NO160521B - ANALOGY PROCEDURE FOR THE PREPARATION OF THERAPEUTICALLY ACTIVE 13ALFA ALKYLGONANES. - Google Patents
ANALOGY PROCEDURE FOR THE PREPARATION OF THERAPEUTICALLY ACTIVE 13ALFA ALKYLGONANES. Download PDFInfo
- Publication number
- NO160521B NO160521B NO842394A NO842394A NO160521B NO 160521 B NO160521 B NO 160521B NO 842394 A NO842394 A NO 842394A NO 842394 A NO842394 A NO 842394A NO 160521 B NO160521 B NO 160521B
- Authority
- NO
- Norway
- Prior art keywords
- hydroxy
- methyl
- group
- general formula
- carbon atoms
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims description 8
- 238000002360 preparation method Methods 0.000 title description 6
- 150000001875 compounds Chemical class 0.000 claims description 20
- 125000004432 carbon atom Chemical group C* 0.000 claims description 11
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 9
- 239000001257 hydrogen Substances 0.000 claims description 8
- 229910052739 hydrogen Inorganic materials 0.000 claims description 8
- 125000000217 alkyl group Chemical group 0.000 claims description 7
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 7
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 6
- 238000005935 nucleophilic addition reaction Methods 0.000 claims description 6
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 5
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 3
- 238000003776 cleavage reaction Methods 0.000 claims description 3
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 3
- 230000007017 scission Effects 0.000 claims description 3
- 125000004825 2,2-dimethylpropylene group Chemical group [H]C([H])([H])C(C([H])([H])[H])(C([H])([H])[*:1])C([H])([H])[*:2] 0.000 claims description 2
- VGGSQFUCUMXWEO-UHFFFAOYSA-N Ethene Chemical compound C=C VGGSQFUCUMXWEO-UHFFFAOYSA-N 0.000 claims description 2
- 239000005977 Ethylene Substances 0.000 claims description 2
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 2
- 125000004423 acyloxy group Chemical group 0.000 claims description 2
- 125000004356 hydroxy functional group Chemical group O* 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims description 2
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 2
- 238000009281 ultraviolet germicidal irradiation Methods 0.000 claims description 2
- 230000008030 elimination Effects 0.000 claims 1
- 238000003379 elimination reaction Methods 0.000 claims 1
- 125000002345 steroid group Chemical group 0.000 claims 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 69
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 42
- 239000000243 solution Substances 0.000 description 35
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 30
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 29
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 24
- 239000012043 crude product Substances 0.000 description 20
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 15
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 15
- 239000005457 ice water Substances 0.000 description 13
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 12
- 238000006243 chemical reaction Methods 0.000 description 12
- 229960000583 acetic acid Drugs 0.000 description 10
- 238000002425 crystallisation Methods 0.000 description 10
- 230000008025 crystallization Effects 0.000 description 10
- 239000000203 mixture Substances 0.000 description 10
- 239000002904 solvent Substances 0.000 description 10
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 9
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 9
- 238000001816 cooling Methods 0.000 description 9
- 239000000047 product Substances 0.000 description 8
- 238000004587 chromatography analysis Methods 0.000 description 7
- 150000002168 ethanoic acid esters Chemical class 0.000 description 7
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 6
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 6
- 239000003418 antiprogestin Substances 0.000 description 6
- 239000003054 catalyst Substances 0.000 description 6
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 5
- 239000012230 colorless oil Substances 0.000 description 5
- 230000000694 effects Effects 0.000 description 5
- 238000005984 hydrogenation reaction Methods 0.000 description 5
- TWNQGVIAIRXVLR-UHFFFAOYSA-N oxo(oxoalumanyloxy)alumane Chemical compound O=[Al]O[Al]=O TWNQGVIAIRXVLR-UHFFFAOYSA-N 0.000 description 5
- 239000000725 suspension Substances 0.000 description 5
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 4
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 4
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 4
- RJKFOVLPORLFTN-LEKSSAKUSA-N Progesterone Chemical compound C1CC2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H](C(=O)C)[C@@]1(C)CC2 RJKFOVLPORLFTN-LEKSSAKUSA-N 0.000 description 4
- 206010000210 abortion Diseases 0.000 description 4
- 231100000176 abortion Toxicity 0.000 description 4
- 238000010521 absorption reaction Methods 0.000 description 4
- TZCXTZWJZNENPQ-UHFFFAOYSA-L barium sulfate Chemical compound [Ba+2].[O-]S([O-])(=O)=O TZCXTZWJZNENPQ-UHFFFAOYSA-L 0.000 description 4
- 238000002474 experimental method Methods 0.000 description 4
- -1 hydroxypropenyl group Chemical group 0.000 description 4
- ARNWQMJQALNBBV-UHFFFAOYSA-N lithium carbide Chemical compound [Li+].[Li+].[C-]#[C-] ARNWQMJQALNBBV-UHFFFAOYSA-N 0.000 description 4
- 230000035935 pregnancy Effects 0.000 description 4
- 230000009467 reduction Effects 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 3
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 230000002378 acidificating effect Effects 0.000 description 3
- 229910052783 alkali metal Inorganic materials 0.000 description 3
- 150000001340 alkali metals Chemical class 0.000 description 3
- 238000010828 elution Methods 0.000 description 3
- UKWHYYKOEPRTIC-UHFFFAOYSA-N mercury(ii) oxide Chemical compound [Hg]=O UKWHYYKOEPRTIC-UHFFFAOYSA-N 0.000 description 3
- 230000007935 neutral effect Effects 0.000 description 3
- 229910000510 noble metal Inorganic materials 0.000 description 3
- 229910052763 palladium Inorganic materials 0.000 description 3
- 238000000746 purification Methods 0.000 description 3
- 239000000741 silica gel Substances 0.000 description 3
- 229910002027 silica gel Inorganic materials 0.000 description 3
- 239000008259 solid foam Substances 0.000 description 3
- 238000010626 work up procedure Methods 0.000 description 3
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 2
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 2
- 229940126062 Compound A Drugs 0.000 description 2
- NLDMNSXOCDLTTB-UHFFFAOYSA-N Heterophylliin A Natural products O1C2COC(=O)C3=CC(O)=C(O)C(O)=C3C3=C(O)C(O)=C(O)C=C3C(=O)OC2C(OC(=O)C=2C=C(O)C(O)=C(O)C=2)C(O)C1OC(=O)C1=CC(O)=C(O)C(O)=C1 NLDMNSXOCDLTTB-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 2
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 2
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- 241000700159 Rattus Species 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- 230000009471 action Effects 0.000 description 2
- HSFWRNGVRCDJHI-UHFFFAOYSA-N alpha-acetylene Natural products C#C HSFWRNGVRCDJHI-UHFFFAOYSA-N 0.000 description 2
- 150000001412 amines Chemical class 0.000 description 2
- 238000011097 chromatography purification Methods 0.000 description 2
- 230000002860 competitive effect Effects 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- GRXPVLPQNMUNNX-MHJRRCNVSA-N estrane Chemical class C1CC2CCCC[C@@H]2[C@@H]2[C@@H]1[C@@H]1CCC[C@@]1(C)CC2 GRXPVLPQNMUNNX-MHJRRCNVSA-N 0.000 description 2
- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 description 2
- 239000006260 foam Substances 0.000 description 2
- 230000036571 hydration Effects 0.000 description 2
- 238000006703 hydration reaction Methods 0.000 description 2
- 239000007943 implant Substances 0.000 description 2
- 150000002500 ions Chemical class 0.000 description 2
- 229910052744 lithium Inorganic materials 0.000 description 2
- QSHDDOUJBYECFT-UHFFFAOYSA-N mercury Chemical compound [Hg] QSHDDOUJBYECFT-UHFFFAOYSA-N 0.000 description 2
- 229910052753 mercury Inorganic materials 0.000 description 2
- DVSDBMFJEQPWNO-UHFFFAOYSA-N methyllithium Chemical compound C[Li] DVSDBMFJEQPWNO-UHFFFAOYSA-N 0.000 description 2
- VLTRZXGMWDSKGL-UHFFFAOYSA-N perchloric acid Chemical compound OCl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-N 0.000 description 2
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 2
- 229910052700 potassium Inorganic materials 0.000 description 2
- 239000011591 potassium Substances 0.000 description 2
- 229960003387 progesterone Drugs 0.000 description 2
- 239000000186 progesterone Substances 0.000 description 2
- 239000000583 progesterone congener Substances 0.000 description 2
- TVDSBUOJIPERQY-UHFFFAOYSA-N prop-2-yn-1-ol Chemical class OCC#C TVDSBUOJIPERQY-UHFFFAOYSA-N 0.000 description 2
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 2
- 125000006239 protecting group Chemical group 0.000 description 2
- 229920006395 saturated elastomer Polymers 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 150000003431 steroids Chemical group 0.000 description 2
- 239000000758 substrate Substances 0.000 description 2
- 210000004291 uterus Anatomy 0.000 description 2
- XYZWMVYYUIMRIZ-UHFFFAOYSA-N 4-bromo-n,n-dimethylaniline Chemical compound CN(C)C1=CC=C(Br)C=C1 XYZWMVYYUIMRIZ-UHFFFAOYSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonium chloride Substances [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- 229910021591 Copper(I) chloride Inorganic materials 0.000 description 1
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 1
- DOJXGHGHTWFZHK-UHFFFAOYSA-N Hexachloroacetone Chemical compound ClC(Cl)(Cl)C(=O)C(Cl)(Cl)Cl DOJXGHGHTWFZHK-UHFFFAOYSA-N 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- 239000004015 abortifacient agent Substances 0.000 description 1
- 231100000641 abortifacient agent Toxicity 0.000 description 1
- 230000021736 acetylation Effects 0.000 description 1
- 238000006640 acetylation reaction Methods 0.000 description 1
- FDTGUDJKAXJXLL-UHFFFAOYSA-N acetylene Chemical compound C#C.C#C FDTGUDJKAXJXLL-UHFFFAOYSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 238000010306 acid treatment Methods 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 230000001476 alcoholic effect Effects 0.000 description 1
- 150000001345 alkine derivatives Chemical class 0.000 description 1
- XXROGKLTLUQVRX-UHFFFAOYSA-N allyl alcohol Chemical compound OCC=C XXROGKLTLUQVRX-UHFFFAOYSA-N 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 235000011114 ammonium hydroxide Nutrition 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 230000003042 antagnostic effect Effects 0.000 description 1
- 239000005557 antagonist Substances 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 229910052786 argon Inorganic materials 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- SIPUZPBQZHNSDW-UHFFFAOYSA-N bis(2-methylpropyl)aluminum Chemical compound CC(C)C[Al]CC(C)C SIPUZPBQZHNSDW-UHFFFAOYSA-N 0.000 description 1
- 210000002459 blastocyst Anatomy 0.000 description 1
- UORVGPXVDQYIDP-UHFFFAOYSA-N borane Chemical class B UORVGPXVDQYIDP-UHFFFAOYSA-N 0.000 description 1
- 229910000085 borane Inorganic materials 0.000 description 1
- 239000012876 carrier material Substances 0.000 description 1
- 239000004359 castor oil Substances 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- RYPRIXSYXLDSOA-UHFFFAOYSA-L chromium(2+);sulfate Chemical compound [Cr+2].[O-]S([O-])(=O)=O RYPRIXSYXLDSOA-UHFFFAOYSA-L 0.000 description 1
- 229910000334 chromium(II) sulfate Inorganic materials 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- OXBLHERUFWYNTN-UHFFFAOYSA-M copper(I) chloride Chemical compound [Cu]Cl OXBLHERUFWYNTN-UHFFFAOYSA-M 0.000 description 1
- 150000001983 dialkylethers Chemical class 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 230000035558 fertility Effects 0.000 description 1
- IYWCBYFJFZCCGV-UHFFFAOYSA-N formamide;hydrate Chemical compound O.NC=O IYWCBYFJFZCCGV-UHFFFAOYSA-N 0.000 description 1
- 238000001640 fractional crystallisation Methods 0.000 description 1
- 239000012362 glacial acetic acid Substances 0.000 description 1
- 238000007654 immersion Methods 0.000 description 1
- 238000011065 in-situ storage Methods 0.000 description 1
- 230000036512 infertility Effects 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 1
- 239000012280 lithium aluminium hydride Substances 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 238000012423 maintenance Methods 0.000 description 1
- 230000013011 mating Effects 0.000 description 1
- 229940101209 mercuric oxide Drugs 0.000 description 1
- 150000002730 mercury Chemical class 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 235000010755 mineral Nutrition 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 238000006053 organic reaction Methods 0.000 description 1
- 150000002900 organolithium compounds Chemical class 0.000 description 1
- 150000002901 organomagnesium compounds Chemical class 0.000 description 1
- 150000002902 organometallic compounds Chemical class 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 229910052697 platinum Inorganic materials 0.000 description 1
- 239000003880 polar aprotic solvent Substances 0.000 description 1
- NNFCIKHAZHQZJG-UHFFFAOYSA-N potassium cyanide Chemical compound [K+].N#[C-] NNFCIKHAZHQZJG-UHFFFAOYSA-N 0.000 description 1
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 239000000044 progesterone antagonist Substances 0.000 description 1
- MWWATHDPGQKSAR-UHFFFAOYSA-N propyne Chemical compound CC#C MWWATHDPGQKSAR-UHFFFAOYSA-N 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 239000012266 salt solution Substances 0.000 description 1
- ODZPKZBBUMBTMG-UHFFFAOYSA-N sodium amide Chemical compound [NH2-].[Na+] ODZPKZBBUMBTMG-UHFFFAOYSA-N 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000005556 structure-activity relationship Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- BDHFUVZGWQCTTF-UHFFFAOYSA-N sulfonic acid Chemical compound OS(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-N 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 238000004809 thin layer chromatography Methods 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 238000012876 topography Methods 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 150000003623 transition metal compounds Chemical class 0.000 description 1
- VFJYIHQDILEQNR-UHFFFAOYSA-M trimethylsulfanium;iodide Chemical compound [I-].C[S+](C)C VFJYIHQDILEQNR-UHFFFAOYSA-M 0.000 description 1
- 230000007306 turnover Effects 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J41/00—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring
- C07J41/0033—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005
- C07J41/0077—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005 substituted in position 11-beta by a carbon atom, further substituted by a group comprising at least one further carbon atom
- C07J41/0083—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005 substituted in position 11-beta by a carbon atom, further substituted by a group comprising at least one further carbon atom substituted in position 11-beta by an optionally substituted phenyl group not further condensed with other rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J71/00—Steroids in which the cyclopenta(a)hydrophenanthrene skeleton is condensed with a heterocyclic ring
- C07J71/0005—Oxygen-containing hetero ring
- C07J71/001—Oxiranes
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Description
Oppfinnelsen angår en analogifremgangsmåte ved fremstilling av terapeutisk aktive 13a-alkylgonaner med den generelle formel: The invention relates to an analogous method for the production of therapeutically active 13a-alkylgonanes with the general formula:
hvor R<1> er where R<1> is
hvor R1 og R11 er hydrogen eller alkyl med where R1 and R11 are hydrogen or alkyl with
1-4 carbonatomer, 1-4 carbon atoms,
OR111 hvor R111 er methyl, ethyl eller propyl, OR111 where R111 is methyl, ethyl or propyl,
R 2er hydrogen, en methyl- eller ethylgruppe, R 2 is hydrogen, a methyl or ethyl group,
R 3 betegner alkyl med 1-5 carbonatomer eller alk-l-enyl som begge kan være substituert med en terminal hydroxygruppe, alk-1-ynyl med 2 eller 3 carbonatomer, -(CI^)nCH2~CNR 3 denotes alkyl with 1-5 carbon atoms or alk-1-enyl which can both be substituted with a terminal hydroxy group, alk-1-ynyl with 2 or 3 carbon atoms, -(CI^)nCH2~CN
hvori n=0-2, eller en acetylgruppe, og wherein n=0-2, or an acetyl group, and
R 4betegner en hydroxy- eller alkanoyloxygruppe med 1-4 R 4 denotes a hydroxy or alkanoyloxy group with 1-4
carbonatomer, og hvor carbon atoms, and where
R 3 er i a-konflgurasjon og R 3 is in the a configuration and
R 4 er i [3-konfigurasjon, eller R 4 is in the [3 configuration, or
R 3 er i f3-konf iguras jon og R 3 is in f3 configuration and
R 4 er i a-konfiguras]on i forhold til steroidstrukturen, R 4 is in the α-configuration in relation to the steroid structure,
og and
R~* er et hydrogenatom eller en i a- eller (3-stilling stående alkylgruppe med 1 til 4 carbonatomer. ;Forbindelsene med den generelle formel I har en sterk affinitet til gestagenreseptoren uten selv å ha gestagen aktivitet. De er konkurrerende antagonister av progesteron (anti-gestagener) og er egnet til utløsning av aborter, da de fortrenger det til opprettholdelse av svangerskapet nød-vendige progesteron fra reseptoren. Forbindelsene er derfor verdifulle og interessante med henblikk på deres anvendelse som terapeutisk aktive forbindelser. ;Tilsvarende forbindelser i estranrekken er allerede beskrevet som antigestagent virksomme forbindelser i Fertility and Sterility 40 (1982), side 253. ;De hittil kjente struktur-virkningsforhold for konkurrerende progesteron-antagonister tyder på at en 1,3-diaksial anordning av llfi-arylrest og 133-alkylgruppe er tvingende nødvendig for utfoldelsen av antigestagen aktivitet. Desto mer overraskende er den sterke og selektive antagonistiske virkning av 13a-alkylgonaner av formel I hvor en helt annen molekyltopografi sammenlignet med estranrekken, oppvises. ;Til erkjennelse av den antigestagene virkning av forbindelsene ifølge oppfinnelsen ble den abortive virkning i en tidligere fase post nidation (forsøk I) og i en fremskreden fase post nidtation (forsøk II) undersøkt. ;Forsøkene ble utført på hunnrotter i en vekt på ca. ;200 g. Etter parring ble svangerskapsbegynnelsen sikret ved påvisning av spermier i vaginalavstrykninger. Dagen for spermiepåvisningen regnes som dag 1 av graviditeten (= d 1 p.c.). ;Behandlingen av dyrene med den forbindelse f.eks. opp-løsningsmidlet som skal undersøkes, skjer efter nidation av blastocystene fra d 5 p.c. til d 7 p.c. (forsøk I) hhv. ;d 13 p.c. til d 15 p.c. (forsøk II). På d 9 p.c. hhv. ;d 17 p.c. ble dyrene avlivet og deres uteri undersøkt på implantater og resorpsjonssteder. Av alle uteri ble det tatt bilder. Mangelen på implantater ble bedømt som abort. ;Som antigestagener ble følgende undersøkt: ;A: 113-(4-dimethylaminofenyl)-17&-hydroxy-17a-propynyl-4,9- estradien-3-on (referanseforbindelse). ;B: 113-(4-dimethylaminofenyl)-173~hydroxy-17a-(3-hydroxy-propyl)-13a-methyl-4,9-gonadien-3-on (ifølge oppfinnelsen) . ;C: 113-(4-dimethylaminofenyl)-17a-hydroxy-173~(3-hydroxy-propyl)-13a-methyl-4,9-gonadien-3-on (ifølge oppfinnelsen) . ;Forsøksforbindelsene ble oppløst i en benzylbenzoat-ricinusoljeblanding (forhold 1:4). Bæremiddelvolumet pr. enkeltdose utgjorde 0,2 ml. Behandlingen skjedde subcutant (s.c .) . ;Forbindelsene B og C ifølge oppfinnelsen virker ved tidlig gravide rotter i doseringer på = 1,0 mg/d fullstendig abortfremkallende (abortrat: 4/4). I motsetning til dette oppviser referanseforbindelsen A maksimal abortutløsning (antigestågen) virkning først ved doser på = 3,0 mg/d (tabell 1) . ;Ved en fremskreden fase av svangerskapet (d 13 - 15 p.c.) utgjør prosentsatsen for komplette aborter ved 3 ganger dag-lig s.c. tilføring av 3,0 mg/d for B 35,4%, for C 52,3% og for sammenligningsforbindelsen A 3,5% (tabell 2). ;13a-alkylgonaner med den generelle formel I kan finne anvendelse i form av farmasøytiske preparater. Fremstill-ingen av preparatene skjer ved i og for seg kjente galeniske metoder ved blanding med organisk eller uorganisk inert bæremateriale som er egnet for enteral, percutan eller par-enteral anvendelse. ;Doseringen av virkestoffene ifølge oppfinnelsen ligger hos mennesker ved ca. 10 til 1000 mg pr. dag. ;Alkylgruppene i R<1> og R<11> i den generelle formel I skal inneholde 1 til 4 carbonatomer, idet methyl- og ethylgruppen ;er foretrukket. ;Analogifremgangsmåten ifølge oppfinnelsen er kjenne-tegnet ved at en forbindelse med den generelle formel: ;17 5 hvor R , R" og R er som ovenfor angitt, og Z er en ethylen-eller 2,2-dimethylpropylengruppe, bestråles med ultrafiolett lys, og det ved UV-bestråling erholdte 13-episteroid med den generelle formel: ;hvor R 1, R 2 , R 5og Z er som ovenfor angitt, på i og for seg kjent vis ved nucleofil addisjon på 17-ketonet, spaltning av 3-ketalbeskyttelsen og vannavspaltning fra 4,5-stillingen, overføres til forbindelsene med den generelle formel I. ;Ved bestråling med ultrafiolett lys overføres 133-alkylsteroidene med den generelle formel II i godt utbytte til 13-episteroidene (13a-alkylsteroider) med den generelle formel III. Forbindelsene av generell formel IT kan fremstilles som beskrevet i US patentskrift 4 233 296 og 4 386 085. ;Det gode utbytte av omvandlingsproduktet er overraskende. Det har riktignok lenge vært kjent at 17-oxosteroider av normalrekken ved UV-bestråling er overførbare til 13-episteroider (A. Butenandt et al., Ber. Deutsch. Chém. Ges. 74, 1308 (1941)); men man får imidlertid alltid blandinger av utgangsmateriale og epimerisert forbindelse, bestrålings-tidene utgjorde flere timer, og utbyttet var overordentlig lavt. Derfor har også søkingen etter en alternativ, kjemisk tilgang på 13-epi-rekken stadig vært aktuell som et tidligere arbeide av Barton et al., J.C.S. Perkin I, 2163 (1977), viser. Dette alternativ er imidlertid ikke egnet til fremstilling av forbindelser av type I. Det ble funnet at bestrålingen av forbindelsene av type II under bestemte betingelser tar et vesentlig gunstigere forløp enn i rekken av 11-usubstituerte 17-oxosteroider. Således utgjør de gjennomsnittlige be-strålingstider bare 10 - 30 minutter, og utbyttet på 13-episteroid ligger mellom 60 - 80%. Bestrålingsproduktene kan eventuelt omsettes videre uten kromatografisk rensing. En vesentlig forutsetning for et godt utbytte er det riktige valg av oppløsningsmiddel, konsentrasjonen av substratet som skal bestråles og den nøyaktige overholdelse av bestrål-ingsvarigheten. Disse parametere må bestemmes spesielt for hvert nytt substrat. ;Bestrålingen utføres med det fulle lys av en Hg-høy-trykkslampe i kvartsglassapparaturen. Temperaturen på reak-sjonsoppløsningen innstilles på ca. 25°C, konsentrasjonen av oppløsningen utgjør 0,1 - 1,0 vekt%. Som oppløsningsmiddel anvendes fortrinnsvis tetrahydrofuran og dioxan, men også upolare aprotiske oppløsningsmidler som hexan, cyclohexan, benzen, toluen og blandinger derav, kan anvendes. Bestrål-ingsvarigheten utgjør ca. 10 - 50 minutter. ;De på denne måte erholdte 13-episteroider III overføres ved de vanlige prosesser ved nucleofil addisjon på 17-ketonet og etterfølgende reaksjoner til sluttforbindelsen med den generelle formel I. Den nucleofile addisjon på III forløper i alminnelighet under dannelse av to mulige, isomere former ved C-17 som imidlertid er lett skillbare ved kromatografi eller fraksjonert krystallisasjon. I mange tilfelle er begge isomerer farmakologisk virksomme selv om det foreligger forskjeller i virkningsstyrken. ;Den nucleofile addisjon av acetylen (ethyn) eller propyn skjer ved hjelp av et middel som avgir gruppen -C=CH eller -CsC-CH^. Slike midler er f.eks. alkalimetallacetylider som f.eks. kalium- og lithiumacetylid, hhv. -methylacetylid. ;Den metallorganiske forbindelse kan også dannes in situ og bringes til reaksjon med 17-ketonet med formel III. Således kan man f.eks. i et egnet oppløsningsmiddel la acetylen og et alkalimetall, særlig kalium, natrium eller lithium, innvirke på 17-ketonet i et egnet oppløsningsmiddel i nærvær av en alkohol eller i nærvær av ammoniakk. Alkalimetallet kan også bringes til innvirkning i form av f.eks. methyl-eller butyllithium. Som oppløsningsmiddel er særlig dialkyl-ether, tetrahydrofuran, dioxan, benzen og toluen egnet. ;17-ethynyl-17-hydroxyforbindelsene lar seg hydratisere ;i alkoholisk oppløsning under kvikksølvkatålyse til 17-acetyl-17-hydroxyforbindelsene (Chem. Ber. 111 (1978) 3086 - 3093). ;Innføringen av 3-hydroxypropan, hhv. 3-hydroxypropen i 17-stillingen, skjer ved omsetning av 17-ketonet med metal-liserte derivater av propargylalkohol, f.eks. med l-lithium-3-tetrahydropyran-2'-yloxy-propyn-1, til 17-(3-hydroxy-l-propynyl) -17-hydroxyforbindelsene , som derpå hydreres til 17-(3-hydroxypropyl-, hhv. 3-hydroxypropenyl)-17-hydroxy-forbindelsene . Hydrogeneringen må utføres under betingelser som bare tillater angrep på C-C-trippelbindingen uten å av-mette den tetrasubstituerte 9(10)-dobbeltbinding. Innføring av de homologe hydroxyalkan- og hydroxyalken-grupper av generell formel -CH=CH-(CH2)n0H eller -CH2~CH2-(CH2)n0H skjer på tilsvarende måte med homologer av propargylalkohol. Dette skjer f.eks. ved hydrogenering ved værelsetemperatur og normaltrykk i oppløsningsmidler som methanol, ethanol, propanol, tetrahydrofuran (THF) eller eddikester under tilsetning av edelmetallkatalysatorer som platina eller palladium. ;Forbindelsen med den Z-konfigurerte dobbeltbinding i hydroxypropenylgruppen oppstår ved hydrogenering av den acetyl-eniske trippelbinding med en desaktivert edelmetallkatalysator (J. Fried, J.A. Edwards: Organic Reactions in Steroid Chemistry, Van Nostrand Reinhold Company 1972, side 134, og H.O. House: Modern Synthetic Reactions 1972, side 19). Som desaktiverte edelmetallkatalysatorer kommer eksempelvis 10% palladium på bariumsulfat i nærvær av et amin eller 5% palladium på calciumcarbonat under tilsetning av bly(II)-acetat på tale. Hydreringen avbrytes etter opptagelse av en ekvivalent hydrogen. ;Forbindelsen med den E-konfigurerte dobbeltbinding i hydroxypropenylgruppen dannes ved reduksjon av den acetylen-iske trippelbinding på i og for seg kjent vis. I littera-turen er en hel rekke metoder til overføring av alkyner til trans-olefiner beskrevet, eksempelvis ved reduksjon med natrium i flytende ammoniakk (J. Am." Chem. Soc. 6_3 (1941) 216), med natriumamid i flytende ammoniakk (J. Chem. Soc. 1955, 3558), med lithium i lavmolekylære aminer (J. Am. Chem. Soc. Il (1955) 3378), med boraner (J. Am. Chem. Soc. 93. ;(1971) 3395 og 9J (1971) 6560), med diisobutylaluminiumhydrid og methyllithium (J. Am. Chem. Soc. 8j) (1967) 5085) og særlig med lithiumaluminiumhydrid/alkoholat (J. Am. Chem. Soc. 89 (1967) 4245). En annen mulighet er reduksjonen av trippelbindingen med krom(II)-sulfat i nærvær av vann eller dimethylformamid i svakt surt miljø (J. Am. Chem. Soc. 8j> ;(1964) 4358) såvel som vanligvis reduksjonen ved innvirkning av overgangsmetallforbindelsene under forandring av oxyda-sjonstrinnet. ;Oppbyggingen av 17-cyanmethyl-sidekjeden skjer på i og for seg kjent vis fra 17-ketonet med den generelle formel III, f.eks. over 17-spiroepoxydet og spaltning av spiroepoxydet med HCN ifølge Z. Chem. 18 (1978) 259 - 260. Innføring av cyanalkansidekjeden -(CH2)n~CH2CN med n = 1 - 3 skjer eksempelvis ved addisjon av Li-(CH2)n~CH2CN på 17-ketonet. ;Også innføringen av 17-hydroxyacetyl-sidekjeden skjer på i og for seg kjent vis, eksempelvis ifølge den i J. Org. Chem. 4_7 (1982), 2993 - 2995, beskrevne metode. ;Frie hydroxygrupper i 17-stillingen kan på i og for ;seg kjent vis forestres. ;Etter omsetning (nucleofil addisjon) av 17-ketonet blir forbindelsene med formel III behandlet til vannavspaltning under dannelse av 4(5)-dobbeltbindingen og til samtidig ketalspaltning og fjerning av eventuelt tilstedeværende ytterligere med syre avspaltbare beskyttelsesgrupper med syre eller en annen sur ioneutbytter. ;Den sure behandling skjer på i og for seg kjent vis idet forbindelsen med formel III som inneholder en 3-ketal-gruppe og en 5a-hydroxygruppe og en eventuelt O-beskyttet 17-(3-hydroxypropyl)-gruppe, oppløses i et med vann blandbart oppløsningsmiddel, som vandig methanol, ethanol eller aceton, og at man lar katalytiske mengder av mineral- eller sulfonsyre, som saltsyre, svovelsyre, fosforsyre, perklor-syre eller p-toluensulfonsyre eller en organisk syre, som eddiksyre, innvirke så lenge på oppløsningen inntil vann er avspaltet og beskyttelsesgruppene er fjernet. Omsetningen, som forløper best ved temperaturer fra 0 til 100°C, kan også foretas med en sur ioneutbytter. Forløpet av omsetningen kan følges med analytiske metoder, f.eks. ved tynnskikts-kromatografi på uttatte prøver. ;Eksempel 1 ;a) En oppløsning av 2,0 g 11(3- (4-dimethylaminofenyl)-3, 3-(2,2-dimethylpropan-l,3-dioxy)-5a-hydroxy-9(10)-estren-17-on ;(smp. 143-145°C) i 300 ml absolutt tetrahydrofuran (THF) bestråles i 16 minutter ved 25°C med en Hg-høytrykkslampe (Philips HPK 125, neddykningslampe, kvartsglassreaktor). Derpå avdestilleres oppløsningsmidlet i vakuum, og residuet kromatograferes over aluminiumoxyd (Merck, nøytral, trinn III) med hexan/eddiksyreester. Man får 1,46 g 113-(4-dimethylaminofenyl)-3,3-(2,2-dimethylpropan-l,3-dioxy)-5a-hydroxy-13a-methyl-9(10)-gonen-17-on som farveløs olje. ;b) Absolutt THF (248 ml) mettes med acetylen ved 5°C ved 30 minutters innledning. Derpå tildryppes langsomt 51 ml av ;en 15%-ig oppløsning av n-butyllithium i hexan, og det om-røres i ytterligere 15 minutter under isvannkjøling. En opp-løsning av 2,7 g 113-(4-dimethylaminofenyl)-3,3-(2,2-dimethyl-propan-l, 3-dioxy)-5a-hydroxy-13a-methyl-9-gonen-17-on i 40 ml absolutt THF tildryppes i løpet av 15 minutter til suspensjonen av lithiumacetylidet, og det omrøres i ytterligere 2 timer ved værelsetemperatur. For opparbeidelse helles i isvann og ekstraheres med eddiksyreester. Det således erholdte råprodukt (2,85 g) anvendes uten ytterligere rensning i det følgende trinn. c) 2,8 g av det under b) erholdte råprodukt suspenderes i 29 ml 70%-ig vandig eddiksyre og omrøres i 3 timer ved 50°C. ;Etter avkjøling fortynnes med ca. 100 ml vann, og det innstilles ved tilsetning av konsentrert vandig NH^-oppløsning på en pH-verdi på 10,5. Etter ekstraksjon med eddiksyreester får man en oljeaktig isomerblanding som skilles ved søyle-kromatografi på kiselgel med hexan/eddiksyreester. Man får i elueringsrekkefølge: 1. 530 mg 113-(4-dimethylaminofenyl)-17a-ethynyl-173-hydroxy-13a-methyl-4,9-gonadien-3-on med smp. 120-123°C (eddiksyreester/diisopropylether) og 2. 1,33 g 113-(4-dimethylaminofenyl)-173~ethynyl-17a-hydroxy-13a-methyl-4,9-gonadien-3-on med smp. 201-204°C (eddiksyreester). d) En suspensjon av 1,02 g kvikksølvoxyd (HgO, rødt) i 20 ml vann blir etter tilsetning av 0,87 ml konsentrert svovelsyre omrørt i 30 minutter ved 60°C. 9 ml av denne kvikksølvsaltoppløsning helles i en oppløsning av 3,25 g 113-(4-dimethylaminofenyl)-173-ethynyl-17ct-hydroxy-13a-methyl-4,9-gonadien-3-on i 32 ml iseddik. Derpå omrøres i 2 timer ved 60°C. Til opparbeidelse heller man den avkjølte reak-sjonsoppløsning i isvann, innstiller ved tilsetning av konsentrert vandig NH^-oppløsning en pH-verdi på 10,5 og ekstraherer med ethylacetat. Det således erholdte oljeaktige råprodukt krystalliseres fra methylenklorid/diisopropyl-ether. Man får 2,37 g 113-(4-dimethylaminofenyl)-17a-hydroxy-13a-methyl-18,19-dinor-4,9-pregnadien-3,20-dion med smp. 224-225°C. e) En suspensjon av 2,3 g 113-(4-dimethylaminofenyl)-17a-hydroxy-13a-methyl-18,19-dinor-4,9-pregnadien-3,20-dion i 58 ml toluen blir etter tilsetning av 11/6 ml acetanhydrid og 5,8 g 4-dimethylaminopyridin omrørt i 20 timer ved 25°C. Derpå helles i mettet NaHCO^-oppløsning og ekstraheres med ethylacetat. Råproduktet kromatograferes på 200 g silicagel med hexan/ethylacetat. Etter krystallisasjon av hovedfraksjonen fra hexan/ethylacetat får man 1,71 g 17ct-acetoxy-113-(4-dimethylaminofenyl)-13a-methyl-18,19-dinor-4,9-pregna-dien-3,20-dion med smp. 194-195°C. ;Eksempel 2 ;a) En oppløsning av 1,8 g 113-(4-diethylaminofenyl)-3,3-(2,2-dimethylpropan-l,3-dioxy)-5a-hydroxy-9-estren-17-on ;(smp. 223-226°C) i 300 ml THF bestråles under betingelsene i eksempel la) i 26 minutter. Etter kromatografi av råproduktet får man 1,58 g 113-(4-diethylaminofenyl)-3,3-(2,2-dimethyl-propan-l ,3-dioxy)-5a-hydroxy-13a-methyl-9-gonen-17-on som en farveløs olje. ;b) Av 3,94 g 3-tetrahydropyran-2<1->yloxy-l-propyn i 85 ml absolutt THF og 23,1 ml av en 15%-ig oppløsning av n-butyllithium i hexan fremstilles ved 0°C den lithiumorganiske forbindelse. Derpå tildryppes en oppløsning av 3,53 g av det under 2a) beskrevne produkt i 71 ml absolutt THF og omrører i 4 timer ved værelsetemperatur. Reaksjonsoppløsningen helles derpå i isvann og ekstraheres med eddiksyreester. Råproduktet (3,85 g) 113-(4-diethylaminofenyl)-3,3-(2,2-dimethylpropan-1,3-dioxy)-13a-methyl-17a-[3-(tetrahydropyran-2-yloxy)-1-propynyl]-9-gonen-5a,173-diol og 113-(4-diethyl-aminof enyl) -3,3-(2,2-dimethylpropan-l,3-dioxy)-13a-methyl-173-[3-(tetrahydropyran-2-yloxy)-1-propynyl]-9-gonen-5a,17a-diol blir uten ytterligere rensning anvendt til hydrogener ingen. c) 3,85 g av det under 2b) erholdte råprodukt blir, i 95 ml ethanol etter tilsetning av 400 mg 10%-ig palladiumkull, hydrogenert ved værelsetemperatur og normaltrykk. Etter opptagelse av 191 ml hydrogen frafiltrerer man katalysatoren og inndamper. d) Det under 2c) erholdte hydrogeneringsråprodukt (3,85 g) omrøres i 30 ml 70%-ig eddiksyre i 2 timer ved 60°C. Etter avkjøling opparbeider man som under lc) og kromatograferer den erholdte isomerblanding. I elueringsrekkefølge får man: 1. 410 mg lip-(4-diethylamlnofenyl)-17a-(3-hydroxypropyl)-173-hydroxy-13a-methyl-4,9-gonadien-3-on som en gulfarget olje. UV (methanol): l266 = 19080' £309 = 1911°-2. 1,39 g 113-(4-diethylaminofenyl)-173-(3-hydroxypropyl)-17a-hydroxy-13a-methyl-4,9-gonadien-3-on som fast skum. ;Eksempel 3 ;a) En oppløsning av 1,75 g 3,3-(2,2-dimethylpropan-l,3-dioxy)-5a-hydroxy-113~(4-methoxyfenyl)-9-estren-17-on i 290 ml ;dioxan bestråles i 19 minutter under betingelsene i eksempel la). Etter kromatografi får man 1,45 g 3,3-(2,2-dimethylpropan-1,3-dioxy)-5a-hydroxy-113_(4-methoxyfenyl)-13a-methyl-9-gonen-17-on som farveløs olje. ;b) Til en suspensjon av lithiumacetylid, fremstilt fra en mettet oppløsning av acetylen i 4 50 ml THF og 130 ml av en ;15%-ig oppløsning av n-butyllithium i hexan, drypper man en oppløsning av 8,2 g 3,3-(2,2-dimethylpropan-l,3-dioxy)-5a-hydroxy-113-(4-methoxyfenyl)-13a-methyl-9-gonen-17-on i 130 ml THF. Derpå omrører man i 3 timer ved værelstemperatur, heller deretter reaksjonsoppløsningen i ca. 3 1 isvann og ekstraherer med ethylacetat. Råproduktet kromatograferes pa aluminiumoxyd med hexan/ethylacetat. I elusjonsrekkefølge får man: ;1. 1,8 g 3,3-(2,2-dimethylpropan-l,3-dioxy)-17a-ethynyl-113-(4-methoxyfenyl)-13a-methyl-9-gonen-5a,173-diol som farveløs olje. 2. 5,1 g 3,3-(2,2-dimethylpropan-l,3-dioxy)-173-ethynyl-113-(4-methoxyfenyl)-13a-methyl-9-gonen-5a,173-diol som fast skum. c) En oppløsning av 3,28 g 3,3-(2,2-dimethylpropan-l,3-dioxy)-17f3-ethynyl-113- (4-methoxyfenyl) -13ct-methyl-9-gonen-5a,17a-diol i 33 ml 70%-ig vandig eddiksyre omrøres i 30 minutter ved 60°C. Etter avkjøling heller man i isvann, ekstraherer med methylenklorid, vasker methylenkloridekstraktet med mettet natriumbicarbonatoppløsning og inndamper. Krystallisasjon av råproduktet fra ethylacetat gir 2,0 g 170-ethinyl-17a-hydroxy-ll|3- (4-methoxyfenyl) -13a-methyl-4, 9-gonadien-3-on med smp. 186-187°C. ;Eksempel 4 ;20 minutters bestråling av 1,84 g lip-(4-dimethylaminofenyl) -3, 3- (2,2-dimethylpropan-l,3-dioxy)-5a-hydroxy-18-methyl-9-estren-17-on i 280 ml THF under betingelsene i eksempel la) fører til 1,36 g 110-(4-dimethylaminofenyl)-3,3-(2,2-dimethylpropan-l,3-dioxy)-13a-ethyl-5a-hydroxy-9-gonen-17-on som skum. ;6,1 g 113-(4-dimethylaminofenyl)-3,3-(2,2-dimethyl-propan-l, 3-dioxy)-13a-ethyl-5a-hydroxy-9-gonen-17-on omsettes under betingelsene i eksempel lb) med lithiumacetylid, og det således erholdte råprodukt spaltes under betingelsene i eksempel lc) med eddiksyre. Etter kromatografi og krystallisasjon fra ethylacetat/diisopropylether får man 3,2 g 113-(4-dimethylaminofenyl)-173-ethynyl-13a-ethyl-17a-hydroxy-4,9-gonadien-3-on med smp. 197-198°C, [a]^<5> + 450,4° (CHCl3, ;c = 0,505). ;Ved kvikksølvsalt-katalysert hydratlsering analogt med eksempel ld) og etterfølgende acetylering analogt med eksempel le) får man av 1,3 g 113-(4-dimethylaminofenyl)-173_ethynyl-13a-ethyl-17a-hydroxy-4,9-gonadien-3-on etter kromatografisk rensning 720 mg 17a-acetoxy-113-(4-dimethyl-aminof enyl) -13a-ethyl-18 , 19-dinor-4 ,9-pregnadien-3,20-dion som fast skum. ;Eksempel 5 ;a) Ved omsetning av 7,3 g 110-(4-dimethylaminofenyl)-3,3-(2,2-dimethylpropan-l,3-dioxy)-5a-hydroxy-13a-methyl-9-gonen-17-on med 10,7 g 3-tetrahydropyran-2 *-yloxy-l-propy.n under betingelsene i eksempel 2b) får man etter kromatografi av råproduktet på aluminiumoxyd med hexan/ethylacetat 4,83 g 110-(4-dimethylaminofenyl)-3,3-(2,2-dimethylpropan-l,3-dioxy)-13a-methyl-170-[3-(tetrahydropyran-2-yloxy)-1-propynyl]-9-gonen-5a,17a-diol som gulfarget skum. b) En oppløsning av 2,2 g av det under a) erholdte addukt i 67 ml ethanol og 0,56 ml triethylamin hydreres etter tilsetning av 210 mg palladium på bariumsulfat (10%) ved værelsetemperatur og normaltrykk. Etter opptagelse av 83,5 ml hydrogen blir katalysatoren frafiltrert, og det inndampes. Det således erholdte hydreringsråprodukt spaltes med 14 ml 70%-ig eddiksyre under betingelsene i eksempel lc). Etter krystallisasjon fra ethylacetat/diisopropylether får man 1,1 g 110-(4-dimethylaminofenyl)-17a-hydroxy-170-(3-hydroxy-l(Z)-propenyl)-13a-methyl-4,9-gonadien-3-on med smp. 133-135°C. R~* is a hydrogen atom or an alkyl group in the a- or (3-position) with 1 to 4 carbon atoms. The compounds of the general formula I have a strong affinity for the progestogen receptor without themselves having progestogen activity. They are competitive antagonists of progesterone (anti-gestagens) and are suitable for triggering abortions, as they displace the progesterone necessary for the maintenance of pregnancy from the receptor. The compounds are therefore valuable and interesting with a view to their use as therapeutically active compounds. Corresponding compounds in the estran series are already described as antigestagen active compounds in Fertility and Sterility 40 (1982), page 253. ;The hitherto known structure-activity relationships for competitive progesterone antagonists suggest that a 1,3-diaxial arrangement of 11fi-aryl residue and 133-alkyl group is imperative necessary for the unfolding of antigestagen activity All the more surprising is the strong and selective antagonistic action a v 13a-alkylgonanes of formula I where a completely different molecular topography compared to the estran series is exhibited. In recognition of the antigestagen effect of the compounds according to the invention, the abortive effect in an earlier phase post nidation (experiment I) and in an advanced phase post nidtation (experiment II) was examined. The experiments were carried out on female rats weighing approx. ;200 g. After mating, the onset of pregnancy was ensured by detection of sperm in vaginal swabs. The day of the sperm detection is considered day 1 of the pregnancy (= d 1 p.c.). ;The treatment of the animals with that connection e.g. the solvent to be examined occurs after nidation of the blastocysts from d 5 p.c. to d 7 p.c. (experiment I) or ;d 13 p.c. to d 15 p.c. (attempt II). On d 9 p.c. respectively ;d 17 p.c. the animals were euthanized and their uteri examined for implants and resorption sites. Photographs were taken of all uteri. The lack of implants was judged as abortion. As antigestagens, the following were investigated: A: 113-(4-dimethylaminophenyl)-17β-hydroxy-17α-propynyl-4,9-estradien-3-one (reference compound). ;B: 113-(4-dimethylaminophenyl)-173~hydroxy-17a-(3-hydroxy-propyl)-13a-methyl-4,9-gonadien-3-one (according to the invention). ;C: 113-(4-dimethylaminophenyl)-17a-hydroxy-173~(3-hydroxy-propyl)-13a-methyl-4,9-gonadien-3-one (according to the invention). ;The test compounds were dissolved in a benzyl benzoate-castor oil mixture (ratio 1:4). The carrier volume per single dose was 0.2 ml. The treatment took place subcutaneously (s.c.). ;Compounds B and C according to the invention act in early pregnant rats in dosages of = 1.0 mg/d as completely abortive (abortion rate: 4/4). In contrast, the reference compound A exhibits maximal abortifacient (antigestagen) action only at doses of = 3.0 mg/d (Table 1). At an advanced stage of pregnancy (d 13 - 15 p.c.) the percentage of complete abortions with 3 times daily s.c. addition of 3.0 mg/d for B 35.4%, for C 52.3% and for the comparison compound A 3.5% (Table 2). ;13a-alkylgonanes of the general formula I can find use in the form of pharmaceutical preparations. The preparations are made by per se known galenic methods by mixing with organic or inorganic inert carrier material which is suitable for enteral, percutaneous or parenteral use. ;The dosage of the active substances according to the invention is in humans at approx. 10 to 1000 mg per day. The alkyl groups in R<1> and R<11> in the general formula I must contain 1 to 4 carbon atoms, the methyl and ethyl groups being preferred. The analogous method according to the invention is characterized by the fact that a compound with the general formula: 17 5 where R , R" and R are as indicated above, and Z is an ethylene or 2,2-dimethylpropylene group, is irradiated with ultraviolet light, and the 13-episteroid obtained by UV irradiation with the general formula: where R 1 , R 2 , R 5 and Z are as indicated above, in a manner known per se by nucleophilic addition on the 17-ketone, cleavage of 3- the ketal protection and water removal from the 4,5-position are transferred to the compounds of the general formula I. ;On irradiation with ultraviolet light, the 133-alkylsteroids of the general formula II are transferred in good yield to the 13-episteroids (13a-alkylsteroids) of the general formula III. The compounds of general formula IT can be prepared as described in US patents 4,233,296 and 4,386,085. only to 13-episteroids (A. Butenandt et al., Ber. Deutsch. Chem. Ges. 74, 1308 (1941)); however, one always obtains mixtures of starting material and epimerized compound, the irradiation times were several hours, and the yield was exceedingly low. Therefore, the search for an alternative, chemical approach to the 13-epi series has also been relevant as a previous work by Barton et al., J.C.S. Perkin I, 2163 (1977), shows. However, this alternative is not suitable for the preparation of compounds of type I. It was found that the irradiation of the compounds of type II under certain conditions takes a significantly more favorable course than in the series of 11-unsubstituted 17-oxosteroids. Thus, the average irradiation times are only 10 - 30 minutes, and the yield of 13-episteroid is between 60 - 80%. The irradiation products can optionally be reacted further without chromatographic purification. An essential prerequisite for a good yield is the correct choice of solvent, the concentration of the substrate to be irradiated and the exact observance of the irradiation duration. These parameters must be determined specifically for each new substrate. ;The irradiation is carried out with the full light of a Hg high-pressure lamp in the quartz glass apparatus. The temperature of the reaction solution is set to approx. 25°C, the concentration of the solution amounts to 0.1 - 1.0% by weight. Tetrahydrofuran and dioxane are preferably used as solvents, but non-polar aprotic solvents such as hexane, cyclohexane, benzene, toluene and mixtures thereof can also be used. The irradiation duration amounts to approx. 10 - 50 minutes. ;The 13-episteroids III obtained in this way are transferred by the usual processes by nucleophilic addition to the 17-ketone and subsequent reactions to the final compound with the general formula I. The nucleophilic addition of III generally proceeds with the formation of two possible, isomeric forms by C-17 which are, however, easily separable by chromatography or fractional crystallization. In many cases, both isomers are pharmacologically active, even if there are differences in potency. ;The nucleophilic addition of acetylene (ethyne) or propyne takes place with the aid of an agent which emits the group -C=CH or -CsC-CH^. Such funds are e.g. alkali metal acetylides such as e.g. potassium and lithium acetylide, respectively -methylacetylide. The organometallic compound can also be formed in situ and reacted with the 17-ketone of formula III. Thus, one can e.g. in a suitable solvent allow acetylene and an alkali metal, especially potassium, sodium or lithium, to act on the 17-ketone in a suitable solvent in the presence of an alcohol or in the presence of ammonia. The alkali metal can also be brought into effect in the form of e.g. methyl or butyllithium. Dialkyl ether, tetrahydrofuran, dioxane, benzene and toluene are particularly suitable as solvents. The 17-ethynyl-17-hydroxy compounds can be hydrated in alcoholic solution under mercury catalysis to the 17-acetyl-17-hydroxy compounds (Chem. Ber. 111 (1978) 3086 - 3093). ;The introduction of 3-hydroxypropane, respectively 3-hydroxypropene in the 17-position occurs by reaction of the 17-ketone with metalized derivatives of propargyl alcohol, e.g. with 1-lithium-3-tetrahydropyran-2'-yloxy-propyn-1, to the 17-(3-hydroxy-1-propynyl)-17-hydroxy compounds, which are then hydrogenated to 17-(3-hydroxypropyl-, respectively 3 -hydroxypropenyl)-17-hydroxy compounds. The hydrogenation must be carried out under conditions which only allow attack on the C-C triple bond without desaturating the tetrasubstituted 9(10) double bond. Introduction of the homologous hydroxyalkane and hydroxyalkene groups of general formula -CH=CH-(CH2)n0H or -CH2~CH2-(CH2)n0H occurs in a similar way with homologues of propargyl alcohol. This happens e.g. by hydrogenation at room temperature and normal pressure in solvents such as methanol, ethanol, propanol, tetrahydrofuran (THF) or acetic acid with the addition of noble metal catalysts such as platinum or palladium. ;The connection with the Z-configured double bond in the hydroxypropenyl group occurs by hydrogenation of the acetylenic triple bond with a deactivated noble metal catalyst (J. Fried, J.A. Edwards: Organic Reactions in Steroid Chemistry, Van Nostrand Reinhold Company 1972, page 134, and H.O. House: Modern Synthetic Reactions 1972, page 19). Deactivated noble metal catalysts include, for example, 10% palladium on barium sulphate in the presence of an amine or 5% palladium on calcium carbonate with the addition of lead(II) acetate. The hydrogenation is interrupted after absorption of an equivalent of hydrogen. The connection with the E-configured double bond in the hydroxypropenyl group is formed by reduction of the acetylenic triple bond in a manner known per se. In the literature, a whole series of methods for the transfer of alkynes to trans-olefins are described, for example by reduction with sodium in liquid ammonia (J. Am." Chem. Soc. 6_3 (1941) 216), with sodium amide in liquid ammonia ( J. Chem. Soc. 1955, 3558), with lithium in low molecular weight amines (J. Am. Chem. Soc. Il (1955) 3378), with boranes (J. Am. Chem. Soc. 93. ;(1971) 3395 and 9J (1971) 6560), with diisobutylaluminum hydride and methyllithium (J. Am. Chem. Soc. 8j) (1967) 5085) and especially with lithium aluminum hydride/alcoholate (J. Am. Chem. Soc. 89 (1967) 4245). Another possibility is the reduction of the triple bond with chromium(II) sulfate in the presence of water or dimethylformamide in a weakly acidic environment (J. Am. Chem. Soc. 8j> ;(1964) 4358) as well as usually the reduction by the action of the transition metal compounds under change of the oxidation step. The build-up of the 17-cyanmethyl side chain takes place in a manner known per se from the 17-ketone with the general formula III, e.g. over the 17-spiroepoxide o g cleavage of the spiroepoxide with HCN according to Z. Chem. 18 (1978) 259 - 260. Introduction of the cyanalkane side chain -(CH2)n~CH2CN with n = 1 - 3 takes place, for example, by addition of Li-(CH2)n~CH2CN to the 17-ketone. ;Also the introduction of the 17-hydroxyacetyl side chain takes place in a manner known per se, for example according to that in J. Org. Chem. 4_7 (1982), 2993 - 2995, described method. Free hydroxy groups in the 17-position can be esterified in a known manner. ;After reaction (nucleophilic addition) of the 17-ketone, the compounds of formula III are treated for water splitting to form the 4(5) double bond and for simultaneous ketal splitting and removal of any further acid-cleavable protective groups with acid or another acidic ion exchanger. The acid treatment takes place in a manner known per se as the compound of formula III, which contains a 3-ketal group and a 5a-hydroxy group and an optionally O-protected 17-(3-hydroxypropyl) group, is dissolved in a water-miscible solvent, such as aqueous methanol, ethanol or acetone, and allowing catalytic amounts of mineral or sulphonic acid, such as hydrochloric acid, sulfuric acid, phosphoric acid, perchloric acid or p-toluenesulphonic acid or an organic acid, such as acetic acid, to act for a long time on the solution until water is split off and the protecting groups are removed. The reaction, which proceeds best at temperatures from 0 to 100°C, can also be carried out with an acidic ion exchanger. The progress of the turnover can be followed with analytical methods, e.g. by thin-layer chromatography on withdrawn samples. ;Example 1 ;a) A solution of 2.0 g of 11(3-(4-dimethylaminophenyl)-3, 3-(2,2-dimethylpropane-1,3-dioxy)-5a-hydroxy-9(10)- estren-17-one; (m.p. 143-145°C) in 300 ml of absolute tetrahydrofuran (THF) is irradiated for 16 minutes at 25°C with a Hg high-pressure lamp (Philips HPK 125, immersion lamp, quartz glass reactor). The solvent is then distilled off in vacuum, and the residue is chromatographed over aluminum oxide (Merck, neutral, stage III) with hexane/acetic acid ester.1.46 g of 113-(4-dimethylaminophenyl)-3,3-(2,2-dimethylpropane-1,3-dioxy )-5a-hydroxy-13a-methyl-9(10)-gonen-17-one as a colorless oil.;b) Absolute THF (248 ml) is saturated with acetylene at 5°C for 30 minutes. 51 ml of a 15% solution of n-butyllithium in hexane is then slowly added dropwise, and the mixture is stirred for a further 15 minutes under ice water cooling. A solution of 2.7 g of 113-(4-dimethylaminophenyl)-3,3-(2,2-dimethyl-propan-1,3-dioxy)-5a-hydroxy-13a-methyl-9-gonen-17 -one in 40 ml of absolute THF is added dropwise over the course of 15 minutes to the suspension of the lithium acetylide, and it is stirred for a further 2 hours at room temperature. For processing, pour into ice water and extract with acetic acid ester. The crude product thus obtained (2.85 g) is used without further purification in the following step. c) 2.8 g of the crude product obtained under b) is suspended in 29 ml of 70% aqueous acetic acid and stirred for 3 hours at 50°C. ;After cooling, dilute with approx. 100 ml of water, and it is adjusted to a pH value of 10.5 by adding concentrated aqueous NH 3 solution. After extraction with acetic acid ester, an oily isomer mixture is obtained which is separated by column chromatography on silica gel with hexane/acetic acid ester. One obtains in order of elution: 1. 530 mg of 113-(4-dimethylaminophenyl)-17a-ethynyl-173-hydroxy-13a-methyl-4,9-gonadien-3-one with m.p. 120-123°C (acetic acid ester/diisopropyl ether) and 2. 1.33 g of 113-(4-dimethylaminophenyl)-173~ethynyl-17a-hydroxy-13a-methyl-4,9-gonadien-3-one with m.p. 201-204°C (acetic acid ester). d) A suspension of 1.02 g of mercuric oxide (HgO, red) in 20 ml of water is stirred for 30 minutes at 60°C after the addition of 0.87 ml of concentrated sulfuric acid. 9 ml of this mercury salt solution is poured into a solution of 3.25 g of 113-(4-dimethylaminophenyl)-173-ethynyl-17ct-hydroxy-13a-methyl-4,9-gonadien-3-one in 32 ml of glacial acetic acid. Then stir for 2 hours at 60°C. For work-up, pour the cooled reaction solution into ice water, set a pH value of 10.5 by adding concentrated aqueous NH 3 solution and extract with ethyl acetate. The oily crude product thus obtained is crystallized from methylene chloride/diisopropyl ether. 2.37 g of 113-(4-dimethylaminophenyl)-17a-hydroxy-13a-methyl-18,19-dinor-4,9-pregnadiene-3,20-dione are obtained with m.p. 224-225°C. e) A suspension of 2.3 g of 113-(4-dimethylaminophenyl)-17a-hydroxy-13a-methyl-18,19-dinor-4,9-pregnadiene-3,20-dione in 58 ml of toluene becomes after the addition of 11/6 ml of acetic anhydride and 5.8 g of 4-dimethylaminopyridine stirred for 20 hours at 25°C. It is then poured into saturated NaHCO 3 solution and extracted with ethyl acetate. The crude product is chromatographed on 200 g of silica gel with hexane/ethyl acetate. After crystallization of the main fraction from hexane/ethyl acetate, 1.71 g of 17ct-acetoxy-113-(4-dimethylaminophenyl)-13a-methyl-18,19-dinor-4,9-pregna-diene-3,20-dione are obtained with m.p. 194-195°C. ;Example 2 ;a) A solution of 1.8 g of 113-(4-diethylaminophenyl)-3,3-(2,2-dimethylpropan-1,3-dioxy)-5a-hydroxy-9-estren-17-one (m.p. 223-226°C) in 300 ml of THF is irradiated under the conditions of example la) for 26 minutes. After chromatography of the crude product, 1.58 g of 113-(4-diethylaminophenyl)-3,3-(2,2-dimethyl-propan-1,3-dioxy)-5a-hydroxy-13a-methyl-9-gonen- 17-on as a colorless oil. ;b) From 3.94 g of 3-tetrahydropyran-2<1->yloxy-l-propyne in 85 ml of absolute THF and 23.1 ml of a 15% solution of n-butyllithium in hexane is prepared at 0°C the organolithium compound. A solution of 3.53 g of the product described under 2a) in 71 ml of absolute THF is then added dropwise and stirred for 4 hours at room temperature. The reaction solution is then poured into ice water and extracted with acetic acid ester. The crude product (3.85 g) 113-(4-diethylaminophenyl)-3,3-(2,2-dimethylpropan-1,3-dioxy)-13a-methyl-17a-[3-(tetrahydropyran-2-yloxy)- 1-propynyl]-9-gonen-5α,173-diol and 113-(4-diethyl-aminophenyl)-3,3-(2,2-dimethylpropane-1,3-dioxy)-13α-methyl-173- [3-(tetrahydropyran-2-yloxy)-1-propynyl]-9-gonen-5a,17a-diol is used without further purification to hydrogenate none. c) 3.85 g of the crude product obtained under 2b) is, in 95 ml of ethanol after the addition of 400 mg of 10% palladium charcoal, hydrogenated at room temperature and normal pressure. After absorption of 191 ml of hydrogen, the catalyst is filtered off and evaporated. d) The hydrogenation crude product (3.85 g) obtained under 2c) is stirred in 30 ml of 70% acetic acid for 2 hours at 60°C. After cooling, work up as under lc) and chromatograph the isomer mixture obtained. In order of elution, one obtains: 1. 410 mg of lip-(4-diethylamlnophenyl)-17a-(3-hydroxypropyl)-173-hydroxy-13a-methyl-4,9-gonadien-3-one as a yellow colored oil. UV (methanol): 1266 = 19080' £309 = 1911°-2. 1.39 g of 113-(4-diethylaminophenyl)-173-(3-hydroxypropyl)-17α-hydroxy-13α-methyl-4,9-gonadien-3-one as solid foam. ;Example 3 ;a) A solution of 1.75 g of 3,3-(2,2-dimethylpropan-1,3-dioxy)-5a-hydroxy-113~(4-methoxyphenyl)-9-estren-17-one in 290 ml; dioxane is irradiated for 19 minutes under the conditions of example la). After chromatography, 1.45 g of 3,3-(2,2-dimethylpropan-1,3-dioxy)-5a-hydroxy-113_(4-methoxyphenyl)-13a-methyl-9-gonen-17-one are obtained as colorless oil. b) A solution of 8.2 g 3, 3-(2,2-dimethylpropan-1,3-dioxy)-5α-hydroxy-113-(4-methoxyphenyl)-13α-methyl-9-gonen-17-one in 130 mL THF. You then stir for 3 hours at room temperature, then pour the reaction solution for approx. 3 1 ice water and extract with ethyl acetate. The crude product is chromatographed on aluminum oxide with hexane/ethyl acetate. In order of elution, you get: ;1. 1.8 g of 3,3-(2,2-dimethylpropane-1,3-dioxy)-17a-ethynyl-113-(4-methoxyphenyl)-13a-methyl-9-gonen-5a,173-diol as colorless oil . 2. 5.1 g of 3,3-(2,2-dimethylpropane-1,3-dioxy)-173-ethynyl-113-(4-methoxyphenyl)-13a-methyl-9-gonen-5a,173-diol as solid foam. c) A solution of 3.28 g of 3,3-(2,2-dimethylpropane-1,3-dioxy)-17f3-ethynyl-113-(4-methoxyphenyl)-13ct-methyl-9-gonen-5a,17a -diol in 33 ml of 70% aqueous acetic acid is stirred for 30 minutes at 60°C. After cooling, pour into ice water, extract with methylene chloride, wash the methylene chloride extract with saturated sodium bicarbonate solution and evaporate. Crystallization of the crude product from ethyl acetate gives 2.0 g of 170-ethynyl-17a-hydroxy-11|3-(4-methoxyphenyl)-13a-methyl-4, 9-gonadien-3-one with m.p. 186-187°C. ;Example 4 ;20 minute irradiation of 1.84 g lip-(4-dimethylaminophenyl)-3, 3-(2,2-dimethylpropane-1,3-dioxy)-5a-hydroxy-18-methyl-9-estrene- 17-one in 280 ml of THF under the conditions of example la) leads to 1.36 g of 110-(4-dimethylaminophenyl)-3,3-(2,2-dimethylpropan-1,3-dioxy)-13a-ethyl-5a -hydroxy-9-gonen-17-one as foam. 6.1 g of 113-(4-dimethylaminophenyl)-3,3-(2,2-dimethyl-propan-1,3-dioxy)-13a-ethyl-5a-hydroxy-9-gonen-17-one is reacted under the conditions in example lb) with lithium acetylide, and the crude product thus obtained is cleaved under the conditions in example lc) with acetic acid. After chromatography and crystallization from ethyl acetate/diisopropyl ether, 3.2 g of 113-(4-dimethylaminophenyl)-173-ethynyl-13a-ethyl-17a-hydroxy-4,9-gonadien-3-one with m.p. 197-198°C, [α]^<5> + 450.4° (CHCl 3 ; c = 0.505). By mercury salt-catalyzed hydration analogous to example ld) and subsequent acetylation analogous to example le) one obtains from 1.3 g 113-(4-dimethylaminophenyl)-173_ethynyl-13a-ethyl-17a-hydroxy-4,9-gonadien- 3-one after chromatographic purification 720 mg 17a-acetoxy-113-(4-dimethyl-aminophenyl)-13a-ethyl-18,19-dinor-4,9-pregnadiene-3,20-dione as solid foam. ;Example 5 ;a) By reacting 7.3 g of 110-(4-dimethylaminophenyl)-3,3-(2,2-dimethylpropane-1,3-dioxy)-5a-hydroxy-13a-methyl-9-gonene -17-one with 10.7 g of 3-tetrahydropyran-2*-yloxy-1-propyn under the conditions of example 2b) gives, after chromatography of the crude product on aluminum oxide with hexane/ethyl acetate, 4.83 g of 110-(4- dimethylaminophenyl)-3,3-(2,2-dimethylpropan-1,3-dioxy)-13a-methyl-170-[3-(tetrahydropyran-2-yloxy)-1-propynyl]-9-gonen-5a,17a -diol as a yellow foam. b) A solution of 2.2 g of the adduct obtained under a) in 67 ml of ethanol and 0.56 ml of triethylamine is hydrated after adding 210 mg of palladium on barium sulphate (10%) at room temperature and normal pressure. After absorption of 83.5 ml of hydrogen, the catalyst is filtered off and evaporated. The thus obtained hydration crude product is cleaved with 14 ml of 70% acetic acid under the conditions in example lc). After crystallization from ethyl acetate/diisopropyl ether, 1.1 g of 110-(4-dimethylaminophenyl)-17a-hydroxy-170-(3-hydroxy-1(Z)-propenyl)-13a-methyl-4,9-gonadien-3 is obtained -on with m.p. 133-135°C.
Eksempel 6 Example 6
Fremstilling av 110-(4-dimethylaminofenyl)-170-ethynyl-160-ethyl- 17a- hydroxy- r3a- methyl- 4, 9- gonadien- 3- on a) En suspensjon av 29,3 g 3,3-(2,2-dimethylpropan-l,3-dioxy)-5(10),9(11)-estradien-17-on og 28,6 g bis-dimethyl-amino-t-butoxymethan omrøres under argon i 60 minutter ved 160°C. Etter avkjøling rives råproduktet med ca. 50 ml ethylacetat, filtreres, og filterresiduet omkrystalliseres fra ethylacetat. På denne måte får man 27,6 g 16-dimethyl-aminomethylen-3,3-(2,2-dimethylpropan-l,3-dioxy)-5-(10),9(11)-estradien-17-on med smp. 208-211°C. b) En oppløsning av 14,4 g 16-dimethylaminomethylen-3,3-(2,2-dimethylpropan-l,3-dioxy)-5(10),9(11)-estradien-17-on i Preparation of 110-(4-dimethylaminophenyl)-170-ethynyl-160-ethyl-17a-hydroxy-r3a-methyl-4,9-gonadien-3-one a) A suspension of 29.3 g of 3,3-(2 ,2-dimethylpropan-1,3-dioxy)-5(10),9(11)-estradien-17-one and 28.6 g of bis-dimethyl-amino-t-butoxymethane are stirred under argon for 60 minutes at 160° C. After cooling, the raw product is shredded with approx. 50 ml of ethyl acetate are filtered, and the filter residue is recrystallized from ethyl acetate. In this way, 27.6 g of 16-dimethyl-aminomethylene-3,3-(2,2-dimethylpropan-1,3-dioxy)-5-(10),9(11)-estradien-17-one are obtained with m.p. 208-211°C. b) A solution of 14.4 g of 16-dimethylaminomethylene-3,3-(2,2-dimethylpropan-1,3-dioxy)-5(10),9(11)-estradien-17-one in
220 ml toluen blir under isvannkjøling dråpevis tilsatt 85 ml av en 5%-ig oppløsning av methyllithium i diethylether. 220 ml of toluene is added dropwise to 85 ml of a 5% solution of methyllithium in diethyl ether under ice-water cooling.
Etter tilsetningen omrøres i 15 minutter ved +5 til +10°C, overskytende reagens spaltes ved forsiktig tilsetning av ca. 20 ml vann, reaksjonsoppløsningen helles derpå i ca. 3 1 isvann og ekstraheres med methylenklorid. Råproduktet kromatograferes på nøytralt aluminiumoxyd med hexan/ethylacetat. Etter krystallisasjon av hovedfraksjonen fra ethylacetat får man 13,0 g 3,3-(2,2-dimethylpropan-l,3-dioxy)-16(E)^ethyliden-5(10),9(11)-estradien-17-on med smp. 121-123°C. After the addition, stir for 15 minutes at +5 to +10°C, excess reagent is decomposed by careful addition of approx. 20 ml of water, the reaction solution is then poured for approx. 3 1 ice water and extracted with methylene chloride. The crude product is chromatographed on neutral aluminum oxide with hexane/ethyl acetate. After crystallization of the main fraction from ethyl acetate, 13.0 g of 3,3-(2,2-dimethylpropane-1,3-dioxy)-16(E)^ethylidene-5(10),9(11)-estradien-17 are obtained -on with m.p. 121-123°C.
c) Til en oppløsning av 9,4 g 3,3-(2,2-dimethylpropan-l,3-dioxy)-16(E)-ethyliden-5(10),9(11)-estradien-17-on i 43 ml c) To a solution of 9.4 g of 3,3-(2,2-dimethylpropan-1,3-dioxy)-16(E)-ethylidene-5(10),9(11)-estradien-17-one in 43 ml
methylenklorid, 0,34 ml hexakloraceton og 0,01 ml pyridin dryppes under isvannavkjøling 4,3 ml 30%-ig hydrogenperoxyd, og det omrøres derpå i 16 timer ved 25°C. Til opparbeidelse fortynner man reaksjonsoppløsningen med ca. 100 ml methylenklorid, ettervasker med 5%-ig Na2S002_oppløsning og vann, tørrer methylenkloridf asen over Na-^SO^ og inndamper. Den således erholdte 5,10-epoxydblanding blir på A^O^, nøytral, trinn III, kromatografert med hexan/ethylacetat. Man får 4,7 g 3,3-(2,2-dimethylpropan-l,3-dioxy)-5a,10a-epoxy-16(E)-ethyliden-9(11)-estren-17-on med smp. 139-141°C (ethylacetat/diisopropylether). methylene chloride, 0.34 ml of hexachloroacetone and 0.01 ml of pyridine are added dropwise under ice water cooling to 4.3 ml of 30% hydrogen peroxide, and it is then stirred for 16 hours at 25°C. For preparation, the reaction solution is diluted with approx. 100 ml of methylene chloride, wash with 5% Na2S002_solution and water, dry the methylene chloride phase over Na-^SO^ and evaporate. The 5,10-epoxide mixture thus obtained is chromatographed on A^O^, neutral, stage III, with hexane/ethyl acetate. 4.7 g of 3,3-(2,2-dimethylpropan-1,3-dioxy)-5a,10a-epoxy-16(E)-ethylidene-9(11)-estren-17-one are obtained with m.p. 139-141°C (ethyl acetate/diisopropyl ether).
d) En oppløsning av 8,2 g 3,3-(2,2-dimethylpropan-l,3-dioxy)-5a,10a-epoxy-16(E)-ethyliden-9(11)-estren-17-on i d) A solution of 8.2 g of 3,3-(2,2-dimethylpropan-1,3-dioxy)-5a,10a-epoxy-16(E)-ethylidene-9(11)-estren-17-one in
400 ml ethanol blir etter tilsetning av 930 mg palladiumkull (10%) hydrert ved værelsetemperatur og normaltrykk. Etter opptak av 510 ml hydrogen blir katalysatoren frafiltrert, og det inndampes i vakuum. Man får 7,7 g 3,3-(2,2-dimethyl-propan-l, 3-dioxy)-5a,lOa-epoxy-163~ethyl-9(11)-estren-17-on som farveløs olje. After adding 930 mg of palladium charcoal (10%), 400 ml of ethanol is hydrated at room temperature and normal pressure. After absorption of 510 ml of hydrogen, the catalyst is filtered off and evaporated in vacuo. 7.7 g of 3,3-(2,2-dimethyl-propan-1,3-dioxy)-5a,10a-epoxy-163-ethyl-9(11)-estren-17-one are obtained as a colorless oil.
e) Fra 1,4 g magnesium, 0,05 ml methyljodid og 17,9 g 4-brom-N,N-dimethylanilin i 150 ml absolutt THF fremstilles den e) From 1.4 g of magnesium, 0.05 ml of methyl iodide and 17.9 g of 4-bromo-N,N-dimethylaniline in 150 ml of absolute THF, the
magnesiumorganiske forbindelse. Etter tilsetning av 344 g CuCl omrøres i 15 minutter ved 0°C, og det tilsettes så dråpe-vls en oppløsning av 7,7 g av det under d) erholdte produkt i 70 ml absolutt THF. Derpå omrøres i 3,5 timer ved værelse- organomagnesium compounds. After adding 344 g of CuCl, the mixture is stirred for 15 minutes at 0°C, and a solution of 7.7 g of the product obtained under d) in 70 ml of absolute THF is then added dropwise. Then stir for 3.5 hours at room-
temperatur. Til opparbeidelse heller man reaksjonsoppløs-ningen i en blanding av isvann og NH^-oppløsning og ekstraherer med ethylacetat. Etter kromatografi av råproduktet på aluminiumoxyd med hexan/ethylacetat og krystallisasjon av hovedfraksjonen fra diisopropylether/ethylacetat får man 6,5 g HØ-(4-dimethylaminofenyl)-3,3-(2,2-dimethylpropan-l,3-dioxy)-16p-ethyl-5a-hydroxy-9(10)-estren-17-on med smp. 180-181°C. f) En oppløsning av 4,0 g av det under e) erholdte produkt i 600 ml dioxan bestråles under betingelsene i eksempel la). temperature. For work-up, the reaction solution is poured into a mixture of ice water and NH 3 solution and extracted with ethyl acetate. After chromatography of the crude product on aluminum oxide with hexane/ethyl acetate and crystallization of the main fraction from diisopropyl ether/ethyl acetate, 6.5 g of HØ-(4-dimethylaminophenyl)-3,3-(2,2-dimethylpropane-1,3-dioxy)- 16β-ethyl-5α-hydroxy-9(10)-estren-17-one with m.p. 180-181°C. f) A solution of 4.0 g of the product obtained under e) in 600 ml of dioxane is irradiated under the conditions of example la).
Etter krystallisasjon av bestrålingsråproduktet fra diiso-propylether får man 1,74 g 11(3- (4-dimethylaminofenyl) -3, 3-(2, 2-dimethylpropan-l, 3-dioxy) -16p-ethyl-5a-hydroxy-13P-methyl-9(10)-gonen-17-on med smp. 192-194°C. After crystallization of the irradiation raw product from diisopropyl ether, 1.74 g of 11(3-(4-dimethylaminophenyl)-3,3-(2,2-dimethylpropane-1,3-dioxy)-16p-ethyl-5a-hydroxy- 13P-methyl-9(10)-gonen-17-one with mp 192-194°C.
g) Under betingelsene i eksempel lb) blir 1,4 g av det under f) erholdte produkt omsatt med lithiumacetylid. Etter g) Under the conditions in example lb), 1.4 g of the product obtained under f) is reacted with lithium acetylide. After
krystallisasjon av råproduktet fra ethylacetat/diisopropyl-ether får man 960 mg 11(3- (4-dimethylaminofenyl)-3, 3-(2, 2-dimethylpropan-1, 3-dioxy) -17p-ethynyl-16p-ethyl-13a-methyl-9(10)-gonen-5a,17a-diol med smp. 132-134°C. crystallization of the crude product from ethyl acetate/diisopropyl ether yields 960 mg of 11(3-(4-dimethylaminophenyl)-3, 3-(2, 2-dimethylpropane-1, 3-dioxy)-17p-ethynyl-16p-ethyl-13a -methyl-9(10)-gonen-5a,17a-diol with mp 132-134°C.
h) Under betingelsene i eksempel lc) omsetter man 760 mg h) Under the conditions in example lc), 760 mg is converted
av det under g) erholdte produkt med 8 ml 70%-ig eddiksyre. of the product obtained under g) with 8 ml of 70% acetic acid.
Krystallisasjon av råproduktet fra hexan/diethylether gir 460 mg lip- (4— dimethylaminofenyl) -17p-ethynyl-16P-ethyl-17ct-hydroxy-13a-methyl-4,9-gonadien-3-on med smp. 195-197°C. Crystallization of the crude product from hexane/diethyl ether gives 460 mg of lip-(4-dimethylaminophenyl)-17p-ethynyl-16P-ethyl-17ct-hydroxy-13a-methyl-4,9-gonadien-3-one with m.p. 195-197°C.
Eksempel 7 Example 7
Fremstilling av 17p-cyanmethyl-lip-(4-dimethylaminofenyl)-17a- hydroxy- 13a- methyl- 4, 9- gonadien- 3- on Preparation of 17p-cyanmethyl-lip-(4-dimethylaminophenyl)-17a-hydroxy-13a-methyl-4,9-gonadien-3-one
a) En suspensjon av 5,0 g lip-(4-dimethylaminofenyl)-3,3-(2,2-dimethylpropan-l,3-dioxy)-5a-hydroxy-13a-methyl-9(10)-gonen-17-on og 4,74 g trimethylsulfoniumjodid i 60 ml dimethylformamid blir under isvannavkjøling porsjonsvis tilsatt 2,63 g kalium-t-butylat. Man omrører i 4 timer ved 25°C, heller derpå i isvann og ekstraherer med ethylacetat. Etter fjernelse av oppløsningsmidlet krystalliseres derpå det oljeaktige råprodukt fra ethylacetat/diisopropyletner, og man får på denne måte 4,2 g lip-(4-dimethylaminofenyl)-3,3-(2,2-dimethylpropan-1,3-dioxy)-5a-hydroxy-13a-methyl-9(10)-gonen-17a-spiro-l',2'-oxiran med smp. 234-236°C. b) 2,0 g av det under a) erholdte spiro-oxiran, oppløses i 84 ml ethanol og oppvarmes etter tilsetning av 4,6 g kalium-cyanid i 4 timer under tilbakeløp. Den avkjølte oppløsning helles i mettet natriumbicarbonatoppløsning og ekstraheres med ethylacetat. Det etter inndampning erholdte råprodukt blir uten videre rensning tatt opp i 26 ml 70%-ig eddiksyre og omrørt i 60 minutter ved 60°C. Etter avkjøling heller man det i isvann, innstiller ved tilsetning av ammoniakkoppløsning en pH-verdi på 10,5 og ekstraherer med methylenklorid. Etter kromatografi av råproduktet på silicagel med hexan/aceton og krystallisasjon av hovedfraksjonen fra ethanol får man 1,4 g 173— cyanmethyl-113-(4-dimethylaminofenyl)-17a-hydroxy-13a-methyl-4,9-gonadien-3-on med smp. 135-137°C. a) A suspension of 5.0 g of lip-(4-dimethylaminophenyl)-3,3-(2,2-dimethylpropane-1,3-dioxy)-5a-hydroxy-13a-methyl-9(10)-gonene- 17-one and 4.74 g of trimethylsulfonium iodide in 60 ml of dimethylformamide, 2.63 g of potassium t-butylate are added in portions under ice water cooling. The mixture is stirred for 4 hours at 25°C, then poured into ice water and extracted with ethyl acetate. After removal of the solvent, the oily crude product is then crystallized from ethyl acetate/diisopropyl ether, and in this way 4.2 g of lip-(4-dimethylaminophenyl)-3,3-(2,2-dimethylpropane-1,3-dioxy)- 5α-hydroxy-13α-methyl-9(10)-gonen-17α-spiro-1',2'-oxirane with m.p. 234-236°C. b) 2.0 g of the spiro-oxirane obtained under a) are dissolved in 84 ml of ethanol and heated after the addition of 4.6 g of potassium cyanide for 4 hours under reflux. The cooled solution is poured into saturated sodium bicarbonate solution and extracted with ethyl acetate. The crude product obtained after evaporation is, without further purification, taken up in 26 ml of 70% acetic acid and stirred for 60 minutes at 60°C. After cooling, it is poured into ice water, adjusted to a pH value of 10.5 by adding ammonia solution and extracted with methylene chloride. After chromatography of the crude product on silica gel with hexane/acetone and crystallization of the main fraction from ethanol, 1.4 g of 173-cyanmethyl-113-(4-dimethylaminophenyl)-17a-hydroxy-13a-methyl-4,9-gonadien-3- on with m.p. 135-137°C.
Claims (1)
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NO863964A NO160522C (en) | 1983-06-15 | 1986-10-03 | 13-EPISTEROIDER. |
NO863963A NO161895C (en) | 1983-06-15 | 1986-10-03 | ANTI-CONCEPTING AGENT CONTAINING 13ALFA ALKYLGONANES AS A SUBSTANTIAL COMPONENT. |
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DE3321826A DE3321826A1 (en) | 1983-06-15 | 1983-06-15 | 13 alpha -Alkylgonanes, the preparation thereof and pharmaceutical products containing these |
DE19843413036 DE3413036A1 (en) | 1984-04-04 | 1984-04-04 | 13a-Alkylgonanes, the preparation thereof and pharmaceutical products containing these |
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JP (1) | JPH02167296A (en) |
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DE3446661A1 (en) * | 1984-12-18 | 1986-06-19 | Schering AG, 1000 Berlin und 4709 Bergkamen | NEW 13 (ALPHA) -ALKYL-17 (BETA) - (3-ACYLOXYPROPYL) GONANA |
DE3506785A1 (en) * | 1985-02-22 | 1986-08-28 | Schering AG, Berlin und Bergkamen, 1000 Berlin | 11SS-N, N-DIMETHYLAMINOPHENYL ESTRADIENE, THE PRODUCTION THEREOF AND PHARMACEUTICAL PREPARATIONS CONTAINING THEM |
DE3630030A1 (en) * | 1986-09-01 | 1988-03-03 | Schering Ag | 13 (ALPHA) -ALKYLGONAN- (DELTA) (UP ARROW) 9 (UP ARROW) (UP ARROW) ((UP ARROW) (UP ARROW) 1 (UP ARROW) 1 (UP ARROW)) (UP ARROW) -5, 10-EPOXIDE |
US4774236A (en) * | 1986-09-17 | 1988-09-27 | Research Triangle Institute | 17α-(substituted-methyl)-17β-hydroxy/esterified hydroxy steroids and pharmaceutical compositions containing them |
IE60780B1 (en) * | 1987-01-23 | 1994-08-10 | Akzo Nv | New 11-aryl steroid derivatives |
EP0310542B1 (en) * | 1987-10-01 | 1994-06-08 | Schering Aktiengesellschaft | Antigestagenic and antioestrogenic compounds for the treatment of hormone-dependent tumours |
BE1004905A4 (en) * | 1987-12-30 | 1993-02-23 | Roussel Uclaf | NOVEL 17BETA-OH 19-NOR DERIVATIVES SUBSTITUTED IN 17ALPHA, THEIR PREPARATION PROCESS, THEIR APPLICATION AS MEDICAMENTS AND THE PHARMACEUTICAL COMPOSITIONS CONTAINING THEM. |
US4954490A (en) * | 1988-06-23 | 1990-09-04 | Research Triangle Institute | 11 β-substituted progesterone analogs |
DE3822770A1 (en) * | 1988-07-01 | 1990-01-04 | Schering Ag | 13-ALKYL-11SS-PHENYLGONANE |
DE3832303A1 (en) * | 1988-09-20 | 1990-04-12 | Schering Ag | 11SS-PHENYL-14SSH STEROIDS |
US5364847A (en) * | 1989-03-10 | 1994-11-15 | Endorecherche | Inhibitors of sex steroid biosynthesis and methods for their production and use |
US5372996A (en) * | 1989-03-10 | 1994-12-13 | Endorecherche, Inc. | Method of treatment of androgen-related diseases |
DE69032648T2 (en) * | 1989-07-07 | 1999-04-08 | Endorecherche Inc | Androgen derivatives to inhibit the activity of sex steroids |
EP0595796B1 (en) * | 1989-07-07 | 2003-01-15 | Endorecherche Inc. | Method of treatment of androgen-related diseases |
JP3202224B2 (en) * | 1989-08-04 | 2001-08-27 | シエーリング アクチエンゲゼルシヤフト | 11β-aryl-gon-4,9-dien-3-ones, process for their preparation and pharmaceutical preparations containing them |
FR2654337B1 (en) * | 1989-11-15 | 1994-08-05 | Roussel Uclaf | NOVEL BIODEGRADABLE INJECTABLE MICROSPHERES PREPARATION METHOD AND INJECTABLE SUSPENSIONS CONTAINING THEM. |
DE4008584A1 (en) * | 1990-03-15 | 1991-09-26 | Schering Ag | METHOD FOR PRODUCING INTERMEDIATE PRODUCTS FOR THE ANTIGESTAGE SYNTHESIS (ONAPRISTONE SYNTHESIS) |
US5407928A (en) * | 1990-08-15 | 1995-04-18 | Schering Aktiengesellschaft | 11β-aryl-gona-4,9-dien-3-ones |
RU2082762C1 (en) * | 1990-08-18 | 1997-06-27 | Шеринг АГ Берлин унд Бергкамен | Process for preparing 17-oxosteroids |
US5472854A (en) * | 1990-08-18 | 1995-12-05 | Schering Aktiengesellschaft | Process for the production of 17-oxosteroids via the fermentative oxidation of 17β-hydroxysteroids by Mycobacterium |
MX9301121A (en) | 1992-03-02 | 1993-09-01 | Schering Ag | METHOD AND EQUIPMENT FOR ORAL CONTRACEPTION AND REGULATION OF MENSTRUATION WITH ESTROGEN / PROGESTIN / ANIPROGESTIN. |
US7704983B1 (en) | 1992-03-02 | 2010-04-27 | Eastern Virginia Medical School | Antiprogestin method for reducing side effects associated with low dosage HRT and oral contraception |
US5439913A (en) | 1992-05-12 | 1995-08-08 | Schering Aktiengesellschaft | Contraception method using competitive progesterone antagonists and novel compounds useful therein |
CZ286894A3 (en) * | 1992-05-21 | 1995-09-13 | Endorecherche Inc | Pharmaceutical preparation |
DE4413185A1 (en) * | 1994-04-12 | 1995-10-19 | Schering Ag | 11beta, 19-bridged 13alpha alkyl steroids |
DE4415590A1 (en) * | 1994-04-28 | 1995-11-02 | Schering Ag | Process for the stereoselective introduction of an alkynyl side chain to 11β-aryl-substituted 13alpha-alkylgonan-17-ones |
DE4434488A1 (en) | 1994-09-14 | 1996-03-21 | Schering Ag | Steroid esters and amides, processes for their preparation and their pharmaceutical use |
ZA9510926B (en) | 1994-12-23 | 1996-07-03 | Schering Ag | Compounds with progesterone-antagonistic and antiestrogenic action to be used together for female contraception |
US6900193B1 (en) | 1996-05-01 | 2005-05-31 | The United States Of America As Represented By The Department Of Health And Human Services | Structural modification of 19-norprogesterone I: 17-α-substituted-11-β-substituted-4-aryl and 21-substituted 19-norpregnadienedione as new antiprogestational agents |
PT900234E (en) | 1996-05-01 | 2000-12-29 | Us Gov Health & Human Serv | PROGESTERONE DERIVATIVES SUBSTITUTED IN 21 WHICH MAY BE USED AS NEW ANTI-PROBESTATIVE AGENTS |
RU2017112748A (en) | 2014-11-17 | 2018-12-19 | Арно Терапьютикс, Инк. | ONAPRISTON COMPOSITIONS OF LONG-TERM ACTIONS AND METHODS |
WO2017053793A1 (en) | 2015-09-25 | 2017-03-30 | Arno Therapeutics, Inc. | Methods of making onapristone intermediates |
US10548905B2 (en) | 2015-12-15 | 2020-02-04 | Context Biopharma Inc. | Amorphous onapristone compositions and methods of making the same |
WO2018102369A1 (en) | 2016-11-30 | 2018-06-07 | Arno Therapeutics, Inc. | Methods for onapristone synthesis dehydration and deprotection |
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FR2377418A1 (en) * | 1977-01-13 | 1978-08-11 | Roussel Uclaf | NEW 4,9-DIENIC 11B-SUBSTITUTE STEROID DERIVATIVES, THEIR PREPARATION PROCESS AND THEIR APPLICATION AS MEDICINAL PRODUCTS |
ZA8231B (en) * | 1981-01-09 | 1982-11-24 | Roussel Uclaf | New 11 -substituted steroid derivatives, their preparation, their use as medicaments, the compositions containing them and the new intermediates thus obtained |
DE3347126A1 (en) * | 1983-12-22 | 1985-07-11 | Schering AG, 1000 Berlin und 4709 Bergkamen | 11SS-ARYL-ESTRADIENE, THEIR PRODUCTION AND THE PHARMACEUTICAL PREPARATIONS CONTAINING THEM |
CA1304916C (en) * | 1984-10-18 | 1992-07-14 | Wilhelm Bannwarth | Apparatus for the parallel performance of a plurality of chemical reaction sequences |
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1984
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- 1984-06-13 DE DE8484730062T patent/DE3468030D1/en not_active Expired
- 1984-06-13 GR GR75001A patent/GR82210B/el unknown
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- 1984-06-13 DD DD84264102A patent/DD218624A5/en not_active IP Right Cessation
- 1984-06-13 EP EP84730062A patent/EP0129499B1/en not_active Expired
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- 1984-06-14 AU AU29361/84A patent/AU572849B2/en not_active Ceased
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EP0129499A2 (en) | 1984-12-27 |
ES533260A0 (en) | 1985-02-01 |
AU572849B2 (en) | 1988-05-19 |
ES8502612A1 (en) | 1985-02-01 |
JPH0369919B2 (en) | 1991-11-05 |
HUT36139A (en) | 1985-08-28 |
FI78709B (en) | 1989-05-31 |
FI78709C (en) | 1989-09-11 |
IE841484L (en) | 1984-12-15 |
EP0129499B1 (en) | 1987-12-09 |
PT78732A (en) | 1985-01-01 |
AU2936184A (en) | 1984-12-20 |
IL72085A (en) | 1987-09-16 |
DE3468030D1 (en) | 1988-01-21 |
CA1307784C (en) | 1992-09-22 |
JPH02167296A (en) | 1990-06-27 |
NZ208441A (en) | 1988-01-08 |
DK288184D0 (en) | 1984-06-12 |
NO842394L (en) | 1984-12-17 |
PT78732B (en) | 1986-06-03 |
DK288184A (en) | 1984-12-16 |
GR82210B (en) | 1984-12-13 |
NO160521C (en) | 1989-04-26 |
DK166729B1 (en) | 1993-07-05 |
FI842395A (en) | 1984-12-16 |
IE57620B1 (en) | 1993-02-10 |
HU191131B (en) | 1987-01-28 |
FI842395A0 (en) | 1984-06-13 |
IL72085A0 (en) | 1984-10-31 |
EP0129499A3 (en) | 1985-10-09 |
DD218624A5 (en) | 1985-02-13 |
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