CH632772A5 - Process for preparing novel derivatives of 9-chloroprednisolone - 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 fluorine, chlorine, hydroxyl, alkanoyloxy having 1 to 8 carbon atoms, or benzoyl, are prepared. These compounds are obtained by opening the epoxide ring, located in the 9,11 position, of a corresponding prednisolone using HCl. The novel compounds can be used for treating inflammations.

Description

632 772

2nd

PATENT CLAIM Process for the production of new derivatives of 9-chloroprednisolone of the formula ch2x

C = 0

..OR,

(I)

wherein

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

X represents a fluorine atom, a chlorine atom, the hydroxyl group, an alkanoyloxy group having 1 to 8 carbon atoms or the benzoyloxy group, characterized in that the epoxy ring of a compound of the formula

CH-X i à

c = o

(in)

opens with hydrogen chloride.

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

The 9-chloroprednisolone (= 9a-chloro-11ß, 17a, 21-tri-hydroxy-l, 4-pregnadien-3,20-dione) has been known for a long time. (J. Amer. Chem. Soc., 77, 1955, 4181). This corticoid is unsuitable as an active ingredient for pharmaceutical preparations which are 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

(I)

wherein

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

X represents a fluorine atom, a chlorine atom, the hydroxy group, an alkanoyloxy group having 1 to 8 carbon atoms 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 should be understood to mean a group which is derived from a straight-chain or branched fatty acid, 5 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 Rt and alkanoyl-lo oxy groups X are those which are derived from an alkane carboxylic acid containing 2 to 6 carbon atoms.

Examples of 9-chloroprednisolone derivatives of the general formula I with X in the meaning of a chlorine atom and fluorine atom are:

17a-acetoxy-9a, 21-dichloro-11β-hydroxy-1,4-pregna-diene-3,20-dione,

9a, 21-dichloro-11ß-hydroxy-17a-propionyloxy-l, 4-pre-gnadien-3,20-dione,

2Q the 17a-butyryloxy-9a, 21-dichloro-11ß-hydroxy-l, 4-pregna-diene-3,20-dione,

9a, 21-dichloro-11β-hydroxy-17a-isobutyryloxy-1,4-pre-gnadiene-3,2Q-dione,

the 17 a-acetoxy-9a-chloro-21-fluoro-11β-hydroxy-1,4-pre-25 gnadiene-3,20-dione, the 9a-chloro-21-fluoro-11ß-hydroxy-17a-propionyloxy -l, 4-pregnadiene-3.20-dione,

the 17 a-butyryloxy-9a-chloro-21-fluoro-l 1 ß-hydroxy-1,4-pregnadiene-3,20-dione, 30 the 17a-benzoyloxy-9a-chloro-21-fluoro-11ß-hydroxy- 1,4-pregnadiene-3,20-dione,

the 9a-chloro-21-fluoro-11ß-hydroxy-17a-isobutyryloxy-l, 4-pregnadiene-3,20-dione.

the 9a, 21-dichloro-11ß-hydroxy-17a-väieryloxy-l, 4-pre-35 gnadien-3,20-dione and the 17a-benzyloxy-9a, 21 -dichloro-11 ß-hydroxy-1,4- pregna-dien-3.20-dione.

Examples of 9-chloroprednisolone derivatives of the general formula I with X in the meaning of a hydroxyl group are: 40 the 17 a-acetoxy-9a-chloro-11β, 21-dihydroxy-1,4-pregna-diene-3,20-dione ,

9a-chloro-11ß, 21-dihydroxy-17a-propionyloxy-l, 4-pre-gnadien-3,20-dione,

the 17a-butyryloxy-9a-chloro-11ß, 21-dihydroxy-l, 4-pregna-45 diene-3,20-dione, the 9a-CMor-llß, 21-dihydroxy-17a-isobutyryloxy-l, 4-pre -gnadien-3.20-dion,

the 9a-chloro-11ß, 21-dihydroxy-17a-valeryloxy-l, 4-pregna-diene-3,20-dione and 50 the 17a-benzoyloxy-9a-chloro-11ß, 21-dihydroxy-l, 4-pre -gnadien-3.20-dion.

These compounds are not only important as pharmacologically active substances. They can also be used as intermediates for the preparation of 9-chloro-55 prednisolone derivatives of the formula I with X in the meaning of a chlorine atom, an alkanoyloxy group or a benzoyloxy group.

9-Chlorprednisolone derivatives of the formula I with X meaning an alkanoyloxy group or a benzoyloxy group 60 pe are preferably those in which the radicals R 1 and X together have 3 to 14 carbon atoms. Such chloropre-dnisolone derivatives are, for example: 17a, 21-diacetoxy-9a-chloro-11ß-hydroxy-l, 4-pregna-diene-3,20-dione, 65 the 17a-acetoxy-9a-chloro-11ß- hydroxy-21-propionyloxy-l, 4-pregnadiene-3,20-dione,

das21-acetoxy-9a-chloro-11ß-hydroxy-17a-propiony! oxy-l, 4-pregnadien-3,20-dione,

3rd

632 772

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

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

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

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

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

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

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

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

9a-chloro-lß-hydroxy-17a, 21-dipropionyloxy-l, 4-pre-gnadiene-3,20-dione,

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

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

the 9a-chloro-l 1 ß-hydroxy-17a-isobutyryloxy-21-propio-

nyloxy-l, 4-pregnadiene-3,20-dione,

the 9a-chloro-lß-hydroxy-21-isobutyryloxy-17a-propio-

nyloxy-l, 4-pregnadiene-3,20-dione,

9a-chloro-l 1 ß-hydroxy-17a-propionyloxy-2 l-valeryl-oxy-1,4-pregnadiene-3,20-dione,

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

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

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

the 17 a, 21 -dibutyryloxy-9a-chloro-l 1 ß-hydroxy-1,4-pre-gnadien-3,20-dione,

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

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

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

the 21-butyryloxy-9a-chloro-11β-hydroxy-17a-valery Ioxy-l, 4-pregnadiene-3,20-dione,

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

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

the 9a-chloro-11β-hydroxy-17,21-diisobutyryloxy-1,4-pre-gnadiene-3,20-dione and the 9a-chloro-11ß-hydroxy-17a, 21-divaleryloxy-l, 4-pregna- dien-3.20-dione

The new 9-chloroprednisolone derivatives are produced according to the invention by the epoxy ring of a compound of the formula i 2 'C = 0

opens with hydrogen chloride.

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. As a result, the new compounds can be prepared from diosgenin in a total yield of approximately 15% with relatively little effort. In contrast, the io 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 adequate starting materials for corticoid synthesis 15 and in view of the high active ingredient costs with which drug-containing medicinal specialties are contaminated.

As already mentioned, the compounds produced according to the invention have a star-20 ke anti-inflammatory activity when applied topically, but are only very weakly effective when applied systematically.

The pharmacological properties of the new compounds were determined using the following tests:

25 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% essential croton oil solution. This test solution is used to impregnate felt strips attached to the inside of specimen tweezers 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. The animals are killed three hours after application and 9 mm discs are punched out of their ears. The difference in weight between the disc of the right and that of the left ear is a measure of the edema formed.

4o The dose of test substance is determined at which a 50% inhibition of edema formation is observed after three hours.

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

45 SPF rats weighing 130 to 150 g are injected into the right hind paw to produce an inflammatory focus 0.1 ml of a 0.5% Mycobacterium butyricum suspension (available from the American company Difko). The rat's paw volume is measured before the injection. 24 hours 50 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 a further 24 hours, the 55 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 benzyl benzoate-castor oil mixture.

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

C) Thymolytic effect after oral application:

SPF rats weighing 70 to 110 g are adrenalectomized under ether anesthesia. 6 animals each form a 65 test group, each of which receives a defined amount of test substance orally over 3 days.

On the fourth day, the animals are sacrificed and their thymus weight determined.

632 772

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 a conventional manner from the thymus weights obtained.

In these tests, the structurally analogous 9-chloroprednisolone and its 21-acetate and the beclomethasone-17,21-dipropionate (= 9 <x-chloro-11β-hydr-oxy-16ß-methyl-17a, 21-dipropionyloxy- 1,4-pregnadiene-3,20-dione).

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

No substance

I 9a-chloro-lß, 17a, 21-trihydroxy-l, 4-pregnadiene-3,20-dione

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

III 9a-chloro-11ß-hydroxy-16ß-methyl-17cx,

21 -dipropionyloxy-1,4-pregnadiene-3,20-dione

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

V 9a-chloro-11β, 21 -dihydroxy-17a-pro-pionyloxy-l, 4-pregnadiene-3,20-dione

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

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

ED50 in mag / kg A) rat ear- B) adjuvant- C) thymolysis test edema test

1.4 6.3 0.4

1.5

1.4 0.16 0.45 0.026

1.5

6.3

6.0

> 30

> 30

30th

25th

> 30

0.6

2.0

9.5

4.8

4.8

VIII 17 a-Benzoyloxy-9cx-chloro-11 ß-hydroxy-21-pro-

pionyloxy-1,4-pregnadiene-3,20-dione

1.5

> 30

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.

40

Example of use:

Pharmaceutical preparations

A. Composition of an ointment

45 0.03% 21-acetoxy-9a-chloro-11ß-hydroxy-17a-propionyl-oxy-1,4-pregnadiene-3,20-dione

2.50% allercurhexachlorophenate, micronized, particle size approx. 8 | x (Allercur = registered trademark for lp-chlorobenzyl-2-pyrrolidyl-methylbenzimidazole) 50 6.00% Hostaphat KW 340 (R) (tert. Ester from O- Phosphoric acid and wax alcohol tetraglycol ether)

0.10% sorbic acid 10.00% neutral oil (Migloyol 812 (R)

3.5% stearyl alcohol 55 1.50% wool fat, anhydrous DAB 6 76.36% demineralized water

B. Preparation of an inhalant

1,000 g micronized 21-acetoxy-9a-chloro-11ß-hydr-oxy-17a-propionyloxy-l, 4-pregnadien-3,20-dione (average 60 grain size smaller than 7 | i and 39,000 g of ground lactose are mixed.

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

C.