1-phenyl-4-(1-[2-aryl]cyclopropyl)methylpiperazine...

Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...

Reexamination Certificate

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Details

C544S392000, C544S394000

Reexamination Certificate

active

06284761

ABSTRACT:

BACKGROUND OF THE INVENTION
1. Field of the Invention
This invention relates to 1-phenyl-4-(1-[2-aryl]cyclopropyl)methylpiperazine 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.
SUMMARY OF THE INVENTION
This invention provides novel compounds of Formula I which interact with dopamine subtypes. Accordingly, a first aspect of the invention is directed to a compound of Formula I:
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, nitro, perfluoro(C
1
-C
6
)alkyl or perfluoro(C
1
-C
6
)alkoxy;
R
3
and R
4
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, perfluoro(C
1
-C
6
)alkyl or perfluoro(C
1
-C
6
)alkoxy;
A is an alkylene group of 1-3 carbon atoms; and
R
5
, R
6
, R
7
, and R
8
are the same or different and represent 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 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.
Additionally, when appropriately labeled, compounds of this invention are useful as probes for the localization of dopamine receptors. Localization of receptors may be performed in vitro, e.g., via autoradiography of tissue sections, or in vivo, e.g., via positron emission tomography (PET).
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.
The invention also provides methods for preparing the compounds of the invention.
DETAILED DESCRIPTION OF THE INVENTION
The invention encompasses the compounds of Formula I described above.
Preferred compounds of Formula I are those where R
5
, R
6
, R
7
, and R
8
are C
1
-C
3
alkyl, and more preferably, hydrogen or methyl. Even more preferred compounds of Formula I are those where R
5
, R
6
, R
7
and R
8
are hydrogen. In the more preferred compounds of Formula I the hydrogens at positions R
5
and R
8
are in a trans configuration to one another. Particularly preferred compounds of Formula I have R
1
, R
2
, R
3
and R
4
as hydrogen, halogen or lower alkyl.
In other preferred compounds of I, when R
1
and R
3
-R
8
are all hydrogen, R
2
is not tert-butyl, or more preferably not C
1
-C
6
alkyl.
In addition, the invention encompasses compounds of Formula II.
R
1
and R
2
are same or different and represent hydrogen, halogen, C
1
-C
6
alkyl, C
1
-C
6
alkoxy, C
1
-C
4
alkylthio, hydroxy, amino, mono- or di(C
1
-C
6
)alkylamino, cyano, nitro, perfluoro(C
1
-C
6
)alkyl or perfluoro(C
1
-C
6
)alkoxy;
R
3
and R
4
are the same or different and represent hydrogen, halogen, C
1
-C
6
alkyl, C
1
-C
4
alkoxy, C
1
-C
4
alkylthio, hydroxy, amino, mono- or di(C
1
-C
6
)alkylamino, cyano, nitro, perfluoro(C
1
-C
6
)alkyl or perfluoro(C
1
-C
6
)alkoxy; and
R
5
, R
6
, R
7
, and R
8
are the same or different and represent hydrogen or C
1
-C
3
alkyl;
provided that R
2
is not t-butyl when R
1
and R
3
-R
8
are all hydrogen.
In preferred compounds of Formula II, R
5
and R
8
are trans to each other. In yet more preferred compounds of Formula II, R
5
, R
6
, R
7
, and R
8
are hydrogen or methyl. More preferred compounds of Formula II are those where R
5
, R
6
, R
7
and R
8
are hydrogen. In the most preferred compounds of Formula I the hydrogens at positions R
5
and R
8
are in a trans configuration to one another. Particularly preferred compounds of Formula I have R
1
, R
2
, R
3
and R
4
as hydrogen, halogen or lower alkyl.
In other preferred compounds of Formula I, one of R
1
and R
2
may be halogen, preferably in the para position on the phenyl ring, while the other is hydrogen. In these preferred compounds R
3
and R
4
are preferably in the para and one of the ortho, i.e., the 4 and 2) positions with respect to the point of attachment to the phenyl ring and are hydrogen, halogen or C
1
-C
3
alkyl, provided that at least one of R
3
and R
4
is not hydrogen.
In addition, the invention encompasses compounds of Formula III:
wherein
R
1
and R
2
independently represent hydrogen, halogen, C
1
-C
3
alkyl, C
1
-C
4
alkoxy, C
1
-C
4
alkylthio, hydroxy, amino, mono- or di(C
1
-C
6
)alkylamino, cyano, nitro, perfluoro(C
1
-C
6
)alkyl or perfluoro(C
1
-C
6
)alkoxy;
R
3
and R
4
are the same or different and represent hydrogen, halogen, C
1
-C
6
alkyl, C
1
-C
4
alkoxy, C
1
-C
4
alkylthio, hydroxy, amino, mono- or di(C
1
-C
6
)alkylamino, cyano, nitro, perfluoro(C
1
-C
6
)alkyl or perfluoro(C
1
-C
6
)alkoxy; and
R
5
, R
6
, R
7
, and R
8
are the same or different and represent hydrogen or C
1
-C
3
alkyl.
Preferred compounds of Formula III are those where R
1
and R
2
are independently hydrogen, halogen, methyl, or ethyl. In more preferred compounds of Formula III, R
1
and R
2
are both hydrogen.
In other preferred compounds of Formula III, at least one of R
1
and R
2
is not h

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