Indole derivatives as 5-.alpha.-reductase-1-inhibitors

Details Indole derivatives as 5-.alpha.-reductase-1-inhibitors Indole derivatives as 5-.alpha.-reductase-1-inhibitors

1996-02-15

1999-06-15

Ford, John M.

Organic compounds -- part of the class 532-570 series

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

C07D40506, C07D40514

Patent

active

059123575

DESCRIPTION:

BRIEF SUMMARY
This invention relates to indole derivatives which have steroid 5.alpha.-reductase inhibitory activity.
More particularly this Invention relates to certain 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 testes produce these hormones in the greatest amounts. Over-production of these hormones in the body results in many undesirable physical manifestations and disease states, e.g. acne vulgaris, alopecia, seborrhoea, female hirsutism, benign prostatic hypertrophy and male pattern baldness.
The principal androgen secreted by the testes is testosterone and it is the primary androgen present in male plasma. The principal 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 (DHT) which is formed locally in the above organs by the action of testosterone 5.alpha.-reductase. The presence of elevated levels of dihydrotestosterone in many disease states has therefore focussed attention on the synthesis of testosterone 5.alpha.-reductase inhibitors.
The enzyme 5.alpha.-reductase mediates the conversion of testosterone to the more potent androgen DHT locally, in the target organ. It has been postulated, and demonstrated, that inhibitors of 50.alpha.-reductase should block the formation of DHT and bring about amelioration of the above undesirable physiological conditions. Testosterone 5.alpha.-reductase inhibitors may also be useful in the treatment of human prostate adenocarcinomas. Recently, two 5-.alpha.-reductase isozymes (designated types 1 and 2) have been described in humans, Andersson et al., Proc. Natl. Acad. Sci. U.S.A., 87, 3640-3644 (1990; Andersson et al., Nature, 354, 159-161 (1991). In addition to certain structural differences, the two isozymes exhibit some differences with respect to their biochemical properties, expression patterns, genetics, and pharmacology, Andersson et al., Nature, 354, 159-161 (1991); Jenkins, et al., Journal of Clinical Investigation,89, 293-300 (1992). Further elucidation of the roles that the two 5.alpha.-reductase isozymes play In androgen action is currently the subject of intense research. These isozymes are generally described as 5.alpha.-reductase 1 or 2, or type 1 or type 2 5.alpha.-reductase.
Compounds reportedly useful for inhibiting 5.alpha.-reductase are generally steroid derivatives such as the azasterolds in Rasmusson, et al., J. Med. Chem., 29, (11), 2298-2315 (1986); and benzoylaminophenoxy-butanoic acid derivatives such as those disclosed in EPO 291 245. as 5-.alpha.-reductase inhibitors. Certain Indole derivatives having steroid 5-.alpha.-reductase inhibitory activity are generally disclosed by International Patent Application No. PCT/EP93/00380 (WO/93/17014).
It has now been surprisingly found that the present compounds are more potent and selective inhibitors of a single isozyme of human testosterone 5.alpha.-reductase (i.e. 5.alpha.-reductase-1) which leads to the therapeutic advantages that the compounds are more efficacious and that they can be administered at lower doses, in particular for the treatment of male pattern baldness which is known to be primarily responsible for hairloss in the human scalp as well as female hirsutism, acne vulgaris, seborrhea and prostatic cancer.
The present Invention provides compounds of the formula: ##STR3## and the pharmaceutically acceptable base salts thereof, wherein R is --CO.sub.2 R.sup.12 where R.sup.12 is H or a biolabile ester-forming group, or R is tetrazol-5-yl, ##STR4## and R.sup.2 is F, Cl, Br, I, CH.sub.3 or CF.sub.3 or (b) R.sup.1 is C.sub.3 -C.sub.6 alkyl and R.sup.2 is C.sub.2 -C.sub.4 alkyl.
Alkyl groups containing three or more carbon atoms may be straight- or branched-chain.
The term "biolabile ester-forming group" is well understood in medici

REFERENCES:
patent: 5696146 (1997-12-01), Blagg

Affiliated with

Also associated with

Rating

Indole derivatives as 5-.alpha.-reductase-1-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 5-.alpha.-reductase-1-inhibitors, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Indole derivatives as 5-.alpha.-reductase-1-inhibitors will most certainly appreciate the feedback.

Rate now

Comments { 0 }

Profile ID: LFUS-PAI-O-403513