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Covalent polycompound of water-soluble polysaccharide and taxane compound, and preparation method and medical application of covalent polycompound

A water-soluble polysaccharide technology, which is applied in chemical instruments and methods, active ingredients of silicon compounds, compounds of group 4/14 elements of the periodic table, etc., can solve the problems of difficult covalents and low yields, etc. Achieve the effect of good water solubility and single structure

Active Publication Date: 2014-03-19
王晖
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, this method has two disadvantages in practical application: one is the free primary amine, which can remove the benzoyl group on the side chain of paclitaxel; the other is that the yield is low
The reason is that docetaxel has 4 free alcoholic hydroxyl groups, among which the 7-position, 10-position, and 2′-position alcoholic hydroxyl groups can participate in chemical reactions, so it is difficult to prepare covalent bodies of docetaxel and polysaccharides with a single structure bigger

Method used

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  • Covalent polycompound of water-soluble polysaccharide and taxane compound, and preparation method and medical application of covalent polycompound
  • Covalent polycompound of water-soluble polysaccharide and taxane compound, and preparation method and medical application of covalent polycompound
  • Covalent polycompound of water-soluble polysaccharide and taxane compound, and preparation method and medical application of covalent polycompound

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0231] Embodiment 1: the synthesis of compound 1

[0232] Into a 250mL round bottom flask, add 9.32g (11.53mmol) of docetaxel, 2.20g (33.84mmol) of imidazole and 20mL of dimethylformamide solvent, and then add 5.21g (34.59mmol) of tert-butyldimethyl chloride silane. Stir for 12 hours at room temperature. After the reaction was complete, the reaction mixture was partitioned between saturated sodium chloride solution (250 mL) and ethyl acetate (250 mL), and the ethyl acetate layer was separated. The ethyl acetate layer was further washed twice with saturated sodium chloride solution (250mL×2) and dried over anhydrous magnesium sulfate, filtered, spin-dried, and subjected to silica gel column chromatography (eluent: ethyl acetate: petroleum ether / 10-70 %) to obtain 9.89g compound 1. Yield: 93%.

[0233] NMR analysis: 1 H NMR (300MHz, DMSO-D 6):δ7.98(d,2H,J=7.2Hz),7.72(t,1H,J=7.2Hz),7.63(t,2H,J=7.2Hz),7.58(d,1H,J=9.0Hz ),7.37(m,4H),7.15(brs,1H),5.77(t,1H,J=9.0Hz),5.39(d,1H,...

Embodiment 2

[0236] Embodiment 2: the synthesis of compound 2

[0237] Under the protection of nitrogen, 3.00g (3.25mmol) of compound 1 and 30mL of anhydrous tetrahydrofuran solvent were successively added to a 100mL round bottom flask, cooled to -70°C, and then 7.15mL (7.15mmol) of bis(trimethylsilyl)amino Lithium tetrahydrofuran solution, stirred for 1 hour. Then, 1.22 g of benzyl chloroformate (7.15 mmol) were added and the coolant was removed. After 2 hours, the reaction naturally rose to room temperature, at which point 3.0 mL of acetic acid was added to stop the reaction. After spinning to dryness, the reaction mixture was partitioned between saturated sodium chloride solution (100 mL) and ethyl acetate (100 mL), and the ethyl acetate layer was separated. The ethyl acetate layer was further washed twice with saturated sodium chloride solution (100mL×2) and dried over anhydrous magnesium sulfate, filtered, spin-dried, and subjected to silica gel column chromatography (eluent: ethyl ...

Embodiment 3

[0241] Embodiment 3: the synthesis of compound 3

[0242] Into a 100 mL round-bottomed flask, 3.50 g of compound 2, 10 mL of tetrahydrofuran and tetrabutylammonium fluoride (1.0 mmol×5.88 mL) were sequentially added, and stirred at room temperature for 2 hours. After the reaction was completed, the product was spin-dried and subjected to silica gel column chromatography (eluent: ethyl acetate: petroleum ether / 10-50%) to obtain 2.82 g of compound 3. Yield: 96%.

[0243] NMR analysis: 1 H NMR (300MHz, CDCl 3 ):δ8.10(d,2H,J=7.2Hz),7.63(t,1H,J=7.2Hz),7.51(t,2H,J=7.2Hz),7.32–7.40(m,10H),6.28 (s,1H),6.20(brs,1H),5.70(d,1H,J=7.2Hz),5.54(t,1H,J=9.0Hz),5.42(d,1H,J=7.2Hz),5.29 (d,1H,J=7.2Hz),5.20(m,4H),4.95(d,1H,J=9.0Hz),4.66(s,1H),4.32(d,1H,J=9.0Hz),4.18 (d,1H,J=9.0Hz),3.93(d,1H,J=6.6Hz),3.41(s,1H),2.62(m,1H),2.40(s,3H),2.33(m,1H) ,2.10(s,3H),1.97(m,4H),1.84(s,3H),1.65(m,1H),1.43(m,1H),1.37(s,9H),1.24(s,3H), 1.17(s,3H);

[0244] 13 C NMR (125MHz, CDCl 3 ):δ201.5, 174.9, 172.3...

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Abstract

The invention relates to a covalent polycompound of water-soluble polysaccharide and taxane, and a preparation method and medical application of the covalent polycompound. The method disclosed by the invention comprises the following step: connecting the taxane compound to the water-soluble polysaccharide through a covalent bond by adopting selective protection and selective deprotection methods and a plurality of degradable structure units, so as to obtain the covalent polycompound which can retain the biological activity of the taxane compound and is relatively simplex in structure. The novel covalent polycompound is good in water solubility, and can replace an existing clinical taxane preparation free of a cosolvent with toxic and side effects.

Description

technical field [0001] The invention relates to a kind of water-soluble polysaccharide taxane copolymer compound, its preparation method and its medical application. The present invention also relates to an intermediate compound of a water-soluble polysaccharide taxane, and the compound or copolymer compound has antitumor activity. Background technique [0002] Clinically used taxane anticancer agents include paclitaxel (Paclitaxel, Taxol) and docetaxel (also known as docetaxel, Docetaxel, Docetere). [0003] [0004] This type of compound is a tubulin stabilizer with significant anticancer activity and has been approved for marketing in more than 40 countries. of therapeutic drugs. However, taxane therapeutic agents are poor in water solubility, and paclitaxel and docetaxel preparations for clinical use need to add co-solvents such as Cremophor EL (containing polyoxyethylene castor oil) and Tween-80. However, Cremophor EL can cause severe allergic reactions and seriou...

Claims

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Application Information

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IPC IPC(8): C08B37/00C08B37/08C08B31/12A61K31/721A61K31/715A61K31/728A61K31/718C07D305/14C07D405/12C07F7/18C07F9/655A61K31/337A61K31/4192A61K31/695A61K31/665A61P35/00A61P35/02C07K5/062A61K47/48
Inventor 王晖周莉亚王岳南胡威郝春瑞吴代友王乐平王学华胡小鹏程前应王学平周有全吴结旺胡晓弟王金焰郭东升王业东储金花程海军
Owner 王晖
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