NL8501111A - NEW TRIAZOLOPYRIMIDINE COMPOUNDS AND METHOD FOR THE PREPARATION THEREOF. - Google Patents

Description

* 4 * VO 7158

Title: Novel triazolopyrimidine compounds and method for their preparation.

The invention relates to novel triazolopyrimidines substituted in the 5- and 7-position by basic groups, as well as to processes for their preparation. The new compounds can be used as a medicine.

Based on the knowledge of the coronary activities of the basic substituted compounds described in DD 61269, it has surprisingly been found that hitherto unknown compounds of this class have cardiac circulatory actions, which exceed the actions of the known compounds by a plurality and at the same time 10 have low toxicity, that they can be used as a medicine.

The new compounds correspond to general formula I of the formula sheet, wherein the substituents have the following meanings: - and represent a hydrogen atom, an alkyl group with one to three carbon atoms or a halogen atom; 15 "R4 represents a straight or branched chain alkyl group of four to nine carbon atoms, optionally substituted aralkyl groups of alkoxy or alkyl groups of one to three carbon atoms, 2,5-dioxaheptyl or 3-oxahexyl groups; -R ^ represents a hydrogen atom, a alkyl group with one to three carbon atoms, a hydroxyethyl or hydroxypropyl group, respectively - R- and R_ are hydrogen atoms, a straight or branched alkyl group o7 with one to five carbon atoms, wherein R and R_ can also be part of a cycloaliphatic ring.

The substituents at the 5 and 7 position can also be exchanged against each other.

Of the many possible compounds of the indicated substituents of formula 1, the following compounds have been found to be particularly effective in their cardiac circulation activity: - 5-Piperidino-7- (N- (n-pentyl) -N- (b-hydroxyethyl) - amino) -s- triazolo (1,5-a) pyrimidine - 5-Diethylamino-7- (N- (n-pentyl) -N- (b-hydroxyethyl) -amino) -s-triazolo (1,5- a) pyrimidine 05611ί 1 -2- - 5-Diethylamino-7- (N- (n-hexyl) -N- (b-hydroxyethyl) -amino) -s-triazolo (1,5-a) pyrimidine - 5-Piperidino -7- (N- (n-hexyl) -N- (b-hydroxyethyl) -amino) -s-triazolo (1,5-a) pyrimidine 5-5-Morfolino-7- (N- (n-butyl)) -N- (b-hydroxyethyl) -amino) -s- triazolo (1,5-a) pyrimidine - 5-Piperidino-7- (N- (ethoxyethyl) -N- (b-hydroxyethyl) -amino) -s- triazolo (1,5-a) pyrimidine - 5-Diethylamino-7- (N- (ethoxyethyl) -N- (b-hydroxyethyl) -amino-10-triazolo (1,5-a) pyrimidine.

The compounds of the formula I can be used particularly well in the form of their physiologically tolerable salts. Hydrogen chloride, hydrogen bromide or hydrogen iodide, sulfuric acid and nitric acid, oxalic acid, malonic acid and tartaric acid are particularly suitable for salt formation.

The compounds of the formula I according to the invention can be prepared analogously to the compounds of according to DD 61269 by reacting triazolopyrimidines of the formula II, in which and R 1 have the indicated meanings and Hal represents a chlorine or bromine atom, with amines with formula III, wherein R. _ have the indicated meanings 4,5,6 and 7. The reactions were performed in solvents such as water, water / alcohol mixtures, alcohols, toluene or gasoline. The reaction proceeds in two stages with the appropriate amines.

At temperatures below 293 K, the halogen atom at the 7-position is first replaced by amine and at temperatures up to the boiling point of the solvent used, the halogen atom at the 5-position. To scavenge the two hydrogen halides formed, the excess amines of formula III or triethylamine, alkali carbonates or atalkalis are used. The work-up of the crude products is carried out in the usual manner. The final products were separated from the by-products by extraction, distillation or recrystallization and purified. Disturbing discolourations can be removed by adding adsorbents, such as activated carbon, aluminum oxide or bleaching earth.

The compounds obtained can be converted into their salts with acids. When stereoisomeric compounds are obtained, 85 0 1 1 ';'.

These are separated into their constituents by known methods.

The compounds of the invention, in particular the individually named compounds, have very effective and therapeutically interesting properties in animal experiments. At the center of this is an inhibition of platelet agregation in vitro and in vivo, which outperform similar effects of known drugs, such as acetylsalicylic acid or trapidil, with the multiple. They develop coronary dilation and positive inotropic activity from isolated heart and atrial preparations. Blood pressure is preferably lowered at baseline hypertonic. They prevent hyperosmolar-induced loss of deformation of the erythrocytes as well as their tendency to aggression and thereby improve flow conditions in the microcirculation range. By influencing the arachidonic acid metabolism, they reduce the formation of thromboxan or promote the synthesis of agreegate inhibiting prostaglandins, in particular of prostacycline.

The compounds appear to be anti-arrhythmic.

An essential property of the new compounds consists in influencing the calcium metabolism, in particular the voltage-dependent transmembrane Ca-2 influx into biological cells. They appear to be calcium antagonists of high specificity in the sense of Pleckenstein (Fleckenstein, A .: Calcium antagonism in heart and smooth muscle, J. Wiley & Sons, New York, 1983).

2+

Their particular advantages over Ca antagonists are evidenced by their high specificity and potency of their readily reversible action as well as the development of their activity, particularly in high frequency stimulation of stimulatable cells.

Their versatile pharmacological spectrum of action and their low acute toxicity allow the use of the compounds of the invention as therapeutic agents for ischemic heart and circulation ailments and advantageously distinguish them hitherto known compounds. The use takes place as injection solutions in the form of a 5% aqueous solution or in the form of granules coated according to the known method with the composition 58% active substance, 20% lactose, 19% water and 3% magnesium sterate.

«5C11 11 -4-

The invention is further illustrated by the following examples: Example 1 18.9 g of 5,7-dichloro-s-triazolo (1,5-a) pyrimidine is dissolved or suspended in 50 ml of ethanol and suspended at 278/283 K with the solution of 26.1 g of n-amylethanolamine in 25 ml of ethanol are slowly mixed. The mixture is stirred and kept at 283/288 K for an additional hour after the addition is complete. The solution of 17.0 g of piperidine in 20 ml of ethanol at 293/10 298 K is then added to the suspension formed and kept at 313/323 K for three hours and evaporated. Then it is taken up in 100 ml of methylene chloride, three of which are washed with 75 ml of water each, the water is separated. The methylene chloride is evaporated, the residue crystallized. Recrystallized from petrol, 26.5 g of piperidino-7- (N- (n-pentyl) -N- (b-hydroxyethyl) -amino) -15 s-triazolo (1,5-a) pyrimidine (80% of theory) with a melting point of 390/391 K.

Example 2 18.9 g of 5,7-dichloro-s-triazolo (1,5-a) pyrimidine are respectively dissolved in 50 ml of ethanol dissolved and at 278/283 K with the solution of 26.1 g of n-amylethanolamine in 25 ml ethanol slowly mixed. The liquid is stirred and left at 283/288 K for an additional hour after the addition is complete. The suspension formed is suctioned off, suspended in 50 ml of ethanol and mixed with the solution of 14.6 g of diethylamine at 293/298 K.

The liquid is then boiled under pressure cooling for three hours and then evaporated under reduced pressure. The residue is taken up in 100 ml of methylene chloride, the methylene chloride phase is washed with 50 ml of water and separated. The methylene chloride is evaporated and the residue crystallized and recrystallized from ether.

The 5-diethylamino-7- (N- (n-pentyl) -N- (b-hydroxyethyl) -amino) -s-triazolo- (1,5-a) pyrimidine formed having a melting point of 352/353 K is obtained in a yield of 225 g (70% of theory).

850 1 1 1 1 -5-

Example 3

18.9 g of 5,7-dichloro-s-triazolo (1,5-a) pyrimidine were suspended in 50 ml of ethanol. At 5-10 ° C, 29.4 g of n-hexylaminoethanol are added dropwise with stirring, the temperature of the liquid is allowed to rise to 293 K and the liquid is stirred at this temperature for one hour. The resulting compound is then filtered off with suction, resuspended in 150 ml of ethanol. 15 g of diethylamine are added at room temperature and the mixture is then heated to boiling point for three hours. The liquid is evaporated under reduced pressure, the residue is taken up in 75 ml of chloroform and washed with water. After washing, the organic phase is evaporated, the resulting 5-diethylamino-7- (n-hexyl) -N- (b-hydroxylethyl) -amino) -s-triazolo (1,5-a) pyrimidine recrystallized from petroleum ether. The melting point is 335/336 K and the yield 16.2 g (50% of theory).

Example 4

The reaction is carried out in the manner described in Example 3. 17.1 g of piperidine is used instead of diethylamine. The 5-piperidin-7- (N- (n-hexyl) -N- (b-hydroxyethyl) -amino) -s-triazolo- (1,5-a) pyrimidine formed is recrystallized from benzene. The yield is 28 g and the melting point is 354 K.

Example 5 18.9 g of 5,7-dichloro-s-triazolo (1,5-a) pyrimidine is suspended in a mixture of 50 ml ethanol / 50 ml water. At a temperature of 278/283 K, 23.6 g of n-butylaminoethanol are slowly added and the liquid is stirred at room temperature for three hours. The precipitated compound is then aspirated, resuspended in 150 ml of methanol, 17.4 g of morpholine is slowly added and the liquid is boiled under pressure cooling for two hours. The methanol is evaporated, the residue is taken up in 75 ml of methylene chloride and washed twice with 50 ml of water each time. After evaporation, the 5-morpholino-7- (n-butyl) -N- (b-hydroxyethyl) -amino) -s-triazolo (1,5-a) pyrimidine having a melting point of 375 K remains in a yield of 16 g (50% of the theory).

350 1 1 1 1 -6-

Example 6

18.9 g of 5.7-dichloro-s-triazolo (1,5-a) -pyrimidine are suspended in 200 ml of methanol. At 5/283 K, 26.6 N- (ethoxyethyl) -N- (b-hydroxyethyl) -N- (b-hydroxyethyl) -amine is added and the liquid is stirred at 288/293 K for an additional two hours. The reaction product is then filtered off with suction, resuspended in 75 ml of methanol, mixed with 17 g of piperidine and kept at the boiling point for three hours. The suspension is evaporated, the residue crystallized. The 5-piperidin-7- (N- (ethoxyethyl) -N- (b-hydroxyethyl) -amino) -s-triazolo-10 (1,5-a) pyrimidine, crystallized from acetic acid ethyl ester, has a melting point of 393/394 K in a yield of 22 g (65% of the theory).

Example 7 The test was carried out as described in Example 6, however, using 14.6 g diethylamine instead of 17 g piperidine. Recrystallized from petrol, 17.4 g (54% of theory) of 5-diethylamino-7- (N- (ethoxyethyl) -N- (b-hydroxyethyl) -amino) -s-triazolo (1,5-a pyrimidine with a melting point of 342/343 K.

850 1 1 1 1

Claims (8)

1. New s-triazolo (1,5-a) pyrimidines of the formula I of the formula sheet, wherein the substituents have the following meanings: - 1 * 2 and R 2 represent a hydrogen atom, an alkyl group of one to three carbon atoms or a halogen atom; 5. R4 represents a straight or branched chain alkyl group of four to nine carbon atoms, optionally substituted aralkyl groups of alkoxy or alkyl groups of one to three carbon atoms, 2,5-dioxaheptyl or 3-oxahexyl groups; - Rg represents a hydrogen atom, an alkyl group with one to three carbon atoms, a hydroxyethyl or hydroxypropyl group, respectively; - Rc and R represent hydrogen atoms, a straight or branched chain alkyl group of one to five carbon atoms, where Rg and R7 may also be part of a cycloaliphatic ring, and the substituents 15 at the 5 and 7 positions also can be exchanged against each other. Novel s-triazolo (1,5-a) pyrimidines according to claim 1, in particular: 20 - 5-piperidino-7- (N- (n-pentyl) -N- (b-hydroxyethyl) -amino) - s-triazolo (1,5-a) pyrimidine - 5-diethylamino-7- (N- (n-pentyl) -N- (b-hydroxyethyl) -amino) -s-triazolo (1,5-a) pyrimidine - 5-diethylamino-7- (N- (n-hexyl) -N- (b-hydroxyethyl) -amino) -s- triazolo (1,5-a) pyrimidine - 5-piperidino-7- (n-hexyl) -N- (b-hydroxyethyl) -amino) -s-triazolo (1,5-a) pyrimidine - 5-morpholino-7- (N- (n-butyl) -N- (b-hydroxyethyl) -amino) - s-triazolo (1,5-a) pyrimidine 30 - 5-piperidino-7- (N- (ethoxyethyl) -N- (b-hydroxyethyl) -amino-s-triazolo (1,5-a) pyrimidine - 5- diethylamino-7- (N- (ethoxyethyl) -N- (b-hydroxyethyl) -amino-s-triazolo (1,5-a) pyrimidine. f5011 7 7 ^ w -8- Process for the preparation of compounds of formula I as defined in claim 1, in particular compounds as defined in claim 2, characterized in that compounds of formula II, wherein and R 1 have the meanings indicated and Hal for a chlorine or bromine atom, with amines of formula III, in which ^ have the meanings mentioned, are converted in two stages in the presence of solvents, the first stage taking place at temperatures up to 293 K and the second stage taking place at temperatures up to boiling point of the solvent. Medicament, characterized in that it is a compound of formula I as defined in claim 1, in particular one of the compounds: 15 - 5-piperidino-7- (N- (n-pentyl) -N- (b -hydroxyethyl) -amino) -s-triazolo (1,5-a) pyrimidine-5-diethylamino-7- (N- (n-pentyl) -N- (b-hydroxyethyl) -amino) -s-triazolo (1 , 5-a) pyrimidine - 5-diethylamino-7- (N- (n-hexyl) -N- (b-hydroxyethyl) -amino) -s- triazolo (1,5-a) pyrimidine - 5-piperidino- 7- (n-hexyl) -N- (b-hydroxyethyl) -amino) -s-triazolo (1,5-a) pyrimidine-5-morpholino-7- (N- (n-butyl) -N- (b -hydroxyethyl) -amino) -s-triazolo (1,5-a) pyrimidine 25-5-piperidino-7- (N- (ethoxyethyl) -N- (b-hydroxyethyl) -amino) -s-triazolo (1, 5-a) pyrimidine - 5-diethylamino-7- (N- (ethoxyethyl) -N- (b-hydroxyethyl) -amino) -s-triazolo (1,5-a) pyrimidine. 35 0 1 1 1 1 -y- ENGINEERED PATENT OFFICES o.a..no. 8501111, • msavenhagï (HouAMO) jaw. "when writing dd. September 5, 1985. Ln / 654 I τ> 1 T _ I I ’v. A Γ.E | I -4SEPI985 J Improvement (s) of erratun (a) in the description associated with patent application No. 8501lil, proposed by applicant (star) under date dd. September 5, 1985. -OOC - page 1, lines 29, 31) page 2, lines 1, 3, 5, 7, 9 (page 4, lines 14, 31). Change "b-hydroxyethyl" in page 5, lines 12, 18, 31. no. 3) β-hydroxyethyl p. 6, lines 4, 9, 18) p. 7, lines 20, 22, 24, 26, j 28, 30, 32) p. 8, lines 15, 17, 19, 21, j 23, 25, 27) page 4, line 14 - change "piperidino" to "" 5-piperidino "page 4, rule 32 j., _", Ntriazolo- (1,5-a) "change to" triazolo (1,5-a) "p. 5, line 19) J - p. 4, line 33 - change" 225 g "to" 22.5 g "p. 5, line 3 - Change "5-10oC" to "278-283 K" page, 5, line 12) page 7, line 26 j - Change "7- (n-hexyl)" to "7 (N- ( n-hexyl) "page 8, line 21) page 5, line 26 - delete" again "page 6, line 4 - delete" -N- (b-hydroxyethyl) "page 6, line 19 -" ( 1,5-a) -pyrimidine "change to" (1,5-a) pyrimidine "page 5, line 31 -" 7- (n-butyl) "change to" 7 (N- (n-butyl) ") 85 0 1 1 1 1