CN1060471A - New 16, the 17-acetal replaces the preparation method of etioallocholane-17 β-ketone - Google Patents

Abstract

The invention relates to the compound that a class has anti-inflammatory activity, is feature with such structural formula Or its steric isomer compound, in structural formula, the definition of each group all with specification sheets in identical, 1, the 2-position is saturated bond or a pair of key.

The present invention is also about the Preparation Method And Their Intermediate of these compounds, contains the pharmaceutical preparation of a kind of compound in this compounds and to the methods of treatment of inflammatory conditions.

Description

New 16, the 17-acetal replaces the preparation method of etioallocholane-17 β-ketone

This be one about the new compound that pharmacologically active is arranged, about its intermediate and the invention for preparing their method.The invention still further relates to those pharmaceutical formulations that contain this compounds and with the inflammation of these compounds for treating muscle and bone or skin, the method for allergic symptoms etc.

Theme of the present invention provides a kind of glucocorticosteroid (glucocorticosteroids＜GCS 〉) that has high anti-inflammatory action and low glucocorticosteroid systemic effect at application site.

Known that some glucocorticosteroid (GCS) can be used for topical therapeutic respiratory tract (asthma for example, rhinitis), skin (eczema, psoriasis) or enteron aisle (ulcerative colitis, Crohn disease＜Morbus Crohn 〉) inflammation, the disease of allergy or immunity.With this partial glucocorticoid treatment, people have obtained to surmount the clinical benefit of whole body therapeutic (for example giving the glucocorticosteroid sheet), particularly aspect the effect that reduces those unwanted glucocorticosteroids beyond disease location.For example in the disease of serious respiratory tract, reach such clinical benefit, GCS must have a kind of suitable pharmacological action.They should have height intrinsic glucocorticoid activity at application site but also can enter systemic circulation hydrolysis afterwards and rapid inactivation at for example target organ or in absorption.

Because the essential condition of the effectiveness that is combined into its generation anti-inflammatory and allergy disease of GCS and glucocorticoid receptor is so the ability of steroide (steroids) and its receptors bind can be used as a kind of proper method of the physiologically active of measuring GCS.Shown that with rabbit dropsy of ear test direct relation is arranged between the bonding force of GCS class and its acceptor and its anti-inflammatory effect.(some is new, efficiently 16 α-, 17 α-acetal replace the chemical structure of glucocorticoids, the relation between receptors bind and the physiologically active.E.Dahlberg, A.Thalen, R.Brattsand, J-A Gustafsson, U.Johansson, K.Rocmpke, and T.Saartok, Mol.pharmacol.25 rolls up (1984), 70 pages)

The present invention is based on and observe some 3-oxygen-androstane-1,4-diene-17 β-carboxylic acid esters has and glucocorticosteroid acceptor height bonded avidity.The compounds of this invention can be used for treatment and controls inflammation.

The compounds of this invention is to characterize with the following formula

Ⅰ

Wherein

1, the 2-position is-saturated bond or two key

X ₁Be selected from hydrogen, fluorine, chlorine and bromine

X ₂Be selected from hydrogen, fluorine, chlorine and bromine

R ₁Be selected from hydrogen or have the hydrocarbon R of the straight or branched of 1～4 carbon atom ₂Be selected from hydrogen or have the hydrocarbon R of the straight or branched of 1～10 carbon atom ₃Be selected from

Y is O or S

R ₄Be selected from hydrogen or have 1～10 carbon atom straight or branched hydrocarbon or be selected from phenyl

R ₅Be selected from hydrogen or methyl

R ₆Be selected from hydrogen, have the straight or branched of 1～10 carbon atom, saturated or hydrocarbon chain that insatiable hunger is closed, a kind of alkyl that is replaced by a halogen atom at least, a kind of heterocycle series that in ring system, contains 3～10 carbon atoms,

(m=0,1,2; N=2,3,4,5,6), do not have replace or by one or more alkyl, nitro, carboxyl, alkoxyl group, halogen, cyano group, phenyl or benzyl group that carbalkoxy or trifluoromethyl replace,

Work as R ₂During for hydrogen, R then ₁Be C ₁-C ₄The straight or branched alkyl.

Each steric isomer composition that is present in the mixture of the steroide with above-mentioned formula I can be illustrated in the following manner:

Each steric isomer composition that is present in the mixture with following various steroide 17 β-carboxylicesters can be illustrated with following manner, and wherein St is the steroidal part:

In the picture II, III, VI, VII, in the diastereomer of VIII and IX, the difference of its configuration only is above in several unsymmetrical carbons one.This diastereomer is called epimer.

Alkyl in above-mentioned is the straight or branched hydrocarbon chain of a tool 1-5 carbon atom, preferably tool 1-4 carbon.

Alkoxyl group in above-mentioned is one-O-alkyl, the definition of giving on wherein moieties has.

Halogen in above-mentioned is chlorine, bromine or a fluorine atom preferably.

Carbalkoxy in above-mentioned is one-Coo-alkyl, the definition of giving on wherein moieties has.

Heterocyclic ring system is for comprising heteroatoms such as N, the ring system of O or S.

Better heterocyclic system is pyrryl, pyridyl, pyrimidyl, pyrazinyl, furyl, pyranyl, benzofuryl, indyl and thienyl.

Be well especially in the The compounds of this invention:

1 '-ethoxy carbonyl oxygen ethyl 6 α, 9 alpha-difluoro-11 betas-hydroxy-16 alpha-,

17 α-((1-methyl ethylidene) two (oxygen))-androstane-1,4-diene-3-ketone-17 β-carboxylicesters, its epimer A+B mixture and epimer B.

1 '-the different third oxygen carbonyl oxygen ethyl, 9 α-fluoro-11 beta-hydroxies-16 α,

17 α-((1-methyl ethylidene) two (oxygen))-androstane-1,4-diene-3-ketone-17 β-carboxylicesters, epimer B.

1 '-the third oxygen carbonyl oxygen ethyl, 6 α, 9 alpha-difluoro-11 betas-hydroxy-16 alpha-,

17 α-((1-methyl ethylidene) two (oxygen))-androstane-1,4-diene-3-ketone-17 β-carboxylicesters, epimer B.

1 '-the different third oxygen carbonyl oxygen ethyl, 6 α, 9 alpha-difluoro-11 betas-hydroxy-16 alpha-,

17 α-((1-methyl ethylidene) two (oxygen)-androstanes-1,4-diene-3-ketone-17 β-carboxylicesters, epimer A+B mixture and epimer B.

1 '-acetyl oxygen ethyl (20R)-9 α-fluoro-11 beta-hydroxies-16 α,

17 α-propyl group methylene radical dioxygen androstane-1,4-diene-3-ketone-17 β-carboxylicesters, epimer B.

1 '-ethoxy carbonyl oxygen ethyl (22R)-9 α-fluoro-11 beta-hydroxies-16 α,

17 α-propyl group methylene radical dioxygen androstane-1,4-diene-3-ketone-17 β-carboxylicesters, epimer B.

1 '-different third oxygen carbonyl oxygen ethyl (20R)-9 α-fluoro-11 beta-hydroxies-16 α,

17 α-propyl group methylene radical dioxygen androstane-1,4-diene-3-ketone-17 β-carboxylicesters, epimer B.

1 '-ethoxy carbonyl oxygen ethyl (20R)-6 α, 9 alpha-difluoro-11 betas-hydroxy-16 alpha-, 17 α-propyl group methylene radical dioxygen androstane-1,4-diene-3-ketone-17 β-carboxylicesters, epimer A+B mixture and epimer B.

The preparation method

The compounds of this invention is a kind of formula X, and the compound oxidation of XI and XII becomes corresponding 17 β-carboxylic acid to prepare:

Ⅻ

Wherein

Solid line between C-1 and C-2 and dotted line are represented a singly-bound or two key, X ₁, X ₂, R ₁And R ₂The implication of giving before having, R ₇Be hydrogen or a kind of acyl group group by the straight or branched arrangement with 1-10 carbon atom.

Then this kind 17 β-carboxylic acid being carried out that esterification obtains with formula I-IX is the compound of sign, wherein

, X ₁, X ₂, R ₁, R ₂And R ₃Has implication as preceding giving.

Of the present inventionly make a kind of formula X, the technology that XI or XII compound change corresponding 17 β-carboxylic acid into is to carry out in a kind of suitable like low-grade alkane alcohol of oxygenated hydrocarbon solvent.Methyl alcohol and ethanol are better, particularly the former.Add a kind of suitable like alkaline carbonate of weak mineral alkali in the reaction medium and make it into weakly alkaline, sodium for example, the carbonate of lithium or potassium.The latter is better.The formula X, XI or XII compound change accepted way of doing sth I, II or II (R ₃=H) 17 β-carboxylic acid can take place for example 20-25 ℃ in room temperature.

Reaction needs aerobic to exist.Can flow bubbling to air or oxygen feeds in the reaction mixture.

The formula X, 17 β of XI and XII-side chain compound be degraded to the also available periodic acid of 17 β-carboxylic acid, sodium hypobromite or sodium bismuthate carry out.Reaction is to finish in the mixture of water and a kind of suitable like rudimentary ether of oxygenated hydrocarbon solvent.Diox and tetrahydrofuran (THF) are better, particularly the former.

The formula I, II and III (R ₃=H) the parent 17 β-carboxylic acid of compound can be with the currently known methods esterification to obtain 17 β of the present invention-carboxylicesters.For example, can make this 17 β-carboxylic acid and suitable alcohol and a kind of carbodiimide,, in a kind of suitable solvent, react as dicyclohexyl carbodiimide, solvent such as ether, tetrahydrofuran (THF), methylene dichloride or pyridine, temperature of reaction is suitable at 25～100 ℃.On the other hand, can make a kind of an alkali metal salt of this 17 β-carboxylic acid, lithium for example, sodium or sylvite, or the salt of quarternary ammonium salt compound such as triethylamine or Tributylamine or tetrabutylammonium, be preferably in the polarity solvent medium with a kind of suitable fusing agent and react, suitable temperature range is 25～100 ℃, and alkylating agent is acyloxyalkyl group halogenide or alkylhalide group alkyl carbonate for example, polarity solvent such as acetone, methylethylketone or dimethyl methyl methane amide, dimethyl sulfoxide (DMSO), methylene chloride-based or chloroform.

The ester derivative after separating of the thick steroide that generates is at a kind of suitable material Sephadex for example

The Jiao of LH-type connection Pu Ju Tang Rubber goes up and makes with extra care with chromatography, makes eluent with the solvent that suits, halogenated hydrocarbon for example, ethers, ester class such as ethylhexoate or acetonitrile.

At 16 α, in the 17 alpha-hydroxy acetalations or each epimer that in the esterification of 17 β-carboxylic acid, forms have in fact consistent dissolubility property.Therefore, proved with the method for conventional fractionation epimer for example fractional crystallization (tractionated Crystallization) from the epimer mixture separately and emanate that they are impossible.In order to obtain each epimer respectively, can be with the formula I, the epimer mixture of IV and V carries out column chromatography to be separated, so can owing to its flowability different on stationary phase separate II, III, VI, VII, VIII and IX epimer.Chromatographic separation can be at for example Sephadex

LH(such as Sephadex

LH-20) type is handed on the poly-sugared Rubber in connection Portugal and is carried out, and makes eluent with a kind of suitable organic solvent.Sephadex

LH-20 is a kind of Pu Ju Tang Rubber of hydroxypropyl alcoholization of pearl, and wherein dextran chain is the crosslinked three-dimensional polysaccharide lattice of formation, is by Uppsala, SWE (Uppsala), and Pharmacia Fine Chemicals AB makes.As eluent, successfully used halogenated hydrocarbon for example chloroform or a kind of hexane-chloroform-ethanol with 0-50: 50-100: the mixture of 10-1 ratio, preferably 20: 20: 1 mixture.

The formula X, XI and XII compound can be used as starting raw material of the present invention.They are by the following structural compound:

ⅩⅢ

Wherein solid line between C-1 and C-2 and dotted line are represented a singly-bound or two key, X ₁, X ₂And R ₇The implication of giving before having, the aldehyde phase reaction of following formula prepares.

R wherein ₂The implication of giving before having.

Aldehyde is acetaldehyde preferably, propionic aldehyde, butyraldehyde, isobutyric aldehyde, valeral, 3-methyl butyraldehyde, 2,2-dimethyl propionic aldehyde, hexanal, enanthaldehyde, octanal, aldehyde C-9 and capraldehyde.Reaction is steroide to be added in aldehyde and a kind of acid catalyst solution together carry out, and acid catalyst is for example crossed chloric acid, and is right-toluenesulphonic acids, hydrochloric acid is reflected in a kind of ether and carries out, preferably diox, or halogenated hydrocarbon, preferably methylene dichloride or chloroform.

The compound X, XI and XII can also be from corresponding 16 α, 17 α-acetone solvate

Wherein at C ₁And C ₂Between solid line and dotted line represent a singly-bound or two key, X ₁, X ₂And R ₇The implication of giving before having, the aldehyde of following formula prepares through transacetalation (transacetalisation).

R wherein ₂The implication of giving before having.

Aldehyde is acetaldehyde preferably, propionic aldehyde, butyraldehyde, isobutyric aldehyde, valeral, 3-methyl butyraldehyde, 2,2-dimethyl propionic aldehyde, hexanal, enanthaldehyde, octanal, aldehyde C-9 and capraldehyde.Reaction is steroide to be added in aldehyde and a kind of strong inorganic acid solution together of making catalyzer carry out, catalyzer is preferably crossed chloric acid or hydrochloric acid, is reflected in the ether and carries out, preferably diox or tetrahydrofuran (THF), or a kind of halohydrocarbon, preferably methylene dichloride or chloroform, or a kind of aromatic hydrocarbon, preferably toluene, or a kind of alicyclic hydrocarbon, preferably hexanaphthene, or a kind of aliphatic hydrocarbon, preferably hexane or octane-iso.Under the kind condition of back, the preparation of epimer II and XII can be saved the chromatography step.

The preparation of medicine

The compounds of this invention can be according to inflammation part topical by different way, for example through skin, parenteral route or with inhalation at the respiratory tract topical.An important goal of prescription design is the best bioavailability that reaches with active steroide composition.In the prescription that is percutaneous dosing, have high heating power and learn that this target just can reach well in the active carrier as steroide is dissolved in.This can reach by using a kind of suitable solvent system, and solvent comprises suitable di-alcohols, and like propylene glycol or 1,3 butylene glycol can use separately or be used in combination with water.

To borrow a kind of tensio-active agent be solubility promoter with this steroide or be dissolved in a kind of lipophilic in whole or in part this also can reach in mutually.Preparation through skin can be oily lamb, oil-in-water emulsion, water in oil emulsion or lotion.The system that contains the dissolved activeconstituents in emulsion carrier can constitute disperse phase and also can constitute external phase.This steroide also can make micronized solids and be present in the above-mentioned preparation.

The compression aerosol of this steroide is the inhalation that is used for oral cavity or nose.This aerosol is to be that the active steroide of 10～1000 micrograms designs to provide each to discharge dosage, and best dosage is 20～250 micrograms.The most effective this steroide can be lower the dosage range administration.Micronized steroide by the granulometric composition of reality less than 5 microns; it is suspended in adds a kind of dispersion agent in a kind of mixture of casting charge for helping; sorbitan trioleate (Sorbitan trioleate) for example; oleic acid, the lithium or the sodium salt of Yelkin TTS dioctyl sulfo-succinic acid.

Working example

The present invention will further illustrate with the example of following indefiniteness.In example, in the preparative chromatography operation, use one 2.5 milliliters/centimeter ²Hour ^-1Flow velocity.Molecular weight is measured with the electron impact mass spectroscopy in all examples.Fusing point is measured with the hot platform microscope of Leitz Wetzlar (hot stage microscope).As not having an other explanation, all efficient liquid phase chromatographic analysis (HPLC) are that flow velocity with one 1.0 ml/min is at Waters μ Bondapak C ₁₈Finish on the post (300 * 3.9 millimeters internal diameters), moving phase is that its proportioning of alcohol-water is between 50: 50 and 60: 40.

Example 1.A this example narration preparation (22RS)-(22R)-reach (22S)-11 β, 16 α, 17 α, 21-four hydroxyls pregnant steroid-1,4-diene-3,20-diketone 16 α, the method for 17 α-acetal.

(22RS)-, (22R)-and (22S)-16 α, 17 α-butylidene dioxy-6 α, 9 alpha-difluoro-11 betas, 21-dihydroxy pregnant steroid-1,4-diene-3,20-diketone.

A. 0.32 milliliter of fresh distillatory butyraldehyde-n and 2 milliliter 72% are crossed chloric acid and joined 1.0 grams, 6 α are arranged in 500 milliliters of methylene dichloride, 9 alpha-difluoro-11 betas, 16 α, 17 α, 21-four hydroxyls pregnant steroid-1,4-diene-3 is in the suspension of 20-diketone.Under agitation reaction mixture was placed 24 hours in room temperature.Reaction mixture is used anhydrous sodium sulfate drying with 10% wet chemical and water washing, steams and removes solvent.Residue is dissolved in the ethyl acetate and obtains 883 milligrams of (22RS)-16 α with petroleum ether precipitation, 17 α-butylidene dioxy-6 α, 9 alpha-difluoro-11 betas, 21-dihydroxy pregnant steroid-1,4-diene-3,20-diketone.High-efficient liquid phase analysis shows that purity is 99%, and the ratio of 22S-and 22R-epimer is 16: 84.Molecular weight 466(calculates 466.5).(22RS) the epimer mixture is gone up chromatographic separation at Sephadex LH-20 post (76 * 3 centimetres), uses heptane: chloroform: ethanol, make moving phase at 20: 20: 1.Collect cut 12315-13425 milliliter (A) and 13740-15690 milliliter (B), steam and remove solvent, residue is dissolved in methylene dichloride, use petroleum ether precipitation.Fraction A get 62 milligrams (22S)-, fraction B gets 687 milligrams of (22R)-16 α, 17 α-butylidene dioxy-6 α, 9 alpha-difluoro-11 betas, 21-dihydroxy pregnant steroid-1,4-diene-3,20-diketone.(22S)-epimer: molecular weight 466(calculates 466.5), fusing point 196-200 ℃.(22R)-epimer: molecular weight 466(calculates 466.5), fusing point 169-72 ℃.

B. 0.30 milliliter of fresh distillatory butyraldehyde-n and 2 milliliter of 72% mistake chloric acid are added to 1.0 grams, 6 α, 9 alpha-difluoro-11 betas, 21-sodium catchol disulfonate 6 α, 17 α-((1-methyl ethylidene) two (oxygen))-pregnant steroid-1,4-diene-3, the 20-diketone is in the solution of 500 milliliters of methylene dichloride.With reaction mixture under agitation 33 ℃ placed 24 hours, with wet chemical and water washing, use dried over sodium sulfate, steam except that solvent.Residue is dissolved in methylene dichloride and uses petroleum ether precipitation, gets 848 milligrams of (22RS)-16 α, 17 α-butylidene dioxy-6 α, 9 alpha-difluoro-11 betas, 21-dihydroxy pregnant steroid-1,4-diene-3,20-diketone.High-efficient liquid phase analysis shows that purity is 93%, and the ratio between 22S-and the 22R-epimer is 12/88.

B '. 1.2 milliliters of fresh distillatory butyraldehyde-ns and 3.8 milliliters are crossed chloric acid (72%) be added to 4.0 grams, 6 α are arranged in 100 milliliters of heptane, 9 alpha-difluoro-11 betas, 21-sodium catchol disulfonate 6 α, 17 α-((methyl ethylidene) two (oxygen))-pregnant steroid-1,4-diene-3 is in the suspension of 20-diketone.Reaction mixture was placed 5 hours in room temperature under fierce the stirring, and with wet chemical and water washing, dried over sodium sulfate is also steamed and removed solvent, get 4.0 gram (22RS)-16 α, 17 α-butylidene dioxy-6 α, 9 alpha-difluoro-11 betas, 21-dihydroxy pregnant steroid-1,4-diene-3,20-diketone.High-efficient liquid phase analysis shows that purity is 98.5%, and the ratio between 22S-and 22R-epimer is 3/97.After twice usefulness chloroform-sherwood oil recrystallization 3.1 gram 22R-epimers, wherein containing only is 22S-epimer and 1.3% other impurity of 1.1%.

C. similarly, by the rules of stating in the example, with 11 β-, 16 α, 17 α, 21-four hydroxyls pregnant steroid-1,4-diene-3,20-diketone, 9 α-fluoro-and 6 α-fluoro-11 β, 16 α, 17,21-four hydroxyls pregnant steroid-1,4-diene 3,20-diketone or corresponding acetone solvate replace 6 α, 9 alpha-difluoro-11 betas, 16 α, 17 α, 21-four hydroxyls pregnant steroid-1,4-diene 3,20-diketone, from acetaldehyde, propionic aldehyde, butyraldehyde, isobutyric aldehyde, valeral, 3-methyl butyraldehyde, 2,2-dimethyl propionic aldehyde, hexanal, enanthaldehyde, octanal aldehyde C-9 and lauric aldehyde prepare floride-free that replace and asymmetrical (22RS) that fluorine replaces-, (22R)-and (22S)-11 β, 16 α, 17 α, 21-four hydroxyls pregnant steroid-1,4-diene-3,16 α of 20-diketone, 17 α-acetal thing.

Example 2

A. with desonide (Prednacinolcne) 16 α, (250 milligrams of 17 α-acetone solvate; 0.6 millimole) be dissolved in 75 milliliters of methylene dichloride, add (130 milligrams of butyraldehyde-ns; 1.8 millimole) and 70% cross chloric acid (0.025 milliliter).Solution stirred 15 hours at 33 ℃.Yellow solution washs with 2 * 10 milliliter of 10% wet chemical and 4 * 10 ml waters, and drying is steamed and removed solvent.Receive: 257 milligrams (97.7%).High-efficient liquid phase analysis purity is 91.1%.7.4% unreacted ketone is arranged in the impurity.The epimer ratio is 14.6/85.4.

B. with 16 α, (0.5 restrains 17 α-acetonization tramcinolone (Triamcinolone); 1.1 millimole) be dissolved in 150 milliliters of methylene dichloride, add (260 milligrams of butyraldehyde-ns; 3.6 millimole) and 70% cross chloric acid (0.22 milliliter).This mixture was stirred 16 hours at 33 ℃.Methylene dichloride is moved on in the separating funnel mutually, with 10 milliliters of salt of wormwood and each several washing reaction bottle of methylene dichloride.Use the washing of 2 * 10 milliliter of 10% salt of wormwood and 4 * 10 ml waters then, drying, evaporation.Receive: 438 milligrams (84.9%).It is 80.2% that high-efficient liquid phase analysis gets purity.The epimer ratio is 19/81.

C. with 16 α, (0.5 restrains 17 α-acetonization fluocinonide (Fluocinolone); 1.1 millimole) be dissolved in 150 milliliters of methylene dichloride.Add (260 milligrams of butyraldehyde-ns; 3.6 millimole) and 70% cross chloric acid (0.22 milliliter).Mixture stirred 24 hours at 33 ℃.Methylene dichloride is moved into a separating funnel mutually.The washing reaction bottle is for several times separately with 15 milliliter of 10% salt of wormwood and methylene dichloride.With 2 * 15 milliliter of 10% salt of wormwood and 4 * 15 ml water washing reaction liquid, drying, evaporation.Receive: 513 milligrams (100%).High-efficient liquid phase analysis purity is 97.4%.Epimer is than being 8.6/91.4.

3. example narrations of example preparation, 11 beta-hydroxies-16 α, 17 α-((1-methyl ethylidene) two (oxygen))-and (20RS)-, (20R)-and (20S)-11 beta-hydroxy-16 α, 17 alpha-alkyl methylene radical dioxy androstanes-1,4-diene-3-ketone-17 β-carboxylic acid and 11 beta-hydroxies-16 α, 17 α ((1-methyl ethylidene) two (oxygen))-and (20RS)-, (20R)-and (20S)-11 β hydroxy-16 alpha-, the method for 17 alpha-alkyl methylene radical dioxy androstane-4-alkene-3-ketone-17 β-carboxylic-acids.6 α, 9 alpha-difluoro-11 betas-hydroxy-16 alpha-, 17 α-((1-methyl ethylidene)-two (oxygen)) androstane-1, the preparation of 4-diene-3-ketone-17 β-carboxylic acid.

A. to 1.99 gram fluocinonide (fluocinolone), 16 α, 17 α-acetone solvate adds 40 milliliter of 20% wet chemical in the solution of 120 ml methanol.Under agitation made bubbling about 20 hours in room temperature to this solution bubbling air stream.Boil off and add 200 ml waters behind the methyl alcohol in the residue.With this solution of dichloromethane extraction, with dilute hydrochloric acid esterification water layer.Filter collecting precipitation and dry 1.34 grams, 6 α, 9 alpha-difluoro-11 betas-hydroxy-16 alpha-, 17 α-((1-methyl ethylidene)-two (oxygen)) androstane-1,4-diene-3-ketone-17 β-carboxylic acid, fusing point 264-68 ℃, the molecular weight 438 of getting.High pressure liquid phase analysis purity is 94.0%.The water layer ethyl acetate extraction.Solvent steams except that after drying gets another part acid 0.26 and restrains.Purity: 93.7%

B. the solution that periodic acid (15.1 gram) is arranged in 16.5 ml waters being added to has fluocinonide (fluocinolone) 16 α in 55 milliliters of dioxs, in the solution of 17 α-acetone solvate (5.0 gram).With reaction mixture stirring at room 20 hours, with saturated sodium bicarbonate aqueous solution neutralization evaporation then.Residue is dissolved in 200 milliliters of methylene dichloride also with 8 * 100 milliliter of 10% wet chemical washing.Water layer uses the concentrated hydrochloric acid acidifying also with 6 * 100 milliliters of ethyl acetate extraction.Dry back is steamed and is removed solvent.Residue is dissolved in 400 milliliters of ethyl acetate and with sherwood oil and makes it precipitation, gets 3.96 grams, 6 α, 9 alpha-difluoro-11 betas-hydroxy-16 alpha-, 17 α-((1-methyl ethylidene) two (oxygen))-androstane-1,4-diene-3-ketone 17 β-carboxylic acid.It is 99.5% that high performance liquid phase is measured purity.

C. similarly, by the process of stating in the example, use 11 β, 16 α, 17 α, 21-four hydroxyls pregnant steroid-1,4-diene-3-20 diketone, 6 α-fluoro-11 β, 16 α, 17 α, 21-four hydroxyls pregnant steroid-1,4-diene-3,20-diketone and tramcinolone 16 α, 17 α-acetonide replaces fluocinonide (fluocinolone) 16 α, and 17 α-acetone solvate prepares 11 beta-hydroxies-16 α, 17 α-((1-methyl ethylidene) two (oxygen)) androstane-1,4-diene-3-ketone-17 β-carboxylic-acid.With 16 alpha-hydroxy prednisonlones, 6 α-fluoro-16 alpha-hydroxy prednisonlones, tramcinolone and fluocinonide and acetaldehyde, propionic aldehyde, butyraldehyde, isobutyric aldehyde, valeral, 3-methyl butyraldehyde, 2,2-dimethyl propionic aldehyde, hexanal, enanthaldehyde, octanal, 16 α that generate between aldehyde C-9 and the lauric aldehyde, 17 α-acetal compound replaces 16 α, 17 α-acetone solvate and prepare (20RS)-(20R)-and (20S)-11 beta-hydroxy-16 α, 17 alpha-alkyl methylene radical dioxy androstanes-1, the 4-diene and-the ester class of 4-alkene-3-ketone-17 β-carboxylic acid.

Example 4.1 '-ethoxy carbonyl oxygen ethyl 6 α, 9 alpha-difluoro-11 betas-hydroxy-16 alpha-, 17 α-((1-methyl ethylidene) two (oxygen)) androstane-1,4-diene-3-ketone-17 β-carboxylicesters.

A. with 6 α, 9 alpha-difluoro-11 betas-hydroxy-16 alpha-, 17 α-((1-methyl ethylidene) two (oxygen))-androstane-1,4-diene-3-ketone-17 β-carboxylic acid (600 milligrams) and saleratus (684 milligrams) are dissolved in 45 milliliters of dimethyl formamides.Add (2 milliliters) 1-bromotrifluoromethane ethyl-carbonate and with reaction mixture in stirred overnight at room temperature.Add 200 ml waters, with this mixture of dichloromethane extraction.The extract that merges uses chloroform give moving phase with 5% sodium bicarbonate water liquid and water washing, residue at the enterprising circumstances in which people get things ready for a trip spectrometry purifying of Sephadex LH-20 post (72 * 6.3 centimetres).Collect 1515-2250 milliliter part, after the evaporation 480 milligram 1 '-ethoxy carbonyl oxygen ethyl 6 α, 9 alpha-difluoro-11 betas-hydroxy-16 alpha-, 17 α-((1-methyl ethylidene) two (oxygen))-androstane-1,4-diene-3-ketone-17 β-carboxylicesters.It is 98.1% that high performance liquid phase is measured purity, and the ratio of epimer A/B is 48/52.Fusing point: 218-27 ℃.(α) ²⁵ _D=+63.2 ° of (C=0.214; Methylene dichloride).Molecular weight 554.

With this 1 '-ethoxy carbonyl oxygen ethyl 6 α, 9 alpha-difluoro-11 betas-hydroxy-16 alpha-, 17 α-(1-methyl ethylidene) two (oxygen)) androstane-1,4-diene-3-ketone-17 β-carboxylicesters (480 milligrams) is gone up chromatography at Sephadex LH-20 post (76 * 6.3 centimeters) and separated, and uses heptane: chloroform: ethanol is to make moving phase at 20: 20: 1.Collect the 2325-2715 ml fraction, evaporation makes it precipitation with the methylene dichloride dissolution residual substance and with sherwood oil, gets 200 milligrams of compounds (A), and purity 97.3%(high-efficient liquid phase analysis is measured).Fusing point: 246-50 ℃ (α) ²⁵ _D=+100.5 ° of (C=0.214; Methylene dichloride).Molecular weight 554.

4140-5100 milliliter stream part gets 250 milligrams of compounds (B), purity 99.0%.Fusing point: 250-55 ℃ (α) ²⁵ _D=+28.5 ° of (C=0.246; Methylene dichloride).Molecular weight 554.The methyne signal of ester group B in the nuclear-magnetism spectrum moves 0.13ppm than A to downfield, and the spectrographic rest part is near consistent.The electronic impact mass spectrum of A and B all is consistent except the intensity of mass peak.Difference on these spectroscopy shows that with similar aspect A and B are because the epimer that chiral centre causes in ester group.

B. with 6 α, 9 alpha-difluoro-11 betas-hydroxy-16 alpha-, 17 α-((1-methyl ethylidene) two (oxygen)) androstane-1,4-diene-3-ketone-17 β-carboxylic acid (200 milligrams) is dissolved in 25 milliliters of dimethyl formamides.Add 1-chloroethyl ethyl-carbonate (100 milligrams), saleratus (70 milligrams) and hexaoxacyclooctadecane-6-6.Reaction mixture was stirred 3 hours at 80 ℃, and cooling use dichloromethane extraction, dry also evaporate to dryness after adding 150 ml waters.With the method identical with process A with crude product refining get 207 milligram 1 '-ethyl ester oxygen carbonyl oxygen ethyl 6 α, 9 alpha-difluoro-11 betas-hydroxy-16 alpha-, 17 α-((1-methyl ethylidene) two (oxygen)) androstane-1,4-diene-3-ketone-17 β-carboxylic ester ester.Purity (high performance liquid phase) 98.4%, epimer A/B ratio is 54/46.

C. with 6 α, 9 alpha-difluoro-11 betas-hydroxy-16 alpha-, 17 α-((1-methyl ethylidene) two (oxygen)) androstane-1,4-diene-3-ketone-17 β-carboxylic acid (200 milligrams) and 1,5-diaza-bicyclo (5.4.0)+-carbene-5(140 milligram) be suspended in 25 milliliters of benzene and be heated to backflow.To have the solution of 1-bromotrifluoromethane ethyl-carbonate (175 milligrams) to add in 5 milliliters of benzene, mixture refluxes half an hour.The cooling back adds 50 milliliters of methylene dichloride, and with water washing, drying is evaporated with this solution.Thick product is used with rules A same procedure refining, 207 milligram 1 '-ethoxy carbonyl oxygen ethyl 6 α, 9 alpha-difluoro-11 betas-hydroxy-16 alpha-, 17 α-((1-methyl ethylidene) two (oxygen)) androstane-1,4-diene-3-ketone-17 β-carboxylicesters.Purity (high performance liquid phase) 96.4%, epimer A/B ratio is 44/56.

D. in 25 milliliters of acetone, 6 α are arranged, 9 alpha-difluoro-11 betas-hydroxy-16 alpha-, 17 α ((1-methyl ethylidene) two (oxygen)) androstane-1 adds 175 milligrams of alpha-brominated diethyl carbonate and 45 milligrams of Anhydrous potassium carbonates in the solution of 4-diene-3-ketone-17 β-carboxylic acid (100 milligrams).Mixture heating up refluxed 6 hours.In reaction mixture impouring 150 ml waters that this is cold, use dichloromethane extraction.Extract washes with water, with dried over sodium sulfate and steam to remove solvent get 65 milligrams of solid 1 '-ethyl ester oxygen carbonyl oxygen ethyl 6 α, 9 alpha-difluoro-11 betas-hydroxy-16 alpha-, 17 α-((1-methyl ethylidene) two (oxygen)) androstane-1,4-diene-3-ketone-17 β-carboxylicesters.It is 97.6% that high performance liquid phase is measured purity, and epimer A/B ratio is 49/51.

E. with 6 α, 9 alpha-difluoro-11 betas-hydroxy-16 alpha-, 17 α-((1-methyl ethylidene) two (oxygen)) androstane-1,4-diene-3-ketone-17 β-carboxylic acid (500 milligrams) and hydrogen sulfate TBuA (577 milligrams) are added in the sodium hydroxide of 3 milliliters of 1M.To in 50 milliliters of methylene dichloride, there be the solution of 435 milligrams of 1-bromotrifluoromethane ethyl-carbonates to add.This mixture under agitation refluxed spend the night the two separate that will be divided into.Organic layer washs with 2 * 10 ml waters, drying, and evaporation, it is refining that thick product is gone up chromatography at Sephadex LH-20 post (72 * 6.3 centimetres), uses chloroform give moving phase.Collect the 1545-1950 ml fraction, the evaporation, residue from methylene dichloride-petroleum ether precipitation get 341 milligram 1 '-ethoxy carbonyl oxygen ethyl 6 α, 9 alpha-difluoro-11 betas-hydroxy-16 alpha-, 17 α-((1-methyl ethylidene)-two (oxygen)) androstane-1,4-diene-3-ketone-17 β-carboxylicesters.It is 99.2% that high performance liquid phase is measured purity, and the ratio of epimer A/B is 56/44.

F. with 6 α, 9 alpha-difluoro-11 betas-hydroxy-16 alpha-, 17 α-((1-methyl ethylidene) two (oxygen)) androstane-1,4-diene-3-ketone-17 β-carboxylic acid (200 milligrams) and tricaprylylmethylammchloride chloride (tricaprylmethylammonium chloride) (200 milligrams) are added in 5 milliliters of saturated sodium bicarbonate water liquid.To there be the solution of 100 milligrams of 1-bromotrifluoromethane ethyl-carbonates to add in 10 milliliters of methylene dichloride.This mixture stirred 20 hours at 45 ℃, with 10 milliliters of methylene dichloride dilutions, to be same as the method separation and purification of rules E, 254 milligram 1 '-ethoxy carbonyl oxygen ethyl 6 α, 9 alpha-difluoro-11 betas-hydroxy-16 alpha-, 17 α-((1-methyl ethylidene) two (oxygen)) androstane-1,4-diene-3-ketone-17 β-carboxylicesters.Purity (high performance liquid phase) is 97.4%, and epimer A/B ratio is 60/40).

G. with 6 α, 9 alpha-difluoro-11 betas-hydroxy-16 alpha-, 17 α-((1-methyl ethylidene) two (oxygen)) androstane-1,4-diene-3-ketone-17 β-carboxylic acid (200 milligrams), 1-bromotrifluoromethane ethyl-carbonate (135 milligrams) and triethylamine (275 milligrams) are dissolved in 20 milliliters of dimethyl formamides.This mixture was stirred 3 hours at 80 ℃, with 200 milliliters of methylene dichloride dilutions, with water washing, drying, evaporation.Crude product uses the method identical with rules A refining, 69 milligram 1 '-ethoxy carbonyl oxygen ethyl 6 α, 9 alpha-difluoro-11 betas-hydroxy-16 alpha-, 17 α-((1-methyl ethylidene) two (oxygen)) androstane-1,4-diene-3-ketone-17 β-carboxylicesters.Purity (high performance liquid phase) 97.8%, the ratio of epimer A/B is 48/52.

Example 5.1 '-acetyl oxygen ethyl 6 α, 9 alpha-difluoro-11 betas-hydroxy-16 alpha-, 17 α-((1-methyl ethylidene) two (oxygen))-androstane-1,4-diene-3-ketone-17 β-carboxylicesters.

With 6 α, 9 alpha-difluoro-11 betas-hydroxy-16 alpha-, 17 α-((1-methyl ethylidene) two (oxygen)) androstane-1,4-diene-3-ketone-17 β-carboxylic acid (500 milligrams) and saleratus (575 milligrams) are dissolved in 40 milliliters of dimethyl formamides.Add (1 milliliter) 1-chloroethyl acetic ester and with this reaction mixture stirring at room 40 hours.In reaction mixture impouring 50 ml waters, use dichloromethane extraction, extract is with sodium bicarbonate aqueous solution and water washing, and drying is also evaporated.Residue is gone up chromatography at Sephadex LH-20 post (72 * 6.3 centimetres) and is separated, and uses chloroform give moving phase.Collect 1755-2025 milliliter and 2026-2325 ml fraction and evaporation.

Go up chromatographic separation from 1755-2025 ml fraction gained solid product at Sephadex LH-20 post (76 * 6.3 centimeter inner diameter) and re-refine, use heptane-chloroform-ethanol to make moving phase with 20: 20: 1 mixture.Collect the 2505-2880 ml fraction, evaporation.Residue is dissolved in the methylene dichloride and gets 167 milligrams of solid products (A) with petroleum ether precipitation.It is 99.1% that high performance liquid phase is measured purity.Fusing point 238-59 ℃.(α) ²⁵ _D=+94 ° of (C=0.192; Methylene dichloride).Molecular weight 524.

The solid that derives from above-mentioned 2026-2325 milliliter is used refining with last identical chromatography.Collect the 5100-5670 ml fraction, evaporation.Residue is dissolved in the methylene dichloride and gets 165 milligrams of solid products (B) with petroleum ether precipitation.High performance liquid phase is measured purity 99.4%.Fusing point 261-65 ℃.(α) ²⁵ _D=+34 ° of (C=0.262; Methylene dichloride) molecular weight 524.

A and B's ¹H nuclear-magnetism spectrum almost is consistent except the methyne quartet of its ester group, and the methyne quartet in the compd B is than moving 0.16ppm to downfield in the compd A.Form of chips except A the intensity of mass peak and B in the electronic impact mass spectrum is consistent.The spectroscopic properties of A and B shows that they are epimers that the chiral centre owing to ester group causes.

Its preparation of the compound that the table 1-3 of example 6-88 in the back given, separate and refining be similar described in example 4 and 5.

The preparation of example 89 medicines

The non-limiting prescription example of enumerating below is to use for different topical formulations.The amount of active steroide is generally the 0.001-0.2%(w/w in the percutaneous dosing prescription), best 0.01-0.1%(w/w).

Prescription 1, ointment

Micronized steroide 0.025 gram

White oil 10.0 grams

White sunshine adds to 100.0 grams

Prescription 2, ointment

Steroide 0.025 gram

Propylene glycol 5.0 grams

Anhydro sorbitol sesqui oleic acid ester 5.0 grams

White oil 10.0 grams

White sunshine adds to 100.0 grams

Prescription 3, the oil-in-water creme

Steroide 0.025 gram

Cetyl alcohol 5.0 grams

Glycerol monostearate 5.0 grams

White oil 10.0 grams

Cetomacrogol 1000 list cetyl ether 2.0 grams

（Cetomacrogol 1000）

Citric acid 0.1 gram

Trisodium Citrate 0.2 gram

Propylene glycol 35.0 grams

Water adds to 100.0 grams

Prescription 4, the oil-in-water creme

Micronized steroide 0.025 gram

White sunshine 15.0 grams

White oil 5.0 grams

Cetyl alcohol 5.0 grams

Polycondensation sorbitan stearate 2.0 grams

（Sorbimacrogol stearate）

Arlacel-60 0.5 gram

Sorbic Acid 0.2 gram

Citric acid 0.1 gram

Trisodium Citrate 0.2 gram

Water adds to 100.0 grams

Prescription 5, the water-in-oil creme

Steroide 0.025 gram

White sunshine 35.0 grams

White oil 5.0 grams

Anhydro sorbitol sesqui oleic acid ester 5.0 grams

Sorbic Acid 0.2 gram

Citric acid 0.1 gram

Trisodium Citrate 0.2 gram gram

Water adds to 100.0 grams

Prescription 6, lotion

0.25 milligram of steroide

0.5 milliliter of Virahol

3 milligrams of carboxy vinyl polymers

Sodium hydroxide is an amount of

Water adds to 1.0 grams

Prescription 7, suspending injection

Micronize steroide 0.05-10 milligram

7 milligrams of Xylo-Mucines

7 milligrams in sodium-chlor

Polyoxyethylene (20) dehydration

0.5 milligram of sorbitol monooleate

8 milligrams of phenylcarbinols

The water of sterilization adds to 1.0 milliliters

Prescription 8, mouthful with the inhalation aerosol of nose

Micronized steroide 0.1% w/w

Sorbitan trioleate 0.7% w/w

Trichlorofluoromethane 24.8% w/w

Dichloro tetrafluoro ethane 24.8% w/w

Refrigerant 12 49.6% w/w

Prescription 9, atomized liquid

7.0 milligrams of steroides

Propylene glycol 5.0 grams

Water adds to 10.0 grams

Prescription 10 sucks pulvis

With the following mixture gelatine capsule of packing into

0.1 milligram of micronize steroide

20.0 milligrams of lactose

Suck this pulvis with a suction apparatus.

Pharmacology

New androstane-17's class is to the avidity of glucocorticoid receptor

Be compound according to all steroides of the present invention with physiologically active.This new androstane-17's class is used as a kind of model of measuring anti-inflammatory intensity to the avidity of glucocorticoid receptor.The strong dragon of hydroxyl (budesonide) ((22R has contracted its acceptor avidity and butyraldehyde, S)-16 α, 17 α-butylidene dioxy-11 β, 21-dihydroxy pregnant steroid-1,4-diene-3,20-diketone) compare, the butyraldehyde strong dragon of hydroxyl (budesonide) that contracts is a kind of high reactivity glucocorticosteroid (Thalen and Bratsand with better part and systemic effect ratio, Arzneim ,-Forsh.29 volume, 1687-90 page or leaf (1979)).

Use the male Sprague-Dawley rat at one to two monthly age in the research process.Extract its thymus gland and be put in the ice-cold physiological saline, this is organized in the Potter Elvehjem homogenizer at 10 milliliters of Tutofusin triss (Tris) that contain 20 millimoles, pH7.4, the 10%(w/v) glycerine, 1 millimole ethylenediamine tetraacetic acid (EDTA) (EDTA), 20 millimole NaMoO ₄, homogenization in the damping fluid of 10 millimole mercaptoethanols.With homogenate 20000 * centrifugal 15 minutes of gram.Will be 20,000 * part (230 microlitre) and 100 microlitre phenylmethylsulfonyl fluoride (a kind of esterification enzyme inhibitors, final concn 0.5 millimole) of the supernatant liquor of gram, unlabelled competition thing of 20 microlitres and 50 microlitres ³The dexamethasone of H-mark (dexamethasone) (final concn 3 nMs) was 0 ℃ of insulation 24 hours.With this mixture and 60 microlitre 2.5%(w/vs) activated carbon and 0.25%(w/v) dextran 170 is suspended in 20 millimole Tutofusin triss (Tris), pH7.4,1 millimole ethylenediamine tetraacetic acid (EDTA) (EDTA) and 20 millimole NaMoO ₄Bonded was separated in 10 minutes with the free steroide 0 ℃ of insulation.500 * gram centrifugation 10 minutes after, with 230 microlitre supernatant liquors in 10 milliliters of Insta-Gel with the Packard spectrophotometer counting that glitters.With supernatant liquor and a) ( ³H) dexamethasone, b) ( ³H) dexamethasone adds 1000 times of excessive unlabelled dexamethasone and c) ( ³H) dexamethasone add 0.03-300 doubly the competition thing of " excessive " be incubated together.When 1000 times of excessive unlabelled dexamethasones are added to ( ³H)-measure its non-specific combination during the dexamethasone of mark.

The radioactivity of the bind receptor that the radioactivity that the bind receptor that the competition thing exists arranged exists divided by uncontested thing multiply by 100 percentage ratios of specific combination that obtain the dexamethasone of mark again.The competition thing of each concentration with the radioactive percentage ratio of its specific combination with the competition substrate concentration logarithm as figure.Curve is compared and is benchmark with the butyraldehyde strong dragon of hydroxyl that contracts in 50% specific combination level, and the latter's relative binding affinity (relative binding affinity＜RBA 〉) be decided to be 1.

Relative binding affinity (RBA) totalizing meter to glucocorticoid receptor of some compounds that have been studied of table 4.

The relative bonding force of compound by instance number

（RBA）

The butyraldehyde strong dragon of hydroxyl (Budesonide) 1 that contract

4 epimer B 0.30

5 epimer B 0.17

27 0.50

38 0.04

Continuous table 4.

The relative bonding force of compound by instance number

（RBA）

55 0.20

64 0.05

67 0.04

69 0.44

84 1.03

87 0.63

Claims (1)

1, a kind of method for preparing following formula: compound or its steric isomer compound,

In structural formula

1, the 2-position is saturated bond or two key

X ₁Be selected from hydrogen, fluorine, chlorine and bromine

X ₂Be selected from hydrogen, fluorine, chlorine and bromine

R ₂Be selected from straight and ramose hydrocarbon chain with 1-10 carbon atom

R ₇For hydrogen or one have the 1-10 carbon atom by acyl group straight or that branch arranges,

It is characterized in that

A kind of compound that will have following formula

Having in the presence of a kind of acid catalyst and the following formula: compound reaction,

X wherein ₁, X ₂, R ₂, R ₇And

Described as defined above.