US 2011/0257168 A1Published application

Derivatives of oxabispidine as neuronal nicotinic acetylcholine receptor ligands

AssigneeTargacept, Inc.

InventorsSrinivasa R. Akireddy, Scott R. Breining, Nikolai Fedorov, David Kombo, Anatoly A. Mazurov, Lan Miao, Srinivasa V. Murthy, Todd Showalter, Yunde Xiao, Daniel Yohannes

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Abstract

The present invention relates to compounds of formula (I) that bind to and modulate the activity of neuronal nicotinic acetylcholine receptors, to processes for preparing these compounds, to pharmaceutical compositions containing these compounds, and to methods of using these compounds for treating a wide variety of conditions and disorders, including those associated with dysfunction of the central nervous system (CNS).

Claims17

Dependent claims

A compound of Formula I:

wherein:
X1 is aryl (optionally substituted with one or more R groups) or heteroaryl (optionally substituted with one or more R groups);
each R independently is C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-8 cycloalkyl, —(CH2)qC3-8 cycloalkyl, heterocyclyl, —(CH2)qheterocyclyl, aryl, —(CH2)qaryl, heteroaryl, —(CH2)qheteroaryl, halo, —ORI, —NRIRII, C1-6 haloalkyl , —CN, —NO2, —C2RI, —SRI, —N3, —C(═O)NRIRII, —NRIC(═O)RII, —OC(═O)NRIRII, —NRIC(═O)ORII, —SO2RI, —SO2NRIRII, or —NRISO2RII;
each of RI and RII independently is hydrogen, C1-6 alkyl, C1-6 haloalkyl, C3-8 cycloalkyl, —(CH2)qC3-8 cycloalkyl, heterocyclyl, —(CH2)qheterocyclyl, aryl (optionally substituted with or more C1-6 alkyl, halogen, or C1-6 haloalkyl), —(CH2)qaryl (optionally substituted with one or more C1-6 alkyl, halogen, or C1-6 haloalkyl), heteroaryl (optionally substituted with one or more C1-6 alkyl, halogen, or C1-6 haloalkyl), or —(CH2)qheteroaryl (optionally substituted with one or more C1-6 alkyl, halogen, or C1-6 haloalkyl), or
RI and RII can combine together with the atoms to which they are attached to form a three to ten membered ring;
each q independently is 1, 2, 3, 4, 5, or 6;
X2 is hydrogen, C1-6 alkyl, cycloalkyl, —(CH2)qC3-8cycloalkyl, —(CH2)qaryl, or —(CH2)qheteroaryl;
or a pharmaceutically acceptable salt thereof.

5 more elements

A compound selected from:

3-(6-chloropyridazin-3-yl)-9-oxa-3,7-diazabicyclo[3.3.1]nonane;
3-(5-methoxypyridin-3-yl)-9-oxa-3,7-diazabicyclo[3.3.1]nonane;
3-(5-isopropoxypyridin-3-yl)-9-oxa-3,7-diazabicyclo[3.3.1]nonane;
3-(5,6-dichloropyridin-3-yl)-9-oxa-3,7-diazabicyclo[3.3.1]nonane;
3-(5-trifluoromethylpyridin-3-yl)-9-oxa-3,7-diazabicyclo[3.3.1]nonane;
3-(5-methoxy-6-chloropyridin-3-yl)-9-oxa-3,7-diazabicyclo[3.3.1]nonane;
3-(5-(cyclopropylmethoxy)pyridin-3-yl)-9-oxa-3,7-diazabicyclo[3.3.1]nonane;
3-(5-bromopyridin-3-yl)-9-oxa-3,7-diazabicyclo[3.3.1]nonane;
3-(pyrimidin-5-yl)-9-oxa-3,7-diazabicyclo[3.3.1]nonane;
3-(pyridin-3-yl)-9-oxa-3,7-diazabicyclo[3.3.1]nonane;
3-(5-(3,4-dichlorophenoxy)pyridin-3-yl)-7-methyl-9-oxa-3,7-diazabicyclo[3.3.1]nonane;
3-(pyridin-4-yl)-7-methyl-9-oxa-3,7-diazabicyclo[3.3.1]nonane;
3-(6-trifluoromethyl-pyridin-3-yl)-7-methyl-9-oxa-3,7-diazabicyclo[3.3.1]nonane;
3-(5-fluoropyridin-3-yl)-7-methyl-9-oxa-3,7-diazabicyclo[3.3.1]nonane;
3-(6-fluoropyridin-3-yl)-7-methyl-9-oxa-3,7-diazabicyclo[3.3.1]nonane;
3-(2,3-difluorophenyl)-7-methyl-9-oxa-3,7-diazabicyclo[3.3.1]nonane;
3-(6-phenylpyridazin-3-yl)-7-methyl-9-oxa-3,7-diazabicyclo[3.3.1]nonane;
3-(4-cyanopyridin-3-yl)-7-methyl-9-oxa-3,7-diazabicyclo[3.3.1]nonane;
3-(pyrimidin-5-yl)-7-methyl-9-oxa-3,7-diazabicyclo[3.3.1]nonane;
3-(6-dimethylaminopyridin-3-yl)-7-methyl-9-oxa-3,7-diazabicyclo[3.3.1]nonane;
3-(3-methoxypyridin-2-yl)-7-methyl-9-oxa-3,7-diazabicyclo[3.3.1]nonane;
3-(5-methylpyridin-3-yl)-7-methyl-9-oxa-3,7-diazabicyclo[3.3.1]nonane;
3-(5-chloropyridin-3-yl)-7-methyl-9-oxa-3,7-diazabicyclo[3.3.1]nonane;
3-(3-methoxyphenyl)-7-methyl-9-oxa-3,7-diazabicyclo[3.3.1]nonane;
3-(3,5-difluorophenyl)-7-methyl-9-oxa-3,7-diazabicyclo[3.3.1]nonane;
3-(5-cyanopyridin-3-yl)-7-methyl-9-oxa-3,7-diazabicyclo[3.3.1]nonane;
3-(6-chloropyridazin-3-yl)-7-methyl-9-oxa-3,7-diazabicyclo[3.3.1]nonane;
3-(6-methoxypyridin-3-yl)-7-methyl-9-oxa-3,7-diazabicyclo[3.3.1]nonane;
3-(6-chloropyridin-3-yl)-7-methyl-9-oxa-3,7-diazabicyclo[3.3.1]nonane;
3-(5-(2-chlorophenoxy)pyridin-3-yl)-7-methyl-9-oxa-3,7-diazabicyclo[3.3.1]nonane;
3-(6-methoxypyridin-2-yl)-7-methyl-9-oxa-3,7-diazabicyclo[3.3.1]nonane;
3-(6-methylpyridin-3-yl)-7-methyl-9-oxa-3,7-diazabicyclo[3.3.1]nonane;
3-(6-(furan-3-yl)pyridazin-3-yl)-7-methyl-9-oxa-3,7-diazabicyclo[3.3.1]nonane;
3-(2,3-dichlorophenyl)-7-methyl-9-oxa-3,7-diazabicyclo[3.3.1]nonane;
3-(6-cyanopyridin-3-yl)-7-methyl-9-oxa-3,7-diazabicyclo[3.3.1]nonane;
3-(pyridin-2-yl)-7-methyl-9-oxa-3,7-diazabicyclo[3.3.1]nonane;
3-(3-methoxypyridin-2-yl)-9-oxa-3,7-diazabicyclo[3.3.1]nonane;
3-(2,3-difluorophenyl)-9-oxa-3,7-diazabicyclo[3.3.1]nonane;
3-(4-methoxypyridin-3-yl)-9-oxa-3,7-diazabicyclo[3.3.1]nonane;
3-(4-chloropyridin-3-yl)-9-oxa-3,7-diazabicyclo[3.3.1]nonane;
3-(6-fluoropyridin-3-yl)-9-oxa-3,7-diazabicyclo[3.3.1]nonane;
3-(6-cyanopyridin-3-yl)-9-oxa-3,7-diazabicyclo[3.3.1]nonane;
3-(5-methylpyridin-3-yl)-9-oxa-3,7-diazabicyclo[3.3.1]nonane;
3-(6-dimethylaminopyridin-3-yl)-9-oxa-3,7-diazabicyclo[3.3.1]nonane;
3-(pyrazin-2-yl)-9-oxa-3,7-diazabicyclo[3.3.1]nonane;
3-(pyridin-2-yl)-9-oxa-3,7-diazabicyclo[3.3.1]nonane;
3-(6-methoxypyridin-3-yl)-9-oxa-3,7-diazabicyclo[3.3.1]nonane;
3-(pyridin-4-yl)-9-oxa-3,7-diazabicyclo[3.3.1]nonane;
3-(5-(3,4-dichlorophenoxy)pyridin-3-yl)-9-oxa-3,7-diazabicyclo[3.3.1]nonane;
3-(4-cyanopyridin-3-yl)-9-oxa-3,7-diazabicyclo[3.3.1]nonane;
3-(3,5-difluorophenyl)-9-oxa-3,7-diazabicyclo[3.3.1]nonane;
3-(6-chloropyridin-3-yl)-9-oxa-3,7-diazabicyclo[3.3.1]nonane;
3-(6-methoxypyridin-2-yl)-9-oxa-3,7-diazabicyclo[3.3.1]nonane;
3-(2,3-dichlorophenyl)-9-oxa-3,7-diazabicyclo[3.3.1]nonane;
3-(6-methylpyridin-3-yl)-9-oxa-3,7-diazabicyclo[3.3.1]nonane;
3-(6-phenylpyridazin-3-yl)-9-oxa-3,7-diazabicyclo[3.3.1]nonane;
3-(5-(2-chlorophenoxy)pyridin-3-yl)-9-oxa-3,7-diazabicyclo[3.3.1]nonane;
3-(5-fluoropyridin-3-yl)-9-oxa-3,7-diazabicyclo[3.3.1]nonane;
3-(3-methoxyphenyl)-9-oxa-3,7-diazabicyclo[3.3.1]nonane;
3-(6-trifluoromethylpyridin-3-yl)-9-oxa-3,7-diazabicyclo[3.3.1]nonane;
3-(5-chloropyridin-3-yl)-9-oxa-3,7-diazabicyclo[3.3.1]nonane;
3-(2-phenylpyrimidin-5-yl)-9-oxa-3,7-diazabicyclo[3.3.1]nonane;
3-(6-(furan-3-yl)pyridazin-3-yl)-9-oxa-3,7-diazabicyclo[3.3.1]nonane;
3-(6-(pyridin-3-yl)pyridazin-3-yl)-9-oxa-3,7-diazabicyclo[3.3.1]nonane;
3-(5-cyanopyridin-3-yl)-9-oxa-3,7-diazabicyclo[3.3.1]nonane;
3-(pyrazin-2-yl)-7-methyl-9-oxa-3,7-diazabicyclo[3.3.1]nonane;
3-(2-phenylpyrimidin-5-yl)-7-methyl-9-oxa-3,7-diazabicyclo[3.3.1]nonane;
3-(6-(pyridin-3-yl)pyridazin-3-yl)-7-methyl-9-oxa-3,7-diazabicyclo[3.3.1]nonane;
3-(4-chloropyridin-3-yl)-7-methyl-9-oxa-3,7-diazabicyclo[3.3.1]nonane;
3-(2-bromopyrimidin-5-yl)-9-oxa-3,7-diazabicyclo[3.3.1]nonane;
3-(4-methoxypyridin-3-yl)-7-methyl-9-oxa-3,7-diazabicyclo[3.3.1]nonane;
or
3-(2-bromopyrimidin-5-yl)-7-methyl-9-oxa-3,7-diazabicyclo[3.3.1]nonane;
3-(furo[3,2-b]pyridin-6-yl)-9-oxa-3,7-diazabicyclo[3.3.1]nonane;
3-(5-fluoro-pyridine-1-oxide-3-yl)-9-oxa-3,7-diazabicyclo[3.3.1]nonane;
3-methyl-7-(pyridin-3-yl)-9-oxa-3,7-diazabicyclo[3.3.1]nonane;
3-methyl-7-(5,6-dichloropyridin-3-yl)-9-oxa-3,7-diazabicyclo[3.3.1]nonane;
3-(furo[2,3-b]pyridin-5-yl)-9-oxa-3,7-diazabicyclo[3.3.1]nonane;
3-(5-(difluoromethoxy)pyridin-3-yl)-9-oxa-3,7-diazabicyclo[3.3.1]nonane;
3-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-9-oxa-3,7-diazabicyclo[3.3.1]nonane;
3-(6-chloro-5-(difluoromethoxy)pyridin-3-yl)-9-oxa-3,7-diazabicyclo[3.3.1]nonane;
3-(6-cyano-5-(difluoromethoxy)pyridin-3-yl)-9-oxa-3,7-diazabicyclo[3.3.1]nonane;
3-(5-cyano-6-fluoropyridin-3-yl)-9-oxa-3,7-diazabicyclo[3.3.1]nonane;
3-(5-methoxy-6-fluoropyridin-3-yl)-9-oxa-3,7-diazabicyclo[3.3.1]nonane;
3-(5-cyclopropylpyridin-3-yl)-9-oxa-3,7-diazabicyclo[3.3.1]nonane;
3-(2,2-difluoro-[1,3]dioxolo[4,5-b]pyridine-5-yl)-9-oxa-3,7-diazabicyclo[3.3.1]nonane;
3-(5-cyclopropyl-6-chloropyridin-3-yl)-9-oxa-3,7-diazabicyclo[3.3.1]nonane;
3-(5-(3-fluoropropoxy)-6-chloropyridin-3-yl)-9-oxa-3,7-diazabicyclo[3.3.1]nonane;
3-(5-(4-fluorobutoxy)-6-chloropyridin-3-yl)-9-oxa-3,7-diazabicyclo[3.3.1]nonane;
and
3-(5-(2-fluoroethoxy)-6-chloropyridin-3-yl)-9-oxa-3,7-diazabicyclo[3.3.1]nonane;
or a pharmaceutically acceptable salt thereof.

89 more elements

Dependencies are inferred from the claim text.

Facts

Application: 13/055,085Filed 1 Jul 2009
Priority: 3 Jul 2008
Published: 20 Oct 2011
Term ends: Not estimatedThe source records don’t support an estimate.

Classification6 codes

C07D 498/04
In which the condensed system contains two hetero rings: ortho-condensed systems
A61P 25/00
Drugs for disorders of the nervous system
A61P 25/04
Drugs for disorders of the nervous system: centrally acting analgesics, e.g. opioids
A61P 29/00
Non-central analgesic, antipyretic or antiinflammatory agents

Family

Application61/078,005Us provisional application · filed 3 Jul 2008
US 2011/0257168 A1This patent

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

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