• 专利附录
  • 专利说明
  • 权利要求
  • 类似技术
  • 同族专利
  • 引用文献
  • 法律状态
  • 优先权
    • 专利摘要:
    The invention concerns new compounds of the formula (I) <IMAGE> (I) <IMAGE> wherein R1 is hydrogen, phenyl or phenyl substituted with at least one alkyl having 1 to 4 carbon atoms, halogen, alkoxy having 1 to 4 carbon atoms or nitro; R2 is alkyl having 1 to 4 carbon atoms, cycloalkyl having 5 to 7 carbon atoms, phenyl, or phenyl substituted with at least one alkyl having 1 to 4 carbon atoms, halogen, alkoxy having 1 to 4 carbon atoms or nitro; R3 is alkoxy having 1 to 4 carbon atoms or hydrogen, R4 is hydrogen, alkyl having 1 to 4 carbon atoms unsubstituted or substituted with alkoxy having 1 to 4 carbon atoms, benzyloxy or cyano, phenyl, or phenyl substituted with at least one alkyl having 1 to 4 carbon atoms, halogen, alkoxy having 1 to 4 carbon atoms or nitro, or phenyl-(C1-4alkyl)-alkyl, in which the phenyl moiety may bear an alkoxy substituent having 1 to 4 carbon atoms or a halogen; m and n are each 0, 1 or 2 or a pharmaceutically acceptable acid addition or quaternary salt thereof. The compounds are potent vasodilators and exert a favorable influence on the extremital blood flow. They also show a heart function influencing activity. Methods for the preparation of said compounds and pharmaceutical compositions containing them are also the subject of the invention.
    公开号:SU1087519A1
    申请号:SU802993201
    申请日:1980-10-10
    公开日:1984-04-23
    发明作者:Такач Кальман；Кишш Илона；Шимаи Антал；Литерати Надь Петер；Хетьей Мариа；Эгери Мариан；Секереш Ласло；Папп Дьюла；Вираг Шандор；Удварди Ева
    申请人:Хиноин Дьедьсер Еш Ведьесети Термекек Дьяра Рт (Фирма)；
    IPC主号:
    专利说明:

    eo
     : p The invention relates to new biologically active compounds - salts of 1,2,4-oxadiazolin-5-one derivatives of the formula g4g :: Cg--сн rj If 7 where H is phenyl, 3,4-dimethoxybeneyl benzyl ; R. - hydrogen, 3,4-dimethoxyben R- - hydrogen, methoxy group, exhibiting the properties of regulators of cardiovascular activity of the ref-ftj cardiovascular system. Known substituted 1,2,4-oxa-diazolin-3-ones, which can be used in agriculture. The aim of the invention is to expand the arsenal of means of influencing a living organism that exhibit the properties of regulators of the activity of the cardiovascular system. This goal is achieved by the salts of 1,2,4-oxadia-oolin-5-one derivatives of general formula (l), which exhibit the properties of cardiovascular regulators. The compounds of the general formula (region I) have a strong peripheral vasoregative effect and have a very favorable effect on the blood circulation of the extremities. In addition, they act on the function of the heart, have a very significant antiarrhythmic and anti-antiginous action. The compounds of general formula (I) can be applied in pharmacopoeia in the form of preparations containing an effective substance, as well as inert solid or lix, inorganic or organic carriers. The preparations are made by lime methods used in the manufacture Preparations may be in the form of tablets, dragees, solutions, emulsions, etc. The content of the effective substance in the preparations may vary in the air limits and lie in the range of 0.005 - 90a. The daily dose of the effective substance may vary. a wide range and depends on the age, weight and condition of the patient, in addition to the type of the finished product, as well as the activity of the corresponding substance. The daily dose is usually 1-500 mg / kg. These data are indicative in nature and, depending on the requirements of each individual case and medical prescriptions, may deviate in one direction or another. Experiments with animals were carried out in each case with the corresponding salts. Example 1, To a thermal solution of 5.1 g of 3-phenyl-1- {3-chloro-2-hydroxypropyl) -D-1, 2, 4-oxadiaeolin-5-one and 4.0 g of 6,7-dimethoxy -1,2,3,4-tetrahydro-isoquinoline in 30 ml of hot absolute ethanol was added dropwise with 7.5 ml of 10% aqueous sodium hydroxide solution for one hour. The reaction mixture was stirred for another hour at boiling point, after which the mixture was cooled and diluted with water. 6.3 g of 3-phenyl-4- 3- (6,7-di-methoxy-1, 2,3,4-tetrahydro-2-isoquino-lil) -2-hydroxypropyl -D -1,2,3 are obtained, 4-oxadiazolin-5-one. Tf, 159-161 C (from absolute ethanol) WELL,%: C 64.22; H 6.12; and 10.21. C22 “2,, Found,%: C 64.57; H 6.41; By 9.90, the hydrochloride hydrochloride of the product is obtained in methanol solution by the addition of hydrochloric acid methanol. The hydrochloride salt melts at 2102-13 ° C. Analysis of Hj Cl -ijOy. Calculated,%: C1 7.92 Found,%: C1 7.88. Example 2. K2.18g 3-phenyl 4- (2, 3-epoxy-propyl, 2, 4-oxadiazolin-5-one) was added 20 ml of absolute ethanol and 2.0 g of 6.7-dimethoxy-1, 2, 3, 4-tetrahydro-eoquinoline. The reaction mixture is boiled for one hour under reflux temperature. After cooling, the mixture is diluted with water. 3.42 g of 3-feiyl-4-3- (6,7-dimethoxy-1, 2,3,4-tetrahydro-2-isoquinolyl) -2-hydroxypropyl -1 -1, 2,3,4-oxadiazolin-5-one., The product is identical with the product obtained according to Example 1 Effect on the circulatory system .m determined on anesthetized dogs (Nembut 25 mg / kg intravenously) With a weight of 10–20 kg. The animal's chest was opened and an artificial dissection was applied throughout the study. The cardiac minute volume was measured with the help of the nicotron 376 electromagnetic measuring instrument of blood flow, while the measuring head was set on the aorta and the artery of the head and around the artery femoralis. The results will result in Table 1. The compound reduces the use of the peripheral resistance indicated in Table 1 for (mit) 40.63 or 69%. A dose of 1 mg / kg intravenously reduces the blood pressure of anesthetized dogs by 19%. The compound administered intravenously exerts an anti-anginal effect in the same order as papaverine in simulated angina in rats, caused by glanduitrin. At a dose of 1 mg / kg, an intravenous compound increases the minute volume of the heart muscle in anesthetized dogs by 10 &amp; , the coronary flow is 39% and reduces coronary resistance by 28%. Example 3. In the same way as described in Example 2, as a result of the interaction of 3-phenyl-4- (2,3epoxypropyl), 2,3,4-oxadiazine 5-one lin with 1,2,3,4-tetrahydro- Paverine gives 3nyl-4-3-l- (3,4-dimethoxybenzyl) -6, 7-dimethoxy-1,2,3,4-tetrahydro-2-isoquinolyl-2-hydroxypropyl-4-oxadiazoline-5- hydrochloride hydrochloride. she is. 218-220 ° С (from 96% ethanol). Included,%: C, 62.25; H 6.07; N 7.03; C1 5.93. Cz, H feClFUO Found,%: C 61.98; H 6.30; And 6.77; C1 5.83. - Antiarrhythmic effect; the compounds were determined on the basis of the effect exerted on electrofibrillary edema by the atrial and heart myapans. Studies were performed on anesthetized cats. The results are shown in table 2. ,, Table Compound Electro-fabulous edema, ED, mg / kg
    Atrium Heart
    The effect of the compounds of Examples 3 and 4 on the circulatory system was determined on cats under anesthesia. Experimental abdomen - the chest was opened and artificial experience was applied in the course of the experiment. The effect of the compounds is defined as
    this is described in Exhibit 2. Example 4. In the same way as described in Example 2, as a result of the interaction of Z-benzyl-4- {Z-chloro-2-hydroxypropyl), 2,3,4-ob. -one with 1, 2,3, 4-tetrahydro-isoquinoline get hydrochloride 3-benzyl-4-c- (1,2,3,4-tetrahydro-2-isoquinolyl) -2-oxypropyl - -D -1,2 , 4-oxadiazolin-5-one. mp 194-197 ° C (after recrystallization from 96% ethanol). Calculated,%: C 62.76; H 6.02f N 10.46; C1 8.82 Cr, H.ClH-jOFound,%: C 63.18; H%, 13 | K 10.18; C1 8.75 Example 5. In the same manner as described in Example 2, by reacting 3- (3,4-dimethoxy-benzyl) -4- (3-chloro-2-oxypropyl) -l -1.2 , 4-oxadiazolin-5-one with 1,2,3,4-tetrahydro-isoquinoline get 3- (3,4-dimethoxy-benzyl) hydrochloride (1,2,3,4-tetrahydro-2-isoquinolyl) - 2-hydroxy-propyl -, 2,4-oxadiazolin-5-one. T (from 96% alcohol). You shsleno,%: C 59.80; H 6.11; N 9.10; C1 7.68 Ca HjgClN.Oj Found: C 60.01; H 6.20; N 8.79; C1 7.90. At a dose of 1 m1 / kg, the compound reduces the total peripheral resistance of anesthetized dogs by 41%. At a dose of 2 mg / kg intravenously in rats, the compound knocks down the increase in T-wave caused by glanduitrin by 53.9%. The relative activity of the compound of reading to papaverine is 1.29. At a dose of 1 mg / kg, intravenously, the compound reduces arterial blood pressure by 26%. Example 6. In the same manner as described in Example 2, by reacting 3-benzyl-4 (3-chloro-2-hydroxypropyl), 2,4-oxadiazolin-5-one with 6,7-dimethoxy-1, 2 , 3,4-tetrahydro-isoquinolin get 2-benzyl-4-z hydrochloride (6,7-dimethoxy-1,2,3,4-tetrahydro-2-isoquinolyl) -2-oxypropyl -1,2,2,4 -oxadiazolin-5-one. Trp 190 C {from alcohol). Calculated,%: C 59.80; H 6.11; 10.46; C1 7.67 C21 28CHO C1 Found: C 59.50; H 8.73; C1 7.31
    rtpH this obtained ved in tabl.Z.
    T Antiarrhythmic effect. Experiments were performed on cats weighing 2.2-3.5 kg. The animals were anesthetized and their chest was opened and artificial respiration was used during the experiment. The fibrillary threshold was determined by the method of Srekeres et al. Irritating electrodes were inserted through a hole in the pericardium and attached to the anterior surface of the right ventricle or glued to the right; the atria. Electrodes with an interval of 4 s were applied to rectangular current pulses with a duration of 1 ISS and a frequency of 2 Hz. The intensity of irritation was increased to the occurrence of cardiac flutter, confirmed by ECG data, a sharp decrease in blood pressure and direct observations of the heart. Under these conditions, a threshold threshold for trembling of the heart indicates an anti-fibrillation effect of the tested compounds. The relative activity of the compound of Example 3 according to the determination of the fibrillar threshold of the ventricle of the heart is given in Table 4. T a b l and c a 4
    Continued table. four
    3.0
    1.7 5.1 1.0
    Anti-anginal effect of compounds -. Neither 1 was tested by the example of angina caused by glanduitrin
    (pituitrinom). Experiments were carried out on male Nebutal (45 mg / kg, intraperitoneally) male rats (CPE strain) that were anesthetized. At a dose of 2 mg / kg (intravenously), the compound exhibited a 42.5% protective effect. The hemodynamic effect of compound 1 was determined on dogs weighing 15–20 kg under anesthesia. The animals were opened to the chest and artificial respiration was used during the experiment. The results are shown in Table 3.
    Table 5 Blood pressure 0.5 5 -191 1.0 5-221 2.0 5 -231 Heart rate 1.0 5 169 2.0. 5 2410 4.0 5 30111 With a dose of 1.0 mg / kg, the above compound 1 increases the minute volume by 10% for 4 minutes, reduces the total peripheral resistance by -35% for 3 minutes and intensifies the activity of the left ventricle of the heart by + 18% within 5 min. Coronary perfusion for 12 min increases by 39%. At a dose of 1.0 mg / kg, the coronary resistance decreased by -28% over 11 minutes. In the experiments on the study of the femoral blood supply, the results are given in Table. b.
    Table 6
    -t-78%
    1.0
    10 The effect of the compounds of Example 6 on the circulatory system was determined, as described in Example 4, on anesthetized cats. At the same time, a dose of 0.5 mg / kg (intravenously) of the compound of Example b reduces arterial blood pressure by 8%, a dose of 1 mg / kg - by 17%, a dose of 2 mg / kg by 28%. The antiarrhythmic effect of this compound : A dose of 2 mg / kg of the compound increases the value of the fibrillary threshold of the ventricle by 9%, and the atria — by 18%.
    The compounds of general formula (I) are of low toxicity.
    Data on the toxicity of the compounds in examples 4-6 are as follows: Compound 4.
    LDjjj 175.97 mg / kg subcutaneously, male mice.
    LDjg 180.61 mg / kg subcutaneously, female mice. Compound 5.
    LDjg 310.72 mg / kg subcutaneously, male mice. 264.44 mg / kg sc. 50 female mice. Connection 6. LDgo 360,87 mg / kg subcutaneously. Myoshi males. 332.9 mg / kg sc. Ms.I-females. The toxicity of the compounds according to Example 2. i.p. 1000 mg / kg in mice LDj-Q P.O. 3000 mg / kg in mice. The toxicity of the compounds of example 3. LD i.r. 1000 mg / kg in mice.
    权利要求:
    Claims (1)
    [1]
    Salts of 1,2,4-oxadiazolin-5-one derivatives of the general formula
    R-0-N-CHr
    N C == 0
    V where (C is phenyl, 3,4-dimethoxybenzyl, benzyl;
    1 2 “hydrogen, 3,4-dimethoxybenzyl;
    Rj is hydrogen, ‘a methoxy group, exhibiting the properties of regulators of the activity of the cardiovascular system!
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