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Thieno 2,4-substituted pyrimidine compound, and pharmaceutical composition and application thereof

A technology of compounds and pyrimidines, applied in drug combination, antipyretics, organic chemistry, etc., can solve the problems of drug-induced drug resistance gene mutation and narrow clinical application range

Inactive Publication Date: 2013-08-14
GUANGZHOU INST OF BIOMEDICINE & HEALTH CHINESE ACAD OF SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In fact, most of the current Aurora kinase inhibitor anti-tumor drugs have drug-induced drug-resistant gene mutations and face problems such as narrow clinical application

Method used

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  • Thieno 2,4-substituted pyrimidine compound, and pharmaceutical composition and application thereof
  • Thieno 2,4-substituted pyrimidine compound, and pharmaceutical composition and application thereof
  • Thieno 2,4-substituted pyrimidine compound, and pharmaceutical composition and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0127] Example 1 N 4 -(5-Methyl-1H-pyrazole-3-substituted)-N 2 - Preparation of (3-methylbenzyl)thieno[3,2-d]pyrimidine-2,4-diamine (LD4484)

[0128] N 4 -(5-Methyl-1H-pyrazole-3-substituted)-N 2 -(3-methylbenzyl)thieno[3,2-d]pyrimidine-2,4-diamine The synthetic route is as follows:

[0129]

[0130]

[0131] Specifically include the following steps:

[0132] (1), the synthesis of thieno[3,2-d]pyrimidine-2,4-dione, its chemical structural formula is: The synthesis steps are:

[0133] Add methyl 3-aminopyrimidine-2-carboxylate (50 g, 0.318 mol) and urea (110 g, 1.96 mol) into a round bottom flask, heat to 150° C. and reflux for 8 hours. Cool down to 90°C, add water and stir overnight, filter and dry in vacuo to obtain a white solid, which is thieno[3,2-d]pyrimidine-2,4-dione (50.2 g, yield: 94%).

[0134] The characterization data of this compound are:

[0135] 1 H NMR (400MHz, d-DMSO), δ 11.22(t, J=8Hz, 2H), 8.04(m, J=6.8Hz, 1H), 6.90(m, J=6.4Hz, 1H).

[0136]...

Embodiment 2

[0151] Example 2 N 2 -(3-Bromobenzyl)-N 4 - Preparation of (5-methyl-1H-pyrazole-3-substituted)thieno[3,2-d]pyrimidine-2,4-diamines (LD4481)

[0152] N 2 -(3-Bromobenzyl)-N 4 The chemical structural formula of -(5-methyl-1H-pyrazole-3-substituted)thieno[3,2-d]pyrimidine-2,4-diamine is: Its synthesis steps are the same as in Example 1.

[0153] The characterization data of this compound are:

[0154] h 1 NMR (400MHz, d-DMSO), δ12.26(br, 1H), 10.31(br, 1H), 8.06(s, 1H), 7.98(br, 1H), 7.56(s, 1H), 7.42(d, J=7.6Hz, 1H), 7.35(t, J=14Hz, 1H), 7.28(t, J=15.2Hz, 1H), 7.16(d, J=5.2Hz, 1H), 6.21(br, 1H), 4.58(t, J=6Hz, 2H), 2.20(s, 3H).

[0155] MS (ESI), m / z: 416 (M + +H + ).

Embodiment 3

[0156] Example 3 N 2 -(4-Bromo-2-fluorobenzyl)-N 4 - Preparation of (5-methyl-1H-pyrazole-3-substituted)thieno[3,2-d]pyrimidine-2,4-diamines (LD4478)

[0157] N 2 -(4-Bromo-2-fluorobenzyl)-N 4 The chemical structure of -(5-methyl-1H-pyrazole-3-substituted)thieno[3,2-d]pyrimidine-2,4-diamine is Its synthesis steps are the same as in Example 1.

[0158] The characterization data of this compound are:

[0159] 1 H NMR (400MHz, d-DMSO), δ12.12(br, 1H), 9.69(br, 1H), 7.91(d, J=3.6Hz, 1H), 7.69(t, J=10.4Hz, 2H), 7.43(m, J=71.6Hz, 1H), 7.186(brs, 1H), 7.05(d, J=3.6Hz, 1H), 4.52(d, J=6Hz, 2H), 2.17(s, 3H).

[0160] MS (ESI), m / z: 434 (M + +H + ).

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Abstract

The invention discloses a thieno 2,4-substituted pyrimidine compound of which the general formulas are (I), (II), (III) and (IV), or pharmaceutically acceptable salt or stereisomer or a prodrug molecule, and a pharmaceutical composition and application thereof. The thieno 2,4-substituted pyrimidine compound can effectively restrain abnormal expression of Aurora kinase, has specific inhibited effect on Aurora-A and Aurora-B, can be applied to a novel field of molecular targeting treatment, and has strong inhibitory activity on an excessive hyperplasia disease, especially cervical tumor cells, human macrophage line leukemia cell, and human t-lymphocyte line cancer cell.

Description

technical field [0001] The invention relates to the field of chemistry and medicine, in particular to thieno 2,4 substituted pyrimidine compounds and their pharmaceutical composition and application. Background technique [0002] Tumor molecular targeted therapy is a treatment method based on the selective killing of tumor cells by chemical or biological means to key molecules closely related to tumor growth. The characteristics of targeted therapy are: high specificity, strong selectivity, and mild side effects; when used in combination, it can strengthen the curative effect of traditional chemotherapy and radiotherapy, and reduce postoperative recurrence. Gleevec (STI571, imatinib, commodity The targeted drug represented by Gleevec has ushered in a new era for cancer chemotherapy. Tumor targeted therapy has developed rapidly in just a few years. The emergence of tumor targeted therapy has had an impact on traditional drug administration concepts and modes. For example, d...

Claims

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Application Information

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IPC IPC(8): C07D495/04A61K31/519A61K31/5377A61K31/551A61P35/00A61P31/00A61P29/00A61P37/00A61P19/02A61P25/28A61P13/12A61P35/02A61P17/00
Inventor 蔡倩涂正超刘丹罗金凤
Owner GUANGZHOU INST OF BIOMEDICINE & HEALTH CHINESE ACAD OF SCI
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