Production and use for taxol and muramic acyl dipeptide conjugate substance of immune reinforcer

A technology of muramyl dipeptide and paclitaxel derivatives, which is applied in medical preparations of non-active ingredients, organic chemistry, and pharmaceutical formulations, and can solve problems such as fatalities, low water solubility of paclitaxel, and allergic reactions

Inactive Publication Date: 2005-12-28
INST OF MATERIA MEDICA AN INST OF THE CHINESE ACAD OF MEDICAL SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

But the water solubility of paclitaxel is very low (0.025mg / ml), must add 50% polyethoxylated castor oil (Cremophor EL) emulsifier and 50% ethanol in its formula, administer after diluting with normal saline then, Its biggest shortcoming is that Cremophor EL can cause severe allergic reaction, even death (Science, 1992, 256: 311.)

Method used

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  • Production and use for taxol and muramic acyl dipeptide conjugate substance of immune reinforcer
  • Production and use for taxol and muramic acyl dipeptide conjugate substance of immune reinforcer
  • Production and use for taxol and muramic acyl dipeptide conjugate substance of immune reinforcer

Examples

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Embodiment 1

[0038] Example 1: Synthesis of 7-silyletherified-10-deacetyl-Baccatin III:

[0039] Dissolve 1.1g (2.0mmol) of 10-deacetyl-Baccatin III in 20ml of anhydrous pyridine, blow in nitrogen gas, slowly add 3.4ml (20mmol) of triethylsilyl chloride dropwise under stirring at room temperature, react for 10 hours, and add an appropriate amount of acetic acid Ethyl ether was diluted, and the dilutions were sequentially washed with saturated CuSO 4 solution (200ml×3) and water, and the organic layer was washed with anhydrous Na 2 SO 4 Dried and concentrated to obtain 1.1 g of white powder with a yield of 84%.

Embodiment 2

[0040] Embodiment 2: Synthesis of 7 silicon etherification-Baccatin III:

[0041] Dissolve 0.5g (0.76mmol) of 7-silicate-10-deacetyl-Baccatin III in 30ml of anhydrous pyridine, blow in nitrogen, add 1.5ml of acetic anhydride (15.4mmol) under ice-cooling, and place at room temperature Stir for 72 hours, add an appropriate amount of ethyl acetate to dilute, and then wash with saturated CuSO 4 solution (200ml×3) and water, and the organic layer was washed with anhydrous Na 2 SO 4 After drying and concentration, 335 mg of white powder was obtained, with a yield of 63%.

Embodiment 3

[0042] Example 3: Synthesis of 7-acetoxy-Baccatin III:

[0043] Dissolve 2.0 g (3.676 mmol) of 10-deacetyl-Baccatin III in 100 ml of anhydrous pyridine, add 15 ml of acetic anhydride at room temperature, and stir at room temperature for 3 days. Concentrate under reduced pressure to remove excess pyridine, and recrystallize with methanol / water to obtain 2.31 g of white needle crystals (containing 19% of 7,10,13-triacetoxy Baccatin III), with a yield of 81.0%, which can be used for protection without recrystallization. Synthesis of Taxol. Purify by column chromatography to obtain pure 7-acetoxy-Baccatin III.

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Abstract

Production of paclitaxel and muramic acid dipeptide conjugale as immunopotentiator and its use are disclosed. The process is carried out by combination of solid-phase chemistry and liquid-phase chemistry. It improves water solubility of paclitaxel.

Description

technical field [0001] The invention relates to a conjugate of anticancer prodrug paclitaxel and muramyl dipeptide (muramyl alanyl isoglutamine) and a preparation method thereof. Specifically, three series of compounds conjugated with muramyl dipeptide at the 7-O position, 2'-O position and 3'-N position of paclitaxel and their preparations. Compared with paclitaxel, the conjugate involved in the invention has better water solubility and good biological activity. Background technique [0002] Paclitaxel is one of the natural diterpenoids isolated from the genus Taxus. As early as 1962, the U.S. Department of Agriculture (USDA) collected Pacific yew (Taxus brevifolia) bark for the U.S. National Cancer Institute (NCI) to screen anticancer active ingredients. In 1963, Wall and Wani extracted the crude extract; in 1969, it was determined that the active ingredient in the crude extract was paclitaxel. In 1971, Wani et al isolated pure paclitaxel and determined its structure by...

Claims

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Application Information

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IPC IPC(8): A61K47/64C07D305/14
Inventor 刘刚程桂芳王楠李旭琴于君丽徐嵩方起程
Owner INST OF MATERIA MEDICA AN INST OF THE CHINESE ACAD OF MEDICAL SCI
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