Patent GB-1055203-A (GB)
Title: -ß-carboline derivatives, a process for their manufacture, and compositions containing them
Inventor: ATKINSON JOHN DAVID
IPC: C07D471/04
Filed: 1964-09-16
Abstract: Novel b -carboline derivatives of formula <FORM:1055203/C2/1> wherein R6 stands for an alkyl radical of not more than 8 carbon atoms or for a cycloalkyl, or bicycloalkenyl radical, or for an aryl radical optionally substituted by one or more radicals selected from alkyl, alkoxy, alkoxycarbonyl, hydroxy or amino, or for a heterocyclic radical, and R7 stands for hydrogen, or wherein R6 and R7 together with the adjacent carbon atom of the b -carboline nucleus form a carbocyclic ring; wherein R8 stands for hydrogen or for an alkyl radical; and wherein the benzene ring B may optionally be further substituted by an alkyl radical, and the acid addition salts thereof, but excluding the known compounds 1-methyl, 1-ethyl, 1-n-butyl, 1-phenyl, 1-o-tolyl, 1-m-methoxy phenyl, and 1-pmethoxyphenyl-b -carboline, and also the novel derivatives of formulae <FORM:1055203/C2/2> wherein R9 stands for an aryl or heterocyclic radical either of which may optionally be substituted by one or more alkyl or hydroxy radicals and wherein R10 stands for an acyl radical, are prepared:-  (a) By ring closure of a compound of formula <FORM:1055203/C2/3> wherein R6, R7, R8 and B are as defined above for the first general formula, preferably by heating in a solvent in the presence of an acidic catalyst.  (b) Compounds of the first general formula above, where R7 is hydrogen, by reduction, for example with hydrogen in the presence of platinum oxide, or with sodium borohydride, of the corresponding dihydro-b -carboline derivative. (c) Compounds of the first general formula above, where R7 is hydrogen by decarboxylation of the corresponding b -carboline-1-carboxylic acid derivative, preferably by heating in a solvent, in the presence of a mineral acid.  (d) Compounds in which R10 is acyl, in the second general formula above, by ring closure of a compound of formula <FORM:1055203/C2/4> where R9 is as defined above, in the presence of an acylating agent derived from the acid of formula R10-OH, where R10 is as defined above, or by acylation of the corresponding b -carboline derivative where R10 is hydrogen, with an acid halide R10-Cl or an acid anhydride R10-O-R10, where R10 is as defined above.  Compounds of the previous general formula above are prepared by the reaction of tyrptamine with an aldehyde R9-CHO, R9 being as defined above.  1,2,3,4 - Tetrahydro - 1,6 - dimethyl - b  - carboline -1-carboxylic acid is prepared by reaction of 5-methyl tyrptamine in a mixture of aqueous sodium acetate and aqueous acetic acid with pyruvic acid.  3,4 - Dihydro - 1 - p - tolyl - b  - carboline is prepared by reacting p-toluic acid chloride and tyrptamine and treating the product with POCl3.ALSO:Pharmaceutical compositions comprising as active ingredient one or more b -carboline derivatives of the formula:  <FORM:1055203/A5-A6/1> wherein R1 stands for hydrogen or for an alkyl radical, R2 stands for hydrogen, alkyl, haloalkyl, cycloalkyl, cycloalkenyl, bicycloalkenyl, aryl, substituted aryl, aralkyl, carboxy alkoxy carbonyl or heterocyclic radical, and R3 stands for hydrogen or for an alkyl or acyl radical; or wherein, R1 and R2 together with the adjacent carbon atom of the b -carbolene nucleus, form a carbocyclic ring and R3 stands for hydrogen or for an alkyl or acyl radical; or wherein R1 stands for hydrogen and R2 and R3 together with the adjacent carbon and nitrogen atoms of the b -carboline nucleus, form a heterocyclic ring, optionally substituted by an oxo radical; wherein R4 and R5 which may be the same or different stand for hydrogen or for alkyl radicals, and wherein the benzene ring A may optionally be further substituted by one or more alkyl or alkoxy radicals, and acid addition salts thereof, in association with a pharmaceutically acceptable diluent or carrier therefor but excluding simple non-sterile solutions of the active ingredients in water or in common organic solvents, and excluding aqueous suspensions of the active ingredients in the absence of a suspending agent.  Such compositions have analygesic activity, and may be administered orally or rectally, in the form of tablets, coated tablets, powders, granules, capsules, solutions, aqueous or oils suspensions, emulsions, syrups, elixirs, or suppositories, and may also contain other known therapeutic agent such as acetylsalicylic acid, codeine, salicylamide, p-acetamido phenol phenacetin, phenobarbitone, cortisone, prednisolone phenylbutazone chloropromacine, chloroquine, quinine, caffeine and theobromine.