CS248727B2 - Production method of the 6alfa methylcorticoid derivatives - Google Patents

Description

The present invention relates to a process for the preparation of novel 6α-methylcorticoid derivatives of the general formula (Ib).

O

C..r / ₃ (fb) in which

-----: means a single or double bond,

R‘ represents an alkyl group having at most 7 carbon atoms or a phenyl group and

X 'represents a hydroxy group or a chlorine atom.

It has been found that the novel 6α-methyl corticoids of the general formula Ib produced by the process according to the invention often have significantly greater potency when applied topically than the hitherto known 6α-methyl corticoids. This potency 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- dion (ie 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 general formula (Ib) produced by the process according to the invention are therefore suitable, in combination with carriers customary in galenical pharmacy, for topical treatment of contact dermatitis, eczema of various kinds, neurodermatoses, erythrodermia, burns, itchy vulva and anus; , psoriasis, flat red and flounder lichen 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 application form. For lotions and ointments, a concentration of active compound in the range of 0.001 to 1% is preferred.

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 nasal mucositis.

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-methyl corticoid derivatives of the formula Ib, which is carried out by cleaving the orthoester moiety of a corticoid of the formula V hydrolytically or using trimethylchlorosilane

in which a R ‘is as defined above and

R 'represents an alkyl radical having 1 to 4 carbon atoms.

The conditions for the preparation of the compounds according to the invention are described in one of the German publication no. No. 2,645,104; 2,645,105; 2,340,591; 1,958,569; U.S. Patent No. 3,383,394; and in J. Org. Chem. 38, 4,203 (1973).

The process according to the invention is illustrated in more detail in the following examples:

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 ° C was distilled through a water separator with 150 ml of benzene. To the reaction solution, 10 ml of triethyl ortho-acetic acid is slowly added while hot, and 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) -11β-hydroxy-6α-methyl-1,4-pregnadien-3,20-dione is isolated as an oil.

b) Crude 9α-chloro-17α, 21- (ethoxyethylidenedioxy) -1 H -methyl-6α-methyl-1, 4-pregnadien-3,20-dione was dissolved in 150 mL of methanol and stirred for 1 h at a bath temperature of 100 ° C with a mixture of 54 ml of 0.1 N acetic acid and 6 ml of 0.1 M aqueous sodium acetate solution. The reaction mixture was then concentrated to 1/3 of its volume, water was added and the acetic acid ester extracts were washed until neutral. After drying and concentration, the crude product is purified on 500 g of silica gel using methylene chloride / 0-20% acetone as eluent. 4.6 g of 17α-acetoxy-9α-chloro-11β, 3,21-dihydroxy-6α-methyl-1,4-pregnadien-3,20-dione, m.p. 216-218 ° C, are obtained.

Example 2 and 2.0 g of 9α-chloro-11 (S, 17α, 21-trihydroxy-6α-methyl-1,4-pregnadien-3,20-dione) are reacted with triethyl orthopropionate in a manner similar to Example 1a. formation of 9α-chloro-17α, 21- (ethoxy-propylidenedloxy) -11- (6-hydroxy-6α-methyl-1,4-pregnadien-3,20-dione as an oil).

bj Crude 9α-chloro-17α, 21- (ethoxypropylidenedioxy) -1 H- 3 -hydroxy-6α-methyl-1,4-pregnadien-3,20-dione was reacted in analogy to Example 1b), then worked up and purified as described in Example 1bj. 1.6 g of 9? -Chloro-11?, 21-dihydroxy-6? -Methyl-17? -Propionyloxy-1,4-pregnadien-3,20-dione, m.p. 201-203 ° C, are isolated.

Example 3

(a) 5.0 g of 17α, 21-dihydroxy-6α-methyl-1,4,9 (11) -pregnatriene-3,20-dione are reacted as described in example 1aj with 10 ml of triethyl orthopropionate to give 17a, 21- (ethoxypropylidenedioxy) -6α-methyl-1,4,9 (11β-propynatriene-3,20-dione as an oil).

b) The crude 17α, 21- (ethoxypropylidenedioxy) -6α-methyl-1,4,9 (11) -pregnatriene-3,20-dione was stirred for 20 hours at a bath temperature of 80 ° C with a mixture of 250 mL of dimethylformamide and 5 mL of methyl ester. ml trimethylchlorosilane. The reaction mixture is then evaporated to dryness and the crude product is purified on 600 g of silica gel using methylene chloride / 0-12% acetone as eluent. The yield is

3.5 g of 21-chloro-6'-methyl-17α-propionyloxy-1,4,9 (11'-pregnatriene-3,20-dione).

Example 4

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

b) The crude 17α, 21- (ethoxybutylidenedioxy) -6α-methyl-1,4,9 (11) -pregnatriene-3,20-dione is treated with a mixture of 0.1 N acetic acid under the conditions described in Example 1b) and 0.1 M sodium acetate solution was then worked up and purified. It is obtained

1.5 g of 17α-butyryloxy-21-hydroxy-6α-methyl-1,4,9 (11) -pregnatriene-3,20-dione.

EXAMPLE 5 aj Following the procedure described in Example 1a), 5.0 g of 17α, 21-dihydroxy-6α-methyl-1,4,9 (11β-pregnatriene-3,20-dione) was reacted with 10 mL of triethyl orthobenzoate to give 17α, 21- (ethoxybenzylidenedioxy) -6α-methyl-1,4,9 (11β-pregnatriene-3,20-dione) was then worked up in the usual manner.

b) Crude 17α, 21- (ethoxybenzylidenoxy) -6α-methyl-1,4,9 (11) -pregnatriene-3,20-dione was reacted with trimethylchlorosilane under the conditions described in Example 3b and treated with the resulting reaction product. and purify. 3.2 g of 17'-benzoyloxy-21-chloro-6'-methyl-1,4,9 (11) -pregnatriene-3,20-dione is isolated.

Claims (1)

SUBJECT A process for the preparation of 6α-methylcorticoid derivatives of the general formula Ib OF THE INVENTION chlorine, characterized in that the orthoester moiety of a corticoid of formula V in which it represents a single or double bond is cleaved hydrolytically or using trimethylchlorosilane, R‘ represents an alkyl group having at most 7 carbon atoms or a phenyl group and X 'represents a hydroxy group or an atom in which -r ~~. and R ‘are as defined above, and R znamená is an alkyl radical of 1 to 4 carbon atoms.