Neuro-attenuating ketamine and norketamine compounds, derivatives thereof, and methods
The present invention is directed to novel neuro-attentuating norketamine (NANKET) compounds according to any one of formulas (I—shown below), (I-A) and (I-B), or any of the compounds described in Tables A-D, or in any of the Examples provided herein, and pharmaceutically acceptable salts thereof, novel pharmaceutical formulations and novel methods of uses thereof. The present invention also features novel oral neuro-attenuating ketamine (NAKET) and neuro-attenuating norketamine (NANKET) modified-release pharmaceutical formulations, and novel methods of administration thereof, which ensure the steady release of a therapeutically effective amount of ketamine, norketamine, or derivatives thereof from the oral modified-release pharmaceutical formulations without neurologically toxic spikes in plasma concentration of the ketamine, norketamine, or derivatives during the release periods.
1. A pharmaceutical composition comprising:
a) a therapeutically effective amount of a compound of formula (I):
or a pharmaceutically acceptable salt thereof,
wherein
X 1 , X 2 , X 3 , X 4 , X 5 , X 6 , X 7 , X 8 , X 9 , X 10 , X 11 , X 12 , X 13 , and X 14 are each independently selected from the group consisting of hydrogen and deuterium,
and wherein
at least one of X 1 , X 2 , X 3 , X 4 , X 5 , X 6 , X 7 , X 8 , X 9 , X 10 , X 11 , X 12 , X 13 , and X 14 is deuterium, and when each of X 1 , X 2 , X 3 , and X 4 is deuterium, then at least one of X 5 , X 6 , X 7 , X 8 , X 9 , X 10 , X 11 , X 12 , X 13 , and X 14 is deuterium; and
b) a pharmaceutically acceptable carrier.
2. The pharmaceutical composition of claim 1 , wherein each of X 1 , X 2 , X 3 , and X 4 is hydrogen.
3. The pharmaceutical composition of claim 1 , wherein X 5 , X 6 , X 7 , X 8 , X 9 , X 10 , X 11 , and X 12 are deuterium.
4. The pharmaceutical composition of claim 1 , wherein X 13 and X 14 are both deuterium, or X 13 and X 14 are both hydrogen.
5. The pharmaceutical composition of claim 1 , wherein X 5 and X 6 are both deuterium.
6. The pharmaceutical composition of claim 1 , wherein X 7 , X 8 , X 9 , X 10 , X 11 , and X 12 are each hydrogen.
7. The pharmaceutical composition of claim 1 , wherein at least one of X 7 , X 8 , X 9 , X 10 , X 11 , and X 12 is deuterium.
8. The pharmaceutical composition of claim 5 , wherein X 13 and X 14 are both deuterium, or X 13 and X 14 are both hydrogen.
9. The pharmaceutical composition of claim 1 , wherein the compound is the S-enantiomer.
10. The pharmaceutical composition of claim 1 , wherein the compound of formula (I) has a purity of at least 50% by weight of the total amount of isotopologues of formula (I) present.
11. The pharmaceutical composition of claim 1 , wherein the compound of formula (I) has a minimum deuterium incorporation of at least 45%.
12. The pharmaceutical composition of claim 1 , wherein the compound has the following structure:
13. The pharmaceutical composition of claim 1 , wherein the compound has the following structure:
14. The pharmaceutical composition of claim 1 , wherein the compound has the following structure:
15. The pharmaceutical composition of claim 1 , wherein the compound has the following structure:
16. The pharmaceutical composition of claim 1 , wherein the compound has the following structure:
17. The pharmaceutical composition of claim 1 , wherein the compound has one of the following structures:
18. The pharmaceutical composition of claim 1 , wherein the composition is adapted for oral administration.
19. The pharmaceutical composition of claim 12 , wherein the composition is adapted for oral administration.
20. The pharmaceutical composition of claim 13 , wherein the composition is adapted for oral administration.
21. The pharmaceutical composition of claim 14 , wherein the composition is adapted for oral administration.
22. The pharmaceutical composition of claim 15 , wherein the composition is adapted for oral administration.
23. The pharmaceutical composition of claim 16 , wherein the composition is adapted for oral administration.
24. The pharmaceutical composition of claim 17 , wherein the composition is adapted for oral administration.