JPH04202128A - Hepatopathy-treating medicine - Google Patents

Abstract

PURPOSE:To provide a hepatopathy-treating medicine containing a zingerol derivative as an active ingredient and especially active on viral hepatitis. CONSTITUTION:Agent containing a compound of formula I [R1 is H, lower alkyl; X is CH2-CH2, CH=CH; Y is methyl, CH=CH-(CH2)8-CH3, a group of formula II or III), e.g. 4-(4-hydroxy-3-methoxyphenyl)-3-butene-2-one as an active ingredient or further added with a conventional medicinal carrier, a conventional excipient, etc., by a conventional method. The agent can be formed into a shape such as tablets, sugar-coated tablets, powder, capsules, granules, suspensions, emulsions or injections, etc. The dose of the compound of formula I is 100-3000mg, preferably 200-500mg divided in one-three times a day for an adult. The compound of formula I is obtained by the Claisen's reaction of a benzylidene acetone derivative with capric acid imidazole amide.

Description

DETAILED DESCRIPTION OF THE INVENTION [Industrial Field of Application] The present invention relates to a therapeutic agent for liver damage that contains a gingerol derivative as an active ingredient and is particularly effective against viral hepatitis.

[Prior Art and Problems to be Solved by the Invention] The liver is the center of the body's substance metabolism, including metabolism of various substances, detoxification, and bile secretion, and has a wide variety of functions. These functions may be impaired acutely or chronically due to causes such as hepatitis viruses, various drugs and poisons, alcohol intake, and nutritional deficiencies. Each of these causes diseases such as viral hepatitis, drug-induced liver damage, alcoholic hepatitis, fatty liver, and yellow scars. At present, the basic treatments for these diseases include diet therapy and rest therapy, as well as the administration of various liver-protecting agents, but it cannot be said that they are sufficiently effective. Furthermore, antiviral agents such as interferon are administered to treat viral hepatitis, which accounts for the majority of hepatitis cases in Japan, but the hepatitis virus has not yet been reliably eliminated. Furthermore, side effects such as fever cannot be ignored, and they are expensive.

[Means for Solving the Problems] As a result of intensive studies on the gingerol derivative [formula (■) above] according to the present invention, the present inventors have found that it has a strong inhibitory effect on liver disorders including viral hepatitis. The present invention has been completed based on this discovery.

That is, what solves the above-mentioned problems is the drug for treating liver disorders represented by the formula (I).The present invention will be described in detail below.

The gingerol derivative represented by the formula (1) of the present invention has the formula (II), where R2 represents a methoxymethyl group or a hydrogen atom]
It can be obtained by performing a Claisen reaction between a benzylidene acetone derivative having the formula and capric acid imidazolamide or an aldol reaction with capric aldehyde, followed by a deprotection reaction. Further, these adducts can be obtained by further performing catalytic reduction and dehydration reactions.

When the gingerol derivative (I) of the present invention is used as a drug for treating liver disorders, the daily dose for adults is generally 100 to 3000 mg, preferably 200 mg, although the dosage varies depending on the symptoms.
The dosage is ~500 mg, and it is best to administer it in 1 to 3 doses depending on the symptoms. The administration method can take any form suitable for administration, and oral administration is particularly preferred, but intravenous injection is also possible.

The compound of the present invention can be used as an active ingredient or one of the active ingredients alone or mixed with a pharmaceutical carrier or excipient in a conventional manner, and can be used as a tablet, sugar-coated tablet, powder, capsule, granule, suspension, emulsion, or injection. It can be applied in various forms such as liquid formulations. Examples of carriers or excipients include: calcium carbonate, calcium phosphate, starch, glucose, lactose,
Examples include dextrin, alginic acid, mannitol, talc, and magnesium stearate. □Next, the present invention will be specifically explained by showing synthesis examples and examples, but the present invention is not limited thereto.

[Compound 1] 4-(4-hydroxy-3-methoxyphenyl)-3-buten-2-one (manufactured by Aldrich) represented by the following formula (m) was purchased and used in the following test examples.

[Synthesis Example 1] Under an argon atmosphere, 8.74 g of diisopropylamine was dissolved in 200 ml of dry tetrahydrofuran, and the mixture was heated at -15°C.
After cooling to , 55.7 ml of a 1.6 M n-butyllithium hexane solution was added dropwise. dry tetrahydrofuran 2
After dropping 19.2 g of 4-(3,4-dimethoxymethyloxyphenyl)-3-buten-2-one dissolved in 0.00ml at -15°C, the mixture was stirred at the same temperature for 05 hours. After cooling to −78° C., 23.6 g of capricaldehyde dissolved in 60 ml of dry tetrahydrofuran was added dropwise, and the mixture was stirred at the same temperature for 2.5 hours. After adding 30 ml of methanol, the mixture was returned to room temperature, saturated brine was added, the organic layer was separated, and the aqueous layer was extracted with diethyl ether. The organic layer is washed with 2N hydrochloric acid, a saturated aqueous sodium bicarbonate solution, and saturated brine, dried over anhydrous magnesium sulfate, and then the solvent is distilled off under reduced pressure. The residue was subjected to silica gel column chromatography, and 1-
27.8 g of (3,4-dimethoxymethyloxyphenyl)-5-hydroxy-1-tetradecen-3-one is obtained.

After dissolving 19.3 g of titanium tetrachloride in 50 ml of methylene chloride and cooling it to -78°C, 19.3 g of this aldol reaction adduct dissolved in 250 ml of methylene chloride was added dropwise.
Stir at the same temperature for 0.5 hour.

After raising the temperature to room temperature, add 1500 ml of ethyl acetate and 50 ml of water.
Qml is added, the organic layer is separated and the aqueous layer is extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium bicarbonate solution and a saturated saline solution, dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure.

The obtained crude crystals were mixed with ethanol-methylene chloride (3:97
V/V) to obtain 8.33 g of 1-(3,4-dihydroxyphenyl)-5-hydroxy-1-tetradecen-3-one (rv). Spectroscopic data of this product support the structure of formula (IV) below.

'HNMR (DMSO-66): 0, 85 (311,t, J=511z), 1.03-
1.67 (1611, m), 2, 63 (211, d,
J=611z), 3.67-4.10(Ill, m)
, 6.38 (Ill, d, J=1611z), 6.
67-7, 10 (311, m), 7, 33 (ill,
d, J-1,611z) [Synthesis Example 2] Under argon atmosphere, 12°50 g of diinpropylamine
was dissolved in 100 ml of dry tetrahydrofuran, -15
After cooling to °C, 82.37 ml of a hexane solution of 1.6M n-butyllithium was added dropwise, and the mixture was stirred at the same temperature for 10 minutes. After cooling to -78℃, dry tetrahydrofuran 100m
22.58 g of 4-(4-benzyloxy-3-methoxyphenyl)-3-buten-2-one dissolved in 1 was added dropwise, and the mixture was stirred at the same temperature for 40 minutes. To this was added 1 ml of capricaldehyde dissolved in 30 ml of dry tetrahydrofuran.
9.31 g was added dropwise and stirred at the same temperature for 4 hours.

The reaction mixture is diluted with ether, saturated brine is added, the aqueous layer is separated, and the aqueous layer is extracted with ether. Combine the organic layers and add 2N hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution,
After washing with saturated saline and drying with anhydrous magnesium sulfate,
The solvent is removed under reduced pressure.

The residue was subjected to silica gel column chromatography, and 1-(4-benzyloxy-3
18.87 g of -methoxyphenyl)-5-hydroxy-1-tetradecen-3-one are obtained. This one obtained
-(4-benzyloxy-3-methoxyphenyl)-5
-Hydroxy-1-tetradecen-3-one 11.09
g was dissolved in 200 ml of methanol, 1.00 g of 10% palladium on carbon was added, and the reaction mixture was reacted for 15 hours under a hydrogen gas atmosphere. The reaction mixture was then filtered and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography,
From the fraction eluted with methylene chloride, 1=(4-hydroxy-3-
6.10 g of methoxyphenyl)-5-hydroxy-3-tetradecanone ([101-gingerol) are obtained.

Spectroscopic data of this product support the structure of formula (V) below.

IN NMR (CDC13) δ: 0, 88 (3H, t, J=5tlz), 1.05-1
．． 58 (168, m), 2, 50 (21+, d, J
=6112), 2.65-2.95 (411, m), 3
, 79 (311, s), 6.41-6.85 (3
H, m), [Synthesis Example 3] 3.30 g of 1-(3,4-hydroxyphenyl)-5-hydroxytetradecan-3-one and 0.30 g of p-toluenesulfonic acid hydrate were mixed in methanol and benzene. (
1:10 V/V) in 66 ml and heated under reflux for 4 hours.

A saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution, the organic layer was separated, the aqueous layer was extracted with ethyl acetate, the organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure. The residue was subjected to silica gel column chromatography, and 3.00 g of 1-(3,4-dihydroxyphenyl)-4-tetradecen-3-one (Vl) was obtained from the fraction eluted with methanol-methylene chloride (1:9 v/v). get. Spectroscopic data of this product support the structure of the following formula (Vl).

'HNMR (CDCj!s) δ: 0, 86 (3H, t, J=5+1z), 1.03-2
．． 38 ('16 summer 19m), 2, 60-2.90 (4H
, m), 6.08 (Ill, d, J=1611z)
, 6, 28-7.23 (4H, m) [Example 1] Liver damage inhibitory effect (inhibitory effect on galactosamine liver damage) Body weight 200
Galactosamine hydrochloride dissolved in physiological saline (adjusted to pH 7.0) was intraperitoneally administered to male Wistar rats aged around 1.5 g at a rate of 500 mg/kg, and the virus was experimentally transmitted to humans. It caused liver damage similar to that seen in the previous study.

The sample was suspended in a 5% gum arabic solution and administered intraperitoneally at a rate of 100 mg/kg 1 hour before galactosamine administration. Twenty-four hours after galactosamine administration, blood was collected from the abdominal aorta under ether anesthesia. Blood is 3000r
Serum was collected by centrifugation at pm for 15 minutes. Regarding this serum, GOT (glutamate/oxaloacetate transaminase) and GPT (glutamate/pyruvate transaminase), which are indicators of liver damage, were detected using POP-TOO3.
It was measured by the method.

The liver damage inhibition rate was calculated using the following formula. In addition, - group 5 each
Physiological saline was administered in place of the galactosamine solution to the normal group, and a 5% gum arabic aqueous solution was administered in place of the sample to the normal and control groups. The results are shown in Table 1.
Shown below.

Liver damage suppression rate (%) - Normal group value: Normal group serum GOT (GPT) value Control group value: Control group serum GOT (GPT) value Administration group value: Drug administration group serum GOT ( GPT) [Example 2] Suppressive effect on liver damage (suppressive effect on basic liver protein-immunized liver-damaged mice) Mae's method (Hokkaido Medical Journal Vol. 57, p. 491, 1)
Basic liver protein (Basic Liver Prote
inp; BLP) was prepared, and rabbits were immunized with it according to a conventional method to obtain anti-BLP serum.

Next, the method of Mizuben et al. (Inflammation Vol. 6, p. 361, 198)
6), DBA/2 mice were given 0 anti-BLP serum.
85 doses were administered intravenously to induce liver damage based on an immunological mechanism.

The sample was suspended in a 5% aqueous gum arabic solution and anti-BLP
100 twice, one hour before and 24 hours after administering the serum.
It was administered intraperitoneally at a rate of mg/kg.

48 hours after administration of the anti-BLP serum, blood was collected from the abdominal vena cava under ether anesthesia. Serum was obtained in the same manner as in the case of galactosamine liver injury, GOT and GPT were measured, and Example 1
The liver damage inhibition rate was calculated using the same formula. The results are shown in Table 2.
Shown below.

General formula (I) Table 1 General formula RXY Liver damage suppression rate *m
CH3-CH=CH--CI+,
41%47% IV II -CH=C11-011
72%■ -CH2-Cl+-(CH2)8-CI+3 68%V
C113-CH2-Ck-OH79%-CI
+2-C11-(CH2)a-CH379%VI
II -CI+2-CH2--C■=C1l
-(CH2)a-Cl3 67%70% l -C11□-C1l-(CI2)11-CI+3 9
5%V C1+3-CIl□-CH2-OH60
%-CH2-CI-(C112)II-CI+3 6
5% From the results in Tables 1 and 2, it is clear that the gingerol derivatives of the present invention have an excellent liver damage suppressing effect.

[Acute toxicity] The gingerol derivatives shown in Tables 1 and 2 are
Even when 500 mg/kg was administered intraperitoneally to R mice, no toxicity such as weight loss was observed.

[Effects of the Invention] As described above, the gingerol derivative represented by the general formula (I) of the present invention has an inhibitory effect on galactosamine liver damage and basic liver white matter immune liver damage, so it is used as an active ingredient. The drug is effective for liver disorders including viral hepatitis.

Claims (1)

[Claims] (1) General formula (I) ▲Mathematical formulas, chemical formulas, tables, etc.▼(I) [In the formula, R represents a hydrogen atom or a lower alkyl group, and X represents a
-CH_2-CH_2- or -CH=CH-,
Y is a methyl group or -CH=CH-(CH_2)_8
-CH_3 Or, ▲There are mathematical formulas, chemical formulas, tables, etc.▼ Or, ▲There are mathematical formulas, chemical formulas, tables, etc.▼. ]
A drug for the treatment of liver disorders containing the compound shown in the following as an active ingredient.