CH606115A5 - 9-Alpha-11-beta-dihalo-D-homo-pregn-4-en-3,20-diones - Google Patents
9-Alpha-11-beta-dihalo-D-homo-pregn-4-en-3,20-dionesInfo
- Publication number
- CH606115A5 CH606115A5 CH1528577A CH1528577A CH606115A5 CH 606115 A5 CH606115 A5 CH 606115A5 CH 1528577 A CH1528577 A CH 1528577A CH 1528577 A CH1528577 A CH 1528577A CH 606115 A5 CH606115 A5 CH 606115A5
- Authority
- CH
- Switzerland
- Prior art keywords
- acid
- homo
- bond
- pregn
- diones
- Prior art date
Links
- 238000000034 method Methods 0.000 claims description 8
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 5
- 150000000795 D-homosteroids Chemical class 0.000 claims description 5
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Chemical group BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 5
- 229910052794 bromium Inorganic materials 0.000 claims description 5
- 229910052801 chlorine Inorganic materials 0.000 claims description 5
- 239000000460 chlorine Chemical group 0.000 claims description 5
- 229910052736 halogen Inorganic materials 0.000 claims description 5
- 150000002367 halogens Chemical class 0.000 claims description 5
- CUILPNURFADTPE-UHFFFAOYSA-N hypobromous acid Chemical compound BrO CUILPNURFADTPE-UHFFFAOYSA-N 0.000 claims description 5
- 238000002360 preparation method Methods 0.000 claims description 5
- 229910052739 hydrogen Inorganic materials 0.000 claims description 4
- 239000001257 hydrogen Substances 0.000 claims description 4
- QWPPOHNGKGFGJK-UHFFFAOYSA-N hypochlorous acid Chemical compound ClO QWPPOHNGKGFGJK-UHFFFAOYSA-N 0.000 claims description 4
- 150000003839 salts Chemical class 0.000 claims description 4
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical group [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 3
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical group FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 3
- 125000004423 acyloxy group Chemical group 0.000 claims description 3
- 229910052731 fluorine Inorganic materials 0.000 claims description 3
- 239000011737 fluorine Chemical group 0.000 claims description 3
- 229910019142 PO4 Inorganic materials 0.000 claims description 2
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 2
- 125000001142 dicarboxylic acid group Chemical group 0.000 claims description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 2
- 239000010452 phosphate Substances 0.000 claims description 2
- QAOWNCQODCNURD-UHFFFAOYSA-L sulfate group Chemical group S(=O)(=O)([O-])[O-] QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 claims description 2
- 150000002431 hydrogen Chemical group 0.000 claims 2
- MALIONKMKPITBV-UHFFFAOYSA-N 2-(3-chloro-4-hydroxyphenyl)-n-[2-(4-sulfamoylphenyl)ethyl]acetamide Chemical group C1=CC(S(=O)(=O)N)=CC=C1CCNC(=O)CC1=CC=C(O)C(Cl)=C1 MALIONKMKPITBV-UHFFFAOYSA-N 0.000 claims 1
- 150000003627 tricarboxylic acid derivatives Chemical class 0.000 claims 1
- 230000003110 anti-inflammatory effect Effects 0.000 abstract description 2
- 230000002124 endocrine Effects 0.000 abstract description 2
- 230000000694 effects Effects 0.000 abstract 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- -1 unsaturated aliphatic monocarboxylic acid Chemical class 0.000 description 5
- VLTRZXGMWDSKGL-UHFFFAOYSA-N perchloric acid Chemical compound OCl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-N 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 3
- 239000002253 acid Substances 0.000 description 3
- 239000012876 carrier material Substances 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 2
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Chemical compound OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 2
- OFOBLEOULBTSOW-UHFFFAOYSA-N Malonic acid Chemical compound OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 2
- JRNVZBWKYDBUCA-UHFFFAOYSA-N N-chlorosuccinimide Chemical compound ClN1C(=O)CCC1=O JRNVZBWKYDBUCA-UHFFFAOYSA-N 0.000 description 2
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric Acid Chemical compound [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- 150000001875 compounds Chemical group 0.000 description 2
- 125000004435 hydrogen atom Chemical class [H]* 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- VBTQNRFWXBXZQR-UHFFFAOYSA-N n-bromoacetamide Chemical compound CC(=O)NBr VBTQNRFWXBXZQR-UHFFFAOYSA-N 0.000 description 2
- 239000000825 pharmaceutical preparation Substances 0.000 description 2
- WLJVXDMOQOGPHL-UHFFFAOYSA-N phenylacetic acid Chemical compound OC(=O)CC1=CC=CC=C1 WLJVXDMOQOGPHL-UHFFFAOYSA-N 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 239000001384 succinic acid Substances 0.000 description 2
- 230000009885 systemic effect Effects 0.000 description 2
- 239000003826 tablet Substances 0.000 description 2
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 2
- 150000003628 tricarboxylic acids Chemical class 0.000 description 2
- HFVMEOPYDLEHBR-UHFFFAOYSA-N (2-fluorophenyl)-phenylmethanol Chemical compound C=1C=CC=C(F)C=1C(O)C1=CC=CC=C1 HFVMEOPYDLEHBR-UHFFFAOYSA-N 0.000 description 1
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 description 1
- FALRKNHUBBKYCC-UHFFFAOYSA-N 2-(chloromethyl)pyridine-3-carbonitrile Chemical compound ClCC1=NC=CC=C1C#N FALRKNHUBBKYCC-UHFFFAOYSA-N 0.000 description 1
- ZRPLANDPDWYOMZ-UHFFFAOYSA-N 3-cyclopentylpropionic acid Chemical compound OC(=O)CCC1CCCC1 ZRPLANDPDWYOMZ-UHFFFAOYSA-N 0.000 description 1
- QISOBCMNUJQOJU-UHFFFAOYSA-N 4-bromo-1h-pyrazole-5-carboxylic acid Chemical compound OC(=O)C=1NN=CC=1Br QISOBCMNUJQOJU-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- 239000005711 Benzoic acid Substances 0.000 description 1
- QDHHCQZDFGDHMP-UHFFFAOYSA-N Chloramine Chemical class ClN QDHHCQZDFGDHMP-UHFFFAOYSA-N 0.000 description 1
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Natural products OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- 229920000084 Gum arabic Polymers 0.000 description 1
- 241000978776 Senegalia senegal Species 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 239000000205 acacia gum Substances 0.000 description 1
- 235000010489 acacia gum Nutrition 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- 150000003863 ammonium salts Chemical class 0.000 description 1
- 235000010233 benzoic acid Nutrition 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 150000008280 chlorinated hydrocarbons Chemical class 0.000 description 1
- 235000015165 citric acid Nutrition 0.000 description 1
- HJZLEGIHUQOJBA-UHFFFAOYSA-N cyclohexane propionic acid Chemical compound OC(=O)CCC1CCCCC1 HJZLEGIHUQOJBA-UHFFFAOYSA-N 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 150000003949 imides Chemical class 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 239000001630 malic acid Substances 0.000 description 1
- 235000011090 malic acid Nutrition 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 150000002888 oleic acid derivatives Chemical class 0.000 description 1
- 230000003204 osmotic effect Effects 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 235000019271 petrolatum Nutrition 0.000 description 1
- 239000003279 phenylacetic acid Substances 0.000 description 1
- 229960003424 phenylacetic acid Drugs 0.000 description 1
- 229920001515 polyalkylene glycol Polymers 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 150000003128 pregnanes Chemical class 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 235000010265 sodium sulphite Nutrition 0.000 description 1
- 239000002904 solvent 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
- 150000003431 steroids Chemical class 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 229940014800 succinic anhydride Drugs 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
- 235000012222 talc Nutrition 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 238000004809 thin layer chromatography Methods 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J63/00—Steroids in which the cyclopenta(a)hydrophenanthrene skeleton has been modified by expansion of only one ring by one or two atoms
- C07J63/008—Expansion of ring D by one atom, e.g. D homo steroids
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Steroid Compounds (AREA)
Abstract
9-Alpha-11-beta-dihalo-D-homo-pregn-4-en-3,20-diones with selective endocrinal (esp. antiinflammatory) activity
Description
Die vorliegende Erfindung betrifft ein Verfahren zur Herstellung von neuen D-Homosteroiden aus der Pregnanreihe der Formel
EMI1.1
worin Rs Wasserstoff, Fluor, Chlor, Brom oder Methyl; R9 Chlor oder Brom R21 Halogen oder R, R einen Sulfat- oder Phosphatrest oder den Rest einer Di oder Tri-carbonsäure in Form eines wasserlöslichen Sal zes und Rl7 & Hydroxy oder Acyloxy darstellen und die gestrichelte
1,2-Bindung fakultativ ist.
Der Ausdruck Halogen umfasst Fluor, Chlor, Brom und Jod. Eine Acyloxygruppe kann sich von einer gesättigten oder ungesättigten aliphatischen Monocarbonsäure, einer cycloaliphatischen, araliphatischen oder einer aromatischen Monocarbonsäure mit vorzugsweise bis zu 15 C-Atomen ableiten.
Beispiele solcher Säuren sind Ameisen-, Essig-, Pivalin-, Propion-, Butter-, Capron-, Oenanth-, Undecylen-, öl-, Cyclopentylpropion-, Cyclohexylpropion-, Phenylessig- und Ben zoesäure. Besonders bevorzugt sind C1 ¯ 7-Alka:loyloxygruppen.
Ein Rest einer Di- oder Tricarbonsäure kann sich z. B. ableiten von der Oxal-, Malon-, Bernstein-, Fumar-, Äpfel-, Weinoder Zitronensäure, vorzugsweise von der Bernsteinsäure. Als wasserlösliche Salze solcher Säurereste kommen vor allem die Alkalimetallsalze wie Na-, K- oder Ammoniumsalze in Frage.
Von den in 6-Stellung substituierten Verbindungen sind die 6e-Isomeren bevorzugt.
Das erfindungsgemässe Verfahren ist dadurch gekennzeichnet, dass man in an sich bekannter Weise an die 9,11 Doppelbindung eines D-Homosteroids der Formel
EMI1.2
worin R214 Wasserstoff, Halogen oder R darstellt und R, Rs, R17s sowie die gestrichelte 1,2-Bindung die oben angegebenen Bedeutungen haben, unterchlorige oder unterbromige Säure anlagert.
Zwecks Durchführung des erfindungsgemässen Verfahrens löst man das Ausgangssteroid III zweckmässigerweise in einem geeigneten Lösungsmittel, z. B. einem Äther, wie Tetrahydrofuran oder Dioxan, einem chlorierten Kohlenwasserstoff, wie Methylenchlorid oder Chloroform, oder einem Keton, wie Aceton, und lässt unterchlorige bzw. unterbromige Säure einwirken. Die unterchlorige oder unterbromige Säure wird zweckmässigerweise im Reaktionsgemisch selbst erzeugt; z. B. aus N-Brom- oder N-Chloramiden oder -imiden, wie N-Chlorsuccinimid oder N-Bromacetamid, und einer starken Säure, vorzugsweise Perchlorsäure.
Die Ausgangsstoffe können, soweit sie nicht bekannt oder nachstehend beschrieben sind, in Analogie zu bekannten oder in den Beispielen beschriebenen Methoden dargestellt werden.
Die D-Homosteroide der Formel I sind endokrin, insbesondere antiinflammatorisch wirksam. Sie sind durch Selektivität der Wirkung gekennzeichnet, z. B. stark topisch wirksam bei schwächerer systemischer Wirkung.
Die Verfahrensprodukte können als Heilmittel in Form pharmazeutischer Präparate Verwendung finden, welche sie in Mischung mit einem für die enterale, perkutane oder parenterale Applikation geeigneten organischen oder anorganischen inerten Trägermaterial, wie z. B. Wasser, Gelatine, Gummi arabicum, Milchzucker, Stärke, Magnesiumstearat, Talk, pflanzliche Öle, Polyalkylenglykole, Vaseline usw., enthalten. Die pharmazeutischen Präparate können in fester Form, z. B. als Tabletten, Dragees, Suppositorien, Kapseln; in halbfester Form, z. B. als Salben; oder in flüssiger Form, z. B. als Lösungen, Suspensionen oder Emulsionen, vorliegen.
Gegebenenfalls enthalten sie Hilfsstoffe, wie Konservierungs-, Stabilisierungs-, Netz- oder Emulgiermittel, Salze zur Veränderung des osmotischen Druckes oder Puffer. Sie können auch noch andere therapeutisch wertvolle Stoffe enthalten.
Als Richtlinie für den Dosisbereich topischer Präparate kann etwa 0,01-1 /0, bei systemischen Präparaten etwa 0,1-10 mg pro Applikationseinheit gelten.
Die Herstellung der Arzneimittel kann in an sich bekannter Weise erfolgen, indem man die Verbindungen der Formel I mit zur therapeutischen Verabreichung geeigneten, nicht-toxischen, an sich in solchen Präparaten üblichen festen und/oder flüssigen Trägermaterialien, wie z. B. den vorstehend genannten, vermischt und gegebenenfalls in die gewünschte Form bringt.
Beispiel
450 mg 17a,21-Dihydroxy-D-homopregna-4,9(1 1)-dien- 3,20-dion-21-hemisuccinat werden in 20 ml Dioxan und 5 ml Wasser mit 270 mg N-Bromacetamid und 1,85 ml 100/obiger Perchlorsäure versetzt und 15 Minuten bei Raumtemperatur gerührt. Dann werden 1,5 g Natriumsulfit und 30 ml Wasser zugegeben. Nach kurzem Rühren wird mit Methylenchlorid extrahiert, mit Wasser gewaschen, getrocknet und eingedampft. Man erhält 540 mg dünnschichtchromatographisch einheitliches llss, 17a,21-Trihydroxy-9-brom-D-homo-pregn4-en-3,20-dion-21-hemisuccinat. UV: e2S9 = 14850.
Das Ausgangsmaterial kann wie folgt hergestellt werden: 21-Acetoxy-17a-hydroxy-D-homopregna-4,9(11)-dien- 3,20-dion werden in methanolischer Lösung mit Kaliumcarbonat verseift, wobei man 17a,21-Dihydroxy-D-homopregna4,9(11)-dien-3,20-dion erhält. UV: e239 = 15800.
Dieses wird in Tetrachlorkohlenstoff mit Bernsteinsäureanhydrid in Gegenwart von Pyridin bei erhöhter Temperatur ins 17a,21-Dihydroxy-D-homopregna-4,9 (1 1)-dien-3,20-dion- 21-hemisuccinat übergeführt. W: e239 = 16200.
The present invention relates to a process for the preparation of new D-homosteroids from the pregnane series of the formula
EMI1.1
wherein Rs is hydrogen, fluorine, chlorine, bromine or methyl; R9 is chlorine or bromine R21 is halogen or R, R is a sulfate or phosphate radical or the radical of a di or tricarboxylic acid in the form of a water-soluble salt and R17 & hydroxy or acyloxy and the dashed line
1,2 bond is optional.
The term halogen includes fluorine, chlorine, bromine and iodine. An acyloxy group can be derived from a saturated or unsaturated aliphatic monocarboxylic acid, a cycloaliphatic, araliphatic or an aromatic monocarboxylic acid with preferably up to 15 carbon atoms.
Examples of such acids are formic, acetic, pivalic, propionic, butyric, caproic, oenanthic, undecylene, oleic, cyclopentylpropionic, cyclohexylpropionic, phenylacetic and benzoic acid. C1 ¯ 7 alka: loyloxy groups are particularly preferred.
A residue of a di- or tricarboxylic acid can be, for. B. derived from oxalic, malonic, succinic, fumaric, malic, tartaric or citric acid, preferably from succinic acid. The alkali metal salts such as Na, K or ammonium salts are especially suitable as water-soluble salts of such acid residues.
Of the compounds substituted in the 6-position, the 6e isomers are preferred.
The process according to the invention is characterized in that, in a manner known per se, the 9.11 double bond of a D-homosteroid of the formula
EMI1.2
where R214 is hydrogen, halogen or R and R, Rs, R17s and the dashed 1,2-bond have the meanings given above, adding hypochlorous or hypobromous acid.
To carry out the process according to the invention, the starting steroid III is expediently dissolved in a suitable solvent, e.g. B. an ether such as tetrahydrofuran or dioxane, a chlorinated hydrocarbon such as methylene chloride or chloroform, or a ketone such as acetone, and allows hypochlorous or hypobromous acid to act. The hypochlorous or hypobromous acid is expediently generated in the reaction mixture itself; z. B. from N-bromo or N-chloroamides or imides, such as N-chlorosuccinimide or N-bromoacetamide, and a strong acid, preferably perchloric acid.
If they are not known or are not described below, the starting materials can be presented in analogy to known methods or methods described in the examples.
The D-homosteroids of the formula I are endocrine, in particular anti-inflammatory. They are characterized by the selectivity of the action, e.g. B. highly effective topically with a weaker systemic effect.
The products of the process can be used as remedies in the form of pharmaceutical preparations, which they can be mixed with an organic or inorganic inert carrier material suitable for enteral, percutaneous or parenteral administration, such as. B. water, gelatin, gum arabic, milk sugar, starch, magnesium stearate, talc, vegetable oils, polyalkylene glycols, petroleum jelly, etc. contain. The pharmaceutical preparations can be in solid form, e.g. B. as tablets, coated tablets, suppositories, capsules; in semi-solid form, e.g. B. as ointments; or in liquid form, e.g. B. as solutions, suspensions or emulsions.
They may contain auxiliaries, such as preservatives, stabilizers, wetting agents or emulsifiers, salts to change the osmotic pressure or buffers. They can also contain other therapeutically valuable substances.
A guideline for the dose range of topical preparations can be about 0.01-1 / 0, for systemic preparations about 0.1-10 mg per application unit.
The pharmaceuticals can be produced in a manner known per se by mixing the compounds of the formula I with non-toxic solid and / or liquid carrier materials which are customary in such preparations, such as, for example, solid and / or liquid carrier materials suitable for therapeutic administration. B. the above, mixed and optionally brought into the desired shape.
example
450 mg of 17a, 21-dihydroxy-D-homopregna-4,9 (1 1) -diene-3,20-dione-21-hemisuccinate are dissolved in 20 ml of dioxane and 5 ml of water with 270 mg of N-bromoacetamide and 1.85 ml of 100 / above perchloric acid are added and the mixture is stirred at room temperature for 15 minutes. Then 1.5 g of sodium sulfite and 30 ml of water are added. After brief stirring, the mixture is extracted with methylene chloride, washed with water, dried and evaporated. 540 mg of IIss, 17a, 21-trihydroxy-9-bromo-D-homo-pregn4-en-3,20-dione-21-hemisuccinate are obtained, which are uniform according to thin-layer chromatography. UV: e2S9 = 14850.
The starting material can be prepared as follows: 21-Acetoxy-17a-hydroxy-D-homopregna-4,9 (11) -diene-3,20-dione are saponified in methanolic solution with potassium carbonate, 17a, 21-dihydroxy- D-homopregna4,9 (11) -diene-3,20-dione. UV: e239 = 15800.
This is converted in carbon tetrachloride with succinic anhydride in the presence of pyridine at elevated temperature into 17a, 21-dihydroxy-D-homopregna-4,9 (11) -diene-3,20-dione-21-hemisuccinate. W: e239 = 16200.
Claims (1)
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CH1528577A CH606115A5 (en) | 1973-09-26 | 1973-09-26 | 9-Alpha-11-beta-dihalo-D-homo-pregn-4-en-3,20-diones |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CH1528577A CH606115A5 (en) | 1973-09-26 | 1973-09-26 | 9-Alpha-11-beta-dihalo-D-homo-pregn-4-en-3,20-diones |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CH606115A5 true CH606115A5 (en) | 1978-10-13 |
Family
ID=4407856
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CH1528577A CH606115A5 (en) | 1973-09-26 | 1973-09-26 | 9-Alpha-11-beta-dihalo-D-homo-pregn-4-en-3,20-diones |
Country Status (1)
| Country | Link |
|---|---|
| CH (1) | CH606115A5 (en) |
-
1973
- 1973-09-26 CH CH1528577A patent/CH606115A5/en not_active IP Right Cessation
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PL | Patent ceased | ||
| PL | Patent ceased |