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Pyrimidone derivative and application thereof

A derivative, pyrimidinone technology, applied in the direction of drug combination, medical preparations containing active ingredients, organic active ingredients, etc., can solve the problems of poor selectivity, easy to produce drug resistance, etc., and achieve the effect of significant activity inhibition.

Inactive Publication Date: 2018-06-08
EAST CHINA UNIV OF SCI & TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0003] So far, the clinically used antimalarial drugs mainly include artemisinin derivatives such as chloroquine, artemether and artether, pyrimethamine and sulfadoxine, etc. These drugs have unavoidable toxic and side effects, poor selectivity, and are prone to Disadvantages such as drug resistance

Method used

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  • Pyrimidone derivative and application thereof
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  • Pyrimidone derivative and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0029] Synthesis of 3-methyl-1-(naphthalene-2-yl)-2,3-dihydro[2,3-d]pyrimidine-4,5(1H,6H)-dione (compound represented by formula Ia)

[0030]

[0031] (1) Synthesis of ethyl 2-(2-naphthylamino)-4-carbonyl-4,5-dihydrofuran-3-carboxylate (compound shown in formula IIIa):

[0032]

[0033] Add 3mmol of sodium hydrogen (60% purity) and 1.8mL of anhydrous tetrahydrofuran (THF) into a 50mL flask, add 6mmol of diethyl malonate in 3mL of anhydrous THF dropwise in an ice-water bath, and then Add 3mmol of chloroacetyl chloride in 3mL of anhydrous THF dropwise, and stir at 40°C to 45°C for at least 1 hour;

[0034] At room temperature, add 2-naphthylamine dropwise to the above reaction solution, stir at 45°C to 55°C for at least 12 hours, adjust the pH of the reaction solution to 6-7 with 5% dilute hydrochloric acid solution, and use ethyl acetate to Extraction, washing with saturated brine twice, concentration of the organic layer, drying, silica gel column chromatography (petrol...

Embodiment 2

[0051] 1-(2-naphthyl)-3-ethyl-2,3-dihydrofuro[2,3-d]pyrimidine-4,5-(1H, 6H)-dione (compound shown in formula Ib) synthesis:

[0052]

[0053] Except that the ethylamine aqueous solution was used to replace the methylamine aqueous solution in Example 1 (in step (3)), other conditions and steps were the same as in Example 1 to obtain a white solid (compound represented by formula Ib) with a yield of 37.3%.

[0054] 1 H NMR (400MHz, CDCl 3 ):δ8.03-7.73(m,4H),7.60-7.42(m,3H),5.51(s,2H),4.88(s,2H),3.05(q,J=7.6 3H),1.33(t, J=7.6 3H).

[0055] 13 C NMR (100MHz, CDCl 3 )δ193.6, 182.4, 162.3, 135.4, 133.3, 132.3, 131.8, 128.4, 128.2, 127.5, 127.2, 124.2, 123.6, 97.6, 38.6, 38.5, 14.9.

[0056] LC-MS (ESI) calcd for C 18 h 16 N 2 o 3 [M+H] + 309.02, found 309.09.

Embodiment 3

[0058] 1-(2,3-dihydro-1H-inden-5-yl)-3-ethyl-2,3-dihydrofuro[2,3-d]pyrimidine-4.5(1H,6H)-dione ( Compound shown in formula Ic) synthesis:

[0059]

[0060] Except replacing 2-naphthylamine in Example 1 (in step (1)) with the compound shown in formula c, and replacing methylamine aqueous solution in Example 1 with ethylamine aqueous solution (in step (3)), other conditions and steps Same as Example 1, a white solid (compound represented by formula Ic) was obtained with a yield of 39.1%.

[0061] 1 H NMR (400MHz, CDCl 3 )δ7.32(d, J=8.0Hz, 1H), 7.27(s, 1H), 7.16(d, J=8.0Hz, 1H), 4.22(q, J=7.2Hz, 2H), 4.17(s, 2H), 3.65(s, 2H), 2.89(t, J=7.6Hz, 4H), 2.09-2.02(m, 2H), 1.26(t, J=7.2Hz, 3H).

[0062] 13 C NMR (100MHz, CDCl 3 )δ190.9, 183.5, 165.6, 145.7, 144.2, 135.8, 125.4, 123.6, 121.6, 97.1, 88.3, ​​59.7, 38.4, 32.8, 32.4, 25.7, 14.9.

[0063] LC-MS (ESI) calcd for C 17 h 18 N 2 o 3 [M+H] + 299.13, found 299.17.

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Abstract

The invention relates to a pyrimidone derivative and application thereof. The pyrimidone derivative is a compound shown as a formula I or pharmaceutically-acceptable salt thereof. An activity inhibition experiment discovers that the pyrimidone derivative provided by the invention has a significant activity inhibition effect on dihydroorotate dehydrogenase of plasmodium falciparum. The invention lays a foundation for the preparation of a novel anti-malarial drug. In the formula I, R1 is a straight chain and a branched chain of C1-C6 or cyclic alkyl or amino; and A is a 5 to 6-membered saturatedor unsaturated carbocyclic group.

Description

technical field [0001] The present invention relates to a pyrimidinone derivative and its application. Background technique [0002] Malaria is a vector-borne infectious disease caused by parasitic Plasmodium that seriously endangers human health, and is still one of the most serious parasitic diseases in the world. [0003] So far, the clinically used antimalarial drugs mainly include artemisinin derivatives such as chloroquine, artemether and artether, pyrimethamine and sulfadoxine, etc. These drugs have unavoidable toxic and side effects, poor selectivity, and are prone to Disadvantages such as drug resistance. With the rapid development of life science and technology, some key enzymes of malaria-related signal transduction pathways are used as drug screening targets, and the development of anti-drugs with good therapeutic effect and low side effects has become an important direction of new antimalarial drug research. . Contents of the invention [0004] The present ...

Claims

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Application Information

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IPC IPC(8): C07D491/048A61K31/519A61P33/06
CPCC07D491/048Y02A50/30
Inventor 赵振江李洪林朱丽丽徐乐李文杰刁妍妍
Owner EAST CHINA UNIV OF SCI & TECH
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