Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1997-12-18
1999-11-16
Chang, Ceila
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
546196, A61K 31445, C07D40514
Patent
active
059858966
DESCRIPTION:
BRIEF SUMMARY
This application is a 371 of PCT/GB96/01477 filed Jun. 20, 1996.
This invention relates to a class of aromatic compounds which are useful as tachykinin antagonists. More particularly, the compounds of the invention contain an amnine-substituted azo-heterocyclic moiety.
The tachykinins are a group of naturally occurring peptides found widely distributed throughout mammalian tissues, both within the central nervous system and in peripheral nervous and circulatory systems.
At present, there are three known mammalian tachykinins referred to as substance P, neurokinin A (NKA, substance K, neuromedin L) and neurokinin B (NKB, neuromedin K) (for review see J. E. Maggio, Peptides (1985) 6(suppl. 3), 237-242). The current nomenclature designates the three tachykinin receptors mediating the biological actions of substance P, NKA and NKB as the NK.sub.1, NK.sub.2 and N.sub.3 receptors, respectively.
Evidence for the usefulness of tachykinin receptor antagonists in pain, headache, especially migraine, Alzheimer's disease, multiple sclerosis, attenuation of morphine withdrawal, cardiovascular changes, oedema, such as oedema caused by thermal injury, chronic inflammatory diseases such as rheumatoid arthritis, asthma/bronchial hyperreactivity and other respiratory diseases including allergic rhinitis, inflammatory diseases of the gut including ulcerative colitis and Crohn's disease, ocular injury and ocular inflammatory diseases, proliferative vitreoretinopathy, irritable bowel syndrome and disorders of bladder function including cystitis and bladder detruser hyper-reflexia is reviewed in "Tachykinin Receptors and Tachykinin Receptor Antagonists", C. A. Maggi, R. Patacchini, P. Rovero and A Giachetti, J. Auton. Pharmacol. (1993) 13, 23-93.
For instance, substance P is believed inter alia to be involved in the neurotransmission of pain sensations [Otsuka et al, "Role of Substance P as a Sensory Transmitter in Spinal Cord and Sympathetic Ganglia" in 1982 Substance P in the Nervous System, Ciba Foundation Symposium 91, 13-34 (published by Pitman) and Otsuka and Yanagisawa, "Does Substance P Act as a Pain Transmitter?" TIPS (1987) 8, 506-510], specifically in the transmission of pain in migraine (B. E. B. Sandberg et al, J. Med Chem, (1982) 25, 1009) and in arthritis [Levine et al Science (1984) 226, 547-549]. Tachykinins have also been implicated in gastrointestinal (GI) disorders and diseases of the GI tract such as inflammatory bowel disease [Mantyh et al Neuroscience (1988) 25(3), 817-37 and D. Regoli in "Trends in Cluster Headache" Ed. Sicuteri et al Elsevier Scientific Publishers, Amsterdam (1987) page 85)] and emesis [F. D. Tattersall et al, Eur. J. Pharmacol., (1993) 250, R5-R6]. It is also hypothesised that there is a neurogenic mechanism for arthritis in which substance P may play a role [Kidd et al "A Neurogenic Mechanism for Symmetrical Arthritis" in The Lancet, Nov. 11, 1989 and Grbnblad et al, "Neuropeptides in Synovium of Patients with Rheumatoid Arthritis and Osteoarthritis" in J. Rheumatol. (1988) 15(12), 1807-10]. Therefore, substance P is believed to be involved in the inflammatory response in diseases such as rheumatoid arthritis and osteoarthritis, and fibrositis [O'Byrne et al, Arthritis and Rheumatism (1990) 33, 1023-8]. Other disease areas where tachykinin antagonists are believed to be useful are allergic conditions [Hamelet et at, Can. J. Pharmacol. Physiol. (1988) 66, 1361-7], immunoregulation [Lotz et al, Science (1988) 241, 1218-21 and Kimball et al, J. Immunol. (1988) 141(10), 3564-9] vasodilation, bronchospasm, reflex or neuronal control of the viscera [Mantyh et al, PNAS (1988) 85, 3235-9] and, possibly by arresting or slowing .beta.-amyloid-mediated neurodegenerative changes [Yankner et al, Science (1990) 250, 279-82] in senile dementia of the Alzheimer type, Alzheimer's disease and Down's Syndrome.
Tachykinin antagonists may also be useful in the treatment of small cell carcinomas, in particular small cell lung cancer (SCLC) [Langdon et al, Cancer Research (1992) 52, 4554-7].
Substance P may
REFERENCES:
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Burger "A guide to the chemical basis of drug design" Wiley-Interscience, p. 15, 1983.
Amour et al. "Tetrazole NK1 receptor antagonists . . . " Bioorg. Med. Chem. v.6, No. 9, pp. 1015-1020, 1996.
Baker Raymond
Elliott Jason Matthew
Stevenson Graeme Irvine
Swain Christopher John
Chang Ceila
Merck Sharp & Dohme Ltd.
Rose David L.
Thies J. Eric
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