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GLP-1 (glucagon-like peptide-1) derivative and application thereof

A drug and compound technology, applied in the field of glucagon-like peptide-1 derivatives, can solve the problems of limiting the clinical application of GLP-1, instability of GLP-1, etc., and achieve remarkable effects, long plasma half-life, and chemical properties stable effect

Inactive Publication Date: 2011-11-02
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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  • GLP-1 (glucagon-like peptide-1) derivative and application thereof
  • GLP-1 (glucagon-like peptide-1) derivative and application thereof
  • GLP-1 (glucagon-like peptide-1) derivative and application thereof

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Experimental program
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Effect test

Embodiment 1

[0027] Embodiment 1 prepares the compound shown in structural formula I

[0028] I, synthetic intermediate (called Dimer)

[0029] The structure of Dimer is as follows:

[0030]

[0031] The specific synthesis method is as follows:

[0032] 1. Preparation of compound 01·HCl

[0033] 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.

[0034] 2. Preparation of Compound 02

[0035] 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 extra...

Embodiment 2

[0065] Example 2 Determination of glucose tolerance

[0066] 1. Test group:

[0067] 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 represented by structural formula I (compound group for short). The Vehicle group was only injected with normal saline, and the compound group was injected with the compound represented by structural formula I in the normal saline.

[0068] 2. Test process:

[0069] The first batch of animals: mice were grouped according to blood sugar after fasting overnight, administered subcutaneously on Day 1, the dose of the compound group was 0.3 mg / kg, and mice in each group were given 2 g / kg sugar load 2 hours after administration After 30 and 60 minutes, blood was collected to measure blood sugar. On Day 4, mice in each group were fasted overnig...

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Abstract

The invention relates to a glucagon-like peptide-1 and an application thereof. The structure of a GLP-1 derivative is shown as a formula. The invention also relates to an officinal salt, a solvate, a chelate or a non-covalent compound, a prodrug based on the compound, or a mixture thereof, which are composed of the compound shown by the formula. The compound provided by the invention has stable chemical property and is difficult to be degraded by interior dipeptidyl peptidase IV (DPP-IV). When the compound or a drug, which is prepared by taking the compound as active ingredient, is used for reducing the interior blood sugar concentration, a plasma half-life is very long (more than 30 hours) and a sugar-reducing effect is obvious. In the formula, Aib is methylalanine and X is selected from glycine 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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IPC IPC(8): C07K14/605A61K38/26A61P1/00A61P1/04A61P1/14A61P3/00A61P3/04A61P3/06A61P3/10A61P5/50A61P9/10A61P9/12A61P25/28
Inventor 谭芬来王印祥丁列明王燕萍马存波李彩娜胡云雁曹红胡邵京龙伟韩斌
Owner BETTA PHARM CO LTD
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