Neuro-attenuating ketamine and norketamine compounds, derivatives thereof, and methods

1. A substantially pure, isotopically-enriched 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.

2. The compound of claim 1 , wherein each of X 1 , X 2 , X 3 , and X 4 is hydrogen, or a pharmaceutically acceptable salt thereof.

3. The compound of claim 1 , wherein X 5 , X 6 , X 7 , X 8 , X 9 , X 10 , X 11 , and X 12 are deuterium,

or a pharmaceutically acceptable salt thereof.

4. The compound of claim 1 , having a structure that is

or a pharmaceutically acceptable salt thereof.

5. A pharmaceutically acceptable salt of an isotopically-enriched compound according to formula (I):

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.

6. The pharmaceutically acceptable salt of claim 5 , wherein the compound of formula (I) is at a purity of at least 50% by weight of the total amount of isotopologues of formula (I) present.

7. A pharmaceutical composition comprising

(a) a compound of formula (I) according to claim 1 , or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt of a compound of formula (I) according to claims 5 ; and

(b) a pharmaceutically acceptable excipient.

8. A method of inhibiting N-methyl-d-aspartate (NMDA) receptor activity, said method comprising: contacting the NMDA receptor of a subject with an effective amount of the compound of formula (I) according to claim 1 .

9. A method of treating a disease or condition in a subject comprising the step of administering said subject an effective amount of a compound of formula (I) according to claim 1 ,

wherein the disease or condition is levodopa-induced dyskinesia; dementia, tinnitus, depression, pain, agitation resulting from or associated with Alzheimer's disease, pseudobulbar effect, autism, Bulbar function, anxiety, Alzheimer's disease, schizophrenia, diabetic neuropathy, suicidality, post-traumatic stress disorder, treatment resistant depression, major despressive disorder, generalized anxiety disorder, neuropathic pain, acute pain, chronic pain, schizophrenia, a mood disorder, substance induced psychosis, major depressive disorder, bipolar disorder, bipolar depression, anxiety, or obsessive compulsive disorder.

10. An isolated, deuterium-enriched neuro-attenuating norketamine (NANKET) compound or a pharmaceutically acceptable salt thereof.

11. The isolated, deuterium-enriched neuro-attenuating norketamine (NANKET) compound of claim 10 , wherein the compound has the following structure:

or a pharmaceutically acceptable salt thereof, or

or a pharmaceutically acceptable salt thereof, or

or a pharmaceutically acceptable salt thereof, or

or a pharmaceutically acceptable salt thereof, or

or a pharmaceutically acceptable salt thereof, or

a compound is selected from a group of compounds having a Formula I-A structure:

or a pharmaceutically acceptable salt thereof,

wherein

X 1 , X 2 , X 3 , X 4 , 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 6 , X 7 , X 8 , X 9 , X 10 , X 11 , X 12 , X 13 , and X 14 is deuterium, or

a compound or any salt thereof is selected from a group of compounds having a Formula I-B structure:

or a pharmaceutically acceptable salt thereof,

wherein

X 1 , X 2 , X 3 , X 4 , X 6 , 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 6 , X 8 , X 9 , X 10 , X 11 , X 12 , X 13 , and X 14 is deuterium.

12. The isolated, deuterium-enriched neuro-attenuating norketamine (NANKET) compound of claim 10 , wherein the compound is selected from a group compounds consisting of those of the following structures 11 through 101 or any pharmaceutically acceptable salt thereof:

13. A synthetic composition of matter comprising deuterium-enriched neuro-attenuating norketamine (NANKET) compound or a pharmaceutically acceptable salt thereof.

14. The synthetic composition of matter of claim 13 , wherein the deuterium-enriched neuro-attenuating norketamine (NANKET) compound has the following structure:

or a pharmaceutically acceptable salt thereof, or

or a pharmaceutically acceptable salt thereof, or

or a pharmaceutically acceptable salt thereof, or

or a pharmaceutically acceptable salt thereof, or

or a pharmaceutically acceptable salt thereof.

15. An oral, modified-release pharmaceutical composition for oral administration to a subject for treating the subject diagnosed with, suffering from or susceptible to a disease, disorder or condition, such as those for which ketamine treatment may be indicated, considered or recommended, wherein the subject is in need of treatment with said oral, modified-release pharmaceutical composition, said oral, modified-release pharmaceutical composition comprising:

(a) a drug selected from a group consisting of ketamine, a deuterium-enriched neuro-attenuating ketamine (NAKET) compound, norketamine, and/or a deuterium-enriched neuro-attenuating norketamine (NANKET) compound or a pharmaceutically acceptable salt thereof in an effective amount for treating, preventing and/or managing the disease, disorder, or condition in the subject; and

(b) a pharmaceutically acceptable excipient;

whereby, upon oral administration of the modified-release pharmaceutical composition to the subject, a steady release of said drug from the modified-release pharmaceutical composition is maintained so that no neurologically toxic spike in the subject's plasma occurs during the release period of said drug from said pharmaceutical composition.

16. The oral, modified-release pharmaceutical composition of claim 15 , wherein the drug has the following structure:

or a pharmaceutically acceptable salt thereof, or

or a pharmaceutically acceptable salt thereof, or

or a pharmaceutically acceptable salt thereof, or

or a pharmaceutically acceptable salt thereof, or

or a pharmaceutically acceptable salt thereof.

17. The oral, modified-release pharmaceutical composition of claim 15 , wherein the drug is selected from a group of compounds consisting of the following structures 11 through 101 or any pharmaceutically acceptable salt thereof:

18. The oral, modified-release pharmaceutical composition of claim 15 wherein the drug is ketamine.

19. The oral, modified-release pharmaceutical composition of claim 15 wherein the drug is a deuterium-enriched neuro-attenuating ketamine (NAKET) compound.

20. The oral, modified-release pharmaceutical composition of claim 15 wherein the drug is norketamine.

21. The oral, modified-release pharmaceutical composition of claim 15 wherein the drug is

or a pharmaceutically acceptable salt thereof.

22. The oral, modified-release pharmaceutical composition of claim 15 wherein the drug is

or a pharmaceutically acceptable salt thereof.

23. The compound of claim 1 , wherein each of X 1 , X 2 , X 3 , and X 4 is hydrogen,

or a pharmaceutically acceptable salt thereof.

24. The compound of claim 1 , wherein X 5 , X 6 , X 7 , X 8 , X 9 , X 10 , X 11 , and X 12 are deuterium,

or a pharmaceutically acceptable salt thereof.

25. The compound of claim 1 , wherein X 13 and X 14 are both deuterium, or X 13 and X 14 are both hydrogen,

or a pharmaceutically acceptable salt thereof.

26. The compound of claim 1 , wherein X 5 and X 6 are both deuterium,

or a pharmaceutically acceptable salt thereof.

27. A compound of claim 1 that has the following structure:

or a pharmaceutically acceptable salt thereof.

28. A compound of claim 1 that has the following structure:

or a pharmaceutically acceptable salt thereof.

29. A compound of claim 1 that has the following structure:

or a pharmaceutically acceptable salt thereof.

30. A compound of claim 1 that has the following structure:

or a pharmaceutically acceptable salt thereof.

31. A compound of claim 1 that has the following structure

or a pharmaceutically acceptable salt thereof.

32. A compound of claim 1 that has the following structure

or a pharmaceutically acceptable salt thereof.

33. The method of 9 wherein the subject is suffering from or susceptible to pain.

34. The method of 9 wherein the subject is suffering from or susceptible to depression.

35. The method of claim 9 wherein the subject is suffering from or susceptible to treatment resistant depression.

36. The method of claim 9 wherein the subject is suffering from or susceptible to obsessive compulsive disorder.

37. The method of claim 9 wherein the subject is suffering from or susceptible to bipolar disorder.

38. The method of claim 9 wherein the subject is suffering from or susceptible to post traumatic stress disorder.

39. A method for treating a subject suffering from or susceptible to levodopa-induced dyskinesia; dementia, tinnitus, depression, pain, agitation resulting from or associated with Alzheimer's disease, pseudobulbar effect, autism, Bulbar function, anxiety, Alzheimer's disease, schizophrenia, diabetic neuropathy, suicidality, post-traumatic stress disorder, treatment resistant depression, major depressive disorder, generalized anxiety disorder, neuropathic pain, acute pain, chronic pain, schizophrenia, a mood disorder, substance induced psychosis, major depressive disorder, bipolar disorder, bipolar depression, anxiety, or obsessive compulsive disorder, comprising:

administering to the subject an effective of a compound selected from:

or a pharmaceutically acceptable salt thereof, or

or a pharmaceutically acceptable salt thereof, or

or a pharmaceutically acceptable salt thereof, or

or a pharmaceutically acceptable salt thereof, or

or a pharmaceutically acceptable salt thereof, or

or a pharmaceutically acceptable salt thereof.

40. The method of 39 wherein the subject is suffering from or susceptible to pain.

41. The method of 39 wherein the subject is suffering from or susceptible to depression.

42. The method of claim 39 wherein the subject is suffering from or susceptible to treatment resistant depression.

43. The method of claim 39 wherein the subject is suffering from or susceptible to obsessive compulsive disorder.

44. The method of claim 39 wherein the subject is suffering from or susceptible to bipolar disorder.

45. The method of claim 39 wherein the subject is suffering from or susceptible to post traumatic stress disorder.

46. The method of claim 39 wherein the compound is

or a pharmaceutically acceptable salt thereof.

47. The method of claim 39 wherein the compound is

or a pharmaceutically acceptable salt thereof.

48. The method of claim 39 wherein the compound is

or a pharmaceutically acceptable salt thereof.