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A kind of coumarin derivative used as caspase-3 activator and application thereof

A technology of coumarins and derivatives, applied in drug combination, organic chemistry, anti-tumor drugs, etc., can solve the problems that anti-tumor drugs cannot inhibit the growth of tumor cells, cannot be delivered correctly, and achieve significant activation of caspase-3 The effect of action

Active Publication Date: 2021-04-20
HUAQIAO UNIVERSITY +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

What's more worth mentioning is that procaspase-3 belongs to the downstream protein in the apoptosis signaling pathway. If the occurrence of cancer is caused by the mutation of the downstream protein, the upstream apoptosis signal will not be correctly transmitted to the downstream protein, resulting in the effect of Antineoplastic drugs targeting mid / upstream apoptotic signals will not be able to inhibit tumor cell growth

Method used

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  • A kind of coumarin derivative used as caspase-3 activator and application thereof
  • A kind of coumarin derivative used as caspase-3 activator and application thereof
  • A kind of coumarin derivative used as caspase-3 activator and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0081] Preparation of Step A, 8-hydroxyl-2-oxo-2H-chromene-3-carboxylic acid:

[0082] Add 0.1mol of 2,3-dihydroxybenzaldehyde and 0.11mol of McFarlandic acid into 80ml of water, react and stir at 80°C for 2h, cool after the reaction, and filter with suction to obtain the product intermediate A with a yield of 92.5%, MS (ESI)m / z(%):205.1[M-H] - ; 1 H NMR (400 MHz, DMSO) δ 10.35 (s, 1H), 8.68 (s, 1H), 7.35–7.29 (m, 1H), 7.24–7.18 (m, 2H).

[0083] The preparation of step B, N-ethyl-N-(4-nitrobenzyl) ethylamine (1)

[0084] 20g of p-nitrobenzyl bromide (0.092mol) and 14.14g of diethylamine (0.19mol) were added to 80ml of acetonitrile, stirred at room temperature for 5h, after the reaction was complete, 200ml of water and 200ml of dichloromethane were added to the reaction solution, Extracted to obtain an organic layer, dried over anhydrous sodium sulfate, evaporated to dryness, yield 73.1%, MS (ESI) m / z (%): 208.4 [M+H] + ;1H NMR (400MHz, CDCl3) δ8.21–8.13(d, J=8.6Hz, 2H), 7...

Embodiment 2

[0092] With reference to step A in Example 1, 2-hydroxyl 3-methoxybenzaldehyde was used as raw material to prepare 8-methoxy-2-oxo-2H-chromene-3-carboxylic acid, yield 88.7%, MS (ESI) m / z (%): 219.1 [M-H] - ; 1 H NMR (400 MHz, DMSO) δ 8.71 (s, 1H), 7.46–7.43 (m, 1H), 7.43–7.39 (m, 1H), 7.37–7.30 (m, 1H), 3.93 (s, 3H).

[0093] With reference to step B, step C, and step D in Example 1, 6-(diethylaminomethyl) benzo[d]thiazol-2-amine (B-2) is prepared, and finally with reference to Example 1 Step E, with 8-methoxy-2-oxo-2H-chromene-3-carboxylic acid and 6–(diethylaminomethyl) benzo[d]thiazol-2-amine (B- 2) As a raw material, N-[2-(6-(diethylaminomethyl)benzo[d]thiazolyl)]-8-methoxy-2-oxo-2H-benzopyran was prepared -3-Carboxamide, the structure is shown in Table 1, yield: 46.2%; MS (ESI) m / z (%): 437.0 [M+H] + ; 1 H NMR (400MHz,DMSO)δ9.02(s,1H),8.20(s,1H),7.98–7.85(m,1H),7.65–7.53(m,2H),7.53–7.47(m,1H), 7.46–7.37 (m, 1H), 4.41 (s, 2H), 3.97 (s, 3H), 3.22–3.02 (d, J=7.0Hz, 4H...

Embodiment 3

[0095] Referring to Step A in Example 1, 8-hydroxy-2-oxo-2H-chromene-3-carboxylic acid was prepared.

[0096] Referring to step B in Example 1, using p-nitrobenzyl bromide and 4-methylpiperidine as raw materials, prepare 4-methyl-1-(4-nitrophenyl)piperidine (1), refer to the implementation Step C of Example 1, using 4-methyl-1-(4-nitrophenyl)piperidine as raw material, prepares 4-(4-methylpiperidinylmethyl)aniline (B-1), refer to The method of step D in the embodiment one, use 4-(4-methylpiperidylmethyl)aniline as raw material, prepare 6-(4-methylpiperidylmethyl)benzo[d]thiazole- 2-amine (B-2), yield: 85.3%; MS (ESI) m / z (%): 262.1 [M+H] + ; 1 H NMR (400MHz, DMSO) δ7.75(s, 1H), 7.65(s, 2H), 7.38(d, J=8.0Hz, 1H), 7.30(d, J=8.0Hz, 1H), 4.22(s ,2H),3.33(m,2H),2.77(m,2H),1.77(m,2H),1.56(m,1H),1.29(m,2H),0.90(d,J=5.4Hz,3H) .

[0097] Finally, with reference to step E in Example 1, 8-hydroxy-2-oxo-2H-benzopyran-3-carboxylic acid and 6-(4-methylpiperidinylmethyl)benzo[d] Thiazo...

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Abstract

The present invention discloses a coumarin derivative used as a caspase-3 activator, which has no similar structural design and use in similar products. The compound has significant caspase-3 activating effect and can be used for treatment caspase-related diseases. The present invention also aims to provide the application of the above coumarin derivatives in the preparation of medicines for the treatment and / or prevention of cancer and other proliferative diseases.

Description

technical field [0001] The invention relates to the technical field of medicine preparation, in particular to a coumarin derivative used as a caspase-3 activator and its application in the preparation of medicines for treating and / or preventing cancer and other proliferative diseases. Background technique [0002] Tumor is a disease that seriously threatens human life and health. In recent years, the incidence and mortality of tumors have been increasing year by year. Cytotoxic drugs can kill tumor cells, but they lack selectivity for cancer cells and normal cells, so they have strong toxic and side effects. Looking for targeted anti-tumor drugs that can selectively kill cancer cells and have no effect on normal proliferating cells Drugs have become an important direction for the development of new anticancer drugs. [0003] Apoptosis refers to an autonomous and orderly death process regulated by genes. It is generally believed that malignant transformation of tumor cells i...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D417/12C07D417/14C07D405/12A61P35/00
CPCA61P35/00C07D405/12C07D417/12C07D417/14
Inventor 马俊杰倪欣黄坤王翠芳
Owner HUAQIAO UNIVERSITY