US 5,854,268 AGranted

Azetidine, pyrrolidine and piperidine derivatives

AssigneeMerck Sharp & Dohme Corp.

InventorsRaymond Baker, Sylvie Bourrain, Jose Luis Castro Pineiro, Mark Stuart Chambers, Alexander Richard Guiblin, Sarah Christine Hobbs, Richard Alexander Jelley, Andrew Madin, Victor Giulio Matassa, Austin John Reeve, Michael Geoffrey Russell, Graham Andrew Showell, Francine Sternfeld, Leslie Joseph Street, Monique Bodil Van Niel

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Abstract

A class of substituted azetidine, pyrrolidine and piperidine derivatives are selective agonists of 5-HT.sub.1 -like receptors, being potent agonists of the human 5-HT.sub.1D.alpha. receptor subtype whilst possessing at least a 10-fold selective affinity for the 5-HT.sub.1D.alpha. receptor subtype relative to the 5-HT.sub.1D.beta. 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-HT.sub.1D receptors is indicated, whilst eliciting fewer side-effects, notably adverse cardiovascular events, than those associated with non-subtype-selective 5-HT.sub.1D receptor agonists.

Claims10

Dependent claims

A compound of formula I, or a pharmaceutically acceptable salt thereof:

##STR24## 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 4 carbon atoms, optionally substituted in any position by a hydroxy group;
T represents CH;
U represents C--R.sup.2 ;
V represents N--R.sup.3 ;
R.sup.2 and R.sup.3 independently represent hydrogen or C.sub.1-6 alkyl;
M represents the residue of an azetidine, pyrrolidine or piperidine ring;
R represents a group of formula --W--R.sup.1 ;
W represents a chemical bond or a straight or branched alkylene chain containing from 1 to 4 carbon atoms, optionally substituted in any position by a hydroxy group;
R.sup.1 represents --OR.sup.x, --SR.sup.x, --SOR.sup.x, --SO.sub.2 R.sup.x or --NR.sup.x R.sup.y ;
R.sup.x and R.sup.y independently represent hydrogen or a hydrocarbon group;
wherein
hydrocarbon is selected from the group consisting of:
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, indanyl, aryl and aryl(C.sub.1-6)alkyl;
aryl is phenyl or naphthyl;
aryl(C.sub.1-6)alkyl is benzyl, phenylethyl, phenylpropyl or naphthylmethyl;
and wherein the hydrocarbon group may in turn be optionally substituted by one or more groups selected from C.sub.1-6 alkyl, adamantyl, phenyl, halogen, C.sub.1-6 haloalkyl, C.sub.1-6 aminoalkyl, trifluoromethyl, hydroxy, C.sub.1-6 alkoxy, aryloxy, keto, C.sub.1-3 alkylenedioxy, nitro, cyano, carboxy, C.sub.2-6 alkoxycarbonyl, C.sub.2-6 alkoxycarbonyl(C.sub.1-6)alkyl, C.sub.2-6 alkylcarbonyloxy, arylcarbonyloxy, aminocarbonyloxy, C.sub.2-6 alkylcarbonyl, arylcarbonyl, C.sub.1-6 alkylthio, C.sub.1-6 alkylsulphinyl, C.sub.1-6 alkylsulphonyl, arylsulphonyl, --NR.sup.v R.sup.w, --NR.sup.v COR.sup.w, --NR.sup.v CO.sub.2 R.sup.w, --NR.sup.v SO.sub.2 R.sup.w, --CH.sub.2 NR.sup.v SO.sub.2 R.sup.w, --NHCONR.sup.v R.sup.w, --CONR.sup.v R.sup.w, --SO.sub.2 NR.sup.v R.sup.w and --CH.sub.2 SO.sub.2 NR.sup.v R.sup.w, in which R.sup.v and R.sup.w independently represent hydrogen, C.sub.1-6 alkyl, aryl or aryl(C.sub.1-6)alkyl, or R.sup.v and R.sup.w together represent a C.sub.2-6 alkylene group;
or R.sup.x and R.sup.y together represent a C.sub.2-6 alkylene group, which alkylene group may be optionally substituted by one or more substituents selected from C.sub.1-6 alkyl, aryl and hydroxy, or fused with a phenyl ring;
and
R.sup.a represents hydrogen, hydroxy, or a hydrocarbon group, as defined above.

18 more elements

A compound selected from:

4-(N-benzyl-N-methyl)aminomethyl-1-3-(5-(1,2,4-triazol-4-yl)-1H-indol-3-yl )propyl!piperidine;
1-3-(5-(1,2,4-triazol-4-yl)-1H-indol-3-yl)propyl!-4-(R)-.alpha.-(methyl)b enzylamino!piperidine;
1-3-(5-(1,2,4-triazol-4-yl)-1H-indol-3-yl)propyl!-4-(S)-.alpha.-(methyl)b enzylamino!piperidine;
1-3-(5-(1,2,4-triazol-4-yl)-1H-indol-3-yl)propyl!-4-(S)-.alpha.-(hydroxym ethyl)benzylamino!piperidine;
1-3-(5-(1,2,4-triazol-4-yl)-1H-indol-3-yl)propyl!-4-(R)-.alpha.-(hydroxym ethyl)benzylamino!piperidine;
1-3-(5-(1,2,4-triazol-4-yl)-1H-indol-3-yl)propyl!-4-(S)-(1-hydroxymethyl- 2-phenyl)ethylamino!piperidine;
1-3-(5-(1,2,4-triazol-4-yl)-1H-indol-3-yl)propyl!-4-(1R,2S)-(2-hydroxy-1 -methyl-2-phenyl)ethylamino!piperidine;
1-3-(5-(1,2,4-triazol-4-yl)-1H-indol-3-yl)propyl!-4-(1S,2R)-(2-hydroxy-1- methyl-2-phenyl)ethylamino!piperidine;
1-3-(5-(1,2,4-triazol-4-yl)-1H-indol-3-yl)propyl!-4-(1R,2R)-(2-hydroxy-1- methyl-2-phenyl)ethylamino!piperidine;
1-3-(5-(1,2,4-triazol-4-yl)-1H-indol-3-yl)propyl!-4-2-(4-acetylaminopheny l)ethylamino!piperidine;
1-3-(5-(1,2,4-triazol-4-yl)-1H-indol-3-yl)propyl!-4-(R)-.alpha.-(methyl)b enzylamino!methylpiperidine;
1-3-(5-(1,2,4-triazol-4-yl)-1H-indol-3-yl)propyl!-4-(S)-.alpha.-(methyl)b enzylamino!methylpiperidine;
1-3-(5-(1,2,4-triazol-4-yl)-1H-indol-3-yl)propyl!-4-(S)-1-(4-acetylaminop henyl)ethylamino!methylpiperidine;
1-3-(5-(1,2,4-triazol-4-yl)-1H-indol-3-yl)propyl!-4-(R)-1-(4-acetylaminop henyl)ethylamino!methylpiperidine;
1-3-(5-(1,2,4-triazol-4-yl)-1H-indol-3-yl)propyl!-4-N-(R)-.alpha.-(hydro xymethyl)benzyl!-N-methylamino!piperidine;
1-3-(5-(1,2,4-triazol-4-yl)-1H-indol-3-yl)propyl!-4-N-(S)-.alpha.-(hydro xymethyl)benzyl!-N-methylamino!piperidine;
1-3-(5-(1,2,4-triazol-4-yl)-1H-indol-3-yl)propyl!-4-N-(2-(4-acetylaminoph enyl)ethyl)-N-methylamino!piperidine;
1-3-(5-(1,2,4-triazol-4-yl)-1H-indol-3-yl)propyl!-4-N-(4-acetylaminobenzy l)-N-methylamino!methylpiperidine;
1-3-(5-(1,2,4-triazol-4-yl)-1H-indol-3-yl)propyl!-4-(R)-.alpha.-(hydroxym ethyl)benzylamino!methylpiperidine;
(3S)-3-(4-acetylaminobenzyl)aminomethyl-1-2-(5-(1,2,4-triazol-4-yl)-1H-ind ol-3-yl)ethyl!pyrrolidine;
(3R)-3-(N-benzyl)aminomethyl-1-2-(5-(1,2,4-triazol-4-yl)-1H-indol-3-yl)eth yl!pyrrolidine;
3-(N-benzyl)aminomethyl-1-2-(5-(1,2,4-triazol-4-yl)-1H-indol-3-yl)ethyl!az etidine;
4-benzyl-4-hydroxy-1-3-(5-(1,2,4-triazol-4-yl)-1H-indol-3-yl)propyl!piperi dine;
3-(N-benzyl)aminomethyl-1-3-(5-(1,2,4-triazol-4-yl)-1H-indol-3-yl)propyl!a zetidine;
4-(N-benzyl)aminomethyl-4-hydroxy-1-3-(5-(1,2,4-triazol-4-yl)-1H-indol-3-y l)propyl!piperidine;
4-(N-benzyl-N-methyl)aminomethyl-4-hydroxy-1-3-(5-(1,2,4-triazol-4-yl)-1H- indol-3-yl)propyl!piperidine;
3-(N-benzyl-N-methyl)aminomethyl-1-2-(5-(1,2,4-triazol-4-yl)-1H-indol-3-yl )ethyl!azetidine;
(3S)-3-N-(R)-.alpha.-(methyl)benzyl!aminomethyl-1-2-(5-(1,2,4-triazol-4-y l)-1H-indol-3-yl)ethyl!pyrrolidine;
(3S)-3-N-(S)-.alpha.-(methyl)benzyl!aminomethyl-1-2-(5-(1,2,4-triazol-4-y l)-1H-indol-3-yl)ethyl!pyrrolidine;
(3S)-3-N-(furan-2-ylmethyl)amino!methyl-1-2-(5-(1,2,4-triazol-4-yl)-1H-in dol-3-yl)ethyl!pyrrolidine;
and pharmaceutically acceptable salts and prodrugs thereof.

28 more elements

A compound selected from:

(3S)-3-N-(R)-.alpha.-(hydroxymethyl)benzyl!aminomethyl-1-2-(5-(1,2,4-tria zol-4-yl)-1H-indol-3-yl)ethyl!pyrrolidine;
(3S)-3-N-(S)-.alpha.-(hydroxymethyl)benzyl!aminomethyl-1-2-(5-(1,2,4-tria zol-4-yl)-1H-indol-3-yl)ethyl!pyrrolidine;
(3S)-3-N-benzyl-N-(2-hydroxy)ethyl!aminomethyl-1-2-(5-(1,2,4-triazol-4-yl )-1H-indol-3-yl)ethyl!pyrrolidine;
(3S)-3-N-(2-phenylethyl)amino!methyl-1-2-(5-(1,2,4-triazol-4-yl)-1H-indol -3-yl)ethyl!pyrrolidine;
(3S)-3-N-(2-phenylethyl)-N-methylamino!methyl-1-2-(5-(1,2,4-triazol-4-yl) -1H-indol-3-yl)ethyl!pyrrolidine;
(3S)-3-(N-.alpha.-dimethylbenzyl)aminomethyl-1-2-(5-(1,2,4-triazol-4-yl)-1 H-indol-3-yl)ethyl!pyrrolidine;
(3S)-3-N-(S)-.alpha.-methylbenzyl!aminomethyl-1-2-(5-(1,2,4-triazol-1-yl) -1H-indol-3-yl)ethyl!pyrrolidine;
(3S)-3-N-(R)-.alpha.-(hydroxymethyl)benzyl!aminomethyl-1-2-(5-(1,2,4-tria zol-1-yl)-1H-indol-3-yl)ethyl!pyrrolidine;
(3S)-3-(N-benzyl)aminomethyl-1-2-(5-(1,2,4-triazol-1-ylmethyl)-1H-indol-3- yl)ethyl!pyrrolidine;
(3S)-3-N-(S)-.alpha.-methylbenzyl!aminomethyl-1-2-(5-(1,2,4-triazol-1-ylm ethyl)-1H-indol-3-yl)ethyl!pyrrolidine;
(3S)-3-N-(R)-.alpha.-(hydroxymethyl)benzyl!aminomethyl-1-2-(5-(1,2,4-tria zol-1-ylmethyl)-1H-indol-3-yl)ethyl!pyrrolidine;
(3S)-3-(N-benzyl-N-methyl)aminomethyl-1-2-(5-(imidazol-1-yl)-1H-indol-3-yl )ethyl!pyrrolidine;
(3S)-3-(N-benzyl-N-methyl)aminomethyl-1-2-(5-(1,2,4-triazol-1-ylmethyl)-1H -indol-3-yl)ethyl!pyrrolidine;
(3R)-3-N-methyl-N-(S)-.alpha.-methylbenzyl!aminomethyl-1-2-(5-(1,2,4-tria zol-1-ylmethyl)-1H-indol-3-yl)ethyl!pyrrolidine;
(3R)-3-N-methyl-N-(R)-.alpha.-hydroxymethylbenzyl!aminomethyl-1-2-(5-(1,2 ,4-triazol-1-ylmethyl)-1H-indol-3-yl)ethyl!pyrrolidine;
(3R)-3-N-methyl-N-(S)-.alpha.-methylcyclohexylmethyl!aminomethyl-1-2-(5-( 1,2,4-triazol-1-ylmethyl)-1H-indol-3-yl)ethyl!pyrrolidine;
(3R)-3-3-(R)-hydroxy-2-(R)-phenylpiperidin-1-yl!methyl-1-2-(5-(1,2,4-tria zol-1-ylmethyl)-1H-indol-3-yl)ethyl!pyrrolidine;
(3R)-3-3-(R)-hydroxy-2-(R)-phenylpiperidin-1-yl!methyl-1-2-(5-(1,2,4-tria zol-1-yl)-1H-indol-3-yl)ethyl!pyrrolidine;
4-hydroxy-4-(phenylsulfinyl)methyl-1-3-(5-(1,2,4-triazol-4-yl)-1H-indol-3- yl)propyl!piperidine;
(3R)-3-2-(R,S)-phenylpiperidin-1-yl!methyl-1-2-(5-(1,2,4-triazol-1-ylmeth yl)-1H-indol-3-yl)ethyl!pyrrolidine;
4-(3,3-dimethylpiperidin-1-yl)methyl-4-hydroxy-1-3-(5-(1,2,4-triazol-4-yl) -1H-indol-3-yl)propyl!piperidine;
4-hydroxy-4-(1,2,3,4-tetrahydroisoquinolin-2-yl)methyl-1-3-(5-(1,2,4-triaz ol-4-yl)-1H-indol-3-yl)propyl!piperidine;
4-hydroxy-4-(N-isobutyl-N-methyl)aminomethyl-1-3-(5-(1,2,4-triazol-4-yl)-1 H-indol-3-yl)propyl!piperidine;
4-N-benzyl-N-(2-hydroxyethyl)amino!methyl-4-hydroxy-1-3-(5-(1,2,4-triazol -4-yl)-1H-indol-3-yl)propyl!piperidine;
4-N-(2,2-dimethylpropyl)-N-methylamino!methyl-4-hydroxy-1-3-(5-(1,2,4-tri azol-4-yl)-1H-indol-3-yl)propyl!piperidine;
4-N-(R)-.alpha.-hydroxymethylbenzyl-N-methylamino!methyl-4-hydroxy-1-3-(5 -(1,2,4-triazol-4-yl)-1H-indol-3-yl)propyl!piperidine;
4-hydroxy-4-(2-methylphenylmethyl)aminomethyl-1-3-(5-(1,2,4-triazol-4-yl)- 1H-indol-3-yl)propyl!piperidine;
4-hydroxy-4-N-(2-methylphenylmethyl)-N-methylamino!methyl-1-3-(5-(1,2,4-t riazol-4-yl)-1H-indol-3-yl)propyl!piperidine;
3-(benzylamino)methyl-3-hydroxy-1-3-(5-(1,2,4-triazol-4-yl)-1H-indol-3-yl) propyl!pyrrolidine;
3-(benzylamino)methyl-3-hydroxy-1-2-(5-(1,2,4-triazol-4-yl)-1H-indol-3-yl) ethyl!pyrrolidine;
1-3-(5-(1,2,4-triazol-4-yl)-1H-indol-3-yl)propyl!-4-(R)-.alpha.-(carbamoy l-oxymethyl)benzylamino!piperidine;
1-3-(5-(1,2,4-triazol-4-yl)-1H-indol-3-yl)propyl!-4-(1R,2S)-2-hydroxy-1-p henylpropylamino!piperidine;
1-3-(5-(1,2,4-triazol-4-yl)-1H-indol-3-yl)propyl!-4-(1R,2R)-2-hydroxy-1-p henylpropylamino!piperidine;
1-3-(5-(1,2,4-triazol-4-yl)-1H-indol-3-yl)propyl!-4-(R,S)-1-hydroxy-2-phe nylprop-2-ylamino!piperidine;
1-3-(5-(1,2,4-triazol-4-yl)-1H-indol-3-yl)propyl!-4-(R)-2-hydroxy-1-(4-fl uorophenyl)ethylamino!piperidine;
1-3-(5-(1,2,4-triazol-4-yl)-1H-indol-3-yl)propyl!-4-(1R,2R)-2-hydroxyinda n-1-ylamino)piperidine;
1-3-(5-(1,2,4-triazol-4-yl)-1H-indol-3-yl)propyl!-4-(R,S)-indan-1-ylamino !piperidine;
1-3-(5-(1,2,4-triazol-4-yl)-1H-indol-3-yl)propyl!-4-(R,S)-1-(4-fluorophen yl)ethylamino!piperidine;
1-3-(5-(1,2,4-triazol-4-yl)-1H-indol-3-yl)propyl!-4-(R)-1-phenylprop-2-yl amino!piperidine;
1-3-(5-(1,2,4-triazol-4-yl)-1H-indol-3-yl)propyl!-4-N-(3,3-dimethylallyl) -N-methylamino!piperidine;
1-3-(5-(1,2,4-triazol-4-yl)-1H-indol-3-yl)propyl!-4-(N-allyl-N-methylamino )piperidine;
1-3-(5-(1,2,4-triazol-4-yl)-1H-indol-3-yl)propyl!-4-(indan-1-ylaminomethyl )piperidine;
1-3-(5-(1,2,4-triazol-4-yl)-1H-indol-3-yl)propyl!-4-N-(R)-.alpha.-(hydrox ymethyl)benzyl-N-methylaminomethyl!piperidine;
(3R)-3-(benzylthio)methyl-1-2-(5-(1,2,4-triazol-4-yl)-1H-indol-3-yl)ethyl! pyrrolidine;
(.+-.)-1-3-(5-(1,2,4-triazol-4-yl)-1H-indol-3-yl)propyl!-4-(1-benzylamino- 2-hydroxyethyl)piperidine;
1-3-(5-(1,2,4-triazol-1-yl)-1H-indol-3-yl)propyl!-4-(R)-.alpha.-(hydroxym ethyl)benzylamino!piperidine;
1-3-(5-(imidazol-1-yl)-1H-indol-3-yl)propyl!-4-(R)-.alpha.-(methyl)benzyl amino!piperidine;
1-3-(5-(imidazol-1-yl)-1H-indol-3-yl)propyl!-4-(R)-.alpha.-(hydroxymethyl )benzylamino!piperidine;
1-3-(5-(1,2,4-triazol-1-ylmethyl)-1H-indol-3-yl)propyl!-4-(R)-.alpha.-(hy droxymethyl)benzylamino!piperidine;
1-3-(5-(1,2,4-triazol-4-yl)-1H-indol-3-yl)propyl!-4-(R)-.alpha.-(methoxym ethyl)benzylamino!piperidine;
1-3-(5-(1,2,4-triazol-4-yl)-1H-indol-3-yl)propyl!-4-N-(R)-.alpha.-(methox ymethyl)benzyl-N-methylamino!piperidine;
1-3-(5-(imidazol-1-yl)-1H-indol-3-yl)propyl!-4-(R)-.alpha.-(methoxymethyl )benzylamino!piperidine;
1-3-(5-(1,2,4-triazol-1-ylmethyl)-1H-indol-3-yl)propyl!-4-(R)-1-(4-fluoro phenyl)-2-methoxyethylamino!piperidine;
1-3-(5-(1,2,4-triazol-1-ylmethyl)-1H-indol-3-yl)propyl!-4-N-(4-fluorobenz yl)-N-methylamino!piperidine;
1-3-(5-(1,2,4-triazol-4-yl)-1H-indol-3-yl)propyl!-4-(2-phenylpiperidin-1-y l)piperidine;
1-3-(5-(1,2,4-triazol-4-yl)-1H-indol-3-yl)propyl!-4-(R)-1-(4-fluorophenyl )-2-methoxyethylamino!piperidine;
(3R)-3-(benzylsulfinyl)methyl-1-2-(5-(1,2,4-triazol-4-yl)-1H-indol-3-yl)et hyl!pyrrolidine;
(3R)-3-(4-fluorobenzylthio)methyl-1-2-(5-(1,2,4-triazol-1-ylmethyl)-1H-ind ol-3-yl)ethyl!pyrrolidine;
(3R)-3-(4-fluorobenzylsulfinyl)methyl-1-2-(5-(1,2,4-triazol-1-ylmethyl)-1H -indol-3-yl)ethyl!pyrrolidine;
(3R)-3-(4-fluorobenzylsulfonyl)methyl-1-2-(5-(1,2,4-triazol-1-ylmethyl)-1H -indol-3-yl)ethyl!pyrrolidine;
4-(4-fluorobenzylsulfinyl)-1-3-(5-(1,2,4-triazol-4-yl)-1H-indol-3-yl)propy l!piperidine;
and pharmaceutically acceptable salts and prodrugs thereof.

59 more elements

Dependencies are inferred from the claim text.