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Glycogen phosphorylase inhibitor cholic acid derivative containing bio-cleavable dipeptide and preparation method and medical application thereof

A use and pharmaceutical technology, applied in the field of glycogen phosphorylase inhibitor bile acid derivatives, can solve the problems of high homology, muscle tissue myotoxicity, lack of liver glycogen phosphorylase selectivity and the like

Active Publication Date: 2014-03-12
CHENGDE MEDICAL UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Due to the high homology of the three isoenzymes of this enzyme, currently reported inhibitors of this target generally lack selectivity to liver glycogen phosphorylase, resulting in myotoxic reactions to muscle tissue, and the clinical application is limited

Method used

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  • Glycogen phosphorylase inhibitor cholic acid derivative containing bio-cleavable dipeptide and preparation method and medical application thereof
  • Glycogen phosphorylase inhibitor cholic acid derivative containing bio-cleavable dipeptide and preparation method and medical application thereof
  • Glycogen phosphorylase inhibitor cholic acid derivative containing bio-cleavable dipeptide and preparation method and medical application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0044] (S)-2-tert-butoxycarbonylamino-3-(4-fluorophenyl)-1-(4-hydroxypiperidin-1-yl)acetone

[0045] Dissolve BOC-4-fluoro-L-phenylalanine (15.6g, 55.1mmol) in anhydrous dichloromethane (160mL), add HATU (25g, 66.1mmol) and DIPEA (8.54g, 66.1 mmol), stirred at room temperature for 10 minutes, then added 4-hydroxypiperidine (6.7 g, 66.1 mmol), stirred at room temperature overnight. The reaction solution was washed with saturated brine, anhydrous Na 2 SO 4 It was dried, filtered and concentrated, and the residue was separated by reverse phase HPLC to give a white solid (50mg, 29.8%). Flash column chromatography (petroleum ether / ethyl acetate l / l, V / V) gave a white solid (19.7 g, 98%).

[0046] ESI-MS m / z: 367.2[M+H] + .

[0047] 1 H NMR (CDCl 3 , 400MHz): 7.14-7.18(m, 2H), 6.95-7.00(m, 2H), 5.47(dd, J=8.8, 14.8Hz, 1H), 4.83(dd, J=6.0, 13.6Hz, 1H), 3.81-4.01(m, 2H), 3.46-3.62(m, 1H), 3.15-3.33(m, 1H), 2.89-3.00(m, 2H), 1.73-1.83(m, 2H), 1.42-1.52(m , 2H), 1.40(s, 9H).

...

Embodiment 2

[0075] (S)-2-[(S)-2-tert-butoxycarbonylamino-3-phenylpropanylamino]-6-(benzyloxyamido)hexanoic acid methyl ester

[0076] In a similar manner to the preparation of (S)-2-(2-tert-butoxycarbonylamino-3-methyl-n-butyramide)propionic acid methyl ester, lysine methyl ester hydrochloride (2.49 g, 7.6 mmlo) Reaction with N-tert-butoxycarbonyl-L-phenylalanine (2 g, 7.6 mmol) gave a white solid (3 g, 73%).

[0077] ESI-MS m / z: 542.3[M+H] + .

[0078] 1 H-NMR (CDCl 3 , 400MHz): 7.38(d, J=4.4Hz, 4H), 7.29-7.35(m, 5H), 7.20-7.27(m, 3H), 6.49(d, J=7.2Hz, 1H), 5.11(dd, J=12.4, 16.4Hz, 2H), 4.54-4.59(m, 1H), 4.35-4.40(m, 1H), 3.72(s, 3H), 3.16(dd, J=6.0, 12.0Hz, 2H), 3.07 (t, J=6.0Hz, 2H), 1.77-1.88(m, 1H), 1.64-1.71(m, 1H), 1.49-1.56(m, 2H), 1.40(s, 9H), 1.27-1.36(m , 2H).

[0079] (S)-2-[(S)-2-tert-butoxycarbonylamino-3-phenylpropanylamino]-6-(benzyloxyamido)hexanoic acid

[0080] According to the similar method of preparing (S)-2-(2-tert-butoxycarbonylamino-3-methyl n-butyramide) ...

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Abstract

The invention relates to a glycogen phosphorylase inhibitor cholic acid derivative containing bio-cleavable dipeptide, a preparation method thereof and a pharmaceutical composition containing the same. The glycogen phosphorylase inhibitor cholic acid derivative is a liver-targeted pro-drug for glycogen phosphorylase; compared with a glycogen phosphorylase inhibitor, the concentration of the glycogen phosphorylase inhibitor in a liver can be increased after the glycogen phosphorylase inhibitor cholic acid derivative is taken orally, so that the glycogen phosphorylase inhibitor cholic acid derivative can serve as a preferred drug for lowering blood sugar, particularly for treating impaired fasting glucose. The compound can be used for preventing and treating diabetes and complications thereof, hyperlipidemia, obesity, high-glucagon disease, insulin resistance, impaired fasting glucose, hypertension and complications thereof, atherosclerosis, metabolic syndrome or tumor.

Description

technical field [0001] The invention relates to a kind of glycogen phosphorylase inhibitor cholic acid derivatives containing biocleavable dipeptides, their preparation method and their drug combination. Glycogen phosphorylase inhibitors Bile acid derivatives are liver-targeting prodrugs of glycogen phosphorylase, and compared with glycogen phosphorylase inhibitors, oral administration of glycogen phosphorylase inhibitors can increase The concentration can be used as the preferred drug for lowering blood sugar, especially for the treatment of fasting hyperglycemia. Such compounds can be used to prevent and treat diabetes and its complications, hyperlipidemia, obesity, hyperglucagonism, insulin resistance, fasting hyperglycemia, hypertension and its complications, atherosclerosis, metabolic Syndrome or tumor. Background technique [0002] Type 2 diabetes is a group of metabolic syndromes characterized by fasting and postprandial hyperglycemia caused by genetic defects and a...

Claims

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Application Information

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IPC IPC(8): C07K5/06A61K38/05A61P3/10A61P3/06A61P3/04A61P9/12A61P9/10A61P35/00
Inventor 张丽颖
Owner CHENGDE MEDICAL UNIV
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