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Glycinamide derivative, and intermediate, preparation method, pharmaceutical composition and application thereof

A compound and pharmaceutical technology, applied in the fields of drug combination, bulk chemical production, cardiovascular system diseases, etc., can solve problems such as large side effects, poor therapeutic effect, and poor safety.

Inactive Publication Date: 2015-01-14
SHANGHAI INST OF PHARMA IND +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0008] The technical problem to be solved by the present invention is to overcome the defects of poor therapeutic effect, slow onset, large side effects and poor safety of existing drugs for treating hyperhomocysteinemia, and to provide a drug with a completely different structure from the prior art Glycylamide derivatives, intermediates, preparation methods, pharmaceutical compositions and applications of

Method used

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  • Glycinamide derivative, and intermediate, preparation method, pharmaceutical composition and application thereof
  • Glycinamide derivative, and intermediate, preparation method, pharmaceutical composition and application thereof
  • Glycinamide derivative, and intermediate, preparation method, pharmaceutical composition and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0593] Example 1 Compound 20 Preparation of (Method 1)

[0594] 1-methyl-5-nitro-1H-indazole and 2-methyl-5-nitro-2H-indazole preparation of

[0595] Put 17.6g of NaH with a mass percentage of 60% (the mass percentage refers to the percentage of the mass of sodium hydride in the total mass of sodium hydride reagent) and 100mL DMF into the three-necked flask, stir and cool to 0°C, and slowly add Mixture of 60g 5-nitroindazole and 200mL DMF, control the reaction temperature below 10°C, after the dropwise addition, react at room temperature for 30 minutes, then cool to 0°C, slowly add dropwise a mixture of 62.68g methyl iodide and 60mLDMF solution, after the dropwise addition was completed, the reaction was carried out at room temperature for 12 hours. Add 1000mL water to the reaction solution, extract with 400mL×3 dichloromethane, combine the organic phases, wash twice with water, once with saturated NaCl, and wash with anhydrous MgSO 4 Dry and concentrate to dryness to ...

Embodiment 2

[0596] Example 2 Compound 19 preparation of

[0597] Preparation of 1-methyl-1H-indazol-5-amine

[0598] Drop into 60g1-methyl-5-nitro-1H-indazole in there-necked flask, 1200mL ethanol, 3g mass percent is 10% Pd / C (the described mass percent refers to the quality of palladium to the total mass of palladium-carbon reagent %), stirred at room temperature (25°C) and continuously fed H 2 After bubbling (about 10.08g), react for 12 hours, filter, and concentrate to obtain 49.9g of brown-yellow solid, yield 100%. ESI-MS(m / z):148.09[M+H] + .

Embodiment 3

[0599] Example 3 Compound 20 preparation of

[0600] Preparation of 1-(4-nitrophenyl)-1H-pyrrole (Method 2)

[0601] Put 60g of 4-fluoronitrobenzene, 88.15g of potassium carbonate, 400ml of DMSO and 57.05g of pyrrole into the three-necked flask, stir and heat up to 90°C, and react for 5 hours. After the reaction is completed, pour the reaction solution into 1500ml of water, and a large amount of The white solid was filtered, and the obtained solid was dried at 45° C. to obtain 64 g of white solid, with a yield of 80.0%.

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PUM

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Abstract

The invention discloses a glycinamide derivative, and an intermediate, a preparation method, a pharmaceutical composition and an application thereof. The invention provides the compound represented by the formula 1 or a pharmaceutically acceptable salt thereof. The invention also provides the preparation method of the compound represented by the formula 1 or the pharmaceutically acceptable salt thereof. The preparation method comprises the following steps: in a solvent and in the presence of a condensing agent and a catalyst, a compound 13 and a compound 14 undergo a condensation reaction to obtain the compound represented by the formula 1. The invention also provides the application of the compound represented by the formula 1 or the pharmaceutically acceptable salt thereof in preparation of drugs for prevention and / or treatment of diseases caused by S-adenosyl homocysteine hydrolase. The glycinamide derivative has a good inhibitory effect on S-adenosyl homocysteine hydrolase, has small toxic and side effects, can be used for preparation of the drugs for prevention and / or treatment of hyperhomocysteinemia, and has good market development prospects.

Description

technical field [0001] The present invention relates to glycinamide derivatives, intermediates, preparation methods, pharmaceutical compositions and applications. Background technique [0002] Homocysteine ​​(Hcy), also known as homocysteine ​​or homocysteine, is a sulfur-containing amino acid and an intermediate metabolite of methionine, one more than cysteine methyl. Ueland confirmed that in plasma, Hcy has four forms: about 1% exists in free form; 70-80% is bound to serum proteins in the form of disulfide bonds; 20-30% is in the form of homocysteine ​​dimers or Other mercapto compounds exist in the form. [0003] In 1969, McCully proposed that high levels of Hcy in plasma may be related to cardiovascular and cerebrovascular diseases, but it did not attract enough attention. Until 1976, Wilcken demonstrated for the first time that there was a link between abnormal blood Hcy metabolism and coronary artery disease in the general population. Later, it was proposed that th...

Claims

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Application Information

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IPC IPC(8): C07D231/56C07D403/12A61K31/416A61K31/454A61P9/10C07D207/325A61K31/4035
CPCY02P20/55C07D231/56C07D207/325C07D403/12
Inventor 谭相端邓轶方王攀峰张瑱黄晓玲刘珉宇肖璘蔡立王国平刘全海
Owner SHANGHAI INST OF PHARMA IND
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