DE1643665C - Novel digoxinethers and methods of making the same - Google Patents

Description

The present invention relates to new digoxinilther of the general formula ¹

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in which R (digitoxose) ₃ and in which one or two hydroxyl groups of the digitoxose radicals are etherified by the methyl or ethyl radical, the alkyl radicals optionally being substituted by the methoxy or ethoxy group, as well as a method for producing the same.

These new derivatives of digoxin are better absorbed enterally than digoxin itself and are suitable therefore excellent as orally administrable therapeutics for heart failure in humans.

The inventive method for producing the new digoxin ether is characterized in that that digoxin is reacted in a manner known per se with customary O-alkylating agents; come for this Alkyl halides, dialkyl sulfates and dhizoalkanes are possible.

To carry out the process according to the invention, digoxin is used, for example, in the presence a base, optionally with gentle heating, with about 1 or 2 equivalents of an alkyl halide or dialkyl sulfate reacted and worked up in the usual way, with conditions / u are to be avoided in which the reaction mixture with mineral acids or other strong aqueous acids comes into contact, as this splits off digitoxosis. Depending on the amount of alkylating agent used one receives predominantly mono- or diether of digoxin.

Another variant of the process is digoxin in the presence of a mild acidifying Catalyst (such as boric acid, boric acid trialkyl esters, aluminum isopropylate, iron (III) chloride, etc.) with Diazoaicans to implement. Here, too, it should be noted that some of the Catalysts such as boron fluoride are too acidic and lead to a high degree of decomposition products. This variant usually only leads to the mono-alkyl derivatives of digoxin.

The constitution of the new derivatives has not yet been fully clarified. In the monoethhema the 3 "or 4" position of the terminal digitoxosis is probably etherified, and in the dieters one hydroxyl group each of the terminal and central digitoxosis is etherified. There are also certain indications that, depending on the reaction conditions, either the '.V " or 4"' derivatives of digoxin f> o are obtained. The enhanced absorption in enteral Ciabe is found aber'in same Ma (Je for all of the derivatives Digouns in which one or two are verälhcrl Hydmxylgruppen in the manner mentioned. As soon as three or more hydroxyl groups etherified 5 ^h and are Alkylgruppcn with substantially more Knhlensloll. ilomiMi were introduced, the Wiik.amki.11! i / v ». ■ lit- fiiter.iU · l <e, urbit'rharkeil del substances -n stubbornly, that no advantages are achieved over dom digoxin, Eh is Therefore, when using strong alkylating agents, it is important to ensure that the etherification does not go too far and that not more than two hydroxyl groups are alkylated

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In the following examples this is in accordance with the invention Procedure explained in more detail. The ones reproduced there /iR,.~ values were obtained from paper chromatograms determined according to Chem. Ber "88/1955, P. 556.

example 1

I g of digoxin and 500 mg of aluminum isopropylate are dissolved in 4 ml of dimethylformamide and 10 ml of methylene chloride dissolved and with stirring at room temperature within 60 minutes with 60 ml of a 3% igcn Diazomethane solution in methylene chloride was added. After 2 hours, it is diluted with water and mixed with Shaken out chloroform. The chloroform phases are dried over anhydrous sodium sulfate, concentrated in vacuo and for the separation of by-products of a multiplicative distribution mn the phase mixture chloroform-benzene-methanol-water (2: 1: 2: 1) subjected. The organic Phase provides after concentration and crystallization from chloroform-ether-petroleum ether 690 mg digoxin monomethyl ether, Mp 227-231 C; JiR ,; 49. This is probably the 3 "'- monomethyl compound.

QjH _6n O ₁ , (794.94):

Calculated ... C 63.45, H 8.36;
found .... C 63.32, H 8.51.

Example 2

Ig Digox'i. 12 ml of dimethylformamide are dissolved and, after the addition of 1.3 g of barium _oxyut ... λ 1.3 g of barium hydroxide, 2.9 ml of dimethyl sulfate are added dropwise with stirring at room temperature. After the internal pressure increases. it is cooled to 45.degree. The reaction ^ according to; «! ·» ··! "! ·· '" 150 ml of chloroform are thinned, drained and the filtrate is washed out with water. After adding 1 g of calcium carbonate, the organic phase is concentrated in vacuo, the residue is dissolved in ethyl acetate, filtered through silica gel and washed with ethyl acetate. The ethyl acetate filtrate is concentrated in vacuo and, dissolved in benzene / ethyl acetate (9: 1), fractionated over silica gel, the additions of ethyl acetate being increased increasingly. After crystallization from chloroform-ether-petroleum ether, the benzene-ethyl acetate fractions (about 60 to 70% ethyl acetate) yield 630 mg digoxin monomethyl ether, melting point 226 to 229 C; hR _r . 49. This is probably the 4 "'-monomethy! Compound.

C ₊ ^ H ₁₁₁₁ O ₁₊ (794.94):

Calculated ... C 63.45, H 8.36;
found .... C 63.34, HH, 41.

I) e i s ρ i e I 3

I g Digoxiii and 50OmU Aluiniiiium-isopropylal graze -I ml of dimethylformamide and IO nil Melhylenehlorid iieliist and under cooling at room temperature inneihalli U) minutes uiü -Iu "iuen I) ia / (iiilhanlösiim ml of a V '! In Meihylciiihlnrid Versel / l After ¹ hour win! Mil W 'ι ■ -.' ■ r u-rdiimu and with (1; 1 ■ · 11> -

form iiusgoHchUuelt. The chloroform phases are dried over anhydrous sodium sulphate, concentrated in vacuo and dissolved in benzene / ethyl acetate (7: 3), fractionated over silica gel / After crystallization from chloroform ether, 640 mg of digoxin monoethyl ether are obtained, mp, 191 to 194 ⁰ C: HR, : 65,

C ₄₃ H ₍₁ "O ₁₄ (808.97):

Calculated .... C 63.84, H 8.47;
found .... C 63.72, H 8.51.

Example 4

I g of digoxin as described in Example 2, reacted with 3.2 ml of dimethyl sulfate, stirred for 30 minutes at 45 'C ¹ and worked up. Mp 189 after crystallization from chloroform-ether-petroleum ether, 480 mg of digoxin-dimethyl ether, ¹ to 191 C;: by fractionation on silica gel obtained from the benzene-Essigestcr fractions (4 6). hR _F : 77.

C ₄₃ H ₆₈ O ₁₄ (808.97):

Calculated ... C 63.86, H 8.47;
found .... C 64.00, H 8.71.

Example 5

1 g of digoxin is dissolved in 10 ml of dimethylformamide and 10 ml of dimethylaniline, mixed with 1.25 g of ethyl chloromethyl ether and heated to 40 ° C. for 20 hours. It is then concentrated in vacuo and the residue is fractionated over aluminum oxide. With the chloroform-methanol fractions (97: 3), multiplicative distributions with the phase mixtures chloroform-carbon tetrachloride-methanol-water (1: 1: 1: 1) and carbon tetrachloride-ethyl acetate-methanol-water (3: 1: 2: 2) carried out. After shaking out with chloroform, concentrating and crystallizing from chloroform-ether-petroleum ether, the aqueous phase yields 380 mg of digoxin-mono-ethoxy-methyl ether, melting point 138 to 141 ° _{C.; hR t} : 50.

C ₄₄ H ₇₀ O ₁₅ · H ₂ O (857.0):

Calculates ... C *! 6 '<. H \*.·,
fcciüüJc ".... L" 1, / ü, H 8.51.

Example 6

'Ig digoxin is in IO mi dimethylformamide and IC ml of dimethylaniline dissolved, with 1.25 g of chloromethyl

methyl ether is added and the mixture is warmed to 40 for 20 hours. It is then concentrated in vacuo and the 'residue fractionated over aluminum oxide. The chloroform-Mctrmnol fractions (1.5% methanol) are divided by multiplicative distribution with the

ίο Phase mixture of carbon tetrachloride / Bssigester / methanol / water (3: 1: 2: 2) purified further. After shaking out with chloroform, concentrating and crystallizing from chloroform-ether-petroleum ether, the aqueous phase yields 410 mg digoxin-di-melho-kymethyl ether, melting point 113 to 116 "C; hR _t - \ 80,

C ₄₅ H ₇₂ O ₁ ,, (869.03):

Calculated ... C 62.19, H 8.34;
found .... C 62.31, H 8.45.

Claims (2)

Patent claims:
1. Digoxin ether of the general formula I H, C RO wherein R (digitoxose) represents ₃ and in which one or two hydroxyl groups of the digiloxose radicals are etherified by the methyl or ethyl radical, it being possible for the alkyl radicals to be optionally substituted by the methoxy or ethoxy group. 2. Process for the preparation of digoxin ethers according to claim i, characterized by that digoxin is reacted with customary O-alkylating agents in a manner known per se.