Pyrimido diazepine compound as well as pharmaceutical composition and application thereof

A technology of diazepines and compounds, applied in the field of pyrimidodiazepines and their pharmaceutical compositions, which can solve problems such as poor selectivity, clinical pressure of drug resistance, wild-type cell toxicity and side effects

Active Publication Date: 2013-10-30
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

Method used

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  • Pyrimido diazepine compound as well as pharmaceutical composition and application thereof
  • Pyrimido diazepine compound as well as pharmaceutical composition and application thereof
  • Pyrimido diazepine compound as well as pharmaceutical composition and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0211] N-(3-(2-(2-methoxy-4-(4-methylpiperazine-1-substituted)aniline)-6-methyl-5,8-dioxo-7,8- Dihydro-5H-pyrimido[4,5-e][1,4]diazatable-9(6H)-substituted)phenyl)acrylamide (SL02)

[0212] (N-(3-(2-(2-methoxy-4-(4-methylpiperazin-1-yl)phenylamino)-6-methyl-5,8-dioxo-7,8-dihydro-5H-pyrimido[4, 5-e][1,4]diazepin-9(6H)-yl)phenyl)acrylamide)

[0213]

[0214] Step 1. Ethyl 4-(3-tert-butoxycarbonylaminoaniline)-2-methylmercaptopyrimidine-5-carboxylate (1)

[0215] (ethyl 4-(3-(tert-butoxycarbonylamino)phenylamino)-2-(methylthio)pyrimidine-5-carboxylate)

[0216]

[0217] 4-Chloro-2-methylmercaptopyrimidine-5-ethyl carbonate (12.63g, 54.27mmol), N-Boc m-phenylenediamine (11.29g, 54.27mmol), K 2 CO 3 (15g, 108.54mmol) was dissolved in 200ml of anhydrous DMF, heated to 80°C under the protection of argon, and stirred overnight. After cooling to room temperature, 500 ml of ice water was added with stirring, and a large amount of solids precipitated out. It was filtered under...

Embodiment 2

[0267] N-(3-(2-(2-methoxy-4-(4-methylpiperazine-1-substituted)anilino)-5,10-dioxo-8,9,9a,10-tetra Hydrogen-5H-pyrimido[4,5-e]pyrrolo[1,2-a][1,4]diazatable-11(7H)-substituted)phenyl)acrylamide (SL01)

[0268] N-(3-(2-(2-methoxy-4-(4-methylpiperazin-1-yl)phenylamino)-5,10-dioxo-8,9,9a,10-tetrahydro-5H-pyrimido[4,5 -e]pyrrolo[1,2-a][1,4]diazepin-11(7H)-yl)phenyl)acrylamide

[0269]

[0270] The synthesis method is as in Example 1.

[0271] 1 H NMR (400MHz, CDCl 3 )δ8.95(s, 1H), 7.91(s, 1H), 7.78(s, 1H), 7.73(s, 1H), 7.44(t, J=7.6Hz, 1H), 7.38(s, 1H), 7.00(s, 1H), 6.93(d, J=7.2Hz, 1H), 6.42-6.38(m, 2H), 6.22-6.16(m, 1H), 6.09(s, 1H), 5.74(d, J= 10.0Hz, 1H), 4.34(d, J=5.2Hz, 1H), 3.80(s, 3H), 3.77(s, 1H), 3.67-3.65(m, 1H), 3.12(br, 4H), 2.79( s, 1H), 2.60 (br, 4H), 2.38 (s, 3H), 2.14-2.05 (m, 3H).

[0272] 13 C NMR (125MHz, CDCl 3 )δ169.16,163.27,162.40,159.46,158.28,148.79,147.51,140.23,139.17,131.05,130.10,127.96,124.35,120.46,120.31,119.64,119.53,113.04,110.43,107.76...

Embodiment 3

[0275] N-(3-(2-(2-methoxy-4-(4-methylpiperazine-1-substituted)anilino)-5,11-dioxo-7,8,9,10,10a , 11-hexahydropyrrolo[1,2-a]pyrimido[4,5-e][1,4]diazatable-12(5H)-substituted)phenyl)acrylamide (SL09)

[0276] N-(3-(2-(2-methoxy-4-(4-methylpiperazin-1-yl)phenylamino)-5,11-dioxo-7,8,9,10,10a,11-hexahydropyrido[1, 2-a]pyrimido[4,5-e][1,4]diazepin-12(5H)-yl)phenyl)acrylamide

[0277]

[0278] The synthesis method is as in Example 1.

[0279] 1 H NMR (400MHz, CDCl 3 )δ8.87(s, 1H), 7.97(s, 1H), 7.90(s, 1H), 7.77(s, 1H), 7.43(t, J=8.0Hz, 1H), 7.40(s, 1H), 7.08(s, 1H), 6.92(d, J=7.6Hz, 1H), 6.40-6.36(m, 2H), 6.27-6.20(m 1H), 6.09(s, 1H), 5.72(d, J=10.8 Hz, 1H), 4.50-4.47(m, 1H), 4.43-4.40(m, 1H), 3.79(s, 3H), 3.15(br, 4H), 3.06-2.99(m, 1H), 2.67(br, 4H), 2.42 (s, 3H), 2.27 (s, 1H), 1.95-1.90 (m, 1H), 1.83-1.62 (m, 4H).

[0280] 13 C NMR (125MHz, CDCl 3 )δ169.68,166.07,163.26,162.49,159.44,158.26,148.78,147.61,139.42,139.06,131.02,130.05,127.95,124.47,120.39,120.33,119.70,119...

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Abstract

The invention discloses a 5,8-dioxo-pyrimido[4,5-e][1,4]diazepine compound of a structural formula (1) or a pharmaceutically acceptable salt or stereoisomer or prodrug molecule thereof. The 5,8-dioxo-pyrimido[4,5-e][1,4]diazepine compound has the effects of effectively inhibiting the growth of various tumor cells and the generation of the EGFR (epidermal growth factor receptor), can be used for preparing anticancer medicaments and can overcome the resistance of the existing medicaments including the gefitinib, the erlotinib and the like.

Description

technical field [0001] The invention belongs to the field of chemistry and medicine, and in particular relates to pyrimidodiazepine 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 every...

Claims

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Application Information

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IPC IPC(8): C07D487/04C07D487/14C07D471/04C07D471/14A61K31/5513A61P35/00A61P35/02
Inventor 丁克徐石林常少华张连文涂正超许永陆小云
Owner GUANGZHOU INST OF BIOMEDICINE & HEALTH CHINESE ACAD OF SCI
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