Acyclic anc cyclic amides as neurotransmitter release enhancers
AssigneePfizer Inc.
InventorsRobert A. Volkmann, Vytautas J Jasys, Gene M Bright, Anabella Villalobos, Patricia A Seymour
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Abstract
This invention relates to compounds of formula (IA), (IB), (IC) or (ID), wherein m, X, Z, R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.14 and the dotted lines are as defined below, their pharmaceutically acceptable salts, pharmaceutical compositions containing them and methods of using them to treat Alzheimer's disease, age-associated memory impairment, Parkinson's disease and other central nervous system disorders. The claimed compounds have the ability to enhance the release of neurotransmitters such as acetylcholine, dopamine and serotonin. ##STR1##
Claims43
A compound of the formula ##STR17## wherein both dotted lines represent optional double bonds;
- m is an integer from zero to four;
- Z is oxygen or sulfur when it is double bonded to ring A and Z is hydroxy, (C.sub.1 -C.sub.10) alkyl-S-,adamant-2-yl-S-, benzyl-S-,phenyl-C(=O)CH.sub.2 -S-, (C.sub.1-C.sub.6)alkyl--O--C(=O)CH.sub.2 --S--or (H, H) when Z is single bonded to ring A;
- X is CH.sub.2 CH.sub.2, NR.sup.1, CHR.sup.1 or a direct link between the carbon to which Z is attached and the carbon to which R.sup.3 and R.sup.4 are attached;
- R.sup.2 and R.sup.6 are independently selected from naphthyl, phenyl, (C.sub.1 -C.sub.6)alkylphenyl, 1-adamantyl, 2-adamantyl, (C.sub.1 -C.sub.8) straight or branched alkyl, (C.sub.3 -C.sub.10) cycloalkyl and (C.sub.8 -C.sub.30)bicyclic or tricyclic alkyl;
- wherein said (C.sub.3 -C.sub.10)cycloalkyl and said (C.sub.8 -C.sub.30) bicyclic or tricyclic alkyl may optionally be substituted with a hydroxy group;
- and
- wherein said adamantyl groups may optionally be substituted with from one to three substituents independently selected from (C.sub.1 -C.sub.6)alkyl, halo and hydroxy;
- R.sup.3 and R.sup.4 are independently selected from benzyl, wherein the phenyl moiety of said benzyl may optionally be substituted with an amino or nitro group;
- hydrogen, phenyl, (N.tbd.C)-(C.sub.1 -C.sub.6)alkyl, (C.sub.1 -C.sub.6)alkyl--O--C(=O)-(C.sub.1 -C.sub.6)alkyl and Het-CH.sub.2,wherein Het is selected from 2-, 3- or 4-pyridinyl, furyl, tetrahydrofuryl, pyrimidyl, pyrazinyl, pyrazolyl, isoxazolyl, thiophenyl and triazolyl;
- R.sup.5 is hydrogen, phenyl-(C.sub.1 -C.sub.6)alkyl, (C.sub.1 -C.sub.10)alkyl or (C.sub.1 -C.sub.6)alkyl--C(=O)--;
- W is hydrogen, OR.sup.7, hydroxy, R.sup.11 or NR.sup.12 R.sup.13 ;
- each of R.sup.7 and R.sup.11 is independently selected from (C.sub.1 -C.sub.3)alkyl;
- each of R.sup.12 and R.sup.13 is independently selected from (C.sub.1 -C.sub.3)alkyl;
- and
- R.sup.14 is hydrogen, (C.sub.1 -C.sub.4)alkyl, benzyl or phenyl;
- with the proviso that (a) no more than one of the two dotted lines in formula IA can represent a double bond in any one compound, (b) when Z is (H, H), X is CH.sub.2 or CH.sub.2 CH.sub.2, (c) when Z is oxygen or (H, H) and X is CHR.sup.1, R.sup.1 must be hydrogen, (d) when Z is sulfur and X is NR.sup.1, R.sup.1 must be hydrogen, and (e) one of R.sup.3 and R.sup.4 must be Het-CH.sub.2 ;
- or a pharmaceutically acceptable salf of such compound.
A compound of the formula IB wherein R.sup.14 is hydrogen.
Dependencies are inferred from the claim text.