• 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:
    A compound of the formula (I) <IMAGE> (I) in which the three methoxy radicals are in the 3,4,5, or 2,4,6 or 2,4,5 or 2,3,5 or 2,3,6 positions, in which either A and B together represent a double bond or else A represents a hydrogen atom and B represents a hydroxy radical, and in which R represents a hydrogen atom or an alkyl containing 1 to 5 carbon atoms, in the various possible stereoisomeric forms, as well as the alkali metal, alkaline-earth metal, or amine salts thereof in which R represents a hydrogen atom, methods of producing the same, pharmaceutical compositions containing the same and treatment of various gastric ailments are disclosed.
    公开号:SU1264836A3
    申请号:SU823423751
    申请日:1982-04-16
    公开日:1986-10-15
    发明作者:Кристидис Йани；Фурне Робер
    申请人:Руссель-Юклаф (Фирма)；
    IPC主号:
    专利说明:


    The invention relates to a method for producing (E) 4- (3,4,5-trimethoxyphenyl) -4-oxo-2-buteic acid, which has cytoprotective action. The purpose of the invention is to develop a process for the preparation of compounds with enhanced cytoprotective action. Example 1. 4- (3,4,5-Trimetho sipennl) -4-- oxo-2-hydroxybutane w slot. 29.6 g of glyoxyl kilogram (50% aqueous solution) are heated under reduced pressure to remove 80% of the water present, and 84.1 g of 3,4,5-trimethoxy acetophenone are introduced into the reaction medium after cooling. They are heated for 2 hours at 95–100 0 under a reduced pressure (40–50 mmHg) distillation simultaneously, and os1-stream water is present. After cooling 1 and the medium, 120 cm of water containing 11.6 g of sodium carbonate are added and the ether is decanted, the water is taken up with ether and the aqueous layer is acidified to hydrochloric acid (half the amount). The desired product is extracted with ethyl ether. After removal of the solvent and recrystallization from 1,2-dichloroethane, 31.5 g of the expected product, tn / i .119-120 ° C, are obtained. Calculated,%: C 54.93; H 5.67. Greater%: C 54.9; H 5.7. Lpdimetry 98.3% (from TeopiHi). PRI me R, 2. (E) 4- (3,4,5-Trimethoxyphenyl) -4-oxo-2-butane lotion. On 6.5 hours, under reflux, 15.8 g of 4- (3,4,5-trimethoxyphenyl) -4-oxy-2-g alkaline acid obtained in Example 1, 20 cm of acetic acid and 20 cm of concentrated hydrochloric acid were obtained under Example 1 (,18). The reaction mixture is cooled and precipitated with 13 Sludge. The precipitate formed is filtered off to obtain 12 g of crude target product, t; n, .140 ° C. After recrystallization in 40 cm of a mixture (1: 1) of ethanol-water, 10.5 pure products, tnh, are obtained. 144 ° C. Calculated,%: C 58.64; P 5.30. Pavdeno,%: C 58.4; H 5.3. AshzDimetri 98.7 + 0.5% (from theory). NMR spectrum: the constant pairing of vinyl protons is 16 Hz, indicating trans-isomerism. A study of cytosis of the cytine effect of products A and B. Female rats weighing 200 g after 6 hours of hunger strike (water if desired) were placed in an individual cage and deprived not only of writing, but also of water for another 18 hours. Rats (10 per group) were injected through the mouth: products in the indicated doses and after 1 h were given through the mouth 1 ml of one of the following necrosis-inducing agents: absolute ethanol, 0.6 n HCl ,. 0.2 n. NaOH. After 1 h, animals were exposed to ether, their stomachs were taken for analysis and opened according to a large bend. Conducted a study of the gastric mucosa under a microscope Stereozoom./A. 0.570 /, the lesions were counted and determined. For each stomach, the general indicator of the lesion was calculated, the values of each lesion were added according to the following scheme: 1 - for less than 0.5 mm, 2 - for 0.5-1.5 mm, 3 - for 1.5-3 mm, 4-caller more than 3 mm. The test results are given in table. 1. All three agents caused significant damage to the gastric mucosa, which appeared as bands elongated and parallel to the longitudinal axis of the stomach (red with ethanol and 0.2N NaOH and black with 0.6N, HC1). (E) -4- (3,4,5-Trimethoxyphenyl) -4-oxo-2-butenoic acid (product A) at a dose of 1.25 mg / kg when administered through the mouth has a cytosteric effect on ethanol and NaOH 0.6 mg / kg. Zimetidin-K-cyano-N-methyl-N--1 2 (5-methyl-1H-imidazol-4-yl) methylthio-ethyl | -guanidine (product B) even at elevated doses (12.5-2550-100 mg / kg) was inactive. The cytoprotective effect of product A on the effect of necrosis caused by ethanol rm (comparison with cimetidine) is given in Table. 2. Cytoprotective activity of the product A or necrosis caused by ethanol. pf is at a small dose (0.6 mg / kg through the mouth), and with a lesion caused by 0.2 n. NaOH, pr 1.25 mg / kg. The LDso of product A, given orally to mice, is 600 mg / kg. Example 3. 4 (2,4,5-Trimetho-syphenyl) -4-oxo-2-hydroxybutanoic acid. 19.3 g of glyoxal kilotone (50% aqueous solution) are heated under reduced pressure to remove about 80% of the water present, then cooled and 54.6 g of 2,4,5-trimethoxy-acetophenone are introduced into the reaction medium. Heat 3 hours at 90 ° C under reduced pressure (50 mmHg) distillation simultaneously residual water. After cooling the medium, 200 cm of toluene and 400 cm of water containing 7.5 g of sodium carbonate are introduced. The aqueous layer is decanted, agglomerated with toluene, and then acidified to hydrochloric acid (half the amount). The target product is then extracted with ethyl acetate. After removal of the solvent and recrystallization in 200 cm of 1,2-dichloroethane, 24.6 g of 4-C2,4,5-trimethoxyphenyl) -4-oxo-2-hydroxybutanoic acid are obtained, tn 146 ± 1 ° C. Calculated,%: C 54.93; H 5.67. Found,%: C 54.9; H 5.7. NMR spectrum: according to structure. Acidimetry 100.5 ± 0.5% (from theory). II p and measures 4. (E) 4- (2,4,5-Trimethoxyphenyl) -4-oxo-2-butenoic acid. 11 g are obtained under reflux for 2.5 h. Obtained in Example 3 is 4- (2,4,5-trimethoxyphenyl) -4-oxo-2-hydroxybutanoic acid, 30 cm of acetic acid and 2 cm of concentrated hydrochloric acid ( d 1.18). The resulting solution is cooled to room temperature, after adding 100 cm of water, the formed precipitate is filtered off, 7 g of crude target product t 207–208С are obtained. After recrystallization in 20 cm of acetic acid, 6.3 g of pure product are obtained, t., 210 ° C. Calculated,%: C 58.64; H 5.30. 8364 Found: C 58.6; H 5.3. NMR spectrum: the constant pairing of vinyl protons is 16 Hz, indicating trans-isomerism. Example 5. (E) 4- (2,4,6-trimethoxyphenyl) -4-oxo-2-butenoic acid. 3.3 g of potassium hydroxide tablets are mixed in 100 cm of absolute ethanol, 31.5 g of 2,4,6-trimethoxy acetophenone are introduced and 30 ml of 1% 80% aqueous solution of 4.6 g of glyoxylic acid are added dropwise over 30 minutes. 50 cm of absolute ethanol .: A half-finished solution is heated for 6 hours under reflux, and then evaporated to dryness under reduced pressure. The residue is taken in 300 cm of water, filtered, collected. a filtrate that is acidified to pH 1 using concentrated acid. The desired product crystallizes, is sucked off, then dried to constant weight at 60 ° C under reduced pressure. Obtain 0.7 g of the target product, which is crystallized in methyl ethyl ketone, tp 152 ± IC. Calculated, 58.64 H 5.30. C, 3N, O / (266.30) Found,%: C 58.7; H 5.5. NMR spectrum: the constant pairing of vinyl protons is 16 Hz, indicating trans-isomerism. Example 6. Methyl ester (E) 4- (3,4,5-trimethoxyphenyl) -4-oxo-2-butenoic acid. A mixture of 20 g of (E) 4- (3,4,5-trimethoxyphenyl) -4-oxo-2-buteic acid, 150 cm of methanol and O, 15 g of p-toluenesulfonic acid is heated under reflux for 5 hours. The resulting solution was cooled to room temperature, 0.2 g of sodium acetate was added and evaporated under reduced pressure. 200 cm of toluene was added to the residue, washed with an aqueous solution of sodium bicarbonate and then with water. The solvent is removed under reduced pressure, the residue is recrystallized in methanol-water (1: 1) and 10.7 g of the expected product are obtained, t 94 ° C. Example 7. The salt of morpholine (E) 4- (3,4,5-trimethoxyphenyl) -4-oxo-2-butenoic acid. 50 cm of ethyl ether, containing 1.788 g of morpholine, is poured into a solution containing 5.375 g of (E) 4S1264836 “
    - (3,4,5-trimethoxyphenyl) -4-oxo under reduced pressure at 20 ° C.
    -2-butenoic acid. Filtered-: 7 g of the expected product is obtained, t,
    the precipitate formed is washed-250 ° C
    ethyl ether and dried under
    reduced pressure. 6.5 g of s are obtained. Example 9. Piperidine salt. Target product, tn 140 C. (E) 4- (3,4,5-trimethoxyphenyl) -4-ok Example 8. Sodium salt (E) is c6-2-butenoic acid.
    4- (3,4,5-trimethoxyphenyl) -4-oxo-50 cm ethyl ester, containing 2-butenoic acid, 1,988 g of piperidine, was added
    When Yu.S., 28 cm 1 n. water- Yu to a solution of 6.215 g of (E) 4- (3,4,5-tric sodium hydroxide solution in a mixture of methoxyphenyl) -4-oxo-2-6 utene
    7.7 g of (E) 4- (3,4,5-trimethoxyphenyl) acid in 1200 cm-ethyl ether.
    -A-oxo-2-6utene acid and 30 cm; the resulting precipitate is filtered off,
    water. Filter and evaporate to reduce it with ethyl ether and dried pressure. The resulting solid 5 shat iodine reduced pressure. The substance is taken up with acetone, filtered out; 7.3 g of the desired product is obtained, t, dry, washed with acetone and dried at 124 ° C.
    Means, challenge- Damage rate
    necrosis
    1 MP / rat Mean ES var,
    Control Product A,
    Absolute
    ethanol 31,3 + 6,32,3 + 1, 7
    0.6 N HC114.0 + 5.810.6 ± 3,, 3
    0.2H.NaOH25.1 + 3.51.0 + 0,, 0
    P 0.05 P 0.01.
    Product Damage Rate
    (by mouth) average vel,
    0.52
    0.16 0.30 0.60
    Tsiyetidin
    12.5
    Table 1 1.25 mg / kg by mouth
    Table 2
    rank ± ES
    -34.1 -34.1 -59.2
    8.7 + 9.5
    -17,8
    2557.1 + 11.9
    5050.9 + 11.3
    10087.9 + 13.3
    If
    P 0.05 ft “P 0.01.
    -3.7 -14, 2
    +48.2
    权利要求:
    Claims (3)
    [1]
    METHOD FOR PRODUCING (E) 4- (3,4,5-TRIMETOXYPHENYL) -4-OKS0-
    [2]
    2-BUTENIC ACID, characterized in that they react glyoxylic acid with
    [3]
    3,4,5-trimethoxyacetophenone at 95-100 ° C and a pressure of 40-50 mm RT. Art. followed by dehydration of the resulting 4- (3,4,5-trimethoxyphenyl) -4-oxo-2-hydroxybutanoic acid at the boiling point of the reaction mixture in acetic and concentrated hydrochloric acid.
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