Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2002-01-30
2003-10-21
Morris, Patricia L. (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S300000, C546S018000, C546S121000
Reexamination Certificate
active
06635652
ABSTRACT:
TECHNICAL FIELD
The present invention relates to azaindolizinone derivatives or pharmacologically acceptable salts thereof, and cognitive enhancers comprising the azaindolizinone derivatives as effective components, represented by the formula I
wherein R
1
represents hydrogen atom, halogen atom or C
1
-C
6
alkyl,
R
2
represents hydrogen atom, C
1
-C
6
alkyl, C
1
-C
6
alkoxy, hydroxy, halogen atom, amino, acetylamino, benzylamino, trifluoromethyl or —O—(CH
2
)
n
—R
5
(wherein R
5
represents vinyl, C
3
-C
8
cycloalkyl or phenyl, n being 0 or 1),
R
3
and R
4
respectively represent C
1
-C
6
alkyl or —CH(R
7
)—R
6
(wherein R
6
represents vinyl, ethynyl, phenyl (which may be substituted by C
1
-C
6
alkyl, C
1
-C
6
alkoxy, hydroxy, one or two halogen atoms, di C
1
-C
6
alkylamino, cyano, nitro, carboxy or phenyl), plienethyl, pyridyl, thienyl or furyl and R
7
represents hydrogen atom or C
1
-C
6
alkyl) or R
3
is coupled with R
4
to form indan or dihydrophenalene.
More specifically, it relates to azaindolizinone derivatives useful as cognitive enhancers in connection with treatments on memory disturbance, memory acquirement and retention disturbance in, for example, senile dementia and Alzheimer's disease.
BACKGROUND ART
In recent years and with prolonged average life span, diseases such as senile dementia with memory disturbance present medically and socially great problems.
Dementia is a condition that cerebral functions once acquired have been continually disturbed into impairment in memory, decision and thinking, resulting in problems in ordinary social life. Alzheimer's disease, cerebrovascular dementia and mixture thereof amount to eight- or nine-tenths of underlying diseases for senile dementia, a core symptom of which is memory disturbance. Known with respect to Alzheimer's disease are the facts that the activity of choline acetyltransferase (ChAT), which is an acetylcholine sythesizing enzyme in the cerebral cortex, is lowered in comparison with normal control group of the same age [Bowen et al., Brain, 99, 459 (1976)] and that the nucleus basalis of Meynert, which is the nucleus of origin in cholinergic nerve of the cerebral cortex, is eminently exfoliated [Whitehouse et al., Science, 215, 1237-1239 (1982)]. Moreover, it is known, for example, that cognitive function in terms of mental test score is interrelated with lowering in activity of ChAT of the cerebral cortex [Perry et al., Br. Med. J. 25, 1457-1459 (1978)] and that scopolamine, which is a pharmacologically muscarinic receptor antagonist, will clinically cause amnesia [Drachman, Neurology, 27, 783-790 (1977)]. Set up against these backgrounds was a cholinergic hypothesis, where memory is deeply linked with cholinergic nerve function [Bartus et al., Science, 217, 408-417 (1982)]; nowadays, approaches based on cholinergic hypothesis have been made on development of medicines for treatment of senile dementia. Especially, experimental animal models with learning and memory disturbance induced by anti-cholinergic medicines (e.g., scopolamine) have been widely utilized in quest of medicines effective for learning and memory disturbance due to various causes of diseases (e.g., senile dementia including Alzheimer's disease).
Development of medicines effective against senile dementia has been strongly demanded; up to the present, antidementia medicines such as linopirdine, tacrine or aricept have been proposed and some of them have been marketed.
However, none of developed and marketed antidementia medicines are satisfactory for improvement and remedy of dementia symptom. There are still, therefore, strong demands on development of more effective antidementia medicines.
DISCLOSURE OF THE INVENTION
We, the inventors, who made devoted researches to pursue compounds having improved effects against cognitive dysfunction through central nervous system, especially cholinergic nervous system, found azaindolizinone derivatives of the formula I having significant antiamnesia effects against scopolamine-induced amnesia of rats, thus accomplishing the present invention.
The compounds of the present invention are represented by the formula I. The terms used for definition of letters in the formula will be defined and exemplified in the following.
The term “C
1
-C
6
” refers to a group having 1 to 6 carbon atoms unless otherwise indicated.
The term “C
3
-C
8
” refers to a group having 3 to 8 carbon atoms unless otherwise indicated.
The “C
1
-C
6
alkyl” refers to a straight- or branched-chain alkyl group such as methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, sec-butyl, n-pentyl or n-hexyl.
The “C
1
-C
6
alkoxy” refers to a straight- or branched-chain alkoxy group such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentyloxy, n-hexyloxy.
The “C
3
-C
8
cycloalkyl” refers to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl.
The “halogen atom” refers to fluorine, chlorine, bromine or iodine atom.
The compounds of the present invention may be as follows, though the present invention is not limited to these compounds.
3,3-dimethylimidazo[1,2-a]pyridin-2(3H)-one
3,3-dipropylimidazo[1,2-a]pyridin-2(3H)-one
3,3-dibutylimidazo[1,2-a]pyridin-2(3H)-one
3,3-diallylimidazo[1,2-a]pyridin-2(3H)-one
3,3-diallyl-8-benzyloxyimidazo[1,2-a]pyridin-2(3H)-one
3,3-di(2-propenyl)imidazo[1,2-a]pyridin-2(3H)-one
3,3-dibenzylimidazo[1,2-a]pyridin-2(3H)-one
3,3-dibenzyl-8-methylimidazo[1,2-a]pyridin-2(3H)-one
3,3-dibenzyl-5,7-dimethylimidazo[1,2-a]pyridin-2(3H)-one
3,3-dibenzyl-8-hydroxyimidazo[1,2-a]pyridin-2(3H)-one
3,3-dibenzyl-8-methoxyimidazo[1,2-a]pyridin-2(3H)-one
3,3-dibenzyl-8-ethoxyimidazo[1,2-a]pyridin-2(3H)-one
8-allyloxy-3,3-dibenzylimidazo[1,2-a]pyridin-2(3H)-one
3,3-dibenzyl-8-isopropoxyimidazo[1,2-a]pyridin-2(3H)-one
3,3-dibenzyl-8-cyclopropylmethyloxyimidazo[1,2-a]-pyridin-2(3H)-one
3,3-dibenzyl-8-cycloheptyloxyimidazo[1,2-a]pyridin-2(3H)-one
3,3-dibenzyl-6-chloroimidazo[1,2-a]pyridin-2(3H)-one
3,3-dibenzyl-6,8-dichloroimidazo[1,2-a]pyridin-2(3H)-one
3,3-dibenzyl-8-chloro-6-trifluoromethylimidazo[1,2-a]-pyridin-2(3H)-one
3,3-dibenzyl-8-benzyloxyimidazo[1,2-a]pyridin-2(3H)-one
8-amino-3,3-dibenzylimidazo[1,2-a]pyridin-2(3H)-one
8-acetylamino-3,3-dibenzylimidazo[1,2-a]pyridin-2(3H)-one
3,3-dibenzyl-8-benzylaminoimidazo[1,2-a]pyridin-2(3H)-one
3,3-bis(3-chlorobenzyl)imidazo[1,2-a]pyridin-2(3H)-one
3,3-bis(3-fluorobenzyl)imidazo[1,2-a]pyridin-2(3H)-one
3,3-bis(4-fluorobenzyl)imidazo[1,2-a]pyridin-2(3H)-one
3,3-bis(2,4-dichlorobenzyl)imidazo[1,2-a]pyridin-2(3H)-one
3,3-bis(4-dimethylaminobenzyl)imidazo[1,2-a]pyridin-2(3H)-one
3,3-bis(4-methoxybenzyl)imidazo[1,2-a]pyridin-2(3H)-one
3,3-bis(4-biphenylmethyl)imidazo[1,2-a]pyridin-2(3H)-one
3,3-bis(4-cyanobenzyl)imidazo[1,2-a]pyridin-2(3H)-one
3,3-bis(4-hydroxybenzyl)imidazo[1,2-a]pyridin-2(3H)-one
3,3-bis(3-phenyl-1-propyl)imidazo[1,2-a]pyridin-2(3H)-one
3,3-bis(2,4-difluorobenzyl)imidazo[1,2-a]pyridin-2(3H)-one
3,3-bis(4-nitrobenzyl)imidazo[1,2-a]pyridin-2(3H)-one
3,3-bis(4-carboxybenzyl)imidazo[1,2-a]pyridin-2(3H)-one
8-benzyloxy-3,3-bis(1-phenylethyl)imidazo[1,2-a]-pyridin-2(3H)-one
8-benzyloxy-3,3-bis(3-methylbenzyl)imidazo[1,2-a]-pyridin-2(3H)-one
8-benzyloxy-3,3-bis(4-methylbenzyl)imidazo[1,2-a]-pyridin-2(3H)-one
3-benzyl-3-(4-fluorobenzyl)imidazo[1,2-a]pyridin-2(3H)-one
3-ethyl-3-(4-fluorobenzyl)imidazo[1,2-a]pyridin-2(3H)-one
8-methyl-3,3-bis(3-pyridylmethyl)imidazo[1,2-a]-pyridin-2(3H)-one
8-methyl-3,3-bis(4-pyridylmethyl)imidazo[1,2-a]-pyridin-2(3H)-one
3,3-bis(2-thienylmethyl)imidazo[1,2-a]pyridin-2(3H)-one
3,
Fukuda Naoki
Higashi Masaya
Kawashima Seiichiro
Matsuno Toshiyuki
Saitoh Kenichi
Morris Patricia L.
Zenyaku Kogyo Kabushiki Kaisha
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