Substituted triazolo-pyridazine derivatives
This invention relates to novel substituted triazolo-pyridazines 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 an α1-GABA A receptor antagonist or an α2- and/or an α3-GABA A receptor partial agonist.
1. A method of treating a subject suffering from, or susceptible to, a disease or condition selected from anxiety, convulsions, and neuropathic pain, comprising the step of administering to the subject in need thereof an effective amount of a compound of Formula I:
or a pharmaceutically acceptable salt thereof, wherein:
R 1 is —CH 3 , or —CH 2 CH 3 , wherein R 1 is optionally substituted with deuterium;
R 2 is —CZ(R 3 ) 2 ;
Z is —OH or —CH 3 , wherein the —CH 3 of Z is optionally substituted with deuterium;
each R 3 is —CH 3 wherein each R 3 is optionally substituted with deuterium;
each Y 1 is independently hydrogen or deuterium; and
Y 2 is hydrogen or deuterium;
with the proviso that when R 1 is unsubstituted —CH 3 or unsubstituted —CH 2 CH 3; Z is unsubstituted —CH 3 ; and R 2 is not substituted with deuterium; then at least one of Y 1 and Y 2 is deuterium.
2. The method of claim 1 , wherein the subject is suffering from or susceptible to anxiety or convulsions.
3. The method of claim 1 , wherein, in the compound of Formula I, R 1 is —CH 3 , —CD 3 , —CH 2 CH 3 , —CD 2 CH 3 , —CH 2 CD 3 , or —CD 2 CD 3 .
4. The method of claim 3 , wherein, in the compound of Formula I, R 1 is —CH 2 CH 3 , —CD 2 CH 3 , —CH 2 CD 3 , or —CD 2 CD 3 .
5. The method of claim 3 , wherein, in the compound of Formula I, Y 1a and Y 1b are hydrogen.
6. The method of claim 3 , wherein, in the compound of Formula I, Y 1a and Y 1b are deuterium.
7. The method of claim 3 wherein, in the compound of Formula I, Y 2 is hydrogen.
8. The method of claim 3 wherein, in the compound of Formula I, —CZ(R 3 ) 2 is —C(CH 3 ) 3 or —C(CD 3 ) 3 .
9. The method of claim 8 , wherein, in the compound of Formula I, —CZ(R 3 ) 2 is —C(CD 3 ) 3 .
10. The method of claim 3 wherein, in the compound of Formula I, —CZ(R 3 ) 2 is —C(CD 3 ) 2 OH.
11. The method of claim 3 wherein, in the compound of Formula I, —CZ(R 3 ) 2 is —C(CH 3 ) 2 OH.
12. The method of claim 4 , wherein, in the compound of Formula I, Y 1a and Y 1b are the same; Y 2 is hydrogen; and —CZ(R 3 ) 2 is —C(CH 3 ) 3 or —C(CD 3 ) 3 .
13. The method of claim 3 wherein, in the compound of Formula I, Y 2 is hydrogen; —CZ(R 3 ) 2 is —C(CD 3 ) 3 ; and the compound is selected from any one of the compounds set forth in the table below
Compound
R 1
Y 1a
Y 1b
101
CH 2 CH 3
D
D
102
CH 2 CH 3
H
H
103
CH 2 CD 3
H
H
104
CH 2 CD 3
D
D
105
CD 2 CD 3
H
H
106
CD 2 CD 3
D
D
107
CD 2 CH 3
H
H
108
CD 2 CH 3
D
D
or a pharmaceutically acceptable salt of any of the foregoing, wherein any atom not designated as deuterium is present at its natural isotopic abundance.
14. The method of claim 3 wherein, in the compound of Formula I, Y 2 is hydrogen; —CZ(R 3 ) 2 is
and the compound is selected from any one of the compounds set forth in the table below
Compound
R 1
R 3
Y 1a
Y 1b
201
CH 2 CH 3
CD 3
D
D
202
CH 2 CH 3
CD 3
H
H
203
CH 2 CD 3
CD 3
H
H
204
CH 2 CD 3
CD 3
D
D
205
CD 2 CD 3
CD 3
H
H
206
CD 2 CD 3
CD 3
D
D
207
CD 2 CH 3
CD 3
H
H
208
CD 2 CH 3
CD 3
D
D
209
CH 2 CH 3
CH 3
D
D
210
CH 2 CH 3
CH 3
H
H
211
CH 2 CD 3
CH 3
H
H
212
CH 2 CD 3
CH 3
D
D
213
CD 2 CD 3
CH 3
H
H
214
CD 2 CD 3
CH 3
D
D
215
CD 2 CH 3
CH 3
H
H
216
CD 2 CH 3
CH 3
D
D
or a pharmaceutically acceptable salt of any of the foregoing, wherein any atom not designated as deuterium is present at its natural isotopic abundance.
15. The method of claim 3 , wherein the compound is selected from compound 109 and compound 110:
or a pharmaceutically acceptable salt of the foregoing.
16. The method of claim 3 wherein, in the compound of Formula I, any atom not designated as deuterium is present at its natural isotopic abundance.
17. A method of antagonizing an al subunit of a GABA A receptor, and partially agonizing α2 and α5 subunits of a GABA A , comprising the step of administering to the subject in need thereof an effective amount of a compound of Formula I:
or a pharmaceutically acceptable salt thereof, wherein:
R 1 is —CH 3 , or —CH 2 CH 3 , wherein R 1 is optionally substituted with deuterium;
R 2 is —CZ(R 3 ) 2 ;
Z is —OH or —CH 3 , wherein the —CH 3 of Z is optionally substituted with deuterium;
each R 3 is —CH 3 wherein each R 3 is optionally substituted with deuterium;
each Y 1 is independently hydrogen or deuterium; and
Y 2 is hydrogen or deuterium;
with the proviso that when R 1 is unsubstituted —CH 3 or unsubstituted —CH 2 CH 3; Z is unsubstituted —CH 3 ; and R 2 is not substituted with deuterium; then at least one of Y 1 and Y 2 is deuterium.
18. The method of claim 17 wherein, in the compound of Formula I, any atom not designated as deuterium in any of the embodiments set forth above is present at its natural isotopic abundance.
19. The method of claim 18 , wherein the compound is selected from compound 109 and compound 110:
or a pharmaceutically acceptable salt of the foregoing.