Application of hypnopyrine to the preparation of 2-type antidiabetic drugs

A technology of type 2 diabetes and Hypno, applied in the field of biomedicine, can solve the problems of poor selection specificity, reduced druggability, poor chemical and biological stability, etc., and achieve novel action targets, long-term use price, and good prevention and treatment efficacy Effect

Inactive Publication Date: 2009-10-21
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mainly including ciglitazone, troglitazone and rosiglitazone, but due to severe liver toxicity, ciglitazone has been withdrawn from the market; (4), Benzo[b]naphthol[2,3-d]furans and thiophenes: benzbromarone A series of Benzo[b]naphthol[2,3-d]furans and thiophenes designed and synthesized as lead compounds have shown good hypoglycemic activity in mice, but there are still many obstacles to be overcome before finally becoming a drug for treating diabetes , such as high electronegativity, poor cell membrane permeability, and poor selectivity, etc., the above factors all reduce the druggability of these inhibitors; there is no research report on bromophenol compounds as PTP1B inhibitors for anti-diabetes

Method used

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  • Application of hypnopyrine to the preparation of 2-type antidiabetic drugs
  • Application of hypnopyrine to the preparation of 2-type antidiabetic drugs
  • Application of hypnopyrine to the preparation of 2-type antidiabetic drugs

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0019] Example 1 Preparation and structure identification of "Hipnuo"

[0020] Turpentine algae (dry weight 20kg) was crushed and extracted with 100L of 95% ethanol, and the extract was concentrated under reduced pressure; the concentrate was suspended in 10L of distilled water, extracted with an equal volume of ethyl acetate, and concentrated under reduced pressure. The ethyl acetate extraction part was subjected to silica gel column chromatography, and the gradient elution was carried out with petroleum ether-acetone (100:0~1:1) until the volume ratio of the two was 1:1 (petroleum ether in the mixed eluent of petroleum ether and acetone) The volume concentration of chloroform changes from 100%-50% along the gradient), and chloroform-methanol (100:0~0~100) gradient elution is used instead (the volume concentration of chloroform in the chloroform-methanol mixed eluent changes from 100% along the gradient to -0% change), finally eluted with 95% ethanol, checked by thin-layer ch...

Embodiment 2

[0025] Example 2 Determination of protein tyrosine phospholipase 1B inhibitory activity

[0026] The test compound (3-bromo-4-[2',3'-dibromo-4',5'-dihydroxyphenyl]methyl-5-(ethoxy)-1,2-diphenol) Prepare the test solution with different concentrations in DMSO, take 2 μL of the test solution and add it to the standard bioassay system (50mM Tris-HCl, pH 6.5, 2mM pNPP, 2% DMSO, 30nM hGST-PTP1B), negative control : DMSO, positive control: sodium orthovanadate (2μM), the reaction temperature is 30°C, the light absorption at the wavelength of 405nm is dynamically measured, and the time is 3min. The inhibition rate and IC of compound PTP1B enzyme activity are calculated according to the following formula 50 (LOGIT method). 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.

[0027] Table 1 Inhibition rate (%) and IC of protein tyrosine phospholipase 1B 50

[0028] Tabl...

Embodiment 3

[0031] Embodiment 3 acute toxicity observation test

[0032] 20 Kunming mice were randomly divided into 4 groups, 3 females and 2 males in each group, separated into cages, and adaptively fed for 3 days; fasted for 16 hours before administration on the fourth day, drinking water was not limited, and 5000mg / kg, 500mg / kg and 50mg / kg doses were intragastrically administered ig, observed for 24 hours, and the number of mice died was 0.

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PUM

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Abstract

The invention relates to a novel euglycemic agent hypnopyrine, and pharmically acceptable salts, esters, ethers and other obvious chemical equivalents thereof. The hypnopyrine has a chemical structural formula in a graph, wherein a radical connected by a 6-bit carbon, a 7-bit carbon and a 2'-bit carbon of a benzene ring is hydrogen; and an 8-bit carbon is connected with an oxyethyl group. The hypnopyrine has the English name: 3-bromo-4-[2', 3'-dibromo-4', 5'-dihydroxypheny] methyl-5-(ethoxymethyl)1, 2-benzenediol. The compound and derivatives thereof inhibit the activity of protein tyrosine phosphatase 1B, enhance the sensitivity of insulin receptors and have favorable curable effect on the insulin-resistant 2-type diabetes mellitus.

Description

technical field [0001] The present invention relates to biomedicine, in particular to a preparation method, pharmacological activity and pharmaceutical use of a marine natural active compound "Hipno". As an insulin sensitizer, the compound and its derivatives can be used for treating insulin-resistant type 2 diabetes. Background technique [0002] Diabetes Mellitus (DM) is a chronic metabolic and secretory endocrine 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 the total diabetic patients. More than 90. 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 designed for the disease rather than for the molecular target drug o...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/075A61P3/10
Inventor 史大永韩丽君许凤范晓李敬郭书举
Owner INST OF OCEANOLOGY - CHINESE ACAD OF SCI
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