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US 5,843,949 AGranted
1-(1H-indolyloxyalkyl)-4-(heteroaryl)piperazines and related compounds useful as antipsychotics and analgesics
AssigneeHoechst Marion Roussel, Inc.
InventorsJoseph T. Strupczewski, Kenneth J. Bordeau
Life of this patent
Estimating the term…
Abstract
Heteroarylpiperidines, pyrrolidines, and piperazines are useful as antipsychotic and analgesic agents. The compounds are especially useful for treating psychoses by administering to a mammal a psychoses-treating effective amount of one of the compounds. Depot derivatives of the compounds are useful for providing long acting effects of the compounds. The compounds are also useful as analgesics by administering a pain-relieving effective amount of one of the compounds to a mammal.
Claims49
##STR133## wherein, X is --O--, --S--, ##STR134## R.sub.2 is selected from the group consisting of lower alkyl, aryl lower alkyl, aryl, cycloalkyl, aroyl, alkanoyl, and phenylsulfonyl groups, wherein aryl is as defined hereinafter;
- p is 1 or 2;
- Y is hydrogen, lower alkyl, hydroxy, chlorine, fluorine, bromine, iodine, lower alkoxy, trifluoromethyl, nitro, or amino, when p is 1;
- Y is lower alkyl, hydroxy or halogen when p is 2 and X is --O--;
- in which (R.sub.1) is R.sub.20, R.sub.21, or R.sub.22, wherein:
- R.sub.20 is --(CH.sub.2).sub.n --, where n is 2, 3, 4 or 5;
- R.sub.21 is
- --CH.sub.2 --CH.dbd.CH--CH.sub.2 --,
- --CH.sub.2 --C.tbd.C--CH.sub.2 --,
- --CH.sub.2 --CH.dbd.CH--CH.sub.2 --CH.sub.2,
- --CH.sub.2 --CH.sub.2 --CH.dbd.CH--CH.sub.2 --,
- --CH.sub.2 --C.tbd.C--CH.sub.2 --CH.sub.2 --, or
- --CH.sub.2 --CH.sub.2 --C.tbd.C--CH.sub.2 --,
- the --CH.dbd.CH-- bond being cis or trans;
- R.sub.22 is R.sub.20 or R.sub.21 in which one or more carbon atoms of R.sub.20 or R.sub.21 are substituted by at least one C.sub.1 -C.sub.6 linear alkyl group, phenyl group or ##STR135## where Z.sub.1 is lower alkyl, --OH, lower alkoxy, --CF.sub.3 --NO.sub.2, --NH.sub.2 or halogen;
- and
- R.sub.3 is hydrogen or --OCH.sub.3 ;
- in which aryl is phenyl or ##STR136## where R.sub.5 is hydrogen, lower alkyl, lower alkoxy, hydroxy, chlorine, fluorine, bromine, iodine, lower monoalkylamino, lower dialkylamino, nitro, cyano, trifluoromethyl, trifluoromethoxy;
- all geometric, optical, and stereoisomers thereof, or a pharmaceutically acceptable acid addition salt thereof.
15 more elements
A compound of the formula:
- ##STR137## wherein, X is --O--, --S--, --NH--, or --N(R.sub.2)--;
- R.sub.2 is selected from the group consisting of lower alkyl, aryl lower alkyl, aryl, cycloalkyl, aroyl, alkanoyl, alkoxycarbonyl, and phenylsulfonyl groups;
- aryl is as defined hereinafter;
- p is 1 or 2;
- Y is hydrogen, lower alkyl, hydroxy, chlorine, fluorine, bromine, iodine, lower alkoxy, trifluoromethyl, nitro, or amino;
- R.sub.1 is --CR.sub.24 R.sub.27 --(CR.sub.23 R.sub.24).sub.n --CR.sub.24 R.sub.27 --, where n is 0, 1, 2 or 3;
- or
- --CHR.sub.24 CH.dbd.CH--CHR.sub.24 --,
- --CHR.sub.24 --C.tbd.C--CHR.sub.24 --,
- --CHR.sub.24 --CH.dbd.CH--CR.sub.23 R.sub.24 --CHR.sub.24 --,
- --CHR.sub.24 --CR.sub.23 R.sub.24 --C.dbd.CH--CHR.sub.24 --,
- --CHR.sub.24 --C.tbd.C--CR.sub.23 R.sub.24 --CHR.sub.24 --, or
- --CHR.sub.24 --CR.sub.23 R.sub.24 --C.tbd.C--CHR.sub.24 --,
- the --CH=CH-- bond being cis or trans;
- R.sub.23 is hydrogen, (C.sub.1 -C.sub.18) linear alkyl, phenyl, hydroxy, (C.sub.1 -C.sub.18)alkoxy, aryloxy, aryl(C.sub.1 -C.sub.10)alkyloxy, (C.sub.1 -C.sub.18)alkanoyloxy, hydroxy(C.sub.1 -C.sub.6)alkyl, (C.sub.1 -C.sub.18)alkoxy(c.sub.1 -C.sub.6)alkyl, aryl(C.sub.1 -C.sub.18)alkyloxy(C.sub.1 -C.sub.6)alkyl, (C.sub.1 -C.sub.18) alkanoyloxy (C.sub.1 -C.sub.6) alkyl or ##STR138## where Z.sub.1 is lower alkyl, --OH, lower alkoxy, --CF.sub.3, --NO.sub.2, --NE.sub.2, or halogen, and p is as previously defined, wherein aryl is as defined hereinafter;
- R.sub.24 is hydrogen, (C.sub.1 -C.sub.18) linear alkyl, phenyl, hydroxy(C.sub.1 -C.sub.6)alkyl, (C.sub.1 -C.sub.18) alkoxy (C.sub.1 -C.sub.6) alkyl, phenyl(C.sub.1 -C.sub.6)alkyloxy, aryl(C.sub.1 -C.sub.18) alkoxy(C.sub.1 -C.sub.6)alkyl, (C.sub.1 -C.sub.18)alkanoyloxy(C.sub.3 -C.sub.6)alkyl or ##STR139## where Z.sub.1 and p are as previously defined, wherein aryl is as defined hereinafter;
- R.sub.27 is hydrogen or R.sub.24 and R.sub.27 taken together with the carbon to which they are attached form C.dbd.O or C.dbd.S;
- with the proviso that R.sub.23 is not hydrogen, (C.sub.1 -C.sub.18)linear alkyl, phenyl, or ##STR140## when R.sub.27 is hydrogen and R.sub.24 is hydrogen, (C.sub.1 -C.sub.18)linear alkyl, phenyl, or ##STR141## with the proviso that R.sub.24 is not hydrogen, (C.sub.1 -C.sub.18)linear alkyl, phenyl, or ##STR142## when R.sub.27 is hydrogen and n is 0, or when R.sub.27 is hydrogen and R.sub.23 is hydrogen, (C.sub.1 -C.sub.187)linear alkyl, phenyl, or ##STR143## or when R.sub.1 is --CHR.sub.24 --CH.dbd.CH--CHR.sub.24 -- or --CHR.sub.24 --C.dbd.C--CHR.sub.24 --;
- R.sub.3 is hydrogen or --OCH.sub.3 ;
- aryl is phenyl or ##STR144## wherein R.sub.5 is hydrogen, lower alkyl, lower alkoxy, hydroxy, chlorine, fluorine, bromine, iodine, lower monoalkylamino, lower dialkylamino, nitro, cyano, trifluoromethyl, or trifluoromethoxy;
- and, any hydroxyl group attached to an aliphatic or aromatic carbon atom, or any primary or secondary nitrogen atom may be acylated with a (C.sub.4 -C.sub.18)alkanoyl group, in addition, any nitrogen atom may alternatively be acylated with a (C.sub.4 -C.sub.18)alkoxycarbonyl group;
- all geometric, optical, and stereoisomers thereof, or a pharmaceutically acceptable acid addition salt thereof.
19 more elements
A compound of the formula:
- ##STR145## wherein, X is --O--, --S--, --NH--, or --N(R.sub.2)--;
- R.sub.2 is selected from the group consisting of lower alkyl, aryl lower alkyl, aryl, cycloalkyl, aroyl, alkanoyl, alkoxycarbonyl, and phenylsulfonyl groups;
- aryl is as defined hereinafter;
- p is 2;
- Y is lower alkyl, hydroxy, chlorine, fluorine, bromine, iodine, lower alkoxy, trifluoromethyl, nitro, or amino when X is --S--, --NH--, or --N(R.sub.2)--;
- Y is lower alkyl, trifluoromethyl, nitro, or amino when X is --O--;
- R.sub.1 is --CR.sub.24 R.sub.27 --(CR.sub.23 R.sub.24).sub.n --CR.sub.24 R.sub.27 --, where n is 0, 1, 2 or 3;
- or
- --CHR.sub.24 CH.dbd.CH--CHR.sub.24 --,
- --CHR.sub.24 --C.tbd.C--CHR.sub.24 --,
- --CHR.sub.24 --CH.dbd.CH--CR.sub.23 R.sub.24 --CHR.sub.24 --,
- --CHR.sub.24 --CR.sub.23 R.sub.24 --CH.dbd.CH--CHR.sub.24 --,
- --CHR.sub.24 --C.tbd.C--CR.sub.23 R.sub.24 --CHR.sub.24 --, or
- --CHR.sub.24 --CR.sub.23 R.sub.24 --C.tbd.-C--CHR.sub.24 --,
- the --CH=CH-- bond being cis or trans;
- R.sub.23 is hydrogen, (C.sub.1 -C.sub.18) linear alkyl, phenyl, hydroxy, (C.sub.1 -C.sub.18)alkoxy, aryloxy, aryl(C.sub.1 -C.sub.18)alkyloxy, (C.sub.1 -C.sub.18)alkanoyloxy, hydroxy (C.sub.1 -C.sub.6) alkyl, (C.sub.1 -C.sub.18) alkoxy (C.sub.1 -C.sub.6) alkyl, aryl(C.sub.1 -C.sub.18)alkyloxy(C.sub.1 -C.sub.6)alkyl, (C.sub.1 -C.sub.18)alkanoyloxy(C.sub.1-C.sub.6)alkyl or ##STR146## where Z.sub.1 is lower alkyl, --OH, lower alkoxy, --CF.sub.3, --NO.sub.2, --NH.sub.2, or halogen, and p is as previously defined, wherein aryl is as defined hereinafter;
- R.sub.24 is hydrogen, (C.sub.1 -C.sub.18) linear alkyl, phenyl, hydroxy(C.sub.1 -C.sub.6)alkyl, (C.sub.1 -C.sub.18)alkoxy(C.sub.1 -C.sub.6)alkyl, phenyl(C.sub.1 -C.sub.6)alkyloxy, aryl(C.sub.1 -C.sub.18)alkoxy(C.sub.1 -C.sub.6)alkyl, (C.sub.1 -C.sub.18) alkanoyloxy (C.sub.1 -C6) alkyl or ##STR147## where Z.sub.1 and p are as previously defined, wherein aryl is as defined hereinafter;
- R.sub.27 is hydrogen or R.sub.24 and R.sub.27 taken together with the carbon to which they are attached form C.dbd.O or C.dbd.S;
- R.sub.3 is hydrogen or --OCH.sub.3 ;
- aryl is phenyl or ##STR148## wherein R.sub.5 is hydrogen, lower alkyl, lower alkoxy, hydroxy, chlorine, fluorine, bromine, iodine, lower monoalkylamino, lower dialkylamino, nitro, cyano, trifluoromethyl, or trifluoromethoxy;
- and, any hydroxyl group attached to an aliphatic or aromatic carbon atom, or any primary or secondary nitrogen atom may be acylated with a (C.sub.4 -C.sub.18)alkanoyl group, in addition, any nitrogen atom may alternatively be acylated with a (C.sub.4 -C.sub.18)alkoxycarbonyl group;
- all geometric, optical, and stereoisomers thereof, or a pharmaceutically acceptable acid addition salt thereof.
19 more elements
A depot pharmaceutical composition, which comprises a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound having the formula:
- ##STR149## wherein, X is --O--, --S--, ##STR150## R.sub.2 is selected from the group consisting of lower alkyl, aryl lower alkyl, aryl, cycloalkyl, aroyl, alkanoyl, alkoxycarbonyl, and phenylsulfonyl groups, wherein aryl is as defined hereinafter;
- p is 1 or 2;
- Y is hydrogen, lower alkyl, hydroxy, chlorine, fluorine, bromine, iodine, lower alkoxy, trifluoromethyl, nitro, or amino, when p is 1;
- Y is lower alkyl, hydroxy or halogen when p is 2 and X is --O--;
- in which (R.sub.1) is R.sub.20, R.sub.21 or R.sub.22, wherein:
- R.sub.20 is --(CH.sub.2).sub.n --, where n is 2, 3, 4 or 5;
- R.sub.21 is
- --CH.sub.2 --CH.dbd.CH--CH.sub.2 --,
- --CH.sub.2 --C.tbd.C--CH.sub.2 --,
- --CH.sub.2 --CH.dbd.CH--CH.sub.2 --CH.sub.2 --,
- --CH.sub.2 --CH.sub.2 --CH.dbd.CH--CH.sub.2 --,
- --CH.sub.2 --C.tbd.C--CH.sub.2 --CH.sub.2 --, or
- --CH.sub.2 --CH.sub.2 --C.tbd.C--CH.sub.2 --,
- the --CH.dbd.CH-- bond being cis or trans;
- R.sub.22 is R.sub.20 or R.sub.21 in which one or more carbon atoms of R.sub.20 or R.sub.21 are substituted by at least one C.sub.1 -C.sub.6 linear alkyl group, phenyl group or ##STR151## where Z.sub.1 is lower alkyl, --OH, lower alkoxy, --CF.sub.3, --NO.sub.2, --NH.sub.2 or halogen;
- R.sub.3 is hydrogen or --OCH.sub.3 ;
- in which aryl is phenyl or ##STR152## where R.sub.5 is hydrogen, lower alkyl, lower alkoxy, hydroxy, chlorine, fluorine, bromine, iodine, lower monoalkylamino, lower dialkylamino, nitro, cyano, trifluoromethyl, trifluoromethoxy;
- and, any hydroxyl group attached to an aliphatic or aromatic carbon atom, or any primary or secondary nitrogen atom may be acylated with a (C.sub.4 -C.sub.18)alkanoyl group, in addition, any nitrogen atom may be acylated with a (C.sub.4 -C.sub.18)alkoxycarbonyl group;
- all geometric, optical, and stereoisomers thereof, or a pharmaceutically acceptable acid addition salt thereof.
16 more elements
Dependencies are inferred from the claim text.