KR100233233B1 - Novel carbapenem compounds - Google Patents

Abstract

The present invention relates to a carbapenem compound represented by the following general formula (I), a pharmaceutically acceptable nontoxic salt thereof, a physiologically hydrolysable ester thereof, a hydrate, a solvate or an isomer thereof.

Wherein R ¹ represents 1-hydroxyethyl, 1-aminoethyl, 1-fluoroethyl or hydroxymethyl, R ² represents hydrogen, a C _1-4 alkyl group, aminomethyl or 2-aminoethyl, R ³ represents hydrogen, a C _1-4 alkyl group, a C _3-6 alkenyl group, a C _3-7 cycloalkyl group or an acyloxyalkyl group, and R ⁴ and R ⁵ each independently represent hydrogen, a C _1-4 alkyl group, or an aralkyl group. Or NRR 'wherein R and R' are each independently hydrogen, a C _1-4 alkyl group, a C _3-6 alkenyl group, a C _3-7 cycloalkyl group, or R ⁴ and R ⁵ are carbons to which they are attached Together with the atoms, they may form saturated or unsaturated 3-6 membered rings which may contain one or more heteroatoms.

Compounds of the invention are useful as antibiotics.

Description

New Carbapenem Antibiotics

The present invention provides novel carbapenem compounds of the following general formula (I) useful as antibiotics, pharmaceutically acceptable nontoxic salts thereof, physiologically hydrolysable esters, hydrates and solvates thereof and isomers thereof, methods for their preparation, And intermediates in the manufacturing process and methods for their preparation.

Wherein, R ¹ is 1-hydroxyl-Ciel butyl, 1-aminoethyl, 1-Flo Oro ethyl or represents a hydroxymethyl, R ² is a hydrogen, C _1-4 alkyl, aminomethyl or 2-aminoethyl , R ³ represents hydrogen, C _1-4 alkyl group, C _3-6 alkenyl group, C _3-7 cycloalkyl group or acyloxyalkyl group, R ⁴ and R ⁵ are each independently hydrogen, C _1-4 alkyl group, Alkyl group or —NRR ′ wherein R and R ′ each independently represent hydrogen, C _1-4 alkyl group, C _3-6 alkenyl group, C _3-7 cycloalkyl group, or R ⁴ and R ⁵ are attached And a saturated or unsaturated 3 to 6 membered ring which may include one or more hetero atoms together with the carbon atom.

In addition, the present invention includes epimeric, diastereo isomers and topper isomers which may be represented by general formula (I).

In 1976, thienamycin, a beta-lactam ring with a structure completely different from conventional penicillin or cephalosporin antibiotic structures, was first isolated from the culture of Streptomyces cattl eya (J. Am. Chem. Soc. 1978, 100, 6491). The study of carbapenem antibiotics began with the discovery that this new structure of compounds has a broad spectrum of antimicrobial activity.

Imipenem was then developed by Merck, which overcomes chemical instability due to the structural specificity of thienamycin (J. Med. Chem. 1979, 22. 1435). However, like thienamycin, imipenem has been found to be degraded by the dihydropeptidase (DHP-I, Dehydropeptidase-I) secreted by the kidney, and as a result, with Cilastatin, a DHP-I inhibitor It is required to be used (J. Antimicrob. Chemother. 1983. 12. (Suppl: D), 1).

Carbapenem antibiotics are widely used to treat diseases caused by pathogenic bacteria, and are particularly useful for treating diseases caused by bacteria that are resistant to other antibiotics, such as penicillin compounds, and for treating penicillin-sensitive patients. However, the discovery of resistant strains due to too frequent use of imipenem has become a problem recently.

Research on new carbapenem derivatives has been ongoing since then, and related patents and reports have been published. On the other hand, the development of antibiotics with a broader and stronger antimicrobial force is required by the constant expression of resistant bacteria.

Carbaphenyl derivatives have been reported that have excellent antimicrobial activity against gram positive and negative bacteria, and are very stable against β-lactamase of bacteria as well as DHP-I secreted from the kidney. The representative compound is Meropenem of the general formula (A) as reported by Sumimoto.

(J. Antibiot. 1990. 519).

Since this compound is stable in vivo and is generally nontoxic in warm-blooded animals, other compounds with structures similar to compound (a) have been developed for the purpose of finding antibiotics with a broader range of antimicrobial activities.

This development was made through several changes, including the introduction of specific groups at the C-2 ′ position of the 4-pyrrolidinyl group at the C-1, C-6 and C-2 positions of the carbapenem nucleus.

For example, the European Patents (Dec. 92-302904GH and 92-302905) published by ICI in 1991 describe carbapenem derivatives represented by the following general formula (B).

Wherein R ¹ represents 1-hydroxyethyl, 1-fluoroethyl or hydroxymethyl, R ² represents hydrogen or a C _1-4 alkyl group, R ³ represents hydrogen or a C _1-4 alkyl group

R ⁴ is hydrogen or a carboxy group and the benzene ring is halogen, cyano, C _1-4 alkoxycarbonyl, carbamoyl, C _1-4 alkylcarbamoyl, di-C _1-4 alkylcarbamoyl, amino , C _1-4 alkyl S (0) n, where n is 0-2, NC _1-4 alkanesulfonamido, C _1-4 alkanoylamino or C _1-4 alkanoyl (NC _1-4 Mono- or di-substituted by alkyl) amino.

In addition, the compound of the general formula (C) published in European Patent No. 518,558 to Sankyo in 1992 also has a similar structure as follows.

Wherein R ¹ is hydrogen, an unsaturated alkyl group of C _1-6 , an alkenyl group of C _2-6 , an alkyl group substituted by a substituted C _3-6 alkyl group or a C _2-6 alkynyl group, and the like,

R ² is a C _1-6 alkyl group equal to R ¹ or substituted by a —C— (═NH) R group and the like, R ³ and R ⁴ are each hydrogen, an unsaturated alkyl group or halogen that is C _1-6 , C _1-6 unsaturated alkyl group substituted by hydroxy, carbonyl group, cyano group and the like.

The compound of general formula (D), published in 1993 by Daiichi Corporation (WO 93/00344), also has a similar structure:

Wherein Z represents a single bond, oxygen, sulfur, -CR ¹¹ R ^12- , -NR ¹³ CO-, -CONR ^14- , or -NR ^15- , m represents 0-6, R ¹ is lower An alkyl or hydroxy lower alkyl group, R ² R ¹³ and R ¹⁴ represent a hydrogen or lower alkyl group, R ³ represents an esterified carboxyl group, and R ⁴ , R ⁸ , R ¹⁰ and R ¹⁵ represent an amino protecting group, hydrogen Or a lower alkyl group, R ⁵ , R ⁶ , R ¹¹ and R ¹² represent hydrogen, hydroxy, lower alkyl, hydroxy lower alkyl or halogen (R ⁵ and R ⁶ , R ¹¹ and R ¹² are bonded to each other Alkylene may be formed)

R ⁷ represents hydrogen, lower alkyl, carboxyl, carbamoyl or —CONR ¹⁶ R ¹⁷ where R ¹⁶ and R ¹⁷ represent hydrogen or lower alkyl, R ⁸ represents hydrogen, lower alkyl, hydroxy lower alkyl group , R ⁷ and R ⁸ may combine with each other to form alkylene.

Accordingly, the present inventors have conducted studies to introduce various derivatives at the C-2 position of carbapenem, and as a result, a carbapenem compound having a [2- (substituted pyrroline-carbonyl) pyrrolidin-4-yl] thio group was introduced. The discovery of strong activity against a wide range of pathogens has led to the completion of the present invention for compounds represented by the general formula (I).

The compounds according to the invention comprise geometric isomers or mixtures of isomers. In addition, solvates (including hydrates) of the compound of formula (I) are also included in the scope of the present invention.

Pharmaceutically acceptable non-toxic salts of the compounds of formula (I) are salts with inorganic acids such as hydrochloric acid, bromic acid, phosphoric acid, sulfuric acid or acetic acid, trifluoroacetic acid, citric acid, formic acid, maleic acid, hydroxyl acid, succinic acid, benzoic acid, With organic carboxylic acids such as tartaric acid, fumaric acid, manderic acid, ascorbic acid, dried acid or salts with sulfonic acids such as methanesulfonic acid, para-toluenesulfonic acid and with other acids known and used in the art of penicillin and cephalosporin Salts. These acid addition salts are prepared by conventional techniques.

Compounds of formula (I) may also form non-toxic salts. Bases used herein include alkali metal hydroxides (e.g. caustic soda, caustic), alkaline earth metal hydroxides (e.g. calcium hydroxide, sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium carbonate, calcium carbonate) Inorganic bases and organic bases such as amino acids.

Examples of esters capable of physiological hydrolysis of the compound of general formula (I) include indanyl, phthalidyl, methoxymethyl, pivaloyloxymethyl, glycyloxymethyl, phenylglycyloxymethyl, 5-methyl- 2-oxo-1,3-dioxoren-4-yl methyl and other physiologically hydrolyzable esters known and used in the art of phenylsilin and cephalosporin. Such esters are prepared by known methods.

The general formula (I) compound exhibits high antimicrobial activity against various Gram-negative bacteria and is used for prevention and treatment of bacterial infections in animals including humans.

Formula (I) compounds are formulated by known methods using known pharmaceutical carriers and excipients and are in unit dosage form or in multidose containers.

The composition is in the form of a solution, suspension or emulsion in oil or aqueous medium and may contain conventional dispersants, suspensions or stabilizers.

In addition, the composition may be, for example, in the form of a dry powder that is dissolved before use with sterile, pyrogen-free water.

Compounds of formula (I) may also be formulated as suppositories using conventional suppository bases such as cocoa butter or other glycerides. If desired, the compounds of the present invention may be administered in combination with other antibacterial agents such as penicillin or cephalosporin.

When forming the composition in the unit dosage form, it is preferable to contain about 50 to 1,500 mg of the active ingredient of the compound of formula (I). The dosage of the compound of formula (I) depends on the doctor's prescription depending on factors such as the patient's weight and age and the specific nature and severity of the disease. However, the dosage required for adult treatment typically ranges from about 500 to 5,000 mg per day, depending on the frequency and route of administration. The total dosage of about 150 to 3,000 mg per day will be sufficient, usually in single doses for intramuscular or intravenous administration to adults, but a higher daily dosage is preferred for some strains of infection.

The compounds according to the invention exhibit a wide range of antimicrobial activities, which are generally highly active against Gram-positive bacteria, and this activity also applies to many Gram-negative bacteria producing β-lactamases. In particular, the penicillin-resistant strain MRSA (Methicillin-resistant St aphyolococcus aureus) has significantly higher antimicrobial activity than the control drug Meropenem (Meropenem). MRSA bacteria are very resistant to antibiotics, and the usefulness of the compound according to the present invention is very high considering that the bacteria are not easy to treat against infection.

Compounds of formula (I) according to the present invention, pharmaceutically acceptable non-toxic salts thereof, physiologically hydrolysable esters, hydrates or solvates thereof are prepared by the following formula (II) in the presence of a solvent React with a compound of formula (III), and if necessary, remove the hydroxy protecting group or acid protecting group before or after the reaction to obtain compound (IV) having the following structure, and to obtain the amino protecting group or acid protecting group of compound (IV) Prepared by removing it.

Wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ are as described above, R ⁶ is hydrogen or formyl, arylalkyl (eg benzyl, p-methoxybenzyl, p-nitrobenzyl, 2,4-dimethoxybenzyl, triphenylmethyl, etc.), di-4-anisylmethyl group, furylmethyl group, lower alkenyloxycarbonyl group (e.g. allyloxycarbonyl, etc.), lower alkoxycarbonyl group (e.g. t-butoxy Carbonyl, etc.), aryl (lower) alkoxycarbonyl groups (e.g. benzyloxycarbonyl, p-methoxybenzyloxycarbonyl, o-nitrobenzyloxycarbonyl, p-nitrobenzyloxycarbonyl, etc.), alkylidene groups ( Examples are amino protecting groups such as methylidene), benzylidene group, substituted benzylidene group, phthalimido and the like, R ⁷ is hydrogen, C _1-4 alkyl group, C _3-6 alkenyl group, C _3-7 cycloalkyl group , Acyloxyalkyl group or carboxyl protecting group, which are usually those which are easily removed under mild conditions, and are suitable, for example, with or without egg (C _1-12) group (such as iso captive field, t- butyl, etc.), lower alkoxy lower alkyl groups (e.g. methoxymethyl, ethoxymethyl, isobutoxy methyl, etc.), lower aliphatic alkoxy lower alkyl group (e.g., acetoxy Methoxy methyl, propionyl oxymethyl, botyryloxymethyl, pivaloyloxymethyl, etc.), lower alkoxycarbonyloxy lower alkyl groups (e.g., methoxycarbonyloxymethyl, 1-ethoxycarbonyloxymethyl, etc.), aryl Lower alkyl groups (e.g. p-methoxybenzyl, o-nitrobenzyl, p-nitrobenzyl, benzhydryl, phthalidyl, etc.), tri (lower alkyl) silyl groups (e.g. trimethylsilyl, t-butyldimethylsilyl, etc.) ), Diaryl (lower alkyl) silyl (e.g. t-butyldiphenyl silyl, etc.), tri (lower alkyl) silyl lower alkyl groups (e.g. trimethylsilylethyl, etc.), alkenyl (C _2-6 ) groups (e.g. allyl, and vinyl acetate, etc.), R ⁸ is 1-ethyl flow Oro or -CH (R ^a) -OR ^b group, where R ^a is a hydrogen or C _1-4 alkyl, R ^b is hydrogen in As the hydroxy protecting group, lower alkenyl groups (e.g. allyl etc.), lower alkanoyls (e.g. acetyl etc.), lower alkoxycarbonyl groups (e.g. t-butoxycarbonyl etc.), lower alkenyloxycarbonyl groups (e.g. allyloxy Carbonyl, etc.), aryl lower alkoxy carbonyl groups (e.g. benzoyloxycarbonyl, p-methoxybenzoyloxycarbonyl, etc.), trilower alkylsilyl groups (e.g. trimethylsilyl, t-butyldimethylsilyl, etc.), aryl lower alkyl groups Hydroxy protecting groups, such as benzyl etc., are preferable.

Suitable solvents for the reaction of compounds (II) and (III) are organic solvents such as chloroform and dichloromethane, and with tertiary organic amines such as triethylamine using an amide condensation reagent such as hydroxybenzotriazole. It proceeds well in the presence and the reaction temperature is suitable between -25 ℃ and 35 ℃.

Compounds (II) and (III) will be described in detail in the preparation examples of Method 1 described below.

The compound of general formula (II) can remove hydroxy protecting group, amino protecting group or carboxyl protecting group by conventional methods if necessary. That is, these protecting groups are removed by a suitable and easy method such as acid, base, metal or enzyme catalyst hydrolysis or reduction while minimizing the degree of destruction of the basic structure.

From the reaction product of the reaction, the desired compound of formula (I) can be separated or purified by various methods such as recrystallization, iontophoresis, silica gel column chromatography or ion exchange resin chromatography.

The compound of the present invention preferably relates to a compound having the structure of the following general formula (I ′).

Wherein R ³ , R ⁴ and R ⁵ are each as mentioned in claim 1.

Among the compounds according to the present invention, a preferred compound having high antibacterial activity is a compound of formula (I) wherein R 1 is 1-hydroxyethyl and R ² is methyl, ie, the following general formula (I-a) .

Ⅰ-a: (1R, 5S, 6S) -2-[(22'S, 4'S)-[2-[(2,3-dioxooctahydropipolo [3.4-b] pyrazine-6-carr Carbonyl) pyrrolidin] -4-yl] thio] -6-[(1'R) -hydroxyethyl] -1] -methylcarbafen-2-m-3-carboxylic acid

Compound (I) according to the present invention and its nontoxic salts (preferably alkali metal salts, alkyrito metal salts, organic salts, salts of inorganic acids and organic acid salts or amino acids) with respect to a wide range of pathogenic bacteria, including various Gram-positive and negative bacteria It has a high antimicrobial activity and is useful for the treatment of bacterial infections in animals including humans. The usefulness was evaluated by determining the minimum inhibitory concentration (Minimun Inhibitory Concentration) for the standard strain using the known compound meropenem as a control agent. The minimum inhibitory concentration was obtained by diluting the test compound by a 2-fold dilution method, spraying it on Muller-Hinton Ag ar medium, and inoculating 2 ml of the test strain having 10 ⁷ CFU / ml. It was obtained by incubating for 20 hours at ℃, the results are shown in Table 1.

As shown in Table 1, the compounds of the general formulas (I-a) to (I-d) show excellent antimicrobial activity against the MRSA strain, which has recently been a problem.

TABLE 1

In the following preparations and examples will be described in detail the process for preparing compound (I) of the present invention.

[Production example]

Compounds (II ') and (III) used in the following examples among the compounds of the general formulas (II) and (III) of the present invention are easily prepared according to the following method 1 or 2, Will be explained.

[Method 1]

[Method 2]

[Production Example 1]

2,5-dihydropyrrole-1-carboxylic acid t-butyl ester (2)

3.456 g (0.05 mol) of 2,5-dihydropyrroline (1) was added to chloroform (25 mL) and dissolved, and triethylamine (9.1 mL) was added at room temperature, and the solution was dissolved in chloroform (10 mL). Added di-t-butyl dicarbonate (13.12 g) solution is added dropwise and stirred for 30 minutes. The solution is diluted with dichloromethane (40 ml), washed with dilute hydrochloric acid, caustic soda solution and brine, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure to obtain the desired target compound (10.75 g).

[Production Example 2]

6-oxybicyclo [3.1.0] hexane-3-carboxylic acid t-butyl ester (3)

10.75 g (0.05 mole) of Compound (2) synthesized in Preparation Example 1 was dissolved in chloroform (80 ml), and at 0 ° C., a solution of MCPBA (17.26 g, 1.2 equivalents) dissolved in chloroform (40 ml) was added dropwise. After stirring at room temperature overnight. The resulting solution was filtered and diluted with dichloromethane (100 ml), washed with 10% sodium sulfate solution, gas solution soda solution and brine in that order, dried over anhydrous magnesium sulfate, evaporated under reduced pressure and purified by column chromatography to obtain the desired compound. (7.967 g, 86%).

[Manufacture example 3]

3-azido-4-hydroxy-2,5-dihydropyrrolidine-1-carboxylic acid-t-butyl ester (4)

7.967 g (0.043 mole) of Compound (3) synthesized in Preparation Example 2 was dissolved in a solvent of acetone: water (1: 1) ratio, and then sodium azide 13.98 g (5 equivalents) and ammonium chloride 4.60 g (2) Equivalent) and then refluxed for 16 hours. 50 ml of brine was added to the solution, followed by extraction four times with 50 ml of ether, dried, evaporated, and purified by column chromatography to obtain 10.48 g of the target compound in quantitative yield.

[Production Example 4]

3-azido-4-methanesulfonyloxy-2,5-dihydropyrrolidine-1-carboxylic acid t-butyl ester (5)

39.7 g (0.174 mole) of Compound (4) synthesized in Preparation Example 3 was dissolved in 300 ml of dichloromethane, and 34.13 ml of triethylamine was added. At 0 ° C., 16.15 ml of methanesulfonyl chloride dissolved in 100 ml of dichloromethane. (1.2 equiv) was added dropwise and stirred at room temperature for 3 hours. The solution was diluted with 200 ml of dichloromethane and extracted with a 0.5N HCl aqueous solution. The pH of the water was adjusted to 6, extracted with 100 ml of dichloromethane, washed with brine, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure to quantify the target compound. Got as.

Production Example 5

3,4-diazido-2,5-dihydropyrrolidine-1-carboxylic acid t-butyl ester (6)

18.38 g (0.06 mole) of Compound (5) synthesized in Preparation Example 4 was added to 9.75 g (2.5 equivalents) of sodium azide and 180 ml of dimethylformamide, and stirred for 2 hours while heating to 110 to 120 ° C. The reaction mixture was filtered, distilled under reduced pressure, and purified by column chromatography to obtain the target compound (11.67 g, yield 76.8%).

[Manufacture example 6]

3,4-diamino-2,5-dihydropyrrolidine-1-carboxylic acid t-butyl ester (7)

10.61 g (41.88 mmole) of the compound (6) synthesized in Preparation Example 5 was dissolved in tetrahydrofuran, and 21.97 g (2.0 equivalents) of triphenylphosphine was added at 0 ° C., and stirred at room temperature for 30 minutes, followed by 1 ml of water. Put in and stir at room temperature for 20 hours. The reaction mixture was evaporated under reduced pressure and purified by column chromatography to obtain 7.78 g (92.4%) of the title compound.

[Manufacture example 7]

2,3-dioxooctahydropyrrolo [3.4-b] -pyrazine-6-carotene t-butyl ester (8)

300 mg (1.4 mmole) of Compound (7) synthesized in Preparation Example 6 was dissolved in dichloromethane, 30 ml of diethyl oxalate was added, and the mixture was stirred at 100 ° C. overnight. The reaction mixture was extracted with water, evaporated under reduced pressure and purified by column chromatography to obtain 350 mg of the target compound.

[Manufacture example 8]

2,3-dioxooctahydropyrrolo [3.4-b] pyrazine trifluoroacetic acid salt (III ′)

300 mg (1.175 mmole) of Compound (8) synthesized in Preparation Example 7 was dissolved in 20 ml of trifluoroacetic acid at 0 ° C., and five drops of anisole were added dropwise, followed by further stirring for 30 minutes and evaporation under reduced pressure to obtain a desired compound quantitatively. .

[Manufacture example 9]

Allyl (1R, 5S, 6S) -2-[(2'S, 4'S)-[2- [1-allyloxycarbonyl-2-carboxyl) pyrrolidin] -4-yl] thio]- 6-[(1'R) -hydroxyethyl] -1-methylcarbafen-2-m-3-carboxylate (II ')

423 mg (0.77 mmole) of the known active phosphate compound (9) is dissolved in acetonitrile, and then 0.15 ml (1.2 equivalents) of diisopropylethylamine is added dropwise at -30 占 폚. 4-mercapto-pyrrolidine-1,2-dicarboxylic acid 1-allyl ester dissolved in 5 ml of acetonitrile was slowly added dropwise to the reaction mixture, stirred at 0 ° C. for 3 hours, and then distilled under reduced pressure to give column chromatography. Purification by the chromatography method yields 120 mg of the desired solid compound.

EXAMPLE

(A) Allyl (1R, 5S, 6S) -2- [2'S, 4'S)-[2- [1-allyloxycarbonyl-2,3-dioxooctahydropyrrolo [3.4-b] Pyrazine-6-carbonyl] pyrrolidin-4-yl] thio] -6-[(1'R) -hydroxyethyl] -1-methylcarbafen-2-m-3-carboxylate

Compound (II ′) (120 mg) synthesized in Preparation Example 9, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDC, 76.68 mg, 1.6 equivalents), 1-hydroxybenzotria Sol hydrate (HOBT, 54.05 mg, 1.6 equiv) is dissolved in dimethylformamide, and then 80.75 mg (1.2 equiv) of compound (III ′) synthesized in Preparation Example 8 is added.

Subsequently, 41.81 mg (1.2 equivalents) of triethylamine was added, followed by stirring at room temperature for 3 hours. The reaction mixture was evaporated under reduced pressure, diluted with dichloromethane, washed with water, the organic layer was dried over anhydrous magnesium sulfate, evaporated under reduced pressure, and purified by column chromatography to obtain the title compound (80 mg).

(B) (1R, 5S, 6S) -2-[(2'S, 4'S)-[2,3-dioxooctahydropyrrolo [3.4-b] pyrazine-6-carbonyl] pyrrolidine 4-yl] thio] -6-[(1'R) -hydroxyethyl] -1-methylcarbafen-2-m-3-carboxylic acid (I-a)

80 mg (0.1295 mmole) of the compound obtained in Example I (a) were dissolved in 3 ml of dimethylformamide under a nitrogen atmosphere, and 2,2-dimethyl-1,3-dioxane-4,6-dione (Meldrum's acid) 74.67 Add mg (4 equiv) and slowly add a catalytic amount of tetrakis (triphenylphosphine) palladium (0) (Pd (PPh ₃ ) ₄ ) solution dissolved in tetrahydrofuran. Light is blocked from the reactor and stirred for 2.5 hours before ether is added to form a precipitate. This precipitate is filtered and purified by column chromatography to give 9 mg of the desired pale yellow solid.

Claims (4)

Carbapenem compound represented by the following general formula (I), a pharmaceutically acceptable non-toxic salt thereof, or an isomer thereof. Wherein R ¹ represents a 1-hydroxy lower alkyl group, R ² represents hydrogen or a lower alkyl group, R ³ represents hydrogen or a C _3-6 alkenyl group, and R ⁴ and R ⁵ represent the carbon atom to which they are attached And form a six-membered ring containing two nitrogen atoms. The compound of claim 1, wherein R ¹ is 1-hydroxyethyl. The compound of claim 1, wherein R ² is hydrogen or methyl. A compound according to claim 1, wherein the compound of general formula (I) is represented by general formula (I-a): (1R, 5S, 6S) -2- (2'S, 4'S)-[2-[(2, 3-dioxooctahydropyrrolo [3,4-b] pyrazine-6-carbonyl) pyrrolidin] -4-yl] thio] -6-[(1'R) -hydroxyethyl] -1] A compound that is -methylcarbafen-2-m-3-carboxylic acid, or a pharmaceutically acceptable non-toxic salt thereof or an isomer thereof.