CS197287B2 - Method of producing new quaternary derivatives of sandwicine - Google Patents

Abstract

Novel sandwicinium salts of the formula I <IMAGE> in which R represents an alkyl group having up to 5 carbon atoms, are obtained by reacting sandwicin with an appropriate alkyl halide. In order to convert the halide into another salt of the formula I', in which X denotes the anion of an organic or inorganic acid, the halide is converted with alkali into the corresponding, open-ring, aldehyde base, which, together with an appropriate acid, yields the desired salt. The novel salts exhibit adrenolytic and cardiac-rhythm-promoting activity. <IMAGE>

Description

R represents a straight or branched chain alkyl group having up to 5 carbon atoms, in particular a methyl, ethyl or propyl group, and

X is an anion of an inorganic or organic acid.

The anion of an inorganic or organic acid is in particular an anion of oxalic, citric, tartaric and phosphoric acids.

The novel compounds of formula (I) are prepared by reacting sandwicin with an alkyl halide, the alkyl group of which:

R is as previously defined.

Then, the ring-opened aminoaldehydes are reacted with organic or inorganic acids whose anions are physiologically harmless.

In the process according to the invention, the starting materials are usually used in equimolar amounts, but the alkyl halides can also be used in excess, while at the same time acting as a solvent. More preferably, the quaternization is carried out at the boiling point of an organic solvent which is inert to the reactants. However, the temperature may be below

boiling point. Suitable solvents are, for example, acetonitrile, chloroform, dimethylformamide.

The corresponding ring-opened amino aldehydes are obtained either by reaction sandwiciniumhalogenidů with 10% sodium hydroxide, or by reaction with another aqueous alkali, such as with sodium hydrogen ^Uhl: C'tan bicarbonate or sodium carbonate solution !. It is more expedient to work in the presence of a suitable extractant. All inert, water-immiscible solvents, such as chloroform, ether and others, in which the bases are sufficiently soluble are suitable. After distilling off the extractant, preferably by vacuum distillation, the bases are in amorphous form.

The bases thus prepared (open ring aminoaldehydes) are then reacted with a physiologically acceptable inorganic or organic acid, preferably tartaric, oxalic, citric and phosphoric acids.

The quaternary derivatives produced according to the invention from sandwicine exhibit an adrenolytic and cardiac rhythm regulating effect when used in medicine. Surprisingly, however, the novel compounds are substantially more potent and physiologically tolerable than the known epimers of the sandwicine derivatives. Thus, the new sandwicin derivatives already have a comparable effect on the isolated guinea pig papillary muscle at a factor 10 dose compared to the known epimeric ajmaline derivatives. In addition, undesirable negative inotropy is weaker than that of epimeric ajmaline derivatives, at the same time greater therapeutic breadth.

These results conclude that the steric placement of the hydroxyl group on the C17 atom is of particular importance for the pharmacological effect of the novel sandwicin compounds, as this is the only configuration difference from the sandwicin epimers. Sandwicin belonging to the Rauwolfi alkaloid family is described in detail by M. Garman et al., Tetraheron 1, 328 (1957).

The active ingredients produced according to the invention are stable both in aqueous solution and in solid form and can therefore be used therapeutically in the same dosage forms.

The pharmacological data required for comparison were obtained in a known manner by measuring the functional refractory period and contraction force on the paired guinea pig papillary muscles (male and female, 300-350 g).

The following examples illustrate the invention in more detail.

Example 1

A: N-methylsandwicinium iodide

12.0 g of sandwicin are heated at reflux for about 7-9 hours with 12.0 ml of methyl iodide in 500 ml of acetonitrile and then evaporated to dryness. 16.0 g of N-methylsandwicimum iodide are obtained as a yellow, amorphous product. Yield: 93%.

B: Open ring aldehyde base

16.0 g of N-methylsandwicinium iodide are suspended in 500 ml of water, 12.0 ml of 10% sodium hydroxide are added and stirred for 30 minutes with 1000 ml of chloroform. After separation of the chloroform phase, the aqueous phase is again stirred with 500 ml of chloroform. The combined chloroform phases were dried over sodium sulfate. There remains an amorphous residue of 11.5 g of the open ring aldehyde base. Yield: quantitative.

C: N-methylsandwicinium hydrogen tartrate

11.5 g of the open ring aldehyde base are dissolved in 150 ml of methanol, 4.1 g of L-tartaric acid dissolved in a small amount of methanol are added, and, with good stirring, are added to 1500 ml of ethylnatolio acetate. After aspiration of the light precipitate and washing with ethyl acetate, it is dried at 50 ° C to constant weight. 135 DEG-137 DEG C. (decomposition). Yield: 11.4 g = 69% of theory.

Example 2

A: N-propylsandwicinium bromide

22.0 g of sandwicin is heated to reflux with 22 ml of n-propyl bromide for about 7-9 hours in 1000 ml of acetonitrile, whereby a light precipitate forms. The precipitate is filtered off with suction, washed with acetonitrile and dried at 50 DEG. 20.8 g of N-propyl-sandwicinium bromide are obtained. Melting point: 314-316 ° C. Yield: 69%.

B: Open ring aldehyde bases

Suspend 20.8 g of N-propylsandwicinium bromide in 200 ml of water, add 20 ml of 10% sodium hydroxide and mix with 200 ml of chloroform over 30 minutes. After separation of the chloroform phase, it is stirred twice with 200 ml of chloroform. The combined chloroform phases were dried over sodium sulfate and evaporated in vacuo. The residue was 16.2 g of an amorphous aldehyde base. Yield: quantitative.

C: N-propylsandwicinium hydrogen tartrate

16.2 g of the ring-opened aldehyde base are dissolved in 50 ml of methanol, 7.0 g of L-tartaric acid dissolved in a small amount of methanol are added, and the mixture is added to 2000 ml of ethyl acetate with vigorous stirring. The white precipitate is filtered off with suction, washed with ethyl acetate and dried to constant weight at 50 ° C. 21.5 g of N-propylsandwicinium hydrogen tartrate having a melting point of 205 DEG-207 DEG C. are obtained. (The obtained N-propylsandwicinium tartrate contains a small amount of the corresponding iso-form). Yield: 94%.

OBJECT OF THE INVENTION

Claims (1)

OBJECT OF THE INVENTION A process for the preparation of novel quaternary sandwicin derivatives of the general formula I, in which: R denotes an alkyl group having a straight or branched chain. a branched chain of up to 5 carbon atoms, in particular a methyl, ethyl or propyl group, X is an anion of an inorganic or organic acid, characterized in that the sandwicin is first reacted with an alkyl halide whose alkyl group is as previously defined for R, in which he has R is as previously defined, and these are optionally reacted with an organic or inorganic acid. Sevcrografia, n. P., Plant 7, Most