DE1568216B - Cardenohd digitoxoside carrying cyclic ethers in the 3, 4-position and processes for their preparation - Google Patents

Description

1 2

The present invention relates to cyclic ethers of cardenolide digitoxosides of the general formula I.

C = O

R ₁ R ₂

in which R _{1 is} hydrogen or a lower alkyl group, R _{2 is} a lower alkyl, alkenyl or alkynyl group, R _{3 is} a methyl, aldehyde or optionally acylated methylol group, R _{4 is} hydrogen or a hydroxyl group, R ₅ and R _{6 are} hydrogen Mean hydroxyl group or a lower acyloxy group.

The compounds encompassed by the general formula are thus monodigitoxosides of strophanthidin, strophanthidol, gitoxigenin, 16-acyloxy-gitoxigenin (e.g. gitaloxigenin and oleandigenin), Digoxigenin, diginatigenin and digitoxigenin, which have the two free hydroxyl groups closed in the 3 ', 4' position of the digitoxose by the formation of cyclic acetals and ketals are.

In the group of cardenolid-digitoxoside, tridigitoxoside is used for the oral treatment of heart failure an important role, e.g. B: digoxin, acetyldigoxin, digitoxin, acetyldigitoxin. Monodigitoxoside have not yet found their way into oral heart therapy. So is z. B. known that strophanthidindigitoxosid (Helveticosid) and its reduction product strophanthidol-digitoxosid (Helveticosol) intravenous application in animal experiments and in humans a very strong comparable to strophanthin However, just like strophanthin, they show only very little effect when administered orally are effective. Likewise z. B. with gitoxigenin-digitoxoside in animal experiments only a low absorption verifiable. All of these glycosides cannot therefore be used as oral presentations.

It has now been found, surprisingly, that the ketals and acetals of these poorly resorbable Cardenolide-Digitoxoside show an excellent enteral effectiveness and that even a relatively good absorbable glycoside such as lanadoxin (16-formylgitoxigenin-digitoxoside) still experiences a demonstrable increase in absorption. This means that digitoxosides that have previously been useless orally are for oral use Heart failure therapy has become accessible; in particular, the ketals and acetals of the Helveticosids and Helveticosols are used as "oral strophanthines".

The process according to the invention for the preparation of the cyclic ethers of cardenolide-digitoxosides is characterized in that in a known manner cardenolide-digitoxosides of the general Formula II

HO

(H)

OH

in which R ₃ , R ₄ , R ₅ and R _{6 have} the abovementioned meaning, with aldehydes or ketones of the general

Formula III

C = O

(III)

The process according to the invention is explained in more detail in the following examples.

in which R ₁ and R _{2 have} the abovementioned meaning, or their reactive derivatives are converted in the presence of a catalyst and, if R _{3 is} an aldehyde group, if desired subsequently reduced to the methylol group and in the event that the radicals R ₃ , R ₅ or R ₆ represent or contain a free hydroxyl group, if desired subsequently acylated with the reactive derivative of a lower carboxylic acid.

In principle, all those customary for the production of cyclic acetals and ketals can be used as catalysts Catalysts are used; however, they must not be so strongly acidic that they remove the digitoxosides columns. Freshly melted zinc chloride and anhydrous copper sulfate have proven to be particularly effective as well as anhydrous calcium sulfate and phosphorylated cellulose preparations (e.g. that for thin layer chromatography used "MN cellulose powder 300 G / P").

Suitable aldehydes or ketones III are in principle all saturated and unsaturated, straight-chain or branched lower aldehydes and ketones, preferably those with not more than 7 carbon atoms, ie, R ₁ and R ₂ together have up to 6 carbon atoms.

The polymeric and oligomeric aldehydes, in particular, come as reactive derivatives of substances III, the lower dialkyl ketals or acetals and the diacyl derivatives in question.

To carry out the inventive method, the compounds II are preferably dissolved in an excess of the ketones or aldehydes III, admixed with the catalyst and either a long time at room temperature or correspondingly shorter time at elevated temperature (eg., 40 to 6O ⁰ C) allowed to stand . In order to avoid the autoxidation of substances II, it is advisable to add small amounts of an antioxidant such as hydroquinone to the reaction mixture.

The subsequent reduction of the aldehyde group to the methylol group is preferably according to German Patent 1114188, e.g. with complex metal hydrides such as sodium borohydride or aluminum isopropylate, accomplished.

_{The primary and secondary hydroxyl groups (R 3} = methylol; R ₅ and R ₆ = hydroxyl) which may still be present in substances I can, if desired, be subsequently added with all acylating agents customary in the chemistry of cardiac glycosides (e.g. acid anhydrides, acid halides, acid imidazolides) be acylated. One should avoid reaction conditions in which the substances I come into contact with mineral acids or other strong aqueous acids, since the digitoxosides are split in this way.

The process products I are isolated from the reaction mixture in a manner known per se. In particular, shaking out the reaction mixture mixed with water with chlorinated hydrocarbons has proven useful (e.g. chloroform). The concentrated extracts may first crystallize after chromatographic purification.

B is ρ ie 1 1
3 ', 4'-isopropylidene-helveticoside

Option A)

1 g Helveticosid (strophanthidin- / 5-D-digitoxosid) and 10 mg hydroquinone are in a solution of 400 mg of zinc chloride dissolved in 12 ml of acetone and left to stand for 3 days at room temperature. After that is diluted with water, extracted with chloroform, the chloroform phase is concentrated in vacuo and the residue crystallized from chloroform-ether. 860 mg of 3 ', 4'-isopropylidene helveticoside are obtained from m.p. 207 to 211 ° C.

Variant b)

1 g of helveticoside, 10 mg of hydroquinone and 3 g of copper sulfate (anhydrous) are shaken in 50 ml of acetone for 3 days at room temperature, filtered, concentrated and fractionated over silica gel with benzene / ethyl acetate. The benzene-ethyl acetate (1: I) fractions provide 740 mg of 3 ', 4'-isopropylidene helveticoside, melting point 206 to 210 ^° C., after crystallization from chloroform-ether.

Example 2
3 ', 4'-isobutylidene-helveticoside

1 g of helveticoside, 10 mg of hydroquinone and 6 g of zinc chloride are dissolved in 50 ml of methyl ethyl ketone. After standing for 5 days at room temperature, it is diluted with water, extracted with chloroform, concentrated and fractionated over silica gel with benzene / ethyl acetate. Crystallization from chloroform- Ether provides 680 mg of S '^' - isobutylidene-helveticoside, Mp. 181 to 184 ° C.

Example 3
3 ', 4'-isopentylidene-helveticoside

1 g of helveticoside and 10 mg of hydroquinone are dissolved in 50 ml of pentanone (3) and mixed with 2 g of copper sulfate (anhydrous) added, shaken for 3 days at room temperature and worked up as described in Example 1b. 580 mg of 3 ', 4'-isopentylidene helveticoside, melting point 105 to 108 ° C., are obtained.

B is ρ ie 1 4
3 ', 4'-isopropylidene-helveticosol

1 g Helveticosol and 6 g zinc chloride are dissolved in 50 ml acetone and 5 days at room temperature ditched. It is worked up as described in Example 2 and 680 mg of 3 ', 4'-Isopropylidenhelveticosol are obtained. Mp. 183 to 186 ° C.

Example 5
3 ', 4'-isobutylidene-helveticosol

1 g of Helveticosol and 6 g of zinc chloride are dissolved in 50 ml of methyl ethyl ketone and kept for 3 days at room temperature ditched. It works up as described in Example 2 and receives 620 mg of 3 ', 4'-isobutylidene-helveticosol, Mp. 112 to 115 ° C.

Example 6
3 ', 4'-ethylidene-helveticoside

Ig Helveticosid, 10 mg hydroquinone and 6 g zinc chloride are dissolved in 50 ml paraldehyde and Left to stand for 2 days at room temperature. It is worked up as described in Example 2 and obtained 830 mg of 3 ', 4'-ethylidene-helveticoside, m.p. 169 to 172 ° C.

Example 7
3 ', 4'-n-propylidene-helveticoside

1 g of helveticoside, 10 mg of hydroquinone and 400 mg of zinc chloride are dissolved in 50 ml of propionaldehyde, Left to stand for 4 days at room temperature and worked up as described in Example 2. You get so 760 mg 3 ', 4'-n-propylidene-helveticoside, melting point 157 to 159 ° C.

Example 8
3 ', 4'-n-butylidene-helveticoside

1 g of helveticoside, 10 mg of hydroquinone and 400 mg of zinc chloride are dissolved in 50 ml of n-butyraldehyde and left to stand for 4 days at room temperature. The procedure is as described in Example 2 and 590 mg of 3 ', 4'-n-butylidene-helveticoside, melting point 102 to 104 ^° C., are obtained.

Example 9
3 ', 4'-n-propylidene-helveticosol

1 g of 3 ', 4'-n-propylidene-helveticoside (see. Example 7) are dissolved in 80 ml of dioxane containing 20% water, mixed with 500 mg of sodium borohydride in 10 ml of dioxane (+ 20% water) and 4 Left to stand for hours at room temperature. 2N sulfuric acid is added to pH 6, diluted with 200 ml of water, extracted with chloroform, the chloroform phase is washed with soda solution and water, dried over sodium sulfate, concentrated and crystallized from chloroform-ether-petroleum ether. 680 mg of 3 ', 4'-n-propylidene-helveticosol, melting point 108 to HO ⁰ C. are obtained.

works up as described in Example 2 and receives 630 mg of 3 ', 4'-butene- (2) -ylidene-helveticoside, melting point 109 bis 112 ° C.

Example 11

3 ', 4'-isopropylidene-gitoxigenin-mono-digitoxoside

1 g of gitoxigenin-mono-digitoxoside and 6 g of zinc chloride are dissolved in 50 ml of acetone and left to stand for 3 days at room temperature. It is worked up as described in Example 2 and 660 mg of 3 ', 4' - isopropylidene - gitoxigenin - mono - digitoxoside, melting point 201 to 204 ° C. are obtained.
15th

Example 12
3 ', 4'-n-propylidene-gitoxigenin-mono-digitoxoside

1 g of gitoxigenin mono-digitoxoside and 400 mg of zinc chloride are dissolved in 50 ml of propionaldehyde and Left to stand for 3 days at room temperature. It is worked up as described in Example 2 and obtained 630mg 3 ', 4-n-propylidene-gitoxigenin-mono-digitoxoside, melting point 183 to 185 ° C.

Example 13
3 ', 4'-n-propylidene-lanadoxine

700 mg of 3 ', 4'-n-propylidene-gitoxigenin-mono-digitoxoside (cf. Example 12) are dissolved in 3.5 ml of pyridine and at room temperature, dropwise with 20 ml of a mixture of formic acid and acetic anhydride (1: 1) offset. After 60 minutes, it is diluted with 250 ml of water, extracted with chloroform, concentrated in vacuo and crystallized from chloroform petroleum ether. 520 mg are obtained 3 ', 4'-n-propylidene-lanadoxin, m.p. 149 to 152 ° C.

Example 10
3 ', 4'-butene- (2) -ylidene-helveticoside

1 g of helveticoside, 10 mg of hydroquinone and 400 mg of zinc chloride are dissolved in 60 ml of crotonaldehyde and left to stand at room temperature for 3 days. Man

Example 14
3 ', 4'-isopropylidene-lanadoxine

700 mg of 3 ', 4'-isopropylidene-gitoxigenin-mono-digitoxoside (see. Example 11) are dissolved in 3.5 ml of pyridine and as described under Example 13 with Formic acid-acetic anhydride (1: 1) reacted and worked up. 580 mg of 3, 4'-Isopropylidenlanadoxin are obtained, Mp. 189 to 191 ° C.

Example 15

3 ', 4'-Isopropylidene-16-acetyl-gitoxigenin-monodigitoxoside

500 mg of 3 ', 4'-isopropylidene-gitoxigenin-mono-digitoxoside (see Example 11) are in 5 ml of pyridine dissolved, treated with 2.5 ml of acetic anhydride, left to stand for 24 hours at room temperature, with water diluted, extracted with chloroform, concentrated and crystallized from acetone-ether. You get 430 mg S '^' - isopropylidene-lo-acetyl-gitoxigenin-mono-digitoxoside, Mp. 186-189 ° C.

Claims (1)

7 8 Patent claims:
1. Cardenolide digitoxosides of the general formula I bearing cyclic ethers in the 3 ', 4' position in which R _{1 is} hydrogen or a lower alkyl group, R _{2 is} a lower alkyl, alkenyl or alkynyl group, R _{3 is} a methyl, aldehyde or optionally acylated methylol group, R _{4 is} hydrogen or a hydroxyl group, R ₅ and R _{6 are} hydrogen Mean hydroxyl group or a lower acyloxy group. 2. Process for the preparation of compounds of general formula I, characterized in that one cardenolide digitoxoside of the general formula II in a manner known per se HO C = O OH in which R ₃ , R ₄ , R ₅ and R _{6 have} the abovementioned meaning, with aldehydes or ketones of the general formula III (III) in which R ₁ and R _{2 have} the abovementioned meaning 50 have, or reacts their reactive derivatives in the presence of a catalyst and for the case. that R ₃ denotes an aldehyde group, if desired subsequently reduced to the methylol group and in the event that the radicals R ₃ , R ₅ or R ₍ represent or contain a free hydroxyl group, if desired subsequently acylated with the reactive derivative of a lower carboxylic acid. 109 529/3