CH627191A5 - Process for the preparation of corticoids - Google Patents

Description

627191

PATENT CLAIMS 1. Process for the preparation of new corticoids of the formula wherein

X is a fluorine, chlorine or bromine atom,

Ri represents a hydrogen atom, a hydroxyl group or a

Acyloxy group and R2 represent a free or esterified hydroxy group,

characterized,

that the epoxy ring of a compound of the formula

The invention relates to a method for producing new corticoids of the formula

CH2R2

CD,

(II),

wherein Ri and R2 have the meaning given above, by means of hydrogen halide.

2. The method according to claim 1, characterized in that

that one saponifies existing ester groups in compounds of formula I obtained.

3. The method according to claim 1, characterized in

that esterified hydroxy groups present in the compounds obtained are esterified.

4. The method according to claim 1, characterized in

that 6a, 12a-difluoro-11ß, 21-dihydroxy-16a-methyl-l, 4-pregnadiene-3,20-dione is produced.

5. The method according to claim 1, characterized in

that 6a, 12a-difluoro-11ß-hydroxy-16a-methyl-21-valeryloxy-1,4-pregnadiene-3,20-dione is produced.

6. The method according to claim 1, characterized in

that 21-acetoxy-6a, 12a, difluoro-11ß-hydroxy-16a-methyl-1,4-pregnadiene-3,20-dione is produced.

7. The method according to claim 1, characterized in

that 12a-chloro-6a-fluoro-11ß-hydroxy-16a-methyl-21-v leryloxy-l, 4-pregnadien-3,20-dione is produced.

wherein

20 X a fluorine, chlorine or bromine atom,

Ri is a hydrogen atom, a hydroxy group or a

Acyloxy group and R2 mean a free or esterified hydroxy group.

The new corticoids of formula I are pharmacologically active substances for 2s, which are characterized in particular by the fact that, when applied topically, they have good anti-inflammatory activity and cause only minor systemic side effects.

The onset and duration of action of the new 30 corticoids, as well as their solubility in physiologically compatible solvents, as in the case of the known corticoids, depend in particular on whether and, if appropriate, with which acid a hydroxyl group which is in the 17- and / or 21-position is esterified.

3s The esterified 21-hydroxy groups R2 are preferably acyloxy groups with 1 to 16 carbon atoms in the acyl radical, sulfate groups or phosphate groups. Suitable acyloxy groups are, for example, those which are derived from straight-chain or branched, saturated or unsaturated 40 aliphatic mono- or dicarboxylic acids, which can be substituted in a customary manner, for example by hydroxyl groups, amino groups or halogen atoms.

Also suitable as acyloxy groups are residues of cyclo-45 aliphatic, aromatic, mixed aromatic-aliphatic or heterocyclic acids, which can also be substituted in the usual way. Examples of suitable acyloxy groups are:

so the formyloxy, acetoxy, propionyloxy, butyryloxy, pentanoyloxy, hexanoyloxy, octanoyloxy, undecanoyloxy, di-methylacetoxy, trimethylacetoxy, diethylacetoxy, tert-butylacetoxy, benzoyyloxy, phenac , Cyclopentyl-propionyloxy-, hydroxyacetoxy-, monochloroacetoxy-, di-55 chloroacetoxy-, trichloroacetoxy-, also the dimethylamino-acetoxy-, the trimethylaminoacetoxy-, the diethylamino-acetoxy-, the piperidinoacetoxy-, the nicotinoyloxy-ionoxy-, the -carbox and the carboxypentanoyloxy group.

To produce water-soluble active ingredients, the 21-acyloxy compounds with a basic nitrogen group in the acyl radical can be converted into the corresponding acid addition salts, such as the hydrochlorides, hydrobromides, sulfates, phosphates, oxalates, tartrates or maleates. Furthermore, the 21-dicarboxylic acid monoesters and the 65 sulfuric and phosphoric acid esters can be converted into their alkali metal salts, such as the sodium or potassium salts, to increase their solubility in water

Particularly preferred esterified hydroxyl groups are R2

Acyloxy groups with 1 to 8 carbon atoms in the acyl radical.

Suitable esterified 17-position hydroxyl groups R 1 are acyloxy groups which preferably have 1 to 8 carbon atoms in the acyl radical. Particularly suitable acyloxy groups are alkanoyl groups such as, for example, the acetoxy, the propionyloxy group, the butyryloxy group, the pentanoyloxy group or the hexanoyloxy group.

According to the invention, the new corticoids of the formula I are produced by means of a process which is characterized in that the epoxy ring of a compound of the formula fH2R2

C = 0

F

wherein Ri and R2 have the meaning given above, by means of hydrogen halide. If desired, existing ester groups can be saponified and / or existing hydroxy groups can be esterified.

The process according to the invention is preferably carried out in the presence of an inert solvent capable of absorbing hydrogen halide. Suitable solvents are, for example, lower alcohols such as methanol, ethanol or isopropanol, ethers such as diethyl ether, glycol monomethyl ether, dioxane or tetrahydrofuran, chlorinated hydrocarbons such as dichloromethane, chloroform or tetrachlorethylene, dipolar aprotic solvents such as dimethylformamide, or hexamethylphosphoric acid triamide. The reaction is preferably carried out at a reaction temperature of from −500 ° C. to +50 ° C.

The optionally subsequent saponification of acyloxy groups in the 17- and / or 21-position is usually carried out using the customary processes, for example by reacting the esters in water-containing or alcohol-containing solutions or solvent mixtures in the presence of strong acids, such as sulfuric acid or hydrogen chloride , p-toluenesulfonic acid or trifluoroacetic acid or by reacting the esters in water-containing or alcohol-containing solutions or solvent mixtures in the presence of alkali metal alcoholates, alkali metal hydroxides or alkali metal carbonates.

Is z. B. saponification carried out under mild conditions, it is possible to selectively saponify the 17a-21-diacyloxy-steroids of the formula I to the 21-hydroxy-17a-acyloxy-steroids.

Any subsequent esterification of free hydroxyl groups in the 17 and / or 21 position can also be carried out with the aid of the working methods known per se. For example, the hydroxysteroids can be esterified with acyl chlorides or acyl anhydrides in the presence of acids such as, for example, hydrogen chloride-p-toluenesulfonic acid, trifluoroacetic acid or in the presence of bases such as potassium carbonate, pyridine, collidine or p-dimethylaminopyridine. On the other hand, it is possible to esterify the hydroxy compounds with carboxylic acids in the presence of trifluoroacetic anhydride. If you carry out these esterifications z. B. mil627191

as is known, only the primary hydroxyl groups are esterified, while any tertiary hydroxyl group which may be present is not reacted.

The alkali metal sulfates of the 21-monosulfuric acid esters can be prepared from the 21-hydroxy compounds of the general formula I in a manner known per se, for example by reacting the 21-hydroxy compounds with sulfur trioxide in pyridine and converting the resulting sulfuric acid ester into the alkali metal salt by treatment with alkali bases.

As already mentioned, the new corticoids are characterized by good anti-inflammatory activity when applied topically; For example, the 6a, 12a-difluoro-11ß, 21-dihydroxy-16a-methyl-l, 4-pregnadien-3,20-dione in the vasoconstriction test shows an antiinflammatory activity just as good as that of the known 6a, 9a-diflouror-11ß, 21- dihydroxy-16a-methyl-l, 4-pregnadiene-3,20-dione (German Patent No. 1 211194).

The vasoconstriction test was carried out as follows:

On the back of volunteers, the stratum corneum is disassembled with twenty scraps of tape with a scotch tape, creating a pronounced hyperemia. Within the stripped area, 50 mg of ointment, each containing 0.1% or 0.01% of the substance to be tested or the reference substance in a water-oil basis, is applied to 4 cm2 marked areas. 1, 2, 3 and 4 hours after the application, the extent of the vasoconstriction is determined.

When administered systemically, the new corticoids are significantly less effective than the structurally analogous previously known 9a-halogen corticoids. For example, the 6a, lla-difluoro-lß, 21-dihydroxy-16a-methyl-l, 4 * -pregna-dien-3,20-dione shows in the adjuvant edema test a five times weaker efficacy than the 6a, 9a- Difluoro-llß, 21-dihydroxy-16a-methyl-l, 4-pregnadiene-3,20-dione. The adjuvant edema test was carried out as follows:

SPF rats weighing 130 to 150 g are injected into the right hind paw to produce an inflammatory focus with 0.1 ml of a 0.5% Mycobacterium butyricum suspension (available from the American company Difko). The rat's paw volume is measured before the injection. 24 hours after the injection, the paw volume is measured again to determine the extent of the edema. The rats are then injected subcutaneously with different amounts of the test substance - dissolved in a mixture of 29% benzyl benzoate and 71% castor oil. After another 24 hours, the paw volume is determined again.

The control animals are treated in the same way, with the difference that they are injected with a test substance-free benzyl benzoate-castor oil mixture. The percentage edema inhibitory effect is calculated in the usual way from the paw volumes obtained.

The highly effective corticoids previously used to treat skin inflammation always have a pronounced systemic effect in addition to the topical effect. These corticoids can get into the bloodstream even when administered opically as a result of absorption through the inflamed skin or as a result of skin injuries, where they act as hormone-active substances in a variety of ways on the body's functions.

This disadvantage is alleviated in the case of the topically highly active, systemically but slightly active compounds of the present invention. They are therefore very well suited for the local treatment of inflammation.

The new compounds are suitable in combination with the carriers customary in galenical pharmacy for the local treatment of contact dermatitis and eczema

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various types, neurodermatitis, erythroderma, burns, pruritis vulvae et ani, rosacea, erythematosus cutaneus, psoriasis, lying ruber planus et verrucosus and similar skin diseases.

The new corticoids are also suitable for the treatment of allergic diseases of the respiratory tract, such as rhinitis or bronchial asthma.

The preparation of the pharmaceutical specialties can be carried out in the usual way by the active ingredients z. B. with suitable additives in the desired application form such as: solutions, lotions, ointments, creams, plasters or inhalants. In the pharmaceuticals formulated in this way, the active ingredient concentration depends on the form of administration. For lotions and ointments, an active ingredient concentration of 0.001% to 2% is preferably used.

The starting compounds of the general formula II for the process according to the invention can be prepared by methods which are generally known to the person skilled in the art and which are explained using the example of typical representatives in the preparations below.

The following examples serve to explain the invention further:

Preparation 1

300 g of 6a-fluoro-llla-hydroxy-16a-methyl-21-valeryloxy-l, 4-pregnadiene-3,20-dione are dissolved in 1500 ml of hexamethyl-phosphoric acid triamide with 500 g of methyltriphenoxyphosphonium iodide in 1 hour at 90 ° C internal temperature stirred in an argon atmosphere. After cooling, the solution is introduced into 1015% ice-cold potassium hydroid solution, the precipitated product is suctioned off and taken up in ethyl acetate. The ethyl acetate extract is washed with water and evaporated in vacuo. From the crude product thus obtained, which according to the NMR spectrum contains 70% 6a-fluoro-16a-methyl-21-valeryloxy-l, 4.9 (ll) -pregnatrien-3,20-dione and 30% 6a-fluoro-16a- contains methyl-21-valeryloxy-l, 4, ll-pregna-trien-3,20-dione, the latter is separated by fractional crystallization from methanol and 49.4 g of pure product with a melting point of 96-97 ° C. are obtained.

Preparation 2

40 g of 6a-fluoro-16a-methyl-21-valeryloxy-1,4, ll-pregnatrien-3,20-dione are dissolved in 800 ml of dimethylformamide, the solution is cooled to -10 ° C., with 20 g of N- Bromosuccinimide added and 90 ml IN perchloric acid added dropwise. The solution is kept at + 2 ° C. for 18 hours and then stirred into 8 liters of ice water to which 20 g of sodium bisulfite and 30 g of sodium acetate have been added. The precipitated product is filtered off, taken up in methylene chloride and the methylene chloride solution washed with water. The solution is concentrated to a volume of 300 ml and pentane is added. The crystallized 12a-bromo-6a-fluoro-11ß-formyl-oxy-16a-methyl-21-valeryloxy-l, 4-pregnadien-3,20-dione (39.7 g) is filtered off with suction and recrystallized again from methanol. Melting point 177-178 ° C.

Preparation 3

26 g of 12a-bromo-6a-fluoro-11ß-formyloxy-16a-methyl-21-valeryloxy-l, 4-pregnadien-3,20-dione are refluxed in 500 ml of ethanol with 30 g of potassium acetate for 2 hours. After cooling, the solution is precipitated in ice water, the product is suctioned off, washed with water and dried. After recrystallization from acetone / hexane, 18.5 g6a

Fluorine-ll, 12ß-epoxy-16a-methyl-21-valeryloxy-l, 4-pregna-diene-3,20-dione, melting point 165-166 ° C.

example 1

A solution of 16.4 g of 6a-fluoro-ll, 12β-epoxy-16a-methyl-21-valeryloxy-l, 4- is added to a solution of 34 ml of hydrogen fluoride, 165 ml of chloroform and 17 ml of ethanol at −20 ° C. pregnadien-3,20-dione added dropwise in 165 ml of chloroform and stirred at 0-5 ° C for 2 hours. The solution is poured into ice water containing potassium bicarbonate, the precipitated product is suctioned off, washed with water and dried. After chromatography on Süicagel and recrystallization from methanol, 13.1 g of 6cx, 12a-difluoro-11ß-hydroxy-16a-methyl-21-valeryloxy-l, 4-pregnadiene-3,20-dione with a melting point of 207.5-209 are obtained ° C.

Example 2

3.2 g of 6a, 12a, difluoro-11ß-hydroxy-16a-methyl-21-valeryl-oxy-l, 4-pregnadien-3,20-dione are dissolved in 25 ml of methylene chloride and 25 ml of methanol, at 0 ° C cooled and treated with argon gassing with a solution of 180 mg of potassium hydroxide in 5 ml of methanol. The solution is stirred for 3 hours at 0-50 C, neutralized with glacial acetic acid, concentrated in vacuo and the residue taken up in methylene chloride. The methylene chloride phase is washed neutral with water, evaporated in vacuo and the residue is crystallized from acetone-hexane. 2.35 g of 6a, 12a-difluoro-11ß-21-dihydroxy-16a-methyl-l, 4-pregnadiene-3,20-dione are obtained (with decomposition).

Example 3

1.8 g of 6a-fluoro-11ß, 12ß-epoxy-16a-methyl-21-valeryloxy-l, 4-pregnadiene-3,20-dione are dissolved in 60 ml of methylene chloride and cooled to -5 ° C. Dry hydrogen chloride is passed into this solution for 15 minutes so that the temperature does not rise above + 5 ° C. The mixture is stirred for 1 hour at 0 ° to + 2 ° C, diluted with methylene chloride and washed neutral with water. After evaporation in vacuo and crystallization from acetone-hexane, 12a-chloro-6a-fluoro-11ß-hydroxy-16a-methyl-21-valeryloxy-l, 4-pregnadiene-3,20-dione is obtained.

Example 4

10 g of 6a, 12a-difluoro-11ß, 21-dihydroxy-16a-methyl-l, 4-pregnadiene-3,20-dione are stirred in 32 ml of pyridine and 16 ml of acetic anhydride at 0 to 5 ° C. for 90 minutes. Then it is poured into ice water, the precipitated product is suctioned off, washed with water and dried. After recrystallization from acetone-hexane, 21-acetoxy-6a, 12a-difluoro-11ß-hydroxy-16a-methyl-l, 4-pregnadiene-3,20-dione is obtained.

Preparation 4

2 g of 6a-fluoro-11ß, 12ß-epoxy-16a-methyl-21-valeryloxy-l, 4-pregnadiene-3,20-dione are dissolved in 20 ml of methylene chloride and 20 ml of methanol, at 0 ° C to 5 ° C cooled and treated with argon gas with a solution of 150 mg of potassium hydroxide in 6 ml of methanol. The solution is stirred for 90 minutes at 0-5 °, neutralized with acetic acid, evaporated in vacuo and worked up. After recrystallization from acetone / hexane, 1.5 g of 6a-fluoro-11β, 12β-epoxy-21-hydroxy-16a-methyl-l, 4-pregnadiene-3,20-dione with a melting point of 162-165 ° C. are obtained.

Preparation 5

1.5 g of 6a-fluoro-11ß, 12ß-epoxy-21-hydroxy-16a-methyl-l, 4-pregnadiene-3,20-dione in 6 ml of pyridine with 3 ml of s

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627191

Acetic anhydride stirred at 20 ° C for 18 hours. Then it is precipitated in ice water, the product is suctioned off, washed with water and dried. After crystallization from acetone / hexane, 1.5 g of 21-acetoxy-6a-fluoro-11ß, 12ß-epoxy-16a-methyl-1, 4-pregnadiene-3,20-dione with a melting point of 215.5-216.5 ° C.

Example 5

1.4 g of 21-acetoxy-6a-fluoro-11ß, 12ß-epoxy-16a-methyl-

1,4-pregnadiene-3,20-dione are dissolved in 22 ml of chloroform, 22 ml of a chloroform solution saturated with hydrogen chloride are added and the mixture is stirred at 0 ° for 10 minutes. It is then diluted with chloroform, washed with water and evaporated in vacuo. Crystallization from methylene chloride, methanol and ethyl acetate gives 1.38 g of 21-acetoxy-12a-chloro-6a-fluoro-11β-hydroxy-16a-methyl-1,4-pregna-diene-3,20-dione from melting point 3050 C (decomposition).

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