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Details for Patent: 5,658,911

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Details for Patent: 5,658,911

Title: Heteroarylpiperidines, and their use as antipsychotics and analgetics
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. The compounds are also useful as analgesics by administering a pain-relieving effective amount of one of the compounds to a mammal.
Inventor(s): Strupczewski; Joseph T. (Flemington, NJ), Bordeau; Kenneth J. (Upper Black Eddy, PA), Glamkowski; Edward J. (Warren, NJ), Chiang; Yulin (Convent Station, NJ), Helsley; Grover C. (Stockton, NJ)
Assignee: Hoechst Marion Roussel, Inc. (Kansas City, MO)
Filing Date:Sep 20, 1994
Application Number:08/309,395
Claims:1. A compound of the formula: ##STR163## wherein, X is --O--, --S--, --NH--, --N(R.sub.2);

R.sub.2 is selected from the group consisting of lower alkyl, aryl lower alkyl, aryl, (C.sub.3 -C.sub.10) cycloalkyl, aroyl, (C.sub.2 -C.sub.11) alkanoyl, 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 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 ##STR164## where Z.sub.1 is lower alkyl, --OH, lower alkoxy, --CF.sub.3, --NO.sub.2, --NH.sub.2 or halogen, p is as previously defined;

R is hydrogen, lower alkyl, lower alkoxy, hydroxyl, carboxyl, chlorine, fluorine, bromine, iodine, amino, lower mono or dialkylamino, nitro, lower alkyl thio, trifluoromethoxy, cyano, acylamino, trifluoromethyl, trifluoroacetyl, aminocarbonyl, monoalkylaminocarbonyl, dialkylaminocarbonyl, formyl, ##STR165## alkyl is lower alkyl; aryl is phenyl or ##STR166## where R.sub.5 is hydrogen, lower alkyl, lower alkoxy, hydroxy, chlorine, fluorine, bromine, iodine, lower monoalkylamino, lower dialkylamino, nitro, cyano, trifluoromethyl, or trifluoromethoxy;

heteroaryl is ##STR167## Q.sub.3 is --O--, --S--, --NH--, --CH.dbd.N--; W is CH.sub.2 or CHR.sub.8 or N--R.sub.9 ;

R.sub.7 is hydrogen, lower alkyl, or alkanoyl;

R.sub.8 is lower alkyl;

R.sub.9 is hydroxy, alkoxy, or --NHR.sub.10 ; and

R.sub.10 is hydrogen, lower alkyl, C.sub.1 -C.sub.3 acyl, aryl, ##STR168## where aryl and heteroaryl are as defined above; and m is 1, 2, or 3;

with the exclusion of compounds wherein X is O or S, Y is hydrogen, and R is hydrogen, C.sub.1 =14 C.sub.4 alkyl, chlorine, fluorine, bromine, iodine, cyano, C.sub.1 -C.sub.4 alkoxy, or --COOR.sub.23 where R.sub.23 is C.sub.1 -C.sub.4 alkyl;

with the exclusion of compounds wherein X is --S--, R.sub.1 is R.sub.20, R is H, and m=1;

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

2. A compound as claimed in claim 1, wherein X is --O--, --S--, --NH--.

3. A compound as claimed in claim 1, wherein Y is hydrogen, chlorine, bromine, or fluorine.

4. A compound as claimed in claim 1, wherein n is 2, 3, or 4.

5. A compound as claimed in claim 1, wherein X is --O--.

6. A compound as claimed in claim 1, wherein X is --S--.

7. A compound as claimed in claim 1, wherein X is --NH--.

8. A compound as claimed in claim 1 , wherein X is ##STR169##

9. A compound as claimed in claim 1, wherein X is --O--, --S--, or --NH--; Y is H, Cl, F, --CF.sub.3 ; R is selected from the group consisting of hydrogen, C.sub.1 -C.sub.3 alkyl, C.sub.1 -C.sub.3 alkoxy, --OH, Cl, F, Br, I, acyl, C.sub.1 -C.sub.3 monoalkylamino, acylamino, --NO.sub.2 --, --OCF.sub.3, --CF.sub.3 ; and n is 2, 3, or 4.

10. A compound as claimed in claim 9, wherein the substituent Y is in the 5- or 6-position.

11. A compound as claimed in claim 10, wherein m is 2.

12. A compound as claimed in claim 10, wherein n is 3.

13. A compound as claimed in claim 10, wherein p is 1.

14. A compound as claimed in claim 1, which is 1-[4-[3-[4-(1H-indazol-3-yl)-1-piperazinyl]propoxy]-3-methoxyphenyl]ethano ne or a pharmaceutically acceptable acid addition salt thereof.

15. A compound as claimed in claim 1, which is 1-[4-[4-[4-(1H-indazol-3-yl)-1-piperazinyl]butoxy]-3-methoxyphenyl]ethanon e fumarate or a pharmaceutically acceptable acid addition salt thereof.

16. A compound as claimed in claim 1, which is 1-[4-[3-[4-(6-fluoro-1H-indazol-3-yl)-1-piperazinyl]propoxy]-3-methoxyphen yl]ethanone or a pharmaceutically acceptable acid addition salt thereof.

17. A compound as claimed in claim 1, which is 1-[4-[4-[4-(6-fluoro-1H-indazol-3-yl)-1-piperazinyl]butoxy]-3-methoxphenyl ]ethanone or a pharmaceutically acceptable acid addition salt thereof.

18. A compound as claimed in claim 1, which is 1-[4-[3-[4-(6-chloro-1H-indazol-3-yl)-1-piperazinyl]propoxy]-3-methoxpheny l]ethanone or a pharmaceutically acceptable acid addition salt thereof.

19. A compound as claimed in claim 1, which is 1-[4-[4-[4-(1,2-benzisothiazol-3-yl)-1-piperazinyl]butoxy]-3-methoxyphenyl ]ethanone or a pharmaceutically acceptable acid addition salt thereof.

20. A compound as claimed in claim 1, which is 1-[4-[3-[4-(1-benzoyl-6-fluoro-1H-indazol-3-yl)-1-piperazinyl]-propoxy]-3- methoxyphenyl]ethanone sesquifumarate or a pharmaceutically acceptable acid addition salt thereof.

21. A compound as claimed in claim 1, which is 1-[4-[4-[4-(6-chloro-1H-indazol-3-yl)-1-piperazinyl]butoxy]-3-methoxypheny l]ethanone or a pharmaceutically acceptable acid addition salt thereof.

22. A compound as claimed in claim 1, which is 1-[4-[3-[4-(1,2-benzisothiazol-3-yl)-1-piperazinyl]propoxy]-3-methoxypheny l]ethanone hemifumarate or a pharmaceutically acceptable acid addition salt thereof.

23. A compound as claimed in claim 1, which is 1-[4-[2-[4-(1,2-benzisothiazol-3-yl)-1-piperazinyl]ethoxy]-3-methoxyphenyl ]ethanone or a pharmaceutically acceptable acid addition salt thereof.

24. A compound as claimed in claim 1, which is 1-[4-[2-[4-(6-chloro-1H-indazol-3-yl)-1-piperazinyl]ethoxy]-3-methoxypheny l]ethanone or a pharmaceutically acceptable acid addition salt thereof.

25. A compound of the formula: ##STR170## wherein X is --O--, --S--, --NH--, or --N--R.sub.2 ; p is 1 or 2;

Y is hydrogen, Cl, Br, or F when p is 1;

Y is lower alkoxy or halogen when p is 2 and X is -O--; R.sub.2 is selected from the group consisting of lower alkyl, aryl lower alkyl, aryl, (C.sub.3 -C.sub.10) cycloalkyl, aroyl, (C.sub.2 -C.sub.11) alkanoyl, and phenyl sulfonyl groups;

aryl is phenyl or ##STR171## where R.sub.5 is hydrogen, lower alkyl, lower alkoxy, hydroxy, chlorine, fluorine, bromine, iodine, lower monoalkylamino, lower dialkylamino, nitro, cyano, trifluoromethyl, or trifluoromethoxy;

n is 2, 3, or 4;

R is hydrogen, C.sub.1 -C.sub.3 alkyl, C.sub.1 -C.sub.3 alkoxy, hydroxyl, acyl, (C.sub.2 -C.sub.11) alkanoyl, Cl, F, Br, I, amino, C.sub.1 -C.sub.3 mono- or dialkylamino, acylamino, --NO.sub.2, --OCF.sub.3, --CF.sub.3, ##STR172## ##STR173## alkyl is lower alkyl; R.sub.7 is hydrogen, lower alkyl, or acyl; and

m is 1, 2, or 3;

or a pharmaceutically acceptable acid addition salt thereof.

26. A compound of the formula: ##STR174## wherein X is --O--; p is 1 or 2;

Y is hydrogen, hydroxy, Cl, Br, or F, when p is 1;

Y is lower alkoxy, hydroxy, or halogen when p is 2;

n is 2, 3, or 4;

R is hydrogen, C.sub.1 -C.sub.3 alkyl, C.sub.1 -C.sub.3 alkoxy, hydroxyl, acyl, (C.sub.2 -C.sub.11) alkanoyl, Cl, F, Br, I, amino, C.sub.1 -C.sub.3 mono- or dialkylamino, acylamino, --NO.sub.2, --OCF.sub.3, --CF.sub.3, ##STR175## alkyl is lower alkyl; R.sub.7 is hydrogen, lower alkyl, or acyl; and

m is 1, 2, or 3;

or a pharmaceutically acceptable acid addition salt thereof.

27. A compound of the formula: ##STR176## wherein X is --S--; p is 1 or 2;

Y is hydrogen, Cl, Br, or F, when p is 1;

Y is lower alkoxy or halogen when p is 2;

n is 2, 3, or 4;

R is hydrogen, C.sub.1 -C.sub.3 alkyl, C.sub.1 -C.sub.3 alkoxy, hydroxyl, acyl, (C.sub.2 -C.sub.11) alkanoyl, Cl, F, Br, I, amino, C.sub.1 -C.sub.3 mono- or dialkylamino, acylamino, --NO.sub.2, --OCF.sub.3, --CF.sub.3, ##STR177## alkyl is lower alkyl; R.sub.7 is hydrogen, lower alkyl, or acyl; and

m is 1, 2, or 3;

or a pharmaceutically acceptable acid addition salt thereof.

28. A compound of the formula: ##STR178## wherein X is --NH--; p is 1 or 2;

Y is hydrogen, Cl, Br, or F, when p is 1;

Y is lower alkoxy or halogen when p is 2;

n is 2, 3, or 4;

R is hydrogen, C.sub.1 -C.sub.3 alkyl, C.sub.1 -C.sub.3 alkoxy, hydroxyl, acyl, (C.sub.2 -C.sub.11) alkanoyl, Cl, F, Br, I, amino, C.sub.1 -C.sub.3 mono- or dialkylamino, acylamino, --NO.sub.2, --OCF.sub.3, --CF.sub.3, ##STR179## alkyl is lower alkyl; R.sub.7 is hydrogen, lower alkyl, or acyl; and

m is 1, 2, or 3;

or a pharmaceutically acceptable acid addition salt thereof.

29. A compound of the formula: ##STR180## wherein X is ##STR181## p is 1 or 2; Y is hydrogen, Cl, Br, or F, when p is 1;

Y is lower alkoxy or halogen when p is 2;

R.sub.2 is selected from the group consisting of lower alkyl, aryl lower alkyl, aryl, (C.sub.3 -C.sub.10) cycloalkyl, aroyl, (C.sub.2 -C.sub.11) aroyl, alkanoyl, and phenylsulfonyl groups;

aryl is phenyl or ##STR182## where R.sub.5 is hydrogen, lower alkyl, lower alkoxy, hydroxy, chlorine, fluorine, bromine, iodine, lower monoalkylamino, lower dialkylamino, nitro, cyano, trifluoromethyl, or trifluoromethoxy;

n is 2, 3, or 4;

R is hydrogen, C.sub.1 -C.sub.3 alkyl, C.sub.1 -C.sub.3 alkoxy, hydroxyl, acyl, (C.sub.2 -C.sub.11) alkanoyl, Cl, F, Br, I, amino, C.sub.1 -C.sub.3 mono- or dialkylamino, acylamino, --NO.sub.2, --OCF.sub.3, --CF.sub.3, ##STR183## alkyl is lower alkyl; R.sub.7 is hydrogen, lower alkyl, or acyl; and

m is 1, 2, or 3;

or a pharmaceutically acceptable acid addition salt thereof.

30. A pharmaceutical composition, which comprises a compound of the formula: ##STR184## wherein X is --O--, --S--, --NH--, or ##STR185## R.sub.2 is selected from the group consisting of lower alkyl, aryl lower alkyl, aryl, (C.sub.3 -C.sub.10) cycloalkyl, aroyl, (C.sub.2 -C.sub.11) alkanoyl, and phenylsulfonyl groups;

where aryl is 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 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 --C.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 on C.sub.1 -C.sub.6 linear alkyl group, phenyl group, or ##STR186## where Z.sub.1 is lower alkyl, --OH, lower alkoxy, --CF.sub.3, --NO.sub.2, --NH.sub.2 or halogen, and p as previously defined;

R is hydrogen, lower alkyl, lower alkoxy, hydroxyl, carboxyl, chlorine, fluorine, bromine, iodine, amino, lower mono or dialkylamino, nitro, lower alkyl thio, trifluoromethoxy, cyano, acylamino, trifluoromethyl, trifluoroacetyl, aminocarbonyl, monoalkylaminocarbonyl, dialkylaminocarbonyl, formyl, ##STR187## alkyl is lower alkyl; aryl is phenyl or ##STR188## where R.sub.5 is hydrogen, lower alkyl, lower alkoxy, hydroxy, chlorine, fluorine, bromine, iodine, lower monoalkylamino, lower dialkylamino, nitro, cyano, trifluoromethyl, or trifluoromethoxy;

heteroaryl is ##STR189## Q.sub.3 is --O--, --S--, --NH--, --CH.dbd.N--; W is CH.sub.2 or CHR.sub.8 or N--R.sub.9 ;

R.sub.7 is hydrogen, lower alkyl, or (C.sub.2 -C.sub.11) alkanoyl;

R.sub.8 is lower alkyl;

R.sub.9 is hydroxy, alkoxy, or --NHR.sub.10 ; and

R.sub.10 is hydrogen, lower alkyl, C.sub.1 -C.sub.3 acyl, aryl, ##STR190## where aryl and heteroaryl are as defined above; and m is 1, 2, or 3;

with the exclusion of compounds wherein X is O or S, Y is hydrogen, and R is hydrogen, C.sub.1 -C.sub.4 alkyl, chlorine, fluorine, bromine, iodine, cyano, C.sub.1 -C.sub.4 alkoxy, or --COOR.sub.23 where R.sub.23 is C.sub.1 -C.sub.4 alkyl;

with the exclusion of compounds wherein X is --S--, R.sub.1 is R.sub.20, R is H, and m=1;

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

31. An antipsychotic composition, which comprises a compound of the formula: ##STR191## wherein X is --O--, --S--, --NH--, or ##STR192## R.sub.2 is selected from the group consisting of lower alkyl, aryl lower alkyl, aryl, (C.sub.3 -C.sub.10) cycloalkyl, aroyl, (C.sub.2 -C.sub.11) alkanoyl, and phenylsulfonyl groups;

where aryl is 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 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 on C.sub.1 -C.sub.6 linear alkyl group, phenyl group, or ##STR193## where Z.sub.1 is lower alkyl, --OH, lower alkoxy, --CF.sub.3, --NO.sub.2, --NH.sub.2 or halogen, a p is as previously defined;

R is hydrogen, lower alkyl, lower alkoxy, hydroxyl, carboxyl, chlorine, fluorine, bromine, iodine, amino, lower mono or dialkylamino, nitro, lower alkyl thio, trifluoromethoxy, cyano, acylamino, trifluoromethyl, trifluoroacetyl, aminocarbonyl, monoalkylaminocarbonyl, dialkylaminocarbonyl, formyl, ##STR194## alkyl is lower alkyl; aryl is phenyl or ##STR195## where R.sub.5 is hydrogen, lower alkyl, lower alkoxy, hydroxy, chlorine, fluorine, bromine, iodine, lower monoalkylamino, lower dialkylamino, nitro, cyano, trifluoromethyl, or trifluoromethoxy;

heteroaryl is ##STR196## Q.sub.3 is --O--, --S--, --NH--, --CH.dbd.N--; W is CH.sub.2 or CHR.sub.8 or N--R.sub.9 ;

R.sub.7 is hydrogen, lower alkyl, or (C.sub.2 -C.sub.11) alkanoyl;

R.sub.8 is lower alkyl;

R.sub.9 is hydroxy, alkoxy, or --NHR.sub.10 ; and

R.sub.10 is hydrogen, lower alkyl, C.sub.1 -C.sub.3 acyl, aryl, ##STR197## where aryl and heteroaryl are as defined above; and m is 1, 2, or 3;

with the exclusion of compounds wherein X is O or S, Y is hydrogen, and R is hydrogen, C.sub.1 -C.sub.4 alkyl, chlorine, fluorine, bromine, iodine, cyano, C.sub.1 -C.sub.4 alkoxy, or --COOR.sub.23 where R.sub.23 is C.sub.1 -C.sub.4 alkyl;

with the exclusion of compounds wherein X is --S--, R.sub.1 is R.sub.20, R is H, and m=1;

all geometric, optical, and stereoisomers thereof, or a pharmaceutically acceptable acid addition salt thereof, in an amount sufficient to produce an antipsychotic effect, and a pharmaceutically acceptable carrier therefor.

32. A method of treating psychoses, which comprises administering to a mammal a psychoses-treating effective amount of a compound of the formula: ##STR198## wherein X is --O--, --S--, --NH--, or ##STR199## R.sub.2 is selected from the group consisting of lower alkyl, aryl lower alkyl, aryl, (C.sub.3 -C.sub.10) cycloalkyl, aroyl, (C.sub.2 -C.sub.11) alkanoyl, and phenylsulfonyl groups;

where aryl is 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 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.22 are substituted by at least on C.sub.1 -C.sub.6 linear alkyl group, phenyl group, or ##STR200## 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;

R is hydrogen, lower alkyl, lower alkoxy, hydroxyl, carboxyl, chlorine, fluorine, bromine, iodine, amino, lower mono or dialkylamino, nitro, lower alkyl thio, trifluoromethoxy, cyano, acylamino, trifluoromethyl, trifluoroacetyl, aminocarbonyl, monoalkylaminocarbonyl, dialkylaminocarbonyl, formyl, ##STR201## alkyl is lower alkyl; aryl is phenyl or ##STR202## where R.sub.5 is hydrogen, lower alkyl, lower alkoxy, hydroxy, chlorine, fluorine, bromine, iodine, lower monoalkylamino, lower dialkylamino, nitro, cyano, trifluoromethyl, or trifluoromethoxy;

heteroaryl is ##STR203## Q.sub.3 is --O--, --S--, --NH--, --CH.dbd.N--; W is CH.sub.2 or CHR.sub.8 or N--R.sub.9 ;

R.sub.7 is hydrogen, lower alkyl, or (C.sub.2 -C.sub.11) alkanoyl;

R.sub.8 is lower alkyl;

R.sub.9 is hydroxy, alkoxy, or --NHR.sub.10 ; and

R.sub.10 is hydrogen, lower alkyl, C.sub.1 -C.sub.3 acyl, aryl, ##STR204## where aryl and heteroaryl are as defined above; and m is 1, 2, or 3;

with the exclusion of compounds wherein X is O or S, Y is hydrogen, and R is hydrogen, C.sub.1 -C.sub.4 alkyl, chlorine, fluorine, bromine, iodine, cyano, C.sub.1 -C.sub.4 alkoxy, or --COOR.sub.23 where R.sub.23 is C.sub.1 -C.sub.4 alkyl;

with the exclusion of compounds wherein X is --S--, R.sub.1 is R.sub.20, R is H, and m=1;

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

33. An analgesic composition, which comprises a compound of the formula: ##STR205## 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, (C.sub.3 -C.sub.10) cycloalkyl, aroyl, (C.sub.2 -C.sub.11) alkanoyl, and phenylsulfonyl groups;

where aryl is defined hereinafter;

p is 1 or 2;

Y is hydrogen, lower alkyl, hydroxy, chlorine, fluorine, bromine, iodine, lower alkoxy, trifluoromethyl, nitro, or

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 on C.sub.1 -C.sub.6 linear alkyl group, phenyl group, or ##STR206## 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;

R is hydrogen, lower alkyl, lower alkoxy, hydroxyl, carboxyl, chlorine, fluorine, bromine, iodine, amino, lower mono or dialkylamino, nitro, lower alkyl thio, trifluoromethoxy, cyano, acylamino, trifluoromethyl, trifluoroacetyl, aminocarbonyl, monoalkylaminocarbonyl, dialkylaminocarbonyl, formyl, ##STR207## alkyl is lower alkyl; aryl is phenyl or ##STR208## where R.sub.5 is hydrogen, lower alkyl, lower alkoxy, hydroxy, chlorine, fluorine, bromine, iodine, lower monoalkylamino, lower dialkylamino, nitro, cyano, trifluoromethyl, or trifluoromethoxy;

heteroaryl is ##STR209## Q.sub.3 is --O--, --S--, --NH--, --CH.dbd.N--; W is CH.sub.2 or CHR.sub.8 or N--R.sub.9 ;

R.sub.7 is hydrogen, lower alkyl, or (C.sub.2 -C.sub.11) alkanoyl;

R.sub.8 is lower alkyl;

R.sub.9 is hydroxy, alkoxy, or --NHR.sub.10 ; and

R.sub.10 is hydrogen, lower alkyl, C.sub.1 -C.sub.3 acyl, aryl, ##STR210## where aryl and heteroaryl are as defined above; and m is 1, 2, or 3;

with the exclusion of compounds wherein X is O or S, Y is hydrogen, and R is hydrogen, C.sub.1 -C.sub.4 alkyl, chlorine, fluorine, bromine, iodine, cyano, C.sub.1 -C.sub.4 alkoxy, or --COOR.sub.23 where R.sub.23 is C.sub.1 -C.sub.4 alkyl;

with the exclusion of compounds wherein X is --S--, R.sub.1 is R.sub.20, R is H, and m=1;

all geometric, optical, and stereoisomers thereof, or a pharmaceutically acceptable acid addition salt thereof, in an amount sufficient to produce a pain-relieving effect, and a pharmaceutically acceptable carrier therefor.

34. A method of alleviating pain, which comprises administering to a mammal a pain-relieving effective amount of a compound as claimed in claim 33.

35. A pharmaceutical composition, which comprises a compound as claimed in claim 1, 25, 26, 27, 28, or 29, and a pharmaceutically acceptable carrier therefor.

36. An antispsychotic composition, which comprises a compound as claimed in claim 1, 25 ,26, 27, 28, or 29, in an amount sufficient to produce an antipsychotic effect, and a pharmaceutically acceptable carrier therefor.

37. A method of treating psychoses, which comprises administering to a mammal a psychoses-treating effective amount of a compound as claimed in claim 1, 25, 26, 27, 29 or 29.

38. An analgesic composition, which comprises a compound as claimed in claim 1, 25, 26, 27, 28, or 29, in an amount sufficient to produce a pain-relieving effect, and a pharmaceutically acceptable carrier therefor.

39. A method of alleviating pain which comprises administering to a mammal a pain-relieving effective amount of a compound as claimed in claim 1, 25, 26, 27, 28, or 29.

40. An antipsychotic composition, which comprises a compound as claimed in claim 1, in an amount sufficient to produce an antipsychotic effect, and a pharmaceutically acceptable carrier therefor.

41. A method of treating psychoses, which comprises administering to a mammal a psychoses-treating effective amount of a compound as claimed in claim 1.

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

43. A method of alleviating pain, which comprises administering to a mammal a pain-relieving effective amount of a compound as claimed in claim 1.

44. The compound of any one of claims 1, 25, 26, 27, 28, and 29, wherein said pharmaceutically acceptable acid addition salt is selected from the group consisting of salts of mineral acids, salts of monobasic carboxylic acids, salts of dibasic carboxylic acids, and salts of tribasic carboxylic acids.

45. The compound of claim 44, wherein said pharmaceutically acceptable acid addition salt is selected from the group consisting of salts of hydrochloric acid, sulfuric acid, nitric acid, acetic acid, propionic acid, maleic acid, fumaric acid, carboxysuccinic acid, and citric acid.
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