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Details for Patent: 6,140,345

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Details for Patent: 6,140,345

Title: 1-(aryloxyalkyl)-4-(heteroaryl)piperidines and related compounds useful as antipsychotics and analgesics
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), Bordeau; Kenneth J. (Kintnersville, PA), Glamkowski; Edward J. (Warren, NJ), Chiang; Yulin (Covent Station, NJ), Helsley; Grover C. (Stockton, NJ)
Assignee: Aventis Pharmaceuticals Inc. (N/A)
Filing Date:Jun 06, 1995
Application Number:08/468,611
Claims:1. The compound 4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidinyl]-2-hydroxy-1-propoxy]p henyl methyl ether and its pharmaceutically acceptable acid addition salts.

2. The compound 2-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidinyl]-2-hydroxy-1-propoxy]- 3-methoxyphenylmethanone and its pharmaceutically acceptable acid addition salts.

3. The compound 1-[(4-aceto-2-methoxy)phenoxy]-3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-pip eridinyl]-2-propyl decanoate and its pharmaceutically acceptable acid addition salts.

4. A compound of the formula ##STR134## wherein X is --NH-- or --N(R.sub.2)--;

p is 1;

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

R.sub.2 is selected from the group consisting of lower alkyl, aryl lower alkyl, aryl, cycloalkyl, aroyl, alkanoyl, and phenylsulfonyl groups;

n is 2, 3, 4 or 5;

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,

--C(.dbd.O)-alkyl,

--C(.dbd.O)--O-alkyl,

--C(.dbd.O)-aryl,

--C(.dbd.O)-heteroaryl, or

--CH(OR.sub.7)alkyl;

where

alkyl is (C.sub.1 -C.sub.6)alkyl;

aryl is phenyl or ##STR135## where R.sub.5 is hydrogen, lower alkyl, lower alkoxy, hydroxy, chlorine, fluorine, bromine, iodine, lower monoalkylamino, nitro, cyano, trifluoromethyl, trifluoromethoxy;

heteroaryl is ##STR136## where Q.sub.3 is --O--, --S--, --NH--, --CH.dbd.N--;

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

and

m is 1, 2, or 3;

or a pharmaceutically acceptable acid addition salt thereof.

5. The compound of claim 4, wherein X is --N(R.sub.2)--.

6. The compound of claim 4, wherein R.sub.2 is (C.sub.2 -C.sub.16)alkanoyl.

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

8. A method of treating psychoses, which comprises administering to a mammal a psychoses-treating effective amount of the compound of claim 4.

9. An analgesic composition, which comprises the compound of claim 4 in an amount sufficient to produce a pain-relieving effect, and a pharmaceutically acceptable carrier therefor.

10. A method of alleviating pain, which comprises administering to a mammal a pain-relieving effective amount of the compound of claim 4.

11. A pharmaceutical composition which comprises the compound of claim 4 and a pharmaceutically acceptable carrier therefor.

12. A compound of the formula ##STR137## wherein X is --O--, --S--, --NH-- or --N(R.sub.2)--;

R.sub.2 is selected from the group consisting of lower alkyl, aryl lower alkyl, aryl, cycloalkyl, aroyl, alkanoyl, alkoxycarbonyl, and phenylsulfonyl groups;

aryl is as defined hereinafter;

p is 1 or 2;

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

(R.sub.1) is --CR.sub.24 C.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.ident.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.ident.C--CR.sub.23 R.sub.24 --CHR.sub.24 --, or

--CHR.sub.24 --CR.sub.23 R.sub.24 --C.ident.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 ##STR138## 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

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 ##STR139## where Z.sub.1 is as previously defined, and p is as previously defined;

R.sub.27 is hydrogen or R.sub.24 and R.sub.27 taken together with the carbon to which they are attached form C.dbd.O or C.dbd.S;

with the proviso that R.sub.23 is not hydrogen, (C.sub.1 -C.sub.18)linear alkyl, phenyl, or ##STR140## when R.sub.27 is hydrogen and R.sub.24 is hydrogen, (C.sub.1 -C.sub.18)linear alkyl, phenyl, or ##STR141## with the proviso that R.sub.24 is not hydrogen, (C.sub.1 -C.sub.18)linear alkyl, phenyl, or ##STR142## when R.sub.27 is hydrogen and n is 0; or when R.sub.27 is hydrogen and R.sub.23 is hydrogen, (C.sub.1 -C.sub.18)linear alkyl, phenyl, or ##STR143## or when R.sub.1 is --CHR.sub.24 --CH.dbd.CH--CHR.sub.24 -- or --CHR.sub.24 --C.ident.C--CHR.sub.24 --;

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,

--C(.dbd.O)-alkyl,

--C(.dbd.O)--O-alkyl,

--C(.dbd.O)-aryl,

--C(.dbd.O)-heteroaryl,

--CH(OR.sub.7)-alkyl,

--C(.dbd.W)-alkyl,

--C(.dbd.W)-aryl, or

--C(.dbd.W)-heteroaryl;

where

alkyl is (C.sub.1 -C.sub.18 alkyl;

aryl is phenyl or ##STR144## where R.sub.5 is hydrogen, lower alkyl, lower alkoxy, hydroxy, chlorine, fluorine, bromine, iodine, lower monoalkylamino, lower dialkylamino, nitro, cyano, trifluoromethyl, trifluoromethoxy;

heteroaryl is ##STR145## where 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, lower alkoxy, or --NHR.sub.10 ; and

R.sub.10 is hydrogen, lower alkyl, C.sub.1 -C.sub.3 acyl, aryl, --C(.dbd.O)-aryl or --C(.dbd.O)-heteroaryl,

where

aryl and heteroaryl are as defined above; and

m is 1, 2, or 3;

any, 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 salt thereof.

13. The compound of claim 12, wherein X is --N(R.sub.2)--.

14. The compound of claim 13, wherein R.sub.2 is (C.sub.2 -C.sub.18)alkanoyl or (C.sub.1 -C.sub.18)alkoxycarbonyl.

15. The compound of claim 13, wherein (R.sub.1) is --CH.sub.2 CH(OH)CH.sub.2 -- or --CH.sub.2 CH[OC(.dbd.O) (C.sub.1 -C.sub.18)alkyl]CH.sub.2 --.

16. The compound of claim 13, wherein R is independently selected from the group consisting of hydrogen, (C.sub.1 -C.sub.6)alkoxy, and (C.sub.2 -C.sub.18)alkanoyl; and m is 1 or 2.

17. The compound of claim 13, wherein X is --O--.

18. An antipsychotic composition, which comprises the compound of claim 13 in an amount sufficient to produce an antipsychotic effect, and a pharmaceutically acceptable carrier.

19. A method of treating psychoses, which comprises administering to a mammal a psychoses-treating amount of the compound of claim 13.

20. An analgesic composition, which comprises the compound of claim 12 in an amount sufficient to produce a pain-relieving effect, and a pharmaceutically acceptable carrier.

21. A method of alleviating pain, which comprises administering to a mammal a pain-relieving effective amount of the compound of claim 12.

22. A depot pharmaceutical composition, which comprises a pharmaceutically acceptable carrier and a therapeutically effective amount of the compound of claim 12, wherein the compound contains a hydroxy group, an amino group, or a nitrogen at the 1-position of an indazole ring, which has been acylated.

23. The depot pharmaceutical composition of claim 22, 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.

24. The composition of claim 22, which contains a pharmaceutically acceptable oil.

25. The composition of claim 24, 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.

26. The composition of claim 23, which contains a pharmaceutically acceptable oil.

27. The composition of claim 26, 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.

28. A method of providing a long-acting antipsychotic effect, which comprises injecting into a mammal an amount of the composition of claim 22 sufficient to produce a long-acting antipsychotic effect.

29. A method of providing a long-acting antipsychotic effect, which comprises injecting into a mammal an amount of the composition of claim 23 sufficient to produce a long-acting antipsychotic effect.

30. A method of providing a long-acting antipsychotic effect, which comprises injecting into a mammal an amount of the composition of claim 27 sufficient to produce a long-acting antipsychotic effect.

31. 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 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 C.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.ident.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.ident.C--CR.sub.23 R.sub.24 --CHR.sub.24 --, or

--CHR.sub.24 --CR.sub.23 R.sub.24 --C.ident.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; 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 ##STR148## where Z.sub.1 is as previously defined, and p is as previously defined;

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 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,

--C(.dbd.O)-alkyl,

--C(.dbd.O)--O-alkyl,

--C(.dbd.O)-aryl,

--C(.dbd.O)-heteroaryl,

--CH(OR.sub.7)alkyl,

--C(.dbd.W)-alkyl,

--C(.dbd.W)-aryl, or

--C(.dbd.W)-heteroaryl;

where

alkyl is (C.sub.1 -C.sub.18)alkyl;

aryl is phenyl or ##STR149## where R.sub.5 is hydrogen, lower alkyl, lower alkoxy, hydroxy, chlorine, fluorine, bromine, iodine, lower monoalkylamino, lower dialkylamino, nitro, cyano, trifluoromethyl, trifluoromethoxy;

heteroaryl is ##STR150## where 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, lower alkoxy, or --NHR.sub.10 ; and

R.sub.10 is hydrogen, lower alkyl, C.sub.1 -C.sub.3 acyl, aryl, --C(.dbd.O)-aryl or --C(.dbd.O)-heteroaryl,

where

aryl and heteroaryl are as defined above; and

m is 1, 2, or 3;

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.

32. The compound of claim 31, wherein X is --N(R.sub.2)--.

33. The compound of claim 32, wherein R.sub.2 is (C.sub.2 -C.sub.18)alkanoyl or (C.sub.1 -C.sub.18)alkoxycarbonyl.

34. The compound of claim 31, wherein (R.sub.1) is --CH.sub.2 CH(OH)CH.sub.2 -- or --CH.sub.2 CH[OC(.dbd.O) (C.sub.1 -C.sub.18 alkyl]CH.sub.2 --.

35. The compound of claim 31, wherein R is independently selected from the group consisting of hydrogen, (C.sub.1 -C.sub.6)alkoxy, and (C.sub.2 -C.sub.18)alkanoyl; and m is 1 or 2.

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

37. An antipsychotic composition, which comprises the compound of claim 31 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 31.

39. An analgesic composition, which comprises the compound of claim 31 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 pin-relieving effective amount of the compound of claim 31.

41. A depot pharmaceutical composition, which comprises a pharmaceutically acceptable carrier and a therapeutically effective amount of the compound of claim 31, wherein the compound contains a hydroxy group, an amino group, or a nitrogen at the 1-position of an indazole ring, which has been acylated.

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, cotton seed 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, cotton seed oil, corn oil, soybean oil, olive oil, and esters of fatty acids and polyfunctional alcohols.

47. A method of 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 of 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 of 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 depot pharmaceutical composition, which comprises a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound having the formula: ##STR151## wherein X is --O--, --S--, --NH-- or --N(R.sub.2)--;

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--;

R.sub.2 is selected from the group consisting of lower alkyl, aryl lower alkyl, aryl, cycloalkyl, aroyl, alkanoyl, alkoxycarbonyl, and phenylsulfonyl groups;

(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.ident.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.ident.C--CH.sub.2 --CH.sub.2 --, or

--CH.sub.2 --CH.sub.2 --C.ident.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 ##STR152## where Z.sub.1 is lower alkyl, --OH, lower alkoxy, --CF.sub.3, --NO.sub.2, --NH.sub.2 or halogen;

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,

--C(.dbd.O)-alkyl,

--C(.dbd.O)--O-alkyl,

--C(.dbd.O)-aryl,

--C(.dbd.O)-heteroaryl,

--CH(OR.sub.7)-alkyl,

--C(.dbd.W)-alkyl,

--C(.dbd.W)-aryl, or

--C(.dbd.W)-heteroaryl;

where

alkyl is (C.sub.1 -C.sub.18)alkyl;

aryl is phenyl or ##STR153## where R.sub.5 is hydrogen, lower alkyl, lower alkoxy, hydroxy, chlorine, fluorine, bromine, iodine, lower monoalkylamino, lower dialkylamino, nitro, cyano, trifluoromethyl, trifluoromethoxy;

heteroaryl is ##STR154## where 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, lower alkoxy, or --NHR.sub.10 ; and

R.sub.10 is hydrogen, lower alkyl, C.sub.1 -C.sub.3 acyl, aryl, --C(.dbd.O)-aryl or --C(.dbd.O)-heteroaryl,

where

aryl and heteroaryl are as defined above; and

m is 1, 2, or 3;

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;

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;

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

51. The depot pharmaceutical composition of claim 50, which contains a pharmaceutically acceptable oil.

52. The depot pharmaceutical composition of claim 51, 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.

53. A method for providing a long acting antipsychotic effect, which comprises injecting into a mammal an amount of the depot pharmaceutical composition of claim 50 sufficient to produce a long acting antipsychotic effect.

54. A compound of the formula ##STR155## wherein X is --NH-- or --N(R.sub.2)--;

p is 1;

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

R.sub.2 is selected from the group consisting of lower alkyl, aryl lower alkyl, aryl, cycloalkyl, aroyl, alkanoyl, and phenylsulfonyl groups;

(R.sub.1) is

--CH.sub.2 --CH.dbd.CH--CH.sub.2 --;

--CH.sub.2 --C.ident.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.ident.C--CH.sub.2 --CH.sub.2 --, or

--CH.sub.2 --CH.sub.2 --C.ident.C--CH.sub.2 --,

the --CH.dbd.CH-- bond being cis or trans,

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, dialkylaminocarbonyl, formyl,

--C(.dbd.O)-alkyl,

--C(.dbd.O)--O-alkyl,

--C(.dbd.O)-aryl,

--C(.dbd.O)-heteroaryl,

--CH(OR.sub.7)-alkyl,

--C(.dbd.W)-alkyl,

--(C.dbd.W)-aryl, or

--C(.dbd.W)-heteroaryl;

where

alkyl is (C.sub.1 -C.sub.6)alkyl;

aryl is phenyl or ##STR156## where R.sub.5 is hydrogen, lower alkyl, lower alkoxy, hydroxy, chlorine, fluorine, bromine, iodine, lower monoalkylamino, lower dialkylamino, nitro, cyano, trifluoromethyl, trifluoromethoxy;

heteroaryl is ##STR157## where 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 acyl;

R.sub.8 is lower alkyl;

R.sub.9 is hydroxyl, lower alkoxy, or --NHR.sub.1 ; and

R.sub.10 is hydrogen, lower alkyl, C.sub.1 -C.sub.3 acyl, aryl, --C(.dbd.O)-aryl or --C(.dbd.O)-heteroaryl,

where

aryl and heteroaryl are as defined above; and

m is 1, 2, or 3;

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

55. The compound of claim 54, wherein X is --N(R.sub.2)--.

56. The compound of claim 54, wherein R.sub.2 is (C.sub.2 -C.sub.11)alkanoyl.

57. An antipsychotic composition, which comprises the compound of claim 54 in an amount sufficient to produce an antipsychotic effect, and a pharmaceutically acceptable carrier therefor.

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

59. An analgesic composition, which comprises the compound of claim 54 in an amount sufficient to produce a pain-relieving effect, and a pharmaceutically acceptable carrier therefor.

60. A method of alleviating pain, which comprises administering to a mammal a pain-relieving effective amount of the compound of claim 54.

61. A compound of the formula ##STR158## wherein X is --NH-- or --N(R.sub.2)--;

p is 1;

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

R.sub.2 is selected from the group consisting of lower alkyl, aryl lower alkyl, aryl, cycloalkyl, aroyl, alkanoyl, and phenylsulfonyl groups;

(R.sub.1) 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 ##STR159## where Z.sub.1 is lower alkyl, --OH, lower alkoxy, --CF.sub.3, --NO.sub.2, --NH.sub.2 or halogen;

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.ident.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.ident.C--CH.sub.2 --CH.sub.2 --, or

--CH.sub.2 --CH.sub.2 --C.ident.C--CH.sub.2 --,

the --CH.dbd.CH-- bond being cis or trans;

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,

--C(.dbd.O)-alkyl,

--C(.dbd.O)--O-alkyl,

--C(.dbd.O)-aryl,

--C(.dbd.O)-heteroaryl,

--CH(OR.sub.7)alkyl,

--C(.dbd.W)-alkyl,

--C(.dbd.W)-aryl, or

--C(.dbd.W)-heteroaryl;

where

alkyl is (C.sub.1 -C.sub.18)alkyl;

aryl is phenyl or ##STR160## where R.sub.5 is hydrogen, lower alkyl, lower alkoxy, hydroxy, chlorine, fluorine, bromine, iodine, lower monoalkylamino, lower dialkylamino, nitro, cyano, trifluoromethyl, trifluoromethoxy;

heteroaryl is ##STR161## where 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 acyl;

R.sub.8 is lower alkyl;

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

R.sub.10 is hydrogen, lower alkyl, C.sub.1 -C.sub.3 acyl, aryl, --C(.dbd.O)-aryl or --C(.dbd.O)-heteroaryl,

where

aryl and heteroaryl are as defined above; and

m is 1, 2, or 3;

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

62. The compound of claim 61, wherein X is --N(R.sub.2)--.

63. The compound of claim 61, wherein R.sub.2 is (C.sub.2 -C.sub.11)alkanoyl.

64. An antipsychotic composition, which comprises the compound of claim 61 in an amount sufficient to produce an antipsychotic effect, and a pharmaceutically acceptable carrier therefor.

65. A method of treating psychoses, which comprises administering to a mammal a psychoses-treating effective amount of the compound of claim 61.

66. An analgesic composition, which comprises the compound of claim 61 in an amount sufficient to produce a pain-relieving effect, and a pharmaceutically acceptable carrier therefor.

67. A method of alleviating pain, which comprises administering to a mammal a pain-relieving effective amount of the compound of claim 61.
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