Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-09-15
2001-09-18
Lambkin, Deborah C. (Department: 1626)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S274000, C514S275000, C514S326000, C514S330000, C514S335000, C544S297000, C544S298000, C544S332000, C546S209000, C546S210000, C546S211000
Reexamination Certificate
active
06291467
ABSTRACT:
TECHNICAL FIELD
The present invention relates to dopamine D
4
receptor antagonist compounds useful as antipsychotic drugs.
BACKGROUND ART
Antipsychotic agents are used not only for treating schizophrenia and problem behaviors associated with cerebrovascular diseases and senile dementia (e.g. aggressive behaviors, psychogenic excitement, ecdemomania or delirium). However, dopamine D
2
receptor antagonists, prior art antipsychotic drugs, 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 distributions. The intracerebral distribution of dopamine D
4
receptors is such that they are present in a high concentrations in the corticocerebral frontal lobe concerned with the onset of schizophrenia and are present in a low concentration in the striatum concerned with the onset of extrapyramidal diseases. Accordingly, unlike dopamines D
2
receptor antagonists, dopamine D
4
receptor antagonists are very likely to become novel therapeutic agents of schizophrenia without extrapyramidal diseases as side effects (Nature, 350, 610-614 (1991); Nature, 358, 109 (1992); Nature, 365, 393 (1993); Nature, 365, 441-445 (1993)).
Among such compounds is included 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 a clinical investigation of clozapine, unlike dopamine D
2
receptor, clozapine is effective on drug-resistant schizophrenia and negativism and hardly causes extrapyramidal diseases (Arch. Gen. Psych., 45, 789-796 (1988)). However, clozapine has a serious defect of causing blood disorder called agranulocytosis, and cases of death therefrom have been reported (Summary and Clinical Data, Sandoz, Canada Inc. (1990)).
Accordingly, dopamine D
4
receptor antagonists without such side-effects are very useful as therapeutic agents of schizophrenia which are very unlikely to cause extrapyramidal diseases.
An object of the present invention is to provide dopamine D
4
receptor antagonist compounds which have an antipsychotic action without causing extrapyramidal diseases.
DISCLOSURE OF THE INVENTION
As a result of extensive researches about aromaheterocyclic derivatives, the present inventors have found novel aromaheterocyclic derivatives having a high affinity for dopamine D
4
receptor, thus the present invention has been accomplished.
The present invention is explained as bellow:
The present invention is directed to an aromaheterocyclic derivative represented by Formula [I]:
wherein Z is a group represented by the following Formula [II], [III], [IV] or [V]:
wherein Ar
1
is a phenyl group or a phenyl group substituted with a halogen atom or an alkyl group of 1 to 5 carbon atoms, R
2
is an alkyl group of 1 to 5 carbon atoms, Y is a hydrogen atom, a mercapto group, an alkylthio group of 1 to 5 carbon atoms, an amino group or an amino group substituted with one or two alkyl groups having 1 to 5 carbon atoms, Ar
2
is a phenyl group of one or two substituents selected from the group consisting of a halogen atom, an alkyl group of 1 to 5 carbon atoms, an alkoxy group of 1 to 5 carbon atoms, a hydroxyl group and a trifluoromethyl group, or a phenyl group, B
1
-B
2
is CH—CO or C═C(R
1
) (wherein R
1
is a hydrogen atom or an alkyl group of 1 to 5 carbon atoms), and n is an integer of 1 to 4; or a pharmaceutically acceptable salt thereof.
In the present invention, the alkyl group of 1 to 5 carbon atoms refers to a straight or branched alkyl group, and examples thereof are a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group and an isobutyl group. The alkylthio group of 1 to 5 carbon atoms refers to a straight or branched alkylthio group, and examples thereof are a methylthio group, an ethylthio group, a propylthio group, an isopropylthio group, a butylthio group and an isobutylthio group. The halogen atom refers to a fluorine atom, a chlorine atom, a bromine atom or an iodine atom. Accordingly, examples of the phenyl group of one or two substituents selected from the group consisting of a halogen atom, an alkyl group of 1 to 5 carbon atoms, an alkoxy group of 1 to 5 carbon atoms, a hydroxyl group and a trifluoromethyl group are a 2-fluorophenyl group, a 3-fluorophenyl group, a 4-fluorophenyl group, a 4-chlorophenyl group, a 4-bromophenyl group, a 3,4-dichlorophenyl group, a 4-methylphenyl group, a 3-trifluoromethylphenyl group, a 4-methoxyphenyl group, a 3,4-dimethoxyphenyl group and a 4-hydroxyphenyl group.
In addition, the pharmaceutically acceptable salt in the present invention includes salts with mineral acids such as sulfuric acid, hydrochloric acid or phosphoric acid, and salts with organic acids such as acetic acid, oxalic acid, lactic acid, tartaric acid, fumaric acid, maleic acid, trifluoroacetic acid or methanesulfonic acid.
Preferred compounds in the present invention can be indicated as follows:
That is, when Z is a group represented by Formula [II] or [III] in Formula [I], preferred compounds are those wherein Ar
1
is a fluorophenyl group, Ar
2
is a phenyl group substituted with a halogen atom, B
1
-B
2
is CH—CO or C═CH and n is 2, and especially preferred compounds are those wherein Ar
2
is a fluorophenyl group and B
1
-B
2
is C═CH. When Z is a group represented by Formula [IV] in Formula [I], preferred compounds are those wherein Ar
1
is a phenyl group or a phenyl group substituted with a fluorine atom or a methyl group, Ar
2
is a phenyl group substituted with a halogen atom or an alkyl group of 1 to 5 carbon atoms, B
1
-B
2
is CH—CO or C═CH and n is 2, and especially preferred compounds are those wherein Ar
2
is a phenyl group substituted with a fluorine atom or a methyl group and B
1
-B
2
is C═CH. When Z is a group represented by Formula [V] in Formula [I], preferred compounds are those wherein Ar
1
is a fluorophenyl group, Ar
2
is a phenyl group substituted with a halogen atom, Y is a hydrogen atom, a mercapto group or a methylthio group, B
1
-B
2
is CH—CO or C═CH and n is 2, and especially preferred compounds are those wherein Ar
2
is a fluorophenyl group and B
1
-B
2
is C═CH.
In the present specification, a imidazolyl ring or a pyrazolyl ring is, for the sake of convenience, indicated by one of the tautomers thereof, but both are included within the scope of the present invention.
The compound of Formula [I] can be prepared by the following methods. In the following reaction formulae, Ar
1,
Ar
2,
R
1,
R
2,
B
1
-B
2
and n are as defined above, R
3
is an alkyl group of 1 to 5 carbon atoms, R
4
and R
5
are each a methyl group, or R
4
and R
5
taken together with the nitrogen atom to which they are attached form a pyrrolidino group, a piperidino group, a morpholino group or an N-methylpiperazino group, R
6
is a protecting group of the nitrogen atom such as, for example, an alkoxycarbonyl group (e.g. a t-butoxycarbonyl group or an ethoxycarbonyl group), an acyl group (e.g. an acetyl group or a benzoyl group), a sulfonyl group (e.g. a tosyl group), an alkyl group of 1 to 5 carbon atoms or a benzyl group, R
7
is an alkyl group of 1 to 5 carbon atoms, M is, for example, a sodium atom, a potassium atom or NH
4
, X
1
is a chlorine atom, a bromine atom or an iodine atom, X
2
is an inorganic acid (e.g. HCl, HBr, HI or 1/2H
2
SO
4
), and Y is an alkyl group of 1 to 5 carbon atoms, an alkylthio group of 1 to 5 carbon atoms or an amino group.
<Preparation Method 1>
A ketone derivative (1) is halogenated with a halogenating agent in an inert solvent, and reacted with a thiocyanate (2) in an inert solvent, followed by an acid treatment to give 2-hydroxythiazole derivative (3).
The inert solv
Chaki Shigeyuki
Gotoh Makoto
Kumagai Toshihito
Nagamine Masashi
Nakazato Atsuro
D'Souza Andrea M
Lambkin Deborah C.
Manelli Denison & Selter PLLC
Taisho Pharmaceutical Co. Ltd.
White, Jr. Paul E.
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