Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1995-06-06
1997-08-26
Ivy, C. Warren
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
514330, 546226, 546229, 546232, 546236, A61K 31445, C07D21126
Patent
active
056611625
DESCRIPTION:
BRIEF SUMMARY
This application is the U.S. national stage application of PCT/GB93/02535 filed Dec. 10, 1993 which is published as WO 94/13639 on Jun. 23, 1994.
This invention relates to a class of azacyclic compounds, which are useful as tachykinin antagonists. More particularly, the compounds of the invention comprise an azacyclic ring system substituted by an arylmethylamino 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 as follows:
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 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 hyperreflexia 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).
In view of their metabolic instability, peptide derivatives are likely to be of limited utility as therapeutic agents. It is for this reason that non-peptide tachykinin antagonists are sought.
In essence, this invention provides a class of potent non-peptide tachykinin antagonists.
The present invention provides a compound of formula (I), or a salt or prodrug thereof: ##STR2## wherein
x is NR.sup.4 or SO or SO.sub.2
m is 2, 3 or 4;
n is 0, 1 or 2 when m is 2 or 3, and n is 0 or 1 when m is 4;
R.sup.1 represents phenyl optionally substituted by 1, 2 or 3 groups 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, SO.sub.2 R.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 each independently represent H, C.sub.1-6 alkyl, phenyl or trifluoromethyl;
R.sup.2 represents phenyl optionally substituted by 1, 2 or 3 groups 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, SO.sub.2 R.sup.a, --NR.sup.a R.sup.b,
REFERENCES:
patent: 2538107 (1951-01-01), Kwartler et al.
patent: 2773870 (1956-12-01), Elpern
patent: 3083205 (1963-03-01), Janssen et al.
Naranjo, J.R. et al, Eur. J. Pharmacol. 1984(Feb. 10), 98(1), pp. 133-136.
Archiv. Pharm., 319(6), 505-515 (1986), "4-Piperidinylmethanamine".
Chemical Abstracts, 60(9), AB. No. 11242h, (Apr. 27,1964).
Chemical Abstracts, 62(8), AB. No. 9114c, (Apr. 12, 1965).
Chemical Abtracts, 89(5), AB. No. 43033t, (Jul. 31, 1978).
Chemical Abstracts, 86(13), AB. No. 89539d, (Mar. 28, 1977).
Chemical Abstracts, 94, (23), AB. No. 192068p, (Jun. 8, 1981).
Journ. of Med. Chem., 10(2) 174-177 (1967) "Histamine Releasers . . . ".
MacLeod Angus Murray
Stevenson Graeme Irvine
Dahler Garth M.
Ivy C. Warren
Merck Sharp & Dohme Limited
Rose David L.
Thies J. Eric
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