US 7,888,358 B2Granted

8-aza-bicyclo[3.2.1]octane derivatives and their use as monoamine neurotransmitter re-uptake inhibitors

AssigneeNeuroSearch A/S

InventorsDan Peters, Birgitte L. Eriksen, Elsebet Østergaard Nielsen, Jørgen Scheel-Krüger, Gunnar M. Olsen

Life of this patent

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Abstract

This invention relates to novel 8-aza-bicyclo[3.2.1]octane derivatives useful as monoamine neurotransmitter re-uptake inhibitors. In other aspects the invention relates to the use of these compounds in a method for therapy and to pharmaceutical compositions comprising the compounds of the invention.

Claims2

Dependent claims

An 8-aza-bicyclo[3.2.1]octane compound, which is:

endo-3-(3,4,5-Trichlorothiophen-2-yloxy)-8-methyl-8-azabicyclo[3.2.1]octane;
endo-3-(3,4-Dichlorothiophen-2-yloxy)-8-methyl-8-azabicyclo[3.2.1]octane;
exo-3-(3,4,5-Trichlorothiophen-2-yloxy)-8-methyl-8-azabicyclo[3.2.1]octane;
exo-3-(1,2-Benzoisothiazol-3-yloxy)-8-methyl-8-azabicyclo[3.2.1]octane;
exo-3-(5-Bromothiazol-2-yloxy)-8-methyl-8-azabicyclo[3.2.1]octane;
exo-3-(Benzothiazol-2-yloxy)-8-methyl-8-azabicyclo[3.2.1]octane;
exo-3-(6-Chlorobenzothiazol-2-yloxy)-8-methyl-8-azabicyclo[3.2.1]octane;
exo-3-(Quinoxalin-2-yloxy)-8-methyl-8-azabicyclo[3.2.1]octane;
exo-3-(Quinolin-2-yloxy)-8-methyl-8-azabicyclo[3.2.1]octane;
exo-3-(Benzoxazol-2-yloxy)-8-methyl-8-azabicyclo[3.2.1]octane;
exo-3-(6-Chloro-pyridazin-3-yloxy)-8-methyl-8-azabicyclo[3.2.1]octane;
exo-3-(5-Bromopyridin-2-yloxy)-8-methyl-8-azabicyclo[3.2.1]octane;
exo-3-(5-Bromopyrimidin-2-yloxy)-8-methyl-8-azabicyclo[3.2.1]octane;
exo-3-(Quinazolin-2-yloxy)-8-methyl-8-azabicyclo[3.2.1]octane;
exo-3-(5-Trifluoromethylpyridin-2-yloxy)-8-methyl-8-azabicyclo[3.2.1]octane;
exo-3-(3,4,5-Tribromothiophen-2-yloxy)-8-methyl-8-azabicyclo[3.2.1]octane;
exo-3-(4-Bromothiophen-2-yloxy)-8-methyl-8-azabicyclo[3.2.1]octane;
endo-3-(3-Bromo-5-chloro-thiophen-2-yloxy)-8-methyl-8-azabicyclo[3.2.1]octane;
endo-3-(4-Bromo-5-chloro-thiophen-2-yloxy)-8-methyl-8-azabicyclo[3.2.1]octane;
exo-3-(2,3-Dichlorophenoxy)-8-methyl-8-azabicyclo[3.2.1]octane;
exo-3-(3,4-Dichlorophenoxy)-8-methyl-8-azabicyclo[3.2.1]octane;
exo-3-(3-Chloro-4-fluorophenoxy)-8-methyl-8-azabicyclo[3.2.1]octane;
exo-3-(4-Chloro-3-fluorophenoxy)-8-methyl-8-azabicyclo[3.2.1]octane;
exo-3-(2-Chloro-3-trifluoromethylphenoxy)-8-methyl-8-azabicyclo[3.2.1]octane;
exo-3-(3-Chloro-phenoxy)-8-methyl-8-azabicyclo[3.2.1]octane
exo-3-(Fluoren-9-one-2-yloxy)-8-methyl-8-azabicyclo[3.2.1]octane;
exo-3-(3,4-Dichlorophenylthio)-8-methyl-8-azabicyclo[3.2.1]octane;
exo-3-(1-Naphthyloxy)-8-methyl-8-azabicyclo[3.2.1]octane;
exo-3-(2-Naphthyloxy)-8-methyl-8-azabicyclo[3.2.1]octane;
exo-3-(4-Chloro-3-trifluoromethylphenoxy)-8-methyl-8-azabicyclo[3.2.1]octane;
exo-3-(3-Chloro-4-cyanophenoxy)-8-methyl-8-azabicyclo[3.2.1]octane;
exo-3-(2-Dibenzofuranyloxy)-8-methyl-8-azabicyclo[3.2.1]octane;
exo-3-(4-Chloronaphthalen-1-yloxy)-8-methyl-8-azabicyclo[3.2.1]octane;
exo-3-(4-Chloro-3-methylphenoxy)-8-methyl-8-azabicyclo[3.2.1]octane;
exo-3-(4-Methoxyphenoxy)-8-methyl-8-azabicyclo[3.2.1]octane;
exo-3-(7-Methoxynaphthalen-2-yloxy)-8-methyl-8-azabicyclo[3.2.1]octane;
exo-3-(6-Methoxynaphthalen-2-yloxy)-8-methyl-8-azabicyclo[3.2.1]octane;
exo-3-(4-Bromo-3-chloro-phenoxy)-8-methyl-8-azabicyclo[3.2.1]octane;
exo-3-(Isoquinolin-5-yl)-8-methyl-8-azabicyclo[3.2.1]octane;
exo-3-(6-Bromo-naphthalen-2-yloxy)-8-methyl-8-azabicyclo[3.2.1]octane;
exo-3-(3-Methoxyphenoxy)-8-methyl-8-azabicyclo[3.2.1]octane;
exo-3-(4-Cyanophenoxy)-8-methyl-8-azabicyclo[3.2.1]octane;
exo-3-(Quinolin-6-yloxy)-8-methyl-8-azabicyclo[3.2.1]octane;
exo-3-(1,2,3,4-Tetrahydronaphthalen-6-yloxy)-8-methyl-8-azabicyclo[3.2.1]octane;
exo-3-(8-Quinolinyl)-8-methyl-8-azabicyclo[3.2.1]octane;
exo-3-(5-Indanyloxy)-8-methyl-8-azabicyclo[3.2.1]octane;
exo-3-(4-Methoxynaphthalen-1-yloxy)-8-methyl-8-azabicyclo[3.2.1]octane;
exo-3-(Indol-5-yloxy)-8-methyl-8-azabicyclo[3.2.1]octane;
exo-3-(3-Trifluoromethoxyphenoxy)-8-methyl-8-azabicyclo[3.2.1]octane;
exo-3-(4-Trifluoromethoxyphenoxy)-8-methyl-8-azabicyclo[3.2.1]octane;
exo-3-(4-Fluoro-3-trifluoromethylphenoxy)-8-methyl-8-azabicyclo[3.2.1]octane;
endo-3-(3,4-Dichlorophenoxy)-8-methyl-8-azabicyclo[3.2.1]octane;
exo-3-(3,4-Dichlorophenoxy)-8-(2-hydroxyethyl)-8-azabicyclo[3.2.1]octane;
exo-3-(3,4-Dichlorophenoxy)-8-(cyanomethyl)-8-azabicyclo[3.2.1]octane;
exo-3-(3,4-Dichlorophenoxy)-8-(cyclopropylmethyl)-8-azabicyclo[3.2.1]octane;
exo-3-(3,4-Dichlorophenoxy)-8-(allyl)-8-azabicyclo[3.2.1]octane;
exo-3-(3,4-Dichlorophenoxy)-8-(methoxyethyl)-8-azabicyclo[3.2.1]octane;
exo-3-(6-Methoxypyridin-2-yloxy)-8-methyl-8-azabicyclo[3.2.1]octane;
exo-3-(6-Ethoxypyridin-2-yloxy)-8-methyl-8-azabicyclo[3.2.1]octane;
exo-3-(6-Hydroxy-pyridin-2-yloxy)-8-methyl-8-azabicyclo[3.2.1]octane;
exo-3-(6-Cyano-naphthalen-2-yloxy)-8-methyl-8-azabicyclo[3.2.1]octane
exo-(3,4-Dichloro-phenyl)-(8-methyl-8-aza-bicyclo[3.2.1]oct-3-yl)-amine;
endo-(3,4-Dichloro-phenyl)-(8-methyl-8-aza-bicyclo[3.2.1]oct-3-yl)-formylamine;
exo-(3,4-Dichloro-phenyl)-(8-methyl-8-aza-bicyclo[3.2.1]oct-3-yl)-formylamine;
or any of its isomers or any mixture of its isomers, or a pharmaceutically acceptable salt thereof.

62 more elements

Dependencies are inferred from the claim text.

Facts

Application: 12/216,213Filed 1 Jul 2008 · continuation
Priority: DK 2003 0093924 Jun 2003
Published: US 2008/0269229 A130 Oct 2008
Granted: 15 Feb 2011
Term ends: Not estimatedThe source records don’t support an estimate.

Classification25 codes

C07D 451/04
Containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic…:…
A61P 1/02
Drugs for disorders of the alimentary tract or the digestive system: stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
A61P 1/04
Drugs for disorders of the alimentary tract or the digestive system: for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of…
A61P 3/04
Drugs for disorders of the metabolism: anorexiants; Antiobesity agents

Family

Application60/482,566Us provisional application · filed 26 Jun 2003
Application60/509,808Us provisional application · filed 10 Oct 2003
Application60/544,210Us provisional application · filed 13 Feb 2004
PCT/EP2004/51167Parent of this continuation · filed 18 Jun 2004
US 2008/0269229 A1Pre-grant publication · published 30 Oct 2008
Application10/561,417Parent of this continuation
US 7,407,970 B2Parent of this continuation
US 2006/0142331 A1Published application
US 7,888,358 B2This patent

From the US filing history. Foreign family members aren’t listed.

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Abstract

An 8-aza-bicyclo[3.2.1]octane compound, which is:

endo-3-(3,4,5-Trichlorothiophen-2-yloxy)-8-methyl-8-azabicyclo[3.2.1]octane;
endo-3-(3,4-Dichlorothiophen-2-yloxy)-8-methyl-8-azabicyclo[3.2.1]octane;
exo-3-(3,4,5-Trichlorothiophen-2-yloxy)-8-methyl-8-azabicyclo[3.2.1]octane;
exo-3-(1,2-Benzoisothiazol-3-yloxy)-8-methyl-8-azabicyclo[3.2.1]octane;
exo-3-(5-Bromothiazol-2-yloxy)-8-methyl-8-azabicyclo[3.2.1]octane;
exo-3-(Benzothiazol-2-yloxy)-8-methyl-8-azabicyclo[3.2.1]octane;
exo-3-(6-Chlorobenzothiazol-2-yloxy)-8-methyl-8-azabicyclo[3.2.1]octane;
exo-3-(Quinoxalin-2-yloxy)-8-methyl-8-azabicyclo[3.2.1]octane;
exo-3-(Quinolin-2-yloxy)-8-methyl-8-azabicyclo[3.2.1]octane;
exo-3-(Benzoxazol-2-yloxy)-8-methyl-8-azabicyclo[3.2.1]octane;
exo-3-(6-Chloro-pyridazin-3-yloxy)-8-methyl-8-azabicyclo[3.2.1]octane;
exo-3-(5-Bromopyridin-2-yloxy)-8-methyl-8-azabicyclo[3.2.1]octane;
exo-3-(5-Bromopyrimidin-2-yloxy)-8-methyl-8-azabicyclo[3.2.1]octane;
exo-3-(Quinazolin-2-yloxy)-8-methyl-8-azabicyclo[3.2.1]octane;
exo-3-(5-Trifluoromethylpyridin-2-yloxy)-8-methyl-8-azabicyclo[3.2.1]octane;
exo-3-(3,4,5-Tribromothiophen-2-yloxy)-8-methyl-8-azabicyclo[3.2.1]octane;
exo-3-(4-Bromothiophen-2-yloxy)-8-methyl-8-azabicyclo[3.2.1]octane;
endo-3-(3-Bromo-5-chloro-thiophen-2-yloxy)-8-methyl-8-azabicyclo[3.2.1]octane;
endo-3-(4-Bromo-5-chloro-thiophen-2-yloxy)-8-methyl-8-azabicyclo[3.2.1]octane;
exo-3-(2,3-Dichlorophenoxy)-8-methyl-8-azabicyclo[3.2.1]octane;
exo-3-(3,4-Dichlorophenoxy)-8-methyl-8-azabicyclo[3.2.1]octane;
exo-3-(3-Chloro-4-fluorophenoxy)-8-methyl-8-azabicyclo[3.2.1]octane;
exo-3-(4-Chloro-3-fluorophenoxy)-8-methyl-8-azabicyclo[3.2.1]octane;
exo-3-(2-Chloro-3-trifluoromethylphenoxy)-8-methyl-8-azabicyclo[3.2.1]octane;
exo-3-(3-Chloro-phenoxy)-8-methyl-8-azabicyclo[3.2.1]octane
exo-3-(Fluoren-9-one-2-yloxy)-8-methyl-8-azabicyclo[3.2.1]octane;
exo-3-(3,4-Dichlorophenylthio)-8-methyl-8-azabicyclo[3.2.1]octane;
exo-3-(1-Naphthyloxy)-8-methyl-8-azabicyclo[3.2.1]octane;
exo-3-(2-Naphthyloxy)-8-methyl-8-azabicyclo[3.2.1]octane;
exo-3-(4-Chloro-3-trifluoromethylphenoxy)-8-methyl-8-azabicyclo[3.2.1]octane;
exo-3-(3-Chloro-4-cyanophenoxy)-8-methyl-8-azabicyclo[3.2.1]octane;
exo-3-(2-Dibenzofuranyloxy)-8-methyl-8-azabicyclo[3.2.1]octane;
exo-3-(4-Chloronaphthalen-1-yloxy)-8-methyl-8-azabicyclo[3.2.1]octane;
exo-3-(4-Chloro-3-methylphenoxy)-8-methyl-8-azabicyclo[3.2.1]octane;
exo-3-(4-Methoxyphenoxy)-8-methyl-8-azabicyclo[3.2.1]octane;
exo-3-(7-Methoxynaphthalen-2-yloxy)-8-methyl-8-azabicyclo[3.2.1]octane;
exo-3-(6-Methoxynaphthalen-2-yloxy)-8-methyl-8-azabicyclo[3.2.1]octane;
exo-3-(4-Bromo-3-chloro-phenoxy)-8-methyl-8-azabicyclo[3.2.1]octane;
exo-3-(Isoquinolin-5-yl)-8-methyl-8-azabicyclo[3.2.1]octane;
exo-3-(6-Bromo-naphthalen-2-yloxy)-8-methyl-8-azabicyclo[3.2.1]octane;
exo-3-(3-Methoxyphenoxy)-8-methyl-8-azabicyclo[3.2.1]octane;
exo-3-(4-Cyanophenoxy)-8-methyl-8-azabicyclo[3.2.1]octane;
exo-3-(Quinolin-6-yloxy)-8-methyl-8-azabicyclo[3.2.1]octane;
exo-3-(1,2,3,4-Tetrahydronaphthalen-6-yloxy)-8-methyl-8-azabicyclo[3.2.1]octane;
exo-3-(8-Quinolinyl)-8-methyl-8-azabicyclo[3.2.1]octane;
exo-3-(5-Indanyloxy)-8-methyl-8-azabicyclo[3.2.1]octane;
exo-3-(4-Methoxynaphthalen-1-yloxy)-8-methyl-8-azabicyclo[3.2.1]octane;
exo-3-(Indol-5-yloxy)-8-methyl-8-azabicyclo[3.2.1]octane;
exo-3-(3-Trifluoromethoxyphenoxy)-8-methyl-8-azabicyclo[3.2.1]octane;
exo-3-(4-Trifluoromethoxyphenoxy)-8-methyl-8-azabicyclo[3.2.1]octane;
exo-3-(4-Fluoro-3-trifluoromethylphenoxy)-8-methyl-8-azabicyclo[3.2.1]octane;
endo-3-(3,4-Dichlorophenoxy)-8-methyl-8-azabicyclo[3.2.1]octane;
exo-3-(3,4-Dichlorophenoxy)-8-(2-hydroxyethyl)-8-azabicyclo[3.2.1]octane;
exo-3-(3,4-Dichlorophenoxy)-8-(cyanomethyl)-8-azabicyclo[3.2.1]octane;
exo-3-(3,4-Dichlorophenoxy)-8-(cyclopropylmethyl)-8-azabicyclo[3.2.1]octane;
exo-3-(3,4-Dichlorophenoxy)-8-(allyl)-8-azabicyclo[3.2.1]octane;
exo-3-(3,4-Dichlorophenoxy)-8-(methoxyethyl)-8-azabicyclo[3.2.1]octane;
exo-3-(6-Methoxypyridin-2-yloxy)-8-methyl-8-azabicyclo[3.2.1]octane;
exo-3-(6-Ethoxypyridin-2-yloxy)-8-methyl-8-azabicyclo[3.2.1]octane;
exo-3-(6-Hydroxy-pyridin-2-yloxy)-8-methyl-8-azabicyclo[3.2.1]octane;
exo-3-(6-Cyano-naphthalen-2-yloxy)-8-methyl-8-azabicyclo[3.2.1]octane
exo-(3,4-Dichloro-phenyl)-(8-methyl-8-aza-bicyclo[3.2.1]oct-3-yl)-amine;
endo-(3,4-Dichloro-phenyl)-(8-methyl-8-aza-bicyclo[3.2.1]oct-3-yl)-formylamine;
exo-(3,4-Dichloro-phenyl)-(8-methyl-8-aza-bicyclo[3.2.1]oct-3-yl)-formylamine;
or any of its isomers or any mixture of its isomers, or a pharmaceutically acceptable salt thereof.

62 more elements

Facts

Application

12/216,213Filed 1 Jul 2008 · continuation

Priority

DK 2003 0093924 Jun 2003

Published

US 2008/0269229 A130 Oct 2008

Granted

15 Feb 2011

Term ends

Not estimatedThe source records don’t support an estimate.

Classification25 codes

C07D 451/04
Containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic…:…
A61P 1/02
Drugs for disorders of the alimentary tract or the digestive system: stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
A61P 1/04
Drugs for disorders of the alimentary tract or the digestive system: for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of…
A61P 3/04
Drugs for disorders of the metabolism: anorexiants; Antiobesity agents

Family

Application60/482,566Us provisional application · filed 26 Jun 2003

Application60/509,808Us provisional application · filed 10 Oct 2003

Application60/544,210Us provisional application · filed 13 Feb 2004

PCT/EP2004/51167Parent of this continuation · filed 18 Jun 2004

US 2008/0269229 A1Pre-grant publication · published 30 Oct 2008

Application10/561,417Parent of this continuation

US 7,407,970 B2Parent of this continuation

US 2006/0142331 A1Published application

US 7,888,358 B2This patent

From the US filing history. Foreign family members aren’t listed.