• 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:
    Novel 2,2 min -iminobisethanol derivatives of the formula <CHEM> the pharmaceutically acceptable acid addition salts and possible stereochemically isomeric forms thereof, which compounds are useful for the treatment and/or prevention of disorders of the coronary vascular system; compositions containing such compounds as an active ingredient; novel intermediates useful in the preparation of such compounds and methods of preparing said compounds, pharmaceutical compositions and intermediates.
    公开号:SU1428199A3
    申请号:SU843826501
    申请日:1984-12-04
    公开日:1988-09-30
    发明作者:Розалия Эжен Ван Ломмен Ги；Франс Леопольд Де Бруйн Марсель；Франсис Йозефин Сровен Марк
    申请人:Жансен Фармасетика Н.В. (Фирма)；
    IPC主号:
    专利说明:

    The salt is added to the base additive with an alkali acid, and / or the acid additive salt is basified with an alkali, and / or converted into a stereochemically isomeric form. 2 s, p. f-ly, And table.
    one
    The invention relates to a process for the preparation of new prodopod-Hbix 2,2-amino-bis-ethanol compounds, which possess p-adreno-blocking activity.
    : The aim of the invention is to obtain the 2.2 derivative of aminobisethanol, which possess valuable biologically active properties. .
    Example 1. During the week, stir for 1.3 hours, (B) -5-bromo-3, D-dihydro-2-oxiranyl 2H-1-benzpiran in 64 parts of the metabolol saturated with ammonia. The product is filtered (and set aside) and the filtrate is evaporated. The residue is taken up in methanol and treated with 2.1 parts of (B) -6-bromo-3,4-dihydro-2-oxyranyl-2H-1-benzpyran, after which n (stirred at reflux for 3 hours. The product is filtered and crystallized together with the precipitated product - from aceto-nitrile to obtain 0.96 parts (36.4%)
    (B, B) -o (, o (- iminobis (methylene 5 | bis. 6-bromo-3,4-dihydro-2H-1-benzpyran-2-methanol, mp 195.4 ° C (1) .
    PRI mme R 2. A mixture of 1.5 hours. (A) —A3.4-dihydro-2-oxiranyl-2H-1-benzpyran-6-carbonitrile; 1.45 parts of (B) -o (- (aminomethyl) -3,4-dihydro-2H-1-benzpyran-2-methanol and 40 parts of ethanol are stirred under reflux for 24 hours. The product is crystallized with cooling, filtered and dried to obtain 1.2 parts (40.5%) (A; c) -2-G2-2- (3,4-dihydro-2H-1-benzpyran-2-yl) -2-hydroxyethyl amino -1 -hydroxyethyl-3,4-dihydro-- 2H-1-benzpyran-6-carbonitrile, mp 154 C (2).
    Using a similar procedure, equivalent amounts of the corresponding starting products were obtained.
    tab. 1 formula A
    Example 3. According to the procedure of Example 2, using the appropriate starting materials, the compounds
    Q
    50
    five
    ABOUT
    five
    0
    NIN presented in table. 2 and 3 formulas B and B.
    In a similar way, the following were also obtained: (A, A) -0 (, sU - (iminobismethyl) bis 2, 3-dihydro-2-benzpyranmethanol3, mp. 154.2 C (compound 65); (A, A) - ( X- 2- (3,4-dihydro-2-H-1-benzpyran 2-yl) -2-hydroxyethyl7 amino1-methyl-3,4-dihydro-2-methyl-2H, 1-benzpyran-2-methanol, thtanoate, mp 179 s (compound 66); (A, A) (iminobismetylen) bis H3, 4-dihydro-2-methyl-2H-1-benzpyran-2-methanol, chlorohydrate, monohydrate, tons. mp 134.5 C (compound 67); (A, B) -o ((3,4-dihydro-2H-1-benzpyran-2-yl) -2-hydroxyethyl amino-J-methylJ-3, 4-dihydro-2-methyl-2H-1-benzpyran-2-methanol, ethanedioate (1: 1), monohydrate, m.p..165.8 (compound 68); (B, A) (3.4 - igidro-2H-1-benzpyran-2-yl) -2-hydroxyethyl7aminoT methyl 1-3,4-DIGIDRO-2-methyl-2H-1-benzpiranyl-2-methanol, ethanedioate (1: 1), t. pl 165.2 s (compound 69).
    Example 4. In 120 parts of ethanol, transfer 11 parts of (A, B) -o (., O-iminobis (methylene) 3 bis b-fluoro-3,4-dihydro-2H-benzpyran-2-methanol 1 and the resulting mixture was added 8 parts of 2-propanol, saturated with hydrogen chloride. After stirring for 1 hour, the product was filtered and crystallized twice from ethanol. The resulting product was filtered and transferred to trichloromethane. The organic layer was washed successively with a 5% sodium hydroxide solution, 1% sodium hydroxide solution and water, dried, filtered and evaporated. The solid residue is taken up in a boiling ac etonitrile, and the product is crystallized to give 0.9 parts of (AB) | -0, o (. - (iminobis (methylene) bis b-fluoro-3,4-dihydro-2H-1-benzpyran-2-methanol1 , mp 156, C (compound 70).
    Example W12PH ethanol was transferred 11 hours. (L, B), - o (, cC - imino-bis (methylene) bis b-fluoro-3,4-dihydro-2H-1-benzpyran-2-methanolT and to the mixture obtained are added 8 parts of 2-propanol scaled with hydrogen chloride. The precipitate is filtered off and the filtrate is evaporated. The residue is taken up in 80 parts of boiling ethanol. The precipitate is filtered off and the filtrate is evaporated. The residue is taken up in trichloromethane. washed successively with 10% sodium hydroxide solution and with water, dried, filtered and evaporated. The residue was recrystallized twice from acetonitrile. filtered and dried to give 2 hours. (A, B) 4-0, o - iminobis (methylene), 4-dihydro-2H-1-benzpyran-2-methanol1, mp 161, (compound 71 U.
    Example 6 p 6. In 30 parts of ethanol are dissolved 10 parts of hydrochloride () - ° C, ct-Ciminobis (methylene) bis 1, 4-di-HYDRO-2H-1-benzpyran-2-methanolJ, after which 20 parts of a 10% sodium hydroxide solution are added. Then the mixture is extracted three times with trichloromethane. The combined organic phases are evaporated and the residue is dried in vacuo at 80 ° C to obtain 4.4 parts of (A A) - "i, o (- iminobis (methylene) bis 3,4-DIHYDRO-2H-1-benzpyrano- 2-methanol, mp: 130.8 ° C, (0) 589 +121.50 (with 1% CHjOH) (compound 7).
    The beneficial characteristics of the β-adrenoreceptor-blocking activity of compounds (1) are illustrated by in vitro tests using guinea pigs in the right atrium and guinea pigs with the tracheal ring.
    1. Test on the right atrium of guinea pigs ().
    In guinea pigs (400 + 50 g), spontaneously beating right atria are excised. The triangular strip of the atrium, including the sinus node, is cut out along with the anterior vena cava. The vein is fastened to the glass holder and the opposite atrial muscle is connected to an isometric Grasse sensor. The atria are suspended with the application of an optimal preload in 10P ml of Krebs-Henzel-Ggg solution containing 2 g / l of glucose at 37.5 ° C aerator0
    five
    0
    five
    0
    five
    0
    five
    0
    five
    95% Oj and 5% CO. Frequency reduction. The research institutes and the reducing force are recorded using the Grass FT03C isometric sensor. Output signals are usi-. An amplifier of an isometric sensor (J.S.1) is inserted through a cardiotachometer (J.S.1) and recorded in the XYY -script writer Hannwell. After a 45-minute stabilization period, isoprenaline is infused with linearly increasing doses over a period of 7 minutes. This causes a dose-related increase in the frequency of contractions (a). After a leaching of isoprenaline follows a 15-minute stabilization period. Then, over the course of 30 minutes, the test drug is added to the bath medium. During this incubation period, the possible direct chronotropic and inotropic effects of the drug are determined. Following this, a second dose-response curve for isoprenaline is obtained by infusion over 10 minutes (b). I Graphically estimate the angle of reduction in the frequency of contractions for each period of isoprenaline addition and calculate the ratio b / a. Based on experiments using solvents, a ratio less than 0.70 is considered a criterion of inhibitory activity. Values are estimated graphically.
    2. Test on the tracheal ring of guinea pigs ((j).
    In guinea pigs (400 + 50 g), the trachea is excised. Four rings with an approximate width of 8 mm are cut out from each trachea. The trap areas of the tracheal ring are placed horizontally between two metal straps, one of which is attached to the glass holder of the organ, and the other is connected to an isometric date. Chick Grass. Thanks to this design smoothly trachea podveshi-. is optimal, i.e. between the cartilage sites. The prepared rings are suspended in a 100 ml organ chamber filled with a Tyrode solution kept at 15 ° C and aerated with 95% Oj and 5% COg. The preparation is kept under tension with a force of 1.5 g throughout the experiment. The recorded changes in tension are thus expressed. contraction or relaxation. After a period of stabilization
    where R and R are hydrogen or G, -C-alkyl; .
    EZ and Kd - hydrogen, or methyl; RJ is hydrogen; Rg is hydrogen, methyl or methoxy;
     - hydrogen or halogen; A C-C4 alkyl, acetylamino, cyano, hydroxy or methylsulfonylamino group; Rj is hydrogen or C -C-apkil;
    R c is hydrogen; hydrogen or halogen,. hydroxy group or
    C-SL-alkyl,
    whether their acid addition salts, whether their stereochemically isomeric orms, characterized in that the amine of the general formula
    Bh
    , one
    Bi7-C-C5H2- NH2
    F
    where R has the indicated meanings;
    D; j-group
    "eight
    where Rj, Rj-Rj have the specified values,
    exposed to ethylene oxide
    Hgc
    /%
    WITH
    I R,
    D,
    where R2 has the indicated meanings

    40 DJ group where R, R and have the indicated values,
    in the medium of lower alkanol at boiling and the target product is isolated as a base or as an acid addition salt with the action of the corresponding acid, and / or the salt is converted to
    base with alkali and / or stereochemically isomeric form.
    2, Method for preparing 2.2 -iminobisethanol derivatives of formula
    TO.
    Ka
    Ri OHON
    C-CHg-H-CH2-C R,
    RI and Rj are hydrogen or C.-C1-6alkyl; R; and R is hydrogen or methyl;
    RS is hydrogen; . Rg is hydrogen, methyl or
    methoxy group; .Rf is hydrogen or C-C halogen-alkyl, acetylamino, cyano, hydroxy or methylsulphonylamino; Rg is hydrogen or C-Cd-alkyl;
    Rg is hydrogen; R is hydrogen or halogen, hydroxy or C, -C-alkyl,
    their acid addition salts, their stereochemical isomeric, characterized in that the amine of the general formula
    OH Dg-C-CH NHg
    R2
    K4, has the indicated values, ynna
    OH but
    II


    Salt with ethanedicarboxylic acid (1: 1).
    T iT-vOv
    where RO and have the indicated meanings
    exposed to ethylene oxide of general formula
    ,ABOUT
    15
    where R has the indicated meanings.
    20
    D -group
    in a lower alkanol medium at boiling and the target product is isolated as base or converted into an acid additive salt with the action of the corresponding acid, and / or the acid additive salt is converted into the base with alkali, and / or
    translates it into the stereochemical isomeric form,

    Table 1
    7
    eight
    9
    10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25
    26 27
    28 29
    H
    H
    H
    H
    H
    H
    H
    H
    H
    H
    H
    H
    CHj
    H
    H
    H
    H
    H
    CHj
    H N
    H N
    H
    H
    H
    H
    H
    H
    H
    H
    H
    H
    H
    H
    SNS
    H
    H
    H
    H
    H
    H
    H
    H
    H N
    N N N N N N N N N F
    SNH F
    CHj CHZ CHE. F N
    CH5 CHjCONH
    CHfiCGNH
    Ethandioate (1: 1).
    table 2
    CH2-C
    (B)
    j
    cc
    AB AA AA-B
    A b
    A VA VA B
    A b
    AB
    AB
    AB
    AA
     AA AA AA AA
    AB
    VA AA
    156.2 147.5 146
    163
    165.5
    162
    161
    163
    141
    139.2
    144
    140
    158
    143
    142
    138
    177
    146 175
    167 172
    +121.4
    +12.49
    -4,53
    Continued tabl. 4
    权利要求:
    Claims (2)
    [1]
    The ratio of the ED 50 values obtained for the tracheal ring test (and the right atrial test (βι) can be considered as the index of cardio selectivity of the test drug. ”Typical results obtained in experiments on a number of compounds of formula (I) are given in Table. 4. Table 4 shows that the compounds of formula (1) have a higher index of cardio selectivity, mula of the invention, Method for the preparation of iminobisethanol derivatives of formula (I)
    Of the total sokim, F about r
    one.
    [2]
    2,2 'where R i and R 4 R 5
    Re them them to R
    C, —C 4 —al— or methyl;
    where Rj, R5-R3 have the indicated values, are reacted with ethylene oxide
    - hydrogen keel;
    - hydrogen, or
    - hydrogen;
    - hydrogen, methyl or methoxy;
    - hydrogen or halogen; Cd — Cd — alkyl, acetylamino, cyano, hydroxy or methylsulfonylamino;
    - hydrogen or Cd-C A -alkyl;
    - hydrogen;
    - hydrogen or halogen,. hydroxy group or
    -Cd-alkyl, acid addition salts, stereochemically isomeric but
    R / 0 or or 'forms, characterized in that the amine of the General formula
    OH 1
    DjT-C- ch 2 -nh 2 k
    where R * has the indicated meanings;
    / °
    H 2 C --- C — D,
    I
    And where Rg has the indicated values, * 9
    Dj-group * 10 have the indicated values of alkanol with a lower boiling medium and isolate the target product in the form of a base or as an acid addition salt by the action of the corresponding acid, and / or transfer the salt to 50 base by the action of alkali, and / or transfer its stereochemically isomeric form.
    2, a method of obtaining derivatives
    2,2-iminobisethanol of the formula
    Dj — group
    Rq and R ^ o have the indicated meanings, are reacted with ethylene oxide of the general formula / ° x
    H 2 C --- s — c,
    Whereand Rjhydrogen or C 4 -Cd alkyl; R 3 and R 4- hydrogen or methyl; R 3 - hydrogen; 5 R ehydrogen, methyl or methoxy; R rhydrogen or halogen, C ^ -C ^ -alkyl, acetylamino, cyano, hydroxy or methylsulfonylamino; 10 r 8hydrogen or SC-Cd alkyl; fifteen R 9 - hydrogen; R < 0 hydrogen or halogen, hydroxy or C, -Cd-alkyl, or them acid addition salts, twenty or them stereochemically isomeric
    where forms, characterized in that the amine of General formula
    OH 25
    I
    D 2 - s - CHg-'NHg
    I
    R 2 where R v has the indicated meanings, 30
    Dj-rpynna n 10 where R 4 has
    D ^ is the group in the medium of lower alkanol during boiling and the target product is isolated in the form of a base or it is converted into an acid addition salt by the action of the corresponding acid, and / or the acid addition salt is transferred to the base by the action of alkali, and / or it is converted stereochemically isomeric form.
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    法律状态:
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    申请号 | 申请日 | 专利标题
    US55808183A| true| 1983-12-05|1983-12-05|LV920225A| LV5028A3|1983-12-05|1992-11-27|Acquisition of 2,2'-iminobisetanol derivatives or their cleavage-aditive islands or their stereochemically isomeric forms|
    LTRP369A| LT2068B|1983-12-05|1993-02-26|THE BUDGET FOR RECYCLING OF 2.2-IMINOBISETANOL OR OR SALT OR STEREOCHEMICAL ISOMER |
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