American Home Products Corporation

Rhone-poulenc Rorer Pharmaceuticals Inc.

Rorer Pharmaceutical Corporation

Other

Sanofi-aventis

Anthony C Scotese

Arthur Attilio Santilli

Kent W Neuenschwander

Robert L Morris

Donald P Strike

John R Regan

Keith S Learn

Robert A Groneberg

Stanley Charles Bell

Dilip V Amin

John W Ullrich

Stevan Wakefield Djuric

Volkmar Wehner

Hans Matter

Markus Follmann

Christopher J Burns

Joseph M Salvino

Reinhard Kirsch

Henning Steinhagen

Robert D Groneberg

Martin Lorenz

William P Dankulich

Matthew M Morrissette

Hauke Szillat

Marvin E Rosenthale

Rudolph M Tomarelli

Steven M Condon

Gerald M McGeehan

Terence J Kiesow

Rudolph R Tomarelli

The present invention relates to compounds of formula I, The compounds of formula I are valuable pharmacologically active compounds. They exhibit a strong anti-thrombotic effect and are suitable, for example, for the therapy and prophylaxis of cardio-vascular disorders like thromboembolic diseases or restenoses. They are inhibitors of the blood clotting enzymes, especially factor VIIa and can in general be applied in conditions in which an undesired activity of factor VIIa is present or for the cure or prevention of which an inhibition of factor VIIa is intended. The invention furthermore relates to processes for the preparation of compounds of formula I, their use, in particular as active ingredients in pharmaceuticals, and pharmaceutical preparations comprising them.

Malonamide derivatives with antithrombotic activity

This invention is directed to compounds of formula I: ##STR1## wherein the variables are as described herein. Compounds within the scope of the present invention possess useful properties, more particularly pharmaceutical properties. They are especially useful for inhibiting the production or physiological effects of TNF in the treatment of a patient suffering from a disease state associated with a physiologically detrimental excess of tumor necrosis factor (TNF). Compounds within the scope of the present invention also inhibit cyclic AMP phosphodiesterase, and are useful in treating a disease state associated with pathological conditions that are modulated by inhibiting cyclic AMP phosphodiesterase, such disease states including inflammatory and autoimmune diseases, in particular type IV cyclic AMP phosphodiesterase. Compounds within the scope of the present invention may also inhibit an MMP, and are useful in treating a disease state associated with pathological conditions that are modulated by inhibiting MMPs, such disease states involve tissue breakdown and those associated with a physiologically detrimental excess of TNF. The present invention is therefore also directed to the pharmaceutical use of the compounds, pharmaceutical compositions containing the compounds, intermediates leading thereto and methods for the preparation of the compounds and their intermediates.

Substituted (aryl, heteroaryl, arylmethyl or heteroarylmethyl)

This invention relates to a class of novel amino bi- and tri-carbocyclic alkane compounds having bis-aryl substitution which exhibit squalene synthase inhibition properties. The bi- and tri-carbocyclic alkane ring contains an amino group and the ring is further linked or bridged to two mono- and/or bicyclic rings. Compounds of this invention reduce levels of serum cholesterol in the body without significantly reducing mevalonic metabolite synthesis. This invention relates also to pharmacological compositions and method of treatment for lowering serum cholesterol levels using the compounds of this invention.

Amino bi- and tri-carbocyclic alkane bis-aryl squalene synthase

This invention relates to a class of novel aliphatic amino bis-aryl compounds containing at least four carbon atoms and an amino group either substituted thereon or incorporated therein and is further linked or bridged to two mono- and/or bicyclic rings. Compounds of this invention reduce levels of serum cholesterol in the body without significantly reducing mevalonic metabolite synthesis. This invention relates also to pharmacological compositions and method of treatment for lowering serum cholesterol levels using the compounds of this invention.

Aliphatic amino bis-aryl squalene synthase inhibitors

This invention relates to polycyclic compounds containing two mono- and/or bicyclic rings and a basic tertiary amino group capable of forming an ammonium ion at biological pH and which reduces levels of serum cholesterol in the body without significantly reducing mevalonic metabolite synthesis. This invention relates also to pharmacological compositions and method of treatment for lowering serum cholesterol levels using the compounds of this invention.

Multicyclic tertiary amine polyaromatic squalene syntase inhibitors

This invention relates to a class of novel polycyclic compounds containing a cycloalkyl ring having substituted thereon a primary amine and which is further linked or bridged to two mono- and/or bicyclic rings and which reduces levels of serum cholesterol in the body without significantly reducing mevalonic metabolite synthesis. This invention relates also to pharmacological compositions and method of treatment for lowering serum cholesterol levels using the compounds of this invention.

Cycloalkyl amine bis-aryl squalene synthase inhibitors

Amino Bi- and tri-carbocyclic aklane bis-aryl squalene synthase

This invention relates to polycyclic compounds containing two mono- and/or bicyclic rings and a basic tertiary amino group capable of forming an ammonium ion at biological pH and which reduces levels of serum cholesterol in the body without significantly reducing mevalonic metabolite synthesis. This invention relates also to pharmacological compositions and method of treatment for lowering serum cholesterol levels using the compounds of this invention. The compounds of this invention are described by the formula ##STR1## where Ar I is phenylene or naphthylene, Ar II is phenyl or naphthyl and A is 1-azabicyclo[2.2.2]octan-3-yl.

Multicyclic tertiary amine polyaromatic squalene synthase inhibitors

This invention relates to 2-substituted-imidazo[4,5-c]pyridines, to the process for their preparation, to pharmaceutical compositions containing said 2-substituted-imidazo[4,5-c]pyridines and to the use of said 2-substituted-imidazo[4,5-c]pyridines for modifying the balance between bone production and bone resorption in a host animal, including man.

Imidazo(4,5-C)pyridines as antiosteoporotic agents

Disclosed are novel 3-hydroxy-3-methylglutarylcoenzyme A reductase inhibitors useful as antihypercholesterolemic agents represented by the formula ##STR1## and the corresponding ring-opened hydroxy acids and esters derived therefrom and pharmaceutically acceptable salts thereof. Pharmaceutical compositions containing said compounds and method of inhibiting the biosynthesis of cholesterol therewith are also disclosed.

HMG-COA reductase inhibitors

Disclosed are novel 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors useful as antihypercholesterolemic agents represented by the formula ##STR1## and the corresponding ring-opened hydroxy acids and esters derived therefrom and pharmaceutically acceptable salts thereof. Pharmaceutical compositions containing said compounds and method of inhibiting the biosynthesis of cholesterol therewith are also disclosed.

Novel HMG-CoA reductase inhibitors

Disclosed are novel 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors useful as antihypercholesterolemic agents represented by the formula ##STR1## and the corresponding ring-opened hydroxy acids derived therefrom and pharmaceutically acceptable salts thereof. Pharmaceutical compositions containing said compounds and method of inhibiting the biosynthesis of cholesterol therewith are also disclosed.

Novel hmg-coa reductase inhibitors

A process for preparing certain benzo- and thieno-fused heterocyclic compounds having H.sub.2 -receptor antagonist and antisecretory activity, which comprises the amide reduction of N-substituted carbamoyl-containing benzo- or thieno-fused heterocyclic intermediates; and said N-substituted carbamoyl-containing benzo- or thieno-fused heterocyclic intermediates.

Precursors of benzo- and thieno-fused heterocyclic anti-ulcer agents

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King of Prussia, PA, United States of America

Anthony C Scotese