DD256134A1 - METHOD FOR THE PREPARATION OF DERIVATIVES OF CARDENOLIDES AND CARDENOLIDE ANALOGIC COMPOUNDS - Google Patents

Abstract

Process for the preparation of 3-morpholinoformyloxy-cardenolides and 3-morpholinoformyloxy-cardenolide analogues suitable as cardiovascular drugs. 3-hydroxy-cardenolides or 3-hydroxy-cardenolide analogues are reacted with a reactive derivative of carbonic acid to form chloroformates of 3-hydroxy-steroids or to reactive mixed esters of 3-hydroxy-steroids and then the reactive radicals are replaced by morpholine.

Description

wherein R ¹ = H or a CH ₃ group, R ² = H or R ¹ and R ^{2 is} a CH ₂ group, R ³ = H, R ⁴ = OH or R ³ and R ^{4 is} an olefinic bond, R ⁵ = CH ₃ , R ⁶ = H or R ⁵ and R ⁶ signify a CH ₂ group. The 3-morpholinoformyloxy group may be in the a or the ^ position.

Characteristic of the known technical solutions

The compounds are new and have not previously been described in the chemical literature and in patents.

Object of the invention

The aim of the invention is the economically favorable preparation of 3-morpholinoformyloxy-cardenoliden and 3-morpholinoformyloxy-cardenolide analogues.

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Explanation of the essence of the invention

The invention has for its object to provide a technically simple method that allows to convert 3-hydroxycardenolides and 3-hydroxy-cardenolide analogues in their Morpholinoformylderivate.

According to the invention the object is achieved by reacting the corresponding 3-hydroxy-cardenolides or 3-Hydroxycardenolidanalogen with a reactive derivative of carbonic acid, such as phosgene or a suitable chloroformate, such as p-nitrophenyl chloroformate, in the presence of a base such as pyridine, to a chloroformate of 3-hydroxycardenolide or hydroxy-cardenolide analog or a mixed carbonic acid ester, such as that of the p-nitrophenol and 3-hydroxy-cardenolide and this then reacted with morpholine, wherein replacing the chlorine or reactive radical, such as the p-nitrophenyloxy group, 3-morpholinoformyloxy-cardenolide and 3-morpholinoformyloxycardolide analogues, respectively

 The method is illustrated by the following scheme:

"egg

^{0 = 0} ^ ° O π

HO Card _: ^. XGOO- <EW-i = £ - ». 0,, N - COO Card

Py \ S

X = Cl. OR (R =

The compounds according to the invention are distinguished by good cardiac activity, in particular by a good increase in contractility with a simultaneous increase in the therapeutic width in comparison to the standard glycosides digitoxin and digoxin. The positive inotropic effect (improvement of the contraction force of the heart) can be demonstrated on various animal species (guinea pigs, cats, pigs and dogs). Digitoxigenin-3-morpholinoformiatund the inotropy increased 19-nor-digitoxigenin-3-morpholinoformiat for example, in the dog in equimolar doses to digitoxin (2 10 ~ ⁷ mol / kg) to about 50%, and showed increasing the dose, a broader therapeutic range, ie the arrhythmogenic dose was 3-fold higher than from digitoxin.

On awake beagle dogs, digitoxigenin-3-morpholinoformate showed extracardiac side effects only in the 2.1-fold dose of digitoxin. Arrhythmias did not occur in the compound according to the invention on the awake dog.

In the guinea pig, the therapeutic width is measured as the quotient ED ₃₀ : DA (30% effective dose: arrhythmogenic dose) as 1:54 in contrast to digoxin 1: 2.7 and digitoxin 1:15.

It is particularly favorable for the compounds according to the invention that they are absorbed in the gastrointestinal tract after oral administration and are thus suitable for long-term therapy and oral administration. The absorption ratios of the compounds are between 30 and 85%.

The positive inotropic effect of digitoxigenin-3-morpholinoformate and 19-nor-digitoxigenin-3-morpholinoformiat was also demonstrated in anesthetized dogs after intraduodenal administration. In addition to the increase in contractility, especially the brodyard effect is noticeable. The heart rate is lowered in the therapeutic range up to 25%, resulting in the insufficient heart to normalize the increased pulse rate.

The substances are well tolerated even after repeated oral administration, as demonstrated in subchronic toxicity experiments on rats.

embodiments

1.) 19-Nor-digitoxigenin-3-morpholinoformate

To 360 mg 19-Nor-digitoxigenin (1 mmol) in 6 ml of methylene chloride and 1.2 ml of pyridine 800 mg of chloroformic acid p-nitrophenyl ester (4 mmol) are added dropwise in 4 ml of methylene chloride at about 20 ⁰ C with stirring. After about 20 minutes, 1 ml of morpholine (11 mmol) is added and worked up 30 minutes later. For this purpose, the approach mitverd. Sodium bicarbonate solution added, extracted with methylene chloride, the extract washed with dil. Natriumhydrogencarbona't solution several times and dried over sodium sulfate. The residue (1 g) is subjected to a gradient chromatography on silica gel with benzene-ether and benzene-ether-acetone, to obtain 470 mg of ^ -nor-digitoxigenin-S-morpholinoformiat, which is recrystallized from acetonitrile. Yield: 440 mg (93%), mp .: 234 to 236 ° C, [αψ: + 30 ° (c = 1, CHCl ₃ ).

2.) Digitoxigenin-3-morpholinoformate

375 mg of digitoxigenin (1 mmol) are reacted and worked up as described in the example. 490 mg of digitoxigenin-3-morpholinoformate are obtained, which are recrystallized from isopropanol-water. Yield: 425 mg (87%), mp .: 238 to 242 ° C, Md ⁵ : 22 ° (c = 1, CHCl ₃ ).

3.) S-epi-digitoxigenin-S-morpholinoformate

375 mg of 3-epi-digitoxigenin (1 mmol) are reacted and worked up as a suspension as described in Example 1. This gives 490 mg of 3-epi-digitoxigenin-3-morpholinoformiat, which is brought to crystallization with benzene-cyclohexane and recrystallized from methanol-water. Yield .: 400 mg (82%), m.p .: 222-226 ⁰ C, Md ^5: + 35 ° (c = 1; CHCl _3).

4.) Methyl 4-hydroxy-S / S-morpholinoformyloxy-BiS-estrane-N-E-Acyl Ester 363 mg / 3,14 / 3-dihydroxy-5/3-estrane-17β-E-acrylic acid methyl ester (1 mmol) is as described implemented and worked up in the example. This gives 475 mg of Mß-hydroxy-Sß-morpholinoformyloxy-S / S-Estran- ^ ß-E-acrylic acid methyl ester, which is recrystallized from ether. Yield .: 425mg (90%), F .: 172 to 174 ⁰ C, Md ^S: + 36 ° (c = 1; CHCl _3).

5.) 3j3-morpholinoformyloxy-19-nor-5/3-card-8 (14), 20 (22) -dienolide

342 mg of 3-hydroxy-19-nor-50-card-8 (14), 2O (22) -dieno! Id (1 mmol) are reacted and worked up as described in the example. This gives 455 mg of 3β-morpholinoformyloxy-19-nor-5/3-card-8 (14), 20 (22) -didolide, which is recrystallized from methanol. Yield .: 380 mg (83%), m.p .: 205-210 ⁰ C, Md ^5: + 48 ° (c = 1; CHCl _3).

6.) Methyl S-B-morpholinoformyloxy-S-estr-SiMl-en-ITß-E-Acrylate 345mg 3/3-hydroxy-5/3-estr-8 (14) -en-17/3-E-acrylic acid methyl ester ( 1 mmol) are reacted and worked up as indicated in the example. This gives 450 mg of S / S-morpholinoforrhyloxy-Bß-estr-SiMi-en-iy / JE-acrylic acid methyl ester which is recrystallized from ether-hexane. Yield: 365mg (80%), mp .: 123 to 127 ° C, [<x] g ^s : + 64 ° (c = 1, CHCl ₃ ).

Claims (1)

Invention claim: Process for the preparation of novel cardioactive derivatives of cardenolides and cardenolide analogues of the general formula wherein R ¹ = H or a CH ₃ group, R ² = H or R ¹ and R ^{2 is} a CH ₂ group, R ³ = H, R ⁴ = OH or R ³ and R ^{4 is} an olefinic bond, R ⁵ = CH ₃ , R ⁶ = H or R ⁵ and R ^{6 is} a CH ₂ group and the morpholinoformyloxy radical can be in the a or the ^ position, characterized in that the corresponding 3-hydroxy-cardenolides or 3-hydroxy cardenolide analogues with a reactive derivative of carbonic acid, such as phosgene or a suitable chloroformate, such as p-nitrophenyl chloroformate, in the presence of a base, such as pyridine, to form a chloroformate of 3-hydroxycardenolide or 3-hydroxy-cardenolide analogues or a mixed carbonic acid ester, as that of the p-nitrophenol and the 3-hydroxy-cardenolide or 3-hydroxy-cardenolide analogues and this then reacted with morpholine to react, with the replacement of the chlorine or the reactive radical, such as the p-nitrophenyloxy group, 3 -Morpholinoformyloxy-cardenolide or 3-morpholinoformyloxy-cardenolide analogues are obtained. Field of application of the invention The invention relates to a process for the preparation of novel cardioactive derivatives of cardenolides and cardenolide analogues of the general formula