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6-fructosamine-4-arylamidoquinazoline derivative and purpose thereof

A technology of arylaminoquinazoline and its derivatives, which is applied in the field of antineoplastic drugs and can solve the problems of low clinical efficacy and drug resistance

Inactive Publication Date: 2014-09-24
东莞南方医大代谢医学研发有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

These drugs are used in the clinical treatment of tumors, some of which have a low clinical efficacy rate, and some have developed drug resistance

Method used

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  • 6-fructosamine-4-arylamidoquinazoline derivative and purpose thereof
  • 6-fructosamine-4-arylamidoquinazoline derivative and purpose thereof
  • 6-fructosamine-4-arylamidoquinazoline derivative and purpose thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0027] Example 1: Preparation of 4-(3-chloro-4-fluoroanilino)-6-{2-[D-(1-deoxy-1-fructosylamino)]acetamido}quinazoline (A)

[0028] a) Preparation of intermediate 4-(3-chloro-4-fluoroanilino)-6-tert-butoxycarbonylaminoacetamidoquinazoline

[0029] Under nitrogen protection, 4-(3-chloro-4-fluoroanilino)-6-aminoquinazoline 0.98g, tert-butoxycarbonylaminoacetic acid 0.85g, diisopropylcarbodiimide 0.5mL, diiso A mixture of 0.8 mL of propylethylamine and 20 mL of tetrahydrofuran was reacted at 20° C. for 10 h, and the reaction mixture was separated by silica gel column chromatography (chloroform / methanol) to obtain 0.76 g of the product with a yield of 50.3%. MS: 446.2, 287.1.

[0030] b) Preparation of intermediate 4-(3-chloro-4-fluoroanilino)-6-aminoacetamidoquinazoline

[0031] A mixture of 4-(3-chloro-4-fluoroanilino)-6-tert-butoxycarbonylaminoacetamidoquinazoline 0.76g, dichloromethane 8mL and trifluoroacetic acid 2mL was stirred at room temperature for 6h, and saturated bic...

Embodiment 2

[0034] Example 2: 4-(3-chloro-4-fluoroanilino)-6-{2-[D-(1-deoxy-1-fructosylamino)]acetamido}quinazoline hydrochloride (B) preparation of

[0035] Add 40 mL of ethanol to 0.2 g of Compound A (the product obtained in step C in Example 1), shake it sufficiently to dissolve it, and add hydrogen chloride ethanol solution (about 2 mol L -1 ) 2mL, shake, stand still, filter with suction, and dry in the air to obtain 0.20g of a yellow solid. Yield 93.5%. MS: 508.1 (M+1), 317.1.

Embodiment 3

[0036] Example 3: 7-methoxy-4-[3-chloro-4-(3-fluorobenzyloxy)anilino]-6-{4-N-methyl-4-N-[D-(1 Preparation of -deoxy-1-fructose) amino] butyryl} amino quinazoline (C)

[0037] a) Intermediate 7-methoxy-4-[3-chloro-4-(3-fluorobenzyloxy)anilino]-6-(4-N-methyl-4-N-tert-butoxycarbonylamino The preparation of butyrylamino) quinazoline

[0038] Under nitrogen protection, 7-methoxy-4-[3-chloro-4-(3-fluorobenzyloxy)anilino]-6-aminoquinazoline 0.73g, 4-N-methyl-4- A mixture of 1.20 g of N-tert-butoxycarbonylaminobutyric acid, 1.1 g of dicyclohexylcarbodiimide, 0.5 mL of diisopropylethylamine and 20 mL of tetrahydrofuran was reacted at 20°C for 10 h, and the reaction mixture was separated by silica gel column chromatography (chloroform / methanol), to obtain product 0.84g, yield 79.3%. MS: 625.2 (M+1), 423.1.

[0039] b) Preparation of intermediate 7-methoxy-4-(3-chloro-4-fluoroanilino)-6-(4-N-methylaminobutanylamino)quinazoline

[0040] 7-methoxy-4-(3-chloro-4-fluoroanilino)-6-(4-N-...

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Abstract

The invention discloses a 6-fructosamine-4-arylamidoquinazoline derivative with the structural formula of formula I or a pharmaceutically acceptable salt thereof, and relates to a preparation method and a purpose of above compounds. According to the invention, fructose is connected to a 4-arylamidoquinazoline derivative, so the water solubility of the compounds and the selectivity of the compounds to tumor cells are improved.

Description

technical field [0001] The invention belongs to the field of antineoplastic drugs, and in particular relates to a 6-fructosamino-4-arylaminoquinazoline derivative and its application in synthesis and preparation of antineoplastic drugs. Background technique [0002] World Health Organization (WHO) officials warned at the 2008 International Oncology Annual Meeting held in Atlanta, USA that by 2010 cancer will replace cardiovascular disease as the disease with the largest number of deaths in the world. The previously dreaded cardiovascular diseases (stroke and myocardial infarction) will take a backseat to the second place. According to WHO statistics, in 2007, there were as many as 12 million newly diagnosed tumor patients in the world, and in the past few years, more than 7 million patients worldwide died of cancer every year. This figure is very close to the number of people who die from acute cardiovascular disease. At present, the treatment methods for tumors are still ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07H7/02C07H1/00A61K31/7064A61P35/00
Inventor 惠宏襄张三奇左淼孙大力丁雯
Owner 东莞南方医大代谢医学研发有限公司
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