CN102477064A - Novel 16,17-ketal intermediate for preparing ciclesonide - Google Patents
Novel 16,17-ketal intermediate for preparing ciclesonide Download PDFInfo
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- CN102477064A CN102477064A CN2010105567833A CN201010556783A CN102477064A CN 102477064 A CN102477064 A CN 102477064A CN 2010105567833 A CN2010105567833 A CN 2010105567833A CN 201010556783 A CN201010556783 A CN 201010556783A CN 102477064 A CN102477064 A CN 102477064A
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Abstract
The invention relates to a novel 16,17-ketal intermediate for preparing ciclesonide, which discloses a compound of formula (III), a method for synthesizing the compound of formula (III) from a compound of formula (I), and a method for synthesizing ciclesonide from the compound of formula (III).
Description
Technical field:
The present invention relates to the application in the preparation ciclesonide of a kind of new pregnane compound and this compound.
Background technology:
In March, 2004, the treatment asthma new drug ciclesonide (ciclesonide) of German pharmaceutical manufacturer A Ertana is obtained in Australian listing and is checked and approved.Soon go on the market on Britain, Brazil, Mexico and other places respectively again.Ciclesonide, chemistry 16 α by name, 17 α-22R-cyclohexylmethylene-11 β, 21-dihydroxyl-1,4-pregnen diethylene-3,20-diketone-21-isobutyrate, molecular formula is C32H44O7.
Ciclesonide
Ciclesonide is the non-halo enzyme sugar of the imbedibility of an a new generation cortex steroidal, has higher local anti-inflammatory ability.It is a kind of ester class prodrug, does not have oral bioavailability basically, its activation through the cracking of endogenous esterase." site activation " advantage (on-site-activation) is included in target activation in the lung, thereby systemic side effects and pharyngeal spinoff are extremely low.
1961, SeymourBernstein etc. found 16 α, and 17 α-two substituted methylene dioxygen structure steroide thinks that this compound has higher anti-inflammatory activity, has also introduced the building-up process of 22 no stereoselective Hydroxyprednisolone Acetonides simultaneously.Under the effect of hydrochloric acid,, promptly generate 16 α with 16 alpha-hydroxy prednisonlones with the acetone reaction, the pregnant steroid ketal compounds of 17 alpha-dihydroxy-s (), reaction formula is following.
1975, R.Brnasttnad etc. (US3928326,3929768) reported that other aldehydes or ketones replaces acetone and the reaction of 16 alpha-hydroxy prednisonlones, obtains having the adrenocortical hormone of higher anti-inflammatory action.They react with butyraldehyde-n and 16 alpha-hydroxy prednisonlones, have synthesized ciclesonide, analyze two kinds of isomer proportion 22R: 225=50 with HPLC: 50, and be respectively two kinds of capable signs of isomer with NMR and mass spectrum.Rat is carried out the anti-inflammatory experiment, confirm with respect to the fluticasone acetonide, the local anti-inflammatory effect that ciclesonide is higher, the low 4-7 of its whole body specific activity fluticasone acetonide is doubly simultaneously.Reaction process is that the Zai diox is done in the solvent, makes catalyzer with 70% perchloric acid, makes butyraldehyde-n and 16 alpha-hydroxy prednisonlones at room temperature react 3h.After reaction finishes,, regulate the pH value with 10% wet chemical again, then with anhydrous magnesium sulfate drying with the methylene dichloride dilution.With methylene dichloride, sherwood oil recrystallization, filter after the underpressure distillation, drying obtains content and is 94.4% ciclesonide, and HPLC analyzes R, the S isomer proportion is 50: 50.
Relevant ciclesonide synthetic has five pieces of patents, four kinds of methods, and existing the summary as follows:
(1) article one route by the three isobutyl esterifications earlier of four hydroxyl things of Calatayud (US5482934) report is difficult to obtain high-load 22 (R) optical body.
(2) Gutterer gets acetal (4) earlier with four hydroxyl things (1) with the hexahydrobenzaldehyde condensation; The embodiment R/S that has in this patent is up to 92/8 (US5733901); Introduce 21-position isobutyryl then and ciclesonide, to improve the method for R/S ratio should be synthetic route (WO9809982) preferably to recrystallization again.
(3) Gutterer (US5728826) with acetal thing elder generation silicon etherificate again recrystallization improving the R/S ratio, after the method for hydrolysis silicon ether again, the result makes the total reaction step increase for two steps on foot, should be very unwise move.
(4) usefulness of Gutterer (WO0238584) method of acetone thing (6) and hexahydrobenzaldehyde reaction that contracts, acetal thing R/S is than up to 98%.
In sum; Ciclesonide mainly is to synthesize for raw material through 16 alpha-hydroxy prednisonlones (1); But there is hydroxyl in 16 alpha-hydroxy prednisonlones owing to 21, in the acetalation process, can produce impurity and not easily separated, in 21 hydroxyl processes of preparation, often all use iodate, replacing process, hydrolysis process just can obtain 21 hydroxyls simultaneously; Again through the isobutyric anhydride esterification; For directly carrying out the isopropylformic acid replacing process after 21 iodate, be equivalent to increase two-step reaction, to 21 for using pure iodine in the hydroxyl iodate technology as iodinating agent; Because pure iodine value lattice are very expensive, so cost is more cheap when the rear end of iodination reaction at synthesis technique.
Summary of the invention:
The invention discloses the formula III compound, become formula III compound method with formula (I) compounds, and the method for the synthetic ciclesonide of formula III compound.
Formula (I) compound can be by the formula II compound through following method preparation.
Wherein the preparation method of formula II compound can obtain in WO9818813.
A kind of method for preparing the formula III compound is that the mixture by formula (I) compound and hexahydrobenzaldehyde, acid, organic solvent or organic solvent and water reacts, and reaction is finished, and obtains the formula III compound.
Said preparation method, acid is mineral acid in the reaction.Be selected from hydrofluoric acid, hydrochloric acid, Hydrogen bromide, hydroiodic acid HI, perchloric acid, tosic acid, acetic acid, pyridine hydrochloride.Preferred acid is a pyridine hydrochloride.
Described preparation method, organic solvent is nitrile, ether, the haloalkane of 1-4 carbon.Be preferably diox, acetonitrile, THF, N, dinethylformamide, methylene dichloride, chloroform, Nitromethane 99Min..More preferably Nitromethane 99Min., acetonitrile, THF, methylene dichloride, chloroform.
Described preparation method is characterized in that reaction is complete, can use mineral alkali to regulate pH value and be neutrality.
Described preparation method is characterized in that reaction is complete, can obtain the formula III compound through dilution, recrystallization.
A kind of method for preparing ciclesonide, ((IV), 21 positions are got ciclesonide in return to obtain compound by 21 iodate of formula III compound.
In the said formula IV-I (I
2) explain that the iodo thing of this moment is two iodine thing-CHI
2Or single iodine thing-CH
2I,
The preparation method of said ciclesonide is characterized in that the mixture dissolving of (III) compound at the liquid haloalkane of the alcohol of 1-2 carbon, a 1-2 carbon, adds quicklime, below 5 ℃, drips the reaction of iodine liquid, obtains the formula IV compound; Formula IV compound, sodium methacrylate that the last step was obtained are placed on N, react in the dinethylformamide, obtain ciclesonide.
The compound method 1 of formula (I) compound:
Formula II compound 10mmol, acetone 50ml, formic acid 0.5ml add in the there-necked flask, stir, and ice-water bath adds KMnO4 solution [1.5g KMnO4 is dissolved in the 15mL water], is stirred to red-purple and takes off to the greatest extent, adds 10%Na
2CO
3Aqueous solution 12mL stirs 0.5h, is warming up to 40 ℃, and filtered while hot is washed washing leaching cake while hot with small amount of acetone, and the filtrating rotary distillation is concentrated into a large amount of crystal and separates out, suction filtration, and washing, dry constant weight gets formula (I) compound 9.2mmol.
The compound method 2 of formula (I) compound:
30molK
3[Fe (CN)
6], 30molK
2CO
3With 0.04mmol K
2OsO
2(OH)
4, in the solution of 100ml butanol/water (2: 1), under the vigorous stirring solution is chilled to 0 ℃, add formula II compound 10mmol in batches, stir 17h, add 8g solid Na
2SO
3, stir 2h.Add the 100mL methylene dichloride, tell organic layer.Water layer is used CH again
2Cl
2Extraction (50mlX3).Merge organic layer, anhydrous MgSO
4Drying, concentrating under reduced pressure is used recrystallizing methanol, filters, and part is reclaimed in vacuum-drying, and the recovery is 97%, gets formula (I) compound.
The compound method 3 of formula (I) compound:
Acetone-water (10: 1, V/V) 40ml, OsO
40.05mmol, behind the stirring 10min, add N-methyl-N-oxygen beautiful jade (NMO) 13mmol; Said mixture is cooled to 0 ℃, and formula II compound 10mmol is dissolved in the 20mL acetone, slowly drops in the reaction flask in the 2h; 0 ℃ is continued to stir 6h, and pressure reducing and steaming acetone divides the chloroform that adds precooling for three times to amount to 30ml and extracts; Combined chloroform liquid, recrystallizing methanol is crossed and is filtered formula (I) compound 9.2mmol.
The invention also discloses the application of acceptable solvent compound in preparation treatment people or Mammals medicine on described formula III compound and the physiology thereof.
The invention also discloses the application of acceptable solvent compound in preparation treatment people or Mammals anti-inflammatory or Claritin on said formula III compound and the physiology thereof.Particularly preferably in preparation treatment people or mammal skin inflammation, like eczema, psoriasis, allergic dermatitis, neurodermatitis, itch and hypersensitivity reaction; Airway inflammation such as bronchial asthma, rhinallergosis, chronic obstructive pulmonary disease, interstitial pneumonia, pulmonary fibrosis; Eye inflammation such as conjunctivitis; Inflammatory bowel such as ulcerative colitis or Crohn disease; Osteoarthropathy such as rheumatic arthritis, rheumatoid arthritis, and the medicine of autoimmune disease such as diseases such as lupus erythematosus, pemphigus in application." treatment " of the present invention can extend to the prevention and the diagnosis of disease.
The dosage of formula III compound disclosed by the invention in treatment people or mammalian diseases medicine is 0.2 μ g-50mg/kg/ days, preferred 1 μ g-2mg/kg/ days.During as treatment people's disease, people's body weight is generally calculated according to 50kg, so the dosage of human described in the present invention can calculate according to ABW, also can calculate according to above-mentioned dosage * 50.
The invention also discloses a kind of pharmaceutical composition, it is characterized in that containing as described any one or a few the compound and one or more pharmaceutically useful auxiliary materials of the formula III of activeconstituents.
The present invention is disclosed to be that the pharmaceutical composition of activeconstituents includes but are not limited to the pharmaceutical composition that is applicable to oral administration, drug administration by injection, orally administering, sublingual administration, parenteral admin, part or rectal administration with the formula III compound; Be preferably the pharmaceutical composition of whole body administration, special preferred oral administration, drug administration by injection.
The common preparation that tablet, capsule, oral liquid formulations, suspensoid, aqua or the like are arranged through gastrointestinal absorption of the preparation of oral administration, the common preparation that has injection, infusion solution etc. to absorb of injecting and administering preparations through muscle, vein.
The pharmaceutical composition of described topical includes but are not limited to inhalation such as aerosol, atomized powder, sprays; Nasal formulations such as nasal spray, nasal drop, external preparation comprise like ointment, ointment, gelifying agent, lotion, foaming agent, patch, powder; The orally administering preparation is as chewing the tablet that maybe can suck or pill, oral cavity sticking tablet; Local cavity preparation such as suppository, vaginal suppository, enema,retention; Ophthalmic preparation such as eye drops; And liposome or microcapsule formulation.Be preferably inhalation, nasal formulations and external preparation.
Described is that pharmaceutical composition dosage when treatment people or mammalian diseases of activeconstituents is counted 0.2 μ g-5mg/kg/ days with the formula III compound, preferred 1 μ g-2mg/kg/ days with the formula III compound.Described pharmaceutical composition is counted 0.2 μ g-5mg/kg/ days at the dosage of treating people or Mammals supersensitivity, diseases associated with inflammation with the formula II compound; Preferred 1 μ g-2mg/kg/ days; Described pharmaceutical composition adopts every day 1 time or more administering mode in use; Preferred every day 1～3 time, also can adopt medication in many days administering mode once, dosage is the stack of Dan Tian.
When described said be that the pharmaceutical composition of activeconstituents is processed oral or during injection, said pharmaceutically acceptable auxiliaries is the pharmaceutical excipient of conventional oral or injection with the formula III compound, concrete kind can be referring to relevant textbook or document with relevant method for making.
When described said be the pharmaceutical composition of activeconstituents when being made as the aerosol of inhalation with the formula III compound, said pharmaceutically acceptable auxiliaries is propellent and one or more low volatility component.
Described propellent can include but are not limited to one or more in freon hydrocarbon, fluorohydrocarbon class, pressurized gas, the ethers, comprises 1,1,1; 2-Tetrafluoroethane (HFA134a) and 1,1,1.2,3; 3,3-HFC-227 (HFA227), Trichloromonofluoromethane (CCl3F), chlorodifluoromethane (CCl2F2); Dichloro tetrafluoro ethane (CClF2-CClF2), propane (C3H8), Trimethylmethane (III so-C4H10), normal butane (n-C4H10); Carbonic acid gas, nitrous oxide, nitrogen is preferably in the fluorohydrocarbon compounds one or more.Be preferably a kind of or its combination among HFA134a and the HFA227 especially.
Described low volatility component can include but are not limited to, one or more in solvent, latent solvent, suspending agent, stablizer, correctives, the sanitas.And also can be applicable to the aerosol or the sprays of non-suction.
Described suitable latent solvent can be but be not limited only to ethanol or oleic acid, and preferably use ethanol, suitable solvent is a glycerine, and Ucar 35 or polyoxyethylene glycol preferably use glycerine.Solvent and latent solvent also can be referred to as thinner herein.
Said low volatiles can also be but be not limited only to following component; Comprise other pure and mild glycol, for example alkanol; Sugar alcohol, glycofural (tetrahydrofuran base methyl alcohol) and DPG like decyl alcohol (decyl alcohol), Sorbitol Powder, mannitol, Saccharum lactis, maltose alcohol comprise that vegetables oil, organic acid are as comprising dodecylic acid and saturated carboxylic acids such as tetradecanoic acid and Triple Pressed Stearic Acid; Comprise Sorbic Acid, particularly unsaturated carboxylic acid such as oleic acid.The known stablizer that is applied to aerosol, sprays, suspending agent, correctives like asccharin, xitix, cyclamic acid, amino acid or ASPARTAME POWDER BP/USP; Alkane such as dodecyl and octadecane; Terpenes such as Therapeutic Mineral Ice, eucalyptol, PC 560; Sugar is like lactose, glucose, sucrose; Polysaccharide such as TKK 021, Expex; Inhibitor such as Yoshinox BHT, Sodium Pyrosulfite, butylated hydroxyanisol; Polymkeric substance such as Z 150PH, polyvinyl acetate, Vinylpyrrolidone polymer; Amine such as thanomin, diethylolamine, trolamine; Steroid class such as SUV, cholesteryl ester.
Should be appreciated that because of known reason like the retention of activeconstituents in suction apparatus, the amount of every kind of activeconstituents that the patient sucks can be different from the amount of metering.Therefore the applicating ratio between the activeconstituents can be different from the ratio of metering.The ratio of preferably using is in described indicated metered proportions.
Of the present invention is the aerosol that the pharmaceutical composition of activeconstituents is made as inhalation with the formula III compound; Described atomized powder is made up of dried powder; The method that obtains dried powder is for pulverizing activeconstituents of the present invention and pharmaceutical excipient with known breaking method such as mechanical disintegration or spray-dired mode; Be preferably the micronized dried powder of mid-diameter less than 10 μ m, powder mass, preferred mid-diameter is from 0.1 to 5 μ m.As a kind of replacement, activeconstituents in small, broken bits can with one or more pharmaceutically useful non-active ingredients, like additive, diluent or carrier etc. form specified form of mixtures.The composition that uses among the present invention can known by one of skill in the art method obtain these preferred forms.Add nonionogenic tenside when utilizing spray-drying process to reach median size in the carrier to increase flowability, preferred nonionic is a Prist.Activeconstituents: the Prist weight ratio is 1: (0.01～5).The composition that uses among the present invention can known by one of skill in the art method obtain these preferred forms.
Described is that the pharmaceutical composition of activeconstituents is when processing nasal formulations with the formula III compound; Said pharmaceutically acceptable auxiliaries can include but are not limited to pH regulator agent, carrier, osmotic pressure regulator, viscosity modifier,, suspending agent, inhibitor, tensio-active agent, stablizer, antibacterial sanitas etc. all be applicable in the pharmaceutical excipient of local nose administration one or more.
Described carrier can include but are not limited to one or more in water, Ucar 35, Xylo-Mucine, Vltra tears, hydroxypropylcellulose, whiteruss, vegetables oil, Vaseline, yolk, the crosslinked polypropylene acid resin.When said pharmaceutical composition is processed gelifying agent; Described carrier contains water and crosslinked acrylic resin, and employed crosslinked polypropylene acid resin is preferably the carbomer resin, is preferably carbomer 934 especially; Consumption is 0.1%～1% of a pharmaceutical composition weight, preferred 0.2% to 0.5%.The consumption of water is 90% to 99% of a pharmaceutical composition weight.
Described pH regulator agent can be enumerated but is not limited only to phosphoric acid and salt, boric acid and salt thereof, Citric Acid and salt thereof, acetic acid and salt thereof, tartrate and salt thereof, sodium hydroxide, Pottasium Hydroxide, yellow soda ash, salt of wormwood, sodium hydrogencarbonate, saleratus, tromethane etc.
Described suspending agent can include but are not limited to, asccharin, xitix, cyclamic acid, amino acid or ASPARTAME POWDER BP/USP; Alkane such as dodecyl and octadecane; Terpenes such as Therapeutic Mineral Ice, eucalyptol, PC 560; Sugar is like lactose, glucose, sucrose; In polysaccharide such as TKK 021, the Expex one or more.
Described inhibitor can include but are not limited to Yoshinox BHT, Sodium Pyrosulfite, butylated hydroxyanisol; Amine such as thanomin, diethylolamine, trolamine; Steroid class such as SUV, cholesteryl ester.
Described osmotic pressure regulator to include but are not limited to osmotic pressure regulator and can enumerate but be not limited only to glycerine, Ucar 35, sodium-chlor, Repone K, Sorbitol Powder, N.F,USP MANNITOL one or more etc.
Said viscosity modifier can be enumerated but be not limited only to one or more of polyvinyl alcohol, carboxy vinyl polymer, PVP K120, foregoing crosslinked polypropylene acid resin, Xylo-Mucine, Vltra tears, hydroxypropylcellulose, also can be used as viscosity modifier.
Said stablizer can include but are not limited to YD 30 and alkaline metal salt thereof, preferred EDTA Disodium.
Described tensio-active agent can be enumerated but be not limited only to tween-80, Polyoxyethylene hydrogenates the Oleum Ricini 60, polyoxyethylene glycol-stearate; Macrogol 4000; Yelkin TTS, sucrose ester, Voranol EP 2001; The polyoxy stearate, one or more in T 46155, polyoxypropylene diols and the analogue thereof.
Described antibacterial sanitas can include but are not limited to, in the benzalkonium chloride, benzethonium chloride, Sorbic Acid, POTASSIUM SORBATE GRANULAR WHITE, methyl paraben (Tegosept M), nipagin A (ethyl p-hydroxybenzoate) propylben (propylben), chlorobutanol one or more.
Ucar 35 in the said pharmaceutically useful auxiliary material, glycerine can also use other alcohols to replace; The available alcohols can include but are not limited to other alcohols and glycols, for example alkanol, like decyl alcohol (decyl alcohol), comprise sugar alcohol, glycofural (tetrahydrofuran base methyl alcohol) and the DPG of Sorbitol Powder, mannitol, Saccharum lactis, maltose alcohol.
Described is that the pharmaceutical composition of activeconstituents is when processing external preparation with the formula III compound; Preferably process ointment, said pharmaceutically acceptable auxiliaries includes but are not limited to the inhibitor that is used for the said pharmaceutical composition of preservation, the pH buffer reagent; Wetting Agent for Printing Inks; Oil-phase component, antibiotic antiseptic, the water of surplus in addition.
Described oil-phase component comprises one or more in solid in the oil-phase component, consistency modifiers, the emulsifying agent.
Solid in the said oil-phase component includes but are not limited to one or more of Triple Pressed Stearic Acid, paraffin, beeswax, higher alcohols; Described higher alcohols is the monohydroxy-alcohol of 16～22 carbon atoms; Preferred hexadecanol and/or stearyl alcohol; Described consistency modifiers includes but are not limited to one or more in Vaseline, whiteruss, the vegetables oil, preferred Vaseline and/or Liquid Paraffin, described emulsifying agent; Include but are not limited to the verivate of soap class emulsifying agent, Soxylat A 25-7, described higher alcohols also plays influence of surfactant simultaneously in emulsifiable paste.
It is said that the composition of the above pharmaceutical composition is not limited only to technical scheme of the present invention; Also comprise any composition that can be used for the pharmaceutical excipient of above-mentioned preparation; The composition of said pharmaceutical excipient can be with reference to disclosed scheme in " pharmaceutics " (the 5th edition, Cui Fude published in 2003).
Compare with glucocorticosteroid of the prior art; New formula III compound 21 provided by the invention is not for there being hydroxyl; But still produced curative effect during anti-inflammatory, compared with similar compounds, curative effect does not reduce; But the long-time skin atrophy situation that causes of using has had obvious improvement, uses in long-term or general to have better effect.
Embodiment:
Embodiment 1
Formula (I) compound 10mmol, Nitromethane 99Min. 15ml, hexahydrobenzaldehyde 13mmol add in the there-necked flask, stir, and in-5 to 0 ℃ drip perchloric acid 30mmol; Drip to finish in 2 hours, 15 ℃ of stirred overnight then, next day, discoverys had a large amount of solids to separate out, filtration; Filter cake is used N, and dinethylformamide (DMF) dissolving is freezing down in ice bath, drips the 10%NaHCO3 aqueous solution and is neutralized to neutrality; Use ethyl acetate extraction then, organic phase is used recrystallizing methanol with dried over sodium sulfate and concentrating under reduced pressure, suction filtration; Washing, dry constant weight gets formula III compound 8.6mmol, 22R: 22S=95: 5.
Ultimate analysis: C, 70.95; H, 8.24; O, 20.81
Embodiment 2
Methylene dichloride 50ml, tosic acid 15mmol, hexahydrobenzaldehyde 15mmol add in the there-necked flask, stir, and slow adding formula (I) compound 10mmol in room temperature 1h is behind the stirring 5h; Add the 10%NaHCO3 aqueous solution and regulate pH value to 7, layering, water layer is with 5mlX3 washing of chloroform, combined chloroform; Rotary distillation concentrates, recrystallizing methanol, suction filtration, washing; Dry constant weight gets formula III compound 8.4mmol, 22R: 22S=92: 8.，
Embodiment 3
Formula (I) compound 10mmol, acetonitrile 20ml, methylene dichloride 20ml, hydrofluoric acid 18mmol add in the there-necked flask, stir, and in 25 ℃, slowly drip hexahydrobenzaldehyde 20mmol; After stirring 4h, regulate pH value to 7, add 20ml water, standing demix with the 10%NaHCO3 aqueous solution; Water layer divides three extractions with methylene dichloride, each 10ml, and rotary distillation concentrates behind the combined dichloromethane, uses recrystallizing methanol; Suction filtration, dry constant weight gets formula III compound 8.1mmol, 22R: 22S=93: 7.
The compound method of embodiment 4 formula III compound ciclesonides
Technology by (III) compound ciclesonide is existing common process, specifically can be referring to CN 200510122250.3, CN 200510122249.0.
The preparation of formula IV compound
Add 15mL methyl alcohol, (III) compound, add chloroform then and make (III) compound 10mmol dissolving, wait to dissolve to be cooled to after clear and add the 0.3g quicklime below 10 ℃, continue to reduce to 0 ℃ ± 2 ℃, drip iodine liquid 12mmol, dripped the Bi Jixu insulated and stirred 1 hour.Reduce to and add static 30 minutes below 0 ℃, chloroform layer is filtered, water layer is used 12mL, and the chloroform that adds precooling divides four extractions, combined chloroform liquid, and recrystallizing methanol is crossed and is filtered light yellow solid formula IV compound.
The preparation of ciclesonide
Formula IV compound, 15mmol sodium methacrylate that the last step was obtained are placed on 25mlN, in the dinethylformamide (DMF), slowly are warming up to 50 ℃ with 6 hours; Be incubated after 2 hours; Cool to 0 ℃, be diluted in the frozen water, obtain ciclesonide 8.6mmol (R/S=92/8).
Making with extra care of ciclesonide
Ciclesonide bullion 2g (R/S=92/8) is dissolved in the 6mL acetone, adds the 1.3mL pure water under the stirring and refluxing, leave standstill the nature cooling, crystallization and filtration to be separated out; 75% acetone washing, drying gets white crystals 1.5g; Yield 72%, R=98%, m.p.204-207 ℃.
FORMULATION EXAMPLE 1
Activeconstituents
Formula III compound 100.0g
Auxiliary material: pregelatinized Starch 100g
Microcrystalline Cellulose 130g
Lactose 200g
Carboxymethylstach sodium 4g
Micropowder silica gel 5g
Magnesium Stearate 3g
The polyvidone aqueous solution is an amount of
Process 1000 altogether
Take by weighing activeconstituents, pregelatinized Starch, Microcrystalline Cellulose, lactose according to recipe quantity, cross the 60-100 mesh sieve respectively, after mixing; Add the polyvidone aqueous solution and make softwood in right amount, 20 mesh sieve system particles, drying; Whole grain adds Magnesium Stearate; Carboxymethylstach sodium, micropowder silica gel mixes the back and adopts suitable punch die to be pressed into tablet.Every contains formula III compound 100mg.
FORMULATION EXAMPLE 2
Formula III compound 5.0g
Auxiliary material: Microcrystalline Cellulose 130g
Lactose 200g
Magnesium Stearate 3g
Process 1000 altogether
Activeconstituents, Microcrystalline Cellulose, lactose are crossed 80 mesh sieves respectively, after mixing, add the Magnesium Stearate of recipe quantity, promptly get in the suitable capsule of packing into after mixing.Every contains formula III compound 5g.
FORMULATION EXAMPLE 3
Formula III compound 100.0g
Auxiliary material: pregelatinized Starch 100g
Microcrystalline Cellulose 130g
Lactose 200g
Carboxymethylstach sodium 4g
Micropowder silica gel 5g
Magnesium Stearate 3g
The polyvidone aqueous solution is an amount of
Process 1000 altogether
Take by weighing activeconstituents, pregelatinized Starch, Microcrystalline Cellulose, lactose according to recipe quantity, cross the 60-100 mesh sieve respectively, after mixing; Add the polyvidone aqueous solution and make softwood in right amount, 20 mesh sieve system particles, drying; Whole grain adds Magnesium Stearate; Carboxymethylstach sodium, micropowder silica gel mixes the back and adopts suitable punch die to be pressed into tablet.Every contains formula III compound 100mg.
FORMULATION EXAMPLE 4
Formula III compound 40.0g
Auxiliary material: pregelatinized Starch 100g
Microcrystalline Cellulose 130g
Lactose 200g
Carboxymethylstach sodium 4g
Micropowder silica gel 5g
Magnesium Stearate 3g
The polyvidone aqueous solution is an amount of
Process 1000 altogether
Take by weighing activeconstituents, pregelatinized Starch, Microcrystalline Cellulose, lactose according to recipe quantity, cross the 60-100 mesh sieve respectively, after mixing; Add the polyvidone aqueous solution and make softwood in right amount, 20 mesh sieve system particles, drying; Whole grain adds Magnesium Stearate; Carboxymethylstach sodium, micropowder silica gel mixes the back and adopts suitable punch die to be pressed into tablet.Every contains formula III compound 4mg.
FORMULATION EXAMPLE 5
Formula III compound 5.0g
Auxiliary material: lactose 100g
Magnesium Stearate 3g
Process 1000 altogether
Activeconstituents, lactose are crossed 80 mesh sieves respectively, after mixing, add the Magnesium Stearate of recipe quantity, promptly get in the suitable capsule of packing into after mixing.Every contains formula III compound 5g.
FORMULATION EXAMPLE 6
Formula III compound 10.0g
Auxiliary material: pregelatinized Starch 100g
Microcrystalline Cellulose 130g
Lactose 200g
Carboxymethylstach sodium 4g
Micropowder silica gel 5g
Magnesium Stearate 3g
The polyvidone aqueous solution is an amount of
Process 1000 altogether
Take by weighing activeconstituents, pregelatinized Starch, Microcrystalline Cellulose, lactose according to recipe quantity, cross the 60-100 mesh sieve respectively, after mixing; Add the polyvidone aqueous solution and make softwood in right amount, 20 mesh sieve system particles, drying; Whole grain adds Magnesium Stearate; Carboxymethylstach sodium, micropowder silica gel mixes the back and adopts suitable punch die to be pressed into tablet.Every contains formula III compound 100mg.
FORMULATION EXAMPLE 7
Formula III compound 200.0g
Auxiliary material: pregelatinized Starch 100g
Microcrystalline Cellulose 80g
Lactose 180g
Carboxymethylstach sodium 4g
Micropowder silica gel 5g
Magnesium Stearate 3g
The polyvidone aqueous solution is an amount of
Process 1000 altogether
Take by weighing activeconstituents, pregelatinized Starch, Microcrystalline Cellulose, lactose according to recipe quantity, cross the 60-100 mesh sieve respectively, after mixing; Add the polyvidone aqueous solution and make softwood in right amount, 20 mesh sieve system particles, drying; Whole grain adds Magnesium Stearate; Carboxymethylstach sodium, micropowder silica gel mixes the back and adopts suitable punch die to be pressed into tablet.Every contains formula III compound 200mg.
FORMULATION EXAMPLE 8
Formula III compound 50.0g
Auxiliary material: pregelatinized Starch 100g
Microcrystalline Cellulose 130g
Lactose 200g
Carboxymethylstach sodium 4g
Micropowder silica gel 5g
Magnesium Stearate 3g
The polyvidone aqueous solution is an amount of
Process 1000 altogether
Take by weighing activeconstituents, pregelatinized Starch, Microcrystalline Cellulose, lactose according to recipe quantity, cross the 60-100 mesh sieve respectively, after mixing; Add the polyvidone aqueous solution and make softwood in right amount, 20 mesh sieve system particles, drying; Whole grain adds Magnesium Stearate; Carboxymethylstach sodium, micropowder silica gel mixes the back and adopts suitable punch die to be pressed into tablet.Every contains formula III compound 100mg.
FORMULATION EXAMPLE 9
Activeconstituents: formula III compound 5g
Pharmaceutical excipient: hydroxypropyl 30g
CMC 99.5 50g
Ucar 35 200g
Ethyl p-hydroxybenzoate 5g
Zero(ppm) water adds to 1000ml
Activeconstituents and hydroxypropyl are crossed 100 mesh sieves respectively, take by weighing according to recipe quantity, mixing adds an amount of sterile distilled water and fully grinds; With CMC 99.5 and Ucar 35 mixing; Add an amount of hot distilled water then, place wait to be swelled into gel after, add the activeconstituents that contains after the grinding and the aqueous solution of hydroxypropyl and urea and ethyl p-hydroxybenzoate again; Add water to 1000ml and get final product, press the 10ml packing.Every ml contains formula III compound 30mg.
Pharmacology embodiment 1
Laboratory animal: 60 of CXA-1 recombinant inbred strain small white mouses (Bengbu Medical College's animal center provides); Body weight 18～22g; Divide control group, experimental group A, B, it is activeconstituents that experimental group A, B group adopt HYDROCORTISONE INJECTIONS, formula III compound respectively, and the active component content that makes according to FORMULATION EXAMPLE 9 methods is that 0.5% external preparation coating experiment mice auris dextra is inboard; To be coated with dose identical for each group, and simultaneously at the emulsifiable paste matrix of left ear coating same amount as contrast.Control group two ears are coating substrate all.
Chronic dermatitis eczema Animal Model Making: adopt 7%DNCB (DNT) acetone soln 100 μ L to be coated with mouse back sensitization outward; Being coated with 0.1%DNCB acetone soln 5 μ L outside after 5 days excites in the mouse right ear inboard; Every separated 72h excites once; Experimental group is exciting back 24h to begin coating first, and every day, coating twice, and to be coated with dose identical at every turn.Excite back 72h to put to death mouse in the 5th, measure the swelling degree and the incrustation rate of mouse right ear.Swelling degree=(auris dextra weight-left ear weight)/(left ear weight) * 100%.
Experimental data adopts spss to handle and carries out the t check
Experimental data sees the following form
| Group | Swelling degree % | Incrustation rate % |
| Contrast | 151.9±11.5 | 50 |
| A | 109.7±7.9 | 20 |
| B | 116.3±8.8 | 15 |
Show that through experiment experimental group A-B compares with control group, significant difference (P＜0.05) is all arranged when the swelling of treatment mouse ear; Especially; Compare with HYDROCORTISONE INJECTIONS, compound provided by the invention is in the treatment to mouse chronic dermatitis Eczema Model, and there were significant differences for the swelling degree of mouse ear (P＜0.05); And the incrustation rate of mouse ear is also identical, show compound provided by the invention when being used to treat the Mammals local inflammation and HYDROCORTISONE INJECTIONS have similar curative effect.
Pharmacology embodiment 2 local actions cause atrophy effect contrast
Laboratory animal: 40 of white cavys childhood, body weight 300g ± 20g is divided into experiment A, B group, and respectively with HYDROCORTISONE INJECTIONS, the formula III compound is an activeconstituents, makes 0.5% external preparation according to embodiment 9 methods and organizes medication for experiment A, B.
Experimental technique: every guinea pig back left and right sides antimere selected the zone of 3cm * 3cm, shave hair, the left side uses experimental group to be coated with the pastille emulsifiable paste; Right side coating emulsifiable paste matrix, medication every day 2 times is coated with same amount at every turn; Continuous use; After medication the 20th day with every group of cavy drug withdrawal, medication district, back and check plot skin are put to death and got respectively to cavy, the ratio of measuring medication district skin thickness and check plot skin thickness is to confirm the skin atrophy degree.The result sees the following form
Last table data declaration is compared with existing HYDROCORTISONE INJECTIONS, and compound provided by the invention causes the skin atrophy effect when local application have remarkable reduction (P＜0.05).Can draw thus, use compound provided by the invention to be used for the treatment of local inflammation, spinoff is littler, and medication is safer.
Claims (10)
1. formula III compound.
2. method for preparing the formula III compound is that the mixture by formula (I) compound and hexahydrobenzaldehyde, acid, organic solvent or organic solvent and water reacts, and reaction is finished, and obtains the formula III compound.
3. preparation method as claimed in claim 2 is characterized in that acid is mineral acid in the reaction.
4. preparation method as claimed in claim 2 is characterized in that organic solvent is nitrile, ether, the haloalkane of 1-4 carbon.
5. preparation method as claimed in claim 2 is characterized in that reaction is complete, can use mineral alkali to regulate pH value and be neutrality.
6. preparation method as claimed in claim 2 is characterized in that reaction is complete, can obtain the formula III compound through dilution, recrystallization.
7. method for preparing ciclesonide, ((IV), 21 positions are got ciclesonide in return to obtain compound by 21 iodate of formula III compound.
8. preparation method as claimed in claim 7 is characterized in that the mixture dissolving of (III) compound at the liquid haloalkane of the alcohol of 1-2 carbon, a 1-2 carbon, adds quicklime, below 5 ℃, drips the reaction of iodine liquid, obtains the formula IV compound; Formula IV compound, sodium methacrylate that the last step was obtained are placed on N, react in the dinethylformamide, obtain ciclesonide.
9. formula III compound as claimed in claim 1 is characterized in that the application in preparation people or Mammals anti-inflammatory or Claritin.
10. a pharmaceutical composition is characterized in that containing formula III compound and one or more pharmaceutical excipients as activeconstituents.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2013124395A1 (en) * | 2012-02-23 | 2013-08-29 | Boehringer Ingelheim International Gmbh | Novel method for manufacturing of ciclesonide |
| CN108267531A (en) * | 2016-12-31 | 2018-07-10 | 天津金耀集团有限公司 | A kind of related substance HPLC assay methods of ciclesonide |
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| US2990401A (en) * | 1958-06-18 | 1961-06-27 | American Cyanamid Co | 11-substituted 16alpha, 17alpha-substituted methylenedioxy steroids |
| US5482934A (en) * | 1990-09-07 | 1996-01-09 | Especialidades Latinas Medicamentos Universales, S.A. (Elmu, S.A.) | Pregna-1,4-diene3,20-dione-16-17-acetal-21 esters, process for their preparation, composition, and methods for the treatment of inflammatory conditions |
| CN1810824A (en) * | 2005-12-09 | 2006-08-02 | 天津理工大学 | Momertasone furoate intermediate 21-ester and its prepn |
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US2990401A (en) * | 1958-06-18 | 1961-06-27 | American Cyanamid Co | 11-substituted 16alpha, 17alpha-substituted methylenedioxy steroids |
| US5482934A (en) * | 1990-09-07 | 1996-01-09 | Especialidades Latinas Medicamentos Universales, S.A. (Elmu, S.A.) | Pregna-1,4-diene3,20-dione-16-17-acetal-21 esters, process for their preparation, composition, and methods for the treatment of inflammatory conditions |
| CN1810824A (en) * | 2005-12-09 | 2006-08-02 | 天津理工大学 | Momertasone furoate intermediate 21-ester and its prepn |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2013124395A1 (en) * | 2012-02-23 | 2013-08-29 | Boehringer Ingelheim International Gmbh | Novel method for manufacturing of ciclesonide |
| JP2015509493A (en) * | 2012-02-23 | 2015-03-30 | ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング | New method for producing ciclesonide |
| US9109005B2 (en) | 2012-02-23 | 2015-08-18 | Boehringer Ingelheim International Gmbh | Method for manufacturing of ciclesonide |
| CN108267531A (en) * | 2016-12-31 | 2018-07-10 | 天津金耀集团有限公司 | A kind of related substance HPLC assay methods of ciclesonide |
| CN108267531B (en) * | 2016-12-31 | 2022-01-11 | 天津金耀集团有限公司 | HPLC (high performance liquid chromatography) determination method for ciclesonide related substances |
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