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CA-4 derivatives and preparation method and medicinal application thereof

A use and drug technology, applied in the field of Combretastatin A-4 derivatives, in the field of tumor blood vessel inhibitory effect, can solve the problems of affecting the clinical use effect, easy to produce drug resistance, etc.

Active Publication Date: 2013-07-03
CHINA PHARM UNIV +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, due to the angiogenesis rescue response and the susceptibility and complexity of cancer gene mutations, the existing single-target or multi-target TAIs based on tumor signaling pathways are prone to drug resistance, which affects their clinical use. Effect

Method used

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  • CA-4 derivatives and preparation method and medicinal application thereof
  • CA-4 derivatives and preparation method and medicinal application thereof
  • CA-4 derivatives and preparation method and medicinal application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0089] N-(2,3,4,6-tetra-O-acetyl-1-deoxy-β-D-glucopyranosyl)-4-((Z)2'-methoxy-5'-(3 ", 4", 5 "-trimethoxystyryl) phenoxy) -4-oxobutyramide (I-2) preparation

[0090] (E)-3-(3’-Hydroxy-4’-methoxy)phenyl-2-(3”, 4”, 5”-tri-methoxy)phenyl-acrylic acid (1)

[0091] Add 3,4,5-trimethoxyphenylacetic acid (50g, 0.22mol), 3-hydroxyl-4-methoxybenzaldehyde (34g, 0.22mol), 62.5ml triethylamine and 150ml Acetic anhydride, stir and heat up to 140°C, react for 4h, stop heating, cool to 10°C, slowly add 200ml of concentrated hydrochloric acid dropwise, and leave overnight at room temperature. A khaki solid precipitated out, the reaction was stopped and the solid was filtered out, and recrystallized with about 100ml of ethanol to obtain 47.5g of a pure yellow needle, with a yield of 61%, m.p.184-186°C (literature value: 184-186°C [Bioorg . Med. Chem., 2005, 13(11): 3853-3864])

[0092] 1 HNMR (300MHz, DMSO), δ (ppm): 12.42 (1H, s, COOH), 8.95 (1H, s, OH), 7.57 (1H, s, =CH), 6.81 (1H, d, J ...

Embodiment 2

[0106] N-(2,3,4,6-tetra-O-acetyl-1-deoxy-β-D-galactopyranosyl)-4-((Z)2'-methoxy-5'-( 3 ", 4 ", 5 "-trimethoxystyryl) phenoxy) -4-oxobutyramide (I-5) preparation

[0107] Will G 2 -NH 2 (0.8g, 2.3mmol) was dissolved in DMF (12ml). Then 2b (0.92g, 2.3mmol), EDCI (0.44g, 2.3mmol), HOBt (0.31g, 2.3mmol) were added in batches successively, and stirred at room temperature for 24h. Add dichloromethane (80ml) to the reaction solution, wash with water (2×100ml), wash with saturated brine (3×100ml), dry, filter with suction, evaporate the solvent under reduced pressure, and perform silica gel column chromatography (petroleum ether / ethyl acetate=3 / 2), to obtain 1.08g of light yellow solid, yield 63.0%, m.p.85-87°C;

[0108] 1 H-NMR (300MHz, CDCl 3 ) δ (ppm): 7.12 (1H, dd, J = 8.4Hz, J = 1.8Hz, 4'-ArH), 7.01 (1H, d, J = 1.8Hz, 6'-ArH), 6.83 (1H, d , J=8.7Hz, 3'-ArH), 6.50(2H, s, 2"&6"-ArH), 6.45(2H, s, 1aH&1a'H), 6.38(1H, d, J=8.7Hz, NH) , 5.44(1H, s, H-4), 5.30~5.13(3H, m, H-1, ...

Embodiment 3

[0113] N-(1,3,4,6-tetra-O-acetyl-2-deoxy-β-D-glucopyranosyl)-4-((Z)2'-methoxy-5'-(3 ", 4", 5 "-trimethoxystyryl) phenoxy) -4-oxobutyramide (I-7) preparation

[0114] Will G 3 -NH 2 .HCl (0.77g, 2mmol) was dissolved in DMF (10ml). Dry triethylamine (0.28ml, 2mmol) was slowly added dropwise. Then 2b (0.83g, 2mmol), EDCI (0.38g, 2mmol), HOBt (0.27g, 2mmol) were added in batches successively, and stirred at room temperature for 24h. Add dichloromethane (80ml) to the reaction solution, wash with water (2×100ml), wash with saturated brine (3×100ml), dry, filter with suction, evaporate the solvent under reduced pressure, and perform silica gel column chromatography (petroleum ether / ethyl acetate=2 / 1), 0.82g of white solid was obtained, the yield was 55.0%, m.p.78-79°C;

[0115] 1 H-NMR (300MHz, CDCl 3 ) δ (ppm): 7.12 (1H, dd, J = 8.4Hz, J = 1.8Hz, 4'-ArH), 6.98 (1H, d, J = 1.8Hz, 6'-ArH), 6.82 (1H, d , J=8.4Hz, 3'-ArH), 6.49 (2H, s, 2"&6"-ArH), 6.45 (2H, s, 1aH&1a'H), 5.73~5...

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Abstract

The invention relates to the field of pharmaceutical chemistry, in particular to CA-4 derivatives (I) and a preparation method thereof, and the inhibitory effect of the CA-4 derivatives on tumor blood vessels. Pharmacological experiments prove that the compounds can be used for treating angiogenesis-related diseases such as various cancers and chronic inflammation, and other angiogenic diseases.

Description

technical field [0001] The invention relates to the field of medicinal chemistry, in particular to a class of Combretastatin A-4 derivatives, their preparation method, and their inhibitory effect on tumor blood vessels. Background technique [0002] Combretastatin A-4 (CA-4 for short) is one of the substances with the best anti-tumor activity among Combretastatins compounds. It is isolated from the South African tree Combretum Caffnom and can utilize the physiological differences between tumor tissue and normal tissue endothelial cells. Selectively inhibit the activity of tumor tubulin, change the skeleton structure and morphology of endothelial cells, enhance the permeability of blood vessels, disturb the blood flow, thereby causing the apoptosis of tumor vascular endothelial cells and leading to the death of secondary tumor cells. However, the water solubility of CA-4 is very poor, which limits its clinical application. And its water-soluble prodrug CA-4 phosphate disodiu...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07H15/12C07H1/00A61K31/7028A61P35/00A61P29/00
Inventor 徐云根吴梦茜屠哲玮司崇静何书英何广卫孙丽卞金磊戴宇驰
Owner CHINA PHARM UNIV