CH631997A5 - Process for the preparation of novel derivatives of 9-chloro-prednisolone - Google Patents

Abstract

Novel derivatives of 9-chloroprednisolone of the formula <IMAGE> in which R1 denotes alkanoyl having 1 to 8 carbon atoms or benzoyl and X represents alkanoyloxy having 1 to 8 carbon atoms or benzoyloxy, are prepared. These compounds are obtained by esterifying an appropriate 9-chloro derivative of prednisolone in the 21-position. The novel compounds can be used for the treatment of inflammations.

Description

The invention relates to a process for the preparation of new derivatives of 9-chloroprednisolone.

The 9-chloroprednisoIon (= 9 <x-chloro-11ß, 17a, 21-tri-hydroxy-l, 4-pregnadien-3,20-dione) has long been known. (J. Amer. Chem. Soc., 77, 1955, 4181). This corticoid is unsuitable as an active ingredient for pharmaceutical preparations used for the topical treatment of inflammatory diseases, since it has very strong systemic effects.

It has been found that previously unknown derivatives of 9-chloroprednisolone are systemically almost ineffective, but surprisingly, when applied topically, they have a strong anti-inflammatory activity, which usually exceeds that of the most effective commercially available corticoids.

The new derivatives of 9-chloroprednisolone have the following formula

Ri represents an alkanoyl group having 1 to 8 carbon atoms or the benzoyl group and

X represents an alkanoyloxy group having 1 to 8 carbon atoms 20 or the benzoyloxy group.

An alkanoyl group Rj containing 1 to 8 carbon atoms and an alkanoyloxy group X containing 1 to 8 carbon atoms is to be understood as a group which is derived from a straight-chain or branched fatty acid, such as, for example, formic acid, acetic acid, propionic acid, butyric acid, isobutyric acid, valeric acid, isovaleric acid Derive tri-methyl acetic acid, caproic acid, tert-butylacetic acid or Ca-pryl acid.

Particularly preferred alkanoyl groups Rx and alkanoyl-30 oxy groups X are those which are derived from an alkane carboxylic acid containing 2 to 6 carbon atoms.

9-chloro-prednisolone derivatives of the formula I with X meaning an alkanoyloxy group or the benzoyloxy group are preferably those in which the radicals Rx and X together have 3 to 14 carbon atoms. Such chlorine prednisolone derivatives are, for example: 17a, 21-diacetoxy-9a-chloro-11ß-hydroxy-l, 4-pregna-diene-3,20-dione,

17 a-acetoxy-9a-chloro-11 ß-hydroxy-21-propionyloxy-40 l, 4-pregnadiene-3,20-dione,

the 21-acetoxy-9ot-chloro-11β-hydroxy-17 a-propionyloxy-1,4-pregnadiene-3,20-dione,

the 17 a-acetoxy-21-butyryloxy-9a-chloro-11β-hydroxy-1,4-pregnadiene-3,20-dione, 45 the 21-acetoxy-17a-butyryloxy-9cc-chloro-11ß-hydroxy-l , 4-pregnadiene-3.20-dione,

17a-acetoxy-9a-chloro-lß-hydroxy-21-isobutyryloxy-1,4-pregnadiene-3,20-dione,

the 21-acetoxy-9a-chloro-11β-hydroxy-17 a-isobutyryloxy-50 l, 4-pregnadiene-3,20-dione,

17 a-acetoxy-9a-chloro-11β-hydroxy-21-valeryloxy-1,4-pregnadiene-3,20-dione,

the 21-acetoxy-9a-chloro-11β-hydroxy-17a-valeryloxy-l, 4-pregnadiene-3,20-dione,

55 the 17 a-acetoxy-21-benzoyloxy-9a-chloro-11β-hydroxy-l, 4-pregnadiene-3,20-dione,

21-acetoxy-17a-benzoyloxy-9a-chloro-l 1β-hydroxy-1,4-pregnadiene-3,20-dione,

das9ct-ChIor-11ß-hydroxy-17ot, 21-dipropionyloxy-l, 4-pre-60 gnadien-3,20-dione, das 17a-Butyryloxy-9a-chlor-llß-hydroxy-21-propionyl-oxy-1, 4-pregnadiene-3.20-dione,

the 21-butyryloxy-9a-chloro-11ß-hydroxy-17a-propionyl-oxy-l, 4-pregnadiene-3,20-dione, 65 the 9a-chloro-11ß-hydroxy-17a-isobutyryloxy-21-propio- nyloxy-1,4-pregnadiene-3,20-dione,

das9a-chloro-11ß-hydroxy-21-isobutyryloxy-17a-propio-nyloxy-1,4-pregnadiene-3,20-dione,

3rd

631997

the 9 <x-chloro-1 1 ß-hydroxy-17ct-propionyloxy-21-valeryl-oxy-1,4-pregnadiene-3,20-dione,

9a-chloro-11ß-hydroxy-21-propionyloxy-17a-valeryl-oxy-1,4-pregnadiene-3,20-dione,

the 17 a-benzoyloxy-9a-chloro-11β-hydroxy-21-propionyl-oxy-1,4-pregnadiene-3,20-dione,

21-benzoyloxy-9a-chloro-l 1β-hydroxy-17a-propionyl-oxy-1,4-pregnadiene-3,20-dione,

17 a, 2 l-DibutyryIoxy-9a-chloro-l 1 ß-hydroxy-1,4-pre-gnadien-3,20-dione,

the 17a-butyryloxy-9a-chloro-1 1β-hydroxy-21-isobutyryl-oxy-1,4-pregnadiene-3,20-dione, the 21-butyryloxy-9a-chloro-11ß-hydroxy-17a-isobutyryl- oxy-1,4-pregnadiene-3,20-dione,

17a-butyryloxy-9a-chloro-11ß-hydroxy-21-valeryIoxy-1,4-pregnadiene-3,20-dione,

21-butyryloxy-9a-chloro-11 ß-hydroxy-17 a-valeryloxy-1,4-pregnadiene-3,20-dione,

the 17a-benzoyloxy-21-butyryIoxy-9a-chloro-lß-hydroxy-1,4-pregnadiene-3,20-dione,

the 21-benzoyloxy-17 a-butyryloxy-9a-chloro-11β-hydroxy-1,4-pregnadiene-3,20-dione,

the 9a-chloro-lß-hydroxy-17,21-diisobutyryloxy-l, 4-pre-gnadien-3,20-dione and the 9a-chloro-11 ß-hydroxy-17a-21-divaleryloxy-1,4- pre-gnadien-3.20-dione.

The new 9-chloroprednisolone derivatives are produced according to the invention by using a 9-chloro derivative of the formula

CHo0H I 2

c = o where

Rj has the meaning given above, esterified accordingly in the 21 position.

The process according to the invention can be carried out under the conditions described in US Pat. Nos. 3,678,034,3,718,671 and 3,828,083.

As is known, the starting compounds for the process according to the invention can be prepared in a simple manner and in high yields from prednisolone, which in turn can be synthesized relatively easily from diosgenin. The result of this is that the new compounds can be prepared from diosgenin in a total yield of approximately 15% with relatively little effort. In contrast, the syntheses of the well-known highly effective corticoids from diosgenin are much more complex and the overall yields achieved are significantly lower (approx. 0.5 to 5%). This is not without significance in view of the growing difficulties in procuring suitable starting materials for the corticoid synthesis in sufficient quantities and in view of the high active ingredient costs with which drug-containing specialty medicinal products are contaminated.

As already mentioned, the compounds obtained according to the invention have a strong anti-inflammatory activity when applied topically, but are only very weakly effective when applied systemically.

The pharmacological properties of the new Verbin-io fertilizers were determined using the following tests:

(A) Anti-inflammatory activity when applied locally to the rat ear:

The substance to be tested is dissolved in an irritant consisting of 4 parts of pyridine, 1 part of distilled water, 5 parts of ether and 10 parts of a 4% ethereal croton oil solution. This test solution is used to impregnate felt strips, which were attached to the inside of a specimen tweezer, and press them lightly onto the right ear of male rats weighing 100 to 160 g for 15 seconds. The left ear remains untreated and serves as a comparison. Three hours after the application, the animals are killed and 9 mm discs are punched out of their ears. The difference in weight between the disc of the right ear and that of the left ear is a measure of the edema formed.

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

30th

B) Anti-inflammatory activity with subcutaneous application to the rat paw:

SPF rats weighing 130 to 150 g are injected into the right hind paw to produce an inflammatory focus with 0.1 ml of a 0.5% Myco-35 bacterium butyricum suspension (available from the American company Difko). The rat's paw volume is measured before the injection. 24 hours after the injection, the paw volume is measured again to determine the extent of the edema. The rats are then injected subcutaneously with different amounts of the test substance - dissolved in a mixture of 29% benzyl benzoate and 71% castor oil. After another 24 hours, the paw volume is determined again.

The control animals are treated in the same way, with the difference that they are injected with a test substance-free benzylbenzoate-castor oil mixture.

The amount of test substance required to achieve a 50% healing of the paw edema is determined in the usual way from the paw volumes obtained.

50

C) Thymolytic effect after oral application:

SPF rats weighing 70 to 110 g are under

Adrenalectomy ether anesthesia. 6 animals each form a test group, each of which receives a defined amount of Test-55 substance orally for 3 days.

On the fourth day, the animals are sacrificed and their thymus weight determined. The control animals are treated in the same way, but are given a benzyl benzoate-castor oil mixture without test substance. The amount of test substance in which 50% thymolysis is observed is determined in the usual manner from the thymus weights obtained.

In these tests, the structurally analogous 9-chloroprednisolone and its 21-acetate and the beclomethasone-17,21-dipropionate (= 9a-chloro-11β-hydr-65 oxy-16ß-methyl-17a, 21-dipropionyloxy-l , 4-pregnadiene-3,20-dione).

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

631 997

4th

No substance

I 21-acetoxy-9a-chloro-11ß, 17a-dihydroxy-l, 4-pregnadien-3,20-dione

II 9cc-chloro-11β-hydroxy-16β-methyl-17a, 21-dipropionyloxy-l, 4-pregnadiene-3,20-dione

III 21-acetoxy-9a-chloro-11β-hydroxy-17a-pro-pionyloxy-1,4-pregnadiene-3,20-dione

IV 21 - acetoxy-17 a-benzoyloxy-9a-chloro-11β-hydroxy-1,4-pregnadiene-3,20-dione

V 17a-benzoyloxy-9a-chloro-11ß-hydroxy-21-propionyloxy-1,4-pregnadiene-3,20-dione

EDS0 in mg / kg

A) rats- B) adjuvant- C) thymo-

ear test edema test lysis test

1.5

1.4

0.026

1.5 1.5

6.0

> 30

25th

> 30

> 30

0.6

2.0

4.8

Similar results are obtained if the pharmacological activity of the 9-chloroprednisolone derivatives obtained according to the invention is determined using the known vaso-constriction test or the known sodium-potassium retention test.

The new compounds are suitable in combination with the carriers commonly used in pharmaceutical pharmacy for the local treatment of contact dermatitis, various types of eczema, neurodermatoses, erythroderma, burns, pruritis vulvae et ani, rosacea, erythematosus cuta-neus, psoriasis, Lieben ruber planus et verrucosus and similar skin diseases.

The pharmaceutical specialties can be produced in the usual way by converting the active ingredients into the desired application form, such as: solutions, lotions, ointments, creams or plasters, using suitable additives. In the pharmaceuticals formulated in this way, the active substance concentration depends on the form of administration. For lotions and ointments, an active ingredient concentration of 0.001% to 1% is preferably used.

In addition, the new compounds, if appropriate in combination with the usual carriers and auxiliaries, are also well suited for the production of inhalants which are used for the therapy of allergic diseases of the respiratory tract, such as e.g. bronchial asthma or rhinitis.

The following examples serve to explain the invention.

Synthesis

example 1

0.5 g of 17a-benzoyloxy-9a-chloro-11ß-, 21-dihydroxy-l, 4-pregnadiene-3,20-dione are stirred with 10 ml of formic acid for 24 hours at room temperature. Then the reaction mixture is poured into ice water, extracted with dichloromethane, the organic phase is washed, dried over sodium sulfate, concentrated in vacuo and 400 mg of 17a-benzoyloxy-9a-chloro-21-formyloxy-11ß-hydroxy-l, 4 are obtained -pregnadien-3,20-dione as a glassy solidifying mass.

[a] = + 58 ° (chloroform).

Example 2

1.5 g of 17 a-benzoyloxy-9a-chloro-11β, 21 -dihydroxy-1,4-pregnadiene-3,20-dione are mixed with 17 ml of pyridine and 8.0 ml of acetic anhydride and for one hour at 0 ° C stirred. Then the reaction mixture is poured into ice water and filtered

20th

the excreted product, dissolves it in dichloromethane, washes the organic phase, dries it with sodium sulfate and concentrates it in vacuo. The residue is chromatographed on a silica gel column using a methylene chloride-acetone gradient, recrystallized from acetone-hexane, and 1.2 g of 21-acetoxy-17a-benzoyloxy-9a-chloro-11ß-hydr-oxy-l, 4-pregnadiene are obtained -3,20-dione with a melting point of 221 ° C (decomposition.

30th

35

40

Example 3

1.5 g 17a-benzoyloxy-9a-chloro-11ß, 21dihydroxy-l, 4-pregnadiene-3,20-dione are mixed with 17 ml of pyridine and 8.0 ml of propionic anhydride and stirred at 0 ° C for one hour . Mine works up the reaction mixture as described in Example 3 and receives 960 mg of 17a-benzoyloxy-9a-chloro-11β-hydroxy-21-propionyloxy-1,4-pregnadiene-3,20-dione with a melting point of 226 ° C. (decomposition ).

Example 4

2.3 g 17a-benzoyloxy-9a-chloro-11ß, 21-dihydroxy-l, 4-

pregnadien-3,20-dione are added to 50 ml pyridine and 25 ml butyric anhydride and stirred for 16 hours at room temperature.

The reaction mixture is worked up as described in Example 3 and 2.0 g of 17a-benzoyloxy-21-butyryloxy-9a-chloro-11ß-hydroxy-l, 4-pregnadiene-3,20-dione with a melting point of 226 ° C. ( Decomposition).

50

Example 5

2.3 g of 17a-benzoyloxy-9a-chloro-11ß-21-dihydroxy-l, 4-pregnadiene-3,20-dione are mixed with 50 ml of pyridine and 25 ml of valeric anhydride and 16 hours at room-55 temperature touched. The reaction mixture is worked up as described in Example 3, and 1.63 g of 17a-benzoyl-oxy-9a-chloro-11β-hydroxy-21-valeryloxy-1,4-pregnadiene-3,20-dione with a melting point of 208 is obtained ° C.

60

Example 6

2.3 g of 17a-benzoyloxy-9a-chloro-11ß, 21-dihydroxy-l, 4-pregnadiene-3,20-dione are mixed with 50 ml of pyridine and 25 ml of tri-methylacetic anhydride and 16 hours at room-65 temperature touched. The reaction mixture is worked up as described in Example 3, and 1.72 g of 17a-benzoyl-oxy-9a-chloro-11β-hydroxy-21-trimethylacetoxy-l, 4-pregna-diene-3,20-dione is obtained Melting point 236 ° C.

5

631 997

Example 7

2.3 g of 17a-benzoyloxy-9a-chloro-11ß, 21-dihydroxy-l, 4-pregnadiene-3,20-dione are mixed with 50 ml of pyridine and 25 ml of isobutyric anhydride and stirred for 16 hours at room temperature.

The reaction mixture is worked up as described in Example 3, and 2.1 g of 17a-benzoyloxy-9a-chloro-11β-hydroxy-21-isobutyryloxy-l, 4-pregnadiene-3,20-dione are obtained as a glassy mass.

[a] Y) = + 68 ° (chloroform).

Example 8

2.3 g of 17a-benzoyloxy-9a-chloro-11ß, 21-dihydroxy-l, 4-pregnadiene-3,20-dione are mixed with 50 ml of pyridine and 20 ml of iso-valeric acid chloride and stirred at 0 ° C for 2 hours .

The reaction mixture is worked up as described in Example 3, and 2.1 g of 17a-benzoyloxy-9a-chloro-11β-hydroxy-21-isovaleryloxy-l, 4-pregnadiene-3,20-dione with a melting point of 197 ° C. are obtained .

Example 9

2.3 g of 17a-benzoyloxy-9a-chloro-11ß, 21-dihydroxy-l, 4-pregnadiene-3,20-dione are mixed with 50 ml of pyridine and 30 ml of oenanthic anhydride and stirred for 16 hours at room temperature. The reaction mixture is poured into ice water, heated and the excess oenanthic acid is removed by steam distillation. The mixture is then extracted with dichloromethane, the organic phase is worked up as described in Example 3 and 2.03 g of 17a-benzoyloxy-9a-chloro-21-heptanoyloxy-11ß-hydroxy-l, 4-pregnadiene-3.20- dionals oily product.

Md = + 64 ° (chloroform).

Example 10

2.3 g of 17a-benzoyloxy-9a-chloro-11ß, 21-dihydroxy-l, 4-pregnadiene-3.20 dione are stirred with 45 ml of pyridine and 1 ml of benzoyl chloride for one hour at room temperature.

The reaction mixture is worked up as described in Example 3, and 2.5 g of 17a, 21-dibenzoyloxy-9a-chloro-11ß-hydroxy-l, 4-pregnadiene-3,20-dione with a melting point of 221 ° C. are obtained.

Example 11

1.0 g of 17a-acetoxy-9a-chloro-11ß, 21-dihydroxy-l, 4-pre-gnadien-3,20-dione is mixed with 20 ml of pyridine and 5 ml of acetic hydride and stirred for one hour at room temperature . Then the reaction mixture is poured into ice water, the separated product is suctioned off, dissolved in dichloromethane, the organic phase is washed and concentrated in vacuo. The residue is recrystallized from acetone-hexane and 860 mg of 17a, 21-diacetoxy-9a-chloro-11β-hydroxy-l, 4-pregnadiene-3,20-dione with a melting point of 222 ° C. (decomposition).

Example 12

Under the conditions of Example 3, 1.0 g of 17a-acetoxy-9a-chloro-11β, 21-dihydroxy-1,4-pregnadiene-3,20-dione is reacted with propionic anhydride, processed and 940 mg of 17a-acetoxy are obtained -9a-chloro-llß-hydroxy-21-pro-pionyloxy-l, 4-pregnadiene-3,20-dione with a melting point of 219 ° C (decomposition).

Example 13

Under the conditions of Example 5, 1.0 g of 17a-acetoxy-9a-chloro-11ß, 21-dihydroxy-l, 4-pregnadiene-3.20-

dione reacted with valeric anhydride, processed and 660 mg of 17 a-acetoxy-9a-chloro-11β-hydroxy-21-di-hydroxy-l, 4-pregnadiene-3,20-dione with a melting point of 220 ° C. (decomposition) .

5

Example 14

Under the conditions described in Example 1, 1.2 g of 9a-chloro-11ß, 21-dihydroxy-17a-propionyloxy-l, 4-pregnadien-3,20-dione are reacted with formic acid, purified and 400 mg are obtained oily 9a-chloro-21-formyloxy-11β-hydroxy-17 a-propionyloxy-1,4-pregnadiene-3,20-dione.

[a] + 67 ° (chloroform).

Example 15

700 mg of 9a-chloro-11ß, 21-dihydroxy-17a-propionyloxy-l, 4-pregnadiene-3,20-dione are reacted with acetic anhydride as described in Example 2, processed and 320 mg of 2C 21 - acetoxy-9a are obtained. chloro-11 ß-hydroxy-17 a-propionyloxy-1,4-pregnadiene-3,20-dione with a melting point of 210 ° C (decomposition).

Example 16

700 mg 9a-chloro-11ß, 21-dihydroxy-17a-propionyloxy-251,4-pregnadiene-3,20-dione are reacted with propionic anhydride under the conditions described in Example 3, processed and 420 mg of 9a-chloro-1 are obtained lß-hydroxy-17a, 21 -dipropionyloxy-1,4-pregnadiene-3,20-dione, melting point 215 ° C (decomposed).

30th

Example 17

650 mg of 9a-chloro-11ß, 21-dihydroxy-17a-propionyloxy-l, 4-pregnadiene-3,20-dione are reacted with butyric anhydride under the conditions described in Example 4, 35 processed and 360 mg of 21-butyryloxy- 9a-chloro-11β-hydroxy-17a-propionyloxy-1,4-pregnadiene-3,20-dione with a melting point of 208 ° C (decomposition).

Example 18

40 Under the conditions of Example 5, 700 mg of 9a-chloro-11β, 21 -dihydroxy-17a-propionyloxy-1,4-pregnadiene-3,20-dione are reacted with valeric anhydride, processed and 520 mg of 9a-chloro are obtained. 11 β-hydroxy-17a-propio-nyloxy-21-valeryloxy-l, 4-pregnadiene-3,20-dione from melting point 45 ° C (decomposition).

Example 19

3.0 g of 9a-chloro-11ß, 21-dihydroxy-17a-propionyloxy-l, 4-pregnadiene-3,20-dione are mixed with 30 ml of pyridine and 15 ml of 50 caproic anhydride and stirred for 90 minutes at room temperature.

The reaction mixture is worked up as described in Example 2, and 2.6 g of 9a-chloro-21-hexanoyloxy-11ß-55 hydroxy-17a-propionyloxy-l, 4-pregnadiene-3,20-dione are obtained.

Example 20

Under the conditions of Example 9, 2.1 g of 9a-chloro-11ß, 21 -dihydroxy-17-propionyloxy-1,4-pregnadiene-60 3,20-dione are reacted with oenanthic anhydride, processed and 1.02 is obtained g 9a-chloro-21-heptanoyloxy-11ß-hydroxy-17 a-propionyloxy-1,4-pregnadiene-3,20-dione.

65 Example 21

Under the conditions of Example 6, 1.4 g of 9a-chloro-11β, 21-dihydroxy-17a-propionyloxy-1,4-pregnadiene-3,20-dione are reacted with trimethylacetic anhydride and processed

631997

and 670 mg of 9a-chloro-11ß-hydroxy-17a-propio-nyloxy-21-trimethylacetoxy-l, 4-pregnadiene-3,20-dione are obtained.

Example of use:

Pharmaceutical preparations A. Composition of an ointment 0.03% 21-acetoxy-9a-chloro-11ß-hydroxy-17a-propionylyloxy-1,4-pregnadiene-3,20-dione

2.50% Allercurhexachlorophenate, micronized, particle size approx. 8 ^ (Allercur = registered trademark for l-p-chlorobenzyl-2-pyrrolidyl-methyl-benzimidazole)

6.00% Hostaphat KW 340 (R) (tert. Ester from O-phosphoric acid and wax alcohol tetra-glycol ether)

0.10% sorbic acid 10.00% neutral oil (Migloyol 812 3.50% stearyl alcohol 1.50% wool fat, anhydrous DAB 6 5 76.36% demineralized water

B. Preparation of an inhalant

1,000 mg of micronized 21-acetoxy-9a-chloro-11ß-hydr-oxy-17a-propionyloxy-1,4-pregnadiene-3,20-dione (average lo size less than 7 fx and 39,000 g of ground lactose are mixed.

A dose of 20 mg inhalation agent is used per inhalation.

C.

Claims (2)

631 997 2nd PATENT CLAIM Process for the preparation of new derivatives of 9-chloroprednisolone of the formula CH 2X CH2X c = o c = o ... OR, (i) 15 where a) wherein Rj represents an alkanoyl group having 1 to 8 carbon atoms or the benzoyl group and X represents an alkanoyloxy group with 1 to 8 carbon atoms or the benzoyloxy group, characterized in that a 9-chloro derivative of the formula CHo0H I 2 C = 0 (Ia) bliss Rj has the meaning given above, esterified accordingly in the 21-position.