Patent GB-1245502-A (GB)
Title: Benzisoindoline compounds
IPC: C07D307/77
Filed: 1969-09-25
Abstract: 1,245,502. Benzisoindoline derivatives. E.I. DU PONT DE NEMOURS & CO. 25 Sept., 1969 [26 Sept., 1968], No. 47366/69. Heading C2C. Novel compounds I in which R<SP>1</SP> is H, NO 2 , OR<SP>4</SP> (R<SP>4</SP> is H, 1-3C alkyl, or -COR<SP>5</SP>, where R<SP>5</SP> is H or 1-3C alkyl) or -COR<SP>6</SP> (R<SP>6</SP> is 1-6C alkyl); R<SP>2</SP> is H, 1-5C alkyl, 3-5C alkenyl in which the double bond is not in the 1-position, propargyl, cyclopropylmethyl, benzyl or phenethyl; R<SP>3</SP> is H, 1-3C alkyl, benzyl or phenethyl; X is carbonyl or =CR<SP>7</SP>R<SP>8</SP>; R<SP>7</SP> is H, or OR<SP>9</SP> (R<SP>9</SP> is H or 1-3C alkyl); R<SP>8</SP> is H or 1-3C alkoxy (R<SP>8</SP> is H if R<SP>9</SP> is H) or R<SP>7</SP> and R<SP>8</SP> together form part of a cyclic alkylene ketal group wherein the alkylene moiety has 2-3C; are prepared by (a) converting in manner known per se a compound of Formula II wherein Z is a protected carbonyl group and any ketonic groups in R 1  may be similarly protected, into a compound I, (b) reducing a compound I where R 1  is H or OR 4  and X is carbonyl to give I where X is CH 2 , (c) reducing a compound III followed by deprotection of the protected carbonyl group Z, (d) converting in manner known per se a compound I where R 1  is NH 2 , X is CHOH and R 2  is other than H to give a compound I where R 1  is OH or (e) oxidizing a compound I where X is CHOH to one in which X is carbonyl. Intermediates isolated are exo - N - methyl- 1,2,3,4 - tetrahydro - 9 - oxo - 1,4 - ethanonaphthalene - 2,3 - dicarboximide, prepared from the corresponding anhydride and CH 3 NH 2 ; exo-N- methyl - 1,2,3,4 - tetrahydro - 9,9 - dimethoxy-1,4- ethanonaphthalene - 2,3 - dicarboximide, prepared by protection of the first-named intermediate; exo - N - (cyclopropylmethyl, phenethyl, or allyl)- 1,2,3,4 - tetrahydro - 9 - oxo - 1,4 - ethanonaphthalene-2,3-dicarboximide, prepared similarly to the first intermediate; exo - N - (cyclopropylmethyl, phenethyl or allyl) - 1,2,3,4 - tetrahydro - 9,9 - dimethoxy - 1,4 - ethanonaphthalene- 2,3-dicarboximide, prepared similarly to the second intermediate; exo - 1,2,3,4 - tetrahydro- 8 - nitro - 9 - oxo - 1,4 - ethano - naphthalene-2,3- dicarboxylic acid and its anhydride, prepared by hydrolysis of the dimethyl ester and dehydration of the acid; exo-N-methyl-1,2,3,4-tetrahydro - 8 - nitro - 9 - oxo - 1,4 - ethanonaphthalene-2,3-dicarboximide, prepared by reaction of methylamine with the above anhydride; exo-N- methyl - 1,2,3,4 - tetrahydro - 8 - amino - 9 - oxo- 1,4 - ethanonaphthalene - 2,3 - dicarboximide, prepared by reduction of the NO 2  group in the previous intermediate; exo- 1 ,2,3,4-tetrahydro-6- acetyl - 9 - oxo - 1,4 - ethanonaphthalene - 2,3- dicarboxylic anhydride, prepared by reaction of 2 - methoxy - 6 - acetyl naphthalene with HBr/CH 3 COOH, followed by reaction with maleic anhydride; exo - 1,2,3,4 - tetrahydro-N- methyl - 6 - acetyl - 9 - (exo or protected oxo)-1,4- ethanonaphthalene - 2,3 - dicarboximide, prepared similarly to the first and second intermediates; exo - 1,2,3,4 - tetrahydro - 4 - benzyl - 9 - oxo - 1,4- ethanonaphthalene - 2,3 - dicarboxylic anhydride, prepared from 1 - benzyl-2-naphthol and maleic anhydride; N - methyl - 1,2,3,4 - tetrahydro - 9- hydroxy 1,4 - ethanonaphthalene - 2,3 - dicarboximide, prepared by reduction of the 9-oxo compound; N - methyl - 1,2,3,4 - tetrahydro-9- methoxy - 1,4 - ethanonaphthalene - 2,3 - dicarboximide, prepared by methylation of the previous intermediate; endo - N - methyl - 1,2,3,4 - tetrahydro - 9 - oxo - 1,4 - ethano - naphthalene-2,3- dicarboximide, prepared similarly to the first intermediate and which can be protected similarly to the second intermediate; and exo- N - methyl - 1,2,3,4 - tetrahydro - 9,9 - ethylenedioxy - 1,4 - ethanonaphthalene - 2,3 - dicarboximide, prepared by reaction of the first intermediate with ethylene glycol. Pharmaceutical compositions comprise a compound I together with a suitable carrier, are administered enterally or parenterally and have analgesic activity.