Aromatic nitrile-base thiazole derivatives for inhibiting xanthine oxidase activity, preparation method and application

A technology of xanthine oxidase and aromatic nitrile thiazole, which is applied in the directions of organic active ingredients, organic chemistry, drug combination, etc., can solve the problems of expensive raw materials, harsh operating conditions, and many reaction steps, and achieves simple operation and easy purification of products. , the effect of high yield

Active Publication Date: 2009-03-18
HANGZHOU ADAMERCK PHARMLABS INC
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0016] The chemical preparation methods disclosed above are difficult to realize in industrial production due to expensive raw materials, many reaction steps, and harsh operating conditions. In addition, it is reported that almost every step of the reaction requires column purification, resulting in high cost
[0017] CN 1642546 thinks that (2-(3-cyano-4-isobutoxy

Method used

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  • Aromatic nitrile-base thiazole derivatives for inhibiting xanthine oxidase activity, preparation method and application
  • Aromatic nitrile-base thiazole derivatives for inhibiting xanthine oxidase activity, preparation method and application
  • Aromatic nitrile-base thiazole derivatives for inhibiting xanthine oxidase activity, preparation method and application

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0039]

[0040] Ethyl 4-nitrobenzoate (19.5g, 0.1mol) and NaCN (4.9g, 0.1mol) were heated to 80°C in dry DMSO (50ml) and stirred for 3 hours. The reaction solution was cooled, and potassium carbonate ( 6.9g, 0.05mol) and isobutyl bromide (13.8g, 1mol), reacted at 60°C for 24 hours, poured the reaction solution into water, extracted with ethyl acetate, dried the organic layer with anhydrous sodium sulfate, concentrated to obtain an oil Product 4-isobutoxy-3-carbonitrile ethyl benzoate 1a, yield 83%. H1NMR (DMSO-D6): 1.02 (6H, d); 1.37 (3H, tri); 2.20 (H, m); 3.90 (2H, d); 4.27 (2H, m); 7.20 (1H, d); (H, dd); 8.15 (H, d); MS: m / z: 248 (M+1).

[0041]Ethyl 4-nitrobenzoate (19.5g, 0.1mol) and NaCN (7.35g, 0.15mol) were heated to 100°C in dry DMSO (500ml) and stirred for 1 hour. The reaction solution was cooled, and potassium carbonate ( 27.6g, 0.2mol) and isobutyl bromide (548g, 4mol), reacted at 150°C for 5 hours, recovered DMSO by rotary evaporation under reduced pressure, ...

Embodiment 2

[0049]

[0050] Add 2.47 grams of 4-isobutoxy-3-carbonitrile ethyl benzoate (0.01mol) and 5 ml of ethanol in the reaction flask, add 8% aqueous solution of 6 ml of sodium hydroxide, and hydrolyze at 30 C for 5 hours, and react The solution was neutralized with 0.5N hydrochloric acid solution, extracted by adding 10ml of ethyl acetate, washed with water, dried over anhydrous sodium sulfate, concentrated to dryness under reduced pressure, added 1ml of anhydrous ether, 2ml of SOCl 2 , in CaCl 2 Under the protective device, after stirring at room temperature for 1 hour, add 0.1ml of DMF, heat to an internal temperature of 40°C, react for 2 hours, stop the reaction, the reaction solution is clear and transparent, concentrate under reduced pressure at 40°C, and after concentrating to near dryness, add 20ml CH 2 Cl 2 , after mixing, drop 5ml of CH in 5ml of concentrated ammonia water precooled to 0C 2 Cl 2 In the solution, 30 minutes after the dropwise reaction, TLC showed tha...

Embodiment 3

[0059]

[0060] Under the flow of dry nitrogen, add 60 g of phosphorus pentasulfide and 300 ml of phenetole in the reaction bottle and heat to reflux, react at 130 °C for 9 hours until all the solids are completely dissolved, accompanied by a large amount of H2S gas, use 10% NaOH Aqueous solution absorption. Stop heating when the H2S gas is no longer generated, and block crystals will form after cooling to room temperature. After the crystals were filtered and washed with ethyl acetate, they were vacuum-dried at room temperature to obtain 65 g of solid.

[0061] Under the flow of dry nitrogen, the above 8.5 grams of solids were added to a solution of 8.9 grams of 4-isobutoxy-3-carbonitrile benzamide in 50 mL of anhydrous THF, and after reacting at 50 C for 2 hours, The solvent THF was removed under reduced pressure, and the resulting residue was extracted with ethyl acetate. The organic layer was washed 3 times with water, dried over anhydrous sodium sulfate, and concentra...

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Abstract

The invention disclosed an aryl nitrile group thiazole derivative for inhibiting the activity of xanthine oxidase, a method for preparing the same and application thereof. In the aryl nitrile group thiazole, R1 is methyl, ethyl, propyl, isopropyl, isobutyl, methyl cyclopropane, methyl cyclobutane, isoamyl, methyl cyclopentane, methyl cyclohexane or aromatic ring methyl, R2 is methyl or trifluoromethyl, and R3 is formic acid, sodium formate, potassium formate, lithium formate, methyl formate, or ethyl formate. Simultaneously, the invention discloses a method for synthesizing the aryl nitrile group thiazole derivative by using inexpensive raw materials, which has the advantages of simple operation, high yield, easy purification of products, application to industrial production and the like, and can obtain an efficient compound with low toxicity through screening; besides, the effective compound is expected to be widely applied to inhibit the activity of the xanthine oxidase required on animals and humans, and to become a new generation of antigout drugs and hyperuricemia drugs with special effect.

Description

technical field [0001] The invention relates to an aromatic cyanothiazole derivative inhibiting xanthine oxidase activity, a preparation method and application. Background technique [0002] According to WO 9209279, 2-(3-cyano-4-isobutoxyphenyl)-4-methyl-5-thiazolecarboxylic acid, one of the 2-arylthiazole compounds, is a new xanthine oxidation Non-purine selective enzyme preparations can reduce uric acid production. The compound is effective for the vast majority of patients suffering from gout and hyperuricemia, can reduce and stabilize the blood uric acid level below 6.0mg / dl, and reduce acute gout attacks. [0003] WO 9209279 discloses the chemical preparation of 2-(3-cyano-4-isobutoxyphenyl)-4-methyl-5-thiazolecarboxylic acid and its use in the treatment of gout and hyperuricemia. [0004] JP06293746 published between 1994 and 1998; JP06329647; JP06345724; JP09188670; JP10045733; A new method is proposed, as shown in Reaction Formulas 1 to 5 respectively: [0005] ...

Claims

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Application Information

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IPC IPC(8): C07D277/56A61K31/426A61P19/06A61P19/02A61P9/04
Inventor 漆又毛揭清张冯敏
Owner HANGZHOU ADAMERCK PHARMLABS INC
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