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WO1994006819A1 - 4,5;11,12-estradienes a activite gestagene, leur procede de preparation, medicaments contenant ces estradienes ainsi que leur utilisation pour preparer des medicaments - Google Patents

4,5;11,12-estradienes a activite gestagene, leur procede de preparation, medicaments contenant ces estradienes ainsi que leur utilisation pour preparer des medicaments Download PDF

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Publication number
WO1994006819A1
WO1994006819A1 PCT/EP1993/002573 EP9302573W WO9406819A1 WO 1994006819 A1 WO1994006819 A1 WO 1994006819A1 EP 9302573 W EP9302573 W EP 9302573W WO 9406819 A1 WO9406819 A1 WO 9406819A1
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WIPO (PCT)
Prior art keywords
homoestra
hydroxy
propynyl
group
general formula
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PCT/EP1993/002573
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German (de)
English (en)
Inventor
Wolfgang Schwede
Wolfgang Halfbrodt
Günter Neef
Eckhard Ottow
Klaus Schöllkopf
Rolf Krattenmacher
Karl-Heinrich Fritzemeier
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Schering Aktiengesellschaft
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Priority to AU51086/93A priority Critical patent/AU5108693A/en
Publication of WO1994006819A1 publication Critical patent/WO1994006819A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J21/00—Normal steroids containing carbon, hydrogen, halogen or oxygen having an oxygen-containing hetero ring spiro-condensed with the cyclopenta(a)hydrophenanthrene skeleton
    • C07J21/001—Lactones
    • C07J21/003—Lactones at position 17
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J1/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, not substituted in position 17 beta by a carbon atom, e.g. estrane, androstane
    • C07J1/0051—Estrane derivatives
    • C07J1/0081—Substituted in position 17 alfa and 17 beta
    • C07J1/0088—Substituted in position 17 alfa and 17 beta the substituent in position 17 alfa being an unsaturated hydrocarbon group
    • C07J1/0096—Alkynyl derivatives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J21/00—Normal steroids containing carbon, hydrogen, halogen or oxygen having an oxygen-containing hetero ring spiro-condensed with the cyclopenta(a)hydrophenanthrene skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J7/00—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms
    • C07J7/0005—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms not substituted in position 21
    • C07J7/001—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms not substituted in position 21 substituted in position 20 by a keto group
    • C07J7/004—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms not substituted in position 21 substituted in position 20 by a keto group substituted in position 17 alfa
    • C07J7/0045—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms not substituted in position 21 substituted in position 20 by a keto group substituted in position 17 alfa not substituted in position 16

Definitions

  • Estradienes process for their preparation, medicaments containing them and their use in the production of medicaments
  • the present invention relates to 4,5; 11,12-estradienes of the general formula I
  • W represents an oxygen atom, the hydroxyimino group N ⁇ OH or two hydrogen atoms
  • R 14 , R 15 and R 16 each for a hydrogen atom or R 14 for an ⁇ -hydrogen atom and R 15 and R 16 together for an additional bond between the carbons atoms C 15 and C 16 or R 16 represent a hydrogen atom and R 14 and R 15 represent an additional bond between the carbon atoms C14 and C15,
  • R 1 and R 3 have the meaning of a hydrogen atom, a C 1 -C 4 alkyl or a C 1 -C 4 alkanoyl group,
  • R 2 in the meaning of a C 1 -C 3 alkyl group, in the meaning of a hydrogen atom, the cyano group, of CO 2 R 4 or OR 5 , where R 4 is C 1 -C 4 alkyl and R 5 is hydrogen, C 1 -C 4 alkyl or C 1 -C 4 alkanoyl, B has the meaning of a hydrogen atom, a C 1 -C 4 alkyl group, a fluorine, chlorine, bromine or iodine atom, a hydroxyalkyl, alkoxyalkyl or alkanoyloxyalkyl group each having 1-4 carbon atoms in the alkyl, alkoxy and alkanoyloxy part ,
  • D has the meaning of a hydrogen atom, a hydroxy, C 1 -C 4 alkoxy or C 1 -C 4 alkanoyloxy group, n has the meaning 0, 1, 2 or 3, m has the meaning 0, 1 or 2, p is 0 or 1, k is 0, 1 or 2 and
  • R 18 represents a hydrogen atom or a methyl group.
  • R 11 is C 1 -C 2 -alkyl radicals and the C 1 -C 4 alkyl group which occurring under R 1 and R 3 is C 1 -C 4 alkyl group
  • the possible for R 2 is C 1 -C 3 alkyl group
  • the possible for R 4 and R 5 is C 1 -C 4 alkyl groups
  • said C 1 -C 4 alkyl under B come under the corresponding definition in each case aile falling possible alkyl radicals, namely methyl, ethyl, n- Propyl, i-propyl, n-butyl, i-butyl and tert-butyl.
  • a methyl group is preferred in each case.
  • R 1 , R 3 and R 5 a formyl, acetyl, propionyl, butyryl or isobutyryl group is intended.
  • R 1 , R 3 and / or R 5 denotes an alkanoyl group, it is an acetyl radical.
  • D is a C 1 -C 4 alkoxy group, this can be the methoxy, ethoxy, propoxy, isopropoxy, n, iso or tert-butoxy group.
  • the C 1 -C 4 alkanoyloxy group D can be a formyloxy, acetyloxy, propionyloxy, butyryloxy or isobutyryloxy radical.
  • Preferred according to the present invention are those compounds of the general formula I in which
  • R 11 represents a hydrogen atom, a C 1 -C 4 alkyl group, in particular a methyl group, a chlorine or bromine atom, an ethenyl (vinyl) or ethynyl group,
  • R 14 represents a hydrogen atom
  • R 15 and R 16 each represent a hydrogen atom or together for an additional bond between the carbon atoms C15 and C16,
  • R 17 ⁇ is an ethynyl, 1-propynyl, 1-butynyl, 1-pentynyl or 1-hexynyl group or an acetyloxy, propionyloxy or butyryloxy radical,
  • R 17ß for a free, etherified with a C 1 -C 4 alkyl radical or with a C 1 -C 4 alkanoyl esterified hydroxy group or a C 1 -C 4 alkanoyl group or R 17 ⁇ and R 17.beta. together represent a ring of the partial formula
  • R 18 represents a methyl radical or a hydrogen atom.
  • the new compounds of general formula I can be used alone or in combination with estrogen (s) in contraceptive preparations.
  • the dosage of the compounds according to the invention in contraceptive preparations should preferably be 0.01 to 2 mg per day.
  • the gestagenic and estrogenic active ingredient components are preferably administered orally together in contraceptive preparations.
  • the daily dose is preferably administered once.
  • Preferred estrogens are synthetic estrogens such as ethinyl estradiol, 14 ⁇ , 17 ⁇ -ethano-1,3,5 (10) -estratrien-3,17ß-diol (WO 88/01275), 14 ⁇ , 17 ⁇ -ethano-1,3,5 ( 10) -estratrien-3,16 ⁇ , 17ß-triol (WO 91/08219) into consideration.
  • the estrogen is administered in an amount equal to that of 0.01 to 0.05 mg of ethynyl estradiol.
  • the new compounds of the general formula I can also be used in preparations for the treatment of gynecological disorders and for substitution therapy. Because of their favorable activity profile, the verb according to the invention Particularly suitable for the treatment of premenstrual complaints, such as headaches, depressive moods, water retention and mastodynia.
  • the daily dose for the treatment of premenstrual complaints is about 1 to
  • the pharmaceutical preparations based on the new compounds are formulated in a manner known per se by adding the active ingredient, if appropriate in combination with a
  • Estrogen processed with the carrier substances, diluents, possibly flavoring agents etc. used in galenics and converted into the desired application form.
  • Tablets, coated tablets, capsules, pills, suspensions or solutions are particularly suitable for the preferred oral application.
  • Oily solutions such as solutions in sesame oil, castor oil and cottonseed oil are particularly suitable for parenteral administration.
  • solubilizers such as benzyl benzoate or benzyl alcohol, can be added.
  • the new compounds can advantageously also be applied by means of a transdermal system
  • the new compounds can also be used as a gestagen component in the recently known compositions for female fertility control, which are characterized by the additional use of a competitive progesterone antagome, (H. B Croxatto and AM Salvatierra in Female Contraception and Male Fertility Regulation ed . by Runnebaum, Rabe &. Kiesel - Vol. 2 Advances in Gynecological and Obstetric Research Series, Parthenon Publishing Group - 1991, page 245.
  • a competitive progesterone antagome H. B Croxatto and AM Salvatierra in Female Contraception and Male Fertility Regulation ed . by Runnebaum, Rabe &. Kiesel - Vol. 2 Advances in Gynecological and Obstetric Research Series, Parthenon Publishing Group - 1991, page 245.
  • the dosage is in the range already specified
  • Formulation can be carried out as with conventional OC preparations.
  • the additional, competitive progesterone antagonist can also be applied sequentially.
  • R 11 , R 14 , R 15 , R 16 , R 17 ⁇ , R 17ß and R 18 in formula I and R 17 ⁇ ' and R 17ß' together also mean an oxygen atom and K is a keto protective group, by acid treatment in one converted into the ⁇ 4 -3 keto system with water-miscible solvents, possibly modifying an R 17 ⁇ ' or R 17ß' group or any 17 keto group still present (R 17 ⁇ ' and R 17ß together 0) by nucleophilic addition of the Substituents R 17 ⁇ or a reactive precursor of R 17 ⁇ , optionally hydrogenating an unsaturated C 17 side chain in a compound of the general transferred my formula I with the ultimately desired meaning of R 17 ⁇ and R 17ß and optionally with hydroxylamine hydrochloride in the presence of tertiary amines at a temperature between - 20 ° and + 40 ° C in the 3-position of the hydroxyimino group> N ⁇ OH ( ⁇ means syn - or anti-OH) or
  • K can also mean a protected hydroxyl group and a hydrogen atom, the hydroxyl group then being protected, for example, as methoxymethyl, methoxyethyl, tetrahydropyranyl or silyl ether.
  • the compound of general formula B can then be coupled in the presence of a transition metal catalyst with alkyl-, cycloalkyl- or alkenylstannannes or corresponding organoboron compounds quite analogously to that described in international patent application WO 91/18917 (there for the introduction of a substituted aryl radical in the 11-position), the radical R 11 'being established to obtain a compound of the general formula C (PJ Stang, M. Hanack, LR Subramanian, Synthesis (1982), p. 85; WJ Scott, GT Crisp, JK Stille, J. Am. Chem Soc. 106, 4630 (1984); WJ Scott, JK Stille, J. Am. Chem. Soc. 108, 3033 (1986)).
  • L in the compound of the general formula B is preferably the trifluoromethylsulfonyloxy or the nonafluorobutylsulfonyloxy group.
  • Palladium tetrakistriphenylphoshin is preferably used as the transition metal catalyst for coupling; however, nickel tetrakistriphenylphosphine or similar transition metal catalysts could also be used.
  • the alkyl, cycloalkyl or alkenyl groups can also be introduced by reacting a compound of the general formula B with appropriate cuprates (JE McMurry, WJ Scott, Tet. Lett. 21, 4313 (1980); JE McMurry, S.
  • R 11 'represents a group of the type C ⁇ CV can be produced, for example, from the 11-acetyl compounds.
  • the 11-acetyl compounds are converted into the corresponding enolphosphorus compounds or the enoltrif luormethanesulfonyl compounds, from which the triple bond is then produced by elimination using strong bases (for example diisopropylamide) (BE Marron, KC Nicolaou, Synthesis (1989), 537; E. Negishi, AD King, WL Klima, J. Org. Chem. 45, 2526 (1980); PJ Stang, MG Mangun, DP Fox, P.
  • strong bases for example diisopropylamide
  • radical V can be achieved by deprotonation of the terminal acetylene (for example with butyllithium or sodium amide) and reaction of the organometallic compound formed with alkyl halides or by halogenation (see for example H. Hofmeister, K. Annen, H. Laurent and R. Wiechert , Angew. Chem. 96, 720 (1984)).
  • R 11 is hydrogen
  • compounds in which R 11 is hydrogen can also be prepared from a compound of the general formula B by reaction with trialkyltin hydrides (preferably tributyltin hydride) or with other reducing agents (for example ammonium formates) in the presence of transition metal catalysts (S. Cacchi, E. Morera , G. Ortar, Tet. Lett. 25, 4821 (1984); J. Tsuji, T. Yamakawa. Tet. Lett. (1979), p. 613; JR Weir, BA Patel, RF Heck, J. Org. Chem 45, 4926 (1980).
  • transition metal catalysts S. Cacchi, E. Morera , G. Ortar, Tet. Lett. 25, 4821 (1984); J. Tsuji, T. Yamakawa. Tet. Lett. (1979), p. 613; JR Weir, BA Patel, RF Heck, J. Org. Chem 45, 4926 (1980).
  • R 11 represents a halcenator
  • R 11 represents a halcenator
  • R 11 represents a halcenator
  • L represents a perfluoroalkylsulfonyloxy group, preferably trifluoromethylsulfonyloxy group, with hexabutylditin or hexamethylditin in the corresponding vinyltin compounds
  • halogens I 2
  • CsSO 4 F cesium fluoroxysulfate
  • the keto protective group can be selectively cleaved in the 17 position with a weak acid (acetic acid, oxalic acid).
  • the next steps then possibly include functionalizations in the D-ring.
  • a 15, 16 double bond (R 15 ' and R 16' form a common additional bond) is introduced, for example, by a modified Saegusa oxidation (I. Minami, K. Takahashi, I. Shimizu, T. Kimura, J. Tsuji, Tetrahedron 42 (1986), p. 2971; EP-A 0 299 913) of the corresponding enol compounds of 17-ketone.
  • the double bond can be isomerized according to position 14.
  • the 15,16-en compounds are treated with, for example, silica gel / triethylamine (S. Scholz et al. Lieb. Ann. Chem. 1989, p. 151).
  • nucleophiles are introduced with the addition of cerium salts (T. Imamoto, N. Takiyana, K. Nakamura, Y. Sugiura, Tet. Lett. 25, 4233 (1984)).
  • the introduction of the substituent C ⁇ CY as R 17 ⁇ ' with the meanings given for Y is carried out with the aid of the metalated compounds, which can also be formed in situ and reacted with the 17-ketone.
  • the metalated compounds are formed, for example, by reacting the corresponding acetylenes with alkali metals, in particular potassium, sodium or lithium, in the presence of an alcohol or in the presence of ammonia.
  • the alkali metal can also act in the form of, for example, methyl or butyllithium.
  • 3-Hydroxy-l-propyne is introduced in the 17-position by reacting the 17-ketone with the dianion of propargyl alcohol (3-hydroxypropine), e.g. the dipotassium salt of propargyl alcohol generated in situ or with corresponding derivatives protected on the hydroxy function, such as e.g. the lithium compound of 3 - [(tetrahydro-2H-pyran-2-yl) oxyl] -1-propyne.
  • propargyl alcohol 3-hydroxypropine
  • the dipotassium salt of propargyl alcohol generated in situ or with corresponding derivatives protected on the hydroxy function such as e.g. the lithium compound of 3 - [(tetrahydro-2H-pyran-2-yl) oxyl] -1-propyne.
  • the hydroxypropyl and hydroxypropenyl compounds can be prepared from the hydroxypropinyl derivatives.
  • the hydroxypropyl chain is represented e.g. by hydrogenation at room temperature and normal pressure in solvents such as methanol, ethanol, tetrahydrofuran or ethyl acetate with the addition of noble metal catalysts such as platinum or palladium.
  • Compounds with a Z configuration double bond in the side chain are prepared by hydrogenating the acetylenic triple bond with a deactivated noble metal catalyst, e.g. 10% palladium on barium sulfate in the presence of an amine or 5% palladium on calcium carbonate with the addition of lead (II) acetate. The hydrogenation is stopped after the absorption of one equivalent of hydrogen.
  • a deactivated noble metal catalyst e.g. 10% palladium on barium sulfate in the presence of an amine or 5% palladium on calcium carbonate.
  • Connections with an E-configured double bond in the side chain are created by reducing the triple bond, for example with sodium in liquid ammonia (KN Cambell, LT Eby, J. Am. Chem. Soc. 63 (1941), p. 216), with sodium amide in liquid ammonia or with lithium in low molecular weight amines (RA Benkeser et al., J. Am. Chem. Soc. 77 (1955), p. 3378).
  • hydroxyalkenes and hydroxyalkanes can also be introduced directly by reacting the 17-ketone with metalated derivatives (EJ Corey, RH Wollenberg, J. Org. Chem. 40, 2265 (1975); HP On, W. Lewis, G. Doubt, Synthesis 1981, p. 999; G. Gohiez, A. Alexakis, JF Normant, Tet. Lett. 1978, p. 3013; PE Eaton et al., J. Org. Chem. 37, 1947).
  • the introduction of homologous hydroxyalkyne, hydroxyalkene and hydroxyalkane groups is possible in a corresponding manner.
  • the 17-cyanomethyl side chain is built up from the 17-ketone either directly by adding acetonitrile or by cleaving the spiroepoxide with HCN according to K. Ponsold et al., Z. Chem. 18 (1978), 259-260.
  • the 17-ketone is reacted, for example, with acetone cyanohydrin in suitable solvent systems, for example ethanol or methanol and dichloromethane at a suitable (mostly slightly basic) pH value (is adjusted to NaOH by adding KCN or NaCN or KOH). Crystallization of the 17 ⁇ -cyano compound can be achieved under these reaction conditions.
  • the 17 ⁇ -hydroxy function is then protected and then the cyano group is allowed to react, for example, with alkyl lithium (methyl lithium) or alkyl magnesium halides, in order then to obtain the 17 ⁇ -hydroxy-17 ⁇ -alkanoyl compound after acidic cleavage.
  • the 17 ⁇ -alkanoyloxy derivatives can then be obtained in a known manner.
  • the 3-keto function is released to form the 4 (5) double bond by treatment with acid or an acidic ion exchanger.
  • the acidic treatment is carried out in a manner known per se by adding the corresponding 3-ketal in a water-miscible solvent, such as aqueous methanol, ethanol or acetone, dissolves and act on the solution catalytic amounts of mineral or sulfonic acid, such as hydrochloric acid, sulfuric acid, phosphoric acid, perchloric acid or p-toluenesulfonic acid, or an organic acid, such as acetic acid, as long as leaves until existing protective groups are removed.
  • the reaction which takes place at temperatures from 0 to 100 ° C, can also be carried out with an acidic ion exchanger. The course of the reaction can be followed using analytical methods, for example samples taken by thin-layer chromatography.
  • the compounds of general formula I with X equal to oxygen can be obtained by reaction with hydroxylamine hydrochloride in the presence of tert. Amines are converted into the oximes at temperatures between - 20 and + 40 ° C (general formula I with X in the meaning of N OH, where the hydroxyl group can be syn or antististant).
  • Lithium diisopropylamide is prepared from 27 ml diisopropylamine and 120 ml n-butyllithium (1.6 molar solution in hexane) in 300 ml absolute tetrahydrofuran at -30 ° C. A solution of 25 g of 3,3,17,17-bis [1,2-ethanediylbis (oxy)] - 18a-homoestr-5-en-11-one in 250 ml of absolute tetrahydrofuran is then added and the mixture is left at 0 ° C. stir for an hour.
  • Example 1d Analogously to Example 1d), 1.3 g of the substance prepared under 1c) are reacted with 24 ml of a 1.6 molar solution of n-butyllithium in hexane and propyne gas in absolute absolute tetrahydrofuran. After purification, 1.31 g 2a) is obtained.
  • Lithium diisopropylamide is prepared from 6.65 ml of diisopropylamine and 30 ml of a 1.6 molar solution of n-butyllithium in hexane in 200 ml of absolute tetrahydrofuran at -30 ° C. Subsequently, a solution of 6 g of the substance produced under lc) in 60 ml added dropwise to absolute tetrahydrofuran. The mixture is stirred for one hour at -30 ° C and then 8.4 ml of trimethylsilyl chloride are added. The mixture is stirred at room temperature for 30 minutes and worked up in aqueous form (B, F). The crude product obtained (7.3 g) is used in the next stage without purification.
  • Example 3b Analogously to Example 3b), 2.4 g of the substance described under 5a) are reacted with 1.35 g of PaUadium (II) acetate in 50 ml of acetonitrile. After purification, 1.43 g 5b) is obtained as a white foam.
  • Example le Analogously to Example le), 1.40 g of the substance produced under 5c) are reacted with 5 ml of 4 normal hydrochloric acid in 25 ml of acetone. After purification, 995 mg 5d) is obtained as a white foam.
  • Example 1c Analogously to Example 1c), 4.5 g of the compound described under a) are reacted with 16 g of silica gel and 1.6 ml of saturated aqueous oxalic acid solution in dichloromethane. After recrystallization from diisopropyl ether, 2.9 g of 6b) are obtained.
  • Example 2a Analogously to Example 2a), 650 mg of the compound described under b) are reacted with 11 ml of a 1.6 molar solution of n-butyllithium in hexane and propyne gas. The crude product obtained (700 mg) is used in the next stage without purification.
  • Example 3b Analogously to Example 3b), 1.2 g of the compound described under 7a) are reacted with 700 mg of palladium (II) acetate in 20 ml of acetonitrile. After purification, 690 mg 7b) are obtained.
  • Example le Analogously to Example le), 770 mg of the compound described under c) are reacted with 4 normal hydrochloric acid in acetone. After recrystallization from diisopropyl ether, 408 mg 7d) are obtained.
  • Washed sodium hydrogen carbonate solution and saturated aqueous sodium chloride solution After purification, 4 g 8a) are obtained.
  • Trifluoromethanesulfonic anhydride added. Then leave for two hours
  • Example 1c Analogously to Example 1c), 2.1 g of the compound described under b) are reacted with 7.3 g of silica gel and 0.73 ml of saturated aqueous oxalic acid solution in dichloromethane. After recrystallization from diisopropyl ether, 1.3 g 8c) are obtained.
  • Example 1c Analogously to Example 1c), 2.4 g of the substance described under b) are reacted with saturated aqueous oxalic acid solution and 5 g of silica gel in dichloromethane. After recrystallization from diisopropyl ether, 1.3 g 9c) are obtained.

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  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
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Abstract

L'invention concerne des nouveaux 4,5;11,12-estradiènes de la formule générale (I) dans laquelle les substituants W, R?11, R14, R15, R16, R17α, R17β, R18¿ ont la notation mentionnée dans la description. L'invention concerne en outre un procédé permettant de les préparer. Les nouveaux composés ont une forte activité gestagène et peuvent être utilisés dans des médicaments , par exemple comme constituants gestagènes dans des préparations de contraception hormonale.
PCT/EP1993/002573 1992-09-22 1993-09-22 4,5;11,12-estradienes a activite gestagene, leur procede de preparation, medicaments contenant ces estradienes ainsi que leur utilisation pour preparer des medicaments WO1994006819A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU51086/93A AU5108693A (en) 1992-09-22 1993-09-22 Gestagen-effective 4,5;11,12-estradienes, process for their production, medicaments containing these estradienes and their use in producing medicaments

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Application Number Priority Date Filing Date Title
DE19924232521 DE4232521A1 (de) 1992-09-22 1992-09-22 Gestagen wirksame 4,5;11,12-Estradiene, Verfahren zu ihrer Herstellung, diese Estradiene enthaltende Arzneimittel sowie deren Verwendung zur Herstellung von Arzneimitteln
DEP4232521.8 1992-09-22

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WO1994006819A1 true WO1994006819A1 (fr) 1994-03-31

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0700926A1 (fr) * 1994-09-09 1996-03-13 INDUSTRIALE CHIMICA S.r.l. Procédé de préparation de Gestodene
JP2011507924A (ja) * 2007-12-29 2011-03-10 バイエル・シエーリング・ファーマ アクチエンゲゼルシャフト １７−ヒドロキシ−１９−ノル−２１−カルボン酸−ステロイドγ−ラクトン誘導体、それらの使用および前記誘導体を含有する医療製品
JP2011507925A (ja) * 2007-12-29 2011-03-10 バイエル・シエーリング・ファーマ アクチエンゲゼルシャフト １７−（１’−プロペニル）−１７−３’−オキシドエストラ−４−エン−３−オン誘導体、その使用及び当該誘導体を含む医薬品

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JP2011507925A (ja) * 2007-12-29 2011-03-10 バイエル・シエーリング・ファーマ アクチエンゲゼルシャフト １７−（１’−プロペニル）−１７−３’−オキシドエストラ−４−エン−３−オン誘導体、その使用及び当該誘導体を含む医薬品
US8937058B2 (en) 2007-12-29 2015-01-20 Ulrich Klar 17-hydroxy-19-nor-21-carboxylic acid-steroid γ-lactone derivative, use thereof, and medicament containing the derivative
US9034856B2 (en) 2007-12-29 2015-05-19 Bayer Intellectual Property Gmbh 17-(1′propenyl)-17-3′-oxidoestra-4-en-3-one derivative, use thereof, and medicament containing said derivative

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DE4232521A1 (de) 1994-03-24

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