Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1994-09-08
1996-04-23
Haley, Jacqueline
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
514383, 514397, 514414, 548256, 5482664, 5483121, 548466, A61K 3141, C07D40314
Patent
active
055103626
DESCRIPTION:
BRIEF SUMMARY
This application is a National Stage application of PCT/GB93/00474 filed Mar. 5, 1993 which published as WO/93/18029 on Sep. 16, 1993.
The present invention relates to a class of substituted imidazole, triazole and tetrazole derivatives which act on 5-hydroxytryptamine (5--HT) receptors, being selective agonists of so-called "5--HT.sub.1 -like" receptors. They are therefore useful in the treatment of clinical conditions for which a selective agonist of these receptors is indicated.
5--HT.sub.1 -like receptor agonists which exhibit selective vasoconstrictor activity have recently been described as being of use in the treatment of migraine (see, for example, A. Doenicke et al., The Lancet, 1988, Vol. 1, 1309-11). The compounds of the present invention, being selective 5--HT.sub.1 -like receptor agonists, are accordingly of particular use in the treatment of migraine and associated conditions, e.g. cluster headache, chronic paroxysmal hemicrania, headache associated with vascular disorders, tension headache and paediatric migraine.
EP-A-0313397 and WO-A-91/18897 describe separate classes of tryptamine derivatives substituted by various five-membered heteroaliphatic rings, which are stated to be specific to a particular type of "5--HT.sub.1 -like" receptor and thus to be effective therapeutic agents for the treatment of clinical conditions, particularly migraine, requiring this activity. However, neither EP-A-0313397 nor WO-A-91/18897 discloses or suggests the imidazole, triazole and tetrazole derivatives provided by the present invention.
EP-A-0497512, published on 5th Aug. 1992, describes a class of substituted imidazole, triazole and tetrazole derivatives which are stated to be selective agonists of 5--HT.sub.1 -like receptors and hence to be of particular use in the treatment of migraine and associated conditions.
The present invention provides a compound of formula I, or a salt or prodrug thereof: ##STR2## wherein the broken circle represents two non-adjacent double bonds in any position in the five-membered ring;
two, three or four of V, W, X, Y and Z represent nitrogen and the remainder represent carbon provided that, when two of V, W, X, Y and Z represent nitrogen and the remainder represent carbon, then the said nitrogen atoms are in non-adjacent positions within the five-membered ring;
A.sup.1 represents hydrogen, hydrocarbon, a heterocyclic group, halogen, cyano, trifluoromethyl, --OR.sup.x, --SR.sup.x, --NR.sup.x R.sup.y, --NR.sup.x COR.sup.y, --NR.sup.x CO.sub.2 R.sup.y, --NR.sup.x SO.sub.2 R.sup.y, or --NR.sup.z CTNR.sup.x R.sup.y ;
A.sup.2 represents a non-bonded electron pair when four of V, W, X, Y and Z represent nitrogen and the other represents carbon; or, when two or three of V, W, X, Y and Z represent nitrogen and the remainder represent carbon, A.sup.2 represents hydrogen, hydrocarbon, a heterocyclic group, halogen, cyano, trifluoromethyl, --OR.sup.x, --SR.sup.x, --NR.sup.x R.sup.y, --NR.sup.x COR.sup.y, --NR.sup.x CO.sub.2 R.sup.y, --NR.sup.x SO.sub.2 R.sup.y, or --NR.sup.z CTNR.sup.x R.sup.y ;
E represents a bond or a straight or branched alkylene chain containing from 1 to 4 carbon atoms;
F represents a group of formula ##STR3##
U represents nitrogen or C--R.sup.2 ;
B represents oxygen, sulphur or N--R.sup.3 ;
R.sup.1, R.sup.2 and R.sup.3 independently represent hydrogen or C.sub.1-6 alkyl;
R.sup.x and R.sup.y independently represent hydrogen, hydrocarbon or a heterocyclic group, or R.sup.x and R.sup.y together represent a C.sub.2-6 alkylene group;
R.sup.z represents hydrogen, hydrocarbon or a heterocyclic group;
T represents oxygen, sulphur or a group of formula .dbd.N.G; and
G represents hydrocarbon, a heterocyclic group or an electron-withdrawing group.
For use in medicine, the salts of the compounds of formula I will be non-toxic pharmaceutically acceptable salts. Other salts may, however, be useful in the preparation of the compounds according to the invention or of their non-toxic pharmaceutically acceptable salts. Suitable pharmaceutically acceptable salts of the compounds of t
Matassa Victor G.
Reeve Austin J.
Routledge Helen
Sternfeld Francine
Street Leslie
Haley Jacqueline
Merck Sharp and Dohme Limited
North Robert J.
Winokur Melvin
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