Details for Patent: 5,840,727

Title:	(4-heteroaryl)-1-[(2,3-dihydro-1H-isoindol-2-yl) alkyl] piperazines and related compounds and their therapeutic utility
Abstract:	Heteroarylpiperidines, pyrrolidines, and piperazines are useful as antipsychotic and analgesic agents the compounds are especially useful for treating psychoses by administering to a mammal a psychoses-treating effective amount of one of the compounds. Depot derivatives of the compounds are useful for providing long acting effects of the compounds. The compounds are also useful as analgesics by administering a pain-relieving effective amount of one of the compounds to a mammal.
Inventor(s):	Strupczewski; Joseph T. (Flemington, NJ), Bordeau; Kenneth J. (Kintnersville, PA), Glamkowski; Edward J. (Warren, NJ), Chiang; Yulin (Covent Station, NJ), Nemoto; Peter A. (Raritan, NJ), Tegeler; John J. (Bridgewater, NJ)
Assignee:
Filing Date:	Jun 06, 1995
Application Number:	08/468,960
Claims:	1. A compound of the formula: wherein ##STR133## X is --O--, --S--, --NH--, or --N(R.sub.2)--; R.sub.2 is selected from the group consisting of lower alkyl, aryl lower alkyl, aryl, cycloalkyl, aroyl, alkanoyl, alkoxycarbonyl, and phenylsulfonyl groups; aryl is as defined hereinafter; p is 1 or 2; Y is hydrogen, lower alkyl, hydroxy, chlorine, fluorine, bromine, iodine, lower alkoxy, trifluoromethyl, nitro, or amino; R.sub.1 is --CR.sub.24 R.sub.27 --(CR.sub.23 R.sub.24) .sub.n --CR.sub.24 R.sub.27 --, where n is 0, 1, 2 or 3; or --CHR.sub.24 CH.dbd.CH--CHR.sub.24 --, --CHR.sub.24 --C.tbd.C--CHR.sub.24 --, --CHR.sub.24 --CH.dbd.CH--CR.sub.23 R.sub.24 --CHR.sub.24 --, --CHR.sub.24 --CR.sub.23 R.sub.24 --CH.dbd.CH--CHR.sub.24 --, --CHR.sub.24 --C.tbd.C--CR.sub.23 R.sub.24 --CHR.sub.24 --, or --CHR.sub.24 --CR.sub.23 R.sub.24 --C.tbd.C--CHR.sub.24, the --CH.dbd.CH-- bond being cis or trans; R.sub.23 is hydrogen, (C.sub.1 -C.sub.18) linear alkyl, phenyl, hydroxy, (C.sub.1 -C.sub.18)alkoxy, aryloxy, aryl(C.sub.1 -C.sub.18)alkyloxy, (C.sub.1 -C.sub.18) alkanoyloxy, hydroxy(C.sub.1 -C.sub.6)alkyl, (C.sub.1 -C.sub.18)alkoxy(C.sub.1 -C.sub.6)alkyl, aryl(C.sub.1 -C.sub.18)alkyloxy(C.sub.1 -C.sub.6)alkyl, (C.sub.1 -C.sub.18) alkanoyloxy(C.sub.1 -C.sub.6)alkyl or ##STR134## where Z.sub.1 is lower alkyl, --OH, lower alkoxy, --CF.sub.3, --NO2, --NH.sub.2, or halogen, and p is as previously defined; R.sub.24 is hydrogen, (C.sub.1 -C.sub.18) linear alkyl, phenyl, hydroxy(C.sub.1 -C.sub.6)alkyl, (C.sub.1 -C.sub.18,)alkoxy(C.sub.1 -C.sub.6)alkyl, phenyl(C.sub.1 -C.sub.6)alkyloxy, aryl(C.sub.1 -C.sub.18)alkyoxy(C.sub.1 -C.sub.6)alkyl, (C.sub.1 -C.sub.18)alkanoyloxy(C.sub.1 -C.sub.6)alkyl or ##STR135## where Z.sub.1 and p are as previously defined; R.sub.27 is hydrogen or R.sub.24 and R.sub.27 taken together with the carbon to which they are attached form C.dbd.O or C.dbd.S; R.sub.4 is hydrogen, lower alkyl, lower alkoxy, hydroxy, tri(C.sub.1 -C.sub.6)alkylsilyloxy, hydroxy lower alkyl, alkanoyloxy lower alkyl, amino, mono- or dialkylamino, (C.sub.1 -C.sub.18)acyl amino, (C.sub.1 -Cl.sub.8)alkanoyl, trifluoromethyl, chlorine, fluorine, bromine, nitro, --O--C(.dbd.O)--C.sub.1 -C.sub.18 straight or branched chain)alkyl or --C(.dbd.O)-aryl; R.sub.2 is hydrogen, (C.sub.1 -C.sub.6)alkyl, aryl(C.sub.1 -C.sub.6)alkyl or aryl, in which aryl is phenyl or ##STR136## where R.sub.5 is hydrogen, lower alkyl, lower alkoxy, hydroxy, chlorine, fluorine, bromine, iodine, lower monoalkylamino, lower dialkylamino, nitro, cyano, trifluoromethyl, or trifluoromethoxy; q is 1, 2, 3, or 4; and, any hydroxyl group attached to an aliphatic or aromatic carbon atom, or any primary or secondary nitrogen atom may be acylated with a (C.sub.4 -C.sub.18)alkanoyl group, in addition, any nitrogen atom may alternatively be acylated with a (C.sub.4 -C.sub.18)alkoxycarbonyl group; all geometric, optical, and stereoisomers thereof, or a pharmaceutically acceptable acid addition salt thereof. 2. The compound of claim 1, wherein X is --N(R.sub.2)--. 3. The compound of claim 2, wherein R.sub.2 is (C.sub.1 -C.sub.18)alkanoyl or (C.sub.1 -C.sub.18) alkoxycarbonyl. 4. The compound of claim 1, wherein X is --NH--. 5. The compound of claim 4, which is 4-(1H-indazol-3-yl)-1-[2-(2,3-dihydro-5-fluoro-1H-isoindol-2-yl) ethyl]piperazine and its pharmaceutically acceptable acid addition salts. 6. The compound of claim 4, which is 4-(6-fluoro-1H-indazol-3-yl)-1-[2-(2,3-dihydro-4-methyl-1H-isoindol-2-yl)e thyl]piperazine and its pharmaceutically acceptable acid addition salts. 7. The compound of claim 4, which is 4-(6-fluoro-1H-indazol-3-yl)-1-[2-(2,3-dihydro-5-methyl-1H-isoindol-2-yl)e thyl]piperazine and its pharmaceutically acceptable acid addition salts. 8. The compound of claim 4, which is 4-(6-fluoro-1H-indazol-3-yl)-1-[2-(5-fluoro-2,3-dihydro-1H-isoindol-2-yl)e thyl]piperazine and its pharmaceutically acceptable acid addition salts. 9. The compound of claim 4, which is 4-(1H-indazol-3-yl)-1-[2-(2,3-dihydro-1H-isoindol-2-yl) ethyl]piperazine and its pharmaceutically acceptable acid addition salts. 10. The compound of claim 5, which is 4-(6-fluoro-1H-indazol-3-yl)-1-[2-(2,3-dihydro-1H-isoindol-2-yl)ethyl]pipe razine and its pharmaceutically acceptable acid addition salts. 11. The compound of claim 5, which is 4-(6-fluoro-1H-indazol-3-yl)-1-[3-(2,3-dihydro-1H-isoindol-2-yl) propyl]piperazine and its pharmaceutically acceptable acid addition salts. 12. The compound of claim 2, which is 4-(1-decanoyl-6-fluoro-1H-indazol-3-yl)-1-[2-(2,3-dihydro-1H-isoindol-2-yl )ethyl]piperazine and its pharmaceutically acceptable acid addition salts. 13. An antipsychotic composition, which comprises the compound of claim 1 in an amount sufficient to produce an antipsychotic effect, and a pharmaceutically acceptable carrier therefore. 14. A method of treating psychoses, which comprises administering to a mammal a psychoses-treating effective amount of the compound of claim 1. 15. An analgesic composition, which comprises the compound of claim 1 in an amount sufficient to produce a pain-relieving effect, and a pharmaceutically acceptable carrier therefor. 16. A method of alleviating pain, which comprises administering to a mammal a pain-relieving effective amount of the compound of claim 1. 17. A depot pharmaceutical composition, which comprises a pharmaceutically acceptable carrier and a therapeutically effective amount of the compound of claim 1, wherein the compound contains an acylated hydroxy group, or an acylated amino group. 18. The depot pharmaceutical composition of claim 17, wherein the hydroxy group is acylated with an (C.sub.4 -C.sub.18)alkanoyl group, or the amino group is acylated with an (C.sub.4 -C.sub.18)alkanoyl group or an (C.sub.4 -C.sub.18)alkoxycarbonyl group. 19. The composition of claim 17, which contains a pharmaceutically acceptable oil. 20. The composition of claim 19, wherein the oil is selected from the group consisting of coconut oil, peanut oil, sesame oil, cotton seed oil, corn oil, soybean oil, olive oil, and synthetic esters of fatty acids and polyfunctional alcohol. 21. The composition of claim 18, which contains a pharmaceutically acceptable oil. 22. The composition of claim 21, wherein the oil is selected from the group consisting of coconut oil, peanut oil, sesame oil, cotton seed oil, corn oil, soybean oil, olive oil, and synthetic esters of fatty acids and polyfunctional alcohols. 23. A method for providing a long acting antipsychotic effect, which comprises injecting into a mammal an amount of the composition of claim 19 sufficient to produce a long acting antipsychotic effect. 24. A method for providing a long acting antipsychotic effect, which comprises injecting into a mammal an amount of the composition of claim 18 sufficient to produce a long acting antipsychotic effect. 25. A method for providing a long acting antipsychotic effect, which comprises injecting into a mammal an amount of the composition of claim 22 sufficient to produce a long acting antipsychotic effect.