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Pyrimidinone compound and composition prepared from pyrimidinone compound

A technology of pyrimidones and compounds, applied in the field of pyrimidones and their prepared compositions, can solve the problems of poor selectivity, inability to solve the clinical pressure of drug resistance, wild-type cell toxicity and side effects, and achieve the goal of overcoming drug resistance sexual effect

Inactive Publication Date: 2019-07-23
东莞市恩联干细胞生物科技研究院
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0009] In short, the current EGFR-TKI still cannot solve the clinical pressure caused by drug resistance, and most of the existing drugs are EGFR reversible or irreversible inhibitors based on quinazoline or quinolineamine Toxic side effects caused by poor selectivity of wild-type cells are also inevitable
Therefore, it is of great significance to develop a new generation of drugs to overcome problems such as drug resistance and poor selectivity, and to improve clinical effects.

Method used

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  • Pyrimidinone compound and composition prepared from pyrimidinone compound
  • Pyrimidinone compound and composition prepared from pyrimidinone compound
  • Pyrimidinone compound and composition prepared from pyrimidinone compound

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0043] In the present embodiment, pyrimidinone compound, the structural formula of the compound is as follows:

[0044]

[0045] Wherein, R1 is methyl, R2 is methoxy, R3 is H, and R4 is H.

[0046] This compound is referred to as compound D1, and the preparation method of described compound D1 comprises the following steps:

[0047] (1) 4-Chloro-2-methylmercaptopyrimidine-5-ethyl carbonate (23.3g, 100mmol), N-Boc m-phenylenediamine (20.8g, 1.0eq), K 2 CO 3 (27.6g, 2.0eq) was dissolved in 300ml of anhydrous DMF, heated to 80°C under nitrogen protection, and stirred overnight. After cooling to room temperature, 1000 ml of ice water was added with stirring, and a large amount of solids precipitated out. It was filtered under reduced pressure and dried in vacuo to obtain 38.8 g (96%) of a white solid.

[0048] 1 H NMR (400Hz, CDCl3) δ10.37(s, 1H), 8.76(s, 1H), 7.90(s, 1H), 7.34(d, J=8.0Hz, 1H), 7.24 (t, J=8.0Hz , 1H), 7.02(d, J=8.0Hz, 1H), 6.53(s, 1H), 4.38(q, J=7.2, 14....

Embodiment 2

[0067] In the present embodiment, pyrimidinone compound, the structural formula of the compound is as follows:

[0068]

[0069] Wherein, R1 is isopropyl, R2 is methyl, R3 is t-butyl, R4 is phenyl.

[0070] This compound is denoted as compound D2, and the preparation method of said compound D2 refers to compound D1.

[0071] 1 H NMR (400Hz, DMSO-d6) δ8.25(s, 1H), 7.95(s, 1H), 7.53(s, 1H), 7.38(d, J=7.6Hz, 1H), 7.23-7.27(m, 1H), 6.88(d, J=7.6Hz, 1H), 6.32(d, J=16.4Hz, 1H), 6.12(dd, J=10.0, 16.4Hz, 1H), 5.64(d, J=10.0Hz, 1H), 4.41(s, 2H), 3.52(m, 4H), 3.10(s, 3H), 2.30(m, 4H), 2.25(s, 3H). LCMS (ESI): m / z 408.2 [M+ H] + .

Embodiment 3

[0073] In the present embodiment, pyrimidinone compound, the structural formula of the compound is as follows:

[0074]

[0075] Wherein, R1 is phenyl, R2 is methoxy, R3 is H, and R3 is hydroxyl.

[0076] This compound is denoted as compound D3, and the preparation method of said compound D3 refers to compound D1.

[0077] 1 H NMR (400Hz, DMSO-d6) δ10.31(s, 1H), 8.11(s, 1H), 7.81(d, J=7.6Hz, 1H), 7.56(s, 1H), 7.48(s, 1H) , 7.43(t, J=8.0Hz, 1H), 7.27(d, J=8.4Hz, 1H), 6.95(d, J=8.0Hz, 1H), 6.51(s, 1H), 6.44(dd, J= 10.0, 16.8Hz, 1H), 6.25(d, J=16.8Hz, 1H), 6.02(d, J=8.0Hz, 1H), 5.76(d, J=10.0Hz, 1H), 4.46(s, 2H) , 3.76(s, 3H), 2.99(m, 4H), 2.96(s, 3H), 2.50(m, 4H), 2.22(s, 3H). LCMS(ESI): m / z 529.2[M+H] + .

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Abstract

The invention relates to the technical field of chemical medicine, and particularly discloses a pyrimidinone compound, a pharmaceutical composition prepared from the pyrimidinone compound and application of the pyrimidinone compound. The structural formula of the pyrimidinone compound is as follows: the pyrimidinone compound disclosed by the invention can serve as a protease inhibitor and furtherinhibit multiple kinds of tumor cells from growth effectively, generates an inhibiting effect on the protease of EGFR and Her families such as EGFR L858R / T790M and EGFR E745_A750 / T790, can be used forpreparing antitumor drugs and overcome drug resistance induced by current drugs. The compound, to which the invention is related, and a pharmaceutically acceptable composition of the compound can beused for preparing the antitumor drugs for mankind and other mammals.

Description

technical field [0001] The invention relates to the technical field of chemistry and medicine, and in particular discloses a class of pyrimidinone compounds and the prepared composition thereof. Background technique [0002] With the development of economy and society, people's living standards continue to improve, but the incidence of various diseases continues to increase, whether in the world or in China, malignant tumors (cancer), cardiovascular diseases Chronic diseases (or non-communicable diseases) represented by diabetes and others are becoming a more important long-term threat. The World Health Organization clearly pointed out in its latest report that non-communicable diseases are becoming the deadliest killer of human beings. Among them, cancer ranks first. In recent years, although the discovery of various treatment approaches and drugs has brought hope to cancer patients, the disadvantages of conventional treatment, large side effects, poor treatment effect, t...

Claims

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Application Information

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IPC IPC(8): C07D487/04A61K31/519A61P35/00
CPCA61P35/00C07D487/04
Inventor 李治寰张一心刘冬羽林立龙
Owner 东莞市恩联干细胞生物科技研究院