3-Substituted-2(arylalkyl)-1-azabicycloalkanes and methods of use thereof
View Patent ↗The present invention relates to pharmaceutical compositions incorporating compounds capable of affecting nicotinic acetylcholinergic receptors (nAChRs), for example, as modulators of specific nicotinic receptor subtypes (specifically, the α 7 nAChR subtype). The present invention also relates to methods for treating a wide variety of conditions and disorders, particularly those associated with dysfunction of the central and autonomic nervous systems.
1. A compound of formula (I):
wherein:
m is 2;
n is 1;
p is 1, 2, 3 or 4;
X is oxygen or NR′;
Y is oxygen or sulfur;
Z is NR′, a covalent bond, or a linker species, A;
A is selected from the group —CR′R″—, —CR′R″—CR′R″—, —CR′═CR′—, and —C 2 —;
wherein when Z is a covalent bond or A, X must be nitrogen;
Ar is an unsubstituted or substituted furanyl, pyrrolyl, thienyl, oxazolyl, isoxazolyl, pyrazolyl, imidazolyl, thiazolyl, or isothiazolyl;
Cy is an unsubstituted or substituted pyridinyl,
and the substituents are selected from the group consisting of alkyl, alkenyl, heterocyclyl, cycloalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, halo (e.g., F, Cl, Br, or I), —OR′, —NR′R″, —CF 3 , —CN, —NO 2 , —C 2 R′, —SR′, —N 3 , —C(═O)NR′R″, —NR′C(═O)R″, —C(═O)R′, —C(═O)OR′, —OC(═O)R′, —O(CR′R″) r C(═O)R′, —O(CR′R″) r NR″C(═O)R′, —O(CR′R″) r NR″SO 2 R′, —OC(═O)NR′R″, —NR′C(═O)OR″, —SO 2 R′, —SO 2 NR′R″, and —NR′SO 2 R″, where R′ and R″ are individually hydrogen, straight chain or branched C 1 -C 8 alkyl, C 3-8 cycloalkyl, heterocyclyl, aryl, or arylalkyl, and R′ and R″ can combine to form a cyclic functionality; and
r is an integer from 1 to 6
or a pharmaceutically acceptable salt thereof.
2. The compound of claim 1 , wherein Cy is 3-pyridinyl.
3. The compound of claim 1 , wherein Ar is substituted thienyl.
4. The compound of claim 1 , wherein Ar is thienyl substituted with one or more alkyl.
5. The compound of claim 1 , wherein Z is a covalent bond.
6. The compound of claim 1 , wherein Y is O.
7. The compound of claim 1 , wherein X is NH.
8. The compound of claim 1 , wherein p is 1.
9. (R,R; R,S; S,R; and S,S)—N-(2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]oct-3-yl)-5-methylthiophene-2-carboxamide or a pharmaceutically acceptable salt thereof.
10. A pharmaceutical composition comprising a compound of formula (I):
wherein:
m is 2;
n is 1;
p is 1, 2, 3 or 4;
X is oxygen or NR′;
Y is oxygen or sulfur;
Z is NR′, a covalent bond or a linker species, A;
A is selected from the group —CR′R″—, —CR′R″′CR′R″—, —CR′═CR′—, and —C 2 —;
wherein when Z is a covalent bond or A, X must be nitrogen;
Ar is an unsubstituted or substituted furanyl, pyrrolyl, thienyl, oxazolyl, isoxazolyl, pyrazolyl, imidazolyl, thiazolyl, or isothiazolyl;
Cy is an unsubstituted or substituted pyridinyl,
and the substituents are selected from the group consisting of alkyl, alkenyl, heterocyclyl, cycloalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, halo (e.g., F, Cl, Br, or I), —OR′, —NR′R″, —CF 3 , —CN, —NO 2 , —C 2 R′, —SR′, —N 3 , —C(═O)NR′R″, —NR′C(═O)R″, —C(═O)R′, —C(═O)OR′, —OC(═O)R′, —O(CR′R″) r C(═O)R′, —O(CR′R″) r NR″C(═O)R′, —O(CR′R″) r NR″SO 2 R′, —OC(═O)NR′R″, —NR′C(═O)OR″, —SO 2 R′, —SO 2 NR′R″, and —NR′SO 2 R″, where R′ and R″ are individually hydrogen, straight chain or branched C 1 -C 8 alkyl, C 3-43 cycloalkyl, heterocyclyl, aryl, or arylalkyl, and R′ and R″ can combine to form a cyclic functionality;
r is an integer from 1 to 6
or a pharmaceutically acceptable salt thereof; and
a pharmaceutically acceptable carrier.
11. The pharmaceutical composition of claim 10 , wherein Cy is 3-pyridinyl.
12. The pharmaceutical composition of claim 10 , wherein Ar is substituted thienyl.
13. The pharmaceutical composition of claim 10 , wherein Ar is thienyl substituted with one or more alkyl.
14. The pharmaceutical composition of claim 10 , wherein Z is a covalent bond.
15. The pharmaceutical composition of claim 10 , wherein Y is O.
16. The pharmaceutical composition of claim 10 , wherein X is NH.
17. The pharmaceutical composition of claim 10 , wherein p is 1.
18. A pharmaceutical composition comprising (R,R; R,S; S,R; and S,S)—N-(2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]oct-3-yl)-5-methylthiophene-2-carboxamide or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.