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Selective glycosidase inhibitors and uses thereof

An optional, compound technology, applied in the field of compounds that selectively inhibit glycosidase, can solve the problems of lack of selectivity, interference with multiple cellular processes, unfavorable use, etc.

Inactive Publication Date: 2009-12-02
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

[0194] 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)

[0195]

[0196] 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...

Embodiment 2

[0200] Compounds 3 and 4: diacetic acid (3aR, 5R, 6S, 7R, 7aR)-5-(acetoxymethyl)-2-(difluoromethane base)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazole-6,7-diyl ester (3) and (3aR, 5R, 6S, 7R, 7aR)-2-(difluoromethyl)-5-(hydroxymethyl)-5,6,7,7a-tetrahydro-3aH-pyran And[3,2-d]thiazole-6,7-diol (4)

[0201]

[0202]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 ...

Embodiment 3

[0206] Compounds 5 and 6: diacetic acid (3aR, 5R, 6S, 7R, 7aR)-5-(acetoxymethyl)-2-(trifluoromethane base)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazole-6,7-diyl ester (5) and (3aR, 5R, 6S, 7R, 7aR)-5-(hydroxymethyl)-2-(trifluoromethyl)-5,6,7,7a-tetrahydro-3aH-pyran And[3,2-d]thiazole-6,7-diol (6)

[0207]

[0208] 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...

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Abstract

The invention 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] Cross References to Related Applications [0002] 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 [0003] The present application relates to compounds selectively inhibiting glycosidases and uses thereof. Background technique [0004] 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 responsible for the post-translational linking of β-N-acetylglucosamine (GlcNAc) to specific serine and threonine residues of various nucleoplasmic proteins is O-GlcNAc transferase (OGTase) 2-5 . Another enzyme called O-GlcNAc 6，7 The enzyme removes ...

Claims

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Application Information

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IPC IPC(8): C07D513/04C07D513/14A61K31/429C12Q1/34
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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