CH638537A5 - Water-soluble corticoids - Google Patents

Water-soluble corticoids Download PDF

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CH638537A5
CH638537A5 CH357378A CH357378A CH638537A5 CH 638537 A5 CH638537 A5 CH 638537A5 CH 357378 A CH357378 A CH 357378A CH 357378 A CH357378 A CH 357378A CH 638537 A5 CH638537 A5 CH 638537A5
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methyl
dioxo
hydroxy
pregnadien
compound according
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CH357378A
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German (de)
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Ulrich Kerb
Rudolf Wiechert
Joachim-Friedrich Kapp
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Schering Ag
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J51/00—Normal steroids with unmodified cyclopenta(a)hydrophenanthrene skeleton not provided for in groups C07J1/00 - C07J43/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J5/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane and substituted in position 21 by only one singly bound oxygen atom, i.e. only one oxygen bound to position 21 by a single bond
    • C07J5/0007—Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane and substituted in position 21 by only one singly bound oxygen atom, i.e. only one oxygen bound to position 21 by a single bond not substituted in position 17 alfa
    • C07J5/0023—Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane and substituted in position 21 by only one singly bound oxygen atom, i.e. only one oxygen bound to position 21 by a single bond not substituted in position 17 alfa substituted in position 16
    • C07J5/003—Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane and substituted in position 21 by only one singly bound oxygen atom, i.e. only one oxygen bound to position 21 by a single bond not substituted in position 17 alfa substituted in position 16 by a saturated or unsaturated hydrocarbon group including 16-alkylidene substitutes
    • C07J5/0038—Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane and substituted in position 21 by only one singly bound oxygen atom, i.e. only one oxygen bound to position 21 by a single bond not substituted in position 17 alfa substituted in position 16 by a saturated or unsaturated hydrocarbon group including 16-alkylidene substitutes by an alkyl group

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  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
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  • Animal Behavior & Ethology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Cardiology (AREA)
  • Pulmonology (AREA)
  • Steroid Compounds (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
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Description

Die Erfindung betrifft neue, wasserlösliche Kortikoide, Arzneimittel, die diese Verbindungen enthalten sowie ein Verfahren zur Herstellung der neuen Verbindungen. The invention relates to new, water-soluble corticoids, drugs containing these compounds and a process for the preparation of the new compounds.

Die erfindungsgemässen, neuen wasserlöslichen Kortikoide weisen folgende Formel auf The new water-soluble corticoids according to the invention have the following formula

ÇH OCO(CH ) COOY <■ 2 n ÇH OCO (CH) COOY <■ 2 n

C = 0 C = 0

CH. CH.

(I) (I)

worin n die Ziffern 2 oder 3, where n is the numbers 2 or 3,

X Wasserstoff, Fluor oder Chlor und Y Wasserstoff, ein Alkalimetallatom oder den N-Methylglu-caminrest bedeuten. X is hydrogen, fluorine or chlorine and Y is hydrogen, an alkali metal atom or the N-methylglucamine residue.

Die neuen wasserlöslichen Kortikoide zeichnen sich durch ein günstiges Verhältnis zwischen Therapieeffekt und Toleranz aus. Gegenüber den vorbekannten wasserlöslichen The new water-soluble corticoids are characterized by a favorable relationship between therapeutic effect and tolerance. Compared to the previously known water-soluble

Derivaten von Kortikoiden der allgemeinen Formel II (Britische Patentschrift 1 286 093) zeichnen sich die neuen Kortikoide durch einen wesentlich rascheren Wirkungsbeginn aus. Derivatives of corticosteroids of the general formula II (British patent specification 1 286 093) are characterized by the new corticosteroids by a considerably faster onset of action.

Die therapeutische Wirksamkeit der neuen wasserlöslichen 6S Kortikoide kann beispielsweise mit Hilfe des bekannten Endotoxin-Schock-Testes, des Eosinophilen-Testes oder des Adjuvans-Ödem-Testes ermittelt werden. Zur Bestimmung der unerwünschten systemischen Nebenwirkungen, und The therapeutic effectiveness of the new water-soluble 6S corticoids can be determined, for example, with the aid of the known endotoxin shock test, the eosinophil test or the adjuvant edema test. To determine the undesirable systemic side effects, and

638537 638537

somit der Toleranz der neuen Kortikoide, kann beispielsweise der bekannte Thymolyse-Test, der Leberglykogen-Test oder der Natrium-Kalium-Retentions-Test oder der Verträglichkeitstest verwendet werden. thus the tolerance of the new corticoids, for example the well-known thymolysis test, the liver glycogen test or the sodium-potassium retention test or the tolerance test can be used.

Die neuen wasserlöslichen Kortikoide können in üblicher s Weise zu Arzneimittelspezialitäten verarbeitet werden, indem man sie gegebenenfalls mit geeigneten Zusätzen, Trägersubstanzen, Lösungsvermittlern, Stabilisatoren und Geschmackskorregentien in die gewünschten Applikationsformen, wie Tabletten, Dragees, Kapseln, Lösungen etc. 10 überführt. The new water-soluble corticoids can be processed into pharmaceutical specialties in the customary manner by converting them, if necessary with suitable additives, carriers, solubilizers, stabilizers and flavoring agents, into the desired application forms, such as tablets, dragees, capsules, solutions, etc. 10.

So ist es beispielsweise möglich, definierte Mengen der wasserlöslichen Kortikoide, gegebenenfalls nach Zusatz der üblichen Hilfsmittel unter den in der Galenik üblichen Bedingungen als Trockensubstanzen in Ampullen abzu- is füllen, welche vorzugsweise 10 mg bis 500 mg Wirkstoff enthalten. Der Ampulleninhalt wird vor der Applikation in sterilem destilliertem Wasser gelöst. For example, it is possible to fill defined amounts of the water-soluble corticoids, if appropriate after adding the customary auxiliaries, under the conditions customary in galenics as dry substances into ampoules, which preferably contain 10 mg to 500 mg of active ingredient. The contents of the ampoule are dissolved in sterile distilled water before application.

Die Arzneimittelspezialitäten können vorzugsweise zur Behandlung akuter bedrohlicher Krankheitszustände 20 The pharmaceutical specialties can preferably be used to treat acute, threatening disease states 20

(Schock nach Unfall, Verbrennungen, Operationen, Kreislaufversagen nach Vergiftungen, Herzinfarkt, Lungenembolie, schweren Asthmaanfällen etc.) verwendet werden. (Shock after accident, burns, surgery, circulatory failure after poisoning, heart attack, pulmonary embolism, severe asthma attacks etc.) can be used.

Zur Behandlung werden den Patienten je nach Schwere des Krankheitszustandes vorzugsweise 10 bis 1000 mg des Wirk- 2s stoffes intravenös appliziert. Depending on the severity of the disease, 10 to 1000 mg of the active substance are administered intravenously to the patient for treatment.

Die Herstellung der neuen Kortikoide kann nach einem dem Fachmann wohlbekannten Verfahren erfolgen. The new corticoids can be prepared by a process which is well known to the person skilled in the art.

Das erfindungsgemässe Verfahren zur Herstellung der neuen Verbindungen der Formel I ist dadurch gekenn- 30 The process according to the invention for the preparation of the new compounds of the formula I is thereby characterized

zeichnet, dass man ein Kortikoid der Formel records that one is a corticoid of the formula

CH Oli 1 2 CH Oli 1 2

35 35

C = 0 C = 0

(II) (II)

45 45

worin X weiter oben definiert ist, mit Bernsteinsäureanhydrid oder Glutarsäureanhydrid partiell verestert und erhal- so tene Kortikoide, worin Y Wasserstoff bedeutet, gegebenenfalls in ihre Alkalimetallsalze oder N-Methylglucaminsalze überführt. wherein X is further defined above, partially esterified with succinic anhydride or glutaric anhydride and corticoids obtained in which Y is hydrogen are optionally converted into their alkali metal salts or N-methylglucamine salts.

Das erfindungsgemässe Verfahren wird vorzugsweise in Gegenwart von Basen, wie zum Beispiel Pyridin, Lutidin, ss Kaliumhydrogencarbonat, Natriumcarbonat, Kaliumcar-bonat, Natriumhydroxyd, Kaliumhydroxyd etc., ausgeführt. Die genannten Salze der Kortikoide der Formel I werden vorzugsweise durch Umsetzen der freien Säure mit Alkalime-tallhydroxyden, Alkalimetallcarbonaten, Alkalimetallhydro- «o gencarbonaten oder Alkalimetallalkoholaten erhalten. The process according to the invention is preferably carried out in the presence of bases, such as, for example, pyridine, lutidine, potassium hydrogen carbonate, sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, etc. The corticoids of the formula I mentioned are preferably obtained by reacting the free acid with alkali metal hydroxides, alkali metal carbonates, alkali metal hydrogen carbonates or alkali metal alcoholates.

Mit Hilfe des erfindungsgemässen Verfahrens können beispielsweise hergestellt werden: With the aid of the method according to the invention, for example, the following can be produced:

das (6a, 9a-Difiuor-l 1 ß-hydroxy-16a-methyl-3,20-dioxo-1,4-pregnadien-21 -yl)-hemiglutarat, sowie dessen N atrium- «s oder Kaliumsalze sowie das (9a-Chlor-6a-fluor-l lß-hydroxy-16a-methyl-3,20-dioxo-1,4-pregnadien-21 -yl)-hemiglutarat und dessen Natrium- und Kaliumsalz. das (6a, 9a-Difiuor-l 1 ß-hydroxy-16a-methyl-3,20-dioxo-1,4-pregnadien-21 -yl) -hemiglutarat, as well as its sodium or potassium salts as well as the (9a -Chlor-6a-fluoro-lß-hydroxy-16a-methyl-3,20-dioxo-1,4-pregnadien-21-yl) hemiglutarate and its sodium and potassium salt.

Die nachfolgenden Beispiele dienen zur Erläuterung des erfindungsgemässen Verfahrens. The following examples serve to explain the method according to the invention.

Beispiel 1 example 1

2 g 6a, 9a-Difluor-11 ß, 21 -dihydroxy-16a-methyl-1,4-pregnadien-3,20-dion werden in 10 ml Pyridin gelöst, 1 g Bernsteinsäureanhydrid zugegeben und 30 Minuten unter Argonbegasung zum Sieden erhitzt. Nach dem Abkühlen wird in Eiswasser eingerührt, mit verdünnter Schwefelsäure angesäuert, das ausgefallene Produkt abgesaugt, neutral gewaschen und getrocknet. Nach Umkristallisation aus Aceton-Hexan erhält man 2,1 g (6a, 9a-Difluor-l lß-hydroxy-16a-methyl-3,20-dioxo-1,4-pregnadien-21 -yl)-hemisuccinat vom Schmelzpunkt: 199-201°C. 2 g of 6a, 9a-difluoro-11β, 21 -dihydroxy-16a-methyl-1,4-pregnadiene-3,20-dione are dissolved in 10 ml of pyridine, 1 g of succinic anhydride is added and the mixture is heated to boiling under gassing with argon for 30 minutes. After cooling, the mixture is stirred into ice water, acidified with dilute sulfuric acid, the precipitated product is filtered off with suction, washed neutral and dried. After recrystallization from acetone-hexane, 2.1 g (6a, 9a-difluoro-l-lß-hydroxy-16a-methyl-3,20-dioxo-1,4-pregnadien-21-yl) hemisuccinate with a melting point of: 199 are obtained -201 ° C.

b) 700 mg Hemisuccinat werden in 10 ml abs. Methanol mit 9,4 ml 0,1 normaler Kaliummethylat Lösung unter Verwendung eines pH-Meters auf pH 8 eingestellt. Die Lösung wird im Vakuum konzentriert und in 600 ml Äther gefällt. Das ausgefällte Kaliumsalz wurde abgesaugt, mit Äther gewaschen und im Vakuum über Phosphorpentoxid getrocknet. Man erhält 670 mg Kalium (6a, 9a-difluor-l lß-hydroxy-3,20-dioxo-16a-methyl-1,4-pregnadien-21 -yl)-suc-cinat. Schmelzpunkt: 170-180°C, UV: 6238 = 16600. b) 700 mg hemisuccinate in 10 ml abs. Methanol was adjusted to pH 8 with 9.4 ml of 0.1 normal potassium methylate solution using a pH meter. The solution is concentrated in vacuo and precipitated in 600 ml of ether. The precipitated potassium salt was filtered off, washed with ether and dried in vacuo over phosphorus pentoxide. 670 mg of potassium (6a, 9a-difluoro-1 lß-hydroxy-3,20-dioxo-16a-methyl-1,4-pregnadien-21-yl) -suc-cinate are obtained. Melting point: 170-180 ° C, UV: 6238 = 16600.

c) 650 mg Hemisuccinat werden in 10 ml absoluten Methanol mit 11,4 ml 0,1 normaler Natriummethylat-Lösung auf pH 8 eingestellt. Die Lösung wird im Vakuum konzentriert, und in eine auf +3°C gekühlte Mischung aus 500 ml Äther und 100 ml Pentan eingerührt. Das ausgefallene Produkt wird abgesaugt und im Vakuum getrocknet. Man erhält so 630 mg Natrium (6a, 9a-difluor-l lß-hydroxy-3,20-dioxo- c) 650 mg of hemisuccinate are adjusted to pH 8 in 10 ml of absolute methanol with 11.4 ml of 0.1 normal sodium methylate solution. The solution is concentrated in vacuo and stirred into a mixture of 500 ml of ether and 100 ml of pentane, cooled to + 3 ° C. The precipitated product is filtered off and dried in vacuo. This gives 630 mg of sodium (6a, 9a-difluoro-lß-hydroxy-3,20-dioxo-

16a-methyl-1,4-pregnadien-21 -yl)-succinat. Schmelzpunkt: 175-180°C, UV: 8238 = 16500. 16a-methyl-1,4-pregnadien-21-yl) succinate. Melting point: 175-180 ° C, UV: 8238 = 16500.

Beispiel 2 Example 2

a) 5 g 6a-Fluor-11 ß, 21 -dihydroxy-16a-methyl-1,4-preg-nadien-3,20-dion werden in 25 ml Pyridin mit 5 g Bernsteinsäureanhydrid analog Beispiel la umgesetzt und aufgearbeitet. Nach Umkristallisation aus Essigester erhält man 5,2 g (6a-Fluor-11 ß-hydroxy-16a-methyl-3,20-dioxo-1,4-pregna-dien-21-yl)-hemisuccinat. Schmelzpunkt: 210-212°C. a) 5 g of 6a-fluoro-11β, 21 -dihydroxy-16a-methyl-1,4-preg-nadiene-3,20-dione are reacted in 25 ml of pyridine with 5 g of succinic anhydride analogously to Example la and worked up. After recrystallization from ethyl acetate, 5.2 g (6a-fluoro-11β-hydroxy-16a-methyl-3,20-dioxo-1,4-pregna-dien-21-yl) hemisuccinate are obtained. Melting point: 210-212 ° C.

b) 10 g Hemisuccinat werden in 400 ml absoluten Methanol mit 17,9 ml 0,1 normaler Natriummethylat Lösung auf pH 8 eingestellt und gefällt wie unter 1 c) beschrieben. Man erhält so 9,6 g Natrium(6a-Fluor-l 1 ß-hydroxy-16a-methyl-3,20-dioxo-l,4-pregnadien-21-yl)-succinat. UV: 8242 = 16100. Schmelzpunkt 163-170°C (Zers.). b) 10 g of hemisuccinate are adjusted to pH 8 in 400 ml of absolute methanol with 17.9 ml of 0.1 normal sodium methylate solution and precipitated as described under 1 c). This gives 9.6 g of sodium (6a-fluoro-1 1 β-hydroxy-16a-methyl-3,20-dioxo-l, 4-pregnadien-21-yl) succinate. UV: 8242 = 16100. Melting point 163-170 ° C (dec.).

Beispiel 3 Example 3

a) 5 g 6a-Fluor-11 ß, 21 -dihydroxy-16a-methyl-1,4-preg-nadien-3,20-dion werden in 20 ml Pyridin mit 2 g Glutarsäureanhydrid 45 Minuten unter Argonbegasung zum Sieden erhitzt. Nach dem Abkühlen wird in Eiswasser eingerührt, mit verdünnter Schwefelsäure angesäuert, das ausgefallene Produkt abgesaugt, neutral gewaschen und getrocknet. Das Rohprodukt wurde in Essigester gelöst und mit 5%iger Sodalösung ausgeschüttelt. Die abgetrennte wässrige Phase wird mit Salzsäure angesäuert, mit Essigester extrahiert, der Essigesterextrakt neutralgewaschen und im Vakuum eingedampft. Man erhält so 5,2 g (6a-Fluor-l 1 ß-hydroxy-16a-methyl-3,2—dioxo-1,4-pregnadien-21 -yl)-hemiglutarat. Schmelzpunkt 171-173°C. a) 5 g of 6a-fluoro-11β, 21 -dihydroxy-16a-methyl-1,4-preg-nadiene-3,20-dione are heated to boiling in 20 ml of pyridine with 2 g of glutaric anhydride for 45 minutes while gassing with argon. After cooling, the mixture is stirred into ice water, acidified with dilute sulfuric acid, the precipitated product is filtered off with suction, washed neutral and dried. The crude product was dissolved in ethyl acetate and shaken out with 5% sodium carbonate solution. The separated aqueous phase is acidified with hydrochloric acid, extracted with ethyl acetate, the ethyl acetate extract is washed neutral and evaporated in vacuo. This gives 5.2 g (6a-fluoro-1 1 β-hydroxy-16a-methyl-3,2-dioxo-1,4-pregnadien-21-yl) hemiglutarate. Melting point 171-173 ° C.

b) 2,5 g Hemiglutarat werden analog Beispiel lc in das Natriumsalz übergeführt. Man erhält so 2,4 g Natrium(6a-Fluor-11 ß-hydroxy-16a-methyl-3,20-dioxo-1,4-pregnadien-21-yl)-glutarat. UV: 824i = 16000. Schmelzpunkt 167°C (Zers.) b) 2.5 g of hemiglutarate are converted into the sodium salt analogously to Example 1c. This gives 2.4 g of sodium (6a-fluoro-11β-hydroxy-16a-methyl-3,20-dioxo-1,4-pregnadien-21-yl) glutarate. UV: 824i = 16000. Melting point 167 ° C (dec.)

Beispiel 4 Example 4

a) 1 g 6a-Fluor-9a-chlor-l lß, 21 -dihydroxy- 16a-methyl- a) 1 g of 6a-fluoro-9a-chloro-lß, 21 -dihydroxy- 16a-methyl-

5 5

638537 638537

l,4-pregnadien-3,20-dion wird in 5 ml Pyridin, mit 0,5 g Bernsteinsäureanhydrid, 30 min unter Argonbegasung zum Sieden erhitzt. Nach Aufarbeitung wie im Beispiel la beschrieben und Umkristallisation aus Aceton-Essigester erhält man 1,23 g (6a-Fluor-9a-chlor-11 ß-hydroxy-16a-methyl-3,20-dioxo-1,4-pregnadien-21 -yl)-hemisuccinat, Schmp. 249°C (Zers.). 1,4-pregnadiene-3,20-dione is heated to boiling in 5 ml of pyridine, with 0.5 g of succinic anhydride, for 30 min while gassing with argon. After working up as described in Example la and recrystallization from acetone-ethyl acetate, 1.23 g (6a-fluoro-9a-chloro-11β-hydroxy-16a-methyl-3,20-dioxo-1,4-pregnadiene-21 -yl) hemisuccinate, mp. 249 ° C (dec.).

b) 700 mg Hemisuccinat werden in 15 ml Methanol mit 0,1 normaler Natriummethylat-Lösung in das Natriumsalz übergeführt. Man erhält 570 mg Natrium(6a-fluor-9a-chlor-l lß-hydroxy-16a-methyl-3,20-dioxo-1,4-pregnadien-21 -yl) suc-cinat. Schmp. 165°C (Zers.). b) 700 mg of hemisuccinate are converted into the sodium salt in 15 ml of methanol with 0.1 normal sodium methylate solution. 570 mg of sodium (6a-fluoro-9a-chloro-1-beta-hydroxy-16a-methyl-3,20-dioxo-1,4-pregnadien-21-yl) suc-cinate are obtained. Mp 165 ° C (dec.).

Beispiel 5 Example 5

Analog wie im Beispiel 3 beschrieben, wurde das 6a-Fluor- Analogously to that described in Example 3, the 6a-fluoro-

9a-chlor-11 ß, 21 -dihydroxy-16a-methyl-1,4-pregnadien-3,20-dion in das (6a-Fluor-9a-chlor-l 1 ß-hydroxy- 16a-methyl-3,20-dioxo-1,4-pregnadien-21 -y l)-hemiglutarat übergeführt (Schmp. 182-183,5°C Zers.) und dieses weiter zum s Natrium (6a-fluor-9a-chlor-11 ß-hydroxy-16a-methyl-3,20-dioxo- 1,4-pregnadien-21 -yl) glutarat umgesetzt. Schmp. 124°C (Zers.). 9a-chloro-11β, 21 -dihydroxy-16a-methyl-1,4-pregnadiene-3,20-dione into the (6a-fluoro-9a-chloro-1 1ß-hydroxy-16a-methyl-3.20 -dioxo-1,4-pregnadien-21 -yl) -hemiglutarat converted (mp. 182-183.5 ° C dec.) and this further to s sodium (6a-fluoro-9a-chloro-11 ß-hydroxy-16a -methyl-3,20-dioxo- 1,4-pregnadien-21 -yl) glutarate implemented. Mp 124 ° C (dec.).

Beispiel 6 Example 6

1,5 g (6a-Fluor-l 1 ß-hydroxy-16a-methyl-3,20-dioxo-1,4-io pregnadien-21-yl)-hemisuccinat und 0,646 g N-Methylglu-camin werden in 30 ml bidestilliertem Wasser gelöst und die klare Lösung über 24 Stunden gefriergetrocknet. Man erhält so 2,07 g amorphes N-Methylglucamin-(6a-fluor-l lß-hydroxy-16a-methyl-3,20-dioxo-1,4-pregnadien-21 -yl)-suc-«s cinat. 1.5 g (6a-fluoro-1 1 ß-hydroxy-16a-methyl-3,20-dioxo-1,4-io pregnadien-21-yl) hemisuccinate and 0.646 g of N-methylglucamine are added in 30 ml dissolved double-distilled water and the clear solution freeze-dried for 24 hours. This gives 2.07 g of amorphous N-methylglucamine- (6a-fluoro-1β-hydroxy-16a-methyl-3.20-dioxo-1,4-pregnadien-21-yl) -suc- «s cinate.

B B

Claims (3)

638537 638537 2. Natrium-(6a,9a-difluor-llß-hydroxy-16a-methyl-3, 20-dioxo-l,4-pregnadien-21-yl)-succinat als Verbindung gemäss Anspruch 1. 2. sodium (6a, 9a-difluoro-11ß-hydroxy-16a-methyl-3, 20-dioxo-l, 4-pregnadien-21-yl) succinate as a compound according to claim 1. 3. Natrium-(6a-fluor-l 1 ß-hydroxy-16a-methyl-3,20-dioxo-1,4-pregnadien-21-yl)-succinat als Verbindung gemäss Anspruch 1. 3. sodium (6a-fluoro-1 1 ß-hydroxy-16a-methyl-3,20-dioxo-1,4-pregnadien-21-yl) succinate as a compound according to claim 1. 4. Natrium-(6cc-fluor-11 ß-hydroxy-16a-methyl-3,20-dioxo-l,4-pregnadien-21-yl)-glutarat als Verbindung gemäss Anspruch 1. 4. Sodium (6cc-fluoro-11β-hydroxy-16a-methyl-3,20-dioxo-l, 4-pregnadien-21-yl) glutarate as a compound according to claim 1. 5. Natrium-(9a-chlor-6cc-fluor-11 ß-hydroxy-16a-methyl-3,20-dioxo-l,4-pregnadien-21-yl)-succinat als Verbindung gemäss Anspruch 1. 5. Sodium (9a-chloro-6cc-fluoro-11β-hydroxy-16a-methyl-3,20-dioxo-l, 4-pregnadien-21-yl) succinate as a compound according to claim 1. 6. Kalium-(6a, 9a-difluor-11 ß-hydroxy-16a-methyl-3, 20-dioxo-1,4-pregnadien-21 -yl)-succinat als Verbindung gemäss Anspruch 1. 6. Potassium (6a, 9a-difluoro-11β-hydroxy-16a-methyl-3, 20-dioxo-1,4-pregnadien-21-yl) succinate as a compound according to claim 1. 7. (6a, 9a-Difluor-11 ß-hydroxy-16a-methyl-3,20-dioxo- 7. (6a, 9a-difluoro-11β-hydroxy-16a-methyl-3,20-dioxo- l,4-pregnadien-21-yl)-hemisuccinat als Verbindung gemäss Anspruch 1. 1,4-pregnadien-21-yl) hemisuccinate as a compound according to claim 1. 8. (6a-Fluor-llß-hydroxy-16a-methyl-3,20-dioxo-l,4-pregnadien-21-yl)-hemisuccinat als Verbindung gemäss 8. (6a-fluoro-11ß-hydroxy-16a-methyl-3,20-dioxo-l, 4-pregnadien-21-yl) hemisuccinate as a compound according to 25 Anspruch 1. 25 Claim 1. 9. (6a-Fluor-11 ß-hydroxy-16a-methyl-3,20-dioxo-1,4-pregnadien-21-yl)-hemiglutarat als Verbindung gemäss Anspruch 1. 9. (6a-fluoro-11β-hydroxy-16a-methyl-3,20-dioxo-1,4-pregnadien-21-yl) hemiglutarate as a compound according to claim 1. 10. (9a-Chlor-6a-fIuor-l lß-hydroxy-16a-methyl-3,20-30 dioxo-1,4-pregnadien-21 -yl)-hemisuccinat als Verbindung gemäss Anspruch 1. 10. (9a-chloro-6a-fluorine-1-beta-hydroxy-16a-methyl-3.20-30 dioxo-1,4-pregnadien-21-yl) hemisuccinate as a compound according to claim 1. 11. Natrium-(9a-chlor-6a-fluor-11 ß-hydroxy- 16a-methyl-3,20-dioxo-l,4-pregnadien-21-yl)-glutarat als Verbindung gemäss Anspruch 1. 11. sodium (9a-chloro-6a-fluoro-11β-hydroxy-16a-methyl-3,20-dioxo-l, 4-pregnadien-21-yl) glutarate as a compound according to claim 1. 35 12. N-Methylglucamin-(6a-fIuor-llß-hydroxy-16a-methyl-3,20-dioxo-l,4-pregnadien-21-yl)-succinat als Verbindung gemäss Anspruch 1. 35 12. N-methylglucamine- (6a-fluorine-11ß-hydroxy-16a-methyl-3,20-dioxo-l, 4-pregnadien-21-yl) succinate as a compound according to claim 1. 13. Pharmazeutische Präparate, dadurch gekennzeichnet, dass sie als Wirkstoffkomponente mindestens eine neue Ver-40 bindung der Formel 13. Pharmaceutical preparations, characterized in that they contain at least one new compound of the formula as active ingredient ÇH OCO(CH ) COOY *£ n ÇH OCO (CH) COOY * £ n C=0 C = 0 (I) (I) worin n die Ziffern 2 oder 3, where n is the numbers 2 or 3, X Wasserstoff, Fluor oder Chlor und X is hydrogen, fluorine or chlorine and Y Wasserstoff, ein Alkalimetallatom oder den N-Methylglu- Y is hydrogen, an alkali metal atom or the N-methylglu caminrest bedeuten, enthalten. caminrest mean contain. 14. Verfahren zur Herstellung neuer, wasserlöslicher Kor-«s tikoide der Formel 14. Process for the preparation of new, water-soluble corrosives of the formula 2 2nd PATENTANSPRÜCHE 1. Wasserlösliche Kortikoide der Formel PATENT CLAIMS 1. Water soluble corticoids of the formula H„OCO(CH ) COOY 2 n H „OCO (CH) COOY 2 n CH. CH. (I) (I) worin n die Ziffern 2 oder 3, where n is the numbers 2 or 3, X Wasserstoff, Fluor oder Chlor und Y Wasserstoff, ein Alkalimetallatom oder den N-Methylglu-caminrest bedeuten. X is hydrogen, fluorine or chlorine and Y is hydrogen, an alkali metal atom or the N-methylglucamine residue. 3 3rd 638537 638537 ÇH OCO(CH ) COOY 2 2 n ÇH OCO (CH) COOY 2 2 n C = 0 C = 0 CH. CH. (I) (I) worin n die Ziffern 2 oder 3, where n is the numbers 2 or 3, X Wasserstoff, Fluor oder Chlor und X is hydrogen, fluorine or chlorine and Y Wasserstoff, ein Alkalimetallatom oder den N-Methylglu-caminrest bedeuten, dadurch gekennzeichnet, dass man ein Kortikoid der Formel Y is hydrogen, an alkali metal atom or the N-methylglucamine residue, characterized in that a corticoid of the formula CH Oll c = o CH Oll c = o .CH. .CH. (II) (II) worin X weiter oben definiert ist, mit Bernsteinsäureanhy- benenfalls in ihre Alkalimetallsalze oder N-Methylglucamin-drid oder Glutarsäureanhydrid partiell verestert und erhal- salze überführt. wherein X is defined further above, partially esterified with succinic acid hybene in its alkali metal salts or N-methylglucamine dride or glutaric anhydride and converted to salts. tene Verbindungen, in welchen Y Wasserstoff bedeutet, gege- Compounds in which Y represents hydrogen
CH357378A 1977-04-06 1978-04-03 Water-soluble corticoids CH638537A5 (en)

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