Unlock instant, AI-driven research and patent intelligence for your innovation.

4,4-dimethyllithocholato-2,3-N-arylpyrazole derivatives and preparation method and application thereof

A technology of dimethyl lithosperm and aryl pyrazole, which is applied in the field of medicine, can solve the problems of fat solubility, poor membrane permeability, low bioavailability, poor selectivity, etc. Effect

Active Publication Date: 2015-09-09
EAST CHINA NORMAL UNIV +1
View PDF1 Cites 2 Cited by
  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] Most of the small-molecule PTP1B inhibitors found in current research are tyrosine phosphate analogs, such as difluoromethylene phosphate, N-oxamidobenzoic acid, substituted acetophenone, salicylic acid, substituted malonate tyrosine Amino acid, sulfamic acid, these compounds are competitive inhibitors with high charge density, so they have poor fat solubility, membrane permeability, low bioavailability, and poor selectivity to other homologous enzymes of the PTP family

Method used

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
View more

Image

Smart Image Click on the blue labels to locate them in the text.
Viewing Examples
Smart Image
  • 4,4-dimethyllithocholato-2,3-N-arylpyrazole derivatives and preparation method and application thereof
  • 4,4-dimethyllithocholato-2,3-N-arylpyrazole derivatives and preparation method and application thereof
  • 4,4-dimethyllithocholato-2,3-N-arylpyrazole derivatives and preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0025] Embodiment 1 prepares compound Ia-1 of the present invention (R 1 =4-CH 3 O, R 2 =H)

[0026] Compound II (0.50g, 1.1mmol) was dissolved in 20ml of ethanol, 1g of 4-methoxyphenylhydrazine hydrochloride was added, heated to 70°C under nitrogen protection, cooled to room temperature after 2 hours of reaction, the reaction liquid was concentrated, added 30ml of water, extracted with ethyl acetate (30ml×3), collected the organic phase, washed with 10ml of water, washed with 10ml of saturated brine, dried over anhydrous sodium sulfate, concentrated organic solvent by distillation under reduced pressure and then chromatographed on a silica gel column (petroleum ether: ethyl acetate Ester=10:1) separation and purification to obtain 0.35g compound III (R i =4-CH 3 O, R 2 = H).

[0027] 0.35g compound III (R i =4-CH 3 O, R 2 =H) Dissolve in 10ml of methanol, add 1ml of water, 0.3g of lithium hydroxide monohydrate, react at room temperature for 36 hours, add dropwise 1M ...

Embodiment 2

[0028] Embodiment 2 prepares compound Ia-2 of the present invention (R 1 =4-C1, R 2 =H) Preparation of MSW-134

[0029] The preparation method was similar to Example 1, except that 4-chlorophenylhydrazine hydrochloride was used instead of 4-methoxyphenylhydrazine hydrochloride to obtain 0.28 g of compound Ia-2 with a yield of 56%; 1 H-NMR (CDCl 3 / MeOD, 400MHz): δ=7.39(d, 2H), 7.28(m, 3H), 5.63(dd, 1H), 2.69(d, 1H), 2.34~0.64(m, 35H), of which 1.22(s, 3H), 1.09(s, 3H), 0.88(d, 3H), 0.86(s, 3H), 0.64(s, 3H); HRMS(ESI): Calcd for C 33 h 44 ClN 2 o 2 [M+H] + , 535.3086; Found: [M+H] + =535.3133, [M+Na] + =557.2945.

Embodiment 3

[0030] Embodiment 3 prepares compound Ia-3 of the present invention (R 1 =4-CH 3 , R 2 =H) Preparation of MSW-142

[0031] The preparation method was similar to Example 1, except that 4-methylphenylhydrazine hydrochloride was used instead of 4-methoxyphenylhydrazine hydrochloride to obtain 0.38 g of compound Ia-3 with a yield of 76%; 1 H-NMR (CDCl 3 / MeOD, 400MHz): δ=7.18(m, 5H), 5.62(dd, 1H), 2.69(d, 1H), 2.36(s, 3H), 2.35~0.64(m, 35H), of which 1.22(s, 3H), 1.07(s, 3H), 0.87(d, 3H), 0.86(s, 3H), 0.64(s, 3H); HRMS(ESI): Calcd for C 34 h 47 N 2 o 2 [M+H] + , 515.3632; Found: [M+H] + =515.3683.

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to View More

PUM

No PUM Login to View More

Abstract

The invention belongs to the medicine technical field, and in particular, discloses 4,4-dimethyllithocholato-2,3-N-arylpyrazole derivatives having a structure represented by the formula (I). The invention also discloses a preparation method of the 4,4-dimethyllithocholato-2,3-N-arylpyrazole derivatives; a first method comprises the steps of with a compound II as a raw material and under the protection of nitrogen, taking ethanol as a solvent, carrying out a cyclization reaction with a compound a to obtain a compound III, in the presence of lithium hydroxide, and carrying out a hydrolysis reaction to obtain a compound Ia; or a second method comprises the steps of obtaining the compound III by the same way as the first method, in an acetone solvent and under the condition of the presence of glacial acetic acid and N-hydroxyphthalimide, oxidizing by using sodium dichromate to obtain a compound IV, reducing the compound IV by sodium borohydride to obtain a compound V, and then in the presence of lithium hydroxide, carrying out a hydrolysis reaction to obtain a compound Ib. The 4,4-dimethyllithocholato-2,3-N-arylpyrazole derivatives have relatively good inhibitory activity on PTPlB, and is suitable for preparing drugs for treatment of diabetes, obesity and other diseases.

Description

technical field [0001] The invention belongs to the technical field of medicine, and in particular relates to a 4,4-dimethyllithocholic acid-2,3-N-arylpyrazole derivative, a preparation method and application thereof, and a protein tyrosine phosphate derivative thereof The esterase 1B (PTP1B for short) inhibitor is used for the application in the preparation of the medicine for treating diabetes and obesity. Background technique [0002] Diabetes and obesity are endocrine disorders and metabolic diseases that seriously endanger people's health. They are often accompanied by decreased insulin sensitivity in insulin-sensitive tissues, that is, insulin resistance, which causes imbalances in glucose and lipid metabolism in muscle, liver, and adipose tissue. Type 1 diabetes is the inability of the body to produce insulin, and type 2 diabetes is the inability to produce insulin in the body, also known as insulin resistance. [0003] In recent years, research on the pathogenesis o...

Claims

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to View More

Application Information

Patent Timeline
no application Login to View More
IPC IPC(8): C07J71/00A61K31/58A61P3/10
CPCC07J71/0047
Inventor 杨帆毛世伟李佳汤杰李静雅高立信李念盛丽刘婷
Owner EAST CHINA NORMAL UNIV