• 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:
    Die Erfindung umfaßt 9-Fluor-prostanderivate der allgemeinen Formel l, worin R1 den Rest CH2OH oder mit R2 in der Bedeutung eines Wasserstoffatoms, eines Alkyl-, Cycloalkyl-, Aryl- oder heterocyclischen Restes oder R, den Rest mit R3 in der Bedeutung eines Säurerestes oder des Restes R2 und A eine -CH2-CH2- oder cis-CH=CH-Gruppe, B eine -CH2-CH2-, oder trans-CH=CH- oder eine -C≡C- Gruppe, W eine freie oder funktionell abgewandelte Hydroxymethylengruppe, wobei die OH-Gruppe a- oder ß-ständig sein kann, D und E gemeinsam eine direkte Bindung oder D eine gerad- oder verzweigtkettige Alkylengruppe mit 1-10 C-Atomen, die gegebenenfalls durch Fluoratome substituiert sein kann, E ein Sauerstoff- oder Schwefelatom, eine direkte Bindung, eine -C≡C-Bindung oder eine -CR6=CR7-Gruppe darstellt, wobei R6 und R7 sich unterscheiden und ein Wasserstoffatom, ein Chloratom oder eine Alkylgruppe bedeuten, R4 eine freie oder funktionell abgewandelte Hydroxygruppe, R5 ein Wasserstoffatom, eine Alkyl-, eine Halogen-substituierte Alkyl-, eine Cycloalkyl-, eine gegebenenfalls substituierte Aryl- oder eine heterocyclische Gruppe und falls R2 die Bedeutung eines Wasserstoffatoms hat, deren Salze mit physiologisch verträglichen Basen bedeuten, ihre Herstellung und Verwendung als Luteolytika oder Abortiva.
    公开号:SU1301308A3
    申请号:SU823456800
    申请日:1982-06-24
    公开日:1987-03-30
    发明作者:Скубалла Вернер；Радюхель Бернд；Шварц Норберт；Форбрюгген Хельмут；Эльгер Вальтер；Логе Олаф；Таун Михаель-Гарольд
    申请人:Шеринг Аг (Фирма)；
    IPC主号:
    专利说明:

    one
    The invention relates to the production of new prostaglandin derivatives, namely, 9-fluoro-prostane derivatives of the general formula

    Y B-W-D-E-RS
    13
    R /,
    where where
    R (group or
    -WITH
    /
    h
    OR
    R, O
    a hydrogen atom, or an alkyl- on C, -Cg-rpynna, or R (is a CONHR group, where K is a lower alkanoyl, or a C, -C-alkanesulphonyl group, or a hydrogen atom;
    And - or CIS-CH CH-group
    B - trans-CH CH-group,
    W is a free or protected tetrahydropyranyl group hydroxymethyl group, the hydroxy group of which can be in the web or | 3-position;
    Together together or
    D is an alkylene group with 1-2 carbon atoms with a straight or branched chain, optionally substituted by a fluorine atom,
    E is an oxygen atom, a direct bond or an Il1 group, where one of R
    and the other is low R — a hydrogen atom, pshy alkyl;
    Rj is a hydroxy group free or protected by a tetrahydropyranyl group.
    Rg is a hydrogen atom, a phenyl group, or a single alkyl, and if R is in the COORj group, a hydrogen atom, or their salts with physiologically acceptable bases, having a prostaglandin-like activity with higher productivity, selectivity and higher activity compared with natural prostaglandins.
    The purpose of the invention is to obtain new prostaglandin derivatives with improved pharmacological properties.
    Example 1. Methyl ester 5Z, 13E3-9R, IIR, 15R 11,16-β-dihydroxy-9-fluoro-16-phenoxy-17, 18,19,20-tetranor-5,13-prostadiene acid.
    Into the solution and, 5.7 g of (methyl ester 5Z, 1 1R, 15R-9-rHApOKCH-l1,15-bis- (tetrag "d-ropyran-2-yloxy) 16-phenoxy-17,18, 19 , 20-tetranor-5,13-prostadiene acid (obtained from the corresponding 1301308
    five
    0
    five
    0
    five
    0
    five
    0
    five
    acid in methylene chloride with a 0.5-molar solution of diazomethane at OS) in 18 ml of pyridine was added at 0 ° C with 3.8 g of p-toluene sulfonyl chloride, peremiguyut 16 hours at an ice bath temperature and 48 hours at room temperature. Then it is mixed with 15 ml of water, stirred for 3 hours at 20 ° C, diluted with ether, and stirred in turn with water, 50% sulfuric acid, 5% sodium bicarbonate and water. Dry over magnesium sulfate and evaporate in vacuo. After chromatography of the residue on silica gel, 5 g of 9-tosylate (colorless oil) are obtained with hexane-ethyl acetate (3 + 2).
    1R: 2950, 2875, 1733, 1600; 1590, 1496, 1365, 1240, 974 / cm. To a solution of 5.2 g of the obtained 9-tosylate in 75 ml of absolute dimethylsulfoxide, 13 g of tetrabutylammonium fluoride (dried by repeated concentration with toluene) are added and the solution is stirred for 1.5 hours at 22 ° C. under argon atmosphere. Then it is diluted with ether and stirred up four times with water, dried over magnesium sulphate and evaporated in vacuo. The residue is purified by chromatography on silica gel. With hexane-ethyl acetate (9 + 1), the corresponding 8, 9 corresponding U-compounds are obtained as solvent, and
    as the more polar component, 0.72 g of methyl ester 5Z, llR,, 15-bic- - (tetrahydropyran-2-yloxy) -9-fluoro--16-phenoxy-17,18,19,20-tetranor-17 5 13-prostadiene acid (colorless oil). 1R: 2955, 1733, 1600, 1588, 1495, 970 / cm.
    To remove the protective groups, 0.72 g of the obtained α-fluoro compound was stirred for 16 hours at 22 ° C with 20 ml of a mixture of acetic acid, water, tetrahydrofuran (65 + 35 + 10) and then evaporated in vacuo. The residue is purified by chromatography on silica gel. With ether as solvent, 370 mg of compound I (colorless oil) are obtained.
    1R: 3600, 3430 (broad), 2952, 2930, 2870, 1730, 1600, 1588, 1495, 970 / cm.
    PRI mme R 2. Methyl ester 5Z,, 11R,, 153130
    dihydroxy-9 fluoro-6-feioxy-1 7,18, 19,20-1 tetranor-5,13-prostadiene acid.
    To a solution of 4.8 g of 5Z, methylate ester, 1 1R, 15K -9-hydroxy-11,15-bis- (tetrahydropyran-2-yloxy) -16-phenoxy-17,18, 19, 2p- tetranor-5,13-prostadiene acid (obtained from the corresponding acid in methylene chloride with 5 M solution of diazomethane in ether at 0 ° C) in 27 ml of pyridine was added at 20 ° C with 3.4 g of p-toluenesulfuryl chloride ) acid and move for 20 h at 20 ° C. Then it is mixed with 12 ml of water, stirred for 3 hours at 20 ° C, diluted with ether, shaken in turn with water, 5% sulfuric acid, 5% sodium bicarbonate and water. Dry over magnesium sulfate and evaporate in vacuo. This gives 6.05 g of 9-tosylate as a colorless oil.
    1R: 2950, 2873, 1730, 1599, 1588, 1360, 972 / cm.
    To a solution of 6.05 g of the above-obtained 9-tosylate in 180 ml of absolute tetrahydrofuran, 13.3 g of tetrabutylammonium fluoride (dried by repeated concentration with toluene) are added and the solution is refluxed for 1 hour under reflux under argon atmosphere. Then it is diluted with ether, stirred four times with water, dried over magnesium sulphate and evaporated in vacuo. The residue is purified by chromatography on silica gel. With hexane-ether (7 + 3), 2.2 g of methyl ester 5Z, 13EJ-9S, 11R, 15kZ-11,15-bis (tetrahydropyran-2-yloxy) -9-fluoro-16- are obtained. phenoxy-17,18,19,20-tetranor-5,13-prostadiene acid as a colorless oil.
    1R: 2956, 1731, 1599, 1588, 1495, 972 / cm.
    For the cleavage of the protective groups, 2.2 g of the above 9 ° C-fluorine compound are stirred for 16 hours with 90 ml of a mixture of acetic acid-water-tetrahydrofluoride (65 + 35 + 10) at 20 ° C and then evaporated in vacuo. The residue is purified by chromatography on silica gel. With ether as solvent, 1.45 g of the title compound is obtained as a colorless oil.
    84
    1R: 3600, 3420 (broad), 2930, 2860, 1730, 1600, 1589, 1434, 970 / cm.
    PRI me R 3. Methyl ester, 11R,, 15-dihydroxy-9-fluoro-16-phenoxy-17, 18,19, 20-tetranor-13-prostoic acid. In analogy to Example 1, 2.5 g of methyl ester, 11R, 15R-9-hydroxy-lI, is obtained
    I5-bis- (tetrahydropyran-2-yloxy) - -16-phenoxy-17,18,19,20-tetranor-13-prostagon acid 0.39 g of methyl ester l, IIR, -11,15-bis (Tetrahydropyran-2-yloxy) -9-fluoro-16-phenoxy-17,18,19,20-β-tetranor-1 W-Prostoic acid as a colorless oil.
    1R: 2956, 1732, 1600, 1588, 1495, 970 / cm.
    After removing the protective groups of Example 1, 0.24 g of the title compound (colorless oil) is obtained. 1R: 3600, 3440 (broad), 2953, 2930, 2870, 1730, 1600, 1588, 1495,
    970 / cm
    PRI me R 4. Methyl ester, 11R, 1,15-dihydroxy-9-fluoro-I6-phenoxy-17,18, 19,20-tetranor-13-prostoic acid.
    Analogously to Example 2, 2.1 g of methyl ester, 1IR, 15R-9-hydroxy-Chl, 15-bis- (tetrahydropyran-2-yloxy) -16-phenoxy-17, 18,19,20-tetranor-13- -prostoic acid, 0.9 g of methyl ester, 11R, 15-bis- (tetrahydropyran-2-yloxy) -9-fluoro-16-phenoxy-17,18,19,
    20-tetranor-13-prostoic acid as a colorless oil ..
    1R: 2955, 1732, 1599.1588, 1495, 971 / cm.
    After cleavage of the protecting groups
    in Example 1, 0.52 g of the title compound (colorless oil) was obtained.
    1R: 3600, 3450 (broad), 2930, 2860, 1731, 1600, 1589, 1494, 970 / cm. PRI me R 5. Complex methyl
    5Z, IIR, I5R-11, 15-dihydroxy-16,16-dimethyl-9-fluoro-5,13-prostadiene acid ester. I
    Analogously to example 1 is obtained from
    2.9 g of methyl ester 5Z, 11R,, 15-bis- (tetrahydropyran-2-yloxy) -16,16-dimethyl- -9-HYDROXY-5,13-prostadiene acid 0.35 g of methyl complex
    5Z, IIR, 15RJ-11, 15-bis- (tetrahydropyran-2-yloxy) -16,16-dimethyl-9-fluoro-5,13-protic enoic acid ester as a colorless oil.
    1R: 2960, 2855, 1732, 974 / cm.
    After cleavage of the protecting groups of Example 1, 0.23 g of the title compound (colorless oil) is obtained.
    1R: 3610, 3400 (wide), 2940, 2860, 1732, 974 / cm,
    EXAMPLE 6 Methyl ester of 5Z, 13P G), llR,, 15-dihydroxy-16,16-dimesh1-9-fluoro-5,13-prostadiene acid.
    Analogously to Example 2, prepared from 1 g of methyl ester 5Z, 11R, 15R-9-hydroxy-II, 15-bis- (tetrahydropyran-2-yloxy) -16,16-dimethyl-5,13-prostadiene acid 0, 44 g of methyl ester 5Z, 13BO- 98, UR, 15-bis- (tetrahydropyran-2-yloxy) -16,16-dimethyl-9-fluoro-5,13-prostadane enoic acid as an oil.
    1R: 2960, 2856, 1731, 974 / cm.
    After cleavage of the protecting groups of Example 2, 0.28 g of the title compound (oil) is obtained.
    1R: 3600, 3440 (broad), 2935, 2860, 1732, 964 / cm.
    The starting material for this compound is prepared as follows.
    6a. Methyl ester SZ, UR, 15K -9-hydroxy-P, 15-bis- (tetrahydropyran-2-yloxy) - -16,16-dimethyl-5,13-prostadiene acid.
    To a solution of 18 g of methyl ester 5Z, l5Rl- -II, 15-bis- (tetrahydropyran-2-yloxy) -16,16-dimethyl-9-oxo-5,13-prodienoic acid in 400 ml of methano - is added at 6.5 g of sodium borohydride and stirred for 30 minutes at 0 ° C. It is then diluted with ether, stirred four times with water, dried over magnesium sulphate and evaporated in a vacuum. The residue is purified by chromatography on a column of strength Kagel. G ether-hexane (4 + 1) as a solvent, first get 6.8 g of the corresponding 9 ° C hydroxy compound, and also as the polar component 6.05 g of the specified compound (colorless oil).

    O
    45
    1R: 3600, 3420 (broad), 2960, 2855, 1731, 972 / cm.
    PRI me R 7. Methyl ester, 11R, 15-di-5 hydroxy-16,16-dimethyl-9-fluoro-13-prostoic acid.
    Analogously to Example 1, 1.5 g of methyl ester, 11R, 15-bis- (tetrahydropyran-2-yloxy) -16,16-dimethyL-9-HYDROXY-13-prostoic acid, 180 mg of methyl methyl ester, 11R,, 15-bis- (tetrahydropyran-2-ylokei) -16,16-dimethyl-5-9-fluoro-13-prostoic acid as an oil.
    1R: 2952, 2855, 1731, 972 / cm.
    After cleavage of the protecting groups of example 1, 105 mg of the title compound are obtained as a colorless oil.
    1R: 3600, 3440 (shchi), 2935, 2860, 1731, 972 / cm.
    EXAMPLE 8 Methyl-5 ester of 5Z,, I 1R, -11.15 -dihydroxy-9-fluoro-16-methyl-5.13-prostadiene acid.
    In analogy to Example 1, from 3 g of methyl ester 0 3Z, is obtained. 13E3-9S, IIR, 16RF -11,15- -bis- (tetrahydropyran-2-shtoksi) -9-- (hydroxy-I6-methyl-5,13-prostadiene acid 0.33 g of methyl ester 5Z,, 1 , ,, 1,15о6-bis (tetrahydropyran-2- -yloxy) -9-fluoro-16-methyl-5,13-prostadiene acid as a colorless oil.
    IR: 2965, 2855, 1732, 970 / cm.
    After cleavage of the protecting groups of Example 1, 0.2 g of the title compound (oil) is obtained.
    1R: 3600, 3430 (shchi), 2935, 2860, 1732, 970 / cm.
    PRI me R 9. Methyl 5Z ester,, 11R, 154. 4-dihydroxy-9-fluoro-16-methyl-5,13-prostadiene acid.

    50 In analogy to Example 2, 1.3 g of methyl ester, IIR,, 156i-bic- (tetrahydropyran-2-yloxy) -9-hydroxy--16-methyl-5,13-prostadiene acid 0, 58 g of methyl ester 5Z, IIR, 15-bis (tetrahydropyran-2-yloxy) -9-fluoro-16-methyl-5.13-prostadiene acid (colorless oil).
    0
    IR: 2966, 2858, 1732, 971 / cm.
    After cleavage of the protecting groups of example 2, 0.45 g of compound 1 (oil) is obtained.
    1R: 3600, 3440 (broad), 2935, 2860, 1732, 971 / cm.
    The starting material for compound J is prepared as follows.
    9a, Methyl ester 5Z,, 11R,, 15-bic- (te rahydropyran-2-yloxy) -9-hydroxy--16-methyl-5, 13-prostadiene acid.
    Analogously to Example 6a, 7 g of methyl ester {, 5Z, IR, 1.5 ° (.-Bis- (tetrahydropyran-2-yloxy) -16-methyl-9-ox-5,13-prostadiene acid) is obtained 2.4 Compound I (oil).
    1R: 3610, 3440 (wide), 2960,
    2856.1732, 971 / cm,
    Example 10 Methyl ester 5Z,, 11R,, 15-DIHYDROX-9,16-difluoro-5,13-prostadiene acid.
    Analogously to the example, from 4.2 g of t5Z methyl ester, 11R, 5-bc- (te rahydropyran-2-yloxy) -9-hydroxy-16-fluoro-5,13-prostadiene acid 490 mg of methyl ester are obtained 5Z, 11R, 15R, 16RS; -, (tetrahydropyran-2-yloxy) -9,16-difluoro-5,13-prostadiene acid (oil),
    1R: 2960, 1735, 976 / cm.
    After cleavage of the protecting groups of example 1, 285 mg of compound 1 (oil) are obtained.
    .1R: 3600, 3430 (wide), 2930,
    2857.1734, 976 / cm. Example 11. Methyl ester 5Z, flR, 15R,
    , 15-DIHYDROXI-9 j16-difluoro-5,13-prostadiene acid.
    In analogy to Example 2, 0.8 g of t5Z, IIR, 15R,, 15-bis- (tetrahydropyran-2-yloxy) -9-hydroxy-16-fluoro-5, I3-prostadiene acid (prepared from of the corresponding 9-ketone according to example 6a 0.37 g of methyl ester 5Z,, 11R, 15R,, 15-bis- (tetrahydropyran-2-yloxy) -9-hydroxy-16-fluoro-5,13-prostadiene acid ( colorless oil).
    1R: 2958, 1734, 974 / cm. After cleavage of the protecting groups of Example 2, 240 mg of the title compound (oil) are obtained. 1R: 3600, 3440 (broad), 2932, 2856, 1732, 974 / cm.
    Example 12. Methyl ester 5Z, I3E3-9R, llR, -11.1 5 ° C-dihydroxy-16,19-dimethyl-9-fluoro-5,13,18-prostadiene acid.
    In analogy to Example 1, 2.8 g of methyl ester 5Z, llR, 15-bis- (tetrahydropyran-2-yloxy) -16,19-dimethyl-9-hydroxy-5,13,18-prostag of trienoic acid, 0.38 g of methyl ester 5Z, 11R, 16RS3-11, 15o-bis- (tetrahydropyran--2-yloxy) -16, 19-dimethyl-9-fluoro-5, 13,18-prostatrienoic acid ( colorless oil),
    IRr 2960, 1731, 972 / cm. After cleavage of the protecting groups of example 1, 0.29 g of compound I (oil) is obtained,
    1R: 3600, 3440 (wide), 2935,
    2855.1731, 972 / cm.
    Example 13. Complex methyl
    5Z,, 11R, 11, 15c-dihydroxy-16,19-dimethyl-H-fluoro-5,13,18-prostatrienoic acid ester.
    In analogy to Example 2, 0.6 g of tSZ methyl ester is obtained,
    , 11 R, 15oC-bic- - (tetrahydropyran-2-yloxy) -l 6,19-dimethyl-9-hydroxy-5,13,18-prostatrienoic acid 0.24 g methyl ester 5Z, 13E3-9S , 11R,
    16RSJ -11.15 oO-bis- (tetrahydropyran-2-yloxy), 19-dimethyl-9-fluoro-5.13, 18-prostatrienoic acid (colorless oil),
    1R: 2962, 1832, 970 / cm,
    After cleavage of the protecting groups of example 1, 140 mg of compound 1 (oil) are obtained,
    1R: 3600, 3420 (wide), 2935,
    2856.1731, 970 / cm,
    Source material for the specified
    the compounds are prepared by the following method.
    13a. Methyl ester, 11R, 16RSl-II, 15o-bic- (terahydropyran-2-yloxy) -16,19-dimethyla-9-HYDROXY-5,13,18-prostatrienoic acid.
    Analogously to Example 6a, from 4,2 g of methyl ester 5Z, 1R, 1, 15-6-bis- (tetrahydropyran-2-yloxy) -16,19-dimethyl-9-OXO-5,13,18-prostatriene an acid obtained from the corresponding acid with a solution of diazomethane in ether at OC, 1.7 g of compound I (colorless oil),
    1R: 3600, 3420 (broad), 2965, 2855, 1733, 970 / cm.
    Example 14. Methyl ester, IIR, 16RSl-n, I5oi, - dihydroxy-16,19-dimethyl-9-fluoro-13,18-prostadiene acid,
    Analogously to Example H, 1.3 g of methyl ester l3EJ-9S, nR, 15-bis- (tet rahydropyran-2-yloxy) -16,19-dimethyl-9-HYDROXY-13,18-prostadiene acid is obtained from 1.3 g 170 mg of methyl ester 13F, 9R, 1 1R, 1.15 (i, -bis- (tetrahydropyran-2-yloxy-16,19-fluoro-13,18-prostadiene acid (colorless oil).
    1R: 2962, 1730, 971 / cm.
    After cleavage of the protecting groups of example 5, 95 mg of compound I (colorless oil) are obtained.
    1R: 3610, 3450 (broad), 2937, 2855, 1730, 961 / cm.
    Example 15. Methyl ester, 11R,, 156-d-i-hydroxy-16, 9-dimethyl-9-fluoro-13,18-prostadiene acid.
    Analogously to example 2 is obtained from 0.9 g of complex methyl g / ovogo eff, 11R, l, 15c "-bis- - (tetrahydropyran-2-yloxy) -1 6, 19-dimetyp-9-hydroxy-13,18-prostadiene acids, 0.38 g of methyl ester, I1R, -11.15y.-bis- (tetrahydropyran-2-yl-oxy), 19-dimethyl-9-fluoro-13,18- -prystadiene acid (colorless oil),
    1R: 2960, 1831, 970 / cm.
    After cleavage of the protecting groups of example 2, 220 mg of compound G (colorless oil) are obtained.
    1R: 3600, 3440 (broad), 2936, 2853, 1731, 970 / cm.
    The starting material for this compound is prepared as follows.
    15a. OZE methyl ester, 11R, 11.15 (X.-bis- (tetra
    five
    ABOUT
    ,
    Q
    five
    Q
    ,
    hydropyran-2-yloxy) -16,19-dimethyl-9-hydroxy-13,18-prostadiene acid.
    In analogy to Example 6a, 5.1 g of methyl 1R, 1, 5-cC-bis- (tetrahydropyran-2-yloxy) -16,19-dimethyL-9-OXO-13,18-prostadiene acid is obtained from 5.1 g (obtained from the corresponding acid with a solution of diazomethane in ether at OS) 2.2 g of compound I (colorless oil),
    1R: 3600, 3440 (wide), 2963, 2855, 1732, 970 / cm,
    Example 16. Methyl ester 5Z, IIR, 15-dihydroxy-9-fluoro-16,16,19-trimethyl-5,13,18-prostatrienoic acid.
    Analogously to example 1, prepared from 2.9 g of 5Z,, 1 1R,, 15-bis- (tetrahydropyran-2-yloxy) -9-hydroxy-16,16,19-trimethyl-5,13, 18-prostatrienoic acid 350 mg of methyl ester 5Z, 13EZ, MR, 16-bic- (Tetra-hydropyran-2-yloxy) -9-fluoro-16,16, 19-trimethyl-5,13,18-prostatrienoic acid (colorless oil).
    1R: 2960, 2855, 1732, 974 / cm.
    After cleavage of the protecting groups of Example 1, 190 mg of Compound I (oil) are obtained.
    1R: 3600, 3440 (broad), 2942, 2850, 1732, 973 / cm.
    Example 17. 5Z,, 11R,, 15-dihydroxy-9-fluoro-16-phenoxy-17,18,19,20-tetranor-5,13-prostadiene acid.
    350 mg of methyl ester prepared in Example 1 are stirred for 5 hours with 10 ml of a solution of potassium hydroxide in ethanol and water (2 g of potassium hydroxide is dissolved in 75 ml of ethanol and 25 ml of water). It is then acidified with 10% -Hbnsi citric acid solution to pH 4, extracted three times with methylene chloride, the organic extract is washed once with brine, dried over magnesium sulfate and evaporated in vacuo. After chromatography of the residue from silica gel with methylene chloride - isopropanol (9 + 1), 300 mg of the indicated compound are obtained as a solvent (colorless oil).
    1R: 3580, 3400 (broad), 2925, 2863, 1710, 1598, 1588, 1492, 370 / cm.
    Example 18. 5Z,, 1IR,, 15-dihydroxy-9-fluoro-16-phenoxy-17,18,19,20-f etranor-5, 13-prostadiene acid.
    In analogy to example 17, 0.42 g of the methyl ester prepared according to example 2, 0.34 g of compound I is obtained in the form of an oil.
    1R: 3590, 3410 (broad)., 2925, 2865, 1708, 1598, 1588, 1493, 970 / cm.
    Example 19., 11R, 15-dihydroxy-9-fluoro-16-phenoxy-17,18,19,20-tetranor-13-β-prostanoic acid.
    Analogously to Example 17, 0.26 g of Compound T (best crystals) prepared from 0.26 g of methyl ester prepared in Example 3, m.p. 98-99 c.
    1R: 3600, 3400 (wide), 2924,
    2864.1709, 1599, 1588, 1493, 971 / cm.
    Example 20, 11R, 15RJ-11,15-dihydroxy-9-fluoro-16-phenoxy-17,18,19,20-tetranor-13-simple simple acid.
    In analogy to example 17, from 0.32 g of methyl ester prepared in example 4, 0.26 g of compound I (colorless crystals), m.p. 86-87 ° C.
     iR: 3590, 3400 (pshroky), 2924,
    2865.1708, 1598, 1588, 1493, 970 / c. PRI me R 21. 5Z,,
    11R, 15-dihydroxy-15,16-dimethyl-9-fluoro-5,13-prostadiene acid.
    Analogously to Example 17, 0.11 g of Compound I (oil) prepared from 0.15 g of methyl ester prepared according to Example 5 was prepared.
    IR: 3600, 3405 (wide), 2952, 2860, 1710, 964 / cm.
    PRI me R 22. 5Z, 11R,), 15-dihydroxy-16,16-di methyl-9-fluoro-5, I3-prostadiene acid.
    Analogously to Example I7, 0.10 g of Compound 1 (oil) is prepared from 0.15 g of methyl ester prepared in Example 6.
    1R: 3600, 3405 (wide), 2950, 2858, 1710, 975 / cm.
    Example 23. 11R, 15Rj-l1,15-DIHYDROXI-16,16-dimethyl-9-fluoro-13-prostadiene acid.
    Analogously to example 17 is obtained from 0.2 g prepared according to example
    7-methyl ester 0.16 g of compound I (oil).
    1R: 3600, 3410 (broad), 2952, 2862, 1708, 974 / cm. PRI me R 24. 5Z,, 1 1R, 16RS -11.1 5c-dihydroxy-9-ftsr-16-methyl-5,13-prostadiene acid.
    Analogously to example 17 is obtained from 0.2 g prepared according to example
    8); methyl ester 0.16 g of compound I (oil).
    IR: 3600, 3405 (broad), 2945, 2848, 1710, 976 / cm. I
    Example 25 5Z, 1 1 R, 16RS -11.1 5oC-Dihydroxy-9-fluoro-16-methyl-5,13-prostadiene acid.
    Analogously to example 17 is obtained from 0.2 g prepared according to example
    9 methyl ester 0.17 g of compound I (oil).
    1R: 3600, 3405 (broad), 1950, 2852, 1710, 976 / cm.
    EXAMPLE 26. 5Z,, 11R, 15R, 1, 15-DIGYDROXI-9, 16-difluoro-5,13-prostadiene acid.
    Analogously to example 17 is obtained from 0.15 g prepared according to example
    10 methyl ester 0.12 g of compound I (oil).
    1R: 3600, 3410 (broad), 2955, 2860, 1708, 976 / cm.
    EXAMPLE 27. 5Z,, 11R, 15R,, 15-dihydroxy-9, 16-difluoro-5, I3-prostadiene acid.
    Analogously to Example 17, 0.11 g of the compound prepared from Example D, methyl ester, 0.11 g of Compound G (oil) was prepared.
    1R: 3600, 3405 (broad), 2954, 2858, 1708, 974 / cm.
    Example 28 5Z,, 11R, 1.15 "C-dihydroxy-16,19-dimethyl-9-fluoro-5,13,18-prostatric acid.
    As in Example 17, from 0.30 g of methyl ester prepared in Example 12, 0.26 g of Compound I (oil).
    1R: 3600, ZA10 (broad), 2938, 2856, 1710, 976 / cm.
    Example 29, 52,., IIR,, 1HCl-dihydroxy-16,19-dimethyl-9-fluoro-5,13,18-prostatric acid.
    Similarly, r; example 17 obtained from 90 mg prepared according to example
    13 mg of methyl ester 75 mg of compound I (oil).
    1R: 3600, ZA10 (broad), 2940 2856, 1710, 974 / cm.
    EXAMPLE 30, 11R, l6RSl-l 1, 15 ° C-dihydroxy-1b, 19-dimethyl-9-fluoro-13,18-prostadiene acid.
    Analogously to example 17, prepared from 80 mg prepared according to example
    14 methyl ester 50 mg of Compound T (oil).
    1R: 3600, 3405 (broad), 2952, 2840, 1710, 974 / cm.
    EXAMPLE 31. l3F.t9S, 11R, 16Rsl- 1, 15 ° (.- dihydroxy-16, 1 9-dimethyl-9-fluoro-13,18-prostadiene acid.
    Analogously to example 17, from 150 mg of the methyl ester prepared according to example 5, 110 mg of compound I (oil) are obtained.
    1R: 3600, 3405 (broad), 2940, 2862, 1710, 974 / cm.
    EXAMPLE 32. 5Z,, IIR,, 15-dihydroxy-9-fluoro-16,16,19-trimethyl-5,13,18-prostastatriic acid.
    Analogously to example 17, from 70 mg of methyl ester prepared according to example 16, 70 mg of compound T (oil).
    1R: 3600, 3400 (broad), 2958, 2850, 1710, 976 / cm.
    PRI me R 33., IIR 5R3 9-fluor-l, 11,15-trihydroxy-16-phenoxy-17,18,19,20-tetranor-13-is simple.
    To a solution of 200 mg of methyl ester, llR, 15R -P, 15-dihydroxy-9-fluoro-16-phenoxy-17,18,19,20-tetranor-13 proteno acid (prepared according to example 3) in 10 ml of tetrahydrofuran add
    Q
    at about C and stirring in portions of 300 mg of lithium aluminum hydride and flowed it is stirred for 30 minutes at 25 ° C. Destroy the excess reagent at 0 ° C by adding dropwise acetic ether, add 2 ml of water and 60 ml of ether and stir vigorously for 3 hours at 25 ° C. It is filtered, the residue is washed with ether, the ether solution is dried over magnesium sulphate and evaporated in vacuo. After chromatography of the residue on silica gel with acetic acid
    ether — hexane (4: 1) gives 150 mg of compound I (oil).
    1R: 3600, 3420 (broad), 2942, 2860, 1600, 1588, 1498, 976 / cm.
    EXAMPLE 34.., 11R, 15RJ-9-fluorop-l, 11,15-trihydroxy-17-phenoxy, 17,18,19,20-tetranor-3- -simple.
    Analogously to example 33 receive
    from 200 mg of methyl ester, 1 1R, 1, 1 5-dihydroxy-9-fluoro-16-phenoxy-17,18,19,20-α-tetranor-13 prostoic acid (prepared according to example 4) 160 mg
    Compound I (oil).
    1R: 3600, 3420 (broad), 2948, 2860, 1600, 1588, 1495, 975 / cm.
    PRI me R 35. 5Z, 11R, 15R1-16,16-dimethyl-9-fluoro-1,
    I1 15-trihydroxy-5,13-prostadiene. Analogously to example 33, from 100 mg of methyl ester 5Z, 11R, 15-dihydroxy-16,16-dimethyl-9-fluoro-5,13-prostadiene acid (prepared according to example 5), 70 mg of compound T (oil ).
    1R: 3600, 3410 (broad), 2952, 2858, 978 / cm.
    EXAMPLE 36., 11R, 16RS3-16,19-dimethyl-9-fluoro-1, 11.1 5-6-trihydroxy-13,18-prostadiene.
    Analogously to example 33 is obtained from 100 mg of the methyl ester
    , llR, 16Rr, -l 1, 15o (.- dihydroxy-16,19-dimethyl-9-fluoro-13,18-β-prostadiene acid (prepared according to example 14) 72 mg of compound 1 (oil).
    1R: 3600, 3420 (wide), 2962, 2840, 97 / cm.
    EXAMPLE 37 Methylsulfonamide, 11R,, 15-dihydroxy-9-fluoro-16-phenoxy-17, -18,19,20-tetranor-13-prostanic acid.
    To a solution of 200 mg, 11R,, 15-dihydroxy-9-fluoro-16-phenoxy-17,18,19,20-tetranor-13-protenoic acid (prepared according to example 19) in 5 ml of dimethylformamide is added at 0 ° C, 90 mg of isobutyl ester of chloroformic acid and 70 mg of triethylamine. After 30 minutes, 300 mg of sodium methylsulfonamide salt (obtained from methylsulfonamide and sodium methylate) and 2 ml of hexamethylphosphoric acid triamide are added and stirred
    5 hours at 20 ° C. Then diluted with citrate buffer solution (pH 4), extracted with ethyl acetate, the extract is washed with brine, dried over magnesium sulfate and evaporated in vacuo. After chromatography of the residue on silica gel with methylene chloride, 15 mg of compound are obtained (oil).
    1R: 3600, 3405, 2950, 2856, 1718, 1600, 1588, 978 / cm.
    PRI me R 38. ethyl sulfonamide, 11R, 15-dihydroxy-9-fluorop-16-phenoxy-17, 18,19,20-β-tetranor-13-prostoic acid.
    In analogy to Example 37, 100 mg, 11R, 15-dihydroxy-9-fluoro-16-phenoxy-17, 18,19,20-tetranor-13-prostoic acid (prepared according to example 20), 60 mg of compound I (oil) are obtained from.
    1R: 3600.3410, 2950, 2856, 1720, 1600, 1588, 978 / cm.
    EXAMPLE 39 Methylsulfonamide, 11R, 15 ° C dihydroxy-16,19-dimethyl-9-fluoro-13,18-prostadiene acid.
    In analogy to Example 37, 100 mg, IIR, 16RSl-II, 1 5 1 -dihydroxy-16,19-dimethyl-9-fluoro-13,18-prostadiene acid (prepared according to example 30) and 65 mg of compound I (oil) are obtained.
    1R: 3600, 3420, 2958, 2852, 1720 1480, 976 / cm.
    PRI me R 40. Isopropylsulfonamide, llR, 1,15-di-hydroxy-9-fluoro-16-phenoxy-17,18, 19,20-tetranor-13-prostoic acid.
    Analogously to example 37, but sodium salt of isopropyl sulfonamide is used instead of sodium salt of me. - I 3-prostoic acid (prepared according to Example 19) 105 mg of Compound I (oil).
    1R: 3600, 3410, 2955, 2848, 1717, 1600, 1588, 976 / cm.
    PRI me R 41. Acetylamide rGHG) -, llR,, 15-DIHYDROXI-9-fluoro-16-phenoxy-17,18,19,20-tetranor-1 3-prostoic acid.
     R. solution of 600 mg of methyl ester, 1 1R, -11,1 5-bis- (tetrahydropyran-2-yloxy) -9-fluoro-16-phenoxy-17,18,19,20-tetranor-13 -prostoic acid (prepared according to example 3) in 10 ml of methanol is stirred with 2.5 ml of sodium hydroxide for 5 hours under argon atmosphere. The mixture is concentrated in vacuo, diluted with brine, acidified with citric acid to pH 4.5 and extracted several times with ethyl acetate. The organic extract is washed with brine,
    dried over magnesium sulphate and concentrated in vacuo. As a residue, 560 mg of l3E3-9R, I1R, 15-bis- (tetrahydropyran-2-yloxy) -9-fluoro-I6-phenoxy-17.18 are obtained,
    19,20-tetranor-prostoic acid. To form acetylamine, the acid is dissolved in 15 ml of aetonitrile, mixed with 135 mg of triethylamine and a solution of 106 mg is instilled at O C
    acetyl isocyanate in 10 ml of acetonitrile. After 2 h, when diluted with a nitrate buffer solution (pH 4), it is extracted with ether and the extract is washed with brine, dried over
    magnesium sulfate and vacuum in vacuum. To remove the protective groups, the residue is stirred from 15 ml of glacial acetic acid - water - tetrahydrofuran () for 4 h at
    and then evaporated in vacuo. The residue is chromatographed on silica gel with methylene chloride with the addition of 0.2-1% isopropyl alcohol.
    250 mg of compound I (oil) are obtained.
    1 1R: 3600, 3410, 2952, 2858, 1712,
    1600, 1588, 976 / cm.
    PRI me R 42. Amide,
    11R, 15-dihydroxy-9-fluoro-1 6-phenoxy-17,18,19,20-tetranor-1.3-β-prostanoic acid.
    In a solution of 200 mg Cl3E - 9R, 11R,, 15-dihydroxy-9-fluoro-16-phenoxy-17,18,19,20-tetranor-1345-prostanoic acid (prepared according to example 19) in 5 ml of tetrahydrin 80 mg of isobutyl ester of chloroformic acid and 60 mg of triethylamine are added to the cream and over stirred for 1 hour at 0 ° C, then gaseous ammonia is added during 15 minutes and left for 1 hour at 25 ° C. Then it is diluted with water and extracted several times methylene chloride
    55 wash the combined extracts with brine, dry over magnesium sulfate and evaporate in vacuo. Silica gel chromatography with methylene chloride (0.2-1% isopropyl alcohol) is performed for purification. Obtain 145 m of compound I (oil),
    1R: 3600, 3505, 3410, 2955, 2848 1670, 1605, 1590, 978 / cm.
    Example43. Tris (hydroxime-1 yl) aminomethane salt 5Z,, 11R, 15-DIHYDROXI-9-fluoro-16-phenoxy-17,18,19,20-tetra-nor-5,13-prostadiene acid.
    To a solution of 200 mg of 5Z,, 11R,, 15-hydroxy-9-β-fop-16-phenoxy-17,18,9,20-tetra-nor-5,13-prostadiene acid (prepared according to example 17) in 35 ml of acetonitrile is added at 65 ° C with a solution of 60 mg of tris (hydroxy methyl) aminomethane in 0.2 ml of water. While stirring, cool to 20 ° C. Decant from the solvent and dry the residue in vacuo. 180 mg of compound 1 is obtained as a viscous oil.
    The table shows the comparative results of tests proposed and known drugs (Sulprostanon) in pregnant guinea pigs. Thus, guinea pigs on the 43rd and 44th day of gestation were given subcutaneously with the proposed compounds. On the 50th day, animals were killed and their uterus were examined.
    a) a torus of a compound, e.g. known compounds, namely analogously compound 9-chloro.
    Significant differences were found between 57, 13E-C-9R, IIR, -fluoro-1I, 15-DIHYDROXI-16-phenoxy--17,18,19,20-tetranor-5,13-prostandenic acid (Example 17) and 5Z, 11R, 15R-9-hlop-I 1, 15-DIHYDROXY-16-phenoxy-17,18,19, 20-tetranor-5,13-prostadiene acid.
    Abortive action. The 9th-fluorine derivative has a significantly greater aborting efficiency compared to the 9p-chlorine derivative. For example, if at a dose of 0.03 mg of a chlorine derivative per day (subcutaneous injection) only one to three guinea pigs were aborted, then the application of the fluorine derivative at the same a dose per day subcutaneously, as well as a dose of 0.01 mg, abortion occurred in three animals (3/3). Only when applied
    doses of 0.003 mg / day subcutaneously, the fluorine derivative exhibited the same efficacy as the chlorine derivative, i.e. aborted pregnancy 1-3 sea
    pigs.
    Toxicity. Despite superior (desired) abortion activity, a fluoride derivative has significantly less toxicity.
    compared to a similar derivative of chlorine. After subcutaneous administration of O, I mg / day of the fluorine derivative, all treated guinea pigs died, and after the corresponding dose
    fluorine derivative - only from 1-3 animals.
    The value of bb of the proposed 9-fluorine compound is more favorable, therefore, by a factor of 3 to 4
    compared with the LD value for the chlorine derivative.
    权利要求:
    Claims (1)
    [1]
    Invention Formula
    1 Method for preparing 3-fluoro-prostane derivatives of general formula I
     ...
    R
    B-W-D-E-R5
    OR,
    where R, is a group or C., where
    Rj is a hydrogen atom, or an alkyl C, -Cg-rpynna
    or K, is the CONHR5 group, where is R, is a lower alkanoyl, or alkanesulfonyl group, or an atom of hydrogen;
    A-CHj-CH or cis-CH CH-group.
    B - trans-CH CH-group,
    W is a free or purified tetrahydrolyranyl group of the oximethylene group, the hydroxy group of which may be in the (, - or A-position;
    D and E together right hand or
    D is an alkylene group with 1-2 carbon atoms with a straight or branched chain, optionally substituted by a fluorine atom;
    E is an oxygen atom, a direct bond, or -CRg CR7-rpynna, where one of Rg and RY is a hydrogen atom and the other is lower alkyl;
    R is a hydroxy group protected by a tetrahydropyranyl group;
    Rj is a hydrogen atom, phenyl rpynija or lower alkyl, and if R, j in the COOR group is a hydrogen atom,
    or their salts with a physiologically acceptable base and, in that the compound of the general formula
     B-W-D-E-R5
    where the OH group may be in the ct or PI position;
    SZ, IIR, -11,15-dioxy-9-fluoro-16-phenoxy-17,18,19,20-tetra-nor-5,13-prostadiene acid
    , IIR,, 15- -dioxy-9-fluoro-16-phenoxy-17,18,19,20-tetranor-13-prostanoic acid
    tSZ, IIR, -11,5-dioxy-16,16-dimethyl-9-fluoro-5,13-prostadiene acid
    Methylsulfonylamide SZ,, llR, 12R,, 5-dioxy-9-fluoro-16-phenoxy-17,
    18,19,20-tetranorprostadiene acid (Sulproston)
    ,, 11R, -11,15-dioxy-9-fluoro-16-phenoxy-17,18, I9,20-tetranor-5, 13-prostadiene acid
    Acetylamide sZ,, IIR 15Rl-11,15-DIOXI-9-FTOR-16-phenoxy-17,18,19,20-tetra-Hop-5,13-prostadiene acid
    RJ has the meaning of the group COORj or CONHR,.;
    A, B, D, E, have the indicated meanings,
    interact through an intermediate ester of h-toluenesulfonic acid with tetraalkylammonium fluoride, after which, if necessary, remove the protective tetrahydropyranyl group | Py from the hydroxy groups and in an arbitrary order the etherified carboxyl group is omitted or restored or the free carboxyl group is converted to amide.
    21
    Methylsulfonamide SZ,, 11R,, 15-dioxy-9-fluoro-16-phenoxy-17, 18,19,
    20-tetranor-3, 13-prostadiene acid
    Methyl ester 5Z, 11R,, 15-AHOKH-9-fluoro-16-phenoxy-17,18,19, 20-tetranor-5,13-prostadiene acid
    , MR,, 15- -dioxy-9-fluoro-16,16,19-trimethyl-13,18-prostadiene acid
    , IIR,, 15- -dioxy-9-fluoro-16-phenoxy--12,18,19,20-tetranor-14-prostanoic acid
    130130822
    Table continuation
    类似技术:
    公开号 | 公开日 | 专利标题
    SU1301308A3|1987-03-30|Method for producing 9-fluorine-prostan derivatives or their salts with physiologically acceptable bases
    CA1196327A|1985-11-05|Pharmaceutically active 9-chloroprostaglandins
    CA1079725A|1980-06-17|Prostaglandin-acetylene analogues and process for their manufacture
    EP0024943B1|1983-08-17|5,6,7-trinor-4,8-inter-m-phenylene pgi2 derivatives and pharmaceutical compositions containing them
    IL43589A|1980-01-31|16-phenoxy-15-hydroxy derivatives of 17,18,19,20-tetranorprostaglandins and their preparation
    US4217360A|1980-08-12|Novel 1,3-benzodioxaneprostanoic acid derivatives and process for the preparation thereof
    CA1248525A|1989-01-10|Carbacyclins, process for their manufacture and their use as medicaments
    US4195183A|1980-03-25|ω-Nor-aromatic-13,14-dehydro-prostaglandins and process for their preparation
    CA1092102A|1980-12-23|11-oxo-prostaglandin derivatives and processes for their manufacture
    DE2539116C2|1984-08-02|? -Nor-cycloalkyl-13,14-dehydro-prostaglandins, processes for their preparation and pharmaceutical compositions containing them
    DE2610718A1|1976-10-14|NEW 16-PHENOXY-PROSTAGLANDIN COMPOUNDS
    US4229585A|1980-10-21|Fluoro-prostaglandins
    DD241254A5|1986-12-03|PROCESS FOR PREPARING 16-SUBSTITUTED PHENOXY PROSTATRIENSAE DERIVATIVES
    HU183114B|1984-04-28|Process for producing new prostacyclin derivatives
    US3931285A|1976-01-06|Substituted tolyl esters of PGE1
    US4018820A|1977-04-19|Chemical synthesis
    US4304926A|1981-12-08|Phenacyl-type esters of PGE-types compounds
    US3979440A|1976-09-07|Phenacyl-type esters of phenyl-substituted PGE-type compounds
    CA1076570A|1980-04-29|Phenacyl-type esters of pgf and process
    US4012427A|1977-03-15|Substituted phenyl esters of PGE1 -type prostaglandins
    US3988355A|1976-10-26|Substituted phenyl and naphthyl esters of PGE1
    US4055589A|1977-10-25|20-Alkoxy-16-alkyl prostadienoic acid derivatives
    CA2036386A1|1991-01-15|9-fluoroprostaglandin derivatives, process for their production and their pharmaceutical use
    US3948970A|1976-04-06|Substituted tolyl esters of PGA1
    US3932486A|1976-01-13|Substituted tolyl esters of PGA2
    同族专利:
    公开号 | 公开日
    IE53907B1|1989-04-12|
    DK154073C|1989-02-27|
    ES513645A0|1983-03-16|
    AU8552882A|1983-01-06|
    JPS588059A|1983-01-18|
    DK154073B|1988-10-10|
    EP0069696B1|1986-01-15|
    AU559449B2|1987-03-12|
    AT17475T|1986-02-15|
    IE821611L|1983-01-03|
    IL66165D0|1982-09-30|
    CS236484B2|1985-05-15|
    IL66165A|1986-01-31|
    HU190692B|1986-10-28|
    US4454339A|1984-06-12|
    EP0069696A2|1983-01-12|
    EP0069696A3|1983-03-16|
    JPH0443906B2|1992-07-20|
    US4789685A|1988-12-06|
    DK123587D0|1987-03-10|
    DK123587A|1987-03-10|
    DE3126924A1|1983-01-20|
    ES8304078A1|1983-03-16|
    DE3268528D1|1986-02-27|
    DK294382A|1983-01-04|
    CA1218060A|1987-02-17|
    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    US3997587A|1975-06-26|1976-12-14|Syntex Inc.|D1- and 8R-9-fluoro-prostadienoic acid derivatives|
    DE2950027A1|1979-12-10|1981-06-11|Schering Ag Berlin Und Bergkamen, 1000 Berlin|9-CHLORINE PROSTAGLAND DERIVATIVES, METHOD FOR THE PRODUCTION AND USE AS A MEDICINAL PRODUCT|US4822909A|1983-06-10|1989-04-18|Asashi Glass Company Ltd.|7-fluoroprostaglandins and process for their production|
    DE3325175A1|1983-07-08|1985-01-17|Schering AG, 1000 Berlin und 4709 Bergkamen|11-HALOGEN PROSTANE DERIVATIVES, METHOD FOR THE PRODUCTION THEREOF AND THEIR USE AS MEDICINAL PRODUCTS|
    US4549980A|1983-10-11|1985-10-29|Mobay Chemical Corporation|White modification of a bis-triazinyl amino stilbene optical brightener and a process for making the same|
    DE3347128A1|1983-12-22|1985-07-11|Schering AG, 1000 Berlin und 4709 Bergkamen|9-HALOGEN- 2-PROSTAGLAND IN DERIVATIVES, METHOD FOR THE PRODUCTION THEREOF AND THEIR USE AS MEDICINAL PRODUCTS|
    DE3504044A1|1985-02-04|1986-08-07|Schering AG, Berlin und Bergkamen, 1000 Berlin|9-HALOGEN PROSTAGLANDIN CLATHRATE AND THEIR USE AS A MEDICINAL PRODUCT|
    DE3510978A1|1985-03-22|1986-09-25|Schering AG, Berlin und Bergkamen, 1000 Berlin|NEW 9-HALOGEN PROSTAGLANDINE, METHOD FOR THE PRODUCTION THEREOF AND THEIR USE AS MEDICINAL PRODUCTS|
    DE3608088C2|1986-03-07|1995-11-16|Schering Ag|Pharmaceutical preparations containing cyclodextrin clathrates of carbacyclin derivatives|
    AU624078B2|1987-07-17|1992-06-04|Schering Aktiengesellschaft Berlin Und Bergkamen|9-halogen--prostaglandin derivatives, process for manufacturing them, and their use as drugs|
    HU206084B|1987-07-17|1992-08-28|Schering Ag|Process for producing 9-halogen-/z/-prostaglandin derivatives and pharmaceutical compositions comprising such active ingredient|
    US5891910A|1987-07-17|1999-04-06|Schering Aktiengesellschaft|9-halogen- prostaglandin derivatives, process for their production and their use as pharmaceutical agents|
    DE3831222A1|1988-09-09|1990-03-22|Schering Ag|6-OXO-9-FLUOR-PROSTAGLANDIN DERIVATIVES PROCESS FOR THEIR PRODUCTION AND THEIR PHARMACEUTICAL USE|
    DE3923797A1|1989-07-14|1991-01-24|Schering Ag|9-FLUOR-PROSTAGLANDIN DERIVATIVES, METHOD FOR THE PRODUCTION THEREOF AND THEIR PHARMACEUTICAL USE|
    DE4024347A1|1990-07-27|1992-01-30|Schering Ag|CYCLOPENTANE DERIVATIVES, METHOD FOR THE PRODUCTION THEREOF AND THEIR PHARMACEUTICAL USE|
    US5385945A|1992-10-21|1995-01-31|Allergan, Inc.|7- andheptyl alcohols, heptylamines and heptanoic acid amides, and method of lowering intraocular pressure in the eye of a mammal by administration of these novel compounds|
    US5721273A|1993-12-15|1998-02-24|Alcon Laboratories, Inc.|Use of certain 9-halo-13,14-dihydroprostaglandins to treat glaucoma and ocular hypertension|
    US5807892A|1994-09-30|1998-09-15|Alcon Laboratories, Inc.|Use of certain prostaglandin analogues to treat glaucoma and ocular hypertension|
    US6103765A|1997-07-09|2000-08-15|Androsolutions, Inc.|Methods for treating male erectile dysfunction|
    AU742787B2|1997-07-09|2002-01-10|Androsolutions, Inc.|Improved methods and compositions for treating male erectile dysfunction|
    US6593369B2|1997-10-20|2003-07-15|Vivus, Inc.|Methods, compositions, and kits for enhancing female sexual desire and responsiveness|
    WO1999021562A1|1997-10-28|1999-05-06|Asivi, Llc|Treatment of female sexual dysfunction|
    US5877216A|1997-10-28|1999-03-02|Vivus, Incorporated|Treatment of female sexual dysfunction|
    US6235780B1|1998-07-21|2001-05-22|Ono Pharmaceutical Co., Ltd.|ω-cycloalkyl-prostaglandin E1 derivatives|
    US20040266880A1|2002-02-22|2004-12-30|Fumie Sato|Antipruritics|
    US7737182B2|2002-08-09|2010-06-15|Taisho Pharmaceutical Co., Ltd.|Pharmaceuticals for xerosis|
    KR100904583B1|2002-08-09|2009-06-25|다이쇼 세이야꾸 가부시끼가이샤|Antipruritic Agent|
    WO2004043471A1|2002-11-13|2004-05-27|Taisho Pharmaceutical Co., Ltd.|Antipruritic drug|
    法律状态:
    优先权:
    申请号 | 申请日 | 专利标题
    DE19813126924|DE3126924A1|1981-07-03|1981-07-03|9-FLUOR PROSTAGLAND DERIVATIVES, METHOD FOR THE PRODUCTION AND USE AS A MEDICINAL PRODUCT|
    [返回顶部]