CH618444A5 - Process for the preparation of C22-substituted derivatives of alpha- and beta-methyldigoxin. - Google Patents

Abstract

C22-Substituted derivatives of alpha - and beta -methyldigoxin of the formula I in which R1 is a saturated or unsaturated alkyl group, an aralkyl or epoxyalkyl group, and one of the radicals R2 and R3 is in each case a methyl group and the other is a hydrogen atom, are prepared by the O-methylation of digoxin which is substituted by the radical R1 on carbon atom 22. The compounds can be used for the preparation of cardioactive pharmaceuticals. <IMAGE>

Description

618444

2nd

PATENT CLAIM

1. Process for the preparation of new C22-substituted derivatives of a- and ß-methyldigoxins of the formula I.

(I),

25th

in which Ri represents a saturated or unsaturated alkyl group, an aralkyl or epoxyalkyl group and in each case one of the radicals R2 and R3 is a methyl group, the other represents a hydrogen atom, characterized in that digoxin which is substituted on the carbon atom 22 by the radical Ri, O-methylated.

The invention relates to a process for the preparation of new C22-substituted derivatives of a- and ß-methyldigo-xins of the formula I.

R-.0 ■> OR

(I),

in which Ri denotes a saturated or unsaturated alkyl group, an aralkyl or epoxyalkyl group and in each case one of the radicals R2 and R3 denotes a methyl group, the other represents a hydrogen atom.

The compounds of formula I obtainable according to the invention can be used for the production of cardioactive drugs.

The new compounds have a positive inotropic cardiac activity with a reduced cardiotoxicity compared to their starting substances and are better absorbed than the known derivatives of C22 substituted on

Digoxins. The digoxin derivatives according to the invention are therefore particularly suitable for oral therapy of cardiac insufficiency.

The new compounds are prepared according to the invention by O-methylating digoxin which is substituted on the carbon atom 22 by the radical R 1.

The O-methylation can be carried out, for example, by reaction 65 with customary methylating agents, such as methyl halides, dimethyl sulfate or diazomethane, the process conditions described in Swiss Patents 506 511 and 537 378 preferably being used.

3rd

The compounds of the formula I obtainable according to the invention can be administered enterai and parenterally in liquid or solid form. Water is preferably used as the injection medium, which contains the additives customary for injection solutions, such as stabilizing agents, solubilizers and buffers. Such additives are e.g.

Tartrate and citrate buffers, ethanol, complexing agents (such as ethylenediaminetetraacetic acid and its non-toxic salts), high molecular weight polymers (such as liquid polyethylene oxide) for viscosity regulation. Solid carriers are e.g. Starch, lactose, mannitol, methyl cellulose, talc, highly disperse silicic acids, higher molecular fatty acids (such as stearic acid), gelatin, agar, calcium phosphate, magnesium stearate, animal and vegetable fats, solid high molecular weight polymers (such as polyethylene glycols); Preparations suitable for oral administration can, if desired, contain flavorings and sweeteners.

Example 1 C22-methyl-ß-methyldigoxin

500 mg methyl p-toluenesulfonate and 225 mg stronium hydroxide [Sr (OH2 • 8H2O] in 3.7 ml dimethylformamide are stirred for 3 hours at room temperature, then 500 mg of C22-methyldigoxin are added. The reaction mixture is stirred for a further 20 hours at room temperature For working up, the mixture is diluted with 38 ml of chloroform, suction filtered through diatomaceous earth 2S, washed with 38 ml of chloroform, mixed with 6.25 ml of pyridine and concentrated in vacuo until a viscous residue remains, which is taken up in 38 ml of chloroform, twice with 5 each ml of 5% aqueous sodium bicarbonate solution and shaken out once with 5 ml of water. The 30 washings collected are shaken out twice with 5 ml of chloroform each. Then the combined chloroform phases, after drying over NaaSCU, are concentrated in vacuo / Methyl ethyl ketone 3: 1 passed over a cellulose column impregnated with formamide and separated.

618444

After crystallization from chloroform / methanol / ether, the chromatographically uniform fractions yield 260 mg of C22-methyl-ß-methyldigoxin; Mp 221-224 ° C.

Example 2 C22-ethyl-ß-methyldigoxin 500 mg of methyl p-toluenesulfonate, 225 mg of strontium hydroxide and 500 mg of C22-ethyldigoxin in 3.7 ml of dimethylformamide are reacted and worked up as described in Example 1. The crude product is passed with xylene / methyl ethyl ketone 3: 1 over a cellulose column impregnated with formamide and separated. After crystallization from chloroform / methanol / ether, the chromatographically uniform fractions yield 240 mg of C22-ethyl] -ß-methyldigoxin; Mp 281 to 285 ° C.

The following connections can be made in an analogous manner:

C22-methyl-a-methyldigoxin,

Mp 272-276 ° C;

C22-isopropy] -ß-methyldigoxin,

Mp 168-171 ° C;

C22-allyl-ß-methyldigoxin,

Mp 243 to 247 ° C;

C22-EpoxypropyI-ß-methyldigoxin,

Mp 158-162 ° C;

C22-n-butyl-β-methyldigoxin,

Mp 244 to 248 ° C;

C22-Benzyl-ß-methyldigoxin mp 157 to 160 ° C;

C22-isobutyl-a-methyldigoxin,

Mp 161-166 ° C;

C22-isoamyl-a-methyldigoxin,

Mp 279 to 283 ° C.

B