DE1768673B1 - 6alpha, 9alpha-difluorprednisolone-17,21-diester - Google Patents

Description

application are of limited activity. 30 psoriasis and other allergic

It has been found that the 17,21-diesters of 6a, 9a-difluorprednisolone according to the invention have a External use shows a significantly increased effectiveness, as can be demonstrated by biological tests. that respond to topical use of anti-inflammatory steroids. These External anti-inflammatory medicines are applied to the affected areas several times a day

there that are especially applied for the measurement of the antiphlo- 35.

Gistic effect of a substance with external The compounds according to the invention are there

produced by that a 17-monoester of 6a, 9a-Difluorprednisolons the formula

CH ₇ OH

-CO-R

HO

Application (e.g. a vasoconstriction experiment and an experiment on granuloma pockets). the 17,21-diesters according to the invention additionally show remarkable effectiveness against edema, if they are tested against edema of the rat paw caused by carraghenin. the remarkable activity of the compounds according to the invention appears due to the combination of the ester groups in the 17 and 21 positions of the 6ct, 9a-difluorprednisolone to be provoked, creating powerful anti-inflammatory steroids, which are particularly valuable for use in animals or humans.

Preferred 6a, 9a-difluorprednisolone-17,21-diester 50 |

are those of the formula I in which the substituent R F

has the same number or more carbon atoms than the substituent R ¹ , such as, for. B. the 17-propionate

21-acetate, the 17-butyrate-21-acetate, the 17-butyrate in the R has the meaning mentioned, is esterified with a 21-propionate, the 17-butyrate-21-isobutyrate, the 17-iso-55 acylating agent, the from a fatty butyrate-21-acetate, the 17-isobutyrate-21-propionate, the acid of the formula R ¹ —COOH is derived in the

R ^{1 has} the stated meaning in the presence of a pyridine base.

The esterification is carried out under reaction conditions known per se in the production of steroid esters performed, e.g. B. by treating with the appropriate carboxylic acid anhydride, such as acetic anhydride, Propionic anhydride, butyric anhydride or isobutyric anhydride in the presence

17,21-diacetate, 17,21-dipropionate and 17,21-dibutyrate of 6a, 9a-difluorprednisolone. Particularly preferred diesters are 17-butyrate-21-acetate and 17,21-dipropionate.

Medicaments according to the invention contain the 17,21-diesters of 6a, 9a-difluorprednisolone in combination with one or more non-toxic carriers or bases for pharmaceutical purposes. These

therapeutically useful preparations can be found in 65 of pyridine.

various application forms can be used, the 17-mono-

z. B. as a means for parenteral, oral, rectal or ester is obtained by 6a, 9a-difluoro

external use. prednisolone with a lower alkyl orthoester of

Formula R - C (OX) ₃ , in which R has the meaning mentioned and X is a lower alkyl radical, treated according to the process described in German Patent 1 195 748 and then the 17a, 21-lower alkyl orthoester of 6a, 9a- Difluorprednisolons hydrolyzed in an acidic medium according to the method described in German Patent 1214,677.

The 17,21-diesters of the formula I can also be prepared by adding a corresponding 17,21-diester of 9 / 5,11 / 3-oxido-6a-fluorzl ⁴ -pregnen-17a, 21-diol-3, 20 - dions of the formula

CH ₂ O

in which R and R ^{1 have} the meaning mentioned, hydrofluorinated and subjected to a 1 (2) dehydrogenation. These two stages can be done in any order.

The 17,21-diester of 9 / 3.11 ₁ S- oxido-6a-fluoro ^ -pregnen-17a, 21-diol-3,20-dione of the formula III can be prepared by starting from zl ^{4-9 (11)} -Pregnadien-17a, 21-diol-3,20-dione starts out and converts this compound into the compounds of the formula I by a reaction sequence according to the following scheme.

CHoOH

CH ₇ O

CO

OH

Ortho esterification

OX

hydrolysis

R ¹ -CO-O

CH ₂ O-CO-R ¹

CO

: 0-CO-R

Esterification

VII

CH ₂ OH

CO
ν O-CO-R

Fluorination

CH ₂ O-CO-R ¹

O-CO-R

HO

HOBr addition

VIII

CH ₂ O-CO-R ¹

CO

0-CO-R

HO

O = *

CH ₂ O-CO-R ¹

CO
ς Ο — CO — R

Epoxidation

CH ₂ O-CO-R ¹

Hydrofluorination

1 (2) -Dehydrogenation

III

1 (2) dehydration

HO

O = ¹

CH ₂ O-CO-R ¹

CO
r-O-CO-R

Hydrofluorination O = ¹

CH ₂ O-CO-R ¹

CO
- _O _ _CO _ _R

That used as the starting material
Gnadien-17a, 21-diol-3,20-dione IV is reacted with a lower alkyl orthoester such as methyl or ethyl orthoacetate, orthopropionate, orthobutyrate or orthoisobutyrate, a mixture of the two epimeric orthoesters V being obtained. These can be hydrolyzed directly to the corresponding 17-monoesters VI in an organic solvent in the presence of an acidic catalyst according to Gazzetta Chimica Italiana, Vol. 93, pp. 413 to 450, 1963.

The 17-monoester is then esterified by reacting with the corresponding acid anhydride such as acetic anhydride, propionic anhydride, butyric anhydride or isobutyric anhydride in the presence an acidic catalyst is reacted, and gives the Trieste VII.

If the triester to be produced is 3,17,21-triacetate, tripropionate, tributyrate or triisobutyrate, the method of direct esterification of zl ⁴ · ⁹¹¹¹ '- pregnadiene - 17a, 21-diol is preferred instead of the three-stage process mentioned -3,20-dione (IV) is used with the corresponding anhydride, whereby strong acylation conditions are observed so that the esterification of the hydroxyl groups in 17a and 21-position and the enol esterification of the 3-keto group take place at the same time.

The triester VII is fluorinated in the 6-position by treating it with perchloryl fluoride, and the reaction product, which is obtained from a mixture of 6 / i-fluoro-I ⁴ - ^{9 (11)} -pregnadiene-17a, 21-diol-3, 20-dione-XI

17.21 - diester and the corresponding epimeric 6a-fluoro compound, e.g. B. by treatment

converted with acid into the 6a-fluoro-z1 ^{4> 9 (11)} -pregnadiene-17a, 21-diol-3.20-dione-17.21-diester VIII. By treating Compound VIII with a source of hypobromous acid, e.g. B. with N-bromo-acetamide in the presence of perchloric acid, the bromohydrin compound TLC is obtained, from which z. B. with potassium acetate the desired 6a - fluoro - 9 / 3.1 Iß - oxido - Δ ⁴ - pregnen-17a, 21 - diol - 3.20 - dione - 17.21 - diester III is obtained.

When the epoxy ring is opened with hydrogen fluoride, the 6a, 9a-difluorohydrocortisone-17,21-diesterX obtain. The double bond in the 1 (2) position can be converted into the compound X by known chemical processes be introduced, e.g. B. by exposure to selenium dioxide or preferably by use of dichlorodicyanobenzoquinone.

If the hydrofluorination and the 1 (2) -dehydrogenation are carried out in the reverse order, the 1 (2) double bond can also be introduced before the opening of the oxidation and thereby the starting material III, the 6a-fluoro-9 / ?, lljS- oxydo-J ⁴ -pregnen-17a, 21-diol-3,20-dione-17,21 -diester in the corresponding 6a - fluorine - 9jS, l Iß - oxydo-J ¹ - ⁴ -pregnadiene-17a, 21-diol -3,20-dione-17,21-diester transfer. The latter compound XI can then be treated with hydrogen fluoride and gives the desired 6a, 9a-difluorprednisolone-17,21-diester I.

The invention is illustrated by the following examples.

I. Preparation of 6a, 9a-Difluorprednisolon-

17-monoesters (Formula II)

A mixture of 1 g of 6a, 9a-Difluorprednisolon, 10 mg p-toluene-sulfonic acid, 5 cc of dimethylformamide and 3 cc Methylorthobutyrat is heated for 15 hours on an oil bath at 105 ⁰ C while a slow stream of nitrogen is passed through the mixture so that the methanol formed as a by-product is distilled off. After adding a few drops of pyridine to neutralize the acidic catalyst, the reaction mixture is evaporated in vacuo and a solid residue is obtained, which is taken up in methanol and filtered. The product is recrystallized from a mixture of methylene chloride and methanol and gives 6a, 9a-difluorprednisolone-17a, 21-methylorthobutyrate, mp 194 to 198 ° C, [α] ff = + 58 ° (dioxane, c = 0.5% ).

In the same way, 6a, 9a-difluorprednisolone-17a, 21-methyl-orthopropionate, melting point 215 to 219 ° C., [α] ff = + 64.5 ° (dioxane, c = 0.5%); 6a, 9a-Difluorprednisolon-17a, 21-methyl-orthoisobutyrate, mp 230 to 232 ⁰ C, [a] f = + 55.5 ° (dioxane, c = 0.5%) and 6aSa- Difluorprednisolon -17a, 21 - methyl - orthoacetate, F. (c = 0.5% dioxane) produced 217-219 ⁰ C, [a] f = + 69.5 °.

A suspension of 1 g of oa ^ a-Difiuorprednisolon-17a, 21-methylorthobutyrate in 10 ecm of methanol is treated with 2 ecm of an aqueous 2 η-oxalic acid solution and heated on a water bath at 40 to 50 ° C for about 5 to 10 minutes and the mixture then concentrated in vacuo. The residue is then shaken with water, the insoluble product is filtered off and then dried. The solid material is recrystallized from acetone / ether, and 6a, 9a-Difluorprednisolon 17-butyrate, mp 193-196 ⁰ C, [a] f = + 6.5 ° (dioxane, c = 0.5%) was obtained.

In the same way, 6a, 9a-difluorprednisolone-17-propionate, mp 212 to 215 ° C, [α] ff = + 9 ° (dioxane, c = 0.5%); 6a, 9u-Difluorprednisolon-17-isobutyrat, M. 219 to 221 ⁰ C, [α] ² / = + 7.5 ° (dioxane, c = 0.5%), and 6a, 9a-Difluorprednisolon-17-acetate , M.p. 218 to 222 ° C, [a] f = + 10.5 ° (dioxane, c = 0.5%).

^TT Production of 9β, iIß- Oxydo-6a-fluor1 ⁴ -pregnen-17a, 21 -diol-S ^ O-dione-17,21 -diester

(Formula III, R = R ¹ )

Esterification

10 g 1 ⁴ · ^9αυ - pregnadiene - 17a, 21 - diol - 3,20 - dione (... Prepared according to J. Am Chem Soc 79, pp 1130.1957) are mixed with 500 cc of acetic anhydride and 2.4 g of p -Toluenesulfonic acid treated and the mixture heated to 80 ° C for 1 hour under nitrogen. The acetylated product is then poured into ice water and the crystalline product obtained is filtered off, washed with water and recrystallized from a mixture of methanol and methylene chloride and 3.17 «, 21 - triacetoxy - j ³ · ⁵ · ⁹ ' ¹¹¹ - pregnatriene - 20 - one (compound VII), mp 176-184 ^C C (decomposition). Fluorination

6 g of this triester are dissolved in 330 ecm of dioxane with 35% water and ^{perchloryl fluoride is bubbled into the solution for 1} 1/2 hours at room temperature in order to carry out the fluorination in the 6-position. The excess perchloryl fluoride is expelled by passing a stream of nitrogen through the mixture and the product formed is precipitated by adding water, filtered off and washed with water. A mixture of the epimeric 6a and 6/3 fluoro derivatives is obtained which is converted into the 6a fluoro compound by dissolving the mixture in acetic acid, saturating the solution with anhydrous hydrogen chloride and allowing the mixture to stand overnight at room temperature.

Addition of hypobromous acid
and epoxidation

The acidic mixture mentioned is poured into ice water, and the product of 6a-fluoro-.J ^{49 <} n'-pregnadiene -17a, 21-diol-3.20-dione -17.21-diacetate (compound VIII) is filtered off and dissolved in 60 ecm anhydrous dioxane. 4.5 ecm of 0.46N perchloric acid and then 2.1 g of N-bromoacetamide are added to the solution obtained. The mixture is stirred for 2 hours and excess N-bromoacetamide is destroyed by adding 9 ecm of a 10% aqueous solution of sodium bisulfite. Pouring the mixture into ice water gives a precipitate which consists of 6a-fluoro-9a-bromo-hydrocortisone-17,21-diacetate (compound IX), which is dissolved in 80 ecm acetone after drying. 2 g of anhydrous potassium acetate are then added to this solution and the mixture is refluxed for 17 hours. The solvent is evaporated in vacuo and the residue is diluted with water and gives the desired 9 / 3.1 iß- Oxydo-6a-fluoro-J ⁴ - pregnen -17a, 21 - diol - 3.20 - dione -17.21 - diacetate (compound III), mp 223 ° C (decomposition).

The 17,21-dipropionate and the 17,21-dibutyrate of 9 / 3.11 / 3-oxydo-6a-fluoro-.J ⁴ -pregnen-17a, 21-diol-3,20-dione are prepared analogously.

III. Production of 9 / 9,11 / 3-Oxydo-6a-fluoro

l ⁴ -pregnen-17a, 21 -diol-3,20-dione-17,21-diester

(Formula III)

Ortho esterification and hydrolysis

A mixture of 20 g of J ⁴ · ⁹ ' ¹¹ ' -Pregnadien-17a, 21-diol-3,20-dione (prepared according to J. Am. Chem. Soc, Vol. 79, p. 1130; 1957), 200 mg p-Toluenesulfonic acid, 80 ecm of dimethylformamide and 30 ecm of methyl orthobutyrate is heated to 105 ° C. for 7 to 8 hours while a slow stream of nitrogen is passed through the mixture so that the methanol formed as a by-product is distilled off. After adding 1 ecm of pyridine to neutralize the acidic catalyst, the reaction mixture is concentrated in vacuo and the semisolid residue from an epimeric mixture of 17a, 21-orthobutyrates (compound V) is suspended in 200 ecm of methanol. This suspension is ECM 30 with a 2 treated n-oxalic acid solution in water and heated for a few minutes at 40 to 5O ⁰ C on a water bath to hydrolyze the Orthoester.

Esterification

The resulting mixture is then concentrated in vacuo, and the residue from 17a-Butyroxyl ^{4-9 <I1 |} Pregnadien-21-ol-3,20-dione (compound VI) is added with 500 ecm acetic anhydride and 2.4 g

109 542/378

Treated p-toluenesulfonic acid and heated ^{the mixture to 80 0 C under nitrogen for 1 hour.} The acetylated product is then poured into ice water and the crystalline product filtered off, washed with water and recrystallized from a mixture of methanol and methylene chloride and the 3,21-diacetoxy - 17a - butyroxy - j ³ - ⁵ - ^{9 (11)} - pregnatrien - 20 - one (compound VII) obtained.

By fluorinating the compound so prepared, treating it with hypobromous acid and epoxidizing it, as in II, the 9j3, II / J-Oxydo-6a-fluoro- ^{I 4} - pregnen - 17a, 21 - diol - 3,20 - dione - 17 - butyrate, 21-acetate (compound III) obtained.

In the same way, the 17-butyrate, 21-propionate, the 17-butyrate, 21-isobutyrate, the 17-isobutyrate, 21-acetate and the 17-isobutyrate, 21-propionate of 9β, 11β - oxydo - 6a - fluorine - J ⁴ - pregnen-17a, 21 -diol-3,20-dione.

example 1

A solution of 500 mg of 6a, 9a-Difluorprednisolon 17-butyrate (prepared according to I) in 2.5 cc of pyridine is treated with 1.25 cc of acetic anhydride and allowed to stand, the reaction mixture overnight at 0 C ^c. The reaction mixture is then poured into ice water and the crystalline precipitate formed is filtered off and recrystallized from a mixture of methylene chloride and ether and petroleum ether and 494 mg of 6α, 9α - Difluorprednisolon -17 - butyrate-21-acetate, mp 191 to 194 ° C, [ a] S * = + 31.7 ° (dioxane, c = 0.5%), UV: A _max 237 to 238 ma, EJ * _m = 320 (ethanol) obtained.

In the same way, 6a, 9a-difluorprednisolone-17-propionate-21-acetate, F. 229 to 232 ⁰ C. [α]? = + 30.5 ° (dioxane, c = 0.5%), UV: λ, _ηαχ 237 to 238 ΐημ, EJl = 326 (ethanol); 6a, 9a-difluorprednisolone-17-propionate-21-butyrate, mp 213 to 215 ° C, [α]? = + 36 ° (dioxane, c = 0.5%), UV: A _mox III to 238 Γημ, Ej * _m = 296 (ethanol); 6a, 9a-Difluorprednisolone-17-isobutyrate-21 _{-acetat, M.p.} ^{186 to 190 0} C, [a] F = + 29.5 ° (dioxane, c = 0.5%), UV: A 1110x 237 to 238 ηΐμ, Ε} * = 302 (ethanol); 6a, 9a-difluorprednisolone-17-acetate-21-butyrate, F. 246 to 248 ^Cl C, IaJf = +36 ^C (dioxane, c = 0.5%), UV: A _1110x 237 to 238 Γημ, E} * "= 321 (ethanol); and 6a, 9a-Difluorprednisolone-17,21-diacetate, m.p. 280 to 283 ° C, [a] F = + 31 ° (dioxane, c = 0.5%), UV: ?. _max 237 to 238 Γημ, egg * _m = 328 (ethanol) made.

Analogously, by treating 6a, 9a-difluorprednisolone-17-butyrate with propionic anhydride in pyridine 6α, 9α-difluorprednisolone -17-butyrate-21-propionate from mp 198 to 201 ⁰ C, [a] f = + 33 ° (dioxane , c = 0.5%), UV: X _max 237 to 238 ma, EJ * = 322 (ethanol).

In the same way, 6a, 9a-difluorprednisolone-17,21-dipropionate, mp 227 to 231 ° C, [o] f = +33 ^: (dioxane, c = 0.5%), UV: A _1110x 237 to 238 πΐμ, EJ * _m = 290 (ethanol), and 6a, 9a-difluorprednisolone-17-isobutyrate-21-propionate, mp 208 to 212 ° C, [a] F = + 32 ° (dioxane, c = 0.5 %), UV: X _max 237 to 238 Γημ, EJ * = 298 (ethanol).

Example 2

A solution of 500 mg 6a, 9u-difluorprednisolone-17-butyrate in 2.5 ecm pyridine is treated with 1.25 ecm isobutyric anhydride and the reaction mixture is left to stand at ⁰ ° C. overnight. By working as in the esterification stage in Example 1, 6α, 9α-Difluorprednisolon-17-butyrat-21-isobutyrat from MP 223 to 225 ° C, [α] if = + 33 ° (dioxane, c = 0.5%) , UV: A _1110x 237 to 238 Γημ, Eu = 302 (ethanol). In an analogous manner, treatment of 6α, 9α-difluorprednisolone -17-butyrate with butyric anhydride in pyridine gives 6a, 9a-difluorprednisolone-17,21-dibutyrate; F. 208 to 211 ° C, [α] »= + 32.5 ° (dioxane, c = 0.5%), UV: X _max 237 to ίο 238 ηΐμ, Eil = 287 (ethanol).

Example 3 Hydrofluorination and 1 (2) dehydrogenation

A solution of Ig 9 / j, ll / i-Oxydo-6a-fluoro-J ⁴ - pregnen - 17 _a , 21 - diol - 3.20 - dione -17.21 - diacetate (obtained according to II) in 10 ecm anhydrous of chloroform is cooled to -5o ⁰ C and a solution of 5.2 cc of tetrahydrofuran and 5 of a solution of 2 parts 1 part of hydrogen fluoride in tetrahydrofuran ECM treated. The reaction mixture formed is kept at -25 ° C. for 4 hours and then poured into a mixture of 33 g of anhydrous potassium carbonate, 120 ecm of ice water and 70 ecm of chloroform.

The aqueous phase is extracted with chloroform and the organic layer with water until neutral washed. After the washing water has been separated off and the solvent has evaporated in vacuo the residue taken up with ether and the ether filtered off, whereby 6α, 9α - difluorohydrocortisone-17,21-diacetate (Compound X) remains.

A solution of 500 mg 6a, 9u-difluorohydrocortisone-17,21-diacetate and 350 mg of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone in 5 ecm of anhydrous dioxane is refluxed for 24 hours, then the solvent is removed in vacuo and the The residue was taken up with methylene chloride. The crystalline dichlorodicyanohydroquinone is filtered off and the solution is chromatographed on 10 g of aluminum oxide. Eluting with methylene chloride becomes the 6α, 9α - Difluorprednisolon - 17,21 - diacetate, mp 280 to 283 ° C, obtained with the in Example 1 obtained product is identical.

In the same way, 6a, 9a-difluorprednisolone-17,21-dipropionate, F. 227 to 23 Γ C, and 6a, 9a-Difluorprednisolon-17,21-dibutyrat, Mp 208-211 ° C.

Example 4 1 (2) dehydrogenation and hydrofluorination

By treating 9 / i, ll | 8-oxydo-6a-fluoro- ^{I 4} - pregnen - 17a, 21 - diol - 3.20 - dione -17.21 - diacetate (compound IH) with dichlorodicyanobenzoquinone according to that in Example 3 The procedure mentioned is the corresponding 9β, 11/5-Oxydo- 6a - fluoro-J ^l - ⁴ -pregnadien-17a, 21-diol-3,20-dione-17,21-diacetate (compound XI) obtained and to 6α, 9α-Difluorprednisolone-17,21-diacetate (Compound I) converted by treatment with hydrogen fluoride as according to the hydrofluorination step of Example 3.

Example 5

1 (2) -Dehydrogenation and Hydrofluorination By treating the 9ß, \ lß- Oxydo-6a-fluorine

y tats (compound III) with dichlorodicyanobenzoquinone

according to Example 3, the corresponding 9 / i, ll / i-Oxydo-6a-fluoro-J ^K4 -pregnadien-17a, 21-diol-3,20-dione-17-butyrate, 21-acetate (compound XI) is obtained and by treatment with hydrogen fluoride according to the hydrofluorination stage of Example 3 to 6a, 9a-Difluorprednisolon-17-butyrate-21-acetate, mp 191 to 194 C, converted.

- By working according to this procedure, the following compounds are obtained: 6a, 9a-Difluorprednisolon-17-butyrate-21-propionate, mp 198 to 201 ° C; 6α, 9α - difluorprednisolone - 17 - isobutyrate-21-acetate, mp 186-190 ° C; 6a, 9 ″ -Difluorprednisolone-17-isobutyrate-21-propionate, mp 208-212 ° C; 6 ', 9 "- Difluorprednisolon -17.21 - dibutyrate, F. 208 to 211 ^c C and 6a, 9a - Difluorprednisolon -1 7 - butyrate 21-isobutyrate, F. 223-225 ° C.

Example 6

There is an ointment of the following composition for external use according to the usual pharmaceutical procedure.

Components Weight percent Distilled water
Benzyl alcohol
Liquid paraffin
White soft paraffin 5.00
0.50
20.00
68.95

Components Weight percent ou ^ a-Difluorprednisolon- 17-butyrate-21-acetate 0.025 Beeswax 5,000 Anhydrous lanolin 5,000 White soft paraffin 20,000 Ointment base (known under the Trade names Amphocerin K; Dehydag, Deutsche Hydrierwerke GmbH, Düsseldorf) 25,000 Liquid paraffin 14,900 Distilled water 30.075

The beeswax, lanolin, white soft the Paraffln and the liquid paraffin are melted at 70 ⁰ C, the active ingredient is added and then added to the mixture of "Amphocerin K" and water. It gets refined twice.

In the same way, other ointments are made in which the oa ^ a-Difluorprednisolon-n-butyrate-21-acetate is replaced by one of the following compounds:

6a.9ee-difluorprednisolone-17-propionate-21-acetate,

oa ^ ct-Difluorprednisolon-17-isobutyrat-21-acetate,

6u, 9a-Difluorprednisolon-17,21 -diacetate,

6a, 9 (z-Difluorprednisolone-17-butyrate-21-isobutyrate.

Example 7

An ointment for external use of the following composition is prepared:

Components Weight percent oti ^ u-Difluorprednisolon-
17-butyrate-21-acetate
Cetyl alcohol
Anhydrous lanolin 0.05
0.50
5.00

Cetyl alcohol and benzyl alcohol are melted, the liquid paraffin and the white soft paraffin added at 75 ° C, the active ingredient and then the lanolin previously mixed with water added. It gets refined twice.

Other ointments are produced in the same way, the 6α, 9α - Difluorprednisolon -17 - butyrate-21-acetate is replaced by one of the following compounds:

oa ^ a-Difluorprednisolon-n-propionate-

21-acetate,
oa ^ a-Difluorprednisolon-n-isobutyrat-

21-acetate,

6a, 9a-Difluorprednisolone-17,21 -diacetate,
6a, 9a-difluoroprednisolone-17-butyrate-

21-isobutyrate.

Example 8

A cream for external use is made of the following composition:

Components

6a, 9a-Difluorprednisoion-

17-butyrate, 21-acetate,

"Propylparaben" (trade name for

p-hydroxybenzoic acid propyl ester)
»Methylparaben« (trade name for

p-hydroxybenzoic acid methyl ester)

Sodium lauryl sulfate

Propylene glycol

Stearyl alcohol

White soft paraffin

Liquid paraffin

100% distilled water

Weight percent

0.025
0.015

0.025
1,000
12,000
15,000
12,500
22,500

Stearyl alcohol and the white soft paraffin are melted on a steam bath and reduced to about Heated to 75 ° C, a solution of the active ingredient in propylene glycol was added and then the other ingredients, which were previously dissolved in water and heated to 75 ° C, added. The mixture will stirred until it gels.

In this cream, sodium lauryl sulfate can be made up of polyoxyl 40 stearate, which is a mixture from mono- and diesters of stearic acid with a polyoxyethylene diol mixture and the corresponding Parts of glycols, the polyoxyethylene chain containing an average of about 40 oxyethylene units (cf. Remington's Pharmaceutical Sciences, Verlag Mack, p. 1426), replaced in an amount of 5 percent by weight will.

In the same way, other creams can be produced, the 6a, 9a-Difluorprednisolon-17-butyrat-21-acetate is replaced by one of the following compounds:

oa ^ a-Difluorprednisolon-n-propionate-

21-acetate,
oa ^ a-Difluorprednisolon-n-isobutyrat-21-acetate,

6a, 9a-Difluorprednisolone-17,21-diacetate, öa ^ a-Difluorprednisolone-17-butyrate-21-isobutyrate.

Example 9

A cream for external use of the following composition is prepared:

Components

6a, 9a-Difluorprednisolone-17-butyrate-21 -propionate

Cetostearyl alcohol

White soft paraffin.

Liquid paraffin

Isopropyl stearate

Propylene glycol

"Methyl paraben"

"Propyl paraben"

Tween 80 (trade name for sorbitol anhydrides partially esterified with fatty acids)

Polyethylene glycol 6000

Distilled water

Percent by weight of 21-acetate replaced by one of the following compounds will:

6a, 9a-Difluorprednisolon-17 ~ propionate-

21-acetate,
6ct, 9a-Difluorprednisolon-17-isobutyrat-21-acetate,

oa ^ a-Difluorprednisolon-n ^ l-diacetate, oa ^ a-Difluorprednisolone-17-butyrate-21-isobutyrate.

Example 11

An eye ointment is made of the following composition:

0.050 12.000 6.480 6.480 3.240 3.240 0.180 0.050

0.200

4,950

63,130 components

6a, 9a-Difluorprednisolone-17-butyrate-21-acetate ...

Liquid paraffin

White soft paraffin.

Weight percent

0.025 29.975 70.000

The cetostearyl alcohol, white soft paraffin which, the liquid paraffin and isopropyl are melted at about 70 ⁰ C, was added a solution of the active ingredient in propylene glycol and then the previously mixed with water and added, heated to 70 ° C ingredients. It gets refined twice.

Other creams are produced in the same way, with the 6α, 9α - Difluorprednisolon -17 - butyrate-21-propionate is replaced by one of the following compounds:

6a, 9a-Difluorprednisolon-17,21-dipropionat, oa ^ a-Difluorprednisolon-n-isobutyrat-

21-propionate,
6a, 9a-Difluorprednisolone-17,21-diacetate, 6a, 9a-Difluorprednisolone-17,21-dibutyrate.

Example 10

An ointment for external use is made with the following composition:

The active product is added to the other ingredients which were previously sterilized by heating at 12O ⁰ C for 1 hour. It is refined twice and filled into sterile tubes.

Other eye ointments are produced in the same way, the 6α, 9α - Difluorprednisolon-17-butyrat-21-acetate is replaced by one of the following compounds:

6a, 9a-difluorprednisolone-17-propionate-

21-acetate,
6a, 9a-difluorprednisolone-17-isobutyrate-21-acetate,

oa ^ a-Difluorprednisolon-n ^ l-diacetate, 6a, 9a-Difluorprednisolone-17-butyrate-21-isobutyrate.

Example 12

An ointment is made for external use of the following composition:

Components

Components

6a, 9a-Difluorprednisolone-17-butyrate-21-acetate ...

Pure cholesterol

Stearyl alcohol

White soft paraffin.
Liquid paraffin

Weight percent 6a, 9a-difluorprednisolone-17-butyrate-21-acetate ...

Pure cholesterol

Stearyl alcohol

White soft paraffin.
Liquid paraffin

Weight percent

0.025

3,000

8,000

51.075

37,900

0.1

3.0

8.0

51.0

37.9

The active ingredient is added to the other ingredients that were previously heated to 75 ° C and the mixture was stirred until it gelled.

Other ointments are produced in the same way, the 6α, 9α-Difluorprednisolon-17-butyrat-Die Production takes place according to Example 10.

Other ointments are produced in the same way, the 6α, 9α - Difluorprednisolon - 17 - butyrate-21-acetate is replaced by one of the following compounds:

6a, 9a-difluorprednisolone-17-propionate-

21-acetate,
oa ^ a-Difluorprednisolon-n-isobutyrat-21-acetate,

6a, 9a-Difluorprednisolone-17,21-diacetate, 6a, 9ct-Difluorprednisolon-17-butyrat-21-isobutyrat.

15th

example

A lotion is produced with the following composition.

Components

Components

6 ", 9" -Difluoroprecinisolone-17-butyrate-21-acetate ..

Ethyl alcohol 95 ^;

Propyienglykoi

Distilled water ...

Weight percent

Propyienglykoi

Stearyl alcohol

White soft paraffin

100% distilled water

Weight percent

12,000
25,000
25,000

0.03 50.00 20.00 29.97

The active ingredient dissolves in alcohol and becomes a clear mixture of the other ingredients added.

Other lotions are made in the same way, where the öa ^ a-difluorprednisolone-n-butyrate-21-acetate is replaced by one of the following compounds:

6a, 9u-Difluorprednisolon-17-propionat-

21-acetate, öa ^ a-difluorprednisolone-n-isobutyrate-

21-acetate,

öa ^ q-Difluorprednisolon-n ^ l-diacetate, öuita-Difluorprednisolon-n-Butyrat- ^ l -isobutyrat.

Example 14

A lotion of the following composition is made:

Components

j weight percent

o ", 9" -difluorprednisolone-17-butyrate-21-propionate

Ethyl alcohol 95 °

Glycerin

Propyienglykoi.

Distilled water

0.05 40.00 10.00 30.00 19.95

The production takes place according to the example

Other lotions are produced in the same way, with oa ^ a-Difluorprednisolon-n-Butyrat-21-Propionat is replaced by one of the following compounds:

6 ", 9rt-Di1uorprednisolon-17,21 -dipropionat, 6a.9a-difluorprednisolone-17-isobutyrate-21-propionate,

6a, 9a-Difluorprednisolone-17,21 -diacetate, 6ci, 9a-difluoroprednisolone-17,21-dibutyrate.

example

A hydrophilic ointment is made of the following composition:

The stearyl alcohol and white soft paraffin are melted on a steam bath and heated to about 75 ° C, is added a solution of the active ingredient in Propyienglykoi and then the other components which were previously dissolved in water and heated to 75 ⁰ C added. The mixture is stirred until it gels.

In this hydrophilic ointment, the sodium lauryl sulfate can be replaced by "polyoxyl-40-stearate" in one Amount of 5 percent by weight to be replaced.

Hydrophilic ointments are produced in the same way, the 6a, 9a-Difluorprednisolon-17-butyrate-21-propionate is replaced by one of the following compounds:

6a, 9a-difluorprednisolone-17,21-dipropionate,
6 «, 9a-Difluorprednisolon-17-isobutyrat-

21-propionate,

oa ^ a-Difluorprednisolon-17,21 -diacetate,
6a, 9a-difluoroprednisolone-17,21-dibutyrate.

Example 16

Tablets of the following composition are made:

6 ", 9a-Difluorprednisolon-

17-butyrate-21-acetate 2.000 mg

Lactose, spray dried 97,500 mg

Calcium stearate 0.500 mg

The spray-dried lactose is passed through a 60 mesh British Standard sieve (sieve opening 0.251 mm). The active ingredient is dissolved in about 0.03 ecm of ethyl alcohol 95 °. The clear one Solution is added to the sieved lactose, mixed well and the solvent at room temperature evaporated in the usual way. The calcium stearate is added to the dried mass, mixed again and pressed into tablets of 6 mm diameter with two-part punches.

Eg 1 17

Tablets of the following composition are made:

6a, 9a-difluoroprednisolone-17-butyrate-

21-acetate 0.2 mg

Lactose, spray dried 99.3 mg

Calcium stearate 0.5 mg

Production takes place as in example 16.

55

Components

6 ", 9" -difluorprednisolone-17-butyrate-21 -propionate

"Propyl paraben"

"Methyl paraben"

Sodium Laurel Sulphate

60

Weight percent

0.025 0.015 0.025 1.000 Test report

An experiment was carried out with a number of compounds according to the invention on female Wistar rats according to A. Robert and J. E. N e ζ a m i s in Acta End. 25, p. 105 (1957), where the effect of steroids in preventing an inflammatory process caused by croton oil was determined. The rats were up

109 542/378

the back was shaved and 25 ml of air was injected into the center of the back with a 26 mm needle. Then 0.5 ml of a 1% solution of croton oil in corn oil was injected into the air sac. The steroid compounds were put into the airbag on the 5th day

The following values were obtained:

cavity injected in sesame oil solution. On day 10 the rats were sacrificed and the exudate collected and measured, the volume of exudate being inversely proportional to the anti-inflammatory effect the trial connection is.

link Single dose
μΜ Body,
at first weight
at the end Exudate
ml Comparative experiment 163 183 14.3 ± 2.20 6a, 9a-difluoroprednisolone-17-butyrate-
21-acetate 0.01
0.1 163
163 171
176 5.8 ± 0.81
4.9 ± 1.02 oa ^ a-Difluorprednisolone-n-butyrate-
21-isobutyrate 0.01
0.1 166
161 182
169 6.6 ± 1.00
5.7 ± 1.14 oa ^ a-Difluorprednisolone-17,21-dipropionate 0.01
0.1 161
161 182
179 10.8 ± 1.75
11.1 ± 1.31 oa ^ a-Difluorprednisolone-17,21 -diacetate 0.01
0.1 166
166 185
183 12.0 ± 1.80
8.8 ± 1.43 6 «.9> i-Difluorprednisolone-17-isobutyrate-
21-acetate 0.01
0.1 165
169 179
174 7.3 ± 0.90
5.1 ± 0.80

It turns out that the compound 6a, 9a-difluorprednisolone-17-butyrate-21-acetate is the most effective.

Claims (3)

Claims: 1.6a, 9 <z-Difluorprednisolon-17,21-diester of the general formula CH ₂ O-CO-R ¹ HO CO
- O — CO — R in which R and R ^{1 are} lower alkyl radicals having 1 to 3 carbon atoms. 2. 6a, 9a-Difluorprednisolone-17-butyrate-21-acetate. 3. Agent containing 6a, 9o-Difluorprednisolonverbindungen according to claim 1 or 2 in addition to the usual pharmacologically acceptable carriers and / or auxiliaries.