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1-substituted-2-substituted-4- aryl substituted-butyl-2-alkene 1, 4-diketone compound, its preparation method and application

A compound, C1-C20 technology, applied in the field of medicine, can solve problems such as high acidity, difficulty in becoming a drug candidate compound, and poor ability to enter cells

Inactive Publication Date: 2011-11-09
SHANGHAI INST OF MATERIA MEDICA CHINESE ACAD OF SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0009] In recent years, the research on PTP1B selective inhibitors has made some progress, but most of them are peptide or peptidoid phosphomimetics, although these peptide and peptidoid inhibitors have strong inhibitory activity and certain selective However, most of them contain phosphate groups, are highly acidic, and have poor ability to enter cells, so it is difficult to become drug candidate compounds

Method used

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  • 1-substituted-2-substituted-4- aryl substituted-butyl-2-alkene 1, 4-diketone compound, its preparation method and application
  • 1-substituted-2-substituted-4- aryl substituted-butyl-2-alkene 1, 4-diketone compound, its preparation method and application
  • 1-substituted-2-substituted-4- aryl substituted-butyl-2-alkene 1, 4-diketone compound, its preparation method and application

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0111] Example 1: 4-[3-(2-Fluoro-benzyl)-phenyl]-2-hydroxy-4-oxo-but-2-enoic acid (Compound 2-1)

[0112] Step 1: Preparation of 4-[3-(2-fluoro-benzyl)-phenyl]-2-hydroxy-4-oxo-but-2-enoic acid methyl ester (Compound 1-1)

[0113]

[0114] Under the protection of nitrogen, add sodium methoxide (2.91g, 53.95mmol) and 45mL of anhydrous toluene to a dry reaction flask, cool to 0°C, add dimethyl oxalate (3.18g, 26.97mmol) and 1-[3- (2-Fluoro-benzyl)-phenyl]ethanone (2.461g, 10.79mmol) in ethylene glycol dimethyl ether solution 45mL was slowly added dropwise to the above system, stirred at 0℃ for 0.5 hours, and gradually heated to 60℃ After stirring overnight, the above system was quenched with 1N HCl solution, the aqueous phase was extracted with ethyl acetate, the organic phases were combined, washed with saturated brine, and anhydrous Na 2 SO 4 dry. It was concentrated to obtain 2.066 g of yellow oily compound 1-1, which was directly used in the next reaction.

[0115] Mp: 58-59°C. 1 ...

Embodiment 2

[0120] Example 2: Preparation of 4-[3-benzyloxyphenyl]-2-hydroxy-4-oxo-but-2-enoic acid methyl ester (Compound 1-2)

[0121]

[0122] Except that the compound 1-[3-benzyloxy)phenyl]ethanone was used in place of the 1-[3-(2-fluoro-benzyl)-phenyl]ethanone in step 1 of Example 1, the same as in Example 1 The same method as step 1 was used to prepare compound 1-2 (87%) as a pale yellow powder.

[0123] Mp: 70-71℃, 1 H NMR(400MHz, CDCl 3 ): δ15.22(br, 1H), 7.61-7.59(m, 2H), 7.47-7.34(m, 5H), 7.25-7.21(m, 2H), 7.08(s, 1H), 5.14(s, 2H) ), 3.96(s, 3H).EI-MS(M / Z): 312(M + ). Molecular formula C 18 H 16 O 5 Elemental analysis data: calculated value C 69.22, H 5.16, measured value C 69.18, H 5.19.

Embodiment 3

[0124] Example 3: Preparation of 4-[3-benzyloxyphenyl]-2-hydroxy-4-oxo-but-2-enoic acid (compound 2-2)

[0125]

[0126] Except that the compound 4-(3-benzyloxyphenyl)-2-hydroxy-4-oxo-but-2-enoic acid methyl ester was used instead of 4-[3-(2-fluoro-benzyl in step 2 of Example 1 Except for )-phenyl]-2-hydroxy-4-oxo-but-2-enoic acid methyl ester, the same method as in step 2 of Example 1 was used to prepare compound 2-2 (75.4%) as a pale yellow powder.

[0127] 1 H NMR(300MHz, CDCl 3 ): δ7.61-7.59 (m, 2H), 7.47-7.34 (m, 6H), 7.25-7.21 (m, 1H), 7.15 (s, 1H), 5.14 (s, 2H), EI-MS (M / Z): 298(M + ). Molecular formula C 11 H 14 O 5 Elemental analysis data: calculated value C 68.45, H 4.73, measured value C 68.52, H 4.38.

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Abstract

The invention discloses a 1-substituted-2-substituted-4- aryl substituted-butyl-2-alkene 1, 4-diketone compound, or its isomers, pharmacy-acceptable salts, preparation method and applications, and medicine compositions containing the compound. The protein-tyrosine phosphatase 1B inhibition test proves that the compound has good inhibitive activity of PTP1B, and can be used for treating diabetes mellitus, obesity and complications triggered by diabetes mellitus and obesity.

Description

Technical field [0001] The present invention relates to the field of medical technology. Specifically, the present invention relates to a 1-substituted-2-substituted-4-aryl-substituted-but-2-ene 1,4-dione compound or its isomer or its pharmaceutical Acceptable salts, their preparation methods, their use in the preparation of inhibitors of protein tyrosine phosphatase 1B and pharmaceutical compositions containing the compounds. The compound or the pharmaceutical composition containing the compound can be used as a high-efficiency inhibitor of protein tyrosine phosphatase 1B for the treatment of diabetes, obesity and complications caused thereby. Background technique [0002] Diabetes is a group of clinical syndromes caused by the interaction of genetic and environmental factors. It is a metabolic disease characterized by lack of insulin or decreased insulin sensitivity in the body. Therefore, the body cannot control the metabolism of sugar, protein and fat, causing a series of me...

Claims

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Application Information

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IPC IPC(8): C07C69/738C07C59/90C07C205/56C07C233/63C07C229/44C07C233/54C07D209/18C07D209/08C07D209/22C07C235/78C07D295/192C07D209/16C07C237/20C07D209/20C07D471/08C07C27/02C07C67/343C07C201/12C07C231/12C07C227/18A61K31/216A61K31/192A61K31/196A61K31/404A61K31/165A61K31/495A61K31/4045A61K31/496A61K31/405A61K31/4353A61P3/10A61P3/04
Inventor 龙亚秋曾立凡薛婷
Owner SHANGHAI INST OF MATERIA MEDICA CHINESE ACAD OF SCI
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