DE1618028A1 - Process for the preparation of methylacyloxymethyl ketals from prednisolone derivatives with 3 to 5 carbon atoms in the acyl group - Google Patents

Description

The present invention relates to a method for Production of methyl acyl oxyinethylketal en from Prednisolonderi «* vaten with 3-5 carbon atoms in the acyl group.

■■ "" ^: "; - Γ ■ -. - :. ■ ■ j It is known that alkyl acyl oxy alkyl ketals from Prednisolönderi-

'.- ■ ^: ■''-■■' ■■ - - · - '■ ■■ -' ■■ -. "■" ■ "■ ν - i

to produce fathers. These connections show a good j

anti-inflammatory effect, especially when the acyl group

Contains 1-2 carbon atoms. Try other acetals and ketals have shown that the number of carbon atoms in the acetal · and ketal- group should be low. Methylacyloxymethyl ketals better known Art are, inter alia, in English Patent No. 1 020 309 and the Belgian patent 660 5 ^ 9.

00984A / 1793

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iew. SKCHTZIEtMSNCHm

A lengthy research has surprisingly and im In contrast to usual experiences with acetals and ketals from cortisone derivatives according to the invention show that a higher Number of carbon atoms in the acyl group of the ketal has an apparently improved anti-inflammatory effect in relation to that gives anti-inflammatory effect, which is obtained with ketals according to the patents mentioned. The number of carbon atoms in the The acyl group should be at least 3 and at most 5.

The compound of the present invention has the following general formula:

HO

- O - C - R,

00984V / 1793

where IL is an alkyl group _t has at least 3 carbon atoms and at most 5 carbon atoms, in which P denotes fluorine and X denotes hydrogen or fluorine,

Only one example is given for the preparation of the compounds that fall under the above formula »da. the other connections can be made in exactly the same way »
example 1

. ₆ iiinex ^ suspension of 300 mg of triameinolone in 7.5 ml of dioxane ('dried and redistilled) 2.5 g of caproyloxyacetone and 25 ^{% of 75:} 5% perchloric acid are added. The reaction device is stirred for 5 hours at 20-30 ° C. in a nitrogen gas atmosphere. Gradually a homogeneous acidic solution is formed, which is neutralized to pH 6.5 with 5% sodium bicarbonate solution. The solution is extracted with chloroform, after which the chloroform layer is dried and evaporated in vacuo. The reaction product is uracrystallized from approx. 10 ml of a mixture of ethyl acetate and ligroin in the ratio i: i. The Triaincinolonkaproyloxyazetonid is obtained with a yield of $ 82 and a melting point of 229 -

The following table shows the melting points of the Connections emerge under the previous general Fall formula.

-3 -

009844/1793

Table 1

Corticosteroid derivatives according to R. X SclinieΙζχ) item formula C above

Triamciholonbutyroyloxyazetonide Triamcinolone valeroyloxyazetonide triamcinolone caproyloxyazetonide

Triameinolori-3,3, dimethylbutyroyloxyazetonide

Fluocinolone valeroyloxyacetonide

C ₃ Ii ₇ II 218 - 220 II 210 - 215 ^C 5 ⁿ il II 229 - 230 C ₅ Ii ₁₁ II 207 - 209 Fl 108 - 110

The anti-inflammatory effect of the substances in Table 1 is with Triamcinolgnacetyloxyaze $ iid according to the above Patents by the granuloma test, see Experientia 6, 1950, pp 469-471, on adrenalectomized mice, i.e. mice with removed adrenal glands. This has been carried out on two groups of test animals. The one In the animal group, one of the corticosteroids according to Table 1 was administered subcutaneously, while the other group served as controls. Thereafter, the weight increases of the "cott.onpellets" used in the animals that received corticosteroid with the Compared animals not receiving corticosteroid treatment. The results in the experiments mentioned will be summarized in the following table:

BAD ORIGINAL 0 9 8 4 4/1793

Tabel

No.. Corticosteroid Daytime
dose
in mg Anasahl
animals Granuloma weight
% of the granuloma
weight of ver
search bulls. 1 Triamcinolonaeetyloxyacetonld IQ 48 69 2 Triamcinolone butyroyloxyacetonide 10 8th 67 3 Triamc inolone valeroyloxyacetonide 10 •8th 5Q 4th Triamcinolone caproyloxyacetonide 10 8th 64, 5 Triameinolone *} * 3-dimethylbutyroyl-
Qxyacetonide " 10 6th Fluocinolone valeroyloxyacetonide 10 .8th 62 7th Triame iholon.acetyloxyace tonid 3.3 36 85 8th Triamcinolone butyroyloxyacetonide 3.3 a 87 9 Triamcinolone valeroyloxyacetonide 3.3 24 ; ^: - 73 ';. 10 Triamc inolonkaproyloxyacetonid 3.3 16 82 11th Triamcinolone - ^^ - ciinietylbutyroyl-
oxyacetonide 3.3 8th 99 12th Fluocinonone valeroyloxyacetonide 3.3 16 ; 75

From the foregoing it is clear that the Valeroyloxyacetonide in relation to the other compound products have a demonstrably better anti-inflammatory effect <.

Claims (4)

Claims Process for making compounds with the formula: 21 CH ₂ -OH HO in which R, is an alkyl group, and in which P is fluorine and X is hydrogen or fluorine, characterized in that a cortisone derivative with the hydroxyl groups in positions 16 and 17 forms a whole acetal with a methylacyloxymethyl ketone with the following formula: - IL ₁ in which R has at least 3 C atoms and at most 5 C atoms, for React brings. 2. The method according to claim 1, characterized in that that the reaction takes place at low temperature. 3. The method according to claim 1, characterized in that that the derivative used from 9 "-Pluor-löOf -Hydroxyprednisolon consists, 4. The method according to claim 1, characterized in that that the derivative of 6Of, 9Oi, - Difluor-loÄ-Hydroxypredniaolon consists. 0 09844717 9 3