Three protein tyrosine phosphatase 1B (PTP1B) inhibitors and synthesis and application thereof

An inhibitor, chemical synthesis technology, applied in the field of brominated compounds, can solve the problems of high electronegativity, not much, poor selection specificity, etc.

Inactive Publication Date: 2011-04-20
INST OF OCEANOLOGY - CHINESE ACAD OF SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] 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

Method used

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  • Three protein tyrosine phosphatase 1B (PTP1B) inhibitors and synthesis and application thereof
  • Three protein tyrosine phosphatase 1B (PTP1B) inhibitors and synthesis and application thereof
  • Three protein tyrosine phosphatase 1B (PTP1B) inhibitors and synthesis and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0036] Example 1 Chemical synthesis and structural identification of target compounds (compounds 6, 7 and 8)

[0037] (1) Chemical Synthesis and Structure Identification of 5-Bromovanillin

[0038] Under ice-water bath, add 2.8ml of Br dropwise to 60ml of methanol dissolved with 7.6g of vanillin 2 , 2 hours after adding, stirred at room temperature for 1 hour, then added dropwise 25ml of water (with precipitation), 20min after adding, continued to stir for 15min, filtered the precipitate, washed the precipitate with ice water, and drained to obtain 10.7g of white crystals , After spectral analysis, it was confirmed that the compound was 5-bromovanillin.

[0039] (2) Chemical Synthesis and Structure Identification of 5-Bromoveratraldehyde

[0040] At room temperature, add 1.7ml methyl iodide dropwise to the suspension of 40ml N,N-dimethylformamide of compound 5-bromovanillin prepared in 4.26g reaction (1) and 3.84g potassium carbonate, and keep stirring After 24 hours, the r...

Embodiment 2

[0051] Example 2 Determination of protein tyrosine phospholipase 1B inhibitory activity

[0052] Compounds 6, 7, and 8 to be tested were formulated with DMSO to form test solution with a concentration of 20 μg / mL and 5 μg / mL, and 2 μL of the test solution was added to a standard bioassay system (50 mM Tris-HCl, PH 6.5, 2mM pNPP, 2% DMSO, 30nM hGST-PTP1B), negative control: DMSO, positive control: sodium orthovanadate, the reaction temperature is 30°C, and the light absorption at the wavelength of 405nm is dynamically measured for 3 minutes, as follows The formula calculates 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.

[0053] Table 1 Inhibition rate of protein tyrosine phospholipase 1B (%)

[0054] Table 1 Inhibitory Ratio(%) of PTP1B

[0055]

[0056] When the compound concentration i...

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Abstract

The invention relates to a chemical complete synthesis method for three novel PTP1B inhibitors and application of the PTP1B inhibitors in medicines for treating type II diabetes. The chemical structural formulas of the PTP1B inhibitors are shown as follows: a compound 6 (4, 5-di-(2, 3-dibromo-4, 5-dimethoxybenzyl)-1, 2-dimethoxyphenyl): groups connected with C of 2', 3', 2'' and 3'' sites of a benzene ring are bromine atoms, and C of 1, 2, 4', 5', 4'' and 5' sites is connected with methoxyl; a compound 7 (3-bromo-4, 5-di-(2, 3-dibromo-4, 5-dimethoxybenzyl)-1): the groups connected with C of 3, 2', 3', 2'' and 3'' sites of the benzene ring are bromine atoms, and C of 1, 2, 4', 5', 4'' and 5' sites is connected with the methoxyl; and a compound 8 (3-bromo-4, 5-di-(2, 3-dibromo-4, 5-dyhydroxylbenzyl)-1, 2-dihydroxybenzene): the groups connected with C of 3, 2', 3', 2'' and 3'' sites of the benzene ring are bromine atoms, and C of 1, 2, 4', 5', 4'' and 5'' is connected with hydroxyl. The three compounds enhance the sensitivity of an insulin receptor through inhibiting the activity of protein tyrosine phosphatase 1B and have good therapeutic action on insulin resistant type II diabetes.

Description

technical field [0001] The present invention relates to biomedicine, specifically three brominated compounds 4,5-bis-(2,3-dibromo-4,5-dimethoxybenzyl)-1,2-dimethoxy Benzene, 3-bromo-4,5-bis-(2,3-dibromo-4,5-dimethoxybenzyl)-1,2-dimethoxybenzene, 3-bromo-4,5 - Di-(2,3-dibromo-4,5-dihydroxybenzyl)-1,2-diphenol and its chemical total synthesis method, pharmacological activity and pharmaceutical use. The above compounds and derivatives thereof are used as insulin sensitizers and can be used for treating insulin resistance type 2 diabetes. Background technique [0002] Diabetes (Diabetes Mellitus, DM) is a chronic endocrine and metabolic disease. Currently, the drugs used to treat type 2 diabetes (Type 2 Diabetes Mellitus, T2DM) mainly include biguanides, sulfonylureas, α-glucosidase inhibitors and thiazolidine diuretics. Ketones, etc., have various disadvantages because they are mostly designed for symptoms rather than molecular target drugs for etiology. Therefore, the market...

Claims

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Application Information

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IPC IPC(8): C07C43/225C07C41/22C07C39/367C07C37/055A61K31/09A61K31/055A61P3/10
Inventor 史大永范晓崔永超郭书举卢伟伸
Owner INST OF OCEANOLOGY - CHINESE ACAD OF SCI
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