Glycosidase inhibitors and uses thereof

Patent metadata

Field	Value
Publication number	US-9809537-B2
Application number	US-201314424873-A
Country	US
Kind code	B2
Filing date	Aug 29, 2013
Priority date	Aug 31, 2012
Publication date	Nov 7, 2017
Grant date	Nov 7, 2017

Abstract

The invention provides compounds for 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 1 is selected from the group consisting of: CH 2 NR 8 R 9 , wherein R 8 is H and R 9 is C 1-6 acyl, and (CH 2 ) n C(O)NR 10 2 , wherein n is 1, and one R 10 is H and the other R 10 is C 1-6 alkyl;
R 2 is H and R 3 is OH, or R 2 is H and R 3 is H, or R 2 is H and R 3 is F, or R 2 is F and R 3 is H, or R 2 is F and R 3 is F, or R 2 is OH and R 3 is H;
R 4 is H and R 5 is OH, or R 4 is H and R 5 is H, or R 4 is H and R 5 is F, or R 4 is F and R 5 is H, or R 4 is F and R 5 is F, or R 4 is OH and R 5 is H;
R 6 is selected from the group consisting of: CH 3 , CH 2 F, and CHF 2 ; and
R 7 is selected from the group consisting of: C 1-18 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 7-20 arylalkyl, C 8-20 arylalkenyl, and C 8-20 arylalkynyl, each 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,
with the proviso that the compound excludes N-(((2R,3R,4R,5R)-3,4-dihydroxy-5-methylpyrrolidin-2-yl)methyl)acetamide.

2. The compound of claim 1 wherein the compound is selected from the following group:
N-ethyl-2-((2R,3R,4R,5S)-5-(fluoromethyl)-3,4-dihydroxy-1-phenethylpyrrolidin-2-yl)acetamide;
2-((2R,3R,4R,5S)-5-(difluoromethyl)-3,4-dihydroxy-1-phenethylpyrrolidin-2-yl)-N-ethylacetamide;
2-((2R,3R,4R,5S)-5-(fluoromethyl)-3,4-dihydroxy-1-(3-phenylpropyl)pyrrolidin-2-yl)-N-methylacetamide;
2-((2R,3R,4R,5S)-5-(difluoromethyl)-3,4-dihydroxy-1-(3-phenylpropyl)pyrrolidin-2-yl)-N-methylacetamide;
2-((2R,3R,4R,5R)-3,4-dihydroxy-5-methyl-1-(3-phenylpropyl)pyrrolidin-2-yl)-N-methylacetamide;
2-((2R,3R,4R,5S)-3-fluoro-5-(fluoromethyl)-4-hydroxy-1-(3-phenylpropyl)pyrrolidin-2-yl)-N-methylacetamide;
2-((2R,3S,4R,5S)-5-(difluoromethyl)-3-fluoro-4-hydroxy-1-(3-phenylpropyl)pyrrolidin-2-yl)-N-methylacetamide;
N-(((2R,3R,4R,5S)-5-(fluoromethyl)-3,4-dihydroxy-1-(3-phenylpropyl)pyrrolidin-2-yl)methyl)propionamide;
N-(((2R,3R,4R,5S)-5-(difluoromethyl)-3,4-dihydroxy-1-(3-phenylpropyl)pyrrolidin-2-yl)methyl)propionamide;
N-(((2R,3R,4R,5R)-3,4-dihydroxy-5-methyl-1-(3-phenylpropyl)pyrrolidin-2-yl)methyl)propionamide;
N-(((2R,3R,4R,5S)-3-fluoro-5-(fluoromethyl)-4-hydroxy-1-(3-phenylpropyl)pyrrolidin-2-yl)methyl)propionamide;
N-(((2R,3S,4R,5S)-5-(difluoromethyl)-3-fluoro-4-hydroxy-1-(3-phenylpropyl)pyrrolidin-2-yl)methyl)propionamide;
or a pharmaceutically acceptable salt of any of the foregoing compounds.

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

4. A pharmaceutical composition comprising a compound of claim 2 or a pharmaceutically acceptable salt thereof in combination with a pharmaceutically acceptable carrier.

5. The compound of claim 1 wherein the compound is selected from the following group:
N-ethyl-2-((2R,3R,4R,5S)-5-(fluoromethyl)-3,4-dihydroxy-1-phenethylpyrrolidin-2-yl)acetamide;
2-((2R,3R,4R,5S)-5-(difluoromethyl)-3,4-dihydroxy-1-phenethylpyrrolidin-2-yl)-N-ethylacetamide;
2-((2R,3R,4R,5S)-5-(fluoromethyl)-3,4-dihydroxy-1-(3-phenylpropyl)pyrrolidin-2-yl)-N-methylacetamide;
2-((2R,3R,4R,5S)-5-(difluoromethyl)-3,4-dihydroxy-1-(3-phenylpropyl)pyrrolidin-2-yl)-N-methylacetamide;
N-(((2R,3R,4R,5S)-5-(fluoromethyl)-3,4-dihydroxy-1-(3-phenylpropyl)pyrrolidin-2-yl)methyl)propionamide;
N-(((2R,3R,4R,5S)-5-(difluoromethyl)-3,4-dihydroxy-1-(3-phenylpropyl)pyrrolidin-2-yl)methyl)propionamide;
or a pharmaceutically acceptable salt of any of the foregoing compounds.

6. A pharmaceutical composition comprising a compound of claim 5 or a pharmaceutically acceptable salt thereof in combination with a pharmaceutically acceptable carrier.

Assignees

• Alectos Therapeutics Inc
• Merck Sharp & Dohme

Inventors

• Mceachern Ernest J
• Sun Jianyu
• Vocadlo David J
• Zhou Yuanxi
• Zhu Yongbao
• Selnick Harold G

Classifications

• A61K31/4439

  containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole (nicotine A61K31/465) · CPC title

• A61K31/40

  having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil · CPC title

• C12N9/99

  Enzyme inactivation by chemical treatment · CPC title

• A61K31/428

  condensed with carbocyclic rings · CPC title

• C07D417/06

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