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Novel derivative of 2-[3-cyano-4-isobutoxyphenyl]-4-methylthiazol-5-formic acid, preparation method for novel derivative and application of novel derivative

A technology based on alkyloxycarbonyl and phenyl groups, applied in the field of prevention and treatment of hyperuricemia diseases, can solve the problems of loss of motor function, unsatisfactory effect of lowering uric acid, and single mechanism of action

Active Publication Date: 2016-01-06
XIANGBEI WELMAN PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0016] (6) Chronic gouty arthritis causes fibrosis of joint tissue and deposition of tophi in articular cartilage, synovium, and ligaments caused by repeated acute arthritis attacks, which gradually destroys and deforms the diseased joints and loses motor function
[0031] However, since febuxostat exerts the effect of lowering uric acid mainly by inhibiting the production of uric acid, the mechanism of action is relatively simple, the effect of lowering uric acid is still not ideal, and there is room for further improvement. Therefore, the development of curative effect is better and the safety is better The febuxostat derivatives still have very important clinical significance

Method used

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  • Novel derivative of 2-[3-cyano-4-isobutoxyphenyl]-4-methylthiazol-5-formic acid, preparation method for novel derivative and application of novel derivative
  • Novel derivative of 2-[3-cyano-4-isobutoxyphenyl]-4-methylthiazol-5-formic acid, preparation method for novel derivative and application of novel derivative
  • Novel derivative of 2-[3-cyano-4-isobutoxyphenyl]-4-methylthiazol-5-formic acid, preparation method for novel derivative and application of novel derivative

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Experimental program
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preparation example Construction

[0080] The preparation of embodiment 1F1-1

[0081] 1.1 The preparation of p-[(dipropylamino)sulfonyl]benzoyl chloride

[0082]

[0083] 2.85g of p-[(dipropylamino)sulfonyl]benzoic acid was added to 25ml of toluene, then 1ml of thionyl chloride was added, then refluxed at 50°C for 2 hours and then concentrated to dryness under reduced pressure to obtain 3.12g The pale yellow solid was directly used in the next reaction.

[0084] 1.2 Preparation of p-[(dipropylamino)sulfonyl]ethylene glycol monobenzoate

[0085]

[0086] Add 3.12g of p-[(dipropylamino)sulfonyl]benzoyl chloride and 10g of ethylene glycol into 50ml of tetrahydrofuran, stir at room temperature for 10 minutes, then add 2ml of triethylamine under stirring, then react at 50°C for 2 Stop the reaction after 1 hour, concentrate to dryness under reduced pressure, dissolve the product with 50ml ethyl acetate, wash 3×10ml with saturated brine and water successively, then dry with anhydrous sodium sulfate and concen...

Embodiment 2

[0096] The preparation of embodiment 2 compound F2-1

[0097] 2.1 Preparation of intermediate p-[(dipropylamino)sulfonyl]benzoic acid N-methyl-N-hydroxyethyl ethyl ester

[0098]

[0099] 3.13g of p-[(dipropylamino)sulfonyl]benzoyl chloride and 35g of diethanolamine prepared according to the method described in step 1.1 of Example 1 were added to 50ml of tetrahydrofuran, and stirred at room temperature for 10 minutes under stirring Add 2ml of triethylamine, then stop the reaction at 50°C for 2 hours, concentrate to dryness under reduced pressure, dissolve the product in 50ml of ethyl acetate, wash 7×10ml with saturated brine, dry with anhydrous sodium sulfate and reduce Concentrate under pressure to constant weight to obtain 2.65 g of white powdery solid with a yield of 76.3%.

[0100] 1 H-NMR (400MHz, d 6 DMSO): δ8.24-8.26 (d, 2H), 8.08-8.10 (d, 2H), 4.37-4.40 (t, 2H), 3.61-3.64 (t, 2H), 3.15-3.19 (t, 2H), 2.82-2.85 (t, 2H), 2.52-2.55 (t, 4H), 2.11 (s, 3H), 1.48-1.52 (...

Embodiment 3

[0106] The preparation of embodiment 3 compound F3-1

[0107] 3.1 Preparation of 2-methyl-2-(4-(4-chlorobenzoyl)phenoxy)propionyl chloride

[0108]

[0109] It was prepared according to the method described in step 1.1 in Example 1, and was directly used in the next reaction.

[0110] 3.2 Preparation of intermediate 2-methyl-2-(4-(4-chlorobenzoyl)phenoxy)propanoic acid N-methyl-N-hydroxyethyl ethyl ester

[0111]

[0112] Referring to the method described in step 2.1 in Example 1, a white solid was prepared with a yield of 81%.

[0113] 1 H-NMR (400MHz, d 6 DMSO): δ7.53-7.66 (m, 4H), 7.25-7.27 (d, 2H), 7.08-7.10 (d, 2H), 4.21-4.24 (t, 2H), 3.67-3.69 (t, 2H), 2.61-2.64 (t, 2H), 2.59 (t, 2H), 2.34 (s, 3H), 1.68 (s, 6H).

[0114] 3.3 Preparation of compound F3-1

[0115]

[0116] Referring to the method described in 2.2 of Example 1, the product of step 3.1 and the product of step 3.2 were respectively used to prepare the target product, which was a white solid wit...

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Abstract

The invention provides a compound as shown in a formula (I), or a pharmaceutical salt of the compound or stereisomers of the compound. The formula (I) is as shown in the specification. The compound as shown in the formula (I), or the pharmaceutical salt of the compound or the stereisomers of the compound applied to preventing and treating hyperuricemia have more superior uric-acid-reducing effect and more excellent safety compared to those of febuxostat.

Description

technical field [0001] The invention belongs to the field of medicine, more specifically, the invention relates to 2-[3-cyano-4-isobutoxyphenyl]-4-methylthiazole-5-carboxylic acid derivatives and salts thereof, and stereoisomers thereof body, and a pharmaceutical preparation comprising at least one compound of formula (I) or its salt or its stereoisomer as an active ingredient, and its application in the prevention and treatment of hyperuricemia diseases. Background technique [0002] Gout is a group of syndromes caused by abnormal purine metabolism in the human body, and hyperuricemia is a stage in the development of its lesions. According to the cause of the disease, it can be divided into two types: primary gout and secondary gout. [0003] Primary gout has obvious familial genetic tendency, and it is prone to occur in middle-aged and elderly people. The peak incidence is 30 to 50 years old. About 95% of them are men, and 5% of women are often postmenopausal. The etiolo...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D277/56C07D417/12C07D417/14A61K31/426A61K31/427A61P19/06
Inventor 王海勇陈晓峰孙天宇
Owner XIANGBEI WELMAN PHARMA CO LTD
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