Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2001-12-11
2004-09-28
Lambkin, Deborah C. (Department: 1626)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C549S058000, C548S179000, C548S207000
Reexamination Certificate
active
06797726
ABSTRACT:
TECHNICAL FIELD
The present invention relates to novel N-alkoxyalkyl-N,N-dialkylamine derivatives or salts thereof.
BACKGROUND OF THE INVENTION
Dementia is classified into cerebrovascular dementia and neurodegenerative dementia, and a variety of agents such as ameliorants of cerebral circulation, ameliorants of cerebral function, etc. are used for treating these diseases.
The 1,2-ethanediol derivatives or salts thereof described in JP-A-3-232830 and JP-A-4-95070 are useful as the ameliorants of cerebral function, among which especially preferable is (R)-1-(benzo[b]thiophen-5-yl)-2-[2-(N,N-diethylamino)ethoxy]ethanol hydrochloride (hereinafter referred to as T-588).
Among the neurodegenerative dementia, the most popular is Alzheimer's disease (hereinafter referred to as AD), which is characterized by appearance of senile plaque of which the main component is an amyloid &bgr; protein (hereinafter referred to as A&bgr;) derived from a &bgr; amyloid precursor protein [Biochemical and Biophysical Research Communications, Vol. 120, Page 885 (1984)].
A&bgr; is considered to deposit on the nerve cells or blood vessels and to cause a symptom of dementia, etc. [Annual Review of Cell Biology, Vol. 10, Page 373 (1994)].
Further, it has also been reported that A&bgr; itself causes the apoptosis of cultured nerve cells (shrinkage of cell volume, a cell death, via the expression of gene, characterized by fragmentation of DNA) [Brain Research, Vol. 661, Page 147 (1994); Molecular Neurobiology, Vol. 10, Page 19 (1995)].
On the other hand, a rise in the quantity of 4-hydroxy-2-nonenal (hereinafter referred to as HNE) in the brain of AD patients has been reported [American Journal of Pathology, Vol. 150, Page 437 (1997)], and it has also been reported that HNE takes part in the cell death of cultured nerve cells caused by A&bgr; through intermediation of peroxidation of lipids [The Journal of Neuroscience, Vol. 17, Page 1046 (1997)].
It has also been reported that a cell death is caused if HNE is applied to upon cultured nerve cells, and that this cell death is apoptosis [The Journal of Neuroscience, Vol. 17, Page 5089 (1997)].
Further, a possibility that HNE is produced by an oxidation stress in various neurodegenerative diseases and the HNE exerts damage to nerve cells in the brain and spinal cord. For example, a rise in the quantity of HNE has been reported in the brain of patients of the Parkinson's disease [Proceedings of the National Academy of Sciences of the United States of America, Vol. 93, Page 2696 (1996)], and in the spinal cord of patients of the amyotrophic lateral sclerosis [Annals of Neurology, Vol. 44, Page 696 (1998)].
For these reasons, agents for controlling the neurocytotoxicity caused by A&bgr; and HNE are being studied for treating the neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, etc.
Now, it is well known that neurotrophic factors such as a nerve growth factor (NGF) affecting the growth and regeneration of nerves exist in living organisms.
The neurotrophic factors are reported to interact not only to the central nervous diseases such as Alzheimer's disease but also to the peripheral nervous diseases such as diabetic neuropathy, drug-induced neuropathy, etc., and attempts are being made to use the neurotrophic factors for treatment of these diseases [Nou to Shinkei, Vol. 43, No. 12, Page 1101 (1991)].
Further, it has been reported that the impairment in the neuronal conduction in model animals with crushed sciatic nerve can be ameliorated by the regeneration of nerves promoted by NGF [Microsurgery, Vol. 16, Page 547 (1995)]. However, since neurotrophic factor is a protein of high molecular weight, there are many unsolved technical problems to apply it to nervous diseases.
Thus, it is demanded to develop a low molecular weight compound which is the same in function as the neurotrophic factor.
T-588 which is useful as a cerebral function ameliorant exhibits a protective action on the nerve cell death caused by A&bgr; [Society for Neuroscience, Abstracts, Vol. 24, No. 1, Page 228 (1998)], and further has an activity of reinforcing the function of NGF (WO96/12717), and is useful as an agent for treating the diseases of the central and peripheral nervous systems. However, a low molecular compound having yet stronger nerve cell-protecting and nerve regeneration-promoting activities with an intense anti-hypoxic activity is awaited.
DISCLOSURE OF THE INVENTION
The present inventors have conducted extensive studies with the aim of solving the problem mentioned above. As a result, it has been found that N-alkoxyalkyl-N,N-dialkylamine derivatives represented by the following general formula [1]:
wherein R
1
and R
2
are the same or different and represent at least one group selected from the group consisting of a hydrogen atom, a halogen atom, an unsubstituted or substituted alkyl, aryl, aralkyl, alkoxy, aryloxy, alkylthio, arylthio, alkenyl, alkenyloxy, amino, alkylsulfonyl, arylsulfonyl, carbamoyl or heterocyclic group, an unprotected or protected amino, hydroxyl or carboxyl group, a nitro group and an oxo group; R
3
and R
4
are the same or different and represent an unsubstituted or substituted alkyl, cycloalkyl or aralkyl group; each of mR
5′
s, mR
6′
s, nR
7′
s and nR
8′
s are the same or different and represent a hydrogen atom or an alkyl group; the ring D represents a 5- or 6-membered heterocyclic or hydrocarbon ring; m represents an integer of 1-5; and n represents an integer of 1-6,
or its salt have an anti-hypoxic activity, a nerve-protecting activity and a nerve regeneration promoting activity and are useful as an agent for treating neurodegenerative diseases. Based on this finding, the present invention has been accomplished.
Hereunder, the present invention will be explained in detail.
As used in this specification, the terms have the following meanings, unless otherwise indicated. The term “halogen atom” means a fluorine atom, a chlorine atom, a bromine atom or an iodine atom; “alkyl group” means a straight or branched chain C
1-12
alkyl group such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, hexyl, heptyl, octyl and the like; “lower alkyl group” means a straight or branched chain C
1-6
alkyl group such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, hexyl and the like; “cycloalkyl group” means a cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl group; “aryl group” means a phenyl, naphthyl, indanyl or indenyl group; “aralkyl group” means an ar-C
1-6
-alkyl group such as benzyl, diphenylmethyl, trityl, or phenethyl group; “alkoxy group” means a straight or branched chain C
1-12
alkyloxy group such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert-butoxy, pentyloxy, hexyloxy, heptyloxy, octyloxy and the like; “lower alkoxy group” means a straight or branched chain C
1-6
alkyloxy group such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert-butoxy, pentyloxy, hexyloxy and the like; “aryloxy group” means a phenyloxy, naphthyloxy, indanyloxy or indenyloxy group; “alkylthio group” means a C
1-12
alkylthio group such as methylthio, ethylthio, propylthio, isopropylthio, butylthio, isobutylthio, tert-butylthio, pentylthio, hexylthio, heptylthio, octylthio and the like; “lower alkylthio group” means a C
1-6
alkylthio group such as methylthio, ethylthio, propylthio, isopropylthio, butylthio, isobutylthio, tert-butylthio, pentylthio, hexylthio and the like; “arylthio group” means a phenylthio, naphthylthio, indanylthio or indenylthio group and the like; “alkenyl group” means a C
2-12
alkenyl group such as vinyl, propenyl, butenyl, pentenyl, hexenyl, heptenyl, octenyl and the like; “lower alkenyl group” means a C
2-6
alkenyl group such as vinyl, propenyl, butenyl, pentenyl, hexenyl and the like; “alkenyloxy group” means a C
2-12
alkenylo
Iwakami Noboru
Nakagawa Masaya
Ono Satoshi
Saitoh Akihito
Yamaguchi Sumie
Lambkin Deborah C.
Small Andrea D.
Toyama Chemical Co., Ltd.
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