• 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:
    This invention provides novel benzene derivatives which are leukotriene antagonists, formulations of those derivatives, intermediates for preparing the derivatives, and a method of using those derivatives for the treatment of conditions characterized by an excessive release of leukotrienes.
    公开号:SU1516011A3
    申请号:SU843775301
    申请日:1984-07-16
    公开日:1989-10-15
    发明作者:Делейн Диллард Роберт
    申请人:Эли Лилли Энд Компани (Фирма)；
    IPC主号:
    专利说明:

    This invention relates to. method of producing a new chemical compound, in particular to (4-acetyl-3-hydroxy-2-propylbenzyloxy) benzyl-tetrazole of formula
    .N-n
    h, h
    SzN7
    R
    C
    -N
    which is a leukotriene antagonist and can be used in the treatment of allergic diseases, such as asthma.
    The purpose of the invention is to find a method for producing a new tetrazole derivative, which, compared with its analogue, has a higher activity in the structure of the same purpose.
     . th - to
    N
    -N
    bark
    as
    Example 1.6.9 g (0.021 mol) of 4- (4-acetyl-3-hydroxy-2-propylbenzyloxy) phenylacetonitrile and 13.2 g (0.084 mol) of tetramethylguanidinyl azide are dissolved in 50 ml of dimethylformamide under an argon atmosphere and the mixture is heated at 120-123 ° C. overnight. The mixture is then poured into 1 liter of water and acidified with concentrated hydrochloric acid.
    The product is extracted with ethyl acetate, and the ethyl acetate solution is washed three times with water, then dried with sodium sulfate. The resulting product is recovered from this solution by high performance liquid chromatography. Yield (A-acetyl-3-hydroxy-2-propylbenzylSP
    O5
     CM
    hydroxy) benzyl} tetrazole is 55.8%; mp. 155-157 seconds
    Found,%: C 65.54; H 6.00j N 15.00, CaoHjaN Oj
    Calculated,%: C 65.56; H 6.05; N 16.29.
    The compound obtained is a leukotriene antagonist,
    Leukotriene antagonism was demonstrated as follows.
    Example 2. Male Hartley guinea pigs weighing 200-450 g are killed. A part of the terminal ilium is removed, the cavity is cleaned and the tissue is divided into 2.5 cm segments.
    The air is set in 10 ml tissue baths containing Krebs bicarbonate solution having the following composition, mmol x / l: KC1 4.6; CaCl, 1.2; 1.2; MgS04 7H O 1,2; NaCl 118.2; NaHCOj 24.8, dextrose 10.0.
    The liquid in the bath is maintained at 37 ° C and aerated with a mixture of 95% oxygen and 5% CO. In addition, such a biffer contains 1x10 M atropine in order to reduce iliac spontaneous activity. The isometric measurements are carried out with the aid of the Grass power displacement transducer and recorded on the Grass polygraph as a change in force.
    A passive force of about 0.5 g is applied to the tissue. After an appropriate period of equilibrium, single submaximal control rations are obtained on a pure ITD. After 5 min of exposure of the ilium, the action of the experimental drug is injected into the tissue bath in the control concentration of the ilium. Ileal reaction the bones on ITD4 in the presence of a medicament are compared to a reaction in the absence of a drug.
    Example 3, Conducting a t-experiment for a more detailed analysis of 1TD antagonism.
    In these experiments, get a com. multiplicative curves in concentration coordinates - 1 response to ITD of the ileum and guinea-pig trachea. These results are obtained after 30 min of incubation in the presence of various concentrations of experimental drugs. Then the concentration curve - the response to ITD - is re-obtained in the presence of a ditdongist,
    For a single tissue sample, only one concentration of antoronium is used. Calculate the KB value by the Furhgott method using the following equation:
    L 2I§E22S lJ
     dose ratio 1
    where the antagonist is the concentration of the obtained compound
    The dose ratio refers to the concentration of antagonist that is required to cause 50% of the maximum response in the presence of an antagonist divided by EDgj in the absence of an antagonist.
    The calculations are carried out using a computer and plotting curves. Then pA is calculated as negative log Kg, in the case when the slope of the shield sigil is slightly different from unity.
    The test results are presented in the table.
    The resulting compound is low toxic,
    The proposed compound has a longer service life (the half-life of guinea pig serum is 6 hours, the half-life for the known 7- (3- (A-acetyl-3-ox-2-propane phenoxy) -2-hydroxypropoxy-4-oxo- 3-propyl-4c) 1-benzopyran-2-carboxylic acid is 0.6 minutes,
    权利要求:
    Claims (1)
    [1]
    Invention Formula
    Method for preparing 5-CA- (4-acetyl-3-hydroxy-2-prothbenzyloxy) benz zyl-tetrazole of the formula
    A compound of the formula
    by that
    II
     but
    CH2O
    CH2CN
    subjected to interaction with tetramethylguanidini azide,
    51516011
    Concentration
     I 1x10 M 3x10 M 1x10 M 1 pA 9A 92 81 31 8.12
    negative logarithm;
    negative logarithm of the concentration at which 50% inhibition is performed.
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    ZA845408B|1986-02-26|
    AU3075184A|1985-01-24|
    FI842844A0|1984-07-16|
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    法律状态:
    优先权:
    申请号 | 申请日 | 专利标题
    US06/514,428|US5105017A|1983-07-18|1983-07-18|Leukotriene antagonist intermediates|
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