Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1997-12-19
1999-11-30
Gerstl, Robert
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
514342, 546275, 546280, C07D41304, A61K 3144
Patent
active
059943734
DESCRIPTION:
BRIEF SUMMARY
CROSS-REFERENCE TO RELATED APPLICATIONS
This application is a 35 U.S.C. 371 national application of PCT/DK96/00291 filed Jun. 28, 1996 and claims priority under 35 U.S.C. 119 of Danish application 0755/95 Filed Jun. 29, 1995, the contents of which are fully incorporated herein by reference.
1. Field of the Invention
The present invention relates to heterocyclic compounds which are cholinergic ligands selective for neuronal nicotinic channel receptors, to methods for their preparation, to pharmaceutical compositions comprising them, and to their use in treating cognitive, neurological and mental disorders, which are characterized by decreased cholinergic function. The invention also relates to a method of treating Parkinson's disease by modulating the process of dopamine secretion, a method of treating or preventing withdrawal symptoms caused by cessation of chronic or long term use of tobacco products, as well as a method for treating obesity.
2. Background of the Invention
Nicotinic and muscarinic receptors are the two distinct types of cholinergic receptors named after their selectivity for muscarine and nicotine, respectively. The cholinergic system is the neurotransmitter system that best correlates with memory and cognitive functions. Traditionally, the cholinergic hypothesis for senile dementia of the Alzheimer type (SDAT) has focused on muscarinic acetylcholine receptors (mAChR), and only recently an interest in the role of the nicotinic acetylcholine receptors (nAChR) in SDAT has emerged. This interest was spurred by the relatively recent discovery that nAChR are not only located on the skeletal muscle but also in the brain.
It has been shown that the number of nAChR was decreased in SDAT patients (Nordberg et al. J. Neurosci. Res.Vol. 31, pp. 103-111 (1992); Giacobini Advances in Experimental Medicine and Biology, Vol. 296, pp.9205-9295, (1993); Schroeder et al., Neurobiol. of Aging, Vol. 12, pp. 259-262, (1991); Whitehouse et al., Neurology, Vol. 38, pp. 720-723, (1988); Flynn and Mash, J. Neurochem., Vol. 47, pp. 8702--8702, (1993)). Similar deficiencies in choline acetyltransferase activity and acetylcholine synthesis suggest that presynaptic receptors on cholinergic nerve terminals are preferentially lost in SDAT (Nordberg, J. Reprod. Fert. Suppl., Vol 46, pp. 145-154, (1993)). Therefore, it has been assumed that the loss of nAChR may correlate with age related onset of disorders of memory and cognitive functions, and that nicotinic replacement therapy may prove beneficial in SDAT. Indeed nicotine improved attention and memory in healthy humans (Warburton, Prog. Neuro. Psychopharmacol. Biol. Psychiatry, Vol. 16, pp. 181-191, (1992)) as well as in Alzheimer's disease patients, (Jones et al. Psychopharmacology, Vol. 108, pp. 485-494, (1992); Gitelman and Prohovnik, Neurobiol. of Aging, Vol. 13, pp. 313-318, (1992); Newhouse et al., Psychopharmacology, Vol. 95, pp. 171-175, (1988); Sahakian et al., Br. J. Psychiatry, Vol.154, pp. 9004-904, (1993)). Further the nicotinic antagonist mecamylamine has been shown to cause cognitive impairment in an age related way, (Newhouse et al., Neuropsychopharmacology, Vol 10, pp. 93-107, (1 994)). p Parkinson's disease (PD) is a debilitating neurodegenerative disease, presently of unknown etiology, characterized by tremors and muscular rigidity. There is evidence that nicotine may also have beneficial effects in PD. Studies show that smoking may protect against the development of PD, (Ishikawa and Mmiyatake, J. Neurol. Sci., Vol. 117, pp. 28-32, (1993); Godwin-Austen et al., J. Neurol. Neurosurg. Psychiat., Vol. 45, pp. 577-581, (1982); Reavill, in Nicotine psychopharmacology: Molecular, cellular and behavioral aspects, pp. 307-340, Oxford University Press, (1990)), and that chronic nicotine may protect against cell loss in the substantia nigra caused by lesioning (Janson and Moller, Neuroscience, Vol. 57, 931-941, (1993)). Nicotine has also shown beneficial effects in Tourette's syndrome (Sanberg et al., Biomed. Phamacother., Vol. 43, pp. 19-23, (1989)). Allev
REFERENCES:
patent: 4530927 (1985-07-01), Winters
Gerstl Robert
Novo Nordisk A/S Novo Alle DK 2880
Rozek Carol E.
Zelson Steve T.
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