JP2934283B2 - Carbapenem derivatives - Google Patents

Description

Description: TECHNICAL FIELD The present invention relates to a novel antibiotic having a carbapenem skeleton.

2. Description of the Related Art Penicillins and cephalosporins are excellent in safety and widely used for treating infectious diseases. However, these are not effective for all strains, and the range of application is being limited by the emergence of strains that have acquired resistance. It has been reported that this resistance is caused by preventing the drug from penetrating into cells or by producing β-lactamase to inactivate the drug.

Thienamycin having a carbapenem skeleton discovered in 1976 was also effective against bacteria resistant to the previous antibiotics and exhibited excellent antibacterial activity.

PROBLEMS TO BE SOLVED Thienamycin and many other carbapenem-derived couples that have since been reported have the disadvantages of being physicochemically unstable and easily degraded by enzymes such as renal dehydropeptidase (DHP). Must be used as a combination with DHP inhibitors.

JP-A-60-233076 discloses a 1-β-methylcarbapenem compound which is stable to β-lactamase-producing bacteria, is stable in physicochemical properties and exhibits strong antibacterial activity. However, these compounds are still not satisfactory.

The present inventors have conducted intensive studies to find even more excellent carbapenem derivatives, and as a result, completed the present invention.

Means for Solving the Problems <Constitution of the Invention> The present invention provides a compound of the general formula I (Wherein R ¹ represents a lower alkyl group, a hydroxy lower alkyl group or a protected hydroxy lower alkyl group,
² is a carboxyl group, a carboxylate anion or a protected carboxyl group, R ³ is a hydrogen atom or a lower alkyl group, R ⁴ is a hydrogen atom or a lower alkyl group,
R ⁵ represents a 4- to 8-membered saturated cyclic heterocyclic group containing 2 to 3 nitrogen atoms. ) And the salts thereof.

In the present specification, carbapenem means a compound having the following skeleton, and the present invention relates to a carbapenem derivative having various substituents on this skeleton.

The substituent in Formula I will be described.

R ¹ has ^{1 to} 6 carbon atoms such as a methyl group, an ethyl group, an n-propyl group, an isopropyl group and an n-butyl group (C ₁ −
C ₆ ) alkyl groups, which may have a hydroxyl group. Of these, a 1-hydroxyethyl group, particularly a 1-hydroxyethyl group, is bonded to the 6-position carbon atom of the carbapenem skeleton in an S configuration, and the hydroxyl group is bonded to the 1-position of the ethyl group (generally, the 8-position of carbapenem Is referred to as an R configuration.

As R ² , a hydrogen atom or a linear or branched C ₁ -C ₆ alkyl group such as methyl, ethyl, isobutyl, tertiary butyl, C ₁ -C ₆ such as methoxymethyl, methoxyethyl, etc.
Examples thereof include C ₂ -C ₇ aliphatic acyloxymethyl groups such as alkoxy C ₁ -C ₆ alkyl groups and pivaloyloxymethyl groups, and phthalidyl groups. Further, as an ester residue which also serves as a protecting group for a carboxyl group and can be easily removed under mild conditions, for example, an aralkyl group such as p- or o-nitrobenzyl, benzhydryl or 2-naphthylmethyl, 2,2,2- Examples thereof include a C ₁ -C ₆ alkylsilyl group such as a trichloroethoxycarbonyl group, an allyl group, and trimethylsilyl. In the synthesis, an ester residue suitable as a carboxyl-protecting group is a p-nitrobenzyl group, an allyl group or the like.

R ² may be an ester residue capable of being metabolized, and preferred examples thereof include a pivaloyloxymethyl group,
Examples include a phthalidyl group and an acetoxycarbonyloxymethyl group.

Examples of R ³ include a hydrogen atom and a linear or branched lower alkyl group having 1 to 4 carbon atoms such as methyl, ethyl and propyl, and a methyl group is particularly preferable. At this time, the configuration of the asymmetric carbon atom at the 1-position is suitably an R configuration.

R ⁴ is preferably a hydrogen atom or a linear or branched lower alkyl group having 1 to 4 carbon atoms such as methyl, ethyl and propyl.

R ⁵ is preferably a substituent composed of a 4- to 8-membered saturated nitrogen-containing heterocyclic ring, and the number of nitrogen atoms is preferably 2 to 3. Preferred examples of such a substituent include an imidazolidino group, a piperazino group and a homopiperazino group.

Some of the compounds of the present invention and intermediates for producing the same may have a tautomeric structure. These are represented herein by one type of structural formula, but this is not meant to be limiting.

The compounds of the present invention may be used as pharmacologically acceptable salts, examples of which include:

That is, non-toxic salts of carboxylic acids, for example, metal salts such as sodium, potassium, aluminum and magnesium, ammonium salts and salts with triethylamine, procaine and benzylamine, and salts used for salt formation of penicillins and cephalosporins And salts with non-toxic amines such as Particularly preferred salts include sodium and potassium salts.

Since the carbapenem derivative of the present invention has a basic group, a pharmaceutically acceptable acid addition salt, for example, a mineral acid such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid or acetic acid, citric acid, succinic acid, ascorbic acid Acids and salts with organic acids such as methanesulfonic acid can also be used. Particularly suitable salts include hydrochlorides and sulfates. The compounds of formula I may also be various solvates, for example,
It may be used as a hydrate.

The compound of the present invention has excellent antibacterial activity against Pseudomonas aeruginosa, including Escherichia coli, Proteus, Klebsiella, Enterobacter, Salmonella, Serratia, Streptococcus, Staphylococcus, etc.・ Effective in treating secondary infections and purulent diseases caused by burns and surgical wounds.

Compounds of the present invention are commonly used pharmaceutical carriers, stabilizers,
It can be formulated by a usual method using a solubilizing agent and an excipient. There are various methods for administration such as oral administration of tablets, pills, capsules, granules and the like, and parenteral administration such as intravenous injection, intramuscular injection, suppository and the like. Usually, intravenous injection is suitable. The dose is usually 250 mg to 3,000 mg per day for an adult, and the dose is divided into several doses. The dose can be appropriately adjusted depending on age, sex, and symptoms.

The compound of the present invention can be produced by a method exemplified by the following reaction formula.

Known methods (Heterocycles (1984) 21 , 29 DHShihe
tal) and a method analogous thereto, the compound II (wherein R ¹ , R ² and R ³ are the same as described above) is reacted with diphenylphosphoryl chloride to give an active intermediate II
I can lead to

This reaction is carried out using triethylamine, alkylamines such as diisopropylethylamine, DBU, alicyclic amine streams such as N-methylmorpholine, quinuclidine, organic bases such as 3-quinuclidinol, hydroxyl, sodium chloride, potassium hydroxide, potassium carbonate, It is preferably carried out in the presence of an inorganic base such as sodium carbonate, metal alcoholates such as potassium t-butoxide and sodium methoxide, sodium amide, sodium hydroxide and the like, and diisopropylethylamine and DBU are preferred.

Usually, it is appropriate to carry out the reaction in a solvent that does not adversely affect the starting materials and products, and ketones such as acetone and methyl ethyl ketone, acetonitrile, dimethylformamide (DMF), diethylacetamide, dimethylsulfoxide (DMSO) ), Tetrahydrofuran (TH
F), dichloromethane, chloroform and a mixed solvent thereof can be exemplified.

The reaction temperature is preferably from -50 ° C to room temperature, especially from -40 ° C to 0 ° C. The reaction time is preferably from 15 minutes to 8 hours, particularly preferably from 30 minutes to 8 hours.

The active intermediate III can be isolated or unisolated and subjected to a substitution reaction with thiol compound IV to lead to compound I.

The thiol compound IV has high reactivity when coexisting with a base, and the reaction proceeds favorably. However, the reaction proceeds without a base. Examples of usable bases include those exemplified in the reaction in the previous step, and diisopropylethylamine and DBU are preferable. This base is preferably used in an equivalent amount to the thiol compound IV, but when the thiol compound is an acid addition salt, good results can be obtained by further adding an amount of the base necessary for neutralizing the added acid. Can be obtained.

This reaction is also generally carried out in a solvent that does not adversely affect the starting materials and products, and those exemplified in the preceding reaction can be used. If the intermediate III is not isolated, it is preferable to continue the reaction with the same solvent.

The compound of formula IV is 1 to 3 equivalents relative to the compound of formula III,
The reaction is preferably performed in an amount of 1 to 2 equivalents.

The reaction temperature is preferably from -50 ° C to room temperature, especially from -40 ° C to 0 ° C. The reaction time is preferably from 30 minutes to one day, particularly from 1 hour to 6 hours.

The substitution product can be isolated by usual post-treatment, and if necessary, can be purified by column chromatography on silica gel using chloroform, ethyl acetate, dichloromethane, methanol or a mixed solvent thereof. it can.

When a protecting group is present in the above-mentioned substitution reaction product, the protecting group can be eliminated as desired. Examples of the elimination method include reductive decomposition by hydrogenation, chemical reduction, and hydrolysis by using an acid, a base or an enzyme.

In the compounds of general formula I, the substituent R ² is an ester residue, for example, P- nitrobenzyl group, a benzyl group, when it is benzhydryl or 2-naphthylmethyl group, palladium on carbon, platinum oxide, other It can be deprotected by catalytic reduction using a known metal catalyst to give a carbapenem derivative of the general formula I in which COOR ² is a carboxyl group or a carboxylate anion. As a reaction solvent, dioxane, THF, water, and a buffer (including a mixed solvent) are used, and preferably, a mixed solvent of hydrated dioxane, a phosphate buffer and THF is used, and the reaction is carried out under a hydrogen pressure of 1 to 4 atm. ~ 50 ° C, preferably 10 ~ 30 ° C, 30 minutes ~ 16
Time, usually 10 minutes to 1 hour,
Carbapenem derivatives I wherein OR ² is a carboxyl group or a carboxylate anion can be obtained.

When R ^{2 of the} compound I is a p-nitrobenzyl group, the compound is further reacted with an aqueous solution of ammonium chloride and iron powder in a water-soluble organic solvent such as THF or dioxane to further form R ^2. When it is an allyl group, the compound is further treated with tetrakistriphenylphosphine palladium (O), triphenylphosphine and 2-ethylhexanoic acid in an aprotic solvent such as THF or methylene chloride to further reduce R ² to 2,2. , 2-trichloroethyl group, COOR ²
Is a carboxyl group or a carboxylate anion.

The target compound I can be purified by conventional isolation means, that is, extraction, concentration, and, if necessary, recrystallization, reprecipitation, chromatography, or the like. Further, Compound I can be obtained in a high purity by crystallization, and a preferable result can be obtained by converting it into a salt for this purpose. At that time, the salt does not necessarily need to be a non-toxic acid addition salt, and is crystallized as a toxic salt, and after purification, the acid is removed or converted to a pharmacologically acceptable salt to give the target compound with high purity. Obtainable.

In order to produce esters metabolized in the body, according to the method used for penicillins and cephalosporins (see, for example, J. Med. Chem. (1970), 13 , 607),
What is necessary is just to put in advance as R ² of COOR ² in the general formula I, or to esterify a compound of a carboxyl group or a carboxylate anion.

Hereinafter, the production method of the compound of the present invention will be described more specifically with reference to Examples and Reference Examples. PNB in the structural formula is p-
Nitrobenzyl, PMB p-methoxybenzyl, PNZ
Means p-nitrobenzyloxycal.

Example 1 (1) p-Nitrobenzyl (1R, 5S, 6S, 8R) -6- (1
-Hydroxyethyl) -2-{[2S, 4S) -1-p-nitrobenzyloxycarbonyl-2- (4-p-nitrobenzyloxycarbonylpiperazin-1-yl) carbonylpyrrolidin-4-yl] thio}- 1-methylcarbapenem-3-carboxylate 3.62 g of p-nitrobenzyl (1R, 5S, 6S, 8R) -6- (1-hydroxyethyl) -1-methyl-2-oxocarbapenam-3-carboxylate was added to 36 ml of acetonitrile.
And cooled and stirred in a cold bath at -2 ° C. Under an argon stream, 1.92 ml of diisopropylethylamine was added dropwise over 3 minutes. Then 2.28 ml of diphenyl phosphoryl chloride
Was added dropwise. After stirring at the same temperature for 30 minutes and cooling to -35 ° C, 1.92 ml of diisopropylethylamine was further added.
6.36 g of (2S, 4S) -1- (p-nitrobenzyloxycarbonyl) -2- (4-p-nitrobenzyloxycarbonylpiperazin-1-yl) carbonyl-4-mercaprolidine was added and stirred at the same temperature for 16 hours. did. The solvent was distilled off under reduced pressure, and the residue was subjected to silica gel chromatography to obtain 9.43 g of the title compound.

_{NMR (CDCl 3) δ: 1.28} (3H, d), 1.36 (3H, d), 1.80-2.2
0 (1H, m), 2.50-2.80 (1H, m), 3.0-5.0 (16H, m), 5.2
2 (1H, d), 5,24 (4H, s), 5.52 (1H, d), 7.30-8.40 (10
H, m) (2) (1R, 5S, 6S, 8R, 2'S, 4'S) -6- (1-hydroxyethyl) -2-{[2- (1-piperazinecarbonyl) pyrrolidine-4- Yl] thio} -1-methylcarbapenem-3-carboxylic acid 3.00 g of the compound obtained in Example 1- (1) was dissolved in 70 ml of THF, 70 ml of a phosphate buffer was added, and 10% palladium-carbon
With 6 g (total use amount), catalytic reduction was carried out under a hydrogen gas atmosphere at 4 atm. After removing the catalyst by filtration, the solvent was concentrated under reduced pressure, and the residue was subjected to column chromatography packed with Diaion HP-20 (Nippon Rensui Co., Ltd.). After concentrating the eluate, the residue was subjected to high performance liquid chromatography (hereinafter referred to as HPLC).
Abbreviated. ) To give 520 mg of the title compound.

_{NMR (D 2 O) δ:} 1.24 (3H, d), 1.32 (3H, d), 1.71-1.77
(1H, m), 2.77−2.86 (1H, m), 3.16−3.34 (6H, m), 3.4
2 (1H, dq), 3.47 (1H, dd), 3.74-3.86 (4H, m), 3.87
(1H, m), 4.25 (1H, dd), 4.28 (1H, m) Minimum inhibitory concentration (MIC) of this substance against various bacteria
E. coli, NIHJ <0.1, Pr. Bulgaris, 08
602 0.10, K. pneumoniae, TYPE 1 <0.1, Ps. Aeruginosa, 32122 0.10, S. aureus, 209P <0.1.

Example 2 (1R, 5S, 6S, 8R, 2'S, 4'S) -6- (1-hydroxyethyl) -2-{[2- (1-homopiperazinecarbonyl) pyrrolidin-4-yl] thio ｝ -1-methylcarbapenem-3-carboxylic acid p-Nitrobenzyl (1R, 5S, 6S, 8R) -6- (1-hydroxyethyl) -2-diphenylphosphoryloxo-
0.297 g of 1-methylcarbapenem-3-carboxylate
Was dissolved in 3 ml of acetonitrile, and (2S, 4S) -1- (p-
0.353 g of nitrobenzyloxycarbonyl) -2- (4-p-nitrobenzyloxycarbonylhomopiperazin-1-yl) carbonyl-4-mercaptopyrrolidine and 0.55 g of diisopropylethylamine were added at -35 ° C, and the mixture was heated for 18.5 hours under an argon stream. Stirred. The solvent was distilled off under reduced pressure, an aqueous citric acid solution and ethyl acetate were added to the residue, and the mixture was shaken. The organic layer was separated, washed with water and dried over sodium sulfate. The solvent was evaporated under reduced pressure to give an oily residue, which was purified by silica gel chromatography and purified by p-nitrobenzyl (1R, 5S, 6S, 8R) -6- (1-hydroxyethyl) -2. -{[2S, 4S) -1-p-nitrobenzyloxycarbonyl-2- (4-p-nitrobenzyloxycarbonylhomopiperazin-1-yl) carbonylpyrrolidin-4-yl] thio} -1-methylcarbapenem-
293 mg of 3-carboxylate were obtained (NMR (CDCl ₃ ) δ: 1.
30 (3H, d), 1.34 (3H, d), 1.60 (3H, m), 2.52 (1H, m),
3.10−4.40 (16H, m), 5.18 (2H, s), 5.21 (1H, d), 5.23
(2H, s), 5.51 (1H, d), 7.35-7.72 (6H, m), 8.10 (6H,
m)).

0.290 g of this compound was dissolved in 14 ml of THF, 14 ml of phosphate buffer was added, 300 mg of 10% palladium-carbon was further added, and catalytic reduction was carried out under a hydrogen gas atmosphere at 4 atm. After removing the catalyst by filtration, the solvent was concentrated under reduced pressure, and the residue was
It was subjected to column chromatography packed with -20. The eluate was concentrated and the residue was purified by HPLC to give 13.3 mg of the title compound.

_{NMR (D 2 O) δ:} 1.24 (3H, d), 1.32 (3H, d), 1.67-1.76
(1H, m), 2.07−2.23 (2H, m), 2.77−2.86 (1H, m), 3.1
0−3.40 (6H, m), 3.40−3.48 (2H, m), 3.62−4.00 (5H, m
m), 4.18-4.30 (3H, m) Minimum inhibitory concentration (MIC) of this against various bacteria
E. coli, NIHJ <0.1, Pr. Bulgaris, 08
602 0.10, K. pneumonia TYPE 1 <0.1, Ps. Aeruginosa, 32122 0.10, S. aureus, 209P <0.1.

Example 3 (1R, 5S, 6S, 8R, 2'S, 4'S) -6- (1-hydroxyethyl) -2-{[2- (1-imidazolidinylcarbonyl) pyrrolidin-4-yl] thio ｝ -1-methylcarbapenem-3-carboxylic acid 0.291 g of p-nitrobenzyl (1R, 5S, 6S, 8R) -6- (1-hydroxyethyl) -1-methyl-2-oxocarbapenam-3-carboxylate was added to 2 ml of acetonitrile.
And cooled and stirred in a cold bath at -2 ° C. Under an argon stream, 0.182 ml of diisopropylethylamine was added dropwise over 3 minutes. Then diphenyl phosphoryl chloride 0.21
6 ml was added dropwise. After stirring at the same temperature for 30 minutes, 0.35 ml of diisopropylethylamine was further added under cooling to -35 ° C, and then (2S, 4S) -1- (p-nitrobenzyloxycarbonyl) -2- (3-p-nitro 0.425 g of benzyloxycarbonylimidazolidin-1-yl) carbonyl-4-mercaptopyrrolidine was added, and the mixture was stirred at the same temperature for 4 hours. The solvent was distilled off under reduced pressure, the residue was purified by silica gel chromatography, and p-nitrobenzyl (1R, 5S,
6S, 8R) -6- (1-hydroxyethyl) -2-{[(2
(S, 4S) -1-p-nitrobenzyloxycarbonyl-2
-(3-p-nitrobenzyloxycarbonylimidazolidin-1-yl) carbonylpyrrolidin-4-yl]
0.456 g of thio｝ -1-methylcarbapenem-3-carboxylate was obtained (NMR (CDCl ₃ ) δ: 1.2-1.4 (6H, m), 1.
8−2.2 (1H, m), 2.5−3.0 (1H, m), 3.2−5.0 (14H, m),
5.1-5.6 (6H, m), 7.4-7.8 (6H, m), 8.21 (6H, d)).
Dissolve 0.455 g of this compound in 15 ml of THF, and add
l, and the mixture was subjected to catalytic reduction using 4 g of 10% palladium-carbon in a hydrogen gas atmosphere at 4 atm. After removing the catalyst by filtration, the solvent was concentrated under reduced pressure, and the residue was subjected to Diaion HP-
It was subjected to column chromatography packed with 20. The eluate was concentrated and the residue was purified by HPLC to give the title compound 2
8.6 mg were obtained.

_{NMR (D 2 O) δ:} 1.25 (3H, d), 1.33 (3H, d), 1.69-1.75
(1H, m), 2.75-2.83 (1H, m), 3.10-3.14 (1H, m), 3.1
7−3.21 (1H, m), 3.22−3.29,3.40−3.51,3.56−3.61
(6H, m), 3.82−3.88 (1H, m), 3.99 & 4.07 (1H, t), 4.2
5 (1H, dd), 4.28 (1H, dq), 4.35,4.37,4.39 and 4.51
(2H, d) Minimum inhibitory concentration (MIC) of this substance against various bacteria
E. coli, NIHJ <0.1, Pr. Bulgaris, 08
602 <0.1, K. pneumonia TYPE 1 <0.1, Ps. Aeruginosa, 32122 0.20, S. aureus, 209P <0.1.

The thiol compound of the general formula IV can be obtained by the method exemplified below.

Reference Example 1 (1) (2S, 4R) -1- (p-nitrobenzyloxycarbonyl) -4-hydroxypyrrolidine-2-carboxylic acid 25 g of (2R, 4R) -4-hydroxypyrrolidine-2-carboxylic acid was added to water. The mixture was dissolved in 100 ml, 100 ml of dioxane was added, and the mixture was stirred under ice cooling. To this solution, 41.1 g of p-nitrobenzyl chloroformate was added and stirred for 3 hours. The reaction solution was concentrated under reduced pressure, 100 ml of a 10% aqueous citric acid solution was added to the residue, and the mixture was acidified and extracted with 2-butanone. The organic layer was washed with water, dried over sodium sulfate, and the solvent was distilled off under reduced pressure to obtain 54.3 g of the title compound.

_{NMR (DMSO-d 6) δ} : 1.80-2.15 (3H, m), 3.00-3.60 (4
H, m), 4.05-4.25 (1H, m), 4.31 (2H, s), 7.60 (2H,
d), 8.22 (2H, d) (2) p-methoxybenzyl (2R, 4R) -1- (p
-Nitrobenzyloxycarbonyl) -4-hydroxypyrrolidine-2-carboxylate 54.3 g of the compound obtained in Reference Example 1- (1) was dissolved in 540 ml of DMF, and 47.5 ml of p-methoxybenzyl chloride and 51.2 ml of triethylamine were added. The mixture was heated to 70 ° C. and stirred under an argon stream. After 14 hours, the solvent was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain 57.1 g of the title compound.

_{NMR (CDCl 3) δ: 1.80-2.40} (2H, m), 3.60-3.90 (2H,
m), 3.80 (1H, s), 4.40-4.47 (2H, m), 5.00-5.32 (4
H, m), 6.70-8.40 (8H, m) (3) p-methoxybenzyl (2S, 4S) -1- (p
-Nitrobenzyloxycarbonyl) -4-benzoylthiopyrrolidine-2-carboxylate 27.5 g of triphenylphosphine was dissolved in 400 ml of THF,
The mixture was cooled to −20 ° C. and stirred. When 16.5 ml of diethyl azodicarboxylate was added and stirred for 20 minutes, white crystals precipitated. A THF solution of 30.1 g of the compound obtained in Reference Example 1- (2) and 12.4 ml of thiobenzoic acid was added dropwise, and the cooling bath was removed.
Stirred for hours. The solvent was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography to obtain 37.5 g of the title compound.

_{NMR (CDCl 3) δ: 1.95-2.40} (1H, m), 2.50-3.05 (1H,
m), 3.40-3.75 (1H, m), 3.74 (3H, s), 3.95-4.35 (2
H, m), 4.35-4.70 (1H, m), 4.90-5.35 (4H, m), 6.60-
8.30 (13H, m) (4) (3S, 4S) -1- (p-nitrobenzyloxycarbonyl) -4-benzoylthiopyrrolidine-2-carboxylic acid To 37.5 g of the compound obtained in Reference Example 1- (3), Anisole 15m
l was added and stirred under ice cooling. 100 ml of trifluoroacetic acid was added, and the mixture was further reacted at room temperature for 2 hours. Trifluoroacetic acid was concentrated under reduced pressure, 50 ml of xylene was added to the residue, and the mixture was concentrated again under reduced pressure. After standing under reduced pressure for 2 hours, chloroform was added to precipitate crystals. This was filtered to give the title compound in 19.9.
g obtained.

_{NMR (DMSO-d 6) δ} : 1.80-2.25 (1H, m), 2.60-3.65 (3
H, m), 3.95-4.60 (2H, m), 5.25 (2H, m), 7.40-8.30
(9H, m) (5) (2R, 4R) -1- (p-nitrobenzyloxycarbonyl) -2- (4-p-nitrobenzyloxycarbonylpiperazine-1-) carbonyl-4-benzoylthiopyrrolidine Reference Example 6.45 g of the compound obtained in 1- (4) was dissolved in 300 ml of THF and stirred under ice-cooling, and 2.53 g of 1-hydroxybenzotriazole and 9.29 g of dicyclohexylcarbodiimide were obtained.
Was added and stirred at room temperature for 2 hours. The reaction solution was ice-cooled again,
(P-nitrobenzyloxycarbonyl) piperazine 3.
62 g was added and the mixture was stirred at room temperature for 2 hours. After evaporating the solvent under reduced pressure, the residue was subjected to silica gel column chromatography to obtain 8.56 g of the title compound.

NMR (CDCl ₃ ) δ: 1.8-2.20 (1H, m), 2.60-3.00 (1H,
m), 3.00-4.00 (10H, m), 4.05-4.25 (1H, m), 4.65-
4.95 (1H, m), 7.35-8.45 (13H, m) (6) (2S, 4S) -1- (p-nitrobenzyloxycarbonyl) -2- (4-p-nitrobenzyloxycarbonylpiperazine-1- Il) Carbonyl-4-mercaptopyrrolidine 8.56 g of the compound obtained in Reference Example 1- (5) was added to methanol 100
The mixture was dissolved in a mixed solvent of 100 ml of THF and 100 ml of THF, and stirred under ice cooling.
Add 1.88 g of sodium methoxide under an argon stream and add 3
Stirred for 0 minutes. The reaction solution was acidified by adding a 10% aqueous citric acid solution, water was further added, and the solvent was distilled off under reduced pressure. The oily residue was extracted with ethyl acetate, and the extract was washed with water and dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography to obtain 6.23 g of the title compound.

Reference Example 2 (1) (2S, 4S) -1- (p-nitrobenzyloxycarbonyl) -2- (4-p-nitrobenzyloxycarbonylhomopiperazin-1-yl) carbonyl-4-
Benzoylthiopyrrolidine) Dissolve 1.08 g of (2S, 4S) -1- (p-nitrobenzyloxycarbonyl) -4-benzoylthiopyrrolidine-2-carboxylic acid in 30 ml of THF, add 0.42 g of 1-hydroxybenzotriazole under ice cooling and 0.57 g of dicyclohexylcarbodiimide was added and stirred for 3 hours. In this, 1- (p
-Nitrobenzyloxycarbonyl) homopiperazine 0.
77 g was added and the mixture was stirred at room temperature for 18 hours. The precipitated dicyclohexylurea was removed by filtration, and the mother liquor was dried under reduced pressure. Acetonitrile was added to the residue, and dicyclohexylurea was filtered off again. Acetonitrile was distilled off under reduced pressure, ethyl acetate and 1N hydrochloric acid were added to the residue, and the mixture was shaken. The organic layer was separated and washed with water. After the organic layer was dried over sodium sulfate, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography to obtain 1.57 g of the title compound.

NMR (CDCl ₃ ) δ: 1.60-1.70 (1H, m), 1.80-2.00 (2H,
m), 2.60-3.00 (1H, m), 3.20-3.80 (10H, m), 4.60-
4.80 (1H, m), 5.21 (4H, s), 7.45 (2H, d), 8.21 (4H,
d) (2) (2S, 4S) -1- (p-nitrobenzyloxycarbonyl) -2- (4-p-nitrobenzyloxycarbonylhomopiperazin-1-yl) carbonyl-4-
Mercaptopyrrolidine 1.48 g of the compound obtained in Reference Example 2- (1) was treated with methanol 20m
The mixture was dissolved in a mixture of l and 5 ml of dioxane, and 0.46 g of sodium methoxide was added at room temperature, followed by stirring for 15 minutes. The solvent was distilled off under reduced pressure, and the residue was shaken with ethyl acetate and 1N hydrochloric acid. The organic layer was separated and washed with water. The organic layer was dried over sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound 0.85.
g was obtained.

NMR (CDCl ₃ ) δ: 1.70-2.00 (2H, m), 3.20-3.90 10H,
m), 4.45−4.80 (1H, m), 5.20 (2H, s), 5.24 (2H, s),
7.47 (2H, d), 7.49 (2H, d), 8.23 (4H, d) Reference Example 3 (1) (2S, 4S) -1- (p-nitrobenzyloxycarbonyl) -2- (3-p- Nitrobenzyloxycarbonylimidazolidin-1-yl) carbonyl-4-
Benzoylthiopyrrolidine 0.72 g of (2S, 4S) -1- (p-nitrobenzyloxycarbonyl) -4-benzoylthiopyrrolidine-2-carboxylic acid is dissolved in 10 ml of dichloromethane, and 0.32 ml of oxalic acid chloride and 1 drop of DMF are added at room temperature. Was added and stirred for 75 minutes. After evaporating the solvent under reduced pressure, 0.5 g of 1- (p-nitrobenzyloxycarbonyl) imidazoline in dichloromethane
ml of the solution and 0.37 ml of triethylamine were added, and the mixture was stirred for 2 hours. The reaction solution was diluted with chloroform, washed with water, and dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography to obtain 1.04 g of the title compound.

NMR (CDCl ₃ ) δ: 1.90-2.40 (1H, m), 2.60-3.00 (1H,
m), 3.50-5.1 (10H, m), 5.25 (4H, br.s), 7.4-7.6, 7.
9-8.0 (9H, m), 8.21 (4H, d) (2) (2S, 4S) -1- (p-nitrobenzyloxycarbonyl) -2- (3-p-nitrobenzyloxycarbonyl imidazolidine-1 -Yl) carbonyl-4-
Mercaptopyrrolidine 0.66 g of the compound obtained in Reference Example 3- (1) was treated with methanol 10m
dissolved in l, add sodium methoxide 0.14 g at room temperature,
Stir for 2 hours. The solvent was distilled off under reduced pressure, and the residue was shaken with ethyl acetate and 1N hydrochloric acid, and the organic layer was dispersed and washed with water. The organic layer was dried over sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography to obtain 0.43 g of the title compound.

NMR (CDCl ₃ ) δ: 1.8-2.2 (1H, m), 2.5-2.9 (1H, m),
3.50−5.1 (10H, m), 5.21 (2H, s), 5.26 (2H, s), 7.4−
7.7 (4H, m), 8.22 (4H, d) Effect of the Invention The novel carbapenem derivatives of the present invention show strong antibacterial activity against Gram-positive bacteria, negative bacteria, and even obligate anaerobic bacteria, and penicillin It has an extremely broad antibacterial spectrum, including high sensitivity to cephalosporin-resistant bacteria. Furthermore, the compounds of the present invention are excellent in physicochemical properties, are less susceptible to enzymatic degradation by kidney dehydropeptidase, β-lactamase and the like, and are expected as pharmaceuticals.

──────────────────────────────────────────────────続 き Continuing on the front page (72) Inventor Takeshi Hayano 1-16-13 Kita-Kasai, Edogawa-ku, Tokyo Examiner, Kazuyuki Yoshizumi, Central Pharmaceutical Research Laboratory, Daiichi Pharmaceutical Research Institute (56) References JP-A-60-19787 (JP) JP-A-60-58987 (JP, A) JP-A-60-1004088 (JP, A) JP-A-60-233076 (JP, A) JP-A-3-264586 (JP, A) 4-211083 (JP, A) (58) Fields investigated (Int. Cl. ⁶ , DB name) C07D 477/20 CA (STN) REGISTRY (STN)

Claims (8)

(57) [Claims] 1. Formula I (Wherein R ¹ represents a lower alkyl group, a hydroxy lower alkyl group or a protected hydroxy lower alkyl group,
² is a carboxyl group, a carboxylate anion or a protected carboxyl group, R ³ is a hydrogen atom or a lower alkyl group, R ⁴ is a hydrogen atom or a lower alkyl group,
R ⁵ represents a 4- to 8-membered saturated cyclic heterocyclic group containing 2 to 3 nitrogen atoms. ) Represented compounds and salts thereof 2. The compound according to claim 1, wherein R ¹ is a 1-hydroxyethyl group. 3. The compound according to claim 1, which is a (6S, 8R) -6- (1-hydroxyethyl) -carbapenem derivative. 4. The compound according to claim 1, which is a (1R, 5S, 6S, 8R) -6- (1-hydroxyethyl) -1-methylcarbapenem derivative. ^5. The compound according to claim 4, wherein R ⁵ is an imidazolidino group, a piperazino group or a homopiperazino group. (6) (Wherein R ² represents a hydrogen atom or a carboxylate anion as COOR ² ). (7) (Wherein R ² and COOR ² are the same as defined above). (8) (Wherein R ² and COOR ² are the same as defined above).