Bionumerik Pharmaceuticals, Inc.

Harry Kochat

Frederick H Hausheer

Qiuli Huang

Xinghai Chen

Kesavaram Narkunan

Ye Wu

Zejun Xiao

Andrey Malakhov

Jianyan Wang

Vincent Gerusz

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

Novel compositions and formulations are disclosed that have use as toxicity-reducing agents for various chemotherapeutic agents and as treatment for certain diseases and conditions. The compositions of matter are amino acid and peptide heteroconjugated disulfides of 2-mercaptoethane sulfonate sodium.

Compounds and methods for reducing undesired toxicity of chemotherapeutic agents

Disclosed herein are novel platinum-based analogs with a single substituted azole ligand: RN&#x2550;NR, wherein the RN&#x2550;NRfunctional group is covalently bonded to the platinum through nitrogen of NR. The analogs also have nitrogen donor ligands capable of forming hydrogen bonds with the bases in DNA or RNA, and one or more leaving groups which can be displaced by water, hydroxide ions or other nucleophiles, which is thought to form active species in vivo, and then, form cross-linked complexes between nucleic acid strands, principally between purines in DNA (or RNA), i.e., at the Guanine or Adenine bases, thereof. These platinum analogs may also be more easily transported into tumor cells, due to their increased lipophilicity and are likely to be useful as anti-neoplastic agents, and in modulating or interfering with the synthesis or replication or transcription of DNA or translation or function of RNA in vitro or in vivo, as they are potentially capable of forming a platinum coordinate complex with an intact or nascent DNA or RNA and thereby interfering with cellular synthesis, transcription or replication of nucleic acid polynucleotides.

Monoazole ligand platinum analogs

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

Disclosed herein are novel platinum-based analogs with a single substituted imine ligand: RRC&#x2550;NR, wherein the RRC&#x2550;NRfunctional group is covalently bonded to the platinum through nitrogen. The analogs also have nitrogen donor ligands capable of forming hydrogen bonds with the bases in DNA or RNA, and one or more leaving groups which can be displaced by water, hydroxide ions or other nucleophiles, which is thought to form active species in vivo, and then, form cross-linked complexes between nucleic acid strands, principally between purines in DNA (or RNA), i.e., at the Guanine or Adenine bases, thereof. These platinum analogs may also be more easily transported into tumor cells, due to their increased lipophilicity and are likely to be useful as anti-neoplastic agents, and in modulating or interfering with the synthesis or replication or transcription of DNA or translation or function of RNA in vitro or in vivo, as they are potentially capable of forming a platinum coordinate complex with a intact or nascent DNA or RNA and thereby interfering with cellular synthesis, transcription or replication of nucleic acid polynucleotides.

Monoimine ligand platinum analogs

The invention claimed herein relates to an improvement in a process for synthesizing a compound of formula Ib: 

Process for synthesizing 6-quinazolinyl-ethyl-benzoyl and related antifolates

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

Process for making camptothecin derivatives

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.

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San Antonio, TX, United States of America

Harry Kochat