Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1995-03-10
1996-10-08
Davis, Zinna Northington
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
546336, 560 9, 560 60, 562470, 564162, 564182, 568 55, 568442, 568659, 558410, 514520, 514546, 514557, 514617, C07D21340, C07C23506, A61K 3144, A61K 31085
Patent
active
055631614
DESCRIPTION:
BRIEF SUMMARY
This application is a 371 application of PCT/GB/01863 filed Sep. 9, 1993.
This invention relates to a class of azabicyclic compounds, which are useful as tachykinin antagonists. More particularly, the compounds of the invention comprise an aromatic moiety and an hydroxy or alkoxy moiety.
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.
GB1377350 discloses compounds of formula (A): ##STR2## wherein: R is C.sub.1-4 alkyl;
The compounds are said to have analgesic and morphine-antagonistic actions.
GB 1443441 and GB 1448437 discloses compounds of formula (B): ##STR3## wherein: R.sup.1 is H, R.sup.9 or COR.sup.9, where R.sup.9 is phenyl, benzyl or C.sub.1-6 alkyl optionally substituted by NR.sup.10 R.sup.11 ;
The compounds are said to be useful in the treatment of depression.
E. J. Corey and T. M. Eckrich in Tetrahedron Letters, vol. 24, No. 31, pp. 3163-3164 (1983) disclose the preparation of the compound 1-hydroxy-1-phenyl-2-benzyloxyethane from the reaction of bromomethyl benzyl ether with benzaldehyde in the presence of n-butyllithium.
T. Akiyama et al in Synlett, No. 5, pp. 415-416 (May 1992) disclose the compound 1-hydroxy-1-phenyl-2-(4-methoxyphenylmethyl)oxyethane as an example of a benzyl ether which may be selectively cleaved by trimethylsilyl chloride-tin(II) chloride-anisole to yield 1-phenylethane-1,2-diol.
The present invention provides a compound of formula (I), or a salt or prodrug thereof: ##STR4## wherein Q represents optionally substituted phenyl or optionally substituted benzhydryl;
REFERENCES:
patent: 3960960 (1976-06-01), Hollinger et al.
Mar., Advanced Organic Chemistry, Third Edition, 1985, pp. 342-343.
"A New and Simple Synthesis of Alkoxy-and Aryloxymethyllithium Reagents (ROCH.sub.2 Li)", E. J. Corey and T. M. Eckrich, Tetrahedron Letters, (1983), vol. 24, No. 31, pp. 3163-3164.
"Trimethylsilyl Chloride-Tin(II) Chloride-Anisole: A Novel Selective p-Methoxybenzyl Ether Cleavage Reagent", T. Akiyama, et al., Synlett, (May 1992), No. 5, pp. 415-416.
Huscroft Ian T.
Stevenson Graeme I.
Williams Brain J.
Davis Zinna Northington
Merck Sharp & Dohme Ltd.
North Robert J.
Winokur Melvin
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