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Chemical synthesis method of bromphenol PTP1B inhibitor

A chemical synthesis and inhibitor technology, which is applied in the field of chemical total synthesis of the brominated compound "bis-methane", can solve the problems of high electronegativity, small amount, and poor selectivity

Inactive Publication Date: 2009-12-09
INST OF OCEANOLOGY - CHINESE ACAD OF SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] There are not many studies on PTP1B inhibitors in the world, mainly in the following categories: (1) Peptides: peptide substrates containing phosphorylated tyrosine residues (pTyr) have a higher affinity with PTP1B, But its chemical and biological stability are poor; (2), naphthoquinones Naphthnoquinone: inhibit the activity of enzyme by modifying the active site of PTPase; (3), thiazolidinediones Azolidinediones: increase the insulin sensitivity of target organ Improve blood sugar control, mainly including ciglitazone, troglitazone and rosiglitazone, but due to severe liver toxicity, ciglitazone has been withdrawn from the market; (4), Benzo[b]naphthol[2,3-d]furans and thiophenes: benzbromarone (PTP1B inhibitor, IC 50 =26μM) as the lead compound designed and synthesized as a series of Benzo[b]naphthol[2,3-d]furans and thiophenes compounds, which showed good hypoglycemic activity in mice, but it still needs to be used as a drug for treating diabetes. Overcoming many obstacles, such as high electronegativity, poor cell membrane permeability, and poor selective specificity, all of which make these inhibitors less druggable

Method used

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  • Chemical synthesis method of bromphenol PTP1B inhibitor
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  • Chemical synthesis method of bromphenol PTP1B inhibitor

Examples

Experimental program
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Embodiment 1

[0035] Example 1 The chemical synthesis and structural identification of "bis-(2,3-dibromo-4,5-dihydroxy-phenyl)-methane"

[0036] (1) Chemical synthesis and structure identification of Bis-(3,4-dimethoxy-phenyl)-methanone 3

[0037] Add 44.16g (240mmol) veratrol (compound 1), 33.84g (240mmol) veratrol (compound 2) and 200g polyphosphoric acid into a 1000ml three-necked reaction flask according to the molar ratio of 1:1, and stir at 80°C for reaction 1h; Cool to 60°C and add 500ml of ice water dropwise to the reactant within 30min, at this time, a large amount of water-insoluble pink solid precipitates out of the reactant; after removing water by filtration, dissolve the obtained solid in 200ml of dichloromethane , washed three times with an equal volume of 3% sodium hydroxide solution and distilled water successively; after drying the dichloromethane phase with anhydrous sodium sulfate, concentrate under reduced pressure to obtain a pink solid; wash the solid with petroleum e...

Embodiment 2

[0047] Example 2 Determination of protein tyrosine phospholipase 1B inhibitory activity

[0048] Prepare the test compound bis-(2,3-dibromo-4,5-dihydroxy-phenyl)-methane with DMSO into different concentrations of the test solution, take 2 μL of the test solution and add it to the standard test solution respectively. Live system (50mM Tris-HCl, PH6.5, 2mM pNPP, 2% DMSO, 30nM hGST-PTP1B), negative control: DMSO, positive control: sodium orthovanadate, the reaction temperature is 30°C, and the kinetic measurement wavelength is 405nm Light absorption, time 3min, according to the following formula to calculate the inhibitory rate of compound PTP1B enzyme activity. Inhibition rate=(experimental group A value-negative control group A value) / (control group A value-negative control group A)×100%, the results are shown in Table 1.

[0049] Table 1 protein tyrosine phospholipase 1B inhibition rate (%)

[0050] Table 1 Inhibitory Ratio(%)of PTP1B

[0051]

[0052] The test results s...

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Abstract

The invention relates to a novel chemical synthesis method of bromphenol PTP1B inhibitor which has a chemical structural formula as follows: wherein a group connected with 2,2' and the number 3, 3' carbon of benzene ring is bromine atom; 4,4' and the number 5, 5' carbon of the benzene ring are connected with hydroxy; and the PTP1B inhibitor has a chemical name in English: Bis-(2,3-dibromo-4,5-dimethoxy-phenyl)-methane. The compound negatively regulating an insulin signal transduction path by restricting the activity of protein tyrosine phospholipase 1B and has favorable curing effect for type 2 diabetes in insulin resistance types.

Description

technical field [0001] The present invention relates to biopharmaceutical compound bis-(2,3-dibromo-4,5-dihydroxy-phenyl)-methane, specifically a brominated compound "bis-(2,3-dibromo-4 , 5-dihydroxy-phenyl)-methane" chemical total synthesis method. The compound can increase insulin sensitivity by inhibiting PTP1B enzyme activity, and is used for treating insulin-resistant type 2 diabetes. Background technique [0002] Diabetes Mellitus (DM) is a chronic endocrine and metabolic disease. According to the International Diabetes Federation (IDF) data in 2007, the number of adult diabetic patients in the world is about 246 million, of which type 2 diabetes (T2DM) patients account for 90% of the total diabetic patients above. By 2025, the number of people with diabetes worldwide is expected to reach 380 million. The drugs currently used to treat T2DM mainly include biguanides, sulfonylureas, α-glucosidase inhibitors, and thiazolidinediones, etc., because most of them are desig...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C39/16C07C37/00A61P3/10
Inventor 史大永李敬韩丽君郭书举袁毅
Owner INST OF OCEANOLOGY - CHINESE ACAD OF SCI
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