Preparation and therapeutic applications of (2S,3R)-N-2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]OCT-3-yl)-3,5-difluorobenzamide
View Patent ↗The present invention relates to compounds 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).
1. A compound (2S,3R)-N-2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]oct-3-yl-3,5-difluorobenzamide (Formula I) or a pharmaceutically acceptable salt thereof
2. The compound of claim 1 , which is substantially free of one or more of (2R,3S)-N-2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]oct-3-yl-3,5-difluorobenzamide, (2R,3R)-N-2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]oct-3-yl-3,5-difluorobenzamide, and (2S,3S)-N-2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]oct-3-yl-3,5-difluorobenzamide.
3. The compound of claim 1 , as an acid addition salt, wherein the acid is selected from hydrochloric acid, methanesulfonic acid, maleic acid, phosphoric acid, 1-hydroxy-2-naphthoic acid, malonic acid, L-tartaric acid, fumaric acid, citric acid, L-malic acid, R-mandelic acid, S-mandelic acid, succinic acid, 4-acetamidobenzoic acid, adipic acid, galactaric acid, di-p-toluoyl-D-tartaric acid, oxalic acid, D-glucuronic acid, 4-hydroxybenzoic acid, 4-methoxybenzoic acid, (1S)-(+)-10-camphorsulfonic acid, (1R,3S)-(+)-camphoric acid, and p-toluenesulfonic acid.
4. The compound of claim 3 , wherein the molar ratio of acid to (2S,3R)-N-2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]oct-3-yl-3,5-difluorobenzamide is 1:2 or 1:1.
5. A compound selected from:
(2S,3R)-N-2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]oct-3-yl-3,5-difluorobenzamide mono-hydrochloride;
(2S,3R)-N-2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]oct-3-yl-3,5-difluorobenzamide mono-phosphate;
(2S,3R)-N-2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]oct-3-yl-3,5-difluorobenzamide mono-4-hydroxybenzoate; and
(2S,3R)-N-2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]oct-3-yl-3,5-difluorobenzamide hemi-4-hydroxybenzoate.
6. A compound, (2S,3R)-N-2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]oct-3-yl-3,5-difluorobenzamide or a pharmaceutically acceptable salt thereof containing less than 25% (2R,3R)-, (2S,3S)-, or (2R,3S)-N-2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]oct-3-yl-3,5-difluorobenzamide, either individually or in combination, by weight.
7. The compound of claim 6 , containing less than 15% (2R,3R)-, (2S,3S)-, or (2R,3S)-N-2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]oct-3-yl-3,5-difluorobenzamide, either individually or in combination, by weight.
8. The compound of claim 6 , containing less than 5% (2R,3R)-, (2S,3S)-, or (2R,3S)-N-2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]oct-3-yl-3,5-difluorobenzamide, either individually or in combination, by weight.
9. The compound of claim 6 , containing less than 2% (2R,3R)-, (2S,3S)-, or (2R,3S)-N-2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]oct-3-yl-3,5-difluorobenzamide, either individually or in combination, by weight.
10. The compound of claim 6 , containing less than 1% (2R,3R)-, (2S,3S)-, or (2R,3S)-N-2-((3-pyridinyl)methyl-1-azabicyclo[2.2.2]oct-3-yl)-3,5-difluorobenzamide, either individually or in combination, by weight.
11. A compound (2S,3R)-N-2-((3-pyridinyl)methyl-1-azabicyclo[2.2.2]oct-3-yl-3,5-difluorobenzamide (Formula I) or a pharmaceutically acceptable salt thereof
which is substantially crystalline.
12. A polymorphic form of a compound (2S,3R)-N-2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]oct-3-yl-3,5-difluorobenzamide hydrochloride characterized by an x-ray diffraction pattern comprising one or more peaks within ±0.5 degrees 2θ of the following peaks:
2θ
8.4
8.8
11.9
13.2
15.2
16.0
17.6
18.4
18.9
19.9
20.1
21.3
23.1
25.4
26.2.
13. A polymorphic form of a compound (2S,3R)-N-2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]oct-3-yl-3,5-difluorobenzamide hydrochloride characterized by an x-ray powder diffraction pattern that substantially corresponds to FIG. 9 .
14. A method for treating a disease or dysfunction, comprising administering a therapeutically effective amount of a compound of claim 1 , wherein the disease or dysfunction is early onset Alzheimer's disease, dementia of the Alzheimer's type, mild to moderate dementia of the Alzheimer's type, Alzheimer's disease, dyslexia, schizophrenia, schizophreniform disorder, schizoaffective disorder, cognitive deficits in schizophrenia, and cognitive dysfunction in schizophrenia.
15. A pharmaceutical composition comprising a compound of claim 1 , and one or more pharmaceutically acceptable carrier.