CH631999A5 - Process for the preparation of polyhalogenated steroids - Google Patents
Process for the preparation of polyhalogenated steroids Download PDFInfo
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- CH631999A5 CH631999A5 CH683181A CH683181A CH631999A5 CH 631999 A5 CH631999 A5 CH 631999A5 CH 683181 A CH683181 A CH 683181A CH 683181 A CH683181 A CH 683181A CH 631999 A5 CH631999 A5 CH 631999A5
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J7/00—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms
- C07J7/008—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms substituted in position 21
- C07J7/0085—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms substituted in position 21 by an halogen atom
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J21/00—Normal steroids containing carbon, hydrogen, halogen or oxygen having an oxygen-containing hetero ring spiro-condensed with the cyclopenta(a)hydrophenanthrene skeleton
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J31/00—Normal steroids containing one or more sulfur atoms not belonging to a hetero ring
- C07J31/006—Normal steroids containing one or more sulfur atoms not belonging to a hetero ring not covered by C07J31/003
-
- 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
- C07J5/0046—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 substituted in position 17 alfa
- C07J5/0061—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 substituted in position 17 alfa substituted in position 16
- C07J5/0069—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 substituted in position 17 alfa substituted in position 16 by a saturated or unsaturated hydrocarbon group
- C07J5/0076—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 substituted in position 17 alfa substituted in position 16 by a saturated or unsaturated hydrocarbon group by an alkyl group
-
- 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
- C07J71/0015—Oxiranes at position 9(11)
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- General Health & Medical Sciences (AREA)
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- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Pain & Pain Management (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Rheumatology (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Steroid Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
Description
Die Erfindung betrifft die Herstellung von neuen mehrfach halogenierten Steroiden, und zwar von 9a,21-Dihalogen- The invention relates to the production of new multi-halogenated steroids, namely 9a, 21-dihalogen
(I) (I)
worin Xj Chlor, X2 Brom oder Chlor, Ri Wasserstoff oder 20 Chlor, und R2 den Acylrest Ac einer Carbonsäure darstellen, und von 1,2-Dihydroderivaten solcher Verbindungen, worin Rx Wasserstoff ist, in der im Patentanspruch 1 definierten Weise. wherein Xj is chlorine, X2 is bromine or chlorine, Ri is hydrogen or 20 chlorine, and R2 is the acyl radical Ac of a carboxylic acid, and of 1,2-dihydro derivatives of such compounds, in which Rx is hydrogen, in the manner defined in claim 1.
Nachstehend mit «nieder» bezeichnete kohlenstoffhaltige Verbindungen und Reste erhalten vorzugsweise bis und mit 7 25 Kohlenstoffatome. Carbon-containing compounds and radicals hereinafter referred to as "lower" preferably contain up to and including 7 25 carbon atoms.
Eine Acylgruppe Ac leitet sich vorzugsweise von den in der Steroidchemie gebräuchlichen Carbonsäuren z.B. mit höchstens 18 Kohlenstoffatomen, insbesondere von entsprechenden aliphatischen, cycloaliphatischen, cycloaliphatisch-aliphatischen, 30 aromatischen oder araliphatischen Carbonsäuren ab. Der Rest Ac ist insbesondere gegebenenfalls, z.B. durch gegebenenfalls veräthertes oder verestertes Hydroxy, wie Niederalkoxy, z.B. Methoxy oder Äthoxy, oder Phenoxy, oder Halogen, z.B. Chlor, oder Carboxy substituiertes Niederalkanoyl, wie geradkettiges 35 oder verzweigtes Niederalkanoyl, z.B. Acetyl, Propionyl, Buty-ryl, Isobutyryl, Valeryl, Isovaleryl, Pivaloyl, 2-Äthyl-butyryl, 2,2-oder 3,3-Dimethyl-butyryl, Hexanoyl oder Heptanoyl, Hydroxyniederalkanoyl, z.B. 3-Hydroxypropionyl, Phenoxy-niederalkynoyl, z.B. Phenoxyacetyl, Halogenniederalkanoyl, 40 z.B. Chloracetyl, oder Carboxyniederalkanoyl, z.B. 3-Carboxy-propionyl oder 4-Carboxy-butyryl, Alkenoyl, z.B. Undecyle-noyl, Cycloalkylniederalkanoyl, z.B. Cyclopentylpropionyl oder Cyclohexylacetyl, gegebenenfalls substituiertes Benzoyl, z.B. Benzoyl, oder gegebenenfalls substituiertes Phenylniederalk-45 anoyl oder -niederalkenoyl, z.B. Phenylacetyl, sowie ein Carboxyniederalkanoyl in Form eines Salzes, in erster Linie eines Alkalimetall-, wie Natrium-oder Kaliumsalzes. Dabei ist das Natriumsalz einer Verbindimg der Formel I besonders bevorzugt, worin R2 für 3-Carboxypropionyl steht. An acyl group Ac is preferably derived from the carboxylic acids customary in steroid chemistry, e.g. with at most 18 carbon atoms, in particular from corresponding aliphatic, cycloaliphatic, cycloaliphatic-aliphatic, 30 aromatic or araliphatic carboxylic acids. The rest Ac is in particular optionally, e.g. by optionally etherified or esterified hydroxy, such as lower alkoxy, e.g. Methoxy or ethoxy, or phenoxy, or halogen, e.g. Chlorine or carboxy substituted lower alkanoyl such as straight chain or branched lower alkanoyl e.g. Acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, 2-ethyl-butyryl, 2,2- or 3,3-dimethyl-butyryl, hexanoyl or heptanoyl, hydroxy-lower alkanoyl, e.g. 3-hydroxypropionyl, phenoxy-lower alkynoyl, e.g. Phenoxyacetyl, halogeno lower alkanoyl, 40 e.g. Chloroacetyl, or carboxy lower alkanoyl, e.g. 3-carboxy-propionyl or 4-carboxy-butyryl, alkenoyl, e.g. Undecyle-noyl, cycloalkyl-lower alkanoyl, e.g. Cyclopentylpropionyl or cyclohexylacetyl, optionally substituted benzoyl, e.g. Benzoyl, or optionally substituted phenyl lower alk-45 anoyl or lower alkenoyl, e.g. Phenylacetyl, and a carboxy-lower alkanoyl in the form of a salt, primarily an alkali metal, such as sodium or potassium salt. The sodium salt of a compound of the formula I in which R 2 is 3-carboxypropionyl is particularly preferred.
Die erfindungsgemässen Verbindungen besitzen wertvolle pharmakologische Eigenschaften. So zeichnen sie sich durch eine hervorragende antiinflammatorische Wirksamkeit bei einer verminderten systemischen Wirkung aus. So z.B. bei lokaler Anwendung im Rohwattegranulomtest an der Ratte kann man 55 die Hemmung der entzündlichen Vorgänge im Dosisbereich von etwa 0,001 bis etwa 0,10 mg/Pellet feststellen, wobei aber die ersten Anzeichen einer systemischen Wirkung erst an oder sogar oberhalb der oberen Grenze dieses Dosisbereichs bemerkbar sind, und zwar die Gewichtsabnahme des Thymus oberhalb 60 0,03 mg/Pellet und des gesammten Körpers erst bei 1,0 mg/ Pellet. Bei der topischen Verabreichung (Rattenohr-Test nach Tonelli) liegt ED50 sogar bei etwa 10-30 mcg/ml. - Wegen diesen biologischen Eigenschaften sind die neuen Verbindungen in allen Indikationen, für die sich Glucocorticoid-Steroide mit entzündungshemmenden Eigenschaften eignen, insbesondere jedoch als topisch anzuwendende antiinflammatorische Glucocor-ticoide, z.B. zur Behandlung von entzündlichen Dermatosen, wie Ekzemen, Dermatiden, oder partiell corticoidresistenten The compounds according to the invention have valuable pharmacological properties. They are characterized by an excellent anti-inflammatory effectiveness with a reduced systemic effect. So e.g. When used locally in the raw cotton granuloma test in the rat, 55 the inhibition of inflammatory processes can be determined in the dose range from approximately 0.001 to approximately 0.10 mg / pellet, although the first signs of a systemic effect are noticeable only at or even above the upper limit of this dose range are, namely the weight loss of the thymus above 60 0.03 mg / pellet and the entire body only at 1.0 mg / pellet. For topical administration (rat ear test according to Tonelli) ED50 is even around 10-30 mcg / ml. Because of these biological properties, the new compounds are in all indications for which glucocorticoid steroids with anti-inflammatory properties are suitable, but in particular as topically applicable anti-inflammatory glucocorticoids, e.g. for the treatment of inflammatory dermatoses, such as eczema, dermatids, or partially corticoid-resistant
50 50
3 3rd
631 999 631 999
Dermatosen, z.B. Psoriasis, verwendbar. Sie können zudem als wertvolle Zwischenprodukte zur Herstellung anderer nützlicher Stoffe, insbesondere anderer pharmakologisch wirksamer Steroide, Anwendung finden. Dermatoses, e.g. Psoriasis, usable. They can also be used as valuable intermediates for the production of other useful substances, in particular other pharmacologically active steroids.
Die Erfindung betrifft vorzugsweise diejenigen Verbindungen der Formel I, worin X! Chlor, X2 Chlor, Rj Wasserstoff und R2 Niederalkanoyl, z.B. Propionyl, darstellen, sowie die entsprechenden 1,2-Dihydroderivate. The invention preferably relates to those compounds of the formula I in which X! Chlorine, X2 chlorine, Rj hydrogen and R2 lower alkanoyl, e.g. Propionyl, represent, and the corresponding 1,2-dihydro derivatives.
Die Erfindung betrifft in erster Linie Verbindungen der Formel I, worin Xt Chlor, X2 Chlor, Rj Chlor und R2 Niederalkanoyl, z.B. Propionyl, darstellen. The invention relates primarily to compounds of formula I wherein Xt is chlorine, X2 is chlorine, Rj is chlorine and R2 is lower alkanoyl, e.g. Propionyl.
Die Erfindung betrifft vor allem insbesondere die in den Beispielen genannten Verbindungen der Formel I. The invention relates in particular to the compounds of the formula I mentioned in the examples.
Erfindungsgemäss werden Verbindungen der Formel I, bzw. ihre 1,2-gesättigten 2-unsubstituierten Analogen in an sich bekannter Weise hergestellt, wenn man an die 9,11-Doppelbindung einer Verbindung der Formel According to the invention, compounds of the formula I, or their 1,2-saturated 2-unsubstituted analogs, are prepared in a manner known per se if the 9,11 double bond of a compound of the formula
(Formel S. 7) (Formula p. 7)
CIL CIL
™2X2 ™ 2X2
CH., CO CH., CO
/\l J . / \ l J.
.OR, .OR,
\ ^ \l/ \ / \ / \ \ ^ \ l / \ / \ / \
CH, CH,
<? <?
'' \ f \ / '' \ f \ /
(VII) (VII)
worin Rl5 R2 und X2 die obgenannten Bedeutungen haben, bzw. eines entsprechenden 1,2-gesättigten 2-unsubstituierten Analogen davon, unterchlorige Säure anlagert. where Rl5 R2 and X2 have the meanings given above, or a corresponding 1,2-saturated 2-unsubstituted analogue thereof, hypochlorous acid.
Gemäss obiger Reaktion werden an die 9,11-Doppelbin-dung der oben erwähnten Ausgangsstoffe in an sich bekannter Weise die Elemente der unterchlorigen Säure angelagert. Dabei arbeitet man z.B. mit wässriger unterchloriger Säure, oder man kann ein die unterchlorige Säure abgebendes Mittel, wie ein N-Chlor-carbonsäureamid oder -imid (vgl. US-Patentschrift 3 057 886) verwenden. Die Reaktion führt man in einem inerten Lösungsmittel, wie einem tertiären Alkohol, z.B. tert.-But-anol, einem Äther, z.B. Diäthyläther, Methylisopropyläther, Dioxan oder Tetrahydrofuran, oder einem Keton, z.B. Aceton, in Gegenwart von Wasser und gegebenenfalls einer starken Säure durch. According to the above reaction, the elements of hypochlorous acid are added to the 9, 11 double bond of the above-mentioned starting materials in a manner known per se. One works e.g. with aqueous hypochlorous acid, or one can use a hypochlorous acid releasing agent such as an N-chlorocarboxylic acid amide or imide (see US Pat. No. 3,057,886). The reaction is carried out in an inert solvent such as a tertiary alcohol e.g. tert-but-anol, an ether, e.g. Diethyl ether, methyl isopropyl ether, dioxane or tetrahydrofuran, or a ketone, e.g. Acetone, in the presence of water and possibly a strong acid.
Die Anlagerung der unterchlorigen Säure an die 9,11-Dop-pelbindung des obgenannten Ausgangsmaterials kann auch in nicht-wässrigem Medium erfolgen. Eine besonders vorteilhafte Ausführungsform dieser Modifikation stellt die Verwendung von Niederalkylhypochloriten, in erster Linie von tert.-Butylhy-pochlorit, in einem inerten, mit Wasser nicht mischbaren Lösungsmittel, wie z.B. einem Nitrokohlenwasserstoff, üblicherweise in Gegenwart von Perchlorsäure dar (vgl. Deutsche Patentschrift 2 011 559). The hypochlorous acid can also be attached to the 9,11-double bond of the above-mentioned starting material in a non-aqueous medium. A particularly advantageous embodiment of this modification is the use of lower alkyl hypochlorites, primarily tert-butyl hypochlorite, in an inert, water-immiscible solvent, such as e.g. a nitrocarbon, usually in the presence of perchloric acid (cf. German Patent 2,011,559).
Die Ausgangsstoffe der Formel VII, bzw. ihre 2-unsubstituierten 1,2-Dihydroanalogen, können in an sich bekannterWeise hergestellt werden, z.B. durch Abspalten von Wasser aus einer 6a-Fluor-llß-hydroxy-16ß-methyl-2-Ri-17a-OR2-21-X2-[pregn-4-en- oder -pregna-l,4-dien]-3,20-dion-Verbindung, z.B. durch Behandeln mit einem geeigneten Säurechlorid, wie Phosphoroxychlorid oder Methansulfonsäurechlorid, in Gegenwart einer Base, z.B. Pyridin. The starting materials of formula VII, or their 2-unsubstituted 1,2-dihydroanalogens, can be prepared in a manner known per se, e.g. by splitting off water from a 6a-fluoro-11β-hydroxy-16ß-methyl-2-Ri-17a-OR2-21-X2- [pregn-4-en- or -pregna-l, 4-diene] -3, 20-dione compound, e.g. by treatment with a suitable acid chloride such as phosphorus oxychloride or methanesulfonic acid chloride in the presence of a base, e.g. Pyridine.
Verfahrensgemäss erhältliche Verbindungen der Formel I Compounds of the formula I obtainable according to the process
(einschliesslich ihrer 1,2-Dihydroanalogen) mit salzbildenden Eigenschaften, d.h. Verbindungen, worin R2 einen Carboxy-niederalkanoylrest darstellt, können in an sich bekannter Weise durch Behandeln mit einer geeigneten Base, wie einem Alkali-5 metall-, wie Natrium- oder Kaliumhydroxid, -carbonat oder hy-drogencarbonat (wobei man vorzugsweise die äquivalente Menge der Base verwendet), üblicherweise in einem wässrigen oder wässrig-alkoholischen Medium, in ihre Salze überführt werden. (including their 1,2-dihydroanalogues) with salt-forming properties, i.e. Compounds in which R2 is a carboxy-lower alkanoyl radical can be prepared in a manner known per se by treatment with a suitable base, such as an alkali metal, such as sodium or potassium hydroxide, carbonate or hydrogen bicarbonate (preferably using the equivalent amount the base used), usually in an aqueous or aqueous-alcoholic medium, are converted into their salts.
Umgekehrt kann man ein verfahrensgemäss erhältliches io Salz einer Verbindung der Formel I mit salzbildenden Eigenschaften in die freie Verbindung überführen, z.B. ein entsprechendes Salz mit einer Säure, wie einer anorganischen Säure behandeln (z.B. durch Ansäuern eine Lösung des Salzes in einem wässrigen oder wässrig-organischen Medium auf einen pH-15 Wert von etwa 1-2 bringen. Conversely, a processable io salt of a compound of formula I with salt-forming properties can be converted into the free compound, e.g. treat an appropriate salt with an acid, such as an inorganic acid (e.g., by acidifying a solution of the salt in an aqueous or aqueous-organic medium to a pH of about 1-2.
Vorzugsweise setzt man in den obigen Verfahrensschritten diejenigen Ausgangsstoffe ein, die zu vorstehend als besonders bevorzugt beschriebenen Verbindungen führen. In the above process steps, preference is given to using those starting materials which lead to the compounds described above as being particularly preferred.
Die gemäss der vorliegenden Erfindung hergestellten End-20 stoffe können als pharmazeutische Präparate enthaltend eine erfindungsgemässe Verbindung der Formel I oder ein 1,2-gesät-tigtes 2-unsubstituiertes Derivat einer solchen Verbindung als Wirkstoff, sowie zur Herstellung von solchen pharmazeutischen Präparaten, Verwendung finden. The end-20 substances produced according to the present invention can be used as pharmaceutical preparations containing a compound of the formula I according to the invention or a 1,2-saturated 2-unsubstituted derivative of such a compound as an active ingredient, and for the production of such pharmaceutical preparations .
25 Dabei kommen in erster Linie topisch anwendbare pharmazeutische Präparate, wie Cremen, Salben, Pasten, Schäume, Tinkturen und Lösungen, in Frage, die von etwa 0,005 % bis etwa 0,1 % des Wirkstoffs enthalten, ferner Präparate zur oralen Verabreichung, z.B. Tabletten, Dragées und Kapseln, und par-30 enteralen Verabreichung. Die Herstellung solcher Präparate erfolgt in an sich bekannter Weise. 25 Primarily topical pharmaceutical preparations, such as creams, ointments, pastes, foams, tinctures and solutions, which contain from about 0.005% to about 0.1% of the active substance, and also preparations for oral administration, e.g. Tablets, dragées and capsules, and par-30 enteral administration. Such preparations are produced in a manner known per se.
Die gemäss der vorliegenden Erfindung hergestellten neuen Verbindungen verwendet man vorzugsweise zur Behandlung von Entzündungen, in erster Linie als lokal anzuwendende anti-35 inflammatorische Glucocorticoide, üblicherweise in Form von pharmazeutischen Präparaten, besonders in Form von topisch anwendbaren pharmazeutischen Präparaten. The new compounds produced according to the present invention are preferably used for the treatment of inflammation, primarily as locally applicable anti-35 inflammatory glucocorticoids, usually in the form of pharmaceutical preparations, especially in the form of topically applicable pharmaceutical preparations.
Die nachfolgenden Beispiele illustrieren die oben beschriebene Erfindung; sie sollten jedoch diese in ihrem Umfang in 40 keiner Weise einschränken, Temperaturen werden in Celsiusgraden angegeben. The following examples illustrate the invention described above; however, you should not restrict the scope in any way, temperatures are given in degrees Celsius.
Beispiel 1 example 1
Eine gerührte Suspension von 7,45 g 21-Chlor-6a-fluor-45 17a-hydroxy-16ß-methyl-pregna-4,9(l l)-dien-3,20-dion-17-propionat in 150 ml t-Butylalkohol wird unter Stickstoff nacheinander mit 7,55 ml einer 10%-igen Perchlorsäurelösung und 2,15 ml t-Butylhypochlorit versetzt, 3,5 Stunden bei Zimmertemperatur weiter gerührt und auf Eiswasser aufgegossen. 50 Der Niederschlag wird abgenutscht, mit Wasser gründlich gewaschen und in Chloroform und wenig Methanol gelöst. Die Lösung wird mit Natriumsulfat getrocknet und im Wasserstrahlvakuum eingedampft. Durch Umlösen des verbleibenden Rückstandes aus Methylenchlorid-Methanol-Äther resultiert das 55 9a,21-Dichlor-6a-fluor-llß,17a-dihydroxy-16ß-methyl-pregn-4-en-3,20-dion-17-propionat, welches bei 198° mit Zersetzung schmilzt. A stirred suspension of 7.45 g of 21-chloro-6a-fluoro-45 17a-hydroxy-16ß-methyl-pregna-4,9 (ll) -diene-3,20-dione-17-propionate in 150 ml of t- 7.55 ml of a 10% perchloric acid solution and 2.15 ml of t-butyl hypochlorite are added to butyl alcohol in succession under nitrogen, stirring is continued for 3.5 hours at room temperature and poured onto ice water. 50 The precipitate is filtered off, washed thoroughly with water and dissolved in chloroform and a little methanol. The solution is dried with sodium sulfate and evaporated in a water jet vacuum. Redissolving the remaining residue from methylene chloride-methanol ether results in 55 9a, 21-dichloro-6a-fluoro-11ß, 17a-dihydroxy-16ß-methyl-pregn-4-en-3,20-dione-17-propionate, which melts at decomposition at 198 °.
Beispiel2 Example2
In derselben Weise wie im Beispiel 1 wird eine Suspension 60 von 2,95 g 21-Chlor-6a-fluor-17a-hydroxy-16ß-methyl-pre-gna-l,4,9(ll)-trien-3,20-dion-17-propionat in 60 ml t-Butylal-kohol mit 2,95 ml einer 10%-igen Perchlorsäurelösung und 0,85 ml t-Butylhypochlorit versetzt und weiterverarbeitet. Es resultiert 9 a,21 -Dichlor-6a-f luor-11 ß, 17 a-dihydroxy-6516ß-methyl-pregna-l,4-dien-3,20-dion-17-propionat, Smp. 212—213 ° (Zersetzung). In the same manner as in Example 1, a suspension 60 of 2.95 g of 21-chloro-6a-fluoro-17a-hydroxy-16β-methyl-pre-gna-1,4,9 (ll) -triene-3,20 -dion-17-propionate in 60 ml of t-butyl alcohol with 2.95 ml of a 10% perchloric acid solution and 0.85 ml of t-butyl hypochlorite and processed further. The result is 9 a, 21-dichloro-6a-fluorine-11 β, 17 a-dihydroxy-6516β-methyl-pregna-l, 4-diene-3,20-dione-17-propionate, mp. 212-213 ° (Decomposition).
C C.
Claims (6)
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| LU75903A LU75903A1 (en) | 1976-09-29 | 1976-09-29 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CH631999A5 true CH631999A5 (en) | 1982-09-15 |
Family
ID=19728370
Family Applications (9)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CH1549976A CH624967A5 (en) | 1976-09-29 | 1976-12-09 | Process for the preparation of polyhalogenated steroids |
| CH1172177A CH632279A5 (en) | 1976-09-29 | 1977-09-26 | Process for the preparation of polyhalogenated steroids |
| CH853780A CH625808A5 (en) | 1976-09-29 | 1980-11-18 | Process for the preparation of polyhalogenated steroids |
| CH853980A CH625810A5 (en) | 1976-09-29 | 1980-11-18 | Process for the preparation of polyhalogenated steroids |
| CH853880A CH625809A5 (en) | 1976-09-29 | 1980-11-18 | Process for the preparation of polyhalogenated steroids |
| CH683281A CH632000A5 (en) | 1976-09-29 | 1981-10-26 | Process for the preparation of polyhalogenated steroids |
| CH683181A CH631999A5 (en) | 1976-09-29 | 1981-10-26 | Process for the preparation of polyhalogenated steroids |
| CH683081A CH631998A5 (en) | 1976-09-29 | 1981-10-26 | Process for the preparation of polyhalogenated steroids |
| CH4682A CH632521A5 (en) | 1976-09-29 | 1982-01-06 | Process for the preparation of polyhalogenated steroids |
Family Applications Before (6)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CH1549976A CH624967A5 (en) | 1976-09-29 | 1976-12-09 | Process for the preparation of polyhalogenated steroids |
| CH1172177A CH632279A5 (en) | 1976-09-29 | 1977-09-26 | Process for the preparation of polyhalogenated steroids |
| CH853780A CH625808A5 (en) | 1976-09-29 | 1980-11-18 | Process for the preparation of polyhalogenated steroids |
| CH853980A CH625810A5 (en) | 1976-09-29 | 1980-11-18 | Process for the preparation of polyhalogenated steroids |
| CH853880A CH625809A5 (en) | 1976-09-29 | 1980-11-18 | Process for the preparation of polyhalogenated steroids |
| CH683281A CH632000A5 (en) | 1976-09-29 | 1981-10-26 | Process for the preparation of polyhalogenated steroids |
Family Applications After (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CH683081A CH631998A5 (en) | 1976-09-29 | 1981-10-26 | Process for the preparation of polyhalogenated steroids |
| CH4682A CH632521A5 (en) | 1976-09-29 | 1982-01-06 | Process for the preparation of polyhalogenated steroids |
Country Status (24)
| Country | Link |
|---|---|
| JP (1) | JPS5356652A (en) |
| AT (3) | AT363197B (en) |
| AU (1) | AU514200B2 (en) |
| BE (1) | BE859120A (en) |
| CA (1) | CA1101410A (en) |
| CH (9) | CH624967A5 (en) |
| CY (1) | CY1178A (en) |
| DD (1) | DD133150A5 (en) |
| DE (1) | DE2743069A1 (en) |
| DK (1) | DK146017C (en) |
| ES (1) | ES462763A1 (en) |
| FR (1) | FR2366311A1 (en) |
| GB (1) | GB1563638A (en) |
| HK (1) | HK16683A (en) |
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| IE (1) | IE46047B1 (en) |
| IL (1) | IL53012A (en) |
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| LU (1) | LU75903A1 (en) |
| MY (1) | MY8400092A (en) |
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| SE (1) | SE436751B (en) |
| SG (1) | SG3383G (en) |
| ZA (1) | ZA775800B (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5972922A (en) * | 1990-06-11 | 1999-10-26 | Alcon Laboratories, Inc. | Steroids which inhibit angiogenesis |
Families Citing this family (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| NL187577C (en) * | 1978-04-05 | 1991-11-18 | Sibla Srl | 3-ACETOXY-9BETA, 11BETA-EPOXY-PREGNA-1,3,5-TRIEN, PROCESS FOR THE PREPARATION THEREOF, AND PROCESS FOR THE PREPARATION OF 6-alpha-halogen-1,4-diene-3-ones. |
| DE3227312A1 (en) * | 1982-07-19 | 1984-01-19 | Schering AG, 1000 Berlin und 4709 Bergkamen | NEW 6.16 DIMETHYL CORTICOIDS, THEIR PRODUCTION AND USE |
| EP0523132A1 (en) * | 1990-03-27 | 1993-01-20 | Schering Corporation | PROCESS FOR 9$g(a)-HYDROXY STEROID DEHYDRATION |
| MXPA04005188A (en) | 2001-11-29 | 2004-08-11 | Taro Pharma Ind | Method for the production of 6-alpha-fluoro corticosteroids. |
| US8809307B2 (en) | 2010-11-22 | 2014-08-19 | Dow Pharmaceutical Sciences, Inc. | Pharmaceutical formulations containing corticosteroids for topical administration |
| US11957753B2 (en) | 2010-11-22 | 2024-04-16 | Bausch Health Ireland Limited | Pharmaceutical formulations containing corticosteroids for topical administration |
| ES2812451T3 (en) | 2015-06-18 | 2021-03-17 | Bausch Health Ireland Ltd | Topical compositions comprising a corticosteroid and a retinoid to treat psoriasis |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB898292A (en) * | 1959-03-18 | 1962-06-06 | Upjohn Co | Improvements in or relating to steroids and the manufacture thereof |
| US3644340A (en) * | 1970-03-19 | 1972-02-22 | Syntex Corp | Preparation of 21-chloro steroids |
| US3992422A (en) * | 1975-08-14 | 1976-11-16 | Schering Corporation | Process for the preparation of 21-halogeno-21-desoxy-17α-acyloxy-20-keto-pregnenes |
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1976
- 1976-09-29 LU LU75903A patent/LU75903A1/xx unknown
- 1976-12-09 CH CH1549976A patent/CH624967A5/en not_active IP Right Cessation
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1977
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- 1977-09-24 DE DE19772743069 patent/DE2743069A1/en active Granted
- 1977-09-26 CH CH1172177A patent/CH632279A5/en not_active IP Right Cessation
- 1977-09-27 FR FR7729043A patent/FR2366311A1/en active Granted
- 1977-09-27 CA CA287,560A patent/CA1101410A/en not_active Expired
- 1977-09-27 GB GB40131/77A patent/GB1563638A/en not_active Expired
- 1977-09-27 AU AU29148/77A patent/AU514200B2/en not_active Expired
- 1977-09-27 CY CY1178A patent/CY1178A/en unknown
- 1977-09-27 DD DD7700201226A patent/DD133150A5/en unknown
- 1977-09-28 IL IL53012A patent/IL53012A/en unknown
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- 1977-09-28 HU HU77CI1774A patent/HU175218B/en unknown
- 1977-09-28 BE BE181243A patent/BE859120A/en not_active IP Right Cessation
- 1977-09-28 AT AT0691077A patent/AT363197B/en not_active IP Right Cessation
- 1977-09-29 JP JP11619377A patent/JPS5356652A/en active Granted
- 1977-09-29 ES ES462763A patent/ES462763A1/en not_active Expired
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1979
- 1979-02-28 AT AT0151279A patent/AT363202B/en not_active IP Right Cessation
- 1979-02-28 AT AT0151379A patent/AT363203B/en not_active IP Right Cessation
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1980
- 1980-11-18 CH CH853780A patent/CH625808A5/en not_active IP Right Cessation
- 1980-11-18 CH CH853980A patent/CH625810A5/en not_active IP Right Cessation
- 1980-11-18 CH CH853880A patent/CH625809A5/en not_active IP Right Cessation
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1981
- 1981-10-26 CH CH683281A patent/CH632000A5/en not_active IP Right Cessation
- 1981-10-26 CH CH683181A patent/CH631999A5/en not_active IP Right Cessation
- 1981-10-26 CH CH683081A patent/CH631998A5/en not_active IP Right Cessation
-
1982
- 1982-01-06 CH CH4682A patent/CH632521A5/en not_active IP Right Cessation
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1983
- 1983-01-20 SG SG33/83A patent/SG3383G/en unknown
- 1983-01-21 KE KE3258A patent/KE3258A/en unknown
- 1983-05-19 HK HK166/83A patent/HK16683A/en not_active IP Right Cessation
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1984
- 1984-12-30 MY MY92/84A patent/MY8400092A/en unknown
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5972922A (en) * | 1990-06-11 | 1999-10-26 | Alcon Laboratories, Inc. | Steroids which inhibit angiogenesis |
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Legal Events
| Date | Code | Title | Description |
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| PFA | Name/firm changed |
Owner name: CIBA-GEIGY AG TRANSFER- NOVARTIS AG |
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| PL | Patent ceased |