CS207754B2 - Method of making the ,in position 17,substituted 11 beta-hydroxysteroids - Google Patents

Description

The present invention provides a process for the preparation of novel 17-substituted 11β-hydroxysteroids of the pregnane series of formula I

(fa

OCtiOfa (IJ in which it indicates bonds ..... single bonds or double bonds,

X is hydrogen, fluorine, chlorine or methyl,

Y is a hydrogen atom;

Z is hydrogen, fluorine or chlorine, or

Y and Z together form a carbon-carbon bond

Y group (3-hydroxymethylene, β-chloromethylene or carbonyl),

W a methylene group, an ethylidene group or a vinylidene group,

R1 is an alkyl group having 1 to 8 carbon atoms, optionally interrupted by an oxygen atom, or a bezyl group,

R 5 is hydrogen or C 1 -C 4 alkyl;

R1 and R2 together are trimethyl or tetramethylene,

R 1 is a hydrogen atom, a fluorine atom, a chlorine atom or a free or esterified hydroxy group, preferably an acyloxy group having 1 to 16 carbon atoms in the acyl residue, a sulfate group or a phosphate group.

It has long been known that the topical activity of anti-inflammatory 17α-hydroxycorticolds can be increased when their 17-hydroxy group is esterified (cf. Thomas L. Popper and Arthur S. Watnick, "Antiinflammatory Steroids in Antiinflammatory Agents", Vol. 1, Academic Press, New York, San Francisco, London (1974), pages 268-271).

It has now been found that topical activity and / or dissociation between desirable topical anti-inflammatory activity and undesirable systemic activity may be further increased when the hydrogen atom of the 17α-hydroxy groups of these corticoids is not substituted with an ester but substituted with an acetal or thioacetal residue.

The novel corticoids of formula (I) may carry straight or branched chain alkyl groups having 1 to 8 or preferably 1 to 6 carbon atoms as R 1 substituents. These alkyl radicals are, for example, methyl, ethyl, propyl, isopropyl, hutyl, isobutyl, tert-butyl, pentyl, isopentyl, hexyl, heptyl or octyl.

However, the alkyl radical of R 1 may also be interrupted by an oxygen atom. Such residues are, for example, 2-methoxyethoxy, 3-methoxypropyloxy or 2-ethoxyethoxy.

As substituents R 2, the corticoids of the formula I can carry an alkyl group having 1 to 4 carbon atoms, for example methyl, ethyl, propyl or butyl. Of note are those corticoids of formula I in which R2 represents a hydrogen atom, since they cannot form diastereomeric mixtures.

The onset and duration of action of the new corticoids, as well as their solubility in physiologically acceptable solvents, also depend, as in the case of known corticoids, on whether or not which acid is the esterified hydroxy group at the 21-position.

Suitable esterified 21-hydroxy groups R @ 3 are preferably acyloxy groups having 1 to 16 carbon atoms in the acyl radical, the sulfate group or the phosphate group. Suitable acyloxy groups are, for example, those derived from straight or branched chain aliphatic monocarboxylic or dicarboxylic acids, saturated or unsaturated, which can be substituted in the usual manner, for example, by hydroxy, amino or halogen atoms.

Also suitable as acyloxy groups are cycloaliphatic acid residues, aromatic acids, mixtures of aromatic-aliphatic or heterocyclic acid residues, which can also be substituted in the usual manner.

Suitable acyloxy mention include the formyloxy, acetoxy, propionyloxy, butyryloxy, pentanoyloxy, hexanoyloxy, oktanoyloxyskupinu, undekanoyloxyskupinu, dimethylacetoxyskupinu, trimethylacetoxyskupinu, diethylacetoxyskupinu, terc.butylacetoxyskupinu, benzoyloxy, fenacetyloxyskupinu, cyklopentylpropionyloxyskupinu, hydroxyacetoxy, monochloracetoxyskupinu, dichloroacetoxy, trichloracetoxyskupinu further dimethylaminoacetoxyskupinu, trimethylaminoacetoxyskupinu , diethylaminoacetoxy, piperidinoacetoxy, nicotinoyloxy, ω-carboxypropionyloxy and ω-carboxypentanoyloxy.

For the production of water-soluble active substances, the 21-acyloxy compounds having a basic nitrogen group in the acyl radical can be converted into the corresponding acid addition salts, such as, for example, hydrochlorides, hydrobromides, sulfates, phosphates, oxalates, tartrates or maleates.

Furthermore, the 21-monoesters of the dicarboxylic acids, as well as the sulfuric and phosphoric acid esters, can be converted into their alkali metal salts, for example sodium or potassium salts, to increase their water solubility.

The novel carticoids of the formula I can be prepared by starting from the 17α-hydroxysteroid of the formula II

......, X, Y, Z, V, W are as defined for formula I,

R 3 denotes a hydrogen atom, a fluorine atom, a chlorine atom or an esterified hydroxy group, optionally after intermediate protection of the 11/3-hydroxy group, with an acetal of the formula III

R2HC (ORi) 2 (III), wherein R1 and R2 are as defined for formula I, and at the 1 and 2 positions saturated corticoids are optionally dehydrogenated at the 1,2 position and / or the 11/3-hydroxy group is oxidized to the oxo group and and / or the 21-ester groups are saponified and / or the 21-hydroxy groups are esterified or replaced by fluorine or chlorine atoms.

The process of the invention can be carried out under conditions known in the art (Synthesis 1975, 2786, J. Chem. Soc. 66), 1974, 431, J. Amer. Chem. Soc. 74, (1952), 1239, U.S. Patent No. 3,383,394 and Angew. Chemie 90 (1978) 289).

Thus, for example, the steroids of the formula II can be reacted with an acetal of the formula III in the presence of acidic catalysts, for example perchloric acid, p-toluenesulfonic acid or, preferably, phosphorus pentoxide. This reaction may be carried out in the absence of other solvents or in the presence of inert solvents (chloroform, methylene chloride, carbon tetrachloride, carbon tetrachloride, toluene, diethyl ether, tetrahydrofuran, dioxane, etc.). The reaction is usually carried out at a reaction temperature of -20 to + 50 ° C and is particularly suitable for the preparation of steroids of formula 1 with R 2 as hydrogen.

When 11/3-hydroxycorticoids of the formula II are used as starting compounds for the process according to the invention, it is expedient to protect the 11β-hydroxyl group intermedially in order to prevent partial acetalization thereof. This can be done, for example, by converting the 11β-hydroxy group into the corresponding nitrates, formates or trihaloacetates (especially trifluoroacetates) prior to acetalisation and then cleaving the esters after the process.

The esterification of 11-hydroxycorticoids with nitric acid can be carried out, for example, with acetyl nitrate produced by mixing fuming nitric acid with acetic anhydride. After the acetalisation has been carried out, the nitrates can then be converted into 11β-hydroxycorticoids, for example by reaction with zinc dust in acetic acid.

The esterification of 11β-hydroxycorticoids with formic acid can be carried out, for example, with formic acid and acetic anhydride, using 4-dimethylaminopyridine as catalyst. After 17? -Acetalisation, the obtained 11β-formyl corticoids can then be converted into the corresponding 11β-hydroxysteroids by basal hydrolysis (e.g. with sodium methylate solution) or by enzymatic saponification.

The esterification of 11 / β-hydroxycorticoids with trihaloacetic acid, in particular trifluoroacetic acid, can be carried out, for example, by reacting 11 / β-hydroxycorticoids with trihaloacetanhydride in pyridine. After 17α-acetalisation, the trhaloacyl group can then be cleaved again by hydrolysis (e.g. in a low alcohol with the addition of weakly basic catalysts, e.g. sodium acetate or triethylamine).

The products obtained by the process according to the invention can optionally be further transformed by dehydrogenating in the 1,2-position the saturated corticoids at the 1,2-position and / or the 11/3-hydroxy group of these compounds is oxidized to the 11-oxo group and / or 21-ester the saponification groups and / or the 21-hydroxy groups are esterified or exchanged for fluorine or chlorine atoms.

A preferred method is to esterify the 21-hydroxy group with a sulfonic acid, preferably methanesulfonic acid or p-toluenesulionic acid, and then exchange the sulfonic acid group with a halogen. Esterification of the 21-hydroxy group is carried out, for example, by treating the 21-hydroxysteroids with sulfonic acid chloride in the presence of an organic base such as pyridine or in the presence of an aqueous alkali. The halogenation of the sulfonic acid group is preferably carried out by reacting the sulfonic acid 21-ester with an alkali metal halide such as lithium chloride or potassium hydrogen fluoride in the presence of a polar solvent such as dimethylformamide at a reaction temperature of 50-180 ° C.

It is known to produce anti-inflammatory II / t-hydroxystsroids (e.g. corticoids: hydrocortisone, prednisolone, dexamethasone, betamethasone, prednylidene, triamcinolone, fluocinolone or flurandrenolone) using very costly multi-step synthesis from natural steroids (such as diosgenin) sufficient quantity. During the multistage synthesis of these compounds, the most expensive and most lossy microbiological introduction of the 11β-hydroxy group into the steroid structure is generally the most costly and lossy. Acylation of the 17-hydroxy group is expensive, and the yields obtained are often unsatisfactory.

Hydrolysis of 11-hydroxy-17'-acyloxysteroids is also difficult, since by-products are formed and thus costly and very lossy purification of the obtained products is required to meet the purity criteria required for drug active ingredients.

The dehydrogenation at the 1-position of the saturated A- ^4- steroids of the general formula I, as a possible measure, can be carried out both by microbiological working methods and also by purely chemical methods. Thus, for example, A ⁴ -steroids can be dehydrogenated at the 1-position under normal conditions of culture of the bacteria Bacillus (e.g., Bacillus lentus or Bacillus sphaericus) or Arthrobacter (e.g., Arthrobacter simplex), but is otherwise also possible and carried out by ^one -dehydrogenaci way that the ^{4 4} -steroids are heated in an inert solvent with the oxidizing agents customary for this reaction, for example with selenium oxide or

2,3-dichloro-5,6-dicyanobenzoquinone.

The products obtained can be cleaved in a simple manner into the corresponding 11 (3,17 ', 21-trihydroxysteroids).

The cleavage is carried out under conditions conventionally used for the hydrolysis or alcoholysis of acetals. For example, the compounds can be cleaved by digesting them in a low alcohol such as methanol or ethanol or in a water-containing organic solvent such as glycol monomethyl ether, tetrahydrofuran, dioxane , dimethylformamide, dimethylsulfoxide, hexamethylphosphoric triamide, acetone, are reacted with a mineral acid such as hydrochloric, sulfuric, phosphoric, perchloric, sulfonic, such as p-toluenesulfonic acid, or a strongly acidic carboxylic acid, such as formic, acetic, trifluoroacetic acid, with acid ion exchangers or with Lewis acid, such as boron trifluoride, zinc chloride, zinc bromide or titanium tetrachloride.

The novel corticosteroids of the formula (I), as already mentioned, have a very good anti-inflammatory activity when topically applied and have a very favorable dissociation between the desired topical effect and the undesirable systemic side effect.

2B7754

Topical efficacy can be determined by a vasoconstriction assay as follows:

the ss test is performed on 8 healthy individuals of both sexes who have not been treated locally with corticosteroids for the past two weeks. After removal of Stratum corneum to Stratum lucidum on the backs of the test subjects (20-40 pieces of tesafilm), 0.1 g of the preparation is applied to 4 cm ² large patches without occlusive dressing. To prevent application of the same preparation to identical skin areas, it is applied in a rotating order.

Vasoconstriction is assessed visually after 4 and 8 hours according to efficacy levels: 1 = absolute fading, 2 = small residual erythem, 3 = moderate erythem, medium intensity of red stained, untreated and intact skin 4 = erythem with little clarification, 5 = no erythema fading or thickening.

From the individual results the center was taken.

Dlflucortolone-21-valeran (= 6α, 9α-difluoro-11 / S-hydroxy-16α-methyl-21-valeryloxy-1,4-pregnadien-3,20-dione = DFV) was used as reference substance in each experimental series. ).

The difference between the mean degrees of DFV activity and the test substance found in the individual experimental series is always determined. Positive deviations A show a favorable assessment of the test substance, negative deviations indicate a favorable assessment of the test substance compared to DFV.

The following tables show the observed test results obtained in the treatment of individuals with a formulation containing 0.1 ppm of active ingredient.

The systemic activity of the compounds can be determined by adjuvant edema assay as follows:

SPF rats weighing 130-150 g are injected with 0.1 ml of a 0.5 percent Mycobacterium butyricum suspension into the right hind paw to create an outbreak of inflammation. The paw volume is measured before injection; 24 hours after injection, the paw volume is measured again to determine the extent of edema. Thereafter, rats are administered orally or subcutaneously with different amounts of test substance dissolved in a mixture of 29% benzyl benzoate and 71% castor oil. After a further 24 hours, the paw volume is again determined.

Control animals are treated in the same manner except that they are injected with a mixture of benzyl benzoate with castor oil without the test substance.

The amount of test substance required to achieve a 50% reduction in the experimentally generated paw edema is determined in the usual manner from the obtained paw volumes.

The results of the tests are shown in the tables below, in which the substances according to the invention are always compared with structurally analogous, previously known corticoids, contained in commercial preparations.

No. Substance

Table 1

Test results of hydrocortisone derivatives

Vasoconstriction test Adjuvant edema test (mg / kg animal j after 4 h after 8 h ED50 p.o. ED50 s.c.

17α-Butyryloxy-11 (S, 21-dihydroxy-4-pregnene-3,20-dione (hydrocortisone-17-butyrate) -0,21,1,21-Dihydroxy-17α-methoxymethoxy-4-pregnen-3), 20-dione +0.3

17α-Ethoxymethoxy-11β, 21-dihydroxy-4-pregnene-3,20-dione 0.0 µl / 3,21-Dihydroxy-17α-propoxymethoxy-4-pregnene-3,20-dione +0.4 µl , 21-Dihydroxy-17α-isopropoxymethoxy-4-pregnene-3,20-di.one +0.9

17α-Butoxymethoxy-11,2,21-dihydroxy-4-pregnene-3,20-dione +0.9 11 / 3,21-Dihydroxy-17α- (2'-tetrahydropyranyloxy) -4-pregnene-3,20 -dione j + 0.8 —0.3 + 0.7 + 0.7 + 0.4 + 0.5 + 0.6 + 0.6

13

13

14,5 ca. 10> 30 (43%)

The novel compounds, in combination with carriers customary in galenical pharmacy, are suitable for the topical treatment of contact dermatitis, eczema of various types of neurodermatoses, erythrodermias, burns, pruritis vulvae et ani, cutaneous lupus rosacea Erythematodes Cutaneus psoriasis, Lichen ruber planus et verrucos .

The manufacture of medicament specialties is carried out in the usual manner by converting the active ingredients with suitable additives into the desired dosage forms, for example, solutions, lotions, ointments, creams or patches. In the medicaments thus formed, the concentration of active ingredient is dependent on the form of administration. For lotions and ointments, a concentration of active compound of 0.001 to 1% is preferably used.

In addition, the novel compounds, optionally in combination with conventional carriers and excipients, are also well suited for the preparation of inhalants which can be used for the treatment of allergic diseases of the respiratory tract, for example bronchial asthma or rhinitis.

Furthermore, the novel corticoids in the form of capsules, tablets and dragee tablets, which preferably contain 10 to 200 mg of active ingredient and are administered orally, or in the form of suspensions, preferably containing 100 to 500 mg of active ingredient and administered rectally, are also suitable for the treatment of allergic intestinal tract diseases such as ulcerative and granulomatous colitis.

Example 1 g Cortisone acetate is dissolved in 120 ml of formaldehyde dimethyl acetal and 120 ml of methylene chloride and a mixture of 12 g of phosphorus pentoxide and 24 g of diatomaceous earth is added under ice-cooling. After stirring for 4.5 hours, it is filtered, neutralized with trimethylamine and the solvents are distilled off in vacuo. The residue is chromatographed on silica gel with toluene-ethyl acetate to give 385 g of 21-acetoxy-17'-methoxymethoxy-4-pregnene-3,11,20-trione which melts at 160-161 ° C after recrystallization from methanol.

EXAMPLE 2 9a-Fluorohydocortisone acetate is dissolved in 67.4 ml of methylene chloride and 134.8 ml of ¹ methylal and cooled with an ice-methanol bath. To this solution was added 10 g of phosphorus pentoxide mixed with 20 g of diatomaceous earth and stirred for 5 hours at -15 ° C. The solution was filtered and neutralized with trimethylamine. After distillation of the solvent, it was distilled off with methanol and the residue crystallized from methanol. The products were separated by chromatography on silica gel with methylene chloride + 5% methanol to give 3.28 g of 21-acetoxy-9α-fluoro-11β, 17'-dimethoxymethoxy-4-pregnene-3,20-dione, m.p. 132-134. ° C, 0.56 g of 21-acetoxy-9α-fluoro-11β-hydroxy-17'-methoxy-methoxy-4-pregnene-3,20-dione, m.p. 211-214 ° C, and 0.79 g of 21- acetoxy-9? -fluoro-17? -hydroxy-11? -methoxymethoxy-4-pregnene-3,20-dione, m.p.

Mp 196-199 ° C.

Example 3

5.0 g of 21-Acetoxy-9'-chloro-11'-hydroxy-17'-methoxymethoxy-4-pregnene-3,20-dione is suspended in 10 ml of methylene chloride and 20 ml of methanol and cooled to +3 °. C. A solution of 0.31 g of potassium hydroxide in 11 ml of methanol is added dropwise over 5 minutes and stirred for 80 minutes. The reaction mixture was neutralized with 0.34 ml of glacial acetic acid and precipitated in 350 ml of water. The crystallisate is aspirated and dried. 2.32 g of 9'-chloro-11 ', 5'-dihydroxy-17'-methoxymethoxy-4-pregnene-3,20-dione are obtained, which, after recrystallization from methanol / methylene chloride, has a melting point of 188-189 ° C. .

EXAMPLE 4 aj 20.0 g of 9'-fluoro-11 (3,17a-dihydroxy-21-propionyloxy-1,4-pregnadien-3) are added to a mixture of 100 ml of pyridine and 12 ml of trifluoroacetic anhydride at -10 degrees Celsius. After stirring for 10 minutes at -10 [deg.] C. After precipitation with ice-water, it is filtered off and the residue is taken up in methylene chloride, and after washing and drying of the organic solution, it is concentrated under vacuum to isolate 22.0 g of 9 ' 17α-hydroxy-21-propionyloxy-11β-trifluoroacetoxy-1,4-pregnadien-3,20-dione.

bj 22.0 g of the crude product is dissolved in anhydrous methylene chloride and treated with 90 ml of formaldehyde dimethyl acetal and a mixture of 6.0 g of diatomaceous earth (W20 and 3.0 g of phosphorus pentoxide) is added in portions. 9α-Fluoro-17α-methoxymethoxy-21-propionyloxy-11β-trifluoroacetoxy-1,4-pregnadien-3,20-dione is isolated as a crude product.

cj The crude 9α-fluoro-17α-methoxymethoxy-2-propionyloxy-11,3-trifluoroacetoxy-1,4-pregnadien-3,20-dione was dissolved in 50 mL of methanol and stirred at room temperature for 30 minutes after the addition of 25 mL of triethylamine. . The reaction mixture is concentrated to dryness in vacuo and the residue is chromatographed on 2.25 kg of silica gel using a gradient elution of methylene chloride-acetone (0-12% acetone). Yield 12.3 g of 9α-fluoro-11β-hydroxy-17α-methoxymethoxy-21-propionyloxy-1,4-pregnadien-3,20-dione.

Mp 241 ° C.

Example 5

a) Under the conditions of Example 4a, 1.0 g of 21-butyryloxy-9α-fluoro-11,17-dihydro-1,4-pregnadien-3,20-dione was reacted with trifluoroacetic anhydride and worked up.

207734

0.9 g of 21-butyryloxy-9α-fluoro-17H-hydroxy-11β-trifluoroacetoxy-1,4-pregnadien-3,20dione is isolated.

b) 800 mg of the above crude product was treated analogously to Example 4b with 3.6 ml of formaldehyde dimethyl acetal. After work-up, 1.1 g of crude 21-butyryloxy-9α: -fluoro-17α-methoxymethoxy-11β-trifluoroacetoxy-1,4-pregnadien-3,20-dione are obtained.

c) Analogously to Example 4b, 1.1 g of crude 21-butyryloxy-9α-fluoro-17α-methoxymethoxy-11 H -trifluoroacetoxy-1,4-pregnadien-3,20-dione was reacted with triethylamine. The crude product is chromatographed on 75 g of silica gel using a gradient elution with methylene chloride-acetone (0-15%). Yield: 540 mg of 21-butyryloxy-9o; -fluoro-S l _{1-hydroxy-17.alpha.-methoxymethoxy-l} 4_pregnadiene-3,20-dione. Mp 247 ° C.

Example 6

Analogously to Example 4b, 2.0 g of 21-butyryloxy-9α-fluoro-17α-hydroxy-1,4-pregnadien-3,11,120-trione was treated with 9 ml of formaldehyde dimethyl acetal and worked up. The crude product is purified on 300 g of silica gel using grandient elution with methylene chloride-acetone (0-10% acetone). Yield 2.07 g of 21-butyryloxy-9α-fluoro-17α-methoxy-1,4-pregnadien-3,11,20-trione. Melting point 192 RC.

Example 7

700 g of 21-B-utyryloxy-9.alpha.-fluoro-17.beta.-hydroxy-1,4-pregnadien-3,11,20-trione in anhydrous acetonitrile were treated with 1.54 ml of methoxyethoxymethyl chloride. The crude product is purified on 135 g silica gel using a gradient elution with methylene chloride-acetone (0 to 5% acetone). Yield 430 mg of 21-butyryloxy-9α-fluoro-17- (1,3,6-trioxaheptyl) -1,4-pregnadien-3,11,20-trione.

Melting point 126 ° C.

Example 8

(a) to 15,2 g of 9α: -fluoro-11β, 17α-dihydroxy-16β-methyl-21-propionyloxy-1,4-pregnadien-3,20-dione, made from 9α-fluoro-11 / S, 17ai, 21-Trihydroxy-16,3'-methyl-1,4-pregnadien-3,20-dione and propionic anhydride are treated with 9.1 ml of trifluoroacetic anhydride, analogous to Example 4a. 15.4 g of 9? -Fluoro-17? -Hydroxy-16? -Methyl-21-propionyloxy-11? -Trifluoroacetoxy-1,4-pregnadien-320-dione are obtained.

b) 15.4 g of the above crude product is treated with 9-fluoro-17-methoxymethoxy-16,5-methyl-21-propionyloxy-11H-trifluoroethoxy-1,4-pregnadien under the conditions of Example 4b with formaldehyde dimethyl acetal. -3.20-dione.

Yield 16.9 g of crude product.

c) A solution of crude 9 ' -fluoro-17.alpha.-methoxymethoxy-.beta.-methyl-11-propynyloxy-11,5-trifluoroacetoxy-1,4-pregnadien-3,20-dione in 250 ml of methanol was treated analogously to Example 4c. ml of triethylamine. After work-up, the crude product is purified on 1.5 kg of silica gel using a gradient elution with methylene chloride-acetone (0-10% acetone). Yield 9.6 g of 9.alpha.-fluoro-11.beta.-hydroxy-17.alpha.-methoxyinethoxy-16.beta.-methyl-21-propionyloxy-1,4-pregnadien-3,20-dione.

Melting point 169 ° C.

Example 9

600 mg of 9α-fluoro-11 H -hydroxy-17α-methoxymethoxy-16/3-methyl-21-propionyloxy-1,4-pregnadien-3,20-dione are hydrogenated with 500 mg of tristriphenylphosphine rhodium in a mixture of methanol and benzene. (I) chloride and worked up. After chromatography of the crude product on 65 grams of silica gel using a gradient elution of methylene chloride-acetone (0 to 10 percent acetone), 347 mg of 9α-fluoro-11'-hydroxy-17α-methoxymethoxy-16β-methyl-21-prionyloxy-4 is isolated. -pregnene-3,20-dione. Melting point 165 ° C.

He did

Suspension of 6.9 g of 9 α-fluoro-11β-hydroxy-17α-methoxymethoxy-16- (3-methyl-21-propionyoxy-1,4-pregnadien-3,20-dione in 80 mL of methanolic 0.2 N of potassium hydroxide solution was stirred at 0 ° C for 45 minutes, neutralized with 10% acetic acid and precipitated with ice water and worked up to give the crude product which was purified on 450 g silica gel by gradient elution with methylene chloride-acetone (0 to 20% acetone). . Yield 4.1 g of 9.alpha.-Fluoro-.alpha., 1,21-dihydroxy-17.alpha.-methoxymethoxy-10.alpha.-methyl-1.alpha.-pregnadien-S, O-dione. Melting point 220 ° C.

Example 11

a) A solution of 1.7 g of 9α-fluoro-11 / 3,21-dihydroxy-17G-methoxymethoxy-16H-methyl-1,4-pregnadiefl-3,20-dione in 17 ml of pyridine at room temperature for 1 hour with 2.04 g of tosyl chloride. After precipitation with ice water, the precipitate is taken up in methylene chloride and worked up as usual. The crude product is purified on 135 g silica gel using a gradient elution of methylene chloride-acetone (0-10 percent acetone). Yield 876 mg.

(b) 876 mg of the above product is stirred with 880 mg of lithium chloride in 80 ml of hexamethylphosphoric triamide at 80 ° C for 1 hour. It is poured into ice water and the precipitate is filtered off. After the usual work-up, the crude product is recrystallized from hexane / 207575

Table 2

Prednisolone derivative test results

Vasoconstriction test Adjuvant edema test (mg / kg animal)

No. Substance Δ after 4 h Δ after 8 h EDso p.o. ED 50 s.c. 8 µl (3 ', 17α, 21-Trihydroxy-1,4-pregnadien-3,20-dione (- prednisolone) —0.9 —0.8 3 „-6 2.6 9 11 (2,21-Dihydroxy-17α-methoxymethoxy-1,4-pregnadien-3,20-dione -0.2 —0.3 9.8 10 21-Acetoxy-11 / Miydroxy-17α-methoxymethoxy-1,4-pregnadien-3,20-dione + 0.7 + 0.4 > 3 (26%) 11 21-Butyryloxy-11 H -hydroxy-17 α-methoxymethoxy-1,4-pregnadien-3,20-dione + 0.2 + 0.2 ca. 3 No substance Table 3 Test results of 9-chlorocorticoids Vasoconstriction test Δ after 4 h Δ after 8 h Adjuvant edema test [mg / kg animal] EDso p. EDso p. 12 9a-Chloro-11 (3-hydroxy-16,22-methyl-17 ', 21-dipropionyloxy-1,4-pregnadien-3,20-dione (—beclomethasone dipropionate) —0.3 0.0 22nd 3.0 13 21-Acetoxy-9a-chloro- -ll (3-hydroxy-17α-methoxy- methoxy-4-pregnene-3,20- -dion + 0.4 + 0.7 3.2 14 21-Acetoxy-9α-chloro- -11 / 2-hydroxy-17α-methoxy- methoxy-1,4-pregnadien- -3.20-dione + 0,9 + 1.0 ca. 1

21-Acetoxy-9α-chloro-11β-hydroxy-17α- (2‘-methoxyethoxymethoxy) -1,4-pregnadien-3,20-dione + 1.0 +1.3 ca. 3

Table 4

Test results of 9-fluorocorticoids

Vasoconstriction test Adjuvant edema test (mg / kg animal)

No. Substance Δ after 4 h Δ after 8 h ED50 p. o. ED50 p.

16 9α-Fluoro-11β-hydroxy-16β-methyl-17α, 21-dipropionyloxy-1,4-pregnadien-3,20-dione (= betamethasone dipropionate) —0.5 -0.7 2.1 17 21-Chloro-9a-fluoro- 11β-hydroxy-16 H -methyl-17α-propionyloxy-1,4-propyladien-3,20-dione (clobetasol propionate) +0,5 + 1,1 0.13 18 21-Chloro-9a-fluoro- -11 / 3-hydroxy-17α-methoxy- methoxy-1,4-pregnadien- -3.20-dione + 0.5 + 0.5 1.9 19 21-Acetoxy-9a-fluoro- -11 / 3-hydroxy-17α-methoxy- methoxy-4-pregnene-3,20- -dion +0.6 + 0.5 2,0 20 9 -Fluoro-11/3-hydroxy-17α-methoxymethoxy- -21-propionyloxy-1,4-preg- nadien-3,20-dione + 0.2 + 0.7 3.0 21 9tf-Fluoro-11 (3-hydroxy- -17 α-methoxymethoxy-16β-methyl-21-propynyloxy-1,4-pregnadien-3,20-dione + 0.5 + 1.0 3.0

Table 5

Test results of 6-fluoro- and 6-methylcorticoids

Vasoconstriction test Adjuvant edema test (mg / kg animal)

No. Substance Δ after 4 h Δ after 8 h ED50 p. o. ED50 p.

22 6α-Fluoro-11 / 3,21-dihydroxy-16α-methyl-1,4-pregnadien-3,20-dione -1.1 -0.8 3.5 23 6α-Fluoro-11 / 3,21-dihydroxy-17α-methoxymethoxy-4-pregnene-3,20-dione + 0.1 + 0.1 4.0 24 11 / 3,17α, 21-Trihydroxy-6α-methyl-1,4-pregnadien-3,20-dione (= 6-Methylprednisolone) —0.8 —0.9 25 11 / 3,21-Trihydroxy-17of- (1‘-methoxy ethoxy) -6α-methyl-4-pregnene-3,20-dione + 0.6 + 0.6 22nd

1S

-acetone. Yield 485 mg of 21-chloro-9α-fluoro-11,11-hydroxy-1'-methoxymethoxy-1β / 5-methyl-1,4-pregnadien-3,20-dione. Mp 204 ° C.

Example 12

a) To a suspension of 11.2 g of 9.alpha.-fluoro-11.beta.-hydroxy-17.alpha.-methoxymethoxy-21-propionyloxy-1,4-pregnadien-3,20-dione is added 129 ml of methanolic or 02 N potassium hydroxide solution. The mixture was stirred at room temperature for one hour and worked up as described in Example 10. P-Chromatography on 1.5 kg silica gel using gradient elution with methylene chloride-acetone (0 to 35% acetone) isolated 7.5 g of 9'-fluoro- 11,11,21-dihydroxy-17α-methoxymethoxy-1,4-pregnadien-3,20-dione.

b) Analogously to Example 11a, 1.0 g of said crude product was reacted with 2.0 g of tosyl chloride. The crude product was purified on 200 g silica gel using gradient elution with methylene chloride-acetone (0-10% acetone). Yield 886 mg of 9α-fluoro-11 (ω-hydroxy-17α-methoxymethoxy-21-tosyloxy-1,4-pregnadien-3,20-dione).

c) 886 mg of 9'-fluoro-11/1-hydroxy-17α-methoxymethoxy-21-tosyloxy-1,4-pregnadien-3,20-dione was treated with lithium chloride under the conditions of Example 11b and worked up. Purification is accomplished by recrystallization from acetone-hexane. Yield: 392 mg of 21-chloro-9a-fluoro-ll ^{(3-hydroxy-17.alpha.-methoxymethoxy-l} 4_pregnadiene-3,20-dione.

Melting point 225 ° C.

Example 13

a) 20.0 g of 21-Acetoxy-9α-fluoro-11 (S ', 17-dihydroxy-4-pregnene-3,20-dione, analogously to Example 4a) are reacted with 12 ml of trifluracetic anhydride to 21-acetoxy 9a-fluoro-17a-hydroxy-l _i 3'-trifluoroacetoxy-4-pregnene-3,20-dione.

(b) 5.0 g of said crude product in anhydrous methylene chloride are treated with 22.5 ml of formaldehyde dimethyl acetal and a mixture of 6.0 g of diatomaceous earth (W20) and 3.0 g of phosphorus pentoxide is added in portions. 21-Acetoxy-9α-fluoro-17α-methoxymethoxy-11β-trifluoroacetoxy-4-pregnene-3,20-dione is obtained. Yield 5.3 g.

cj Analogously to Example 4c, 5.3 g of 21-acetoxy-9.alpha.-fluoro-17.beta.-methoxymethoxy-11 / 3'-trifluoroacetoxy-4-pregnene-3,20-dione was treated with triethylamine. The crude product is purified on 500 g of silica gel using a gradient elution of methylene chloride-acetone (0 to 8 acetone). Yield 560 mg of 21-acetoxy-9α-fluoro-11 (β-hydroxy-17'-methoxymethoxy-4-pregnene-3,20-dione).

Melting point 213 ° C.

Example 14 and Analogously to Example 10, 28.0 g of 21-acetoxy-9.alpha.-fluoro-11.beta.-hydroxy-17.alpha.-methoxymethoxy-4-pregnene-3,20-dione are saponified with 0.2N methanolic potassium hydroxide solution to give 9a. fluoro-11 (3,21-dihydroxy-17β-methoxymethoxy-4-pregnene-320-dione).

b) A solution of 500 mg of 9α-fluoro-11β, 1,2-dihydroxy-17α-methoxymethoxy-4-pregnene-3,20-dione in 5 mL of pyridine was stirred with 7.5 mL of n-valeric anhydride at room temperature for 1 hour. . After precipitation with ice water, it is filtered off and worked up as usual. The crude product was purified on 400 g silica gel using a gradient elution of hexane-ethyl acetate (0 to 30% ethyl acetate). Yield 235 mg of 9α-fluoro-11 H -hydroxy-17-methoxyinethoxy-21-valeryloxy-4-pregnene-3,20-dione.

Mp 181 ° C.

Example 15

(a) 10.0 g of prednisolone-21-acetate are dissolved with 40 g of 4-dimethylaminopyridine in 500 millimeters of methylene chloride, cooled to -15 ° C and 25 ml of acetic anhydride are added. 10 ml of formic acid are added dropwise over 10 minutes and stirred for a further 135 minutes at -10 to -15 ° C. Extract the solution with water, 4% hydrochloric acid and sodium bicarbonate solution, dry the organic phase over sodium sulfate and concentrate in vacuo. The residue was recrystallized from methanol with the addition of a small amount of methylene chloride to give 9.34 g of 21-acetoxy-11 (3-formyloxy-17α-hydroxy-1,4-pregnadien-3,20-dione, m.p. 221-223 ° C). .

b) 5.0 g of 21-Acetoxy-11β-formyloxy-17α-hydroxy-1,4-pregnadien-3,20-dione are dissolved in 150 ml of methylene chloride and 30 ml of formaldehyde diethyl acetal and cooled to 0 ° C. While stirring, 5 g of phosphorus pentoxide and 10 g of diatomaceous earth are added and the mixture is stirred in an ice bath for 2.5 hours. The mixture was filtered, washed with methylene chloride and adjusted to pH 9 with triethylamine. After distilling off the solvents, 10.5 g of crude 21-acetoxy-17α-ethoxymethoxy-11H-formyloxy-1,4-pregnadien-3,20-dione were obtained as semi-solid mass.

c) 0.34 g of crude 21-acetoxy-17'-ethoxymethoxy-11 / S-formyloxy-1,4-pregnadien-3,20-dione is dissolved in 13 ml of methanol and treated with 0.126 g of hydrogen under argon. sodium carbonate in 1.32 ml of water at 60 ° C. The mixture was heated to reflux for 10 minutes, cooled, water was added and extracted with methylene chloride. The methylene chloride solution was dried with sodium sulfate, concentrated, and the residue chromatographed on silica gel with toluene-ethyl acetate. 0.1 g is obtained

17a-ethoxymethoxy-11,21,2-dihydroxy-1,4-pregnadien-3,20-dione, m.p. 149.5-152 ° C.

Example 16

a) 6.0 g Hydrocortisone 21-acetate-11-formate is dissolved in 150 ml methylene chloride with 63 g formaldehyde dihexylacetal and cooled to 10 ° C. Under argon, a mixture of 6 g of phosphorus pentoxide and 12 g of diatomaceous earth was added portionwise, and the mixture was stirred at 10 ° C for 1 hour and at 15 ° C for 1 hour. The mixture was filtered, washed with methylene chloride and adjusted to pH 8 with triethylamine. The methylene chloride was evaporated in vacuo and the residue was cooled in an ice bath. The solution was decanted from the precipitated oil and chromatographed on silica gel with toluene-ethyl acetate. 4.2 g of 21-acetoxy-11? -Formyloxy-17? -Hexyoxymethoxy-4-pregnene-3,20-dione are obtained, which melts at 110 DEG C. after recrystallization with pentane.

bj 0.38 g of 21-Acetoxy-11 (3'-formyloxy-17α-hexyloxymethoxy-4-pregnene-3,20-dione) was reacted under the conditions described in Example 15c to give 0.1 g of 11,11,21-dihydroxy -17α-hexyloxymethoxy-4-pregnene-3,20-dione.

Example 17 and 6.0 g of Hydrocortisone 21-acetate-11-formate are dissolved in 150 ml of methylene chloride and 65 g of formaldehyde dibenzylacetal, and a mixture of 6 g of phosphorus pentoxide and 12 g of is added in portions under stirring under argon under stirring. diatomaceous earth. After four hours, the mixture was filtered, washed with methylene chloride and adjusted to pH 8 with triethylamine. The methylene chloride was evaporated in vacuo and the residue was chromatographed on silica gel with toluene-ethyl acetate. 3.0 g of 21-acetoxy-17? -Benzyloxymethoxy-11? -Formyloxy-4-pregnene-3,20-dione are obtained.

bj 0.38 g of 21-Acetoxy-17'-benzyloxymethoxy-11 (3-formyloxy-4-pregnene-3,20-dione) was reacted under the conditions of Example 15c to give 0.11 g of 17a-benzyloxymethoxy-11 '. 21-dlhydroxy-4-pregnene-3,20-dione.

Example 18

3.0 g of 11 / 3,21-Dihydroxy-17α-methoxymethoxy-16-methylene-4-pregnene-3,20-dione are dissolved in 12 ml of pyridine at + 20 ° C and 2.37 ml of acetic anhydride are added. . The reaction mixture was stirred at +20 ° C for 2 hours and then precipitated in 144 mL of ice water. Stir for an hour. The crystallisate is filtered off with suction, washed with water and dried. Recrystallization from ethyl acetate yielded 2.74 g of 21-acetoxy-11 H -hydroxy-17α-methoxymethoxy-16-methylene-4-pregnenedione, m.p. 166-167 ° C.

Claims (1)

SUBJECT A process for the preparation of the 17-position of the substituted β-hydroxysteroids of the pregnane series of formula I YNÁLEZU W a methylene group, an ethylidene group or a vinylidene group, R1 is an alkyl group having 1 to 8 carbon atoms, optionally interrupted by an oxygen atom, or a benzyl group, R2 is hydrogen or C1-C4alkyl; R1 and R2 together are trimethylene or tetramethylene, Ra is hydrogen, fluorine, chlorine or a free or esterified hydroxy group, preferably an acyloxy group having 1 to 16 carbon atoms in the acyl radical, a sulfate group or a phosphate group, characterized in that the 17α-hydroxysteroid of formula II is a bond. .... single or double bonds, X is hydrogen, fluorine, chlorine or methyl, Y a hydrogen atom, Z is hydrogen, fluorine or chlorine, or Y and Z together form a carbon-carbon bond, A Y group (N-hydroxymethylene, β-chloromethylene or carbonyl, in which ......, X, Y, Z, V, W are as previously defined and R 3 'represents a hydrogen atom, a fluorine atom, a chlorine atom or an esterified hydroxy group, optionally after intermediate protection of 11 (3-hydroxy group) with an acetal of formula III R ₂ HC (OR 1) ₂ (III), wherein R 1 and R ₂ are as previously defined, and at the 1 and 2 positions saturated corticoids are optionally dehydrogenated at the 1,2 position and / or 11 (3-hydroxy group is oxidized to the oxo group and and / or the 21-ester groups are saponified and / or the 21-hydroxy groups are esterified or replaced by fluorine or chlorine atoms.