• 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:
    Compounds of the general formula <IMAGE> in which R' is hydrogen or a methyl radical; R is a hydroxyl, acetoxy, arylaminocarbonyloxy, alkylaminocarbonyloxy radical; Z is hydrogen or a lower alkyl, or R and Z together are oxygen. These compounds exhibit a very favorable separation of desirable contraceptive and undesirable uterine and antigonadotrophic properties.
    公开号:SU1087525A1
    申请号:SU792781813
    申请日:1979-06-27
    公开日:1984-04-23
    发明作者:Понсольд Курт；Проуза Рихард；Оеттель Михаэль；Штреке Йоахим；Хоффманн Херберт
    申请人:Феб Йенафарм (Инопредприятие)；
    IPC主号:
    专利说明:

    The invention relates to new chemical compounds, ISiX- and 14H, 15p-methylene derivatives of an estranyl series of the general formula CH3 HH1: 1gOn: where a is hydrogen or, if I am about a methyl group, then 14, The 15-methyl group has an /, -configuration having an interceptive effect. Some 3-labels of the si-17-hydroxy derivatives of the estrano series (for example, mestranol) are known to have an interceptive effect I. The disadvantage of these compounds is the presence of side effects caused by uterotropic and antigon anti-troptin activity. The reaction of a steroid containing a double bond with a methylene dihalide in the presence of a zinc-copper pair or with diazomethane in the presence of zinc iodide is known, leading to the formation of a corresponding methyl methane PT. The aim of the invention is to expand the means of action on a living organism. This goal achieves the properties of compounds - 14 ° (, 15 ° C or 141, 15 -methylenodioerated countries of the general formula ij, having an interceptive effect. The proposed compounds are obtained by the method of ocHOBanHMvs on the known reaction of preparing methylene derivatives and including in the synthesis of the same. 3-methoxy-1, 3.5 (Yu), 14-getraen-17-ol derivative is treated with methylene iodide or methylene bromide in the presence of a zinc copper pair or diazomethane in the presence of zinc iodide in an inert organic solvent, such diethyl ether. Example 1. 3-Methoxy-14 f, 15Y methylene-estra-1,3,5 (10) -trien-17P-OL. a To 1 g of 3-methoxyester-1,3,5 (10 14-tetraene-17P 2 g of zinc-copper vapor obtained by the method of Shank and Shakhtar are added to 20 ml of diethyl ether, then 2 drops of methylene iodide are added dropwise. The reaction mixture is then stirred under nitrogen or argon, first at room temperature. and then for 4-6 hours, and, moreover, more than 1.5 ml of methyl thio-iodide and 2 g of zinc-copper pair of Yosle are added, after which the mixture is filtered, diluted with ether or a mixture of benzene npoMtiisamT Water with a solution of ammonium chloride and water, organic phase is dried with sodium sulfate and evaporated, and the oily residue is crystallized from petroleum ether. Output 800 mg (75.2%), so pl. 137-138 ° C, "about + 119.5 ° (, СНСе.,), B) To 1.5 g of active zinc-copper complex obtained by the method of Le Goff, in 40 ml of absolute diethyl ether, add 1 ml of methylene bromide and heated to a nitrogen or argon atmosphere. Then, 1 g of 3-methoxyestra-1,3,5 (10), 14-tetraene-17 | -ola, dissolved in 5 ml of absolute diethyl ether, and additionally 1.2 ml of methylene bromide and stirred for 1 g for 5 h at 40 ° C. Then, DIETHLOEYG is diluted with ether and benzo EOL; The solution is filtered, the filtrate is repeatedly washed with a saturated aqueous solution of ammonium chloride and water, the organic phase is dried with sodium sulfate and evaporated. The crystalline residue is recrystallized from petroleum ether and methanol. Yield 745 mg (70%). c) 2.4 g of zinc iodide are suspended in 10 ml of absolute diethyl ether, the suspension is cooled to 0 ° C and 30 gdl of a 0.5 M ethereal solution of diazomethane are added dropwise. The reaction mixture is concentrated on a rotary evaporator to half the volume and then 300 mg of 3-methoxy-estra-1, 3, 5 (10), 14-tetraene-17 3-ol in 10 ml of ether are added, and the mixture is stirred for 30 minutes at room temperature. The temperature is heated and then it is heated to 40 ° C for another 4 hours. The reaction mixture is filtered, diluted with diethyl 5N-ether and re-washed with a saturated ELM aqueous solution of aIvImonium chloride and water. The oily residue remaining after evaporation is crystallized from petroleum ether. The output of 1.4 g (b%). Example 2. Z-Methoxy-14bA, 15 "Z-methylenestra-1,3, 5 (10) -trien17" - ol. To 1 g of 3-methoxy-estra-, 3, 5 (10), 14-tetraen-17 °; -ol, dissolved in 25 ml of ethylene glycol dimethyl ether and 25 ml of diethyl ether, add 3 g of zinc-copper pair and, in accordance with example 1 3 ml of methylene iodide. Under nitrogen or argon, first at room temperature, and then at 40 ° C, stir for 2-3 hours, then the mixture is filtered, diluted with diethyl ether or ether / rbenzene mixture, and washed again with saturated aqueous ammonium chloride solution, dissolved in sodium sulfate and evaporated. The residue is crystallized from petroleum ether. Yield 780 mg (73.3%) m.p. 143-145 ° С,, 8 ° (. С 1, СНСе). Example 3. 3-Methoxy-14р, 15 | -methylene-1,3, 5 (10) -trien17o (. -ol.
    To 400 mg of 3-methoxy-14p, ISfi-Methylenestra-1, 3.5-C10) -trien-17-ol, dissolved in 300 ml of methanol, 380 mg of sodium borohydride was added at 0 ° C and left overnight at at room temperature, then the mixture is evaporated in vacuo to half the volume and poured into ice water, acidified with acetic acid. The precipitate is dried and after preparative thin layer chromatography using silica gel mobile phase: benzene / acetone 3: 2), 90 mg of 3-methoxy-14,15 p-methylene eshr-1, 3, 5 (, 10) -triene-17 - are obtained ol and 210 mg of 3-methoxy-14p, 15-methylenestra-1, 3.5 (10) triene-17o-ol, so pl. 117-119 ° С ,, 0 ° (, SNSbz),.
    Example 4. Z-Methoxy-1400, 151 | - methyleneestra-1,3, 5 (10 trien17Я-OL.
     100 mg of 3-methoxy-14 ° C, 15 ° (, methylenestra-1, 3.5 (10 -triene-17pna, dissolved in 150 ml of methanol, with OC), sodium etheoxy 400 mg of fiopyihydride and left overnight
    . at room temperature. The mixture was poured into ice water acidified with acetic acid, the precipitate was dried, and after preparative thin layer chromatography using kieselgel (mobile phase: benol / acetone / methanol 45: 5: 1), 180 mg of 3-methoxy-14O1. 1, 3, 5 Xu-trien-17 (C-ol and 220 mg of 3-methoxy-14o (., 15o-methyleneestra-1, 3.5 (S) triene-17p-ola, mp. 118- 120 ° C ,, 0 ° (, CHCet,
     100 mg of 3-methoxy-147,15 (methylene-1, 3.5 (10 -trien-17-ol dissolved in 12 ml of absolute
    tetrahydrofuran, 100 mg of lithium hydride hydrate was added at 0 ° C and left for 1.5 hours at room temperature. After addition of ethyl acetate and dithyl ether, the mixture is washed with saturated aqueous -1 solution of ammonium chloride and water, the organic layer is separated, dried with sodium sulfate and evaporated in vacuo. After preparative thin layer chromatography using silica gel (mobile phase: benzol / acetone / methanol 45: 5: 1, 60 mg of 3-metoxy-14s (., 15o (.-Methylene ether-1,3,5 (S) triene-17 (-ol and 26 mg of 3-MeTOKCH-14o 151) |; -methylene-1,3, 5 (10) -triene17 / -ola.
    Example 5. 3-Methoxy-17c methyl-14p, 15 -methlenlestra-1,3,5 (10) -trien-17p-ol.
    To 500 mg of 3-methoxy-17o; -methyl ester-1, 3.5 (10), 14-tetraen-17/3-ol,
    dissolved in 12 ml of dimethyl ether of ethylene glycol and 12 ml of diethyl ether, 1.5 g of zinc-copper pair are added according to example 1, and then dropwise
    1.5 ml of methylene iodide are added.
    Under nitrogen or argon, the mixture is first stirred at room temperature and then 40 ° C for 2 hours. The reaction mixture is then filtered, diluted with diethyl ether and benzene, re-washed with a saturated solution of ammonium chloride and water, and the organic phase is evaporated. The remainder of the cross - steel
    from methanol. Yield 300 mg (60%),
    m.p. 158-160 ° C, .. + 120.8 ° (,
    sns)
    . The pharmacological properties of the proposed compounds are studied using 3-methoxy-141,15 -methylene ether 1, 3, 5 (10 -trien-17p-ol (control designation CTC 593). The interceptive effect of this compound in rats-females, assigned to, has the same the order of the known compound is mestranol. It is approximately twice as effective compared with 1 {o with ethinyl estradyl (Tables 1 and 2). I
    The estrogenic properties of CTC 593, studied in the Allen-Doyz test on ovari-ectomized mice, are 9 times weaker than the analogous properties of these nilestradiol. The urotrotropic effect in infantile rats is only 70% of the effect of the standard compound mestranol (Table 3), while the antiestrogenic properties are 1.4 times higher than those of clomifencitrate.
      Longitudinal activity
    HUNDRED 593 in rats (Table 4) is about 4 times weaker than mestranol activity, the effective dose for TD is 0.65 mg / kg body weight /
    5 days while mestranol causes the same effect already at 0.15 mg / kg body weight / 5 days.
    Androgenic, anabolic and antiandrogenic. the effect of combining STS 593 was not observed in infantile rats of rats after a total dose of 0.75 or 3.0 mg / animal, administered orally for 6 days. It is also ineffective from the point of view of the manifestation of progestogenic activity, however, at a dose of 50 mg / kg administered to the rabbits, it exhibits anti-progestogenic properties. Braking action (TD), paBtioe
    97/3%, is reliable (Table 5). Thus, 3-methoxy-14 | 3, 15p-methylene-estra-1.3,5 (U) -trien17p-ol, compared with mestranol, has less pronounced undesirable (astrogenic, antigonadotropic, progestin) side effects. In addition, the compound exhibits anti-estrogenic and anti-progestogenic effects that are relevant to the therapeutic use of the compound. In particular, it has a .6 times less pronounced in comparison with mestranol postiplantno undesirable fruit-damaging properties. Pharmacological properties of the remaining compounds are presented in table 6. Moreover, 3-methoxy-14o, (methylenestra-1, 3, 5 (lO) -trien-17 | „-ol (control designation CTC 65: 1, t-abl. 3 and 3-methoxy-17y6-methyl-14 F, 15 i-methylenestra-1,3,5 (10) -trien17y-ol (control designation CTC b 81) are characterized by the highest interceptual activities in relation to DTI. They are followed by 3methoxy-14o (,, 15cC- methyleneestra-1,3,5 TSO) -Trien-17s51-ol (control designation CTC 652) and Z-methoxy-14 15p-methyleneestra-1, 3, 5 (Yu) -trien17o (-ol (control designation CTC 592) , moreover, 3-methoxy-14oi, lSoCmetilenestra-1, 3.5 (10) -trien-17rol has the strongest uterotropic effect e (Table 6, uterotrope activity is represented by the dose required to double the weight of the uterus) 3-methoxy-17c1-methyl-14 p, 15p methylene-1, 3.5 (10) -trien-17 -ol, 3-- methoxy-14o (., 15 () C-methylenestra-1, 3, 5 (10) -trien-17o.-ol and, first of all, 3-methoxy-14 p, 15p-methyl Nestra, 3, 5 (10) -trien-17 ° C-ol exhibit lesser uterotropic effects. From Table 6, it shows that 3-methoxy 14 p, 15p-methylene-1, 3, 5 (10) -trien-17 (, -ol has the most high implantation inhibition activity CTC 593 compared to mestranol in fertilized rats when administered on the 1st day of pregnancy. adverse side effect in mice. DTB (modernity retardation effect and DTI (implantation retardation action) refers to the inhibition of all pregnancies and implantations, respectively, and DTB and DTT - to the inhibition of normal pregnancies and, accordingly, implantations within each group. Pregnancy is considered normal when they show at least At least one normal implantation. The parameters of DTB, DTB-2, DTI and DTI are calculated using DTB (%) formula for DTI (%) 1 where the number of fertilized females (group); experimental group; control group (sesame oil); 4HCJiO everything x pregnancies (DTB) and, respectively, normally pregnant (DTB) females (group), the average number of all implantations (DTI) and respectively normal implantations (DTI) in each fertilized female within the group. The relative frequency of pregnancy is compared by Ryan test, the number of implants are compared according to the Dan test. With respect to DTB and DTB2, the effective doses (ED) for the inhibitory activity (TD) are determined using proit analysis, equal to 5.50 and 95%. Effective doses () for DTI and TI are determined by graphic means. The results are shown in Table. , 2 and 6. -Table
    5 ml
    14 12
    14
    0.2 11
    14
    12.5 12.5., 6.8 0.2 8.3 91.7 45.3 98.7
    Delivered reliable at P CO, 05.
    Comparison of the interceptive effect of the CTC 593 and the CTC 651 in fertilized rats in comparison with mestranol and ethinyl estradiol (according to the impeding inhibition test when administered on the 1st day of pregnancy)
    Continued table. one
    T a
    persons Data of example 2 table.1. In example 1, Noah 0.175 mg / kg body weight inside, and for the body inside. T GTEOITTGCH Guterotropic activity of STS 595 compared to mestranol in infantile female rats
    Wistar Reliably at, 05. Antigonadotropic activity
    Prs L-Laeni tas.l, L
    persons 3
    It was determined for DTI, RDddiz - equal to 0.155 mg / kg by weight Table 4 of the compound STS 593
    权利要求:
    Claims (2)
    [1]
    . 14s1, 15s6- or 14 β, 15/3-Methylene derivatives of an estrano-row about
    where K. is hydrogen or, if C is a <& - methyl group, then 14, 15-methylene group has β, β-configuration, having an interceptive effect ^
    (L
    with
    □ about
    m
    SP
    N3
    SP
    one
    1087525
    [2]
    2
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    同族专利:
    公开号 | 公开日
    GB2027030B|1982-09-02|
    CA1134346A|1982-10-26|
    NO792162L|1980-01-02|
    DD145919B1|1982-06-30|
    IT7949530D0|1979-06-25|
    DD145919A1|1981-01-14|
    IT1164106B|1987-04-08|
    DK260579A|1979-12-29|
    ES481985A1|1980-07-01|
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    HU180482B|1983-03-28|
    DE2911612A1|1980-01-10|
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    US4231946A|1980-11-04|
    CS208981B1|1981-10-30|
    FR2429797A1|1980-01-25|
    SE7905658L|1979-12-29|
    FR2429797B1|1981-02-27|
    BR7903124A|1981-01-13|
    FI792032A|1979-12-29|
    GB2027030A|1980-02-13|
    JPS559071A|1980-01-22|
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    法律状态:
    优先权:
    申请号 | 申请日 | 专利标题
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