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    • 专利摘要:

    公开号:SU993817A3
    申请号:SU802942500
    申请日:1980-07-03
    公开日:1983-01-30
    发明作者:Россель Жильбер；Нокин Пьер
    申请人:С.А.Лябаз Н.В. (Фирма)；
    IPC主号:
    专利说明:

    (S) METHOD FOR OBTAINING INDOLYSINE DERIVATIVES
    The invention relates to the production of derivatives of indolysin with biological activity, which can be used in medicine. A known halogenation reaction, preferably bromine, in the medium of an organic solvent in the presence of an alkali metal acetate, in particular sodium acetate Cl3. The purpose of the invention is to obtain new compounds with valuable pharmacological properties. This goal is achieved by the fact that according to the method for producing indolysin derivatives of the general formula T Bg. K O 2. where R is straight or branched al, kil Cf-Cfl, phenyl, 3 chloro-methylphenyl, 3, dichlorophenyl or phenyl substituted by one chlorine, fluorine or bromine atom or methyl or methoxy, X-, and X2 are the same or different,. hydrogen, chlorine, bromine or methoxy, a benzoyl indolysine derivative of the general formula where R, X and 2 are as indicated. nor, is subjected to interaction with bromine in the medium of the solvent in the presence of an alkali metal. Dioxane is used as a solvent, and sodium acetate as an alkali metal acetate. Acetic acid can be used as another solvent. However, this solvent should be used only when the starting compound of formula (P). is a monosubstituted by benzoyl residue of the chlorine atom, bromine or methoxy group by a chlorine atom. Indolysine derivatives have been found to have valuable pharmacological properties, namely: they are inhibitors of the action of xanthine oxidase and adenosine deaminase, as well as uricosuric. In addition, these compounds enhance the cardiovascular action of catechols on. Therefore, compounds (I) can be used to treat physiological disorders caused by an excess of uric acid and disorders of this immunization topic. An example of physiological disorders caused by an excess of uric acid is gout or tophaceous gout. When treating such on the ccI nII, the daily dose of the compounds (|) for a patient weighing 60 kg is, for example, 300 mg. The physiological disorders caused by disorders of the immunization system that can be treated with compounds (1) are the prevention of organ transplant rejection. In order to assess the pharmacological action of compounds (I), tests were carried out to assess the inhibition effect on xanthine oxidase and adenosine diaminase in vitro in the absorption cell of the UV spectrophotometer; /; l Evaluation of the uricosure effect and inhibitory effect on the action of adenosine diaminase carried out in vitro experiments. Inhibition of the action of xanthine okidase. The test was carried out with xenthine oxidase found in milk. The activity of the enzyme sample is measured by the formation of hypoxanthin uric acid. the presence of oxygen and phosphate buffer solution. In the absorption cell is placed 1.5 ml of 0.1 M phosphate buffer solution (,), saturated with oxygen, 0.3 ml of 1 M solution of ethylene diamine tetraacetate; 0.8 ml of water, 0.01 ml of a solution of industrial xanthine oxidase with a lime concentration of the enzyme, 0.01 L of a molar ethanolic solution of the test compound. The contents of the absorption cell are thermostatic for 2 min, then the enzymatic reaction is started, and the introduction of a 10 M solution of hypoxanthine into the absorption cell with 0.3 ml. The progress of the reaction is followed spectrophotometrically, recording the rate of hypoxanthine oxidation at 293 nm and 37 ° C. Optical density recording is carried out automatically. The same measurements were carried out on a control solution containing all of the named ingredients, with the exception of the test compound. Thus, the curves of the change in optical density over time are measured for solutions containing and not containing inhibitor. The slope of both curves is determined and is expressed in moles of uric acid formed in 1 minute. In tab. Table 1 shows the results of experimental and calculated data on the inhibition of the action of xanthine oxidase under the action according to the proposed method. The uricose effect is evaluated in humans after oral administration of 30 ml of 2-ethyl-3- (3,5-dibromo-oxy-benzoyl) -indolysin. The content of uric acid in the urine increased by 1 hour after administration of the drug. The average increase over 2h hours was 22. Urine volume over 2k hours did not change significantly. Uritsemi decreased by 9% to the 5th, and by that time the test compound was at its highest plasma level. Inhibition of the action of adenosine diaminase. Experience in Vi tgo. The test was carried out with adenosine diaminase derived from calf intestine. 2.7 ml of a 0.1 M phosphate buffer solution (,), 0.3 ml of a 5-10 M solution of adenosine in a phosphate buffer solution (final concentration of adenosine DAAI), 0.01 ml of 3-10 M ethanolic solution are placed in the absorption cell. test compound (about 10 milliliters). The potent absorption cell was incubated for 2 minutes, then the enzymatic reaction was started, and 0.03 ml of a solution of industrial adenosine diaminase with a known concentration of the enzyme was started. The reaction proceeds at 30 ° C, which is followed spectrophotometrically, recording a decrease in absorption at 2–5 nm due to the transition of adenosine to inosine in the presence of adenosine diaminase. 599 The enzymatic reaction can be schematically represented by the equation adenosine diaminase Adenosine + Hob INOSIN 1 NN3. The same measurements are carried out on a control solution containing the same ingredients (with the exception of the test compound), then the time absorption curves obtained for solutions containing the inhibitor and the control are plotted. The slope of both curves is determined and expressed in moles of inosine, resulting in 1 minute. The percent inhibition activity of adenosine diaminase in the presence of the compound of the present invention is then calculated. The results are presented in table. 2 Comparative experiments carried out with 2-ethyl-3 - (- oxybenzoyl) -benzofuran and 2-phenyl-3- (3 5 dibromo-oxy-benzoyl) -benzofyran, showed that these compounds provide only inhibition of the effect of adenosine diaminase upon 10 M adenosine, respectively. Compounds 2-ethyl-, 2-isopropyl 2-n-butyl-3 (3,5-dibromo-β-oxy-benzoyl) -benzofurans, and also 2-ethyl-3- (3.5 Diodo-oxy-benzoyl) -benzof They do not inhibit the action of adenosine diaminase in adenosine. When the concentration of M is 1-bromo-2-phenyl and 1-bromo-2- (4-fluoro-phenyl) -3 - (3-bromo-β-oxy-benzoyl) -indolysin, respectively, the inhibition of the effect of adenosine diaminase Bo and 961 is ensured in vitro . Inhibition of the effect of adenosine diaminase by two compounds was also tested on intact cells by growing ascites cells (Krebs) in the presence of adenosine at a concentration of 5-10 M and measuring the amount of inosine and hypoxanthine produced. Adenosine diaminirrination due to ascitic cells was inhibited by 50% in the presence of 2-10 M 1-bromo-2-phenyl-3- {3-bromo-oxybenzene) -indolysin and 1-bromo-2 ("-fluorophenyl) -3- (3-bromo- | -oxy-benzoyl) -indolizine. Experience in vitro. The experiment was carried out to determine the effect of adenine arazinooside (Ara-A) and the proposed compounds on the occurrence of deprived skin areas and 76 mortality of mice infected with HSV-1 (KOS) Athymic, devoid of hair (pi / pi). Mice aged 2025 days are intramuscularly infected with HSV-l (KOS) with (plain-forming units) per mouse. Ara-A and the proposed compound are applied to the skin at a concentration of% in dimethyl sulfoxide once a day for 0.1, 2.3 and a day. The number of mice with epidermal lesions (necrosis of at least 5 10 mm in length) per total number of live mice is determined. The results of the study show that the proposed compound enhances the antiviral effect of adenine arazinoside. Toxicity. To determine acute toxicity, experiments were performed on mice with the proposed compounds. With intravenous administration of 20 mg / kg 1-bromo-2-phenyl- or 1-bromo-2 - (-fluorophenyl) -3- (3 bromo - + - oxy-benzoyl) -indolysin, no deaths were observed after days . . Intra-intestinal administration of 1500 mg / kg of 1-bromo-2-isopropyl- or 2-ethyl-3- (3,5-dibromo-oxy-benzoyl) -indolizin gave the same results. The proposed compound has an inhibitory effect, which they have on adenosine diaminase, as mentioned above. Since some known compounds, for example, co-formicin and 2-deoxycicoforcin, which possess antiparasitic properties, also have this effect, it is quite possible that the proposed compounds also have antiparasitic properties, is extremely important for therapy. With the therapeutic use of the inventive compound, it can be administered in the form of pharmaceutical and veterinary compositions in dosage form. PRI and MER 1. 1-Bromo-2-ethyl-3- (hydroxy-benzoyl) -indolizin. To a mixture of 5.3 g (0.02 M) 2-ethyl-3-oxy-benzoyl) -indolizin, 5.6 g (0, M) of sodium acetate trihydrate and 50 ml are added dropwise over 3.75 hours acetic acid, as well as 3.25 g (0.021 M) of bromine in 50 ml of acetic acid at 20-22 ° C. Stir for 0.75 hours, then add 150 ml of water. The mixture is stirred for another 1 m and the precipitated precipitate is filtered off on a vacuum filter. This residue is converted into a paste in 50 ml, and then into 100 ml of benzene, resulting in a gain of 6.53 g of solid. It is recrystallized from 90 ml of methanol. In this way, k, k g of T-bromo-2-ethyl-3 (-oxy-benzoyl) -indo lysine is obtained. Exit 63.9. T. pl. 160-161.5 ° C. In tab. 3 shows the compounds prepared according to Example 1. PRI mme R 2. 1-Bromo-2-ethyl-3 (3-bromo-oxy-benzoyl) -indolizin. To a mixture of 1.3 g (0.00 M) 2-ethyl-3- (3-bromo-β-oxy-benzoyl) -indolysis and 0.6 g (0.09 m) of anhydrous sodium acetate and 10 ml of acetic acid are added dropwise m for 3 3 / h with stirring, poured 0.6 g (0, OOA M) bromine in 10 ml of acetic acid at 20-22 ° C. The solution is stirred for another 5 minutes and then poured into 50 ml of water. The precipitation is filtered on a vacuum filter, washed until neutral. Thus, 1.4 g of substance are obtained, from which, after recrystallization from 20 ml of chloroform, 0.7 g of 1-bromo-2-ethyl-3 (3-bromo-4-hydroxy-benzoyl) -indolysin is obtained. Yield 5%. T. pl. 213-21 ° C. In Table. Compounds obtained according to Example 2 are given. EXAMPLE 3 3-1-Bromo-2-ethyl-3 (3, -dibromo-4-oxyl-benzoyl) -indolysin. To a solution of k, 2 g (0.01 M) of 2-ethyl-3- (3,5-dibromo-4-hydroxybenzoyl-indolyzine in 100 ml of dioxane, add 1.6 (0.02 m) anhydrous acetate sodium solution. With vigorous stirring, a solution of 1.6 g: (O, 01 M) bromine in 20 ml of dioxane is added dropwise. The temperature is maintained at 20-22 ° G. After stirring the solution for 1 h, the reaction product is poured into 250 ml The precipitated yellowish-green precipitate is filtered and washed until the filtrate is neutral. After drying under vacuum, 5.2 g of crude product are obtained, which is recrystallized from 50 ml of dichloroethane. Thus, after treatment with activated carbon, 2 g of 1-bromo-2-ethyl-3 (3.5 dibromo-oxy-benzoyl) -indolysin are obtained. The yield is 83.6. M.P. 1E5 ° C. Table 5 Compounds obtained according to Example 3 are given: 4-bromo-2-ethyl-3 (3 5-dibromo-oxy-benzoyl) -indolizin to a mixture of 5.3 g (0.02 M) 2 (ethyl-3-) -oxybenzyl-indolysin, 17.7 g (0.13 M) of sodium acetate trihydrate and 50 ml of acetic acid, 10.55 g (066 M) of bromine are added dropwise over 3 hours to 50 ml of acetic acid, temperature 20-22 ° C. Stir for 18 h, the precipitate is filtered on a vacuum filter and washed with acetic acid and water. 50 ml of water are added to the filtrate and the solution is filtered again. Two precipitates are combined and the recrystalline is made from carbon tetrachloride. 7.9 g of 1-bromo-2-ethyl-3- (3,5-dibromo-oxy-benzoyl) -indolizin are thus obtained. Yield 79%. EXAMPLE 5- 1-Bromo-2-methyl-3- (3,5-Dichloro-oxy-benzoyl) -indolizin. to a solution of 3.2 g (0.01 M) of 2-methyl-3- (3,5-dichloro-1-hydroxy-benzoyl) -indolizin in 100 ml of dioxane was added 1.6 g (0.02 m) of anhydrous sodium acetate. With vigorous stirring, 1.6 g (0.01 M) of bromine are added dropwise at 20 ° C. During the operation, the temperature is 20-22 ° C. After stirring the mixture for 1 hour, the reaction product is poured into 250 ml of water. The yellowish-green precipitate formed is filtered and washed with water until the filtrate is neutral. After drying under vacuum, the crude product is recrystallized from dichloroethane / heptane-80/20. Thus, after treatment with activated carbon, it receives 1.7 g of 1-bromo-2-methyl-3- (3,5-dichloro-oxy-benzoyl) -indolizine. The output of k2,6%, T. pl. 240 ° C. In tab. 6 given compounds obtained according to example 59
    993817
    lO Table1
    n
    Compound
    1-Bromo-2-methyl-CS Oxy-benzoyl) -indolizin
    1-Bromo-2-n-butyl-3- (A-hydroxy-benzoyl) -indolizina
    1-Bromo-2-n-pentyl-3 (-oxy-benzoyl) -indolizin
    1-Bromo-2-n-hexyl-3 - (- hydroxy-benzoyl) -indolysin
    1-Bromo-2-n-heptyl-3- (4-hydroxy-benzoyl) -indolizin
    1-Bromo-2-n-octyl-3- (f-hydroxy-benzoyl) -indolizIN.
    1-Brom-2-phenyl-3- (-oxy-benzoyl) -indolizin
    1-Bromo-2- (-methyl-phenyl-3 -) - oxy-benzyl
    indolysin
    1-Brsm-2- (4-bromo-phenyl) -3- (-oxy-benzoyl) -indolizin
    993817 Continued table. 2
    Table 3 T. pl. , with
    238-239 (dichloroethane)
    160-162 (benzene)
    155-157 (dichloroethane)
    1b2-1bZ (dichloroethane)
     (benzene)
    132-138 (dichloroethane)
    210 (dioxane)
    197-198 (dichloroethane)
    220-225 (benzene)
    13
    Compound
    1-Bromo-2- (3 bromo-phenyl) -3 (hydroxybenzoyl) -indolizin
    1-Bromo-2- (3 chloro-4-methyl-phenyl) -3 - (- hydroxy-benzoyl) -indolizin
    1-Bromo-2- (3 LDhlor-phenyl) -3- {-oxy-benzoyl) -indolizi) b
    Compound
    1 - Bromo-2-methyl-3 (3 6rom- -oxy-benz-indolizin
    1-Bromo-2-n-prop yl-3 (3-bromo-oxy-beta-indolizin
    I.
    1-, Brom-2-isopropyl-3- (3-bromo-oxy-benzoyl) -indolysin
    1 - Bromo-2-n-butyl or 3 (3-bromo-i-oxy-benzoyl) -indolizin
    1-Bromo-2-n-pentyl-3- (3-bromo-C-hydroxy-benzoyl) -indolysin
    1-Bromo-2-n-hexyl-3- (3-bromo-β-oxy-benzoyl) -indolizin
    1-Bromo-2-n-heptyl-3- (3-bromo-β-oxy-benzoyl) -indolizin
    1-Bromo-2-n-oxyl-3- (3 bromo-oxy-benzoyl) -indolizin
    1-Bromo-2-pentyl-3- (3 bromo-yoke and-benzoyl) -indolizin
    1-Bromo-2- ("-methyl-phenyl) -3- (3-bromo-oxy-benzoyl) -indolysin
    1-Bromo-2- (methoxy-phenyl) -3- (3-bromo-4-oxy-benzoyl) -indolizin
    1-Bromo-2- (-fluorophenyl) -3- (Z-bromo-yokei-benzoyl) indolizin
    1-Bromo-2- (4-chloro-phenyl) -3- (Zbromo-β-oxy-benzoyl) -indolizina
    U
    EE3817 Continued table. 3
    T. pl., C
    225 (carbon tetrachloride)
    210 (benzene) 2 "0 (dichloroethane)
    Table j
    T pl. ° C
    2j5-2 6 (dichloroethane) 189-191 (benzene) 130-132 {benzene) 183-18 (benzene) lyt-US (dichloroethane). 175-177 (dichloroethane) 165-166 (dichloroethane) 161.5-163 (dichloroethane) 18.5-186 (benzene) 231 (dichloroethane) (dichloroethane) 196 (benzene) 228-230 (benzene)
      -K jeygV
    Compound
    1-Bromo-2- (-bromo-phenyl) -3 (3 bromo-oxy-benzoyl) -indolizin
    1-Bromo-2- (Zbrom-phenyl) -2- (Zbrom-A-hydroxy-benzoyl) -indolysin
    1-Bromo-2- (2-bromo-phenyl) 3 (Zbrom-4-hydroxy-benzoyl) -indolysin
    1-Bromo-2- (3 chloro-methyl-phenyl) -3- (Zbrom-A-hydroxy-benzoyl) -indolizin
    1-Brpm-2- (3, Dichloro-phenyl) -3 - (3 bromo-4-hydroxy-benzoyl) -indolizin
    1-Bromo-2-methyl-3 (3 chloro-oxm benzoyl) indolizin
     1-Bromo-2-ethyl-3 (3 chloro-4-hydroxy-hydroxy-beisoyl-indolizin
    1-Bromo-2-n-propyl-3 (3-chloro-oxy-benzoyl) -indolizin
    1-Bromo-2-isopropyl-3 {3Chloro-oxy-bvzoyl-indolysin
    1-Bromo-2-n-util-3 (3 chloro-oxy-benzoyl) -indolizin
    1-Bromo-2-phenyl 3- (3 chloro-4-hydroxy-benzoyl) -indolizin
    1-Bromo-2- (4-chloro-phenyl) -3- (3-chloro-oxy-benzoyl) -indolizin
    1-Bromo-2- (3 bromo-phenyl) -3 (Z-chloro-A-hydroxy-benzoyl) -indolysin
    1-Bromo-2- {4-bromo-phenyl) -3- (3-chloro-4-hydroxy-benzoyl) -indolizin
    1-Bromo-2-methyl-3- (3-methoxy-β-oxybenzoyl) indolysin
    1-Bromo-2-ethyl-3- (3-methoxy-C-hydroxy-benzoyl) indolysin
    Continued table. M.p.
     (dichloroethane)
    185-186 (carbon tetrachloride)
    213-21i (benzene) 201-202 (dichloroethane) 207-209 (benzene)
    228 (dioxane)
      .
    191-192 (dichloroethane) I80-t8l (isopropanol) (benzene)
    177-178 (dichloroethane) 198-193 (benzene) 212-213 (dichloroethane) 126-128 (beizol) 231-232 (dichloroethane) 155 (methanol)
    1bO (methanol)
    Compound
    1-Bromo-2-methyl-3 (3.5 Dibromo-β-oxy-benzoyl) -indolizin
    1-Bromo-2-n-propyl-3 (3,5 Dibromo-β-oxy-benzoyl) -indolysin.
    1-Bromo-2-isopropyl-3- (3,5-Diebromo-β-oxy-benzoyl) -indolizin
    1-Bromo-2-n-butyl-3 (3,5-Dibromo. 1-hydroxy-benzoyl) indolysin
    1-Bromo-2-n-pentyl-3 {3.5 Dibromo-oxy-benzoyl} -indolysine
    1-Bromo-2-n-hexyl-3 (3,5 Dibromo-β-oxy-benzoyl) -indolysin
    1-Brpm-2-n-heptyl-3 (3,5 Dibromo-A-hydroxy-benzoyl) -indolysin
    1-Bromo-2-n-oxyl-3- (3,5 Dibromo-β-oxy-benzoyl) -indolysin
    1 -Brom-2- (|) yenyl-3- (3,5-Dibrs - | -oxy-benzoyl) hindolizina
    1-Bromo-2- (-methylphenyl) -3 (3.5 dibromo-A-hydroxy-benzoyl) -indolysin
    1-Bromo-2- (4-methoxy-phen14l) -3-dibromo-4-hydroxy-benzoyl) -indolizin
    1-Bromo-2- (t-fluoro-phenyl) -3- (3.5-Dibromo- | -oxy-benzoyl) -indolizin
    1 -Brom-2-C-chloro-phenyl) -3- (3Л5-Dibromo-oxy-benzoyl) -indolizin
    1-Bromo-2- (-bromo-phenyl) -3 (3 5 Dibrom-4-Oxy-benzoyl) -indolysin
    1-Bromo-2- (3-bromo-phenyl) -3- (3,5-Dibromo-4-hydroxy-benzoyl) -indolizin
    1-Bromo-2- (g-bromo-phenyl) -3,5 Dibromo-4-hydroxybenzoyl) -indolizin
    Table 5 T. pl., S.
     (dichloroethane)
    183-IB (benzene)
    188-183 (CCit).
    162-163 (heptane)
    (tetrachloride carbon)
    152-153. (benzene) 167-168 (benzene) 153-15 (benzene) 211-212 (benzene)
    1 8-150 (cyclohexane) (carbon tetrachloride)
    16 / -168 (isopropanol)
    191-192 (benzene)
    203-20 (carbon tetrachloride)
    203-20 (carbon tetrachloride)
    269-270 (dichloroethane)
    17b-177 (carbon tetrachloride)
    Compound
    1-5 ppm-2- (3 chloro-4-methyl-phenyl) -3- (3,5-dibromo-oxy-benzoyl) -indolizin
    1 - Bromo-2 (3, -dichloro-phenyl) -3 (3,5-Dibromo-k-hydroxy-benzoyl) -indolizin
    Compound
    1-Bromo-27ETHYL-3- (3,5-Dichloro-4-hydroxy-benzoyl) -indolizin
    1-Bromo-2-phenyl-3- (З, 5 Dichloro-4-hydroxy-benzoyl) -indolizin
    Continued table. 5 .T. pl., ° C
    2 Th-215,5 (dichloroethane) 2k (benzene)
    Table 6
    t-fJ IT. square WITH
    17
    236 / dichloroethane / heptane-90/1 O
    权利要求:
    Claims (2)
    [1]
    Claim
    1. The method of obtaining derivatives of 3 indolysin of the General formula
    Bg
    O 'where R is straight or branched C ^ ~ 3- Cs alkyl, phenyl, 3 “chloro-4-methylphenyl, 3,4-dichlorophenyl or phenyl substituted with one fluorine atom, chlorine or bromine, or one methyl or methoxy;
    Xd and X 2 are the same or different, hydrogen, chlorine, bromine or Methoxy, characterized in that the benzoylindolisine derivative of the general formula wherein R, X 1 and X2 are as defined, are reacted with bromine in a solvent in the presence of alkali metal acetate.
    [2]
    2. The method of pop. 1, characterized in that dioxane is used as a solvent, and sodium acetate is used as an alkali metal acetate.
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    FI67217C|1985-02-11|
    PL225479A1|1981-10-30|
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    法律状态:
    优先权:
    申请号 | 申请日 | 专利标题
    GB7923599|1979-07-06|
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