• 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:
    Griseolic acid derivatives of formula (I): wherein A represents: have enzyme-inhibitory activity, especially against cAMP PDE and cGMP PDE. When formulated as compositions with appropriate carriers or diluents, they may be used for the treatment of a variety of organic disorders and show toxicities less than griseolic acid itself.
    公开号:SU1468421A3
    申请号:SU853961256
    申请日:1985-10-03
    公开日:1989-03-23
    发明作者:Канеко Масакатсу；Кимура Мисако；Мурофуси Есинобу；Ямазаки Митсуо；Ивата Нобуеси；Накагава Фумио
    申请人:Санкио Компани Лимитед (Фирма)；
    IPC主号:
    专利说明:

    I
    This invention relates to a process for the preparation of 6-desamino-6-grizeolic acid, a new biologically active compound that can be used in medicine.
    The purpose of the invention is a method of obtaining a new biologically active compound that is practically non-toxic and has a higher activity in terms of its ability to inhibit the action of cyclic adenosine monophosphate phosphodiesterase.
    Example 1. 6 Dezaminr-6-hydroxygrizoic acid.
    5.81 g of griseolic acid is dissolved by heating in an 80% (May / vol) aqueous solution of acetic acid.
    acid, after which the solution is cooled to room temperature. Then, 960 g of sodium nitrite is added. The air in the vessel containing this solution is replaced with nitrogen, the vessel is sealed tightly and left to stand for 16 hours. The solvent is removed under reduced pressure to obtain a residue to which ethanol is added, and then distilled until the odor of acetic acid disappears. The residue was dissolved in 50 ml of water, the pH of the solution was adjusted to 1.0 with concentrated hydrochloric acid while cooling with ice. The solution is left in the refrigerator for 16 hours, and then the precipitate is collected by filtration and
    Yu
    washed with a small amount of sweat; the precipitate is then recrystallized from aqueous acetone, which gives 1.66 g of the intended compound. By condensing the mother liquor, 2.20 g of crude crystals are obtained. These crude crystals are then recrystallized from aqueous acetone, to give an additional 1.2 g of the title compound (54% yield) o
    Ultraviolet Absorption Spectrum (), nm (6): 247 (11800) 270 (3700). ,
    NMR spectrum (hexadeuterated dimethyl sulfoxide) S, ppm; 4.50- (W, singlet); 4.57 (IK, doublet, I 6.0 Hz) | 5.12 (IH, doublet, I 3.0 Hz); 5.88 (1H, doublet of doublets, I 3.0 and 6.0 Hz); 6.50 (1K, singlet); 8.17 (GN, singlet); 8.38 (IHj singlet).
    C 43.29 | H 3
    , 26 |
    %: C 43.19 g H 3.455
    Found,% N, 14.42,
     1/2 lUO Calculated
    N 14.39.
    Example 2 In accordance with Example 1, using phosphoric acid instead of acetic acid, the process is carried out at 40 ° C for 10 hours and a compound of Example 1 is obtained
    Example 3 According to the procedure of Example 1, the process was performed at O C - for 50 hours to obtain the desired compound.
    Biological tests of 6-deamino-6-griseolic acid are carried out. you.
    Toxicity.
    Subject to the test of griseol acid and 6-desamino-6-griseol acid. Experimental animals - male rats of the Fisher strain (groups of five
    rats for each experience).
    Test compounds were administered as c, c, 500, or 100 mg / kg daily doses over four days of testing.
    At a dose of 50 mg / kg, the proposed compound showed a 0/5 mortality at the end of the test (i.e., from 5 rats in each experimental group, none died), at a dose of 100 mg / kg, the mortality caused by griseolic acid was 3 / 5 (0/5 in the first two days and 3/5 after 3 days), with a dose of 200 mg / kg - 4/5, Indicators are mortal


    thirty

    40

    -e

    At doses of 00 and 200 mg / kg, 0/5 by the end of the trial, i.e. mortality was absent. These results show that the proposed compound is practically non-toxic.
    Phosphodiesterase (PBE) inhibitor activity.
    The compound of the invention was tested together with theophylline, taken for comparison.
    The test is carried out using the Pihardil Chang method. As a source of cAMP PDE, a crude enzyme solution, taken from the rat brain, was used.
    The substrate used was labeled C CAIR, which was used in a 0.2 M buffer solution of Tris-hydrochloric acid (pH 8.0) in an amount sufficient to obtain a final concentration of 0.14 µM (Tris is Tris- hydroxymethyl) aminonethane). The substrate solution was mixed with an appropriate amount of the test compound dissolved in 2-5 µl of dimethyl sulfoxide, with 20 µl of snake solution and and. 40 μl of crude enzyme solution. Enough Tris-hydrochloric acid buffer was added to achieve a total volume of 100 µl. The mixture was reacted at 30 ° C for 20 minutes. At the end of this period, the reaction mixture was treated with Amberlite resin (trade mark) 1GR-59, and the level of residual radioactivity of adenosine in the product was determined. The experiment was carried out at a number of concentration levels of each active compound, and using these data, the values of 50% inhibition were calculated.
    dso).
    The experiment was repeated with the exception that cyclic guanosine monophosphate (cGMP) was used as a substrate along with cAMP. Also; I Q versus CMP PDE was calculated.
    The magnitude of the inhibition of phosphodiesterase cyclic adeno-z-monophosphate is given in the table.
    five
    A known compound used for comparison is teofellin, which inhibits both cAffP PDE and cGtff PDE and is used for this purpose as a therapeutic agent. The least effective of the compounds tested according to the invention has an Ijp value of about lower than the corresponding value for teofellin, while the most effective of the three compounds has a value of about 3-4 orders of magnitude lower, indicating that the activity indicators of the compounds in this strain as PDE inhibitors are high .
    The proposed compound can be used as therapeutic agents against various circulatory torremoid cerebral disorders.} Such as complications after brain apoplexy and complications or residual effects of cerebral infarction, and brain metabolism activators, for example, for treating the elderly weakly. mi or traumatic cerebral infarction. The compound may be administered orally or non-orally (capillary, subcutaneously or intravenously by injection).
    Conducted tests showed that 6 desamino-6-griseol acid.pot obtained by the method described above is a practically non-toxic compound; however, it has a higher ability to inhibit oTHODjeHHH
    21b
    PIA action of phosphodia: 5-stera; -1 1; 1; a1 nical adeiszinmopofosfat with
    five
     F o p -i u l a and e o b p
    The method is obtained ..; 6-desamin-griseolic acid
     4 -: - v
     one /
    B1 n
    noos / N {M
    noos- {he he
    About tl and h and y and with that ,, griseololto acid formula
    Po.dvayut Biackoo with nptp sodium E acidic conditions at a temperature from 0 C to room temperature for 16-50 h
    Editor B, Petrash
    Tehred L "Serdyukov
    Order 1218/58 Circulation 352. Subscription
    VIIISH-i of the State Committee on Inventions and Discoveries at the State Committee on Science and Technology of the USSR 113035, Moscow, F-ZZ Raushsk nab. 4/5
    Proofreader VvRomznenko
    权利要求:
    Claims (1)
    [1]
    Formula and about the b r. Te n p
    The method of obtaining .; 6-deamino-b-griseolova acid formula
    "N
    Pb 6
    ; -h:
    coos
    Hoos-Wh ^
    he
    About tl and h and y and n with the fact that griseol acid of the formula
    'interact with nitrate nitrate under acidic conditions with a temperature ranging from 0 ° C to room temperature for 16-50 hours.
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    同族专利:
    公开号 | 公开日
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    KR850003415A|1985-06-17|
    JPH0432837B2|1992-06-01|
    EP0143557B1|1988-12-21|
    SU1468422A3|1989-03-23|
    ES537154A0|1985-12-01|
    ES8701193A1|1986-11-16|
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    FI81357B|1990-06-29|
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    EP0143557A2|1985-06-05|
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    引用文献:
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    US3862189A|1973-08-14|1975-01-21|Warner Lambert Co|Aralkyl-substituted purines and pyrimidines as antianginal bronchodilator agents|
    GB1523865A|1974-09-02|1978-09-06|Wellcome Found|Purine compunds and salts thereof|
    US4138562A|1977-02-09|1979-02-06|The Regents Of The University Of Minnesota|Adenosine deaminase resistant antiviral purine nucleosides and method of preparation|
    JPS6215560B2|1979-11-10|1987-04-08|Sankyo Kk|
    DE3028273C2|1980-07-25|1989-12-14|Dr. Willmar Schwabe Gmbh & Co, 7500 Karlsruhe, De|
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    法律状态:
    优先权:
    申请号 | 申请日 | 专利标题
    JP58202362A|JPH0432837B2|1983-10-28|1983-10-28|
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