DE1568924B - Proscillaridine ketals and process for their preparation - Google Patents

Description

O = C

R ₁

wherein in each case R and R _{1 represent} methyl or ethyl radicals, is reacted in a manner known per se.

Proscillaridin has recently gained considerable importance as a therapeutic agent for the treatment of heart failure attained. Compared to the previously known cardiac glycosides, it is interesting in several respects Properties on.

The rate of absorption of proscillaridin after oral administration is 35%. It therefore seemed interesting Attempts to further increase the portion of the dose transferred into the bloodstream. As far as this chemical changes of the glycoside molecule came into question, offered due to the Prior art suggests two basic approaches.

The first option is to esterify any hydroxyl groups present in the molecule with acetic acid. According to the findings of R. M e g e s and K. R e ρ k e (Naunyn Schmiedebergs Archiv der Experimental Pathologie, 241, 534 [1961]) resulted in an improved absorption of proscillaridine expected with full preservation of the cardiac effectiveness.

The second possibility concerns the conversion of hydroxyl groups of the glycoside sugar with ketones with the formation of ketals. In the case of acetonides of proscillaridine, according to the scanty literature with a slight increase in resorption, but also with a limitation of the cardiac effects can be expected because the improved resorption rate overcompensates for the loss of effectiveness (K. Linger, K. Irmscher, W. Küssner, R. Hotovy, J. Gilliss en, Drug Research, 13, 142 [1963]). Surprisingly, it turns out just the opposite. The Proscillaridin triacetate shows a considerable reduction in cardiac efficiency, while proscillaridin acetonide does at about half the effectiveness has a double rate of absorption.

Table 1

toxicity Toxicity. Enteral sea
piggy cat Absorption intravenous intravenous cat mg / kg mg / kg % Proscillaridin ... 0.447 0.214 34 Proscillaridin Acetonide 0.445 0.429 77 Proscillaridin Triacetate 3.5 - -

·

On the other hand, it was to be expected that

Proscillaridin acetate would be easy to prepare, but the synthesis of acetonide would be difficult could. The reactions that normally lead to glycoside acetonides are in fact simultaneous Reactions leading to the splitting of the cardiac (i ί> Kosides are used in sugar and aglucon (C. M annich and F. Borowski, Archiv der Pharmazie, 276, 234 [1938], C. Mannich and G. S ie worth, Reports of the German Chemical Society, 2, 737 [1942]). The danger that especially with proscillaridin considerable losses and the formation of undesired by-products can be expected had to was great. So mention z. B. A. S t o 11 and

W. K rei s (Helvetica Chimica Acta, 34, 1431 [1951]) »When the rhamnose residue is split off by acid Hydrolysis always loses 1 mole of water, even under the mildest conditions, so it has so far has not yet succeeded in grasping the intact aglucon «. It is all the more surprising that with correct Reaction from proscillaridin and acetone almost exclusively the acetonide is formed. A Part of the proscillaridine used is recovered because there is a state of equilibrium, which can also be achieved from pure acetonide.

The formation of ketals of proscillaridine is possible with all means that are described in the literature for the manufacture of which has been described.

The process is therefore carried out in such a way that proscillaridin with ketones of the general formula

O = C

R ₁

wherein R and R ₁ each represent methyl or ethyl radicals, is reacted in a manner known per se. The implementation is very quick. About education

To avoid undesired by-products, the reaction must start immediately after the acetonide formation has ended canceled. It is advisable to start the reaction before equilibrium is reached to end, as this creates the least amount of by-products. The unreacted proscillaridin can be easily removed by filtration through silica gel. It can be recovered quantitatively. The use of pure proscillaridins is not necessary, as accompanying substances in the Do not interfere with the reaction and can easily be separated from the proscillaridin acetonide formed.

The reaction of proscillaridin with acetone in the presence of dilute mineral acids takes place rapidly. With 0.1 η-hydrochloric acid, the reaction is already over after 10 minutes, with 15% degradation products while about 20% proscillaridin remains unchanged. With 0.02 η-hydrochloric acid it takes time 60 to 80 minutes for equilibrium to be reached. The yield of acetonide is around 80%. In addition, 10% unchanged proscillaridin and 10% degradation products are obtained.

The concentration of proscillaridine when the reaction is carried out has only a slight influence on the Implementation. It is advisable to use acetone not only as a reaction component, but also as a solvent. The solubility of proscillaridin in acetone is 1%. But one can essentially use larger quantities. Since the acetonide formed is easily soluble, proscillaridin is constantly being redissolved. The values for a reaction time of 1 hour at 0.05 η-hydrochloric acid in acetone are shown in Table 2.

Table 2

Initial solution
% Proscillaridin
in acetone
g / ml Acetonide
yield
% Back
won
Proscillaridin
% Dismantling
Products
% 0.1
1
5
10 71.5
71
69
67 9.5
10.5
14th
9? 19th
18.5
17th
11

35

40

45

The reaction in the presence of copper sulfate takes place much more slowly, but it does occur also fewer by-products in the reaction. Acetonide formation takes place even more slowly in the presence of zinc chloride.

Working up the reaction mixture does not present any difficulties. The acetone solution is poured on Ice, neutralized with lye and extracted with ethyl acetate or another suitable solvent, z. B. chloroform or toluene. After washing and drying, the solution is evaporated and used for Separation of the by-products in a suitable solvent, such as chloroform, toluene, at ten fold Amount of silica gel filtered. The proscillaridin still present is then eluted with methanol. It is obtained in such a pure form that it can be used immediately for further reactions.

A particularly simple form of implementation is that you put copper sulfate in a column and the acetone solution, which is almost saturated with proscillaridin, is allowed to run through the column. The one below removed acetone solution is used to separate off unreacted proscillaridin over silica gel filtered.

example 1

3p! - (2 ', 3'-Isopropylidene-rhamnosido) -14ß-hydroxy-
^ "•" -bufatrienolid

a) 10 g are added to a mixture of 100 ml of acetone and 0.2 ml of 10 η hydrochloric acid with stirring Proscillaridin. The proscillaridin dissolves completely in about 20 to 30 minutes at room temperature. 90 minutes after the start of the reaction, the clear solution is poured onto 20 g of ice and stirred with 2 ml of 1N sodium hydroxide solution and extracted the neutral solution three times with 100 ml of ethyl acetate each time. The combined extracts are washed with a little water, dried with sodium sulfate and the solvent in vacuo evaporated. 10 to 11 g of residue are obtained, 80% of which consists of proscillaridin acetonide and 10% unchanged Proscillaridin and 10% by-products. The by-products are around scillaridin, scillarenin and acetonides of accompanying glycosides.

The residue is dissolved in a little acetone, mixed with the same amount of toluene and the mixture chromatographed on a column filled with 100 g of silica gel. Elution takes place with toluene. The acetonide The fractions containing are separated off and freed from the solvent in vacuo. By recrystallization Proscillaridin acetonide gives a very pure product.

F. 191 ° C (from ethyl acetate / hexane), 144 ⁰ C (from methanol) extinction at ^{355n ^ 80; [a] 2} _D ° = -58 ⁰ C (in methanol).

b) The same end product is obtained if 10 g of proscillaridin in 400 ml of acetone with 40 g anhydrous copper sulfate stirred for 24 hours at room temperature.

The work-up corresponds to that after filtering off the copper sulfate and evaporation of the solvent in the vacuum of that of Example 1 a). The yield of the crude product is 10 to 12 g. The physical Acetonide data correspond to those of Example 1 a).

c) The same result is obtained if one uses a solution of proscillaridin in acetone (0.5% g / ml) runs slowly over a column which is filled with a mixture of 130 g of copper sulfate and 500 g of sand was filled. The dripping solution is filtered, evaporated and worked up as indicated under a).

Example 2

3 /? - [2 ', 3' - (3 "-Pentyliden) -rhamnosido] _{-14-hydroxy-l} 8 zl ⁴ - ²⁰ - ²² -bufatrienolid

Following the procedure of Example la), the corresponding one is obtained from proscillaridin and diethyl ketone Proscillaridin Ketal.

F. 127 to 128 ⁰ C (from ethyl acetate / hexane), extinction α at 355 πΐμ 71; [Vp ₀ ⁰ = -53 ⁰ C.

Claims (2)

Patent claims: 1. Proscillaridine ketals
formula the general H, wherein R and R ₁ each represent methyl or ethyl radicals. 2. A method for the preparation of compounds according to claim 1, characterized in that man proscillaridin with ketones of the general formula