Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2002-04-12
2004-10-19
Rotman, Alan L. (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S326000, C546S187000, C544S253000
Reexamination Certificate
active
06806275
ABSTRACT:
TECHNICAL FIELD
The present invention relates to arylpiperidine derivatives having antipsychotic effect.
BACKGROUND ART
Antipsychotic agents are used not only for treating schizophrenia but also for treating problem behaviors associated with cerebrovascular diseases or senile dementia (e.g. aggressive behaviors, psychogenic excitement, ecdemomania and delirium). However, dopamine D
2
receptor antagonists, conventional antipsychotic agents, cause serious extrapyramidal diseases as side effects, which has been a serious problem.
On the other hand, recently found dopamine D
4
receptors are similar to dopamine D
2
receptors in structure and properties but are utterly different from dopamine D
2
receptors in intracerebral distribution. The intracerebral distribution of dopamine D
4
receptors is such that they are present in a high concentration in cerebral cortex frontal lobe concerned with the onset of schizophrenia and are present in a low concentration in striatum involved in the onset of extrapyramidal diseases. Therefore, unlike the dopamine D
2
receptor antagonists, dopamine D
4
receptor antagonists are very likely to become novel therapeutic agents for schizophrenia which do not cause extrapyramidal diseases as side effects (Nature, 350, 610-614(1991); Nature, 358, 109(1992); Nature 365, 393(1993); Nature 365, 441-445(1993)).
As such a compound, there is clozapine. It has been reported that the affinity of clozapine for dopamine D
4
receptors is higher than that for dopamine D
2
receptors (Nature, 350, 610-614(1991)). It has also been reported that in clinical investigation of clozapine, unlike the dopamine D
2
receptor antagonists, clozapine is effective on drug-resistant schizophrenia and negativism and hardly causes extrapyramidal diseases (Arch. Gen. Psych., 45, 789-796(1988)). Clozapine, however, causes a blood disease called agranulocytosis and deaths due to this disease have been reported (Summary and Clinical Data. Sandoz, Canada Inc. (1990)), and this is an serious defect of clozapine.
Accordingly, dopamine D
4
receptor antagonists which do not have such a side effect are very useful as therapeutic agents for schizophrenia and the like which are very unlikely to cause extrapyramidal diseases.
DISCLOSURE OF THE INVENTION
An object of the present invention is to provide a dopamine D
4
receptor antagonistic compound which has antipsychotic effect without causing extrapyramidal diseases.
The present inventors earnestly investigated arylpiperidine derivatives and consequently found novel arylpiperidine derivatives having a high affinity for dopamine D
4
receptors, whereby the present invention has been accomplished.
The present invention is explained below.
The present invention is an arylpiperidine derivative represented by the formula (I):
[wherein D is a carbon atom or a nitrogen atom, E is a CH group or a nitrogen atom, G is an oxygen atom, a sulfur atom, a nitrogen atom or an NH group, Y
1
is a hydrogen atom or a halogen atom, n is an integer of 1 to 4, and R
1
is a group represented by the formula (i):
(wherein R
2
is a hydrogen atom, an alkyl group of 1 to 5 carbon atoms, an amino group, a monoalkylamino group of 1 to 5 carbon atoms, a hydroxyl group, an alkoxycarbonyl group of 2 to 6 carbon atoms, a carbamoyl group, a carboxyl group, or a metal salt of carboxyl group, and Ar is a substituted or unsubstituted phenyl group or a thienyl group), a group represented by the formula (ii):
(wherein R
3
is an alkyl group of 1 to 5 carbon atoms, each of X
1
and X
2
, which are different from each other, is a nitrogen atom or an NH group, and Ar is a substituted or unsubstituted phenyl group or a thienyl group), a group represented by the formula (iii):
(wherein X
1
and X
2
are as defined above, and Ar is a substituted or unsubstituted phenyl group or a thienyl group), or a group represented by the formula (iv):
(wherein R
4
is a hydrogen atom, a mercapto group, or an alkylthio group of 1 to 5 carbon atoms, and Ar is a substituted or unsubstituted phenyl group or a thienyl group)] or a pharmaceutically acceptable salt thereof.
In the present invention, the substituted phenyl group refers to a phenyl group having one or two substituents selected from halogen atoms, alkyl groups of 1 to 5 carbon atoms, alkoxy groups of 1 to 5 carbon atoms and trifluoromethyl group, and is, for example, a 2-fluorophenyl group, 3-fluorophenyl group, 4-fluorophenyl group, 4-chlorophenyl group, 4-bromophenyl group, 3,4-dichlorophenyl group, 4-methylphenyl group, 3,4-dimethylphenyl group, 4-methoxyphenyl group, 3,4-dimethoxyphenyl group, 2-trifluoromethylphenyl group, 3-trifluoromethylphenyl group or 4-trifluoromethylphenyl group.
The halogen atom is a fluorine atom, chlorine atom, bromine atom or iodine atom.
The alkyl group of 1 to 5 carbon atoms is a linear, branched or cyclic alkyl group such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, t-butyl, cyclopropylmethyl, pentyl, isopentyl or the like.
The alkoxy group of 1 to 5 carbon atoms is a linear or branched alkoxy group such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, t-butoxy, pentoxy, 3-methylbutoxy or the like.
The monoalkylamino group of 1 to 5 carbon atoms is, for example, a methylamino group, ethylamino group, propylamino group, isopropylamino group or the like.
The alkylthio group of 1 to 5 carbon atoms is, for example, a methylthio group, ethylthio group, propylthio group, isopropylthio group, butylthio group, isobutylthio group or the like.
The alkoxycarbonyl group of 2 to 6 carbon atoms is, for example, a methoxycarbonyl group, ethoxycarbonyl group, propoxycarbonyl group, isopropoxycarbonyl group, butoxycarbonyl group or the like.
The pharmaceutically acceptable salt of the present invention is, for example, a salt with a mineral acid such as sulfuric acid, hydrochloric acid, phosphoric acid or the like, or a salt with an organic acid such as acetic acid, oxalic acid, lactic acid, tartaric acid, fumaric acid, maleic acid, trifluoroacetic acid, methanesulfonic acid, pamoic acid, decanoic acid, enanthic acid or the like.
Arylpiperidine derivatives of the formula (I) in which R
1
is represented by the formula (ii) or (iii) have tautomers due to their chemical structures, and the present invention includes these tautomers.
The compound of the present invention is preferably an arylpiperidine derivative represented by the formula (II):
(wherein R
2
, Ar, D, E, G, Y
1
and n are as defined above) or a pharmaceutically acceptable salt thereof.
Said compound is more preferably an arylpiperidine derivative represented by the formula (III):
(wherein Y
1
is as defined above, Y
2
is a hydrogen atom or a halogen atom, J is an oxygen atom, a sulfur atom or an NH group, and R
5
is an alkyl group of 1 to 5 carbon atoms, an amino group or a carbamoyl group) or a pharmaceutically acceptable salt thereof.
The compound of the formula (I) can be produced by any of the following processes.
In the following reaction formulas, Ar, D, E, G, R
3
, R
4
, X
1
, X
2
, Y
1
and n are as defined in the above formula (I), R
6
is a hydrogen atom, an alkyl group of 1 to 5 carbon atoms, an amino group, or a monoalkylamino group of 1 to 5 carbon atoms, R
7
and R
8
are taken together with the adjacent nitrogen atom to represent a pyrrolidino group, a piperidino group, a morpholino group, an N-methylpiperazino group or the like, Z is a chlorine atom, a bromine atom or an iodine atom, M
1
is, for example, sodium, potassium or NH
4
, and M
2
is an alkali metal ion (e.g. sodium, potassium, lithium or calcium), an alkaline earth metal ion or a hydrogen atom.
A ketone derivative (1) is halogenated with a halogenating agent in an inert solvent and then reacted with a thiourea derivative or thioamide derivative of the formula (2) or with a urea derivative or amide derivative of the formula (3) and a sulfurizing agent, in an inert solvent in the presence or absence of a dehydrating agent to obtain a compound (4). Subsequently, the compound (4) is reacted with a piperidine derivative of the formu
Chaki Shigeyuki
Gotoh Makoto
Kumagai Toshihito
Nagamine Masashi
Nakazato Atsuro
Manelli Denison & Selter PLLC
Nihon Nohyaku Co. Ltd.
Robinson Binta
Rotman Alan L.
White, Jr. Paul E.
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