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Details for Patent: 5,998,417

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Details for Patent: 5,998,417

Title: N-[(4-heteroaryl-1-piperazinyl) alkyl]phthalimides and related compounds and their therapeutic utility
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.
Inventor(s): Glamkowski; Edward J. (Warren, NJ), Chiang; Yulin (Covent Station, NJ), Strupczewski; Joseph T. (Flemington, NJ), Nemoto; Peter A. (Raritan, NJ), Tegeler; John J. (Bridgewater, NJ)
Assignee: Hoechst Marion Roussel, Inc. (Kansas, MO)
Filing Date:Jun 06, 1995
Application Number:08/468,065
Claims:1. A compound having the formula ##STR133## wherein X is --O--, --S--, ##STR134## or ##STR135## 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--CH.dbd.CH.sub.2 --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 C.sub.1 -C.sub.6 linear alkyl group, phenyl group or ##STR136## where Z.sub.1 is lower alkyl, --OH, lower alkoxy, --CH.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, ##STR137## or ##STR138## in which aryl is phenyl or ##STR139## where R.sub.5 is hydrogen, lower alkyl, lower alkoxy, hydroxy, chlorine fluorine, bromine, iodine, lower monoalkylamino, lower dialkylamino, nitro, cyano, trifluoromethyl, trifluoromethyl;

q is 1, 2, 3, or 4;

with the proviso that R.sub.4 is not H when X is --S--, Y is hydrogen, hydroxy, cyano, lower alkyl, lower alkoxy, halogen, or trifluoromethyl, R.sub.1 is R.sub.20, and n is 2, 3, 4 or 5;

all geometric, optical, and stereoisomers thereof, or a pharmaceutically acceptable acid addition salt thereof.

2. The compound of claim 1, wherein X is --N(R.sub.2)--.

3. The compound of claim 1, wherein R.sub.2 is (C.sub.1 -C.sub.18)alkanoyl.

4. The compound of claim 1, wherein R.sub.1 is --CH.sub.2 --CH.sub.2 --, --CH.sub.2 CH.sub.2 CH.sub.2 --, --CH.sub.2 CH(CH.sub.3)--, or --CH(CH.sub.3)CH.sub.2 --.

5. The compound of claim 1, wherein X is --NH--.

6. An antipsychotic composition, which comprises the compound of claim 1 in an amount sufficient to produce an antipsychotic effect, and a pharmaceutically acceptable carrier therefor.

7. A method of treating psychoses, which comprises administering to a mammal a psychoses-treating effective amount of the compound of claim 1.

8. An analgesic composition, which comprises the compound of claim 1 in an amount sufficient to produce a pain-relieving effect, and a pharmaceutically acceptable carrier therefor.

9. A method of alleviating pain, which comprises administering to a mammal a pain-relieving effective amount of the compound of claim 1.

10. A method for providing a long acting antipsychotic effect, which comprises injecting into a mammal an amount of the composition of claim 1 sufficient to produce a long acting antipsychotic effect.

11. A pharmaceutical composition which comprises the compound of claim 1 and a pharmaceutically acceptable carrier therefor.

12. A depot pharmaceutical composition, which comprises a pharmaceutically acceptable carrier and a therapeutically effective amount of the compound of claim 1.

13. A method for providing a long acting antipsychotic effect, which comprises injecting into a mammal an amount of the composition of claim 12 sufficient to produce a long acting antipsychotic effect.

14. A compound of formula ##STR140## 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;

A is --C(.dbd.O)--, --C(.dbd.S)--, --C(.dbd.CH.sub.2)--, --CH.sub.2 CH.sub.2 --, --CR.sub.26 .dbd.N--, or --CR.sub.25 R.sub.26 --;

R.sub.25 is hydrogen, (C.sub.1 -C.sub.6)alkyl, hydroxy, or (C.sub.1 -C.sub.8) alkanoyloxy;

R.sub.26 is hydrogen, (C.sub.1 -C.sub.6)alkyl;

either one of B.sub.y and B.sub.z is Ch or N and the other is CH;

U is O or S;

q is 1, 2, 3, or 4;

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 --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)alkoxy, (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 or (C.sub.1 -C.sub.18)alkanoyloxy(C.sub.1 -C.sub.6)alkyl, or ##STR141## where Z.sub.1 is a lower alkyl, --OH, lower alkoxy, --CF.sub.3, --NO.sub.2, --NH.sub.2, or halogen, and p is as previously defined, and wherein aryl is as defined hereinafter; and

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)alkyloxy(C.sub.1 -C.sub.6)alkyl, (C.sub.1 -C.sub.18)alkanoyloxy(C.sub.1 -C.sub.6)alkyl, or ##STR142## where Z.sub.1 is as previously defined, and p is 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--O or C--S;

with the proviso that R.sub.23 is not hydrogen, (C.sub.1 -C.sub.18)linear alkyl, phenyl, or ##STR143## when R.sub.27 is hydrogen and R.sub.24 is hydrogen, (C.sub.1 -C.sub.18)linear alkyl, phenyl, or ##STR144## with the proviso that R.sub.24 is not hydrogen, (C.sub.1 -C.sub.18)linear alkyl, phenyl, or ##STR145## 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 ##STR146## 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 --;

R.sub.4 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, (C.sub.1 -C.sub.18)alkanoyl, trifluoromethyl, chlorine, fluorine, bromine, nitro, --O--C(.dbd.O)--(C.sub.1 -C.sub.18 straight or branched chain)alkyl or --C(.dbd.O)--aryl, wherein aryl is as defined hereinafter;

in which aryl is phenyl or ##STR147## wherein R.sub.5 is hydrogen, lower alkyl, lower alkoxy, hydroxy, chlorine, fluorine, bromine, iodine, lower monoalkylamino, lower dialkylamino, nitro, cyano, trifluoromethyl, or trifluoromethyl;

and, any hydroxyl group attached to an aliphatic or aromatic carbon atom, or any primary or secondary nitrogen atom may to 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.

15. A compound of the formula ##STR148## 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 phenysulfonyl;

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--;

A is --C(.dbd.O)--, --C(.dbd.S)--, --C(.dbd.CH.sub.2)--, --C(.dbd.O)CH.sub.2 --, --CH.sub.2 CH.sub.2 --, --CR.sub.26 .dbd.N--, or --CR.sub.25 R.sub.26 --;

R.sub.25 is hydrogen, (C.sub.1 -C.sub.6 alkyl, hydroxy, or (C.sub.1 -C.sub.8) alkanoyloxy;

R.sub.26 is hydrogen or (C.sub.1 -C.sub.6)alkyl;

either one of B.sub.y and B.sub.z is CH or N and the other is CH;

U is O or S;

q is 1, 2, 3, or 4;

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 --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)alkoxy, (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 or (C.sub.1 -C.sub.18)alkanoyloxy(C.sub.1 -C.sub.6)alkyl, or ##STR149## 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, and wherein aryl is as defined hereinafter; and

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)alkyloxy(C.sub.1 -C.sub.6)alkyl, (C.sub.1 -C.sub.18)alkanoyloxy(C.sub.1 -C.sub.6)alkyl, or ##STR150## where Z.sub.1 is as previously defined, and p is as previously defined, and 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.1 -C.sub.6)alkylsilyloxy, hydroxy lower alkyl, alkanoyloxy lower alkyl, amino, mono- or dialkylamino, (C.sub.1 -C.sub.18)acyl amino, (C.sub.1 -C.sub.18)alkanoyl, trifluoromethyl, chlorine, fluorine, bromine, nitro, --O--C(.dbd.O)--(C.sub.1 -C.sub.18 straight or branched chain)alkyl or --C(.dbd.O)--aryl, wherein aryl is as defined hereinafter;

in which aryl is phenyl or ##STR151## wherein R.sub.5 is hydrogen, lower alkyl, lower alkoxy, hydroxy, chlorine, fluorine, bromine, iodine, lower monoalkylamino, lower dialkylamino, nitro, cyano, trifluoromethyl, or trifluoromethyl;

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.

16. A compound of formula ##STR152## 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;

A is --C(.dbd.O)--, --C(.dbd.S)--, --C(.dbd.CH.sub.2)--, --CH.sub.2 CH.sub.2 --, --CR.sub.26 .dbd.N--, or --CR.sub.25 R.sub.26 --;

R.sub.25 is hydrogen, (C.sub.1 -C.sub.6)alkyl, hydroxy, or (C.sub.1 -C.sub.8) alkanoyloxy;

R.sub.26 is hydrogen, (C.sub.1 -C.sub.6)alkyl;

either one of B.sub.y and B.sub.z is Ch or N and the other is CH;

U is O or S;

q is 1, 2, 3, or 4;

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 --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)alkoxy, (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 or (C.sub.1 -C.sub.18)alkanoyloxy(C.sub.1 -C.sub.6)alkyl, or ##STR153## 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, and wherein aryl is as defined hereinafter; and

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)alkyloxy(C.sub.1 -C.sub.6)alkyl, (C.sub.1 -C.sub.18)alkanoyloxy(C.sub.1 -C.sub.6)alkyl, or ##STR154## where Z.sub.1 is as previously defined, and p is as previously defined, and 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.1 -C.sub.6)alkylsilyloxy, hydroxy lower alkyl, alkanoyloxy lower alkyl, amino, mono- or dialkylamino, (C.sub.1 -C.sub.18)acyl amino, (C.sub.1 -C.sub.18)alkanoyl, trifluoromethyl, chlorine, fluorine, bromine, nitro, --O--C(.dbd.O)--(C.sub.1 -C.sub.18 straight or branched chain)alkyl or --C(.dbd.O)--aryl, wherein aryl is as defined hereinafter;

in which aryl is phenyl or ##STR155## wherein R.sub.5 is hydrogen, lower alkyl, lower alkoxy, hydroxy, chlorine, fluorine, bromine, iodine, lower monoalkylamino, lower dialkylamino, nitro, cyano, trifluoromethyl, or trifluoromethyl;

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;

with the proviso that when A is --C(.dbd.O)--, R.sub.23 is not hydrogen, (C.sub.1 -C.sub.18)linear alkyl, phenyl, or ##STR156## when R.sub.27 is hydrogen and R.sub.24 is hydrogen, (C.sub.1 -C.sub.18)linear alkyl, phenyl, or ##STR157## with the proviso that when A is --C(.dbd.O)--, R.sub.24 is not hydrogen, (C.sub.1 -C.sub.18)linear alkyl, phenyl, or ##STR158## 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 ##STR159## 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 --;

with the proviso that when A is --CH.sub.2 CH.sub.2 --, or when A is --CR.sub.25 R.sub.26 -- and R.sub.25 and R.sub.26 are both hydrogen or (C.sub.1 -C.sub.6)alkyl, then B.sub.y and B.sub.z are not both CH, unless X is --NR.sub.2 and R.sub.2 is not alkyl, or unless R.sub.1 is subject to the proviso that R.sub.23 is not hydrogen or (C.sub.1 -C.sub.18)linear alkyl when R.sub.27 is hydrogen and R.sub.24 is hydrogen or (C.sub.1 -C.sub.18)linear alkyl, and the proviso that R.sub.24 is not hydrogen or (C.sub.1 -C.sub.18)linear alkyl when R.sub.27 is hydrogen and n is 0, or when R.sub.27 is hydrogen and R.sub.23 is hydrogen or (C.sub.1 -C.sub.18)linear alkyl, 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 --;

with the proviso that A is not --CR.sub.26 .dbd.N-- when B.sub.y and B.sub.z are both CH;

all geometric, optical, and stereoisomers thereof; or a pharmaceutically acceptable acid addition salt thereof.

17. A compound of formula ##STR160## 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;

A is --C(.dbd.O)--, --C(.dbd.S)--, --C(.dbd.CH.sub.2)--, --C(.dbd.O)CH.sub.2 --, --CH.sub.2 CH.sub.2 --, --CR.sub.26 .dbd.N--, or --CR.sub.25 R.sub.26 --;

R.sub.25 is hydrogen, (C.sub.1 -C.sub.6)alkyl

either one of B.sub.y and B.sub.z is N and the other is CH;

U is O or S;

q is 1, 2, 3, or 4;

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 --CR.sub.23 R.sub.24 --C.tbd.C--CHR.sub.24 --, or

--CHR.sub.24 --CR.sub.23 R.sub.24 --C.tbd.C--CHR.sub.24 --,

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 or (C.sub.1 -C.sub.18)alkanoyloxy(C.sub.1 -C.sub.6)alkyl, or ##STR161## 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, and wherein aryl is as defined hereinafter; and

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)alkyloxy(C.sub.1 -C.sub.6)alkyl, (C.sub.1 -C.sub.18)alkanoyloxy(C.sub.1 -C.sub.6)alkyl, or ##STR162## where Z.sub.1 is as previously defined, and p is as previously defined, and 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 from C.dbd.O or O.dbd.S;

R.sub.4 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, (C.sub.1 -C.sub.18)alkanoyl, trifluoromethyl, chlorine, fluorine, bromine, nitro, --O--C(.dbd.O)--(C.sub.1 -C.sub.18 straight or branched chain)alkyl or --C(.dbd.O)--aryl;

in which aryl is phenyl or ##STR163## wherein R.sub.5 is hydrogen, lower alkyl, lower alkoxy, hydroxy, chlorine, fluorine, bromine, iodine, lower monoalkylamino, lower dialkylamino, nitro, cyano, trifluoromethyl, or trifluoromethyl;

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;

with the proviso that if U is O, then A is not --C(.dbd.O)--;

all geometric, optical, and stereoisomers thereof; or a pharmaceutically acceptable acid addition salt thereof.

18. A method of treating psychoses, which comprises administering to a mammal a psychoses-treating amount of a compound of the formula ##STR164## wherein SX 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;

A is --C(.dbd.O)--, --C(.dbd.S)--, --C(.dbd.CH.sub.2)--, --CH.sub.2 CH.sub.2 --, --CR.sub.26 .dbd.N--, or --CR.sub.25 R.sub.26 --;

R.sub.25 is hydrogen, (C.sub.1 -C.sub.6)alkyl, hydroxy, or (C.sub.1 -C.sub.8) alkanoyloxy;

R.sub.26 is hydrogen, (C.sub.1 -C.sub.6)alkyl;

either one of B.sub.y and B.sub.z is Ch or N and the other is CH;

U is O or S;

q is 1, 2, 3, or 4;

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 --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)alkoxy, (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 or (C.sub.1 -C.sub.18)alkanoyloxy(C.sub.1 -C.sub.6)alkyl, or ##STR165## 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, and wherein aryl is as defined hereinafter; and

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)alkyloxy(C.sub.1 -C.sub.6)alkyl, (C.sub.1 -C.sub.18)alkanoyloxy(C.sub.1 -C.sub.6)alkyl, or ##STR166## where Z.sub.1 is as previously defined, and p is as previously defined, and 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.1 -C.sub.6)alkylsilyloxy, hydroxy lower alkyl, alkanoyloxy lower alkyl, amino, mono- or dialkylamino, (C.sub.1 -C.sub.18)acyl amino, (C.sub.1 -C.sub.18)alkanoyl, trifluoromethyl, chlorine, fluorine, bromine, nitro, --O--C(.dbd.O)--(C.sub.1 -C.sub.18 straight or branched chain)alkyl or --C(.dbd.O)--aryl, wherein aryl is as defined hereinafter;

in which aryl is phenyl or ##STR167## wherein R.sub.5 is hydrogen, lower alkyl, lower alkoxy, hydroxy, chlorine, fluorine, bromine, iodine, lower monoalkylamino, lower dialkylamino, nitro, cyano, trifluoromethyl, or trifluoromethyl;

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. The compound of any one of claims 14-16, wherein X is --N(R.sub.2)--.

20. The compound of any one of claims 14-16, wherein R.sub.2 is (C.sub.1 -C.sub.18),alkanoyl or (C.sub.1 -C.sub.18)alkoxycarbonyl.

21. The compound of claim 15 or 16, wherein R.sub.1 is --CH.sub.2 --CH.sub.2 --, --CH.sub.2 CH(OH)CH.sub.2 --, --CH.sub.2 CH.sub.2 CH.sub.2 --, --CH.sub.2 CH(CH.sub.3)--, --CH(CH.sub.3)CH.sub.2 --, or --CH.sub.2 CHCH.sub.2 --.

22. The compound of any one of claims 14-16, wherein A is --C(.dbd.O)--, B.sub.y and B.sub.z are CH, and U is O.

23. The compound of any one of claims 14-16, wherein X is --NH--.

24. The compound of claim 22, wherein X is --NR.sub.2 --.

25. The compound of claim 24, which is N-[2-[4-(1-decanoyl-6-fluoro-1H-indazol-3-yl)-1-piperazinyl]ethyl]phthalim ide and its pharmaceutically acceptable acid addition salts.

26. The compound of claim 24, which is N-[2-[4-(1-decanoyl-6-fluoro-1H-indazol-3-yl)-1-piperazinyl]ethyl]phthalim ide and its pharmaceutically acceptable acid addition salts.

27. The compound of any one of claims 14-16, wherein A is --CH(OH)--, B.sub.y and B.sub.z are CH, and U is O.

28. The compound of claim 27, wherein X is --O--.

29. The compound of claim 27, wherein X is --S--.

30. The compound of claim 27, wherein X is --NH--.

31. The compound of claim 30, which is 2-[2-[4-(6-fluoro-1H-indazol-3-yl)-1-piperazinyl]ethyl]-2,3-dihydro-3-hydr oxy-1H-isoindol-1-one and its pharmaceutically acceptable acid addition salts.

32. The compound of any one of claims 14-16, wherein A is --C(.dbd.S)--, B.sub.y and B.sub.z are CH, and U is O.

33. The compound of claim 31, wherein X is --O--.

34. The compound of any one of claims 14-16, wherein A is --C(.dbd.S)--, B.sub.y and B.sub.z are CH, and U is S.

35. The compound of claim 34, wherein X is --O--.

36. The compound of any one of claims 14-16, wherein A is --C(CH.sub.3) (OH)--, B.sub.y and B.sub.z are CH, and U is O.

37. The compound of claim 36, wherein X is --O--.

38. The compound of any one of claims 14-16, wherein A is --CH(CH.sub.3)--, B.sub.y and B.sub.z are CH, and U is O.

39. The compound of claim 38, wherein X is --O--.

40. The compound of any one of claims 14-16, wherein A is --C(.dbd.CH.sub.2)--, B.sub.y and B.sub.z are CH, and U is O.

41. The compound of claim 40, wherein X is --O--.

42. The compound of any one of claims 14-16, wherein A is --CH.sub.2 --, B.sub.y and B.sub.z are CH, and U is O.

43. The compound of claim 42, wherein X is --O--.

44. The compound of any one of claims 14-16, wherein A is --C(.dbd.O)CH.sub.2 --, B.sub.y and B.sub.z are CH, and U is O.

45. The compound of claim 44, wherein X is --O--.

46. The compound of any one of claims 14-16, wherein A is --C(.dbd.O)--, B.sub.y is CH, B.sub.z is N, and U is O.

47. The compound of claim 46, wherein X is --O--.

48. The compound of any one of claims 14-16, wherein A is --CR.sub.26 .dbd.N--, B.sub.y and B.sub.z are CH, and U is O.

49. The compound of claim 48, wherein X is --O--.

50. An antipsychotic composition, which comprises the compound of any of claims 14-16 in an amount sufficient to produce an antipsychotic effect, and a pharmaceutically acceptable carrier therefor.

51. A method of treating psychoses, which comprises administering to a mammal a psychoses-treating effective amount of the compound of any of claims 14-16.

52. An analgesic composition, which comprises the compound of any of claims 14-16 in an amount sufficient to produce a pain-relieving effect, and a pharmaceutically acceptable carrier therefor.

53. A method of alleviating pain, which comprises administering to a mammal a pain-relieving effective amount of the compound of any of claims 14-16.

54. A depot pharmaceutical composition, which comprises a pharmaceutically acceptable carrier and a therapeutically effective amount of the compound of any of claims 14-16, wherein the compound contains an acylated hydroxy group, or an acylated amino group.

55. The depot pharmaceutical composition of claim 54, wherein the hydroxy group is acylated with an (C.sub.4 -C.sub.18)alkanoyl group, or the amino group is acylated with an (C.sub.4 -C.sub.18)alkanoyl group or an (C.sub.4 -C.sub.18)alkoxycarbonyl group.

56. The composition of claim 54, which contains a pharmaceutically acceptable oil.

57. The composition of claim 56, wherein the oil is selected from the group consisting of coconut oil, peanut oil, sesame oil, cotton seed oil, corn oil, soybean oil, olive oil, and esters of fatty acids and polyfunctional alcohols.

58. The composition of claim 55, which contains a pharmaceutically acceptable oil.

59. The composition of claim 58, wherein the oil is selected from the group consisting of coconut oil, peanut oil, sesame oil, cotton seed oil, corn oil, soybean oil, olive oil, and esters of fatty acids and polyfunctional alcohols.

60. A method for providing a long acting antipsychotic effect, which comprises injecting into a mammal an amount of the composition of claim 54 sufficient to produce a long acting antipsychotic effect.

61. A method for providing a long acting antipsychotic effect, which comprises injecting into a mammal an amount of the composition of claim 55 sufficient to produce a long acting antipsychotic effect.

62. A method for providing a long acting antipsychotic effect, which comprises injecting into a mammal an amount of the composition of claim 59 sufficient to produce a long acting antipsychotic effect.

63. The compound of claim 14, wherein R.sub.1 is --CH.sub.2 CH(OH)CH.sub.2 -- or --CH.sub.2 CHCH.sub.2 --.

64. A depot pharmaceutical composition, which comprises a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound having the formula ##STR168## wherein, X is --O--, --S--, ##STR169## or ##STR170## 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 ##STR171## 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, ##STR172## or ##STR173## in which aryl is phenyl or ##STR174## where R.sub.5 is hydrogen, lower alkyl, lower alkoxy, hydroxy, chlorine, fluorine, bromine, iodine, lower monoalkylamino, lower dialkylamino, nitro, cyano, trifluoromethyl, trifluoromethyl;

q is 1, 2, 3, or 4;

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;

with the proviso that R.sub.4 is not H when SX is --S--, Y is H, hydroxy, cyano, lower alkyl, lower alkoxy, halogen, or trifluoromethyl, R.sub.1 is R.sub.20, and n is 2, 3, 4, or 5;

all geometric, optical, and stereoisomers thereof, or a pharmaceutically acceptable acid addition salt thereof.

65. The depot pharmaceutical composition of claim 64, wherein the hydroxy group is acylated with a (C.sub.4 -C.sub.18)alkanoyl group, or the amino group is acylated with an (C.sub.4 -C.sub.18)alkanoyl group or an (C.sub.45 -C.sub.18)alkoxycarbonyl group.

66. The composition of claim 64, which contains a pharmaceutically acceptable oil.

67. The composition of claim 66, wherein the oil is selected from the group consisting of coconut oil, peanut oil, sesame oil, cotton seed oil, corn oil, soybean oil, olive oil, and esters of fatty acids and polyfunctional alcohols.

68. The composition of claim 65, which contains a pharmaceutically acceptable oil.

69. The composition of claim 68, wherein the oil is selected from the group consisting of coconut oil, peanut oil, sesame oil, cotton seed oil, corn oil, soybean oil, olive oil, and esters of fatty acids and polyfunctional alcohols.

70. A method for providing a long acting antipsychotic effect, which comprises injecting into a mammal an amount of the composition of claim 64 sufficient to produce a long acting antipsychotic effect.

71. A method for providing a long acting antipsychotic effect, which comprises injecting into a mammal an amount of the composition of claim 65 sufficient to produce a long acting antipsychotic effect.

72. A method for providing a long acting antipsychotic effect, which comprises injecting into a mammal an amount of the composition of claim 69 sufficient to produce a long acting antipsychotic effect.
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