• 专利附录
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    • 专利摘要:
    1505543 Benzodiazepines RICHTER GEDEON VEGYOSZETI GYAR RT 23 May 1975 [29 May 1974] 22696/75 Heading C2C Racemic and optically active compounds of the general formula (R 1 = H, halogen, CF 3 , NH 2 , NO 2 ; R 2 = H, alkyl; R 3 = acyl group derived from carbonic acid or a derivative thereof or an optionally substituted aliphatic, alicyclic or aromatic carboxylic acid; R 6 = phenyl, halophenyl; provided that if the compound is racemic, R 2 is C 1-6 alkyl and (a) R 1 is H or halogen, R 3 is not a carbamoyl group having a C 1-6 alkyl, C 2-6 alkenyl, cyclohexyl, phenyl or benzyl substituent, or (b) R 1 is halogen or CF 3 , R 3 is not C 2-7 alkanoyl) are prepared by acylation, optionally followed by introduction of an amino or substituted amino group and/or alkylation. An amino substituent in the acylating agent may be protected during the reaction. The above compounds are tranquillo-sedatives, and may be administered in the form of pharmaceutical preparations containing them in association with a carrier.
    公开号:SU1318158A3
    申请号:SU782663501
    申请日:1978-09-18
    公开日:1987-06-15
    发明作者:Рерихт Юлия；Кишфалудь Лайош；Юрегди Ласло；Палоши Ева；Себереньи Саболч；Спорни Ласло
    申请人:Рихтер Гедеон Ведьесети Дьяр Рт (Инопредприятие)；
    IPC主号:
    专利说明:

    one
    The invention relates to a method for the study of new derivatives of 4-substituted 1,3,4,5-tetrahydro-2H-1,4-benzodiazepin-2-one of the general formula
    conHo
    where R is Cl or a nitro group;
     R - is an alkyl radical containing 1-4 carbon atoms with tranquilizing activity.
    The aim of the invention is to develop a method for producing 1,3,4,5-tetrahydro-2H-1,4-benzodiazepin-2-one derivatives with higher tranquilizing activity compared to the structural analogue 1-methyl-5- phenyl-7-chloro-1,3,4,5-tetrahydro-2H-1,4-benzodiazepin-2-one and diazepam and chlordiazepoxide, which are not inferior in activity to standard preparations, and less toxic than the latter.
    Example 1. 1-Methyl-4-carbamoyl-5-phenyl-7-chloro-1, 3,4,5-tetra, - HYDRO-2H-1,4-benzodiazepin-2-one.
    Suspension 1.7 g (4.87 mmol) of 1-methyl-4-chlorocarbonide-5-phenyl-7-chloro--1,3,4,5-tetrahydro-2H-1,4-benzodiazepin-2- It is in 3.5 ml of a concentrated ammonia solution and 7 ml of methanol. The mixture is stirred at room temperature overnight. The mixture is diluted with 30 ml of water, the crude product recovered is filtered off and recrystallized from ethanol without drying. 1.16 g (72%) of 1-methyl-4-carbomoyl-5-phenyl-7-chloro-1 ,, 3,4, 5-tetrahydro-2H-1,4-benzodiazepin-2-β-one is obtained; m.p. 212-215 ° C.
    Example 2. 1-Methyl-4-carbamoyl-5-phenyl-7-chloro-1,3,4,5-tetra-HYDRO-2H-1,4-benzodiazepin-2-one.
    Starting from an equivalent amount of 1-methyl-4-chlorocarbonyl-5-phenyl-7-nitro-1,3,4,5-tetrahydro-2H--1,4-benzodiazepin-2-one 5, in the conditions of example 1, target product with T.PL. 188-190 0 (from acetonitrile). Pharmacological testing. .
    On CFL R-mice of both sexes weighing 18–22 g. During defensive tests of chemo
    15
    20
    25
    81582
    The products were injected with viutribrushin one hour before the start of the study, and the reference compounds (diazepam and chlordiazepoxide) were orally administered also 5 hours before the start of the study. The study of anticonvulsant activity.
    1. The initial series of studies was performed according to the method of Everett and Richards. Test animals were injected subcutaneously with 125 mg / kg. One hour after administration, animals protected from the spasm of the tonic extensor and surviving animals were counted. The values of EDU, determined from these data by test analysis.
    2. Maximum electroshock irritation (100 Hz, 30 V, 0.2 s) was applied according to the Pig Rd method.
    and others. Animals that did not show tonic extension on the hind paw during irritation were considered protected.
    Antagonism of strychnine spasm. The spasm of the tonic extensor is made by administering an intraperitoneal dose of 2 mg / kg strychnine to animals. Animals not showing occurrence of spasm were considered protected.
    I
    Muscular Impairment Study
    coordination and ataxia.
    a.A rotating bar test was performed according to the method. The contour rollovers could simply last for 120 s on a rod rotating at a speed of 12 revolutions per minute. Values were calculated from the percentage of animals falling over
    40 120 s
    b. A pull test was also carried out according to the method. Two front paws of test animals are placed on a horizontal rod.
    45 so that animals can grab the rod. Control animals push their back paws onto the rod within 5 s. The UU values were calculated from the percentage of animals that show a negative reaction.
    Investigation of the anesthetic effect.
    As it is known, the liver cannot metabolize the sodium barbiturate. After 1 hour after administration of the compounds that were tested at different doses, 100 mg / kg of sodium barbiturate was administered intraperitoneally to the animals. Values
    They were calculated from the percentage of animals who fell asleep (control animals that received only sodium barbiturate at the indicated dose did not fall into the sleeping state).
    The enhancement effect on hexabarbital anesthesia was determined by the method of Riimke et al. By administering hexarbital at a dose of 60 mg / kg to the tail vein of mice one hour after administration of the compound in question. The change in the sleep period was expressed as a percentage relative to the control.
    Acute toxicity study.
    Tests were carried out at room temperature (), and the death of animals was observed within a week.
    Pharmacological data of 1-methyl-4-carbamoyl-5-phenyl-7 chloro-1,3,4,5, -tet 5-hydro-2H-1,4-benzodiazepin-2--one (compound A), determined with the indicated the tests are listed in Table 1, where for comparison the corresponding data of reference substances (diazepam and chlorodiapoxide) are also presented,
    As follows from Table 1, the inhibiting effect on tetrachoric spasm in 1-methyl-4-carbamoyl-5-phenyl-7-chloro-1,3,4,5-tetrahydro-2H-1,4-benzodiazepine -2-it is almost the same with that of diazepam, whereas this compound causes relaxation
    muscle and sedation only at higher doses. According to the received
    to the results, the indications of a new compound are more closely related to the indications of chlordiazepoxide than diazam pam, but as regards the doses that cause impaired muscle coordination, prolonged relaxation and increased effect of anesthesia relative to the dose causing anticonvulsant effects, the new compound A is noticeably more active, than reference substances
    The indicated dosage coefficients are listed in table 2.
    From Table 2 it can be seen that the anticonvulsant effect of 1-methyl-4-carbamoyl-5-phenyl-7-chloro-1, 3,4,5-tetrahydro-2H-1,4-benzodiazepin-2-one is the same with the action of diazelam, whereas its sedative effect and effect on muscle relaxation are weaker, and its therapeutic index is more preferable. A single intravenous dose of 5 kg / kg of the new compound prevents 50% of the animals from metrazol spasm even 7 hours after the administration.
    Thus, the compounds obtained by this method are superior in activity to the structural analogue and are not inferior in useful properties to the reference drugs, diazepam and chlordiasepoxide.
    权利要求:
    Claims (1)
    [1]
    Invention Formula
    The method of obtaining 4-substituted-1,3,4,5-tetrahydro-2H-1,4-benzodiazepin-2-one derivatives of the general formula.
     .0
    y / k (.
     Go1 I.
    where R is C1 or nitro;
    R is an alkyl radical containing 1 to 4 carbon atoms.: Characterized in that the compound of the general formula
    where R and R. have the indicated meanings, are reacted with a concentrated ammonia solution in a lower alcohol medium.
    2,470,66
    (1.06-6.41) (0.26-0.93)
    23, 519.3
    (15.9-34.3) (13.2-25.5)
    28, 426.0
    -
    Disappearance
    reflex-2.38
    p ml (193.9-275.3)
    Acute toxicity
    H.)
    815
    Compound
    Aitimetraol a, mg / kg
      .
    Diaeepai
    Chlo {) diazepoxide
    Companie A.
    When tested on the doctor
    rod,
     Antnstrihninova. U enhance the effects on anesthesia;
    Table 1

    1400
    1678 (1516-2564)
    Table 2
    4.3 7.6 5.2
    4.9 11.5 3.3
    10.2 39.4 13.3
    Structural
    1-methyl-5-phenyl-7-chloro-1, 3.4 analog,
    5-tetrahydro-2H-1, 4-benzodiazepin-2-one
    1-Methyl-4-β-carbamoyl-5-phenyl-7-chloro-1,3,4, 5-tetrahydro-2H-1,4-benzodiazine PIN-2-OH (compound A)
    1-Methyl-4-carbamoyl-5-phenyl-7-nitro-1, 3.4
    5-tetrahydride
    ro-2H-1,4-bezodiazepin-2-one
    Editor M. Kelemesh
    Compiler Konnova
    Tehred N.Glushchenko Proofreader L.Pnlipenko
    Order 2439/57 Circulation 372 Subscription
    VNIIII USSR State Committee
    for inventions and discoveries 113035, Moscow, Zh-35, Raushsk nab., 4/5
    Production and printing company, Uzhgorod, st. Project, 4
    Table 3
    41.3
    15.2 529.4
    19.3
    6.7 167,
    1.8
    2.4 500
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