CS244662B2 - Production method of new 9-chlorprednisolone derivatives - Google Patents

Abstract

The invention relates to a process for the preparation of derivatives 9-chloropropednisolone of the formula Wherein R 1 is an alkanoyl group having 1 to 8 carbon atoms or benzoyl, and X is atom fluorine, chlorine, hydroxyl. These new 9-chlorprednisolone derivatives are almost ineffective, but appears to be local application surprisingly strong anti-inflammatory effect that mostly exceeds the effect of the most effective commercially common corticoids.

Description

The present invention relates to a process for the preparation of novel 9-chloropredisolone derivatives.

9-chlorprednisolone (= 9α-chloro-11β-17α-21-trihydroxy-1,4,4-pregnadien-3,20-dione) has been known for a long time (J. Amer. Chem. Soc. 77, 1955, 4181). This corticoid is not suitable as an active ingredient in pharmaceutical preparations for the topical treatment of inflammatory diseases because it has very potent systemic effects.

The previously unknown 9-chloropredisolone derivatives have been found to be virtually ineffective systemically, but have a surprisingly potent anti-inflammatory activity when administered topically, which usually outperforms the most potent commercial corticoids.

The new 9-chloropredisolone derivatives have the general formula I

C ^h 2X

in which it denotes

R 1 -C 1 -C 8 alkanoyl or benzoyl; and

X is fluorine, chlorine or hydroxyl.

The derivatives of 9-chloropredisolone of the formula I in which X is a chlorine and fluorine atom are, for example:

17alpha-acetoxy-9alpha-21-dichloro-11beta-hydroxy-1,4-pregnadien-3,20-dione,

9alpha-21-dichloro-11beta-hydroxy-17alpha-propionyloxy-1,4-pregnadien-3,20-dione,

17alpha-butyryloxy-9alpha-21-dichloro-11beta-hydroxy-1,4-pregnadien-3,20-dione,

9alpha, 21-dichloro-11beta-hydroxy-17alpha-isobutyryloxy-1,4-pregnadien-3,20-dione,

17alpha-acetoxy-9alpha-chloro-21-fluoro-11beta-hydroxy-1,4-pregnadien-3,20-dione,

9alpha-chloro-21-fluoro-11beta-hydroxy-17alpha-propionyloxy-1,4-pregnadien-3,20-dione,

17α-butyryloxy-9α-chloro-21-fluoro-11β-hydroxy-1,4-pregnadien-3,20-dione,

17alpha-benzoyloxy-9alpha-chloro-21-fluoro-11beta-hydroxy-1,4-pregnadien-3,20-dione,

9alpha-chloro-21-fluoro-11beta-hydroxy-17alpha-isobutyryloxy-1,4-pregnadien-3,20-dione,

9alpha-21-dichloro-11beta-hydroxy-17alpha-valeryloxy-1,4-pregnadien-3,20-dione; and

17alpha-benzoyloxy-9alpha, 21-diohloro-11beta-hydroxy-1,4-pregnadien-3,20-dione.

9-Chloropredisolone derivatives of the formula I in which X has the meaning of a hydroxyl group are, for example:

17alpha-acetoxy-9alpha-chloro-11beta, 21-dihydroxy-1,4-pregnadien-3,20-dione,

9alpha-chloro-11beta-21-dihydroxy-17alpha-propionyloxy-1,4-pregnadien-3,20-dione,

17alpha-butyryloxy-9alpha-chloro-11beta, 21-dihydroxy-1,4-pregnadien-3,20-dione,

9alpha-chloro-11beta, 21-dihydroxy-17alpha-isobutyryloxy-1,4-pregnadien-3,20-dione,

9alpha-chloro-11beta, 21-dihydroxy-17alpha-valeryloxy-1,4-pregnadien-3,20-dione; and

17α-Benzoyloxy-9α-chloro-11β, 21-dihydroxy-1,4-pregnadien-3,20-dione.

The novel 9-chloro-prednisolone derivatives are prepared according to the invention by the method of orthoester IV

OR (IV),

in which

R 8 represents a hydrogen atom or an alkyl group having 1 to 7 carbon atoms or a phenyl group

R 2 denotes an alkyl group having 1 to 4 carbon atoms, cleaved hydrolytically or by treatment with trimethylsilyl halide or triphenylmethyl halide.

The process of the invention can be carried out under the conditions described in U.S. Pat. No. 3,152,154 and German publications Nos. 2,613,875 and 2,436,747.

The starting compounds for the process of the invention can be prepared, as is known, simply and in high yields from prednisolone, which can be relatively easily synthesized from diosgenin. As a result, the compounds of the invention can be prepared at relatively low cost from diosgenin in an overall yield of about 15%.

In contrast, the synthesis of known high-performance corticoids from diosgenin is considerably more expensive and the overall yields achieved are significantly lower (about 0.5 to 5%). This is not insignificant when taking into account the increasing difficulty of providing suitable starting products for the synthesis of corticoids in sufficient quantities and in view of the high cost of the active substances which burden the curative specialties containing corticoids.

As already mentioned, the compounds of the present invention have potent anti-inflammatory activity when topically applied, but are very poor in systemic administration.

The pharmacological properties of the compound were determined by the following tests:

(A) anti-inflammatory activity when applied topically to the rat ear:

the test substance is dissolved in an irritant consisting of 4 parts pyridine, part distilled water, 5 parts ether and 10 parts 4% croton oil ether solution. This test solution impregnates felt strips, which are mounted on the inside of the microscope tweezers and are lightly pressed for 15 seconds on the right ear of a male rat of 100-160 g. The left ear remains untreated and serves as a control. Three hours after application, the animals are sacrificed and the size discs are cut from their ears. 9 mm. The weight difference between the right and left ear disc is a measure of the edema formed.

The dose of the test substance is determined after which a 50% inhibition of edema formation is observed after three hours.

B) Anti-inflammatory activity by subcutaneous administration to rat paws:

SPF rats weighing 130 to 150 g are injected into the right hind paw with 0.1 ml of a 0.5% suspension of Mycobaoterium butyricum to form an inflammatory deposit. Rat paw volume is measured prior to injection; 24 hours after injection, the paw volume is again measured to determine the extent of edema. Subsequently, different rats were injected subcutaneously with rats 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 the same except that they are injected with a mixture of benzyl benzoate and castor oil without the test substance.

From the paw volume values obtained, the amount of test substance required to achieve 50% healing of paw edema is determined in a conventional manner.

C) Thymolytic effect after oral administration:

SPF rats weighing 70-110 g are adrenalectomized under ether anesthesia. In each case, 6 animals form a test group which is administered orally defined amount of test substance for 3 days. On day 4, the animals are sacrificed and their thymus weight is determined.

Control animals do the same, but receive a mixture of benzyl benzoate with castor oil without the test substance. The amount of test substance at which 50% thymolysis can be observed is determined from the thymic mass values obtained in a conventional manner.

Structurally analogous 9-chlorprednisolone and its 21-acetate as well as beclomethasone-17,21-dipropionate (= 9alpha-chloro-11beta-hydroxy-16beta-methyl-17alpha, 21-dipropionyloxy-1, 9-chloro-11-dipropionate) were used as reference substances in these tests. 4-pregnadien-3,20-dione).

The results obtained in these tests are shown in the table below:

Number Substance

A) Rat ear test

ED ₅₀ in mg / kg

B) Adjuvant Test. C) Thymoledema test

9alpha-chloro-11beta, 17alpha, 21-trihydroxy-1,4-propylene-3,20-dione

1.4

6.3

0.4

II 2-acetoxy-9alpha-chloro-11beta, 17alpha-dihydroxy-1,4-pregnadien-3,20-dione

1.5

6.0

0.6

III 9alpha-chloro-11beta-hydroxy-16beta-methyl-17a-1f a, 21-dipropionyloxy-1,4-pregnadien-3,20-dione

1,4> 30

2,0

IV 17alpha-acetoxy-9alpha-chloro-11beta, 21-dihydroxy-1,4-pregnadien-3,20-dione

0.16> 30

9.5

9alpha-chloro-11beta, 21-dihydroxy-17alpha-propionyloxy-1,4-pregnadien-3,20-dione

0.45> 30

4.8

Similar results are obtained when the pharmacological activity of the 9-chloropredisolone derivatives of the invention is determined by a known vasoconstriction test or a known sodium and potassium retention test.

The novel compounds are useful in combination with carriers customary in galenic pharmacy for topical therapy of contact dermatitis, eczema of various kinds, neurodermatoses, erythroderma, burns, prurit vulvae et ani, rosacea, erytheraatodes cutaneus, psoriasis, lichen ruber planus and verrucosus.

Medicinal specialties are prepared in conventional manner by converting the active ingredients with appropriate additives into the desired dosage form, such as solutions, lotions, ointments, creams or patches. In the medicaments thus prepared, the concentration of active ingredient depends on the dosage form. In ointments and lotions, the active compound concentration is preferably from 0.001 to 1.0% by weight.

In addition, the novel compounds are suitable, optionally in combination with conventional carriers and excipients, for the preparation of inhalants which can be used in the treatment of allergic respiratory diseases such as bronchial asthma or rhinitis.

The following examples serve to illustrate the invention.

Example 1

a) 5.0 g of 9alpha-chloro-11beta, 17alpha, 21-trihydroxy-1,4-pregnadiene, 3,20-dione are mixed with 500 ml of benzene, 40 ml of dimethylformamide and 500 mg of absolute pyridine tosylate. The mixture was heated, 50 ml of solvent was distilled off at a bath temperature of 130 ° C, 60 ml of orthobenzoic acid triethyl ester was added and the remaining benzene was distilled off over 2 and 1/2 hours. The residue is stirred with 2.4 ml of pyridine and evaporated in vacuo to give 17alpha, 21- (1-ethoxy-benzylidenedioxy) -9alpha-chloro-11beta-hydroxy-1,4-pregnadien-3,20-dione as crude oil product.

b) The crude product obtained is mixed with 150 ml of methanol, 54 ml of 0.1 N aqueous acetic acid and 6 ml of 0.1 N aqueous sodium acetate solution and heated to reflux for 90 minutes. Then the reaction mixture is evaporated in vacuo, the residue is stirred with water and extracted with ethyl acetate.

The organic phase was washed with water, evaporated in vacuo, the residue purified by silica gel column chromatography and recrystallized from acetone-hexane to give 3.7 g of 17alpha-benzoyloxy-9alpha-chloro-11beta, 21-dihydroxy-1,4-pregnadien 216 DEG C. (dec.).

Example 2

a) 7.5 g of 9alpha-chloro-11beta, 17alpha, 21-trihydroxy-1,4-pregnadien-3,20-dione were reacted with triethyl orthoacetic acid under the conditions described in Example 1a and worked up. There was thus obtained 17alpha, 21- (1-ethoxy-ethylidenedioxy) -9alpha-chloro-11beta-hydroxy-1,4-pregnadien-3,20-dione as an oily crude product.

b) The crude product obtained is reacted under the conditions described in Example 1b and treated to give 5.2 g of 17α-acetoxy-9α-chloro-11beta, 21-dihydroxy-1,4-pregnadien-3,20-dione mp 205 ° C (dec.).

Example 3

a) Under the conditions described in Example 1a, 7 g of 9alpha-chloro-11beta, 17alpha, 21-trihydroxy-1,4-pregnadien-3,20-dione are reacted with triethyl orthopropionate and worked up to give 17alpha, 21a, 21a, 21a, 21a, 21a, - (1-ethoxy-propylidenedioxy) -9alpha-chloro-11beta, hydroxy-1,4-pregnadien-3,20-dione as a crude product.

b) The obtained crude product is subjected to the following conditions; Example 1b was reacted and worked up to give 2.9 g of 9alpha-chloro-11beta, 21i-dihydroxy-17alpha-propionyloxy-1,4-pregnadien-3,20-dione, m.p. decomposition).

EXAMPLE 4 g of 17alpha, 21- (1-ethoxy-benzylidenedioxy) -9alpha-chloro-11beta, hydroxy-1,4-pregnadien-3,20-dione, prepared analogously to Example 1a, is stirred in 40 ml of dimethylformamide with 4 ml. trimethylsilyl fluoride for 2 hours at room temperature. After precipitation with ice water and usual work-up, evaporate in vacuo. The crude product is purified on 120 g of silica gel with a methylene chloride-acetone gradient (0-10% acetone). Yield 240 mg of 17α-benzoyloxy-9α-chloro-21-fluoro-11β, hydroxy-1,4-pregnadien-3,20-dione.

EXAMPLE 5 g of crude 17alpha, 21- (1-ethoxy-ethylidenedioxy) -9alpha-chloro-11beta, hydroxy-1,4-pregnadien-3,20-dione, prepared analogously to Example 1a from 9alpha-chlorprednisolone and triethyl orthoacetic acid ester, The mixture was refluxed in 30 ml of methylene chloride with 3 g of triphenylmethyl chloride for 1 hour under a nitrogen atmosphere. The solvent was distilled off and the residue was purified on 350 g of silica gel with methylene chloride-acetone gradient (0 to 15% acetone). Yield 1.3 g of 17α-acetoxy-9α, 21-dichloro-11β-hydroxy-1,4-pregnadien-3,20-dione. Mp 222 ° C (dec.); [.alpha.] + 124 DEG C. (pyridine). UV: epsilon = g = 15,200 (methanol).

Example 6 g of crude 17alpha, 21- (1-ethoxy-propylidenedioxy) -9alpha-chloro-11beta-hydroxy-1,4-pregnadien-3,20-dione, prepared analogously to Example 1a from 9alpha-chlorprednisolone and triethyl orthopropionate, in 50 ml of dimethylformamide was stirred with 5 ml of trimethylsilyl chloride for 2 hours at room temperature.

After precipitation with ice water and usual work-up, 1.4 g of 9alpha, 21-dichloro-11beta-hydroxy-17alpha-propionyloxy-1,4-pregnadien-3,20-dione is isolated, which is purified by crystallization from acetone-hexane. Mp 232 ° C; [.alpha.] = + 78 DEG C. (chloroform). UV; epsilon = g = 15,200 (methanol).

Claims (1)

A process for the preparation of the novel 9-chloro-prednisolone derivatives of the general formula X ch ₂ x (I), in which it denotes R 1 -C 8 alkanoyl or benzoyl; and X is fluorine, chlorine or hydroxyl. characterized in that the orthoester of formula IV ch ₂ o. (IV) in which R @ 1 represents a hydrogen atom or a C1 -C7 alkyl group or a phenyl group and denotes a C1 -C4 alkyl group. is cleaved hydrolytically or by treatment with trimethylsilyl halide or triphenylmethyl halide