• 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:
    The compound of formula (I) …<CHEM>… and acid addition salts thereof are of value in medicine in the treatment or prophylaxis of pain, inflammation or fever. The compound and its salts may be administered alone or as a pharmaceutical formulation. The compound may be prepared by methods analogous to those known in the art or, for example by cyclisation of a 4-halo-N-(3,4-methylene dioxy phenyl)butyramide in the presence of aqueous sodium hydroxide and a phase transfer catalyst such as triethylbenzyl ammonium chloride.
    公开号:SU1241992A3
    申请号:SU823402605
    申请日:1982-03-05
    公开日:1986-06-30
    发明作者:Левис Ходгсан Гордон (Младший)
    申请人:Дзе Велкам Фаундейшн Лимитед (Фирма)；
    IPC主号:
    专利说明:

    N5
    4ib
    CO SO
    tNd
    I1241992
    This invention relates to methods for preparing a new compound (1,3-enzodioxol-5-yl) -2-pyrrolidinone of the formula.
    (1 tv
    25 hp re on lion about fi wa sta dn pr pr pr
    Gg)
    having an analgesic effect.
    The aim of the invention is to develop a process for the preparation of a novel compound having a valuable pharmacological property of enhanced action,
    PRI me R, Getting 1- (1, 3 benzodioxole 5-yl) -2-pyrrolidinone,
    Method A.
    A mixture of 3 5 4 - (methylenedioxy) aniline (200 g, 1.46 mol) and -butyrolactone (225 ml) is heated under an atmosphere of dry nitrogen with stirring in an oil bath at 200 s for two days. The product obtained is recovered from the reaction mixture by distillation in vacuo (t, bp 156 C, 334), the product is filtered on silica gel 60 (trade name), eluted with ethyl acetate, the eluate is concentrated and the crystalline product is recovered and washed with diethyl ether and petroleum ether, resulting in a result. .1 (1, 3-benzodioxol-5-yl) -2-pyrrolidinone (153.4 g, 51%), m.p., 89-91 C. This product appears as one spot when analyzed by thin-layer chromatography.
    The elemental analysis data:
    Calculated,%: C 64.38; H 5.40; N 6.83,
    C L E N03
    Found,%: C 64.30; H 5.33; N 6.81.
    Method B.
    4-Chlorobutyl chloride (1095.5 g, 7.77 mol) is introduced at 10-25 ° C into a mixture comprising 3.4- (methyldioxy) aniline (1000.0 g, 7.29 mol), three ethylamine (749.0 g, 7.40 mol) and methylene chloride (2500 ml). After stirring for 18 hours at room temperature, diethyl ether is added and the intermediate product butyramide is filtered off and then re-suspended in water. Wet. Butyr amide mixed with methylene chloride
    five
    0
    five
    but
    five
    0
    (10 L) 5 50% (w / w) aqueous sodium hydroxide solution (2000.0 g,
    25.0 mol) and benzyltriethylammonium-hporide (50.0 g. Oh, 22 mol). After stirring for 2.5 hours at room temperature, the mixture is diluted with water and the aqueous layer is separated, Methi-. The larch layer is washed with water, decolorized with Darco-60 and Fi. Etro E.-I9, and then concentrated in vacuo. Ether is added to the concentrate, the mixture is frozen and the solid product is recovered and the methylene chloride-ether mixture is recrystallized from the mixture, resulting in the production of 2,245.0 g (75% yield) of the desired product.
    Method C
    3,4-methylenedioxyaniline (3.3 g,.
    24.1 mml) is mixed with ethyl 4-bromobutyate (3.5 ml, 24.1 mol) and 2 methoxyethanol (100 ml) is added to the mixture. The mixture is heated at the temperature of reflux distilled (in an atmosphere of dry nitrogen) for 30 hours with stirring. Zyz solvent is evaporated in vacuo and an oily solid is obtained. The oil is treated with ethyl acetate and filtered. The solution is absorbed by about 10 g of silica gel 60 and placed in a column with 60 g of silica gel 60. After elution with a mixture of ethyl acetate and petrol: m ether 10:30, combining
    and blending the appropriate fractions and recrystallizing the crude solid from a mixture of dichloromethane and petroleum ether (30-40), give - (, 3-benzodioxol-5-yl) -2-pyrrolidine (0.5 g), piece 99 ,, 5 ° C.
    Elemental analysis:
    Calculated,%: C 64.38; P 5.40; 1 6.83.
    N
    C H and Shz Found,% 6.78,
    C, 64.21; H 5,
    (one)
     at
    The resulting compound of the formula has an analgesic effect ranging from mild to moderate. strong. As an analgesic agent, a compound of formula (T) is analogous to morphine; and codeine, but is stronger than aspirin or acetaniline, as established in trypsin tests and hot plate tests. Unlike morphine or codeine, the analgesic effect of compound (1) is not reduced by naloxone and is not bound to the receptor.
    3
    morphine. Thus, compound (1) is considered as a non-narcotic agent. The duration of the analgesic effect of the compound
    Formulas (1) are more than
     -. codeine or morphine.
    It was found that compound (G) has a strong long-lasting anti-inflammatory effect on the organism of rats; this was revealed in tests on rats infected with carrageenic pleurisy. Compound (I) is similar to acetaniline in terms of the severity of the anti-inflammatory effect, and causes a stronger and more prolonged anti-inflammatory effect at comparable doses.
    Compound (I), as well as acetanilin, has antipyretic and hypothermic effects, as established when tested in rats with hypothermia caused by yeast. In other words, the compound of formula (1) reduces the heat in rats in the same way as aspirin and acetaniline,
    Analgesic effect.
    Acetic Acid Test (AAWT).
    Using the well-known methodology (Koster et al. Fed, Proc, 18, 412, 1959, Vinegar et al., Reference Guide to Experimental Pharmacology, 50-2, Ch. 26, Anti-inflammatory drugs.
    Ed, J, R, Vane and S, H, .Ferreira, 1978),
    Acetic acid test was carried out in mice and rats, during which a weak analgesic effect of the compound of formula (I) was demonstrated. The following values of EDg (mg / kg) were obtained by testing compounds administered through the mouth in rats
    Compound (I) Acetanilin Aspirin Codeine Phosphate
    36 - 7.1
    127 16.4 21 - 3.4 30 ± 2.7 Modified trial with increased pain sensitivity to trypsin (THA),
    In this trial, the absence of pain sensitivity is quantified; it is ineffective when using compounds with anti-inflammatory effects. A known technique is used (Vinegar et al., Eur. J. Pharmacoi, 37, 23 1976) to demonstrate
    92-4 The anesthetic action of the compound of formula (I) and some known anesthetics. Anesthetic agents are administered to the rat 30 minutes after the administration of trypsin. Moreover, an anesthetic agent is introduced into the body 15 minutes before the subcutaneous injection of trypsin (0.10 ml of a 10% solution of trypsin in water, free of pyrogenic substances). In both tests, the THA pain index was determined 60 minutes after the trypsin injection. The results are reported in Table 1, Compound (I). active when exposed to 7.5 kg of weight, as well as when exposed to 6.0 kg of weight, while acetaniline is inactive when exposed to 7.5 kg of weight.
    Table 1

    The compound (T).
    Acetaniline
    Aspirin
    24-5.3 23-3.5
    95-17,2 Inactive at 200
    Inactive at 180
    40
    Codeine Force Fat
    10-1.7 8.8-2.77
    five
    Q
    Each dose of the preparation is tested on 6 rats, at least three doses are applied.
    Hot plate test performed on rats.
    Known testing with hot plates (Eddy et al. J, Pharmacot, Exp, Ther, 98, -12J-137, 1950) is known. In this experiment, the diameter of the cylindrical (water-filled) copper plate was increased to 25 cm for enable the testing of rats instead of mice and use a temperature controller to regulate a 250-watt infrared heating lamp that comes from a thermistor probe attached to the bottom surface
    top of the copper plate. In this way, the surface temperature is maintained (28 measurements of the temperature of the hot plate under experimental conditions). The time during which a rat, placed on a plate, reacts to stimulation of the front or rear parts of the limbs (rise, trembling, beating), is expressed in tenths of a second. In the studies, only those animals that react in the preliminary test for 6-13 s. Drugs are suspended in a 0.5% solution of sodium carboxymethyl cellulose and administered through a stomach tube administered through the mouth in an amount of 1.00 ml per 100 g of body weight 60 minutes before the test: 1
    86-16,5
    Inactive Inactive at 360 at 360
    Duration of action, h
    5.0
    Dose,
    mg / kg (oral)
    120
    The duration of the test in rats using a hot plate is the time during which the EDOo with the hot plate is reduced by a factor of 1.5 to 40% inhibition.
    Rapid anti-inflammatory action.
    Testing, with carragenous pleurisy (CPA).
    By performing the procedure described by Vinegar et al. (Progos, Soc. Exp, Biof, Med 151,556, 1976), the rapid anti-inflammatory effect of the compound of formula (I) is compared with the anti-inflammatory effect of the known anti-inflammatory agents when tested in rats. For each treated group of rats, an average 3-hour volume was determined.
    which reacts are considered
    neither, animals,
    her than 18.3
    as unprotected, and animals that do not react in less than 18.3 s are considered to be protected. The response time of 18.3 s is an average duration of 3 and a preliminary test of 40 optional
    working rats and time corresponding to three standard deviations from the mean. The values of EDU and their standard errors are determined by the graphic dose-response curves with
    using the standard MifHer and Tamter method (Proc. Sec. Exp, BioL. Med. 57, 261-262, 1944). The analgesic effects of the compound (1) / :, standard pain medications are compared.
    means (table 2).
    table 2
    57-35 6
    17-3,6
    t h J, J
    2.5
    (90)
    (thirty)
    and calculate the percent inhibition relative to the control animals in which the solvent is injected, with the EDIT being the dose required to reduce the volume of the 3-hour effusion by 50%. Test compounds entered through the mouth. gave the following values of ED5s, mg / kg:
    Aspirin28 -3,2
    Acetaniline 1
    72-22,4
    Compound (1)
    4810, 5
    Antipyretic effect,
    The test was carried out on rats with yeast-induced hypothermia according to a well-known method (Khatiti-Varasteh et al., Arch. Int. Pharmacot. 219, 1976) with the aim of demonstrating the antipyretic effect of compound (1) and some well-known
    7 12419928
    antipyretics, In the testCompound (I) 67-A, 2
    The following values of ED5T, Aspirin50-8.1 are obtained.
    mg / kg: Acetaniline72 8.6
    权利要求:
    Claims (3)
    [1]
    METHOD FOR PRODUCING 1- (1,3- 'BENZODIOXOL-5-IL) -
    [2]
    2-pyrrolidinone of the general formula
    Ή υ characterized in that
    [3]
    The 3,4-methylenedioxyaniline of the formula “2” is reacted with an internal ester or acid halide or acid anhydride, and the corresponding compound thus formed is subjected to cyclization.
    >
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