Patent GB-939512-A (GB)
Title: Derivatives of pyrimido-[4, 5-d]-pyrimidines and the preparation thereof
IPC: C07D487/04
Filed: 1960-06-17
Abstract: The invention comprises substituted pyrimido-[5,4-d]-pyrimidines of the general formula <FORM:0939512/IV(a)/1> wherein 0-3 of the symbols R, which may be the same or different, represent hydrogen or a halogen atom or an alkyl, aryl, aralkyl, alkoxy, hydroxy, thio, alkylmercapto, amino or mono- or dialkylamino group, or a cyclic amino group, and from 1-4 of the symbols R represent a group of the formula <FORM:0939512/IV(a)/2> wherein X represents hydrogen or an alkyl group, a group of the formula -(CH2)n-CHY-OR11, Y represents hydrogen or an alkyl group, n represents an integer from 1 o 8, R1 represents an alkyl group (which may be unsubstituted or substituted by a halogen atom or by a hydroxy or amino group) or an alkenyl, aryl, aralkyl or heterocyclic group, or the residue of an inorganic acid, a carbalkoxyl residue, the acyl residue of an aliphatic, aromatic, heterocyclic or araliphatic acid (which may be unsubstituted or substituted with halogen or with one or more acid, ester, quaternary ammonium, or sulpho, groups or substituted on unsubstituted hydroxy, amino or thio group), or a carbohydrate residue attached by a glucoside-like link (which residue may bear an acid, ester, amino or substituted amino group, and the hydroxy groups of which may be wholly or partially esterified or etherified) or the residue <FORM:0939512/IV(a)/3> wherein R111 represents hydrogen, a carboxy group, or an alkyl group (which may be substituted by a halogen or by a hydroxy or amino group) or an aryl, aralkyl or heterocyclic group, and R11 represents a hydrogen atom or has the same significance as R1, and salts thereof with physiologically acceptable acids or bases, and the preparation thereof by esterifying, etherifying or acetalating at least one of the hydroxy groups of a hydroxyalkyl residue of a pyrimido-[5,4-d]-pyrimidine of the general formula <FORM:0939512/IV(a)/4> wherein 0-3 of the substituents A, which may be the same or different, represent a hydrogen or a halogen atom or an alkyl, aryl, aralkyl, alkoxy, hydroxy, thio, alkylmercapto, amino, or alkylamino group, or a cyclic amino group, and 1-4 of the substituents A represent the group <FORM:0939512/IV(a)/5> wherein Z represents a hydrogen atom or an alkyl group, or the residue -(CH2)n-CHOH, Y represents a hydrogen atom or an alkyl group, and n is an integer from 1 to 8.  The esterification may be carried out by reacting an appropriate inorganic acid or halide, organic acid, acid halide, acid anhydride, including mixed carboxylic-carbonic acid anhydrides, an acid ester of a lower alcohol, a ketene or a diketene with the hydroxyalkyl group of the pyrimido-pyrimidine reactant, by reacting a metal salt of a carboxylic acid with the pyrimido-pyrimidine reactant in which at least one of the hydroxyalkyl groups is replaced by a halogenoalkyl group, or by reacting the pyrimido-pyrimidine reactant with a carboxylic acid in the presence of a carbodiimide to bind the water of reaction. The esters 2,6-bis(diethanolamino)-4,8-dipiperidinopyrimido- [5, 4-d]- pyrimidinetetra (morpholino acetic acid) ester and tetrabetaine-ester chloride are also prepared by reacting the p corresponding tetra-chloroacetate ester with morpholine and trimethylamine respectively.  The etherification may be carried out by reacting the pyrimido-pyrimidine reactant with an alkylene oxide such as ethylene oxide, or alkylene imine, by reacting an alkali metal alcoholate of the pyrimido-pyrimidine reactant with an appropriate halide, or by reacting a pyrimido-pyrimidine reactant in which at least one hydroxyalkyl group is replaced by a halogenoalkyl group with an appropriate alkali metal alcoholate. The acetalisation may be carried out by reacting the pyrimido-pyrimidine reactant with an appropriate aldehyde or functional derivative thereof such as a halogeno-derivative of a carbohydrate to form an acetal or hemiacetal or, in the case of the preparation of a glucuronide pyrimido-pyrimidine of the first general formula above by administering intravenously to a rat, dog or rabbit the pyrimido-pyrimidine reactant and recovering the glucuronide from the bile secretion, for example, extracting with alkali such as alkaline butanol or barium hydroxide.  The Specification refers to a large number of esterifying and acetalising reactants that may be used in the above processes drived from carbonic, carboxylic and sulphonic acids, sulphuryl chloride, phosphoric acid, chlorosulphonic acid, ethyl nitrite, aldehydes, monosuccharides including ribosephosphoric acid, amino-sugars, uronic acids and oligosaccharides. Pharmaceutical compositions having cardiovascular and spasmolytic activity contain as the active ingredient pyrimido-[5,4-d]-pyrimidines of the first general formula above or salts thereof with physiologically acceptable acids and bases and a physiologically acceptable carrier or diluent.  The compositions may be in the form of injectable solutions, tablets, capsules, pastilles, syrups, emulsions, suspensions, dragees, drops or suppositories. Specification 807,826 is referred to.