JP2003183281A - Carbapenem compound - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To obtain a new carbapenem compound having excellent resistance to β-lactamase and kidney dehydropeptidase and strong antimicrobial activity. <P>SOLUTION: This carbapenem compound is represented by formula (I) (R<SP>1</SP>is a hydrogen atom or a carboxy group protecting group, R<SP>2</SP>and R<SP>3</SP>are each the same or different and a hydrogen atom, a substituted or nonsubstituted alkyl group or a phenyl group; ring A is a six-membered or seven-membered heterocycle containing one nitrogen atom and one sulfur atom, respectively) or its pharmacologically acceptable salt. <P>COPYRIGHT: (C)2003,JPO

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention relates to carbapenem antibiotics, and more particularly, to β at the 1-position of the carbapenem skeleton.
The present invention relates to a carbapenem compound having a -positioned methyl group and having a specific functional group introduced into the side chain at the 2-position, and an antibacterial agent containing them as an active ingredient.

[0002]

2. Description of the Related Art Thienamycin [US Pat.
0,357; Am. Chem. Soc. , 10
0,313 (1987)], various synthetic compounds have been vigorously studied as carbapenem antibiotics. Among them, imipenem (INN) is a practical carbapenem antibiotic.
Has been developed and marketed, and has been widely used clinically.

However, imipenem, which first appeared as a carbapenem antibiotic, exhibits excellent antibacterial activity against a wide range of Gram-positive and Gram-negative bacteria, but in vivo renal dehydropeptidase (DH).
P) has a drawback that decomposition / inactivation occurs in a short time. Therefore, imipenem cannot be administered alone and must be used in combination with a DHP inhibitor to suppress its degradation and inactivation. Therefore, a practical formulation of this compound is a DHP inhibitor, cilastatin (I).
It is a combination prescription of imipenem / cilastatin in combination with NN).

By the way, as an antibacterial agent used clinically, it is preferable that the original antibacterial activity of the antibacterial agent is exerted as it is, and the DHP inhibitor used in combination has undesirable side effects in other tissues in the living body. Needless to say, it is better to avoid compounding and prescribing as much as possible, as it may be exerted. Therefore, there has been a strong demand for the development of a carbapenem compound having antibacterial activity and resistance to DHP.

Thereafter, as a compound for achieving the above-mentioned object, a 1-methylcarbapenem compound having a methyl group introduced at the 1-position appeared, and this compound was resistant to DHP-I and further had a 1-methyl substituent group. It has been confirmed that it is chemically more stable than the corresponding carbapenem compound.

Therefore, in order to develop a compound having more excellent antibacterial activity based on such a background, various substituents at the other site, especially the substituent at the 2-position, in the 1-methylcarbapenem compound are converted. As a result, meropenem, biapenem and the like have been developed as carbapenem antibiotics that can be administered alone.

[0007]

The carbapenem compounds show antibacterial activity against a wide variety of bacterial species.
It is expected that a resistant bacterium, which is a problem with β-lactam antibiotics that are currently commonly used in clinical settings, will emerge. That is, even for new carbapenem antibiotics,
Although it is initially effective, it is fully expected that resistant bacteria will gradually emerge with long-term use. Therefore, in the field of antibacterial agents, there is a constant demand for the development of novel and highly effective compounds.

Under the present circumstances as described above, the present invention
-An object of the present invention is to provide a novel carbapenem compound which has excellent resistance to lactamase and renal dehydropeptidase and is expected to have a strong antibacterial activity.

[0009]

In order to solve such a problem, the present invention has the following formula (I):

[0010]

[Chemical 2]

(Wherein R ¹ represents a hydrogen atom or a protecting group for a carboxy group, R ² and R ³ are the same or different and represent a hydrogen atom, a substituted or unsubstituted lower alkyl group or a phenyl group, and a ring A Represents a 6- or 7-membered heterocycle containing one nitrogen atom and one sulfur atom respectively) or a pharmaceutically acceptable salt thereof.

The carbapenem compound provided by the present invention is
It is a novel compound in which a specific functional group which has not been studied so far is introduced into the 2-position side chain of a 1-methylcarbapenem compound, and has excellent antibacterial activity. Therefore, the present invention also provides, as a further aspect, an antibacterial agent containing a carbapenem compound represented by the above formula (I) as an active ingredient.

The compounds of the present invention will be described in more detail below, and the terms used in the specification have the following meanings.

The term "lower" means that the group or compound to which this term is attached has about 1 to 7 carbon atoms, preferably 1 to
It means that there are four.

The "lower alkyl group" may be linear or branched, and is, for example, methyl,
Ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, n-hexyl, isohexyl,
Examples thereof include n-heptyl and isoheptyl.

Substituents that can be substituted on these lower alkyl groups include hydroxyl groups; lower alkyloxy groups; halogen atoms such as chlorine and bromine atoms; monosubstituted amino groups; and diamines such as dimethylamino, diethylamino and methylethylamino. Examples thereof include a substituted amino group; an amidino group; a guadinino group; a nitro group; and an acetyl group.

Examples of the "carboxy protecting group" represented by R ¹ include ester residues, and examples of such ester residues include methyl, ethyl, n-propyl, iso-propyl, n-, iso
Lower alkyl ester residues such as-, tert-butyl, n-hexyl ester; benzyl, p-nitrobenzyl, o-nitrobenzyl, m-nitrobenzyl, 2,4
Aralkyl ester residues such as -dinitrobenzyl, p-chlorobenzyl, p-bromobenzyl, p-methoxybenzyl; acetoxymethyl, acetoxyethyl, propionyloxymethyl, n-, iso-butyryloxymethyl, pivaloyloxymethyl And lower aliphatic acyloxymethyl and the like.

Therefore, when the representative examples of the substituent at the 2-position in the carbapenem compound provided by the present invention are shown, the following substituents can be exemplified.

[Chemical 3]

As the carbapenem compound provided by the present invention, the compounds shown in Table 1 below can be given as particularly preferable specific compounds.

[0020]

[Table 1] Table 1

In the carbapenem compound of the present invention,
An asymmetric carbon atom may be present in the substituent on the side chain at the 2-position, but these isomers can be easily stereoselectively synthesized using an optically active starting material compound.
It can also be separated from a mixture of these isomers by a usual isolation and purification means. Further, there may be isomers in the three-dimensional structure, and such isomers can also be separated by a usual isolation and purification means such as chromatography. Therefore, it goes without saying that not only a mixture of these isomers but also each isomer itself is a compound included in the present invention.

The pharmacologically acceptable salt of the carbapenem compound provided by the present invention includes inorganic and organic non-toxic salts that are ordinarily acceptable as pharmaceuticals. Examples of the inorganic salt include alkali metal salts such as sodium salt and potassium salt; alkaline earth metal salts such as calcium salt and magnesium salt; ammonium salt. As the organic salt, for example, triethylamine salt, pyridine salt,
Examples thereof include salts with a base such as organic amines such as picoline salt, ethanolamine salt, triethanolamine salt, dicyclohexylamine salt and N, N′-dibenzylethylenediamine salt.

Further, hydrochloride, nitrate, hydrobromide,
Salts with inorganic acids such as sulfates and phosphates; formates, acetates,
Examples thereof include salts with organic acids such as trifluoroacetates, maleates, tartrates, methanesulfonates and benzenesulfonates; salts with basic amino acids such as arginine, aspartic acid and glutamic acid.

The following reaction formula is schematically shown for the production method of the carbapenem compound of the present invention.

[0025]

[Chemical 4]

In the above reaction formula, R ^a represents an acyl group, R ⁴ represents a carboxy protecting group, and R ^{1 to} R ³
And ring A is the same as defined above.

An "acyl group" represented by R ^a is
Not only the remaining atomic groups obtained by removing the OH group from the carboxyl group of the organic carboxylic acid, but also broadly includes an acyl group derived from an organic sulfonic acid or an organic phosphoric acid, for example,
Lower alkanoyl group such as acetyl, propionyl, butyryl; (halo) lower alkylsulfonyl group such as methanesulfonyl, trifluoromethanesulfonyl; benzenesulfonyl, p-nitrobenzenesulfonyl, p-bromobenzenesulfonyl, toluenesulfonyl, 2,4,6
-A substituted or unsubstituted arylsulfonyl group such as a triisopropylbenzenesulfonyl group; and a diphenylphosphoryl group.

The "carboxy-protecting group" represented by R ⁴ has the same meaning as the carboxy-protecting group represented by R ¹ described above, and specific examples thereof include ester residues. Examples of such ester residue include lower alkyl ester residues such as methyl, ethyl, n-propyl, iso-propyl, n-, iso-, tert-butyl, n-hexyl ester; benzyl, p-nitrobenzyl, Aralkyl ester residues such as o-nitrobenzyl, m-nitrobenzyl, 2,4-dinitrobenzyl, p-chlorobenzyl, p-bromobenzyl, p-methoxybenzyl; acetoxymethyl, acetoxyethyl, propionyloxymethyl, n- , Is
Lower aliphatic acyloxymethyl such as o-butyryloxymethyl, pivaloyloxymethyl and the like can be mentioned. Of these, p-nitrobenzyl group is preferably used.

In the synthetic route represented by the above reaction scheme, the step (a) is performed by adding the compound of formula (II) to the compound of formula (II).
A step of reacting the compound of I) to obtain the compound of formula (IV). In the reaction, for example, a compound of the formula (II) and a compound of the formula (III) in a molar amount of about 0.5 to about 5 times, preferably about 0.8 to about 3 times, a tetrahydrofuran,
Dichloromethane, dioxane, dimethylformamide,
In a suitable solvent such as dimethyl sulfoxide, acetonitrile, hexamethylphosphorane, etc., preferably in the presence of a base such as sodium hydrogen carbonate, potassium carbonate, triethylamine, diisopropylethylamine, etc., particularly preferably diisopropylethylamine, etc. About 25
A temperature in the range of ℃, preferably about 30 minutes to about 2 under ice cooling.
It can be carried out by reacting for 4 hours.

The reaction is preferably carried out in a stream of an inert gas such as nitrogen gas or argon gas, but it is not always essential.

The compound of formula (IV) obtained in this step is
Although it can be directly subjected to the next reaction, it can be purified by an ordinary purifying means such as filtration, extraction, washing, solvent removal, drying and chromatography.

The resulting compound of formula (IV) is then
Step (b) is converted to a carbapenem compound of formula (I) which is a compound of the invention by subjecting it to a deprotecting group reaction known per se, eg solvolysis or hydrogenation.

Specifically, the compound of formula (IV) is added to, for example, an acetic acid buffer having a pH of about 5 to 7, a morpholinopropanesulfonic acid-sodium hydroxide buffer, or a phosphate buffer, these buffers and an alcohol. Liquid with organic solvent and / or tetrahydrofuran, or tetrahydrofuran-water containing dipotassium hydrogen phosphate, disodium hydrogen phosphate, sodium bicarbonate, etc., tetrahydrofuran-ethanol-water, dioxane-water, dioxane-
In a mixed solvent of ethanol-water, n-butanol-water, etc., hydrogen of about 1-5 atm is used, and in the presence of a hydrogenation catalyst such as platinum oxide, palladium-activated carbon, palladium hydroxide-activated carbon, etc. It can be performed by treating at a temperature in the range of 0 to about 50 ° C. for about 0.25 to about 5 hours.

The elimination of the protecting group R ⁴ can also be carried out by treating with zinc in a buffer solution. For example, a compound of formula (IV) is added to a buffer solution having a pH of about 5 to 7,
For example, it can be carried out by treating with zinc in a phosphate buffer solution, an acetate buffer solution, a morpholinopropanesulfonic acid buffer solution, or an N-methylmorphophosphate buffer solution.

The zinc that can be used includes, for example, zinc powder, white zinc and granular zinc, and the amount used is not particularly limited, but generally 1 to 10 parts by weight per 1 part by weight of the compound to be reacted. , Preferably 1 to 5 parts by weight. In the elimination reaction,
If necessary, an organic solvent may be used in combination. Examples of such a solvent include alcohol solvents such as ethanol, propanol and n-butanol; ether solvents such as diethyl ethanol, tetrahydrofuran and dioxane; acetonitrile, dimethylformamide, Examples thereof include dimethylacetamide. The reaction is usually from about -20 ° C to about 5 ° C.
It can be completed by treating at 0 ° C., preferably at room temperature to about 30 ° C., for about 0.1 to 5 hours.

Thus, a carbapenem compound represented by the formula (I) (wherein R ¹ is a hydrogen atom), which is the object compound of the present invention, can be obtained, and the compound can be any of the usual compounds described above. In addition to purification by means, it can be isolated in high purity by purification using an ion exchange resin or a polymer adsorption resin, if necessary.

Among the target compounds represented by the formula (I) of the present invention, the compound in which R ¹ is a carboxy protecting group is prepared by subjecting the compound in which R ¹ is a hydrogen atom to the corresponding esterification reaction. It can be manufactured.

In the above-mentioned production method, the compound of the formula (III) used as a starting material is
It can be appropriately produced according to the method according to the Examples described later.

The carbapenem compound provided by the present invention is a completely novel compound which has not been disclosed in the conventional literature as described above, and is characterized in that it has a particularly excellent antibacterial activity. The excellent antibacterial activity of the compounds of the present invention is proved by the results of the following antibacterial test.

[Antibacterial test] 1. Test method Japanese Society of Chemotherapy Standard Method [Chemotherapy, vol. 29, 76
~ 79 (1981)] according to the agar plate dilution method. That is, an overnight culture at 37 ° C. on a Muller-Hinton (MH) agar liquid medium of a test bacterium was diluted with a buffered saline gelatin (BSG) solution to about 10 ⁶ cells / ml, and then micro MH containing test compound using planter
Approximately 5 μl of the agar medium was inoculated and incubated at 37 ° C for 18 hours
Minimu has the minimum concentration that does not show the growth of test bacteria.
m inhibitory concentration (MIC).

Standard strains were used as the strains used here. Further, as test compounds, compounds (1), (3) and (5) obtained in Examples described later and imipenem (IP which is clinically used as a carbapenem antibiotic agent)
M) was used.

2. result The results are shown in Table 2 below.

[0043]

[Table 2] Table 2: MIC (μg / ml)

From the above results, it is clear that the carbapenem compound of the present invention has excellent antibacterial activity. Furthermore, the compound of the present invention has a structure in which a methyl group is introduced in the β-configuration at the 1-position, and a structural group having a specific functional group as a substituent at the 2-position, renal dehydropeptidase ( It is extremely stable against attack by DHP) and has high chemical and physical stability.

[Toxicity test] Ten male ddy mice having a body weight of 20 to 23 g were used, and the solution containing the carbapenem compound of the present invention obtained in the following Examples was subcutaneously administered and observed for one week. As a result, it was observed that the carbapenem compound of the present invention survived without any abnormality even at the administration of 500 mg / kg.

Therefore, the compounds of the present invention are
It is not necessary to use it in combination with an inhibitor, and it can be used alone, and is expected to be an antibacterial agent useful for treating and preventing bacterial infections caused by various pathogenic bacteria.

The carbapenem compound of the present invention or a pharmacologically acceptable salt thereof, when used as an antibacterial agent, is used in the form of a pharmaceutical composition containing an antibacterial effective amount thereof, including humans. Can be administered to a mammal. The dose depends on the age, weight, and
It can be varied over a wide range depending on the symptoms, drug administration form, doctor's diagnosis, etc.
Dosages in the range of about 200 mg to about 3,000 mg per day are standard and can be administered orally, parenterally or topically once or several times a day.

The above-mentioned pharmaceutical composition thus comprises an inorganic or organic solid or liquid pharmaceutical carrier, or a diluent, which is conventionally used in the preparation of pharmaceuticals, especially antibiotics.
For example, excipients such as starch, lactose, sucrose, crystalline cellulose, calcium hydrogen phosphate; binders such as acacia, hydroxypropyl cellulose, alginic acid, gelatin, polyvinylpyrrolidone; stearic acid, magnesium stearate, talc, hydrogenated vegetable oils, etc. Lubricants; Disintegrants such as modified starch, calcium carboxymethyl cellulose, low-substituted hydroxypropyl cellulose; Oral, parenteral or topical with dissolution aids such as nonionic surfactants and anionic surfactants It can be formulated into a dosage form suitable for administration.

Suitable dosage forms for oral administration include solid preparations such as tablets, coatings, capsules, troches, powders, fine granules, granules and dry syrups, or liquid preparations such as syrups. . Suitable dosage forms for parenteral administration include, for example, injections, drops, suppositories, etc., and suitable dosage forms for topical administration include ointment, tincture,
Examples include creams and gels. These preparations can be prepared by a method known per se in the field of pharmaceutical science. Among them, the carbapenem compound of the present invention is particularly preferably administered parenterally in the form of an injection.

[0050]

EXAMPLES The carbapenem compound of the present invention will be described in more detail below with reference to Production Examples, Examples, Formulation Examples, etc.
Needless to say, the present invention is not limited to the following description.

In the following description, the numbers given to the compounds mean the compound numbers, and each symbol has the following meaning. Me: Methyl Et: Ethyl Ac: Acetyl PNB: p-nitrobenzyl PNZ: p-nitrobenzyloxycarbonyl Trt: Trityl

Example 1: (4R, 5S, 6S) -3-
[1- (4H, 5H, 6H-1,3-thiazin-2-yl) azetidin-3-ylthio] -6-[(R) -1-
Production of hydroxyethyl] -4-methyl-7-oxo-1-azabicyclo [3.2.0] hept-2-ene-2-carboxylic acid [compound (1)]

[0053]

[Chemical 5]

1,3-thiazinane-2-thione (10) 3-aminopropanol (9) (5.0 mL, 65.4 mmo
l), carbon disulfide (8.0 mL, 132 mmol) and potassium hydroxide (8.7 g, 132 mmol) in ethanol (82 mL) and water (20 mL).
The mixed solution was reacted at 90 ° C. for 19 hours. After concentrating the solvent under reduced pressure, water (80 mL) was added to adjust the pH to 6,
Extracted 3 times with ethyl acetate. The organic layers were collected, washed with water and saturated brine, dried and subjected to silica gel column chromatography (eluent: hexane: ethyl acetate = 2: 1) to give 694 mg of the title compound (10) as white crystals (yield:
8.0%) was obtained.

¹ H-NMR (CDCl ₃ , 270 MHz) δ: 2.13-2.22
(m, 2H), 3.01 (t, 2H, J = 5.6Hz), 3.48 (dt, 2H, J = 3.
0, 5.6Hz), 9.01 (br, 1H).

2-Methylthio-5,6-dihydro-4H
-[1,3] Thiazine (11) Compound (10) obtained above (694 mg, 5.2 mmol) and methyl iodide (1.62 mL, 26.0 mmol) in acetonitrile (52
mL) solution at room temperature in a nitrogen stream at Hunig's base (1.10
(mL, 6.3 mmol) was added and reacted for 4 hours. The solvent was concentrated under reduced pressure, water was added, and the mixture was extracted 3 times with ethyl acetate. The organic layers were collected, washed with water and saturated brine, dried and subjected to silica gel column chromatography (eluent: hexane: ethyl acetate = 5: 1) to give the title compound (11) as a pale yellow oil (542 mg, Yield: 70.7%).

¹ H-NMR (CDCl ₃ , 270 MHz) δ: 1.87-1.95
(m, 2H), 2.38 (s, 3H), 3.07 (t, 2H, J = 5.6Hz), 3.75
(t, 2H, J = 5.6Hz).

1- (5,6-dihydro-4H- [1,
3] -thiazin-2-yl) azetidine-3-thiol
Hydrochloride (12) Compound (11) obtained above (542 mg, 3.7 mmol) and 3-
A solution of mercaptoazetidine hydrochloride (510 mg, 3.7 mmol) in methanol (7.5 mL) was refluxed in a nitrogen stream for 2 hours. The solvent was concentrated under reduced pressure, water was added, and the mixture was washed with ethyl acetate. The aqueous layer was concentrated under reduced pressure, further azeotropically distilled with 2-propanol, and then subjected to silica gel column chromatography (eluent: chloroform: methanol = 9: 1) to obtain 626 mg of the title compound (12) as a colorless oil (yield. : 75.
7%) was obtained.

¹ H-NMR (CDCl ₃ , 270 MHz) δ: 2.11-2.20
(m, 2H), 3.19 (t, 2H, J = 5.9Hz), 3.62 (t, 2H, J = 5.6
Hz), 3.90-4.00 (m, 1H), 4.25 (br, 2H), 4.84 (br, 2
H).

P-nitrobenzyl (4R, 5S, 6
S) -3- [1- (4H, 5H, 6H-1,3-thiadi
N-2-yl) azetidin-3-ylthio] -6-
[(R) -1-Hydroxyethyl] -4-methyl-7-
Oxo-1-azabicyclo [3.2.0] hept-2-
En-2-carboxylate (14)

Compound (12) obtained above (520 mg, 2.8
mmol) in acetonitrile (13 mL) at −15 ° C. to give compound (1R, 5R, 6S) -p-nitrobenzyl-
2-Diphenylphosphoryloxy-6-[(R) -1-
Hydroxyethyl] -1-methyl-carbapenem-3-
Carboxylate [compound (13)] (content 95.4%, 1.
57 g, 2.5 mmol) and Hunig's base (1.0 mL, 5.6 mmo
l) was added, and the mixture was reacted at the same temperature for 2 hours in a nitrogen stream.
The solvent was concentrated under reduced pressure and then subjected to silica gel column chromatography (eluent: chloroform: methanol = 10: 1) to obtain 1.26 g (yield: 93.7%) of the title compound (14) as a pale yellow amorphous substance. .

¹ H-NMR (CDCl ₃ , 270 MHz) δ: 1.18 (d, 3
H, J = 7.3Hz), 1.33 (d, 3H, J = 6.3Hz), 1.96 (m, 2H),
3.08 (t, 2H, J = 5.9Hz), 3.14-3.25 (m, 2H), 3.42 (m,
2H), 3.96-4.07 (m, 1H), 4.10-4.17 (m, 3H), 4.29 (d
d, 1H, J = 2.3, 9.2Hz), 4.52 (br, 1H), 4.65 (br, 1H),
5.25 (d, 1H, J = 13.9Hz), 5.49 (d, 1H, J = 13.9Hz), 7.6
6 (d, 2H, J = 8.9Hz), 8.22 (d, 2H, J = 8.6Hz).

(4R, 5S, 6S) -3- [1- (4
H, 5H, 6H-thiazin-2-yl) azetidine-3
-Ilthio] -6-[(R) -1-hydroxyethyl]
-4-Methyl-7-oxo-1-azabicyclo [3.
2.0] Hept-2-ene-2-carboxylic acid [compound
(1)]

The above compound (14) (554 mg, 1.0 mmo
l) and 10% palladium-carbon (50% water content, 278 mg)
0.05 mol / L phosphate buffer (pH 6.0, 28 mL), tetrahydrofuran (5.5 mL) and n-butanol (22 mL)
Was added and the hydrogenation reaction was carried out for 1.5 hours in a hydrogen stream (400 kPa). After filtering the reaction solution, the residue was washed with water / n-butanol. After the separation, the pH of the aqueous layer was adjusted to 6.0 and 8.3
Water was concentrated under reduced pressure to g. The resulting aqueous solution is HP-2
By purification using 1 resin (42 mL, 15% acetonitrile aqueous solution), 162 mg (yield: 39.2%) of the title compound (1) was obtained as a pale yellow amorphous substance.

¹ H-NMR (D ₂ O, 270 MHz) δ: 1.17 (d, 3H,
J = 7.3Hz), 1.28 (d, 3H, J = 6.3Hz), 2.11-2.17 (m, 2
H), 3.12-3.25 (m, 1H), 3.23 (t, 2H, J = 5.6Hz), 3.40
-3.49 (m, 3H), 4.05-4.12 (m, 2H), 4.18-4.21 (m, 2
H), 4.29-4.36 (m, 1H), 4.63 (m, 2H). IR (KBr): 3355, 1752, 1625, 1587 cm ^-1 .λ ^max (H ₂ O): 220, 295 nm.

Example 2: (4R, 5S, 6S) -3-
[1- (5,5-dimethyl-5,6-dihydro-4H-
[1,3] -thiazin-2-yl) azetidin-3-i
Ruthio] -6-[(R) -1-hydroxyethyl] -4
-Methyl-7-oxo-1-azabicyclo [3.2.
0] hept-2-ene-2-carboxylic acid [compound
(2)] manufacturing

[0067]

[Chemical 6]

5,5-Dimethyl- [1,3] thiazinane
2-Thion (16) 3-amino-2,2-dimethylpropan-1-ol (15) (6.2 g, 60 mmol), triethylamine (8.4 m
L, 60 mmol) in dichloromethane (120 mmol) and benzyloxy chloroformate (9.0 g, 50
mmol) was added dropwise. After stirring under ice-cooling for 1 hour and room temperature for 1 hour, the reaction solution was washed with a 1N aqueous hydrochloric acid solution, a saturated aqueous sodium hydrogencarbonate solution and brine, and dried over anhydrous magnesium sulfate. The residue obtained by concentration of the solvent under reduced pressure was dissolved in dichloromethane (120 mL), and triethylamine (9.1
mL, 65 mmol) was added, followed by mesityl chloride (4.7
(mL, 60 mmol) was added dropwise. The organic layer was washed with a 1N aqueous hydrochloric acid solution, a saturated aqueous sodium hydrogen carbonate solution and brine, dried over anhydrous magnesium sulfate, and concentrated. The residue was mixed with ethanol (100 mL) / 2N hydrochloric acid-methanol mixture (30 mL,
It was dissolved in 60 mmol), 10% palladium-carbon (4 g, containing 50% water) was added, and catalytic reduction was carried out at 400 kPa for 1.5 hours in a hydrogen atmosphere. After removing the catalyst by filtration, the residue obtained by concentration under reduced pressure was dissolved in dichloromethane (100 mL), and triethylamine (21 mL, 150 mmol) and carbon disulfide (4.5 mL) were added under ice cooling.
(mL, 75 mmol) was added. After stirring overnight at room temperature, the precipitated solid was suction filtered, washed twice with a 1N aqueous hydrochloric acid solution and once with pure water, and air-dried to give the title compound (6) as a colorless solid.
3 g (yield 78%) was obtained. ¹ H-NMR (CDCl ₃ ) δ: 1.18 (s, 6H), 2.75 (s, 2H), 3.1
2 (s, 2H).

5,5-dimethyl-2-methylthio-5,
6-Dihydro-4H- [1,3] thiazine (17) The compound (16) (1.61 g, 10 mmol) obtained above was dissolved in methanol (30 mL), and methyl iodide (1.2 m) was added under reflux.
L, 20 mmol) was added dropwise. After dropwise addition, the mixture was refluxed for 30 minutes, cooled to room temperature, and the solvent of the reaction solution was distilled off. The residue was dissolved in dichloromethane, washed with 10% and 50% aqueous potassium carbonate solution, dried over anhydrous potassium carbonate and concentrated to give 1.73 g of the title compound (17) as a colorless oil.
(Yield: quantitative) was obtained. ¹ H-NMR (CDCl ₃ ) δ: 1.06 (s, 6H), 2.39 (s, 3H), 2.
78 (s, 2H), 3.43 (s, 2H).

5,5-dimethyl-2- (3-tritylchi
Oazetidin-1-yl) -5,6-dihydro-4H-
[1,3] Thiazine (18) Compound (17) obtained above (1.73 g, 10 mmol) and 3
-Tritylthioazetidine hydrochloride (1.84 g, 5 mmol) was dissolved in ethanol (20 ml), and the mixture was refluxed for 4 hours. After evaporating the solvent under reduced pressure, the residue was dissolved in dichloromethane, washed with a 1N aqueous hydrochloric acid solution and a 50% aqueous potassium carbonate solution, dried over anhydrous potassium carbonate and concentrated to give 2.04 g of the title compound (18) as a colorless solid ( Yield: 89%).

¹ H-NMR (CDCl ₃ ) δ: 0.98 (s, 6H), 2.66
(s, 2H), 3.18 (s, 2H), 3.36-3.38 (m, 1H), 3.51-3.5
5 (m, 2H), 3.65-3.69 (m, 2H), 7.19-7.37 (m, 15H).

P-nitrobenzyl (4R, 5S, 6
S) -3- [1- (5,5-Dimethyl-5,6-dihydride
B-4H- [1,3] thiazin-2-yl) azetidine
-3-ylthio] -6-[(R) -1-hydroxyethyl
]]-4-Methyl-7-oxo-1-azabicyclo
[3.2.0] Hept-2-ene-2-carboxylate
To (19)

Compound (18) obtained above (2.04 g, 4.12
mmol) in dichloromethane (2 ml) and trifluoroacetic acid (3 mL) and triethylsilane (0.724 mL, 6.
75 mmol) was added and the mixture was stirred for 3 hours. The reaction mixture was concentrated under reduced pressure, and the resulting residue was mixed with a 2N hydrochloric acid aqueous solution / methanol mixture (4
(mL) and concentrated under reduced pressure. The residue was treated with anhydrous acetonitrile (50
Compound (13) under ice cooling (2.6 g, 4.12 mmo)
l) and then diisopropylethylamine (2.5 m
L, 14.4 mmol) was added and stirred for 1 hour. After evaporating the solvent under reduced pressure, the residue was dissolved in chloroform, washed with a 10% aqueous potassium carbonate solution and brine, and dried over anhydrous magnesium sulfate. The residue obtained by concentrating the solvent under reduced pressure was crystallized from ethyl acetate to obtain 1.44 g (yield: 49%) of the title compound (19).

¹ H-NMR (CDCl ₃ ) δ: 1.04 (s, 6H), 1.2
3 (d, 3H, J = 7.2Hz), 1.35 (d, 3H, J = 6.3Hz), 2.74
(s, 2H), 3.18-3.27 (m, 4H), 3.83-3.89 (m, 2H), 4.0
5-4.07 (m, 1H), 4.21-4.29 (m, 4H), 5.25 (d, 1H, J =
13.7Hz), 5.51 (d, 1H, J = 13.7Hz), 7.66 (d, 2H, J = 8.
7Hz), 8.23 (d, 2H, J = 8.7Hz).

(4R, 5S, 6S) -3- [1- (5,
5-Dimethyl-5,6-dihydro-4H- [1,3]-
Thiazin-2-yl) azetidin-3-ylthio] -6
-[(R) -1-hydroxyethyl] -4-methyl-7
-Oxo-1-azabicyclo [3.2.0] hept-2
-Ene-2-carboxylic acid [Compound (2)] Compound (19) (0.56 g, 1 mmol) obtained above was added to n-butanol (20 ml), pure water (43 ml) and 10% palladium-carbon ( 0.28 g, 50% water content), and under a hydrogen atmosphere,
The catalytic reduction was carried out at 00 kPa for 1.5 hours. After the catalyst was filtered off, the aqueous layer was separated and concentrated under reduced pressure. Concentrate HP-40
Attach to a resin column (40 ml), water (2 volumes) and 15%
It was eluted with an aqueous acetonitrile solution and freeze-dried to obtain 0.35 g (yield: 82%) of the title compound (2).

¹ H-NMR (D ₂ O) δ: 0.97 (s, 6H), 1.02
(d, 3H, J = 7.2Hz), 1.13 (d, 3H, J = 6.4Hz), 2.87 (s,
2H), 3.02 (s, 2H), 3.03-3.06 (m, 1H), 3.27 (dd, 1
H, J = 2.5, 6.2Hz), 3.96-4.00 (m, 2H), 4.03-4.09 (m,
2H), 4.15-4.19 (m, 1H), 4.47-4.52 (m, 2H).

Example 3: (4R, 5S, 6S) -3-
[1- (2H, 3H, 6H-1,4-thiazin-5-i
Ru) Azetidin-3-ylthio] -6-[(R) -1-
Hydroxyethyl] -4-methyl-7-oxo-1-a
Zabicyclo [3.2.0] hept-2-en-2-cal
Production of boric acid [compound (3)]

[0078]

[Chemical 7]

Thiomorpholin-3-one (21) 2-mercaptoethylamine hydrochloride (20) (2.28 g,
Ethanol (50 mL) was added to 20 mmol) and potassium hydroxide (2.64 g, 40 mmol), and it cooled at 0 degreeC. Next, ethyl bromoacetate (2.44 mL, 22 mmol) was added dropwise to the reaction solution over 5 minutes, and the temperature was raised to room temperature, followed by stirring for 24 hours. The insoluble material was filtered off, and the reaction solution was concentrated under reduced pressure. The obtained residue is purified by silica gel column chromatography (eluent: chloroform: methanol = 9: 1),
1.99 g of the title compound (21) as colorless needle crystals
(Yield: 85%) was obtained. ¹ H NMR (270 MHz, CDCl ₃ ) δ: 2.80-2.84 (m, 2H), 3.3
1 (s, 2H), 3.60-3.66 (m, 2H), 6.70 (br, 1H).

Thiomorpholin-3-thione (22 ) To a solution of the compound (21) (351 mg, 3 mmol) obtained above in anhydrous tetrahydrofuran (3 mL) was added Lawesson's reagent (607 mg, 1.5 mmol) under a nitrogen atmosphere. The mixture was stirred with heating under reflux for 2 hours. Water was added to the reaction solution, extracted with ethyl acetate, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the obtained residue was purified by silica gel column chromatography (eluent: chloroform: methanol = 19: 1) to give the title compound (22) as pale yellow needle crystals in an amount of 328 m.
g (yield: 82%) was obtained. ¹ H NMR (270 MHz, CDCl ₃ ) δ: 2.92 (t, 2H, J = 5.6Hz),
3.60-3.66 (m, 2H), 3.80 (s, 2H), 8.51 (br, 1H).

5-Methylsulfanyl-3,6-dihydride
B-2H- [1,4] thiazine iodate (23) Methyl iodide (12 mL, 18 mL) was added to a solution of the compound (22) (5.0 g, 37.5 mmol) obtained above in dichloromethane (150 mL).
7.5 mmol) was added, and the mixture was stirred at room temperature for 23 hours. The precipitate was collected by filtration, washed with dichloromethane, and dried under reduced pressure to give the title compound (23) as a white solid (9.57 g, yield:
93%) was obtained. ¹ H NMR (270 MHz, DMSO-d ₆ ) δ: 2.66 (s, 3H), 3.02
(t, 2H, J = 5.6Hz), 3.84 (t, 2H, J = 5.6Hz), 3.93 (s, 2
H).

1- (5,6-dihydro-2H- [1,
4] thiazin-3-yl) azetidin-3-thiol
Hydrochloride (24) 3-Mercaptoazetidine hydrochloride (384 mg, 3 mmol) in chloroform (5 mL) was added to the above compound (23) free compound (530 mg, 3.6 mmol) in chloroform (3 m).
L) solution was added and stirred at room temperature for 21 hours. The reaction solution was concentrated under reduced pressure, and the resulting residue was subjected to silica gel column chromatography (eluent: chloroform: methanol = 4:
Purification in 1) gave 571 mg (yield: 83%) of the title compound (24) as a pink foamy solid.

¹ H NMR (270 MHz, CDCl ₃ ) δ: 2.95 (t, 2
H, J = 5.6Hz), 3.31 (brs, 2H), 3.73-3.78 (m, 2H), 3.
92-4.00 (m, 1H), 4.27-4.53 (m, 2H), 4.72-5.14 (m,
2H).

P-nitrobenzyl (4R, 5S, 6
S) -3- [1- (2H, 3H, 6H-1,4-thiadi
(N-5-yl) azetidin-3-ylthio] -6-
[(R) -1-Hydroxyethyl] -4-methyl-7-
Oxo-1-azabicyclo [3.2.0] hept-2-
En-2-carboxylate (25)

Compound (24) obtained above (436 mg, 2.3
mmol) and compound (13) (1.44 g, 2.3 mmol) were dissolved in anhydrous acetonitrile (10 mL) under a nitrogen atmosphere, and 0
Cooled to ° C. Next, diisopropylethylamine (1 mL, 5.75 mmol) was added to the reaction solution, and the mixture was stirred at the same temperature for 2 hours. The precipitate was collected by filtration, washed with acetonitrile, and dried under reduced pressure to give the title compound (25) as a white solid (61%).
3 mg (yield: 50%) was obtained.

¹ H NMR (270 MHz, CDCl ₃ ) δ: 1.24 (d, 3
H, J = 7.3Hz), 1.35 (d, 3H, J = 6.3Hz), 2.64 (t, 2H, J
= 5.6Hz), 2.91 (s, 2H), 3.16-3.22 (m, 1H), 3.27 (d
d, 1H, J = 2.3, 6.6Hz), 3.64 (t, 2H, J = 5.6Hz), 3.84-
3.92 (m, 2H), 4.02-4.12 (m, 1H), 4.21-4.35 (m, 4
H), 5.25 (d, 1H, J = 13.9Hz), 5.51 (d, 1H, J = 13.9H
z), 7.66 (d, 2H, J = 8.6Hz), 8.23 (d, 2H, J = 8.9Hz).

(4R, 5S, 6S) -3- [1- (2
H, 3H, 6H-1,4-thiazin-5-yl) azeti
Zin-3-ylthio] -6-[(R) -1-hydroxy
Ethyl] -4-methyl-7-oxo-1-azabicyclo
[3.2.0] hept-2-ene-2-carboxylic acid
Compound (3)]

Compound (25) obtained above (613 mg, 1.15)
mmol) and 10% palladium-carbon (50% water content, 307
mg), and tetrahydrofuran (31 mL), 0.05 M
Add phosphate buffer (pH 6.0, 31 mL), 400 kPa
Under hydrogen atmosphere for 2 hours. After the reaction solution was filtered and the filtrate was adjusted to pH 6, water (60 mL) and n-butanol (60 mL) were added for liquid separation. The obtained aqueous layer is n
-After washing with butanol, the pH was adjusted to 6 again. The aqueous layer under reduced pressure was concentrated to 9 mL and subjected to HP-21 resin column chromatography (eluent: water: acetonitrile = 1: 0-
Purified at 9: 1). The elution fraction obtained was decompressed under 9 mL.
The mixture was concentrated to lyophilized and freeze-dried to obtain 320 mg (yield: 70%) of the title compound (3) as a colorless foamy solid.

¹ H NMR (400 MHz, D ₂ O) δ: 1.06 (d, 3H,
J = 7.2Hz), 1.16 (d, 3H, J = 6.3Hz), 2.82-2.85 (m, 2
H), 3.07-3.21 (m, 1H), 3.31-3.37 (m, 3H), 3.49-3.5
2 (m, 2H), 3.96-4.24 (m, 5H), 4.50-4.77 (m, 2H) .IR (KBr): 1751, 1663, 1588, 1390 cm ^-1 .λ ^max (MeOH): 220, 290 nm.

Example 4: (4R, 5S, 6S) -6-
[(R) -1-hydroxyethyl] -3-{[1- (2
S) -2-Methyl-5,6-dihydro-2H-1,4-
Thiazin-3-yl] azetidin-3-ylthio} -4
-Methyl-7-oxo-1-azabicyclo [3.2.
0] hept-2-ene-2-carboxylic acid [compound
(5)] manufacturing

[0091]

[Chemical 8]

Methyl (R) -2-methanesulfonyl ester
Xylpropionate (27) Under a nitrogen stream, methyl (R) -2-hydroxypropionate (26) (2.412 g, 23.2 mmol) in dichloromethane (2
5 mL) solution with triethylamine (3.55
mL, 25.5 mmol) and mesyl chloride (1.97 mL, 25.5 mmol)
mmol) was sequentially added dropwise. The mixture was stirred as it was under ice cooling for 15 minutes, water was added, and the mixture was washed twice with a separating funnel. The organic layer was washed once with saturated brine, dried over magnesium sulfate, filtered, concentrated under reduced pressure and dried under reduced pressure to obtain 3.175 g (yield: 75.2%) of the title compound (27) as a yellow liquid. .

¹ H-NMR (400 MHz; CDCl3) δ: 1.62 (d,
J = 7.0Hz, 3H), 3.15 (s, 3H), 3.81 (s, 3H), 5.15 (q,
J = 7.0Hz, 1H).

(S) -2-Methyl-thiomorpholine-3
-ON (28) While cooling with ice, potassium hydroxide (361.3 mg, 6.44 mmo
l) and mercaptoethylamine hydrochloride (368 mg, 3.24
mmol) was suspended in ethanol (6 mL). Then, the solution obtained by dissolving the compound (27) (590 mg, 3.24 mmol) obtained above in ethanol (3 mL) was added dropwise. After dropping, ethanol (6 mL) was added, and the mixture was stirred as it was at room temperature for 75 minutes. Dichloromethane (20 mL) was added to the reaction solution, stirred for a while and then filtered, and the filtrate was concentrated under reduced pressure.
The concentrated residue was dissolved in chloroform and separated and washed with a 1 mol / L hydrochloric acid aqueous solution. The organic layer was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: chloroform: methanol = 95: 5) to obtain 137.4 mg (yield: 3) of the title compound (28) as a colorless solid.
2.3%) was obtained.

¹ H-NMR (400 MHz; CDCl ₃ ) δ: 1.47 (d,
J = 7.0Hz, 3H), 2.90 (m, 2H), 3.56 (m, 2H), 3.64 (m,
1H), 6.91 (br, 1H).

(S) -2-Methyl-thiomorpholine-3
-Thion (29) To a solution of the compound (28) (764 mg, 5.82 mmol) obtained above in tetrahydrofuran (6 mL), Lawesson's reagent (1.18
g, 2.91 mmol) was added, and the mixture was stirred at 50 ° C. for 1 hr and concentrated under reduced pressure. The obtained concentrated residue was purified by silica gel column chromatography (eluent: chloroform) to obtain 725.7 mg of the title compound (29) as a colorless solid (yield:
84.6%).

¹ H-NMR (400 MHz; CDCl ₃ ) δ: 1.66 (d,
J = 6.9Hz, 3H), 2.98 (m, 2H), 3.54 (m, 1H), 3.58 (m,
1H), 3.67 (m, 1H), 8.80 (br, 1H).

(S) -6-methyl-5-methylthio-
3,6-Dihydro-2H- [1,4] thiazine-iodinated
Hydrogenate (30) Compound (29) obtained above (350 mg, 2.38) under a nitrogen stream.
Methyl iodide (0.740 mL, 11.9 mmol) was added to a dichloromethane (12 mL) solution of (mmol) and stirred at room temperature for 22.5 hours. The generated crystals were collected by suction filtration. The filtrate was concentrated under reduced pressure, the resulting crystals were collected by suction filtration again, and all the crystals were combined. The crystals were suspended and washed three times with diethyl ether and dried under reduced pressure to obtain 641.4 mg (yield: 93.3%) of the title compound (30) as pale yellow crystals.

¹ H-NMR (400 MHz; CDCl ₃ ) δ: 1.66 (d,
J = 6.8Hz, 3H), 3.11 (m, 1H), 3.14 (s, 3H), 3.31 (m,
1H), 3.78 (m, 1H), 4.05 (q, J = 6.8Hz, 1H), 4.72
(m, 1H).

(S) -6-methyl-5- (3-trityl
Thioazetidin-1-yl) -2,3-dihydro-6H
-[1,4] Thiazine hydrochloride (31) At room temperature, the compound (30) obtained above (289.2 mg, 1.0 mmo
A saturated aqueous solution of sodium hydrogencarbonate (5 mL) was added to a solution of l) in dichloromethane (10 mL), and the solution was separated and washed three times, and then washed once with saturated brine. The dichloromethane solution was dried over magnesium sulfate and then concentrated under reduced pressure to a total volume of 1.5 mL. 3-Tritylthioazetidine hydrochloride (306.6 mg, 0.833 mmol) was added to the solution, and the mixture was stirred at room temperature for 3 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: chloroform: methanol = 9: 1) to obtain 407.9 mg (yield: quantitative) of the title compound (31) as a colorless amorphous solid. Obtained.

¹ H-NMR (400 MHz; CDCl ₃ ) δ: 1.47 (m,
3H), 2.78 (m, 1H), 2.95 (m, 1H), 3.11 (q, J = 7.2Hz,
1H), 3.49-4.00 (m, 5H), 4.10 (m, 1H), 4.51 (m, 1
H), 7.23-7.40 (m, 15H).

P-nitrobenzyl (4R, 5S, 6
S) -6-[(R) -1-Hydroxyethyl] -3-
{[1- (2S) -2-methyl-5,6-dihydro-2
H-1,4-thiazin-3-yl] azetidin-3-i
Ruthio} -4-methyl-7-oxo-1-azabicyclo
[3.2.0] Hept-2-ene-2-carboxylate
(32) The compound (31) (400 mg, 0.831 mmol) obtained above was dissolved in trifluoroacetic acid (2 mL), triethylsilane (116 mg, 0.998 mmol) was added at room temperature, and the mixture was stirred for 15 minutes.
Then, the reaction solution was concentrated under reduced pressure to obtain a white residue. Dissolve the residue in acetonitrile (8 mL), and under a nitrogen stream,
The compound (13) (494 mg, 0.831 mmol) was added while cooling with ice. Diisopropylethylamine (0.178 mL, 0.99
(8 mmol) and the mixture was stirred for 1 hour. The obtained reaction solution was concentrated under reduced pressure, the residue was dissolved in ethyl acetate, washed three times with a saturated aqueous sodium hydrogen carbonate solution and once with a saturated saline solution,
The extract was dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was suspended and washed with diethyl ether three times. The crystals were purified by silica gel column chromatography (eluent: chloroform: methanol = 9: 1) to obtain 1/2 diphenyl phosphate of the title compound (32) as pale yellow crystals.
0.7 mg (yield: 46.7%) was obtained.

¹ H-NMR (400 MHz; CDCl ₃ ) δ: 1.19 (d,
J = 7.3Hz, 3H), 1.33 (d, J = 6.2Hz, 3H), 2.71 (m, 1
H), 2.90 (m, 1H), 3.23 (m, 1H), 3.31 (m, 2H), 3.52
(m, 2H), 4.11 (m, 2H), 4.24 (m, 2H), 4.34 (d, J =
9.1Hz, 1H), 4.78 (m, 1H), 4.91 (m, 1H), 5.26 (d, J =
13.7Hz, 1H), 5.48 (d, J = 13.7Hz, 1H), 7.03 (m, 1H),
7.24 (m, 4H), 7.65 (d, J = 8.5Hz, 2H), 8.22 (d, J =
8.5Hz, 2H).

(4R, 5S, 6S) -6-[(R) -1
-Hydroxyethyl] -3-{[1- (2S) -2-me
Cyl-5,6-dihydro-2H-1,4-thiazine-3
-Yl] azetidin-3-ylthio} -4-methyl-7
-Oxo-1-azabicyclo [3.2.0] hept-2
-Ene-2-carboxylic acid [compound (5)]

1/2 diphenyl phosphate (364 mg, 0.542 mmol) of compound (32) obtained above, 10% palladium-carbon (50% water content, 364 mg), 0.05 mol / L phosphate buffer solution (PH 6.0, 18 mL), tetrahydrofuran (18 m
L) The solution was subjected to hydrogenation reaction in a hydrogen stream under pressure of 400 kPa at room temperature for 1.5 hours. After completion of the reaction, the catalyst was removed by suction filtration, and n-butanol (20 mL) was added to the filtrate.
And water (25 mL) were added and the layers were separated. The n-butanol layer was washed twice with water (25 mL) and a 0.05 mol / L phosphate buffer solution (pH 6.
0) (25 mL) and re-extract and collect all the resulting aqueous layers to 1 m
The pH was adjusted to 5.73 with an ol / L sodium hydroxide aqueous solution. The solution was concentrated under reduced pressure until the total volume was 10 mL.
The concentrated solution was purified by HP-21 resin column chromatography (eluent: water, 5% acetonitrile solution, 10% acetonitrile solution, 20% acetonitrile solution in this order), and the obtained elution fraction was concentrated under reduced pressure. Lyophilize to give the title compound (5) 5 as a colorless amorphous solid.
4.6 mg (yield: 24.5%) was obtained.

¹ H-NMR (400 MHz; D ₂ O) δ: 0.94 (d, J =
7.2Hz, 3H), 1.05 (d, J = 6.4Hz, 3H), 1.37 (d, J = 7.2H
z, 3H), 2.64 (m, 1H), 2.87-2.99 (m, 2H), 3.20 (m,
1H), 3.35 (m, 1H), 3.43-3.51 (m, 2H), 3.75-4.18
(m, 5H), 4.30-4.75 (m, 2H). IR cm ^-1 (KBr): 3356 (br), 1753, 1655, 1587, 1388,
1261.UV nm (H ₂ O): 218, 296.

The following compounds were prepared according to the above examples. These compounds are listed along with their NMR data.

Example 5:

[0109]

[Chemical 9]

¹ H-NMR (400 MHz; D ₂ O) δ: 0.99 (d, J
= 7.2Hz, 3H), 1.09 (d, J = 6.4Hz, 3H), 1.48 (s, 6H),
2.84 (m, 2H), 3.02 (m, 1H), 3.25 (m, 1H), 3.47 (m,
2H), 4.00-4.14 (m, 4H), 4.45-4.55 (m, 3H).

Example 6:

[0112]

[Chemical 10]

¹ H-NMR (400 MHz; D ₂ O) δ: 1.03 (d, J
= 7.1Hz, 3H), 1.13 (d, J = 6.4Hz, 3H), 1.45 (d, J = 7.2
Hz, 3H), 2.72 (dt, J = 4.5Hz, 14.1Hz, 1H), 2.96-3.09
(m, 2H), 3.29 (dd, J = 2.5Hz, 6.2Hz, 1H), 3.44 (m,
1H), 3.55 (m, 1H), 3.97 (m, 1H), 4.03-4.23 (m, 4H),
4.48 (m, 1H), 4.62-4.74 (m, 1H).

Example 7:

[0115]

[Chemical 11]

¹ H-NMR (400 MHz; D ₂ O) δ: 0.92 (brs,
3H), 1.11 (d, J = 6.3Hz, 3H), 2.66-2.80 (m, 2H), 2.8
0-3.00 (m, 1H), 3.23 (m, 1H), 3.53 (m, 1H), 3.65
(m, 1H), 3.75-4.15 (m, 5H), 4.58 (m, 2H), 4.88 (s,
1H), 7.22-7.37 (m, 5H).

Example 8:

[0118]

[Chemical 12]

¹ H-NMR (400 MHz; D ₂ O) δ: 0.88 (d, 3
H, J = 7.53Hz), 0.99 (d, 3H, J = 6.02Hz), 1.40-1.45
(m, 2H), 1.72-1.78 (m, 2H), 2.75-2.78 (m, 2H),
2.87−2.95 (m, 1H), 3.13−3.14 (m, 1H), 3.27−3.29
(m, 2H), 3.79−4.01 (m, 5H), 4.33−4.37 (m, 1H).

Formulation examples using the carbapenem compound of the present invention are shown below.

Formulation Example 1 (Injection) (1) Suspension Injection Compound (1) 250 mg Methylcellulose 500 mg Polyvinylpyrrolidone 50 mg Methyl paraoxybenzoate 100 mg Polysorbate 80 100 mg Lidocaine hydrochloride 500 mg Distilled water Total amount 100 ml The above ingredients are mixed, Make a suspension injection with a total volume of 100 ml.

(2) In the case of freeze-drying A proper amount of distilled water was added to 20 g of the compound (3) to give a volume of 500.
Set to ml. 12.5 ml of the above aqueous solution in one vial
Or 25 ml (500 mg or 1 compound, respectively)
(Containing 000 mg) and lyophilized. When in use,
About 3-4 ml of distilled water is added to make an injection.

(3) Filling with powder In one vial, 250 mg of the compound (1) is filled as powder. At the time of use, about 3 to 4 ml of distilled water is added to make an injection.

Formulation Example 2 (tablets) Compound (1) 250 mg Lactose 250 mg Hydroxypropyl cellulose 1 mg Magnesium stearate 10 mg 1 tablet 511 mg

The above components are kneaded, granulated, and then tableted by a conventional method to give tablets. After tableting, sugar-coated or film-coated tablets may be coated with sugar or film, if necessary.

Formulation Example 3 (Capsule) Compound (3) 500 mg Magnesium stearate 10 mg 1 capsule 510 mg The above ingredients are mixed and filled into a usual hard gelatin capsule to give a capsule.

[0127]

INDUSTRIAL APPLICABILITY As described above, the present invention provides a novel carbapenem compound having excellent antibacterial activity and resistance to renal dehydropeptidase.

   ─────────────────────────────────────────────────── ─── Continued front page    F-term (reference) 4C050 KA12 KB05 KB12 KB16                 4C086 AA01 AA03 CC08 GA10 MA01                       MA04 NA14 ZB35

Claims (2)

[Claims] 1. The following formula (I): (In the formula, R ¹ represents a hydrogen atom or a protecting group for a carboxy group,
R ² and R ³ are the same or different and each represents a hydrogen atom, a substituted or unsubstituted lower alkyl group or a phenyl group, and the ring A is a 6- or 7-membered heterocycle containing one nitrogen atom and one sulfur atom, respectively. Represent ) The carbapenem compound shown by these or its pharmacologically acceptable salt. 2. An antibacterial agent containing the carbapenem compound according to claim 1 or a pharmacologically acceptable salt thereof as an active ingredient.