Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1996-07-19
1999-05-11
Morris, Patricia L.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
5482664, A61K31/41
Patent
active
059028190
DESCRIPTION:
BRIEF SUMMARY
The present invention relates to a class of substituted triazole 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.
WO-A-94/02477, published on 3rd February 1994, 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 one of Y and Z represents nitrogen and the other represents C-A.sup.2 ; 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 ; from 1 to 4 carbon atoms; ##STR3## B represents oxygen, sulphur or N--R.sup.3 ; U represents nitrogen or C--R.sup.4 ; carbon atoms; p+q is 2, 3 or 4; C.sub.2-6 alkynyl, C.sub.3-7 cycloalkyl, C.sub.3-7 cycloalkyl(C.sub.1-6)alkyl, aryl, aryl(C.sub.1-6)alkyl, aryloxy(C.sub.1-6)alkyl, aryl(C.sub.2-6)alkenyl, aryl(C.sub.2-6)alkynyl, C.sub.3-7 heterocycloalkyl(C.sub.1-6)alkyl, heteroaryl, heteroaryl(C.sub.1-6)alkyl, heteroaryl(C.sub.2-6)alkenyl or heteroaryl(C.sub.2-6)alkynyl, any of which groups may be optionally substituted;
R.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, --NR.sup.Z CTNR.sup.X R.sup.y, --COR.sup.X, --CO.sub.2 R.sup.X, or --CONR.sup.X R.sup.y ; heterocyclic group, or R.sup.X and R.sup.y together represent a C.sub.2-6 alkylene group; group.
For use in medicine, the salts of the compounds of formula I will be pharmaceutically acceptable salts. Other salts may, however, be useful in the preparation of the compounds according to the invention or of their 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 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 at least one heteroatom preferably selected from oxygen, nitrogen and sulphu
Matassa Victor Giulio
Sternfeld Francine
Street Leslie Joseph
Durette Philippe L.
Merck Sharp & Dohme Ltd.
Morris Patricia L.
Winokur Melvin
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