DE2149187A1 - NEW, ENTERAL EFFECTIVE PERIPLORHAMNOSIDE DERIVATIVES AND THE METHOD FOR THEIR PRODUCTION - Google Patents

Description

New, enterally active periplorhamnoside derivatives and processes for their preparation

The invention relates to new, enterally active periplorhamnoside derivatives of the general formula I.

₃ ,

where R ₁ is hydrogen, methyl, ethyl, methoxymethyl, ethoxymethyl or the acyl radical of a carboxylic acid with 1-5 C atoms

.individually
men means that R ₂ and R ₃ / ″ are identical or different and represent a lower alkyl radical or, together with the common carbon atom, form a 5- or 6-membered alicyclic ring.

Periplorhamnoside, the aL-rhamnoside of periplogenin, occurs in the seeds of Antiaris toxicaria Lesch (Reichstein et al., HeIv. 47 , 2164 (1964)) and in the flowers and leaves of Convalla-

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ria majalis l>. (Kubelka et al., Monatsh. Chera. J48, 1262 (1967)) and is also partially synthetically accessible from convallatoxin (Reichstein et al., HeIv. 46, 117 (1963)) or periplogenin. Due to the structure of its aglycon (methyl group on C-rlO), periplorhamnoside occupies an interesting intermediate position between the cardiac glycosides of the digitalis and strophanthus types. In its biological effect it surpasses the convallatoxin, however, like this, it is only weak when administered enterally. nig reabsorbed.

It was surprisingly found that the compounds according to the invention have a good enteral effectiveness, in some cases even enterally more effective than parenterally, whereby periplorhamnoside first made usable for the oral therapy of heart failure can be.

The compounds according to the invention are according to known per se Process prepared by treating periplorhamnoside with a ketone in the presence of a dehydrating agent and a as Catalyst acting acid at room temperature or moderately elevated Temperature, and the compound thus obtained desired- " if necessary, alkylated or acylated under customary conditions.

The reaction can be carried out in an inert solvent such as dioxane, Tetrahydrofuran or, preferably, in an excess of the amount to be reacted Carbonyl compound take place.

The usual dehydrating agents are used to carry out the ketalization Reagents suitable; Anhydrous copper sulfate is preferred. In order to achieve a good yield, it has been found to be proved to be advantageous, the reaction additionally in the presence of an acid serving as a catalyst, preferably p-toluenesulfonic acid monohydrate, perform. As a result, the reaction proceeds quickly and the formation of by-products becomes almost complete suppressed.

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A second variant of the process for the production of the ketal derivatives consists in the reketalization of suitable dialkyl ketals by periplorhamnoside in the presence of catalytic amounts Acid such as p-toluenesulfonic acid monohydrate.

The alkylation of the ketal derivatives is carried out in a manner known per se by reaction with suitable alkylating agents such as, for example Dialkyl sulfates or alkyl halides at room temperature or moderately elevated temperature in the presence of an acid acceptor.

The acylation is carried out according to known methods with reactive acid derivatives such as acid halides, anhydrides or mixed anhydrides at temperatures of 0 ° -25 ° C in one inert solvent made in the presence of an acid-binding agent. It is advantageous to use excess pyridine, which then also serves as a solvent.

After working up, the process products are isolated in the customary manner either by means of chromatographic purification on silica gel or directly by crystallization.

The compounds according to the invention exercise various kinds of effects on the heart muscle Mammalian species have a positive inotropic effect. They can be used in oral form or as injections for the cardiac and circulatory therapy can be used. To do this, they are mixed with the carriers and auxiliaries commonly used in pharmaceuticals processed and then converted into the ultimately desired dosage form in a manner known per se. Come as such Tablets. Coated tablets. Capsules, suppositories, drops and ampoules in question. The size and frequency of the dosage are determined according to the severity of the disease to be treated. as The recommended dose is 0.1 to 1.0 mg of active ingredient. The following. Examples serve to explain the production method the new compounds according to the invention.

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example 1

2 ' , S'-O-isopropylidene-periplorhamnoside

300 mg of periplorhamnoside are dissolved in 10 ml of distilled acetone and with 1 g of anhydrous copper sulfate and 50 mg of p-toluenesulfonic acid monohydrate Stirred for 3.5 hours at room temperature. The mixture is then filtered, the piltrate with 5% sodium bicarbonate solution added and concentrated in vacuo. It is then extracted with chloroform and the extract is washed with water and, after drying and evaporation, obtains a colorless foam which is chromatographed on silica gel (Merck, 0.05-0.2 mm) will. Eluting with chloroform / methanol 98: 2 (v / v) gives 216 mg Product. Reprecipitation from chloroform with petroleum ether gives 2 ', 3'-0-isopropylidene-periplorhamnoside as a white amorphous powder, m.p. 145-148 ° C.

C32H48O9 66. 64 H 8th .39 0 24. 97 Ber. : C 66. 61 8th .49 24. 63 Found:

IR spectrum (KBr): intetfalia 1776/1736, 1618, 1381, 1075, 1041 cm " ¹ NMR spectrum (CDCl ₃ , j in ppm): 0.89 (s, 3H), 0.92 (s, 3H) , 1.26 (d, 3H) ' 1.34 (s, 3H), 1.5O (s, 3H), 4.88 (m, 2H), 5.10 (s, IH), 5.88 ( m, lH)

Example 2

2 ' , S'-O-cyclohexylidene periplorhamnoside

300 mg of periplorhamnoside are dissolved in 15 ml of cyclohexanone, with 2 g of anhydrous copper sulfate and with 50 mg of p-toluenesulfonic acid monohydrate offset. The mixture is stirred for 2 hours at room temperature, filtered and the filtrate is taken up in chloroform. The solution is washed first with 5% sodium bicarbonate solution, then with water. After drying and evaporation in vacuo, the residue

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was chromatographed on silica gel (Merck, 0.05-0.2 mm). Egg with chloroform and reprecipitating from chloroform / petroleum ether 2OO mg cyclohexylidene periplorhamnoside as a white amorphous Powder, m.p. 146-148 ° C.

C3 5H ₅₂ O ₉ -V ₂ H ₂ O H 8th .52 0 24 .29 Ber. : C 67.17 8th .35 24 .29 Found: 67.38

1 IR spectrum (KBr): inter alia 1779/1742, 1621, 1041 cm

Nuclear Magnetic Resonance Spectrum (CDCl ₃ , S in ppm):

O.9O (s, 3H), O.95 (s, 3H), 1.27 (d, 3H), 4.92 (m, 2S), 5.14 (s, 1H), 5.9O (m, lH)

Example 3

4'-O-acetyl-2 ', S'-O-isopropylidene-periplorhamnoside

150 mg of isopropylidene periplorhamnoside (cf. Example 1) are dissolved in 5 ml of pyridine, and 5 ml of acetic anhydride are added. Man left to stand overnight at room temperature, then poured into 50 ml of ice water and extracted the product with chloroform. Usual Working up and crystallization from methanol / water yields 106 mg of crystalline product with a melting point of 233-237 ° C.

Ber. : C. 65 .99 H 8th .15 O 25th .86 Found: 65 .85 7th .84 26th .05

IR spectrum (KBr): inter alia 1761/1718,] 618, 1376/1364, 1227,

1063, 1037, 1024 cm " ¹ NMR spectrum (CDCl ₃ , S in ppm):

0.89 (s, 3H), 0.95 (s, 3H), 1.13 (d, 3H), 1.33 (s, 3H), 1.55 (s, 3H), 2.09 (8.31), 4.81 (m, 1H), 4.86 (m, 2H), 5, 10 (s, III), 5.84 (m-, IH)

¹ I.

Example 4,.

4 ^? -0-acetyl-2 *, S'-O-cyclohexylidene-periplorhamnoside

400 mg of cyclohexylidene periplorhamnoside (cf. Example 2) are dissolved in 5 ml of pyridine, and 5 ml of acetic anhydride are added. Man left to stand for 12 hours at room temperature, poured into ice water and extracted the product with chloroform. Usual work-up and Chromatography of the crude product on silica gel (Merck, 0.05-0.2 mm; eluent: chloroform) yields 378 mg of product after it has fallen white amorphous powder, m.p. 134-135 ° C.

Ber. : C. 67 .47 H 8th .26 O 24.29 Found: 67 .69 8th .22 24.44

IR spectrum (KBr): inter alia 1764/1724, 1610, 1362, 1222, 1036cm " ¹ NMR spectrum (CDCl ₃ , 5 in ppm):

O, 85 (s, 3H) _? 0.88 (S.3H), 1.13 (d, 3H), 2.09 (s, 3H), 4.81 (m, 1H), 4.89 (m, 2H), 5.12 (s .lH), 5.85 (m, lH)

Example 5 .

4 ^> -O-acetyl-2 *, S'-O-sec-butylidene-periplorhamnoside

300 mg of periplorhamnoside are dissolved in 10 ml of methyl ethyl ketone and mixed with 2 ml of 2,2-dimethoxybutane and 25 mg of p-toluenesulfonic acid monohydrate offset. The mixture is stirred for 1 hour at room temperature, neutralized with Seiger aqueous sodium bicarbonate solution, concentrated in vacuo and the product extracted with chloroform. After drying and evaporation, the ketal formed is dissolved in 5 ml Dissolved pyridine and treated with 5 ml of acetic anhydride. One leaves Stand overnight at room temperature and work up as in Example 3. After chromatography on silica gel and precipitation from chloroform ' Petroleum ether gives 184 mg of product as an amorphous white powder. M.p. 126-29 C.

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Calc .: C 66.43 H 8.28 O 25.29 Found: 66.50 7.97 25.27

IR spectrum (KBr): inter alia 1767/1730, 1613, 1370, 1225,

1035 cm " ¹

Nuclear Magnetic Resonance Spectrum (CDCl ₃ , ύ in ppm):

0.89 (s, 3H), 0.95 (s, 3H), 1.16 (d, 3H), 2.10 (s, 3H), 4.84 (m, 1H), 4.90 (m, 2H), 5, ll (s, lH), 5.86 (m, lH)

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Claims (2)

2H9187 claims 1. New enterally active periplorhamnoside derivatives of the general Formula I. O J) where R. is hydrogen, methyl, ethyl, methoxy or ethoxymethyl or is the acyl radical of a carboxylic acid with 1-5 carbon atoms, R ₂ and R are individually identical or different and represent a lower alkyl radical or together with the common carbon atom form a 5- or 6-membered alicyclic ring. 2. Process for the preparation of the periplorhamnoside derivatives according to claim 1, characterized in that periplorhamnoside with a ketone in the presence of a dehydrating By means of and optionally a catalytically active acid at room temperature or moderately increased 309814/1216 2U9187 Temperature converts or a suitable dialkyl ketal with periplorhamnoside in the presence of a catalytic effective acid and that the ketal obtained is optionally treated with a suitable alkylation or acylating agents are alkylated or acylated in the presence of an acid acceptor. 30 ^ 814/1216