Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2002-09-18
2004-03-16
Seaman, D. Margaret (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C546S340000, C546S343000
Reexamination Certificate
active
06706741
ABSTRACT:
TECHNICAL FIELD
The present invention relates to a novel acetylcholinesterase inhibitor.
PRIOR ART
Usefulness of an acetylcholinesterase inhibitor as an agent for treating and improving senile dementia such as Alzheimer type senile dementia, or cerebrovascular dementia, attention deficit hyperactivity disorder etc. came to be clinically highly regarded. In particular, donepezil hydrochloride (1-benzyl-4-[(5,6-dimethoxy-1-indanone)-2-yl]methylpiperidine hydrochloride) found with efforts of the present inventors is the only acetylcholinesterase inhibitor at present which can be sufficiently useful in respect of pharmacological activity, side effects, administration frequency, administration form etc., and fulfilling hopes of many patients and their families in nursing and clinical fields. In addition to donepezil hydrochloride, there are known acetylcholinesterase inhibitors such as rivastigmine (3-[1-(dimethylamino)ethyl]phenyl N-ethyl-N-methylcarbamate), metrifonate (dimethyl 2,2,2-trichloro-1-hydroxyethyl)phosphate), tacrine hydrochloride (1,2,3,4-tetrahydro-9-acridinamine), galanthamine hydrobromide, neostigmine, physostigmine etc. On one hand, there are some reports on processes for producing donepezil derivatives including donepezil hydrochloride, and for example JP-A 8-225527 and JP-A 11-263774 disclose a process for producing benzylpiperidylmethyl indanones, characterized by hydrogenating pyridinium salts with hydrogen in the presence of a hydrogenating catalyst.
It has been desired to provide highly useful acetylcholinesterase inhibitors in addition to donepezil hydrochloride.
DISCLOSURE OF THE INVENTION
In view of the circumstances described above, the present inventors made extensive study through which they found that both a compound represented by the formula:
(wherein the “a” moieties are the same as or different from each other and each represents a hydrogen atom or a C
1-6
alkoxy group; n is an integer from 1 to 4; and X′
(−)
represents a halide ion) and a compound represented by the formula:
(wherein b, c, d and e are the same as or different from each other and each represents a hydrogen or a linear or branched C
1-6
alkyl, C
1-6
alkoxy, C
1-6
alkoxy carbonyl, C
1-6
alkyl aminocarbonyloxy, di (C
1-6
alkyl)-aminocarbonyloxy or a halogen; and X″
(−)
represents an anion in the series of chloride, bromide, iodide and sulfate) exhibit an excellent inhibitory action on acetylcholinesterase. Further, on the basis of these findings, they found that a 1-benzylpyridinium salt represented by the formula:
(wherein R
1
, R
2
, R
3
and R
4
are the same or different, and represent a hydrogen atom, a halogen atom, a hydroxyl group, a nitrile group, a C
1-6
alkyl group, a C
1-6
alkoxy group, a C
1-6
alkoxy carbonyl group, a C
1-6
alkyl aminocarbonyloxy group or a di (C
1-6
alkyl)-aminocarbonyloxy group; R
5
represents a hydrogen atom, a halogen atom, a C
1-6
alkyl group, a C
2-6
alkenyl group or a C
2-6
alkynyl group; the partial structure:
is a group represented by the formula >C(R
6
)—CH
2
— (wherein R
6
is a hydrogen atom or a halogen atom) or >C═CH—; X
−
represents a halide ion or organic sulfonic acid ion; and m is 0 or an integer from 1 to 5) exhibits an excellent inhibitory action on acetylcholinesterase, and accomplished the present invention.
That is, the first aspect according to the present invention is (1) an acetylcholinesterase inhibitor comprising a 1-benzylpyridinium salt represented by the above formula (I). Further, (2) in the above item (1), R
1
, R
2
, R
3
and R
4
may be the same as or different from each other and each represents a hydrogen atom or a C
1-6
alkoxy group; (3) in the above item (1), R
1
, R
2
R
3
and R
4
may be the same as or different from each other and each represents a hydrogen atom or a methoxy group; (4) in the above item (1) , R
1
and R
4
may represent a hydrogen atom; and R
2
and R
3
may represent a methoxy group; (5) in the above item (1), R
5
may be a hydrogen atom; (6) in the above item (1), the partial structure:
may be a group represented by the formula >C (R
6
) —CH
2
— (wherein R
6
is a hydrogen atom or a halogen atom) ; (7) in the above item (1), m may be 0, 2 or 4; (8) in the above item (1), the halide ion represented by X
−
maybe a chloride ion, bromide ion or iodide ion, preferably a chloride ion or bromide ion; (9) in the above item (1), the organic sulfonic acid ion represented by X
−
may be a methanesulfonate ion, trifluoromethanesulfonate ion, ethanesulfonate ion, benzenesulfonate ion, toluenesulfonate ion or camphor sulfonate ion; (10) in the above item (1), the 1-benzylpyridinium salt may be a compound represented by the formula:
wherein R
1
, R
2
, R
3
, R
4
and X
−
have the same meanings as defined above; and n is an integer from 1 to 6; (11) in the above item (1), the 1-benzylpyridinium salt may be a compound represented by the formula:
wherein R
1
, R
2
, R
3
, R
4
and X
−
have the same meanings as defined above; and p is 0 or an integer from 1 to 5; (12) in the above item (1), the preparation may be an agent for treating, preventing or improving senile dementia, cerebrovascular dementia or attention deficit hyperactivity disorder; and (13) in the above item (12), the senile dementia may be Alzheimer type senile dementia.
The second aspect according to the present invention is (14) a pharmaceutical preparation comprising a 1-benzylpyridinium salt represented by the formula:
wherein R
1
, R
2
, R
3
, R
4
, R
5
, the partial structure:
X
−
and m have the same meanings as defined above. Further, the third aspect according to the present invention is (15) use of a 1-benzylpyridinium salt represented by the formula:
(wherein R
1
, R
2
, R
3
, R
4
, R
5
, the partial structure:
X
−
and m have the same meanings as defined above) for producing an acetylcholinesterase inhibitor.
The present invention provides a method of preventing, treating or improving a disease against which an inhibitory action on acetylcholinesterase is efficacious for prevention, treatment or improvement, by administering a pharmacologically effective dose of the 1-benzylpyridinium salt represented by the above formula (I) to a patient.
In the present invention, the disease against which an inhibitory action on acetylcholinesterase is efficacious for prevention, treatment or improvement includes senile dementia such as Alzheimer type senile dementia, and cerebrovascular dementia and attention deficit hyperactivity disorder.
Hereinafter, the meanings of symbols, terms etc. used in the specification are described, and the present invention is described in detail.
In the specification, the structural formulae of the compound may, for convenience' sake, indicate a certain isomer, but the present invention encompasses all possible isomers which can occur in the structures of the compound, for example geometric isomer, optical isomer based on asymmetrical carbon, stereoisomer and tautomer, and a mixture of such isomers, so the compound according to the present invention may be any isomers or a mixture thereof without limitation to the formulae shown for convenience' sake. Accordingly, the compound according to the present invention can have an intramolecular asymmetrical carbon, thus occurring as optically active isomers or racemic modifications, and any of such compounds are included in the present invention without limitation. When there is crystal polymorphism, the compound according to the present invention may be in a single crystal form or a mixed crystal form without limitation. Compound (I) or salts thereof may be anhydrides or hydrates, any of which fall under the claims in the specification. Further, metabolites formed by decomposition of Compound (I) in vivo, and prodrugs of Compound (I) or salts thereof, also fall under the claims in the specification.
The “halogen atom” used in the specification refers to an atom such as a fluorine atom, a chlorine atom, a bromine atom or an iodine atom, pr
Iimura Yoichi
Kosasa Takashi
Eisai Co. Ltd.
Seaman D. Margaret
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