KR100246953B1 - Novel carbapenem compounds - Google Patents

Abstract

The present invention relates to novel carbapenem derivatives of the following general formula (I), salts, esters, solvates and isomers thereof which are useful as antibacterial agents.

Where

R ¹ represents 1-hydroxy ethyl, 1-aminoethyl, 1-fluoroethyl or hydroxy methyl, R ² represents hydrogen, a C _1-4 alkyl group, aminomethyl or 2-aminoethyl group,

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,

R ⁴ is hydrogen, C _1-4 alkyl group, aralkyl group or —NRR ′ wherein R and R ′ are each independently hydrogen, C _1-4 alkyl group, C _3-6 alkenyl group, C _3-7 cycloalkyl group or acyl Oxy alkyl group), R ⁵ and R ⁶ each independently represent hydrogen, a C _1-4 alkyl group, a C _3-6 alkenyl group, a C _3-7 cycloalkyl group, an acyloxyalkyl group.

Description

New Carbapenem Antibiotics

The present invention provides novel carbapenem compounds of formula (I), pharmaceutically acceptable non-toxic salts thereof, physiologically hydrolyzable esters, hydrates and solvates thereof, isomers thereof and methods for preparing the same, useful as antibiotics It is about the intermediates in the process and their preparation.

Where

R ¹ represents 1-hydroxy ethyl, 1-aminoethyl, 1-fluoroethyl or hydroxy methyl,

R ² represents hydrogen, a C _1-4 alkyl group, aminomethyl or 2-aminoethyl group,

R ³ is hydrogen, a C _1-4 alkyl group. C _3-6 alkenyl group. A C _3-7 cycloalkyl group or acyloxyalkyl group,

R ⁴ is hydrogen, C _1-4 alkyl group, aralkyl group or —NRR ′ wherein R and R ′ are each independently hydrogen, C _1-4 alkyl group, C _3-6 alkenyl group, C _3-7 cycloalkyl group or acyl Oxyalkyl group),

R ⁵ and R ⁶ each independently represent hydrogen, a C _1-4 alkyl group, a C _3-6 alkenyl group, a C _3-7 cycloalkyl group, an acyloxyalkyl group.

The present invention also encompasses epimeric, diastereo isomers and tautomeric isomers which may be represented by 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 catt1eya (J. Am. Chem. Soc. 1978). , 100, 6491). As it turns out that this new structure of compound has a broad spectrum of antimicrobial activity, the study of carbapenem antibiotics begins. Imipenem was then developed by Merck (J. Med. Chem. 1979, 22, 1435), which overcomes chemical instability due to the structural specificity of thienamycin. However, like thietamycin, imipenem has been found to be degraded by the dihydropeptidase (DHP-I, Dehydropeptidase-I) secreted by the kidney. As a result, it is used in combination with Cilastatin, a DHP-I inhibitor. (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. In particular, carbapenem derivatives have been reported that have excellent antibacterial 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. A representative compound is Meropenem, reported by Sumitomo (J. Antibiot. 1990, 519). On the other hand, the development of antibiotics with a broader and stronger antimicrobial force is required due to the constant expression of resistant bacteria.

Various derivatives have been studied in which the C-2 position of the carbapenem nucleus is linked to a substituted heterocyclic alkylthio group.

For example, Kim et al. (J. Antibiot. 1987, 1702) describe carbapenem antibiotics of the following general formula (A).

Where

n is 1 or 2,

Het is quaternary amine, quaternary heterocompound, sulfonium derivative and the like.

Some of these derivatives have been reported to have a slightly improved antimicrobial activity compared to imipenem.

However, due to the absence of 1β-methyl group, it does not overcome the disadvantage of degradation by the dihydropeptidase secreted by the kidney.

Kim et al. (J. Antibiot. 1989, 681) described the following carbapenems

It describes antibiotics.

Where

Het is a substituted pyridinium derivative, a substituted imidazolium derivative, and the like. As a first example of a 2-alkylthiocarbapenem derivative incorporating a 1-methyl group at the C-2 position of the carbapenem nucleus, the stability to the dihydropeptidase secreted by the kidney was greatly improved. However, antimicrobial activity against Pseudomonas aeruginosa is still in need of improvement compared to imipenem, and various inducers have not been synthesized. Onoue et al. (J. Antibiot. 1989, 1100) describe carbapenem antibiotics of the following general formula (C).

Where

R ¹ is acetylaminomethyl, aminomethyl, substituted 4-pyridinium, and the like.

However, the process of introducing 7α-methyl group is multi-step, and also in antibacterial activity

There is no great advantage and still has the disadvantage of being degraded by the dihydropeptidase secreted by the kidney.

Heck et al. Through South African Patent No. 8,900,971,

Carbapenem antibiotics are described.

Where

R ¹ is hydrogen or a methyl group.

R ² is hydrogen, fluorine, chlorine or the like.

However, no mention is made of the antimicrobial activity of these derivatives.

Ruediger et al. (J. ○ rg. Chem. 1991, 56, 3183) through the following structural formula

(E) Carbapenem antibiotics are described.

However, the process of introducing 6-hydroxyethyl group is multistep, and there is no great advantage in antibacterial activity.

Mazthalers et al. Describe J. Med. Chem. 1992, 953 for carbapenem antibiotics of the following general formula:

Where

R ¹ is hydroxymethyl, aminomethyl, substituted hydroxypropenyl, substituted aminopropenyl, and the like,

R ² is a substituted pyridine derivative and the like.

However, the process according to the 6-position transformation of the carbapenem nucleus is multistep and has no advantage in terms of antimicrobial activity or stability to dihydropeptidase. That is, 6-hydro or aminomethyl derivatives have the disadvantage of being easily degraded by the dihydropeptidase secreted by the kidney, and substituted 6-hydro or aminopropenyl derivatives have been reported to have a markedly low antibacterial activity. Martel et al. Describe in European Patent No. 433,759 the carbapenem antibiotic of the following general formula.

Where

R ¹ is hydrogen, C _1-2 alkyl, hydroethyl and the like,

A is an unsubstituted or substituted C _1-10 alkylene group, and the like,

R ² is hydroxy, halogen, C _1-4 alkoxy, nitrile, azido, quaternary amminio, amino, azetidinyl, 5- or hexagonal heterocyclic group and the like,

R ³ is an organic group,

R ⁴ is hydrogen, a removable carboxylic acid protecting group, or a physiologically hydrolysable ester group,

B is a straight or branched C _1-6 alkylene group, or R ³ is a direct bond to carbon by sulfur.

This patent describes derivatives obtained by varying the C-1 position of the carbapenem nucleus and their antimicrobial activity. The process of obtaining stereoselective 1β-alkyl intermediates is complicated. There is not enough antibacterial data reported. Accordingly, the present inventors have conducted studies to introduce various derivatives at the C-2 position of carbapenem, and thus, (1,5,6-substituted-4-aminopyrimidin-2-yl) thioethyl, which is the core of the present invention, has been studied. The discovery of the fact that a carbapenem compound with a thio group shows strong activity against a wide range of pathogens has led to the completion of the present invention for the compound represented by the above 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. Furthermore, since the compound of general formula (I) may have the same resonance structure as general formula (I ′), such a resonance structure is 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, 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. Or 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 formula (I) include indanyl and phthalidyl. Methoxymethyl, pivaloyloxymethyl, glycyloxymethyl, phenylglycosyloxymethyl, 5-methyl-2-oxo-1,3-dioxoren-4-yl betyl and penicillin and cephalosporin It is known and includes other physiologically hydrolysable esters used. Such esters can be prepared by known methods.

Formula (I) compound has high antimicrobial activity against various Gram-negative bacteria and is used for prevention and treatment of bacterial infection 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 compositions are in the form of solutions, suspensions or emulsions in oil or aqueous media and may contain conventional dispersing agents, suspending agents or stabilizers. In addition, the composition may be in the form of a dry powder used, for example, as sterile, pyrogen-free water, dissolved before use. The 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 1500 mg of the active ingredient of the compound of formula (I). The dosage of the compound of general formula (I) depends on the doctor's prescription depending on factors such as the weight and age of the patient and the specific nature and severity of the disease.

However, dosages required for adult treatment typically range from about 500 to 5,000 mg per day, depending on the frequency and route of administration. A total daily dosage of about 150 to 3,000 mg per day will be sufficient, separated into single doses for intramuscular or intravenous administration to adults, but higher daily dosages are 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 Sta-phylococcus aureus) has a significantly higher antimicrobial activity than the control drug Meropenem (Meropenem). MRSA is a bacterium that is very resistant to antibiotics, and considering that its treatment is not easy for infectious diseases, the usefulness of the compound according to the present invention is very high.

Compounds of formula (I), pharmaceutically acceptable non-toxic salts thereof, physiologically hydrolysable esters, hydrates or solvates thereof according to the present invention may be prepared by the following compounds of formula (II) It is prepared by reacting with a compound of formula (III) and removing the hydroxy protecting group or acid protecting group before or after the reaction if necessary.

Where

R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ are as described above,

R ⁷ is hydrogen, a C _1-4 alkyl group, C _3-6 alkenyl group, C _3-7 cycloalkyl group, acyloxyalkyl group or carboxyl protecting group, and an alkyl (C _1-12 ) group (e.g. isopropyl, t- Butyl, etc.), lower alkoxy, lower alkyl groups (e.g. methoxymethyl, ethoxymethyl, isobutoxymethyl, etc.) lower aliphatic alkoxy lower alkyl groups (e.g. acetoxy methyl, propionyl oxymethyl, butyrylxycimethyl, fibaroyl Oxymethyl), 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-butyldi Phenyl silyl, etc.), tri (lower alkyl) silyl lower alkyl groups (eg trimethylsilylethyl, etc.), alkenyl (C _2-6 ) groups (eg allyl, vinylethyl, etc.) ⁸ is a 1-fluoro ethyl, or —CH (R ^a ) —OR ^b group. R ^a represents hydrogen or a C _1-4 alkyl group, R ^b is a hydrogen or hydroxy protecting group, lower alkenyl group (e.g. allyl etc.), lower alkanoyl (e.g. acetyl etc.), lower alkoxycarbonyl group (e.g. t -Butoxycarbonyl, etc.), lower alkenyl oxycarbonyl groups (e.g. allyl oxycarbonyl, etc.), aryl lower alkoxy carbonyl groups (e.g. benzoyl oxycarbonyl, p-methoxybenzoyloxycarbonyl, etc.), trilower alkylsilyl Group (e.g. trimethylsilin, t-butyldimethylsilyl, etc.) or an aryl lower alkyl group (e.g. benzyl, etc.),

X is halogen, alkanoyloxy group, alkanesulfonyloxy, arylsulfonyloxy, alkoxycarbonyloxy or phosphoric ester such as chlorine, bromine or iodine.

Suitable solvents for the reaction of compounds (II) and (III) are organic solvents of the same kind as dimethyl formamide, acetonitrile, and proceed well in the presence of inorganic salts such as alkali metals (e.g. potassium halides). Suitable is between 25 ° C and 35 ° C.

Compound (II) is well known in the literature for other carbapenems, such as US Pat. No. 5,064,954 and the like. The compound of general formula (II) may remove hydroxy protecting group or carboxyl protecting group by conventional methods if necessary. That is, these protecting groups are acid, base, with a minimum degree of destruction of the basic structure. It is removed by a suitable and easy method such as hydrolysis or reduction of metal or enzyme catalyst. 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.

Examples of preferred compounds having high antimicrobial activity among the compounds according to the present invention include compounds of formula (I) wherein R ¹ is 1-hydroxyethyl, R ² is methyl, R ⁴ is methyl or amino, i.e. In Ia) is a compound of (Ih) and a non-toxic salt thereof.

Ia: (4R, 5S, 6S) -3- [2-[(4-aminopyrimidin-2-yl) thio] ethylthio] -6-[(1'R) -hydroxyethyl] -4-methyl -7-oxo-1-azabicyclo [3.2.0] hept-2-ene-2-carboxylic acid

Ib: (4R, 5S, 6S) -3- [2-[(4,6-diaminopyrimidin-2-yl) thio] ethylthio1-6-[(1'R) -hydroxyethyl]- 4-Methyl-7-oxo-1-azabicyclo [3.2.0] hept-2-ene-2-carboxylic acid

Ic: (4R, 5S, 6S) -3- [2-[(4-amino-1-methylpyrimidin-2-yl) thio] ethylthio] -6-[(1'R) -hydroxyethyl -4-methyl-7-oxo-1-azabicyclo [3.2.0] hept-2-ene-2-carboxylate

Id: (4R, 5S, 6S) -3- [2-[(4,6-diamino-1-methylpyrimidin-2-yl) thio] ethylthio] -6-[(1'R)- Hydroxyethyl] -4-methyl-7-oxo-1-azabicyclo [3.2.0] hept-2-ene-2-carboxylate

Ie: (4R, 5S, 6S) -3- [2- (4,5,6-triaminopyrimidin-2-yl) thio] ethylthio] -6-[(1'R) -hydroxyethyl ] -4-methyl-7-oxo-1-azabicyclo [3.2.0] hept-2-ene-2-carboxylate

If: (4R, 5S, 6S) -3- [2-[(1,4-diaminopyrimidin-2-yl) thio] ethylthio] -6-[(1'R) -hydroxyethyl] -4-methyl-7-oxo-1-azabicyclo [3.2.0] hept-2-ene-2-carboxylate

Ig: (4R, 5S, 6S) -3- [2-[(1,4,6-triaminopyrimidin-2-yl) thio] ethylthio] -6-[(1'R) -hydroxy Ethyl] -4-methyl-7-oxo-1-azabicyclo [3.2.0] hept-2-ene-2-carboxylate

Ih: (4R, 5S, 6S) -3- [2-[(1,4,6-triaminopyrimidin-2-yl) thio] ethylthio] -6-[(1'R) -hydroxy Ethyl] -4-methyl-7-oxo-1-azabicyclo [3.2.0] hept-2-ene-2-carboxylate

General formula (I) compounds and their nontoxic salts (preferably alkali metal salts, alkali metal salts, organic salts, salts with inorganic and organic acid salts or amino acids) according to the invention are a wide variety of pathogenic bacteria, including various Gram-positive and negative bacteria. It has high antimicrobial activity against and is useful for the treatment of bacterial infections in animals including humans.

The usefulness was evaluated by calculating the minimum inhibitory concentration (Minimum Inhibitory Concentration) for the standard strain using the known compound Meropenem as a control drug. The minimum inhibitory concentration was obtained by diluting the test compound by a 2-fold dilution method, dispersing it in Muller-Hinton Agar medium, and then inoculating 2 ml of a test strain having 10 ⁷ CFU / ml at 37 ° C. Incubation was performed for 20 hours, and the results are shown in Table 1.

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

TABLE 1

Minimum inhibitory concentrations of test and control compounds.

Table 1 (continued)

In the following Examples, the process for preparing Compound (I) of the present invention will be described in detail.

[Production example]

Allyl (4R, 5S, 6S) -3-[(2-iodoethyl) thio] -6-[(1'R) -hydroxyethyl] -4-methyl- as starting material for Examples 1-8 7-oxo-1-azabicyclo [3.2.0] hept-2-ene-2-carboxylate is obtained by the following method.

Step 1: Allyl (4R, 5S, 6S) -3-[(2-hydroxyethyl) thio] -6-[(1'R) -hydroxyethyl] -4-methyl-7-oxo-1-aza Synthesis of Bicyclo [3.2.0] hept-2-ene-2-carboxylate Allyl (4R, 5S, 6S) -3-hydroxy-6-[(1'R) -hydroxyethyl] -4- 13.0 g (48.5 mmol) of methyl-7-oxo-1-azabicyclo [3.2.0] hept-2-ene-2-carboxylate are dissolved in anhydrous acetonitrile (200 ml) under nitrogen, and then cooled to 0 ° C. Let's do it. 15.l ml (72.8 mmol) of diisopropylethylamine are added dropwise to the reaction mixture, followed by 10.1 ml (58.2 mmol) of diphenylchlorophosphate. After stirring for 30 minutes at 0 ° C., 10.hnl (58.2 mmol) of diisopropylethylamine was added dropwise, and a solution of 4.10 ml (58.2 mmol) of 2-mercaptoethanol dissolved in anhydrous acetonitrile (30 ml) was slowly added dropwise. Then, the mixture is further stirred at 0 ° C. for 3 hours. Dilute with ethyl acetate (1.50 L), wash sequentially with water (1.50 L), 20% aqueous H ₃ PO ₄ solution (750 ml), and brine. The organic layer is dried over magnesium sulfate, filtered and distilled under reduced pressure. Hexane and ethyl acetate (1: 5) mixed solvents were purified by column chromatography on silica gel using eluent to yield the title compound as an off-white solid (5.91 g. 43% yield).

Step 2: Allyl (4R, 5S, 6S) -3-[(2-methanesulfonyloxyethyl) thio] -6-[(1'R) -hydroxyethyl] -4-methyl-7-oxo-1 Synthesis of azabicyclo [3.2.0] hept-2-ene-2-carboxylate 1.75 g (5.11 mmol) of the compound synthesized in Step 1 was dissolved in 100 ml of tetrahydrofuran under nitrogen, followed by -40 ° C. 855 μℓ of triethylamine in

(6.13 mmol) is added dropwise and 440 μL (5.62 mmol) of methanesulfonylchloride is added dropwise. The half temperature is raised to 0 ° C. over 1 hour and stirred for 20 minutes. Dilute with ethyl acetate (300 ml),

Wash twice with aqueous ammonium chloride solution and brine. Magnesium Sulfate Organic Layer

Dried over water, filtered and distilled under reduced pressure. Purified by column chromatography on silica gel using hexane and ethyl acetate (1: 3) as a eluent to obtain the title compound (1.82 g, yield: 85%).

Step 3: Allyl (4R, 5S, 6S) -3-[(2-iodoethyl) thio] -6-[(1'R) -hydroxyethyl-4-methyl-7-oxo-1-azabicycle Synthesis of Rho [3.2.0] hept-2-ene-2-carboxylate

1.50 g (3.56 mmol) of the compound synthesized in Step 2 is dissolved in 100 ml of acetone, and then 1.10 g (7.12 mmol) of sodium iodide is added dropwise. The reaction mixture is heated to reflux for 4 hours and cooled. The solvent was removed by distillation under reduced pressure, dichloromethane (50 ml) and ether (10.0 ml) were added dropwise and stirred, and the residue was filtered. The filtrate was distilled under reduced pressure to give the title compound as an off-white solid (1.31 g, yield: 90%).

Example 1

end. Allyl (4R, 5S, 6S) -3- [2-[(4-aminopyrimidin-2-yl) thio] ethylthio] -6-[(1'R) -hydroxyethyl] -4-methyl- 7-oxo-1-azabicyclo [3.2.0] hept-2-ene-2-carboxylate allyl (4R, 5S, 6S) -3-[(2-iodoethyl) thio] -6- [ 400 mg (0.94 mmol) of (1'R) -hydroxyethyl] -4-methyl-7-oxo-1-azabicyclo [3.2.0] hept-2-ene-2-carboxylate was added to 3.00 ml of dimethyl. It is dissolved in formamide, 119 mg (0.94 mmol) of 4-aminopyrimidine-2-thiol is added, followed by the dropwise addition of 180 µl (1.04 mmol) of diisopropylethylamine, followed by stirring at room temperature for 3 hours. The reaction mixture was distilled under reduced pressure to remove the solvent, and a dichloromethane and methanol (20: 1) mixed solvent was purified by silica chromatography on silica gel as an eluent to obtain the title compound as an off-white solid (240 mg, 6 l%).

I. (4R, 5S, 6S) -3- [2-[(4-aminopyrimidin-2-yl) thio] ethylthio] -6-[(1'R) -hydroxyethyl] -4-methyl-7 -Oxo-1-azabicyclo [3.2.0] hept-2-ene-2-carboxylic acid (Ia)

Example 1 220 mg (0.52 mmol) of the compound synthesized in (A) and 2,2-dimethyl-1,3-

188 mg (1.30 mmol) of dioxane-4,6-dione (Meldrum's acid) was dissolved in dimethylformamide (1.00 ml) and dichloromethane (8.00 ml) under nitrogen, and then tetrakis (triphenylphosphine) palladium (0) Add 70 mg (0.06 mmol). Light was blocked in the reactor and stirred for 3 hours before ether (20.0 ml) was added to form a precipitate. The precipitate is filtered, washed with dichloromethane and ether, and then purified by column chromatography on silica gel using a mixture of acetonitrile and distilled water (12: 1) as an eluent to obtain the title compound.

(126 mg. Yield 6 I%).

Example 2

end. Allyl (4R, 5S, 6S) -3- [2-[(4,6-diaminopyrimidin-2-yl) thio] ethylthio] -6-[(1'R) -hydroxyethyl] -4 -Methyl-7-oxo-1-azabicyclo [3.2.0] hept-2-ene-2-carboxylate

A desired compound is obtained in a similar manner to Example 1 (A).

I. (4R, 5S, 6S) -3- [2-[(4,6-diaminopyrimidin-2-yl) thio] ethylthio] -6-[(1'R) -hydroxyethyl] -4- Methyl-7-oxo-1-azabicyclo [3.2.0] hept-2-ene-2-carboxylic acid (Ib)

A desired compound is obtained in a similar manner to Example 1 (b).

Example 3

end. Allyl (4R, 5S, 6S) -3- [2-[(4-amino-1-methylpyrimidin-2-yl) thio] ethylthio] -6-[(1'R) -hydroxyethyl] 4-Methyl-7-oxo-1-azabicyclo [3.2.0] hept-2-ene-2-carboxylate iodine salt

The desired compound is obtained in a similar manner to Example 1 (A).

I. (4R, 5S, 6S) -3- [2-[(4-amino-1-methylpyrimidin-2-yl) thio] ethylthio] -6-[(1'R) -hydroxyethyl]- 4-methyl-7-oxo-1-azabicyclo [3.2.0] hept-2-ene-2-carboxylate (Ic)

In the same manner as in Example 1 (b), the desired compound is obtained.

Example 4

end. Allyl (4R, 5S.6S) -3- [2-[(4,6-diamino-1-methylpyrimidin-2-yl) thio] ethylthio] -6-[(1'R) -hydrate Oxyethyl] -4-methyl-7-oxo-1-azabicyclo [3.2.0] hept-2-ene-2-carboxylate iodine salt

A desired compound is obtained in a similar manner to Example 1 (A).

I. (4R, 5S, 6S) -3- [2-[(4,6-diamino-1-methylpyrimidin-2-yl) thio] ethylthio] -6-[(1'R) -hydroxy Ethyl] -4-methyl-7-oxo-1-azabicyclo [3.2.0] hept-2-ene-2-carboxylate (Id)

In the same manner as in Example 1 (b), the desired compound is obtained.

Example 5

end. Allyl (4R, 5S, 6S) -3- [2-[(4.5,6-triaminopyrimidin-2-yl) thio] ethylthio] -6-[(1'R) -hydroxyethyl]- 4-methyl-7-oxo-1-azabicyclo [3.2.0] hept-2-ene-2-carboxylate iodine salt

A desired compound is obtained in a similar manner to Example 1 (A).

I. (4R, 5S, 6S) -3- [2-[(4,5,6-triaminopyrimidin-2-yl) thio] ethylthio] -6-[(1'R) -hydroxyethyl] 4-Methyl-7-oxo-1-azabicyclo [3.2.0] hept-2-ene-2-carboxylate (Ie)

In the same manner as in Example 1 (b), the desired compound is obtained.

Example 6

end. Allyl (4R, 5S, 6S) -3- [2-[(1,4-diaminopyrimidinium-2-yl) thio] ethylthio] -6-[(1'R) -hydroxyethyl]- 4-methyl-7-oxo-1-azabicyclo [3.2.0] hept-2-ene-2-carboxylate iodine salt

A desired compound is obtained in a similar manner to Example 1 (A).

I. (4R, 5S, 6S) -3- [2-[(1,4-diaminopyrimidin-2-yl) thio] ethylthio] -6-[(1'R) -hydroxyethyl] -4 -Methyl-7-oxo-1-azabicyclo [3.2.0] hept-2-ene-2-carboxylate

(I-f)

In the same manner as in Example 1 (b), the desired compound is obtained.

Example 7

end. Allyl (4R, 5S, 6S) -3- [2-[(1,4,6-triaminopyrimidin-2-yl) thio] ethylthio] -6-[(1'R) -hydroxyethyl ] -4-methyl-7-oxo-1-azabicyclo [3.2.0] hept-2-ene-2-carboxylate iodine salt

A desired compound is obtained in a similar manner to Example 1 (A).

I. (4R, 5S, 6S) -3- [2-[(1,4,6-triaminopyrimidin-2-yl) thio] ethylthio] -6-[(1'R) -hydroxyethyl] 4-Methyl-7-oxo-1-azabicyclo [3.2.0] hept-2-ene-2-carboxylate (Ig)

In the same manner as in Example 1 (b), the desired compound is obtained.

Example 8

(A) Allyl (4R, 5S, 6S) -3- [2-[(1,4,6-triaminopyrimidin-2-yl) thio] ethylthio] -6-[(1'R)- Hydroxyethyl-4-methyl-7-oxo-1-azabicyclo [3.2.0] hept-2-ene-2-carboxylate iodine salt

A desired compound is obtained in a similar manner to Example 1 (A).

(B) (4R, 5S, 6S) -3- [2-[(1,4,6-triaminopyrimidinium-2-yl) thio] ethylthio] -6-[(1'R) -hydrate Oxyethyl] -4-methyl-7-oxo-1-azabicyclo [3.2.0] hept-2-ene-2-carboxylate (Ih)

In the same manner as in Example 1 (b), the desired compound is obtained.

Claims (4)

Carbapenem compound represented by the following general formula (I), pharmaceutical Acceptable nontoxic salts thereof or isomers thereof. Where R ¹ represents a 1-hydroxy lower alkyl group, R ² represents hydrogen or a lower alkyl group, R ³ and R ⁴ are not present in any of the substituents, When R ³ is hydrogen or a C _3-6 alkenyl group, R ⁴ is not present; When R ³ is not present, R ⁴ represents a lower alkyl group or an amino group High, R ⁵ and R ⁶ each independently represent hydrogen or amino. The compound of claim 1, wherein R ¹ is 1-hydroxyethyl. The compound of claim 1, wherein R ² is hydrogen or methyl. The compound according to claim 1, wherein the compound of formula (I) is selected from the following (I-a) to (I-h), or a pharmaceutically acceptable non-toxic salt thereof or an isomer thereof. I-a: (4R, 5S, 6S) -3- [2-[(4-aminopyrimidin-2-yl) thio] ethylthi O] -6-[(1'R) -hydroxyethyl] -4-methyl-7-oxo-1-azabicyclo [3.2.0] hept-2-ene-2-carboxylic acid I-b: (4R, 5S, 6S) -3- [2-[(4,6-diaminopyrimidin-2-yl) thio] ethylthi O] -6-[(1'R-hydroxyethyl] -4-methyl-7-oxo-1-azabicyclo [3.2.0] hept-2-ene-2-carboxylic acid Ic: (4R, 5S, 6S) -3- [2-[(4-amino-1-methylpyrimidin-2-yl) thio] ethylthio] -6-[(1'R) -hydroxyethyl ] -4-methyl-7-oxo-1-azabicyclo [3.2.0] hept-2-ene-2-carboxylate Id: (4R, 5S, 6S) -3- [2-[(4,6-diamino-1-methylpyrimidin-2-yl) thio] ethylthio] -6-[(1'R)- Hydroxyethyl] -4-methyl-7-oxo-1-azabicyclo [3.2.0] hept-2-ene-2-carboxylate Ie: (4R, 5S, 6S) -3- [2- (4,5,6-triaminopyrimidin-1-methyl-2-yl) thio] ethylthio] -6-[(1'R) -Hydroxyethyl] -4-methyl-7-oxo-1-azabicyclo [3.2.0] hept-2-ene-2-carboxylate If: (4R, 5S, 6S) -3- [2-[(1,4-diaminopyrimidin-2-yl) thio] ethylthio] -6-[(1'R) -hydroxyethyl] -4-methyl-7-oxo-1-azabicyclo [3.2.0] hept-2-ene-2-carboxylate Ig: (4R, 5S, 6S) -3- [2-[(1,4,6-triaminopyrimidin-2-yl) thio] ethylthio] -6-[(1'R) -hydroxy Ethyl] -4-methyl-7-oxo-1-azabicyclo [3.2.0] hept-2-ene-2-carboxylate Ih: (4R, 5S, 6S) -3- [2-[(1,4,6-triaminopyrimidinium-5-methyl-2-yl) thio] ethylthio] -6-[(1'R ) -Hydroxyethyl] -4-methyl-7-oxo-1-azabicyclo [3.2.0] hept-2-ene-2-carboxylate