Selective sigma-1 receptor ligands
The invention provides compounds of the formulas described herein and compositions thereof. The invention further provides methods of using the compounds and compositions. The compounds of the invention can provide high affinity binding to sigma-1 receptors in a mammal. The compounds can exhibit selectivity for the sigma-1 receptor over the sigma-2 receptor. The compounds and compositions of the invention can also be used to treat conditions that involve the sigma-1 receptor, such as addiction, cardiovascular conditions, and cancer, for example, cancer of the breast, lung, prostate, ovarian, colorectal, or the CNS.
1. A compound of formula XI:
wherein
R 1 is substituted phenyl, or substituted benzyl; and
when R 1 is phenyl, the phenyl of R 1 is substituted with one to five halo, amino, azido, alkyl, or trifluoromethyl groups, or a combination thereof;
when R 1 is benzyl, the benzyl of R 1 is substituted with:
one to five amino, azido, or alkyl groups, or a combination thereof;
one to four azido groups and one to four halo, amino, alkyl, or trifluoromethyl groups, or a combination thereof;
one to four alkyl groups and one to four halo, amino, azido, or trifluoromethyl groups, or a combination thereof;
two to four amino groups and one to three halo, azido, alkyl, or trifluoromethyl groups, or a combination thereof;
three to five halo groups and one to two amino, azido, alkyl, or trifluoromethyl groups, or a combination thereof; or
three to five trifluoromethyl groups and one to two halo, amino, azido, or alkyl groups, or a combination thereof;
or a salt thereof.
2. The compound of claim 1 wherein the compound exhibits selectivity for the σ-1 receptor over the σ-2 receptor.
3. The compound of claim 1 wherein the compound exhibits selectivity for the σ-2 receptor over the σ-1 receptor and the σ-2 K D :σ-1 K D ratio is about 0.4 or less.
4. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable diluent or carrier.
5. A compound of claim 1 wherein the compound is:
6. A pharmaceutical composition comprising a compound of claim 5 and a pharmaceutically acceptable diluent or carrier.
7. A method of modulating a sigma-1 receptor in a mammal comprising administering to the mammal an effective amount of a compound of claim 1 , so that the sigma-1 receptor is modulated, wherein the modulating comprises agonism of the sigma-1 receptor or antagonism of the sigma-1 receptor.
8. The compound of claim 1 wherein R 1 is substituted phenyl.
9. The compound of claim 8 wherein the phenyl of R 1 is substituted with an amino group.
10. The compound of claim 8 wherein the phenyl of R 1 is substituted with a halo group.
11. The compound of claim 10 wherein the phenyl of R 1 is substituted with an iodo group.
12. The compound of claim 11 wherein the phenyl of R 1 is substituted with an amino group.
13. The compound of claim 1 wherein R 1 is substituted benzyl.
14. The compound of claim 13 wherein the benzyl of R 1 is substituted with a halo group.
15. The compound of claim 14 wherein the benzyl of R 1 is substituted with an iodo group.
16. The compound of claim 13 wherein the benzyl of R 1 is substituted with an azido group or an amino group.
17. A compound of claim 1 wherein the compound is:
18. A compound of claim 1 wherein the compound is:
19. A compound of claim 1 wherein R 1 is benzyl, and the benzyl of R 1 is substituted with one to five azido or alkyl groups, or a combination thereof.