Heteroarylpiperidines, pyrrolidines and piperazines and their use as antipsychotics and analgesics
View Patent ↗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 amounts 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.
1. A compound of the formula:
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 1 ) is R 20 , R 21 , or R 22 , wherein:
R 20 is —(CH 2 ) n — where n is 2, 3, 4 or 5;
R 21 is
—CH 2 —CH═CH—CH 2 —,
—CH 2 —C≡C—CH 2 —,
—CH 2 —CH═CH—CH 2 —CH 2 ,
—CH 2 —CH 2 —CH═CH—CH 2 —,
—CH 2 —C≡C—CH 2 —CH 2 —, or
—CH 2 —CH 2 —C≡C—CH 2 —,
the —CH═CH— bond being cis or trans;
R 22 is R 20 or R 21 in which one or more carbon atoms of R 20 or R 21 are substituted by at least one C 1 -C 6 linear alkyl group, pheny group or
where Z 1 is lower alkyl, —OH, lower alkoxy, —CF 3 , —NO 2 , —NH 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(═O)-alkyl, —C(═O)—O-alkyl, —C(═O)-aryl, —C(═O)-heteroaryl, —CH(OR 7 )-alkyl, —C(═W)-alkyl, —C(═W)-aryl, and —C(═W)-heteroaryl; or —CH( OR 7 )- alkyl;
wherein alkyl is lower alkyl;
aryl is phenyl or
wherein R 5 is hydrogen, lower alkyl, lower alkoxy, hydroxy, chlorine, fluorine, bromine, iodine, lower monoalkylamino, lower dialkylamino, nitro, cyano, trifluoromethyl, or trifluoromethoxy;
heteroaryl is
wherein Q 3 is —O—, —S—, —NH—, or —CH═N—;
W is CH 2 or CHR 8 or N—R 9 ;
R 7 is hydrogen, lower alkyl, or acyl;
R 8 is lower alkyl;
R 9 is hydroxy, lower alkoxy, or —NHR 10 ; and
R 10 is hydrogen, lower alkyl, C 1 -C 3 acyl, aryl,
—C(═)-aryl or —C(═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.
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-methoxyphenyl]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]-3-methoxyphenyl]ethanone 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-methoxyphenyl]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]ethanone 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-methoxyphenyl]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-methoxyphenyl]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-α-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-hydroxyphenyl]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-methoxyphenyl]ethanone or a pharmaceutically acceptable acid addition salt thereof.
12. A compound as claimed as claim 1 , which is 1-[4-[4-[4-(6-chloro-1,2-benzisoxazol-3-yl)-1-piperindyl]-butoxy]-3-methoxyphenyl]ethanone 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-methoxyphenyl]ethanone or a pharmaceutically acceptable acid addition salt thereof.
14. A compound as claimed in claim 1 , which is 6-fluoro-3-[1-[1-[3-(2-methoxyphenoxy)propyl]-4-piperidinyl]-1,2-benzisoxazole or a pharmaceutically acceptable acid 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-methoxyphenyl]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-methoxyphenyl]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-benzisoxzol-3-yl)-1-piperidinyl]-propoxy]phenyl]ethanone 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-3yl)-1-piperidinyl]-propoxyl]-2-methylphenyl]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-methylphenyl]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-methoxyphenyl]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-methylphenyl]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]ethanone or a pharmaceutically acceptable acid addition salt thereof.
23. A compound as claimed in claim 1 , which is 4-[3-[4-(6-fluoro-1,2-1,2-benzisoxazol-3-yl)-1-piperidinyl]-propoxy]-3-methoxybenzonitrile 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]propoxy]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-methylmercaptophenyl]ethanone 1 - [ 4 - [ 3 - [ 4 -( 6 - fluoro - 1 , 2 - benzisoxazol - 3 - yl )- 1 - piperidinyl]propoxy] - 3 - methylmercaptophenyl]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-methoxyphenyl]phenylmethanone or a pharmaceutically acceptable acid addition salt thereof.
29. A compound as claimed in claim 1 , which is 3-[1-[3-[4-ethoxyethyl)-2-methoxyphenoxy]propyl]-4-piperidinyl]-6-fluoro-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-fluoro-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-methoxyphenyl]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-methylbenzeneamine 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-benzisoxazole 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-methoxyphenyl]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-methoxybenzamide 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-(methylamino)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-ethoxyphenyl]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]acetamide, 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-dimethylaminophenyl]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-methoxyphenyl]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-α-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-benzisoxazole, 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]propoxy]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-benzisoxaxol-3-yl)-1-piperidinyl]-propoxy]phenyl]acetamide, 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]-4-methoxyaniline, 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-methylaminophenyl]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-methoxyphenyl]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-methoxyphenyl]ethanone, or a pharmaceutically acceptable acid addition salt thereof.
52. A compound as claimed in claim 1 132 , which is N,N-dimethyl-4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-methoxybenzamide, or a pharmaceutically acceptable acid addition salt thereof.
53. A compound as claimed in claim 1 132 , which is 1-[4-[3-[4(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]-propoxy]-3-(methylamino)phenyl]ethanone oxime, or a pharmaceutically acceptable acid addition salt thereof.
54. A compound as claimed in claim 1 132 , which is 1-[4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]-propoxy]methoxyphenyl]ethanone oxime O-methyl ether, or a pharmaceutically acceptable acid addition salt thereof.
55. A compound as claimed in claim 1 132 , which is 1-[4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]-propoxy]-3-methoxyphenyl]ethanone hydrazone, or a pharmaceutically acceptable acid addition salt thereof.
56. A compound as claimed in claim 1 132 , which is 6-fluoro-3-[1-[3-[2-methoxy-4-(1-methylethenyl)phenoxy]propyl]-4-piperidinyl]-1,2-benzisoxazole, or a pharmaceutically acceptable acid addition salt thereof.
57. A compound as claimed in claim 1 87 , which is (Z)-1-[4-[[4-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]-2butenyl]oxy]-3-methoxyphenyl]ethanone, or a pharmaceutically acceptable acid addition salt thereof.
58. A compound as claimed in claim 1 87 , 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]oxy]-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-benzisoxazol-3-yl)-1-piperidinyl]-propoxy]-3-bromophenyl]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-methoxyphenyl]-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-fluoro-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-benzisothazol-3-yl)-1-piperidinyl]-propoxy]-3-hydroxyphenyl]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-methoxy-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 104 , which is 1 -( R )-(−)-[ 4 - [ 3 - [ 4 -( 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 1 104 , which is 1-(S)-(+)-[4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]-2-methyl-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, slats 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 1 is —CH 2 —CH═CH—CH 2 —.
77. The compound of claim 1 , wherein R is selected from the group consisting of hydrogen, C 1 -C 3 alkyl, C 1 -C 3 alkoxy, hydroxyl, —COCF 3 , C 1 -C 6 alkanoyl, Cl, F, Br, I, C 1 -C 3 alkylamino, —NO 3 , —NO 2 , —CF 3 , —OCF 3 , and —C(═O)-lower alkyl.
78. A compound of the formula:
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 1 -C 3 alkyl, C 1 -C 3 alkoxy, hydroxyl, alkanoyl, Cl, F, Br, I, amino, C 1 -C 3 mono or dialkyl amino, acylamino, —NO 2 , —OCF 3 , —CF 3 , alkyl-C(═O)—, CF 3 —C(═O)—, or —CH(OR 7 )-alkyl;
alkyl is lower alkyl
R 7 is hydrogen, lower alkyl-C(═O)—, or CF 3 —C(═O)—;
and m is 1, 2, or 3;
R is hydrogen, C 1 -C 3 alkyl, C 1 -C 3 alkoxy, hydroxyl, alkanoyl, Cl, F, Br, I, amino, C 1 -C 3 mono or dialkyl amino, acylamino, —NO 2 , —OCF 3 , —CF 3 , alkyl-C(═O)—, CF 3 —C(═O)—, or —CH(OR 7 )-alkyl;
alkyl is lower alkyl;
R 7 is hydrogen, lower alkyl, lower alkyl-C(═O)—, or CF 3 —C(═O)—;
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:
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 1 -C 3 alkyl, C 1 -C 3 alkoxy, hydroxyl, acyl, alkanoyl, Cl, F, Br, I, amino, C 1 -C 3 mono or dialkyl amino, acylamino, —NO 2 , —OCF 3 , —CF 3 , alkyl-C(═O)—, CF 3 —C(═O)—, or —CH(OR 7 )-alkyl;
alkyl is lower alkyl;
R 7 is hydrogen lower alkyl, or lower alkyl-C(═O)—, or CF 3 —C(═O)—;
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:
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 1 ) is R 20 , R 21 , or R 22 , wherein:
R 20
R 21 is
—CH 2 —CH═CH—CH 2 —,
—CH 2 —C≡C—CH 2 —,
—CH 2 —CH═CH—CH 2 —CH 2 —,
—CH 2 —CH 2 —CH═CH—CH 2 —,
—CH 2 —CH≡C—CH 2 —CH 2 —, or
—CH 2 —CH 2 —C≡C—CH 2 —,
the —CH═CH— bond being cis or trans;
R 22 is R 20 is R 21 in which one or more carbon atoms of R 20 or R 21 are substituted by at least one C 1 -C 6 linear alkyl group, phenyl group or
wherein Z 1 is lower alkyl, —OH, lower alkoxy, —CF 3 , —NO 2 , —NH 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, —C(═O)-alkyl, —C(═O)—O-alkyl, —C(═O)-aryl, —C(═O)-heteroaryl, —CH(OR 7 )-alkyl, —C(═W)-alkyl, —C(═W)-aryl, and —C(═W)-heteroaryl;
alkyl is lower alkyl;
aryl is phenyl or
where R 5 is hydrogen, lower alkyl, lower alkoxy, hydroxy, chlorine, fluorine, bromine, iodine, lower monoalkylamino, lower dialkylamino, nitro, cyano, trifluoromethyl, trifluoromethoxy;
heteroaryl is
Q 3 is —O—, —S—, —NH—, —CH═N—;
W is CH 2 or CHR 8 or N—R 9 ;
R 7 is hydrogen, lower alkyl, or acyl;
R 8 is lower alkyl;
R 9 is hydroxy, lower alkoxy, or —NHR 10 ; and
R 10 is hydrogen, lower alkyl, C 1 -C 3 acyl, aryl, —C(═O)-aryl or —C(═O)-heteroaryl,
where aryl and heteroaryl are as defined above; and as claimed in claim 1 with the proviso that when m is 3, R is not —C(═O)-heteroaryl or —C(═W)-heteroaryl;
all geometric, optical and stereoisomers thereof, or a pharmaceutically acceptable acid addition salt thereof.
81. A compound as claimed in claim 1 87 , which is (E)-1-[4-[[4-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]-2-butenyl]oxy]-3-methoxyphenyl]ethanone, or a pharmaceutically acceptable acid addition salt thereof.
82. A pharmaceutical composition, which comprises a compound as claimed in any one of claims 1 - 81 1 - 75 and 77 - 81 , and a pharmaceutically acceptable carrier therefor.
83. An antipsychotic composition which comprises a compound as claimed in any one of claims 1 - 81 1 - 75 and 77 - 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 1 - 75 and 77 - 81 .
85. An analgesic composition which comprises a compound as claimed in any one of claims 1 - 81 1 - 75 and 77 - 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 1 - 75 and 77 - 81 .
87. A compound of the formula
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 1 ) is
—CH 2 —CH═CH—CH 2 —,
—CH 2 —C≡C—CH 2 —,
—CH 2 —CH═CH—CH 2 —CH 2 —,
—CH 2 —CH 2 —CH═CH—CH 2 —,
—CH 2 —C≡C—CH 2 —CH 2 —, or
—CH 2 —CH 2 —C≡C—CH 2 —,
the —CH═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 ( ═O )- alkyl, —C ( ═O ) —O - alkyl, —C ( ═O )- aryl, —C ( ═O )- heteroaryl, —CH ( OR 7 )- alkyl, —C ( ═W )- alkyl, —C ( ═W )- aryl, or —C ( ═W )- heteroaryl;
wherein alkyl is lower alkyl;
aryl is phenyl or
wherein R 3 is hydrogen, lower alkyl, lower alkoxy, hydroxy, chlorine, fluorine, bromine, iodine, lower monoalkylamino, lower dialkylamino, nitro, cyano, trifluoromethyl, or trifluoromethoxy;
heteroaryl is
wherein Q 3 is —O—, —S—, —NH—, or —CH═N—;
W is CH 2 or CHR 8 or N—R 9 ;
R 7 is hydrogen, lower alkyl, or acyl;
R 8 is lower alkyl;
R 9 is hydroxy, lower alkoxy, or —NHR 10 ; and
R 10 is hydrogen, lower alkyl, C 1 -C 3 acyl aryl, —C ( ═O )- aryl, or —C ( ═O )- heteroaryl,
wherein 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.
88. The compound of claim 87 , wherein the pharmaceutically acceptable addition salt is selected from the group consisting of salts of minerals acids, salts of monobasic carboxylic acids, salts of dibasic carboxylic acids, and salts of tribasic carboxylic acids.
89. The compound of claim 88 , 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.
90. The compound of claim 87 , wherein Y is in the 5 position.
91. The compound of claim 87 , wherein Y is in the 6 position.
92. The compound of claim 87 , wherein Y is selected from the group consisting of hydrogen, chlorine, bromine and fluorine.
93. The compound of claim 92 , wherein Y is fluorine.
94. The compound of claim 93 , wherein Y is in the 6 position.
95. The compound of claim 87 , wherein p is 2 , X is —O—, and Y is selected from the group consisting of lower alkoxy, hydroxy, and halogen groups.
96. The compound of claim 95 , wherein Y is a methoxy group.
97. The compound of claim 87 , wherein R 7 is —CH 2 —CH═CH—CH 2 .
98. The compound of claim 87 , wherein R is selected from the group consisting of hydrogen, C 1 —C 3 alkyl, C 1 —C 3 alkoxy, hydroxyl, —COCF 2 , C 1 -C 6 alkanoyl, Cl, F, Br, I, C 1 -C 3 alkylamino, —NO 2 , —CF 3 , —OCF 2 , and alkylamino,
99. A pharmaceutical composition, which comprises a compound as claimed in claim 87 , and a pharmaceutically acceptable carrier therefor.
100. An antipsychotic composition which comprises a compond as claimed in claim 87 , in an amount sufficient to produce an antipsychotic effect, and a pharmaceutically acceptable carrier therefor.
101. A method of treating psychoses, which comprises administering to a mammal a psychoses- treating effective amount of a compound as claimed in claim 87 .
102. An analgesic composition which comprises a compound as claimed in claim 87 , in an amount sufficient to produce a pain- relieving effect, and a pharmaceutically acceptable carrier therefor.
103. A method of alleviating pain, which comprises administering to a mammal a pain- relieving effective amount of a compound as claimed in claim 87 .
104. A compound of the formula
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, or halogen when p is 2 and X is —O—;
( R 1 ) is R 20 or R 21 in which one or more carbon atoms of R 20 or R 21 are substituted by at least one C 1 -C 6 linear alkyl group, phenyl group or
wherein Z 1 is lower alkyl, —OH, lower alkoxy, —CF 3 , —NO 2 , —NH 2 , or halogen.
105. The compound of claim 104 , 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.
106. The compound of claim 105 , 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.
107. The compound of claim 104 , wherein Y is in the 5 position.
108. The compound of claim 104 , wherein Y is in the 6 position.
109. The compound of claim 104 , wherein Y is selected from the group consisting of hydrogen, chlorine, bromine and fluorine.
110. The compound of claim 109 , wherein Y is fluorine.
111. The compound of claim 110 , wherein Y is in the 6 position.
112. The compound of claim 104 , wherein p is 2 , X is —O—, and Y is selected from the group consisting of lower alkoxy, hydroxy and halogen groups.
113. The compound of claim 112 , wherein Y is a methoxy group.
114. The compound of claim 104 , wherein R is selected from the group consisting of hydrogen, C 1 -C 3 alkyl, C 1 -C 3 alkoxy, hydroxyl, —COCF 3 , C 1 -C 6 alkanoyl, Cl, F, Br, I, C 1 -C 3 alkylamino,
115. A pharmaceutical composition, which comprises a compound as claimed in claim 104 , and pharmaceutically acceptable carrier therefor.
116. A antipsychotic composition which comprises a compound as claimed in claim 104 , in an amount sufficient to produce an antipsychotic effect, and a pharmaceutically acceptable carrier therefor.
117. A method of treating psychoses, which comprises administering to a mammal a psychoses- treating effective amount of a compound as claimed in claim 104 .
118. An analgesic composition which comprises a compound as claimed in claim 104 , in an amount sufficient to produce a pain- relieving effect, and a pharmaceutically acceptable carrier therefor.
119. A method of alleviating pain, which comprises administering to a mammal a pain- relieving effective amount of a compound as claimed in claim 104 .
120. A compound as claimed in claim 87 , with the proviso that when m is 3 , R is not —C(═ O )- aryl, or —C ( ═O )- heteroaryl, all geometric, optical and stereoisomers thereof, or a pharmaceutically acceptable acid addition salt thereof.
121. A pharmaceutically composition, which comprises a compound as claimed in claim 120 , and a pharmaceutically acceptable carrier therefor.
122. An antipsychotic composition which comprises a compound as claimed in claim 120 , in an amount sufficient to produce an antipsychotic effect, and a pharmaceutically acceptable carrier therefor.
123. A method of treating psychoses, which comprises administering to a mammal a psychoses- treating effective amount of a compound as claimed in claim 120 .
124. An analgesic composition which comprises a compound as claimed in claim 120 , in an amount sufficient to produce a pain- relieving effect, and a pharmaceutically acceptable carrier therefor.
125. A method of alleviating pain, which comprises administering to a mammal a pain- relieving effective amount of a compound as claimed in claim 120 .
126. A compound as claimed in claim 104 , with the proviso that when m is 3 , R is not —C( ═O )- aryl, or —C (═ O )- heteroaryl, all geometric, optical and stereoisomers thereof, or a pharmaceutically acceptable acid addition salt thereof.
127. A pharmaceutical composition, which comprises a compound as claimed in claim 126 , and a pharmaceutically acceptable carrier therefor.
128. An antipsychotic composition which comprises a compound as claimed in claim 126 , in an amount sufficient to produce an antipsychotic effect, and a pharmaceutically acceptable carrier therefor.
129. A method of treating psychoses, which comprises administering to a mammal a psychoses- treating effective amount of a compound as claimed in claim 126 .
130. An analgesic composition which comprises a compound as claimed in claim 126 , in an amount sufficient to produce a pain- relieving effect, and a pharmaceutically acceptable carrier therefor.
131. A method of alleviating pain, which comprises administering to a mammal a pain- relieving effective amount of a compound as claimed in claim 126 .
132. A compound of formula
wherein
X is —O— or —S—;
p is 1 or 2 ;
Y is hydrogen, lower alkyl, hydroxy, chorine, 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—;
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, dialkylaminocarbonyl, formyl, —C ( ═O )- alkyl, —C ( ═O )- O - alkyl, —C ( ═O )- aryl, —C ( ═O )- heteroaryl, —CH ( OR 7 )- alkyl, —C ( ═W )- alkyl, —C (═ W )- aryl, or —C ( ═W )- heteroaryl;
wherein alkyl is lower alkyl;
aryl is phenyl or
wherein R 5 is hydrogen, lower alkyl, lower alkoxy, hydroxy, chlorine, fluorine, bromine, iodine, lower monoalkylamino, nitro, cyano, trifluoromethyl, or trifluoromethoxy;
heteroaryl is
wherein Q 3 is —O—, —S—, —NH—, or —CH═N—;
W is CH 2 or CHR 8 or N—R 9 ;
R 7 is hydrogen, lower alkyl, or acyl;
R 8 is lower alkyl;
R 9 is hydroxy, lower alkoxy, or —NHR 10 ; and
R 10 is hydrogen, lower alkyl, C 1 -C 3 acyl, aryl, —C ( ═O )- aryl or —C ( ═O )- heteroaryl;
wherein aryl and heteroaryl are as defined above; and
m is 1 , 2 , or 3 ;
with the proviso that at least one R is selected from the group consisting of dialkylaminocarbonyl, formyl, —C ( ═W )- alkyl, —C ( ═W )- aryl, and —C ( ═W )- heteroaryl;
all geometric, optical and stereoisomers thereof, or a pharmaceutically acceptable acid addition salt thereof.
133. The compound of claim 132 , 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.
134. The compound of claim 133 , 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, furmaric acid, carboxysuccinic acid, and citric acid.
135. The compound of claim 132 , wherein Y is in the 5 position.
136. The compound of claim 132 , wherein Y is in the 6 position.
137. The compound of claim 132 , wherein Y is selected from the group consisting of hydrogen, chlorine, bromine and fluorine.
138. The compound of claim 137 , wherein Y is fluorine.
139. The compound of claim 138 , wherein Y is in the 6 position.
140. The compound of claim 132 , wherein p is 2 , X is —O—, and Y is selected from the group consisting of lower alkoxy, hydroxy and halogen groups.
141. The compond of claim 140 , wherein Y is a methoxy group.
142. The compound of claim 132 , wherein one R group is selected from the group consisting of hydrogen, C 1 -C 3 alkyl, C 1 -C 3 alkoxy, hydroxyl, —COCF 3 , C 1 -C 6 alkanoyl, Cl, F, Br, I, C 1 -C 3 alkylamino,
143. A pharmaceutical composition, which comprises a compound as claimed in claim 132 , and a pharmaceutical acceptable carrier therefor.
144. An antipsychotic composition which comprises a compound as claimed in claim 132 , in an amount sufficient to produce an antipsychotic effect, and a pharmaceutically acceptable carrier therefor.
145. A method of treating psychoses, which comprises administering to a mammal a psychoses- treating effective amount of a compound as claimed in claim 132 .
146. An analgesic composition which comprises a compound as claimed in claim 132 , in an amount sufficient to produce a pain- relieving effect, and a pharmaceutically acceptable carrier therefor.
147. A method of alleviating pain, which comprises administering to a mammal a pain- relieving effective amount of a compound as claimed in claim 132 .