Title of Invention

EPOTHILONE DERIVATIVES AND THEIR SYNTHESIS

Abstract

The invention relates to epothilone analog represented by formula (I) wherein (i) R2 is absent or oxygen; "a" can be either a single or double bond; "b" can be either absent or a single bond; and "c" can be either absent or a single bond, with the proviso that if R2 is oxygen then "b" and "c" are both a single bond and "a" is a single bond; if R2 is absent then **b" and "c" are absent and "a" is a double bond; and if "a" is a double bond, then R2, "b" and "c" are absent; R3 is a radical selected from the group consisting of hydrogen; lower alkyl; -CH=CH2; -CCH; -CH2F; -CH2C1; -CH2-0H; -CH2-0-(Cl-C6-alkyl); and -CH2-S-(Cl-C6-alkyl); R4 and R5 are independently selected from hydrogen, methyl or a protecting group; and Rl is as defined in the specification, or a salt of a compound of formula (I) where a salt-forming group is present. A further aspect of the invention is related to the synthesis of epothilone E. These compounds have inter alia microtubule depolymerisation inhibiting activity and are e.g. useful against proliferative diseases.

Full Text

The present invention relates to epothilone analogs having side chain modifications and to methods for producing such compounds, their use in the therapy of diseases or for the manufacture of pharmaceutical preparations for the treatment of diseases, as well as to novel intermediates used in the synthesis of such analogs and new methods of synthesis. Background of the invention The epothilones (1-5) are natural substances which exhibit cytotoxicity even against paclita-xel-resistant tumor cells by promoting the polymerization of a- and p-tubulin subunits and stabilizing the resulting microtubule assemblies. Emotions displace palliate (the active principle of TAXOL ") from its microtubule binding site and are reported to be more potent than palliate with respect to the stabilization of microtubules. What is needed are analogs of epothilone A and B that exhibit superior pharmacological properties, especially one or more of the following properties: an enhanced therapeutic index (e.g. a larger range of cytotoxic doses against e.g. proliferative diseases without toxicity to normal cells), better pharmacokinetic properties, better phannacodynamic properties, better solubility in water, better efficiency against tumor types that are or become resistant to treatment with one or more other chemotherapeutics, better properties to agitate manufacture of formulations, e.g. better solubility in polar solvents, especially those composing water, enhanced stability, convenient manufacture of the compounds as such, improved inhibition of proliferation at the cellular level, high levels of microtubule stabilizing effects, and/or specific phannacologic profiles. Detailed description of the invention: The present invention relates to new compounds that surprisingly have one or more of the above-mentioned advantages. One major aspect of the invention relates to an epottiilone analog compound represented by the formula I wherein the waved bond indicates that bond "a" is present either in the or in the trans form; (1) R2 is absent or oxygen; "a" can be either a single or double bond; 'b" can be either absent or a single bond; and "c" can be either absent or a single bond, with the proviso that if Rj is oxygen then "b" and V are both a single bond and V is a single bond; if R2 is absent then V and "c" are absent and V is a double bond; and if "a" is a double bond, then Rj, V and "c" are absent; a radical selected from the group consisting of hydrogen; lower alkyl, especially methyl, ethyl, n-propyl. iso-propyl, n-butyl. iso-butyl, tert-butyl. n-pentyl, n-hexyl; -CH=CH2; ; -CH2F; -CH2CI; -CH2-OH; -CH2-0 especially -CHj-O-CHs; and -CHj-S- especially -CH2-S-CH3; R4 and R5 are independently selected from hydrogen, methyl or a protecting group, preferably hydrogen; and WE CLAIM: 1. An epothilone compound represented by the formula I Wherein The waved bond indicates that bond "a" is present either in the is or in the trans form; Wherein has the meanings given under formula I in claim 1.

Documents:

in-pct-2000-841-che-abstract.pdf

in-pct-2000-841-che-assignment.pdf

in-pct-2000-841-che-claims filed.pdf

in-pct-2000-841-che-claims granted.pdf

in-pct-2000-841-che-correspondence-others.pdf

in-pct-2000-841-che-correspondence-po.pdf

in-pct-2000-841-che-descripition(complete) filed.pdf

in-pct-2000-841-che-descripition(complete) granted.pdf

in-pct-2000-841-che-form 1.pdf

in-pct-2000-841-che-form 26.pdf

in-pct-2000-841-che-form 3.pdf

in-pct-2000-841-che-form 5.pdf

in-pct-2000-841-che-other documents.pdf

in-pct-2000-841-che-pct.pdf