Patent GB-761944-A (GB)
Title: Novel xanthine derivatives and a process for the manufacture thereof
IPC: C07D473/08
Filed: 1954-09-09
Abstract: The invention comprises compounds of the general formula <FORM:0761944/IV(b)/1> wherein R1 and R2 are alkyl groups of up to 5 carbon atoms, R3 is a tertiary amino group and X is a keto-alkylene or keto-alkylidene group (excluding acyl groups) of 3 or 4 carbon atoms and having the radical -CH2-R3 attached thereto at either of the carbon atoms adjacent to the keto group thereof, and acid addition salts thereof; and their preparation by reacting the appropriate 7-keto-alkyl xanthine with formaldehyde or a compound yielding formaldehyde under the reaction conditions and a secondary amine, by heating under acid conditions or mixing at about 20 DEG C. under alkaline conditions to form respectively either an acid addition salt from which the free base may be liberated or the free base itself which may then be converted into an acid addition salt. It is stated that when the keto-alkyl group contains 3 carbon atoms alkaline conditions give a product in which the radical -CH2-R3 is substituted on the xanthine side of the keto group whereas under acid conditions substitution on the side remote from the xanthine nucleus occurs. When the keto alkyl group contains 4 carbon atoms two series of products also occur but their constitution is not disclosed.  The acid reaction may be carried out using a salt of the secondary amine, preferably in a high-boiling inert solvent under reflux, and the alkaline reaction may be carried out in a hydrophilic solvent or water.  Compounds forming formaldehyde include paraformaldehyde, dialkyl-acetals of formaldehyde and chloro-methyl alkyl ethers, a solvent, e.g. ethanol, preferably being used with the latter two classes under alkaline conditions. In examples: (1) 7-acetonyl-theophylline heated on a water bath with piperidine hydrochloride and aqueous formaldehyde gives the hydrochloride of 7-(31-piperidinomethyl-21-keto-propyl)-theophylline; (2)-(4) the hydrochlorides of morpholine, dimethylamine and diethylamine are similarly used; (5) 7-acetonyltheophylline, piperidine hydrochloride and aqueous formaldehyde refluxed in dioxan containing HCl gas give the product of Example (1); (6)-(9) the hydrochlorides used in Examples (2)-(4) are similarly used, except that aqueous formaldehyde is replaced by paraformaldehyde.  In further examples: (1) 7-acetonyl-theophylline, aqueous formaldehyde, piperidine, water and benzene are shaken at room temperature to give 7 - (11 - piperidinomethyl - 21 - keto - propyl)-theophylline; (2) piperidine is replaced by morpholine in the method of (1).  In still further examples: (1) sodium theophyllinate and 1-chloro - butanone - (2) give 7 - (21 - ketobutyl)-theophylline which is then shaken with piperidine, aqueous formaldehyde, water and benzene to give a 7 - (piperidinomethyl - 21 - keto-butyl)-theophylline of m.p. 120-122 DEG C.; (2) theophylline and methyl vinyl ketone in the presence of sodium methoxide and pyridine give 7 - (31 - keto - butyl) - theophylline which on treatment as in (1) gives a 7-(piperidinomethyl - 31 - keto - butyl) - theophylline of m.p. 114-116 DEG C. Hydrochlorides corresponding to all the above free bases and free bases corresponding to the above hydrochlorides are also described. Specification 759,981 is referred to.