Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Carbohydrate doai
Patent
1994-08-02
1998-06-16
Richter, Johann
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Carbohydrate doai
514382, 514414, 514418, 514419, 548253, 548452, 548454, 548492, 548493, A01N 4338, A61K 3141
Patent
active
057671397
DESCRIPTION:
BRIEF SUMMARY
This application is a 371 of PCT EP93/00380 filed Feb. 16, 1993
This invention relates to indole derivatives which have steroid 5.alpha.-reductase inhibitory activity.
More particularly this invention relates to indoles, 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 mediator of androgenic activity in certain organs such as the prostate and sebaceous gland 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. 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.
EP-A-0458207 discloses indole derivatives with testosterone 5.alpha.-reductase inhibitory activity.
The present invention provides compounds of the formula: ##STR2## and pharmaceutically acceptable salts thereof, wherein alkylene, C.sub.2 -C.sub.4 alkenylene or C.sub.2 -C.sub.4 alkynylene, said alkylene, alkenylene and alkynylene being optionally substituted by C.sub.1 -C.sub.4 alkyl or aryl; C.sub.2 -C.sub.6 alkenylene or C.sub.2 -C.sub.6 alkynylene, all of which may be optionally substituted by C.sub.1 -C.sub.6 alkyl, or is a group of the formula: ##STR3## wherein m and n are each independently selected from O and an integer of from 1 to 5, with the proviso that the sum of m and n is not greater than 5, and p is an integer of from 2 to 6; H, C.sub.1 -C.sub.4 alkyl, C.sub.1 -C.sub.4 alkoxy, OH, halo, --CF.sub.3, --CO.sub.2 (C.sub.1 -C.sub.4 alkyl) , --CONH.sub.2, --CONH(C.sub.1 -C.sub.4 alkyl) and --CON(C.sub.1 -C.sub.4 alkyl).sub.2 ; ##STR4## R.sup.7 is a biolabile ester-forming group; R.sup.8 and R.sup.9 are each independently selected from H and C.sub.1 -C.sub.4 alkyl; C.sub.1 -C.sub.4 alkyl, C.sub.1 -C.sub.4 alkoxy, --OH, halo and halo(C.sub.1 -C.sub.4 alkyl); -C.sub.10 alkyl, C.sub.1 -C.sub.10 alkoxy, C.sub.2 -C.sub.6 alkenyl, C.sub.2 -C.sub.6 alkynyl, C.sub.3 -C.sub.8 cycloalkyl, --CO.sub.2 (C.sub.1 -C.sub.4 alkyl), --CONR.sup.8 R.sup.9, --CN, halo(C.sub.1 -C.sub.6 alkyl), aryl and heteroaryl, said alkyl and alkoxy groups being optionally substituted by C.sub.1 -C.sub.6 alkoxy, C.sub.3 -C.sub.7 cycloalkyl, --OH, --CO.sub.2 (C.sub.1 -C.sub.4 alkyl), --CONR.sup.8 R.sup.9, --CN, aryl, aryloxy or heteroaryl, and said alkenyl and alkynyl groups being optionally substituted by aryl, with the proviso that R.sup.13 and R.sup.14 are not both H, or R.sup.13 and R.sup.14, taken together with the carbon atom to which they are attached, represent optionally benzo-fused spiro(C.sub.3 -C.sub.8)cycloalkane, said spirocycloalkane group and the benzo-fused portion being optionally substituted by C.sub.1 -C.sub.6 alkyl, C.sub.1 -C.sub.6 alkoxy, C.sub.3 -C.sub.8 cycloalkyl, --OH, --CO.sub.2 (C.sub.1 -C.sub.4 alkyl), --CONR.sup.8 R.sup.9, --CN, halo(C.sub.1 -C.sub.6 alkyl), aryl or heteroaryl, or R.sup.13 and R.sup.14, taken together with the carbon atom to which they are attached, represent spiropyrrolidine or spiropiperidine, both of which may be optionally N-substituted by C.sub.1 -C.sub.6 alkyl, C.sub.2 -C.sub.6 alkanoyl, C.sub.2 -C.sub.6 alkanoyl(C.sub.1 -C.sub.4 alkyl)- or arylcarbonyl; optionally substituted by C.sub.1 -C.sub.6 alkyl, C.sub.1 -C.sub.6 alkoxy, C.su
REFERENCES:
patent: 5696146 (1997-12-01), Blagg et al.
Blagg Julian
Finn Paul William
Greengrass Colin William
Maw Graham Nigel
Fuller Jr. Grover F.
Ginsburg Paul H.
Pfizer Inc.
Richardson Peter C.
Richter Johann
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