IL43967A - Pyrimido(5,4-d)pyrimidines their preparation and pharmaceutical compositions containing them - Google Patents

Abstract

1432731 Pyrimidopyrimidines DR KARL THOMAE GmbH 7 Jan 1974 [8 Jan 1973] 00586/74 Heading C2C Compounds of the general formula (R 1 = C 1 -C 3 alkoxy-(C 2 -C 3 alkyl); R 2 = C 2 -C 4 hydroxyalkyl or C 3 dihydroxyalkyl; R 3 = C 1 -C 3 alkoxy-(C 2 -C 3 alkyl) or C 2 -C 3 hydroxyalkyl; R 4 = di(C 2 -C 4 alkyl)amino, diallylamino, piperidino or hexamethyleneimino) and their acid addition salts are prepared by (a) reacting a compound of the formula (one Z 1 = replaceable atom or group and the other = NR 1 R 2 or NR 2 R 3 , or both symbols Z 1 = replaceable atoms or groups) with R 1 R 2 NH or R 2 R 3 NH or (b) reacting a compound of the formula (one Z 2 = replaceable group and the other = R 4 , or both symbols Z 2 = replaceable groups) with R 4 H, optionally followed in either case by salt formation. The above compounds increase blood pressure, affect blood oxygen transport, inhibit thrombocyte aggregation, enhance blood flow and are coronary dilators. They may be administered in the form of pharmaceutical preparations containing them in association witha carrier. [GB1432731A]

Description

onaan ,ο*¾πη e'j'TD' s /"d -4,57 π'β' . amis a' 'san nin n 'Ttt m Novel pyrimido /5 ,4-d7pyrimidines, their preparation and"~pharmaceutical compositions containing them Dr. Karl Thomae GmbH C. 41935 The present invention relates to new pyrimido [5,4-d]-pyrimidines having interesting pharmacological properties .

The compounds according to the invention fall within the general scope of Israel Patent Specification No. 12055, however, none of the new compounds are specifically disclosed or even mentioned therein. It has been determined that a closely related compound known from the Israel Patent Specification, 2, 6-bis- (diethanolamino) -4 , 8-dipiperidino-pyrimido- [5 , 4-d] pyrimidin$ which is also disclosed in Japanese Patent Specification No. 70 19, 308, possesses blood-pressure lowering effects. In contrast thereto the compounds according to the invention surprisingly exhibit, among others, blood-pressure increasing activity.

According to one feature of the present invention there are provided compounds of general formula [wherein R^ represents an alkyl group containing 2 or 3 carbon atoms substituted by an alkoxy group containing from 1 to 3 carbon atoms; represents a hydroxyalkyl group containing from 2 to 4 carbon atoms or a dihydroxyalkyl group containing 3 carbon atoms; ^ represents an alkyl group containing 2 or 3 carbon atoms substituted by an alkoxy group containing from 1 to 3 carbon atoms or by a hydroxy1 group; and R^ In general the new compounds of general formula I and physiologically compatible acid addition salts thereof possess valuable pharmacological properties , in particular a blood-pressure increasing activity and a favourable activity on the oxygen-transport function of the blood as well as an inhibiting activity on the thrombocyte aggregation and a blood-flow enhancing coronary dilating activity.

The following compounds are preferred by virtue of their particularly favourable pharmacological activity:-4,8-Bis(diethylamino)-2,6-bis(2,-hydroxyethyl-2"-methoxy-ethylamino)-pyrimido[5,4-d]pyrimidine and physiologically compatible acid addition salts thereof; 4,8-Bis(diethylamino)-2,6-bis(2' ,3 ' -dihydrox p opyl-2,,-methox eth lamino)-pyrimido[ 5 ,4-d]pyrimidine and physiologically compatible acid addition salts thereof; 4,8-Bis(ethyl-butylamino)-2,6-bis(2,-hydroxyethyl-2M-methoxyethylamino)-pyrimido[ 5 ,4-d]pyrimidine and physiologically compatible acid addition salts thereof; 4,8-Bis(diallylamino)-2,6-bis(2'-hydroxyethyl-2"-methoxyethylamino)-pyrimido[ 5,4-d]pyrimidine and physiologically compatible acid addition salts thereof; 4,8-Bis(diethylamino)-2,6-bis(2,-hydroxypropyl-2"- methoxyethylamino) -pyrimido[ 5 , 4-d]pyrimidine and physiologically compatible acid addition salts thereof; 4,8-Bis(diethylamino)-2-(2' ,31 -dihydroxypropyl-2"- methoxyethyalmino) -6- ( 2 ' -hydroxyethy1- 2"-methoxyethy1- amino)-pyrimido[5,4-<|pyrimidine and physiologically compatible acid addition salts thereof.

The new compounds of general formula I as hereinbefore defined may be prepared by either of the following processes, which processes constitute further features of the invention:- with an amine of formula ^R-, ^ R (Ilia) or H - N " 2 (Illb) R2 R3 [wherein R-^, 2> ^ and R^ are as hereinbefore defined and either one of the groups represents an exchangeable group and the other represents one of the groups (wherein R, , R_ and ^ are as hereinbefore defined) or both of the groups represent exchangeable groups]; and b) Reaction of a compound of formula with an amine of formula H - R. IV 4 (wherein R^, R^* ^ and R^ are as hereinbefore defined and either one of the groups represents an exchangeable group and the other is as hereinbefore defined for R, 4 or both of the groups ∑2 represents exchangeable groups).

In each case the reaction is effected at temperatures determined by the reactivity of the exchangeable group, generally at temperatures of from 100 to 250°C, preferably, however, at temperatures from 150 to 200°C. The reaction is optionally effected in the presence of an acid-binding agent and, if required, in the presence of a solvent, such as glycol dimethyl ether or dimethyl- sulfoxide, preferably, however, in an excess of the amine of formula III or IV used. The reaction may if desired be carried out in the absence of a solvent. In certain cases it is advantageous to carry out the reaction in the presence of a reaction accelerator, e.g. in the presence of a copper salt or a salt of the amine or formula III or IV used. As acid-binding agents inorganic bases such as sodium carbonate or potassium carbonate and tertiary organic bases such as triethyl-amine or pyridine for example are suitable as acid-binding agents. A tertiary organic base used as acid-binding agent may simultaneously serve as solvent.

Suitable exchangeable groups represented by include for example halogen atoms, e.g. the chlorine atom, and sulfonyl groups, e.g. chlorosulfonyl , methylsulfonyl , ethylsulfonyl and phenylsulfonyl groups and suitable groups represented by include for example substituted mercapto groups, e.g. methylthio, phenylthio and benzyl-thio groups.

The compounds of general formula I obtained may if desired, be converted into their acid addition salts, preferably their physiologically compatible acid addition salts with inorganic or organic acids. Suitable acids include for example hydrochloric acid, hydrobromic acid, sulfuric acid and phosphoric acid.

The starting compounds of general formulae Ila and lib may for example be prepared from the corresponding halo-pyrimido[5,4-d]pyrimidines by reaction with the corresponding amines (see German Federal Patent 1,116,676) and conversion of the thio-pyrimido[5,4-d]pyrimidines thus obtained by oxidation, e.g. with chlorine or hydrogen peroxide into the corresponding sulfonyl compounds (see German Offenlegungsschrift 2,003,043).

As hereinbefore stated, the new compounds of general formula I and physiologically compatible acid addition salts thereof in general possess valuable pharmacological properties, those which have been tested showing especially a blood-pressure increasing activity and a favourable activity on the oxygen-transport function of the blood, as well as an inhibiting activity on the thrombocyte aggregation, and a blood- flow enhancing and coronary dilating activity.

The biological activities of the following compounds have been tested: A - 4,8-Bis(diethylamino)-2,6-(2,-hydroxyethyl-2"-methoxyethylamino) -pyrimido [5, 4-dJpyrimidine hydrochloride , B = 4,8-Bis(ethyl-butylamino)-2,6-bis(2'-hydroxyethyl-2"-methoxyethylamino) -pyrimido [ 5 , 4-dJpyrimidine hydrochloride , C = 4,8-Bis(diallylamino)-2,6-bis(2,-hydroxyethyl-2u-methoxyethylamino)-pyrimido[5,4-d]pyrimidine hydrochloride , D = 4,8-Bis(diethylamino)-2,6-bis(2'-hydroxypropyl-2"-methoxyethylamino) -pyrimido [ 5, 4-dJpyrimidine hydrochloride , E = 4,8-Bis(diethylamino)-2,6-bis(2' ,3 ' -dihydroxypropyl-2ll-methoxyethylamino)-6-(2 ' -hydroxyethyl-2M-methoxy-ethylamino) -pyrimido [5, 4-dJpyrimidine hydrochloride and F = 4,8-Bis(diethylamino)-2,6-bis(2' >3,-dihydroxy-propyl-2M-methox ethylamino)-pyrimido[5,4-d]pyrimidine hydrochloride . 1. Activity on Circulation: The circulation tests were carried out in dogs under nembutal-chloralose-urethane narcosis (10 + 54 + 270 mg/kg i.v.)« The test substances were injected intravenously into the vena saphena and the following parameters were registered on a Grass-polygraph: a) The arterial blood-pressure was measured in the arteria carotis by a Statham-pressure transducer.

The following values have been obtained.

Substance Dose mg/kg Increase of Duration of i.v. blood pressure activity in minutes in mm Hg A 0.025 +11/7 25 A 0.05 +23/19 >30 A 0.1 +33/25 >32 B 0.1 +17/14 >27 C 0.1 +16/12 > 20 D 0.1 +22/19 >37 E 0.1 +23/17 >22 b) The blood-flow of the ramus descendens of the left coronary artery was determined by • an electromagnetic flowmeter. The following values have been obtained: Substance Dose mg/kg coronary duration in i.v. blood-flow minutes increase in % A 0.025 12 >15 A 0.05 14 17 A 0.1 28 >26 A 0.25 42 >13 c) The blood-flow of the arteria femoralis was determined by an electromagnetic flowmeter and the heart- frequency by electrocardiogram. The following values was obtained: Substance Dose mg/kg blood- flow heart frequency i.v. in femoralis alteration in minutes increase duration in % in minutes A 0.05 31 18 -15 A 0.1 57 >15 -20 A 0.25 34 >20 -25 2. Influence on the oxygen-transport function of erythrocytes Recently, an adaptation mechanism to lack of oxygen in the human organism was disclosed, based on a shifting to the right of the oxygen-dissociation curve of the blood as a result of an increase in the intraerythrocyte concentration of 2 ,3-diphosphoglycerate (2,3-DPG). The favourable effect of a 2 ,3-DPG-conditioned shifting to the right of the oxygen-dissociation curve of the blood is based upon the fact that at the oxygen tension normally prevailing in the tissue, greater quantities of the haemoglobin-bound oxygen are released, thus when releasing equal quantities of oxygen, higher oxygen tensions can be maintained. The uptake of oxygen in the lung, however, at normal alveolar PC^-values is only slightly influenced by changes in the 2 ,3-DPG-concentration.

Method : Newly drawn blood from healthy test persons was admixed with crystalline heparin (0.2 mg/ml of blood) and, subsequently, centrifuged (5 minutes at 4,500 xg) . After separation of the plasma as well as of the upper layer containing leukocytes and thrombocytes, the erythrocytes were washed twice in a triple volume of phosphate-Locke- solution. Then, the erythrocytes were resuspended in their own plasma corresponding to a haematocrit of 40%. The plasma was admixed with 5 mmol of glucose and acidified with empirically determined quantities of hydrochloric acid to such an extent that always after addition of the erythrocytes the desired pH-value was reached.

The erythrocyte-suspensions were first pre-incubated for 15 to 30 minutes to allow for pH and temperature adjustment to pH 7.34 and 37°C and were subsequently distributed into several incubation vessels, the latter containing the compounds to be examined in a volume of 0.2 ml of a 0.9% sodium chloride solution.

Incubation of the trial batches, the total volume of which amounted to 5 ml, was effected within sealed polyethylene tubes (50 ml capacity, air atmosphere) whilst shaking them uniformly (40 minutes) within a water-bath at 37 + 0.1°C. During the 4-hour incubation period, the pH-value of the batches was controlled at intervals of 15 to 30 minutes by means of a single-rod glass electrode (Metrohm EA 125X) in combination with a precision-pH-meter (Knick pH 35). 0.3N sodium hydroxide solution or 0.3N hydrochloric acid were added when necessary to keep the pH at 7.34 with a maximum deviation of + 0.02 pH units. Such a precise control of the pH-value proved to be necessary, as the 2 ,3-DPG-metabolism reacts very sensitively to the slightest deviations from the pH-value of 7.34.

Before and after the 4-hours' incubation period, 4 ml of the batches in the same volume of 1.2N perchloric acid at 0°C were extracted. The extracts were neutralized with potassium hydroxide solution, and the 2,3-DPB, ATP and inorganic phosphate concentrations therein were quantitatively determined using paper-chromatographic separation methods. The intraery-throcyte concentrations were calculated based on the haematocrit value determined by double measurement.

Result: The following Table shows the percentage inhibition of the spontaneous decrease in 2,3-DPG-concentration in human erythrocytes (average from 3 trials each) : Substance Concentration Mol/ltr. Inhibition in % F 5xlO~A 98 + 10 F 5x10" 5 13 + 3 Finally the new compounds of the present application which have been tested possess a low acute toxicity. Thus, for example, compound A shows the following acute toxicities in the mouse: mouse i.v.: 133 mg/kg LDgQ mouse p.o.: ^3 g/kg The compounds of the present application possess unexpected novel activities compared with all known basically substituted pyrimido-pyrimidines. All previously known pyrimido-pyrimidines lower the arterial blood-pressure, whereas an increase in blood-pressure was observed after application of the new compounds.

Of the compounds which have been tested, this activity was strongest for compound A which was thoroughly pharmacologically investigated. Thereby it was shown that the long- lasting blood-pressure increase after both oral and parenteral administration was due to the effect on the sympathetic circulatory centres. The complete lack of simultaneous psychomotor or central stimulating components was particularly advantageous.

According to a yet further feature of the present invention there are provided pharmaceutical compositions comprising as active ingredient at least one compound of formula I as hereinbefore defined or a physiologically compatible acid addition salt thereof in association with a pharmaceutical carrier or excipient.

The compositions may, for example, be presented in a form suitable for oral, rectal or parenteral administration. Thus for example compositions for oral administration may be solid or liquid and may take the form of tablets, coated tablets or drops, such compositions comprising carriers and excipients conventionally used in the pharmaceutical art.

For parenteral administration, the carrier may be a parenterally acceptable liquid, such as sterile, water, or a parenterally acceptable oil, e.g. arachis oil, contained in ampoules. For rectal administration compositions may take the form of suppositories, the carrier comprising a suppository base.

Advantageously the compositions may be formulated as dosage units. Each dosage unit preferably contains from 2 to 15 mg, preferably 5 to 10 mg, of active ingredient for parenteral administration or from 25 to 200 mg, preferably from 50 to 100 mg, of active ingredient for oral administration.

The following Examples serve to illustrate the preparation of compounds according to the invention and of pharmaceutical compositions containing the same.

Example 1 2 ,6-Bis( 2 ' -hydroxyethy1-2"-methoxyethylamino) - 4,8- dipiperidino-pyrlmido[ 5 f4-d]pyrimidine 11.0 g (0.03 mol) of 2 ,6-dichloro-4,8-dipiperidino- pyrimido[5,4-dlpyrimidine were heated for 3 hours at about 200°C with 50 g of 2-hydroxyethyl-2 ' - methoxyethylamine. The orange-coloured reaction mixture was added to water yielding 2,6-bis-(2'- hydroxyethyl-2M-methoxyethylamino) -4, 8-dipiperidino- pyrimido[5,4-d]pyrimidine as a resinous precipitate. The precipitate was filtered off, dissolved in 2N ammonia and reprecipitated from 0.2N hydrochloric acid. The reaction product was again filtered of, washed with water and dried. The yield was 13.6 g (85% of theory); honey-coloured resin, R^-value^ 0.5 (DC-prefabricated sheet silica gel F, Macherey Nagel, eluent: ethyl acetate).

C26H44N8°4 532·6) Calculated: C 58.62 H 8.33 N 21.04 Found: 58.60 8.29 21.41 The same compound may be obtained in an analogous manner from 2-chloro-6-chlorosulfonyl-4,8-dipiperidino- -pyrimido [ 5, -d]pyrimidine by heating for 4 to 5 hours with 2-hydroxyethyl- 2 ' -methoxy-ethylamine at about 200°C.

Example 2 2 , 6-Bis( 21 -hydroxyethyl- 2"-methoxyethylamino) -4 , 8-dipiperidino-pyrimido[ 5 , 4-d]pyrimidine 2.3 g (0.005 mol) of 2,6-bis(2'-hydroxyethyl-2"-methoxyethylamino) -4, 8-bis (methylthio) -pyrimido [5,4-d]pyrimidine (m.p. 126 to 128 °C) were heated for 4 hours in a sealed tube with 50 ml of piperidine in the presence of piperidine hydrochloride at approximately 200°C. The reaction solution was evaporated in vacuo as far as possible. The remaining residue was admixed with about 100 ml of water yielding the 2 , 6-bis ( 2 ' -hydroxyethyl-2"-methoxyethylamino) - 4,8-dipiperidino-pyrimido-[5,4-d]pyrimidine as a resinous mass. The product was purified by precipitation from 0.2N hydrochloric acid after dissolving it in 2N ammonia.

Yield: 1.8 g (68% of theory), honey-coloured resin.

The same compound was obtained in an analogous manner from 4,8-bis(benzylthio)-2,6-bis(2'-hydroxy-ethyl-2"-methoxyethylamino)-pyrimido[5,4-d]pyrimidine (m.p. 131 to 133°C) or from the 2 ,6-bis(2 ' -hydroxyethyl-2"-methoxyethylamino)-4,8-bis(phenylthio)-pyrimido[5,4-d] pyrimidine (m.p. 160 to 163°C) by heating for 2 to 3 hours with piperidine at 200°C under pressure.

Example 3 2 ,6-Bis(2 ' -hydroxyethy1-2"-methoxyethylamino) - 4,8-dipiperidino-pyrimido[5,4-d]pyrimidine. 1.0 g (0.002 mol) of 2 ,6-bis(chlorosulfonyl) - 4,8-dipiperidino-pyrimido[5,4-d]pyrimidine (m.p. 207 to 209°C, decom .) and 0.9 g (0.002 mol) of 2 ,6-bis(methyl-sulfonyl)-4,8-dipiperidino-pyrimido[5,4-d]pyrimidine (m.p. 218 to 220°C) respectively were heated with 5 g portions of 2-hydroxyethyl-2'-methoxyethylamine for 5 hours at about 200°C. The reaction mixtures were poured into water, thus precipitating 2,6-bis(2'-hydroxyethyl-2"-methoxyethylamino)-4, 8-dipiperidino-pyrimido[5,4-d]pyrimidine as a resin. After decanting off the water, washing and drying, the yield from each reaction was 0.6 to 0.7 g (56 to 66% of theory).

Purification was effected by means of a silica gel column (eluent: benzene/acetone/ethanol = 15/3/2), honey-coloured resin.

The same compound may be obtained in a similar manner from 2 ,6-bis(ethylsulfonyl)-4,8-dipiperidino-pyrimido[5,4-d]pyrimidine (m.p. 159 to 160°C) or from 2 ,6-bis(phenylsulfony1)-4, 8-dipiperidino-pyrimido-[5,4-d]pyrimidine (m.p. 257 to 259°C) by heating for 10 or 15 hours respectively with 2-hydroxyethyl-2'-methoxyethylamine at about 200°C.

Example 4 4,8-bis(diethylamino)-2,6-bis(2'-hydroxyethyl-2"-methoxyethyiamino)-pyrimido[ 5, 4-d]pyrimidine 17.2 g (0.05 mol) of 2 ,6-dichloro-4,8-bis(diethyl-amino) -pyrimido[5, -d]pyrimidine (m.p. 134 to 136°C) were heated for 4 hours at 200°C with 90 g of 2-hydroxyethyl-2'-methoxyethylamine. The orange reaction solution obtained was poured into 400 ml of water whilst stirring when still hot, whereby the reaction product separated first as a resinous precipitate.

After solidification the product was suction filtered, washed with water and dried.

Yield: 23. 4 g (96% of theory).

For purification the substance was crystallized once from 0.2N hydrochloric acid by first dissolving it in 2N ammonia (up to a pH of approximately 5) and was then recrystallized once from c clohexane/ethyl- acetate = 5/1. The 4,8-bis(diethylamino)-2 ,6-bis- (2 ' -hydroxyethy1- 2"-methoxyethylamino) -pyrimido[ 5 , 4-d] - pyrimidine thus obtained melted at 84 to 86°C.

Yield: 20.6 g (81 % of theory).

C24H44N8°4 (508·7) Calculated: C 56.67 H 8.72 N 22.03 Found: 56.90 8.73 22.00 The same substance was obtained analogously from the 2-chloro-4,8-diethylamino-6-(2 ' -hydroxyethy1- 2"-methoxyethylamino) -pyrimido [ 5, 4-d]pyrimidine and 2-hydroxyethyl-2 ' -methoxy-ethylamine.

Example 5 4,8-Bis(diethylamino)-2,6-bis(2,-hydroxyethyl-2n- methoxyeth lamino) -pyrimido[ 5 , -d]pyrimidine 17.2 g (0.05 mol) of 2,6-dichloro-4,8-bis(diethyl- amino) -pyrimido[5, 4-d]pyrimidine were heated at 150°C with 90 g of 2-hydroxyethyl-2 ' -methoxyethylamine for 56 hours or at 170°C for 32 hours. Processing of the batches and purification of the crude products was effected as described in Example 4. After recrystallization from eyelohexane/ethyl acetate = 5/1 the yield was 43 and 78% of theory respectively, m.p. : 84 to 86°C.

Example 6 4,8-Bis(diethylamino)-2,6-bis(2,-hydroxyethyl-2"-methoxyethylamino) -pyrimido[ 5 , 4-d]pyrimidine 3.1 g (0.005 mol) of 4,8-bis(benzylthio)-2,6-bis ( 2 ' -hydroxyethy1-2"-methoxyethylamino) -pyrimido-[5,4-d]pyrimidine (m.p. 131 to 133°C) were heated in a sealed tube at 200°C for 3 hours with 60 ml of diethylamine in the presence of diethylamine hydrochloride or with a slight quantity of copper sulfate. The reaction solution obtained was evaporated as far as possible.

The remaining residue was poured into water (80 ml) and the crude 4,8-bis(diethylamino)-2,6-bis(2,-hydroxy-ethyl-2M-methoxyethylamino) -pyrimido[5 , -d]pyrimidine separated as a resinous mass. After precipitating once from 0.2N hydrochloric acid by first dissolving in 2N ammonia, the yield was 1.3 g (51% of theory).

After purification by passage through a silica gel column (eluent: benzene/acetone/ethanol = 15/3/2) the substance melted at 84 to 86°C.

Example 7 4,8-Bis(diethy.lamino)-2,6-bis(3'-hydroxypropyl-2u-methoxyethylamino)-pyrimido[5,4-d]pyrimidine The above compound was prepared from 2,6-dichloro-4,8-bis(diethylamino)-pyrimido[5,4-d]-pyrimidine and 3-hydroxypropyl-2 ' -methoxyethylamine analogously to Example 4.

Yield: 76% of theory, m.p. 89 to 91°C.

Example 8 4,8-Bis(diethylamino)-2,6-bis(2'-hydroxypropyl-2"-methoxyethylamino)-pyrimido[5,4-d]pyrimidine Prepared from 2 ,6-dichloro-4,8-bis(diethylamino) pyrimido[5,4-d]pyrimidine and 2-hydroxypropyl-2 ' -methoxyethylamine analogously to Example 4.

Yield: 78 % of theory, m.p. 85 to 87°C.

Example 9 4,8-Bis(diethylamino)-2,6-bis(2-hydroxy-2,2-dimethy ethy1-2"-methoxyethylamino)-pyrimido[ 5,4-d]pyrimidine Prepared from 2 ,6-dichloro-4,8-bis(diethylamino) -pyrimido[5,4-d]pyrimidine and 2-hydroxy-2 ,2-dimethyl-ethyl-2'-methoxyethylamine analogously to Example 4 (reaction time about 8 hours). After purification by passage through a silica gel column (eluent: acetone/ benzene = 1/5) and recrystallization from cyclohexane/ ethyl acetate = 6/1, the yield was 53% of theory, m.p. 101 to 102°C Example 10 4,8-Bis(dipropylamino)-2 ,6-bis(2' -hydroxyethyl-2"-methoxyethylamino)-pyrimido [ 5 , 4-d]pyrimidine Prepared from 2 ,6-dichloro-4,8-bis-(dipropylamino)-pyrimido[5,4-d]pyrimidine (m.p. 163 to 164°C) and 2-hydroxyethyl-2'-methoxyethylamine analogously to Example 4.

Yield: 71% of theory, m.p. 70 to 73°C.

Example 11 4,8-Bis(diisopropylamino)-2 ,6-bis(21 -hydroxyeth l-2"-methoxyethylamino) -pyrimido[ 5 , 4-d]pyrimidine Prepared from 2 ,6-dichloro-4,8-bis(diisopropyl-amino)-pyrimido[5,4-d]pyrimidine analogously to Example 4.

Yield: 82% of theory, m.p. 165 to 167°C.

Example 12 4,8-Bis (N-ethyl N-butylamino) -2 , 6-bis (2 * -hydroxyethyl-2"-methoxyethy1amino) -pyrimido [5 , 4-d] pyrimidine Prepared from 4 , 8-bis (N-ethyl N-butylamino) -2 , 6-dichloro-pyrimido[5,4-d]pyrimidine m.p. 96 to 98°C) and 2-hydroxyethyl-2 ' -methoxyethylamine analogously to Example 4.

Yield: 79% of theory, m.p. 79 to 80°C.

Example 13 4,8-Bis(diallylamino)-2,6-bis(2,-hydroxyethyl-2"-methoxyethylamino) -pyrimido[ 5 , 4-d]pyrimidine Prepared from 2 ,6-dichloro-4,8-bis(diallylamino)-pyrimido[5,4-d]pyrimidine (m.p. 100 to 101°C) and 2-hydroxyethyl-2' -methoxyethylamine analogously to Example 4. After purification by passage through a silica gel column (eluent: ethyl acetate/petroleum ether - 10/1) the yield was 56% of theory, m.p. 58 to 60°C.

Example 14 4,8-Bis(diethylamino)-2,6-bis(2' ,3'-dihydroxypropyl- 2"-methoxyethylamino)-pyrimido[ 5,4-d]pyrimidine 6.9 g (0.02 mol) of 2 ,6-dichloro-4,8-bis diethyl- -amino)-pyrimido[5,4-d]pyrimidine were heated for about 4 hours at about 200°C with 40 g of 2 ,3-dihydroxypropyl- 2' -methoxyethylamine. The orange reaction solution was added to approximately 300 ml, of water, whereby the reaction product separated out as a viscous mass.

The product was precipitated once from O.lN hydrochloric acid after first dissolving in 2N ammonia, and was then washed with water and dried. After recrystallization from benzene/petroleum ether = 1/1, the 4,8-bis(diethyl- amino)-2 ,6-bis(2 ' ,3 ' -dihydroxyprop l-2u-methox ethyl- amino)-pyrimido[5,4-d]pyrimidine melted at 101 to 103°C.

Yield: 8.6 g (76% of theory).

C26H48N8°6 568·8) Calculated: C 54.91 H 8.51 N 19.70 Found: 55.20 8.44 19.80 In a similar way, the same substance was obtained from 2 ,6-bis(ethylsulfonyl)-4,8-bis(diethylamino)- pyrimido[5,4-d]pyrimidine (m.p. 126 to 128°C) by heating for about 16 hours at 200°C with 2,3- dihydroxypropyl-2 ' -methoxyethylamine. Purification was appropriately carried out by passage through a silica gel column.

Example 15 4,8-Bis(diethylamino)-2,6-bis(2' ,3'-dihydroxypropyl-3i'-methoxypropy1amino) -pyrimido[ 5 ,4-d]pyrimidine Prepared from 2 ,6-dichloro-4,8-bis(diethylamino) -pyrimido[5,4-d]pyrimidine and 2 ,3-dihydroxypropyl-3 ' -methoxypropylamine analogously to Example 14.

Yield: 67% of theory; resin, Rf-value: 0.7 to 0.8 (DC-prefabricated sheet silica gel F, Macherey Nagel, eluent: acetone).

Example 16 4,8-Bis(hexamethyleneimino)-2 ,6-bis(2 ' -hydroxyethyl-2"-methoxyethylamino)-pyrimido[ 5 , -d]pyrimidine Prepared from 2 ,6-dichloro-4,8-bis(hexamethyl-eneimino)-pyrimido[5,4-d]pyrimidine (m.p. 170 to 172°C) and 2-hydroxyethyl-2'-methoxy-ethylamine analogously to Example 1. After recrystallizatio from benzene/ petroleum ether = 1/1 the yield was 79% of theory, m.p. 99 to 101°C.

Example 17 2-Bis Chydroxyethylamino) -4 f 8-bis (diethylamino) -6- (2 · -hydroxy-ethyl-2"-methoxyethylamino) -pyrimido [5 , 4-d] pyrimidine 4.3 g (0.01 mol) of 2-chloro-4,8-bis(diethylamino)- 6- ( 2 ' -hydroxyethyl-2"-methoxyethylamino)-pyrimido - \ [ 5,4-djpyrimidine (resin prepared from 2 ,6-dichloro- 4,8-bis(diethylamino)pyrimido[5,4-d]pyrimidine by heating for 2 hours with 2-hydroxyethyl-2 '-methoxyethylamine at 120°C) were heated with 15 mg of di (hydroxyethyl) amine for 2 hours at about 180°C. The orange solution obtained was added to water, whereupon the reaction product separated as a viscous oil. The product was precipitated from 0.2N hydrochloric acid after first dissolving in 2N ammonia and recrystallized from ethyl acetate/petroleum ether = 1/3.

Yield: 3.4 g (73% of theory), m.p. ,112 to 114°C.

C23H42N8°4 (494'7) ' Calculated: C 55.85 H 8.56 N 22.66 Found: 56.00 8.82 22.70 The same compound was obtained in an analogous manner from the 2-chloro-6-diethanolamino-4,8-bis(diethyl- amino)-pyrimido[ 5,4-d]pyrimidine by heating, for 2 hours with 2-hydroxyethyl-2' -methoxyethylamine at approximately 200°C.

Example 18 4, 8-Bis (diethylamino) -2- ( 2 ' ,3 * -dihydroxypropy1- 2"-methoxyethylamino) -6- ( 2 ' -hydroxyethyl-2"-methoxyethy1-amino) -pyrimido[ 5 , 4-d]pyrimidine Prepared from 2-chloro-4,8-bis(diethylamino)-6- ( 2 ' -hydroxyeth 1- 2"-methoxyethylamino) -pyrimido-[5,4-d]pyrimidine and 2 ,3-dihydroxypropyl-2 ' -methoxy-ethylamine analogously to Example 17. After purification by passage through a silica gel column (eluent: acetone/benzene = 1/1) the yield was 58% of theory, m.p. 67 to 70°C.

Example 19 4, 8-Bis (diethylamino) -2,6-bis( 2 '-hydroxyethy1-3"-methoxypropylamino) -pyrimido[ 5 , 4-d]pyrimidine Prepared from 2 ,6-dichloro-4, 8-bis(diethylamino) -pyrimidof 5, 4-dIpyrimidine and 2-hydroxyethyl-3 ' -methoxy-propylamine analogously to Example 4. After recrystallization from benzene/petroleum ether = 1/2. yield: 79% of theory, m.p. 82 to 84°C.

Example 20 2,6-Bis(3'-ethoxypropy1-2"-hydroxyethylamino) -4, 8-bis(diethylamino) -pyrimido[ 5 , 4-dIpyrimidine Prepared from 2 ,6-dichloro-4,8-bis(diethylamino)-pyrimido[5,4-d]pyrimidine and 3-ethoxypropyl-2 hydroxyethylamine analogously to Example 4 (reaction time 6 hours) . After recrystallization from cyclohexane/ ethyl acetate = 3/1, yield: 71% of theory, m.p. 77 to 79°C.

Example 21 4,8-Bis(diethylamino)-2,6-bis(2'-hydroxye isopropoxypropylamine) -pyrimido[5,4-d]pyrimidine Prepared from 2 ,6-dichloro-4,8-bis(diethylamino)-pyrimido[5 ,4-d]pyrimidine and 2-hydroxyethyl-3 ' -iso-propoxypropylamine analogously to Example 20. After purification by passage through a silica gel column (eluent: benzene/acetone = 3/1) the yield was 49% of theory; resin, R^-value: 0.6 (DC-prefabricated sheet silica gel F, Macherey Nagel, eluent: benzene/ acetone = 3/1.).

Example 22 2,6-Bis(2',3'-dihydroxypropy1- 2"-methoxyethylamino) -4,8-bis(dipropylamino)pyrimido[5,4-d]pyrimidine Prepared from 2 ,6-dichloro-4,8-bis(dipropylamino)' pyrimido[5,4-d]pyrimidine and 2 ,3-dihydroxypropyl-2 ' - methoxyethylamine analogously to Example 14.

Yield: 75% of theory, m.p. 88 to 91°C (from ethyl acetate/petroleum ether = 1/4).

Example 23 Tablets containing 100 mg of 4,8-bis(diethylamino)-2 ,6- bis ( 2 ' -hydroxyethyl-2"-methoxyethylamino) -pyrimido- [ 5 , 4-d]pyrimidine Composition: 1 tablet contains: Active ingredient 100.0 mg lactose 50.0 mg polyvinylpyrrolidone 25 5.0 mg carboxymethylcellulose 19.0 mg magnesium stearate 1.0 mg 175.0 mg Method of preparation: Active ingredient and lactose were homogeneously moistened with aqueous PVP- solution.

Moist screening: 1.5 mm Drying: drying cabinet with forced air circulation at 50°C.

Dry screening: 1mm The remaining excipients were admixed with the granulate and the final mixture was pressed into tablets Weight of tablet: 175 mg Punch: 8 mm 0 Example 24 Coated tablets containing 50 mg of 4, 8-bis(diethyl- amino) -2 , 6-bis ( 2 ' -hydroxyethyl-2"-methoxyethylamino) - pyrimido[ 5 , -d]pyrimidine Composition: 1 coated tablet core contains: Active ingredient 50.0 mg corn starch, dried 20.0 mg soluble starch 2.0 mg carboxymethylcellulose 7.0 mg magnesium stearate 1.0 mg 80.0 mg Method of preparation: Active ingredient and starch were homogeneously moistened with an aqueous solution of soluble starch Moist screening: 1.0 mm Dry screening: 1.0 mm Drying: 50°C in a drying cabinet with forced air circulation. Granulate and remaining excipients were admixed and pressed into cores.

Weight of core: 80 mg Punch: 6 mm Radium of curvature: 5 mm The finished cores were covered with a sugary coat in the coating pan according to a known method.

Weight of coated tablet: 120 mg.

Example 25 Suppositories containing 75 mg of 4,8-bis(diethylamino) 2 ,6-bis(2 ' -h droxyethyl-2,,-methox ethylamino)pyrimido- [5>4-d]pyrimidine Composition: 1 suppository contains: Active ingredient 75.0 mg Suppository mass (e.g. Witepsol H 19 and 1625.0 mg Witepsol W 45) _ c 1700.0 mg Method of preparation: The suppository mass was melted. At 38°C the granulated active ingredient was dispersed homogeneously in the melt. The mixture was cooled to 35°C and poured into pre-cooled suppository moulds.

Weight of suppository: 1.7 g Example 26 2 ml ampoules containing 10 mg of 4,8-bis(diethylamino)-2 ,6-bis(2 ,-hydroxyethyl-2"-methoxyethylamino)-pyrimido- [ 5 ,4-dlpyrimidine 1 ampoule contains: Active ingredient 10.0 mg polyethyleneglycol 600 100.0 mg 1 N hydrochloric acid q.s. ad pH 3 distilled water ad 2.0 ml Method of preparation: The polyethyleneglycol was dissolved in water and the active ingredient was suspended therein. The substance was dissolved by the addition of 1 N hydrochloric acid and the mixture was adjusted to alkaline pH.

Distilled water was added to the indicated volume and the solution was filtered sterile.

Filling: into colourless 2ml-ampoules under a protective gas atmosphere.

Sterilization: 20 minutes at 120°C.

Example 27 Drop solution containing 25 mg of 4,8-bis(diethylamino)- 2 ,6-bis( 2' -hydroxyethyl- 2M-methoxyethylamino)-pyrimido- [5,4-dlpyrimidine per 0.5 ml Composition; 100 ml of drop solution contain: Active ingredient 5.0 g tartaric acid 0.5 g cane sugar 30.0 g sorbic acid 0.1 g flavour (e.g. Bitteressenz of Messrs. H & R) . 4.0 g ethano]-, pure 20.0 g polyethyleneglycol 600 20.0 g distilled water ad 100.0 ml Method of preparation: The sorbic acid was dissolved in alcohol and the same quantity of water was added. The active ingredient and tartaric acid were dissolved therein whilst stirring (solution 1). The sugar was dissolved in the remaining water (solution 2).

Solution 2, the polyethyleneglycol and the flavour were added to solution 1 whilst stirring. The mixture was filtered through a suitable filter.

Claims (31)

1. Compounds of general formula [wherein R^ represents an alkyl group containing 2 or 3 carbon atoms, substituted by an alkoxy group containing from 1 to 3 carbon atoms; represents a hydroxyalkyl group containing from 2 to 4 carbon atoms or a dihydroxyalkyl group containing 3 carbon atoms; R^ represents an alkyl group containing 2 or 3 carbon atoms substituted by an alkoxy group containing 1 to 3 carbon atoms or by a hydroxy1 group; and R^ represents a dialkylamino group(wherein each alkyl group contains from 2 to 4 carbon atoms) , a diallylamino group, or a piperidino or hexamethyleneimino ring] and acid addition salts thereof.

2. 4,8-Bis(diethylamino)-2 ,6-bis(2 ' -hydroxyethy1- 2"-methoxyethylamino)-pyrimido[ 5,4-d]pyrimidine and physiologically compatible acid addition salts thereof. 43967/2

3., 4,8-Bis(diethylamino)-2,6-bis(2' ,3 * -dihydroxy- propyl-2"-methoxyethylamino)-pyrimido[ 5, 4-d]pyrimidine and physiologically compatible acid addition salts thereof.

4. 4 ,8-Bis (N-ethyl N-butylamino) -2 , 6-bis (2 ' -hydroxyethyl 2,,-methoxyethylamino)-pyrimido[5,4-dlpyrimidine and physiologically acid addition salts thereof.

5. 4,8-Bis(diallylamino)-2,6-bis(2'-hydroxyethyl- 2"-methoxyethylamino)-pyrimido[5,4-d]pyrimidine and physiologically compatible acid addition salts thereof.

6. 4,8-Bis(diethylamino)-2,6-bis(2'-hydroxypropyl- 2,,-methoxyethylamino)-pyrimido[ 5 , 4-d]pyrimidine and physiologically compatible acid addition salts thereof.

7. 4,8-Bis(diethylamino)-2-(2' ,3'-dihydroxypropyl- 2,l-methoxyethylamino)-6-(2 ' -hydroxyethyl-2M-methoxy- ethylamino)-pyrimido[5,4-d]pyrimidine and physiologically compatible acid addition salts thereof.

8. Compounds as claimed in claim 1 other than those claimed in claims 2 to 7 as herein specifically disclosed.

9. A process for the preparation of compounds of general formula I as defined in claim 1 which comprises reacting a compound of formula with an amine of fonmula H - N Ilia or H - N Illb R3 [wherein R^, R^* R^ and R^ are as defined in claim 1 and either one of the groups represents an exchangeable group and the other represents one of the groups R2 and R^ are as hereinbefore defined) or both of the groups represent exchangeable groups].

10. A process for the preparation of compounds of general formula I as defined in claim 1 which comprises reacting a compound of formula with an amine of formula H - R. IV 4 (wherein R^, JL^ t ^3 an^ ^ are as defined in claim 1 and either one of the groups represents an exchangeable group and the other is as defined for ^ in claim 1 or both of the groups represents exchangeable groups).

11. A process as claimed in claim 9 or claim 10 wherein the reaction is effected at temperatures from 100 to 250°C.

12. A process as claimed in claim 11 wherein the reaction is effected at temperatures from 150 to 200°C.

13. A process as claimed in any of claims 9 to 12 wherein the reaction is effected in the presence of a solvent.

14. A process as claimed in any of claims 9 to 13 wherein the reaction is effected in the presence of an acid-binding agent.

15. A process as claimed in any of claims 9 to 14 wherein the reaction is effected in the presence of a reaction accelerator.

16. A process as claimed in any of claims 9 and 11 to 15 wherein the group or groups in the compound of formula Ila represent chlorine atoms or chlorosul-fonyl, methylsulfonyl , ethylsulfonyl or phenylsulfonyl groups.

17. A process as claimed in any of claims 10 to 16 wherein the group or groups in the compound of formula lib represent methylthio, phenylthio or benzylthio groups.

18. A process as claimed in any of claims 9 to 17 wherein the compound of formula I obtained is subsequently converted into an acid addition salt thereof.

19. A process for the preparation of compounds as claimed in claim 1 as herein specifically described.

20. A process for the preparation of compounds as claimed in claim 1 as herein specifically described with reference to Examples 1 to 22.

21. Compounds of general formula I as defined in claim 1 and acid addition salts thereof when prepared by a process as claimed in any of claims 9 to 20

22. Pharmaceutical compositions comprising as active ingredient at least one compound of formula I as defined in claim 1 or physiologically compatible acid addition salts thereof in association with a pharmaceutical carrier or excipient.

23. Compositions as claimed in claim 22 in a form suitable for oral, rectal or parenteral administration.

24. Compositions as claimed in claim 23 in the form of tablets, coated tablets, drops, ampoules or suppositories.

25. Compositions as claimed in any of claims 22 to 24 in the form of dosage units.

26. Compositions as claimed in claim 25 for parenteral administration wherein each dosage unit contains from 2 to 15 mg of active ingredient.

27. Compositions as claimed in claim 26 wherein each dosage unit contains from 5 to 10 mg of active ingredient.

28. Compositions as claimed in claim 25 for oral administration wherein each dosage unit contains from 25 to 200 mg of active ingredient.

29. Compositions as claimed in claim 28 wherein each dosage unit contains from 50 to 100 mg of active ingredient.

30. Compositions according to claim 1 substantially as herein described.

31. Compositions according to claim 1 substantially as herein described with reference to Examples 23 to 27.