CS207756B2 - Method of making,in position 17,substituted 11 beta hydroxysteroids of the pregnan series - Google Patents

Description

(54) A method for producing in the position of the pregnane series of substituted 11β-dihydroxysteroids

The present invention relates to a process for the preparation of novel, 17-substituted 11β-hydroxysteroids of the pregnane family of formula (I)

R _z

OCHQR ₁ (II in which the bonds are single bonds or double bonds,

X is hydrogen, fluorine, chlorine or methyl,

Y a hydrogen atom,

Z is hydrogen, fluorine or chlorine;

Y and Z together form a carbon-carbon bond,

Y a 1-hydroxymethylene group, a β-chloromethylene group or a carbonyl group,

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

Q an oxygen atom or a sulfur atom,

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

R 2 is hydrogen or C 1 -C 4 alkyl;

R1 and R2 together are trimethylene or tetramethylene,

R3 is hydrogen, fluorine, chlorine 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 17'-hydroxycorticoids can be enhanced when their 17-hydroxy group is esterified [cf. Thomas L. Popper and Arthur S. Watnick, "Antiinflammatory Sterolds in Antiinflammatory Agents", Volume 1, Academic Press, New York, San Francisco, London (1974), pp. 268-271],

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

2D7756

The novel corticoids of formula (I) may carry, as R 1 substituents, a straight or branched chain alkyl radical having 1 to 8 or preferably 1 to 6 carbon atoms. These alkyl radicals are, for example, methyl, ethyl, propyl, isopropyl, butyl, 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, in particular on whether and optionally which acid is the esterified hydroxy group standing at position 21.

Suitable esterified 21-liydroxy groups R3 are preferably acyloxy groups having 1 to 18 carbon atoms in the acyl radical, sulphate group or phosphate group.

Suitable acyloxy groups are, for example, those derived from straight or branched chain aliphatic monocarbioxy or ik 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 for instance: formyloxysupinu, acetoxy, propionyloxy, butyryloxy, pentanoyloxy, hexanoyloxy, oktanoyloxyskupinu, undekanoyloxyskupinu, dimethylacetoxyskupinu, trimethylacetoxyskupinu, diethylacetoxyskupinu, terc.butylacetoxyskupinu, benzoyloxy, fenacetyloxyskupinu, cyklopentylpropionyloxyskupinu, hydroxyacetoxy, monochloracetoxyskupinu, dichloroacetoxy, further dlmethylaminoacetoxyskupinu, trimethylaminoacetoxyskupinu, diethylaminoacetoxyskupinu , 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 esters, can be converted into their alkali metal salts, for example sodium or potassium salts, to increase their water solubility.

The process for the preparation of the novel corticoids of the formula I is characterized in that the 9,11-dehydrosteroid of the formula II

in which

..., X, W, Q, R 1, R 2 and R 3 are as defined above for chlorine or hypochlorous acid, and the corticoids saturated at the 1,2-position are optionally dehydrogenated at the 1,2-position and / or or the 11β-hydroxy group is oxidized to an oxo group and / or the 21-ester groups are saponified and / or the 21-hydroxy groups are esterified or exchanged for fluorine or chlorine atoms.

The process according to the invention can be carried out under conditions which are known (U.S. Pat. Nos. 3,678,034, 3,718,671, 3,845,085 and 3,894,063). Thus, for example, 9,11-dehydrosteroids of formula II are a solvent (acetic acid, tetrahydrofuran, dioxane, acetonitrile, etc.) is reacted with reagents which, in the presence of water and acids (sulfuric acid, phosphoric acid, perchloric acid, etc.) liberate hypochlorous acid during the reaction, in particular with halogen cation forming reagents, such as N-chloracylamides (especially N-chloroacetamide) or N-chloroacylimides (especially N-chlorosuccinimide) In this reaction, the 9a-chloro-11/3-hydroxycorticoids of the formula I are obtained as the main products, The 9 ', 11β-dichlorocorticoids of the formula I. The last are obtained as the main products when the reaction is carried out with the exclusion of water in the presence of hydrogen chloride as an acid.

The starting substances for the process according to the invention, i.e. the compounds of the general formula II, can be prepared by acetylating the corresponding 17 ' -hydroxysteroids or from 17-acetalized 9-position unsubstituted corticoids by dehydrating them to 9.11 -dehydrosteroids of formula II.

The products obtained according to the invention can optionally be further transformed by hydrogenating in the 1,2-position saturated corticoids at the 1,2-position de207756 and / or the 11β-hydroxy group of these compounds is oxidized to the 11-oxo group and / or the 21-ester group is saponified 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-toluenesulfonic acid, and then exchange the sulfonic acid group with a halogen. Esterification of the 21-hydroxy group is carried out, for example, by allowing the sulfonic acid chloride to act on the 21-hydroxysteroids in the presence of an organic base such as pyridine or in the presence of an aqueous alkali. Halogenation of the sulfonic acid group is preferably carried out by treating the 21-alkali acid ester, for example with lithium chloride or potassium hydrogen fluoride, in the presence of a polar solvent, for example dimethylformamide, at a reaction temperature of 50 to 180 ° C.

The dehydrogenation at the 1-position of the saturated Δ- ^4- steroids of the formula I, as a follow-up 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 e., Otherwise it is possible to perform -dehydrogenaci A ⁴ in such a way that The asteroids are heated in an inert solvent with the oxidizing agents customary for this reaction, such as selenium dioxide or 2,3-dichloro-5,6-dicyanobenzoquinone.

The products obtained can be cleaved in a simple manner into the corresponding 11β, ΐ7α, 21-trihydrosteroids.

The cleavage is carried out under conditions conventionally used for hydrolysis or alcoholysis of acetals. Thus, for example, the compounds can be cleaved by reacting with a mineral acid 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. , such as hydrochloric, sulfuric, phosphoric, perchloric, sulfonic, such as p-toluenesulfonic acid, or a strongly acidic carboxylic acid, such as formic, acetic, trifluoroacetic acid, acidic ion exchangers or 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.

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

the 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 Stratumcorneum up to Stratum lucidum on the back of test subjects (20 to 40 pieces of tesafilm, apply 0.1 g of preparations per 4 cm ² large patches without occlusive bandage. To prevent application of the same product to identical skin areas, apply 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 — intermediate grade eryth, medium intensity of red stained, untreated and undamaged skin, 4 = erythem with little clarification , 5 = no erythema fading or thickening.

From the individual results the center was taken.

Diflucortolone-21-valeran (= 6α, 9α-difluoro-11 / β-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 systeinic activity of the compounds can be determined by the adjuvant edema test as follows:

SPF rats weighing 130-150 g are injected with 0.1 ml of a 0.5% suspension of Mycobacterium butyricum 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 the 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 and castor oil without the test substance.

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

The results of the tests are shown in the table 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 - Test results Vasoconstriction test Δ after 4 h Δ after 8 h

Adjuvant edema test (mg / kg animal)

EDso p. EDso p.

9α-Chloro-11 H -hydroxy-16β-methyl-17α, 21-dipropionyloxy-1,4-pregnadien-3,20dione (- beclomethasone dipropionate)

21-Acetoxy-9α-chloro-11; 3-hydroxy-17α-methoxymethoxy-4-pregnene-3,20-dione

21-Acetoxy-9α, -chloro-11β-0,3 0,0 22 + 0,4 i + 0,7

-liydroxy-17α-methoxymethoxy-1,4-pregnadien-3,20-dione +0,9

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

3.0

3.2 + 1.0 ca. 1 + 1.3 ca. 8

The novel compounds, in combination with carriers customary in galenic pharmacy, are suitable for the topical treatment of contact dermatitis, eczema of various kinds, neurodermatoses, erythrodermias, burns, pruritis vulvae et ani, rosacea, cutaneous lupus Erythematodss cutaneus psoriasis, Lichen ruber planus diseases .

The manufacture of medicament specialties is carried out in the customary 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 respiratory diseases such as bronchial asthma or rhinitis.

Furthermore, the novel corticoids in the form of capsules, tablets or dragees, which preferably contain 10 to 200 mg of active ingredient and 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

5.0 g of 21-Acetoxy-17α-methoxymethoxy-4,9 (11) -pregnadien-3,20-dione is suspended in ml of tetrahydrofuran and 20.56 ml of 1 N perchloric acid and 2.78 g are added at + 20 ° C.

N-chlorosuccinide. Stirring is continued for 24 hours while 3.52 ml of 70% perchloric acid is added. The reaction mixture is precipitated into a solution of 5.14 g of sodium sulfite and 350 ml of ice water. The crystallizate is filtered off with suction, washed with water until neutral and the wet crystallizate is recrystallized from methanol / water. 1.5 g of 21-acetoxy-9.alpha.-chloro-11.beta.-hydroxy-17.alpha.-methoxymethoxy-4-pregnene-3,20-dione are obtained, which, after recrystallization from ethyl acetate and acetone, melts at 189 DEG-192 DEG.

Example 2 aj To a suspension of 6.0 g of 21-acetoxy-17α-hydroxy-1,4,9-pregnatriene-3,20-dione in 46 ml of anhydrous acetonitrile was added 11.5 ml of methoxyethoxymethyl chloride and 11.5 ml of diisopropylethylamine and stirred with 7.5 hours at 30 degrees Celsius. After precipitation with ice water, the suction precipitate is dissolved in methylene chloride, washed neutral and then dried. Purification of the reaction product is carried out on 800 g of silica gel using a gradient elution of hexane-ethyl acetate (0 to 30% ethyl acetate) to yield 4.9 g of 21-acetoxy-17a- (1,3,6-trioxaheptyl) -1,4, 9-pregnatriene-3,20-dione.

Melting point 140 ° C.

bj To a solution of 1.0 g of 21-acetoxy-17α- (1,3,6-trioxaheptyl) -1,4,9-pregnatriene-3,20-dione in 10 ml dioxane is added 900 mg of N-chlorosuccinimide and 5 ml. After stirring at room temperature for 3.5 hours, ice-water-sodium salt-sodium hydrogen sulfate was added to the solution, filtered and the residue was taken up in methylene chloride, washed neutral and dried over sodium sulfate. The crude product is purified on 100 g of silica gel using methylene chloride-acetone (0-15% acetone) as the eluent.

Yield: 760 mg of 21-acetoxy-9α-chloro-11/3-hydroxy-17- (1,3,6-trioxaheptyl) -1,4-pregnadien-3,20-dione (m.p. 204 ° C); 180 mg of 21-acetoxy-9α, 11β-dichloro-17 '- (1,3,6-trioxaheptyl) -1,4-pregnadien-3,20-dione (m.p. 148 ° C).

Example 3

(a) Dissolve 4,0 g of 21-Acetoxy-17α-hydroxy-1,4,9-pregnatriene-3,20-dione in 28 ml of anhydrous methylene chloride and 18 ml of formaldehyde dimethylacetal and add in succession a mixture of 6,0 g of diatomaceous earth ( W 20) and 3.0 g of phosphorus pentoxide.

It is stirred for 45 minutes at room temperature, filtered off with suction and the residue is further eluted with methylene chloride containing 3-5% triethylamine. The crude product is purified on 750 g of silica gel using a gradient elution of methylene chloride-acetone (0 to 12 percent acetone) to yield 3.3 g of 21-acetoxy-17α-methoxymethoxy-1,4,9-pregnatriene-3,20-dione mp 160 ° C.

bj 1.6 g of 21-Acetoxy-17α-methoxymethoxy-1,4,9-pregnatriene-3,20-dione are dissolved in 16 ml of dioxane and 1.5 g of N-chlorosuccinimide are added. 8 ml of 10% aqueous perchloric acid is added dropwise and stirred for a further 3 hours at room temperature and then ice water-sodium salt-sodium bisulfite is added to the solution. Filter and work up. The crude product is purified on 175 g of silica gel using a gradient elution of methylene chloride-acetone (0 to 12% acetone). Yield 1.1 g of 21-acetoxy-9α-chloro-11H-hydroxy-17α-methoxymethoxy-1,4- pregnadien-3,20-dione (m.p. 224 ° C) and 250 mg of 21-acetoxy-9α, 11β-dichloro-17α-methoxymethoxy-1,4-pregnadien-3,20-dione, mp 162 ° C .

Example 4

(a) 3.2 g of Tris-triphenylphosphine-rhodium (III) are dissolved in a mixture of 100 ml of methanol and 300 ml of benzene and prehydrogenated for 1.5 hours. After addition of 4.0 g of 21-acetoxy-17α-methoxymethoxy-1,4,9- The solution is concentrated on a rotary evaporator and the residue is purified on 400 g of silica gel using a gradient elution of methylene chloride-acetone (0-12% acetone). 1 g of 21-acetoxy-17α-methoxymethoxy-4,9-pregnadien-3,20-dione.

b) Analogously to Example 3b, 1.1 g of 21-acetoxy-17, .alpha.-methoxymethoxy-4,9-pregnadien-3,20-dione was treated with N-chlorosuccinimide and perchloric acid. After purification, 430 mg of 21-acetoxy-9α-chloro-11β-hydroxy-17'-methoxymethoxy-4-pregnene-3,20-dione is isolated. Mp 195 ° C.

Example 5 and 17.5 g of 21-Chloro-17'-hydroxy-4,9-pregnadien-3,20-dione were treated analogously to Example 3a with 236 ml of formaldehyde dimethyl acetal and worked up. The crude product is purified on 2.25 kg silica gel using a gradient elution of methylene chloride-acetone (0 to 4% acetone). Yield 7.6 g of 21-chloro-17α-methoxymethoxy-4,9-pregnadien-3,20-dlone. Melting point 152 ° C.

b) 1.8 g of 21-chloro-17.alpha.-methoxymethoxy-4,9-pregnadien-3,20-dione are treated analogously to Example 3b with N-chlorosuccinimide and perchloric acid. The crude product was purified on 100 g silica gel eluting with a gradient of methylene chloride-acetone (0-10% acetone). 126 mg of 9?, 21-dichloro-11? -Hydroxy-17? -Methoxyoxy-4-pregnene-3,20-dione are isolated. Melting point 197 ° C (dec.).

Example 6

a) 3.0 g of 21-Fluoro-17.alpha.-hydroxy-1,4,9-pregnatriene-3,20-dione were reacted, analogously to Example 3a, with 14 ml of formaldehyde dimethyl acetal. Work up and purify the crude product on 450 g silica gel by gradient elution with methylene chloride-acetone (0 to 8% acetone). Yield 1.5 g of 21-fluoro-17.alpha.-methoxymethoxy-1,4,9-pregnatriene-3,20-dione.

b) Under the conditions of Example 3b, 500 mg of 21-fluoro-17α-methoxymethoxy-1,4,9-pregnatriene-3,20-dione was reacted with N-chlorosuccinide and perchloric acid. 420 mg of 9α-chloro-21-fluoro-11 H -hydroxy-1 H -methoxymethoxy-1,4-pregnadiene-3,20-dione was isolated as described in the working-up and purification on silica gel. Melting point: 245 degrees Celsius,

Example 7

a) 1.0 g of 17α-hydroxy-1,4,9-pregnadien-3,20-dione was treated with formaldehyde dimethyl acetal under the conditions of Example 3a. 823 mg of 17α-methoxy-1,4,9-pregnatriene-3,20-dione is isolated as a crude product.

b) 823 mg of said crude product, analogously to Example 3b, was reacted with N-chlorosuccinimide and perchloric acid and treated and purified under the conditions described. Yield 410 mg of 9'-chloro-11β-hydroxy-17α-methoxymethoxy-1,4-pregnadien-3,20-dione. Melting point 227 ° C.

Example 8

a) Analogously to Example 7, 3.4 g of 21-fluoro-17α-methoxymethoxy-4,9-pregnadien are prepared from 7.6 g of 21-fluoro-17α-hydroxy-4,9-pregnadien-3,20-dione and 68 ml of formaldehyde dimethylacetal. -3,20-dione.

b) Under the conditions of Example 5b, to 1.4 g

21-Fluoro-17α-methoxymethoxy-4,9-pregnadien-3,20-dione is treated with N-chlorosuccinimide and chloroboric acid. The crude product was purified on 100 g silica gel using gradient elution with methylene chloride-acetone (0-10% acetone). Yield 380 mg of 9α-chloro-21-fluoro-11a-hydroxy-17'-methoxymethoxy-4-pregnene-3,20-dione.

214 ° C (dec.).

Claims (1)

SUBJECT OF THE INVENTION A method for producing the 17-substituted 11-hydroxysteroid pregnane series of the general formula I CH ₂ in which R bonds ...... single bonds or double bonds, X is hydrogen, fluorine, chlorine or methyl, Y a hydrogen atom, Z is hydrogen, fluorine or chlorine; Y and Z together form a carbon-carbon bond, A Y group, a 1-hydroxymethylene group, a 5-chloromethylene group or a carbonyl group, W a methylene group, an ethylidene group or a vinylidene group, O. an oxygen atom or a sulfur atom, 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, R3 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 radical, a sulphate group or a phosphate group, characterized in that ......, X, W, Q, R 1, R 2 and R 3 are as previously defined, chlorine or hypochlorous acid is added and the corticoids saturated at the 1,2-position are optionally dehydrogenated at the 1,2-position and / or The? -Hydroxy group is oxidized to the oxo group and / or the 21-ester groups are saponified and / or the 21-hydroxy groups are esterified or exchanged for fluorine or chlorine atoms.