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Details for Patent: 5,364,866

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Details for Patent: 5,364,866

Title: Heteroarylpiperidines, pyrrolidines and piperazines and their use as antipsychotics and analetics
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), Helsley; Grover C. (Stockton, NJ), Chiang; Yulin (Convent Station, NJ), Bordeau; Kenneth J. (Upper Black Eddy, PA), Glamkowski; Edward J. (Warren, NJ)
Assignee: Hoechst-Roussel Pharmaceuticals, Inc. (Somerville, NJ)
Filing Date:Oct 30, 1992
Application Number:07/969,383
Claims:1. A compound of the formula: ##STR163## wherein X is --O-- or --S--;

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 and halogen when p is 2 and X is --O--;

(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 ##STR164## 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, ##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, trifluoromethoxy;

heteroaryl is ##STR167## Q.sub.3 is --O--, ##STR168## --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, ##STR169## 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.

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

3. A compound as claimed in claim 1, which is 1-[4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-metho xyphenyl]ethanone or a pharmaceutically acceptable acid addition salt thereof.

4. A compound as claimed in claim 1, which is 1-[4-[4-[4-(1,2-benzisoxazol-3-yl)-1-piperidinyl]butoxy]-3methoxyphenyl]et hanone or a pharmaceutically acceptable acid addition salt thereof.

5. A compound as claimed in claim 1, which is 1-[4-[4-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]butoxy]-3-methox yphenyl]ethanone or a pharmaceutically acceptable acid addition salt thereof.

6. A compound as claimed in claim 1, which is 1-[4-[2-[4-(1,2-benzisoxazol-3-yl)-1-piperidinyl]ethoxy]-3-methoxyphenyl]e thanone or a pharmaceutically acceptable acid addition salt thereof.

7. A compound as claimed in claim 1, which is 1-[4-[2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethoxy]-3-methox yphenyl]ethanone or a pharmaceutically acceptable acid addition salt thereof.

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

9. A compound as claimed in claim 1, which is 4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-methoxy- .alpha.-methylbenzenemethanol or a pharmaceutically acceptable acid addition salt thereof.

10. A compound as claimed in claim 1, which is 1-[4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-hydro xyphenyl]ethanone or a pharmaceutically acceptable acid addition salt thereof.

11. A compound as claimed in claim 1, which is 1-[4-[3-[4-(6-chloro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-metho xyphenyl]ethanone or a pharmaceutically acceptable acid addition salt thereof.

12. A compound as claimed in claim 1, which is 1-[4-[4-[4-(6-chloro-1,2-benzisoxazol-3-yl)-1-piperidinyl]butoxy]-3-methox yphenyl]ethanone fumarate or a pharmaceutically acceptable acid addition salt thereof.

13. A compound as claimed in claim 1, which is 1-[4-[3-[4-(5-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-metho xyphenyl]ethanone or a pharmaceutically acceptable acid addition salt thereof.

14. A compound as claimed in claim 1, which is 6-fluoro-3-[1-[3-(2-methoxyphenoxy)propyl]-4-piperidinyl]-1,2-benzisoxazol e fumarate or a pharmaceutically acceptable acid addition salt thereof.

15. A compound as claimed in claim 1, which is 1-[3-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-4-metho xyphenyl]phenylmethanone or a pharmaceutically acceptable acid addition salt thereof.

16. A compound as claimed in claim 1, which is 1-[4-[2-[4-(6-chloro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethoxy]-3-methox yphenyl]ethanone or a pharmaceutically acceptable acid addition salt thereof.

17. A compound as claimed in claim 1, which is 1-[3-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]phenyl]e thanone or a pharmaceutically acceptable acid addition salt thereof.

18. A compound as claimed in claim 1, which is 1-[4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-2-methy lphenyl]ethanone or a pharmaceutically acceptable acid addition salt thereof.

19. A compound as claimed in claim 1, which is 1-[2-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-5-methy lphenyl]ethanone or a pharmaceutically acceptable acid addition salt thereof.

20. A compound as claimed in claim 1, which is N-[3-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-4-metho xyphenyl]acetamide or a pharmaceutically acceptable acid addition salt thereof.

21. A compound as claimed in claim 1, which is 1-[4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-methy lphenyl]ethanone or a pharmaceutically acceptable acid addition salt thereof.

22. A compound as claimed in claim 1, which is 1-[4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]phenyl]e thanone or a pharmaceutically acceptable acid addition salt thereof.

23. A compound as claimed in claim 1, which is 4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-methoxyb enzonitrile or a pharmaceutically acceptable acid addition salt thereof.

24. A compound as claimed in claim 1, which is 1-[3,5-dibromo-4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]prop oxy]phenyl]ethanone or a pharmaceutically acceptable acid addition salt thereof.

25. A compound as claimed in claim 1, which is 6-fluoro-3-[1-(3-phenoxypropyl)-4-piperidinyl]-1,2-benzisoxazole or a pharmaceutically acceptable acid addition salt thereof.

26. A compound as claimed in claim 1, which is 1-[4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl]-1-piperidinyl]propoxy]-3-methy lmercaptophenyl]ethanone or a pharmaceutically acceptable acid addition salt thereof.

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

28. A compound as claimed in claim 1, which is 1-[4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-metho xyphenyl]phenylmethanone or a pharmaceutically acceptable acid addition salt thereof.

29. A compound as claimed in claim 1, which is 3-[1-[3-[4-(1-ethoxyethyl)-2-methoxyphenoxy]propyl]-4-piperidinyl]-6-fluor o-1,2-benzisoxazole or a pharmaceutically acceptable acid addition salt thereof.

30. A compound as claimed in claim 1, which is 3-[1-[3-[4-(1-acetoxyethyl)-2-methoxyphenoxy]propyl]-4-piperidinyl]-6-fluo ro-1,2-benzisoxazole or a pharmaceutically acceptable acid addition salt thereof.

31. A compound as claimed in claim 1, which is 1-[4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-metho xyphenyl]pentanone or a pharmaceutically acceptable acid addition salt thereof.

32. A compound as claimed in claim 1, which is 2-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-N-methylbe nzeneamine or a pharmaceutically acceptable acid addition salt thereof.

33. A compound as claimed in claim 1, which is 3-[1-[3-(4-bromo-2-methoxyphenoxy)propyl]-4-piperidinyl]-6-fluoro-1,2-benz isoxazole or a pharmaceutically acceptable acid addition salt thereof.

34. A compound as claimed in claim 1, which is 1-[4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-metho xyphenyl]propanone or a pharmaceutically acceptable acid addition salt thereof.

35. A compound as claimed in claim 1, which is 4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-methoxyb enzamide or a pharmaceutically acceptable acid addition salt thereof.

36. A compound as claimed in claim 1, which is 1-[4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-(meth ylamino)phenyl]ethanone or a pharmaceutically acceptable acid addition salt thereof.

37. A compound as claimed in claim 1, which is 1-[4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-ethox phenyl]ethanone or a pharmaceutically acceptable acid addition salt thereof.

38. A compound as claimed in claim 1, which is N-[2-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]phenyl]a cetamide, or a pharmaceutically acceptable acid addition salt thereof.

39. A compound as claimed in claim 1, which is 1-[4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-dimet hylaminophenyl]ethanone, or a pharmaceutically acceptable acid addition salt thereof.

40. A compound as claimed in claim 1, which is 1-[4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-2-metho xyphenyl]ethanone, or a pharmaceutically acceptable acid addition salt thereof.

41. A compound as claimed in claim 1, which is 4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-hydroxy- .alpha.-methylbenzene methanol, or a pharmaceutically acceptable acid addition salt thereof.

42. A compound as claimed in claim 1, which is 2-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]aniline, or a pharmaceutically acceptable acid addition salt thereof.

43. A compound as claimed in claim 1, which is N-[5-acetyl-2-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy ]phenyl]acetamide, or a pharmaceutically acceptable acid addition salt thereof.

44. A compound as claimed in claim 1, which is 3-[1-[3-(4-ethyl-2-methoxyphenoxy)propyl]-4-piperidinyl]-6-fluoro-1,2-benz isoxazole, or a pharmaceutically acceptable acid addition salt thereof.

45. A compound as claimed in claim 1, which is 1-[3,5-dimethoxy-4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]pr opoxy]phenyl]ethanone, or a pharmaceutically acceptable acid addition salt thereof.

46. A compound as claimed in claim 1, which is N-[3-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]phenyl]a cetamide, or a pharmaceutically acceptable acid addition salt thereof.

47. A compound as claimed in claim 1, which is 3-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]aniline, or a pharmaceutically acceptable acid addition salt thereof.

48. A compound as claimed in claim 1, which is 3-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-4methoxyan iline, or a pharmaceutically acceptable acid addition salt thereof.

49. A compound as claimed in claim 1, which is 1-[4-[3-[4-(6-fluoro-1,2-benzisothiazol-3-yl)-1-piperidinyl]propoxy]-3-met hylaminophenyl]ethanone, or a pharmaceutically acceptable acid addition salt thereof.

50. A compound as claimed in claim 1, which is N-[3-[3-[4-(6-fluoro-1,2-benzisothiazol-3-yl)-1-piperidinyl]propoxy]-4-met hoxyphenyl]acetamide, or a pharmaceutically acceptable acid addition salt thereof.

51. A compound as claimed in claim 1, which is 1-[4-[3-[4-(6-fluoro-1,2-benzisothiazol-3-yl)-1-piperidinyl]propoxy]-3-met hoxyphenyl]ethanone, or a pharmaceutically acceptable acid addition salt thereof.

52. A compound as claimed in claim 1, which is N,N-dimethyl-4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propox y]-3-methoxybenzamide, or a pharmaceutically acceptable acid addition salt thereof.

53. A compound as claimed in claim 1, which is 1-[4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-metho xyphenyl]ethanone oxime, or a pharmaceutically acceptable acid addition salt thereof.

54. A compound as claimed in claim 1, which is 1-[4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]methoxyp henyl]ethanone oxime O-methyl ether, or a pharmaceutically acceptable acid addition salt thereof.

55. A compound as claimed in claim 1, which is 1-[4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-metho xyphenyl]ethanone hydrazone, or a pharmaceutically acceptable acid addition salt thereof.

56. A compound as claimed in claim 1, which is 6-fluoro-3-[1-[3-[2-methoxy-4-(1-methylethenyl)phenoxy]propyl]-4-piperidin yl]-1,2-benzisoxazole, or a pharmaceutically acceptable acid addition salt thereof.

57. A compound as claimed in claim 1, which is (Z)-1-[4-[[4-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]-2butenyl]o xy]-3-methoxyphenyl]ethanone, or a pharmaceutically acceptable acid addition salt thereof.

58. A compound as claimed in claim 1, which is (E)-1-[3-[4-[[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]-2-butenyl] oxy]-4-hydroxyphenyl]ethanone, or a pharmaceutically acceptable acid addition salt thereof.

59. A compound as claimed in claim 1, which is (E)-1-[3-[4-[[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]-2butenyl]o xy]-4-benzyloxyphenyl]ethanone, or a pharmaceutically acceptable acid addition salt thereof.

60. A compound as claimed in claim 1, which is 1-[4-[3-[4-(6-Fluoro-1,2-benziosoxazol-3-yl)-1-piperidinyl]propoxy]-3-brom ophenyl]ethanone or a pharmaceutically acceptable acid addition salt thereof.

61. A compound as claimed in claim 1, which is 1-[4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-metho xyphenyl]-2,2,2-trifluoroethanone, or a pharmaceutically acceptable acid addition salt thereof.

62. A compound as claimed in claim 1, which is 3-[1-[3-[4-(1-methoxyethyl)-2-hydroxyphenoxyl]propyl]-4-piperidinyl]-6-flu oro-1,2-benzisoxazole, or a pharmaceutically acceptable acid addition salt thereof.

63. A compound as claimed in claim 1, which is 1-[4-[3-[4-(6-fluoro-1,2-benzisothiazol-3-yl)-1-piperidinyl]propoxy]-3-hyd roxyphenyl]ethanone, or a pharmaceutically acceptable acid addition salt thereof.

64. A compound as claimed in claim 1, which is 4-[3-[4-(6-fluoro-1,2-benzisothiazol-3-yl)-1-piperidinyl]propoxy]-3-methox y-alpha-methylbenzenemethanol, or a pharmaceutically acceptable acid addition salt thereof.

65. A compound as claimed in claim 1, which is 1-(R)-(-)-[4-[3-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]-2-methyl-1 -propoxy]-3-methoxyphenyl]ethanone, or a pharmaceutically acceptable acid addition salt thereof.

66. A compound as claimed in claim 1, which is 1-(S-)(+)-[4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]-2-methy l-1-propoxy]-3-methoxyphenyl]ethanone, or a pharmaceutically acceptable acid addition salt thereof.

67. The compound of claim 1, wherein the pharmaceutically acceptable 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.

68. The compound of claim 67, wherein said pharmaceutically acceptable addition salts are 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.

69. The compound of claim 1, wherein Y is in the 5 position.

70. The compound of claim 1, wherein Y is in the 6 position.

71. The compound of claim 1, wherein Y is selected from the group consisting of hydrogen, chlorine, bromine and fluorine.

72. The compound of claim 71, wherein Y is fluorine.

73. The compound of claim 72, wherein Y is in the 6 position.

74. The compound of claim 1, wherein p is 2, X is --O--, and Y is selected from the group consisting of lower alkoxy, hydroxy and halogen groups.

75. The compound of claim 74, wherein Y is a methoxy group.

76. The compound of claim 1, wherein R.sub.1 is --CH.sub.2 --CH.dbd.CH.dbd.CH.sub.2 --.

77. The compound of claim 1, wherein R is selected from the group consisting of hydrogen, C.sub.1 -C.sub.3 alkyl, C.sub.1 -C.sub.3 alkoxy, hydroxyl, --COCF.sub.3, C.sub.1 -C.sub.6 alkanoyl, Cl, F, Br, I, C.sub.1 -C.sub.3 alkylamino, --NO.sub.3, --CF.sub.3, --OCF.sub.3, and ##STR170##

78. A compound of the formula: ##STR171## wherein p is 1 or 2; Y is hydrogen, 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, alkanoyl, Cl, F, Br, I, amino, C.sub.1 -C.sub.3 mono or dialkyl amino, acylamino, --NO.sub.2, --OCF.sub.3, --CF.sub.3, ##STR172## alkyl is lower alkyl; R.sub.7 is hydrogen, lower alkyl, ##STR173## and m is 1, 2, or 3;

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

79. A compound of the formula: ##STR174## wherein p is 1 or 2; Y is hydrogen, 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, alkanoyl, Cl, F, Br, I, amino, C.sub.1 -C.sub.3 mono or dialkyl amino, acylamino, --NO.sub.2, --OCF.sub.3, --CF.sub.3, ##STR175## alkyl is lower alkyl; R.sub.7 is hydrogen, lower alkyl, or ##STR176## and m is 1, 2, or 3;

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

80. A compound of the formula: ##STR177## wherein X is --O-- or --S--;

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 and halogen when p is 2 and X is --O--,

is --(CH.sub.2).sub.n -- where n is 2, 3, 4 or 5;

(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.dbd.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 ##STR178## where Z.sub.1 is lower alkyl, --OH, lower alkoxy, --CF.sub.3, --NO.sub.2, --NH.sub.2 or halogen; and R and m are as defined hereinafter;

m is 1, 2, or 3; and

when m is 1, 2, or 3, 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, ##STR179## alkyl is lower alkyl; aryl is phenyl or ##STR180## 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 ##STR181## Q.sub.3 is --O--, --S--, ##STR182## --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, ##STR183## where aryl and heteroaryl are as defined above; and when m is 3, R is not ##STR184## all geometric, optical and stereoisomers thereof, or pharmaceutically acceptable acid addition salt thereof.

81. A compound as claimed in claim 1, which is (E)-1-[4-[[4-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]-2-butenyl] oxy]-3-methoxphenyl]ethanone, or a pharmaceutically acceptable acid addition salt thereof.

82. A pharmaceutical composition, which comprises compound as claimed in any one of claims 1-81, and a pharmaceutically acceptable carrier therefor.

83. An antipsychotic composition which comprises a compound as claimed in any one of claims 1-81, in an amount sufficient to produce an antipsychotic effect, and a pharmaceutically acceptable carrier therefor.

84. A method of treating psychoses, which comprises administering to a mammal a psychoses-treating effective amount of a compound as claimed in any one of claims 1-81.

85. An analgesic composition which comprises a compound as claimed in any one of claims 1-81, in an amount sufficient to produce a pain-relieving effect, and a pharmaceutically acceptable carrier therefor.

86. A method of alleviating pain, which comprises administering to a mammal a pain-relieving effective amount of a compound as claimed in any one of claims 1-81.
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