Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1994-09-30
1997-06-17
Richter, Johann
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
5483147, A61K 31415, C07D40304
Patent
active
056397755
DESCRIPTION:
BRIEF SUMMARY
1. FIELD OF THE INVENTION
The present invention relates to novel compounds having potent activity as histamine H.sub.3 -receptor ("H.sub.3 ") antagonists, and methods of using such compounds.
2. BACKGROUND OF THE INVENTION
Dementias tend to be characterized by cognitive disorders and often by depression. A particularly devastating dementia is Alzheimer's disease (AD). AD affects more than 30% of humans over 80 years of age, and as such, represents one of the most important health problems in developed countries (Evans et al., J.A.M.A. 262: 2551-2556 (1989); Katzman and Saitoh, FASEB J. 280: 278-286 (1991)). This neurodegenerative disorder of unknown etiology is clinically characterized by gradual impairment of cognitive function. The large buildup of intracytoplasmic neurofibrillary tangles and neurite plaques observed histopathologically in Ad plausibly leads to degeneration of affected nerve cells. At least one study showed decreases in histamine and histidine levels in frontal, temporal and occipital cortices and in the caudate nucleus of brains from AD patients examined post mortem (Mazurkiewics and Wsonwah, Can. J. Physiol. Pharmacol., 67: 75-78 (1989)).
Histamine is a chemical messenger involved in various complex biological actions. It is widely distributed in the plant and animal kingdoms. In mammals, including man, it occurs mainly in an inactive bound form in most body tissues. When released, histamine interacts with specific macromolecular receptors on the cell surface or within a target cell to elicit changes in many different bodily functions. Histamine (4(2-aminoethyl) imidazole) is a base. Its chemical structure is: ##STR1## Histamine receptor pharmacology has revealed three subtypes of receptors which mediate (or are associated with) the activity of histamine. These receptors are most commonly referred to as H.sub.1, H.sub.2, and H.sub.3. The most recently discovered of these receptors is the H.sub.3 histamine receptor. Early studies suggested the presence of another histamine receptor when it was demonstrated that histamine inhibits its own synthesis and release in brain slices by a negative feedback process operating at the level of histaminergic nerve-endings (see, for example, Arrang, J. M. et al. Nature 302: 832-837 (1983)). More recently, the H.sub.3 receptor has been shown to function as a pre-synaptic autoreceptor inhibiting histamine synthesis and histamine release from neurons, especially in the control nervous system (Arrang, et al. Nature 327: 117-123 (1987)). The presence of H.sub.3 receptors in peripheral tissues has also been reported and here too they appear to be involved with the nervous system. Thus, histamine depresses sympathetic neurotransmission in the guinea pig mesenteric artery by interacting with H.sub.3 receptors on the perivascular nerve terminals (Ishikawa and Sperelakis, Nature 327: 158 (1987)). This important observation suggests that histamine may control the release of other neurotransmitters (Tamura et al., Neuroscience 25: 171 (1988)). Inhibitory histamine H.sub.3 receptors also exist in the guinea pig ileum where their role appears to be to modify the magnitude of histamine contraction, rather than affecting histamine release (Trzeciakowski, J. Pharmacol. Exp. Therapy 243: 847 (1987)). Particularly intriguing is the discovery of H.sub.3 receptors in the lung (Arrang et al. supra (1987)). The presence of histamine H.sub.3 receptors in the lung raises the question of whether they control histamine release in anaphylaxis and whether they may be manipulated to provide therapy in asthma. Indeed it has been suggested that H.sub.3 receptors may have a modulating role on excitatory neurotransmission in airways. Generally, however, H.sub.3 receptor inhibition tends to increase histamine activity, with potentially detrimental effects. Thus, it is desirable to avoid introducing H.sub.3 receptor antagonists that act on peripheral tissues.
Histamine H.sub.3 receptor activation was found to inhibit acetylcholine release in a guinea pig ileum model (Poli et al., Ag
REFERENCES:
patent: 4707487 (1987-11-01), Arrang et al.
patent: 4767778 (1988-08-01), Arrang et al.
patent: 5034539 (1991-07-01), Arrang et al.
patent: 5070101 (1991-12-01), Kaminski
patent: 5290790 (1994-03-01), Arrang et al.
Arrang et al., 1983, "Auto-inhibition of brain histamine release mediated by a novel class (H.sub.3) of histamine receptor," Nature 302:832-837.
Janssens et al., 1985, "New antihistaminic N-heterocyclic 4-piperidinamines. 3. Synthesis and antihistaminic activity of N-(4-piperidinyl)-3H-imidazo [4,5-b] pyridin-2-amines," J. Med. Chem. 28:1943-1947.
Arrang et al., 1985, "Steroselectivity of the histamine H.sub.3 -presynaptic autoreceptor," Eur. J. Pharmacol. 117:109-114.
Arrang et al., 1987, "Highly potent and selective ligands for histamine H.sub.3 -receptors," Nature 327:117-123.
Arrang et al., 1988, "H.sub.3 -receptors control histamine release in human brain," J. Neurochem. 51:105-108.
Arrang et al., 1988, "Interet potential de ligands puissants et specifiques du recepteur H.sub.3 de l'histamine," Allergie Immunol. 20:327-331.
Arrang et al., 1988, "Highly potent and selective ligands for a new class H.sub.3 of histamine receptor," Invest. Radiol. 23 (Suppl. 1):S130-S132.
Timmerman, 1990, "Histamine H.sub.3 ligands: just pharmacological tools or potential therapeutic agents," J. Med. Chem. 33:4-11.
Cooper et al., 1990, "Histamine receptors," In Comprehensive Medicinal Chemistry, vol. 3, Pergamon Press, Chapter 12.5, pp. 323-421.
Schwartz et al., 1990, "A third histamine receptor subtype: characterization, localization and functions of the H.sub.3 -receptor," Agents and Actions 30:13-23.
West et al., 1990, "Identification of two H.sub.3 -histamine receptor subtypes," Mol. Pharmacol. 38:610-613.
Lipp et al., 1991, "Novel chiral H.sub.3 -receptor agonists," in New Perspectives in Histamine Research, Birkhauser Verlag: Basel, pp. 277-282.
Poli et al., 1991, "Histamine H.sub.3 -receptor activation inhibits acetylcholine release from the guinea pig myenteric plexus," Agents and Actions 33:167-169.
Bent et al., 1991, "The influence of H.sub.1, -H.sub.2 -and H.sub.3 -receptors on the spontaneous and Con A induced histamine release from human adenoid mast cells," Agents and Actions 33:67-70.
Ganellin et al., 1991, "Synthesis of pyridyl isosteres of this peramide as H.sub.3 -receptor histamine antagonists," Collect. Czech. Res. Commun. 56:2448-2455.
Arrang et al., 1991, "The histamine H.sub.3 -receptor: pharmacology, roles and clinical implications studied with agonists", in New Perspectives In Histamine Research, Birkhauser Verlag: Basel, pp. 55-67.
Leurs et al., 1992, "The histamine H.sub.3 -receptor: a target for developing new drugs", Prog. Drug Res. 39:127-165.
Yoshimatsu et al., 1993, "Abnormalities in obese zuckers: defective control of histaminergic functions," Physiology & Behavior 54:487-491.
Khan et al., 1993, "Synthesis and H.sub.3 -receptor affinities of isomeric N-methyl-and N-benzyl-imidazole derivatives of thioperamide," Med. Chem. Res. 3:428-437.
Durant Graham J.
Khan Amin M.
Peabody John
Richter Johann
The University of Toledo
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