Organic compounds -- part of the class 532-570 series – Organic compounds – Nitrogen attached directly or indirectly to the purine ring...
Reexamination Certificate
1999-06-30
2001-01-23
Bernhardt, Emily (Department: 1611)
Organic compounds -- part of the class 532-570 series
Organic compounds
Nitrogen attached directly or indirectly to the purine ring...
C544S377000
Reexamination Certificate
active
06177566
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
This invention relates to 6-(4-arylalkylpiperazin-1-yl) benzodioxanes and 6-(4-arylalkylpiperazin-1-yl)chromanes 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.
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:
or pharmaceutically acceptable addition salts thereof wherein:
A is C
1
-C
4
alkylene optionally substituted with C
1
-C
2
alkyl;
R
1
, R
2
, R
3
, R
4
and R
5
independently 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, perfluoroalkyl or perfluoroalkoxy; and
R
6
, R
7
, R
8
, and R
9
independently represent hydrogen or C
1
-C
6
alkyl; and
X is oxygen, a bond, C
1
-C
2
alkylene, or methyleneoxy.
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.
REFERENCES:
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patent: 5462942 (1995-10-01), Hartog et al.
patent: 5464834 (1995-11-01), Peglion et al.
patent: 5550129 (1996-08-01), Noldner et al.
patent: 5684020 (1997-11-01), Peglion et al.
patent: 5753662 (1998-05-01), Peglion et al.
patent: 5859246 (1999-01-01), Thurkauf et al.
patent: WO 97/41108 (1997-11-01), None
patent: WO 97/44334 (1997-11-01), None
patent: WO 97/45419 (1997-12-01), None
patent: 9833784 (1998-08-01), None
Boyfield, I. et al., Bioorganic & Medicinal Chemistry Letters (1996), vol. 6, No. 11, pp. 1227-1232, “n-substituted-phenyl)piperazines: Antagonists with High Binding and Functional Selectivity for Dopamine D4 Receptors”.
Hadley, Michael S., Medicinal Research Reviews (1996), vol. 16, No. 6, pp. 507-526, “D4 Receptors and their Antagonists”.
Sarati, S. et al., Psychopharmacology (1991), vol. 105, pp. 541-545, “Kinetics of Piribedil and Effects on Dopamine Metabolism; Hepatic Biotransformation is not a Determinant of its Dopaminergic Action in Rats”.
Reitz, Allen B. et al., J. Med. Chem. (1995), vol.38, No. 21, pp. 4211-4222, “n-aryl-n′-benzylpiperazines as Potential Antipsychotic Agents”.
Van Steen et al.,J. Med. Chem. 37, p. 2761-2773 (1994).
Thurkauf Andrew
Tran Jennifer N.
Bernhardt Emily
McDonnell & Boehnen Hulbert & Berghoff
Neurogen Corporation
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