Merrell Pharmaceuticals, Inc.

Merrell Dow Pharmaceuticals

Aventis Pharmaceuticals Inc.

Cynthia A Gates

Philip M Weintraub

Michael R Angelastro

Norton P Peet

Joseph P Burkhart

Chi-Hsin Richard King

Timothy Thomas Curran

Gary A Flynn

J O'Neal Johnston

Thomas R Blohm

Timothy T Curran

James R Pribish

Gary Alan Flynn

The invention relates to 20&xgr;-fluoropregna-4,17(20)-dien-3-on-21-oic acid ethyl ester, 20&xgr;-fluoro-3&bgr;-hydroxypregna-5,17(20)-dien-21-oic acid ethyl ester, 20&xgr;-fluoro-21-hydroxypregna-4,17 (20)-dien-3-one, 20&xgr;-fluoropregna-5,17(20)-dien-3&bgr;,21-diol and related compounds and to compositions incorporating these compounds, as well as the inhibition of C lyase, 5&agr;-reductase and C -hydroxylase, and to the use of these compounds in the treatment of androgen and estrogen mediated or dependent disorders, including benign prostatic hyperplasia, prostate cancer, breast cancer and DHT-mediated disorders such as acne and hirsutism. Treatment of disorders related to the over synthesis of cortisol, for example, Cushing's Syndrome are also included. The treatment of androgen-dependent disorders also includes a combination therapy with known androgen-receptor antagonists, such as flutamide. The compounds of the invention have the following general formulae:

20-fluoro-17(20)-vinyl steroids

The invention related to 4-aza-17&bgr;-(cyclopropoxy)-androst-5&agr;-androstan-3-one, 4-aza-17&bgr;-(cyclopropylamino)-androst-4-en-3-one and related compounds and to compositions incorporating these compounds, as well as the inhibition of C lyase, 5&agr;-reductase and C -hydroxylase and to the use of these compounds in the treatment of androgen and estrogen mediated disorders, including benign prostatic hyperplasia, androgen mediated prostate cancer, estrogen mediated breast cancer and to DHT-mediated disorders such as acne. Disorders relating to the oversynthesis of cortisol, for example, Cushing's Syndrome, are also included. The treatment of androgen-dependent disorders also includes a combination therapy with known androgen-receptor antagonists, such as flutamide. The compounds of the invention have the following general formula:

4-aza steroids

The present invention provides 4-nitro-.DELTA..sup.4 -3-ketosteroids, their use as steroid C.sub.17-20 lyase and 5.alpha.-reductase inhibitors and to a novel process for preparing a compound of the formula: ##STR1## comprising sequentially: a) reacting a starting compound of the formula ##STR2## with an effective amount of a strong base at an elevated or suitable temperature for a time sufficient to create the corresponding thermodynamic dienolate, followed by addition of a neutral nitrating agent to produce the 4-nitrosteroid; and then;

Process for the preparation of 4-amino-.DELTA.4-3-ketosteroids via

The present invention relates to methods and compositions using .DELTA..sup.16 unsaturated steroids which are useful as steroid C.sub.17-20 lyase inhibitors.

Methods and compositions using .DELTA..sup.16 unsaturated C.sub.17

The present invention relates to .DELTA..sup.16 unsaturated steroids which are useful as steroid C.sub.17-20 lyase inhibitors.

.increment..sup.16 unsaturated C.sub.17 heterocyclic steroids useful as

The invention discloses 3-ketosteroids of the following formula used to inhibit steroid C.sub.17-20 lyase: ##STR1## wherein R is OH, C.sub.1 -C.sub.6 alkanoyl, C.sub.1 -C.sub.6 alkanoyloxy, C.sub.1 -C.sub.4 alkanol, COCH.sub.2 OH, CO.sub.2 H, CONR.sub.7 R.sub.8, cyclopropyloxy, cyclopropylamino, acetylthioalkane, 2,2-dimethyldioxolan4-yl, 1,2-dihydroxyethyl and C.sub.1-4 alkylthiol;

Process for the preparation of 4-amino-.DELTA..sup.4 -3-ketosteroids via

The invention discloses 3-ketosteroids of the following formula used to inhibit steroid 5.alpha.-reductase: ##STR1## wherein R is OH, C.sub.1 -C.sub.6 alkanoyl, C.sub.1 -C.sub.6 alkanoyloxy, C.sub.1 -C.sub.4 alkanol, COCH.sub.2 OH, CO.sub.2 H, CONR.sub.7 R.sub.8, cyclopropoxy, acetylthioalkane, cyclopylamino, 2-2-dimethyldioxolan-4-yl, 1,2-dihydroxyethyl and C.sub.1-4 alkanethiol;

Certain 3-ketosteroids used to inhibit steroid 5.alpha.-reductase

Process for the preparation of 4-amino- 4-3-ketosteroids via 4-nitro-

16 unsaturated C17 heterocyclic steroids useful as steroid C17-20 lyase

This invention is directed to 4-amino-17.beta.-(cyclopropyloxy)androst-4-en-3-one, 4-amino-17.beta.-(cyclopropylylamino)androst-4-en-3-one and related compounds, a process for their synthesis, a pharmaceutical composition having C.sub.17-20 lyase and 5.alpha.-reductase inhibitory activity, the use of the present compounds as C.sub.17-20 lyase and 5.alpha.-reductase inhibitors and also to a method for using such compounds in the treatment of androgen and/or estrogen dependent disorders, including bengin prostatic hyperplasia, breast cancer and prostatic cancer. The 4-amino compounds are prepared by the reaction of the appropriate 4,5-epoxide with sodium azide in an inert solvent in the presence of a catalytic amount of strong acid under appropriate reaction conditions. Alternatively, the 4-amino compounds are prepared by first nitration and then reduction of the appropriate steroid under appropriate reaction conditions.

4-amino-17.beta.-(cyclopropyloxy)androst-4-en-3-one,

The present invention relates to a method for the inhibition of C.sub.17-20 lyase enzyme which comprises administering to a patient in need of such inhibition, an effective amount of certain 4-amino-17-(hydroxyalkyl or dihydroxyalkyl)steroids or their esters or ethers. Certain of the aminosteroids used in the process are novel compounds.

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Fairfield, OH, United States of America

Cynthia A Gates