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PTP1B inhibitor as well as synthesis method and application thereof in preparation of medicine for curing type 2 diabetes

A type 2 diabetes and inhibitor technology, applied in the field of biomedicine, can solve the problems of poor chemical and biological stability, not much, high electronegativity, etc., achieve good industrial production prospects, simple process operation, and reduce reaction costs.

Inactive Publication Date: 2012-07-04
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mainly including ciglitazone, troglitazone and rosiglitazone, but due to severe liver toxicity, ciglitazone has been withdrawn from the market; (4), Benzo[b] naphthol[2,3-d] furans and thiophenes: benzbromarone (PTP1B inhibitor, IC 50 =26μM) as the lead compound designed and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

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  • PTP1B inhibitor as well as synthesis method and application thereof in preparation of medicine for curing type 2 diabetes
  • PTP1B inhibitor as well as synthesis method and application thereof in preparation of medicine for curing type 2 diabetes
  • PTP1B inhibitor as well as synthesis method and application thereof in preparation of medicine for curing type 2 diabetes

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0029] Example 1 Chemistry of "(2'-bromo-4',5'-dimethoxy-phenyl)-(2,3-dibromo-4,5-dimethoxy-phenyl)-methane" Total synthesis and structure identification

[0030] (1) Chemical synthesis and structure identification of Bis-(3,4-dimethoxy-phenyl)-methanone3

[0031] According to the molar ratio of 1:1, 22.08g (120mmol) veratrol (compound 1), 16.92g (120mmol) veratrol (compound 2) and 100g polyphosphoric acid were added to a 250ml three-necked reaction flask, and the reaction was stirred at 80°C. 1h; cooled to 60°C and added dropwise 250ml of ice water to the reactant within 30min, a large amount of water-insoluble pink solid was precipitated in the reactant; after filtration to remove water, the obtained solid was dissolved in 100ml of dichloromethane , washed three times with equal volumes of 3% sodium hydroxide solution and distilled water in turn; after drying the dichloromethane phase with anhydrous sodium sulfate, concentrated under reduced pressure to obtain a pink solid;...

Embodiment 2

[0039] Example 2 Determination of protein tyrosine phospholipase 1B inhibitory activity

[0040]The test compound "(2'-bromo-4',5'-dimethoxy-phenyl)-(2,3-dibromo-4,5-dimethoxy-phenyl)-methane" was used DMSO was prepared into different concentrations of the test solution, and 2 μL of the test solution was added to the standard test system (50mM Tris-HCl, PH6.5, 2mM pNPP, 2% DMSO, 30 nM hGST-PTP1B), negative Control: DMSO, positive control: sodium orthovanadate, the reaction temperature was 30°C, the light absorption at the wavelength of 405nm was dynamically measured for 3 minutes, and the inhibitory rate of the compound PTP1B enzyme activity was calculated according to the following formula. Inhibition rate=(A value of experimental group-A value of negative control group) / (A value of control group-A value of negative control group)×100%, the results are shown in Table 1.

[0041] Table 1 Protein tyrosine phospholipase 1B inhibition rate (%)

[0042] Table 1 Inhibitory Ratio ...

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Abstract

The invention relates to a novel chemical synthesis method of PTP1B inhibitor and the application thereof in the medicine for curing type 2 diabetes, wherein the PTP1B inhibitor has a chemical structural formula as follows: wherein a group connected with 2 site, 2' site and 3 site carbon of benzene ring is bromine atom; 4,4' and the number 5, 5' carbon of the benzene ring are connected with methoxyl; and the PTP1B inhibitor has a chemical name in English: (2'-bromo-4',5'-dimethoxy-phenyl)-(2,3-dibromo-4,5-dimethoxy-phenyl)-methane. The compound can enhance the sensibility of insulin receptor 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 biomedicine, specifically a brominated compound "(2'-bromo-4',5'-dimethoxy-phenyl)-(2,3-dibromo-4,5-di Methoxy-phenyl)-methane" and its total chemical synthesis method, pharmacological activity and pharmaceutical use. The compound and its derivatives can be used as insulin sensitizers for the treatment of insulin resistance 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 adults with diabetes in the world is about 246 million, of which type 2 diabetes (T2DM) patients account for 90% of the total diabetes patients. above. By 2025, the number of people with diabetes worldwide is expected to reach 380 million. At present, the drugs used to treat T2DM mainly include biguanides, sulfonylureas, α-glucosidase inhibitors and thiazolidinediones. Because they are mostly designe...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07C43/225C07C41/18A61K31/09A61P3/10
Inventor 史大永李敬韩丽君郭书举袁毅
Owner INST OF OCEANOLOGY - CHINESE ACAD OF SCI