• 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:
    This invention relates to a process for making a compound of formula I in the form of a stereoisomer or mixture thereof, wherein R is hydrogen, lower alkyl; X is hydrogen, halo, trifluoromethyl, lower alkyl or lower alkoxy, and the wavy lines represent the a or β configuration with the proviso that when one wavy line is α the other is β, or a pharmaceutically acceptable, non-toxic salt of the compound wherein R is hydrogen; novel intermediates useful for preparing these compounds; processes for making the intermediates; and a stereoisomer of the compound of formula I wherein R is methyl and X is hydrogen and a process for making same.
    公开号:SU1342411A3
    申请号:SU853955489
    申请日:1985-09-24
    公开日:1987-09-30
    发明作者:Фрэнсис Купер Гари；Лесли Рен Дуглас；Рейнольдс Ван Хорн Альберт；Ти Ли Тсунг；Чарльз Бирд Колин
    申请人:Синтекс (Ю.С.А.) Инк (Фирма)；
    IPC主号:
    专利说明:

    eleven
    The invention relates to a process for the preparation of a novel specific stereoisomer 1b-phenoxy-substituted derivative 4,5,13 (E) of prostatrienic acid, namely (4,5,6R, 8R) methyl ester 9-OXO-1 1Y, 1 5c6-dihydroxy-16 -phenoxy-7,18,19,20-tetranoprosta-4, 5, 1 3 (E) -trienoic acid, which is an inhibitor of acid gastric secretion.
    The purpose of the invention is to obtain a new stereoisomer of the prostaglandin series with improved pharmacological activity in comparison with an identical compound as a mixture of stereoisomers.
    Example 1 Preparation of (4,5,6R 8R) methyl 9-oxo-11 cii, 1 hydroxy-16-phenoxy 17,18,19,20-tetranorprost-4,5,13 (E) -trienoic acid.
    An aliquot of 0.3 mg (4,5,6R, 8R) 9-oxy-11y e15y-dihydroxy-16-phenoxy-17, 18,19,20-tetranorprost-4,5,13 (H) - trienoic acid dissolved in 10 ml of anhydrous diethyl ether, to which an excess of diazomethane is added at room temperature. The reaction is monitored by thin layer chromatography and, after completion of the reaction, the ether and excess diazomethane are removed under vacuum to give the desired methyl ester having the following NMR spectral data .С: 173.58; 33.08; 23.70; 90.37; 204.75; OMe 51.63; 88.77; 26.70; 53.43; 213.62; 45.94; 71.94; 54.13; 131.90; 133.49; 70.86; 71.54; 158.39; 114.63; 129.62; 121.40.
    Example 2. Biological activity of (4,5,6, 8R) methyl ester 9-OXO-1 lui, 1 5 °, -dihydroxy-1 6-phenoxy-17,18,19,20-tetranorprost-4,5,13 ( E) -trienoic acid (analysis of acid gastric secretion caused by histamine).
    In the test were used by myself
    As the Sprague-Dawley rat (Hilltop), the animals had a circular plastic collar, buttoned around their neck, to prevent them from accessing food or faeces and to ensure an empty stomach within 48 hours of fasting. The target compound was orally administered with a gastric probe during the morning experiment.
    five
    0
    5 0 5 0
    five
    0
    g
    30 min before surgery. During this procedure, the animals were anaesthetized with ether and one ligature was placed on the duodenal abdominis adjacent to the pyloric sphincter, and the other was placed on the esophagus after the larynx. The abdominal cavity was closed with brackets and histamine diphosphate 40 mg / kg was administered subcutaneously with a single dose during a 3-hour study of stimulated acidic gastric secretion. After 3 h, the rats were euthanized, the gastric juice was extracted from the stomach and its volume was measured .. An aliquot of juice was titrated to 0.02 n. sodium hydroxide to rc 7, OtO, l at the end point on the pH meter, the acidity of gastric secretion was calculated as milliequiva-tapes per 100 g of live weight. The treated groups were statistically compared with the control. In this trial (4,5,6R, 8R) methyl ester-9-oxo-1 1 vol, 15o (, - dihydroxy-16-phenoxy-17,18, 19,20-tetranorprost-4,5,13 (E ) -trienoic acid, used at doses of 0.5–4 µg / kg, was found to have an extrapolated ED of 6 µg / kg in y.
    Example 3. Toxicity (4,5, 6R, 8R) of methyl ester 9-OKco-llci,, -dihydroxy-6-phenoxy-17,18,19, 20-tetranorprost-4,5,13 (Ej-trienoic acid.
    (4,5,6R, 8RJ methyl ester 9-oxo-1 Id, 15cX-hydroxy-16-phenoxy-17,18,19,20-tetranorprost-4,5,13 (E) -trienoic acid was introduced intraperitoneally to male mice (Sim (IGRJ FBR) at doses of 0.125-0.5 mg / kg. At these doses, the mortality of the test animals was not observed.
    Comparative stability data.
    (4,5,6R, 8R) Methyl ether 9-oxo-11 oi, 15a: .- dihydroxy-16-phenoxy-17, 18,19,20-tetranorprost-4,5,13 (E) - triene acids (compound I) and the known compound, namely (dl) methyl ester 9-oxo-Py, 15 () b-dihydroxy-16-phenoxy-17,18,19,20-tetranorprost-4,5 , 13 (E) -trienoic acid (compound II), was stored at 45 ° C for 4 weeks. Both samples were protected from light. After 4 weeks, the samples were investigated using the EHVD to obtain the results shown in table 1.
    313A241
    Table 1
    100
    96.2
    100
    73.5
    When storing compounds G and I at a relative humidity of 40 and 79.5%, respectively, the results were obtained, 20 are given in Table 2.
    Table 2
    Relative
    The remaining amount, 25%, when stored at 40 С
    Comparative test on the biological activity of compounds I and P.
    In the test, 10 male Sprague-Dawley rats were used (NI-ItopK. The animals had a plastic ring collar buttoned around their neck in order to prevent them from accessing food or feces, and to guarantee an empty stomach for 48 hours of starvation. the compound was applied orally using a gastric probe during the morning experiment 30 minutes before the surgical intervention.
    VNIIPI Order 4447/58 Circulation 371
    Random polygons pr-tie, Uzhgorod, st. Project, 4
    0
    15
    20
    25
    thirty
    35
    40
    45 gQ gg
    They were anesthetized with ether, and one ligature was placed on the duodenum adjacent to the pyloric sphincter, and the other was placed on the esophagus after the larynx. The abdominal cavity was closed with brackets and histamine diphosphate 40 mg / kg was administered subcutaneously with a single dose during a 3-hour study of stimulated acidic gastric secretion. After 3 h, the rats were euthanized, gastric juice was isolated from the stomach and its volume was measured. An aliquot of juice was titrated with 0.02 n. sodium hydroxide to pH 7.0 i ± 0.1 at the end point on the pH meter. The acidity of gastric secretion was calculated as milliequivalents per 100 g of live weight. In this trial (4,5,6R, 8R) methyl ester 9-oxo-11s-15.-dihydroxy-16-phenoxy-1 7,18, 19,20-tetranorprost-4,5,13 (Е) - trienoic acid, used at doses of 0.5-4.0 µg / kg, proved to be an effective inhibitor of acidic gastric secretion at a dose of 0.5 µg / kg. (dl) 9-oxo-11cC methyl ester, 1 dihydroxy-16-phenoxy-17,18,19,20-tetranorprost-4,5,13 (E) -trienoic acid, prepared according to a known method and used at doses of 4, 0-16 µg / kg was found to be an effective inhibitor of acidic gastric secretion at a dose of 16 µg / kg. Thus, the specific stereoisomer obtained according to the proposed method inhibits:. acid gastric secretion at a dose 32 times less than the required dose of a known compound, which is a mixture of 4 stereoisomers in equal proportions in the mixture.
    权利要求:
    Claims (1)
    [1]
    Invention Formula
    Method for preparing (4,5,6R, 8R) 9-oxo-11 ° C methyl ester, 156-dihydroxy-16-phenoxy-17,18,19,20-tetra-naphthate-4,5,13 (E) -trienoic acid characterized in that {4,5,6R, 8RJ 9-oxo-1i, 15 1 di-hydroxy-16-phenoxy-17,18,19,20-tetranorprost-4,5,13 (E) -triene acid esterified with diazomethane.
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    优先权:
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