Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
1998-09-03
2001-02-13
Kifle, Bruck (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S253040, C514S253090, C514S253110, C514S254060, C544S359000, C544S362000, C544S366000, C544S371000, C544S376000
Reexamination Certificate
active
06187774
ABSTRACT:
TECHNICAL FIELD
The present invention relates to a novel fused heterocyclic compound having affinity for dopamine D
4
(hereinafter to be referred to as D
4
, the same abbreviation to be employed with regard to the following dopamine receptor subtypes) receptor and serotonin 2 (hereinafter to be referred to as 5-HT
2
) receptor, which blocks NMDA receptor hypofunction, and which is used in the medical field as a central nervous agent, particularly as an antipsychotic agent.
BACKGROUND ART
The following patent applications have been published with regard to central nervous agents having affinity for D
4
receptor. WO94/10162, WO94/21630 and WO94/21626 disclose heterotricyclic aromatic compounds having affinity for D
4
receptor; WO94/21627, WO94/21628 and WO94/24105 disclose indole derivatives having affinity for D
4
receptor; WO94/20459 and WO94/20497 disclose pyrropyridine derivatives having affinity for D
4
receptor; and WO94/21615 and WO94/22839 disclose benzimidazol derivatives having affinity for D
4
receptor. WO94/10145 and WO94/20471 disclose pyrazole derivatives and quinolone derivatives each having affinity for D
4
receptor.
Japanese Patent Unexamined Publication No. 157576/1979 discloses that cydoalkyltriazoles represented by dapiprazole [3-(2-(4-(2-tolyl)-1-piperazinyl)ethyl)-5,6,7,8-tetrahydro-s-triazole-[4,3-a]pyridine] can be used for the therapy of glaucoma, psychosis and the like.
Almost all antipsychotic agents applicable to schizophrenia show a common pharmacological action of blocking the receptor of dopamine which is one of the cerebral neurotransmitters, and exhibit particularly potent D
2
receptor blocking action. These medicaments (typical antipsychotic agents) are effective against positive symptoms centering on hallucination and delusion characteristic of the acute stage of schizophrenia, but are barely effective against negative symptoms of apathy, abulia and autism. In addition, they are associated with serious problems of side effects such as extrapyramidal symptoms (e.g., delayed dyskinesia, acute dystonia, akathisia, etc.) and endocrine disturbance (e.g., hyperprolactinemia) observed upon acute administration and long term consecutive administration.
Dopamine receptor has been conventionally classified into two receptor subtypes by pharmacological methods according to the type of ligand binding and association mode with adenylate cyclase [Nature, vol. 227, p. 93 (1979)]. That is, a D
1
receptor type that promotes adenylate cyclase via acceleratory G protein to produce cyclic AMP, and a D
2
receptor type that suppresses adenylate cyclase via suppressive G protein to suppress production of cyclic AMP. Due to the revolutionary development of molecular biology in recent years, five different genes of dopamine receptors were cloned and the dopamine receptors are now classified into D
1
and D
5
receptors belonging to the D
1
fans, and D
2
, D
3
and D
4
receptors belonging to the D
2
family [Trends in Pharmacol. Sci., vol. 15, p. 264 (1994)].
It has been documented that haloperidol, which is a typical antipsychotic agent, has higher affinity for D
2
receptor than for D
4
receptor, and clozapine, which is associated with less extrapyramidal side effects and also effective against negative symptoms, has 10 times higher affinity for D
4
receptor than for D
2
receptor [Nature, vol. 350, p. 610 (1991)], [Trends in Pharmacol. Sci., vol. 15, p. 264 (1994)]. It has been also reported that the effective therapeutic plasma concentration of clozapine correlates with the affinity constant for D
4
receptor [Trends in Pharmacol. Sci., vol. 15, p. 264 (1994)]. A report has been documented on a binding test using the postmortem brain of a schizophrenic patient, that D
4
receptor showed 6 times greater level than in a healthy subject [Nature, vol. 365, p. 441 (1993)]. Therefrom it appears that D
4
receptor highly likely causes schizophrenia or is present at the action site of a therapeutic agent. There have been found variations in the distribution of dopamine receptor in the brain due to subtypes, wherein D
2
receptor is most frequently found in the corpus striatum, and D
4
receptor is most often found in the frontal lobe of cerebral cortex which is responsible for the emotional functions.
From clinical applications, it has been made clear that the concurrent use of ritanserin (which is a 5-HT
2
receptor blocker) with a typical antipsychotic agent improves negative symptoms and emotional disorders such as anxiety [Current Therapeutics Research, vol. 10, p. 492 (1986)]. Of the side effects caused by antipsychotic agents, malignant syndromes that are most serious and deadly, though low in incidence is, according to one hypothetical view, caused by the imbalance of dopamine/serotonin nervous functions in the body temperature control center [Japanese Journal of Psychopharmacology, vol. 11, p. 17 (1989)], and suppression of the onset of the disease by the application of the 5-HT
2
receptor blocking action is expected.
There is also a hypothetical view on the cause of schizophrenia, that says that the degradation of the function of the NMDA (N-methyl-D-aspartic acid) nervous system that is projected from the cerebral cortex to subcortex impairs the suppressive feed-back function of the information control circuit, which in turn aggravates the schizophrenia state, like the excessive promotion of the activity of the subcortical dopamine nervous system, and clozapine has been reported to show blockage of NMDA receptor hypofunction besides the action on dopamine and serotonin nervous systems [Trends Neurosci., vol. 13, p. 272 (1990)].
From the foregoing, a compound having a D
4
receptor and 5-HT
2
receptor blocking action, and which blocks NMDA receptor hypofunction, is expected to make an antipsychotic agent associated with less extrapyramidal side effects and effective against both positive and negative symptoms. It is therefore an object of the present invention to provide a compound exhibiting strong blocking action on D
4
receptor and 5-HT
2
receptor, as well as blockage of NMDA receptor hypofunction, which is effective against both negative symptoms and positive symptoms as compared to conventional compounds and which is associated with less side effects.
DISCLOSURE OF THE INVENTION
The present inventors have conducted intensive studies and found that a novel fused heterocyclic compound of the following formula (I), an optical isomer thereof and a pharmaceutically acceptable salt thereof have stronger blocking action on D
4
receptor and 5-HT
2
receptor than on D
2
receptor, and that they show blockage of NMDA receptor hypofunction. The present inventors have further found that these compounds can make useful antipsychotic agents effective against not only positive symptoms centering on hallucination and delusion characteristic of the acute stage of schizophrenia, but also negative symptoms of apathy, abulia and autism, that cause less side effects such as extrapyramidal symptoms and endocrine disturbance observed when conventional antipsychotic agents having D
2
receptor blocking action are administered, which resulted in the completion of the present invention.
Accordingly, the present invention relates to a fused heterocyclic compound of the formula (I)
wherein
R is a group selected from the group consisting of the groups having the following formulas (1), (2), (3), (4), (5), (6), (7), (8) and (9)
wherein
Y is a linear or branched C
1
-C
4
alkylene optionally having a substituent
R
1a
at an optional position, wherein R
1a
is hydrogen, alkyl, hydroxy, alkoxy, amino or alkylamino,
A is void, or an oxygen atom, a sulfur atom, SO, SO
2
or N—R
7
wherein R
7
is hydrogen, alkyl, arylalkyl or acyl,
B is a linear or branched C
1
-C
4
alkylene optionally having a substituent
R
1b
at an optional position, wherein R
1b
is hydrogen, alkyl, hydroxy, alkoxy, amino or alkylamino,
R
2a
, R
2b
and R
2c
are the same or different and each
Fujio Masakazu
Futamura Takashi
Ishibuchi Seigo
Kuroita Takanobu
Tanaka Hiroshi
Kifle Bruck
Wenderoth , Lind & Ponack, L.L.P.
Yoshitomi Pharmaceutical Industries Ltd.
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