R 5 and Pi e both methyl, R, R, R 2 R 3 R 4 Re and R 9 are all H and Y is -(CH 2 3 that R' 0 is not COCH or COOC 2 H, C t when the compound of the formula is in the racemic form; V) when R 7 is bis(4-(2-methylpropyl)phenyl)- mehot Rt R R, R, R R Re and R 9 are all H and Y is -(CH 2 3 that R' 0 is not oorH; 119 vi) when R 6 is bis(4-(2-methylpropyl)phenyl)-methoxy, R, R 1 R 2 R 3 R 4 R 5 R 6 R 7 R 8 and R 9 are all H and Y is -(CH 2 3 that R 1 0 is not COOH; and vii) when R 6 is 4-(2-methylpropyl)phenoxymethyl or 3-(2- methylpropyl)phenoxymethyl, R, R 1 R 2 R 3 R 4 R 5 R 7 R 8 and R 9 are all H and Y is (CH 2 3 that R 10 is not COOH or COOC 2 H 5 17. A process as claimed in claim 15(a) or 16 where the cleavage is carried out by acidic or basic hydrolysis of a compound of the formula (II). 18. A process as claimed in claim 15(a), 16 or 17 wherein R 15 is C 1 -C 6 alkyl. 19. A process as claimed in claim 17 or 18 where the cleavage is carried out by basic hydrolysis using sodium or potassium hydroxide under aqueous conditions. A process as claimed in claim 15(e) or 16 where the base salt of a compound of the formula (VIII) is a sodium or potassium salt. 21. A process as claimed in claim 15(e), 16 or 20 wherein Z 3 is halo, CI-C 4 alkanesulphonyloxy or C 1 -C 4 alkylphenylsulphonyloxy 22. A process as claimed in claim 21 wherein Z 3 is bromo. 23. A process as claimed in claim 15(h) or 16 where a base salt of a compound of the formula (XVIII) is used. 24. A process as claimed in claim 23 where the base salt is a sodium or potassium salt. 25. A process as claimed in claim 15(h), 16, 23 or 24 wherein Z 7 is halo, C1-C 4 alkanesulphonyloxy or C 1 -C 4 alkylphenylsulphonyloxy. 26. A process as claimed in claim 25 wherein Z 7 is bromo. 27. A process as claimed in claim 15(i), 15(k) or 16 where the dehydrating agent used is a combination of diethyl azodicarboxylate and triphenylphosphine. 28. A process as claimed in claim 15(j) or 16 wherein Z 8 is halo, C 1 -C 4 alkanesulphonyloxy or C1-C 4 alkylphenylsulphonyloxy. S"29. A process as claimed in any one of claims 15 to 28 wherein R 10 is COOH or COOR 11 A process as claimed in claim 29 wherein R 11 is C1-C 6 alkyl. i 30 31. A process as claimed in any one of claims 15 to 26 or 28 wherein R 1 0 is S. COOH. C)2 \A k [N:\LIBAA]00201:EAR -120- 32. A process as claimed in any one of claims 15 to 31 wherein Y is CI-C 6 alkylene; R is H or C 1 -C 4 alkyl; R 1 R R 3 and R 4 are each H; one of R 6 R 7 and R 8 is a group of the formula:- R14 R 14 -OCH-Aryl or -CHO-Aryl, and the remainder, together with R 5 and R 9 are each independently selected from H and C 1 -C 4 alkyl; R 1 4 is H, CI-C 4 alkyl, C 4 -C 6 cycloalkyl or phenyl substituted by C-C 4 alkyl; and "aryl", when used in the definitions of R 6 R 7 and R B means phenyl optionally substituted by from i to 3 substituents each independently selected from CI-Cg alkyl and halo. 33. A process as claimed in claim 32 wherein Y is methylene, propylene, butylene or pentylene; R is H or methyl; R 7 is a group of the formula:- T4 R14 R14 R I -OCH-Aryl or -CHO-Aryl, and R 5 R 6 R 8 and R 9 are each independently a selected from H and C 1 -C 4 alkyl; .t 25 R 1 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 S 30 chloro. cc c C O 'I -121- 34. A process as claimed in any one of claims 15 to 27 or 29 to 31 wherein Y is propylene; R is H; R 2 R 3 and R 4 are each H; R 7 is a group of the formula:- R 14 -OCH-Aryl, and R 5 R 6 R 8 and R 9 are each H; R 14 is methyl; and "aryl" means phenyl, 4-methylphenyl, 4-ethylphenyl, 4-(n-propyl)phenyl, 4-isobutylphenyl or 3,4-dichlorophenyl. A process as claimed in any one of claims 15 to 34 wherein "aryl" means 4-isobutylphenyl. 15 36. A process as claimed in claim 15 or 16 which is used to prepare a compound of the formula wherein one of R 6 R 7 and R 8 is a group of the formula:- S(S) Aryl *,t t ,CC and the remainder, together with Y, R, R 1 R 2 R 3 R 4 R, R R 1 1 R, R 3 and "aryl", are as defined in A L2 .N1 122 37. A process as claimed in claim 15 or 16, in part, which is used to prepare (R,S)-4-(3-[4-(1-[4-(2-Methylpropyl)phenyl]ethoxy)benzoyl]indol-l-yl)butanoic acid, 4-(3-[4-(1-[4-(2-Methylpropyl)phenyl]ethoxy)benzoyl]indol-l-yl)butanoic acid, Methyl-3-[4-(1-[4-(2-methylpropyl)phenyl]ethoxy)benzoyl]indol-l-yl)butanoic acid or 4-(2-Methyl-3-[4-(1-[4-(2-methylpropyl)phenyl]ethoxy)benzoyl]indol--yl)butanoic acid: or a pharmaceutically acceptable salt thereof. 38. A process for the preparation of a pharmaceutical composition which comprises combining a compound of the formula or a pharmaceutically acceptable salt thereof, which has been prepared by a process as claimed in any one of claims 15 to 37 together with a pharmaceutically acceptable diluent or carrier. 39. A process for the preparation of a 3-(arylmethyoxybenzoyl)-indol-l-yl carboxylic acid derivative substantially as hereinbefore described with reference to any one of the Examples. The product of the process of any one of claims 15 to 39. 41. A pharmaceutical composition comprising a compound of the formula or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 1 to 14 or together with a pharmaceutically acceptable diluent or carrier. 42. The use of a compound of the formula or of a pharmaceutically acceptable salt as claimed in any one of claims 1 to 14 or 40 or a composition as claimed in claim 41, for the manufacture of a medicament for inhibiting a steroid 43. The use of a compound of the formula or of a pharmaceutically acceptable salt as claimed in any one of claims 1 to 14 or 40 or a composition as claimed in claim S..41, for the manufacture of a medicament for the curative or prophylactic treatment of C c 4 acne vulgaris, alopecia, seborrhoea, female hirsutism, benign prostatic hypertrophy or t 25 male pattern baldness. 44. The use of a compound of the formula or of a pharmaceutically acceptable S C salt as claimed in any one of claims 1 to 14 or 40 or a composition as claimed in claim 41, for the manufacture of a medicament for the curative or prophylactic treatment of a human prostate adenocarcinoma. 30 45. A method of treatment of a human to inhibit a steroid 5ca-reductase in a human in need of such treatment, which method comprises treating said human with an effective amount of a compound of the formula as claimed in any one of claims 1 to 14 or 40 or a composition as claimed in claim 41.

46. 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 in a human in need of such treatment, which method iN:\LIBAA]00201:EAR 123 comprises treating said human with an effective amount of a compound of the formula (I) as claimed in any one of the claims 1 to 14 or 40 or a composition as claimed in claim 41. Dated 21 October, 1994 Pfizer Inc. Patent Attorneys for the Applicant/Nominated Person SPRUSON FERGUSON It e e4 e as u r* r a* i /.si t ~a~t [NAIBAA]00201:EAR INTERNATIONAL SEARCH REPORT International Applicak-vNo PCT/EP 92/01625 1. CLASSIFICATION OF SUBJECT MATTER (if several classification symbols apply, indicate all) 6 Accrding to International Patent Classification or to both National Classification and IPC C 07 D 209/12 A 61 K 31/405 11. FIELDS SEARCHED inimnum Documentation Serld Doctumentation Searched other than Minimum Documentation to the Extent that such Documents are Included In the Fields Searched2 Ea. DOCUMENTS CONSIDERED TO BE RELEVANT 9 Category o Citation of Document, 11 with indication, where appropriate, of the relevant passage$ 12 Relevant to Claim No.- 3 X European Journal of Medicinal Chemistry Chimica 19 Therapeutica, vol. 10, no. 2, March-April 1975, (Paris, FR), A. ALLAIS et al.: "Recherche d'analgdsiques non narcotiques et d'anti-inflammatoires dans la sdrie des carboxyalcoyl-1 acyl-3 indoles", pages 187-199, see page 188, compound 15602 P,X EP,A,0458207 (FUJISAWA 1,2,12 PHARMACEUTICAL CO., LTD) 27 November 1991 (cited in the application) Special categories of dted documents to1 later document published after the international filing date docuentdefningthegenralstat oftheart hic IsDotor priority date and not in conflict with the application hut W doumet dnnin th geera stae o th in hic isnotcited to understand the priaciple or theory underlying the considered to be of particular relevance invention 'E earlier document hut published on or after the international 'XI document of particular relevance; the claimed invention filing date cannot be considered novel or cannot be considered to IV document which may throw doubts on priority claim(s) or involve to inventive stop which is cited to establish the publication date of another IY document of particular relevance; the claimed invention citation or other special reason (as specified) cannot be considered to involve an inventive step when the document referring to an oral disclosure use, tohibltlon or document is combined with one or more other such docu- Alther means ments, such combination being obvious to a person skilled document published prior to the International filing date but in the art later than the priority date claimed W document member of the same patent family IV. CERTIFICATION :1 Date of the Actual Completion of the International Search Date of Mailling of this International Search Report I 20-08-1992 [International Searching Authority [~EUROPEN PATENT OFFCE F411 PCT/SAJI lo t 61111 Iu iaes) JI P' INTERNATIONAL SEARCH REPORT Box I Oervations where certain claims were found u i r j LihL.. t AL rk- N i NU. PCT/ EP 92/ 01625 nsearchable (Continuation of item I of first sheet) I This international search report has not been established in respect of certain claims under Article 17(2Xa) for the following reasons: 1. Claim Nos.: because they relate to subject matter not required to be searched by this Authority, namely: Remark: Although claims 17 and 18 are directed to a method of treatment of the human/animal body the search has been carried out and based on the alleged effects of the compound/composition. 2. Claims Nos.: because they relate to parts of the international application that do not comply with the prescribed requirements to such an extent that no meaningful international search can be carried out, specifically: 3. Claims Nos.: because they are dependent claims and are not drafted in accordance with the second and third sentences of Rule 6.4(a). Box II Observations where unity of invention is lacking (Continuation of item 2 of first sheet) This International Searching Authority found multiple inventions in this international application, as follows: 1. O As all required additional,search fees were timely paid by the applicant, this international search report covers all searchable claims. 2. As all searchable claims could be searches without effort justifying an additional fee, this Authority did not invite payment of any additional fee, 3. O As only some of the required additional search fees were timely paid by the applicant, this international search report covers only those claims for which fees were paid, specifically claims Nos: 4. No required additional search fees were timely paid by the applicant. Consequently, this international search report is restricted to the invention first mentioned in the claims; it is covered by claims Nos.: Remark on ProeAt O The additional search fees were accompanied by the applicant's protest. No protest accompanied the payment of additional search fees. Form PCT/ISA/210 (continuation of first sheet (July 1992) ANNEX -ON INT TO THE INTERNATIONAL SEARCH REPORT ERNATIONAL PATENT APPLICATION NO. EP 9201625 SA 62241 This annex lists the patent fantulY miembers relating to the patent documents cited in the above-mentioned international search report. The members are as contained in the European Patent Office EDP ile on 11/09/92 The European Patent Office is in no way liable for these particulars which are merely given for the purpose of information. Patent document Publication Patent family Publication cie nsearch report date member(s) date EP-A- 0458207 27-11-9 1 AU-A- 7711691 21-11-91 CN-A- 1056685 04-12-91 Q For more details about this annex :see Official Journal of the European Patent Office, No. 12/8.