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 compound of Formula I:
or a pharmaceutically acceptable salt thereof, wherein:
R 1 is —O—(C 2 -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 ; and
wherein for each site designated as deuterium, deuterium incorporation is at least 90%.
2. The compound of claim 1 , wherein for each site designated as deuterium, deuterium incorporation is at least 95%.
3. The compound of claim 1 or 2 , wherein R 1 is —O—(C 2 -C 4 )alkyl substituted with one or more deuterium atoms.
4. The compound of claim 1 or 2 , wherein R 2 is CH 3 or CD 3 .
5. The compound of claim 1 or 2 , wherein R 1 is —O—CD 2 CD 3 , —O—CD 2 CH 3 , —O—CH 2 CD 3 , —O—CD(CD 3 ) 2 , —O—CH(CD 3 ) 2 , —O—CD(CH 3 ) 2 , —O—CD 2 CH(CH 3 ) 2 , —O—CH 2 CD(CH 3 ) 2 , —O—CH 2 CH(CD 3 ) 2 , —O—CD 2 CD(CH 3 ) 2 , —O—CD 2 CH(CD 3 ) 2 , —O—CH 2 CD(CD 3 ) 2 , or —O—CD 2 CD(CD 3 ) 2 .
6. The compound of claim 5 , wherein R 1 is —O—CD 2 CD 3 , —O—CD 2 CH 3 , —O—CH 2 CD 3 , —O—CD(CD 3 ) 2 , —O—CH(CD 3 ) 2 , or —O—CD(CH 3 ) 2 .
7. The compound of claim 6 , wherein R 1 is —O—CD 2 CD 3 or —O—CD(CD 3 ) 2 .
8. The compound of claim 7 , wherein R 1 is —O—CD(CD 3 ) 2 .
9. The compound of claim 5 , wherein the compound is selected from any one of the compounds set forth in the table below:
Compound No.
R 1
R 2
100
—O—CD 2 CD 3
CD 3
101
—O—CD 2 CH 3
CD 3
102
—O—CD(CD 3 ) 2
CD 3
103
—O—CD(CH 3 ) 2
CD 3
104
—O—CD 2 CD 3
CH 3
105
—O—CD 2 CH 3
CH 3
106
—O—CD(CD 3 ) 2
CH 3
107
—O—CD(CH 3 ) 2
CH 3
or a pharmaceutically acceptable salt thereof, wherein any atom not designated as deuterium is present at its natural isotopic abundance.
10. The compound of claim 1 , wherein any atom not designated as deuterium is present at its natural isotopic abundance.
11. A pyrogen-free pharmaceutical composition comprising the compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein for each site designated as deuterium, deuterium incorporation is at least 90%, and a pharmaceutically acceptable carrier.
12. The composition of claim 11 , wherein for each site designated as deuterium, deuterium incorporation is at least 95%.
13. The composition of claim 11 , further comprising a second therapeutic agent useful in treating a patient suffering from or susceptible to pain.
14. The composition of claim 11 , further comprising a second therapeutic agent useful in treating a patient suffering from or susceptible to conditions related to exposure to chemical agents.
15. A compound having the structure:
or a pharmaceutically acceptable salt thereof, wherein any atom not designated as deuterium is present at its natural isotopic abundance, and wherein for each site designated as deuterium, deuterium incorporation is at least 90%.
16. A compound having the structure:
or a pharmaceutically acceptable salt thereof, wherein any atom not designated as deuterium is present at its natural isotopic abundance and wherein for each site designated as deuterium, deuterium incorporation is at least 90%.
17. A compound having the structure:
or a pharmaceutically acceptable salt thereof, wherein any atom not designated as deuterium is present at its natural isotopic abundance and wherein for each site designated as deuterium, deuterium incorporation is at least 90%.
18. The compound of any one of claims 15 , 16 or 17 wherein for each site designated as deuterium, deuterium incorporation is at least 95%.