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Selective glycosidase inhibitors and uses thereof

A name, hydroxymethyl technology, applied in the field of compounds that selectively inhibit glycosidase, can solve the problems of interfering with multiple cellular processes, unfavorable use, lack of selectivity, etc.

Inactive Publication Date: 2017-10-17
SIMON FRASER UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Despite their potency, NAG-thiazolines have disadvantages in their use in complex biological settings due to their lack of selectivity, interfering with multiple cellular processes

Method used

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  • Selective glycosidase inhibitors and uses thereof
  • Selective glycosidase inhibitors and uses thereof
  • Selective glycosidase inhibitors and uses thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0195] Compounds 1 and 2: diacetic acid (3aR, 5R, 6S, 7R, 7aR)-5-(acetoxymethyl)-2-(fluoromethyl)-5,6, 7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazole-6,7-diyl ester (1) and (3aR,5R,6S,7R,7aR)-2-(fluoromethyl )- 5-(Hydroxymethyl)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazole-6,7-diol (2)

[0196]

[0197] Add triethylamine (0.8 mL) and anhydrous pyridine (20 mL) to 2-amino-2-deoxy-1,3,4,6 tetra-O-acetyl-β-D-glucopyranose hydrochloride (1 g ) in a cold (0 °C) solution in DMF (100 mL). Sodium fluoroacetate (1.8 g) was added to a stirred solution containing dry Dowex 50-H + Resin (12g) in anhydrous DMF (90mL) mixture. After 1 hour, DCC (3.2 g) and 30 mL of fluoroacetic acid solution were added via cannula to the reaction vessel containing the hydrochloride salt. The resulting solution was allowed to stand at 0°C for 16 hours, after which time the reaction was judged complete by TLC analysis. Part of the solvent was removed in vacuo, EtOAc (300 mL) and saturated sodium chlo...

Embodiment 2

[0201] Compounds 3 and 4: diacetic acid (3aR, 5R, 6S, 7R, 7aR)-5-(acetoxymethyl)-2-(difluoromethyl)-5, 6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazole-6,7-diyl ester (3) and (3aR,5R,6S,7R,7aR)-2-(di Fluoromethamine base)-5-(hydroxymethyl)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazole-6,7-diol (4)

[0202]

[0203] Add triethylamine (0.8 mL) and anhydrous pyridine (20 mL) to 2-amino-2-deoxy-1,3,4,6 tetra-O-acetyl-β-D-glucopyranose hydrochloride (1 g ) in a cold (0 °C) solution in DMF (100 mL). Dicyclohexylcarbodiimide (DCC, 3 g) and difluoroacetic acid (1.2 mL) were added to the reaction mixture via syringe. The resulting solution was allowed to stand at 0° C. for 16 hours, after which 0.5 mL of difluoroacetic acid was added. After standing at room temperature for another 3.5 hours, the reaction was judged to be complete by TLC analysis. Part of the solvent was removed in vacuo, EtOAc (300 mL) and saturated sodium chloride solution (100 mL) were added. The organic laye...

Embodiment 3

[0207] Compounds 5 and 6: diacetic acid (3aR, 5R, 6S, 7R, 7aR)-5-(acetoxymethyl)-2-(trifluoromethyl)-5, 6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazole-6,7-diyl ester (5) and (3aR,5R,6S,7R,7aR)-5-(hydroxy First base)-2-(trifluoromethyl)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazole-6,7-di-ol (6)

[0208]

[0209] Add triethylamine (0.8 mL) to 2-amino-2-deoxy-1,3,4,6-tetra-O-acetyl-β-D-pyridine dissolved in anhydrous dichloromethane (20 mL) In a cold (0°C) solution of glucopyranose hydrochloride (1g). Trifluoroacetic anhydride (0.6 mL) was added via syringe and the resulting solution was allowed to stand at 0°C for 16 hours after which time the reaction was judged complete by TLC analysis. The solution was diluted in 50mL EtOAc and washed successively with water, saturated NaHCO 3 aqueous solution (2x) and finally brine solution. with MgSO 4 The organic extracts were dried and filtered, and the solvent was removed in vacuo to give a colorless syrup. The desired produc...

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Abstract

The invention relates to s elective glycosidase inhibitors and uses thereof and provides compounds of formula (I) for selectively inhibiting glycosidases, prodrugs of the compounds, and pharmaceutical compositions including the compounds or prodrugs of the compounds. The invention also provides methods of treating diseases and disorders related to deficiency or overexpression of O-GlcNAcase, accumulation or deficiency of O-GlcNAc.

Description

[0001] This application is a divisional application of a Chinese patent application with an application date of August 31, 2007, an application number of 200780040905.X, and an invention title of "Selective Glycosidase Inhibitor and Its Use". [0002] Cross References to Related Applications [0003] This application claims the benefit of US Provisional Applications 60 / 841,196, filed August 31, 2006, and 60 / 895,663, filed March 19, 2007, both of which are hereby incorporated by reference. technical field [0004] The present application relates to compounds selectively inhibiting glycosidases and uses thereof. Background technique [0005] Many cellular proteins (nuclear and cytoplasmic) are synthesized by the addition of the monosaccharide 2-acetamido-2-deoxy-β-D-glucopyranoside (β-N-acetylglucosamine) linked via O-glycosidic bonds. post-translationally modified 1 . This modification is commonly referred to as O-linked N-acetylglucosamine or O-GlcNAc. The enzyme respons...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07H9/06A61K31/7056A61P25/28A61P35/00A61P3/10A61P3/00
CPCC07H9/06
Inventor 大卫·沃恰德洛埃内斯特·麦凯歇恩格瑞特·惠特沃马修·麦考利朱利安·海诺宁基思·斯图布斯李同双
Owner SIMON FRASER UNIVERSITY
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