Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2000-08-04
2002-08-13
Shah, Mukund J. (Department: 1611)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S230500, C544S051000, C544S105000
Reexamination Certificate
active
06432946
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
This invention relates to certain 3-aminoalkylamino-2H-1,4-benzoxazines and 3-aminoalkylamino-2H-1,4-benzothiazines and pharmaceutical compositions containing such compounds. It also relates to the use of such compounds in the treatment or prevention of psychotic disorders such as schizophrenia and other central nervous system diseases.
2. Description of the Related Art
The therapeutic effect of conventional antipsychotics, known as neuroleptics, is generally believed to be exerted through blockade of dopamine receptors. However, neuroleptics are frequently responsible for undesirable extrapyramidal side effects (EPS) and tardive dyskinesias, which are attributed to blockade of D
2
receptors in the striatal region of the brain. The dopamine D
4
receptor subtype has recently been identified (Nature, 347: 146, Sokoloff et al., 1990; Nature, 350: 610, Van Tol et al., 1991). Its unique localization in limbic brain areas and its differential recognition of various antipsychotics indicates that the D
4
receptor plays a major role in the etiology of schizophrenia. Selective D
4
antagonists are considered effective antipsychotics free from the neurological side effects displayed by conventional neuroleptics.
SUMMARY OF THE INVENTION
This invention provides novel compounds which interact with dopamine subtypes. Accordingly, in a broad aspect, the invention provides compounds of Formula I:
or the pharmaceutically acceptable acid addition salts thereof, wherein:
Ar represents aryl or heteroaryl of the formula
where Y and Z independently represent CH or nitrogen;
R
1
, R
2
, R
3
and R
4
are the same or different and represent hydrogen, halogen, C
1
-C
6
alkyl, C
1
-C
4
alkoxy, cycloalkoxy, alkylthio, hydroxy, amino, mono- or dialkylamino where each alkyl is C
1
-C
6
alkyl, cyano, nitro, trifluoromethyl or trifluoromethoxy; or
R
3
and R
4
together represent a C
1
-C
2
alkylene dioxy group or a C
1
-C
3
alkylene oxy group;
R
5
is hydrogen or C
1
-C
6
alkyl;
W represents CH or nitrogen;
X is oxygen or sulfur; and
A represents an alkylene group of 2 to 5 carbon atoms, each of which carbon atoms is optionally substituted with one or two alkyl groups having from 1 to 4 carbon atoms.
Dopamine D
4
receptors are concentrated in the limbic system (
Science
, 265:1034 (Taubes, 1994)) which controls cognition and emotion. Therefore, compounds that interact with these receptors are useful in the treatment of cognitive disorders. Such disorders include cognitive deficits which are a significant component of the negative symptoms (social withdrawal and unresponsiveness) of schizophrenia. Other disorders include those involving memory impairment or attention deficit disorders.
Compounds of the present invention demonstrate high affinity and selectivity in binding to the D
4
receptor subtype. These compounds are therefore useful in treatment of a variety of neurospychological disorders, such as, for example, schizophrenia, psychotic depression and mania. Other dopamine-mediated diseases such as Parkinsonism and tardive dyskinesias can also be treated directly or indirectly by modulation of D
4
receptors.
Thus, in another aspect, the invention provides methods for treatment and/or prevention of neuropsychochological or affective disorders including, for example, schizophrenia, mania, dementia, depression, anxiety, compulsive behavior, substance abuse, memory impairment, cognitive deficits, Parkinson-like motor disorders, e.g., Parkinsonism and dystonia, and motion disorders related to the use of neuroleptic agents. In addition, the compounds of the invention are useful in treatment of memory-impairment or Alzheimer's disease by modulation of D
4
receptors which selectively exist in limbic area known to control emotion and cognitive functions. Further, the compounds of the present invention are useful for the treatment of other disorders that respond to dopaminergic blockade, e.g., substance abuse and obsessive compulsive disorder. These compounds are also useful in treating the extrapyramidal side effects associated with the use of conventional neuroleptic agents.
In yet another aspect, the invention provides pharmaceutical compositions comprising compounds of Formula I.
DETAILED DESCRIPTION OF THE INVENTION
The compounds of Formula I can be used in in the treatment of affective disorders such as schizophrenia, depression, Alzheimer's disease and certain movement disorders such as Parkinsonism and dystonia. Furthermore compounds of this invention can be used in treating the extrapyramidal side effects associated with the use of conventional neuroleptic agents. The compounds of the present invention are also useful for the treatment of other disorders which respond to dopaminergic blockade such as substance abuse and obsessive compulsive disorder.
As mentioned above, the invention encompasses 3-aminoalkylamino-2H-1,4-benzoxazines and 3-aminoalkylamino-2H-1,4-benzothiazines of Formula I. Preferred compounds of Formula I are those where R
1
and R
2
are hydrogen, and A is alkylene of from 2-4 carbon atoms.
In addition to compounds of general Formula I described above, the invention encompasses compounds of Formula IA:
wherein:
Y and Z independently represent CH or nitrogen;
R
1
, R
2
, R
3
and R
4
are the same or different and represent hydrogen, halogen, C
1
-C
6
alkyl, C
1
-C
4
alkoxy, alkylthio, hydroxy, amino, mono- or dialkylamino where each alkyl is C
1
-C
6
alkyl, cyano, nitro, trifluoromethyl or trifluoromethoxy;
R
5
is hydrogen or C
1
-C
6
alkyl;
W represents CH or nitrogen;
X is oxygen or sulfur; and
A represents an alkylene group of 2 to 5 carbon atoms each of which carbon atoms is optionally substituted with one or two alkyl groups having from 1 to 4 carbon atoms.
Preferred compounds of Formula IA are those where Z and Y are both nitrogen. More preferably, W, Y and Z are all nitrogen. Other preferred compounds of Formula IA are those where R
1
and R
2
are hydrogen and R
5
is hydrogen, methyl, or ethyl.
The present invention also provides compounds of Formula IB:
wherein:
Y and Z independently represent CH or nitrogen;
R
1
, R
2
, R
3
and R
4
are the same or different and represent hydrogen, halogen, C
1
-C
6
alkyl, C
1
-C
4
alkoxy, alkylthio, hydroxy, amino, mono- or dialkylamino where each alkyl is C
1
-C
6
alkyl, cyano, nitro, trifluoromethyl or trifluoromethoxy;
R
5
is hydrogen or C
1
-C
6
alkyl;
W represents CH or nitrogen;
X is oxygen or sulfur; and
A represents an alkylene group of 2 to 5 carbon atoms each of which carbon atoms is optionally substituted with one or two alkyl groups having from 1 to 4 carbon atoms.
Preferred compounds of Formula IB are those where Z and Y are both nitrogen. More preferred compounds of Formula IB are where W, Y and Z are nitrogen and R
5
is hydrogen, methyl, or ethyl. Particularly preferred compounds of Formula IB are where W, Y and Z are nitrogen, R
5
is hydrogen, methyl, or ethyl, and R
1
and R
2
are both hydrogen.
The invention further provides compounds of Formula IC.
wherein:
Y and Z independently represent CH or nitrogen;
R
1
, R
2
, R
3
and R
4
are the same or different and represent hydrogen, halogen, C
1
-C
6
alkyl, C
1
-C
4
alkoxy, alkylthio, hydroxy, amino, mono- or dialkylamino where each alkyl is C
1
-C
6
alkyl, cyano, nitro, trifluoromethyl or trifluoromethoxy;
R
5
is hydrogen or C
1
-C
6
alkyl;
W represents CH or nitrogen;
X is oxygen or sulfur; and
A represents an alkylene group of 2 to 5 carbon atoms each of which carbon atoms is optionally substituted with one or two alkyl groups having from 1 to 4 carbon atoms.
Preferred compounds of Formula IC are those where Z and Y are both nitrogen. More preferred compounds of Formula IC are where W, Y and Z are nitrogen and R
5
is hydrogen, methyl, or ethyl. Particularly preferred compounds of Formula IC are where W, Y and Z are nitrogen, R
5
is hydrogen, methyl, or ethyl, and R
1
and R
2
are both hydrogen.
The invention further encompasses compounds of Formula II:
wherein:
Y and Z
McDonnell & Boehnen Hulbert & Berghoff
Neurogen corporation
LandOfFree
3-aminoalkylamino-2H-1,4-benzoxazines and... does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with 3-aminoalkylamino-2H-1,4-benzoxazines and..., we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and 3-aminoalkylamino-2H-1,4-benzoxazines and... will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-2879222