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Epothilones derivatives, their synthesis and uses

A compound, single bond technology, applied in the field of epsilon analogs, can solve the problem of unsuitable coupling of 24 with vinylstannane 8q

Inactive Publication Date: 2005-03-09
NOVARTIS AG +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0307] Unfortunately, these conditions are not suitable for the coupling of 24 with vinylstannane 8q (see Scheme 5)

Method used

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  • Epothilones derivatives, their synthesis and uses
  • Epothilones derivatives, their synthesis and uses
  • Epothilones derivatives, their synthesis and uses

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0237] Example 1: 5-Methylpyridine Analog D of Epsilon B

[0238] Process 1B

[0239]

[0240] To a solution of B (20 mg, 0.035 mmol) in degassed dimethylformamide (=DMF; 350 μl, 0.1 M) was added C (17 mg, 0.077 mmol, 2.1 eq) followed by AsPh 3 (4 mg, 0.4 equiv), PdCl 2 (MeCN) 2(2 mg, 0.2 equiv) and CuI (1 mg, 0.1 equiv), and the resulting slurry was placed in an oil bath at 80-85°C for 25 minutes. The reaction mixture was then cooled to room temperature and DMF was distilled off. The residue was dissolved in ethyl acetate and filtered through a small plug of silica eluting with hexane / ethyl acetate (1 / 1, v / v). The solution was then concentrated in vacuo and purified by preparative TLC (hexanes / ethyl acetate 1 / 2) to give compound D: MS (electrospray): Expected: (M+H) + =502, measured: 502.

[0241] 1 H-NMR (600MHz, CDCl 3 ): 8.37 (s, 1H, pyridine H); 7.50 (d, l = 7,5Hz, 1H, pyridine H); 7.19 (d, l = 7.5Hz, 1H, pyridine H), 6.59 (s, 1H, = CH pyridine).

[0242] raw...

Embodiment 2

[0246] Example 2: Analogously to Example 1, the following examples were prepared:

[0247]

[0248]

Embodiment 3

[0249] Example 3: Total Synthesis of Epsilon E and Related Side Chain Modified Analogs by Stille Coupling Strategy

[0250] The first general synthesis of epsilone E(3) was accomplished via a strategy in which the key step was the Stille coupling between vinyl iodide 7 and the thiazole moiety (8h, Scheme 2a) (Stille et al. "International English Edition of Applied Chemistry" 1986, 25, 508-524; Farina et al. "Journal of Organic Reactions" 1997, 50, 1-65). The macrolactone core fragment 7 prepared by ring-closing olefin displacement (RCM) was then used to provide suitable and feasible various side-chain modified epsilon analogs (9) for biological evaluation ( Process 2b). The RCM reaction used to obtain 7 also provided the trans-macrolactone (11, Scheme 2b), which served as an alternative template for the Stille coupling process, providing an alternative arrangement of the analog 10.

[0251] Process 2:

[0252] a) Retrosynthetic analysis and strategy for the total synthesis ...

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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; -CH2Cl; -CH2-OH; -CH2-O-(C1-C6-alkyl); and -CH2-S-(C1-C6-alkyl); R4 and R5 are independently selected from hydrogen, methyl or a protecting group; and R1 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 microtubuli depolymerization inhibiting activity and are e.g. useful against proliferative diseases.

Description

Summary of the invention [0001] The present invention relates to epothilone analogues with side chain modifications, methods for preparing the compounds, their use in the treatment of diseases or in the preparation of pharmaceutical preparations for treatment of diseases, and in the analogues Novel intermediates and new synthetic methods in the synthesis of . [0002] government rights [0003] This invention was made with government support under Grant No. CA 46446 awarded by the National Institutes of Health. The US Government has certain rights in this invention. Background of the invention [0004] Epsilone (1-5) are natural substances that exhibit cytotoxicity even against paclitaxel-resistant tumor cells by promoting the polymerization of α- and β-tubulin subunits and stabilizing the resulting Microtubule Assembly. Epsilon displaces paclitaxel (the active ingredient of TAXOL™) from its microtubule-binding site and is reported to be more effective than paclitaxel in...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): A61K31/335A61K31/34A61K31/365A61K31/381A61K31/4178A61K31/422A61K31/427A61K31/4427A61P35/00A61P35/04A61P43/00C07D303/00C07D313/00C07D405/06C07D407/06C07D409/06C07D413/06C07D417/06C07D417/14C07D493/00C07D493/04
CPCC07D417/06C07D493/04C07D313/00Y02P20/55A61P35/00A61P35/02A61P35/04A61P43/00A61K31/335
Inventor K·C·尼古拉奥N·P·金M·R·V·芬雷Y·何F·罗施安格D·沃尔-路密斯H·瓦尔博格A·比高特
Owner NOVARTIS AG
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