Patent GB-983118-A (GB)
Title: Improvements in and relating to substituted pteridine compounds
IPC: C07D475/10
Filed: 1962-05-10
Abstract: The invention comprises substituted pteridines of the general formula <FORM:0983118/C2/1> wherein Ar represents an aryl radical which is unsubstituted or which bears a trifluoromethyl substituent, or an alkyl or alkoxy substituent containing up to 4 carbon atoms, or a halogen substituent, R and R1 are the same or different and represent hydrogen or an alkyl radical having up to 4 carbon atoms, n represents 1 or 2, and R11 and R111 represent alkyl or hydroxyalkyl radicals containing 1 to 4 carbon atoms or R11 and R111 together represent with the nitrogen atom to which they are attached a pyrrolidino, piperidino or morpholino radical, and the acid addition salts thereof, and the preparation of the above-substituted pteridines by condensing at a temperature in the range of 50 DEG  to 100 DEG  C. and in the presence of a basic catalyst a pyrimidine compound of the general formula <FORM:0983118/C2/2> wherein Ar has the above significance, with an acetonitrile derivative of the general formula <FORM:0983118/C2/3> to form a pteridine compound of the general formula <FORM:0983118/C2/4> wherein X represents the amide group of the formula <FORM:0983118/C2/5> wherein R and R1 have the above significance and R2 and/or R3 represent hydrogen or have the same significance as R11 and R111, or a carboxylic acid radical, or a radical of the formula <FORM:0983118/C2/6> wherein M represents an oxygen atom and Z represents a halogen atom, the remaining residue of a carboxylic ester or anhydride group, or the group of the formula <FORM:0983118/C2/7> wherein R, R1 and n have the above significance, or M represents = NH and Z represents an ether residue and, when X represents the radical of the formula <FORM:0983118/C2/8> forming this radical after the condensation to form a pteridine of the fourth formula above, and converting the radical X in the pteridine of the fourth formula above into an amide radical of the formula <FORM:0983118/C2/9> by condensing with an amine of the formula <FORM:0983118/C2/100> wherein R, R1, R2 and R3 have the above significance, and Y represents a hydrogen atom or a group of the formula <FORM:0983118/C2/111> and when R2 and/or R3 represent hydrogen, alkylating the product, for example with ethylene oxide or with methyl iodide, to convert R2 and/or R3 into alkyl or hydroxyalkyl radicals and, if desired, forming acid addition salts of said pteridine compounds.  The acetonitrile reactant of the general formula <FORM:0983118/C2/122> defined above may be:-  (a) An acetonitrile derivative of the formula <FORM:0983118/C2/133> wherein n, R, R1, R2 and R3 have the above significance.  (b) An ester of cyanacetic acid and the product of condensation, i.e. a 2-aryl-4,7-diamino-6-pteridine carboxylic ester, is then condensed with an amine of the formula <FORM:0983118/C2/144> wherein Y represents the radical of the formula <FORM:0983118/C2/155> R, R2 and R3 having the above significance.  (c) An acetonitrile derivative of the formula <FORM:0983118/C2/166> wherein R and R1 have the above significance, and the resulting pteridine of the formula <FORM:0983118/C2/177> wherein Ar, R and R1 have the above significance, is treated with a halogenating agent to replace the hydroxy group by a halogen atom and the halo-product is then reacted with an amine of the formula <FORM:0983118/C2/188> wherein R2 and R3 have the above significance.  (d) Cyanacetic acid in which case the resulting pteridine is of the general formula <FORM:0983118/C2/199> and the carboxylic group thereof is converted to a carboxylic acid ester, carboxylic anhydride or carboxylic acid halide group and the resultant product is condensed with an amine of the formula <FORM:0983118/C2/200> (e) An ester of cyanacetic acid and the resultant pteridine 6-carboxylic ester is condensed with an amine of the formula <FORM:0983118/C2/211> wherein n, R and R1 have the above significance, to form a pteridine of the formula <FORM:0983118/C2/222> the hydroxy group is replaced by a halogen atom and the resultant corresponding halo compound is reacted with an amine of the formula <FORM:0983118/C2/233> (f) Malononitrile and the resultant 2-aryl-4,7-diamino-6-cyano-pteridine is converted to the corresponding 6-imino ether with an alcohol and acid which is then reacted with an amine of the formula <FORM:0983118/C2/244> and then the imino function is removed by hydrolysis.  Therapeutic compositions having diuretic and natriuretic activity and an anti-inflammatory action contain as the active ingredient a pteridine of the first general formula above, or an acid addition salt thereof. The composition may be in the form of a tablet, capsule, or aqueous liquid suspension for oral administration, and may contain a solubilizing or preserving agent.  Substituted cyanoacetamides of the general formula <FORM:0983118/C2/255> wherein R, R1, R2, R3 and n have the above significance, are prepared by reacting an alkyl cyanoacetate and the required disubstituted aminoalkyl amine of the formula <FORM:0983118/C2/266>