Compositions, synthesis, and methods of utilizing quinazolinedione derivatives
View Patent ↗The present invention provides quinazolinedione derivatives of Formulae Ia and Ib, which can be advantageously used for treating schizophrenia and related psychoses such as acute manic, bipolar disorder, autistic disorder, depression and dementia.
1. A compound according to Formula (1):
wherein:
A is —O—(CH 2 ) n —, —S—(CH 2 ) n —, —CH 2 —O—(CH 2 ) n —, —(CH 2 ) n —O—CH 2 —CH 2 —, —CH 2 —S—(CH 2 ) n —, or —(CH 2 ) n —S—CH 2 —CH 2 —, wherein n is an integer from 1 to 7;
H is
R 1 , R 2 , R 3 , R 4 , R 5 , and R 6 is each independently hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, cycloalkyl, substituted cycloalkyl, alkoxy, alkylthio, amino, alkylamino, arylalkylamino, dialkylamino, arylalkoxy, carboxy, carbamoyl, carbamate, carbonate, cyano, halo, or hydroxy, wherein each hydrogen of R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and A is optionally substituted with 2 H (deuterium);
or a pharmaceutically acceptable salt, racemate or diastereomeric mixture thereof.
2. The compound of claim 1 having Formula 1a:
3. The compound of claim 1 having Formula 1b:
4. The compound of claim 1 , 2 or 3 wherein A is —O—(CH 2 ) n .
5. The compound of claim 3 wherein R 3 and R 4 are hydrogen.
6. The compound of claim 1 , 2 or 3 wherein one or both of R 1 and R 2 are independently halogen-or alkoxy.
7. A pharmaceutical composition comprising the compound of any one of claims 1 - 3 and a pharmaceutically acceptable carrier.
8. The compound according to claim 3 , wherein said compound is
or a pharmaceutically acceptable salt thereof, wherein one or both of R 1 and R 2 are independently halogen or alkoxy.
9. The compound according to claim 8 , wherein said compound is
10. The compound according to claim 8 , wherein the pharmaceutically acceptable salt is a hydrochloride.
11. The compound according to claim 8 , wherein R 1 is H and R 2 is methoxy.
12. A compound according to Formula (1b):
wherein:
A is —(CH 2 ) n —, —O—(CH 2 ) n —, —S—(CH 2 ) n —, —S(O)(O)—(CH 2 ) n —, —NH—(CH 2 ) n —, —CH 2 —O—(CH 2 ) n —, —(CH 2 ) n —O—CH 2 —CH 2 —, —CH 2 —S—(CH 2 ) n —, —(CH 2 ) n —S—CH 2 —CH 2 —, —CH 2 —S(O)(O)—(CH 2 ) n —, —(CH 2 ) n —S(O)(O)—CH 2 —CH 2 —, —O—C(O)—(CH 2 ) n —, —S—C(O)—(CH 2 ) n —, —NH—C(O)—(CH 2 ) n —, —CH 2 —C(O)—O—(CH 2 ) n —, —CH 2 —C(O)—NH—(CH 2 ) n —, —CH 2 —C(O)—S—(CH 2 ) n —, —(CH 2 ) n —C(O)—O—CH 2 —CH 2 —, —(CH 2 ) n —C(O)—NH—CH 2 —CH 2 —, —(CH 2 ) n —C(O)—S—CH 2 —CH 2 —, —CH 2 —O—C(O)—(CH 2 ) n —, —CH 2 —NH—C(O)—(CH 2 ) n —, —CH 2 —S—C(O)—(CH 2 ) n —, —(CH 2 ) n —O—C(O)—CH 2 —CH 2 —, (CH 2 ) n —NH—C(O)—CH 2 —CH 2 —, or (CH 2 ) n —S—C(O)—CH 2 —CH 2 —, wherein n is an integer from 1 to 7;
R 1 , R 2 , R 3 , R 4 , R 5 , and R 6 is each independently hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, cycloalkyl, substituted cycloalkyl, alkoxy, alkylthio, amino, alkylamino, arylalkylamino, dialkylamino, arylalkoxy, carboxy, carbamoyl, carbamate, carbonate, cyano, halo, or hydroxy, wherein each hydrogen of R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and A is optionally substituted with 2 H (deuterium);
or a pharmaceutically acceptable salt, racemate or diastereomeric mixture thereof.
13. A pharmaceutical composition comprising the compound of claim 12 and a pharmaceutically acceptable carrier.
14. The compound of claim 12 , wherein A is —(CH 2 ) n —.
15. The compound of claim 14 , wherein R 3 and R 4 are hydrogen.
16. The compound of claim 15 , wherein R 5 and R 6 are hydrogen.
17. The compound of claim 16 , wherein one or both of R 1 and R 2 are independently halogen-or alkoxy.
18. The compound of claim 5 , wherein R 5 and R 6 are hydrogen.
19. The compound of claim 18 , wherein one or both of R 1 and R 2 are independently halogen-or alkoxy.
20. A method of treating one of psychoses, schizophrenia, acute mania, bipolar disorder, or depression comprising administering to a patient in need thereof the compound of any one of claims 1 - 3 and 8 - 10 .
21. A method of treating schizophrenia comprising administering to a patient in need thereof the compound of any one of claims 1 - 3 and 8 - 10 .
22. A method of treating bipolar disorder comprising administering to a patient in need thereof the compound of any one of claims 1 - 3 and 8 - 10 .
23. A method of treating one of psychoses, schizophrenia, acute mania, bipolar disorder, or depression comprising administering to a patient in need thereof the compound of claim 12 .
24. A method of treating schizophrenia comprising administering to a patient in need thereof the compound of claim 12 .
25. A method of treating bipolar disorder comprising administering to a patient in need thereof the compound of claim 12 .