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Imidazo pyrido imidazole-3-substituted benzyl acetates, and synthesis, antineoplastic activities and application thereof

A technology of azolopyridimidazole and benzyl acetate, which is applied to imidazopyrimidazole-3-substituted benzyl acetate, its synthesis, antitumor activity and application fields, can solve the problem of low toxicity and side effects and poor curative effect of antitumor drugs. ideal, high toxicity

Inactive Publication Date: 2015-07-08
CAPITAL UNIVERSITY OF MEDICAL SCIENCES
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The clinical application of anti-tumor drugs has defects such as unsatisfactory curative effect and high toxicity, which makes research on new anti-tumor drugs with good curative effect and low toxicity and side effects has always been one of the hot spots in drug research.

Method used

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  • Imidazo pyrido imidazole-3-substituted benzyl acetates, and synthesis, antineoplastic activities and application thereof
  • Imidazo pyrido imidazole-3-substituted benzyl acetates, and synthesis, antineoplastic activities and application thereof
  • Imidazo pyrido imidazole-3-substituted benzyl acetates, and synthesis, antineoplastic activities and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0020] Example 1 Preparation of (6S)-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridine-6-carboxylic acid (1)

[0021]Add 6 mL of concentrated sulfuric acid dropwise to 30.00 g (0.193 mol) of L-histidine and 120 mL of distilled water under an ice bath, and stir evenly to dissolve completely. Then add 60 mL of formaldehyde solution (40%), and react in an oil bath at 60° C. for 8 hours. The reactant was cooled to room temperature, adjusted to pH 6 with concentrated ammonia water in an ice bath, and filtered. The obtained colorless precipitate was washed with water and then with acetone. Obtained 28.04 g (87%) of the title compound as a colorless solid. ESI-MS(m / z)167[M+H] + .

Embodiment 2

[0022] Example 2 Preparation of (6S)-N 3 , N 5 -di-Boc-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridine-6-carboxylic acid (2)

[0023] Disperse 10.52g (0.063mol) of (6S)-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridine-6-carboxylic acid (1) in 100mL of distilled water, ice bath 12.6 mL of aqueous NaOH (6N) was added dropwise. Add 31.59g (Boc) to the reaction solution 2 ° and 113mL of dioxane solution, adjust the pH to 9 with NaOH aqueous solution (6N). The reaction mixture was stirred at room temperature for 24 hours, TLC (chloroform:methanol:glacial acetic acid=15:1:0.06) showed that compound 1 disappeared. The reaction solution was adjusted to neutrality with saturated potassium hydrogensulfate aqueous solution under ice cooling. Concentrate under reduced pressure to remove dioxane, add 50 mL of distilled water to the residue, add saturated potassium bisulfate aqueous solution dropwise under ice bath to adjust the pH to 2, and extract with ethyl acetate (100 mL×1, 50 mL×2). Th...

Embodiment 3

[0024] Example 3 Preparation of (6S)-N 3 , N 5 -di-Boc-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridine-6-formylglycine benzyl ester (3a)

[0025] To 14.94g(40.7mmol)(6S)-N 3 , N 5 -di-Boc-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridine-6-carboxylic acid (2) and 200mL of anhydrous tetrahydrofuran (THF) solution, add 5.49g (40.7mmol) HOBt, after dissolving, add 9.15g (44.4mmol) DCC under stirring in an ice bath, and activate for 30min. Suspend 12.47g (37mmol) Tos Gly-OBzl in 200mL of anhydrous THF, adjust the pH to neutral with NMM, then add the suspension to the above activated reaction solution, and finally adjust the pH of the reaction solution to 8, reacted at room temperature for 16 hours, TLC showed that 2 basically disappeared, and filtered to remove dicyclohexyl urea (DCU). Concentrate the filtrate to dryness under reduced pressure and dissolve it with ethyl acetate, then filter again to remove DCU, and the filtrate is successively washed with saturated NaHCO 3 Aqueous s...

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Abstract

The invention discloses 15 kinds of imidazo pyrido imidazole-3-substituted benzyl acetates represented by the general formula I [wherein R is a side chain of L-amino acid, particularly is H, CH3, CH(CH3)2, CH2CH(CH3)2, CH(CH3)CH2CH3, CH2C6H5, CH(OH)CH3, CH2CO2Bzl, CH2C6H4OH-p, (CH2)3NHC(NH)NH(NO2), CH2CONH2, (CH2)2CONH2, Indole-5-yl-CH2, (CH2)2CO2Bzl or (CH2)2SCH3], discloses preparation of the imidazo pyrido imidazole-3-substituted benzyl acetates, and in-vitro and in-vivo antineoplastic activities of the imidazo pyrido imidazole-3-substituted benzyl acetates, and thus discloses clinical application prospects of the imidazo pyrido imidazole-3-substituted benzyl acetates as antineoplastic drugs.

Description

field of invention [0001] The present invention relates to 15 imidazopyridoimidazole-3-substituted benzyl acetates of general formula I [R in the formula is the side chain of L-amino acid, specifically H, CH 3 , CH(CH 3 ) 2 , CH 2 CH(CH 3 ) 2 , CH(CH 3 )CH 2 CH 3 , CH 2 C 6 h 5 , CH(OH)CH 3 , CH 2 CO 2 Bzl, CH 2 C 6 h 4 OH-p, (CH 2 ) 3 NHC(NH)NH(NO 2 ), CH 2 CONH 2 , (CH 2 ) 2 CONH 2 , Indole-5-yl-CH 2 , (CH 2 ) 2 CO 2 Bzl or (CH 2 ) 2 SCH 3 ], related to their preparation, related to their anti-tumor activity in vitro and in vivo, and thus related to their clinical application prospects as anti-tumor drugs. The invention belongs to the field of biomedicine. [0002] Background technique [0003] World Health Organization (WHO) officials stated at the "International Oncology" annual meeting held in Atlanta, USA in early 2009 that malignant tumors are seriously threatening human life and health, and by 2010 cancer will surpass cardiovascular...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D471/14A61K31/437A61P35/00
Inventor 彭师奇赵明王玉记吴建辉裘佳
Owner CAPITAL UNIVERSITY OF MEDICAL SCIENCES