ES2359708A1 - 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 PDFInfo
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- ES2359708A1 ES2359708A1 ES200930999A ES200930999A ES2359708A1 ES 2359708 A1 ES2359708 A1 ES 2359708A1 ES 200930999 A ES200930999 A ES 200930999A ES 200930999 A ES200930999 A ES 200930999A ES 2359708 A1 ES2359708 A1 ES 2359708A1
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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
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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
- 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
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- 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
Abstract
Description
Procedimiento de preparación de la (11\beta,16\alpha)-9-fluoro-11-hidroxi-16,17-[1-metil-etilidenebis(oxi)]-21-[1-oxo-[4-(nitrooximetil)benzoxi]]pregna-1,4-dien-3,20-diona.Procedure for preparing the (11β, 16α) -9-fluoro-11-hydroxy-16,17- [1-methyl-ethylidenebis (oxy)] - 21- [1-oxo- [4- (nitroxymethyl) benzoxy]] pregna -1,4-dien-3,20-diona.
La presente invención se refiere a un nuevo procedimiento de preparación del compuesto (11 \beta,16\alpha)-9-fluoro-11-hidroxi-16,17-[1-metil-etilidenebis(oxi)]-21-[1-oxo-[4-(nitrooximetil)benzoxi]]pregna-1,4-dien-3,20-diona, de utilidad como antiinflamatorio tópico.The present invention relates to a new compound preparation procedure (11 β, 16?) -9-fluoro-11-hydroxy-16.17- [1-methyl-ethylidenebis (oxy)] - 21- [1-oxo- [4- (nitrooxymethyl) benzoxy]] pregna-1 , 4-dien-3,20-diona, Useful as a topical anti-inflammatory.
El compuesto
(11\beta,16\alpha)-9-fluoro-11-hidroxi-16,17-[1-metil-etilidenebis(oxi)]-21-[1-oxo-[4-(nitrooximetil)benzoxi]]pregna-1,4-dien-3,20-diona,
de fórmula (I), es un corticosteroide descrito previamente en la
solicitud
WO2007025632 (Ejemplo 1). Es un compuesto
especialmente útil en el tratamiento de ciertas enfermedades
inflamatorias tales como la dermatosis sensible a los
corticosteroides, la dermatitis atópica, la dermatitis de contacto,
la psoriasis y la dermatitis seborreica.The compound (11β, 16α) -9-fluoro-11-hydroxy-16,17- [1-methyl-ethylidenebis (oxy)] - 21- [1-oxo- [4- (nitroxymethyl) benzoxy] ] pregna-1,4-dien-3,20-dione, of formula (I), is a corticosteroid previously described in the application
WO2007025632 (Example 1). It is an especially useful compound in the treatment of certain inflammatory diseases such as corticosteroid sensitive dermatosis, atopic dermatitis, contact dermatitis, psoriasis and seborrheic dermatitis.
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Dicho compuesto se aplica por vía tópica preferentemente mediante cremas, pomadas, lociones y geles, y formulaciones similares.Said compound is applied topically preferably by creams, ointments, lotions and gels, and Similar formulations
El compuesto de fórmula (I) se obtiene en el ejemplo 1 de la solicitud WO2007025632 por reacción de la triamcinolona acetónido (II) con ácido 4-(nitrooximetil)benzoico (III) en presencia de 1-etil-3-(3-dimetilaminopropil)carbodiimida (IV) y 4-dimetilaminopiridina (V), de acuerdo con el Esquema 1.The compound of formula (I) is obtained in the Example 1 of application WO2007025632 by reaction of the triamcinolone acetonide (II) with acid 4- (nitroxymethyl) benzoic (III) in the presence of 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide (IV) and 4-dimethylaminopyridine (V), according to Scheme 1.
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(Esquema pasa a página siguiente)(Scheme turns to page next)
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Esquema 1Scheme one
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El rendimiento de esta reacción es del 34.4%, lo que la hace inviable industrialmente. Además, el precio de la diimida utilizada (IV) es también un inconveniente para utilizarla en los procesos industriales.The yield of this reaction is 34.4%, which which makes it industrially unfeasible. In addition, the price of the used diimide (IV) is also an inconvenience to use it in industrial processes.
Así pues, es necesario disponer de otro procedimiento que proporcione industrialmente el compuesto (I) con un alto rendimiento y que utilice productos de partida más baratos.Thus, it is necessary to have another process that industrially provides the compound (I) with high performance and use more starting products cheap.
Los autores de la presente invención han logrado un nuevo procedimiento industrial para la obtención de (I), que conduce al producto con mucho mayor rendimiento y además reemplaza la diimida (IV) por la N,N'-diisopropilcarbodiimida (VI), más barata. Por otra parte, se ha encontrado que el producto resultante es de gran pureza. Además, el nuevo procedimiento comprende también una etapa final de precipitación controlada que proporciona el producto final con un tamaño de partícula adecuado para la preparación de formulaciones tópicas.The authors of the present invention have achieved a new industrial procedure for obtaining (I), which leads to the product with much higher performance and also replaces diimide (IV) by N, N'-diisopropylcarbodiimide (VI), cheaper. On the other hand, it has been found that the product resulting is of great purity. In addition, the new procedure it also includes a final stage of controlled precipitation that provides the final product with an appropriate particle size for the preparation of topical formulations.
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En un único aspecto, la invención proporciona un nuevo procedimiento industrial de preparación de la (11\beta,16\alpha)-9-fluoro-11-hidroxi-16,17-[1-metil-etilidenebis(oxi)]-21-[1-oxo-[4-(nitrooximetil)benzoxi]]pregna-1,4-dien-3,20-diona (I), con buen rendimiento, partiendo de productos económicamente asequibles y que proporciona un producto final con pureza y tamaño de partícula adecuados.In a single aspect, the invention provides a new industrial procedure for preparing the (11β, 16α) -9-fluoro-11-hydroxy-16,17- [1-methyl-ethylidenebis (oxy)] - 21- [1-oxo- [4- (nitroxymethyl) benzoxy]] pregna -1,4-dien-3,20-diona (I), with good performance, starting from products economically affordable and that provides a final product with purity and size of suitable particle.
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El procedimiento de preparación de la (11\beta,16\alpha)-9-fluoro-11-hidroxi-16,17-[1-metil-etilidenebis(oxi)]-21-[1-oxo-[4-(nitrooximetil)benzoxi]]pregna-1,4-dien-3,20-diona (I), que constituye el único aspecto de la invención, comprende las siguientes etapas:The procedure for preparing the (11β, 16α) -9-fluoro-11-hydroxy-16,17- [1-methyl-ethylidenebis (oxy)] - 21- [1-oxo- [4- (nitroxymethyl) benzoxy]] pregna -1,4-dien-3,20-diona (I), which constitutes the only aspect of the invention, comprises the following stages:
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- (i)(i)
- reacción de la triamcinolona acetónido (II)triamcinolone acetonide reaction (II)
- con ácido 4-(nitrooximetil)benzoico (III), 4-dimetilaminopiridina (V) y N,N'-diisopropilcarbodiimida (VI)with acid 4- (nitroxymethyl) benzoic (III), 4-dimethylaminopyridine (V) and N, N'-diisopropylcarbodiimide (VI)
- en un disolvente inerte, seguido de la eliminación por filtración o centrifugación del sólido formado, constituido mayoritariamente por N,N'-diisopropilurea, acidificación de la fase líquida, neutralización y lavado de la misma con agua, adición de un anti-disolvente inerte a la fase orgánica y separación por filtración o centrifugación del compuesto (I) así formado;in a solvent inert, followed by removal by filtration or centrifugation of the solid formed, consisting mostly of N, N'-diisopropylurea, phase acidification liquid, neutralization and washing thereof with water, adding a inert anti-solvent to the organic phase and separation by filtration or centrifugation of the compound (I) as well formed;
- (ii)(ii)
- cristalización del compuesto (I) formado en la etapa (i) en una mezcla de un disolvente y un anti-disolvente; ycrystallization of compound (I) formed in step (i) in a mixture of a solvent and a anti-solvent; Y
- (iii)(iii)
- precipitación del compuesto (I) cristalizado en la etapa (ii) en una mezcla de un disolvente y un anti-disolvente.precipitation of compound (I) crystallized in step (ii) in a mixture of a solvent and a anti-solvent
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En una realización preferida, el disolvente de la etapa (i) se selecciona del grupo consistente en hidrocarburos halogenados como el diclorometano, amidas como la dimetilformamida y la dimetilacetamida, éteres cíclicos como el tetrahidrofurano, cetonas como la acetona y la metil isobutil cetona, ésteres como el acetato de etilo y el acetato de isopropilo, nitrilos como el acetonitrilo, sulfóxidos como el dimetilsulfóxido, y disolventes similares, y sus mezclas. Preferentemente el disolvente es diclorometano.In a preferred embodiment, the solvent of step (i) is selected from the group consisting of hydrocarbons halogenates such as dichloromethane, amides such as dimethylformamide and dimethylacetamide, cyclic ethers such as tetrahydrofuran, ketones such as acetone and methyl isobutyl ketone, esters such as ethyl acetate and isopropyl acetate, nitriles such as acetonitrile, sulfoxides such as dimethyl sulfoxide, and solvents similar, and their mixtures. Preferably the solvent is dichloromethane
En otra realización preferida, la acidificación se efectúa con un ácido seleccionado del grupo consistente en ácidos minerales como el ácido clorhídrico, el ácido sulfúrico, el ácido fosfórico y el ácido bromhídrico, ácidos carboxílicos como el ácido acético, el ácido trifluoroacético y el ácido fórmico, ácidos sulfónicos como el ácido metansulfónico, el ácido trifluorometansulfónico y el ácido p-toluenesulfónico, y otros ácidos similares, y sus mezclas. Preferentemente el ácido es ácido clorhídrico.In another preferred embodiment, the acidification is carried out with an acid selected from the group consisting of mineral acids such as hydrochloric acid, sulfuric acid, phosphoric acid and hydrobromic acid, carboxylic acids such as acetic acid, trifluoroacetic acid and formic acid. , sulfonic acids such as methanesulfonic acid, trifluoromethanesulfonic acid and p- toluenesulfonic acid, and other similar acids, and mixtures thereof. Preferably the acid is hydrochloric acid.
En otra realización preferida, la neutralización se efectúa con una base seleccionada del grupo consistente en bicarbonatos alcalinos como el bicarbonato sódico y el bicarbonato potásico, y carbonatos alcalinos como el carbonato sódico y el carbonato potásico. Preferentemente la base es bicarbonato sódico.In another preferred embodiment, neutralization it is done with a base selected from the group consisting of alkaline bicarbonates such as sodium bicarbonate and bicarbonate potassium, and alkali carbonates such as sodium carbonate and potassium carbonate Preferably the base is bicarbonate sodium
En otra realización preferida, el
anti-disolvente de la etapa (i) se selecciona del
grupo consistente en alcanoles
C_{1}-C_{4} como etanol, metanol e isopropanol,
hidrocarburos aromáticos como el tolueno y los xilenos, así como
agua, y otros anti-disolventes similares, y sus
mezclas. Preferentemente el anti-disolvente es
etanol.In another preferred embodiment, the anti-solvent of step (i) is selected from the group consisting of alkanols.
C 1 -C 4 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. Preferably the anti-solvent is ethanol.
En otra realización preferida, el disolvente de la etapa (ii) se selecciona del grupo consistente en hidrocarburos halogenados como el diclorometano, amidas como la dimetilformamida y la dimetilacetamida, éteres cíclicos como el tetrahidrofurano, cetonas como la acetona y la metil isobutil cetona, ésteres como el acetato de etilo y el acetato de isopropilo, nitritos como el acetonitrilo, sulfóxidos como el dimetilsulfóxido, y disolventes similares, y sus mezclas. Preferentemente el disolvente es diclorometano.In another preferred embodiment, the solvent of step (ii) is selected from the group consisting of hydrocarbons halogenates such as dichloromethane, amides such as dimethylformamide and dimethylacetamide, cyclic ethers such as tetrahydrofuran, ketones such as acetone and methyl isobutyl ketone, esters such as ethyl acetate and isopropyl acetate, nitrites such as acetonitrile, sulfoxides such as dimethyl sulfoxide, and solvents similar, and their mixtures. Preferably the solvent is dichloromethane
En otra realización preferida, el anti-disolvente de la etapa (ii) se selecciona del grupo consistente en alcanoles C_{1}-C_{4} como etanol, metanol e isopropanol, hidrocarburos aromáticos como el tolueno y los xilenos, así como agua, y otros anti-disolventes similares, y sus mezclas. Preferentemente el anti-disolvente es etanol.In another preferred embodiment, the anti-solvent of step (ii) is selected from group consisting of C 1 -C 4 alkanols as ethanol, methanol and isopropanol, aromatic hydrocarbons such as toluene and xylenes, as well as water, and others similar anti-solvents, and mixtures thereof. Preferably the anti-solvent is ethanol.
En otra realización preferida, el disolvente de la etapa (iii) se selecciona del grupo consistente en ésteres como el acetato de etilo y el acetato de isopropilo, amidas como la dimetilformamida y la dimetilacetamida, éteres cíclicos como el tetrahidrofurano, cetonas como la acetona y la metil isobutil cetona, nitritos como el acetonitrilo, hidrocarburos halogenados como el diclorometano, y sulfóxidos como el dimetilsulfóxido, y disolventes similares, y sus mezclas. Preferentemente el disolvente es acetato de etilo.In another preferred embodiment, the solvent of step (iii) is selected from the group consisting of esters as ethyl acetate and isopropyl acetate, amides such as dimethylformamide and dimethylacetamide, cyclic ethers such as tetrahydrofuran, ketones such as acetone and methyl isobutyl ketone, nitrites such as acetonitrile, halogenated hydrocarbons such as dichloromethane, and sulfoxides such as dimethyl sulfoxide, and similar solvents, and mixtures thereof. Preferably the solvent It is ethyl acetate.
En otra realización preferida, el anti-disolvente de la etapa (iii) se selecciona del grupo consistente en hidrocarburos alifáticos C_{6}-C_{9} como el heptano, éteres alifáticos como el isopropil éter y el etil éter, el grupo consistente en alcanoles C_{1}-C_{4} como etanol, metanol e isopropanol, y anti-disolventes similares, y sus mezclas. Preferentemente el anti-disolvente es heptano.In another preferred embodiment, the anti-solvent of step (iii) is selected from group consisting of aliphatic hydrocarbons C 6 -C 9 such as heptane, aliphatic ethers such as isopropyl ether and ethyl ether, the group consisting of C 1 -C 4 alkanols such as ethanol, methanol and isopropanol, and similar anti-solvents, and their mixtures Preferably the anti-solvent is heptane
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Esquema 2Scheme 2
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Se añadieron a 284 L de diclorometano, 12.92 Kg
de triamcinolona acetónido (II), 6.50 Kg de ácido
4-(nitrooxi-
metil)benzoico (III), 401 g de
4-dimetilaminopiridina (V) y 5.8 L de
N,N'-diisopropilcarbodiimida (VI). Se llevó la
solución a temperatura ambiente y se mantuvo en agitación hasta
completar la reacción. Se añadieron 13 L de diclorometano.To 284 L of dichloromethane, 12.92 Kg of triamcinolone acetonide (II), 6.50 Kg of 4- (nitroxy) acid were added
methyl) benzoic acid (III), 401 g of 4-dimethylaminopyridine (V) and 5.8 L of N, N'-diisopropylcarbodiimide (VI). The solution was brought to room temperature and kept under stirring until the reaction was complete. 13 L of dichloromethane were added.
Se eliminó por filtración el sólido formado (N,N'-diisopropilurea) y se lavó el filtro con diclorometano.The solid formed was filtered off (N, N'-diisopropylurea) and the filter was washed with dichloromethane
Se reunieron los extractos de diclorometano y se añadieron 203 L de HCl 0.5 N. Se añadieron a la fase orgánica 203 L de HCl 0.5 N y después 129 L de NaHCO_{3} 0.25 N. Se lavó con agua hasta que el pH de la fase acuosa fue similar al del agua añadida.The dichloromethane extracts were collected and 203 L of 0.5 N HCl was added. 203 L was added to the organic phase. of 0.5 N HCl and then 129 L of 0.25 N NaHCO 3 was washed with water until the pH of the aqueous phase was similar to that of water added.
Se añadieron a la fase orgánica 465 L de etanol absoluto y se destiló a presión atmosférica hasta un volumen final entre 465 L y 504 L, y se dejó llegar a temperatura ambiente.465 L of ethanol were added to the organic phase absolute and distilled at atmospheric pressure to a final volume between 465 L and 504 L, and allowed to reach room temperature.
Se filtró la suspensión y se lavó el sólido húmedo con etanol.The suspension was filtered and the solid was washed wet with ethanol.
Se secó el sólido húmedo en vacío obteniéndose 15.59 Kg del compuesto (I).The wet solid was dried in vacuo to obtain 15.59 Kg of compound (I).
Rendimiento = 85.5%. Pureza HPLC = 98.41%.Yield = 85.5%. HPLC purity = 98.41%.
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Se añadieron 15.56 Kg del sólido obtenido en la etapa anterior a 467 L de diclorometano. Se calentó hasta reflujo y se destiló a presión atmosférica hasta un volumen final de 47 L. Se dejó llegar a temperatura ambiente y se añadieron 560 L de etanol.15.56 Kg of the solid obtained in the stage prior to 467 L of dichloromethane. It was heated to reflux and it was distilled at atmospheric pressure to a final volume of 47 L. allowed to reach room temperature and 560 L of ethanol.
Se filtró la suspensión y se lavó el sólido húmedo con etanol.The suspension was filtered and the solid was washed wet with ethanol.
Se secó el sólido húmedo en vacío.The wet solid was dried in vacuo.
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Se añadieron 11.21 Kg del sólido obtenido en la etapa anterior a 516 L de acetato de etilo. Se calentó hasta reflujo y se agitó hasta disolución. Se enfrió hasta 40-50ºC. Se añadieron 538 L de heptano y se llevó hasta temperatura ambiente. Se filtró la solución a través de un filtro de 0.2 \mum. Se lavó con acetato de etilo y se agitó al menos durante 3 horas a temperatura ambiente.11.21 Kg of the solid obtained in the step prior to 516 L of ethyl acetate. It was heated to reflux and stirred until dissolved. It cooled down 40-50 ° C. 538 L of heptane were added and carried up to room temperature The solution was filtered through a 0.2 µm filter. It was washed with ethyl acetate and stirred at less for 3 hours at room temperature.
Se filtró la suspensión y se lavó el sólido húmedo con heptano.The suspension was filtered and the solid was washed moist with heptane.
Se secó el sólido húmedo en vacío.The wet solid was dried in vacuo.
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La distribución del tamaño de partícula del producto obtenido en la etapa final del Ejemplo 1 presentó una distribución de Gauss caracterizada por los valores d(0.9) = 10.79 \mum; d(0.5) = 5.26 \mum; y d(0.1) = 2.34 \mum.The particle size distribution of product obtained in the final stage of Example 1 presented a Gaussian distribution characterized by the values d (0.9) = 10.79 µm; d (0.5) = 5.26 µm; and d (0.1) = 2.34 \ mum.
Claims (17)
- (i)(i)
- reacción de la triamcinolona acetónido (II)triamcinolone acetonide reaction (II)
- con ácido 4-(nitrooximetil)benzoico (III), 4-dimetilaminopiridina (V) y N,N'-diisopropilcarbodiimida (VI)with acid 4- (nitroxymethyl) benzoic (III), 4-dimethylaminopyridine (V) and N, N'-diisopropylcarbodiimide (VI)
- en un disolvente inerte, eliminación por filtración o centrifugación del sólido formado, acidificación de la fase líquida, neutralización y lavado de la misma con agua, adición de un anti-disolvente inerte a la fase orgánica y separación por filtración o centrifugación del compuesto (I) así formado;in a solvent inert, filtration removal or centrifugation of the solid formed, acidification of the liquid phase, neutralization and washing thereof with water, adding an anti-solvent inert to the organic phase and separation by filtration or centrifugation of the compound (I) thus formed;
- (ii)(ii)
- cristalización del compuesto (I) formado en la etapa (i) en una mezcla de un disolvente y un anti-disolvente; ycrystallization of compound (I) formed in step (i) in a mixture of a solvent and a anti-solvent; Y
- (iii)(iii)
- precipitación del compuesto (I) cristalizado en la etapa (ii) en una mezcla de un disolvente y un anti-disolvente.precipitation of compound (I) crystallized in step (ii) in a mixture of a solvent and a anti-solvent
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Priority Applications (15)
| 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. |
| TW099135537A TW201130861A (en) | 2009-11-16 | 2010-10-19 | Process for preparing (11β,16α)-9-fluoro-11-hydroxy-16,17-[1-methyl-ethylidenebis(oxy)]-21-[1-oxo-[4-(nitrooxymethyl)benzoxy]]pregna-1,4-dien-3,20-dione |
| ARP100104079A AR078909A1 (en) | 2009-11-16 | 2010-11-04 | PREPARATION PROCEDURE OF THE (11B, 16A) -9-FLUORO-11-HIDROXI-16.17- [1-METHYL-ETHYLIDENEBIS (OXI)] - 21- [1-OXO- (4- (NITROOXIMETHYL) BENZOXI]] PREGNA-1,4-DIEN-3,20-DIONA |
| BR112012011552A BR112012011552A2 (en) | 2009-11-16 | 2010-11-15 | process for preparing (11beta, 16alpha) -9-fluoro-11-hydroxy-16,17- [1-methyl-ethylidene-bis (oxy)] -21- [1-oxo- [4- (nitro-oxy-methyl ) benzoxyl] 17pregna-1,4-diene-3,20-dione |
| AU2010317895A 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 |
| KR1020127015331A KR20120084788A (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 |
| MX2012005616A MX2012005616A (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)benz oxy]]pregna-1,4-dien-3,20-dione. |
| JP2012538352A JP2013510826A (en) | 2009-11-16 | 2010-11-15 | (11β, 16α) -9-Fluoro-11-hydroxy-16,17- [1-methyl-ethylidenebis (oxy)]-21- [1-oxo- [4- (nitrooxymethyl) benzoxy]] pregna- Process for preparing 1,4-diene-3,20-dione |
| CN2010800517342A CN102612522A (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. |
| UY0001033032A UY33032A (en) | 2009-11-16 | 2010-11-15 | PREPARATION PROCEDURE FOR (11 B (BETA), 16 A (ALFA)) -9-FLUORO-11-HIDROXI-16,17- [1-METHYL-ETILDENEBIS (OXI)] - 21- [1-OXO- [ 4- (NITROOXIMETIL) BENZOXI]] PREGNA-1,4-DIEN-3,20-DIONA |
| EP10776364A EP2501710A2 (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 |
| PE2012000618A PE20121315A1 (en) | 2009-11-16 | 2010-11-15 | PROCEDURE FOR THE PREPARATION OF (11BETA, 16ALPHA) -9-FLUORO-11-HYDROXY-16,17- [1-METHYL-ETHYLIDENEBIS (OXI)] - 21- [1-OXO- [4- (NITROOXIMETIL) BENZOXI]] PREGNA-1,4-DIEN-3,20-DIONA |
| 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 |
| RU2012124815/04A RU2012124815A (en) | 2009-11-16 | 2010-11-15 | METHOD FOR PRODUCING (11β, 16α) -9-FLUOR-11 - HYDROXY-16, 17- [1-METHYL-ETHYLIDENBIS- (OXY)] - 21- [1-OXO- [4-NITROXYMETHYL) BENZOXY]] PREGNA-1 , 4-DIEN-3,20-DIONA |
| CA2780139A CA2780139A1 (en) | 2009-11-16 | 2010-11-15 | Process for preparing (11.beta., 16.alpha.)-9-fluoro-11-hydroxy-16,17-[1-methyl-ethylidenebis(oxy)]-21-[1-oxo-[4-(nitrooxymethyl)benzoxy]]pregna-1,4-dien-3,20-dione |
Applications Claiming Priority (1)
| 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. |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| ES2359708A1 true ES2359708A1 (en) | 2011-05-26 |
| ES2359708B1 ES2359708B1 (en) | 2012-03-30 |
Family
ID=43896867
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| ES200930999A Expired - Fee Related 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. |
Country Status (15)
| Country | Link |
|---|---|
| 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) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106632562B (en) * | 2015-10-30 | 2020-02-18 | 天津法莫西医药科技有限公司 | Fluorometholone refining process |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2007025632A2 (en) * | 2005-09-02 | 2007-03-08 | Nicox S.A. | Nitrooxy derivatives op glucocorticoids |
Family Cites Families (7)
| 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 |
| 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 |
-
2009
- 2009-11-16 ES ES200930999A patent/ES2359708B1/en not_active Expired - Fee Related
-
2010
- 2010-10-19 TW TW099135537A patent/TW201130861A/en unknown
- 2010-11-04 AR ARP100104079A patent/AR078909A1/en unknown
- 2010-11-15 WO PCT/EP2010/067443 patent/WO2011058161A2/en active Application Filing
- 2010-11-15 MX MX2012005616A patent/MX2012005616A/en not_active Application Discontinuation
- 2010-11-15 BR BR112012011552A patent/BR112012011552A2/en not_active IP Right Cessation
- 2010-11-15 UY UY0001033032A patent/UY33032A/en unknown
- 2010-11-15 CN CN2010800517342A patent/CN102612522A/en active Pending
- 2010-11-15 CA CA2780139A patent/CA2780139A1/en not_active Abandoned
- 2010-11-15 AU AU2010317895A patent/AU2010317895A1/en not_active Abandoned
- 2010-11-15 RU RU2012124815/04A patent/RU2012124815A/en unknown
- 2010-11-15 EP EP10776364A patent/EP2501710A2/en not_active Withdrawn
- 2010-11-15 JP JP2012538352A patent/JP2013510826A/en active Pending
- 2010-11-15 PE PE2012000618A patent/PE20121315A1/en not_active Application Discontinuation
- 2010-11-15 KR KR1020127015331A patent/KR20120084788A/en not_active Application Discontinuation
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2007025632A2 (en) * | 2005-09-02 | 2007-03-08 | Nicox S.A. | Nitrooxy derivatives op glucocorticoids |
Also Published As
| Publication number | Publication date |
|---|---|
| RU2012124815A (en) | 2013-12-27 |
| CA2780139A1 (en) | 2011-05-19 |
| UY33032A (en) | 2011-05-31 |
| WO2011058161A3 (en) | 2011-07-07 |
| KR20120084788A (en) | 2012-07-30 |
| AU2010317895A1 (en) | 2012-05-24 |
| TW201130861A (en) | 2011-09-16 |
| WO2011058161A2 (en) | 2011-05-19 |
| MX2012005616A (en) | 2012-10-15 |
| EP2501710A2 (en) | 2012-09-26 |
| CN102612522A (en) | 2012-07-25 |
| JP2013510826A (en) | 2013-03-28 |
| ES2359708B1 (en) | 2012-03-30 |
| BR112012011552A2 (en) | 2015-10-06 |
| PE20121315A1 (en) | 2012-10-06 |
| AR078909A1 (en) | 2011-12-14 |
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