Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2001-04-20
2004-01-06
Bernhardt, Emily (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S326000, C544S367000, C546S209000
Reexamination Certificate
active
06673800
ABSTRACT:
BACKGROUND OF THE INVENTION
Field of the Invention
The present invention relates to 4,5-dihydroisoxazolylalkylpiperazine derivatives having selective biological activity at dopamine D
3
or D
4
receptors represented by the following formula (1), and its preparation method through reductive amination reaction in the presence of a reducing agent,
wherein R
1
represents aryl, arylalkyl, diarylalkyl, and heteroaryl, where the aryl groups may have one or more substituents selected from C
1
-C
6
alkyl, C
1
-C
6
alkoxy and a halogen atom, for example, phenylmethyl, diphenylmethyl, (2-trifluoromethylphenyl)methyl, phenyl, 2-methylphenyl, 2-methoxyphenyl, 3-methoxyphenyl, 2-ethoxyphenyl, 2-fluorophenyl, 4-fluorophenyl, 2-chlorophenyl, 4-chlorophenyl, 2-pyrimidyl, 4-chlorobenzhydryl, or 4,4′-difluorobenzhydryl group;
R
2
represents aryl, arylalkenyl and heteroaryl group, where the aryl groups may have one or more substituents selected from a halogen atom, nitro, C
1
-C
6
alkyl and C
1
-C
6
alkoxy group, for example, phenyl, 4-fluorophenyl, 4-chlorophenyl, 3-nitrophenyl, 2,4-dimethoxyphenyl, 3,4-dimethoxyphenyl, 3-phenoxyphenyl, styryl, 2-thienyl or 2-thiazol group
X represents CH or a nitrogen atom; and
n represents 3 or 4.
Dopamine is a neurotransmitter found in the brain of animals including human, which is indispensable in the transmission of nerve signals. The dopamine antagonist inhibits the binding of dopamine and dopamine receptor as an antipsychotic, and it is used for the treatment of mental disorder like schizophrenia.
According to recent publications, there are more than one type of dopamine receptors that function through G-protein, and some dopamine antagonists inhibit one type of dopamine receptor preferentially to the others. As the representative dopamine receptors early found, there are D
1
receptor that induces the activation of adenylyl cyclase and D
2
receptor that inhibits it. Afterwards totally 5 dopamine receptors were found, and they have been classified into two groups: D
1
group (D
1
and D
5
) and D
2
group (D
2
, D
3
and D
4
).
Mental disease is related with central dopaminergic nerve system, and central postsynaptic receptor antagonists or presynaptic receptor (autoreceptor) agonists can be used as antipsychotics. Especially the D
2
group receptor antagonist haloperidol, a typical antipsychotic, gives extrapyramidal side effect (EPS) in case of long-term treatment. Such side effects occur from hypersensitive reaction due to the long-term inhibition of central dopamine receptor, and include involuntary movement (tardive dyskinesia) and hyperprolactinaemia caused by the inhibition of dopamine receptor at the pituitary gland. On the other hand, the antagonists that selectively act on dopamine D
3
or D
4
receptors are known to have no side effects like extrapyramidal side effect and tardive dyskinesia.
Accordingly, in the treatment of mental disease like schizophrenia, development of drugs having few side effects, i.e. new compounds that selectively acts on dopamine D
3
or D
4
receptor is of great importance.
SUMMARY OF THE INVENTION
As a result of the efforts to develop novel chemical compounds that selectively act on dopamine D
3
or D
4
receptors, the inventors found that novel compounds obtained by introducing various substituents to 4,5-dihydroisoxazolylalkylpiperazine skeleton have superior and selective antagonistic activity against dopamine D
3
or D
4
receptors.
Accordingly, the present invention aims at providing novel compounds useful for the treatment of mental disease, preparation methods thereof and pharmaceutical compositions containing them respectively as effective components.
REFERENCES:
patent: 4397853 (1983-08-01), Kawakita et al.
patent: 6166033 (2000-12-01), Nakazato et al.
patent: WO99/43670 (1998-02-01), None
patent: 98/15541 (1998-04-01), None
Hery et al. Medline Abstract for Encephale,vol. 19,pp. 525-532 (1993).*
Mason et al. Medline Abstract for Eur. J. Pharmacol.,vol. 221, pp. 397-398 (1992).*
“Advanced Organic Chemistry” by jerry March (2nd ed.),pp. 819-820.*
“Enantio- and Diastereocontrolled Dopamine D1, D2, D3 and D4 Receptor Binding of N-(3-Pyrrolidinylmethyl) benzamides Synthesized from Aspartic Acid”, C Thomas et al., Bioorg. Med Chem Lett 9 (1999) pp. 841-846.
“4-Heterocyclylpiperidines as Selective High-Affinity Ligands at the Human Dopamine D4 Receptor”, Journal of Medicinal Chemistry, 1997, vol. 40, No. 15, pp. 2374-2375.
“Substituted [(4-Phenylpiperazinyl)-methyl]benzamindes: Selective Dopamine D4 Agonists”, Shelly A. Glase, et al., Journal of Medicinal Chemistry, 1997, vol. 40, No. 12 (1771-1772).
Cho Yong Seo
Choi Kyung Il
Jeong Dae Young
Jung Ji Young
Jung Sun Ho
Bernhardt Emily
Korea Institute of Science and Technology
Lowe Hauptman & Gilman & Berner LLP
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