Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2002-10-18
2004-04-06
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...
C546S278400
Reexamination Certificate
active
06716857
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to novel tetrahydropyridine derivatives having substituted pyrrolidinone and oxime, which act on muscarinic acetylcholine receptors and thus useful as nootropics and therapeutic agents for neural diseases; and pharmaceutically acceptable salts thereof; processes for the preparation thereof; and pharmaceutical compositions comprising these compounds or salts.
BACKGROUND OF THE INVENTION
Due to the increase in the number of the elderly population, the number of geriatric diseases such as dementia have increased dramatically. Senile dementia, as represented by Alzheimer's disease, is a degenerative neural disease characterized by disorders of mental capacity including loss of memory, judgment and cognitive function. Patients suffering from Alzheimer's disease show up to 90% degeneration of pre-synapse muscarinic acetylcholine neurons of the basal ganglia, which project into the frontal lobe and hippocampus, both of which manage learning, association, consolidation, and cognitive function such as perception in the cerebrum. However, the post-synapse muscarinic neurons in the forebrain and hippocampus are relatively unchanged. These facts suggest the strategy of medicinal development based on cholinergic deficiency hypothesis, which focuses on the stimulation of post-synapse receptors [See; R. T. Bartus, et al. Science, 217, 408-417 (1982)].
Tacrine is an acetylcholine esterase inhibitor that enhances available acetylcholine, which was developed as an agent involved in cognitive function. However, Tacrine had adverse effects. Recently, Aricept (donepezil, Eisai America, Inc., 1996), Exelon (rivastigmine, Novartis Pharmaceuticals Corporation, 2000) and Reminyl (galantamine hydrobromide, Janssen Research, 2001) having enhanced efficacy were developed [See; W. Greenlee, et al. I1 Farmaco, 2001, 56, 247-250]. However, oxotremorine, RS-86 and the like, which is a nonselective cholinergic agonist for directly stimulating cholinergic receptors, had adverse effects [See; R. Plate et al., Bioorg. Med. Chem., 2000, 8, 449-454].
Muscarinic choline receptors exist in the central and peripheral nervous systems in five subtype forms to play an important role in brain cognitive function. As the post-synapse muscarinic neurons in the forebrain and hippocampus are known to be relatively unchanged in patients suffering from Alzheimer's disease, research in nootropics and therapeutic agents for Alzheimer's disease, focus on developing muscarinic agonists selective for the central nervous system and M1 receptors to decrease adverse effects and increase the efficacy of a cholinergic drug.
Known muscarinic agonists active on the central nervous system include Talsaclidin (1997), YM-796 (1990), CI-1017 (2000), Xanomelin (1997), Milameline (1997), Sabcomeline (SB-202026, 1997), Alvameline (LU 25-109, 1997), AF-102 (1997), etc. [See; A. Fisher, Drug Dev. Res. 2000, 50, 291-297]. Additionally, drugs with pyrrolidine rings and active on the nervous system include agents to ameliorate conditions of Alzheimer's disease such as oxotremorine compound [See; E. J. Trybulski et al., Bioorg. Med. Chem. Lett. 1992, 2, 827-832] and nootropics [See; D. Manetti et al., J. Med. Chem. 2000, 43, 1969-1974]. Although oxadiazole compounds of high affinity and excellent efficacy have been reported, they are known to have adverse effects. Recently, muscarinic agonists such as Pilocarpine (Salagen Tablets, MGI Pharma, Inc., 1998) and Cevimeline (AF102B, EVOXAC™, SnowBrand Pharmaceuticals, Inc., 2000) were approved by FDA as therapeutic agents for xerostomia originating from studies on the Sjogren's syndrome, a variety of autoimmune diseases affecting exocrine glands [See; Drugs of the future, 2000, 25(6), 558-562].
Muscarinic receptors are involved in psychosis, Alzheimer's disease and Parkinson's disease. Compounds that have activity on muscarinic acetylcholine receptors are useful for treatment of pain, glaucoma, schizophrenia, anxiety, manic-depressive psychosis (circular insanity), bipolar psychosis, depression, somnipathy, epilepsy, cerebral ischemia, fecal incontinence, gastrointestinal mobility and gastric secretion disorder [See; L. M. Merritt et al., U.S. Pat. No. 5,998,404].
Recently, the muscarinic receptor in post- and pre-synapse of the cholinergic nervous system, which is known to play an important role in learning and memory, was also found to regulate the process of forming amyloid precursor protein, which plays some role in precipitating beta-amyloid in patients suffering from Alzheimer's disease. Further, muscarinic receptor agonist is known to accelerate secretion of soluble amyloid precursor protein and decrease phosphorylation of tau-protein. Accordingly, to develop nootropics and therapeutic agents for Alzheimer's disease wherein beta-amyloid plaque and nerve fiber entanglement are accumulated, it is important to develop novel muscarinic receptor agonists with muscarinic acetylcholine receptor activity and high efficacy, low cholinergic adverse effects and selectivity for other receptors [See; C. C. Felder et al., J. Med. Chem. 2000, 43, 23, 4334-4353].
However, some compounds active on the muscarinic acetylcholine receptor have adverse effects such as hypersialosis, tearing and gastropathy. Accordingly, there is a need to develop novel compounds that have muscarinic acetylcholine receptor activity, selectivity for other receptors or subtypes, high efficacy and low cholinergic adverse effects.
SUMMARY OF THE INVENTION
The object of the present invention is to provide novel tetrahydropyridine derivatives having appropriately substituted pyrrolidinone and oxime, which show high efficacy, low cholinergic adverse effects and high affinity for muscarinic acetylcholine receptors; and pharmaceutically acceptable salts thereof; processes for the preparation thereof; and pharmaceutical compositions comprising these compounds or salts.
DETAILED DESCRIPTION OF THE PRESENT INVENTION
The present invention provides tetrahydropyridine derivatives of formula 1,
wherein m is 0 or 1, n is 1 or 2, R
1
is hydrogen, C
1-4
alkyl, C
2-4
alkynyl or aryl, and R
3
is C
1-4
alkyl; and pharmaceutically acceptable salts thereof.
C
1-4
alkyl as used herein represents a straight or branched alkyl group comprising 1 to 4 carbon atoms, such as ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, and most preferably methyl.
C
2-4
alkynyl as used herein represents a straight or branched hydrocarbon group having one triple bond and comprising 2 to 4 carbon atoms, such as ethynyl, propynyl (generally known as propargyl) butynyl, and most preferably propargyl.
Aryl as used herein represents phenyl, naphthyl or benzyl, and most preferably benzyl.
Most preferable are compounds of formula 1 according to the present invention wherein R
1
is hydrogen, methyl, propargyl or benzyl and R
3
is methyl.
Preferable compounds of formula 1 are
1-[3-benzyloxyimino-3-(1-methyl-1,2,5,6-tetrahydro-pyridin-3-yl)-propyl]-pyrrolidin-2-one,
1-[2-benzyloxyimino-3-(1-methyl-1,2,5,6-tetrahydro-pyridin-3-yl)-propyl]-pyrrolidin-2-one,
1-[3-methoxyimino-3-(1-methyl-1,2,5,6-tetrahydro-pyridin-3-yl)-propyl]-pyrrolidin-2-one,
1-[2-methoxyimino-3-(1-methyl-1,2,5,6-tetrahydro-pyridin-3-yl)-propyl]-pyrrolidin-2-one,
1-[3-hydroxyimino-3-(1-methyl-1,2,5,6-tetrahydro-pyridin-3-yl)-propyl]-pyrrolidin-2-one,
1-[2-hydroxyimino-3-(1-methyl-1,2,5,6-tetrahydro-pyridin-3-yl)-propyl]-pyrrolidin-2-one,
1-[3-(1-methyl-1,2,5,6-tetrahydro-pyridin-3-yl)-3-propyn-2-yloxyimino-propyl]-pyrrolidin-2-one,
1-[3-(1-methyl-1,2,5,6-tetrahydro-pyridin-3-yl)-2-propyn-2-yloxyimino-propyl]-pyrrolidin-2-one,
1-[2-hydroxyimino-2-(1-methyl-1,2,5,6-tetrahydro-pyridin-3-yl)-ethyl]-pyrrolidin-2-one,
1-[2-methoxyimino-2-(1-methyl-1,2,5,6-tetrahydro-pyridin-3-yl)-ethyl]-pyrrolidin-2-one,
1-[2-(1-methyl-1,2,5
Jang Min Seok
Jeong Dae Young
Kang Soon Bang
Keum Gyochang
Kim Youseung
Jones Day
Korea Institute of Science and Technology
Seaman D. Margaret
LandOfFree
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