CH534674A - 9-alpha fluoro-16-fluoro methylene - pred - nisolone 21-oenanthate (i) - Google Patents
9-alpha fluoro-16-fluoro methylene - pred - nisolone 21-oenanthate (i)Info
- Publication number
- CH534674A CH534674A CH1648172A CH1648172A CH534674A CH 534674 A CH534674 A CH 534674A CH 1648172 A CH1648172 A CH 1648172A CH 1648172 A CH1648172 A CH 1648172A CH 534674 A CH534674 A CH 534674A
- Authority
- CH
- Switzerland
- Prior art keywords
- fluoro
- oenanthate
- fluoromethylene
- alpha
- prednisolone
- Prior art date
Links
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 10
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 9
- 239000000126 substance Substances 0.000 claims description 8
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 6
- 238000002360 preparation method Methods 0.000 claims description 6
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 claims description 4
- 239000003795 chemical substances by application Substances 0.000 claims description 4
- 230000002906 microbiologic effect Effects 0.000 claims description 4
- 238000000034 method Methods 0.000 claims description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 3
- 239000000706 filtrate Substances 0.000 claims description 2
- 229910052938 sodium sulfate Inorganic materials 0.000 claims description 2
- 235000011152 sodium sulphate Nutrition 0.000 claims description 2
- 239000002904 solvent Substances 0.000 abstract description 3
- 201000004681 Psoriasis Diseases 0.000 abstract description 2
- 230000032050 esterification Effects 0.000 abstract description 2
- 238000005886 esterification reaction Methods 0.000 abstract description 2
- 229960000890 hydrocortisone Drugs 0.000 abstract description 2
- 208000017520 skin disease Diseases 0.000 abstract description 2
- 239000002253 acid Substances 0.000 abstract 1
- 125000005907 alkyl ester group Chemical group 0.000 abstract 1
- 229960005205 prednisolone Drugs 0.000 abstract 1
- OIGNJSKKLXVSLS-VWUMJDOOSA-N prednisolone Chemical compound O=C1C=C[C@]2(C)[C@H]3[C@@H](O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 OIGNJSKKLXVSLS-VWUMJDOOSA-N 0.000 abstract 1
- 238000005809 transesterification reaction Methods 0.000 abstract 1
- 150000001875 compounds Chemical class 0.000 description 7
- 241000371644 Curvularia ravenelii Species 0.000 description 5
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- 230000000699 topical effect Effects 0.000 description 3
- 241000589151 Azotobacter Species 0.000 description 2
- 241000193830 Bacillus <bacterium> Species 0.000 description 2
- 241000577959 Calonectria Species 0.000 description 2
- 241000193386 Lysinibacillus sphaericus Species 0.000 description 2
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 2
- 241000203720 Pimelobacter simplex Species 0.000 description 2
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- 230000001028 anti-proliverative effect Effects 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 244000005700 microbiome Species 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- LQNUZADURLCDLV-UHFFFAOYSA-N nitrobenzene Chemical compound [O-][N+](=O)C1=CC=CC=C1 LQNUZADURLCDLV-UHFFFAOYSA-N 0.000 description 2
- 238000010998 test method Methods 0.000 description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- HZNVUJQVZSTENZ-UHFFFAOYSA-N 2,3-dichloro-5,6-dicyano-1,4-benzoquinone Chemical compound ClC1=C(Cl)C(=O)C(C#N)=C(C#N)C1=O HZNVUJQVZSTENZ-UHFFFAOYSA-N 0.000 description 1
- YLZOPXRUQYQQID-UHFFFAOYSA-N 3-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)-1-[4-[2-[[3-(trifluoromethoxy)phenyl]methylamino]pyrimidin-5-yl]piperazin-1-yl]propan-1-one Chemical compound N1N=NC=2CN(CCC=21)CCC(=O)N1CCN(CC1)C=1C=NC(=NC=1)NCC1=CC(=CC=C1)OC(F)(F)F YLZOPXRUQYQQID-UHFFFAOYSA-N 0.000 description 1
- UHPMCKVQTMMPCG-UHFFFAOYSA-N 5,8-dihydroxy-2-methoxy-6-methyl-7-(2-oxopropyl)naphthalene-1,4-dione Chemical compound CC1=C(CC(C)=O)C(O)=C2C(=O)C(OC)=CC(=O)C2=C1O UHPMCKVQTMMPCG-UHFFFAOYSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- 241000589220 Acetobacter Species 0.000 description 1
- 241000223600 Alternaria Species 0.000 description 1
- 241001273385 Boeremia lycopersici Species 0.000 description 1
- 241000222199 Colletotrichum Species 0.000 description 1
- 241000186216 Corynebacterium Species 0.000 description 1
- 241000190096 Cucurbitaria Species 0.000 description 1
- 241000723247 Cylindrocarpon Species 0.000 description 1
- 241000555695 Didymella Species 0.000 description 1
- 241000186811 Erysipelothrix Species 0.000 description 1
- 241000223218 Fusarium Species 0.000 description 1
- 239000001828 Gelatine Substances 0.000 description 1
- 241000896533 Gliocladium Species 0.000 description 1
- JYGXADMDTFJGBT-VWUMJDOOSA-N Hydrocortisone Natural products O=C1CC[C@]2(C)[C@H]3[C@@H](O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 JYGXADMDTFJGBT-VWUMJDOOSA-N 0.000 description 1
- 241000908271 Ilyonectria destructans Species 0.000 description 1
- 241000581650 Ivesia Species 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- 241000187654 Nocardia Species 0.000 description 1
- 241000190509 Ophiobolus Species 0.000 description 1
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 1
- 241000586779 Protaminobacter Species 0.000 description 1
- 241000589516 Pseudomonas Species 0.000 description 1
- 240000005319 Sedum acre Species 0.000 description 1
- 241000607720 Serratia Species 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 241000222646 Stereum Species 0.000 description 1
- 241000187747 Streptomyces Species 0.000 description 1
- 241000187389 Streptomyces lavendulae Species 0.000 description 1
- 241000601794 Trichothecium Species 0.000 description 1
- KXKVLQRXCPHEJC-UHFFFAOYSA-N acetic acid trimethyl ester Natural products COC(C)=O KXKVLQRXCPHEJC-UHFFFAOYSA-N 0.000 description 1
- 239000000443 aerosol Substances 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 125000001589 carboacyl group Chemical group 0.000 description 1
- 235000012000 cholesterol Nutrition 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 238000004040 coloring Methods 0.000 description 1
- 229940125904 compound 1 Drugs 0.000 description 1
- 125000000017 cortisol group Chemical group 0.000 description 1
- 239000006071 cream Substances 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 238000000855 fermentation Methods 0.000 description 1
- 230000004151 fermentation Effects 0.000 description 1
- 229960002650 fluprednidene acetate Drugs 0.000 description 1
- DEFOZIFYUBUHHU-IYQKUMFPSA-N fluprednidene acetate Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1CC(=C)[C@@](C(=O)COC(=O)C)(O)[C@@]1(C)C[C@@H]2O DEFOZIFYUBUHHU-IYQKUMFPSA-N 0.000 description 1
- 235000011389 fruit/vegetable juice Nutrition 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 150000002367 halogens Chemical class 0.000 description 1
- 235000015243 ice cream Nutrition 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 239000006210 lotion Substances 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 235000019271 petrolatum Nutrition 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 230000000750 progressive effect Effects 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- QDLAHUFDHRJWOE-UHFFFAOYSA-N tert-butyl 3-nitropyrrolidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCC([N+]([O-])=O)C1 QDLAHUFDHRJWOE-UHFFFAOYSA-N 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- -1 tinctures Substances 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
- A61K31/573—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone substituted in position 21, e.g. cortisone, dexamethasone, prednisone or aldosterone
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
-
- 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
-
- H—ELECTRICITY
- H01—ELECTRIC ELEMENTS
- H01R—ELECTRICALLY-CONDUCTIVE CONNECTIONS; STRUCTURAL ASSOCIATIONS OF A PLURALITY OF MUTUALLY-INSULATED ELECTRICAL CONNECTING ELEMENTS; COUPLING DEVICES; CURRENT COLLECTORS
- H01R4/00—Electrically-conductive connections between two or more conductive members in direct contact, i.e. touching one another; Means for effecting or maintaining such contact; Electrically-conductive connections having two or more spaced connecting locations for conductors and using contact members penetrating insulation
- H01R4/02—Soldered or welded connections
-
- H—ELECTRICITY
- H01—ELECTRIC ELEMENTS
- H01R—ELECTRICALLY-CONDUCTIVE CONNECTIONS; STRUCTURAL ASSOCIATIONS OF A PLURALITY OF MUTUALLY-INSULATED ELECTRICAL CONNECTING ELEMENTS; COUPLING DEVICES; CURRENT COLLECTORS
- H01R9/00—Structural associations of a plurality of mutually-insulated electrical connecting elements, e.g. terminal strips or terminal blocks; Terminals or binding posts mounted upon a base or in a case; Bases therefor
- H01R9/22—Bases, e.g. strip, block, panel
- H01R9/28—Terminal boards
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Medicinal Chemistry (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Organic Chemistry (AREA)
- Steroid Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Cpd. (I) is used to treat skin diseases (e.g. psoriasis). It is prepd. by esterification or transesterification of the prednisolone or lower alkyl ester thereof, or by treating the 21-oenanthate of 9-alpha-fluoro-11 beta-21-dihydroxy-16alpha, 17 alpha-epoxy-16 beta-fluoromethyl-1,4-pregnadiene-3,20-dione with a hydrohalic acid (not HI) in an anhydrous solvent, or by dehydrogenating chemically or microbiologically 9 alpha-fluoro-16-fluoromethylene-hydrocortisone.
Description
Es wurde gefunden, dass das bisher unbekannte 9cc -Fluor- 1 6-tluormethylen-prednisolon-21 -önonthat (I) etwa 4,5mal stärker antiproliferativ wirkt als das bekannte Handeispräparat Fluprednyliden -21 - acetat (Mäuseschwanztest; Testmethodik vgl. Arzneimittelforschung, Band 18, Seite 19 ff. (1968). Andererseits weist I einige in diesem Zusammenhang unerwünschte Nebenwirkungen nur in geringerem Masse auf. So wirkt I z. B. etwa 2,4mal schwächer glyconeogenetisch und etwa 2,2mal schwächer nebennierengewichtshenlmend als Fluprednyliden-21-acetat (Testmethodik vgl.
Arzneimittelfor schung, Band 18, Seite 15 ff. (1968)1. I ist daher in besonderem Masse als vorzugsweise topisch (lokal) anwendbares Heilmittel geeignet, beispielsweise zur Behandlung von Hautkrankheiten (z.B. Psoriasis).
Gegenstand der Erfindung ist ein Verfahren zur Herstellung der Verbindung I, das darin besteht, dass man 9cc-Fluor-16-fluormethylen-hydrocortison-21-önanthat mit chemischen oder mikrobiologischen, in 1(2)-Stellung dehydrierenden Mitteln behandelt.
Als chemisches Dehydrierungsmittel eignet sich insbesondere 2,3 > 1Dichlor-5,6-dicyan-benzochinon, das man zweckmässig in Gegenwart eines Lösungsmittels wie Äthanol, Butanol, tert.-Butanol, tert.Butylessigsäuremethylester, Methylacetat, Äthylacetat, Tetrahydrofuran, Dioxan, Essigsäure, Benzol, Aceton, verwendet. Es ist vorteilhaft, dem Reaktionsgemisch geringe Mengen Nitrobenzol zuzumischen. Die Reaktionszeiten liegen in der Regel zwischen 5 und 48 Stunden, wenn man die Umsetzung bei der Siedetemperatur des Lösungsmittels durchführt.
Für die mikrobiologische Einführung des 1(2)-ständigen Doppelbindung eignen sich insbesondere Mikroorganismen, die den folgenden Gattungen angehören: Acetobacter, Aerobacter, Alvaligenes, Alternaria, Arthobacter, Azotobacter, Azotomonas, Bacillus (besonders Bacillus cyclooxydans und Bacillus sphaericus), Calonectria (besonders Calonectria decora), Colletotrichum, Corynebacterium, Cucurbitaria, Cylindrocarpon (besonders Cylindrocarpon radicicola), Didymella (besonders Didymella lycopersici), Erysipelothrix, Fusarium, Gliocladium, Gloeosporium, Helminthosporium, Leptospaerium, Listeria, Micromonospora, Mycobacterium (besonders Mycobacterium lacticola und Mycobacterium smegmatis), Nocardia, Ophiobolus, Protaminobacter, Pseudomonas, Pycnodothis, Septomyxa (besonders Septomyxa affinis), Serratia, Stereum,
Streptomyces (besonders Streptomyces lavendulae), Trichothecium, Vermicularia.
Die Fermentation benötigt etwa 4 bis 24 Stunden, je nachdem, welcher Mikroorganismus verwendet wird. Be sonders bevorzugt sind Kulturen von Bacillus sphaericus var. fusiformis und Corynebacterium simplex.
Die Verbindung I kann im Gemisch mit festen, flüssigen und/oder halbflüssigen Arzneimittelträgern in der Human- oder Veterinärmedizin eingesetzt werden. Als Trägersubstanzen kommen solche organischen oder anorganischen Stoffe in Frage, die für die parenterale, enterale od. insbesondere topische Applikation geeignet sind und die mit I nicht in Reaktion treten, wie beispielsweise
Wasser, pflanzliche öle, Polyäthylenglykole, Gelatine,
Milchzucker, Stärke, Magnesiumstearat, Talk, Vaseline,
Cholesterin. Zur parenteralen Applikation dienen insbe sondere Lösungen, vorzugsweise ölige Lösungen, sowie
Suspensionen oder Emulsionen. Für die enterale Ap plikation eignen sich ferner Tabletten, Dragees, Sirupe, Säfte und Suppositorien, für die topische Anwendung Salben, Cremes, Lotionen, Tinkturen, Aerosole oder Puder.
Die angegebenen Zubereitungen können gegebenenfalls sterilisiert oder mit Hilfsstoffen, wie Konservierungs-, Stabilisierungs- oder Netzmitteln, Salzen zur Beeinflussung des esmotischen Druckes, Puffersubstanzen, Farb-, Geschmacks- und/oder Aromastoffen versetzt werden.
Die Verbindung I wird oral vorzugsweise in einer Dosierung von 0,3 bis 6, insbesondere 1 bis 3 mg pro Dosierungseinheit verabfolgt. Der Gehalt an I in Zubereitungen für die topikale Applikation liegt vorzugsweise zwischen 0,1 und 1, insbesondere zwischen 0,025 und 0,1 Gewichtsprozent.
In der USA-Patentschrift 3 065 239 ist eine Verbindungsklasse der Formel
EMI1.1
worin unter anderem Rl auch OH, R2 auch niederes Alkanoyl, R auch H und X und Y auch Halogen bedeuten können, genannt. Zwar wird in dieser Patentschrift auch gesagt, dass bei den Verbindungen der obigen allgemeinen Formel anti-inflammatorische Aktivitäten vorkommen, jedoch ist weder die spezielle Verbindung 1, die den Gegenstand der vorliegenden Erfindung bildet noch deren hervorragende anti-proliferative Wirkung beschrieben.
Die spezielle Verbindung 9oc-Fluor-16-fluormethylen- -prednisolon-21-önanthat (I) war am Ammeldetag der vorliegenden Erfindung im patentrechtlichen Sinn somit neu. Insbesondere konnte auch der Fachmann die ausserordentlich wertvollen und fortschrittlichen Eigenschaften der neuen Verbindung keineswegs voraussehen.
Beispiel I
Eine in einem 10-1-Fermenter in an sich üblicher Weise gezüchtete Kultur von Corynebacterium simplex -erhält bei pH 6,8 einen Zusatz von 3 g 9cc-Fluor-16-fluor- methylen-hydrocortison-21-önanthat (erhältlich durch Veresterung von 9Fluor-16-fluormethylen-hydrocorti- son in 21-Stellung) in 100 ml ç ethanol. Nach 8stündigem Rühren ist die Umsetzung beendet. Das Gemisch wird fünfmal mit je 2 1 Dichlormethan extrahiert. Man dampft die vereinigten Auszüge ein, versetzt den Rückstand mit Petroläther, lässt über Nacht stehen, saugt ab, reinigt chromatographisch auf und erhält 9oo-Fluor-16- -fluormethylen-prednisolon-21-önanthat vom F. 2022040.
Beispiel 2
2 g 9cciFluor-16-fluormethylen-hydrocortison-21-ön- anthat und 1,8 g 2,3-Dichlor-5,6-dicyan-1,4-benzochinon werden in 20 ml wasserfreiem Benzol 12 Stunden ge kocht. Man kühlt ab, filtriert und giesst das Filtrat in 200 ml einer 2%igen wässerigen Natriumhydroxidlösung.
Man extrahiert mit Äther, wäscht mit Wasser, trocknet über Natriumsulfat, dampft ein und erhält 9α-Fluor-16- -fluormethylen-prednisolon-21-önanthat, F. 202-204 (aus Äther).
PATIiiN'iANSPRUCH
Verfahren zur Herstellung von 9α-Fluor-16-fluorme- thylen-prednisolon-21-önanthat, dadurch gekennzeichnet, dass man 9α-Fluor-16-fluormethylen-hydrocortison-21- -önanthat mit chemischen oder mikrobiologischen, in 1(2)-Stellung Idehydrierenden Mitteln behandelt.
**WARNUNG** Ende DESC Feld konnte Anfang CLMS uberlappen**.
It was found that the previously unknown 9cc -fluoro-16-tluoromethylene-prednisolone-21-oenonthat (I) has an antiproliferative effect about 4.5 times more than the well-known hand ice cream preparation fluprednylidene -21-acetate (mouse tail test; test method cf. Arzneimittelforschung, volume 18, page 19 et seq. (1968). On the other hand, I has some undesirable side effects in this context only to a lesser extent. acetate (test method cf.
Pharmaceutical research, Volume 18, page 15 ff. (1968) 1. I is therefore particularly suitable as a remedy that can be applied topically (locally), for example for the treatment of skin diseases (e.g. psoriasis).
The invention relates to a process for the preparation of the compound I which consists in treating 9cc-fluoro-16-fluoromethylene-hydrocortisone-21-enanthate with chemical or microbiological agents which dehydrate in the 1 (2) position.
A particularly suitable chemical dehydrogenating agent is 2,3> 1-dichloro-5,6-dicyanobenzoquinone, which is expediently added in the presence of a solvent such as ethanol, butanol, tert-butanol, methyl tert-butylacetate, methyl acetate, ethyl acetate, tetrahydrofuran, dioxane, acetic acid , Benzene, acetone, are used. It is advantageous to add small amounts of nitrobenzene to the reaction mixture. The reaction times are generally between 5 and 48 hours if the reaction is carried out at the boiling point of the solvent.
Microorganisms belonging to the following genera are particularly suitable for the microbiological introduction of the 1 (2) double bond: Acetobacter, Aerobacter, Alvaligenes, Alternaria, Arthobacter, Azotobacter, Azotomonas, Bacillus (especially Bacillus cyclooxydans and Bacillus sphaericus), Calonectria (especially Calonectria decora), Colletotrichum, Corynebacterium, Cucurbitaria, Cylindrocarpon (especially Cylindrocarpon radicicola), Didymella (especially Didymella lycopersici), Erysipelothrix, Fusarium, Gliocladium, Gloeosporaium, Helminthosporium, Lactosporaium, Helminthosporium, Myromoncobisterium, Leptosporaerium, Helminthosporium, Myromoncobisterium, especially Myromosporaerium, Helminthosporium, Myromoncospaerium, Helminthosporium, Myromoncobisterium Nocardia, Ophiobolus, Protaminobacter, Pseudomonas, Pycnodothis, Septomyxa (especially Septomyxa affinis), Serratia, Stereum,
Streptomyces (especially Streptomyces lavendulae), Trichothecium, Vermicularia.
The fermentation takes about 4 to 24 hours, depending on the microorganism used. Cultures of Bacillus sphaericus var. Fusiformis and Corynebacterium simplex are particularly preferred.
The compound I can be used as a mixture with solid, liquid and / or semi-liquid pharmaceutical carriers in human or veterinary medicine. Suitable carrier substances are those organic or inorganic substances which are suitable for parenteral, enteral or, in particular, topical application and which do not react with I, such as, for example
Water, vegetable oils, polyethylene glycols, gelatine,
Lactose, starch, magnesium stearate, talc, petroleum jelly,
Cholesterol. Special solutions, preferably oily solutions, are used for parenteral administration
Suspensions or emulsions. Tablets, coated tablets, syrups, juices and suppositories are also suitable for enteral application, and ointments, creams, lotions, tinctures, aerosols or powders are suitable for topical application.
The specified preparations can optionally be sterilized or mixed with auxiliaries such as preservatives, stabilizers or wetting agents, salts to influence the esotic pressure, buffer substances, coloring, flavoring and / or aromatic substances.
The compound I is administered orally, preferably in a dosage of 0.3 to 6, in particular 1 to 3 mg per dosage unit. The content of I in preparations for topical application is preferably between 0.1 and 1, in particular between 0.025 and 0.1 percent by weight.
In U.S. Patent 3,065,239 there is a class of compounds of the formula
EMI1.1
where, inter alia, Rl can also mean OH, R2 can also mean lower alkanoyl, R also H and X and Y can also mean halogen. Although this patent specification also states that the compounds of the above general formula have anti-inflammatory activities, neither the specific compound 1, which forms the subject of the present invention, nor its excellent anti-proliferative effect is described.
The special compound 9oc-fluoro-16-fluoromethylene-prednisolone-21-oenanthate (I) was therefore new on the date of registration of the present invention in terms of patent law. In particular, even a person skilled in the art could not foresee the extraordinarily valuable and progressive properties of the new compound.
Example I.
A culture of Corynebacterium simplex cultivated in a 10-1 fermenter in the usual manner contains at pH 6.8 an addition of 3 g of 9cc-fluoro-16-fluoro-methylene-hydrocortisone-21-enanthate (obtainable by esterification of 9fluoro-16-fluoromethylene hydrocortisone in position 21) in 100 ml of ethanol. After stirring for 8 hours, the reaction has ended. The mixture is extracted five times with 2 liters of dichloromethane each time. The combined extracts are evaporated, petroleum ether is added to the residue, left to stand overnight, filtered off with suction, purified by chromatography and 900-fluoro-16-fluoromethylene-prednisolone-21-enanthate of F. 2022040 is obtained.
Example 2
2 g of 9cciFluoro-16-fluoromethylene-hydrocortisone-21-oenanthate and 1.8 g of 2,3-dichloro-5,6-dicyan-1,4-benzoquinone are boiled in 20 ml of anhydrous benzene for 12 hours. It is cooled, filtered and the filtrate is poured into 200 ml of a 2% aqueous sodium hydroxide solution.
It is extracted with ether, washed with water, dried over sodium sulphate, evaporated and 9α-fluoro-16-fluoromethylene-prednisolone-21-oenanthate, mp 202-204 (from ether) is obtained.
PATIiiN'i CLAIM
Process for the preparation of 9α-fluoro-16-fluoromethylene-prednisolone-21-oenanthate, characterized in that 9α-fluoro-16-fluoromethylene-hydrocortisone-21-oenanthate is mixed with chemical or microbiological, in 1 (2 ) -Position treated with dehydrating agents.
** WARNING ** End of DESC field could overlap beginning of CLMS **.
Claims (1)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE1906586A DE1906586C3 (en) | 1969-02-11 | 1969-02-11 | 9 Alpha-fluoro-16-fluoromethylene-prednisolone-21-oenanthate, process for its production and pharmaceutical preparation containing it |
| CH96870A CH534673A (en) | 1969-02-11 | 1970-01-23 | Process for the preparation of 9a-fluoro-16-fluoro-methylenprednisolone-21-enanthate |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CH534674A true CH534674A (en) | 1973-03-15 |
Family
ID=25686249
Family Applications (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CH1648172A CH534674A (en) | 1969-02-11 | 1970-01-23 | 9-alpha fluoro-16-fluoro methylene - pred - nisolone 21-oenanthate (i) |
| CH1648272A CH534675A (en) | 1969-02-11 | 1970-01-23 | Process for the preparation of 9a-fluoro-16-fluoro-methylenprednisolone-21-enanthate |
Family Applications After (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CH1648272A CH534675A (en) | 1969-02-11 | 1970-01-23 | Process for the preparation of 9a-fluoro-16-fluoro-methylenprednisolone-21-enanthate |
Country Status (1)
| Country | Link |
|---|---|
| CH (2) | CH534674A (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP1970779A1 (en) | 2007-03-16 | 2008-09-17 | Richemont International S.A. | Watch and casing method |
| CN114384782A (en) * | 2020-10-16 | 2022-04-22 | 斯沃奇集团研究及开发有限公司 | Device for locking the movement of a timepiece |
-
1970
- 1970-01-23 CH CH1648172A patent/CH534674A/en not_active IP Right Cessation
- 1970-01-23 CH CH1648272A patent/CH534675A/en not_active IP Right Cessation
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP1970779A1 (en) | 2007-03-16 | 2008-09-17 | Richemont International S.A. | Watch and casing method |
| CN114384782A (en) * | 2020-10-16 | 2022-04-22 | 斯沃奇集团研究及开发有限公司 | Device for locking the movement of a timepiece |
| EP3985450B1 (en) * | 2020-10-16 | 2024-08-28 | The Swatch Group Research and Development Ltd | Device for locking a movement of a clock piece |
Also Published As
| Publication number | Publication date |
|---|---|
| CH534675A (en) | 1973-03-15 |
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| PL | Patent ceased |