DE1643174B2 - PROCESS FOR THE PRODUCTION OF 16-ACYL-GITOXIN - Google Patents

Description

Koside is taken up in chloroform, the aqueous one Solution then extracted with chloroform. The combined chloroform solutions are over Dried sodium sulfate and concentrated to dryness in vacuo. The resulting melt contains Gitoxin (on average 60%) and 16-acetyl-gitoxin (on average 40%). Yield: 13.3 g. That partially deacetylated substance mixture (a) is now determined by multiplicative distribution according to O'Keef f e (cf. E. Meeker, Distribution Process in the Laboratory, Verlag Chemie, 1955, Weinheim, Bergstrasse) separated into 5 elements.

Solvent: methanol to water to chloroform to carbon tetrachloride = 3: 2: 1.4: 0.7; per distribution step

600 ml upper phase,
50 ml lower phase,
600 mg substance (a),

admittedly in the middle position.

Yield from the lower phase: 4.0 g of 16-acetylgitoxin with 85% purity, 6.85 g of gitoxin with small traces of 16-acetyl-gitoxin from the upper phase. the the remaining substance remains in the apparatus and is processed again in later distribution processes.

Claims (1)

onset and easily controllable effect. Incoming pharmacological studies of Claim: 16-acetyl-gitoxin confirm this assumption. With a minimum LD ₁₀₀ of about 0.3 mg / kg for iv.-In- Process for the production of 16-Acetylgit- 5 fusion in the cat counts 16-Acetyl-gitoxiii to the oxins, characterized in that relatively strongly effective glycosides (for lanatoside C one obtainable according to the example and digoxin LD ₁₀₀ values of 0.23 to di- and triacetylgitoxin at room temperature with 0.28 mg / kg given in the literature). With a timeless 1.15-fold molar excess of subsequent observation, the LD ₅₀ after intraducted aqueous sodium bicarbonate solution, after administration to the cat, was about 0.1 mg / kg. Certainly added to the gitoxin used, added and that the resorption rate of the mixture of gitoxin and 16-acetyl cat obtained in the usual way is found within the period of gitoxin a multiplicative distribution of 3 to 5 hours after the intraduodenal administration pulls. minimum LD ₁₀₀ a resorption of about 60 * ..,. 15 The maximum absorption of penta-acetyl-giioxin the cat is much later. Based on the animal experiments, therefore, a clinical effect of 16-acetyl-gitoxins can be predicted that roughly corresponds to that of lariat aglycosides. First climate 20 niche experiments confirm this prediction. The question of technical production is therefore more economical Meaning. The representation of 16-acetyl-gitoxin has been described several times in the literature (cf. The invention relates to a method for producing 25 K. M i y a t a k e, A. O k a η ο, K. M ο j i, T. M i k i, treatment of 16-acetylgitoxin. A. Sakashita, Chem. Pharmac. Bull. [Japan], 8, Gitoxin is a cardanolide glycoside from Digitalis-1144 [1960] and G. Baumgarten, Cach. Phararten, especially the Digitalis purpurea, which because of maz., 295, 305 [1962]). For a representation in Mcns of his bad physical properties, such as those required for therapy, cannot be used for technical reasons. Examinations 30 den, these procedures can not be used,
with acyl compounds of gitoxin, which in the final aim and object of the invention was therefore a th years ago (Kaiser, 1956: suitable production method for 16-acyl-16-formylgitoxin; Repke and Megges, 1963: to determine gitoxine. Penta-acetyl-gitoxin and others) showed that the substituents were found to be practically only tion of a formyl group on the C16 atom of the genin 35 16-acetylgitoxin and gitoxin-containing mixture or a peracetylation of all free hydroalkyl groups through precise acetylation of the gitoxin and subsequent to pharmacologically and clinically effective gentle saponification, which leads to glycosides. Since formylgitoxin in its pure form has a limited shelf life, a method of distribution using the Menur, it is only mixed with other glycosides 40 in natural association with a suitable phase, e.g. B. carbon tetrachloride chloroiorm (digitoxin, gitoxin and verodoxin) and resorption methanol-water, in 16-acetylgitoxin and gitoxin require medical use (German interpretation can be separated. The inventive document 1 063 160). Driving 16-acylgitoxins with homologs is characterized in that one geder formic acid, z. B. acetic acid, or a mixture of di- and trio-acid, which is available as an example, have a 45% acetylgitoxin at room temperature with a considerably higher stability than 16-formylgitoxin with a 1.15-considerably higher stability, but they are difficult to produce a molar excess of dilute aqueous bar . They have a special sodium bicarbonate solution for the following reason: Pentaacetylgitoxin has become a gitoxin and the resulting mixture of long-acting glycoside has been shown to have an effect of oxin and 16-acetylgitoxin with a multiplicative digestion in the range of digoxin-digitoxin . Own 50 undergoes division. The recovered gitoxin from systematic animal studies can be used again.
(Förster) with numerous mono- and polyacetyl Compounds of Gitoxin showed that the improved _. . . serte oral effect in a specific way to the ac e 1 s ρ 1 e 1 tylation of the 16-hydroxyl group is bound (ahn- 55 Hch the 16-formylgitoxin), while a sugar- 13.6 g of pure gitoxin are hot in 450 ml of pyridine acetylation alone (acetylgitoxin- * or -ß) does not dissolve and at room temperature for 2 hours 10 minutes there is a substantial increase in the oral efficacy. It is poured into 4.5 l of distilled kung while stirring. Because the enzymatic desacety- 60 water and sucks off the precipitated product. After the ponta-acetylgitoxin has settled in the organism, after washing with water and drying, things seem slow and 14.0 g of acetylated gitoxin are obtained (diacetylgitoxin and triacetylgitoxin, which is considerably longer than that of gitoxin). The acetylated gitoxin is to be explained in the long run, it was to be assumed that one dissolved in 2.7 _{l of methanol and with 1.68 g of sodium hy- · der 16-Hydroxylgrur, r} _ des Genius targeted mono-drug carbonate in 300 ml of water 65 Hours with acetylated gitoxin, which the human organism deacetylates at room temperature. It is neutralized and can degrade faster than a highly acylated den- 0.1 η-hydrochloric acid and concentrated in vacuo to 200 ml of vat, an orally effective cardiac, with a rapidly aqueous solution. The partially failed GIy-