Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1999-06-30
2001-09-18
Bernhardt, Emily (Department: 1611)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C544S368000
Reexamination Certificate
active
06291463
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
This invention relates to 1-(benzothiazol-2-yl)-4-(1-phenylmethyl)piperazines 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, 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.
J. Heterocycl. Chem., 32: 707-718 (Orjales et al., 1995) discloses piperazinebenzothiazole derivatives said to be useful as antihistaminics.
J. Med. Chem., 37: 1320-1325 (Monge et al., 1994) discloses piperazinebenzothiazole derivatives as 5-HT
3
antagonists and 5-HT
4
agonists.
Published International Application WO 9420494 discloses piperazinebenzothiazole derivatives said to be capable of stimulating gastrointestinal motility.
SUMMARY OF THE INVENTION
This invention provides novel compounds of Formula I which interact with dopamine receptor subtypes. Accordingly, a broad aspect of the invention is directed to a compound of Formula I:
or pharmaceutically acceptable addition salts thereof wherein:
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 or trifluoromethyl;
Ar represents aryl or heteroaryl, each of which is optionally substituted with R
3
, R
4
and/or R
6
;
R
7
, R
8
, R
9
, and R
10
are the same or different and represent hydrogen or C
1
-C
6
alkyl;
R
3
, R
4
, and R
6
independently represent hydrogen, halogen, hydroxy, C
1
-C
6
alkyl, C
1
-C
6
alkoxy, perfluoro(C
1
-C
6
)alkyl, perfluoro(C
1
-C
6
)alkoxy, or SO
2
NH
2
, provided that when Ar is phenyl and two or three of R
3
, R
4
, and R
6
are methoxy, no two methoxy groups may be positioned ortho to each other on the phenyl ring; or
R
3
and R
4
together with the atoms to which they are attached represent a ring having 5-7 atoms;
R
5
represents hydrogen or C
1
-C
6
alkyl.
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 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 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 noted above, this invention provides compounds of Formula I which interact with dopamine subtypes.
Preferred compounds of Formula I are those where R
1
and R
2
are hydrogen. More preferred compounds of Formula I are those wherein R
1
and R
2
are hydrogen and Ar is not unsubstituted phenyl, i.e., phenyl substituted with at least one non-hydrogen substituent. Particularly preferred compounds of Formula I are those where Ar is phenyl or naphthyl, each of which is optionally substituted with up to three of the groups listed above. In these particularly preferred compounds, when Ar is phenyl and R
1
and R
2
are hydrogen, R
3
, R
4
, and R
6
may not all be hydrogen simultaneously. Other preferred compounds of Formula I are those where R
7
, R
8
, R
9
, and R
10
are hydrogen or C
1
-C
2
alkyl.
In preferred compounds, when Ar is phenyl and two or three of R
3
, R
4
, and R
6
are methoxy or ethoxy, no two methoxy groups may be methoxy groups positioned ortho to each other; more preferably no methoxy group may be positioned ortho to another methoxy group or to an ethoxy group. Even more preferably, when Ar is phenyl and two or three of R
3
, R
4
, and R
6
are methoxy or ethoxy, no methoxy or ethoxy group may be in an ortho position on the phenyl ring with respect to another methoxy or ethoxy group. Highly preferred compounds of the invention include those where one and only one of R
3
, R
4
, and R
6
is C
1
-C
6
alkoxy when Ar is phenyl.
More preferred compounds of Formula I are those where Ar is
Preferred compounds of the invention include those of Formula II:
wherein
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 or trifluoromethyl;
R
3
and R
4
are the same or different and represent hydrogen, halogen, hydroxy, C
1
-C
6
alkyl, trifluoromethyl, trifluoromethoxy, or SO
2
NH
2
, provided that not both R
3
and R
4
are hydrogen simultaneously; and
R
5
represents hydrogen or C
1
-C
6
alkyl.
Preferred compounds of Formula II include those where R
5
is hydrogen. Other preferred compounds of Formula II include those where R
5
is hydrogen, and R
3
is halogen or C
1
-C
6
alkyl. More preferred compounds of Formula II are where R
4
is halogen, R
5
is hydrogen, and R
3
is halogen or C
1
-C
6
alkyl. Particularly preferred compounds of Formula II are those where R
1
and R
2
are hydrogen, R
4
is halogen, R
5
is hydrogen, and R
3
is halogen or C
1
-C
6
alkyl. A highly preferred group of compounds are those where R
4
is halogen in the meta position of the phenyl ring, R
5
is hydrogen, and R
3
is halogen or C
1
-C
6
alkyl.
Highly preferred compounds of Formula II are those where the phenyl carrying R
3
and R
4
is selected from:
Other preferred compounds of the invention are those of Formula III:
wherein:
R
1
and R
2
are the same or different and represent hydrogen,
Bernhardt Emily
McDonnellBoehnen Hulbert & Berghoff
Neurogen Corporation
Sarussi Steven J.
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