[go: up one dir, main page]
More Web Proxy on the site http://driver.im/

CA2112678A1 - Indoles - Google Patents

Indoles

Info

Publication number
CA2112678A1
CA2112678A1 CA002112678A CA2112678A CA2112678A1 CA 2112678 A1 CA2112678 A1 CA 2112678A1 CA 002112678 A CA002112678 A CA 002112678A CA 2112678 A CA2112678 A CA 2112678A CA 2112678 A1 CA2112678 A1 CA 2112678A1
Authority
CA
Canada
Prior art keywords
formula
alkyl
compound
aryl
group
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Abandoned
Application number
CA002112678A
Other languages
French (fr)
Inventor
Julian Blagg
Kelvin Cooper
Peter L. Spargo
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Pfizer Inc
Original Assignee
Individual
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Individual filed Critical Individual
Publication of CA2112678A1 publication Critical patent/CA2112678A1/en
Abandoned legal-status Critical Current

Links

Classifications

    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D209/00Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04Indoles; Hydrogenated indoles
    • C07D209/10Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C07D209/12Radicals substituted by oxygen atoms
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00Drugs for disorders of the urinary system
    • A61P13/02Drugs for disorders of the urinary system of urine or of the urinary tract, e.g. urine acidifiers
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00Drugs for genital or sexual disorders; Contraceptives
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00Drugs for dermatological disorders
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00Drugs for disorders of the metabolism
    • A61P3/06Antihyperlipidemics
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Engineering & Computer Science (AREA)
  • Public Health (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Diabetes (AREA)
  • Hematology (AREA)
  • Obesity (AREA)
  • Urology & Nephrology (AREA)
  • Dermatology (AREA)
  • Endocrinology (AREA)
  • Reproductive Health (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Saccharide Compounds (AREA)

Abstract

The present invention provides compounds of formula (I) and pharmaceutically acceptable salts thereof, wherein X is O, NH, N(C1-C4 alkyl), C1-C4 alkylene, C2-C4 alkenylene or C2-C4 alkynylene, said alkylene, alkenylene and alkynylene groups being optionally substituted by C1-C4 alkyl or aryl; Y is C1-C6 alkylene optionally substituted by C1-C6 alkyl; R is H, OH, halo, C1-C4 alkyl or C1-C4 alkoxy; R1, R2, R3 and R4 are each independently selected from H, C1-C4 alkyl, C1-C4 alkoxy, OH, halo and CF3; one of R6, R7 and R8 is C1-C15 alkyl or a group of the formula -Z(C1-C15 alkyl), -Z(aryl) or -Z(C3-C7 cycloalkyl), said alkyl group being optionally interrupted by O, S(O)q, NH or N(C1-C6 alkyl), and said alkyl group and the alkyl group of said -Z(C1-C15 alkyl) group being optionally substituted by C1-C10 alkoxy, aryl, C3-C7 cycloalkyl or a group of the formula -Z(aryl), and the remainder of R6, R7 and R8 and R5 and R9 are each independently selected from H, C1-C4 alkyl, C1-C4 alkoxy, halo and halo(C1-C4 alkyl); R10 is COOH, COOR11 or CONR12R13; R11 is a biolabile ester-forming group; R12 and R13 are each independently selected from H and C1-C4 alkyl; Z is O, S(O)q, NH or N(C1-C6 alkyl); q is 0, 1 or 2; and ''aryl'' used in the definitions of X, R6, R7 and R8, means phenyl optionally substituted by C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl, OH, halo, CF3, halo(C1-C6 alkyl), nitro, amino, C2-C6 alkanamido, C2-C6 alkanoyl or phenyl: together with pharmaceutical compositions containing, processes for the preparation of and uses of, such compounds.

Description

' `'93~02~1 2 112 ~ 7 8 PCT/EP92/01626 INDOL~S
This invention relates to indole derivatives which have steroid 5o~reductase inhibitory activity.
More particularly this invention relates to indoles, their preparation and their use as testosterone-So~
reductase inhibitors.
The androgen class of steroi~al 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.~. acne ! vulgaris t alopecia, seborrhoea, female hirsutism, benign prostatic hypertrophy and male pattern baldness.
The principal androgen secreted by the testes is testosterone and it is the primary androgen present in male plasma. The principal mediator of androgenic activity in certain organs such as the prostate and sebaceous gland are the 5o~reduced androgens.
Testosterone is therefore the prohormone of 50~
dihydrotestosterone which is formed locally in the above organs by the action of testosterone-So~reductase. The presence of elevated levels of dihydrotestosterone in many disease states has therefore focussed attention on the synthesis of testosterone 5o~reductase inhibitors.
~ Testosterone So~reductase inhibitors may also be r,~ useful in the treatment of human prostate adenocarcinomas.
EP-A-0458207 discloses certain indole derivatives which have testosterone 50~reductase inhibitory activity.

W~93/02051 PCT/EP92~0162fi ~ 6~ -2-The present invention provides compounds of the formula:-X ~ -R7 Rl y and pharmaceutically acceptable salts thereof, wherein X is O, NH, N(C1-C4 alkyl), Cl-C4 alkylene, C2-C4 alkenylene or C2-C4 alkynylene, said alkylene, alkenylene and alkynyléne groups being optionally substituted by Cl-C4 alkyl or aryl;
Y is Cl-C6 alkylene optionally substituted by Cl-C6 alkyl;
R is H, OH, halo, Cl-C4 alkyl or Cl-C4 alkoxy;
Rl, R2~ R3 and R4 are each independently selected from H, Cl-C4 alkyl, Cl-C4 alkoxy, OH, halo and CF3;
one of R6, R7 and RB-is Cl-C1s alkyl or ~ group of the formula -Z(Cl-Cls alkyl), -Z(aryl) or -ZtC3-C7 cycloalkyl), said alkyl group being optionally interrupted by O, S(O)q~ NH or N~C1-C6 alkyl), and said alkyl group and the alkyl group of said -Z(C1-CI5 alkyl) group being optionally su~stituted by Cl-Cl0 alkoxy, aryl,-C3-C7 cycloalkyl or a group of the formula -Z(aryl), and the remainder of R6, R7 and R8 and Rs and R9 are each independently selected from H, C1-C4 alkyl, C~-C4 alkoxy, halo and halo~Cl-C4 alkyl);

~ 93/02~1 PC~/EP92/01626 21~267~
R10 is COOH, COOR11 or CoNRl2R~3i R1l is a biolabile ester-forming group;
R12 and R13 are each independently selected from H and Cl-C4 alkyl;
Z is O, S(O]q~ NH or N(C1-C6 alkyl);
q is O, l or 2;
and "aryl", used in the definitions of X, R6, R7 and R~, means phenyl optionally substituted by C1-C6 alkyl, C1-C6 alkoxy, C2-C6 al~.enyl, OH., halo, CF3, halo(C1-C6 alkyl), nitro, amino, c2-C6 alkanamido, C2-c6 alkanoyl or phenyl.

Alkyl, haloalkyl, alkenyl and alkoxy groups containing three or more carbon atoms and alkanamido and alkanoyl groups containing four or more carbon atoms may be straight- or branched-chain.
The term "halo" means fluoro, chloro, bromo or iodo.
: The term 9'biolabile ester-forming group" is well . understood in medicinal chemistry as meaning a group ~`si which forms an ester which can be readily cleaved in vivo i~ to liberate the corresponding acid of the formula (I~
wherein R10 is COOH. A number of such ester groups are well-known, for example in the penicillin area or in the case of the angiotensin-converting enzyme (ACE) inhibitor ~ntihypertensive agents.

,~
, . .
~.

~, .~
r 'S.~

. ~
:~, ~ 4_ PCT/EP92/0162 Esters of the formula (I) wherein Rl is -CO2(C~-C6 alkyl) are steroid S~reductase inhibitors per se but, in general, where Rl is COORll such compounds are useful as pro-drugs to provide compounds of the formula (I) wherein Rl is COOH in vivo following oral administration. Such esters are also useful as intermediates for the preparation of compounds of the formula (I) wherein Rl 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. t Examples of suitable biolabile ester-forming groups are alkyl (e.g. C~-C6 alkyl), alkanoyloxyalkyl(including alkyl, cycloalkyl or aryl substituted derivatives thereof), arylcarbonyloxyalkyl (including aryl substituted d~rivatives thereof), aryl, arylalkyl, indanyl and haloalkyl: wherein alkanoyl groups have from 2 to 8 carbon atoms and alkyl groups have from 1 to ~
carbon atoms, all of which may be straight- or branched-chain, and aryl means phenyl or naphthyl, both of which may be optionally substituted by Cl-C4 alkyl, Cl-C4 alkoxy or halo.
In addition to Cl-C6 alkyl, specific examples of other biolabile ester-forming groups are benzyl, 1-~2,2-diethylbutyryloxy)ethyl, 2-ethylpropionyloxymethyl, 1-(2-ethylpropionyloxy)ethyl, 1-(2,4-dimethylbenzoyloxy)ethyl, o~benzoyloxybenzyl, l-(benzoyloxy)ethyl, 2-methyl-1-propionyloxy-l-propyl, 2,4,6-trimethylbenzoyloxymethyl, 1-(2,4,6-trimethylbenzoyloxy)ethyl, pivaloyloxymethyl, phenethyl, phenpropyl, 2,2,2-trifluoroethyl, 1- or 2-naphthyl, 2,4-dimethylphenyl, 4-t-butylphenyl and 5-indanyl.
The pharmaceutically acceptable salts of the ~ compounds of the formula (I~ are the acid addition and 3 the base salts thereof.

-2112~78 ~93/02051 PCT/EP92/01626 Suitable acid addition salts are formed from acidswhich form non-toxic salts and examples are the hydrochloride, hydrobromide, hydroiodide, sulphate, bisulphate, phosphate, hydrogen phosphate, acetate, maleate, fumarate, lactate, tartrate, citrate, gluconate, benzoate, methanesulphonate, benzenesulphonate and ~-toluenesulphonate salts.
Suitable base salts are formed from bases which form non-toxic salts and examples are the aluminium, calci~lm, lithium, magnesium, potassium, sodium, zinc and diethanolamine salts.
For a review on suitable salts 5ee Berge et al, J.
Pharm. Sci., 66, l-19 (l97~).

In the above definitions relating to the present invention:

Preferably X is O, NH, C1-C4 alkylene or C2-C4 ~ alkenylene.
¦ More preferably X is O, NH, methylene, ethylene or ethenylene.
Most preferably X is methylene.

Preferably Y is C1-C6 alkylene.
Most preferably Y is propylene.
:J ~ ~ , Preferably R is H or Cl-C4 alkyl.
Most preferably R is H.

Preferably R1, R2, R3 and R4 are each H.
~, , .~ _, . ..

WO93/02~1 ~ ~ PCT/EPg2/016 Preferably one of R6, R7 and RB is -O(C1-C15 alkyl), the alkyl of said -O(C1-C1s alkyl) group being optionally substituted by aryl, and the remainder of R6, R7 and R8 and R5 and R9 are each H.
More preferably one of R6, R7 and R9 is -O5H2(aryl) or : -OCH(C1-C~ alkyl)(aryl) and the remainder of R6, R7 and X~
and Rs and R9 are each H.
:- Most preferably R7 is -OCH(CH3)(aryl) and R5, R6, R~
and R9 are each H.

Preferably R10 is COOH or COOR11.
~. Most preferably R10 is COOH.
',~
Preferably R11 is C1-C6 alkyl.
Most preferably R11 is ethyl.

Preferably Z is O.

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

9 In a preferred aspect of the present invention "aryl" means phenyl optionally substituted by C1-C6 alkyl, C1-C6 alkoxy, halo, CF3, nitro or phenyl and more preferably means phenyl optionally substituted by n-~ propyl, isobutyl, methoxy, chloro, CF3, nitro or phenyl.
.~`-; Yet more preferably "aryl" means phenyl, 4-(n-propyl)phenyl, 4-isobutylphenyl, 4-methoxyphenyl, 2,4-dichlorophenyl, 3,4-dichlorophenyl, 4-tri~luoromethylphenyl, 4-nitrophenyl or 4-phenylphenyl and most preferably means 4-isobutylphenyl.

, . . .

s:~

~93no~ PCT/EP92/01626 _7_ 2 1 ~ 8 A compound of the formula (I) may contain one or ~ore asymmetric carbon atoms and/or one or more alkenyl groups and may therefore exist in two or more stereoisomeric forms. The present invention includes both the individual stereoisomers of the compounds of the formula (I) together with mixtures thereof. Separation of diastereoisomers or cis and trans isomers may be achieved by conventional techniques, e.g. by fractional crystallisation, chromatography or H.P.L.C. of a stereoisomeric mixture of a compound of the formula (I) or a suitable salt or derivative thereof. An individual enantiomer of a compound of the formula (I) may also be prepared from a corresponding optically pure intermediate or by resolution, such as by H.P.L.C. of a racemate using a suitable chiral support or by fractional crystallisation of the diastereoisomeric ~alts formed by I reaction of a racemate with a suitable optically active I acid or base.
¦ Particularly preferred embodiments of the compounds of the formula (I) are ~ (R,S)-4-(-3-t4-(l-t4-(2-methylpropyl)phenyl~ethoxy)-¦ phenylethanoyl]indol-l-yl)butanoic acid and I (S)-4-(3-~4-(l-[4-(2-methylpropyl)phenyl~ethoxy)-i phenylethanoyl]indol-l-yl)butanoic acid:
~ and the pharmaceutically acceptable salts thereof.
I The compounds of formula (I) provided by the , . , . .................. ~,....... .
invention;may be prepared by the following methods:-l) The compounds of the formula (I) wherein R10 is COOHand X, Y, R and R1 to R9 are as previously defined for a compound of the formula (I) may be prepared by cleavage of an ester of the formula:-:~ ' .

WO93~U~1 PCT/EP92/0162~

.ol~

R2 r~ R ....

R1 y COOR

wherein R14 is a suitable ester-forming group and X, Y, R and R1 to R9 are as previously defined for a compound of the formula (I).

;:
A plethora of suitable ester-forming groups that may be cleaved ~o provide the corresponding carboxylic acid are known to the skilled man, see, e.g., T.W.
Greene and P.G. Wuts, "Protective Groups in Organic Synthesis", Wiley-Interscience (2nd edition, lg9l).

Where R14 is an ester-form.ing group that may be removed by hydrolysis, e.g. Cl-C6 alkyl or an alternative biolabile ester-forming group as previously defined (i.e. a compound of the fonmula (Ij wherein R10 is COOR1l), the hydrolysis may be carried out under acidic or basic conditions, e.g.
using an aqueous solution of sither 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.
;

r,`' : `

~93/O~K1 2 1 1 2 S 7 ~ PCT/EP92/01626 _9_ tetrahydrofuran or a C1-C4 alkanol such as methanol.
The hydrolysis is typically carried out at from room temperature to the reflux temperatur~ and preferably is carried out at room temperature. The product is obtained as a base salt which may be-converted to thie carboxylic acid by acidif ication in the work-up procedure.

Where R14 is an ester-forming group that may be removed by reduction, e.g. benzyl, the reduction may be carried out by catalytic hydrogenation using, e.g., palladium-on-charcoal, as the catalyst.

2) The compounds of the formula (I) wherein R10 is COOH
and X, Y, R and R1 to R9 are as previously defined for a compound of the formula (I3 may be prepared by ~ hydrolysis of a compound of the formula (I) wherein - R10 is CoN~12R13 and X, Y, R, R1 to R9, R12 and R13 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 ~o either a suitable mineral acid, e.g. hydrochloric or 3 sulphuric acid, or a suitable inorganic ~ase, e.g.
sodium or potassium hydroxide, at from room temperature to the reflux tempPratur~. When basic hydrolysis conditions are used the product is obtained as a base salt which may be converted to the carboxylic acid by acidification in the work-up procedure.

3) The compounds of the formula (I) wherein R10 is COO~
and X, Y, R and R1 to R9 are as previously defined for a compound of the formula (I) may be prepared by hydrolysis of a compound of the formula:-~6 WO93/02~1 PCT/EP92/016~
q 6~ ~ -10-R4 0 R9 ,12 R~ X ~R7 R2~ R R5 R~
Rl l wherein X, Y, R and R1 to R9 are as previously defined for a compound cf ~he formula (I) and Rls is H or C1-C~ alkyl.

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

~'9 93/02~1 2 ~ ~ 2 ~ ~ 8 PCT/EP92/01626 4) The compounds of the formula (I) wherein R10 is COOH
and X, Y, R and Rl to R9 are as previously de~ined for a compound of the formula (I) may be prepared by hydrolysis of a compound of the formula:-R3 x.~R ,.. ,(IV) R2~r R R5 R6 R1 y CN
.

wherein X, Y, R and Rl to R9 are as previously ~, defined for a compound of the formula (I).
.
The hydrolysis may he carried out under acidic orbasic conditions, e.g. using an aqueous ~olution of either a suitable acid, e.g. hydrochloric or sulphuric acid, or a suitable inorganic base, ~.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 ~s a base salt which may be converted to the carboxylic acid by acidification in the work-up procedure.

~.
; ~
, ~, ,,~

., W093/0205~ ~ ~?,6~ PCT/EP92/0162 . -12-S) The compo~nds of the formula (I) wherein R10 is COOH
and X, Y, R and R1 to R9 are as previously defined for a co~pound of the formula (I) may be prepared by acidic hydrolysis of a compound of the formula:-R~ R7 R1 y r wherein X, Y, R and R1 to R9 are as previouslydefined for a compound of the formula (I) and Rl~ and R17 taken together represent ethylene, said ethylene group being optionally substituted by phenyl or C1-C4 alkyl ~preferably methyl). Preferably R16 and R17 ta~èn together represent -CH2C(CH3) 2- .

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

., .

93/02051 21 ~ 2 6 7 8 PcT/Ep92lol626 The compounds of the formula (I) wherein R10 is CONH2 and X, Y, R and R1 to R9 are as previously defined for a compound of the formula (I) may be prepared by partial hydrolysis of a compound of the formula (IV~
wherein X, Y, R and R1 to R9 are as previously defined for a compound of the formula (I). The hydrolysis may be carried out using concentrated sulphuric acid at from 0OC to room temperature.

The compounds of the formula (I) wherein Rl is COOR
and X, Y, R, R1 to R9 and R1l are as previously defined for a compound of the formula (I) may be prepared by esterification of a compound of the formula (I) wherein Rl is COOH and X, Y, R and Rl to R9 are as previously defined for a compound of the formula (I) with an alcohol of the formula R1lOH
wherein R1l is as previously defined for this method.

The reaction may be carried out under classical esterification conditions such as by using an excess of the alcohol and with acid catalysis, e.g~ by sulphuric acid or p-toluenesulphonic acid, at from room temperature to the reflux temperature. The water generated during the reaction may be removed by azeotropic distillation or by the use of a dehydrating agent or a molecular sieve.
~he esterification may also be carried out ~y reacting the acid with the alcohol in the presence of a dehydrating agent, e.g.
dicyclohexylcarbodiimide or diethylazodicarboxylate/
triphenylphosphine (see O. Mitsunobu, Synthesis, 19~1, 1).

g WO93/U~ PCT/EP92/01626 - 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 n situ with the alcohol of the formula RllOH. An `~ activated ester may be formed by reacting the carboxylic acid with l-hydroxybenzotriazoie in the presence of a suitable dehydrating agent, e.g. l-(3-N,N-dimethylaminopropyl)-3-ethylcarbodiimide, and in a suitable solvent, e.g. dichloromethane, at room temperature. An imidazolide may be formed by ~ reacting the carboxylic a~id with l,l'-; carbonyldiimidazole in a suitable solvent, e.g.
- dichloromethane, at room temperature.

8) The compounds of the formula tI) wherein R10 is COOR~
wherein X, Y, R, R1 to R9 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:-,~
"s ~j X~R

. . R1 y ~r~ coz1 S ~ .

." ~

j.~
r ' ~''~93/02051 2 1 ~ 2 v 7 8 PCT/EP52/016~

wherein X, Y, R and R1 to R9 are as previously defined for a compound of the formula (I) and Z1 is a suitable leaving group, e.g. chloro or bromo, with an alcohol of the formula R11OH wherein R11 is as previously defined for this method.
....
The reaction may be carried out in the presence of an acid acceptor, e.g. pyridine, and in a suitable solvent, e.g. dichloromethane, at from OC to room temperature.
.
9) The compounds of the formula (I) wherein R10 is COOR
1 wherein X, Y, R, R1 to R9 and R11 are as previously ! defined for a compound of the formula ~I) may be , prepared by reaction of a base salt of a compound of ! the formula (I~ wherein R10 is COOH and X, Y, R and to R9 are as previously defined for a compound of the formula (I) (i.e. a car~oxylate base salt) with a compound of the formula R11Z2 wherein R11 is as previously defined for a compound of the formula (I) and Z2 i5 a suitable leaving group, e.g. halo, preferably bromo or iodo, or p-toluenesulphonyloxy.
Preferred base salts of the compounds of the formula (I) for use in this method are the sodium and potassium salts. The reaction ~ay be carried out in a~suitable solvent, e.g. dimethylformamide or tetrahydrofuran, at from room temperature to the reflux temperature.
:
10) The compounds of the.formula (I) wherein Rl~ is CoNR12R13 and X, Y, R, R1 to R9, Rl2 and R13 are as previously defined for a compound of the formula (I) may be prepared by reaction of a compound of the ~-~ formula tI) wherein R10 15 COOH and X, Y, R and R1 to , ~, .

6~ ~
; WO9~1 PCT/EP92/01626 R9 are as previously defined for a compou~d of the formula (I), with an amine of the formula Rl2R13NH
wherein R12 and R13 are as previously defined for this method, in the presence of a dehydrating agent, e.g.
dicyclohexylcarbodiimide. The reaction may be carried out in a suitable organic solvent, e.g.
dichloromethane, at from room temperature to the reflux temperature.

Alternatively the reaction may be carried out by first forming an activated ester or imidazolide derivative of the carboxylic acid, followed by reaction of the activated ester or imidazolide in ~ij situ with the amine of the formula R12R13NH. Suitable procedures for the formation of an activated ester or imidazolide are described in method (7).

11) The compounds of the formula (I) wherein Rl is CoNR12R13 and X, Y, R, R1 to R9, Rl2 and Rl3 are as previously defined for a compound of the formula (I) may be prepared by reaction of a compound of the formula (VI) wherein X, Y, R, R1 to R9 and Z~ are as previously defined for a compound of the formula (VI), with an amine of the formula R12R13NH wherein Rl2 and R13 are as previously defined for this method.
The reaction may~-be carried out in the prèsence of an acid acceptor,~e.g. pyridine, and in a suitable solvent, e.g. dichloromethane, at from 0C to room temperature.

12) The compounds of the formula (I) wherein R10 is CoNR12R13 and X, Y, R, R1 to R9, Rl2 and Rl3 are as previously defined for a compound of the formula (I) may be prepared by reaction of a compound of the W.093/02051 2 I ~ ~ ~ 7 ~ PCT/EP92/01626 formula (II) wherein R14 is a suitable ester-forming group, e~g. C1-C6 alkyl or an alternative biolabile ester-forming group as previously defined (i.e. a compound of the formula (I) wherein Rl is COOR11), or p-nitrophenyl, and X, Y, R and R1 to R9 are as previously defined for a compound of the formula (I), with an amine of the formula R12R13NH wherein R12 and R13 are as previously defined for this method.
The reaction may be carried out in a suitable solvent, e.g. a C1-C4 alkanol, at from room temperature to the reflux temperature. The reaction is usually carried using an excess of the amine~ and in a sealed reaction vessel.

.
13) The compounds of the formula (I) wherein R10 is COOH
or CoNR12R13, X is C1-C4 alkylene, C2-C4 alkenylene or C2-C4 alkynylene, said alkylene, alkenylene and ' alkynylene ~roup~ being optionally substituted by C1-~ C4 alkyl or aryl, and Y, R, R1 to R9, R12 and R13 are Ji as previously defined for a compound of the formula , may be prepared by acidic hydrolysis of a compound of the formula:-R7 ....

R
. COR20 ., ., , W093/02~ PCT/EP92/01626 wherein X, Y, R and Rl to R9 are as previously defined for this method, Rl8 and Rl9 are either each C~-C4 alkyl or when taken together represent c2-c3 alkylene, said alkylene group being optionally substituted by C1-C4 alkyl, and R20 is OH, OR21 wherein R21 is a suitable ester-forming group that may be removed by hydrolysis, e.g. Cl-.C6 alkyl or an alternative biolabile ester-forming group as previously defined, or NR12R13 wherein R~2 and ~13 are as previously defined for this method. The hydrolysis may be carried out using a suitable acid, .
e.g. hydrochloric acid or p-toluenesulphonic acid, in the presence of water.

..
A compound of the formula (VII) may be prepared by first forming the corresponding ketal of a compound of the formula (VIII) wherein X, R and R1 to Rg are as pre~iously defined for this method ~y reacting with the corresponding alcohol under acidic conditions, e.g. see T.W. Greene, "Protective Groups in Organic Synthesis", Wiley-Interscience (1981), followed by N-alkylation of the ketal by a similar procedure to that described in method (14) for alkylation of compounds of the formula (VIII).
, ~ 14) All the compounds of the formula (I) wherein X, Y, R
j and Rl to Rl are as previously defined for a compound of the formula (I) may be prepared by alkylation of a base salt (i.e. the N-deprotonated form) of a compound of the ~ormula:-~S
' ~93/02051 PCT/EP92/01626 2 ~ ~ 8 R4 o R~ ,R8 R3~``X ~R7 R2~q~ R Rs R6 ., ~
wherein X, R and R1 to R9 are as previously defined for a compound of the formula (I), with a compound of the formula Z3-Y-cooR22, Z3-y CoN~12~13 or a b salt of a compound of the formula Z3-Y-CooH, as appropriate, wherein Y. R1~ and R~3 are as previously defined for a com~ound of the formula (I), Z3 iS a leaving group, e.g. halo, preferably chloro, bromo or iodo, methanesulphonyloxy or p-toluenesulphonyloxy, and R22 is a biolabile ester-forming group as previously defined for Rll. The preferred ~ase salts of the compounds of the formula Z3-Y-CooH are the alkali metal and alkaline earth metal salts, e.g. the sodium and potassium salts.
Thé preferred base salts of the compounds of the , formula (VIII) are the alkali metal salts, e.g. the ,~ sodium and potassium salts.
, . . .

~, ~, " , . . ..

W093/02~1 PCT/EP92/01626 ~ 6 ~ -20-The reaction may be performed by initial deprotonation of the compound of the formula (VIII) with a suitable base, e.g. sodium hydride, Eollowed by reaction of the resulting anion with the compound f th formula Z3-Y-cooR22~ Z3-Y-coNRI2R13 or a base salt of the compound of the formula Z3-Y-CooH, as required. The reaction may be carried o~t in a suitable solvent, e.g. N,N-dimethylformamide or tetrahydrofuran, at from 0C to the reflux temperature and preferably at about room temperature. The reaction may also be carried out using potassium carbonate as the base and in 2-butanone as the solven~ at about the reflux temperature of the solvent.

Alternatively the reaction ~ay be carried out under phase transfer conditions where a suitable ba~e is sodium or potassium hydroxide.

Where a compound of the formula (I) wherein Rl is COOH is required the product is obtained as a base salt which may be converted to the carboxylio acid by acidification in the work-up procedure.
-15) The compounds of the formula (I) wherein X is C1-C4 alkylene, C2-C4 alkenylene or C2-C4 alkynylene, said alkylene, alkenylene and alkynylene groups being optionally substituted by C1-C~ alkyl or aryl, and Y, R and R1 to R10 are as previously defined for a compound of the formula (I), may be prepared by acylation of an indole of the formula:-r~ , ~, ~ . . .

~ 93/02~1 21 ~ 2 ~ 78 PCT/EP92/01626 R3~
R2~r R
R1 y ~oR~3 or, where R is OH, a base salt thereof, or of a base salt of an indole of the formula:-R3 ~4 R2~1 ~ R
R~ Y

wherein Y, R and R~ to R4 are as previously definedfor a compo~nd of the for~ula (I) and R23 is either oR24 wherein R24 iS a biolabile ester-forming group as previously dèfined for R11, or is NR12R13 wherein R12 and R13 are as previously defined for a compound of the formula (I), with a compound of the formula:-O
Il ~ ~
Z4~1\ X~ R7 ~ (XI) >=<
~5 ~6 wherein X and Rs to R9 are as previously defined for this method and Z4 is a leaving group, e.g. halo, preferably c~loro, and in the presence of a Lewis acid where R is not OH and optionally in the presence of a Lewis acid where R is OH. Suitable Lewis acids include aluminium chloride and diethylaluminium chloride.

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

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

Where a compound of the formula (I) wherein R is OH
is required the compounds of the formulae (IX) and (X) must be in the form of an enolate salt.
Accordingly'an indole of the formula (IX~ where R is OH or a base salt of an indole of the formula (X) where R is OH should first be treated with one equivalent of a suitable biase, 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 work-up procedure affords the compound of the formula (I) wherein R is OH.
~
.

,Y,~
, !

,. . .
',,j ~'~93/02051 21~ 2 ~ 7 & PCT/EP92/01626 16) The compounds of the formula (I) wherein Rl is COOH, X is 0, NH, N(CI-C,~ alkyl) or C1-C~ alkylene, said alkylene group being optionally substituted by C1-C~
alkyl or aryl, and Y, R and R1 to R9 are as previously defined for a compound of the formula (I), may be prepared by oxidative cleavage of a compound of the formula:-R ~ ~ X ~ R7 R2 ~1 r R R5 R6 wherein Zs is -CH=CH2, -CH=CH(Cl-C4 alkyl), -CH=C(Cl-C4 alkyl) 2 or -CECH and X, Y, R and Rl to R9 are as previously defined for this method.

The reaction may be carried out by ozonolysis or by treatment with aqueous potassium permanganate solution.

i, 17) The compounds of the formula (I) wherein X is 0, R
is either COOR11 or CoNR~2Rl3 and Y, R, R1 to R9, R11, R12 and R13 are as previously defined for a compou~d of the formula (I~, may be prepared by esterification of a compound of the formula:-~, li .,, ~' ,i ~, W093/~2~1 ~16~ PCT/EP92/01626 R~co2H
R1 y Co(oRll or NR12R13~

wherein Y, R, R1 to R4, R11 R12 and R13 previously defined for this method, with a phenol of the formula:-t . ` .
~9 ~R8 HO~27 ~..(XIV) , R5 R~

!.~wherein Rs to R9 are as previously defined for ,...
~d this method. A similar esterification proced~re to any one of those described in method (7) may be used.
., ~
,~
, i, .

~,, ~,;

~93/02~1 ~112 6 7 8 PCT/EP92/01626 18) The compounds of the ~ormula (I) wherein X, Y, R and Rl to Rl are as defined for a compound of the formula (I~ in method (17) may be prepared by reaction of a compound of the formula:-R3~CoZ6 CO(ORl1 or NRl2Rl3) wherein Y, R, R1 to R4, R11 Rl2 and R13previously defined for this method and Z6 iS a leaving group, e.g. chloro or bromo, with a phenol of the formula (XIV) wherein Rs to R9 are as . ~ pre~iously 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 OC to room temperature.

19) Th~ compounds of the formula (I) wherein X is NH or N(Cl-C4 alkyl), R10 is either COORll or CoNRl2Rl3 and Y, R, R1 to R9, R11, R12 and R13 are as previously defined for a compound of the formula (I), may be prepared by reaction of a compound of the formula (XIII) or - an activated ester or imidazolide thereof, wherein R Rl to R4 R11 R12 and Rl3 are as previou51Y
defined for this method, with an amine of the formula:-'' .

WO93/02~1 ~ PCT/EP92/016 R9 ~8 ~R7 .... (X
)=<~
i R5 R6 wherein R24 is H or C1-C4 alkyl and R5 to R9 are as previously defined for this method.

The reaction may be carried out in the presence of a suitable dehydrating agent, e.g.
dicyclohexylcarbodiimide, and in a suitable organic ; solvent, e.g. dichloromethane, at from room temperature to the reflux temperature.

Alternatively the reaction may be carried out by first forming an activated ester or imidazslide derivative of the carboxylic acid, followed by reaction of the activated ester or imidazolide in_situ with the amine. Suitable procedures for the formation of an actiYated ester or imidazolide are described in method (7).

.~

,, ,~

~093/02~1 2 1 ~ 2 6 7 8 PCT/EP92/016~

20) The compounds of the formula (I) wherein X, Y, R and Rl to R10 are as defined for a compound of the formula (I) in method (19) may be prepared by reaction of a compound of the formula (XV) wherein Y, R, Rl to R4, R11, R12 and R1~ are as previously defined for this method and Z6 iS as previously defined for a compound of the formula (XV), with an amine of the formula (XVI) wherein R5 to R9 and R24 are as previously defined for an amine of the formula (XVI). The reaction may be carried out in the presence of an acid acceptor, e.g. pyridine, and~
in a suitable solvent, e.g. dichloromethane, at from 0C to room temperature.

21) The compounds of the formula (I) wherein X is NH or N(C1-C4 alkyl), R10 is COOH or CoNR~2R13 and Y, R, R1 to ; R9, R12 and R13 are as defined for a compound of the formula (I), may be prepared by reaction of a compound of the formula:-,~

~ R3~COOR2s ,, 1 11 1 1 .... (XVII) 7! R2~r~R
" R1 y ,. I
~ CO~ ) , .
~.

~ or a base salt thereof, ~.

., WO93/020~ q~ PCT/EP92/01 wherein Y, R, R1 to R4, R12 and R13 are as previously defined for this ~ethod and R2s is a suitable ester-forming group, e.g. C~-C4 alkyl or p-nitrophenyl, with an amine of the formula (XVI) wherein Rs to R9 are as previously defined for this method and R24 iS
as previously defined for a compound of the formula : (XVI~.
~, The reaction may be carried out in a suitable solvent, e.g. a C1-C4 alkanol, at from room temperature to the reflux temperature.

22) The compounds of the formula (I) wherein R10 i.s COOH
and X, Y, R and R1 to R9 are as previously defined for a compound of the formula ~I), may be prepared J by oxidation of a compound of the formula:--~!

, ~ R4 O R~ ~8 r~ x~ Q~V~

;' wherein X, Y, R and R1 to R~ are as previously defined for a compound of the formula (I). A
suitable oxidising agent for this purpose is chromium trioxide in pyridine.

~'.

~g3n~51 PCT/EP92/01626 211267~
. -29-23~ The compounds of the formula (I) wherein X is C2-C4 alkylene optionally substituted by C1-C~ alkyl or aryl, and Y, R and R1 to R10 are as previously defined for a compound of the formula (I), may be prepared by reduction of a compound of the formula (I) wherein X is C2-C4 alkenylene or C2-C~ alkynylene, said al~enylene or alkynylene group being optionally substituted by Cl-C4 alkyl or aryl, and Y, R and to R10 are as previously defined for a compound of the formula (I).

The reduction may be carried out using hydrogen in the presence of a suitable catalyst, e.g. palladium-on-charcoal, and in a suitable solvent, e.g. ethanol or ethyl acetate, at from room temperature to the reflux temperature and at a pressure of from one to five atmospheres (l.Ol x 105 to 5. 07 X 105 Pa).
,, .
The compounds of the formula (I) wherein one of R6, R7 and RB is a group of the formula -Z(C1-Cl5 alkyl) or -Z (C3-C7 cycloalkyl), the alkyl of said -Z(C1-C15 alkyl) group being optionally substituted by C1-C1o alkoxy, aryl, C3-C7 cycloalkyl or a group of the formula ~Z(aryl), Z i5 0, S, NH or N(Cl-C6 alkyl) and the remainder of R6~ R7 and R8,-R5, R9, X, Y, R, R1 to R~, R10 and "aryln~are as previously defined for a compound of the formula (I), may be prepared by reaction of a compound of the formula:-.

~,.
~, , ,, J

W093/0~ PCT/EPg2/016 ~ X ~ R~ ....
R2 ~ ~ R R26 R27 ! Rl Y

or a base salt thereof, wherein one of RZ7, R28 and ~29 iS a group of theformula -Z7-H wherein Z7 iS 0, S, NH or N(Cl-C6 alkyl) and the remainder of R27, R28 and R29 are as previously defined for this method for the remainder of R6, R7 and R8, R2~ and R30 are as pre~iously defined for this method for R5 and R9 and X, Y, R, Rl to R4 and Rl are as previously defined for this method, with a compound of the formula R3lZ8 wherein R3l is C~ s alkyl or C3-C7 cycloalkyl, as appropriate, said alkyl group being optionally substituted by Cl-C10 alkoxy, aryl, C3-C7 cycloalkyl or a group of the formula -Z(aryl), wherein "aryl" and Z are as previously defined for this method, and Z8 iS a suitable leaving group, e.~. halo, preferably chloro, ~romo or iodo, methanesulphonyloxy or p-toluenesulphonyloxy.
j:

,. ~.

~93/02051 2 ~ 1 2 6 7 8 PCT/EP92/01626 The preferred base salts of the compounds of the formula (XIX) are the sodium and potassium salts.

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

Where Z7 is NH or N(C1-C6 alkyl) a compound of` the formula (XIX) may be reacted with a compound of the formula R31Z8 in the presence of an additional acid ' acceptor, e.g. pyridine, and in a suitable organic solvent, e.g. dichloromethane.

25) The compounds of the formula (I) wherein R10 i5 COOR
or CoNR12R13, one of R6~ R7 and R~ is a group of the ~ formula -O(Cl-Cls alkyl), -O(aryl) or -O(C3-C7 i cycloalkyl), the alkyl of said -O(C1-C~5 alkyl) group ~ being optionally substituted by C1-C10 alkoxy, aryl, ~,.
C3-C7 cycloalkyl or a group of the formula ~(a~yl~, . and the remainder of R6, R7 and R'3, R5, R9, X~ Y, Z, - R, ~1 to R4, R11, R12, R13 and "~ryl" are as previously ,r" defined for a csmpound of the formula (I), may be ~ prepared by reaction of a compound of the formula -. (XIX) wherein one of R27, R28 and R29 is OH and the remainder of R27l R23 and R29 and R26 and R30 , ., . previously defined for a compound of the formula .
'J (XIX) in method (24) and X, Y, R, R1 to R4 and R10 are as previously defined for this method, with a compound of the formula R32oH wherein R32 is C1-C15 alkyl, aryl or C3-C7 cycloalkyl, as appropriate, , .
5~ Pcr/Ep92/ol6~2 said alkyl group being optionally ~:ubstituted by Cl-C10 alkoxy, aryl, C3-C7 cycloalkyl or a group of the formula -Z(aryl), wherein "aryl" and Z are as previously defined for this method, in the presence of a suitable dehydrating agent, e.g.
diethylazodicarboxylate/triphenylphosphine. The reaction may be carried out in a suitable solvent, e.g. tetrahydrofuran, at from room temperature to the reflux temperature.

26) The compounds of the formula (I~ wherein X is CH(Cl- ' C lkyl) Rl is coo~1' or CoNR12R13 and Y, R, R to R , ~ ~1l, R12 and Rl3 are as previously defined for a - compound of the formula (I), may be prepared by alkylation of a base salt of a compound of the ~i formula (I~ wherein X is CH2 and Y, R and Rl to R13 are as previously defined for this method, with a compound of the formula (Cl-C4 alkyl)Z9 wherein Z9 is a suitable leaving group, e.g. halo, preferably chloro, bromo or iodo, methanesulphonyloxy or p-toluenesulphonyloxy.

The preferred base salts of the csmpounds of the formula (I) for use in this method are the sodium and potassium salts.

The reaction may be carried out by first reacting a compound of the formula (Ij wherein X is CH2 with a suitable base, e.g. sodium hydride, and in a suitable solvent, e.g. N,N-dimethylformamide, at ~, , , ~ from 0C to room temperature, followed by in situ ¦ alkylation of the base salt formed with a compound of the formula (C~-C4 alkyl)Z9.

~,-~ 93/02051 21 1~ ~ 7 8 PCT/EP92/01626 All of the above reactions and the preparations of novel starting mater~als used in the preceding methods are conventional and appropriate reagents and reaction conditions for their performance or preparation as well as procedures for isolating the desired products will be well known to those skilled in the art with reference to literatu~e precedents and the Examples and Preparations hereto.

A pharmaceutically acceptable salt of a compound of the formula ~I) may be readily prepared by mixing together solutions of a compound of the for~ula (I) and the desired acid or base, as appropriate. The salt may precipitate from solution and ~e collected by filtration or is recovered by evaporation of the solvent.
~, The compounds of the ~ormula (I) are steroid 5o~
reductase inhibitors and they are therefore useful in the curative or prophylartic treatment of diseases or conditions such as acne vulgaris, alopecia, seborrhoea, female hirsutism, benign prostatic hypertrophy and male pattern baldness.
Certain compounds of the formula (I) are alco useful in the treatment of human prostate adenocarcinomas. ~ -The compounds of the formula (I) may be tested invitro for steroid So~reductase inhibitory activity ,, using prostate tissue from rats or humans.
~, The compounds of the formula (I) may be tested for potency in inhibiting rat steroid 5c~reductase using ventral prostate tissue from male rats. In determining inhibitory potency against rat prostatic 50~reductase the following procedure was employed:-~., ,~
i~
.:

W093/0205~ & PCT/EP92/01626 Rat prostates were minced into small pieces. The tissue was homogenised in Buffer A (20mM sodium phosphate, pH 6.5, buffer containing 0.32M sucrose and lmM dithiothreitol) with a Brinkman Polytron (Kinematica, Luzern, GmBH), and then homogenised with a motor driven (lOOOrpm) Potter Elvehjem (teflon-to-glass) homogeniser. Prostate particles were obtained by centrifugation at 105,000G for 60 minutes. The pellet was washed in 4 volumes of Buffer A and recentrifuged at 105,000G. The resulting pellet was dispersed in Buffer A (lml per g of prostate tissue originally used) with a motor driven Potter Elvehjem homogeniser as described above. The particulate suspension was stored as lml samples at -70C.

The following components, dissolved in Buffer B
(40mM sodium phosphate buffer, pH 6.5~, were added to a test tube: 500~1 of ~3H]-testosterone (l~Ci, lnmol; Du Pont, NEN Research Products, Stevenage, U.K.), 100~1 of 0.5mM NADPH, a compound of the formula (I) dissolved in 5~1 of dimethyl sulphoxide, and Buffer B to give a final reaction volume of lml.
The mixture was warmed to 37C and the reaction started by addition of an aliquot of prostate particulate suspension. The reaction mixture was incubated at 37C for 30 minutes and then quenched by addition with vigorous ~ixing of 2ml of ethyl acetate containing 20~g each of testosterone and 5c~
dihydrotestosterone as carriers. The aqueous and organic layers were separated by centrifugation at 2000G for 10 minutes. The organic layer was transferred to a second test tube and evaporated to dryness under nitrogen. The residue was dissolved in 50-80~1 of absolute ethanol and spotted onto a silica gel 60 F254 TLC plate (E. Merck, Darmstadt, Germany) and developed in chloroform:acetone ~18~:15).

~}

~'~93/02051 21 ~ ~ 6 7 8 PCT/EP92/01626 The radiochemical content in the bands of the substrate (testosterone) and the product (5o~
dihydrotestosterone) was determined with a RITA
Radio TLC Analyser (Raytest Instruments Ltd., Sheffield, U.K.). The percent of recovered radiolabel converted to 5o~dihydrotestosterone was calculated and used to determine enzyme activity.
All incubations were conducted so that no more than 15% of substrate (testosterone) was converted to product .

The experimentally obtained data for a range of inhibitor concentrations was computer fitted to a sigmoidal dose-response curve and concentrations of compound giving 50% inhibition of 50~reductase activity (IC50's) were calculated using a SIGFIT
p~ogram (De Lean, A., Munson, P.J~ and Rodbard, D., American Journal of Physiology~ 235, E97 (1978)).
J
The compounds of the formula ~I) may be tested for potency in inhi~iting human steroid 5~reductase using tissue-from hyperplastic human prostates. In determining inhibitory potency against human prostatic 5o~reductase the following procedure was employed:-,, ; . .
.. . .
~ Frozen human prostate tissue was pulverised in 7~j liquid nitrogen using a steel mortar and pestle.
. The powdered tissue was homogenised in 4 volumes of Gi Buffer A (20mM sodium phosphate, pH 6.5, containing O.32M sucrose, lmM dithiothreitol and 50~M NADPH~
with an Ultra-Turrax (Janke and Kunkel GmBH & Co., ~' Staufen i.BR., Germany). The homogenate was ': centrifuged at 500G for 5 minutes, to remove large particles of tissue, and the supernatant was then centrifuged at lOO,OOOG for l hour. The resulting . i WO93/020~ 36- PCT/EPg2/01 pellet was dispersed in Buffer A (lml per g of prostate tissue originally used) with the Ultra-Turrax homogeniser. This particulate preparation was then filtered through 2 layers of cheesecloth and the filtrate was stored as lml samples at -70C.

., The following components, dissolved in Buffer B
(20mM citrate phosphate buffer, pH 5.2), were added to a test tube: SOO~l of r3H] testosterone (l~Ci, lnmol; Du Pont, NEN Research Products, Stevenage, U.K.), lOO~l of NADPH regeneration system (5mM
NADPH, 50mM glucose 6-phosphate, 5 units/ml glucose 6-phosphate dehydrogenase), a compound of the formula (I) dissolved in 5~1 of dimethyl sulphoxide, and Buffer B to give a final reaction volume o lml.
~1 The mixture was warmed to 37OC and the reaction started by addition of an aliquot of prostate particulate suspension. The reaction mixture was incubated at 37C for 30 minutes and then quenched by addition with vigorous mixing of 2ml of ethyl acetate containing 20~g each of testosterone and 5c~
dihydrotestosterone as carriers. The aqueous and organic layers were separated by centrifugation at 2000G for lO 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).

~", 7i?

" .

':

~093tO2~1 21.~ 2 ~ 7 ~ PCT/EP92/01626 The radiochemical content in the bands of the substrate (testosterone) and the product (5c~
dihydrotestosterone) was determined with a RITA
Radio TLC Analyser (Raytest Instruments Ltd., Sheffield, U.K.). The percent of recovered radiolabel converted to 5o~dihydrotestosterone was calculated and used to determine enzyme activity.
All incu~ations were co~ducted so that no more than lS% of substrate (testosterone~ was converted o product.

The experimentally obtained data for a range of inhibitor concentrations was computer fitted to a sigmoidal dose-response curve and concentrations of compound giving 50% inhibition of 5~reductase activity (ICso's) were calculated using a SI~FIT
prsgram (De Lean, A., Munson, P.~. and Rodbard, D., Ameri~an Journal of Physiology, 235, E97 tl97&)).

The compounds of the formula (I) may be tested for potency in inhibiting steroid 5~reductase activity in human prostate adenocarcinomas using cell lines DUl45 and HPC36M. In determining inhibitory potency against 5~reductase the following procedure was employed:-- .. . . .
Human prostate adenocarcinoma cell lines were grown in Dulbecco's Modified Eagles medium (DMEM) containing 5~ serum. The cells were recovered from the medium by centrifugation, washed in serum free ~MEM and suspended at 5-lO x 106 cells/ml. in serum f ree medium .

~, ç

WOg3/0205l ~ PCT/EPY2/016~6 The following components were added to a test tube:
10~1 of ~3H]-testosterone (l~Ci, 20 pmol) dissolved in ethanol (Du Pont, NEN ~esearch Products, Stevenage, U.K.) and 5~1 of an ethanol solution of a compound of the formula (I). The ethanol was evaporated under nitrogen and the testosterone and the compound redissolved in 0.25ml of serum free medium containing 0.25~mol NADPH. The mixture was warmed to 37C and the reaction started by addition of 0.25ml of cell suspension (1.2-2.5 x 106 cells).
The reaction mixture was incubated at 37C for 2 hours and then quenched by addition w~th vigorous mixing of 1.5ml of ethyl acetate containing 20~g each of testosterone and 5o~dihydrotestosterone as carriers. The aqueous and organic layers were separated by centrifugation at 2000G for 10 minutes.
The organic layer, containing testosterone and its metabolites, was transferred to a ~econd test tube and evaporated to dryness under nitrogen. The residue was dissolved in 50-80~1 of absolute ethanol, spotted onto a silica gel 60 F254 TLC plate (E. Merck, Darmstadt, Germany) and developed in dichloromethane:acetone (185:15)~
.
The radiochemical content in the bands of the substrate (testosterone) and the product (5o~
dihydrotestosterone) was determined wi~h a RITA
Radio TLC Analyser (Raytest Instruments Ltd., Sheffield, U.K.). The percentage of recovered radiolabel converted to S~dihydrotestosterone was calculated and used to determine enzyme activity~
All incubations were conducted so that no more than 15% of substrate (testosterone~ was converted to product.

~.

~93/02~1 21 1 2 6 7 8 PCT/EP92/01626 The experimentally obtained data for a range of inhi~itor concentrations was computer fitted to a sigmoidal dose-response curve and concentrations of compound giving 50% inhibition of 5o~reductase activity (IC50's) were calculated using a SIGFIT
program (De Lean, A., Munson, P.J. and Rodbard D., American Journal of Physiology, 235, E97 (1978)).

For human use, the compounds of the formula (I) can be administered alone but will generally be administered in admixture with a pharmaceutical carrier selected with regard to the intended route of administration and standard pharmaceutical practice. For example, they can be administered orally in the form of tablets containing such . excipients as starch or lactose, or in capsules or . ovules either alone or in admixture with excipients, ~ or in the form of elixirs, solutions or suspensions r~ containing flavouring or colouring agents. They can be injected parenterally, for example, 1 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 gluc~sP to make the solution isotonic with blood.

~7 For oral and parenteral administration to human patients the daily dosage level of the compounds of the formula (I) will be from O.Ol to 2Q mg/kg (in single or divided doses3 and preferably will be from O.l to lOmg/kg except for the treatment of human prostate adenocarcinomas where doses of up to 20mg/kg may be used. Thus tablets or capsules of the compounds will contain from lmg to 0.5g of active compound for administration singly or two or more at a time, as appropriate. The physician in ,,i~, 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 respons~ of the particular patient. The above dosages are exemplary of the average case; ~here can, of course, be individual instances where higher or lower dosage ranges are merited and such are within the scope of this invention.

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

The compounds of the formula (I) may also be administered together with an ~antagonist (e.g.
prazosin or doxazosin), an antiandrogen (e.g.
flutamide) or an aromatase inhibitor (e.g.
atamestane), particularly for the curative or prophylactic treatment of benign prostatic hypertrophy.

Thus the invention further provides:-i) a pharmaceutical composition comprisin~ a compound of the formula (I), or a ~J pharmaceutically acceptable salt thereof, `' together with a pharmaceutically acceptable diluent or carrier;

., .
',' ,, ~93/02051 21 ~ 2 6 7 8 PCT/EP92/01626 ii) a compound of the formula (I), or a pharmaceutically acceptable salt or composition thereof, for use as a medicament;
iii) the use of a compound of the formula (I), or of a pharmaceutically acceptable salt or composition thereof, for the manufacture of a medicament for inhibiting a steroid So~
reductase;
iv) the use of a compound of the formula (I), or of a pharmaceutically acceptable salt or composition thereof, for the manufacture of a medicament for the curative or prophylactic treatment of acne vulgaris, alopecia, seborrhoea, female hirsutism, benign prostatic hypertrophy, male pattern baldness or a human prostate adenocarcinoma;
iv) a ~ethod of treatment of a human to inhibit a -steroid 5~reductase which comprises ~reating said human with an ef~ective amount of a compound of the f ormula (I) or with a pharmaceutically acceptable salt or composition ~,~
thereof;
.-~vi) a metho~ of treatment of a human to cure or prevent acne vulgaris, alope~ia, seborrhoea, female hirsutism, benign prostatic hypertrophy, male pattern baldness or a human prostate adenocarcinoma which comprises treating said ~-.human with an effective amount of a compound of the formula (I) or with a pharmaceutically acceptable salt or composition thereof; and Vii) novel intermediates of the formulae (II) (with the proviso that R14 is not as defined for R11), (IV), (VIII) or a base salt thereof and (XIX) or a base salt thereof.
;:i ,~

~,, }~ 1 ,. ..

W093/02051 ~ PCT/EP92/016 The following Examples illustrate the preparation of the compounds of the formula (I):-(R . S ~ -4 - ( 3- r 4- ( 1- r 4-(2-Methvlpro~Yl)phen~llethoxy)-benzovllindol-l-yl~butanoic acid A solution of (R,S)-4-(3-[4-(l-t4-(2-methylpropyl)phenyl]ethoxy)benzoyl]indol-l-yl)butanoic acid ethyl ester (3.8g) in tetrahydrofuran(THF) ~35ml) and methanol (35ml) was treated with 2N sodium hydroxide solution ~35ml). After stirring at room temperature for ' 2 hours the mixture was cautiously concentrated in vacuo to a volume of about 50ml then cooled in an ice-bath and .acidified with 2N hydrochloric acid solution. The acid phase was extracted with ethyl acetate (lOOml3, the organic extract dried (sodium sulphate) and concentrated in vacuo to provide the title compound as a white foam, I (3.27g)-i EXAMPLES 1 to 18 The following compounds of the general formula:-:!
. O
~X~ R7 ~' (CH2)3cooH
, .

~, or base salts thereof, were prepared by hydrolysis of the corresponding ethyl esters (see Examples l9 to 36) by similar methods to that used in illustrative Method 1.

v ?

~) 93/020~;1 2 1 ~ 2 68 PCI`/EP92/01626 ~, ,~, _ ," ," . N I ~ I
c~l, ~ ~ t--I I I I I - ~ o D ~ ~ ~ ~ N C~l ~ ~ ~D O I ^ ~' S_ E~ o ~ ~ OZ,~

o ~ ~ ~ 11 t ) a) z ~ Q

- !
rT = ~ o I ~ , ~ ~

~ _ ~ ~

WO93/02051 ?~ PCr/EW2NI6 r O N ~ I I N l N ~ N ~ a~ I N ~ E I o I ¦

~ u~ ' ~--u~ ~ ~) ~ I U) l ~ ~ .30 ~N . E ~ ~ = Y ~ E N ~ E ~

~ O C~ Z I E ~ O C~ , N ~

Ir ~ ~

~ I ~ l~o ~ O C~
1~
L~

~Y!D93/02051 2 11 2 G 7 8 PCI/EP92/01626 _ . I
N ~ ~~ I ~ N C) N ~ I

I ~ I ~' t`i ~ ~ N a:) '7i¦ t~GII~ ~J Q ¦ ~ I ~ ~ I O I

¦ C~~ I ~--Uq C I <D Z E N N C
l . _~ ~ ~ IL ~.) (~ _ _~ ~ OD
I_ .~

¦ N I_ + ~ ~
E_ _ _ I

1~
~ - _ I

~ . _ .

W093~02 1 ?,6 (3 PCl`/EP92/016~
q~

. . _ . - . _ I
~ o I ~ , E ~ ~'~ o I ~
~ ~ ~ ~ O ^O N ~ N C~l In ^
Z co ~ Z ~ C~i ~n ~ ~
~ ~ I I co ~n c~ . I g u~ l ~ ~ l o) a ~ ~ C"e :~ s~ ~ N ~ ~0 "o "~ ~ G

~: ~ I ~ z u~ ' ~ ~ I ~Z N 11) 0 0 O ~u~ I E N ~ C Q r~ N ~t .
r ~ 0 E _ .
t X O , .

F
Ul Z _ ~0 93/02051 21 i 2 1~ 7 8 PCI`/EP92/01626 r ~ ~ I ~ _ l c~ o c~ ~i ..... ~ I o O

~ ~ .
I

~ ~n o WO 93/020~ PCI/EP92/016~ ~
,6 _48 _ _ z ~ '`'--~ Q Z ~, ~ ~ 0 c~
un o ~ C~l I I I ~ o '`' I o I

G ~ Z ~ ~ ~ E ~ Z o ~ ~ ~ a I .

. __ _ ~ U~ ~
I . _ .

_ _ X O
~ , . .
~ ~ _ ~ . ~ -~ 93/02051 2 1 1 2 ~ 7 8 PCI`/EP92/01626 --49-- .
~ _ -- .

Z ~ o E I ~ c~ o N o ,~ ,_ ~ ~ ~j ~' o ~o:

u~ ~ O Z ~ I I " ~'Z ~ I I I: I
C I a:~ ~ I O ~O ~Oru~ O XU) I ~ C~ ~ 0 a O I ~ N U~ ~ t~ O~ I N ~ r~

1~
~Z ~ ~
L~ _, _ 6 ' PCr/EPg2/016~

~ - ^ I I I . _~ I ~

~ _ ~ 93/02051 21 1 2 6 7 8 PCI~/EP92/01626 r . _ .
I -o I ~ ~ e~
Z a, ~." a, ~ E Z ~ Q
, ;~ o ~ Q _ a) ~ Co _ , N ~ N ~ ~ _ N N

c ~ ",a) ~ E _,- C7 ~ ~ ",~ ~ ~ E E E c~ E E
6 C I ~ Z c ~ ~ , I ~ Z o o ~n o ~ ~ o ' a~ O ~ 1 ~ o o ~ () O ~ ~_~

~ -- -.

X O C~
~ -Q
U~Z .- oo W0 93/02051 ~ PCI'/EP92~016;~

~ ,S) -4-(3-r4-~l-r4-(2-Methvlprot~vl)~henvll-ethoxY)benzovl~indol-l-yl)butanoic acid ethyl_ester A suspension of sodium hydride (60% dispersion in oil, 716mg) in dry dimethylformamide(DMF) (15ml) at ooc and under a nitrogen atmosphere was treated dropwise with a solution of 4-(3-t4-hydroxybenzoyl]indol-1-yl)butanoic acid ethyl ester (5.24g) in dimethylformamide (30ml).
After stirring for one hour at room temperature a solution of o~methyl-4-(2-methylpropyl)benzyl bromide (3.95g) in dimethylformamide (5ml) was added to the mixture at 0C. The resultant mixture was stirred overnight at room temperature. The reaction was partitioned between lN hydrochloric acid solution (lOOml) and ethyl acetate (200ml). The separated organic layer was washed successively with lN sodium hydroxide solution (lOOml), saturated aqueous brine (lOOml) and then water (lOOml). The organic layer was dried (MgSO4) and :-concentrated in vacuo to provide a yellow oil. Column chromatography (silica, 4.1 hexane/ethyl acetate) provided, after e~aporation of the appropriate fractions, the title compound, (3.8g).

~-~93tO2~1 21 12 6 7 8 PCT/EP92/01626 EXAMPLES 19 to 30 The following compounds of the general formula:-~" ~ R7 r (CH2)3CO2CH2CH3 were prepared by alkylation of the corresponding phenol derivatives (see Preparation 4 and Example 37~ with the corresponding alkyl bromides (see, e.g., Preparations 11 to 13~ by similar methods to that used in illustrative Method 2.

WO 93/020~ ?~6~ PCI~/EP92/01626 r - - ~ - --I N I N ~ - I N
~ U~ O I C l ~
o0~ z ~

a ~ S ~ O ~ z ~

I _ ~
~ 0 E c~l ~ ~n ~
IQ~
I ~- ~ , .

~ ~' ~

~O 93/020~;1 2 1 ~ 2 ~ 7 ~ PCI /EP92/01626 _ , _ _ _ _ I N I N N ~
C~ _ I U~ In I

I I I I ~--I o E
~ ~ .

Z ~ ~ Q ~
a7 I--I I I ~ I I ~I I ~ -~-E ~ ~ E E ~ E c ~n E ~ I
~:Z u~ ~7 o ~ ~n Z o o u~ , .
CD . _ ~C ~ ~ +
.

E _ . .
I _ . _ .

. _ .~

E :
~Z ~ ~
-WO 93/~ PCr/EP92/016 _ - I U~ - I C~

N V 0 ' I I I I ~ I I I I
~ 11 C~ ~
Z I o Z --~ ~' ~ E (~ N ~. CD ~ G

.~n ~ ~I I ~--I _ (~) I I I I I
~ C~ o N I I ~ I ~ E ~n 'n E E
~ C I C~ Z o o ~ ~ ~ Z ~ ~
3 ~- ~ NOO~X~ IC~100~ .
IL ( ) o I ~ ~ ~i ~ ~
. _ ~
+ ~+
~:~
- . - -Q~ . l . . _ _ _ _ _ _ _ X O O
_ _ T _ _ I ~
Ll~Z ~ __ ~ _ .

'~ 93/02051 _57- 21 1 2 6 7 8 PCI~EP92/01626 ~ S ~ ~ ~ S ~

=~

WO 93/02051 ~Q~ PCI`/EP92/016 ~_ ' _ - . ., ~D I
_ _ U~
0 I 0 N cn _ I E

11 0 ~ . Q . ~ ~ E ~, -~, Z C) ~ N ~ ~ E I 2~O ~ N --~ ~ E
_I I I ~ ~ Z~ I ~ I I I I I I
C ~ _ E ~--I c "a~ ~ _ CJ ~
~: Z u~ o o u~ ~ I Z u~ o o ' C~ ` 00 ~ O ~ - o ~ c~ -I ~ ~ . <o m LL (.) I I ~ ~ c~

~ .

._ t~ _ ~T~
O O
. /

~iVO 93/02051 21 12 B 7 ~ PCI`/EP92/01626 . -I I I I I I I
I I _~ ~
_ _ ~ I I I ~--~ ~ E v ~'` U~ . . ~
S ~ I ~` > 0 ~ E
~o --I I I o I --I I I o I
C~ ~ C`~ ~ ~ C~
c ~ ~ ~ s ~ E
z o o o u~ Z u~ o ~ o~ o I tD ) C~l ~ Q I ~) C~ ~
~ . ~

t ~

. ... .

UIZ C~l .

WO93~02051 ~ ~ PCT/EP92/01626 4-~3- r 2-(4- r 1-(4- r 2-Methvl~ro ~ll~h~nYl)ethoxyl-PhenYl~ro~anoyllindol-l-yl)butanoic acid ethyl ester (racemate) ~0~ CH3 ~"~ CH3 r (C~2)3co2cH2cH3 lî ~u CH3 ~t~3J~ ~' CH3 (CH2)3CO2CH2CH3 A solution of (R,S)-4-[3-(4-~ 4-[2-methylpropyl]phényl)ethoxy]phenylethanoyl)indol-l-yl~butanoic acid ethyl ester (see Example 19) (522mg) in DMF (5ml) was treated with sodium hydride (60% dispersion in oil, 43mg) and stirred at room temperature for 10 minutes. Methyl iodide (62~1) was added and stirring was continued for 16 hours at room temperature. The mixture was diluted with ethyl acetate (30ml) and washed with lN
hydrochloric acid solution (30ml) and water (30ml). The organic layer was dried (MgS04) and evaporated to give a yellow oil which was purified by flash chromatography ~silica, 3:1 hexane/ethyl acetate) to give, after evaporation of the appropriate fractions, the title compound as a yellow oil (247mg).

W093/02~1 PCT/EP92/01626 21~2678 H-NMR (CDCl3): ~ = O.90(d,6H), 1.30(t,3H), 1.50(d,2H), 1.55(d,3H), 1.80(m,1H), 2.15(m,2H), 2.24~m,2H), 2.40(m,2H), 4.10(m,4H), 4.38(q,lH), 5.20(q,lH), 6.78(d,2H), 7.05(d,2H), '7.10-7.40(m,7H), 7.62~d,1H), 8.40(m,1H) ppm.

(R.S)-4-(3- r N-(4- r 1- r4-~-MethvlproP~l~ehenyl)-ethoxylPhenvl~carbamovl1indol-1-yl)butanoic acid ethyl ester NH ~ OH

--co2cH2cH3 1) NaH,DMF
2~ S

Br~cH3 O Ç~3 ~NH ~ }0 ~CH3 W~93/020~1 PCT/EP92/016 A solution of 4-(3-~N-(4-hydroxyphenyl)carbamoyl]-indol-1-yl)~utanoic acid ethyl ester (see Preparation 2) (220mg) in ~MF (5ml) was treated with sodium hydride (60%
dispersion in oil, 26mg). After stirring for 30 minutes a solution of o~methyl-4-(2-methylpropyl)benzyl bromide (see Preparation 12) (174mg) in DMF (2ml) was added and stirring continued for 4S minutes. The mixture was diluted with ethyl acetate (30ml) and washed ~uccessively with 2N hydrochlo~ic acid solution (SOml), water (S x 3Oml) and saturated brine (2 x 3Oml).

The organic layer was dried (MgSO~) and evaporated to give a yellow oil (265mg). Flash chromatography (silica, 3:1 hexane/ethyl acetate) gave, after evaporation of the appropriate fractions, the title compound as a gum which crystallised from diethyl ether, (193mg), m.p. 101-103C.
Pound C,7S.S6; H,6.97; N,S-39; C33H38N204 requires:
C,75.30; H,7.28; N,5.32%.

H-NMR (CDCl3): ~ = O.90(d,6H), 1.25(t,3H), 1.60(d,3H), 1.81(m,1H), 2.15(m,2H), 2.30(t,2H), 2.45(d,2H), 4.10(q,2H), 4.20(t,2H), 5.25(q,1H), 6.85(d,2H), 7.10(d,2H), 7.25-7.50(m,7H), 7.55(s,1H), 7.75(s,~H), 8.00(m,1H) ppm.

93/020~ 2 S 7 ~ PCI/EP92/01626 ,4-(3-rN-(4-Benzyloxyphenvl)car-bamo~ ind vl) butanoic acid ethvl ester C~NH ~oCH2~3 NaH,DMF
~, 2) E~r~~CO2c H2cH3 ~NH ~OCH2 ~3 cs)2cH2~H3 W093/02~1 ~ PCT/EP92/016 A solution of 3-(N-[4-benzyloxyphenyl]carbamoyl)-lH-indole (see Preparation 3) (4.0g) in DMF (60ml) was added to a suspension of sodium hydride t60% dispersion in oil, 515mg) in DMF (20ml~ After stirring for 30 minutes at 20C a solution of ethyl 4-bromobutyrate (2.52g) in DMF
(20ml) was added. After stirring for 30 minutes at 20C
the DMF was removed in vacuo. The resultant off-white solid was triturated with ethyl acetate and filtered.
The filtrate was absorbed onto silica gel and chromatographed (silica, 1:1 ethyl acetate/hexane) to give, after evaporation of the appropriate fractions, the, desired product, (850mg), m.p. 124-126C. Found:
C,73.91; H,6.38; N,6.14; C28H28N204 requires: C,73.66;
H,6.18; N,6.13%.
..
lH-NM~ (CDCl3): ~ = 1.20(t,3H), 2.15(m,2H), 2.25(t,2~), 4.10(q,2H), 4.20~t,2H), 5.04(s,2H3, 6.95ld,2H), 7.25-7.50(m,8H), 7.55(d,2H), 7.65(s,1H), 7.75(s,1H), 8.0~(m,lH) ppm.

EXAMPLES 34 to 36 The following compounds of the general formula:-e~x~ -}ocH2{~3 (cH2)3co2cH2cH3 were prepared by similar methods to that used in Example 33 using the corresponding lH-indoles (see Preparations 4 to 6) and ethyl 4-bromobutyrate as the starting materials~
.

~093/02~1 2 ~ 7 `~PCT/EP92/01626 , ~ .-Example m.p.
No. X (C) m/z Analysis/NMR
I . _ _ _ 34 0 96- _ Found: C,73.07; H,5.87;
97 N,3.03;
C29H27N05 requires: C,73.34;
H,5.94; N,3.05%.
H-NM~ (CDCl~ = 1.30 (t,3H), 2.25(m,2H), 2.40 (t,2H), 4.20~q,2H), 4.35 (t,2H), 5.10(s,2H), 7.05 (d,2H), 7.20(d,2H), 7.30-7.50(m,8H), 8.00(s,1H), 8.30(m,1H) ppm.

, _ _ . , CH=CH 83- 468 Found: C,77.00; H,6.11;
ttrans) 84 (M+l)+ N,3.01;
C2~H2sN04 requires: C,77.06;
H,6.25; N,3.00%.
H-NMR (CDCl3): ~ - 1.28 (t,3H), 2.30 (m,2H~, 2.40(m,2H), 4O20 (m,2H), 4.35(m,2H), 5.15 (s,2H), 7.02~d,2H~, 7.28-7.55 (m,9H), 7~65~d,2H), 7.84 (d,lH~, 7.94 (s,lH), 8.55(m,1H~ ppm.

__ _ _ _ WO93/02051 PCT/EP92/016~
~b ``
7 &

, _ -Example m.p.
No. X (C) m/z Analysis/NMR
, . _ 361 CH2 _ _ Found: C,76.22; H,6.29;
N,2.98;
C~gH29NOI requ~res: C, 76. 46;
H,6.42; N,3.07%.
H-NMR (CDC13): ~ - 1c30 (t,3H), 2.20(m,2H), 2.35 (t,2H~, 4.10(s,2H), 4.15 (q,2H), 4.25(t,2H), 5.05 , (s,2~), 6.95(d,2H), 7.25-7.45(m,10H), 7.80(s,lH), 8.45(m,1H) ppm.

1, . .
The reaction mixture work-up was to add lN
hydrochloric acid solution and extract the mixture with ethyl acetate. The organic layer was washed with }:~rine and then water, dried and concentrated in vacuo to provide the required product. The chromatographic work-up used in Example 33 was hence unnecessary.

.~, ~IU )93/02051 21 i 2 6 Y PCI/EP92/01626 4- ( 3- r 3- ( 4-BenzYloxyphenYl ) propano~l 1 indol-1-Yl ) butanoic acid ethyl ester r~ 0 3 co2cH2cH3 H2, Pd/C, '1, CH3CO2C2H5 ~ 1 1 o~3 I CO2CH2~H3 co2~H2cH3 WO93/02051~?~ PCT/EP92/016~

A solution of (E)-4-(3-~3-(4-benzyloxyphenyl)-propenoyl~indol-l-yl)butanoic acid ethyl ester (see Example 35) (lg) in ethyl acetate (25ml) wa~ hydrogenated in the presence of 10% palladium-on-charcoal (250mg) at 4.15 x 105 Pa for 4.5 hours. The reaction was filtered through a cellulose-based filter aid and the filtrate concentrated in vacuo. The residual oil was chromatographed (silica, 40% ethyl acetate/hexane) to first provide, after combination and evaporation of the appropriate fractions, the title compound, (580mg), m.p.
123-5C, m/z-= 442 (M+l)~. Found: C,75.89; H,6.20;
N,3.17; Cz8H2~NO4 requires: C,76.17; H,6.16; N,3.17%.

lH-MMR (d6-DMSO): ~ = 2.00 (quintet,2H), 2.25(t,2H), 2.90(t,2H), 3.12(t,2H), 4.2S(t,2H), 5.05(s,2H), 6.90(d,2H), 7.20-7.48(m,9H), 7.60(d,1H), 8.20(d,1H), 8.40(s,1H), 12.25(s,br,1H) ppm.

Further elution provided, after combination and evaporation of the appropriate fractions, 4-(3-t3-(4-hydroxyphenyl)propanoyl]indol-1-yl)butanoic acid ethyl ester, (24Omg).

lH-NMR (CDCl3): ~ = 1.25(t,3H~, 2.14(quintet,2H), 2.28(t,2H), 3.02(m,2H), 3.12(m,2H), 4.02-4.26(m,4H), 5.62(s,lH), 6.75(d,2H), 7.10(d,2H), 7.22-7.40(m,3H), 7.54(s,1H), 8.40(m,1H) ppm.

!~093/02~1 2 1 1 ~ 6 7 ~ PCT/EP92/01626 ~69-The following Preparations illustrate the preparation of certain starting materials used in the previous Examples:-ILLUSTRATIVE METHOD 34-(3~4-Hvdroxvbenzovllindol-l-yl)butanoic acid ethYl ester A solution of 4-(3-[4-benzyloxybenzoyl3indol-l-yl)butanoic acid ethyl ester (13.4g) in ethyl acetate (300ml) was hydrogenated at 4.15 x lOs Pa in the presence of 10% palladium-on-charcoal (3g3 at room temperature for 4 hours. The catalyst was removed by fi~tration of the reaction through a cellulose-based filter aid and the filtrate was concentrated in vacuo to a pale pink solid.
Trituration with cold diethyl ether gave a white powder, (8.24g).

PREPARATIONS_1 an~d 2 The following compounds of the general formula:-~X~3OH

(CH2)3GO2cH2cH3 were prepared by hydrogenation of the correspondingbenzyl ethers (see Examples 33 and 36) by similar methods to that used in illustrative Method 3.

WO93/02~1 PCT/EP92/016 Prep. m.p.
No. X (~C) m/z Analysis/NMR
_ 1 CH2 _ 366 lH-NMR (CDCl3): ~ =
(M+l)+ 1.25(t,3H), 2.20(m,2H), 2.35(t,2H), 4.10(s,2H), 4.15(q,2H), 4.25(t,2H~, 6.80(d,2H), 7.20(d,2H~, 7.25-7.45(m,3H), 7.75(s,1H), 8.40(m,lH) ppm~

21 NH 193- _ Found: C,68.88; H,5.98;
196 N,7.40;
~2lHz2N204 requires C,68.83; H,6.05; N,7064%.
H-NMR (d6-DMS0~: ~ =
l-O5(t,3H), 2.00(m,2H) r 2.15(t,2H), 3.90(g,2H), 4.05(t,2H), 6.60(d,2H), 7.10(m,2H), 7.25(d,lH), 7.30(d,2H), 7.75(s,1H), 8.05(d,lH), 8.45(s,lH), 8.55(s,lH) ppm.

~ ~ I _~ ~
1 Hydrogenation carried out at 40C.

`-~ 93/02051 21 2 6 7 PCT/FP92/01626 3-(N- r 4-Benz~loxvPhenvllca~bamoyl)-lH-indole ~,COOH ~N~O

H H

A stirred solution of lH-indole-3-carboxylic acid (6.0g) in dichloromethane (lOOml) was treated with 1-hydroxybenzotriazole hydrate (5.Og) and 1-(3-N,N-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (14.2g) followed by triethylamine (21ml) and 4-benzyloxyaniline hydrochloride (9.65g). The mixture was stirred at room temperature for 2 hours, diluted with di~hloromethane and washed successively with water (2 x l90ml), 2N hydrochloric acid (4 x lOOml3 and saturated aqueous brine t~ x 50ml). The organic layer was dried (Na2SO4), filtered and evaporated. During the evaporation the desired product crystallised as a white solid and was collected by filtration (5.89g). The mother liquors were evaporated ~o a pale brown oil and chromatographed (silica, 1:1 ethyl acetate/hexane3 to give a further crop of the desired product, ~995mg), m.p. 211-214C.
Found: C,77.55; H,5.51; N,8.26; C22HlBN202 requires:
C,77.18; H,5.30; ~,8.18%.

IH-NMR (d6-DMSO): ~ = 5.05(s,2H), 6.95(d,2H), 7.10(m,2H), 7.25-7.45(m,6H), 7.60(d,2H), 8.10(s,1H~, 8.15(d,1H), 9.60(s,1H), 11.70(s,br,1H) ppm.

WO93~02~1 PCT/EP92/0162 lH-Indole-3-carbo*ylic acid 4-ben~yloxvphenvl est~

COOH

N
H

1) (cocl)2~cH2cl2~DMF

~3CH2o ~;30H,pyridine,C~CI2 ~3OCH2 ~3 A suspension of lH-indole-3-carboxylic acid (l0g) in dichloromethane (250ml) was cooled to OC and treated wit~ oxalyl chloride (8.9ml) and dimethylformamide (DMF) ~5 drops). After stirring for one hour the clear solution was evaporated and azeotroped three times with dichloromethane to give the acid chloride as a brown crystalline solid.

~ 93~02051 PCT/EP92/01626 2112~78 To a solution of 4-benzyloxyphenol (12.40g) in dichloromethane (200ml) was added pyridine (7.Sml) followed by a solution of the acid chloride prepared above in dichloromethane (200ml). After stirring overnight the mixture was evaporated and partitioned between ethyl acetate (lOOml) and 2N hydrochloric acid (50ml). The separated organic layer was washed with 2N
hydrochloric acid (2 x 50ml) and then saturated brine (2 x 50ml). The organic layer was dried (MgSO4), evaporated and the residue crystallised from dichloromethane to give the title compound as a white solid, (19.57g), m.p. 188- ' 189C.
Found: C,77.07; H,4.77; N,4.05; C22HI7No3 requires:
C,76.95; H,4.99; N,4.08%.

lH-NMR (CDCl3): ~ = 4.90(s,2H), 6.85(d,2H), 7.00(d,2H), 7.05-7.40(m,8H), 7.90(s,lH), 8.00(m,lH), ll.OO(s,br,lH) ppm.

3-(4-Benzvloxvbenzovl)-lH-indole A mechanically stirred solution of indole (30.0g) in sodium dried diethyl ether (450ml) was treated dropwise -with methylmagnesium iodide (8~ml of 3.OM solution in diethyl ether). After stirring for one hour at 20C
4-benzyloxybenzoyl ch~oride (67.3g) was added. Stirring was continued for two hours at 20C and then lN
hydrochloric acid (250ml) added to the mixture and the reaction was allowed to stand overnight. The resulting precipitate was filtered off and triturated with hot ethyl acetate (3 x lOOml) to give the desired compound as a pale pink solid, ~40.9g).

WO 93/02051 PCIIEP92~016s,~

PREPARATIO~S _ 5 and 6 The following indoles of the general formula:-¢~X~OCH

N
H

were prepared from lH-indole and the corresponding acid chlorides tsee Preparations 7 and 8) using similar methods to that used in illustrative Method 4.

~ ` ') 93/0205l PCI /EP92/01626 l _ _ . _ I :
Prep . X ( PC j m/ Z Analysis/NMR
No._ . __.

CH2 - 341 lH-N~ (d6-DMS0) i5 =
5.00(s,2~I~, 6 . 90 (d, 2EI), 7 .10-7 . 40 (m, lOH), 8.10(d,1H), 8.45(s,1H~, 12.00(s,br,1H) ppm.

_ . _ _ _ I
Ç CH--CH ~ (M541), 5 15 (s 2H), 7 . lo-8 . 3 0 (d , 1H) , 8 . 65 (d, lH) ppm.

___ . - . ~

4-Benzvloxv-2.3-dimethylbenzovl chloride 4-Benzyloxy-2,3-dimethylbenzoic acid (2.0g) was suspended in dichloromethane (lOml) and treated with oxalyl chloride (l.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).

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

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

l-(4-n-Pro~vl~henvl~butan-l-ol ~ solution of 4-n-propylbenzaldehyde (7.4g) in diethyl ether (60ml) was cooled to 0C and treated with a 2.OM solution of n-propylmagnesium chloride in diethyl ether (27.5ml). The react~on was stirred overnight, diluted with diethyl ether and quenched with saturated aqueous ammonium chloride solution. The organic layer was separated, washed with saturated aqueous ammonium chloride solution and dried (MgSO4). The organic layer was filtered and evaporated to give a colourless oil which was purified by chromatography (silica, 4:l - hexane/ethyl acetate) to provide, after evaporation of the appropriate fractions, the desired product, (4.06~), m/z = 192(M')-Wo93/02051 2112 ~ 7 8 PCT/EP92/01626 ~H-NMR (CDC13): ~ = l.OO(m,6H), 1.20-1.40(m,2H), 1.70(q,2H), 1.75-l.90(m,3H), 2.60(t,2H), 4.60(m,lH), 7.10(d,2H), 7.30(d,2H) ppm.

(R,S)-1-(4- r 2-Methvl~ropy~ henYl)ethanol A solution of 4-isobutyrylacetophenone (lO.og) in methanol (50ml) was cooled to 0C and treated portionwise with sodium borohydride (3.23g). After stirring overnight at room temperature the reaction was quenched with lN hydrochloric acid (SOml) and ethyl acetate (lOOml) added. The organic layer was separated, dried (MgSO4) and evaporated to give the title compound as a clear oil, (10.02g), m/z = 178(M~). Found: C,79.69;
H,9.90; C12H180.1/7 H20 requires: C,79.68; H,10.~9%.

1H-NMR (cDel3): ~ = O . 9o (d,6H), 1. 50 (d, 3H~, 1. 85 (m ~lH), 2.50(d,2H), 4.85(q,lH), 7.15(d,2H), 7.30(d,2H) ppm.

PREPAR~TIONS 11 to 13 The following alkyl bromides were prepared by dissolving the corresponding alcohol (see, e.gO, Preparations 9 and 10) in dichloromethane and cooling the solution in an ice-bath whilst saturating with dry hydrogen bromide. After stirring the mixture for a ~hort period the reaction was evaporated in vacuo to provide the desired alkyl bromlde which was used directly without characterisation.
._ _ ~ I
Preparation . Alkyl bromide No. . .
11- 1-Bromo-1-~4-n-propylphenyl)butane.
. . _ . . I
12 ~Methyl-4-t2-methylpropyl)benzyl bromide.
131 c~(4-n-Propylphenyl~-4-n-propylbenzyl bromide.
I _ _ , 1 For starting material see EP-A-291245.

WO93/02~1 PCT/EP92/016 Pharmacoloqical activitY

A selection of compounds of the formula (I) was tested in vitro for steroid 5o~reductase inhibitory activity using ventral prostate tissue from male rats according to the procedure outlined on pages 33 to 35 of the specification. The results obtained are`presented in Table l.

Table l ~ ~ -- .
Example No. ~ IC ; n~) lO00 12 ~

In addition, the compound of Example 36 was tested n vitro for steroid 5o~reductase inhibitory activity using tissue from hyperplastic human prostates by the procedure outlined on pages 35 to 37 of the specification. An IC50 value of 89.7nM was obtained for this compound.

Claims (33)

-79-
1. A compound of the formula:- ....(I) or a pharmaceutically acceptable salt thereof, wherein X is O, NH, N(C1-C4 alkyl), C1-C4 alkylene, C2-C4 alkenylene or C2-C4 alkynylene, said alkylene, alkenylene and alkynylene groups being optionally substituted by C1-C4 alkyl or aryl;
Y is C1-C6 alkylene optionally substituted by C1-C6 alkyl;
R is H, OH, halo, C1-C4 alkyl or C1-C4 alkoxy;
R1, R2, R3 and R4 are each independently selected from H, C1-C4 alkyl, C1-C4 alkoxy, OH, halo and CF3;
one of R6, R7 and R3 is C1-C15 alkyl or a group of the formula -Z(C1-C15 alkyl), -Z(aryl) or -Z(C3-C7 cycloalkyl), said alkyl group being optionally interrupted by O, S(O)q, NH or N(C1-C6 alkyl), and said alkyl group and the alkyl group of said -Z(C1-C15 alkyl) group being optionally substituted by C1-C10 alkoxy, aryl, C3-C7 cycloalkyl or a group of the formula -Z(aryl), and the remainder of R6, R7 and R3 and R5 and R9 are each independently selected from H, C1-C4 alkyl, C1-C4 alkoxy, halo and halo (C1-C4 alkyl);
R10 is COOH, COOR11 or CONR12R13;
R11 is a biolabile ester-forming group;
R12 and R13 are each independently selected from H and C1-C4 alkyl;
Z is O, S(O)q, NH or N(C1-C6 alkyl);
q is 0, 1 or 2;
and "aryl", used in the definitions of X, R6, R7 and R8, means phenyl optionally substituted by C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl, OH, halo, CF3, halo(C1-C6 alkyl), nitro, amino, C2-C6 alkanamido, C2-C6 alkanoyl or phenyl.
2. A compound as claimed in claim 1 wherein X is O, NH; C1-C4 alkylene or C2-C4 alkenylene;
Y is C1-C6 alkylene;
R is H or C1-C4 alkyl;
R1, R2, R3 and R4 are each H;
one of R6, R7 and R8 is -O(C1-C15 alkyl), the alkyl of said -O(C1-C15 alkyl) group being optionally substituted by aryl, and the remainder of R6, R7 and R8 and R5 and R9 are each H;
R10 is COOH or COOR11; and "aryl" means phenyl optionally substituted by from 1 to 3 substituents each independently selected from C1-C6 alkyl, C1-C6 alkoxy, halo, CF3, nitro and phenyl.
3. A compound as claimed in claim 2 wherein X is O, NH, methylene, ethylene or ethenylene;
Y is propylene;
R is H;
one of R6, R7 and R8 is -OCH2(aryl) or -OCH(C1-C4 alkyl)(aryl) and the remainder of R6, R7 and R8 and R5 and R9 are each H;
and R10 is COOH or COO(C1-C6 alkyl).
4. A compound as claimed in claim 3 wherein X is methylene;
R7 is -OCH(CH3)(aryl) and R5, R6, R8 and R9 are each H;
R10 is COOH or COOC2H5; and "aryl" means phenyl optionally substituted by 1 or 2 substituents each independently selected from n-propyl, isobutyl, methoxy, chloro, CF3, nitro or phenyl.
5. A compound as claimed in claim 4 wherein R10 is COOH and "aryl" means phenyl, 4-(n-propyl)phenyl, 4-isobutylphenyl, 4-methoxyphenyl, 2,4-dichlorophenyl, 3,4-dichlorophenyl, 4-trifluoromethylphenyl, 4-nitrophenyl or 4-phenylphenyl.
6. A compound as claimed in claim 5 wherein "aryl" means 4-isobutylphenyl.
7. (R,S)-4-(3-[4-(1-[4-(2-Methylpropyl)phenyl]ethoxy)-phenylethanoyl]indol-1-yl)butanoic acid or (S)-4-(3-[4-(1-[4-(2-Methylpropyl)phenyl]ethoxy)-phenylethanoyl]indol-1-yl)butanoic acid: or a pharmaceutically acceptable salt thereof.
8. A pharmaceutical composition comprising a compound of the formula (I), or a pharmaceutically acceptable salt thereof, as claimed in any one of the preceding claims, together with a pharmaceutically acceptable diluent or carrier.
9. A compound of the formula (I), or a pharmaceutically acceptable salt or composition thereof, as claimed in any one of claims 1 to 7 and 8 respectively, for use as a medicament.
10. The use of a compound of the formula (I), or of a pharmaceutically acceptable salt or composition thereof, as claimed in any one of claims 1 to 7 and 8 respectively, for the manufacture of a medicament for inhibiting a steroid 5.alpha.-reductase.
11. The use of a compound of the formula (I), or of a pharmaceutically acceptable salt or composition thereof, as claimed in any one of claims 1 to 7 and 8 respectively, for the manufacture of a medicament for the curative or prophylactic treatment of acne vulgaris, alopecia, seborrhoea, female hirsutism, benign prostatic hypertrophy or male pattern baldness.
12. The use of a compound of the formula (I), or of a pharmaceutically acceptable salt or composition thereof, as claimed in any one of claims 1 to 7 and 8 respectively, for the manufacture of a medicament for the curative or prophylactic treatment of a human prostate adenocarcinoma.
13. A method of treatment of a human to inhibit a steroid 5.alpha.-reductase which comprises treating said human with an effective amount of a compound of the formula (I) or with a pharmaceutically acceptable salt or composition thereof as claimed in any one of claims 1 to 7 and 8 respectively.
14. A method of treatment of a human to cure or prevent acne vulgaris, alopecia, seborrhoea, female hirsutism, benign prostatic hypertrophy, male pattern baldness or a human prostate adenocarcinoma which comprises treating said human with an effective amount of a compound of the formula (I) or with a pharmaceutically acceptable salt or composition thereof as claimed in any one of claims 1 to 7 and 8 respectively.
15. A compound of the formula:- ....(II) ;

....(IV) ;

....(VIII) or a base salt thereof; or ....(XIX) or a base salt thereof:
wherein X, Y, R and R1 to R10 are as defined in claim 1, R14 is an ester-forming group that may be cleaved to provide a compound of the formula (I) wherein R10 is COOH with the proviso that R14 is not as defined for R11 in claim 1, one of R27, R28 and R29 is a group of the formula -Z7-H wherein Z7 is O, S, NH or N(C1-C6 alkyl) and the remainder of R27, R28 and R29 are as defined in claim 1 for the remainder of R6, R7 and R8, and R26 and R30 are as defined in claim 1 for R5 and R9.

16. A process for the preparation of a compound of the formula:- ....(I) , or a pharmaceutically acceptable salt thereof, wherein X is O, NH, N(C1-C4 alkyl), C1-C4 alkylene, C2-C4 alkenylene or C2-C4 alkynylene, said alkylene, alkenylene and alkynylene groups being optionally substituted by C1-C4 alkyl or aryl;
Y is C1-C6 alkylene optionally substituted by C1-C6 alkyl;
R is H, OH, halo, C1-C4 alkyl or C1-C4 alkoxy;
R1, R2, R3 and R4 are each independently selected from H, C1-C4 alkyl, C1-C4 alkoxy, OH, halo and CF3;
one of R6, R7 and R8 is C1-C15 alkyl or a group of the formula -Z(C1-C15 alkyl), -Z(aryl) or -Z(C3-C7 cycloalkyl), said alkyl group being optionally interrupted by O, S(O)q, NH or N(C1-C6 alkyl), and said alkyl group and the alkyl group of said -Z(C1-C15 alkyl) group being optionally substituted by C1-C10 alkoxy, aryl, C3-C7 cycloalkyl or a group of the formula -Z(aryl), and the remainder of R6, R7 and R8 and R5 and R9 are each independently selected from H, C1-C4 alkyl, C1-C4 alkoxy, halo and halo(C1-C4 alkyl);

R10 is COOH, COOR11 or CONR12R13;
R11 is a biolabile ester-forming group;
R12 and R13 are each independently selected from H and C1-C4 alkyl;
Z is O, S(O)q, NH or N(C1-C6 alkyl);
q is 0, 1 or 2;
and "aryl", used in the definitions of X, R6, R7 and R8, means phenyl optionally substituted by C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl, OH, halo, CF3, halo(C1-C6 alkyl), nitro, amino, C2-C6 alkanamido, C2-C6 alkanoyl or phenyl, which comprises, (a) for the preparation of a compound of the formula (I) wherein R10 is COOH and X, Y, R
and R1 to R9 are as previously defined for a compound of the formula (I), cleavage of an ester of the formula:- ....(II) wherein R14 is an ester-forming group that may be cleaved to provide a compound of the formula (I) wherein R10 is COOH and X, Y, R and R1 to R9 are as previously defined for a compound of the formula (I);

(b) for the preparation of a compound of the formula (I) wherein R10 is COOH and X, Y, R and R1 to R9 are as previously defined for a compound of the formula (I), acidic or basic hydrolysis of a compound of the formula (I) wherein R10 is CONR12R13 and X, Y, R, R1 to R9, R12 and R13 are as previously defined for a compound of the formula (I);

(c) for the preparation of a compound of the formula (I) wherein R10 is COOH and X, Y, R and R1 to R9 are as previously defined for a compound of the formula (I), acidic or basic hydrolysis of a compound of the formula:- ....(IV) wherein X, Y, R and R1 to R9 are as previously defined for a compound of the formula (I);

(d) for the preparation of a compound of the formula (I) wherein R10 is COOR11 and X, Y, R1 to R9 and R11 are as previously defined for a compound of the formula (I), esterification of a compound of the formula (I) wherein R10 is COOH and X, Y, R and R1 to R9 are as previously defined for a compound of the formula (I), with an alcohol of the formula R11OH wherein R11 is as previously defined for a compound of the formula (I);

(e) for the preparation of a compound of the formula (I) wherein X, Y, R and R1 to R10 are as previously defined for a compound of the formula (I), alkylation of a base salt of a compound of the formula:- ....(VIII) wherein X, R and R1 to R9 are as previously defined for a compound of the formula (I), with a compound of the formula Z3-Y-COOR11 or Z3-Y-CONR12R13 or with a base salt of a compound of the formula Z3-Y-COOH, wherein Y, R11, R12 and R13 are as previously defined for a compound of the formula (I) and Z3 is a leaving group;

(f) for the preparation of a compound of the formula (I) wherein X is NH or N(C1-C4 alkyl), R10 is COOR11 or CONR12R13 and Y, R, R1 to R9, R11, R12 and R13 are as previously defined for a compound of the formula (I), reaction of a compound of the formula:- ....(XIII) or an activated ester or imidazolide thereof, wherein Y, R, R1 to R4, R11, R12 and R13 are as previously defined for a compound of the formula (I), with an amine of the formula:- ....(XVI) wherein R24 is H or C1-C4 alkyl and R5 to R9 are as previously defined for a compound of the formula (I);

(g) for the preparation of a compound of the formula (I) wherein X, Y, R and R1 to R10 are as defined in claim 16(f), reaction of a compound of the formula:- ....(XV) wherein Y, R, R1 to R4, R11, R12 and R13 are as previously defined for a compound of the formula (I) and Z6 is a leaving group, with an amine of the formula (XVI) wherein R24 is H or C1-C4 alkyl and R5 to R9 are as previously defined for a compound of the formula (I);

h) for the preparation of a compound of the formula (I) wherein one of R6, R7 and R8 is a group of the formula -Z(C1-C15 alkyl) or -Z (C3-C7 cycloalkyl), the alkyl of said -Z(C1-C15 alkyl) group being optionally substituted by C1-C10 alkoxy, aryl, C3-C7 cycloalkyl or a group of the formula -Z(aryl), Z is O, S, NH or N(C1-C6 alkyl) and the remainder of R6, R7 and R8, together with X, Y, R, R1 to R5, R9, R10 and "aryl", are as previously defined for a compound of the formula (I), reaction of compound of the formula:- ....(XIX) or a base salt thereof, wherein one of R27, R28 and R29 is a group of the formula -Z7-H wherein Z7 is O, S, NH or N(C1-C6 alkyl) and the remainder of R27, R28 and R29 are as previously defined for the remainder of R6, R7 and R8 for a compound of the formula (I), R26 and R30 are as previously defined for R5 and R9 for a compound of the formula (I) and X, Y, R, R1 to R4 and R10 are as previously defined for a compound of the formula (I), with a compound of the formula R31Z8 wherein R31 is C1-C15 alkyl or C3-C7 cycloalkyl, said alkyl group being optionally substituted by C1-C10 alkoxy, aryl, C3-C7 cycloalkyl or a group of the formula -Z(aryl), "aryl" and Z are as previously defined for this part (h) and Z8 is a leaving group; or (i) for the preparation of a compound of the formula (I) wherein R10 is COOR11 or CONR12R13, one of R6, R7 and R8 is a group of the formula -O(C1-C15 alkyl), -O(aryl) or -O(C3-C7 cycloalkyl), the alkyl of said -O(C1-C15 alkyl) group being optionally substituted by C1-C10 alkoxy, aryl, C3-C7 cycloalkyl or a group of the formula -Z(aryl), and the remainder of R6, R7 and R8, together with X, Y, Z, R, R1 to R5, R9, R11, R12, R13 and "aryl", are as previously defined for a compound of the formula (I), reaction of a compound of the formula (XIX) wherein one of R27, R28 and R29 is OH and the remainder of R27, R28 and R29 and R26 and R30 are as defined in
claim 16(h) and X, Y, R, R1 to R4 and R10 are as previously defined for this part (i), with a compound of the formula R32OH wherein R32 is C1-C15 alkyl, aryl or C3-C7 cycloalkyl, said alkyl group being optionally substituted by C1-C10 alkoxy, aryl, C3-C7 cycloalkyl or a group of the formula -Z(aryl), wherein "aryl" and Z are as previously defined for a compound of the formula (I), in the presence of a dehydrating agent: any one of said processes (a) to (i) being optionally followed by conversion of the product of the formula (I) to a pharmaceutically acceptable salt thereof.
17. A process as claimed in claim 16(a) 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 17 wherein R14 is C1-C6 alkyl.
19. A process as claimed in claim 17 or 18 where the basic hydrolysis is carried out using sodium or potassium hydroxide under aqueous conditions.
20. A process as claimed in claim 16(e) where the base salt of a compound of the formula (VIII) is a sodium or potassium salt.
21. A process as claimed in claim 16(e) or 20 wherein Z3 is halo, C1-C4 alkanesulphonyloxy or C1-C4 alkylphenylsulphonyloxy.
22. A process as claimed in claim 21 wherein Z3 is bromo.
23. A process as claimed in claim 16(h) where a base salt of a compound of the formula (XIX) 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 16(h), 23 or 24 wherein Z8 is halo, C1-C4 alkanesulphonyloxy or C1-C4 alkylphenylsulphonyloxy.
26. A process as claimed in claim 25 wherein Z8 is bromo.
27. A process as claimed in any one of claims 16 to 26 wherein X is O, NH, C1-C4 alkylene or C2-C4 alkenylene;
Y is C1-C6 alkylene;
R is H or C1-C4 alkyl, R1, R2, R3 and R4 are each H;
one of R6, R7 and R8 is -O(C1-C15 alkyl), the alkyl of said -O(C1-C15 alkyl) group being optionally substituted by aryl, and the remainder of R6, R7 and R8 and R5 and R9 are each H;
R10 is COOH or COOR11; and "aryl" means phenyl optionally substituted by from 1 to 3 substituents each independently selected from C1-C6 alkyl, C1-C6 alkoxy, halo, CF3, nitro and phenyl.
28. A process as claimed in claim 27 wherein X is O, NH, methylene, ethylene or ethenylene;
Y is propylene;
R is H;
one of R6, R7 and R8 is -OCH2(aryl) or -OCH(C1-C4 alkyl)(aryl) and the remainder of R6, R7 and R8 and R5 and R9 are each H;
and R10 is COOH or COO(C1-C6 alkyl).
29. A process as claimed in claim 28 wherein X is methylene;
R7 is -OCH(CH3)(aryl) and R5, R6, R8 and R9 are each H;
R10 is COOH or COOC2H5; and "aryl" means phenyl optionally substituted by 1 or 2 substituents each independently selected from n-propyl, isobutyl, methoxy, chloro, CF3, nitro or phenyl.
30. A process as claimed in claim 29 wherein R10 is COOH and "aryl" means phenyl, 4-(n-propyl)phenyl, 4-isobutylphenyl, 4-methoxyphenyl, 2,4-dichlorophenyl, 3,4-dichlorophenyl, 4-trifluoromethylphenyl, 4-nitrophenyl or 4-phenylphenyl.
31. A process as claimed in claim 30 wherein "aryl" means 4-isobutylphenyl.
32. A process as claimed in any one of claims 16 to 26 which is used to prepare (R,S)-4-(3-[4-(1-[4-(2-methylpropyl)phenyl]ethoxy)-phenylethanoyl]indol-1-yl)butanoic acid or (S)-4-(3-[4-(1-[4-(2-methylpropyl)phenyl]ethoxy)-phenylethanoyl]indol-1-yl)butanoic acid:
or a pharmaceutically acceptable salt thereof.
33. A process for the preparation of a pharmaceutical composition which comprises combining a compound of the formula (I), or a pharmaceutically acceptable salt thereof, which has been prepared by a process as claimed in any one of claims 16 to 32, together with a pharmaceutically acceptable diluent or carrier.
CA002112678A 1991-07-24 1992-07-20 Indoles Abandoned CA2112678A1 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GB9115951.7 1991-07-24
GB919115951A GB9115951D0 (en) 1991-07-24 1991-07-24 Indoles

Publications (1)

Publication Number Publication Date
CA2112678A1 true CA2112678A1 (en) 1993-02-04

Family

ID=10698873

Family Applications (2)

Application Number Title Priority Date Filing Date
CA002112689A Abandoned CA2112689A1 (en) 1991-07-24 1992-07-20 Indoles
CA002112678A Abandoned CA2112678A1 (en) 1991-07-24 1992-07-20 Indoles

Family Applications Before (1)

Application Number Title Priority Date Filing Date
CA002112689A Abandoned CA2112689A1 (en) 1991-07-24 1992-07-20 Indoles

Country Status (20)

Country Link
EP (2) EP0598750A1 (en)
JP (2) JPH06511483A (en)
CN (2) CN1068817A (en)
AU (2) AU655662B2 (en)
BR (1) BR9206306A (en)
CA (2) CA2112689A1 (en)
CZ (1) CZ13694A3 (en)
FI (2) FI940311A0 (en)
GB (1) GB9115951D0 (en)
HU (1) HU9400199D0 (en)
IE (2) IE922387A1 (en)
IL (2) IL102545A0 (en)
MX (1) MX9204342A (en)
NO (1) NO940237D0 (en)
NZ (1) NZ243687A (en)
PT (2) PT100718A (en)
SK (1) SK8494A3 (en)
TW (1) TW223060B (en)
WO (2) WO1993002051A1 (en)
ZA (2) ZA925546B (en)

Families Citing this family (15)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB9204024D0 (en) * 1992-02-25 1992-04-08 Fujisawa Pharmaceutical Co Indole derivatives
GB9302577D0 (en) * 1993-02-10 1993-03-24 Fujisawa Pharmaceutical Co Indole derivatives
WO1994022821A1 (en) * 1993-04-05 1994-10-13 Fujisawa Pharmaceutical Co., Ltd. Indole derivatives as testosterone 5 alpha-reductase inhibitors
GB9310092D0 (en) * 1993-05-17 1993-06-30 Fujisawa Pharmaceutical Co Indole derivatives
GB9317096D0 (en) * 1993-08-17 1993-09-29 Pfizer Ltd Indoles
EP0753511B1 (en) * 1994-03-30 2001-07-11 Zeria Pharmaceutical Co., Ltd. 4-indol-1-yl butyric acid derivatives, their preparation and their use as inhibitors of alpha1-adrenergic receptors and testosterone 5alpha-reductases
GB9409583D0 (en) * 1994-05-13 1994-07-06 Pfizer Ltd Indoles
US5543417A (en) * 1994-10-21 1996-08-06 Merck & Co., Inc. Combination method of treating acne using 4-AZA-5α-cholestan-ones and 4-AZA-5α-androstan-ones as selective 5α-reductase inhibitors with anti-bacterial, keratolytic, or anti-inflammatory agents
SK285695B6 (en) 1997-05-14 2007-06-07 Atherogenics, Inc. Use of monosuccinic acid ester of probucol for the treatment of cardiovascular and inflammatory diseases
US6670398B2 (en) 1997-05-14 2003-12-30 Atherogenics, Inc. Compounds and methods for treating transplant rejection
US7417063B2 (en) 2004-04-13 2008-08-26 Bristol-Myers Squibb Company Bicyclic heterocycles useful as serine protease inhibitors
FR2893615B1 (en) * 2005-11-18 2008-03-07 Sanofi Aventis Sa 3-ACYLINDOLE DERIVATIVES, THEIR PREPARATION AND THEIR THERAPEUTIC APPLICATION
PE20090159A1 (en) 2007-03-08 2009-02-21 Plexxikon Inc INDOL-PROPIONIC ACID DERIVED COMPOUNDS AS PPARs MODULATORS
CN101686676A (en) 2007-03-26 2010-03-31 沙路特里亚制药有限责任公司 Methods and compositions of derivatives of probucol for the treatment of diabetes
US10703969B2 (en) * 2016-09-27 2020-07-07 Kaohsiung Medical University Detection method for quaternary ammonium compound having γ-carboxyl group

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB9011335D0 (en) * 1990-05-21 1990-07-11 Fujisawa Pharmaceutical Co Indolebutyric acid derivatives and process for preparation thereof
WO1993005020A1 (en) * 1991-09-06 1993-03-18 Merck & Co., Inc. Indoles as inhibitors of hiv reverse transcriptase

Also Published As

Publication number Publication date
IL102545A0 (en) 1993-01-14
AU2327192A (en) 1993-02-23
ZA925546B (en) 1994-01-24
MX9204342A (en) 1994-03-31
GB9115951D0 (en) 1991-09-11
BR9206306A (en) 1994-11-08
WO1993002050A1 (en) 1993-02-04
EP0598754A1 (en) 1994-06-01
JPH06509336A (en) 1994-10-20
FI940310A0 (en) 1994-01-21
JPH06511483A (en) 1994-12-22
IE922386A1 (en) 1993-01-27
NO940237L (en) 1994-01-24
SK8494A3 (en) 1994-11-09
CA2112689A1 (en) 1993-02-04
FI940310A (en) 1994-01-21
CZ13694A3 (en) 1994-07-13
ZA925547B (en) 1994-01-24
AU655662B2 (en) 1995-01-05
NZ243687A (en) 1994-12-22
WO1993002051A1 (en) 1993-02-04
PT100718A (en) 1993-08-31
PT100717A (en) 1993-08-31
IE922387A1 (en) 1993-01-27
CN1068816A (en) 1993-02-10
CN1068817A (en) 1993-02-10
HU9400199D0 (en) 1994-05-30
AU2327092A (en) 1993-02-23
NO940237D0 (en) 1994-01-24
FI940311A (en) 1994-01-21
FI940311A0 (en) 1994-01-21
IL102544A0 (en) 1993-01-14
TW223060B (en) 1994-05-01
EP0598750A1 (en) 1994-06-01

Similar Documents

Publication Publication Date Title
JP5036648B2 (en) Acetylene derivatives having MGLUR5 antagonist activity
US6136843A (en) Indole derivatives useful as endothelin receptor antagonists
CA2112678A1 (en) Indoles
EP0628040B1 (en) Indole derivatives as steroid 5 alpha-reductase inhibitors
JP2833865B2 (en) Indole derivatives as 5-alpha-reductase-1-inhibitors
US5840758A (en) Oxime derivatives of fenamates as inhibitors of prostaglandin biosynthesis
US5922747A (en) Indole derivatives as steroid 5α-reductase inhibitors
US4906667A (en) Phenyl hydroxamic acids including a hetero-containing substituent
JPH0560462B2 (en)
WO1995031453A1 (en) Indole derivatives as 5 alpha-reductase 1 inhibitors
WO1995023143A1 (en) Indole derivatives as testosterone-5-alpha-reductase inhibitors
JPH0912566A (en) Oxaindene derivative and method for preparing the same

Legal Events

Date Code Title Description
EEER Examination request
FZDE Discontinued