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Hydroxypyrimidinone compounds and preparation method and application thereof

A technology of hydroxypyrimidinone and compound, applied in the field of hydroxypyrimidinone compounds, can solve the problems of emergence of drug-resistant virus, toxic and side effects, inability to clear virus and the like

Inactive Publication Date: 2015-11-25
SHANDONG UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

HAART consists of reverse transcriptase inhibitors, protease inhibitors, and fusion inhibitors. Although it can successfully control HIV-1 RNA titers below monitoring levels, it cannot clear the virus from blood monocytes and T lymphocytes. , and long-term treatment will induce the emergence of drug-resistant virus and produce serious toxic side effects

Method used

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  • Hydroxypyrimidinone compounds and preparation method and application thereof
  • Hydroxypyrimidinone compounds and preparation method and application thereof
  • Hydroxypyrimidinone compounds and preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0092] The preparation of embodiment 1. compound 5a~5t

[0093] (1) Preparation of substituted benzamide oxime or substituted phenylacetamide oxime 2

[0094] Put hydroxylamine hydrochloride (200mmol) and potassium carbonate (200mmol) in 200mL ethanol and stir at room temperature for 30 minutes. Substituted benzonitrile or phenylacetonitrile was added, the reaction solution was refluxed for 12 hours, filtered to remove inorganic salts, and the solvent was evaporated under reduced pressure. Compound 2 was obtained by silica gel column chromatography, and the elution system was petroleum ether / ethyl acetate 2:1 volume ratio.

[0095] The above-mentioned substituted benzonitriles or phenylacetonitriles are respectively selected from benzonitrile, p-fluorobenzonitrile, 2-fluorobenzonitrile, 3-fluorobenzonitrile, p-chlorobenzonitrile, p-bromoxynil, and p-fluorobenzonitrile to obtain the following intermediates respectively Compound 2.

[0096] 2a: 4-fluorobenzamide oxime, white s...

Embodiment 2

[0139] Example 2. Preparation of Compounds 14, 15, 16a~16n, 17a, 17c, 17d, 17f, 17g

[0140] (1) Preparation of trimethylacetamide oxime 6

[0141] Put hydroxylamine hydrochloride (200mmol) and potassium carbonate (200mmol) in 200mL ethanol and stir at room temperature for 30 minutes. Trimethylacetonitrile 6 (75 mmol) was added, the reaction solution was refluxed for 12 hours, filtered to remove inorganic salts, the solvent was evaporated under reduced pressure, and the obtained residue was recrystallized with ether / petroleum ether to obtain compound 7.

[0142] 7: Trimethylacetamide oxime, white solid, yield 76.5%, mp: 119.4~120.6°C. 1 HNMR (DMSO-d 6 )δ (ppm): 8.86 (s, 1H), 5.22 (s, 2H), 1.08 (s, 9H).

[0143] (2) Preparation of dimethyl 2-(((1-amino-2,2-dimethylpropylene)amino)hydroxy)maleate 8

[0144] Trimethylacetamide oxime 7 (20 mmol) was dissolved in 50 ml of dry methanol. 1.2 times the amount of dimethyl butynedioate (24 mmol) was added under ice-bath conditions....

Embodiment 3

[0188] Example 3. Determination of compound's inhibitory activity on HIV-1 integrase, antiviral activity and cytotoxicity.

[0189] Compounds 5a-5t, 14, 15, 16a-16n, 17a, 17c, 17d, 17f, 17g prepared in Examples 1 and 2 were tested for biological activity according to the following method, and the results are listed in Table 1 and Table 2.

[0190] The inhibitory activity of the compound on HIV-1 integrase, the assay method of antiviral activity and cytotoxicity, adopt the method reported in the literature, see for details:

[0191] S. Yu, L. Zhang, S. Yan, P. Wang, T. Sanchez, F. Christ, Z. Debyser, N. Neamati, G. Zhao, Nitrogen-containing polyhydroxylated aromatics as HIV-1 integrase inhibitors: synthesis, structure-activity relationship analysis, and biological activity, JEnzyme Inhib MedChem, 27 (2012) 628-640.

[0192] Table 1. Compounds 5a~5t have HIV-1 integrase inhibitory activity, antiviral activity and cytotoxicity assay data

[0193]

[0194]

[0195]

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Abstract

The invention discloses a hydroxy-pyrimidone compound shown as the general formula (I). In the general formula (I), the R1 represents tertiary butyl, phenyl or substituent phenyl and benzyl; the R2 represents hydrogen or substituent propyl, the R3, R4, R5, R6 and R7 respectively represent hydrogen, methyl, methoxy, hydroxyl or halogen individually, and the n is equal to one or two. The hydroxy-pyrimidone compound has good HIV-1 (human immunodeficiency virus) integrase inhibitory activity and HIV-1 antiviral activity, wherein integrase inhibitory activities IC50(inhibitory concentration) of compounds 5a, 5b, 5c, 5d, 5e, 5i, 5n and 5q are all lower than or equal to 1 micromole, compounds 5a, 5h and 5s have high antiviral activity, and EC50(effective concentration) of the compounds 5a,5h and 5s are respectively 1.72 micromoles, 1.91 micromoles and 1.3 micromoles, and accordingly, the hydroxy-pyrimidone compound can be used for preparing anti-AIDs drugs.

Description

technical field [0001] The invention relates to a hydroxypyrimidinone compound, a preparation method thereof and an application in pharmacy, belonging to the field of organic compounds and medical applications. Background technique [0002] HIV-1 is the main pathogen that causes AIDS. HIV-1 invades the host body and along with CD4 + The replication of lymphocytes will eventually lead to the loss of lymphocytes and the decline of human immunity. Currently, highly active antiretroviral therapy (HAART) is the main method for the clinical treatment of HIV-1 infection. HAART consists of reverse transcriptase inhibitors, protease inhibitors, and fusion inhibitors. Although it can successfully control HIV-1 RNA titers below monitoring levels, it cannot clear the virus from blood monocytes and T lymphocytes. , and long-term treatment will induce the emergence of drug-resistant virus and produce serious side effects. Therefore, it is highly desirable to find inhibitors that act o...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D239/557C07D409/12C07D405/12C07D403/12A61K31/635A61K31/513A61P31/18
Inventor 赵桂森于生辉努瑞·尼玛缇刘建珍刘洋李奕静王远游
Owner SHANDONG UNIV
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