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Substituted cinnamic acid nitrogen-containing derivative having tumor cytotoxic activity

A technology of cinnamon acid and its derivatives, which is applied in the fields of antineoplastic drugs, drug combinations, organic chemistry, etc., can solve the problems of low selectivity, unsatisfactory, and limited general applicability of drugs, and achieves low-cost, high-efficiency synthetic methods Simple, good cytotoxic effect

Inactive Publication Date: 2011-08-31
WENZHOU MEDICAL UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the specific drugs for the treatment of tumor diseases are not satisfactory, and the malignant killing of normal cells caused by the low selectivity of cytotoxic drugs currently used in anti-tumor clinics limits the general applicability of such drugs

Method used

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  • Substituted cinnamic acid nitrogen-containing derivative having tumor cytotoxic activity
  • Substituted cinnamic acid nitrogen-containing derivative having tumor cytotoxic activity
  • Substituted cinnamic acid nitrogen-containing derivative having tumor cytotoxic activity

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0037] Example 1 : the preparation of compound I-a i.e. N-(2'-morpholine ethyl)-6,7-dimethoxymethoxycinnamic amide (2E)

[0038]

[0039]This example relates to a class of substituted cinnamon amide derivatives with cytotoxic activity as shown in formula (I) and its key intermediate as N, N'-dicyclohexylguanidine cinnamate shown in formula (II) A general method for the synthesis of derivatives. It specifically relates to the synthesis of compound N-(2'-morpholine ethyl)-6,7-dimethoxymethoxycinnamic amide. The compound 3,4-dimethoxymethoxycinnamic acid (536 mg, 2.0 mmol, obtained from 3,-dihydroxybenzaldehyde through condensation with malonic acid after protection with methoxymethoxy) was dissolved in chloroform , then added dicyclohexylcarbodiimide (DCC, 448 mg, 2.0 mmol), kept stirring at 45 ° C for 1 hour, then added substituted morpholine ethylamine (286 mg, 2.2 mmol), and refluxed for 8 hours Lowered to room temperature, filtered, and the filtrate was concentrated to...

Embodiment 2-10

[0043] According to the method of Example 1, the compounds of Examples 2-10 shown in the following Table 1 were prepared:

[0044]

[0045] Table I

[0046]

[0047] List the physicochemical data of each compound in Table 1 below:

[0048] I-b: Yield: 67.1%; White solid; Rf (dichloromethane / methanol 12:1) 0.49; H NMR 1 H NMR (400MHz, deuterated chloroform CDCl 3 ): δ7.58 (1H, bimodal, J=15.6Hz, H-3), 7.11 (1H, double bimodal, J=8.4, 1.6Hz, H-9), 7.05 (1H, bimodal, J= 1.6Hz, H-5), 6.87(1H, doublet, J=8.4Hz, H-8), 6.31(1H, doublet, J=15.6Hz, H-2), 6.15(1H, broad singlet, NH), 3.93-3.92 (6H, unimodal, CH 3 0-6, 7), 3.75 (4H, triplet, J=4.4Hz, H-3″, 5″), 3.51 (2H, quartet, J=5.6Hz, H-1′), 2.56 (2H , triplet, J=6.0 Hz, H-2'), 2.49 (4H, multiplet, H2", 6").

[0049] I-c: Yield: 53.6%; Pale yellow solid; Rf (dichloromethane / methanol 12:1) 0.66; H NMR 1 H NMR (400MHz, deuterated chloroform CDCl 3 ): δ8.18 (1H, singlet, H-1″), 7.65 (1H, doublet, J=8.0Hz, H-7″), 7.55 (1H, ...

Embodiment 2

[0063] This experiment shows that such substituted cinnamon amide derivatives have strong cytotoxicity to Eca-109 cells, and may be developed into new drugs with anti-esophageal cancer effects. Pharmacological Example 2 : Cytotoxic activity of compound I-d on poorly differentiated gastric adenocarcinoma tumor cells (BGC 823) cells

[0064] Gastric adenocarcinoma tumor cells (BGC 823) were cultured in RPMI 1640 medium containing 5% calf serum, 100 U / ml penicillin and 100 U / ml streptomycin. cells in 4×10 per well 3 The concentration was added to a 96-well plate, and cultured for 24 hours at 37°C in an incubator containing 5% carbon dioxide humidified air.

[0065] Cell viability was determined by the modified MTT method. After the cells were incubated for 24 hours, the newly prepared dimethyl sulfoxide solution of compound I-d was added to each well with a concentration gradient, so that the final concentrations of the compounds in the wells were 100 μg / ml, 33.3 μg / ml, and 11...

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Abstract

The invention relates to a substituted cinnamic acid nitrogen-containing derivative which has a structure of formula (I) and cytotoxic activity and the medical salts and solvates, and the invention further relates to a preparation method of the compounds with the formula (I), a pharmaceutical composition and a medical usage. The compound of the invention has stronger activity to inhibit the growth of the tumor cells of human esophageal cancer (Eca-109) and poorly differentiated gastric adenocarcinoma (BGC 823), which can be expected to be used as an antitumor drug.

Description

technical field [0001] The present invention relates to the fields of organic chemistry, medicinal chemistry and pharmacology, in particular, the present invention relates to a preparation method of a class of substituted cinnamic acid nitrogen-containing derivatives and intermediates thereof, and the effect of these compounds on human esophageal cancer cells (Eca- 109) and the cytotoxic activity of poorly differentiated human gastric adenocarcinoma cells (BGC823). Such compounds are found to have certain biological activity of inhibiting the growth of the tumor cells, and can be expected to be used as antitumor drugs. Background technique [0002] At present, due to environmental pollution and other problems brought about by industrial development, the quality of human living environment continues to decline, and the incidence and mortality of tumor diseases are also increasing. However, the specific drugs for the treatment of tumor diseases are not satisfactory, and the m...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D295/13C07D209/16C07C275/70A61K31/5375A61K31/404A61P35/00
Inventor 邹宏斌黄可新李校堃巫秀美赵昱瞿佳
Owner WENZHOU MEDICAL UNIV
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