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N-substituted indole carboxylic acid derivative and its preparation method and medical use

A technology of indole carboxylic acid and its derivatives, which is applied in the fields of drug combination, antineoplastic drugs, organic chemistry, etc., and can solve problems such as poor selectivity and easy drug resistance

Inactive Publication Date: 2016-08-24
CHINA PHARM UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] Most of these inhibitors act on the ATP-binding pocket of PLK1 and are ATP-competitive inhibitors, which have side effects such as poor selectivity to different kinases and easy drug resistance common to kinase inhibitors

Method used

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  • N-substituted indole carboxylic acid derivative and its preparation method and medical use
  • N-substituted indole carboxylic acid derivative and its preparation method and medical use
  • N-substituted indole carboxylic acid derivative and its preparation method and medical use

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0030] Synthesis of 1-(oxirane-2-ylmethyl)-1H-indole-3-carboxylic acid methyl ester (b-1):

[0031] Add methyl 3-indolecarboxylate (8.25g, 0.047mol) and 50ml DMSO into a 250ml three-necked flask, stir to dissolve, add 60% sodium hydrogen (2.84 g, 0.071mol), stirred at room temperature for 30 minutes. A solution of epichlorohydrin (13.07 g, 0.141 mol) in DMSO (30 ml) was slowly added dropwise to the reaction flask under an ice bath (internal temperature 0-10° C.). After dropping, the temperature was naturally raised to room temperature and the reaction was stirred for 12 hours. Add 250ml of water for dilution, extract with ethyl acetate (120ml×3), combine the organic phases, wash with water and saturated brine, concentrate the organic phase and perform column chromatography (eluent: petroleum ether: ethyl acetate 8:1) , to obtain 3.65 g of brown oil, yield 33.5%.

[0032] 1 H-NMR (300MHz, CDCl 3 ), δ (ppm): 8.11-7.17 (m, 5H), 4.36 (dd, J 1 =2.76Hz,J 2 =15.21Hz, 1H), 4.05...

Embodiment 2

[0035] Synthesis of 2-(1-(oxirane-2-ylmethyl)-1H-indol-3-yl)methyl acetate (b-2):

[0036] The target compound was prepared by a method similar to Example 1 as a yellow oil with a yield of 33.6%.

[0037] 1 H-NMR (300MHz, CDCl 3 ), δ (ppm): 7.68-7.16 (m, 5H), 4.36 (dd, J 1 =2.82Hz,J 2 =15.27Hz, 1H), 4.08(dd, J 1 =5.37Hz,J 2 =15.24Hz, 1H), 3.84(s, 2H), 3.76(s, 3H), 3.25(m, 1H), 2.80(t, J=4.32Hz, 1H), 2.48(dd, J 1 =2.40Hz,J 2 =4.26Hz, 1H)

[0038] MS(ESI)m / z: 246[M+H] +

Embodiment 3

[0040] Synthesis of 3-(1-(oxirane-2-ylmethyl)-1H-indol-3-yl)propionic acid methyl ester (b-3):

[0041] The target compound was prepared by a method similar to Example 1 as a white translucent oil with a yield of 19.3%.

[0042] 1 H-NMR (300MHz, CDCl 3 ), δ (ppm): 7.58-6.88 (m, 5H), 4.30 (dd, J 1 =3.21Hz,J 2 =15.24Hz, 1H), 4.07(dd, J 1 =5.28Hz,J 2 =15.27Hz, 1H), 3.64(s, 3H), 3.20(m, 1H), 3.10(t, J=7.11Hz, 2H), 2.72-2.78(m, 3H), 2.40(dd, J 1 =2.55Hz,J 2 =4.71Hz, 1H)

[0043] MS(ESI)m / z: 260[M+H] +

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Abstract

The invention belongs to the field of pharmaceutical chemistry and relates to an N-substituted indole carboxylic acid derivative (I), wherein R1, R2 and n are defined through the specification. An in-vitro tumor cell growth inhibition activity test result shows that the N-substituted indole carboxylic acid derivative has strong tumor cell growth inhibition activity and the individual compound has very strong tumor cell growth inhibition activity. The invention also discloses a preparation method of the N-substituted indole carboxylic acid derivative.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, and specifically relates to a class of N-substituted indole carboxylic acid derivatives, its preparation method and its medical application as a tumor therapeutic agent, and a pharmaceutical composition containing the compound. Background technique [0002] At present, malignant tumors are still one of the major diseases that threaten people's lives. Although the currently marketed anticancer drugs have certain curative effects, most of them are cytotoxic drugs with serious toxic and side effects. Therefore, how to start from effective anti-tumor drug targets to study targeted new anti-cancer drugs has become a top priority. [0003] As an important target in the research of targeted anti-tumor drugs, protein kinase has always been the focus of drug researchers. At present, kinase inhibitors of various structural types have been developed, many small molecule inhibitors have entered the clini...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D209/42C07D209/18A61P35/00
Inventor 江程刘孟徐云根陈东星
Owner CHINA PHARM UNIV
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