JP2003026569A - Remedy for liver disease - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a remedy for liver diseases, having an excellent hepatopathy inhibiting effect. SOLUTION: This remedy for the liver diseases contains an epoxysuccinamide derivative expressed by the formula (I) (R<1> is H, an alkyl or an aminoalkyl which may have a protective group, and R<2> is an aminoalkyl which may have a substituent, an aryl which may have a substituent, an aralkyl which may have a substituent, a heterocyclic group which may have a substituent or an alkyl substituted by a heterocyclic group which may have a substituent, or R<1> and R<2> form a nitrogen-containing heterocyclic group which may have a substituent together with the adjacent nitrogen atom; and R<3> and R<4> are each H, an alkyl or an aralkyl, and are identical to or different from each other) or its salt as an essential ingredient.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a therapeutic agent for liver diseases, which comprises an epoxysuccinamide derivative or a salt thereof as an essential component.

[0002]

2. Description of the Related Art The liver is an important organ responsible for most of the substance metabolism and its regulation in vivo and various detoxification actions. When this organ is damaged by alcohol, drugs, viruses, or autoimmunity, it causes alcoholic liver damage, drug-induced liver damage, viral liver damage, and autoimmune liver damage. Reach

[0003]

However, no effective drug for these liver disorders has been developed so far. In addition, interferon (IFN), which was developed as a therapeutic agent for viral liver injury, has not been as effective as expected [hepato-biliary-pancreatic, 24, 107-116 (199
2)]. Therefore, development of a drug effective against various liver disorders is desired. An object of the present invention is to provide a therapeutic agent for liver disease, which has an excellent inhibitory effect on liver damage.

[0004]

The present invention relates to a therapeutic agent for liver diseases, which comprises an epoxysuccinamide derivative represented by the formula (I) or a salt thereof as an essential component.

[0005]

[Chemical 4]

[Wherein R ¹ represents a hydrogen atom, an alkyl group or an aminoalkyl group which may have a protecting group, and R 1
² is an aminoalkyl group which may have a substituent, an aryl group which may have a substituent, an aralkyl group which may have a substituent, and a heterocycle which may have a substituent. Group or a heterocyclic ring which may have a substituent represents a substituted alkyl group, or R ¹ and R ² together with an adjacent nitrogen atom may have a nitrogen-containing heterocyclic group which may have a substituent. You may form a ring. R ³ and R ⁴ are the same or different and each represents a hydrogen atom, an alkyl group or an aralkyl group. ]

The epoxysuccinamide derivative represented by the formula (I) or a salt thereof according to the present invention has excellent cathepsin inhibitory activity and is known as a therapeutic agent for bone metabolic disease (International Publication 98/47887). (See Japanese Patent Laid-Open Publication), it was not known to be useful as a therapeutic agent for liver diseases.

[0008]

BEST MODE FOR CARRYING OUT THE INVENTION In the formula (I), the alkyl group represented by R ¹ is preferably an alkyl group having 1 to 6 carbon atoms, for example, a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, Examples thereof include an isobutyl group, a pentyl group, an isopentyl group, a hexyl group, and an isohexyl group.

The aminoalkyl group represented by R ¹ is preferably an aminoalkyl group having 1 to 6 carbon atoms,
Examples thereof include aminomethyl group, aminoethyl group, aminopropyl group, aminobutyl group, aminopentyl group and aminohexyl group. The amino group of the aminoalkyl group has a total carbon number of 2 to 2 such as tert-butoxycarbonyl group.
7 may be protected by an alkyloxycarbonyl group. Of these, R ¹ is preferably a hydrogen atom, a methyl group or an aminoethyl group, and particularly preferably a hydrogen atom.

In formula (I), the aminoalkyl group represented by R ² is preferably an aminoalkyl group having 1 to 6 carbon atoms, and examples thereof include aminomethyl group, aminoethyl group, aminopropyl group, aminoisopropyl group and amino. Butyl group,
Examples thereof include aminoisobutyl group, aminopentyl group, aminoisopentyl group, aminohexyl group, aminoisohexyl group and the like, of which aminoethyl group is particularly preferable.

Further, these aminoalkyl groups may have a substituent on the amino group, and as the substituent, an alkyloxycarbonyl group having a total of 2 to 7 carbon atoms (methoxycarbonyl group, ethoxycarbonyl group, Propoxycarbonyl group, isopropoxycarbonyl group, butoxycarbonyl group, tert-butoxycarbonyl group, pentyloxycarbonyl group, hexyloxycarbonyl group, etc.); Aralkyloxycarbonyl group having a total of 8 to 14 carbon atoms (benzyloxycarbonyl group, phenylethyl) Oxycarbonyl group, phenylpropyloxycarbonyl group, naphthylmethyloxycarbonyl group, etc.); carbon number 1
~ 6 alkylsulfinyl group (methylsulfinyl group, ethylsulfinyl group, propylsulfinyl group,
Butylsulfinyl group, pentylsulfinyl group, hexylsulfinyl group, etc.); alkylsulfonyl group having 1 to 6 carbon atoms (methylsulfonyl group, ethylsulfonyl group,
Propylsulfonyl group, butylsulfonyl group, pentylsulfonyl group, hexylsulfonyl group, etc.);
10 arylsulfinyl groups (benzenesulfinyl group, toluenesulfinyl group, naphthalene sulfinyl group, etc.); arylsulfonyl groups having 6 to 10 carbon atoms (benzenesulfonyl group, toluenesulfonyl group, naphthalenesulfonyl group, etc.); amino group or nitro group Examples thereof include optionally substituted heterocyclic groups (pyridyl group, nitropyridyl group, aminopyridyl group, aminopyrimidyl group, etc.) and the like. Of these substituted aminoalkyl groups, total carbon number is 2
~ 7 alkyloxycarbonyl group, total carbon number 8-14
Is more preferably an aminoalkyl group having 1 to 6 carbon atoms substituted with an aralkyloxycarbonyl group, a benzenesulfonyl group, or a heterocyclic group (which may be further substituted with an amino group or a nitro group), and a heterocyclic group (further More preferred is an aminoethyl group substituted by an amino group or a nitro group), and an aminoethyl group substituted by a pyridyl or pyrimidyl group (which may be further substituted by an amino group or a nitro group). Is particularly preferable.

In formula (I), the aryl group represented by R ² preferably has 6 to 10 carbon atoms, and examples thereof include a phenyl group and a naphthyl group. Of these, a phenyl group is more preferable. Further, these aryl groups may have 1 to 3 substituents at arbitrary positions, and the substituents include aryloxy groups having 6 to 10 carbon atoms (phenoxy group, naphthyloxy group, etc.). ); Aralkyloxycarbonyl group having 8 to 14 carbon atoms (benzyloxycarbonyl group, phenylethyloxycarbonyl group, phenylpropyloxycarbonyl group, naphthylmethyloxycarbonyl group, etc.); Alkyloxycarbonylamino having 2 to 7 carbon atoms Groups (methoxycarbonylamino group, ethoxycarbonylamino group, propoxycarbonylamino group, isopropoxycarbonylamino group, butoxycarbonylamino group, tert-butoxycarbonylamino group, pentyloxycarbonylamino group, hexyloxycarbonylamino group, etc.); total Carbon number -14 aralkyloxycarbonyl group (benzyloxycarbonylamino group, phenylethyl oxycarbonyl amino group, phenylpropyl aryloxycarbonylamino group, naphthylmethyl-butyloxycarbonylamino group);

Alkylthio groups having 1 to 6 carbon atoms (methylthio group, ethylthio group, propylthio group, butylthio group,
Pentylthio group, hexylthio group, etc.); C1-6 alkylsulfinyl group (methylsulfinyl group, ethylsulfinyl group, propylsulfinyl group, butylsulfinyl group, pentylsulfinyl group, hexylsulfinyl group, etc.); Alkylsulfonyl group (methylsulfonyl group, ethylsulfonyl group, propylsulfonyl group, butylsulfonyl group, pentylsulfonyl group, hexylsulfonyl group, etc.); Arylthio group having 6 to 10 carbon atoms (phenylthio group, naphthylthio group, etc.);
Arylsulfinyl group having 6 to 10 carbon atoms (benzenesulfinyl group, toluenesulfinyl group, naphthalene sulphinyl group, etc.); Arylsulfonyl group having 6 to 10 carbon atoms (benzenesulfonyl group, toluenesulfonyl group,
Naphthalenesulfonyl group, etc.); Arylsulfonylamino group having 6 to 10 carbon atoms (benzenesulfonylamino group,
A toluenesulfonylamino group, a naphthalenesulfonylamino group, etc.); an alkyl group which may have a substituent and has 1 to 6 carbon atoms (methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, tert- Examples thereof include a butyl group, a pentyl group, an isopentyl group, a neopentyl group, a hexyl group, and an isohexyl group. Examples of the substituent that the alkyl group may further have include a hydroxy group, an amino group, and an acylamino group (acetylamino group, propanoyl group). Amino group, benzoylamino group, etc.), total carbon number 2
7 alkyloxycarbonylamino groups, total carbon number 8 to
14 aralkyloxycarbonylamino groups, 6 carbon atoms
Protected amino groups such as arylsulfonylamino groups of 10 to 10 are mentioned. ); C2-C6 alkenyl group (ethenyl group, propenyl group, butenyl group, pentenyl group,
Hexenyl group); hydroxy group, amino group, amidino group, acetamidino group, guanidino group, cyano group, carboxyl group, carbamoyl group, acyl group, acylamino group, 1-piperidino group, 1-piperazino group, 5-nitropyridine- Examples include 2-yl group and aminosulfonyl group.

The aryl group which may be substituted is preferably a phenyl group which may be substituted by an alkyl group which may have a substituent and has 1 to 6 carbon atoms. Is more preferably a phenyl group which may be substituted with an alkyl group, and particularly preferably a phenyl group which may be substituted with a methyl group or an ethyl group.

In the formula (I), the aralkyl group represented by R ² is preferably an aralkyl group having 7 to 12 carbon atoms,
Examples thereof include benzyl group, phenethyl group, phenylpropyl group, phenylbutyl group, and other phenyl group-substituted C1-6 alkyl groups. The aralkyl group has the substituent represented by R ² described above. The same as the substituents on the optionally substituted aryl group can be mentioned.

In the formula (I), the heterocyclic group represented by R ² is a monocyclic or condensed ring having 5 to 10 ring members, and 1 to 3 of nitrogen, oxygen and sulfur are heteroatoms constituting the ring. Preferably saturated or unsaturated heterocyclic group having a piperidinyl group, pyrrolyl group, imidazolyl group, pyrazolyl group, furyl group, thienyl group, oxazolyl group, isoxazolyl group, thiazolyl group, isothiazolyl group, flazanyl group, pyridyl group, Examples thereof include a pyrazinyl group, a pyrimidinyl group, a pyridazinyl group, a triazinyl group, a quinolyl group, an isoquinolyl group, and a benzimidazolyl group, and the heterocyclic substituent may have the substituent represented by R ² described above. The same as the substituents in the good aryl group can be mentioned, but the phenyl group may be substituted and has 1 to 6 carbon atoms. Alkyl group is preferred.

Of these heterocyclic groups which may have a substituent, the phenyl group may have a carbon number of 1 which may be substituted.
Is more preferably a piperidinyl group, pyridyl group, quinolyl group or isoxazolyl group which may be substituted by an alkyl group of 6 and further preferably a piperidinyl group, pyridyl group or isoxazolyl group which may be substituted by a benzyl group or a methyl group. .

In the formula (I), the alkyl group substituted by the heterocyclic group represented by R ² is an alkyl group having 1 to 6 carbon atoms which is substituted with a saturated nitrogen-containing heterocyclic ring such as morpholino group, piperidinyl group and piperazinyl group. A monocyclic or condensed ring having 5 to 10 ring members and 1 to 6 carbon atoms substituted with an aromatic heterocyclic group having 1 to 3 of nitrogen, oxygen and sulfur as hetero atoms constituting the ring. Groups. Examples of the aromatic heterocyclic group include a pyrrolyl group, an imidazolyl group, a pyrazolyl group, a furyl group, a thienyl group, an oxazolyl group, an isoxazolyl group, a thiazolyl group, an isothiazolyl group, a flazanyl group, a pyridyl group, a pyrazinyl group, a pyrimidinyl group, a pyridazinyl group. , Triazinyl group, quinolyl group, isoquinolyl group, benzimidazolyl group, naphthyridinyl group, phthalazinyl group, indolyl group, benzofuranyl group, benzotriazolyl group, benzoxazolyl group, and the like. , Ethyl group, n-propyl group and the like. Examples of the substituent of the heterocycle include the same substituents as those for the aryl group which may have a substituent represented by R ² .

As these heterocyclic-substituted alkyl groups,
A heterocyclic group selected from a piperidinyl group, a morpholino group, a thiazolyl group, an imidazolyl group, a pyrrolyl group, a pyridyl group, a pyrazinyl group, a pyrimidyl group and a benzimidazolyl group (these rings have an alkyloxycarbonylamino group having 2 to 7 carbon atoms in total). 1 to 3 carbon atoms selected from a group, an amino group, a dialkylpyrrolyl group, an alkyl group having 1 to 6 carbon atoms and a nitro group).
Is preferably an alkyl group having from 6 to 6, more preferably an alkyl group having 1 to 6 carbon atoms substituted with a heterocyclic group selected from a morpholino group, a thiazolyl group, an imidazolyl group, a pyridyl group, a pyrazinyl group and a benzimidazolyl group, and a pyridyl group is preferably a pyridyl group. Substituted methyl or ethyl groups are particularly preferred.

In formula (I), the nitrogen-containing heterocyclic ring which may have a substituent formed by R ¹ and R ² together with the adjacent nitrogen atom has 5 to 7 ring members and is a ring. Those having 1 to 3 of nitrogen, oxygen and sulfur as a hetero atom constituting are preferable, and pyrrolidine, imidazolidine, piperidine, piperazine, morpholine and the like are exemplified, and such a substituent is represented by R ² described above. Examples of the substituents in the aryl group which may have a substituent include the phenyl group, the phenyl group having 1 to 6 carbon atoms, and the alkyloxy group having 2 to 7 carbon atoms. Carbonyl group, methylenedioxyphenyl having 1 to 6 carbon atoms
An alkyl group, a pyrimidinyl group, an aminopyrimidinyl group and the like are more preferable.

In the formula (I), examples of the alkyl group represented by R ³ and R ⁴ include alkyl groups having 1 to 6 carbon atoms similar to the alkyl group represented by R ¹ , of which a methyl group,
Ethyl group and n-propyl group are more preferable, and methyl group is particularly preferable.

In the formula (I), the aralkyl group represented by R ³ and R ⁴ has a carbon number of 1 substituted by a phenyl group similar to the aralkyl group which may have a substituent represented by R ^2.
To 6 alkyl groups, of which benzyl group and phenethyl group are particularly preferable.

In the present invention, preferred compounds include R ¹
Is a hydrogen atom, R ² is an alkyl group substituted by an aryl group which may have a substituent or a heterocyclic group which may have a substituent, and R ³ and R ⁴ are the same or different. And a compound which is a hydrogen atom or an alkyl group.
As a more preferable compound, R ¹ is a hydrogen atom,
Examples include compounds in which R ² is a phenyl group which may have a lower alkyl group as a substituent or a lower alkyl group having a pyridyl group as a substituent, and R ³ and R ⁴ are the same or different and are alkyl groups. . More preferable compounds are compounds in which R ¹ is a hydrogen atom, R ² is a phenyl group having an ethyl group as a substituent or an ethyl group having a pyridyl group as a substituent, and R ³ and R ⁴ are methyl groups. Is mentioned. Particularly preferable compounds are the following compounds (1) and (2).

[0024]

[Chemical 5]

[0025]

[Chemical 6]

The epoxysuccinamide derivative represented by the formula (I) of the present invention or a pharmaceutically acceptable salt thereof is synthesized by a generally known method, for example, the production method described in International Publication 98/47887. You can

The epoxysuccinamide derivative of the present invention can form a pharmaceutically acceptable salt. Specific examples thereof include, for example, when an acidic group is present, lithium salt, sodium salt, potassium salt, magnesium salt, alkali salt and alkaline earth metal salt such as calcium salt, or ammonium salt, methylammonium salt, dimethylammonium salt, It is capable of forming ammonium salts such as trimethylammonium salt, and when basic groups are present, mineral salts such as hydrochloride, hydrobromide, sulfate, nitrate and phosphate, acetate, propione. Organic acid salts such as acid salts, tartrate salts, fumarate salts, maleate salts, malate salts, citrate salts, methanesulfonate salts, paratoluenesulfonate salts can be formed. The epoxysuccinamide derivative of the present invention also includes a hydrate.

Regarding the stereochemistry of the epoxy moiety of the epoxysuccinamide derivative of the present invention represented by the above formula (I), depending on the configuration of the epoxysuccinic acid as the starting material, (R, R), ( S, R), (R, S),
Although four types of (S, S) can be taken, the present invention includes all the configurations. Further, other asymmetric carbons include both R and S. Specific examples of preferable compounds are shown in Tables 1 to 8.
In the table, Ac: acetyl group, Boc: ter-butoxycarbonyl group, Bz: benzoyl group, Bzl: benzyl group, Cbz: benzyloxycarbonyl group, Ph:
Indicates a phenyl group.

[0029]

[Table 1]

[0030]

[Table 2]

[0031]

[Table 3]

[0032]

[Table 4]

[0033]

[Table 5]

[0034]

[Table 6]

[0035]

[Table 7]

[0036]

[Table 8]

The application of the epoxysuccinamide derivative represented by the formula (I) of the present invention or a pharmaceutically acceptable salt thereof to the treatment of liver diseases in mammals including human is usually orally or parenterally. Is administered. The dosage is age, sex, weight,
Although it is not constant depending on the medical condition etc., it is usually 0.1 to 1000 mg, preferably 1 to 1000, per adult per day.
mg, more preferably 5 to 500 mg, orally or parenterally in 1 to 3 divided doses.

In the present invention, an effective amount thereof is blended with a pharmaceutically acceptable carrier to give tablets, capsules, granules,
It can be orally or parenterally administered as a solid preparation such as a powder or a liquid preparation such as a syrup and an injection.

As the pharmaceutically acceptable carrier, various organic or inorganic carrier substances that are commonly used as a formulation material are used. Excipients, lubricants, binders, disintegrants in solid formulations, solvents in liquid formulations, It is used as a solubilizing agent, suspending agent, isotonicity agent, buffer, soothing agent and the like. Also,
If necessary, formulation additives such as antiseptics, antioxidants, coloring agents and sweeteners can be used. Suitable examples of excipients include lactose, D-mannitol, starch, crystalline cellulose, light anhydrous silicic acid and the like. Preferable examples of the lubricant include magnesium stearate, calcium stearate, talc, colloidal silica and the like. Preferable examples of the binder include crystalline cellulose, sucrose, D-mannitol, dextrin, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, polyvinylpyrrolidone and the like. Suitable examples of the disintegrant include, for example, starch, carboxymethylcellulose, carboxymethylcellulose calcium, croscarmellol sodium,
Carboxymethyl starch sodium etc. are mentioned.

Preferable examples of the solvent include water for injection, alcohol, propylene glycol, macrogol, sesame oil, corn oil and the like. Preferable examples of the solubilizing agent include, for example, polyethylene glycol, propylene glycol, D-mannitol, benzyl benzoate, ethanol, trisaminomethane, cholesterol, triethanolamine, sodium carbonate,
Examples include sodium citrate. Suitable examples of the suspending agent include, for example, stearyl triethanolamine, sodium lauryl sulfate, lauryl aminopropionic acid, lecithin, benzalkonium chloride, benzethonium chloride, surfactants such as glyceryl monostearate, for example, polyvinyl. Examples thereof include hydrophilic polymers such as alcohol, polyvinylpyrrolidone, sodium carboxymethyl cellulose, methyl cellulose, hydroxymethyl cellulose, hydroxyethyl cellulose and hydroxypropyl cellulose. Preferable examples of the buffer include buffers such as phosphate, acetate, carbonate and citrate. Preferable examples of soothing agents include benzyl alcohol and the like. Preferable examples of preservatives include paraoxybenzoic acid esters, chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid, sorbic acid and the like. Preferable examples of the antioxidant include sulfite, ascorbate and the like.

[0041]

The present invention will be described in detail below with reference to examples, but the present invention is not limited to these examples.

Example 1 Liver Injury Inhibition Test (1) Efficacy determination as a liver disease therapeutic agent is usually carried out by administering a test substance and a liver injury inducing substance to a test animal and examining the inhibitory effect on liver injury. . Although carbon tetrachloride, chloroform, thioacetamide, D-galactosamine and the like are known as hepatopathy-inducing substances, in this test, it is known that the histopathological image is very similar to human viral hepatitis. The known D-galactosamine (D-GalN) was used. In addition, the liver damage-inhibiting effect of the test substance is increased by reflecting glutamate necrosis of hepatocytes, and glutamic oxaloacetic transaminase (GOT) and alanine-α-ketoglutarate-transaminase (GPT) activities in serum are used as indicators. searched.
When liver damage is caused by D-galactosamine, deviation of cell components occurs due to damage to the hepatic cell membrane, and GOT and GPT activities in serum remarkably increase.
-To know the level of liver damage caused by galactosamine and the inhibitory effect of the test substance on the damage, serum GOT
And this method of measuring GPT activity is most suitable.
Compound 29 in the above table was used as a test compound.
D-GalN was intraperitoneally administered to 5 rats at 0.5 g / Kg, and 6 hours later, Compound 29 was administered at 10 mg / Kg (three times).
After administration, serum GOT and GPT were measured. The results are shown in Table 9.

[0043]

[Table 9]

(2) Instead of Compound 29, Compound 56 was used as a test compound, and GOT and GPT in serum were measured by the same method as in Test (1) above. The results are shown in Table 10.

[0045]

[Table 10]

From the above, Compounds 29 and 56 significantly improved the serum GOT and GPT values, which were significantly high by the administration of D-GalN. Also, these 2
The side effect of this compound was examined by measuring the body weight change when the compound was continuously orally administered to CDF1 mice for 7 days. The results are shown below. (1) Compound 29; dose 25 mg / kg, body weight change 2.
7 ± 0.7, non-administered group; body weight change 1.6 ± 0.7 (2) Compound 56; dose 50 mg / kg, body weight change 2.
4 ± 0.9, non-administered group; body weight change 2.2 ± 1.3 Compounds 29 and 56 were not administered at doses 2.5 and 5.0 times the dose of 10 mg / kg, which shows the effect of improving liver function. No mortality of mice and no suppression of body weight increase were observed in comparison with the administration group, indicating that the toxicity of these two compounds by oral administration is extremely low.

Formulation Example 1 Powder 29 parts by weight of Compound 29 is uniformly mixed with 95 parts of lactose to prepare a powder. Formulation Example 2 Granules 5 parts by weight of Compound 29 are mixed with 93 parts of lactose,
Granulate according to conventional methods using 2 parts of hydroxypropyl cellulose as binder. Formulation Example 3 Tablets 5 parts by weight of compound 56 are mixed with 91 parts of lactose,
After granulating according to the usual procedure with 2 parts of hydroxypropyl cellulose as binder, 1 part of talc and 1 part
Parts of magnesium stearate are added and compression molded to give tablets.

Formulation Example 4 Capsules 5 parts by weight of compound 56 were mixed with 93 parts of lactose,
Granules are prepared in the usual manner using 2 parts of hydroxypropyl cellulose as binder and filled into hard gelatin capsules. Formulation Example 5 Injection 1 part by weight of Compound 56 is heated and mixed with 2.5 parts of polyoxyethylene hydrogenated castor oil and 96.5 parts of physiological saline, followed by sterilization to obtain an injection.

[0049]

INDUSTRIAL APPLICABILITY The therapeutic agent for liver diseases of the present invention is preferably used as a therapeutic agent for liver diseases including alcoholic liver injury, drug-induced liver injury, viral liver injury and autoimmune liver injury.

Claims (5)

[Claims] 1. A therapeutic agent for liver diseases, which comprises an epoxysuccinamide derivative represented by the formula (I) or a salt thereof as an essential component. [Chemical 1] [In the formula, R ¹ represents a hydrogen atom, an alkyl group or an aminoalkyl group which may have a protecting group, and R ² represents an aminoalkyl group which may have a substituent or a substituent group. Represents an optionally substituted aryl group, an optionally substituted aralkyl group, an optionally substituted heterocyclic group or an optionally substituted heterocyclic group. Alternatively, R ¹ and R ² may combine with an adjacent nitrogen atom to form a nitrogen-containing heterocycle which may have a substituent. R ³ and R ⁴ are the same or different and each is a hydrogen atom,
An alkyl group or an aralkyl group is shown. ] 2. R ³ is a hydrogen atom, R ² is an alkyl group substituted by an aryl group which may have a substituent or a heterocyclic group which may have a substituent, and R ³ And R
^{4. The} therapeutic agent for liver diseases according to claim 1, wherein ⁴ is an epoxysuccinamide derivative or a salt thereof which is the same or different and is a hydrogen atom or an alkyl group. Wherein R ¹ is a hydrogen atom, a lower alkyl group having a pyridyl group as R ² is a phenyl group or a substituted group may have a lower alkyl group as a substituent, R ³ and R ⁴ 3. The therapeutic agent for liver diseases according to claim 2, which comprises an epoxysuccinamide derivative having the same or different alkyl groups or a salt thereof as an essential component. 4. R¹Is a hydrogen atom, and R^TwoIs a substituent
The phenyl group having an ethyl group or a pyrene as a substituent.
Is an ethyl group having a dil group, R^ThreeAnd R ^FourIs methyl
Group epoxy succinamide derivative or its salt
The hepatic disease therapeutic agent according to claim 3, which comprises an ingredient. 5. The therapeutic agent for liver diseases according to claim 4, which comprises an epoxysuccinamide derivative represented by the following (1) or (2) or a salt thereof as an essential component. [Chemical 2] [Chemical 3]