Napro Biotherapeutics, Inc.

Bristol-myers Squibb Compnay

Merck Sharp + Dohme Corp.

Schering Corporation

Virginia Tech Intellectual Properties, Inc.

Xian Liang

James D McChesney

Jan J Zygmunt

Nicholas J Sisti

Herbert R Brinkman

Madhavi C Chander

Jesse K Wong

Paul E McNamara

John F Kadow

Duane A Burnett

John W Clader

Hubert B Josien

Wen-Lian Wu

Mark D Wittman

Dmitri A Pissarnitski

Hongmei Li

Zhiqiang Zhao

Thavalakulamgara K Sasikumar

David G Kingston

Ruo Xu

Thomas A Bara

Martin Domalski

Jianshe Kong

Tao Meng

Medhavi C Chander

Thomas J Altstadt

Yan Jin

Martin S Domalski

Paul Mcnamara

Disclosed are novel gamma secretase inhibitors of the formula. Also disclosed are methods of inhibiting gamma-secretase, methods of treating neurodegenerative diseases, and methods of treating Alzheimer's Disease. Also disclosed are processes for preparing alkenes in one reaction step using a mixture of an aldehyde (or ketone) and an alkyl substituted with two electron withdrawing groups, and reacting the mixture with: (a) a sulfonyl halide (e.g., a sulfonyl chloride) and a basic tertiary amine, or, (b) a sulfonyl anhydride and a basic amine, or (c) an aryl-C(O)-halide and a basic tertiary amine, or (d) an aryl-C(O)&#x2014;O&#x2014;C(O)-aryl and a basic tertiary amine, or (e) an heteroaryl-C(O)-halide and a basic tertiary amine, or (f) a heteroaryl-C(O)&#x2014;O&#x2014;C(O)-heteroaryl and a basic tertiary amine. 

Tetrahydropyranochromene gamma secretase inhibitors

This application discloses a novel process to synthesize 3-amino-4-substituted pyrazole derivatives, which may be used, for example, as intermediates to prepare compounds having, for example, pharmaceutical utility.

Synthesis of 3-amino-4-substituted pyrazole derivatives

The present invention relates to a method of producing paclitaxel or a paclitaxel analog comprising the esterification of C-7, C-10 di-CBZ 10-deacetylbaccatin III with an N-carbamate protected, C-2-protected 3-phenyl isoserine side chain. The C-7, C-10 carbobenzyloxy groups are then replaced with hydrogen and an acyl group is substituted at the C-3&prime; nitrogen. The resulting compound is acylated at the C-10 hydroxyl position, and deprotected at the C-2&prime; position by replacing the hydroxyl protecting group with hydrogen to produce paclitaxel or a paclitaxel analog. The present invention also relates to alternative methods of acylating a 10-hydroxy paclitaxel analog. The first method comprises dissolving a 10-hydroxy paclitaxel analog in an acceptable ether solvent therefor to form a first solution at a first temperature. The first solution is then cooled to a second temperature, and an alkali base is added to form an intermediate compound having a metal alkoxide at the C-10 position thereof, after which an acylating ageht is then added. The second method comprises dissolving a 10-hydroxy paclitaxel analog in an acceptable ether solvent therefor. An alkali salt is added, and a trialkyl amine base or pyridine is next added, followed by the addition of an acylating agent. The present invention is additionally directed to a C-10 metal alkoxide chemical intermediate for use in producing paclitaxel or paclitaxel analogs.

Methods and useful intermediates for paclitaxel synthesis from C-7, C-10 di-cbz 10-deacetylbaccatin III

A method of acylating C-2' O-protected-10-hydroxy taxol selectively at the C-10 hydroxyl position over the C-7 hydroxy position thereof to produce C-2' O-protected taxol is accomplished first by dissolving C-2' O-protected-10-hydroxy taxol in an acceptable ether solvent therefor, such as tetrahydrofuran, to form a first solution at a first temperature. The first solution is then cooled to a second temperature, and a lithium base, preferably n-butyl lithium, is added to form an intermediate compound having a lithium alkoxide at the C-10 position thereof. An acylating agent, such as acetyl chloride, is then added. The resulting solution may be quenched, for example with ammonium chloride, to eliminate excess of the acylating agent and the lithium base. The result is a solution containing C-2' O-protected taxol. This solution may then be washed, concentrated and purified. The present invention is also directed to C-10 lithium alkoxide intermediate compounds for the production of paclitaxel.

Method for conversion of C-2'-O-protected-10-hydroxy taxol to

A method of acylating C-2' O-protected-10-hydroxy taxol selectively at the C-10 hydroxyl position over the C-7 hydroxy position thereof to produce C-2' O-protected taxol is accomplished first by dissolving C-2' O-protected-10-hydroxy taxol in an acceptable ether solvent therefor, such as tetrahydrofuran. A lithium salt, preferably lithium chloride, is added. A trialkylamine base or pyridine is next added, followed by the addition of an acylating agent, such as acetyl chloride. The resulting solution may be quenched, for example with ammonium chloride, to eliminate excess of the acylating agent. This solution may then be diluted with ethyl acetate to form an organic phase and an aqueous phase, with the organic phase being washed and thereafter reduced. Recrystallization and column chromatography may be employed to purify the C-2' O-protected taxol.

Method for selective acylation of C-2'-O-protected-10-hydroxy-taxol at

A method of acylating 10-deacetylbaccatin III at the C-10 position over the C-7 hydroxy position thereof to produce baccatin IIII is accomplished first by dissolving 10-deacetylbaccatin III in an acceptable ether solvent therefor, such as tetrahydrofuran. A lithium salt, preferably lithium chloride, is added. A trialkylamine base or pyridine is next added, followed by the addition of an acylating agent, such as acetyl chloride. The resulting solution may be quenched, for example with ammonium chloride, to eliminate excess of the acylating agent. The result is baccatin III in solution. This solution may then be diluted with ethyl acetate to form an organic phase and an aqueous phase, with the organic phase being washed and thereafter reduced. Recrystallization and column chromatography may be employed to purify the baccatin III.

Alternate method for acylating 10-deacetylbaccatin III selectively at

The present invention concerns novel paclitaxel derivatives, their use as antitumor agents, and pharmaceutical formulations.

7-deoxy-6-substituted paclitaxels

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Boulder, CO, United States of America

Xian Liang