WO1992010176A1

WO1992010176A1 - Therapeutic agent for hepatic disease

Info

Publication number: WO1992010176A1
Application number: PCT/JP1991/001700
Authority: WO
Inventors: Susumu Otomo; Shohei Higuchi; Iwao Arai; Michihiro Ohnaka; Shugo Matsuno; Mari Misawa
Original assignee: Taisho Pharmaceutical Co., Ltd.; Nippon Zeon Co., Ltd.
Priority date: 1990-12-07
Filing date: 1991-12-07
Publication date: 1992-06-25

Abstract

A therapeutic agent for hepatic diseases, which contains a malonic acid derivative represented by the general formula (I) as the active ingredient. In said formula, A represents hydrogen, or an optionally substituted lower aliphatic, cycloaliphatic, aromatic or heterocyclic group; R1 represents lower alkoxy or halogenated phenyl; R2 represents lower alkyl; and n represents a number of 0 or 1.

Description

Description Liver disease therapeutic agent Technical field

The present invention relates to a therapeutic agent for liver disease. More specifically, the present invention relates to a therapeutic agent for a liver disease of a highly active mammal, particularly a human, comprising a malonic acid derivative as an active ingredient.

Background art

In the liver of humans and other mammals, complex and diverse chemical reactions, such as detoxification, sugar metabolism, protein metabolism, lipid metabolism, bile production and secretion, hormonal regulation, blood coagulation prothrombin formation, liver Cell regeneration and storage of various vital components (fat, carbohydrate, protein, and vitamin) are being carried out. The liver, which has these complex physiological functions, is sometimes acutely or chronically damaged by alcohol, malnutrition, viral infection, and various factors of chemical toxins, resulting in hepatic necrosis and fat. It causes hepatic and biliary disorders and cirrhosis. Glycyrrhizin is known as a drug widely used for the treatment and prevention of these diseases, but this glycyrrhizin is effective for liver damage, cirrhosis, hepatitis, liver protection after surgery, etc. However, its efficacy was observed only by intravenous administration, and no efficacy was demonstrated by oral administration. There is a restriction that.

Therefore, the development of a drug that is effective by oral administration has been strongly desired.

In such a situation, various therapeutic agents for liver diseases that can be orally administered have been proposed. However, any of these conventional drugs useful for oral administration have a desired physiological level. At present, it has no activity.

The present invention has been made in view of such circumstances, and has been developed to provide a new drug that is more active than the conventionally proposed therapeutic agent for liver disease and is effective for treating liver disease in mammals, particularly humans. It is intended to provide.

Disclosure of the invention

The present invention solves the above-mentioned problem by providing a formula (I)

^ CO a

A-NH- (NH) n-C H = C (I)

, C 0 0.R ₂

(A in the formula represents a hydrogen atom, a lower chain aliphatic group, a cycloaliphatic group, an aromatic ring group or a heterocyclic group, and when A is other than a hydrogen atom, it may have a substituent. Represents a lower alkoxy group or a halogenated phenyl group, R ₂ represents a lower alkyl group, and n represents a number of 0 or 1.)

Characterized by the malonic acid derivative represented by A therapeutic agent for liver disease.

Examples of the lower-chain aliphatic group of A include a lower alkyl group such as a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isopropyl group, a tert-lipyl group, a vinyl group, and a butyl group. Examples thereof include lower alkenyl groups such as benzyl group, butenyl group and crotyl group, and lower alkynyl groups such as 1-propynyl group, propargyl group and butynyl group. Of these, a lower alkyl group and a lower alkenyl group are preferred.

Examples of the cycloaliphatic group for A include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, norbornyl and the like. .

Examples of the aromatic ring group of A include a phenyl group, a naphthyl group, a tetrahydronaphthyl group, an indanyl group and the like. Of these, a phenyl group and a tetrahydronaphthyl group are preferred.

Examples of the heterocyclic group of A include pyrrolidinyl, pyridyl, pyrimidyl, imidazolyl, benzoimidazolyl, triazolyl, benzotriazolyl, oxazolyl, Examples include a benzoxazolyl group, an oxazinyl group, a thiazolyl group, a benzothiazolyl group, and a thiazinyl group. Of these, a thiazolyl group and a benzothiazolyl group are preferred.

In addition, when A is other than a hydrogen atom, it has a substituent May be. Examples of the substituent include halogen atoms such as chlorine, bromine, iodine, and fluorine atoms, lower alkyl groups such as methyl, ethyl, propyl, isopropyl, butyl, and isobutyl groups, methoxy, ethoxy, isopropoxy, butoxy, and the like. Lower alkoxy groups such as isobutoxy group, chloromethyl, chloroethyl, bromomethyl, dichloromethyl, fluoromethyl, trifluoromethyl, chlorofluoroethyl, halogenated alkyl groups such as methoxymethyl group, methylenedioxy, ethylenedioxy, petylenedioxy Examples thereof include a lower alkylenedioxy group such as a group.

The lower alkoxy group of R bonded to the carbonyl group is a methoxy, ethoxy, propoxy, isopropoxy, butoxy, or isobutoxy group having 1 to 4 carbon atoms, and the halogenated phenyl group is chlorine, bromine, or iodine. , With 1 to 5 fluorine atoms bonded, for example, 2-chlorophenyl, 4-chlorophenyl, 2,3-dichlorophenyl, 2-bromophenyl, 2-odophenyl, 2-fluorophenyl, 2,4-difluorophenyl, zoヽ⁰ —Fluorophenyl group power << exemplified. Examples of the lower alkyl group of R ₂ constituting the ester bond include a methyl, ethyl, propyl, isopropyl, butyl, isoptyl and tertiary butyl group having 1 to 4 carbon atoms.

BEST MODE FOR CARRYING OUT THE INVENTION

As an active ingredient used in the therapeutic agent for liver disease of the present invention, Specific examples of the malonic acid derivative include, for example, the following compounds when classified according to the characteristics of the above A.

1) A: hydrogen atom

Jechil Hydra Zino Methylen Malonate,

Jechil Amino Mem Lenmaronet

2) A: lower chain aliphatic group

Jetyl normal propyl urea mino methylene malonate, Jetil tertiary butyl hydrazino dimethylene malonate,

Jethyl crotyl hydra-dino-methylene malonate, Jethil propargyl hydra-dino-methylen malonate,

3) A: Cycloaliphatic group

Getyl cyclopropirua minomethylenmaronete, getyl cyclopropyrudra drazinomethylenmaronete,

Getyl cyclohexylaminomethylamine malonate, getyl cyclohexinolehydra dino dimethylenemalonate,

Jetyl norebornyla minomethylenmalonate, Jetyl norbornylhydra dinomethylenmalonate, Jetyl cyclohexenylaminomethylenmalonate, 1-c. 1-fluorophenylcarbonyl 1 1-ethoxycarbonyl-2-yl cyclopropirua ,

A) A: Aromatic ring group 'Jetylphenylaminomethylenemalonate, Jethylphenylhydrazinomethylenemalonate, Dimethyl 2 -chloronophenylphenylaminomethylenemalonate,

Getyl 2—chloronophenylaminomethylenmalonate,

Getyl 2-chlorophenylhydra dino methylenmalonate,

Jetil 41-Chlorophenylaminomethylenmalonate,

Jetil 4-chlorophenylhydra dino methylenmalonate

Diisopropyl 4—chlorophenylhydrazino methylmalonate,

Dimethyl 4-bromophenylaminomethylmalonate,

Getyl 2-promophenylaminomethylene malonate,

Jetil 4—Promoenilua Mino Methylene Malonet,

Getyl 4 monofluorophenyl hydrazino methyl lemma ronet, Getyl 2,4—difluorophenylhydra dinomethylenemaloneate,

Zinolmarbro pill 2 — eodofenylamino melamine malonate,

Getyl 3,4-dichlorophenylaminomethyl methacrylate,

Getyl 3, 4 — dichlorfenyl hydra dino methylene maloneto,

Jetil 2 — methyl diaminoaminomethylamine ronate,

Jethil 3 — methylenilaminomethylamine ronate,

Jetil 4 — methylenilaminomethylmalonate,

Jethil 2 — methyl hydrhydrazino methyl lemmalonate,

Jetil 4 — methyl phenyl hydrazino methylene malonate,

Jetil 4 ethylamine aminomethylamine ronate,

Dimethyl 4—Nozolemalpropyruenilamine

Dimethyl 2 — Methoxif Enilua Mino Methylene Lemone

One, Dimethyl 4-methoxyphenylamine

Ethyl methyl 2—Ethoxyphenyl inomethylene malonate,

Jethil 2 — methoxypheniramine

One,

Jetil 4-Methoxyphenylhydra dinomethylen

Jethil 4—Cloflemetylphenylaminomethylene malonet,

Jechir 4 Fluorometyl phenylamine Minome Tylene malonate

Jetil 4 — Trifluoremyl phenylamine amino lemmalonete,

Jethil 2 — Trifluorome thiphenylalumino lemmaronet,

Getyl 3,4—methylenedioxyphenylaminomethylethylenemalonate,

1-Perfluorophenylcarbonyl-1-1-ethoxycarbonyl-2-yl (2-chlorophenyl) aminonethylene,

1-Chloronolephenylcarbonyl-1- (ethoxyethoxycarbonyl) -2-((4-fluorophenyl) aminoethylene, 1-ha. 1-ethoxycarbonylcarbonyl 2- (2,4-difluorophenyl) hydrazinoethylene,

Getyl 1 Naphthylaminomethylenmalonate, Getyl2—Naphthylaminomethylenmaronate, Getyl 1— (5,6,7,8—Tetrahydronaphthyl) Aminomethylenmalonate,

Jetil 1 — (5, 6, 7, 8 — Tetrahydronaftyl) hydra dinomethylenmalonate,

Jetyl 5—Indanylaminomethylenmalonate,) A: Heterocyclic group

Getyl 4—pyrrolidinylaminomethylenemalonate, Jethil 41-pyridylaminomethylenemalonate, Jetil 2—chloro-1 4—pyridylylaminomethylenemalonate,

Getyl 2 — Pyridylhydra dinomethylenmalone, Getyl 4 — Pyridylhydra dinomethylenmalonate, Getyl 2 — Pyridimidinylmethylenmalonate, Dimethyl 2 —Benzimidazolidhidra dinomethylenmalonate,

Dimethyl 3 — triazolinoleuminomethylenmalonate, Jetyl 3 —benzotriazolinylaminomethylenmalonate,

Diisopro pill 2 —oxazoli rua Net,

Getyl (3-chloro-1-oxazolyl) amino methylenmalonate,

Getyl 2-benzoxazolyl alumino methylenmalonate,

Getyl 2—Benzoxazoli Ruhi Drazino Methylene Malonate,

Dimethyl 2-thiazolyl amino methylene malonate, Jetyl 2-thiazolyl amino methylene malonate, Jetyl (3- chloro-1- 2-thiazolyl) amino methylene malonetone,

Getyl 2—Venzothiazolyl Mino Methylene Malonet,

Getyl 2-benzothiazolyl hydra dino dimethylene ronet,

Getyl 2—thiazinylaminomethylenemalonate, 1—perfluorophenylcarbonyl 1—ethoxycarbonyl-2-yl (2-pyrimidinyl) amine Such malonic acid derivatives are, for example, getyl 2-benzo Thiazolyl amino methylene manage and getyl 2 monobenzothiazolyl hydrazinomethylene malonate are useful as active ingredients of therapeutic agents for liver diseases.

The malonic acid derivative represented by the formula (I) according to the present invention is known in the art. It can be manufactured by any method including the method described above. For example, the expression (Π)

A-NH- (NH) _N -H (Π) and formula (m)

X-CH = C (m)

, C 00R ₂

(X is a group having a reactivity such as an alkoxy group). This reaction is carried out without solvent or in the presence of an inert solvent. Examples of the inert solvent include aromatic hydrocarbons such as benzene and toluene, halogenated hydrocarbons such as chloroform and chlorobenzene, dimethylformamide, dimethylsulfoxide, and ethanol. it can.

The compound represented by the formula (I) has extremely low toxicity to human mammals. In addition, the compound represented by the formula (I) is useful for the treatment of various disease models experimentally created by administration of drugs such as carbon tetrachloride, D-galactosamine, α-naphthyl isocyanate, and etyonin. When administered to a test animal with a disability, it has a significant effect of suppressing or improving liver function. 1700 The therapeutic agent of the present invention can be used as a compound represented by the formula (I) in an amount of 0.1 to 30 nigZ 1 ^ body weight Z day 1 to 3 per day when administered orally to an adult. Administer in divided doses. This dose can be adjusted appropriately according to the patient's age, weight, and symptoms.

The therapeutic agent of the present invention is obtained by adding a conventional carrier to the compound represented by the formula (I) by a conventional method, and preparing a solid preparation for oral administration such as tablets, granules, powders and capsules, a liquid preparation and a suspension. It can be used by preparing it into a liquid preparation for oral administration or parenteral administration such as a turbidity agent, an emulsion or an injection.

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 methylcellulose, carboxymethyl. Binders such as cellulose, polyvinyl alcohol, gelatin, and gum arabic; wetting agents such as glycerin and ethylene glycol; corn starch, potato starch, calcium carboxymethyl cellulose, low substitution degree Disintegrants such as hydroxypropylcellulose, lubricants such as calcium stearate, magnesium stearate, talc, polyethylene glycol, hydrogenated oil, etc., and other surfactants and coloring agents as required Use of seasonings, etc. It can be.

Diluents that can be used to prepare liquid preparations for oral administration include: Water, ethanol, glycerin, propylene glycol, polyethylene glycol, agar, tragacanth, etc.Use dissolution aids, buffers, preservatives, fragrances, coloring agents, seasonings, etc. as necessary. be able to.

Example

Hereinafter, synthesis examples, examples and test examples of the compound represented by the formula (I) will be shown, and the present invention will be described in more detail.

Synthesis example

Synthesis of getyl 2-chlorophenylamino methylene malonate

To a reactor equipped with a cooling tube were added 4.3 g of ethoxymethylene malonate gel and 2.6 g of 2-chloroaniline, and the mixture was stirred at 140 ° C. for 2 hours in a filter bath. After cooling, the solidified crude product was recrystallized by adding n-hexane. 3.2 g of the target compound of the formula (I) was obtained.

Similarly, the following compounds (2) and (2 3) were synthesized, and the melting points were measured.

Melting point 79 ~ 80 ° C

Melting point 42 ~ 4 3 ° C

CH: Melting point 38-39 ° C

CH. Melting point 6 2〜6 3 ° C

OCH. Melting point 4 7〜 4 8 ° C

Melting point 66-68 ° C

Melting point 45-47 ° C

Melting point 1 1 5 7. C

Melting point 105-106 ° C

Melting point 95.5 ~ 97 ° C

(1 5)

Melting point 1 1 1.5 to 1 13 ° C

Melting point 1 2 8 to 130 ° C CH ₃

I

COOCH

\

CH ₃

Melting point 1 3 3 to 1 3 4 ° C

C 00 C 2 H

CH≤C-NH-NH-CH = C

(1 8)

C 00 C 2 H Melting point 67-70 ° C

C00C ₂ "

H 2 N-NH— CH = C <(1 9)

C 00 C 2 H 5

Melting point 96 ~ 97 ° C (Ρ · Ήί) OS 'Π

(Ρ ΉΙ) S8 '8

(P 'HI)' i

(Ρ Ήί) 56 '9

(b Ή) SO Ί

(1 ') WI ■ 9

(SWJ, / ^€ 10α3) ΗΗΝ-Η

ο. s8〜ο8

(Ρ ΉΙ) OS Ι

(Ρ ΉΙ) SE "8

: ω ') 86 '09 .9

(s 'J' HI) U .9

(b Ή) ZO "i- (1 'U) U Ί: 9

/ ^ε ιοαο) mw

. [~ Ε τ τ ^ 賴

H ^z 3 oo α

I0 / I6df / JOd 81 9 I0I / 36 OM

1 H-NMR (CDC / TMS)

5: 1.20 (3H, t)

1.25 (3H, t)

1.4 (! ~ 2.10 (10H, m)

3.00-3.20 (IH, m)

4.05 (2H, q)

4.15 (2H, q)

8.00 (IH, d)

9.00 (IH, br.d)

i6 U091 // d iledfJD

CO CM cr

«G

tE3

O

CM

Example

Compound (1) 200 g, microcrystalline cellulose 40 g, and corn starch 40 g were mixed to form a uniform mixed powder, and 15 g of hydroxypropyl cellulose was used as a binder, and wet processing was performed. Granules were prepared by a granulation method.

After mixing with 3 g of magnesium stearate, the mixture was tableted to give tablets having a diameter of 9 mm and a weight of 30 Omg.

Example 2

600 g of compound (5), 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 a No. 1 hard strength tablet at a dose of 300 mg per capsule to obtain a capsule.

Example 3

Compound (6) (200 g), mannitol (300 g), and corn starch (450 g) were mixed to form a uniform mixed powder, and hydroxypropyl cellulose (50 g) was bound. Granules were prepared by a wet granulation method as granules to obtain granules.

Example 4

A powder was prepared by uniformly mixing 400 g of the compound (9) and 1500 g of lactose, and the powder was divided into 100 mg each to obtain a powder.

[Effects on Acute Liver Injury Induced by Carbon Tetrachloride in Mice] Test Example 1 1 CR male mice (7 weeks old, weighing about 30 g) were tested in groups of 8 to 10 mice. The test drug was prepared at a concentration of 1 OmgZnii by suspending the sample in 5% Arabia gum solution.

The test drug (10 nilZkg body weight) was orally administered to each group of animals (100 iu / kg body weight), and after standing for 60 minutes, a 0.3% carbon tetrachloride oil solution (10 ml Zkg body weight) was orally administered. Was administered.

After standing for 24 hours, the animals were bled under ether anesthesia and centrifuged, and then the GPT value of the serum was measured with a fully automatic biochemical analyzer (B150).

As a control, 1% OmlZkg body weight of a 5% arabia gum solution was orally administered to animals in a separate group, and the GPT value of the serum was measured according to the treatment described above.

The hepatoprotective effect was determined based on the rate of inhibition of serum GPT in the control group that increased.

Test drug G P T rise Test drug G P T rise

Compound suppression rate% Compound suppression rate%

1 83.1 1 0 63, 1

3 89.8 2 0 94.6

5 63.6 2 1 100.0

7 69.3 2 2 72.5

8 85.3 1 1 95.5

9 Π. 6 Test example 2

The test drug 1 OmlZkg body weight was orally administered to a separate group of animals (3 OmgZkg body weight) in the same manner as in Test Example 1 except that the test drug was prepared so that the sample concentration was 3 mgZml. In the same manner, the serum GPT value was measured.

[Effect of rats on carbon tetrachloride-induced acute liver injury]

Test example 3

The test was conducted with 6 rats of a male Wister line (8 weeks old, weighing about 200 g) in one group. The test sample was suspended in 5% Arabia gum solution to prepare a test drug with a concentration of 10 mgZml.

Test drug 5 mlZkg body weight was orally administered to each group of animals (10 OmiZkg body weight), left for 60 minutes and then 10% tetrachloride 5 ml Zkg body weight of carbon oil solution was orally administered.

After standing for 24 hours, the animals are bled under ether anesthesia, centrifuged, and serum GPT values are measured using a fully automated biochemical analyzer (Hitachi 7

150).

As a control, 5 ml of a 5% arabic gum solution was orally administered to a separate group of animals at 5 ml Zkg body weight.

GPT values were measured.

[Effect on colorectosamin-induced acute liver injury]

Test example 4

Male Wistar rats (8 weeks old, weighing about 200 g) were subjected to the test with 6 rats per group. The test drug was prepared at a concentration of 2 O mgZmi by suspending the sample in a 5% arabia gum solution.

Test drug 5 ml ZJcg body weight was orally administered to each group of animals (10 O mgZkg body weight), and after standing for 30 minutes, D-galactosamine solubilized in purified water and adjusted to pH 7.0 was added. It was intraperitoneally administered to give 300 mg / kg body weight. After standing for 24 hours, the animals were bled under ether anesthesia, centrifuged, and the GPT value of the serum was measured with a fully automatic biochemical analyzer (Hitachi 710). one

As a control, 5 ml 1Z kg body weight of a 5% arabia gum solution was orally administered to animals in separate groups, and the GPT value of the serum was measured according to the treatment described above.

Test example 5

Prepare the test drug so that the concentration of the sample is 10 mg / ml. Except for the test drug, 5 mlZkg body weight is orally administered to each animal in a separate group in the same manner as in Test Example 4 except that the test drug concentration is 10 mg / ml (5 OmgZkg body weight). Thereafter, the same treatment was performed, and the GPT value of the serum was measured.

As a control, 5 in lZkg body weight of a 5% arabia gum solution was orally administered to animals in separate groups, and the GPT value of the serum was measured according to the treatment described above.

The hepatoprotective effect was determined by the rate of inhibition of serum GPT in the control group that increased. Destroyed-^ rz GPT Uvi iv Jrtb GP Ding up

Compound suppression rate% Compound suppression rate%

1 2 48.5 1 9 7 4

1 4 47.8 1 7 58.8

1 5 45. 3

[Acute toxicity]

Test example 6

Ten ICR mice (5 weeks old, weighing about 25 g) were provided for the test as a group. A specimen containing Compound 16 and Compound 13 was prepared in a 5% arabia gum solution, and 500 mg / kg of the specimen was orally administered to the animals, and the presence or absence of death for 14 days after the administration was observed.

As a result, no deaths were observed at 500 mg / kg by oral administration. Therefore, LD _{5 for} oral administration of the test drug. A value of 500 mg / kg or more was judged to be very stable.

Industrial applicability

The compounds of the present invention represented by formula (I) are useful for treating acute or chronic liver diseases in humans caused by various causes, such as fatty liver, alcoholic hepatitis, toxic liver injury, and depression. It has an excellent effect on the treatment of blood liver, cholestatic liver injury or cirrhosis which is the terminal image thereof, and the therapeutic agent of the present invention containing a compound represented by the formula (I) as an active ingredient has been described above. It can be used as a therapeutic agent for liver diseases.

Claims

The scope of the claims

1. Formula (I)

A-NH- (NH) n -CH = C (I)

COOR ₂

(In the formula, A represents a hydrogen atom, a lower chain aliphatic group, a cycloaliphatic group, an aromatic ring group or a heterocyclic group, and when A is other than a hydrogen atom, it may have a substituent. A liver disease characterized by comprising a malonic acid derivative represented by a lower alkoxy group or a halogenated phenyl group, R ₂ being a lower alkyl group, n being 0 or 1.) as an active ingredient. Therapeutic agent.

2. A therapeutic agent for liver disease, characterized in that in the formula (1), A is a hydrogen atom, a lower chain aliphatic group or a cycloaliphatic group, and the malonic acid derivative according to claim 1 as an active ingredient.

3. A therapeutic agent for liver disease, comprising the malonic acid derivative according to claim 2 as an active ingredient, wherein R 1 is a lower alkoxy group.

4. A therapeutic agent for liver disease, comprising the malonic acid derivative according to claim 3 wherein n is 0 as an active ingredient.

5. A therapeutic agent for liver disease, comprising the malonic acid derivative according to claim 3 as an active ingredient, wherein n is 1.

6. A therapeutic agent for liver disease, characterized in that, in the formula (I), A is an optionally substituted aromatic ring group, which comprises the malonic acid derivative according to claim 1 as an active ingredient.

7. A remedy for liver disease comprising the malonic acid derivative according to claim 6, wherein the aromatic ring group is a phenyl group or a tetrahydronaphthyl group.

8. A therapeutic agent for liver disease, comprising a malonic acid derivative according to claim 6, wherein the substituent is a halogen atom, a lower alkyl group, a lower alkoxy group, a halogenated alkyl group, or an alkylenedioxy group.

9. A therapeutic agent for liver disease, comprising the malonic acid derivative according to claim 6, wherein R α is a lower alkoxy group.

7. A therapeutic agent for liver disease, comprising as an active ingredient the malonic acid derivative of claim 6 which is a phenyl group that is strongly hydrogenated.

7. A therapeutic agent for liver disease, comprising the malonic acid derivative of claim 6 as an active ingredient, wherein n is 0.

2. A therapeutic agent for liver disease, comprising as an active ingredient the malonic acid derivative according to claim 6, wherein n is 1.

3. A therapeutic agent for liver disease, characterized in that in the formula (I), A is a heterocyclic group, and the malonic acid derivative according to claim 1 as an active ingredient.

4. The claim wherein the heterocyclic group contains a nitrogen atom and a sulfur atom. A therapeutic agent for liver disease, comprising a malonic acid derivative of 13 as an active ingredient.

5. A therapeutic agent for liver disease, comprising the malonic acid derivative according to claim 13 as an active ingredient, wherein the heterocyclic group is a thiazolyl group.

6. A therapeutic agent for liver disease, comprising the malonic acid derivative according to claim 13 as an active ingredient, wherein the heterocyclic group is a benzothiazolyl group.

7. A therapeutic agent for liver disease, comprising the malonic acid derivative according to claim 13 as an active ingredient, wherein R 1 is a lower alkoxy group.

8. A therapeutic agent for liver disease, comprising the malic acid derivative of claim 13 as an active ingredient, wherein R 1 is a halogenated phenyl group.

9. A therapeutic agent for liver disease, comprising the malonic acid derivative according to claim 13 as an active ingredient, wherein n is 0.

14. A therapeutic agent for liver disease, which comprises the malonic acid derivative according to claim 13 as an active ingredient, wherein 0.1 is 1.