JPS591279B2 - A novel hellebrigenin acyl derivative, its production method, and a positive cardiotactic action drug containing the derivative - Google Patents

Description

[Detailed description of the invention] The present invention relates to novel hellebrigenin acyl derivatives.

A helebrigenin monoacetate corresponding to the formula: is known.

This compound exhibits digitalis-like effects when tested in cats [Journal of Pharmacology End.
Experimental Theracopy'' (J.Phar
mcol. expert. Therapy), 99
, pp. 395-400 (1950)]. The present invention is based on the general formula: [wherein R is a C3-C6-alkenyl group, C3-Cl2
-alkyl group, C3-C6-cycloalkyl group, C3-C6-alkoxyalkyl group substituted by carboxy group, phenyl group, phenyl group or group substituted by nitro group -NR1R2 (R1 and R2
is a C3-C6-alkenyl group or the group -NR1R2 may further contain one oxygen atom and is a heterozygous group which may be substituted by Cl-C6-alkyl or one or two hydroxy groups C1-C6-alkyl group containing a cyclic saturated 5- or 6-membered ring), R3 is a -CHO group or a -CH2OH group].

Alkyl groups and substituted alkyl groups, alkenyl groups and substituted alkenyl groups, and alkoxy groups may be linear or branched. In particular, R is a C3-C6-alkenyl group or C
In the case of a 3 -C6 -alkyl radical, this radical may be branched. When R is a straight-chain alkyl group, it consists of 3 to 12 carbon atoms. Alkyl groups containing 1 to 6 carbon atoms and substituted alkyl groups preferably consist of 1 to 4 carbon atoms, in particular 1, 2 or 3 carbon atoms. Alkenyl or substituted alkenyl groups in particular consist of 3 or 4 carbon atoms. When R is a C2-C6-alkoxyalkyl group substituted by a carboxy group,
The number of carbon atoms listed is the number of carbon atoms in the entire alkoxyalkyl group, ie the sum of the number of carbon atoms in the alkyl group and the number of carbon atoms in the alkoxy group. Particularly relevant radicals are alkoxy having 1 or 2 carbon atoms and alkyl having 1 or 2 carbon atoms, such as methoxymethyl, ethoxyethyl, methoxyethyl, ethoxymethyl. In particular, the carboxy group is located on the alkoxy component. If R is a branched C3-C6-alkyl group, the alkyl group in question contains from 3 to
It is an alkyl group having 4 alkyl groups. When R is a linear alkyl group, the corresponding alkyl group has, for example, 8 to 8 carbon atoms.
It is an alkyl group or propyl group having 12 atoms, especially 9 to 10 atoms. When R is a substituted phenyl group, in particular
This phenyl group is substituted with a nitro group. base
When NR, R2 form a heterocyclic 5- or 6-membered ring, the corresponding ring is advantageously a 6-membered ring such as a morpholine ring or a piperidine ring. If this ring is substituted, preferred substituents are C1-C3-alkyl groups, especially methyl, ethyl and/or hydroxy groups. In this case, the corresponding ring is, for example, a morpholine ring substituted with two methyl groups, a piperidine ring substituted with a hydroxy group or a methyl group, and an alkylene ring between the -NRlR2 group and the -CO-0 group. The bridge is advantageously a methylene group. If R is an alkyl group containing -NRlR2, the group in question is advantageously a group -CH2-NRl
It is R2. If R is a phenyl group substituted in two positions as described above, these two substituents are in particular in the 3,5-1 position. The compounds according to the invention are distinguished by advantageous cardiac effects.

In contrast to known compounds which are not absorbed after oral ingestion, the compounds according to the invention are significantly absorbed in the gastrointestinal system after oral ingestion and have, for example, an intestinal absorption rate of 30-90%. In contrast, the intestinal absorption rate of known compounds is O. Therefore, known compounds cannot be administered orally. In contrast, the compounds according to the invention are suitable for oral administration and therefore for long-term therapy.

In particular, the compounds according to the invention can be used, for example, in isolated organs (Langendorff's Heart).
rt), the atria of the heart) or have a positive myocardial effect (improvement of the contractile force of the heart) as observed in whole animals (dogs). For example, one dose of Hatche
rdOse) is in an extremely preferable range of 0.99 to 1 K/K.
', a particularly advantageous range of 0.1 to 0.5 mv/Kf.
A single dose of Hatschia is the lowest dose that causes death in cats 60-90 minutes after intravenous infusion and is the standard measure for evaluating the effects of potent cardioactive compounds. Furthermore, the compounds according to the invention have a pronounced bradycardic effect, which is manifested in a reduction in heart rate by up to 30% (in the therapeutic range), thus leading to normalization of the increased heart rate of the damaged heart.

Furthermore, reduced levels of the compounds according to the invention in cats (Ab
atement level) is in a therapeutically advantageous range, for example 20-26% in cats.

This level of attenuation prevents significant accumulation of the active ingredient and therefore avoids the occurrence of toxic phenomena after repeated administration. This is particularly important in the case of cardioactive compounds. Furthermore, the compounds according to the invention have only negligible side effects. For example, no nausea was recorded during infusion in cats. They also exhibit high gastric tolerability (eg no ulcerative effects were observed in rats). The compounds according to the invention are, for example, compounds corresponding to the formula: [wherein Z is a hydroxyl group or a halogen atom]; ) and optionally the product of this reaction has the formula:
reacting with a compound corresponding to RlR2NH in which R1 and R2 are as defined above and/or converting Motokawa and R2 in the product thus obtained into the other mentioned above, and Optionally, the resulting compound in which R3 is a formyl group can be reduced to a -CH2OH group to produce the compound.

When an acid of the formula containing an active carboxyl group is used in the reaction, in particular when Z is a hydroxy group, the corresponding compound has the general formula: [wherein R is as defined above and X is a halogen atom or -0C0-R, in which R is as defined above.

If X is a halogen atom, preference is given to chlorine, bromine or iodine. The reaction with a compound of formula or is carried out, for example, in a conventional solvent or suspending agent, such as water, optionally with a solubility promoter
For example, it is carried out in the presence of a lower aliphatic alcohol, a lower aliphatic ketone, dimethylformamide) or an inert agent.

For example, suitable solvents or suspending agents include low molecular weight aliphatic ethers (e.g. having 4 to 10 carbon atoms); low molecular weight aliphatic ketones (e.g. having 3 to 6 carbon atoms); saturated cyclic ethers; For example tetrahydrofuran, dioxane; low molecular weight saturated chlorinated or fluorinated hydrocarbons having 1 to 5 carbon atoms, each C-atom optionally containing one or several (2 or 3) chlorine and/or fluorine atoms. )
substituted with, for example chloroform, methylene chloride; aromatic hydrocarbons, optionally substituted with chlorine or bromine, such as benzene, toluene, xylene,
These are chlorobenzene, dimethylformamide, dimethylsulfoxide, tetramethylurea, pyridine, and N-methylpyrrolidone. It is also obvious that mixtures of the abovementioned solvents can be used. The reaction is carried out in the temperature range from 0 to 200°C, in particular from 15 to 150°C.

In many cases, especially when X (formula) is a halogen atom or a group -0C
If 0R, the reaction is carried out using an acid binder such as an alkali metal hydroxide, alkali metal carbonate, alkali metal hydrogen carbonate, alkali metal acetate, alkaline earth metal carbonate, trialkylamine, dialkylamine, pyridine, etc. Or, it is best carried out in the presence of an excess of the compound.

Acid binders can also be used as solvents, either alone or in admixture with other conventional solvents (eg pyridine). Care should be taken to carefully neutralize and remove unreacted starting materials, especially in the case of acid chlorides. It is often desirable to purify the reaction product by chromatography on a silicic acid gel, for example using taloloform/
A mixture of ethanol (e.g. 1-5% ethanol content)
). When using a free acid (formula), a condensing agent,
For example, synchhexylcarbodiimide, tetraethylpyrophosphite, 5-(3'-sulfophenyl)-ethylisooxazole, sulfite-bis-alumylamide (e.g. SO[N(CH3)2]2,N,N'-monocarbonyldiimidazole, etc.) should be activated by the presence of ``1Organic Reactions'' (0rgani
cReacti0ns), Volume 12, Pages 205-239 (
1962)].

The reaction component having the formula may be a compound in which one of the groups R1 or R1 is a protecting group of the type normally used for amino groups.

For example, protecting groups commonly used in the synthesis of peptides and also in methods for their general removal can be used. In this regard, especially Jesse P. Greenstein and Milton Winitz, “Chemistry of Amino Acids”
(Volume 2, e.g. 88
3 pages and below, 1961, JOhn Wileyand SO
ns, nc. Published in New York).

In the final product, protecting groups of the relevant type can be removed by means of mineral acids such as hydrochloric acid or sulfuric acid in alcoholic or aqueous/alcoholic solutions or by bases such as alcoholic lyes (e.g. methanolic KOH) at a temperature of 20°C.
It can be desorbed at ~100°C. Groups which can be eliminated by reduction can be removed, for example, by hydrogenation with hydrogen in ethanol, especially under normal conditions and in the presence of a hydrogenation catalyst (eg palladium, palladium/activated charcoal). The radicals R1 and R2 can be introduced successively into the amino group by alkenylation.

For example, a suitable alkenylating agent has the formula: R1'Hal!
．． , ArSO2ORζ and SO2(0R1)2 [in the formula H
at is a halogen atom, especially chlorine, bromine or iodine,
Ar is, for example, an aromatic group such as a phenyl or naphthyl group, optionally substituted by one or more lower alkyl groups, and R is an ester of C3-C6-alkenyl. The alkenylation reaction is carried out in an inert solvent such as alcohol, dioxane, dimethylformamide,
dimethyl sulfoxide, aromatic hydrocarbons such as benzene, toluene or acetone or mixtures of these solvents at temperatures from 0 to 150°C, optionally alkali metal carbonates, pyridine or other conventional tertiary amines. carried out in the presence of an acid binder. If only one of the groups R1 or R2 is introduced, it is most advantageous to carry out the alkenylation in the presence of a protecting group present in the starting material and to remove the protecting group after the alkenylation is complete. Alkenylation is carried out by reacting the corresponding oxo compound after removal of the protective group at temperatures from 0 to 100 °C under conventional or elevated pressure and in customary solvents or suspending agents, with simultaneous or subsequent reduction. It can also be implemented by For example, suitable reducing agents include nascent hydrogen in a neutral or basic medium, electrolytic reduction, sodium/alcohol, sodium or aluminum amalgam, hydrogen in the presence of conventional hydrogenation catalysts (e.g. Raney nickel, platinum, palladium) or Complex hydrates, such as lithium aluminum hydride. If the benzyl group is to be removed during the hydrogenation condensation reaction, it is advantageous to use palladium catalysts, i.e. to form the product directly by condensation first and then reduce it, optionally after isolation and purification. do. R is a group -N
Final products of formula I, which are C1-C6-alkyl groups substituted by RlR2, are obtained by reacting compounds of formula I, where R is a C3-C6-alkenyl group, with amines of the corresponding formula: HNRlR2. It will be done. This reaction is
in a solvent or suspending agent such as anhydrous lower alcohol, dioxane, organic acid amide, acetic acid, etc. at a temperature range of 20 to 1
It can be carried out at 50°C (reaction time is several hours to several days). When reducing a compound of formula I in which R3 is a formyl group (-CHO group) to the corresponding compound in which R3 is a -CH2OH group, it can be converted into a complex metal hydride (
(e.g. sodium borohydride, cyanoborohydride, tri-t-butoxyaluminum hydride) or by Meerwein and Pondorf (P).
OnndOrf) using aluminum alcoholate (e.g. aluminum isopropylate) to
It is carried out at 150°C, especially from 20 to 100°C.

Suitable solvents or suspending agents for this reaction are, for example, lower aliphatic alcohols, dioxane, tetrahydrofuran, water and aromatic hydrocarbons, such as benzene, toluene, and mixtures thereof. Compounds containing asymmetric carbon atoms and which are generally obtained in racemic form can be resolved into optically active isomers in known manner, for example with optically active bases.

However, it is also possible to use optically active starting materials from the beginning, in which case the corresponding optically active forms are obtained as final products. The starting material for the compound of the formula in which R3 is a -CH2OH group and Z is a halogen atom, if not known, can be obtained from the corresponding compound in which Z is a hydroxy group by a known halogenating agent (hydrogen halide). acid, thionyl chloride, phosphorus halide, sulfuryl chloride, phosphorus oxychloride, phosgene, benzotrichloride) in a conventional manner.

The compounds according to the invention are suitable for the production of pharmaceutical compositions and preparations.

This pharmaceutical composition or medicament contains as active substance one or more compounds according to the invention, optionally in a mixture with other pharmacologically or pharmaceutically active substances, in particular potassium or magnesium aspartate. contains. The medicament can be prepared with conventional pharmaceutical excipients and adducts. For example, the medicament can be administered enterally, parenterally, orally, sublingually or in the form of a spray.

For example, they can be used as tablets, capsules, pills, sugar coatings,
It can be formed in the form of suppositories, solutions or aerosols. Examples of suitable solutions include oily or aqueous solutions or suspensions;
Emulsions are injectable aqueous or oily solutions or suspensions. Suitable bases and auxiliaries are, for example, the substances recommended or mentioned in the pharmaceutical, cosmetic and related fields in the following document: ``Ullmans Enticlopedei 1 der Technissien Hiemi 1''.
(UIlmannsEncyklOp'Adieder
technischenChemie, 4 volumes, 1ゞ39
Page (1953); “Journal of Pharmaceutical Sciences”
mechanical sciences), vol. 52, 9
18 pages and below (1963); H. v. Getsch-L
Indenwald, 1 Hilfsst Offe Ver Pharma
zieundangrenzendeGebiete)
;゛Pharm. Ind. ``No. 2, 72 pages and below (196
1 year); Dr.
H. P. ``Lexikon der Hilfsschützführer Vermärtswicz Cosmeteik und Angrenzende Gebite'' (
LexikOnderHilfs-StOffe “U3
rPharmazie, KOsmetikundang
renzendeGebiete), CantOrKG
．． AulendOrfi. Wu'Rff. (1971). Examples of this are gelatin, natural sugars such as sucrose or lactose, lecithin, pectin, starch (e.g. corn starch), alginic acid, methylcellulose, talc, stone pine,
silicic acid (e.g. colloidal), cellulose, cellulose derivatives (e.g. cellulose ethers in which the cellulose hydroxy groups are partially etherified with lower saturated aliphatic alcohols and/or lower saturated aliphatic oxyalcohols, e.g. methyloxypropyl cellulose), Stearates, aliphatic (especially saturated) magnesium and calcium salts having 12 to 22 C atoms (e.g. stearate), emulsifiers, fats and oils, especially vegetable oils (e.g. peanut oil, castor oil, olive oil, sesame oil, Cottonseed oil, corn oil, wheat germ oil, sunflower seed oil, cod liver oil, saturated fatty acids Cl2H24O2 to Cl8H36O2,
di- and triglycerides and mixtures thereof), pharmaceutically acceptable mono- or polyhydric alcohols and polyglycols,
For example, polyethylene glycol and its derivatives, aliphatic saturated or unsaturated fatty acids (2 to 22 carbon atoms, especially 10 to 18 carbon atoms), monohydric aliphatic alcohols (1 to 20 carbon atoms), Esters with alcohols such as glycols, glycerin, diethylene glycol, pentaerythritol, solpit, mannite, etc. (which may optionally be etherified), benzyl benzoate, dioxolane, glycerin formal, tetrahydrofurfuryl alcohol , polyglycol ether with Cl-Cl2-alcohol, dimethylacetamide, lactamide, lactate, ethyl carbonate,
Silicone (particularly medium viscosity dimethylpolysiloxane), magnesium carbonate, etc. To prepare the solution, for example water or a physiologically acceptable organic solvent such as ethanol,
Examples include 1,2-propylene glycol, polyglycol and its derivatives, dimethyl sulfoxide, fatty alcohol, triglyceride, partial ester of glycerin, paraffin, and the like.

In preparing the preparations, known and customary solubilizing agents or emulsifiers can be used.

Suitable solubilizers and emulsifiers are, for example, polyvinylpyrrolidone, sorbitan fatty acid esters such as sorbitan trioleate, lecithin, acacia, tragacanth, polyoxyethylated sorbitan monooleate, polyoxyethylated fats, polyoxy polyethylene oxide condensation products of ethylated oleotriglycerides, linolized oleotriglycerides, fatty alcohols, alkylphenols or fatty acids; polyoxyethylated here means that the substances in question generally have a degree of polymerization of 2 to 40
1 represents the presence of polyoxyethylene chains, especially 10 to 20. For example, such polyoxyethylated substances can be obtained by reacting a hydroxyl group-containing compound (for example a mono- or diglyceride or an unsaturated compound such as containing oil acid residues) with ethylene oxide (for example 1 mole of glyceride). 40 moles of ethylene oxide).

Examples of oleotriglycerides are olive oil, peanut oil, castor oil, sesame oil, cottonseed oil, corn oil [Dr.
．． H. P. Written by Fiedler, “Lexik Onder”
HilfsstOffefirPharmazie,K
OsichiMetikundangrenzendeGeb
See also iete'5191-195 (1971)]
.

Furthermore, it is possible to add preservatives, stabilizers, buffers, such as calcium hydrogen phosphate, colloidal aluminum hydroxide, corrigendants, antioxidants and complex builders (eg ethylenediaminotetraacetic acid). Optionally, a pH value of about 3 to 7 can be adjusted with physiologically acceptable acids or buffers for stabilization of the active substance molecule. in general,
The pH value is as neutral to weakly acidic (up to PH5) as possible. Examples of oxidizing agents include sodium metabisulfite, ascorbic acid, gallic acid, gallic acid alkyl esters, butylhydroxyanisole, nordihydroguacerate, tocopherol and tocopherol +
Synergists (substances that bind heavy metals by complex formation, such as lecithin, ascorbic acid, phosphoric acid) are used. Addition of synergists significantly enhances the antioxidant activity of tocopherols. For example, preservatives include zorpic acid, p-hydroxybenzoic acid esters (e.g. lower alkyl esters),
These include benzoic acid, sodium benzoate, trichloroisobutyl alcohol, phenol, cresol, benzethonium chloride and formalin derivatives. Pharmacological and Gallenian treatments of the compounds according to the invention are carried out by conventional standard methods.

For example, the active substance and the auxiliaries or bases are thoroughly mixed by stirring or homogenization (e.g. in a colloid mill, spherical mill), generally at a temperature of 20 to 80°C, in particular 20°C.
Operate at ~50°C. Administration of the active substance or medicament can be carried out on the skin or mucous membranes or into the body, for example orally, enterally, pulmonaryly, rectally, nasally, vaginally, tonally, intravenously, intraarterially, intracardially, intramuscularly,
It is administered intraperitoneally, intradermally, or subcutaneously.

Owing to their good intestinal absorption (eg absorption rate 40-90%), the compounds according to the invention are particularly suitable for oral administration.

The addition of other pharmaceutical active substances is possible. The compound according to the present invention can be used in isolated guinea pig hearts (Langendorff hearts).
shows good positive myocardial action.

For example, in the test method described above, the contractile force is 20 μr/heart.
An increase of ~50% is observed. This positive myocardial action can be contrasted with the action of the known pharmaceutical digitoxin (10-30 μy). The minimum effective dose in the above animal studies is, for example, 0.3 μ7/heart (in vitro).

For example, general dose ranges (in all animals) for myocardial effects include oral 0.05-0.25 η/K', especially 0.1 m7/Kf; intravenous 9.05-0.25 η/K'. ′
, especially 0.1 m7/Kf. Indications in which the compounds according to the invention can be used: all severe and forms of heart failure, senile hearts.

Generally, pharmaceutical preparations contain 0.0 of the active ingredient according to the invention.
Contains 1 to 5 watts. For example, administration can be in tablets, capsules, pills, dragees, suppositories, ointments, jellies, creams, powders, powders, aerosols or liquid forms.

For example, the following are suitable as liquid application forms: oily or alcoholic or aqueous solutions and suspensions and emulsions. The best application form is the active substance 0.02
Tablets containing ~5 skill, active substance 0.001~10! )
It is a solution containing. A single dose of active ingredient according to the invention may be as follows. a) Oral pharmaceutical form 0,01
~2m9 b) Parenteral pharmaceutical forms (e.g. intravenous, intramuscular) 0.01~
2, for example, 1 to 3 tablets with a content of 0.01 to 2 units of active substance per day 3 times or a content of 0.25 to 5 rms containing 0.01 to 2 units of active substance! Intravenous injection of ampoule 1
~2 times/day is preferable.

For example, for oral administration, the minimum daily dose is 0.01 m7;
For oral administration, the maximum daily dose should not exceed 5 m7.
Generally, oral doses for treating dogs and cats are about 0.002 to 1 mq/K9 (body weight).

For example, acute toxicity of compounds according to the invention in mice (LD5Oη/Kf; co-authored by Miller and Tainter, ゞ3Pr0c.S0c
．． Expert. B101. a. Med. '゛, 57 volumes,
261 (1944)) is orally administered to
It is ZZ5OO Takumi/K'.

This measurement was performed for three different doses. Four mice were tested for each dose. Therefore, 12 animals were used per test substance. The drug can be used alone or in mixtures with other pharmacologically active substances in human medicine, veterinary medicine and agriculture.

It is clear from the following experimental reports that the compounds according to the present invention have high efficacy.

Experimental report Measurement of cardiac effects in relation to intestinal absorption [Greef
, Schwarzmann and Waschulzik, 6Arznermitte1-FOrschug-
Vol. 15, pp. 483-486 (1965)] All doses are listed as the active substance per 1 Kf of body weight of the experimental animal. The test was carried out after abdominal incision in cats lightly anesthetized with urethane chloralose. A sublethal dose (non-lethal dose) of the desired compound is injected into the intestine.

Generally, this sublethal dose is selected to correspond to about half of a single dose of Hatchery. A single dose of Hatchiya is the immediate dose per kilogram of body weight of a laboratory animal that, upon intravenous administration, leads to cardiac arrest, ie death. The purpose of this experiment was to
Of the injected amount - [ヮw is to measure the amount absorbed into the blood from the intestines. Therefore, the infusion solutions of cardioactive compounds must be controlled so that they do not escape into the stomach or other intestinal regions, where no or only limited absorption takes place. Regurgitation of the administered compound is
- [w Avoided by tying the intestine directly below the injection site and on the other side at the level of the pylorus (sphincter at the exit of the stomach). For example, this tying can be done using non-absorbable burning thread, which is used to sew leather. This is a commonly used pharmaceutical method. Therefore, the infusion solution remains in the closed intestinal segment for a certain period of time (2 hours) and is only absorbed from this segment. - [w Since the solution injected into the intestine is not a lethal dose, to determine the toxic dose, the same substance is injected intravenously until cardiac arrest after 2 hours of absorption time. Because of the difference between this dose and the intravenous lethal dose in unpretreated animals,
Absorption, ie the rate of absorption from the duodenum 1, can be calculated. This method is commonly used and is described, for example, in the literature Handbook of Experimental Research.
Makoroji (HandbOOkOfExperiment
alPharmacOlOgy) 1, 56/1 volume, 14
It is described on page 2. 7 The absorption rate I (or rate of action) is calculated by the following formula: Results are listed in the following table.

In the case of cardiac glycosides, it is common to state the minimum dose (one dose) that causes death when administered intravenously to cats as a measure of effectiveness.

It is therefore clear from the above table that the compounds according to the invention have a high absorption rate and are therefore particularly suitable for intestinal absorption. Next, the present invention will be explained in detail with reference to examples.

Example 1 Helebrigenin-3α-butyrateHelebrigenin 2.08 V (0.005 mol) is dissolved in 20 me of pyridine and 15 me of n-butyric anhydride is added to the product solution.

The mixture is allowed to stand for 60 hours, after which diethyl ether is added. On standing overnight in the cooler, crystals precipitate and are taken off under suction, washed with ether and dried. The product obtained is chromatographed on silica gel and recrystallized from 50% monoaqueous ethanol. 1.2 tons of white needles are obtained. M. p. 2l2℃
. Example 2 Helebrigenin-3β-isobutyrate 2.08y (0.005 mol) of helebrigenin was added to pyridine 20r11f. 10me of isobutyric anhydride dissolved in
is added to the product solution.

After 24 hours, 400 me of diethyl ether is added and the mixture is then left in a cooler overnight to crystallize.

This material is purified by column chromatography on silica gel and recrystallized from 50% monoaqueous ethanol. Yield: 1.57, m. p. 250'CO Example 3 1., 1*) 3β-isovaleric acid ester of herebrigenin 2.087 (0.005 mol) of helebrigenin and isovaleric anhydride 1
0r71e to pyridine 20r! Heat at boiling point in 1e for 1 hour.

After cooling, 400 d of diethyl ether are added. On standing in a cooler, the crude product crystallizes and is purified by column chromatography, followed by recrystallization from 50% monoaqueous ethanol. Yield 1.57, m. p. 196
~199℃. The 3β" added before the name of phosphoric acid indicates that the hydroxyl group at the 3β-1 position of hellebrigenin is bonded to an acid group.

This also applies to the following examples. Example 4 3β-(3,3-dimethyl-acrylic acid ester) of hellebrigenin 20t (0,
048 mol) is suspended in 400 me of dry dichloromethane.

Freshly distilled dimethylacrylic acid chloride 20d = 20y
(0.148 mol) and heated under reflux with stirring for 1.5 hours. At this time, care must be taken to block moisture. Herebrigenin dissolves. 20 ml of absolute methanol are added for cooling and to destroy excess acid chloride. Severe hydrochloric acid generation occurs. Boil under reflux for a further 30 minutes to completely decompose the acid chloride residues. The resulting reaction mixture was poured into a separatory funnel with 100 g of water, then 10 g
3 times with 0 me saturated NaHCO3 solution and again with water 10
Shake 0rr11.

The dichloromethane solution is dried over anhydrous sodium sulfate and concentrated in vacuo. The yellow oil formed is taken up in 50ml of anhydrous chloroform and stirred into 1500ml of petroleum benzine (boiling point 50-70°C), the reaction product precipitating out (24.87). Purification at 20℃
silicic acid gel (GeduranSlOO,O,O63~0
．． 200? ) by column chromatography. The crude product is taken up in chloroform/ethanol (98% chloroform, 2% ethanol) 50 rf1e and poured onto a 132 cTn length column (inner diameter 6 CWL).

Elution is carried out with the same developer mixture. A brown cooling jacket is used to further protect against light and maintain a constant temperature of 20°C. The flow rate is 115rr! l/min. Collect each component separately. For the desired main products, the process can be shortened by increasing polarity. The main fraction is concentrated to almost dryness in vacuo, then taken up in a CHct35 orlle and precipitated with 1.51 g of petroleum benzine (boiling point 50-70 DEG C.), filtered off with suction and dried at 50 DEG C. in vacuo. Yield: 1
5y (62.6(f)), melting point 220-222°C o Example 5
The 3β-crotonic acid ester of helebrigenin 6.8 t (0.0163 mol) of helebrigenin was dissolved in chloroform 21
Boil under reflux for 1 hour and 6 d of chlorocrotonic acid.

The reaction mixture is worked up using the same force method as in Example 4. The reaction product is recrystallized twice from methanol. Yield 0.8t,
m. P. 202-204 crystal C0 Example 6 Heleprigenin-3β-(3,3-dimethyl-butyrate)Helebrigenin 2.8y (0.0067 mol) and 3,3-dimethylbutyric acid chloride 15Tn1 were dissolved in methylene chloride 6
0r1! ! Boil under reflux for 2 hours.

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 is distilled off. Add diethyl ether to the residue and then leave it overnight. As a result, the reaction product (crude product)
crystallizes. It is recrystallized from 120 ml of methanol. Yield: 1.8t,. m. p. 237°C Example 7 3β-caprylic acid ester of hellebrigenin 2.08y (0.005 mol) of hellebrigenin was added to 20r of pyridine!
Heat under reflux for 2 hours in Le and 10 d of anhydrous furylic acid.

The crude product was precipitated with diethyl ether, chromatographed on a silica gel column and 50%
Recrystallize from monoaqueous ethanol. Yield: 1.17,
m. p. 189-19 "CO Example 8 3β-decanoic acid ester of hellebrigenin 2.08t (0.005 mol) of hellebrigenin was dissolved in pyridine 20W1e
and boil under reflux for 3 hours in 10 me of decanoic anhydride.

After cooling, the crude product is precipitated by addition of 500 rrLe of water, chromatographed on a silica gel column and recrystallized from 66 (:f) monoaqueous ethanol. Yield: 1.67, m. p. 188℃. Example 9 Helebrigenin-3β-benzoate Helebrigenin 37 (0.007 mol) was added to pyridine 25
me. 2.8 t of benzoic anhydride are added and the mixture is boiled under reflux for 5 hours.

Following addition of diethyl ether, the crude product is precipitated and first chromatographed on a silica gel column and then recrystallized from 50 (Ft) monoaqueous ethanol. Yield: 0.87, m. p. 238-240℃
. Example 10 Helebrigenin-3β-(3,5-diturobenzoate) Helebrigenin 2.087 (0.005 mono(c)) is boiled under reflux for 8 hours in 20 me. of pyridine and 5 t of 3,5-dinitrobenzoyl chloride. .

The reaction product is precipitated with water, talomatographed on silica gel, dissolved in chloroform and precipitated with petroleum ether. Yield: 0.5t, m. p. 172℃
Example 11 Helebrigenin - 3β-hemidiglycolateHelebrigenin 2 (i/(0.005 mol)) dissolved in pyridine 10me and diglycolic anhydride 5 in pyridine 10d
Add the solution of t to the product solution.

The solution is left at room temperature for 24 hours. 2.67 of the target substance crystallized and was mixed with 80% - ethanol 230m! Recrystallize from. Yield: 1.67, m. p. 239-2400C
Example 12 Helebrigenin - 3β-diallylaminoacetate Helebrigenin 20y (0.048 mol) was dissolved in methylene chloride 3
00me. and boiled under reflux for 2 hours in 200ml of chloroacetyl chloride.

The reaction mixture is worked up analogously to Example 4. The obtained reaction product (22 t) is recrystallized from 900 me methanol while adding activated carbon. Herebrigenin-3β-chloroacetate (=3β-
Yield of chloracetylhelebrigenin: 16t, m.
P. 197-198°C. 2t (0.004 mol) of 3-chloroacetylhelebrigenin was mixed with 201ml of acetone and 20ml of diallylamine. Heat under reflux for 2 hours.

After cooling, the diallylamine hydrochloride is filtered off, the solvent is distilled off and the remaining reaction product is treated with 100 rrl of water and recrystallized from isopropanol. Melting point of the base: 189° C. Preparation of the hydrochloride The base 2,47 is neutralized with isopropanolic hydrochloric acid in ethanol 2577!11, diethyl ether is added and the reaction mixture is left overnight.

2.2 t of hydrochloride are precipitated and recrystallized from 80 me of ethanol with addition of 50 ml of diethyl ether. Yield: 1.2m7, m. p. 230-231℃.
Example 13 Helebrigenin - 3β-(2,6-dimethylmorpholinoacetate) 3-chloroacetylherebrigenin 2.5V (0.005 mol) was mixed with 25T of acetone! 1! ．．
and 2,6-dimethylmorpholine 51ne for 2 hours under reflux.

The solvent is distilled off and the residue is stirred with 2007 ml of water for 1 hour. The described substance (base) is obtained, which melts at 196 DEG -198 DEG C. after recrystallization from isopropanol.
Production of hydrochloride: base 2y which melts at 196-198°C is mixed with acetonone 20
Hydrochloride (2y) was dissolved in diethyl ether 307 by dissolving it in methane and neutralizing it with isopropanolic hydrochloric acid.
Precipitate by adding 7!11 and ethanol 30mf
, recrystallized from .

Yield: 1r, m. p. (Hydrochloride) 178-18
0°C (hygroscopicity) Example 14 Helebrigenin-3β-(4-hydroxypiperidinoacetate 3-chloroacetylhelebrigenin 2.57(
0.005 mol) in acetone 40 m! and boiled under reflux for 1 hour in 2 t of 4-hydroxypiperidine.

After cooling, the reaction mixture is filtered, the solvent is distilled off and the residue is poured with 200 m of water! and stir for 2 hours. To achieve complete precipitation of the base, the aqueous suspension is saturated with sodium chloride. 1.8 t of the described substance (base) are obtained, which melts at 219-220 DEG C. after recrystallization from isopropanol. This hydrochloride is produced analogously to Example 16.

Hydrochloride 1.47 to diethyl ether 20rf1
1 and recrystallize from methanol/ethanol (2:1). Yield: M. of 1y1 hydrochloride. p. 2
36-237℃. Example 15 3β-cyclopropanecarboxylic acid ester of hellebrigenin hellebrigenin 800T! l (l is CH2C45O
m! cyclopropanecarboxylic acid chloride 17 is added and boiled at reflux for 4 hours.

Work-up and column chromatographic purification are carried out as described in Example 4. Yield: 500 m. p. l4Ou/240. . Example 16 Helebrigenol - 3β-(3,3-dimethyl-butyrate) Helebrigenin - 3β-(3,3-dimethyl-butyrate) 2.83r was mixed with 90ml of dioxane and 30ml of water.
Dissolve in m1.

Add 0.68 y of sodium borohydride dissolved under stirring in 45 d of dioxane and 15 d of water, stir for 3 hours and acidify with 2N H2SO4. After concentration and shaking with 3×200 me of chloroform, the combined chloroform phases are dried over sodium sulfate and concentrated. The crude product thus obtained is dissolved in 500 mf of methanol and 500 mf of 0.1N monosulfuric acid and boiled for 1 hour under reflux with 10 mf of Romanite.

After concentration, shaking out with chloroform and washing the chloroform phase with aqueous 2N soda solution and drying over sodium sulfate, 2.3 t of crude still are obtained. Column chromatography on silicic acid gel using chloroform/ethanol (96:4) gives 764 m9 of pure hellebrigenol-3β-(3,3-dimethyl-butyrate). Similarly, herebrigenin-3β-isobutyrate was converted to herebrigenol-3β-isobutyrate.
-isobutyrate is obtained.

Example 17 Helebrigenol - 3β-isobutyrate Helebrigenin - 3β-isobutyrate 1.5 t (0.0031 mol) in anhydrous tetrahydrofuran 607ne and freshly prepared lithium tri-t-butoxy aluminum hydride in tetrahydrofuran. (Li(Al!
．． 60rr1e of a reducing solution of H4) prepared from 1.57 and 6 V of tert-butanol are added at room temperature.

After stirring for 2 days at room temperature, the reaction mixture was charged with 5(:Ft)
Add monoacetic acid and shake out with chloroform. The resulting solution was concentrated, the reaction product was precipitated by addition of petroleum ether and column chromatographed on silicic acid gel (eluent 95% by volume of taroloform/5% by volume of ethanol 0I).
). Yield: 3001), melting point 1
95℃. Example 18 herebrigenol-3β-(3,3-dimethyl-acrylate) herebrigenin-3β-(3,3-dimethyl-acrylate)
3-dimethyl-acrylate) 17 (0.002 mono(
c) 60m of anhydrous tetrahydrofuran! 60 me of a freshly prepared reducing solution of lithium-trit-butoxyaluminum hydride in tetrahydrofuran is added at room temperature.

After a reaction time of 1 hour, 5% monoacetic acid is added and extracted several times with taloloform.

The solution is concentrated and the reaction product is precipitated out by addition of petroleum ether. Yield: 49.8%, melting point 140-142
°C Example 19 3β-cyclohexanecarboxylic acid ester of hellebrigenin hellebrigenin 27 was CH2C! 100me, then cyclohexanecarboxylic acid chloride 47
71e and boil under reflux for 4 hours.

After cooling, about 2 me of anhydrous methanol is added to destroy the acid chloride excess and heated under reflux for 30 minutes. The cooled reaction mixture was added in a separatory funnel to 10ml of water and then 10ml each of saturated bicarbonate solution. 3 times, again Wednesday 107
Shake at 71e.

Claims (1)

[Claims] 1. General formula: ▲There are mathematical formulas, chemical formulas, tables, etc.▼(I) [In the formula, R is a C_3-C_6-alkenyl group, C_3-C_1_2-
Alkyl group, C_3-C_6-cycloalkyl group, C_2-C_6-alkoxyalkyl group substituted by carboxy group, phenyl group, phenyl group or group substituted by nitro group -NR_1R_2 (R_1 and R_2 are C_3-C_6 A heterocyclic saturated 5- which is an alkenyl group or the group -NR_1R_2 may further contain one oxygen atom and may be substituted by one or two C_1-C_6-alkyl groups or hydroxy groups. or forming a 6-membered ring) containing C_1-
C_6-alkyl group, R_3 represents -CHO group or -CH_2OH group), an optically active form thereof, or a salt thereof. 2 I In the formula R is a branched alkyl group having 3 to 5 carbon atoms, a branched alkenyl group having 4 to 5 carbon atoms, and a methoxy or ethoxy group additionally containing a carboxy group. ethoxymethyl group or methoxymethyl group, phenyl group, dinitrophenyl group, morpholinomethyl group, morpholinomethyl group substituted with one or two methyl groups, piperidinomethyl group, piperidinomethyl group substituted with hydroxy group or nitrogen A derivative according to claim 1, which is an aminomethyl group substituted by an alkenyl group containing 3 or 4 carbon atoms. 3 R is a C_3-C_6-alkenyl group, especially C_3-
C_5-alkenyl group; or C_3-C_1_2-alkyl group, especially C_4-C_1_0-alkyl group; or phenyl group optionally substituted by 1 or 2 nitro groups; or di-C_3-C_6-alkenylamino-C_1
~C_6-alkyl group, especially di-C_3-C_4-alkenylamino-C_1-C_4-alkyl group; or substituted by a pyrrolidino group, morpholino group, piperidino group, homopiperidino group, hydroxypiperidino group or dimethylmorpholino group C_1-C_6-alkyl group,
In this case, this basic group is in particular present in the ω-position of the alkyl group; or a C_2-C_3-alkoxy-C_1-C_4-alkyl group which is substituted in particular in the ω-position by a carboxy group; and R_3 is Group -CHO or -CH_2OH
A derivative according to claim 1 having the formula I. 4 General formula; ▲There are mathematical formulas, chemical formulas, tables, etc.▼(I) [In the formula, R is a C_3-C_6-alkenyl group, C_3-C_1_2-
Alkyl group, C_3-C_6-cycloalkyl group, C_2-C_6-alkoxyalkyl group substituted by carboxy group, phenyl group, phenyl group or group substituted by nitro group -NR_1R_2 (R_1 and R_2 are C_3-C_6 a heterocyclic saturated 5- which is an alkenyl group or the group -NR_1R_2 may further contain one oxygen atom and may be substituted by a C_1-C_6-alkyl group or one or two hydroxy groups. or forming a 6-membered ring) C_1 to C
_6-alkyl group, R_3 is -CHO group or -
When producing a novel hellebrigenin acyl derivative, its optically active form, or its salt corresponding to the CH_2OH group], the formula: ▲Mathematical formula, chemical formula, table, etc.▼(II)
The herebrigenin or herebrigenin derivative [wherein R_3 represents the above and Z represents a hydroxy group or a halogen atom] is represented by the formula: R-COOH (III) [
1. A method for producing a novel hellebrigenin acyl derivative, which is characterized by reacting it with an acid in which R represents the above-mentioned one and the carboxyl group may be activated. 5 General formula: ▲There are mathematical formulas, chemical formulas, tables, etc.▼(I) [In the formula, R is C_3-C_6-alkenyl group, C_3-C_1_2-
Alkyl group, C_3-C_6-cycloalkyl group, phenyl group substituted by C_2-C_6 substituted by carboxy group or group -NR_1R_2(R_
1 and R_2 are C_3-C_6-alkenyl groups or the group -NR_1R_2 may further contain one oxygen atom and is substituted by one or two C_1-C_6-alkyl or hydroxy groups; (forming a good heterocyclic saturated 5- or 6-membered ring)
_1-C_6-alkyl group, R_3 is -CH_
In producing a new hellebrigenin acyl derivative, its optically active form, or its salt corresponding to 2OH group], formula: ▲ Numerical formula, chemical formula, table, etc. ▼ (II) [In the formula, R_3 is -CHO group and Z represents a hydroxy group or a halogen atom] is represented by the formula: R-COOH (III) [wherein R represents the above and the carboxyl group may be activated] and in the reaction product thus obtained, the formyl group R_
A method for producing a novel hellebrigenin acyl derivative, which comprises reducing 3 to a -CH_2OH group. 6 General formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (I) [In the formula, R is the group -NR_1R_2 (R_1 and R_2 are C_3 to C_
6-Alkenyl group or group -NR_1R_2
may further contain one oxygen atom and C_1
- C_1-C_6-alkyl group containing -C_6-alkyl group or forming a heterocyclic saturated 5- or 6-membered ring which may be substituted with 1 or 2 hydroxy groups), R_3 is -CHO group or -CH_2OH group] corresponding to the novel hellebrigenin acyl derivative, its optically active form, or its salt, the formula: ▲ Numerical formula, chemical formula, table, etc. ▼ (II) [In the formula, R_3 is represents the above and Z represents a hydroxy group or a halogen atom] and a hellebrigenin derivative of the formula: R-COOH (III)
_6-halogenalkyl group and the carboxyl group may be activated] and the reaction product thus obtained has the formula: HNR_1R_2 [wherein R_1 and R_2 are the above-mentioned ones]. 1. A method for producing a novel hellebrigenin acyl derivative, which comprises reacting it with a compound shown below. 7 General formulas: ▲There are mathematical formulas, chemical formulas, tables, etc.▼(I) [In the formula, R is the group -NR_1R_2 (R_1 and R_2 are C_3 to C_
6-Alkenyl group or group -NR_1R_2
may further contain one oxygen atom and C_1
- C_1-C_6-alkyl group containing -C_6-alkyl group or forming a heterocyclic saturated 5- or 6-membered ring which may be substituted with 1 or 2 hydroxy groups, R_3 is -CH_2OH group When producing a novel hellebrigenin acyl derivative, its optically active form, or its salt corresponding to and Z represents a hydroxy group or a halogen atom) or a herebrigenin derivative with the formula: R-
COOH (III) [wherein R represents a C_1-C_6-halogenalkyl group and the carboxyl group may be activated] is reacted with an acid of the formula: NHR_1R_2 [wherein R_1 and R_2 are the above-mentioned ones] 1. A method for producing a novel hellebrigenin acyl derivative, which comprises reacting with a compound represented by the following formula and converting a formyl group, R_3, into a -CH_2OH group in the obtained compound. 8 General formulas: ▲Mathematical formulas, chemical formulas, tables, etc.▼(I) [In the formula, R is the group -NR_1R_2, (R_1 and R_2 are C_3 to C
_6-alkenyl group or group -NR_1R_
2 may further contain one oxygen atom and C_
represents a C_1-C_6-alkyl group containing 1 to C_6-alkyl group (forming a heterocyclic saturated 5- or 6-membered ring which may be substituted with 1 or 2 hydroxy groups), and R_3 is -CHO or -CH_2OH group], a novel hellebrigenin acyl derivative corresponding to
When producing its optically active form or its salt, the formula: ▲Mathematical formula, chemical formula, table, etc.▼(II) [In the formula, R is C_1
~ C_6-halogenalkyl group and R_3 represents the above] is expressed by the formula: HNR_1R_2 [
1. A method for producing a novel hellebrigenin acyl derivative, characterized by reacting it with a compound of the formula [wherein R_1 and R_2 represent the above-mentioned compounds]. 9 General formulas: ▲Mathematical formulas, chemical formulas, tables, etc.▼(I) [In the formula, R is the group -NR_1R_2 (R_1 and R_2 are C_3 to C_
6-Alkenyl group or group -NR_1R_2
may further contain one oxygen atom and C_1
- C_1-C_6-alkyl group containing -C_6-alkyl group or forming a heterocyclic saturated 5- or 6-membered ring which may be substituted with 1 or 2 hydroxy groups, R_3 is -CH_2OH group In producing a novel hellebrigenin acyl derivative, its optically active form, or its salt corresponding to the general formula: ▲mathematical formula, chemical formula,
There are tables, etc.▼(I) [In the formula, R is C_1 to C_6-
represents a halogenalkyl group, and R_3 represents a -CHO group], a compound of the formula: HNR_1R_2 [in the formula R_1
A method for producing a novel hellebrigenin acyl derivative, which is characterized by reacting the compound with the compound [and R_2 represents the above-mentioned] and reducing the formyl group R_3 in the obtained compound to a -CH_2OH group. 10 An acid of formula III containing an active carboxyl group has the formula:
R-COX (IV) [wherein R represents the above-mentioned one, and X represents a halogen atom or -OCOR, in which case R represents the above-mentioned one] The method according to any one of paragraph 9. 11 General formula: ▲There are mathematical formulas, chemical formulas, tables, etc.▼(I) [In the formula, R is a C_3-C_6-alkenyl group, C_3-C_1_2-
Alkyl group, C_3-C_6-cycloalkyl group, C_2-C_6-alkoxyalkyl group substituted by carboxy group, phenyl group, phenyl group or group substituted by nitro group -NR_1R_2 (R_1 and R_2 are C_3-C_6 A heterocyclic saturated 5- which is an alkenyl group or the group -NR_1R_2 may further contain one oxygen atom and may be substituted by one or two C_1-C_6-alkyl groups or hydroxy groups. or forming a 6-membered ring) containing C_1~
C_6-alkyl group, R_3 represents -CHO group or -CH_2OH group], an optically active form thereof, or at least one salt thereof. 12. The medicament according to claim 11, which is contained together with at least one conventional pharmaceutical excipient and/or diluent.