Alpha position heteroatom substituted gamma aryl ketobutyric acid derivative, process, pharmaceutical combination and uses thereof

A compound and heterocyclic group technology, applied in the field of butanone acid derivatives, can solve the problems of skeletal muscle and joint damage, no obvious anti-tumor or anti-inflammatory effect, no significant curative effect, etc.

Inactive Publication Date: 2005-01-19
INST OF MATERIA MEDICA AN INST OF THE CHINESE ACAD OF MEDICAL SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Clinical trials have found that many antineoplastic or anti-inflammatory drugs currently used as MMPs inhibitors have no significant curative effect compared with placebo in the test, and there is no obvious anti-tumor or anti-inflammatory effect when used alone, and they generally have adverse effects on skeletal muscle and Joint damage, mainly manifested as muscle soreness and joint stiffness

Method used

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  • Alpha position heteroatom substituted gamma aryl ketobutyric acid derivative, process, pharmaceutical combination and uses thereof
  • Alpha position heteroatom substituted gamma aryl ketobutyric acid derivative, process, pharmaceutical combination and uses thereof
  • Alpha position heteroatom substituted gamma aryl ketobutyric acid derivative, process, pharmaceutical combination and uses thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0171] 2-(2-Hydroxyethylamino)-4-oxo-4-(4'-biphenyl)-butyric acid (A): Preparation of 3-(4-phenylbenzoyl)acrylic acid:

[0172] Dissolve 23.13 grams of biphenyl and 14.71 grams of maleic anhydride in 300 milliliters of dichloromethane, add 40.00 grams of anhydrous aluminum trichloride in four batches under cooling in an ice-water bath, slowly rise to room temperature, continue to react for 5 hours, and concentrate To dryness, add a mixture of crushed ice and concentrated hydrochloric acid to the obtained viscous liquid, carry out hydrolysis, filter the obtained yellow solid, wash with water until neutral, then wash several times with petroleum ether, after draining, recrystallize with glacial acetic acid to obtain 37.26 gram of yellow crystals, yield: 93.19%, melting point: 168-170°C (literature value: 172-175°C).

[0173] (B): Preparation of 2-(2-hydroxyethylamino)-4-oxo-4-(4'-biphenyl)-butyric acid:

[0174] Suspend 5.045 grams of 3-(4-phenylbenzoyl)acrylic acid in 100 mill...

Embodiment 2

[0177] 2-Benzylamino-4-oxo-4-(4’-biphenyl)-butanoic acid

[0178] The method is the same as in Example 1 (B), except that 5.434 grams of 3-(4-phenylbenzoyl) acrylic acid, 2.308 grams of benzylamine, and 100 milliliters of ether are used as solvent to obtain 6.877 grams of white powdery solid, yield: 88.83%, melting point: 177-179°C (decomposition).

[0179] 1 HNMR (300MHz, DMSO): δ (ppm) = 3.361 (dd, 1H, J: 7.5Hz, 17.1Hz), 3.456 (dd, 1H, J: 5.4Hz, 17.1Hz), 3.654 (t, 1H, J: 5.4Hz, 6.9Hz), 3.87 (d, 1H, J: 13.5Hz), 3.968 (d, 1H, J: 13.2Hz), 7.159-8.055 (m, 14H).

Embodiment 3

[0181] 2-n-Butylamino-4-oxo-4-(4’-biphenyl)-butanoic acid

[0182] The method is the same as in Example 1 (B), except that 1.261 grams of 3-(4-phenylbenzoyl) acrylic acid is used, 0.366 grams of n-butylamine, and 25 milliliters of ether are used as solvents to obtain 1.502 grams of white powdery solids, yield : 92.32%, melting point: 172.6-174.0°C (decomposition).

[0183] 1 HNMR (300MHz, DMSO): δ (ppm) = 0.867 (t, 3H, J: 7.5Hz), 1.303 (q, 2H, J: 7.5Hz), 1.541 (m, 2H), 2.742 (t, 1H, J : 7.5Hz), 2.883(dd, 1H, J: 7.2Hz, 13.2Hz), 3.552(m, 2H), 3.679(m, 1H), 7.486(m, 3H, J: 7.5Hz), 7.745(d, 2H, J: 7.5), 7.836 (d, 2H, J: 8.4Hz), 8.039 (d, 2H, J: 8.4Hz).

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Abstract

The invention relates to a gamma methyl ethyl ketone acid derivative represented by general formula (I), and contains gamma-aryl-alpha-amido-beta, its preparing process, pharmaceutical compositions containing them and use as medicament, in particular as medicament for treating osteoarthritis and tumor.

Description

technical field [0001] The present invention relates to butyronic acid derivatives, their preparation method, their pharmaceutical composition, and their use as medicine, especially as medicine for treating osteoarthritis and tumor. Background technique [0002] Matrix metalloproteinases (Matrix Metalloproteinases, MMPs) is a general term for a class of endopeptidases whose active sites contain zinc ions, and exist on the extracellular matrix and membrane surface. It is mainly secreted by fibroblasts, neutrophils, macrophages and tumor cells in the form of inactive zymogen, and activated by corresponding enzymes in the extracellular matrix (Extra Cellular Matrix, ECM). MMPs can hydrolyze different protein substrates, such as: collagen, gelatin, proteoglycan, fibroblast, elastin, etc. It is regulated in three ways in vivo: mediated by cytokines and growth factors; activation of zymogens; participation of endogenous inhibitors (TIMPs, Tissue Inhibitors of Matrix Metalloprotei...

Claims

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Application Information

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IPC IPC(8): A61K31/18A61K31/19C07C59/84C07C229/36C07C259/06C07C323/56C07D207/404C07D211/34C07D295/145
Inventor 杨光中葛轶昱杜冠华贾红任德成杨秀颖
Owner INST OF MATERIA MEDICA AN INST OF THE CHINESE ACAD OF MEDICAL SCI
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