CS244147B2 - Method of 6-alpha-methylprednisolone derivatives production - Google Patents
Method of 6-alpha-methylprednisolone derivatives production Download PDFInfo
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- CS244147B2 CS244147B2 CS849880A CS988084A CS244147B2 CS 244147 B2 CS244147 B2 CS 244147B2 CS 849880 A CS849880 A CS 849880A CS 988084 A CS988084 A CS 988084A CS 244147 B2 CS244147 B2 CS 244147B2
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- methylprednisolone
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- methylprednisolone derivatives
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- 238000000034 method Methods 0.000 title claims description 3
- VHRSUDSXCMQTMA-PJHHCJLFSA-N 6alpha-methylprednisolone Chemical class C([C@@]12C)=CC(=O)C=C1[C@@H](C)C[C@@H]1[C@@H]2[C@@H](O)C[C@]2(C)[C@@](O)(C(=O)CO)CC[C@H]21 VHRSUDSXCMQTMA-PJHHCJLFSA-N 0.000 title description 5
- 238000004519 manufacturing process Methods 0.000 title description 4
- 125000006239 protecting group Chemical group 0.000 claims abstract description 5
- -1 anhydride carboxylic acids Chemical class 0.000 claims abstract description 4
- LEVJVKGPFAQPOI-UHFFFAOYSA-N phenylmethanone Chemical compound O=[C]C1=CC=CC=C1 LEVJVKGPFAQPOI-UHFFFAOYSA-N 0.000 claims abstract description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 claims abstract description 3
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 claims description 6
- QAEDZJGFFMLHHQ-UHFFFAOYSA-N trifluoroacetic anhydride Chemical compound FC(F)(F)C(=O)OC(=O)C(F)(F)F QAEDZJGFFMLHHQ-UHFFFAOYSA-N 0.000 claims description 6
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 claims description 2
- 102100023877 E3 ubiquitin-protein ligase RBX1 Human genes 0.000 claims description 2
- 101001111722 Homo sapiens E3 ubiquitin-protein ligase RBX1 Proteins 0.000 claims description 2
- 101000574654 Homo sapiens GTP-binding protein Rit1 Proteins 0.000 claims description 2
- 150000001244 carboxylic acid anhydrides Chemical class 0.000 claims 1
- 125000004432 carbon atom Chemical group C* 0.000 abstract description 2
- PLBHSZGDDKCEHR-LFYFAGGJSA-N methylprednisolone acetate Chemical compound C([C@@]12C)=CC(=O)C=C1[C@@H](C)C[C@@H]1[C@@H]2[C@@H](O)C[C@]2(C)[C@@](O)(C(=O)COC(C)=O)CC[C@H]21 PLBHSZGDDKCEHR-LFYFAGGJSA-N 0.000 abstract description 2
- VHRSUDSXCMQTMA-UWKORSIYSA-N 6-methylprednisolone Chemical class C([C@@]12C)=CC(=O)C=C1C(C)C[C@@H]1[C@@H]2[C@@H](O)C[C@]2(C)[C@@](O)(C(=O)CO)CC[C@H]21 VHRSUDSXCMQTMA-UWKORSIYSA-N 0.000 abstract 1
- 230000037431 insertion Effects 0.000 abstract 1
- 238000003780 insertion Methods 0.000 abstract 1
- 239000004480 active ingredient Substances 0.000 description 4
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- MTHSVFCYNBDYFN-UHFFFAOYSA-N diethylene glycol Chemical compound OCCOCCO MTHSVFCYNBDYFN-UHFFFAOYSA-N 0.000 description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 206010009887 colitis Diseases 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 239000012043 crude product Substances 0.000 description 2
- 239000002552 dosage form Substances 0.000 description 2
- 239000006210 lotion Substances 0.000 description 2
- 230000000699 topical effect Effects 0.000 description 2
- 201000004624 Dermatitis Diseases 0.000 description 1
- 206010012442 Dermatitis contact Diseases 0.000 description 1
- 206010012455 Dermatitis exfoliative Diseases 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- QNQASIVIHNEIHB-RGYDLLTOSA-N [(6s,8s,9s,10r,11s,13s,14s,17r)-17-(2-acetyloxyacetyl)-17-hydroxy-6,10,13-trimethyl-3-oxo-7,8,9,11,12,14,15,16-octahydro-6h-cyclopenta[a]phenanthren-11-yl] 2,2,2-trifluoroacetate Chemical compound C([C@@]12C)=CC(=O)C=C1[C@@H](C)C[C@@H]1[C@@H]2[C@@H](OC(=O)C(F)(F)F)C[C@]2(C)[C@@](O)(C(=O)COC(C)=O)CC[C@H]21 QNQASIVIHNEIHB-RGYDLLTOSA-N 0.000 description 1
- FZDVVMLGENWGDM-DIMDDDPFSA-N [2-oxo-2-[(8S,9S,10R,13S,14S,16R,17S)-10,13,16-trimethyl-3-oxo-6,7,8,9,11,12,14,15,16,17-decahydrocyclopenta[a]phenanthren-17-yl]ethyl] 3-hydroxypentanoate Chemical compound OC(CC(=O)OCC([C@H]1[C@@H](C[C@H]2[C@@H]3CCC4=CC(C=C[C@]4(C)[C@H]3CC[C@]12C)=O)C)=O)CC FZDVVMLGENWGDM-DIMDDDPFSA-N 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 208000026935 allergic disease Diseases 0.000 description 1
- 208000028004 allergic respiratory disease Diseases 0.000 description 1
- 150000008064 anhydrides Chemical class 0.000 description 1
- 208000006673 asthma Diseases 0.000 description 1
- 208000010668 atopic eczema Diseases 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 208000010247 contact dermatitis Diseases 0.000 description 1
- 239000012050 conventional carrier Substances 0.000 description 1
- 239000003246 corticosteroid Substances 0.000 description 1
- 229960001334 corticosteroids Drugs 0.000 description 1
- 239000006071 cream Substances 0.000 description 1
- FDSGHYHRLSWSLQ-UHFFFAOYSA-N dichloromethane;propan-2-one Chemical compound ClCCl.CC(C)=O FDSGHYHRLSWSLQ-UHFFFAOYSA-N 0.000 description 1
- 239000008298 dragée Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000006266 etherification reaction Methods 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 208000030603 inherited susceptibility to asthma Diseases 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- WYVAMUWZEOHJOQ-UHFFFAOYSA-N propionic anhydride Chemical compound CCC(=O)OC(=O)CC WYVAMUWZEOHJOQ-UHFFFAOYSA-N 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 206010039083 rhinitis Diseases 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 208000017520 skin disease Diseases 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 238000010626 work up procedure Methods 0.000 description 1
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- Steroid Compounds (AREA)
Abstract
Farmakologiclcy účinné 6 alfa-methylprednisolonová deriváty obecného vzorce I CH2OCOCH3 kde R značí 1-oxoalkylový zbytek se 3 až 6 atomy uhlíku nebo benzoylový zbytek, se vyrábějí z odpovídajícího 6 alfa-methy.lprednisolon-21-acetátu eterlfikací nebo eaterifikaeí v poloze 11 pro vnesení chránící skupiny, načež se acyluje V poloze 17 chloridem nebo anhydridem karboxylové kyseliny obecných vzorců R0C1 nebo (R0)20,kde R znamená totéž jako v obecném vzorci I. načež se chránící skupina z polohy 11 odštěpí.Pharmacologically effective 6-methylprednisolone derivatives of formula (I) CH2OCOCH3 where R is 1-oxoalkyl having 3 to 6 carbon atoms or benzoyl radical, with are made from the corresponding 6 alpha-methylprednisolone-21-acetate eterlfication or eject at position 11 for insertion the protecting group, whereupon it is acylated At position 17 with chloride or anhydride carboxylic acids of the general formulas R 0C 1 or (R 0) 20, where R is the same as in formula (I), whereby it is protected the group from position 11 splits off.
Description
(54) Způsob výroby 6<x--methylprednisolonových derivátů(54) A method for producing 6? -Methylprednisolone derivatives
Farmakologiclcy účinné 6 alfa-methylprednisolonová deriváty obecného vzorce IPharmacologically active 6 alpha-methylprednisolone derivatives of the general formula I
CH2OCOCH3 CH 2 OCOCH 3
kdewhere
R značí 1-oxoalkylový zbytek se 3 až 6 atomy uhlíku nebo benzoylový zbytek, se vyrábějí z odpovídajícího 6 alfa-methy.lprednisolon-21-acetátu eterlfikací nebo eaterifikaeí v poloze 11 pro vnesení chránící skupiny, načež se acyluje V poloze 17 chloridem nebo anhydridem karboxylové kyseliny obecných vzorců R0C1 nebo (R0)20,kde R znamená totéž jako v obecném vzorci I. načež se chránící skupina z polohy 11 odštěpí.R represents a 1-oxoalkyl radical having 3 to 6 carbon atoms or a benzoyl radical, is prepared from the corresponding 6 alpha-methylprednisolone-21-acetate by etherification or eaterification at the 11-position to introduce a protecting group, then acylated at position 17 with chloride or anhydride carboxylic acids of the general formula ROCl or (R0) 20 , wherein R is the same as in the general formula I, whereupon the protecting group from position 11 is cleaved off.
2441 472441 47
Vynález se týká způsobu výroby nových 6alfa-methylprednisolonových derivátů obecného vzorce I ch2ococh3 The present invention relates to a process for the preparation of novel 6α-methylprednisolone derivatives of the general formula I ch 2 ococh 3
(I), ve kterém R značí I-oxaalkylový zbytek se 3 až 6 atomy uhlíku nebo benzoylový zbytek.(I) wherein R is a 3-C6 carbon-1-oxaalkyl or benzoyl radical.
Bylo zjištěno, že výše uvedené deriváty 6alfa-methylprednisolonu mají překvapivě často při topické aplikaci význačnž vyšší účinnost než dříve známé deriváty 6alfa-methylprednisolonu; tato účinnost je často dokonce jeStě význačně silnějěí než u difluorovaných tzv. ušlechtilých kortikoidů, jako na příklad u 6alfa,9alfa-difluor-1,bet6-hydroxy-16alfa-methyl-21-valeryloxy-1 ,4-pregnadien-3,20-dionu (= Nerisona).Surprisingly, it has been found that the abovementioned 6α-methylprednisolone derivatives have surprisingly often higher efficacy in topical application than the previously known 6α-methylprednisolone derivatives; this activity is often even significantly more potent than with difluorinated so-called noble corticoids, such as 6alpha, 9alpha-difluoro-1, beta-hydroxy-16alpha-methyl-21-valeryloxy-1,4-pregnadien-3,20- dione (= Nerison).
Při systémové aplikaci jsou tyto deriváty éalfa-methylprednisolonu překvapivě často méně účinné než odpovídající dříve známé deriváty 6alfa-methylprednisolonu.Surprisingly, when used systemically, these .alpha.-methylprednisolone derivatives are often less effective than the corresponding prior art .alpha.-methylprednisolone derivatives.
Nové deriváty 6alfa-methylprednlsolonu výše uvedeného obecného vzorce I jsou tudíž vhodné v kombinaci s nosiči obvyklými v galenlcké farmacii k lokální terapii kontaktní dermatitidy, ekzémů nejrůznějšíha druhu, nerodermatóz, erytrodermie, popálenin, prutitus vulvae et ani, rosacey, erythematodes cutanesus, psoriasis, lichen ruber planus et verrucosus a podobných kožních onemocnění.Accordingly, the novel 6α-methylprednlsolone derivatives of formula (I) above are useful in combination with carriers customary in galenical pharmacy for topical therapy of contact dermatitis, eczema of various kinds, nerodermatoses, erythroderma, burns, prutitus vulvae et ani, rosacey, erythorisis cuts ruber planus et verrucosus and similar skin diseases.
Výroba léčivých specialit se provádí obvyklým způsobem tak, že účinné látky se převádějí s vhodnými přísadami v požadovanou aplikační formu, jako jsou například roztoky lotiony, masti, krémy nebo náplasti. V takto formulovaných léčivech závisí koncentrace účinné látky ne aplikační formě. U lotionů a mstí se používá s výhodou koncentrace účinné látky od 0,001 až do 1 %.The manufacture of medicinal specialties is carried out in a conventional manner by converting the active ingredients with suitable additives into the desired dosage form, such as lotion solutions, ointments, creams or patches. In such formulations, the concentration of the active ingredient depends on the dosage form. In lotions and vices, a concentration of active compound of from 0.001 to 1% is preferably used.
Kromě toho jsou nové sloučeniny, případně i v kombinaci s obvyklými nosiči a pomocnými látkami rovněž vhodné k výrobě inhalačních prostředků, které mohou být používány k léčbě alergických onemocnění dýchacích cest, jako například bronchiálního astmatu nebo rinitidy.In addition, the novel compounds, optionally in combination with conventional carriers and excipients, are also suitable for the manufacture of inhalants which can be used to treat allergic respiratory diseases such as bronchial asthma or rhinitis.
Nové kortikoidy jsou déle vhodné rovněž ve formě tobolek, tablet nebo dražé, které obsahuji s výhodou 10 až 200 mg účinné látky a jsou aplikovány orálné ve fomrě suspenzí, které ob obsahují s výhodou 100 až 500 mg účinné látky v dávkové jednotce a jsou aplikovány rektálně. Jsou vhodné rovněž k léčbě alergických onemocnění střevního traktu, jako je colitis ulcerosa a colitis gramulomatosa.The novel corticosteroids are also suitable in the form of capsules, tablets or dragees, which preferably contain 10 to 200 mg of active ingredient and are administered orally in a suspension form, which preferably contain 100 to 500 mg of active ingredient per dosage unit and are administered rectally . They are also suitable for the treatment of allergic diseases of the intestinal tract such as colitis ulcerosa and colitis gramulomatosa.
Nové óalfa-methylpFednisolonové deriváty lze připravovat níže uvedeným způsobem, který lze provádět za podmínek, popsaných v západoněmeckých zveřejněných patentových přihláškách DOS č. 2 645 104, 2 645 105, 2 340 591 a 1 959 549, jakož 1 v US patentu č. 3 383 394.The novel alpha-methylpFednisolone derivatives can be prepared as described below, which can be carried out under the conditions described in West German Published Patent Applications 2,645,104, 2,645,105, 2,340,591 and 1,959,549, as well as 1 in US Patent No. 3 383 394.
Nové óalfa-methylprednisolonové deriváty obecného vzorce I (uvedeného výše) se podle vynálezu připravují tak, že 6alfa-methylprednisolon-2,-acetát vzorce IIIThe novel alpha-methylprednisolone derivatives of the general formula I (above) are prepared according to the invention in that 6alpha-methylprednisolone-2, acetate of the formula III
CH2OCOCH3 CH 2 OCOCH 3
(III), se v poloze 11 éterifikuje trimethylsily1sloučeninou nebo esteriflkuje anhydridem kyseliny trifluoroctové, poté se v poloze 17 acyluje chloridem nebo anhydridem karboxylové kyseliny, obecného vzorců ROC1 nebo (ROlgO, v nichž R má stejný význam jako ve výše uvedeném obecném vzorci I, v přítomnosti 4-dimethylaminopyridinu, a chránící skupina v poloze 11 se odštěpí(III) is etherified at the 11-position with a trimethylsilyl compound or esterified with trifluoroacetic anhydride, then at the 17-position acylated with a carboxylic acid chloride or anhydride of the formula ROC1 or (R17g) in which R has the same meaning as in formula I above; presence of 4-dimethylaminopyridine, and the protecting group at position 11 is cleaved off
Vynález je blíže objasněn následujícím příkladem provedeni:The invention is illustrated by the following example:
a) Roztok 5,0 g 21-acetoxy-11 beta,17-dihydroxy-6alfa-methyl-1,4-pregnadien-3,20-dionu ve 25 ml pyridinu se uvádí do reakce při teplotě -15 °C s přikapanými 3 ml anhydridu kyseliny trifluoroctové a míchá se po dobu 10 minut při teplotě -10 °C. Nalije se do roztoku chloridu sodného v ledové vodě a sraženina se odfiltruje. Zbytek se vyjme do methylenchloridu, promyje do neutrální reakce a po vysušení síranem sodným se koncentruje ve vakuu. Výtěžek 5,4 g 21-acetoxy-17-hydroxy-6alfa-methyl~!1beta-trifluoracetoxy-1,4-pregnadien-3,20-dionu.a) A solution of 5.0 g of 21-acetoxy-11 beta, 17-dihydroxy-6alpha-methyl-1,4-pregnadien-3,20-dione in 25 ml of pyridine is reacted at -15 ° C with the dropwise addition of 3 ml of trifluoroacetic anhydride and stirred for 10 minutes at -10 ° C. It is poured into a solution of sodium chloride in ice water and the precipitate is filtered off. The residue was taken up in methylene chloride, washed neutral and dried over sodium sulfate and concentrated in vacuo. Yield 5.4 g of 21-acetoxy-17-hydroxy-6alpha-methyl-11beta-trifluoroacetoxy-1,4-pregnadien-3,20-dione.
tj 4,0 g surového produktu získaného podle odstavce a) se míchají v 50 ml diethylenglykoldiraathyletheru a 6,0 ml anhydridu kyseliny propionové s 6,5 g 4-dimethylaminopyridinu po dopij ia hodin pří teplotě místnosti. ?o obvyklém zpracováni se izoluji 4,5 g 21-acetoxy-balra-me'.hyi - 17-propí onyluxy -11 beta-trlfluorac» ; xy- i ,4-pregnadlen-3,20-dionu.ie 4.0 g of the crude product obtained under (a) are stirred in 50 ml of diethylene glycol di-ether ethyl ether and 6.0 ml of propionic anhydride with 6.5 g of 4-dimethylaminopyridine for a few hours at room temperature. 4.5 g of 21-acetoxy-bal-methyl-17-propoxy-11-beta-trifluoroacetate are isolated from the usual work-up; xy-1,4-pregnadlene-3,20-dione.
r; 3,5 g <2!~acetoxy-6alfa-methyl~’7-propionyloxy-1 lbeta-trifluoraeetoxy-1 ,4-pregnadien-3,20-dionu se míchají v 80 ml methanolu a 4,2 g triethylaminu po dobu 4 hodin při teplotě místnosti. Surový produkt se čistí na 600 g křemeiiny gradientem methylenchlorid-aceton (0 až 15 % acetonu) a izolují se 2,3 g 21-acetoxy-11beta-hydroxy-6alfa-methyl-17-propionyloxy-1,4-pregnadien-3,20-dionu.r; 3.5 g of <2-acetoxy-6-alpha-methyl-7-propionyloxy-11beta-trifluoroethoxy-1,4-pregnadien-3,20-dione are stirred in 80 ml of methanol and 4.2 g of triethylamine for 4 hours. hours at room temperature. The crude product is purified to 600 g of silica with methylene chloride-acetone gradient (0-15% acetone) and 2.3 g of 21-acetoxy-11beta-hydroxy-6α-methyl-17-propionyloxy-1,4-pregnadien-3 are isolated, 20-dione.
PŘEDMĚT VYNÁLEZUSUBJECT OF THE INVENTION
Claims (1)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19813133081 DE3133081A1 (en) | 1981-08-18 | 1981-08-18 | NEW 6 (ALPHA) METHYLPREDNISOLONE DERIVATIVES, THEIR PRODUCTION AND USE |
| CS826061A CS244115B2 (en) | 1981-08-18 | 1982-08-18 | Method of 6 alpha-methyl-foresolonetz derivatives production |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CS244147B2 true CS244147B2 (en) | 1986-07-17 |
Family
ID=25746302
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CS849880A CS244147B2 (en) | 1981-08-18 | 1984-12-17 | Method of 6-alpha-methylprednisolone derivatives production |
Country Status (1)
| Country | Link |
|---|---|
| CS (1) | CS244147B2 (en) |
-
1984
- 1984-12-17 CS CS849880A patent/CS244147B2/en unknown
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