CN102079769A - Cyclopropyl pregnene compound and application thereof - Google Patents
Cyclopropyl pregnene compound and application thereof Download PDFInfo
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- CN102079769A CN102079769A CN2009102287912A CN200910228791A CN102079769A CN 102079769 A CN102079769 A CN 102079769A CN 2009102287912 A CN2009102287912 A CN 2009102287912A CN 200910228791 A CN200910228791 A CN 200910228791A CN 102079769 A CN102079769 A CN 102079769A
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- 0 C[C@](C[C@@]1O)(C(CC2)C(CC3)C1[C@@](C)(C=C1)C3=CC1=O)[C@]2(C(C*)=O)OC(C1CC1)=O Chemical compound C[C@](C[C@@]1O)(C(CC2)C(CC3)C1[C@@](C)(C=C1)C3=CC1=O)[C@]2(C(C*)=O)OC(C1CC1)=O 0.000 description 1
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Abstract
The invention discloses a cyclopropyl pregnene compound and application thereof, and discloses a novel adrenocortical hormone compound shown in a formula (I), a medicine composition containing the compound shown in the formula (I) as an active component and one or more pharmaceutic adjuvants, and application of the compound shown in the formula (I) or physiologically acceptable salt or solvate thereof as a medicine for treating of the diseases of mammal especially human, especially local inflammation.
Description
Invention field
The present invention relates to a kind of ring propyl ester pregnane compound glucocoricoid and uses thereof.The present invention also relates to contain the preparation of medicinal preparations and this compound of this compound, particularly to the treatment of inflammatory diseases, allergic disease, anaphylactic disease.
Background technology:
It is well-known that glucocorticosteroid has antiinflammatory property, and be widely used in the treatment of struvite disorder or diseases associated with inflammation such as asthma, rhinitis, eczema etc., play the effect of relief of symptoms, in these treatment of diseases, often need long-term prescription, so also can cause the various untoward reactions of whole body, common untoward reaction is osteoporosis and vertebral compression fracture, substance metabolism and water and salt metabolic disturbance, cataract and glaucoma for example.In order to reduce the untoward reaction of glucocorticosteroid, scientist constantly seeks the strong but less glucocorticosteroid of systemic adverse reactions of local action.
In order to reduce adverse drug reaction, the mankind work out prodrug gradually, and prodrug (pro drug) principle means with chemical process activated former medicine is transformed into the non-activity derivative, discharges former medicine and bring into play curative effect through enzymatic or non-enzymatic reaction in vivo.The basic structure that keeps medicine, only in some functional group, make the method that certain chemical structure changes, if being called chemical structure modifies. the compound that medicine obtains after modifying through chemical structure, there is not or seldom has an activity external, effect by enzyme in organism or human body is converted into original medicine again when bringing into play drug effect, then becoming original medicine is parent drug, and the compound that obtains after the modification is a prodrug, is called for short prodrug.
(2006 (1): 55-58) " the prodrug design has become an important directions of pharmaceutical chemistry development to bibliographical information for the progress of prodrug, world's clinical medicine.By chemical process carrier molecule is connected with former medicine, can not only increases the absorption of medicine, and can also improve medicine selectivity in vivo, so it also can regard a kind of carrier prodrug as.The correct selection of carrier molecule is depended in the success of prodrug design to a great extent, and the development of carrier is constantly promoting the development of prodrug.Relying on the prodrug design of carrier molecule progress and using to make prodrug play an increasingly important role in the pharmaceutical chemistry field." by glucocorticosteroid has been carried out the number of chemical modification, for example 21 of glucocorticosteroids or 17 are carried out esterification, can form the prodrug of corresponding different esters.Though the structure of ester seems similar, but different esters for the influence of curative effect and untoward reaction be have very huge different, for example among the patent CN01816662.8 17 furoates specific activity parent compound in vitro tests of Instructions Page 2 explanation fluticasone low＞1000 times, fast 5 times of the acid that is converted into non-activity in vivo than corresponding propionic ester, this will effectively improve safety curve; The Wang Changzheng report (sucks the characteristic of hormone and the validity and the security of treatment, " China breathes and the critical illness monitoring magazine ", 2004 31 phases of volume, 60-62,21) furoic acid momisone is the ICS of up-to-date release, its steroid nucleus parent ring structure is similar to beclometasone, and difference replaces the dipropionic acid structure of BDP (beclometasone) with the furoate group on the D ring, be one of the strongest ICS of present anti-inflammatory activity; On this medicine of ciclesonide, similar embodiment is arranged also in addition; as document (Kaliner MA.Pharmacologic characteristics and adrenal suppression with newer inhaledcorticosteroids:A comparison of ciclesonide and fluticasone propionate[J] .Clin Ther; 20o6; 28 (3): mention ciclesonide 319-331.) and belong to prodrug; have only through inhaling to be converted into 21 of active metabolites by esterase effect hydrolysis after the people arrives lung and to take off isobutyryl ciclesonide (promptly removing 21 isobutyrates), could finally bring into play anti-inflammatory effect in conjunction with glucocorticoid receptor.Lung's activating property of ciclesonide, activity form take off isobutyryl ciclesonide tool height receptor binding affinity and up to about 99% plasma protein binding ratio.In fact; ciclesonide with 21 isobutyrates is lower than 21 of isobutyrate with 21 and takes off the isobutyryl ciclesonide above 100 times in external activity; this just means that it only just can be activated after being inhaled into lung, untoward reaction will obviously descend.
Actual glucocorticosteroid uses in the part, widely used clinically is the prodrug with replacement formation of different esters, as treat ciclesonide, the fluticasone propionate of respiratory tract disease, treat dermopathic furoic acid momisone (Eloson), hydrocortisone butyrate (You Zhuoer), dexamethasone acetate, furoic acid momisone of treatment rhinitis or the like.
Summary of the invention:
In order better to obtain good effect, the glucocorticosteroid prodrug that untoward reaction is little, we obtain a kind of new glucocorticosteroid by continuous research, a kind of formula (I) compound and derivative thereof, the derivative of Chinese style of the present invention (I) compound is meant the salt or the solvate of formula (I) compound, and wherein solvate comprises hydrate.In one aspect of the invention, also relate to the medicinal preparations that contains this compound and the preparation of this compound, particularly to the treatment of inflammatory diseases, allergic disease, anaphylactic disease.
A kind of formula (I) compound of novel adrenocortical hormone,
Formula (I)
Wherein
R1=H, Cl, OH or, OCOR2, R2 be six carbon with interior alkyl,
R3=H or methyl,
R4=H or halogen,
R5=H, halogen or methyl,
1,2 dotted line is represented singly-bound or two key.
Above-mentioned formula (I) compound, wherein preferred:
R1=Cl, OH or, OCOR2, R2 be six carbon with interior alkyl,
R3=H or methyl,
R4=H or F,
R5=H, F or methyl,
1,2 dotted line is represented singly-bound or two key.
Above-mentioned compound, wherein preferred:
R1=Cl, OH or, OCOR2, R2 be six carbon with interior alkyl,
R3＝H，
R4=H or F,
R5=H or methyl,
1,2 dotted line is represented singly-bound or two key.
Above-mentioned compound, wherein preferred:
R1=Cl, OH or, OCOR2, R2 be six carbon with interior alkyl,
R3＝H，
R4=H or F,
R5=H or methyl,
1,2 two key of dotted line representative.
Above-mentioned compound, wherein preferred:
Pregnant steroid-1,4-diene-3,20-diketone-11,17,21-trihydroxy--17-ethylene-acetic acid ester
Pregnant steroid-1,4-diene-3,20-diketone-11,17,21-trihydroxy--17-ethylene-acetic acid ester-9 α-fluoro-16 Beta-methyls
Pregnant steroid-1,4-diene-3,20-diketone-11,17,21-trihydroxy--17-ethylene-acetic acid ester-21-acetic ester
Pregnant steroid-1,4-diene-3,20-diketone-11,17,21-trihydroxy--17-ethylene-acetic acid ester-21-isobutyrate
Pregnant steroid-1,4-diene-3,20-diketone-11,17,21-trihydroxy--17-ethylene-acetic acid ester-21-acetic ester-6 Alpha-Methyl
Pregnant steroid-1,4-diene-3,20-diketone-11,17,21-trihydroxy--17-ethylene-acetic acid ester-21-acetic ester--9 α-fluoro-16 Beta-methyls
Pregnant steroid-1,4-diene-3,20-diketone-11,17,21-trihydroxy--17-ethylene-acetic acid ester-21-acetic ester-6 α, two fluoro-16 Beta-methyls of 9-
Pregnant steroid-1,4-diene-3,20-diketone-11, the two hydroxyls of 17--17-ethylene-acetic acid ester-9, two chloro-16 Beta-methyls of 21-
Pregnant steroid-4-alkene-3,20-diketone-11,17,21-trihydroxy--17-ethylene-acetic acid ester
Pregnant steroid-4-alkene-3,20-diketone-11,17,21-trihydroxy--17-ethylene-acetic acid ester-21 acetic ester
Pregnant steroid-4-alkene-3,20-diketone-11,17,21-trihydroxy--6 Alpha-Methyls-17-ethylene-acetic acid ester-21-isobutyrate.
Above-mentioned compound, wherein preferred:
Pregnant steroid-1,4-diene-3,20-diketone-11,17,21-trihydroxy--17-ethylene-acetic acid ester-21-acetic ester
Pregnant steroid-1,4-diene-3,20-diketone-11,17,21-trihydroxy--17-ethylene-acetic acid ester-9 α-fluoro-16 Beta-methyls
Pregnant steroid-1,4-diene-3,20-diketone-11,17,21-trihydroxy--17-ethylene-acetic acid ester-21-isobutyrate
Pregnant steroid-1,4-diene-3,20-diketone-11,17,21-trihydroxy--17-ethylene-acetic acid ester-21-acetic ester-6 Alpha-Methyl
Pregnant steroid-1,4-diene-3,20-diketone-11,17,21-trihydroxy--17-ethylene-acetic acid ester-21-acetic ester--9 α-fluoro-16 Beta-methyls
Pregnant steroid-1,4-diene-3,20-diketone-11, the two hydroxyls of 17--17-ethylene-acetic acid ester-9, two chloro-16 Beta-methyls of 21-
Pregnant steroid-4-alkene-3,20-diketone-11,17,21-trihydroxy--17-ethylene-acetic acid ester
Pregnant steroid-4-alkene-3,20-diketone-11,17,21-trihydroxy--17-ethylene-acetic acid ester-21-acid esters.
Pregnant steroid-4-alkene-3,20-diketone-11,17,21-trihydroxy--6 Alpha-Methyls-17-ethylene-acetic acid ester-21-isobutyrate.
Above-mentioned compound, wherein preferred:
R1＝OCOCHCH3CH3，
R3=H or methyl,
R4=H or halogen,
R5=H, halogen or methyl,
1,2 two key of dotted line representative.
Above-mentioned compound, wherein preferred:
R1＝OCOCHCH3CH3，，
R3＝H，
R4＝H，
R5=H or methyl,
1,2 two key of dotted line representative.
Above-mentioned formula (I) compound, the application in its feature preparation treatment inflammation medicine.
Above-mentioned formula (I) compound, the application in its feature preparation treatment respiratory tract infection disease drug.
Above-mentioned formula (I) compound, the application in its feature preparation treatment eye inflammation medicine.
Above-mentioned formula (I) compound, the application in its feature preparation treatment nosal inflammation medicine.
Above-mentioned formula (I) compound, the application in its feature preparation treatment skin inflammation medicine.
Above-mentioned formula (I) compound, the application in its feature preparation treatment osteoarthritis disease drug.
Above-mentioned formula (I) compound, the application in its feature preparation treatment osteoarthritis disease drug.
Above-mentioned formula (I) compound, its feature prepares the application in the anti-rejection medication.
A kind of pharmaceutical composition is characterized in that containing formula (I) compound and one or more pharmaceutical excipients as activeconstituents.As above-mentioned pharmaceutical composition, it is characterized in that pharmaceutical excipient can be the pharmaceutical excipient that is applicable to preparation oral preparations, injection formulations, transdermal absorption formulation, sprays, Foradil Aerolizer formoterol fumarate.As above-mentioned pharmaceutical composition, it is characterized in that pharmaceutical excipient can be the pharmaceutical excipient that is applicable to preparation oral preparations, injection formulations, transdermal absorption formulation, sprays, Foradil Aerolizer formoterol fumarate.
A kind of pharmaceutical composition, it is characterized in that by as formula (I) compound of activeconstituents, antiseptic-germicide and and one or more pharmaceutical excipients form.As above-mentioned pharmaceutical composition, it is characterized in that antiseptic-germicide is the medicine that can be used for treating dermatophytes, infectation of bacteria, pharmaceutical excipient is the excipient substance that can be used for transdermal absorption formulation.
A kind of pharmaceutical composition is characterized in that by forming as non-corticosteroids medicine and one or more pharmaceutical excipients of formula (I) compound of activeconstituents, treatment asthma and obstructive pneumonia.Above-mentioned pharmaceutical composition, the non-corticosteroids medicine that it is characterized in that treating asthma and obstructive pneumonia is the medicine of beta 2 receptor agonist, theophylline, anticholinergic agents, LTRA, mastocyte membrane stabilizer, antihistamine drug, immunomodulator class.
Acceptable salt or solvate be as the application in the medicine of treatment mammalian diseases on above formula (I) compound or its physiology, and be especially human.The preferred local inflammation of disease, for example dermatosis such as eczema, psoriasis, allergic dermatitis, neurodermatitis, rash are itched and the hypersensitivity reaction; The inflammatory diseases of nose, throat or lung such as asthma (comprising the asthma reaction that allergy causes), rhinitis (comprising spring fever), nasal polyp, chronic obstructive pulmonary disease, matter pulmonary disorder and fibrosis; Eye inflammation comprises conjunctiva and conjunctivitis; Inflammatory bowel disease such as ulcerative colitis and Crohn disease; Or autoimmune disease such as rheumatic arthritis.
Acceptable salt or solvate are used the disease of inflammatory, allergy or the preferred respiratory tract of anaphylactic disease on above formula (I) compound or its physiology in the medicine of production for treating inflammatory, allergy or anaphylactic disease.
A kind of medicinal compositions, said composition comprise above each formula (I) compound or its physiology on acceptable salt or solvate.This medicinal compositions, it mixes with acceptable diluent or carrier on one or more physiology.
This medicinal compositions can be mixed with the preparation of suction, oral, oral cavity, hypogloeeis, non-enteron aisle, injection, heeling-in, local application or rectal administration.Said composition also comprises another kind of therapeutic activity agent, and another kind of therapeutic activity agent is preferably β
2Adrenoceptor agonists.
A kind of medicinal compositions, said composition comprise acceptable salt or solvate and PDE4 inhibitor on formula (I) compound of above each or its physiology.
A kind of medicinal aerosol formulations, said preparation contain acceptable salt or solvate on above formula (I) compound or its physiology, and as the fluorocarbons or the hydrogenous cfc of propellent.It can also contain tensio-active agent.
One of skill in the art will appreciate that related here treatment comprise confirm the prevention and the treatment of illness.
One of skill in the art will appreciate that related solvate comprises the solvate of hydrate and organic solvent here.
As mentioned above, the compound of formula (I) can be used for people or veterinary drug, particularly can be used as antiphlogiston, resistance is answered disease, anti-allergy agent, is particularly useful for treatment once a day.Therefore, the present invention provides on the other hand and has been used for people or veterinary drug, especially for acceptable solvent thing on the formula that the patient who suffers from inflammatory diseases and/or allergic disease is treated (I) compound or its physiology.Interested especially is the pharmaceutical composition that is used for administration once a day.According to another aspect of the present invention, it provides the patient that the acceptable solvent thing is used to prepare suffering from inflammatory diseases and/or allergic disease on the compound of formula (I) or its physiology to treat, in particular for the application in the medicine that carries out treatment once a day.
Another or selective aspect, it provides a kind of method that human or animal's individuality of suffering from inflammatory diseases and/or allergic disease is treated of being used for, this method comprises acceptable solvent thing on formula (I) compound that gives said human or animal's individual effective dose or its physiology, carries out administration especially once a day.Can be prepared it can be carried out administration in any mode easily, therefore compound of the present invention.The present invention also comprises the pharmaceutical composition of acceptable solvent thing on the compound of inclusion formula (I) or its physiology in its scope, and again if necessary, this drug regimen also comprises acceptable diluent or carrier on one or more physiology.
In addition, it also provides a kind of method for preparing such pharmaceutical composition, and it comprises each composition is mixed.
Compound of the present invention for example can be prepared to the form that is used to carry out oral administration, cheek administration, sublingual administration, parenteral admin, topical or upright enteral administration, especially topical, used here topical comprise by being blown into and administration is carried out in suction.The various types of examples of formulations that are used for topical comprise ointment, lotion, frost, gel, foam, be used for the preparation that transmits by transdermal patch, pulvis, spraying, aerosol, the capsule or cartridge case or the drops (for example eye drops or nasal drop) that are used for sucker or insufflator, the solution that is used to spray, suppository, vagina is fastened, be detained enema and can chew tablet or piller (for example being used for the treatment of aphthous ulcer) or liposome or the microencapsulation preparation that maybe can suck.
Be used for topical and can comprise dry powder composite and spray composite to the preparation of lung.
Be used for localized delivery and may reside in capsule and the cartridge case that is used for sucker for example or insufflator to the dry powder composite of lung.Preparation generally comprises and is used for powdered mixture that The compounds of this invention is sucked and powdery matrix such as lactose, starch or the amino acid that suits.The preferred lactose that uses.But the compound of the general inclusion 20 μ g-10mg formulas (I) of each capsule or cartridge case, it can comprise or not comprise other activeconstituents.Perhaps, compound of the present invention can not have vehicle.The packing of said preparation can be suitable for the transmission of unitary dose or multiple doses.
Interested especially be not supercharging and be suitable for to carry out the pharmaceutical preparation (especially these preparations that do not contain vehicle maybe can be used diluent or carrier such as lactose or starch, most preferably are these preparations that are prepared with lactose) of administration in the dry powder form of lung by oral cavity local medication.Spray composite for example can be prepared to the form of aqueous solution or suspension or be prepared to be packaged in pressurized package as the use in the sucker that has measured dosage the aerosol form of suitable liquefied propellant.The aerosol combination that is suitable for sucking can be suspension or solution form, and comprises compound and the propelling agent such as the fluorocarbon that suit of formula (I) as another or wrap hydrogenous Chlorofluorocarbons (CFCs) or its mixture, particularly hydro fluoroalkanes, especially 1,1,1,2-Tetrafluoroethane, 1,1,1,2,3,3,3-seven fluoro-n-propanes or its mixture.This aerosol combination is inclusion or comprise in the prior art well-known additional formulations vehicle such as tensio-active agent such as oleic acid or Yelkin TTS and solubility promoter ethanol for example not.
An example of preparation is not contain vehicle and substantially by the compound of formula (I) (form of preferred not solvation is 1 type for example) be selected from 1,1,1,2-Tetrafluoroethane, 1,1,1,2,3,3, the propelling agent of 3-seven fluoro-n-propanes and composition thereof is formed (its can comprise or not other therapeutic activity composition of inclusion).
Another example of preparation comprise granular formula (I) compound, be selected from 1,1,1,2-Tetrafluoroethane, 1,1,1,2,3,3, propelling agent of 3-seven fluoro-n-propanes and composition thereof and the suspension agent that is dissolvable in water this propelling agent be the described lact-acid oligomer of W094/21229 (oligolactic acid) or derivatives thereof for example.Preferred propelling agent is 1,1,1, the 2-Tetrafluoroethane.As in this manual shown in other place, the compound that seems formula (I) is not with 1,1,1, the 2-Tetrafluoroethane forms solvate.The preparation of supercharging generally is retained in a kind of closed and be installed in container (for example aluminum container) on a kind of driving mechanism of being furnished with mouth-piece with valve (for example metering valve).Be used for having controlled granularity ideally by the medicine of inhalation.The optimum size that is used for being drawn into bronchi is generally 1 μ m-10 μ m, is preferably 2-5 μ m.When being inhaled into,, granularity generally is difficult to arrive tracheole too greatly thereby being higher than the particle of 20 μ m.In order to obtain these granularities, can for example reduce the granularity of formula (I) compound of manufacturing by ordinary method with micronization.Can required part be separated by pneumatic jig or screening.Preferably, this particle is crystalline, and it for example is that conventional method is prepared.When using vehicle such as lactose, the granularity of vehicle generally is higher than the granularity that is inhaled into medicine among the present invention far away.When this vehicle was lactose, it generally existed with the form of the lactose that carried out grinding, wherein at the most the particle diameter of 85% lactose granule 60 μ m-90 μ m's and again the particle diameter of at least 15% lactose granule less than the MMD of 15 μ m.
MMD is meant mass median diameter (mass median diameter).
Topical comprises pressurised aerosol and the aqueous formulation that delivers medicine to nose by force (forcing) pump in the preparation (preparation that for example is used for the treatment of rhinitis) of nose.Interested especially is not pressurize and be suitable for the preparation of topical in nasal cavity.Said preparation preferably comprises the water as diluent or carrier that is used for this purpose.The aqueous formulation that is used to deliver medicine to lung or nose can be prepared with conventional excipients such as buffer reagent, tension regulator or the like.Aqueous formulation can also be delivered medicine to nose by atomizing.Other possible existence form is as follows: ointment, frost and gel for example can use or oleaginous base be prepared by adding suitable thickening material and/or jelling agent and/or solvent.Therefore, such matrix for example comprises water and/or oil, as whiteruss or vegetables oil such as peanut oil or Viscotrol C; Or solvent such as polyoxyethylene glycol.Can comprise soft wax, aluminum stearate, cetostearyl alcohol, polyoxyethylene glycol, lanolin, beeswax, carboxylic polymethylene (carboxypolymethylene) and derivatived cellulose and/or Zerol and/or nonionic emulsifying agent according to thickening material and the jelling agent that the character of matrix is used.Lotion can use or oleaginous base be not prepared, and generally go back one or more emulsifying agents of inclusion, stablizer, dispersion agent, suspensoid or thickening material.The powder that is used for applications can form by means of any suitable powder matrix, and wherein said suitable powder is talcum powder, lactose or starch for example.Drops can use or non-aqueous matrix be prepared, and go back one or more dispersion agents of inclusion, solubilizing agent, suspension agent or sanitas again.Advantageously, can preparation of the present invention not cushioned by adding suitable buffer reagent.The ratio of active formula (I) compound depends on the definite type that is produced preparation in topical composition of the present invention, but general in the scope of 0.001% to 15% weight.But generally speaking, for most of preparation types, used ratio advantageously is 0.005% to 5% and is preferably 0.01% to 1%.But for the powder that is used to suck or be blown into, used ratio is in 0.1% to 5% scope.Preferably with the single dose of aerosol formulation such as sprays for comprising 20 μ g-2000 μ g, the compound of the formula (I) of preferred about 20 μ g-500 μ g.Can be administered once in one day or administration in a day several times, for example 2,3,4 or 8 times, each time administration is 1,2 or 3 dosage for example.The total per daily dose of this aerosol will be between 50 μ g-10mg, preferably between 200 μ g-2000 μ g.By total per daily dose that capsule and cartridge case transmitted in sucker or the insufflator and dosing generally be these dosage of transmitting with aerosol one to twice.
Can topical formulations be carried out administration by applying it on the disease sites once a day or several times; On skin part, can advantageously use occlusive dressing.Can be undertaken continuously or long-term the transmission by adherent store system.
For inner administration, compound of the present invention can be prepared to the form that is used for oral, parenteral or rectal administration in routine rule mode.The preparation that is used for oral administration comprises syrup, pulvis, granule, tablet and capsule, and it generally comprises conventional excipients such as tackiness agent, weighting agent, lubricant, disintegrating agent, wetting agent, suspensoid, emulsifying agent, sanitas, buffering salt, correctives, tinting material and/or sweeting agent according to required situation.But dosage unit form is preferably as described below.
The preferred formulation form that is used for inner administration is a dosage unit form, i.e. tablet and capsule.Such dosage unit form comprises 0.1mg to 20mg, preferred 1mg to 10mg compound of the present invention.
Carry out generally can giving compound of the present invention in the illness of the suprarenal gland of general-cortex treatment at needs by inner administration.Generally speaking, being used for the terms " formulation " of inner administration can be according to the activeconstituents of employed preparation type inclusion 0.05% to 10%.According to the continuous action time of illness of being treated and required treatment, per daily dose can change between 0.1mg to 60mg, for example is 5mg to 30mg.
Slowly-releasing or casing preparation may be favourable, and be particularly more favourable for the inflammatory bowel illness.Pharmaceutical composition of the present invention can also comprise other therapeutic activity agent, for example beta 2 adrenoreceptor agonists, antihistaminic or anti-allergy agent.Therefore, the present invention also provides a kind of compound or its physiologically acceptable solvate and other therapeutic active substance, for example combination of beta-2-adrenoreceptor agonists, antihistaminic, anti-allergy agent or anticholinergic that comprises formula (I).
The example of beta-2-adrenoreceptor agonists comprises Salmeterol (for example being the carbonaphthoic acid salt form), salbutamol (for example being sulphate form), formoterol (for example being the fumarate form), Partusisten or terbutaline (for example being sulphate form).Preferred long-acting beta-2-adrenoreceptor agonists, especially these have the material of therapeutic action in 24 hours time.
The example of antihistaminic comprises methapyrilene or Loratadine.The example of anti-allergy agent comprises cromoglycate (for example Sodium Cromoglicate), ketotifen and nedocromil (as its sodium-salt form).The example of anticholinergic comprises Rinovagos (for example ipratropium bromide), tiotropium (tiotropium), coromegine or oxitropine (oxitropium).Any above-mentioned substance can be employed with its selective salt or solvate forms.Other suitable combination comprises for example other anti-inflammatory agent, for example NSAID (for example PDE-4 inhibitor, leukotriene antagonist, iNOS inhibitor, tryptase and elastase inhibitor, β 2 integral protein antagonists and adenosine 2a agonist)) or anti-infective (for example microbiotic, antiviral drug).Interested especially is the combined utilization of the compound and phosphodiesterase 4 (PDE-4) inhibitor of formula (I).Be used for this specific PDE-4 inhibitor on the one hand of the present invention and can be knownly can suppressing any compound of PDE-4 enzyme or finding that it can be used as any material of PDE4 inhibitor, it only is the PDE-4 inhibitor, is not the compound that suppresses PDE other member of family and PDE-4.It is general preferably to use and has about 0.1 or the PDE-4 inhibitor of higher IC50 ratio.NSAID is meant NSAID (non-steroidal anti-inflammatory drug).
A kind of method by formula (II) compound formula (I) compound,
Method 1: when the R1 of formula (II) compound is not hydroxyl, modus ponens (II) compound is dissolved in the pyridine, the solution of gained is cooled to 0～5 ℃, add little amount of catalyst, as 4,4-dimethylaminopyridine is then under temperature is 5-10 ℃ condition, slowly add the cyclopropyl formyl chloride, stir resultant mixture then under 5-10 ℃ condition, reaction 4h afterreaction drop adds the hydrochloric acid of 2N, regulates pH value 2-3, be diluted in the frozen water, and with three aqueous phase extracted of methylene dichloride, organic phase merges, and pH is transferred to 5-6 and washes with water with sodium hydrogen carbonate solution, organic phase concentrates, recrystallizing methanol.
Method 2: when the R1 of formula (II) compound is hydroxyl, get the formula that R1 is OCOCH3 (II) compound obtains corresponding formula (I) compound according to method 1 dichloromethane solution, the 0-5 degree drips 2% NaOH/ methanol solution to this solution under nitrogen, react after 3 hours, utilize acetic acid to regulate PH and be 6-7, obtain the formula that R1 is a hydroxyl (II) compound by column chromatography.
When wherein the R1 of (II) compound is OCOR2 (R2 is that six carbon are with interior alkyl), can carry out according to 21 general bit esterified methods of pregnant steroid, for example can prepare according to ciclesonide 21 bit esterified methods, as DE-4129535, US5733901, disclosed preparation method among the CN200410086732.
Embodiment:
Column chromatography method among the present invention:
The minimum 70cm of the length of chromatography column, 90% filling 254-silica gel in the post, and will need isolating organism to be dissolved in minimum chloroform entirely: methyl alcohol=in 1: 1, this solution absorption is placed on the top of silica gel in the chromatography column with minimum 254-silica gel, use the moving phase wash-out, chromatography column connects the solution that obtains through column chromatography with several 10ml test tubes down, the control flow velocity is 10ml/3min, the solution of each test tube is analyzed with HPLC, the test tube solution that retention time is identical merges, the compound of getting principal point carries out recrystallization, obtains corresponding product.
Determine the method for principal point: will need isolating organism to analyze with HPLC, the point of peak area maximum is defined as principal point, and its retention time is the retention time of principal point.
The condition of HPLC:
Equipment: HP 1084B liquid chromatograph, HP 79850 BLC terminals and UV detector
Column material: Hypersil C18,5um, 125 * 4.6mm
Detect wavelength: 242nm
Moving phase: ethanol: water=6.7: 3.3
Column temperature: 40 ℃
Flow velocity: about 1.1ml/ branch
Embodiment 1:9 α-fluoro-11 β, 17 α, 21-trihydroxy--16 Beta-methyl-pregnant steroid-1,4-diene-3, the preparation of 20-diketone-17-ethylene-acetic acid ester-21-acetic ester
With 9 α-fluoro-11 β, 17 α, 21-trihydroxy--pregnant steroid-1,4-diene-3,20-diketone-21-acetic ester 10mmol, be dissolved in the 50ml pyridine, the solution of gained is cooled to 0～5 ℃, add 4,4-dimethylaminopyridine 0.2g, under temperature is 5-10 ℃ condition, slowly add cyclopropyl formyl chloride 12mmol then, under 5-10 ℃ condition, stir resultant mixture then, reaction 4h afterreaction drop adds the hydrochloric acid of 2N, regulate pH value 2-3, be diluted in the frozen water, and with three aqueous phase extracted of methylene dichloride, methylene dichloride merges, pH is transferred to 5-6 and wash with water with sodium hydrogen carbonate solution, organic phase concentrates, and recrystallizing methanol obtains target compound 4.2mmol.
Ultimate analysis measured value: C28H35FO7 C, 66.85; H, 7.04; F, 3.79; O, 22.32
13C-NMR：13.1(CH)，8.3(CH2)，8.3(CH2)，94.5(C)，47.2(C)，43.5(CH)，46.7(CH)，32.9(CH2)，100.3(C)，185.9(C)，70.5(CH)，33.5(CH)，36.2(CH2)，167.3(C)，124.3(CH)，128.3(CH)，152.9(CH)，48.3(C)，27.3(CH2)，30.5(CH2)，
171.3(C)，170.4(C)，212.0(C)，68.2(CH2)，17.3(CH3)，19.5(CH3)，22.8(CH3)，20.2(CH3)。
Embodiment 2:9 α-fluoro-11 β, 17 α, 21-trihydroxy--16 Beta-methyl-pregnant steroid-1,4-diene-3, the preparation of 20-diketone-17-ethylene-acetic acid ester
With the pH among the embodiment 1 is 5-6 and the methylene dichloride phase that washes with water, drips 2% NaOH/ methanol solution to this organic phase at the 0-5 degree under nitrogen, react after 3 hours, utilizes acetic acid adjusting PH to be 6-7, obtains target compound 3.2mmol by column chromatography.
Ultimate analysis measured value: C26H33FO6 C, 67.78; H, 7.21; F, 4.14; O, 20.87
Embodiment 3: pregnant steroid-1,4-diene-3,20-diketone-11,17, the preparation of 21-trihydroxy--17-ethylene-acetic acid ester-21-acetic ester
With pregnant steroid-1,4-diene-3,20-diketone-11,17,21-trihydroxy--21-acetic ester is a raw material, according to the technology synthesising target compound 5.2mmol of embodiment 1.
Ultimate analysis measured value: C27H34O7 C, 68.92; H, 7.28; O, 23.80
13C-NMR：13.2(CH)，8.4(CH2)，8.4(CH2)，101.9(C)，41.2(C)，50.3(CH)，22.9(CH2)，24.1(CH)，186.0(C)，68.9(CH)，31.5(CH)，40.3(CH2)，168.2(C)，124.5(CH)，128.7(CH)，158.8(CH)，44.3(C)，59.2(CH)，32.3(CH2)，32.9(CH2)，171.5(C)，170.4(C)，212.1(C)，68.0(CH2)，17.0(CH3)，19.1(CH3)，20.6(CH3)。
Embodiment 4: pregnant steroid-1,4-diene-3,20-diketone-11,17, the preparation of 21-trihydroxy--17-ethylene-acetic acid ester
With the pH among the embodiment 3 is 5-6 and the methylene dichloride phase that washes with water, according to the technology of embodiment 2, title compound 4.0mmol.
Ultimate analysis measured value: C25H32O6 C, 70.05; H, 7.54; O, 22.41
Embodiment 5: pregnant steroid-1,4-diene-3,20-diketone-11,17, the preparation of 21-trihydroxy--17-ethylene-acetic acid ester-21-isobutyrate
With pregnant steroid-1,4-diene-3,20-diketone-11,17,21-trihydroxy--21-isobutyrate 10mmol be raw material according to the method among the embodiment 1, obtain title compound 4.3mmol.
Ultimate analysis measured value: C29H38O7 C, 69.83; H, 7.68; O, 22.49
13C-NMR：13.2(CH)，8.4(CH2)，8.4(CH2)，101.9(C)，41.2(C)，50.3(CH)，22.9(CH2)，24.1(CH)，186.0(C)，68.9(CH)，31.5(CH)，40.3(CH2)，168.2(C)，124.5(CH)，128.7(CH)，158.8(CH)，44.3(C)，59.2(CH)，32.3(CH2)，32.9(CH2)，171.5(C)，170.0(C)，211.1(C)，68.4(CH2)，17.0(CH3)，19.0(CH3)，50.9(CH)，19.1(CH3)，19.1(CH3)。
Embodiment 6: pregnant steroid-1,4-diene-3,20-diketone-11,17,21-trihydroxy--6 Alpha-Methyl--the preparation of 17-ethylene-acetic acid ester-21-acetic ester
With pregnant steroid-1,4-diene-3,20-diketone-11,17,21-trihydroxy--6 alpha-methyl-2 1-acetic ester 10mmol be raw material according to the method among the embodiment 1, obtain title compound 3.9mmol.
Ultimate analysis measured value: C28H36O7 C, 69.43; H, 7.50; O, 23.07
13C-NMR：13.2(CH)，8.4(CH2)，8.4(CH2)，101.9(C)，41.2(C)，50.3(CH)，22.9(CH2)，24.1(CH)，186.0(C)，68.9(CH)，27.0(CH)，40.3(CH2)，174.5(C)，124.5(CH)，128.7(CH)，155.6(CH)，37.0(C)，59.5(CH)，35.9(CH2)，33.8(CH2)，171.5(C)，170.4(C)，212.1(C)，68.0(CH2)，20.0(CH3)，17.0(CH3)，19.4(CH3)，20.6(CH3)。
Embodiment 7: pregnant steroid-1,4-diene-3,20-diketone-11,17,21-trihydroxy--17-ethylene-acetic acid ester-21-acetic ester-6 α, the preparation of two fluoro-16 Beta-methyls of 9-
With pregnant steroid-1,4-diene-3,20-diketone-11,17,21-trihydroxy--21-acetic ester-6 α, the two fluoro-16 Beta-methyl 10mmol of 9-be raw material according to the method among the embodiment 1, obtain title compound 3.3mmol.
Ultimate analysis measured value: C28H34F2O7 C, 64.63; H, 6.57; F, 7.30; O, 21.50
13C-NMR：13.1(CH)，8.3(CH2)，8.3(CH2)，94.5(C)，47.2(C)，43.6(CH)，46.7(CH)，32.9(CH2)，100.3(C)，185.7(C)，70.5(CH)，33.7(CH)，36.2(CH2)，163.2(C)，119.5(CH)，128.1(CH)，152.8(CH)，47.9(C)，33.7(CH2)，87.8(CH)，171.3(C)，170.4(C)，212.0(C)，68.2(CH2)，17.3(CH3)，19.5(CH3)，22.8(CH3)，20.3(CH3).
Embodiment 8: pregnant steroid-1,4-diene-3,20-diketone-11, the two hydroxyls of 17--17-ethylene-acetic acid ester-9, the preparation of two chloro-16 Beta-methyls of 21-
With pregnant steroid-1,4-diene-3,20-diketone-11, the two hydroxyls-9 of 17-, the two chloro-16 Beta-methyl 10mmol of 21-be raw material according to the method among the embodiment 1, obtain title compound 5.2mmol.
Ultimate analysis measured value: C26H32Cl2O5 C, 63.07; H, 6.50; Cl, 14.30; O, 16.13
13C-NMR：13.1(CH)，8.4(CH2)，8.4(CH2)，95.3(C)，46.3(C)，42.5(CH)，46.2(CH)，32.3(CH2)，73.3(C)，185.7(C)，70.0(CH)，37.8(CH)，35.2(CH2)，168.2(C)，124.2(CH)，128.3(CH)，149.5(CH)，62.9(C)，29.0(CH2)，32.5(CH2)，46.7(CH2)，171.5(C)，204.7(C)，17.3(CH3)，19.5(CH3)，27.8(CH3)
Embodiment 9: pregnant steroid-4-alkene-3,20-diketone-11,17, the preparation of 21-trihydroxy--17-ethylene-acetic acid ester-21 acetic ester
With pregnant steroid-4-alkene-3,20-diketone-11,17,21-trihydroxy--21 acetic ester 10mmol be raw material according to the method among the embodiment 1, obtain title compound 4.7mmol.
Ultimate analysis measured value: C27H36O7 C, 68.60; H, 7.69; O, 23.71
13C-NMR(CDCl
3)：13.2(CH)，8.4(CH2)，8.4(CH2)，101.9(C)，41.2(C)，50.2(CH)，22.9(CH2)，24.0(CH)，199.0(C)，68.1(CH)，33.0(CH)，40.0(CH2)，170.2(C)，124.2(CH)，34.2(CH2)，35.6(CH2)，39.7(C)，56.2(CH)，32.0(CH2)，32.5(CH2)，171.5(C)，170.4(C)，212.1(C)，68.0(CH2)，17.0(CH3)，19.4(CH3)，20.6(CH3)。
Embodiment 10: pregnant steroid-4-alkene-3,20-diketone-11,17, the preparation of 21-trihydroxy--17-ethylene-acetic acid ester
With pregnant steroid-4-alkene-3,20-diketone-11,17,21-trihydroxy--21 acetic ester 10mmol be raw material according to the method in embodiment 1 and 2, obtain title compound 3.3mmol.
Ultimate analysis measured value: C25H34O6 C, 69.72; H, 7.97; O, 22.31
Embodiment 11: pregnant steroid-4-alkene-3,20-diketone-11,17, the preparation of 21-trihydroxy--6 Alpha-Methyls-17-ethylene-acetic acid ester-21-isobutyrate
With pregnant steroid-4-alkene-3,20-diketone-11,17,21-trihydroxy--6 alpha-methyl-2 1-isobutyrate 10mmol be raw material according to the method among the embodiment 1, obtain title compound 4.3mmol.
Ultimate analysis measured value: C30H42O7 C, 69.98; H, 8.24; O, 21.78
13C-NMR(CDCl3)：13.2(CH)，8.4(CH2)，8.4(CH2)，101.9(C)，41.2(C)，50.5(CH)，22.9(CH2)，24.1(CH)，199.0(C)，68.1(CH)，26.8(CH)，40.0(CH2)，169.5(C)，124.1(CH)，34.2(CH2)，35.6(CH2)，28.6(C)，59.4(CH)，35.9(CH2)，33.3(CH)，171.5(C)，170.0(C)，211.1(C)，68.4(CH2)，17.0(CH3)，19.6(CH3)，50.9(CH)，19.1(CH3)，19.1(CH3)。
The preparation of example of formulations 1 aerosol
Compound 5 20g
Ethanol 750g
Glycerine 150g
HFA227 1500g
Preparation technology: the compound 1-a1 of recipe quantity is added in the ethanol and glycerine that stirs, stir, heat in warm water bath, make material dissolution, sand core funnel filters, the divided dose can, sealing-in dosage valve system, the HFA227 that pressurizes again respectively, promptly, theoretical canned 1000 bottles, the can yield is more than 85%.Through 45-50 ℃ of water-bath leak detection 30 minutes, do not have and leak.Press for every bottle 100, whenever press and contain compound 200 μ g.
The preparation of example of formulations 2 nasal drops
Compound 9 0.1g (particle diameter 5～20 μ m)
Sodium-chlor 0.08g
SODIUM PHOSPHATE, MONOBASIC 0.65g
Sodium phosphate dibasic 0.5g
Benzalkonium chloride 0.01g
Vltra tears 0.3g
Tween-80 0.1g
Water for injection is to 100ml
Getting benzalkonium chloride is dissolved in recipe quantity 50% water for injection, be heated to 40-50 ℃, adding SODIUM PHOSPHATE, MONOBASIC, Sodium phosphate dibasic, tween-80 make dissolving, No. 4 sintered filter funnels filter conduct＜1〉liquid is stand-by, in addition Vltra tears is dissolved in the distilled water of recipe quantity 30, filter with the B that is lined with 200 order nylon cloths, be heated to 60-70 ℃, add compound 1-a and stir evenly, insulation 30min is cooled to 40-50 ℃, again with＜1〉the liquid merging, add the injection water to capacity, 200 order nylon mesh filter twice, packing, sterilize, seal.
The preparation of example of formulations 3 powder inhalations
Compound 8 200mg
Formoterol Fumarate 100mg
Lactose 25000mg
Preparation technology: compound 8, Formoterol Fumarate and lactose are mixed, with fluid energy mill medicine is carried out abundant micronization processes after, the can of medicine carrying powder to capsule, is got final product theoretical can 1000 capsules.Every capsules includes micronized compound 8200 μ g (amounting to methylprednisolone 500 μ g), lactose 25mg.
The preparation of example of formulations 4 powder inhalations
Compound 5 200mg
Lactose 20000mg
Preparation technology: compound 5 and lactose are mixed, with fluid energy mill medicine is carried out abundant micronization processes after, the can of medicine carrying powder to capsule, is got final product theoretical can 1000 capsules.Every capsules includes micronized compound 5200 μ g, lactose 20mg.
The preparation of example of formulations 5 ointments
Compound 3 1g, white vaseline 30g, stearyl alcohol 120g, glyceryl monostearate 20g, whiteruss 10g, peregal A-20 50g, glycerine 120g, EDTA-2Na 2g, phenylcarbinol 5g, hydroxypropylcellulose, 3g, purified water 639g
By the accurate weighing of above proportioning, moisture is two portions: 380g and 259g, gets ready, and the emulsifiable paste process for preparation is as follows:
(1) oil phase preparation:, get white vaseline, stearyl alcohol, glyceryl monostearate, whiteruss, peregal A-20 places container, is heated to fusion, and temperature remains on 72 ± 2 ℃;
(2) water preparation: by the accurate weighing of above proportioning, get glycerine, EDTA-2Na and 380g water place container, heating, and temperature remains on 70 ± 2 ℃;
(3) close phase: pour the oil phase of step (1) preparation the aqueous phase of step (2) preparation into, stir, maintain the temperature at 75 ± 2 ℃, add phenylcarbinol;
(4) main ingredient suspension: compound 3,259g water, polyethylene pyrrole network alkane ketone are placed container, and stirring or ultrasonic obtains the main ingredient suspension;
(5) controlled temperature is at 60 ± 2 ℃, and the main ingredient suspension that obtains in the step (4) is added in the solution that step (3) obtains, and the limit edged stirs, and is cooled to cream.Obtain emulsifiable paste 1kg.
The preparation of example of formulations 6 ointments
Compound 1 1.3g, an amount of propylene glycol
The prescription of oil phase:
White vaseline 100g stearyl alcohol 30g Liquid Paraffin 50g glyceryl monostearate 20g peregal a-20 20g Tegosept M 0.5g propylben 0.05g alpha-tocopherol 1g
The prescription of water:
Disodium ethylene diamine tetraacetate (EDTA-2Na) 1g, glycerine 50g
The phosphate buffer distilled water that emulsifiable paste is buffered to pH=6.5 is to 1000g (in the emulsifiable paste gross weight)
Preparation:
(1) compound 1 is dissolved in an amount of propylene glycol
(2) preparation of oil phase
The oil-phase component of getting recipe quantity is heated to 70 ℃, adds the Tegosept E that is dissolved in an amount of organic solvent, and the compound 1-b1 that will be dissolved into again in the propylene glycol joins in the oil phase, stirs while adding to evenly promptly.
(3) preparation of water
The water-phase component that takes by weighing recipe quantity joins stirring and dissolving in the distilled water of recipe quantity,
(4) preparation of emulsifiable paste
Water is heated to 70 ± 10 ℃ of oil-phase components that will be heated to 70 ± 10 ℃ joins aqueous phase, stir while adding evenly to condensation promptly.Make compound 1 and be the emulsifiable paste of activeconstituents.
Pharmacologically active:
Pharmacologically active can adopt the active function in vitro tests of glucocorticoid agonists to estimate.
According to K.P.Ray etc. (Biochem J. (1997), 328, the 707-715) function test of Miao Shuing provides a kind of trans inhibition activity test method of glucocorticoid agonists.Under 37 ℃, handle the A549 cell 1 hour that stable transfection has reporter gene with the test-compound of suitable dosage, this report gene contains the response NF.KB element that connects sPAP (secretion property phospholipase) gene from the ELAM promotor.(TNF 10ng/ml) stimulated this cell 16 hours, and tested the content of alkaline phosphatase that produce this moment with the colorimetry of standard to use tumour necrosis factor then.Make up dose response curve, and can pass through curve estimation EC
50Value.
The EC of the compound of embodiment 1 to 11
50Value is less than 20nM.
The EC50 value of embodiment 1,3,5 is less than 5nM.
Pharmacology embodiment 1
Relatively blank, budesonide, compound 1-11 suck the influence that histamine is induced the rat asthma attack
1. laboratory animal: choose healthy childhood of rat, 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, according to the powder inhalation of the budesonide of example of formulations 4 methods preparation, compound 1-11, according to the blank powder inhalation that does not contain activeconstituents of example of formulations 4 methods preparation.
4 data processing: adopt the check of t in groups of SAS system.
Three, experimental technique
Choose rat childhood, male and female all can, body weight is 180-220g, puts into the lens about 5 liters, sprays into 2% Ovisot and 15 seconds of 0.1% histamine phosphate's volume mixed solution with the pressure of 400mmHg.After spraying stops, observing drawing of rat and breathe heavily latent period (asthma promptly takes place, breathe and be the devil), draw and breathe heavily the phase of diving and to select for use greater than 120 seconds rat until the time that tic is fallen.Learn from else's experience to measure to draw and breathe heavily 260 of qualified rats in latent period, be equally divided into 13 groups latent period at random by drawing to breathe heavily, every group gives corresponding medicine, the corresponding respectively powder inhalation that gives compound 1-11 of 1-11 group, 12 groups of powder inhalations that give budesonide, control group is according to the powder inhalation that does not contain activeconstituents of embodiment 4 preparations, behind the inhalation 30min, spraying gives 0.25% 2 hydrochloric acid histamine respectively, observes to give and draws the variation of breathing heavily latent period and tic incidence (draw when breathing heavily animal do not occur the person of falling in 6 minutes to breathe heavily latent period be 360s to draw) before and after the medicine
Four, experimental result: a few treated animal generation asthma, difference is all arranged, see Table 1 until the time that tic is fallen:
Table 1 pair histamine phosphate's spraying sucks the influence of inducing asthma attack
(n＝20，X±s，)
Show by this experiment, compound 1-11 all can the significant prolongation mouse be breathed heavily latent period drawing of bringing out by histamine phosphate, (P＜0.01), and existing budesonide is compared, under Isodose, use and to draw that to breathe heavily latent period similar after the administration of 5-8 group of The compounds of this invention, illustrate that thus compound 1-11 provided by the invention all has the effect of treatment asthma.
Pharmacology embodiment 2
Laboratory animal: 260 of CXA-1 recombinant inbred strain small white mouses, body weight 18～22g, be equally divided into 13 groups at random, the 1-11 group is corresponding respectively to be the paste that activeconstituents is prepared into according to example of formulations 5 methods with compound 1-11,12 groups of correspondences are the paste that activeconstituents is prepared into according to example of formulations 5 methods with the furoic acid momisone, the paste of control group, 1-12 group is coated experiment mice auris dextra inboard, every experiment mice coating same amount emulsifiable paste, and simultaneously at the emulsifiable paste matrix of left ear coating same amount in contrast.Control group two ears all are coated with the paste that does not contain activeconstituents according to the preparation of example of formulations 6 methods.
Chronic dermatitis eczema Animal Model Making: adopt 7%DNCB (dinitrotoluene (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, excite once every 72h, experimental group is exciting back 24h to begin coating first, 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
(X±s，n＝20)
| Group | Activeconstituents | Dosage/μ g/kg | Swelling degree % | Incrustation rate % |
| Contrast | Do not have | 0 | 163.2±9.2 | 70 |
| 1 | Embodiment 1 | 10 | 116.4±6.3 | 15 |
| 2 | Embodiment 2 | 10 | 122.0±7.9 | 25 |
| 3 | Embodiment 3 | 10 | 117.1±6.9 | 25 |
| 4 | Embodiment 4 | 10 | 124.3±7.8 | 25 |
| 5 | Embodiment 5 | 10 | 111.2±5.9 | 10 |
| 6 | Embodiment 6 | 10 | 116.8±6.1 | 15 |
| 7 | Embodiment 7 | 10 | 118.4±7.3 | 15 |
| 8 | Embodiment 8 | 10 | 107.1±6.6 | 10 |
| 9 | Embodiment 9 | 10 | 126.8±7.9 | 20 |
| 10 | Embodiment 10 | 10 | 132.1±6.5 | 25 |
| 11 | Embodiment 11 | 10 | 128.4±7.8 | 30 |
| 12 | Furoic acid momisone | 10 | 110.1±4.9 | 10 |
Show through experiment, compound provided by the invention is in the treatment to mouse chronic dermatitis Eczema Model, there were significant differences for the swelling degree of mouse ear and incrustation rate (P＜0.05), show that compound provided by the invention has and existing potent cortin furoic acid momisone when being used for the treatment of the Mammals local inflammation, comparing to have similar curative effect.
Claims (10)
1. the formula of a novel adrenocortical hormone (I) compound,
Formula (I)
Wherein
R1=H, Cl, OH or, OCOR2, R2 be six carbon with interior alkyl,
R3=H or methyl,
R4=H or halogen,
R5=H, halogen or methyl,
1,2 dotted line is represented singly-bound or two key.
2. formula as claimed in claim 1 (I) compound is characterized in that
Wherein
R1=Cl, OH or, OCOR2, R2 be six carbon with interior alkyl,
R3=H or methyl,
R4=H or F,
R5=H, F or methyl,
1,2 dotted line is represented singly-bound or two key.
3. compound as claimed in claim 1 is characterized in that
Wherein
R1=Cl, OH or, OCOR2, R2 be six carbon with interior alkyl,
R3＝H，
R4=H or F,
R5=H or methyl,
1,2 dotted line is represented singly-bound or two key.
4. formula as claimed in claim 1 (I) compound is characterized in that
Wherein
R1=Cl, OH or, OCOR2, R2 be six carbon with interior alkyl,
R3＝H，
R4=H or F,
R5=H or methyl,
1,2 two key of dotted line representative.
5. formula as claimed in claim 1 (I) compound is
Pregnant steroid-1,4-diene-3,20-diketone-11,17,21-trihydroxy--17-ethylene-acetic acid ester,
Pregnant steroid-1,4-diene-3,20-diketone-11,17,21-trihydroxy--17-ethylene-acetic acid ester-9 α-fluoro-16 Beta-methyls,
Pregnant steroid-1,4-diene-3,20-diketone-11,17,21-trihydroxy--17-ethylene-acetic acid ester-21-acetic ester,
Pregnant steroid-1,4-diene-3,20-diketone-11,17,21-trihydroxy--17-ethylene-acetic acid ester-21-isobutyrate,
Pregnant steroid-1,4-diene-3,20-diketone-11,17,21-trihydroxy--17-ethylene-acetic acid ester-21-acetic ester-6 Alpha-Methyl,
Pregnant steroid-1,4-diene-3,20-diketone-11,17,21-trihydroxy--17-ethylene-acetic acid ester-21-acetic ester-9 α-fluoro-16 Beta-methyls,
Pregnant steroid-1,4-diene-3,20-diketone-11,17,21-trihydroxy--17-ethylene-acetic acid ester-21-acetic ester-6 α, two fluoro-16 Beta-methyls of 9-,
Pregnant steroid-1,4-diene-3,20-diketone-11, the two hydroxyls of 17--17-ethylene-acetic acid ester-9, two chloro-16 Beta-methyls of 21-,
Pregnant steroid-4-alkene-3,20-diketone-11,17,21-trihydroxy--17-ethylene-acetic acid ester,
Pregnant steroid-4-alkene-3,20-diketone-11,17,21-trihydroxy--17-ethylene-acetic acid ester-21 acetic ester,
Pregnant steroid-4-alkene-3,20-diketone-11,17,21-trihydroxy--6 Alpha-Methyls-17-ethylene-acetic acid ester-21-isobutyrate.
6. formula (I) compound is according to claim 1:
Pregnant steroid-1,4-diene-3,20-diketone-11,17,21-trihydroxy--17-ethylene-acetic acid ester-21-acetic ester,
Pregnant steroid-1,4-diene-3,20-diketone-11,17,21-trihydroxy--17-ethylene-acetic acid ester-9 α-fluoro-16 Beta-methyls,
Pregnant steroid-1,4-diene-3,20-diketone-11,17,21-trihydroxy--17-ethylene-acetic acid ester-21-isobutyrate,
Pregnant steroid-1,4-diene-3,20-diketone-11,17,21-trihydroxy--17-ethylene-acetic acid ester-21-acetic ester-6 Alpha-Methyl,
Pregnant steroid-1,4-diene-3,20-diketone-11,17,21-trihydroxy--17-ethylene-acetic acid ester-21-acetic ester--9 α-fluoro-16 Beta-methyls,
Pregnant steroid-1,4-diene-3,20-diketone-11, the two hydroxyls of 17--17-ethylene-acetic acid ester-9, two chloro-16 Beta-methyls of 21-,
Pregnant steroid-4-alkene-3,20-diketone-11,17,21-trihydroxy--17-ethylene-acetic acid ester,
Pregnant steroid-4-alkene-3,20-diketone-11,17,21-trihydroxy--17-ethylene-acetic acid ester-21-acid esters.
7. as the described formula of claim 1-6 (I) compound, it is characterized in that the application in preparation treatment inflammation medicine.
8. a pharmaceutical composition is characterized in that containing formula (I) compound and one or more pharmaceutical excipients as activeconstituents.
9. compound as claimed in claim 1 is characterized in that
Wherein
R1＝OCOCHCH3CH3，
R3=H or methyl,
R4=H or halogen,
R5=H, halogen or methyl,
1,2 two key of dotted line representative.
10. compound as claimed in claim 1 is characterized in that
Wherein
R1＝OCOCHCH3CH3，，
R3＝H，
R4＝H，
R5=H or methyl,
1,2 two key of dotted line representative.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2009102287912A CN102079769A (en) | 2009-11-26 | 2009-11-26 | Cyclopropyl pregnene compound and application thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2009102287912A CN102079769A (en) | 2009-11-26 | 2009-11-26 | Cyclopropyl pregnene compound and application thereof |
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| CN103012545A (en) * | 2011-09-26 | 2013-04-03 | 重庆医药工业研究院有限责任公司 | Impurity of ciclesonide and preparation method thereof |
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| CN103012545A (en) * | 2011-09-26 | 2013-04-03 | 重庆医药工业研究院有限责任公司 | Impurity of ciclesonide and preparation method thereof |
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