DE1768140B - Process for the preparation of cardiac glycoside derivatives and drugs - Google Patents

Description

Cardiac glycosides derived from the genin k-strophanthidin or strophanthidol, e.g. B. convallatoxin, Con vallatoxol, k-strophanthin, cymarin, cymarol, Helveticosid and Helveticosol, due to their special effectiveness, have una effect properties 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, e.g. B. of helveticoside and cymarin, are 0 and 20 to 30%. Therefore, when administered enterally, these compounds are therapeutically inadequate Effectiveness.

Numerous attempts have been made to obtain better absorbable cardiac glycosides from strophic

The thidine type can be found or through chemical changes in the molecules, e.g. through the acylation of hydroxyl groups, to improve the resorptive properties. Up to now, however, no type of glycoside thidine has become known which would do justice to the therapeutic properties sought (cf. Arzneimittelforschung, Vol. 13 [1963], pp. 142 to 149, and Dutch laid-open specification 6 702 085.
The object of the invention is to provide a Veuahren

ig to create a new class of cardiac glycoside derivatives which are very readily absorbable from the gastrointestinal tract and show only minor side effects.
The invention relates to a process for the preparation of cardiac glycoside derivatives of the general formula I.

CH ₃

In the general formula I, R denotes the aldehyde formula IV
group (CHO; Genin = strophanthidin) or the

Methylol group (CH ₂ OH; Gemn = strophanthidol). R ₁

The sugar residue is derived from digitoxosis. ^N

_{R 1} and R 2 can be the same or different

and a saturated or olefinically unsaturated one. 35 ,

unbranched or branched alkyl radical with 1 to R-,

IO mean carbon atoms.

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

(IV)

R ₁ - C - R ₂

from a ketone all derives from those given below, in which R ₁ and R _{2 have} the same meaning.

The names of the cardiac glycoside derivatives of the invention given in the examples were given for reasons chosen for clarity; they are inconsistent with the IUPAC nomenclature.

The method according to the invention is characterized in that that one helveticoside, d. H. Strophanthidindigitoxosid. of formula II

• = O

OH

CH,

with an excess of a ketal of the general formula III _n r> _D

\ /
C (III)

in the

R ₂ OR.,

and R _{2 have} the above meaning and R, is a lower alkyl radical, in the presence of a cation exchanger in the acid form (H ⁺ form) and optionally in the presence of an inert solvent at temperatures from 15 to 90 ° C, and optionally the cyclic ketal obtained of the general formula I, in which R is the formyl group. reduced in a manner known per se to the corresponding Hclveticosoldcrivat (R = CH _{2 OH).}

The methyl oUers are preferred as ketals Ethyl ketals used.

Examples of aliphatic, saturated or olefinically unsaturated, branched or unbranched ketones, which are used in the form of their ketals are acetone, ethyl methyl ketone, diethyl ketone, methyl n-propyl ketone, Isopropyl methyl ketone, ethyl n-propylene ketone, butyl methyl ketone, ethyl isopropyl ketone, isobutyl methyl ketone, sec-butyl methyl ketone, pinacolin, di-n-propyl ketone, ethyl butyl ketone, n-amyl methyl ketone, ! sopropyl propyl ketone, 3-ethyl pentanone (2), butyl propyl ketone, ethyl n-amyl ketone, ethyl isobutyl ketone, Decyl methyl ketone, 7-ethyl-2-methylnonanone- (4), 2,6,8-trimethylnonanone- (4), di-n-hexyl ketone, n-amyl-n-heptyl ketone, butyl octyl ketone, decyl ethyl ketone, Decyl propyl ketone, diheptyl ketone, 6 - methyl - 5 - heptenone - (2), propyl isoamyl ketone, Hexyl methyl ketone, isobutyl propyl ketone. Btyl isopropyl ketone, ethyl isoamyl ketone, 5 - methylhepta bon - (3), 3 - methylheptanone - (2), dibutyl ketone, II - amyl propyl ketone, ethyl hexyl ketone, heptyl diethyl ketone, n-Amy! isopropyl ketone, diisobutyl ketone, isopentyl isopropyl ketone, di-tert.-butyl ketone, Hexyl propyl ketone, ethyl heptyl ketone, methyloctyl acetone. 3-methylnonanone- (2), hexyl isopropyl ketone, dipentyl ketone, butyl hexyl ketone, heptyl propyl ketone, Ethyl octyl ketone, methyl nonyl ketone, 3-butylheptanone - (2), diisopentyl ketone, butylheptyl ketone, Octyl propyl ketone and noiyl ethyl ketone.

For the conversion of the ketals of the general formula III with helveticoside, a cation exchanger in the H ⁺ form is used, which is stable in the temperature range of the conversion and under the retraction conditions. Organic exchangers are preferred. After conversion into the H ⁺ form by treatment with an inorganic Itarken acid, the exchanger is washed free of water with organic solvents and dried. When the reaction has ended, the reaction mixture is sucked off from the exchanger. In this way, one avoids additional neutralization of the reaction mixture, which under certain circumstances can lead to properly controllable side reactions.

The process with a ketal of the general formula III using a cation exchanger in the H ⁺ form is technically more advantageous because of the greater range of applications, the shorter reaction times, the higher yields and the lower formation of byproducts than :, in Offenlegungsschrift 1 568 216 proposed procedures.

The ketal is used in excess and, if appropriate, is used at the same time as a solvent for the helveticoside. If the helveticoside is sparingly soluble in the ketal used, it can also be used tin solvent inert under the reaction conditions, z. B. a lower aliphatic alcohol. Dioxane, tetrahydrofuran or a halogenated hydrocarbon, such as chloroform or carbon tetrachloride. The same applies in the event that the Ketal itself is in a solid state.

In order to avoid hydrolytic cleavage between genin and sugar crust, the reaction must be carried out be carried out in a largely anhydrous medium.

The process of the invention is carried out at temperatures from 15 to 90 "C, preferably at about 40 to 75 ° C. accomplished. 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 The progress of the implementation is best followed by means of a thin-layer chromatographic analysis. As soon as no more Helveticoside can be detected in the thin-layer chromatogram, the Work-up of the reaction mixture started.

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.

The reaction product is worked up after the cation exchanger has been filtered off, 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. Are the distillation temperatures however ··.> high that decomposition would result, then there is nan the reaction mixture in 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. One can use the reaction product also diluted with petroleum ether on silica gel chromatographically of the unreacted Separate the ketal and finally elute the cardiac glycoside derivative.

_{The corresponding helvcticosol 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 hydride 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 just described.

From the general preparative. organic chemistry is applied dip in the process of the invention Method known as transacetalization. It is specially used for the ketalization of sensitive carbonyl compounds used.

From sugar chemistry is the production of isopropylidene compounds and benzylidene compounds known from acetone and sugar or benzaldehyde and sugar in the presence of acids. at the direct reaction of cardiac glycosides with aldehydes or ketones in the presence of acids however, various by-products are also obtained. This is with the well-known instability of acetates and ketals can also be expected in the presence of hydrogen ions. By C. M a η η i c h and G. S i e w e r t, Ber. German former Ges. 75 (1942), P. 737, the reaction of cardiac glycosides with acetone and mineral acids using the example of g-slrophanthin used to split off the sugar residue.

The method according to the invention delivers in high

Yield uniform products. The success of the Transacetalization in the case of the cardiac glycoside helveticoside is surprising because in addition to the 1,2-hydroxyl groups various other reactive groups are present in the digitoxose residue of the molecule. which could react either preferentially or in parallel under the reaction conditions. So could in the opposite way, that is, in analogy to the customary application of transacetalization, the aldehyde group acetalized in the ΙΟ position of the steroid structure by the alcohol component of the respective ketal will. Furthermore, in a certain analogy to the Mannich-Siewert cleavage mentioned, according to the conditions a transacetalization of the sugar with cleavage into genin and sugar acetal or ketal ij take place.

The helveticoside used in the method of the invention can e.g. B. according to the method of German Patent I 082 007 or the German Auslegeschrift I 221 764 can be won. The ketals are made from the appropriate using methods known per se Ketones, e.g. B. by reaction with orthoformic acid esters. manufactured.

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

The enteral absorption rates were calculated from the ratio of lethal doses during intraduodenal infusion calculated for the lethal doses in the case of intravenous infusion or by intravenous titration determined intraduodenal specification. Table I shows some examples of the high effectiveness and high Absorption rate of the compounds which can be prepared according to the invention.

Table I.

Absorption rates of ketone derivatives
of Helveticoside and Helveticosol in cats

45

connection : Absorption rate
; Acetone-helveticoside .... .... 30th Acetone-helveticosol ·. - 54 Methyl propyl ketone helveticoside 100 Di-n-propyl ketone helveticoside 100 Hexen-l-one-5-helveticoside 4 =! Ethyl-hexyl-ketone-helveticosid 69 o-methylheptene-S-on-Z-helveticoside. 83 Ethyl-octvlketon-helveticosid > ·> k-StroDhanthin- 1 .... 7th Helveticoside 0

The compounds which can be prepared by the process according to the invention can be used for oral administration z. B. as tablets. Pills. Capsules or dragees can be used. Oral preparations can also be provided with an enteric coating.

Injection preparations that contain a cardiac glycoside derivative that can be produced according to the invention are even if made in the usual way. The substances are made with the help of biologically compatible solutions Mediators brought into an aqueous solution and durcl basic substances adjusted to a neutral to slightly alkaline pH value. The solutions will be filled into ampoules and sterilized in a known manner by heating.

In the drawing, some IR-Ab sorption spectra of those produced according to the invention are exemplified Cardiac glycoside derivatives are reproduced in potassium bromide

The examples illustrate the inventive method. The optical rotation values were adjusted to one Solution of 1 g of the compound in 100 ml of chloroform was determined.

Example I.

a) acetone helveticoside

1.5 g of helveticoside are added to 20 ml of 2,2-dimethoxypropane 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, heated to 50 ° C. with stirring; the helveticoside goes into solution. The course of the reaction is followed by thin-layer chromatography (silica gel: 10% methanol in chloroform as solvent). After a while, crystals separate out of the solution. After a reaction time of 6 hours, no more helveteticoside can be detected. The ion exchanger is suctioned off. The crystals adhering to the ion exchanger are dissolved with a little warm ethanol. The solution is added to the filtrate and evaporated. The residue is recrystallized with a mixture of ether and ethanol. Yield 1 g of acetone helveticoside with a melting point of 202 to 207 "C: [«] + 38 "; Lactone carbonyl band at 1730 and 1775 cm " ^1. Aldehyde carbonyl band at 1703 cm" ¹ . CC double bond band at 1612 cm "'. Geminal methyl group band at 1362 and 1372 cm" ¹ .

C ₃₂ H ₄₈ O ₀ (molecular weight 576.7):
Calculated ... C 66.6. H 8.4%:
found .... C 66.4. H 8.0%.

b) acetone-helveticosol

1.5 g of acetone helveticoside are dissolved in 20 ml of 80% strength aqueous dioxane and added dropwise within A solution of 0.35 g of sodium borohydride in 20 ml of 75% strength dioxane is added for 1 hour. The The reaction mixture is stirred for 1 hour, after which acetone-helveticoside can no longer be detected. The solution is adjusted to pH 7 with dilute sulfuric acid and dioxane is reduced under reduced pressure Pressure evaporated in the reaction evaporator. The aqueous phase is extracted several times with chloroform. The combined chloroform extracts are dried with anhydrous sodium sulfate and evaporated. The residue is purified by chromatography on silica gel. The solvent used is chloroform used. Yield 750 me acetone-helveticosol from F. 157 to 166 = C: [<;]: + 24 \

The aldehyde group can no longer be detected in the IR spectrum. Next to the reinforced hydroxyl band

1 5 - A

The L.acton carbon fiber bands remain in the 3500 cm range and get the double bonds.

In the same way as described in example la). If the Helvcticnsidderivate listed in Table II by reacting Helveticosid with the corresponding Ketalcn in yields between lind 80% of theory, based on ί if used Helveticoside. manufactured.

By reducing the obtained Helveticosidderivate with sodium hydride according to Example I b) obtained the corresponding Helveticosol derivatives.

Table Il Example,

llelvelicoMil- h / w. llelveticosoldcrnate

l ·. C.

2 a methyl propyl ketone

i helveticosid

2b j Victhylprop '/ iKetone helveticosol

3; Diethyl ketone

helveticosid

4a! Di-n-propyl ketone

I helveticosid

4b ■ di-n-propyl ketone

j helveticosol

5 j butyl ethyl ketone

I helveticosid

(S 'methylisopropyl-I ketone-helveticoside

7 I methyl isobutyl

¹ ketone-helveticoside S hexen-l-one-5-hel-

veticosid

Witches-l-on-5-heI-

veticosol

10 ^j methyl decyl ketone

helveticosid

Ethyl hexyl ketone

helveticosid

6-methyl-hepten-on-2-helveticosid ....

13; n-amyl-methyl-

ketone-helveticoside

14 methyl ethyl ketone

helveticosid

15 methyl ethyl ketone

heKeticosol

to 118! +

i 152 to

105 to

j 45 to

j 136 to

17th

+

+ 17 "

77 to 83 j ^ 31

123 to 132 j +30

114 to 123 j - ^ 32.4

103 to 117 j +30

137 to 144 ^: +18 6X to 78! +

S3 to 95 j +28 "86 to 93; ^ 97 to 102! -31

ISl to 1S4

112 to

45

In German Offenlegungsschrift 1,568,216 tin process for preparing cyclic ether of t'ardenolid-Digitoxosiden (cyclic ethers, among others, of Helveticosid and Helvcticosol is * vorgelchiagen in which Helveticosid or Helveticoso with liiedrigmolekiilarcn aliphatic, possibly un- <*> |.! Csättigten . t ketones or reactive derivatives thereof. B. the lower Dialkylkelalen. be implemented. as defined in the general formula Ilaben the radicals R ₁ and R, together up / u 6 carbon atoms. For this Ketalisicrungsrcakiion be as Ka ^fl 5 analyzers e.g. freshly melted zinc chloride, anhydrous copper sulfate, anhydrous calcium sulfate, phosphorylated cellulose preparations.

Gen. Fs is stated that the catalysts used must not be so strongly acidic that; they split the digitoxoside.

Cation exchangers contain carboxyl and / or sulfonic acid groups. some considerably stronger The degree of dissociation shows, for example, the phosphorylated cellulose mentioned in the laid-open specification. This can be done by comparing the rate of esterification of acetic acid and ethanol (mol ratio about 2: 1) in the presence of equal amounts of grams and in the presence of equal amounts of equivalent (based on the FI 'capacity). The acetic acid consumed in the esterification was according to known Methods determined litrimetrically. The H * capacity of the ion exchanger was determined according to det Regulation in H e 1 f ft; r i c h. »Ion exchanger«. Vol. 1. P. 81 to 83. for the dried ion exchanger definitely.

Lcwatit * p. 100
MN 300 GP *).

Capacity: 5.9 meq. G.
Capacity: 0.62 meq. / G.

* l Phosphor ;, lated cellulose pair by makers and Nacel

Approach 75 ml of glacial acetic acid. 25 ml of ethanol, reflux.

■ I / eil I

Esterification

[S. HK) j MN. '(MKiP

60 minutes
120 minutes
240 minutes

62%
70%
SI ⁰ ,,

26%
33 ° o
50%

MN 300 OP

43%
54%
57%

Apart from the fact that the Eins & iz is so big Catalyst quantities such as 30 g MN 300GP for a reaction batch of IOP ml are economically unfavorable is. the reaction rate was considerably slower despite the same equivalents. With the ion exchanger Lewatit S. ' 100 the theoretical maximum yield was reached after about 4 hours and the reaction ended. The yield of 57% after 4 hours with the exchanger MN 300 GP corresponded to the degree of esterification with Lewatit S. "100 after about 45 minutes.

For comparison, the reactions between helveticoside and ethylhexylketone diethylketal were carried out in the presence of Lewatit S. ⁼ 100. MN 300 GP and anhydrous CuSO ₄ and followed by thin-layer chromatography.

Approach: 1 g of helveticoside. 20 ml ethyl hexyl ketone diethyl ketal. 10 ml water-free ethanol and Is Lewatit S * 100 or 5.8 ε MN 300 GP or 2 g anhydrous CuSO ₄ .

It was found that the reaction under the conditions of the process according to the invention an hour was almost complete. the reaction was in the presence of the MN 300 GP catalyst after 4 hours it is estimated to have expired by 10%, in addition to helveticoside and the desired helveticoside derivative however, there was also considerable mense of strophanthidin. in the reaction mixture with copper sulfate the conversion ratios were approximately the same after 5 hours as in the approach with Lewatit S * 100 after 1 hour.

109 551/506

The comparative experiments show.

1. that contrary to the postulate of the Offenlegungsschrift 1 568 216 strongly acidic cation exchange ^ " used as catalysts in the production of cyclic ethers of Helveticoside with advantage can be

2. that said reaction in the presence of

strongly acidic, cation exchangers considerably cheaper in chemical, technical and economic terms Respect runs.

3. that substances are also converted under the conditions of the process according to the invention can that do not enter into the implementation or only with low yields. This is particularly true for aliphatic long-chain ketones.

Claims (2)

Patent claims:
I. Process for the preparation of cardiac glycoside derivatives of the general formula I. in which R is the formyl (CHO) or methylol (CH ₂ OH) group and R ₁ and R ₂ . which are identical or different are a saturated or olefinically unsaturated, unbranched or branched alkyl radical having from 1 to 10 carbon atoms, characterized in that helveticoside of the formula II O H \ / CH ₃ C (H) with an excess of a ketal of the general formula III R, OR ₃ (III) OR ₃ in which R ₁ and R _{2 have} the above meaning and R _{3 is} a lower alkyl radical. in the presence of a cation exchanger in the acid form (H ⁺ form) and optionally in the presence of an inert solvent at temperatures from 15 to 90 ° C. and optionally the resulting cyclic ketal of the general formula I, in which R is the formyl group, in itself reduced in a known manner to the corresponding HeI-veticosolderivat (R = CH _{2 OH).} 2. Medicaments containing a cardiac glycoside derivative prepared according to claim 1 in addition to the usual, pharmacologically acceptable carriers and auxiliaries. 1 sheet of drawings