CS248729B2 - Production method of the 6alfa methylcorticoid derivatives - Google Patents

Description

The invention relates to a process for the preparation of novel 6α-methylcorticoid derivatives of the general formula I

CHoX 'i

O O

(I) ch ₃ in which

---- means a single or double bond,

R is acyloxy having no more than 8 carbon atoms, and

X ‘represents a chlorine atom or an acyloxy group having at most 8 carbon atoms.

The novel 6'-methyl corticoids of the formula I can contain as acyloxy groups R, aliphatic, cycloaliphatic or aromatic radicals such as acetyl, propionyl, butyryl, isobutyryl, valeryl, 3-methylbutyryl, trimethylacetyl or hexanoyl or benzoyl.

It has been found that the novel 6α-methyl corticoids of formula (I) produced by the process of the invention often have significantly greater potency when topically applied than the prior art 6α-methyl corticoids. This activity is often even more potent than that of double fluorinated "noble" corticoids such as 6α, 9α-difluoro-11β-hydroxy-16α-methyl-21-valeryloxy-1,4-pregnadien-3, 20-dione (i.e., Nerison).

Surprisingly, in systematic administration, these 6α-methylcorticoids are often less potent than the corresponding 6α-methylcorticoids known to date.

The novel 6α-methyl corticoids of the formula (I) according to the invention are therefore suitable, in combination with carriers customary in galenic pharmacy, for the topical treatment of contact dermatitis, eczema of various kinds, neurodermatoses, erythrodermia, burns, itch vulva and anus, tru243729 erythematode, psoriasis, fox is a flat red and warty and similar skin diseases.

These special medicaments are manufactured in conventional manner by converting the active ingredients with suitable additives into the desired dosage forms, such as solutions, lotions, ointments, creams or patches. In such formulations, the concentration of active ingredient depends on the dosage form. For lotions and ointments, a concentration of active compound in the range of 0.001 to 1% is preferably used.

In addition, the novel compounds produced by the process of the invention, optionally in combination with conventional carriers and excipients, are also well suited for the manufacture of inhalants which can be used to treat allergic respiratory diseases, such as bronchial asthma or mucosal inflammation.

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

SUMMARY OF THE INVENTION The present invention provides a process for the preparation of 6α-methylcorticoid derivatives of the formula I which is carried out by reacting 6a-methylcorticoids of the formula III

HIM

CO, A ~ ° ^H

(nO in which X and X ‘are as defined above), the hydroxy group at position 11 is protected by etherification or esterification, whereupon the resulting compound is acylated at position 17 with the chloride or anhydride of the corresponding carboxylic acid in the presence of 4-dimethylaminopyridine.

The conditions for the preparation of the compounds according to the invention are described in one of German Offenlegungsschrift No. 2,645,104, 2,645,105, 2,340,591, 1,958,549, U.S. Pat. No. 3,383,394, and in J. Org. Chem. 38, 4,203 (1973).

The process according to the invention is explained in more detail in the examples below.

Example 1

a) From a solution of 5.0 g of 9a-chloro-11 / 3,17a, 21-trihydroxy-6a-methyl-1,4-pregnadien-3,20-dione and 0.5 g of pyridinium tosylate in 35 ml of dimethylformamide and 350 ml of benzene at 130 ^DEG C. was distilled through a water separator with 150 ml of benzene. 10 ml of triethyl orthoacetate are slowly added to the reaction solution while hot, and then a further amount of benzene and other readily volatile reactants are distilled off. Pyridine (4 ml) was added and the mixture was evaporated to dryness under reduced pressure. 9α-Chloro-17α, 21- (ethoxyethylidenedioxy) -1 H -hydroxy-6α-methyl-1,4-pregnadien-3,20-dione is isolated as an oil.

b) Crude 9α-chloro-17α, 21- (ethoxyethylidenedioxy) -β-hydroxy-6α-methyl-1, 4-pregnadien-3,20-dione was dissolved in 150 mL of methanol and stirred for 1 h at bath temperature of 100 DEG C. with a mixture of 54 ml of 0.1 N acetic acid and 6 ml of 0.1 N aqueous sodium acetate solution, then the reaction mixture is concentrated to 1/3 of its volume, water is added and the acetic acid ester extracts are washed to neutral. After drying and concentrating, the crude product is purified on 500 g of silica gel using methylene chloride with 0 to 20% acetone as the eluant. 4.6 g of 17a-acetoxy-9a-chloro-l _l s-21-dihydro Oxy-6α-methyl-1,4-pregnadien-3,20-dione, m.p. 216-218 ° C.

Example 2

a) Following a procedure similar to that described in Example 1a, 2.0 g of 17α, 21-dihydroxy-6α-methyl-1,4,9 (11) -pregnatriene-3,20-dione was reacted with triethyl orthobutyrate to give 17α, 21- (ethoxybutylidenedioxy) -6α-methyl-1,4,9 (11β-pregnatriene-3,20-dione as an oil).

bj Crude 17α, 21- (ethoxybutylidenedioxy) -6α-methyl-1,4,9 (11β-prenatriene-3,20-dione was treated under conditions described in Example 1b) with 0.1 N acetic acid with 0.1 N The reaction mixture was worked up and purified to give 1.5 g of 17α-butyryloxy-21-hydroxy-6α-methyl-1,4,9 (11β-prenatriene-3,20-dione).

c) A solution of 1.0 g of 17α-butyryloxy-21-hydroxy-6α-methyl-1,4,9 (11) -pregnatriene-3,20-dione in 10 ml of pyridine was stirred with 5.0 ml of anhydride for 1 hour at room temperature. acetic acid, and then working up the reaction mixture in a conventional manner. After recrystallization from acetone-hexane, 930 mg of 21-acetoxy-17α-butyryloxy-6α-methyl-1,4,9 (11β-pregnatriene-3,20-dione) was isolated.

Example 3

(a) To a suspension of 12.2 g of cuprous iodide in 240 ml of anhydrous tetrahydrofuran at 0 ° C, 60 ml of a 1.6 M methyllithium solution are added dropwise under argon. The mixture was left for 15 min. After stirring at 10 ° C, the yellowish solution was cooled to -30 ° C. After dropwise addition of a solution of 9.6 g of 17? -Hydroxy-6? -Methyl-21-valeryloxy-1,4,9 (11) -pregnatriene-3,20-dione, the reaction mixture was stirred at -30 ° C for 40 min. The reaction mixture was poured into ice-cold saturated ammonium chloride solution and extracted with ethyl acetate. The organic extracts are worked up in the usual manner and the crude product is purified on 100 g of silica gel using mixtures of methylene chloride and 0-12% acetone. Yield: 7.3 g of 21-hydroxy-6α-methyl-17α-valeryloxy-1,4,9 (11) -pregnatrene-3,20-dione.

b) In a similar manner to that described in Example 2c), 5.0 g of 21-hydroxy6 was used

The 6α-methyl-17α-valeryloxy-1,4,9 (11) -pregnatriene-3,20-dione is reacted with propionic anhydride and the reaction mixture is then purified and purified. 4.6 g of 6α-methyl-21-propionyloxy-17'-valeryloxy-1,4,9 (11) -pregnatriene-3,20-dione are isolated.

EXAMPLE 4 aj A solution of 6.5 g of 21-acetoxy-17.alpha.-hydroxy-6.alpha.-methyl-1,4,9 (11) -propylnatriene-3,20-dione in 80 ml. Of diethylglycol dimethyl ether was stirred at 80 ^{DEG C.} for 5 hours ^. C with 20.0 g of 4-dimethylaminopyridine and 20.0 ml of pivalic anhydride. The crude product, precipitated by pouring the reaction mixture into ice water, was worked up in the usual manner and purified on 750 g of silica gel using mixtures of methylene chloride and 0 to 8% acetone as eluent. Isolate

4.6 g of 21-acetoxy-6? -Methyl-17? -Trimethylacetoxy-1,4,9 (11? -Pregnatriene-3,20-dione, m.p. 238-240 ° C).

Claims (1)

A process for the preparation of 6α-methylcorticoid derivatives of the general formula I The invention is characterized in that in the 6α-methylcorticoid of the formula III ch ₂ of I ^x c = o CH ₃ in which zzrri: represents a single or double bond, R is acyloxy having no more than 8 carbon atoms, and X 'represents a chlorine atom or an acyloxy group having at most 8 carbon atoms in which —rr and X' are as defined above, the hydroxy at the 11-position is protected by etherification or esterification, whereupon the resulting compound is acylated at position 17 with the chloride or anhydride of the corresponding carboxylic acid in the presence of 4-dimethylaminopyridine and the protecting group at position 11 is cleaved off.