Details for Patent: 5,654,319
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Title: | N-[(4-heteroaryl-1-piperidinyl)alkyl]-2,3-naphthalimides 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): | Glamkowski; Edward J. (Warren, NJ), Chiang; Yulin (Covent Station, NJ) |
Assignee: | Hoechst Marion Roussel, Inc. (Kansas City, MO) |
Filing Date: | Jun 06, 1995 |
Application Number: | 08/470,704 |
Claims: | 1. A compound of the formula: ##STR133## wherein, X is --O--, --S--, --NH--, or --N(R.sub.2)--; R.sub.2 is selected from the group consisting of lower alkyl, aryl lower alkyl, aryl, cycloalkyl, aroyl, alkanoyl, alkoxycarbonyl, and phenysulfonyl 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 --.ident.C--CHR.sub.24 --, --CHR.sub.24 ----CH.dbd.CH--CR.sub.23 R.sub.24 --CHR.sub.24 --, --CHR.sub.24 --CR.sub.23 R.sub.24 --CH.dbd.CH--CHR.sub.24 --, --CHR.sub.24 --C.ident.C--CR.sub.23 R.sub.24 --CHR.sub.24 --, or --CHR.sub.24 --CR.sub.23 R.sub.24 --C.ident.C--CHR.sub.24, the --CH.dbd.CH-- bond being cis or trans; R.sub.23 is hydrogen, (C.sub.1 -C.sub.18)linear alkyl, phenyl, hydroxy, (C.sub.1 -C.sub.18) alkoxy, aryloxy, aryl (C.sub.1 -C.sub.18) alkyloxy, (C.sub.1 -C.sub.18) alkanoyloxy, hydroxy (C.sub.1 -C.sub.6) alkyl, (C.sub.1 -C.sub.18) alkoxy (C.sub.1 -C.sub.6)alkyl, phenyl (C.sub.1 -C.sub.6) alkoxy, 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, --NO.sub.2, --NH.sub.2, or halogen, and p is as previously defined, wherein aryl is as defined hereinafter; and R.sub.24 is hydrogen, (C.sub.1 -C.sub.18) linear alkyl, phenyl, hydroxy (C.sub.1 -C.sub.6) alkyl, (C.sub.1 -C.sub.18) alkoxy (C.sub.1 -C.sub.6)alkyl, phenyl (C.sub.1 -C.sub.6)alkyloxy, aryl (C.sub.1 -C.sub.6) alkyloxy (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 is as previously defined, and p is as previously defined, wherein aryl is as defined hereinafter; 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 -C.sub.18)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, wherein aryl is as defined hereinafter; aryl is phenyl or wherein R.sub.5 is hydrogen, lower alkyl, lower alkoxy, hydroxy, chlorine, fluorine, bromine, iodine, lower monoalkylamino, lower dialkylamine, nitro, cyano, trifluoromethyl, or trifluoromethoxy; m is 1, 2, or 3; and, any hydroxyl group attached to an aliphatic or aromatic carbon atom, or any primary or secondary nitrogen atom may be acylated with a (C.sub.4 -C.sub.18)carboxylic 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 R.sub.1 is --CH.sub.2 --CH.sub.2 --. 3. The compound of claim 2, which is N-2-[2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl]-2,3-naphth alimide and its pharmaceutically acceptable acid addition salts. 4. The compound of claim 1, wherein X is --N(R.sub.2)--. 5. The compound of claim 4, wherein R.sub.2 is (C.sub.1 -C.sub.18)alkanoyl or (C.sub.1 -C.sub.18) alkoxycarbonyl. 6. An antipsychotic composition, which comprises the compound of claim 1 in an amount sufficient to produce an antipsychotic effect and a pharmaceutically acceptable carrier. 7. A method of treating psychoses, which comprises administering to a mammal a psychoses-treating amount of the compound of claim 1. 8. 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. 9. A method of alleviating pain, which comprises administering to a mammal a pain-relieving effective amount of the compound of claim 1. 10. A pharmaceutical composition, which comprises a pharmaceutically acceptable carrier and a therapeutically effective amount of the compound of claim 1, wherein the compound contains or a nitrogen at the 1-position of an indazole ring, which has an acylated hydroxy group, or an acylated amino group. 11. The depot pharmaceutical composition of claim 10, wherein the hydroxy group or amino group is acylated, or the amino group is acylated with a (C.sub.4 -C.sub.18)alkanoyl group or a (C.sub.4 -C.sub.18)alkoxycarbonyl group. 12. The composition of claim 10, which contains a pharmaceutically acceptable oil. 13. The composition of claim 12, 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. 14. The composition of claim 11, which contains a pharmaceutically acceptable oil. 15. The composition of claim 14, 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. 16. A method for providing a long acting antipsychotic effect, which comprises injecting into a mammal an amount of the composition of claim 10 sufficient to produce a long acting antipsychotic effect. 17. A method for providing a long acting antipsychotic effect, which comprises injecting into a mammal an amount of the composition of claim 11 sufficient to produce a long acting antipsychotic effect. 18. A method for providing a long acting antipsychotic effect, which comprises injecting into a mammal an amount of the composition of claim 15 sufficient to produce a long acting antipsychotic effect. |