DE1768054C - Process for the manufacture of cardiac glycosides and drugs - Google Patents

Description

Cardiac glycosides derived from the genin k-strophanthidin or strophanthidol, e.g. B. convallatoxin, Convallatoxol, k-strophanihin, cymarin. Cymarol, Helveticosid and Helveticosol, due to their special effectiveness and properties, are of particular importance for cardiac therapy. The application remains essentially limited to the injection, since these glycosides only to a small extent are absorbed from the gastrointestinal tract. The absorption rates z. B. from Helveticoside and cymarin are 0 and 20 to 30%, respectively.

Therefore, when administered enterally, these compounds are therapeutically inadequate.

Numerous attempts have been made to find more absorbable cardiac glycosides from Strophan thidintyp or by chemical changes in the molecules, eg. B. by acylation of hydroxyl groups to improve the resorptive properties. Up to now, however, no glycoside derivative of the strophapthidine type has become known which would do justice to the therapeutic properties sought (cf. Arzneimittelehorschung. Vol. 13 [1963], pp. 142 to 149. and Dutch laid-open specification 6 702 085).

The object of the invention is to provide a process for the preparation of 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 formula I.

CH ₃

^ O _x / CH ₂

In general formula I, R denotes the aldehyde group (CHO; Genin = strophanthidine) or the methylol group (CH ₂ OH; Genin = strophanthidol). The sugar residue is derived from digitoxosis.

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 alkyl radicals with 1 to 6 carbon atoms.

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

R ₁ C

45

R ₁ C = O (IV)

derives.

The names of the cardiac glycoside derivatives of the invention mentioned in the examples have been derived from Founder chosen for clarity; they are inconsistent with the IUPAC nomenclature.

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

with an excess of a ketal of the general 60 in which R has the above meaning and R _{2 is} a lower one

formula III

OR,

OR ₂

(IN THE) Alkyl radical is, in the presence of an acidic reacting! Kondcnsationsmittelii and optionally in the presence of an inert solvent at tempera doors from 15 to 90 ⁰ C and optionally f> 5 the resulting cyclic ketal of the general F01 mcl I, in which R is the formyl group, in a manner known to them to the corresponding Helveticosol derivative (R = CH ₂ OH) reduced.

The ketals are preferably the methyl or Use Alhylkctalc).

Examples of cycloaliphatic, unsubstituted or substituted ketones, which are used in the form of their ketals, are cyclobutanone, Cyelopenianüii 5 and its alkyl derivatives such as 3-methylcyclopentanone and 3,4-dimethylcyclcipentanone, cyclohexanone and its allvyl derivatives, such as 2-, 3- and 4-methylcyciohexanone, 4-ethyl- and 4-ICrL-BuIyICyClOhCXaHOn, 3,5,5-trimethylcyclohexanone (= dihydroisophorone), menthone, cycloheptanone and its alkyl derivatives, Cyclooctanone, cyclononanone, cyclodecanone, cyclododecanone, camphor and bicyclo [2.2, l] heptan-l-one (Norkampfer).

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 ke'ale 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. In this way, additional neutralization of the reaction mixture, which under certain circumstances can lead to uncontrollable side reactions, is avoided.

The process with a ketal of the general formula III using a cation exchange ^^ in the H ⁺ form is particularly preferred because of the greater range of applications, the shorter reaction times, the greater yields and the lower formation of by-products.

The ketal is used in excess and optionally also serves as a solvent for the Helveticoside. Is the Helveticcsid in the used Ketal sparingly soluble, you can also use a solvent that is 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 to the case that the Ketal itself is in the solid state. v>

To avoid the hydrolytic cleavage between Genin and sugar residue, the implementation in largely anhydrous medium.

The method of the invention, in Temperaluren of 15 to 90 ⁰ C, preferably at about 40 to 75 ° C is performed. 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 using thin-layer chromatography. see analysis. As soon as no more Helveticoside can be detected in the thin-layer chromatogram, Treat yourself to working up the reaction mixture.

In the case of sensitive, easily oxydableti ketals, the method of the invention is preferably carried out in a f '

In-gas atmosphere, e.g. B. performed under nitrogen.

The reaction product is worked up depending on the type of condensing agent used after neutralization of the condensation agent or after filtering off the condensation agent ;;. Excess ketal is distilled off under reduced pressure or in a high vacuum at low temperature, in order to avoid decomposition of the helveticoside derivative. Are the distillation temperatures but so high that decomposition would result, the reaction mixture is added in excess, low-boiling petroleum ether, the reaction product precipitating. Received in an analogous manner by rubbing the distillation residue with ether, gasoline or petroleum ether, or by precipitating it that is miscible with aliphatic hydrocarbons Solvents, wi. ' Dissolved chloroform Distillation residue with petroleum ether the crystalline Helveticoside derivatives. The reaction product can also be diluted with petroleum ether on silica gel Separate chromatographically from unreacted ketal 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 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 ier 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. Mannich and G. You worth, Ber. German former Ges. 75 (1942), p. 737, the reaction of cardiac glycosides with acetone and mineral acids is exemplified by the g-strophanthin used to split off the sugar residue.

The preferred procedure of the invention provides uniform products in high yield. The Successful transacetalization with the cardiac glycoside helveticoside is surprising because in addition to the 1,2-permanent Hydroxyl groups in the digitoxose residue of the molecule as well as various other reactive groups are present, which could react either preferentially or in parallel under the reaction conditions.

This could be done in the opposite way, that is to say in analogy to the customary application of transacetalization. the aldehyde group in the 10-position of the steroid structure can be acetalized by the alcohol component of the respective ketal. Furthermore, in certain ana- ^; Logy for the Mannich-Siewert cleavage mentioned, according to the conditions, a transacetalization of the sugar with cleavage into genin and sugar acetal or ketal take place.

The HeI veticoside used in the process of the invention can e.g. B. by the method of German patent specification 1 082 007 or the German Auslegeschrift 1 221 764 can be obtained. The ketals are made according to methods known per se from the corresponding ketones, ζ. B. by reaction with orthoformic acid esters produced.

The novel cardiac glycoside derivatives which can be prepared by the process according to the invention are shown in In contrast to the starting compounds, which only add to the strophanthin when administered intravenously show comparable effect, surprisingly a high enteral absorption rate, so that they are oral can be used to treat heart failure. Pharmacological testing of the new Compounds were carried out in a known manner on cats by determining the lethal dose when administered intravenously 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 Up titration determined according to intraduodenal specifications.

Table I shows some examples of the high effectiveness and high absorption rate of the compounds.

Table I.

C'irbonvlcomponent of (il \ kosidderival <

i. ν effective dose
DL _irn in mg lci!

Cyclopentanone helveticoside ..

Cyclohexanone helveticoside ..

2-methylcyclohexanone helveticoside

4-methylcyclohexanone helveticoside

Cycloheptanone

helveticosid

k-strophanthin- .;

Helveticoside

0.26

0.34 to 0.67
0.39
1.29

1.24

1.28
0.09

tion quotc

75

58

65

65

67

40

45

Those producible by the process according to the invention Compounds can be used for oral administration z. B. as tablets. Pills. Capsules or coated tablets. The oral preparations can also be made with a gastric juice-resistant one Be provided with a coating.

Injectables. which can be produced according to the invention Cardiac glycoside derivatives are also prepared in the usual way. The substances are made with the help of biologically compatible solubilizers Brought into an aqueous solution and neutralized by basic substances slightly alkaline pH adjusted. The Lösuneen are filled in ampoules and in well-known Wefse sterilized by heating.

Fig. I gives the thin-film diromatographic Analyzes of the products prepared according to Example I and other products again. The investigations were stirred on silica gel plates. A mixture of petroleum ether served as the flow agent and ethyl acetate (30:70). The chromatograms were made with vanillic phosphoric acid reagent at 120 "C Developed in the drying cabinet. Some chromatograms show minor impurities, e.g. B. Helveticosid and strophanthidin, but we did not remove them because they were lower Proportion is without influence on the medical use.

In Fig. 2 are some IR absorption spectra by way of example of the new cardiac glycoside derivatives in potassium bromide.

The following examples illustrate the process according to the invention. The optical rotation values were determined on solutions of 1 g of compound in 100 ml of chloroform.

example 1

a) Cyclohexanone helveticoside

1.5 g of Helveticoside are dissolved in 20 ml of cyclohexanone diethylketai 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. The mixture is heated to 55 ° C. with stirring and the course of the reaction is followed by thin layer chromatography. 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 850 mg of cyclohexanone helveticoside.

Purification: The solution is added to a chromatography column (80 g of 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. [«K + 34 °.

IR bands in relation to the helveticoside: decrease in the hydroxyl ^{band at 3500 cm "1.} Increase in the CH ₂ band at 2925 and 1447 cm"'compared to the carbonyl intensities. Lactone carbonyl band at Π40 and 1776 cm " ^1. Aldehyde carbonyl band at 1710 cm" ¹ . CC double bond at 1620 cm " ¹ .

C ₃₅ H ₅ , 0 ₉ :

Calculated ... C 68.ZH 8.5 ⁰ O: found .... C 69.1 H 8.5%.

b) Cyclohexanone-helveticosol

1.5 g of cyclohexanone helveticoside are dissolved in 20 ml of 80% strength aqueous dioxane and added dropwise a solution of 0.35 g of sodium borohydride in 20 ml of 75% strength dioxane was added within 1 hour. The reaction mixture is stirred for 1 hour, after which no cyclohexanone heheicoside can be found prove more. 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 is several times with Chloroform extracted.

The combined chloroform extracts are dried with anhydrous sodium sulfate and concentrated eViV.pft. The residue is chromatot'apiiisch on silica gel cleaned. Chloroirm is used as a solvent. Yield 750 mg cyclohexanone elveticosol from F. 155 to 164 C. [<i] +23.

The aldehyde group is no longer detectable in the IR spectrum. In addition to the reinforced hydroxyl ^{band in the 3500 cm "1} area, the lactone carbonyl band and the double bond band are retained.

Table II ' ⁵

,. Hclvettcosid- lv »

Ik'example [lclvelicosolilcrival

l · '.. C

2a i cyclopentanone- j 190 to 192 j helveticosid

2 b j cyclopentanone- 179 to 184

I helveticosol j

3 a j cycloheptanone 118 to 124

liid

12 '

+ 28 '

+ 2.V

I helveticosid

3b! Cycloheptanone- j 135 to 141 I helveticosol |

4 i Cyclododecanon- | 129 to 139 j +21 I helveticosid ι

5 I 4-methylcycloj hexanone

! helveticosid

128 to 135; +29

20th

25th

Hot example

Helvclicosid- h / w. Helvcticosolderival

K. C

7 8 9

10

11 12

13 2-methylcyclo-

hexanone- j

helveticosid j

Dihydroisophorone-115 bis

helveticosid,

Menthone

helveticosid 2-butylcyclo-

hexanone

helveticosid 2-cyclohexyl-

cyclohexanone

helveticosid ( ⁺ ) camphor

helveticosid 3-methylcyclo-

hexanone

helveticosid

Cyclobutanone helveticoside

*) Mp of the crude product.

(80 to 110) *) 70 *)

70 *)

78 to 80 *) 128 to

117 to

Η · '

129 to 130 '+27

+

The compounds listed in Table II were prepared according to Examples Ia and 1b.

Claims (3)

Patent claims: 1. Process for the preparation of cardiac glycoside derivatives of the general formula I O, CH, _χ / CH CH-O- \ CH / OH OH CH, in which R is the formula iCHOi or methylol (CH ₂ OH) group and R ₁ together with the cooling substance forms a cycloaliphatic radical with 4 to M carbon atoms in the ring, which is optionally substituted by alkylene radicals with 1 to 6 carbon atoms . characterized in that one helveticoside of the formula II CH; HO-CH CH-O-. HO-CH O CH CH, OH OH 209 617 / 2f with an addition of a ketal of the general Formula III OR, OR, in which R _{1 has} the above meaning and R _{2 is} a lower alkyl radical. in the presence of an acidic condensing agent and optionally in the presence of an inert solvent by means of reacting at temperatures of 15 to 90 C and optionally reducing the resulting cyclic ketal of the general formula I. in which R is the formyl group, in a manner known per se to the corresponding Helveticosol derivative (R = CH ₂ OH)! .. 2. The method according to claim I. characterized in that a cation exchanger in the acid form (H ⁺ form) is used as the acidic .reagierendes condensation agent. 3. Medicament containing a cardiac glycoside derivative prepared according to claim 1 and 2 in addition to the usual, pharmacologically acceptable carriers and auxiliaries. For this purpose 2 sheets of drawings