Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2001-08-30
2004-01-13
Shah, Mukund J. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S333000, C514S467000, C514S682000, C514S679000, C546S195000, C546S206000, C546S207000, C546S281700, C546S283700, C546S285000, C549S430000, C549S492000, C544S253000
Reexamination Certificate
active
06677330
ABSTRACT:
This application is the national phase under 35 U.S.C. §371 of PCT International Application No. PCT/JP00/01232 which has an International filing date of Mar. 2, 2000, which designated the United States of America.
TECHNICAL FIELD
The present invention relates to a novel compound useful as a medicament, specifically as an acetylcholinesterase inhibitor, more specifically as an agent for preventing, treating or ameliorating various types of senile dementia, cerebrovascular dementia or attention deficit hyperactivity disorder (ADHD), and further specifically as an agent for preventing, treating and ameliorating various senile dementia especially Alzheimer-type senile dementia, and to a process for producing it.
PRIOR ART
With a rapidly increasing population of the older generation, it is strongly desired to establish a method of treating senile dementia such as Alzheimer-type senile dementia, cerebrovascular dementia and attention deficit hyperactivity disorder.
Development of treating agents for these diseases has been studied from various points of view, and in a prominent point of view, development of acetylcholine precursors and acetylcholinesterase inhibitors is proposed because these diseases are accompanied by a reduction in cholinergic functions in the brain, and actually, such compounds are clinically applied. Typical acetylcholinesterase inhibitors include donepezil hydrochloride (1-benzyl-4-[(5,6-dimethoxy-1-indanon)-2-yl]methylpiperidine hydrochloride), 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.
However, among these medicaments, denepezil hydrochloride is only the compound that is confirmed to have a pharmaceutical effect on the diseases in actual clinical application and is recognized to have satisfactory usefulness from the viewpoint of side effects and frequency of administration. The other medicaments have some drawbacks such as poor effects, undesirable side effects, necessity for frequent administration per day, and limited use in an injection because of their inapplicability to oral administration. Therefore, there is no or little choice but to choose denepezil hydrochloride at present. As mentioned above, denepezil hydrochloride is a superior medicament. It is needless to say, however, that the presence of acetylcholinesterase inhibitors having more superior effects would be more preferred for a wider choice of medicaments in clinical application. Accordingly, the object of the present invention is to provide a novel compound useful as a medicament, specifically as an acetylcholinesterase inhibitor, more specifically as an agent for preventing, treating or ameliorating various types of senile dementia, cerebrovascular dementia and attention deficit hyperactivity disorder, and further specifically as an agent for preventing, treating or ameliorating Alzheimer-type senile dementia, and a process for producing it.
DISCLOSURE OF THE INVENTION
The present inventors have extensively studied on various compounds for a long period of time for the development of medicaments having more superior effects and higher safety. As a result, they have found that a novel 4-substituted piperidine compound fluoride represented by the following formula (I), a pharmaceutically acceptable salt thereof or hydrates thereof (provided that 1-benzyl-4-[(5,6-dimethoxy-2-fluoro-1-indanon)-2-yl]methylpiperidine, a pharmaceutically acceptable salt thereof and hydrates thereof are excluded) can achieve the above object, and have completed the present invention.
In the formula, R
1
represents any one selected from the group consisting of the following substituents:
(wherein each R
3
are the same as or different from each other and each represents hydrogen atom, a halogen atom, hydroxyl group, a C
1-6
alkyl group, a C3cycloalkyl group, a C
1-6
alkoxy group, a C
1-6
alkoxyalkoxy group, a halogeno C
1-6
alkyl group, a hydroxy C
1-6
alkyl group, a cyano C
1-6
alkyl group, a halogeno C
1-6
alkoxy group, a hydroxy C
1-6
alkoxy group, a cyano C
1-6
alkoxy group, a lower acyl group, a nitro group, an optionally substituted amino group, an optionally substituted amide group, mercapto group or a C
1-6
thioalkoxy group; R
4
represents hydrogen atom or a C
1-6
alkyl group; the bond represented by the following formula:
is a single or double bond; m is 0 or an integer of 1 to 6; n is an integer of 1 to 4; and p is an integer of 1 or 2); and
R
2
represents a C
3-8
cycloalkylmethyl group, 2,2-(alkylenedioxy)ethyl group or a group represented by the formula:
(wherein the ring A is benzene ring or a heterocyclic ring; each R
1
are the same as or different from each other and each represents hydrogen atom, a halogen atom, hydroxyl group, nitrile group, a C
1-6
alkyl group, a C
3-8
cycloalkyl group, a C
1-6
alkoxy group, a C
1-6
alkoxyalkoxy group, an aryloxy group, an aralkyloxy group, a halogeno C
1-6
alkyl group, a hydroxy C
1-6
alkyl group, a cyano C
1-6
alkyl group, a halogeno C
1-6
alkoxy group, a hydroxy C
1-6
alkoxy group, a cyano C
1-6
alkoxy group, a lower acyl group, a nitro group, an optionally substituted amino group, an optionally substituted amide group, mercapto group or a C
1-6
thioalkoxy group, and two of the R
5
groups may together form an aliphatic ring, an aromatic ring, a heterocyclic ring or an alkylenedioxy ring; and q is 0 or an integer from 1 to 5).
That is, the first aspect of the present invention is:
1) a 4-substituted piperidine compound fluoride represented by the above formula (I), a pharmaceutically acceptable salt thereof or hydrates thereof;
2) in the above 1), R
1
may be a group represented by the formula:
wherein R
3
, m and n have the same meanings as defined above;
(3) in the above 1), R
2
may be a group represented by the formula:
wherein R
5
and q have the same meanings as defined above;
4) in the above 3), the ring A may be a group represented by the formula:
wherein R
5
and q have the same meanings as defined above;
5) in the above 3), the ring A may be an aromatic heterocyclic ring;
6) in the above 3), the ring A may be pyridine ring;
7) in the above items 1) to 6), q may be an integer of 1 or 2; and
8) in the above 1), the 4-substituted piperidine compound fluoride may be the one selected from:
(1) 1-benzyl-4-[(5,6-diethoxy-2-fluoro-1-indanon)-2-yl]methylpiperidine;
(2) 1-benzyl-4-[(5,6-dimethoxy-2-fluoro-1-indanon)-2-yl)piperidine;
(3) 1-benzyl-4-[2-[(5,6-dimethoxy-2-fluoro-1-indanon)-2-yl]ethyl]piperidine;
(4) 4-[(5,6-dimethoxy-2-fluoro-1-indanon)-2-yl]methyl-1-(3-fluorobenzyl)piperidine;
(5) 4-[(5,6-dimethoxy-2-fluoro-1-indanon)-2-yl]methyl-1-(3-methylbenzyl)piperidine;
(6) 1-cyclohexylmethyl-4-[(5,6-dimethoxy-2-fluoro-1-indanon)-2-yl]methylpiperidine;
(7) 4-[(5,6-dimethoxy-2-fluoro-1-indanon)-2-yl]methyl-1-(1,3-dioxolan-2-yl)methylpiperidine; and
(8) 1-(4-benzyloxybenzyl)-4-[(5,6-dimethoxy-2-fluoro-1-indanon)-2-yl]methylpiperidine;
(9) 3-(1-benzylpiperidin-4-yl)-2-fluoro-1-(2,3,4,5-tetrahydro-1H-1-benzazepin-8-yl)-1-propanone;
(10) 3-(1-benzylpiperidin-4-yl)-2,2-difluoro-1-(2,3,4,5-tetrahydro-1H-1-benzazepin-8-yl)-1-propanone;
(11) 5,7-dihydro-3-[1-fluoro-2-[1-phenylmethyl]-4-piperidinyllethyl]-6H-pyrolo[4,5-f]-1,2-benzisooxasol-6-on;
(12) 5,7-dihydro-3-[1,1-difluoro-2-[1-phenylmethyl]-4-piperidinyl]ethyl]-6H-pyrolo[4,5-f]-1,2-benzisooxasol-6-on;
(13) 1-(2-methyl-6-benzothiazoryl)-3-[1-phenylmethyl]-4-piperidinyl]-2-fluoro-1-propanone; and
(14) 1-(2-methyl-6-benzothiazoryl)-3-[1-phenylmethyl]-4-piperidinyl]-2,2-difluoro-1-propanone.
The second aspect of the present invention is:
9) a pharmaceutical preparation comprising, as an active ingredient, the 4-substituted piperidine compound fluoride of the above 1
Iimura Yoichi
Kosasa Takashi
Shibata Tetsuo
Sugimoto Hachiro
Suzuki Emiko
Eisai Co. Ltd.
Patel Sudhaker B.
Shah Mukund J.
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