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    • 专利摘要:
    The invention relates to phenylazalkanes, in particular compounds of the general formula 1 (CN) - (CH2) 3-NRffCONG CHECK (CH2) j-K2, where, R, Kj-Rj, R7, Rg-C H2-; Ri-H, C -WITH; -alkyl, CFj, C -C-alkoxy- or C, -C; -alkyl-mercapto, halogen, R2, R, R: y, Rg-H, C -C-alkoxyl; R is a straight saturated or unsaturated al-kil; Rf-H, C-C-alkyl; , alkoxy, halogen; R2 is ethylenedioxy- or 1,3-dioxatetramethylene group; , - ethylenedioxy- or methylenedioxy-group, as well as their oxalates, hydrochlorides and amide sulfonates, which have pharmacological activity. To reveal the last environment of phenylazalkanes, new I was obtained. Their synthesis is carried out from the corresponding K-CHR4-C N and X- (CE2 -NRj- - (CHj) j-K2, where K, K2, R4 are indicated above; X is halogen , followed by release of I in free form or in the form of the indicated salts. Tests I show that they are of little toxic and have antihypertensive, antiarrhythmic cardioprotective, antiallergic effect and show the ability to inhibit platelet aggregation, and these effects are better known, for example, verapamil .5 CO table of co.
    公开号:SU1308195A3
    申请号:SU823419898
    申请日:1982-04-09
    公开日:1987-04-30
    发明作者:Эрманн Оскар；Рашак Манфред；Гриз Йосеф；Кречмар Рольф；Дитер Леманн Ханс；Фридрих Людвиг；Вупперманн Дирк；Циммерманн Франк；Сейтц Вернер；Эрг Трейбер Ханс；Денгель Фердиненд；Франк Вольфрам；Курбювейт Ханс-Георг；Д.Мюллер Клаус
    申请人:Басф Аг (Фирма)；
    IPC主号:
    专利说明:

    This invention relates to a process for the preparation of new derivatives of omegacyano-1, omega-diphenylamine alkanes of the general formula
    IN
    five
    - (Rik
    where R is hydrogen, C -C alkyl, trifluoromethyl,. - alkoxyS-C - alkyl mercapto group halide;

    R, +
    R.
    hydrogen is an alkoxy group; R. is a straight saturated or non-saturated alkyl; R5 is hydrogen,. - alkyl; R is hydrogen, - alkoxy-,
    halogen, m 3; n 2; R is ethylenedioxy, 1,3 dioxatetramethylene; + R7 ethylenedioxy-, methylenedioxy,
    as well as to the method of their oxalate, hydrochloride, amidosulfonate production. These compounds have pharmacological activity.
    The aim of the invention is to obtain new derivatives of diphenylase alkanes, which, compared with compounds with a similar structure, have a higher activity and breadth of therapeutic action.
    The method is carried out as follows.
    Example 1. Preparation of 1,7-bis (3-ethoxyphenyl) -3-methylase-7-cyano-nadecane.
    In a three-necked flask equipped with a stirrer, an addition funnel, a reflux condenser, and a thermometer, 20.4 g (0.06 mol) of 1-cyan-1- (3-ethoxyphenyl) -tridecane (obtained in a two-phase system in the presence of a catalyst by alkylation of 3-ethoxyphenylacetonitrile with 1-bromodecane) and 16.9 g (0.06 mol) of 1-CHLOR-4-mets-1-6- (3-ethoxy-1) hexane (obtained from N-metsh-1-beta- (3- ethylene, siphenyl) -ethylamine and 1-bromo-3-chloropropane), which are dissolved in 100 ml of dry toluene. To the prepared solution with stirring and distemper
    In a round of 30 minutes, 9.3 g (0.07 mol) of a 30% sodium amide suspension in toluene is added dropwise, after which the mixture is stirred
    for the next 90 minutes at reflux temperature. The resulting reaction solution was poured into 200 ml of ice-cooled water, the toluene phase was separated.
    and washed twice with water. The toluene solution is mixed with hydrochloric acid, the toluene is distilled off under reduced pressure, after which the resulting residue is recrystallized from acetone. The result is 29.7 g (82%) of hydrochloride with so pl. 132-134 C. In a dialogous manner (Examples 2-42), the following compounds were prepared:
    2. Hydrochloride 1,7-bis- (2-methoxy-phenyl) -3-methylase-7-cyanonedecane,
    m.p. 60-69 ,, yield 70%.
    3. Hydrooxalate 1,7-bis- (3-methoxy-cyphenyl) -3-methylaza-7-cyanonadecane, m.p. 97-98 C. Monohydrate hydrochloride has so pl. 60-60,5 ° C, yield 89%.
    4. Hydrochloride 1,7-bis (4-methoxy-phenyl) -3-methylase-7-cyanonadecane, m.p. 114-116 0, yield 92%.
    5.Hydrochloride 1,7-diphenyl-3-methylase-7-cyanononecane, so pl. 112-115 ° C, yield 90%.
    0
    50
    6. Hydrooxalate 1,7-bis- (3-methoxyphenyl) -3-methylase-7-cyanocosane,
    5 m.p. 100-102 s, yield 88%.
    7. 1-Phenyl-3-methylase-7-cyano- (3-methoxyphenyl) -nonadecane hydroxalate, m.p. 91-93 s, yield 86%.
    8.Hydroxalate 1- (3-methoxyphenyl) -3-methylase-7-cyan-7-phenylnono-cana, m.p. 100-102 ° C, yield 91%.
    9.Hydrochloride, 1,7-bis- (3-ethoxyphenyl) -3-methylase-7-cyano-docosane, m.p. 100-113 s, yield 89%.
    10.Hydrochloride 1,7-diphenyl-3-methylase-7-cyanhexadecane, m.p. 109-111 ° C, yield 90%.
    11.1- (3-Methoxyphenyl) -3-methylase-7-cyan-7-phenylhexadecane, yield 88%.
    Calculated,%: C 71.3; H8.6; N 5.2. Found,%: C 71.1; H 8.6; N 5.2.
    12.1-Phenyl-3-methylase-7-cyan-7- (3-methoxyphenyl) -hexadecane, yield 91%.
    Calculated,%: C, 71.3; H, 8.6; N 5.2. Found,%: C -71.0; H 8.6; N5.3.
    13.1,7-Bis- (3-methoxyphenyl) -3-methylase-7-cyanhexadecane, yield 92%.
    Calculated,%: C69.7; H 8.5; N 4.9
    3130
    Found,%: C 69.7; H 8.5; N 5.0.
    14. Monohydrate of hydrochloride of 1- (3-chlorophenyl) -3-methylase-7-cyano-7- (3-methoxyphenyl) -nonadecane, so pl. 68-7GS, yield 87%.
    15.1- (3-Methoxyphenyl) -3-methylase-7-cyan-7- (4-chlorophenyl) -nonadecane, yield 94%.
    Calculated,%: C75.5; H, 9.4; N 5.3;
    C1 6.8:
    Found,%: C 75.5; H 9.4; N 5.3;
    C1 6.6:
    16.1- (3-methoxyphenyl) -3-methylase-7-cyano-7- (1,3-beneodioxanyl-6) -nadecan, yield 85%.
    Calculated%: C 76.6; H 9.6; N 5.1. Found,%: C 76.6; H 9.6; N 5.2
    17.1-Fensch-3-metalase-7-cyan-7- (1,3-benzodioxanyl-6) -nonadecan, yield 82%.
    Calculated,%: C 78.7; H9.7; N5,4. Found,%: C 78.4; H 9.7; N 5.5.
    18.1- (3-Methoxyphenyl) -3-methylase-7-cyano-7- (3-trifluoromethylphenyl) -none-decane, yield 89%.
    Calculated,%: C 73.0; H8.8; N 5.0 Found: C 73.1; H 8.8; N 5.0.
    19. 1- (3-methoxyphenyl) -3-methylase-7-cyano-7- (3,4-dimethoxyphenyl) -nonadecane hydrochloride, m.p. 96-98 ° C yield of 90%.
    20. Hydrochloride 1- (3-methoxyphenyl) -3-methylase-7-cyano-7- (3,4,5-trimethoxyphenyl) -nonadecane, m.p. 9395 C, yield 92%.
    21.1,7-Bis- (3-chlorofensh1) -3-methylase-7-cyannonadecane, yield 85%.
    Calculated,%: C, 72.6; H 8.8; N5.3; C1 13.4.
    Found,%: C 72.8; H 8.6; N5.5; C1 13.4 /
    22.1- (3-Methoxyphenyl) -3-metshlaaza-7-cyan-7- (3-chlorophenyl) -nonadecane, yield 87%.
    Calculated,%: C 75.5; H 9.4; N 5.5; C1 6.8.
    Found,%: C 75.6; H 9.4; N 5.3; C1 6.8
    23.1- (3-Methoxyphenyl) -3-methylase-7-cyano-7- (3,4-ethylenedioxyphenyl) -nadecane, yield 92%.
    Calculated,%: C76.6; H, 9.6; N, 5.1; Found: C, 76.4; H 9.3; N 5.1. 24. 1- (3-Methoxyphensh1) -3-methylaz7-cyan-7- (3-tolyl) -nonadecane, you
    move 92%.
    Calculated,%: C 80.9; H10.4; N 5.5. Found,%: C 80.6; H 10.1; N 5.5.
    five
    one
    five
    0
    -five
    0
    five



    954
    25.1,7-Bis- (3-methoxyphenyl) -3-methylase-7-cyanoctadecane, yield 90%.
    Calculated,%: C78.2; H, 9.9; N 5.5. Found,%: C 78.1; H 9.8; N 5.5.
    26.1- (3-Methoxyphenyl) -3-methylase-7-cyano-7- (3-n-butoxyphenyl) -nonadscan, yield 78%.
    Calculated,%: C78.9; H 10.4; N5.0. Found,%: C 78.8; NU, 5; N5,2.
    27.1- (3-n-Butoxyphenyl) -3-metsh-1-sa-7-cyano-7- (3-methoxyphenyl) -nonadecan, 75% yield.
    Calculated,%: C 78.9; H 10.4; N 5.0. Found,%: C 78.8; H 10.3; N 5.1.
    28. Hydrochloride 1,7--6 cis (3-n-butoxy-cyphenyl) -3-methylaza-7-cyano-dedecane, m.p. 127-129 ° C, yield 79%.
    29.1,7-Bis- (3-methoxyphenyl) -3-methylase-7-dian-17-octadecane, yield 88%.
    Calculated,%: C 78.5; H9.6; N 5.5. Found%: C. H 9.6; N 5.4.
    30.1 (3-Methoxyphenyl) -3-methylaz7-cyan-7- (3-fluorophenyl) -nonadecane, yield 85%.
    Calculated,%: C77.9; H, 9.7; N5.5, Found,%: C 78.0; H 9.7; N 5.5
    31.1- (3-Fluorophenyl) -3-methylase-7-cyan-7- (3-methoxyphenyl) -nonadecane, yield 92%.
    Calculated,%: C 77.9; H 9.7; N5,5. Found,%: C 78.0; H 9.6; N 5.4
    32.1,7-Bis- (3-fluorophenyl) -3-methyl-aza-7-cyannonadecane, yield 88%.
    Calculated,%: C77.4; H, 9.3; N 5.6 Found: C 77.2; H 9.3; N 5.6.
    33.1- (3-Methoxyphenyl) -3-methylase-7-cyano-7- (3-tert-butoxyphensh1) -nonadecane, yield 74%.
    Calculated,%: C 79.0; H 10.4; N 5.0. Found,%: C 78.8; H 10.3; N 4.9
    34.1- (3-tert-Butoxyphenyl) -3-methylase-7-cyan-7- (3-methoxyphenyl) -nadecane, yield 70%.
    Calculated,%: C 79.0; H 10.4; N5.0. Found,%: C 78.9; H 10.5; N 5.0.
    35.1,7-Bis- (3-tert-butoxyfennl) -3-methylase-7-cyannonadecan, 75% yield.
    Calculated,%: C 79.4; H 10.7; N 4,6 - Found,%: With 79.5; H 10.6; N 4.7. In a similar manner, the following compounds can be prepared;
    36.1- (4-tert-Butylphenyl) -3-methyl-aza-7-cyan-7- (3-methoxyphenyl) -nonadecane, yield 82%.
    Calculated,%: C 81.3; H 10.7; N 5.1. Found,%: С81.1; H, 10.6; N5,2.
    37.1- (4-Fluorophenyl) -3-methylase-7-cyano-7- (3-methoxyphenyl) -nonadecane, yield 77%.
    Calculated,%: C 77.9; H 9.7; F 3.7:
    N 5.5.
    Found,%: C 78.1; H 9.6; N 5.4.
    38.1- (3,4-Dimethoxyphenyl) -3-methylase-7-cyan-7- (4-bromophenyl) -eko-eane, yield 86%.
    Calculated,%: C 68.5; H 8.7; Br 13.0; N 4,6 Found,%: C 68,4; H 8.5; Br 13.2; N 4.7.
    39.1- (4-Ethyl mercaptophenyl) -3-methylase-7-cyano-7- (3-methoxyphenyl) non-decane, yield 89%.
    Calculated,%: C76.3; H9.9; N5.1; S 5.8.
    Found,%: C 76.4; H 10.0; N5.0; S 5,6.
    40.1,7-Bis- (3-methylmercaptophenyl) 3-methylase-7-cyannonadecane, 81% yield
    Calculated,%: C 73.9; H 9.5; N5.1; S 11.6.
    Found,%: C 73.7; H 9.4; N 5.2; S 11.8.
    41.1- (3,4-Dichlorofensh1) -3-methyl: - for-7-cyano-7- (3-methoxyphenyl) -nonadecan, yield 78%.
    Calculated,%: C 70.8; H 8.7; C1 12.7
    N 5,0
    Found,%: C 70.6, H 8.6; C1 12.8; N5.1.
    42. 1- (3-Fluorophenyl) -3-methylase-7-cyan-7- (3-chlorophenyl) -nonadecane, yield 76%.
    Calculated,%: C, 74.9; H 9.0; C1 6.9; F 3.7; N 5.5.
    Found,%: C 74.8; H 9.1; C17.0; N5.6.
    Example 43. Preparation of 1,7-bis- (3,4-dimethoxyphenyl) -3-methylase-7-cyanonadecane
    In a three-necked flask equipped with a stirrer, an addition funnel, and a reflux condenser, 34.5 g (0.1 mol) of alpha-dodecyl veratryl cyanide are introduced and dissolved at 40 ° C in 15 ml of toluene. To the prepared solution was added 26 g of powder. different potassium hydroxide and 0.2 g of tetrabutylammonium iodide. Under stirring, a solution of 27 g (0.1 mol) of N-methyl-N-gomo-ratriylamino-gamma-clapropane in 20 ml of toluene is added to the mixture in such a way that the temperature of the reaction mixture is not anticipated. After the addition is complete, the reaction mixture is stirred for a further 2.5 hours at the same temperature. The cooled reaction mixture is washed with 100 ml of water. After distilling off the solvent, 55 g of the final product are obtained in the form of a yellow colored oily substance, yield 94%. The hydroxalate of the obtained compound has an mp. 93-96 S.
    In a similar way (examples 44-50), the following compounds are obtained;
    44.1- (3,4-Dimethoxyphenyl) -3-methylase-7-cyano-7- (3-chlorophenyl) -none-decane, yield 92%.
    Calculated,%: C 73.5; H 9.3; N 5.0; C1 b, 4.
    Found,%: C 73.6; H 9.3; N5.0; C1 6.4.
    45.1- (3,4-Dimethoxyphenyl) -3-methylase-7-cyano-7- (1,3-benzodioxanyl-6 -) - nonadecan, yield 89%.
    Calculated,%: C74.7; H, 9.4; N4.8; Found: C, 74.6; H 9.2; N 4.9.
    46. Amidosulfonate 1- (3,4-dimethoxyphenyl) -3-methylase-7-cyano-7- (3, 4,5-trimethoxyphenyl) nonadecane, m.p. 99-102 0, yield 88%.
    47. Hydrochloride 1- (3,4-dimethoxy-fensh1) -3-metshlaza-7-cyano-7- (3-ethoxy phenyl) docosane, so pl. 109-112 С, yield 90%.
    . 48. 1- (3,4-dimethoxy-phenyl) -3-methylase-7-cyano-7- (3-ethoxy-phenyl) -nonadecane hydrochloride, m.p. 111-113 ° C yield 92%.
    49. 1- (3,4-dimethoxy-phenyl) -3-methylase-7-cyano-7- (3,4,5-trimethoxyphenyl) -pentacosane hydrochloride,
    m.p. 98-101 ° C, yield 89%.
    50. 1- (3,4-dimethoxyphenyl) -3-methylase-7-cyano-7- (3,4,5-trimethoxyphenyl) -heptadecane amidosulfonate,
    m.p. 97-100 s, yield 85%.
    Example 51. Preparation of 1- (3-methoxyphenyl) -3-methylase-7-cyano-7- (3,4,5-trimethoxyphenyl) -eicosane.
     20.7 g (0.1 mol) of 3,4,5-trimethoxyphenylacetonitrile are dissolved at 40 ° C in 15 ml of toluene and the resulting solution is mixed with 52 g (0.8 mol) of 85% powdered potassium hydroxide and 0, 2 g of tetrabutylammonium iodide. While stirring, 26.3 g (0.1 mol) of tridecyl bromide in 20 ml of toluene was added to the mixture in such a way that the temperature of the reaction mixture exceeded 90 ° C. After completion at 713
    The reaction mixture is further stirred for 2 hours at the same temperature and then a solution of 24.2 g (0.1 mol) of 1-chloro-A-methylase-6- (3-methyloxyphenyl) -hexane in 20 ml is added to it. toluene at 90 ° C. The reaction mixture is stirred at 90 ° C for 3 hours, after cooling it is mixed with 100 ml of water, after which the toluene phase is separated. After distilling off the solvent, the crude base is obtained in the form of a yellow colored oily substance, which is chromatographed on silica gel using ethyl acetate acetic acid as a precipitating agent. Yield 89%. R (methylene chloride / methanol 97: 7): 0.44.
    Calculated,%: C 74.7; H 9.8; N 4.7. Found,%: C74.7; H, 9.4; N 4.8.
    Hydroxalate 1,7-bis (3-methoxyphenyl) -Zmethylase-7-cyanonadecane
    Hydrochloride-1- (3-methoxyphenyl) -3-methylase-7-cyano-7- (3, 4-dimethoxyphenyl) .nonadecane
    1- (3-methoxyphenyl) -3-methylase-7-cyano-7- (3,4,5-trimethoxyphenyl) -nonadecane hydrochloride 1,7-Bic- (3-methoxyphenyl) -3-methyl-3-cyano octane decane 1- (3, 4-dimethoxyphensh1) -3-methylase-7-cyano-7- (3, 4,5-trimethoxyphenyl) -nadecane amidosulfonate
    Verapamil
    958
    Pharmacological activity was determined for these compounds.
    Antihypertensive activity The test substance was administered through the mouth to male rats arbitrarily suffering from hypertension (PHC) of the Okamoto strain (weight 300-400 g). The systolic blood pressure before and after 2,6,24 and 30 hours after the administration was bloodlessly determined on the tails of the rats using a piezocrystalline sensor.
    As an ED of 20%, taking into account the values obtained on untreated control animals, the dose was determined, which reduced the systolic pressure by 20%. Verapamil was used as a reference substance.
    The results are shown in Table. one,
    Table 1
    14.1 1.46
    18.7
    1.04
    3.12 2.02
    46.4
    12.5 46.4
    58.3
    20.6 1.00
    913
    Antiarrhythmic action.
    To determine antiarrhythmias. The test substance was administered through the mouth to rats (Spraque - Dawley strain, weight 200-250 g). After 5 hours, the animals were anesthetized with sodium thiobutabarbital (100 mg / kg i.p.). Aconitin was used as a substance leading to arrhythmias, which was administered intravenously 6 hours after administration of the test substance (dosing rate 0.005 mg / kg-min). In untreated animals, after 2.7410.07 minutes, an arrhythmia was observed on the electrocardiogram (ECG), the onset of which was delayed depending on the dose, under the action of the claimed anti-arrhythmic substance. The relative lengthening of the time from the moment of administration of aconitine (D%) under the action of the test substances at a dose of 46; 4 mg / kg was determined.
    Verapamil was used as a reference substance.
    The results are presented in Table. 2
    table 2



    Hydroxalate 1,7-bis- (3-
    methoxyphenyl) -3-methylase-7-cyanoneadecane
    Hydrochloride 1,7-diphenyl 3-methylase-7-cyanononecane
    Hydroxalate 1-phenyl-Zmetylaza-6-Dian-7- (3methoxyphenyl) -nonadecane
    1- (3-methoxyphenyl) -3-methylase-7 cyan-7-phenyl-nadecane hydroxalate
    1-Phenyl-3-methylase-7-cyano-7- (3-methoxy-phenyl) -hexadecane
    1,7-Bis- (3-methoxy-phenyl) -3-methylase-7-cyanhexadecane
    10 Continued table. 2
    one
    -
    1- (3-Chlorophenyl) -3-methylase-7-cyano-7- (3-methoxyphenyl) -nonadecane hydrochloride monohydrate
    -
    1- (3-Methoxyphensh1) -3-methylase-7-cyan-7- (4-chlorophenyl) -nonadecane
    1- (3-Methoxyphenyl) -3-methylase-7-cyan-7- (1, 3-benzodioxanyl-6 -) - nona-decane
    Hydrochloride 1- (3-methoxy phenyl) -3-methylase-7-cyan 7- (3,4-dimethoxyphensh1) - nonadecane
    1- (3-Methoxyphenyl) -3-methylase-7-cyan-7- (3,4-ethyldioxyphenyl) -none-decane
    1- (3-Methoxyphenyl) -3-methylase-7-cyan-7- (3-tolsh1) - nonadecan
    1,7-Bis- (3-methoxy-1) -3-methylase-7-cyanoctane decane
    1,7-Bis- (3-methoxyphenyl) -3-methyl-7-cyan-1 7-octadecane
    1,7-Bis- (3,4-dimethoxyphenyl) -3-methylase-7 cyannonadecane
    1- (3,4-Dimethoxyphenyl) -3-methylase-7-cyan-7- (3-chlorophenyl) -nonadecane Amidosulfonate 1- (3,4-dimethoxyphenyl) -3-metshlaza-7-cyan-7- (3 , 4,5-. Trimethoxyphenyl) heptadecane Verapamil
    68
    186
    155
    54
    104
    63 29
    55 Mostly.
    Cardioprotective action against hypoxic - metabolic disorders in the heart.
    u4
    Anesthetized animals (Wistar strain, weight 250–350 g, anesthesia — thiobutabarbital 100 mg / kg1) using standard breathing with oxygen deficiency (2% oxygen) created the characteristic depletion of myocardium with energy-rich phosphates. Definition of creatine phosphate - it was produced using the freezing technique (liquid nitrogen) in the muscle samples of the apex of the heart according to the Lamprecht method,
    The test substance was injected into awake animals 6 hours before they were placed in an atmosphere with a lack of oxygen. Determine the percentage difference in creatine phosphate concentrations in the myocardium in animals previously treated with the test substance and untreated, suffering from hypoxia.
    Verapamil was used as a reference substance.
    The results are shown
    in tab. 3
    I
    Table 3



    45
    40 +77
    50
    20 +69
    55
     .
    40 +49
    12 Continued table. 3
    one
    Izi
    1- (3-methoxyphenyl) -3-methylase-7-cyano-7-phenyl-nadecane hydroxalate
    Hydrochloride 1,7diphenyl-3-methylase7 cyanhexadecane
    1 (3 Methoxyphenyl) Zmetylaz-7-cyan-7 (1,3-benzodiox nyl-b -) - nonadecan
    1Phenyl-3-methylase 7 cyan-7- (1,3-benzodioxanyl-6 -) - nonadecan
    1- (3-methoxyphenyl) -3-methylase-7-cyano-7 (3,4-dimethyl-oxyphenyl) -non-decane hydrochloride
    1- (3methoxyphenyl) -3 methylase-7-cyan7- (3,4,5-trimethoxyphenyl) hydrochloride
     Slightly.
    Antiaggregatory activity (ability to inhibit platelet aggregation).
    The test substance was administered through the mouth to male rats of the Spraque - Dawley strain (weight 200-250 g). One hour after administration, animals anesthetized with ether took blood, after which by centrifuging 300 g for 10 minutes, platelet-rich plasma was obtained. Photometric determination of platelet aggregation was carried out with the addition of magnesium chloride (final concentration 10 mmol / l) and collage Stage (final concentration 0.02 mg / ml) on a Vogp aggregometer Mk 3. The maximum extinction change per second was used as a measure of aggregation.
    1313081
    As an ED, a 33% dose was determined which, by 33%, inhibited platelet aggregation caused by collagen. Verapamil was used as a comparison agent. 5
    The results are summarized in table. four.
    Table 4
    Inhibition of 10 aggregation ED 33% / mg / kg /
    1.7-bis- (3-methoxyphenyl) -3-methazaz-7-cyanonadecane hydroxalate
    1.7-bis (3-methoxyphenyl) -3-methylase-7-cyanodosane hydroxalate
    Verapamil
     A dose of 46.4 mg / kg is not capable of inhibiting gas.
    In the case of PG-rats, the proposed antihypertensive activity in most cases is more pronounced than that of verapamil (Table 1). In addition, there is a significant increase in the duration of action. In contrast to verapamil, which in a sublethal dose of 100 mg / kg, after 24 hours, ceases to be active, the remaining substances (especially the substances described in examples 3 and 20) even show antihypertensive activity even at this point.
    Given in Table. 2 The proposed joints extend Rem from
    one
    five
    0
    five
    0
    five
    9514
    Antiallergic activity.
    For the study, a model of passive cutaneous anaphylaxis (PKA) was applied.
    Anesthetized rats (100-140 g) were sensitized by intradermal injection (into the trimmed skin of the back) with 0.1 ml ovalbumin antisera.
    After a period of sensitization of approximately 48 hours, the treatment was performed (the test substance was injected through the mouth). After different latent periods (2,6,12 and 24 h), a test solution of antigen and Eransblau was administered intravenously to the experimental animals. After 30 minutes, the animals were sacrificed, the skin of the back was separated and the sizes of round blue spots on the inner surface were determined.
    Antiallergic activity was considered as a relative decrease (4%) of the diameter of stained spots. Verapamil was used as a reference substance.
    Antiallergic activity after administration of 21.5 mg / kg of the test substance to rats is presented in Table. five.
    Table. five
    the moment of introduction of aconitine at 50 (example 19) - 188% (example 13), i.e. they differ significantly from verapamil, which, at a dose of 46.4 mg / kg in rats, has a slight effect on arrhythmia caused by aconitine.
    Given in Table. 3 proposed compounds at doses of 2-40 mg / kg P.O. have a significant cardiac activity. The compounds corresponding to examples 3 and 5 are particularly potent. Verapamil in doses of 40 mg / kg P.O. under the conditions chosen for the experiments, does not exhibit a significant protective effect.
    151
    The compound of Example 3, when administered to rats through the mouth, exhibits a greater inhibitory effect on platelet aggregation (Table 4). Verapamil under the same experimental conditions to the maximum acceptable dose of 46.4 mg / kg does not affect platelet aggregation.
    In addition, this compound, after oral administration to rats, exhibits anti-allergic activity on. models of passive cutaneous anaphylaxis (Table 5). A study of the duration of action showed that the compound after the latent periods of 12 and 24 hours exhibited a significantly stronger activity than verapamil and, therefore, had a longer period of activity.
    The proposed compounds are usually administered orally or parenterally. At the same time, similarly to verapamil (control substance), no lethal effects were observed until a dosage of at least 100 mg / kg.
    权利要求:
    Claims (1)
    [1]
    Invention Formula
    The method of obtaining omega-cyano-1, omega-diphenylazalkane derivatives of the general formula
    QT 5 R6 / rC- (CH2lhrN- (CH) n- Ri,
    where R is hydrogen, C-C4-alkyl, trifluoromethyl, is an alkoxy-SI,.-alkylmercapto group, halo;
    Prioritize


    by prize
    9516
    R-, Rg is hydrogen, C-C-alkoxy;
    R is a straight, straight or unsaturated Cg-C g-alkyl; Rj. - hydrogen, C-C4 alkyl; I
    R - hydrogen, - alkoxy
    halogen, m 3; n 2; R + R-ethylenedioxy, 1,3 dioxate tetramethylene; R-, R - ethylenedioxy-, methylenedioxy,
    their oxalates, hydrochlorides, amido sulfonates, characterized in that the phenylacetonitrile of the general formula
    where - have the indicated values, are reacted with 1-phenyl-azaalkan of the general formula
     :
    X (CH2V- N- (CH2) n4J
    where RJ RJ - have the indicated meanings; X is halogen;
    with the subsequent selection of the target product in free form or in the form of oxalates, or hydrochlorides, or amidosulfonates.
    04/10/81 with RI - H, C-C4-alkoxy;
    RI and R3 is H; n 2; m 3;
    RV is H, GI-C4-alkoxy; Rg
    RS is methyl, oxalates, hydrochlorides, amidosulfonates; 11.11.81 with R - trifluoromethyl, C-C-alkyl, chlorine; R2 and RI are C-C4-alkoxy, chlorine;
    Rg is H, C2-C4-alkyl;
    R -1-Rj is an ethylenedioxy group, 1,3-dioxyl tetramethyl; radical; R + E.J - methylenedioxy.
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    同族专利:
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    ES511260A0|1983-07-01|
    FI821252L|1982-10-11|
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    CS238636B2|1985-12-16|
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    AU8249082A|1983-04-21|
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    CS238621B2|1985-12-16|
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    DE3144150A1|1982-12-09|
    ES8307210A1|1983-07-01|
    FI821252A0|1982-04-07|
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    法律状态:
    优先权:
    申请号 | 申请日 | 专利标题
    DE3114497|1981-04-10|
    DE19813144150|DE3144150A1|1981-04-10|1981-11-06| -CYAN-1,-DIPHENYL-AZAALKAN DERIVATIVES, THEIR PRODUCTION AND THE MEDICINAL PRODUCTS CONTAINING THEM|
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