Selective glycosidase inhibitors and uses thereof

Patent metadata

Field	Value
Publication number	US-9718854-B2
Application number	US-201214008388-A
Country	US
Kind code	B2
Filing date	Mar 20, 2012
Priority date	Mar 31, 2011
Publication date	Aug 1, 2017
Grant date	Aug 1, 2017

Abstract

The invention provides compounds of formula (I) with substituents as specified in claim 1 for selectively inhibiting glycosidases, prodrugs of the compounds, and pharmaceuticals compositions including the compounds or prodrugs of the compounds. The invention also provides methods of treating diseases and disorders related to over-expression of O-GlcNAcase or accumulation of O-GlcNac.

First claim

What is claimed is:

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

wherein
each R 1 is independently H or C 1-6 acyl;
R 2 is selected from the group consisting of: OCH 3 , OC(O)NR 5 2 , NHR 7 , O(SO 2 )N(CH 3 ) 2 , azetidin-1-yl, 3-hydroxyazetidin-1-yl, and pyrrolidin-2-one-1-yl;
R 3 is H or CH 3 ;
R 4 is CH 3 , CH 2 CH 3 , or (CH 2 ) 2 CH 3 ;
each R 5 is independently H or an optionally substituted C 1-6 alkyl;
and
R 7 is selected from the group consisting of: C 1-6 acyl, C 1-6 alkyl, C 2-6 alkenyl, C 3-6 cycloalkyl, tetrahydro-2H-pyran-4-yl, benzyl, and 1H-pyrazol-3-yl, said C 1-6 alkyl optionally substituted with 1 to 2 substituents selected from OH, OCH 3 , CN, CO 2 H, and CO 2 CH 3 .

2. The compound of claim 1 wherein:
R 2 is NHR 7 , azetidin-1-yl, or 3-hydroxyazetidin-1-yl.

3. The compound of claim 1 wherein:
R 2 is OCH 3 , OC(O)NR 5 2 , or O(SO 2 )N(CH 3 ) 2 .

4. The compound of claim 1 wherein:
each R 1 is independently H or C(O)CH 3 ; and
R 2 is selected from the group consisting of: OCH 3 , OC(O)NHCH 3 , OC(O)NHCH 2 CH 3 , OC(O)N(CH 3 ) 2 , OC(O)N(CH 2 CH 3 ) 2 , O(SO 2 )N(CH 3 ) 2 , NHCH 3 , NHCH 2 CH 3 , NH(CH 2 ) 3 CH 3 , NHCH(CH 3 ) 2 , NHCH 2 CH═CH 2 , NH(CH 2 ) 2 OCH 3 , NH(benzyl), NH(cyclopropyl), NH(cyclobutyl), NH(cyclopentyl), NH(cyclohexyl), NH(tetrahydro-2H-pyran-4-yl), NH(CH 2 ) 3 OH, azetidin-1-yl, 3-hydroxyazetidin-1-yl, NH(CH 2 ) 2 OH, NH(CH 2 ) 3 OH, NH(CH 2 )CH(OH)(CH 2 OH), NH(CH 2 CN), NH(CH 2 )CO 2 H, NH(CH 2 )CO 2 CH 3 , NH(1H-pyrazol-3-yl), NHC(O)CH 3 , and pyrrolidin-2-one-1-yl.

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

6. The compound of claim 1 wherein the compound is selected from the following group:
(3aR,5R,6S,7R,7aR)-2-(ethylamino)-5-(methoxymethyl)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazole-6,7-diol;
((3aR,5R,6S,7R,7aR)-6,7-dihydroxy-2-(methylamino)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazol-5-yl)methyl ethylcarbamate;
((3aR,5R,6S,7R,7aR)-6,7-dihydroxy-2-(methylamino)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazol-5-yl)methyl methylcarbamate;
((3aR,5R,6S,7R,7aR)-2-(dimethylamino)-6,7-dihydroxy-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazol-5-yl)methyl methylcarbamate;
((3aR,5R,6S,7R,7aR)-6,7-dihydroxy-2-(propylamino)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazol-5-yl)methyl ethylcarbamate;
((3aR,5R,6S,7R,7aR)-2-(dimethylamino)-6,7-dihydroxy-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazol-5-yl)methyl ethylcarbamate;
((3aR,5R,6S,7R,7aR)-2-(ethyl(methyl)amino)-6,7-dihydroxy-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazol-5-yl)methyl ethylcarbamate;
((3aR,5R,6S,7R,7aR)-6,7-dihydroxy-2-(methyl(propyl)amino)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazol-5-yl)methyl ethylcarbamate;
((3aR,5R,6S,7R,7aR)-6,7-dihydroxy-2-(methylamino)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazol-5-yl)methyl dimethylcarbamate;
((3aR,5R,6S,7R,7aR)-6,7-dihydroxy-2-(propylamino)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazol-5-yl)methyl dimethylcarbamate;
((3aR,5R,6S,7R,7aR)-2-(dimethylamino)-6,7-dihydroxy-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazol-5-yl)methyl dimethylcarbamate;
((3aR,5R,6S,7R,7aR)-6,7-dihydroxy-2-(methylamino)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazol-5-yl)methyl diethylcarbamate;
((3aR,5R,6S,7R,7aR)-6,7-dihydroxy-2-(propylamino)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazol-5-yl)methyl diethylcarbamate;
((3aR,5R,6S,7R,7aR)-2-(dimethylamino)-6,7-dihydroxy-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazol-5-yl)methyl diethylcarbamate;
((3aR,5R,6S,7R,7aR)-2-(ethyl(methyl)amino)-6,7-dihydroxy-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazol-5-yl)methyl diethylcarbamate;
((3aR,5R,6S,7R,7aR)-6,7-dihydroxy-2-(methylamino)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazol-5-yl)methyl dimethylsulfamate;
(3aR,5R,6S,7R,7aR)-5-((butylamino)methyl)-2-(ethylamino)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazole-6,7-dial,
(3aR,5R,6S,7R,7aR)-2-(ethylamino)-5-((isopropylamino)methyl)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazole-6,7-diol;
(3aR,5R,6S,7R,7aR)-5-((benzylamino)methyl)-2-(ethylamino)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazole-6,7-dial;
N-(((3aR,5R,6S,7R,7aR)-2-(ethylamino)-6,7-dihydroxy-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazol-5-yl)methyl)acetamide;
(3aR,5R,6S,7R,7aR)-2-(methylamino)-5-((methylamino)methyl)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazole-6,7-dial;
(3aR,5R,6S,7R,7aR)-2-(ethylamino)-5-((methylamino)methyl)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazole-6,7-dial;
(3aR,5R,6S,7R,7aR)-5-((ethylamino)methyl)-2-(methylamino)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazole-6,7-dial;
(3aR,5R,6S,7R,7aR)-2-(ethylamino)-5-((ethylamino)methyl)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazole-6,7-dial;
(3aR,5R,6S,7R,7aR)-2-(dimethylamino)-5-((ethylamino)methyl)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazole-6,7-dial;
(3aR,5R,6S,7R,7aR)-2-(ethyl(methyl)amino)-5-((ethylamino)methyl)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazole-6,7-dial;
(3aR,5R,6S,7R,7aR)-5-((allylamino)methyl)-2-(methylamino)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazole-6,7-dial;
(3aR,5R,6S,7R,7aR)-5-((allylamino)methyl)-2-(ethylamino)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazole-6,7-dial;
(3aR,5R,6S,7R,7aR)-5-(((2-methoxyethyl)amino)methyl)-2-(methylamino)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazole-6,7-dial;
(3aR,5R,6S,7R,7aR)-2-(ethylamino)-5-(((2-methoxyethyl)amino)methyl)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazole-6,7-dial;
(3aR,5R,6S,7R,7aR)-5-((cyclopropylamino)methyl)-2-(methylamino)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazole-6,7-dial;
(3aR,5R,6S,7R,7aR)-5-((cyclopropylamino)methyl)-2-(ethylamino)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazole-6,7-diol;
(3aR,5R,6S,7R,7aR)-5-((cyclopropylamino)methyl)-2-(dimethylamino)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazole-6,7-diol;
(3aR,5R,6S,7R,7aR)-5-((cyclopropylamino)methyl)-2-(ethyl(methyl)amino)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazole-6,7-diol;
(3aR,5R,6S,7R,7aR)-5-((cyclobutylamino)methyl)-2-(methylamino)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazole-6,7-diol;
(3aR,5R,6S,7R,7aR)-5-((cyclobutylamino)methyl)-2-(ethylamino)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazole-6,7-diol;
(3aR,5R,6S,7R,7aR)-5-((cyclopentylamino)methyl)-2-(methylamino)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazole-6,7-diol;
(3aR,5R,6S,7R,7aR)-5-((cyclopentylamino)methyl)-2-(ethylamino)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazole-6,7-diol;
(3aR,5R,6S,7R,7aR)-5-((cyclopentylamino)methyl)-2-(dimethylamino)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazole-6,7-diol;
(3aR,5R,6S,7R,7aR)-5-((cyclopentylamino)methyl)-2-(ethyl(methyl)amino)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazole-6,7-diol;
(3aR,5R,6S,7R,7aR)-5-((cyclohexylamino)methyl)-2-(methylamino)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazole-6,7-diol;
(3aR,5R,6S,7R,7aR)-5-((cyclohexylamino)methyl)-2-(ethylamino)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazole-6,7-diol;
(3aR,5R,6S,7R,7aR)-2-(methylamino)-5-(((tetrahydro-2H-pyran-4-yl)amino)methyl)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazole-6,7-diol;
(3aR,5R,6S,7R,7aR)-2-(ethylamino)-5-(((tetrahydro-2H-pyran-4-yl)amino)methyl)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazole-6,7-diol;
(3aR,5R,6S,7R,7aR)-5-(((3-hydroxypropyl)amino)methyl)-2-(methylamino)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazole-6,7-diol;
(3aR,5R,6S,7R,7aR)-5-(azetidin-1-ylmethyl)-2-(methylamino)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazole-6,7-diol;
(3aR,5R,6S,7R,7aR)-5-((3-hydroxyazetidin-1-yl)methyl)-2-(methylamino)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazole-6,7-diol;
(3aR,5R,6S,7R,7

Assignees

• Kaul Ramesh
• Mceachern Ernest J
• Vocadlo David J
• Zhou Yuanxi
• Liu Kun
• Selnick Harold G
• Wei Zhongyong
• Mu Changwei
• Wang Yaode
• Wang Xiaona
• Alectos Therapeutics Inc
• Merck Sharp & Dohme

Inventors

• Kaul Ramesh
• Mceachern Ernest J
• Vocadlo David J
• Zhou Yuanxi
• Liu Kun
• Selnick Harold G
• Wei Zhongyong
• Mu Changwei
• Wang Yaode
• Wang Xiaona

Classifications

• C07H15/12

  attached to a nitrogen atom of the saccharide radical · CPC title

• C07D513/04

  Ortho-condensed systems · CPC title

• C07H9/06

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

• C07H15/04

  attached to an oxygen atom of the saccharide radical · CPC title

• C07H19/24 Primary

  Heterocyclic radicals containing oxygen or sulfur as ring hetero atom · CPC title