IL32739A - 2,6-bis-(di-(hydroxyalkyl)-amino)-pyrimido(5,4-d)pyrimidines,their preparation and pharmaceutical compositions containing them - Google Patents

Description

32739/2 DR. KARL THDHAE GmbH 030860 This invention pyrimido[5, -d] pyrimidines having interesting physiological activities and processes for the preparation thereof.

German Patent No. 1,116,676 and U.S. Patent No. 3,322,755 describe numerous basically substituted pyrimido[5,4-d] pyrimid-j ines having coronary dilating activity. The present invention Ji-(hydrox alk 1)-amino -is based upon the discovery of new 2 , 6-bis-^d4«¾¾«!H^-«nrirtt^)-<--pyrimido-[5,4-d]pyrimidines which not only show interesting physiological activities on the heart and circulation but are also inhibiters of thrombocyte aggregation,, According to one feature of the invention there are provided compounds of the formula wherein R, represents an alkyl group containing from 1 to 3 ally! . carbon atoms or an -ebUi .. or benzyl group; and Rg represents an alkyl group containing from 1 to 3 carbon atoms or an allyl group; or R^ and Rg together with the adjacent nitrogen atom represent a piperidino group substituted by 1 or 2 alkyl groups- each containing 1 or 2 carbon atoms in the 2,3 iitd/or 6-positions , a 1,2,5,6- or 1, 2, 3,4-tetrahydroisoquinolino group; and and which may he the same or different each represents a hydroxyalkyl group containing 2 or 3 carbon atoms.

As stated above, the compounds according to the invention in general exhibit physiological actions on the heart and circulation, and also are inhibitors of thrombocyte aggregation. Preferred compounds according to the invention by virtue of their physiological activities include those where and Rg each represent methyl, ethyl or isopropyl groups or together with the intervening nitrogen atom form a piperidino group a *£e*r advantageously may he substituted by one QV two methyl groups for example to form a 3-methylpiperidino or 2, 6-dimethyl-piperidino group whilst R^ and R^ preferably each represents an ethanol or propanol groups .

The particularly preferred compounds according to the invention by virtue of their especially interesting physiological activities include:- 2, 6-bis-( ethanolpropanolamino)-8=>diethylaminopyrimido[5, -d] pyrimidine , 2 , 6-bis-( dipropanolamino )-8-diethylamino-pyrimido[ 5 , -d] pyrimidine, 2 , 6-bis-( ethanolpropanolamino )-8-hexamethyleneiminopyrimido 5s -d] pyrimidine, 2, 6-bis-(diethanolamino)-8-diethylaminopyrimido [5, 4-d] pyrimidine, and 2 , 6-bis-( diethanolamino)-8-hexamethyleneiminopyrimido [ 5 , -d] pyrimidine.

The compounds of formula I may bo proparod,—for examp-l-e , 32739/2 The U.S. Patent Specification 3f031»45O describes compounds having the formula wherein two, three or all four of the substituents to are basic groups, that is primary, secondary or tertiary amino groups; and, if only two or three of them are basic groups, the remaining substituent or substituents are hydrogen, halogen, hydroxy, mercapto, lower alkyl, phenyl, phenoxy, lower alkoxy, lower alkoxy-lower alkoxy, (di-lower alkyl-amino)-lower alkoxy, lower alkyl-mercapto, phenyl-merca to, benzyl-mercapto or oarboxy-lower alkyl-mercapto* The term "tertiary amino groups" as used above is also understood to include substituents wherein the nitrogen is part of a heterocyclic rlng such as morpholyl, piperidyl, pyrrolidyl, plperazyl, tetrahydroprldyl and tetrahydroquinolyl, which in turn may carry substituents of its own, especially lower alkyl substituents* The aforesaid known compounds are stated to have a cardio vascular activity. The U.S. speci ication does not specifically describe the compounds of formula I above, which have surprisingly cardio been found to possess, in addition to the/vascular activity, a trom-bocyte agglomeration inhibiting effect.

The compounds of formula ∑ may be prepared, fo example, according to the following processes whic provide further features of the inventio di-(hydrox alkyl)-amino7 l) Treating a 2 , 6-bis-^a.tetkan<)¾«mirto-)--pyrimido [ 5 , ~dj pyrimidine of formula with a reducing agent followed by oxidation of the hydrogen- ated intermediate compound thus obtained whereby a compound of formula I is produced.

Preferred reducing agents include mascent or catalytically ί activated hydrogen and electrolytic reduction. The reduction is generally carried out in the presence of a solvent, especially in a polar solvent, preferably in a weakly afcil solution for example at a pH of approx. 2 to 5. When nascent hydrogen is used as the reducing agent, it may conveniently be prepared by the reaction, for example, a metal o a-H-a-i-kal'liie eai-t meta¾r e.g. zinc, with the weakly aci'j -ilc solution. The acid used may, for example, be a carboxylic acid such as formic or acetic acid at a concentration, for example, of from 10 to 30$. The obtained hydrogenated compound may, if desired, be isolated generally with the exclusion of air before oxidation. However, direct oxidation or iodine solution, hydrogen peroxide or an alkali metal bromate or permanganate preferably the potassium salts „ The pH of the reaction mixture is advantageously adjusted according to the oxidation agent used. For example, if a solution of bromine or iodine is used the pH advantageously adjusted to approx. 6„ However, a more strongly acidic solution may be used when potassium permanganate or hydrogen peroxide are used as oxidising agents i„e. the pH is advantageously less than 6, 2) Reaction of a compound of formula and (wherein A, A^ and A≥ may be interchanged /represent f0r example halogen atoms or hydroxy or mercapto groups substituted by alkyl, benzyl or phenyl groups 1 or 2 of the substituents A, A-. and A„ representing an appropriate hydroxyalkyl ' arHta-»»i-amino group of formula or -N ) with a compound of formula (wherein R^ and Rg are as hereinbefore defined) and/or ajn alkanolamine of formula H - N V \ The reaction is generally effected in the presence of an acid binding agent for example a high boiling solvent such as dimethylformamide, but it is preferred to use a corresponding excess of the compound of formula IV or V simultaneously as both solvent and as acid binding agent.

The starting materials of formulae II and III may be prepared for example, according to the process described in:: German Patent 1,116, 6760 According to a yet further feature of the invention there are ^provided pharmaceutical compositions comprising at least one of the compounds of the invention as herein defined as active ingredient in association with a pharmaceutical carrier or excipient. The compositions may 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 granules, tablets, coated tablets, capsules, syrups, emulsions, suspensions or drops, such compositions comprising carriers or excipients conventionally used in the pharmaceutical art. Thus, for example, suitable tablet-ting excipients include lactose, potato and soluble starches and magnesium stearate.

For parenteral administration, the carrier may be a sterile, pa^renterally acceptable liquid such as sterile, water, or a parenterally acceptable oil e.g. arachis oil, contained in ampoules. Compositions for rectal administration may take the form of supporitories , the carrier comprising fixed dose of active ingredient. Tablets, coated tablets, capsules, suppositories and ampoules are examples of suitable dosage unit forms. Each dosage unit preferably contains 10 to 500 mg, and especially 30 to 300 mg, of active ingredient, The following examples illustrate the preparation of compounds according to the invention, and also pharmaceutical compositions containing such compounds as active ingredients :-Example 1 2.6-Bis-( ethanolpropanolamino )-8-diethylaminopyrimido Γ 5.4-d]-¾yrimidine To a solution of 5»! g (0.01 mol) of 2 , 6-bis-( ethanol-propanolamino-)- , 8-bis-( diethylamino )-pyrimido[ 5 , 4-d] pyrimidine (m.p. : 118 - 121°C) in approx. 100 ml of 10 acetic acid were added 2.6 g. (0.04 mol) of zinc powder with stirring and heating for about 20 minutes on a boiling water bath. The unused zinc powder was sucked and then removed by filtration with suction and with the addition of concentrated ammonia solution, an almost colourless solution was obtained which was adjusted to approx. pH 6. 25 ml of a 10% methanolic iodine solution was added dropwise and the hydrogenated compound was converted into 2,6-bis-(ethanol-propanolamino )-8-diethylaminopyrimido[ 5 , -d]pyrimidine. The 0 completion of the oxidation was monitored by starch solution, a slight excess of iodine being removed by the addition of a sodium bisulfite solution. With the addition of concentrated ammonia to approx," pH 8, the reaction product was completely precipitated. The precipitate was filtered off with suction after a short period, washed with water, and dried. For Example 2 2 , 6-Bis- ( ethanolpropanolamino )-8-dlethylaminopyrimldo Γ « 4-dl -pyrimidine 3,6 g (0.01 mol) of 2(6)-chloro-6(2)-ethanol propanolamino-8-diethylaminopyrimido[ 5, 4-d]pyrimidine were heated with 15 g of ethanolpropanolamine for 1 hour et approx. 190°Ce On taking up the orange-coloured solution obtained in about 200 ml of water, 2, 6-bis-( ethanolpropanolamino)-8-diethyl-aminopyrimido[ 5, 4-d]pyrimidine formed a yellow precipitate.

The product was filtered off with suction, washed with water and dried. For purification it was recrystallized from water. Yield: 6 $ of theory, m.p. : 97 - 108°C:.

The same compound may be obtained by reaction under pressure of 8-ethylthio-2, 6-bis-( ethanolpropanolamino)-pyrimido[5,4-d] pyrimidine with diethylamine.

Example 3 8-Diethylamino-216-bis-( dipropanolamino)-pyrimido Γ .4-dl pyrimidine Prepared from 4, 8-bis-(diethylamino)-2y 6-bis-(dipropanol-amino J-gyrimidof , 4-d] pyrimidine (m.p.: 146 - 148°C) analogously to Example 1.

Yield: 86$ of theory, m.p. : 122 - 124°C.: Example 4 2.6-Bis-( ethanolpropanolamino)-8-hexamethyleneiminopyrimido-Γ i4-dlpyrimidine Prepared from 2, 6-bis-(ethanolpropanolamino) -4, 8-bis-(hexa-methyleneimino)-pyrimido[5,4-d]pyrimidine (m.p.: 132 - 134°C) analogously to Example 1, the reaction being effected in Example 5 2, 6-Bis-( dlpropanolamlno )-8-hexamethyleneiminopyrimido-' Γ 5.4-d] -pyrimidine Prepared from 2,6-bis-(dipropanolamino)-4,8-bis- (hexamethyleneimino)-pyrimido[5,4-d]pyrimidine (m.p. : I65 - 167°C) analogously to Example 4.

Yield: 90 of theory, m.p.: l62 - 163°C0 Example 6 2.6-Bis-( ethanolisopropanolamino )-8-diethylaminopyrimidoΓ 5.4-d] pyrimidine Prepared from 2,6-bis-(ethanolisopropanolamino)-4,8-bis- (diethylamino)-pyrimido[5,4-d] pyrimidine (m.p.s 142 - 144°C) analogously to Example 10 Yield; 69 of theory, m.p.: 141 - 143°C.

Example 7 2.6-Bis-( diethanolamino )-8-diethylaminopyrimidpr 5.4-d] To a solution of 4.8 g (O.Ol mol) of 2, 6-bis-(diethanol- amino)-4 , 8-bis-(diethylamino)-pyrimido[ 5, 4-d]pyrimidine (m.p. : I67 - 168°C) in approx. 100 ml of 10$ acetic acid or formic acid were added 2.6 g (0,04 mol) of zinc powder and with stirring, the mixture was heated for about 15 minutes on a boiling water bath. The unused zinc powder was then removed by suction filtration and on the addition of concentrated ammonia, an almost colourless solution was obtained which was adjusted to approx. pH 6. On adding dropwise 25 ml of a 10$ methanolicciiodine solution, the partially hydrogenated compound was converted into 2, 6- using starch solution and a slight excess of iodine was removed by the addition of a sodium bisulfite solution.

On addition of concentrated ammonia to approx. pH 8 , the reaction product separated quantitatively as a yellow precipitate, which was filtered off with suction after a Short period, washed with water and dried. It was re-crystallized once from water for purification.

Yield: 3. 2 g ( 78 of theory), m.p. : 163 - l65°C.

Example 8 2 , 6-Bis-( diethanolamino ) -8-hexamethyleneiminopyrimidor 5. -dl-pyrimldine Prepared from 2 , 6-bis-(diethanolamino)~¾, 8-bis-(hexamethyl eneiminopyrimido[5, -d]pyrimidine (m,p. : 208 - 209 °C ) analogous ly to Example 7. (Solvent: 20 acetic acid) Yield: 73$ of theory, m.p.: 157 - 159°C (from ethyl acetate). Example 9 2 « 6-Bis-(diethanolamino') g8-hexamethyleneiminopyrimidor 5 « -d1- i pyrimidine 3.7 g ( 0.01 mol) of 6 ( 2)-chloro-2 ( 6)-diethanolamino-8-hexamethyleneiminopyrimido[ 5, -d]pyrimidine (m.p.: 129 - 132°C) were heated for 2 hours with 15 g of diethanolamine at approx. 190°C. On taking up the orange-coloured solution in about 200 ml of water, 2 , 6-bis(diethanolamino) -8-hexamethylene-iminopyrlmido[5j4-d]pyrimidine separated as a yellow precipitate. It was filtered off with suction, washed with water, dried and for purification recrystallized from ethyl acetate. Yield: 6* of theory, m.p.: 157 - 159°C.

Example 10 were heated for 6 hours with 15 g of diethanolamine at approx. 190°C. On taking up the orange-coloured solution in about 200 ml of water 2,6-bis-(diethanolamino)-8-hexamethyl|ne- * J iminopyrimido[5,4-d]pyrimidine separated as a yellow pre-cipitate. It was filtered off with suction, washed with water, dried and for purification recrystallized from ethyl acetate.

Yield: 53 # of theory, m.p. : 156 - 158°C.

Example 11 2 , 6-Bis-(diethanolamino )-8-hexamethyleneiminopyrimid r t -dl pyrimidine 4 g (0.01 mol) of 8-ethylthio-2,6-bis-(diethanolamino)-pyrimido[5,4-d] pyrimidine (m.p.: 144 - 145°C) were refluxed for 8 hours with 20 ml of hexamethyleneimine. Half the excess amine was then distilled off in vacuo, the remaining orange-coloured solution was added to about 200 ml of water and 2, 6-bis-(diethanolamino)-8-hexamethyleneiminopyrimido-[5>½-d]pyrimidine separated as a yellow precipitate. It was filtered off with suction, washed with water, dried and purifica-fced by recrystallisation from ethyl acetate.

Yield: 56 of theory, m.p.: 156 - 158°C.

Example 12 2.6-Bis-( diethanolamino)-8-diethylaminopyrimidof 5, 4-d] pyrimidine 4?6--g (O.Ol mol) oJ.8-benzylthio-2, 6-bis-(d±ethanolamino)-pyrimido[5,4-d]pyrimidine were heated for 4 hours with 20 ml of diethylamine in a closed vessel at approx; 190°C. On taking up the reaction mixture in water, '2,6^bis-(diethanol- Example 13 2, 6-Bis-(diethanolamino )-8-dlmethylaminopyrimidor .4-dlpyrimi-dine Prepared from 2, 6-his-(diethanolamino)-4, $-bis-( dimethyl-aminoj-pyrimidb^^-dlpyrimidine (m.py: 198 - 200°C) analogously to Example, 7.

Yield: 84$ of theory, m.p.: 195 - 197°C.

Example 14 216-Bls-( diethanolamino )-8-diisopropylaminopyrimidoΓ5.4-dl-pyrlmidlne Prepared from 2,6-bis-(diethanolamino)-4,8-bis-(diiso-propylamino)pyrimido[5,4-d]pyrimidine (m.p.; 256 - 258°C) analogously to Example 7. Solvent: 30 acetic acid.

Yield: 57$ of theory, m.p.: 155 - 156°C.

Example 15 2.6-Bis-( diethaholamino )-8-diallylaminopyrimidor « 4-d]pyrimi-dine Prepared from 2,6-bis-(diethanolamino)-4,8-bis-(diallyl-amino)-pyrimido[5,4-d]pyrimidine (m.p.: 110 - 111°C) analogously to Example 14.

Yield: 78 of theory, m.p.: 122 - 124°C.

Example l6 2.6-Bls-(diethanolamino )-8-(N-benzyl-N-methylamino)-pyrimidof 5«4-d"lpyrimidine N-methylamino)-pyrimido[5,4-d]pyrimidine (m.p.: 195 - 197°C) analogously to Example 14.

Yield: 6l of ; theory, m.p.: 135 - 137°C. (heptamethyleneimino)-pyrimido[574-d]pyriinidine (m.p.: 205 - 207°C) analogously to Example 7. (Solvent: 0 acetic acid). Yield; 82% of theory, m.p.: 145 - 147°C.

Example 18 8-( 3.6-Ethylenehexamethyleneimino )-2.6-bis-( diethanolamino )-pyrimido Γ 5.4-dl yrimidine Prepared from 4,8-bis-(3»6-ethylenehexamethyleneimino)-2,6-bis-(diethanolamino)-fiyrimido[5,4-d] pyrimidine (m.p. s 232 -233°C) analogously to Example 17.

Yield: 63% of theory, m.p.: 150-152°C.

Example 19 216-Bis~( diethanolamino )~8-indolinopyrlmidor .4-dlpyrimidine Produced from 2,6-bis-(diethanolamino)-4,8-bis-(indolino)-pyrimido[5,4-fl]pyrimidine (m.p.: 220 - 222°C) Analogously to Example 7. (Solvent: 50 acetic acid).

Yield: 93% of theory, m.p.: 175 - 177°C.

Example 20 2.6-Bis-( diethanolamino)-8-( 1.2, 3o4-tetrahydroisoquinolino)-pyrimidpr 5. -d yrimidine ■ Prepared from 2, 6-bis-(diethanolamino)-4 , 8-bis (l , 2, 3,4-tetrahydroisoquinolino)-pyrimido[5,4-d]pyrimidine (m.p. : 209-211°C) analogously to Example 17.

Yield: 72% of theory, m.p.: 162 - l65°C.

Exkmple 21 2, 6-Bis( ethanolpropanolamino)~8-( 3~methylpiperidino)-pyrimido Γ 5 « 4-d yrimidine ΐ Prepared from 2,6-bis-(ethanolpropanolamino)-4,8-bis-(3-methylpiperldino)-pyrimido 5 4-d yrimidine m. .: 129 - Example 22 2. -Bis-( diethanolamino)-8-( 1.2.5.6-tetrahydropyri¾ de )-pyrimidof «4-dl pyrimidine To a solution of 5.0 g (0.01 mol) of 2,6-bis-(diethanol-amino )-4 , 8-bis-(1,2,5, 6-tetrahydropyridino )-pyrimido [ , 4-d] pyrimidine (m.p.: 150 - 152°C) in approx. 100 ml of 10$ acetic acid or formic acid were added 3.3 g (0.05 mol) of zinc powder and the mixture heated on a water bath with stirring for 5 minutes. The remaining zinc powder was then filtered off with suction and on the addition of concentrated ammonia an almost colourless solution was obtained which was adjusted to approximately pH 7. 10 ml of a molar . methanolic iodine solution were added dropwise the pH being maintained by the addition of ammonia. The hydrogenated compound obtained was converted into 2,6-bis-(diethanolamino)-8-(l , 2, , 6-tetrahydropyridino )-pyrimido-[5> -d]pyrimidine. The completion of the oxidation was monitored by a starch solution, a flight excess of iodine being removed by the addition of a sodium bisulfite solution. The reaction product which separated as a iyellow precipitate was filtered off with suction after standing for a short while, washed with„water and dried. It was recrystalllsed once from methanol for purification.

Yield: 3\5 g (83 of theory), m.p.: 146 - 148°C.

Example 23 2.6-Bis-( diethanolamino )-8-(1.2.5, 6-tetrahydropyridino )-pyrimidoΓ5.4-dl yrimidirie 3.5 g (O.Ol mol) of 6-chloro-2-diethanolamino-8-(l,2, ,6- obtained in approximately 200 ml of water, after leaving it for a short period 2,6-bis-(diethanolamino)-8-(l,2, 5,6-tetrahydropyridino)-pyrimido[5,4-d]pyrimidine separated as a yellow precipitate. On suction filtration, washing of the solid with water and drying, it was recrystallized from methanol for purification.

Yield: 3.1 g (74 f> of theory), m.p. : 146 - 148°C.

Example 24 2, 6-Bis-(diethanolamino)-8-( 5-methylpiperidino )-pyrimido Γ5.4-d~l -pyrimidine Prepared from 2,6-bis-(diethanolamino)-4,8-(3-methyl-piperidino)-pyrimido[5,4-d]pyrimidine (m,p„ : 188 - 190°C) analogously to example 22.

Yield; 78 of theory, m.p. : 159 - l6l°C (from methanol). Example 25 2, 6-Bis-(diethanolamino )-8-( 2, 6-dimethylpiperidino )-pyrimido-Γ « 4-dlpyrimidine Prepared from 2, 6-bis-(diethanolamino)-4, 8~bis-(2, 6-dimethylpiperidino)-pyrimido[5,4-d]pyrimidine (m.p. : 230 -233°C) analogously to Example 22.

Yield: 69$ of theory, m.p.: 160 - 162°C (from ethylene chloride).

Example 26 > Tablets containing 100 mg of 2, 6-bis-(diethanolamino)-8-diethylaminopyrimidoΓ « 4-dlpyrimidine Composition: 1 tablet contains: 2, 6-bis (diethanolamino)-8-diethylaminopyrimido^, 4-d]pyrimidine 100.0 mg Preparation; The mixture of active ingredient¾ lactose and potato starch was moistened with a 15 alcoholic solution of the polyvinylpyrrolidone, granulated through a 1 . 5 mm screen and dried at 5°C. The granulate obtained was passed once more-through a screen, mixed with magnesium stearate and pressed into tablets..

Weight of tablet: 220 mg Die: 9 nun Example . 27 Sugar coated tablets containing 100 mg of 2 , 6-bis-(diethanol-amino )-8-diethylaminopyrimido Γ , -dlpyrimidine The tablets produced according to Example 26 were coated with a shell in a conventional way, the shell consisting essentially of sugar and talcum. The finished sugar coated tablets were polished with beeswax.

Example 28, Gelatin capsules containing 200 mg of 2 , 6-bis-( ethanol-propanolamino)-8-diethylaminopyrimidor 5. -dl yrimidine Composition: 1 capsule contains: 2 , 6-bis ( ethanolpropanolamino)-8-diethylaminopyrimido [ 5 , 4-d]pyrimidine 200, 0 mg corn starch 90. 0 mg talcum 10. 0 mg 300, 0 mg Preparation: The substances were intimately mixed %nd used to fille size 1 gelatin capsules, Example 29 Ampoules containing 30 mg of 2„ 6-bis-(diethanolamino)-8-diethylaminopyrimido Γ 5 « -d"lpyrimidine Composition. 1 ampoule contains: 2, 6-bis-(diethanolamino)-8-diethylaminopyrimido[5, -d]pyrimidine 30,0 mg polyethyleneglycol 600 100,0 mg IN hydrochloric acid ad pH 3.0 q,s, distilled water ad 2.0 ml Preparation; The polyethyleneglycol was dissolved in water and the 2 , 6-bis-( diethanolamino )-8-diethylaminopyrimido[ 5 , 4-d]; „ was pyrimidine woro- suspended therein. Under addition of N hydrochloric acid, the substance was dissolved and the pH adjusted. The suspension was mixed with distilled water to the indicated volume4 and the solution was filtered sterile.

Filling: into colourless 2 ml ampoules wi~th protective inert gas treatment, Sterilisation: 20 minutes at 120°C, Example 30 Drop solution containing 50 mg of 2.6-bis-( ethanol-prOpanolamino)-8-diethylaminopyrimido Γ 5. -dlpyrimidine Composition: ! 100 ml of drop solution contain: 2 , 6-bis ( ethanolpropanolamino ) 8-diethyl- aminopyrimido[ , -d]pyrimidine 5o0 g tartaric acid 0,5 g ethanol, pure 20.0 g polyethyleneglycol 600 20.0 g distilled water ad 100.0 ml Preparation: Sorbic acid was dissolved in alcohol and an equal quantity of water was added. The active substance and the tartaric acid were dissolved therein with stirrjLng (solution I). The sugar was dissolved in the remaining water (solution 2). Solution 2, the polyethyleneglycol flavor and the were added to solution 1 with stirring.

The mixture filtered through a suitable filter. 1 ml of drop solution contains 50 mg of 2 , 6-bis-( ethanol-propanolamino )-β-^άβthylaminopyrimido[ , -d-d]pyrimidine. Example 31 Tablets containing 160 mg of 2.6-bis-(diethanolamino)--8-hexamethyleneiminopyrimidor 5. -dlpyrimidine Compositions : 1 tablet contains: 2, 6-bis-(diethanolamino)-8-hexamB±hylene- iminopyrimido[5, -d]pyrimidine l6000 mg potato starch 52.0 mg gelatin 6.0 mg magnesium stearate 2.0 mg 220.0 mg Preparations A mixture of active ingredient and potato starch was granulated with a 10 aqueous solution of the gelatin through a screen of 1.5 mm and dried at 5°C. The dried granulate was passed once more through the above screen, Example 32 Sugar coated tablets containing l60 mg of 2, 6-bis-(diethanol-amino )-8-hexamethyleneiminopyrimidoΓ . -d] pyrimidine The tablets prepared according to the m'ethod of Example 31 were coated with a shell in a conventional way, the shell consisting essentially of sugar and talcum. The finished sugar coated tablets were polished with beeswax. l Example 33 ·' Suppositories containing 300 mg of 2.6-bis diethanolamino)-8-di-ethylaminopyrimidoΓ , -d] pyrimidine Composition; 1 suppository contains: 2, 6-bis-(diethanolamino)-8-diethylamino- pyrimidino[5, -d]pyrimidine 300»0 mg suppository base (e.g. itepsol W 45) 1450.0 mg I75O.O mg Preparation; The finely pulverized active ingredient was suspended with the aid of an immersion homogenizer in the molten suppository base cooled to 37°C and poured into slightly pre-cooled moulds.

Weight of suppository: 1.75 g.

Claims (3)

1. I. Compounds of the formula wherein R-, represents an alkyl group containing from 1 to 3 or albenzyl carbon atoms, e - an allyl/group, and Rg represents an alkyl group containing from 1 to 3 carbon atoms or an allyl group; or R^ and R2 together with the adjacent nitrogen atom represent a piperidino group substituted by 1 or 2 alkyl groups each containing 1 or 2 carbon atoms in the 2,3 a« or 6-positions, a 1 , 2 , 5 » 6-tetrahydro-pyrimido, hexamethyleneimino or heptameth leneimino group, or a 3, 6-ethylenehexamethyleneimi.no, indolino or 1,2,3,4-tetrahydroisoquinolino group; and R^and R^ which may be the same or different each represents a hydroxyalkyl group containing 2 or 3 carbon atoms.
2. 2. Compounds as claimed in claim 1 wherein R-^ and R^ · each represents a methyl, ethyl or isopropyl group, or R^ and R^ together with the adjacent nitrogen atom represent a piperidino group substituted by one or two methyl .groups.
3. 3. Compounds as claimed in claim 2 wherein R^ and R^ together with the adjacent nitrogen atom represent a 3-methylpiperidino or 2 , 6-dimethylpiperidino group „ 4. Compounds as claimed in any of the preceding pyrimido [ 5 , pyrimidine . 6. 2 , 6-bis-(i)ipropanolamino )-8-diethylamino-pyrimido- [ 5 , -d]pyrimidine . 7 o 2 , 6-bis-(Ethanolpropanolamino)-8~hexamethylenimino-pyrimido[ 5 , 4-d]pyrimidine . 8. 2, 6-bis-(DiethanQlamino)-.8-diethylaminopyrimido[5,4-d] pyrimidine. 9v 2, 6-bis-(Diethanolamino)-8-hexamethyleneiminopyrimido [ 5 , -d]pyrimidine . 10. Compounds as claimed in claim 1 as herein specifically disclosed with the exception of those as claimed in any of claims 5 "to 9. 11. A process for the preparation of compounds aa claimed ai-(hydroxyalkyl)-amino/ in claim 1 wherein a 2 , 6-bis-(^4«lfe'0>nol-Oi'ii>'ii¾o --pyrimido [5>^-d]pyrimidine of formula (wherein R , R2>, R^ and R^ are as defined in claim 1 R with the two groups -N ^ 1 having the same meaning) is reduced and the compound thus obtained is subsequently oxidised to form a compound of formula I. 12. A process as claimed in claim 11 wherein the reduction step is effected using {nt'sce t or catalytically activated 14. A process as claimed in claim 13 wherein the reduction is effected in a polar solvent. 15. A process as claimed in claim 14 wherein the reduction is effected in a weakly acidiis solution. 16. A process as claimed in claim 15 wherein the reduction is effected ±ώ s&iulion at a pH of 'approximately 2 to 5. 17. A process as claimed in claim 12 wherein the reduction; step is effected using nascent hydrogen prepared by the a metal reaction of aJ?feari-3ri*»-ea¾'th mo a-1 with a weakly acidic solvent. 18 A process as claimed in claim 17 wherein the weakly acidic solvent comprises formic or acetic acid. 19. A process as claimed in any of claims 11 to 18 wherein the oxidation step is effected using a lower alkanolic solution of a halogen, hydrogen peroxide or an alkali metal bromate or permangamate as oxidising agent. 20. A process as claimed in claim 19 wherein the oxidising agent comprises a methanolic solution of bromine or iodine, or potassium bromate or potassium permangamatee 21. A process as claimed in claim 20 wherein the oxidising agent comprises a solution of bromine or iodine and the pH of the solution being oxidised is approximately 6, 22. A process as claimed in claim 20 wherein the oxidising n agent coiftprises potassium permanganate or hydrogen peroxide and the pH oii'the solution being oxidised is less than 6. 23. A process as claimed in any of claims 11 to 22 wherein the compound obtained by reduction of the .compound of 24. A process as claimed in any of claims 11 to 22 wherein the compound obtained by reduction of the compound of formula II is separated from the reaction mixture prior to oxidation. 25. A process as claimed in claim 24 wherein the compound obtained by reduction of the compound of formula II is separated in an air-free atmosphere. 26. A process as claimed in claim 11 substantially as herein described. 27. A process for, the preparation of compounds as claimed in claim 1 substantially as herein described in any of Examples 1,3 to 6 and 21. 28. A process for the preparation of compounds as claimed in claim 1 substantially as herein described in any of Examples 7, 8 and !3 to 20. 29. A process for the preparation of compounds as claimed in claim 1 substantially as herein described in any of Examples 22, 24 and 25, 30. Compounds as claimed in claim 1 when prepared by a process as claimed in any of claims 11 to 26„ 31. Compounds as claimed in claim 1 when prepared by a process as claimed in claim 27. 32. Compounds as claimed in claim 1 when prepared by a process as claimed in claim 28. 33» Compounds as claimed in claim 1 when prepared by a process, as claimed in claim 29. 34. A process for the preparation of compounds as claimed in claim 1 wherein a compound of formula (wherein at least one of A, A^ and A≥ is a radical which may he interchanged by reaction with an amine and 1 or 2 of the substituents A, present an appropriate group of formula ) Is reacted with a compound of formula /R- H - N IV R, (wherein and R0 are as defined in claim l) and/or an fc 1 2 ' alkanolamine of formula H - N V R, (wherein R^ and R^ are as defined in claim l) whereby a compound of formula I is produced. 35 · A process as claimed in claim 3 wherein ino the compound of formula III at least one of A, A^ and A2 represents a halogen atom or an alkyl, benzyl or phenyl substituted hydroxy or mercapto group. 36. A process as claimed in claim 34 or claim 35 in which the reaction is effected at an elevated temperature. 37 o A process as claimed in claim 36 wherein the reaction is effected at a temperature above 150°C. * ■ Λ wherein the reaction is effected- in the presence of a high boiling solvent. 40γ¾ A process as claimed in claim 39 wherein the solvent comprises dimethylformaiqide or an excess of a compound of formula IV or V. 41. A process as claimed in claim 34 substantially as herein described. 42. A process for the preparation of compounds as claimed in claim 1, substantially as herein described in Example 2. 43. A process for the preparation of compounds as claimed in claim 1, substantially as herein described in any of Examples 9 to 12. 44. A process fdr the preparation of compounds as claimed in claim 1, substantially as herein described in Example 23. 45· Compounds as claimed in claim 1 when prepared by a process as claimed in any of claims 34 to 41. 46. 2, 6-Bis-( ethanolpropanolamino)-8-diethylamino-pyrimido[51>4-d]pyrimidine when prepared by a process as claimed in claim 42. 47. Compounds as claimed in claim 1 when prepared bye a.process as claimed in claim 43. 48. 2 , 6-Bis-( diethanolamino )-8-( 1 ,2,5, 6-tetrahydro-pyridino)-pyrimido[5,4-d]pyrimidine when prepared by a process! as claimed in claim 44. ί ■ 49» Pharmaceutical compositions comprising at least one compound as claimed in claim 1 as active ingredient in association with a pharmaceutical carrier or excipient. 50. Compositions as claimed in claim 49 in "forms syrups, emulsions, suspensions, drops, suppositories or injection aqlutions, 52. Compositions as claimed in any of claims 49 to 51 in the form of dosage units. 53. Compositions as claimed in claim 52 wherein each dosage unit contains from 10 to 500 mg of active ingredient. 54. Compositions as claimed in claim 53 wherein each dosage unit contains from 30 to 300 mg of active ingredient. 55 » Compositions as claimed in claim 49 substantially as herein described. 56. Pharmaceutical compositions substantially as herein described in any of Examples 26 to 33. ■ ¾ -„—Each and every novel oompound;—proooss} method— and composition horoin disclosed-.