CS268550B2 - Method of new steroids production - Google Patents

Abstract

Cpds. of formula (I) and stereoisomers are new where the 1,2-posn. is an opt. double bond; X1 and X2 each = H, F, Cl or Br; R1 = H or 1-4C opt. branched hydrocarbyl; R2 = H or 1-10C opt. branched hydrocarbyl; R3 = -CR4R5-O-CO-R6 or -CR4R5-O-CO-Y-R6; Y = O or S; R4 = a value of R2 or phenyl; R5 = H or Me; and R6 = H, 1-10C opt. branched, opt. unsatd. hydrocarbyl, haloalkyl, 3-10 membered heterocyclic system, 3-7C cycloalkyl (-1-2C-alkyl) or phenyl or benzyl opt. substd. by alkyl, NO2, carboxy, halogen CN, (carbo)alkoxy and/or CF3 gp(s).; provided that when R2 = H, R1 = Me. Also new are the corresp. free acid intermediates (I; R3 = H).

Description

ANDERSSON PAUL HAKAN, SODRA SANDBY ANDERSSON PER TURE, LUND AXELSSON BENGT INGEMAR, 6ENARP THALEN BROR ARNE, BjXRRED TROFAST JAN WILLIAM, LUND / SE /

AKTIEBOLAGET DRACO, LUND / SE / (55)

(57) A method for producing sterols of formula XXX wherein the 1/2 position is saturated or contains a double bond,

X ^ represents a hydrogen atom, a fluorine atom, a chlorine atom or a bromine atom,

X- represents a hydrogen, fluorine, chlorine or bromine atom,

R _? It means a straight or branched hydrocarbon group with hydrogen ^£ 1 ai 10 carbon atoms and

R is hydrogen or an acyl group ^f having 1 to 10 carbon bhllku straight or branched chain, and their stereolsomernich Forms 1, characterized in that the compound of formula XX, wherein

X, X _{2, R?} and having the above meanings, acts with a compound of formula (XXI) in which:

R ₂ has the abovementioned meaning, in the presence of an acid catalyst. The products serve as starting materials for the production of compounds with valuable pharmacological, in particular anti-inflammatory properties.

CS 268550 02

CS 268550 02

The invention relates to a process for the preparation of novel pharmacologically active compounds and intermediates necessary for their preparation. The invention also relates to pharmaceutical compositions containing the pharmacologically active compounds according to the invention and which can be used for the treatment of inflammatory, allergic, musculoskeletal or dermatological diseases.

It is an object of the present invention to provide a process for producing strolls serving as a starting material. substances for the production of glucocorticosteroids having high potency at the apllkakaee site and low glucocorticosteroid systemic activity.

It is known that certain glucocorticosteroids (GSS) can be used for the topical therapy of inflammatory diseases, allergic diseases or immunological diseases of the respiratory tract (e.g. asthma and rhinitis), skin diseases / eczema, psoriasis / or intestinal tract diseases such as ulcer inflammation, Such topical glucocorticoid therapy can provide clinical benefits in excess of general therapy (e.g., with glucocorticoid tablets), particularly with a view to reducing the adverse effects of glucocorticoid outside the treatment site. To achieve such clinical benefits, for example in severe respiratory diseases, the glucocorticosteroid must have an appropriate pharmacological profile. It should exhibit high glucocorticoid activity at the site of administration but also rapid inactivation, for example by hydrolysis in the target organ or after administration in the general circulatory system.

Since the binding of glucocorticosteroid to the glucocorticosteroid receptor is a prerequisite for its anti-inflammatory efficacy and anti-allergic effects, it is clear that the ability of the steroid to bind to its receptor (s) may be used as an adequate method for determining the biological activity of glucocorticosteroid. The direct relationship between the affinity of the g lucocorticosteroid to the receptor and its anti-inflammatory effects has been demonstrated using the rat ear edema test Qrov · Correlation between chemical structure, receptor binding, and biology actvity of some novel, 16e /, 17cZ-acetaIsubst1tuted glucocorticoids , E. Oahlberg, A. Thalen, R. Brattsand, JA. Gudtafsson, U. Johansson, K. Roenpke, and T. Saartok, Mol. Pharmacol. 25 70 (1984).

Certain esters of 3-oxaandrosta-1,4-diene-17β-carboxylic acid have been found to have high binding affinity for the glucocorticosteroid receptor. Such compounds which can be used к treatment and control of inflammatory processes present new compounds, 16,17-acetalsubst1tuovaných androstane-17/3-carboxy _y -dicarboxylic acids of the general formula I

C>

wherein the position 1,2 is saturated or contains a double bond.

represents a hydrogen atom, a fluorine atom, a chlorine atom or a bromine atom,

X ₂ represents a hydrogen, fluorine, chlorine or bromine atom,

R ^ represents a hydrogen atom or a straight or branched hydrocarbon group having 1 to 4 carbon atoms.

CS 268550 К

R? represents a hydrogen atom or a straight or branched hydrocarbon group having from 1 to 10 carbon atoms; and

R 1 represents a group of the formula

O o

CR ₄ R _{5 O} OCR or CR ^ ^ wherein RjOCYR

Y is oxygen or sulfur,

R ^ represents a hydrogen atom, a straight or branched hydrocarbon group having up to 10 carbon atoms or a phenyl group,

R 1 represents a hydrogen atom or a methyl group and represents a hydrogen atom, a straight or branched, saturated or unsaturated hydrocarbon group having 1 to 10 carbon atoms, an alkyl group substituted with at least one halogen atom, a heterocyclic ring system having 3 to 10 atoms in the ring system,

- / CH - »/ СН / СН- /, wherein m is 0, 1 or 2 and n is m, n, 2, 3, 4, 5 or 6, phenyl or benzyl, these groups being optionally substituted once or a plurality of alkyl! groups nitroskupinaml, karboxyskupinaml, an alkoxy, halogen, kyanoskupinaml, not aIkoxykarbonylovýni groups • bo trifluoromethyl groups, with the proviso that when R ₂ is hydrogen then R is methyl.

The individual sterolsomer components present in the steroid mixture of formula (I) above may be described as follows:

STEED

i (II · episer S)

O

(III; epimer phi)

Individual sterol isomeric tables present in a mixture of boxylic acid having the formula IV or V-teroidic esters of 17/3-car or wherein:

St is pure can be described as ⁰

II II $ tC0CR _{4 5 5} 0CR ₆

0

II II

StC0CR ₄ R _with 0CYR ₆ steroid, not following ·) general formulas; *

0 и I и

StCOCOCR,

I ⁶

AND

I ^R 5

I * o o> StCOCOCR,

I ^R 5 / IV / / VI / / VII *?

II I II

StCOCOCYR, t '

I ^R 5

I o

II 'II

StCOCOCTft,

I ⁶ * 5 / VIII / IX /

In the dlasteroitoners of formulas II, III, VI, VII, VIII and IX, the configurations have been cast on only one of several asymmetric carbon atoms. Such diastereo toners are referred to as epomers.

The alkyl group in the above definitions is represented by a pH or a branched hydrocarbon group having 1 to 5 carbon atoms, preferably 1 to 4 carbon atoms

The alkoxy group in the above definitions represents an -O-alkyl group in which the alkyl moiety is as defined above for an alkyl group.

Halogen in the above definitions is preferably chlorine, bromine or fluorine.

The alkoxycarbonyl group in the above definitions is represented by a -COOalkyl group in which the alkyl moiety is as defined above for an alkyl group.

The heterocyclic ring system is a ring system containing as heteroatoms nitrogen, oxygen or sulfur ·

Preferred systems are pyrryl, pyrimidyl, pyrimidyl, pyrazyl, furyl, pyranyl, benzofuranyl,

Indotyl and thienyl.

Particularly preferred compounds are:

CS 268550 02

6-Difluoro-11'-hydroxy-16'Z, 17 (Z- [7'-methylethylidene / bis / oxy / Jandrosta-1,4-dien-3-one-1'-carboxylic acid) - ethoxycarbonyloxyethyl / mixture of epimers A + в and epimer В /, /

9-Fluoro-11Z-hydroxy-16- [17-methylethyl] -dis (bls) -thi-1-androsta-1,4-dien-3-one 1-isopropoxycarbonyloxyethyl ester 17β-carboxylic acids, epimer B, i

1'-proposycarbonyloxyethyl ester 6,6,9-difluoro-11 (1-hydroxy-16,6,17-O- [(1-ethylethylene)] (bis) oxo-1,4-diene -3-on-1 7D-carboxylic acid, epimer 8, J /

6-Propoxycarbonyloxyethyl ester 6-fluoro-1,4-hydroxy-16- [1,1-a] methyl-1-methylthiidene / bis / oxy / landrosta-1,4-diene-3 -one-174-carboxylic acid, epimer mixture \

A + 8 and epimer B, i

acetoxyethyl ester (20R) - (4R-fluoro-11Z-hydroxy-1C), 17-6-propylmethylenedioxyandrosine;

tk-1,4-dien-3-one-17β-carboxylic acid, epimer B,?

<1 * -ethoxycarbonyloxyethyl ester (2 2R) -% (-fluoro-114-hydroxy-16 <1, 1, 2-ol) methylenedioxyandro-ta-1,4-dien-3-one -17 / 3-carboxylic acids, epimer B, ·

720R (-9-Fluoro-11/3-hydroxy-16,6,17-propylmethylenedioxyandrosta-1,4-dien-3-one) -17-carboxylic acid 1-isopropoxycarbonyloxyethyl ester acids, epimer B, *

^Z 1 - ethoxycarbonyl yloxy thylester / 20R7-6 © / 9 N -di Ί fluoro-1-hydroxy-1-6o / 1 7a <lmethylendioxyandrosta propyl-1,4-dien-3-one-17/3 -carboxylic acids, a mixture of epimer A + V and epimer

8. ·

AND

Compounds of formula (I) may be prepared by oxidizing compounds of formulas (X), (XI) and (XIIj)

(XI)

in which the solid and dotted lines between the carbon atom at the 1-position and the carbon atom at the 2-position represent a single or double bond, and

X 1, ^R 1 ^{and R} 2 as defined above and

R? represents a hydrogen atom or an acyl group having 1 to 10 carbon atoms in a straight or branched chain, to give the corresponding 17/1-carboxylic acids.

The N-carboxylic acid is then esterified to give compounds of formulas I-IX in which -> -. X 1, X ₂ , R 1, R ₂ and R 2 have the above meanings.

The process for converting compounds of formulas X, XI or XII to the corresponding 17 carboxylic acid is carried out in a suitable oxidized hydrocarbon solvent such as a lower alkanol. Preferred solvents are methanol and ethanol, especially methanol. The reaction medium is slightly alkalinized by the addition of a suitable weak inorganic base, such as an alkali metal carbonate, for example sodium carbonate, lithium carbonate or potassium carbonate. Preferably potassium carbonate is used. The conversion of compounds of formula X, XI or XII to 1'-carboxylic acids is carried out at room temperature, i.e. at temperatures between 20 and 25 ° C.

The reaction requires the presence of oxygen. Oxygen can be replaced by supplying an air stream to the reaction mixture or by supplying oxygen to the reaction mixture.

Oxidative degradation of the side chain at the 17 'position of the compounds of formulas X, XI and XII to give the corresponding 17β-carboxylic acids can also be accomplished by periodic acid, sodium broaate or sodium vizate. This reaction is carried out in a mixture of water and a suitable oxygenated hydrocarbon solvent, such as a lower ether. Particularly preferred are dioxane and tetrahydrofuran, especially tetrahydrofuran.

The 7β-carboxylic acid of the general formulas can be esterified in a known manner to give 17β-carboxylic acid esters. For example, 17β-carboxylic acid can be reacted with a suitable alcohol and a carbodiimide, for example dicyclohexylcarbodiimide, in a suitable solvent such as diethyl ether, tetrahydrofuran, methylene chloride or pyridine, preferably at a temperature of 25 to 100 ° C. Alternatively, an alkali metal salt of 17α-carboxylic acid, for example a lithium, sodium or potassium salt, a salt with a quaternary ammonium compound, such as a triethyl or tributylamine salt, or a tetrabutylammonium salt with a suitable alkyCS 268550 B2 fastener, e.g. an alkoxyalkyl halide or a haloalkylcarbonate, preferably in a polar solvent such as acetone, methyl ethyl ketone or diaethylformamide, dimethylsulfone, methylene chloride or chloroform as the reaction medium, usually at temperatures in the range of 25 to 100 ° C. The reaction may also be carried out in the presence of a crown ether.

The resulting crude steroid esters are purified by chromatography on a suitable material, for example, on Sephadex-type crosslinked dextran gels using suitable solvents as eluents, for example halogenated hydrocarbons, ethers, esters such as ethyl acetate or acetonitrile.

The individual epimers produced during the acetalization of 16? 17,? -Hydroxy groups or esterification of 174-carboxylic acids have practically identical dissolution characteristics. For these reasons, it is not possible to separate and isolate from the epithelial mixture by conventional stereoisomeric separation methods, for example fractional crystallization. Thus, to obtain individual epimers, sterolsomer mixtures of the compounds of formulas I, IV and above are subjected to column chromatography to separate epimeric compounds. formulas II, III, VI, VII, VIII and IX based on different mobility at the stationary phase ·

Chromatography can be carried out, for example, on crosslinked dextran type / О / / О / gels

Sephadex LH, for example Sephadex LH-20 in combination with a suitable organic solvent (eluent), as eluent. Sephadex LH-20, prepared by Pharmacia Fine Chemicals AB, Uppsala, Sweden, is a hydroxypropyl dextran bead gel, wherein the dextran chains are crosslinked to form a three-dimensional polysaccharide network. Halogenated hydrocarbons, for example chloroform or a mixture of heptane, chloroform and ethanol in a ratio of 5 to 50: 50 to 100: 10 to 1, preferably in a ratio of 20: 20: 1, are used as eluent.

The present invention provides a process for the preparation of compounds of formulas (X), (XI) and (XII), which are further used to produce compounds of formula (I).

of formula XX in the transacetalization of the corresponding compounds

The compounds of formula (X), (XI) and (XII) are prepared according to the process of the present invention by 16% (acetone)

wherein the solid and dashed lines between the carbon atom at the 1-position and the carbon atom at the 2-position represent a single or double bond, and

X ^ а X? and R? have the above-mentioned meanings, by the action of aldehydes of general XXI

/ XXI /

As defined above, to give compounds of formula XXX wherein:

wherein position 1, 2 is saturated or contains a double bond,

X _1Z X ^, and R ^ are as defined above and their stereolsonernich forms.

the aldehyde is preferably acetaldehyde, propanal, butanal, isobutanal, pentanal, 3-methylbutanal, 2,2-dimethylpropanal _of hexanal, heptanal, octanal, nonanal and dodecanal. The reaction is carried out by adding the steroid to a solution of the aldehyde together with a strong inorganic acid catalyst, preferably perchloric acid or hydrochloric acid, in an ether, preferably dioxane or tetrahydrofuran, in a halogenated hydrocarbon, preferably methylene chloride or chloroform, in an aromatic hydrocarbon, preferably toluene. , an all-cyclic hydrocarbon, preferably cyclohexane or an aliphatic hydrocarbon, preferably heptane or isooctane, and the chromatographic step for the preparation of epimers of formulas XII and XII may be omitted under the conditions mentioned above.

The compounds of formula (I) obtainable using the compounds prepared by the process of the present invention can be used for various routes of topical administration depending on the site of inflammation, for example, percutaneous administration, parenteral administration or topical administration by inhalation into the airways. An important purpose of the formulations is to achieve perfect biological utilization of the active steroid component. In the case of compositions intended for percutaneous administration, this can be advantageously achieved by dissolving the steroid in a vehicle with high thermodynamic activity. This can be achieved using a suitable solvent system consisting of suitable glycols such as propylene glycol or 7,3-butanediol either as such or in admixture with water.

It is also possible to dissolve the steroid of formula I either wholly or partially in the lipophilic phase with the addition of a surfactant or co-solvent. The percutaneous preparations may be an ointment, an oil in water cream, a water in oil cream or a lotion. In the novel emulsion-type compositions, the system containing the dissolved active ingredient may be either a dispersed phase or a continuous phase. Thus, the steroid may be present in the above compositions in the form of a micronized solid.

Steroid pressure sprays are designed for oral or nasal inhalation. The aerosol system is adapted so that each delivered dose contains 10 to 1000 µg, preferably up to 250 µg of active steroid. The most effective steroids are administered at the bottom of the dose range. The micronized steroid comprises particles substantially smaller than 5 µm which are suspended in the propellant mixture in the presence of a diapering agent such as sorbitan trioleate, oleic acid, lecithin or dioctylsulfosuccinic acid sodium salt.

The present invention is illustrated by the following non-limiting examples.

Example 1

Process for the preparation of 16X, 17c (-acet) and lu (22RS) -, (22R) - and (22S) -11 (1,16f, 17o), (21-tetrahydroxypregna-1,4-diene-3,20-diene)

Method of Production of (22RS) -, (22R) - (22S) -16 <17C-Butylidenedioxy-6C-SK-difluoro-11J, 21-dlhydroxypregna-1,4-dl-ene-3,20-dione

A. To a solution of 1.0 g _of 6-z-9-difluoro-11xj) -21-dihydroxy-16,44,7- (1-methylethylidene) bis (oxy) J pregna-1,4-diene-3,20-dione in 500 ml of methylene chloride is added 0.30 ml of fresh pre-treated n-butanol and 2 ml of 72X chloric acid. The reaction mixture is then left under stirring for 24 hours at 33 ° C and then extracted with aqueous potassium carbonate solution · water, dried with sodium sulphate and evaporated. The residue was dissolved in methylene chloride and the product was precipitated with petroleum ether. Yield: C488 mg (22RS) -1.6cZ, 17oZ-butylidene dioxy-6e, .gamma.-fluoro-11 (3,21-d1 hydroxypregna). 1,4-diene-3,20-dl. High Performance Liquid Chromatography 1 revealed 93X product purity and a ratio between 22S and 22R epimers of 12: 88 ·

B. X suspension 4.0 g of 6 (9,6-difluoro-11 R), 21-dihydroxy-16 ° 417X * C (1-ethylethylidene / bis / oxy) -pregna-1,4-diene-3 Of 20-dione in 100 ml of heptane is added 1.2 ml of freshly distilled n-butanol and 3.8 ml of 72X chloric acid. The reaction mixture is then left at room temperature with vigorous stirring for one hour, then extracted with aqueous potassium carbonate solution and water. It is dried over sodium sulphate and evaporated to give 4.0 g (22RS) -16σ, 17'-butyldenedioxy-6,449b-difluoro-11 / 3,21-dihydroxypregna-1,4-diene-3. , 20-dione · 98.5X purity of product and ratio between 22S and 22R 3: 97 were determined by HPLC. 3.1 Recrystallized from chloroform / petroleum ether to give 3.1 g of an epimer containing only 1.1X epimer 22S and 1.3 X other impurities ·

Epimer / 22S /:

Molecular Weight: 466, Calculated: 466.5 Melting point: 196-200 ° C

Epimer / 22R /:

MW: 466, calculated 466.5; melting point: 169-172 ° C.

C. In an analogous manner to that described in the preceding example, with the substitution of 6α-9c / -difluoro-11/3, 16c /, 17o-1,2-tetrahydropregna-1,4-dlen-3,20-dlone 11 / β, 16 (Z, 17 '), 21-tetrahydroxypregna-1,4-dlene-3,20-dione prepared by 9'-fluoro- and 6'-fluoro-1] (1') * Z, 21-tetrahydroxypregna-1,4-diene-3,20-dione or the corresponding 16β-17o (acetonitrile of non-fluorinated 16C-acetyl (22RS) -, (22R) - and (22S) -11 / 3,1 o oCl 7 (1,2-tetrahydroxypregna-1,4-diene) 3,20-dtones from the corresponding acetaldehyde, propanal, butanal, isobutanal, pentanal, 3-methylbutanal, 2,2 dimethylpropanal, hexanal, heptanal, octanal, nonanal and dodecanal.

Example 2

A. 250 mg (0.6 mmol) of 16%, 17% acetonitrile of predonaconone was dissolved in 75 ml of methylene chloride. Then, 130 mg (1.8 mmol) of n-butanal and 0.025 ml of 70X chloCS 268550O2 radish were added. The solution was stirred at 33 ° C for 15 hours. The yellow solution was washed twice with 1 L of potassium carbonate solution and four times with 10 L of water, dried and evaporated. Yield: 257 ng 797/7 X Theory / High Performance Liquid Chronatography shows a product purity of 91.1 X Unreacted acetonide contains 7.4X impurities Epimer ratio 14.6: 85> 4.

0.5 g (1.1 mol) of 117 mg of amcinolone tonide was dissolved in 150 L of methylene chloride. 260 mg (3.6 mmol) of n-butanal and 0.22 ml of 70X perchloric acid are then added. The reaction mixture was stirred at 33 ° C for 16 h. The methylene chloride solution was transferred to a separatory funnel and the contents of the reaction vessel were washed several times with 10 ml of potassium carbonate and methylene chloride. The solution was washed twice with 10 ml of 10X potassium carbonate solution each time and then washed four times with 10 ml of water each time. yield 438 ng (84.9% of theory) · product purity determined by high performance liquid chromatography is 80.2% · epimer ratio 19: 81 ·

C. 0.5 g (1.1 mmol) of (16c) -17c] fluocinol acetonide are dissolved in 150 µl of methylene chloride. Then 260 mg (3.6 mmol) of n-butanal and 0.22 µl of 70X perchloric acid were added to the solution. The mixture was stirred at 33 ° C for 24 hours and then transferred to the separatory funnel with a non-ethylened lorid phase. The reaction vessel is washed several times with 15 µl of a 10X potassium carbonate solution and methylene chloride. The solution is then washed twice with 15 µl of 1X potassium carbonate solution each time and four times with 15 µl of water each time, dried and evaporated. Yield: 513 mg (100% of theory). According to high performance liquid chromatography, the purity of the product was 97.4%. The epimer ratio was 8.6 ± 91.4.

Claims (1)

SUBJECT OF THE INVENTION A process for the preparation of steroids of formula XXX wherein the 1,2 position is saturated or contains a double bond, is hydrogen, fluorine, chlorine or bromine, denotes hydrogen, fluorine, chlorine or bromine, represents a straight or branched hydrocarbon group having 1; up to 10 carbon atoms and stereoisomeric forms thereof. characterized in that a compound of the formula XX is hydrogen or a C1-C10 acyl group, straight or branched. CS 268550 02 acts with a compound of formula XXI From XXI / in them ·! as defined above, in the presence of an acid catalyst.