Tetrahydroisoquinoline derivatives
View Patent ↗This invention relates to novel tetrahydroisoquinoline derivatives, their derivatives, 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 dual OX-1/OX-2 orexin antagonist.
1. A compound of the formula:
or a pharmaceutically acceptable salt thereof, wherein:
each Z is independently selected from hydrogen and deuterium;
each R is independently selected from CD 3 , CD 2 H, CDH 2 , and CH 3 ; and
when each R is CH 3 , at least one Z is deuterium.
2. The compound of claim 1 , wherein R 1 and R 2 are the same.
3. The compound of claim 2 , wherein each R is independently selected from CD 3 , and CH 3 .
4. The compound of claim 3 , wherein Z 1 =Z 2 , Z 3 =Z 4 , Z 5 =Z 6 , and Z 7 =Z 8 .
5. The compound of claim 4 , wherein Z 1 =Z 2 =Z 3 =Z 4 , and Z 5 =Z 6 =Z 7 =Z 8 .
6. The compound of claim 5 , wherein Z 9 is deuterium.
7. The compound of claim 6 , wherein Z 10 is deuterium.
8. The compound of claim 1 , wherein the compound is selected from any one compound in the table below:
Compound
R 1
R 2
R 3
Z 1
Z 2
Z 3
Z 4
Z 5
Z 6
Z 7
Z 8
Z 9
Z 10
100
CD 3
CD 3
CD 3
D
D
D
D
D
D
D
D
D
D
101
CD 3
CD 3
CD 3
H
H
H
H
H
H
H
H
H
H
102
CD 3
CD 3
CD 3
D
D
H
H
H
H
D
D
D
D
103
CD 3
CD 3
CD 3
H
H
H
H
D
D
D
D
H
D
104
CD 3
CD 3
CD 3
H
H
H
H
D
D
D
D
H
H
105
CD 3
CD 3
CD 3
D
D
D
D
H
H
H
H
H
H
106
CD 3
CD 3
CD 3
H
H
H
H
H
H
H
H
D
D
107
CD 3
CD 3
CD 3
H
H
H
H
H
H
H
H
D
H
108
CD 3
CD 3
CH 3
D
D
D
D
D
D
D
D
D
D
109
CD 3
CD 3
CH 3
H
H
H
H
H
H
H
H
H
H
110
CD 3
CD 3
CH 3
D
D
H
H
H
H
D
D
D
D
111
CD 3
CD 3
CH 3
H
H
H
H
D
D
D
D
H
D
112
CD 3
CD 3
CH 3
H
H
H
H
D
D
D
D
H
H
113
CD 3
CD 3
CH 3
D
D
D
D
H
H
H
H
H
H
114
CD 3
CD 3
CH 3
H
H
H
H
H
H
H
H
D
D
115
CD 3
CD 3
CH 3
H
H
H
H
H
H
H
H
D
H
116
CH 3
CH 3
CD 3
D
D
D
D
D
D
D
D
D
D
117
CH 3
CH 3
CD 3
H
H
H
H
H
H
H
H
H
H
118
CH 3
CH 3
CD 3
D
D
H
H
H
H
D
D
D
D
119
CH 3
CH 3
CD 3
H
H
H
H
D
D
D
D
H
D
120
CH 3
CH 3
CD 3
H
H
H
H
D
D
D
D
H
H
121
CH 3
CH 3
CD 3
D
D
D
D
H
H
H
H
H
H
122
CH 3
CH 3
CD 3
H
H
H
H
H
H
H
H
D
D
and
123
CH 3
CH 3
CD 3
H
H
H
H
H
H
H
H
D
H
or a pharmaceutically acceptable salt thereof.
9. The compound of claim 1 , wherein any atom not designated as deuterium is present at its natural isotopic abundance.
10. A pyrogen-free pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier.
11. The composition of claim 10 , further comprising a second therapeutic agent useful in the treatment or prevention of a disease or a condition selected from an eating disorder, a sleep disorder and memory impairment.
12. The composition of claim 11 , wherein the second therapeutic agent is useful in the treatment or prevention of a disease or a condition selected from obesity, bulimia, anorexia nervosa, insomnia, narcolepsy, sleep apnea, jetlag syndrome, and short-, middle- or long-term memory impairment.
13. A method of inhibiting the activity of OX-1 or OX-2 in a brain cell, comprising the step of contacting the cell with a compound of claim 1 .
14. A method of treating a patient suffering from, or susceptible to, a disease or condition selected from an eating disorder, a sleep disorder and memory impairment comprising the step of administering to the patient in need thereof a composition of claim 10 .
15. The method of claim 14 , wherein the patient is suffering from, or susceptible to, a disease or condition selected from obesity, bulimia, anorexia nervosa, insomnia, narcolepsy, sleep apnea, jetlag syndrome, and short-, middle- or long-term memory impairment.
16. The method of claim 15 , wherein the patient is suffering from, or susceptible to insomnia.
17. The method of claim 14 , comprising the additional step of co-administering to the patient in need thereof a second therapeutic agent useful in the treatment or prevention of a disease or a condition selected from an eating disorder, a sleep disorder and memory impairment.
18. The method of claim 17 , wherein the second therapeutic agent is useful in the treatment or prevention of a disease or a condition selected from obesity, bulimia, anorexia nervosa, insomnia, narcolepsy, sleep apnea, jetlag syndrome, and short-, middle- or long-term memory impairment.
19. The method of claim 18 , wherein the second therapeutic agent is useful in the treatment or prevention of insomnia.