DE1159946B - Process for the preparation of therapeutically active steroid compounds - Google Patents
Process for the preparation of therapeutically active steroid compoundsInfo
- Publication number
- DE1159946B DE1159946B DEU8307A DEU0008307A DE1159946B DE 1159946 B DE1159946 B DE 1159946B DE U8307 A DEU8307 A DE U8307A DE U0008307 A DEU0008307 A DE U0008307A DE 1159946 B DE1159946 B DE 1159946B
- Authority
- DE
- Germany
- Prior art keywords
- preparation
- steroid compounds
- therapeutically active
- active steroid
- compounds
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- -1 steroid compounds Chemical class 0.000 title claims description 11
- 238000000034 method Methods 0.000 title claims description 5
- KRHYYFGTRYWZRS-UHFFFAOYSA-N Fluorane Chemical compound F KRHYYFGTRYWZRS-UHFFFAOYSA-N 0.000 claims description 6
- 229910000040 hydrogen fluoride Inorganic materials 0.000 claims description 6
- 229930195733 hydrocarbon Natural products 0.000 claims description 5
- 239000004215 Carbon black (E152) Substances 0.000 claims description 4
- 150000001875 compounds Chemical class 0.000 claims description 3
- 239000001257 hydrogen Substances 0.000 claims description 3
- 229910052739 hydrogen Inorganic materials 0.000 claims description 3
- 125000004423 acyloxy group Chemical group 0.000 claims description 2
- 239000003795 chemical substances by application Substances 0.000 claims description 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 2
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 15
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N methyl pentane Natural products CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- JYGXADMDTFJGBT-VWUMJDOOSA-N hydrocortisone Chemical compound O=C1CC[C@]2(C)[C@H]3[C@@H](O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 JYGXADMDTFJGBT-VWUMJDOOSA-N 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- FUFLCEKSBBHCMO-UHFFFAOYSA-N 11-dehydrocorticosterone Natural products O=C1CCC2(C)C3C(=O)CC(C)(C(CC4)C(=O)CO)C4C3CCC2=C1 FUFLCEKSBBHCMO-UHFFFAOYSA-N 0.000 description 1
- 206010007559 Cardiac failure congestive Diseases 0.000 description 1
- MFYSYFVPBJMHGN-ZPOLXVRWSA-N Cortisone Chemical compound O=C1CC[C@]2(C)[C@H]3C(=O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 MFYSYFVPBJMHGN-ZPOLXVRWSA-N 0.000 description 1
- MFYSYFVPBJMHGN-UHFFFAOYSA-N Cortisone Natural products O=C1CCC2(C)C3C(=O)CC(C)(C(CC4)(O)C(=O)CO)C4C3CCC2=C1 MFYSYFVPBJMHGN-UHFFFAOYSA-N 0.000 description 1
- 206010019280 Heart failures Diseases 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 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
- 239000003470 adrenal cortex hormone Substances 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 229940088710 antibiotic agent Drugs 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 208000019425 cirrhosis of liver Diseases 0.000 description 1
- 230000000295 complement effect Effects 0.000 description 1
- 229960004544 cortisone Drugs 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 208000002296 eclampsia Diseases 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 125000001153 fluoro group Chemical group F* 0.000 description 1
- 229960000890 hydrocortisone Drugs 0.000 description 1
- 230000002757 inflammatory effect Effects 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- HCWCAKKEBCNQJP-UHFFFAOYSA-N magnesium orthosilicate Chemical compound [Mg+2].[Mg+2].[O-][Si]([O-])([O-])[O-] HCWCAKKEBCNQJP-UHFFFAOYSA-N 0.000 description 1
- 239000000391 magnesium silicate Substances 0.000 description 1
- 229910052919 magnesium silicate Inorganic materials 0.000 description 1
- 235000019792 magnesium silicate Nutrition 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 235000010755 mineral Nutrition 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 201000011461 pre-eclampsia Diseases 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 229940124530 sulfonamide Drugs 0.000 description 1
- 150000003456 sulfonamides Chemical class 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 208000011580 syndromic disease Diseases 0.000 description 1
- FKHIFSZMMVMEQY-UHFFFAOYSA-N talc Chemical compound [Mg+2].[O-][Si]([O-])=O FKHIFSZMMVMEQY-UHFFFAOYSA-N 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
Classifications
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J75/00—Processes for the preparation of steroids in general
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Steroid Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
DEUTSCHESGERMAN
PATENTAMTPATENT OFFICE
U 8307 IVb/12 »U 8307 IVb / 12 »
ANMELDETAG: 8. SEPTEMBER 1959REGISTRATION DATE: SEPTEMBER 8, 1959
BEKANNTMACHUNG
DER ANMELDUNG
UND AUSGABE DER
AUSLEGESCHRIFT: 27. DEZEMBER 1963 NOTICE
THE REGISTRATION
AND ISSUE OF THE
EDITORIAL: DECEMBER 27, 1963
Gegenstand der Erfindung ist ein Verfahren zur Herstellung von therapeutisch wirksamen Steroidverbindungen der allgemeinen FormelThe invention relates to a process for the production of therapeutically active steroid compounds the general formula
Verfahren zur HerstellungMethod of manufacture
von therapeutisch wirksamenof therapeutically effective
SteroidverbindungenSteroid compounds
in der R Wasserstoff oder der Acylrest einer niederen Kohlenwasserstoffcarbonsäure ist.in which R is hydrogen or the acyl radical of a lower hydrocarbon carboxylic acid.
Diese Verbindungen werden erfindungsgemäß da- 2a durch erhalten, daß man eine Ve; bindung der allgemeinen FormelAccording to the invention, these compounds are da- 2a by getting that one a Ve; binding the general formula
CH2-O-AcCH 2 -O-Ac
r- OHr- OH
CH3 CH 3
in der Ac der Acylrest einer niederen Kohlenwasserstoffcarbonsäure ist, in an sich bekannter Weise mit Fluorwasserstoff oder einem Fluorwasserstoff abgebenden Mittel behandelt und gegebenenfalls anschließend die 21 ständige Acyloxygruppe hydrolysiert. in Ac the acyl radical of a lower hydrocarbon carboxylic acid is, in a manner known per se, donating with hydrogen fluoride or a hydrogen fluoride Treated agent and then optionally hydrolyzed the 21 acyloxy group.
Die erfindungsgemäß herstellbaren 2-Fluorverbindungen besitzen ausgeprägte therapeutische Wirksamkeit und sind bezüglich ihrer Wirkung auf den Mineral- und Wasserstoffwechsel den natürlichen Nebennierenrindenhormonen, wie Hydrocortison und Cortison, sowie anderen bekannten Steroidverbindungen ohne Fluorsubstituenten in 2-Stellung überAnmelder: The 2-fluorine compounds which can be prepared according to the invention have pronounced therapeutic effectiveness and are with regard to their effect on the Mineral and hydrogen change the natural adrenal cortex hormones, such as hydrocortisone and Cortisone, as well as other known steroid compounds without fluorine substituents in the 2-position via applicant:
The Upjohn Company, Kalamazoo, Mich. (V. St. A.)The Upjohn Company, Kalamazoo, Mich. (V. St. A.)
Vertreter: Dr. W. Beil,
A. Hoeppener und Dr. H. J. Wolff,Representative: Dr. W. Beil,
A. Hoeppener and Dr. HJ Wolff,
Rechtsanwälte,
Frankfurt/M.-Höchst, Antoniterstr. 36Lawyers,
Frankfurt / M.-Höchst, Antoniterstr. 36
Beanspruchte Priorität:
V. St. v. Amerika vom 8. September \·ά8 (Nr. 759 432)Claimed priority:
V. St. v. America of September 8th \ ά8 (No. 759 432)
Alan Hart Nathan, John Alexander Hogg
und William Paul Schneider, Kalamazoo, Mich.Alan Hart Nathan, John Alexander Hogg
and William Paul Schneider, Kalamazoo, Mich.
(V. St. A.),
sind als Erfinder genannt worden(V. St. A.),
have been named as inventors
legen. Auf Grund ihrer guten entzündungswidrigen Wirkung und ihrer geringen Salz- und Wasserretention
sind sie besonders wertvoll bei der Behandlung von Entzündungserscheinungen, die in Verbindung
mit chronischer, kongestiver Herzschwäche, Lebercirrhose, Nierensyndromen, sowie Eklampsie
und Präeklampsie auftreten.
Die neuen 2-Fluorverbindungen gemäß der Erfindung können, gegebenenfalls unter Verwendung der
hierfür üblichen Träger und Verdünnungsmittel, oral, parenteral oder örtlich angewendet werden. Dabei
kann die Zumischung anderer, die Wirkung der Steroidverbindungen ergänzender oder verstärkender
Arzneimittel, z. B. von Antibiotika und Sulfonamiden, von Vorteil sein. Sie können ferner durch
Einführung eines 21-Fluorsubstituenten oder durch Umwandlung in Verbindungen, die in 21-Stellung
keinen Substituenten tragen, in weitere therapeutischplace. Due to their good anti-inflammatory effect and their low salt and water retention, they are particularly valuable in the treatment of inflammatory symptoms that occur in connection with chronic, congestive heart failure, liver cirrhosis, kidney syndromes, as well as eclampsia and preeclampsia.
The new 2-fluoro compounds according to the invention can be administered orally, parenterally or topically, if appropriate using the carriers and diluents customary for this purpose. The admixture of other drugs that complement or enhance the effect of the steroid compounds, e.g. B. antibiotics and sulfonamides, be beneficial. They can also be used therapeutically by introducing a 21-fluorine substituent or by converting them into compounds which do not have any substituents in the 21-position
-,0 wertvolle Substanzen übergeführt werden.-, 0 valuable substances are transferred.
Das folgende Beispiel erläutert das erfindungsgemäße Verfahren.The following example explains the method according to the invention.
' ' · 309 770/484'' · 309 770/484
a)a)
y&
4-pregnen-3,20-dion-21 -acetaty &
4-pregnen-3,20-dione-21 acetate
Einer Lösung von 230 mg 2-Fluor-6a-methyl-9^,11/3-oxido-17a,21 -dioxy^-pregnen-S^O-dion-21-acetat in 5 ml Methylenchlorid wurden 1,2 ml einer 48°/oigen Fluorwasserstofflösung zugesetzt. Das entstandene 2-Phasensystem wurde 20 Stunden gerührt, dann mit 15 ml Methylenchlorid verdünnt und vorsichtig in 40 ml Wasser, das 4 g Natriumbicarbonat enthielt, gegossen. Das Gemisch wurde geschüttelt, um den überschüssigen Fluorwasserstoff zu neutralisieren, das Methylenchlorid abgetrennt und die wäßrige Phase nochmals mit Methylenchlorid extrahiert. Die vereinigten Methylenchloridauszüge wurden über wasserfreiem Natriumsulfat getrocknet, mit 25 ml Äther verdünnt und über 20 g Magnesiumsilikat, bekannt unter dem Handelsnamen »Florisil«, chromatographiert. Die Säule wurde mit Hexankohlenwasserstoffen, bekannt unter dem Handelsnamen »Skellysolve B«, die steigende Mengen Aceton enthielten, eluiert. Man erhielt praktisch reines 2,9a-Difluor-6a-methyl-ll/J,17a-21-trioxy-4-pregnen-3,20-dion-21-acetat vom Schmelzpunkt 206 bis 2080C.A solution of 230 mg of 2-fluoro-6a-methyl-9 ^, 11/3-oxido-17a, 21 -dioxy ^ -pregnen-S ^ O-dione-21-acetate in 5 ml of methylene chloride was 1.2 ml of a 48% hydrogen fluoride solution added. The resulting 2-phase system was stirred for 20 hours, then diluted with 15 ml of methylene chloride and carefully poured into 40 ml of water containing 4 g of sodium bicarbonate. The mixture was shaken in order to neutralize the excess hydrogen fluoride, the methylene chloride was separated off and the aqueous phase was extracted again with methylene chloride. The combined methylene chloride extracts were dried over anhydrous sodium sulfate, diluted with 25 ml of ether and chromatographed over 20 g of magnesium silicate, known under the trade name "Florisil". The column was eluted with hexane hydrocarbons, known under the trade name "Skellysolve B", which contained increasing amounts of acetone. One practically give pure 2.9A-difluoro-6a-methyl-ll / J, 17a-21 trioxy-4-pregnene-3,20-dione 21-acetate of melting point 206 to 208 0 C.
Analyse für C24H32F2O6:
Berechnet ... C 63,42, H 7,10, F 8,36%;
gefunden ... C 64,19, H 7,60, F 8,48%.Analysis for C24H32F2O6:
Calculated ... C 63.42, H 7.10, F 8.36%;
Found ... C 64.19, H 7.60, F 8.48%.
b) 2,9a-Difluor-6a-methyl-l 10,l7a,21-trioxy-4-pregnen-3,20-dion b) 2,9a-Difluoro-6a-methyl-l 10,17a, 21-trioxy-4-pregnen-3,20-dione
100 mg 2,9a-Difluor-6a-methyl-ll/S,17a,21-trioxy-4 - pregnen - 3,20 - dion - 21 - acetat wurden in einer Mischung aus 2 ml Methanol und 0,1ml Wasser, die zuvor mit Stickstoff vom Luftsauerstoff befreit worden war, gelöst. Die Lösung wurde darauf mit 50 mg Kaliumcarbonat versetzt, 6 Stunden bei Zimmertemperatur unter Stickstoff stehengelassen, darauf mit 5%iger wäßriger Salzsäure neutralisiert, mit 5 ml Wasser verdünnt und gekühlt. Dann wurde abfiltriert und der feste Stoff aus Aceton-wSkellysolve B« umkristallisiert; F. = 213 bis 216°C.100 mg of 2,9a-difluoro-6a-methyl-II / S, 17a, 21-trioxy-4 - pregnen - 3.20 - dione - 21 - acetate were in a mixture of 2 ml of methanol and 0.1 ml of water, which had previously been freed from atmospheric oxygen with nitrogen, dissolved. The solution was based on it 50 mg potassium carbonate added, left to stand for 6 hours at room temperature under nitrogen, then neutralized with 5% aqueous hydrochloric acid, diluted with 5 ml of water and cooled. Then became filtered off and the solid substance from acetone-wSkellysolve B «recrystallized; M.p. = 213 to 216 ° C.
Claims (1)
-OHCO
-OH
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US894604XA | 1958-09-08 | 1958-09-08 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| DE1159946B true DE1159946B (en) | 1963-12-27 |
Family
ID=22217769
Family Applications (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DEU6441A Pending DE1115246B (en) | 1958-09-08 | 1959-08-21 | Process for the preparation of therapeutically active steroid compounds |
| DEU8307A Pending DE1159946B (en) | 1958-09-08 | 1959-09-08 | Process for the preparation of therapeutically active steroid compounds |
Family Applications Before (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DEU6441A Pending DE1115246B (en) | 1958-09-08 | 1959-08-21 | Process for the preparation of therapeutically active steroid compounds |
Country Status (3)
| Country | Link |
|---|---|
| DE (2) | DE1115246B (en) |
| FR (1) | FR1453202A (en) |
| GB (1) | GB894604A (en) |
-
1959
- 1959-08-21 DE DEU6441A patent/DE1115246B/en active Pending
- 1959-09-07 GB GB30469/59A patent/GB894604A/en not_active Expired
- 1959-09-07 FR FR804508A patent/FR1453202A/en not_active Expired
- 1959-09-08 DE DEU8307A patent/DE1159946B/en active Pending
Also Published As
| Publication number | Publication date |
|---|---|
| FR1453202A (en) | 1966-06-03 |
| GB894604A (en) | 1962-04-26 |
| DE1115246B (en) | 1961-10-19 |
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