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Thiazole Inner Salt Compounds, and Preparation Methods and Uses Thereof

a technology of thiazole inner salt and compound, which is applied in the field of pharmaceutical chemicals, can solve the problems of abnormal lipoprotein metabolism, reduced vascular elasticity, and reduced vascular compliance, and achieves stable pharmacokinetics, easy quality control, and equivalent activity.

Inactive Publication Date: 2016-05-19
INST OF PHARMACOLOGY & TOXICOLOGY ACAD OF MILITARY MEDICAL SCI P L A
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The compound in this patent has the same effect as a different compound in breaking down harmful substances in the body, but has more stable properties and is easier to control the quality of. This makes it more suitable for use in pharmaceutical and cosmetic industries.

Problems solved by technology

AGEs form cross-linked structures which make collagen aging, accelerate arteriosclerosis, change matrix components, cause platelet aggregation, result in decrease of vascular elasticity, reduction of vascular compliance and generation of abnormal lipoprotein metabolism, thereby impairing function of cardiovascular system.
However, in the following researchers, the compound of Formula A is unstable in physical and chemical properties, difficult in control of product quality in large scale production process, and its sample is unstable in storage at room temperature and easy to absorb moisture and change color, so that it is not suitable to be further developed as a medicament.
The compound of Formula A shows great pharmacological activity and good pharmacokinetic properties in vitro and in vivo, but its form of onium bromide is unstable in physical and chemical properties and thus is not suitable to be used as a medicament.

Method used

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  • Thiazole Inner Salt Compounds, and Preparation Methods and Uses Thereof
  • Thiazole Inner Salt Compounds, and Preparation Methods and Uses Thereof
  • Thiazole Inner Salt Compounds, and Preparation Methods and Uses Thereof

Examples

Experimental program
Comparison scheme
Effect test

example 2

Preparation of 3-methylcarbonyloxy-4-methyl-thiazole inner salt (n=0)

[0101]10 g 3-carboxymethyl-4-methyl-thiazolium bromide white solid was dissolved in 50 mL distilled water, added then with 7.31 g 1,2-epoxypropane, stirred at room temperature for 12 h, after the end of reaction, the reaction solution was extracted with 30 mL of dichloromethane, for 3 times, dichloromethane layer was discarded; the water layer was evaporated at a reduced pressure to obtain a light yellow oily substance. A defined amount of acetone was added into the oily substance, and light yellow particles were obtained via precipitation; recrystallization was performed with ethanol-ethyl ether system (wherein the most preferable recrystallization ratio was: 1 g of yellow particles was heated and dissolved in 4.5 mL ethanol, then added with 2 mL ethyl ether), to obtain white crystal 5.15 g, yield 78%, mP=169° C.

[0102]MS: 158 [M+H]+, 315 [2M+H]+, 472 [3M+H]+; 1H-NMR (400 MHz, DMSO-d6), 2.41 (d, 3H), 4.76 (s, 2H), ...

example 3

Preparation of 3-methylcarbonyloxy-4-methyl-thiazole inner salt monohydrate (n=1)

[0107]2 g of the 3-methylcarbonyloxy-4-methyl-thiazole inner salt (n=0) as prepared in Example 2 was dissolved at 20° C. in a mixture solvent of 100 mL methanol and 1 mL water, after complete dissolution, 300 mL ethyl acetate solution was added slowly; after mixing homogeneously, standing was performed at 5° C. for 12 h, the precipitated crystal was 3-methylcarbonyloxy-4-methyl-thiazole inner salt monohydrate (n=1).

[0108]Test of Crystal Structure Determination with X-Ray Single Crystal Diffraction:

[0109]2 mg of 3-methylcarbonyloxy-4-methyl-thiazole inner salt white crystal was added with 0.1 mL of anhydrous methanol, after the particles were dissolved, 0.6 mL ethyl acetate was added drop-wisely, standing was carried out until crystal particles grew slowly to form monocrystals (3-methylcarbonyloxy-4-methyl-thiazole inner salt monohydrate, n=1). Crystal structure was determined with X-single crystal diffr...

example 4

Stability Test

[0113]Three batches of sample (prepared according to Example 2) were taken according to the Chinese Pharmacopoeia, 2010 Edition, packaged like packaging for sale (high-density polyethylene bags were used for drug packaging), placed under conditions of RT 40° C., RH 75% (NaCl saturated solution) to carry out accelerated test, after 1, 2, 3, 6 months, sampled for observation of the compound of Formula I and the compound of Formula A, compared to the data of the 0th day, and the results were shown in Table 1 and Table 2.

[0114]One batches of sample as prepared according to Example 3 were taken, packaged like packaging for sale (high-density polyethylene bags were used for drug packaging), placed under conditions of RT 40° C., RH 75% (NaCl saturated solution), after 1, 2, 3 months, sampled and compared to the data of the 0th day, and the results were shown in Table 3.

[0115]Three batches of sample of the compound of Formula A were taken according to the Chinese Pharmacopoeia...

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Abstract

The present invention pertains to field of pharmaceutical chemicals, and relates to thiazole inner salt compounds, preparation methods and uses thereof. Specifically, the present invention relates to a compound of Formula I, hydrates or pharmaceutically acceptable salts thereof. The compound of Formula I of the present invention is a potent cross-linking protein cleavage agent, has a stable structure, good physical and chemical properties, and good pharmacological activities, and is suitable for large scale production to obtain samples with stable, controllable and reliable quality, thereby being suitable for pharmaceutical development.

Description

TECHNICAL FIELD[0001]The present invention pertains to field of pharmaceutical chemicals, and relates to thiazole inner salt compounds, and their preparation methods and uses.BACKGROUND ART[0002]Advanced glycation end products (AGEs) are covalent addition products which are formed by spontaneous reaction under non-enzymatic catalysis between a macromolecule such as protein, lipoprotein or nucleic acid and a glucose or other reducing sugar in vivo in physiological environment with human aging and diabetic development. The formation of AGEs cross-linked structure is a slow procedure, in which a terminal reducing amino group of macromolecule and an aldehyde group of glucose molecule form reversible early glycation products (Schiff bases) via addition; after several days, the unstable Schiff bases gradually form more stable Amadoric type early glycation products via rearrangement reaction, and the Amadoric products form AGEs via a series of dehydrogenation, oxidation and rearrangement r...

Claims

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Application Information

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IPC IPC(8): C07D277/22A61Q11/00A61K8/49A61Q19/08A61K31/426A61K31/4422
CPCC07D277/22A61K31/426A61Q11/00A61K8/49A61Q19/08A61K31/4422C07D277/30A61P1/02A61P13/12A61P17/00A61P17/16A61P19/02A61P25/02A61P27/00A61P27/02A61P27/12A61P37/02A61P43/00A61P9/00A61P9/04A61P9/10A61P9/12A61P3/10
Inventor LI, SONGZHONG, WUCAO, SHUANGWANG, LILIZHENG, ZHIBINGXIAO, JUNHAIZHOU, XINBO
Owner INST OF PHARMACOLOGY & TOXICOLOGY ACAD OF MILITARY MEDICAL SCI P L A
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