CN102850426B - A kind of 21 is the glucocorticosteroid of N-acetylcystein ester - Google Patents
A kind of 21 is the glucocorticosteroid of N-acetylcystein ester Download PDFInfo
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- CN102850426B CN102850426B CN201110184121.2A CN201110184121A CN102850426B CN 102850426 B CN102850426 B CN 102850426B CN 201110184121 A CN201110184121 A CN 201110184121A CN 102850426 B CN102850426 B CN 102850426B
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Abstract
A kind of 21 is the glucocorticosteroid of N-acetylcystein ester, N-acetylcystein is combined the formula of being formed (I) compound with glucocorticosteroid, and the application of acceptable solvated compounds in preparation treatment people or inflammation in mammals medicine on formula (I) compound and physiology thereof.
Description
Technical field:
The present invention relates to a kind of novel glucocorticosteroid and synthetic method thereof and preparing the application in the medicine for the treatment of diseases related.
Background technology:
It is well-known that glucocorticosteroid has antiinflammatory property, and be widely used in inflammatory disorders or diseases associated with inflammation as the treatment of asthma, rhinitis, eczema etc., play the effect of relief of symptoms, in the treatment of these diseases, often need long-term prescription, so also can cause the various untoward reactions of whole body, how improving curative effect of medication thus to reduce drug use, the generation reducing untoward reaction just becomes the key of medicament research and development.
The phlegm dissolving agent of N-acetylcystein system, has stronger phlegm dissolving effect.In its molecule, contained sulfydryl (-SH) can make the disulfide linkage (-S-S-) in phlegm in glycoprotein polypeptide chain rupture, and reduces the viscosity of phlegm, and makes it liquefaction.This product can also make the DNA fiber in purulent sputum rupture, therefore can not only dissolve the sticky phlegm of white and can dissolve purulent sputum.
In glucocorticoid treatment respiratory tract disease, extensive employing inhalation is treated, but because respiratory disease patient often has denseer sputum in respiratory tract, glucocorticosteroid major part in by respiratory tract process is adhered to by sputum, cannot play a role.
Summary of the invention:
Contriver is by constantly research, N-acetylcystein is combined with glucocorticosteroid and forms novel formula (I) compound, effectively reduce the absorption of sputum to glucocorticosteroid, improve the curative effect of anti-inflammatory, be highly suitable for general action and long-time use.
The invention provides a kind of formula (I) compound,
R2=OH ,-OCOR6, R6 is alkyl within six carbon or furyl;
R3=H, OH or methyl;
R2，R3＝
R4=H or halogen;
R5=H, halogen or methyl;
1,2 represented by dotted arrows singly-bounds or double bonds.
Preferred:
R2=H ,-COR6, R6 is alkyl within three carbon or 2-furyl;
R3=H or methyl;
R2，R3＝
R4=H or F;
R5=H, F or methyl;
1,2 represented by dotted arrows singly-bounds or double bonds.
More preferably:
R2=H ,-COR6, R6 is methyl or 2-furyl;
R3＝H；
R2、R3＝
R4=H or F;
R5=H or methyl;
1,2 represented by dotted arrows singly-bounds or double bonds.
Further preferably:
R2=H ,-COR6, R6 is methyl;
R3＝H；
R2，R3＝
R4=H or F;
R5=H or methyl;
1,2 represented by dotted arrows double bonds.
Further preferably following several:
Pregnant steroid-Isosorbide-5-Nitrae-diene-3,20-diketone-11 β, 17,21-trihydroxy--21-(N-acetyl)-Cys ester;
Pregnant steroid-Isosorbide-5-Nitrae-diene-3,20-diketone-11 β, 17,21-trihydroxy--21-(N-acetyl)-Cys ester-9 α-fluoro-16 Beta-methyls;
Pregnant steroid-Isosorbide-5-Nitrae-diene-3,20-diketone-11 β, 17,21-trihydroxy--17-acetic ester-21-(N-acetyl)-Cys ester;
Pregnant steroid-Isosorbide-5-Nitrae-diene-3,20-diketone-11 β, 17,21-trihydroxy--21-(N-acetyl)-Cys ester-6 Alpha-Methyl;
Pregnant steroid-Isosorbide-5-Nitrae-diene-3,20-diketone-11 β, 17,21-trihydroxy--17-(2-furans)-manthanoate-21-(N-acetyl)-chloro-16 Alpha-Methyls of Cys ester-9-;
Pregnant Gona-4-ene-3,20-diketone-11 β, 17,21-trihydroxy--21-(N-acetyl)-Cys ester;
Pregnant Gona-4-ene-3,20-diketone-11 β, 17,21-trihydroxy--17-butyric ester-21-(N-acetyl)-Cys ester;
Two hydroxyl-21-(N-the acetyl)-Cys ester-16,17-[(R) cyclohexylmethylene] two (oxygen) of pregnant steroid-Isosorbide-5-Nitrae-diene-3,20-diketone-11 β, 21-];
Pregnant steroid-Isosorbide-5-Nitrae-diene-3,20-diketone-11 β, 21-two hydroxyl-21-(N-acetyl)-Cys ester-16,17-[(R, S) propylmethylene] two (oxygen)];
Two hydroxyl-the 21-(N-acetyl) of pregnant steroid-Isosorbide-5-Nitrae-diene-3,20-diketone-11 β, 21--Cys ester-16 α, 17-[(methyl ethylidene) two (oxygen)].
Most preferably following several:
Two hydroxyl-21-(N-the acetyl)-Cys ester-16,17-[(R) cyclohexylmethylene] two (oxygen) of pregnant steroid-Isosorbide-5-Nitrae-diene-3,20-diketone-11 β, 21-];
Pregnant steroid-Isosorbide-5-Nitrae-diene-3,20-diketone-11 β, 21-two hydroxyl-21-(N-acetyl)-Cys ester-16,17-[(R, S) propylmethylene] two (oxygen)];
Two hydroxyl-the 21-(N-acetyl) of pregnant steroid-Isosorbide-5-Nitrae-diene-3,20-diketone-11 β, 21--Cys ester-16 α, 17-[(methyl ethylidene) two (oxygen)].
The invention also discloses a kind of synthetic method of formula (I) compound:
Synthetic method:
By formula (II) compound dissolution to N, in dinethylformamide, be warming up to 60 DEG C, add 4-dimethylaminopyridine, dicyclohexylcarbodiimide, N-acetylcystein, stir and carry out esterification, Temperature fall under room temperature after 30 minutes, react under room temperature, reaction is complete to be diluted in frozen water, filters after regulating pH value neutrality, dry after rinsing with water, obtain formula (I) compound.
Substituting group cotype (I) compound of formula (II) compound.
The invention also discloses the application of acceptable solvated compounds in preparation treatment people or Mammals medicine on described formula (I) compound and physiology thereof.
The invention also discloses the application of acceptable solvated compounds in preparation treatment people or inflammation in mammals medicine on described formula (I) compound and physiology thereof.React particularly preferably in preparation treatment people or mammal skin inflammation such as eczema, psoriasis, allergic dermatitis, neurodermatitis, itch and hypersensitivity; Airway inflammation is as bronchial asthma, rhinallergosis, chronic obstructive pulmonary disease, interstitial pneumonia, pulmonary fibrosis; Eye inflammation is as conjunctivitis; Inflammatory bowel is as ulcerative colitis or Crohn disease; And autoimmune disease is as the application in the medicine of the diseases such as rheumatic arthritis, rheumatoid arthritis, lupus erythematosus, pemphigus." treatment " of the present invention can extend to prevention and the diagnosis of disease.
The dosage of formula disclosed by the invention (I) compound in treatment people or mammalian diseases medicine is 0.2 μ g-50mg/kg/ days, preferably 1 μ g-2mg/kg/ days.During disease as treatment people, the body weight of people generally calculates according to 50kg, so people described in the present invention can calculate according to ABW with dosage, also can calculate according to above-mentioned dosage × 50.
The invention also discloses a kind of pharmaceutical composition, it is characterized in that containing any one or a few the compound described in the formula (I) as activeconstituents and one or more pharmaceutical excipients.
The pharmaceutical composition being activeconstituents with formula (I) compound disclosed in this invention includes but are not limited to the composition being applicable to Formulations for systemic administration, topical, the described composition being applicable to Formulations for systemic administration includes but are not limited to the pharmaceutical composition being applicable to oral administration, drug administration by injection, orally administering, sublingual administration, parenteral admin, local or rectal administration, the pharmaceutical composition of preferred oral administration or drug administration by injection.
The preparation of oral administration is common has tablet, capsule, oral liquid formulations, suspensoid, aqua etc. by the preparation of gastrointestinal absorption, and injecting and administering preparations is common has injection, infusion solution etc. by the preparation of muscle, venous absorption.
The described pharmaceutical composition being suitable for topical includes but are not limited to inhalation as aerosol, Foradil Aerolizer formoterol fumarate, sprays; Nasal formulations such as nasal spray, nasal drop, external preparation comprise as ointment, ointment, gelifying agent, lotion, foaming agent, patch, powder; The tablet that orally administering preparation maybe can be sucked as chewed or pill, oral cavity sticking tablet; Local cavity preparation is as suppository, vaginal suppository, enema,retention; Ophthalmic preparation is as eye drops; And liposome or microcapsule formulation.Be preferably inhalation, nasal formulations and external preparation.
Described is that pharmaceutical composition dosage when treating people or mammalian diseases of activeconstituents counts 0.2 μ g-5mg/kg/ days with formula (II) compound, preferably 1 μ g-2mg/kg/ days with formula (I) compound.Described pharmaceutical composition treatment people or Mammals supersensitivity, diseases associated with inflammation dosage count 0.2 μ g-5mg/kg/ days with formula (II) compound, preferably 1 μ g-2mg/kg/ days, described pharmaceutical composition adopts the administering mode of every day 1 time or more in use, preferred every day 1 ~ 3 time, also can adopt medication in many days administering mode once, dosage is the superposition of Dan Tian.
When the described pharmaceutical composition that is activeconstituents with formula (I) compound makes oral or injection, described pharmaceutically acceptable auxiliaries is the pharmaceutical excipient of traditional oral or injection, and concrete kind and relevant method for making can see relevant textbook or documents.
When the described pharmaceutical composition that is activeconstituents with formula (I) compound is made as the aerosol of inhalation, described pharmaceutically acceptable auxiliaries is propellent and one or more low volatility component.
Described propellent can include but are not limited to fluorochloroparaffins, hydrocarbon polymer, fluorohydrocarbon class, pressurized gas, one or more in ethers, comprise 1, 1, 1, 2-Tetrafluoroethane (HFA134a) and 1, 1, 1.2, 3, 3, 3-heptafluoro-propane (HFA227), Trichloromonofluoromethane (CCl3F), chlorodifluoromethane (CCl2F2), dichloro tetrafluoro ethane (CClF2-CClF2), propane (C3H8, ), Trimethylmethane (iso-C4H10), normal butane (n-C4H10), carbonic acid gas, nitrous oxide, nitrogen, be preferably one or more in fluorohydrocarbon compounds.Be particularly preferably the one in HFA134a and HFA227 or its combination.Most preferably be HFA134a.
Described low volatility component can include but are not limited to, one or more in solvent, latent solvent, suspending agent, stablizer, correctives, sanitas.And also can be applicable to aerosol or the sprays of non-suction.
The described latent solvent be applicable to can be but be not limited only to ethanol or oleic acid, and preferably use ethanol, applicable solvent is glycerine, and propylene glycol or polyoxyethylene glycol, preferably use glycerine.Solvent and latent solvent also can be referred to as thinner herein.
Described low volatiles can also be but be not limited only to following component, comprise other alcohol and glycol, such as alkanol, as the sugar alcohol of decyl alcohol (decyl alcohol), Sorbitol Powder, mannitol, Saccharum lactis, maltose alcohol, glycofural (tetrahydrofuran base methyl alcohol) and dipropylene glycol, comprise vegetables oil, organic acid as comprised dodecylic acid and the saturated carboxylic acid such as tetradecanoic acid and stearic acid; Comprise Sorbic Acid, particularly the unsaturated carboxylic acid such as oleic acid.Known be applied to aerosol, the stablizer of sprays, suspending agent, correctives as asccharin, xitix, cyclamic acid, amino acid or aspartame; Alkane is as dodecane and octadecane; Terpenes is as menthol, eucalyptol, limonene; Sugar is as lactose, glucose, sucrose; Polysaccharide is as ethyl cellulose, dextran; Antioxidant as Yoshinox BHT, Sodium Pyrosulfite, butylated hydroxyanisol; Polymkeric substance is as polyvinyl alcohol, polyvinyl acetate, polyvinylpyrrolidone; Amine is as thanomin, diethanolamine, trolamine; Steroid class is as cholesterol, cholesteryl ester.
When described pharmaceutical composition makes aerosol, screening formulation is: active component content is 1-8mg/ml; Ethanol weight percent content as latent solvent is 5-20%, and the propellent of surplus.
Should be appreciated that because known reason, as the retention of activeconstituents in suction apparatus, the amount of often kind of activeconstituents that patient sucks can be different from the amount of metering.Therefore the applicating ratio between activeconstituents can be different from the ratio of metering.The ratio preferably used is in the described metered proportions indicated.
The pharmaceutical composition that is activeconstituents with formula (I) compound of the present invention is made as the powder inhalation of inhalation, and described powder inhalation is made up of dried powder, and described excipient substance comprises carrier and additives.
Obtain the method for dried powder for pulverize activeconstituents of the present invention and pharmaceutical excipient with known breaking method such as mechanical disintegration or spray-dired mode,
The preferred median size of preferred described activeconstituents micro mist is 1 ~ 8 μm, and particularly preferably median size is 2 ~ 5 μm, and the median size of preferably described carrier micro mist is 20 ~ 60 μm.
Median size of the present invention is mass median diameter (massmeandiameter).
Described carrier is one or more in carbohydrate carrier, amino acid, and described amino acid includes but are not limited to glycine, α-amino-isovaleric acid.Described carbohydrate comprises monose, disaccharides and/or its derived carbohydrate, described monose includes but are not limited to N.F,USP MANNITOL, fructose, glucose, described disaccharides includes but are not limited to maltose, trehalose, cellobiose, lactose, sucrose, described derived carbohydrate includes but are not limited to eight cellulose acetate two sugar esters, sucrose octa-acetate, eight acetic acid lactose esters, five acetic acid glucose esters, six acetic acid Nitranitols and eight acetic acid marine alga sugar esters, described derived carbohydrate can also with reference to derived carbohydrate example disclosed in the specification sheets of international monopoly WO99/33853, preferably as carrier in derived carbohydrate is eight acetic acid-D-cellobiose esters, in above-mentioned various carrier, most preferably carrier is lactose.Described lactose is alpha-lactose monohydrate, β-lactose hydrous, one or more in amorphous spray-dried lactose, crystallizing and drying lactose, particularly preferably crystallizing and drying lactose.
Preferably in described carrier micro mist, add additives, described additives include but are not limited to tensio-active agent, lubricant, static inhibitor.The consumption of described additives and kind can with reference to any known prior art and documents, disclosed in " pharmaceutics " (Cui Fude etc., 2006-11-1, People's Health Publisher).
The preferred poloxamer of described tensio-active agent.Activeconstituents: poloxamer weight ratio is 1: 0.01 ~ 5.Poloxamer is also as static inhibitor.Described lubricant can also include but are not limited to one or more in Magnesium Stearate, micropowder silica gel, talcum powder, and consumption is 0.01% ~ 1% of carrier micropowder weight.
Described activeconstituents and the weight ratio of carrier are 1: 10 ~ 1000; Preferably 1: 10 ~ 200.
The method of micronization of described activeconstituents can adopt spray-drying process, fluidized-bed supersonic jet mill method, and speed lapping method, ball milled, fluid energy mill method, solvent method etc., preferably adopt spray-drying process.
Powder inhalation provided by the invention can adopt the packaged of single or multiple dosage, and preferably adopt the mode packing of capsule, each capsule contains the above-mentioned powder inhalation of 5 ~ 40mg.Preferably containing the above-mentioned powder inhalation of 10 ~ 30mg.
Capsule containing powder inhalation provided by the invention can adopt known powder inhalation capsule inhaler to suck.Described sucker is such as disclosed in WO94/28958.
Activeconstituents micro mist is changed into the micro mist of 0.5 ~ 10 μm by the preparation method of powder inhalation of the present invention, then carrier and additives micro mist is changed into the micro mist of 20 ~ 60 μm, by above-mentioned two kinds of micro mists mixing, is contained in capsule after crossing 200 mesh sieve 3 times
When the described pharmaceutical composition that is activeconstituents with formula (I) compound makes nasal formulations, described pharmaceutically acceptable auxiliaries can include but are not limited to pH adjusting agent, carrier, osmotic pressure regulator, viscosity modifier, suspending agent, antioxidant, tensio-active agent, stablizer, bacteriostatic preservative etc. all be applicable to local nose administration pharmaceutical excipient in one or more.
Described carrier can include but are not limited to one or more in water, propylene glycol, Xylo-Mucine, Vltra tears, hydroxypropylcellulose, whiteruss, vegetables oil, Vaseline, lanolin, CP.When described pharmaceutical composition makes gelifying agent, described carrier contains water and crosslinked acrylic resin, and the CP used is preferably carbomer resin, is particularly preferably carbomer 934, consumption is 0.1% ~ 1% of pharmaceutical composition weight, preferably 0.2% to 0.5%.The consumption of water is 90% to 99% of pharmaceutical composition weight.
Described pH adjusting agent can be enumerated but be not limited only to phosphoric acid and salt, boric acid and salt thereof, Citric Acid and salt, acetic acid and salt thereof, tartrate and salt, sodium hydroxide, potassium hydroxide, sodium carbonate, salt of wormwood, sodium bicarbonate, saleratus, tromethane etc.
Described suspending agent can include but are not limited to, asccharin, xitix, cyclamic acid, amino acid or aspartame; Alkane is as dodecane and octadecane; Terpenes is as menthol, eucalyptol, limonene; Sugar is as lactose, glucose, sucrose; Polysaccharide is as one or more in ethyl cellulose, dextran.
Described antioxidant can include but are not limited to Yoshinox BHT, Sodium Pyrosulfite, butylated hydroxyanisol; Amine is as thanomin, diethanolamine, trolamine; Steroid class is as cholesterol, cholesteryl ester.
Described osmotic pressure regulator with include but are not limited to osmotic pressure regulator and can enumerate but be not limited only to glycerine, propylene glycol, sodium-chlor, Repone K, Sorbitol Powder, N.F,USP MANNITOL one or more etc.
Described viscosity modifier can enumerate but be not limited only to polyvinyl alcohol, carboxy vinyl polymer, Polyvinylpyrolidone (PVP) one or more, foregoing CP, Xylo-Mucine, Vltra tears, hydroxypropylcellulose, also can be used as viscosity modifier.
Described stablizer can include but are not limited to ethylenediamine tetraacetic acid (EDTA) and alkaline metal salt thereof, preferred disodium ethylene diamine tetraacetate.
Described tensio-active agent can be enumerated but be not limited only to tween-80, HCO60, polyoxyethylene glycol-stearate, Macrogol 4000, Yelkin TTS, sucrose ester, Voranol EP 2001, polyoxy stearate, one or more in polyoxyethylene, polyoxypropylene diols and analogue thereof.
Described bacteriostatic preservative can include but are not limited to, one or more in benzalkonium chloride, benzethonium chloride, Sorbic Acid, potassium sorbate, methyl p-hydroxybenzoate (Tegosept M), nipagin A (ethyl p-hydroxybenzoate) propylparaben (propylben), chlorobutanol.
Propylene glycol in described pharmaceutically useful auxiliary material, glycerine can also replace with other alcohols, available alcohols can include but are not limited to other alcohols and glycols, such as alkanol, as decyl alcohol (decyl alcohol), comprise Sorbitol Powder, mannitol, Saccharum lactis, the sugar alcohol of maltose alcohol, glycofural (tetrahydrofuran base methyl alcohol) and dipropylene glycol.
When the described pharmaceutical composition that is activeconstituents with formula (I) compound makes external preparation, preferably make ointment, described pharmaceutically acceptable auxiliaries includes but are not limited to the antioxidant for pharmaceutical composition described in preservation, pH buffer reagent, wetting Agent for Printing Inks, oil-phase component, antibiotic antiseptic, also has the water of surplus.
Described oil-phase component comprises one or more in solid in oil-phase component, consistency modifiers, emulsifying agent.
Solid in described oil-phase component include but are not limited to stearic acid, paraffin, beeswax, higher alcohols one or more, 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, vegetables oil, preferred Vaseline and/or Liquid Paraffin, described emulsifying agent, include but are not limited to the derivative of soap class emulsifying agent, Soxylat A 25-7, described higher alcohols also plays the effect of tensio-active agent in emulsifiable paste simultaneously.
The composition of the above pharmaceutical composition is not limited only to described in technical solution of the present invention, also comprise any composition that may be used for the pharmaceutical excipient of above-mentioned preparation, the composition of described pharmaceutical excipient can with reference to " pharmaceutics " (the 5th edition, Cui Fude, within 2003, publish, People's Health Publisher) in disclosed scheme.
Compared with glucocorticosteroid of the prior art, new formula (I) compound provided by the invention, beyond thought effect is created when inhalation, be used alone with glucocorticosteroid, N-acetylcystein and compare, curative effect all increases, and is conducive to reducing dosage, is conducive at life-time service, meanwhile, new formula (I) compound provided by the invention also can be prepared into Formulations for systemic administration preparation (as oral preparations) and uses for whole body.
Embodiment:
Pillar layer separation method in the present invention:
The minimum 70cm of length of chromatographic column, inner filling 254-silica gel, and will the organism be separated be needed entirely to be dissolved in minimum chloroform: methyl alcohol=1: in 1, with minimum 254-silica gel, this solution is absorbed the top being placed on silica gel in chromatography column, use moving phase wash-out, connect with several 10ml test tubes the solution obtained through column chromatography under chromatography column, coutroi velocity is 10ml/3min, the solution HPLC of each test tube is analyzed, test tube solution identical for retention time merged and carries out recrystallization, obtaining corresponding product.Elution flow adopts chloroform mutually: methyl alcohol=1: the mixed solvent of 3 (volume ratios).
Determine the method for target compound: by different products respectively refining laggard row element analysis and
13c-NMR analyzes, with the chemical structure of deterministic compound
Analytical instrument: HP1084B liquid chromatograph, HP79850BLC terminal and UV detector
Column material: HypersilC18,5 μm, 150 × 4.6mm
Determined wavelength: 242nm
Moving phase: methyl alcohol: water=5.5: 4.5
Column temperature: 45 DEG C
Flow velocity: about 1.2ml/ divides
DMF is DMF
D90 is the particle diameter corresponding when reaching 90% of the cumulative particle sizes distribution number of a sample.
The pregnant steroid of embodiment 1-Isosorbide-5-Nitrae-diene-3,20-diketone-11,17,21-trihydroxy--21-(N-acetyl)-Cys ester
By pregnant steroid-1,4-diene-3,20-diketone-11,17,21-trihydroxy-(II-1) 10mmol puts in 80mlDMF, be warming up to 60 DEG C, add 0.30g4-dimethyl aminopyridine, 4g dicyclohexylcarbodiimide, N-acetylcystein 15mmol, stir and carry out esterification, Temperature fall under room temperature after 30 minutes, react 24 hours under room temperature, reaction is complete to be diluted in frozen water, filters after regulating pH value neutrality, dry after rinsing with water, product pillar layer separation, recrystallizing methanol obtains title compound 4.8mmol.
Ultimate analysis: C, 61.53; H, 6.99; N, 2.79; O, 22.31; S, 6.38
13C-NMR：
| C position | 11 | 17 | 20 | 21 | 22 | 23 | 24 | 25 | 26 |
| Numerical value | 69.4 | 90.1 | 207.5 | 68.4 | 172.1 | 53.1 | 26.9 | 179.6 | 23.3 |
The pregnant steroid of embodiment 2-Isosorbide-5-Nitrae-diene-3,20-diketone-11 β, 17,21-trihydroxy--21-(N-acetyl)-Cys ester-9 α-fluoro-16 Beta-methyls
By pregnant steroid-1,4-diene-3,20-diketone-11 β, 17,21-trihydroxy--9 α-fluoro-16 Beta-methyls (II-2) 10mmol puts in 100mlDMF, be warming up to 60 DEG C, add 0.33g4-dimethyl aminopyridine, 4g dicyclohexylcarbodiimide, N-acetylcystein 15mmol, stir and carry out esterification, Temperature fall under room temperature after 30 minutes, react 24 hours under room temperature, reaction is complete to be diluted in frozen water, filters after regulating pH value neutrality, dry after rinsing with water, product pillar layer separation, recrystallizing methanol obtains title compound 5.3mmol.
Ultimate analysis: C, 60.18; H, 6.77; F, 3.54; N, 2.63; O, 20.90; S, 5.98
13C-NMR：
| C position | 11 | 17 | 20 | 21 | 22 | 23 | 24 | 25 | 26 |
| Numerical value | 71.2 | 90.9 | 205.9 | 68.4 | 172.3 | 53.0 | 26.9 | 180.2 | 23.5 |
The pregnant steroid of embodiment 3-Isosorbide-5-Nitrae-diene-3,20-diketone-11 β, 17,21-trihydroxy--17-acetic ester-21-(N-acetyl)-Cys ester
By pregnant steroid-1,4-diene-3,20-diketone-11 β, 17,21-trihydroxy--17-acetic ester (II-3) 10mmol puts in 100mlDMF, be warming up to 60 DEG C, add 0.34g4-dimethyl aminopyridine, 4g dicyclohexylcarbodiimide, N-acetylcystein 15mmol, stir and carry out esterification, Temperature fall under room temperature after 30 minutes, react 24 hours under room temperature, reaction is complete to be diluted in frozen water, filters after regulating pH value neutrality, dry after rinsing with water, product pillar layer separation, recrystallizing methanol obtains title compound 5.1mmol.
Ultimate analysis: C, 61.30; H, 6.83; N, 2.56; O, 23.43; S, 5.88
13C-NMR：
| C position | 11 | 17 | 20 | 21 | 22 | 23 | 24 | 25 | 26 |
| Numerical value | 69.1 | 101.9 | 211.9 | 68.5 | 171.9 | 53.0 | 26.8 | 179.2 | 23.5 |
The pregnant steroid of embodiment 4-Isosorbide-5-Nitrae-diene-3,20-diketone-11 β, 17,21-trihydroxy--21-(N-acetyl)-Cys ester-6 Alpha-Methyl
By pregnant steroid-1,4-diene-3,20-diketone-11 β, 17,21-trihydroxy--6 Alpha-Methyl 10mmol (II-4) is put in 100mlDMF, be warming up to 60 DEG C, add 0.35g4-dimethyl aminopyridine, 4g dicyclohexylcarbodiimide, N-acetylcystein 15mmol, stir and carry out esterification, Temperature fall under room temperature after 30 minutes, react 24 hours under room temperature, reaction is complete to be diluted in frozen water, filters after regulating pH value neutrality, dry after rinsing with water, product pillar layer separation, recrystallizing methanol obtains title compound 5.7mmol.
Ultimate analysis: C, 62.40; H, 7.18; N, 2.70; O, 21.55; S, 6.17
13C-NMR：
| C position | 11 | 17 | 20 | 21 | 22 | 23 | 24 | 25 | 26 |
| Numerical value | 69.2 | 90.0 | 207.4 | 68.4 | 172.0 | 53.1 | 26.9 | 179.6 | 23.3 |
The pregnant steroid of embodiment 5-Isosorbide-5-Nitrae-diene-3,20-diketone-11 β, 17,21-trihydroxy--17-(2-furans)-manthanoate-21-(N-acetyl)-chloro-16 Alpha-Methyls of Cys ester-9-
By pregnant steroid-1, 4-diene-3, 20-diketone-11 β, 17, 21-trihydroxy--17-(2-furans)-manthanoate-9-chloro-16 Alpha-Methyls (II-5) 10mmol puts in 100mlDMF, be warming up to 60 DEG C, add 0.35g4-dimethyl aminopyridine, 4g dicyclohexylcarbodiimide, N-acetylcystein 15mmol, esterification is carried out in stirring, Temperature fall under room temperature after 30 minutes, react 24 hours under room temperature, reaction is complete to be diluted in frozen water, filter after regulating pH value neutrality, dry after rinsing with water, product pillar layer separation, recrystallizing methanol obtains title compound 5.0mmol.
Ultimate analysis: C, 59.43; H, 5.99; Cl, 5.85; N, 2.31; O, 21.15; S, 5.29
13C-NMR：
| C position | 11 | 17 | 20 | 21 | 22 | 23 | 24 | 25 | 26 |
| Numerical value | 70.4 | 100.3 | 211.4 | 67.6 | 172.1 | 53.2 | 26.9 | 179.1 | 23.3 |
The pregnant Gona-4-ene-3 of embodiment 6,20-diketone-11 β, 17,21-trihydroxy--21-(N-acetyl)-Cys ester
By pregnant Gona-4-ene-3,20-diketone-11 β, 17,21-trihydroxy-(II-6) 10mmol puts in 100mlDMF, be warming up to 60 DEG C, add 0.35g4-dimethyl aminopyridine, 4g dicyclohexylcarbodiimide, N-acetylcystein 15mmol, esterification is carried out in stirring, Temperature fall under room temperature after 30 minutes, reacts 24 hours under room temperature, and reaction is complete to be diluted in frozen water, filter after regulating pH value neutrality, dry after rinsing with water, product pillar layer separation, recrystallizing methanol obtains title compound 5.2mmol.
Ultimate analysis: C, 61.49; H, 7.36; N, 2.76; O, 22.08; S, 6.32
13C-NMR：
| C position | 11 | 17 | 20 | 21 | 22 | 23 | 24 | 25 | 26 |
| Numerical value | 68.4 | 90.0 | 207.5 | 68.3 | 172.1 | 53.1 | 26.9 | 179.6 | 23.3 |
The pregnant Gona-4-ene-3 of embodiment 7,20-diketone-11 β, 17,21-trihydroxy--17-butyric ester-21-(N-acetyl)-Cys ester
By pregnant Gona-4-ene-3,20-diketone-11 β, 17,21-trihydroxy--17-butyric ester (II-7) 10mmol puts in 100mlDMF, be warming up to 60 DEG C, add 0.35g4-dimethyl aminopyridine, 4g dicyclohexylcarbodiimide, N-acetylcystein 15mmol, esterification is carried out in stirring, Temperature fall under room temperature after 30 minutes, reacts 24 hours under room temperature, and reaction is complete to be diluted in frozen water, filter after regulating pH value neutrality, dry after rinsing with water, product pillar layer separation, recrystallizing methanol obtains title compound 5.9mmol.
Ultimate analysis: C, 62.340; H, 7.51; N, 2.42; O, 22.17; S, 5.55
13C-NMR：
| C position | 11 | 17 | 20 | 21 | 22 | 23 | 24 | 25 | 26 |
| Numerical value | 68.3 | 101.5 | 211.5 | 68.4 | 172.0 | 53.1 | 26.9 | 179.4 | 23.4 |
| C position | 27 | 28 | 29 | 30 | |||||
| Numerical value | 173.9 | 36.8 | 18.5 | 13.5 |
Two hydroxyl-21-(N-the acetyl)-Cys ester-16,17-[(R) cyclohexylmethylene] two (oxygen) of the pregnant steroid of embodiment 8-Isosorbide-5-Nitrae-diene-3,20-diketone-11 β, 21-]
By pregnant steroid-1, 4-diene-3, 20-diketone-11 β, the two hydroxyl-16 of 21-, 17-[(R) cyclohexylmethylene] two (oxygen)] (II-8) 10mmol puts in 100mlDMF, be warming up to 60 DEG C, add 0.35g4-dimethyl aminopyridine, 4g dicyclohexylcarbodiimide, N-acetylcystein 15mmol, esterification is carried out in stirring, Temperature fall under room temperature after 30 minutes, react 24 hours under room temperature, reaction is complete to be diluted in frozen water, filter after regulating pH value neutrality, dry after rinsing with water, product pillar layer separation, recrystallizing methanol obtains title compound 4.1mmol.
Ultimate analysis: C, 64.35; H, 7.37; N, 2.27; O, 20.80; S, 5.22
13C-NMR：
| C position | 11 | 17 | 20 | 21 | 22 | 23 | 24 | 25 | 26 |
| Numerical value | 69.1 | 100.9 | 203.9 | 68.8 | 172.5 | 53.2 | 26.8 | 179.3 | 23.4 |
| C position | 27 | 28 | 29 | 30 | 31 | 32 | 33 | 16 | |
| Numerical value | 101.6 | 36.4 | 24.3 | 26.2 | 26.0 | 26.2 | 24.3 | 84.9 |
The pregnant steroid of embodiment 9-Isosorbide-5-Nitrae-diene-3,20-diketone-11 β, 21-two hydroxyl-21-(N-acetyl)-Cys ester-16,17-[(R, S) propylmethylene] two (oxygen)]
By pregnant steroid-1, 4-diene-3, 20-diketone-11 β, the two hydroxyl-16 of 21-, 17-[(R, S) propylmethylene] two (oxygen)] (II-9) 10mmol puts in 100mlDMF, be warming up to 60 DEG C, add 0.35g4-dimethyl aminopyridine, 4g dicyclohexylcarbodiimide, N-acetylcystein 15mmol, esterification is carried out in stirring, Temperature fall under room temperature after 30 minutes, react 24 hours under room temperature, reaction is complete to be diluted in frozen water, filter after regulating pH value neutrality, dry after rinsing with water, product pillar layer separation, recrystallizing methanol obtains title compound 4.4mmol.
Ultimate analysis: C, 62.59; H, 7.18; N, 2.43; O, 22.23; S, 5.57
13C-NMR：
| C position | 11 | 17 | 20 | 21 | 22 | 23 | 24 | 25 | 26 |
| Numerical value | 69.2 | 100.8 | 203.8 | 68.8 | 172.5 | 53.3 | 26.7 | 179.2 | 23.3 |
| C position | 27 | 28 | 29 | 30 | 16 | ||||
| Numerical value | 98.1 | 36.6 | 13.2 | 14.5 | 84.5 |
Two hydroxyl-the 21-(N-acetyl) of the pregnant steroid of embodiment 10-Isosorbide-5-Nitrae-diene-3,20-diketone-11 β, 21--Cys ester-16 α, 17-[(methyl ethylidene) two (oxygen)].
By pregnant steroid-1, 4-diene-3, 20-diketone-11 β, the two hydroxyl-16 of 21-, 17-[(methyl ethylidene) two (oxygen)] 10mmol puts in 100mlDMF, be warming up to 60 DEG C, add 0.35g4-dimethyl aminopyridine, 4g dicyclohexylcarbodiimide, N-acetylcystein 15mmol, esterification is carried out in stirring, Temperature fall under room temperature after 30 minutes, react 24 hours under room temperature, reaction is complete to be diluted in frozen water, filter after regulating pH value neutrality, dry after rinsing with water, product pillar layer separation, recrystallizing methanol obtains title compound 4.4mmol.
Ultimate analysis: C, 61.99; H, 7.00; N, 2.49; O, 22.80; S, 5.72
13C-NMR：
| C position | 11 | 17 | 20 | 21 | 22 | 23 | 24 | 25 | 26 |
| Numerical value | 69.0 | 97.5 | 203.6 | 68.7 | 172.0 | 53.1 | 26.7 | 179.1 | 23.3 |
| C position | 27 | 28 | 29 | 16 | |||||
| Numerical value | 111.9 | 26.6 | 26.6 | 81.8 |
Example of formulations 1
Activeconstituents
Pregnant steroid-Isosorbide-5-Nitrae-diene-3,20-diketone-11,17,21-trihydroxy--21-(N-acetyl)-Cys ester (I-1) 100.0g auxiliary material:
Activeconstituents, pregelatinized Starch, Microcrystalline Cellulose, lactose is taken according to recipe quantity, cross 60-100 mesh sieve respectively, after mixing, add polyvidone aqueous solution softwood processed in right amount, 20 mesh sieve particles, drying, whole grain, adds, Magnesium Stearate, carboxymethylstach sodium, micropowder silica gel, mixes rear employing and is applicable to punch die and is pressed into tablet.
Example of formulations 2
Activeconstituents:
Pregnant steroid-Isosorbide-5-Nitrae-diene-3,20-diketone-11 β, 17,21-trihydroxy--21-(N-acetyl)-Cys ester-9 α-fluoro-16 Beta-methyls (I-2) 5.0g
Auxiliary material:
Activeconstituents, Microcrystalline Cellulose, lactose are crossed 80 mesh sieves respectively, after mixing, adds the Magnesium Stearate of recipe quantity, mix in rear loading suitable capsule and get final product.
Example of formulations 3
Activeconstituents: pregnant steroid-Isosorbide-5-Nitrae-diene-3,20-diketone-11 β, 17,21-trihydroxy--17-acetic ester-21-(N-acetyl)-Cys ester (I-3) 100.0g
Auxiliary material:
Activeconstituents, pregelatinized Starch, Microcrystalline Cellulose, lactose is taken according to recipe quantity, cross 60-100 mesh sieve respectively, after mixing, add polyvidone aqueous solution softwood processed in right amount, 20 mesh sieve particles, drying, whole grain, adds, Magnesium Stearate, carboxymethylstach sodium, micropowder silica gel, mixes rear employing and is applicable to punch die and is pressed into tablet.
Example of formulations 4
Activeconstituents: pregnant steroid-Isosorbide-5-Nitrae-diene-3,20-diketone-11 β, 17,21-trihydroxy--21-(N-acetyl)-Cys ester-6 Alpha-Methyl (I-4) 40.0g
Auxiliary material:
Activeconstituents, pregelatinized Starch, Microcrystalline Cellulose, lactose is taken according to recipe quantity, cross 60-100 mesh sieve respectively, after mixing, add polyvidone aqueous solution softwood processed in right amount, 20 mesh sieve particles, drying, whole grain, adds, Magnesium Stearate, carboxymethylstach sodium, micropowder silica gel, mixes rear employing and is applicable to punch die and is pressed into tablet.
Example of formulations 5
Pregnant steroid-Isosorbide-5-Nitrae-diene-3,20-diketone-11 β, two hydroxyl-the 21-(N-acetyl) of 21--Cys ester-16 α, 17-[(methyl ethylidene) two (oxygen)] (I-5) 2g, white vaseline 30g, stearyl alcohol 120g, glyceryl monostearate 20g, whiteruss 10g, peregal A-2050g, glycerine 120g, EDTA-2Na2g, phenylcarbinol 5g, hydroxypropylcellulose, 3g, purified water 639g
By above proportioning accurate weighing, moisture is two portions: 380g and 259g, gets ready, and emulsifiable paste process for preparation is as follows:
(1) oil phase preparation:, get white vaseline, stearyl alcohol, glyceryl monostearate, whiteruss, peregal A-20 is placed in container, is heated to melting, and temperature remains on 72 ± 2 DEG C;
(2) aqueous phase preparation: by above proportioning accurate weighing, get glycerine, EDTA-2Na and 380g water is placed in container, heating, temperature remains on 70 ± 2 DEG C;
(3) phase is closed: poured into by the oil phase that step (1) is prepared in the aqueous phase that step (2) prepares, stir, maintain the temperature at 75 ± 2 DEG C, add phenylcarbinol;
(4) main ingredient suspension: activeconstituents, 259g water, polyvinylpyrrolidone are placed in container, stirring or ultrasonic, obtains main ingredient suspension;
(5) control temperature is at 60 ± 2 DEG C, and added by the main ingredient suspension obtained in step (4) in the solution that step (3) obtains, limit edged stirs, and is cooled to cream.Obtain emulsifiable paste 1kg.
Example of formulations 6
Activeconstituents:
) pregnant steroid-Isosorbide-5-Nitrae-diene-3,20-diketone-11 β, 17,21-trihydroxy--17-(2-furans)-chloro-16 Alpha-Methyl 10.0g of manthanoate-21-(N-acetyl)-Cys ester-9-
Auxiliary material:
Activeconstituents, pregelatinized Starch, Microcrystalline Cellulose, lactose is taken according to recipe quantity, cross 60-100 mesh sieve respectively, after mixing, add polyvidone aqueous solution softwood processed in right amount, 20 mesh sieve particles, drying, whole grain, adds, Magnesium Stearate, carboxymethylstach sodium, micropowder silica gel, mixes rear employing and is applicable to punch die and is pressed into tablet.
Example of formulations 7
Activeconstituents:
Pregnant Gona-4-ene-3,20-diketone-11 β, 17,21-trihydroxy--21-(N-acetyl)-Cys ester (I-6) 200.0g
Auxiliary material:
Activeconstituents, pregelatinized Starch, Microcrystalline Cellulose, lactose is taken according to recipe quantity, cross 60-100 mesh sieve respectively, after mixing, add polyvidone aqueous solution softwood processed in right amount, 20 mesh sieve particles, drying, whole grain, adds, Magnesium Stearate, carboxymethylstach sodium, micropowder silica gel, mixes rear employing and is applicable to punch die and is pressed into tablet.
Example of formulations 8
Activeconstituents:
Pregnant Gona-4-ene-3,20-diketone-11 β, 17,21-trihydroxy--17-butyric ester-21-(N-acetyl)-Cys ester (I-7) 50.0g
Auxiliary material:
Activeconstituents, pregelatinized Starch, Microcrystalline Cellulose, lactose is taken according to recipe quantity, cross 60-100 mesh sieve respectively, after mixing, add polyvidone aqueous solution softwood processed in right amount, 20 mesh sieve particles, drying, whole grain, adds, Magnesium Stearate, carboxymethylstach sodium, micropowder silica gel, mixes rear employing and is applicable to punch die and is pressed into tablet.
Example of formulations 9-1
Activeconstituents:
Pregnant steroid-1,4-diene-3, two hydroxyl-21-(N-the acetyl)-Cys ester-16,17-[(R) cyclohexylmethylene] two (oxygen) of 20-diketone-11 β, 21-] (I-8) (particle diameter is the micro mist of D90≤5 μm) 100mg
Auxiliary material:
Lactose (particle diameter is D90 at the micro mist of 30 μm) 20g
Magnesium Stearate 0.5g
Make 1000 altogether
Activeconstituents, lactose are crossed 80 mesh sieves respectively, after mixing, adds the Magnesium Stearate of recipe quantity, mix in rear loading suitable capsule and get final product.
Example of formulations 9-2
Activeconstituents:
Pregnant steroid-1, two hydroxyl-21-(N-the acetyl)-Cys ester-16 of 4-diene-3,20-diketone-11 β, 21-, 17-[(R, S) propylmethylene] two (oxygen)] (I-9) (particle diameter is the micro mist of D90≤5 μm) 100mg
Auxiliary material:
Lactose (particle diameter is D90 at the micro mist of 30 μm) 20g
Magnesium Stearate 0.5g
Make 1000 altogether
Activeconstituents, lactose are crossed 80 mesh sieves respectively, after mixing, adds the Magnesium Stearate of recipe quantity, mix in rear loading suitable capsule and get final product.
Example of formulations 9-3
Activeconstituents:
Pregnant steroid-1,4-diene-3,20-diketone-11 β, 17,21-trihydroxy--17-(2-furans)-chloro-16 Alpha-Methyls (I-5) of manthanoate-21-(N-acetyl)-Cys ester-9-(particle diameter is the micro mist of D90≤5 μm) 100mg
Auxiliary material:
Lactose (particle diameter is D90 at the micro mist of 30 μm) 20g
Magnesium Stearate 0.5g
Make 1000 altogether
Activeconstituents, lactose are crossed 80 mesh sieves respectively, after mixing, adds the Magnesium Stearate of recipe quantity, mix in rear loading suitable capsule and get final product.
Preparations. Control embodiment 1
Activeconstituents:
Ciclesonide (particle diameter is the micro mist of D90≤5 μm) 100mg
Auxiliary material:
Lactose (particle diameter is D90 at the micro mist of 30 μm) 20g
Magnesium Stearate 0.5g
Make 1000 altogether
Activeconstituents, lactose are crossed 80 mesh sieves respectively, after mixing, adds the Magnesium Stearate of recipe quantity, mix in rear loading suitable capsule and get final product.
Preparations. Control embodiment 2
Activeconstituents:
Budesonide (particle diameter is the micro mist of D90≤5 μm) 100mg
Auxiliary material:
Lactose (particle diameter is D90 at the micro mist of 30 μm) 20g
Magnesium Stearate 0.5g
Make 1000 altogether
Activeconstituents, lactose are crossed 80 mesh sieves respectively, after mixing, adds the Magnesium Stearate of recipe quantity, mix in rear loading suitable capsule and get final product.
Preparations. Control embodiment 3
Activeconstituents:
Furoic acid momisone (particle diameter is the micro mist of D90≤5 μm) 100mg
Auxiliary material:
Lactose (particle diameter is D90 at the micro mist of 30 μm) 20g
Magnesium Stearate 0.5g
Make 1000 altogether
Activeconstituents, lactose are crossed 80 mesh sieves respectively, after mixing, adds the Magnesium Stearate of recipe quantity, mix in rear loading suitable capsule and get final product.
Preparations. Control embodiment 4
Activeconstituents:
N-acetylcystein (particle diameter is the micro mist of D90≤5 μm) 100mg
Auxiliary material:
Lactose (particle diameter is D90 at the micro mist of 30 μm) 20g
Magnesium Stearate 0.5g
Make 1000 altogether
Activeconstituents, lactose are crossed 80 mesh sieves respectively, after mixing, adds the Magnesium Stearate of recipe quantity, mix in rear loading suitable capsule and get final product.
Pharmacological Examples 1
Comparative formulations embodiment 9-1 to 9-3, preparations. Control embodiment 1-4 suck the impact of histamine induced rat asthma attack
1. laboratory animal: choose healthy infant rats, body weight 180 ~ 220g, male and female are not limit.
2 laboratory apparatuss: the bell glass of air compressor, aerosol shower nozzle, mercury manometer, base, 4L
3 experimental drugs: 2% Ovisot, 0.1% histamine phosphate, example of formulations 9-1 (A group), 9-2 (B group), 9-3 (C group), preparations. Control embodiment 1 (D group), preparations. Control embodiment 2 (E group), preparations. Control embodiment 3 (F group), preparations. Control embodiment 4 (G group)
4 data processing: the independent samples t-test adopting SAS system.
Three, experimental technique
Choose infant rats, male and female, body weight is 180-220g, puts into the lens of about 5 liters, sprays into 2% Ovisot and 0.1% histamine phosphate's volume mixed solution 15 second with the pressure of 400mmHg.After spraying stops, observing the asthmatic latent period (namely asthma occur, breathe be the devil, until twitch time of falling) of rat, draw and breathe heavily the rat that the latent phase is greater than 120 seconds and will not select.Learn from else's experience and measure the qualified rat 120 of asthmatic latent period, 6 groups are divided into by asthmatic latent period stochastic averagina, give A-G group medicine respectively, after inhalation 30min, spraying gives 0.25% 2 hydrochloric acid histamine respectively, observes the change (draw animal when breathing heavily and do not occur in 6 minutes that the person of falling take asthmatic latent period as 360s) of asthmatic latent period and tic incidence before and after drug
Four, experimental result: a few treated animal generation asthma until the time of falling of twitching have difference, in table 1:
Table 1 sucks the impact of induced asthma outbreak to histamine phosphate's spraying
(n＝20，
)
Shown by this experiment, compound of the present invention all can the asthmatic latent period that brought out by histamine phosphate of significant prolongation rat compared with control group, (P < 0.01), and under Isodose, to use after the administration of asthmatic latent period and contrast D-G group after the administration of the A-C tetra-groups of the compounds of this invention asthmatic latent period respectively compared with, all there is significance (P < 0.05), illustrating that the present invention provided by the invention has more significant effect when treating asthma compared with the medicine of existing approximate construction thus.
Pharmacological Examples 2 sputum secretion test (phenol red method)
1. laboratory animal: choose Kunming mouse, male and female are not limit.
2 laboratory apparatuss: the bell glass of air compressor, aerosol shower nozzle, mercury manometer, base, 4L
3 experimental drugs: example of formulations 9-1 (A group), 9-2 (B group), 9-3 (C group), preparations. Control embodiment 1 (D group), preparations. Control embodiment 2 (E group), preparations. Control embodiment 3 (F group), preparations. Control embodiment 4 (G group)
4 data processing: the independent samples t-test adopting SAS system.
Three, experimental technique
Kunming mouse 160, male and female half and half, be divided into 8 groups at random, namely blank group, A-G group, then give A-G group medicine respectively, inhalation 30min, blank group gives the micro mist lactose that 0.8mgD90 particle diameter is 30 μm, every day 1 time, successive administration 3d, after last administration 0.5h, by abdominal injection 0.5% phenol red solution 0.5mL/ only.After 30min, cervical dislocation puts to death mouse, facing upward position is fixed on operation plate, cut off throat skin, be separated tracheae, peel off tracheae surrounding tissue, cut one section of tracheae to tracheae bifurcation from thyroid cartilage, put in the test tube filling 3mL physiological saline and rinse, then add 5% sodium hydrogen carbonate solution 0.1mL.By centrifugal for lavage of trachea liquid, get supernatant liquor, measure OD value (optical density(OD)) OD value height by microplate reader (wavelength 570nm) and represent that in discharge sputum, phenol red total amount is higher, also show that sputum discharge total amount is higher, the index that eliminates the phlegm is each experimental group OD value and the blank ratio organized.
Shown by this experiment, compound of the present invention all significantly can increase the eliminating of mouse sputum compared with control group D-F, (P < 0.01), and under Isodose, after using A-C tri-groups of administrations of the compounds of this invention, expectoration amount is compared with after the administration of contrast D-F tri-groups, all there is significance (P < 0.05), but expectoration amount is not enough to some extent compared with control group G after using A-C tri-groups of administrations of the compounds of this invention, illustrate thus compound provided by the invention compared with the medicine of existing approximate construction in sputum discharge time have more significant effect.
Claims (43)
1. a formula (
) compound,
Formula (
)
R2=OH ,-OCOR6, R6 is alkyl within six carbon or furyl;
R3=H, OH or methyl;
R2、R3=
；
R4=H or halogen;
R5=H, halogen or methyl;
1,2 represented by dotted arrows singly-bounds or double bonds.
2. formula as claimed in claim 1 (
) compound, it is characterized in that
R2=-OCOR6, R6 are alkyl within three carbon or 2-furyl;
R3=H or methyl;
R2、R3=
；
R4=H or F;
R5=H, F or methyl;
1,2 represented by dotted arrows singly-bounds or double bonds.
3. compound as claimed in claim 1, is characterized in that
R2=-OCOR6, R6 are methyl or 2-furyl;
R3=H；
R2、R3=
；
R4=H or F;
R5=H or methyl;
1,2 represented by dotted arrows singly-bounds or double bonds.
4. formula as claimed in claim 1 (
) compound, it is characterized in that
Wherein
R2=-OCOR6, R6 are methyl;
R3=H；
R2、R3=
；
R4=H or F;
R5=H or methyl;
1,2 represented by dotted arrows double bonds.
5. formula as claimed in claim 1 (
) compound is pregnant steroid-1, 4-diene-3, 20-diketone-11 β, 17, 21-trihydroxy--21-(N-acetyl)-pregnant steroid-1 of Cys ester, 4-diene-3, 20-diketone-11 β, 17, 21-trihydroxy--21-(N-acetyl)-Cys ester-9 α-pregnant steroid-1 of fluoro-16 Beta-methyl, 4-diene-3, 20-diketone-11 β, 17, 21-trihydroxy--17-acetic ester-21-(N-acetyl)-pregnant steroid-1 of Cys ester, 4-diene-3, 20-diketone-11 β, 17, 21-trihydroxy--21-(N-acetyl)-pregnant steroid-1 of Cys ester-6 Alpha-Methyl, 4-diene-3, 20-diketone-11 β, 17, 21-trihydroxy--17-(2-furans)-manthanoate-21-(N-acetyl)-pregnant Gona-4-ene-3 of chloro-16 Alpha-Methyl of Cys ester-9-, 20-diketone-11 β, 17, 21-trihydroxy--21-(N-acetyl)-pregnant Gona-4-ene-3 of Cys ester, 20-diketone-11 β, 17, 21-trihydroxy--17-butyric ester-21-(N-acetyl)-pregnant steroid-1 of Cys ester, 4-diene-3, 20-diketone-11 β, two hydroxyl-21-(N-the acetyl)-Cys ester-16 of 21-, 17-[(R) cyclohexylmethylene] two (oxygen)] pregnant steroid-1, 4-diene-3, 20-diketone-11 β, two hydroxyl-21-(N-the acetyl)-Cys ester-16 of 21-, 17-[(R, S) propylmethylene] two (oxygen)] pregnant steroid-1, 4-diene-3, 20-diketone-11 β, two hydroxyl-21-(N-acetyl)-Cys ester-16 α of 21-, 17-[(methyl ethylidene) two (oxygen)].
6. as claimed in claim 1 formula (
) compound is:
Pregnant steroid-1,4-diene-3,20-diketone-11 β, two hydroxyl-21-(N-the acetyl)-Cys ester-16 of 21-, 17-[(R) cyclohexylmethylene] two (oxygen)] pregnant steroid-1,4-diene-3,20-diketone-11 β, 21-two hydroxyl-21-(N-acetyl)-Cys ester-16,17-[(R, S) propylmethylene] two (oxygen)] pregnant steroid-1,4-diene-3, two hydroxyl-the 21-(N-acetyl) of 20-diketone-11 β, 21--Cys ester-16 α, 17-[(methyl ethylidene) two (oxygen)].
Formula as described in 7. as arbitrary in claim 1-6 (
) synthetic method of compound, its synthetic method be by formula II compound dissolution in DMF, be warming up to 60 DEG C, add 4-dimethylaminopyridine, dicyclohexylcarbodiimide, N-acetylcystein, esterification is carried out in stirring, after 30 minutes Temperature fall under room temperature, reacts under room temperature, reaction is complete to be diluted in frozen water, filter after regulating pH value neutrality, dry after rinsing with water, obtain formula (
) compound,
formula II compound N-acetyl-Cys formula (
) compound.
Formula as described in 8. as arbitrary in claim 1-6 (
) application of compound in preparation treatment anti-inflammatory drugs.
Formula as described in 9. as arbitrary in claim 1-6 (
) application of compound in preparation treatment airway inflammation medicine.
Formula as described in 10. as arbitrary in claim 1-6 (
) application of compound in preparation treatment eye inflammation medicine.
11. as arbitrary in claim 1-6 as described in formula (
) application of compound in preparation treatment skin inflammation medicine.
12. as arbitrary in claim 1-6 as described in formula (
) application of compound in preparation treatment inflammatory bowel medicine.
13. as arbitrary in claim 1-6 as described in formula (
) application of compound in preparation autoimmune disease medicine.
14. 1 kinds of pharmaceutical compositions, is characterized in that containing any one or a few the compound described in the formula as claimed in claim 1 (I) as activeconstituents and one or more pharmaceutical excipients.
15. pharmaceutical compositions as claimed in claim 14, is characterized in that described composition is the pharmaceutical composition being applicable to Formulations for systemic administration or topical.
16. pharmaceutical compositions as claimed in claim 14, the composition being applicable to Formulations for systemic administration described in it is characterized in that is the pharmaceutical composition of oral administration or drug administration by injection.
17. pharmaceutical compositions as claimed in claim 15, is characterized in that the pharmaceutical composition of described topical is inhalation, nasal formulations, external preparation, orally administering preparation, ophthalmic preparation and liposome or microcapsule formulation.
18. pharmaceutical compositions as claimed in claim 16, is characterized in that described composition is inhalation, nasal formulations and external preparation.
19. pharmaceutical compositions as claimed in claim 17, is characterized in that described inhalation is the one of aerosol, Foradil Aerolizer formoterol fumarate, sprays.
20. pharmaceutical compositions as claimed in claim 19, when it is characterized in that described pharmaceutical composition is aerosol, described pharmaceutical excipient comprises the pharmaceutically useful propellent and one or more low volatility component that are applicable to aerosol.
21. pharmaceutical compositions as claimed in claim 20, is characterized in that described propellent is one or more in fluorohydrocarbon compounds.
22. pharmaceutical compositions as claimed in claim 20, is characterized in that described propellent is one in HFA 134a and 1,1,1.2,3,3,3-heptafluoro-propane or its combination.
23. pharmaceutical compositions as claimed in claim 20, is characterized in that described propellent is HFA134a.
24. pharmaceutical compositions as claimed in claim 20, is characterized in that low volatility component is one or more in solvent, latent solvent, suspending agent, stablizer, correctives, sanitas.
25. pharmaceutical compositions as claimed in claim 24, is characterized in that described latent solvent is ethanol.
26. pharmaceutical compositions as claimed in claim 24, is characterized in that described solvent is glycerine.
27. as pharmaceutical composition as described in arbitrary in claim 24,25, and when it is characterized in that making aerosol, filling a prescription is: active component content is 1-8mg/ml; Ethanol weight percent content as latent solvent is 5-20%, and the propellent of surplus.
28. pharmaceutical compositions as claimed in claim 19, when it is characterized in that making Foradil Aerolizer formoterol fumarate, described powder inhalation is made up of dried powder, and described excipient substance comprises carrier and additives.
29. pharmaceutical compositions as claimed in claim 28, described carrier is one or more in carbohydrate carrier, amino acid.
30. pharmaceutical compositions as claimed in claim 29, described amino acid comprises glycine, α-amino-isovaleric acid, and described carbohydrate comprises monose, disaccharides and/or its derived carbohydrate.
31. pharmaceutical compositions as claimed in claim 30, described monose comprises N.F,USP MANNITOL, fructose, glucose, described disaccharides comprises maltose, trehalose, cellobiose, lactose, sucrose, and described derived carbohydrate comprises eight cellulose acetate two sugar esters, sucrose octa-acetate, eight acetic acid lactose esters, five acetic acid glucose esters, six acetic acid Nitranitols and eight acetic acid marine alga sugar esters.
32. pharmaceutical compositions as claimed in claim 31, as carrier in described derived carbohydrate is eight acetic acid-D-cellobiose esters.
33. pharmaceutical compositions as claimed in claim 29, is characterized in that the preferred lactose of described carrier.
34. pharmaceutical compositions as claimed in claim 33, is characterized in that described lactose is alpha-lactose monohydrate, β-lactose hydrous, one or more in amorphous spray-dried lactose, crystallizing and drying lactose.
35. pharmaceutical compositions as claimed in claim 33, is characterized in that the preferred crystallizing and drying lactose of described lactose.
36. pharmaceutical composition as claimed in claim 28, the additives described in its feature contain one or more in tensio-active agent, lubricant, static inhibitor.
37. pharmaceutical compositions as claimed in claim 36, the preferred poloxamer of tensio-active agent described in its feature, the weight ratio of activeconstituents and poloxamer is 1:0.01 ~ 5.
38. pharmaceutical compositions as claimed in claim 36, it is characterized in that described lubricant is one or more in Magnesium Stearate, micropowder silica gel, talcum powder, consumption is 0.01% ~ 1% of carrier micropowder weight.
39. pharmaceutical compositions as claimed in claim 28, is characterized in that the summation of described activeconstituents and the weight ratio of carrier are 1:10 ~ 1000.
40. pharmaceutical compositions as claimed in claim 28, is characterized in that the summation of described activeconstituents and the weight ratio of carrier are 1:10 ~ 200.
41. as arbitrary in claim 19 as described in pharmaceutical composition, it is characterized in that when being prepared into Foradil Aerolizer formoterol fumarate can the packaged of single or multiple dosage, and adopt the mode packing of capsule, each capsule contains the above-mentioned powder inhalation of 5-40mg.
42. pharmaceutical compositions as claimed in claim 41, is characterized in that each capsule contains the above-mentioned powder inhalation of 10-30mg.
43. pharmaceutical compositions as claimed in claim 15, is characterized in that the pharmaceutical composition of described topical is for local cavity preparation.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201110184121.2A CN102850426B (en) | 2011-07-01 | 2011-07-01 | A kind of 21 is the glucocorticosteroid of N-acetylcystein ester |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
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