JPH03287534A - Remedy for liver disease - Google Patents

Abstract

PURPOSE:To obtain the title remedy containing a cyclic dicarboxylic acid imide compound as an active ingredient, excellent in treatment for liver disease, e.g. fatty liver, alcoholic hepatitis of highly active mammal, especially human, having low toxicity and capable of orally administrating. CONSTITUTION:The aimed remedy containing a compound expressed by formula l [A is formula II, formula III (X and Y are H, lower alkyl or halogen; Z is lower alkylidene; dotted line is single bond or double bond) ; R is phenyl which may be replaced by 1-5 groups selected from lower alkyl, hydroxyl group and lower alkoxy group or phenyl replaced by lower alkylene dioxy group; n is 0-3] as an active ingredient. The remedy is used as a solid pharmaceutical preparation for oral administration such as tablet or granule, liquid agent, etc. The compound expressed by formula I and having active ingredient is synthesized by subjecting a compound expressed by formula IV to condensation through dehydration with a compound expressed by formula V.

Description

[Detailed description of the invention] (Industrial application field) This invention relates to a therapeutic agent for liver diseases.

More specifically, this invention provides a highly active nursing product containing a cyclic dicarboxylic acid imide compound as an active ingredient! ! The present invention relates to therapeutic agents for human liver diseases.

<Conventional technology and its challenges> In the liver of asthmatic mammals including humans, a wide variety of complex chemical reactions occur, such as detoxification, sugar metabolism, protein metabolism, lipid metabolism, production and secretion of liver juice, and hormones. regulation, blood coagulation protropin formation, hepatic till cyst formation,
Various essential biological components (fats, carbohydrates, proteins, and vitamins) are stored. The liver, which performs such complex physiological functions, is sometimes damaged acutely or chronically by various factors such as alcohol, nutritional deficiencies, viral infections, and chemical toxins, resulting in liver necrosis, fatty liver, and hepatic fluid. It causes diseases such as secretion disorder and liver cirrhosis. Glycyrrhizin is known as a drug that is widely used for the treatment and prevention of these diseases.Although this glycyrrhizin is effective for liver damage, liver cirrhosis, hepatitis, liver protection after surgery, etc., its medicinal efficacy is limited. It has the limitation that it is only approved for intravenous administration and has no medicinal efficacy when administered orally.

Therefore, there has been a strong desire to develop a drug that is effective when administered orally.

Under these circumstances, the inventors of the present invention conducted extensive research for the purpose of developing a liver disease treatment agent with even better efficacy and practicality, and found that the compound represented by the following general formula (n) It has already been discovered that oral or parenteral administration to various disease model animals brings about a remarkable effect of suppressing or improving liver function decline (Japanese Patent Application Laid-Open No. 1983-1999 (in the formula, -Am is a succinimide compound). bonded to two carbon atoms denoted as α and β in
Formula (wherein, R1 represents a lower alkyl group) (wherein, R2
and R> is a lower alkyl group (in the formula, -B- represents a -〇- bond or a lower alkylene bond) (in the formula, R4 represents a lower alkyl group) The present invention provides a therapeutic agent for liver diseases containing an active ingredient.

Indicates a cyclic group represented by , or a double bond formed together with an existing single bond between α and 8.

In addition, X and Y each represent a halogen atom.) However, in the case of these cyclic dicarboxylic acid imide compounds, subsequent studies revealed that any one of them does not necessarily have the desired level of physiological activity. It's becoming clear.

This invention was made based on the results of subsequent more detailed studies, and is a new highly active drug for liver diseases in mammals, especially humans, that exceeds the levels of the previously known dicarboxylic acid imide compounds. The purpose is to provide therapeutic agents.

(Means for Solving the Problems) The present invention solves the above-mentioned problems, in which A, R and n represent the following.

A: Formula X, Y: Same or different hydrogen atom, lower alkyl group,
Halogen atom Z: lower alkylidene group...: single bond or double bond R: phenyl group optionally substituted with 1 to 5 groups selected from lower alkyl groups, hydroxyl groups and lower alkoxy groups, Phenyl group substituted with lower alkylene dioxy group neo~3> Here, as the lower alkyl group of the above substituents X and Y,
Methyl, ethyl, and propyl groups having 1 to 3 carbon atoms, chlorine, bromine, and iodine atoms as halogen atoms, and methylidene, ethylidene, and propylidene groups having 1 to 3 carbon atoms as 2 lower alkylidene groups, R Examples of lower alkyl groups include methyl, ethyl, and propyl groups having 1 to 3 carbon atoms;
Examples of lower alkoxy groups include methoxy, ethoxy, and propoxy groups having 1 to 3 carbon atoms, and examples of lower alkylenedioxy groups include methylenedioxy, ethylenedioxy, and propylene dioxy groups having 1 to 3 carbon atoms. I can do it.

The above formula (I) which is an active ingredient in this liver disease therapeutic agent
The dicarboxylic acid imide compound is essentially different from the known compound of the above formula <n) in that this known compound has a dihalogen-substituted phenyl group as an essential requirement; In the case of the compound of formula (I) of the invention, the number of substituents and their positions also correspond to formula (n).
They are also different in that they do not have any special limitations like the known compounds.

Specific examples of the dicarboxylic acid imide compound as an active ingredient used in the therapeutic agent for liver diseases of the present invention include the following compounds.

N-(2,6-dimethylphenyl)-2-methylmaleimide, N-(2,6-dimethylphenyl)-itaconimide, N-(2-methylphenyl)-2-methylmaleimide, N-(3,5- dimethylphenyl)-2-methylmaleimide, N-(2-ethyl-6-methylphenyl)-2-methylmaleimide, N-(2,6-dimethylphenyl)-2-methylmaleimide, N-<2.4. 6-drimethylphenyl)-2-methylmaleimide, N-(4-hydroxy-2-methylphenyl)-2-methylmaleimide, N-(3,5-dimethoxyphenyl)-2-methylleimide, N-(2 ,6-dimethylphenyl)-2,3-dimethylmaleimide, N-(2,6-dimethylphenyl)-2,3-dichloromaleimide, N-phenyl-2-methylmaleimide, N-(3-methylphenyl) -2-methylmaleimide, N-(2,3-dimethylphenyl)-2-methylmaleimide, N-(2-ethyl-6-methylphenyl)-2-methylmaleimide, N-(2-phenylethyl)-2 -Methylmaleimide, N-(2-hydroxy-5-methylphenyl)-2,3
-dichlormaleimide, N-(3-hydroxyphenyl)-2,3 dichlormaleimide, N-(4-hydroxy-2-methylphenyl)-23-
Dichlormaleimide, N-(3-phenylglobil)-2,3-dichlorsuccinimide, N-(2-phenylethyl)-2-bromomaleimide, N-<2.6-dimethylphenyl>-2-chlor Maleimide, N-<3,4-methylenedioxyphenyl)-succinimide, N-(3,4-methylenedioxyphenyl)-23-dichloromaleimide, N-(2-phenylethyl)-2,3dichlor maleimide, N-<2-phenylethyl)-itaconimide.

The dicarboxylic acid imide compound represented by the formula (I) of the present invention can be produced by any method including known methods, for example, the following formula (1) % formula % (1 [) It can be produced by dehydration condensation with the compound NV).

In this reaction, it is preferable to use a solvent, and suitable solvents include acetic acid and lower fatty acids with 10 pionic oxygen atoms. Furthermore, when the reaction is carried out using an aromatic liquid compound such as benzene or toluene, a halogenated hydrocarbon such as chloroform or chlorobenzene, or a ketone such as acetone or methyl ethyl getone as a solvent, the reaction product is in the form of a monoamide. The desired general formula can be obtained by heat treatment or using an acidic catalyst such as p-toluenesulfonic acid, WR acid, or hydrochloric acid, a basic catalyst such as sodium acetate or triethylamine, or a dehydration catalyst such as acetic anhydride or thionyl chloride. A compound represented by (I) can be obtained.

The compound represented by formula (I) above has extremely low toxicity to humans and mammals.

The compound represented by formula (I) above is carbon tetrachloride,
Oral administration of drugs such as D-galactosamine, α-naphthylisocyanate, and ethionine to test animals with liver damage in various pathological models created experimentally results in a marked decline in liver function. It has a suppressive or ameliorating effect.

The therapeutic agent of the present invention is administered orally to adults as a compound represented by the formula (I) to 1 to 30 μ/dimension weight 7
Administer in 1 to 3 divided doses per day. This dose is
The dosage can be increased or decreased as appropriate depending on the age, weight, and symptoms of the patient.

In addition, the therapeutic agent of the present invention can be prepared by diluting and dispersing the compound represented by the general formula (I) using a commonly used carrier to prepare a solid form for oral administration such as tablets, granules, powders, and capsules. It can be used as a liquid preparation for oral administration such as a preparation, solution, suspension, or emulsion.

Carriers that can be used to prepare solid preparations for oral administration include:
Excipients such as lactose, glucose, crystalline cellulose, mannitol, corn starch, sugar, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, carboxymethyl cellulose, binders such as polyvinyl alcohol, gelatin, gum arabic, wetting agents such as glycerin, ethylene glycol, corn Disintegrants such as starch, potato starch, calcium carboxymethylulose, and low-substituted hydroxypropylcellulose, lubricants such as calcium stearate, magnesium stearate, talc, polyethylene glycol, and hydrogenated oil, and other surfactants as necessary. Agents, colorants, seasonings, etc. can be used.

Diluents that can be used to prepare liquid preparations for oral administration include water, ethanol, glycerin, propylene glycol, polyethylene glycol, agar, tragacanth, and, if necessary, solubilizing agents, buffers, preservatives, fragrances,
Coloring agents, flavoring agents, etc. can be used.

(Example) Hereinafter, the present invention will be specifically explained by giving synthesis examples, examples, and test examples of six compounds represented by formula (I).

Synthesis Example> Synthesis of N-(2,6-dimethylphenyl)-2-methylmaleimide 2-methylmaleic anhydride and 2,6-dimethylaniline were refluxed in equimolar ratios in 100 ml of acetic acid for 4 hours. and reacted. After cooling, 1j of water was poured, and the precipitated crude crystals were collected and recrystallized from ethanol to obtain the desired product (compound (1)). The melting point of this compound (1) was 114-116°C.

In the same manner, the following compounds (2) to (14) were synthesized and their melting points were measured.

Melting point (''C) Example 1 300 g of compound (1), 60 g of crystalline cellulose, and 63 g of corn starch were mixed to form a uniform mixed powder, and granules were prepared by wet granulation using 22 g of hydroxypropyl cellulose as a binder. .

This was mixed with 5 g of magnesium stearate and then tableted to obtain tablets with a diameter of 8 o 1 ml and a weight of 300 cm.

Example 2 600 g of compound (4), 150 g of crystalline cellulose, 140 g of corn starch, and 10 g of magnesium stearate were uniformly mixed.

This mixed powder was filled into No. 1 hard capsules at a rate of 300 square centimeters per capsule to obtain capsules.

Kneeling Example 3 400 g of compound (7), 60 g of mannitol, and 900 g of corn starch were mixed to form a uniform mixed powder, and granules were prepared by wet granulation using 100 g of hydroxypropyl cellulose as a binder to obtain granules. Ta.

Example 4 Compound (12) 200. A powder was prepared by uniformly mixing 800 g of lactose, and the powder was packaged into 1000 ml portions.

Test Example 1 [Effect on carbon tetrachloride-induced acute liver injury] ICR male neutral mice 6 weeks old, weight 30 g > 1 group 8-10
The animals were used for the test. A specimen was suspended in a 5% gum arabic solution, test drugs of various concentrations were prepared, and a 5% gum arabic solution was used as a control group. 10 μ/kir of the test drug and 10 ml/kg body weight of a 5% gum arabic solution were orally administered to individual animals, and after standing for 60 minutes, 0.03 ml of a carbon tetrachloride solution diluted with olive oil was administered! /kg was administered orally.

After leaving the animal for 18 hours, blood was collected from the animal under ether anesthesia, and after centrifugation, the serum GPT value was measured using a fully automatic biochemical analyzer! <Hitachi, 7
150). The hepatoprotective effect was determined by the inhibition rate against serum GPT in the control group.

The results are shown in Table 1.

Table 1 Test drugs of various concentrations were prepared by suspending them in a gum arabic solution, and a 5% gum arabic solution was used as a control group.

100 μ/kg body weight of the test drug and 5% gum arabic solution were orally administered to individual animals, and after being left for 30 minutes, D-galactosamine 300 w/kg was solubilized in purified water and adjusted to pH 7.0. kg was administered intraperitoneally. After leaving the animal for 24 hours, blood was collected from the animal under ether anesthesia, and after centrifugation, the serum GPT value was measured using a fully automatic biochemical analyzer (Hitachi 7150). The hepatoprotective effect was determined by the inhibition rate against serum GPT in the control group. The results are shown in Table 2.

Comparative Example 1 is based on the formula (
Comparative Example 2 shows a compound of the following formula among the compounds of It), and Comparative Example 2 shows a commercially available compound of the following formula, n1160-61°C, pale yellow crystals, isobrothiolane, a drug for paddy blast disease. It was discovered during research and has the effect of promoting protein metabolism in liver cells.
It was developed as a treatment for chronic liver disease.

Test Example 2 [Effect on galactosamine-induced acute liver injury] Wistar male rats (born T & 8 weeks old, body weight approx. 200 g)
) One group of 6 animals was used for the test. Table 1 Test Example 3 [Acute Toxicity Test] Ten ICR mice (5 weeks old, weight 25 g) were subjected to the test. According to Test Example 1, a sample containing compound (1) in a 5% gum arabic solution was prepared. Compound < 1
) 100 kg/kg was orally administered to animals, and the presence or absence of death was observed for the first day of administration.

As a result, no deaths were observed. Therefore, L D s upon oral administration of compound (1). The value is 1000■/
It was more than kg.

(Effects of the Invention) As explained in detail above, the compound of the present invention represented by formula (I) can be used to treat acute or chronic liver diseases in humans and mammals caused by various causes, such as fatty liver and alcoholic hepatitis. The present invention, which has an excellent effect on the treatment of toxic liver disorder, congestive liver disorder, cholestatic liver disorder, or liver cirrhosis, which is the terminal stage thereof, and which contains a compound represented by the formula (I>) as an active ingredient. The therapeutic agent can be used as a therapeutic agent for these liver diseases.

Claims (1)

[Claims] (1) A liver disease therapeutic agent containing a compound represented by the following formula (I) as an active ingredient. ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (I) (A, R, and n in the formula indicate the following. A: Formula ▲There are mathematical formulas, chemical formulas, tables, etc.▼ or ▲Mathematical formulas, chemical formulas, There are tables, etc.▼ phenyl group optionally substituted with 1 to 5 of the following, phenyl group substituted with lower alkylenedioxy group n: 0 to 3).