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Glycogen phosphorylase inhibitor bile acid derivatives containing biocleavable dipeptide, its preparation method and medical application

A pharmacy and compound technology, which is applied in the field of glycogen phosphorylase inhibitor bile acid derivatives, can solve the problems of high homology, lack of liver glycogen phosphorylase selectivity, and clinical application limitations.

Active Publication Date: 2016-11-23
CHENGDE MEDICAL UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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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 bile acid derivatives containing biocleavable dipeptide, its preparation method and medical application
  • Glycogen phosphorylase inhibitor bile acid derivatives containing biocleavable dipeptide, its preparation method and medical application
  • Glycogen phosphorylase inhibitor bile acid derivatives containing biocleavable dipeptide, its preparation method and medical application

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 kind of glycogen phosphorylase inhibitor cholic acid derivatives containing biocleavable dipeptides, their preparation method and their drug combination. The derivatives are liver-targeting prodrugs of glycogen phosphorylase, and the biocleavable dipeptide can be cleaved by enzymes in vivo to release glycogen phosphorylase inhibitors. 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.

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