• 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 alkane derivatives of the formula (I) …<CHEM>… or a pharmaceutically acceptable salt thereof, wherein:… R1 is hydrogen, C1-C6 alkyl, C3-C8 cycloalkyl, or phenyl;… R2 is hydrogen, C1-C6 alkyl, or C2-C6 alkenyl;… R3 is hydrogen, C1-C10 alkyl, phenyl, C1-C10 alkyl-substituted phenyl, biphenyl, or benzylphenyl;… R4 is -COOR7, -CONR8R9 -CONHOH, -NR8R9, -SC(=NH)NH2, cyano, cyanothio, …<CHEM>… where R7 is hydrogen or C1-C4 alkyl,… R8 and R9 are each independently hydrogen, C1-C3 alkyl, or when taken together with the nitrogen atom form a morpholine or N-methyl piperazine ring,… R is hydrogen, C1-C4 alkyl, or -CH2COOR7, and p is 0, 1, or 2;… R5 and R6 are each independently hydrogen or C1-C3 alkyl;… and n is 0-10 are leukotriene antagonists.
    公开号:SU1433412A3
    申请号:SU833662253
    申请日:1983-11-02
    公开日:1988-10-23
    发明作者:Стэнли Маршалл Винстон；Помфрет Вердж Джон
    申请人:Эли Лилли Энд Компани (Фирма)；
    IPC主号:
    专利说明:


    CM
    The invention relates to a process for the preparation of a novel compound (4-acetyl-3-hydroxy-2-propylpheno X) butyl, a tetrazole of the formula
    H
    (,
    but
    Cznt
    N
    N N K N N which can be used in medicine as antagonistale-: otrienov, causing allergic reactions.
    The purpose of the invention is to develop a method for producing antagonists.
    leukotrienes, which have a higher activity compared to. compound similar in structure.
    Example 1. (4-Lcetil-3- --OXI-2-propylphenoxy) butsh tetrazole
    A solution of 20.73 g (75 mmol) (4-acetyl-3-hydroxy-2-propylphenoxy) pentanenitrile, 14.63 g (225 mmol) of sodium azide and 12.04 g (225 mmol) of ammonium shsorid in 200 ml of dimethyl - formamide is heated at 125 ° C for 17 hours. After that, 9.75 g (150 mmol) of azide sodium and 8.02 g (150 mmol) of ammonium chloride are added, and heating is continued for another 6 hours.
    The reaction mixture is filtered while hot and evaporated in vacuo to give a thick, capacious oil. The residue is treated with dilute hydrochloric acid and extracted with ethyl acetate. The ethyl acetate layer is dried over sodium sulfate and evaporated in. vacuum To produce an oil that crystallizes upon cooling.
     The crystals are boiled in ethyl acetate coal for 30 minutes. The solution is filtered off while hot and the filtrate is cooled to give an amber color. The crystals are filtered off, washed with ethyl acetate and 6.49 g of the expected product are obtained, t; 113.5-115 С
    Elemental analysis.
    Calculated,%: C 60.36; H 6.97; N17.60; 015.08.
    C.gK.,
    Found,%: C 60.14; H 6.86; N. 17.75; 015.12,
    o
    five
    0
    0 5
    0 5
    P
    five
    Example 2. Leukotriene antagonism (MMPB-L).
    Male guinea pigs weighing 200-450 g are killed by decapitation. The part of the end of the ileum is removed, the lumen is cleaned and the tissue is divided into 2.5 cm segments. The segments of the ileum are placed in a bicarbonate solution of the following composition, mmol / l: KC1 4.6; CAC 21120 1.2; USTR 1,2; MgS04 7K.jO 1,2; NaCl 118.2; NaHCO, 24.8; dextrose 10, .0. ,,
    In addition, the buffer solution contains 1 10 M atropine to suppress the spontaneous activity of the ileum. Said liquid, which has a temperature, is placed in a bath and an air mixture consisting of 95% oxygen and 5% CO is passed through it.
    In studies with MRI-A, 1 10 M pyridylethylamine is used to weaken the effect of histamine present, along with that of biologically active leukotrienes. The isometric measurements are carried out on the Gross force transducer and recorded the change in the force effect.
    A passive force of 0.5 g is applied to the tissue.
    After an appropriate equilibration period, single submaximal control reactions are obtained both on and on LTD (leucotrienes).
    After a five-minute ileum exposure of the experimental drug to the bath, where the ileum tissue segments are located, control concentrations of MPB-A or LTD4 are added.
    The reaction of the ileum to MRV-A or LTD4 in the presence of a drug is compared with the reaction of its drug. For some drugs in this series, a detailed analysis is performed on LTD.
    antagonism. I
    Cumulative curves are obtained: concentration — effect on LTD in the ileum and trachea of the guinea pigs. After that, incubation is carried out for 30 minutes with various concentrations of the experimental drug. Cone curve The centering effect on LTD is then re-prepared in the presence of an antagonist. On one segment of tissue
    314
    use only one concentration of antagonist.
    Calculate the value
    KR 1 E121
    Dose ratio - T
    where the numerator is the concentration of antagonist for the 50% response;
    denominator - relationship
    EDjjg (in the presence of an antagonist) ЁUR Tv absence of an antagonist)
    EDyp is the antagonist concentration required to induce a 50% maximum response.
    The log is then determined. For the proposed compound, the percentage inhibition of LTD, which caused a contraction of the ileum, is as follows: at a concentration of 3x10 M 100; 1x10 M 89; pA 7.2, its duration in guinea pig serum is 60 min, while for a known antagonist, (4-acetyl-3-hydroxy-2-propylphenoxy) -2-oxypropoxy, α-4-oxo-8- propyl-4H-benzopyran-2-carboxylic acid is 0.6 minutes.
    The activity (pA; i) of the known antagonist - (4-acetyl-3-hydroxy) - phenyl -1H-tetrazole - is 7.1.
    12
    The resulting (4-acetyl-3-hydroxy--2-propylphenoxy) bybutyl tetrazole belongs to the group of low-toxic compounds.
    权利要求:
    Claims (1)
    [1]
    Invention Formula
    The method of obtaining (4-acetyl-β-Z-hydroxy-2-propylphenoxy) butyl tetrazole a of formula
     P
    -o-CHj- (cHi)
    Cznt
    N N N
    V
    n
    a different compound of the formula
    by that
    ABOUT
    sno
    (-0-CHj- (CH2) 2-CHt-CN СзН7
    is reacted with alkali metal azide and ammonium chloride in an environment of inert high boiling solvent, such as M, N-dimethylformamide, at a temperature of from 60 ° C to reflux temperature.
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    同族专利:
    公开号 | 公开日
    DE3373899D1|1987-11-05|
    FI81343C|1990-10-10|
    GR78946B|1984-10-02|
    IE56204B1|1991-05-22|
    PH21170A|1987-08-07|
    HU197871B|1989-06-28|
    IE832551L|1984-05-03|
    ZA838118B|1985-06-26|
    CS247076B2|1986-11-13|
    ES8601829A1|1985-11-01|
    JPH0347256B2|1991-07-18|
    AT30023T|1987-10-15|
    KR860001570B1|1986-10-08|
    AU572806B2|1988-05-19|
    PL139647B1|1987-02-28|
    PL244401A1|1985-03-12|
    EP0108592B1|1987-09-30|
    KR840006805A|1984-12-03|
    FI834002A0|1983-11-01|
    GB2129797B|1986-07-02|
    MY102027A|1992-02-29|
    DD215083A5|1984-10-31|
    NZ206111A|1986-03-14|
    CA1242194A|1988-09-20|
    JPS59104344A|1984-06-16|
    EG16819A|1992-06-30|
    IL70093A|1988-03-31|
    GB2129797A|1984-05-23|
    HUT35234A|1985-06-28|
    GB8329099D0|1983-12-07|
    RO88317A|1985-12-30|
    PT77592A|1983-12-01|
    AR240318A1|1990-03-30|
    RO88317B|1985-12-31|
    EP0108592A1|1984-05-16|
    ES526940A0|1985-11-01|
    CS810683A2|1985-06-13|
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    PT77592B|1986-05-05|
    AU2087583A|1984-05-10|
    US4661505A|1987-04-28|
    DK499883D0|1983-11-01|
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    法律状态:
    优先权:
    申请号 | 申请日 | 专利标题
    US06/439,239|US4661505A|1982-11-03|1982-11-03|Leukotriene antagonists|
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