Piperazine, piperidine and tetrahydropyridine derivative of indol-3-alkyl as 5-HT1D- alpha agonists

摘要

PCT No. PCT/GB95/01129 Sec. 371 Date Nov. 15, 1996 Sec. 102(e) Date Nov. 15, 1996 PCT Filed May 18, 1995 PCT Pub. No. WO95/32196 PCT Pub. Date Nov. 30, 1995 <IMAGE> (I) Compounds of formula (I), or a salt or prodrug thereof, wherein Z represents an optionally substituted five-membered heteroaromatic ring selected from furan, thiophene, pyrrole, oxazole, thiazole, isoxazole, isothiazole, imidazole, pyrazole, oxadiazole, thiadiazole, triazole and tetrazole; E represents a chemical bond or a straight or branched alkylene chain containing from 1 to 4 carbon atoms; Q represents a straight or branched alkylene chain containing from 1 to 6 carbon atoms, optionally substituted in any position by a hydroxy group; T represents nitrogen or CH; U represents nitrogen or C-R2; V represents oxygen, sulphur or N-R3; -F-G- represents -CH2-N-, -CH2-CH- or -CH=C-; R1 represents C3-6alkenyl, C3-6alkynyl, aryl(C1-6)alkyl or heteroaryl(C1-6)alkyl, any of which groups may be optionally substituted; and R2 and R3 independently represent hydrogen or C1-6alkyl are selective agonists of 5-HT1D receptors, being potent agonists of the human 5-HT1Dalpha receptor subtype, while possessing at least a 10-fold selective affinity for the 5-HT1Dalpha receptor subtype, relative to the 5-HT1Dbeta subtype; they are therefore useful in the treatment and/or prevention of clinical conditions, in particular migraine and associated disorders, for which a subtype-selective agonist of 5-HT1D receptors is indicated, while eliciting fewer side-effects, notably adverse cardiovascular events, than those associated with non-subtype-selective 5-HT1D receptor agonists.