Bionumerik Pharmaceuticals, Inc.

Andrey Malakhov

Frederick H Hausheer

Harry Kochat

Xinghai Chen

Qiuli Huang

The present invention discloses and claims five (5) novel, highly efficient synthetic routes for the total synthesis of enantiomerically-pure (i.e., 99%) 7-(2'-trimethylsilyl)ethyl camptothecin (BNP1350; Karenitecin; Cositecan). These aforementioned synthetic schemes are the first to disclose the total syntheses of 7-(2&#x2032;-trimethylsilyl)ethyl camptothecin using a highly novel direct, non-linear and convergent synthetic strategy which involves annealing the key C7-(trimethylsilyl)ethyl side chain-bearing A ring key synthons to an enantiomerically-pure tricyclic pyridone; rather than through the conventional methodology which incorporates the C7-(trimethylsilyl)ethyl side chain as the final synthetic step on a totally synthesized camptothecin parent compound. The current novel synthetic approaches reported herein since utilize desirably functionalized A-ring with preinstalled trimethyl silyl ethyl side chain, the aforementioned synthetic methodologies have a wider scope of making wide range of pharmaceutically relevant A-ring substituted BNP1350 analogs by substituting desirably functionalized nitro or protected amino phenyl carboxy A-ring as the starting material.

Methods for the total chemical synthesis of enantiomerically-pure 7-(2'-trimethylsilyl)ethyl camptothecin

The present invention discloses: (i) two novel deuterated Karenitecin&#xae; analogs, pharmaceutically-acceptable salts, and/or derivatives thereof; (ii) methods of synthesis of said novel deuterated Karenitecin&#xae; analogs, pharmaceutically-acceptable salts, and/or derivatives thereof; (iii) pharmaceutically-acceptable formulations comprising said novel deuterated Karenitecin&#xae; analogs, pharmaceutically-acceptable salts, derivatives thereof; and/or, optionally, one or more additional chemotherapeutic agents; and (iv) methods of administration of said novel deuterated Karenitecin&#xae; analogs, pharmaceutically-acceptable salts, derivatives thereof; and/or, optionally, one or more additional chemotherapeutic agents, to subjects in need thereof.

Deuterated analogs of (4S)-4-ethyl-4-hydroxy-11-[2- (trimethylsilyl)ethyl]-1H-pyrano[3', 4&#x2032;:6,7] indolizino [1,2-b]quinoline-3,14(4H, 12H)-dione and methods of use thereof

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San Antonio, TX, United States of America

Andrey Malakhov