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Novel ansamycin derivatives

A technology of ansamycin and derivatives, applied in the field of derivatives of ansamycin compounds, can solve problems such as side effects

Inactive Publication Date: 2008-08-27
BIOTICA TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0021] While these derivatives exhibit reduced hepatotoxicity, they still have only limited water solubility and require the use of solubilizing carriers (e.g. Cremophore(R), DMSO-lecithin), which themselves may produce side effects in some patients

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0271] Embodiment 1: Synthesis of 18-O-(N, N'-dimethylethylenediamine-N'-carbamoyl)-18,21-dihydromacbecin hydrochloride, 1 (route 1)

[0272] Conversion of Macbecin to 18,21-dihydromacbecin

[0273] Macbecin (107.8 mg, 0.193 mmol) was dissolved in ethyl acetate (25 mL) and treated with 96 mM sodium dithionite solution (3 x 5 mL). For each treatment, the phases were mixed vigorously in a separatory funnel and the aqueous layer was drained off. The organic layer turned from dark yellow to essentially colorless. The organic layer was then washed with water (3×10 mL), then dried over anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure to give 18,21-dihydromacbecin as an off-white glassy solid (105.0 mg, 0.187 mmol, 97% isolated yield). 18,21-Dihydromacbecin was used without further purification.

[0274] LCMS: macbecin, RT = 8.2 minutes ([M-H]- , m / z=557.5, [M+Na] + , m / z=581.2) UVλ 最大 =256 (shoulder) nm; 18,21-dihydromacbecin, RT=3.5 minut...

Embodiment 2

[0283] Embodiment 2: Synthesis of 18-O-(N, N'-dimethylethylenediamine-N'-carbamoyl)-18,21-dihydromacbecin hydrochloride, 1 (route 2)

[0284] Preparation of 18-O-(4-nitrophenylcarbonate)-18,21-dihydromacbecin

[0285] Macbecin II (0.30 g, 0.54 mmol) was dissolved in anhydrous dichloromethane (72 ml). To this solution was added solid 4-nitrophenyl chloroformate (0.183 g, 0.91 mmol), followed by 2,6-lutidine (0.217 ml, 1.87 mmol). Under an argon atmosphere at 50°C (oil bath), the reaction mixture was heated to reflux for 5 hours, the reactant was cooled to ambient temperature, washed successively with an equal volume of 1N HCl and water, washed over Na 2 SO 4 Dry, filter and remove the solvent under reduced pressure. The resulting material was purified on silica gel eluting with a stepwise gradient of acetone in hexanes (5-40% acetone in 5% increments) to afford the title compound. Isolated yield: 0.310 g (79%). in CDCl 3 NMR spectra obtained at medium and 400 MHz were con...

Embodiment 3

[0295] Embodiment 3: Synthesis of 18-O-(N-methylethylenediamine-N'-carbamoyl)-18,21-dihydromacbecin hydrochloride, 2

[0296] Preparation of N-trityl-N-methylethylenediamine

[0297] Under argon atmosphere, N-methylethylenediamine (5.96 g, 80.41 mmol) was dissolved in dichloromethane (100 mL). The stirred mixture was cooled to 0°C, then a solution of trityl chloride (6.47g, 23.21mmol) in dichloromethane (40ml) was added dropwise slowly. After the addition of the solution was complete, the reaction mixture was stirred at 0°C for an additional 30 minutes at which time the cooling bath was removed and the reaction was allowed to warm to room temperature. The mixture was stirred overnight at room temperature under an argon atmosphere. The solvent was removed from the resulting solution, ethyl acetate (200 mL) and saturated NaHCO were added 3 aqueous solution (200 mL). The resulting mixture was shaken, separated and the aqueous layer was extracted with another equal volume of e...

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Abstract

The present invention provides inter alia derivatives of a benzenoid ansamycin which contain a 1,4-dihydroxyphenyl moiety bearing at position 6 an amino carboxy substituent, in which position 2 and the carboxy substituent at position 6 are connected by an aliphatic chain of varying length characterised in that one or both of the 1-hydroxy and the 4-hydroxy position(s) of the phenyl ring are independently derivatised by an aminoalkyleneaminocarbonyl group, which alkylene group, which may optionally be substituted by alkyl groups, has a chain length of 2 or 3 carbons and which derivatising group(s) increase the water solubility and / or the bioavailability of the parent molecule but which are capable of being removed in-vivo. Such compounds are described for the treatment of cancer or B-cell malignancies.

Description

technical field [0001] The present invention relates to derivatives of ansamycin compounds, which are useful, for example, in the treatment of cancer or B-cell malignancies, in particular said derivatives are prodrugs of ansamycin compounds. The invention also provides methods for the production of these compounds and their use in medicine, especially in the treatment and / or prevention of cancer or B-cell malignancies. Background technique [0002] The development of highly specific anticancer drugs with low toxicity and favorable pharmacokinetic properties constitutes a major challenge in anticancer therapy. [0003] The 90 kDa heat shock protein (Hsp90) is a large number of chaperones involved in protein folding and assembly, many of which are involved in signaling pathways (see Neckers, 2002; Sreedhar et al., 2004a; Wegele et al., 2004 and references therein). Nearly 50 of these so-called clients have been identified and include steroid receptors, non-receptor tyrosine ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D225/06A61K31/395A61P35/00
CPCC07D225/06A61P35/00A61K31/395
Inventor A·R·古布林B·威尔金森S·J·摩斯M-Q·张A·D·麦克尔西尼C·J·马丁
Owner BIOTICA TECH
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