Selective glycosidase inhibitors and uses thereof

Patent metadata

Field	Value
Publication number	US-9701693-B2
Application number	US-201214129169-A
Country	US
Kind code	B2
Filing date	Jun 27, 2012
Priority date	Jun 27, 2011
Publication date	Jul 11, 2017
Grant date	Jul 11, 2017

Abstract

The invention provides compounds 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.

First claim

What is claimed is:

1. A compound of Formula (I) or a pharmaceutically acceptable salt thereof:

wherein
R 2 and R 4 are OH and R 1 and R 3 are H
R 5 is H and
each R 6 is independently C 1-3 alkyl.

2. The compound of claim 1 wherein:
R 1 and R 3 are H;
R 2 and R 4 are OH; and
each R 6 is independently selected from the group consisting of: CH 3 , CH 2 CH 3 , and (CH 2 ) 2 CH 3 .

3. The compound of claim 1 wherein the compound is selected from the following group:
(3aR,5R,6S,7S,7aR)-2-(ethylamino)-5-(hydroxymethyl)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazole-6,7-diol;
(3aR,5R,6S,7S,7aR)-5-(hydroxymethyl)-2-(methylamino)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazole-6,7-diol;
(3aR,5R,6S,7S,7aR)-5-(hydroxymethyl)-2-(propylamino)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazole-6,7-diol;
(3aR,5R,6S,7S,7aR)-2-(dimethylamino)-5-(hydroxymethyl)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazole-6,7-diol
or a pharmaceutically acceptable salt of any of the foregoing compounds.

4. The compound of claim 1 wherein the compound selectively inhibits an O-glycoprotein 2-acetamido-2-deoxy-β-D-glucopyranosidase (O-GlcNAcase), selectively binds an O-GlcNAcase, selectively inhibits the cleavage of 2-acetamido-2-deoxy-β-D-glucopyranoside (O-GlcNAc), or does not substantially inhibit a mammalian β-hexosaminidase.

5. The compound of claim 4 wherein the O-GlcNAcase is a mammalian O-GlcNAcase.

6. A pharmaceutical composition comprising the compound of claim 3 , or a pharmaceutically acceptable salt thereof, in combination with a pharmaceutically acceptable carrier.

7. A pharmaceutical composition comprising the compound of claim 1 , or a pharmaceutically acceptable salt thereof, in combination with a pharmaceutically acceptable carrier.

Assignees

• Li Tong-Shuang
• Mceachern Ernest J
• Vocadlo David J
• Zhou Yuanxi
• Zhu Yongbao
• Selnick Harold G
• Alectos Therapeutics Inc
• Merck Sharp & Dohme

Inventors

• Li Tong-Shuang
• Mceachern Ernest J
• Vocadlo David J
• Zhou Yuanxi
• Zhu Yongbao
• Selnick Harold G

Classifications

• G01N2500/04

  Screening involving studying the effect of compounds C directly on molecule A (e.g. C are potential ligands for a receptor A, or potential substrates for an enzyme A) · CPC title

• C07H9/06

  the hetero ring containing nitrogen as ring hetero atoms · CPC title

• C12Q1/34

  involving hydrolase · CPC title

• G01N2333/924

  acting on glycosyl compounds (3.2) · CPC title

• C12Q1/37

  involving peptidase or proteinase · CPC title