DK159118B - 6ALFA METHYLPREDNISOLON DERIVATIVES AND PHARMACEUTICAL PREPARATIONS CONTAINING THEM - Google Patents
6ALFA METHYLPREDNISOLON DERIVATIVES AND PHARMACEUTICAL PREPARATIONS CONTAINING THEM Download PDFInfo
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
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- C07J21/00—Normal steroids containing carbon, hydrogen, halogen or oxygen having an oxygen-containing hetero ring spiro-condensed with the cyclopenta(a)hydrophenanthrene skeleton
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- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J5/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane and substituted in position 21 by only one singly bound oxygen atom, i.e. only one oxygen bound to position 21 by a single bond
- C07J5/0046—Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane and substituted in position 21 by only one singly bound oxygen atom, i.e. only one oxygen bound to position 21 by a single bond substituted in position 17 alfa
- C07J5/0053—Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane and substituted in position 21 by only one singly bound oxygen atom, i.e. only one oxygen bound to position 21 by a single bond substituted in position 17 alfa not substituted in position 16
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Abstract
Description
DK 159118 BDK 159118 B
iin
Opfindelsen angår hidtil ukendte 6a-methylprednisolon-deriva-ter og farmaceutiske præparater, der indeholder sådanne derivater. De omhandlede derivater er ejendommelige ved det i krav l's kendetegnende del anførte.The invention relates to novel 6α-methylprednisolone derivatives and pharmaceutical compositions containing such derivatives. The derivatives in question are peculiar to the characterizing part of claim 1.
55
De hidtil ukendte 6a-methylprednisolon-derivater med den almene formel I ifølge krav 1 kan som 1-oxoalkylgrupper Rj og R2 f . eks. have en acetyl gruppe, en prop i ony1 gruppe, en butyryl -gruppe, en i sobutyryl gruppe, en valerylgruppe, en 3-methylbu-10 tyrylgruppe, en trimethylacetylgruppe eller en hexanoylgruppe.The novel 6α-methylprednisolone derivatives of the general formula I according to claim 1 can be as 1-oxoalkyl groups R 1 and R 2 f. for example, having an acetyl group, a plug in ony1 group, a butyryl group, one in sobutyryl group, a valeryl group, a 3-methylbutylryl group, a trimethylacetyl group or a hexanoyl group.
Fra fransk patentskrift nr. 2.366.312 kendes en række beslægtede forbindelser, der blandt andet omfatter forbindelser med formlenFrench Patent Specification No. 2,366,312 discloses a number of related compounds which include, inter alia, compounds of the formula
15 CH.Y15 CH.Y
I 2 c»oI 2 c »o
gQ . · *.XgQ. · * .X
20 C>20 ° C
OISLAND
hvor Y blandt andet kan være hydroxy eller en acyloxygruppe med 1-10 carbonatomer og X kan være en acyloxygruppe med 1-10 25 carbonatomer.wherein Y may be, inter alia, hydroxy or an acyloxy group of 1-10 carbon atoms and X may be an acyloxy group of 1-10 carbon atoms.
6a-methylprednisolon-derivaterne ifølge den foreliggende opfindelse har ved lokal eller topisk anvendelse et væsentligt gunstigere teraptutisk indeks, dvs. gunstig stor ønsket virk-30 ning i forhold til uønskede systemiske bivirkninger, sammenlignet med de forbindelser, der er kendt fra det nævnte franske patenskrift.The 6α-methylprednisolone derivatives of the present invention have, by local or topical use, a significantly more favorable therapeutic index, i.e. favorably desired effect relative to undesirable systemic side effects, compared with the compounds known from the aforementioned French patent specification.
De heri omhandlede hidtil ukendte 6a-methylprednisolon-deri-35 vater med den almene formel I ifølge krav 1, egner sig som følge heraf i kombination med de i den galeniske farmaci sædvanlige bærermidler til lokal behandling af kontaktdermatitis,The novel 6a-methylprednisolone derivatives of the general formula I according to claim 1, as a consequence thereof, are suitable in combination with the usual carriers for local contact dermatitis in the galenic pharmacy.
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2 eksemer af de mest forskellige arter, neurodermatoser, ery-throdermi, forbrændinger, pruritis vulvae et ani, rosacea, erythematodes cutaneus, psoriasis, lichen ruber pianus et verrucosus og lignende hudsygdomme.2 eczema of the most diverse species, neurodermatoses, erythrodermia, burns, pruritis vulvae et ani, rosacea, erythematodes cutaneus, psoriasis, lichen ruber pianus et verrucosus and similar skin diseases.
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Den lokale aktivitet hos forbindelserne blev bestemt ved hjælp af følgende vasokonstriktionsprøve:The local activity of the compounds was determined by the following vasoconstriction test:
Prøven gennemførtes på 8 raske forsøgspersoner af begge køn, 10 som i de·to sidste uger ikke havde modtaget nogen lokal corti-kosteroidbehandling. Efter fjernelse af Stratum corneum til Stratum lucidum på forsøgspersonernes ryg (20-40 tesafilm-af-rivninger) blev 0,1 g af det undersøgte præparat påført på et 4 cma stort felt uden okklusionsforbinding. For at sikre, at 15 det samme præparat blev administreret på et identisk hudareal, blev disse påført i en roterende rækkefølge.The test was conducted on 8 healthy subjects of both sexes, 10 who had not received any local cortical corticosteroid treatment in the last two weeks. Following removal of the Stratum corneum to Stratum lucidum on the subjects' backs (20-40 thesafilm tear-offs), 0.1 g of the investigated preparation was applied to a 4 cma field without occlusion dressing. To ensure that the same composition was administered on an identical skin area, these were applied in a rotating order.
Vasokonstriktionen blev bedømt visuelt efter 8 timer efter følgende virkningsgrade: 20 1 = absolut blegning, 2 = små resterythemer, 3 = erythemer af middelgrad, rødfarvningsintesitet i det mellemliggende område mellem afrevet, ubehandlet og ikke-beskadiget hud, 4 = erythemer med lidt blegning, 5 = ingen blegning eller forstærkning 25 af erythemerne.Vasoconstriction was assessed visually at 8 hours according to the following efficacy: 20 1 = absolute bleaching, 2 = small residual rhythms, 3 = middle grade erythema, red staining intensity in the intermediate region between stripped, untreated and non-damaged skin, 4 = slight bleaching erythema, 5 = no bleaching or strengthening of the erythema.
De enkelte vurderinger blev opnoteret.The individual assessments were recorded.
Ved hver forsøgsrække blev der som referenceforbindelse an-30 vendt dif lucortolon-21-valerianat (=6a,9a-dif luor-ll/3-hydro- xy-16a-methyl-21-valeryloxy-l,4-pregnadien-3,20-dion = DFV).For each test series, diflucortolone-21 valerianate (= 6a, 9a-difluoro-11/3-hydroxy-16a-methyl-21-valeryloxy-1,4-pregnadien-3) was used as the reference compound. 20-dione = DFV).
Differencen Δ mellem de ved de enkelte forsøgsrækker opnåede gennemsnitlige virkningsgrader for DFV og prøveforbindelse 35 blev bestemt. En positiv afvigelse viser en gunstig og en negativ afvigelse viser en ugunstig virkning hos prøveforbindelserne i sammenligning med DFV.The difference Δ between the average efficiencies obtained for the individual test series for DFV and test compound 35 was determined. A positive deviation shows a favorable and a negative deviation shows an adverse effect on the test compounds in comparison with DFV.
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3 I den efterfølgende tabel er vist de iagttagne prøveresultater, som blev opnået ved behandling af forsøgspersonerne med et præparat indeholdende forskellige koncentrationer af virksomt stof.3 The following table shows the observed test results obtained by treating the subjects with a preparation containing different concentrations of active substance.
55
De systemiske bivirkninger blev bestemt ved hjælp af thymo-Tyseprøven, som blev udført på følgende måde: SPF-rotter med en vægt på 70 - 110 g blev adrenalektomeret 10 under ethernarkose. 6 dyr dannede en prøvegruppe, som i n dage modtog en opløsning af 2 ml af en 0,1%'s prøvestofopløsning på et 5 x 5 cm stort hudareal. På den efterfølgende dag blev dyrene aflivet, og deres thymusvægt blev bestemt. Kontroldyrene blev behandlet på samme måde, men modtog imidlertid kun 2 ml 15 opløsning fri for virksomt stof. Ud fra de bestemte thymusvæg-te blev på sædvanlig måde den procentuelle thymolytiske effekt beregnet.The systemic side effects were determined by the Thymo-Tyse test, which was carried out as follows: SPF rats weighing 70 - 110 g were adrenalectomized under ether anesthesia. Six animals formed a sample group that received a solution of 2 ml of a 0.1% test substance solution on a 5 x 5 cm skin area for nine days. On the following day, the animals were sacrificed and their thymus weight determined. The control animals were treated in the same way, but received only 2 ml of active substance-free solution. From the specific thymus weights, the percent thymolytic effect was calculated in the usual way.
Den efterfølgende tabel angiver de opnåede forsøgsresultater.The following table indicates the experimental results obtained.
20 I tabellen er også til sammenligning vist resultater for to forbindelser (I og II), der er kendt fra det ovennævnte franske patentskrift nr. 2.366.312.20 The table also compares results for two compounds (I and II) known from the aforementioned French Patent Specification No. 2,366,312.
25 30 35 DK 159118 425 30 35 DK 159118 4
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55
Fremstillingen af lægemiddel special iteterne sker på sædvanlig måde, idet man med egnede tilsætninger overfører de virksomme stoffer i de ønskede applikationsformer, som f.eks. opløsninger, lotioner, salver, creme eller plaster. I de således for-5 mulerede lægemidler er koncentrationen af virksomt stof afhængig af applikationsformen. Ved lotioner og salver anvendes fortrinsvis en koncentration af virksomt stof på 0,001 - 1%.The preparation of the drug specialties is carried out in the usual way, with suitable additives transferring the active substances in the desired application forms, such as e.g. solutions, lotions, ointments, creams or plastics. In the drugs thus formulated, the concentration of active substance is dependent on the form of application. For lotions and ointments, a concentration of active substance of 0.001 - 1% is preferably used.
De hidtil ukendte forbindelser er desuden eventuelt i kombi-10 nation med sædvanlige bærermidler og hjælpestoffer også velegnede til fremstillingen af inhalationsmidler, som kan anvendes til behandlingen af allergiske sygdomme i luftvejene, som f.eks. bronkial astma eller rhinitis.In addition, the novel compounds, optionally in combination with conventional carriers and excipients, are also well suited for the preparation of inhalants which can be used for the treatment of allergic diseases of the respiratory tract, such as e.g. bronchial asthma or rhinitis.
15 De hidtil ukendte cortikoider er desuden også egnede i form af kapsler, tabletter eller drageer, som fortrinsvis indeholder 10 - 200 mg virksomt stof og indgives oralt, eller i form af suspensioner, som fortrinsvis indeholder 100 - 500 mg virksomt stof pr. dosisenhed og indgives rektalt, også til behandlingen 20 af allergiske sygdomme i tarmkanalen såsom kolitis ulcerosa og kolitis granulomatosa.In addition, the novel corticoids are also useful in the form of capsules, tablets or dragees which preferably contain 10 - 200 mg of active substance and are administered orally, or in the form of suspensions which preferably contain 100 - 500 mg of active substance per day. dosage unit and administered rectally, also for the treatment of 20 allergic diseases of the intestinal tract such as colitis ulcerosa and colitis granulomatosa.
De hidtil ukendte 6a-methylprednisolon-derivater kan fremstilles ved at man på i og for sig kendt måde afspalter hydrogen-25 bromid fra et cortikoid med den almene formel IIIThe novel 6α-methylprednisolone derivatives can be prepared by decolorising in a known manner hydrogen bromide from a corticoid of the general formula III
CH2°R2° CH 2 R 2
OOISLAND ISLAND
-- -0R! 30 II] (iii) I ! Br 35 hvori Rj og R2 har ovennævnte betydning. Denne fremgangsmåde kan gennemføres under de betingelser, som er beskrevet i de- -0R! 30 II] (iii) I! Br 35 wherein R 1 and R 2 are as defined above. This process can be carried out under the conditions described in the
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6 tyske patentansøgninger nr. 26 45 104, 26 45 105 og 23 40 591 samt i US patent nr. 3.383.394 eller publikationen J. Amer. Chem. Soc., 79, 1957, 1515.6 German Patent Applications Nos. 26,454,104, 26,455,105, and 23,409,591; Chem. Soc., 79, 1957, 1515.
5 De efterfølgende udførelseseksempler tjener til belysning af opfindelsen.The following exemplary embodiments serve to illustrate the invention.
Eksempel 1 10 A) En suspension af 34,0 g 21-acetoxy-9a-brom-ll/3,17-di hydro-xy-6a-methyl-1,4-pregnadien-3,20-dion i 1,36 1 methanol og 120 ml 70% perchlorsyre omrøres i 20 timer ved stuetemperatur. Efter isvandfældning frasuges bundfaldet, vaskes neutralt med vand og tørres i vakuumtørreskab. Der fås 28,3 g 9a-brom-110, 15 17,21-trihydroxy-6a-methyl-1,4-pregnadien-3,20-dion, smelte punkt 159-160°C.Example 1 A) A suspension of 34.0 g of 21-acetoxy-9a-bromo-11 / 3,17-dihydroxy-6a-methyl-1,4-pregnadiene-3,20-dione in 1.36 1 methanol and 120 ml 70% perchloric acid are stirred for 20 hours at room temperature. After ice water precipitation, the precipitate is aspirated, washed neutral with water and dried in a vacuum drying cabinet. 28.3 g of 9α-bromo-110, 17,21-trihydroxy-6α-methyl-1,4-pregnadiene-3,20-dione are obtained, m.p. 159-160 ° C.
B) En opløsning af 4,3 g 9a-brom-ll|3,17,21-tri hydroxy-6a-me-thy1-1,4-pregnadi en-3,20-dion og 430 mg pyridi ni umtosy1 at i 20 34,5 ml dimethylformamidd og 300 ml benzen af dest i 11 eres ved 130°C over en vandudskiller 129 ml benzen. Man lader 10,3 ml orthosmørsyretrimethylester dryppe til denne varme reaktions-opløsning og afdestillerer derpå yderligere benzen og andre letflygtige reaktionskomponenter. Der tilsættes 5 ml pyridin 25 og inddampes i vakuum til tørhed. Der isoleres 9a-brom-ll/3-hydroxy-17a,21-(1-methoxy-buty1idendioxy)-6a-methyl-l,4-preg-nadien-3,20-dion som en olie.B) A solution of 4.3 g of 9α-bromo-11β,17,21-tri hydroxy-6α-methyl-1,4-pregnadi en-3,20-dione and 430 mg of pyridinylmethyl 20, 34.5 ml of dimethylformamide and 300 ml of benzene of dest in 11 are heated at 130 ° C over a water separator 129 ml of benzene. Dissolve 10.3 ml of ortho-butyric acid trimethyl ester to this hot reaction solution and then further distill benzene and other volatile reaction components. Add 5 ml of pyridine 25 and evaporate in vacuo to dryness. 9α-Bromo-11/3-hydroxy-17α, 21- (1-methoxy-butylidenedioxy) -6α-methyl-1,4-preg-nadien-3,20-dione is isolated as an oil.
C) Den rå 9<z-brom-llø-hydroxy-17a, 21-(1-methoxybuty 1 idendio-30 oxy)-6a-methyl-l,4-pregnadien-3,20-dion opløses i 129 ml methanol og omrøres med en blanding af 46,4 ml 0,1N vandig eddikesyre og 5,2 ml 01M vandig natriumacetatopløsning i en time ved en badtemperatur på 80eC. Man inddamper opløsningen til 1/3 af dens volumen, tilsætter vand og vasker eddikeestereks- 35 trakten neutral. Efter tørring og inddampning renses råproduktet på 200 g kieselgel med en hexan-acetone-gradient (0-60% acetone). Der isoleres 3,7 g 9a-brom-17a-butyryloxy-ll/S, 21-di-C) The crude 9 (z-bromo-11-hydroxy-17a, 21- (1-methoxybutyl-idendioxy) -6a-methyl-1,4-pregnadiene-3,20-dione is dissolved in 129 ml of methanol and Stir with a mixture of 46.4 ml of 0.1N aqueous acetic acid and 5.2 ml of 01M aqueous sodium acetate solution for one hour at a bath temperature of 80 ° C. The solution is evaporated to 1/3 of its volume, water added and the vinegar extract extract washed neutral. After drying and evaporation, the crude product is purified on 200 g of silica gel with a hexane-acetone gradient (0-60% acetone). 3.7 g of 9α-bromo-17α-butyryloxy-11 / S, 21-di
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7 hydroxy-6a-methyl-l,4-pregnadien-3,20-dion, smeltepunkt 158-159°C.7 hydroxy-6α-methyl-1,4-pregnadiene-3,20-dione, mp 158-159 ° C.
D) En suspension af 3,0 g 9a-brom-17a-butyry 1 oxy-11/3,21-di hy- 5 droxy-6a-methyl-l,4-pregnadien-3,20-dion i 60 ml hexamethyl- phosphorsyretriamid omrøres med 3,0 g 1ithiumchlorid i en time ved en badtemperatur på 80°C. Efter isvandfældning filtreres resten fra, vaskes med vand og derpå renses råproduktet på 105 g kieselgel med en methy1ench1 orid-acetone-gradient (0-20% 10 acetone). Der isoleres 938 mg 17a-butyryloxy-110,21-dihydroxy- 6a-methyl-1,4,8-pregnatrien-^3,20-dion som et skum. [a]25 =D) A suspension of 3.0 g of 9a-bromo-17a-butyry 1 oxy-11 / 3,21-dihydroxy-6a-methyl-1,4-pregnadiene-3,20-dione in 60 ml of hexamethyl - Phosphoric acid triamide is stirred with 3.0 g of lithium chloride for one hour at a bath temperature of 80 ° C. After ice-water precipitation, the residue is filtered off, washed with water and then the crude product is purified on 105 g of silica gel with a methylene chloride-acetone gradient (0-20% 10 acetone). 938 mg of 17α-butyryloxy-110,21-dihydroxy-6α-methyl-1,4,8-pregnatriene-3,20-dione is isolated as a foam. [a] 25 =
DD
-53,8° (chloroform).-53.8 ° (chloroform).
15 Eksempel 2 A) Analogt som beskrevet i eksempel IB) omsættes 17,4 g 9a-brom-11/3,17a,21-tri hydroxy-6a-methy1-1,4-pregnadien-3,20-dion med 42 ml orthobenzoesyretriethylester, og der oparbejdes. Der 20 i soleres 9a-brom-l7a, 21- {1-ethoxybenzyl idendioxy)-ll/3-hydroxy-6a-methyl-l,4-pregnadien-3,20-dion som en olie.Example 2 A) Analogously as described in Example 1B), 17.4 g of 9α-bromo-11 / 3,17a, 21-tri hydroxy-6α-methyl-1,4-pregnadiene-3,20-dione are reacted with 42 ml orthobenzoic acid triethyl ester and reprocessing. There is solubilized in 9a-bromo-17a, 21- (1-ethoxybenzylidendioxy) -1,3-hydroxy-6a-methyl-1,4-pregnadiene-3,20-dione as an oil.
B) Den rå 9a-brom-17a, 21-(1-ethoxybenzyl idendioxy)-11/3-hydro-xy-6a-methyl-l,4-pregnadien-3,20-dion hydrolyseres under de i 25 eksempel 1C) beskrevne betingelser og oparbejdes. Råproduktet renses på 1 kg kieselgel med en hexan-acetone-gradient (0-50% acetone). Udbytte: 12,47 g 17a-benzoyloxy-9a-brom-ll/3,21-dihy-droxy-6a-methyl-l,4-pregnadien-3,20-dion. Smeltepunkt l59eC.B) The crude 9α-bromo-17α, 21- (1-ethoxybenzylidenedioxy) -11 / 3-hydroxy-6α-methyl-1,4-pregnadiene-3,20-dione is hydrolyzed under the conditions of Example 1C) described conditions and worked up. The crude product is purified on 1 kg of silica gel with a hexane-acetone gradient (0-50% acetone). Yield: 12.47 g of 17α-benzoyloxy-9α-bromo-11 / 3,21-dihydroxy-6α-methyl-1,4-pregnadiene-3,20-dione. Melting point 155 ° C.
30 c) En opløsning af 2,0 g 17a-benzoyloxy-9a-brom-ll/3,21-dihy- doxy-6a-methyl-1,4-pregnadien-3,20-dion omsættes med 2,0 g li-thiumchlorid analogt som beskrevet i eksempel ID) og oparbejdes. Råproduktet renses på 105 g kieselgel med en methylen-chlorid-acetone-gradient (0-20% acetone). Udbytte: 1,2 g 17a-35 benzoyl oxy-11/3,21-di hydroxy-6a-methy 1-1,4,8-pregnatr i en-3,20- dion. Smeltepunkt 206-208°c.C) A solution of 2.0 g of 17α-benzoyloxy-9α-bromo-11 / 3,21-dihydroxy-6α-methyl-1,4-pregnadiene-3,20-dione is reacted with 2.0 g of -thium chloride analogously as described in Example ID) and reprocessed. The crude product is purified on 105 g of silica gel with a methylene chloride-acetone gradient (0-20% acetone). Yield: 1.2 g of 17α-35-benzoyl oxy-11 / 3,21-di hydroxy-6α-methyl-1,1,4,8-pregnatene in one-3,20-dione. Melting point 206-208 ° C.
88
DK 159118BDK 159118B
Eksempel 3 A) 3,0 g l7a-benzoyloxy-9a-brom-llø,21-dihydroxy-6a-methyl- 1.4- pregnadien-3,20-dion omrøres i 30 ml pyridin med 15 ml 5 acetanhydrid i 3 timer ved stuetemperatur. Efter oparbejdning på sædvanlig måde fås 3,2 g 21-acetoxy-17a-benzoyloxy-9a-brom-ll/3-hydroxy-6a-methyl-l, 4-pregnadien-3,20-dion. Smeltepunkt 172-173°C.Example 3 A) 3.0 g of 17α-benzoyloxy-9α-bromo-11, 21-dihydroxy-6α-methyl-1,4-pregnadiene-3,20-dione are stirred in 30 ml of pyridine with 15 ml of acetanic anhydride for 3 hours at room temperature. . After working up in the usual manner, 3.2 g of 21-acetoxy-17α-benzoyloxy-9α-bromo-11β-hydroxy-6α-methyl-1,4-pregnadiene-3,20-dione are obtained. Melting point 172-173 ° C.
10 B) 3,3 g 21-acetoxy-17a-benzoyloxy-9a-brom-ll/3-hydroxy-6a-me- thyl-1,4-pregnadien-3,20-dion omsættes analogt som beskrevet i eksempel ID) med 3,3 g 1ithiumchlorid og oparbejdes. Råproduktet renses på 200 g kieselgel med en methylenchlorid-acetone-gradient (0-15% acetone). Udbytte: 1,78 g 21-acetoxy-17a-ben-15 zoyloxy-110-hydroxy-6a-methy1-1,4,8-pregnatrien-3,20-dion.B) 3.3 g of 21-acetoxy-17α-benzoyloxy-9α-bromo-11β-hydroxy-6α-methyl-1,4-pregnadiene-3,20-dione are reacted analogously as described in Example ID). with 3.3 g of lithium chloride and worked up. The crude product is purified on 200 g of silica gel with a methylene chloride-acetone gradient (0-15% acetone). Yield: 1.78 g of 21-acetoxy-17α-benzoyloxy-110-hydroxy-6α-methyl-1,4,4-pregnatrien-3,20-dione.
Smeltepunkt 229-230°C.Melting point 229-230 ° C.
Eksempel 4 s 20 A) Analogt som beskrevet i eksempel 3A) omsættes 3,0 g 17a- benzoyloxy-9a-brom-ll/3,21-di hydroxy-6a-methyl -1,4-preg nat ri en- 3,20-dion med propionsyreanhydrid og oparbejdes. Der fås 3,1 g 17a-benzoyToxy-9a-brom-ll/J-hydroxy-6a-methyl-21-propionyloxy- 1.4- pregnadien-3,20-dion. Smeltepunkt 155-156°C.Example 4 s 20 A) Analogously as described in Example 3A), 3.0 g of 17α-benzoyloxy-9α-bromo-11 / 3,21-di hydroxy-6α-methyl-1,4-pre-natri-3 is reacted 20-dione with propionic anhydride and reprocessed. 3.1 g of 17α-benzoyltoxy-9α-bromo-11β-hydroxy-6α-methyl-21-propionyloxy-1,4-pregnadiene-3,20-dione are obtained. Melting point 155-156 ° C.
25 B) 3,2 g 17a-benzoyloxy-9a-brom-llø-hydroxy-6a-methyl-21-pro-pionyloxy-l,4-pregnadien-3,20-dion omsættes under de i eksempel ID) beskrevne betingelser med 1ithiumchlorid, oparbejdes og renses. Der isoleres 1,96 g 17a-benzoyloxy-llj5-hydroxy-6a- 30 methyl-21-propionyloxy-l,4,8-pregnatrien-3,20-dion. Smelte punkt 225-226°C.B) 3.2 g of 17α-benzoyloxy-9α-bromo-11α-hydroxy-6α-methyl-21-propionyloxy-1,4-pregnadiene-3,20-dione are reacted under the conditions described in Example 1D with 1ithium chloride, worked up and purified. 1.96 g of 17α-benzoyloxy-11β-hydroxy-6α-methyl-21-propionyloxy-1,4,8-pregnatrien-3,20-dione is isolated. Melting point 225-226 ° C.
3535
Claims (5)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19823248435 DE3248435A1 (en) | 1982-12-23 | 1982-12-23 | NEW 6 (ALPHA) METHYLPREDNISOLONE DERIVATIVES THEIR PRODUCTION AND USE |
| DE3248435 | 1982-12-23 |
Publications (4)
| Publication Number | Publication Date |
|---|---|
| DK597783D0 DK597783D0 (en) | 1983-12-23 |
| DK597783A DK597783A (en) | 1984-06-24 |
| DK159118B true DK159118B (en) | 1990-09-03 |
| DK159118C DK159118C (en) | 1991-02-11 |
Family
ID=6182025
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DK597783A DK159118C (en) | 1982-12-23 | 1983-12-23 | 6ALFA METHYLPREDNISOLON DERIVATIVES AND PHARMACEUTICAL PREPARATIONS CONTAINING THEM |
Country Status (21)
| Country | Link |
|---|---|
| EP (1) | EP0112467B1 (en) |
| JP (1) | JPS59130300A (en) |
| AT (1) | ATE28878T1 (en) |
| AU (1) | AU2220283A (en) |
| CA (1) | CA1250571A (en) |
| CS (1) | CS236900B2 (en) |
| DD (1) | DD210694A5 (en) |
| DE (2) | DE3248435A1 (en) |
| DK (1) | DK159118C (en) |
| ES (1) | ES528323A0 (en) |
| GB (1) | GB2132620B (en) |
| GR (1) | GR79453B (en) |
| HU (1) | HU187939B (en) |
| IE (1) | IE56400B1 (en) |
| IL (1) | IL70452A (en) |
| NO (1) | NO156410C (en) |
| PL (1) | PL141513B1 (en) |
| PT (1) | PT77880B (en) |
| RO (1) | RO88666A (en) |
| SU (1) | SU1299514A3 (en) |
| ZA (1) | ZA839573B (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE19644679C2 (en) * | 1996-10-28 | 1999-06-02 | Freudenberg Carl Fa | Mop cover |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB1026160A (en) * | 1964-04-29 | 1966-04-14 | American Cyanamid Co | Pregnatrienes |
| DE2645104C2 (en) * | 1976-10-04 | 1986-04-24 | Schering AG, 1000 Berlin und 4709 Bergkamen | 11β-Hydroxy-1,4,8-pregnatriene-3,20-dione derivatives and processes for their preparation |
-
1982
- 1982-12-23 DE DE19823248435 patent/DE3248435A1/en not_active Withdrawn
-
1983
- 1983-11-03 EP EP83110948A patent/EP0112467B1/en not_active Expired
- 1983-11-03 AT AT83110948T patent/ATE28878T1/en active
- 1983-11-03 DE DE8383110948T patent/DE3372970D1/en not_active Expired
- 1983-11-16 CA CA000441287A patent/CA1250571A/en not_active Expired
- 1983-12-08 AU AU22202/83A patent/AU2220283A/en not_active Abandoned
- 1983-12-14 IE IE2944/83A patent/IE56400B1/en not_active IP Right Cessation
- 1983-12-15 IL IL70452A patent/IL70452A/en not_active IP Right Cessation
- 1983-12-16 SU SU833673977A patent/SU1299514A3/en active
- 1983-12-19 GB GB08333741A patent/GB2132620B/en not_active Expired
- 1983-12-20 DD DD83258236A patent/DD210694A5/en unknown
- 1983-12-20 RO RO83112962A patent/RO88666A/en unknown
- 1983-12-21 PL PL1983245246A patent/PL141513B1/en unknown
- 1983-12-21 GR GR73318A patent/GR79453B/el unknown
- 1983-12-21 HU HU834382A patent/HU187939B/en not_active IP Right Cessation
- 1983-12-22 NO NO834759A patent/NO156410C/en unknown
- 1983-12-22 ES ES528323A patent/ES528323A0/en active Granted
- 1983-12-22 PT PT77880A patent/PT77880B/en unknown
- 1983-12-22 ZA ZA839573A patent/ZA839573B/en unknown
- 1983-12-23 JP JP58242345A patent/JPS59130300A/en active Granted
- 1983-12-23 DK DK597783A patent/DK159118C/en not_active IP Right Cessation
- 1983-12-23 CS CS839879A patent/CS236900B2/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| PL245246A1 (en) | 1984-10-22 |
| EP0112467B1 (en) | 1987-08-12 |
| PL141513B1 (en) | 1987-08-31 |
| JPS59130300A (en) | 1984-07-26 |
| CA1250571A (en) | 1989-02-28 |
| DE3372970D1 (en) | 1987-09-17 |
| RO88666A (en) | 1986-02-28 |
| JPH0415800B2 (en) | 1992-03-19 |
| ES8502128A1 (en) | 1985-01-01 |
| PT77880A (en) | 1984-01-01 |
| ZA839573B (en) | 1984-08-29 |
| PT77880B (en) | 1986-04-09 |
| NO156410C (en) | 1987-09-30 |
| GR79453B (en) | 1984-10-30 |
| IL70452A (en) | 1987-12-31 |
| CS236900B2 (en) | 1985-05-15 |
| HU187939B (en) | 1986-03-28 |
| IL70452A0 (en) | 1984-03-30 |
| NO156410B (en) | 1987-06-09 |
| AU2220283A (en) | 1984-06-28 |
| SU1299514A3 (en) | 1987-03-23 |
| GB2132620A (en) | 1984-07-11 |
| GB8333741D0 (en) | 1984-01-25 |
| ATE28878T1 (en) | 1987-08-15 |
| DK159118C (en) | 1991-02-11 |
| DK597783D0 (en) | 1983-12-23 |
| EP0112467A1 (en) | 1984-07-04 |
| IE832944L (en) | 1984-06-23 |
| DE3248435A1 (en) | 1984-06-28 |
| IE56400B1 (en) | 1991-07-17 |
| ES528323A0 (en) | 1985-01-01 |
| DK597783A (en) | 1984-06-24 |
| DD210694A5 (en) | 1984-06-20 |
| GB2132620B (en) | 1986-06-04 |
| NO834759L (en) | 1984-06-25 |
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| PBP | Patent lapsed |