Heterocyclic compound capable of inversing tumor cell drug tolerance, preparation method and application thereof

A technology for heterocyclic compounds and tumor cells, applied in the field of heterocyclic compounds and heterocyclic compounds that can reverse the drug resistance of tumor cells, can solve the loss of clinical efficacy, drug resistance, multi-drug resistance and cross-drug resistance of anti-tumor drugs, etc. problem, to achieve the effect of reducing the multiplier of drug resistance

Inactive Publication Date: 2008-08-13
CAPITAL UNIVERSITY OF MEDICAL SCIENCES
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0002] Although the clinical treatment of tumors faces many problems, such as low selectivity, poor tolerance and strong side effects of chemotherapy drugs, it is necessary to continuously find excellent anti-tumor drugs with high selectivity, good tolerance and low side effe

Method used

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  • Heterocyclic compound capable of inversing tumor cell drug tolerance, preparation method and application thereof
  • Heterocyclic compound capable of inversing tumor cell drug tolerance, preparation method and application thereof
  • Heterocyclic compound capable of inversing tumor cell drug tolerance, preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0028] Example 1 1-(1'-Benzyloxycarbonyl-2'-methyl)butyl-2,2-dimethyl-4-oxo-tetrahydroimidazo[1',2':1,5] Preparation of pyrido[3,4-b]indole (compound 1)

[0029] 1) Preparation of S-carboline carboxylic acid

[0030] Put 400ml of water in a 500ml round bottom flask, and slowly add 0.2ml of concentrated sulfuric acid. Add 5.0 g (24.5 mmol) of L-tryptophan to the obtained dilute sulfuric acid aqueous solution and ultrasonically shake until the L-tryptophan is completely dissolved. To the resulting solution was added 10 ml of a 35% formaldehyde solution. The reaction mixture was stirred at room temperature for 6 hours. The disappearance of L-tryptophan was detected by thin layer chromatography, and the reaction was terminated. Concentrated ammonia water was slowly added dropwise to the reaction solution, the reaction mixture was adjusted to pH 6, and left to stand for half an hour. The resulting precipitate filtered out under reduced pressure was washed with water, and the fi...

Embodiment 2

[0037] Example 2 N-(1'-Benzyloxycarbonyl-2'-methyl)propyl-2,2-dimethyl-4-oxo-tetrahydroimidazo[1',2':1,5] Preparation of pyrido[3,4-b]indole (compound 2)

[0038] 1) Preparation of N-Boc-S-carbolinyl-L-valine benzyl ester

[0039] According to the operation of preparing N-Boc-S-carbolinyl-L-isoleucine benzyl ester in Example 1, 3.90 g (94%) of the target was obtained from 2.00 g (8.21 mmol) of L-valine benzyl hydrochloride Compound, a colorless solid. ESI / MS 506[M+H] + .

[0040] 2) N-(1'-Benzyloxycarbonyl-2'-methyl)propyl-2,2-dimethyl-4-oxo-tetrahydroimidazo[1',2':1,5]pyridine Preparation of a[3,4-b]indole (2)

[0041]According to Example 1, N-(1'-benzyloxycarbonyl-2'-methyl)butyl-2,2-dimethyl-4-oxo-tetrahydroimidazo[1',2':1, 5] The operation of pyrido[3,4-b]indole, 1.06g (60%) of the target compound was obtained from 2.00g (3.96mmol) N-Boc-S-carbolinyl-L-valine benzyl ester , a colorless solid. Mp 196-198°C; ESI + -MS(m / e)446[M+H] + ; 1 H-NMR (DMSO-d 6 , 300MHz) ...

Embodiment 3

[0042] Example 3 1-(1'-Benzyloxycarbonyl-3'-methyl)butyl-2,2-dimethyl-4-oxo-tetrahydroimidazo[1',2':1,5] Preparation of pyrido[3,4-b]indole (compound 3)

[0043] 1) The preparation of N-Boc-S-carboxyloyl-L-leucine benzyl ester according to the operation of Example 1 to prepare N-Boc-S-carborinyl-L-isoleucine benzyl ester, from 1.70g (6.61 mmol) L-leucine benzyl hydrochloride yielded 3.23 g (98%) of the title compound as a colorless solid. ESI + -MS(m / e)520[M+H] + ;

[0044] 2) 1-(1'-Benzyloxycarbonyl-3'-methyl)butyl-2,2-dimethyl-4-oxo-tetrahydroimidazo[1',2':1,5]pyridine Preparation of a[3,4-b]indole (3)

[0045] According to Example 1, N-(1'-benzyloxycarbonyl-2'-methyl)butyl-2,2-dimethyl-4-oxo-tetrahydroimidazo[1',2':1, 5] The operation of pyrido[3,4-b]indole, 0.97g (55%) of the target compound was obtained from 2.00g (3.85mmol) N-Boc-S-carbolinyl-L-leucine benzyl ester , a colorless solid. Mp 190-192°C; ESI + -MS(m / e)460[M+H] + ; 1 H-NMR (DMSO-d 6 , 300MHz) δ=10....

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Abstract

The invention discloses a heterocyclic compounds capable of reversing drug resistance of tumor cells. Preparation and usage thereof are further disclosed. The inventive heterocyclic compound has a structure indicated by formula (I). Preparation includes steps of: preparing carboline carboxylic acid by conventional process; coupling secondary amino group of carboline carboxylic acid with L-amino acid benzyl esters to generate a N position protected carboline carboxylic -L-amino acid benzyl esters after protected by protecting group; condense with acetone in methanol under catalysis of triethylamine after detraction of protecting group. It is indicated in the in vitro test, the inventive heterocyclic compound can effectively reverse drug resistance of tumor cell towards anti-tumor drug, can be used as drug resistance inhibitor of tumor cell in clinic.

Description

technical field [0001] The present invention relates to a class of heterocyclic compounds, in particular to heterocyclic compounds capable of reversing the drug resistance of tumor cells; the present invention also relates to the preparation method of the heterocyclic compound and the application of the heterocyclic compound as an inhibitor of tumor multidrug resistance, It belongs to the field of biomedicine. Background technique [0002] Although the clinical treatment of tumors faces many problems, such as low selectivity, poor tolerance and strong side effects of chemotherapy drugs, it is necessary to continuously find excellent anti-tumor drugs with high selectivity, good tolerance and low side effects, but the clinical The biggest challenge facing treatment is drug resistance of tumor cells, including multi-drug resistance and cross-drug resistance. The drug resistance acquired by tumor cells makes more and more excellent anti-tumor drugs lose their clinical efficacy ...

Claims

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Application Information

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IPC IPC(8): C07D471/14A61K31/4375A61P35/00
CPCY02P20/55
Inventor 彭师奇赵明崔国辉崔纯莹刘佳望
Owner CAPITAL UNIVERSITY OF MEDICAL SCIENCES
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