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Details for Patent: 5,889,004

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Details for Patent: 5,889,004

Title: 4-heteroaryl-1-piperazinealkylthiols and derivatives thereof 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): Strupczewski; Joseph T. (Flemington, NJ), Glamkowski; Edward J. (Warren, NJ), Chiang; Yulin (Covent Station, NJ), Bordeau; Kenneth J. (Kintnersville, PA), Nemoto; Peter A. (Raritan, NJ), Tegeler; John J. (Bridgewater, NJ)
Assignee: Hoechst Marion Roussel, Inc. (Kansas City, MO)
Filing Date:Jun 06, 1995
Application Number:08/471,393
Claims:1. A compound having the formula: ##STR134## wherein, X is --O--, --S--, ##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.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 ##STR136## where Z.sub.1 is lower alkyl, --OH, lower alkoxy, --CF.sub.3, --NO.sub.2, --NH.sub.2 or halogen;

where R.sub.12 is selected from the group consisting of:

hydrogen, ##STR137## where R.sub.13 is selected from the group consisting of hydrogen and (C.sub.1 -C.sub.12) alkyl groups;

where R.sub.14 is selected from the group consisting of hydrogen and (C.sub.1 -C.sub.12) alkyl groups;

where NR.sub.15 R.sub.16 taken together form a ring structure selected from the group consisting of piperidinyl, morpholinyl and piperazinyl;

where R.sub.17 is selected. from the group consisting of lower alkyl and aryl groups;

in which aryl is phenyl or ##STR138## where R.sub.5 is hydrogen, lower al.kyl, 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.

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

3. The compound of claim 2, wherein R.sub.2 is C.sub.2 -C.sub.11)alkanoyl.

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

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

6. 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.

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

8. A depot pharmaceutical composition, which comprises a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound having the formula: ##STR139## wherein, X is --O--, --S--, ##STR140## 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 ##STR141## where Z.sub.1 is lower alkyl, --OH, lower alkoxy, --CF.sub.3, --NO.sub.2, --NH.sub.2 or halogen;

where R.sub.12 is selected from the group consisting of:

hydrogen, ##STR142## where R.sub.13 is selected from the group consisting of hydrogen and (C.sub.1 -C.sub.12) alkyl groups;

where R.sub.14 is selected from the group consisting of hydrogen and (C.sub.1 -C.sub.12) alkyl groups;

where NR.sub.15 R.sub.16 taken together form a ring structure selected from the group consisting of piperidinyl, morpholinyl and piperazinyl;

where R.sub.17 is selected from the group consisting of lower alkyl and aryl groups;

in which aryl is phenyl or ##STR143## 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.

9. The depot pharmaceutical composition of claim 8, 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.

10. The composition of claim 8, which contains a pharmaceutically acceptable oil.

11. The composition of claim 10, 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.

12. The composition of claim 9, which contains a pharmaceutically acceptable oil.

13. The composition of claim 12, wherein the oil is selected from the gtoup 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.

14. A method for providing a long acting antipsychotic effect, which comprises injecting into a mammal an amount of the composition of claim 8 sufficient to produce a long acting antipsychotic effect.

15. A method for providing a long acting antipsychotic effect, which comprises injecting into a mammal an amount of the composition of claim 9 sufficient to produce a long acting antipsychotic effect.

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

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

18. A compound of the formula: ##STR144## 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.18) alkanoyl, (C.sub.1 -C.sub.18) 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 --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 ##STR145## 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 ##STR146## 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 ##STR147## when R.sub.27 is hydrogen and R.sub.24 is hydrogen, (C.sub.1 -C.sub.18)linear alkyl, phenyl, or ##STR148## with the proviso that R.sub.24 is not hydrogen, (C.sub.1 -C.sub.18)linear alkyl, phenyl, or ##STR149## 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 ##STR150## or when R.sub.1 is --CHR.sub.24 --CH.dbd.CH--CHR.sub.24 --or --CHR.sub.24 --.dbd.C--CHR.sub.24 --;

R.sub.12 is selected from the group consisting of:

hydrogen,

alkyl,

--C (.dbd.O)--(C.sub.1 -C.sub.18 straight chain or branched)alkyl,

--C (.dbd.O)--NR.sub.13 R.sub.14,

--C (.dbd.O)--NR.sub.15 R.sub.16,

--S (.dbd.O).sub.2 --R.sub.17, and ##STR151## where R.sub.13 is selected from the group consisting of hydrogen and (C.sub.1 -C.sub.18)alkyl groups;

where R.sub.14 is selected from the group consisting of hydrogen and (C.sub.1 -C.sub.18)alkyl groups;

where NR.sub.15 R.sub.16 taken together form a ring structure selected from the group consisting of piperidinyl, morpholinyl and piperazinyl;

where R.sub.17 is selected from the group consisting of (C.sub.1 -C.sub.18)alkyl and aryl groups;

where 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, nitro, mono- or dialkylamino, (C.sub.1 -C.sub.18) acyl amino, (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;

where m is 1, 2, or 3;

aryl is phenyl or ##STR152## 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. The compound of claim 18, wherein X is --N(R.sub.2)--.

20. The compound of claim 19, wherein R.sub.2 is (C.sub.1 -C.sub.18)alkanoyl or (C.sub.1 -C.sub.18)alkoxycarbonyl.

21. An antipsychotic composition, which comprises the compound of claim 18 in an amount sufficient to produce an antipsychotic effect and a pharmaceutically acceptable carrier.

22. A method of treating psychoses, which comprises administering to a mammal a psychoses-treating amount of the compound of claim 18.

23. An analgesic composition, which comprises the compound of claim 18 in an amount sufficient to produce a pain-relieving effect and a pharmaceutically acceptable carrier.

24. A method of alleviating pain, which comprises administering to a mammal a pain-relieving effective amount of the compound of claim 18.

25. A depot pharmaceutical composition, which comprises a pharmaceutically acceptable carrier and a therapeutically effective amount of the compound of claim 18, wherein the compound contains an acylated hydroxy group, or an acylated amino group.

26. The depot pharmaceutical composition of claim 25, 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.

27. The composition of claim 25, which contains a pharmaceutically acceptable oil.

28. The composition of claim 27, wherein the oil is selected from the group consisting of coconut oil, peanut oil, sesame oil, cottonseed oil, corn oil, soybean oil, olive oil, and esters of fatty acids and polyfunctional alcohols.

29. The composition of claim 26, which contains a pharmaceutically acceptable oil.

30. The composition of claim 29, wherein the oil is selected from the group consisting of coconut oil, peanut oil, sesame oil, cottonseed oil, corn oil, soybean oil, olive oil, and esters of fatty acids and polyfunctional alcohols.

31. A method for providing a long acting antipsychotic effect, which comprises injecting into a mammal an amount of the composition of claim 25 sufficient to produce a long acting antipsychotic effect.

32. A method for providing a long acting antipsychotic effect, which comprises injecting into a mammal an amount of the composition of claim 26 sufficient to produce a long acting antipsychotic effect.

33. A method for providing a long acting antipsychotic effect, which comprises injecting into a mammal an amount of the composition of claim 30 sufficient to produce a long acting antipsychotic effect.

34. A compound of the formula: ##STR153## 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) 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 ##STR154## 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 ##STR155## 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.12 is selected from the group consisting of:

hydrogen,

alkyl,

--C(.dbd.O)--(C.sub.1 C.sub.18 straight chain or branched)alkyl,

--C(.dbd.O)--NR.sub.13 R.sub.14,

--C(.dbd.O)--NR.sub.15 R.sub.16,

--S(.dbd.O).sub.2 --R.sub.17, and ##STR156## where R.sub.13 is selected from the group consisting of hydrogen and (C.sub.1 -C.sub.18)alkyl groups;

where R.sub.14 is selected from the group consisting of hydrogen and (C.sub.1 -C.sub.18)alkyl groups;

where NR.sub.15 R.sub.16 taken together form a ring structure selected from the group consisting of piperidinyl, morpholinyl and piperazinyl;

where R.sub.17 is selected from the group consisting of (C.sub.1 -C.sub.18)alkyl and aryl groups;

where 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, nitro, mono- or dialkylamino, C.sub.1 -C.sub.18) acyl amino, (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(=O)--aryl;

where m is 1, 2, or 3;

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.

35. The compound of claim 34, wherein X is --N(R.sub.2)--.

36. The compound of claim 34, wherein R.sub.2 is (C.sub.1 -C.sub.18)alkanoyl or (C.sub.1 -C.sub.18)alkoxycarbonyl.

37. An antipsychotic composition, which comprises the compound of claim 34 in an amount sufficient to produce an antipsychotic effect and a pharmaceutically acceptable carrier.

38. A method of treating psychoses, which comprises administering to a mammal a psychoses-treating amount of the compound of claim 34.

39. An analgesic composition, which comprises the compound of claim 34 in an amount sufficient to produce a pain-relieving effect and a pharmaceutically acceptable carrier.

40. A method of alleviating pain, which comprises administering to a mammal a pain-relieving effective amount of the compound of claim 34.

41. A depot pharmaceutical composition, which comprises a pharmaceutically acceptable carrier and a therapeutically effective amount of the compound of claim 34, wherein the compound contains an acylated hydroxy group, or an acylated amino group.

42. The depot pharmaceutical composition of claim 41, 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.

43. The composition of claim 41, which contains a pharmaceutically acceptable oil.

44. The composition of claim 43, wherein the oil is selected from the group consisting of coconut oil, peanut oil, sesame oil, cottonseed oil, corn oil, soybean oil, olive oil, and esters of fatty acids and polyfunctional alcohols.

45. The composition of claim 42, which contains a pharmaceutically acceptable oil.

46. The composition of claim 45, wherein the oil is selected from the group consisting of coconut oil, peanut oil, sesame oil, cottonseed oil, corn oil, soybean oil, olive oil, and esters of fatty acids and polyfunctional alcohols.

47. A method for providing a long acting antipsychotic effect, which comprises injecting into a mammal an amount of the composition of claim 41 sufficient to produce a long acting antipsychotic effect.

48. A method for providing a long acting antipsychotic effect, which comprises injecting into a mammal an amount of the composition of claim 42 sufficient to produce a long acting antipsychotic effect.

49. A method for providing a long acting antipsychotic effect, which comprises injecting into a mammal an amount of the composition of claim 46 sufficient to produce a long acting antipsychotic effect.

50. A compound of the formula: ##STR158## 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.18)alkanoyl, (C.sub.1 -C.sub.18)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 --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 ##STR159## 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 ##STR160## 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.12 is ##STR161## where 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, nitro, mono- or dialkylamino, (C.sub.1 -C.sub.18) acyl amino, (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;

where m is 1, 2, or 3;

aryl is phenyl or ##STR162## 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.

51. The compound of claim 50, wherein X is --N(R.sub.2)--.

52. The compound of claim 51, wherein R.sub.2 is (C.sub.1 -C.sub.18)alkanoyl or (C.sub.1 -C.sub.18)alkoxycarbonyl.

53. An antipsychotic composition, which comprises the compound of claim 50 in an amount sufficient to produce an antipsychotic effect and a pharmaceutically acceptable carrier.

54. A method of treating psychoses, which comprises administering to a mammal a psychoses-treating amount of the compound of claim 50.

55. An analgesic composition, which comprises the compound of claim 50 in an amount sufficient to produce a pain-relieving effect and a pharmaceutically acceptable carrier.

56. A method of alleviating pain, which comprises administering to a mammal a pain-relieving effective amount of the compound of claim 50.

57. A depot pharmaceutical composition, which comprises a pharmaceutically acceptable carrier and a therapeutically effective amount of the compound of claim 50, wherein the compound contains an acylated hydroxy group, or an acylated amino group.

58. The depot pharmaceutical composition of claim 57, 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.

59. The composition of claim 57, which contains a pharmaceutically acceptable oil.

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

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

62. The composition of claim 61, wherein the oil is selected from the group consisting of coconut oil, peanut oil, sesame oil, cottonseed oil, corn oil, soybean oil, olive oil, and esters of fatty acids and polyfunctional alcohols.

63. A method for providing a long acting antipsychotic effect, which comprises injecting into a mammal an amount of the composition of claim 57 sufficient to produce a long acting antipsychotic effect.

64. A method for providing a long acting antipsychotic effect, which comprises injecting into a mammal an amount of the composition of claim 58 sufficient to produce a long acting antipsychotic effect.

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