JPH072856A - 1-methylcarbapenem derivative - Google Patents

Abstract

PURPOSE:To obtain a new derivative, composed of a 1-methylcarbapenem derivative, having strong antimicrobial activity, stable to dehydropeptidase I and a high recovery ratio in urine and effective in treating, etc., microbism due to a wide range of pathogenic bacteria. CONSTITUTION:A compound having formula I (R<3> is carboxy-protecting group) such as 4-nitrobenzyl (1R,5R,6S)-6-[(1R)-1-hydroxyethyl]-1-methyl-2-oxo-1- carbapenam-3-carboxylate is reacted with a dialkylphosphoryl halide, etc., in the presence a base and resultant product without isolation is then reacted with a mercaptan having the formula R<1>-SH [R<1> is (substituted)lower alkyl, (substituted) aryl, etc.] in the presence a base. The carboxy-protecting group is subsequently removed to afford the objective 1-methylcarbapen-2-em-3- carboxylic acid derivative having formula II and excellent antimicrobial action.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a novel 1-methylcarbapenem derivative having an excellent antibacterial action.

[0002]

BACKGROUND OF THE INVENTION Thienamycin derivatives have excellent antibacterial activity, but they are degraded by dehydropeptidase I, which is an inactivating enzyme of thienamycin derivatives present in the human body, and lose their activity, resulting in low urinary recovery. (H. Kropp et al., Antimicrob. Agents. Che
mother., 22, 62, (1982): SR Norrby et al., ibi
d., 23, 300 (1983)).

[0003]

DISCLOSURE OF THE INVENTION The present inventors have conducted various studies to solve this drawback of thienamycin derivatives, and the novel carbapenem derivative (1) has a stronger antibacterial activity than the thienamycin derivatives and exhibits dehydropeptidase I. The present invention has been completed by discovering that it is stable against urine and has a high recovery rate in urine.

[0004]

The present invention is based on the formula

[0005]

[Chemical 2]

1-methylcarbapenem derivatives having and salts thereof and esters thereof.

In the formula, R ¹ is carbamoyloxy or the following group substituted with carbamoyl, a lower alkyl group,
A cycloalkyl group, an aralkyl group, an aryl group, a heteroaryl group, a heteroaralkyl group, or an alkylheteroaralkyl group is shown.

Suitable R ¹ is 2-carbamoyloxyethyl, 1-carbamoyloxy-2-propyl,
A carbamoyloxy-substituted alkyl group such as 2-carbamoyloxypropyl, 3-carbamoyloxypropyl, or 3-carbamoyloxycyclobutyl; 2-
Carbamoyloxy-substituted cycloalkyl groups such as carbamoyloxycyclopentyl or 4-carbamoyloxycyclohexyl; carbamoyloxy-substituted aralkyl groups such as 4-carbamoyloxybenzyl or 2-carbamoyloxyphenethyl; carbamoyl such as 3-carbamoyloxyphenyl Oxy-substituted aryl group; 4-carbamoyloxy-2-thienyl or 3
Carbamoyloxy-substituted heteroaryl groups such as carbamoyloxy-2-furyl; carbamoyloxy-substituted heteroaralkyl groups such as 4-carbamoyloxy-2-thenyl or 5-carbamoyloxymethylfurfuryl; 4-carbamoyloxymethylfurfuryl A carbamoyloxy-substituted alkylheteroaralkyl group such as; carbamoylmethyl, 2-carbamoylethyl, 1
A carbamoyl-substituted alkyl group such as carbamoylethyl, 3-carbamoylpropyl or 1-carbamoyl-2-propyl; 2-carbamoylcyclopropyl,
2-carbamoylcyclobutyl, 3-carbamoylcyclopentyl, 2-carbamoylcyclopentyl or 4
A carbamoyl-substituted cycloalkyl group such as carbamoylcyclohexyl; a carbamoyl-substituted aralkyl group such as 4-carbamoylbenzyl; a carbamoyl-substituted aryl group such as 4-carbamoylphenyl; 4-carbamoyl-2-thiazolyl or 4-carbamoyl-2
A carbamoyl-substituted heteroaryl group such as -thienyl; a carbamoyl-substituted heteroaralkyl group such as 4-carbamoylthenyl, 4-carbamoylfurfuryl or a carbamoyl-substituted alkylheteroaralkyl group such as 4-carbamoylmethylfurfuryl.

The salt of compound (1) is, for example, lithium,
Inorganic or ammonium salts such as sodium, potassium, calcium, magnesium, triethylamine,
Examples thereof include salts with organic bases such as diisopropylamine and cyclohexylamine, and sodium and potassium salts are preferable.

The ester of the compound (1) is an ester which is metabolized and hydrolyzed in the living body, and the ester residue thereof is -CR ⁹ R ¹⁰ OCOOR ¹¹ group, -CR ⁹ R ¹⁰ OCOR ¹¹ group ( R ⁹ , R ¹⁰
Are the same or different and represent a hydrogen atom or an alkyl group, and the alkyl group is, for example, methyl, ethyl, propyl, isopropyl or butyl. R ¹¹ is an alkyl group; a cycloalkyl group, an alkenyl group, a cycloalkenyl group or an alkynyl group which may be substituted with an alkyl group; an aralkyl group or a cycloalkylalkyl which may be substituted with an alkyl group, an alkoxy group or an acyloxy group The alkyl group represented by R ¹¹ is, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, S-butyl, t-butyl, pentyl or 3-pentyl, and is substituted with the alkyl group represented by R ^11. Examples of the cycloalkyl group and the cycloalkyl group of the cycloalkylalkyl group include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, menthyl, 3-pinanyl or adamantyl, which may be substituted with the alkyl group of R ^11. Good al Kenyl groups are, for example, allyl, butenyl,
Examples of the alkenyl group which may be substituted with an alkyl group of R ¹¹ include cyclohexenyl and cyclopentenyl, and an alkynyl group which may be substituted with an alkyl group of R ¹¹ is propargyl,
Examples include butynyl and pentinyl.

The aralkyl group which may be substituted with an alkyl group, an alkoxy group or an acyloxy group for R ¹¹ is, for example, benzyl or phenethyl, and the alkoxy group as the substituent is, for example, methoxy or ethoxy.
Acyloxy groups include acetoxy, propionyloxy and pivaloyloxy.

Cycloalkyl group substituted with an alkyl group of R ^11, an alkenyl group, a cycloalkenyl group, an alkyl group of an alkynyl group and aralkyl group such as methyl, ethyl, propyl, isopropyl, butyl or isobutyl are exemplified, R ¹¹ The cycloalkylalkyl group of is, for example, cycloalkylmethyl, 1-cycloalkylethyl, 2-cycloalkylethyl or 1-cycloalkylpropyl. ),

[0013]

[Chemical 3]

(R ¹² and R ¹³ are the same or different and each represents a hydrogen atom, an alkyl group, an aryl group or R ¹² and R ^13.
Together, ¹³ represent an alkylene group. The alkyl group is, for example, methyl, ethyl, propyl, isopropyl, butyl or s-butyl, the aryl group is, for example, phenyl, and the alkylene group is, for example,-(CH ₂ ) _3- or-( CH ₂ ) ₄ -can be mentioned. )
Alternatively, a phthalidyl group may be used.

A preferred ester residue is acetoxymethyl,
1-acetoxyethyl, 1-acetoxypropyl, pivaloyloxymethyl, 1- (pivaloyloxy) ethyl, 1- (pivaloyloxy) propyl, 2- (pivaloyloxy) propyl, isobutyryloxymethyl, 1
-(Isobutyryloxy) ethyl, 1- (isobutyryloxy) propyl, cyclohexanecarbonyloxymethyl, 1- (cyclohexanecarbonyloxy) ethyl, 1- (cyclohexanecarbonyloxy) propyl, (1-methylcyclohexane-1- Yl) carbonyloxymethyl, 1-[(1-methylcyclohexane-
1-yl) carbonyloxy] ethyl, cyclopentanecarbonyloxymethyl, 1- (cyclopentanecarbonyloxy) ethyl, 1- (cyclopentanecarbonyloxy) propyl, (1-methylcyclopentane-1-
Yl) carbonyloxymethyl, 1-[(1-methylcyclopentan-1-yl) carbonyloxy] ethyl,
Cyclobutanecarbonyloxymethyl, 1- (cyclobutanecarbonyloxy) ethyl, cyclopropanecarbonyloxymethyl, 1- (cyclopropanecarbonyloxy) ethyl, cycloheptanecarbonyloxymethyl, 1- (cycloheptanecarbonyloxy) ethyl,
1- (cyclohexylmethylcarbonyloxy) ethyl, 1- (cyclopentylmethylcarbonyloxy) ethyl, 1- (cyclobutylmethylcarbonyloxy) ethyl, 1- (cyclopropylmethylcarbonyloxy)
Ethyl, methoxycarbonyloxymethyl, 1- (methoxycarbonyloxy) ethyl, ethoxycarbonyloxymethyl, 1- (ethoxycarbonyloxy) ethyl, isopropoxycarbonyloxymethyl, 1- (isopropoxycarbonyloxy) ethyl, 1- (iso Propoxycarbonyloxy) propyl, 1- (ethoxycarbonyloxy) propyl, t-butoxycarbonyloxymethyl, 1- (t-butoxycarbonyloxy)
Ethyl, cyclohexyloxycarbonyloxymethyl, 1- (cyclohexyloxycarbonyloxy) ethyl, 1- (cyclohexyloxycarbonyloxy)
Propyl, 2-cyclohexylcarbonyloxy) propyl, cyclopentyloxycarbonyloxymethyl,
1- (cyclopentyloxycarbonyloxy) ethyl, 1- (cyclopentyloxycarbonyloxypropyl, cyclobutyloxycarbonyloxymethyl, 1
-(Cyclobutyloxycarbonyloxy) ethyl, cycloheptyloxycarbonyloxymethyl, 1- (cycloheptyloxycarbonyloxy) ethyl, menthyloxycarbonyloxymethyl, 1- (menthyloxycarbonyloxy) ethyl, 3-pinanyloxycarbonyl Oxymethyl, 1- (3-pinanyloxycarbonyloxy) ethyl, 1- (cyclohexylmethoxycarbonyloxy) ethyl, 1- (2-cyclohexylethoxycarbonyloxy) ethyl, 1- (cyclopentylmethoxycarbonyloxy) ethyl, 1- (Cyclobutylmethoxycarbonyloxy) ethyl, 1- (cyclopropylmethoxycarbonyloxy) ethyl, 2-cyclohexenyloxycarbonyloxymethyl, 1- (2
-Cyclohexenyloxycarbonyloxy) ethyl,
4-pivaloyloxybenzyl, 3-methoxy-4-pivaloyloxybenzyl, 4-acetoxybenzyl, 4
-Acetoxy-3-methoxybenzyl, 3-methyl-1
-Buten-3-ylcarbonyloxymethyl, phthalidyl, 5-methyl-2-oxo-1,3-dioxolene-
4-ylmethyl or 5-phenyl-2-oxo-1,
3-dioxolen-4-ylmethyl is exemplified, and particularly preferable ester residues include acetoxymethyl, 1-acetoxyethyl, pivaloyloxymethyl, 1- (pivaloyloxy) ethyl, isobutyryloxymethyl, 1
-(Isobutyryloxy) ethyl, (1-methylcyclohexan-1-yl) carbonyloxymethyl, (1-
Methylcyclopentan-1-yl) carbonyloxymethyl, cyclohexanecarbonyloxymethyl, 1-
(Cyclohexanecarbonyloxy) ethyl, 1-
[(1-Methylcyclohexan-1-yl) carbonyloxy] ethyl, 1- (methoxycarbonyloxy) ethyl, 1- (ethoxycarbonyloxy) ethyl, 1-
(Isopropoxycarbonyloxy) ethyl, 1- (t
-Butoxycarbonyloxy) ethyl, 1- (cyclohexyloxycarbonyloxy) ethyl, cyclohexyloxycarbonyloxymethyl, cyclopentyloxycarbonyloxymethyl, 1- (cyclopentyloxycarbonyloxy) ethyl, 1- (cyclohexylmethoxycarbonyloxy) ethyl, ( 1R, 2S, 5R)-(l) Menthyloxycarbonyloxymethyl, 1-[(1R, 2S, 5
R)-(l) Menthyloxycarbonyloxy] ethyl, 5
-Methyl-2-oxo-1,3-dioxolen-4-ylmethyl or phthalidyl.

The compound having the formula (1) has various isomers based on the asymmetric carbon. Formula (1) represents one or a mixture of these isomers. Preferred among these isomers are the (1R, 5S, 6S) coordination and 6-position substituents.
A compound in which the hydroxyl group at the position is R-coordinated can be mentioned.

The 1-methylcarbapenem derivative having the general formula (1) can be produced by the method (method A) shown below.

Method A:

[0019]

[Chemical 4]

R ³ represents a protecting group for a carboxy group, for example, an alkyl group such as methyl, ethyl, or t-butyl; an aralkyl group such as benzyl, diphenylmethyl, 4-nitrobenzyl or 2-nitrobenzyl;
Alkenyl groups such as allyl, 2-chloroallyl or 2-methylallyl; halogenoalkyl groups such as 2,2,2-trichloroethyl, 2,2-dibromoethyl or 2,2,2-tribromoethyl or 2-trimethylsilyl An ethyl group can be mentioned.

R ⁴ is an alkanesulfonyl group such as methanesulfonyl, ethanesulfonyl, propanesulfonyl, isopropanesulfonyl or butanesulfonyl; an arylsulfonyl group such as phenylsulfonyl, tolylsulfonyl or naphthylsulfonyl;
A dialkylphosphoryl group such as dimethylphosphoryl, diethylphosphoryl, dipropylphosphoryl, diisopropylphosphoryl, dibutylphosphoryl or dipentylphosphoryl or a diarylphosphoryl group such as diphenylphosphoryl or ditolylphosphoryl is shown.

In this synthetic method, a compound having the formula (3) is produced by reacting a compound having the formula (2) with an alkanesulfonic anhydride, an arylsulfonic acid anhydride, a dialkylphosphoryl halide or a diarylphosphoryl halide in the presence of a base. Then, without isolating the obtained compound (3), a mercaptan having the formula (4) is reacted in the presence of a base to produce a compound having the formula (5), and the protective group R ³ for the carboxy group is removed. It is subjected to a reaction to produce a target compound having the general formula (1).

Examples of the alkanesulfonic anhydride used in the reaction for obtaining the compound (3) from the compound (2) include methanesulfonic anhydride, ethanesulfonic acid anhydride,
Examples of the aryl sulfonic anhydride include benzene sulfonic anhydride, p-toluene sulfonic anhydride, dialkylphosphoryl halides such as dimethylphosphoryl chloride and diethylphosphoryl chloride, and diarylphosphoryl halides such as diphenylphosphoryl chloride and diphenylphosphoryl bromide. However, among these agents, p-toluenesulfonic anhydride or diphenylphosphoryl chloride is particularly preferable. The solvent used is not particularly limited as long as it does not participate in this reaction, and examples thereof include halogenated hydrocarbons such as methylene chloride, 1,2-dichloroethane and chloroform; nitriles such as acetonitrile or N, N-dimethyl. Formamide, N, N-
Examples thereof include amides such as dimethylacetamide.
The base used is not particularly limited as long as it does not affect the other part of the compound, particularly the β-lactam ring, but preferably an organic base such as triethylamine, diisopropylethylamine, 4-dimethylaminopyridine. Can be given.

The reaction temperature is not particularly limited, but it is desirable to carry out at a relatively low temperature in order to suppress side reactions, and usually −
It is performed at about 20 to 40 ° C. The reaction time is mainly the reaction temperature,
Depending on the type of reaction reagent, it is 10 minutes to 5 hours.

The compound (3) thus obtained can be treated without isolation with the mercaptan having the formula (4) in the presence of a base. The base used in this step is not particularly limited, but preferred examples include organic bases such as triethylamine and diisopropylethylamine, and inorganic bases such as potassium carbonate and sodium carbonate.

The reaction temperature is not particularly limited, but usually-
It is performed at 20 ° C to room temperature. The reaction time is 30 minutes to 108 hours.

After completion of the reaction, the target compound (5) of this reaction is collected from the reaction mixture according to a conventional method. For example, it can be obtained by adding an organic solvent immiscible with water to the reaction mixture or the residue obtained by distilling off the solvent of the reaction mixture, washing with water and distilling off the solvent. The desired compound thus obtained can be further purified, if necessary, by a conventional method such as recrystallization, reprecipitation or chromatography. If desired, the desired compound (5) can be subjected to the next carboxy group removal reaction without isolation. The obtained compound (5) can be converted into a carboxylic acid derivative by performing a treatment for removing the protecting group R ^{3 for} the carboxy group, if necessary, according to a conventional method. The removal of the protecting group depends on its type, but it is removed by a method generally known in the art. Preferably, the reaction is carried out by contacting a compound having a reducing group such as a halogenoalkyl group, an aralkyl group, a benzhydryl group or the like, in which the substituent R ³ of the compound having the formula (5) is removable with a reducing agent. To be achieved. Examples of the reducing agent used in this reaction include a protecting group for a carboxy group such as 2,2-dipromoethyl,
Zinc and acetic acid are preferred when they are halogenoalkyl groups such as 2,2,2-trichloroethyl, and when the protecting group is an aralkyl or benzhydryl group such as benzyl, 4-nitrobenzyl. Preferred are catalytic reduction catalysts such as hydrogen and palladium-carbon or alkali metal sulfides such as sodium sulfide or potassium sulfide. The reaction is carried out in the presence of a solvent, and the solvent used is not particularly limited as long as it does not participate in this reaction, but alcohols such as methanol and ethanol; ethers such as tetrahydrofuran and dioxane; acetic acid Fatty acids such as and mixed solvents of these organic solvents and water are preferred. Reaction temperature is usually 0 ° C
To about room temperature, and the reaction time is usually from 5 minutes to 12 hours, varying depending on the kinds of the raw material compound and the reducing agent.

After completion of the reaction, the target compound for the reaction for removing the protecting group for the carboxy group is collected from the reaction mixture according to a conventional method. For example, it can be obtained by filtering off the insoluble matter precipitated from the reaction mixture and then distilling off the solvent.

The desired compound thus obtained can be purified, if necessary, by a conventional method such as recrystallization, preparative thin layer chromatography, column chromatography and the like. If necessary, it can be purified as its salt.

On the other hand, the 1-methylcarbapenem derivative having the formula (1) of the present invention can also be produced by the method (method B) shown below.

Method B:

[0032]

[Chemical 5]

In the formula, R ³ has the same meaning as described above,
R ⁵ is an alkyl group such as methyl, ethyl, propyl or isopropyl; halogeno such as fluoromethyl, chloromethyl, fluoroethyl, chloroethyl, fluoropropyl, difluoromethyl, difluoroethyl, dichloroethyl, trifluoromethyl or trifluoroethyl Alkyl group: 2-acetylaminoethyl group; 2
-Acetylaminovinyl group; aryl groups such as phenyl or naphthyl which may have a substituent, and these aryl groups may have 1 to 3 substituents which are the same or different as shown below. The groups are fluorine, chlorine, bromine,
Methyl, ethyl, propyl, isopropyl, methoxy,
Heteroaryl groups such as pyridyl or pyrimidinyl, which may be ethoxy, propoxy, isopropoxy, methoxycarbonyl, ethoxycarbonyl, t-butoxycarbonyl, nitro, hydroxyl or cyano groups or which may have a substituent, these heteroaryl The group may have 1 to 3 identical or different substituents shown below, which substituents include fluorine, chlorine, bromine, methyl, ethyl, propyl or isopropyl.

The compound having the formula (6) in this synthetic method is disclosed in JP-A-62-30781. Formula (6)
The reaction of reacting the compound having the formula with mercaptan in the presence of a base to produce the compound having the general formula (5) is carried out in an inert solvent. The solvent used is not particularly limited as long as it does not participate in this reaction, and examples thereof include tetrahydrofuran, acetonitrile, dimethylformamide, dimethylsulfoxide, water and a mixed solvent thereof.
Further, as the base used, other parts of the compound, particularly β
-There is no particular limitation as long as it does not affect the lactam ring, but organic bases such as diisopropylethylamine, triethylamine, N-methylpiperidine, 4-dimethylaminopyridine, inorganic bases such as potassium carbonate, sodium bicarbonate, etc. can give. The reaction temperature is not particularly limited, but it is desirable to carry out at a relatively low temperature in order to suppress side reactions, and usually it is carried out at -20 ° C to 40 ° C. The reaction time varies depending mainly on the reaction temperature and the type of reaction reagent, but is usually 15 minutes to 75 hours. After completion of the reaction, the target compound (5) of this reaction can be collected from the reaction mixture according to a conventional method.

The compound having the formula (1) can be obtained by subjecting the compound having the formula (5) to the reaction for removing the protecting group for the carboxy group described in Method A. The compound having the general formula (1) thus obtained by Method A or Method B can be converted into its salt and its ester by methods and techniques known in the field of β-lactam antibiotics. it can.

[0036]

INDUSTRIAL APPLICABILITY The 1-methylcarbapenem derivative having the formula (1) of the present invention exhibits an excellent antibacterial action having a broad spectrum and a β-lactamase inhibitory activity. Furthermore, although thienamycin compounds are easily metabolized by mammals, they show excellent stability against dehydropeptidase I, which is known as an enzyme that catalyzes inactivation of thienamycin. It has excellent properties. Regarding the antibacterial action, its activity was measured by the agar plate dilution method. Showed strong activity against a wide range of pathogens including anaerobic bacteria such as Gram-negative bacterium and Bacteroides fragilis.

Accordingly, such compounds are useful as antibacterial agents for treating cell infections caused by these pathogens.
Examples of the dosage form for that purpose include oral administration by tablets, capsules, granules, powders, syrups and the like, or parenteral administration by intravenous injection, intramuscular injection and the like. The dose varies depending on the age, body weight, symptoms, etc., as well as the mode of administration and frequency of administration, but usually about 100 mg to 3000 mg daily is administered to an adult in single or divided doses.

[0038]

【Example】

Example 1 Sodium (1R, 5S, 6S) -2- (2-carbamoyloxyethylthio) -6-[(1R) -1-hydroxyethyl] -1-methylcarbapene-2-em-3-carboxylate

[0039]

[Chemical 6]

(1R, 5R, 6S) -6-[(1R) -1-Hydroxyethyl] -1-methyl-2-oxo-1-carbapenamu-3-carboxylic acid 4-nitrobenzyl ester (250 mg) was dried. Dissolve in acetonitrile (5 ml) and cool with ice, diisopropylethylamine (126 μl) and diphenylphosphoryl chloride (150 μl).
Was added and the mixture was stirred at 0 to 5 ° C for 1 hour. Then, under ice-cooling, diisopropylethylamine (144 μl) and 2-carbamoyloxyethyl mercaptan (100 mg) were added, and the mixture was stirred at 0 to 5 ° C. for 7 hours and then left overnight in the refrigerator. The reaction solution was diluted with ethyl acetate, the ethyl acetate layer was washed twice with brine and dried over anhydrous magnesium sulfate. The solvent was distilled off, and the obtained crude product was tetrahydrofuran (20 ml), 0.1M phosphate buffer solution.
It was dissolved in a mixed solution of (pH 7.1, 20 ml) and hydrogenated at room temperature for 2.5 hours in the presence of 10% palladium-carbon catalyst (331 mg).
After the reaction, the insoluble matter was filtered off using Celite, the filtrate was washed with diethyl ether, the aqueous layer was concentrated under reduced pressure, and attached to a column of Diaion HP-20AG (manufactured by Mitsubishi Kasei Kogyo Co., Ltd.),
The crude target compound was obtained by concentrating under reduced pressure and freeze-drying from the portion eluted with water. Further, using a Rover column (Merck & Co., Inc., Licroprep RP-8, size B), the portion eluted with 2% methanol water was concentrated under reduced pressure and freeze-dried to obtain the target compound (58 mg) as a colorless powder. . Ultraviolet absorption spectrum λ H ₂ O max. Nm: 300 Nuclear magnetic resonance spectrum (270MHz, D ₂ 0) δ ppm: 0.99 (3
H, d, J = 7.33Hz), 1.10 (3H, d, J = 6.59Hz), 2.75 (1H, dt, J = 14.
29,6.23Hz), 2.99 (1H, dt, J = 14.29,6.23Hz), 3.20 ~ 3.34 (2
H, m), 3.98-4.10 (4H, m).

Example 2 Sodium (1R, 5S, 6S) -2- (carbamoylmethylthio) -6-[(1R) -1-hydroxyethyl] -1-methylcarbapene-2-em-3-carboxylate

[0042]

[Chemical 7]

(1R, 5R, 6S) -6-[(1R) -1-Hydroxyethyl] -1-methyl-2-oxo-1-carbapenamu-3-carboxylic acid 4-nitrobenzyl ester (250 mg) was dried. Dissolve in acetonitrile (5 ml) and cool with ice, diisopropylethylamine (126 μl) and diphenylphosphoryl chloride (150 μl).
l) was added, and the mixture was stirred at 0 to 5 ° C for 1 hr. Then under ice cooling,
Diisopropylethylamine (144 μl) and mercaptoacetamide (75 mg) were added, the mixture was stirred at 0 to 5 ° C. for 2 hours, and then left in a refrigerator overnight. The reaction solution was diluted with ethyl acetate, the ethyl acetate layer was washed twice with brine and dried over anhydrous magnesium sulfate. The solvent was distilled off, and the resulting crude product was tetrahydrofuran (20 ml), 0.1M phosphate buffer (pH 7.1, 20 ml).
Dissolved in a mixed solution of 10% palladium-carbon catalyst (331 mg)
Was hydrogenated at room temperature for 2.5 hours. After the reaction, the insoluble matter was filtered off using Celite, the filtrate was washed with diethyl ether, and the aqueous layer was depressurized and then Diaion HP-20AG.
The product was attached to a column (manufactured by Mitsubishi Kasei Co., Ltd.), concentrated under reduced pressure and freeze-dried from the portion eluted with water to obtain a crude target compound.
Rover column (Merck, Licroprep RP-
8, size B) was used to concentrate under reduced pressure from the portion eluted with water and freeze-drying to obtain the target compound (56 mg) as a colorless powder. Ultraviolet absorption spectrum λ H ₂ O max. Nm: 298 Nuclear magnetic resonance spectrum (270MHz, D ₂ 0) δ ppm: 0.99 (3H,
d, J = 7.33Hz), 1.10 (3H, d, J = 6.23Hz), 3.13〜3.25 (1H, m),
3.27 (1H, dd, J = 6.23,2.57Hz), 3.33 (1H, d, J = 5.75Hz), 3.43
(1H, d, J = 5.75Hz), 3.99 (1H, dd, J = 9.16,2.57Hz), 3.99 ~
4.11 (1H, m).

Example 3 (1R, 5S, 6S) -2- (5-carbamoyloxymethylfurfurylthio) -6-[(1R) -1-hydroxyethyl] -1-methylcarbapene-2-em-3 -Sodium carboxylate

[0045]

[Chemical 8]

(1R, 5R, 6S) -6-[(1R) -1-Hydroxyethyl] -1-methyl-2-oxo-1-carbapenamu-3-carboxylic acid 4-nitrobenzyl ester (250 mg) was dried. Dissolve in acetonitrile (5 ml), diisopropylethylamine (126 μl) and diphenylphosphoryl chloride (150 μl) under ice cooling.
Was added and the mixture was stirred at 0 to 5 ° C for 1 hour. Then, under ice-cooling, diisopropylethylamine (144 μl) and 5-carbamoyloxymethylfurfurylmercaptan (155 mg) were added to 0.
The mixture was stirred at -5 ° C for 2.5 hours and left overnight. This was treated and purified in the same manner as in Example 1 to obtain the target compound (9 mg) as a colorless powder. Ultraviolet absorption spectrum λ H ₂ O max. Nm: 301.

Example 4 (1R, 5S, 6S) -2- (4-carbamoylbenzylthio) -6-[(1R) -1-hydroxyethyl] -1-
Methylcarbapene-2-em-3-carboxylate sodium salt

[0048]

[Chemical 9]

(1R, 5R, 6S) -6-[(1R) -1-Hydroxyethyl] -1-methyl-2-oxo-1-carbapenamu-3-carboxylic acid 4-nitrobenzyl ester (250 mg) was dried. Dissolve in acetonitrile (5 ml) and cool with ice, diisopropylethylamine (126 μl) and diphenylphosphoryl chloride (150 μl).
μl) was added and the mixture was stirred at 0 to 5 ° C. for 1 hour. Then, under ice cooling, diisopropylethylamine (144 μl) and 4-carbamoylbenzyl mercaptan (138 mg) were added, and the mixture was stirred at 0-5 ° C.
Leave it in the fridge for 2.5 hours and overnight. The reaction solution was diluted with ethyl acetate, the ethyl acetate layer was washed with brine and dried over anhydrous magnesium sulfate. The solvent was distilled off, and the obtained crude product was dissolved in a mixed solution of tetrahydrofuran (20 ml) and 0.1 M phosphate buffer (pH 7.1, 20 ml), and in the presence of 10% palladium-carbon catalyst (331 mg). Hydrogenated at room temperature for 2 hours. After the reaction, the insoluble matter was filtered off using Celite, the filtrate was washed with diethyl ether, and the aqueous layer was concentrated under reduced pressure.
The crude target compound was obtained by attaching to a column of Diaion HP-20AG (manufactured by Mitsubishi Kasei Co., Ltd.) and concentrating under reduced pressure and freeze-drying from the portion eluted with 5% acetone water. Rover column (Merck, Licroprep RP-8, size B)
Was concentrated under reduced pressure and freeze-dried from a portion eluted with 10% aqueous methanol to obtain the target compound (36.3 mg) as a colorless powder.

Ultraviolet absorption spectrum λ H ₂ O max. Nm: 31
4,237 Nuclear magnetic resonance spectrum (270MHz, D ₂ 0) δ ppm: 0.94 (3H,
d, J = 7.33Hz), 1.07 (3H, d, J = 6.23Hz), 3.06 to 3.20 (2H, m),
3.72~4.07 (4H, m), 7.32,7.58 (4H, A 2 B 2, J = 8.43Hz).

Example 5 (1R, 5S, 6S) -2- (4-carbamoylphenylthio) -6-[(1R) -1-hydroxyethyl] -1-
Methylcarbapene-2-em-3-carboxylate sodium salt

[0052]

[Chemical 10]

(1R, 5R, 6S) -6-[(1R) -1-Hydroxyethyl] -1-methyl-2-oxo-1-carbapenamu-3-carboxylic acid 4-nitrobenzyl ester (250 mg) was dried. Dissolve in acetonitrile (3 ml), and cool with ice, diisopropylethylamine (126 μl) and diphenylphosphoryl chloride (150
μl) was added and the mixture was stirred at 0 to 5 ° C. for 1 hour. Then, under ice cooling, a dry acetonitrile solution (2 ml) of diisopropylethylamine (144 μl) and 4-carbamoylphenylmercaptan (127 mg) was added, and the mixture was left in a refrigerator for 3 days. The reaction solution was diluted with ethyl acetate, the ethyl acetate layer was washed twice with brine and dried over anhydrous magnesium sulfate. The solvent was distilled off, and the resulting crude product was tetrahydrofuran (20 ml), 0.1
It was dissolved in a mixed solution of M phosphate buffer (pH 7.1, 20 ml), and hydrogenated at room temperature for 2 hours in the presence of 10% palladium-carbon catalyst (331 mg). After the reaction, the insoluble matter was filtered off using Celite, the filtrate was washed with diethyl ether, the aqueous layer was concentrated under reduced pressure, and attached to a column of Diaion HP-20AG (manufactured by Mitsubishi Kasei Kogyo Co., Ltd.) to obtain 5%. The crude target compound was obtained by concentrating under reduced pressure and freeze-drying from the portion eluted with acetone water. In addition, this is a Rover column (Merck, Licroprep RP-
8, size B) was used, and the target compound (14 mg) was obtained as a colorless powder by concentration under reduced pressure and freeze-drying from the portion eluted with 10% aqueous methanol. Ultraviolet absorption spectrum λ H ₂ O max.nm: 315,227 Nuclear magnetic resonance spectrum (270MHz, D ₂ 0) δ ppm: 0.78 (3H,
d, J = 7.33Hz), 1.05 (3H, d, J = 6.23Hz), 2.88 ~ 3.02 (1H, m),
3.22 (1H, dd, J = 6.05,2.74Hz), 3.98 ~ 4.07 (2H, m), 7.44,7.
62 (4H, A ₂ B ₂ , J = 8.43Hz).

Example 6 (1R, 5S, 6S) -2- (carbamoyl-2
-Thiazolylthio) -6-[(1R) -1-hydroxyethyl]
-1-Methylcarbapene-2-em-3-carboxylate sodium

[0055]

[Chemical 11]

(1R, 5R, 6S) -6-[(1R) -1-Hydroxyethyl] -1-methyl-2-oxo-1-carbapenamu-3-carboxylic acid 4-nitrobenzyl ester (250 mg) was dried. Dissolve in acetonitrile (3 ml), and cool with ice, diisopropylethylamine (126 μl) and diphenylphosphoryl chloride (150
μl) was added and the mixture was stirred at 0 to 5 ° C. for 1 hour. Then, under ice-cooling, a solution of diisopropylethylamine (144 μl) and 4-carbamoyl-2-mercaptothiazole (131 mg) in dry acetonitrile (2 ml) was added, and the mixture was left in a refrigerator for 3 days. The reaction solution was diluted with ethyl acetate, the ethyl acetate layer was washed twice with brine and dried over anhydrous magnesium sulfate. The solvent was distilled off, and the resulting crude product was added with tetrahydrofuran (20 ml),
Dissolve in a mixture of 0.1M phosphate buffer (pH 7.1, 20 ml),
Hydrogenated for 2 hours at room temperature in the presence of% palladium-carbon catalyst (331 mg). After the reaction, the same treatment and purification as in Example 5 were carried out to obtain the target compound (4 mg) as a colorless powder. Ultraviolet absorption spectrum λ H ₂ O max. Nm: 308.

Example 7 Sodium (1R, 5S, 6S) -2- (carbamoylethylthio) -6-[(1R) -1-hydroxyethyl] -1-methylcarbapene-2-em-3-carboxylate

[0058]

[Chemical 12]

(1R, 5R, 6S) -6-[(1R) -1-Hydroxyethyl] -1-methyl-2-oxo-1-carbapenamu-3-carboxylic acid 4-nitrobenzyl ester (250 mg) was dried. Dissolve in acetonitrile (5 ml) and cool with ice, diisopropylethylamine (126 μl) and diphenylphosphoryl chloride (150 μl).
μl) was added and the mixture was stirred at 0 to 5 ° C. for 1 hour. Then, under cooling with ice, diisopropylethylamine (144 μl) and 3-mercaptopropionamide (87 mg) were added, and the mixture was left at 0 to 5 ° C. for 2.5 hours and then left in the refrigerator overnight. The reaction solution was diluted with ethyl acetate, the ethyl acetate layer was washed with brine and dried over anhydrous magnesium sulfate. The solvent was distilled off, and the resulting crude product was added to tetrahydrofuran (20 ml), 0.1M phosphate buffer solution.
It was dissolved in a mixed solution of (pH 7.1, 20 ml) and hydrogenated at room temperature for 2 hours in the presence of 10% palladium-carbon catalyst (331 mg). After the reaction, the same treatment and purification as in Example 5 were carried out to obtain the target compound (23.4 mg) as a colorless powder. Ultraviolet absorption spectrum λ H ₂ O max.nm: 302 Nuclear magnetic resonance spectrum (270MHz, D ₂ 0) δ ppm: 1.01,1.0
2 (3H, d × 2, J = 7.33,6.96Hz), 1.11,1.12 (3H, d × 2, J = 6.2
2,6.60Hz), 2.34 ~ 2.52 (2H, m), 2.72 ~ 3.02 (2H, m), 3.2
1 ~ 3.35 (2H, m), 3.98 ~ 4.12 (2H, m).

Example 8 (1R, 5S, 6S) -2-[(1R) -1-carbamoylethylthio) -6-[(1R) -1-hydroxyethyl]
-1-Methylcarbapene-2-em-3-carboxylate sodium

[0061]

[Chemical 13]

(1R, 5R, 6S) -6-[(1R) -1-Hydroxyethyl] -1-methyl-2-oxo-1-carbapenamu-3-carboxylic acid 4-nitrobenzyl ester (250 mg) was dried. Diisopropylethylamine (126 μl) and diphenylphosphoryl chloride (150 μl) in acetonitrile (5 ml) solution under ice cooling.
Was added and the mixture was stirred at 0 to 5 ° C for 1 hour. Then, diisopropylethylamine (144 μl) and (2R) -2-mercaptopropionamide (87 mg) were added at the same temperature, and the mixture was stirred for 5 hours and then left in the refrigerator overnight in the refrigerator. The reaction solution was diluted with ethyl acetate, the ethyl acetate layer was washed twice with brine and dried over anhydrous magnesium sulfate. The solvent was distilled off, the resulting crude product was tetrahydrofuran (20 ml), 0.1M phosphate buffer (pH
7.1, 20 ml), and hydrogenated at room temperature for 2.5 hours in the presence of 10% palladium-carbon catalyst (331 mg). After the reaction, insoluble materials were removed by filtration through Celite, the aqueous layer was concentrated under reduced pressure, and then attached to a column of Diaion HP-20AG (manufactured by Mitsubishi Kasei Co., Ltd.), and the portion eluted with water was concentrated under reduced pressure and freeze-dried. The crude target compound was obtained. Furthermore, using a Rover column (Merck, Licroprep RP-8, size B), 2%
The portion eluted with methanol water was concentrated under reduced pressure and freeze-dried to obtain the target compound (65 mg) as a colorless powder. Ultraviolet absorption spectrum λ H ₂ O max.nm: 299 Nuclear magnetic resonance spectrum (270MHz, D ₂₀ ) δ ppm: 0.98 (3H,
d, J = 7.33Hz), 1.11 (3H, d, J = 6.23Hz), 1.30 (3H, d, J = 7.33H
z), 3.13 to 3.24 (1H, m), 3.26 (1H, dd, J = 6.23,2.57Hz), 3.
70 (1H, q, J = 7.33Hz), 4.01 ~ 4.11 (2H, m).

Example 9 (1R, 5S, 6S) -2-[(1S) -1-carbamoylethylthio) -6-[(1R) -1-hydroxyethyl]
-1-Methylcarbapene-2-em-3-carboxylate sodium

[0064]

[Chemical 14]

(1R, 5R, 6S) -6-[(1R) -1-Hydroxyethyl] -1-methyl-2-oxo-1-carbapenamu-3-carboxylic acid 4-nitrobenzyl ester (250 mg) was dried. Dissolve in acetonitrile (5 ml) and cool with ice, diisopropylethylamine (126 μl) and diphenylphosphoryl chloride (150 μl).
l) was added, and the mixture was stirred at 0 to 5 ° C for 1 hr. Then, diisopropylethylamine (144 μl) and (2S) -2-mercaptopropionamide (87 mg) were added at the same temperature, and the mixture was stirred for 1.5 hours and left in the refrigerator overnight. Dilute the reaction solution with ethyl acetate,
The extract was washed twice with brine and dried over anhydrous magnesium sulfate. The solvent was distilled off and the resulting crude product was tetrahydrofuran (20 ml), 0.1M phosphate buffer (pH 7.1, 20 ml)
Dissolved in a mixed solution of 10% palladium-carbon catalyst (331
(mg) and hydrogenated at room temperature for 2.5 hours. After the reaction, it was treated and purified in the same manner as in Example 8 to give the target compound as a colorless powder.
(26 mg) was obtained. Ultraviolet absorption spectrum λ H ₂ O max. Nm: 298 Nuclear magnetic resonance spectrum (270MHz, D ₂ 0) δ ppm: 1.00 (3H,
d, J = 7.32Hz), 1.10 (3H, d, J = 6.23Hz), 1.29 (3H, d, J = 7.33H
z), 3.12 to 3.24 (1H, m), 3.25 (1H, dd, J = 6.23,2.56Hz), 3.7
0 (1H, q, J = 7.33Hz), 3.99 (1H, dd, J = 9.16,2.56Hz), 4.00〜
4.12 (1H, m)

 ─────────────────────────────────────────────────── ─── Continuation of the front page (72) Inventor Masayuki Iwata 1-2-2 Hiromachi, Shinagawa-ku, Tokyo Sankyo Stock Company

Claims (1)

[Claims] 1. The formula: 1-Methylcarbapenem derivatives and salts thereof and esters thereof. In the formula, R ¹ represents carbamoyloxy or the following group substituted with carbamoyl, a lower alkyl group, a cycloalkyl group, an aralkyl group, an aryl group, a heteroaryl group, a heteroaralkyl group, or an alkylheteroaralkyl group.