US 5,854,263 AGranted

1-(1,4-benzodioxanyl)alkyl!-3-(heteroaryl) pyrrolidines and related compounds and their therapeutic utility

AssigneeHoechst Marion Roussel, Inc.

InventorsEdward J. Glamkowski, Yulin Chiang

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.

Claims43

Dependent claims

A compound having the formula:

##STR136## wherein, X is --O--, --S--, ##STR137## 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 alkoxy, 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 ##STR138## where Z.sub.1 is lower alkyl, --OH, lower alkoxy, --CF.sub.3, --NO.sub.2, --NH.sub.2 or halogen;
R.sub.4 is hydrogen, lower alkyl, lower alkoxy, hydroxy, amino, mono- or dialkylamino, C.sub.1 -C.sub.3 acyl amino, C.sub.1 -C.sub.6 alkanoyl, trifluoromethyl, chlorine, fluorine, bromine, ##STR139## in which aryl is phenyl or ##STR140## 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.

14 more elements

A depot pharmaceutical composition, which comprises a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound having the formula:

##STR141## wherein, X is --O--, --S--, ##STR142## 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 alkoxy, 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 ##STR143## where Z.sub.1 is lower alkyl, --OH, lower alkoxy, --CF.sub.3, --NO.sub.2, --NH.sub.2 or halogen;
R.sub.4 is hydrogen, lower alkyl, lower alkoxy, hydroxy, amino, mono- or dialkylamino, C.sub.1 -C.sub.3 acyl amino, C.sub.1 -C.sub.6 alkanoyl, trifluoromethyl, chlorine, fluorine, bromine, ##STR144## in which aryl is phenyl or ##STR145## 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;
wherein the compound contains an acylated hydroxy group, or an acylated amino group, and further wherein the hydroxy group is acylated with a (C.sub.4 -C.sub.18)alkanoyl group, or the amino group is acylated with a (C.sub.4 -C.sub.18)alkanoyl group or a (C.sub.4 -C.sub.18)alkoxycarbonyl group.

17 more elements

A compound of the formula:

##STR146## 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.2 --,
--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.dbd.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 ##STR147## 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 -C.sub.6)alkyl or ##STR148## 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 ##STR149## when R.sub.27 is hydrogen and R.sub.24 is hydrogen, (C.sub.1 -C.sub.18)linear alkyl, phenyl, or ##STR150## with the proviso that R.sub.24 is not hydrogen, (C.sub.1 -C.sub.18)linear alkyl, phenyl, or ##STR151## 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.18)linear alkyl, phenyl, or ##STR152## R.sub.4 or when R.sub.1 is --CHR.sub.24 --CH.dbd.CH--CHR.sub.24 -- or --CHR.sub.24 --C.tbd.C--CHR.sub.24 is hydrogen, lower alkyl, lower alkoxy, hydroxy, tri(C.sub.1 -C.sub.6)alkylsilyloxy, hydroxy lower alkyl, alkanoyloxy lower alkyl, amino, mono- or dialkylamino, (C.sub.1 -C.sub.18)acyl amino, nitro, (C.sub.1 -C.sub.18)alkanoyl, trifluoromethyl, chlorine, fluorine, bromine, --O--C(.dbd.O)--(C.sub.1 -C.sub.18 straight or branched chain)alkyl or --C(.dbd.O)-aryl;
aryl is phenyl or ##STR153## 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.

18 more elements

A compound of the formula:

##STR154## 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.dbd.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 ##STR155## 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 -C.sub.6)alkyl or ##STR156## 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.4 is hydrogen, lower alkyl, lower alkoxy, hydroxy, tri(C.sub.l -C.sub.6)alkylsilyloxy, hydroxy lower alkyl, alkanoyloxy lower alkyl, amino, mono- or dialkylamino, (C.sub.1 -C.sub.18)acyl amino, nitro, (C.sub.1 -C.sub.18)alkanoyl, trifluoromethyl, chlorine, fluorine, bromine, --O--C(.dbd.O)--(C.sub.1 -C.sub.18 straight or branched chain)alkyl or --C(.dbd.O)-aryl;
aryl is phenyl or ##STR157## 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

Dependencies are inferred from the claim text.

Facts

Application: 08/469,501Filed 6 Jun 1995 · division
Priority: 19 May 1989
Granted: 29 Dec 1998
Term ends: Not estimatedThe source records don’t support an estimate.

Classification33 codes

C07D 231/56
Condensed with carbocyclic rings or ring systems: benzopyrazoles; Hydrogenated benzopyrazoles
A61P 23/00
Anaesthetics
A61P 25/00
Drugs for disorders of the nervous system
A61P 25/04
Drugs for disorders of the nervous system: centrally acting analgesics, e.g. opioids

Family

Serial354,411Parent of this continuation-in-part · filed 19 May 1989
Serial456,790Parent of this continuation · filed 29 Dec 1989
Serial619,825Parent of this continuation · filed 29 Nov 1990
Serial944,705Parent of this continuation-in-part · filed 5 Sep 1991
Serial788,269Parent of this continuation-in-part · filed 5 Nov 1991
Serial969,383Parent of this continuation-in-part · filed 30 Oct 1992
Serial144,265Parent of this continuation-in-part · filed 28 Oct 1993
Serial329,000Parent of this division · filed 25 Oct 1994
US 5,776,963 AParent of this division
US 5,364,866 AParent of this continuation-in-part
US 5,602,158 ARelated patent
US 5,854,263 AThis patent

From the US filing history. Foreign family members aren’t listed.

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Abstract

Facts

Application

08/469,501Filed 6 Jun 1995 · division

Priority

19 May 1989

Granted

29 Dec 1998

Term ends

Not estimatedThe source records don’t support an estimate.

Classification33 codes

C07D 231/56
Condensed with carbocyclic rings or ring systems: benzopyrazoles; Hydrogenated benzopyrazoles
A61P 23/00
Anaesthetics
A61P 25/00
Drugs for disorders of the nervous system
A61P 25/04
Drugs for disorders of the nervous system: centrally acting analgesics, e.g. opioids

Family

Serial354,411Parent of this continuation-in-part · filed 19 May 1989

Serial456,790Parent of this continuation · filed 29 Dec 1989

Serial619,825Parent of this continuation · filed 29 Nov 1990

Serial944,705Parent of this continuation-in-part · filed 5 Sep 1991

Serial788,269Parent of this continuation-in-part · filed 5 Nov 1991

Serial969,383Parent of this continuation-in-part · filed 30 Oct 1992

Serial144,265Parent of this continuation-in-part · filed 28 Oct 1993

Serial329,000Parent of this division · filed 25 Oct 1994

US 5,776,963 AParent of this division

US 5,364,866 AParent of this continuation-in-part

US 5,602,158 ARelated patent

US 5,854,263 AThis patent

From the US filing history. Foreign family members aren’t listed.