Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
1998-11-04
2001-01-23
Raymond, Richard L. (Department: 1609)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S228800, C544S105000, C544S336000, C544S098000
Reexamination Certificate
active
06177422
ABSTRACT:
FIELD OF THE INVENTION
This invention relates to compounds that are antagonists at dopamine D4 receptors, to methods of treating psychosis and schizophrenia using a compound that is an antagonist at dopamine D4 receptors, and to pharmaceutically acceptable compositions that contain a dopamine D4 receptor antagonist.
BACKGROUND OF THE INVENTION
Dopamine is a neurotransmitter that is found in the brains of animals, including humans, and is essential for proper nerve signal transmission. It is well-known that certain compounds block or inhibit the binding of dopamine to dopamine receptors. Such compounds are called dopamine receptor antagonists. It is also well-known that dopamine receptor antagonists are useful in the treatment of schizophrenia and psychosis.
Recently, it has been discovered that more than one type of dopamine receptor exists, and that dopamine receptor antagonists can preferentially inhibit one type of dopamine receptor over another. Two major families of dopamine receptors have been identified and named the D1 and D2 families. In the D2 family, three distinct receptor subtypes have been identified as D2, D3, and D4.
The distribution and concentration of the subtypes of receptors varies in different regions of the brain. D2 subtype receptors are located in both the limbic region of the brain, which is associated with cognition and emotional function, and in the striatum, which is associated with motor effects. D4 receptors are found in higher concentrations in the frontal cortex and limbic regions, which are associated with cognitive and emotional function.
Antipsychotic drugs that are D2 subtype receptor antagonists have been used to treat psychosis and schizophrenia, but have undesirable extrapyramidal side effects and produce tardive dyskinesia. In contrast, D4 receptor antagonists show a lack of extrapyramidal side effects and tardive dyskinesia. Moreover, it has been observed that the levels of dopamine D4 receptors are elevated in schizophrenics.
Thus, it would be useful to have compounds that are selective D4 antagonists for the treatment of psychosis and schizophrenia.
SUMMARY OF THE INVENTION
The present invention provides compounds of the Formulas I and II
wherein R
1
and R
2
are independently hydrogen or C
1
-C
6
alkyl;
X is N or CH; and
R
3
is phenyl, naphthyl,heteroaryl, substituted phenyl, substituted naphthyl or substituted heteroaryl, wherein each substituent is independently selected from halogen, C
1
-C
6
alkoxy, C
1
-C
6
alkyl, —CN, —CF
3
, or sulphonamido, and the pharmaceutically acceptable salts, esters, amides, and prodrugs thereof.
In a preferred embodiment of Formula I or II, the group
is attached to the benzoxazinone group at the 6 or 7 pos ition.
In another preferred embodiment, R
1
and R
2
are hydrogen.
In another preferred embodiment, R
3
is phenyl, methyltolyl, tolyl, or sulfonamido.
In another preferred embodiment, X is N.
The present invention also provides compounds of F ormula III,
wherein X is N or CH; R
1
is hydrogen or methyl; and
R
2
is phenyl or substituted phenyl wherein each substituent is independently selected from C
1
-C
6
alkyl or sulphonamido, and the pharmaceutically acceptable salts, esters, amides, and prodrugs thereof.
In a preferred embodiment of Formula III, the group,
is attached to the benzoxazinone group at the 6 or 7 position.
In another preferred embodiment, R
1
is hydrogen.
In another preferred embodiment, R
2
is phenyl, methyltolyl, tolyl, or sulfonamido.
In a most preferred embodiment, the compounds of Formula I, II, and III are:
4-[4-(3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethyl)-piperazin-1-yl]-benzenesulfonamide;
6-[4-(3,4-dimethyl-phenyl)-piperazin-1-ylmethyl)]-4H-benzo[1,4]oxazin-3-one;
6-(4-p-tolyl-piperazin-1-ylmethyl)-4H-benzo[1,4]oxazin-3-one;
6-[4-phenyl-piperazin-1-ylmethyl]-4H-benzo[1,4]oxazin-3-one;
7-(4-p-tolyl-piperazin-1-ylmethyl)-4H-benzo[1,4]oxazin-3-one;
7-(4-phenyl-piperazin-1-ylmethyl)-4H-benzo[1,4]oxazine-3-one;
7-[4-(3,4-dimethyl-phenyl)-piperazin-1-ylmethyl]-4H-benzo[1,4]oxazine-3-one;
6-[4-(5-methyl-pyridin-2-yl)-piperazin-1-ylmethyl]-4H-benzo[1,4]oxazin-3-one;
6-(4-p-tolyl-piperidin-1-ylmethyl)-4H-benxo[1,4]oxazin-3-one;
6-[4-(3,4-Dimethyl-phenyl)-piperidin-1-ylmethyl]-4H-benzo[1,4]oxazin-3-one;
6-(4-thiazol-2-yl-piperazin-1-ylmethyl)-4H-benzo[1,4]oxazin-3-one;
6-(4-benzothiazol-2-yl-piperazin-1-ylmethyl)-4H-benzo[1,4]oxazin-3-one;
6-[4-(4,5-dimethyl-thiazol-2-yl)-piperazin-1-ylmethyl]-4H-benzo[1,4]oxazin-3-one;
6-(4-naphthalen-2-yl-piperazin-1-ylmethyl)-4H-benzo[1,4]oxazin-3-one;
6-[4-(3-chloro-phenyl)-piperazin-1-ylmethyl]-4H-benzo[1,4]oxazin-3-one;
6-[4-(3,4-dichloro-phenyl)-piperazin-1-ylmethyl]-4H-benzo[1,4]oxazin-3-one;
2-[4-(3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethyl)-piperazin-1-yl]-benzonitrile;
6-[4-(4-methoxy-phenyl)-piperazin-1-ylmethyl]-4H-benzo[1,4]oxazin-3-one;
6-[4-(2-chloro-4-methyl-phenyl)-piperazin-1-ylmethyl]-4H-benzo[1,4]oxazin-3-one;
6-[4-(4-Fluoro-phenyl)-piperazin-1-ylmethyl]-4H-benzo[1,4]oxazin-3-one;
6-[4-(3-Trifluoromethyl-phenyl)-piperazin-1-ylmethyl]-4H-benzo[1,4]oxazin-3-one;
6-[4-(3,5-Dimethyl-phenyl)-piperazin-1-ylmethyl]-4H-benzo[1,4]oxazin-3-one;
6-[4-(2-Chloro-phenyl)-piperazin-1-ylmethyl]-4H-benzo[1,4]oxazin-3-one;
6-[4-(4-Trifluoromethyl-phenyl)-piperazin-1-ylmethyl]-4H-benzo[1,4]oxazin-3-one;
6-[4-(4-Chloro-phenyl)-piperazin-1-ylmethyl]-4H-benzo[1,4]oxazin-3-one;
7-[4-(5-Methyl-pyridin-2-yl)-piperazin-1-ylmethyl]-4H-benzo[1,4]oxazin-3-one;
7-[4-(4-Methoxy-phenyl)-piperazin-1-ylmethyl]-4H-benzo[1,4]oxazin-3-one;
7-[4-(4-Chloro-phenyl)-piperazin-1-ylmethyl]-4H-benzo[1,4]oxazin-3-one;
7-[4-(3,4-Dimethyl-phenyl)-piperidin-1-ylmethyl]-4H-benzo[1,4]oxazin-3-one;
6-[4-(4-Methoxy-phenyl)-piperidin-1-ylmethyl]-4H-benzo[1,4]oxazin-3-one;
7-[4-(4-Methoxy-phenyl)-piperidin-1-ylmethyl]-4H-benzo[1,4]oxazin-3-one;
7-(4-Phenyl-piperidin-1-ylmethyl)-4H-benzo[1,4]oxazin-3-one;
7-(4-Naphthalen-2-yl-piperazin-1-ylmethyl)-4H-benzo[1,4]oxazin-3-one; or
7-(4-p-Tolyl-piperidin-1-ylmethyl)-4H-benzo[1,4]oxazin-3-one.
Also provided by the present invention is a method of treating psychosis, the method comprising administering to a patient suffering therefrom a therapeutically effective amount of a compound of Formula I, II, or III.
Also provided by the present invention is a method of treating schizophrenia, the method comprising administering to a patient suffering therefrom a therapeutically effective amount of a compound of Formula I, II, or III.
Also provided by the present invention is a pharmaceutically acceptable composition that comprises a compound of Formula I, II, or III.
DETAILED DESCRIPTION OF THE INVENTION
The present invention provides compounds of the Formulas I and II
wherein R
1
and R
2
are independently hydrogen or C
1
-C
6
alkyl;
X is N or CH; and
R
3
is phenyl, naphthyl, heteroaryl, or substituted phenyl, substituted naphthyl or substituted heteroaryl wherein each substituent is independently selected from halogen, C
1
-C
6
alkoxy,
C
1
-C
6
alkyl-CN, —CF
3
, or sulphonamido, and the pharmaceutically acceptable salts, esters, amides, and prodrugs thereof. The term substituted phenyl included phenyl substituted with one or more substituent.
The present invention also provides compounds of Formula III,
wherein X is N or CH; R
1
is hydrogen or methyl; and
R
2
is phenyl or substituted phenyl, wherein each substituent is independently selected from C
1
-C
6
alkyl or sulphonamido, and the pharmaceutically acceptable salts, esters, amides, and p
Belliotti Thomas R.
Wise Lawrence D.
Wustrow David J.
Ashbrook Charles W.
Atkins Michael J.
Crissey Todd M.
Patel Sudhaker B.
Raymond Richard L.
LandOfFree
Benzoxazinone dopamine D4 receptor antagonists does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Benzoxazinone dopamine D4 receptor antagonists, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Benzoxazinone dopamine D4 receptor antagonists will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-2557723