Adamantane derivative and use thereof

Patent metadata

Field	Value
Publication number	US-10487045-B2
Application number	US-201716072586-A
Country	US
Kind code	B2
Filing date	Jan 26, 2017
Priority date	Jan 26, 2016
Publication date	Nov 26, 2019
Grant date	Nov 26, 2019

Abstract

The present invention provides a pharmaceutical composition for treating or preventing a cognitive disease or disorder, containing a compound represented by Formula (I), an enantiomer thereof, a diastereomer thereof, or a pharmaceutically acceptable salt thereof.

First claim

The invention claimed is:

1. A compound represented by Formula (I):

wherein R 1 represents a hydrogen atom or (C 1-6 alkyl)carbonyl optionally substituted with one or more halogen atoms;
R 2 represents a hydrogen atom or (C 1-6 alkyl)carbonyl optionally substituted with one or more halogen atoms;
X represents O or NR 5 ;
R 3 represents phenyl optionally substituted with one or more substituents selected from X 1 , 5- or 6-membered heteroaryl optionally substituted with one or more substituents selected from X 1 , or COOR 6 ;
R 4 represents a hydrogen atom, a halogen atom, azido, —OR 7 or —NHR 8 ;
R 5 represents a hydrogen atom or C 1-6 alkyl;
R 6 represents a hydrogen atom or C 1-6 alkyl;
R 7 represents a hydrogen atom, C 1-6 alkyl, C 1-6 alkoxy-C 1-6 alkyl or (C 1-6 alkyl)carbonyl optionally substituted with one or more halogen atoms;
R 8 represents a hydrogen atom, C 1-6 alkyl or (C 1-6 alkyl)carbonyl optionally substituted with one or more halogen atoms; and
X 1 represents C 1-6 alkyl, a halogen atom, C 1-6 alkoxy, nitro or cyano,

an enantiomer thereof, a diastereomer thereof, or a pharmaceutically acceptable salt thereof.

2. The compound, an enantiomer thereof, a diastereomer thereof, or a pharmaceutically acceptable salt thereof according to claim 1 , wherein R 4 represents a chlorine atom or azido.

3. The compound, an enantiomer thereof, a diastereomer thereof, or a pharmaceutically acceptable salt thereof according to claim 1 , wherein R 1 represents trifluoroacetyl.

4. The compound, an enantiomer thereof, a diastereomer thereof, or a pharmaceutically acceptable salt thereof according to claim 1 , wherein R 2 represents (C 1-6 alkyl)carbonyl optionally substituted with one or more halogen atoms.

5. The compound, an enantiomer thereof, a diastereomer thereof, or a pharmaceutically acceptable salt thereof according to claim 4 , wherein R 2 represents trifluoroacetyl.

6. The compound, an enantiomer thereof, a diastereomer thereof, or a pharmaceutically acceptable salt thereof according to claim 1 , wherein R 3 represents phenyl optionally substituted with one or more substituents selected from X 1 or pyridyl optionally substituted with one or more substituents selected from X 1 .

7. The compound, an enantiomer thereof, a diastereomer thereof, or a pharmaceutically acceptable salt thereof according to claim 1 , selected from
(R)-((1R,2S,3R,5R,7S)-5-azido-1-hydroxyadamantan-2-yl)(phenyl)methyl acetate;
ethyl (S)-2-acetamido-2-((1R,2S,3R,5R,7R)-5-chloro-1-hydroxyadamantan-2-yl)acetate;
ethyl (R)-2-acetamido-2-((1R,2S,3R,5R,7R)-5-chloro-1-hydroxyadamantan-2-yl)acetate;
(1R,2S,3R,5R,7R)-5-chloro-2-((S)-2-methoxy-2-oxo-1-(2,2,2-trifluoroacetamido)ethyl)adamantan-1-yl 2,2,2-trifluoroacetate;
(1S,2R,3S,5S,7S)-5-chloro-2-((R)-phenyl(2,2,2-trifluoroacetamido)methyl)adamantan-1-yl 2,2,2-trifluoroacetate;
(S)-2-amino-2-((1R,2S,3R,5R,7S)-1,5-dihydroxyadamantan-2-yl)acetic acid;
N—((R)-((1S,2R,3S,5S,7S)-5-chloro-1-hydroxyadamantan-2-yl)(phenyl)methyl)-2,2,2-trifluoroacetamide;
(1S,2R,3S,5R,7S)-2-((R)-phenyl(2,2,2-trifluoroacetamido)methyl)adamantan-1-yl 2,2,2-trifluoroacetate;
(1S,2R,3S,5S,7R)-5-(2-methoxyethoxy)-2-((R)-phenyl(2,2,2-trifluoroacetamido)methyl)adamantan-1-yl 2,2,2-trifluoroacetate;
N—((R)-((1S,2R,3S,5S,7S)-5-chloro-1-hydroxyadamantan-2-yl)(pyridin-3-yl)methyl)-2,2,2-trifluoroacetamide;
2,2,2-trifluoro-N—((R)-((1S,2R,3S,5R,7S)-1-hydroxyadamantan-2-yl)(phenyl)methyl)acetamide; and
(1S,2R,3S,5S,7R)-5-methoxy-2-((R)-phenyl(2,2,2-trifluoroacetamido)methyl)adamantan-1-yl 2,2,2-trifluoroacetate,

or an enantiomer thereof, a diastereomer thereof, or a pharmaceutically acceptable salt thereof.

8. A pharmaceutical composition containing the compound, an enantiomer thereof, a diastereomer thereof, or a pharmaceutically acceptable salt thereof according to claim 1 .

9. The pharmaceutical composition according to claim 8 , for use in treating or preventing a cognitive disease or disorder.

10. The pharmaceutical composition according to claim 9 , wherein the cognitive disease or disorder is selected from Alzheimer's dementia, cerebrovascular dementia, Lewy body dementia, frontotemporal dementia, Parkinson's disease, a mental disease and a neurodegenerative disease.

11. The pharmaceutical composition according to claim 8 , for use in treating or preventing diabetes or a diabetic complication.

12. A Kir6.2 channel inhibitor containing the compound, an enantiomer thereof, a diastereomer thereof, or a pharmaceutically acceptable salt thereof according to claim 1 .

13. The Kir6.1 channel inhibitor containing the compound, an enantiomer thereof, a diastereomer thereof, or a pharmaceutically acceptable salt thereof according to claim 1 .

Assignees

• Univ Tohoku
• Brain Innovation Co Inc

Inventors

• Moriguchi Shigeki
• Fukunaga Koji
• Iwabuchi Yoshiharu

Classifications

• C07C247/14

  with azido groups bound to carbon atoms of rings other than six-membered aromatic rings · CPC title

• A61P25/16

  Anti-Parkinson drugs · CPC title

• A61P25/28 Primary

  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

• C07C229/28 Primary

  the carbon skeleton being saturated and containing rings · CPC title

• C07C233/47 Primary

  having the carbon atom of the carboxamide group bound to a hydrogen atom or to a carbon atom of an acyclic saturated carbon skeleton · CPC title