Glycosidase inhibitors and uses thereof

Patent metadata

Field	Value
Publication number	US-9522883-B2
Application number	US-201314424602-A
Country	US
Kind code	B2
Filing date	Aug 29, 2013
Priority date	Aug 31, 2012
Publication date	Dec 20, 2016
Grant date	Dec 20, 2016

Abstract

The invention provides compounds of Formula (I) for inhibiting gh cosidases, prodrugs of the compounds, and pharmaceutical compositions comprising the compounds or prodrugs of the compounds. The invention also provides method of treating diseases and disorders related to deficiency or over-expression of O-gh coprotein 2-acetamido-2-deoxy-β-D-glucopyranosidase (O-GlcNAcase), accumulation or deficiency of 2-acetamido-2-deoxy-β-D-glucopyranoside (O-GlcNAc).

First claim

What is claimed is:

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

wherein
R 1 is H;
R 2 is C 1-6 acyl;
R 3 is H and R 4 is OH, or R 3 is H and R 4 is H, or R 3 is H and R 4 is F, or R 3 is F and R 4 is H, or R 3 is F and R 4 is F, or R 3 is OH and R 4 is H;
R 5 is H and R 6 is OH, or R 5 is H and R 6 is H, or R 5 is H and R 6 is F, or R 5 is F and R 6 is H, or R 5 is F and R 6 is F, or R 5 is OH and R 6 is H;
R 7 is selected from the group consisting of: CH 3 , CH 2 F, CHF 2 , and CH 2 OH; and
R 8 is selected from the group consisting of: C 2-10 alkenyl, C 2-10 alkynyl, C 8-20 arylalkyl, C 8-20 arylalkenyl, C 8-20 arylalkynyl, each excluding H optionally substituted from one to four substituents with one of more of halo, OH, OCF 3 , CN, SO 2 NH 2 , SO 2 Me, C(O)NH 2 , CH 2 F, CHF 2 , CF 3 , CH 2 CH 2 F, CH 2 CF 3 , CH 2 CH 2 CH 2 F, C 1-6 alkyl, C 1-6 alkoxy, or C 3-7 cycloalkyl.

2. The compound of claim 1 wherein the compound is selected from the following group:
N-((3S,4R,5R,6R)-4,5-dihydroxy-6-(hydroxymethyl)-1-(4-phenylbutyl)piperidin-3-yl)acetamide;
N-((3S,4R,5R,6R)-4,5-dihydroxy-6-(hydroxymethyl)-1-phenethylpiperidin-3-yl)propionamide;
N-((3S,4R,5R,6S)-6-(fluoromethyl)-4,5-dihydroxy-1-phenethylpiperidin-3-yl)propionamide;
N-((3S,4R,5R,6R)-4-fluoro-5-hydroxy-6-(hydroxymethyl)-1-phenethylpiperidin-3-yl)propionamide;
N-((3S,4R,5R,6S)-6-(difluoromethyl)-4,5-dihydroxy-1-phenethylpiperidin-3-yl)propionamide;
N-((3S,4R,5R,6R)-4,5-dihydroxy-6-(hydroxymethyl)-1-(3-phenylpropyl)piperidin-3-yl)propionamide;
N-((3S,4R,5R,6R)-4-fluoro-5-hydroxy-6-(hydroxymethyl)-1-(3-phenylpropyl)piperidin-3-yl)propionamide;
N-((3S,4R,5R,6R)-5-fluoro-4-hydroxy-6-(hydroxymethyl)-1-(3-phenylpropyl)piperidin-3-yl)propionamide;
N-((3S,4R,5R,6S)-6-(fluoromethyl)-4,5-dihydroxy-1-(3-phenylpropyl)piperidin-3-yl)propionamide;
N-((3S,4S,5R,6R)-4-fluoro-5-hydroxy-6-(hydroxymethyl)-1-(3-phenylpropyl)piperidin-3-yl)propionamide;
N-((3S,4R,5S,6R)-5-fluoro-4-hydroxy-6-(hydroxymethyl)-1-(3-phenylpropyl)piperidin-3-yl)propionamide;
N-((3S,4R,5R,6S)-6-(difluoromethyl)-4,5-dihydroxy-1-(3-phenylpropyl)piperidin-3-yl)propionamide;
N-((3S,4R,5R,6S)-6-(difluoromethyl)-4-fluoro-5-hydroxy-1-(3-phenylpropyl)piperidin-3-yl)propionamide;
N-((3S,4S,5R,6S)-6-(difluoromethyl)-4-fluoro-5-hydroxy-1-(3-phenylpropyl)piperidin-3-yl)propionamide;
N-((3R,5S,6R)-5-hydroxy-6-(hydroxymethyl)-1-(3-phenylpropyl)piperidin-3-yl)propionamide;
N-((3S,4S,6S)-4-hydroxy-6-(hydroxymethyl)-1-(3-phenylpropyl)piperidin-3-yl)propionamide;
N-((3S,4R,5R,6R)-4,5-dihydroxy-6-methyl-1-(3-phenylpropyl)piperidin-3-yl)propionamide;
N-((3S,4R,5R)-4,5-dihydroxy-1-(3-phenylpropyl)piperidin-3-yl)propionamide;
N-((3S,4R,5R)-4-fluoro-5-hydroxy-1-(3-phenylpropyl)piperidin-3-yl)propionamide;
N-((3S,4R,5R,6R)-1-(3-(6-fluoropyridin-3-yl)propyl)-4,5-dihydroxy-6-(hydroxymethyl)piperidin-3-yl)propionamide;
N-((3S,4R,5R,6R)-4,5-dihydroxy-6-(hydroxymethyl)-1-(3-(5-(trifluoromethoxy)benzo[d]thiazol-2-yl)propyl)piperidin-3-yl)propionamide;
N-((3S,4R,5R,6R)-4,5-dihydroxy-6-(hydroxymethyl)-1-((Z)-5,5,5-trifluoropent-3-en-1-yl)piperidin-3-yl)propionamide;
N-((3S,4R,5R,6R)-4,5-dihydroxy-6-(hydroxymethyl)-1-(pent-4-yn-1-yl)piperidin-3-yl)propionamide;
N-((3S,4R,5R,6R)-1-cinnamyl-4,5-dihydroxy-6-(hydroxymethyl)piperidin-3-yl)propionamide;
N-((3S,4R,5R,6R)-4,5-dihydroxy-6-(hydroxymethyl)-1-(3-phenylprop-2-yn-1-yl)piperidin-3-yl)propionamide;
N-((3S,4R,5R,6R)-1-((E)-3-(6-fluoropyridin-3-yl)allyl)-4,5-dihydroxy-6-(hydroxymethyl)piperidin-3-yl)propionamide;
N-((3S,4R,5R,6R)-1-(3-(6-fluoropyridin-3-yl)prop-2-yn-1-yl)-4,5-dihydroxy-6-(hydroxymethyl)piperidin-3-yl)propionamide;
or a pharmaceutically acceptable salt of any of the foregoing compounds.

3. The compound of claim 1 wherein the compound selectively inhibits an O-glycoprotein 2-acetamido-2-deoxy-β-D-glucopyranosidase (O-GlcNAcase).

4. The compound of claim 1 wherein the compound selectively binds an O-GlcNAcase.

5. The compound of claim 1 wherein the compound selectively inhibits the cleavage of 2-acetamido-2-deoxy-β-D-glucopyranoside (O-GlcNAc).

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

7. The compound of claim 1 wherein the compound does not substantially inhibit a mammalian β-hexosaminidase.

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

9. A compound selected from the following group:
N-((3S,4R,5R)-1-hexyl-4,5-dihydroxypiperidin-3-yl)acetamide;
N-((3S,4R,5R,6R)-4,5-dihydroxy-6-(hydroxymethyl)-1-(3-phenylpropanoyl)piperidin-3-yl)propionamide;
N-((3S,4R,5R,6R)-4,5-dihydroxy-6-(hydroxymethyl)-1-(4,4,4-trifluorobutyl)piperidin-3-yl)propionamide;
N-((3S,4R,5R,6R)-1-butyryl-4,5-dihydroxy-6-(hydroxymethyl)piperidin-3-yl)propionamide;
N-((3S,4R,5R,6R)-1-(3-(6-fluoropyridin-3-yl)propanoyl)-4,5-dihydroxy-6-(hydroxymethyl)piperidin-3-yl)propionamide;
or a pharmaceutically acceptable salt of any of the foregoing compounds.

Assignees

• Alectos Therapeutics Inc
• Merck Sharp & Dohme

Inventors

• Mceachern Ernest J
• Vocadlo David J
• Zhou Yuanxi
• Selnick Harold G

Classifications

• C07D211/56 Primary

  Nitrogen atoms (nitro radicals C07D211/38) · CPC title

• C07D401/06

  linked by a carbon chain containing only aliphatic carbon atoms · CPC title

• C07D417/06

  linked by a carbon chain containing only aliphatic carbon atoms · CPC title

• A61P25/28

  for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia · CPC title

• A61K31/4523

  containing further heterocyclic ring systems · CPC title