DE1768142C - Process for the preparation of cardiac glycoside derivatives and drugs - Google Patents

Description

Cardiac glycosides, derived from Genin k-strophanthidin or derive strophanthidol, e.g. B. convallatoxin, convallatoxol, k-strophanthin, cymarin, cymarol, Helveticosid and Helveticosol, due to their special effectiveness and properties of action a special meaning for heart therapy. The application remains essentially limited to injection, as only a small proportion of these glycosides come from the gastrointestinal tract be absorbed. The absorption rates z. B. of helveticoside and cymarin are 0% and 20 to 30%. Therefore, when administered enterally, these compounds are therapeutically inadequate.

Numerous attempts have been made to obtain better absorbable cardiac glycosides from strophane to find thidine type or by chemical changes in the molecules, e.g. B. by acylation Hydroxyl groups, the resorptive properties zi

improve. So far, however, no glycoside derivative of the strophanthidine type has become known that would have done justice to the therapeutic properties sought, see. Vol. 13 (1963), pp. 142 to 149, and Dutch

ίο Disclosure Document 6 702 085.

The object of the invention is to provide a method for preparing a new class of cardiac glycoside derivatives to create that are very readily absorbable from the gastrointestinal tract and only minimally Show side effects.

The invention relates to a process for the preparation of cardiac glycoside derivatives of the general kind Formula I.

CH ₃

In the general formula I mean! ^ the aldehyde group (CHO; Genin = strophanthidine) or the methylol group (CH ₂ OH: Genin = strophanthidol). The sugar residue is derived from the Digitoxosc.

R denotes a saturated, unbranched or branched alkyl radical with 1 to 5 carbon atoms and R ₂ denotes a phenylalkyl radical with up to 2 carbon atoms in the alkyl radical. or a phenyl radical which is optionally substituted by up to three methyl or up to two methoxy groups.

It can be seen that the new cardiac glycoside derivatives of the general formula I are cyclic ketals, the remainder being

R ₁ - C - R,
of a ketone of the all-OH given below

common formula IV

C = O

derives, in which R ₁ and R _{2 have} the above meaning.

The names of the heart named in the examples

glycoside derivatives of the invention have been chosen for the sake of clarity; they are not in the Link long with the IUPAC nomenclature.

The method according to the invention is characterized by that one helveticoside, d. H. Strophanthidin-digitoxoside of the formula II

O H CH,

HO HC CH O

I I

HO-IIC O

CII

■ ()

OH

(Π)

OH

ml an excess of a ketal of the general formula III _{R | 0Ri}

(III)

OR, in which R ₁ and R _{2 have} the above meaning and R, is a lower alkyl radical, in the presence of an acidic condensing agent and optionally in the presence of an inert solvent at temperatures of 15 to 90 ° C and optionally the resulting cyclic ketal

general formula I, in which R is the formyl group, reduced in a manner known per se to the corresponding Helveticosol derivative (R = CH _{2 OH).}

The methyl or ethyl ketals are preferably used as ketals,

Examples of aromatic or araliphatic, optionally substituted ketones that are used in the form of their ketals are acetophenone, 2-, 3- or 4-methylacetophenone, 4-tert.-butylacetophenone, 2,4,5- "trimethy! Acetophenone, 2,4,6-trimethylacetophenone, 2-methoxyacetophenone, 4-methoxyacetophenone, 2,4-dimethoxyacetophenone, 2,5-dimethoxyacetophenone. Propiophenone, 1-, 2-, 3- or 4-methylpropiophenone, 4-methoxypropiophenone, 2,4-dimethoxypropiophenone, Butyrophenone, 2-, 3- or 4-methylbutyrophenone, 4-methoxybutyrophenone, valerophenone, caprophenone, isopropylphenyl ketone, isopentyl phenyl ketone, Benzyl methyl ketone, benzyl ethyl ketone, benzyl propyl ketone, benzyl isopropyl ketone, Benzylacetone, phenylethyl ethyl ketone and phenyl ethyl propyl ketone.

Acids such as hydrochloric acid, sulfuric acid or potassium hydrogen sulfate, anhydrous Lewis acids such as iron (III) chloride, zinc chloride or boron trifluoride etherate, or anhydrous copper sulfate can be used as condensation agents in the process of the invention. For the reaction of the ketals of the general formula III with helveticoside, a cation exchanger in the H ⁺ form is preferably used, which is stable in the temperature range of the reaction and under the reaction conditions. Organic exchangers are preferred. After conversion into the H ⁺ form by treatment with an inorganic strong acid, the exchanger is washed free of water with organic solvents and dried. After the reaction has ended, the reaction mixture is filtered off with suction from the exchanger. This avoids additional neutralization of the reaction mixture, which under certain circumstances / can lead to uncontrollable side reactions.

The procedure with a ketal of the general formula III using a cation exhauster in the H ⁺ form is because of the larger size

η turn width, the shorter reaction times, the higher yields and the lower formation of by-products are particularly preferred.

The ketal is used in excess and serves as a solvent for the μαρ ^ ηοηΜ ^ at the same time llelveticoside. If the helveticoside is sparingly soluble in the ketal used, a solvent inert under the reaction conditions, e.g. B. a lower aliphatic alcohol. Dioxane, tetrahydrofuran or a halogenated hydrocarbon such as chloroform or carbon tetrachloride, admit. The same applies in the event that the Ketal itself is in a solid state.

To avoid hydrolytic cleavage between genin and sugar residue , the reaction must be carried out in a largely anhydrous medium.

The method of the invention is conducted at temperatures of from 15 to 9O ^C 'C, preferably carried out at about 40 to 75 C. In this temperature range, the side reactions are limited to a minimum. In the preferred temperature range, the reaction times are between about 2 and 6 hours. The progress of the implementation is best followed on the basis of a thin-layer chromaiographic analysis. As soon as no more Helveticoside can be detected in the thin-layer chromatogram, the processing of the reaction mixture begins.

In the case of sensitive, easily oxidizable ketals, the method of the invention is preferably carried out in one Inert gas atmosphere, e.g. B. performed under nitrogen.

ίο The work-up of the reaction product takes place depending on the type of condensing agent used, after neutralization of the condensing agent or after filtering off the condensing agent, excess ketal is removed under reduced pressure or distilled off in a high vacuum at low temperature to prevent decomposition of the helveticoside derivative to avoid. Are the distillation temperatures but so high that r, 3 would result in decomposition, the reaction mixture is added to excess, low-boiling petroleum ether, the reaction product precipitating. In an analogous way can be obtained by rubbing the distillation residue with ether, gasoline or petroleum ether or through Precipitation of the dissolved in solvents which are miscible with aliphatic hydrocarbons, such as chloroform Distillation residue with petroleum ether, the crystalline Helveticosidderivate. The reaction product can also be diluted with petroleum ether on silica gel chromatographically of the not unsettled ketal

ίο separate and finally the cardiac glycoside derivative elute.

_{The corresponding helveticosol derivatives (R = CH 2} OH) can be prepared by reduction from the cyclic ketals of helveticoside of the general formula I in which R is the formyl group. The cyclic ketal is dissolved in a water-miscible solvent, water is added to the solution and a solution of sodium borohydride in water and the same organic solvent is added dropwise. The progress of the reduction is followed by thin layer chromatography. Particularly suitable water-miscible solvents are dioxane and tetrahydrofuran. After the reduction is complete, the solvent and water are evaporated off under reduced pressure and the Helveticosol compounds are obtained analogously to the procedure described above.

From general preparative organic chemistry is that used in the process of the invention Method known as I ^ nacctalisicrung. she will especially used for ketalization of sensitive carbonyl compounds.

The production of isopropylide compounds and benzylic compounds from acetone and sugar or benzaldehyde and sugar in the presence of acids is known from sugar chemistry. The direct reaction of cardiac glycosides with aldehydes or ketones in the presence of acids, however, also gives various by-products. This is also quite expected in the known instability of Acctalen and ketals in the presence vof <hydrogen ions. By C. Mannich and G. S ie wcrt, Ber. German former Ges. 75 (1942), p. 737, the reaction of cardiac glycosides with acetone and mineral acids is used in the example of c'es g-strophanthin to split off the sugar residue.

The preferred procedure of the invention provides in high detail rinlipWiifii «· η- ~, <.. <- · ..

768

The (icling of the I macetalization in the Her / glycoside Helveticosid is surprising, because in addition to the 1.2-hour Hydroxyl groups in the digitoxose residue of the molecule as well as various other reactive groups which, under the reaction conditions, could react either preferentially or in parallel. This could be done in the opposite way, in analogy to the usual application of 1 macetalization. the Aldehyde group in the 10-position of the steroid structure be acetalized by the alcohol component of the respective ketal. It could also be in some analogy to the aforementioned Mannich-Siewert split according to the conditions a (macetalization of the sugar with cleavage into genin and sugar acetal or ketal take place.

The helveticoside used in the method of the invention can, for. B. according to the procedure of the German Patent specification 1082 007 or the German Auslegeschrift 1 221 764 can be won. The ketals are obtained from the corresponding ' Ketones, e.g. B. by reaction with orthoformic acid esters. manufactured.

The new cardiac glycoside derivatives which can be prepared by the process according to the invention show on the contrary? to the starting compounds, which are only comparable to strophanthin when administered intravenously Show effect, surprisingly, a high enteral absorption rate. so that they can be used orally Therapy of heart failure can be used. Pharmacological testing of the new compounds was carried out in a known manner on cats by determining the lethal dose with intravenous Infusion.

The enleral absorption rates were calculated from the ratio of the lactaldoses to intraduodenal infusion calculated for the lethal doses with intravenous infusion or by intravenous titration after intraduodenal Specification determined.

Table I shows some examples of the high effectiveness and high resorption rate of the new Links.

Table I.

Carbonyte component of Glycoside derivative

ι V

Absorption rate

Ethyl benzyl ketone

helveticosid; 0.77; 86

Benzyl acetone '

helveticosid 0.47 73

Acetophenone ^:

helveticosid 1.28 78

Acetophenone

helveticosol 0.77 46

4-methylacetophenone

helveticosid 0.61 67

l-methylacetophenone

helveticosol 0.87 62

Butyrophenone helveticoside 1.8 60

c-sirophanthin ,. ' 0.128 7

helveticosid 0.09 0

The compounds hertellbaren by the process according to the invention can be used for the oral dosage form, for. B. as tablets. Pills. Capsules or dragees can be used. The oral preparations can also be provided with a magnetic seal.
Injection preparation. which contain an ore glycoside derivative which can be produced according to the invention are also produced in the customary manner. The substances are brought into an aqueous solution with the help of biologically compatible I ΟΜίημ mediators and are converted to a neutral to weakly alkaline solution by means of basic substances.

ίο see pH adjusted. The solutions are in Ampoules filled and sterilized in a known manner by heating.

The P i g. I gives the thin layer chromatographic Analyzes of the products prepared according to Example 1 and other products again. The investigations were carried out on silica gel plates. A mixture of petroleum ether was used as the release agent and ethyl acetate (30:70). The chromatograms were with vanillin-phosphoric acid reagent at 120 (developed in the drying cabinet. Some chromatograms show minor impurities, e.g. B. helveticoside and strophanthidin. for their elimination however, it has been omitted because their small proportion has no influence on medical use in Fig. 2 are some examples of IR absorption spots of the new cardiac glycoside derivatives in potassium bromide.

The examples explain the method according to the invention. The optical rotation values were based on solutions

to determined from 1 g of compound in 100 ml of chloroform

Example I. a) Acetophenone helveticoside

1.5 g of helveticoside are dissolved in 20 ml of acetophenone diethyl ketal and 1.5 g of a cation exchanger in the H 'form (for example the ion exchanger known under the trade name Lewatit S 100) are added. While stirring, the mixture is heated to 55 ° C. and the course of the reaction is followed by thin layer chromatography (silica gel, 10% methanol in chloroform as the mobile phase). After a reaction time of about 4 hours, no more helveticoside can be detected. The ion exchanger is suctioned off and the solvent is distilled off from the filtrate in a water jet vacuum in a rotary evaporator. The residue is digested with petroleum ether. Yield 950 mg of acetophenone helvetiroside.
Purification: on a chromatography column (80 g

Silica gel. Diameter 24 mm) you give the solution of acetophenone-helveticoside in a little chloroform and then eluted with chloroform.

The fractions with pure acetophenone-helveticoside are collected and evaporated. The residue is dissolved with a little chloroform and then precipitated with petroleum ether. Yield 95% of theory.

Instead of the relatively high-boiling acetophenone diet

to distill off acetal as described above. can it is also advantageous to remove the ionic

(o the exchanger, dilute the reaction mixture in a volume ratio of 1: 3 with petroleum ether and, regardless of any precipitated material, place it on a silica gel column (80 g silica gel, diameter 24mmi with petroleum ether

Petroleum ether eluted. until no more ketal expires. It is then eluted with chloroform and the pure acetophenone-helveticoside from F. 125 bis is obtained 134 C (decomposition !: [-0] - »- 1Γ.

hl acetophenone-borrowed icoso I

1.5 g of acetophenone-heheticoside are dissolved in 20 ml of 50% aqueous dioxane and replaced drop by drop for 1 hour with a solution of 0.5 t of niitrium borohydride in 20 ml of 75% of dioxane.

The reaction mixture is stirred for 1 hour, after which acetophenone-hetieoside can no longer be found prove. The solution is adjusted to pH 7 with dilute sulfuric acid and dioxane is added evaporated under reduced pressure in a rotary evaporator. The aqueous phase wild several times with Chloroform extracted.

The combined Chlorofotmextrakle are dried with anhydrous sodium sulfate and evaporated. The residue is chromatographed purified on silica gel. Chloroform is used as the solvent. Yield 750 mg Acetophenonhelveticosol from MP 154 to 164 C: [- / J * 0.

The aldehyde group is no longer in the IR spectrum verifiable. In addition to the reinforced hydroxy band in the 3500 cm 'range, the lactone carbonyl band and the double bond band are retained.

In the same way as described in example la) ^ 5 the hchelicoside derivatives listed in Table II were obtained by reacting llelveticoside with the corresponding ketals in yields between 4 (1 and 80 "η of theory, based on the Helveticoside. manufactured. '■■>

the .ile will be keep

h Reduction of the hall · η I l tiii: Vitriumhi-Hiulrid according to Example I bi

the corresponding Hchetico ^ olderhate he

1.1 Belle Il

KoIi ... ^ n! Ivu

Propionphenone helveticoside

a) Ethyl benzyl ketone helveticosid

b) ^: VJiylbcn />! ketone hcheticosol

4a) Ben / ylacetonhelveticosul

b) benzyl acetone heheticosol

Biiyrophenon

helveticosiil 6a) 4-Methylacetophenonhelveticosid 6bl I Meth \ lacetophenonheheticosol

1 (124 to 105 to 133 to 105 to 136 to I 20 to 131 to

126

114 144 I2 ^l > 141

bi-] S3

Claims (2)

Patent claims: I. Process / ur Mer ^ ellation \ on Her / iihkoMcldenvaten of the general formula I I- I O LU ₂ HC CH UC O O CH CH, OH OH in the R the Fornni- iCHOi or \ leth \ lol- iCH _; ( ¹ Hi (i group. R _{1 is} a saturated, undisturbed oxicv branched alkali radical with 1 to 5 carbon atoms and R is a phenoxy group with up to 2 carbon atoms in the alkali. Or a phen>! re> t. the case by up to / u three melh \! - odjr up to irwei methoxy groups, siihsimiicr * is ^; .. bcdeutci. thereby sckonn / ciJinei. that one he '^ etico-id of the formula II H CH ₁ CH- HO- HC CH - O - HO-HC O CH CH, OH ■ - = OH ill) with a Γ Ιητμ-ΊιιιΙ.Ι emc »KeIdK of general Formula III R, OR, The R 1 and R _{2 have} the above meaning and denotes a lower alkyl radical, in the presence of an acidic condensing agent and, if appropriate, in the presence of an inert solvent at temperatures from 15 to 10 ¹ M) (unisct / <and optionally the obtained cyclic kelal of the general formula I. in which R is the methyl group, reduced in a manner known per se / by the corresponding Helveticosol diva IR - (ICOL). 2. The method according to claim I. characterized in that '· a cation exchange ^! used in the acid form (II ^f form). V medicament containing a according to An Spruch 1 and 2 manufactured Herzglvkosidderivai in addition to the usual, pharmacologically acceptable Ingredients and auxiliaries. 1 sheet of drawings