DE1939173C3 - Cardiac Active Steroids and Processes for Making Acyl Derivatives Cardiac Active Steroids - Google Patents

Description

3 4

They can be substituents on 5- or 6-membered compounds which only carry the acyl radicals introduced in the isocyclic or heterocyclic rings or on alkyl radicals 2nd step. Let yourself be like that. In the case of gitoxin, for example, the OH groups in the 14.16 position, which occur only in a relatively very small amount on the way of direct acetylation, then the OH groups in the α- and ^ -position 5 compounds 12- Acetyl digoxin and 16-acetylacylated. The compounds obtained still contain gitoxin. The choice of reactive boron-free OH groups which, through reaction with reactive or arsenic oxygen or a derivative, becomes acid derivatives capable of being charged, preferably derivatives, through the specificity of these protective group formers, possibly substituted aliphatic araliphatic acids. Boron compounds protect completely betic or aromatic carboxylic acids and carbon, preferably cis-lS-diol groups, whereas lene acid derivatives, partially or completely acylated, require protection from cis-l, 2-diol groups. For example, the esterified gischerer contains conditions and success ·; always only after gitoxin two free, acylated OH groups in γ- the protection of any ciu-l ^ -diol group and <5-position. struggles. An implementation with arsenic compounds

In cases in which acyl derivatives are prepared with water, alcohols, alkalis, adsorptive cis-1,2-diol groups, benzene or basic ion exchangers can be prepared from the products obtained in this way, since the arsenic compounds are preferred with known processes react the corresponding boron cis-1,2-diol groups. In the process, arsenic acid residues are split off. Because of its low price, acyl trioxide is obtained especially for derivatives of cardiac steroids, which are suitable for industrial use,
only the acyl radicals introduced in the second step. The process according to the invention enables the wear. Production of previously unknown or difficult to access

For example, acyl derivatives of cardiac steroids are obtained from gitoxin according to Durchlicher. Through this

management of the appropriate operation according to the invention, the quality of action and thus the therapeutic

nen y, (5-diacetyl derivative, which by way of the direct 25 therapeutic applications of the cardiac

Acetylation is not accessible. seeds steroids modified in many directions

Implementation of the cardiovascular steroids will be with.

reactive arsenic acid or their example is changed by changing the

Derivatives, preferably arsenic oxides such as arsenic lipoid and / or water solubility, which by the

trioxide and arsenic pentoxide, takes place in a molar ratio of 30 acylation of the OH groups is effected, one

from 5: 1 to 1:10 at temperatures between 0 and better absorption and a targeted influence on the

300 ⁰ C, preferably at 20 to 120 ⁰ C. Duration of action via a change in the elimination

In general, the presence of speed is recommended. In addition, the boron and steroid as well as arsenic compounds obtained in the solvents or solvent mixtures, the first stage of the process, are dissolving. In 35 arsenic derivatives for syntheses, worth considering for production, there is, among other things, the mixture of pyridine- full of cardiotonics, in which certain OH groups are water. The implementation according to the invention will also have to be protected, suitable
by fusing the components together. B. that after this method is sufficient. After this reaction, the lo-acetyl-loepi-gitoxin, which cannot be produced, is partially or completely acrylated, preferably with Na-K-activated transport, in the biosecured OH groups in a known manner (ATPase inhibition - inhibition of the partial or complete) Adenosine triphosphatase; reactive derivatives, optionally substituted, for example, BK Repke, KHn. Wschr., 42, 157 [1964]; ated aliphatic, araliphatic or aromatic K. Repke et al., J. biochem. Pharmacol., 14, 1785 Carboxylic acids and Carbonic acid derivatives. Subsequent to 16epi-gitoxin more than 6-fold acting, the cleavage of the arsenic-containing residues carried in the first step, as well as the increase in tone in the sea, takes place by treatment with pig ileum (literature: Haustein et al., Water or Hydrogen sulfide or by Chromatic Pharmacology, 10, 65 [1973]) about 8 times stronger matography or a combination of these steps. is effective.

Increase in tone in guinea pig ileum

connection ATPase Changes ED ₅₀ Changes at inhibition tion tion game
No μπι =% μπι 16epi-gitoxin 16 = 50 0.74 Lö-acetyl-loepi-gitoxin 2.5 = 50 -j- 0.095 + 11.16 Explanation of the designation μπ \: 1 μπι = = 1 · 10- »mol / l.

The invention is to be described in more detail below by means of examples. V. evaporated to dryness and 10 min at 100 ° C

explained. heated. Gitoxin-14,16-boric acid ester remains,

_R · ■ 1 ·. From chloroform - di - η - propyl ether - crystal lumps

^p 65 from melting point 323.5 to 325.5 "C IR spectrum

200 mg gitoxin and 16.0 mg orthoboric acid (Mol- a) B = O 1410 cm- ¹ ; b) C = 0 1745 cm- ';

ratio 1: 1) are heated in 5 ml a) is a little more intense than b). solubility > 10% ir

Pyridine dissolved. After standing for 10 minutes, the solution becomes chloroform, tetrahydrofuran, dioxane; well soluble ir

Methylene chloride, pyridine,> 1% in ethyl acetate. Little with formation of y, <5-di-aceiyl-gitoxin. Needles off

soluble in di-n-propyl ether, benzene, cyclohexane, acetone / cyclohexane, melting point 253 to 259 ^° C.

Carbon tetrachloride, water, ammonia, methanol

and acetone dissolve more than 10%, but separate "* .-»! * trum.

a crystalline precipitate soon formed. At the 5 a) C - O (acetone) ... 1255 cm " ¹ (strong)

Chromatography on aluminum oxide or silica gel b) C = O 1742 cm " ¹ (strong)

can be difficult to dissolve during application - b) is a little more intense than a)
ability of the gitoxin in suitable solvents by the

Use of gitoxin-14,16-boric acid ester overcome Rt = 0.17 (system see example 3). Green fluorescence

which is completely broken down on the adsorbent and OK in UV light after treatment of the chroniatogram

returns pure gitoxin. with trichloroacetic acid chloramine T reagent. test

. on cis-glycol: positive, acetyl migration: negative.

Example 2 Partial acid hydrolysis gives the same products

200 mg gitoxin and 31.2 mg phenylboric acid (molar as described in Example 3,

ratio 1: 1) are implemented according to example 1. It 15 η · · 1 7

results in Gitoxin-Klo-phenylboric acid ester, mp. 170 Example /

up to 171 ° C. The solubility properties correspond to 40 mg of gitoxin and 3.2 mg of orthoboric acid in

largely those of the gitoxin-14,16-boric acid ester. 2 ml of pyridine dissolved. After adding 2 ml Acetanhy-

In adsorption chromatography on silica gel, the mixture is kept at room temperature for 7 days

there is only a partial breakdown to gitoxin. 20 left standing. The reaction product consists of

50% «, / 9, y, <5-tetra-acetylgitoxin.

Example 3 (Rt = 0.76, system as in Example 6) 35% κ, β, γ

-f a, / ?, (5-tri-acetyl-gitoxin (Rf = 0.62) and 15%

The gitoxin-14,16-phenyl-α, / 5-di-acetyl-gitoxin obtained according to Example 2 (Rf = 0.41).

boric acid ester is dissolved in 6 ml of pyridine, with 2 ml of 25. . . _fi

Acetic anhydride is added and the mixture is heated to 100 ° C. for 3 hours. Example"

The obtained «, / 3, y, (5-tetraacetylgitoxin-14,16-phenyl- 100 mg of lanatoside B are mixed with 12.2 mg of phenylboron-

Boric acid ester is made by transesterification with 1,3-proic acid (molar ratio 1: 1) in pyridine at room temperature.

pandiol from the phenyl boric acid esters. It is converted to lanatoside B-14,16-phenylboric acid ester

results the a, / 3, y, (5-tetra-acetylgitoxin. M.p. 184 to 30 sets. 186.5 ° C from chloroform / cyclohexane. R _r = 0.80 im

System propyl ether-tetrahydrofuran 2: 1 / formamide. IK spectrum (KBr) learn J:

Characteristic of the compound is the treatment of the chromatogram with the trichloro according to Be C = O 1735, C = C 1635, CO 1260, BO 1340.

acetic acid chloramine T reagent resulting green 35. After 6 hours, 3.5 ml acetic anhydride are added.

Fluorescence in the UV. The test for cis-glycol and give and 2 hours to 60 to 9O ⁰ C increasing

Acetyl migration is negative. When the partial warms. After evaporation of the solution in vacuo to

acid hydrolysis results in y ^ -di-acetyl-gitoxigenin- to dryness the 2 ', 3', 4 ', 6',} ', <5-hexaacetyl-

bis-digitoxosid, y-acetyl-gitoxigenin-mono-digitoxosid lanatosid B-14,16-phenylboric acid ester (those with 'mar-

and gitoxigenin. 40 marked numbers denote the carbon atoms of the

B e i s ρ i e 1 4 glucose residues).

On 200 mg gitoxin and 93.6 mg phenylboric acid IR spectrum (KBr) [cm- ¹ ]:

(Molar ratio 1: 3) when treated according to Bei- C = O 1730, C = C 1640, C-O 1255, B-O 1345. game 1 Gitcxin-M.lo-phenylboric acid ester-a. / S-pyro- 45

obtained phenylboric acid ester. Mp. 173 to 176 ° C. The phenyl boric acid ester is split off

with 1,3-propylene glycol in acetone 2: 11m 2 ', 3', 4 ', 6', y, ö-

Example 5 Hexaacetyl lanatoside B, from cyclohexane / acetone viable Needles.

200 mg of gitoxin and 312 mg of phenylboric acid (MoJ- so mp: 221 to 225 ° C. Solubility: gul: soluble in acetone, ratio 1:10) are reacted according to Example 1. The chloroform, benzene, ethyl acetate, soluble in methanol, acetylation of the residue is carried out with 2 ml of acetone insoluble in cyclohexane, petroleum ether, propyl ether.
anhydride in 6 ml of pyridine for 4 hours at 100 ° C. The y.ö-di-acetyl-gitoxin-l ^ lo-phenylboric acid ester-lK spectrum:
Ä, j8-pyrophenylboric acid ester melts at 212 to 55 a) C - O (acetate) ... 1250CrI- ¹ ,

217 ° C (long needles made of cyclohexane). Solubility good b) C = O 1750 crn- ¹ ,

in CHCl ₃ , approx. 5% in boiling cyclohexane. c) C = C 1630 cm- ¹ .

IR spectrum:

CO (acetate) ... 1265 cm- ¹ (shoulder) 60

BO 1355 cm- ¹ (very strong)

C = O 1752 cm- ¹ (weak)

Example 6

The y.o-di-acetyl-gitoxin-65 obtained according to Example 5 14,16 - phenylboric acid ester - «, / 5-pyrophenylboric acid

ester is chromatographed on 100 g of silica gel. Acid hydrolysis provides gitoxigenin and not 16-acce

The phenylboric acid residues tyl-gitoxigenin are split off.

Molecular weight: 1237.3, Calculated ... 1230.0. found ... Acetyl groups: 7.0, Calculated ... 7.1. found ...

7 ^ 8

For the 19 phenylboric acid by transesterification with 1., 3-propylene

glycol removed. The subsequent chromatography

200 mg of Lanatoside B are combined with 244 mg of phenylboron on silica gel to provide pure 16-acetyl-16-epi-gitoxin

acid (molar ratio 1:10) in pyridine at room temperature. Mp. = 240 to 243 ° C (acetone-ether).

rature to a mixture of lanatoside B-14,16- and 5 _ __. _ _ "_ _Q ..

4 ', 6', 14-16-phenylboric acid ester implemented. The after t- ₄₃ H _ee Ui _B (VAVb):

6 hours by evaporation of the reaction solution in the calculated ... C 62.70, H 8.08%;

The residue resulting in a vacuum is found with 7 ml of acet- ... C 62.62, H 8.05%.

anhydride held in pyridine at 90 ^° C. for 4 hours. _f vu \

After evaporation to dryness in a vacuum, io ^JK - ^ P ^eKlrum {^ ary.

man 2 ', 3', 4 ', 6>, <5-hexaacetyl-14,16- and 2,' 3 ', y, o-Te- OH 3570, 3430 cm " ¹ ,

traacetyM'.o ^ Hlo-phenylboric acid ester of Lanato- C = O ... 1760, 1730, 1700cm- ¹ ,

sid B. IR spectrum (KBr) of 2.3>, <3-tetraacetyl- C = C ... 1620cm- ¹ ,

4 ', 6'-14,16-phenylboric acid ester: CQ ... 1245cm- ¹ .

C = O 1745 cm ^-1 , C = C 1630 cm " ¹ , ¹⁵ R ₍₁₆ - _ep i-Giioxin - i) = 7 (system see example 13).

C-0 1255cm- ¹ , B-01350cm- ¹ . _. . "". ,,. , _t ,,. _t .

The partial acid hydrolysis gives 16-acetyl-

The splitting off of the phenylboric acid residues from the 16-epi-gitoxigenin, -mono- and -bis-digitoxoside. Mixing takes place as described in Example 8. It mentions the Na-K-activated Tiansport adenosine

results in a mixture of 2 ', 3', y, o-tetra-acetyl-triphosphate: lanatosid B and that already mentioned in Example 8

2 ', 3', 4 ', 6',} ', ö-hexaacetyl-lanatoside B in the ratio 16-epi-Gitoxiii 16 μίτι,

35:65. The 16-acetyl-16-epi-gitoxin 2.5 μίτι isolated by thin layer chromatography.

Tetraacetvl-lanatoside B has a melting point of _. ,. . ..

■? 10b '216 ° C 2- Increase in tone on the guinea pig cnenileum:

16-epi-Gitoxin 0.74 μm,

IR spectrum: 16-alkyl-16-epi-gitoxin 0.095 μm.

a) C - O (acetate) ... 1250 cm- ¹ ,

b) C = O 1745 cm- ¹ . Example 12

Molecular weight: _lg citoxin, 1.56 g of phenylboronic acid and 30 ml of Py ... Calculated 1153.2, ridin are reacted according to Example. 1 The found back ... 1170.0. stand is in 30ml pyridine with 10ml Acetanhydric

Reacted for 17 hours at room temperature. Nact

Acetyl groups: ₃₅ Removal of phenylboric acid by restering

Calculated ... 5.0, with 1,3-propylene glycol the mixture of y- unc

found ... 5.2. o-Acetylgitoxin column chromatography in the system

Ceilulose powder with 30% formamide isopropyl ether

Example 10 Tetrahydrofuran 3: 2, separated in formamide-saturated form

40 R ( ₁₆ -epi-gitoxin) (system see example 13). 400 mg digoxin and 624 mg phenylboric acid (Moi-

ratio 1:10) are dissolved in 12 ml of pyridine. To

It is evaporated to dryness for 10 min and the back y-acetylgitoxin <5-acetylgitoxin

stood in the boiling water bath each 10 mm in the water

jet and oil pump vacuum heated. Then 45

is dissolved in 12 ml of pyridine, with 4 ml of acetic anhydride 2.1 1.6

added and left to stand at 23 ° C. for 4 hours. Then . _. . . ,

the reaction is positive pos.tr by adding 10 ml of methanol cis-glycol sample;

stopped. Negative negative after removal of the phenylboric acid by acetyl migration

Reaction with 1,3-propylene glycol in a conventional 50 p _ar ti _e lle acidic y-acetyl-o-acetyl-gitoxi-

What remains is crude 12-acetyldigoxir. By hydrolysis of gitoxägenin- bis, -mono-chromatography on silica gel, e *. m pure form ^ _ _mono _ digitoxosid

receive. digitoxosid gitoxigenin

Rpigoxin = 4.5 in the system. Gitoxigenin

Di-n-propyl ether-tetrahydrofuran 2: 1 / formamide. ⁵⁵

Fluorescence on the paper chromatogram according to Example 13

Treatment with the trichloroacetic acid chloramine

T reagent: dark yellow. 1 g of digoxin is dissolved in 300 ml of pyridine, mi

60 25.4 ml of 1% aqueous arsenic trioxide solution mixed 2

Example 11 (molar ratio of digoxin to arsenic trioxide = 1: 1)

evaporated to dryness in vacuo Im boiling

1 g of 16-epi-gitoxin, 1.56 g of phenylboric acid (Molver water bath, the residue is in water for 10 min ratio 1:10) and 30 ml of pyridine are heated according to example 1 jet and oil pump vacuum Connect! converted to 16-epi-Gitoxm - «, /? - pyrophenylborate The 65 is mixed with 30 ml of pyridine and 10 ml of acetic anhydride The product is dissolved in 30 ml of pyridine, added with 1.0 ml and left to stand at 22 ° C. After 6 hours we Acetic anhydride is added and the mixture is kept at 26 ° C. for 4 hours - the reaction is stopped by adding methanol calmly. The evaporation residue is taken up from the acetylation product with chloroform

men and washed with water. Chromatography yields pure 12-acetyl digoxin.
Ruigoxin = 4.5 (system di-n-propyl ether-tetrahydrofuran 2: 1 / formamide).

Fluorescent color of the spots in the UV after treatment with the trichloroacetic acid chloramine T reagent: dark yellow.

Example 14

Ig Gitoxin is according to Example 13 with 127 ml of 1% aqueous arsenic trioxide solution (molar ratio 1: 5) implemented and then esterified with acetic anhydride in pyridine. 16-acetylgitoxin is obtained. RGitoxin = 2.7 (system as in Example 1).

Fluorescent color (see Eeispiellö): dark blue.

Chromatographic comparison with authentic 16-acetyl-gitoxin revealed identity.

Example 15

1 g of digitoxin is reacted according to Example 13 with 26.5 ml of arsenic trioxide solution (molar ratio 1: 1) and then esterified with acetic anhydride in pyridine. There are y-acetyldigitoxin and <5-acetyldigitoxin received.

Roigitoxin = 1.7 or 1.4 (system as in Example 13). Fluorescence (cf. Example 13) yellow in both cases.
IR (KBr) [Cm- ¹ ]:

• Acetyl-d.'gitoxin:

C = O 1750, C = C 1630, C-O 1250.

-Acetyl-digitoxin:

C = O 1755, C = C 1625, C-O 1255.

Example 16

2.5 g of 16-epi-gitoxin are dissolved in 25 ml of pyridine, 190 ml of a 1% As ₂ O ₃ solution (molar ratio 1: 3) are added and the mixture is concentrated to dryness. The mixture is then heated for 15 min in vacuum at about 1 mm Hg at 110 to 12O ⁰ C. The residue is mixed with 20 ml of acetic anhydride and refluxed for 1 hour.

The acetic anhydride is i. V. is distilled off and the residue is separated from the byproducts and the As ₂ O ₃ by countercurrent distribution in the system methanol / water / chloroform / petroleum ether 9: 6: 5: 5. 16-acetyl-16-epi-gitoxin is obtained. Acetyl group determination:

Calculated
found

5.2%; 4.5%.

Acetyl group determination:

Calculated ... 7.46% acetyl,
found ... 7.87% acetyl.

Thin-layer chromatography in the system as in Example 16 gave:
Rf 19-acetylhelveticosol: 0.3, Rf helveticosol: 0.13.

Acid hydrolysis: digitoxose and 19-acetylstrophanthidol. Thin layer chromatography in the system ίο as in example 19 resulted in:
Rf strophanthidol 0.45,
Rf 19-acetylstrophanthidol: 0.5.

Example 18
15th

0.1 g of convallatoxin are dissolved in 1 ml of pyridine, _{mixed with 3.6 ml of 1% As 2} O ₃ solution and treated as described in Example 16. 6 ml of pyridine and 1 ml of acetic anhydride are added to the dry residue and the mixture is left to stand for 20 hours.

The 4'-acetylconvallatoxin formed is separated from 2 secondary substances by means of preparative thin-layer chromatography. Thin-layer chromatography in the system as in Example 16 gave:
Rf 4'Acetylconvallatoxin 0.17,
Rf convallatoxin 0.04.

Acetyl group determination:

Calculated ... 7.2%,
found ... 7.2%.

55

Thin layer chromatography in the system methylene chloride / methanol 9: 1 on silica gel Merck Rf: 0.25. Pharmacological data see example 11.

Example 17

1 g Helveticosol are dissolved in 1 ml of pyridine with 26 ml of a 1% IGT η As ₂ O ₃ solution and concentrated as in Example 16 to dryness and heated to 110 ⁰ C.

The residue is mixed with 10ml acetic anhydride, Boiled under reflux for 1 hour and then the acetic anhydride i. V. distilled off.

The 19-acetylhelveticosol formed is separated from minor by-products by chromatography on silica gel (1:30) with chloroform and 1 to 6% methanol
Mp 142-145 ° C.

Example 19

Ig Gitoxin is implemented according to Example 13, wherein Instead of arsenic trioxide solution, 29 ml of 1% arsenic pentoxide solution are used (molar ratio Gitoxin to arsenic pentoxide 1: 1). After purification by chromatography, 16-acetylgitoxin is obtained.

Example 20

A solution of 250 mg of arsenic trioxide in 50 ml of water and 100 ml of pyridine is added to the solution of 1 g of gitoxin in 25 ml of pyridine and i. V. evaporated to dryness. The residue is dissolved in 30 ml of pyridine, 2.7 ml of phenyl isocyanate are added and the mixture is left to stand at room temperature for 1 hour. Work-up according to Example 13 and chromatography using silica gel yield pure gitoxin-16-phenyl-urethane, melting point: 257 to 261, "? = -25.5 °, C = 0.52, CHCl ₃ RGitoxin = 5.0 (system as in Example 16 ), Fluorescent color (see. Example 1): dark blue, test for ice glycol grouping: positive, test for acyl migration: negative. Partial acid hydrolysis provides gitoxigenin-16-phenyl urethane and its bis- and mono-digitoxoside.

Example 21

780 mg of gitoxin are dissolved in 5 ml of pyridine and added 10 ml of an aqueous 1% As ₂ O ₃ solution. The mixture is concentrated to dryness in vacuo and then heated to 110 ° (at 1 torr for 15 min. The gitoxin arsenic acid ester formed dissolves easily in chloroform. Melting point 239 ° ((uncorr).

The gitoxin shows arsenic acid residues in the IR spectrum

a characteristic oscillation (band) for dioxarsolanes at 615 cm- ¹ .

Example 22

According to Example 21 from 780 mg digoxin and 10 ml of a 1% As ₂ O ₃ solution of the digoxin

Arsenic acid ester produced. The compound, unlike digoxin, dissolves easily in chloroform. Melting point 230 ^° C. (uncorr).

In the IR spectrum, the digoxin arsenic acid ester shows an oscillation (band) at 615 cm " ^1, which is characteristic of dioxarsolanes.

Claims (6)

des Digitoxins, Gitoxins, Gitoxigenins, Lanatosids B, claims: Purpureaglykosids B, Digoxins, Lanatosids C, Des- acetyllanatosids C, Strophanthidins, Strophanthidols, 1. Process for the production of acyl derivatives Ouabains, Lanatosids A, Desacetyl-lanatosids A, cardiac steroids by selective acylation, 5 7/3-OH-digitoxigenins, 16-epi-gitoxins, strophanthins, characterized in that cardiac Helveticosids, Convallatoxins, Strophanthols, Cywirksame Steroids with reactive boron or marols, Heiveticosols, Convallatoxols, Proscillar arsenic oxygen acids or their derivatives vice versa, by selective acylation. The steroids that act on the heart contain one more Way partially or fully acylated and the io or less large number of hydroxyl groups, the Boron or arsenic-containing residues are then reacted with reactive acid derivatives be split off. can be acylated (e.g. DL-PS 47 610, DT-AS 2. The method according to claim 1, characterized in 10 63 160). In this way, however, there is only a small amount of evidence that cardiac steroids with reactive part of the theoretically possible acyl derivatives of cardiac boric oxygen acids or their derivatives, 15 effective steroids are accessible. As a result of the preferably boric acid, metaboric acid, poly-reactivity and the steric relationships of the boric acid as well as salts, esters, anhydrides or hydroxy groups, the acyl radicals enter the aryl, alkyl, diaryl or halogen derivative steroid molecule as a whole preferred these acids in a molar ratio of 5: 1 sequence, which can ^{hardly be influenced by changing the reaction conditions up to 1:10 at temperatures between 0 and 300 0} C, ao conditions. If necessary, in the presence of solvents, the setting of gitoxin with acetic anhydride (molar ratio such as solvents such as amines, halocarbons 1:80) at 22 ° C after 10 minutes mainly leads to hydrogen, ketones or alcohols, converted / 3-acetyl derivative. After one hour the free hydroxyl groups of the resulting acetyl derivative are the main product, after 8 hours the boric acid ester with reactive acid derivatives, 25 ”, / ?, 16-triacetate and after 21 hours, for example, possibly substituted aliphatic equal parts χ, β, γ, Ιβ- and &, / 9, <5,16-Tetraacetatischer, araliphatic or aromatic carbon- arisen. Acids and carbonic acid derivatives, in per se, from DL-PS 47 610 finally it is known that known way partially or completely acylated the complete acetylation of the gitoxin by one and then the corresponding boric acid - 30 hour boiling with acetic anhydride is achieved, ester groups are split off again. Direct acetylation therefore produces from the 3. The method according to claim 1, characterized in 31 theoretically possible acetylgitoxins in nominal terms, that heart-active steroids with reactive volume only 6. The rest are only used in capable arsenic oxygen acids or their derivatives are formed in small amounts or not at all. vaten, preferably arsenic oxides such as arsenic trioxide 35 The reaction of heart-active steroids with or arsenic pentoxide, in a molar ratio of 5: 1 tetraacetate borate is known from DL-PS 58 507, up to 1:10 at temperatures between 0 and 300 ⁰ C, from the The heart-active substances used, preferably at 20 to 120 ° C., optionally in steroids, contain 1 to 2 boron-containing derivatives in each case known,
set, the free hydroxyl groups of the resulting- The invention is based on the object of providing a NEN esters with reactive acid derivatives, preferentially drive for the selective acylation of steroids having an effect on the heart to develop optionally substituted aliphatic ide and the extraction so far not or to enable tic, araliphatic or aromatic carbonic acyl derivatives that are difficult to access, acids and carbonic acid derivatives, in per se 45 according to the invention, steroids with an active effect on the heart are also used known way partially or completely acylated reactive boric or arsenic oxygen acids or and then the arsenic-containing groups are converted by their derivatives, the resulting esters Treatment with water or hydrogen sulfide in a manner known per se partially or completely or by chromatography or a combination acylated and the boron- or arsenic-containing groups annation these steps are split off again. 50 then split off again. The implementation of the heat-effective steroids, both 4. a ^ y.o-Tetra-acetyl-gitoxin. for example gitoxin, digitoxin, digoxin, lanatoside B, 5. y.o -diacetylgitoxin. Ouabain with reactive boric oxygen acids or 6. 2 ', 3', y, o-tetra-acetyl-] anatoside B. their derivatives, preferably with boric acid, metabor- 7. γ-acetyl-digitoxin. 55 acids, polyboric acids as well as salts, esters, anhydrides 8. Gitoxin-16-phenyl urethane. or alkyl, aryl, diaryl and halogen derivatives 9. lo-acetyl-lo-epi-gitoxin. of these acids, takes place in a molar ratio of 5: 1 to 10. 19-Acetyl-helveticosol. 1:10 at temperatures between 0 and 300 ⁰ C, gelatinized. 4'-acetyl convallatoxin. if necessary in the presence of solvents such as 12. Hexa-acetyl-Lanatosid B. 60 alcohols, ketones, halogenated hydrocarbons or 13. (5-Acetyl-digitoxin. Amines. Surprisingly, only the corresponding boric acid esters are determined OH groupings of the cardiovascular steroids. In are OH-Crjppinations reacting in this direction 65 preferably 1,2- and 1,3-diol groups, their The invention relates to steroids that act on the heart and OH gnips which are arranged cis to one another a process for the preparation of acyl derivatives heart or can be (with involvement of alkyl-OH). the More effective steroids for example from acyl derivatives OH groups can be primary, secondary or tertiary