1-azatricyclic-4-benzylpiperazines

Details 1-azatricyclic-4-benzylpiperazines 1-azatricyclic-4-benzylpiperazines

2000-06-14

2001-09-25

Kifle, Bruck (Department: 1624)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

C540S520000

Reexamination Certificate

active

06294530

ABSTRACT:

BACKGROUND OF THE INVENTION
1. Field of the Invention
This invention relates to 1-azatricyclic-4-benzylpiperazines, and to compounds that bind to dopamine receptors. This invention also relates to pharmaceutical compositions comprising such compounds and also to the treatment of central nervous system (CNS) diseases, particularly the treatment or prevention of psychotic disorders such as schizophrenia. Additionally this invention relates to the use of compounds as probes for the localization of dopamine receptors in tissue sections.
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 been identified and cloned. Its unique localization in limbic brain areas and its differential recognition of various antipsychotics suggest that the D
4
receptor may play a major role in the etiology of schizophrenia. The dopamine D
4
receptor shares sequence homology with dopamine D
2
and D
3
receptors, however the D
4
receptor possesses a unique pharmacological profile. Selective D
4
antagonists, including the marketed antipsychotic chlozapine, are considered effective antipsychotics free from the neurological side effects displayed by conventional neuroleptics. Compounds that possess a 10-fold or more higher affinity for dopamine D
4
receptors than D
2
receptors are considered particularly desirable as antipsychotics.
Since dopamine D
4
receptors are concentrated in the limbic system which controls cognition and emotion, compounds which interact with these receptors have utility in the treatment of cognitive disorders. Such disorders include the cognitive deficits which are a significant component of the negative symptoms (social withdrawal and unresponsiveness) of schizophrenia. Other disorders involving memory impairment or attention deficit disorder can also be treated with compound that interact specifically with the dopamine D
4
receptor subtype.
SUMMARY OF THE INVENTION
This invention provides 1-azatricyclic-4-benzylpiperazine compounds that bind, preferably with high affinity and selectivity, to the D
4
receptor subtype, including human D
4
receptors. 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.
Thus, the invention provides compounds of Formula I (shown below), and pharmaceutical compositions comprising compounds of Formula I.
The invention further comprises methods of treating patients suffering from CNS disorder with a therapeutically effective amount of a compound of the invention. The patient may be a human or other mammal. Treatment of humans, domesticated companion animals (pets) or livestock animals suffering from CNS disorder with a therapeutically effective amount of a compound of the invention is encompassed by the invention. Particularly methods for the treatment and/or prevention of neuropsychological or affective disorders, 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 are included. In addition, the compounds of the invention are useful in treatment of depression, memory-impairment or Alzheimer's disease by modulation of D
4
receptors which selectively exist in limbic areas 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.
Accordingly, a broad aspect of the invention is directed to compounds of Formula I:
or a pharmaceutically acceptable salt thereof, wherein
A represents phenyl optionally substituted with up to four groups independently selected from halogen, hydroxy, amino, mono- or di(C
1
-C
6
)hydrocarbylamino, aminosulfonyl, C
1
-C
6
hydrocarbylaminosulfonyl, di(C
1
-C
6
)hydrocarbylaminosulfonyl, cyano, nitro, cyclohydrocarbylhydrocarbyl, trifluoromethyl, C
1
-C
6
hydrocarbyl, trifluoromethoxy, C
3
-C
6
cyclohydrocarbyl, and C
1
-C
6
alkoxy;
R
5
and R
6
are the same or different and represent hydrogen or C
1
-C
6
hydrocarbyl; and
R
2
represents hydrogen, halogen, hydroxy, amino, mono- or di(C
1
-C
6
)hydrocarbylamino, aminosulfonyl, C
1
-C
6
hydrocarbylaminosulfonyl, di(C
1
-C
6
)hydrocarbylaminosulfonyl, cyano, nitro, cyclohydrocarbylhydrocarbyl, trifluoromethyl, C
1
-C
6
hydrocarbyl, trifluoromethoxy, C
3
-C
6
cyclohydrocarbyl, or C
1
-C
6
alkoxy; and
n is 0, 1, or 2.
DETAILED DESCRIPTION OF THE INVENTION
The invention encompasses the compounds of Formula I described above.
In preferred compounds of formula I,
A represents phenyl optionally substituted with up to four groups independently selected from halogen, hydroxy, amino, mono- or di(C
1
-C
6
)alkylamino, aminosulfonyl, C
1
-C
6
alkylaminosulfonyl, di(C
1
-C
6
)alkylaminosulfonyl, cyano, nitro, cycloalkylalkyl, trifluoromethyl, (C
1
-C
6
)alkyl, trifluoromethoxy, C
3
-C
6
cycloalkyl, and C
1
-C
6
alkoxy;
R
5
and R
6
are the same or different and represent hydrogen or C
1
-C
6
alkyl; and
R
2
represents hydrogen, halogen, hydroxy, amino, mono- or di(C
1
-C
6
)alkylamino, aminosulfonyl, C
1
-C
6
alkylaminosulfonyl, di(C
1
-C
6
)alkylaminosulfonyl, cyano, nitro, cycloalkylalkyl, trifluoromethyl, (C
1
-C
6
)alkyl, trifluoromethoxy, C
3
-C
6
cycloalkyl, or C
1
-C
6
alkoxy; and
n is 0, 1, or 2.
In other preferred compounds of Formula I, n is 2;
A represents phenyl optionally substituted with up to four groups independently selected from halogen, hydroxy, amino, mono- or di(C
1
-C
6
)alkylamino, cyano, nitro, cycloalkylalkyl, trifluoromethyl, (C
1
-C
6
)alkyl, trifluoromethoxy, C
3
-C
6
cycloalkyl, and C
1
-C
6
alkoxy;
R
5
and R
6
are the same or different and represent hydrogen or C
1
-C
6
alkyl; and
R
2
represents hydrogen, halogen, hydroxy, amino, mono- or di(C
1
-C
6
)alkylamino, cyano, nitro, cycloalkylalkyl, trifluoromethyl, (C
1
-C
6
)alkyl, trifluoromethoxy, C
3
-C
6
cycloalkyl, or C
1
-C
6
alkoxy.
More preferred compounds of Formula I are those where A is a group of the formula:
where R
3
and R
4
independently represent hydrogen, halogen, hydroxy, amino, aminosulfonyl, C
1
-C
6
alkylaminosulfonyl, di(C
1
-C
6
)alkylaminosulfonyl, cyano, nitro, trifluoromethoxy, C
1
-C
6
alkyl, or C
1
-C
6
alkoxy.
These more preferred compounds are represented by Formula II herein.
In preferred compounds of Formula II, R
3
and R
4
are the same or different and are C
1
-C
3
alkyl, chloro, fluoro, bromo, or C
1
-C
3
alkoxy. More preferably, in compounds of Formula II at least one of R
3
and R
4
is attached at the ortho or para position of the phenyl ring. Still more preferably, R
2
in Formula II is hydrogen, fluoro, chloro, or C
1
C
2
alkyl.
In other preferred compounds of II, R
2
is hydrogen. Such compounds are designated as compounds of Formula II-A hereinafter. In these compounds, R
3
and R
4
are the same or different and are C
1
-C
3
alkyl, chloro, fluoro, bromo, or C
1
-C
3
alkoxy. Preferably, compounds of Formula II-A are those where at least one of R
3
and R
4
is in the ortho or para position of the phenyl ring. More preferred compounds of II-A are those wherein R
5
and R
6
independently represent hydrogen or C
1
-C
2
alkyl. Still other more preferred compound

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