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Application of novel 8,10-dediaza-N5-acyl tetrahydrofolic acid compound to antitumor drug

The technology of a compound and a drug is applied in the field of preparing a folic acid metabolism methionine synthase inhibitory effect, and achieves the effects of environmental friendliness, cheap and easily available reagents, and few synthesis steps.

Active Publication Date: 2016-08-24
PEKING UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Because there is no effective prevention, early diagnosis and treatment, chemotherapy (chemotherapy) has become one of the three main clinical treatments

Method used

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  • Application of novel 8,10-dediaza-N5-acyl tetrahydrofolic acid compound to antitumor drug
  • Application of novel 8,10-dediaza-N5-acyl tetrahydrofolic acid compound to antitumor drug
  • Application of novel 8,10-dediaza-N5-acyl tetrahydrofolic acid compound to antitumor drug

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0033] Example 1: Synthesis of (E)-4-[2-(2,4-diaminopyrido[3,2-d]pyrimidin-6-yl)vinyl]benzoic acid

[0034] Dissolve 1mmol 2,4-diamino-6-methylpyrido[3,2-d]pyrimidine (1), 1mmol ethyl p-formylbenzoate (2) and 1mmol p-toluenesulfonamide in 5mL N , in N-dimethylacetamide, heated to reflux for 12 h under nitrogen protection, TLC monitored the disappearance of the reaction raw materials, added an appropriate amount of 1N NaOH to the reaction solution to pH = 12, extracted and washed the solution with dichloromethane three times, collected the aqueous layer, 1N HCl was added to adjust the pH to 5, and a white solid was precipitated, which was filtered by suction and dried to obtain compound 3 with a yield of 90.5%. m.p.>250℃; 1 H NMR (DMSO-d 6 , 400MHz) δ: 6.37 (s, 2H, 2-NH2), 6.45 (d, J=16.0Hz, 1H, CH=CHPh), 7.57 (d, J=8.4Hz, 1H, CH-7, py), 7.74~7.78 (m, 2H, C 6 h 4 and 1H, CH-8, Py), 7.89 (d, J=16.0Hz, 1H, CH=CHPh), 7.94 (d, J=8.0Hz, 2H, C6H4), 11.0 (d, J=7.3Hz, 1H , COOH); ...

Embodiment 2

[0035] Example 2: (E)-4-[2-(2,4-diaminopyrido[3,2-d]pyrimidin-6-yl)vinyl]benzoyl-L-glutamic acid diethyl ester Synthesis

[0036] With 1mmol compound (E)-4-[2-(2,4-diaminopyrido[3,2-d]pyrimidin-6-yl)vinyl]benzoic acid, 1mmol diethyl glutamate and 1mmol 1 , 3-dicyclohexylcarbodiimide (DCC) was dissolved in dichloromethane, stirred at room temperature for 24h, TLC monitored the disappearance of the reaction raw materials, and the mother liquor was washed with CH 2 Cl 2 and saturated brine, and the organic layer was washed with anhydrous Na 2 SO 4 Distilled under reduced pressure after drying to a small amount, separated by column chromatography, and the eluent was CH 2 Cl 2 :CH 3 OH=15:1, 5 g of compound 1.9 was obtained, yellow-green fluorescent solid, yield 31.5%, m.p.133-134°C. 1 H NMR (400MHz, DMSO-d 6 )δ: 1.160~1.204(m, J=7.2Hz, 6H, 2×CH 3 ), 2.019~2.058 (m, 1H, C H a h b CH 2 CO), 2.111~2.184 (m, 1H, CH a H b CH 2 CO), 2.448~2.485(t, 2H, CH2CO), 4.036~4.08...

Embodiment 3

[0037] Example 3: 4-[2-(2,4-diamino-5,6,7,8-tetrahydropyrido[3,2-d]pyrimidin-6-yl)ethyl]benzoyl-L - Synthesis of diethyl glutamate

[0038] 100mg (0.201mmol) (E)-4-[2-(2,4-diaminopyrido[3,2-d]pyrimidin-6-yl)vinyl]benzoyl-L-glutamic acid diethyl Dissolve the ester in 10mL absolute ethanol, add 2mg PtO 2 and 1mL HOAc, catalytic hydrogenation under the condition of 0.4MPa hydrogen, TLC monitoring, stop the reaction after about 120h, filter off PtO 2 , with 5% NaHCO 3 The aqueous solution was neutralized, and the ethanol was distilled off under reduced pressure, and CH 2 Cl 2 and saturated brine, and the organic layer was washed with anhydrous Na 2 SO 4 After drying, it was distilled under reduced pressure to a small amount, separated by column chromatography, and the eluent was V(CH2Cl2):V(CH3OH)=12:1 to obtain 80 mg of compound 4-[2-(2,4-diamino-5,6 , 7,8-tetrahydropyrido[3,2-d]pyrimidin-6-yl)ethyl]benzoyl-L-glutamic acid diethyl ester, light yellow solid, yield 79.0%.m.p...

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Abstract

The invention relates to an application of a novel 8,10-dediaza-N5-acyl tetrahydrofolic acid compound I as shown in general formula to preparation of an antitumor drug or a pharmaceutical composition, and definitions of each group in the formula are shown in the claims. The invention also relates to a preparation method of the compound.

Description

field of invention [0001] This application relates to 8,10-dediazepine-N 5 -Acyl-substituted tetrahydrofolate derivatives, optically pure isomers or diastereomer mixtures thereof, pharmaceutically acceptable salts thereof, and pharmaceutical compositions containing said compounds are used in the preparation of folic acid metabolizing methionine synthase inhibitory use. The present invention also relates to the use of such compounds in the preparation of tumor cell apoptosis-inducing anti-lung cancer, gastric cancer, skin cancer, liver cancer, cervical cancer, breast cancer, colon cancer, prostate cancer, nasopharyngeal cancer, esophageal cancer, brain glioma , and use in pancreatic cancer drugs. technical background [0002] Cancer is a major disease that endangers human life and health. The number of deaths due to cancer in the world is more than 7 million every year, and it is the second largest killer after cardiovascular disease. Because there is no effective preventi...

Claims

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Application Information

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IPC IPC(8): C07D471/04A61K31/519A61P35/00
Inventor 刘俊义田超张志丽王孝伟王锰
Owner PEKING UNIV
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