N-(2,6-dibenzyloxy benzoyl)-N'-substituted urea compound and preparation method and application thereof

A kind of technology of dibenzyloxybenzoyl group and compound, applied in N--N'-substituted urea compound and preparation field thereof, can solve the problems such as no bibliographical report etc.

Inactive Publication Date: 2012-05-16
EAST CHINA UNIV OF SCI & TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0009] Although great progress has been made in the discovery of CypA inhibitors and their biological uses, CypA agonists and their potential biological uses have always been a blank, and there have been no reports in the literature so far

Method used

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  • N-(2,6-dibenzyloxy benzoyl)-N'-substituted urea compound and preparation method and application thereof
  • N-(2,6-dibenzyloxy benzoyl)-N'-substituted urea compound and preparation method and application thereof
  • N-(2,6-dibenzyloxy benzoyl)-N'-substituted urea compound and preparation method and application thereof

Examples

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preparation example Construction

[0039] A method for preparing compounds shown in formula I provided by the present invention, which comprises the following steps:

[0040] 1) Dissolve sodium benzyl alkoxide and 2,6-difluorobenzonitrile in dimethyl sulfoxide, heat up to 110°C-130°C, stir for 5-10 hours, cool to room temperature, add ice water to the reaction solution, After stirring for 30 minutes, a large amount of solid precipitated out, which was suction filtered, washed with water, and dried to obtain a white solid, which was recrystallized to obtain a white flaky crystal 2,6-dibenzyloxybenzonitrile (abbreviation: compound VIII);

[0041] 2) Dissolve compound VIII obtained in step 1) in benzyl alcohol, add potassium hydroxide and a small amount of water, stir at 120°C to 140°C for 10 hours to 15 hours, distill off the solvent under reduced pressure, and add ice to the residue water, stirred for 30 minutes, a large amount of solids were precipitated, suction filtered, washed with water, and dried to obtain...

Embodiment 1

[0048] Preparation of 2,6-dibenzyloxybenzonitrile

[0049]

[0050] Dissolve 0.5 g of sodium benzyl alcohol in 10 ml of dimethyl sulfoxide, and add 2,6-difluorobenzonitrile under stirring. After rapidly raising the temperature to 115°C, stirring was continued for 8 hours. After cooling to room temperature, 100 ml of ice water was poured into the reaction liquid, and stirred for 30 minutes. A large amount of solid precipitated, which was suction filtered, washed with water, and dried to obtain a white solid. Recrystallized from ethanol to obtain compound VIII in the form of white flaky crystals.

[0051] 1 H-NMR (400Hz, DMSO-d 6 )δ: 5.19 (4H, s, -CH 2 ), 6.60 (2H, d, Ar-H), 7.30-7.35 (3H, m, Ar-H), 7.38 (4H, t), 7.45 (4H, d).

Embodiment 2

[0053] Preparation of 2,6-dibenzyloxybenzamide

[0054]

[0055] Dissolve 0.4 g of 2,6-dibenzylbenzonitrile (VIII) in 7 ml of benzyl alcohol, add 0.6 g of KOH and 0.1 ml of water, and stir at 130° C. for 12 hours. The solvent was distilled off under reduced pressure, and 100 ml of ice water was poured into the reaction liquid, stirred for 30 minutes, a large amount of solid precipitated out, filtered with suction, washed with water, and dried to obtain a white solid. Silica gel column chromatography (petroleum ether / ethyl acetate=12 / 1 (v / v)) gave Compound IX as a white powdery solid.

[0056] 1 H-NMR (400Hz, DMSO-d 6 )δ: 5.15 (4H, s, -CH 2 ), 6.60 (2H, d, Ar-H), 7.18-7.48 (12H, m, Ar-H); EI-MS m / z 333.2 (M + ), 91.1 (100%).

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Abstract

The invention relates to a novel N-(2,6-dibenzyloxy benzoyl)-N'-substituted urea compound and a preparation method and an application thereof. Structural general formula of the compound is shown as a formula (I), wherein R1 is a C5-C25 cyclic alkyl, aryl or heterocyclic group, or a substituted C1-C6 straight-chain or branch-chain alkyl (shown in the specification). The current study shows that cyclophilin A (CypA) participates in multiple physiological and pathological processes of a human body. Thus, the compound provided by the invention can be applied to preparation of a cyclophilin A (CypA) excitant or preparation of drugs used for preventing or treating diseases mediated by CypA.

Description

technical field [0001] The invention relates to the fields of medicinal chemistry and chemical biology, in particular to a class of N-(2,6-dibenzyloxybenzoyl)-N'-substituted urea as a small molecule non-peptide agonist of cyclophilin A The compound and its preparation method and biological application, the compound can be used as a small molecule probe for the research on the signal transduction pathway mediated by cyclophilin A. Background technique [0002] The discovery and naming of cyclophilin (Cyclophilin, CyP) originated from its high affinity to cyclosporin (Cyclosporin A, CsA), which is an immunosuppressive drug widely used clinically (Handschumacher RE et al. Science, 1984, 226:544-547). CyP is a conserved protein family (Gothel SF, Marahiel MA. Cell Mo. Life Sci, 1999, 55: 423-436), and there are such proteins from lower prokaryotes to mammals. The common feature of this histone is that it has peptide prolyl cis-trans isomerase (Peptidyl-prolyl cis-trans isomera...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D311/88C07C275/54C07C273/18A61K31/352A61K31/17A61P37/06
Inventor 李剑黄瑾吕茂盛毛小娜马若群沈旭蒋华良
Owner EAST CHINA UNIV OF SCI & TECH
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