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Heteroarylpiperidines, and their use as antipsychotics and analgetics |
| RE39265 |
Heteroarylpiperidines, and their use as antipsychotics and analgetics
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| Patent Drawings: | |
| Inventor: |
Strupczewski, et al. |
| Date Issued: |
September 5, 2006 |
| Application: |
09/708,475 |
| Filed: |
November 9, 2000 |
| Inventors: |
Bordeau; Kenneth J. (Kintnersville, PA)
Chiang; Yulin (Convent Station, NJ)
Glamkowski; Edward J. (Warren, NJ)
Helsley; Grover C. (Stockton, NJ)
Strupczewski; Joseph T. (Flemington, NJ)
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| Assignee: |
Aventis Pharmaceuticals Inc. (Bridgewater, NJ) |
| Primary Examiner: |
Coleman; Brenda |
| Assistant Examiner: |
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| Attorney Or Agent: |
Synnestvedt & Lechner LLP |
| U.S. Class: |
514/217; 514/233.8; 514/234.5; 514/249; 514/253.09; 514/253.1; 514/254.04; 514/254.06; 514/258.1; 514/269; 514/274; 514/296; 514/300; 514/301; 514/307; 514/309; 514/311; 514/312; 514/314; 514/321; 514/322; 514/373; 514/379; 514/403; 514/411; 540/576; 540/588; 544/121; 544/129; 544/132; 544/135; 544/137; 544/279; 544/295; 544/316; 544/317; 544/318; 544/333; 544/353; 544/361; 544/362; 544/364; 544/366; 544/367; 544/368; 544/371; 546/100; 546/113; 546/122; 546/135; 546/141; 546/142; 546/143; 546/144; 546/146; 546/148; 546/149; 546/153; 546/155; 546/156; 546/157; 546/158; 546/183; 546/198; 546/199; 546/271.1; 546/272.1; 546/98; 546/99; 548/110; 548/207; 548/209; 548/219; 548/221; 548/241; 548/361.1; 548/362.5; 548/363.1 |
| Field Of Search: |
514/253.09; 514/253.1; 514/254.04; 514/254.06; 544/364; 544/368; 544/371 |
| International Class: |
A61P 25/04; A61K 31/44; A61K 31/495; A61K 31/55; A61K 31/505; C07D 221/04; C07D 401/04; C07D 403/04; C07D 417/04; C07D 419/04 |
| U.S Patent Documents: |
3950527; 4355037; 4458076; 4590196; 4670447; 4745117; 4780466; 4880930; 4937249; 4954503; 4968792; 4999356; 5001134; 5364866 |
| Foreign Patent Documents: |
353 0089; 2 503 816; 0 261 688; 0 013 612; 0 135 781; 0 196 096; 0 302 423; 0 314 098; 0 329 168; 0 353 821; 0 357 134; 0 398 425; 0 402 644; 0 464 846; 0 542 136; 2 163 432; 233 710; 233 503; 233 525; WO93/09012; WO 93/16073; WO94/18196 |
| Other References: |
Fuller, R.W., Drugs Acting on Serotonergie Neuronal Systems, Biology of Serotonergic Transmission, John Wiley & Sons Ltd., 1982, pp. 221-247.cit- ed by other. |
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| 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. |
| Claim: |
What is claimed is:
1. A compound of the formula: ##STR00166## wherein, X is --O--, --S--, --NH--, --N(R.sub.2) or ##STR00167## R.sub.2 is selected from the group consisting of lower alkyl, aryllower alkyl, aryl, (C.sub.3-C 10) cycloalkyl, aroyl, (C.sub.2-C.sub.11) alkanoyl, and phenylsulfonyl groups; aryl is as defined hereinafter; p is 1 or 2; Y is hydrogen, lower alkyl, hydroxy, chlorine, fluorine, bromine, iodine, lower alkoxy,trifluoromethyl, nitro, or amino, when p is 1; Y is lower alkoxy 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.5, 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.dbd.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.dbd.C--CH.sub.2--CH.sub.2--, or --CH.sub.2--CH.sub.2--C.dbd.CH.sub.2--, the --CH--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 ##STR00168## where Z.sub.1 is lower alkyl, --OH, lower alkoxy, --CF.sub.3,--NO.sub.2, --NO.sub.2, or halogen, p is as previously defined; R is hydrogen, lower alkyl, lower alkoxy, hydroxyl, carboxyl, chlorine, fluorine, bromine, iodine, amino, lower mono a 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, or --CH(OR.sub.7)-alkyl,; --C(.dbd.W)-alkyl,--C(.dbd.W)-aryl, or --C(.dbd.W)-heteroaryl; wherein alkyl is lower alkyl; aryl is phenyl or ##STR00169## wherein R.sub.5 is hydrogen, lower alkyl, lower alkoxy, hydroxy, chlorine, fluorine, bromine, iodine, lower monoalkylamino, lower dialkylamino,nitro, cyano, trifluoromethyl, or trifluoromethoxy; heteroaryl is ##STR00170## Q.sub.3 is --O--, --S--, --NH--, or --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 ; lower alkyl--(C.dbd.O)--; R.sub.8 is lower alkyl; R.sub.9 is hydroxy, alkoxy, or --NRF.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; with the exclusion of compounds wherein X is O or S, Y is hydrogen, and R is hydrogen, C.sub.1=14 C.sub.4 C.sub.1-C.sub.4 alkyl, chlorine, fluorine, bromine, iodine, cyano, C.sub.1-C.sub.4 alkoxy, or --COOR.sub.23 where R.sub.23 is H or C.sub.1-C.sub.4alkyl; with the exclusion of compounds wherein X is --S--, R.sub.1 is R.sub.20, R is H, and m=1; all geometric, optical, and stereoisomers thereof, or a pharmaceutically acceptable acid addition salt thereof.
2. A compound as claimed in claim 1, wherein X is --O--, --S--, or --NH--.
3. A compound as claimed in claim 1, wherein Y is hydrogen, chlorine, bromine, or fluorine.
4. A compound as claimed in claim 1, wherein n is 2, 3, or 4.
5. A compound as claimed in claim 1, wherein X is --O --.
6. A compound as claimed in claim 1, wherein X is --S--.
7. A compound as claimed in claim 1, wherein X is --NH--.
8. A compound as claimed is claim 1, wherein X is ##STR00171##
9. A compound as claimed in claim 1, wherein X is --O--, --S--, or --NH--; Y is H, Cl, F, or CF.sub.3; R is selected from the group consisting of hydrogen, C.sub.1-C.sub.3 alkyl, C.sub.1-C.sub.3 alkoxy, --OH, Cl, F, Br, I acyl,C.sub.1-C.sub.3 monoalkylamino, acylamino, --NO.sub.2--, --NO.sub.2, OCF.sub.3, and --CF.sub.3; and n is 2, 3, or 4.
10. A compound as claimed in claim 9, wherein the substituent Y is in the 5- or 5-position.
11. A compound as claimed in claim 10, wherein m is 2.
12. A compound as claimed in claim 10, wherein n is 3.
13. A compound as claimed is claim 10, wherein p is 1.
14. A compound as claimed in claim 1, which is 1-[4-[3-[4-(1H-indazol-3-yl)-1-piperazinyl]propoxy]-3-methoxyphenyl]ethan- one or a pharmaceutically acceptable acid addition salt thereof.
15. A compound as claimed in claim 1, which is 1-[4-[4-[4-(1H-indazol-3-yl)-1-piperazinyl]butoxy[-3-methoxyphenyl]ethano- ne fumarate or a pharmaceutically acceptable acid addition salt thereof.
16. A compound as claimed in claim 1, which is 1-[4-(3-[4-(6-fluoro-1H-indazol-3-yl)-1-piperazinyl]propoxy]-3-methoxyphe- nyl]ethanone or it pharmaceutically acceptable acid addition salt thereof.
17. A compound as claimed in claim 1, which is 1-[4-[4-[4-(6-fluoro-1H-indazol-3-yl)-1-piperazinyl]butoxy]-3-methoxyphen- yl]ethanone or a pharmaceutically acceptable acid addition salt thereof.
18. A compound as claimed in claim 1, which is 1-[4-[3-[4-(6-chloro-1H-indazol-3-yl)-1-piperazinyl]propoxy]-3-methoxyphe- nyl]ethanone or a pharmaceutically acceptable acid addition salt thereof.
19. A compound as claimed in claim 1, which is 1-[4-[4-[4-(1,2-benzisothiazol-3-yl)-1-piperazinyl]butoxy]-3-methoxypheny- l]ethanone or a pharmaceutically acceptable acid addition salt thereof.
20. A compound as claimed in claim 1, which is 1-[4-[3-[4-(1-benzoyl-6-fluoro-1H-indazol-3-yl)-1-piperazinyl]-propoxy]-3- -methoxyphenyl]ethanone sesquifumarate or a pharmaceutically acceptable acid addition salt thereof.
21. A compound as claimed in claim 1, which is 1-[4-[4-[4-(6-chloro-1H-indazol-3-yl)-1-piperazinyl]butoxy]-3-methoxyphen- yl]ethanone or a pharmaceutically acceptable acid addition salt thereof.
22. A compound as claimed in claim 1, which is 1-[4-[3-[4-(1,2-benzisothiazol-3 yl)-1-piperazinyl]propoxy]-3-methoxyphenyl]ethanone hemifumarate or a pharmaceutically acceptable acid addition salt thereof.
23. A compound as claimed in claim 1, which is 1-[4-[2-(4-(1,2-benzisothiazol-3-yl)-1-piperazinyl)ethoxy)-3-methoxypheny- l]ethanone or a pharmaceutically acceptable acid addition salt thereof.
24. A compound as claimed in claim 1, which is 1-[4-[2-[4-(6-chloro-1H-indazol-3-yl)-1 piperazinyl]ethoxy]-3-methoxyphenyl]ethanone or a pharmaceutically acceptable acid addition salt thereof.
25. A compound of the formula: ##STR00172## wherein X is --O--, --S--, --NH--, or --N--R.sub.2 ##STR00173## p is 1 or 2; Y is hydrogen, Cl, Br, or F when p is 1; Y is lower alkoxy or halogen when p is 2 and X is --O--; R.sub.2 is selectedfrom the group consisting of lower alkyl, aryl lower alkyl, aryl, (C.sub.3-C.sub.10) cycloalkyl, aroyl, (C.sub.2-C.sub.11) alkanoyl, and phenyl sulfonyl phenylsulfonyl groups; aryl is phenyl or ##STR00174## wherein R.sub.5 is hydrogen, lower alkyl,lower alkoxy, hydroxy, chlorine, fluorine, bromine, iodine, lower monoalkylamino, lower dialkylamino, nitro, cyano, trifluoromethyl, or trifluoromethoxy; n is 2, 3, or 4; R is hydrogen, C.sub.1-C.sub.3 alkyl, C.sub.1-C.sub.3 alkoxy, hydroxyl, acyl,(C.sub.2-C.sub.11) alkanoyl, Cl, F, Br, I, amino, C.sub.1-C.sub.3 mono- or dialkylamino, acylamino, --NO.sub.2, --OCF.sub.3, --CF.sub.3, --C(.dbd.O)-alkyl, or --CH(OR.sub.7)-alkyl alkyl is lower alkyl; R.sub.7 is hydrogen, lower alkyl, or aryl; and mis 1, 2, or 3; with the exclusion of compounds wherein X is --O-- or --S--, Y is hydrogen, and R is hydrogen, C.sub.1-C.sub.3 alkyl, chlorine, fluorine, bromine, iodine, or C.sub.1-C.sub.3 alkoxy; with the exclusion of compounds wherein X is --S--, Ris H, and m=1; or a pharmaceutically acceptable acid addition salt thereof.
26. A compound of the formula; ##STR00175## wherein X is --O-- p is 1 or 2; Y is hydrogen, hydroxy, Cl, Br, or F, when p is 1; Y is lower alkoxy, hydroxy, or halogen when p is 2; n is 2, 3, or 4; R is hydrogen, C.sub.1-C.sub.3 alkyl,C.sub.1-C.sub.3 alkoxy, hydroxyl, acyl, (C.sub.2-C.sub.11) alkanoyl, Cl, F, Br, I, amino, C.sub.1-C.sub.3 mono- or dialkylamino, acylamino, --NO.sub.2, --OCF.sub.3, --CF.sub.3, --C(.dbd.O)--alkyl, or --CH(OR.sub.7)--alkyl , ; alkyl is lower alkyl; R.sub.7 is hydrogen, lower alkyl, or acyl; and m is 1, 2, or 3; with the exclusion of compounds wherein Y is hydrogen, C.sub.1-C.sub.3 alkyl, chlorine, fluorine, bromine, iodine, or C.sub.1-C.sub.3 alkoxy; or a pharmaceutically acceptable acidaddition salt thereof.
27. A compound of the formula: ##STR00176## wherein X is --S--; p is 1or 2 ; Y is hydrogen. Cl, Br, or F, when p is 1 ; Y is lower alkoxy or halogen when p is 2; n is 2, 3, or 4; R is hydrogen, C.sub.1-C.sub.3 alkyl, C.sub.1-C.sub.3alkoxy, hydroxyl, acyl, (C.sub.2-C.sub.11) alkanoyl, Cl, F, Br, I, amino, C.sub.1-C.sub.3 mono- or dialkylamino, acylamino, --NO.sub.2, --OCF.sub.3, --CF.sub.3, --C(.dbd.O)--alkyl, or --CH(OR.sub.7)--alkyl, ; alkyl is lower alkyl; R.sub.7 is hydrogen,lower alkyl, or aryl; and m is 1, 2, or 3; with the exclusion of compounds wherein Y is hydrogen and R is hydrogen, C.sub.1-C.sub.3 alkyl, chlorine, fluorine, bromine, iodine, or C.sub.1-C.sub.3 alkoxy; with the exclusion of compounds wherein R is H,and m=1; or a pharmaceutically acceptable acid addition salt thereof.
28. A compound of the formula: ##STR00177## wherein X is --NH--; p is 1or 2 ; Y is hydrogen, Cl, Br, or F, when p is 2; Y is lower alkoxy or halogen when p is 2; n is 2, 3, or 4; R is hydrogen, C.sub.1-C.sub.3 alkyl, C.sub.1-C.sub.3alkoxy, hydroxyl, acyl, (C.sub.2-C.sub.11) alkanoyl, Cl, F, Br, I, amino, C.sub.1-C.sub.3 mono- or dialkylamino, acylamino, --NO.sub.2, --OCF.sub.3, --CF.sub.3, --C(.dbd.O)--alkyl, or --CH(OR.sub.7)--alkyl, ; alkyl is lower alkyl; R.sub.7 is hydrogen,lower alkyl, or acyl; and m is 1, 2, or 3; or a pharmaceutically acceptable acid addition salt thereof.
29. A compound of the formula: ##STR00178## wherein X is ##STR00179## p is 1 or 2 ; Y is hydrogen, Cl, Br, or F, when p is 1 ; Y is lower alkoxy or halogen when p is 2 ; R.sub.2 is selected from the group consisting of lower alkyl, aryl,lower alkyl, aryl, (C.sub.3-C.sub.10) cycloalkyl, aroyl, (C.sub.2-C.sub.11) aroyl, alkanoyl, and phenylsulfonyl groups; aryl is phenyl or ##STR00180## wherein R.sub.5 is hydrogen, lower alkyl, lower alkoxy, hydroxy, chlorine, fluorine, bromine, iodine,lower monoalkylamino, lower dialkylamino, nitro, cyano, trifluoromethyl, or trifluoromethoxy; n is 2, 3, or 4; R is hydrogen, C.sub.1-C.sub.3 alkyl, C.sub.1-C.sub.3 alkoxy, hydroxyl, acyl, (C.sub.2-C.sub.11) alkanoyl, Cl, F, Br, I, amino,C.sub.1-C.sub.3 mono- or dialkylamino, acylamino, --NO.sub.2, --OCF.sub.3, --CF.sub.3, --C(.dbd.O)-alkyl, or --CH(OR.sub.7)-alkyl, ; alkyl is lower alkyl; R.sub.7 is hydrogen, lower alkyl, or acyl; and m is 1, 2, or 3; or a pharmaceuticallyacceptable acid addition salt thereof.
30. A pharmaceutical composition, which comprises a compound of the formula: ##STR00181## wherein X is --O--, --S--, or ##STR00182## R.sub.2 is selected from the group consisting of lower alkyl, aryl lower alkyl, aryl, (C.sub.3-C.sub.10)cycloalkyl, aroyl, (C.sub.2-C.sub.11) alkanoyl, and phenylsulfonyl groups; 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 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--CH.sub.2--, --CH.sub.2--C.dbd.CH--CH.sub.2--,--CH.sub.2--CH.dbd.CH.sub.2--CH.sub.2--, --CH.sub.2--CH.sub.2--CH.dbd.CH--CH.sub.2--, --CH.sub.2--C.dbd.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 1iS R.sub.20 or R.sub.21in which one or more carbon atoms of R.sub.20 or R.sub.21 are substituted by at least on C.sub.1-C.sub.6 linear alkyl group, phenyl group, or ##STR00183## where Z.sub.1 is lower alkyl, --OH, lower alkoxy, --CF.sub.3, --NO.sub.2, --NH.sub.2 or halogen,and p as previously defined; R is hydrogen, lower alkyl, lower alkoxy, hydroxyl, carboxyl, chlorine, fluorine, bromine, iodine, amino, lower mono or dialkylamino, nitro, lower alkyl thio, trifluoromethoxy, cyano, acylamino, trifluoromethyl,trifluoroacetyl, aminocarbonyl, monoalkylaminocarbonyl, dialkylaminocarbonyl, formyl, --C(.dbd.O)--alkyl, --C(.dbd.O)--O--alkyl, --C(.dbd.O)--aryl, --C(.dbd.O)--heteroaryl, or--CH(OR.sub.2)--alkyl, ; --C(.dbd.W)--alkyl, --C(.dbd.W)--aryl, or--C(.dbd.W)--heteroaryl; alkyl is lower alkyl; aryl is phenyl or ##STR00184## where R.sub.5 is hydrogen, lower alkyl, lower alkoxy, hydroxy, chlorine, fluorine, bromine, iodine, lower monoalkylamino, lower dialkylamino, nitro, cyano, trifluoromethyl,or trifluoromethoxy; heteroaryl is ##STR00185## Q.sub.3 is --O--, --S--, NH--, or --CH.dbd.K--; W is CH.sub.2 or CHR.sub.8, or --N.dbd.R.sub.9; R.sub.7 is hydrogen, lower alkyl, or (C.sub.2-C.sub.11) alkanoyl lower alkyl--(C.dbd.O)--, R.sub.8 is loweralkyl; R.sub.9 is hydroxy, alkoxy, or --NHR.sub.10; and R.sub.10 is hydrogen, lower alkyl, C.sub.1-C.sub.3 acyl, aryl, --C(.dbd.O)--aryl or --C(.dbd.O)--heteroaryl, where aryl and heteroaryl are as defined above; and m is 1, 2, or 3; with theexclusion of compounds wherein X is O or S, Y is hydrogen, and R is hydrogen, C.sub.1-C.sub.4 alkyl, chlorine, fluorine, bromine, iodine, cyano, C.sub.1-C.sub.4 alkoxy, or --COOR.sub.23 where R.sub.23 is H or C.sub.1-C.sub.3 alkyl; with the exclusion ofcompounds wherein X is --S--, R.sub.1 is R.sub.20, R is H, and m=1; all geometric, optical, and stereoisomers thereof, or a pharmaceutically acceptable acid addition salt thereof, and a pharmaceutically acceptable carrier therefor.
31. An antipsychotic composition, which comprises a compound of the formula: ##STR00186## wherein X is --O--, --S--, --NH--, or ##STR00187## R.sub.1 is selected from the group consisting of lower alkyl, aryl lower alkyl, aryl (C.sub.3-C.sub.10)cycloalkyl, aroyl, (C.sub.2-C.sub.11) alkanoyl, and phenylsulfonyl groups; 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 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.dbd.C--CH2--,--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.dbd.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 orR.sub.21 in which one or more carbon atoms of R.sub.20 or R.sub.21 are substituted by at least on C.sub.1-C.sub.6 linear alkyl group, phenyl group, or ##STR00188## where Z.sub.1 is lower alkyl, --OH, lower alkoxy, --CF.sub.3, --NO.sub.2, --NH.sub.2 orhalogen, a p is as previously defined; R is hydrogen, lower alkyl, lower alkoxy, hydroxyl, carboxyl, chlorine, fluorine, bromine, iodine, amino, lower mono or dialkylamino, nitro, lower alkyl thio, trifluoromethoxy, cyano, acylamino, trifluoromethyl,trifluoroacetyl, aminocarbonyl, monoalkylaminocarbonyl, dialkylaminocarbonyl, formyl, --C(.dbd.O)--aryl, --C(.dbd.O)--O--alkyl, --C(.dbd.O)--aryl, --C(.dbd.O)--heteroaryl, or --CH(OR.sub.7)--alkyl, ; --C(.dbd.W)--alkyl, --C(.dbd.W)--aryl, or--C(.dbd.W)--heteroaryl; alkyl is lower alkyl; aryl is phenyl or ##STR00189## 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 ##STR00190## Q.sub.3 is --O--, --S--, --NH--, or --CH.dbd.N--; W is CH.sub.2 or CH.sub.8 or N--R.sub.9; R.sub.7 is hydrogen, lower alkyl, or (C.sub.2-C.sub.11) alkanoyl lower alkyl--(C.dbd.O)--; R.sub.8 is lower alkyl; R.sub.9 is hydroxy, alkoxy, or --NHR.sub.10; and R.sub.10 is hydrogen, lower alkyl, C.sub.1-C.sub.3 acyl, aryl, --C(.dbd.O)--aryl or C(.dbd.O)--heteroaryl, where aryl and heteroaryl are as defined above; and m is 1, 2, or 3; with the exclusion ofcompounds wherein X is O or S, Y is hydrogen, and R is hydrogen, C.sub.1-C.sub.4 alkyl, chlorine, fluorine, bromine, iodine, cyano, C.sub.1-C.sub.4 alkoxy, or --COOR.sub.23 where R.sub.23 is H or C.sub.1-C.sub.4 alkyl; with the exclusion of compoundswherein X is --S--, R.sub.1 is R.sub.20, R is H, and m=1; all geometric, optical, and stereoisomers thereof, or a pharmaceutically acceptable acid addition salt thereof, in an amount sufficient to produce an antipsychotic effect, and a pharmaceuticallyacceptable carrier therefor.
32. A method of treating psychoses, which comprises administering to a mammal a psychoses-treating effective amount of a compound of the formula: ##STR00191## wherein X is --O--, --S--, --NH--, or ##STR00192## R.sub.2 is selected from the groupconsisting of lower alkyl, aryl lower alkyl, aryl, (C.sub.3-C.sub.10) cycloalkyl, aroyl, (C.sub.2-C.sub.11) alkanoyl, and phenylsulfonyl groups; where aryl is as defined hereinafter; p is 1 or 2; Y is hydrogen, lower alky, hydroxy, chlorine, fluorine,bromine, iodine, lower alkoxy, trifluoromethyl, nitro, or amino, when p is 1; Y is lower alkoxy 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.dbd.C--CH2--, --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.dbd.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.22 are substitutes by at least on C.sub.1-C.sub.6 linear alkyl group, phenyl group, or ##STR00193## where Z.sub.1 is loweralkyl, --OH, lower alkoxy, --CF.sub.3, NO.sub.2, --NH.sub.2 or halogen, and p is as previously defined; R is hydrogen, lower alkyl, lower alkoxy, hydroxyl, carboxyl, chlorine, fluorine, bromine, iodine, amino, lower mono or dialkylamino, nitro, loweralkyl thio, trifluoromethoxy, cyano, acylamino, trifluoromethyl, trifluoroacetyl, aminocarbonyl, monoalkylaminocarbonyl, dialkylaminocarbonyl, formyl, --(.dbd.O)--alkyl, --C(.dbd.O)--O--alkyl, --C(.dbd.O)--aryl, --C(.dbd.O)--heteroaryl, or--CH(OR.sub.7)--alkyl, ; --C(.dbd.W)--alkyl, --C(.dbd.W)--aryl, or --C(.dbd.W)--heteroaryl; wherein alkyl is lower alkyl; aryl is phenyl or ##STR00194## wherein R.sub.5 is hydrogen, lower alkyl, lower alkoxy, hydroxy, chlorine, fluorine, bromine,iodine, lower monoalkylamino, lower dialkylamino, nitro, cyano trifluoromethyl, or trifluoromethoxy; heteroaryl is ##STR00195## Q.sub.3 is --O--, --S--, --NH--, or --CH.dbd.N--; W is CH.sub.2 or CHR.sub.8 or --N--R.sub.9; R.sub.7 is hydrogen, loweralkyl, or (C.sub.2-C.sub.11) alkanoyl; lower alkyl--(C.dbd.O)--; R.sub.8 is lower alkyl; R.sub.9 is hydroxy, alkoxy, or --NHR.sub.10; and R.sub.10 is hydrogen, lower alkyl, C.sub.1-C.sub.3 acyl, aryl, --C(.dbd.O)--aryl or --C(.dbd.O)--heteroaryl,where aryl and heteroaryl are as defined above; and m is 1, 2, or 3; with the exclusion of compounds wherein X is O or S, Y is hydrogen, and R is hydrogen, C.sub.1-C.sub.4 alkyl, chlorine, fluorine, bromine, iodine, cyano, C.sub.1-C.sub.4 alkoxy, or--COOR.sub.23 wherein R.sub.23 is H or C.sub.1-C.sub.4 alkyl; with the exclusion of compounds wherein X is --S--, R.sub.1 is R.sub.20, R is H, and m=1; all geometric, optical, and stereoisomers thereof, or a pharmaceutically acceptable acid additionsalt thereof.
33. An analgesic composition, which comprises a compound of the formula: ##STR00196## wherein, X is --O --, --S--, --NH--, or --N(R.sub.2) ##STR00197## R.sub.2 is selected from the group consisting of lower alkyl, aryl lower alkyl, aryl,(C.sub.3-C.sub.10) cycloalkyl, aroyl, (C.sub.2-C.sub.11) alkanoyl, sad 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 when p is 2 and X is --O--; R.sub.7 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.dbd.C--CH2--, --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.dbd.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 on C.sub.1-C.sub.6 linear alkyl group, phenyl group, or ##STR00198## where Z.sub.1, lower alkyl, --OH, lower alkoxy, --CF.sub.3,--NO.sub.2, --NH.sub.2 or halogen, and p is as previously defined; R is hydrogen, lower alkyl, lower alkoxy, hydroxyl, carboxyl, chlorine, fluorine, bromine, iodine, amino, lower mono at 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, or --CH(OR.sub.7)--alkyl, ; --C(.dbd.W)--alkyl,--C(.dbd.W)--aryl, or --C(.dbd.W)--heteroaryl; wherein alkyl is lower alkyl; aryl is phenyl or ##STR00199## wherein R.sub.5 is hydrogen, lower alkyl, lower alkoxy, hydroxy, chlorine, fluorine, bromine, Iodine, lower monoalkylamino, lower dialkylamino,nitro, cyano, trifluoromethyl, or trifluoromethoxy; heteroaryl is ##STR00200## wherein Q.sub.3 is --O --, --S--, --NH--, or --CH.dbd.N--; W is CH.sub.2 or CHR.sub.8 or N--R.sub.9; R.sub.7 is hydrogen, lower alkyl, or (C.sub.2-C.sub.11) alkonyl loweralkyl--(C.dbd.O)--; R.sub.8 is lower alkyl; R.sub.9 is hydroxy, alkoxy, or --NHR.sub.10; and R.sub.10 is hydrogen, lower alkyl, C.sub.1-C.sub.3 acyl, aryl, --C(.dbd.O)--aryl, or --C(.dbd.O)--heteroaryl, where aryl and heteroaryl arc as defined above; and m is 1, 2, or 3; with the exclusion of compounds wherein X is O or S, Y is hydrogen, and R is hydrogen C.sub.1--C.sub.4 alkyl, chlorine, fluorine, bromine, iodine, cyano, C.sub.1-C.sub.4 alkoxy, or --COOR.sub.23 wherein R.sub.7 is H orC.sub.1-C.sub.4 alkyl; with the exclusion of compounds wherein X is --S--, R.sub.1 is R.sub.20, m=1; all geometric, optical, and stereoisomers thereof, or a pharmaceutically acceptable acid addition salt thereof, in an amount sufficient to produce apain-relieving effect and a pharmaceutically acceptable carrier therefor.
34. A method of alleviating pain, which comprises administering to a mammal a pain-relieving effective amount of a compound composition as claimed in claim 33.
35. A pharmaceutical composition, which comprises a compound as claimed in claim 1, 25, 26, 27, 28, or 29, and a pharmaceutically acceptable carrier therefor.
36. An, antispsychotic antipsychotic composition, which comprises a compound as claimed in claim 1, 25, 26, 27, 28, or 29, in an amount sufficient to produce an antipsychotic effect, and a pharmaceutically acceptable carrier therefor.
37. A method of treating psychoses, which comprises administering to a mammal a psychoses-treating effective amount of a compound as claimed in claim 1, 25, 26, 27, 29 28 or 29.
38. An analgesic composition, which comprises a compound as claimed in claim 1, 25, 26, 27, 28, or 29, in an amount sufficient to producer a pain-relieving effect, and a pharmaceutically acceptable carrier therefor.
39. A method of alleviating pain which comprises administering to a mammal a pain-relieving effective amount of a compound as claimed in 1, 25, 26, 27, 28, or 29.
40. An antipsychotic composition, which comprises a compound as claimed in claim 1, in an amount sufficient to produce an antipsychotic effect, and a pharmaceutically acceptable carrier therefor.
41. A method of treating psychoses, which comprises administering to a mammal a psychoses-treating effective amount of a compound as claimed in claim 1.
42. An analgesic composition, which comprises a compound as claimed in claim 1, in an amount sufficient to produce a pain-relieving affect and a pharmaceutically acceptable carrier therefor.
43. A method of alleviating pain, which comprises administering to a mammal a pain-relieving effective amount of a compound as claimed in 1.
44. The compound of any one of claims 1, 25, 26, 27, 28, and 29, wherein said pharmaceutically acceptable acid addition salt is selected from the group consisting of salts of mineral acids, salts of monobasic carboxylic acids, salts of dibasiccarboxylic acids, and salts of tribasic carboxylic acids.
45. The compound of claim 44, wherein said pharmaceutically acceptable acid addition salt is selected from the group consisting of salts of hydrochloric acid, sulfuric add, nitric acid, acetic acid, propionic acid, maleic acid, fumaric acid,carboxysuccinic acid, an citric acid.
46. A compound of the formula ##STR00201## wherein X is --O--, --S--, --NH--, or ##STR00202## R.sub.2 is selected from the group consisting of lower alkyl, aryl lower alkyl, aryl(C.sub.3-C.sub.10) cycloalkyl, aroyl, (C.sub.2-C.sub.11) lkanoyl,and phenylsulfonyl groups; aryl is as defined hereinafter; p is 1 or 2: Y 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 pis 2 and X is --O--; (R.sub.1) is --CH.sub.2--CH.dbd.CH--CH.sub.2--, --CH.sub.2--C.dbd.C--CH2--, --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.dbd.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 is hydrogen, lower alkyl, lower alkoxy, hydroxyl, carboxyl, chlorine, fluorine, bromine, iodine, amino, lower mono or dialkylamino, nitro, lower alkyl thio,trifluoromethoxy, cyano, acylamino, fluoromethyl, trifluoroacetyl, aminocarbonyl, dialkylaminocarbonyl, formyl --(.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; wherein alkyl is lower alkyl; aryl is phenyl or ##STR00203## wherein R.sub.5 is hydrogen, lower alkyl, lower alkoxy, hydroxy, chlorine, fluorine, bromine, iodine, lower monoalkylamino, lower dialkylamino, nitro, cyano,trifluoromethyl, or trifluoromethoxy; heteroaryl is ##STR00204## wherein Q.sub.3 is --O--, --S--, --NH--, or --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 lower alkyl--(C.dbd.O)--; R.sub.8 is loweralkyl; 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, wherein aryl and heteroaryl are as defined above; and m is 1, 2, or 3; with theexclusion of compounds wherein X is O or S, Y is hydrogen, and R is hydrogen, C.sub.1-C.sub.4, alkyl, chlorine, fluorine, bromine, iodine cyano, C.sub.1-C.sub.4 alkoxy, or --COOR.sub.23 wherein R.sub.23 is H or C.sub.1-C.sub.4 alkyl; all geometric,optical and stereoisomers thereof, or a pharmaceutically acceptable acid addition salt, thereof.
47. A compound as claimed in claim 46, wherein X is --O--, or --O--, or --NH--.
48. A compound as claimed in claim 46 wherein Y is hydrogen, chlorine , bromine, or fluorine.
49. A compound as claimed in claim 46, wherein X is --O--.
50. A compound as claimed in claim 46, wherein X is --S--.
51. A compound as claimed in claim 46 wherein X is --NH--.
52. A compound as claimed in claim 46 wherein X is ##STR00205##
53. A compound as claimed in claim 46, wherein X is --O--, --S--, or --NH--; Y is H, Cl, F, or --CF.sub.3; R is from the group consisting of hydrogen, C.sub.1-C.sub.3 alkyl, C.sub.1-C.sub.3 alkoxy, --OH, Cl, F, Br, C.sub.1-C.sub.3monoalkylamino, acylamino, --NO.sub.2, --OCF.sub.3, and --CF.sub.3.
54. A compound as claimed in claim 53, wherein the substituent X is in the 5- or 6-position.
55. A compound as claimed in claim 54, wherein m is 2.
56. A compound as claimed in claim 54, wherein p is 1.
57. A pharmaceutical composition, which comprises a compound as claimed in claim 46, and a pharmaceutically acceptable carrier therefor.
58. An antipsychotic composition which comprises a compound as claimed in claim 46, in an amount sufficient to produce an antipsychotic effect, and a pharmaceutically acceptable carrier therefor.
59. A method of treating psychoses, which comprises administering to a mammal a psychoses-treating effective amount of a compound as claimed in claim 46.
60. An analgesic composition which comprises a compound as claimed in claim 46, in an amount sufficient to produce a pain-relieving effect, and a pharmaceutically acceptable carrier therefor.
61. A method of alleviating pain which comprises administering to a mammal a pain-relieving effective amount of a compound as claimed in claim 46.
62. The compound of claim 46, wherein said pharmaceutically acceptable acid addition salt is selected from the group consisting of salts mineral acids, salts of monobasic carboxylic acids, salts of dibasic carboxylic acids, and salts oftribasic carboxylic acids.
63. The compound of claim 62, wherein said pharmaceutically acceptable acid addition salt is selected from the group consisting of salts of hydrochloric acid, sulfuric acid, nitric acid, acetic is acid, propionic acid, maleic acid, fumaricacid, carboxysuccinic acid, and citric acid.
64. A compound of the formula ##STR00206## wherein X is --O--, --S--, --NH--, or ##STR00207## R.sub.2 is selected from the group consisting lower alkyl, aryl lower alkyl, aryl, (C.sub.3-C.sub.10) cycloalkyl, aroyl, (C.sub.2-C.sub.11) alkanoyl,and phenylsulfonyl groups; aryl is as defined hereinafter; p is 1 or 2; Y is hydrogen, lower alkyl, hydroxy, chlorine, fluorine, bromine, iodine, lower alkoxy, trifluoromethyl, nitro or amino, when p is 1; Y is lower alkoxy, alkoxy hydroxy, orhalogen p is 2 and X is --O--; (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.4 linear alkyl group, phenyl group or ##STR00208## wherein Z.sub.1 is lower alkyl,--OH, lower alkoxy, --CF.sub.3, --NO.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.dbd.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.dbd.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 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; wherein alkyl is lower alkyl; aryl is phenyl or ##STR00209## wherein R.sub.5 is hydrogen, lower alkyl,lower alkoxy, hydroxy, chlorine, flourine, bromine, iodine, lower monoalkylamino, lower dialkylamino nitro, cyano, trifluoromethyl or trifluoromethoxy; heteroaryl is ##STR00210## wherein Q.sub.3 is --O--, --S--, --NH--, or --CH.dbd.N--; W is CH.sub.2or CHR.sub.8 or N--R.sub.9; R.sub.7 is hydrogen, lower alkyl, or lower alkyl--(C.dbd.O)--; 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, wherein and heteroaryl are as defined above; and m is 1, 2, or 3; with the exclusion of compounds wherein X is O or S, Y is hydrogen, and R is hydrogen, C.sub.1-C.sub.4 alkyl, chlorine, fluorine, bromine, iodine, cyano,C.sub.1C.sub.4 alkoxy, or --COOR.sub.23 wherein R.sub.23 is H or C.sub.1-C.sub.4 alkyl; with the exclusion of compounds wherein X is --S--, R.sub.1 is R.sub.20, R is H, and m=1; all geometric, optical and stereoisomers thereof, or a pharmaceuticallyacceptable acid addition salt thereof.
65. A compound as claimed in claim 64, wherein X is --O--, --S--, or --NH--.
66. A compound as claimed in claim 64, wherein Y is hydrogen, chlorine, bromine, or fluorine.
67. A compound as claimed in claim 64, wherein n is 2, 3, or 4.
68. A compound and as claimed in claim 64, wherein n is 2, 3, or 4.
69. A compound as claimed in claim 64, wherein X is --S--.
70. A compound as claimed in claim 64, wherein X is --NH--.
71. A compound as claimed in claim 64, wherein X is --N(R.sub.2).
72. A compound as claimed in claim 64, wherein X is --O--, --S--, or --NH--; Y is H, Cl, F, or --CF.sub.3; R is selected from the group consisting of hydrogen, C.sub.2-C.sub.3 alkyl, C.sub.1-C.sub.3 alkoxy, --OH, Cl, F, Br, I, C.sub.1-C.sub.3monoalkylamino, acylamino, --NO.sub.3, --OCF.sub.3, and --CF.sub.3; and n is 2, 3, or 4.
73. A compound claimed in claim 72, wherein the substituent Y is in the 5- or 6-position.
74. A compound as claimed in claim 73, wherein m is 2.
75. A compound as claimed in claim 73, wherein n is 3.
76. A compound as claimed in claim 73, wherein p is 1.
77. A pharmaceutical composition, which comprises a compound as claimed in claim 64, and a pharmaceutically acceptable carrier therefor.
78. An antipsychotic composition which comprises a compound as claimed in claim 64, in an amount sufficient to produce an antipsychotic effect, and a pharmaceutically acceptable carrier therefor.
79. A method of treating psychoses, which comprises a administering to a mammal a psychosis-treating effective amount of a compound as claimed in claim 64.
80. An analgesic composition which comprises a compound as claimed in claim 64, in an amount sufficient to produce a pain-relieving effect and a pharmaceutically acceptable carrier therefor.
81. A method of alleviating pain, which comprises administering a mammal a pain-relieving effective amount of a compound as claimed in claim 64.
82. The compound of claim 64, wherein said pharmaceutically acceptable acid addition salt is selected from the group consisting of salts of mineral acids, salts of monobasic carboxylic acids, salts of dibasic carboxylic is acids, and salts oftribasic carboxylic acids.
83. The compound of claim 82, wherein said pharmaceutically acceptable acid addition salt is selected from the group consisting of salts of hydrochloric acid, sulfuric acid, nitric acid, acetic acid, propionic acid, maleic acid, fumaric acid,carboxysuccinic acid, and citric acid.
84. A pharmaceutical composition, which comprises a compound of the formula ##STR00211## wherein X is --O--, --S--, --NH--, or ##STR00212## R.sub.2 is selected from the group consisting of lower alkyl, aryl lower alkyl, aryl,(C.sub.3-C.sub.10)cycloalkyl, aroyl,(C.sub.2-C.sub.11)alkanoyl, and phenylsulfonyl groups; aryl is defined hereinafter; p is 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 is p is 2 and X is --O--; (R.sub.1) is --CH.sub.2--CH.dbd.CH--CH.sub.2--, --CH.sub.2--C.dbd.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.dbd.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 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 lower alkyl; aryl is phenyl or ##STR00213## where R.sub.5 is hydrogen, lower alkyl, lower alkoxy, hydroxy,chlorine, bromine, iodine, lower monoalkylamino, lower dialkylamino, nitro, cyano, trifluoromethyl, trifluoromethoxy; heteroaryl is ##STR00214## where Q.sub.3 is --O--, --S--, --NH--, or --CH.dbd.N--; W is CH.sub.2 or CHR.sub.8 or N--R.sub.9; R.sub.7is hydrogen, lower alkyl, or lower alkyl--(C.dbd.O)--; 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, wherearyl and heteroaryl are as defined above; and m is 1, 2, or 3; with the exclusion of compounds wherein X is O or S, Y is hydrogen, and R is hydrogen, C.sub.1-C.sub.4, alkyl, chlorine, fluorine, bromine, iodine cyano, C.sub.1-C.sub.4 alkoxy, or--COOR.sub.23 where R.sub.23 is C.sub.1-C.sub.4 alkyl; all geometric, optical and stereoisomers thereof, or a pharmaceutically acceptable acid addition salt thereof, and a pharmaceutically acceptable carrier therefor.
85. A pharmaceutically composition, which comprises a compound of the formula ##STR00215## wherein X is --O--, --S--, --NH--, or ##STR00216## R.sub.3 is selected from the group consisting of lower alkyl, aryl lower alkyl, aryl,(C.sub.3-C.sub.10)cycloalkyl, aroyl,(C.sub.2-C.sub.11) alkanoyl, and phenylsulfonyl groups; aryl is defined hereinafter; p is 1 or 2; Y is hydrogen, lower alkyl, hydroxy, chlorine, fluorine, iodine, lower alkoxy, trifluoromethyl, hydroxy, or amino,when p is 1; Y is lower alkoxy, hydroxy, or halogen when p is 2 and X is --O--; (R.sub.1) s 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 groupor ##STR00217## where Z.sub.1 is lower alkyl, --OH, lower alkoxy, --CF.sub.3, --NO.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.dbd.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.dbd.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 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 lower alkyl; aryl is phenyl or##STR00218## where R.sub.5 is hydrogen, lower alkyl, lower alkoxy, hydroxy, chlorine, flourine, bromine, iodine, lower monoalkylamino, lower dialkylamino nitro, cyano, trifluoromethyl, trifluoromethoxy; heteroaryl is ##STR00219## where Q.sub.3 is --O--,--S--, --NH--, or --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 lower alkyl--(C.dbd.O)--; R.sub.8 is lower alkyl; R.sub.9 is hydroxy, lower alkoxy, or --NHR.sub.10; and R.sub.10 is hydrogen, loweralkyl, C.sub.1-C.sub.3 acyl, aryl, --C(.dbd.O)-aryl, or --C(.dbd.O)-heteroaryl, where and heteroaryl are as defined above; and m is 1, 2, or 3; with the exclusion of compounds wherein X is O or S, Y is hydrogen, and R is hydrogen, C.sub.1-C.sub.4alkyl, chlorine, fluorine, bromine, iodine, cyano, C.sub.1C.sub.4 alkoxy, or --COOR.sub.23 where R.sub.23 is C.sub.1-C.sub.4 alkyl; with the exclusion of compounds wherein X is --S--, R.sub.1 is R.sub.20, R is H, and m=1; all geometric, optical andstereoisomers thereof, or a pharmaceutically acceptable acid addition salt thereof, and a pharmaceutically acceptable carrier therefor.
86. An antipsychotic composition, which comprises a compound of the formula ##STR00220## wherein X is --O--, --S--, --NH--, or ##STR00221## R.sub.2 is selected from the group consisting of lower alkyl, aryl lower alkyl, aryl, (C.sub.3-C.sub.10)cycloalkyl, aroyl,(C.sub.2-C.sub.11) alkanoyl, and phenylsulfonyl groups; aryl is 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--; (R.sub.1) is --CH.sub.2--CH.dbd.CH--CH.sub.2--, --CH.sub.2--C.dbd.C--CH2--, --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.dbd.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 is hydrogen, lower alkyl, lower alkoxy, hydroxyl, carboxyl, chlorine, fluorine, bromine, iodine, amino, lower mono ordialkylamino, 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, 13 C(.dbd.W)-aryl, or --C(.dbd.W)-heteroaryl; where alkyl is lower alkyl; aryl is phenyl or ##STR00222## where R.sub.5 is hydrogen, lower alkyl, lower alkoxy, hydroxy, chlorine, fluorine, bromine, iodine, lowermonoalkylamino, lower dialkylamino, nitro, cyano, trifluoromethyl, trifluoromethoxy; heteroaryl is ##STR00223## where Q.sub.3 is --O--, --S--, --NH--, or --CH.dbd.N--; W is CH.sub.2 or CH.sub.8 or N--R.sub.9; R.sub.7 is hydrogen, lower alkyl, or loweralkyl--(C.dbd.O)--; 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 definedabove; and m is 1, 2 or 3; with the exclusion of compounds wherein X is O or S, Y is hydrogen, and R is hydrogen, C.sub.1-C.sub.4 alkyl, chlorine, fluorine, bromine, iodine, cyano, C.sub.1-C.sub.4 alkoxy, or --COOR.sub.23 where R.sub.23 isC.sub.1-C.sub.4 alkyl; all geometric, optical, and stereoisomers thereof, or a pharmaceutically acceptable acid addition salt thereof, in an amount sufficient to produce an antipsychotic effect, and a pharmaceutically acceptable carrier therefor.
87. An antipsychotic composition, which comprises a compound of the formula ##STR00224## wherein X is --O--, --S--, --NH--, or ##STR00225## R.sub.2 is selected from the group consisting of lower alkyl, aryl lower alkyl, aryl,(C.sub.3-C.sub.10)cycloalkyl, aroyl,(C.sub.2-C.sub.11) alkanoyl, and phenylsulfonyl groups; aryl is defined hereinafter; p is 1 or 2; Y is hydrogen, lower alkyl, hydroxy, chlorine, fluorine, bromine, iodine, lower alkoxy, trifluoromethyl, nitro, oramino, when p is 1; Y is lower alkoxy, hydroxy, or halogen when p is 2 and X is --O--; (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.4 linear alkyl group,phenyl group or ##STR00226## where Z.sub.1 is lower alkyl, --OH, lower alkoxy, --CF.sub.3, --NO.sub.2, or halogen; R.sub.20 is --(CH.sub.2).sub.n--where n is 2, 3, 4 or 5; (R.sub.1) is --CH.sub.2--CH.dbd.CH--CH.sub.2--, --CH.sub.2--C.dbd.C--CH2--,--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.dbd.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 is hydrogen, lower alkyl, loweralkoxy, 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, 13 C(.dbd.W)-aryl, or --C(.dbd.W)-heteroaryl; where alkyl is lower alkyl; aryl is phenyl or ##STR00227## where R.sub.5 ishydrogen, lower alkyl, lower alkoxy, hydroxy, chlorine, fluorine, bromine, iodine, lower monoalkylamino, lower dialkylamino, nitro, cyano, trifluoromethyl, trifluoromethoxy; heteroaryl is ##STR00228## where Q.sub.3 is --O--, --S--, --NH--, or--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 lower alkyl--(C.dbd.O)--; 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.3acyl, 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; with the exclusion of compounds wherein X is O or S, Y is hydrogen, and R is hydrogen, C.sub.1-C.sub.4 alkyl, chlorine,fluorine, bromine, iodine, cyano, C.sub.1-C.sub.4 alkoxy, or --COOR.sub.23 where R.sub.23 is C.sub.1-C.sub.4 alkyl; with the exclusion of compounds wherein X is --S--, R.sub.1 is R.sub.20, R is H, and m=1; all geometric, optical, and stereoisomersthereof, or a pharmaceutically acceptable acid addition salt thereof, in an amount sufficient to produce an antipsychotic effect, and a pharmaceutically acceptable carrier therefor.
88. A method of treating psychoses, which comprises administering to a mammal a psychoses-treating effective amount of a composition as claimed in claim 86.
89. A method of treating psychoses, which comprises administering to a mammal a psychoses-treating effective amount of a composition as claimed in claim 87.
90. An analgesic composition, which comprises a compound of the formula ##STR00229## wherein X is --O--, --S--, --NH--, or ##STR00230## R.sub.2 is selected from the group consisting of lower alkyl, aryl lower alkyl, aryl,(C.sub.3-C.sub.10)cycloalkyl, aroyl,(C.sub.2-C.sub.11) alkanoyl, and phenylsulfonyl groups; aryl is defined hereinafter; p is 1 or 2; Y is hydrogen, lower alkyl, hydroxy, chlorine, fluorine, bromine, iodine, lower alkoxy, trifluoromethyl, nitro, oramino, when p is 1; Y is lower alkoxy, hydroxy, or halogen when p is 2 and X is --O--; (R.sub.1) is --CH.sub.2--CH.dbd.CH--CH.sub.2--, --CH.sub.2--C.dbd.C--CH2--, --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.dbd.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 is hydrogen, lower alkyl, lower alkoxy, hydroxyl, carboxyl, chlorine, fluorine, bromine, iodine, amino, lower mono ordialkylamino, 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, 13 C(.dbd.W)-aryl, or --C(.dbd.W)-heteroaryl; where alkyl is lower alkyl; aryl is phenyl or ##STR00231## where R.sub.5 is hydrogen, lower alkyl, lower alkoxy, hydroxy, chlorine, fluorine, bromine, iodine, lowermonoalkylamino, lower dialkylamino, nitro, cyano, trifluoromethyl, trifluoromethoxy; heteroaryl is ##STR00232## where Q.sub.3 is --O--, --S--, --NH--, or --CH.dbd.N--; W is CH.sub.2 or CHR.sub.8 or N--R.sub.9; R.sub.7 is hydrogen, lower alkyl, orlower alkyl--(C.dbd.O)--; 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.
91. An analgesic composition, which comprises a compound of the formula ##STR00233## wherein X is --O--, --S--, --NH--, or ##STR00234## R.sub.2 is selected from the group consisting of lower alkyl, aryl lower alkyl, aryl,(C.sub.3-C.sub.10)cycloalkyl, aroyl,(C.sub.2-C.sub.11) alkanoyl, and phenylsulfonyl groups; aryl is defined hereinafter; p is 1 or 2; Y is hydrogen, lower alkyl, hydroxy, chlorine, fluorine, bromine, iodine, lower alkoxy, trifluoromethyl, nitro, oramino, when p is 1; Y is lower alkoxy, hydroxy, or halogen when p is 2 and X is --O--; (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.4 linear alkyl group,phenyl group or ##STR00235## where Z.sub.1 is lower alkyl, --OH, lower alkoxy, --CF.sub.3, --NO.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.dbd.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.dbd.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 is hydrogen, lower alkyl, loweralkoxy, 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 lower alkyl; aryl is phenyl or##STR00236## 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 ##STR00237## where Q.sub.3 is--O--, --S--, --NH--, or --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 alkyl 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; with the exclusion of compounds wherein X is O or S, Y is hydrogen, and R is hydrogen, C.sub.1-C.sub.4 alkyl,chlorine, fluorine, bromine, iodine, cyano, C.sub.1-C.sub.4 alkoxy, or --COOR.sub.23 where R.sub.23 is C.sub.1-C.sub.4 alkyl; with the exclusion of compounds wherein X is --S--, R.sub.1 is R.sub.20, R is H, and m=1; all geometric, optical, andstereoisomers thereof, or a pharmaceutically acceptable acid addition salt thereof, in an amount sufficient to produce an antipsychotic effect, and a pharmaceutically acceptable carrier therefor.
92. A method of alleviating pain, which comprises administering to a mammal a pain-relieving effective amount of a composition as claimed in claim 90.
93. A method of alleviating pain, which comprises administering to a mammal a pain-relieving effective amount of a composition as claimed in claim 91.
94. A compound of the formula ##STR00238## wherein X is --O--, --S--, --NH--, or ##STR00239## R.sub.2 is selected from the group consisting lower alkyl, aryl lower alkyl, aryl, (C.sub.3-C.sub.10) cycloalkyl, aroyl, (C.sub.2-C.sub.11) alkanoyl,and phenylsulfonyl groups; aryl is as defined hereinafter; p is 1 or 2; Y is hydrogen, lower alkyl, hydroxy, chlorine, fluorine, bromine, iodine, lower alkoxy, trifluoromethyl, nitro or amino, when p is 1; Y is lower alkoxy, alkoxy hydroxy, orhalogen p is 2 and X is --O--; n is 2, 3, 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(.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; alkylis lower alkyl; aryl is phenyl or ##STR00240## where R.sub.5 is hydrogen, lower alkyl, lower alkoxy, hydroxy, chlorine, flourine, bromine, iodine, lower monoalkylamino, lower dialkylamino nitro, cyano, trifluoromethyl or trifluoromethoxy; heteroaryl is##STR00241## Q.sub.3 is --O--, --S--, --NH--, or --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 lower alkyl--C(.dbd.O)--; R.sub.8 is lower alkyl; R.sub.9 is hydroxy, lower alkoxy, or --NHR.sub.10; andR.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; with the exclusion of compounds wherein X is O or S, Y is hydrogen, and Ris hydrogen, C.sub.1-C.sub.4 alkyl, chlorine, fluorine, bromine, iodine, cyano, C.sub.1-C.sub.4 alkoxy, or --COOR.sub.23 where R.sub.23 is C.sub.1-C.sub.4 alkyl; where R.sub.23 is C.sub.1-C.sub.4 alkyl; with the exclusion of compounds wherein X is--S--, R is H, and m=1; all geometric, optical and stereoisomers thereof, or a pharmaceutically acceptable acid addition salt thereof.
95. A compound as claimed in claim 94, wherein X is --O--, --S--, --NH.
96. A compound as claimed in claim 94, wherein Y is hydrogen, chlorine, bromine, or fluorine.
97. A compound as claimed in claim 94, wherein n is 2, 3, or 4.
98. A compound as claimed in claim 94, wherein X is --O--.
99. A compound as claimed in claim 94, wherein X is --S--.
100. A compound as claimed in claim 94, wherein X is --NH--.
101. A compound as claimed in claim 94, wherein X is ##STR00242##
102. A compound as claimed in claim 94, wherein is --O--, --S--, or --NH--; Y is H, Cl, F, or --CF.sub.3; R is selected from the group consisting of hydrogen C.sub.1-C.sub.3 alkyl, C.sub.1-C.sub.3 alkoxy, --OH, Cl, F, Br, I, C.sub.1-C.sub.3monoalkylamino, acylamino, --NO.sub.2, --OCF.sub.3, or --CF.sub.3; and n is 2, 3, or 4.
103. A compound as claimed in claim 102, wherein the substituent Y is in the 5- or 6-position.
104. A compound as claimed in claim 103, wherein m is 2.
105. A compound as claimed in claim 103, wherein n is 3.
106. A compound as claimed in claim 103, wherein p is 1.
107. A pharmaceutical composition, which comprises a compound as claimed in claim 94, and a pharmaceutically acceptable carrier therefor.
108. An antipsychotic composition which comprises a compound as claimed in claim 94, in an amount sufficient to produce an antipsychotic effect, a pharmaceutically acceptable carrier therefor.
109. A method of treating psychoses, which comprises ministering to a mammal a psychoses-treating amount of a compound as claimed in claim 94.
110. An analgesic composition which comprises a compound as claimed in claim 94, in an amount sufficient to produce a pain-relieving effect, and a pharmaceutically acceptable carrier therefor.
111. A method of alleviating pain, which comprises administering to a mammal a pain-relieving effective amount of a compound as claimed in claim 94.
112. The compound of claim 94, wherein said pharmaceutically acceptable acid addition salt is selected from the group consisting of salts of acids, slats of monobasic carboxylic acids, salts of dibasic carboxylic acids, and salts of tribasiccarboxylic acids.
113. The compound of claim 112, wherein said pharmaceutically acceptable acid addition salt is selected from the group of salts of hydrochloric acid, sulfuric acid, nitric acid, acetic acid propionic acid, maleic acid, fumaric acid,carboxysuccinic acid, and citric acid. |
| Description: |
BACKGROUND OF THE INVENTION
This invention relates to heteroarylpiperidines, pyrrolidines and piperazines. More particularly, this invention relates to heteroarylpiperidines, pyrrolidines and piperazines having antipsychotic activity and to their use as antipsychoticdrugs.
The therapeutic treatment of schizophrenic patients by administration of neuroleptic drugs, such as chlorpromazine, haloperidol, sulpiride, and chemically closely related compounds, is widespread. While control of schizophrenic symptoms has beensuccessful, treatment with these drugs does not cure the psychotic patient, who will almost certainly relapse if medication is discontinued. There exists a continuing need in the art for antipsychotic drugs for the treatment of psychoses.
Moreover, some of the known neuroleptics produce unwanted side effects. For example, the side effects of many antipsychotic drugs include the so-called extrapyramidal symptoms, such as rigidity and tremor, continuous restless walking, andtardive dyskinesia which causes facial grimacing, and involuntary movements of the face and extremities. Orthostatic hypotension is also common. Thus, there also exists a need in the art for antipsychotic drugs that produce fewer or less severemanifestations of these common side effects.
Moreover, there has been a need for drugs that can produce other biological effects. For example, relief from pain has been an age-old aspiration which has led to the discovery of natural and synthetic analgetics. Nevertheless, the need forsafe and effective analgetics has continued to the present day.
SUMMARY OF THE INVENTION
This invention aids in fulfilling these needs in the art by providing a compound of the formula: ##STR00001## wherein ##STR00002## R.sub.2 is selected from the group consisting of lower alkyl, aryl lower alkyl, aryl, cycloalkyl, aroyl, alkanoyl,and phenylsulfonyl groups; 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--; Q.sub.1 isselected from the group consisting of: ##STR00003## where Z is ##STR00004## and Y.sub.2 is selected from the group consisting of: ##STR00005## in which (R.sub.1) is --(CH.sub.2).sub.n-- where n is 2, 3, 4, or 5; or --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 ortrans; and R and m are as defined hereinafter; ##STR00006## where R.sub.3 is H or --OCH.sub.3 and n has the above meaning; ##STR00007## R.sub.4 is hydrogen, lower alkyl, lower alkoxy, amino, mono- or dialkylamino, C.sub.1-C.sub.3 acyl amino,C.sub.1-C.sub.6 alkanoyl, trifluoromethyl, chlorine, fluorine, bromine, or ##STR00008## in which aryl is phenyl or ##STR00009## where R.sub.5 is hydrogen, lower alkyl, lower alkoxy, hydroxy, chlorine, fluorine, bromine, iodine, lower monoalkylamino,lower alalkylamino, nitro, cyano, trifluoromethyl, trifluoromethoxy; where n has the above meaning; ##STR00010## where n and R.sub.4 are as previously defined; ##STR00011## where either one of X.sub.y or X.sub.z is ##STR00012## and the other is--CH.sub.2--; and R.sub.5' is hydrogen, lower alkyl, lower alkoxy, chlorine, fluorine, or bromine; and ##STR00013## where n and R.sub.4 are as previously defined; ##STR00014## where n and R.sub.4 are as previously defined; ##STR00015## where n is aspreviously defined; ##STR00016## where Q.sub.2 is S, NH, or --CH.sub.2--; R.sub.6 is the same as R.sub.1 when Q.sub.2 is S or NH; and when Q.sub.2 is --CH.sub.2--, R.sub.6 is selected from the group consisting of: --CH.sub.2--CH.sub.2----CH.sub.2--CH.sub.2--CH.sub.2-- --CH.sub.2--CH.sub.2--CH.sub.2--CH.sub.2-- --CH.sub.2--CH.dbd.CH.sub.2--CH.sub.2-- --CH.sub.2--CH.sub.2--CH.dbd.CH-- --CH.sub.2--CH.dbd.CH--CH.sub.2-- --CH.sub.2--CH.sub.2--CH.dbd.CH----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--CH.sub.2--CH.sub.2--CH.dbd.CH-- --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--CH.sub.2--CH.sub.2--CH.dbd.CH-- --CH.sub.2--C.ident.C--CH.sub.2 --CH.sub.2--CH.sub.2--C.ident.C-- --CH.sub.2--C.ident.C--CH.sub.2--CH.sub.2-- --CH.sub.2--CH.sub.2--C.ident.C--CH.sub.2-- --CH.sub.2--CH.sub.2--CH.sub.2--CH.sub.2.ident.C-- 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, ##STR00017## alkyl is lower alkyl; aryl is as previously defined; heteroaryl is ##STR00018## 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 ishydrogen, 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, ##STR00019## where aryl and heteroaryl are as defined above; and m is 1, 2, or3; or a pharmaceutically acceptable acid addition salt thereof.
This invention also aids in fulfilling these needs in the art by providing a compound of the formula: ##STR00020## wherein ##STR00021## R.sub.2 is selected from the group consisting of lower alkyl, aryl, lower alkyl, aryl, cycloalkyl, aroyl,alkanoyl, and phenylsulfonyl groups; 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--;Q.sub.1 is selected from the group consisting of: ##STR00022## where Z is ##STR00023## and Y.sub.2 is selected from the group consisting of: ##STR00024## 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--C.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, phenylgroup or ##STR00025## 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; ##STR00026## where R.sub.1 is as previously defined, and R.sub.3 is hydrogen or --OCH.sub.3;##STR00027## where R.sub.1 is as previously defined; and R.sub.4 is hydrogen, lower alkyl, lower alkoxy, hydroxy, amino, mono- or dialkylamino, C.sub.1-C.sub.3 acyl amino, C.sub.1-C.sub.6 alkanoyl, trifluoromethyl, chlorine, fluorine, bromine,##STR00028## in which aryl is phenyl or ##STR00029## where R.sub.5 is hydrogen, lower alkyl, lower alkoxy, hydroxy, chlorine, fluorine, bromine, iodine, lower monoalkylamino, lower dialkylamino, nitro, cyano, trifluoromethyl, trifluoromethoxy;##STR00030## where R.sub.1 and R.sub.4 are as previously defined; ##STR00031## where either one of X.sub.y or X.sub.z is ##STR00032## and the other is --CH.sub.2--; and R.sub.5' is hydrogen, lower alkyl, lower alkoxy, chlorine, fluorine, or bromine; andR.sub.1 is as previously defined; ##STR00033## where R.sub.1 and R.sub.4 are as previously defined; ##STR00034## where q is 1, 2, 3 or 4, and R.sub.1 and R.sub.4 are as previously defined; ##STR00035## where R.sub.1 is as previously defined; ##STR00036##where R.sub.1 is as previously defined; Q.sub.2 is S, NH, or --CH.sub.2--; and R and m are as defined hereinafter; ##STR00037## where R.sub.1 is as previously defined; --R.sub.1--O--R.sub.12 (11) where R.sub.12 is selected from the group consisting of:hydrogen, ##STR00038## 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) alkyl groups; where NR.sub.15R.sub.16 takentogether 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; --R.sub.1--NR.sub.18R.sub.19 (12) where R.sub.18 andR.sub.19 are independently selected from the group consisting of: hydrogen, (C.sub.1-C.sub.12 straight or branched chain) alkyl, ##STR00039## where NR.sub.18R.sub.19 taken together form a ring structure selected from the group consisting of piperidinyl,morpholinyl and piperazinyl; --R.sub.1--S--R.sub.12 (13) where R.sub.1 and R.sub.12 are as previously defined; R is hydrogen, lower alkyl, lower alkoxy, hydroxyl, carboxyl, chlorine, fluorine, bromine, iodine, amino, lower mono or dialkylamino, nitro,lower alkyl thio, trifluoromethoxy, cyano, acylamino, trifluoromethyl, trifluoroacetyl, aminocarbonyl, monoalkylaminocarbonyl, dialkylaminocarbonyl, formyl, ##STR00040## alkyl is lower alkyl; aryl is as previously defined; heteroaryl is ##STR00041##Q.sub.3 is --O--, --S--, ##STR00042## W is CH.sub.2 or CHR.sub.6 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.3acyl, aryl, ##STR00043## where aryl and heteroaryl are as defined above; and m is 1, 2, or 3; with the proviso that in formula (9) Z is not ##STR00044## when X is --S--, Q.sub.2 is --CH.sub.2--, Y is hydrogen, lower alkyl, lower alkoxy, halogen, hydroxyor trifluoromethyl, and p is 1 or 2; with the proviso that in formula (4) R.sub.4 is not H when R.sub.1 is R.sub.20, Z is not ##STR00045## X is --S--, Y is hydrogen, halogen, lower alkyl, lower alkoxy, hydroxy or trifluoromethyl, and p is 1 or 2; withthe proviso that in formula (9) Z is not ##STR00046## when X is ##STR00047## Y is hydrogen, halogen, lower alkyl, lower alkoxy, hydroxy or trifluoromethyl and Q.sub.2 is --CH.sub.2--; with the proviso that in formula (9) Z is not ##STR00048## when X is--O--, Q.sub.2 is --CH.sub.2--, Y is hydrogen, lower alkyl, lower alkoxy, hydroxy or halogen, and p is 1 or 2; with the proviso that in formula (9) Z is not ##STR00049## when X is --S--, Q.sub.2 is --CH.sub.2--, Y is hydrogen, halogen, lower alkyl,lower alkoxy or hydroxy, p is 1 or 2, R is hydrogen, and m is 1; with the proviso that in formula (9) Z is not ##STR00050## when X is ##STR00051## Q.sub.2 is --CH.sub.2--, R is chlorine, fluorine, bromine, iodine, lower alkyl, lower alkoxy, lower alkylthio, lower mono- or dialkylamino, amino, cyano, hydroxy, trifluoromethyl; R.sub.2 is aryl; Y is hydrogen, halogen, lower alkyl, lower alkoxy or hydroxy, p is 1 or 2; with the proviso that in formula (9) Z is not ##STR00052## when X is ##STR00053## whereR.sub.2 is lower alkyl, aryl lower alkyl, or phenylsulfonyl, Y is hydrogen, halogen, lower alkyl, lower alkoxy or hydroxy, p is 1 or 2 and Q.sub.2 is --CH.sub.2--; with the proviso that Y.sub.2 is not the moiety of formula (8) when Z is ##STR00054## X isO, p is 1, and Y is hydrogen, lower alkyl, lower alkoxy, chlorine, fluorine, bromine, iodine or a hydroxyl group; with the proviso that in formula (1) Z is not ##STR00055## when X is O or S, Y is hydrogen, R is hydrogen, C.sub.1-C.sub.4 alkyl, chlorine,fluorine, bromine, iodine, cyano, C.sub.1-C.sub.4 alkoxy, aryl, --COOR.sub.23 where R.sub.23 is C.sub.1-C.sub.4 alkyl; with the proviso that in formula (1) Z is not ##STR00056## when X is --S--, R.sub.1 is R.sub.20, R is H, and m=1; with the proviso thatin formula (7) R.sub.4 is not hydrogen when Y is 6-F, X is --O--, Z is ##STR00057## and n is 2, 3 or 4; with the proviso that in formula (11) R.sub.12 is not H when Z is ##STR00058## X is ##STR00059## where R.sub.2 is lower alkyl, aryl lower alkyl, orphenylsulfonyl Y is hydrogen, lower alkyl, lower alkoxy, chlorine, fluorine, bromine, iodine or a hydroxyl group and p is 1 or 2; with the proviso that in formula (11), R.sub.12 is not H when X is ##STR00060## where R.sub.2 is phenyl, Z is ##STR00061##and Y is hydrogen, lower alkyl, lower alkoxy, chlorine, fluorine, bromine, iodine or a hydroxyl group; with the proviso that in formula (12), R.sub.18 and R.sub.19 are not lower alkyl when Z is ##STR00062## X is ##STR00063## and R.sub.2 is aryl and Y ishydrogen, lower alkyl, lower alkoxy, chlorine, fluorine, bromine, iodine or a hydroxyl group; with the proviso that in formula (12), when X is --O--, Z is ##STR00064## and Y is hydrogen, lower alkyl, lower alkoxy, chlorine, fluorine, bromine, iodine ora hydroxyl group, R.sub.18 and R.sub.19 are not lower alkyl; with the proviso that in formula (12), R.sub.18 and R.sub.19 are not hydrogen when R.sub.1 is R.sub.20, Z is ##STR00065## X is --O--, and Y is 6-F; all geometric optical and stereoisomersthereof, or a pharmaceutically acceptable acid addition salt thereof.
This invention also provides a pharmaceutical composition, which comprises a compound of the invention and a pharmaceutically acceptable carrier therefor. In one embodiment of the invention, the pharmaceutical composition is an antipsychoticcomposition comprising a compound of the invention in an amount sufficient to produce an antipsychotic effect.
In addition, this invention provides a method of treating psychoses, which comprises administering to a patient a pharmaceutically effective amount of a compound of the invention.
Finally, this invention provides a method of alleviating pain by administering to a patient a pain-relieving amount of a compound of the invention.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT
The compounds of this invention are useful as antipsychotic drugs and as analgesic agents. The compounds of the invention can contain a variety of different substituents and chemical groups. As used herein, when the term "lower" is mentioned inconnection with the description of a particular group, the term means that the group it is describing contains from 1 to 6 carbon atoms.
The term "alkyl" as used herein refers to a straight or branched chain hydrocarbon group containing no unsaturation, for example, methyl, ethyl, isopropyl, 2-butyl, neopentyl, or n-hexyl.
The term "alkoxy" as used herein refers to a monovalent substituent comprising an alkyl group linked through an ether oxygen having its free valence bond from the ether oxygen, e.g. methoxy, ethoxy, propoxy, butoxy, or pentoxy.
The term "alkylene" as used herein refers to a bivalent radical of a lower branched or unbranched alkyl group having valence bonds on two terminal carbons thereof, for example, ethylene (--CH.sub.2CH.sub.2--), propylene(--CH.sub.2CH.sub.2CH.sub.2--), or isopropylene ##STR00066##
The term "cycloalkyl" refers to a saturated hydrocarbon group possessing at least one carboxylic ring, the ring containing from 3 to 10 carbon atoms such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclodecyl and the like.
The term "alkanoyl" refers to the radical formed by removal of the hydroxyl function from an alkanoic acid. More particularly, the term "alkanoyl" as used herein refers to an alkyl carbonyl moiety containing from 2 to 11 carbon atoms, e.g.##STR00067## Examples of alkanoyl groups are formyl, acetyl, propionyl, 2,2-dimethylacetyl, hexanoyl, octanoyl, decanoyl, and the like.
The term "alkanoic acid" refers to a compound formed by combination of a carboxyl group with a hydrogen atom or alkyl group. Examples of alkanoic acids are formic acid, acetic acid, propanoic acid, 2,2-dimethylacetic acid, hexanoic acid,octanoic acid, decanoic acid, and the like.
The term "aryl lower alkyl" refers to compounds wherein "aryl" and "loweralkyl" are as defined above.
The term "lower alkylthio" refers to a monovalent substituent having the formula lower alkyl-S--.
The term "phenylsulfonyl" refers to a monovalent substituent having the formula phenyl-SO.sub.2--.
The term "acyl" refers to a substituent having the formula ##STR00068##
The term "lower monoalkylamino" refers to a monosubstituted derivative of ammonia, wherein a hydrogen of ammonia is replaced by a lower alkyl group.
The term "lower dialkylamino" refers to a disubstituted derivative of ammonia, wherein two hydrogens of ammonia are replaced by lower alkyl groups.
The term "acylamino" refers to a primary or secondary amine, wherein a hydrogen of the amine is replaced by an acyl group, where acyl is as previously defined.
The term "dialkylaminocarbonyl" refers to a derivative of an acid, wherein the hydroxyl group of the acid is replaced by a lower dialkylamino group.
The term "aroyl" refers to a disubstituted carbonyl, wherein at least one substituent is an aryl group, where "aryl" is as previously defined.
Unless otherwise indicated, the term "halogen" as used herein refers to a member of the halogen family selected from the group consisting of fluorine, chlorine, bromine, and iodine.
Throughout the specification and appended claims, a given chemical formula or name shall encompass all geometric, optical and stereoisomers thereof where such isomers exist.
A. COMPOUNDS OF THE INVENTION
The compounds of this invention can be represented by the following formula: ##STR00069## wherein ##STR00070## R.sub.2 is selected from the group consisting of lower alkyl, aryl, lower alkyl, aryl, cycloalkyl, aroyl, alkanoyl, and phenylsulfonylgroups; 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--; Q.sub.1 is selected from thegroup consisting of: ##STR00071## and ##STR00072## where Z is ##STR00073## and Y.sub.2 is selected from the group consisting of: ##STR00074## 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.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, phenylgroup or ##STR00075## 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; ##STR00076## where R.sub.1 is as previously defined, and R.sub.3 is hydrogen or --OCH.sub.3;##STR00077## where R.sub.1 is as previously defined; and R.sub.4 is hydrogen, lower alkyl, lower alkoxy, hydroxy, amino, mono- or dialkylamino, C.sub.1-C.sub.3 acyl amino, C.sub.1-C.sub.6 alkanoyl, trifluoromethyl, chlorine, fluorine, bromine,##STR00078## in which aryl is phenyl or ##STR00079## where R.sub.5 is hydrogen, lower alkyl, lower alkoxy, hydroxy, chlorine, fluorine, bromine, iodine, lower monoalkylamino, lower dialkylamino, nitro, cyano, trifluoromethyl, trifluoromethoxy;##STR00080## where R.sub.1 and R.sub.4 are as previously defined; ##STR00081## where either one of X.sub.y or X.sub.z is ##STR00082## and the other is --CH.sub.2--; and R.sub.5' is hydrogen, lower alkyl, lower alkoxy, chlorine, fluorine, or bromine; andR.sub.1 is as previously defined; ##STR00083## where R.sub.1 and R.sub.4 are as previously defined; ##STR00084## where q is 1, 2, 3 or 4, and R.sub.1 and R.sub.4 are as previously defined; ##STR00085## where R.sub.1 is as previously defined; ##STR00086##where R.sub.1 is as previously defined; Q.sub.2 is S, NH, or --CH.sub.2--; and R and m are as defined hereinafter; ##STR00087## where R.sub.1 is as previously defined; --R.sub.1--O--R.sub.12 (11) where R.sub.12 is selected from the group consisting of:hydrogen, ##STR00088## where R.sub.13 is selected from the group consisting of hydrogen and (C.sub.1-C) alkyl groups; where R.sub.14 is selected from the group consisting of hydrogen and (C.sub.1-C) alkyl groups; where NR.sub.15R.sub.16 taken togetherform 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; --R.sub.1--NR.sub.18R.sub.19 (12) where R.sub.18 and R.sub.19 areindependently selected from the group consisting of: hydrogen, (C.sub.1-C.sub.12 straight or branched chain) alkyl, ##STR00089## where NR.sub.18R.sub.19 taken together form a ring structure selected from the group consisting of piperidinyl, morpholinyland piperazinyl; --R.sub.1--S--R.sub.12 (13) where R.sub.1 and R.sub.12 are as previously defined; R is hydrogen, lower alkyl, lower alkoxy, hydroxyl, carboxyl, chlorine, fluorine, bromine, iodine, amino, lower mono or dialkylamino, nitro, lower alkylthio, trifluoromethoxy, cyano, acylamino, trifluoromethyl, trifluoroacetyl, aminocarbonyl, monoalkylaminocarbonyl, dialkylaminocarbonyl, formyl, ##STR00090## alkyl is lower alkyl; aryl is as previously defined; heteroaryl is ##STR00091## Q.sub.3 is--O--, --S--, ##STR00092## --CH.dbd.N--; W is CH.sub.2 or CHR.sub.6 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, ##STR00093## where aryl and heteroaryl are as defined above; and m is 1, 2, or 3; with the proviso that in formula (9) Z is not ##STR00094## when X is --S--, Q.sub.2 is --CH.sub.2--, Y is hydrogen, lower alkyl, lower alkoxy,halogen, hydroxy or trifluoromethyl, and p is 1 or 2; with the proviso that in formula (4) R.sub.4 is not H when R.sub.1 is R.sub.20, Z is not ##STR00095## X is --S--S, Y is hydrogen, halogen, lower alkyl, lower alkoxy, hydroxy or trifluoromethyl, and pis 1 or 2; with the proviso that in formula (9) Z is not ##STR00096## when X is ##STR00097## Y is hydrogen, halogen, lower alkyl, lower alkoxy, hydroxy or trifluoromethyl and Q.sub.2 is --CH.sub.2--; with the proviso that in formula (9) Z is not##STR00098## when X is --O--, Q.sub.2 is --CH.sub.2--, Y is hydrogen, lower alkyl, lower alkoxy, hydroxy or halogen, and p is 1 or 2; with the proviso that in formula (9) Z is not ##STR00099## when X is --S--, Q.sub.2 is --CH.sub.2--, Y is hydrogen,halogen, lower alkyl, lower alkoxy or hydroxy, p is 1 or 2, R is hydrogen, and m is 1; with the proviso that in formula (9) Z is not ##STR00100## when X is ##STR00101## Q.sub.2 is --CH.sub.2--, R is chlorine, fluorine, bromine, iodine, lower alkyl, loweralkoxy, lower alkyl thio, lower mono- or dialkylamino, amino, cyano, hydroxy, trifluoromethyl; R.sub.2 is aryl; Y is hydrogen, halogen, lower alkyl, lower alkoxy or hydroxy, p is 1 or 2; with the proviso that in formula (9) Z is not ##STR00102## when Xis ##STR00103## where R.sub.2 is lower alkyl, aryl lower alkyl, or phenylsulfonyl, Y is hydrogen, halogen, lower alkyl, lower alkoxy or hydroxy, p is 1 or 2 and Q.sub.2 is --CH.sub.2--;
with the proviso that Y.sub.2 is not the moiety of formula (8) when Z is ##STR00104## X is O, p is 1, and Y is hydrogen, lower alkyl, lower alkoxy, chlorine, fluorine, bromine, iodine or a hydroxyl group; with the proviso that in formula (1) Z isnot ##STR00105## when X is O or S, Y is hydrogen, R is hydrogen, C.sub.1-C.sub.4 alkyl, chlorine, fluorine, bromine, iodine, cyano, C.sub.1-C.sub.4 alkoxy, aryl, --COOR.sub.23 where R.sub.23 is C.sub.1-C.sub.4 alkyl; with the proviso that in formula (1)Z is not ##STR00106## when X is --S--, R.sub.1 is R.sub.20, R is H, and m=1; with the proviso that in formula (7) R.sub.4 is not hydrogen when Y is 6-F, X is --O--, Z is ##STR00107## and n is 2, 3 or 4; with the proviso that in formula (11) R.sub.12 isnot H when Z is ##STR00108## X is ##STR00109## where R.sub.2 is lower alkyl, aryl lower alkyl, or phenylsulfonyl Y is hydrogen, lower alkyl, lower alkoxy, chlorine, fluorine, bromine, iodine or a hydroxyl group and p is 1 or 2; with the proviso that informula (11), R.sub.12 is not H when X is ##STR00110## where R.sub.2 is phenyl, Z is ##STR00111## and Y is hydrogen, lower alkyl, lower alkoxy, chlorine, fluorine, bromine, iodine or a hydroxyl group; with the proviso that in formula (12), R.sub.18 andR.sub.19 are not lower alkyl when Z is ##STR00112## X is ##STR00113## R.sub.2 is aryl and Y is hydrogen, lower alkyl, lower alkoxy, chlorine, fluorine, bromine, iodine or a hydroxyl group; with the proviso that in formula (12), when X is --O--, Z is##STR00114## and Y is hydrogen, lower alkyl, lower alkoxy, chlorine, fluorine, bromine, iodine or a hydroxyl group, R.sub.18 and R.sub.19 are not lower alkyl; with the proviso that in formula (12), R.sub.18 and R.sub.19 are not hydrogen when R.sub.1 isR.sub.20, Z is --CH--, X is --O--, and Y is 6-F; all geometric optical and stereoisomers thereof, or a pharmaceutically acceptable acid addition salt thereof.
The compounds of the invention can also be represented by the following formula: ##STR00115##
The substituent X in formula (I) is selected from the group consisting of --O--, --S--, --NH--, or ##STR00116## When the substituent X is --O--, the compounds of the invention contain a 1,2-benzisoxazole nucleus, and when X is --S--, thecompounds of the invention contain a 1,2-benzisothiazole nucleus. When X is --NH-- or ##STR00117## the compounds of the invention contain the indazole nucleus.
When p in formula (I) is 1, the substituent Y is selected from the group consisting of hydrogen, lower alkyl, hydroxyl, halogen, lower alkoxy, --CF.sub.3, --NO.sub.2, and --NH.sub.2. The substituent Y is preferably in the 5- or 6-position of thering. Moreover, in the preferred embodiments of the invention, the substituent Y is hydrogen, chlorine, bromine, or fluorine, and in the particularly preferred compounds of the invention, Y is fluorine, especially in the 6-position of the ring.
When p in formula (I) is 2 and X is --O--, each Y substituent can be independently selected from lower alkoxy, hydroxy or halogen groups, preferably methoxy groups.
When the substituent Y.sub.2 has the formula (b)(1): ##STR00118## and R.sub.1 contains unsaturation, R.sub.1 preferably has the formula --CH.sub.2--CH.dbd.CH--CH.sub.2--
When the substituent Y.sub.2 has the formula (b)(3): ##STR00119## the substituent R.sub.4 is preferably hydrogen or C.sub.1-C.sub.6 alkyl carbonyl and n is 3.
When the substituent Y.sub.2 has the formula (b)(4): ##STR00120## the substituent R.sub.4 is preferably hydrogen or ##STR00121## and n is preferably 1 or 2.
When the substituent Y.sub.2 has the formula (b)(5): ##STR00122## the substituent R.sub.5' is preferably --OCH.sub.3 and n is preferably 3.
When the substituent R.sub.4 has the formula (b)(6): ##STR00123## the substituent R.sub.4 is preferably ##STR00124## and n is preferably 3.
When the substituent Y.sub.2 has the formula (b)(7): ##STR00125## the substituent R.sub.4 is preferably hydrogen and n is preferably or 4.
The substituent Y.sub.2 has the formula (b)(8): ##STR00126## the value of n is preferably 3 or 4.
When the substituent Y.sub.2 has the formula (b)(9): ##STR00127## the substituent R.sub.6 is preferably --CH.sub.2--CH.dbd.CH.sub.2--CH.sub.2-- when R.sub.6 contains unsaturation.
When the substituent R is ##STR00128## the substituent Q.sub.3 is preferably --CH.dbd.N; and the substituent W is preferably CH.sub.2, the substituent R.sub.8 in CHR.sub.6 is preferably CH.sub.3, the substituent R.sub.9 is N--R.sub.9 ispreferably hydroxy, lower alkoxy, or NH.sub.2, and the substituent R.sub.10 in NHR.sub.10 is preferably hydrogen.
The value of n in the foregoing formulas can be 2, 3, 4, or 5, and preferably is 2, 3, or 4. In the particularly preferred compounds of the invention n is 3.
When X in the compounds of the invention is ##STR00129## the substituent R.sub.2 is selected from the group consisting of lower alkyl, aryl lower alkyl, aryl, cycloalkyl, aroyl, alkanoyl, and phenylsulfonyl groups.
The substituent Z can be ##STR00130## in which case the compounds of the invention are heteroarylpiperidine derivatives, or ##STR00131## in which case the compounds are heteroarylpiperazine derivatives. When the substituent Q.sub.1 has theformula ##STR00132## the compounds of the invention are heteroarylpyrrolidines. The preferred compounds of the invention are the heteroarylpiperidines, i.e. compounds in which Z is ##STR00133##
The compounds of the invention can contain one, two, or three R-substituents. The substituent R can be hydrogen, lower alkyl, C.sub.1-C.sub.6 alkoxy, hydroxyl, carboxyl, Cl, F, Br, I, amino, C.sub.1-C.sub.6 mono or dialkyl amino, --NO.sub.2,lower alkyl thio, --OCF.sub.3, cyano, acylamino, --CF.sub.3, trifluoroacetyl ##STR00134## aminocarbonyl ##STR00135## dialkylaminocarbonyl, formyl, ##STR00136## alkyl is lower alkyl; aryl is phenyl or ##STR00137## where R.sub.5 is hydrogen, lower alkyl,C.sub.1-C.sub.6 alkoxy, hydroxy, Cl, F, Br, I C.sub.1-C.sub.6 alkylamino, --NO.sub.2, --CN, --CF.sub.3, --OCF.sub.3; heteroaryl is ##STR00138## Q is --O--, --S--, ##STR00139## --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, ##STR00140## where aryl and heteroaryl are as defined above; and m is 1, 2, or 3. Whenthe compounds of the invention contain two or three R-substituents, each of the R-substituents can be independently selected from the above substituents. Preferably, each of the R-substituents 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.2, --CF.sub.3, --OCF.sub.3, ##STR00141##
The compounds of the present invention are prepared in the following manner. The substituents R, R.sub.1, R.sub.2, R.sub.3, X, Y, and Z and the integers m, n, and p are as defined above unless indicated otherwise.
B. PREPARATION OF COMPOUNDS OF THE INVENTION
The compounds of the invention can be prepared by reacting a piperidine or a piperazine of the formula: ##STR00142## or a pyrrolidine of the formula: ##STR00143## under alkylating conditions with a compound of the formula: ##STR00144## where HALis Cl, Br, or I. The procedures that can be employed for preparing the piperidines, the piperazines, and the pyrrolidines and the alkylating agents identified by the above formulas will now be described in detail. 1. Preparation of3-(1-unsubstituted-4-Piperazinyl)-1H-indazoles
Compounds of the formulae: ##STR00145## and ##STR00146## for use in synthesizing the indazoyl-substituted piperazines of the invention can be prepared as follows.
A substituted aryl ester of formula (7) is selected, ##STR00147## where R.sub.11 is lower alkyl and Hal is a halogen selected from the group consisting of Cl, Br, and I. The ester of formula (7) is reacted with hydrazine, H.sub.2NNH.sub.2, understandard hydrazide formation conditions. Typically, the reaction is carried out in a nonreactive solvent, e.g. ethanol, methanol, or toluene, at a temperature of ambient temperature to the reflux temperature of the solvent for 4 to 16 hours to form ahydrazide of formula (8): ##STR00148##
The hydrazide of formula (8) is reacted with a phenyl sulfonyl halide of the formula ##STR00149## where Hal is a halogen selected from the group consisting of Cl and Br, to form a compound of the formula ##STR00150##
Typically this reaction is carried out in a basic solvent, such as pyridine or collidine, at a temperature of 0.degree. to 30.degree. C. for 2 to 16 hours.
The compound of formula (10) in turn is reacted neat with thionyl chloride at a temperature of 50.degree. to 79.degree. C. (reflux temperature) for 2 to 16 hours to form a compound of formula (11) ##STR00151## Compound (11) is reacted with acompound of formula (12), ##STR00152## where R.sub.11 is lower alkyl, under conventional nucleophilic reaction conditions, for example in an inert solvent, such as tetrahydrofuran (THF), toluene, or diethylether, at a temperature of 5.degree. to50.degree. C. for 1 to 16 hours to form a compound having the formula ##STR00153##
The compound of formula (13) is then reacted with a condensation agent, such as copper, copper-bronze, or cuprous oxide, in a solvent such as dimethylformamide, dimethylacetamide, or tetramethylurea, at a temperature of 120.degree. to177.degree. C. for 1 to 16 hours to form a piperazine-substituted phenylsulfonyl indazole of the formula ##STR00154##
A cyano-substituted piperazine phenylsulfonyl indazole is then formed by reacting the compound of formula (14) with a conventional cyanation source, such as a halo-cyanide, e.g. BrCN or ClCN, under conventional cyanation conditions, typically inan inert solvent, e.g. dimethylsulfoxide (DMSO) or CHCl.sub.3, at ambient temperature for 2 to 16 hours to form a compound of formula ##STR00155## The compound of formula (15) is then subjected to reduction by means of a metal hydride, e.g. lithiumaluminum hydride (LiAlH.sub.4). Typically the reduction is carried out under standard reduction conditions in a solvent, such as tetrahydrofuran or diethyl ether, at a temperature of 35.degree. to 67.degree. C. for 6 to 16 hours to form a compound offormula (16): ##STR00156##
A compound of formula (16) can be formed in an alternative manner by first reacting a compound of formula (14) with a strong base, such as a metal alcoholate, e.g. sodium methoxide, sodium ethoxide, or sodium butoxide, or with KOH intetrahydrofuran to form a compound of formula (17): ##STR00157## This reaction is typically carried out in a polar solvent, such as for example CH.sub.3OH or C.sub.2H.sub.5OH, at a temperature of ambient to 50.degree. C. for 1 to 16 hours.
Alternatively, the compound of formula (17) can be formed by reducing compound (14) with LiAlH.sub.4 under conditions as previously described.
The compound of formula (17) in turn can be reacted with a cyanation reagent, as previously described, to form a cyano substituted piperazine indazole of the formula ##STR00158## which in turn can be reduced with a metal hydride, as previouslydescribed, to form a compound of formula (16).
In an alternative embodiment, a compound of formula (18) can be reacted with an aqueous mineral acid, e.g. H.sub.2SO.sub.4 or HCl, at a temperature of 50.degree. to 120.degree. C. for 2 to 16 hours to form a compound of formula (16).
2. Preparation of 3-(1-unsubstituted-4-piperazinyl)-1,2-benzisoxazoles
A compound of the formula: ##STR00159## can be prepared according to conventional techniques. Suitable procedures are described in J. Med. Chem. 1986, 29:359. Compounds of formula (19) are useful for synthesizing the benzisoxazole substitutedpiperazines of the invention. 3. Preparation of 3-(1-unsubstituted-4-piperazinyl)-1,2-benzisothiazoles
A compound of the formula: ##STR00160## for use in synthesizing the benzisothiazole substituted piperazines of the invention can be prepared according to the techniques described in J. Med. Chem. 1986, 29:359 and United Kingdom Patent (GB) 2 163432 A. 4. Preparation of 3-(1-unsubstituted-4-piperidinyl)-1H-indazoles
A compound of the formula: ##STR00161## or ##STR00162## for use in synthesizing the indazole-substituted piperidines of the invention can be prepared using known techniques. For example, suitable techniques are described in substantial detail inU.S. Pat. No. 4,710,573. Preparation of 3-(1-unsubstituted-4-piperidinyl)-1,2-benzisoxazoles
A compound of the formula: ##STR00163## can be prepared by following the teachings from several sources. For example, U.S. Pat. No. 4,355,037 contains a detailed description of compounds of formula (23) and of methods for preparing thecompounds. Additional disclosure of methods for preparing the compounds of formula (23) can be found in U.S. Pat. No. 4,327,103 and in Strupczewski et al., J. Med. Chem., 28:761-769 (1985). The compounds of formula (23) can be employed in thesynthesis of the benzisoxazole substituted piperidines of the invention. 6. Preparation of 3-(1-unsubstituted-4-piperidinyl)-1,2-benzisothiazoles
Certain 3-(4-piperidinyl)-1,2-benzisothiazoles can be employed in the synthesis of the N-(aryloxyalkyl)heteroaryl piperidines of the invention. Specifically, a benzisothiazole of the formula: ##STR00164## can be reacted with the alkylating agentpreviously described to form the N-(aryloxyalkyl)heteroarylpiperidines of the invention. Compounds of formula (24) and their methods of preparation are described in detail in U.S. Pat. No. 4,458,076. 7. Preparation of alkylating agents
The compounds described in Sections 1-6 above can be reacted with alkylating agents of the formula: ##STR00165## to form the N-(aryloxyalkyl)heteroarylpiperidines, piperazines, and pyrrolidines of the invention. The alkylating agents of formula(4) and methods for preparing the alkylating agents are described in U.S. Pat. No. 4,366,162. Additional disclosure can be found in South African publication EA 86 14522. In addition, procedures for making alkylating agents are described in thefollowing Examples. These procedures can be employed to make other alkylating agents for use in this invention. 8. Alkylation of heteroarylpiperidines, piperazines, and pyrrolidines to form the compounds of the invention
The heteroarylpiperidines, piperazines, and pyrrolidines described in Sections 1-6 above can be reacted under alkylating conditions with the alkylating agents described in Section 7 to form the compounds of this invention. The reaction can becarried out by dissolving the reagents in an inert solvent, such as dimethylformamide, acetonitrile, or butanol, and allowing the reagents to react from a temperature of 50.degree. C. to refluxing of the solvent in the presence of an acid receptor, suchas a base. Examples of suitable bases are alkali metal carbonates, such as potassium carbonate, sodium carbonate, or sodium bicarbonate. The reaction can be carried out with or without a catalytic amount of an alkaline iodide, such as potassium iodideor sodium iodide, for a time sufficient to form a compound of formula (I) of the invention. Generally, the alkylation reaction is carried out for about 4 to about 16 hours, depending on reactivity of the reagents. The reaction temperature can vary fromabout 50.degree. to about 120.degree. C. The products can be isolated by treating the reaction product with water, extracting the product into an organic solvent that is immiscible in water, washing, drying, and concentrating the organic solvent toyield the free base, and then, if indicated, converting the resulting compound to an acid addition salt in a conventional manner.
Following are typical examples of compounds of the invention that can be prepared by following the techniques described above: 1-[4-[3-[4-(1H-indazol-3-yl)-1-piperazinyl]propoxy]-3-methoxyphenyl]ethan- one;1-[4-[3-[4-(1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-methoxyph- enyl]ethanone; 1-[4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-meth- oxyphenyl]ethanone;1-[4-[4-[4-(1,2-benzisoxazol-3-yl)-1-piperidinyl]butoxy]-3-methoxyphenyl]- ethanone; 1-[4-[4-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]butoxy- ]-3-methoxyphenyl]ethanone; 1-[4-[2-[4-(1,2-benzisoxazol-3-yl)-1-piperidinyl]ethoxy]-3-methoxyphenyl]-ethanone fumarate; 1-[4-[4-[4-(1H-indazol-3-yl)-1-piperazinyl]butoxy]-3-methoxyphenyl]ethano- ne fumarate; 1-[4-[2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethoxy]-3-metho- xyphenyl]ethanone;4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-methoxy- -.alpha.-methylbenzenemethanol; 1-[4-[3-[4-(1,2-benzisothiazol-3-yl)-1-piperidinyl]propoxy]-3-methoxyphen- yl]ethanone;1-[4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-hydr- oxyphenyl]ethanone; 1-[4-[3-[4-(6-fluoro-1H-indazol-3-yl)-1-piperazinyl]propoxy]-3-methoxyphe- nyl]ethanone;1-[4-[4-[4-(6-fluoro-1H-indazol-3-yl)-1-piperazinyl]butoxy]-3-methoxyphen- yl]ethanone; 1-[4-[3-[4-(1H-indazol-3-yl)-1-piperidinyl]propoxy]-3-methoxyphenyl]ethan- one; 1-[4-[3-[4-(6-chloro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3--methoxyphenyl]ethanone; 1-[4-[4-[4-(6-chloro-1,2-benzisoxazol-3-yl)-1-piperidinyl]butoxy]-3-metho- xyphenyl]ethanone fumarate; 1-[4-[3-[4-(5-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-meth- oxyphenyl]ethanone;6-fluoro-3-[1-[3-(2-methoxyphenoxy)propyl]-4-piperidinyl]-1,2-benzisoxazo- le fumarate; [4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-methox- yphenyl]phenylmethanone;1-[4-[4-[4-(1H-indazol-3-yl)-1-piperidinyl]butoxy]-3-methoxyphenyl]ethano- ne; 1-[4-[2-[4-(6-chloro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethoxy]-3-me- thoxyphenyl]ethanone; 1-[3-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]phenyl]-ethanone fumarate; 1-[4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-2-meth- ylphenyl]ethanone; 1-[2-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-5-meth- ylphenyl]ethanone;N-[4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-meth- oxyphenyl]acetamide hemifumarate; 6-chloro-3-(1-piperazinyl)-1H-indazole; 1-[4-[3-[4-(6-fluoro-1H-indazol-3-yl)-1-piperidinyl]propoxy]-3-methoxyphe- nyl]ethanone;1-[4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-meth- ylphenyl]ethanone hemifumarate; 1-[4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]phenyl]- ethanone;1-[4-[3-[4-(6-chloro-1H-indazol-3-yl)-1-piperazinyl]propoxy]-3-m- ethoxyphenyl]ethanone; 1-[4-[4-[4-(1,2-benzisothiazol-3-yl)-1-piperazinyl]butoxy]-3-methoxypheny- l]ethanone; 4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-methoxy-benzonitrile; 1-[4-[4-[4-(6-fluoro-1H-indazol-3-yl)-1-piperidinyl]butoxy]-3-methoxyphen- yl]ethanone; 1-[4-[3-[4-(1-benzoyl-6-fluoro-1H-indazol-3-yl)-1-piperazinyl]propoxy]-3-- methoxyphenyl]ethanone sesquifumarate;1-[4-[4-[4-(6-chloro-1H-indazol-3-yl)-1-piperazinyl]butoxy]-3-methoxyphen- yl]ethanone; 1-[4-[3-[4-(1,2-benzisothiazol-3-yl)-1-piperazinyl]propoxy]-3-methoxyphen- yl]ethanone hemifumarate;1-[3,5-dibromo-4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]pro- poxy]phenyl]ethanone; 1-[4-[2-[4-(1,2-benzisothiazol-3-yl)-1-piperazinyl]ethoxy]-3-methoxypheny- l]ethanone; 6-fluoro-3-[1-(3-phenoxypropyl)-4-piperidinyl]-1,2-benzoisoxazole;1-[4-[2-[4-(6-chloro-1H-indazol-3-yl)-1-piperazinyl]ethoxy]-3-methoxyphen- yl]ethanone; 1-[4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-meth- ylmercaptophenyl]ethanone;1-[4-[4-[4-(1,2-benzisothiazol-3-yl)-1-piperidinyl]butoxy]-3-methoxypheny- l]ethanone; 1-[4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-meth- oxyphenyl]phenylmethanone;1-[3-bromo-4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy- ]phenyl]ethanone; 3-[1-[3-[4-(1-ethoxyethyl)-2-methoxyphenoxy]propyl]-4-piperidinyl]-6-fluo- ro-1,2-benzisoxazole hydrochloride;3-[1-[3-[4-(1-acetoxyethyl)-2-methoxyphenoxy]propyl]-4-piperidinyl]-6-flu- oro-1,2-benzisoxazole fumarate; 1-[4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy-3-metho- xyphenyl]pentanone;2-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperdinyl]propoxy]-N-methylbe- nzenamine hemifumarate; 3-[1-[3-(4-bromo-2-methoxphenoxy)propyl]-4-piperidinyl]-6-fluoro-1,2-benz- isoxazole; 1-[4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propo-xy]-3-methoxyphenyl]propanone; 4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-methoxy- benzamide; 1-[4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propo- xy]-3-(methylamino)phenyl]ethanone;1-[4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-etho- xyphenyl]ethanone; N-[2-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]phenyl]- acetamide; 1-[4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propo-xy]-3-dimethylaminophenyl]ethanone; 1-[4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-2-meth- oxyphenyl]ethanone hydrochloride; 1-[4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-meth-oxyphenyl]-2,2,2-trifluoroethanone; 4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-hydroxy- -.alpha.-methylbenzenemethanol; 2-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]aniline dihydrochloride;N-[5-acetyl-2-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propox- y]phenyl]acetamide; 3-[1-[3-(4-ethyl-3-methoxyphenoxy)propyl]-4-piperidinyl]-6-fluoro-1,2-ben- zisoxazole hydrochloride;1-[3,5-dimethoxy-4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]p- ropoxy]phenyl]ethanone; N-[3-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]phenyl]- acetamide hemifumarate;3-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]aniline; 3-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-4-methoxy- aniline; 1-[4-[3-[4-(6-fluoro-1,2-benzisothiazol-3-yl)-1-piperidinyl]propo- xy-3-methylaminophenyl]ethanonefumarate; N-[3-[3-[4-(6-fluoro-1,2-benzisothiazol-3-yl)-1-piperidinyl]propoxy]-4-me- thoxyphenyl]acetamide; 1-[4-[3-[4-(6-fluoro-1,2-benzisothiazol-3-yl)-1-piperidinyl]propoxy]-3-me- thoxyphenyl]ethanone hydrochloride;N,N-dimethyl-4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propo- xy]-3-methoxybenzamide; 1-[4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-meth- oxyphenyl]ethanone oxime;1-[4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-methox- yphenyl]ethanone oxime O-methyl ether; 1-[4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-meth- oxyphenyl]ethanone hydrazone;6-fluoro-3-[1-[3-[2-methoxy-4-(1-methylethenyl)phenoxy]propyl]-4-piperidi- nyl]-1,2-benzisoxazole hydrochloride; (Z)-1-[4-[(4-chloro-2-butenyl)oxy]-3-methoxyphenyl]ethanone; (Z)-1-[4-[[4-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]-2-butenyl-]oxy]-3-methoxyphenyl]ethanone; (E)-1-[3-[[4-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]-2-butenyl- ]oxy]-4-hydroxyphenyl]ethanone hydrochloride; (E)-1-[3-[[4-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]-2-butenyl-]oxy]-4-benzyloxyphenyl]ethanone; 6-(3-chloropropoxy)-5-methoxy indole; 6-fluoro-3-[1-[3-[(5-methoxy-1H-indol-6-yl)oxy]propyl]-4-piperidinyl]-1,2- -benzisoxazole; 6-fluoro-3-[1-[3-[(1H-indol-7-yl)oxy]propyl]-4-piperidinyl]-1,2-benzisoxa- zolehemifumarate; 6-fluoro-3-[1-(3-hydroxypropyl)-4-piperidinyl]-1,2-benzisoxazole; 6-fluoro-3-[1-(2-pyrimidinoxy)propyl]-4-piperidinyl]-1,2-benzisoxazole fumarate; 6-aceto-2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]met- hyl-1,4-benzodioxan;2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]methyl-1,4-benzodioxa- n; 2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl-1,4-benzodiox- an; 6-(3-chloropropoxy)-7-methoxy-1-tetralone;6-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-7-methoxy- -1-tetralone; N-(3-chloropropyl)-2-benzoxazolinone; N-(3-chloropropyl)-6-acetyl-2-benzoxazolinone; N-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propyl]-6-acetyl-2--benzoxazolinone; N-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propyl]phthalimide- ; 1-(3-aminopropyl)-4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidine dihydrochloride; cis-2-(3-(4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl)propyl-hexahyd-ro-1H-isoindole-1,3-dione hydrochloride; N-[4-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]butyl]phthalimide; 1-(4-aminobutyl)-4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidine dihydrochloride;cis-(2-(4-(4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl)butyl)-hexahy- dro-1H-isoindole-1,3-dione hydrochloride; 1-[4-[[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propyl]thio]-3- -methoxyphenyl]ethanone;4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-(2'-methoxyphenyl)butylpiperidine maleate; 4-(4-bromobutyl)-1-(1,3-dithian-2-yl)ethylbenzene; 1-[4-(1,3-dithian-2-yl)ethyl]phenyl-4-(6-fluoro-1,2-benzisoxazol-3-yl)but- ylpiperidine;1-[4-(4'-acetophenyl)butyl]-4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidine; 1-[4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propylamino]-3-- methoxyphenyl]ethanone; (2,4-difluorophenyl)-[1-(phenylmethyl)-3-pyrrolidinyl]methanone oxalate;6-fluoro-3-[1-phenylmethyl)-3-pyrrolidinyl]-1,2-benzisoxazole fumarate; (E)-1-[4-[(4-bromo-2-butenyl)oxy]-3-methoxtrphenyl]ethanone; 4-(3-chloropropoxy)-3-methoxybenzaldehyde; 6-fluoro-3-(3-pyrrolidinyl)-1,2-benzisoxazole hydrochloride;1-[4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propylamino]-3-- hydroxyphenyl]ethanone; 1-[3-acetylamino-4-(3-chloropropoxy)phenyl]ethanone; N-[2-(3-hydroxypropoxy)phenyl]acetamide; 4-(3-chloropropoxy)-3-methoxybenzaldehyde;(.+-.)-1-[4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]-2-methy- lpropoxy]-3-methoxyphenyl]ethanone; (S)-(+)-1-[4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]-2-meth- ylpropoxy]-3-methoxyphenyl]ethanone;(R)-(-)-1-[4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]-2-meth- ylpropoxy]-3-methoxyphenyl]ethanone; 1-[4-[3-[4-[(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]-2,2-dimethylp- ropoxy]-3-methoxyphenyl]ethanone;(.+-.)-1-[4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]-2-pheny- lpropoxy]-3-methoxyphenyl]ethanone; (.+-.)-1-[4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]-2-(3-ch- lorophenyl)propoxy]-3-methoxyphenyl]ethanone;(.+-.)-1-[4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]-2-(phen- ylmethyl)propoxy]-3-methoxyphenyl]ethanone; (.+-.)-1-[4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]-1-methy- lpropoxy]-3-methoxyphenyl]ethanone;(.+-.)-1-[4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]-3-methy- lpropoxy]-3-methoxyphenyl]ethanone; (.+-.)-1-[4-[4-[4-(1,2-benzisoxazol-3-yl)-1-piperidinyl]-3-methylbutoxy]-- 3-methoxyphenyl]ethanone;(.+-.)-1-[4-[4-[4-(1,2-benzisoxazol-3-yl)-1-piperidinyl]-3-phenylbutoxy]-- 3-methoxyphenyl]ethanone; (.+-.)-1-[4-[4-[4-(1,2-benzisoxazol-3-yl)-1-piperidinyl]-2-(2-phenylethyl- )butoxy]-3-methoxyphenyl]ethanone;(.+-.)-[4-[2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]-1-methyle- thoxy]-3-methoxyphenyl]ethanone; (E)-1-[4-[[4-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]-1-methyl-- 2-butenyl]oxy]-3-methoxyphenyl]ethanone;(Z)-1-[4-[[4-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]-3-methyl-- 2-butenyl]oxy]-3-methoxyphenyl]ethanone; (.+-.)-1-[4-[[4-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]-1-prop- yl-2-butynyl]oxy]-3-methoxyphenyl]ethanone;(S)-(+)-1-[4-[3-[4-(6-fluoro-1H-indazol-3-yl)-1-piperazinyl]-2-methylprop- oxy]-3-methoxyphenyl]ethanone; (R)-(-)-1-[4-[3-[4-(6-fluoro-1H-indazol-3-yl)-1-piperazinyl]-2-methylprop- oxy]-3-methoxyphenyl]ethanone;(.+-.)-1-[4-[4-[4-(1,2-benzisothiazol-3-yl)-1-piperazinyl]-3-methylbutoxy- ]-3-methoxyphenyl]ethanone; (.+-.)-1-[4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]-2-pheny- lpropoxy]-3-methoxyphenyl]ethanone; and(.+-.)-6-fluoro-3-[1-[3-(2-methyl-(2-methoxyphenoxy)propyl]-4-piperidinyl- ]-1,2-benzisoxazole.
The compounds of the present invention are useful for treating psychoses by virtue of their ability to elicit an antipsychotic response in mammals. Antipsychotic activity is determined in the climbing mice assay by a method similar to thosedescribed by P. Protais, et al., Psychopharmacol., 50:1 (1976) and B. Costall, Eur. J. Pharmacol., 50:39 (1978).
Subject CK-1 male mice (23-27 grams) are group-housed under standard laboratory conditions. The mice are individually placed in wire mesh stick cages (4''.times.10'') and are allowed one hour for adaption and exploration of the new environment. The apomorphine is injected subcutaneously at 1.5 mg/kg, a dose causing climbing in all subjects for 30 minutes. Compounds to be tested for antipsychotic activity are injected intraperitoneally or given oral doses at various time intervals, e.g. 30minutes, 60 minutes, etc. prior to the apomorphine challenge at a screening dose of 10-60 mg/kg.
For evaluation of climbing, 3 readings are taken at 10, 20, and 30 minutes after apomorphine administration according to the following scale:
TABLE-US-00001 Climbing Behavior Mice with: Score 4 paws on bottom (no climbing) 0 2 paws on the wall (rearing) 1 4 paws on the wall (full climb) 2
Mice consistently climbing before the injection of apomorphine are discarded.
With full-developed apomorphine climbing, the animals are hanging on to the cage walls, rather motionless, over long periods of time. By contrast, climbs due to mere motor stimulation usually only last a few seconds.
The climbing scores are individually totaled (maximal score: 6 per mouse over 3 readings) and the total score of the control group (vehicle intraperitoneally-apomorphine subcutaneously) is set to 100%. ED.sub.50 values with 95% confidencelimits, calculated by a linear regression analysis, of some of the compounds of the present invention as well as a standard antipsychotic agent are presented in Table 1.
TABLE-US-00002 TABLE 1 CLIMBING MOUSE ASSAY COMPOUND (ED.sub.50 mg/kg, ip) 1-[4-[3-[4-(1H-indazol-3-yl)-1- 0.98 piperazinyl]propoxy]-3-methoxy- phenyl]ethanone 1-[4-[3-[4-(1,2-benzisoxazol-3-yl)- 0.67 1-piperidinyl]propoxy]-3-methoxy-phenyl]ethanone 1-[4-[3-[4-(6-fluoro-1,2-benzisoxazol- 0.095 3-yl)-1-piperidinyl]propoxy]-3-methoxy- phenyl]ethanone 1-[4-[4-[4-(1,2-benzisoxazol-3-yl)-1- 1.6 piperidinyl]butoxy]-3-methoxy-phenyl] ethanone 1-[4-[4-[4-(6-fluoro-1,2-benzisoxazol- 0.683-yl)-1-piperidinyl]butoxy]-3-methoxy- phenyl]ethanone 1-[4-[3-[4-(6-fluoro-1,2-benzisothiazol- 0.16 3-yl)-1-piperidinyl]propoxy]-3-methoxy- phenyl]ethanone hydrochloride 2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1- 0.29 piperidinyl]ethyl]-1,4-benzodioxan(Z)-1-[4-[[4-[4-(6-fluoro-1,2-benzisoxazol- 0.61 3-yl)-1-piperidinyl]-2-butenyl]oxy]-3- methoxyphenyl]ethanone 1-[4-(4'-acetophenyl)butyl]-4-(6-fluoro- 0.34 1,2-benzisoxazol-3-yl)-1-piperidine (6-fluoro-3-[1-(3-hydroxypropyl)-4- 4.1piperidinyl]-1,2-benzisoxazole 4-[4-(6-fluoro-1,2-benzisoxazol-3-yl)- 3.31 1-piperidinyl]butyl decanoate fumarate 1-(3-aminopropyl)-4-(6-fluoro-1,2 22.6 -benzisoxazol-3-yl)piperidine dihydro- chloride N-[2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)- 5.01-piperidinyl]ethyl]phthalimide 6-fluoro-3-[1-[3-(isoquinol-5-yl)oxy] 0.172 propyl]-4-piperidinyl]-1,2-benzisoxazole sesquifumarate Chlorpromaxine (standard) 1.3
Antipsychotic response is achieved when the compounds of the present invention are administered to a subject requiring such treatment as an effective oral, parenteral, or intravenous dose of from 0.01 to 50 mg/kg of body weight per day. It is tobe understood, however, that for any particular subject, specific dosage regimens should be adjusted according to the individual need and the professional judgment of the person administering or supervising the administration of the aforesaid compound. It is to be further understood that the dosages set forth herein are exemplary only and they do not, to any extent, limit the scope or practice of the invention.
Some of the compounds of the present invention are | | | |
