Aminopiperazine derivatives

Details Aminopiperazine derivatives Aminopiperazine derivatives

1999-08-17

2001-09-18

Raymond, Richard L. (Department: 1611)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

C514S590000, C514S602000, C514S605000, C514S614000, C514S617000, C514S625000, C544S382000, C564S034000, C564S037000, C564S081000, C564S082000, C564S149000, C564S151000, C564S184000, C564S215000

Reexamination Certificate

active

06291464

ABSTRACT:

TECHNICAL FIELD
This invention relates to new aminopiperazine derivatives and pharmaceutically acceptable salts thereof which are useful as a medicament.
BACKGROUND ART
Some aminopiperazine derivatives have been known as useful anti-amnesia or anti-dementia agents, for example, in PCT International Publication No. WO 91/01979.
DISCLOSURE OF INVENTION
This invention relates to new aminopiperazine derivatives and pharmaceutically acceptable salts thereof.
More particularly, it relates to new aminopiperazine derivatives and pharmaceutically acceptable salts thereof which have the potentiation of the cholinergic activity, to processes for the preparation thereof, to a pharmaceutical composition comprising the same, and to a method for the treatment and/or prevention of disorders in the central nervous system for mammals, and more particularly to method for the treatment of amnesia, dementia, senile dementia and the like. Additionally, the object compound is expected to be useful as therapeutical and/or preventive agents for schizophrenia, depression, stroke, head injury, nicotine withdrawal, spinal cord injury, anxiety, pollakiuria, incontinence of urine, myotonic dystrophy, attention deficit hyperactivity disorder, excessive daytime sleepiness (narcolepsy), Parkinson's disease or autism.
One object of this invention is to provide new and useful aminopiperazine derivatives and pharmaceutically acceptable salts thereof which possess the potentiation of cholinergic activity.
Another object of this invention is to provide processes for preparation of said aminopiperazine derivatives and salts thereof.
A further object of this invention is to provide a pharmaceutical composition comprising, as an active ingredient, said aminopiperazine derivatives and pharmaceutically acceptable salt thereof.
Still further object of this invention is to provide a therapeutic method for the treatment and/or prevention of aforesaid diseases in mammals, using said aminopiperazine derivatives and pharmaceutically acceptable salts thereof.
The aminopiperazine derivatives of this invention are new and can be represented by the following general formula [I]:
wherein
R
1
is lower alkyl, lower alkenyl, lower alkynyl, cyclo (lower) alkyl, aryl, ar (lower) alkoxy, aryloxy, arylamino or a heterocyclic group, each of which may be substituted with suitable substituent(s); or acyl;
R
2
is lower alkyl, lower alkenyl, lower alkynyl, cyclo(lower) alkyl, aryl, ar(lower)alkoxy, lower alkoxy, aryloxy or a heterocyclic group, each of which may be substituted with suitable substituent(s); or acyl;
A is
or —SO
2
—,
Q is
or —N═CH—
 (wherein R
5
is hydrogen, lower alkyl, substituted-lower alkyl, aryl, acyl or a heterocyclic group, and
R
6
is hydrogen or lower alkyl),
X is lower alkylene optionally substituted with suitable substituent(s), and
R
3
and R
4
are each hydrogen or lower alkyl, or are taken together to form lower alkylene optionally condensed with a cyclic hydrocarbon or a heterocyclic ring,
provided that when
R
1
is lower alkyl, aryl, ar(lower)alkoxy or a heterocyclic group, each of which may be substituted with halogen,
R
2
is cyclo(lower)alkyl, aryl or ar(lower)alkyl, each of which may be substituted with halogen,
X is ethylene and
R
3
and R
4
are taken together to form ethylene;
then
1) Q is
 (wherein
R
5
is substituted-lower alkyl, aryl, acyl or a heterocyclic group), or
2) Q is
 (wherein
R
5
is hydrogen, lower alkyl, substituted-lower alkyl, aryl, acyl or a heterocyclic group, and
R
6
is lower alkyl); or
when R
1
is aryl which may be substituted with halogen;
X is ethylene;
R
3
and R
4
are taken together to form ethylene; and
R
2
is lower alkoxy, and
Q is
or
R
2
is aryl, and
Q is —N═CH—;
then A is
and pharmaceutically acceptable salts thereof.
The object compound [I] or its salt can be prepared by processes as illustrated in the following reaction schemes.
wherein R
1
, R
2
, R
3
, R
4
, R
5
A, Q and X are each as defined above,
Y is
(wherein R
6
is as defined above),
Qa is
(wherein R
5
and R
6
are each as defined above),
R
a
5
is lower alkyl or substituted-lower alkyl,
R
a
3
and R
a
4
are each lower alkyl or are taken together to form lower alkylene,
Ya is
(wherein R
a
6
is lower alkyl),
Z is an acid residue,
R
7
is aryl which may be substituted with suitable substituent(s),
R
a
1
is arylamino which may be substituted with suitable substituent(s),
R
b
1
is aryl which is substituted with esterified carboxy,
R
c
1
is aryl which is substituted with carboxy,
R
a
2
is aryl which may be substituted with halogen,
R
d
1
is lower alkyl,
R
b
1
is aryl which is substituted with esterified carboxy,
R
c
1
is aryl which is substituted with carboxy,
R
e
1
is aryl which is substituted with nitro, or
R
f
1
is aryl which is substituted with amino.
In the above and subsequent description of the present specification, suitable examples of the various definitions to be included within the scope of the invention are explained in detail in the following.
The term “lower” is intended to mean a group having 1 to 6 carbon atom(s), unless otherwise provided.
The lower moiety in the terms “lower alkenyl” and “lower alkynyl” is intended to mean a group having 2 to 6 carbon atoms.
The lower moiety in the term “cyclo(lower)alkyl” is intended to mean a group having 3 to 6 carbon atoms.
Suitable “lower alkyl” and lower alkyl moiety in the terms “substituted-lower alkyl”, “ar(lower)alkyl”, “halo (lower) alkyl”, “lower alkylamino”, “lower alkylsilyl”, “lower alkylthio” and “lower alkylsulfonyl” may be a straight or branched C
1
-C
6
alkyl such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, ethylpropyl, hexyl or the like, in which preferable one is methyl.
Suitable “lower alkenyl” may be a straight or branched C
2
-C
6
alkenyl such as ethenyl, propenyl, butenyl, pentenyl, hexenyl, isopropenyl, butadienyl, pentadienyl, hexadienyl or the like, in which preferable one is ethenyl, propentyl or butadienyl.
Suitable “lower alkynyl” may be a straight or branched C
2
-C
6
alkynyl such as ethynyl, propargyl, butynyl or the like, in which preferable one is ethynyl.
Suitable “cyclo(lower)alkyl” may be cyclo(C
3
-C
6
)alkyl such as cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, in which preferable one is cyclopropyl.
Suitable “aryl” and aryl or ar moiety in the terms “ar(lower)alkoxy”, “aryloxy”, “arylamino”, “arylsulfonyl”, “aroyl” and “ar(lower)alkyl” may be phenyl, naphthyl, phenyl substituted with lower alkyl [e.g. tolyl, xylyl, mesityl, cumenyl, di(tert-butyl)phenyl, etc.] and the like, in which preferable one is phenyl or tolyl.
Suitable “ar(lower)alkyl” may be benzyl, phenethyl, phenylpropyl, benzhydryl, trityl and the like, in which preferable one is benzyl.
Suitable “lower alkylene” and lower alkylene moiety in the term “lower alkylenedioxy” may be a straight or branched C
1
-C
6
alkylene such as methylene, ethylene, trimethylene, propylene, tetramethylene, pentamethylene, hexamethyiene, ethylethylene or the like, in which preferable one is methylene, ethylene or trimethylene.
Suitable “lower alkoxy” and lower alkoxy moiety in the terms “ar(lower)alkoxy” and “halo(lower)alkoxy” may be a straight or branched C
1
-C
6
alkoxy such as methoxy, ethoxy, propoxy, isopropoxy, methylpropoxy, butoxy, isobutoxy, tert-butoxy, pentyloxy, hexyloxy or the like, in which preferable one is methoxy or tert-butoxy.
Suitable “ar(lower)alkoxy” may be benzyloxy, phenethyloxy, phenylpropoxy, benzhydryloxy, trityloxy and the like.
Suitable “halogen” and halo moiety in the term “halo(lower)alkyl” may be fluorine, chlorine, bromine and iodine, in which preferable one is fluorine.
Suitable “halo(lower)alkyl” may be lower alkyl substituted with one or more halogens such as chloromethyl, dichloromethyl, fluoromethyl, difluoromethyl, trifluoromethyl, pentachloroethyl or the like, in which preferable one is trifluoromethyl.
Suitable “halo(lower)alkoxyl” may be lower alkoxy substituted with one or more halogens such as chloromethoxy, dich

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