WO1995027725A1 - 13α-ALKYLSTEROIDES PONTES EN POSITION 11β,19 - Google Patents

13α-ALKYLSTEROIDES PONTES EN POSITION 11β,19 Download PDF

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Publication number
WO1995027725A1
WO1995027725A1 PCT/EP1995/001339 EP9501339W WO9527725A1 WO 1995027725 A1 WO1995027725 A1 WO 1995027725A1 EP 9501339 W EP9501339 W EP 9501339W WO 9527725 A1 WO9527725 A1 WO 9527725A1
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Prior art keywords
benzo
dihydro
hydroxy
dione
estr
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PCT/EP1995/001339
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German (de)
English (en)
Inventor
Wolfgang Schwede
Wolfgang Halfbrodt
Joachim Kuhnke
Rolf Krattenmacher
Hans-Peter Muhn
Karl-Heinrich Fritzemeier
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Schering Aktiengesellschaft
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Priority to AU23064/95A priority Critical patent/AU2306495A/en
Publication of WO1995027725A1 publication Critical patent/WO1995027725A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J53/00—Steroids in which the cyclopenta(a)hydrophenanthrene skeleton has been modified by condensation with a carbocyclic rings or by formation of an additional ring by means of a direct link between two ring carbon atoms, including carboxyclic rings fused to the cyclopenta(a)hydrophenanthrene skeleton are included in this class
    • C07J53/002—Carbocyclic rings fused

Definitions

  • the present invention relates to 11 ⁇ , 19-bridged 13 ⁇ -alkyl steroids of the general formula I
  • R 6a and R 6b each represent a hydrogen atom and R 7 represents a hydrogen atom or a straight-chain or branched-chain saturated ⁇ - or ⁇ -substituted C 1 -C 4 -alkyl radical or
  • R 6a and R 6b together for a methylene group or one together with the
  • R 6a represents a fluorine, chlorine, bromine or iodine atom or a straight-chain or branched-chain saturated C 1 -C 4 -alkyl radical, in which case R 6b and R 7 are each one
  • R 7 each represent a hydrogen atom
  • R 6a can be ⁇ or ⁇ , or
  • R 6a represents a hydrogen atom, in which case R 6b and R 7 together represent an ⁇ - or ⁇ -methylene bridge or an additional bond, and
  • R 15 and R 16 each represent a hydrogen atom or together for an additional bond or an ⁇ - or ⁇ -methylene bridge, or
  • R 11 ' and R 19' each represent a hydrogen atom or together represent an additional bond, R 17a / R 17b one of the substituent combinations
  • R 21 and R 23 have the meaning of a hydrogen atom, a C 1 -C 4 alkyl or a C 1 -C 4 alkanoyl group,
  • R 22 has the meaning of a C 1 -C 3 alkyl or a 1-hydroxy-C 1 -C 3 alkyl group
  • A has the meaning of a hydrogen atom, the cyano group, a radical of the formula -COOR 24 or -OR 25 , where R 24 represents a C 1 -C 4 alkyl radical and R 25 represents hydrogen atom, a C 1 -C 4 alkyl or C 1 -C 4 alkanoyl radical,
  • B has the meaning of a hydrogen, fluorine, chlorine, bromine or iodine atom, a C 1 -C 4 -alkyl, C 2 - or C 3 -alkynyl group, a hydroxyalkyl, alkoxyalkyl or alkanoyloxyalkyl group each having 1 to 4 carbon atoms in the alkyl, alkoxy or / 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, 3 or 4,
  • n has the meaning 0, 1 or 2
  • p 0 or 1
  • R 18 represents a hydrogen atom or a methyl group.
  • serpentine lines in the representation of the general formula I mean that the substituent in question can be ⁇ - or ⁇ -permanent.
  • R 6a and R 6b each represent a hydrogen atom or
  • R 6a for a chlorine atom or for a straight-chain saturated, optionally ⁇ or ⁇ , C 1 -C 4 -alkyl radical, or
  • R 6b and R 7 each represent a hydrogen atom or together for an additional bond, or
  • R 15 and R 16 each represent a hydrogen atom or together for an additional bond
  • the compounds according to the invention are distinguished surprisingly through strong agonistic, ie gestagen effectiveness and are very effective in the pregnancy maintenance test on the rat after subcutaneous application.
  • the compounds of general formula I according to the invention have very strong gestagenic activity with only weak androgenic or even weakly antiandrogenic activity (dissociation).
  • the new compounds of general formula I can be used alone or in combination with estrogen 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) or 14 ⁇ , 17 ⁇ -ethano-1,3,5 ( 10) -estratrien-3,16 ⁇ , 17 ⁇ -trioI (WO 91/08219) into consideration.
  • the estrogen is administered in an amount equal to that of 0.01 to 0.05 mg of ethinyl 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 compounds according to the invention are particularly well suited 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 20 mg.
  • the formulation of the pharmaceutical preparations based on the new compounds is carried out in a manner known per se by processing the active ingredient, optionally in combination with an estrogen, with the carrier substances, diluents, optionally flavoring agents, etc. customary in galenics, and in the desired application form transferred.
  • 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, for example, benzyl benzoate or benzyl alcohol, can be added to increase the solubility.
  • 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 antagonist (HB 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).
  • HB 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, the formulation can be carried out as with conventional OC preparations.
  • the additional, competitive progesterone antagonist can also be applied sequentially.
  • the new compounds of general formula I are prepared according to the invention as described below.
  • the synthesis route for the basic structure containing the novel bridging element with a 13 ⁇ -s permanent alkyl group is shown in Scheme 1:
  • K is a common ketal protecting group, for example the ethylenedioxy or the 2,2-dimethylpropylene-1,3-dioxy group. Other common keto protection groups are also considered. K can also represent a protected hydroxyl group and a hydrogen atom, where the hydroxyl group is then protected, for example as methoxymethyl, methoxyethyl, tetra-hydroxypyranyl or silyl ether, for example as tert-butyl-dimethyl-silyl ether. By splitting off the protective group and oxidizing the free hydroxy group, the keto group is obtained.
  • Compound 2 is then converted to compound 3 by oxidation of the 17-hydroxy group by known methods.
  • the configuration at C-13 is then reversed starting from a compound 3 by irradiation with UV light (see, for example, EP-A 0 259 248 or US Pat. No. 5,273,971).
  • the configuration reversal at C-13 can also be carried out, for example, starting from epoxide 1 by oxidation to 17-ketone and irradiation at the epoxide stage (the corresponding 13 ⁇ -epoxide was described, for example, in US Pat. No. 5,273,971 or DE -A 38 22 770).
  • Analogous propargyl addition to the 13 ⁇ -alkyl-17-ketone obtained also leads to a compound 4 in this way.
  • protection of the 17-keto function during the propargyl addition may be necessary in order to prevent an undesired addition of the propargyl residue on the To prevent 17 carbon atom.
  • the groups mentioned above under the definition of K are possible as protective groups.
  • the configuration reversal can also be carried out at a later intermediate stage.
  • Compound 4 is finally brominated by a known method at the terminal end of the triple bond (H. Hofmeister, K. Annen, H. Laurent and R. Wiechert, Angew. Chem. 96, 720 (1984)) and the compound 5 obtained by hydrogenation or hydride transfer converted into the vinyl halide 6.
  • the reaction is preferably carried out by means of diimide reduction.
  • Solvents such as toluene, or the reaction with lithium in liquid
  • reaction in the present case does not proceed selectively to the 6-endo-trig product (11 ⁇ , 19 bridge), but portions of 5-exo product (9 ⁇ , 19 bridge) are also obtained. , but the z. B. by
  • the compounds 7 are central starting product in the preparation of compounds of the general formula I. They belong to the subject of the present invention as compounds of the general formula II.
  • the vinyl bridge is hydrogenated by known processes (if R 11 and R 19 'are each intended to represent a hydrogen atom).
  • the next steps then include the desired 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 and J. Tsuji, Tetrahedron 42, 2971 (1986); EP-A 0299913) of the corresponding enol compounds of 17-ketone.
  • R 15 and R 16 represent a common ⁇ or ⁇ 3-ring
  • this 3-ring is introduced, for example, by implementing the corresponding 15,16-en-17-one verb. with dimethylsulfoxonium methylide (see, for example, DE-A 11 83 500, DE-A 29 22 500, EP-A 0 019 690, US-A 4,291,029; EJ Corey and M. Chaykovsky, J.Am.Chem.Soc. 84, 867 ( 1962)).
  • the addition to C-17 is also not stereoselective in the present case.
  • the ratio of the two isomers to one another varies, the ⁇ addition (entry of the substituent to be added from the rear) being mostly preferred due to the 11 ⁇ , 19 bridge.
  • the introduction of the substituent -C ⁇ CB as R 17a with the meanings given for B takes place 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 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-1-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) oxy] -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) oxy] -1-propyne.
  • the hydroxypropyl and hydroxypropenyl compounds can be prepared from the hydroxypropinyl derivatives.
  • the representation of the hydroxypropyl chain is 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-configured 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 with the addition of lead (II) acetate.
  • 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 and LT Eby, J.Am. Chem. Soc. 63, 216 (1941)), with sodium amide in liquid ammonia or with lithium in low molecular weight amines (RA Benkeser et al., J.Am.Chem.Soc. 77, 3378 (1955)).
  • hydroxyalkenes and hydroxyalkanes can also be introduced directly by reacting the 17-ketone with their metalated derivatives (EJ Corey and RH Wollenberg, J.Org.Cem. 40, 2265 (1975); HP On, W. Lewis and G. Doubt , Synthesis 999 (1981); G. Gohiez, A. Alexakis and JF Normant, Tetrahedron Lett. 3013 (1978); PE Eaton et al., J.Org. Chem. 37, 1947 (1972)).
  • the introduction of homologous hydroxyalkyne, hydroxyalkene and hydroxyalkane groups is possible in an analogous manner.
  • Compounds with a saturated spiroether can also be prepared by hydrogenating the unsaturated spiroethers over platinum or palladium catalysts.
  • the 17-cyanomethyl side chain is either built up directly from the 17-ketone
  • transition metal catalysts with alkoxyvinyltin or zinc compounds can be coupled (see, for example, M. Kosugi, T. Sumiya, Y. Obara, M. Suzuki, H. Sano and T. Migati, Bull.Chem.Soc.Jpn. 60, 767 (1987); PG Ciattini, E. Morera and G. Ortar, Tetrahedron Lett. 31, 1989 (1990)). Acid hydrolysis of the coupling products gives the ⁇ 16 -17-acetyl compounds.
  • enones can be reacted with trimethylsulfoxonium iodide to give 16,17-methylene-17-acetyl compounds according to the processes given above for the cyclopropanation of the ⁇ 15 -17-ketones, or by conjugate addition of alkyl copper compounds into the 16 ⁇ - or ⁇ -alkyl- Transfer progesterone derivatives.
  • R 17a is an alkanoyl radical and R 17b is an alkyl radical
  • R 17a is an alkanoyl radical
  • R 17b is an alkyl radical
  • ⁇ 16 -17-alkanoyl compounds or 17 ⁇ (or ⁇ ) -hydroxy-17 ⁇ (or ⁇ ) -alkanoyl compounds by reducing in with lithium liquid ammonia, mixed with tetrahydrofuran, 17-enolate anions, which can be alkylated with the corresponding alkyl halide to give the desired compounds (see, for example, MJ Weiss, RE Schaub, GR Allen, Jr., JFPoletto, C. Pidacks, RB Conrow and CJ Coscia , Tetrahedron 20, 357 (1964).
  • nitriles can be prepared by separation of the isomers, e.g. deprotonated with lithium diisopropylamide or other strong bases and then alkylated with alkyl halides.
  • the nitriles can finally be converted into the alkanoyl compounds by reaction with alkylmagnesium halides or alkyllithium compounds.
  • the corresponding 17 ⁇ (or .beta.) (2-propenyl) compounds are prepared, for example, by reductive allylation of the ⁇ 16 -17-acetyl compounds mentioned above.
  • the terminal double bond is then oxidative either via hydroboration, for example with 9-BBN (9-borabicyclononane) Work-up and further oxidation to the corresponding C3 aldehyde or converted into the C 2 aldehyde by ozonolytic degradation.
  • the 6-ring or 5-ring spiroketones can then be prepared via an aldol reaction. This produces the ⁇ , ⁇ -unsaturated ketones, which, if desired, can be reduced to the saturated ketones using known methods.
  • the corresponding 17-ketone can be synthesized with trimethylsilyl cyanide in a suitable solvent, such as, for example, dichloromethane, optionally in the presence of crown ethers, for example 18-crown-6, as a mixture of the isomeric 17-cyanohydrins.
  • sily.protected cyanohydrins are then separated, for example by chromatography, and either reacted directly with an alkyl magnesium halide or an alkyl lithium compound, for example methyl lithium, or initially reduced with diisobutyl aluminum hydride (DIBAH) to the aldehydes, which then react with an alkyl magnesium halide or an alkyl lithium compound and reoxidation 20-ketone give the 17 ⁇ - or 17 ⁇ -alkanoyl compounds.
  • DIBAH diisobutyl aluminum hydride
  • the 17 ⁇ -alkanoyloxy derivatives can then be obtained in a known manner by esterification of the 17-hydroxy function.
  • 17 ⁇ -Acetyl-17 ⁇ -fluorine compounds can also be prepared by methods known from the literature.
  • the 17-ketones are initially in ⁇ 17 (20) -20- methoxy- 21-alcohol transferred.
  • 17 ⁇ -fluoro-20-enol ether is then obtained by reaction with DAST (diethylaminosulfur trifluoride) according to a formal S N 2 'process. Acid cleavage of the enol ether finally gives the 17 ⁇ -acetyl-17 ⁇ -fluorine compounds (G. Neef et al., Tetrahedron Lett. 35, 8587 (1994)).
  • the preparation of the 17 ⁇ -acetyl-17 ⁇ -fluorine compounds can also e.g. from the 17 ⁇ -bromo-17 ⁇ -acetyl compounds (see R. Deghenghi et al., Can. J. Chem. 39, 1553 (1961).
  • the subsequent release of the 3-keto function with elimination of water and formation of the 4 (5) double bond takes place by treatment with acids or an acidic ion exchanger.
  • the acidic treatment is carried out in a manner known per se by dissolving the corresponding 5 ⁇ -hydroxy-3-ketal in a water-miscible solvent, such as methanol, ethanol or acetone, and adding catalytic amounts of mineral or sulfonic acid, such as hydrochloric acid, to the solution. Sulfuric acid, phosphoric acid, perchloric acid or p-toluenesulfonic acid, or an organic acid, such as acetic acid, until the protective groups are removed.
  • the reaction takes place at temperatures from 0 to 100 ° C.
  • Dienol ether bromination can be carried out, for example, analogously to the instructions by JA Zderic, Humberto Carpio, A. Bowers and Carl Djerassi in Steroids 1, 233 (1963).
  • the elimination of hydrogen bromide is accomplished by heating the 6-bromo compound with basic agents, such as LiBr or Li 2 CO 3 in aprotic solvents such as dimethylformamide at temperatures of 50-120 ° C. or by heating the 6-bromo compounds in a solvent such as collidine or lutidine .
  • a 6,7-methylene function is introduced from the 4,6-diene-3-one by reaction with dimethylsulfoxonium methylide, giving a mixture of the ⁇ and ⁇ isomers (the ratio depends on the substrates used and is approx 1: 1), e.g. can be separated into the individual isomers by column chromatography.
  • R 7 is an alkyl radical
  • R 7 is an alkyl radical
  • R 6a represents a chlorine atom and R 6b and R 7 form a common additional bond are also prepared starting from the 4,6-diene-3-one compounds.
  • the 6,7-double bond is first used using organic peracids, such as, for example, meta-chloroperbenzoic acid in methylene chloride and, if appropriate, in the presence of sodium hydrogen carbonate (see W. Adam et al., J.Org.Chem. 38, 2269 (1973)) epoxidized. This epoxide is opened and the primarily formed 7 ⁇ -hydroxy group is eliminated, for example, by reaction with hydrogen chloride gas in glacial acetic acid (see, inter alia, DE-A 11 58 966 and DE-A 40 06 165).
  • a 6-methylene group can, for example, starting from a 3-amino-3,5-diene derivative, by reaction with formalin in alcoholic solution to form a 6 ⁇ -hydroxymethyl group and subsequent acidic elimination, e.g. with hydrochloric acid in dioxane / water.
  • acidic elimination e.g. with hydrochloric acid in dioxane / water.
  • the elimination of water can also take place in such a way that the hydroxyl group is first exchanged for a better escape group and then eliminated.
  • escape groups are e.g. the mesylate, tosylate or benzoate are suitable (see DE-A 34 02 3291, EP-A. 0 150 157, US-A 4,584,288; K. Nickisch et al., J. Med. Chem. 34, 2464 (1991)).
  • 6-methylene compounds Another possibility for the production of the 6-methylene compounds consists in the direct reaction of the 4 (5) unsaturated 3-ketones with acetals of formaldehyde in the presence of sodium acetate with e.g. Phosphorus oxychloride or phosphorus pentachloride in suitable solvents such as chloroform (see e.g. K. Annen, H. Hofmeister, H. Laurent and R. Wiechert, Synthesis 34 (1982)).
  • suitable solvents such as chloroform
  • the 6-methylene compounds can be used to prepare compounds of the general formula I in which R 6a is methyl and R 6b and R 7 together form an additional bond.
  • one of D. Burn et al. use the method described in Tetrahedron 21, 1619 (1965), in which isomerization of the double bond by heating the 6-methylene compounds in ethanol with 5% palladium-carbon catalyst, which has been pretreated either with hydrogen or by heating with a small amount of cyclohexene, be achieved.
  • the isomerization can also be carried out with a catalyst which has not been pretreated if a small amount of cyclohexene is added to the reaction mixture is added.
  • the presence of small amounts of hydrogenated products can be prevented by adding an excess of sodium acetate.
  • 6-methyl-4,6-dien-3-one derivatives can also be prepared directly (see K. Annen, H. Hofmeister, H. Laurent and R. Wiechert, Lieb. Ann. 712 (1983)) .
  • R 6a represents an ⁇ -methyl function
  • R 6a represents an ⁇ -methyl function
  • transfer hydrogenation EA Brande, RP Linstead and PWD Mitchell, J. Chem. Soc. 3578 (1954)
  • a suitable solvent such as ethanol
  • 6 ⁇ -methyl derivatives are obtained in very good yields.
  • Small amounts of 6 ⁇ -methyl compound can be acid isomerized (see, for example, D. Burn, DN Kirk and V. Petrow, Tetrahedron 1619 (1965)).
  • the targeted representation of 6 ⁇ -alkyl compounds is also possible.
  • the 4 (5) -unsaturated 3-ketones are e.g. reacted with ethylene glycol, trimethyl orthoformate in dichloromethane in the presence of catalytic amounts of an acid (e.g. p-toluosulfonic acid) to give the corresponding 3-ketals.
  • an acid e.g. p-toluosulfonic acid
  • the double bond isomerizes to position 5 (6).
  • a selective epoxidation of this 5 (6) double bond succeeds e.g. by using organic peracids, e.g. m-chloroperbenzoic acid, in suitable solvents such as dichloromethane.
  • the epoxidation can also be carried out with hydrogen peroxide in the presence of e.g. Hexachloroacetone or 3-nitrotrifluoroacetophenone.
  • the 5,6 ⁇ -epoxides formed can then be opened axially using appropriate alkyl magnesium halides or alkyl lithium compounds. This leads to 5 ⁇ -hydroxy-6 ⁇ -alkyl compounds.
  • the 3-keto protective group can be cleaved to maintain the 5 ⁇ -hydroxy function by treatment under mild acidic conditions (acetic acid or 4N hydrochloric acid at 0 ° C.). Basic elimination of the 5 ⁇ -hydroxy function with e.g. Verd.
  • aqueous sodium hydroxide solution gives the 3-keto-4-ene compounds with a ⁇ -6-alkyl group.
  • ketal cleavage under more severe conditions gives the corresponding 6 ⁇ -alkyl compounds.
  • Suitable tertiary bases are, for example, trimethylamine, triethylamine, pyridine, N, N-dimethylaminopyridine, 1,5-diazabicyclo [4.3.0] non-5-ene (DBN) and 1,5-diazabicyclo [5.4.0] undec-5- en (DBU), where
  • Formula I with W in the meaning of two hydrogen atoms can, for example, according to the specification given in DE-A 28 05 490 by reductive cleavage of a thioketal
  • Example 1b Analogously to Example 1b), 530 mg of the substance described under 3c) are reacted with 600 mg of chromium trioxide and 2.2 ml of pyridine in dichloromethane. After purification by column chromatography, 385 mg 3d) is obtained as a white foam.

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Abstract

L'invention concerne de nouveaux 13α-alkylstéroïdes pontés en position 11β,19, de formule générale (I), où W, R?6a, R6b, R7, R15, R16, R17a et R17b, R18, R11', et R19'¿, ont la notation mentionnée dans la description. L'invention concerne également un procédé permettant de fabriquer ces substances. Ces nouveaux composés présentent une forte action gestagène et se prêtent à la fabrication de médicaments.
PCT/EP1995/001339 1994-04-12 1995-04-12 13α-ALKYLSTEROIDES PONTES EN POSITION 11β,19 WO1995027725A1 (fr)

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AU23064/95A AU2306495A (en) 1994-04-12 1995-04-12 11beta ,19-bridged 13alpha-alkyl steroids

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DEP4413185.2 1994-04-12
DE19944413185 DE4413185A1 (de) 1994-04-12 1994-04-12 11beta,19-überbrückte 13alpha-Alkylsteroide

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002054064A2 (fr) * 2000-12-28 2002-07-11 Schering Ag Procede de criblage de ligands a specificite pour l'isoforme des recepteurs de progesterone et de ligands de recepteurs de progesterone a selectivite tissulaire

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0129499A2 (fr) * 1983-06-15 1984-12-27 Schering Aktiengesellschaft 13-Alpha alcoyle-gonanes, leur préparation et préparations pharmaceutiques les contenant
EP0283428A1 (fr) * 1987-03-18 1988-09-21 Schering Aktiengesellschaft Stéroides 19,11-bêta-pontés, leur préparation et préparations pharmaceutiques les contenant
DE3717169A1 (de) * 1987-05-19 1988-12-01 Schering Ag 19,11ss-ueberbrueckte steroide, deren herstellung und diese enthaltende pharmazeutische praeparate
WO1994009025A1 (fr) * 1992-10-13 1994-04-28 Schering Aktiengesellschaft 4-estrenes pontes en positions 19,11 a action gestagene

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0129499A2 (fr) * 1983-06-15 1984-12-27 Schering Aktiengesellschaft 13-Alpha alcoyle-gonanes, leur préparation et préparations pharmaceutiques les contenant
EP0283428A1 (fr) * 1987-03-18 1988-09-21 Schering Aktiengesellschaft Stéroides 19,11-bêta-pontés, leur préparation et préparations pharmaceutiques les contenant
DE3717169A1 (de) * 1987-05-19 1988-12-01 Schering Ag 19,11ss-ueberbrueckte steroide, deren herstellung und diese enthaltende pharmazeutische praeparate
WO1994009025A1 (fr) * 1992-10-13 1994-04-28 Schering Aktiengesellschaft 4-estrenes pontes en positions 19,11 a action gestagene

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
G. NEEF ET AL: "New Steroids with Antiprogestational and Antiglucocorticoid Activities", STEROIDS, vol. 44, no. 4, SAN FRANCISCO US, pages 349 - 372 *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002054064A2 (fr) * 2000-12-28 2002-07-11 Schering Ag Procede de criblage de ligands a specificite pour l'isoforme des recepteurs de progesterone et de ligands de recepteurs de progesterone a selectivite tissulaire
WO2002054064A3 (fr) * 2000-12-28 2003-10-16 Schering Ag Procede de criblage de ligands a specificite pour l'isoforme des recepteurs de progesterone et de ligands de recepteurs de progesterone a selectivite tissulaire

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