Silent desensitizers of neuronal nAChR and methods of use thereof
One aspect of the present invention relates to heterocyclic compounds that are ligands for nicotinic acetylcholine receptors. A second aspect of the invention relates to the use of a compound of the invention for modulation of a mammalian nicotinic acetylcholine receptor.
1. A compound of formula I:
or a pharmaceutically acceptable tautomer or salt thereof, wherein
Y is O or S;
Het is
wherein R is selected from the group consisting of hydrogen and alkyl;
Z is
A is a bond to R 2 ;
R 1 is hydrogen, halo or alkyl;
R 3 is hydrogen, halo or alkyl;
R 4 is hydrogen, halo or alkyl;
R 2 is
R A is hydrogen or alkyl;
R B is hydrogen or alkyl;
n is 0, 1, 2, 3 or 4; and
X is hydrogen, halo, hydroxyl, alkyloxy, trifluoromethyl or alkyl.
2. The compound of claim 1 , wherein Y is O.
3. The compound of claim 1 , wherein R is hydrogen.
4. The compound of claim 1 , wherein R 1 is hydrogen; R 3 is hydrogen; and R 4 is hydrogen.
5. The compound of claim 4 , wherein R 2 is
6. The compound of claim 4 , wherein R 2 is
7. The compound of claim 2 or 6 , wherein n is 1.
8. The compound of claim 6 , wherein X is halo, hydroxyl, or trifluoromethyl.
9. The compound of claim 8 , wherein X is fluoro or hydroxyl.
10. The compound of claim 8 or 9 , wherein R A is hydrogen.
11. The compound of claim 10 , wherein R B is hydrogen.
12. A compound selected from the group consisting of:
13. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable excipient.
14. The compound
15. A pharmaceutical composition comprising the compound of claim 14 , or a pharmaceutically acceptable tautomer or salt thereof, and a pharmaceutically acceptable excipient.
16. The compound
17. A pharmaceutical composition comprising the compound of claim 16 , or a pharmaceutically acceptable tautomer or salt thereof, and a pharmaceutically acceptable excipient.