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

Abstract

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′-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.

Description

FIELD OF THE INVENTION[0001]The present invention relates to novel chemical strategies for the total synthesis of enantiomerically-pure 7-(2′-trimethylsilyl)ethyl camptothecin (BNP1350; Karenitecin; Cositecan).BACKGROUND OF THE INVENTIONI. Camptothecin (CPT) and Initial Clinical Trials[0002]Camptothecin (CPT; IUPAC Nomenclature: (S)-4-Ethyl-4-hydroxy-1H-pyrano[3′,4′:6,7]indolizino[1,2-b]quinoline-3,14(4H,12H)-dione) and certain of its analogs have been shown to possess varying degrees of anti-neoplastic activity. Presently, two CPT analogs (Irinotecan and Topotecan, as discussed below) have been approved for therapeutic use in the United States by the Food and Drug Administration (FDA) and globally in several other territories by other regulatory agencies for various forms of solid neoplasms.[0003]CPT was initially isolated in 1966 by Wall, et al., from Camptotheca accuminata, (Nyssaceae family) a Chinese yew. See, Wall, M. E., et al., Plant chemotherapeutic agents. I. The Isolation...

AI Technical Summary

Benefits of technology

Karenitecin exhibits potent antitumor activity with reduced toxicity and resistance, maintaining lactone stability and bioavailability, effectively inhibiting Topoisomerase I with improved pharmacokinetic properties compared to other camptothecin derivatives.

Problems solved by technology

By the early 1970's, CPT had reached Phase I and Phase II clinical trials and although it was found to possess anti-tumor activity, there were numerous deleterious physiological side-effects associated with its use.

These toxicities, found during early clinical studies, rendered the drug “unmanageable” during this time period.

However, it was subsequently established that this formulation resulted in hydrolysis of the lactone E-ring of the camptothecin molecule, thus forming the water soluble carboxylate form of CPT which only possessed approximately one-tenth or less of the anti-tumor potency of the original, non-hydrolyzed lactone form of CPT.

The clinical trials performed using the sodium hydroxide-formulated CPT provide to be highly disappointing, due to both the frequently-observed significant systemic toxicities and the lack of anti-neoplastic activity.

This low aqueous solubility of CPT in the lactone form greatly limited the practical clinical utility of the drug because prohibitively large volumes of fluid had to be administered to the subject in order to provide an effective dose of the drug.

Since normal DNA is super-coiled, and tightly fitted in the chromosomes, the DNA-replication fork is unable to synthesize new DNA out of this topological constrained DNA.

Topo I acts in an ATP-independent fashion, by binding to super-coiled DNA and cleaving a phosphodiester bond, resulting in a single-strand break.

These breaks may lead to cell cycle arrest in the S / G2-phase, activation of apoptosis pathways, and finally to cell death.

As a result of this, Topo I inhibitors are only lethal in the presence of ongoing DNA replication or RNA transcription.

Because the S-phase is a relatively short phase of the cell cycle, longer exposure to the drugs results in increased cell killing.

Brief exposure of tumor cells to the drugs produces little or no cell killing, and quiescent cells are refractory.

It may be ascertained from pharmacological and biochemical data, that many of the previously synthesized camptothecin analogs possess a number of inherent limitations which markedly decreases their usefulness as anti-cancer agents.

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