Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2001-08-29
2002-08-13
Bernhardt, Emily (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C054S050000, C054S050000, C544S295000, C544S364000, C544S368000
Reexamination Certificate
active
06432958
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
This invention relates to 2-piperazinoalkylaminobenzoazole derivatives and to 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, 350: 610 (Van Tol et al., 1991); Nature, 347: 146 (Sokoloff et al., 1990)). 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.
U.S. Pat. No. 5,632,898 discloses N-benzothiazol-2-yl-2-(4-phenylpiperazinyl)acetamide.
U.S. Pat. No. 5,229,398 discloses aminomethylpiperidine derivatives.
SUMMARY OF THE INVENTION
This invention provides novel compounds of Formula I which interact with dopamine subtypes. Accordingly, a broad embodiment of the invention is directed to a compound of Formula I:
wherein
A is C
1
-C
6
alkylene optionally substituted with one or two C
1
-C
6
alkyl groups;
R
1
and R
2
are the same or different and represent hydrogen, halogen, C
1
-C
6
alkyl, C
1
-C
6
alkoxy, C
1
-C
6
alkylthio, hydroxy, amino, mono- or di(C
1
-C
6
)alkylamino, cyano, nitro, C
1
-C
6
alkylsulfonyl, sulfonamide or C
1
-C
6
alkyl sulfonamide, perfluoro(C
1
-C
6
)alkyl or perfluoro(C
1
-C
6
)alkoxy;
R
3
, R
4
, R
5
, and R
6
are the same or different and represent hydrogen or C
1
-C
6
alkyl;
X is sulfur, oxygen or NR
7
where R
7
is hydrogen or C
1
-C
6
alkyl;
R
8
is hydrogen or C
1
-C
6
alkyl;
m is 0 or an integer chosen from 1 and 2; and
Ar represents mono or bicyclic aryl or heteroaryl, each of which is optionally substituted independently with up to five groups selected from C
1
-C
6
alkyl, C
1
-C
6
alkoxy, halogen, C
1
-C
6
alkylthio, hydroxy, amino, mono- or di(C
1
-C
6
)alkylamino, cyano, nitro, trifluoromethyl, trifluoromethoxy, C
1
-C
6
alkylsulfonyl, sulfonamide, or alkyl sulfonamide.
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 neuropsychological 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.
Compounds of this invention are also useful in the treatment of depression, memory-impairment or Alzheimer's disease by modulation of D
4
receptors since they exist selectively in areas known to control emotion and cognitive functions.
Thus, in another aspect, the invention provides methods for treatment and/or prevention of neuropsychological 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 depression, memory-impairment or Alzheimer's disease. 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.
In another aspect, the invention provides intermediates useful in the preparation of compounds of Formula I.
DETAILED DESCRIPTION OF THE INVENTION
As mentioned above, the invention relates to compounds of Formula I. Preferred compounds of Formula I include those where R
3
, R
4
, R
5
, and R
6
independently represent hydrogen or methyl; and R
8
is hydrogen. In more preferred compounds of I, m is 0 or 1; and A is unsubstituted C
1
-C
4
, more preferably unsubstituted C
2
, C
3
, or C
4
, alkylene. In preferred compounds of Formula I, Ar is not unsubstituted phenyl when X is S, R
1
and R
2
are both hydrogen, all of R
2
-R
6
are hydrogen, and m is 0.
Preferred Ar groups in Formula I are those having up to three non-hydrogen substituents selected from the group mentioned above. More preferred Ar groups in Formula I are those having no more than two substituents. Particularly preferred compounds of Formula I include those where Ar is selected from
where each of R
9
and R
10
is independently selected from hydrogen, C
1
-C
6
alkyl, C
1
-C
6
alkoxy, halogen, or trifluoromethyl.
In other particularly preferred compounds of I, R
9
and R
10
are independently selected from hydrogen, C
1
-C
3
alkyl, C
1
-C
3
alkoxy, chloro or fluoro, or trifluoromethyl. In yet other highly preferred compounds of Formula I, Ar is
where each of R
9
and R
10
is independently selected from hydrogen, 4-C
1
-C
3
alkyl, 2-C
1
-C
3
alkoxy, 4-halogen, or 3-trifluoromethyl, provided that one of R
9
and R
10
is hydrogen. Even more preferred are compounds where R
9
and R
10
are independently selected from hydrogen, methyl, methoxy, ethoxy, isopropoxy, chloro, or fluoro.
In another group of preferred compounds of Formula I, R
1
and R
2
independently represent hydrogen, halogen, C
1
-C
6
alkoxy, C
1
-C
6
alkyl, C
1
-C
6
alkylsulfonyl, alkyl sulfonamide, or sulfonamide. A highly preferred group of such compounds include those where at least one of R
1
and R
2
is hydrogen and the other is methoxy, methyl, chloro, fluoro, methoxy, ethoxy, or methylsulfonyl. Particularly preferred compounds of this group include those where R
1
is hydrogen and R
2
is in the 4 or 6 position on the nitrogen containing ring system.
In still another group of preferred compounds of Formula I, Ar is a naphthyl group of the formula
where each of R
9
and R
10
is independently selected from hydrogen, C
1
-C
6
alkyl, C
1
-C
6
alkoxy, halogen, or trifluoromethyl. A preferred group of compounds having the above naphthyl and where X is NH.
A preferred group of compounds of the invention is represented by Formula II:
wherein
A is C
2
-C
6
alkylene optionally substituted with one or two C
1
-C
6
alkyl groups;
R
1
and R
2
are as defined above for Formula I;
R
3
, R
4
, R
5
, and R
6
independently represent hydrogen or C
1
-C
3
alkyl, preferably methyl;
R
8
is hydrogen or C
1
-C
2
alkyl;
m is an integer chosen from 0, 1 or 2; and
Ar is as defined above for Formula I.
In more preferred compounds of II, m is 0 or 1; and A is unsubstituted C
1
-C
4
, more preferably unsubstituted C
2
, C
3
, or C
4
, alkylene.
Particularly preferred compounds of Formula II include those where Ar is selected from
where each of R
9
and R
10
is independently selected from hydrogen, C
1
-C
6
alkyl, C
1
-C
6
alkoxy, halogen, or trifluo
Bernhardt Emily
McDonnell & Boehnen Hulbert & Berghoff
Neurogen Corporation
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