Patent GB-1115817-A (GB)
Title: 2-aza-bicyclo[2,2,2]octanones and compositions containing them
Inventor: FEIT PETER WERNER
IPC: C07D453/06
Filed: 1965-08-23
Abstract: <FORM:1115817/C2/1> <FORM:1115817/C2/2> <FORM:1115817/C2/3> <FORM:1115817/C2/4> Novel compounds of Formula I in which R1 is hydrogen, C1- 8 alkyl, aralkyl, halo- or C1- 8 alkylsubstituted benzyl, or CH2Y, where Y is a heterocyclic group, X is hydroxy, alkoxy, aralkoxy or NR3R4, where each of R3 and R4 is hydrogen or C1- 6 alkyl or -NR3R4 is a 5- to 7membered ring, and R2 is hydrogen or C1- 6 alkyl, and pharmaceutically acceptable salts thereof with bases and acids, are prepared by (a) lactamization of a 1-amino-1-cyclohexane carboxylic acid derivative of Formula II, in which A is a radical containing a <FORM:1115817/C2/5> grouping and capable of reacting with the -NHR1 group to form a lactam, or (b) conversion of a compound of Formula I, in which X is OH, into an ester or amide, or (c) alkylation of a compound of Formula I in which R1 is hydrogen, or (d) dealkylation of a compound of Formula I, in which R1 is other than hydrogen, or (e) hydrogenation of a compound of Formula I, in which R1 is an unsaturated radical, to convert R1 into the corresponding saturated radical.  1 - Amino - 1 - cyclohexane carboxylic acid derivatives of Formula II are prepared by neutralizing a compound of Formula III, in which R2 is hydrogen or C1- 6 alkyl, reacting it with an alkali metal cyanide and ammonium carbonate to for a spirohydantoin of Formula IV, and then reacting the spirohydantoin with hydrobromic or hydrochloric acid to form a cis-trans mixture of a 1-amino-1,4-cyclohexanedicarboxylic acid hydrochloride or hydrobromide which may be esterified or further treated to introduce the substituent R1, e.g. by reductive alkylation or aralkylation with an aldehyde, or by reaction with an alkyl- or aralkyl-sulphonyl chloride to give an N-alkyl- or aralkyl-sulphonyl compound which is then treated with an alkylation or aralkylation agent followed by boiling with HBr to give a 1-alkylamino- or 1-aralkyl-amino - trans - 1,4 - cyclohexanedicarboxylic acid hydrobromide.  1 - Methylamino - trans - 1,4 cyclohexanedicarboxylic acid is prepared by boiling methyl N-methyl-2-aza-bicyclo[2,2,2] -octanone-(3)-1-carboxylate in an aqueous mineral acid and subsequently adjusting the pH to 2.5.  N - Benzyl - 2 - aza - bicyclo[2,2,2]octananone-(3)-1-carbonyl chloride is prepared by treating the corresonding acid with thionyl chloride.ALSO:Pharmaceutical compositions comprise a compound of the formula <FORM:1115817/A5-A6/1> in which R1 is hydrogen, C1-8 alkyl, aralkyl, halo- or C1-8 alkyl - substituted benzyl, or CH2Y, where Y is a heterocyclic group, X is hydroxy, alkoxy aralkoxy or NR3R4, where each of R3 and R4 is hydrogen or C1-6 alkyl or NR3R4 is a 5- to 7 - membered ring, and R2 is hydrogen or C1-6 alkyl, or a pharmaceutically acceptable salt thereof with an acid or a base, together with a carrier.  The compositions, which have an analgesic action, may be administered enterally or parenterally in the form of tablets, pills, capsules, suppositories, suspensions or solutions, and may also contain other analgesies, e.g. acetylsalicylic acid, salicylamide, phenacetin, amidopyrine and codeine, barbiturates, tranquilizers, e.g. meprobamate, caffeine, antispasmodics and diuretics.