Amide compounds for the potentiation of cholinergic activity

Details Amide compounds for the potentiation of cholinergic activity Amide compounds for the potentiation of cholinergic activity

2002-11-01

2003-12-16

Davis, Zinna Northington (Department: 1625)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Nitrogen containing other than solely as a nitrogen in an...

C564S161000

Reexamination Certificate

active

06664293

ABSTRACT:

TECHNICAL FIELD
This invention relates to amide compounds and salts thereof which are useful as a medicament.
DISCLOSURE OF INVENTION
This invention relates to amide compounds and salts thereof.
More particularly, it relates to amide compounds and 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 and/or prevention of amnesia, dementia (e.g. senile dementia, Alzheimer's dementia, dementia associated with various diseases such as cerebral vascular dementia, cerebral post-traumatic dementia, dementia due to brain tumor, dementia due to chronic subdural hematoma, dementia due to normal pressure hydrocephalus, post-meningitis dementia, Parkinson's disease type dementia, etc.), 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 amide compounds and salts thereof which possess the potentiation of the cholinergic activity.
Another object of this invention is to provide processes for preparation of the amide compounds and salts thereof.
A further object of this invention is to provide a pharmaceutical composition comprising, as an active ingredient, said amide compounds and 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 the amide compounds and salts thereof.
The amide compounds of this invention can be represented by the following general formula [I]:
wherein
R
1
and R
2
are each aryl or ar(lower)alkyl, or are taken together to form lower alkylene or lower alkenylene, each of which may be substituted with aryl or may be condensed with a cyclic hydrocarbon optionally substituted with lower alkyl, lower alkoxy, aryl, aryloxy or halogen,
R
3
is lower alkyl, lower alkoxy, aryl, arylamino or aryloxy, each of which may be substituted with lower alkoxy or halogen, pyridyl, or pyridylamino,
X is CH or N,
Y is a single bond or —NH—, and
Q is
and 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
, X and Q are each as defined above, and
R
4
is aryl which may be substituted with lower alkoxy or halogen, or pyridyl.
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.
Suitable “lower alkyl” and lower alkyl moiety in the term “ar(lower)alkyl” 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 “aryl” and aryl or ar moiety in the terms “ar(lower)alkyl”, “aryloxy” and “arylamino” may be phenyl, naphthyl, pentyl substituted with lower alkyl [e.g. tolyl, xylyl, mesityl, cumenyl, di(tert-butyl)phenyl, etc.] and the like, in which preferable one is phenyl.
Suitable “halogen” may be fluorine, chlorine, bromine and iodine, in which preferable one is fluorine.
Suitable “ar(lower)alkyl” may be benzyl, phenethyl, phenylpropyl, benzhydryl, trityl and the like, in which preferable one is benzyl.
Suitable “lower alkylene” may be a straight or branched C
1
-C
6
alkylene such as methylene, ethylene, trimethylene, propylene, tetramethylene, pentamethylene, hexamethylene, methylpentamethylene or the like, in which preferable one is tetramethylene or pentamethylene.
Suitable “lower alkenylene” may be a straight or branched C
2
-C
6
alkenylene such as vinylene, propenylene, butenylene, pentenylene, methylpentenylene, hexenylene, pentadienylene or the like, in which preferable one is butenylene, pentenylene or methylpentenylene.
Suitable “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.
Suitable “cyclic hydrocarbon” may be a saturated or unsaturated cyclic hydrocarbon such as cyclopentane, cyclohexane, benzene, naphthalene, indan, indene or the like, in which preferable one is benzene.
Preferred compound [I] is one having aryl or ar(lower)alkyl for R
1
, aryl or ar(lower)alkyl for R
2
, aryl or arylamino, each of which may be substituted with halogen for R
3
, CH or N for X, a single bond or —NH— for Y, and
for Q; or one having lower alkenylene which may be substituted with aryl or may be condensed with benzene optionally substituted with lower alkoxy for R
1
and R
2
to be taken together to form, aryl or arylamino, each of which may be substituted with halogen, pyridyl, or pyridylamino for R
3
, CH or N for X, a single bond or —NH— for Y, and
for Q.
Suitable salts of the object compound [I] are pharmaceutically acceptable conventional non-toxic salts and include acid addition salt such as an inorganic acid addition salt [e.g. hydrochloride, hydrobromide, sulfate, phosphate, etc.], an organic acid addition salt [e.g. formate, acetate, trifluoroacetate, maleate, tartrate, methanesulfonate, benzenesulfonate, toluenesulfonate, etc.], a salt with an amino acid [e.g. aspartic acid salt, glutamic acid salt, etc.], a metal salt such as an alkali metal salt [e.g. sodium salt, potassium salt, etc.] and alkaline earth metal salt [e.g. calcium salt, magnesium salt, etc.] and the like.
The processes for preparing the object compound [I] are explained in detail in the following.
Process 1
The compound [Ia] or its salt can be prepared by reacting a compound [II] or its salt with a compound [III] or its reactive derivative at the carboxy group or a salt thereof.
Suitable salts of the compounds [Ia] and [II] may be the same as those exemplified for the compound [I].
Suitable salts of the compound [III] and its reactive derivative at the carboxy group may be metal salt or alkaline earth metal salt as exemplified for the compound [I].
Suitable reactive derivative at the carboxy group or the compound [III] may include an ester, an acid halide, an acid anhydride and the like. The suitable examples of the reactive derivatives may be an acid halide [e.g. acid chloride, acid bromide, etc.]; a symmetrical acid anhydride; a mixed acid anhydride with an acid such as aliphatic carboxylic acid [e.g. acetic acid, pivalic acid, etc.], substituted phosphoric acid [e.g. dialkylphosphoric acid, diphenylphosphoric acid, etc.]; an ester such as substituted or unsubstituted lower alkyl ester [e.g. methyl ester, ethyl ester, propyl ester, hexyl ester, trichloromethyl ester, etc.], substituted or unsubstituted ar(lower)alkyl ester [e.g. benzyl ester, benzhydryl ester, p-chlorobenzyl ester, etc.], substituted or unsubstituted aryl ester [e.g. phenyl ester, tolyl ester, 4-nitrophenyl ester, 2,4-dinitrophenyl ester, pentachlorophenyl ester, naphthyl ester, etc.], or an ester with N,N-dimethylhydroxylamine, N-hydroxysuccinimide, N-hydroxyphthalimide or 1-hydroxybenzotriazole, 1-hydroxy-6-chloro-1H-benzotriazole, or the like. These reactive derivatives can be optionally selected according to the kind of the compound [III] to be us

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