Pyrimidopyrimidine compound, nucleoside analog derivative thereof, preparation method thereof and use thereof

A compound and pyrimidine technology, applied in the field of pyrimidopyrimidine compounds and their nucleoside analog derivatives, can solve the problems of structural gap and low efficiency, and achieve the effect of inhibiting virus replication, inhibiting hepatitis virus, and excellent effect

Active Publication Date: 2012-06-27
WEST CHINA HOSPITAL SICHUAN UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, ribavirin is mainly composed of triazole and ribose. Compared with natural nucleosides, there is a big difference in structure. It has been found that the efficiency of ribavirin incorporation into the viral genome is low

Method used

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  • Pyrimidopyrimidine compound, nucleoside analog derivative thereof, preparation method thereof and use thereof
  • Pyrimidopyrimidine compound, nucleoside analog derivative thereof, preparation method thereof and use thereof
  • Pyrimidopyrimidine compound, nucleoside analog derivative thereof, preparation method thereof and use thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0040] Example 1 Preparation of 4,7-diamino-5-methoxypyrimido[4,5-d]pyrimidin-2(1H)-one

[0041] The compound structural formula is as follows:

[0042]

[0043] In an ice bath, add 70 mL of N,N-dimethylformamide dropwise to 300 mL of phosphorus oxychloride, stir slowly for 20 minutes and then put it at room temperature. Add 50 g of commercially available 2-amino-4,6-dihydroxy Pyrimidine, after the reaction is fully stirred, raise the reaction to 110 degrees, remove excess phosphorus oxychloride after two hours of reaction, then slowly pour it into the ice-water mixture (about 8000mL), and then increase the temperature to 50 degrees to obtain The yellow precipitate, after drying, reacts with hydroxylamine hydrochloride in glacial acetic acid to obtain a white precipitate, which is refluxed with selenium dioxide and pyridine in toluene, and the solvent is recovered after the reaction to obtain a light red product, which is then mixed with o-benzene Diformyl chloride was react...

Embodiment 2

[0045] Example 2 Preparation of 4,7-diaminopyrimido[4,5-d]pyrimidine-2,5(1H,6H)-dione

[0046] The compound structural formula is as follows:

[0047]

[0048] 4,7-Diamino-5-methoxypyrimido[4,5-d]pyrimidin-2(1H)-one (200mg, 0.96mmol) was added to 20mL CH 3 In CN, 200 mg sodium iodide and 200 μL trimethylchlorosilane were added to the above mixed solution, stirred overnight at room temperature to obtain a white precipitate 4,7-diaminopyrimido[4,5-d]pyrimidine-2,5(1H , 6H)-diketone. 1H NMR (400MHz, [D6]DMSO): δ7.67-9.08 (m, 4H, 2-NH2), 12.16 (s, 2H, -NH), MS (ESI): calcd for: [C6H6N6O2+H]+ : 195.0631, found: 195.0625.

Embodiment 3

[0049] Example 3 Preparation of 4,7-diamino-1-(β-D-ribofuranose)pyrimido[4,5-d]pyrimidine-2,5(1H,6H)-dione

[0050] The compound structural formula is as follows:

[0051]

[0052] 4,7-Diamino-5-methoxypyrimido[4,5-d]pyrimidin-2(1H)-one (1 g, 4.8 mmol) was added to 100 mL of hexamethyldisilazane, trimethyl chloride Silane (1 ml) was used as a catalyst, and after the reaction was completed, it was glycosylated with 1-O-acetyl-2,3,5-tri-O-benzoyl-β-D-ribofuranose in acetonitrile to obtain the nucleus Glycoside, and then remove the protecting group to obtain 4,7-diamino-1-(β-D-ribofuranose)pyrimido[4,5-d]pyrimidine-2,5(1H,6H)-dione. UV (MeOH): 228 (2359), 283 (1216). δH (400MHz; d6-DMSO): 3.41-3.45 (1H, m, OH), 3.59-3.65 (2H, t, 5'CH2), 4.19 ( 1H, s, OH), 4.54-4.56 (1H, d, J=8.0Hz, 2'H), 4.68 (1H, s, 3'H), 4.80-4.81 (1H, bd, J=2.0Hz, OH ), 5.02(1H, s, 4'H), 6.47(1H, s, 1'H), 7.57-8.25(4H, m, NH2×2), 11.72(1H, br, NH).HRMS(ESI- )m / z: Calc.for C11H14N6O6: 325.0896[M-H]-.Foun...

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Abstract

The invention relates to a pyrimidopyrimidine compound and a nucleoside analog derivative thereof. The pyrimidopyrimidine compound and the nucleoside analog derivative thereof prepared in the invention have certain hepatitis virus inhibition activities, and 4,7-diamino-1-(beta-2-deoxy-D-ribofuranose)pyrimido[4,5-d]pyrimidine-2,5(1H,6H)-dione and 4,7-diaminopyrimido[4,5-d]pyrimidine-2,5(1H,6H)-dione perform obvious virus copying inhibition potentials and are better than ribavirin, so a new selection is provided for clinical medicines.

Description

technical field [0001] The present invention relates to a pyrimidopyrimidine compound and its nucleoside analog derivatives, as well as the preparation method and application of these compounds. Background technique [0002] The base mainly refers to the derivatives of purine and pyrimidine, which are the components of nucleic acid and nucleotide. The natural bases mainly include cytosine, guanine, adenine, thymine and uracil, which play an important role in the biological genetic process, but there are few reports on the medical use of bases. Currently, it is reported that cytosine nucleus Glycosides and nucleotides can be used to increase white blood cells. However, in view of the important role of natural bases in organisms, people have also begun to do a lot of research on base analogs, and some people have prepared some base analog derivatives, such as patent application number: CN97192789.8, in this application Disclosed is a pyrimido[5,4-d]pyrimidine compound, which...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07H19/23C07H1/00A61K31/7072A61P31/12A61P31/20A61P31/14A61P1/16
CPCY02P20/55
Inventor 何杨赵行黄文吴晓华阳昊哲
Owner WEST CHINA HOSPITAL SICHUAN UNIV
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