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Pyrimidine, pyrimidone compound, and medical compound and application thereof

A technology of ketone compounds and pyrimidines, which is applied in drug combination, organic chemistry, antineoplastic drugs, etc., can solve the problems that cannot solve the clinical pressure of drug resistance, toxic side effects of wild-type cells, poor selectivity, etc.

Active Publication Date: 2012-12-12
东莞粤港澳干细胞生物科技有限公司
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  • Abstract
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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, new types, especially compounds with novel frameworks, are urgently needed to solve the problems of drug resistance, poor selectivity, etc.

Method used

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  • Pyrimidine, pyrimidone compound, and medical compound and application thereof
  • Pyrimidine, pyrimidone compound, and medical compound and application thereof
  • Pyrimidine, pyrimidone compound, and medical compound and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0129] N-(3-(3-methyl-7-(methylamino)-2-oxo-3,4-dihydropyrimidin[4,5-d]pyrimidine-1(2hydro)-substituted)phenyl)propene Amide (C-EGF21)

[0130] (N-(3-(3-methyl-7-(methylamino)-2-oxo-3,4-dihydropyrimido[4,5-d]pyrimidin-1(2H)-yl)phenyl)acrylamide)

[0131]

[0132] Step 1. 4-(3-tert-butoxycarbonylaminoaniline)-2-methylmercaptopyrimidine-5-ethyl carbonate

[0133] (ethyl 4-(3-(tert-butoxycarbonylamino)phenylamino)-2-(methylthio)pyrimidine-5-carboxylate)

[0134]

[0135] 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.

[0136] 1 H NMR (400Hz, CDCl 3 )δ...

Embodiment 2

[0174] N-(3-(3-methyl-2-oxo-7-(anilino)-3,4-dihydropyrimidin[4,5-d]pyrimidine-1(2hydro)-substituted)phenyl)propene Amide (C-EGF10)

[0175] N-(3-(3-methyl-2-oxo-7-(phenylamino)-3,4-dihydropyrimido[4,5-d]pyrimidin-1(2H)-yl)phenyl)acrylamide

[0176]

[0177] The synthesis method is as in Example 1.

[0178] 1 H NMR (400Hz, DMSO-d 6)δ10.30(s, 1H), 9.41(s, 1H), 8.18(s, 1H), 7.43(d, J=8.0Hz, 1H), 7.66(s, 1H), 7.45(t, J=8.0 Hz, 1H), 7.27(d, J=8.0Hz, 2H), 6.99(d, J=8.0Hz, 1H), 6.93(t, J=7.6Hz, 2H), 6.75(t, J=7.2Hz, 1H), 6.42(dd, J=10.4, 16.8Hz, 1H), 6.24(d, J=16.8Hz, 1H), 5.75(d, J=10.4Hz, 1H), 4.48(s, 2H), 2.97( s, 3H).

[0179] LCMS(ESI): m / z 401.1[M+H] + .

Embodiment 3

[0181] N-(3-(3-methyl-7-(4-methylpiperazine-1-substituted)-2-oxo-3,4-dihydropyrimidine[4,5-d]pyrimidine-1(2hydro )-substituted)phenyl)acrylamide (C-EGF19)

[0182] N-(3-(3-methyl-7-(4-methylpiperazin-1-yl)-2-oxo-3,4-dihydropyrimido[4,5-d]pyrimidin-1(2H)-yl)phenyl)acrylamide

[0183]

[0184] The synthesis method is as in Example 1.

[0185] 1 H NMR (400Hz, DMSO-d 6 )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] + .

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Abstract

The invention provides 7-(substituted amino)-3, 4-dihydro-pyrimidine [4, 5-d] pyrimidone-(1H)-ketone compounds represented as general formula (I) or (II) and application thereof in preparing medicines for treating tumors. According to research, the compounds can restrain proliferation of various tumor cells, can be used for targeted restrain of epidermal growth factor receptor (EGFR) kinase, and particularly can effectively restrain single-point mutation or multipoint mutation cancer cells of an EGFR (T790M) mutant strain. Accordingly, the 7-(substituted amino)-3, 4-dihydro-pyrimidine [4, 5-d] pyrimidone-(1H)-ketone compounds can serve as EGFR inhibitors to be used for anti-cancer medicines and have high application values.

Description

technical field [0001] The invention belongs to the field of chemical medicine, in particular to a class of pyrimidopyrimidinone compounds or pharmaceutically acceptable salts or stereoisomers and prodrug molecules thereof, pharmaceutical compositions containing such compounds and these compounds or Application of the composition in the preparation of medicaments. Background of the invention [0002] Whether in the world or in China, chronic diseases (or non-communicable diseases) represented by malignant tumors (cancer), cardiovascular diseases, and diabetes are becoming more important long-term threats. On May 19, 2008, 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 2004, 7.4 million people died of cancer worldwide, and the situation in China was even more severe. According to the third national retrospective survey on causes of ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D487/04A61K31/519A61K31/5377A61K31/551A61K31/541A61P35/00A61P35/02
CPCA61K31/541C07D487/04A61K31/551A61K31/519A61K31/5377A61P35/00A61P35/02
Inventor 丁克常少华徐石林张连文涂正超丁健耿美玉陈奕
Owner 东莞粤港澳干细胞生物科技有限公司
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