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    • 专利摘要:
    Compounds of the formula: Y-NHCONH-CH2CH2CH2-NH-X wherein: Y is 2,6-dimethylphenyl, 2,5-dimethylphenyl, 5-bromo-2-methylphenyl, or 5-chloro-2-methylphenyl; and X is propyl, isopropyl, n-butyl or isobutyl; and pharmaceutically acceptable acid addition salt therefore possess anit-arrhythmic activity.
    公开号:SU1344245A3
    申请号:SU802891451
    申请日:1980-03-03
    公开日:1987-10-07
    发明作者:С.Салковски Теодор；Л.Берги Джеймс；А.Масситти Альберт
    申请人:Американ Хоум Продакте Корпорейшн (Фирма)；
    IPC主号:
    专利说明:

    The invention relates to methods for the preparation of new L- (3 apkylaminopro-niin) -N-phenylureas of the general formula
    Y NH-CQ-NH-CH2 GHg CHj NHX, where Y is 2,6-dimethylphenyl 5 Z S-flHMe-tylphenyl-5 5-chloro-2-methylfe-. NIL, 5-bromo-2-methylphenylradi
    cal, hn-propyl-j isopropyl-, n-butylradipac5
    or their pharmacologically acceptable salts, which are possessed by a physiologist: nchea activity and can be used in medical practice.
    The aim of the invention is to develop a process for the preparation of phenylurea derivatives, which have a different physiological activity as compared with similar compounds. on the structure of the proposed.
    PRI me R 1. K-Anisilidene-M - -isopropyl-153-diaminopropane.
    A solution of 25 ml, K-isopropyl-1 ,, 3 ™ of diaminopropane, 20.5 g of aldehyde a and 100 ml of toluene is heated under reflux in a flask equipped with a water separator. After 4 h, the solution is cooled and extracted with water. After drying over magnesium sulfate, the solution is evaporated to dryness to obtain 34.5 g of S-anisylidene-c-isopropyl-1 ,, 3-diaminopropane ”
    I IR absorption (film) at,: 3300, 2960, 2830, 1650, 830.
    Nuclear Magnetic Resonance Spectrum (CDC1), 8.18 (s ,, 1H) 7.70 (d, 2H, 1-9 Hz); 6.90 (d, 2H, 9 Hz) 3.73 (s, 3H), 3.66 (m, 2H); 2.75 (m, 3H); 1.87 (m, 2H); 1.05 (с1.6Ш
    1.05 (m, 1H substitution upon deuteration).
    PRI mme R 2. S — NW (Isopropipamino) propyl —N — (2,6-dimethylphenyl) -moe-,
    Method a.
    A solution of 7.4 g of 25.6 dimethylphenyl cyanoate and 50 ml of dichloromethane was added to 12 g of N-anhydride; he-N-isopropyl-1 53-diaminopropane, dissolved in 100 ml of dichloromethane. The solution is heated under reflux for half an hour, then cooled and extracted with water, a saturated solution of sodium carbonate. After drying over magnesium sulfate, the dichloromethane is evaporated to dryness. The residue is dissolved in 100 ml of ethanol. 11 g of hydroxylamine p-toluenesulfonate are added and the mixture is heated under reflux.


    ; .

    44245 .2
    for half an hour. The solution is evaporated to dryness. The residue is triturated with hot ether, then dissolved in hot ethanol. The precipitate separates on standing. After recrystallization from ethanol, H-HZ- (isopropylamino) propyl N- (2,6-dimethylphenyl) urea 5 4-methylphenylsulfonate, 10 m.p. 152-155 s, yield 5.5 g
    Calculated,%; C, 60.66; H 7.64 N 9.65; S 7,, 36.
     C HgSOj Found,%: C 60.61; H 7.85; N 9.70; S 7.07.
    20
    25
    35
    15
    IR (KBG), cm-: 3380, 3280, 2650-3100, 1670, 1550.
    NMR (DMSO), 8.18-8.68 (t, 2H ,.
    exchange with D, 20); 7.78 (s, 1H, exchange with DjO); 6.90-7.64 (m, 7H); 6.48 (m, 1H, exchange s); 2.60-3.50 (ha, 5H); 2.30 (s, 3H); 2.17 (s, 6H); 1.55-2.05 (m, 2H); 1.19 (d, 6H).
    Method b.
    A solution of 73 g of 2,6-dimethylphenyl isocyanate and 150 ml of dichloromethane is added to: a stirred, cooled solution of 150 g of isopropyl-1,3-diaminopropane in 400 ml of dichloromethane. The temperature is maintained between -5 and during addition. Stirring is continued at room temperature for another 3 hours. The mixture is extracted with water, then a total of 500 ml of 20% hydrochloric acid. The acidic solution is made basic with a saturated solution of sodium carbonate. The mixture is extracted with dichloromethane. The dichloromethane solution is dried over magnesium sulfate, then evaporated to dryness. The residue is treated with p-toluene sulfonic acid to form the salt. After recrystallization from ethanol, (isopropylamino) pro- 45 - (2,6 - dimethylphenyl) -urea, 4-methylphenylsulfonate, m.p. 152-154 ° C, yield 72 g
    Calculated,%: C 60.66; H 7.64; N 9.65; S 7.36.
    C, 5 Hjj-N O C, HgS05
    Found,%: C 60.53-, H 7.69i N 9.45; S 7.53.
    Hydroxylp u, so pl. 1b2-164 ° C (recrystallized from ethanol-ether mixture, yield 52 g from 73.6 g of 2,6-dimethylphenyl isocyanate).
    Calculated,%; C, 60.08; H 8.74; N 14.02; C1 11.83.
    C, fH2f N, 0 HC1
    40
    50
    55
    3
    Found,%: C 60.02; H 8.97; N 14.02; C1 11.83.
    Phosphate, so pl. 194-195 ° C (recrystallized from ethanol, yield 4.9 g from 10.0 g of free base).
    Calculated,%: C 49.85; H, 7.81; N 11.63.
     ,
    Found,%: C 49.48; H 7.89; N 11.54.
    PRI me R 3. (n-propylamino) -propsch-1H-2, 6-dimethylfensh1 urine.
    A solution of 14.7 g of 2,6-dimethylphenyl isocyanate and 50 ml of dichloromethane is added to a stirred, cooled solution of 40 g of K-n-propyl-1,3-diaminopropane and 350 ml of dichloromethane. The temperature is kept at room temperature for 45 minutes. The solution is extracted with water, then 200 ml of 20% hydrochloric acid. The acidic solution is made basic with a saturated solution of sodium carbonate. The basic mixture is extracted with dichlorome. The dichloromethane solution is dried over magnesium sulfate, then evaporated to dryness. The residue is treated with p-toluene sulfonic acid to form the salt. After recrystallization from ethanol-ether mixture, (n-propylamino) -PROPIL-N -2,6-dimethylphenyl urea, 4-methylphenylsulfonate, m.p. 157-159 ° С, yield 12 g.
    Calculated,%: C 60.66; H 7.645 N 9.65; S 7.36.
    C yH jNjO- C / rljSOg
    Found,%: C $ 61.01; H, 7.47; N 9.77; S 7.09.
    EXAMPLE 4 N-1H- (isopropyl-amino) propyl —N — (2,5-dimethylphenyl) urea.
    A solution of 14.7 g of 2,5-dimeshphenyl isocyanate and 50 ml of dichloromethane is added to a stirred stirred solution of 35 g of isopropyl-1,3-diaminopropane and 400 ml of dichloromethane. The temperature is maintained between (-) 5 and the addition time. Stirring is continued at room temperature for 1 hour. The solution is extracted with water, then 200 ml of 15% hydrochloric acid (v / v). The acid extract is made basic with a saturated solution of sodium carbonate and extracted with dichloromethane. The dichloromethane solution is dried with magnesium sulfate, then evaporated to dryness. Osta
    44245
    the current is dissolved in ether and saturated with hydrogen chloride. The solid is separated and recrystallized from ethanol-ether to obtain (isopropylamino) propyl-N - (2, 5-dimethylfgnyl) urea, hydrochloride, m.p. 152-154 C, yield 12 g.
    Calculated but%: C 60.08; H 8.74; 10 N 14.02; C1 11.83. HC1: Found: C, 59.97; H 3.77; N 14.03; C1 11.74.
    PRI me R 5. (Isopropyl-15 amine) -propyl J-N - (5-chloro-2-methylphenyl) urea.
    A solution of 16.7 g of 2-methyl-6-chlorofenyl isocyanate and 50 ml of dichloromethane is added to a stirred, cooled 20% solution of 35 g of N-isopropyl-1,3-diaminopropane and 250 ml of dichloromethane. The temperature is maintained at (-) 5 - during the addition. Stirring is continued at room temperature for 25 minutes. The precipitated solid is separated by filtration. The filtrate is extracted with water; then 200 ml of 15% hydrochloric acid (v / v). The acidic extract is made basic with a saturated solution of sodium carbonate, then extracted with dichloromethane. The dichloromethane solution is dried over magnesium sulfate, then evaporated to-35 dry. The residue is dissolved in ethanol and nash; ayut hydrogen chloride. The solution is evaporated to dryness. The residue is ground to powder with ether until it solidifies. The solid is recrystallized from ethanol-ether to give (isopropylamino) -propyl-N - (5-chloro-2-methylphenyl) urea, hydrochloride, m.p. 180-183 ° C, yield 6.5 g.
    45 1
    Calculated,%: C 52.50; H 7.24; . N 13.12; C1 22.14. C, 4 HjjNClO-HC1
    Found,%: C 52.41; .H 7.08 50 N 13.32; C1 21.98.
    PRI me R 6. (H-ByT} inaMH- but) -propyl -N - (2,6-dimethylphenyl) urea.
    A solution of 19.4 g of S-n-butyl-1,3-di-55 aminopropane, 20.5 g of p-anisaldehyde and 200 ml of toluene is refluxed in a flask equipped with a water separator. After 4 hours, the solution is evaporated to dryness in vacuo to give
    36.5 g of H-anisipidin-N n-butyl-1,3-β-dinaminopropane.
    A solution of 20.5 g of 2,6-dimethylphenyl isocyanate in 50 ml of chloroform is slowly added to a solution of the said anisylidene derivative in 100 ml of chloroform. This mixture was heated under reflux for 2 hours after the addition was complete. The solvent was removed in vacuo to give 57 g of H-3- (p-anisylideneaminopropyl) -N-2, .b-dimethylphenyl-M- (n-butyl) -urea as a viscous liquid.
    A mixture of these urea derivatives, 28.7 g of hydroxylamine p-toluene sulfonate and 200 ml of dioxane is refluxed for 15 minutes. The solvent is removed in vacuo. The residue is triturated in boiling ether until it solidifies. The solid is separated and recrystallized from acetonitrile to obtain 17 g of N- (3-butyl-amino) propyl-N - (2,6-dimethylphenyl) - urea, 4-methylbenzenesulfonate, mp 138-140 ° C,
    Calculated,%: C, 61.44; H, 7.85; N, 9.35; S 7.13.
    ,
    SO,
    Found,%: C 61.01; H 7.88; N 9.20; S 7.11.
    PRI me R 7.
    (Isopropylamino) propyl —N - - (2,5-dimethylphenyl) urea (A).
    H- 3- {Isopropylamino) propyl —N - - (5-chloro-2-methylphenyl) urea (B).
    (n-propylamino) propyl -N -. - (2,6-dimethylphenyl) urea (C).
    The above compounds were prepared by the reaction of N-isopropyl-1,3-β-diaminopropane (A and B) or Nn-propyl-1,3-diaminopropane (C) with p-anis aldehyde, carried out according to the method of Example 1 , with the formation of N- -anisylidene-N-isopropyl-1Z3-diamino propane (A and. B) or NI-anisylidin-N-N-PROPSH1-1.3-Dianopropane (C). This anisylidine compound is then reacted with a 2,5-dimethylphenyl isocyanate (A), 5-chloro-2-methylphenyl isocyanate (B) or 2,6-dimethylphenyl isocyanate (C), respectively, in the same way as Method 2a. After isolating the resulting product and dissolving it in an organic solvent, the resulting solution is treated with hydroxylamine p-toluenesulfonate with heating (at
    boiling solvent) in order to simultaneously carry out the removal of the protective group and rearrangement with the formation of the corresponding products
    (A, B, and C) as 4-methylphenylsulfonate. If it is desired to obtain a free base, the 4-methylphenylsulfonate salt is treated with 50% NaOH solution, extracted with methylene chloride, dried over magnesium sulfate and evaporated to dryness. The resulting free base may be converted to another acid salt by treatment
    diluted: an acid such as hydrochloric or phosphoric,
    PRI me R 8. H-3- {Butylamino) - prop-N-t (2,6-dimethylfeNIL) urea.
    The title compound was also prepared by reacting 2,6-dimetry phenyl isocyanate with Mn-butyl-1,3-diaminopropane according to the method of Example 2b.
    PRI me R 9. N-EZ-Sisopropylamino) propyl-K - (5-bromo-2-methylphenyl) - carbamide.
    Following Example 5, a solution of 2-methyl-5-bromophenyl isocyanate (21.1 g) and dichloromethane (50 ml) is added to a stirred, cooled solution of K-isopropyl 1,3-di-aminopropane (35 g) in dichloromethane (250 ml ). During the addition, the temperature is kept in the range from (-) 5 to. Received
    the reaction mixture is stirred at room temperature for 20 minutes. The resulting solid was collected by filtration. The filtrate is extracted with water, then 200 ml of 15% hydrochloric acid (by volume per volume). The acidic extract is made alkaline with a saturated sodium carbonate solution, then extracted with dichloromethane. Dichloromethane
    the solution is dried over. magnesium sulfate, then evaporated to dryness, which gives H-3- (isopropylamino) propyl- (K -5-bromo-2-methylfensh1) urea as an amorphous solid residue.
    50
    Urea free product
    dissolved in ethanol and saturated with hydrogen chloride. The resulting solution is evaporated to dryness in vacuo. The residue 55 is triturated with ether until it solidifies. The solid is recrystallized from ethanol-ether to give (isopropyl-amino) propylJ-N (5-bromo-3-methylfe-7P
    Nile) carbamide, hydrochloride, so pl. 180-2 ° C, yield 7.4 g
    Example 10. Suppression of arrhythmias using compounds of formula I can be demonstrated by the following experiments.
    In each experiment, dogs of both sexes were given 35 mg / kg sodium pentobarbital (intravenous) for anesthesia. Apply positive pressure respiration with room air. Blood pressure is recorded from the femoral artery using a pressure transducer and an oscilloscope.
    Suppression of fibrillation (scintillation) of the ventricle, stimulated by electricity (fibrillation threshold, measure of action).


    The fibrillation threshold is the voltage at which ventricular fibrillation is produced by an external electrical stimulator supplied to the left ventricle during the regeneration phase of the myocardium. In this test, the antiarrhythmic activity of the compound is assessed by its ability to increase the fibrillation threshold in anesthetized dogs.
    Ventricular fibrillation is obtained in
    anesthetized dogs due to stimulation of the left gastric epicardium for 5 seconds with a pulsation duration of 3 ms at a frequency of 60 Hz. Stimulation is obtained using bipolar platinum electrodes; 3.5 mm apart, placed in a plastic casing, measuring 7 x X 12 mm, which is attached to the epicardium. A chain of stimuli is transmitted by an R-wave electrocardiogram with increasing intensity (volts) at intervals of 1 minute until fibrillation occurs. The animal is defibrillated by means of a C-countercurrent (direct current) and this sequence is repeated after 10 minutes. The leukostavo test is administered internally through 5
    10 min. The fibrillation threshold is determined before injection and 10 minutes after the injection of each dose of medication. An increase in the threshold of at least 75 h is considered inactive; + 75-99 V is considered the boundary line-, + 1.0-1.24 V counts with a weak effect; + 1.25-1.99 B- - moderate; and +2.0 V or more - significant.
    eight
    When tested in accordance with the indicated method, the compounds described in examples 2-6 give a moderate or significant increase in the fibrillation threshold at a dose of 10-20 mg / kg (the compounds were tested as an acid addition salt). No differences in the activity of the fibrillation threshold between the phosphates and hydrochlorides of the compounds of Example 2 were observed. An increase in the interval was observed in the compound of Example 5.
    The results of increasing (+ standard deviations) fibrillation threshold 5 for compounds of Examples 2-6 at doses of 10 and 20 mg / kg are given in Table. one.
    Table 1
    O
    20
    25
    35
    4 dogs with 10 mg; 2 dogs are given an additional 10 mg.
    The data for the compound of Example 2 40 refers to both the hydrochloride and tosylate of the compound.
    Suppression of gastric cardiac arrhythmia caused by strophanthin.
    Intravenous administration of strophanthin leads to ventricular arrhythmias. In this experiment, the antiarrhythmic activity of a compound is determined by its ability to restore normal
    heart rate in dogs treated with strophanthin and anesthetized with pentobarbital, strophanthin is administered intravenously, the dogs are anesthetized at an initial dose of 50 µg / kg, and then the doses are increased until the ventricular arrhythmias (rapid ventricular or ventricular tgkycardi). A total dose of 55–60 mcg / kg is usually sufficient to
    cause arrhythmia. Then, the test compound was administered intravenously 3-5 minutes after 20 minutes after administration of strophanthin, and its effect on arrhythmia was observed. Drug administration is stopped when a return to normal heart rhythm is observed. In untreated dogs, arrhythmias last more than 45 minutes.
    The compound of Example 2b as tosilate restores normal heart rate in all of the 4 taken to restore normal heart rhythm (2 dogs)
    Heart rate improvement (1 dog)
    Recovery of normal heart rhythm
    ten
    3.0 Restoration of sinus rhythm. Connecting rhythm (improvement)
    7.5 Restoration of sinus rhythm
    Suppression of ventricular arrhythmias caused by a coronary ligature (imposition of ligature on a vein).
    The ligature of the left anterior descending coronary artery in two stages for 20 minutes leads to a ventricular arrhythmia, which begins after 5-7 hours and lasts about 48 hours. On the third day, the arrhythmias stop and normal rhythm returns. Arrhythmias are especially strong in the first 24 hours after applying a ligature. In this experiment, the activity against arrhythmia of the test compound is evaluated by its ability to restore normal heart rhythm in coronary ligated dogs. On the left anterior descending coronary artery of anesthetized dog, a ligature is applied in two stages at the level of the atrial
    the tank at a dose of 7.5 + 1.7 mg / kg, and the hydrochloride restores normal heart rate in seven out of eight dogs at 6.8 ± 1.1 mg / kg. The remaining dogs in the latter group are observed. reduction of arrhythmia, but due to the absence of a p-wave in the ECG, the connecting rhythm is indicated. However, it is considered that this dog received a greater than normal dose (70 µg / kg) of strophanthin.
    In testing, the compounds of Examples 3-6 yield the results given in Table. -2
    Table 2
    Also
    scion. The animal departs from anesthesia, and the test compound is administered to the dog, which is conscious, intravenously or orally (via the gastric tube) 18-24 hours after applying the ligature. The test compound is administered until normal heart rate is restored.
    When administered intravenously after approximately 24 hours of applying a ligature in accordance with the described method, the compound of Example 2 as tosylate or hydrochloride restores the normal heart rhythm completely to all of the six dogs in production at a dose of 15-20 mg / kg. For two animals, the compound was administered additionally so that the total dose was greater than 40 mg / kg. Hot animal
    P
    deaths
    turned out to be weaker, was not observed. The example compound restores the normal heart rhythm in two of the two taken at a dose of 10 mg / kg. The compound of example 4 restores normal heart rate in three out of four dogs at a dose of 14-15 mg / kg (c, b.). In the fourth dog, no improvement was observed at a dose of 20 mg / kg. The compound of Example 5 restores the normal heart rhythm of four dogs taken at a dose of 8–20 mg / kg (im). The compound of example 6 restores the normal heart rhythm in two of the two taken dogs with the introduction (IV) in accordance with the specified method
    at a dose of 20 mg / kg. I
    When tested in accordance with
    By this method, administered orally after about 24 hours after the ligature was applied, the compound of Example 2, taken as tosylate, restored the heart rate at a dose of 40-50 mg / kg in eight of nine dogs. Although several animals developed temporary weakness, none of the eight dogs showed serious








    or prolonged side effects. At 30, normal recovery is observed.
    A dose of 35 mg / kg in two out of three animals restored a high degree of normal heart rhythm without any side effects.
    When administered orally with Compound 35 of Example 2 as a hydrochloride at a single dose of 50 mg / kg, the normal heart rate is restored, but using the compound gives general weakness and two out of eight dogs died. 40 of the same dose gives a normal heart. Three of the three dogs that were killed die the normal rhythm of six dogs from a six-unit dose of 75 mg / kg. However, upon oral administration of the compound of example 2 in the form of hydrochloride in separate doses, after two hours, which in the total of 45 P P a dose of 25 mg / kg receive a rate of 50 mg / kg, the restored heart rate in two of the three heart rate rhythms without adverse effects. One dog has unsteady
    50
    heart rate in one of the three dogs and do not observe any significant effect in the other two dogs.
    When administered orally with the compound of example 5 as tosylate in an amount of 50 mg / kg, less than 50% of the normal heart rate is observed. Hydrochloride (salt), administered orally at
    In five and six dogs in six, this effect is prolonged from 4 to 6.5 hours. When the compound is given orally, there is a significant improvement in the prevailing normal rhythm in the third dog.
    improvement, and a slight (short) recovery of the normal heart rhythm is observed after an additional dose of 15 mg / kg has been administered. In the second dog and with an initial dose of 25 mg / kg, a slight improvement is obtained, but with an additional dose of 25 mg / kg, a prolonged recovery of the normal heart rate is obtained.
    When administered orally with the compound of Example 6 at a dose of 50 mg / kg, a normal heart rhythm is obtained in one dog, but this dose was the cause of the 55 poor condition of the dog.
    Comparative data of the biological activity of compounds of similar structure are presented in table. 3-6.
    12
    When tested in accordance with the described method when administered orally after about 48 hours after applying the ligature of the compound of the example
    B
    2, taken as tosylate or hydrochloride, restoration of the normal heart rate was observed in four of the five dogs at a dose of 15 µg / kg.
    0 At this dose, a significant improvement is observed in one dog. When the compound of Example 2 is administered in the form of either tosylate or hydrochloride at a dose of 25 mg / kg, recovery is observed
    5 normal heart rhythms in six of seven dogs. Significant improvement is observed in one of the dogs at this dose, and the restoration of a normal heart rhythm is observed in an animal after administration of an additional dose of 15 mg / kg.
    The tosyl salt of the compound of Example 2 is preferred for oral administration, and its hydrochloride salt is preferred for administration by injection.
    When the compound of Example 4 was orally administered in accordance with the described procedure in an amount of 50 mg / kg, the same dose, gives a normal heart rhythm in six dogs from six times the dose of 25 mg / kg given, a normal heart rhythm is obtained in two dogs. three
    heart rate in one of the three dogs and do not observe any significant effect in the other two dogs.
    When administered orally with the compound of example 5 as tosylate in an amount of 50 mg / kg, less than 50% of the normal heart rate is observed. Hydrochloride (salt), administered orally at
    In the same dose, giving a normal heart rhythm in six dogs, from a given dose of 25 mg / kg, a normal heart rhythm is obtained in two of three dogs.
    In five and six dogs, this effect is prolonged from 4 to 6.5 hours. When administered orally with a compound at the same dose, it gives a normal heart rhythm in six dogs from 25 mg / kg received a normal dose of 25 mg / kg. heart rate in two out of three
    dogs and a significant improvement in the prevailing normal rhythm in the third dog.
    When administered orally with the compound of Example 6 at a dose of 50 mg / kg, a normal heart rhythm is obtained in one dog, but this dose was the cause of the 55 poor condition of the dog.
    Comparative data of the biological activity of compounds of similar structure are presented in table. 3-6.
    (Isopropylamino) propyl j-N - (2-chloro-6-methyl-phenate) urea (comparative)
    (Isopropylamino) propyl J-N - (5-chloro-2-methylphenyl) urea (Example 5)
    Strengthening the effect of the proposed compound,%
    (Dimethylamino) propyl JN-2,6-dimethylphenyl urea (comparative) 0.1 + 0.1. 0.75 + 25
    (Isopropylamino) -propyl -2,6-dimethylphenylurea1, 9 + 0.4
    The improvement provided by the proposed connection,%
    Compound
    Increase the threshold. B, with a dose
    10 mg / kg
    L- (3-Isopropylaminopropyl) -m-C2,6-dimethylphenyl) urea (proposed) I N- (3-Diisopropyl-amino-propyl) -n - - (2,6-dimethylphenyl) - urea ( comparative) ii


    Table3
    3.13 + 4
    , 8 + 5
    280
    2.9 + 3
    1900
    386
    T a b l and c a b
    The presence of AU-blockade
    20 mg / kg
    3.1 + 0.3 (g 12)
    No AU-blockade
    4.1 + 1.1 (p 2)
    Two dogs have AU blockade, and the first
    Compound Increase threshold. B, Availability of AU-blockade
    at dose
    10 mg / kg20 mg / kg
    dogs AU-blockade and death at a dose of 10 mg / kg
    N-3-Mono (n-butylamino-n) pproshl-N - (2,6-dimethylphenyl) urea (proposed) III 2.6 + 0.6 4.1 + 1.1 Without AU blockade
    (n-butylamino) - propyl-N - (2,6-dimethylphenyl) urea. .
    (comparative) IV 3,5 + 0,9 - The first dog has a gender (p 3) on AU-blockade with
    a dose of 10 mg / kg, death
     at a dose of 5 mg / kg (2.5 + 2.5 dl for two of three dogs).
    Table
    Test p Dose, Effect Duration, Availability of mg / kgmin compound AU-blockade
    117.1 + 1.1
    15.0
    16.0 BEZZE
    .23,9
    13.0
    13.5 Ambient SR
    SR normal sinus rhythm
    42.8 ± 1.5 Without AU blockade
    20
    AU-blockade and death
    No AU blockade
    Moderate AU blockade
    7
    The results presented in Table 3 show that the proposed 5-chloro-2-methylphenyl compound significantly increases the threshold - by A66% at a dose of 10 mg / kg and by 280% at a dose of 5 .20 mg / kg compared with an increase in the threshold, provided with a reference 2-chloro-6-methylphenyl compound.
    The results presented in table. And, they say that for a comparative compound as an antiaritic agent, the increase in the threshold is not achieved at a dose of 10 mg / kg (it is practically close to zero), and
    3 mg / kg, intravenously. The use of a comparative compound, the K-GZ- (di-n-butylamino) propyl 1-2, 6-dimethylphenylurea standard, results in an increase in FT at a dose of 5 mg / kg, an equivalent increase that was observed when using mono-n-butyl compounds with a dose rate of 10 mg / kg, indicating a slightly higher activity of the first compound. However, in contrast to the mono-n-butyl compound, in the case when the initial dose of the di-n-butyl compound was doubled, in one dog
    at a dose of 20 mg / kg, a slight increase was observed;
    telny. The proposed compound exhibits moderate and pronounced activity at two values of the comparable dose and a percentage increase of 1900 and 386%, respectively, at these two doses compared with the comparative compound.
    The antiarrhythmic efficacy of N-MOHO- and dialksiamino-propsht-K-2,6-dimethylphenylureas is evaluated for two. standard. models of cardiac vaginal arrhythmia in dogs. The fibrillation threshold provides a measure of the electrical stability of the heart, and also allows the determination of drug-induced changes (electrocardiographic changes, example 2) of the normal electrical activity of the heart (see example 9). The second test, Quabain induced arrhythmia, provides an assessment of the antiarrhythmic activity of a non-normal heart (see Example 9). In addition, due to the nature of Quabain's action on atrioventricular conductivity, this test also demonstrates the potential of a drug to block an anti-ventricular conductivity (AU-blockade) - a serious and limiting side effect that may limit the clinical use of the compound.
    (n-Butylamino). Propyl -2, methylphenylurea (Example 6) gives a significant increase in the fibrillation threshold (FT) at a dose of 10 mg / kg. Increasing the dose to 20 mg / kg does not lead to
    The same activity pattern for the n-butyl analog is used to compare the monoisopropyl and di-isopropyl analogs. (Iso-propylamino) propyl -N-2,6-dimethyl-phenylurea (Example 2) gives a significant increase (2.04 + O, ZU) FT at a dose of 10 mg / kg. Increasing the dosage to 20 mg / kg leads to a further increase in FT, and in the 35 dogs tested, the AU-blockade is not observed (P 19); It was established that a mono-isopropyl compound restores FF in all dogs with toxicity at a dose of 7.1 + 1.1 mg / kg. In all tested dogs, no AU-blockade (p 11) was observed with (Diisopropshtamino) pr -2, -6-dimethylphenylurea giving an equivalent increase in FT at doses of 10 and 20 µg / kg. Diisopropyl compound gives a complete AU blockade and results in the death of one dog at a dose of 10 mg / kg. Complete AU-blockade occurs in two other dogs with dosage up to 10-: 20 mg / kg. When a diisopropyl compound is tested against Quabain-arrhythmias, one dog has an AU blockade and is killed at a dose of 5 mg / kg, while
    An AU-blockade, however, further enhances T. This compound also manifests an exceptionally successful transfer of this low efficacy against Quabain-DOS. arrhythmias, providing normal sinus rhythm (SR) in both dogs, which have been tested dose
    Therefore, the potential for the occurrence of a dangerous and even fatal AU blockade during dosing, lying
    five

    424518
    3 mg / kg, intravenously. The use of a comparative compound, the K-GB- (di-n-butylamino) propyl 1-2, 6-dimethylphenylurea standard, results in an increase in FT at a dose of 5 mg / kg, equivalent to the increase observed with the mono-n-butyl compound. at a rate of 10 mg / kg, which indicates a slightly higher activity of the first compound. However, in contrast to the mono-n-butyl compound, in the case when the initial dose of the di-n-butyl compound was doubled, in one dog
    5 was observed full blockade of AU and she
    0
    five
    0
    gp
    perished. The ability of the di-n-butyl analogue to give a complete AU-blockade was further confirmed by Quabain data. At a dose of 3 mg / kg, SR (100%) was restored in one dog for only 20 minutes. At a slightly higher dose (3.5 mg / kg) in one dog, a complete AU-blockade was observed before full recovery of SP.
    The same activity pattern for the n-butyl analog is used to compare the monoisopropyl and di-isopropyl analogs. (Iso-propylamino) propyl -N-2,6-dimethyl-phenyl urea (example 2) gives a significant increase (2.04 + O, ZU) FT at a dose of 10 mg / kg. Increasing the dosage to 20 mg / kg leads to a further increase in FT, and in the 35 dogs tested, no AU-blockade is observed (P 19); It was established that a mono-isopropyl compound restores FF in all dogs with toxicity at a dose of 7.1 + 1.1 mg / kg. No AU-blockade (p 11) with (Diisopropshtamino) pro-2, -6-dimethylphenylurea gives an equivalent increase in FT at doses of 10 and 20 µg / kg in all tested dogs. The diisopropyl compound gives a complete AU blockade and results in the death of one dog at a dose of 10 mg / kg. Complete AU blockade is manifested in two other dogs at doses of 10-: 20 mg / kg. When a diisopropyl compound is tested against Quabain-arrhythmias, one dog is pro-active with an AC blockade and dies at a dose of 5 mg / kg, while
    0
    45
    55 successfully carries this dosu.
      successfully carries this Ozu.
    Therefore, the potential for dangerous and even fatal AU-blockade to occur while lying down
    15
    in the therapeutic range of values, should prevent the clinical use of dialkylaminopropyl substituted analogs, while the proposed monoalkipamino propyl compounds do not possess such a dangerous property.
    权利要求:
    Claims (2)
    [1]
    1. A method for the preparation of common K- (3-alkyl-aminopropyl) -N-phenylmochine. formulas
    Y-NH-CO-NH-CH CH jCH-SHH, where Y is 2,6-dimethylphenip, 2,5-dimethylphenyl, 5-chloro-2-methylphenyl, 5-bromo-2-methylphenyl} X - n-propyl, isopropyl, n-butyl, or their pharmacologically acceptable salts, characterized in that the substituted phenyl isocyanate of the general formula
    ,
    where Y has the indicated meanings, is reacted with diaminopropane of the general formula
    H N-CHjCHjCH HNX, where X has the indicated values, in the medium of an organic solvent at a temperature of (-5) - (+ 24) C, followed by separation of the target product in free form or in the form of pharmacologically acceptable salts.
    [2]
    2. The method of obtaining L- (3-alkyps 20
    25
    Y-NH-CO-NH-CHjCHjCHjNHX,. where Y is 2,6-dimethylphenyl, 2,5-dimethylphenyl, 5-chloro-2-methylphenyl, 5-bromo-2-methylphenyl, X is n-prrpyl, is isopropyl, n-buti or pharmacologically acceptable salts, characterized in that the substituted phenyl isocyanate of the general formula
    ,
    where Y has the indicated meanings, is reacted with a substituted diaminopropane, of the general formula
    Z-Tffi-CH CH CH-NHX, where X has the indicated meanings,
    Z - protective group, to obtain compounds of general formulas
    Y-NH-CO-NH-CH CH CH NHZ, X
    where Y, X, Z have the indicated values, followed by simultaneous deprotection and rearrangement in an organic solvent at boiling point and isolation of the target product in free form or in the form of pharmacologically acceptable salts.
    Priority featured:
    03. 07.78 with Y — 2,6-dimethylphenyl, 2,5-dimethylphenyl, 5-chloro-2-methylphenyl, X — n-propyl, isopropyl, n-butyl radical
    05.21.79 at Y - 5-bromo-2-methylnopropl) -p-phenylurea of the general form-35 phenyl, X - pr opil, isopropyl, n-bromyl ethyl radical.
    Editor N.Egorova Order 4839/58
    Compiled by M. Merkulova
    Tehred I.Popovich Proofreader A.Obruchar
    Circulation 371 Subscription
    VNIIPI USSR State Committee
    for inventions and discoveries 113035, Moscow, Zh-35, Raushsk nab., 4/5
    Production and printing company, Uzhgorod, st. Project, 4
    O
    five
    0
    0
    five
    Y-NH-CO-NH-CHjCHjCHjNHX,. where Y is 2,6-dimethylphenyl, 2,5-dimethylphenyl, 5-chloro-2-methylphenyl, 5-bromo-2-methylphenyl, X is n-prrpyl, is isopropyl, n-butyl, or pharmacologically suitable salts, characterized in that the substituted phenyl isocyanate of the general formula
    ,
    where Y has the indicated meanings, is reacted with a substituted diaminopropane, of the general formula
    Z-Tffi-CH CH CH-NHX, where X has the indicated meanings,
    Z is a protecting group to give compounds of the general formula
    Y-NH-CO-NH-CH CH CH NHZ, X
    where Y, X, Z have the indicated values, followed by simultaneous deprotection and rearrangement in the medium of an organic solvent at boiling point and isolation of the target product in free form or in the form of pharmacologically acceptable salts.
    Priority featured:
    03. 07.78 with Y — 2,6-dimethylphenyl, 2,5-dimethylphenyl, 5-chloro-2-methylphenyl, X — n-propyl, isopropyl, n-butyl radical
    05.21.79 with Y - 5-bromo-2-methyl
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    同族专利:
    公开号 | 公开日
    SG76284G|1985-04-26|
    GB2025406B|1982-11-03|
    DK150902B|1987-07-13|
    EP0007184B1|1982-06-30|
    AU4828479A|1980-01-10|
    JPS55500480A|1980-07-31|
    DE2963228D1|1982-08-19|
    HK100484A|1985-01-04|
    KE3482A|1985-01-04|
    SU1367855A3|1988-01-15|
    PH15733A|1983-03-18|
    CA1109487A|1981-09-22|
    JPH0140026B2|1989-08-24|
    EP0007184A1|1980-01-23|
    GB2025406A|1980-01-23|
    IN150133B|1982-07-31|
    DK150902C|1987-11-16|
    MY8500466A|1985-12-31|
    AU519836B2|1981-12-24|
    DK88480A|1980-02-29|
    CY1272A|1985-03-08|
    WO1980000151A1|1980-02-07|
    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    US2681929A|1950-08-05|1954-06-22|Searle & Co|Aryl and aralkyl derivatives of dialkylaminoalkylureas|
    US2673878A|1952-06-06|1954-03-30|Searle & Co|Derivatives of basically substituted 1-alkyl-3-aryl ureas|
    DE935127C|1952-06-10|1955-11-10|Geigy Ag J R|Process for the preparation of N-aryl-N'-aminoalkylureas|
    US2762842A|1952-06-10|1956-09-11|Geigy Ag J R|N-aryl-n'-aminoalkyl-ureas|
    US2744930A|1954-08-04|1956-05-08|Olin Mathieson|N, n-diphenyl-n'-aminoalkylene-urea derivatives|
    GB778647A|1955-02-24|1957-07-10|Cilag Ltd|Novel ureas and salts thereof and a process for their production|
    US3140286A|1962-01-11|1964-07-07|Searle & Co|Nu--nu-phenyl-nu'-2[-piperidino]-ethyl ureas|
    US3933833A|1974-05-30|1976-01-20|The Dow Chemical Company|Phenyl -thiourea, -carbothioamide and -carbonothioamide derivatives|
    US4066695A|1976-04-15|1978-01-03|Hoffmann-La Roche Inc.|Thiourea derivatives|JPH0213665B2|1985-02-21|1990-04-04|Tokuyama Soda Kk|
    DE3861988D1|1987-07-02|1991-04-18|Warner Lambert Co|N--phenyl)-harnstoff und -carbamat-inhibitoren der acyl-coenzym a:cholesterol-acyltransferase.|
    GB8915131D0|1989-06-30|1989-08-23|Wyeth John & Brother Ltd|Substituted 1,3-diaminopropanes|
    AU6578090A|1989-11-06|1991-05-09|Warner-Lambert Company|Acat inhibitors|
    FR2679555B1|1991-07-25|1993-11-19|Fabre Medicament Pierre|NEW DERIVATIVES OF UREAE, THEIR PREPARATION AND THEIR APPLICATION IN THERAPEUTICS.|
    ES2141763T3|1992-03-31|2000-04-01|Glaxo Group Ltd|SUBSTITUTED PHENYL CARBONATES AND PHENYLENE, THEIR PREPARATION AND USE AS ANTAGONISTS OF 5-HT4.|
    GB9206989D0|1992-03-31|1992-05-13|Glaxo Group Ltd|Chemical compounds|
    CA2142110A1|1992-08-19|1994-03-03|Paul S. Wright|Antiangiogenic oligomers|
    US5384119A|1993-08-12|1995-01-24|Merrell Dow Pharmaceuticals Inc.|Method of preventing neutrophil mediated connective tissue damage|
    JP4607469B2|2003-01-29|2011-01-05|三洋化成工業株式会社|Urethane resin and method for producing powder thereof|
    法律状态:
    优先权:
    申请号 | 申请日 | 专利标题
    US05/921,295|US4224242A|1978-07-03|1978-07-03|N-[3-alkylaminopropyl]-N'-phenylureas|
    US4060879A| true| 1979-05-21|1979-05-21|
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