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US 5,294,618 AGranted
Octahydrobenzisoquinoline derivatives as antipsychotic agents
AssigneeMerck Sharp & Dohme Corp.
InventorsDavid C. Billington, Michael G. N. Russell
Life of this patent
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Abstract
A class of 1,2,3,4,4a,5,6,10b-octahydrobenz[f]isoquinoline compounds and pharmaceutically acceptable salts of formula I: ##STR1## wherein, R.sup.1 represents hydrocarbon; R.sup.2 and R.sup.3 independently represent hydrogen, hydrocarbon, halogen, cyano, trifluoromethyl, nitro, --OR.sup.x, --SR.sup.x, --NR.sup.x R.sup.y, --CO.sub.2 R.sup.x or together represent methylenedioxy; and R.sup.x and R.sup.y independently represent hydrogen or hydrocarbon. The compounds disclosed herein are selective ligands at sigma recognition sites and are therefore useful in the treatment of psychiatric disorders.
Claims13
A compound of formula II:
- ##STR12## wherein R.sup.21 is selected from the group consisting of C.sub.3-6 alkyl, C.sub.2-6 alkenyl, C.sub.3-7 cycloalkyl, C.sub.3-7 cycloalkyl(C.sub.1-6)alkyl, or aryl(C.sub.1-6)alkyl, any of which groups may be optionally substituted with a substituent selected from the group consisting of C.sub.1-6 alkyl, adamantyl, phenyl, halogen, C.sub.1-6 haloalkyl, trifluoromethyl, hydroxy, C.sub.1-6 alkoxy, aryloxy, C.sub.1-3 alkylenedioxy, nitro, cyano, carboxy, C.sub.2-6 alkoxycarbonyl, C.sub.2-6 alkoxycarbonyl(C.sub.1-6)alkyl, C.sub.2-6 alkylcarbonyloxy, C.sub.1-6 alkylthio, C.sub.1-6 alkylsulphinyl, C.sub.1-6 alkylsulphonyl, amino, mono- or di(C.sub.1-6)alkylamino, C.sub.2-6 alkylcarbonylamino and C.sub.2-6 alkoxycarbonylamino;
- and R.sup.22 and R.sup.23 are hydrogen;
- or a pharmaceutically acceptable salt thereof.
The compound represented by formula IIA:
- ##STR13## wherein, R.sup.21 is selected from the group consisting of C.sub.3-6 alkyl, C.sub.2-6 alkenyl, C.sub.3-7 cycloalkyl, C.sub.3-7 cycloalkyl-(C.sub.1-6) alkyl and aryl (C.sub.1-6) alkyl, any of said groups may be optionally substituted with a substituent selected from the group consisting of C.sub.1-6 alkyl, adamantyl, phenyl, halogen, C.sub.1-6 haloalkyl, trifluoromethyl, hydroxy, C.sub.1-6 alkoxy, aryloxy, C.sub.1-3 alkylenedioxy, nitro, cyano, carboxy, C.sub.2-6 alkoxycarbonyl, C.sub.2-6 alkoxycarbonyl (C.sub.1-6) alkyl, C.sub.2-6 alkylcarbonyloxy, arylcarbonyloxy, C.sub.1-6 alkylthio, C.sub.1-6 alkylsulphinyl, C.sub.1-6 alkylsulphonyl, C.sub.2-6 alkylcarbonyl, amino, mono- or di(C.sub.1-6) alkylamino, C.sub.2-6 alkylcarbonylamino and C.sub.2-6 alkoxycarbonylamino and R.sup.22 and R.sup.23 are hydrogen;
- or pharmaceutically acceptable salts thereof.
A compound of formula II:
- ##STR15## selected from the group consisting of 3-butyl-1,2,3,4,4a,5,6,10b-octahydrobenz isoquinoline;
- 3-(4'-methoxybenzyl)-1,2,3,4,4a,5,6,10b-octahydrobenz isoquinoline;
- 3-cyclohexyl-1,2,3,4,4a,5,6,10b-octahydrobenz isoquinoline;
- 3-benzyl-1,2,3,4,4a,5,6,10b-octahydrobenz isoquinoline;
- 1,2,3,4,4a,5,6,10b-octahydro-3-phenethylbenz isoquinoline;
- 3-(4'-nitrobenzyl)-1,2,3,4,4a,5,6,10b-octahydrobenz isoquinoline;
- 3-(4'-chlorobenzyl)-1,2,3,4,4a,5,6,10b-octahydrobenz isoquinoline;
- 3-(4'-t-butylbenzyl)-1,2,3,4,4a,5,6,10b-octahydrobenz isoquinoline;
- 3-1,2,3,4,4a,5,6,10b-octahydrobenz isoquinoline;
- 1,2,3,4,4a,5,6,10b-octahydro-3-(3'-phenylpropyl)-benz isoquinoline;
- 3-(3'-methylbut-2'-enyl)-1,2,3,4,4a,5,6,10b-octahydrobenz isoquinoline;
- 1,2,3,4,4a,5,6,10b-octahydro-3-(prop-2'-enyl)-benz isoquinoline;
- 3-(but-3'-enyl)-1,2,3,4,4a,5,6,10b-octahydrobenz isoquinoline;
- 1,2,3,4,4a,5,6,10b-octahydro-3-propylbenz isoquinoline;
- 3-(1'-adamantyl)-1,2,3,4,4a,5,6,10b-octahydrobenz isoquinoline;
- 3-(2'-adamantyl)-1,2,3,4,4a,5,6,10b-octahydrobenz isoquinoline;
- 3-butyl-7,9-dimethyl-1,2,3,4,4a,5,6,10b-octahydrobenz isoquinoline;
- 3-(2'-naphthylmethyl)-1,2,3,4,4a,5,6,10b-octahydrobenz isoquinoline;
- 3-cyclopropylmethyl-1,2,3,4,4a,5,6,10b-octahydrobenz isoquinoline;
- and salts thereof.
17 more elements
A pharmaceutical composition comprising an effective amount of a compound represented by formula IA:
- ##STR16## wherein, R.sup.11 is selected from the group consisting of C.sub.3-6 alkyl, C.sub.2-6 alkenyl, C.sub.3-7 cycloalkyl, C.sub.3-7 cycloalkyl(C.sub.1-6)alkyl, or aryl(C.sub.1-6)alkyl, any of which groups may be optionally substituted with a substituent selected from the group consisting of C.sub.1-6 alkyl, adamantyl, phenyl, halogen, C.sub.1-6 haloalkyl, trifluoromethyl, hydroxy, C.sub.1-6 alkoxy, aryloxy, C.sub.1-3 alkylenedioxy, nitro, cyano, carboxy, C.sub.2-6 alkoxycarbonyl, C.sub.2-6 alkoxycarbonyl(C.sub.1-6)alkyl, C.sub.2-6 alkylcarbonyloxy, C.sub.1-6 alkylthio, C.sub.1-6 alkylsulphinyl, C.sub.1-6 alkylsulphonyl, amino, mono- or di(C.sub.1-6)alkylamino, C.sub.2-6 alkylcarbonylamino and C.sub.2-6 alkoxycarbonylamino;
- and R.sup.12 and R.sup.13 are hydrogen;
- or a pharmaceutically acceptable salt thereof.
A method for the treatment of disorders requiring administration of a selective ligand at sigma recognition sites which comprises administering to a patient in need of such treatment an effective amount of a compound of formula I:
- ##STR17## wherein R.sup.1 is a hydrocarbon selected from the group consisting of C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-10 cycloalkyl, C.sub.3-7 cycloalkyl(C.sub.1-6)alkyl, aryl, or aryl(C.sub.1-6) alkyl, any of which groups may be optionally substituted by one or more groups selected from the group consisting of C.sub.1-6 alkyl, adamantyl, phenyl, halogen, C.sub.1-6 haloalkyl, trifluoromethyl, hydroxy, C.sub.1-6 alkoxy, aryloxy, keto, C.sub.1-3 alkylenedioxy, nitro, cyano, carboxy, C.sub.2-6 alkoxycarbonyl, C.sub.2-6 alkoxycarbonyl(C.sub.1-6)alkyl, C.sub.2-6 alkylcarbonyloxy, arylcarbonyloxy, C.sub.2-6 alkylcarbonyl, arylcarbonyl, C.sub.1-6 alkylthio, C.sub.1-6 alkylsulphinyl, C.sub.1-6 alkylsulphonyl, amino, mono-or di(C.sub.1-6)alkylamino, C.sub.2-6 alkylcarbonylamino and C.sub.2-6 alkoxycarbonylamino;
- R.sup.2 and R.sup.3 are independently selected from the group consisting of hydrogen, hydrocarbons consisting of C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-10 cycloalkyl, C.sub.3-7 cycloalkyl(C.sub.1-6)alkyl, aryl, or aryl(C.sub.1-6)alkyl, halogen, cyano, trifluoromethyl, nitro, --OR.sup.x, SR.sup.x, --NR.sup.x R.sup.y, --CO.sub.2 R.sup. x, --CONR.sup.x R.sup.y or together represent methylenedioxy;
- and Rx and Ry independently represent hydrogen or hydrocarbons selected from the group consisting of C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-10 cycloalkyl, C.sub.3-7 cycloalkyl(C.sub.1-6)alkyl, aryl, or aryl(C.sub.1-6)alkyl, or a pharmaceutically acceptable salt thereof.
Dependencies are inferred from the claim text.