CH669196A5 - TRIAZOLOPYRIMIDINE AND METHOD FOR THE PRODUCTION THEREOF. - Google Patents

Description

DESCRIPTION

The invention relates to new triazolopyrimidines which are substituted in the 5- and 7-positions by basic groups and as a process for their preparation. The new compounds can be used as drugs.

Based on the knowledge of the coronary effects of the basic substituted compounds described in DD 61 269, it was surprisingly found; that previously unknown compounds of this class have cardiovascular effects which exceed the action of the known compounds many times and at the same time are so low in toxicity that they can be used as medicaments.

The invention relates to the new compounds of the formula

Shark

Shark in the R2 are and

Formulas>

HN ^ Rs and

R6

HN <

R7

N '^ N

(II)

R,

IN

N

(I)

50

R.

and R3 according to claim 1 or 2 defines shark for chlorine or bromine, with amines

55

(III ')

60

(III ")

and of physiologically tolerable salts thereof, where the substituents have the following meanings:

R2 and R3 represent an H atom, an alkyl group of chain length C) to C3 or a halogen atom;

- R4 is a straight-chain or branched-chain alkyl group of chain length C4 to C9, optionally substituted by alkoxy or alkyl groups of chain length C, to C3 substituted aralkyl groups, 2.5 dioxaheptyl or 3-oxahexyl radicals;

- R5 is an H atom, an alkyl group of chain length C to C3, a hydroxyethyl or hydroxypropyl group;

- R6 and R7 H atoms, a straight or branched chain alkyl group of chain length Q and C5, where R6 and R7

65 together with the N atom to which they are attached can also form a heterocyclic ring. The substituents in the 5- and 7-position can also be interchanged. The invention also relates to

3rd

669 196

Compounds 5-piperidino-7- (N- (ethoxyethyl) -N- (ß-hydro-xyethyl) -amino) -s-triazolo (l, 5-a) pyrimidine, 5-diethylamino-no-7- (N- (ethoxyethyl) -N- (β-hydroxyethyl) amino) -s-triazo-lo (1,5-a) pyrimidine and physiologically tolerable salts.

From the large number of possible compounds of the stated substituents according to the present invention, the following compounds were found to be particularly effective with regard to their cardiovascular effect:

- 5-Piperidino-7- (N- (n-pentyl) -N- (ß-hydroxyethyl) -amino-no) -s-triazolo (1,5-a) pyrimidine

- 5-Diethylamino-7- (N- (n-pentyl) -N- (ß-hydroxyethyl) -amino) -s-triazolo (1,5-a) pyrimidine

- 5-Diethylamino-7- (N- (n-hexyl) -N- (ß-hydroxyethyl) -amino) -s-triazolo (l, 5-a) pyrimidine

- 5-Piperidino-7- (N- (n-hexyl) -N- (ß-hydroxyethyl) -amino-no) -s-triazolo (1,5-a) pyrimidine

- 5-Morpholino-7- (N- (n-butyl) -N- (ß-hydroxyethyl) -amino-no) -s-triazolo (1,5-a) pyrimidine

- 5-Piperidino-7- (N- (ethoxyethyl) -N- (β-hydroxyethyl) amino) -s-triazolo (1,5-a) pyrimidine

- 5-Diethylamino-7- (N- (ethoxyethyl) -N- (ß-hydroxy-ethyl) -amino) -s-triazolo (1,5-a) pyrimidine.

The compounds corresponding to formula 1 can be used particularly well in the form of their physiologically well-tolerated salts. Chlorine, bromine or hydroiodic acid, sulfuric and nitric acid, oxalic, malonic and tartaric acid are particularly suitable for salt formation.

The compounds of the formula 1 according to the invention can be prepared analogously to the compounds of DD 61 269 by reacting triazolopyrimidines of the formula

Shark

"') ÔCÂ

Shark no

3rd

in which R2 and R3 have the meanings given and Hai represents a chlorine or bromine atom, with amines of the formula

Ç- (4 or 6)

HN <

R (5 or 7)

(Iii)

where R4 5 6 and 7 have the meanings given. The reactions are usually carried out in solvents such as water, water / alcohol mixture, alcohols, toluene or petrol. The reaction proceeds in two stages with the respectively substituted amines.

At temperatures below 293 K, the halogen atom in the 7-position is first substituted by amines at temperatures up to the boiling point of the solvent used, the halogen atom in the 5-position. The amines of the formula III used in excess or triethylamine, alkali metal carbonates or caustic alkalis are generally used to trap the hydrohalic acids formed in the reaction. The raw products are preferably worked up in a customary manner. The end products can be separated and purified from the by-products by extraction, distillation or recrystallization. Disturbing discolorations can be removed by adding absorbents such as activated carbon, aluminum oxide or bleaching earth.

The contained compounds can with acids in their

Salts are transferred. If stereoisomeric compounds are obtained, they can be broken down into their constituents by known processes.

The compounds according to the invention, in particular the individual compounds mentioned, have highly effective and therapeutically interesting properties in animal experiments. The focus here is on inhibiting platelet aggregation in vitro and in vivo, the corresponding effects of known drugs, such as acetylsalicylic acid or trapidil, being several times greater. On isolated heart and atrial preparations they develop coronary dilation and a positive inotropic effect. The blood pressure is preferably reduced in the hypertonic starting position. They prevent a loss of deformation of the erythrocytes induced by hyperosmolar conditions and their tendency to aggregate and thus improve the flow conditions in the microcirculation area. By influencing the arachidonic acid metabolism, they reduce the formation of thromboxane A2 or promote the synthesis of prostaglandins which inhibit aggregation, in particular prostacyclin. The compounds prove to be antiarrhythmic. An important property of the new compounds is that they influence the calcium metabolism, in particular the voltage-dependent trans-membrane Ca2 + influx into biological cells. They prove to be calcium antagonists with high specificity in the sense of Fleckenstein (Fleckenstein, A .: Calcium antagonism in heart and smooth muscle. J. Wiley & Sons. New York, 1983). Their particular advantages over known Ca2 + antagonists result from their high specificity and potency, their slightly reversible effect and the development of their effectiveness, particularly in the case of cells excitable by high-frequency stimulation. Their diverse range of pharmacological effects and their low acute toxicity allow the compounds according to the invention to be used as therapeutic agents for ischemic heart and circulatory diseases and distinguish them from previously known compounds. It is used as a solution for injection in the form of a 5% aqueous solution or in the form of granules encapsulated by known methods with the composition 58% active ingredient, 20% lactose, 19% water and 3% magnesium stearate.

The invention is illustrated by the following examples:

example 1

18.9 g of 5,7-dichloro-s-triazolo (l, 5-a) pyrimidine are dissolved or suspended in 50 ml of ethanol and at 278 to 283 K with the solution of 26.1 g of n-amylethanolamine in 25 ml Ethanol slowly added. The mixture is stirred and kept at 283 to 288 K for 1 h after the addition has ended. The solution of 17.0 g of piperidine in 20 ml of ethanol at 293 to 298 K is then added to the resulting suspension and the mixture is kept at 313 to 323 K for 3 h and the mixture is concentrated. Then it is taken up in 100 ml of methylene chloride, washed 3 times with 75 ml of water each time, and the water is separated off. The methylene chloride is concentrated, the residue crystallizes. Recrystallized from petrol, 26.5 g of 5-piperidino-7- (N- (n-pentyl) -N- (ß-hydroxyethyl) -amino) -s-triazolo- (l, 5-a) pyrimidine (80 % of theory) from melting point 390 to 391 K.

Example 2

18.9 g of 5,7-dichloro-s-triazolo (l, 5-a) pyrimidine are dissolved or suspended in 50 ml of ethanol and at 278 to 283 K with the solution of 26.1 g of n-amylethanolamine in 25 ml Ethanol slowly added. The mixture is stirred and left at 283 to 288 K for 1 hour after the addition has ended. The resulting suspension is suctioned off,

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suspended in 50 ml of ethanol and mixed with the solution of 14.6 g of diethylamine at 293 to 298 K.

The mixture is then refluxed for 3 hours and then concentrated under vacuum. 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 concentrated, the residue crystallized and recrystallized from ether. The resulting 5-diethylamino-7- (N- (n-pentyl) -N- (ß-hydroxy-ethyl) -amino) -s-triazolo (1,5-a) pyrimidine of melting point 352 to 353 K falls in one Yield of 22.5 g (70% of theory).

Example 3

18.9 g of 5,7-dichloro-s-triazo-lo (1,5-a) pyrimidine are suspended in 50 ml of ethanol. At 278 to 283 K, 29.4 g of n-hexylaminoethanol are added dropwise with stirring, the temperature of the mixture is brought to 293 K and the mixture is stirred at this temperature for 1 hour. Then the resulting compound is suctioned off and resuspended in 150 ml of ethanol. 15 g of diethylamine are added at room temperature and the mixture is then heated to boiling for 3 hours. The mixture is concentrated in vacuo, the residue is taken up in 75 ml of chloroform and washed with water. After washing, the organic phase is concentrated, the 5-diethylamino-7- (N- (n-hexyl) -N- (β-hy-hydroxyethyl) -amino) -s-triazolo (l, 5-a) pyrimidine obtained recrystallized from petroleum ether. The melting point is 335 to 336 K and the yield 16.2 g (50% of theory).

Example 4

The reaction is carried out as described in Example 3. 17.1 g of piperidine are used for diethylamine. The resulting 5-piperidino-7- (N- (n-hexyl) -N- (ß-hydroxyethyl) amino) -s-triazolo (1,5-a) pyrimidine is recrystallized from gasoline. The yield is 28 g and the melting point is 354 K.

Example 5

18.9 g of 5,7-dichloro-s-triazolo (l, 5-a) pyrimidine are suspended in a mixture of 50 ml of ethanol / 50 ml of water. At a temperature of 278 to 283 K, 23.6 g of n-butylaminoethanol are slowly added and the mixture is stirred for 3 hours at room temperature. The precipitated compound is then filtered off with suction, resuspended in 150 ml of methanol, 17.4 g of morpholine are slowly added and the mixture is kept under reflux for two hours. The methanol is concentrated, the residue is taken up in 75 ml of methylene chloride and washed twice with 50 ml of water. After concentration, the 5-morpholino-7- (N- (n-butyl) -N- (β-hydroxyethyl) amino) -s-triazolo (1,5-a) pyrimidine with a melting point of 375 K remains Yield of 16 g (50% of theory).

Example 6

18.9 g of 5,7-dichloro-s-triazo-lo (1,5-a) -pyrimidine are suspended in 200 ml of methanol. At 278 to 283 K, 26.6 g of N - (- ethoxyethyl) -N- (ß-hydroxyethyl) -N-amine are added and the mixture is stirred for a further 2 hours at 288 to 293 K. The reaction product is then suctioned off, again suspended in 75 ml of methanol, mixed with 17 g of piperidine and kept at the boiling point for 3 hours. The suspension is concentrated, the residue crystallizes out. The 5-piperidino-7- (N- (ethoxyethyl) -N- (β-hydroxyethyl) amino) -s-tria-zolo (1,5-a) pyrimidine, recrystallized from ethyl acetate, melting point 393 up to 394 K with a yield of 22 g (65% of theory).

4th

Example 7

The experiment is carried out as described in Example 6, 14.6 g of diethylamine are used for 17 g of piperidine. 17.4 g (54%

5 of theory) 5-diethylamino-7- (N- (ethoxyethyl) -N- (ß-hy-hydroxyethyl) -amino) -s-triazolo (1,5-a) pyrimidine with melting point 342 to 343 K.

Additional examples

10 In Examples 8 to 17, the following letters are used instead of the chemical names:

A = 5-diethylamino-7- (N- (n-hexyl) -N- (ß-hydroxy-

ethyl) amino) -s-triazolo (1,5-a) pyrimidine B = 5-piperidino-7- (N- (n-pentyl) -N- (β-hydroxyethyl) -15 amino) -s-triazolo ( 1,5-a) pyrimidine

C = 5-piperidino-7- (N- (n-hexyl) -N- (β-hydroxyethyl) amino) -s-triazolo (1,5-a) pyrimidine

Example 8

20 Inhibition of transmembrane calcium influx On neuroblastoma x glioma hybrid cells of clones 108 CC 5 and 108 CC 15, the voltage-dependent Ca 2+ influx and its influence by compound A were examined using the cell perfusion volta-ge-clamp technique. The electrophsiological measurement technology used enables the direct detection of the effect of substances on the slow Ca2 + inflow of excitable cells. The registration and evaluation of the data obtained was carried out using an EMG laboratory computer and a signal form analyzer. The compound A was in aqu. least dissolved and in concentrations of 1-100 (iM in the extracellular solution (glucose 5 mM, Tris HCl 130 mM, CaCl2.10 mM, MgCl2 ImM, KCL 4mM, pH 7.4; intracellular solution: Tris P04140 mM, pH -Value 7.2) thinned-35, perfused by 5 - 10 ml continuous perfusion in graduated doses at 22 ° C extracellularly.

1 - 2 min after extracellular application of compound A, the Ca2 + inflow (ICa) could be inhibited depending on the dose. This effect was detectable over the entire potential range, whereby no shift in the volt-ampere characteristic could be determined. The inhibition of ICa was reversible in all cases. The washout time was a few seconds. An increase in the depolarization frequency (use-dependence effect) from 0.1 to 1 45 Hz resulted in a stronger inhibitory effect of the substance on the ICa.

Example 9

Arachidonic acid or U-46619-induced aggregation 50 on human platelets

9 volumes of blood from donors who had not taken any medication in the past 10 days were mixed with 1 volume of 3.8% trisodium citrate solution and centrifuged at 200 g and room temperature for 10 min. 55 The platelet-rich and via plasma (PRP) was siphoned off with a siliconized pipette and kept at room temperature for a maximum of 3 h.

The test compounds were dissolved in a solvent mixture of ethanol / chloroform (1: 1), aliquots were poured into the measuring cell and the organic solvent mixture was blown off using a stream of nitrogen. After adding 0.3 ml PRP and 0.1 ml physiological NaCl solution and preincubating for 2 min at 37 C, the aggregation was triggered with sodium arachidonate (0.4 -65 0.8 mmol / 1) or by the TXA2- Agonists U 46619 (0.2-0.8 mmol). The course of the aggregation was measured according to the method of BORN (Born, 9th V. R. and Cross, U.J .: J. Physiol. 168, 178 (1963):

5

$ 69 196

The concentrations of the test compounds required for 50% inhibition of aggregation were determined in direct comparison to those of the trapidil. As the results in Table 1 show, the derivatives have a significantly stronger antiaggregatory effect compared to trapidil.

Table 1

Influence of platelet aggregation on human PRP by some derivatives compared to trapidil (pIC50 = negative logarithm of the mean molar inhibitory conc.)

Inhibitor of platelet aggregation

(pICso)

AA

U-46619

A

4.68

4.40

B

4.66

5.09

C.

4.33

4.65

Trapidil

3.75

3.74

Example 10

Inhibition of platelet aggregation in rabbits and rats

Platelet-rich plasma was obtained from citrated blood from rabbits or rats by centrifugation at 200 g at room temperature and was kept in plastic syringes at room temperature for the duration of the experiment. In the studies on rabbits, the test substances in 0.9% NaCl solution (50 | il) were added to 0.4 ml PRP in homologous plasma and, after 3 min preincubation at 37 ° C, aggregation with arachidonic acid Na (75- 210 mmol / 1) triggered.

Rat plates were separated and suspended in Michaelis buffer (pH 7.4) and deflaminated homologous plasma (1: 1). 10 ml of 1 preparation solution in ethanol were added to 1.2 ml of this platelet suspension and after 2 min preincubation at 37 ° C the aggregation was started by adding arachidonic acid (2 mmol / 1 final concentration in the cuvette).

The aggregation was measured nephelometrically using the method of BORN (Born, 9.V.R. and Cross, UJ .: J. Physiol. 168, 178 (1963)).

A comparison of the mean molar inhibitory concentrations (Tab. 2) also shows in these experiments a significantly more pronounced antiaggregatory effect of the new test compounds against trapidil.

Table 2

Inhibition of platelet aggregation induced by arachidonic acid in rabbits and rats in vitro pIC50

preparation

Rabbits

rat

Trapidil

4.05

2.49

A

5.47

3.72

B

4.97

3.75

C.

5.05

3.78

Example 11

Influencing platelet aggregation in vivo

Intravenous administration of arachidonic acid causes asphyxiation symptoms and lethal effects in rabbits via platelet aggregation, especially in the lung vessels. Already in lower, tolerated without symptoms

Concentrations can quantitatively determine the aggregating effect of arachidonic acid on the basis of a transient reduction in the number of freely circulating platelets in peripheral blood, which can be demonstrated immediately after the injection, and the effectiveness of previously administered drugs can be demonstrated. In non-anesthetized rabbits of both sexes, the number of platelets was determined using phase contrast microscopy after taking blood from the ear vein. Arachidonic acid Na was then administered in a dose of 0.1 mg / kg IV. injected and the platelet count 1/2, 1, 2, 3, 5 and 10 min thereafter determined again. The area enclosed by the percentage reduction in the number of platelets was used as a quantitative criterion for arachondonic acid-induced thrombocytopenia and its value for the animals in the control group was set equal to 100%. To test the in-vivo effectiveness of the test preparations, they were administered orally after determination of the individual uninfluenced AA reaction as a suspension in ultra-source cellulose by means of a flexible pharyngeal tube and the extent of the thrombocytopenia after arachidonic acid injection 1, 2, 4, 6 in the manner described above and determined again 24 h after administration of the preparation.

Table 3

Influence of arachidonic acid-induced aggregation on rabbits in vivo

Preparation dose inhibition of AA-induced mg / kg thrombocytopenia (%) / h after preparation

advice

p.o.

1

2nd

4th

6

24th

Trapidil

20th

14

24th

6

0

0

50

90

96

74

72

17th

A

10th

97

89

40

51

22

B

10th

45

67

71

48

41

C.

10th

27th

53

8th

0

0

The results (Tab. 3) confirm the superior aggregation-inhibiting effectiveness of the new derivatives compared to trapidil and at the same time demonstrate their effectiveness even under in-vivo conditions.

Example 12 Inhibition of Thromboxan A2 Synthesis

The formation of TXA2 and its influence was examined on rabbit platelets after triggering aggregation with arachidonic acid. Production of the PRP and aggregation batch corresponded to the conditions mentioned under Example 9. 90 s after AA addition, aliquots of the cuvette contents were used for the biological determination of the TXA2 content. The thromboxane A2 content was determined on spirally cut vascular strips from the rabbit's mesenteric artery using the superfusion technique. Tyrode solution was used as the superfusion medium, which to increase the selectivity as a blocking agent propranolol (5 (ig / ml), phentolamine (1 (xg / ml, atropine (0.25 ng / ml), antazoline (0.25 (ig / ml), Methysegid (20 jig / ml) and indomethacin (1 (ig / ml). The sensitivity of the vascular strip was determined with EMA (9,11-Epoxymethano-15 (S) -hydroxy-prosta-5,13-dienoic acid = U-44069 ) tested in a dose range of 1-25 | tg and the contractions recorded on a recorder using an inductive transducer. Compared to the trapidil, the new derivatives are characterized by a more intensive inhibition of thromboxes A2 biosynthesis (Tab. 4).

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Table 4

TXA2 formation in arachindonic acid-stimulated platelets in rabbits under the influence of the test preparations

preparation

dose

Inhibition (%) of the pIC50

jjmol / 1

TXA2 formation

Trapidil

50

23.8

100

52.8

150

75.2

4.03

A

5

22.6

10th

46.3

25th

88.7

5.01

B

5

22.6

10th

62.4

25th

94.9

5.09

C.

1

19.0

5

50.9

10th

83.5

5.42

Example 13

Inotropic effects

The influence on the contractile force of the heart was examined in the isolated guinea pig atrium. Right, spontaneously beating atrial specimens were suspended in 25 ml organ baths in 02-flowed Tyrode solution and their contractions measured semi-isometrically using mechanical-electrical transducers.

All investigated compounds were characterized by a positive inotropic activity on the isolated guinea pig atrial preparation. The doses required for a 50% increase in the contraction force, shown as negative logarithms of the corresponding molar concentrations, are shown in Table 5 and demonstrate an efficacy which is superior to that of trapidil.

Table 5

Increased contraction of the isolated auricle (guinea pig)

Contraction enhancement on isolated atrial specimen (pED50)

Trapidil 3.84

A 4.46

B 4.20

C 4.27

Example 14

Blood pressure effectiveness

Spontaneously hypertensive rats (okamoto-Aoki) were freed from the common carotid artery under pentobarbital anesthesia (60 mg / kg i.p.) and a polyethylene catheter was inserted. Arterial blood pressure was recorded using a mechano-electrical converter on a polygraph (EMT 34; Min-cograph 81, Elema-Schönander, Stockholm).

The preparation was applied to the V. subclavia sinistra in a volume of 0.6 ml in physiological NaCl solution.

In spontaneously hypertensive rats in which trapidil only led to a volatile drop in the mean arterial pressure, the new test compounds have an antihypertensive effect that lasts for a long time. The most effective derivatives in this regard were found to be compounds A and C, which reduced the arterial mean pressure by 15-20% for 2-4 h.

Example 15 Inhibition of Phosphodiesterase

The activity of the PDE was determined according to BUTCHER and SUTHERLAND (Butcher, R.W. and E.W. Sutherland: J. biol. Chem. 237, 1244 (1962)). The mixture (0.9 ml) had the following composition: 1.8 mM MgSO4, 36 mM Tris, 0.5 mM cAMP (from Böhringer, Mannheim) and 15% phosphodiesterase from bovine heart muscle (from Böhringer, Mannheim). The reaction proceeded at pH 8.0 and 37 C and was stopped after 10 min by heating for 1 min boiling water bath. Then 0.1 ml of Crotalus atrox (Sigma, USA) were added and incubated at 37 C for a further 10 min. To determine the orthophosphate, the incubation was stopped by adding 0.1 ml of 5N HC104 and, after centrifugation, the phosphate formed was recorded in a semimicro method according to ALLEN (Allen, R.I.L .: Biochem. J. 38, 858 (1940)).

The example of derivatives A and C shows that the new compounds represent much stronger inhibitors of phosphodiesterase than trapidil. The following were determined as inhibiting constants:

Trapidil K = 1.3 x 10 3M A 5.4 x 10 5M

2.0 x 10 5M

Example 16

acute toxicity

The acute toxicity of the test compounds was determined in male NMRI mice after intraperitoneal or intravenous administration. The compounds were suspended in ultra-source cellulose (i.p.) or dissolved in tartaric acid (i.v.). The LD50 was determined using the method of LITCHFIELD AND WILCO-XON.

Table 6

Acute toxicity of mouse test compounds

LD50

Preparation i.p. i.v.

Trapidil 155 (124-194) 115 (104-127)

A 285 (238-342) 56 (48- 66)

B 230 (193-274) 69 (62- 75)

C 720 (654-792) 59 (54- 65)

With regard to their acute toxicity, the new derivatives proved to be not significantly more toxic than trapidil, so that, taking into account their more intensive pharmacodynamic effects, a wider therapeutic range can be expected.

Example 17

For the clinical use of the active substances according to the invention, they are used in the usual way

50

G

Active ingredient

28

G

Sucrose

3rd

G

Lactose

35.4

G

Potato starch

3rd

G

Talk

0.6

G

Magnesium stearate mixed together and after adding liquid

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nulated. After drying and sieving, tablets are pressed which contain 50 mg of active ingredient per tablet.

Talc and magnesium stearate are added and the mixture is tentened.

Claims (5)

669 196 PATENT CLAIMS 1. s-triazolo (1,5-a) pyrimidine of the formula N N (I) 10th 15 20th wherein R2 and R3 are hydrogen, alkyl having 1 to 3 carbon atoms or halogen; R4 represents straight-chain or branched-chain alkyl having 4-9 C atoms, aralkyl, 2,5-dioxaheptyl or 3-oxahexyl optionally substituted by alkoxy or alkyl groups having 1-3 C atoms; R5 is hydrogen, alkyl having 1 to 3 carbon atoms, hydroxyethyl or hydroxypropyl; R6 and R7 represent hydrogen, straight or branched chain alkyl with 1-5 C atoms or R6 and R7 together with the N atom to which they are attached form a heterocyclic ring and the substituents in 5- and 7- The position of the s-triazolo (1,5-a) pyrimidine nucleus can also be interchanged or 5-piperidino-7- (N- (ethoxyethyl) -N- 25 (ß-hydroxyethyl) amino) -s-triazolo (1,5 -a) pyrimidine or 5-diethylamino-7- (N- (ethoxyethyl) -N- (ß-hydroxyethyl) -amino-no) -s-triazolo (1,5-a) pyrimidine and physiologically acceptable salts thereof. 2. 5-Piperidino-7- (N- (n-pentyl) -N- (ß-hydroxyethyl) -amino-no) - s-triazolo (l, 5-a) pyrimidine, 5-diethylamino-7- (N - (n-pentyl) N- (ß-hydroxyethyl) amino) s-triazolo (l, 5-a) pyrimi-din, 5-diethylamino-7- (N- (n-hexyl) -N- (ß- hydroxyethyl) amino) -s-triazolo (1,5-a) pyrimidine, 5-piperidino-7- (N- (n-he-xyl) -N- (β-hydroxyethyl) amino) - s-triazolo ( 1,5-a) pyrimidine, 5-morpholino-7- (N- (n-butyl) -N- (β-hydroxyethyl) amino) -s-triazolo (1,5-a) pyrimidine, 5-piperidino- 7- (N- (ethoxyethyl) -N- (ß-hydroxyethyl) amino) -s-triazolo (1,5-a) pyrimidine or 5-diethylamino-7- (N- (ethoxyethyl) -N- ( β-hydroxy-ethyl) amino) -s-triazolo (1,5-a) pyrimidine as compounds according to claim 1. 3. Process for the preparation of the compounds according to claim 1 or 2, and of physiologically tolerable salts thereof, characterized in that compounds of the formula 45 30th 35 40 in which R4 to R7 are defined in accordance with claim 1 or 2, are implemented in two stages in the presence of solvents and in an appropriate sequence, in the first stage at temperatures up to 293 K in the 7-position and in the second stage at temperatures up to Boiling point of the solvent is substituted in the 5-position of the triazolopyrimidine, and the compounds obtained are optionally converted into their physiologically tolerable salts. 4. Medicament, characterized in that it contains at least one compound of formula 1 or a physiologically acceptable salt thereof. 5. Medicament according to claim 4, characterized in that it contains at least one of the following compounds: 5-piperidino-7- (N- (n-pentyl) -N- (ß-hydroxyethyl) -amino) -s-triazolo (l , 5-a) pyrimidine, 5-diethylamino-7- (N- (n-pentyl) -N- (β-hydroxyethyl) -amino) -s-triazolo (1,5-a) pyrimi-din, 5-diethylamino -7- (N- (n-hexyl) -N- (β-hydroxyethyl) amino) -s-triazolo (l, 5-a) pyrimidine, 5-piperidino-7- (N- (n-he-xyl ) -N- (ß-hydroxyethyl) amino) -s-triazolo (1,5-a) pyrimidine, 5-morpholino-7- (N- (n-butyl) -N- (ß-hydroxyethyl) amino) -s-triazolo (1,5-a) pyrimidine, 5-piperidino-7- (N- (ethoxyethyl) -N- (β-hydroxyethyl) -amino) -s-triazolo (1,5-a) pyrimidine and 5 -Diethylamino-7- (N- (ethoxyethyl) -N- (ß-hydroxyethyl) -amino-no) -s-triazolo (1,5-a) pyrimidine.