FI58135C - PROCEDURE FOR THE FRAMEWORK OF THERAPEUTIC MEASURES - Google Patents

Description

Piina- r] ΓΒΐ ANNOUNCEMENT C Ω * 1 7 C

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PfttMt · OCh nglltintynlnn Antdktn utlagd och utUkrlfUn publlotrsd 29 * 08.80 (32) (33) (31) Pyr «iyty atuolkaut-toglrt priority IT. 12. j6

Engianti-England (GB) 52T59 / T6 (Tl) Degussa Aktiengesellschaft, Weissfrauenstrasse 9, 6000 Frankfurt 1,

Federal Republic of Germany-Förbundsrepubliken Tyskland (DE) (T2) Otto Isaac, Hanau, Klaus Posselt, Wachtberg-Villiprott, Horst Uthemann, Frankfurt, Klaus Thiemer, Hanau, Federal Republic of Germany-Förbundsrepubliken Tyskland (DE) (5¾) Oy Kolster Ab Process for the preparation of therapeutically useful hellebrigenin acyl derivatives - For the preparation of therapeutically useful hellebrigenic acyl derivatives

Hellebrigenin monoacetate of the formula CH „λ ^ _f Vo o = ch \ y

ch3-co-o - 0H

OH

is known for. This compound has been shown to have a digitalis-like effect in studies in cats. (J. Pharmacol, exper. Therapy 99 (1950) pages 395-toO).

2 58135

The invention relates to a process for the preparation of therapeutically useful helle-brigeninyl acyl derivatives of formula (I)

R-CO-O —L J

wherein R represents a C 1 -C 6 alkenyl group, a C 1 -C 6 alkyl group, a C 1 -C 6 cycloalkyl group, a carboxymethoxymethyl group, a phenyl group, a nitro-substituted phenyl group or a C 1 -C 6 alkyl group containing a group -NR 1 -C 4 alkyl group. , wherein R 1 and R 2 represent a C 1 -C 6 alkenyl group or a group -NR 2 R 4 unsubstituted or monohydroxy-substituted piperidino group or an unsubstituted or mono- or biomethyl-substituted morpholino group, and R 1 is a group -CHO or -CH 2 OH, and to prepare their salts.

Alkyl and substituted alkyl radicals, alkenyl and substituted alkenyl radicals, may be straight-chain or branched. Especially when R is a C 1 -C 4 alkenyl residue or a C 1 -C 4 alkyl residue, this may be branched.

If R is a straight alkyl radical, then this comprises, for example, 5 to 12, in particular 7 to 12, carbon atoms. Alkyl and substituted alkyl radicals each having 1 to 6 carbon atoms contain in particular 1 to U carbon atoms, preferably 1, 2 or 3 carbon atoms. Alkenyl and substituted alkenyl radicals, in particular contain 2, 3 or 1+ C atoms, preferably 3 or 1 * C atoms. If R is a branched C 1 -C 4 alkyl residue, it is in particular an alkyl residue having 3 to 3 C 1-4 atoms. If R is a straight alkyl radical, this is, for example, an alkyl radical having 8 to 12 atoms, preferably 9 to 10 carbon atoms, or also a propyl radical.

If R is a substituted phenyl residue, this may be mono-, di- or trisubstituted by nitro groups. If R is an alkyl group containing the group -NR ^ R ^, then it is preferably a group -CH ^ -NR ^ ^.

3,581 35

If R is a disubstituted phenyl residue as defined above, both substituents are preferably in the 3,5-position.

The compounds according to the invention are characterized by a good cardiac action. In contrast to the known hellebrigenin monoacetate described above, which is not absorbed after oral administration, the compounds of the invention are absorbed in a large amount in the gastrointestinal tract after oral administration and have a resorption rate of 30-90%, for example when administered intravenously. Instead, the entero-resorption ratio of the known compound is 0. Therefore, the known compound cannot be administered orally.

The compounds of the invention are directly suitable for oral administration and are thus suitable for long-term treatment. In particular, the compounds according to the invention have a positive inotropic effect (an effect of improving the contractile force of the heart) which can be demonstrated, for example, in an isolated organ (Langendorff's heart, cardiac) or in the whole experimental animal (dog). Hatcher doses are, for example, in a very preferred range of 0.09 to 1 mg / kg, preferably 0.1 to 0.5 mg / kg. The Hatcher dose is the lowest dose that, when administered intravenously in 60 to 90 minutes, results in death in a cat and is a common measure for evaluating the efficacy of compounds that have a strong effect on the heart.

In addition, the compounds according to the invention have a strong bradycardic effect, manifested by a reduction in the heart rate to 30% (in the therapeutic range) and leading to a normalization of the increased heart rate of the heart failure.

In addition, the training ratios of the compounds of the invention in cats are in a therapeutically advantageous range, e.g. 20-26% in cats. Namely, a training ratio of this magnitude prevents excessive accumulation of the active ingredient and toxic effects due to repeated dosing, which is of particular importance for compounds which affect the heart. In addition, the compounds according to the invention are characterized by a lack of side effects: thus, for example, no vomiting irritation was observed when the cat was injected. Similarly, they are well tolerated by the stomach ^ (for example, no gastric ulcer-causing effect was observed in rats).

Therapeutic blood tests The cardiac effect was determined taking into account enteroresorption by the method described in Greef, Schwarzmann et Waschulzik, Arzneimittelforschung, Bd. 15 (1965), 483- ^ 86.

** 58135

methodology

All doses are expressed in mg of active ingredient per kg of body weight of the test animal.

Cats under urethane-chloralose anesthesia were laparotomized and given a duodenal injection of a sacral dose of test glycoside. This saclet dose is usually selected to correspond to about half the dose of Hatcher, which is a dose in mg / kg body weight of the test animal which, when administered intravenously, causes cardiac arrest, i.e. death. Glykosidimäärän on the back flow of blocked so that the Poh-duodenum were tied directly below the injection site of administration, and on the other side the height of the pylorus. After a resorption time of two hours - the amount of glycoside required for cardiac arrest was added intravenously.

The results are shown in Table I.

Table I

The absorption fraction (i.e., the effect fraction) is calculated according to the following formula • 3C) · · * * X) lethal dose i.v. - added dose l.v.

R (%) = (Hatcher) __ x 100 intraduodenal pre-dose

Compound Absorption rate Hatcher dose

Example No.% mg / kg i.v.

1 38% 0.108 2 89% 0.169 3 50% 0.181 k 90% 0.191 8 85% 0.17 ^ 9 33% 0.801 10 85% 0.769 11 61% 0.187 12 k2% 0.288 13 89% 0.295 1k 57% 0.122 15 96% 0.196 16 91% 0.191 17 91% 0.259 18 100% 0, k6k

Hellebrigenin about 6% 0.186

Hellebrigenin monoacetate 0% 0.05 * ^ = intravenous 5,581 35

The invention is characterized in that a) hellebrigenin of formula

vCbO

(Ii)

OH

wherein R 1 is as defined above is reacted with an acid of formula R-COX (III) wherein R is as defined above and X is a chlorine, bromine or iodine atom or when R is C 1 -C 4 alkyl- or a phenyl group, X may further be an OCOR group, or when R is a carboxymethoxymethyl radical, X may further form together with the hydroxy group of this radical a single bond to a hydroxy oxygen atom, and R 1 and R 8 are optionally attached to the resulting compound by alkylation, or b) a compound of formula I wherein R 1 is a C 1 -C 4 haloalkyl or C 1 -C 4 alkenyl group, is reacted with a compound of the formula 2 ° NHR 1 R 2, wherein R 1 and R 2 are as defined above or both may represent a hydrogen atom, and the resulting if desired, one or both of the substituents R 1 and R 2 are attached to the compound by alkylation, and in the compound obtained according to embodiment a) or b), wherein R 1 is a formyl group, this is reduced to the group -CH 2 OH, and that the obtained compound is optionally m extracted into saline.

The reaction with a compound of formula III is carried out, for example, in a common solvent or suspending agent such as water, optionally with the addition of a solubilizing agent (e.g. lower aliphatic alcohols, lower aliphatic ketones, dimethylformamide), or in ineffective agents. Suitable solvents or suspending agents are, for example: small-molecule aliphatic ethers (e.g. U-10 C atoms); small molecule aliphatic ketones (e.g. 3-6 C atoms); saturated cyclic ethers such as tetrahydrofuran, dioxane; small saturated hydrogen or fluorocarbons having 1 to 5 carbon atoms, the individual C atoms being singly or multiply) substituted by chlorine and / or fluorine, such as chloroform, 6 58135 methylene chloride, optionally substituted aromatic hydrocarbons by chlorine or bromine, such as benzene, toluene, xylene, chlorobenzene, dimethylformamide, dimethylsulfoxide, tetramethylurea, pyridine, N-methylpyrrolidone. Of course, mixtures of these solvents can also be used.

The process is carried out at temperatures between 0 and 200 ° C, preferably between 15 and 150 ° C.

An additional presence of an acid scavenger such as alkali metal hydroxides, alkali metal carbonates, alkali metal bicarbonates, alkali metal acetates, alkaline earth metal carbonates, trialkylamines, dialkylamines, pyridines and the like or also compound II is suitable. In this case, the acid-binding agent can also be used simultaneously alone or in admixture with other customary substances as a solvent (e.g. pyridine). Care must be taken to carefully neutralize and remove the unreacted starting material (III, especially in the case of acid chloride). Chromatographic purification of the reaction product on silica gel is often recommended, eluting with a chloroform / ethanol mixture (e.g. ethanol content 1-5%).

As the reaction component of formula III, a compound in which one of the radicals R 1 or R 2 is a protecting group customary for amino groups can also be used. Examples of suitable protecting groups and peptide cleavage methods in peptide synthesis are possible. This is referred to e.g. In "Chemistry of Amino Acids" by Jesse P. Greenstein and Milton Winitz, N.Y. 1961, John Wiley & Sons, Inc. Volume 2, e.g., pp. 883-. From the final products, such protecting groups can be cleaved with mineral acids such as hydrochloric acid or sulfuric acid in an alcoholic or aqueous-alcoholic solution or with bases such as an alcoholic alkaline liquor (e.g. methanolic KOH) at temperatures between 20-100 ° C. By reduction, the cleavable residues can be hydrogenated off with hydrogen in the presence of a hydrogenation catalyst, (e.g. palladium, palladium / carbon), for example ethanol, preferably under normal conditions.

The residues R1 and R2 can then be attached to the amino group by alkylation. This also includes a similar attachment of an alkenyl group. Suitable alkylating or alkenylating agents are, for example: esters of the formulas R 1 Hal, ArSO 2 R 2 and SC 2 (OR 2) 2, in which Hal is a halogen atom (in particular chlorine, bromine or iodine), and Ar is an aromatic residue, such as, for example, optionally a phenyl or naphthyl residue substituted by one or more lower alkyl radicals, and R | is a C 1 -C 6 alkyl residue, a C 2 -C 6 alkenyl residue or a C 1 -C 6 alkyl or C 1 -C 6 alkylenyl residue substituted by C 1 -C 6 alkoxy groups or halogen atoms. Examples 58135 are p-toluenesulfonic acid alkyl esters, lower dialkyl sulfates, alkyl halides, alkenyl halides, etc. The alkylation or alkenylation reaction is carried out, optionally with the addition of customary acid scavengers such as alkali carbonates, pyridines or other C in inert solvents such as alcohols, dioxane, dimethylformamide, dimethyl sulfoxide, aromatic hydrocarbons such as benzene, toluene or acetone, and mixtures of such solvents. Alkylation with alkyl halides (e.g. iodides) in the presence of NaH can take place e.g. in a mixture of toluene and a little dimethylformamide (0.1-5%, e.g. 0.5%). Instead of the above-mentioned reactants - other chemically customary chemically equivalent substances (see also, e.g., LF and Mary Fieser, "Reagents for Organic Synthesis," John Wiley & Sons, Inc., New York, 1967 »Vol. 1, pp. 1303-1301 + and Vol. 2, p. 1 + 71) · _ If only one of the radicals R 1 or R 2 has to be attached, it is expedient to carry out the alkylation or alkenylation in the presence of a protecting group present in the starting product and then only to cleave the protecting group.

The alkylation or alkenylation can also be carried out by, after cleavage of the protecting group, reacting with the corresponding oxo compound simultaneously or subsequently by reduction under normal or elevated pressure at temperatures between 0 and 100 ° C in a common solvent or suspending agent. Examples of reducing agents are hydrogen formed in a neutral or basic medium, electrolytic reduction, sodium alcohol, sodium or aluminum amalgam, hydrogen in the presence of customary hydrogenation catalysts (e.g. Raney nickel, platinum, palladium) or complex hydrides such as e.g. lithium aluminum. If benzyl groups were to be removed at the same time as the hydrogenation condensation, palladium catalysts are preferably useful, in which case an immediate condensation product is first prepared and then reduced only after any previous isolation and purification.

Process products in which the residue R is a C 1 -C 6 haloalkyl residue can be converted into compounds in which R represents a C 1 -C 6 alkyl group by reacting with the amines of the formula HNR 1 R 4 in which R 1 and R 2 have the same meaning as above. substituted with -NR 2 R 2. This reaction is carried out either 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. Usually working at temperatures between 50-200 ° C. It may be advisable to work in the presence of an acid acceptor, for example potash, soda, etc., An excess of amine can also act as an acid acceptor.

8 58135

Similarly, process products of formula I wherein R is a C 1 -C 6 alkyl group substituted with a residue -NR 1 -C 6 alkyl may be obtained from compounds of formula I wherein R is a C 1 -C 6 alkenyl residue by reacting such compounds with the corresponding amine. of the formula NHR ^ Rg. This reaction can be carried out, for example, in a solvent or suspending agent such as anhydrous lower alcohols, dioxane, organic acid amides, acetic acid, etc. at 20 to 150 ° C (the reaction time is from several hours to a few days).

If the substituent R contains an asymmetric carbon atom (such as when R is a branched alkyl group) and the corresponding racemate is used as starting material, the final product is obtained as a racemate which can be decomposed into 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 correspondingly optically active form is obtained as the final product.

Example 1

Hellebrigenin 3-t-butyrate 2.08 g of hellebrigenin (0.005 mol) are dissolved in 20 ml of pyridine and then 15 ml of n-butyric anhydride are added. The mixture is allowed to stand for 60 hours. Add 300 ml of diethyl ether. On standing in the refrigerator overnight, crystals separate which are filtered off with suction, 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. Melting point 212 ° C.

Example 2

Hellebrigenin-3β-isobutyrate 2.08 g (0.005 mol) of hellebrigenin are dissolved in 20 ml of pyridine and 10 ml of iso-butyric anhydride are added. After 2U, add 100 ml of diethyl ether and allow to crystallize by standing overnight in the refrigerator. The material is purified by column chromatography on silica gel and recrystallized from 50% aqueous ethanol. Melting point 250 ° C; yield: 1.5 g.

Example 3 ... x)

Hellebrigennin-N-isovaleric acid ester 2.88 g (0.005 moles) of hellebrigenin in 20 ml of pyridine are boiled with 10 ml of isovaleric anhydride for 1 hour.

k)

The notation η3β> "before the name of the acid indicates that the hydroxy group of the helle-brigenin at the 3 ^ position is attached to the acid residue. This also applies to all the following examples.

9,581 35 After cooling, 100 ml of diethyl ether are added. While standing in the refrigerator, the crude product crystallizes, which is purified by column chromatography and recrystallized from 50% aqueous ethanol. Melting point 196-199 ° C. Yield: 1.5 g.

Example ^

HeHebrigeniini-3 / * - (3,3-dimethyl-acrylic acid ester)

Suspend 20 g of hellebrigenin (0.0U8 moles) in 100 ml of dry dichloromethane in a stream of nitrogen. Add 20 ml = 20 g (0.18 moles) of freshly distilled dimethylacrylic acid chloride and heat with stirring for 1.5 hours under reflux, taking care to exclude moisture.

Hellebrigenin is soluble. Allow to cool and add 20 ml of absolute methanol to decompose the excess acid chloride. Strong evolution of hydrochloric acid occurs, the mixture is further refluxed for 30 minutes to completely decompose the acid chloride residues.

The cooled reaction mixture is shaken in a separatory funnel with 100 ml of water, then three times with 100 ml of saturated NaHCO3 solution each time and once more with 100 ml of water; the dichloromethane solution is dried over anhydrous sodium sulfate and evaporated in vacuo. The resulting yellow oil is taken up in 50 ml of dry chloroform and mixed with 1500 ml of petroleum gasoline (b.p. 50-70 °), whereupon the reaction product precipitates (2U, 8 g). Further purification is performed using column chromatography on silica gel (Geduran S 100, sieve number 0.063-0.200) at 20 ° C.

The crude product is dissolved in 50 ml of chloroform / ethanol (98% chloroform, 2% ethanol) and poured onto a 132 cm column (inner diameter 6 cm). Elution is performed with the same eluent. The brown-colored cooling jacket provides effective protection from light and keeps the temperature constant at 20 ° C. The flow rate is 115 ml / min. The individual components are recovered separately. As soon as the desired main product arrives, the method can be shortened by increasing the polarity.

The main fraction is evaporated to near dryness in vacuo, then collected in 50 ml of CHCl 3 and precipitated with 1.5 l of petrol (b.p. 50-70 °), filtered off with suction and dried at 50 ° C in vacuo. Yield: 15 g = 62.6%. Melting point 19 * + - 196 ° C.

Example 5

Hellebrigenin-3H-crotonic acid ester 6.8 g (0.0163 mol) of hellebrigenin are boiled in 210 ml of chloroform and 6 ml of crotonic acid chloride under reflux for 1 hour. The work-up 10 581 35 takes place as in Example k. The reaction product is recrystallized twice from methanol. Yield: 0.8 μl Melting point 202-20U ° C.

Example 6

Hellebrigenin-3- (3,3-dimethylbutyrate) 2.8 g (0.0067 mol) of hellebrigenin are refluxed in 60 ml of methylene chloride with 15 ml of 3,3-dimethylbutyric acid chloride for 2 hours. The reaction solution is then washed twice with water and three times with saturated sodium bicarbonate solution, dried over magnesium sulfate and distilled off. The residue is mixed with diethyl ether and allowed to stand overnight, whereupon the reaction product (crude product) crystallizes. Recrystallize from 120 ml of methanol. Yield: 1.8 gj Melting point 237 ° C.

Example 7

Hellebrigenin-3β-caprylic acid ester 2.08 g (0.005 moles) of hellebrigenin are heated under reflux in 20 ml of pyridine and 10 ml of capillic anhydride for 2 hours. The crude product is precipitated with diethyl ether, chromatographed on a silica gel column and recrystallized from 50/2 aqueous ethanol. Yield: 1.1 g; Melting point 189-191 ° C.

Example 8

Hellebrigenin-S-decanoic acid ester 2.08 g (0.005 mol) of hellebrigenin are refluxed in 20 ml of pyridine with 10 ml of 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: 1.6 g Pour point 188 ° C.

Example 9

Hellebrigenin-3A * 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 refluxed for 5 hours. After addition of diethyl ether, the crude product separates, which is first chromatographed on a silica gel column and then recrystallized from 50% aqueous ethanol. Yield: 0.8 g; Melting point 238-2l + 0 ° C. Example 10

Hellebrigenin-3 / 3- (3,5-d.initrobenzoate) 2.08 g (0.005 mol) of hellebrigenin are refluxed 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 stirred with petroleum ether. Yield: 0.5 g; Melting point 1T2 ° C.

Example 11

2 g (0.005 mol) of hellebrigenin are dissolved in 10 ml of pyridine and a solution of 5 g of diglycolic anhydride in 10 ml of pyridine is added. The solution is allowed to stand for 2k hours at room temperature. 2.6 g of the title compound precipitate, which is recrystallized from 230 ml of 80-8% ethanol.

Yield: 1.6 g; Melting point 239 "2 ^ 0 ° 0.

^ Example 12

2 g (0.00U moles) of 3-chloroacetylhebrigenin 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 residual reaction product is treated with 100 ml of water and recrystallized from isopropanol.

Base melting point: 189 ° C.

Preparation of the hydrochloride: 2 g of base are neutralized in 25 ml of ethanol with isopropanol-containing hydrochloric acid, mixed with diethyl ester and allowed to stand overnight. 2.2 g of hydrochloride precipitate, which is recrystallized from 80 ml of ethanol and 50 ml of diethyl ether are added. Yield: 1.2 g; Melting point 230-231 ° C.

Preparation of starting material

Hellebrigenin-3 '"chloroacetate (= 3 / ®" chloroacetyl hellebrigenin) 20 g (0.0i * 8 moles) of hellebrigenin are refluxed in 300 ml of methylene chloride and 20 ml of chloroacetyl chloride for 2 hours.

The work-up is carried out as in Example k. The reaction product obtained (22 g) is recrystallized from 900 ml of methanol, with the addition of activated carbon. Yield: 16 μl _ Freezing point 197 ~ 198 ° C.

Example 13

Hellebrin genin-3β- (2,6-dimethylmorpholine acetate) 2.5 g (0.005 moles) of 3-chloroacetylhellebrigenin are heated under reflux 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. 2 g of the title compound (base) are obtained, which, after recrystallization from isopropanol, melts at 196-198 ° C.

58135

Preparation of hydrochloride: 2 g of a base having a pour point of 196-198 ° C are dissolved in 20 ml of acetone, neutralized with isopropanol-containing hydrochloric acid, precipitated with hydrochloride (2 g) by adding 30 ml of diethyl ether and recrystallized from 30 ml of ethanol. Yield: 1 g, melting point of the hydrochloride 1T8-180 ° C (hygroscopic).

Example 1U

Hellebrigenin-3A- (U-hydroxy-piperidine acetate) 2.5 g (0.005 mol) of 3-chloroacetyl-hellebrigenin are refluxed in 1 * 0 ml of acetone with 2 g of U-hydroxypiperidine for 1 hour. After cooling, filter, distill off the solvent and stir the residue 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 the title compound (base) are obtained, which, after recrystallization from isopropanol, melts at 219-220 ° C.

The hydrochloride is prepared according to Example 12. 1.1 * g of this is recrystallized from methanol / ethanol (2: 1) by adding 20 ml of diethyl ether. Yield: 1 g;

Hydrochloride pour point 236-237 ° C.

Example 15

Hellebrigenin-3β-cyclopropanecarboxylic acid ester 800 mg of hellebrigenin are suspended in 50 ml of CH2Cl2, 1 g of cyclopropanecarboxylic acid chloride are added and the mixture is refluxed for 1 hour. The work-up and column chromatographic purification are carried out as described in Example k.

Yield: 500 mg; Freezing point 1U0 / 2U0.

Example 16

Hellebrigenol-3A-isobutyrate 1.5 g (0.0031 mol) of hellebrigenin-3A-isobutyrate are dissolved in 60 ml of anhydrous tetrahydrofuran and 60 ml of freshly prepared lithium tri-tert-butoxyaluminum hydride reaction component (obtained in 1.5 g) are added at room temperature. (LiiAlH 2) and 6 g of tert-butanol) dissolved in tetrahydrofuran. The reaction mixture is stirred at room temperature for 2 days, and 5% acetic acid is added to the reaction mixture, and the reaction mixture is then shaken with chloroform. The resulting solution is concentrated, the reaction product is precipitated by adding petroleum ether and purified by column chromatography on silica gel (eluent 95 v / v chloroform / 5 v / v ethanol).

Yield: 30%. Melting point 195 ° C.

s 13,581 35

Example 17

Hellebrigenol-3 / M 3,3-dimethylacrylate) 1 g (0.002 mol) of helle'brigenin-3 / α- (3,3-dimethylacrylate) is dissolved in 60 ml of anhydrous tetrahydrofuran and 60 ml of freshly prepared lithium chloride are added at room temperature. the tri-tert-butoxyaluminum hydride reaction component dissolved in tetrahydrofuran. After a reaction time of 1 hour, 5% acetic acid is added to the reaction mixture, and the reaction mixture is extracted several times with chloroform. The solution is concentrated and the reaction product is precipitated by adding petroleum ether. Yield U9.8%. Freezing point lU0-li * 2 ° C.

Example 18

Hellebrigenin-SA-cyclohexanecarboxylic acid ester 2 g of hellebrigenin are suspended in 100 ml of CH2Cl2, U ml of cyclohexanecarboxylic acid chloride are added and the mixture is refluxed for 4 hours.

The reaction mixture is allowed to cool and then about U ml of anhydrous methanol are added to decompose the excess acid chloride and refluxed for a further 30 minutes. The reaction mixture is sprayed to cool and then shaken in a separatory funnel with 10 ml of water, then 3 times with 10 ml of saturated bicarbonate solution each time and then with a further 10 ml of water. The dichloromethane solution is dried over anhydrous sodium sulfate and evaporated to dryness in vacuo. The residue is taken up in a small amount of anhydrous chloroform and triturated with petroleum gas (b.p. 50-70 ° C), whereupon the reaction product precipitates. Yield: 90%. Melting point 211-211 ° C (decomposes).

Example 19

Hellebrigenol-3- (3,3-dimethylacrylate) 3 g (0.0072 moles) of hellebrigenol and 3.2 g (0.0271 moles) of dimethylacrylic acid chloride are reacted and purified as in Example b (eluent CHCl 3). Η, -ΟΗ = 95: 5). Yield 0.5 g = 13.9% · Melting point 1 DEG-1 DEG C., "Example 20

Hellebrigenol ~ 3β ~ obsobutyrate

The title compound is obtained as in Example 3 from 3 g (0.0072 mol) of hellebrigenol and 2.9 g (0.027 mol) of isobutyric acid chloride. Yield 0.63 g = 18%. Melting point 195 ° C.

Claims (1)

A process for the preparation of therapeutically useful hellebrigenin acyl derivatives of the formula .C & O'H OH (I) H-CO-O OH wherein R represents a C 1 -C 6 alkenyl group, a C 1 -C 6 alkyl group, a C 1 -C 6 alkyl group, a C 1 -C 6 alkyl group; a cycloalkyl group, a carboxymethoxymethyl group, a phenyl group, a nitro-substituted phenyl group or a C 1 -C 6 alkyl group containing a group -NR 1 R 8, wherein R 1 and a C 1 -C 6 alkenyl group or a group -NR 1 R 4 form a substituted or for the preparation of a hydroxy-substituted piperidino group or an unsubstituted or mono- or two-methyl-substituted morpholino group and R 1 is a group -CHO or -CH 9 OH, and salts thereof, characterized in that a) hellebrigenin of the formula Γ 1 OH (II) OH OH wherein R 1 is as defined above is reacted with an acid of formula R-COX (III) wherein R is as defined above and X is a chlorine, bromine or iodine atom or when R is C 1 -C 4 alkyl or f an enyl group, X may further be an OCOR group, or when R is a carboxymethoxymethyl radical, X may further form together with the hydroxy group of this radical a simple bond to a hydroxy oxygen atom, and R 581 is optionally attached to the resulting compound by alkylation, or h) a compound of formula I, wherein R is a C 1 -C 6 haloalkyl group, is reacted with a compound of the formula NHR 1 R 8 wherein R 1 and R 2 are as defined above or both may represent a hydrogen atom, and one or both of the substituents R are optionally added to the resulting compound. by alkylation of R 1 and R 2, and in the compound obtained according to embodiment a) or h), wherein R 1 is a fornyl group, this is reduced to -CH 2 OH, and that the compound obtained is, if desired, converted into a salt. 16 581 35 For the preparation of therapeutically active halogenated bromine acyl derivatives with the formula ^ \ H3 / r ~ ° \ I 0H (I) r-co-o — L ^^^ OH color R betecnar en C ^ -Cg-alkenylgrupp, en C 1-4 alkyl-C 1-4 cycloalkyl, carboxymethoxymethyl, phenyl, nitro-substituted phenyl or C 1-6 alkyl, preferably R-alkyl R 2 is an alkyl group having a C 1 -C 4 alkenyl group or a group -NR 4 Rg is a substituent or a hydroxy group substituted with a piperidino group or an substituent or a methyl group substituted with a morpholino group, and the group R CHO or -CH 2 OH, and a derivative of the parent compound having the characteristic R-COX (III) color of the R-COX (III) color of the R-COX (III) color is an alkyl group and X is chloro, bromo or iodo, or R is C 1-4 alkyl or phenyl, X is an alkyl group or an OCOR group, or the R is en carboxymethoxymethyl radical, X is the same as that of the hydroxyl group and the radical group, and