Bionumerik Pharmaceuticals, Inc.

Xinghai Chen

Harry Kochat

Frederick H Hausheer

Qiuli Huang

Kesavaram Narkunan

Vincent Gerusz

Pavankumar Nv Petluru

Andrey Malakhov

Ye Wu

Jianyan Wang

Pavankumar N V Petluru

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

Disclosed herein are novel platinum-based analogs possessing two nitrile substituent groups (bis-nitrile) covalently-bonded to the platinum. Also disclosed herein are the reaction schemes for the synthesis of said platinum complexes, as well as quantitative in vitro IC50 data.

Platinum analogs with bis-nitrile-containing ligands

The novel C10-modified camptothecin analogs, and pharmaceutically-acceptable salts thereof, of the present invention: (i) possess potent antitumor activity (i.e., in nanomolar or subnanomolar concentrations) for inhibiting the growth of human and animal tumor cells in vitro; (ii) are potent inhibition of Topoisomerase I; (iii) lack of susceptibility to MDR/MRP drug resistance; (iv) require no metabolic drug activation: (v) lack glucuronidation of the A-ring or B-ring; (vi) reduce drug-binding affinity to plasma proteins; (vii) maintain lactone stability; (viii) maintain drug potency; and (ix) possess a low molecular weight (e.g., MW&#x3c;600).

C10-substituted camptothecin analogs

The novel C7-modified camptothecin analogs, and pharmaceutically-acceptable salts thereof, of the present invention: (i) possess potent antitumor activity (i.e., in nanomolar or subnanomolar concentrations) for inhibiting the growth of human and animal tumor cells in vitro; (ii) are potent inhibition of Topoisomerase I; (iii) lack of susceptibility to MDR/MRP drug resistance; (iv) require no metabolic drug activation: (v) lack glucuronidation of the A-ring or B-ring; (vi) reduce drug-binding affinity to plasma proteins; (vii) maintain lactone stability; (viii) maintain drug potency; and (ix) possess a low molecular weight (e.g., MW&#x3c;600).

C7-substituted camptothecin analogs

This invention relates to novel salts of medicinal disulfides. The compounds include a terminal sulfonate or phosphonate moiety, and have many uses, such as toxicity reducing agents when administered with many antineoplastic agents.

Medicinal disulfide salts

A process for synthesizing substantially enantiomerically pure L-amino acids, particularly L-&#x3b3;-methylene glutamic acid, and esters and salts thereof. The process includes the derivatization of (2S)-pyroglutamic acid, and the decyclization of the resulting derivative to form the desired end product.

Process for synthesizing L-&#x3b3;-methylene glutamic acid and analogs

A process for synthesizing highly lipophilic derivatives of camptothecin. The process includes reacting dissolved, underivatized camptothecin with an aldehyde in a modified Minisci-type alkylation reaction to produce 7-substituted derivatives of camptothecin.

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San Antonio, TX, United States of America

Xinghai Chen