Exelixis, Inc.

Bristol-myers Squibb Compnay

Other

Syngene International Limited

William P Gallagher

Peter Lamb

Adrian St Clair Brown

Robert C Livingston

Robert Michael Borzilleri

Zhen-Wei Cai

David Marcoux

Qing Shi

Jason J Zhu

Carlos A Guerrero

Candice Lee Joe

Srinivas Kalidindi

Sathasivam Shunmugaraj

John Ryan Coombs

Moorthy Kandasamy

Siva Sankar Bondigela

Rajappa Vaidyanathan

Sanjeewa Rupasinghe

Shankar Tulsidas Tendulkar

Sankar Kuppusamy

Francisco González-Bobes

Adrian St Brown

Disclosed are malate salts of N-(4-{[6,7-bis(methyloxy)-quinolin-4-yl]oxy}phenyl)-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide, including a (L)-malate salt, a (D)-malate salt, a (DL) malate salt, and mixtures thereof; and crystalline and amorphous forms of the malate salts. Also disclosed are pharmaceutical compositions comprising at least one malate salts of N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)-cyclopropane-1,1-dicarboxamide; and methods of treating cancer comprising administering at least one malate salt of N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N′-(4-ffuorophenyl)cyclopropane-1,1-dicarboxamide.

Malate salt of N-(4-{[6,7-bis(methyloxy) quinolin-4-yl]oxy}phenyl)-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide, and crystalline forms thereof for the treatment of cancer

The invention generally relates to a process for preparing compounds, including Compound of Formula (I), useful as key intermediates in the preparation of compounds having ROR&#x3b3;t antagonist properties. 

Synthetic process

Disclosed are malate salts of N-(4-{[6,7-bis(methyloxy)-quinolin-4-yl]oxy}phenyl)-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide, including a (L)-malate salt, a (D)-malate salt, a (DL) malate salt, and mixtures thereof; and crystalline and amorphous forms of the malate salts. Also disclosed are pharmaceutical compositions comprising at least one malate salts of N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N&#x2032;-(4-fluorophenyl)-cyclopropane-1,1-dicarboxamide; and methods of treating cancer comprising administering at least one malate salt of N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N&#x2032;-(4-fluorophenyl)cyclopropane-1, 1-dicarboxamide.

Disclosed are malate salts of N-(4-{[6,7-bis(methyloxy)-quinolin-4-yl]oxy}phenyl)-N'-(4-fluorophenyl)cyclo-propane-1,1-dicarboxamide, including a (L)-malate salt, a (D)-malate salt, a (DL) malate salt, and mixtures thereof; and crystalline and amorphous forms of the malate salts. Also disclosed are pharmaceutical compositions comprising at least one malate salts of N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N&#x2032;-(4-fluorophenyl)-cyclopropane-1,1-dicarboxamide; and methods of treating cancer comprising administering at least one malate salt of N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N&#x2032;-(4-fluorophenyl)cyclopropane-1, 1-dicarboxamide.

Malate salt of N-(4-{[6,7-bis(methyloxy) quinolin-4-yl]oxy}phenyl)- N'-(4-fluorophenyl)cyclopropane-1,1 -dicarboxamide, and crystalline forms thereof for the treatment of cancer

Disclosed are malate salts of N-(4-{[6,7-bis(methyloxy)-quinolin-4-yl]oxy}phenyl)-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide, including a (L)-malate salt, a (D)-malate salt, a (DL) malate salt, and mixtures thereof; and crystalline and amorphous forms of the malate salts. Also disclosed are pharmaceutical compositions comprising at least one malate salts of N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N&#x2032;-(4-fluorophenyl)-cyclopropane-1,1-dicarboxamide; and methods of treating cancer comprising administering at least one malate salt of N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N&#x2032;-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide.

Malate salt of N-(4-{[6,7-bis(methyloxy) quinolin-4-yl]oxy}phenyl)-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide, and crystalline forms therof for the treatment of cancer

Malate salt of N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N'(4-fluorophenyl)cyclopropane-1,1-dicarboxamide, and crystalline forms therof for the treatment of cancer

Disclosed are malate salts of N-(4-{[6,7-bis(methyloxy)-quinolin-4-yl]oxy}phenyl)-N'-(4-fluorophenyl)cyclopropane -1,1-dicarboxamide, including a (L)-malate salt, a (D)-malate salt, a (DL) malate salt, and mixtures thereof; and crystalline and amorphous forms of the malate salts. Also disclosed are pharmaceutical compositions comprising at least one malate salts of N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N&#x2032;-(4-fluorophenyl)-cyclopropane-1,1-dicarboxamide; and methods of treating cancer comprising administering at least one malate salt of N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N&#x2032;-(4-ffuorophenyl)cyclopropane-1,1-dicarboxamide.

(L)-malate salt of N-(4-{[6,7-bis(methyloxy) quinolin-4-yl]oxy}phenyl)-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide

Disclosed herein is a process for preparing a compound of Formula (I), comprising the steps of: (a) reacting an aniline compound of Formula (II) and an carboxylic acid compound of Formula (III) or an activated carboxylic acid compound thereof, to provide a compound of Formula (IV); and (b) converting said protected amine group attached to said compound of Formula (IV) to an amine group to provide said compound of Formula (I); wherein PAm is a protected amine group. Processes to prepare the compounds of Formulae (II), (III), and (IV) are also disclosed. 

4-pyridinone compounds and their use for cancer

As a preferred alternative to whipping a boat-line with tape or a wax material to limit wearing and unraveling over time, the apparatus of the invention affords a secure, more attractive appearance through the use of a pair of cylinders, one of which receives the boat-line, and the other of which threads over it, with the effective screwing of the two together additionally producing a force upon a series of compressible fingers that extend inwardly from the outside surface of the first cylinder in clamping onto and holding the boat-line in position. The two cylinders may be capped in providing a finished-off appearance to the construction when the line is thus secured.

Boat-line tie-off apparatus

Growing community of inventors

Princeton, NJ, United States of America

William P Gallagher