2-(3-cyano-4-alkoxy) phenyl-4-substituted thiazole-5-formic acid compound, composition as well as preparation methods and applications thereof

A technology of phenylthiazole and compound, which is applied in the field of treatment and/or prevention of hyperuricemia and gout, and can solve the problems of undiscovered thiazole-5-carboxylic acid compound composition and preparation method, etc.

Inactive Publication Date: 2013-10-02
SHENYANG PHARMA UNIVERSITY
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] No relevant reports on 2-(3-cyano-4-alkoxy)phenyl-4-substituted thiazole-5-carboxylic acid compounds and their key intermediates, compositions and preparation methods have been found in the prior art

Method used

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  • 2-(3-cyano-4-alkoxy) phenyl-4-substituted thiazole-5-formic acid compound, composition as well as preparation methods and applications thereof
  • 2-(3-cyano-4-alkoxy) phenyl-4-substituted thiazole-5-formic acid compound, composition as well as preparation methods and applications thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0450] Example 1 Preparation of 2-(3-cyano-4-isobutoxy)phenyl-4-phenylthiazole-5-carboxylic acid (general method eight)

[0451] Add 6.1g (0.015mol) ethyl 2-(3-cyano-4-isobutoxyphenyl)-4-phenylthiazole-5-carboxylate (intermediate 85) to a 250mL single-necked bottle, 1.9g ( 0.045mol) lithium hydroxide, 12mL water, 120mL DMF, react at 50°C for 8h, after the reaction is complete, pour the above reaction solution into 500mL water, adjust the pH value to 1 with concentrated hydrochloric acid, let stand at room temperature for 4h, suction filter, and collect The crude product was obtained by filtering the cake, and recrystallized (absolute ethanol: acetone = 1:1) to obtain 4.1 g of white powder, yield: 72.2%, mp: 199.4-199.9°C.

[0452] MS(ESI):m / z377.1[M-H] - ;IR(KBr)3429.7,2963.0,2230.3,1724.8,1652.8,1603.3,1573.6,1512.1,1485.5,1441.4,1386.5,1358.3,1327.4,1297.4,1255.9,1201.6,1179.0,1133.7,1078.8,1023.6,1002.5cm -1 ; 1 H-MNR (300MHz, DMSO-d 6 )δ(ppm):8.37(d,1H,J=2.1Hz,Ar-H),8....

Embodiment 2

[0453] Example 2 Preparation of 2-(3-cyano-4-methoxy)phenyl-4-phenylthiazole-5-carboxylic acid

[0454] According to General Method 8, using (Intermediate 86) as raw material, the crude product was recrystallized (absolute ethanol: acetone = 1:1) to obtain 3.5 g of white powder, yield: 69.4%, mp: 254.8-255.4 °C.

[0455] MS(ESI):m / z337.1[M+H] + ;IR(KBr):3442.3, 2937.9, 2361.4, 2229.7, 1678.0, 1648.4, 1603.2, 1511.1, 1484.4, 1443.9, 1427.6, 1329.3, 1285.0, 1183.8, 1167.8, 1144.2, 11033.1.1, -1 ; 1 H-MNR (300MHz, DMSO-d 6 )δ(ppm):13.47(s,1H,COOH),8.37(d,1H,J=2.1Hz,Ar-H),8.31(dd,1H,J=2.4Hz,J=9.0Hz,Ar-H ),7.81(m,2H,Ar-H),7.46(m,3H,Ar-H),7.40(d,1H,J=9.0Hz,Ar-H),4.00(s,3H,CH 3 ).

Embodiment 3

[0456] Example 3 Preparation of 2-(3-cyano-4-ethoxy)phenyl-4-phenylthiazole-5-carboxylic acid

[0457] According to General Method 8, using (Intermediate 87) as raw material, the crude product was recrystallized (absolute ethanol: acetone = 1:1) to obtain 4.4 g of white powder, yield: 73.9%, mp: 248.1-248.9 °C.

[0458] MS(ESI):m / z349.1[M-H] - ;IR(KBr):3425.6, 2988.6, 2227.1, 1688.3, ​​1654.9, 1603.3, 1517.4, 1486.3, 1434.0, 1392.8, 1327.2, 1292.5, 1177.9, 1144.2, 1128.3, 1041.5cm -1 ; 1 H-MNR (300MHz, DMSO-d 6 )δ(ppm):13.44(s,1H,COOH),8.35(d,1H,J=2.1Hz,Ar-H),8.27(dd,1H,J=2.4Hz,J=8.7Hz,Ar-H ),7.80(m,2H,Ar-H),7.45(m,3H,Ar-H),7.37(d,1H,J=8.7Hz,Ar-H),4.28(q,2H,J=6.9Hz ,CH 2 ),1.40(t,3H,J=6.9Hz,CH 3 ).

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Abstract

The invention relates to a 2-(3-cyano-4-alkoxy) phenyl-4-substituted thiazole-5-formic acid compound which has xanthine oxidase inhibitory activity and is shown in a general formula I, a composition and preparation methods thereof. The invention also relates to applications of the compound and the composition thereof to preparation of medicaments for treating and/or preventing hyperuricemia and gout diseases. In the formula I, R2 is substituted or unsubstituted phenyl or a substituted or unsubstituted heteroaromatic radical, R1 is a substitutive aliphatic group of a straight chain or a branched chain, substituted or unsubstituted alicyclic hydrocarbonyl or substituted or unsubstituted aryl alkyl and A is an oxygen atom, a sulfur atom or a nitrogen atom.

Description

field of invention [0001] The present invention relates to 2-(3-cyano-4-alkoxy)phenyl-4-substituted thiazole-5-carboxylic acid compounds, pharmaceutical compositions and their preparation methods, and their therapeutic and (or) prophylactic Use in hyperuricemia and gout. Background of the invention [0002] Gout is a metabolic disease caused by disturbance of purine metabolism or decreased excretion of uric acid. Its clinical features are: hyperuricemia, acute and chronic arthritis, joint deformity, chronic interstitial nephritis and kidney stones, etc. In severe cases, renal failure and cardiovascular and cerebrovascular diseases may also be life-threatening. According to statistics, gout has become the second largest metabolic disease in the world after diabetes. In recent years, with the improvement of people's living standards and the change of diet structure in our country, the incidence of gout has been increasing year by year, which has brought a heavy burden to the...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D277/56C07D417/04A61K31/426A61K31/427A61P19/06
Inventor 王绍杰施翔林园园
Owner SHENYANG PHARMA UNIVERSITY
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