Eli Lilly and Company

William F Heath, Jr

Richard Dennis DiMarchi

David L Smiley

James E Shields

David B Flora

James A Hoffmann

John H McDonald, Iii

Michael R Jirousek

Christopher J Rito

Brigitte E Schoner

Margret B Basinski

Theo Schotten

Lawrence E Stramm

Wolfgang Stenzel

Colin W Smith

Michael Paal

Jai P Singh

Samantha J Ambler

Jill A Panetta

John Kevin Shadle

Douglas Kirk Ways

Sau-Chi Betty Yan

Gerd Ruhter

Rama M Belagaje

Mei-Huei T Lai

Joseph Vincent Manetta

Harlan B Long

Gerd R Uhter

John R Sportsman

James A Hoffman

This invention provides novel bis-indolemaleimide macrocycle derivatives of the formula: ##STR1## wherein R.sub.1, R.sub.2, X, W, and Y are as defined in the specification. The invention further provides the preparation, pharmaceutical formulations and the methods of use for inhibiting Protein Kinase C in mammals.

Process for preparing bis-indoly macrocycles

The present invention provides anti-obesity proteins, which when administered to a patient regulate fat tissue. Accordingly, such agents allow patients to overcome their obesity handicap and live normal lives with much reduced risk for type II diabetes, cardiovascular disease and cancer.

Anti-obesity proteins

This invention provides novel bis-indolemaleimide macrocycle derivatives of the formula: ##STR1## The invention further provides the preparation, pharmaceutical formulations and the methods of use for inhibiting Protein Kinase C in mammals.

Protein kinase C inhibitors

This invention provides novel bis-indolemaleimide macrocycle derivatives of the formula: ##STR1## The invention further provides the preparation, pharmaceutical formulations and the methods of use for inhibiting Protein Kinase C in mammals. The compounds of the present invention can be used to treat cancer and inhibiting tumor growth in mammals.

Therapeutic treatment of cancer with Protein Kinase C inhibitors

This invention provides novel bis-indolemaleimide macrocycle derivatives of the formula: ##STR1## wherein R1, R2, X, W, and Y are as defined in the specification. The invention further provides the preparation, pharmaceutical formulations and the methods of use for inhibiting Protein Kinase C in mammals.

Process for preparing BIS-indolyl macrocycles

A method for treating endothelial cell dysfunction, such as associated with cardiovascular disease are disclosed, particularly using the isozyme selective PKC inhibitor, (S)-3,4-�N,N'-1,1'-((27'-ethoxy)-3''(O)-4''-(N,N-dimethylamino)-butane)-bi s-(3,3'-indolyl)!-1(H)-pyrrole-2,5-dione hydrochloride salt.

Therapeutic treatment for cardiovascular diseases

Methods of treating diabetic mellitus and its complications

The present invention discloses compounds that are highly isozyme selective protein kinase C beta-1 and beta-2 isozyme inhibitors. Accordingly, the present invention provides a method of selectively inhibiting protein kinase C isozymes beta-1, and beta-2. As isozyme selective inhibitors of beta-1 and beta-2, the compounds are therapeutically useful in treating conditions associated with diabetes mellitus and its complications, as well as other disease states associated with an elevation of the beta-1 and beta-2 isozyme.

This invention provides novel compounds and pharmaceutical methods comprising the administration of a compound of the Formula I: ##STR1## wherein n, m, R.sub.1, R.sub.2, R.sub.3 and R.sub.4 are variables.

Pharmaceutical compounds

Growing community of inventors

Fishers, IN, United States of America

William F Heath, Jr