CH639107A5 - NEW ACYL DERIVATIVES OF HELLEBRIGENIN. - Google Patents

Description

The invention relates to new Hellebrigenin derivatives of the general formula

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R-GO-O

wherein R is a C2-C6-alkenyl group, a Ci-Ce-haloalkyl group, such a C3-Ci8-alkyl group, a C3-C6-cycloalkyl group, a C3-Cio-alkyl group substituted by a Ci-Cs-carbalkoxy group or a carboxy group C2-Có-alkoxyalkyl radical, a C2-C6-alkoxyalkyl radical substituted by a carboxy group, a phenyl radical, a phenyl radical substituted by nitro groups, carboxy groups, ss Ci-C6-alkoxy groups, Ci-Ce-alkyl groups or halogen atoms or a Ci-Cf.-alkyl group which contains the group -NR1R2, where R 1 and R 2 are C 1 -C 6 -alkyl radicals, C 2 -C 6 -alkenyl radicals, C 1 -C 6 -alkoxy groups or halogen atoms substituted C 1 -C 6 -alkyl or 60 C 3 -C 6 -alkenyl radicals and one of the radicals Ri or R2 can also denote a hydrogen atom or the group -NR1R2 forms a saturated heterocyclic 5- or 6-ring which can also contain a further oxygen or nitrogen atom and where such a ring is also mono- or 65-fold by Ci-Cs-alkyl groups, hydroxyethyl groups or H ydroxy groups can be substituted and R3 is a HOC group (formyl group), -CH2OH- or -COOH-

Group is their optically active forms and their salts.

The alkyl and substituted alkyl radicals, the alkenyl and substituted alkenyl radicals, the alkoxy radicals and the carbalkoxy radicals can be straight-chain or branched. In particular, when R is a C2-C6 alkenyl radical or a C3-C6 alkyl radical, this can be branched. If R is a straight alkyl radical, then this consists, for example, of 5-14, in particular 7-12, carbon atoms. The alkyl and substituted alkyl radicals and the alkoxy radicals each having 1-6 carbon atoms consist in particular of 1-4 carbon atoms, preferably of 1,2 or 3 carbon atoms. The alkenyl and substituted alkenyl radicals consist in particular of 2,3 or 4 carbon atoms, preferably 3 or 4 carbon atoms. With the meaning C2-Có-alkoxyalkyl radical, the statement of the number of carbon atoms refers to the number of carbon atoms in the entire group, that is to say the C number alkyl group plus the C number alkoxy group, in particular these are alkoxy groups with 1 or 2 carbon atoms and alkyl groups with 1 or 2 carbon atoms such as methoxymethyl, ethoxy-ethyl, methoxyethyl, ethoxymethyl. If such a C2-C6-alkoxyalkyl radical is substituted by a carboxy group, the carboxy group is preferably located in the alkoxy part of the group. If R is a branched C3-C6-alkyl radical, it is in particular an alkyl radical with 3 or 4 carbon atoms. If R is a straight alkyl radical, it is, for example, an alkyl radical with 8-12 C atoms, preferably 9-10 C atoms, or else the propyl radical.

If R is a C3-C10-alkyl radical which is substituted by a C2-Cs-carb-alkoxy group, then the alkyl radical consists in particular of 7-8 C-atoms and the carbalkoxy group in particular of 2-3 C-atoms, the carbalkoxy group preferably in the omega position; as carbalkoxy group are in particular into consideration: carbmethoxy and carbethoxy.

If R is a substituted phenyl radical, this can be substituted once, twice or three times by identical or different substituents. In particular, the phenyl radical is substituted twice, namely by nitro groups, halogen atoms (chlorine, fluorine or bromine), carboxy groups, methyl or methoxy groups. If the group -NR1R2 forms a heterocyclic 5- or 6-ring, it is in particular a 6-ring, such as the morpholine, or piperidine or piperazine ring, in the case of a substitution of such a ring preferably alkyl groups with 1-3 C atoms, preferably methyl or ethyl groups and / or hydroxyl groups. For example, this is a morpholine ring substituted twice by methyl groups or a piperidine ring substituted by a hydroxy group or a methyl group or a piperazine ring substituted by an oxyethyl group, the alkylene bridge between the -NRiR2 group and the group -CO-O - is preferably the methylene group. If R 1 and / or R 2 are C 1 -C 6 -alkyl radicals, then these can also be substituted by one or two C 1 -C 6 -alkoxy groups or one or two halogen atoms (chlorine, bromine). If R is a Ci-Ce alkyl group which contains the group -NR1R2, then it is preferably the group -CH2-NR1R2.

If R is a phenyl radical which is disubstituted as indicated above, the two substituents are preferably in the 3,5-position.

The compounds according to the invention are notable for good cardiac activity. In contrast to the known compound, which is not absorbed after oral administration, the compounds according to the invention are absorbed to a high degree in the gastrointestinal tract after oral administration and have, for example, enteral absorption quotients between 30 and 90%. The enteral

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In contrast, the absorption quotient of the known compound is 0. The known compound can therefore not be administered orally.

In contrast, the compounds according to the invention are particularly suitable for oral administration and thus for long-term therapy. In particular, the compounds according to the invention have a positive inotropic effect (improvement of the contraction power of the heart), which can be detected, for example, on the isolated organ (Langendorff heart, auricle) or on the whole animal (dog). The hatcher doses are, for example, in the extremely favorable range between 0.09 and 1 mg / kg, preferably between 0.1 and 0.5 mg / kg. The Hatcher dose is the smallest dose that can lead to death in cats after 60-90 minutes of intravenous infusion and is a common measure for assessing the effectiveness of potent cardiac compounds.

In addition, there is a strong bradycardic effect of the compounds according to the invention, which manifests itself in a decrease in the beat frequency of up to 30% (in the therapeutic range) and thus leads to a normalization of an increased pulse frequency of the insufficated heart.

In addition, the decay rates of the compounds according to the invention in cats are in a therapeutically favorable range, for example in cats between 20 and 26%. With a decay rate of this size, the active ingredient is prevented from accumulating too much and toxic effects appear after repeated administration, which is particularly important for cardioactive compounds. Furthermore, the compounds according to the invention are noticeable due to a minor side effect: for example, no nausea was registered during the infusion in the cat. They are also well tolerated by the stomach (for example, no ulcerogenic effect was found in the rat).

The compounds of the formula I according to the invention are prepared according to the invention by adding a compound of the formula

CH,

Z.

OH

wherein Z represents a hydroxy group or a halogen atom, with an acid of the formula

R-COOH III

whose carboxyl group can also be activated. If compounds of the formula I in which R is a Ci-Có haloalkyl group or a C2-C6 alkenyl group are reacted with a compound of the formula RiR2NH, where R 1 and R 2 have the meanings indicated, a compound of the formula I in which R is a Ci -Cö-alkyl group, which contains the group -NR1R2. In the process products, the residues Ri and R2 can be converted into those residues Ri and R2 which have other meanings within the definition given. Compounds of the formula I in which R3 is a formyl group can be reduced to the -CH20H group or oxidized to the -C02H group.

If an acid of formula III with an activated carboxyl group is used in the process, then if Z is a hydroxyl group, it is preferably a compound of the general formula

R-COX IV

wherein R has the meanings indicated, and X is a halogen atom, a group of the formula -OR ', -SR' or a group of the formula -OSO3H, -0-P0 (QH) 2, -OP (OR ') 2, -0 -As (0R ') 2 or -OCO-R "and R' is a C1-C6-alkyl radical or in the case of -OR 'or -SR' also a phenyl radical, one by nitro groups, Ci-C4-alkoxy groups, C1-C4-alkyl groups or halogen atoms (chlorine, fluorine, bromine) substituted phenyl radical, a cyanomethyl radical or a carboxymethyl radical and R "is a straight or branched Ci-Cö-alkyl radical, a Ci-Cs-alkoxy radical, a phenoxy radical or a carbobenzoxy radical or also represents the radical R. If X represents a halogen atom, it is preferably chlorine, bromine or iodine; if R 'or R "are alkyl radicals or alkoxy radicals, these are preferably low molecular weight and consist of 1-4 carbon atoms.

If Z of formula II represents a halogen atom (chlorine, bromine, iodine), then X of formula IV is, for example, an O-alkali atom, preferably O-sodium, O-potassium, O-lithium, or an O-silver atom or also O- MgCl,

0-MgBr.

The reaction with a compound of the formula III or IV is carried out, for example, in a customary solvent or suspending agent such as water, if appropriate with the addition of a solubilizer (for example lower aliphatic alcohols, lower aliphatic ketones, dimethylformamide) or indifferent agents. Examples of suitable solvents or suspending agents are: low molecular weight aliphatic ethers (for example 4-10 C atoms); low molecular weight aliphatic ketones (for example 3-6 C atoms); saturated cyclic ethers such as tetrahydrofuran, dioxane; low molecular weight saturated chlorine and fluorocarbons with 1-5 C atoms, where the individual C atoms can be substituted one or more times (2 to 3 times) by chlorine and / or fluorine, such as chloroform, methylene chloride; Aromatic hydrocarbons optionally substituted by chlorine or bromine such as benzene, toluene, xylene, chlorobenzene, dimethylformamide, dimethyl sulfoxide, tetramethylurea, pyridine, N-methylpyrrolidone. Mixtures of these solvents can of course also be used.

The process is carried out at temperatures between 0 and 20 ° C, preferably 15 and 150 ° C.

Often, especially when X (formula IV) is a halogen atom or the group -OCOR ", is the presence of an acid-binding substance such as alkali metal hydroxides, alkali metal carbonates, alkali metal hydrogen carbonates, alkali metal acetates, alkaline earth metal carbonates, trialkylamines, dialkylamines, pyridine and the like or also excess compound II The acid-binding agent can also be used at the same time as a solvent, alone or in a mixture with other customary agents (for example pyridine). Care must be taken to ensure that unreacted starting substance III or IV, in particular if it is an acid chloride is carefully neutralized and removed Frequently, chromatographic purification of the reaction product over silica gel is recommended, using, for example, a chloroform / ethanol mixture (ethanol content, for example

1-5%) is eluted.

If the free acid (formula III) is used, then

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their activation by the presence of condensing agents such as dicyclohexylcarbodiimide, tetraethylpyrophosphite, 5- (3'-sulfonphenyl) ethylisooxazole, sulfuric acid bis-alkylamides (for example SO [N (CH3) 2] 2), N, N'-carbo -nyldiimidazole and so on required (Organic Reactions, Vol. 12,1962, pages 205 and 239).

A compound in which one of the radicals R 1 or R 2 is a protective group customary for amino groups can also be used as the reaction component of the formula III. For example, the protective groups customary in peptide synthesis and the cleavage methods customary there are suitable. Among other things, the book by Jesse P. Greenstein and Milton Winitz "Chemistry of Amino Acids", N.Y. 1961, John Wiley a. Sons, Inc. Volume 2, for example, page 883 ff. In the end products, such protective groups can be split off using mineral acids such as hydrochloric acid or sulfuric acid in alcoholic or aqueous-alcoholic solution or using bases, for example alcoholic alkali metal hydroxide solution (for example methanolic KOH) at temperatures between 20 and 100 ° C. Residues which can be removed reductively can be hydrogenated with hydrogen in the presence of a hydrogenation catalyst (for example palladium, palladium-carbon), for example in ethanol, preferably under normal conditions.

The residues R 1 and R 2 can then be introduced into the amino group by alkylation. This also includes the analogous introduction of an alkenyl group. Examples of suitable alkylating or alkenylating agents are: esters of the formula R 'ìHal, ArS020 R' 1 and S02 (0R '1) 2, where shark is a halogen atom (in particular chlorine, bromine or iodine) and Ar is an aromatic radical such as, for example is a phenyl or naphthyl radical which is optionally substituted by one or more lower alkyl radicals and R '1 is a Ci-C6-alkyl radical, a C2-C6-alkenyl radical or a Ci-Có-alkyl or C3 substituted by Ci-Cs-alkoxy groups or halogen atoms Is -C6 alkenyl. Examples are alkyl p-toluenesulfonic acid ester, lower dialkyl sulfates, alkyl halides, alkenyl halides and the like. The alkylation or alkenylation reaction is carried out, if appropriate with the addition of customary acid-binding agents such as alkali metal carbonates, pyridine or other customary tertiary amines, at temperatures between 0 and 150 ° C. in inert solvents such as alcohols, dioxane, dimethylformamide, dimethyl sulfoxide, aromatic hydrocarbons such as benzene , Toluene or acetone and mixtures of such solvents. The alkylation using alkyl halides (for example iodides) in the presence of NaH can be carried out, for example, in a mixture of toluene and a little dimethylformamide (0.1 to 5%, for example 0.5%). Instead of the reactants just mentioned, other chemical equivalent agents commonly used in chemistry can also be used (see, for example, also: LF and Mary Fieser "Reagents for Organic Synthesis", John Wiley and Sons, Inc. New York, 1967, Vol. 1, Page 1303-1304 and vol. 2, page 471). If only one of the radicals R 1 or R 2 is to be introduced, it is expedient to carry out the alkylation or alkenylation in the presence of the protective group present in the starting product and only then to remove the protective group.

The alkylation or alkenylation can also be carried out in such a way that, after the protective group has been split off, an appropriate oxo compound is reacted with a simultaneous or subsequent reduction at normal or elevated pressure at temperatures between 0 and 100 ° C. in a conventional solvent or suspending agent. The reducing agent used is, for example, nascent hydrogen in neutral or

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basic medium, electrolytic reduction, sodium alcohol, sodium or aluminum amalgam, hydrogen in the presence of conventional hydrogenation catalysts (for example Raney nickel, platinum, palladium) or complex hydrides such as lithium aluminum hydride. If benzyl groups are to be removed at the same time as the hydrogenating condensation, palladium catalysts should preferably be used by first preparing the immediate condensation product and then only reducing it after prior isolation and purification.

The process products in which the radical R is a Ci-Ce-haloalkyl radical can be converted into compounds in which R represents a Ci-Ca-alkyl group by reaction with amines of the formula HNR1R2, in which R 1 and R 2 have the meanings indicated, which is substituted by the group -NR1R2. This reaction is carried out with or without a solvent at elevated temperatures. Suitable solvents are organic solvents, for example alcohols or hydrocarbons such as benzene, toluene, xylene, dimethylformamide, ethanol, butyl alcohol. In general, temperatures between 50 to 200 ° C. If necessary, it is advisable to work in the presence of an acid acceptor, for example potash, soda and so on. Excess amine can also serve as the acid acceptor.

Process products of the formula I in which R is a C 1 -C 6 -alkyl group which is substituted by the radical -NR1R2 can also be obtained from compounds of the formula I

wherein R is a C2-C6 alkenyl radical, obtained by reacting such compounds with the corresponding amine of the formula HNR1R2. This reaction can be carried out, for example, in a solvent or suspension medium such as anhydrous lower alcohols, dioxane, organic acid amides, acetic acid and the like at 20-150 ° C. (reaction time from several hours to a few days). The reduction of compounds of formula 1 in which R3 is the formyl group (-CHO group) to the corresponding compounds in which R3 is the -CH20H group is carried out in a known manner using complex metal hydrides (for example sodium borohydride, cyanoborohydride, tri-ter). -butoxy-aluminum hydride) or by means of aluminum alcoholates according to Meerwein and Ponndorf (for example by means of aluminum isopropylate) at temperatures between 0-150 ° C, in particular 20-100 ° C. Examples of suitable solvents or suspending agents for this reaction are: lower aliphatic alcohols, dioxane, tetrahydrofuran, water or aromatic hydrocarbons such as benzene, toluene and mixtures of these agents. The oxidation of compounds of formula 1 in which R3 is the formyl group to the corresponding compounds in which R3 is the -C02H group takes place in a known manner by oxidation with, for example, chromium (VI) oxide, chromium oxide-pyridine complex, potassium umdichromate, potassium permanganate, chromic acid in solvents such as lower aliphatic ketones (acetone, cyclohexanone), aromatic hydrocarbons (benzene, toluene), halogenated hydrocarbons (CCU), dimethylformamide at temperatures between 0-150 ° C, especially 20-100 ° C.

The compounds which contain asymmetric carbon atoms and are generally obtained as racemates can be cleaved into the optically active isomers in a manner known per se, for example by means of an optically active base. However, it is also possible to use optically active starting materials from the outset, in which case a corresponding optically active form is obtained as the end product.

The compounds according to the invention are related to the production of pharmaceutical compositions

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wise preparations suitable. The pharmaceutical compositions or pharmaceuticals contain as active ingredient one or more of the compounds according to the invention, optionally in a mixture with other pharmacologically or pharmaceutically active substances, potassium and magnesium aspartate being preferred in particular. The pharmaceuticals can be produced using the known and customary pharmaceutical carriers and auxiliaries.

The drugs can be used, for example, enterai, parenterally, orally, perlingually or in the form of sprays. The administration can take place, for example, in the form of tablets, capsules, pills, dragées, suppositories, liquids or aerosols. Possible liquids are, for example, oily or aqueous solutions or suspensions, emulsions, injectable aqueous or oily solutions or suspensions.

Starting materials of the formula II, in which R.3 is a -CH2OH group and Z represents a halogen atom, if they are not known, can be obtained from the corresponding compounds where Z is a hydroxy group by treatment with known halogenating agents (hydrohalic acids, thionyl chloride, Phosphorus halides, sulfuryl chloride, phosphorus oxychloride, phosgene, benzotrichloride) can be obtained in a conventional manner.

example 1

Hellebrigenin-3ß-butyrate

2.08 g of Hellebrigenin (0.005 mol) are dissolved in 20 ml of pyridine and 15 ml of n-butyric anhydride are added. The mixture remains for 60 hours. 300 ml of diethyl ether are added. When standing in the fridge, crystals separate out overnight, which are suctioned off, washed with ether and dried. The product obtained is chromatographed on silica gel and recrystallized from 50% aqueous ethanol. 1.2 g of white needles are obtained.

F. 212 ° C.

Example 2

Hellebrigenin-3 /? - isobutyrate

2.08 g (0.005 mol) of Hellebrigenin are dissolved in 20 ml of pyridine and 10 ml of isobutyric anhydride are added. After 24 hours, 400 ml of diethyl ether are added and the mixture is left to crystallize overnight while standing in the refrigerator. The substance is purified by column chromatography on silica gel and recrystallized from 50% aqueous ethanol.

F. 250 ° C;

Yield: 1.5 g

Example 3

3j8-isovaleric acid ester of Hellebrigenins *)

2.08 g (0.005 mol) of Hellebrigenin are heated to boiling in 20 ml of pyridine with 10 ml of iso-valeric anhydride for 1 hour. After cooling, 400 ml of diethyl ether are added. When standing in the refrigerator, a crude product crystallizes out, which is purified by column chromatography and recrystallized from 50% aqueous ethanol.

F. 196-199 ° C.

Yield: 1.5 g.

Example 4

3 /? - (3,3-Dimethyl-acrylic acid ester) of the Hellebrigenins

20 g of Hellebrigenin (0.048 mol) are suspended in 400 ml of dry dichloromethane under a stream of N2. You give 20

ml - 20 g (0.148 mol) of freshly distilled dimethyl acrylate chloride and heated under reflux with stirring for 1.5 h, taking care to exclude moisture. The Hellebrigenin dissolves. The mixture is allowed to cool and 20 ml of absolute methanol are added to destroy the excess of acid chloride. There is violent hydrochloric acid development, to completely destroy acid chloride residues, the mixture is boiled under reflux for a further 30 minutes.

The cooled reaction mixture is shaken in a separating funnel with 100 ml of water, then three times with 100 ml of saturated NaHCCb solution and again with 100 ml of water; the dichloromethane solution is dried with anhydrous sodium sulfate and concentrated in vacuo. The yellow oil formed is taken up in 50 ml of dry chloroform and stirred in 1500 ml of petroleum spirit (bp. 50-70 °), the reaction product precipitating (24.8 g). Further purification is carried out by column chromatography over silica gel (Geduran S 100.0.063-0.200 mesh) at 20 ° C.

The crude product is taken up in 50 ml of chloroform / ethanol (98% chloroform, 2% ethanol) and placed on a 132 cm long column (inner diameter 6 cm). The elution takes place with

*) The designation «3/8» before the name of the acid indicates that the 3/3 hydroxyl group of the Hellebrigenin is linked to the acid residue. This also applies to all of the following examples.

the same solvent mixture. A brown colored cooling jacket provides extensive light protection and the temperature is kept constant at 20 ° C. The flow rate is 115 ml / minute. The individual components are collected separately. As soon as the desired main product arrives, the process can be shortened by increasing the polarity.

The main fraction is evaporated to dryness in vacuo, then taken up with 50 ml of CHCb and precipitated with 1.5 liters of petroleum ether (bp. 50-70 °), suction filtered and dried at 50 ° C in vacuo.

Yield: 15 g = 62.6%.

F. 220-222 ° C.

Example 5

3/5-crotonic acid ester of Hellbrigenin

6.8 g (0.0163 mol) of Hellebrigenin are refluxed in 210 ml of chloroform and 6 ml of crotonic acid chloride for 1 hour. Working up is carried out as in Example 4. The reaction product is recrystallized twice from methanol.

Example 6

Hellebrigenin-3 /? - (3,3-dimethyl-butyrate)

2.8 g (0.0067 mol) of Hellebrigenin are boiled under reflux in 60 ml of methylene chloride with 15 ml of 3,3-dimethylbutyric acid chloride for 2 hours. The reaction solution is then washed three times with water and three times with saturated sodium bicarbonate solution, dried over magnesium sulfate and the solvent is distilled off. The residue is mixed with diethyl ether and left to stand overnight, the reaction product (crude product) crystallizing. The product is recrystallized from 120 ml of methanol.

Yield: 1.8 g mp 237 ° C.

Example 7

3j8-Caprylic acid ester of Hellebrigenin

2.08 g (0.005 mol) of Hellebrigenin are refluxed in 20 ml of pyridine and 10 ml of caprylic anhydride for 2 hours

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heated. The crude product is precipitated with diethyl ether, chromatographed on a silica gel column and recrystallized from 50% aqueous ethanol.

Yield: 1.1 g;

Mp 189-191 ° C.

Example 8

3 / J-decanoic acid ester of Hellebrigenin 2.08 g (0.005 mol) Hellebrigenin are boiled under reflux in 20 ml pyridine with 10 ml decanoic anhydride for 3 hours. After cooling, the crude product is precipitated by adding 500 ml of water, chromatographed on a silica gel column and recrystallized from 66% aqueous ethanol.

Yield: 1.6g;

F. 188 ° C.

Example 9 Hellebrigenìn-3/3-benzoate

3 g (0.007 mol) of Hellebrigenin are dissolved in 25 ml of pyridine, 2.8 g of benzoic anhydride are added and the mixture is boiled under reflux for 5 hours. After addition of diethyl ether, a crude product separates out, which is first chromatographed on a silica gel column and then recrystallized from 50% aqueous ethanol.

Yield: 0.8 g;

F. 238-240 ° C.

Example 10 Helebrigenin-3 / i-hemiphthalate

2.08 g (0.005 mol) of Hellebrigenin are esterified according to Example 10 with 10 g of phthalic anhydride in 20 ml of pyridine. After chromatography on silica gel, the reaction product is dissolved in 20 ml of hot ethanol and precipitated with 250 ml of diisopropyl ether.

Yield: 0.8 g;

Mp 163-165 ° C.

Example 11 Hellebrigenin-3 / i- (3,5-dinitro-benzoate)

2.08 g (0.005 mol) of Hellebrigenin are boiled under reflux in 20 ml of pyridine with 5 g of 3,5-dinitrobenzoyl chloride for 8 hours. The reaction product is precipitated with water, chromatographed on silica gel, then dissolved in chloroform and precipitated with petroleum ether.

Yield: 0.5 g;

F. 172 ° C.

Example 12 Hellebrigenin-3 /? - monomethyl sebacate 3 g (0.0072 mol) of Hellebrigenin are boiled under reflux in 100 ml of methylene chloride with 3 ml of triethylamine and 3 ml of 9-chloroformyl-nonanoic acid methyl ester, with 3 ml of triethylamine again after 3 hours and 9 chloroformylnonanoic acid methyl ester are added.

After standing overnight, the reaction solution is filtered, washed three times with water, dried over magnesium sulfate and the solvent is distilled off. The residue is stirred with ether for 2 hours, 3 g of reaction product being obtained, which are successively recrystallized from 30 ml of isopropanol and 15 ml of methanol.

Yield: 1.8 g;

F. 150-152 ° C.

Example 13

Hellebrigenin-3ß-hemidiglycolate 2 g (0.005 mol) Hellebrigenin are dissolved in 10 ml pyridine and a solution of 5 g diglycolic anhydride in 10 ml pyridine is added. The solution is left to stand at room temperature for 24 hours. 2.6 g of the title substance crystallize out and are recrystallized from 230 ml of 80% ethanol.

Yield: 1.6 g;

M. 239-240 ° C.

Example 14

Hellebrigenin-3/3-chloroacetate (= 3 / J-chloroacetyl-hellebri-genin)

20 g (0.048 mol) of Hellebrigenin are boiled under reflux in 300 ml of methylene chloride and 20 ml of chloroacetyl chloride for 2 hours. Working up is carried out as in Example 4. The reaction product obtained (22 g) is recrystallized from 900 ml of methanol with the addition of activated carbon.

Yield: 16 g;

M. 197-198 ° C.

Example 15 Hellebrigenin 3/5 (3-chloropropionate)

10 g (0.024 mol) of Hellebrigenin are heated under reflux in 190 ml of methylene chloride and 10 ml of β-chloropropionyl chloride for 3 hours. Working up is carried out as in Example 4. The reaction product obtained (10 g) is recrystallized from 200 ml of methanol with the addition of activated carbon.

Yield: 8 g;

Mp 168-169 ° C.

Example 16 Hellebrigenin-3ß-diallylaminoacetate 2 g (0.004 mol) of 3-chloroacetylhellebrigenin are heated under reflux in 20 ml of acetone with 20 ml of diallylamine for 2 hours. After cooling, the diallylamine hydrochloride is filtered off, the solvent is distilled off and the reaction product which remains is treated with 100 ml of water and recrystallized from isopropanol.

Base melting point: 189 ° C.

Production of the hydrochloride:

2.4 g of base are neutralized in 25 ml of ethanol with isopropanolic hydrochloric acid, mixed with diethyl ether and left to stand overnight. 2.2 g of hydrochloride precipitate out and are recrystallized from 80 ml of ethanol with the addition of 50 ml of diethyl ether.

Yield: 1.2 g;

F. 230-231 ° C.

Example 17

Hellebrigenin-3ß - [(N-methyl-2,2-dimethoxy-ethylamino) acetate]

4.5 g (0.009 mol) of 3-chloroacetylellebrigenin are boiled under reflux in 70 ml of acetone with 1.3 ml (0.01 mol) of methylaminoacetaldehyde dimethyl acetal and 4.5 ml of triethylamine. After standing overnight, the mixture is filtered, the solvent is distilled off and the residue is

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treated with ether and finally stirred for 1 hour with 150 ml of water. 2.5 g of title substance (base) are obtained, which crystallize with one mole of water and are recrystallized twice from 40 ml of 50% methanol with the addition of activated carbon.

Yield: 1.2 g;

Mp 174-176 ° C.

Example 18

Hellebrigenin-3 /? - (2,6-dimethyl-morpholinoacetate) 2.5 g (0.005 mol) of 3-chloroacetylhellebrigenin are refluxed in 25 ml of acetone with 5 ml of 2,6-dimethylmorpholine for 2 hours. The solvent is distilled off and the residue is stirred with 200 ml of water for 1 hour. This gives 2 g of title substance (base) which melts after recrystallization from isopropanol at 196-198 ° C.

Production of the hydrochloride:

2 g of the base of mp 196-198 ° C are dissolved in 20 ml of acetone, neutralized with isopropanolic hydrochloric acid, by adding 30 ml of diethyl ether, the hydrochloride is precipitated (2 g) and recrystallized from 30 ml of ethanol.

Yield: 1 g;

F. of the hydrochloride 178-180 ° C (hygroscopic).

Example 19

Hellebrigenin-3 / J- (4-hydroxy-piperidinoacetate)

2.5 g (0.005 mol) of 3-chloroacetylellebrigenin are refluxed in 40 ml of acetone with 2 g of 4-hydroxypiperidine for 1 hour. After cooling, the mixture is filtered, the solvent is distilled off and the residue is stirred for 2 hours with 200 ml of water. To completely precipitate the base, the aqueous suspension is saturated with sodium chloride. 1.8 g of title substance (base) are obtained, which melts after recrystallization from isopropanol at 219-220 ° C.

The hydrochloride is prepared as in Example 16. 1.4 g of the same are recrystallized from methanol-ethanol (2: 1) with the addition of 20 ml of diethyl ether.

Yield: 1 g;

F. of hydrochloride 236-237 ° C.

Example 20

Hellebrigenin-3 /? - (3-diethylamino-propionate)

2 g (0.0039 mol) of 3- (3-chloropropionyl) halbrigenin are boiled under reflux in 20 ml of acetone with 20 ml of diethylamine for 2 hours and worked up as in Example 16. The reaction product obtained (1.8 g) is recrystallized from ethanol.

F. base 192 ° C.

The hydrochloride is prepared analogously to Example 16 and recrystallized from ethanol.

Yield 1.3 g from 1.8 g base.

F. of hydrochloride at 206 ° C.

Example 21

3/3 cyclopropanecarboxylic acid ester of Hellebrigenin 800 mg Hellebrigenin are suspended in 50 ml of CH2CI2, 1 g of cyclopropanecarboxylic acid chloride is added and the mixture is refluxed for 4 hours. Working up and column chromatographic purification are carried out as described in Example 4.

Yield 500 mg;

F .: 140 ° / 240 °.

Example 22 Hellebrigenol-3 / J-isobutyrate

1.5 g (0.0031 mol) of Hellebrigenin -3ß-isobutyrate are dissolved in 60 ml of absolute tetrahydrofuran and at room temperature with 60 ml of a freshly prepared reducing solution of lithium-tri-ter.-butoxy-aluminum hydride in tetrahydrofuran (prepared from 1, 5 g of Li (AlH4) and 6 g of tert-butanol) were added at room temperature. After stirring for two days at room temperature, the reaction mixture is mixed with 5% acetic acid and extracted with chloroform. The solution obtained is concentrated, the reaction product is precipitated by adding petroleum ether and purified by column chromatography on silica gel (eluent chloroform 95% by volume / ethanol 5% by volume).

Yield: 30%.

F. 195 ° C.

Example 23 Hellebrigenol-3β- (3,3-dimethyl-acrylate)

1 g (0.002 mol) of helebrigenin-3 / J- (3,3-dimethyl-acrylate) are dissolved in 60 ml of absolute tetrahydrofuran and mixed with 60 ml of a freshly prepared reducing solution of lithium-tri-tert-butoxy-aluminum hydride in tetrahydrofuran Room temperature offset. After a reaction time of one hour, 5% acetic acid is added and the mixture is extracted several times with chloroform. The solution is concentrated and the reaction product is precipitated by adding petroleum ether.

Yield: 49.8%.

F. 140 to 142 ° C.

Example 24

3/3-cyclohexane carboxylic acid ester of Hellebrigenin

2 g of Hellebrigenin and 4 ml of cyclohexane carboxylic acid chloride are reacted analogously *) (without purification by column chromatography).

Yield: 90%.

F. 211 to 214 ° C (decomposition)

*) as described for the preparation of the 3ß-cyclopropanecarboxylic acid ester

8th

5

io

15

20th

25th

30th

35

40

45

50

55

B

Claims (9)

639107 1. Compounds of the general formula wherein R is a C2-C6-alkenyl radical, a C3-Ci8-alkyl radical, a Cs-Cs-cycloalkyl radical, a C3-Cio-alkyl group substituted by a C2-Cs-carbalkoxy group or a carboxy group radical, a C2-C6-alkoxyalkyl radical substituted by a carboxy group, a phenyl radical, a phenyl radical substituted by nitro groups, carboxy groups, Ci-Ca-alkoxy groups, Ci-Cs-alkyl groups or halogen atoms or a Ci-C6-alkyl group which is the Group -NRiR2-contains, wherein Ri and R2 are Ci-Ce alkyl radicals, C2-C6 alkenyl radicals, Ci-Cf.-alkyl or C3-C6 alkenyl radicals substituted by Ci-Ce alkoxy groups or halogen atoms and one of the Ri or R2 may also be a hydrogen atom or the group -NR1R2 forms a saturated heterocyclic 5- or 6-ring which may also contain a further oxygen or nitrogen atom and where such a ring can also be mono- or disubstituted by Ci-Co -Alkyl groups, hydroxyethyl groups or hydroxy group pen can be substituted, and R3 is a -CHO-, -CH2OH- or -COOH group and their salts. 2. Compounds according to claim 1, characterized in that R of formula I is a branched alkyl radical with 3-5 C atoms, a branched alkenyl radical with 4-5 C atoms, an alkyl radical with 8,9,10,11 or 12 C. -Atoms, which can also be substituted by a carbmethoxy or carbethoxy group, an alkyl radical substituted by a methoxy or ethoxy group with 1-2 carbon atoms, an ethoxymethyl or methoxymethyl radical which is still in the methoxy or ethoxy group additionally contains a carboxy group, a phenyl group, a dinitrophenyl group, a morpholino-methyl group, a morpholinomethyl group substituted by one or two methyl groups, a piperazinomethyl group, a piperazinomethyl group substituted by an oxyethyl group, a piperidinomethyl group, a piperidinomethyl group substituted by a hydroxy group or an amino group methyl radical which is substituted on the nitrogen by two alkyl radicals having 1-4 C atoms or two alkenyl radicals having 3 or 4 carbon atoms. 3. Compounds according to claim 1 of formula I, wherein R has the following meanings: Ci-Ce-alkenyl radical, in particular Cs-Cs-alkenyl radical or C3-C12-alkyl radical, in particular C4-C10-alkyl radical, such an alkyl radical also by a Carboxy group can be substituted or C1-C3-alkoxy-Ci-Cs-alkyl radical or phenyl radical which can also be substituted 1 to 2 times by nitro groups or halogen atoms or simply by a carboxy group or di-Ci-Cs-alkylamino-Ci-Co -Alkyl radical, in particular DÌ-C1-C2-alkylamino-Ci-C4-alkyl radical or di-C3-C6-alkenylamino-C1-C6-alkyl radical, in particular di-C3-C4-alkenylamino-Ci-C4-alkyl radical or Ci-Cò -Alkylrest which is substituted by a pyrrolidine group, morpholino group, piperidino group, homopiperidino group, hydroxypiperidino group or a dimethylmorpholino group, these basic radicals preferably sitting in the co-position of the alkyl radical or C2-C3-alkoxy-Ci-C4-alkyl radical, which is preferably in "" Position is substituted by a carboxy group and R3 is the group -CHO, -CH2OH or -CO2H. 4. Process for the preparation of compounds of the general formula OH h wherein R and R3 have the meaning given in claim 1, and their salts, characterized in that Hellebrigenin of the formula in which Z represents a hydroxyl group or a halogen atom, with an acid of the formula 3s R - COOH III whose carboxyl group can also be activated. 5. The method according to claim 4, characterized in that the acid of the general formula III whose carbo- 40 xyl group is activated, a compound of the general formula R-COX IV 4s, in which R has the meanings indicated, and X is a halogen atom, a group of the formula -OR ', -SR' or a group of the formula -OSO3H, -0-P0 (0H) 2 ', -OP (OR') 2 \ -0-As (OR ') 2or-OCO R "and R' a lower alkyl radical or in the case of -OR 'or 50 wise -SR 'also a phenyl radical, a phenyl radical substituted by nitro groups, lower alkoxy groups, lower alkyl groups or halogen atoms, a cyanomethyl radical or a carboxymethyl radical and R "a straight or branched lower alkyl radical, a lower alkoxy radical, 55 represents a phenoxy radical or a carbobenzoxy radical or else the radical R or in which X denotes an O-alkali or O-silver atom or O-MgCl or O-MgBr. 6. A process for the preparation of compounds of formula I, wherein R has the meaning given in claim 1 60 and R3 is the -CH20H group, characterized in that a compound of the formula I in which R is as defined above and R3 is the formyl group is prepared according to claim 4, and the formyl group is then reduced. 7. A process for the preparation of compounds of the formula I in which R has the meaning given in claim 1 and R3 is the -COOH group, characterized in that a compound of the formula I according to claim 4 3rd 639107 wherein R is as defined above and R3 represents the formyl group, and then oxidizes the formyl group. 8. A process for the preparation of compounds of the formula I in which R is a Ci-C6-alkyl group which contains the s group -NR1R2, characterized in that a compound of the formula I in which R is a Ci-Ce-haloalkyl group or a C2-Co-alkenyl group is reacted with a compound of the formula HNRi R2, in which Ri and R2 have the meanings given in claim 1. 10th 9. Medicament containing at least one compound of formula I or a salt thereof. 10. Medicament according to claim 8, characterized in that it contains a pharmaceutical carrier and / or a diluent. 15 Hellebrigenin monoacetate of the formula CH, 0 = CH CH ^ -CO-O 20th OH is known. This connection shows a digitalis-like effect in the studies on the cat. (J. Pharmacol. Exper. Therapy 99 (1950) pages 395-400).