Indole derivatives as steroid 5.alpha.-reductase inhibitors

Details Indole derivatives as steroid 5.alpha.-reductase inhibitors Indole derivatives as steroid 5.alpha.-reductase inhibitors

1995-11-16

1997-12-09

Morris, Patricia L.

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

514382, 548253, 548454, A61K 3140, C07D40514, C07D40506

Patent

active

056961464

DESCRIPTION:

BRIEF SUMMARY
This is a National Phase filing under 35 USC .sctn.371 based on PCT/EP94/01760 which was filed internationally on May 26, 1994.
This invention relates to indole derivatives which have steroid 5.alpha.-reductase inhibitory activity. 1,3-benzodioxolan-5-yl)methylcarbonyl!indole derivatives, their preparation and their use as testosterone 5.alpha.-reductase inhibitors.
The androgen class of steroidal hormones is responsible for the difference in the physical characteristics of males and females. Of all the organs that produce androgens, the tests produce these hormones in the greatest amounts. Over-production of these hormones in the body results in many undesirable physical manifestations and disease states, e.g. acne vulgaris, alopecia, seborrhoea, females 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 mediators of androgenic activity in certain organs such as the prostate and sebaceous glands are the 5.alpha.-reduced androgens. Testosterone is therefore the prohormone of 5.alpha.-dihydrotestosterone which is formed locally in the above organs by the action of testosterone 5.alpha.-reductase, of which two isozymes are known to exist in humans, testosterone 5.alpha.-reductase-1 and testostemne 5.alpha.-reductase-2. The presence of elevated levels of dihydrotestosterone in many disease states has therefore focussed attention on the synthesis of testosterone 5.alpha.-reductase inhibitors.
Testosterone 5.alpha.-reductase inhibitors may also be useful in the treatment of human prostate adenocarcinomas.
Certain compounds of the present invention are generally disclosed by International Patent Publication No. WO 93/17014.
EP-A-0458207 discloses indole derivatives with testosterone 5.alpha.-reductase inhibitory activity.
It has now been surprisingly found that the present compounds are potent inhibitors of both isozymes of human testosterone 5.alpha.-reductase (i.e. 5.alpha.-reductase-1 and 5.alpha.-reductase-2) which leads to the therapeutic advantages that the compounds are more efficacious that they can be administered at lower doses.
The present invention provides compounds of the formula: ##STR2## and the pharmaceutically acceptable base salts thereof, wherein R is --CO.sub.2 H or tetrazol-5-yl;
Alkyl groups containing three or more carbon atoms may be straight-or branched-chain.
A compound of the formula (I) where R is --CO.sub.2 H can be derived in vivo from a corresponding compound of the formula: ##STR3## where R.sup.1 and R.sup.2 are as defined for a compound of the formula (I) and R.sup.3 is a biolabile ester-forming group.
The term "biolabile ester-forming group" is well understood in medicinal chemistry as meaning a group which forms an ester which can be readily cleaved in vivo to liberate the corresponding compound of the formula (I) where R is --CO.sub.2 H. A number of such ester groups are well-known, for example in the penicillin area or in the case of the angiotensin-converting enzyme (ACE) inhibitor antihypertensive agents.
The compounds of the formula (IIA) are not only useful as pro-drugs to provide compounds of the formula (I) wherein R is --CO.sub.2 H in vivo following oral administration, but are also useful as synthetic intermediates for the preparation of compounds of the formula (I) where R is --CO.sub.2 H.
The suitability of any particular ester-forming group for this purpose can be assessed by conventional in vitro or in vivo enzyme hydrolysis studies.
Examples of biolabile ester-forming groups are alkyl, alkanoyloxyalkyl (including alkyl, cycloalkyl or aryl substituted derivatives thereof), arylcarbonyloxyalkyl (including aryl substituted derivatives thereof), aryl, arylalkyl, indanyl and haloalkyl: wherein alkanoyl groups have from 2 to 8 carbon atoms, alkyl and haloalkyl groups have from 1 to 8 carbon atoms and aryl means phenyl or naphthyl, both of which may be optionally substituted by C.sub.1 -C.sub.4 alkyl, C.sub.1 -C.sub.4 alkoxy

Affiliated with

Also associated with

Rating

Indole derivatives as steroid 5.alpha.-reductase inhibitors does not yet have a rating. At this time, there are no reviews or comments for this patent.

If you have personal experience with Indole derivatives as steroid 5.alpha.-reductase inhibitors, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Indole derivatives as steroid 5.alpha.-reductase inhibitors will most certainly appreciate the feedback.

Rate now

Comments { 0 }

Profile ID: LFUS-PAI-O-1608099