CS244663B2 - 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 I wherein R 1 is alkanoyl C1-8 carbon atoms or a benzoyl group, and X is an atom chlorine, alkanoyloxy of 1-8 carbon atoms atoms or benzoyloxy. These new 9-chlorprednisolone derivatives they are systemically ineffective, but it seems with local application surprisingly strong anti-inflammatory effect, which mostly exceeds the effect of the most effective commercially common corticoids.

Description

(54) A process for the preparation of new 9-chloropredisolone derivatives

The invention relates to a process for the preparation of 9-chloropredisolone derivatives of the general formula I in which R 1 represents an alkanoyl group having 1 to 8 carbon atoms or a benzoyl group and X represents a chlorine atom, an alkanoyloxy group having 1 to 8 carbon atoms or a benzoyloxy group.

These new 9-chloro-prednisolone derivatives are systemically almost ineffective, however, they show a surprisingly strong anti-inflammatory effect when topically applied, which usually outweighs the effect of the most effective commercially common corticoids.

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

9-chlorprednisolone (i.e. 9alpha-chloro-11beta, 17alpha, 21-trihydroxy-1,4-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 topical treatment of inflammatory diseases because it has very potent systemic effects.

It has been found that the hitherto unknown 9-chloropredisolone derivatives are systemically almost ineffective, but when administered topically they have a surprisingly potent anti-inflammatory activity which generally outperforms the most potent commercial corticoids.

The novel 9-chloropredisolone derivatives are characterized by the general formula I ch ₂ x

in which it denotes

R | (C 1 -C 8) alkanoyl or benzoyl; and

X is chlorine, C 1 -C 8 alkanoyloxy or benzoyloxy.

C 1 -C 8 alkanoyl Rp and C 1 -C 8 alkanoyloxy X is understood as being derived from a straight or branched chain fatty acid such as formic, acetic, propionic, butyric, isobutyric , valeric, isovaleric, trimethylacetic, caproic, tert -butylacetic or caprylic.

Particularly preferred alkanoyl groups and alkanoyloxy groups X are those derived from an alkanecarboxylic acid having 2 to 6 carbon atoms.

The 9-chloro-prednisolone derivatives of the formula X in which X is a chlorine atom are, for example:

17alpha-Aetoethoxy-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,

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

17a-Benzoyloxy-Salfa, 21-dichloro-11beta-hydroxy-1,4-pregnadien-3,20-dione.

The 9-chloro-prednisolone derivatives of formula (1) in which X is alkanoyloxy or benzoyloxy are preferably those in which the radicals R @ 1 and X taken together have from 3 to 14 carbon atoms. Such chlorprednisolone derivatives are, for example:

17alpha, 2l-diacetoxy-9alpha-chloro-11beta-hydroxy-1,4-pregnadien-3,20-dione,

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

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

17alpha-acetoxy-21-butyryloxy-9alpha-chloro-11beta-hydroxy-1,4-pregnadien-3,2-dione,

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

2l-benzoyloxy-9alpha-chloro-11beta-hydroxy-17alpha-propionyloxy-1,4-pregnadien-3,20-dione,

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

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

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

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

2-butyryloxy-9alpha-chloro-11beta-hydroxy-17alpha-valeryloxy-1,4-pregnadien-3,20-dione,

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

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

9alpha-chloro-11beta-hydroxy-17,21-diisobutyryloxy-1,4-pregradiene-3,20-dione; and

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

The novel derivatives of 9-chlorprednisolonu invention are produced according to a process comprising in that the chloro derivative 9 of the general formula Ia CH ₂ OH

, R | as defined above, at position 21 it is chlorinated or esterified.

The process of the invention can be carried out under the conditions described in U.S. Patent Nos. 3,678,034, 3,718,671 and 3,828,083.

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, given the increasing difficulty of providing suitable starting products for corticoid synthesis in sufficient quantities and in view of the high cost of the active substances that burden corticoid-containing medicinal specialties.

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 compounds 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 weighing 100-160 g.

The left ear remains without application and serves as a control. Three hours after application, the animals are sacrificed and 9 mm discs are cut from their ears. 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 130-150 g are injected into the right hind paw with 0.1 ml of a 0.5% suspension of Mycobacterium 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 determined back.

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 the usual 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-17beta-methyl-17alpha, 21-dipropionyloxy-1, 11-dipropionyloxy) were used as reference substances in these tests. 4-pregnadien-3,20-dione).

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

number Substance

ED ₅₀ in mg / kg

A) Test for B) rat ear

Edema adjuvant test

C) Thymolysis test

9a-Chloro-11beta, 17a-trihydroxy-1,4-pregnadien-3,20-dione 1,4

6.3

0.4

II 21-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-17alpha, 21-dipropionyloxy-1,4-pregnadien-3,20-dione 1,4

IV 21-Acetoxy-9alpha-chloro-11beta-hydroxy-17alpha-propionyloxy-1,4-pregnadien-3,20dione 0,026> 30

2,0

4.8

In 21-acetoxy-17alpha-benzoyloxy-9alpha-chloro-11beta-hydroxy-1,4-pregnadien-3,20-dione 1,5

VI 17alpha-benzoyloxy-9alpha-chloro-11beta-hydroxy-21-propionyloxy-1,4-pregnadien-3.20 dione 1.5> 30> 30

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

The novel compounds are useful in combination with carriers customary in galenical pharmacy for topical therapy of diseases: contact dermatitis, eczema of various kinds, neurodermatosis, erythroderma, burns, pruritus vulvae et ani, rosacea, erythematodes cutaneus, psoriasis, lichen ruber planus and verrucosus diseases.

Medicinal specialties are prepared in a conventional manner, in particular by processing the active ingredients with suitable 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 useful, optionally in combination with conventional carriers and excipients, for the preparation of inhalants which can be used in the treatment of allergic airway 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-pregnadien-3,20-dione are mixed with 500 ml benzene, 40 ml dimethylformamide and 500 mg 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, and the residue was purified by silica gel column chromatography and recrystallized from acetone-hexane to give 3.7 g of 17α-benzoyloxy-9α-chloro-11beta, 21-dihydroxy-1,4- pregnadien-3,20-dione, m.p. 216 DEG C. (dec.).

Example 2

0.5 g of 17α-benzoyloxy-9α-chloro-11beta, 21-dihydroxy-1,4-pregnadien-3,20-dione and 10 ml of formic acid are stirred for 24 hours at room temperature. The reaction mixture was poured into ice water, extracted with dichloromethane, the organic phase was washed, dried over sodium sulfate and evaporated in vacuo to give 400 mg of 17α-benzoyloxy-9α-chloro-21-formyloxy-11-beta-hydroxy-1,4- pregnadien-3,20-dione as a glass setting;

[.alpha.] @ 25 = + 58 DEG C. (chloroform).

Example 3

1.5 g of 17α-benzoyloxy-9α-chloro-11β, 21-dihydroxy-1,4-pregnadien-3,20-dione are mixed with 17 mL of pyridine and 8.0 mL of acetic anhydride and stirred for 1 hour at temperature 0 ° C. The reaction mixture is poured into ice water, the precipitated product is filtered off, dissolved in dichloromethane, the organic phase is washed, dried over sodium sulphate and evaporated in vacuo.

The residue is chromatographed on kieselguhr using methylene chloride-acetone gradients and recrystallized from acetone-hexane to give 1.2 g of 21-acetoxy-17α-benzoyloxy-9α-chloro-11β-hydroxy-1,4-pregnadien-3, M.p. 221 DEG C. (dec.).

Example 4

1.5 g of 17α-benzoyloxy-9α-chloro-11β, 21-dihydroxy-1,4-pregnadien-3,20-dione are mixed with 17 ml of pyridine and 8.0 ml of propionic anhydride and stirred for one hour at temperature 0 ° C. The reaction mixture was worked up as described in Example 3 to give 960 mg of 17α-benzoyloxy-9α-chloro-11β-hydroxy-21-propionyloxy-1,4-pregnadien-3,20-dione, m.p. 226 ° C. decomposition).

Example 5

2.3 g of 17alpha-benzoyloxy-9alpha-chloro-11beta, 21-dihydroxy-1,4-pregnadien-3,20-dione are mixed with 50 ml of pyridine and 25 ml of butyric anhydride and stirred for 16 hours at room temperature. . The reaction mixture was worked up as described in Example 3 to give 2.0 g of 17α-benzoyloxy-21-butyryloxy-9α-chloro-11β-hydroxy-1,4-pregnadiene-3,20-dione, m.p. 226 ° C. (with decomposition).

Example 6

2.3 g of 17alpha-benzoyloxy-9alpha-chloro-11beta, 21-dihydroxy-1,4-pregnadien-3,20-dione are mixed with 50 ml of pyridine and 25 ml of valeric anhydride and stirred for 16 hours at room temperature. . The reaction mixture was worked up as described in Example 3 to give

1.63 g of 17α-benzoyloxy-9α-chloro-11β-hydroxy-21-valeryloxy-1,4-pregnadiene-3,20-dione, m.p. 208 ° C.

Example 7

2.3 g of 17alpha-benzoyloxy-9alpha-chloro-11beta, 21-dihydroxy-1,4-pregnadien-3,20-dione are mixed with 50 ml of pyridine and 25 ml of trimethylacetic anhydride, stirred for 16 hours at a temperature of rooms. The reaction mixture was worked up as described in Example 3 to give 1.72 g of 17α-benzoyloxy-9α-chloro-11β-hydroxy-21-trimethyl-acetoxy-1,4-pregnadien-3,20-dione, m.p. 236 Deň: 32 ° C.

Example 8

2.3 g of 17alpha-benzoyloxy-9alpha-chloro-11beta, 21-dihydroxy-1,4-pregnadien-3,20-dione are mixed with 50 ml of pyridine and 25 ml of isobutyric anhydride and stirred for 16 hours at a temperature of of the room. The reaction mixture was worked up as described in Example 3 to give 2.1 g of 17α-benzoyloxy-9α-chloro-11-beta-hydroxy-21-isobutyryloxy-1,4-pregnadien-3,20-dione as a glassy mass. ; [.alpha.] D @ 20 = + 68 DEG C. (chloroform).

Example 9

2.3 g of 17alpha-benzoyloxy-9alpha-chloro-11beta, 21-dihydroxy-1,4-pregnadien-3,20-dione are mixed with 50ml of pyridine and 20ml of isovaleric chloride and stirred for 2 hours at a temperature of Low: 14 ° C. The reaction mixture was worked up as described in Example 3 to give 2.1 g of 17α-benzoyloxy-9α-chloro-11β-hydroxy-21-isovaleryloxy-1,4-pregnadien-3,20-dione, m.p. 197 ° C. .

Example 10

2.3 g of 17alpha-benzoyloxy-9alpha-chloro-11beta, 21-dihydroxy-1,4-pregnadien-3,20-dione are mixed with 50 ml of pyridine and 30 ml of enanthic anhydride and stirred for 16 hours at a temperature of rooms. The reaction mixture was poured into ice water, warmed and excess acid removed by steam distillation. It is then extracted with dichloromethane and the organic phase is treated as described in Example 3 to give 2.03 g of 17α-benzoyloxy-9α-chloro-21-heptanoyloxy-11β-hydroxy-9α-chloro-21-heptanoyloxy-11β-hydroxy- 1,4-pregnadien-3,20-dione as an oily product; [.alpha.] D @ ²⁵ = + 54 DEG (chloroform).

Example 11

2.3 g of 17.alpha.-benzoyloxy-9.alpha.-chloro-11beta, 21-dibroxy-1,4-pregnadien-3,20-dione are mixed with 45 ml. Of pyridine and 1 ml. Of benzoyl chloride and stirred for 1 hour at a temperature. rooms. The reaction mixture was worked up as described in Example 3 to give 2.5 g of 17α, 21-dibenzoyloxy-9α-chloro-11β-hydroxy-1,4-prnadnaden-3,20-dione; mp 221 ° C.

Example 12

a) 7.5 g of 9alpha-chloro-11beta, 17alpha, 21-trihydroxy-1,4-pregnadien-3, 20-dione were treated with triethyl orthooctoate and treated with the conditions described in Example 1a. 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 13

1.0 g of 17α-acetoxy-9α-chloro-11β, 21-dihydroxy-1,4-pregnadien-3,20-dione is mixed with 20 ml of pyridine and 5 ml of acetic anhydride and stirred for 1 hour at room temperature. The reaction mixture is then poured into water, the precipitated product is filtered off with suction, dissolved in dichloromethane, the organic phase is washed and evaporated in vacuo. The residue was recrystallized from acetone-hexane to give 860 mg of 17α, 21-diacetoxy-9α-chloro-11β-hydroxy-1,4-pregnadien-3,20-dione, m.p. 222 ° C (dec.).

Example 14

Under the conditions described in Example 4, 1.0 g of 17α-α-ethoxy-9α-chloro-11β, 21-dihydroxy-1,4-pregnadien-3,20-dione is reacted with propionic anhydride and worked up to give 940 mg of 17α-α-ethoxy-9α-chloro-11β-hydroxy-21-propionyloxy-1,4-pregnadien-3,20-dione, m.p. 219 ° C (dec.).

Example 15

Under the conditions described in Example 6, 1.0 g of 17α-acetoxy-Salpha-chloro-11beta, 21-dihydroxy-1,4-pregnadien-3,20-dione was reacted with valeric anhydride and worked up to give 660 mg of 17α-acetoxy-9α-chloro-11β-hydroxy-21-valeryloxy-1,4-pregnadien-3,20-dione, m.p. 220 ° C (dec.).

Example 16

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 crude product obtained under the conditions described in Example 1b was reacted and worked up to give 2.9 g of 9alpha-chloro-11beta, 21-dihydroxy-17alpha-propionyloxy-1,4-pregnadien-3,20-dione mp 181 ° C (dec.).

Example 17

Under the conditions described in Example 2, 1.2 g of 9alpha-chloro-11beta, 21-dihydroxy-17alpha-propionyloxy-1,4-pregnadien-3,20-dione was reacted with formic acid and worked up to give 400 mg. oily 9α-chloro-21-formyloxy-11β-hydroxy-17α-propionyloxy-1,4-pregnadien-3,20-dione; [α] ²⁵ D = + 67 ° (chloroform).

Example 18

700 mg of 9alpha-chloro-11beta, 21-dihydroxy-17alpha-propionyloxy-1,4-pregnadien-3,20-dione were reacted with acetic anhydride as described in Example 3 and worked up to give 320mg of 21-acetoxy- 9-.alpha.-chloro-11beta, hydroxy-17.alpha.-propionyloxy-1,4-pregnadien-3,2,7-aione, m.p. 210 DEG C. (dec.).

Example 19

700 mg of 9alpha-chloro-11beta, 21-dihydroxy-17alpha-propionyloxy-1,4-pregnadien-3,20-dione were treated with propionic anhydride under the conditions described in Example 4 and worked up to give 420mg of 9alpha 215 DEG C. (decomposition), 2-chloro-11beta-hydroxy-17.alpha., 21-dipropionyloxy-1,4-pregnadlene-3,20-dione.

Example 20

650 mg of 9alpha-chloro-11beta, 21-dihydroxy-17alpha-propionyloxy-1,4-pregnadien-3,20-dione are reacted with butyric anhydride under the conditions described in Example 5 and worked up to give 360mg of 21%. -butyryloxy-9α-α-chloro-11β-hydroxy-17α-α-propionyloxy-1,4-pregnadien-3,20-dione, m.p. 208 ° C (dec.).

Example 21 - and conditions as in Example 6, 700 mg of 9α-chloro-11beta, 21-dihydroxy-17α-propionyloxy-1,4-pregnadien-3,20-dione were reacted with valeric anhydride and worked up to give 520. mg of 9α-chloro-11β-hydroxy-17α-propionyloxy-21-valeryloxy-1,4-pregna diene-3,20-dione, m.p. 210 ° C (dec.).

Example 22

3.0 9α-Chloro-11β, 21-dihydroxy-17α-propionyloxy-1,4-pregnadien-3,20-dione were mixed with 30 mL of pyridine and 15 mL of caproic anhydride and stirred for 90 minutes at room temperature. The reaction mixture was worked up as described in Example 3 to give 2.6 g of 9α-chloro-21-hexanoyloxy-11β-hydroxy-17α-propionyloxy-1,4-pregnadien-3,20-dione.

Example 23

Under the conditions of Example 10, 2.1 g of 9alpha-chloro-11beta, 21-dihydroxy-17alpha-propionyloxy-14-pregnadien-3,20-dione was reacted with enanthic anhydride and worked up to give 1.02g 9alpha-chloro-21-heptanoyloxy-11beta-hydroxy-17alpha-propionyloxy-1,4-pregnadien-3,20-dione.

Example 24

Under the conditions of Example 7, 1.4 g of 9alpha-chloro-11beta, 21-dihydroxy-17alpha-propionyl oxy-1,4-pregnadien-3,20-dione is reacted with trimethylacetic anhydride and worked up to give 670 mg of 9α-chloro-11β-hydroxy-17α-propionyloxy-21-trimethylacetoxy-1,4-pregnadien-3,20-dione.

EXAMPLE 25 ml of phosphoric acid hexamethyltriamide was treated with 1.3 ml of thionyl chloride at 0 DEG C. and stirred for 30 minutes. 800 mg of 17alpha-acetoxy-9alpha-chloro-11beta, 21-dihydroxy-1,4-pregnadien-3,20-dione are then added to the mixture and stirred for a further 5 1/2 hours at 0 ° C. The reaction mixture was worked up as described in Example 3 to give 540 mg of 17α-acetoxy-9α, 21-dichloro-11beta-hydroxy-1,4-pregnadien-3,20-dione, m.p. 222 ° C ( decomposition).

Example 26

Under the conditions of Example 25, 1.2 g of 9alpha-chloro-11beta, 21-dihydroxy-17alpha-propionyloxy-1,4-pregnadien-3,20-dione was reacted with thionyl chloride and worked up to give 860mg of 9alpha, Dichloro-11beta-hydroxy-17α-propiononyloxy-1,4-pregnadien-3,20-dione, m.p. 232 ° C.

Example 27

Under the conditions of Example 25, 8.5 g of 17alpha-benzoyloxy-9alpha-chloro-11beta, 21-dihydroxy-1,4-pentadien-3,20-dione was reacted and worked up to give 4.1g of 17alpha-benzoyloxy -9alpha-21-dichloro-11beta-hydroxy-1,4-pregnadien-3,20-dione, m.p. 220 ° C.

SUBJECT OF THE INVENTION

Claims (1)

A process for the preparation of the novel 9-chloro-prednisolone derivatives of the general formula I ₅ times I c = o r-O (I) in which it represents an alkanoyl group having 1 to 8 carbon atoms or a benzoyl group and X is chlorine, C 1 -C 8 alkanoyloxy or benzoyloxy, characterized in that the 9-chloro derivative of the formula Ia CH ₂ OH in which (Ia) is as defined above, in position 21 it is chlorinated or esterified.