AU2010317895A1 - Process for preparing (11beta, 16alpha)-9-fluoro-11-hydroxy-16,17-[1-methyl-ethylidenebis(oxy)]-21-[1-oxo-[4-(nitrooxymethyl) benzoxy]]pregna-1,4-dien-3,20-dione - Google Patents

Process for preparing (11beta, 16alpha)-9-fluoro-11-hydroxy-16,17-[1-methyl-ethylidenebis(oxy)]-21-[1-oxo-[4-(nitrooxymethyl) benzoxy]]pregna-1,4-dien-3,20-dione Download PDF

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AU2010317895A1
AU2010317895A1 AU2010317895A AU2010317895A AU2010317895A1 AU 2010317895 A1 AU2010317895 A1 AU 2010317895A1 AU 2010317895 A AU2010317895 A AU 2010317895A AU 2010317895 A AU2010317895 A AU 2010317895A AU 2010317895 A1 AU2010317895 A1 AU 2010317895A1
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acid
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AU2010317895A
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Carlos Alvarez
Luis Anglada
Albert Palomer
Luis Sobral
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Ferrer Internacional SA
Nicox SA
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Ferrer Internacional SA
Nicox SA
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J71/00—Steroids in which the cyclopenta(a)hydrophenanthrene skeleton is condensed with a heterocyclic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J71/00—Steroids in which the cyclopenta(a)hydrophenanthrene skeleton is condensed with a heterocyclic ring
    • C07J71/0005—Oxygen-containing hetero ring
    • C07J71/0026—Oxygen-containing hetero ring cyclic ketals
    • C07J71/0031—Oxygen-containing hetero ring cyclic ketals at positions 16, 17
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/06—Antipsoriatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/08—Antiseborrheics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/08—Antiallergic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J41/00—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring
    • C07J41/0033—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005
    • C07J41/005—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005 the 17-beta position being substituted by an uninterrupted chain of only two carbon atoms, e.g. pregnane derivatives

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Animal Behavior & Ethology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Dermatology (AREA)
  • Pain & Pain Management (AREA)
  • Pulmonology (AREA)
  • Rheumatology (AREA)
  • Immunology (AREA)
  • Epidemiology (AREA)
  • Steroid Compounds (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)

Abstract

This invention relates to a new process for preparing (11 β, 16α)-9-fluoro-11 - hydroxy-16,17-[1 -methyl -ethyl idenebis(oxy)]-21 -[1 -oxo-[4- (nitrooxymethyl)benzoxy]]pregna-1,4-dien-3,20-dione, comprising the steps of (i) reaction of triamcinolone acetonide with 4-(nitrooxymethyl)benzoic, 4- dimethylaminopyridine and N-N'-diisopropylcarbodiimide, (ii) crystallisation, and (iii) controlled precipitation.

Description

WO 2011/058161 PCT/EP2010/067443 1 Process for preparing (111P, 16a)-9-fluoro-1 1 -hydroxy-1 6,17-[l -methyl ethylidenebis(oxy)] -21 -[1 -oxo-[4-(nitrooxymethyl)benzoxy]]pregna-1,4 dien-3,20-dione 5 Field of the invention This invention relates to a new process for the preparation of the compound (11 P, 16a)-9-fluoro-1 1 -hydroxy-1 6,17-[1 -methyl ethyl idenebis(oxy)]-21 -[1 -oxo-[4-(nitrooxymethyl)benzoxy]]pregna-1,4-dien 10 3,20-dione, used as a topic anti-inflammatory drug. Background art Compound (11p, 16a)-9-fluoro-1 1 -hydroxy-1 6,17-[1 -methyl 15 ethylidenebis(oxy)]-21 -[1 -oxo-[4-(nitrooxymethyl)benzoxy]]pregna-1,4-dien 3,20-dione with formula (I) is a corticosteroid previously described in application W02007025632 (Example 1). This compound is especially useful in the treatment of certain inflammatory diseases such as corticosteroid sensitive dermatosis, atopic dermatitis, contact dermatitis, psoriasis and 20 seborrhoeic dermatitis. 0 0 O CH3 HO CH30 0 2 N (I) Said compound is applied topically, preferably using creams, ointments, 25 lotions and gels and similar formulations.
WO 2011/058161 PCT/EP2010/067443 2 The compound of formula (I) is obtained in example 1 of application W02007025632 by the reaction of triamcinolone acetonide (II) with 4 (nitrooxymethyl)benzoic acid (III) in the presence of 1-ethyl-3-(3 dimethylaminopropyl)carbodiimide (IV) and 4-dimethylaminopyridine (V) 5 according to Diagram 1. COOH C 2
H
5 HO H 3 C N CH3 pO
CH
3
OH
3 N HO 00 (11) OFO 10 Diagram 1 The yield of this reaction is of 34.4%, which makes it industrially unviable. Also, the price of the diimide used (IV) is also a drawback for use in 15 industrial processes. It is therefore necessary to find a different process for the industrial production of compound (I) with a high yield and using cheaper starting products.
WO 2011/058161 PCT/EP2010/067443 3 The authors of the present invention have achieved a new industrial process to obtain (I) that produces the product with a much higher yield and also replaces diimide (IV) with N,N'-diisopropylcarbodiimide (VI), which is 5 cheaper. On the other hand, we have found that the resulting product is of very high purity. Moreover, the new process also comprises a final step of controlled precipitation, which provides the end product with a suitable particle size for the preparation of topical formulations. 10 Summary of the invention In a single aspect, the invention provides a new industrial process for preparing (11P, 1 6a)-9-fluoro- 11 -hydroxy-16,17-[1 -methyl-ethyl idenebis(oxy)] 21 -[1 -oxo-[4-(nitrooxymethyl)benzoxy]]pregna-1,4-dien-3,20-dione (I) with a 15 good yield, starting from cost effective products and providing an end product with suitable purity and particle size. Detailed description of the invention 20 The process for preparing 11P, 16a)-9-fluoro-11-hydroxy-16,17-[1 methyl-ethyl idenebis(oxy)]-21 -[1 -oxo-[4-(nitrooxymethyl)benzoxy]]pregna-1,4 dien-3,20-dione (I), which is the single aspect of the invention, comprises the following steps: 25 (i) reaction of triamcinolone acetonide (II) WO 2011/058161 PCT/EP2010/067443 4 HO O
CH
3 HO p
CH
3 HO 0. with 4-(nitrooxymethyl)benzoic acid (III), 4-dimethylaminopyridine (V) and N,N'-diisopropylcarbodiimide (VI) 5 COOH H 3 C CH CH 3
H
3 C CH3 N N N
NO
2 N CH
H
3 C
CH
3 (111) (V) ( I in an inert solvent, followed by the elimination by filtration or centrifuging of the solid formed, which consists mainly of N,N' 10 diisopropylurea, acidification of the liquid phase, neutralising and washout thereof with water, adding an inert anti-solvent to the organic phase and separating the compound (I) thus formed by filtration or centrifuging; 15 (ii) crystallisation of compound (I) formed in step (i) in a mixture of a solvent and an anti-solvent; and (iii) precipitation of the compound (I) crystallised in step (ii) in a mixture of a solvent and an anti-solvent. 20 WO 2011/058161 PCT/EP2010/067443 5 In a preferred embodiment, the solvent of step (i) is chosen from the group consisting of halogenated hydrocarbons such as dichloromethane, amides such as dimethylformamide and dimethylacetamide, cyclic ethers such as tetrahydrofurane, ketones such as acetone and methyl isobutyl ketone, 5 esters such as ethyl acetate and isopropyl acetate, nitriles such as acetonitrile, sulphoxides such as dimethyl sulphoxide and similar solvents and mixtures thereof. The solvent is preferably dichloromethane. In another preferred embodiment, the acidification is performed with an 10 acid chosen from the group consisting of mineral acids such as hydrochloric acid, sulphuric acid, phosphoric acid and hydrobromic acid, carboxylic acids such as acetic acid, trifluoroacetic acid and formic acid, sulphonic acids such as methane sulphonic acid, trifluoromethane sulphonic acid and p-toluene sulphonic acid and other similar acids and mixtures thereof. The acid is 15 preferably hydrochloric acid. In another preferred embodiment, the neutralisation is performed with a base chosen from the group consisting of alkaline bicarbonates such as sodium bicarbonate and potassium bicarbonate and alkaline carbonate such 20 as sodium carbonate and potassium carbonate. The base is preferably sodium bicarbonate. In another embodiment preferred, the anti-solvent of step (i) is chosen from the group consisting of Cr1C4 alkanols such as ethanol, methanol and 25 isopropanol, aromatic hydrocarbons such as toluene and xylenes, as well as water and other similar anti-solvents and mixtures thereof. The anti-solvent is preferably ethanol. In another preferred embodiment, the solvent of step (ii) is chosen from 30 the group consisting of halogenated hydrocarbons such as dichloromethane, amides such as dimethylformamide and dimethylacetamide, cyclic ethers such as tetrahydrofurane, ketones such as acetone and methyl isobutyl ketone, WO 2011/058161 PCT/EP2010/067443 6 esters such as ethyl acetate and isopropyl acetate, nitriles such as acetonitrile, sulphoxides such as dimethyl sulphoxide and similar solvents and mixtures thereof. The solvent is preferably dichloromethane. 5 In another preferred embodiment, the anti-solvent of step (ii) is chosen from the group consisting of C1-C4 alkanols such as ethanol, methanol and isopropanol, aromatic hydrocarbons such as toluene and xylenes, as well as water and other similar anti-solvents and mixtures thereof. The anti-solvent is preferably ethanol. 10 In another preferred embodiment, the solvent of step (iii) is chosen from the group consisting of esters such as ethyl acetate and isopropyl acetate, amides such as dimethylformamide and dimethylacetamide, cyclic ethers such as tetrahydrofurane, ketones such as acetone and methyl isobutyl ketone, 15 nitriles such as acetonitrile, halogenated hydrocarbons such as dichloromethane and sulphoxides such as dimethyl sulphoxide and similar solvents and mixtures thereof. The solvent is preferably ethyl acetate. In another preferred embodiment, the anti-solvent of step (iii) is chosen 20 from a group consisting of C6-C aliphatic hydrocarbons such as heptane, aliphatic ethers such as isopropyl ether and ethyl ether, the group consisting of C1-C4 alkanols such as ethanol, methanol and isopropanol, and similar anti solvents and mixtures thereof. The anti-solvent is preferably heptane. 25 Examples Example 1 Synthesis of (1113, 16a)-9-fluoro-1 1 -hydroxy-1 6,17-[1 -methyl 30 ethyl idenebis(oxv)1-21 -[1 -oxo-[4-(nitrooxymethyl)benzoxyllpreqna-1,4-dien 3,20-dione (I) WO 2011/058161 PCT/EP2010/067443 7 COOH H 3 C CH CH 3 HO H 3 OC NCH3
CH
3 N HO CH3 . NO 2 OCH N
H
3 C OH 3 -. (III) (VI) (V) F H O0 0/ 0 2 N i- H4 (I) 5 Diagram 2 (i) Reaction 12.92 Kg of triamcinolone acetonide (II), 6.50 Kg of 4-(nitrooxymethyl)benzoic 10 acid (III), 401 g of 4-dimethylaminopyridine (V) and 5.8 I of N,N' diisopropylcarbodiimide (VI) were added to 284 I of dichloromethane. The solution was placed at ambient temperature and maintained with stirring until the reaction was completed. 13 I of dichloromethane were added. 15 The solid formed (N,N'-diisopropylurea) was removed by filtration and the filter was washed with dichloromethane. The dichloromethane extracts were placed together and 203 I of 0.5 N HCI were added. 203 I of 0.5 N HCI were added to the organic phase, followed by WO 2011/058161 PCT/EP2010/067443 8 129 I of 0.25 N NaHCO 3 . It was washed with water until the pH of the aqueous phase was similar to that of the water added. 465 I of absolute ethanol were added to the organic phase and it was distilled 5 at atmospheric pressure to a final volume of between 465 I and 504 1, and it was left to reach room temperature. The suspension was filtered and the wet solid was washed with ethanol. 10 The wet solid was dried under vacuum, producing 15.59 Kg of compound (I). Yield = 85.5%. HPLC Purity = 98.41%. (ii) Crystallisation 15 15.56 Kg of the solid obtained in the previous step were added to 467 I of dichloromethane. This was heated to reflux and distilled at atmospheric pressure to a final volume of 47 1. It was left to reach ambient temperature and 560 I of ethanol were added. 20 The suspension was filtered and the wet solid was washed with ethanol. The wet solid was dried under vacuum. (iii) Precipitation 25 11.21 Kg of the solid obtained in the previous step were added to 516 1 of ethyl acetate. It was heated to reflux and stirred until solution. It was cooled to 40-500C. 538 I of heptane were added and it was taken to ambient temperature. The solution was filtered through a 0.2 pm filter. It was washed 30 with ethyl acetate and stirred at least for 3 hours at ambient temperature. The suspension was filtered and the wet solid was washed with heptane.
WO 2011/058161 PCT/EP2010/067443 9 The wet solid was dried under vacuum. Example 2 5 Particle size distribution for (I) The particle size distribution of the product obtained in the final step of Example 1 showed a Gaussian distribution characterised by values d(O.9) = 10 10.79 pm; d(0.5) = 5.26 pm; and d(0.1) = 2.34 pm.

Claims (17)

1. A process for preparing (11P, 16a)-9-fluoro-11-hydroxy-16,17-[1-methyl ethyl idenebis(oxy)]-21 -[1 -oxo-[4-(nitrooxymethyl)benzoxy]]pregna-1,4-dien 5 3,20-dione (I) 0 HO0 Ho 0
2 N (I) comprising the following steps: 10 (i) reaction of triamcinolone acetonide (II) HO O CH
3 HO "p0 CH 3 HO 15 with 4-(nitrooxymethyl)benzoic acid (III), 4-dimethylaminopyridine (V) and N,N'-diisopropylcarbodiimide (VI) WO 2011/058161 PCT/EP2010/067443 11 COOH H 3 CCH ICH 3 H 3 C CH3 N N N /NO2 N OCH ( NH 3 C C H 3 (111) ( vi) in an inert solvent, elimination by filtration or centrifuging of the solid formed, acidification of the liquid phase, neutralising and washout 5 thereof with water, adding an inert anti-solvent to the organic phase and separating the compound (I) thus formed by filtration or centrifuging; (ii) crystallisation of compound (I) formed in step (i) in a mixture of a 10 solvent and an anti-solvent; and (iii) precipitation of the compound (I) crystallised in step (ii) in a mixture of a solvent and an anti-solvent. 15 2. The process according to claim 1, wherein the solvent of step (i) is chosen from the group consisting of dichloromethane, dimethylformamide, tetrahydrofurane, acetone, acetonitrile, ethyl acetate, isopropyl acetate, methyl isobutyl ketone, dimethylacetamide and dimethyl sulphoxide. 20 3. The process according to claim 2, wherein the solvent is dichloromethane.
4. The process according to claim 1, wherein the acidification is performed with an acid chosen from the group consisting of hydrochloric acid, sulphuric acid, acetic acid, trifluoroacetic acid, hydrobromic acid, formic 25 acid, methane sulphonic acid, trifluoromethane sulphonic acid and p toluene sulphonic acid. WO 2011/058161 PCT/EP2010/067443 12
5. The process according to claim 4, wherein the acid is hidrochloric acid.
6. The process according to claim 1, wherein the neutralising is performed with a base chosen from the group consisting of sodium bicarbonate, 5 potassium bicarbonate, sodium carbonate and potassium carbonate.
7. The process according to claim 6, wherein the base is sodium bicarbonate.
8. The process according to claim 1, wherein the anti-solvent of step (i) is 10 chosen from the group consisting of ethanol, methanol, isopropanol, toluene and water.
9. The process according to claim 8, wherein the anti-solvent is ethanol. 15
10.The process according to claim 1, wherein the solvent of step (ii) is chosen from the group consisting of dichloromethane, dimethylformamide, tetrahydrofurane, acetone, acetonitrile, ethyl acetate, isopropyl acetate, methyl isobutyl ketone, dimethylacetamide and dimethyl sulphoxide. 20
11.The process according to claim 10, wherein the solvent is dichloromethane.
12.The process according to claim 1, wherein the anti-solvent of step (ii) is chosen from the group consisting of ethanol, methanol, isopropanol, toluene and water. 25
13.The process according to claim 12, wherein the anti-solvent is ethanol.
14.The process according to claim 1, wherein the solvent of step (iii) is chosen from the group consisting of ethyl acetate, dimethylformamide, 30 tetrahydrofurane, acetone, acetonitrile, dichloromethane, isopropyl acetate, methyl isobutyl ketone, dimethylacetamide and dimethyl sulphoxide. WO 2011/058161 PCT/EP2010/067443 13
15. The process according to claim 14, wherein the solvent is ethyl acetate.
16.The process according to claim 1, wherein the anti-solvent of step (iii) is chosen from the group consisting of heptane, isopropyl ether and 5 isopropanol.
17. The process according to claim 16, wherein the anti-solvent is heptane.
AU2010317895A 2009-11-16 2010-11-15 Process for preparing (11beta, 16alpha)-9-fluoro-11-hydroxy-16,17-[1-methyl-ethylidenebis(oxy)]-21-[1-oxo-[4-(nitrooxymethyl) benzoxy]]pregna-1,4-dien-3,20-dione Abandoned AU2010317895A1 (en)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
ES200930999A ES2359708B1 (en) 2009-11-16 2009-11-16 PREPARATION PROCEDURE OF THE (11BETA, 16ALFA) -9-FLUORO-11-HIDROXI-16,17- [1-METHYL-ETHYLENEBIS (OXI)] - 21- [1-OXO- [4- (NITROOXIMETILE) BENZOXI]] PREÑA-1,4-DIEN-3,20-DIONA.
ESP200930999 2009-11-16
PCT/EP2010/067443 WO2011058161A2 (en) 2009-11-16 2010-11-15 Process for preparing (11beta, 16alpha)-9-fluoro-11-hydroxy-16,17-[1-methyl-ethylidenebis(oxy)]-21-[1-oxo-[4-(nitrooxymethyl)benzoxy]]pregna-1,4-dien-3,20-dione

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AU2010317895A Abandoned AU2010317895A1 (en) 2009-11-16 2010-11-15 Process for preparing (11beta, 16alpha)-9-fluoro-11-hydroxy-16,17-[1-methyl-ethylidenebis(oxy)]-21-[1-oxo-[4-(nitrooxymethyl) benzoxy]]pregna-1,4-dien-3,20-dione

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EP (1) EP2501710A2 (en)
JP (1) JP2013510826A (en)
KR (1) KR20120084788A (en)
CN (1) CN102612522A (en)
AR (1) AR078909A1 (en)
AU (1) AU2010317895A1 (en)
BR (1) BR112012011552A2 (en)
CA (1) CA2780139A1 (en)
ES (1) ES2359708B1 (en)
MX (1) MX2012005616A (en)
PE (1) PE20121315A1 (en)
RU (1) RU2012124815A (en)
TW (1) TW201130861A (en)
UY (1) UY33032A (en)
WO (1) WO2011058161A2 (en)

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CN106632562B (en) * 2015-10-30 2020-02-18 天津法莫西医药科技有限公司 Fluorometholone refining process

Family Cites Families (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE1238912B (en) * 1964-01-31 1967-04-20 Thomae Gmbh Dr K Process for the preparation of new esters of triamcinolone-16alpha, 17alpha-acetonide
US4323512A (en) * 1981-05-13 1982-04-06 Schering Corporation Process for the preparation of steroidal 17α-arylcarboxylates
GB9919693D0 (en) * 1999-08-19 1999-10-20 Rhone Poulenc Rorer Ltd Process
US6696592B2 (en) * 2001-05-22 2004-02-24 Nicox-S.A. Methods of making 21-[4′-(nitrooxyalkyl)benzoate] corticosteroid derivatives and intermediates useful in the synthesis thereof
EP1336602A1 (en) * 2002-02-13 2003-08-20 Giovanni Scaramuzzino Nitrate prodrugs able to release nitric oxide in a controlled and selective way and their use for prevention and treatment of inflammatory, ischemic and proliferative diseases
AU2006286838C1 (en) * 2005-09-02 2013-05-02 Ferrer Internacional S.A. Nitrooxy derivatives of glucocorticoids
EP1964550A1 (en) * 2007-03-01 2008-09-03 NicOx S.A. Glucocorticoid-nitrooxyderivative compositions
ES2324007A1 (en) * 2007-10-25 2009-07-28 Ferrer Internacional, S.A. Amorphous form of (11beta,16alpha)-9-fluoro-11-hydroxy-16,17-[(1-methylethyliden)bis(oxy)]-21-[[4- [(nitrooxy)methyl]benzoyl]oxy]-pregna-1,4-dien-3,20-dione

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MX2012005616A (en) 2012-10-15
CA2780139A1 (en) 2011-05-19
BR112012011552A2 (en) 2015-10-06
ES2359708A1 (en) 2011-05-26
KR20120084788A (en) 2012-07-30
WO2011058161A3 (en) 2011-07-07
CN102612522A (en) 2012-07-25
PE20121315A1 (en) 2012-10-06
JP2013510826A (en) 2013-03-28
AR078909A1 (en) 2011-12-14
RU2012124815A (en) 2013-12-27
WO2011058161A2 (en) 2011-05-19
EP2501710A2 (en) 2012-09-26
UY33032A (en) 2011-05-31
TW201130861A (en) 2011-09-16
ES2359708B1 (en) 2012-03-30

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MK4 Application lapsed section 142(2)(d) - no continuation fee paid for the application