• 专利附录
  • 专利说明
  • 权利要求
  • 类似技术
  • 同族专利
  • 引用文献
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    • 专利摘要:
    s-triazolo(1,5-a)pyrimidine compounds of the Formula (I> <IMAGE> wherein R2 and R3 are the same or different and represent an H atom, a C1 to C3 alkyl group or a halogen atom; R4 represents a straight-chain or branched-chain C4 to C9 alkyl group, an aralkyl group substituted by one or more C1 to C3 alkoxy or alkyl groups; 2,5-dioxaheptyl or 3-oxahexyl residues; R5 represents an H atom, a C1 to C3 alkyl group, a hydroxyethyl group or a hydroxypropyl group; R6 and R7 are the same or different and represent an H atom, a straight-chain or branched-chain C1 to C5 alkyl group, or R6 and R7 together complete a cycloaliphatic ring, the substituents in positions 5 and 7 optionally being mutually exchanged, and the pharmaceutically acceptable salts thereof, their preparation and pharmaceutical compositions comprising them are disclosed as therapeutic aids for cardio-circulatory disorder.
    公开号:SU1468423A3
    申请号:SU853884102
    申请日:1985-04-16
    公开日:1989-03-23
    发明作者:Баллнус Мартина；Тенор Эрнст；Томас Экехард；Паше Руди；Мест Ханс-Юрген；Блок Ханс-Ульрих；Ментц Петер；Хайнрот Ингрид
    申请人:Феб Дойчес Хюдрирверк Родлебен (Фирма)；
    IPC主号:
    专利说明:

    one
    This invention relates to a process for the preparation of a triazolopyrimidine derivative, specifically to a process for the preparation of 5-piperidino-7-TN- (n-pentyl) -N- (L-hydroxyethyl) amino) -S-triazolo (1,5-a) pyrimidine with vasodilator, inotropic, antiarrhythmic action.
    The purpose of the invention is to obtain a new triazolopyrimidine derivative having a greater activity than the structural analogue of such an action, trapidyl.
    Example 1. 18.9 g of 5,7-dichloro-3-triazole (1,5-a) pyrimidine is dissolved or suspended in 50 mp of ethanol and at 278-283 K is slowly (under stirring) mixed with a solution of 26.1 g n-amylethanolamine in 25 ml of ethanol. After completion of the addition, the mixture is held for 1 hour at 10-15 ° C and then added to the resulting suspension at 20-25 with a solution of 17.0 g of piperidine in 20 ml of ethanol. The mixture was incubated for 3 hours at 40-50 seconds, evaporated, dissolved in 100 ml of methylene chloride, the trilzds were washed with 75 ml portions of water and the water was separated. Methylene chloride is distilled off, and the residue is subjected to crystallization. After recrystallization from gasoline, 26.5 g of 5-pi-peredino-7-GN- (n-pentyl) -Y-SYa-hydroxyethyl) -minoJ S-triazol (1,5-a) pyrimidine — compound B (( 80% of theoretical yield) with m. Pl. 117-118 s.
    The following examples illustrate the biological effect of the compound obtained.
    Example 2, Aggregation of human blood plates with arachidonic acid (AA) or and-46619.
    9 blood volumes of donors that did not take any medication for the last 10 days were treated with 1 volume of 3.8% trisodium citrate solution and centrifuged at 200 g at room temperature for 10 minutes. The plasma-enriched plasma (RPF) was taken with a silicone-coated pipette and stored for an experiment (maximum for 3 hours) at room temperature.
    Compound B was dissolved in a mixture of solvents from ethanol and chloroform (1: 1), the same parts were introduced into measuring cuvettes and the mixture of organic solvent was poured in a stream of nitrogen. After adding 0.3 m OPP and 0.1 ml of physiological NaCl solution and preliminary holding for 2 min at 37 ° C, the aggregates were separated by sodium arachidonate (0.4-0.7 mmol / l) or by a TXAg agonist and-46619 (0.2-0.8 mmol / l). Measurement of the course of aggregation was carried out in accordance with the method of BornaVoot 9.V.R. U Cross, UI: I Physiol, 1963, 168, 178).
    The concentrations necessary for 50% inhibition of the aggregation were obtained. test compound in direct comparison with trapidil.
    In tab. Figure 1 shows the effect of human Compound B on platelet aggregation of human OPP compared with trapidil (P1C is equal to the negative logarithm of the average molar inhibition concentration).
    As the results of Table 1 show, the derivatives have a significantly stronger antiaggregative effect compared to trapidil.
    Example 3. Inhibition of platelet aggregation in rabbits and rats.
    0
    five
    0
    five
    0
    five
    0
    five
    0
    five
    Platelet-enriched plasma was obtained from the citrated blood of rabbits and rats by centrifuging at 200 g at room temperature. and during the experiment was stored in polymer syringes at room temperature. In studies on rabbits, a test substance to be added to the homologous plasma in 0.9% NaCl solution (50 µl) was added to 0.4 ml of OPP and, after 3 min of preliminary exposure at 37 s, aggregation was caused by arachidonic acid sodium (75%). -210 mmol / l).
    Rat plates were separated and suspended in buffer. Michael (pH 7.4) and defibrinated homologous plasma (1: 1). 10 µl of a solution of the drug in ethanol was added to 1.2 ml of this slurry suspension and after 2 min of pre-exposure, aggregation began by adding arachidonic acid (2 mmol / 1 final concentration in the cuvette). Measurement of aggregation was done nephelometrically using the Born method (here is 9. VR.U.Cross, UI.:I. Physiol, 1963, 168, 178),
    In tab. 2 shows inhibition of platelet aggregation caused by arachidonic acid in in vitro rabbits and rats.
    A comparison of the average molar inhibitory concentrations (Table 2) also shows in these experiments the significantly more pronounced anti-aggregation effect of the new compound compared with trapidil. Example4. Impact on platelet aggregation in yivp.
    . Intravenous application of arachidonic acid in rabbits causes platelet aggregation, especially in the vessels of the lungs, symptoms of suffocation and. lethal effect. Already in low asymptomatically occurring concentrations of arachidonic acid, the aggregation effect on the base (transienten) immediately after injection of a provable amount of freely circulating platelets in the peripheral blood can be established qualitatively and the effectiveness of the previously administered drugs can be proved. In non-narcotized rabbits of both pop, after taking a sample from the ear vein, the number of blood plates was determined by means of a phase-contrast microscope. Then arachidonic sodium was administered at a dose of 0.1 mg / kg fi.v.) and the platelet count was then determined again after 1/2, 1.2, 3, 5 and 10 minutes. As a quantitative criterion for thrombocytopenia caused by arachidonic acid, the area limited by the percentage reduction in the number of platelets and its value for animals was used, the control group was taken as 100%. To check the in vivo efficacy of the tested drugs, the last, after determining the individual AA, nonexcitability reaction in the form of a suspension in ultrafast swelling cellulose was administered via a soft per oral probe and in the order described, the degree of thrombocytopenia was again determined after arachidonic acid injection through 21, 2, 4 , 6 and 24 hours after drug administration.
    In tab. 3 shows the effect on aggregation by injecting arachidonic acid in rabbits in vivo.
    The results table. 3 show, in comparison with trap, a superior efficacy in inhibiting the aggregation of a new compound and at the same time also proving its effectiveness; . in vivo.
    Froze The formation of TXAj and its effect on the plates of rabbits after the induction of aggregation was investigated using arachidonic acid. Obtaining OPP and inducing aggregation was carried out under the conditions of Example 2. 90 seconds after AA administration, equal parts of the contents of the cuvettes were used for the biological determination of TXA content. Determination of thromboxane A produces
    An elk on a spiral-cut out strip of the A. Mesenterica rabbit vessel with the help of a superfusion technique. As a superfusion fluid, a solution of thyroid was used, which to increase the selectivity of substances Blocker-substanzen contained propranolol (5 mg / ml), pento-amine (1 µg / ml), atropine (0.25 µg / ml). Sensitive. The vascular strips were determined by EMA (9,11-epoxymethano-15-Cz1-hydroxy-simple-5,33-dinovaic acid and -4A069) in the dose range of 1-25 mg, and reductions were recorded on a self-recording device by

    684236
    inductive converter. Compared with trapidil, a new derivative is characterized by a more intense inhibition of thrombus boxes.
    In tab. Figure 4 shows the formation of TXA2 in arachidonic acid-stimulated rabbit plaques when exposed to a new compound.
    10 PRI me R 6. Inotropic action.
    The effect of heart contraction was investigated on an isolated atrial of the guinea pig (Rechle). Spontaneously acting cardiac preparations were suspended in 25-ml organ trays with 0 flowing through the trough electrode, and contractions were measured by means of mechanical transducers half-isometric.
    The new compound was characterized by positive isotropic efficacy on an isolated guinea pig atrium preparation.
    Table 30 requires the required dose reduction in the form of a negative logarithm of the corresponding molar concentrations required for a 50% gain. 5 and confirm superior efficacy compared with trapidyl.
    . Example 7. Acute toxicity.
    The acute toxicity of the new compound was tested on NMRI males, a young after intraperitoneal or intravenous use. The compounds were suspended in rapidly swellable cellulose (i, p.) Or dissolved in tartaric acid (i.y.) and added. The determination was made according to the method of Zitchfield. And Wilcoxon.
    In tab. 6 shows acute toxicity in LD mice.
    25
    40
    45
    权利要求:
    Claims (1)
    [1]
    Invention Formula
    The method of producing 5-piperidino-7t LN- (n-pectyl) -N - ((5-hydroxyethyl) -aminoJ-55 8-triazolo (1,5-a) pyrimidine, characterized in that 5,7-di- chloro-3-triaol (1,5-a) pyrimidine is reacted with n-pentylethanolamine at 10-15 s, and then with piperi-55 Dean at 40-50 ° C, and the whole process is carried out in a lower alcohol, preferably in ethanol, followed by allocation of the target product in a known manner.
    71468423
    Table 1
    Inhibition of aggregation
    platelet count (PICjyi).
    AA and-46619
    T
    e
    4.66 3.75
    5.09
    Table2 PIC
    ten
    Rabbits
    I
     fo rats
    --15
    Table 4
    Trapidil
    4.05 4.97
    2.49 3.75
    - -------. 20
    Table 3
    Dose, mg / kg
    Inhibition of AA-thrombocytopenia,%, in hours
    1 I 2 I 4 16 i 24 -. ----- .------ “..,„ ..
     1 JL--. Connection i.p, | i.v,
    /.o/, (LP 1,
    Trapidil 20 14 24 6 О О
    50. 90 96 74 72 17 zo - P pidil B .10 L5 67 71 48 41B
    150 (124-194) 115 (104 230 (193-274) 62 (6225
    T. Table 6
    150 (124-194) 115 (104-127) 230 (193-274) 62 (6275)
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    法律状态:
    优先权:
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