Morphinan compounds
This invention relates to novel morphinan compounds and pharmaceutically acceptable salts thereof. This invention also provides compositions comprising a compound of this invention and the use of such compositions in methods of treating diseases and conditions that are beneficially treated by administering a σ 1 receptor agonist that also has NMDA antagonist activity.
1. A method of treating a subject suffering from or susceptible to intractable coughing, comprising the step of administering to a subject in need thereof a therapeutically effective amount of a compound of Formula I:
or a pharmaceutically acceptable salt thereof, wherein:
R 1 is —(C 1 -C 4 )alkyl, wherein R 1 is optionally substituted with one or more deuterium atoms; and
R 2 is selected from CH 3 , CH 2 D, CHD 2 , and CD 3 ;
provided that at least one deuterium atom is present at either R 1 or R 2 ;
wherein any atom not designated as deuterium is present at its natural isotopic abundance; and
wherein the amount of the compound administered is in the range from 4.0 mg to 350 mg.
2. The method of claim 1 , wherein the amount of the compound administered is in the range from 10 mg to 90 mg.
3. The method of claim 1 , wherein the amount of the compound administered is in the range from 30 mg to 45 mg.
4. The method of claim 1 , wherein the compound is administered once daily.
5. The method of claim 1 , wherein the compound is administered twice daily.
6. The method of claim 1 , wherein the compound is selected from any one of:
or a pharmaceutically acceptable salt thereof.
7. The method of claim 1 , wherein the deuterium incorporation at each designated deuterium atom is at least 90%.
8. The method of claim 1 , wherein the deuterium incorporation at each designated deuterium atom is at least 95%.
9. A compound selected from:
wherein the (C 1 -C 4 alkyl) is deuterated.
10. The compound of claim 9 , wherein the deuterium incorporation at each designated deuterium atom is at least 90%.
11. The compound of claim 9 , wherein the deuterium incorporation at each designated deuterium atom is at least 95%.
12. A method of treating a subject suffering from or susceptible to a disease or condition selected from neurological disorders and neurodegenerative diseases, diabetic neuropathy, neuropathic pain, epileptic seizures, and methotrexate neurotoxicity, comprising the step of administering to the subject in need thereof a therapeutically effective amount of a compound of Formula I:
or a pharmaceutically acceptable salt thereof, wherein:
R 1 is —(C 1 -C 4 )alkyl, wherein R 1 is optionally substituted with one or more deuterium atoms; and
R 2 is selected from CH 3 , CH 2 D, CHD 2 , and CD 3 ;
provided that at least one deuterium atom is present at either R 1 or R 2 ;
wherein any atom not designated as deuterium is present at its natural isotopic abundance; and
wherein the amount of the compound administered is in the range from 0.4 mg to 400 mg.
13. The method of claim 12 , wherein the amount of the compound administered is in the range from 4.0 mg to 350 mg.
14. The method of claim 12 , wherein the amount of the compound administered is in the range from 10 mg to 90 mg.
15. The method of claim 12 , wherein the amount of the compound administered is in the range from 30 mg to 45 mg.
16. The method of claim 12 , wherein the compound is administered once daily.
17. The method of claim 12 , wherein the compound is administered twice daily.
18. The method of claim 12 , wherein the neurological disorders and neurodegenerative diseases are selected from dementia, amyotrophic lateral sclerosis (ALS), Alzheimer's disease, and multiple sclerosis.
19. The method of claim 12 , wherein the disease or condition is epileptic seizures.
20. The method of claim 12 , wherein the deuterium incorporation at each designated deuterium atom is at least 90%.
21. The method of claim 12 , wherein the deuterium incorporation at each designated deuterium atom is at least 95%.