• 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:
    Method of producing derivatives of 2,3,6,7-tetrahydroaazole
    公开号:SU1145932A3
    申请号:SU823430886
    申请日:1982-05-05
    公开日:1985-03-15
    发明作者:Дебарр Франсуа；Фабр Жан-Луи；Фарж Даниель；Жам Клод
    申请人:Рон-Пуленк Эндюстри (Фирма)；
    IPC主号:
    专利说明:

    I The invention relates to a method for producing kovyh derivatives of 2.3565 tetrahydrothiazolo. (Zu2-a} pyrimidium 5-one with the general formula 1 Kg N g tj 5, - Kl s, C, -alkyl where R ,, is a hydrogen atom, or pheni .l: R, is a hydrogen atom, C,. C: -alkyl Cj-Cr-cycloalkyl., or about pen 1 - yl; "and R together C;, C, 5-alkylene; or Ri is a hydrogen atom or I have antirheumatic and gfy that are deprived of proconvolume yx strength, si can be used t; mezzzicke.,; wwestweg method of obtaining 253-d hydrothiazolo (3,2-a) primidine-5-o of formula III .-. x itoTopbrii is that uh konil an ester of the formula CHjCOCHj-COOC-Hfr is reacted with 2-aminothioazoline of the formula 1y rV ". in ethanol at a temperature of blueen of the reaction mixture Cl Compound of formula III has analgesic activity, the Purpose of the invention is to obtain new thiazolo derivatives (3,2-a) pi pkmidin-3-one, possessing a new type of action. The aim is to obtain compounds of general formula 1, which consists in the fact that 1,2 dibromoethane is subjected to / g interaction with 455 - dihydro-2-thiouracil of general formula II -. 32, I where, RJ have the indicated meanings, in an organic solvent medium at room temperature. Example 1. 5.57, a-dispersion of 5157 g of sodium hydride in maele is added over 25 minutes to a solution of 10 g of a solution of 110 g of 4-phenyl, 5-dihydro-2-t ouracil in 1200 cm of anhydrous dimethylformamide, followed by ensure that the temperature of the reaction mixture remains at 15 ° C. 25 minutes after the end of the addition, 91.7 cm of 1,2-dibromoethane is added dropwise to the reaction mixture over 30 minutes, while maintaining the temperature below 15 ° C. Continue to stir for another 2 hours, then allow the temperature of the mixture to rise to approximately. The pH of the reaction mixture was adjusted to pH 5 by adding 1 and. aqueous solution of hydrochloric acid, the reaction mixture is evaporated to dryness under reduced pressure (1 mm Hg, cent., 0.13 kPa) and temperature below. The residue is dissolved in 500 cm of distilled water, the pH is adjusted to 9 by the addition of 10N aqueous sodium hydroxide solution and extracted 3 times with 1400 cm (total) of methylene chloride. Thus obtained organic. the phase is washed with 300 cm of distilled water, dried over anhydrous sodium sulphate, filtered and evaporated to dryness under reduced pressure (20 mm Hg 5 5 2.7 kPa) and temperature. The resulting residue (Wg) is dissolved in 1100 cm of methylene chloride and chromatographed a column with a diameter of 6.8 cm, containing 1100 g of basic alumina (0.05-0.16 mm), was eluted with methylene chloride, collecting fractions of 250 cm-. The first three fractions are dropped; the next three fractions are combined and evaporated to dryness under reduced pressure (20 mm Hg, 2.7 kPa) and a temperature of 40 ° C. The residue obtained (32.5 g) is dissolved in a boiling mixture of 70 cm of ethanol and 70 cm of isopropyl oxide. After cooling, the formed crystals are separated by filtration and dried under reduced pressure (20 mm Hg, 2.7 aPa) and a temperature of about 20 ° C. Thus obtained 15.6 g of the crude product with m, pl. 1, which is combined with 1.4 g of product. .3 obtained by the same method in another operation and dissolved in 60 cm of boiling ethanol. The solution is heated hot and the filtrate is cooled to 1 hour. The crystals formed are separated by filtration, washed with 5 cm of ethanol, then 5 cm of isopropipoxide and dried under reduced pressure (20 mm Hg, 2.7 kPa) and temperature of about 20 ° C in the presence of potassium hydroxide tablets. In this way, 13 g of 5-oxo-7-fennl-2,3,6, 7-tetragyD1-5H-thiazole (3,2-a) pyrimidine are obtained in the form of white crystals with T.Sh1. . Example 2. A solution of 2.8 g of 4-methyl-4j5-dngydro-2-thiourac | 1a in 25 cm of anhydrous dimethylformamide is added dropwise with stirring to a suspension in 20 cm of anhydrous dimethylm-rmide 2, tg of gishiida sodium as 50 % dispersion in vaseline oil should ensure that the temperature of the reaction mixture remains below. By (the sonchas of the addition continue stirring for 1 h, then in the reaction box (her sprinkle dropwise for 30 min 3.8 cm 1,2-dibrometry, all the while maintaining the temperature #ke. Continue mixing for 2 hours, then the mixture After being cooled, the reaction mixture is evaporated to dryness under reduced pressure (20 mm Hg, 2.7 kPa) and temperature. The resulting residue is dissolved in 50 cm of a saturated aqueous solution of sodium chlorine and extracts 6 times 3 € 0 cm (total): ethyl acetate 4 Organ The combined phases are washed with water to dryness under reduced pressure (20 mm Hg, 2.7 kPa) and temperature. The residue is chromatographed on a 3 cm diameter column containing 65 g of silica (0.040-0.063 mm), eluting with ethyl acetate at a pressure 0.5 bar (51 kPa) and 100-cc sampling. After removal of the first seven fractions and evaporation under reduced pressure (20 mm Hg, 2.7 kPa), 0.15 g are recovered from the five fractions. the product, which is again chromatographed on a column with a diameter of OJ5 cm, containing 1.5 g of neutral glycol32. earth (0.12-0.15 mm). Elute with a mixture of methylene chloride and cyclohexane (50; 50 by volume), collecting 5 cm fractions. The first two fractions are discarded, the next eight fractions are combined and evaporated to dryness under reduced pressure (20 mm Hg, 2.7 kPa) and temperature. 40 mg of 7-methyl-5oxo-2, 3,6,7-tetrahydr-5H-thiazole (3,2-a) pyr-shidin are thus obtained in the form of white crystals with m.p. 95 C. According to the method of example t, but proceeding from the corresponding 2-tauratssh1ov,. get the next products. Froze 7-Ethyl-5-oxo-2, 3,6,7-tetrahydro-5H-thiazole (3,2-a) is pyrimidine with t.cl. . PRI eper4. 7-Isopropyl-5-oxo-2, 3,6,7-tetragndro-5H-thiazole; - (3,2-a) pyrimidine with m.p. 50,. Example 5. 5-Oxo-7-propyl 2, 3,6,7-tetrahydro-5-thiazole (2,3-a) pyrgy1idium with m.p. . Example 7-fpet-Butyl-5oxo-2, 3,6,7-tetrahydro-5H-thiazole (3,2-a) pyrimidine with m.p. . Example 7i of the 7th 9-Butch-1-5oxo-2, 3,6,7-tetrahydro-5H-thiazole (3,2-a) pyrimidine in the form of an oil with n | H, 546. Example8. 5-Oxo-7-propen-1-yl-2 j 3,6,7-tetrag1adro-5H-thiazole (3: 2-a) pyrimidine in the form of an oil with a so-called boiling point, under pressure /. 3.5 mm Hg. P im im 9. 7-Cyclopropyl-5oxo-2, 3,6,7-tetrahydro-5H-thiazole (3,2-a) pyr1B4idin with m. . Example 10. 7-Cyclohexyl 5-oxo-2,3,6,7-tetrahydro-5H-thiazole (3,2-a) is a pyrimidine with so pl. . Example 1. 6-Metip-5-oxo2, 3,6,7-: tetrahydro-5H-thiazole 3,2-a) pyrimidine with m.p. . Example -12. 7,7-Dimetsh1-5okso-2, 3,6,7-tetrahydro-5H-thiazole (3,2-a) pyrimidine with so pl. . PRI me R 13. b-Oxo-2,3,6,7 tetrahydro-spiro-5H-thiazole (3,2-a) pyrimidine-7, 1-cyclohexane with so pl. , Example 14. 5-Oxo-7-trifrp-methyl-2,3,6,7-tetrahydro-5H-thiazole (3,2-a) pyrimidine with m.p. 120C. Anti-rheumatic activity of compounds of general formula I. Description of the test used (paw edema due to the opposite passive reaction of Arthus). Male rats C.O.B.S. (Caesarian Originated Barrier Sustained) origin diabetes, taken in the firm Char les RIVER FPANCt, weighing 16-0-200 g and withstand ;; fasting without food for 24 hours. The test product is administered orally during Tg-1 as a solution or suspension in an aqueous 10% solution of gum arabic or in peanut oil 5 cm / kg each. After rabbit (during TO), 0.1 cm of serum of anti-protein substance (anti-albumin serum) of rabbit (solution with 0; 5 mg / cm) is injected under the hind paw, then 1 cm of ovalbumin solution is injected intravenously (solution of 0.5 mg /cm). After 2 hours after this last injection (during To + 2), the thickness of the paws to which the injection was made is measured using a Z1V micrometer and the results are compared with those observed during TD - 1. For each paw, the tumor size (measured in mm) equal to the difference between the measured, carried out during TO -I- 2 and Tj, -1 Use 8 animals per dose and the results are expressed as the average of the observations corrected for the average standard error (E, S, M), then determined tode student value. The differences in thickness observed for the treated and control animals are statistically significant with an error probability below 0.01, while tode Student is higher than 3. The results are presented in Table 1. Proconvulsive activity. Spent the test used. Injecting intravenously at a constant rate (0.3 cm / min) of pentetrazole in water gives the mouse successively three types of convulsions: Type 1 - twitch or the only effect of the whole body. Type 2 is a pseudo-convulsion or the beginning of a series of clonic movements, usually accompanied by a cry, alternating with rest phases. Type 3 is a final long-lasting convulsion, tonic in control with a thumb. The test product is dissolved or suspended in an aqueous 10% gum arabic solution or in peanut oil. The resulting suspension or solution is injected at a dose of 100 mg / kg orally for 1.5 hours before the injection of polyetrazole. Use 10-15 animals per dose of the product; 10-15 control animals receive one solvent (without the test product) under the same conditions. A decrease in the volume of pentetrazole injected into the treated mice, compared with the volume injected to control mice, calculated for each convulsive phase, results in a decrease in the convulsive threshold of this agent. Statistical analysis is performed using the MANNWHITNEY method. If the observed differences are statistically insignificant, then the product is considered as not proconvulsant; if they are statistically significant (with an error probability lower than 0.05), then the product is considered to be proconvulsant (proconvulsant). in tab. 2 given the results obtained. As can be seen from the table. 2, for a standard product of formula III, the volumes of pentetrazole that can be administered to animals to obtain type 1.2 and 3 convulsions are statistically less than that administered to control animals for. obtaining respectively three types of convulsions, i.e. it has been statistically established that with the technique used, the standard product is proconvulsant (proconvulsive). For the proposed products, the volumes of pentetrazole required to obtain convulsions are not lower than those administered to control mice. Only the product of Example 10 requires higher volumes of pentetrazole, however these deviations are statistically insignificant.
    T and b and c-1 00 D “. | (M O O O O O O ooooo l G 8mm - -shkNo WСЧ Ч «чМ« в О Л «п 4« ч м о о о о о о G »P rt« м «м л сч about Ш м
     Г § § S § чг О С С о го tn fM «о f S § § § § о« -о о о 41 + 1 «N Е 22, § о о 1Л g о
     (
    g {i
    权利要求:
    Claims (1)
    [1]
    METHOD FOR PRODUCING 2,3,6,7-TETRAHYDROTHIAZOLO (3, '2-a) PYRIMIDIN-5-ONE DERIVATIVES of the general formula I where is a hydrogen atom, C ^ -C 4 -alkyl or phenyl;
    Rj is a hydrogen atom, C ^ -C 4 -alkyl,. Cj-C ^ cycloalkyl or-propen1-yl or R) and Rj. together with 4 -C alkylene;
    - a hydrogen atom or C ^ -C 4 -alkyl, characterized in that
    1,2-Dibromethane is reacted with 4,5-dihydro-2-thiouracil of the general formula II where Rt, R 2 and Rj have the indicated meanings in an organic solvent at room temperature.
    Priority by feature.
    07.24.80 when R 3 is a hydrogen atom, a Cy-C ^ alkyl or phenyl and R z and R 3 is a hydrogen atom
    05/15/81 at R 4 - a hydrogen atom, C 4 -C 4 -alkyl or phenyl; .
    AND ^ -C ^ -C ^ -alkyl, C a -C t -cycloalkyl or propen-1-yl or
    R and Rj are together C 4 -C s -alkylene and Rj is a hydrogen atom or C 4 -C 4 -alkyl.
    1 11
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    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    US3888983A|1970-08-14|1975-06-10|Seperic|Derivatives of thiazolino-pyrimidin-6-ones, in inducing analgesia|
    GB1306558A|1970-08-14|1973-02-14|Seperic|Derivatives of thiazolino-pyrimidin-5-ones their preparation and applications|
    BE778911R|1972-02-03|1972-05-30|Seperic|7-substd-2,3-dihydrothiazolo pyrimidin-5-ones - - analgesics|
    HU178910B|1977-08-19|1982-07-28|Chinoin Gyogyszer Es Vegyeszet|Process for preparing 2,3-disubstituted-4-oxo-4h-pyrido/1,2-a/-pyrimidines|FR2530636A1|1982-07-23|1984-01-27|Rhone Poulenc Agrochimie|NOVEL DERIVATIVES OF 2,3,6,7-TETRAHYDRO 5H-THIAZOLOPYRIMIDINE, THEIR PREPARATION AND THEIR USE AS HERBICIDES|
    GB8300728D0|1983-01-12|1983-02-16|Erba Farmitalia|Substituted carboxy-thiazolo / 3 2 - a / pyrimidine derivatives|
    PH23995A|1984-01-09|1990-02-09|Janssen Pharmaceutica Nv|4-methyl and hetero)piperidines|
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    法律状态:
    优先权:
    申请号 | 申请日 | 专利标题
    FR8016319A|FR2487355B1|1980-07-24|1980-07-24|
    FR8109724A|FR2505842B1|1981-05-15|1981-05-15|
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