DE1943902A1 - 3- [2 ', 3'-Dideoxy-delta? -4- (O-alkylrhamnopyranosyl] -cardenolides and -bufadienolides and processes for their preparation - Google Patents

Description

1943302

FARBWERKE HOECHST AG. formerly Master Lucius & Brüning

Patent application: P - Pw 6199

Date: August 27, 1909 - Dr.Hg / sch

J> - £ "2 ', 3' -Dideoxy- * £ $>. ^KJ ' ~ 4 ^! - (0-a.lkyl-rharnnopyranosyl_7-cardenolide and. -Bufadienolide and. Process for their preparation

It is already known that cardiac glycosides .; which have one or more ether groups in the glycidic moiety, have an advantageous positive inotropic effect. "Thus, for example, cymarin, which contains digitose-3'-methylether in the glycoidic moiety, has a tendency towards K-strophanthin, which is much the same as genin K-strophanthin -ün -contains, an essentially better enteral absorption and better lipoid solubility ^ ~ B, Helv / ig, Moderns Arzneimittel, J. Edition (19S7) p. 7 ^ 6J "

The subject of the invention are the previously unknown ^ - / ~ 2 ^r , 3 ^s ~ dideoxy ~ <iiia. ^vV; -4 '- (. G-alkyl-rhamnopyranosyl ^ Z-cardenolide D3W -bufadienolide, ie compounds which carry in position 4 ^f Glykosidteiis of an ether group and a "/ out for the preparation thereof.)

It has been found that 3- / 2 *, 3'-dideoxy- <ώ *. * " ^w ^ -4 '- (0-'alkyl-rharanopyranosyl ^ J-cardenolide and -bufadienoliöe of the general formula

R ₂ O

in the R, a sceroid residue of the 3-Hyüroxyeardeno.lid- bsw. . "5-HydrozybufaaieriOlid series, Rp an aliphatic, eyelealiphatic or araliphatic hydrocarbon radicals, if appropriate

) In the older literature v / ar for ^1! 2,3-.Didesoz5? · The designation 'S ^ -Desoxy-Sj ^ -anh ^ eir-c "üblioh, -

IU 9 O i s / if, i »» Wp

additionally produce one or more double bonds on v / eist

pt (-χ. T%

can by writing 3- / 2 ' ₃ 3 ^! -Dideoxy- ^ sw ^ '-rhamnopyranosyl_7-eardenolide or -bufadienolide siit alkyl, cycloalkyl or aralkyl halides, in which the alkyl or cycloalkyl moiety can have one or more double bonds, reacts in the presence of silver salts in an inert solvent.

As . ■ '. . For example, the following cardanolides or bufadienolides come into question: The 3 ~ / 2 ^? 53 ⁵ "Dideoxy- ^ s ^ ^ ^ -L or- B-rhamnosid_7 des" Digi- 'toxigeninsj, Gitoxigenins, Digoxigenins, Psriplogenins, 19-Ca.rboxyaiethyleri-peripiogsnin-5ß-Iac tons, 19-Cyanmethyien-periplogenins, üzarlmethyien-periplogenins , Canarigenins, K-Strophanthidins, Sciilarenins, Bufalins, - Andr-ost "5-en.-3ß-ol-17S"; / l -. ^ - pyi ⁱ ons and des Androst-5-en ~ j5ß ~ ol "2 The sterolal starting compounds mentioned are prepared, for example, by reacting the corresponding sterol alcohols with acylated rhamnals and subsequent saponification of the 4-acyl group of the glycoside part; according to the method described in patent application P 17 68 165.I (Fw 5693}. Examples of silver salts are silver carbonate, silver bicarbonate or silver oxide.

As the alkyl-s cycloalkyl or Aralkyihalogenide are preferably used%

Methyl iodide, methyl bromide, ethyl iodide _s Ithy3 bromide, propyl bromide «, propyl iodide, butyl iodide, allyl bromide, allyl iodide, cyclohexyl iodide, cyolohexyl bromide, bensyl iodide, benzidomyl bromide, cylotyl chloride, crotidyl bromide, benzyl chloride, crotidyl bromide

As a solvent ^ the .. '. ". At the same time as a water entrainer can be used ..., chlorinated hydrocarbons are preferred such as diofelorethane, chloroform, ethylene " shlorld, 5 methyl chloride or solvents such as benzene, xylene, Dimethylformamide or mixtures of the solvents just mentioned are used «

109811/2194

To carry out the process according to the invention, the steroidal starting compound is dissolved in one of the solvents just mentioned, preferably in dichloroethane *, an excess of the alkyl halide and the silver salt are added and the reaction mixture is then heated, advantageously under a nitrogen atmosphere, for 0 minutes to 2 hours Hours with stirring under reflux, in which case the possibly condensed solvent which has distilled over is preferably allowed to flow back through a water-absorbing material, for example anhydrous calcium sulfate. After the reaction has ended, one works up. by filtering off the insoluble silver salts, evaporating the piltrate and recrystallizing the residue obtained from inert solvents or purifying it by chromatography.

The products of the process have valuable pharmacological properties. Although they no longer have any free hydroxyl groups in the glycoside component, they surprisingly show a high level positive inotropic effect as well as diuretic and antidiarrheal properties. Furthermore, they are characterized by an increased Lipoid solubility.

For example, digltoxigenin-3-WS "", 3 * -di desoxy -. «^ ² ' ⁽³ ' ^ 4'- (O-raethyl) -rhaianoside_7" surprisingly shows a significantly higher cardiotonic effect than that Digitoxin used therapeutically.

109311/2194

Example 1

Digitoxigenin - ^ - L- / 2 ', 3 ^l -dideoxy - = ± ^ ² & ^ -4'-O-methylrhamnoside_7

2 g of digitoxigenin-3-L- / S ', 3'-dideoxy - «^ ^κ:> ' -rhamnosid_7> are dissolved in 50 ml of 1,2-dichloroethane and mixed with 40 ml of methylodide and 2 g of silver carbonate. The reaction mixture is refluxed in a nitrogen atmosphere with stirring for 6 hours, the condensed liquid passing through a small thimble containing anhydrous calcium sulfate as it flows back. After the reaction has ended, the undissolved silver compounds are filtered off and the solvent from the filtrate is distilled off i. Vac. away. The oily residue obtained is crystallized from ether / n-hexane. The digitoxigenin-3-L- / _ 2 ', 3'-dideoxy - <^ ^{KJ ;} -4'-O-methyl-rhamnoside ^ in crystallized form with a melting point of 178-179 ° C (Kofier Bank). Character. IR bands: 3505 (pointed), 1775, 1750 (shoulder), 1735, 1630, 1090, 1030, 1005 cm " ¹ (recorded in KBr).

The parent compound is shown as follows;

^ ¹ -acetate_7

A solution of 1.1 g digitoxigenin in 9.6 ml absol. Tetrahydrofuran is mixed with 1.8 ml of diacetyl-L-rhamnal and 0.07 ml of phosphorus oxychloride. After stirring for 5 hours at 20-25 ° C (heating the reaction mixture to over 40 ° C should be avoided because of the formation of undesirable, poorly separable by-products and the associated impairment of yield), the reaction mixture is poured into 50 ml V / water, the excess NaHCO-, contains, extracted exhaustively with chloroform, the extracts are washed with water, dried and the solvents are distilled i. Vac. away. About 2.5 g of oil remains as a residue, which gradually crystallizes through after trituration with ether. Then you filter off the crystals and wash them with a little cold ether. One obtains 1.01g digitoxigenin-3- ^ ~ 2'-deoxy-2 ', 3'-anhydro-L-rhamnoside-4 ^t -acetat_7 mp .: 137 - l4o ° C ·

1098 11/2194

_ ₅ _ 1943302

(Kofier bench)

Characteristic. IR bands: 3515, Γ780, 1750, 1735, I615, 1230,

1020, 740 cm " ¹ (in KBr)

UV spectrum (methanol): J ^ max = 216-217 mu; £ = 16,600

~ L-rhamnoside 7

To saponify the 4'-acetyl group, 0.99 g of the crystallized reaction product just obtained are dissolved in 32 ml of methanol and a solution of 297 mg of potassium bicarbonate in 2.97 ml of water is added at the boiling point. Boil 20 minutes the reaction mixture. At reflux, then it is cooled down to 20 ⁰ C and poured onto 225 ml of half-saturated aqueous sodium chloride solution to give a crystalline product separates. After 16 hours of standing, the crystals are filtered off, washed with water and dried. This gives 0.84 g of digitoxigenin-3 ~ ^ 2 "',3'-dideoxy -« * ^ ² ^.' -L-rhamnosid_7 mp 188-184 ⁰ C (Kofler bank), which after recrystallization from acetone / ether -n-hexane is 198-201 ^o C.

^{0 = <f} 3 ' ⁰ ° (chloroform; C = 0.5)
(In a further approach carried out analogously,

= + 4.6 ° found).

Character. IR bands (recorded in KBr).

3500, 3400, 3O4o, 1800 (sometimes as shoulder), 1775,

1720, 1620-1625, IO85, 1020, 990, 735 cm " ¹ .

UV spectrum: ^ max = 216-217 mu; £ = 15,100 (in methanol).

10 9 8 11/2194

1943302 - 6 -

Example 2

(19-carboxymethylene-periplogenin-5β-lactone) -3-L- / ~ 2 ', V-di ■ ^v ^ -4' - (0-methyl-rhamnoside_7

.2 g (19- carboxymethylene peri.pl ogenin-5ß-lactone) -3 ~ L- / 2 ', 5 ■ -

2 'i "5 ^f 1 -» ~ "

^v '-rhamnosid_ / v; ground in ^ O mL of 1,2-dichloroethane

dissolved and mixed with 40 ml of methyl iodide and 2 g of silver carbonate. The reaction mixture is treated and worked up as indicated in Example 1. The residue obtained is crystallized from isopropyl ether. The (19-carboxymethylene-periplogenin-5β-lactone) -3-L- / ~ 2 ', 3'-dideoxy- , - is obtained. ^ ^v> / -4 ^t - (0-methyl-rhamnoside _- 7 with melting point "165 - 170 C (Kofier bank) as a pseudocrystalline precipitate. Character. IR bands (in KBr): ^ 480, 1775, 1740 (broad ), I7OO-I7IO (wide), 1620/1090, I070, 10 ^ 5, 1010, 735 cm " ¹ .

Preparation of the starting compound:

(19-carboxymethylene-periplogenin-5ß-lactone) -3-L - / "* 2 ', 3'-dideoxy ^v ^ ^y -rhamnoside /

To a suspension of 345 mg of sodium hydride in 19 ml of abs. Tetrahydrofuran is added dropwise with stirring and cooling 3 * 2 ml of carmethoxymethyl diethylphosphonate. After the evolution of H ₂ has ended, this solution is added to a solution of 2 g of k-strophanthidine in 30 ml of abs. Tetrahydrofuran. It is then rinsed with 20 ml abs. Tetrahydrofuran according to. After stirring for 3 hours and 35 minutes at 23 ° C., the reaction mixture is poured into 400 ml of water, extracted 5 times with chloroform, the extracts are washed with water, dried and the solvent is distilled off. The remaining oil is dissolved from acetone / ether. After some time, the product, which is generally again initially oily, then slowly crystallizes completely. The crystals are filtered off and 1.8 g of 19-carboxymethylene-periplogenin-5β-lactone with a melting point of 240 ° -245 ° C. (before sintering). UV: / max. = 215 mu, £ = 24 400

10 9 8 11/2194

1943302

Character. IR bands: 34.60 (often also preliminary band at 3560 cm "), I77O, 17IO-I73O (wide), I615, three weak but characteristically coherent bands at 129O, I27O and 1250 μ" ^χ , band at 2740-2750 cm " ¹ no longer available.

To a solution of 2 g of 19-carboxymethylene-periplogenin-5ß-lactone in 14 ml of abs. Tetrahydrofuran (if it is sparingly soluble in tetrahydrofuran, a corresponding amount of absolute methylene chloride is added), 2.8 ml of diacetyl-1-rhamnal and 4 drops of phosphorus oxychloride are added. After 4 hours Standing or stirring at 20 ^° C., the dark-colored reaction mixture is poured into 200 ml of water which contains excess sodium hydrogen carbonate. It is extracted several times with chloroform, the extracts are washed neutral, dried and the solvent is distilled off. The residue obtained in this way is sprayed on with ether, whereupon it crystallizes through. 3.05 g of 19-carboxy-methylene-periplogenin-5β-lactone-3 ~ / 4 ^f -O-acetoxy-2 ', 3 ¹ -dideoxy-i ^^^ ^w ' -L-rhamnoside_7 of melting point 221 are obtained -231 ° C, having a melting point after recrystallization from methylene chloride / ether. of 265-267 ⁰ C. Fig. Character IR bands: 3485, 1775, 1730-1740, I615, 123Ο (strong) 1020 cm " ¹ -

UV: X max = 215 - 216 ητμ, £ = 26 500

For saponification, 2.2 g of the reaction product obtained in a) of mp. 265-267 ml of abs ⁰ C in 70. Dissolved methanol. A solution of 66 mg of potassium hydrogen carbonate in 6.6 ml of v / water is added at the boiling point and the reaction mixture is refluxed for 15 minutes. It is then poured into 250 ml v / ater and extracted with chloroform. After washing and drying the chloroform, it is distilled off. After digestion with ether, 1.9 S 19-carboxymethylene-periplogenin-5β-lactone-3- / ~ 2 ', 3'-dideoxy-ji £ iN _k ^ ^} -L-rhamnosid_7, öas according to the obtained from the residue Falling from acetone / ether shows a melting point of 202-208 ° C. Character IR bands: 3450, 1775, 1700-1740 (broad), 1615, 1025 cm " ¹ , UV: / max = 215-216 mu, £ = 23,300

- α- itO (r> - Π £> · WCI ^

- + Ί- ^ C - U, Z) nuoiy

1 0 S ύ < : '■ χ ΐ 9 U

Example 3

& ) -4'-0-methyl-

rhamnosid_7

2 g of K-strophanthidin-> L- / ~ 2S; 5'-dideoxy- ^ N ^ ^ ^ -rhamnosid_7 are dissolved in 50 ml of 1,2-dichloroethane and mixed with 40 ml of methyl iodide and 2 g of silver carbonate. The reaction mixture is treated and worked up as indicated in Example 1. The residue obtained is crystallized from diethyl ether. The K-strophanthidin - ^ - k - / ** 2 ', 3' -dideoxy -x ^ '^' ^ '- O-methyl-rhamnoside ^ / with a melting point of 136 - 139 ° C (Kofier bank)

Character. IR bands (in KBr): 3490, 2745, 1775, 1735, 1710, I62O, 1090, 1025, 1000, 740 cm "" ¹ .

A solution of 10 kg of K-strophanthidine in 70 ml of absolute tetrahydrofuran is mixed with 15 ml of LR.'hamnal ~ 3 ^r , 4 ^f -diacetate and 20 drops of phosphorus oxychloride. After stirring for 5 hours between. At 20-25 ° C., the reaction mixture is poured onto water containing excess sodium bicarbonate and extracted with chloroform. The chloroform extract is washed with water and dried with sodium sulfate. After the solvent has been distilled off, an oil is obtained which is chromatographed on "Merck" silica gel (column: 3 × 25 cm) with first 1.5 liters of benzene and then with 4 liters of ether as the eluent. After distilling off the solvent from the ether eluate, after spraying with isopropyl ether, 11.2 g of amorphous K-strophanthidine-3-L- £ "2 ', 3'-dideoxy-Δ-rhamnoside-4'-acetate_7 with the following characteristic IR bands (in ICBr): 3500 (pointed), 2750, 1775, 1740, 1715 (shoulder), 1230, 1030, -1005 (shoulder) cm ".

To saponify the 4'-acetate group, a solution of 5.2 g of K-strophanthidine ~ 3-L- £ * 2 ', 3'-dideoxy-Λ * ²ⁱ ^ ^3t ^ -rhamnoside-4 ^l- acetateJ7 in 168 ml is added Methanol with a solution of 1.6 g of potassium bicarbonate in 15 ml of water / water and the reaction mixture is refluxed for 25 minutes. It is then stirred into water containing 1.5 l of sodium chloride and extracted with chloroform. After the chloroform has been quenched, a foam remains, which. is sprayed with isopropyl ether. 4.4 g of amorphous K-strophanthidin-3-L- £ "2 ·, 3 '-dideoxy-zi. ² ' ( ³¹ L-rhamnosideJT 'with uncharacteristic melting behavior (melting range: 150-155 ° C.). Character.IR -Bands (in KBr): 3470, 2750, 1775, 1735, 1710 (shoulder), 1620, I020; 990 cm " ^{1 .:}

10 9 8 11/2194

Claims (1)

Claims / 1) Process for the preparation of 3> - / ~ 2 ', 3'-Di (IeSOXy - * ^ ² ' ^ '-4 V - S alkyl-rhamnopyranosyl ^ Z-cardenoliden and -bufadienoliden of the general formula in which R ^ a steroid radical of the jJ-hydroxyeardenolide or 2-hydroxybufadienolide series, Rp an aliphatic, cycloaliphatic or araliphatic hydrocarbon radical, which optionally additionally has one or more double bonds, characterized in that 3- / 2 ¹ Y? ' - Dideoxy- ^ ± sw ^v> '-rhamnopyranosyl ^ Z-cardenolide or -bufadienolide with alkyl, cycloalkyl or aralkyl halides, in which the alkyl or cycloalkyl portion can additionally have one or more double bonds, in the presence of inorganic silver compounds in an inert solvent implements. 2) ^ - / ^ ', ^' - Dideoxy- ^ x ^KP '' - ^ - alkyl-rhamnopyranosylJT'-cardenolide or -bufadienolide of the general formula in which R _{1 is} a steroid radical of the jJ-Hy ^ xwcycardenolid- or 3-hydroxybufadienolide series, R _{2 is} an aliphatic, eycloaliphatic or araliphatic hydrocarbon radical, which optionally additionally has one or more double bonds. 109811/2194 ■ * χ J. * ■ /, ^ | ^ '^ -4' -0-methyl- rhamnosid_7 (ig-Carboxymethvlen-periplogenin-Sß-lacton) -JL - / "2i5'-dideoxy- ^ v ^ ^? 5) K-Strophanthidin-5-L - / "2 ', 5'-dideoxy- ^ N, ² ' ⁽³ '^ -4' -0-methyl- • rhamnoside_7. ·" · 1 0 9 8 Ί 1 /? ι 9