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Pyrimidoheterocyclic compound and its pharmaceutical composition and application

A compound and heterocyclic technology, applied in the field of pyrimido heterocyclic compounds and their pharmaceutical compositions, can solve the problems of poor pharmacokinetic properties, poor selectivity, and inability to solve the clinical pressure of drug resistance

Active Publication Date: 2016-09-07
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, there is an urgent need for new types, especially compounds with novel backbones, to solve the problems of drug resistance, poor selectivity, and poor pharmacokinetic properties.

Method used

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  • Pyrimidoheterocyclic compound and its pharmaceutical composition and application
  • Pyrimidoheterocyclic compound and its pharmaceutical composition and application
  • Pyrimidoheterocyclic compound and its pharmaceutical composition and application

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0127] 1-(1-acryloylpiperidin-4-yl)-3-benzyl-7-(2-methoxy-4-(4-methylpiperazin-1-yl)anilino)-3,4 -Dihydropyrimido[4,5-d]pyrimidin-2(1hydro)-one (XSL1710)

[0128]1-(1-acryloylpiperidin-4-yl)-3-benzyl-7-(2-methoxy-4-(4-methylpiperazin-1-yl)phenylamino)-3,4-d ihydropyrimido[4,5-d] pyrimidin-2(1H)-one

[0129]

[0130] Step 1. 4-(1-tert-butoxycarbonylpiperidinyl-4-amino)-2-methylmercaptopyrimidine-5-ethyl carbonate (2)

[0131] (ethyl4-(1-(tert-butoxycarbonyl)piperidin-4-ylamino)-2-(methylthio)pyrimidine-5-carboxylate)

[0132]

[0133] 4-Chloro-2-methylmercaptopyrimidine-5-ethyl carbonate (5g, 21.5mmol), 4-amino-1-tert-butoxycarbonylpiperidine (4.53g, 22.6mmol), K 2 CO 3 (5.9g, 43mmol) was dissolved in 50mL of anhydrous DMF, heated to 80°C under the protection of argon, and stirred overnight. After cooling to room temperature, 200 mL of ice water was added with stirring, and a large amount of solids precipitated out. It was filtered under reduced pressure and dried i...

Embodiment 2

[0186] 1-(1-acryloylpiperidin-4-yl)-3-benzyl-7-(anilino)-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one (XSL1720)

[0187] 1-(1-acryloylpiperidin-4-yl)-3-benzyl-7-(phenylamino)-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one

[0188]

[0189] The synthesis method is as in Example 1.

[0190] 1 H NMR (400MHz, CDCl 3 )δ7.89(s,1H),7.52(d,J=8.0Hz,2H),7.37-7.30(m,7H),7.12(s,1H),7.04(t,J=7.6Hz,1H), 6.61(dd, J=10.4,16.8Hz,1H),6.29(dd,J=1.6,16.8Hz,1H),5.69(dd,J=1.6,10.4Hz,1H),4.99-4.92(m,1H) ,4.88-4.86(m,1H),4.63(s,2H),4.13(s,2H),4.11-4.09(m,1H),3.13(t,J=9.6Hz,1H),2.80-2.69(m ,3H),1.78-1.72(m,2H).

[0191]13 C NMR (125MHz, CDCl 3 )δ165.48,159.05,157.48,153.73,153.27,139.09,136.19,128.90,128.80,128.12,128.06,127.84,127.42,123.07,119.87,103.08,53.10,51.49,46.17,43.73,42.45,29.29,28.43.

[0192] MS(ESI)m / z469.1[M+H] + .

[0193] HPLC analysis:MeOH-H 2 O(78:22), 8.69min, 97.61%.

Embodiment 3

[0195] 1-(1-acryloylpiperidin-4-yl)-3-benzyl-7-(4-fluoroanilino)-3,4-dihydropyrimido[4,5-d]pyrimidine-2(1H )-ketone (XSL1714)

[0196] 1-(1-acryloylpiperidin-4-yl)-3-benzyl-7-(4-fluorophenylamino)-3,4-dihydropyrimido[4,5-d]pyrimid in-2(1H)-one

[0197]

[0198] The synthesis method is as in Example 1.

[0199] 1 H NMR (400MHz, CDCl 3 )δ7.88(s,1H),7.47-7.44(m,2H),7.37-7.34(m,2H),7.32-7.29(m,3H),7.03-6.99(m,3H),6.61(dd, J=10.4,16.8Hz,1H),6.31(dd,J=1.6,16.8Hz,1H),5.70(dd,J=1.6,10.4Hz,1H),4.95-4.85(m,2H),4.63(s ,2H),4.12(s,2H),4.09-4.08(m,1H),3.12(t,J=12.0Hz,1H),2.81-2.67(m,3H),1.81-1.75(m,2H).

[0200] 13 C NMR (125MHz, CDCl 3 )δ165.44,159.75,159.12,157.82,157.51,153.77,153.31,136.17,135.07,128.81,128.13,127.85,127.65,121.88,121.82,115.63,115.45,103.21,53.08,51.55,46.15,43.72,42.44,29.33,28.41 .

[0201] HPLC analysis:MeOH-H 2 O(78:22), 8.91min, 98.65%.

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Abstract

The invention discloses a pyrimidoheterocyclic compound represented as the formula (I), or a pharmaceutically acceptable salt or a stereisomer thereof, or a prodrug molecule thereof. The pyrimidoheterocyclic compound can effectively inhibit growth of various tumor cells and has an inhibiting effect on EGFR protease. The pyrimidoheterocyclic compound can be used for preparing an anti-tumor drug, and can overcome drug resistance caused by medicines in the prior art, such as gefitinib, erlotinib and the like, has a selectivity on wild non-small cell lung cancer and is excellent in pharmacokinetic property.

Description

technical field [0001] The invention belongs to the field of chemistry and medicine, and in particular relates to pyrimido heterocyclic compounds and their medicinal compositions and applications. 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 major 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 serious. 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; among them, one out of e...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D487/04A61K31/519A61K31/5377A61K31/551A61P35/00A61P35/02
CPCC07D487/04
Inventor 丁克徐石林徐田锋张连文丁芳涂正超陆小云丁健耿美玉
Owner GUANGZHOU INST OF BIOMEDICINE & HEALTH CHINESE ACAD OF SCI
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