DE1047199B - Process for the preparation of a 17 ‡, 21-dioxy or 17 ‡ -oxy-21-acyloxy-1,4-pregnadiene-3,20-dione - Google Patents
Process for the preparation of a 17 ‡, 21-dioxy or 17 ‡ -oxy-21-acyloxy-1,4-pregnadiene-3,20-dioneInfo
- Publication number
- DE1047199B DE1047199B DEU3671A DEU0003671A DE1047199B DE 1047199 B DE1047199 B DE 1047199B DE U3671 A DEU3671 A DE U3671A DE U0003671 A DEU0003671 A DE U0003671A DE 1047199 B DE1047199 B DE 1047199B
- Authority
- DE
- Germany
- Prior art keywords
- pregnadiene
- oxy
- dione
- dioxy
- acyloxy
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 238000000034 method Methods 0.000 title claims description 8
- 230000008569 process Effects 0.000 title claims description 6
- 238000002360 preparation method Methods 0.000 title claims description 5
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 claims description 18
- 239000012285 osmium tetroxide Substances 0.000 claims description 10
- 229910000489 osmium tetroxide Inorganic materials 0.000 claims description 10
- 229910052739 hydrogen Inorganic materials 0.000 claims description 5
- 239000001257 hydrogen Substances 0.000 claims description 5
- 150000003431 steroids Chemical class 0.000 claims description 5
- 125000004432 carbon atom Chemical group C* 0.000 claims description 3
- 150000002431 hydrogen Chemical group 0.000 claims description 3
- 125000000468 ketone group Chemical group 0.000 claims description 3
- 239000000126 substance Substances 0.000 claims description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 2
- 150000001732 carboxylic acid derivatives Chemical class 0.000 claims 2
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 24
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 14
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 12
- 239000007800 oxidant agent Substances 0.000 description 9
- 150000001875 compounds Chemical class 0.000 description 8
- 229960004544 cortisone Drugs 0.000 description 8
- 239000011541 reaction mixture Substances 0.000 description 8
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 description 8
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 6
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 6
- 238000006243 chemical reaction Methods 0.000 description 6
- 230000001590 oxidative effect Effects 0.000 description 6
- 230000033444 hydroxylation Effects 0.000 description 5
- 238000005805 hydroxylation reaction Methods 0.000 description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
- 239000002253 acid Substances 0.000 description 4
- 230000032050 esterification Effects 0.000 description 4
- 238000005886 esterification reaction Methods 0.000 description 4
- 229960000890 hydrocortisone Drugs 0.000 description 4
- 235000010265 sodium sulphite Nutrition 0.000 description 4
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 3
- FUFLCEKSBBHCMO-UHFFFAOYSA-N 11-dehydrocorticosterone Natural products O=C1CCC2(C)C3C(=O)CC(C)(C(CC4)C(=O)CO)C4C3CCC2=C1 FUFLCEKSBBHCMO-UHFFFAOYSA-N 0.000 description 3
- MFYSYFVPBJMHGN-ZPOLXVRWSA-N Cortisone Chemical compound O=C1CC[C@]2(C)[C@H]3C(=O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 MFYSYFVPBJMHGN-ZPOLXVRWSA-N 0.000 description 3
- MFYSYFVPBJMHGN-UHFFFAOYSA-N Cortisone Natural products O=C1CCC2(C)C3C(=O)CC(C)(C(CC4)(O)C(=O)CO)C4C3CCC2=C1 MFYSYFVPBJMHGN-UHFFFAOYSA-N 0.000 description 3
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 239000003960 organic solvent Substances 0.000 description 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 2
- MYMOFIZGZYHOMD-UHFFFAOYSA-N Dioxygen Chemical compound O=O MYMOFIZGZYHOMD-UHFFFAOYSA-N 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- 150000008065 acid anhydrides Chemical class 0.000 description 2
- 239000003470 adrenal cortex hormone Substances 0.000 description 2
- 230000031709 bromination Effects 0.000 description 2
- 238000005893 bromination reaction Methods 0.000 description 2
- 239000003054 catalyst Substances 0.000 description 2
- 229960003290 cortisone acetate Drugs 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 230000008030 elimination Effects 0.000 description 2
- 238000003379 elimination reaction Methods 0.000 description 2
- 150000002148 esters Chemical class 0.000 description 2
- 238000001704 evaporation Methods 0.000 description 2
- 230000008020 evaporation Effects 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 239000012433 hydrogen halide Substances 0.000 description 2
- 229910000039 hydrogen halide Inorganic materials 0.000 description 2
- 238000005984 hydrogenation reaction Methods 0.000 description 2
- 125000001820 oxy group Chemical group [*:1]O[*:2] 0.000 description 2
- VLTRZXGMWDSKGL-UHFFFAOYSA-N perchloric acid Chemical compound OCl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-N 0.000 description 2
- XOFYZVNMUHMLCC-ZPOLXVRWSA-N prednisone Chemical compound O=C1C=C[C@]2(C)[C@H]3C(=O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 XOFYZVNMUHMLCC-ZPOLXVRWSA-N 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- RCIAVJSQHVNHMO-FCMAGTKHSA-N (8s,9s,10r,13s,14s)-17-ethylidene-10,13-dimethyl-7,8,9,11,12,14,15,16-octahydro-6h-cyclopenta[a]phenanthren-3-one Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CCC(=CC)[C@@]1(C)CC2 RCIAVJSQHVNHMO-FCMAGTKHSA-N 0.000 description 1
- QPDURLVAZKHDHG-ZFNNOLHJSA-N 2-[(8S,9S,10R,13S,14S)-10,13-dimethyl-3,11-dioxo-6,7,8,9,12,14,15,16-octahydrocyclopenta[a]phenanthren-17-ylidene]ethyl acetate Chemical compound C(C)(=O)OCC=C1CC[C@H]2[C@@H]3CCC4=CC(C=C[C@]4(C)[C@H]3C(C[C@]12C)=O)=O QPDURLVAZKHDHG-ZFNNOLHJSA-N 0.000 description 1
- XVMSFILGAMDHEY-UHFFFAOYSA-N 6-(4-aminophenyl)sulfonylpyridin-3-amine Chemical compound C1=CC(N)=CC=C1S(=O)(=O)C1=CC=C(N)C=N1 XVMSFILGAMDHEY-UHFFFAOYSA-N 0.000 description 1
- 208000035143 Bacterial infection Diseases 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- ITRJWOMZKQRYTA-RFZYENFJSA-N Cortisone acetate Chemical compound C1CC2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@@](C(=O)COC(=O)C)(O)[C@@]1(C)CC2=O ITRJWOMZKQRYTA-RFZYENFJSA-N 0.000 description 1
- 201000004624 Dermatitis Diseases 0.000 description 1
- 206010012442 Dermatitis contact Diseases 0.000 description 1
- 206010017533 Fungal infection Diseases 0.000 description 1
- 208000031888 Mycoses Diseases 0.000 description 1
- AMQJEAYHLZJPGS-UHFFFAOYSA-N N-Pentanol Chemical compound CCCCCO AMQJEAYHLZJPGS-UHFFFAOYSA-N 0.000 description 1
- 208000025747 Rheumatic disease Diseases 0.000 description 1
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 1
- FMRLDPWIRHBCCC-UHFFFAOYSA-L Zinc carbonate Chemical compound [Zn+2].[O-]C([O-])=O FMRLDPWIRHBCCC-UHFFFAOYSA-L 0.000 description 1
- 238000002835 absorbance Methods 0.000 description 1
- 229960000583 acetic acid Drugs 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 230000010933 acylation Effects 0.000 description 1
- 238000005917 acylation reaction Methods 0.000 description 1
- 230000001548 androgenic effect Effects 0.000 description 1
- HOPRXXXSABQWAV-UHFFFAOYSA-N anhydrous collidine Natural products CC1=CC=NC(C)=C1C HOPRXXXSABQWAV-UHFFFAOYSA-N 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 239000007900 aqueous suspension Substances 0.000 description 1
- 206010003246 arthritis Diseases 0.000 description 1
- 230000001580 bacterial effect Effects 0.000 description 1
- 208000022362 bacterial infectious disease Diseases 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- PPTSBERGOGHCHC-UHFFFAOYSA-N boron lithium Chemical compound [Li].[B] PPTSBERGOGHCHC-UHFFFAOYSA-N 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- UTBIMNXEDGNJFE-UHFFFAOYSA-N collidine Natural products CC1=CC=C(C)C(C)=N1 UTBIMNXEDGNJFE-UHFFFAOYSA-N 0.000 description 1
- 208000010247 contact dermatitis Diseases 0.000 description 1
- 239000006071 cream Substances 0.000 description 1
- 125000004122 cyclic group Chemical group 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 210000005069 ears Anatomy 0.000 description 1
- 150000002081 enamines Chemical class 0.000 description 1
- 150000002084 enol ethers Chemical class 0.000 description 1
- 239000003925 fat Substances 0.000 description 1
- 239000012362 glacial acetic acid Substances 0.000 description 1
- 230000003054 hormonal effect Effects 0.000 description 1
- 229940088597 hormone Drugs 0.000 description 1
- 239000005556 hormone Substances 0.000 description 1
- 229960001067 hydrocortisone acetate Drugs 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 239000012442 inert solvent Substances 0.000 description 1
- 208000018937 joint inflammation Diseases 0.000 description 1
- 239000012280 lithium aluminium hydride Substances 0.000 description 1
- -1 lithium aluminum hydride Chemical compound 0.000 description 1
- 239000006210 lotion Substances 0.000 description 1
- 239000000155 melt Substances 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 150000004967 organic peroxy acids Chemical class 0.000 description 1
- HLVZJMOSXKGJRG-UHFFFAOYSA-N osmium oxolane Chemical compound [Os].O1CCCC1 HLVZJMOSXKGJRG-UHFFFAOYSA-N 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 229940049953 phenylacetate Drugs 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 239000012429 reaction media Substances 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 230000000552 rheumatic effect Effects 0.000 description 1
- 206010039073 rheumatoid arthritis Diseases 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- DUIOPKIIICUYRZ-UHFFFAOYSA-N semicarbazide Chemical compound NNC(N)=O DUIOPKIIICUYRZ-UHFFFAOYSA-N 0.000 description 1
- 150000007659 semicarbazones Chemical group 0.000 description 1
- GFYHSKONPJXCDE-UHFFFAOYSA-N sym-collidine Natural products CC1=CN=C(C)C(C)=C1 GFYHSKONPJXCDE-UHFFFAOYSA-N 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 238000004448 titration Methods 0.000 description 1
- 238000005809 transesterification reaction Methods 0.000 description 1
- 229910000010 zinc carbonate Inorganic materials 0.000 description 1
- 235000004416 zinc carbonate Nutrition 0.000 description 1
- 239000011667 zinc carbonate Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J5/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane and substituted in position 21 by only one singly bound oxygen atom, i.e. only one oxygen bound to position 21 by a single bond
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Steroid Compounds (AREA)
Description
Verfahren zur Herstellung eines 17a,21-Dtoxy- oder 1'7a-Oxy-21 -acyloxy-1,4-pregnadien-3,20-dions Die vorliegende Erfindung bezieht sich auf ein Verfahren zur Herstellung von d- 11-Desoxyhydrocortison, d 1-Hydrocortison und d 1-Cortison sowie deren 21-Estern durch oxydative Hydroxylierung von 11-Oxy,21-acyloxy-1,4,17(20-pregnatrien-3-onen nach folgendem Reaktionsschema in welchem R Wasserstoff, einen fl-ständigen Oxy- oder Ketosauerstoff, Ac den Acylrest einer organischen Carbongruppesäu.re mit vorzugsweise 1 bis einschließlich 8Kohlenstoffatomen und R' Wasserstoff oder das gleiche wie Ac bedeutet.Process for the preparation of a 17a, 21-deoxy- or 1'7a-oxy-21-acyloxy-1,4-pregnadiene-3,20-dione. The present invention relates to a process for the preparation of d-11-deoxyhydrocortisone; 1-hydrocortisone and d 1-cortisone and their 21-esters by oxidative hydroxylation of 11-oxy, 21-acyloxy-1,4,17 (20-pregnatrien-3-ones according to the following reaction scheme in which R is hydrogen, an oxy or keto oxygen in the position, Ac is the acyl radical of an organic carbon group acid with preferably 1 to 8 carbon atoms inclusive and R 'is hydrogen or the same as Ac.
41-Cortison und dessen 21-Ester besitzen eine modifizierte Nebennierenrindenhormonwirksamkeit, wobei die Wirksamkeit der 21-Ester, z. B. hinsichtlich verlängerter Wirksamkeit, verstärkter Wirksamkeit bei bestimmter Verabreichung, größerer Öl- und/oder Wasserlöslichkeit, verbessertem Geschmack, größerer Stabilität, niedrigerem Schmelzpunkt usw. etwas anderes ist. Diese Verbindungen haben starke entzündungswidrige Wirkung und stellen wertvolle Mittel zur Behandlung der Arthritis rheumatica dar. Außerdem besitzen sie Eigenschaften, die Cortison und dessen Ester gewöhnlich nicht aufweisen, z. B. androgene Wirksamkeit.41-cortisone and its 21-ester have a modified adrenal cortex hormone activity, the effectiveness of the 21-ester, e.g. B. in terms of extended effectiveness, increased effectiveness with certain administration, greater oil and / or water solubility, improved taste, greater stability, lower melting point, etc. something other is. These compounds have potent anti-inflammatory effects and pose valuable agents for the treatment of rheumatoid arthritis. Also own they have properties that cortisone and its esters usually do not have, e.g. B. Androgenic Effectiveness.
Die Wirkung der erfindungsgemäß herstellbaren Verbindungen ist in manchen Fällen 10mal so groß wie die eines Rheumamittels, das keine bedeutende Salz zurückhaltende Wirkung besitzt. Außerdem weicht die Wirkungsbreite der erfindungsgemäß herstellbaren Verbindungen in überraschender Weise von der des Cortisons und dessen Estern ab. Ebenso unterscheidet sich auch der Wirkungsgrad des natürlichen Hormons von dem der 41-Verbindung. Ferner sind die erfindungsgemäß herstellbaren neuen Verbindungen häufig zur Behandlung von rheumatischen und anderen Gelenkentzündungen geeignet, bei denen die therapeutische Behandlung mit Cortison oder Cortisonacetat keine Besserung bewirkt. Die neuen AI-Verbindungen, insbesondere 41-Cortison, d l-Hydrocortison, d l-Cortisonacetat und d 1-Hydrocortisonacetat, eignen sich ferner zur Behandlung von Menschen und wertvollen Haustieren, die z. B. an Entzündungen der Haut, Nase, Ohren und Augen leiden, die durch Bakterien- oder Pilzinfektionen, Kontaktdermatitis und schlechtes physiologisches Anpassungsvermögen verursacht wurden. Die erfindungsgemäß herstellbaren Verbindungen werden insbesondere in Form pharmazeutischer Zubereitungen und Mischungen, wie von Salben, Lotionen, Fetten, Cremes, wäßrigen Suspensionen usw., die für den äußerlichen Gebrauch bestimmt sind, verwendet.The effect of the compounds which can be prepared according to the invention is in In some cases 10 times as large as that of a rheumatoid drug that does not contain significant salt has a restrained effect. In addition, the range of action deviates from that according to the invention compounds which can be produced in a surprising manner from that of cortisone and its Esters. The degree of effectiveness of the natural hormone also differs from that of the 41 connection. The novel compounds which can be prepared according to the invention are also included often suitable for the treatment of rheumatic and other joint inflammations, for whom therapeutic treatment with cortisone or cortisone acetate does not improve causes. The new AI compounds, especially 41-cortisone, d l-hydrocortisone, d l-cortisone acetate and d 1-hydrocortisone acetate, are also suitable for treatment of people and valuable pets that z. B. inflammation of the skin, nose, Ears and eyes suffer from bacterial or fungal infections, contact dermatitis and poor physiological adaptability. According to the invention Preparable compounds are in particular in the form of pharmaceutical preparations and mixtures, such as of ointments, lotions, fats, creams, aqueous suspensions etc., which are intended for external use.
Die Verbindungen gemäß der Erfindung, d. h. 41-11-Desoxyhydrocortison, 41-Hydrocortison, 41-Cortison und deren 21-Ester, z. B. das 21-Formiat, -Acetat, -Propionat, -Butyrat, -Cyclopentylpropionat, -Dimethylacetat, -Trimethylacetat, -Phenylacetat, -Phenylpropionat, -Succinat, -Benzoat- u: dgl., lassen sich durch Umsetzung eines 21-Acyloxy-1,4,17(20)-pregnatrien-3-ons (I) mit Wasserstoffsuperoxyd oder einer Substanz, die Wasserstoffperoxyd zu entwickeln. vermag und einer kleinen Menge Osmiumtetröxyd herstellen. Die 21-Acyl oxy-1,4,17(20)-pregnatrien-3-öne werden- aus den nach dem- Verfahren des deutschen Patents 1005 065 hergestellten 3-Keto-1,4,17(20)-pregnatrien 21-carboxysteroiden durch Schützen der Ketogruppe durch - Bildung eines Enoläthers, eines cyclischen Ketals oder vorzugsweise eines Pyrrolidylenamins, Reduktion der 21ständigen Carboxylgruppe mit Lithium-Aluminium-Hydrid, Lithium-Bor-Hydrid od. dgl., Hydrolyse der Enamin- oder sonstigen in 3-Stellung befindlichen Gruppe, vorzugsweise mit Säure und Acylierung der 21ständigen Oxygruppe erhalten. Die erfindungsgemäß hergestellten Verbindungen (II) sind selbst aktiv und können auf bekanntem Wege in physiologisch wirksame Nebennierenrindenhormone umgewandelt werden, z. B. durch Hydrierung der Doppelbindungen, Bromierung der 4-Stellung und anschließende Halogenwasserstoff-Abspaltung. Das gemäß der Erfindung erhältliche d 1-11-Desoxyhydrocortison kann durch Einführung von Sauerstoff in 11-Stellung, z. B. auf mikrobiologischem Wege auch in dl-Hydrocortison und dl-Cortison übergeführt werden.The compounds according to the invention, i.e. H. 41-11-deoxyhydrocortisone, 41-hydrocortisone, 41-cortisone and their 21-esters, e.g. B. the 21-formate, -acetate, -Propionate, -butyrate, -cyclopentylpropionate, -dimethylacetate, -trimethylacetate, -Phenyl acetate, -phenylpropionate, -Succinate, -Benzoate- and the like., Leave by reacting a 21-acyloxy-1,4,17 (20) -pregnatrien-3-one (I) with hydrogen peroxide or a substance that can develop hydrogen peroxide. able and a small one Prepare amount of osmium tetrahydrofuran. The 21-acyl oxy-1,4,17 (20) -pregnatriene-3-tones are- from the 3-keto-1,4,17 (20) -pregnatriene produced by the process of German patent 1005 065 21-carboxysteroids by protecting the keto group through - formation of an enol ether, a cyclic ketal or preferably a pyrrolidyleneamine, reduction of the 21-position carboxyl group with lithium aluminum hydride, lithium boron hydride or. Like., hydrolysis of the enamine or other group in the 3-position, preferably obtained with acid and acylation of the 21-position oxy group. According to the invention Compounds (II) prepared are themselves active and can in a known manner converted into physiologically active adrenal cortex hormones, e.g. B. by Hydrogenation of the double bonds, bromination of the 4-position and subsequent elimination of hydrogen halide. The d 1-11-deoxyhydrocortisone obtainable according to the invention can by introduction of oxygen in the 11-position, e.g. B. microbiologically also in dl-hydrocortisone and dl-cortisone are transferred.
Bei der erfindungsgemäßen oxydativen Hydroxylierung können Wasserstoffsuperoxyd oder Substanzen als Oxydationsmittel verwendet werden, die Wasserstoffsuperoxyd entwickeln, z. B. Diallkylperoxyde, organische Persäuren oder Perchlorsäure. Vorzugsweise verwendet man Wasserstoffsuperoxyd als Oxydationsmittel.In the oxidative hydroxylation according to the invention, hydrogen peroxide can be used or substances are used as oxidants, the hydrogen peroxide develop, e.g. B. Dialkylperoxde, organic peracids or perchloric acid. Preferably hydrogen peroxide is used as an oxidizing agent.
Zur Durchführung der oxydativen Hydroxylierung löst man das Ausgangssteroid vorteilhaft in einem inerten organischen Lösungsmittel, z. B. tertiärem Butylalkohol, Diäthyläther, Tetrahydrofuran od. dgl., und mischt anschließend das Osmiumtetroxyd und das Oxydationsmittel zu. Das Osmiumtetroxyd wird vorteilhaft nach Zusatz des Oxydationsmittels zugesetzt; diese Art der Zugabe ist jedoch nicht unbedingt erforderlich. Ebenso setzt man das Osrniumtetroxyd und das Oxydationsmittel vorzugsweise im Lösungsmittel, das als Reaktionsmedium verwendet wird, zu.To carry out the oxidative hydroxylation, the starting steroid is dissolved advantageously in an inert organic solvent, e.g. B. tertiary butyl alcohol, Diethyl ether, tetrahydrofuran or the like, and then mixes the osmium tetroxide and the oxidizer too. The osmium tetroxide is advantageous after adding the Oxidizing agent added; however, this type of addition is not absolutely necessary. Likewise, the osmium tetroxide and the oxidizing agent are preferably placed in the solvent, which is used as the reaction medium.
Die Menge des zur Reaktion verwendeten Osmiumtetroxyds kann weitgehend variiert werden, z. B. von etwa 0,2 bis 0,001 Moläquivalent. Vorteilhaft verwendet man jedoch nicht mehr als 0,05 Moläquivalente.The amount of osmium tetroxide used for the reaction can largely can be varied, e.g. B. from about 0.2 to 0.001 molar equivalent. Used to advantage however, no more than 0.05 molar equivalents.
Die zur Herstellung eines 17-Oxy 20-keto-21-acyloxysteroids theoretisch erforderliche Menge Oxydationsmittel beträgt 2 Oxydationsäquivalente pro Mol gebildeten Osmiatesters. Es wurde jedoch gefunden, daß zur Erzielung einer vollständigen Reaktion gewöhnlich mehr als die theoretische Menge Oxydationsmittel benötigt wird. Zur Erzielung optimaler Ergebnisse ist es daher gewöhnlich erforderlich, einen Überschuß an Oxydationsmittel zu verwenden. Der Verlauf der oxydativen Hydroxylierung kann leicht durch Titration des in gleichen Proben noch vorhandenen Oxydationsmittels bestimmt werden.Theoretically for the preparation of a 17-oxy 20-keto-21-acyloxysteroids required amount of oxidizing agent is 2 oxidizing equivalents per mole formed Osmiatester. However, it has been found that to achieve a complete response usually more than the theoretical amount of oxidizing agent is required. To achieve therefore, it is usually necessary to use an excess of the oxidizing agent for optimal results to use. The course of the oxidative hydroxylation can easily be determined by titration the oxidizing agent still present in the same samples can be determined.
Die Reaktionstemperatur für die oxydative Hydroxylierung liegt gewöhnlich zwischen etwa 15 und etwa 30°C; es können jedoch auch höhere oder niedrigere Temperaturen, z. B. zwischen etwa -10 und etwa 70°C, angewandt werden. An Stelle der obenerwähnten Lösungsmittel kann jedes inerte Lösungsmittel verwendet werden, das die Reaktionsteilnehmer zu lösen vermag. Geeignete Lösungsmittel sind Diäthyläther, Dioxan, Isopropylalkohol, Tetrahydrofuran, tert. Butylalkohol, tert. Amylalkohol, Äthanol und Methanol.The reaction temperature for the oxidative hydroxylation is usually between about 15 and about 30 ° C; However, higher or lower temperatures can also be used, z. B. between about -10 and about 70 ° C, can be used. Instead of the above Solvents, any inert solvent can be used that the reactants able to solve. Suitable solvents are diethyl ether, dioxane, isopropyl alcohol, Tetrahydrofuran, tert. Butyl alcohol, tert. Amyl alcohol, ethanol and methanol.
Die nachstehenden Beispiele erläutern das erfindungsgemäße Verfahren. Beispiel 1 11ß,17a,21-Trioxy-1,4-pregnadien-3,20-dion (d 1-17a-Oxycorticosteron) Einer Suspension aus 0,124 g (0,00033 Mol) 11ß-Oxy 21-acetoxy=1,4,17(20)-pregnatrien-3-on in 2 ccm tert. Butylalkohol setzte man unter Rühren 0,26 ccm einer 2,6molaren Lösung von Wasserstoffsuperoxyd in tert. Butylalkohol und 0,30 ccm einer Lösung von 1,00 g Osmiumtetroxyd in 100 ccm tert. Butylalkohol zu. Während der nächsten 30 Stunden wurden dem Reaktionsgemisch weitere 0,50 ccm der oben beschriebenen Osmiumtetroxydlösung zugesetzt. Nach 4 Stunden wurde das Reaktionsgemisch dunkel und homogen. Das Reaktionsgemisch wurde gerührt und weitere 84 Stunden bei Raumtemperatur belassen. Anschließend setzte man Wasser und Methylenchlorid zu. Das ganze wurde zur Entfernung der organischen Lösungsmittel bei vermindertem Druck destilliert, das Produkt mit Methylenchlorid aus dem Rückstand extrahiert und anschließend das Extraktionsmittel durch Abdampfen entfernt. Der Rückstand wurde nach dem Auflösen in einer Mischung aus 5 ccm Methanol und 1 ccm einer Lösung aus 0,30 g Natriumsulfit in 5 ccm Wasser 30 Minuten auf einem Dampfbad erhitzt. Das 11ß,17a,21-Trioxy-1,4-pregnadien-3,20-dion wurde durch Extraktion mit Methylenchlorid abgetrennt und das Methylenchlorid anschließend durch Destillation im Vakuum entfernt. Der Rückstand bestand aus llß,17a,21-Trioxy-1,4-pregnadien-3,20-dion (dl-17a-Oxycorticosteron) 11ß,17a-Dioxy-21-acetoxy-1,4-pregnadien-3,20-dion sowie Ilß,17a,20,21-Tetraoxy-1,4-pregnadien-3-on. Dasreine llß,17a,21-Trioxy-1,4-pregnadien-3,20-dion schmilzt bei 232 bis 236,5°C; [a] ö=100° (in Dioxan).The following examples illustrate the process according to the invention. Example 1 11β, 17a, 21-trioxy-1,4-pregnadiene-3,20-dione (d 1-17a-oxycorticosterone) A suspension of 0.124 g (0.00033 mol) 11β-oxy 21-acetoxy = 1.4 , 17 (20) -pregnatrien-3-one in 2 ccm tert. Butyl alcohol was added with stirring 0.26 ccm of a 2.6 molar solution of hydrogen peroxide in tert. Butyl alcohol and 0.30 ccm of a solution of 1.00 g of osmium tetroxide in 100 ccm of tert. Butyl alcohol too. Over the next 30 hours, a further 0.50 cc of the osmium tetroxide solution described above was added to the reaction mixture. After 4 hours the reaction mixture became dark and homogeneous. The reaction mixture was stirred and left at room temperature for a further 84 hours. Then water and methylene chloride were added. The whole was distilled to remove the organic solvents under reduced pressure, the product was extracted from the residue with methylene chloride and then the extractant was removed by evaporation. The residue, after being dissolved in a mixture of 5 cc of methanol and 1 cc of a solution of 0.30 g of sodium sulfite in 5 cc of water, was heated on a steam bath for 30 minutes. The 11β, 17a, 21-trioxy-1,4-pregnadiene-3,20-dione was separated off by extraction with methylene chloride and the methylene chloride was then removed by distillation in vacuo. The residue consisted of 11ß, 17a, 21-trioxy-1,4-pregnadiene-3,20-dione (dl-17a-oxycorticosterone) 11ß, 17a-dioxy-21-acetoxy-1,4-pregnadiene-3,20- dion and Ilß, 17a, 20,21-tetraoxy-1,4-pregnadien-3-one. The pure llß, 17a, 21-trioxy-1,4-pregnadiene-3,20-dione melts at 232 to 236.5 ° C; [a] δ = 100 ° (in dioxane).
Die Ausbeute an llß,17a,21-Trioxy-1,4-pregnadien-3,20-dion wird verbessert, wenn man dem verwendeten Reaktionsgemisch etwa 2 bis 7 Moläquivalent Pyridin (bezogen auf das Ausgangssteroid) zusetzt.The yield of llß, 17a, 21-trioxy-1,4-pregnadiene-3,20-dione is improved, if you add about 2 to 7 molar equivalents of pyridine (based on on the starting steroid).
DurchVeresterung der21-Oxygruppedes 11ß,17a,21-Trioxy-1,4-pregnadien-3,20-dion, z. B. durch Umsetzung mit einem entsprechenden Säureanhydrid, Säurechlorid oder -bromid, mit Säure in Gegenwart eines Veresterungskatalysators durchUmsetzungusw.erhält man l lß,17a-Dioxy-21-acyloxy-1,4-pregnadien-3,20-dione.By esterification of the 21-oxy group of 11ß, 17a, 21-trioxy-1,4-pregnadiene-3,20-dione, z. B. by reaction with an appropriate acid anhydride, acid chloride or -bromide, obtained with acid in the presence of an esterification catalyst by reaction, etc. one lß, 17a-dioxy-21-acyloxy-1,4-pregnadiene-3,20-diones.
Beispiel 2 1 lß,17a-Dioxy-21-acetoxy-1,4-pregnadien-3,20-dion Arbeitet man genau wie im Beispiel 1, zersetzt das Reaktionsgemisch jedoch innerhalb von 30 Minuten bei Raumtemperatur mit wäßrigem Natriumsulfit, so erhält man llß,17a-Dioxy-21-acetoxy-1,4-pregnadien-3,20-dion. Beispiel 3 17a,21-Dioxy-1,4-pregnadien-3,11,20-trion (d 1-Cortison) Einer Suspension von 0,124 g (0,00033 Mol) 21-Acetoxy-1,4,17(20)-pregnatrien-3,11-dion in 2 ccm tert. ButylalkoholsetztemanunterRühren0,26 ccmeiner2,6molaren Lösung von Wasserstoffsuperoxyd in tert. Butylalkohol und 0,30 ccm einer Lösung von 1,00 g Osmiumtetroxyd in 100 ccm tert. Butylalkohol zu, während der nächsten 30 Stunden wurden dem Reaktionsgemisch weitere 0,50 ccm der oben beschriebenen Osmiumtetroxydlösung zugesetzt. Nach 4 Stunden färbte sich das Reaktionsgemisch dunkel und wurde homogen. Das Reaktionsgemisch wurde gerührt und weitere 84 Stunden bei Raumtemperatur belassen; danach setzte man Wasser und Methylencldorid zu. Das Ganze wurde zur Entfernung der organischen Lösungsmittel bei vermindertem Druck destilliert und das Produkt aus dem Rückstand mit Methylenchlorid extrahiert. Anschließend wurde das Extraktionsmittel durch Verdampfen entfernt. Der Rückstand wurde nach dem Auflösen in einem Gemisch aus 5 ccm Methanol und 1 ccm einer Lösung aus 0,30 g Natriumsulfit in 5 ccm Wasser 30 Minuten auf einem Dampfbad erhitzt. Das 17a,21-Dioxy-1,4-pregnadien-3,11,20-trion wurde durch Extraktion mit Methylenchlorid abgetrennt. Das Methylenchlorid wurde anschließend im Vakuum abdestilliert. Der Rückstand bestand aus 17a,21-Dioxy-1,4-pregnadien-3,11,20-trion (41-Cortison), 17a-Oxy-21-acetoxy-1,4-pregnadien-3,11,20-trion sowie 17a,20,21-Trioxy-1,4-pregnadien-3,11-dion. Das 17a-Oxy-21-acetoxy-1,4-pregnadien-3,11,20-trion schmolz bei 229 bis 229,5°C, besaß eine spezifische Drehung [a] D von -f- 169° in Dioxan und eine Extinktion E 24o von 15425.Example 2 1β, 17a-Dioxy-21-acetoxy-1,4-pregnadiene-3,20-dione works exactly as in Example 1, but the reaction mixture decomposes within With aqueous sodium sulfite for 30 minutes at room temperature, llß, 17a-dioxy-21-acetoxy-1,4-pregnadiene-3,20-dione is obtained. Example 3 17a, 21-Dioxy-1,4-pregnadiene-3,11,20-trione (d 1-Cortisone) in a suspension of 0.124 g (0.00033 mol) of 21-acetoxy-1,4,17 (20) -pregnatriene-3,11-dione in 2 ccm of tert. Butyl alcohol was added, with stirring, to 0.26 cc of a 2.6 molar solution of hydrogen peroxide in tert. Butyl alcohol and 0.30 cc of a solution of 1.00 g of osmium tetroxide in 100 ccm tert. Butyl alcohol was added to the reaction mixture over the next 30 hours another 0.50 ccm of the osmium tetroxide solution described above was added. After 4 hours the reaction mixture turned dark in color and became homogeneous. The reaction mixture was stirred and left at room temperature for a further 84 hours; then continued one adds water and methylene chloride. The whole thing became a distance the organic solvent distilled under reduced pressure and the product from the residue extracted with methylene chloride. Subsequently, the extractant removed by evaporation. The residue was after dissolving in a mixture from 5 cc of methanol and 1 cc of a solution of 0.30 g of sodium sulfite in 5 cc of water Heated on a steam bath for 30 minutes. The 17a, 21-dioxy-1,4-pregnadiene-3,11,20-trione was separated by extraction with methylene chloride. The methylene chloride was then distilled off in vacuo. The residue consisted of 17a, 21-dioxy-1,4-pregnadiene-3,11,20-trione (41-cortisone), 17a-oxy-21-acetoxy-1,4-pregnadiene-3,11,20-trione and 17a, 20,21-trioxy-1,4-pregnadiene-3,11-dione. The 17a-oxy-21-acetoxy-1,4-pregnadiene-3,11,20-trione melted at 229 to 229.5 ° C, had a specific rotation [a] D of -f- 169 ° in dioxane and an absorbance E 24o of 15425.
Die Ausbeute an 17a,21-Dioxy -1,4-pregnadien-3,11,20-trion wird verbessert, wenn man dem Reaktionsgemisch etwa 2 bis 7 Moläquivalente Pyridin (bezogen auf das Ausgangssteroid), zusetzt.The yield of 17a, 21-dioxy -1,4-pregnadiene-3,11,20-trione is improved, if you add about 2 to 7 molar equivalents of pyridine (based on the Starting steroid), adds.
Durch Veresterung der 21-Oxygruppe des 17a,21-Dioxy-1,4-pregnadien-3,11,20-trions, z. B. durch Umsetzung mit einem entsprechenden Säureanhydrid, Säurechlorid oder -bromid, mit Säure in Gegenwart eines Veresterungskatalysators, durch Umesterung usw. erhält man 17a-Oxy-21-acyloxy-1,4-pregnadien-3,11,20-trione.By esterification of the 21-oxy group of 17a, 21-dioxy-1,4-pregnadiene-3,11,20-trione, z. B. by reaction with an appropriate acid anhydride, acid chloride or bromide, with acid in the presence of an esterification catalyst, by transesterification etc., 17a-oxy-21-acyloxy-1,4-pregnadiene-3,11,20-trione is obtained.
Beispiel 4 17a-Oxy-21-acetoxy-1,4-pregnadien-3,11,20-trion Arbeitet man genau wie im Beispiel 1, zersetzt das Reaktionsgemisch jedoch innerhalb von 30 Minuten bei Raumtemperatur mit wäßrigem Natriumsulfit, so erhält man 17a-Oxy-21-acetoxy-1,4-pregnadien-3,11,20-trion.Example 4 17a-Oxy-21-acetoxy-1,4-pregnadiene-3,11,20-trione works exactly as in Example 1, but the reaction mixture decomposes within With aqueous sodium sulfite for 30 minutes at room temperature, 17a-oxy-21-acetoxy-1,4-pregnadiene-3,11,20-trione is obtained.
Durch Hydrierung von 17a-Oxy-21-acetoxy-1,4-pregnadien-3,11,20-trion oder 11ß,17a-Dioxy-21-acetoxy-1,4-pregnadien-3,20-dion mit Palladium auf Zinkcarbonat in Methanol erhält man 17a-Oxy-21-acetoxypregnan-3,11,20-trion bzw. 11ß,17a-Dioxy-21-acetoxypregnan-3,20-dion, die durch Bromierung mit Brom in Eisessig und Pyridin in 4-Brom-17a-oxy-21-acetoxypregnan-3,11,20-trion bzw. 4-Brom-11ß,17a-dioxy-21-acetoxypregnan-3,20-dion übergeführt werden. Die Halogenwasserstoffabspaltung mit Pyridin, Collidin oder Semicarbazid und anschließende Zersetzung des Semicarbazon führt in üblicher Weise zum 17a-Oxy-21-acetoxy-4-pregnan-3,11,20-trion bzw. 11ß,17a-Dioxy-21-acetoxy-4-pregnen-3,20-dion.By hydrogenation of 17a-oxy-21-acetoxy-1,4-pregnadiene-3,11,20-trione or 11β, 17a-Dioxy-21-acetoxy-1,4-pregnadiene-3,20-dione with palladium on zinc carbonate 17α-oxy-21-acetoxypregnane-3,11,20-trione or 11β, 17a-dioxy-21-acetoxypregnane-3,20-dione are obtained in methanol, by bromination with bromine in glacial acetic acid and pyridine in 4-bromo-17a-oxy-21-acetoxypregnane-3,11,20-trione or 4-bromo-11ß, 17a-dioxy-21-acetoxypregnane-3,20-dione are converted. The elimination of hydrogen halide with pyridine, collidine or semicarbazide and subsequent decomposition of the semicarbazone leads in the usual way to 17a-oxy-21-acetoxy-4-pregnane-3,11,20-trione or 11β, 17a-dioxy-21-acetoxy-4-pregnen-3,20-dione.
Claims (3)
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US1047199XA | 1954-01-26 | 1954-01-26 |
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| DE1047199B true DE1047199B (en) | 1958-12-24 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DEU3671A Pending DE1047199B (en) | 1954-01-26 | 1954-12-10 | Process for the preparation of a 17 ‡, 21-dioxy or 17 ‡ -oxy-21-acyloxy-1,4-pregnadiene-3,20-dione |
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1954
- 1954-12-10 DE DEU3671A patent/DE1047199B/en active Pending
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