Merrell Dow Pharmaceuticals

Aventis Pharmaceuticals Inc.

Merrell Pharmaceuticals, Inc.

Aventis Pharma Limited

Philip M Weintraub

Cynthia A Gates

Michael R Angelastro

Kwon Yon Musick

Joseph P Burkhart

Thomas R Blohm

Chi-Hsin Richard King

Timothy Thomas Curran

Gary A Flynn

Shujaath Mehdi

Paul Robert Eastwood

John Ziqi Jiang

Neil Moorcroft

Norton P Peet

John G Jurcak

Ramalinga M Dharanipragada

Jack Roger Koehl

Nicholas J Hrib

Michael L Edwards

Stefan Peukert

Gregory H Merriman

David R Borcherding

Brian K Whiteley

J O'Neal Johnston

Matthieu Barrague

Alexandre Gross

Nelsen L Lentz

Timothy A Gillespy

Jeffrey Stephen Sabol

Joseph T Klein

Ashfaq Ahmad Parkar

Uwe Schwahn

Sungtaek Lim

Timothy T Curran

James R Pribish

Yan Du

David Stefany

Philip R Kastner

Gary Alan Flynn

Paul R Eastwood

David W Stefany

The present invention relates to a series of 2,3,5-substituted pyridone derivatives of formula I: wherein R, R, R, Rand Rare as defined herein. This invention also relates to methods of making these compounds. The compounds of this invention are inhibitors of poly(adenosine 5'-diphosphate ribose) polymerase (PARP) and are therefore useful as pharmaceutical agents, especially in the treatment and/or prevention of a variety of diseases, including diseases associated with the central nervous system and cardiovascular disorders.

Substituted pyridones as inhibitors of poly(ADP-ribose) polymerase (PARP)

The present invention relates to a series of substituted aza-indole derivatives of the formula I: wherein R, R, R, R, R, X and Y are as defined herein. This invention also relates to methods of making these compounds. The compounds of this invention are inhibitors of poly(adenosine 5'-diphosphate ribose) polymerase (PARP) and are therefore useful as pharmaceutical agents, especially in the treatment and/or prevention of a variety of diseases, including diseases associated with the central nervous system and cardiovascular disorders.

Substituted AZA-indoles as inhibitors of poly(ADP-ribose) polymerase (PARP)

Thienopyrazoles of formula I, their preparation, pharmaceutical compositions comprising these compounds, and their pharmaceutical uses in the treatment of disease states capable of being modulated by the inhibition of the protein kinases, in particular interleukin-2 inducible tyrosine kinase (ITK). 

Thienopyrazoles

The present invention relates to a series of substituted indole derivatives of the formula I: 

Substituted indoles as inhibitors of poly (ADP-ribose) polymerase (PARP)

This invention discloses and claims a new class of indole derivatives for use in treating allergy, asthma, rhinitis, dermatitis, B-cell lymphomas, tumors and diseases associated with bacterial, rhinovirus or respiratory syncytial virus (RSV) infections. It has now been found that the compounds of this invention are capable of modulating T helper (Th) cells, Th1/Th2, and thereby capable of inhibiting the transcription of interleukin-4 (IL-4) message, IL-4 release or IL-4 production.

Indole derivatives as interleukin-4 gene expression inhibitors

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 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-

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 4-amino-.DELTA..sup.4 -steroids which are useful as inhibitors of 5.alpha.-reductase. The compounds are prepared by the reaction of an appropriate 4-azido steroid with triphenylphosphine in an aqueous inert solvent with heating.

Method of using 4-amino-.DELTA..sup.4 -steroids in the treatment of

The compound (R)-2-[(phenylisopropyl)amino]adenosine whose structure is given below: ##STR1## (R)-2-[(phenylisopropyl)amino]adenosine is about two orders of magnitude greater in its selectivity between the A-1 and A-2 adenosine receptors than its diastereoisomer. This compound is useful for lowering blood pressure.

2-substituted adenosines with A-2 receptor affinity

The present invention relates to 4-amino-.DELTA..sup.4 -steroids which are inhibitors of 5.alpha.-reductase. The compounds are useful for treating DHT-mediated diseases.

4-amino-.DELTA.4-steroids and their use as 5.alpha.-reductase inhibitors

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Cincinnati, OH, United States of America

Philip M Weintraub