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Pyrimidotricyclic or pyrimidotetracyclic compounds and pharmaceutical compositions and applications thereof

A compound and tetracyclic technology, applied in the field of pyrimidotricyclic or pyrimidotetracyclic compounds and their pharmaceutical compositions, can solve poor selectivity, wild-type cytotoxic side effects, and can not solve the clinical pressure of drug resistance And other issues

Active Publication Date: 2016-05-18
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

[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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  • Pyrimidotricyclic or pyrimidotetracyclic compounds and pharmaceutical compositions and applications thereof
  • Pyrimidotricyclic or pyrimidotetracyclic compounds and pharmaceutical compositions and applications thereof
  • Pyrimidotricyclic or pyrimidotetracyclic compounds and pharmaceutical compositions and applications thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0167] N-(3-(2-((2-methoxy-4-(4-methyl-1-piperazinyl)phenyl)amino)-5-oxo-7,8-dihydroimidazo[ 1,2-a]pyrimido[4,5-d]pyrimidin-10(5hydrogen)-yl)phenyl)acrylamide (XTF-01)

[0168]

[0169] Step 1. 4-(3-tert-butoxycarbonylaminoaniline)-2-chloropyrimidine-5-ethyl carbonate (1)

[0170]

[0171] 2,4-dichloro-5-pyrimidinecarboxylic acid ethyl ester (22.1g, 100mmol, 1.0eq), N-Boc m-phenylenediamine (20.8g, 1.0eq), DIPEA (17.4ml, 1.0eq) at room temperature Add in 500ml of acetonitrile, heat to reflux and stir to react for 2 hours, stop heating until the temperature of the system drops to room temperature, solid precipitates, and filter under reduced pressure to obtain 35.3g (90%) of white solid.

[0172] 1 HNMR (400MHz, CDCl 3 )δ10.44(s,1H,),8.81(s,1H),7.79(s,1H),7.36(d,J=7.6Hz,1H),7.31(d,J=8.0Hz,1H),7.18 (d, J=8.0Hz, 1H), 6.55(s, 1H), 4.44(q, J=7.2Hz, 2H), 1.52(s, 9H), 1.42(t, J=7.2Hz, 3H).

[0173] Step 2. 4-(3-tert-butoxycarbonylaminoaniline)-2-chloro-5-pyrimidinecarboxyl...

Embodiment 2

[0192] N-(3-(2-((4-(4-acetyl-1-piperazinyl)-2-methoxyphenyl)amino)-5-oxo-7,8-dihydroimidazo[ 1,2-a]pyrimido[4,5-d]pyrimidine-10(5hydrogen)-substituted)phenyl)acrylamide (XTF-02)

[0193]

[0194] The synthetic method is as embodiment 1

[0195] 1 HNMR (400MHz, Acetic-d 4 )δ9.00(s,1H),8.13(d,J=7.6Hz,1H),7.96(s,1H),7.62(t,J=8.0Hz,1H),7.28-7.34(m,2H), 6.71(s,1H),6.46-6.48(m,1H),6.26(brs,1H),5.84(dd,J=3.6,8.0Hz,1H),4.43(t,J=9.2Hz,2H),4.09 (t,J=9.2Hz,2H),3.84(m,5H),3.74(m,2H),3.18-3.24(m,4H),2.21(s,3H).LCMS(ESI):m / z582. 2[M+H] +

Embodiment 3

[0197] N-(3-(2-((4-(4-(dimethylamino)-1-piperidine)-2methoxyphenyl)amino)-5-oxo-7,8-dihydroimidazo [1,2-a]pyrimido[4,5-d]pyrimidine-10(5hydrogen)-substituted)phenyl)acrylamide (XTF-03)

[0198]

[0199] The synthesis method is as in Example 1.

[0200] 1 HNMR (400MHz, Acetic-d 4 )δ9.03(s,1H),8.14(s,1H),8.03(d,J=7.2Hz,1H),7.64(t,J=8.0Hz,1H),7.43(d,J=8.0Hz, 1H), 7.33(d, J=7.6Hz, 1H), 7.01(s, 1H), 6.60-6.50(m, 2H), 6.46(d, J=16.4Hz, 1H), 5.84(d, J=10.8 Hz,1H),4.45(t,J=8.8Hz,2H),4.11(t,J=8.8Hz,2H),3.87(s,3H),3.81(m,2H),3.70(m,1H), 3.29(t,J=11.2Hz,2H),2.93(s,6H),2.40-2.15(m,4H).LCMS(ESI):m / z582.2[M+H] +

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Abstract

The invention discloses pyrimidotricyclic compounds or pyrimidotetracyclic compounds having a structure represented by the formula (I), (II) or (III), pharmaceutically-acceptable salts, stereoisomers, or prodrug molecules. The compounds can inhibit various tumor cells, and especially, the compounds can selectively act on lung cancer cells of EGFR L858R / T790 and EGFR E745 A750 / T790M. Compared to wild type cancer cells, the IC50 of the compounds is 10 times, 100 times or even 1000 times higher. The compounds are a novel protein kinase inhibitor, which can overcome the drug resistance of EGFR-TKI and has selectivity.

Description

technical field [0001] The invention belongs to the field of chemistry and medicine, and in particular relates to a pyrimidotricyclic or pyrimidotetracyclic compound and its pharmaceutical composition and application. Background technique [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 death released at the end of April 2008, the cancer death rate among urban and rural residents in China has increased by more than 80% in the past 30 years; ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D487/14A61K31/519A61K31/5377A61K31/541A61K31/551A61P35/00A61P35/02
CPCC07D487/14
Inventor 丁克徐田锋常少华张连文罗金凤徐石林肖宜平涂正超
Owner GUANGZHOU INST OF BIOMEDICINE & HEALTH CHINESE ACAD OF SCI
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