Glucagon-likepeptide1 derivatives and use thereof

A technology of drugs and compounds, applied in the direction of glucagon, hormone peptides, specific peptides, etc., can solve the problems of GLP-1 instability and limit the clinical application of GLP-1, achieve long plasma half-life, significant effect, hypoglycemic effect of effect

Active Publication Date: 2011-09-14
BETTA PHARM CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0003] However, the clinical application of GLP-1 is also facing a huge problem. The GLP-1 produced by the human body is very unstable and easily degraded by dipeptidyl peptidase IV (DPP-IV) in the body, and its plasma half-life is only 1~ 2min, that is, continuous intravenous infusion or continuous subcutaneous injection is necessary to produce curative effect, which greatly limits the clinical application of GLP-1

Method used

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  • Glucagon-likepeptide1 derivatives and use thereof
  • Glucagon-likepeptide1 derivatives and use thereof
  • Glucagon-likepeptide1 derivatives and use thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0031] I, synthetic intermediate (called Dimer)

[0032] The structure of Dimer is as follows:

[0033]

[0034] The specific synthesis method is as follows:

[0035] 1. Preparation of compound 01·HCl

[0036] Below -10°C, add 80ml of thionyl chloride dropwise to 250ml of methanol, complete the dropwise addition within 2 hours, and stir at room temperature for 1 hour. Add 40 g of L-alanine and stir overnight. Then, the temperature was raised to reflux for 4 hours. After cooling, the solvent was removed under reduced pressure to constant weight to obtain 80 g of crude compound 01·HCl.

[0037] 2. Preparation of Compound 02

[0038]40g of compound 01·HCl was dissolved in 350ml of DMF, 113g of benzyl bromide was added, and 150g of anhydrous potassium carbonate was added under stirring, and after stirring for 2 hours, the reaction was kept at 50°C for 2 hours. Then, the reaction solution was extracted with 1200ml of water and 400ml of ethyl acetate, separated, the ester l...

Embodiment 2

[0076] When synthesizing the main chain, replace Fmoc-Gly-Wang Resin with Rink Amide Resin, and the others are the same as in Example 1.

[0077] Among the above-mentioned Examples 1 and 2, those not indicating the reaction temperature all refer to normal temperature. Reagents A, B and C are solutions prepared by adding 80% phenol ethanol solution, redistilled pyridine and 5 g ninhydrin to 100 ml ethanol, respectively. Example 3 Determination of Glucose Tolerance

Embodiment 3

[0077] Among the above-mentioned Examples 1 and 2, those not indicating the reaction temperature all refer to normal temperature. Reagents A, B and C are solutions prepared by adding 80% phenol ethanol solution, redistilled pyridine and 5 g ninhydrin to 100 ml ethanol, respectively. Example 3 Determination of Glucose Tolerance

[0078] 1. Test group:

[0079] 90 ICR (Institute of Cancer Research) mice, all male, were divided into three batches according to body weight, 30 in each batch. Each batch of mice was fasted overnight and divided into two groups according to blood sugar: Vehicle group and compound group obtained in Example 1 (referred to as compound group). The vehicle group was only injected with physiological saline, and the compound group was injected with the compound obtained in Example 1 into the physiological saline.

[0080] 2. Test process:

[0081] The first batch of animals: mice were grouped according to blood sugar after fasting overnight, administered...

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PUM

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Abstract

The invention relates to a type of Glucagon-likepeptide1 and the use thereof. The structure of the Glucagon-likepeptide1 derivatives is presented in the following formula. The invention also provides a medical salt, a solvolyte, a chelate or a non-covalent complex formed by the compounds shown by the structure, a prodrug based on the compound, or any mix of the above form. The chemical property of the compounds provided in the invention is stable, unlikely to be degraded by IV (DPP-IV) in body. When used for decreasing blood glucose concentration in body, the compound or the drug adopting the compound as an active ingredient have relatively long plasma half-life (above 30 hours) and an significant effect in decreasing blood glucose concentration. X, in the formula, is selected from glycin or glycinamide.

Description

technical field [0001] The present invention relates to a derivative of glucagon-like peptide-1 (GLP-1) and its application. Background technique [0002] Diabetes has become the third non-communicable disease after cardiovascular and cerebrovascular diseases and tumors. The World Health Organization (WHO) predicts that there will be more than 360 million diabetics in the world in 2030, of which more than 90% are type II diabetes. Type II diabetes, which refers to adult-onset or non-insulin-dependent diabetes, is a common disease, and the global incidence is increasing year by year. Among the existing diabetes treatment drugs and programs, hypoglycemia is a problem that people have been worrying about. To overcome this problem, in recent years, glucagon-like polypeptide-1 ( Glucagon-like peptide-1 , referred to as GLP-1) related research progresses rapidly. GLP-1 is a secreted secreted by intestinal L cells, which has the functions of promoting insulin secretion, inhibiti...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K14/605A61K38/26A61P3/00A61P3/04A61P3/06A61P3/10A61P9/12A61P9/00A61P9/10A61P1/00A61P1/04A61P1/14A61P25/00
Inventor 王印祥谭芬来胡邵京赵向东马存波王燕萍沈晓燕丁列明胡云雁曹红龙伟
Owner BETTA PHARM CO LTD
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