JPH0686419B2 - Cysteine related compounds - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION "Industrial field of application" The present invention provides a novel compound having an effect of suppressing liver damage, an immunomodulatory effect and the like.

"Prior Art" Various studies have been conducted on cysteine derivatives,
Japanese Patent Publication Nos. 56-5388, 56-5390, 59-12119, 6
Published in 0-11888, 62-13922, JP-A-55-51021 and the like, it is known to have a wide range of effects such as liver damage suppression, anti-rheumatic and anti-cataract.

"Problems to be solved by the invention and means for solving the problems" However, almost no report has been made on the effect of introducing or extending an alkylene group in the side chain, or further substituting an alkyl group or the like, and It was necessary to study the synthesis of the novel compound of E. coli and its effect. The present inventors have synthesized these novel compounds and examined the effects, and found that they have excellent effects.

"Constitution of the Invention" The present invention relates to a compound represented by the general formula [I] and salts thereof.

[In the formula, R ¹ and R ² represent the same lower alkyl group.

R ³ and R ⁴ are the same or different and each represents a hydrogen atom, a lower alkyl group, a lower alkanoyl group, a (substituted) phenyl lower alkyl group, a (substituted) phenylcarbonyl group, a furoyl group or a thenoyl group.

R ⁵ represents a hydroxy group, a lower alkoxy group, an amino group or a lower alkylamino group. same as below. The above definition will be described in more detail. The lower alkyl group represents a straight chain or branched alkyl group having 1 to 6 carbon atoms such as methyl, ethyl, propyl, isopropyl, and hexyl, and a lower alkanoyl group. Is a linear or branched alkanoyl group having 1 to 6 carbon atoms such as acetyl, propionyl, pivaloyl, hexanoyl, etc., and (substituted) of a (substituted) phenyl lower alkyl group and a (substituted) phenylcarbonyl group. Indicates that each phenyl group may be unsubstituted or substituted with a lower alkyl group, a lower alkoxy group, a halogen atom or the like.

Various studies have been carried out on cysteine derivatives, which have been published in Japanese Examined Patent Publication No. 56-5388 and the like, and are known to have a wide range of effects such as liver damage suppression, antirheumatic and anticataract. The present inventors further proceeded with the research of cysteine derivatives, introduced or extended an alkylene group in the side chain, and further conducted synthetic research of a compound in which a thiol group was protected with an alkyl group or the like, and as a result of examining the pharmacological effect, It has been found that the compounds of the invention exhibit excellent liver damage inhibitory action and immunomodulatory action and are useful as therapeutic agents for liver diseases and immunomodulators.

The compound of the present invention can be synthesized by various methods, and examples thereof include Japanese Patent Publication Nos. 56-5388, 56-5390, and 59-1211.
The method according to No. 9 etc. can be mentioned.

The compound of the formula [I] can be optionally formed into a salt with a pharmaceutically acceptable inorganic or organic base. Examples of salts include sodium salt, potassium salt, calcium salt, magnesium salt, ammonium salt, diethylamine salt, triethanolamine salt and the like. The compound of the present invention is 1
Stereoisomers exist because they have one or more asymmetric carbon atoms, but these isomers are also included in the scope of the present invention.

As a method for investigating whether a certain compound is useful as a therapeutic drug for liver disease, a method using a carbon tetrachloride liver injury model is widely used. This model causes liver damage by administering carbon tetrachloride to rats, and GOT and GPT levels in serum are used as indicators of the damage. If these values increased due to liver damage are decreased by administration of the compound, it is judged to be effective against liver damage. Therefore, as a result of conducting an experiment using this compound, detailed data will be described in the section of the pharmacological test.However, this compound-administered group significantly decreased the serum transaminase activity as compared with the group to which this compound was not administered. ing. From this, it was revealed that this compound has a liver damage suppressing effect.

In recent years, it is considered that the immunological mechanism is deeply involved in the mechanism of onset and chronicity of liver disease. Therefore, the effect of the present compound on the immune system was examined by using an immune response to mouse sheep erythrocytes, which is often used to examine the immunomodulatory action.
This method uses the number of hemolytic plaque-forming cells of mouse splenocytes as an index, and examines the effect on the immune system by the degree of increase or decrease. As described in the section of pharmacological test, this compound showed an excellent immunosuppressive effect.

A compound having a chemical structure similar to that of this compound is Japanese Patent Publication Sho 56
Although disclosed in -5388, it is generally accepted that a slight difference in the chemical structure of an organic compound greatly affects the effect. Therefore, in order to investigate how the difference in the chemical structure affects the effect and to prove the usefulness of the present compound, the immunosuppressive effect of the compound described in the publication (shown by the following formula [II]) When a comparative test was conducted, this compound showed a superior effect as compared with the compounds described in the publications, as shown in the section of pharmacological test.

From the above results, it was found that the present compound reduces serum GOT and GPT levels and also has an immunosuppressive effect, and can be a new type of excellent liver disease therapeutic agent. Furthermore, since the compound has an excellent immunomodulatory action, it can be used as a therapeutic agent for various diseases related to immunity other than liver disease, for example, autoimmune diseases such as rheumatoid arthritis. .

The compound may be administered orally or parenterally, and its dosage form includes tablets, capsules, powders, granules, suppositories, injections, transdermal absorption agents, eye drops and the like. The dose is determined according to symptoms, dosage form, etc., but usually 1 to 5000 mg daily
Can be administered once or in several divided doses.

The production examples and formulation examples of the present compound are shown below as Examples.

"Example" Example 1 N- (2-mercapto-2-methylpropionyl) -DL
-Production of homocysteine (Compound 1) 2-mercapto-2-methylpropionic acid (40.4 g) in ethyl acetate (200 ml) was added with N, N'-dicyclohexylcarbodiimide (69.3 g) in ethyl acetate (200 ml). Add dropwise while stirring under ice cooling. After completion of the dropwise addition, the insoluble matter is removed after stirring at room temperature for 1 hour. After the solution was concentrated under reduced pressure, 400 ml of N, N-dimethylformamide (DMF) was added to obtain a DMF solution of polythioester.

DL-homocysteine (37.9g), potassium carbonate (77.4
The above polythioester solution is added to a mixed solution of g), water (400 ml) and DMF (100 ml), and the mixture is stirred at room temperature overnight. Water (2 L) is added to the reaction solution, which is washed with ethyl acetate. The aqueous layer is acidified with 6N hydrochloric acid and then extracted with ethyl acetate. The organic layer is washed with saturated brine and dried over anhydrous sodium sulfate. The solvent is distilled off under reduced pressure and the resulting oily substance is purified by silica gel column chromatography and recrystallized from isopropyl ether to obtain 39.8 g (59.9%) of the title compound.

Melting point 102-104 ° C (isopropyl ether) IR (KBr, cm ^-1 ) 3405,3335, 2536, 1714,1599,1524,1412,1296, 1270,1254,1213,1186,658 Example 2 N- (2, 2-dimethyl-3-mercaptopropionyl)
Preparation of -L-Cysteine (Compound 2) 3-mercaptopivalic acid (40.3 g) and N, N'-dicyclohexylcarbodiimide (61.9 g) were used in the same manner as in Example 1 to obtain a DMF solution of polythioester.

The above polythioester solution is added to a mixed solution of L-cysteine / hydrochloride / monohydrate (52.7 g), potassium carbonate (124 g), water (400 ml) and DMF (100 ml), and the mixture is stirred at room temperature overnight. Thereafter, the same procedure as in Example 1 is carried out to obtain 47.2 g of the title compound.
(66.3%) is obtained.

Melting point 83.5-85.5 ° C (isopropyl ether) IR (kBr, cm ^-1 ) 3352,2596,1728, 1630,1528,1424,1403,1296, 1204,870,593 Optical rotation ▲ [α] ²⁵ _D ▼ −3.3 ° (c = 1.0, methanol) ▲ [α] ²⁵ _D ▼ + 57.8 ° (c = 1.0, chloroform) In the same manner as in Example 2, the following compound is obtained.

N-[(2-ethyl-2-mercaptomethyl) butyryl] -L-cysteine (Compound 3) IR (KBr, cm ^-1 ) 3350,1726,1628, 1526 Example 3 S-benzyl-N- (3 -Benzylthio-2,2-dimethylpropionyl) -L-cysteine (Compound 4) S-Benzyl-L-cysteine (11.5 g) was dissolved in 2N aqueous sodium hydroxide solution (68 ml) to give 3-benzylthio-
A solution of 2,2-dimethylpropionyl chloride (14.6 g) in ether (10 ml) was added dropwise with stirring under ice cooling. After completion of the dropwise addition, the reaction solution is stirred under ice cooling for 20 minutes and further at room temperature for 2 hours. The reaction solution is acidified with 6N hydrochloric acid and then extracted with ethyl acetate. The organic layer is washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained oily substance is purified by silica gel column chromatography to obtain 19.4 g (85.1%) of the title compound.

IR (film, cm ^-1 ) 3344,1731,1620, 1514,1495,1236,1199,700 Optical rotation ▲ [α] ²⁵ _D ▼ -31.5 ° (c = 1.1, methanol) To obtain the compound of

S-benzyl-N- (3-benzylthio-2,2-dimethylpropionyl) -D-cysteine (Compound 5) IR (film, cm ^-1 ) 3344,1729,1620, 1513,1495,1236,1200,699 Optical rotation ▲ [α] ²⁵ _D ▼ + 33.0 ° (c = 1.0, methanol) Example 4 N- (2,2-dimethyl-3-mercaptopropionyl)
Preparation of -L-Cysteine (Compound 2) S-Benzyl-N- (3-benzylthio-2,2-dimethylpropionyl) -L-cysteine (18.0 g) was dissolved in liquid ammonia (250 ml) to give sodium metal (5.0 g)
Gradually add. After adding ammonium chloride to the reaction solution, liquid ammonia is distilled off. Water is added to the residue and washed with ethyl acetate. The aqueous layer is acidified with 6N hydrochloric acid and extracted with ethyl acetate. The organic layer is washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained oily substance is purified by silica gel column chromatography and then recrystallized from ethyl acetate-cyclohexane to obtain 7.1 g (69.6%) of the title compound.

The physical properties of the obtained compound were the same as those obtained in Example 2.

The following compound is obtained in the same manner as in Example 4.

N- (2,2-dimethyl-3-mercaptopropionyl) -D-cysteine (compound 6) Melting point 83.5-85.0 ° C (ethyl acetate-cyclohexane) IR (KBr, cm ^-1 ) 3352,2595,1725, 1624, 1522,1421, 1401,1295, 1201,867,590 Optical rotation ▲ [α] ²⁵ _D ▼ -57.1 ° (c = 1.0, chloroform) Example 5 N- [2,2-Dimethyl-3- (methylthio) propionyl]- Production of S-Methyl-L-Cysteine-Dicyclohexylamine Salt (Compound 7) N- (2,2-Dimethyl-3-mercaptopropionyl) -was added to an aqueous solution (150 ml) of potassium carbonate (41.5 g) under ice cooling and stirring. L-Cysteine (23.7 g) is dissolved and methyl iodide (36.9 g) is added dropwise. After completion of the dropwise addition, the mixture is stirred under ice cooling for 30 minutes and further at room temperature for 1 hour. 1N iodine solution (15m
Add l) and wash with ethyl acetate. The resulting aqueous layer is 6N
Acidify with hydrochloric acid and extract with ethyl acetate. The organic layer was washed with an aqueous sodium hydrogen sulfite solution and saturated saline,
After drying over anhydrous sodium sulfate, it is concentrated under reduced pressure. The oily substance obtained is purified by silica gel column chromatography. The obtained oily substance was crystallized by adding dicyclohexylamine, and recrystallized from ethyl acetate-hexane to give the title compound 2
Obtain 9.0g (65.0%).

Melting point 98.0-99.0 ° C (Ethyl acetate-hexane) IR (KBr, cm ^-1 ) 3380,2912,2848, 1635,1561,1498,1409,1392,587 Optical rotation ▲ [α] ²⁵ _D ▼ + 18.6 ° ( c = 1.0, methanol) Example 6 Preparation of N- [2,2-dimethyl-3- (methylthio) propionyl] -L-cysteine dicyclohexylamine salt (Compound 8) L-Cysteine hydrochloride monohydrate (15.6 g) is dissolved in an aqueous solution (150 ml) of potassium carbonate (46.8 g), and 2,2-dimethyl-3- (methylthio) propionyl chloride (15.6 g) is added dropwise with stirring under ice cooling. After the addition is complete, stir at room temperature for 1 hour. The reaction mixture is washed with ethyl acetate, the aqueous layer is acidified with 6N hydrochloric acid and extracted with ethyl acetate. The organic layer is washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The oily substance obtained is purified by silica gel column chromatography. The obtained oily substance was crystallized by adding dicyclohexylamine and then recrystallized from ethyl acetate-hexane to obtain 28.5 g (70.1%) of the title compound.

Melting point 122.0-123.5 ° C (Ethyl acetate-hexane) IR (KBr, cm ^-1 ) 3404,2920,2852, 1629,1560,1483,1412,1383 Optical rotation ▲ [α] ²⁵ _D ▼ + 35.0 ° (c = 1.1, Methanol) Example 7 Preparation of N- (2,2-dimethyl-3- (benzoylthio) propionyl) -S-methyl-L-cysteine (Compound 9) 2,2-Dimethyl-3- (benzoylthio) Propionyl chloride (bp 138-145 ° C / 1.0mmHg, 12.3g) was added dropwise to a mixture of S-methyl-L-cysteine (6.5g) in 1.6M potassium carbonate solution (50ml) and acetone (50ml) under ice-cooling with stirring. To do. After 10 minutes, return to room temperature and stir for 2 hours. The reaction mixture is acidified with 2N hydrochloric acid and extracted with ethyl acetate. The organic layer is washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The resulting oily matter is purified by silica gel column chromatography to obtain 12.4 g (72%) of the title compound as an oily matter.

Melting point 101-102 ℃ (Ethyl acetate-hexane) IR (KBr, cm ^-1 ) 3372,2912,2852, 1632 Optical rotation ▲ [α] ²⁵ _D ▼ + 11.8 ° (c = 1.0, methanol) Example 8 N- (2,2-dimethyl-3-mercaptopropionyl)
Preparation of -S-methyl-L-cysteine (Compound 10) N- [2,2-dimethyl-3- (benzoylthio) purpionyl] -S-methyl-L-cysteine (10.0 g) in methanol solution (20 ml) 28% aqueous ammonia (40 ml) is added, and the mixture is stirred at room temperature for 2 hours. The reaction mixture is washed with ethyl acetate, acidified with 6N hydrochloric acid and extracted with ethyl acetate. The organic layer is washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained oily substance is purified by silica gel column chromatography to obtain 5.8 g (82%) of the title compound as an oily substance.

As dicyclohexylamine salt Melting point 97-99 ° C (Ethyl acetate-hexane) IR (KBr, cm ^-1 ) 3364,2916,2852, 1635,1559 Optical rotation ▲ [α] ²⁵ _D ▼ + 9.5 ° (c = 1.05, Methanol) Example 9 N- (2-mercapto-2-methylpropionyl) -S
-Preparation of trityl-L-cysteine (Compound 11) N- (2-mercapto-2-methylpropionyl) -L
-Cysteine (11.2g) in dimethylformamide (5
Trityl chloride (16.7 g) was gradually added to 0 ml) with stirring at room temperature. The reaction solution is stirred at room temperature for 2 hours, poured into water and extracted with ethyl acetate. The organic layer is washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The resulting oil is purified by silica gel column chromatography to give 14.2 g (60%) of the title compound.

IR (film, cm ^-1 ) 3356,2976,1735 Optical rotation ▲ [α] ²⁵ _D ▼ + 19.1 ° (c = 1.52, methanol) Example 10 Sp-methoxybenzyl-N- (2-p- Preparation of methoxybenzylthio-2-methylpropionyl) -L-cysteine (Compound 12) N- (2-mercapto-2-methylpropionyl) -L
-Dissolve cysteine (2.0g) in ethanol (10ml),
4N aqueous sodium hydroxide solution (7.7m
l), followed by the dropwise addition of paramethoxybenzyl chloride (3.0 ml). After completion of the dropwise addition, the reaction solution is stirred under ice cooling for 2 hours and further at room temperature for 2 hours. Concentrate under reduced pressure, acidify with 2N hydrochloric acid, and extract with ether. The organic layer is washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The precipitated crystals are recrystallized from ether to give the title compound.
Obtain 2.8 g (67%).

Melting point 112-113 ° C (ether) IR (KBr, cm ^-1 ) 2948,2924,1748, 1622,1609,1507,1230,1165, 1028,833 Optical rotation ▲ [α] ²⁵ _D ▼ -22.8 ° (c = 0.95, methanol) Example 11 Preparation of S-p-methoxybenzyl-N- (2-p-methoxybenzylthio-2-methylpropionyl) -L-cysteine methyl ester (Compound 13) S-p-methoxybenzyl-N To a dimethylformamide solution (20 ml) of-(2-p-methoxybenzylthio-2-methylpropionyl) -L-cysteine (3.0 g), sodium hydride (0.3 g) was added at room temperature under a nitrogen stream, and the mixture was stirred for 1 hour. . Methyl iodide (0.5 ml) was added to the reaction mixture, the mixture was stirred at room temperature for 4 hours, water (300 ml) was added, and the mixture was extracted with ether. The organic layer is washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The oily substance obtained is purified by silica gel column chromatography to give 2.8 g (90%) of the title compound.
To get

IR (film, cm ^-1 ) 1742,1665,1610, 1512,1301,1244,1175,1031, 832 Optical rotation ▲ [α] ²⁵ _D ▼ -31.9 ° (c = 0.77, methanol) Example 12 Sp Preparation of -methoxybenzyl-N- (2-p-methoxybenzylthio-2-methylpropionyl) -L-cysteine amide (Compound 14) Sp-methoxybenzyl-N- (2-p-methoxybenzylthio-2 -Methylpropionyl) -L-cysteine methyl ester (2.4 g) is dissolved in methanol saturated with ammonia gas (50 ml), and further ammonia gas is passed through for 20 minutes. The reaction solution is left at room temperature for 2 days and then concentrated under reduced pressure. The obtained crystals are recrystallized from methanol to obtain 1.5 g (65%) of the title compound.

Melting point 116-117 ° C (methanol) IR (KBr, cm ^-1 ) 1691,1621,1617, 1607,1502,1402,1232,1174, 1029 Optical rotation ▲ [α] ²⁵ _D ▼ -1.6 ° (c = 0.74, Methanol) Example 13 N- (2-mercapto-2-methylpropionyl) -L
-Production of cysteine amide (Compound 15) S-p-methoxybenzyl-N- (2-p-methoxybenzylthio-2-methylpropionyl) -L-cysteine amide (500 ml) in a liquid ammonia solution (10 ml) with nitrogen stream. Add sodium metal (0.15 g) at -78 ° C below. After adding ammonium chloride (300 mg), ammonia is evaporated, methanol and methylene chloride are added to the residue, and the insoluble matter is filtered. The filtrate is concentrated and then purified by silica gel column chromatography to obtain 80 mg (32%) of the title compound.

Melting point 124-125 ° C (ethyl acetate-hexane) IR (KBr, cm ^-1 ) 2540,1659,1653, 1633,1530,1126,634 Optical rotation ▲ [α] ²⁵ _D ▼ + 0.3 ° (c = 0.60, Methanol) Example 14 N- (2-mercapto-2-methylpropionyl) -L
-Preparation of cysteine methyl ester (Compound 16) N- (2-mercapto-2-methylpropionyl) -L
-Cysteine (1.0 g) in ether (3 ml) is added dropwise with diazomethane in ether (12 ml) under ice cooling. After completion of the dropwise addition, acetic acid is added to the reaction solution, washed successively with saturated sodium bicarbonate solution and saturated saline solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting oil is purified by silica gel column chromatography to give 1.0 g (94%) of the title compound.

IR (film, cm ^-1 ) 2540,1739,1656, 1502,1437,1347,1212,1177 Optical rotation ▲ [α] ²⁵ _D ▼ -18.2 ° (c = 0.88, methanol) Example 15 N- (2- Mercapto-2-methylpropionyl) -L
-Cysteine N, N-Dimethylamide (Compound 17) Production N- (2-mercapto-2-methylpropionyl) -L
-In a solution of cysteine (1.0 g) in methylene chloride (4 ml),
A methylene chloride solution (4 ml) of dicyclohexylcarbodiimide (0.5 g) is added dropwise under ice cooling in a nitrogen stream. After completion of the dropwise addition, the reaction solution is stirred under ice cooling for 30 minutes and further at room temperature for 1 hour. A solution prepared by dissolving dimethylamine hydrochloride (0.2 g) and triethylamine (0.4 ml) in a mixture of methylene chloride (2 ml) and methanol (1 ml) is added dropwise to the reaction mixture under ice cooling. The reaction solution is stirred under ice-cooling for 15 minutes and further at room temperature for 3 hours, ethyl acetate is added, and the insoluble matter is filtered. The organic layer is washed with water and concentrated under reduced pressure. The resulting oil is purified by silica gel column chromatography to give 0.6 g (50%) of the title compound.

IR (film, cm ^-1 ) 2540,1633,1497, 1464,1400,1135 Optical rotation ▲ [α] ²⁵ _D ▼ -1.8 ° (c = 0.17, methanol) Example 16 (Formulation example) 1) Tablet Compound 2 100 mg Crystalline cellulose 20 mg Lactose 40 mg Hydroxypropyl cellulose-L 5 mg Magnesium stearate 5 mg 170 mg 2) Capsule preparation Compound 2, lactose and magnesium stearate were used to prepare the following capsule preparations.

Compound 2 5 mg Magnesium stearate 3 mg Lactose 142 mg 150 mg By changing the mixing ratio of compound 2 and lactose, capsules containing 10 mg / capsule, 30 mg / capsule, 50 mg / capsule and 100 mg / capsule were prepared.

3) Granules Compound 2 50 mg Lactose 54 mg Crystalline cellulose 20 mg Polyvinylpyrrolidone K-30 5 mg Magnesium stearate 1 mg 130 mg Pharmacological test A rat carbon tetrachloride liver injury model is generally used as an index for examining the usefulness of therapeutic agents for liver diseases. There is. Therefore, the effect of the present compound on liver damage was examined using this model. Furthermore, the immunomodulatory effect of the present compound was examined using a method of immune response to mouse sheep erythrocytes, which is often used to examine the effect on the immune system.

1) Effects on rat carbon tetrachloride liver injury model The test drug was suspended in a tragacanth gum solution and orally administered to male Wistar rats (5 rats per group) at a drug dose of 300 mg / kg, and after 30 minutes, liver damage. Carbon tetrachloride (0.
25 ml / kg) was intraperitoneally administered. The GOT and GPT values of the serum collected 24 hours after carbon tetrachloride administration were measured. As a control, a 0.5% tragacanth gum solution was used. The results using Compound 2 as a representative example of this compound are shown in Table 1.

As shown in Table 1, the serum transaminase activity of the compound administered with the present compound was significantly decreased as compared with the control, indicating that the compound has an excellent effect on liver injury. .

2) Effect on mouse anti-sheep erythrocyte immune response According to the method of Iso et al. (Int. J. Immunotherapy, 1 , 93 (1985)), 5 × 10 ⁸ mice were taken in BALB / C female mice (3-5 mice per group). Sheep red blood cells were intraperitoneally administered to immunize the mice, and the drug suspended in a 1% methylcellulose solution was administered for 4 consecutive days from the day of immunization. The cell number was measured, and the 50% inhibitory dose was determined using this value as an index. As a known compound, Japanese Patent Publication No. 56-5388, which is represented by the formula [II] described in the section "Constitution of the invention", was used.
The same test was carried out using the compounds described in No.

The results of using Compound 2 as a representative example of this compound are shown in Table 2 together with examples of known compounds.

As shown in Table 2, this compound showed an excellent immunosuppressive effect, and it was further found that the effect was far stronger than that of known compounds.

Toxicity test Acute toxicity Compound 2 was suspended in 0.5% methylcellulose solution to prepare a 20% solution. This solution was orally administered to ddY mice (male, 5 weeks old, 6 mice per group) so that the compound amount would be 2,000 mg / kg.

RESULTS: Compound 2 was less toxic, only one died, LD
_{The 50} value is 2,000 mg / kg or more.

[Effects of the Invention] As described above, the present compound reduces serum GOT and GPT levels, exhibits an excellent immunosuppressive action, and is useful as a liver disease therapeutic agent and immunomodulator.

Continuation of the front page (51) Int.Cl. ⁵ Identification number Reference number within the agency FI Technical display location C07C 327/34 7106-4H C07D 307/56 333/38 (56) Reference JP-A-61-165362 (JP, JP, 165362) A) JP-A-58-140065 (JP, A) JP-A-58-69857 (JP, A) JP-A-57-32260 (JP, A) JP-A-54-5916 (JP, A) JP-A-55 -51054 (JP, A) JP-A-58-146558 (JP, A) JP-B-56-5388 (JP, B2)

Claims (3)

[Claims] 1. A compound represented by the following general formula [I] and salts thereof. [In the formula, R ¹ and R ² represent the same lower alkyl group. R ³ and R ⁴ are the same or different and each represents a hydrogen atom, a lower alkyl group, a lower alkanoyl group, a (substituted) phenyl lower alkyl group, a (substituted) phenylcarbonyl group, a furoyl group or a thenoyl group. R ⁵ represents a hydroxy group, a lower alkoxy group, an amino group or a lower alkylamino group. 2. A therapeutic agent for liver diseases, which comprises the compound according to claim 1 as a main component. 3. An immunomodulator comprising the compound according to claim 1 as a main component.