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Alpha-carboline compounds, preparation method thereof and purpose thereof

A compound, unsubstituted technology, applied to the core compound containing α-carboline, the application field in medicine

Active Publication Date: 2016-08-03
SHANGHAI INST OF MATERIA MEDICA CHINESE ACAD OF SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

But at this stage, there is no report on dual inhibitors of DNA topoisomerase Ⅱ and tubulin

Method used

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  • Alpha-carboline compounds, preparation method thereof and purpose thereof
  • Alpha-carboline compounds, preparation method thereof and purpose thereof
  • Alpha-carboline compounds, preparation method thereof and purpose thereof

Examples

Experimental program
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preparation example Construction

[0153] The preparation of formula I compound

[0154] Another object of the present invention is to provide the preparation method of the compound shown in general formula I, and synthetic route is as shown in Scheme 1 or 2:

[0155] plan 1

[0156]

[0157] a) Compound 1 (3-aldehydochromone) and compound 2 (o-nitrophenylacetonitrile) are condensed to generate compound 3 under certain conditions, and the conditions are acetic anhydride / sodium acetate system, or titanium tetrachloride / pyridine system;

[0158] b) Compound 3 is heated and ring-closed under the action of a reducing agent (hydrogen, iron powder, zinc powder, sulfide) to generate compound 4 / I.

[0159] c) Compound 4 is substituted under the action of base (sodium hydride, potassium tert-butoxide, sodium tert-butoxide) to further generate compound I.

[0160] Preferably, the conditions of step a) are: compound 1 and compound 2 are dissolved in acetic anhydride, stirred overnight at 70-100° C. for reaction unde...

Embodiment 1

[0203] Example 1 Preparation of (E / Z)-2-(2-nitrobenzene)-3-(4-oxo-4H-chromone-3-substituted) acrylonitrile (compound 3a)

[0204]

[0205] In a 25mL round bottom flask, add 100mg (0.574mmol) of compound 3-aldehyde-chromone 1a, 93mg (0.574mmol) of o-nitrophenylacetonitrile, 47mg (0.574mmol) of sodium acetate, 5mL of acetic anhydride, and place in an oil bath at 90°C Stir and heat in the pot overnight. The next day, the temperature was cooled to room temperature, and the reaction was quenched by pouring 150 mL of ice water. 50mL DCM was extracted three times, the combined organic phase was washed with 50mL saturated brine, then dried over anhydrous sodium sulfate, the solvent was evaporated to dryness by a rotary evaporator, and the crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate=4:1) to obtain light yellow The solid is 162mg, and the yield is 88%.

[0206] 1 HNMR (300MHz, Chloroform-d) δ9.03(s, 1H), 8.27(d, J=9.4Hz, 1H), 8.18(...

Embodiment 2

[0213] Example 2 Preparation of (E / Z)-2-(2-nitrobenzene)-3-(6-methyl-4-oxo-4H-chromone-3-substituted) acrylonitrile (compound 3b)

[0214]

[0215] 95 mg (0.5 mmol) of 3-formyl 6-methylchromone 1b was used as the raw material, referring to the synthesis process of compound 3a, 146 mg of light yellow solid was obtained, with a yield of 88%.

[0216] 1 HNMR (300MHz, Chloroform-d) δ9.01(s, 1H), 8.18(d, J=8.2Hz, 1H), 8.04(s, 1H), 7.79–7.71(m, 1H), 7.69–7.52(m ,4H),7.46(d,J=8.6Hz,1H),2.49(s,3H).

[0217] LC-MS: 333 (M+1).

[0218] Preparation of (2-hydroxy-5-methylphenyl)(9H-pyrido[2,3-b]indole-3-substituted)methanone (compound Ⅰ-2)

[0219]

[0220] 100mg (0.3mmol) of 3b was used as the starting material, referring to the synthesis process of compound Ⅰ-1, 52mg of yellow solid was obtained, with a yield of 58%.

[0221] 1 HNMR (300MHz, DMSO-d 6 )δ13.62(s,1H),12.11(s,1H),8.68(d,J=7.7Hz,1H),8.19(d,J=8.7Hz,1H),8.05–7.95(m,1H), 7.91(s,1H),7.57–7.42(m,2H),7.33–7.21(m,1H),7...

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Abstract

The invention provides alpha-carboline compounds, a preparation method thereof and a purpose thereof. Concretely, the invention provides a compound with a structure shown in a general formula I, wherein each group is defined in a specification. The compounds in the formula I have dual inhibition effects to topoisomerase II and tubulin, and can inhibit propagation of cancer cells.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry and drug therapy. It specifically relates to a class of α-carboline (9H-pyrido[2,3-b]indole) core compounds, pharmaceutically acceptable salts and hydrates thereof, their preparation methods and their usefulness in the treatment of topoisomerism Constructase Ⅱ and tubulin-related diseases such as tumor drug application. Background technique [0002] As the carrier of genetic information, DNA plays a very important role in the whole life process. In DNA transcription, replication, and gene expression, DNA topoisomerase regulates and maintains the complex topological structure of DNA to make life orderly. Since J.C. Wang discovered the first omega protein that can change the topology of DNA in 1971, researchers have studied DNA topoisomerases in detail. According to the different mechanism of action and biological structure, DNA topoisomerase is divided into topoisomerase I and topoisomerase II...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D471/04A61K31/437A61P35/00A61P35/02
CPCA61K31/437C07D471/04
Inventor 杨春皓缪泽鸿张小飞衣君玫贺茜宦霞娟宋姗姗王迎庆陈奕丁健
Owner SHANGHAI INST OF MATERIA MEDICA CHINESE ACAD OF SCI
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