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Novel purinone and imidazo triazinone derivative with anti-brain glioma activity

A technology for glioma and glioma, which is applied in the field of anticancer drugs, can solve the problems of not becoming a therapeutic drug, and achieve high anti-glioma activity

Inactive Publication Date: 2021-03-05
NANKAI UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Bevacizumab is the only anti-angiogenic glioma drug approved by the FDA. Although it has been shown in some studies to improve the median survival of glioma, it has not become a standard treatment drug

Method used

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  • Novel purinone and imidazo triazinone derivative with anti-brain glioma activity
  • Novel purinone and imidazo triazinone derivative with anti-brain glioma activity
  • Novel purinone and imidazo triazinone derivative with anti-brain glioma activity

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0019] Example 1 Synthesis of ethyl 2-amino-2-cyanoacetate 2

[0020] 640ml of water, 150ml of saturated sodium bicarbonate solution, ethyl 2-oxime cyanoacetate (50g, 0.352mol) were added successively in the 2000ml four-necked reaction flask, and hydrosulfite (62.5g, 0.352mol) was added every two hours after stirring evenly. The reaction was stirred at room temperature for 6 h, extracted four times with dichloromethane, dried over anhydrous sodium sulfate, and precipitated under reduced pressure to obtain 28.42 g of yellow oil, yield: 63.1%. 1 H NMR (400MHz, CDCl 3 )δ4.46(s, 1H, CHNH 2 ), 4.34 (q, J=7.1Hz, 2H, OCH 2 CH 3 ), 2.03(s, 2H, CHNH 2 ), 1.36(t, J=7.2Hz, 3H, OCH 2 CH 3 ).

Embodiment 2

[0021] Example 2 Synthesis of 1-benzyl-2-methyl-5-amino-1H-imidazole-4-ethyl carboxylate 3-1

[0022] Add 120ml of ethyl 2-amino-2-cyanoacetate 2 (9.46g, 78.87 mmol) dissolved in acetonitrile into a 500ml four-necked reaction flask, add triethyl orthoacetate (13.45g, 81.25mmol) and then heat to reflux for 2h. After cooling to room temperature, benzylamine (8.89 g, 0.19 mmol) was added and stirred overnight. Stand still, filter with suction, and recrystallize the filter cake from ethanol to obtain 8.52 g of white solid, yield: 44.5%. 1 H NMR (400MHz, CDCl 3)δ7.42-7.31 (m, 3H, Ar-H), 7.08 (d, J=6.8Hz, 2H, Ar-H), 4.99 (s, 2H, NCH 2 ), 4.72 (bs, 1H, NH 2 ), 4.36 (q, J=7.1Hz, 2H, CH 2 CH 3 ), 2.35(s, 3H, CH 3 ), 1.40(t, J=7.1Hz, 3H, CH 2 CH 3 ).

Embodiment 3

[0023] Example 3 Synthesis of 1-phenyl-2-methyl-5-amino-1H-imidazole-4-ethyl carboxylate 3-2

[0024] Add 90ml of ethyl 2-amino-2-cyanoacetate (18.45g, 144.07mmol) dissolved in acetonitrile into a 500ml four-necked reaction flask, add triethyl orthoacetate (26.23g, 162.23mmol) and heat to reflux for 2h, cool Add aniline (15.10 g, 158.48 mmol) to room temperature and stir for 18 h. The solvent was removed under reduced pressure, the residual liquid was redissolved in dichloromethane, washed twice with 10% sodium hydroxide, washed with saturated brine, and anhydrous Na 2 SO 4 Drying, suction filtration, precipitation, the residue was subjected to petroleum ether: ethyl acetate column chromatography to obtain 5.85 g of white solid, yield: 13.5%. 1 H NMR (400MHz, DMSO-D 6 )δ7.57(m, 3H, Ar-H), 7.40(d, J=7.7Hz, 2H, Ar-H), 5.66(s, 2H, NH 2 ), 4.18 (q, J=7.0Hz, 2H, CH 2 CH 3 ), 1.98(s, 3H, CH 3 ), 1.25(t, J=7.0Hz, 3H, CH 2 CH 3 ).

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Abstract

The invention relates to the technical field of anti-brain glioma drugs, and relates to synthesis of compounds 1H-purine-6(9H)-ketone(A) and 3H-imidazole[4,5-d][1,2,3]-triazine-4(7H)-ketone(B) and theanti-brain glioma activity of the compounds. R is hydrogen, methyl or ethyl; R1 is phenyl, 4-chlorphenyl, 2-pyridyl, benzyl, 1-phenylethyl, 2-phenylethyl, 2-fluorobenzyl, 3-fluorobenzyl, 4-fluorobenzyl, 4-chlorobenzyl and 2,4difluorobenzyl; and R2 is hydrogen, methyl or ethyl. An anti-brain glioma activity result shows that most compounds have good anti-brain glioma activity under a concentrationof 20 [mu]M, compounds A9 (R=CH3, R1=2,4-difluorobenzyl, and R2=CH2CH3), B9 (R=CH3, and R1=4-chlorphenyl) and B12(R=CH3, and R1=4-chlorbenzyl) show good anti-cancer activity, and the IC50 values of the anti-human brain astroblastoma U-118MG are 0.6[mu]M, 0.4[mu]M and 0.8[mu]M, and are better than that of a control drug temozolomide (IC50=1.7[mu]M).

Description

technical field [0001] The present invention relates to the technical field of anticancer drugs, and relates to compounds 1H-purin-6(9H)-ketone (A) and 3H-imidazo[4,5-d][1,2,3]-triazine-4(7H )-Kones (B) synthesis and their glioma activity. Background technique [0002] Glioma is a tumor that occurs in the neuroectoderm of the brain. It is a tumor derived from glial cells. The incidence rate is about 3-10 / 100,000, accounting for 46% of intracranial tumors. The incidence rate of men is higher than that of women. Most were expansive and infiltrating growths. Malignant glioma is the most threatening glioma, accounting for about 50% of gliomas. Brain glioma is not easy to be removed by surgery, and the pathological characteristics of different parts are different, and the degree of malignancy is also different, and the prognosis is relatively poor (Chen Bonian, Wu Jianjuan. Tianjin Pharmacy, 2011, 23(1), 58-62). At present, the treatment of glioma is still a recognized problem...

Claims

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Application Information

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IPC IPC(8): C07D473/30C07D487/04A61P35/00A61K31/522A61K31/53
CPCA61P35/00C07D473/30C07D487/04
Inventor 胡方中徐凤波刘伟杰王泽春李庆山
Owner NANKAI UNIV
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