Tetrahydronaphthalene derivatives
This invention relates to novel tetrahydronaphthalene derivatives, and pharmaceutically acceptable salts thereof according to the following formulae, in one embodiment: as described herein. 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 selective T-type calcium channel blocker.
1. A compound of Formula (I):
or a pharmaceutically acceptable salt thereof, wherein:
R a , R b and R c are each independently selected from —CH 3 and —CD 3 ;
Y 1a and Y 1b are each deuterium;
Y 2a and Y 2b are the same and are selected from hydrogen and deuterium;
Y 3a and Y 3b are each independently selected from hydrogen and deuterium;
Y 4a and Y 4b are each deuterium;
and
R 1 is selected from —CH 3 and —CD 3 ;
wherein any atom not designated as deuterium is present at its natural isotopic abundance.
2. The compound of claim 1 , wherein:
R a , R b and R c are each —CH 3 .
3. The compound of claim 1 wherein R 1 is —CD 3 .
4. The compound of claim 1 , wherein R 1 is —CH 3 .
5. The compound of claim 1 , wherein Y 2a and Y 2b are each hydrogen.
6. The compound of claim 1 , wherein Y 2a and Y 2b are each deuterium.
7. The compound of claim 2 , wherein R 1 is —CD 3 ; and Y 2a and Y 2b are each hydrogen.
8. The compound of claim 2 , wherein R 1 is —CD 3 ; and Y 2a and Y 2b are each deuterium.
9. The compound of claim 2 , wherein the compound is selected from any one of the compounds in the table below:
Cmpd #
Y 1a and Y 1b
R 1
Y 2a and Y 2b
Y 3a and Y 3b
500
D
CH 3
H
H
511
D
CH 3
H
D
512
D
CD 3
H
D
513
D
CH 3
D
D
514
D
CD 3
D
D
or a pharmaceutically acceptable salt thereof.
10. A pyrogen free pharmaceutical composition comprising a compound of claim 1 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
11. The composition of claim 10 , additionally comprising a therapeutic agent selected from a beta blocker, an aldose reductase inhibitor, a NSAID, a 5HT 1D agonist, a dopamine D2 receptor antagonist, a secale alkaloid, a second calcium channel blocker and a neurokinin antagonist.
12. A compound of Formula A:
or a pharmaceutically acceptable salt thereof, wherein:
R a , R b and R c are each independently selected from —CH 3 and —CD 3 ;
Y 1a and Y 1b are each deuterium;
Y 2a and Y 2b are each independently selected from hydrogen and deuterium;
Y 3a and Y 3b are each independently selected from hydrogen and deuterium;
Y 4a and Y 4b are each deuterium;
Y 5a and Y 5b are each independently selected from hydrogen and deuterium;
Y 6a and Y 6b are each independently selected from hydrogen and deuterium;
Y 7a and Y 7b are each independently selected from hydrogen and deuterium;
Y 8 is hydrogen;
Y 9 is hydrogen;
and
R 1 is selected from —CH 3 and —CD 3 ;
and wherein any atom not designated as deuterium is present at its natural isotopic abundance.
13. A compound of claim 12 wherein R a , R b and R c are each —CH 3 ; Y 2a and Y 2b are the same; Y 5a and Y 5b are each hydrogen; Y 6a and Y 6b are each deuterium; Y 7a and Y 7b are each deuterium, and the compound is selected from any one of the compounds in the table below:
Cmpd #
Y 1a and Y 1b
R 1
Y 2a and Y 2b
Y 3a and Y 3b
611
D
CH 3
H
D
612
D
CD 3
H
D
613
D
CH 3
D
D
614
D
CD 3
D
D
or a pharmaceutically acceptable salt thereof.
14. A pyrogen free pharmaceutical composition comprising a compound of claim 12 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
15. A compound of Formula C:
or a pharmaceutically acceptable salt thereof, wherein
R a and R b are each independently selected from —CH 3 and —CD 3 ;
R d and R e are each hydrogen;
R f is OR c wherein R c is —CH 3 ;
Y 3a and Y 3b are each independently selected from hydrogen and deuterium;
Y 5a and Y 5b are each independently selected from hydrogen and deuterium;
Y 8 is hydrogen;
Y 9 is hydrogen;
R 1 is selected from —CH 3 and —CD 3 ; and
each of Y 2a , Y 2b , Y 6a , Y 6b , Y 7a and Y 7b is the same and is either hydrogen or deuterium, and wherein any atom not designated as deuterium is present at its natural isotopic abundance.
16. The compound of claim 15 , wherein the compound is selected from any one of the compounds set forth in the table below, wherein R a and R b are each —CH 3 , and each of Y 3a , Y 3b , Y 5a , and Y 5b is deuterium:
Cmpd #
R 1
Each of Y 2a , Y 2b , Y 6a , Y 6b , Y 7a and Y 7b
700b
CH 3
H
CH 2 OCH 3
701b
CH 3
D
CH 2 OCH 3
700b
CH 3
H
CH 2 OCH 3
702b
CD 3
H
CH 2 OCH 3
703b
CD 3
D
CH 2 OCH 3
or a pharmaceutically acceptable salt thereof.
17. A pyrogen free pharmaceutical composition comprising a compound of claim 15 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
18. The compound of claim 15 , wherein the compound is selected from any one of the compounds set forth in the table below, wherein R a and R b are each —CH 3 , and each of Y 3a , Y 3b , Y 5a , and Y 5b is hydrogen:
Cmpd #
R 1
Each of Y 2a , Y 2b , Y 6a , Y 6b , Y 7a and Y 7b
701a
CH 3
D
CH 2 OCH 3
702a
CD 3
H
CH 2 OCH 3
703a
CD 3
D
CH 2 OCH 3
or a pharmaceutically acceptable salt thereof.
19. The compound of claim 1 , wherein the deuterium incorporation at each atom designated as deuterium is at least 90%.
20. The compound of claim 12 , wherein the deuterium incorporation at each atom designated as deuterium is at least 90%.
21. The compound of claim 15 , wherein the deuterium incorporation at each atom designated as deuterium is at least 90%.