DD219489A1 - PROCESS FOR THE PREPARATION OF CARDA-16,20 (22) -DIIENOLIDES AND CARDA-16,20 (22) -DIOLIDE GLYCOSIDES - Google Patents

Abstract

The invention relates to a process for the preparation of Carda-16,20 (22) -dienoliden and Carda-16,20 (22) -dienolidglykosiden of the formula I, which in addition to the conjugated ungesaettigten double bond system of the 17-term butenolide still another conjugated CC double bond in Own 16.17 position. The compounds show inhibition of the (Na, K) -ATPase in the concentration range typical for cardiac cardenolides. According to the invention, corresponding 16-position-substituted genols or glycosides in dimethylformamide, optionally with the addition of 5% tert-butyl alcohol, are heated to 70-90 C with anhydrous sodium acetate or potassium tert-butylate, whereby the 16-acetoxy group is eliminated. The invention is applicable in medicine, especially for the therapy of heart failure. Formula I

Description

-η-

Di-. C. Lindig B. Streckenbach H. Scheer I. Süranich

"Process for the preparation of Carda 16,20 (22) -dienolides and Carda-16,20 (22) -dienolide-glycosides" .

Field of application of the invention

The invention relates to a process for the preparation of Carda 16,20 (22) -dienoliden and Carda-16,20 (22) -dienolidglykosiden of the general formula I.

1 2

where R 8 is a hydrogen atom or a hydroxy group, R is a hydrogen atom or a hydroxy or acyloxy group, R " ^{5 is} a methyl, hydroxymethyl, acyloxymethyl or aldehyde group and R is a hydrogen atom, an acyl radical, for example an acetyl radical, or an optionally acylated mono- These compounds have, in addition to the conjugated unsaturated double bond system of the 17-butenolide ring recognized as the pharmacophore group, another conjugated C = C double bond in the 16,17-position. The field of application of the invention is medicine, especially therapy of heart failure.

Characteristic of known technical solutions > Some type I compounds are already known. The preparation of 16-anhydro-gitoxigenin from gitoxigenin by heating for 24 hours in dimethylformamide with anhydrous sodium acetate and anhydrous sodium tosylate at 110-13O ⁰ C was described by REICHSTEIN and Mitarb., Yielding 64 % of the target compound (3.H. RÜSSEL, O. SCHINDLER and T. REICHSTEIN, HeIv. Chim. Acta 43, 167 (1960)). Far more conservative is the elimination of the lOS acetoxy group by contact with neutral active alumina in the presence of benzene, which has been repeatedly observed in the purification of glycosides of oleandrigenin, a 16-Q acetylgitoxigenin, by chromatography on alumina (A. HUNGER Acta ZZ, 75 (1950); A. AEBI and T. Reichenstein, Heim. chim. Acta 33, 1013 (195Q)), - and occasionally for the Production of Carda 16,20 (22) -dienolides and their glycosides (K. MEYER, HeIv. Chim. Acta 29, 718 (1945); A * AEBI and T. REICHSTEIN, .. HeIv. Chim. Acta 33, 1013 (1950); G. RABITZSCH uK DRESSLERy Pharmacia 22, 722 (1967)). A disadvantage of this method is that a conversion rate of only 30 % is achieved under the abovementioned reaction conditions, which results in complicated separation by column chromatography from the starting compounds Chromatographically only slightly different Carda-16,20 (22) -dienolide required Finally, the acetoxy-elimination of 16-0-acetyl-gitoxin was described by heating with dry potassium bicarbonate in acetonitrile, but without specifying the yield (K. LINGNER, K. IRMSCHER, W. KOSSNER, R. HOTOVY and others GILLISSEN, Arzneim.-Forsch. (Drug Res.) 13, 142 (1963)).

Object of the invention

The object of the invention is the development of a generally applicable process for the preparation of Carda 16,20 (22) -dienolides and Carda-16,20 (22) -dienolid glycosides of the invention.

 -. 3. -

mel I by Acetoxyelirainierung accordingly in the 16-position. of the steroid skeleton by an acetoxy group of substituted genols or glycosides.

Explanation of the essence of the invention

According to the invention, Carda 16,2Q (22) -dienolides and carda-16,20 (22) -dienolid glycosides of general formula I are prepared by reacting a corresponding Card-20 (22) -enolide or a corresponding Card-2O ( 22) -enolenglycoside of the formula II

0-

OR ⁵ π,

wherein R to R have the meaning mentioned above in formula I and R represents a hydrogen atom or an acetyl radical, optionally after partial acetylation of a compound of formula II in the event that R represents a hydrogen atom, for selective eliraination of the 16-acetoxy group in itself Known manner (C. LINDIG and K. REPKE, DDWP 125 129 ν 27 ♦ 10.1975) in dimethylformamide with a suitable basic catalyst, preferably with anhydrous sodium acetate or potassium tert-butoxide heated. The use of potassium tert-butoxide as a basic catalyst is advantageously carried out in 5 % tert-butyl alcohol-containing dimethylformamide. The reaction is carried out in a temperature range of 60 ° to 120 ⁰ C, preferably at 70 ° - 90 C ₁ in an inert gas atmosphere, for example in a nitrogen or argon atmosphere. The resulting compounds of formula I can

be purified according to known methods such as distribution, chromatography and / or recrystallization. The producibility of the Carda 16,2O (22) -dienolides and the glycosides of the formula I derived therefrom by the process according to the invention is surprising insofar as according to LINGNER et al. (l <· LINGNER, K. IRMSCHER, W. "KÜSSNER, R. J. Hotový u _#J GILLISSEN, Arzneira. ♦-Forsch (Drug Res.) 13, 142 (1963)), other solvents acetonitrile worse than for the Acetoxyeliminierung or are not suitable at all and the potassium bicarbonate used by these authors can not be replaced by another basic agent. The carda-16,20 (22) -dienolides and carda-16,20 (22) -dienolide glycosides prepared according to the invention have valuable cardioactive properties and are suitable for the treatment of cardiac insufficiency ^ In molecular biological value assessment with the coupled optical test in equilibrium (W. SCHONER, C. VON ILBERG, R. KRAMER, and W. SEUBERT, European 0 · Biochem., 1, 334 (1967)) inhibit the (Na, K) -activated adenosine triphosphate phosphohydrolase of the human heart muscle in the human heart muscle cardiogenic cardenolide typical concentration range, which correlates with a positive inotropic effect on the insufficient heart.

The erfindungsgeraäße method will be explained in the following embodiments.

embodiments Example 1 '

A solution of 50 mg of 3,16-Dx-O-acetyl-gitoxigenin in 5 ml of absolute dimethylformamide is heated with 50 mg of anhydrous sodium acetate for 2 hours at 90 ° with exclusion of moisture (argon) * Then the dimethylformamide is removed in vacuo » the residue taken up with 30 ml of methylene chloride, the methylene chloride solution with 0.1 η hydrochloric acid, 0.1 M

KHC0 ₃ solution and water washed neutral and dried over sodium sulfate. After removal of the solvent in vacuo, the residue is chromatographed on 20 g of silica gel H (short column, 21 cm filling height). Elution with methylene chloride-EtOH- (99.25: 0.75) gives 30 mg (70 % of theory) of chromatographically pure SO-acetyl-lβ-anhydro-gitoxigenin (= 3β-aoetoxy-14-hydroxy-5β, 14β -carda-16,2Q (22) -dienolid) .From acetone-heptane needles, melting at 204-206 ⁰ C (Lit. 207-208 ⁰ C; K. Meyer, Helv Chim Acta 29, '718 (1946.. )). UV spectrum: 7? _max 270.5 nra logs 4 # 30). IR spectrum (in KBr): 1236 iu 1254 (COC 3β-acetoxy and butenolide), 1608 u. 1620 (C = C conc.J, 1715 (C = Q.beta.-acetoxy), 1733 and 1779 (C = O conc.-unsaturated ^ f-lactone), 3438 Ui 3538 cm ^-1 (OH).

Example 2 .

As Example 1, but using a mixture of dimethylformamide with 5 percent by volume of tert-butyl alcohol instead of pure dimethylformamide and potassium tert-butylate instead of sodium acetate and at a reaction temperature of 70 ⁰ C, to obtain SO-acetyl-l-anhydro-gitoxigenin in comparable yield as under Example 1. The IR spectra of the preparations prepared according to Example 1 and Example 2 are identical. '

Example 3

A solution of 100 mg of oleandrin in 5 ml of absolute dimethylformamide is heated with 100 mg of anhydrous sodium acetate for 3 hours at 80 ⁰ C with exclusion of moisture (argon). After cooling the batch, the dimethylformamide is stripped off in vacuo, the residue taken up with 30 ml of methylene chloride, the Methylenchlorxd solution with 0.1 «n hydrochloric acid, 0.1 M KHCO ₃ solution and water washed neutral and dried over anhydrous sodium sulfate. After removal of the solvent in vacuo, the residue (86 mg) is suspended on 20 g of silica gel.

gel H (short sump, 22 cm filling height) chromatographed with methylene chloride-EtOH- (98.5: 1.5) and gives 72 mg (79 % of theory) of Lö-deacetyl-he-anhydro-oleandrin. From acetone-heptane flat sticks of F 237.5 - 239 ⁰ C (Ref .: 230 - 234 ⁰ C, A. AEBI and T. REICHSTEIN, HeIv chim. Acta ^ 3, 1013 (1950)). UV spectrum: 7l _max 271 nm (log 4.31). IR spectrum (in KBr): 1614 (C = C conj.), 1703 (C = O subj 4 unsaturated y-lactone), 3453 u. 3533 cm " ¹ (OH).

Example 4

A solution of 1.0 g of 3 ', 3'',3''', 4 ''', 16-penta-Q-acetylgitoxin in 70% absolute absolute dimethylformamide with 820 mg of anhydrous sodium acetate for 3 hours at 80 ⁰ C with exclusion of moisture (Argon) heated. Thereafter, the dimethylformamide is removed in vacuo, the residue is taken up in 100 ml of chloroform, the chloroform solution is washed with saturated sodium chloride solution and water ¹ and dried over sodium sulfate. After removal of the solvent in vacuo, the residue is chromatographed on 100 g of silica gel H (110 cm filling height). Elution with chloroform-ethyl acetate (97: 3) gives 658 mg (71 % of theory) of chromatographically pure 3 ', 3'',3''', 4 * ^fl -fetra-O-acetyl-16-anhydro- gitoxin. From ether-Pentah crystals, melting at 181-183 ⁰ C (Lit. 183-135 ⁰ C; G. RABITZSCH, K. Dressler, Pharm 22 ^ 723 (1967).). UV spectrum: ^ _ 271 nm (log £ 4.23). IR spectrum (in KBr): 1245 (COC butenolide), 1620 (C = C konj.), 1740 and 1775 (C = O conc. Uns. ^ Lactone), 3510 Eis (OH).

Claims (1)

invention claim A process for the preparation of Carda-l6,2Q (22) -dienolides and Carda-16,2Q (22) -dienolid glycosides of the general formula I ₁ . 0- OH y ρ wherein R is a hydrogenator or a hydroxy group, R is a hydrogenator, a hydroxy group or acyloxy group, R a methyl, hydroxymethyl, acyloxymethyl or aldehyde 4 hydrogroup and R is a hydrogen atom, an acyl radical, for example an acetyl radical, or an optionally acylated mono- or oligosaccharide radical in glycosidic bond, characterized in that a corresponding card-20 (22) -enolide or a corresponding card-20 (22) -enolide glycoside of the formula II 0th 14
in which the radicals R to R have the meaning given in formula I and R represents a hydrogenator or an acetyl radical, optionally after selective acetylation of a compound of the formula II in the event that R is a hydrogen. atom, in a conventional manner in Oimethylform- amide, optionally with the addition of 5% tert-butyl alcohol, with a basic catalyst, preferably with anhydrous sodium acetate or potassium tert-butoxide, to 60-120 ⁰ C,
preferably to 70-90 ⁰ C ₁ in an inert gas atmosphere of play, heated at · in a nitrogen or argon atmosphere, and the obtained compounds of formula I according to
known methods such as distribution, chromatography and / or. recrystallize cleans. .