CH615442A5 - Process for the preparation of 17alpha,21-diesters of 17alpha,21-dihydroxysteroids of the pregnane series - Google Patents

Description

The invention relates to a method according to the preamble of patent claim 1.

The compounds of formula I obtainable according to the invention which have a basic 21-ester grouping are distinguished by valuable anti-inflammatory activity.

It is known that certain 17a, 21 diesters of the Pregnan series have topical anti-inflammatory activity, which in some cases can be very strong. These compounds are mainly used for the topical treatment of external inflammatory conditions. The known esters generally have hydrophobic acyloxy ester groups in the 17- and 21-positions and, unless there are water-solubilizing groups, cannot be processed for aqueous preparations for the treatment of inflammation of the ears or eyes.

In contrast, the new 17a, 21 diesters of the Pregnan series obtainable according to the invention have high systemic activity in addition to good topical anti-inflammatory activity. In addition, these compounds contain a water-solubilizing or potentially water-solubilizing ester group in the 21-position. Accordingly, these compounds are well absorbed when administered orally.

In addition, these compounds do not cause any noticeable thinning of the skin, as is frequently found as undesirable side effects by the known topical anti-inflammatory steroids. The absence of the undesirable side effect could be confirmed by experiments with rats.

The compounds of the formula I are also notable for systemic immunosuppressive activity, which is why they can be used for the treatment of allergic disorders and in particular for the treatment of inflammatory disorders with a significant immunological component. In experiments with rats, it was observed that the ratio of immunosuppressive activity to anti-inflammatory activity in the compounds obtainable according to the invention is greater than in the case of β-methasone.

In formula I R2 is a group of the formula - (CH2) ii-NR3R4, then n preferably corresponds to the number 1, while the group NR3R4 preferably a diethvlamino group or an unsubstituted saturated membered heterocyclic ring, e.g. represents a piperidino or morpholino group, with the morpholino group being preferred.

If the group - NR3R4 represents a heterocyclic ring, this can also be a substituent. e.g. Ci-C3-alkyl groups, especially methyl groups.

R1 in formula I advantageously denotes an alkyl group with 1 to 3 carbon atoms, specifically methyl, ethyl, propyl or isopropyl. Of these groups, however, the ethyl group is particularly preferred.

Y preferably represents a fluorine atom, while X preferably represents a β-hydroxy group and represents a double bond.

Of the compounds of the formula I obtainable according to the invention, 9a-fluoro-11β-hydroxy-16ß-methyl-21-morpholino-acetoxy-17-propionyloxypregna-1,4-diene-3,20-di- is due to its particularly favorable anti-inflammatory activity

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one particularly preferred. Further preferred compounds of formula I are

21 -diethylaminoacetoxy-9 a-fluoro-11β-hydroxy-16ß-methyl-17-propionyloxy-pregna-l, 4-diene-3,20-dione; 9 a-fluoro-11β-hydroxy-16ß-methyl-21 -piperidinoacetoxy-17-propionyloxy-pregna-l, 4-diene-3,20-dione and 9a-chloro-21-diethylaminoacetoxy-11ß -hydroxy-16ß -methyl-17-propionyloxy-pregna-l, 4-diene-3,20-dione. The compounds of the formula I can also be present in the form of their acid addition salts, the hydrochlorides being particularly preferred.

The compounds of formula I are prepared using the method defined in the characterizing part of patent claim 1.

Examples of easily exchangeable substituents Z in formula II are: halogens, such as chlorine, bromine or iodine, with chlorine being particularly preferred, or aromatic or aliphatic sulfonyloxy groups, e.g. the p-toluenesulfonyloxy or methanesulfonyloxy group.

The reaction of the compounds of formula II with those of formula III is preferably carried out in a solvent medium. Examples of solvents are Ketones such as acetone or methyl ethyl ketone, acyclic ethers such as diethyl ether, cyclic ethers such as tetrahydrofuran, esters such as ethyl acetate, amides such as dimethylformamide or dimethyl acetamide, or halogenated hydrocarbons such as methylene chloride. The reaction is advantageously carried out at elevated temperature, e.g. at the reflux temperature of the reaction mixture.

If a compound of formula II in which Z represents a halogen atom is used for the reaction, the reaction is conveniently carried out in the presence of an acid acceptor, e.g. a tertiary organic base such as pyridine, collidine or triethylamine. In addition, an excess of the compound of formula III can serve as an acid acceptor.

The conversion of the compounds of formula I prepared according to the invention into their acid addition salts can be carried out by treatment with a suitable acid in water or an organic solvent medium, e.g. an alcohol, such as ethanol, or a hydrocarbon, such as benzene. Suitable acids are, for example, hydrochloric acid, hydrobromic acid, nitric acid, phosphoric acid, sulfuric acid, p-toluenesulfonic acid, methanesulfonic acid, sulfosalicylic acid, maleic acid, fumaric acid, gluconic acid, citric acid, tartaric acid, acetic acid, ascorbic acid, lactic acid and succinic acid.

Should aqueous solutions of the acid addition salts of weakly basic compounds of formula I, e.g. those in which R2 is morpholinomethyl are prepared, the pH of the solution is preferably adjusted to an acidic value. The salts of the compounds of formula I can also be obtained in the form of their hydrates or solvates.

The starting compounds of formula II can be easily prepared by, for example, an appropriate 21-hydroxysteroid with an appropriately substituted acylating agent, e.g. a halide or anhydride, e.g. a chloroacyl chloride or anhydride. This reaction is advantageously carried out in a solvent medium, e.g. in one of the solvents mentioned for the reaction of the compounds of the formulas II and III.

Starting compounds of formula II in which Rs represents an iodo-acyloxy group can, if desired, be reacted by reacting a compound of formula II in which R5 represents a chloroacyloxy group with a source of iodine ions, e.g. an iodide such as sodium iodide. This implementation is advantageously in a polar

Solvent medium carried out. Suitable solvents are e.g. Ketones, such as acetone or methyl ethyl ketone, acyclic ethers, such as diethyl ether, cyclic ethers, such as tetrahydrofuran, or amides, such as diethylacetamide or dimethylformamide.

The compounds of the formula I prepared according to the invention can be processed into pharmaceutical preparations for use in human and veterinary medicine. For this purpose, the compounds of the formula I or their acid addition salts are generally mixed with one or more pharmaceutically acceptable excipients or excipients and, if appropriate, with the addition of other therapeutic agents and brought into the suitable preparation form.

Formulations suitable for topical use are, for example, ointments, lotions, creams, powders and aerosol sprays, also suppositories and retention enemas for the surface treatment of the rectal area, furthermore vaginal inlays, sterile drops and ointments for the treatment of eyes and ears, and slowly disintegrating buccalpel lets, e.g. for the treatment of aphthous ulcers, chewing gum for the slow release of the active ingredient for the treatment of the mucous membranes of the mouth and throat as well as nasal or throat sprays.

Antibiotic agents, e.g. antibiotics, include e.g. antibiotic agents which can be incorporated into pharmaceutical preparations together with the compounds obtainable according to the invention. Aureomycin or neomycin, as well as chemical agents, e.g. Chiniofon (S-hydroxy-7-iodo-5-quinoline sulfonic acid), which can have an advantageous effect on the therapeutic effect.

The content of active steroid in the preparations intended for topical use depends on the form of preparation and is generally 0.0001 to 5% by weight, advantageously 0.001 to 0.5% by weight, and in particular 0.01 to 0 , 25% by weight.

Depending on the type of condition to be treated, the preparations can be administered one or more times a day. In some cases, particularly favorable results are achieved if the steroid is applied to the skin in the form of an occlusal band.

Preparations intended for use in veterinary medicine can be packaged in an analogous manner to that described above. In this case, of course, the form of preparation and especially the dosage must be based on the size of the animal to be treated. In this connection, intramammary preparations should be mentioned in particular.

Because of their systemic activity already mentioned, the compounds obtainable according to the invention can also be processed into preparations for systemic absorption. Preparations for oral, rectal and parenteral administration can be mentioned as examples. Since the compounds of the formula I are very potent, it is generally advisable to prepare them in the form of single doses. Suitable forms of preparation are, for example, tablets or capsules, in particular those with a long-term effect, and also preparations for parenteral administration, which are expediently offered in the form of single doses. Such preparations can be in the form of ampoules or vials which can be accommodated in containers for holding single or multiple doses. In addition, preparations for parenteral administration can be in the form of dry sterile solids, which are reconstituted with a sterile diluent immediately before use.

Suppositories for systemic absorption can be obtained using a suitable suppository base in

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Compound with a carrier that supports the absorption by the colon.

The preparations intended for internal application, like those intended for topical application, can also contain other active ingredients, e.g. antibacterial agents such as neomycin. The preparations intended for internal use are also advantageously offered in the form of single doses if they generally contain from 0.05 to 10.0 mg, preferably 0.50 to 5.0 mg, of the active steroid per single dose. The preparations intended for internal application can contain 0.01 to 50% of active substance, the content in individual cases depending on the type of preparation. Preparations which are intended for use in veterinary medicine generally have different dosages which depend on the size of the animal to be treated and the frequency of administration.

The following examples serve to explain the invention. Unless otherwise stated, optical rotations in dioxane were measured at a concentration of approximately 1%. The ultraviolet spectra were measured in ethanol. The organic extracts were generally dried over magnesium sulfate or sodium sulfate.

example 1

9 a-fluoro-11β-hydroxy-16ß -methyl-21 -morpholinoacet-oxy-17-propionyloxy-pregna-l, 4-diene-3,20-dione

(i) A solution of crude β-methasone-17-propionate-21-chloroacetate (8.3 g) and morpholine (6.9 ml) in anhydrous acetone (275 ml) is refluxed for 1 hour. The mixture is evaporated to give a yellow oil which is dissolved in ethyl acetate (350 ml) and extracted with water (2x350 ml). The dried organic phase is evaporated to a yellow oil which is crystallized from ethanol, the title compound being obtained as a colorless powder (7.5 g), mp. 124 to 125 ° C. An analytical sample as a monohydrate (from ethanol) has an mp of 128 to 130 ° C; [cc] d + 620, Xmax 237 nm (e 15 630).

(ii) A solution of β-methasone-17-propionate-21-iodo-tat (1.8 g) and morpholine (1.27 ml) in acetone (AR, 80 ml) is heated to reflux for 1/2 hour . The mixture is cooled and evaporated in vacuo to a yellow gum which is partitioned between ethyl acetate and water. The pH of the mixture is adjusted to 7 with 2N hydrochloric acid. The aqueous phase is extracted further with ethyl acetate and the combined organic extracts are washed with water, dried and evaporated under reduced pressure to give an almost colorless foam (1.86 g). Crystallization and recrystallization from aqueous methanol gives colorless crystals (1.0 g) of the title compound as a monohydrate, mp 122 to 125 ° C, [a] d + 62 °, Xmax 236.5 nm (e 16,000).

Example 2

9a-fluoro-11β-hydroxy-16ß-methyl-21 -morpholinoacetoxy-

17-propionyloxy-pregna-l, 4-diene-3,20-dione hydrochloride

(i) A solution of β-methasone-17-propionate-21-morpholinoacetate (2 g) in anhydrous ethanol (5 ml) is treated with 0.6 N HCl in ethanol (6 ml), 15 minutes at room temperature in left in a well sealed conical flask and evaporated to give an almost colorless oil. After drying the oil in vacuo at 50 ° C for 3 hours, the remaining glass-like material is dissolved in a minimal amount of acetone and stored at 5 ° C for 3 hours. The product is collected and dried in vacuo at 50 ° C for 3 hours to give colorless crystals of the title compound (1.85 g). An analytical sample (from acetone) in the form of an acetone solvate had a mp.

near 170 ° C; [(x] d + 95 ° (dilute hydrochloric acid;

Xmax 238 nm (e 15 300).

(ii) A sample (2.00 g) of β-methasone-17-propionate-21-morpholinoacetate hydrochloride, prepared as shown in (i) above, by PMR spectroscopy with acetone (approx. 0.5 mol) is solvated, dissolved in warm methanol and the solution is filtered, then evaporated to a small volume by boiling. Ethyl acetate is gradually added and crystallization is induced to give colorless crystals (1.75 g). The recrystallization is carried out in a similar manner and, after drying overnight at 50 ° C./0.1 mm, colorless crystals (1.48 g) of the title compound are obtained as hemihydrate, mp. 175 to 180 ° C., [a] d + 93 ° (approx. 0.1 N hydrochloric acid), [a] D + 81.5 ° (dioxane), Xmax 239 nm (e 15 500). The infrared spectrum (in Nujol) differs from that of the original sample in the same medium and the PMR spectrum (in deuteriochloroform) shows no solvation by methanol, ethyl acetate or acetone.

Example 3

21 -Diethylaminoacetoxy-9 a-fluoro-11β-hydroxy-16ß-methyl-17-propionyloxy-pregna-l, 4-diene-3,20-dione hydrochloride ß-methasone-17-propionate-21-chloroacetate (1st , 9 g) in acetone (100 ml) is treated with dry sodium iodide (2 g) and the mixture is heated under reflux for 2 hours. Dilution with water gives crude 21-iodoacetate, which is dried, dissolved in acetone (80 ml) and refluxed with diethylamine (1.2 ml) for 1.5 hours. Evaporation of the solvent gives a dark red-brown solid which is filtered through Florisil (70 g) in ethyl acetate. The material, eluted with ethyl acetate, is dissolved in benzene and treated with hydrogen chloride at 0 ° C. The solvent and excess hydrogen chloride are removed in vacuo and the residue is divided between water and ether. The aqueous layer is freeze-dried to give the title compound, hydrated with two molecules of water, as an amorphous solid (1.13 g), [<x] d + 84.4 ° (H2Ö), Xmax 237 to 239 nm (e 14 800).

Example 4

9 a-fluoro-11β-hydroxy-16ß -methyl-21 -piperidino-acetoxy-17-propionyloxy-pregna-1,4-diene-3,20-dione hydrochloride A mixture of ß-methasone-17-propionate -21-iodoacetate (1.8 g) and redistilled piperidine (1.44 ml) in acetone (80 ml) is heated under reflux for about 1 2 hours and then evaporated in vacuo at room temperature. The residue is divided between a mixture of benzene (100 ml), ether (50 ml), ethyl acetate (50 ml) and approx. 0.5 N hydrochloric acid (600 ml), the aqueous phase is washed with benzene (2x50 ml), then stirred with chloroform (50 ml) and then ammonia is added until a basic reaction of pH 8.0. The aqueous phase is further extracted with chloroform (3x100 ml) and the combined extracts are washed with water (20 ml), decolorized (activated carbon), dried and evaporated in vacuo. The remaining foam is rubbed with petroleum ether,

whereby 21-piperidinoacetate (1.68 g) is obtained as a pale brown solid, Xmax 237 nm (e 15 200).

A solution of the crude free base (1.43 g) in benzene (50 ml) is cooled to 0 ° C and treated with dry hydrogen chloride for about 30 seconds. The volatile material is removed in vacuo at room temperature, then fresh benzene is added and the evaporation is repeated. The remaining material is partitioned between water and ether and the aqueous phase is freeze-dried to give the hydrochloride as a solid (940 mg) which crystallizes from acetone in the form of colorless needles (799 mg), mp. 165 to 167.5 ° C. ; Concentration of the mother liquors results

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a second batch (23 mg), mp 166.5-167.5 ° C. Recrystallization of the two batches from acetone gives the analytical sample of the title compound, hydrated with half a molecule of water, as colorless, hygroscopic needles (688 mg), mp. 167.5 to 169.5 ° C, [a] d + 80 ° ( highly diluted hydrochloric acid), Xmax 238 nm (e 15 700).

Example 5

9 a-Chloro-21 -diethylaminoacetoxy-11β-hydroxy-16ß-methyl-17-propionyloxy-pregna-l, 4-diene-3,20-dione hydrochloride io A solution of 9a-chloro-21-chloroacetoxy-llß -hydroxy-16ß-methyl-17-propionyloxy-pregna-l, 4-diene-3,20-dione (1.7 g) in acetone (80 ml) is mixed with sodium iodide (1.7 g)

treated and the solution is heated to reflux for 4 hours. The mixture is poured into water (21) and the precipitated material is washed and dried to give 21-iodoacetate (1.9 g).

The above iodoacetate (1.75 g) in acetone (70 ml) is treated with diethylamine (0.88 ml) and the mixture is refluxed for 1½ hours. The acetone is removed in vacuo 20 and water (35 ml) is added. The aqueous mixture is extracted with chloroform to give 21-diethylaminoacetate as a foam (1.6 g). This material, in benzene solution, is treated at room temperature with a solution of hydrogen chloride (106 mg) in benzene (14.5 ml). 25 The benzene is evaporated in vacuo and the residue is divided between water and ether. The aqueous solution is freeze-dried to give the title compound (1.41 g) as an almost colorless, amorphous solid. A portion is purified by continuing to take it up in water, extracting with 30 ether, heating the aqueous solution from a steam bath with activated carbon, filtering, and freeze-drying the resulting solution, the title compound being a colorless, amorphous solid, solvated with 2. 5 molecules of water, obtained, [ci] d + 92.10 (H2O). 35

Preparation of the starting compounds A) 9 a-chloro-21-chloroacetoxy-11 ß -hydroxy-16ß -methyl-

17-propionyloxy-pregna-l, 4-diene-3,20-dione 9cc-chloro-lß, 21-dihydroxy-16ß-methyl-17-propionyloxy-40

pregna-l, 4-diene-3,20-dione (2 g) in dry tetrahydrofuran (60 ml) is treated with pyridine (1.5 ml) and chloroacetic anhydride (1.5 g). The mixture is left to stand at room temperature for 2 hours and then poured into dilute hydrochloric acid (21). The precipitated solid (2.34 g) is filtered off, washed and dried. A portion (640 mg) is recrystallized from acetone-petroleum ether to give the title compound (484 mg), mp. 168 to 170 ° C (capillary), [o] d + 86.8 ° (c 1.37%) , Xmax 238 nm (e 13 780).

B) β-methasone-21-chloroacetate-17-propionate ß-methasone-17-propionate (8.97 g) in dried and distilled tetrahydrofuran (270 ml) is stirred and with chloroacetic anhydride (4.1 g) and then with dry Treated with pyridine (1.57 ml). The mixture is stirred for a further 2 hours at room temperature. Water (50 ml) is added and the mixture is evaporated at 40 ° C. The residue (oil) is dissolved in ethyl acetate (500 ml) and first with a mixture of 2N hydrochloric acid (30 ml) and water (270 ml), then with 10% aqueous sodium hydrogen carbonate solution (100 ml) and finally with water ( 500 ml) extracted until the pH of the washing solutions is neutral. The organic phase is dried and evaporated at 40 ° C. The residue (oil) is dissolved in ethanol at 60 ° C (100 ml) and evaporated to approximately V3 volume. On cooling, a colorless product separates, which is collected and dried in vacuo to give the title compound (9.0 g), mp. 180 to 185 ° C.

C) β-methasone-21-iodoacetate-17-propionate Crude β-methasone-17-propionate-21-chloroacetate (4.5 g) and dry sodium iodide (4.8 g) in acetone (230 ml) are 3 hours on Reflux heated. After cooling, the reaction mixture is poured into water (600 ml) to give, after prolonged stirring, a colorless solid (4.26 g). A portion (194 mg) is recrystallized twice from methanol to give the title compound as colorless crystals (122 mg), mp. 180 to 182 ° C, [a] D + 46 °, Xmax 238 nm (e 16 100).

B

Claims (3)

615442 2. The method according to claim 1, characterized in that a compound of formula II, wherein R5 is a Group of the formula - OCO (CH2) nZ, where Z represents a halogen atom or an aromatic or aliphatic sulfonyloxy group. 2nd PATENT CLAIMS 1. Process for the preparation of a compound of formula I CH2OCOR2 c = o —OCOR "N- CH wherein X is a β-hydroxy group or a keto group; Y is a fluorine or chlorine atom; R1 is hydrogen or an alkyl group having 1 to 3 carbon atoms; R2 is a group of the formula - (CH2) nNR3R4, where n is 1, 2 or 3; and R3 and R4, which may be the same or different, each represent an alkyl group having 1 to 4 carbon atoms; or R3 and R4 together with the adjacent nitrogen atom form a saturated substituted or unsubstituted monocyclic, heterocyclic 4- to 7-membered ring, which can also contain a sulfur or oxygen atom or another nitrogen atom; —- denote a single or double bond, and their acid addition salts, characterized in that a compound of formula II CH "R5 C = 0 - OCOR CH (II) wherein R5 is a group of the formula - OCO (CH2) nZ, where Z is an easily exchangeable substituent, means with a compound of formula III R3 X H-N (III) \ R4 or an acid addition salt thereof, and optionally converting the compound of formula I obtained into an acid addition salt. 3. The method according to claim 1, characterized in that one carries out the reaction in the presence of an acid acceptor if R5 in formula II is a group of the formula - OCO (CH2) nZ, in which Z represents a halogen atom.