Substituted benzoyl urea compound and preparation method and application thereof

A technology of benzoylureas and compounds, applied in the field of substituted benzoylureas compounds and their preparation

Inactive Publication Date: 2010-11-10
SHANGHAI INST OF MATERIA MEDICA CHINESE ACAD OF SCI +2
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0005] Jiang Hualiang et al. (Luo C et al. Biochem Biophys Res Commun, 2004, 321: 557-565) from Shanghai Institute of Materia Medica, Chinese Academy of Sciences found through bioinformatics that although SARS-CoV does not encode CA protein, SARS-CoV N The Val235-Pro369 fragment of the protein has a high sequence similarity (36.7%) with the N-terminal domain (residues 1-151) of the HIV-1 CA protein, so it is speculated that the SARS-CoV N protein may also interact with CypA

Method used

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  • Substituted benzoyl urea compound and preparation method and application thereof
  • Substituted benzoyl urea compound and preparation method and application thereof
  • Substituted benzoyl urea compound and preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 12

[0077] Example 12, 6-dibenzyloxybenzonitrile (intermediate VIII)

[0078]

[0079] 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. Recrystallize from ethanol to obtain intermediate VIII in the form of white flaky crystals. 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

[0080] Example 2 2,6-dibenzyloxybenzamide (intermediate IX)

[0081]

[0082] 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) gave intermediate IX as a white powdery solid. 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%).

Embodiment 3

[0083] Example 3 1-(1-xanthenyl)-3-(2,6-dibenzyloxybenzoyl)urea (intermediate XI-1)

[0084]

[0085] Dissolve 0.5 g of triphosgene in 3 ml of 1,2-dichloroethane, and stir in an ice bath until dissolved. 0.25 g of xanthamine was dissolved in 10 ml of 1,2-dichloroethane, and slowly added dropwise into the reaction solution containing triphosgene, the reaction solution was white and turbid. After continuing the ice bath for 0.5 hours, the temperature was raised to 25° C. for 1 hour, and then heated under reflux until the reaction solution was colorless and transparent, and 1 ml of triethylamine was added to the reaction solution to continue reflux for 0.5 hours. The solvent was distilled off under reduced pressure, 10 ml of toluene was added, and suction filtered. The filtrate was not post-treated, and 0.25 g of 2,6-dibenzyloxybenzamide (IX) was added thereto, and refluxed for 10 hours. The solvent was evaporated under reduced pressure, and water was added to precipitate a s...

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Abstract

The invention relates to a novel substituted benzoyl urea compound and a preparation method and application thereof. The compound has the structure general formula disclosed in (I), wherein definitions of R1, R2, and R3 are described in the specification, and the compound can be used as a micromolecule inhibitor of Cyclophilin A (CypA); the CypA is a protein with the activity of Peptidyl-prolyl cis-trans isomerase (PPIase), and is related to the in vivo protein folding, assembly and transfer. The current research shows that the CrpA takes part in various physiology approaches, such as autoimmunity depression, HIV-1 invasion infection and the like. Therefore, the compound of the invention can become a novel immunosuppressive drug or anti-HIV-1 drug.

Description

technical field [0001] The present invention relates to the field of medicinal chemistry and pharmacotherapeutics, in particular to a class of substituted benzoylurea compounds as small molecule non-peptide inhibitors of cyclophilin A and their preparation methods and pharmacological applications. These compounds can be used as immune Inhibitors and anti-HIV-1 drugs. 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 isomerase, PPIase) activity (Takahashi N, Hayano T, Suzuki M. Nature, 1...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C275/54C07C273/18C07D311/88A61K31/17A61K31/352A61P37/06A61P31/18
CPCC07C275/54C07D311/88C07C323/62C07C2102/08C07C2101/14C07C2103/18A61P31/18A61P37/06C07C2601/14C07C2602/08C07C2603/18
Inventor 蒋华良李剑来鲁华裴剑锋黄瑾沈旭
Owner SHANGHAI INST OF MATERIA MEDICA CHINESE ACAD OF SCI
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