JPH0455193B2 - - Google Patents

Description

[Detailed description of the invention]

FIELD OF THE INVENTION The present invention relates to novel triazolopyrimidines substituted with basic groups at the 5- and 7-positions and a method for producing the same. This new compound can be used as a medicine. (Disclosure of the Invention) Based on the knowledge that the basic substituted compounds described in East German Patent No. 61269 have a coronary effect, it has been proposed that this family of compounds, which was previously unknown, has a cardiac-circulatory effect. show,
It has also been discovered that this action is much superior to that of known compounds, and at the same time it is non-toxic, and furthermore, it can be used as a medicine. This new compound corresponds to the following general formula (). Here, the substituents have the following meanings. _R2 and _R3 are a hydrogen atom, an alkyl group having a chain length of _C1 to _C3 , or a halogen atom. R ₄ is a linear or branched alkyl group with a chain length of C ₄ to _{C 9} , an alkoxy group with a chain length of C ₁ to _{C 3} , or an aralkyl group substituted with an alkyl group, 2,5-dioxaheptyl residue or 3-oxahexyl residue. _R5 is a hydrogen atom, an alkyl group having a chain length of _C1 to _C3 , a hydroxyethyl group, or a hydroxypropyl group. R ₆ and R ₇ are a hydrogen atom, a linear or branched alkyl group having a chain length of C ₁ to _{C 5} , or R ₆ and R ₇ together with a heteroatom form a ring. The substituents at the 5-position and the 7-position may be exchanged with each other. Among the large number of compounds possible by determining substituents from formula (), the following compounds were found to be significantly effective with regard to cardiac-circulatory effects. 5-piperidino-7-(N-(n-pentyl)-
N-(β-hydroxyethyl)-amino)-s-triazolo[1,5-a]pyrimidine 5-diethylamino-7-(N-(n-pentyl)-N-(β-hydroxyethyl)-amino)- s
-triazolo[1,5-a]pyrimidine 5-diethylamino-7-(N-(n-hexyl)-N-(β-hydroxyethyl)-amino)-s
-triazolo[1,5-a]pyrimidine 5-piperidino-7-(N-(n-hexyl)-
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-(β-hydroxyethyl)-amino)-s-
Triazolo[1,5-a]pyrimidine 5-diethylamino-7-(N-(ethoxyethyl)-N-(β-hydroxyethyl-amino)-s
-Triazolo[1,5-a]pyrimidine The compounds corresponding to formula () are preferably used in the form of their physiologically compatible salts. Particularly suitable for salt formation are hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, oxalic acid, malonic acid and tartaric acid. The compound according to the present invention which is similar to the compound described in East German Patent No. 61269 is a triazolopyrimidine of the following general formula (), (wherein R ₂ and R ₃ have the same meanings as above,
Hal indicates a chlorine atom or a bromine atom) With the amine of the following general formula () (In the formula, R ₄ , R ₅ , R ₆ and R ₇ have the above meanings.) The reaction is carried out in a solvent such as water, a water-alcohol mixture, alcohols, toluene or benzine. This reaction passes through two steps with the then substituted amine. First of all, the 7-position halogen is replaced by an amine at a temperature below 293 K, and then the 5-position halogen is replaced at a temperature up to the boiling point of the solvent used. In order to remove the hydrohalic acid formed during this reaction, an excess amount of amine of the general formula () or triethylamine, alkali carbonate or alkali hydroxide is added. Recovery of the crude product is handled in a conventional manner. The desired product is separated from by-products and purified by extraction, distillation or recrystallization. Unwanted stains are removed by the addition of adsorbents such as activated carbon, aluminum oxide or acid clay. The obtained compound may be made into a salt thereof with an acid. If stereoisomeric compounds are included, they can be separated into their components by known methods. The compounds according to the invention, in particular each of the compounds mentioned above, show good efficacy and therapeutically important properties in animal studies. In vitro and in vivo platelet aggregation inhibition is much better than known drugs such as acetylsalicylic acid or Trapidil. Isolated cardiac and atrial samples exhibit coronary dilatation and an increased effect on muscle contraction force. Lowers blood pressure, especially in hypertensive symptoms. The compounds of the invention suppress the deformation and aggregation tendency of red blood cells induced by hyperosmotic conditions, thereby improving the flow conditions in the capillary circulation region. Regarding the effects on arachidonic acid metabolism, it alleviates the formation of thromboxane A ₂ or promotes the synthesis of aggregation-inhibiting prostaglandins, especially frostacyclin.
This compound also exhibits antiarrhythmic effects. The essential feature of this new compound lies in its influence on calcium substance metabolism, in particular on pressure-dependent transmembrane Ca ²⁺ currents (Ca ²⁺ −Einstroms) in living cells. This is explained by A.Fleckenstein, "Calcium antagonism in cardiac and smooth muscle", G. Willey & Sons, New York, 1983).
According to the authors, it exhibits highly selective calcium antagonism in this case. A particular advantage over the known Ca antagonists is the high selectivity and potency of action, ie the mildly variable effect and the development of action upon frequent stimulation of sensitive cells. Owing to their broad pharmacological action spectrum and low acute toxicity, the compounds of the invention can be included in the treatment of locally anemic cardio-circulatory diseases and are superior to previously known compounds. as an injection solution in a 5% aqueous solution or as an active substance at 58%,
It can be used as granules coated in a known manner with a composition of 20% lactose, 19% water, 3% magnesium stearate. Example 1 18.9 g of 5,7-dichloro-s-triazolo[1,5-a]pyrimidine was dissolved or suspended in 50 ml of ethanol and
Slowly add a solution of 26.1 g of n-amylethanolamine. At this time, the mixture is stirred and kept at 283-288 K for 1 hour after the end of the addition. Then, add 293-298K ethanol 20 to the resulting suspension.
Add a solution of 17.0 g of piperidine in ml,
Maintain at 324K for 3 hours to prevent precipitation. then 100
Add ml of methylene chloride and remove the water by washing three times with 75 ml of water. Concentrate methylene chloride,
Crystallize the residue. Recrystallization with benzene yielded 26.5 g of piperidino-7-(N-(n-pentyl)-N-(β-hydroxyethyl)-amino)-s-triazolo[1,5-
a] Pyrimidine (80% of theory) is obtained. Example 2 18.9 g of 5,7-dichloro-s-triazolo[1,5-a]pyrimidine was dissolved or suspended in 50 ml of ethanol and
Slowly add a solution of 26.1 g of n-amylethanolamine. Stir the mixture;
After the addition is complete, the mixture is left at 283-288K for 1 hour.
The suspension obtained is taken out, suspended in 50 ml of ethanol and a solution of 14.6 g of diethylamine at 293-298 K is added. The mixture is then kept under reflux for 3 hours and subsequently concentrated under vacuum. Add the residue to 100 ml of methylene chloride, wash and separate the methylene chloride layer with 50 ml of water. The methylene chloride is concentrated and the residue is crystallized and recrystallized from ether. The obtained 5-diethylamino-7-(N
-(n-pentyl)-N(β-hydroxyethyl)-
The yield of amino)-s-triazolo[1,5-a]pyrimidine is 225 g (70% of theory). Example 3 18.9 g of 5,7-dichloro-s-triazolo[1,5-a]pyrimidine are suspended in 50 ml of ethanol. 29.4 g of n-hexylaminoethanol is added dropwise under stirring at 5-10° C., the temperature of the precipitate is brought to 293 K, and the mixture is stirred at that temperature for 1 hour. The resulting compound is then taken out and resuspended in 150 ml of ethanol. 15 g of diethylamine are added at room temperature and the mixture is then boiled for 3 hours. The precipitate is concentrated under vacuum, 75 ml of chloroform is added to the residue and washed with water. After washing, the organic phase was concentrated and the obtained 5-diethylamino-7-
(n-hexyl)-N-(β-hydroxyethyl)-
Amino)-s-triazolo[1,5-a]pyrimidine is recrystallized from petroleum ether. Melting point is 335
~336K, resulting in a yield of 162g (50% of the theoretical value). Example 4 The reaction is carried out as described in Example 3.
17.1 g of piperidine is used instead of diethylamine. The obtained 5-piperidino-7-(N-(n-
Hexyl)-N-(β-hydroxyethyl)-amino)-s-triazolo[1,5-a]pyrimidine is recrystallized from benzene. Yield: 28g, melting point: 354K. Example 5 18.9 of 5,7-dichloro-s-triazolo[1,5-a]pyrimidine is suspended in a mixture of 50 ml of ethanol and 50 ml of water. 278~283K
23.6 g of n-butylaminoethanol are slowly added at a temperature of 23.6 g and the precipitate is stirred for 3 hours at room temperature. The resulting compound was then removed and again heated to 150
ml of methanol and slowly add 17.4 g of morpholine and hold the precipitate under reflux for 2 hours. The methanol is concentrated and the residue is added to 75 ml of methylene chloride and washed twice with 50 ml of water. After concentration, 5-morpholino-7-((n-butyl)-N
-(β-Hydroxyethyl)-amino)-s-triazolo[1,5-a]pyrimidine exhibits a melting point of 375 K and a yield of 16 g (50% of theory). Example 6 18.9 g of 5,7-dichloro-s-triazolo[1,5-a]pyrimidine are suspended in 200 ml of methanol. At 278-283 K, 26.6 g of N-(ethoxyethyl)-N-(β-hydroxyethyl)-amine are added and the precipitate is stirred for 2 hours at 288-293 K. Subsequently, the reaction product is removed, suspended again in 75 ml of methanol, 17 g of piperidine are added and kept at boiling temperature for 3 hours. The suspension is concentrated and the residue is crystallized. 5-piperidino-7-(N-ethroxyethyl)-N-
(β-Hydroxyethyl)-amino)-s-triazolo[1,5-a]pyrimidine was recrystallized from acetic acid ethyl ester with a melting point of 393-394 K and a yield of 22 g (65% of theory). It is. Example 7 The experiment was carried out as shown in Example 6, using 14.6 g diethylamine instead of 17 g piperidine.
5-diethylamino-7-(N-(ethoxyethyl)-N) with melting point 342-343 K from recrystallization of benzene
-(β-hydroxyethyl)-amino)-s-triazolo[1,5-a]pyrimidine is obtained. In Examples 8 to 15, instead of the chemical name, the following symbols A~
C is given. A 5-diethylamino-7-(N-(n-hexyl)-N-(β-hydroxyethyl)-amino)-
s-(triazolo[1,5-a]pyrimidine B 5-piperidino-7-(N-(n-pentyl)
-N-(β-hydroxyethyl)-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 Arachidonic acid or U- on human platelets
46619-induced agglutination Nine volumes of blood from a blood donor who had not taken any medication over the past 10 days were mixed with 1 volume of 3.8% trisodium citrate solution and centrifuged at 200 g for 10 minutes at room temperature. . Platelet rich plasma (PRP) was removed with a silicone pipet and kept at room temperature for the duration of the study up to 3 hours. The test compound was dissolved in a solvent mixture of ethanol/chloroform (1:1), poured into a meter, and the organic solvent mixture was blown off with a stream of nitrogen.
After addition of 0.3 ml of PRP and saline solution and a 2 min pre-incubation period, sodium arachidonate (0.2-0.8 mmol/1) or TXA ₂ antagonist muscle U-
Aggregation with 46619 (0.2-0.8 mmol/1) was observed. The aggregation process was determined by Born's method (Born, 9.VR
and Cross, UJ: J.Physiol. 168 , 178 (1963))
Measured by. The essential concentrations of test compounds required to inhibit aggregation by 50% were determined by direct comparison of them with trapidil. As shown by the results in Table 1, these derivatives have significantly stronger anti-aggregation effects than Trapidil.

[Table] Example 9 Inhibition of platelet aggregation in rabbits and rats Platelet-rich plasma was obtained from citrate blood of rabbits or rats by centrifugation at 200 g at room temperature, and was kept in plastic at room temperature for the duration of the study. He held the syringe. In rabbit studies, the plasma of conspecifics
The test substance in 0.9% NaCl solution (50 μ) was added to 0.4 ml of PRP, and after a pre-incubation period of 3 minutes, agglutination with sodium arachidonate (75-210 mmol/1) developed at 37°C. Rat platelets were isolated and treated with Michaelis buffer (PH7.4) and fibrin-depleted homologous plasma (1:
1) Suspend in To 1.2 ml of this platelet suspension is added 10 .mu. of the sample ethanol solution, and aggregation is initiated at 37.degree. C. after a pre-incubation period of 2 minutes by the addition of arachidonic acid (final concentration in the container 2 mmol/1).
This agglomeration can be explained by Born's method ((Born, 9.VR and
Cross, JJ: J. Physiol. 168 , 178 (1963)). A comparison of the average molar concentrations of inhibition (Table 2) shows that in this study the new test compounds clearly have a significantly stronger anti-aggregation effect on trapidil.

[Table] Example 10 Effects of platelet aggregation in vivo Intravenous injection of arachidonic acid causes platelet aggregation in rabbits, causing symptoms of suffocation, especially in the lungs, and fatal effects. For asymptomatic and low tolerated concentrations, the aggregating effect of arachidonic acid was quantitatively studied on the basis of an apparent decrease in the number of free circulating platelets in the peripheral blood directly after injection, demonstrating the effectiveness of the previously administered drug. be done. Blood was collected from the ear veins of unanesthetized rabbits of both sexes, and the number of platelets was measured using a phase contrast microscope. This was followed by intravenous injection of sodium arachidonate at a dose of 0.1 mg/Kg and 1/Kg.
The platelet count was measured repeatedly after 2, 1, 2, 3, 5, and 10 minutes. Using a criterion that considers platelet count reduction as a quantitative criterion for arachidonic acid-induced thrombosis, the value for control group animals was set at 100%.
Assigned to be equal to . In testing the in vivo effects of test samples, AA-
Based on response testing, it was administered orally as a suspension in Ultraquellcellulose via a flexible gastric probe. The degree of thrombus after arachidonic acid injection was determined by sample administration using the method described above.
Repeat measurements were taken after 2, 4, 6 and 24 hours.

[Table] The results (Table 3) prove that the new derivative has a superior aggregation inhibiting effect compared to Trapidil, and demonstrate the efficacy of the new derivative under in vivo conditions as well. . Example 11 Inhibition of thromboxane A ₂ synthesis After arachidonic acid induced aggregation of rabbit platelets, TXA ₂ production and its effects were investigated.
Preparation of PRP and coagulated precipitate corresponds to the conditions described in Example 9. After adding AA, add a fraction of the volume of the container.
It was used for biological measurement of _TXA2 content. Determination of the content of thromboxane A ₂ was carried out on helical strips of blood vessels from the rabbit mesentery using the Superfusion technique. Tyrode's solution was used as a supermelting solvent, and it contained propanol (5 μg/ml) and phenetolamine (1 μg/ml) as blocking substances to increase selectivity.
g/ml), atropine (0.25 μg/ml), antazoline (0.25 μg/ml), methylsergide (20 μg/ml),
ml) and indomethacin (1 μg/ml). The susceptibility of blood vessel fragments to EMA (9,11-ethoxymethano-15(s)-hydroquine-prostar)
1 to 5,13-dienoic acid = U-44069)
A range of doses of 25 μg was tested and the contrast of changes occurring was recorded. Table 4 shows that the new derivatives show strong inhibition of thromboxane _A2 biosynthesis compared to trapidil.
It can be seen from

[Table] Example 12 Myocardial action The effect of cardiac contractility was investigated in isolated atria of guinea pigs. The right native and appropriate atrial sample was suspended in a 25 ml tissue bath under _O2 flow and machine-
The shrinkage was measured approximately the same by means of an electrical transducer. All compounds tested show excellent positive myopromoting effects on isolated atrial samples of guinea pigs. The doses required to increase the contractile force by 50% are shown in Table 5 as the negative logarithm of the corresponding concentration, and it can be seen that the efficacy is superior compared to Trapidil.

[Table] Example 13 Blood pressure effect Rats with spontaneous hypertension (Okamoto-Aoki)
Under pentolbarbital anesthesia (60 mg/Kg intraperitoneal ip), the right common carotid artery was dissected and a polyethylene catheter was inserted. Arterial pressure was recorded with a mechano-electrical transducer (EMT34; Mingoklav 81, Elenasienander, Stockholm) with a copier. The sample was administered into the left subclavian vein along with 0.6 ml of physiological saline. In spontaneously hypertensive rats, whereas trapidil causes only a transient reduction in central arterial pressure, the new test compound produces a sustained antihypertensive effect over a long period of time. Compounds A and C proved to be active derivatives in this regard, which lowered the central arterial pressure from 15 to 15 for 2 to 4 hours.
Reduced by 20%. Example 14 Inhibition of phosphodiesterase (PDE) The activity of PDE was inhibited by Butcher and Sutherland (Butcher, RW and Sutherland, EW: J.
biol.Chem. 237 , 1244, (1962)). The deposit (0.9 ml) has the following composition: Namely, 1.8mM MgSO ₄ , 36mM Tris, 0.5mM cAMP (manufactured by Boeringer, Mannheim) and 15 μg of phosphodiesterase from bovine myocardium (manufactured by Boeringer, Mannheim). The reaction was carried out at PH 8.0 and 37 °C, and 10
After a minute it was stopped by heating in a boiling water bath for 1 minute.
Thereafter, 0.1 ml of Crotalus atrox (Sigma, rice grains) was added and incubated for an additional 10 minutes at 37°C. For the determination of orthophosphate, the incubation was stopped by adding 0.1 _ml of 5N HClO4, and the resulting phosphate after centrifugation was analyzed by the semi-micro method of ALLEN (Allen, RIL:
Biochem.J.38, 358 (1940)). As evident from derivatives A and C, the new compounds exhibit significantly stronger inhibition of phosphodiesterase compared to trapidil. That is, the suppression constant was determined. Trapidil Ki=1.3×10 ^-3 M A 5.4×10 ^-5 M C 2.0×10 ^-5 M Example 15 Inhibition of transmembrane calcium flux Neurobuds of Klone 108c.c.5 and 108c.c.15 Cell X glioma hybrid cell (Gliom
Cell perfusions-voltage-clamp technique (Hybridzellen)
The pressure-dependent Ca flow (spannungs abha〓n〓gig
Ca-Einstrom) and its effect with Compound A was tested. This electrophysical measurement method used makes it possible to directly indicate the action of substances on the slow Ca flux of sensitive cells. Recording and evaluation of the obtained data was performed using an EMG research computer and a signal shape analyzer. Compound A was dissolved in distilled water and added to extracellular fluid (glucose 5mM, Tris HCl 130mM, Cacl ₂
10mM, _Mgcl2 1mM, Kcl4mM, PH7.4; Intracellular echo: _TrisPO4 140mM, PH7.2)
Dilute to a concentration of 100 µM and prepare 5 to 5 graded doses at 22 °C.
It was applied extracellularly by continuous perfusion of 10 ml. One to two minutes after extracellular application of Compound A, Ca ²⁺ flux (Ica) was stopped in a dose-dependent manner. This effect was present over the entire range of potentials that could be specified, and no deviation in the volt-ampere characteristics was observed. Ica inhibition was reversible in all cases. The washing time was a few seconds. 0.1 of the depolarization frequency (use-dependent effect)
The increase from 1 Hz to 1 Hz showed a strong inhibitory effect of the substance. Example 16 20.3 g of 5,7-dichloro-3-methyl-s-
Triazolo[1,5-a]pyrimidine was suspended in 200 ml of ethanol and suspended in 25 ml of ethanol.
Slowly add a solution of 26.4 g of n-amylethanolamine. Stir the mixture;
After the addition is complete, the mixture is left at 288-298K for 1 hour.
17.0 g of piperidine are added to the resulting suspension. This is then heated to maintain the mixture under reflux for 5 hours and stirred. After evaporation and recrystallization from ethyl acetate, 25.9 g of 3-methyl-5-piperidino-7-(N-(n-pentyl)-
N-(β-hydroxyethyl)-amino)-s-triazolo[1,5-a]pyrimidine is obtained (75% of theory). The melting point of this substance is 383K. Example 17 18.9 g of 5,7-dichloro-s-triazolo[1,5-a]pyrimidine were suspended in 30 ml of ethanol. Under continuous stirring at 288-298 K, 24.2 g of β-phenylethylamine are slowly added dropwise and stirred for a further 2 hours at this temperature. After the reaction product has been separated, it is suspended in ethanol, 21 g of diethanolamine are added and the mixture is stirred for a further 5 hours at the boiling point. By evaporating and purifying the product obtained, 23.9 g of 5-diethanolamine)-
7-β-phenylamino-s-triazolo(1,
5-a] Pyrimidine (70% of theory) is obtained. Melting point is 387-388K.

Claims (1)

[Claims] 1. A novel s-triazolo[1,5-a]pyrimidine represented by the following general formula (). [In the formula, R ₂ and R ₃ are each the same or different, and are a hydrogen atom or an alkyl group with a chain length of C ₁ to _{C 3} , and R ₄ is a straight or branched chain with a chain length of C ₄ to C ₉ . A chain alkyl group, an aralkyl group substituted with alkoxy or alkyl having a chain length of _C1 to _C3 , and _R5 is a hydrogen atom, an alkyl group having a chain length of _C1 to _C3 , a hydroxyethyl group or a hydroxypropyl group. and R ₆ and R ₇ are each the same or different and are a hydrogen atom or a straight or branched alkyl group with a chain length of C ₁ to _{C 5} , or R ₆ and
Together with R ₇ , they form a piperazine ring or a morpoline ring. In addition, the 5th and 7th positions
The --position substituents may be exchanged with each other. ] 2 5-piperidino-7-(N-(n-pentyl)
-N-(β-hydroxyethyl)-amino)-s-
A novel s-triazolo[1,5-a]pyrimidine according to claim 1, which is a triazolo[1,5-a]pyrimidine. 3 5-diethylamino-7-(N-(n-pentyl)-N-(β-hydroxyethyl)-amino)-s
- triazolo[1,5-a]pyrimidine,
A novel s-triazolo[1,5-a]pyrimidine as claimed in claim 1. 4 5-diethylamino-7-(N-(n-hexyl)-N-(β-hydroxyethyl)-amino)-s
- triazolo[1,5-a]pyrimidine,
A novel s-triazolo[1,5-a]pyrimidine as claimed in claim 1. 5 5-piperidino-7-(N-(n-hexyl)
-N-(β-hydroxyethyl)-amino)-s-
A novel s-triazolo[1,5-a]pyrimidine according to claim 1, which is a triazolo[1,5-a]pyrimidine. 6 5-morpholino-7-(N-(n-butyl)-
The novel s-triazolo[1,5-a]pyrimidine according to claim 1, which is N-(β-hydroxyethyl)-amino)-s-triazolo[1,5-a]pyrimidine. 7 5-piperidino-7-(N-(ethoxyethyl)-N-(β-hydroxyethyl)-amino)-s
- triazolo[1,5-a]pyrimidine,
A novel s-triazolo[1,5-a]pyrimidine as claimed in claim 1. 8 5-diethylamino-7-(N-(ethoxyethyl)-N-(β-hydroxyethyl)-amino)-
The novel s-triazolo[1,5-a]pyrimidine according to claim 1, which is s-triazolo[1,5-a]pyrimidine. 9 In producing a novel s-triazolo[1,5-a]pyrimidine represented by the following general formula (), [In the formula, R ₂ and R ₃ are hydrogen atoms, chain length C ₁ to C ₃
is an alkyl group or a halogen atom, R ₄ is a linear or branched alkyl group with a chain length of C ₄ to _{C 9} ,
an aralkyl group substituted with alkoxy or alkyl having a chain length of _C1 to _C3 , a 2,5-dioxaheptyl residue or a 3-oxahexyl residue, _R5 is a hydrogen atom, and a chain length of _C1 to _C3 is an alkyl group, hydroxyethyl group or hydroxypropyl group, and R ₆ and R ₇ are hydrogen atoms, or linear or branched alkyl groups with a chain length of C ₁ to C ₅ , or R ₆ and R ₇ forms a ring together with the heteroatom. In addition, the substituents at the 5-position and the 7-position may be exchanged with each other. ] The compound represented by the following general formula () is (In the formula, R ₂ and R ₃ have the same meanings as above,
Hal is a chlorine atom or a bromine atom) Together with the amine represented by the general formula below, (wherein R ₄ , R ₅ , R ₆ and R ₇ have the same meanings as above) In the presence of a solvent, two steps of a first temperature up to 293 K and a second temperature up to the boiling point of said solvent are carried out. A novel method for producing s-triazolo[1,5-a]pyrimidine, characterized by 10 The compound of general formula () is 5-piperidino-
7-(N-(n-pentyl)-N-(β-hydroxyethyl)-amino)-s-triazolo[1,5-
a] pyrimidine, the novel method for producing s-triazolo[1,5-a]pyrimidine according to claim 9. 11 The compound of general formula () is 5-diethylamino-7-(N-(n-pentyl)-N-(β-hydroxyethyl)-amino)-s-triazolo[1,5
-a]pyrimidine, the novel method for producing s-triazolo[1,5-a]pyrimidine according to claim 9. 12 The compound of general formula () is 5-diethylamino-7-(N-(n-hexyl)-N-(β-hydroxyethyl)-amino)-s-triazolo[1,5
-a]pyrimidine, the novel method for producing s-triazolo[1,5-a]pyrimidine according to claim 9. 13 The compound of general formula () is 5-piperidino-
7-(N-(n-hexyl)-N-(β-hydroxyethyl)-amino)-s-triazolo[1,5-
a] pyrimidine, the novel method for producing s-triazolo[1,5-a]pyrimidine according to claim 9. 14 The compound of general formula () is 5-morpholino-
7-(N-(n-butyl)-N-(β-hydroxyethyl)-amino)-s-triazolo[1,5-a]
A method for producing the novel s-triazolo[1,5-a]pyrimidine according to claim 9, which is pyrimidine. 15 The compound of general formula () is 5-piperidino-
7-(N-(ethoxyethyl)-N-(β-hydroxyethyl)-amino)-s-triazolo[1,5-
a] pyrimidine, the novel method for producing s-triazolo[1,5-a]pyrimidine according to claim 9. 16 The compound of general formula () is 5-diethylamino-7-(N-(ethoxyethyl)-N-(β-hydroxyethyl)-amino)-s-triazolo[1,
5-a]Claim 9, which is pyrimidine
A method for producing the novel s-triazolo[1,5-a]pyrimidine described in Section 1. 17 Novel s- represented by the following general formula ()
A circulatory organ agent containing triazolo[1,5-a]pyrimidine. [In the formula, R ₂ and R ₃ are a hydrogen atom, an alkyl group with a chain length of C ₁ to C ₃ , or a halogen atom, and R ₄ is a linear or branched alkyl group with a chain length of C ₄ to C ₉ , an aralkyl group substituted with alkoxy or alkyl having a chain length of _C1 to _C3 , a 2,5-dioxaheptyl residue or a 3-oxahexyl residue, _R5 is a hydrogen atom, and a chain length of _C1 to _C3 is an alkyl group, hydroxyethyl group or hydroxypropyl group, and R ₆ and R ₇ are hydrogen atoms, or linear or branched alkyl groups with a chain length of C ₁ to C ₅ , or R ₆ and R ₇ forms a ring together with the heteroatom. In addition, the substituents at the 5-position and the 7-position may be exchanged with each other. ] 18 The compound of general formula () is 5-piperidino-
7-(N-(n-pentyl)-N-(β-hydroxyethyl)-amino)-s-triazolo[1,5-
a] The drug according to claim 17, which is pyrimidine. 19 The compound of general formula () is 5-diethylamino-7-(N-(n-pentyl)-N-(β-hydroxyethyl)-amino)-s-triazolo[1,5
-a] pyrimidine, Claim 17
Drugs listed in section. 20 The compound of general formula () is 5-diethylamino-7-(N-(n-hexyl)-N-(β-hydroxyethyl)-amino)-s-triazolo[1,5
-a] pyrimidine, Claim 17
Drugs listed in section. 21 The compound of general formula () is 5-piperidino-
7-(N-(n-hexyl)-N-(β-hydroxyethyl)-amino)-s-triazolo[1,5-
a] The drug according to claim 17, which is pyrimidine. 22 The compound of general formula () is 5-morpholino-
7-(N-(n-butyl)-N-(β-hydroxyethyl)-amino)-s-triazolo[1,5-a]
18. The drug according to claim 17, which is a pyrimidine. 23 The compound of general formula () is 5-piperidino-
7-(N-(ethoxyethyl)-N-(β-hydroxyethyl)-amino)-s-triazolo[1,5-
a] The drug according to claim 17, which is pyrimidine. 24 The compound of general formula () is 5-diethylamino-7-(N-(ethoxyethyl)-N-(β-hydroxyethyl)-amino)-s-triazolo[1,
5-a]Claim 1, which is pyrimidine
The drug described in item 7.