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Liver-targeted glycogen phosphorylase inhibitor cholic acid derivative and preparation method and medical application thereof

A compound and pharmaceutical technology, applied in the field of glycogen phosphorylase inhibitor bile acid derivatives, can solve the problems of muscle tissue myotoxicity, lack of liver glycogen phosphorylase selectivity, clinical application limitations 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

However, due to the high homology of the three isoenzymes of the enzyme, the target inhibitors generally lack selectivity to liver glycogen phosphorylase, resulting in myotoxic effects on muscle tissue, and the clinical application is limited.

Method used

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  • Liver-targeted glycogen phosphorylase inhibitor cholic acid derivative and preparation method and medical application thereof
  • Liver-targeted glycogen phosphorylase inhibitor cholic acid derivative and preparation method and medical application thereof
  • Liver-targeted glycogen phosphorylase inhibitor cholic acid derivative and preparation method and medical application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0049] (S)-2-tert-butoxycarbonylamino-3-(4-fluorophenyl)-1-(4-hydroxypiperidin-1-yl)acetone

[0050] 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 1 / 1, V / V) gave a white solid (19.7 g, 98%).

[0051] ESI-MS m / z: 367.2[M+H] + .

[0052] 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

[0074] (S)-N-tert-butoxycarbonylalanine-{1-[2-(5-chloro-1H-pyrrolo[2,3-c]pyridine-2-carboxamide)-3-(4-fluoro Phenyl)propionyl]-piperidin-4-yl}ester

[0075] Boc-L-alanine (127mg, 0.67mmol), catalytic amount of DMAP (16mg, 0.13mmol) were dissolved in dichloromethane (10mL), DCC (167mg, 0.81mmol) was added under ice-cooling, and Stir for 45 minutes, then add (S)-1-[2-(5-chloro-1H-pyrrolo[2,3-c]pyridine-2-carboxamide)-3-(4-fluorophenyl)propionyl ]-4-hydroxypiperidine (250mg, 0.56mmol), stirred overnight at room temperature. The reaction mixture was filtered, the filtrate was evaporated to remove the solvent, the residue was dissolved in ethyl acetate, placed in the refrigerator overnight, filtered, the filtrate was evaporated to remove the solvent, and flash column chromatography (petroleum ether / ethyl acetate 2 / 1, V / V) gave a white Solid (160 mg, 46%).

[0076] ESI-MS m / z: 615.9[M+H] + .

[0077] 1 H NMR (CDCl 3 , 400MHz): 9.65(br, 1H), 8.69(s, 1H), 7.60(s, 1H), 7.45(brs,...

Embodiment 3

[0087] N-tert-butoxycarbonyl-O-tert-butyldimethylsilyl-L-serine

[0088] Dissolve N-tert-butoxycarbonyl-L-serine (0.19g, 0.63mmol) in DMF (5ml), slowly add imidazole (0.17g, 2.52mmol), tert-butyldimethylsilyl chloride (0.19g, 1.26 mmol), stirred at room temperature overnight, the reaction solution was poured into ice water (20ml), and extracted with ethyl acetate (30ml×3). Then it was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated to obtain N-tert-butoxycarbonyl-O-tert-butyldimethylsilyl-L-serine. This crude product was directly used in the next reaction without further purification.

[0089](S)-N-tert-butoxycarbonyl-O-tert-butyldimethylsilylserine-{1-[2-(5-chloro-1H-pyrrolo[2,3-c]pyridine-2-methyl Amide)-3-(4-fluorophenyl)propionyl]-piperidin-4-yl}ester

[0090] Prepare (S)-N-tert-butoxycarbonylalanine-{1-[2-(5-chloro-1H-pyrrolo[2,3-c]pyridine-2-carboxamide)-3-(4 -Fluorophenyl)propionyl]-piperidin-4-...

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Abstract

The invention relates to a glycogen phosphorylase inhibitor cholic acid derivative, 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 present invention relates to a kind of bile acid derivatives which are inhibitors of glycogen phosphorylase, and also relates to their preparation method and the medicine combination containing them. 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] The significant increase of hepatic glucose production in diabetic patients is an important cause of hyperglycemia...

Claims

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Application Information

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IPC IPC(8): C07J43/00A61K31/58A61P9/12A61P3/10A61P3/06A61P3/04A61P9/10A61P3/00A61P35/00A61P13/12A61P25/00A61P17/02
Inventor 张丽颖
Owner CHENGDE MEDICAL UNIV
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