DE1151807B - Process for the preparation of pyrimido [5,4-d] pyrimidines - Google Patents

Description

Process for the preparation of pyrimido [5,4-d] pyrimidines The invention relates to a process for the preparation of pyrimido [5, Sd] pyrimidines of the general formula wherein R denotes a hydrogen atom or the 4-methylpiperazino radical.

These new pyrimido [5,4d] pyrimidines are prepared by using a pyrimido [5,4-d] pyrimidine of the general formula in a manner known per se where Z1 is a halogen atom and Z2 is a halogen or a hydrogen atom, is reacted with l-methyl-piperazine at a temperature between the boiling point of l-methyl-piperazine and 250 "C in the presence of an acid-binding agent.

Acid binding agents are e.g. B. alkali hydroxides, alkali carbonates or tertiary amines; optionally can also with an excess of l-methylpiperazine to be worked.

The process can be inert to the reaction in the absence or presence Solution or thinners, e.g. B. acetone, dioxane, benzene, xylene or dimethylformamide, and if necessary with the application of pressure. Also the l-methyl-piperazine can be used in excess as a solvent or diluent.

The required starting materials of the general formula II are advantageous by heating 2,4,6,8-tetrahydroxy- or 2,4,8-trihydroxy-pyrimido [5,4-d] pyrimidine (which, for example, according to the methods of German patents 845 940 and 1 093 801 are available) with inorganic acid halides, preferably phosphorus halides, such as phosphorus oxychloride or phosphorus pentachloride, and subsequent implementation of the obtained halogen compounds with piperidine at low temperatures, preferably produced at room temperature or with cooling.

The pyrimido [5,4-d] pyrimidines prepared by the process according to the invention of the general formula 1 are valuable drugs that are especially heart and are effective for the circulation. They are 2,6-bis- (4'-methyl-piperazino) -4,8-dipiperidino -pyrimido [5,4-d] pyrimidine and the 2- (4'-methyl-piperazino) -4, 8-dipiperidino-pyrimido [5,4-d] pyrimidine with regard to the coronary-expanding effect to the known 2-benzyl-5,7-dimethyl-6,8-dioxo-tetrahydropyrimido [5,4-d] think. They are also according to the invention available connections much less toxic than the known compound, as shown below will.

The coronary blood flow was measured in three experiments (a, b and c) on dogs using a rotameter according to the method of Eckenhoff and co-workers (Amer. Journ. Physiol., 148, 582 [1947]).

The substances to be tested were applied intracoronary in weak hydrochloric acid solution.

The dosage was 1 mg (experiment a) or 0.5 mg (experiments b and c). The comparison substance was 2-benzyl -5,7-dimethyl-6,8-dioxo-tetrahydropyrimido [5,4-d] pyrimidine, in each case in the same dosage and solution. The following table shows the values for the increase in coronary blood flow in percent as well as the individual and mean values for the »coronary effect« (ratios compared to the reference substance = 1). The toxicity (LD50) was determined intraperitoneally on white mice. Coronary effect Increase in (reference substance = I) Coronary blood flow (%) Substance individual values LD50 Attempt attempt medium abcab I c worth 2 - benzyl -5.7 - dimethyl -6.8 - dioxo- tetrahydro - pyrinido [5,4d] pyr- imidine (comparison substance) .... 140 34 89 1 1 1 1 500 mg / kg 2,6- bis (4 '- methyl - piperazino) - 4,8-dipiperidino-pyrimido [5,4-d} - pyrimidine .................... 174 58 113 1.24 1.7 1.27 1.4 800 mg / kg 2 - (4 '- methyl - piperazino) -4,8- di- piperidino-pyrimido [5.4: 1] pyr- imidine ..................... 165 43 153 1.18 1 1.26 1.72 i 1.4> 1 glkg The following examples are intended to illustrate the invention: Example 1 2,6-bis (4'-methyl-piperazino) -4, 8-dipiperidinopyrimido [5,4-d] pyrimidine 7.4 g (0.02 mol) 2, 6- dichloro -4,8-dipiperidino pyrimido [5,4-d] pyrimidine are refluxed with 30 cc of 1-methyl-piperazine for 2 hours or at 200 ° C. in a sealed tube for 2 hours. The reaction product which separated out when the cooled reaction mixture was taken up in about 200 ccm of water was filtered off with suction, washed and dried; Yield: 9.5 g (99 ° lo theory). For purification, it was reprecipitated once from 0.2 n hydrochloric acid and once from 0.5 n acetic acid; slightly greenish microcrystalline prisms were obtained; F. 130 to 132 "C.

Example 2 2- (4'-methyl-piperazino) -4,3-dipiperidinopyrimido [5,4-d] pyrimidine 6.6 g (0.02 mol) of 2-chloro-4,8-dipiperidino-pyrimido [5,4-d] pyrimidine are with 30 cc of 1-methylpiperazine refluxed for about 1 hour; then became about half of the amine distilled off. When pouring the remaining solution into 250 ccm of water separates the reaction product as a viscous, greasy mass.

To clean it, it was reprecipitated once from very dilute hydrochloric acid and recrystallized once from methanol; you got a very weak greenish, microcrystalline powder (prisms); M.p. 127 to 129 "C; Yield: 4.5 g (650/0 der Theory).

Claims (1)

PATENT CLAIM: Process for the preparation of pyrimido [5,4-d] -pyrimidines of the general formula wherein R denotes a hydrogen atom or the 4-methylpiperazino radical, characterized in that a pyrimido [5,4-d] pyrimidine of the general formula is used in a manner known per se where Z1 is a halogen atom and Z2 is a halogen or a hydrogen atom, is reacted with l-methylpiperazine at a temperature between the boiling point of l-methylpiperazine and 250 ° C. in the presence of an acid-binding agent. Documents considered: German Patent No. 845 940; British Patent No. 691427; UNITED STATES. - Patent No. 2,826,580.