Deuterated idebenone
The present invention in one embodiment provides a compound of Formula I:(I), or a pharmaceutically acceptable salt thereof, wherein the variables shown in Formula I are as defined in the specification.
1. A compound of Formula I:
or a pharmaceutically acceptable salt thereof, wherein:
each of R 1 , R 2 and R 3 is independently selected from CH 3 and CD 3 ;
each Y 1 is the same and is hydrogen or deuterium;
each Y 2 is the same and is hydrogen or deuterium;
each Y 3 is the same and is hydrogen or deuterium;
each Y 4 is the same and is hydrogen or deuterium;
each Y 5 is the same and is hydrogen or deuterium;
each Y 6 is the same and is hydrogen or deuterium;
each Y 7 is the same and is hydrogen or deuterium;
each Y 8 is the same and is deuterium;
each Y 9 is the same and is deuterium; and
each Y 10 is the same and is deuterium.
2. The compound of claim 1 , wherein R 1 is CH 3 .
3. The compound of claim 1 , wherein R 1 is CD 3 .
4. The compound of claim 1 , wherein R 2 is CH 3 .
5. The compound of claim 1 , wherein R 2 is CD 3 .
6. The compound of claim 1 , wherein R 3 is CH 3 .
7. The compound of claim 1 , wherein R 3 is CD 3 .
8. The compound of claim 1 , wherein each Y 1 is deuterium; each Y 2 is deuterium; each Y 3 is deuterium; each Y 4 is deuterium; each Y 5 is deuterium; each Y 6 is deuterium; each Y 7 is deuterium; each Y 8 is deuterium; each Y 9 is deuterium; and each Y 10 is deuterium.
9. The compound of claim 1 , wherein the compound is selected from the group consisting of the compounds (Cmpd) set forth in the table below, wherein each Y 1 is hydrogen; each Y 2 is hydrogen; each Y 3 is hydrogen; each Y 4 is hydrogen; each Y 5 is hydrogen; each Y 6 is hydrogen; each Y 7 is hydrogen; and R 3 is CH 3 :
TABLE
Cmpd No.
R 1
R 2
each Y 10
each Y 9
each Y 8
107
CH 3
CH 3
D
D
D
115
CH 3
CD 3
D
D
D
123
CD 3
CH 3
D
D
D
131
CD 3
CD 3
D
D
D
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 the compound is selected from the group consisting of the compounds (Cmpd) set forth in the table below, wherein each Y 1 is hydrogen; each Y 2 is hydrogen; each Y 3 is hydrogen; each Y 4 is hydrogen; each Y 5 is hydrogen; each Y 6 is hydrogen; each Y 7 is hydrogen; and R 3 is CD 3 :
Cmpd No.
R 1
R 2
each Y 10
each Y 9
each Y 8
207
CH 3
CH 3
D
D
D
215
CH 3
CD 3
D
D
D
223
CD 3
CH 3
D
D
D
231
CD 3
CD 3
D
D
D
or a pharmaceutically acceptable salt thereof, wherein any atom not designated as deuterium is present at its natural isotopic abundance.
11. The compound of claim 1 , wherein the compound is selected from the group consisting of the compounds (Cmpd) set forth in the table below, wherein each Y 1 is deuterium; each Y 2 is deuterium; each Y 3 is deuterium; each Y 4 is deuterium; each Y 5 is deuterium; each Y 6 is deuterium; each Y 7 is deuterium; each Y 8 is deuterium; each Y 9 is deuterium; and each Y 10 is deuterium:
Cmpd No.
R 1
R 2
R 3
300
CH 3
CH 3
CH 3
301
CH 3
CH 3
CD 3
302
CH 3
CD 3
CH 3
303
CH 3
CD 3
CD 3
304
CD 3
CH 3
CH 3
305
CD 3
CH 3
CD 3
306
CD 3
CD 3
CH 3
307
CD 3
CD 3
CD 3
or a pharmaceutically acceptable salt thereof, wherein any atom not designated as deuterium is present at its natural isotopic abundance.
12. The compound of claim 1 , wherein any atom not designated as deuterium is present at its natural isotopic abundance.
13. A pharmaceutical composition comprising the compound of claim 1 or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier.
14. A method of reducing oxidative toxicity in mitochondria, comprising contacting mitochondria with a compound of claim 1 .
15. A method of treating a condition that is Duchenne's muscular dystrophy or multiple sclerosis, comprising administering to a subject in need of such treatment a compound of claim 1 .
16. The method of claim 15 , wherein the condition is primary progressive multiple sclerosis.
17. A method of treating a condition that is Duchenne's muscular dystrophy or multiple sclerosis, comprising administering to a subject in need of such treatment a composition of claim 13 .
18. The compound of claim 1 , wherein the deuterium incorporation at each designated deuterium atom is at least 90%.
19. The compound of claim 1 , wherein the deuterium incorporation at each designated deuterium atom is at least 95%.