GB1577633A - Acyl derivatives of hellebrigenin - Google Patents

Description

(54) NEW ACYL DERIVATIVES OF HELLEBRIGENIN (71) We, DEUTSCHE GOLD-UND SILBER-SCHEIDEANSTALT VORMALS ROESSLER a body corporate organised under the laws of Germany of 9 Weissfrauenstrasse, 6 Frankfurt Main 1, Germany, do hereby declare the invention, for which we pray that a patent may be granted to us, and the method by which it is to be performed, to be particularly described in and by the following statement This invention relates to new acyl derivatives of hellebrigenin.

Hellebrigenin monoacetate corresponding to the formula

is known. This compound shows a digitalis-like effect when tested in cats (J. Pharmacol.

exper. Therapy 99 (1950). pages 395 - 400).

The present invention relates to new hellebrigenin derivatives corresponding to the general formula

in which R represents a C2-C6-alkenyl radical. a C3-Clx-alkyl radical. a C3-C6-cvcloalkyl radical, a C3-C",-alkyl radical substituted by a C2-C5-carbalkoxy group or by a carboxy group, a C2-C6-alkoxyalkyl radical substituted by a carboxy group. a phenyl radical. a phenyl radical substituted by one or more nitro groups. carboxy groups. C1-C6-alkoxy groups. C1-C6-alkyl groups or halogen atoms. or a C,-C6-alkyl group substituted by the group -NR,R2. where Rl and R2 are each C,-C6-alkyl radicals, C2-C6-alkenyl radicals, C1-C6-alkyl or C3-C6-alkenvl radicals substituted by one or more Cl-C6-alkoxy groups or halogen atoms or one Rl and R. may also represent a hydrogen atom: alternativelv the group -NR,R2 forms a saturated heterocyclic 5-or 6-membered ring which may contain an oxygen atom or another nitrogen atom and which may be substituted once or twice by C1-C6-alkyl groups. hydroxyethyl groups or hydroxy groups. and R3 represents -CHO, -CH2OH or -CO.H; and their salts.

The alkyl and substituted alkyl radicals. the alkenvl and substituted alkenvl radicals. the alkoxy radicals and the carbalkoxy radicals may be linear or branched. Especially in cases where R is a C.-C,-alkenvl radical or a C3-C6-alkyl radical. this radical may be branched. In cases where R is a linear alkyl radical. it contains for example. from 5 to 14 carbon atoms and more especially of from 7 to 12 carbon atoms. The alkyl and substituted alkyl radicals and the alkoxy radicals containing from 1 to 6 carbon atoms contain in particular from 1 to 4 carbon atoms and preferably 1, 2 or 3 carbon atoms. The alkenyl and substituted alkenyl radicals contain in particular 2, 3 or 4 carbon atoms, preferably 3 or 4 carbon atoms.In the term a "C2-C6-alkoxyalkyl radical", the number of carbon atoms indicated relates to the number of carbon atoms in the group as a whole, i.e. the number of carbon atoms in the alkyl group plus the number of carbon atoms in the alkoxy group. The groups in question are in particular alkoxy groups with 1 or 2 carbon atoms and alkyl groups with 1 or 2 carbon atoms, such as methoxymethyl, ethoxyethyl, methoxyethyl, ethoxymethyl. The C2-C6alkoxyalkyl radical of the type in question is substituted by a carboxy group, the carboxy group preferably being situated in the alkoxy moiety of the group. In cases where R is a branched C3-C6-alkyl radical, the alkyl radical in question is in particular an alkyl radical with 3 or 4 carbon atoms.In cases where R is a linear alkyl radical, the alkyl radical in question, is, for example, an alkyl radical with 8 to 12 carbon atoms, preferably with 9 to 10 carbon atoms, or even the propyl radical. In cases where R is a C3-Ct(,-alkyl radical which is substituted by a C2-C5-carbalkoxy group, the alkyl radical contains in particular from 7 to 8 carbon atoms, whilst the carbalkoxy group contains in particular from 2 to 3 carbon atoms, the carbalkoxy group preferably being in the omega position. The carbalkoxy groups in question are, in particular, carbomethoxy and carboethoxy groups.

In cases where R is a substituted phenyl radical, this phenyl radical may be substituted once, twice or three times by identical or different substitutents. In particular, the phenyl radical is substituted twice by nitro groups, halogen atoms (chlorine, fluorine or bromine), carboxy groups. methyl or methoxy groups. In cases where the group -NR,R2 forms a heterocyclic 5- or 6-membered ring. the ring in question is in particular a 6-membered ring, such as the morpholine or piperidine or piperazine ring. In cases where this ring is substituted. preferred substituents are C1-C3-alkyl groups, preferably methyl or ethyl groups and/or hydroxy groups.In this case, the ring in question is, for example, 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 a hydroxyethyl group, the alkylene bridge between the -NR,R1-group and the group -CO-O- preferably being the methylene group. In cases where Rl and/or R, are alkyl radicals. these alkyl radicals may also be substituted by 1 or 2 alkoxy groups or by 1 or 2 halogen atoms (preferably chlorine or bromine).In cases where R is an alkyl group which contains the group -NR,R,. the group in question is preferably the group -CH,-NR,R,. In cases where R is a phenyl radical substituted twice in the manner indicated above, the two substituents are preferably in the 3,5-position.

A preferred group of compounds are compounds according to formula I in which R represents a C,-C,-alkenyl radical, particularly a C3-Cs-alkenyl radical, or a C3-Cl,-alkyl radical. particularly a C-C",-alkvl radical. this alkyl radical optionally being substituted by a carboxy group. or a phenyl radical which may be substituted once or twice by nitro groups or halogen atoms or once by a carboxy group. or a di-C1-C3-alkylamino-C1-C6-alkyl radical, particularly a di-CI -C2-alkylamino-C,-C,-alkyl radical or a di-C3-C6-alkenylamino-C,-C6- alkyl radical. particularly a di-C3-C-alkenylamino-C,-C4-alkyl radical or a Cl-C6-alkyl radical substituted by a pyrrolidino group. a morpholino group, a piperidino group, a hydroxypiperidino group or a dimethyl-morpholino group, these basic radicals preferably being in the to-position of the alkyl radical. or a C,-C3-alkoxy-CI-C4-alkyl radical substituted, preferably in the to-position. by a carboxy group. and R3 is the group -CHO, -CH,OH or -CO.H.

A further group of preferred compounds are compounds according to formula I in which R is a branched alkyl radical with 3 to 5 carbon atoms. a branched alkenyl radical with 4 or 5 carbon atoms. an alkyl radical with 8. 9. 10. 11 or 12 carbon atoms, which may be substituted by a carbomethoxy or carboethoxv group, an ethoxymethyl or methoxymethyl radical which is substituted by a carboxy group in the methoxy or ethoxy group. a phenyl radical. a dinitrophenvl radical. a morpholinomethyl radical. a morpholinomethyl radical substituted by one or two methyl groups. a piperazinomethyl radical, a piperazinomethyl radical substituted bv a hydroxyethyl group. a piperidinomethyl radical. a piperidinomethyl radical substituted by a hydroxy group or an aminomethyl radical which is substituted on the nitrogen by two alkyl radicals each with 1 to 4 carbon atoms or bv two alkenyl radicals each with 3 or 4 carbon atoms.

The compounds according to the invention are distinguished by favourable cardioactivity. In contrast to the known compound which is not resorbed after oral ingestion, the compounds according to the invention are resorbed to e high degree in the gastro-intestinal tract after oral ingestion and have enteral resorption quotients for example of from 30 to 90 6sic. By contrast. the enteral resorption quotient of the known compound isO. Accordingly, the known compound cannot he orally administered.

Bv contrast. the compounds according to the invention are suitable for oral administra tion and, hence, for long-term therapy. In particular, the compounds according to the invention have a positive inotropic effect (improvement in the power of contraction of the heart), as can be demonstrated for example on the isolated organ (Langendorff's heart, atrium of the heart) or on a complete animal (dog). The Hatcher doses are for example in the extremely favourable range from 0.99 to 1 mg/kg and preferably in the range from 0.1 to 0.5 mg/kg. The Hatcher dose is the lowest dose which produces death in cats after 60 to 90 minutes' intravenous infusion, and is a standard measure for assessing the activity of powerfully cardioactive compounds.

In addition, the compounds according to the invention have a marked bradycardic effect which is reflected in a reduction in heart rate of up to 30 % (in the therapeutic range) and hence results in a normalisation of the increased pulse rate of the damaged heart.

In addition, the abatement levels of the compounds according to the invention in cats are in a therapeutically favourable range, for example between 20 and 26 o/o in cats. With an abatement level of this order, the active principle is prevented from accumulating to an excessive degree and hence from producing toxic phenomena after repeated administration, which is of particular importance in the case of cardio-active compounds. In addition, the compounds according to the invention are distinguished by negligible side effects. For example, no retching was recorded during infusion in cats. They also show high gastric compatibility (for example no ulcerogenic effect was observed in rats).

The compounds according to the invention may be produced for example by reacting a compound corresponding to the formula

in which Z is a hydroxy group or a halogen atom. with an acid corresponding to the formula R-COOH III in which R is as defined above and of which the carboxyl group may be activated, and optionally reacting the products of this reaction with a compound correspondng to the formula R,R2NH, where R, and R2 are as defined above, and/or converting the radicals Rl and R2 in the products thus obtained into other meanings within the scope of the definition given above, and in the resulting compounds, in which R3 is a formyl group, optionally reducing this formyl group into the -CH,OH group or oxidising it into the -CO2H group.

In cases where an acid of formula III containing an activated carboxyl group is used for the reaction, the compounds in question, where Z is a hydroxy group, are preferably compounds corresponding to the general formula R - COX IV in which R is as defined above and X represents a halogen atom. a group of the formula -OR'. -SR' or a group of the formula -OSO3H, -O-PO(OH)2, - OP(OR')2, -O-As(OR'), or -OCO-R" and R' is a C,-C6-alkyl radical or. in the case of -OR' or -SR', also a phenvl radical. a phenyl radical substituted by one or more nitro groups. C1-C4-alkoxy groups.

C1-C4-alkyl groups or halogen atoms (chlorine. fluorine, bromine). a cyanomethyl radical or a carboxymethyl radical, and R" is a linear or branched C1-C6-alkyl radical. a Cl-C6-alkoxy radical, a phenoxy radical or a carbobenzoxy radical or the radical R. In cases where X is a halogen atom. the halogen atom is preferably chlorine. bromine or iodine: in cases where R' and R" represent alkyl radicals or alkoxy radicals, the radicals in question are preferably of low molecular weight and consist of from 1 to 4 carbon atoms.

In cases where Z in formula II is a halogen atom (chlorine. bromine, iodine). X in formula IV is. for example, an alkali metal atom. preferably sodium, potassium or lithium.

a silver atom or even -MgCl or -MgBr.

The reaction with a compound of formula Ill OF IV is carried out for example in a standard solvent or suspending agent such as water, optionally in the presence of a solution promoter (for example lower aliphatic alcohols. lower aliphatic ketones, dimethyl formamide) or indifferent agents.Suitable solvents or suspending agents are. for example, low molecular weight aliphatic ethers (for example with 4 to l() carbon atoms): low molecular weight aliphatic ketones (for example with 3 to 6 carbon atoms); saturated cyclic ethers, such as tetrahydrofuran, dioxane; low molecular weight saturated chlorinated and fluorinated hydrocarbons with 1 to 5 carbon atoms, the individual C-atoms optionally being substituted once or several times (twice to three 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, dimethyl formamide, dimethyl sulphoxide, tetramethyl urea, pyridine, N-methyl pyrrolidone. It is of course also possible to use mixtures of the above-mentioned solvents.

The reaction is carried out at a temperature in the range from 0 to 200"C and preferably at a temperature in the range from 15 to 1500C.

In many cases, especially in cases where X (formula IV) is a halogen atom or the group -OCOR", the reaction is best carried out in the presence of an acid-binding agent, such as alkali metal hydroxides, alkali metal carbonates, alkali metal hydrogen carbonates, alkali metal acetates, alkaline earth metal carbonates, trialkyl amines, dialkyl amines pyridine and the like or even an excess of compound II. The acid-binding agent may also be used as solvent either on its own or in admixture with other standard solvents (for example pyridine). It is important to ensure that unreacted starting substance IV, particularly if it is an acid chloride, is carefully neutralised and removed. In many cases, it is advisable to purify the reaction product by chromatography over silica gel using a mixture of chloroform and ethanol (ethanol content e.g. 1 to 5%) for example as eluent.

In cases where the free acid (formula III) is used, it must be activated by the presence of condensation agents such as dicyclohexyl carbodiimide, tetraethyl pyrophosphite, 5-(3' sulphophenyl)-ethyl iso-oxazole, sulphurous acid-bis-alkylamides (for example SO N(CH3)2]2), N,N'-carbonyl diimidazole and so on (Organic Reactions, Vol. 12, 1962, pages 205 and 239).

The reaction component of formula III may also be a compound in which one of the radicals R, or R. is a protective group of the type normally used for amino groups. For example, it is possible to use protective groups normally encountered in the synthesis of peptides and also the methods by which they are normally eliminated. In this connection, reference is made inter alia to the book by Jesse P. Greenstein and Milton Winitz entitled "Chemistry of Amino Acids'. N.Y. 1961. John Wiley and Sons, Inc. Volume 2. for example pages 883 et seq.In the end products. protective groups of the type in question may be split off by means of mineral acids, such as hydrochloric acid or sulphuric acid in alcoholic or aqueous-alcoholic solution, or by means of bases, for example alcoholic alkali liquor (for example methanolic KOH). at a temperature of from 20 to 10() C. Groups which can be split off by reduction may be eliminated by hydrogenation with hydrogen in the presence of a hydrogenation catalyst (for example palladium, palladium carbon), for example in ethanol, preferably under normal conditions.

The radicals R, and R. may subsequently be introduced into the amino group by alkylation. This also includes the corresponding introduction of an alkenyl group. Suitable alkylating and alkenylating agents are, for example. esters of the formula R,Hal, ArSO2OR, and SO2(OR;)2. where Hal is a halogen atom (especially chlorine, bromine or iodine) and Ar is an aromatic radical such as. for example. a phenyl or naphthyl radical optionally substituted by one or more lower alkyl radicals and R;; is a C,-C6-alkyl radical. C2-C"-alkenyl radical or a C,-C,-alkyl or C-C6-alkenyl radical substituted by one or more C,-C,-alkoxy groups or halogen atoms. Examples are p-toluene sulphonic acid alkyl esters. lower dialkyl sulphates. alkyl halides, alkenyl halides and the like. The alkylation or alkenylation reaction is carried out in inert solvents, such as alcohols, dioxjne, dimethyl formamide. dimethyl sulphoxide. aromatic hydrocarbons such as benzene, toluene or acetone. or mixtures of these solvents, at temperatures of from 0 to 1500C.

optionally in the presence of standard acid-binding agents. such as alkali metal carbdnates, pyridine or other standard tertiary amines. The alkylation reation with alkyl halides (for example iodides) in the presence of NaH may be carried out. for example. in a mixture of toluene and a little dimethyl formamide (0.1 to 5 6/c. for example 0.5 Cho). ). Instead of using the reaction media to which reference has just bcen made. it is also possible to use other chemically equivalent media of the type commonly encountered in chemistry (cf. for example L.F. and Marv Fieser "reagents for Organic Synthesis". John Wiley and Sons, Inc. New York. 1967. Vol. 1. pages ()3-13()4 and Vol 2. page 471). In cases where it is intended to introduce only one of the radicals R or R2. it is best to carrv out alkylation or alkenylation in the presence of the protective group present in the starting material and only to eliminate the protective group on completion of alkvlation or alkenvlation.

Alkylation or alkenvlation may also be carried out by reaction after elimination of the protective group with a corresponding oxo compound. accompanied or followed by reduction. under normal or elevated pressure at a temperature of from () to 100"C and in a standard solvent or suspending agent. Suitable reducing agents are. for example nascent hydrogen in a neutral or basic medium, electrolytic reduction, sodium-alcohol, sodium or aluminium amalgam, hydrogen in the presence of a standard hydrogenation catalyst (for example Raney nickel, platinum, palladium) or a complex hydride, such as for example lithium aluminium hydride.In cases where it is intended to remove benzyl groups during the hydrogenating condensation reaction, it is preferred to use palladium catalysts in other words the direct product of condensation is initially produced and is only reduced thereafter, optionally after isolation and purification.

Intermediate products, in which the radical R is a Cl-C6-halogenoalkyl radical, may be converted by reaction with an amine of the formula HNR1R2, in which R1 and R2 are as defined above, into a compound in which R is a C1-C6-alkyl group substituted by the group -NR1R2. This reaction is carried out at elevated temperature in the presence or absence of solvents. Suitable solvents are organic solvents, for example alcohols or hydrocarbons, such as benzene, toluene, xylene, dimethyl formamide, ethanol, butyl alcohol. The reaction is generally carried out at a temperature of from 50 to 200"C. It may be advisable to carry out the reaction in the presence of an acid acceptor, for example potash, soda and so on. Excess amine may also be used as acid acceptor.

End products of formula I, in which R is a C,-C6-alkyl group substituted by the radical -NRlR2, may also be obtained from compounds of formula I, in which R is a C2-C6-alkenyl radical, by reacting these compounds with the corresponding amine of the formula HNRlR2. This reaction may be carried out, for example, in a solvent or suspending agent, such as anhydrous lower alcohols, dioxane, organic acid amides, acetic acid and the like at a temperature in the range from 20 to 1500C (reaction time several hours to a few days).

The reduction of compounds of formula I, in which R3 is the formyl group (-CHO group), into the corresponding compounds, in which R3 is the -CH2OH group, is carried out in known manner by means of complex metal hydrides (for example sodium borohydride, cyanoborohydride, tri-tert.-butoxy aluminium hydride) or by means of aluminium alcoholates in accordance with the Meerwein-Ponndorf reaction (for example by means of aluminium isopropylate) at a temperature of from 0 to 1500C and more particularly at a temperature of from 20 to 1000C. Suitable solvents or suspending agents for this reaction are, for example, lower aliphatic alcohols. dioxane, tetrahydrofuran, water or aromatic hydrocarbons such as benzene. toluene and mixtures thereof.The oxidation of compounds of formula I, in which R, is the formyl group, into the corresponding compounds, in which R3 is the -CO2H group, is carried out in known manner by oxidation with, for example, chromium (VI) oxide, chromium oxide - pyridine complex. potassium dichromate, potassium permanganate, chromic acid or by oxidation with aliphatic C-C6- or cycloaliphatic C4-C7 ketones in the presence of aluminium isopropylate (Oppenauer oxidation) in solvents such as lower aliphatic ketones (acetone, cyclohexanone), aromatic hydrocarbons (benzene, toluene), halogenated hydrocarbons (CCl4), dimethyl formamide, at a temperature of from 0 to 1500C and more particularly at a temperature of from 20 to 100"C.

The radical R may contain one or several asymmetrical carbon atoms. The mixtures of diastereoisomeric compounds formed in this case could be separated by a known method, for example, by fractional crystallisation. Optically active starting materials corresponding to formula III as well as racemates corresponding to formula III may be used in the production of the compounds according to the invention.

Where they are not already known, starting compounds of formula II, in which R3 is a -CH2OH group or a -CO2H group and Z is a halogen atom, may be obtained from the corresponding compounds, in which Z is a hydroxy group, by treatment with known halogenating agents (hydrohalic acids, thionyl chloride, phosphorus halides, sulphuryl chloride, phosphorus oxychloride. phosgene, benzotrichloride) in the usual way.

The compounds according to the invention are suitable for the preparation of pharmaceutical compositions and preparations. The pharmaceutical compositions or medicaments contain as active principle one or more of the compounds according to the invention, optionally in admixture with other pharmacologically or pharmaceutically active substances. The medicaments are prepared in known manner with the usual pharmaceutical additives and other conventional excipients and diluents.

Examples of excipients and additives of this kind are the substances recommended and specified in the following literature references as additives for pharmacy, cosmetic and related fields: Ullmanns Encyklopadie der technischen Chemie. Vol. 4 (1953), pages 1 to 39: Journal of Pharmaceutical Sciences. Vol. 52 (1963). pages 918 et seq. H.v.

Czetsch-Lindenwald. Hilfsstoffe fur Pharmazie und angrenzende Gebiete: Pharm. Ind., No. 2. 196 1. pages 72 et seq: Dr. H.P. Fiedler. Lexikon der Hilfsstoffe fur Pharmazie, Kosmetik und angrenzende Gebiete Cantor KG. Aulendorf (Wurtt.) 1971.

Examples include gelatin. natural sugars. such as cane sugar or lactose. lecithin. pectin, starch (for example corn starch). alginic acid. tylose. talcum, lycopodium. silica (for example colloidal silica). cellulose. cellulose derivatives (for example cellulose ethers in which the cellulose hydroxy groups are partly etherified with lower saturated aliphatic alcohols and/or lower saturated aliphatic hydroxy alcohols, for example methyl hydroxy propyl cellulose), stearates, magnesium and calcium salts of fatty acids with 12 to 22 carbon atoms, especially the saturated fatty acids (for example stearates), emulsifiers, oils and fats, especially vegetable oils and fats (for example peanut oil, caster oil, olive oil, sesame oil, cottonseed oil, corn oil, wheat germ oil. sunflower seed oil, cod liver oil, mono-, di and tri-glycerides of saturated fatty acids C12H24O2 to C,8HX602 and mixtures thereof), pharmaceutically compatible monohydric or polyhydric alcohols and polyglycols, such as polyethylene glycols and derivatives thereof, esters of aliphatic saturated or unsaturated fatty acids (2 to 22 carbon atoms, especially 10 to 18 carbon atoms) with monohydric aliphatic alcohols (1 to 20 carbon atoms) or polyhydric alcohols, such as glycols glycerol, diethylene glycol, pentaerythritol. sorbitol, mannitol and so on, which optionally may even be etherified, benzyl benzoate, dioxolanes, glycerol formals, tetrahydrofurfuryl alcohol, polyglycol ethers with C1 -C1 2-alcohols, dimethyl acetamide, lactamides, lactates, ethyl carbonates, silicones (especially medium-viscosity dimethyl polysiloxanes). magnesium carbonate and the like.

Solutions can be prepared, for example, with water or physiologically compatible organic solvents, such as for example ethanol, 1,2-propylene glycol, polyglycols and derivatives thereof, dimethyl sulphoxide, fatty alcohols, triglycerides, partial esters of glycerol, paraffins and the like.

Conventional solution promoters and emulsifiers may be used in the preparation of the compositions. Examples of solution promoters and emulsifiers include polyvinyl pyrrolidone, sorbitan fatty acid esters, such as sorbitan trioleate, lecithin, acacia, tragacanth, polyoxyethylated sorbitan monooleate, polyoxyethylated fats, polyoxyethylated oleotriglycerides, linolised oleotriglycerides. polyethylene oxide condensation products of fatty alcohols. alkyl phenols or fatty acids. Polyoxyethylated in this context means that the substances in question contain polyoxyethylene chains with a degree of polymerisation of generally from 2 to 40. more particularly from 10 to 20.

Polyoxyethylated substances of this kind can be obtained by reacting compounds containing hydroxyl groups (for example monoglycerides or diglycerides or unsaturated compounds. such as for example those containing oleic acid residues) with ethylene oxide (for example 40 moles of ethylene oxide per mole of glyceride).

Examples of oleotriglycerides include olive oil, peanut oil, caster oil, sesame oil, cottonseed oil. corn oil (see also Dr. H.P. Fiedler "Lexikon der Hilfsstoffe fur Pharmazie, Kosmetik und angrenzende Gebiete 1971. pages 191 to 195).

In addition. it is possible to add preservatives. stabilisers. buffers. for example calcium hydrogen phosphate. colloidal aluminium hydroxide, flavour correctants, anti-oxidants and complex formers (for example ethylene diaminotetraacetic acid) and the like. To stabilise the active-principle molecule. the pH may have to be adjusted to a range of from about 3 to 7 with physiologically compatible acids or buffers. A neutral to weakly acid (up to pH 5) pH-value is generally preferred.

Examples of suitable antioxidants include sodium metabisulphite, ascorbic acid, gallic acid. gallic acid alkyl esters. butvl hydroxy anisole. nordihydroguaiaretic acid. tocopherols and tocopherols + synergists (substances which bind heavy meatls by complex formation, for example lecithin. ascorbic acid. phosphoric acid). Addition of the synergists greatly increases the antioxygenic effect of the tocopherols.

Examples of preservatives include sorbic acid. p-hydroxy benzoic acid esters (for example lower alkyl esters). benzoic acid. sodium benzoate. trichloroisobutvl alcohol, phenol. cresol. benzethonium chloride and formalin derivatives.

The compounds according to the invention are pharmacologically and galenically handled by the usual standard methods. For example. active principle(s) and additives or excipients are thoroughly admixed bv stirring or homogenisation (for example in colloid mills. ball mills). generally at a temperature of from 20 to 80"C and preferably at a temperature of from 20 to i() C.

The active principles or medicaments may be applied to the skin or mucosa or into the interior of the body. for example orallv. enterallv. pulmonarily. rectally. nasallv. vaginally.

linguallv. intravenouslv. intra-arterially. intracardially. intramuscularly. intraperitoneally.

intracutaneouslv. subcutaneously.

Bv virtue of their good enteral resorption (resorption levels of for example 4() to 90 %).

the compounds according to the invention are also particularly suitable for oral administration. Other medicaments may be added The compounds according to the invention show a good positive inotropic effect on isolated guinea pigs' hearts (Langendorff heart).

For example. an increase in the power of contraction of the heart of 2() to 50 % is observed in the ahove-mentioned test for a dose of 3 ttg/heart.

This positive inotropic effect is comparable with the effect of the known medicament Digoxin (between 10 and 30 g).

The lowest effective dose in the above-mentioned animal test is, for example, 0.3 Fg/heart (in vitro). The general dose range for the inotropic effect (in whole animals) is for example from 0.05 to 0.25 mg/kg oral, particularly 0.1 mg/kg; from 0.05 to 0.25 mg/kg intravenous, particularly 0.1 mg/kg.

Indications for which the compounds according to the invention may be considered include all degrees and forms of cardiac insufficiency, disorders of the heart caused by old age.

The pharmaceutical preparations generally contain from 0.01 to 5 mg of the active component(s) according to the invention.

The compounds according to the invention may be made up for example in the form of tablets, capsules, pills, dragees, suppositories, ointments, jellies, creams, powders, dusting powders, aerosols or in liquid form. Suitable liquid formulations are for example oily or alcoholic or aqueous solutions and suspensions and emulsions. Preferred formulations are tablets containing from 0.02 to 5 mg of active substance or solutions containing from 0.001 to 1 % of active substance.

The individual dose of the active components according to the invention may amount for example to a) from 0.01 to 2 mg for oral formulations, b) from 0.01 to 2 mg for parenteral formulations (for example intravenous, intramuscular formulations).

For example it is possible to prescribe 1 to 3 tablets containing from 0.1 to 2 mg of active substance three times daily or. for example, in the case of intravenous injection a 0.25 to 5 ml ampoule containing from 0.01 to 2 mg of substance one to two times daily. In the case of oral administration, the minimum daily dose is 0.01 mg for example; the maximum daily dose for oral administration should not exceed 5 mg.

In the treatment of dogs and cats, the oral individual dose is generally from about 0.002 to 1 mg/kg body weight.

The acute toxicity of the compounds according to the invention in mice (as expressed by the LD 50 mg/kg; Miller and Tainter's method: Proc. Soc. Exper. Biol. a. Med. 57 (1944) 261) for oral application for example is between 5 and 500 mg/kg.

The medicaments may be used in human medicine, in veterinary medicine and in agricultural medicine either on their own or in admixture with other pharmacologically active substances.

The invention is illustrated by the following Examples. (Examples 14 and 15 describe the preparation of intermediates.) EXAMPLE 1 Hellebrigenin -3ss-butvrate 2.08 g of hellebrigenin (0.005 mole) are dissolved in 20 ml of pyridine and 15 ml of n-butyric acid anhydride are added to the resulting solution. The mixture is left standing for 60 hours, after which 300 ml of diethyl ether are added. On standing overnight in a refrigerator, crystals are precipitated and are filtered off under suction, washed with ether and dried. The product obtained is chromatographed on silica gel and recrystallised from 50 % aqueous ethanol. 1.2 g of white needles are obtained. M.p.: 212"C.

EXAMPLE 2 Hellebrigenin-3ss-isobutvrate 2.08 g (0.005 mole) of hellebrigenin are dissolved in 20 ml of pyridine and 10 ml of isbutvric acid anhydride are added to the resulting solution. After 24 hours. 400 ml of dimethyl ether are added. after which the mixture is left standing overnight in a refrigerator to crvstallise out. The substance is purified by column chromatography on silica gel and is recrystallised from 50 % aqueous ethanol. Yield: 1.5 g. m.p.: 250"C.

EXAMPLE 3 3ss-lsovaleric acid ester of hellebrigenin*) 2.08 g (0.005 mole) of hellebrigenin and 10 ml of isovaleric acid anhydride are heated for 1 hour to boiling point in 20 ml of pyridine. After cooling, 400 ml of diethyl ether are added.

On standing in a refrigerator, a crude product crystallises out and is purified by column chromatography, followed by recrystallisation from 50 % aqueous methanol. Yield: 1.5g, m.p.: 196-199 C.

*) The symbol '30" before the name of the acid indicate that the hydroxy group in the 3ss-position of the hellebrigenin is attached to the acid radical. This also applies to all the following Examples.

EXAMPLE 4 3(j-(3,3-Dirnerhylncrylic acid ester) of hellebrigenin 20 g of hellebrigenin (0.048 mole) are suspended under nitrogen in 400 ml of dry dichloromethane. 20 ml = 20 g (0.148 mole) of freshly distilled dimethyl acrylic acid chloride are added, followed by heating under reflux for 1.5 hours in the absence of moisture. The hellebrigenin dissolves. After cooling, 20 ml of absolute methanol are added to destroy the excess of acid chloride. There is a vigorous evolution of hydrogen chloride, the mixture being boiled under reflux for another 30 minutes in order completely to destroy residues of acid chloride.

The cooled reaction mixture is shaken in a separation funnel first with 100 ml of water, then three times with 100 ml of a saturated NaHCO-solution and finally with another 100 ml of water. The dichloromethane solution is dried with anhydrous sodium sulphate and concentrated in vaciro. The yellow oil formed is taken up in 50 ml of dry chloroform and stirred into 1500 ml of petroleum (B.p. 50-70"C), the reaction product precipitating (24.8 g). Further purification is carried out by column chromatography over silica gel (Geduran S 100. the word "Geduran" being a Registered Trade Mark 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 poured into a 132 cm long column (internal diameter 6 cm). Elution is carried out with the same eluent mixture. A brown coloured cooling jacket provides for the substantial absence of light and the temperature is kept constant at 20"C. The throughflow rate amounts to 115 ml/minute. The individual components are separately collected. As soon as the required main product appears. the process can be shortened by an increase in polarity.

The main fraction is concentrated bi vacito until amost dry, after which it is taken up in 50 ml of CHIC1, and precipitated with 1.5 litres of petroleum (B.p. 50-70"C). filtered under suction and dried hi vaciro at 50"C. Yield: 15 g = 62.6 C/c, M.p. 194-196 C.

EXAMPLE 5 3ss-Crotonic acid ester of hellebrigenhi 6.8 g (0.0163 mole) of hellebrigenin are boiled under reflux for 1 hour in 210 ml of chloroform and 6 ml of crotonic acid chloride. The reaction mixture is worked up in the same way as in Example 4. The reaction product is recrystallised twice from methanol.

Yield: 0.8 g, m.p.: 202 - 2040C.

EXAMPLE 6 Hellebrigenin-3ss-(3,3-dimethyl-butyrate) 2.8 g (0.0067 mole) of hellebrigenin and 15 ml of 3.3-dimethvl butyric acid chloride are boiled under reflux for 2 hours in 60 ml of methylene chloride. The reaction solution is then washed three times with water and three times with saturated sodium bicarbonate solution, dried over magnesium sulphate and the solvent distilled off. Diethvl ether is added to the residue which is then left standing overnight. as a result of which the reaction product (crude product) crvstallises. It is recrystallised from 120 ml of methanol. Yield: 1.8 g, m.p.: 237"C.

EXAMPLE 7 3ss-Capr!lic acid ester of hellehrigeiihi 3.08 z (0.005 mole) of hellebrigenin are heated under reflux for 2 hours in 20 ml of pvridine and 1() ml of caprvlic acid anhydride. The crude product is precipitated with diethyl ether. chromatographed on a column of silica gel and recrvstallised from Sü Yc aqueous ethanol. Yield 1.1 g. m.p.: 189 - 191 C.

EXAMPLE 8 3p-Decanoic acid ester of hellebrigenin 2.08 g (0.005 mole) of hellebrigenin are boiled under reflux for 3 hours in 20 ml of pyridine and 10 ml of decanoic acid anhydride. After cooling. the crude product is precipitated by the addition of 500 ml of water, chromatographed on a column of silica gel and recrystallised from 66 % aqueous ethanol. Yield: 1.6 g, m.p.: 188 C.

EXAMPLE 9 Hellebrigetihi -3 t3-beiizoate 3 g (0.007 mole) of hellebrigenin are dissolved in 25 ml of pyridine, 2.8 g of benzoic acid anhydride are added and the mixture boiled under reflux for 5 hours. Following the addition of diethyl ether, a crude product is precipitated and is first chromatographed on a column of silica gel and then recrystallised from 50 % aqueous ethanol. Yield: 0.8 g, m.p.: 238 - 240 C.

EXAMPLE 10 Hellebrigenin-3ss-l?emiphthalate 2.08 g (0.005 mole) of hellebrigenin are esterified with 10 g of phthalic acid anhydride in 20 ml of pyridine in the same way as in Example 9. 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, m.p.: 163 - 165 C.

EXAMPLE 11 Hellebrigenin-3ss-(3,5-dinitrobenzoate) 2.08 g (0.005 mole) of hellebrigenin are boiled under reflux for 8 hours in 20 ml of pyridine and 5 g of 3,5-dinitrobenzoyl chloride. The reaction product is precipitated with water. chromatographed on silica gel, dissolved in chloroform and precipitated with petroleum ether. Yield: 0.5 g. m.p.: 172 C.

EXAMPLE 12 Hellebrigenin-3B-llonomerlgl sebacate 3 g (0.0072 mole) of hellebrigenin are boiled under reflux for 7 hours in 100 ml of methylene chloride. 3 ml of triethylamine and 3 ml of 9-chloroformyl nonanoic acid methyl ester. another 3 ml of triethvlamine and another 3 ml of 9-chloroformyl nonanoic acid methyl ester being added after 3 hours. After standing overnight. the reaction solution is filtered. washed three times with water. dried over magnesium sulphate and the solvent distilled off. The residue is stirred for 2 hours with ether. giving 3 g of reaction product which is successivelv recrystallised from 30 ml of isopropanol and 15 ml of methanol. Yield 1.8g. m.p.: 150 - 1520C.

EXAMPLE 13 Hellebrigenin-3ss-hemidiglycolate 2 g (0.005 mole) of hellebrigenin are dissolved in 10 ml of pvridine and a solution of 5 g of diglvcolic acid anhydride in 10 ml of pvridine is added to the resulting solution. The solution is left standing for 24 hours at room temperature. 2.6 g of title-substance crystallise out, being recrystallised from 230 ml of 8() % ethanol. Yield: 1.6 g. m.p.: 239 - 240"C.

EXAMPLE 14 Hellehrigenin-3P-chloloacetate (= 3ss-chloroacetyl hellebrigenin) 20 g (0.048 mole) of hellebrigenin are boiled under reflux for 2 hours in 300 ml of methylene chloride and 20 ml of chloroacetvl chloride. The reaction mixture is worked up in the same way as in Example 4. The reaction product obtained (22 g) is recrvstallised from 900 ml of methanol with addition of active carbon. Yield: 16 g. m.p.: 197 - 198 C.

EXAMPLE 15 Hellebrigenin-3ss-(3-chioropropioliate) 10 g (0.024 mole) of hellebrigenin are heated under reflux for 3 hours in 190 ml of methylene chloride and 10 ml of ss-chloropropionyl chloride. The reaction mixture is worked up in the same wav as in Example 4. The reaction product obtained (10 g) is recrvstallised from 20() ml of methanol with addition of active carbon. Yield: 8 g. m.p.: 168 169jC.

EXAMPLE 16 Hellebrigenin-3ss-diallylaminoacetate 2 g (0.004 mole) of 3-chloroacetyl hellebrigenin are heated under reflux for 2 hours in 20 ml of acetone and 20 ml of diallyl amine. After cooling, the diallyl amine hydrochloride is filtered off, the solvent is distilled off and the reaction product left behind is treated with 100 ml of water and recrystallised from isopropanol. Melting point of the base: 189 C.

Production of the hydrochloride: 2.4 g of base are neutralised with isopropanolic hydrochloric acid in 25 ml of ethanol, diethyl ether is added and the reaction mixture left standing overnight. 2.2 g of hydrochloride are precipitated and recrystallised from 80 ml of ethanol with addition of 50 ml of diethyl ether. Yield: 1.2 mg, m.p.: 230 - 231 C.

EXAMPLE 17 Hellebrigenin-3ss-[(N-methyl-2,2-ditnethoxyethylamino) -acetate] 4.5 g (0.009 mole) of 3-chloroacetyl hellebrigenin are boiled under reflux for 3 hours in 70 ml of acetone and 1.3 ml (0.01 mole) of methylaminoacetaldehyde dimethyl acetal. After standing overnight, the reaction mixture is filtered, the solvent is distilled off, the residue is treated with diethyl ether and finally stirred for 1 hour with 150 ml of water 2.5 g of title substance (base) are obtained, being crystallised with 1 mole of water and recrystallised twice from 40 ml of 50 % methanol with addition of active carbon. Yield: 1.2 g, m.p.: 174 176 C.

EXAMPLE 18 Hellebrigen hi -3 p- (2, (2, 6-dinielliyhnorpholltioacetate) 2.5 g (0.005 mole) of 3-chloroacetyl hellebrigenin are heated under reflux for 2 hours in 25 ml of acetone and 5 ml of 2.6-dimethyl morpholine. The solvent is distilled off and the residue is stirred for 1 hour with 200 ml of water. 2 g of title substance (base) are obtained, melting at 196 - 198 C after recrystallisation from isopropanol. Production of the hydrochloride: 2 g of base melting at 196 - 1980C are dissolved in 20 ml of acetone, neutralised with isopropanolic hydrochloric acid. the hydrochloride (2 g) is precipitated by the addition of 30 ml of diethyl ether and recrystallised from 30 ml of ethanol. Yield: 1 g. m.p.: of the hydrochloride: 178 - 1800C (hygroscopic).

EXAMPLE 19 Hellebrigenin-3ss-(4-hydroxypiperidinoacetate) 2.5 g (0.005 mole) of 3-chloroacetyl hellebrigenin are boiled under reflux for 1 hour in 40 ml of acetone and 2 g of 4-hydroxy piperidine. After cooling, the reaction mixture is filtered, the solvent is distilled off and the residue is stirred for 2 hours with 200 ml of water.

In order to obtain complete precipitation of the base, the aqueous suspension is saturated with sodium chloride. 1.8 g of title substance (base) are obtained, melting at 219 - 2200C after recrystallisation from isopropanol.

The hydrochloride is produced in the same way as in Example 16. 1.4 g of the hydrochloride are recrystallised from methanol-ethanol (2:1) with addition of 20 ml of diethyl ether. Yield: 1 g. m.p.: of the hydrochloride: 236 - 237 C.

EXAMPLE 20 Hellebrigeslin-3ss- (3-dieth vlaiiiiiioi)ropio'iate) 2 g (0.0039 mole) of 3-(3-chloropropionvl)-hellebrigenin are boiled under reflux for 2 hours in 20 ml of acetone and 2() ml of diethvlamine and worked up in the same way as in Example 16. The reaction product obtained (1.8 g) is recrystallised from ethanol. M.p. of the base: 192 C.

The hydrochloride is produced in the same way as in Example 16 and recrystallised from ethanol. Yield: 1.3 g from 1.8 g of base. M.p. of the hydrochloride: 206"C.

EXAMPLE 21 3ss-Cvclopropnsle carboxylic acid ester of hellebrigetihi 800 me of hellebrigenin are suspended in 50 ml of CH2Cl2 and 1 g of cyclopropane carboxylic acid chloride is added to the resulting suspension. followed by boiling under reflux for 4 hours. Working up and purification by column chromatography are carried out in the same way as in Example 4. Yield: 500 mg. M.p.: l4()"CP40C.

EXAMPLE 22 Hellebrige/1ol-3lS- ( 3 3-ditiieth5,Ibittvtyite) 2.83 g of hellebrigenin-3ss-(3,3-dimethyl butvrate) are dissolved in 90 ml of dioxane and 30 ml of water. 0.68 g of sodium borohydride dissolved in 45 ml of dioxin and 15 ml of water is then added with stirring over a period of 1 hour, followed by stirring for 3 hours and acidification with 2N H2SO4. Alter substantial concentration and extraction hy shaking with 3 x 200 ml of chloroform. the comllined chloroform phases are dried with sodium sulphate and concentrated.

The crude product thus obtained is dissolved in 500 ml of methanol and 5()() ml of 0. 1 N sulphuric acid and the resulting solution boiled under reflux for l hour with 10 g of D-mannitol. After concentration. extraction by shaking with chloroform and washing the chloroform phase with 2N soda solution and water and drying with sodium sulphate, 2.3 g of crude ester are obtained. Separation by column chromatography on silica gel with chloroform/ethanol (96:4) gives 764 g of pure hellebrigenol-3ss-(3,3-dimethyl butyrate).

Hellebrigenol-3P-isobutyrate is similarly obtained from hellebrigenin-3ss-isobutyrate.

WHAT WE CLAIM IS: 1. Compounds corresponding to the general formula

in which R represents a C2 - C6 alkenyl radical, a C3 - C18 - alkyl radical, a C3-C6-cycloalkyl radical, a C3 - Cl}-alkyl radical substituted by a C2 - C5 -carbalkoxy group or by a carboxy group, a C2 - C6-alkoxyalkyl radical substituted by a carboxy group, a phenyl radical, a phenyl radical substituted by one or more nitro groups, carboxy groups.C, - C6-alkoxy groups, C,-C6 alkyl groups or halogen atoms, or a C1-C6-alkyl group substituted by the group -NRlR2 where R1 and R2 are each C-C6-alkyl radicals, C2-C6-alkenyl radicals, C,-C"-alkyl or C-C6-alkenyl radicals substituted by one or more C1-C6-alkoxy groups or halogen atoms or one of R1 and R. may also represent a hydrogen atom: alternativelv the group -NRlR, forms a saturated heterocvclic 5- or 6-membered ring which may contain an oxygen atom or another nitrogen atom and which may be substituted once or twice bv C1-C6-alkyl groups, hydroxyethyl groups or hydroxy groups, and R3 represents -C HO.

-CH2OH or -CO2H; and their salts.

2. Compounds corresponding to the general formula

in which R represents a C.-C" alkenyl radical, a C-C,8-alkyl radical. a C3-C6-cycloalkyl radical, a C3-C10-alkyl radical substituted by a C,-Cs-carbalkoxy group or bv a carboxv group. a C2-C6-alkoxyalkyl radical substituted by a carboxy group. a phenyl radical. á phenyl radical substituted by one or more nitro groups. carboxy groups. C1-C6-alkoxv groups. C1-C6-alkyl groups or halogen atoms. or a C1-C6-alkyl group substituted bv the group -NR1R2. where R1 and R. are each Cl-C"-alkyl radicals, C.-C"-alkenyl radicals.

C1-C6-alkyl or C-C6-alkenyl radicals substituted by one or more C,-C6-alkoxy groups or halogen atoms or one of R, and R2 may also represent a hydrogen atom: alternativelv the group -NR,R. form a saturated heterocyclic 5- or 6-membered ring which may contain an oxygen atom or another nitrogen atom and which may be substituted once or twice by C1-C6-alkyl groups. hydroxyethyl groups or hydroxy groups; and their salts.

3. Compounds as claimed in claim 1 corresponding to the general formula

in which R represents a C2-C6-alkenyl radical. or a C-Cl.-alkyl radical. this alkyl radical optionally being substituted by a carboxy group. or a phenyl radical which may be substituted once or twice by nitro groups or halogen atoms or once bv a carboxy group. or a di-C1-C3-alkylamino-C1-C6-alkyl radical. or a di-C3-C6-alkenylamino-C1-C6-alkyl radical.

**WARNING** end of DESC field may overlap start of CLMS **.

Claims (22)

1. **WARNING** start of CLMS field may overlap end of DESC **.

   30 ml of water. 0.68 g of sodium borohydride dissolved in 45 ml of dioxin and 15 ml of water is then added with stirring over a period of 1 hour, followed by stirring for 3 hours and acidification with 2N H2SO4. Alter substantial concentration and extraction hy shaking with 3 x 200 ml of chloroform. the comllined chloroform phases are dried with sodium sulphate and concentrated.

   The crude product thus obtained is dissolved in 500 ml of methanol and 5()() ml of 0. 1 N sulphuric acid and the resulting solution boiled under reflux for l hour with 10 g of D-mannitol. After concentration. extraction by shaking with chloroform and washing the chloroform phase with 2N soda solution and water and drying with sodium sulphate, 2.3 g of crude ester are obtained. Separation by column chromatography on silica gel with chloroform/ethanol (96:4) gives 764 g of pure hellebrigenol-3ss-(3,3-dimethyl butyrate).

   Hellebrigenol-3P-isobutyrate is similarly obtained from hellebrigenin-3ss-isobutyrate.

   WHAT WE CLAIM IS: 1. Compounds corresponding to the general formula

   in which R represents a C2 - C6 alkenyl radical, a C3 - C18 - alkyl radical, a C3-C6-cycloalkyl radical, a C3 - Cl}-alkyl radical substituted by a C2 - C5 -carbalkoxy group or by a carboxy group, a C2 - C6-alkoxyalkyl radical substituted by a carboxy group, a phenyl radical, a phenyl radical substituted by one or more nitro groups, carboxy groups.C, - C6-alkoxy groups, C,-C6 alkyl groups or halogen atoms, or a C1-C6-alkyl group substituted by the group -NRlR2 where R1 and R2 are each C-C6-alkyl radicals, C2-C6-alkenyl radicals, C,-C"-alkyl or C-C6-alkenyl radicals substituted by one or more C1-C6-alkoxy groups or halogen atoms or one of R1 and R. may also represent a hydrogen atom: alternativelv the group -NRlR, forms a saturated heterocvclic 5- or 6-membered ring which may contain an oxygen atom or another nitrogen atom and which may be substituted once or twice bv C1-C6-alkyl groups, hydroxyethyl groups or hydroxy groups, and R3 represents -C HO.

   -CH2OH or -CO2H; and their salts.
2. 2. Compounds corresponding to the general formula

   in which R represents a C.-C" alkenyl radical, a C-C,8-alkyl radical. a C3-C6-cycloalkyl radical, a C3-C10-alkyl radical substituted by a C,-Cs-carbalkoxy group or bv a carboxv group. a C2-C6-alkoxyalkyl radical substituted by a carboxy group. a phenyl radical. á phenyl radical substituted by one or more nitro groups. carboxy groups. C1-C6-alkoxv groups. C1-C6-alkyl groups or halogen atoms. or a C1-C6-alkyl group substituted bv the group -NR1R2. where R1 and R. are each Cl-C"-alkyl radicals, C.-C"-alkenyl radicals.

   C1-C6-alkyl or C-C6-alkenyl radicals substituted by one or more C,-C6-alkoxy groups or halogen atoms or one of R, and R2 may also represent a hydrogen atom: alternativelv the group -NR,R. form a saturated heterocyclic 5- or 6-membered ring which may contain an oxygen atom or another nitrogen atom and which may be substituted once or twice by C1-C6-alkyl groups. hydroxyethyl groups or hydroxy groups; and their salts.
3. 3. Compounds as claimed in claim 1 corresponding to the general formula

   in which R represents a C2-C6-alkenyl radical. or a C-Cl.-alkyl radical. this alkyl radical optionally being substituted by a carboxy group. or a phenyl radical which may be substituted once or twice by nitro groups or halogen atoms or once bv a carboxy group. or a di-C1-C3-alkylamino-C1-C6-alkyl radical. or a di-C3-C6-alkenylamino-C1-C6-alkyl radical.

   or a C1-C6-alkyl radical substituted by a pyrrolidino group, a morpholino group, a

   piperidino group a hydroxypiperidino group or a dimethylmorpholino group, these basic radicals preferably being in the o-position of the alkyl radical, or a C2-C3-alkoxy-C1-C4- alkyl radical substituted by a carboxy group, and R3 is the group -CHO, -CH2OH or -COH.
4. 4. Compounds as claimed in claim 3, wherein R represents a Q-C5-alkenyl radical or a C4-C",-alkyl radical, this alkyl radical optionally being substituted by a carboxy group.
5. 5. Compounds as claimed in claim 3 wherein R represents a di-C1-C2-alkylamino-C1- C4-alkyl radical or a di-C-C4-alkenyl amino-C-C4-alkyl radical.
6. 6. Compounds as claimed in claim 3 wherein R represents a C2-C3-alkoxy-C1-C4-alkyl radical substituted in the es-position by a carboxy group.
7. 7. Compounds as claimed in claim 1 in which R is a branched alkyl radical with 3 or 5 carbon atoms, a branched alkenyl radical with 4 or 5 carbon atoms, an alkyl radical with 8, 9, 10, 11 or 12 carbon atoms, which may be substituted by a carbomethoxy or carboethoxy group, an ethoxymethyl or methoxymethyl radical which is substituted by a carboxy group in the methoxy or ethoxy group, a phenyl radical, a dinitrophenyl radical, a morpholinomethyl radical, a morpholinomethyl radical substituted by one or two methyl groups, a piperazinomethyl radical, a piperazinomethyl radical substituted by a hydroxyethyl group, a piperidinomethyl radical, a piperidinomethyl radical substituted by a hydroxy group or an aminomethyl radical which is substituted on the nitrogen by the two alkyl radicals each with 1 to 4 carbon atoms or by two alkenyl radicals each with 3 or 4 carbon atoms.
8. 8. Compounds as claimed in claim 2 in which R is a branched alkyl radical with 3 to 5 carbon atoms, a branched alkenyl radical with 4 or 5 carbon atoms, an alkyl radical with 8, 9, 10, 11 or 12 carbon atoms. which may be substituted by a carbomethoxy or carboethoxy group, an ethoxymethyl or methoxymethyl radical which is substituted by a carboxy group in the methoxy or ethoxy group, a phenyl radical, a dinitrophenyl radical, a morpholinomethyl radical, a morpholinomethyl radical substituted by one or two methyl groups, a piperazinomethyl radical, a piperazinomethyl radical substituted by a hydroxyethyl group, a piperidinomethyl radical. a piperidinomethyl radical substituted by a hydroxy group or an aminomethvl radical which is substituted on the nitrogen by two alkyl radicals each with 1 to 4 carbon atoms or by two alkenyl radicals each with 3 or 4 carbon atoms.
9. 9. The compounds claimed in claim 2 specifically hereinbefore described and exemplified in Example 1 - 3. 5 - 13, and 16 - 20.
10. 10. The compounds according to claim 1 specifically hereinbefore described and exemplified in Examples 4. 21 and 22.
11. 11. A process for the production of compounds as defined in claim 1, comprising a) reacting a hellebrigenin corresponding to the formula

    in which Z is a hydroxy group or a halogen atom with an acid corresponding to the formula R - COOH III in which R is as defined in claim 1 and of which the carboxyl group may be activated. and optionally introducing the radicals R, and R2 into the products of this reaction by alkylation or reacting compounds in which R is a C-C,-halozenoalkvl group or a C,-C,-alkenyl group, with a compound corresponding to the formula HNR1R,. where Rl and R2 are as defined in claim 1. or b) reacting a compound of formula I. in which R is a C1-C6-halogenoalkyl group or a C1-C,-alkenvl group. with a compound of the formula HNR,R2. where Rl and R2 have the meanings defined in claim l for R and R2 or may both represent hydrogen. and optionally introducing one or both radicals R1 and R2 into the compounds obtained by alkylation. and in the reaction products obtained by method a) or b) in which Rl is a formyl group, optionally reducing this formyl group into the -CH20H group or oxidising it into the -CO2H group.
12. 12. A process as claimed in claim 11 wherein the acid of general formula Ill with an activated carboxyl group is a compound corresponding to the general formula R - COX IV in which R is as defined in claim 1 and X represents a halogen atom, a group of the formula -OR', -SR' or a group of the formula -OSO3H, -O-PO(OH), -OP(OR')7, -O-As(OR')2 or -OCO R", and R' represents a C1-C6-alkyl radical, or in the case of -OR' or -SR', also a phenyl radical, a phenyl radical substituted by one or more nitro groups, C1-C6- alkoxy group, Cl-C6-alkyl groups or halogen atoms, a cyanomethyl radical or a carboxymethyl radical and R" represents a linear or branched Ct-C6-alkyl radical, a Cl-C6-alkoxy radical, a phenoxy radical or a carbobenzoxy radical or the radical R, or in which X represents an alkali metal or silver atom or -MgCl or -MgBr.
13. 13. A process as claimed in Claim 11 or 12, wherein, in cases where the radicals R1 or R2 are introduced by alkylation, the amino group contains a standard protective group which is eliminated during or after the reaction.
14. 14. Compounds of general formula (I) when produced by a process as claimed in any of Claims 11 to 13.
15. 15. A process for the production of compounds as defined in Claim 2, comprising a) reacting a hellebrigenin corresponding to the formula

    in which Z is a hydroxy group or a halogen atom with an acid corresponding to the formula R - COOH III in which R is as defined above and of which the carboxyl group may be activated, and optionally introducing the radicals R, and R into the products of this reaction by alkylation, or reacting compounds in which R is a C1-C6-halogenoalkyl group or a C2-C6-alkenyl group. with a compound corresponding to the formula HNR,R2, where R1 and R, are as defined in claim 1, or b) reacting a compound of formula I, in which R is a C,-C,-halogenoalkyl group or a C2-C6-alkenyl group. with a compound of the formula HNR1R2, where R, and R2 have the meanings defined above for R, and R2 or may both represent hydrogen, and optionally introducing one or both radicals R, and R2 into the compounds obtained by alkylation.
16. 16. A process as claimed in Claim 15, wherein the acid of general formula III with an activated carboxyl group is a compound corresponding to the general formula R - COX IV in which R is as defined in claim 1 and X represents a halogen atom. a group of the formula -OR', -SR' or a group of the formula -OSOSH. -O-PO(OH)2. -OP(OR'),. -O-As(OR'), or -OCO R". and R' represents a C,-C"-alkyl radical or, in the case of -OR' or -SR'. also a phenyl radical. a phenyl radical substituted by one or more nitro groups, C1-C6 alkoxy groups, C,-C6-alkyl groups or halogen atoms. a cyanomethyl radical or a carboxymethyl radical and R" represents a linear or branched lower alkyl radical, a C1-C6-alkoxy radica, a phenoxy radical or a carbobenzoxy radical or the radical R, and in which X represents an alkali metal or silver atom or -MgCl or -MgBr.
17. 17. A process as claimed in Claim 15 or 16. wherein. in cases where the radicals Rl and/or R2 are introduced by alkylation, the amino group contains a standard protective group which is eliminated during or after the reaction.
18. 18. Compounds of general formula ( lA) when produced by a process as claimed in any of Claims 15 to 17.
19. 19. A medicament containing as active principle at least one compound as claimed in one or more of Claims 1. 3 to 7 or 1() together with at least one conventional pharmaceutical excipient and/or diluent.
20. 20. A medicament containing as active principle at least one compound as claimed in one or more of Claims 2. 8 or 9 together with at least one conventional pharmaceutical excipient andlor diluent.
21. 21. A process for the production of a medicament. wherein at least one compound as claimed in one or more of Claims l. 3 to 7 or 10 is processed with at least one conventional pharmaceutical excipient or diluent to form a pharmaceutical preparation.
22. 22. A process for the production of a medicament. wherein at least one compound as claimed in one or more of Claims '. 8 or 9 is processed with at least one conventional pharmaceutical excipient or diluent to form a pharmaceutical preparation.