DE1933428A1 - 2,6-Bis-(dialkanolamino)-8-aminopyrimido-(5,4,d)-pyrimidines - Google Patents

Abstract

5,4-d pyrimidines of formula (I): (where R1 = 1-3C alkyl, allyl or PhCH2; R2 = 1-3C alkyl or allyl; or R1 + R2 = piperidino opt. substd. by 1 or 2 1-2C alkyl, 1,2,5,6-tetrahydropyridino, hexa- or hepta-methyleneimino, 3,6-ethylene-hexamethyleneimino, indolino or 1,2,3,4-tetrahydroisoquinolino; R3, R4 = 2-3C hydroxyalkyl), ae new compds. showing a cardiovascular effect and having a strong inhibiting action on platelet aggregation. Prefd. cpds. include 2,6-bis(ethanolpropanolamino)8-diethylaminopyrimido 5,4-d pyrimid- ine (IV).

Description

New 2,6-bis- (diethanolamino) -pyrimido / 5,4-s pyrimidine / T. additive to the DBP. (Patent application P 17 95 030.0)] In the DBP .......... (file number P 17 95 030.0) are new 2, c-bis (diethanolamino) pyrimido [5,4-d] pyrimidines, which in addition to a cardiovascular effect, a very strong inhibitory effect on platelet aggregation have, and processes for their preparation are described.

It has now been found that compounds with other basic radicals in the 8-position, namely the new compounds of the formula I, in which R1 is an alkyl radical with 1-3 carbon atoms, the allyl oGer benzyl radical, R2 is an alkyl radical with 1-3 carbon atoms, the allyl radical or R1 and R2 together with the nitrogen atom in between the hexa- or heptamethyleneimino ring, the 3,6-ethylene -hexamethyleneimino, indolino or 1,2,3,4-tetrahydroisoquinoline, can be prepared by the same processes and have the same valuable pharmaceutical properties.

The new compounds of the formula I can be prepared by the following processes described in DBP .......... (file number P 17 95 030B0): Treatment of a 2,6-bis (diethanolamino) pyrimido [5,4- d] pyrimidines of the formula II, in which the two leftovers are the same and have the meanings mentioned above, with reducing agents and oxidation of the hydrogenated compound obtained as an intermediate.

As a reducing agent, nascent or catalytically aroused Hydrogen and electrolytic reduction have proven to be particularly beneficial, the reduction is carried out in the presence of a solvent, especially a polar one Solvent, preferably in a weakly acidic solution at a pH of about 2-5 carried out, The hydrogenated compound obtained can, expediently with exclusion of air, to be isolated; however, it is advantageous directly with a conventional oxidizing agent oxidized. As an oxidizing agent, for example, a methanolic Br @@ - or Iodine solution, Hydrogen peroxide, potassium bromate, or potassium permanganate be used. The pH of the reaction mixture depends on the used oxidizing agents. If one oxidizes, for example, with a bromine or iodine solution, the pH is expediently adjusted to about 6, but it can also, in particular when using, for example, potassium permanganate or hydrogen peroxide, in more acidic area work.

2. Implementation of a compound of the formula III, in which the radicals A, A1 and A2 are interchangeable radicals, such as halogen atoms, hydroxyl or mercanto groups substituted by alkyl, benzyl or phenyl radicals, as 1-2 of these radicals already mean the diethanolamino group or the rest can mean with a compound of the formula IV, in which R1 and R2 are as defined at the outset, and / or with diethanolamine at elevated temperatures, preferably at temperatures above 150.degree. The reaction is carried out in the presence of an acid-binding agent in a high-boiling solvent, for example in dimethylformamide, but preferably an appropriate excess of the compound of formula III or of diethanolamine is used simultaneously as a solvent and as an acid-binding agent.

The starting materials of the formulas II and III can, for example, according to the process of the German patent specification 1,116,676.

The following examples serve to explain the invention in more detail: Example 1 2,6-bis (diethanolamino) -8-diethylamino-pyrimido [5,4-d] pyrimidine In a Solution of 4.8 g (0.01 mol) of 2,6-bis (diethanolamino) -4,8-bis (diethylamino) pyrimido [5,4-d] pyrimidine (Melting point: 167-168 ° C) in about 100 ml of 10% acetic acid or formic acid one 2.6 g (0.04 May), zinc powder and heated with stirring for about 15 minutes on the boiling water bath. Then the unused. Zinc powder sucked off and the almost colorless solution obtained by adding concentrated ammonia adjusted to a pH of about 6. By dropping 25 ml of a 10% methanolic iodine solution is then the partially hydrogenated compound in the 2,6-bis (diethanolamino) -8-diethylamino-pyrimido / 5,4- pyrimidine transferred. The completeness of the oxidation is checked using Starch solution and then removes a small excess of iodine using sodium bisulfite solution. The reaction product becomes complete by adding concentrated ammonia to about pH 8 precipitated as a yellow precipitate. After standing for a short time, vacuum and wash Water, dries and recrystallizes once from water for further purification.

Yield: 3.2 g (78% of theory), m.p .: 163-16500 Example 2 2,6-bis (diethanolamino) -8-hexamethyleneimino-pyrimido [5,4-d] pyrimidine Manufactured from 2,6-bis (diethanolamino) -4,8-bis (hexamethyleneimin4-pyrimido / 5,4-jdpyrimidine (m.p .: 208-209 ° C) as in example 1.

(Solvent: 20 goat acetic acid) Yield: 73% of theory Th., Schmp .: 157 - 15900 (from ethyl acetate).

Example 3 2,6-bis (diethanolamino) -8-hexamethyleneimino-pyrimido [5,4-d] pyrimidine 3.7 g (0.01 mol) of 6 (2) -chloro-2 (6) -diethanolamino-8-hexamethyleneimino-pyrimido [5 ', 4-d] pyrimidine (Melting point: 129-132 ° C) with 15 g of diethanolamine for 2 hours at about 190 ° C heated. When the orange-colored solution is taken up in about 200 ml of water, one falls the 2,6-bis (diethanolamino) -8-hexamethyleneimino-pyrimido- / 5,4-pyrimidine as yellow Precipitation from. It is filtered off with suction, washed with water, dried and crystallized to further purification from ethyl acetate.

Yield: 64% of theory, m.p .: 157-15900 Example 4 2,6-bis (diethanolamino) -8-hexamethyleneimino-pyrimido [5,4-d] pyri midin 4.2 g (0.01 mol) 6 (2) -phenoxy-2 (6) -diethanolamino-8-hexamethylene imino-pyrimido / §, 4- pyrimidine (m.p .: 179-1800C) are added to 15 g of diethanolamine for 6 hours heated about 1900C. Then the orange solution is in about 200 ml of water added, with the 2,6-bis (diethanolamino) -8-hexamethyleneimino-pyrimido [5,4-d] pyrimidine separates as a yellow precipitate.

It is filtered off with suction, washed with water, dried and crystallized for further use Cleaning from ethyl acetate around.

Yield: 53 ffi of theory, m.p .: 156-15800 example 5 2,6-bis (diethanolamino) -8-hexamethyleneimino-pyrimido [5,4-d] pyrimidine 4 g (0.01 Mol) 8-ethylthio-2,6-bis (Mäthanólamino) -pyrimido / 5,4-S pyrimidine (m.p .: 144 - 1450C) is refluxed for 8 hours with 20 ml of hexamethyleneimine. Afterward about half of the excess amine is distilled off in vacuo and the remaining orange solution in about 200 ml of water, the 2,6-bis (diethanolamino) -8-hexamethyleneimino-pyri mido / g, 4-pyrimidine separates out as a yellow precipitate. You vacuum off, wash with Water, dries and recrystallizes from ethyl acetate for further purification.

Yield: 56 of theory, m.p .: 156-158 ° C. Example 6 2,6-bis (diethanolamino) -8-diethylamino-pyrimido [5,4-d] pyrimidine 4.6 g (0.01 mol) of 8-benzylthio-2,6-bis (diethanolamino) -pyrimido- / 5,4-pyrimidine heated with 20 ml of diethylamine in a pressure tube for 4 hours at about 1900C. That at the uptake of the reaction mixture in water precipitated 2,6-bis (diethanolamino) -8-diethylamino -pyrimido [5,4-d] pyrimidine is recrystallized from water after suction.

Yield: 48% of theory, m.p .: 162-16400 Example 7 2,6-bis (diethanolamino) -8-dimethylamino-pyrimido [5,4-d] pyrimidine Prepared from 2,6-bis (diethanolamino) -4,8-bis (dimethylamino) -pyrimido [5,4-d] pyrimidine (Melting point: 198 - 200 ° C) as in example 1.

Yield: 84% of theory, melting point: 195-197 ° C example 8 2,6-bis (diethanolamino) -8-diisopropylamino-pyrimido [5,4-d] pyrimidine- Prepared from 2,6-bis (diethanolamino) -4,8-bis (diisopropylamino) pyrimido [5,4-d] pyrimidine (m.p .: 256 - 2580C) analogous to example 1.

Solvent: 30% acetic acid Yield: 57% of theory, melting point: 155-1560C Example 9 2,6-Bis (diethanolamino) -8-diallylamino-pyrimido [5,4-d] pyrimidine Prepared from 2,6-bis (diethanolamino) -4,8-bis (diallylamino) -pyrimidoL5,4-pyrimidine (m.p .: 110 - 111 ° C) as in Example 8.

Yield: 78% of theory Th., M.p .: 122-12400.

Example 10 2,6-Bis (diethanolamino) -8- (N-benzyl-methylamino) -pyrimido [5,4-d] -pyrimidine Prepared from 2,6-bis (diethanolamino) -4,8-bis (N-benzyl-methylamino) -pyrimido [5,4-d] pyrimidine (Melting point: 195-197 ° C) as in Example 8.

Yield: 61% of theory Th., M.p .: 135-13700.

Example 11 2,6-bis (diethanolamino) -8-heptamethyleneimino-pyrimido [5,4-d] -pyrimidine Prepared from 2,6-bis (diethanolamino) -4,8-bis (heptamethyleneiminipyrimido [5,4-d] pyrimidine (Mp .: 205-2070C) as in Example 1 (solvent: 40% acetic acid).

Yield: 82% of theory, melting point: 145-1470C example 12 8- (3 ', 6'-ethylene-hexamethyleneimino) -2,6-bis (diethanolamino) -pyrimido [5,4-d] pyrimidine Prepared from 4,8-bis (3 ', 6'-ethylene-hexamethyleneimino) -2,6-biE- (diethanolamino) -pyrimido [5,4-d] pyrimidine (Mp .: 232 - 23300) analogous to example 11.

Yield: 63 ffi d. Th., M.p .: 150-15200 Example 13 2,6-bis (diethanolamino) -8-indolino-nyrimido / 5,4-d7pyrimidine Made from 2,6-bis (diethanolamino) -4,8-bis (indolino) -pyrimido- / 5,4-jdpyrimidine (Melting point: 220-2220C) as in Example 1. (Solvent: 50% acetic acid) Yield: 93 ffi d. Th., Mp .: 175-17700 Example 14 2,6-Bis (diethanolamino) -8- (1 ', 2', 3 ', 4'-tetrahydroisoquinolino) -pyrimido [5,4-d] pyrimidine Prepared from 2,6-bis (diethanolamino) -4,8-bis (1 ', 2', 3 ', 4'-tetrahydroisoquinolino) -pyrimido [5,4-d] pyrimidine (Melting point: 209-211 ° C) as in Example 11.

Yield: 72% of theory Th., M.p .: 162-16500 The new Compounds can be used for therapeutic use in the usual: pharmaceutical Incorporate preparations, the single dose is 10 - 500 mg, preferably 30-300 mg.

Example I Tablets with 100 m 2 of 6-bis (diethanolamino) -8-diethylaminopyrimido [5,4-d] pyrimidine Composition: 1 tablet contains: 2,6-bis (diethanolamino) -8-diethylaminopyrimido [5,4-d] pyrimidine 100.0 mg lactose 70.0 mg potato starch 40.0 mg polyvinylpyrrolidone 8.0 mg Magnesium stearate 2.0 mg 220.0 mg Manufacturing process: The mixture of the active substance With lactose and potato starch, this becomes the result with its own alcoholic solution Polyvinylpyrrolidone moistened, granulated through a 1.5 mm sieve and dried at 450C. The granules obtained in this way are again beaten through a 1 mm sieve with magnesium stearate mixed and compressed into tablets.

Tablet weight: 220 mg Punch: 9 mm Example II Dragées with 100 2,6-bis (diethanolamino) -8-diethylaminopyrimido [5,4-d] pyrimidine mg the Tablets produced according to Example I are coated in a known manner with a dragee shell coated, which consists essentially of sugar and talc. The finished coated tablets are polished with the help of beeswax.

Drage weight: 300 mg Example III Push-fit gelatine capsules with 200 mg 2,6-bis (diethanolamino) -8-hexamethyleneimino-pyrimido [5,4-d] pyrimidine Composition: 1 capsule contains: 2,6-bis (diethanolamino) -8-hexamethyleneimino-pyrimido- [5,4-d] pyrimidine 200.0 mg MaiastärXe 90.0 mg Talc 10.0 mg 300.0 mg Manufacturing process: The substances are mixed intensively and filled into gelatine capsules size 1: t.

Capsule filling: 300 mg Example IV ampoules with 30 mg 2,6-bis (diethanolamino) -8-hexamethyleneimino-pyrimido / 5,4-d / pyrimidine Composition: 1 ampoule contains: 2,6-bis (diethanolamino) -8-hexamethyleneiminopyrimido / 5,4-dopyrimidine 30.0 mg polyethylene glycol 600 100.0 mg 1-N-hydrochloric acid ad pH 3.0 q.s.

Distilled water to 2.0 ml Production process: The polyethylene glycol is dissolved in water and the active substance is suspended in it. By adding 1N hydrochloric acid the substance is dissolved and the pH is adjusted. One fills with dist. water to the specified volume and filter the solution sterile.

Filling: in colorless 2 ml ampoules with protective gassing Sterilization: 20 minutes at 12000.

Example V Drop solution with 50 mg of 2,6-bis (diethanolamino) -8-diethylamino-pyrimido / 5,4-d7pyrimrrfidin Composition: 100 ml of drop solution contain: 2,6-bis (diethanolamino) -8-diethylaminopyrimido [5,4-d] pyrimidine 5.0 g tartaric acid 0.5 g cane sugar 30.0 g sorbic acid 0.1 g flavor (e.g. bitter essence, H. & R.) 4, G g ethanol, pure 20.0 g polyethylene glycol 600 20.0 g dist. Water ad 100.0 ml Manufacturing process: The sorbic acid is dissolved in alcohol and added the same amount of water. In it are the active ingredient and tartaric acid dissolved with stirring (solution 1). ' The sugar is dissolved in the remaining water (solution 2).

Solution (2), the polyethylene glycol and the aroma become the solution (1) added with stirring. Filter through a suitable filter.

1 ml of drop solution contains 50 mg of 2,6-Bi3 (diethanolamino) -8-diethylamino-pyrimido [5,4-d] pyrimidine.

Example VI Tablets containing 160 mg of 2,6-bis (diethanolamino) -8-hexamethyleneimino-pyrimido [5,4-d] pyrimidine Composition: 1 tablet contains: 2,6-bis (diethanolamino) -8-hexamethyleneimino-pyrimido [5,4-d] pyrimidine 160.0 mg potato starch 52.0 mg gelatin 6.0 mg magnesium stearate 2.0 mg 220.0 mg Manufacturing process: The mixture of the active ingredient and potato starch is made granulated with a 10% aqueous solution of gelatin through a sieve 1.5 mm and dried at 450C. The dried granulate is sieved again through the above sieve, mixed with magnesium stearate and compressed into tablets.

Tablet weight: 220 mg Punch: 9 mm Example VII coated tablets with 160 mg 2,6-bis (diethanolamino) -8-hexamethyleneimino-pyrimido [5,4-d] pyrimidine The below Tablets produced in Example VI are coated in a known manner with a filling, the essentially consists of sugar and talc. The finished Dragee are polished with the help of beeswax.

Dragie weight: 300 mg. Example VIII Suppositories with 300 mg of 2,6-bis (diethanolamino) -8-diethylamino-pyrimido / 5,4-d7-pyrimidine Composition: 1 suppository contains: 2,6-bis (diethanolamino) -8-diethylaminopyrimido [5,4-d] pyrimidine 300.0 mg suppository mass 1450.0 mg (e.g. Witepsol W 45) 1750.0 mg Manufacturing process: The finely powdered active ingredient is with the help of an immersion homogenizer in suspended in the melted and cooled to 3700 suppository mass and in slightly pre-cooled forms poured out.

Suppositories weight: 1.75 g.

Claims (2)

Claims 1. New 2,6-bis (diethanolamino) pyrimido [5,4-d] pyrimidines of the formula I, in which R1 is an alkyl radical with 1-3 carbon atoms, the allyl or benzyl radical, R2 is an alkyl radical with 1-3 carbon atoms, the allyl radical or R1 and R2 together with the nitrogen atom in between the hexa- or heptamethylanimino ring, the 3,6-ithylenhexa -methyleneimino, indolino or 1,2,3,4-tetrahydroisoquinolino radical. 2. 2,6-bis (diethanolamino) -8-diethylamino-pyrimido [5,4-d] pyrimidine 3. 26-bis (diethanolamino) -8-hexamethyleneimino-pyrimidoX54-v pyrimidine 4. Process for the preparation of new 2, 6-bis (diethanolamino) pyrimido [5,4-d] pyrimidines of the formula I, in which R1 is an alkyl radical with 1-3 carbon atoms, the allyl or benzyl radical, R2 is an alkyl radical with 1-3 carbon atoms, the allyl radical or R1 and R2 together with the nitrogen atom in between represent the hexa- or heptamethyleneimino ring, the 3,6-ethylene -hexa methylenimino-, indolino- or 1,2,3,4-tetrahydroisoquinolinoreet, characterized in that a compound of the formula II, in which the leftovers lis are identical to one another, have the meanings mentioned at the beginning, are treated with reducing agents and the hydrogenated intermediate compound obtained in the 4-position unsubstituted is preferably oxidized without prior isolation or that b) a compound of the formula III, in which the radicals A, A1 and A2 are interchangeable radicals, such as halogen atoms, hydroxy or mercapto groups substituted by alkyl, benzyl or phenyl radicals, with 1-2 of these radicals already being the diethanolamino group or the radical can mean with a compound of the formula IV, in which R1 and R2 are as defined at the outset, and / or diethanolamine is reacted at elevated temperatures, preferably at temperatures above 150.degree.