PHARMACEUTICAL COMPOUNDS
This application describes substituted 1,3,4,6,7,11b-hexahydro-benzo(a)quinolizine compounds, pharmaceutical compositions containing them, processes for making them and their therapeutic methods.
1 . A compound of the formula (1):
wherein R 1 and R 2 are each selected from hydrogen and methyl; and
X is CHOH or C═O; or
a pharmaceutically acceptable salt or tautomer thereof,
but excluding compounds 2R,3R,11bR-9-O-desmethyl-dihydrotetrabenazine and 2S,3S,11bS-9-O-desmethyl-dihydrotetrabenazine and their tautomers.
2 . The compound of claim 1 having formula (1a):
or a pharmaceutically acceptable salt or tautomer thereof, wherein R 1 and R 2 are each selected from hydrogen and methyl, provided that at least one of R 1 and R 2 is hydrogen; and X is CHOH or C═O; and
provided that the hydrogen atoms in positions 3 and 11b are present in a cis relative orientation when (i) R 1 and R 2 are both hydrogen, or (ii) R 1 is hydrogen and R 2 is methyl.
3 . The compound of claim 1 wherein the hydrogen atoms in positions 3 and 11b are present in a cis orientation relative to each other.
4 . The compound of claim 1 having the formula (2):
and pharmaceutically acceptable salts thereof.
5 . The compound of claim 4 , wherein the compound of formula (2) has the following structure:
6 . The compound of claim 4 having the formula (2a):
and pharmaceutically acceptable salts thereof.
7 . The compound of claim 2 having the formula (2b):
and pharmaceutically acceptable salts thereof.
8 . The compound of claim 7 which is selected from compounds (2b-I) and (2b-II):
and pharmaceutically acceptable salts thereof.
9 . The compound of claim 4 having the formula (2c):
and pharmaceutically acceptable salts thereof.
10 . The compound of claim 2 having the formula (3):
and pharmaceutically acceptable salts thereof.
11 . The compound of claim 10 , wherein formula (3) excludes compounds 2R,3R,11bR-9-O-desmethyl-dihydrotetrabenazine and 2S,3S,11bS-9-O-desmethyl-dihydrotetrabenazine and their salts and tautomers.
12 . The compound of claim 10 having the formula (3a):
and pharmaceutically acceptable salts thereof.
13 . The compound of claim 10 which is selected from compounds (3a-V), (3a-VI), (3a-VII) and (3a-VIII):
and pharmaceutically acceptable salts thereof.
14 . The compound of claim 10 having the formula (3b):
and pharmaceutically acceptable salts thereof.
15 . The compound of claim 14 , which is selected from compounds (3b-I), (3b-II), (3b-III) and (3b-IV):
and pharmaceutically acceptable salts thereof.
16 . The compound of claim 14 , which is selected from the compounds (3b-V), (3b-VI) (3b-VII) and (3b-VIII):
and pharmaceutically acceptable salts thereof.
17 . The compound of claim 10 having the formula (3c):
and pharmaceutically acceptable salts thereof.
18 . The compound of claim 17 , which is selected from compounds (3c-V), (3c-VI) (3c-VII) and (3c-VIII):
and pharmaceutically acceptable salts thereof.
19 . The compound of claim 2 which is (−)-10-desmethyl-γ-dihydrotetrabenazine or a pharmaceutically acceptable salt thereof.
20 . The compound of claim 2 which is (+)-10-desmethyl-γ-dihydrotetrabenazine or a pharmaceutically acceptable salt thereof.
21 . The compound of the formula (1) as defined in claim 1 wherein said compound is selected from the compounds (2a-I) and (2a-II):
and pharmaceutically acceptable salts thereof; and the compounds (2c-I) and (2c-II):
and pharmaceutically acceptable salts thereof; and the compounds (3a-I), (3a-II), (3a-III) and (3-a-IV):
and pharmaceutically acceptable salts thereof; and the compounds (3c-I), (3c-II), (3c-III), (3c-IV):
and pharmaceutically acceptable salts thereof.
22 . The compound of claim 1 in the form of a pharmaceutically acceptable salt.
23 . A pharmaceutical composition comprising a compound of the formula (1):
or a pharmaceutically acceptable salt or tautomer thereof, and combinations thereof;
wherein R 1 and R 2 are each selected from hydrogen and methyl; and
X is CHOH or C═O.
24 . The composition of claim 23 , wherein the composition comprises a therapeutically effective amount of the compound of the formula (1).
25 . The composition of claim 23 , wherein the compound is selected from the following group of compounds:
or a combination thereof, and pharmaceutically acceptable salts thereof.
26 . The composition of claim 23 , wherein the compound is selected from:
and combinations thereof, or pharmaceutically acceptable salts thereof.
27 . The composition of claim 23 , wherein the compound is (−)-10-desmethyl-γ-dihydrotetrabenazine.
28 . A method of treating a movement disorder in a patient in need thereof comprising administrating to the patient the composition of claim 23 to thereby treat the movement disorder in the patient.
29 . The method of claim 28 , wherein the movement disorder is Huntington's disease.
30 . The method of claim 28 , further comprising halting or slowing the development of Huntington's disease.
31 . The method of claim 28 , wherein the movement disorder is Tourette's syndrome.
32 . A method of treating an inflammatory disease in a patient in need thereof comprising administrating to the patient the composition of claim 23 to thereby treat the inflammatory disease in the patient.
33 . A method of treating multiple sclerosis in a patient in need thereof comprising administrating to the patient the composition of claim 23 to thereby treat the multiple sclerosis in the patient.
34 . A method of treating a psychoses in a patient in need thereof comprising administrating to the patient the composition of claim 23 to thereby treat the psychoses in the patient.
35 . The method of claim 34 , wherein the psychoses is schizophrenia.
36 . The method of claim 35 , where the method further treats a cognitive deficit associated with schizophrenia.
37 . A method of treating anxiety in a patient in need thereof comprising administrating to the patient the composition of claim 23 to thereby treat the anxiety in the patient.
38 . A method of treating depression in a patient in need thereof comprising administrating to the patient the composition of claim 23 to thereby treat the depression in the patient.
39 . A method of treating a cognitive deficit in a patient in need thereof comprising administrating to the patient the composition of claim 23 to thereby treat the cognitive deficit in the patient.
40 . A method of treating dementia in a patient in need thereof comprising administrating to the patient the composition of claim 23 to thereby treat the dementia in the patient.
41 . A method of treating asthma in a patient in need thereof comprising administrating to the patient the composition of claim 23 to thereby treat the asthma in the patient.
42 . A method of treating diabetes mellitus in a patient in need thereof comprising administrating to the patient the composition of claim 23 to thereby treat the diabetes mellitus in the patient.