Patent GB-1086530-A (GB)
Title: 4-phenyl and 4-substituted phenyl bicyclo[2,2,2]octane-amines
Inventor: SNYDER JACK AUSTIN
IPC: A61K31/135
Filed: 1965-05-13
Abstract: The invention comprises compounds of the formula <FORM:1086530/C2/1> in which R and R1 each represents a hydrogen atom or a C1- 4 alkyl or allyl group, or together form a -(CH2)ngroup where n is 4, 5 or 6, and X and Y each represents a hydrogen, chlorine, bromine or fluorine atom or a methyl, ethyl, cyano, trifluoromethyl, hydroxy, nitro, amino C1- 4 alkylamino, di(C1- 4 alkyl)amino, carboxy or methoxy- or ethoxy-carbonyl group; and their acid addition salts with acids having non-toxic anions.  The compounds are prepared by (a) hydrolysing or reducing corresponding 1-acylamino-4-phenyl-bicyclo[2,2,2]-octanes to form the corresponding 1-amino or 1-alkylamino compounds, or (b) ammonolysing or aminolysing methane sulphonic esters of 4-hydroxy -4-phenyl-bicyclo[2,2,2]octanes, or (c) reducing 4 - phenyl - bicyclo[2,2,2]oct - 2 - ene-1 -carboxylic acids or their esters to yield 4-phenyl - bicyclo[2,2,2]octane - 1 - carboxylic acids or esters, if necessary saponifying the esters to the free acids, and converting the acids by the Hofmann, Curtius or Schmidt reaction to 4-phenyl - bicyclo[2,2,2]octane - 1 - amines, or (d) alkylation of 4-phenyl-bicyclo[2,2,2]octane-1 -amines or -alkylamines, e.g. by reaction of alkyl halides or dialkyl sulphates in the presence of a base, or by acylation followed by reduction with lithium aluminium hydride of the resulting N -acyl-amine or N -acyl-N -alkylamine.  In a modification of process (d), compounds of Formula I in which R and R1 together form the divalent group -(CH2)nare made by reacting the primary amine with a dicarboxylic acid anhydride to form a corresponding N carboxyacyl-amine which is reduced and cyclized with lithium aluminium hydride.  Starting materials.-1-Acetamido-4-phenyl-bicyclo[2,2,2,]octane is prepared by reacting 4-hydroxy - 1 - phenyl - bicyclo[2,2,2]octan - 2-one with hydrazine to form the corresponding hydrazone, heating this with hydrazine, diethylene glycol and potassium hydroxide to form 4 - phenyl - bicyclo[2,2,2]octan - 1 - ol and reacting this with acetonitrile.  1-Acylamino-4-(substituted phenyl)-bicyclo[2,2,2]octanes are prepared by nitrating a 1-acylamino-4-phenyl-bicyclo[2,2,2]octane, reducing the nitro compound to the corresponding amino compound, diazotizing the amino compound and replacing the diazo group in the resulting compound by a hydroxy group by heating it in an aqueous solution or by a halogen atom or cyano group by reacting it with a cuprous halide or cuprous cyanide.  A resulting phenol may be alkylated to give the corresponding alkoxy compound, or a resulting nitrile may be hydrolysed to the corresponding carboxylic acid which may be converted to an ester or reacted with sulphur tetrafluoride to replace the carboxy group by a trifluoromethyl group.  If, instead of diazotization, the amino group is acylated and reduced with lithium aluminium hydride the corresponding mono- and di-alkylamino compounds are prepared.  Pharmaceutical compositions having anti-depressant activity, for oral or parenteral administration, comprise a compound of the invention together with a pharmaceutical carrier.