Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Patent
1998-03-20
1999-08-10
Higel, Floyd D.
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
514183, 514214, 514249, 514299, 514305, 514413, 540523, 546112, 548515, C07D45302, C07D47108, C07D20506, A61K 31445, A61K 3140
Patent
active
059360887
DESCRIPTION:
BRIEF SUMMARY
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, such as dementia and anxiety, 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.
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 were 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, (1994)).
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)). Alleviation of negative psychotic symptoms, known as the hypofrontality syndrome in schizophrenia, by nicotinic agonists, have been suggested by data showing that nicotine stimulates dopamine release in the nucleus accumbens more potently than in striatum, (Rowell et a
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Higel Floyd D.
Novo Nordisk A S
Rozek Carol E.
Zelson Steve T.
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