DE1668857C - 6 alpha, 9 alpha difluorprednisolone 17 valerate 21 acetate - Google Patents

Description

The invention relates to a new and useful steroid derivative with improved anti-inflammatory properties Effect that is particularly relevant to the use of drugs for the external treatment of Inflammation is suitable. The invention relates to

O = also drugs that contain the compound as an active component.

The new steroid derivative according to the invention is the n-valerate-21-acetate of 6n, 9ii-Dinuorpredni lon of the following structural formula:

CH ₁ -OCOCH,

en

ι.-. I.

■ -Ο —CO —CH, -

The connection made by the simultaneous presence of the valeryl residue in the 17-position and the acetyl group is marked in the 21-position ,. shows anti-inflammatory properties for comparison with the well-known 6 «, 9ii-Difluotprednisolon and its 21-acetate are particularly high.

Because of these special properties, n-valerate-21-acetate is 6 ", 9" -difluorprednisolone useful for the treatment of inflammation centers and diseases, especially when it is external is applied.

The compounds according to the invention contain the active steroid in intimate admixture with one suitable carrier or excipient and can be in solid, semi-solid, liquid or viscous form. The active ingredient can e.g. B. with the usual carriers for powders, ointments, skin lotions, Creams, emulsions, aqueous suspensions and other forms of application be mixed, which is particularly are suitable for use in dermatology. The carriers used are those that have already been proposed for use in the manufacture of external preparations such as e.g. B. Fats of animal origin and vegetable oils, saturated or unsaturated fatty acids, aluminum stearate, Alcohols, polyalcohols, such as. B. glycerine, propylene or polyethylene glycols, waxes, aliphatic Hydrocarbons or lanolin, along with relatively large amounts of water. Other Carriers that can be used are hydrophilic

CH ₂ OH

HO

O = *

Bases. Cholesterol. Hydroxycholesterol, petrolatum, vuseline oil, Silicone greases that are physiologically inert. Sodium alginate and also stabilizer. Thickening and Dyes and perfumes. The preparations according to the invention can also contain preservatives or contain bacteriostatic agents, e.g. B. Esters of p-hydroxybenzcesäure, d. H. Methyl, ethyl or propyl p-hydroxybenzoate, mercury derivatives, such as B. the merthiolate or quaternary ammonium derivatives, such as. B. Cetyltrimethylammonium bromide. that in addition to a surface activity, a good bacteriostatic one Shows effect.

The 17-valerate-21-acotate of 6 ", 9fi-difluorprednisolone is present in the medicaments according to the invention in an amount which is sufficient to produce the desired exert a therapeutic effect on the inflammatory focus or process. Preferably contain the Drug the active ingredient in an amount of from 0.0005 to 5 percent by weight, preferably in an amount of 0.005 to 0.5 percent by weight.

The 17-valerate-21-acetate of 6 ", 9f (-difluorprednisolone can be obtained in a three-step process by reacting the corresponding free 17 ((, 21-diol with a lower alkyl orthovalerate ester in the presence of an acidic catalyst, the resulting \ lu. 21-orthovalerate hydrolyzed and the 17-monovalerate of 6ri, 9n-dif1uorprednisolons formed aeylated according to the reaction scheme

CH ₂ O

OR

CH ₂ OH

ti

wherein R is a lower alkyl group, preferably a methyl group.

The ortho-esterification is carried out at a temperature in the range from 60 to 130 ° C., preferably around 100 to 1 crazy. carried out for 8 to 24 hours, wherein

0-CO-C ₄

the 17a, 2l-orthovalerate of the formula III as a mixture 65 is formed by two epimeric orthoesters. The orthovalerate obtained is then hydrolyzed with a mineral acid or organic acid to 17-Monovalerate IV. This connection is

nut \ * can ie
the
Uiuteri.

ml of the 21-OH group is esterified by treating iüsäureanhydrid in pyridine correspondingly at \ 'ci drive.
The following examples

example 1

f £ i, i mixture of 1 g oc.O.i-difluorprednisolone.

3 cnv of metin orthovalerate and 10 mg of p-toluenesulfonic acid in 5 cm ^{3 of} pyridine are kept overnight under nitrogen at a temperature of 105 ° C. (outside temperature). After adding a few drops of pyridine, the solvent is evaporated in vacuo. The back wall is taken up with methanol and filtered. The 17a.21- (l'-methoxy) -n-pentylidenedioxy- f, n})> - difluoro - I ¹ · ⁴ - pregnadiene - 11 /; - Oil - 3.20 - Dione is obtained as a mixture of epimeric compounds and is ^{suspended in 10 cm 3 of} methanol without further purification and for a few minutes on a water bath at ^{4li to} 50 ° C. with an aqueous solution of 2N- ' ^: Caicic acid in an amount of 0.5 cm ³ heated. The mixture is concentrated in vacuo. The residue is mi. Shaken water, the insoluble product filtered off and dried, the product melting at 176 to 179 C after recrystallization from acetone / ether. The 6 <i, 9rf-difluorprednisolone-17-valerate is dissolved in 80 cm ^{1 of} pyridine and

4 im ^: suspended in liquid anhydride and im! 5 to ^c C held. The mixture is poured into Eisv.a, scr and the precipitate is filtered and extracted from Aiii '.' Petroleum ether crystallizes, the 6u.9 <i-üiiluo; prednisolone-17-valerate-21-acetate being obtained in a yield of 75%. F. 204 to 206 ⁰ C. ["] '■; = + 30 '± T (dioxane, c = 0.5%).

Example 2

40

Fiine ointment of the following composition for external use is prepared according to standard pharmaceutical manufacturing processes:

Components

6 (/, 9. (- Difiuorprednisolon-17-valerate-21-acctat

Beeswax

Anhydrous lanolin

White, soft paraffin

»Amphocerin! (« (Trade name for a Ointment base from Dehydag, Deutsche Hydrierwerke GmbH, Düsseldorf)

Liquid paraffin

Distilled water

Weight percent

0.10

5.00

5.00

20.00

25.00 14.90 30.00

Example 3

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

Components

6.,. 9n-Difluorpredniselon-17-valerai-

21-acetate

C'etylakohol

Anhydrous lanolin

Distilled water

Benzyl alcohol

Liquid paraffin

White, soft paraffin

Weight percent

0.05

0.50

5.00

5.00

0.50

20.00

68.95

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

Example 4

It becomes a hydrophilic ointment of the following composition manufactured:

Components

ou ^ ii-Difluorprednisolone-n-valerate-21-acetate

»» Piupylparaben «(IIandcisnarK.!. 'For Hydroxybenzoic acid propyiester).

»Methylparaben« (trade name for methyl hydroxybenzoate) ·

Sodium lauryl sulfate

Propylene glycol.

Stearyl alcohol

White, soft paraffin

100% distilled water

Weight percent

0.300 0.015

0.025

1,000

12,000

25,000

25,000

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

In this hydrophilic ointment, sodium lauryl sulfate can be replaced by polyoxy-40-stearate in an amount of 5 percent by weight.

Example 5

A cream of the following composition is made:

60 components

The beeswax, lanolin, the white, soft paraffin and the liquid paraffin are made at 70 ° C. melted, the active ingredient added and then the mixture of »Amphocerin K« and Water. It gets refined twice. ori ^ fi-Difluorprednisolon-17-valerate-

21-acetate

Cetostearyl alcohol White, soft paraffin Liquid paraffin

Isopropyl stearate

Weight percent

0.050 12.000 6.480 6.480 3.240

1 668 357

5
continuation

Components

Propylene glycol

"Methyl paraben"

"Propyl paraben"

»Τween 80« (trade name for partially polyoxyethylene derivatives of sorbitan hydrides esterified with fatty acids)

Polyethylene glycol 6000

Distilled water

per / unl

3.240 0.180 0.050

0.200

4,950

63.130

Components Weight
percent 6f (, 9 "-difluorprednisolone-17-valerate-
21-acetate. . 0.3
3.0
8.0
51.0
37.7 Pure cholesterol
0 +,. ,, .... 1,, 1I- ^ U ^ ₁ I
οιι, αι jriaiKciiOi
White, soft paraffin
Liquid paraffin

The active ingredient is added to the other ingredients, which are previously melted to 75 ° C were, and di; Mixture stirred until solidification.

Example 7

A cream of the following composition is made:

Components

of / ^ rz-Dirluorprednisolon-n-valerate-21-acetate

"Propyl paraben"

"Methyl paraben"

Cetyltrimethylammonium bromide

Propylene glycol

Stearyl alcohol

White, soft paraffin

Liquid paraffin

Distilled water

Weight percent

0.025

0.015

0.025

1,000

12,000

15,000

12.775

22,500

36,660

The stearyl alcohol, the white, soft paraffin and the liquid paraffin are melted at 75 ° C, a solution of the active ingredient in propylene glycol is added and then the other ingredients, which were previously mixed with the water and heated to 75 ° C, added. It will be twice refined.

Example 8

An eye ointment of the following composition is prepared:

Components

6 - (, 9, «- Difluorprednisolon-17-valeral-

21-acetate

Liquid paraffin

White, soft paraffin

<icuichiv priceless

0.025 29.975 70.000

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

Example 6

An ointment of the following composition is made:

The active ingredient is added to the other ingredients previously prepared by heating to 120 ° C 1 hour sterilized wan. *; It gets refined twice and filled into sterile tubes.

Example 9

A skin water with the following composition is made:

Components

6 «, 9f (-Difluorprednisolone-17-valerate-21-acetate

Ethyl alcohol, 95 ° C

water

cologne

Weight·"- percent

0.4 40.0 59.0

0.6

The active product is added to a clear mixture of the other ingredients.

Example 10

A skin water with the following composition is made:

Components

Weight pro / ent

6r (, 9-i-difluoroprcdnisolone-17-valerate-

21-acetate 0.03

Ethyl alcohol, 95 ° C 50.00

Propylene glycol 20.00

Distilled water 29.97

The active product is dissolved in the alcohol and becomes a clear mixture of the other parts of the mixture added.

Example 11

A skin water with the following composition is prepared:

Components

6ii, 9fi-Difluorprednisolone-l7-valerate-21-acetate

Ethyl alcohol, 95 ° C

Glycerin

Propylene glycol

Distilled water

Weight percent

0.05 40.00 10.00 30.00 19.95

The production takes place according to example 10.

Claims (2)

Patent claims: 1. 6 «, 9r <-Difluorprednisolone-17-valerate-21-acetate. 2. Agent containing one-n-difluorohydrocortisone-17-valerate-21-acetal in addition to the usual inert and physiologically acceptable carriers and / or auxiliaries.