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2,5-diaryl-1,3,4-oxadiazole compounds and preparation method and application thereof

A technology for oxadiazoles and compounds, which is applied in the fields of drug combination, organic chemistry, medical preparations containing active ingredients, etc., can solve the problems of limited types of compounds, poor activity and bioavailability, and reduce the risk of side effects Effect

Inactive Publication Date: 2013-02-13
SHANGHAI INST OF MATERIA MEDICA CHINESE ACAD OF SCI +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the types of compounds reported are limited, and no drugs have entered clinical research due to problems such as poor activity and bioavailability

Method used

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  • 2,5-diaryl-1,3,4-oxadiazole compounds and preparation method and application thereof
  • 2,5-diaryl-1,3,4-oxadiazole compounds and preparation method and application thereof
  • 2,5-diaryl-1,3,4-oxadiazole compounds and preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0035] Compound I (R 1 =H, R 2 =Cl, R 3 =3,4-Dimethoxybenzyl) Synthesis:

[0036] (A) m-nitrobenzoyl hydrazide (1.3g, 7.3mmol), m-chlorobenzoic acid (1.14g, 7.3mmol), EDC (1.8g, 9.5mmol) and HOBt (1.42g, 9.5mmol) are suspended in two After stirring for 10 min in methyl chloride (20 mL), pyridine (1.5 mL) was added to the above reaction solution, and after stirring and reacting for 18 h, a large amount of solid was precipitated. Add 30 mL of 10% dilute hydrochloric acid to the reaction solution, stir for 30 min, filter, and the filter cake is washed thoroughly with water and dried to obtain an off-white solid i (R 1 =H, R 2 =Cl) 1.55g, yield: 67%.

[0037] (B) The product i(R 1 =H, R 2 =Cl, 3.19g, 10mmol) was suspended in acetonitrile (45mL), followed by phosphorus oxychloride (2.32mL). The above mixture was heated to 75°C to react for 10h, cooled to room temperature and concentrated under reduced pressure to near dryness. Under ice-water bath cooling, add 120 mL each of a dichlor...

Embodiment 2

[0041] Compound I (R 1 =NMe 2 , R 2 =H, R 3 =Me) synthesis:

[0042] (A) m-nitrobenzoyl hydrazide (1.3g, 7.3mmol), 4-N,N-dimethylbenzoic acid (1.2g, 7.3mmol), EDC (2.77g, 14.5mmol) and HOBt (2.2, 14.5mmol) was suspended in dry THF (20mL). After stirring for 10min, 3-methylpyridine (1.5mL) was added to the above reaction solution. After stirring and reacting for 36h, a large amount of solid was precipitated. After filtration, the filter cake is fully washed with water and then dried to obtain an off-white solid. The product i(R 1 =NMe 2 , R 2 =H) 1.35g, yield: 56%.

[0043] (B) Suspend the product i (1.2 g, 3.66 mmol) obtained in the previous step in acetonitrile (15 mL), and then add phosphorus oxychloride (0.51 mL). The above mixture was heated to reflux for 8h, cooled to room temperature and concentrated under reduced pressure to near dryness. Under ice-water bath cooling, add 40 mL each of a dichloromethane / methanol (5 / 1) mixed solution and 5% NaOH solution to the above concen...

Embodiment 3

[0047] Compound I (R 1 =Me, R 2 =Cl, R 3 =3,4-Dimethoxybenzyl) Synthesis:

[0048] Using 4-methyl-3-chlorobenzoic acid as a raw material, it was synthesized by referring to the method in Example 1. The total yield of the four-step reaction was 27.8%. White solid 1 H NMR(500MHz, CDCl 3 ): δ2.41(s,3H), 3.72(s,2H), 3.84(s,3H), 3.85(s,3H), 6.83-6.88(m,3H), 7.32(d,J=7.5Hz, 1H),7.40(t,J=8.0Hz,1H),7.77-7.79(m,2H),7.83(dd,J 1 =1.5Hz, J 2 =7.9Hz,1H),8.01(d,J=1.4Hz,1H),8.07(s,1H),8.18(s,1H); 13 C NMR(125MHz, CDCl 3 ): δ170.0, 164.2, 163.6, 149.3, 148.5, 140.3, 138.7, 135.1, 131.5, 129.7, 127.2, 126.6, 124.9, 124.1, 123.2, 122.6 (2C), 121.6, 117.9, 112.5, 111.6, 55.8 (2C), 44.1,20.2;HRMS(ESI):Calcd for C 25 H 23 ClN 3 O 4 [M+H] + , 464.1377; Found, 464.1377.

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Abstract

The invention relates to 2,5-diaryl-1,3,4-oxadiazole compounds and a preparation method and application thereof. The preparation method comprises the following steps of: condensing benzoic acid of which a 4- site is replaced by R<1> and a 3- site is replaced by R<2> and which is taken as a raw material and m-Nitrobenzoylhydrazine in dichloromethane or tetrahydrofuran to obtain diacylhydrazine i; performing intramolecular dehydration cyclization on the diacylhydrazine i in acetonitrile by taking phosphorus oxychloride as a dehydration reagent to obtain an intermediate ii containing an oxadiazole ring; hydrogenating the intermediate ii under normal pressure under the catalysis of raney nickel to reduce a nitro group to obtain an amino substance iii; and finally, condensing the amino substance iii and acetic anhydride or 3,4-dimethoxyphenylacetic acid under the action of an acid-binding agent to obtain the 2,5-diaryl-1,3,4-oxadiazole compounds I. The invention also discloses application of the 2,5-diaryl-1,3,4-oxadiazole compounds I to the preparation of a medicine for treating type 2 diabetes mellitus.

Description

Technical field [0001] The invention relates to a 2,5-diaryl-1,3,4-oxadiazole compound and its preparation and application. The application means that it can be used as fructose-1,6-bisphosphatase (abbreviated as FBPase). ) Inhibitors belong to the field of medical technology. Background technique [0002] Diabetes is one of the major diseases that seriously threaten human health. Epidemiological statistics show that by 2010, there were about 285 million people with diabetes in the world, and the number of patients with diabetes has been increasing rapidly in recent years. It is estimated that by 2030, the number of patients may reach twice the number in 2010. Also from 2010 statistics, the number of diabetic patients in China exceeded 92 million, that is, about one-tenth of adults suffer from diabetes, and another 148 million people have clinically shown initial symptoms and become high-risk groups of diabetes. [0003] Due to different causes, diabetes can be divided into four ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D271/107A61K31/4245A61P3/10
Inventor 李佳汤杰李静雅何海兵高立信杨帆杨玲玲阿卜杜拉·玉苏普
Owner SHANGHAI INST OF MATERIA MEDICA CHINESE ACAD OF SCI
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