Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1995-04-27
1996-09-10
Ivy, C. Warren
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
514339, 514419, 544143, 544238, 540585, 546133, 546201, 546 14, 5462774, 548127, 548128, 548181, 548213, 548214, 548217, 548235, 548247, 548253, 5482672, 5483051, 5483121, A61K 31445, C07D45300
Patent
active
055546277
DESCRIPTION:
BRIEF SUMMARY
This is the national stage application of PCT/GB93/02213 filed 27 Oct. 1993.
This invention relates to a class of compounds containing carbamate, thiocarbamate or urea functionality which are useful as tachykinin receptor antagonists.
The tachykinins are a group of naturally-occurring peptides found widely distributed throughout mammalian tissues, both within the central nervous system and in the peripheral nervous and circulatory systems. The three known mammalian tachykinins are: substance P, neurokinin A and neurokinin B:
Evidence for the usefulness of tachykinin receptor antagonists in pain, headache, especially migraine, Alzheimer's disease, multiple sclerosis, attenuation of morphine withdrawal, cardivascular 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 rhinitus, inflammatory diseases of the gut including ulcerative colitis and Crohn 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. Tachykinin antagonists are also believed to be useful in allergic conditions [Hamelet et al 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], and as anticonvulsants [Garant et al., Brain Research (1986) 382 372-8]. 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].
It has furthermore been suggested that tachykinins have utility in the following disorders: depression, dysthymic disorders, chronic obstructive airways disease, hypersensitivity disorders such as poison ivy, vasospastic diseases such as angina and Reynauld's disease, fibrosing and collagen diseases such as scleroderma and eosinophillic fascioliasis, reflex sympathetic dystrophy such as shoulder/hand syndrome, addiction disorders such as alcoholism, stress related somatic disorders, neuropathy, neuralgia, disorders related to immune enhancement or suppression such as systemic lupus erythmatosis (European patent application no. 0 436 334), conjuctivitis, vernal conjunctivitis, contact dermatitis, atropic dermatitis, urticaria, and other eczematoid dermatitis (European patent application no. 0 394 989) and emesis (European patent application no. 0 533 280).
We have now found a class of non-peptides which are potent antagonists of tachykinins.
European patent applications nos. 0394989 and 0482539 disclose tachykinin receptor antagonists comprising an indolyl or like moiety. The compounds are structurally remote from those of the present invention.
The present invention provides a compound of formula (I), or a salt or prodrug thereof: ##STR2## wherein
Q.sup.1 represents a phenyl group substituted by one or more halo, optionally substituted naphthyl, optionally substituted indolyl, optionally substituted benzthiophenyl, optionally substituted benzofuranyl, optionally substituted benzyl or optionally substituted fluorenyl; alkoxy, or X and Y together form a group .dbd.O or .dbd.NOR.sup.5 where R.sup.5 is H or C.sub.1-6 alkyl; 2, 3, 4, 5 or 6 carbon atoms; selected from C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, halo, cyano, nitro, trifluoromethyl, trimethylsilyl, OR.sup.a, SR.sup.a, SOR.sup.a, NR.sup.a R.sup.b, NR.sup.a COR.sup.b, NR.sup.a CO.sub.2 R.sup.b, CO.sub.2 R.sup.a or CONR.sup.a R.sup.b, where R.sup.a and R.sup.b independently represent H, C.sub.1-6 alkyl, phenyl or trifluoromethyl; and independently represent H, C.sub.1-6 alkyl, phenyl optionally substituted by one or more of C.sub.1-6 alkyl, C.sub.1-6 alkoxy, halo or trifluoromethyl or ph
REFERENCES:
patent: 4853376 (1989-08-01), King
patent: 5187156 (1993-02-01), Matsuo
patent: 5256671 (1993-10-01), Ladduwhetty
Maggi, C. A.; et al. J. Autonom. Pharmacol (1993), 13, 23-93.
March, J. Advanced Organic Chemistry, Wiley Interscience Publications, (1992), 4th ed, p. 903.
Longmore, J. et al. "Neurokinin Receptors" DN&P8(1), Feb. 1995, pp. 5-23.
Lewis Richard T.
MacLeod Angus M.
Merchant Kevin J.
Dahlen Garth M.
Ivy C. Warren
Merck Sharp & Dohme Ltd.
North Robert J.
Winokur Melvin
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