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Heterocyclic aromatic micromolecule organic compounds and derivatives, preparation method and medical application

A technology of organic compounds and aromatic heterocycles, applied in the field of aromatic heterocycle small molecule organic compounds and their derivatives, preparation and medical application, can solve the increased risk of cardiovascular and sudden death, no toxic side effects, and short time to market To achieve the effect of improving pharmacokinetic properties, excellent therapeutic effect, and changing physical and chemical properties

Active Publication Date: 2014-04-02
EAST CHINA NORMAL UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] At present, the drugs for treating diabetes on the market are mainly divided into three categories, one is the most commonly used metformin and sulfonylurea drugs, which not only have certain toxic and side effects, but also lose their curative effect if taken for a long time
The second category is thiazolidinedione drugs, of which pioglitazone and rosiglitazone were launched in 2000, and they have good results for patients who have no therapeutic effect on metformin and sulfonylureas, but in 2010 FDA This type of drug has an increased risk of cardiovascular and sudden death, and it has been withdrawn from the first-line treatment
The third category is glucagon-like peptide 1 (GLP-1) analogues and dipeptidyl peptidase (DPP-IV) inhibitors, which have been on the market since 2005. They have the largest sales share and the best effect on the market. Due to the short time on the market, there are no obvious reports of toxic and side effects
[0007] However, the application of GLP-1 in clinical practice also faces a problem, that is, the GLP-1 produced by the human body is easily degraded by dipeptidyl peptidase IV (DPP-IV), and its plasma half-life is less than 2 minutes. Instillation or continuous subcutaneous injection can produce curative effect, which greatly limits the clinical application of GLP-1

Method used

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  • Heterocyclic aromatic micromolecule organic compounds and derivatives, preparation method and medical application
  • Heterocyclic aromatic micromolecule organic compounds and derivatives, preparation method and medical application
  • Heterocyclic aromatic micromolecule organic compounds and derivatives, preparation method and medical application

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0189] Example 1: Preparation method of compound

[0190] plan 1

[0191]

[0192] Among them, aromatic thioamide and ethyl bromoacetoacetate or their analogues are heated to 70-100°C for 1-3 hours in a solvent such as ethanol, dioxane, toluene, DMF, and ethylene glycol dimethyl ether. After extraction and purification, it is reduced with borane, lithium aluminum hydride or sodium borohydride to obtain alcohol compounds; the alcohol compounds directly react with halogenated substances to form ethers under the action of potassium tert-butoxide, sodium hydride or potassium carbonate The product, or the alcohol compound after bromination, and alcohol, mercaptan and amine compound to produce ether, thioether and amine compound.

[0193] Scenario 2

[0194]

[0195] Among them, 2-aryl-4-methyl-5-substituent thiazole and N-chlorosuccinimide are refluxed in acetonitrile, tetrahydrofuran, dioxane and toluene to generate chlorinated intermediates, which are combined with alcohols, The merc...

Embodiment 1-1

[0212] Example 1-1, Synthesis of 4-(2-(4-bromobenzyloxy)ethyl)-5-methyl-2-phenylthiazole (LCZ-001)

[0213] Mix thiobenzamide (411mg, 3mmol) and ethyl 4-bromopropionyl acetate (658mg, 4mmol) and dissolve in anhydrous solvent such as ethanol, DMF or ethylene glycol dimethyl ether (25ml), and heat the mixture To 70-100°C. After the completion of the reaction detected by TLC, the obtained mixture was evaporated to dryness of solvent and then extracted twice. The obtained organic phase was washed with saturated brine, evaporated to dryness under reduced pressure, and purified by silica gel column chromatography to obtain the compound ethyl 2-(2- Phenyl-4-thiazolyl-5-methyl)acetate. This compound (741 mg, 3 mmol) was dissolved in 10 ml of ether or dioxane, lithium aluminum hydride (168 mg, 6 mmol) was added under ice bath conditions, the ice bath was removed after stirring for 30 minutes, and the mixture was stirred at room temperature until the reaction was complete. The resulting ...

Embodiment 2

[0214] Example 2: Preparation of compounds LCZ-001 to LCZ-097 (see the reference below for the specific process)

[0215]

[0216]

[0217]

[0218]

[0219]

[0220]

[0221]

[0222] Example 2: The compound of the present invention can significantly promote the secretion of GLP-1

[0223] In order to study the effect of the compound of the present invention on GLP-1 secretion, NCI-H716 was used for drug screening. The result is figure 1 Shown in A. The results show that most of the compounds of the present invention can strongly stimulate NCI-H716 cells to secrete GLP-1, and this effect of promoting GLP-1 secretion has been similarly verified in MIN6, intestinal cells and in vivo experiments in mice ( figure 1 B-D). In addition, the compounds of the present invention can also promote insulin secretion in MIN6. The experimental results indicate that the compound of the present invention may have anti-diabetic effects.

[0224] As mentioned earlier, GLP-1 (glucagon-like peptide 1)...

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PUM

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Abstract

The invention discloses heterocyclic aromatic micromolecule organic compounds as shown in the structural formula (I) and derivatives thereof, or hydrates or pharmaceutically acceptable salts, and a preparation method of the corresponding compounds; the invention also discloses an application of the compounds and pharmaceutical compositions containing the compounds to the treatment of various metabolic syndrome-related diseases. The heterocyclic aromatic micromolecule organic compounds of the invention have excellent treatment effect on metabolic syndromes; experiment results show that the compounds may promote secretion of endogenous GLP-1, and are applicable to the preparation of anti-diabetic and fat-reducing candidate medicaments. Aiming at technical problems of easy degradation and short half life of current medicaments for treating diabetes, the invention provides novel, high-efficient micromolecule compounds for promoting secretion of endogenous GLP-1, and the compounds are applicable to the treatment of metabolic syndrome-related diseases such as diabetes, obesity and the like.

Description

Technical field [0001] The present invention discloses a compound represented by structural formula (I) and related derivatives, or a hydrate or a pharmaceutically acceptable salt, and a corresponding preparation method. The compound of the present invention and a pharmaceutical composition containing such a compound can be It is used as a medicine to treat various metabolic syndrome and other related diseases. Background technique [0002] At this stage, the rapid growth of metabolic syndrome diseases including obesity, diabetes and their complications worldwide has become a serious health problem. Obesity co-existing diseases include: coronary heart disease, hypertension and stroke, some cancers, non-insulin-dependent diabetes, gallbladder disease, osteoarthritis and gout, dyslipidemia, lung disease, sleep apnea and so on. At present, the number of obese people in my country has exceeded 300 million, an increase that exceeds that of the United States and Britain, and the numbe...

Claims

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Application Information

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IPC IPC(8): C07D277/24C07D277/28C07D417/04C07D261/08C07D263/32C07D333/16C07D409/04C07D417/14C07D307/42C07D277/26A61K31/426A61K31/5377A61K31/4439A61K31/42A61K31/421A61K31/381A61K31/4436A61K31/341A61K31/496A61K31/541A61P3/00A61P3/10A61P3/04A61P9/00
CPCC07D261/08C07D263/32C07D277/24C07D277/26C07D277/28C07D307/42C07D333/16C07D417/04C07D417/14
Inventor 陈益华刘明耀郑春兵周文波覃莉雯陈华青罗剑
Owner EAST CHINA NORMAL UNIVERSITY
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