CH633301A5 - Process for preparing novel 21-salicylic acid esters or 21-acetylsalicylic acid esters of steroids of the pregnane series - Google Patents

Description

633 301

PATENT CLAIMS 1. Process for the preparation of new 21-salicylic acid esters or 21-acetylsalicylic acid esters of steroids of the pre-series, the formula

Salicylic acid esters or 21-acetylsalicylic acid esters of steroids of the Pregnan series.

OR

ch2-o-co- <

DH ■ -Z

The present invention relates to a method for producing new steroids which have a particularly high anti-inflammatory activity when administered topically and / or systemically.

The new compounds are 21-salicylic acid esters or 21-acetylsalicylic acid esters of steroids of the Pregnan series of the formula

OR

15

(I)

CHo-0-C0-

I 2

wherein R is hydrogen or acetyl, X is hydrogen, fluorine or chlorine, Y is hydroxyl, oxygen, chlorine or fluorine, X 'is hydrogen, halogen or methyl, Z is hydrogen, a- or β-methyl, hydroxyl or the rest

... 0 — CD -

(I)

30th

mean, characterized in that a compound hydroxyl or the rest of the formula wherein R is hydrogen or acetyl, X is hydrogen, fluorine or chlorine, Y is hydroxyl, oxygen, chlorine or fluorine, X 'is hydrogen, halogen or methyl, Z is hydrogen, a- or ß-methyl,

35

CH2OH

. . .D-CO

40

0R

(II)

esterified with salicylic or acetylsalicylic acid.

2. The method according to claim 1, characterized in that reacting the compound of formula II in the presence of dicyclohexylcarbodiimide with the free acetylsalicylic acid.

3. The method according to claim 1, characterized in that the compound of formula II is first converted into the corresponding 21-mesylate and this is then reacted in a polar solvent with an alkali metal salt of salicylic acid or acetylsalicylic acid.

4. Process according to claims 1 and 3, characterized in that the resulting 21-acetylsalicylic acid ester is cleaved in a nitrogen atmosphere at room temperature by mild alkaline hydrolysis to give the corresponding 21-salicylic acid ester.

5. 21- produced by the method of claim 1

mean.

The method according to the invention is defined in claim 1.

Examples of suitable derivatives of acetylsalicylic acid 45 as an esterifying agent are the corresponding acyl halides, such as the chlorides, or an activated ester. The compounds of the formula (I) can also be prepared by the process according to the invention by reacting the compound of the formula (II) with the free acetylsalicylic acid in the presence of dicyclohexylcarbodiimide.

Good results are also obtained by converting the compound of formula (II) into the corresponding 21-mesylate and reacting the latter in a solution in a polar solvent with an alkali metal salt of 55 acetylsalicylic acid, whereby the desired ester is obtained. The corresponding 21-salicylic acid ester is prepared by mild alkaline hydrolysis of the 21-acetylsalicylic acid ester obtained in this way in a nitrogen atmosphere at room temperature and isolated in a conventional manner. 60 The steroid's 21-salicylic acid ester can be prepared directly by reacting the corresponding 21-mesylate in solution in a polar solvent with an alkali metal salt of salicylic acid.

Pharmaceutical preparations for topical and / or systemic administration which have remarkable anti-inflammatory properties can be produced from the compounds obtained by the process according to the invention.

633 301

They are particularly suitable for the treatment of various inflammatory affects of the mucosa and skin, such as rectal or inflammation of the colon, congiuntivitis or phlogosis of the eye or nose, dermatitis of various etiology, eczema, psoriasis and allergic affections. They are suitable for the treatment of internal inflammatory affects, especially rheumatoid arthritis and allergic diseases.

For topical use, the active compound of the formula (I) can be processed in a customary manner into compatible carriers or excipients for the production of pharmaceutical preparations for topical administration.

Examples of such preparations are ointments, lotions, creams, emulsions, drops, sprays, suppositories as are known in pharmacy. For example, ointments can be formulated for both hydrophilic and hydrophobic use, and when formulations are formulated, they can contain aqueous or non-aqueous bases.

The pharmaceutical excipients which are suitable for such preparations can be, for example: animal fats, vegetable oils, fatty acids, polyalkylene glycols, beeswax, polyester and the like.

The pharmaceutical preparations can also contain other active components such as preservative or bacteriostatic agents.

The amount of active steroid in the pharmaceutical preparations depends on the specific composition and the inflammation to be treated.

A topical preparation preferably contains the active compound in an amount of 0.01 to 5% by weight.

These anti-inflammatory topical preparations can be applied to the affected areas a few times a day.

If desired, other substances such as bacteriostats, antibiotics, antimyotics and local anesthetics can be incorporated into these topical anti-inflammatory preparations.

For systemic administration, the active ingredient can be used in the pharmaceutical preparations for oral or parenteral administration. These pharmaceutical preparations can be solid or liquid, for example, and can be in the form of conventional pharmaceutical preparations as used in human medicine, such as tablets, capsules, granules, solutions or suspensions, also for injection.

The pharmaceutical excipients which are suitable for this formulation can be, for example: talc, gum-mi-arabic, lactose, starch, magnesium stearate, polyethylene-glycol and the like.

For systemic administration, the formulations may contain the active ingredient in an amount of 0.5 to 5 mg for the dosage unit and the daily dose may vary from 1 to 100 mg.

The following examples serve to illustrate the invention.

example 1

9a-fluoro-prednisolone-21-acetylsalicylate

9a-Fluoro-prednisolone (10 g) and a mixture of dry pyridine (30 ml) and dioxane (30 ml) are added to a four-necked container equipped with a stirring thermometer, dropping funnel and a CyCl2 tube. After cooling to 5 ° C., 8 g of acetylsalicyl chloride are dissolved in 16 ml of dioxane and added dropwise to the mixture, which is left to stand at about 2 ° C. overnight with stirring. The suspension is poured onto crushed ice, the solid obtained is separated off by filtration, washed with water and dried.

The crude 9a-fluoro-prednisolone-21-acetylsalicylate obtained in this way is recrystallized from ethyl acetate.

5 Example 2

9a-fluoro-prednisolone-21-salicylate

9a-fluoro-prednisolone-21-acetylsalicylate (10 g) in 120 ml of tetrahydrofuran is treated with 10 ml of 1M methanolic sodium hydroxide belo at room temperature in a stream of nitrogen. Two hours later the mixture is neutralized, evaporated in vacuo, diluted with methanol and poured into water. The crude 9a-fluoro-prednisolone-21-salicylate is recrystallized from ethyl acetate.

15 Example 3

9a-fluoro-prednisolone-21-salicylate

Preparation of the intermediate 9a-fluoro-prednisolone-21-methylate

In a 4-neck flask equipped with a stirrer, thermometer, dropping funnel 20 and a CaCl2 tube, 10 g of 9-fluoro-prednisolone and 20 ml of anhydrous pyridine are added. The solution is cooled to -5 ° C. and 6 ml of methanesulfonyl chloride are added dropwise with stirring. The reaction mixture is kept under stirring at about 25 ° C. for 6 hours, then poured onto crushed ice, the solid obtained is filtered, washed with water and dried.

15 g of sodium salicylate are added to a suspension of 10 g of 21-mesylate in 100 ml of dimethylformamide with stirring at room temperature. The reaction mixture is heated to 100 ° C. with stirring and held under these conditions for a further 2 hours, then poured into 100 ml of cold water. The precipitate is filtered off, washed with water and dried.

The crude product is recrystallized from acetone and he gives 35 g of the pure product which has the following characteristics: F: 209.3 ° C

[a] ^ = +152.07 (c = l dioxane)

40UV — SpectrumXmax = 251 mu: E 476.2

1 cm

IR spectrum (nujol) 3290 -1730 -1710 -1670 -1660 -1610 -1605 -1580 cm-1

45 Example 4

6a, 9a-difluoro-1 6a-methyl-prednisolone-21 salicylate

In the same manner as described in Example 3, the 21-salicylic acid ester of 6a, 9a-difluoro-16a-methyl-predni-solone (also called flumethasone) was produced, which has the following 50 characteristics: F: 242.8 ° C

["] D = + 131'33 ° (c = 1 dioxane)

55

UV spectrum X max 240 mu; D} = 523.46

1 cm

Example 5

In the same manner as described in Examples 1, 2 and 3, the 21-acetylsalicylic acid and 21-salicylic acid esters of the following steroids can be obtained: 6a, 9a-60 difluoroprednisolone, 9a-fluoro-16a-methyl-prednisolone, 9a- Fluoro-16a-hydroxy-prednisolone, 6a-fluoro-16a-methyl-prednisolone, 6a-methyl-prednisolone, 6a-methyl-9a-fluorine-prednisolone, 9a-fluoro-16ß-methyl-prednisolone.

65

Example 6

In the same manner as described in the preceding examples, 9a-fluoro-16a-hydroxy-prednisolone-16,21-disalicylate can also be obtained.

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4th

Biological tests

The topical anti-inflammatory activity of 21-salicylic acid esters and 21-acetylsalicylic acid esters of the compounds prepared by the process according to the invention was determined using the following biological tests:

a) Inhibition of granulomas induced by cotton pellets

This test was carried out according to MEIER R., SCHULER W., DESAULLES P. "Experientia", Volume 6, p. 469,

1950.

Table 1

connection

9a-fluoroprednisolone io21 acetate

9a-fluoropednisolone 21-salicylate

Male albino rats from the Wistar-Morini strain were used. Under mild ether anesthesia, a cotton pellet was inserted subcutaneously on both sides of the back through a medium incision. The pellets were cut from dental cotton rolls (No 1 Johnson & Johnson) and combined in pairs with a weight of 100 ± 1 mg. Before implantation, the pellets were individually immersed in a 1% aqueous suspension of carrageenan (Viscarin carra-geenan REX 7205, Marine colloids Inc., Rockland, Maine -USA), dried overnight on a filter paper and then dried at 121 ° C Treated in an autoclave for an hour.

The anti-inflammatory activity of the two compounds produced by the process according to the invention, in particular 9a-fluoro-prednisolone-21-salicylate and 9a-fluorine-prednisolone-21-acetylsalicylate, is compared with that of 9a-fluoro-prednisolone-21-acetate.

Scalar doses of the compounds to be tested, dissolved in N, N-dimethylformamide, are added to each pellet in an amount of 0.2 ml. As a comparison, pellets are used which contain 0.2 ml of N, N-dimethylformamide. The pellets are allowed to dry in an oven at 60 ° C for 24 hours. Before the implantation, the pellets are immersed individually in a 0.5% antibiotic solution ("Combiotic" Pfizer).

At the end of the test period (8 days after implantation), the animals are killed by asphyxia with CO 2. The pellets with the surrounding granuloma are removed, dried to a constant weight at 60 ° C and weighed.

The amount exceeding 100 mg is the weight of the granuloma and is expressed in mg / 100 g body weight.

The results are shown in the following table.

Table 2

% Inhibition of granuloma formation at the following doses, expressed in ng / pellet

8 40

22.2

38.2

(16) (15)

35

43.3

(15)

(16)

(24) 56.4 (33)

15 9a-fluoroprednisolone 21-acetylsalicylate 40.6

In brackets: number of animals

The statistical evaluation of the data (R. Borth "Simpli-20 fied Mathematics for Multiple Bioassays" Acta Endocrinol. 35, 454, 1960) indicates that 9a-fluoroprednisolone-21-salicylate and 9a-fluoroprednisolone-21-acetylsalicylate 12 and Are 22 times as effective as 9a-fluoroprednisolone-21acetate.

25 b) Inhibition of carrageenin-induced edema of the rat paw

Flumethasone salicylate, suspended in an aqueous vehicle containing NaCl 0.9%, polysorbate 80.04%, CMC 0.5% and benzyl alcohol 0.9%, was albino rats from the strain Wistar, 30 with a weight of 150-175 g, which in 4 Groups of 10 animals were divided and fasted overnight before the start of the experiment. Immediately before administration of the flumethasone salicylate or the aqueous vehicle, 5 ml of water was injected into each animal. An hour 35 later, 0.1 ml of a 0.5% aqueous suspension of carrageenin (REX 7205, Marine Colloids Inc., Springfield, NJ - USA) was injected into the plantar aponeurosis of the right hind paw according to winter using a 5 μm needle et al. ("P.S.E.B.M.", 111, 544, 1962). The volume of the foot was measured with a mercury plethysometer immediately 40 bar before the carrageenin administration and 3 hours after the carrageenin administration. This was done by immersing the paw of the non-anesthetized animal to the point where the mercury had reached the level of the lateral malleolus. 45 The increase in the volume of the paw was calculated from the difference in the values at 0 and 3 hours after the injection of the phlogistic agent. The data in the following table indicate that the ED50 for flumetansone salicylate is 0.34 mg / kg.

50

Oral activity of flumethasone salicylate in inhibiting carrageenin-induced edema of the rat paw

Treatment of aqueous vehicles Flumethasone salicylate Flumethasone salicylate Flumethasone salicylate

Dose mg / kg

0.11 0.33 1

No. of animals

10 10 10 10

65

Rise in paw volume after carrageenin administration Medium ± S.D. % Inhibition

13.05 ± 1.98 8.50 ± 2.25 6.30 ± 2.19 4.95 ± 1.66

34.9 51.7 62.1

The following experiments explain topical and systemic formulations of substances which have been prepared by the process according to the invention.

Trial A

An ointment for topical use is made from the following components:

5

633 301

component

% By weight

9ce-fluoroprednisolone 21 salicylate

0.250

Benzyl alcohol

0.50

Cetyl alcohol

0.50

Distilled water

5.00

lanolin

5.00

white, soft paraffin on 100

Parts by weight

The cetyl and benzyl alcohols and the white, soft paraffin were melted at about 70 ° C., then the active substance and then the lanolin previously mixed with water were added.

Attempt B

An ointment for topical use is the following

Components made:

Component weight%

9a-fluoroprednisolone 2 l salicylate 0.125

Lanolin 24.0 liquid paraffin 7.0

Component weight%

Neomycin sulfate 0.5

white, soft paraffin on 100

Parts by weight

The active ingredient is added to the other components that have been melted before, and then the antibiotic is added with stirring.

Attempt C

Capsules for oral use are made from the following components:

Component mg

9a-fluoroprednisolone-21-acetyl salicylate 4

Lactose 104

Rice starch 26

Magnesium stearate 16

The active compound and magnesium stearate are mixed, sieved and filled into hard gelatin capsules.

Attempt D

Aqueous parenteral solution of the following composition:

6a, 9cc-difIuor-16a-methyl-prednisolone-

21-salicylate 5

Polyethylene Glycol 400 U.S.P. 25th

mg

Polysorbate 80, U.S.P. 10th

distilled water to 2 ml

Clinical trials

General topical administration

The patients were adults of both sexes. The patients selected for this trial had skin conditions that generally respond to steroid treatment.

The following preparations were used:

a) an ointment containing 9a-fluoro-prednisolone-2l-salicylate (FPS) and b) an ointment containing 9a-fluoro-prednisolone-21-acetate (FPA).

All preparations were filled into tubes with the same name, so that the test subjects did not know which preparation they were using. In all cases, the results were evaluated without the identity of the agent used being known.

All patients underwent an occlusive treatment.

Patient No. 1 15 L.A. 50 years old, housewife

Affected by a 7-year-old bilateral palmo-plantar-chronic hyperkeratotic eczema.

Cycles of 3 day administrations with 0.125% FPS (right foot) or 0.125% FPA (left foot) started on April 20, 21, 1977.

After 7 days there was a satisfactory reduction in both erythema and hyperkeratosis of the right foot, while there was only a slight reduction in erythema in the left foot.

After 14 days, the erythema disappeared and there was a marked reduction in hyperkeratosis of the right foot, while there was hardly any noticeable improvement in the left foot.

Patient No. 2 30 G.C. 55 years old, housewife

Affected by a 2-month-old bilateral Palmo-plan-tar-eezematous hyparkeratotic dermatitis.

Treatment with 0.125% FPS (right hand and foot) or 0.125% FPA (left hand and foot) started on June 23, 1977.

After 3 days, the itching and hyperkeratosis of the right hand and right foot decreased, while there was no noticeable improvement in the left hand and foot.

40 After 6 days the erythema and hyperkeratosis of the right hand and right foot decreased, while there was only a reduction in the itching and erythema of the left hand and foot. The patient then received FPS on both sides until a complete recovery occurred.

45

Patient No. 3

M.G. 74 years old, housewife

Affected by long-term psoriasis with large confluent psoriatic spots on the front 50 of the feet.

Treatment with 0.250% FPS (right foot) or 0.250% FPA (left foot) started on June 29, 1977.

After 3 days the erythema of the right foot decreased, while there was no noticeable improvement in the left 55 foot.

After 6 days the erythema continued to improve and the desquamation of the right foot almost completely disappeared, but only a slight improvement in the left foot.

60 The patient then received FPS on both feet until a complete recovery occurred.

Patient No. 4

C.G. 29 years old, worker 65 Infested with a 1-year-old relapsing nummular eczema of the feet with severe involvement of the left foot.

Daily treatment with 0.250% FPS (left foot) or 0.250% FPA (right foot) started on August 12, 1977.

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6

After 7 days, itching and erythema decreased on both feet.

After 14 days, the erythema and desquamation of the left foot improved significantly, while erathema and desquamation, although to a lesser extent, are still on the right foot.

Patient No. 5

C.G. Age 46 years, businessman

Affected by a one-week-old erathemato-vescicu-lar eruption with exudate, desquamation and itching with severe involvement of the right forearm.

Daily treatment with 0.0625% FPS (right forearm) or 0.0625% FPA (left forearm) started on August 14, 1977.

After 7 days the itching and the exudate disappeared on both forearms. Slight decrease in desquamation on the right forearm.

After 14 days the itching and Vesci-cel disappeared on both forearms.

5 The desquamation on the right forearm disappears and remains on the left forearm.

Patient No. 6

B.G. Age 69, retired carpenter io affected by eczema on both hands.

Daily treatment with 0.250% FPS (right hand) or 0.250% FPA (left hand) started on September 16, 1977.

After 7 days, slight improvement on both hands with reduced itching but persistence of desquamation. 15 After 14 days, desquamation on the right hand disappeared and only a slight decrease on the left hand.

C.