Neuro-attenuating ketamine and norketamine compounds, derivatives thereof, and methods
The present invention is directed to novel neuro-attenuating 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 compound of formula (I):
or a pharmaceutically acceptable salt thereof,
wherein
each of X 1 , X 2 , X 3 , and X 4 is hydrogen;
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 5 , X 6 , X 7 , X 8 , X 9 , X 10 , X 11 , and X 12 is deuterium.
2. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein X 13 and X 14 are hydrogen.
3. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein the compound has a structure
4. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein the compound has a structure
5. The compound of claim 2 , or a pharmaceutically acceptable salt thereof, wherein each deuterium has a deuterium incorporation of at least 52.5%.
6. The compound of claim 2 , or a pharmaceutically acceptable salt thereof, wherein each deuterium has a deuterium incorporation of at least 75%.
7. The compound of claim 2 , or a pharmaceutically acceptable salt thereof, wherein each deuterium has a deuterium incorporation of at least 90%.
8. The compound of claim 2 , or a pharmaceutically acceptable salt thereof, wherein each deuterium has a deuterium incorporation of at least 95%.
9. The compound of claim 3 , or a pharmaceutically acceptable salt thereof, wherein each deuterium has a deuterium incorporation of at least 52.5%.
10. The compound of claim 3 , or a pharmaceutically acceptable salt thereof, wherein each deuterium has a deuterium incorporation of at least 75%.
11. The compound of claim 3 , or a pharmaceutically acceptable salt thereof, wherein each deuterium has a deuterium incorporation of at least 90%.
12. The compound of claim 3 , or a pharmaceutically acceptable salt thereof, wherein each deuterium has a deuterium incorporation of at least 95%.
13. The compound of claim 4 , or a pharmaceutically acceptable salt thereof, wherein each deuterium has a deuterium incorporation of at least 52.5%.
14. The compound of claim 4 , or a pharmaceutically acceptable salt thereof, wherein each deuterium has a deuterium incorporation of at least 75%.
15. The compound of claim 4 , or a pharmaceutically acceptable salt thereof, wherein each deuterium has a deuterium incorporation of at least 90%.
16. The compound of claim 4 , or a pharmaceutically acceptable salt thereof, wherein each deuterium has a deuterium incorporation of at least 95%.