A class of nitrogen-atom double-substituted hydroxamic acid compounds containing an oxadiazole structure, its use and its preparation method

A compound, oxadiazole technology, applied in the field of histone deacetylase inhibitors, can solve the problem of unsatisfactory treatment effect of solid tumors

Active Publication Date: 2021-09-14
UNIV OF JINAN
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the HDACi currently on the market are all used for the treatment of hematological cancers, and the therapeutic effect on solid tumors is not very satisfactory. Therefore, the development of new HDACi for the treatment of solid tumors is now a more popular direction

Method used

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  • A class of nitrogen-atom double-substituted hydroxamic acid compounds containing an oxadiazole structure, its use and its preparation method
  • A class of nitrogen-atom double-substituted hydroxamic acid compounds containing an oxadiazole structure, its use and its preparation method
  • A class of nitrogen-atom double-substituted hydroxamic acid compounds containing an oxadiazole structure, its use and its preparation method

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1-1

[0043] Example 1-1, Compound N 1 -Hydroxy-N 7 -(4-Methoxyphenyl)-N 7 Preparation of -((5-phenyl-1,2,4-oxadiazole-3-)methyl)pimelic amide (JX01)

[0044] Dissolve p-methylaniline (3.6 g, 30.0 mmol) in DMF, add potassium carbonate (4.1 g, 30.0 mmol), stir for half an hour, then add bromoacetonitrile (1.4 ml, 20.0 mmol), react at room temperature overnight, extract, overnight Column purification gave solid compound 2 (4 g).

[0045] Dissolve compound 2 (3.3 g, 20.0 mmol) in dioxane, add pimelic anhydride (4.3 g, 30.0 mmol), heat to reflux, neutralize acid and alkali after the reaction, evaporate to dryness to obtain compound 3, and directly carry out In the next step of esterification reaction, compound 4 (3.8 g) was purified.

[0046] Dissolve compound 4 (3.8 g, 12.0 mmol) and hydroxylamine hydrochloride (1.25 g, 17.9 mmol) in methanol / water, add sodium carbonate (954 mg, 9.0 mmol), reflux overnight, extract, and purify through a column to obtain a solid compound 5 (2.35 g,...

Embodiment 1-2

[0049] Embodiment 1-2, compound N 1 -Hydroxy-N 7 -(4-Methoxyphenyl)-N 7 Preparation of -((5-(o-fluorophenyl)-1,2,4-oxadiazole-3-)methyl)pimelic acid amide (JX02)

[0050] Replace benzoyl chloride with o-fluorobenzoyl chloride, and prepare JX02 according to the method for preparing compound JX01. 1 H NMR(600 MHz, DMSO) δ 10.29 (brs, 1H), 8.64 (brs, 1H), 8.02 (dd, J = 7.2, 7.8 Hz,1H), 7.67-7.66 (m, 1H), 7.48 – 7.43 (m, 1H), 7.42 – 7.36 (m, 2H), 7.33 (dd, J = 8.4, 9.0 Hz, 1H), 7.03 (d, J = 8.4 Hz, 1H), 6.98 (d, J = 7.8 Hz, 1H), 5.76(s, 2H), 3.78 (s, 3H), 2.07 (t, J = 7.8 Hz, 2H), 1.87-1.85 (m, 2H), 1.45-1.43(m, 2H), 1.39 – 1.36 (m, 2H), 1.14 – 1.10 (m, 2H).

Embodiment 1-3

[0051] Embodiment 1-3, Compound N 1 -Hydroxy-N 7 -(4-Methoxyphenyl)-N 7 Preparation of -((5-(m-fluorophenyl)-1,2,4-oxadiazole-3-)methyl)pimelic acid amide (JX03)

[0052] Benzoyl chloride was replaced by m-fluorobenzoyl chloride, and JX03 was correspondingly prepared according to the method for preparing compound JX01. 1 H NMR (600 MHz, DMSO) δ 10.31 (brs, 1H), 8.65 (brs, 1H), 7.96 (d, J = 7.8 Hz, 1H),7.89 (d, J = 9.0, 1H), 7.72-7.68 (m, 1H), 7.59 (td, J = 8.4, 2.4 Hz, 1H),7.33 (d, J = 9.0 Hz, 2H), 6.99 (d, J = 9.0 Hz, 2H), 4.99 (s, 2H), 3.77 (s,3H), 2.04 (t, J = 7.2 Hz, 2H), 1.88 (t, J = 7.2 Hz, 2H), 1.48 – 1.42 (m, 2H),1.41 – 1.35 (m, 2H), 1.16 – 1.10 (m, 2H).

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Abstract

In the present invention, the nitrogen atom double substitution structure containing oxadiazole is used as the CAP region and the hydroxamic acid structure to synthesize a new type of nitrogen atom double substitution hydroxamic acid containing the oxadiazole structure to inhibit histone deacetylase agent; the present invention also provides the application of the compound as a novel histone deacetylase inhibitor. The invention also discloses the application of the compound or its pharmaceutical composition in the preparation and treatment of various malignant tumor growth, metastasis, recurrence and other diseases caused by histone acetylation disorder.

Description

technical field [0001] The invention relates to a histone deacetylase inhibitor, in particular to a synthesis method and application of a class of nitrogen-atom double-substituted hydroxamic acid compounds containing an oxadiazole structure. Background technique [0002] Histone deacetylase is an epigenetic enzyme involved in the regulation of the acetylation level of histone lysine residues. Epigenetics refers to the heritability of gene expression without changing the nucleotide sequence of the gene. Variety. Epigenetics mainly includes DNA modification (methylation) and histone modification (acetylation, phosphorylation, ubiquitination, etc.), among which the most studied is histone acetylation modification, including two enzymes: histone acetyltransferase (HAT) and histone deacetylase (HDAC), the function of HAT is to transfer the acetyl group to the lysine residue to prevent the charge interaction between histone and DNA base, make the chromosome loose, and facilitate ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D271/06C07D413/04A61P35/00A61P35/02
CPCA61P35/00A61P35/02C07D271/06C07D413/04
Inventor 张华杨飞飞单佩佩赵娜周志侠张静
Owner UNIV OF JINAN
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