Heteroaromatic 5-hydroxytryptamine receptor agonists

Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...

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Details

514363, 548128, 548138, C07D41712, A61K 3142

Patent

active

055103596

DESCRIPTION:

BRIEF SUMMARY
This application is a 371 of PCT/GB93/00789 dated Apr. 14, 1993.
The present invention relates to a class of substituted five-membered heteroaromatic compounds possessing an imino spacer group. These compounds 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.
The present invention provides a compound of formula I, or a salt or prodrug thereof: ##STR1## wherein the broken circle represents two non-adjacent double bonds in any position in the five-membered ring;
W, X, Y and Z independently represent oxygen, sulphur, nitrogen or carbon, provided that one of W, X, Y and Z represents oxygen or sulphur and at least one of W, X, Y and Z represents carbon;
A 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 ##STR2##
U represents nitrogen or C--R.sup.2 ;
B represents oxygen, sulphur or N--R.sup.3 ;
R.sup.1 represents --CH.sub.2 .multidot.CHR.sup.4 .multidot.NR.sup.6 R.sup.7 or a group of formula ##STR3## in which the broken line represents an optional chemical bond;
R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6 and R.sup.7 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 this invention include acid addition salts which may, for example, be formed by mixing a solution of the compound according to the invention with a solution of a pharmaceutically acceptable non-toxic acid such as hydrochloric acid, sulphuric acid, fumaric acid, maleic acid, succinic acid, acetic acid, benzoic acid, oxalic acid, citric acid, tartaric acid, carbonic acid or phosphoric acid. Furthermore, where the compounds of the invention carry an acidic moiety, suitable pharmaceutically acceptable salts thereof may include alkali metal salts, e.g. sodium or potassium salts; alkaline earth metal salts, e.g. calcium or magnesium salts; and salts formed with suitable organic ligands, e.g. quaternary ammonium salts.
The term "hydrocarbon" as used herein includes straight-chained, branched and cyclic groups containing up to 18 carbon atoms, suitably up to 15 carbon atoms, and conveniently up to 12 carbon atoms. Suitable hydrocarbon groups include C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-7 cycloalkyl, C.sub.3-7 cycloalkyl (C.sub.1-6) alkyl, aryl and aryl (C.sub.1-6) alkyl.
The expression "a heterocyclic group" as used herein includes cyclic groups containing up to 18 carbon atoms and

REFERENCES:
patent: 4785016 (1988-11-01), Evans et al.
patent: 5140034 (1993-08-01), Baker
patent: 5208248 (1993-05-01), Baker
patent: 5298520 (1994-03-01), Baker et al.

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