Patent GB-1262972-A (GB)
Title: Tetracyclic amines and process for their manufacture
IPC: C07C211/31
Filed: 1969-03-31
Abstract: 1,262,972. 11-Aminoalkyl-9,10-etheno-anthracenes; organo-lithium compound. CIBAGEIGY A.G. 31 March, 1969 [3 April, 1968; 23 Jan., 1969], No. 16623/69. Headings C2C and C2J. Novel 11-aminoalkyl-9,10-etheno-anthracenes of the general formula  wherein Ph 1  and Ph 2  are each 1,2-phenylene radicals, alk is a lower alkylene, alkylidene, aralkylene or aralkylidene group, Am is an amino group, R is a hydrogen atom or an etherified or esterified hydroxy group or an aliphatic, araliphatic or aromatic radical and R 1  and R 2  are each a hydrogen atom, a free, etherified or esterified hydroxy group or an aliphatic radical, and N-acyl derivatives thereof derived from aliphatic or araliphatic carboxylic or sulphonic acids, N-oxides, salts and lower alkyl or phenyllower alkyl quaternary ammonium derivatives thereof, in which phenyl groups are optionally substituted by up to two members selected from lower alkoxy, alkyl or alkylthio, halogens, trifluoromethyl, nitro, amino, di-lower alkylamino, lower alkanoyl and lower alkylsulphonyl, are prepared (a) by reaction of a 9-R 1 -10-R 2 - anthracene with an alkyne derivative of the general formula (b) when alk is a methylene group, by reduction of the corresponding 9,10-ethano-11-carbamoylanthracene with lithium aluminium hydride; (c) by reaction of the corresponding 9,10-etheno-11- (halo-alk)-anthracene with ammonia or an amine of the general formula H-Am; (d) by reaction of the corresponding 9,10-etheno-11-(ptoluenesulphonyloxy-alk)-anthracene with ammonia or an amine of the general formula H-Am; (e) by reaction of the corresponding 9,10-etheno- 11-anthracenyl lithium or halomagnesium compound with a reactive esterified aminoalkanol or an optionally N-substituted ethyleneimine; and (f) by reduction of the corresponding 9,10-etheno- 11 - (amino - hydroxyalkyl or nitroalkenyl)- anthracene; followed optionally by conversion of the product to an N-oxide thereof by reaction with hydrogen peroxide or a peracid and/or salification. 11-Dimethylcarbamoyl-9,10-ethenoanthracene is prepared by reaction of anthracene and ethyl propiolate, alkaline hydrolysis of the resulting 11-carbethoxy-9,10-etheno-anthracene, reaction of the resulting 11-carboxy-9,10-etheno-anthracene with thionyl chloride and treatment of the resulting acid chloride with dimethylamine. The 1,2,3 and 4-chloro derivatives are prepared in the same way. 11-Pyrrolidinocarbonyl-9,10-ethenoanthracene is prepared analogously. 11-Dimethylcarbamoyl-12-phenyl-9,10-ethenoanthracene is also prepared analogously, except that oxalyl chloride is used instead of thionyl chloride. 11- Dimethylcarbamoyl - 12 - carboxy - 9,10 - ethenoanthracene is obtained by reaction of anthracene and diethyl acetylene-dicarboxylate, alkaline hydrolysis of the resulting 11,12-dicarbethoxy- 9,10-ethenoanthracene, treatment of the dicarboxylic acid thus obtained with acetic anhydride and reaction of the resulting cyclic anhydride with dimethylamine. 2-Chloro-anthracene-9-carboxyaldehyde is prepared by reaction of 2-chloro-anthracene with phosphorus oxychloride. 9-Hydroxymethyl-10- chloro-anthracene is prepared by reduction of 10- chloro-anthracene-9-carboxaldehyde with sodium borohydride; and 2-chloro-9-hydroxymethyl-anthracene is prepared analogously. 11-(Hydroxy-alk)-9,10-etheno-anthracenes are prepared by reaction of the corresponding anthracene with a (hydroxy-alk)-acetylene and may be converted to 11-(halo-alk)-9,10-ethenoanthracenes by reaction with phosphorus trihalides or to 11-(p-toluene-sulphonyloxy-alk)- 9,10-ethenoanthracenes by reaction with ptoluenesulphonyl chloride. 11-(2-Hydroxyethyl)-9,10-ethenoanthracene is prepared by treatment of 11-chloro-9,10- ethenoanthracene with butyl lithium and reaction of the resulting 11-(9,10-ethenoanthracenyl)- lithium with ethylene oxide. 5-Dimethylamino-2-pentynoic acid hydrochloride is prepared by treatment of N-3-butynyldimethylamine with a Grignard reagent made from ethyl-bromide, followed by carbon dioxide, aqueous ammonium chloride and hydrochloric acid. 11 - (1 - Hydroxy - 2 - dimethylaminoethyl)- 9,10-ethenoanthracene hydrochloride is obtained by reaction of anthracene with butynone, treatment of the resulting 11-acetyl-9,10-ethenoanthracene with N-bromosuccinimide reaction of the 11-bromoacetyl-9,10-ethenoanthracene so obtained with dimethylamine and reduction of the resulting 11-dimethylaminoacetyl-9,10-ethenoanthracene with sodium borohydride, followed by treatment with hydrochloric acid. 11 - (2 - Nitroethenyl) - 9,10 - ethenoanthracene is produced by oxidation of 11-hydroxymethyl- 9,10-etheno-anthracene with manganese dioxide and reaction of the resulting 11-(9,10-ethenoanthracenyl)-carboxaldehyde with nitromethane. 11-(1-Hydroxyethyl)-9,10-ethenoanthracene is prepared by treatment of 11-carboxy-9,10- ethenoanthracene with lithium and methyl iodide in ether and reduction of the resulting 11- acetyl-9,10-ethenoanthracene with lithium aluminium hydride. 11-(2-Hydroxyethyl)-9,10-ethenoanthracene is prepared by reaction of the Grignard reagent prepared from magnesium, 11-chloro-9,10-ethenoanthracene, iodine, methyl iodide and tetrahydrofuran with ethylene oxide, followed by treatment with ammonium chloride. Pharmaceutical compositions having antidepressant activity comprise, as active ingredient, an 11-amino-alkyl-9,10-etheno-anthracene of the first general formula above or an N-acyl derivative, N-oxide or quaternary ammonium derivative thereof as defined above or therapeutically acceptable salt thereof, together with a pharmaceutical carrier, and may be administered enterally or parenterally.