DE1443957C - 9 alpha-chlorine or 9 alpha-fluorine. 16 beta-methyl-prednisolone-17,21-diester and a process for their preparation - Google Patents
9 alpha-chlorine or 9 alpha-fluorine. 16 beta-methyl-prednisolone-17,21-diester and a process for their preparationInfo
- Publication number
- DE1443957C DE1443957C DE1443957C DE 1443957 C DE1443957 C DE 1443957C DE 1443957 C DE1443957 C DE 1443957C
- Authority
- DE
- Germany
- Prior art keywords
- betamethasone
- methyl
- dione
- diene
- pregna
- 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.)
- Active
Links
- 238000002360 preparation method Methods 0.000 title claims description 9
- 239000000460 chlorine Substances 0.000 title claims description 7
- 229910052801 chlorine Inorganic materials 0.000 title claims description 4
- 229910052731 fluorine Inorganic materials 0.000 title claims description 4
- 238000000034 method Methods 0.000 title claims description 4
- 239000011737 fluorine Substances 0.000 title claims 2
- UREBDLICKHMUKA-DVTGEIKXSA-N Betamethasone Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@H](C)[C@@](C(=O)CO)(O)[C@@]1(C)C[C@@H]2O UREBDLICKHMUKA-DVTGEIKXSA-N 0.000 claims description 21
- 229960002537 betamethasone Drugs 0.000 claims description 21
- 150000001875 compounds Chemical class 0.000 claims description 9
- 230000000875 corresponding Effects 0.000 claims description 8
- 125000004432 carbon atoms Chemical group C* 0.000 claims description 6
- VXOWJCTXWVWLLC-REGDIAEZSA-N [(8S,9R,10S,11S,13S,14S,16S,17R)-9-fluoro-11-hydroxy-10,13,16-trimethyl-3-oxo-17-(2-propanoyloxyacetyl)-6,7,8,11,12,14,15,16-octahydrocyclopenta[a]phenanthren-17-yl] butanoate Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@H](C)[C@@](C(=O)COC(=O)CC)(OC(=O)CCC)[C@@]1(C)C[C@@H]2O VXOWJCTXWVWLLC-REGDIAEZSA-N 0.000 claims description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-M acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 claims description 3
- KQNPFQTWMSNSAP-UHFFFAOYSA-M isobutyrate Chemical compound CC(C)C([O-])=O KQNPFQTWMSNSAP-UHFFFAOYSA-M 0.000 claims description 2
- 239000003795 chemical substances by application Substances 0.000 claims 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims 1
- YCKRFDGAMUMZLT-UHFFFAOYSA-N fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 claims 1
- RTZKZFJDLAIYFH-UHFFFAOYSA-N diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 54
- JUJWROOIHBZHMG-UHFFFAOYSA-N pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 42
- 238000004458 analytical method Methods 0.000 description 24
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 23
- 239000003208 petroleum Substances 0.000 description 20
- UHOVQNZJYSORNB-UHFFFAOYSA-N benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 18
- 238000000354 decomposition reaction Methods 0.000 description 15
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 15
- 150000003431 steroids Chemical class 0.000 description 14
- WFDIJRYMOXRFFG-UHFFFAOYSA-N acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 12
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- 238000002425 crystallisation Methods 0.000 description 10
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- UIIMBOGNXHQVGW-UHFFFAOYSA-M NaHCO3 Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 8
- HEDRZPFGACZZDS-UHFFFAOYSA-N chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 8
- 239000012043 crude product Substances 0.000 description 8
- 239000002904 solvent Substances 0.000 description 8
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- JYGXADMDTFJGBT-VWUMJDOOSA-N Cortisol Chemical compound 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 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N HCl Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 6
- VLTRZXGMWDSKGL-UHFFFAOYSA-N Perchloric acid Chemical compound OCl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-N 0.000 description 6
- 229960000890 hydrocortisone Drugs 0.000 description 6
- -1 isobutyryl Chemical group 0.000 description 6
- 238000001953 recrystallisation Methods 0.000 description 6
- 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 description 5
- FPVRUILUEYSIMD-QZIXMDIESA-N [(8S,9R,10S,11S,13S,14S,16S,17R)-9-fluoro-11-hydroxy-17-(2-hydroxyacetyl)-10,13,16-trimethyl-3-oxo-6,7,8,11,12,14,15,16-octahydrocyclopenta[a]phenanthren-17-yl] acetate Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@H](C)[C@@](C(=O)CO)(OC(C)=O)[C@@]1(C)C[C@@H]2O FPVRUILUEYSIMD-QZIXMDIESA-N 0.000 description 5
- PNEYBMLMFCGWSK-UHFFFAOYSA-N al2o3 Chemical compound [O-2].[O-2].[O-2].[Al+3].[Al+3] PNEYBMLMFCGWSK-UHFFFAOYSA-N 0.000 description 5
- 230000003110 anti-inflammatory Effects 0.000 description 5
- 238000006243 chemical reaction Methods 0.000 description 5
- 238000001914 filtration Methods 0.000 description 5
- 239000000463 material Substances 0.000 description 5
- 229960005205 prednisolone Drugs 0.000 description 5
- RZWZRACFZGVKFM-UHFFFAOYSA-N propanoyl chloride Chemical compound CCC(Cl)=O RZWZRACFZGVKFM-UHFFFAOYSA-N 0.000 description 5
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- 230000000694 effects Effects 0.000 description 4
- HWJHWSBFPPPIPD-UHFFFAOYSA-N ethoxyethane;propan-2-one Chemical compound CC(C)=O.CCOCC HWJHWSBFPPPIPD-UHFFFAOYSA-N 0.000 description 4
- 239000005457 ice water Substances 0.000 description 4
- CSNNHWWHGAXBCP-UHFFFAOYSA-L mgso4 Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 4
- 239000000047 product Substances 0.000 description 4
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- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 4
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- 230000000699 topical Effects 0.000 description 4
- DGMOBVGABMBZSB-UHFFFAOYSA-N 2-methylpropanoyl chloride Chemical compound CC(C)C(Cl)=O DGMOBVGABMBZSB-UHFFFAOYSA-N 0.000 description 3
- FEBLZLNTKCEFIT-VSXGLTOVSA-N Fluocinolone acetonide Chemical compound C1([C@@H](F)C2)=CC(=O)C=C[C@]1(C)[C@]1(F)[C@@H]2[C@@H]2C[C@H]3OC(C)(C)O[C@@]3(C(=O)CO)[C@@]2(C)C[C@@H]1O FEBLZLNTKCEFIT-VSXGLTOVSA-N 0.000 description 3
- 210000000245 Forearm Anatomy 0.000 description 3
- YHASWHZGWUONAO-UHFFFAOYSA-N butanoyl butanoate Chemical compound CCCC(=O)OC(=O)CCC YHASWHZGWUONAO-UHFFFAOYSA-N 0.000 description 3
- 238000010790 dilution Methods 0.000 description 3
- 239000000284 extract Substances 0.000 description 3
- BDAGIHXWWSANSR-UHFFFAOYSA-N formic acid Chemical compound OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 3
- XGISHOFUAFNYQF-UHFFFAOYSA-N pentanoyl chloride Chemical compound CCCCC(Cl)=O XGISHOFUAFNYQF-UHFFFAOYSA-N 0.000 description 3
- 239000000843 powder Substances 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 239000002562 thickening agent Substances 0.000 description 3
- WETWJCDKMRHUPV-UHFFFAOYSA-N Acetyl chloride Chemical compound CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 description 2
- CIWBQSYVNNPZIQ-XYWKZLDCSA-N Betamethasone dipropionate Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@H](C)[C@@](C(=O)COC(=O)CC)(OC(=O)CC)[C@@]1(C)C[C@@H]2O CIWBQSYVNNPZIQ-XYWKZLDCSA-N 0.000 description 2
- VZGDMQKNWNREIO-UHFFFAOYSA-N Carbon tetrachloride Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 2
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- CSCPPACGZOOCGX-UHFFFAOYSA-N acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- 239000012346 acetyl chloride Substances 0.000 description 2
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 2
- 150000008065 acid anhydrides Chemical class 0.000 description 2
- 230000002378 acidificating Effects 0.000 description 2
- 125000002252 acyl group Chemical group 0.000 description 2
- 238000005917 acylation reaction Methods 0.000 description 2
- 238000007792 addition Methods 0.000 description 2
- FERIUCNNQQJTOY-UHFFFAOYSA-M butyrate Chemical compound CCCC([O-])=O FERIUCNNQQJTOY-UHFFFAOYSA-M 0.000 description 2
- 125000004063 butyryl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- 239000006071 cream Substances 0.000 description 2
- 239000002270 dispersing agent Substances 0.000 description 2
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- 125000001153 fluoro group Chemical group F* 0.000 description 2
- 239000006210 lotion Substances 0.000 description 2
- 239000000391 magnesium silicate Substances 0.000 description 2
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- YMWUJEATGCHHMB-UHFFFAOYSA-N methylene dichloride Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 2
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- 125000003774 valeryl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
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- JVSFQJZRHXAUGT-UHFFFAOYSA-N 2,2-dimethylpropanoyl chloride Chemical compound CC(C)(C)C(Cl)=O JVSFQJZRHXAUGT-UHFFFAOYSA-N 0.000 description 1
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- 239000006187 pill Substances 0.000 description 1
- 229920000573 polyethylene Polymers 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 230000002335 preservative Effects 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 229960003415 propylparaben Drugs 0.000 description 1
- SMWDFEZZVXVKRB-UHFFFAOYSA-N quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 238000005245 sintering Methods 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 239000007921 spray 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
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
Description
Die Erfindung betrifft neue 9«-Chlor- bzw. 9(/-FIuor-16/i-methyl-prednisolon-17,21-diester mit starker antiinflammatorischer Wirkung bei topischer Anwendung sowie ein Verfahren zu deren Herstellung.The invention relates to new 9 ″ -chlorine or 9 ( / -Fluor-16 / i-methyl-prednisolone-17,21-diesters with a strong anti-inflammatory effect when applied topically and a process for their production.
Es wurde gefunden, daß bestimmte neue 17,21-Diester, die nachfolgend bezeichnet weiden, im allgemeinen nach topischer Applikation eine beträchtlich gesteigerte antiinflammatorische Wirkung im Vergleich zu anderen, nahe verwandten, analogen Verbindungen und/oder den entsprechenden 17a,21-Dihydroxy-Stammverbindungen zeigen. Diese neuen Diester besitzen tatsächlich eine antiinflammatorische Wirkung bei topischer Verabreichung, welche die der besten speziell für topische Anwendungszwecke bisher bekannten Verbindungen wesentlich übersteigt, wie z.B. durch den Pflastertest nach McKenzie und Mitarbeitern, Arch. Derm., 1962, 86, S. 608, nachgewiesen wurde.It has been found that certain new 17,21-diesters, referred to below, are generally found after topical application a considerably increased anti-inflammatory effect in comparison to other, closely related, analogous compounds and / or the corresponding 17a, 21-dihydroxy parent compounds show. These new diesters actually have an anti-inflammatory effect when administered topically, which is similar to that of the best especially for topical purposes previously known compounds, such as e.g. by the plaster test according to McKenzie et al., Arch. Derm., 1962, 86, p. 608 would.
Die erfindungsgemäßen Verbindungen entsprechen der allgemeinen Formel (I)The compounds according to the invention correspond to the general formula (I)
HOHO
3030th
(D(D
in der X ein Chlor- oder Fluoratom, vorzugsweise ein Fluoratom, R einen Alkanoylrest mit 2 bis 6 Kohlenstoffatomen und R1 einen Alkanoylrest mit 1 bis 7 Kohlenstoffatomen bedeutet, wobei die Gesamtzahl von Kohlenstoffatomen in den Gruppen R und R1 zusammen nicht größer als 9 sein soll. Der Ausdruck »Alkanoylrest« umfaßt hierbei geradkettige, verzweigtkettige und Cycloalkanoylgruppen.in which X is a chlorine or fluorine atom, preferably a fluorine atom, R is an alkanoyl radical with 2 to 6 carbon atoms and R 1 is an alkanoyl radical with 1 to 7 carbon atoms, the total number of carbon atoms in the groups R and R 1 together not being greater than 9 should be. The term "alkanoyl radical" here includes straight-chain, branched-chain and cycloalkanoyl groups.
Die Gruppe R kann z. B. einen Acetyl-, Propionyl-, Butyryl-, Isobutyryl- oder Valerylrest bedeuten. R1 kann z. B. einen Formyl-, Acetyl-, Propionyl-, Butyryl-, Isobutyryl-, Valeryl- oder Hexahydrobenzoylrest bedeuten.The group R can e.g. B. mean an acetyl, propionyl, butyryl, isobutyryl or valeryl radical. R 1 can e.g. B. mean a formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl or hexahydrobenzoyl radical.
Die genannten 17a,21-Diester gemäß der Erfindung können nach an sich bekannten Methoden, z. B. durch Acylierung der entsprechenden 17a,21-Diole oder der entsprechenden 17u-Hydroxy-21-alkanoyloxy-verbindungen, hergestellt werden. Diese Reaktion wird vorzugsweise durch Umsetzung des Steroids mit dem geeigneten Säureanhydrid in Gegenwart eines stark sauren Katalysators, wie p-Toluolsulfonsäure. Perchlorsäure oder ein stark saures Kationenaustauscherharz, durchgeführt. Außerdem kann die Reaktion mit oder ohne ein Lösungsmittel durchgeführt werden. Wenn ein Lösungsmittel verwendet wird, nimmt man vorzugsweise ein nichtpolares; Beispiele für geeignete Lösungsmittel sind Tetrachlorkohlenstoff, Benzol, Toluol, Methylenchlorid und Chloroform. Erhitzen kann sich, je nach der Reaktionsfähigkeit der Reaktionskomponenten, als notwendig erweisen.Said 17a, 21-diesters according to the invention can according to methods known per se, for. B. by acylation of the corresponding 17a, 21-diols or the corresponding 17u-hydroxy-21-alkanoyloxy compounds, getting produced. This reaction is preferably carried out by reacting the steroid with the appropriate acid anhydride in the presence of a strongly acidic catalyst such as p-toluenesulfonic acid. Perchloric acid or a strongly acidic cation exchange resin. Also, the reaction can be carried out with or without a solvent. If a solvent is used, one preferably takes a non-polar one; Examples of suitable solvents are carbon tetrachloride, Benzene, toluene, methylene chloride and chloroform. It can heat up, depending on your reactivity of the reaction components, prove necessary.
Falls eine Verbindung hergestellt werden soll, in der R und R1 verschiedene Alkanoylreste bedeuten, kann man zuerst einen entsprechenden 21-Monoester herstellen und diesen dann verestern, um eine verschiedene Alkanoylgruppe in die 17(/-Stellung einzuführen. If a compound is to be produced in which R and R 1 are different alkanoyl radicals, one can first produce a corresponding 21-monoester and then esterify this in order to introduce a different alkanoyl group into the 17 (/ - position.
Die 17f«,21 -Diester nach der Erfindung können auch durch Acylierung der entsprechenden 21-Hydroxy-17(i-monoester, die z. B. nach dem Verfahren der Patentanmeldung P 14 43 958.8 erhältlich sind. hergestellt werden. Diese Veresterung wird vorzugsweise mit dem geeigneten Säureanhydrid oder Säurechlorid unter basischen Bedingungen durchgeführt, vorzugsweise in Gegenwart einer tertiären organischen Base, wie Pyridin,Chinolin, N-Mcthylpipcridin,N-Methylmorpholin oder Dimethylanilin. Zweckmäßigerweise wird ein Überschuß an tertiärer organischer Base als Lösungsmittel verwendet, doch können auch andere Lösungsmittel, wie Benzol, Toluol, Dioxan oder Tetrahydrofuran, verwendet werden. Die Reaktion kann je nach Bedürfnis mit oder ohne Erhitzen durchgeführt werden.The 17f «, 21 diesters according to the invention can also by acylation of the corresponding 21-hydroxy-17 (i-monoester, the z. B. are available by the method of patent application P 14 43 958.8. getting produced. This esterification is preferably carried out with the appropriate acid anhydride or acid chloride carried out under basic conditions, preferably in the presence of a tertiary organic Bases such as pyridine, quinoline, N-methylpipcridine, N-methylmorpholine or dimethylaniline. Appropriately, an excess of tertiary organic Base is used as a solvent, but other solvents such as benzene, toluene, dioxane can also be used or tetrahydrofuran can be used. The reaction can be with or without heating, depending on your needs be performed.
Es muß hervorgehoben werden, daß diese Verfahrensweise auch zur Herstellung von Diestern ge- ' eignet ist, in denen R und R1 verschiedene Alkanoylgruppen bedeuten.It must be emphasized that this procedure is also suitable for the preparation of diesters in which R and R 1 are different alkanoyl groups.
Die aktiven Steroide nach der Erfindung können zu einem Präparat, das für topische Anwendung geeignet ist, in üblicher Weise mit Hilfe eines oder mehrerer Träger- oder Bindemittel verarbeitet werden. Beispiele für Zubereitungsarten umfassen Salben, Lotionen, Cremes, Puder, Tropfen (z. B. Ohren- und Augentropfen), Sprays, Suppositorien, Retentionsklistiere. Kau- oder Lutschtabletten oder Pillen (z. B. zur Behandlung von aphthenischen Ulcera) und Aerosole. Salben und Cremes können z. B. mit einer wäßrigen oder öligen Grundlage unter Zusatz eines geeigneten Verdickungs- und/oder Geliermittels zubereitet werden. Solche Grundlagen können z. B. Wasser und/oder ein öl, wie flüssiges Paraffin oder ein pflanzliches öl, wie Erdnußöl oder Rizinusöl, enthalten. Verdickungsmittel, die entsprechend der Art der Grundlage verwendet werden können, enthalten Weichparaffin, Aluminiumstearat, Ketostearylalkohol, Polyäthylenglykole, Wollfett, hydriertes Lanolin, ( Bienenwachs usw.The active steroids according to the invention can be converted into a preparation suitable for topical application is, can be processed in the usual way with the aid of one or more carriers or binders. Examples of types of preparation include ointments, lotions, creams, powders, drops (e.g. ear and Eye drops), sprays, suppositories, retention enemas. Chewable or lozenges or pills (e.g. for the treatment of aphthous ulcers) and aerosols. Ointments and creams can e.g. B. with a prepared aqueous or oily base with the addition of a suitable thickening and / or gelling agent will. Such bases can e.g. B. water and / or an oil such as liquid paraffin or contain a vegetable oil, such as peanut oil or castor oil. Contain thickeners that can be used according to the type of base Soft paraffin, aluminum stearate, ketostearyl alcohol, polyethylene glycols, wool fat, hydrogenated lanolin, ( Beeswax etc.
Lotionen können mit einer wäßrigen oder öligen Grundlage zubereitet werden und enthalten im allgemeinen auch eine oder mehrere der folgenden Verbindungsklassen, nämlich Emulgiermittel, Dispergiermittel, Suspendiermittel, Verdickungsmittel, Färbemittel, Duftstoffe, Stabilisatoren u. dgl.Lotions can be prepared with an aqueous or oily base and generally contain also one or more of the following classes of compounds, namely emulsifiers, dispersants, Suspending agents, thickening agents, coloring agents, fragrances, stabilizers and the like.
Puder können mit Hilfe jeder geeigneten Pudergrundlage, z. B. mit Talk, Lactose. Stärke usw.. zubereitet werden. Tropfen können mit einer wäßrigen Grundlage, die auch ein oder mehrere Dispergiermittel, Suspendiermittel, löslichkeitserleichternde Mittel usw., enthält, zubereitet werden. Nichtwäßrige Grundlagen können ebenfalls verwendet werden.Powders can be powdered using any suitable powder base, e.g. B. with talc, lactose. Starch etc. prepared will. Drops can be made with an aqueous base, which also contains one or more dispersants, Suspending agents, solubilizing agents, etc., can be prepared. Non-aqueous Basics can also be used.
Die pharmazeutischen Zubereitungen können auch ein oder mehrere Konservierungs- oder bakteriostatische Mittel, z. B. Methylhydroxybenzoat, Propylhydroxybenzoat, Chlorkresol, Benzalkoniumchloride usw., enthalten.The pharmaceutical preparations can also be one or more preservative or bacteriostatic Medium, e.g. B. methyl hydroxybenzoate, propyl hydroxybenzoate, chlorocresol, benzalkonium chlorides etc., included.
Diese Zubereitungen können auch andere aktive Bestandteile, z. B. antimikrobielle Mittel, insbesondere Antibiotika, enthalten.These preparations can also contain other active ingredients, e.g. B. antimicrobials, in particular Antibiotics.
Der Anteil an aktivem Steroid in diesen Zuberei-The proportion of active steroid in these preparations
tunüen hängt von der genauen Art der herzustellenden
Präparate ab, liegt jedoch im allgemeinen im Bereich von 0,0001 bis 5 Gewichtsprozent. Für die meisten
Arten von Zubereitungen liegt der verwendete Steroidanteil jedoch im allgemeinen vorteilhafterweise im
Bereich von 0,001 bis 0,5% und vorzugsweise von 0.01 bis 0,25%.
Die folgenden Beispiele erläutern die Erfindung.Tuna depends on the exact nature of the preparation to be made, but is generally in the range of 0.0001 to 5 percent by weight. For most types of preparations, however, the level of steroid employed is generally advantageously in the range of from 0.001 to 0.5%, and preferably from 0.01 to 0.25%.
The following examples illustrate the invention.
B e i s ρ i e 1 1B e i s ρ i e 1 1
21 -Bu tyry loxy-9(/-fluor-11 /i-hydroxy-17a-isobutyryloxy-16/i-niethyl-pregna-l,4-dien-3,20-dion (Betamethason-17-isobutyrat-21-butyrat)21 -Bu tyryloxy-9 (/ - fluoro-11 / i-hydroxy-17a-isobutyryloxy-16 / i-niethyl-pregna-1,4-diene-3,20-dione (Betamethasone-17-isobutyrate-21-butyrate)
1,08 g 9u-Fluor-l l/i,21 -dihydroxy-»I7u-isobutyryloxy-16/i-methyl-pregna-l,4-dien-3,20-dion inlO ml Pyridin wurden mit 2 ml Buttersäureanhydrid bei Zimmertemperatur umgesetzt und das Gemisch 17 Stunden bei 00C stehengelassen. Verdünnen mit Wasser und Extraktion mit Äther ergab den rohen Diester, der aus Äther—Petroläther bei —80'C kristallisiert wurde und das 21-Butyryloxy-9«-fluor-11/i-hydroxy-ITu-isobutyryloxy-lo/i-methyl-pregnal,4-dien-3,20-dion ergab; F. = 149 bis 150°C (Zersetzung nach vorherigem Erweichen), O]0 = +65,0' k- = 1,0, Dioxan), λ (^«>Η = 237 bis. 240 ma (ρ = 15 550).1.08 g of 9u-fluoro-1 l / i, 21 -dihydroxy- »17u-isobutyryloxy-16 / i-methyl-pregna-1,4-diene-3,20-dione in 10 ml of pyridine were added with 2 ml of butyric anhydride Reacted room temperature and the mixture left to stand at 0 0 C for 17 hours. Dilution with water and extraction with ether gave the crude diester, which was crystallized from ether-petroleum ether at -80 ° C. and 21-butyryloxy-9 "-fluoro-11 / i-hydroxy-ITu-isobutyryloxy-lo / i-methyl -pregnal, 4-diene-3,20-dione; F. = 149 to 150 ° C (decomposition after previous softening), O] 0 = +65.0 'k- = 1.0, dioxane), λ ( ^ « > Η = 237 to. 240 ma (ρ = 15 550).
Analyse: C30H41FO7.Analysis: C 30 H 41 FO 7 .
Berechnet ... C 67,7, H 7,8%; gefunden .... C 67,7, H 7,95%.Calculated ... C 67.7, H 7.8%; found .... C 67.7, H 7.95%.
21 -Acetoxy-9(t-fluor-11 /i-hydroxy-16/i-methy 1-17avaleryloxy-pregna-1,4-dien-3,20-dion (Betamethason-17-valeriat-21-acetat)21-Acetoxy-9 (t-fluoro-11 / i-hydroxy-16 / i-methy 1-17avaleryloxy-pregna-1,4-diene-3,20-dione (Betamethasone-17-valeriate-21-acetate)
300 mg Betamethason- 17-valeriat wurden in 3 ml Pyridin gelöst, mit 0,08 ml Essigsäureanhydrid umgesetzt und über Nacht stehengelassen. Das Gemisch wurde mit 50 ml Wasser behandelt, mit Chloroform extrahiert und die Extrakte mit 1 normaler Salzsäure und Wasser gewaschen, getrocknet und eingedampft.-Kristallisation des Rückstandes aus Essigsäureäthylester—Petroläther ergab 132 mg Betamethason-17-valeriat-21-acetat in Form von feinen Nadeln; F. = 202' C (im geschlossenen Rohr), 01° = +50,5" (c· = 1,1, Dioxan), /^0" = 238 ma (ρ =15 510).300 mg betamethasone 17-valerate were dissolved in 3 ml pyridine, reacted with 0.08 ml acetic anhydride and left to stand overnight. The mixture was treated with 50 ml of water, extracted with chloroform and the extracts washed with 1 normal hydrochloric acid and water, dried and evaporated. Crystallization of the residue from ethyl acetate-petroleum ether gave 132 mg of betamethasone-17-valeriate-21-acetate in the form of fine needles; F. = 202 'C (in a closed tube), 01 ° = +50.5 "(c = 1.1, dioxane), / ^ 0 " = 238 ma (ρ = 15 510).
Analyse: C29H39FO7.Analysis: C 29 H 39 FO 7 .
Berechnet
gefunden .Calculated
found .
C 67,15, H 7,6%; C 66.95, H 7,65%.C 67.15, H 7.6%; C 66.95, H 7.65%.
Form von Prismen: F. = etwa 130' C (Zersetzung), O]0 = +66r; (C= 1,4, Dioxan), Λ £"·■<>" = 239 ma U = 14 870).Shape of prisms: F. = about 130 'C (decomposition), O] 0 = +66 r; (C = 1.4, dioxane), Λ £ "· ■ <>" = 239 ma U = 14 870).
Analyse: C26H33FO7. .Analysis: C 26 H 33 FO 7 . .
Berechnet ... C 65,5,. H 7,0%;
gefunden C 65,65. H 7,35%.Calculated ... C 65.5 ,. H 7.0%;
found C, 65.65. H 7.35%.
Beispiel 4 .Example 4.
17a-Acetoxy-9a-fluor-l 1 /i-hydroxy-16/i-methyl-17a-acetoxy-9a-fluoro-l 1 / i-hydroxy-16 / i-methyl-
21-valeryloxy-prcgna-l,4-dien-3,20-dion21-valeryloxy-prcgna-1,4-diene-3,20-dione
(Betamethason-17-acetat-21-valeriat)(Betamethasone-17-acetate-21-valeriate)
500 mg Betamethason-17-acetat in 10 ml Pyridin wurden mit 0,1 ml Valerylchlorid bei Zimmertemperatur 40 Minuten behandelt. Das Gemisch wurde mit Wasser verdünnt und mit Äther extrahiert. Die Extrakte wurden mit Wasser gewaschen, getrocknet und im Vakuum eingedampft. Umkristallisation des Rückstandes aus Äther—Aceton—Petroläther ergab 300 mg Betamethason-17-acetat-21-valeriat; F. = 124 bis 125JC (Zersetzung), O]0 = +64 (c = 1,09, Dioxan), λ^ΟΗ = 238 ma (ρ = 16 230).500 mg betamethasone-17-acetate in 10 ml pyridine were treated with 0.1 ml valeryl chloride at room temperature for 40 minutes. The mixture was diluted with water and extracted with ether. The extracts were washed with water, dried and evaporated in vacuo. Recrystallization of the residue from ether — acetone — petroleum ether gave 300 mg of betamethasone-17-acetate-21-valerate; F. = 124 to 125 J C (decomposition), O] 0 = +64 (c = 1.09, dioxane), λ ^ ΟΗ = 238 ma (ρ = 16 230).
Analyse: C29H39FO7.Analysis: C 29 H 39 FO 7 .
Berechnet ... C 67,2, H 7,6%;
gefunden .... C 67,5, H 8,1%.Calculated ... C 67.2, H 7.6%;
found .... C 67.5, H 8.1%.
17(i-Acetoxy-9a-fluor-21 -hexahydrobenzoyloxy-17 (i-acetoxy-9a-fluoro-21 -hexahydrobenzoyloxy-
11 /i-hydroxy-16/i-methy 1-pregna-1,4-dien-3,20-dion (Betamethason-17-acetat-21-hexahydrobenzoat)11 / i-hydroxy-16 / i-methy 1-pregna-1,4-diene-3,20-dione (Betamethasone-17-acetate-21-hexahydrobenzoate)
500 mg Betamethason-17-acetat wurden mit 0,1 ml Hexahydrobenzoylchlorid behandelt und das Produkt wie im Beispiel 4 isoliert. Kristallisation des rohen Produkts aus Äther—Aceton—Petroläther ergab 408 mg Betamethason - 17 - acetat - 21 - hexahydrobenzoat; F. = 228 bis 229° C (Zersetzung), O]" = +75,7° (c = 1,95, Dioxan), /C,n,on = 238 bis 239 ma U = 16 390).500 mg betamethasone 17-acetate were treated with 0.1 ml hexahydrobenzoyl chloride and the product isolated as in Example 4. Crystallization of the crude product from ether-acetone-petroleum ether gave 408 mg betamethasone-17-acetate-21-hexahydrobenzoate; F. = 228 to 229 ° C (decomposition), O] ″ = + 75.7 ° (c = 1.95, dioxane), / C, n, on = 238 to 239 ma U = 16,390).
na^l-Diacetoxy^a-fluor-ll/i-hydroxy-16/i-methyl-pregna-1,4-dien-3,20-dion na ^ l-Diacetoxy ^ a-fluoro-II / i-hydroxy-16 / i-methyl-pregna-1,4-diene-3,20-dione
(Betamethason-17,21 -diacetat)(Betamethasone 17.21 diacetate)
1,2g Betamethason-17-acetat in 15 ml eisgekühltem trockenem Pyridin wurden mit 6ml Essigsäureanhydrid bei Zimmertemperatur I1 2 Stunden umgesetzt. Das Gemisch wurde in etwa 1 1 Eiswasser geschüttet und die Festsubstanz durch Filtration isoliert, in Chloroform gelöst und über Magnesiumsulfat getrocknet. Der nach Verdampfen des Chloroforms verbleibende Rückstand wurde aus Aceton—Petroläther kristallisiert und ergab 830 mg Betamethason-17,21-diacetat in1.2 g betamethasone-17-acetate in 15 ml ice-cold dry pyridine were reacted with 6 ml acetic anhydride at room temperature for 1 2 hours. The mixture was poured into about 1 l of ice water and the solid substance was isolated by filtration, dissolved in chloroform and dried over magnesium sulfate. The residue remaining after evaporation of the chloroform was crystallized from acetone-petroleum ether and yielded 830 mg betamethasone-17,21-diacetate in
5555
60 Analyse: C31 60 Analysis: C 31
Berechnet
gefunden .Calculated
found .
H41FO7.H 41 FO 7 .
... C 68,4, H 7,6%;
... C 68,6, H 7,6%.... C 68.4, H 7.6%;
... C 68.6, H 7.6%.
17fi-Acetoxy-9«-fluor-11 /i-hydroxy-21 -isobutyryloxy-17fi-acetoxy-9 "-fluoro-11 / i-hydroxy-21 -isobutyryloxy-
16/i-methyl-pregna-1,4-dien-3,20-dion
(Betamethason-17-acetat-21-isobutyrat)16 / i-methyl-pregna-1,4-diene-3,20-dione
(Betamethasone-17-acetate-21-isobutyrate)
500 mg Betamethason-17-acetat wurden mit 0,1 ml Isobutyrylchlorid behandelt und das Produkt wie im Beispiel 4 isoliert. Umkristallisation des Rohprodukts aus Äther—Aceton—Petroläther ergab 366 mg Betamethason-17-acetat-21-isobutyrat; F. = 211 bis 2120C (Zersetzung). O]= = +70° (c = 1,7, Dioxan), γ c,h,oh = 238 mu U = 16 290).500 mg betamethasone-17-acetate were treated with 0.1 ml isobutyryl chloride and the product isolated as in Example 4. Recrystallization of the crude product from ether — acetone — petroleum ether gave 366 mg of betamethasone 17-acetate-21-isobutyrate; F. = 211 to 212 0 C (decomposition). O] = = + 70 ° (c = 1.7, dioxane), γ c, h, oh = 238 mu U = 16 290).
Analyse: C28H37FO7.Analysis: C 28 H 37 FO 7 .
Berechnet ... C 66,65, H 7,4%;
gefunden .... C 66,5, H 7,35%-Calculated ... C 66.65, H 7.4%;
found .... C 66.5, H 7.35% -
^i-Fluor-ll/Miydroxy-ITu.ZI-diisobutyryloxy-^ i-Fluor-II / Miydroxy-ITu.ZI-diisobutyryloxy-
16(/-mcthyl-pregna-l,4-dien-3,20-dion16 ( / -methyl-pregna-1,4-diene-3,20-dione
(Betamethason-17.21-di-isobutyrat)(Betamethasone 17.21-di-isobutyrate)
500 mg Bclaincthason-17-isobutyrat wurden mit 0,135 ml Isobutyrylchlorid behandelt und das Produkt wie im Beispiel 4 isoliert. Filtration des Rohprodukts in Benzol Chloroform (9:1) durch 30 g Magnesiumsilikat und Kristallisation aus Benzol —Petroläthcr ergab 414 mg Betamethason-17,21-di-isobutyrat; F. = 121 bis 124 C, O]0 = +67,2 (c = 0.9. Dioxan), λ™*ηι = 238 bis 239 m-x U = 15 650).500 mg of Bclaincthasone 17-isobutyrate were treated with 0.135 ml of isobutyryl chloride and the product was isolated as in Example 4. Filtration of the crude product in benzene-chloroform (9: 1) through 30 g of magnesium silicate and crystallization from benzene-petroleum ether gave 414 mg of betamethasone-17,21-di-isobutyrate; F. = 121 to 124 C, O] 0 = +67.2 (c = 0.9. Dioxane), λ ™ * ηι = 238 to 239 mx U = 15,650).
Analyse: C30H41FO7.Analysis: C 30 H 41 FO 7 .
C 67.65. H 7.8%:
C 67.5. H 7.65°,,.C 67.65. H 7.8%:
C 67.5. H 7.65 ° ,,.
Berechnet
gefunden .Calculated
found .
9<i-Fluor-l 1//-hydroxy-KijZ-methyl-l 7fj.21-dipro-9 <i-fluorine-l 1 // - hydroxy-KijZ-methyl-l 7fj.21-dipro-
pionyioxy-pregna-1.4-dien-3,20-dionpionyioxy-pregna-1.4-diene-3,20-dione
(Betamethason-17.21 -dipropionat)(Betamethasone 17.21 dipropionate)
812 mg Betamethason-17-propionat in 10 ml Pyridin wurden mit 0.21 ml Propionylchlorid bei 0 C 1 Stunde behandelt. Verdünnen mit Wasser und Ansäuern mit verdünnter Salzsäure ergab den rohen' Diester. Umkristallisation aus Aceton — Pctroläthcr ergab 649 mg Betamethason-17,21-dipropionat: F. = 117' C (Zersetzung). [«]0 = +62,2" (<· = 0.96. Dioxan), /£1*°" = 238 bis 239 πΐμ (t = 15 100).812 mg betamethasone-17-propionate in 10 ml pyridine were treated with 0.21 ml propionyl chloride at 0 C for 1 hour. Dilution with water and acidification with dilute hydrochloric acid gave the crude diester. Recrystallization from acetone - Pctroläthcr gave 649 mg betamethasone-17,21-dipropionate: M. = 117 ° C (decomposition). [«] 0 = +62.2"(<· = 0.96. Dioxane), / £ 1 * ° "= 238 to 239 πΐμ ( t = 15 100).
Analyse: C2HH37FO7.Analysis: C 2H H 37 FO 7 .
Berechnet
gefunden .Calculated
found .
C 66.65. H 7.4° ο:
C 66.4. H 7.4%.C 66.65. H 7.4 ° ο:
C 66.4. H 7.4%.
21-Acetoxy-9(i-fluor-l l,i-hydroxy-16/f-methyl-21-acetoxy-9 (i-fluoro-l l, i-hydroxy-16 / f-methyl-
lTa-propionyloxy-pregna-U+Klien-S.ZO-dionlTa-propionyloxy-pregna-U + Klien-S.ZO-dione
(Betamethason-17-propionat-21-acetal)(Betamethasone-17-propionate-21-acetal)
902 mg Bctamethason-17-propionat in 10 ml Pyridin wurden mit 0.25 ml Essigsäureanhydrid wie im Beispiel 8 18 Stunden behandelt. Kristallisation des Rohprodukts aus Äther ergab 474 mg Betamethason-17-propionat-21 - acetal: F. = 134 C (Zersetzung). [«]„ - +64.1 U- = 0.92. Dioxan). /^J"" = 238 ma (# = 15 7501.902 mg of bctamethasone 17-propionate in 10 ml of pyridine were treated with 0.25 ml of acetic anhydride as in Example 8 for 18 hours. Crystallization of the crude product from ether gave 474 mg betamethasone-17-propionate-21-acetal: F. = 134 C (decomposition). [«]" - +64.1 U- = 0.92. Dioxane). / ^ J "" = 238 ma (# = 15 7501.
Analyse: C2-H35FO-.Analysis: C 2 -H 35 FO-.
Berechnet ... C 66.16. H 7.2",,:
gefunden .... C 66.1. H 7.3%.Calculated ... C 66.16. H 7.2 ",,:
found .... C 66.1. H 7.3%.
17«-Acetoxy-9«-fiuor-21-formyIoxy-l 1^-hydroxy-16/i-methyl-pregna-1.4-dien-3.20-dion
(Betamethason-n-acetat^l-formiat)17 "-Acetoxy-9" -fluoro-21-formoxy-l 1 ^ -hydroxy-16 / i-methyl-pregna-1,4-diene-3.20-dione
(Betamethasone-n-acetate ^ l-formate)
500 mg 17<i-Acetoxy-9«i-fluor-11//.21 -dihydroxylo/i-methyl-prcgna-l^-dien-i^O-dion in 2 ml Ameisensäure (98 bis KX)",,). die 50mg p-Toluolsulfonsaure enthielt, wurde bei Zimmertemperatur stehengelassen. Nach 5 Stunden wurde die Lösung in KX) ml Eiswasser geschüttet, der feste Niederschlag wurde durch Filtration isoliert, mit verdünnter Natriumbicarbonat lösung und Wasser gewaschen, getrocknet und aus Äther Petroläther umkristallisiert, wobei 333 mn Betamethason-lT-acetat-Zl-formiat erhalten500 mg 17 <i-acetoxy-9 "i-fluoro-11 //. 21 -dihydroxylo / i-methyl-prcgna-l ^ -dien-i ^ O-dione in 2 ml of formic acid (98 to KX) ",,). the 50 mg of p-toluenesulfonic acid was allowed to stand at room temperature. After 5 hours the solution in KX) ml Poured ice water, the solid precipitate was isolated by filtration with dilute sodium bicarbonate solution and water washed, dried and recrystallized from ether petroleum ether, wherein 333 mn betamethasone lT acetate Zl formate was obtained
wurden; F. = 225 C, [«],. = +62,5 (c = 1,0. Dioxan), /. S·011 = 237 bis 240 m<i (/■■ = 14 750).became; F. = 225 C, [«] ,. = +62.5 (c = 1.0. Dioxane), /. S 011 = 237 to 240 m <i (/ ■■ = 14 750).
Analyse: C25H11FO-.Analysis: C 25 H 11 FO-.
Berechnet ... C 64,9, H 6,8%:
gefunden .... C 64,9. H 6.8%.Calculated ... C 64.9, H 6.8%:
found .... C 64.9. H 6.8%.
Beispiel 11Example 11
17ri-Acetoxy-9(i-fluor-11 /i-hydroxy-16/i-methyl-17ri-acetoxy-9 (i-fluoro-11 / i-hydroxy-16 / i-methyl-
21 -propionyloxy-pregna-1,4-dien-3,20-dion21-propionyloxy-pregna-1,4-diene-3,20-dione
(Betamethason-n-aeetat-^l-propionat)(Betamethasone-n-acetate- ^ l-propionate)
5(Xl mg I7u-Acetoxy-9(i-fluor-1 l/i,21-dihydroxy-16(/-mcthyl-pregna-l,4-dien-3,2()-dion wurden in 10 ml5 (Xl mg of 17u-acetoxy-9 (i-fluoro-1 l / i, 21-dihydroxy-16 ( / -methyl-pregna-1,4-diene-3,2 () -dione) were added in 10 ml
is trockenem Pyridin bei 0 C gelöst und mit 0,15 ml Propionylchlorid behandelt. Nach einer Stunde wurde das Gemisch mit Eiswasser verdünnt und die ausgefallene Festsubstanz durch Filtration isoliert, in Äther gelöst und die Lösung durch 20 g Aluminiumoxyd filtriert. Kristallisation des eluierten Materials aus Äther—Aceton Petroläther und anschließend aus Äther—Petroläther ergab 160 mg Betamcthason-17-acetat-21-propionat: F. = 122 C (Zersetzung), [„]., = +65.5 (c = 1.0. Dioxan). /. I,,;,1,1·"" = 236 bis 240 m-i (ι = 14 600).is dissolved dry pyridine at 0 C and treated with 0.15 ml of propionyl chloride. After one hour the mixture was diluted with ice water and the precipitated solid substance was isolated by filtration, dissolved in ether and the solution was filtered through 20 g of aluminum oxide. Crystallization of the eluted material from ether-acetone petroleum ether and then from ether-petroleum ether gave 160 mg betamcthasone-17-acetate-21-propionate: F. = 122 C (decomposition), [„]., = +65.5 (c = 1.0. Dioxane). /. I ,,;, 1 , 1 · "" = 236 to 240 mi (ι = 14,600).
Analyse: C27H15FO-.Analysis: C 27 H 15 FO-.
Berechnet ... C 66.1. H 7.2%:
gefunden C 66.4. H 7.65%. ·Calculated ... C 66.1. H 7.2%:
found C 66.4. H 7.65%. ·
Beispiel 12Example 12
21 -Butyryloxy-9i(-lluor-11 /i-hydroxy-16/i-methy 1-17./-PrOPiOn)IoXy-PrCgIIa-1.4-dien-3,20-dion 21 -Butyryloxy-9i (-lluor-11 / i-hydroxy-16 / i-methy 1-17./-PrOPiOn) IoXy-PrCgIIa-1.4-diene-3,20-dione
(Betamethason-17-propionat-21-butyral)(Betamethasone-17-propionate-21-butyral)
517 mg 9<j-Fluor-ll,i.21-dihydroxy-16/i-methyl-17«-propionyloxy-pregna-l,4-dien-3,20-dion in 10 ml trockenem Pyridin wurden auf 0 C gekühlt und mit 0.24 ml Buttersäureanhydrid behandelt. Nach 2 Tagen wurde die Lösung mit Wasser verdünnt, mit verdünnter Salzsäure angesäuert und das weiße kristalline Material durch Filtration isoliert. Kristallisation aus Äther ergab 439 mg Betamethason-17-propionat-21-butyrat; F. = 161 bis 163 C (Zersetzung). [(£],517 mg of 9 <j-fluoro-II, i.21-dihydroxy-16 / i-methyl-17 "-propionyloxy-pregna-1,4-diene-3,20-dione in 10 ml of dry pyridine were cooled to 0.degree and treated with 0.24 ml of butyric anhydride. After 2 days the solution was diluted with water, acidified with dilute hydrochloric acid and the white crystalline material isolated by filtration. Crystallization from ether gave 439 mg betamethasone 17-propionate-21-butyrate; F. = 161 to 163 C (decomposition). [ (£ ],
.45 = +67.5; (c = 0.95. Dioxan). ;.<m·»·"·' = 238 bis 239 m·* U = 15 900)..45 = +67.5 ; (c = 0.95, dioxane). ;. < m · »·" · '= 238 to 239 m · * U = 15,900).
Analyse: C29H10FO-.Analysis: C 29 H 10 FO-.
Berechnet ... C 67.2. H 7.6" „:
so gefunden .... C 67.45. H 7,9",,.Calculated ... C 67.2. H 7.6 "":
so found .... C 67.45. H 7.9 ",,.
Beispiel 13Example 13
9.t-Fluor-ll/i-hydroxy-21-isobutyryloxy-16,i-methyl-17«-propiony
loxy-prcgna-1.4-dien-3.20-dion
(Betamethason-17-propionat-21-isobutyrat)9. t-Fluoro-II / i-hydroxy-21-isobutyryloxy-16, i-methyl-17 "-propiony loxy-prcgna-1,4-diene-3.20-dione
(Betamethasone-17-propionate-21-isobutyrate)
364 mg 9u-Fluor-1 f-,i.21 -dihydroxy- 16,i-methyl-17 <i-propionyloxy-prcgna-1.4-dien-3.2()-dion in 5 ml trockenem Pyridin wurden mit 0.12 ml Isobutyrylchlorid 1 Stunde bei 0 C behandelt und. wie im Beispiel 12 beschrieben, aufgearbeitet. Kristallisation aus Äther ergab 216 mg Betamethason-17-propionat-21-isobutyrat;F. = 153 C(Zerset/uiml. [.<] =+66.0 (<■ = 1.0. Dioxan). A 1Jx'·"» = 236 bis 239 nvi (·■ = 15 750).364 mg of 9u-fluoro-1f-, i.21-dihydroxy- 16, i-methyl-17 < i -propionyloxy-prcgna-1,4-diene-3.2 () - dione in 5 ml of dry pyridine were mixed with 0.12 ml of isobutyryl chloride 1 Treated hour at 0 C and. as described in Example 12, worked up. Crystallization from ether gave 216 mg betamethasone 17-propionate-21-isobutyrate; F. = 153 C (decomposed / uiml. [. <] = + 66.0 (<■ = 1.0. Dioxane). A 1 J x '· "» = 236 to 239 nvi (· ■ = 15 750).
Analyse: C2UH1OFO-.Analysis: C 2U H 1O FO-.
Berechnet ... C 67.2. H 7.6",,;
gefunden C 67.3. H 7.S",,.Calculated ... C 67.2. H 7.6 "";
found C 67.3. H 7.S ",,.
Beispiel 14Example 14
9«-Fluor-11 /ΐ-hydroxy-16/i-methyI-17«-propionyloxy-21-valeryloxy-pregna-l,4-dien-3,20-dion
(Betamethason-17-propionat-21-valeriat)9 "-Fluoro-11 / ΐ-hydroxy-16 / i-methyl-17" -propionyloxy-21-valeryloxy-pregna-1,4-diene-3,20-dione
(Betamethasone-17-propionate-21-valeriate)
328 g 9« - Fluor -11/^,21 -dihydroxy -I6[i- methyl-17«-propionyloxy-pregna-l,4-dien-3,20-dion in 5 ml Pyridin wurden in 0,12 ml Valerylchlorid 1 Stunde bei 0° C behandelt und, wie im Beispiel 12 beschrieben, aufgearbeitet. Das Rohprodukt wurde in Essigsäureiithyiester—Benzol (1 :9) durch 10 g Magnesiumsilikat filtriert und das eluierte Material zweimal aus Äther—Petroläther umkristallisiert; man erhielt das Betamethason-17-propionat-21-valeriat; F.= 112328 g of 9 "-fluoro-11 / ^, 21 -dihydroxy- 16 [i- methyl-17" -propionyloxy-pregna-1,4-diene-3,20-dione in 5 ml of pyridine were dissolved in 0.12 ml of valeryl chloride Treated 1 hour at 0 ° C and, as described in Example 12, worked up. The crude product was filtered through 10 g of magnesium silicate in ethyl acetate-benzene (1: 9) and the eluted material was recrystallized twice from ether-petroleum ether; the betamethasone-17-propionate-21-valeriate was obtained; F. = 112
bis 240 maup to 240 ma
(,· = 16400).up to 113 "'C (decomposition.
(, · = 16400).
.. C 67,7,.. C 67.7,
.. C 67.7,
gefunden ..Calculated .
found ..
H H
H
7,9%.7.8%;
7.9%.
9i/-Fluor-l 1 //-hydroxy-16/i-methy 1-21 -pi valyloxy-17«-propionyloxy-pregna-1,4-dien-3,20-dion
(Betamethason-17-propionat-21 -pi valat)9i / -Fluor-l 1 // - hydroxy-16 / i-methy 1-21 -pi valyloxy-17 "-propionyloxy-pregna-1,4-diene-3,20-dione
(Betamethasone-17-propionate-21-pi valate)
990 mg 9a-Fluor-ll/i,21-dihydroxy-16/i-methyl-17«-propionyloxy-pregna-l,4-dien-3,20-dion in 10 ml trockenem Pyridin wurden mit 0,35 ml Pivalylchlorid 1 Stunde bei OC behandelt und, wie im Beispiel 12 beschrieben, aufgearbeitet. Umkristallisation des Rohprodukts aus Benzol ergab 800 mg Betamethason-17-propionat-21-pivalat; F. = 214 bis 215" C (Zersetzung), [a]0 = +64,1" (c = 0.91, Dioxan). λ^·"Η = 239 ma U = 15 250).990 mg of 9a-fluoro-II / i, 21-dihydroxy-16 / i-methyl-17 «-propionyloxy-pregna-1,4-diene-3,20-dione in 10 ml of dry pyridine were mixed with 0.35 ml of pivalyl chloride Treated 1 hour at OC and, as described in Example 12, worked up. Recrystallization of the crude product from benzene gave 800 mg of betamethasone 17-propionate-21-pivalate; F. = 214 to 215 "C (decomposition), [a] 0 = +64.1" (c = 0.91, dioxane). λ ^ · " Η = 239 ma U = 15 250).
3m;x U 15 25
Analyse: C30H41FO7.
Bh C 63m; x U 15 25
Analysis: C 30 H 41 FO 7 .
Bh C 6
Berechnet
gefundenCalculated
found
C 67,7, H 7,8%;
C 67,5, H 7.55%.C 67.7, H 7.8%;
C 67.5, H 7.55%.
Beispiel 16Example 16
4C4C
4545
21-Acetoxy-17fi-butyryloxy-9u-f1uor-l 1/i-hydroxy-16,»-methy
l-pregna-1,4-dien-3,20-dion
(Betamethason-17-butyrat-21 -acetal)21-acetoxy-17fi-butyryloxy-9u-fluor-1 1 / i-hydroxy-16, "- methyl-pregna-1,4-diene-3,20-dione
(Betamethasone-17-butyrate-21 -acetal)
700 mg 17«-ButyryIoxy-9«-fluor-l 1^,21-dihydroxy-16/i-methyl-pregna-1.4-dien-3,20-dion in 10 ml trockenem Pyridin wurden mit 0,14 mlAcetylchlorid 1 Stunde bei OC behandelt und,· wie im Beispiel 12 beschrieben, aufgearbeitet. Kristallisation des Rohprodukts aus Äther—Petroläther ergab 420 mg Betamethason-17-butyrat-21-acetat; F. = 168rC, [«]„ = +7Γ (C= 1,1, Dioxan),/'»" = 237 bis 239I^ = 15250).700 mg of 17 "-ButyryIoxy-9" -fluor-l 1 ^, 21-dihydroxy-16 / i-methyl-pregna-1,4-diene-3,20-dione in 10 ml of dry pyridine were treated with 0.14 ml of acetyl chloride for 1 hour Treated at OC and, · as described in Example 12, worked up. Crystallization of the crude product from ether-petroleum ether gave 420 mg betamethasone-17-butyrate-21-acetate; F. = 168 r C, [«]" = + 7Γ (C = 1.1, dioxane), / "" = 237 to 2391 ^ = 15250).
Analyse: C28H37FO-.Analysis: C 28 H 37 FO-.
Berechnet ... C 66,65, H 7,4°;,
gefunden C 66,8.Calculated ... C 66.65, H 7.4 °;
found C, 66.8.
5555
H 7.4%.H 7.4%.
6060
Beispiel 17Example 17
17«-Butyryloxy-9a-fluor-l l/i-hydroxy-16/i-methyI-17 "-Butyryloxy-9a-fluoro-1 l / i-hydroxy-16 / i-methyI-
21 -propionyloxy-pregna-1.4-dien-3,2()-dion21 -propionyloxy-pregna-1.4-diene-3,2 () - dione
(Betamethason-17-butyrat-21-propionat)(Betamethasone-17-butyrate-21-propionate)
700 mg 17.<-Bulyryloxy-9a-fluor-ll,i,21-dihydroxy-16,i-methyl-pregna-l,4-dien-3.20-dion in 10 ml trockenem Pyridin wurden mit 0.17 ml Propionylchlorid bei 0 C 1' 2 Stunden behandelt und. wie im Beispiel 12 beschrieben, aufgearbeitet. Das Rohprodukt wurde in700 mg 17. <- Bulyryloxy-9a-fluoro-ll, i, 21-dihydroxy-16, i-methyl-pregna-1,4-diene-3.20-dione in 10 ml of dry pyridine were treated with 0.17 ml of propionyl chloride at 0 C for 1 '2 hours and. as in example 12 described, worked up. The crude product was in
IOIO
15 Benzol gelöst und die Lösung durch 25 g Aluminiumoxyd filtriert. Das eluierte Material wurde aus Äther— Petroläther umkristallisiert und ergab das Betamethason-17-butyrat-21-propionat; F. = 1450C, [a]0 = +68,5° (c = 0,98, Dioxan), λ^0Η = 238 πΐμ (>· = 15 700). Dissolved 15 benzene and filtered the solution through 25 g of aluminum oxide. The eluted material was recrystallized from ether-petroleum ether to give betamethasone-17-butyrate-21-propionate; F. = 145 0 C, [a] 0 = + 68.5 ° (c = 0.98, dioxane), λ ^ 0Η = 238 πΐμ (> · = 15 700).
Analyse: C29H39FO7.Analysis: C 29 H 39 FO 7 .
Berechnet ... C 67,1, H 7,6%; gefunden .... C 67,2, H 7,5%.Calculated ... C 67.1, H 7.6%; found .... C 67.2, H 7.5%.
17a,21-Dibutyryloxy-9u-fluor-l 1/J-hydroxy-16/i-methyl-pregna-1,4-dien-3,20-dion 17a, 21-dibutyryloxy-9u-fluoro-l 1 / J-hydroxy-16 / i-methyl-pregna-1,4-diene-3,20-dione
(Betamethason-17,21-dibutyrat)(Betamethasone-17,21-dibutyrate)
700 mg nu-Butyryloxy^u-fluor-ll/iUl-dihydroxy-16/i-methyl-pregna-l,4-dien-3,20-dion in 10 ml trockenem Pyridin wurden mit 0,32 ml Buttersäureanhydrid behandelt und die Lösung 5 Stunden bei Zimmertemperatur und dann über Nacht bei 00C stehengelassen. Das Gemisch wurde mit Eiswasser verdünnt, und die sich abscheidende Substanz wurde gesammelt und an 25 g Aluminiumoxyd chromatographiert. Umkristallisation des eluierten Materials aus Äther— Petroläther ergab das Betamethason-17,21-dibutyrat; F. = 125° C, [«]0 = +64° (c = 1,0, Dioxan), λ£*ΟΗ. = 238 ηΐμ (f = 15 900).700 mg of nu-butyryloxy ^ u-fluoro-II / iUl-dihydroxy-16 / i-methyl-pregna-1,4-diene-3,20-dione in 10 ml of dry pyridine were treated with 0.32 ml of butyric anhydride and the The solution was left to stand for 5 hours at room temperature and then at 0 ° C. overnight. The mixture was diluted with ice water and the substance which separated out was collected and chromatographed on 25 g of aluminum oxide. Recrystallization of the eluted material from ether-petroleum ether gave the betamethasone-17,21-dibutyrate; F. = 125 ° C, [«] 0 = + 64 ° (c = 1.0, dioxane), λ £ * ΟΗ . = 238 ηΐμ (f = 15,900).
Analyse: C30H41FO7.Analysis: C 30 H 41 FO 7 .
Berechnet ... C 67,7, H 7,8%; gefunden .... C 67,3, H 7,5%.Calculated ... C 67.7, H 7.8%; found .... C 67.3, H 7.5%.
17(/-Butyryloxy-9a-fiuor-l l/y-hydroxy-16/i-methyl-21-valeryloxy-pregna-l,4-dien-3,20-dion (Betamethason-17-butyrat-21 -valeriat)17 (/ - Butyryloxy-9a-fluorine-l / y-hydroxy-16 / i-methyl-21-valeryloxy-pregna-1,4-diene-3,20-dione (Betamethasone-17-butyrate-21 -valeriate)
700 mg 17a-Butyryloxy-9(i-fluor-ll/i,21-dihydroxy-16/i-methyi-pregna-l,4-dien-3,20-dion in 10 ml trockenem Pyridin wurden mit 0,23 ml Valerylchlorid bei 0 C 40 Minuten behandelt und, wie im Beispiel 12 beschrieben, aufgearbeitet. Das Produkt wurde .aus Äther —Petroläther kristallisiert und ergab das Betamethason-17-butyrat-21-valeriat: F. = 106 bis 107°C, [«]„ = +62 (f = 0,8, Dioxan), X £™ = 237 bis 238 mu U = 15 600).700 mg of 17a-butyryloxy-9 (i-fluoro-II / i, 21-dihydroxy-16 / i-methyi-pregna-1,4-diene-3,20-dione in 10 ml of dry pyridine were mixed with 0.23 ml Treated valeryl chloride at 0 C for 40 minutes and worked up as described in Example 12. The product was crystallized from ether-petroleum ether and gave the betamethasone-17-butyrate-21-valerate: mp = 106 to 107 ° C, [« ] "= +62 (f = 0.8, dioxane), X £ ™ = 237 to 238 mu U = 15,600).
Analyse: C31H43FO7.Analysis: C 31 H 43 FO 7 .
Berechnet ... C 68,1, H 7,9%; gefundenCalculated ... C 68.1, H 7.9%; found
C 68,2, H 7,9%. Beispiel 20C 68.2, H 7.9%. Example 20
21 -Acetoxy-9fi-fluor-11 /^-hydroxy-17u-isobiityryloxy-21 -Acetoxy-9fi-fluoro-11 / ^ - hydroxy-17u-isobiityryloxy-
16/i-methyl-pregna-l,4-dien-3,20-dion (Betamethason-n-isobutyrat-il-acetat)16 / i-methyl-pregna-l, 4-diene-3,20-dione (betamethasone-n-isobutyrate-il-acetate)
1 g 9fi-Fiuor-ll/^,21-dihydroxy-17u-isobutyryIoxy-16/f-methyl-pregna-l,4-dien-3,20-dion in 12 ml trockenem Pyridin, das 0,3 ml Acetylchlorid enthielt, wurde bei 0 C 5 Stunden stehengelassen und dann, wie im Beispiel 12 beschrieben, aufgearbeitet. Kristallisation aus Äther-Petroläther bei —80 C ergab 929 mg Betamethason- 17-isobutyrat-21-acetat; F. = 13PC (Zersetzung). [^], = +56.6 (c = 1,0, Dioxan), /i·1'"11 = 238 bis 239 mu (, = 14 9(M)).1 g of 9fi-fluorine-II / ^, 21-dihydroxy-17u-isobutyryIoxy-16 / f-methyl-pregna-1,4-diene-3,20-dione in 12 ml of dry pyridine containing 0.3 ml of acetyl chloride , was left to stand at 0 C for 5 hours and then, as described in Example 12, worked up. Crystallization from ether-petroleum ether at -80 ° C. gave 929 mg betamethasone-17-isobutyrate-21-acetate; F. = 13PC (decomposition). [^], = +56.6 (c = 1.0, dioxane), / i · 1 '" 11 = 238 to 239 mu (, = 14 9 (M)).
009 635/126009 635/126
i 44ύi 44ύ
Analyse: C28H37FO7.Analysis: C 28 H 37 FO 7 .
Berechnet ... C 66,65, H 7,4%;
gefunden .... C 66,5, H 7,7%.Calculated ... C 66.65, H 7.4%;
found .... C 66.5, H 7.7%.
9a-Fluor-11 /i-hydroxy-17<i-isobutyryloxy-16/i-methy 1-21-propionyloxy-pregna-l,4-dien-3,20-dion
(Betamethason-17-isobutyrat-21-propionat) ■9a-fluoro-11 / i-hydroxy-17 <i-isobutyryloxy-16 / i-methy 1-21-propionyloxy-pregna-1,4-diene-3,20-dione
(Betamethasone 17-isobutyrate-21-propionate) ■
1 g 9(/-Fluor-ll/i,21-dihydroxy-17«-isobutyryloxy-16/?-methyl-pregna-l,4-dien-3,20-dion in 12 ml trockenem Pyridin, das 0,24 ml Propionylchlorid enthielt, wurde bei 0° C 1 Stunde stehengelassen. Die auf Zusatz von Wasser ausgefallene Festsubstanz wurde aus Äther—Petroläther bei — 800C umkristallisiert und ergab 663 mg Betamethason- 17-isobutyrat-21-propionat; F. = 93°C (Zersetzung), [«]D = +61,5° (c = 1,0, Dioxan), λ S£s0H = 237 bis 238 πΐμ (<·= 15 600).1 g of 9 (/ - fluoro-11 / i, 21-dihydroxy-17 «-isobutyryloxy-16 /? - methyl-pregna-1,4-diene-3,20-dione in 12 ml of dry pyridine, the 0.24 ml of propionyl chloride containing, at 0 ° C for 1 hour allowed to stand The precipitated on addition of water solids was prepared from ether-petroleum ether at - recrystallized 80 0 C to give 663 mg of betamethasone 17-isobutyrate-21-propionate;. mp = 93 ° C (decomposition), [«] D = + 61.5 ° (c = 1.0, dioxane), λ S £ s0H = 237 to 238 πΐμ (<· = 15,600).
Analyse: C29H39FO7.Analysis: C 29 H 39 FO 7 .
Berechnet ... C 67,1, H 7,6%;Calculated ... C 67.1, H 7.6%;
gefundenfound
C 67,0, H 7,3%.C 67.0, H 7.3%.
9u-Fluor-l l/Miydroxy-17(x-isobutyryloxy-9u-fluorine-l l / miydroxy-17 (x-isobutyryloxy-
16/J-methy 1-21 - valery loxy-pregna-1,4-dien-3,20-dion (Betamethason-17-isobutyrat-21 - valeriat)16 / J-methy 1-21 - valery loxy-pregna-1,4-diene-3,20-dione (Betamethasone-17-isobutyrate-21 - valeriate)
1 g 9a-Fluor-l 1/^,21 -dihydroxy-17«-isobutyryloxy-16/3-methyl-pregna-l,4-dien-3,20-dion in 12 ml trockenem Pyridin, das 0,34 ml Valerylchlorid enthielt, wurde 30 Minuten bei 00C stehengelassen und dann mit Wasser verdünnt. Die ausgefallene Festsubstanz wurde aus Äther—Petroläther bei -800C kristallisiert und ergab 935 mg Betamethason-17-isobutyrat-21-valeriat; F. = 98°C (Zersetzung), [«]0 = +68,5° (c = 1,0, Dioxan), λ «™)H = 238 bis 239 mF(f = 15 600).1 g of 9a-fluoro-l 1 / ^, 21-dihydroxy-17 "-isobutyryloxy-16/3-methyl-pregna-1,4-diene-3,20-dione in 12 ml of dry pyridine, which is 0.34 ml valeryl contained, was 30 minutes at 0 0 C allowed to stand and then diluted with water. The precipitated solid was recrystallized from ether-petroleum ether at -80 0 C crystallized to give 935 mg of betamethasone 17-isobutyrate-21-valerate; F. = 98 ° C (decomposition), [«] 0 = + 68.5 ° (c = 1.0, dioxane), λ « ™ ) H = 238 to 239 m F ( f = 15,600).
Analyse: C31H43FO7.Analysis: C 31 H 43 FO 7 .
Berechnet ... C 68,1, H 7,9%;
gefunden .... C 68,1, H 7,8%·Calculated ... C 68.1, H 7.9%;
found .... C 68.1, H 7.8%
21 -Acetoxy^ct-chlor-11 /^-hydroxy-16/?-methy 1-17a-propiony loxy-pregna- l,4-dien-3,20-dion21 -Acetoxy ^ ct-chloro-11 / ^ - hydroxy-16 /? - methy 1-17a-propiony loxy-pregna-l, 4-diene-3,20-dione
400 mg 9a-Chlor-ll/i,21-dihydroxy-16/i-methyl-17a-propionyloxy-pregna-l,4-dien-3,20-dion in 1,6 ml trockenem Pyridin, das 1,6 ml Essigsäureanhydrid enthielt, wurden bei Zimmertemperatur 50 Minuten stehengelassen; dann wurde die Lösung mit Wasser verdünnt. Umkristallisation des ausgefallenen Materials aus Aceton—Petroläther ergab 290 mg 21-Acetoxy-9a-chlor-11 /J-hydroxy-16/?-methyl-17a-propionyloxy-pregna-l,4-dien-3,20-dion; F. = 217 bis 219°C nach vorherigem Sintern, [a]0 = +94° (c = 0,96, Chloroform), A^oh = 238 bis 239 mμ (*· = 15 100).400 mg of 9a-chloro-II / i, 21-dihydroxy-16 / i-methyl-17a-propionyloxy-pregna-1,4-diene-3,20-dione in 1.6 ml of dry pyridine, the 1.6 ml Containing acetic anhydride were allowed to stand at room temperature for 50 minutes; then the solution was diluted with water. Recrystallization of the precipitated material from acetone-petroleum ether gave 290 mg of 21-acetoxy-9a-chloro-11 / J-hydroxy-16 /? -Methyl-17a-propionyloxy-pregna-1,4-diene-3,20-dione; F. = 217 to 219 ° C after previous sintering, [a] 0 = + 94 ° (c = 0.96, chloroform), A ^ oh = 238 to 239 mμ (* · = 15 100).
Analyse: C27H35ClO7.Analysis: C 27 H 35 ClO 7 .
Berechnet ... C 63,95, H 7,0, Cl 7,0%;
gefunden .... C 63,75, H 7,1, Cl 7,0%.Calculated ... C 63.95, H 7.0, Cl 7.0%;
found .... C 63.75, H 7.1, Cl 7.0%.
r-ll/i-hydroxy-16/i-methyl-17«,21-dipropionyloxy-pregna-l,4-dien-3,20-dion r-ll / i-hydroxy-16 / i-methyl-17 ", 21-dipropionyloxy-pregna-1,4-diene-3,20-dione
1,4 g 9(i - Chlor -11/)',21-dihydroxy-16/J-methyl-17«-propionyloxy-pregna-l,4-dien-3,20-dion in 17ml trockenem Pyridin, das 0,5 ml Propionylchlorid enthielt, wurde 1 Stunde bei O1C und dann 30 Minuten bei Zimmertemperatur stehengelassen. Verdünnen mit Wasser ergab eine Festsubstanz, die, nach Kristallisieren aus Aceton—Äther bei —80°C, 1,2 g 9a-Chlor- 11/i-hydroxy-16/^-methyl- 17α,21 -dipropionyloxy-pregna-l,4-dien-3,20-dion ergab; F.= 117 bis 120° C (Zersetzung), [>]0 = +98,0° (c = 1,0, Dioxan), λ%£°" = 238 ma (f = 15-990).1.4 g of 9 (i-chloro-11 /) ', 21-dihydroxy-16 / J-methyl-17 "-propionyloxy-pregna-1,4-diene-3,20-dione in 17 ml of dry pyridine, the 0 , 5 ml of propionyl chloride was allowed to stand at O 1 C for 1 hour and then at room temperature for 30 minutes. Dilution with water gave a solid which, after crystallization from acetone-ether at -80 ° C., 1.2 g of 9a-chloro-11 / i-hydroxy-16 / ^ -methyl-17α, 21-dipropionyloxy-pregna-1 , 4-diene-3,20-dione; F. = 117 to 120 ° C (decomposition), [>] 0 = + 98.0 ° (c = 1.0, dioxane), λ% £ ° " = 238 ma (f = 15-990).
Analyse: C28H37ClO7.Analysis: C 28 H 37 ClO 7 .
Berechnet ... C 64,55, H 7,15, Cl 6,8%; gefunden .... C 64,8, H 7,0, Cl 6,75%.Calculated ... C 64.55, H 7.15, Cl 6.8%; found .... C 64.8, H 7.0, Cl 6.75%.
17u,21-Diacetoxy-9a-fluor-l 1//-hydroxy-16/i-methyl-17u, 21-diacetoxy-9a-fluoro-l 1 // - hydroxy-16 / i-methyl-
pregna-l,4-dien-3,20-dion (Betamethason-17,21 -diacetat)pregna-l, 4-diene-3,20-dione (betamethasone-17,21-diacetate)
780 mg Betamethason-21-acetat wurden in 200 ml Benzol suspendiert und mit 24 ml Essigsäureanhydrid, das 0,024 ml 60%ige Perchlorsäure enthielt, versetzt. Die Lösung wurde bei Zimmertemperatur 55 Minuten gerührt und die Reaktion durch Dünnschicht-Chromatographie verfolgt. Die Lösung wurde mit Natriumbicarbonatlösung und Wasser gewaschen, mit Magnesiumsulfat getrocknet und zur Trockene eingedampft. Der zurückbleibende Schaum wurde, in Benzol gelöst und an neutralem Aluminiumoxyd (Aktivitätsgrad III) chromatographiert. Elution mit Benzol und Benzol—Äther ergab zuerst Betamethason-11,17,21 -triacetat und dann eine Fraktion, die, wie durch Dünnschicht-Chromatographie gezeigt werden konnte, aus einem Gemisch aus Betamethason-11,21-diacetat und Betamethason-17,21-diacetat bestand. 780 mg betamethasone-21-acetate were suspended in 200 ml benzene and mixed with 24 ml acetic anhydride, containing 0.024 ml of 60% perchloric acid, added. The solution was at room temperature for 55 minutes stirred and the reaction followed by thin layer chromatography. The solution was with Washed sodium bicarbonate solution and water, dried with magnesium sulfate and dried to dryness evaporated. The remaining foam was dissolved in benzene and dissolved on neutral aluminum oxide (Degree of activity III) chromatographed. Elution with benzene and benzene ether gave first betamethasone-11,17,21 -triacetate and then a fraction as shown by thin layer chromatography could, from a mixture of betamethasone-11,21-diacetate and betamethasone-17,21-diacetate.
B e i s ρ i e 1 26B e i s ρ i e 1 26
17(i,21-Diacetoxy-9a-rluor-l l/i'-hydroxy-lo^-methylpregna-1,4-dien-3,20-dion 17 (i, 21-Diacetoxy-9a-rluoro-l l / i'-hydroxy-lo ^ -methylpregna-1,4-diene-3,20-dione
9a- Fluor-16/i-methyl-11 fi, 17«,21 -trihydroxy-pregnal,4-dien-3,20-dion (0,5 g), das unter Rühren in Suspension in Benzol vorlag, wurde mit einer Mischung von9a- fluoro-16 / i-methyl-11 fi, 17 ", 21 -trihydroxy-pregnal, 4-diene-3,20-dione (0.5 g), which was in suspension in benzene with stirring, was treated with a Mix of
60%iger Perchlorsäure (0,012 ml) und Essigsäureanhydrid (12 ml) behandelt. Nach 23 Minuten wurde eine wäßrige Natriumbicarbonatlösung zugegeben, die Benzolschicht abgetrennt und mit wäßriger Natriumbicarbonatlösung und Wasser gewaschen. Nach60% treated ig e r perchloric acid (0.012 ml) and acetic anhydride (12 ml). After 23 minutes, an aqueous sodium bicarbonate solution was added, the benzene layer was separated and washed with an aqueous sodium bicarbonate solution and water. To
6o· Entfernung des Lösungsmittels von dem getrockneten Extrakt blieb eine Mischung von Estern zurück, die durch Säulen-Chromatographie an neutralem Aluminiumoxyd und nachfolgend durch Dickschicht-Chromatographie an Siliciumdioxyd gereinigt wurde. Das 17,21-Diacetat (6 mg) wurde aus Aceton—Petroläther als kristalliner Feststoff, F. = 134 bis 1380C, mit einem der authentischen Probe gleichen Spektrum erhalten.Removal of the solvent from the dried extract left a mixture of esters which was purified by column chromatography on neutral aluminum oxide and then by thick layer chromatography on silica. The 17,21-diacetate (6 mg) was obtained from acetone-petroleum ether as a crystalline solid, mp = 134-138 0 C, the same with one of the authentic sample spectrum.
Pharmakoloiiischer VersuchsberichtPharmacological test report
Die antiinflammatorische Aktivität einer Reihe von Steroidverbindungen bei deren topischer Verabreichung wurde untersucht. Eine solche Versuchsreihe wurde an freiwilligen Versuchspersonen durch den sogenannten Vasokonstriktionstest nach McK e η ζ i e und Mitarbeitern, in Arch. Derm., 1962, 86, S. 608, und, spezieller, in Arch. Derm., 1964, 89, S. 741 beschrieben, durchgeführt. Zwei experimentelle Aufzeichnungen wurden verwendet, a) eine einfache Probe und b) eine Mehrfachprobe, wobei als Standard-Verbindung in jedem Fall die Verbindung Fluocinolon-16,17-acetonid (6«,9«-Difluor-11 (1,21 -dihydroxy-16</, 17(/-isopropy lidendioxy-prcgnal,4-dien-3,20-dion) verwendet wurde, für die eine Aktivität von 100 angenommen wurde. Fluocinolon-16,17-acetonid ist eines der wirksamsten antiinflammatorischen Steroide für die topische Anwendung am Prioritätstag der vorliegenden Erfindung.The anti-inflammatory activity of a number of steroid compounds when administered topically has been studied. Such a series of tests was carried out on volunteer test subjects by the so-called vasoconstriction test according to McK e η ζ ie and coworkers, in Arch. Derm., 1962, 86, p. 608, and, more specifically, in Arch. Derm., 1964, 89, p. 741 described, carried out. Two experimental recordings were used, a) a single sample and b) a multiple sample, the standard compound in each case being fluocinolone-16,17-acetonide (6 «, 9« -difluoro-11 (1,2 1 - dihydroxy-16 </, 17 (/ - isopropy lidendioxy-prcgnal, 4-diene-3,20-dione) was used, which was assumed to have an activity of 100. Fluocinolone-16,17-acetonide is one of the most effective anti-inflammatory steroids for topical application on the priority date of the present invention.
a) Einfache Probea) Simple sample
Fünf Stellen für die Steroidapplizierung wurden an der Oberfläche des Beugemuskels jedes Unterarms einer Gruppe von zehn gesunden menschlichen Freiwilligen beiderlei Geschlechts markiert. Fünf Dosen der Standard-Verbindung und fünf Dosen des Test-Five steroid application sites were located on the flexor surface of each forearm a group of ten healthy human volunteers of both sexes. Five cans the standard connection and five doses of the test
steroids in 0,02 ml Alkohol wurden auf diese Stellen auf solche Weise aufgebracht, daß jede Dosis bei jeder Versuchsperson, jedoch an einer verschiedenen Stelle, aufgebracht wurde. Das Verhältnis zwischen den folgenden Dosen desselben Steroids betrug 3:1.steroids in 0.02 ml of alcohol were applied to these sites in such a way that each dose at applied to each subject, but at a different point. The relation between the following doses of the same steroid was 3: 1.
b) Mehrfachprobeb) Multiple samples
Sechs Stellen wurden an jedem Unterarm vonSix spots were on each forearm of
ίο zwölf Versuchspersonen beiderlei Geschlechts markiert. Vier Dosen der Standard-Verbindung und je vier Dosen der zwei Teststeroide oder zwei Dosen der vier Teststeroide. alle in 0,02 ml Alkohol, wurden auf diese Stellen aufgebracht. Wie in der einfachen Probe wurde jede Dose bei jeder Versuchsperson, jedoch an einer verschiedenen Stelle, angewandt. Das Verhältnis zwischen folgenden Dosen desselben Steroids betrug 4:1.ίο twelve test persons of both sexes marked. Four doses of the standard compound and four doses each of the two test steroids or two doses of the four test steroids. all in 0.02 ml of alcohol, were applied to these sites. As in the simple one Sample, each can was applied to each subject, but at a different location. The The ratio between the following doses of the same steroid was 4: 1.
Bei allen Proben wurde jede Steroiddosis so gleichmäßig wie möglich auf 2,8 cm2 Kreisfläche der Haut aufgebracht. Wenn das Lösungsmittel verdampft war, wurden die Unterarme vollständig in einer Polythen-Hülle abgeschlossen, die an jedem Ende mit einem Klebepflaster als Verschluß gesichert war. Diese Ver-Schlüsse wurden nach 16 Stunden entfernt und die Arme nach Vasokonstriktionsflecken 1 Stunde später untersucht.In all samples, each steroid dose was applied as evenly as possible to a 2.8 cm 2 circular area of the skin. When the solvent had evaporated, the forearms were completely enclosed in a polythene sleeve, which was secured at each end with an adhesive plaster as a closure. These seals were removed after 16 hours and the arms examined for vasoconstriction spots 1 hour later.
Die erhaltenen Resultate sind in der folgenden Tabelle angegeben:The results obtained are given in the following table:
ErfindungsgemäßAccording to the invention
Verbindungconnection
Betamethason-17-acetat-21-formiat *) Betamethasone-17-acetate-21-formate *)
Betamethason-17,21-diacetat *) Betamethasone-17,21-diacetate *)
Betamethason-17-acetat-21-propionat *) Betamethasone-17-acetate-21-propionate *)
Betamethason-17-acetat-21-valerianat *) Betamethasone-17-acetate-21-valerianate *)
Betamethason-17-acetat-21-isobutyrat Betamethasone 17-acetate-21-isobutyrate
Betamethason-17-acetat-21-hexahydrobenzoat Betamethasone 17 Acetate 21 Hexahydrobenzoate
Betamethason-17-propionat-21-acetat *) Betamethasone-17-propionate-21-acetate *)
Betamethason-17,21-dipropionat *) Betamethasone-17,21-dipropionate *)
Betamethason-17-propionat-21-butyrat « Betamethasone-17-propionate-21-butyrate "
Betamethason-17-propionat-21-valerianat *) Betamethasone-17-propionate-21-valerianate *)
Betamethason-17-propionat-21-isobutyrat Betamethasone 17-propionate-21-isobutyrate
Betamethason-H-propionat^l-pivalat '.'.... Betamethasone H-propionate ^ l-pivalate '.'....
Betamethason-17-butyrat-21-acetat *) Betamethasone-17-butyrate-21-acetate *)
Betamethason-17-butyrat-21-propionat Betamethasone 17-butyrate-21-propionate
Betamethason-17,21-dibutyrat *) Betamethasone-17,21-dibutyrate *)
Betamethason-17-butyrat-21-valerianat Betamethasone-17-butyrate-21-valerianate
Betamethason-17-isobutyrat-21-acetat Betamethasone 17 isobutyrate 21 acetate
Betamethason-H-isobutyrat^l-propionat Betamethasone H-isobutyrate ^ l-propionate
Betamethason-H-isobutyrat^l-butyrat *) Betamethasone-H-isobutyrate ^ l-butyrate *)
Betamethason-17,21-diisobutyrat Betamethasone 17,21-diisobutyrate
17u-Propionyloxy-21 -acetoxy^u-chlor-11 /i-hydroxy-16/i-methyl-17u-propionyloxy-21 -acetoxy ^ u-chloro-11 / i-hydroxy-16 / i-methyl-
pregna-l,4-dien-3,20-dion pregna-l, 4-diene-3,20-dione
naJl-Dipropionyloxy^rj-chlor-ll/i-hydroxy-lo/i-methyl-pregna-naJl-Dipropionyloxy ^ rj-chlor-ll / i-hydroxy-lo / i-methyl-pregna-
1,4-dien-3,20-dion 1,4-diene-3,20-dione
*) Einfache Probe.*) Simple sample.
i 443 957i 443 957
Nicht erfindungsgemäßNot according to the invention
(Fluocinolon-
16,17-acetonid = 100)activity
(Fluocinolone
16,17-acetonide = 100)
an TcststeroidNumber of cans
on steroid
Hydrocortison-H^l-dipropionat
Hydrocortison-H-propionat^l-butyrat
Hydrocortison-n-butyrat^l-propionat
Hydrocortison-n^l-dibutyrat
Hydrocortison-n-butyrat^l-valerianat
Prednisolon-17-propionat-21-acetat
Prednisolon-17,21-dipropionat
Prednisolon-17-propionat-21-butyrat
Prednisolon-17-propionat-21-valerianat
Prednisolon-H-butyrat^l-acctat
Prednisolon-17-butyrat-21-propionat
Prednisolon-17,21-dibuty rat
Prednisolon- 17-butyrat-21-valerianat
Prednisolon-17-valerianat Hydrocortisone H-propionate ^ l-acetate
Hydrocortisone H ^ l-dipropionate
Hydrocortisone H-propionate ^ l-butyrate
Hydrocortisone n-butyrate ^ l-propionate
Hydrocortisone n ^ l -dibutyrate
Hydrocortisone n-butyrate ^ l-valerianate
Prednisolone-17-propionate-21-acetate
Prednisolone 17.21 dipropionate
Prednisolone 17-propionate-21-butyrate
Prednisolone-17-propionate-21-valerianate
Prednisolone-H-butyrate ^ l-acctat
Prednisolone 17-butyrate-21-propionate
Prednisolone 17.21 dibuty rat
Prednisolone 17-butyrate-21-valerianate
Prednisolone-17-valerianate
. 15
40
70
50
35
50
40
40
30
40
65
50
60
40
50
0,7
2.0
<1.015th
. 15th
40
70
50
35
50
40
40
30th
40
65
50
60
40
50
0.7
2.0
<1.0
2
2
2
2
2
2
2
2
2
2
2
2
2
4
4
4
4
42
2
2
2
2
2
2
2
2
2
2
2
2
2
4th
4th
4th
4th
4th
Betamethason 9 <i-fluoro-prednisolone-l 7-acetate
Betamethasone
Claims (7)
Family
ID=
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