• 专利附录
  • 专利说明
  • 权利要求
  • 类似技术
  • 同族专利
  • 引用文献
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    • 专利摘要:

    公开号:SU1245261A3
    申请号:SU843749947
    申请日:1984-06-13
    公开日:1986-07-15
    发明作者:Ренье Жильбер；Гиллонно Клод；Дюольт Жак；Буланже Мишель
    申请人:Адир (Фирма)；
    IPC主号:
    专利说明:

    one
    The invention relates to a method for the preparation of xanthine derivatives, new biologically active compounds with pharmacological activity, which can be used in medicine.
    The purpose of the invention is to obtain new xanthine derivatives with higher bronchodilatory activity with low toxicity.
    The proposed method is illustrated by the following examples.
    Example 1. 1-Methyl-3-isobuty. P-7- (2-hydroxyethyl) -8- / 2- (4-diphenylmethyl piperazinyl) ethyl / xanthine. 1b g of 1-methyl-3-isobutyl-8- / 2- (4- -diphenylmethyl-piperazsh1) -eti l / xantine and 37.6 g of potassium carbonate are stirred in 200 ml of dimethylformamide and the reaction mixture is kept at 100 ° C. 10 ml of glycol chlorohydrin is added to it and stirred for
    1 h at 110 Ci. After the mixture of m is added, 20 ml of glycol chlorohydrin is quickly added to the reaction mixture and maintained for 1 hour with stirring, after which 40 g of potassium carbonate are added, and then 20 ml of glycol chlorohydrin. The total mixture is kept
    at 110 ° C for 3.5 hours, then at room temperature for 72 hours. Then the reaction mixture is concentrated to dryness, the residue is taken up with a mixture of methylene chloride and
    water. The organic phase is dried over sodium sulfate, and then concentrated to dryness. The residue is chromatographed on 750 g of silica (0.04-0.063 mm). Elution
    using methylene chloride first, then pure ethyl acetate, followed by a mixture of ethyl acetate and methanol (95: 5), and finally a mixture of ethyl acetate and methanol (90:10),
    Example 8 of 1.7-Dimethyl-3-isobutyl-8 -, / 3- (4-di-par.a-fluorophenyl methylpiperazinyl) -propsh1 / xanthine. Melting point, Tempera of the tour: Ghavleni corresponding fumrata 180 C (ethanol).
    Example 9. 1.7-Dimethyl-3-n-propyl 8-3- (4-diphenylmethylpiperidyl and nyl) prop: yl / xanthine. Ppa temperature
    In this way, 8.6 g of base are obtained, which is dissolved in 50 ml of isopropanol. An ethereal solution of hydrochloric acid is added to the solution.
    an amount sufficient to create
    subacid environment. The chain hydrochloride is 162 ° C. The melting point of the product is precipitated by a significant fraction of the corresponding fumarate by a dry anhydrous ether. Sediment from- (ethanol).
    divide and rinse with ether. After Example 10. 1.7-Dimethyl-3 drying at and a pressure of 0.6 mm Hg, 8.7 g of 1-methyl-3-isobut1-7- (2-hydroxyethyl) -8- / 2- ( diphenylmethyl piperazinyl) ethyl / xanthine having a temp. -isobutyl-8- / 2- (4-diphenylmethyl 10 x 55 55 perid 11 but) ethyl / xanthine. Melting point 98 ° C. Melting point of the corresponding fumarate in the capillary (n-propanol).
    61
    melting school (in capillary) 190
     (isopropanol / ether), base melting point 86 ° C.
    Example 2 -Methyl-3-isobutyl-7- (2 UZ-dihydroxypropyl) -8- / 2-- (4-diphenylmethyl-piperazinyl) ethyl / xanthine, melting point, dichlorohydrate has a melting point (in the capillary) of 145-155 ° C (isopropanol).
    Example 3, 1,3,7-Trimethyl-8- / 3-i4-diphenylmethylpiperidinyl) - -propyl / xanthine. The temperature is melting. The melting point of the corresponding fumarate is 198 ° C (ethanol).
    Example 4, 7-Dnmethyl-3-isobutyl-8- [3- (4-diphenylmethyl-piperazinyl) propyl / xanthine. Melting point. Melting point of the corresponding fumarate (ethanol / ether).
    Example 5. 1.7-Dimethyl-3-isobutyl-8- [2- (4-diphenipmethyl-piperazini; g1) -ethyl / xanthine. Melting point 157 ° C. The melting point of the corresponding hydrochloride (in the capillary) is 214-2 18 ° C (n-propano l / / ether),
    Example 6. I, 7-Dimethyl-3-phenyl-8- (3- (4-diphenylmethyl piperazine NIL)) - propyl / xanthine. Melting point 150 ° C (isopropanol).
    Example 7. 1,7-Dimethyl-3-isobutyl-8- / 2- (4-di-para-4 torfensh17 metsh:; piperazinyl) ethyl / xanthine. Melting point, Melting point of the corresponding dimaleate (n-propanol).
    Example 8 of 1.7-Dimethyl-3-isobutyl-8 -, / 3- (4-di-par.a-fluorophenylmethylpiperazinyl) -propyi1 / xanthine. Melting point, Temperature: pressure of the corresponding fumarate 180 C (ethanol).
    Example 9: 1,7-Dimethyl-3-n-propyl 8-3- (4-diphenylmethylpiperidyl) prop: yl / xanthine. Temperature
    laziness 162 ° C. Melting point of the corresponding fumarate (ethanol).
    Example 10. 1.7-Dimetnl-3. -isobutyl-8- / 2- (4-diphenylmeth 10-hydroxy-55 perid 11 but) ethyl / xanthine. Melting point 98 ° C. Melting point of the corresponding fumarate in the capillary (n-propanol).
    Pr 11 and 1.7-Dimethyl-3-i-isobutyl-8- [3- (4-diphenylmethyloxypiperidino) progr / xanthine. Melting point, The temperature of the expansion of the bronchi was studied in guinea pigs according to the method of G. Concentt and R. Rossler. When this was established, the compounds were established.
    Lenin corresponding fumarate 194 С s obtained by the proposed method
    (ethanol). .
     EXAMPLE 12 1-Ethyl-3-isobutyl-7-methyl-8- [3- (4-diphenylmethyl-piperazinyl) propyl] / xanthine. Temperature
    when administered intravenously at different doses (depending on the compound from 1 to 5 mg / kg), bronchial spasms caused by the intravenous administration of either histamine, bo serotonin and partially - the effects of acetylcholine and slow-reacting agents completely inhibit.
    melting point 125-C; Melting point of the corresponding maleate 193 C (n-propanol).
    Biological tests of compounds prepared by the intended method were carried out.
    The activity of compounds in relation
    As can be seen from the table, the coexpanding activity, than the concentrations obtained by the proposed method used in the present time, have a low toxicity in medical practice and show a higher bronminophylline.
     Order 3931/60 Circulation 379
    Pro.v.polygres pr-tie, Uzhgorod, st. Project, 4
    bronchial dilatation was studied in guinea pigs according to the method of G. Concentt and R. Rossler, and it was established that they were compounds.
    obtained by the proposed method
    when administered intravenously in various doses (depending on compounds from 1 to 5 mg / kg), bronchial spasms caused by intravenous administration of either histamine or serotonin, and also partially the effects of acetylcholine and slow-reacting agents, are completely inhibited.
    Comparative results of the test - NII for pharmacological activity are given in the table.
    Subscription
    权利要求:
    Claims (1)
    [1]
    (57) A method for producing xanthine derivatives of the general formula
    7 2 ( γ - hydrogen
    - the group-CNT or halogen),
    - (SND (n = 2, 3);
    - piperazinyl, oxypiperidinyl, additive ‘salts
    Ζ
    A or their different derivatives of xanthine mules.
    with acids, that is, what is the common form
    About where R / is methyl;
    R is unbranched or branched alkyl (C-C ^), phenyl;
    Rj is methyl, hydroxyethyl, dioxipropyl;
    where R ( , R 2 , R ^, Z and A have the indicated meanings, are introduced into interaction with halogen derivatives of the general formula
    R 3 is CT where R 3 has the indicated meanings in dimethylformamide at 100-1 10 ^ C in the presence of potassium carbonate taken as an acceptor of hydrogen acid, and the target product is isolated in free form or in the form of additive salts with acids.
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    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    CH409974A|1959-03-25|1966-03-31|Merckle Kg Chem Pharm L|Process for the preparation of new therapeutically active caffeino- -alkylenediamines|
    GB1133989A|1964-12-08|1968-11-20|Chugai Pharmaceutical Co Ltd|Theophylline derivatives, their salts and process for preparing the same|
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