Patent GB-1145055-A (GB)
Title: Improvements in or relating to substituted isoindolo[2,1-d] [1,4]benzodiazepin-6-ones
Inventor: HARDTMANN GOETZ E
IPC: C07D209/50
Filed: 1966-05-31
Abstract: 1,145,055. Substituted isoindolo-[2,1-d]-[1,4]- benzodiazepin-6-ones. SANDOZ Ltd. 31 May, 1966 [11 June, 1965], No. 24279/66. Heading C2C. [Also in Division C7] Novel substituted isoindolo - [2,1 - d] - [1,4]- benzodiazepin-6-ones of the general formula wherein R 1  is a hydrogen, fluorine, chlorine or bromine atom and R 2  is a hydrogen atom or C 1-4  alkyl group, and acid addition salts thereof are prepared (a) by subjection of a substituted 1-phenyl-isoindoline-2-acetic acid alkyl ester of the general formula wherein A is a hydrogen atom or a C 1-4  alkyl group to an intramolecular ring closure; (b) when R 2  is a hydrogen atom, by subjection of a 1-(2-nitrophenyl)-isoindolo-2-acetic acid alkyl ester of the general formula wherein Alkyl is a C 1-4  alkyl group, to reduction and intramolecular ring closure; or (c) when R 2  is a C 1-4  alkyl group, by reaction of a compound of the first general formula above wherein R 2  is a hydrogen atom with an alkyl halide of the general formula R 2 <SP>1</SP>Y, wherein R 2 <SP>1</SP> is a C 1-4  alkyl group and Y is a chlorine, bromine or iodine atom; followed optionally by conversion of the product to an acid addition salt thereof. Pharmaceutical compositions having sedative, hypnotic and tranquillizing activity comprise, as active ingredient, a substituted isoindolo- [2,1-d]-[1,4]-benzodiazepin-6-one of the first general formula above and/or a physiologically acceptable acid addition salt thereof, together with a physiologically acceptable carrier. Substituted 1-phenyl-isoindoline-2-acetic acid alkyl esters of the second general formula above are prepared by subjection of a substituted 1- phenyl-isoindolin-3-one of the general formula to electrolytic reduction in acid solution and reaction of the resulting substituted 1-phenylisoindoline of the general formula with a chloro- or bromo-acetic acid C 1-4  alkyl ester. Substituted 1-phenyl-isoindolin-3-ones of the fifth general formula above are prepared (a) by treatment of a 5,6-dihydro-6,11-dioxomorphanthridine derivative of the general formula with an aqueous alkali, followed by an aqueous acid, and hydrogenation of the resulting benzophenone-2-carboxylic acid derivative of the general formula in the presence of ammonia and Raney nickel; (b) by heating a 5,6-dihydro-6,11-dioxo-morphanthridine derivative of the seventh general formula above in anhydrous liquid ammonia in the presence of sodium and reduction of the resulting substituted 1-phenyl-1-amino-isoindolin- 3-one of the general formula with sodium borohydride; (c) by reduction of a 5,6-dihydro-6,11-dioxomorphanthridine derivative of the seventh general formula above with sodium borohydride, chlorination of the resulting 5,6-dihydro-6-oxo-11-hydroxymorphanthridine derivative of the general formula with thionyl chloride and heating the 5,6-dihydro - 6 - oxo - 11 - chloro - morphanthridine derivative of the general formula so obtained in anhydrous liquid ammonia; or (d) by boiling a 5,6-dihydro-6-oxo-11-chloromorphanthridine derivative of the eleventh general formula above with anhydrous hydrazine and treating the resulting substituted 1- phenyl - 2 - amino - isoindolin - 3 - one of the general formula with an alkali metal nitrite in acid solution. 5,6 - Dihydro - 6,11 - dioxo - morphanthridine derivatives of the seventh general formula above wherein R 2  is a C 1-4  alkyl group are prepared by reaction of the corresponding compound wherein R 2  is a hydrogen atom with an alkyl halide of the fourth general formula above. 1 - (2 - Nitrophenyl) - isoindolo - 2 - acetic acid alkyl esters of the third general formula above are prepared by reaction of o-tolyl magnesium iodide with an o-nitrobenzaldehyde derivative of the general formula oxidation of the resulting 2-methyl-2<SP>1</SP>-nitrobenzohydrol derivative of the general formula with chromium trioxide in glacial acetic acid, bromination of the 2-methyl-2<SP>1</SP>-nitrobenzophenone derivative of the general formula so obtained with N-bromosuccinimide and reaction of the 2-bromomethyl-2<SP>1</SP>-nitrobenzophenone derivative of the general formula thus produced with a glycine C 1-4  alkyl ester.