DE1793686C3 - Helveticoside derivatives and medicinal products containing them - Google Patents

Description

11. Medicinal preparation containing a helveticoside derivative according to claim 1 as medicinal substance and usual Carriers and / or diluents and auxiliaries.

Cardiac glycosides derived from the genin k-strophanthidin or strophanthidol, e.g. B. convallatoxin, Convallatoxol, k-strophanthin, cymarin, cymarol, helveticoside and helveticosol, have due to their special effectiveness and properties of action are of particular importance for cardiac therapy. the However, the application remains essentially to the injection limited, as these glycosides are only reabsorbed to a small extent from the gastric-then-tract will. The absorption rates z. B. of helveticoside and cymarin are 0 and 20 to 30%. Therefore these compounds have a therapeutically inadequate effectiveness when administered enterally.

Numerous attempts have been made to obtain more absorbable cardiac glycosides of the strophane-ihidine type to find or by chemical changes in the molecules, e.g. B. by acylation of Hydroxyl groups to improve the resorptive properties. So far, however, there is still no glycoside derivative made known by the strophanthidine type, which does justice to the therapeutic properties sought would have become; See Arzneimittelforschung, Vol. 13 (1963), pp. 142 to 149 and the Dutch Offenlegungsschrift 67 02 085.

The object of the invention is to create a new class of cardiac glycoside derivatives, which from the The gastrointestinal tract is very absorbable and has only minor side effects. This task is achieved by the invention.

The invention relates to helveticoside derivatives of the general formula I

CH,

CH-O

OH

in which R denotes the aldehyde group (CHO; Genin = strophanthidin) or the methylene group (CH ₂ OH; Genin - strophanthidol), the sugar residue itself
derives from digitoxosis and R ₁ together with

the carbon atom forms a cycloaliphatic radical 5 of the ketone of the following all with 4 to 12 carbon atoms in the ring, the general formula IV
optionally substituted by a methyl group

is. s —-ν

It can be seen that the new heart ^R i C '= O (IV)

glycoside derivatives of the general formula I to cycli- io ^ "

see ketals, with the rest being derived.

^Those j ^"de" record on behalf of the Herzglykosidderivate the invention mentioned were chosen for reasons of clarity, they are not in conformity with the IUPAC nomenclature.

The Helveticosiddenvate of the general formula I can be prepared by reacting Helveticoside, i. H. Strophanthidindigitoxosid, of the formula II

with an excess of a ketal of the general 35 cosid is preferably a cation exchanger in the Formula III H + form used, which is in the temperature range of

Implementation and is stable under the reaction conditions. Come as a cation exchanger

OR, both inorganic and organic exchangers

40 in question. Organic exchangers are preferred (III) After conversion into the H ⁺ form by treatment,

with an inorganic strong acid, the exchanger becomes anhydrous with organic solvents washed and dried. After the end of the reaction, the reaction mixture is removed from the exchange

in which Rj has the above meaning and R ₂ sucked a lower shear. In this way, an alkyl radical is avoided in the presence of an acidic additional neutralization of the reaction mixture, condensation agent and, if appropriate, in the presence of an inert solvent which, under certain circumstances, can lead to non-controllable side reactions at temperatures. The Kondensationsvon 15 to 9O ⁰ C, optionally followed by 50 medium is the general used in catalytic amounts the necessary reduction of the obtained cyclic ketal.

mean formula I, in which R is the aldehyde group, for The process with a ketal of the general

corresponding Helvcticosol derivative (R = CH ₂ OH) formula III using a cation. tauschers in the H '"shape is because of the larger

_ The preferred ketals are the methyl or 55 application breadth, the shorter reaction times, the Ethyl cUals used. higher yields and the lower formation of

Examples of cycloaliphatic, unsubstituted or by-products are particularly preferred,
substituted ketones which, in the form of their ketals, The ketal is used and serves in excess

are used, are cyclobutanone, cyclopentanone, optionally at the same time as a solvent for the 3-methylcyclopentanone, cyclohexanone, 2-, 3- and 60-helveticoside. Is the helveticoside used in the 4-methylcyclohexanone, cycloheptanone, cyclooctanone, ketal sparingly soluble, you can also use one under Cyclononanone, cyclodecanone and cyclododecanone. the reaction conditions inert solvent, e.g. B. Acids, such as salt, a lower aliphatic alcohol, dioxane or can be used as condensation agents add acid, sulfuric acid or potassium hydrogen sulfate, tetrahydrofuran. The same applies to the case anhydrous Lewis acids, such as EisenOII ^ chloride, zinc 65 that the ketal itself is in the solid state, chloride or boron trifluoride etherate or anhydrous. The reaction product is worked up

Copper sulfate, can be used. For the implementation depending on the type of condensing agent used of the ketals of the general formula III with Helveti- after its neutralization or after filtering off.

<f

Excess ketal is removed under reduced pressure or in a high vacuum at low temperature distilled off in order to avoid decomposition of the helveticoside derivative. However, if the distillation temperatures are so high that decomposition occurs the consequence would be, the reaction mixture is given in excess, low-boiling petroleum ether, whereby the reaction product precipitates. By crystallizing the distillation residue with acetone / ether or Acetone / petroleum ether gives the pure compounds.

_{The corresponding helveticosol derivatives (R = CH 1} OHJdUrCh reduction) can be prepared from the cyclic ketals of helveticoside of the general formula I, in which R is the aldehyde group. The reducing agents used are preferably complex metal hydrides with a mild reducing effect that do not attack the lactone ring , especially sodium borohydride.

The cyclic ketal is dissolved in a water-miscible solvent, and the solution is mixed some water and dropwise with a solution of sodium borohydride in water. The progress of the reduction is followed by thin layer chromatography. Suitable as water-miscible solvents especially dioxane and tetrahydrofuran. After the reduction has ended, solvent is distilled off and water under reduced pressure and recovered analogously to that described above. Way of working the Helveticosol compounds.

The helveticoside used can, for. B. according to the method of German patent 10 82 007 or the German Auslegeschrift 12 21764 can be obtained. The ketals are known per se Methods from the corresponding ketones, e.g. B. by reaction with orthoformic acid esters.

In contrast to the starting compounds, the new cardiac glycoside derivatives show only at show an effect comparable to that of strophanthin after intravenous administration, surprisingly a high enteral absorption rate, so that they can be used orally for the therapy of heart failure be able. The pharmacological testing of the new compounds was carried out in a known manner on cats by determining the lethal dose for intravenous

also infusion. The enteral absorption rates were calculated from the ratio of lethal doses in the case of intraduodenal Infusion to the lethal doses calculated with intravenous infusion or by intravenous titration determined intraduodenal specification.

»5 The table shows some examples of the high effectiveness and high resorption rate of the compounds.

Hclveticoside derivative i. v. Effective dose
DL ₁₀₀ in mg / kg Resorption
quota,% Cyclobutanone-helveti-
cosid Cyclopentanone helveti-
cosid 0.26 75 Cyclohexanone helveti-
cosol 1.01 55 Cyclohexanone helveti-
cosid 0.34 58 2-methylcyclohexanone
helveticosid 0.39 65 3-methylcyclohexanone
helveticosid 1.05 60 4-methylcyclchexanone
helveticosid 1.29 65 Cycloheptanone helveti-
cosid 1.24 67 Cyclododecanon-helveti-
cosid k-strophanthin /? 1.28 7th HelveticAsid 0.09 0

Compared to the previously therapeutically used 65 tion. The risk of accumulation and that with it

the aglycone strophanthidin-containing heart-associated therapeutic risk, as dated

glycosides are the compounds that digoxin and its derivatives are known to be by

Invention through a significantly higher enteral absorption - the rapid elimination of the connections

if

reduced. This also ensures that symptoms of intoxication will subside quickly in the event of an overdose. While digoxin and his Derivatives after enteral administration only reach the therapeutically required full effective level several days, the absorption maximum of the compounds mentioned is already 1 hour after Enteral administration achieved. Thus, the daily administration of the full dose of active ingredient is possible. Both named compounds are cardiac glycosides, which due to their pharmacological properties with regard to the enteral Absorbability, the advantages of digoxin and its derivatives, with regard to their onset of action Advantages of the cardiac glycosides containing strophanthidin:

1. The enteral absorption rate of the above Compounds is considerably higher than that of other commercially available, therapeutically used aglycones Strophanthidin-containing cardiac glycosides, such as. B. k-strophanthin /? and k-strophanthin-a (cymarin) as well as that of digoxin.

Enteral absorption rates:

Cardiac effective concentrations (change in the contraction amplitude of isolated cardiac preparations):

Cyclo-k-strophane digoxin

hexanon- thin- /? helveticosid

6.4 x 10- '6.0 x 10-' 6.0 x 10 ~ '

1.8 10- 1.6 10- 1.4 10- (227%) (243%) (230%)

Glycoside Default dose,
based
LD ₁₀ , iv Enteral
Absorption,
% Cyclopentanone
helveticosid / 50%
\ ioo% 64
75 Cyclohexanone
helveticosid 50% 58 2-methylcyclohexanone
helveticosid 50% 65 k-strophanthin-jS - 7th k-strophanthin-a 100% 18th Digoxin 100% 55

2. The biological value corresponds to that of digoxin or / J-acetyldigoxm.

Biological active values: Glycoside LD _1- Lv. Cyclopentanone heveticoside 0.26 ± 0.041 Cyclohexanone helveucoside 0.34 ± 0.042

α-methylcyclohexanone 0.39 ± 0.05 helveticosid

increase

maximum

(Increase)

Decrease to 4.0 x 10 "x 2.9 x 10" x 3.1 x 10- Baseline

Cardiac arrest 5.6-10- 4.8-10- 4.7-10 "

3. Rapid enteral effectiveness, as shown by the example of cyclopentanone helveticoside, is already there Maximum absorption is reached 1 hour after enteral administration. After 1 hour 76%, after

75% after 2 hours, 65% after 3 hours.

The compounds can be used for oral administration, e.g. B. as tablets, pills, capsules or Coated tablets. The oral preparations can also be coated with an enteric coating be provided. Injectables containing a helveticoside derivative are also becoming more common Way made. The substances are with the help of biologically compatible solubilizers in brought an aqueous solution and basic

Substances to a neutral to slightly alkaline

pH adjusted. The solutions are in ampoules bottled and in a known manner by heating sterilized.

The example explains the production of the Helvetia

coside derivatives of the invention. The optical rotations were measured on solutions of 1 g of compound in 100 ml Determined by chloroform.

example a) Cyclohexanone helveticoside

Digoxin / J-acetyldigoxm

0.25 ± 0.01 0.38 ± 0.064

1.5 g of helveticoside are dissolved in 20 ml of cyclohexanone diethyiketal and mixed with 1.5 g of a cation exchanger in the H + form (for example, the one below the trade name Lewatit S 100 known ion exchanger) added. The mixture is warmed up while stirring 55 ° C and follows the course of the reaction by thin-layer chromatography. After a reaction time of about 4 hours, no more Helveticoside can be detected. Man sucks the ion exchanger and distilled from the Fil-entered in a water jet vacuum in a rotary evaporator the solvent off. The residue is digested with petroleum ether. Yield 850 mg of cyclohexanone helveticoside.

Purification: The solution is placed on a chromatography column (80 g silica gel, diameter 24 mm) of cyclohexanone helveticoside in a little chloroform and then eluted with chloroform. The factions with pure cyclohexanone helveticoside are collected and evaporated. The residue is with little Dissolved chloroform and then precipitated with petroleum ether. Yield 95% of theory; F. 129 to 134 ° C,

1 "" 1 + ³⁴ ° x 609651/93

b) Cyclohexanone-helveticosol

1.5 g of cyclohexanone are dissolved helveticosid ml of 80 ° / ₀ aqueous dioxane in 20, and added dropwise over 1 hour with a solution of 0.35 g of sodium borohydride in 20 ml of 75 ° / _o sodium dioxane. The reaction mixture is stirred for 1 hour, after which no more cyclohexanone helveticoside can be detected. The solution is adjusted to pH 7 with dilute sulfuric acid, and dioxane is evaporated off under reduced pressure in a rotary evaporator. The aqueous phase is extracted several times with chloroform.

The combined chloroform extracts are dried with anhydrous sodium trisulfate and evaporated. The residue is purified by chromatography on silica gel. Chloroform is used as the solvent. Yield 750 mg cyclohexanone helveticosol with a temperature of 155 to 164 ° C, [« % °] + 23 °.

The following helveticoside derivatives are produced in the same way:

R ₁ ⁰ C

Cyclopentanone
helveticosid 190 to 192 + 28 ° S. Cyclopentanone
helveticosol 179 to 184 + 12 ° Cycloheptanone
helveticosid 118 to 124 + 28 ° IO Cycloheptanone
helveticosol 135 to 141 + 23 ° Cyclododecanon
helveticosid 129 to 139 + 21 ° »5 4-methylcyclohexanone
helveticosid 128 to 135 + 29 ° 2-methylcyclohexanone
helveticosid 129 to 130 + 27 ^C 20th 3-methylcyclohexanone
helveticosid 128 to 135 + 31 ^C Cyclobutanone
hrlveticosid 117 to 123 + 25 ^C

Claims (10)

Claims: 1. Helicoside derivatives of the general formula I. / O \ ■ ' CH ₂ CH O— * ■ R. CH, j CH 'V / OH \ CH
/ '\ CH N I. C) '\ O vk, .4, I.
OH CH ₃ r -O in which R denotes the aldehyde (CHO) or methylol (CHjjOH) group and R ₁ together with the carbon atom forms a cycloaliphatic radical with 4 to 12 carbon atoms in the ring, which is optionally substituted by a methyl group. 2. Cyclobutanone helveticoside. 3. Cyclopentanone helveticoside. 4. Cyclohexanone-helveticosol. , ₀ 5. Cyclohexanone helveticoside. 6. 2-methylcyclohexanone helveticoside. 7. S-methylcyclohexanone helveticoside. 8. 4-methylcyclohexanone helveticoside. 9. Cycloheptanone helveticoside. 10. Cyclododecanon helveticoside.