The Scripps Research Institute

Boehringer Ingelheim International Gmbh

Boehringer Ingelheim Pharmaceuticals, Inc.

Smithkline Beecham (cork) Ltd

Frank Roschangar

Kyriacos Costa Nicolaou

Yun He

Dionisios Vourloumis

Hans Vallberg

Sacha Ninkovic

Francisco Sarabia

Nigel Paul King

Chris Hugh Senanayake

Zhi-Hui Lu

Nicolas Winssinger

Guisheng Li

Zhen Yang

Ming Shen

Joaquin Pastor

M Ray Finlay

Maurice Raymond Verschoyle Finlay

Antony Bigot

Jianxiu Liu

N Paul King

Nathan K Yee

Jinhua Jeff Song

Jonathan Timothy Reeves

Zhulin Tan

Tianhu Li

Ahmad Khodabocus

Michael Scott McClure

Martin Howard Osterhout

Mark Joseph Sacchetti

Maruice Raymond Verschoyle Finlay

David Hepworth

The invention relates to epothilone analog represented by the formula I wherein(i) Ris absent or oxygen; 'a' can be either a single or double bond; 'b' can be either absent or a single bond; and &#x201c;c&#x201d; can be either absent or a single bond, with the proviso that if Ris oxygen then &#x201c;b&#x201d; and &#x201c;c&#x201d; are both a single bond and &#x201c;a&#x201d; is a single bond; if Ris absent then &#x201c;b&#x201d; and &#x201c;c&#x201d; are absent and &#x201c;a&#x201d; is a double bond; and if &#x201c;a&#x201d; is a double bond, then R, &#x201c;b&#x201d; and &#x201c;c&#x201d; are absent; These compounds have inter alia microtubuli depolymerisation inhibiting activity and are e.g. useful against proliferative diseases.

Epothilone derivatives and their synthesis and use

A process for stereoselective synthesis of a compound of Formula (I) wherein R, R, R, R, and Rare as described herein.

Stereoselective synthesis of certain trifluoromethyl-substituted alcohols

Disclosed are 2-bromoaniline or 2-chloroaniline compounds of formula (I): wherein R, Rand X are as defined. The compounds are useful as intermediates for preparing indole compounds.

2-Bromoanaline and 2-chloroaniline compounds

The present invention provides a process for making a compound of general formula I: wherein: and as described herein.

Process for cross coupling indoles

Epothilone A, epothilone B, analogs of epothilone and libraries of epothilone analogs are synthesized. Epothilone A and B are known anticancers agents that derive their anticancer activity by the prevention of mitosis through the induction and stabilization of microtubulin assembly. The analogs of epothilone are novel. Several of the analogs are demonstrated to have a superior cytotoxic activity as compared to epothilone A or epothilone B as demonstrated by their enhanced ability to induce the polymerization and stabilization of microtubules.

Epothilone analogs

Ditosylate salts of 4-quinazolineamines are described as well as methods of using the same in the treatment of disorde4rs characterized by aberrant erbB family PTK activity.

Quinazoline ditosylate salt compounds

The present invention provides a method for making substituted indole compounds of general formula III comprising the step of: (a) reacting a 2-bromoaniline or 2-chloroaniline of general formula (I) (I)wherein: X, R and Rare defined hereinwith a substituted acetylene of formula (II) wherein Rand Rare defined herein in the presence of a palladium catalyst, a ligand, and a base in a solvent at a suitable temperature to give a compound of formula (III); 

Palladium catalyzed indolization of 2-bromo or chloroanilines

Epothilone A, epothilone B, analogs of epothilone and libraries of epothilone analogs are synthesized. Epothilone A and B are known anticancers agents that derive their anticancer activity by the prevention of mitosis through the induction and stabilization of microtubule assembly. The analogs of epothilone are novel. Several of the analogs are demonstrated to have a superior cytotoxic activity as compared to epothilone A or epothilone B as demonstrated by their enhanced ability to induce the polymerization and stabilization of microtubules.

The invention relates to epothilone analog represented by formula (I) wherein (i) R is absent or oxygen; &ldquo;a&rdquo; can be either a single or double bond; &ldquo;b&rdquo; can be either absent or a single bond; and &ldquo;c&rdquo; can be either absent or a single bond, with the proviso that if R is oxygen then &ldquo;b&rdquo; and &ldquo;c&rdquo; are both a single bond and &ldquo;a&rdquo; is a single bond; if R is absent then &ldquo;b&rdquo; and &ldquo;c&rdquo; are absent and &ldquo;a&rdquo; is a double bond; and if &ldquo;a&rdquo; is a double bond, then R , &ldquo;b&rdquo; and &ldquo;c&rdquo; are absent; R is a radical selected from the group consisting of hydrogen; lower alkyl; &mdash;CH&boxH;CH ; &mdash;C&equiv;CH; &mdash;CH F; &mdash;CH Cl; &mdash;CH &mdash;OH; &mdash;CH &mdash;O&mdash;(C -C -alkyl); and &mdash;CH &mdash;S&mdash;(C -C -alkyl); R and R are independently selected from hydrogen, methyl or a protecting group; and R is as defined in the specification, or a salt of a compound of formula (I) where a salt-forming group is present. A further aspect of the invention is related to the synthesis of epothilone E. These compounds have inter alia microtubuli depolymerization inhibiting activity and are e.g. useful against proliferative diseases

Epothilone A, epothilone B, analogs of epothilone and libraries of epothilone analogs are synthesized. Epothilone A and B are known anticancer agents that derive their anticancer activity by the prevention of mitosis through the induction and stabilization of microtubulin assembly. The analogs of epothilone are novel. Several of the anlogs are demonstrated to have a superior cytotoxic activities as compared to epothilone A or epothilone B as demonstrated by their enhanced ability to induce the polymerization and stabilization of microtubules.

Novel analogs of epothilone A, epothilone B, and epothilone C are synthesized by Stille coupling thazole-stannanes to macrolactone intermediates. The synthetic epothilone analogs selectively prevent mitosis in cancer cells through the induction and stabilization of microtubulin assembly. Selected synthetic epothilone analogs are demonstrated to have greater bioactivity than their corresponding native compound.

Growing community of inventors

Glen Allen, VA, United States of America

Frank Roschangar