Patent GB-766754-A (GB)
Title: New derivatives of 1.3-disubstituted and 1.3.8-trisubstituted xanthines and processes for their production
IPC: C07D473/22
Filed: 1955-01-25
Abstract: The invention comprises substituted xanthines of the general formula: <FORM:0766754/IV(b)/1> wherein R1, R2 and R3 represent aliphatic hydrocarbon radicals, R4 represents hydrogen or an aliphatic hydrocarbon radical, or R3 and R4 together with the nitrogen atom represent the piperidino, pyrrolidino or morpholino radical, R5 represents hydrogen or an aliphatic hydrocarbon radical, and X represents a sulphur or oxygen atom, and the preparation thereof by reacting a hydrocarbon substituted xanthine of the general formula: <FORM:0766754/IV(b)/2> wherein R1, R2 and R5 have the above signi ficance in the form of an alkali or alkaline earth metal salt thereof, with a haloformic ester such as a methyl, ethyl or phenyl ester or phosgene and the resulting 7-carbonic acid derivative of the formula <FORM:0766754/IV(b)/3> where R is derived from the ester group of the haloformic ester or: <FORM:0766754/IV(b)/4> respectively is then reacted with an amine of the formula: <FORM:0766754/IV(b)/5> wherein R3 and R4 have the above significance, or the above hydrocarbon substituted xanthine or an alkali or alkaline earth metal salt thereof is reacted with a carbamic acid halide which contains the radicals R3 and R4 attached to the nitrogen atom thereof, or, in the case where R4 represents hydrogen, the free hydrocarbon substituted xanthine is heated with an isocyanic acid derivative of the general formula R3NCO, wherein R3 has the above significance.  It is advantageous to carry out the reaction with the carbamic acid halide in an inert organic solvent such as ethyl acetate, benzene or toluene. Suitable carbamic acid halides for use in one of the above processes are dimethyl, methylethyl, diethyl, di-n-propyl, di-n-butyl, di-isobutyl, methyl-n-butyl and diallyl carbamic acid chloride and pyrrolidino, piperidino and morpholino carbonyl chloride.  Suitable isocyanate reactants are methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, allyl and methallyl isocyanate. Xanthine reactants of the above general formula referred to are 1,3-dimethyl, 1-ethyl-3-isopropyl, 1,3 - di - n - heptyl, 1 - ethyl - 3-allyl, 1,3,8 - trimethyl, 1,3 - dimethyl - 8 - isobutyl, 1,3 - dimethyl - 8 - allyl, 1,3 - diallyl - 8-sec. - butyl and 1,3,8 - tri - isobutyl xanthine, and 1 - methyl - 3 - ethyl - 2 - thioxanthine. In the examples: 1,3-di-isobutyl-7-dimethylcarbamoyl -, 1,3 - diethyl - 7 - diethylcarbamoyl -, 1,3 - diethyl - 7 - dimethylcarbamoyl -, 1,3 - diethyl - 7 - ethylcarbamoyl -, 1,3 - diethyl - 8 - n-propyl - 7 - ethylcarbamoyl, 1,3 - di - n - butyl-8 - methyl - 7 - dimethylcarbamoyl -, and 1,3-diethyl - 2 - thio - 7 - dimethylcarbamoylxanthine are prepared.  Intermediate products referred to in the examples are obtained by reacting the salt of 1,3-diethyl-xanthine with phosgene and with chloroformic ester to form corresponding xanthines containing the -COCl and -COOC2H5 group respectively in the 7-position.  In addition to the examples, the Specification refers to a large number of xanthines of the above general formula which are prepared by methods similar to those detailed in the examples.