JPH0812676A - 2-((pyridyl-substituted)thio)-carbapenem derivative - Google Patents

Abstract

PURPOSE:To obtain a new derivative having good antimicrobial activity and oral absorbing property. CONSTITUTION:This derivative (salt) is expressed by formula I (A is a covalent bond, a lower alkylene, a lower alkenylene or a lower alkynylene), e.g. (1R,5S,6S)-2-[(2, 3 or 4-pyridyl)thio]-6-[(R)-1-hydroxyethyl]-1methylcarbapen-2- em-3-carboxylic acid. The derivative is obtained by reacting, e.g. a compound of formula II with a (pyridylsubstituted)thiol of formula III in a solvent such as tetrahydrofuran, preferably in an inert gas stream in the presence of a base such as sodium hydrogen carbonate at about-78 deg.C to 0 deg.C for about 30min to 24hr to afford a compound of formula VI, treating the resultant compound in a mixed solvent containing a buffer solution at pH 5.5, dipotassium phosphate, etc., using hydrogen under about 1-4 atmospheric pressure, in the presence of a hydrogenation catalyst such as platinum oxide at about 0-50 deg.C for about 0.25-5hr to eliminate a carboxyl protecting group R'.

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention relates to a novel carbapenem compound, more specifically, a novel carbapenem compound having sufficient antibacterial activity and oral absorbability, and an antibacterial agent containing the compound as an active ingredient, particularly oral. An antibacterial agent for administration is provided.

[0002]

2. Description of the Related Art Up to now, many compounds having a so-called carbapenem skeleton have been found, and among them, some compounds having excellent antibacterial activity have been put to practical use as an antibacterial agent, or development for practical use has been made. It is being advanced. For example, in Japanese Patent Laid-Open No. 1-25779, the following formula (A):

[0003]

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Compounds of the formula: have been described. This compound has a broad antibacterial spectrum and strong antibacterial activity, and overcomes the instability to renal dehydropeptidase, which has been a drawback of conventional carbapenem antibiotics, without using a stabilizer or the like. It has the excellent feature that it can be administered alone.
Therefore, the compound is expected to be a clinically extremely useful antibacterial agent, and development for practical use is underway.

However, most of the carbapenem compounds proposed so far, including the compound of the above formula (A), have poor absorption from the digestive tract, and therefore, they may be clinically administered intravenously as an injection. It's just that.

On the other hand, in a clinical setting, it is desirable to be able to select several administration routes when administering a drug, depending on the purpose of treatment and the patient's circumstances. In particular, oral agents are preferable in that they are easier and more convenient to administer than injectable agents and can be administered at home, and their clinical utility is extremely high.
Therefore, clinically, it is strongly desired to develop a carbapenem compound having a broad antibacterial spectrum and a strong antibacterial activity and capable of oral administration.

Incidentally, JP-A-55-89285 discloses the following general formula (B):

[0008]

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In the formula, R ⁸ represents a substituted or unsubstituted heteroaryl or heteroaralkyl group, and a specific compound having a pyridyl group as the heteroaryl group is exemplified. However, the publication does not disclose the oral absorbability of the above-mentioned specific compounds, nor does it disclose antibacterial activity data. Therefore, it cannot be considered from the description of the publication that the above specific compound is actually obtained. Therefore, the publication discloses specifically the structure and pharmacological action of the compound of the present invention showing excellent oral absorbability,
It does not give any suggestion.

[0010]

In view of the above situation, the present inventors have made earnest studies on orally administrable carbapenem compounds, and as a result, in the present case, a pyridyl group is present in the 2-position substituent. The inventors have found that such a derivative has excellent absorbability that cannot be predicted by oral administration, and confirmed that these derivatives have a sufficiently strong antibacterial activity, thus completing the present invention.

Thus, the present invention has the following formula (I):

[0012]

[Chemical 4]

In the formula, A is a covalent bond or represents a bonding group selected from a lower alkylene group, a lower alkenylene group and a lower alkynylene group, and is represented by (1R, 5S, 6S) -2. -[(Pyridyl-substituted) thio]
-6-[(R) -1-hydroxyethyl] -1-methylcarbapene-2-em-3-carboxylic acid derivative and its pharmacologically acceptable salt, and antibacterial containing the derivative as an active ingredient The present invention provides an agent, particularly an antibacterial agent for oral administration.

The present invention also provides, as a preferred embodiment,
Among the derivatives represented by the above formula (I), a compound in which A is a bonding group selected from a lower alkylene group, a lower alkenylene group and a lower alkynylene group, a pharmacologically acceptable salt thereof, and the derivative The present invention provides an antibacterial agent containing as an active ingredient, particularly an antibacterial agent for oral administration.

The compound of the present invention will be described in more detail below. In the present specification, the term "lower" means that the group or compound to which the term is attached has 1 to 7 carbon atoms.
It means that the number is one, preferably one to four.

"Pyridyl group" is 2-pyridyl, 3-pyridyl or 4-pyridyl.

An "alkylene group" is a straight chain saturated hydrocarbon in which two hydrogen atoms are removed from the carbon atoms at each end of the linear saturated hydrocarbon.
A valent group, for example, methylene, ethylene, trimethylene, tetramethylene, etc.

The term "alkenylene group" means a divalent group in which one or more double bonds are present in the above alkylene groups excluding methylene, and examples thereof include vinylene, propenylene, 2-butenylene and 1,3-butadienylene. is there.

The term "alkynylene group" means a divalent group in which one or more triple bonds are present in the above alkylene groups other than methylene, such as ethynylene, propynylene and 1-.
Examples include butynylene and 2-butynylene.

Among the compounds of formula (I) provided by the present invention, specific examples of preferable ones are as follows. (1R, 5S, 6S) -2-[(2,3 or 4-pyridyl) thio] -6-[(R) -1-hydroxyethyl]-
1-methylcarbapene-2-em-3-carboxylic acid;
(1R, 5S, 6S) -2-[(2,3 or 4-pyridyl) methylthio] -6-[(R) -1-hydroxyethyl] -1-methylcarbapene-2-em-3-carboxylic acid (1R, 5S, 6S) -2- [2- (2,3 or 4)
-Pyridyl) ethyl] thio-6-[(R) -1-hydroxyethyl] -1-methylcarbapene-2-Em-3-
Carboxylic acid; (1R, 5S, 6S) -2- [3- (2,
3 or 4-pyridyl) propyl] thio-6-[(R)-
1-hydroxyethyl] -1-methylcarbapene-2-
Em-3-carboxylic acid; (1R, 5S, 6S) -2-
[(E) or (Z) -2- (2,3 or 4-pyridyl)
Vinyl] thio-6-[(R) -1-hydroxyethyl]
-1-methylcarbapene-2-em-3-carboxylic acid;
(1R, 5S, 6S) -2-[(E) or (Z) -3-
(2,3 or 4-pyridyl) -2-propenyl] thio-
6-[(R) -1-hydroxyethyl] -1-methylcarbapene-2-em-3-carboxylic acid; (1R, 5S,
6S) -2- [3- (2,3 or 4-pyridyl) -2-
Propinyl] thio-6-[(R) -1-hydroxyethyl] -1-methylcarbapene-2-em-3-carboxylic acid and the like.

The present invention also includes pharmacologically acceptable salts of the compound of formula (I), such salts being formed between the nitrogen atom of the pyridyl group and the 3-position carboxylic acid. Inner salt, sodium salt or potassium salt,
Alternatively, an acid addition salt with an organic acid or an inorganic acid may, for example, be mentioned.

The compound of the formula (I) of the present invention can be synthesized, for example, according to the following reaction formula shown schematically.

[0023]

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In the formula, R ^a represents an acyl group, R ′ represents a carboxyl protecting group, and A has the same meaning as defined above.

The "acyl group" represented by R ^a is simply a carboxyl group of an organic carboxylic acid to an OH group.
Not only the remaining atomic groups excluding the group, but in a broad sense, an acyl group derived from an organic sulfonic acid or an organic phosphoric acid is included, and specifically, lower alkanoyl groups such as acetyl, propionyl and butyryl; methanesulfonyl, (Halo) lower alkylsulfonyl group such as trifluoromethanesulfonyl group; substituted or unsubstituted arylsulfonyl such as benzenesulfonyl, p-nitrobenzenesulfonyl, p-bromobenzenesulfonyl, toluenesulfonyl and 2,4,6-triisopropylbenzenesulfonyl. Group; a diphenylphosphoryl group and the like.

Examples of the "carboxyl protecting group" represented by R'include an ester residue, and examples of such an ester residue include methyl, ethyl, n-propyl, isopropyl, n- and iso-. , T
Lower alkyl ester residues such as ert-butyl and n-hexyl ester; allyl ester residues; benzyl, p-
Aralkyl ester residues such as nitrobenzyl, o-nitrobenzyl, m-nitrobenzyl, 2,4-dinitrobenzyl, p-chlorobenzyl, p-bromobenzyl, p-methoxybenzyl; acetoxymethyl, acetoxyethyl, propionyloxymethyl , N-, iso-butyryloxymethyl, and lower aliphatic acyloxymethyl residues such as pivaloyloxymethyl.

In the above reaction scheme, the reaction of the compound of formula (II) with the (pyridyl-substituted) thiol represented by formula (III) can be carried out, for example, by adding the compound of formula (II) to tetrahydrofuran, dichloromethane, dioxane or dimethylformamide. , Dimethylsulfoxide, acetonitrile, hexamethylphosphoramide, etc. in a suitable solvent in an amount of about 1 to about 5 times, preferably about 1 to about 3 times the formula (II).
Optionally prepared from a compound of I) and preferably a base such as sodium hydrogen carbonate, potassium carbonate, triethylamine, diisopropylethylamine, a sodium alkoxide such as sodium methoxide or sodium ethoxide, or diisopropylamine and n-butyllithium. In the presence of lithium diisopropylamide, about -78
It can be carried out by reacting at a temperature of about 0 ° C for about 30 minutes to about 24 hours.

The reaction is preferably carried out in a stream of an inert gas such as nitrogen gas or argon gas.

By this reaction, the compound of formula (IV) is obtained, and the reaction solution can be used as it is in the next step. However, if necessary, the reaction solution is subjected to a conventional purification means such as filtration, decantation, Extraction, washing, solvent evaporation,
The compound of formula (IV) can also be isolated and purified by subjecting it to column or thin layer chromatography, recrystallization, distillation, sublimation and the like.

The compound of formula (IV) obtained by the above reaction can then be converted to the compound of formula (I) by removing the carboxyl protecting group R '.

Removal of the carboxyl protecting group R'can be carried out by a known protecting group reaction such as solvolysis or hydrogenolysis.
V), for example, acetate buffer pH 5.5, p
H5.5 morpholinopropanesulfonic acid-sodium hydroxide buffer, pH 5.5 phosphate buffer, dipotassium phosphate, tetrahydrofuran-water containing sodium bicarbonate, tetrahydrofuran-ethanol-water, dioxane-water, In a mixed solvent of dioxane-ethanol-water, n-butanol-water, etc., hydrogen at about 1 to about 4 atm is used in the presence of a hydrogenation catalyst such as platinum oxide, palladium-activated carbon, palladium hydroxide-activated carbon or the like. Can be carried out at a temperature within the range of about 0 to about 50 ° C. for about 0.25 to about 5 hours.

The elimination of the protecting group R'can also be carried out by treating with zinc in a buffer solution. For example,
The compound of formula (IV) is treated with zinc in a pH 5 to 7 buffer such as phosphate buffer, acetate buffer, citrate buffer, morpholinopropane sulfonate buffer, N-methylmorphophosphate buffer. It can be done by
Examples of zinc that can be used include zinc powder, white zinc,
Granule zinc may be mentioned, and the amount thereof is not particularly limited, but is generally about 1 to 1 part by weight of the compound of the formula (IV).
It can be in the range of about 10 parts by weight, preferably about 1 to about 5 parts by weight. In the present elimination reaction, an organic solvent may be used in combination, if necessary. Examples of such a solvent include alcohol solvents such as ethanol, propanol and n-butanol; ether solvents such as diethylethanol and tetrahydrofuran. Solvents: acetonitrile, dimethylformamide, dimethylacetamide and the like. The reaction can be completed usually by treating at a temperature of about -20 to about 50 ° C, preferably room temperature to about 30 ° C for about 5 minutes to about 5 hours.

Thus, the 2-[(pyridyl-substituted) thio] carbapenem derivative of the formula (I), which is the object compound of the present invention, can be obtained in a high yield, and the compound may be an ion exchange resin or High-purity isolation can be achieved by purification using a polymer adsorption resin.

The compound of formula (I) which is the object compound of the present invention can exist as an inner salt per se. Further, in an appropriate solvent, for example, as an alkali metal salt by treatment with a metal hydroxide such as sodium hydroxide or potassium hydroxide, or as an arbitrary acid addition salt by treatment with an organic acid or an inorganic acid, Each can also be isolated. Examples of the organic acid used to obtain the acid addition salt include lower fatty acids such as formic acid, acetic acid, propionic acid, butyric acid, trifluoroacetic acid and trichloroacetic acid; substituted or unsubstituted benzoic acid, p-nitrobenzoic acid and the like. Benzoic acid; (halo) lower alkyl sulfonic acids such as methanesulfonic acid and trifluoromethanesulfonic acid; benzenesulfonic acid, p-nitrobenzenesulfonic acid, p-bromobenzenesulfonic acid, toluenesulfonic acid, 2,
Substituted or unsubstituted aryl sulfonic acids such as 4,6-triisopropylbenzene sulfonic acid; and organic phosphoric acids such as diphenyl phosphoric acid can be mentioned, and examples of the inorganic acid include hydrochloric acid, sulfuric acid, hydrobromic acid, and iodine. Examples thereof include hydrofluoric acid, borofluoric acid, perchloric acid, and nitrous acid.

The compound of formula (II) used as a starting material in the above-mentioned production method is known per se, and can be produced, for example, by the method described in JP-A-56-123985. Alternatively, or preferably, it can be produced in a highly stereoselective manner by the method described in JP-A-63-284176.

The compound of the above formula (III) is a compound known per se and is easily available, or can be easily produced from a commercially available compound.

The compound (I) of the present invention obtained by the above-mentioned method shows a sufficient antibacterial activity against a wide variety of bacterial species, and is excellent in gastrointestinal absorption by oral administration. Such properties of the compound of the present invention can be verified by the results of the following antibacterial test, pharmacological test and toxicity test.

[Antibacterial Test] 1. Test method Japanese Society of Chemotherapy Standard Method [Chemothrapy, vol 29,76
-79 (1981)].
That is, an overnight culture of Mueller-Hinton (MH) agar liquid medium of a test bacterium at 37 ° C. is diluted with Buffered saline gelatin (BSG) solution to about 10 ⁶ cells / ml and tested using a microplanter. Approximately 5 μl of compound-containing MH agar medium was inoculated and incubated at 37 ° C for 18 hours.
tory concentration (MIC). Here, the standard strain used was used.

As test compounds, compounds (4), (6), (12), (13), and (1) described in Examples below are used.
9) and (24) were used.

2. Results The results are shown in Table 1 below.

[0041]

[Table 1]

From the above results, it was confirmed that the carbapenem compound of the present invention has excellent antibacterial activity against a wide range of bacterial species.

[Pharmacological test] Intestinal absorption test by I in situ loop method Test Method A portion of the lower duodenum of about 30 cm of a 7-week-old Wistar male rat fasted overnight is tied with a thread. After injecting a test compound (20 mg / kg) as a 0.2% physiological saline solution from the upper part of the duodenum using a stomach probe, the region just below the injection site is tied with a thread and immediately returned to the intestinal cavity. 10, after injection of test compound
Approximately 0.4 from the jugular vein after 30, 60 and 120 minutes
Blood was collected in ml and the concentration of the test compound in this plasma was measured by HPL.
It was measured by method C (Hitachi 635A type, column; Wakopack). In addition, the AUC (area under the blood concentration curve) of the test compound 2 hours after the injection was determined from this measured value.
Two rats were used, and as test compounds, the compounds (4), (6), (12) of the present invention produced in the Examples described later,
(19) and (24) were used.

2. Results Maximum blood concentration of test compound and AUC obtained in this test
Is shown in Table 2 below.

[0045]

[Table 2]

From the above results, it is clear that the compound of the present invention is well absorbed from the intestinal tract.

II Oral Administration Test 1. Test method To a 5-week-old ddY male mouse fasted overnight, 100 mg / kg of a test compound as a 1% physiological saline solution is orally administered using a stomach probe. 0.25 after test compound administration,
After 0.5, 1, 2 and 3 hours, about 0.
4 ml blood was collected and the concentration of the test compound was measured by the same method as the above test. In addition, the AUC of the test compound for a certain period of time after administration was determined from this measured value. As the test compound, the compounds (4), (6) of the present invention produced in Examples described later,
(12), (19) and (24) were used.

2. Results The maximum blood concentration and AUC of each compound obtained in this test are shown in Table 3 below.

[0049]

[Table 3]

From the above results, it is clear that absorption of the compound of the present invention from the gastrointestinal tract is good even in oral administration in vivo.

[Toxicity test] CrjC weighing 20 to 23 g
Ten male D (SD) mice were used, and the carbapenem compounds (4), (6) of the present invention described in Examples below were used.
Each of the aqueous solutions of (12), (13), (19) and (24) was subcutaneously administered and observed for one week. As a result, it was observed that all the compounds of the present invention survived without any abnormality at the dose of 500 mg / kg.

As described above, the carbapenem compound of the formula (I) provided by the present invention is a compound showing excellent antibacterial activity against a wide variety of bacterial species and having high safety, but not only that. , Orally, it has excellent absorption from the digestive tract. Therefore, the compound represented by the formula (I) of the present invention can be used not only as an injection but also as an oral preparation and a useful antibacterial agent for treating and preventing bacterial infections caused by various pathogenic bacteria. Be expected.

The compound of the formula (I) or a pharmaceutically acceptable salt thereof can be prepared by using the compound as an antibacterial agent.
It can be administered to mammals including human being in the form of a pharmaceutical composition containing the antibacterial effective amount. The dose can be varied over a wide range depending on the age, weight, symptoms of the patient to be treated, drug administration form, doctor's diagnosis, etc., but in general, for adults, about 200 to about 3 per day. A dose in the range of 1,000 mg is standard, and it may be administered orally, parenterally or topically in one or several divided doses per day.

Thus, the above-mentioned pharmaceutical composition comprises an inorganic or organic solid or liquid pharmaceutical carrier or diluent conventionally used in the preparation of pharmaceuticals, especially antibiotics, such as starch, lactose, sucrose, Crystalline cellulose,
Excipients such as calcium hydrogen phosphate; binders such as acacia, hydroxypropylcellulose, alginic acid, gelatin, polyvinylpyrrolidone; lubricants such as stearic acid, magnesium stearate, calcium stearate, talc, hydrogenated vegetable oils; processed starch , Calcium carboxymethylcellulose, low-substituted hydroxypropylcellulose, and other disintegrants; dosage forms suitable for oral, parenteral or topical administration together with dissolution aids such as nonionic surfactants and anionic surfactants Can be formulated into

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 and the like. In addition, dosage forms suitable for topical administration include ointments, tinctures, creams, gels and the like. These preparations can be prepared by a method known per se in the field of pharmaceutics.

Next, the production of the carbapenem compound of the present invention will be described in more detail with reference to Examples and Preparation Examples, but it goes without saying that the present invention is not limited to the following description.

In the following description, each abbreviation has the following meaning. Me: Methyl Ac: Acetyl Ph: Phenyl Ms: Methanesulfonyl PNB: p-Nitrobenzyl

Example 1

[0059]

[Chemical 6]

(A) p-nitrobenzyl (1R, 5
S, 6S) -2- (diphenylphosphoryloxy) -6
-[(R) -1-Hydroxyethyl] -1-methylcarbapene-2-em-3-carboxylate (1) 1.2
g of 2-mercaptopyridine (2) (222 mg) in anhydrous acetonitrile was cooled to 0 ° C., 0.4 ml of diisopropylethylamine was added to this solution in a nitrogen gas stream, and the mixture was stirred at the same temperature for 2 hours. The reaction mixture was concentrated under reduced pressure and the obtained residue was subjected to silica gel column chromatography (eluting solvent: chloroform-ethyl acetate) to obtain 819 mg of compound (3) as a white powder. ¹ H-NMR (CDCl ₃ ) δ: 1.01 (d, 3H,
J = 7.6 Hz), 1.34 (d, 3H, J = 6.3H)
z), 1.60 (bs, 1H), 3.28 (dd, 1)
H, J = 2.8, 6.8 Hz), 3.80 (m, 1
H), 4.20-4.40 (m, 2H), 5.28.
(D, 1H, J = 13.9 Hz), 7.20 (m, 1
H), 7.48 (m, 1H), 7.60 to 7.70.
(M, 3H), 8.23 (d, 2H, J = 8.9H
z), 8.54 (m, 1H)

(B) Tetrahydrofuran 10 ml, n-
20 ml butanol and 0.1M phosphate buffer (pH
7.0) 500 mg of the compound (3) obtained in the above (a) was dissolved in 20 ml of a mixed solvent, and 125 ml of 10% palladium carbon was added to this solution, and the mixture was kept under hydrogen atmosphere (4 atm) at room temperature for 2 hours. Stir vigorously. The filtrate obtained by filtering the reaction solution was washed with n-butanol, the pH of the aqueous layer was adjusted to 6.0, and the residue obtained by concentrating under reduced pressure was added to D.
iaion SP-207 (manufactured by Mitsubishi Kasei Co., Ltd.)
Column chromatography (elution solvent: 25% isopropyl alcohol water) according to the method of (1R,
5S, 6S) -2-[(2-pyridyl) thio] -6-
280 mg of [(R) -1-hydroxyethyl] -1-methylcarbapene-2-em-3-carboxylic acid (4) was obtained as a pale yellow solid. ¹ H-NMR (CDCl ₃ ) δ: 0.90 (d, 3H,
J = 7.3 Hz), 1.19 (d, 3H, J = 6.3H)
z), 3.18 (m, 1H), 3.37 (m, 1H),
4.10 to 4.25 (m, 2H), 7.30 (m, 1)
H), 7.55 (m, 1H), 7.75 (m, 1H),
8.40 (m, 1H)

Example 2

[0063]

[Chemical 7]

(A) 2-pyridinemethanol 746 mg
To a solution of dichloromethane in 30 ml of triethylamine 1.
Add 73 ml and cool to 0 ° C. After 0.9 ml of methanesulfonyl chloride was added dropwise to this solution, the mixture was stirred at room temperature for 1 hour. Dichloromethane (10 ml) is added to the reaction solution, and the mixture is washed successively with water and saturated brine. After drying over magnesium sulfate, the solvent is distilled off under reduced pressure and the resulting residue is dissolved in 70 ml of acetone. After adding 1.17 g of potassium thioacetate to this solution, it is heated under reflux for 1 hour. 70 ml of dichloromethane is added to the reaction solution, which is washed successively with water and saturated saline. After drying with magnesium sulfate,
The solvent was evaporated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (eluting solvent: dichloromethane-ethyl acetate) to give 2-pyridinylmethylthioacetate as a yellow oil (854 mg, yield: 74.8). %)
Obtained. ¹ H-NMR (CDCl ₃ ) δ: 2.35 (s, 3
H), 4.25 (s, 2H), 7.08 to 8.55.
(M, 4H)

(B) Compound 417 obtained in (a) above
A solution of 125 mg of methanol in 125 ml is cooled to 0 ° C., and 40 ml of a saturated ammonia-methanol solution is added dropwise to this solution. After stirring at the same temperature for 30 minutes, the solvent was evaporated under reduced pressure and the obtained residue was subjected to silica gel column chromatography (eluting solvent: chloroform-ethyl acetate) to give 2-pyridinemethylthiol (5) as a yellow oil. As a product, 167 mg (yield: 53.5%) was obtained.

(C) Using the 2-pyridinemethylthiol obtained in (b) above as a starting material and following the method described in Example 1 above, (1R, 5S, 6S) -2- of the present invention.
[(2-Pyridyl) methylthio] -6-[(R) -1-
280 mg of hydroxyethyl] -1-methylcarbapene-2-em-3-carboxylic acid (6) as a pale yellow solid.
Obtained. ¹ H-NMR (D ₂ O) δ: 1.039 (d, 3H, J
= 7.26 Hz), 1.199 (d, 3H, J = 6.2)
7Hz), 3.221 to 3.336 (m, 2H), 3.
963 (dd, 1H, J = 2.31Hz, 9.24H
z), 4.023 (d, 1H, J = 13.86 Hz),
4.085 to 4.178 (m, 1H), 4.152
(D, 1H, J = 13.86 Hz), 7.259-7.
305 (m, 1H), 7.449 (d, 1H, J = 7.
92 Hz), 7.445 to 7.801 (m, 1H),
8.379 (d, 1H, J = 4.29Hz)

Example 3

[0068]

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(A) A suspension of 825 mg of sodium hydride in 40 ml of dry tetrahydrofuran was added at -25 ° C to -3.
A solution of 4.237 g of triethylphosphonoacetate in 40 ml of dry tetrahydrofuran is added dropwise at 5 ° C., and the mixture is stirred at the same temperature for 30 minutes. Furthermore, 1.947 g of picolinaldehyde (7) in dry tetrahydrofuran of 15 m was added to the reaction solution.
1 solution is added dropwise over 15 minutes and stirred at the same temperature for 1 hour. After completion of the reaction, water is added and the mixture is extracted with ethyl acetate, and the obtained organic layer is washed with saturated saline. The solution was dried over magnesium sulfate, the solvent was evaporated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (eluting solvent: ethyl acetate-n-hexane) to give compound (8) as a colorless transparent oil. 3.007 g as a product (yield: 9
4.3%) was obtained. ¹ H-NMR (CDCl ₃ ) δ: 1.34 (t, 3H,
J = 7 Hz), 4.28 (d, 2H, J = 7 Hz),
6.92 (d, 1H, J = 16 Hz), 7.26 (d
d, 1H, J = 6 Hz, 5 Hz), 7.43 (d, 1
H, J = 8 Hz), 7.69 (d, 1H, J = 16H
z), 7.71 (dd, 1H, J = 8Hz, 6Hz),
8.65 (d, 1H, J = 5Hz)

(B) Compound (8) obtained in (a) above
21.99 ml of a tetrahydrofuran (1 molar concentration) solution of diisobutylaluminum hydride was added dropwise to a solution of 1.299 g of dry methylene chloride in 11 ml at −78 ° C. over 30 minutes, and the mixture was stirred for 30 minutes. Methanol is added to the reaction solution, the temperature is gradually raised to 0 ° C., 1N aqueous sodium hydroxide solution is further added, the temperature is raised to room temperature, the mixture is filtered through Celite, and the obtained filtrate is washed with saturated saline. The solution was dried over magnesium sulfate, the solvent was evaporated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (eluting solvent: chloroform-acetone) to give compound (9) as a light brown oil (855 mg, Yield: 8
6.3%) was obtained. ¹ H-NMR (CDCl ₃ ) δ: 4.37 (d, 2H,
J = 4 Hz), 4.86 (brs, 1H), 6.74
(D, 1H, J = 16 Hz), 6.82 (dt, 1H,
J = 16 Hz, 4 Hz), 7.09 (dd, 1H, J =
5Hz, 6Hz), 7.27 (d, 1H, J = 8H
z), 7.59 (dd, 1H, J = 8Hz, 6Hz),
8.48 (d, 1H, J = 5Hz)

(C) Triphenylphosphine 2.891
to 8 ml of a dry tetrahydrofuran solution at 0 ° C, 1.919 g of diethylazodicarboxylate was added to
Stir for minutes. A solution of 745 mg of the compound (9) obtained in (b) above in 3 ml of dry tetrahydrofuran was added dropwise to this solution, and the mixture was stirred for 10 minutes.
Add 5 ml and stir for 10 minutes. After completion of the reaction, the solvent is distilled off under reduced pressure and the resulting residue is subjected to silica gel column chromatography (eluting solvent: ethyl acetate-n-hexane).
And the compound (10) as a reddish brown oil 448
mg (yield: 46.7%) was obtained. ¹ H-NMR (CDCl ₃ ) δ: 2.36 (s, 3
H), 3.74 (d, 2H, J = 6 Hz), 6.6-
6.8 (m, 2H), 7.12 (dd, 1H, J = 5H
z, 8 Hz), 7.25 (d, 1H, J = 8 Hz),
7.61 (t, 1H, J = 8Hz), 8.54 (d, 1
H, J = 5Hz)

(D) Compound (1) obtained in the above (c)
0) To a solution of 2.044 g of dry methanol in 35 ml, under ice cooling, a solution of 2.040 g of sodium methoxide in 28% methanol is added and stirred for 10 minutes. After the reaction,
12.3 hydrochloric acid (42.3 ml) is added, the mixture is concentrated under reduced pressure, azeotropically distilled with ethanol and acetonitrile in this order, and then dried under vacuum. The obtained residue was suspended in 130 ml of dry acetonitrile,
To this is added 6.281 g of compound (1). To this suspension, under ice-cooling, 4.420 m of diisopropylethylamine
1 at room temperature, then return to room temperature for 1 hour, and
Stir for 0 minutes. After completion of the reaction, the solvent was distilled off under reduced pressure,
The obtained residue is dissolved in chloroform and washed with saturated aqueous sodium hydrogen carbonate and saturated brine. After the solution was dried over magnesium sulfate, the solvent was distilled off under reduced pressure and the resulting residue was subjected to silica gel column chromatography (eluting solvent: chloroform-acetone) to give compound (11) as a pale yellow amorphous substance. 854 g (yield: 70.2%)
Obtained. ¹ H-NMR (CDCl ₃ ) δ: 1.31 (d, 3H,
J = 7 Hz), 1.37 (d, 3H, J = 6 Hz),
1.7-1.8 (br, 1H), 3.27 (dd, 1
H, J = 3 Hz, 7 Hz), 3.4 to 3.6 (m, 1
H), 3.62 (dd, 1H, J = 6Hz, 14H
z), 3.79 (dd, 1H, J = 6Hz, 14H
z), 4.20 (dd, 1H, J = 3Hz, 9Hz),
4.1-4.2 (m, 1H), 5.25 (d, 1H, J
= 14 Hz), 5.51 (d, 1H, J = 14 Hz),
6.66 (d, 1H, J = 16 Hz), 6.76 (d
t, 1H, J = 16 Hz, 6 Hz), 7.17 (dd,
1H, J = 5Hz, 8Hz), 7.26 (d, 1H, J
= 8 Hz), 7.65 (t, 1H, J = 8 Hz), 7.
66 (d, 2H, J = 9 Hz), 8.22 (d, 2H,
J = 9 Hz), 8.55 (d, 1H, J = 5 Hz)

(E) Compound (1) obtained in the above (d)
1) To a solution of 1.15 g of dry ethyl acetate in 12 ml, 1.78 g of lithium iodide was added, and the mixture was heated under reflux for 2 hours.
After completion of the reaction, the reaction solution is extracted with water, the resulting aqueous solution is washed with ethyl acetate and then concentrated under reduced pressure. This concentrate is D
Column chromatography (elution solvent: water and 10) by iaion HP-40 (manufactured by Mitsubishi Kasei Co., Ltd.)
% Acetonitrile water) to give (1R, 5
S, 6S) -2-([(E) -3- (2-pyridyl)-
253 mg of 2-propenyl] thio) -6-[(R) -1-hydroxyethyl] -1-methylcarbapene-2-em-3-carboxylic acid (12) as white amorphous.
(Yield: 31.6%) was obtained. ¹ H-NMR (D ₂ O) δ: 0.61 (d, 3H, J =
7 Hz), 0.68 (d, 3H, J = 6 Hz), 2.7
9 (dd, 1H, J = 3 Hz, 6 Hz), 2.8-3.
0 (m, 1H), 2.99 (dd, 1H, J = 4Hz,
14 Hz), 3.21 (dd, 1H, J = 5 Hz, 14
Hz), 3.52 (dd, 1H, J = 3Hz, 9H
z), 3.5 to 3.7 (m, 1H), 6.0 to 6.2.
(M, 2H), 6.71 (dd, 1H, J = 5Hz, 6
Hz), 6.93 (d, 1H, J = 8 Hz), 7.23
(Dd, 1H, J = 6 Hz, 8 Hz), 7.84 (d,
1H, J = 5Hz)

Example 4

[0075]

[Chemical 9]

Compound (12) 5 obtained in Example 3 above
To 0 mg of 1 ml of tetrahydrofuran solution, 1 ml of 0.1 mol phosphate buffer (pH 7.0) and 50 mg of 10% palladium carbon (containing 50% water) were added, and the mixture was vigorously stirred at room temperature for 2 hours under hydrogen atmosphere (4 atm). . After completion of the reaction, the reaction solution is filtered through Celite, the obtained filtrate is washed with ethyl acetate, and then concentrated under reduced pressure. Dilute this concentrate
Column chromatography with aion HP-40 (manufactured by Mitsubishi Kasei Co., Ltd.) (elution solvent: water and 20%)
(1R, 5S,
6S) -2- [3- (2-pyridyl) propyl] thio-
6.9 mg (yield: 25.6%) of 6-[(R) -1-hydroxyethyl] -1-methylcarbapene-2-em-3-carboxylic acid (13) was obtained as a white amorphous. ¹ H-NMR (D ₂ O) δ: 0.95 (d, 3H, J =
7 Hz), 1.17 (d, 3H, J = 7 Hz), 1.8
~ 2.0 (m, 2H), 2.5-2.7 (m, 1H),
2.7-2.9 (m, 3H), 2.9-3.1 (m, 1)
H) 3.23 (dd, 1H, J = 2Hz, 6Hz),
3.96 (dd, 1H, J = 2Hz, 9Hz), 4.0
-4.2 (m, 1H), 7.23 (dd, 1H, J = 5)
Hz, 8 Hz), 7.30 (d, 1H, J = 7 Hz),
7.74 (dd, 1H, J = 7Hz, 8Hz), 8.3
2 (d, 1H, H = 5Hz)

Example 5

[0078]

[Chemical 10]

(A) 3-Bromopyridine (14) 3.0
0 g, methyl acrylate 3.42 ml, palladium diacetate 140 ml and triphenylphosphine 65
4 mg are suspended in 5 ml triethylamine and the mixture is stirred in a sealed tube at 140 ° C. for 24 hours. After the reaction,
The residue obtained by distilling off triethylamine under reduced pressure is dissolved in water, and potassium carbonate is added to this aqueous solution to make it alkaline. The resulting solution was extracted with chloroform, the organic layer was dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The resulting residue was subjected to silica gel column chromatography (eluting solvent: ethyl acetate-n-hexane). 2.874 g of the compound (15) as light brown crystals (yield:
92.8%) was obtained. ¹ H-NMR (CDCl ₃ ) δ: 3.83 (s, 3
H), 6.52 (d, 1H, J = 16 Hz), 7.34
(Dd, 1H, J = 5 Hz, 8 Hz), 7.64 (d,
1H, J = 16Hz), 7.84 (d, 1H, J = 8H
z), 8.61 (d, 1H, J = 5 Hz), 8.75
(S, 1H)

(B) Compound (1) obtained in (a) above
5) In a solution of 1.30 g of dry methylene chloride in 12 ml,
At 78 ° C., 1.01 ml of trifluoroborane ether complex is added dropwise and stirred for 30 minutes. 21.5 ml of a tetrahydrofuran solution (1 molar concentration) of diisobutylaluminum hydride was slowly added dropwise to the reaction solution, and 1
Stir for hours. After the reaction is completed, a solution of 1.23 ml of acetic acid in 3.0 ml of methylene chloride is slowly added, the temperature is raised to room temperature, a small amount of aqueous potassium carbonate solution is added, and the mixture is extracted with chloroform. The resulting organic layer is dried over potassium carbonate,
The solvent was evaporated under reduced pressure and the obtained residue was subjected to silica gel column chromatography (eluting solvent: chloroform-acetone) to give compound (16) as a pale brown oily substance 7
80 mg (yield: 72.4%) was obtained. ¹ H-NMR (CDCl ₃ ) δ: 4.35 (d, 2H,
J = 5 Hz), 4.8 to 5.0 (br, 1H), 6.4
3 (dt, 1H, J = 16Hz, 5Hz), 6.60
(D, 1H, J = 16 Hz), 7.26 (dd, 1H,
J = 5Hz, 8Hz), 7.71 (d, 1H, J = 8H
z), 8.41 (d, 1H, J = 5 Hz), 8.54
(S, 1H)

(C) Triphenylphosphine 1.911
g in dry tetrahydrofuran 10 ml solution, under ice cooling,
1.269 g of diethyl azodicarboxylate are added dropwise and stirred for 30 minutes. Then, 780 mg of the compound (16) obtained in (b) above, 6 m of dry tetrahydrofuran
1 solution was added dropwise and stirred for 5 minutes.
ml is added dropwise, and the mixture is cooled to room temperature for 1 hour and then stirred at room temperature for 2 hours. After completion of the reaction, the solvent is distilled off under reduced pressure, methylene chloride-n-hexane is added, and the precipitated crystals are filtered off. The residue obtained by concentrating the solvent of this filtrate under reduced pressure was subjected to silica gel column chromatography (eluting solvent: ethyl acetate-n-hexane) to give 671 mg of compound (17) as a light brown oil (yield: 60 .2%) was obtained. ¹ H-NMR (CDCl ₃ ) δ: 2.40 (s, 3
H), 3.71 (d, 2H, J = 7Hz), 6.24
(Dt, 1H, J = 16Hz, 7Hz), 6.56
(D, 1H, J = 16 Hz), 7.24 (dd, 2H,
J = 5Hz, 8Hz), 7.67 (d, 1H, J = 8H
z), 8.46 (d, 1H, J = 5 Hz), 8.57
(S, 1H)

(D) Compound (1) obtained in the above (c)
7) To a solution of 671 mg of dry methanol in 12 ml, a solution of 670 mg of sodium methoxide in 28% methanol was added dropwise under ice cooling, and the mixture was stirred for 15 minutes. Chloroform is added to the reaction solution, and the mixture is extracted with 1N hydrochloric acid. The aqueous layer is made alkaline with 1N aqueous sodium hydroxide solution, extracted again with chloroform, and the resulting solution is dried over magnesium sulfate. Residue 338 obtained by distilling off the solvent under reduced pressure
mg and 787 mg of the compound (1) are dissolved in a 13 ml solution of dry acetonitrile, 0.308 ml of diisopropylethylamine is added dropwise to this solution under ice cooling, and the mixture is stirred for 2 hours. After completion of the reaction, the solvent is evaporated under reduced pressure and the obtained residue is dissolved in chloroform and washed with saturated aqueous sodium hydrogen carbonate and saturated brine. The solution was dried over magnesium sulfate, the solvent was evaporated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (eluting solvent: chloroform-acetone) to give compound (18) as a yellow crystal.
21 mg (yield: quantitative) was obtained. ¹ H-NMR (CDCl ₃ ) δ: 1.31 (d, 3H,
J = 7 Hz), 1.36 (d, 3H, J = 6 Hz),
3.29 (dd, 1H, J = 2Hz, 6Hz), 3.4
-3.6 (m, 1H), 3.6-3.9 (m, 2H),
4.2-4.4 (m, 2H), 5.23 (d, 1H, J
= 14 Hz), 5.51 (d, 1H, J = 14 Hz),
6.31 (dt, 1H, J = 16Hz, 7Hz), 6.
58 (d, 1H, J = 16Hz), 7.2-7.3
(M, 1H), 7.6 to 7.8 (m, 3H), 8.19
(D, 2H, J = 9 Hz), 8.47 (d, 1H, J =
5Hz), 8.55 (s, 1H)

(E) Compound (1) obtained in the above (d)
8) To a solution of 600 mg of tetrahydrofuran in 10 ml,
21 ml of a 0.35 mol phosphate buffer (pH 6.0) and 4.80 g of zinc dust (activated) are added, and the mixture is stirred at room temperature for 2.5 hours. The reaction solution was filtered through Celite, and the obtained filtrate was concentrated under reduced pressure to obtain Diaion HP-40.
(1R, 5S, 6S) -2- of the present invention by subjecting it to column chromatography (manufactured by Mitsubishi Kasei Co., Ltd.) (elution solvent: water and 20% acetonitrile water).
([(E) -3- (3-pyridyl) -2-propenyl]]
Thio) -6-[(R) -1-hydroxyethyl] -1-
Methylcarbapene-2-em-3-carboxylic acid (19)
217 mg (yield: 52.
1%) was obtained. ¹ H-NMR (D ₂ O) δ: 1.14 (d, 3H, J =
7 Hz), 1.20 (d, 3H, J = 6 Hz), 3.3
2 (dd, 1H, J = 3Hz, 6Hz) 3.3 to 3.
5 (m, 1H), 3.49 (dd, 1H, J = 14H
z, 6 Hz), 3.70 (dd, 1H, J = 14 Hz,
8Hz), 4.04 (dd, 1H, J = 3Hz, 9H
z), 4.0 to 4.2 (m, 1H), 6.37 (m, 1)
H), 6.58 (d, 1H, J = 16Hz), 7.33
(Dd, 1H, J = 5 Hz, 8 Hz), 7.85 (d,
1H, J = 8Hz), 8.30 (d, 1H, J = 5H
z), 8.43 (s, 1H)

Example 6

[0085]

[Chemical 11]

(A) 3- (pyridin-4-yl) -2-
A suspension of 2.8 g of propenal oxalate (20) in methylene chloride was washed with saturated aqueous sodium hydrogen carbonate and saturated brine, dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was dissolved in 27 ml of dry dichloromethane, and-
12.54 ml of a toluene solution of diisobutylaluminum hydride (1.5 molar concentration) is added dropwise at 78 ° C. over 30 minutes, and the mixture is stirred at the same temperature for 30 minutes. After completion of the reaction, 10 ml of methanol is added, the temperature is slowly raised, the temperature is returned to room temperature, 1N aqueous sodium hydroxide is added, and the mixture is extracted with methylene chloride. The obtained organic layer is dried over magnesium sulfate, and the solvent is distilled off under reduced pressure to obtain a residue, which is then subjected to silica gel column chromatography (eluting solvent: chloroform-
Compound (21) was obtained as white crystals in an amount of 510 mg (yield: 30.1%). ¹ H-NMR (CDCl ₃ ) δ: 2.4 to 2.8 (b
r, 1H), 4.39 (d, 2H, J = 2Hz), 6.
60 (s, 1H), 6.60 (t, 1H, J = 2H
z), 7.25 (d, 2H, J = 6 Hz), 8.52
(D, 2H, J = 6Hz)

(B) Triphenylphosphine 1.979
1.314 g of diethyl azodicarboxylate is added to a solution of g of dry tetrahydrofuran in 6.8 ml under ice cooling, and the mixture is stirred for 30 minutes. Then, a solution of 510 mg of the compound (21) obtained in (a) above in 1.7 ml of dry tetrahydrofuran was added dropwise, and then 0.270 ml of thioacetic acid was added.
And stirred for 30 minutes under ice cooling. After completion of the reaction, the solvent is distilled off under reduced pressure, methylene chloride-n-hexane is added to the residue, and the precipitated crystals are filtered off. The residue obtained by concentrating the solvent of the filtrate under reduced pressure was subjected to silica gel column chromatography (eluting solvent: n-hexane-ethyl acetate) to give the compound (22) as a light brown oil, 507 mg.
(Yield: 69.5%) was obtained. ¹ H-NMR (CDCl ₃ ) δ: 2.37 (s, 3
H), 3.70 (d, 2H, J = 7 Hz), 6.38
(Dt, 1H, J = 16Hz, 7Hz), 6.51
(D, 1H, J = 16Hz), 7.21 (d, 2H, J
= 6 Hz), 8.52 (d, 2H, J = 6 Hz)

(C) Compound (2) obtained in the above (b)
2) To a solution of 319 mg of dry methanol in 5.5 ml, a solution of 318 mg of sodium methoxide in 28% methanol was added under ice cooling, and the mixture was stirred for 10 minutes. After the reaction,
After adding 6.60 ml of 1N hydrochloric acid and concentrating under reduced pressure, azeotropically azeotropically distilling with ethanol and acetonitrile and then vacuum-drying, the residue obtained by drying 22 ml of dry acetonitrile was added with 1.027 g of compound (1) and further iced. While cooling, add 0.719 ml of diisopropylethylamine, and add 1 at the same temperature.
Return to room temperature and stir for 30 minutes. After the reaction,
The solvent is evaporated under reduced pressure and the obtained residue is dissolved in chloroform and washed with saturated aqueous sodium hydrogen carbonate and saturated brine. The solution was dried over magnesium sulfate, the solvent was evaporated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (eluting solvent: chloroform-acetone) to give compound (23) as white crystals (412 mg, yield). Rate: 48.
1%) was obtained. ¹ H-NMR (CDCl ₃ ) δ: 1.31 (d, 3H,
J = 7 Hz), 1.37 (d, 3H, J = 6 Hz),
3.29 (dd, 1H, J = 2Hz, 7Hz) 3.3
~ 3.5 (m, 1H), 3.63 (dd, 1H, J = 5)
Hz, 14 Hz), 3.76 (dd, 1H, J = 7H
z, 14 Hz), 4.23 (dd, 1H, J = 2 Hz,
9 Hz), 4.1 to 4.3 (m, 1H), 5.23
(D, 1H, J = 14 Hz), 5.52 (d, 1H, J
= 14 Hz), 6.3 to 6.6 (m, 2H), 7.21
(D, 2H, J = 6 Hz), 7.66 (d, 2H, H =
9 Hz), 8.21 (d, 2H, J = 9 Hz), 8.5
4 (d, 2H, J = 6Hz)

(D) Compound (2) obtained in the above (c)
3) To a solution of 50 mg of dry ethyl acetate in 4 ml, 77 mg of lithium iodide is added, and the mixture is heated under reflux for 2 hours. After completion of the reaction, the reaction solution is extracted with water, the aqueous layer is washed with ethyl acetate, and this solution is concentrated under reduced pressure. The obtained concentrate is D
Column chromatography (elution solvent: water and 10) by iaion HP-40 (manufactured by Mitsubishi Kasei Co., Ltd.)
% Acetonitrile water) to give (1R, 5
S, 6S) -2-([(E) -3- (4-pyridyl)-
15 mg of 2-propenyl] thio) -6-[(R) -1-hydroxyethyl] -1-methylcarbapene-2-em-3-carboxylic acid (24) as a pale red amorphous substance.
(Yield: 34.7%) was obtained. ¹ H-NMR (D ₂ O) δ: 1.21 (d, 3H, J =
7 Hz), 1.28 (d, 3H, J = 6 Hz), 3.3
~ 3.5 (m, 1H), 3.40 (dd, 1H, J = 2
Hz, 6 Hz), 3.57 (dd, 1H, J = 15H
z, 2 Hz), 3.79 (dd, 1H, J = 15 Hz,
2Hz), 4.11 (dd, 1H, J = 2Hz, 9H
z), 4.1 to 4.3 (m, 1H), 6.6 to 6.7.
(M, 2H), 7.44 (d, 2H, J = 6Hz),
8.43 (d, 2H, J = 6Hz)

Next, the 2-
A formulation example using a [(pyridyl-substituted) thio] -carbapenem derivative is shown below.

Formulation Example 1 (Tablet) Compound (6) 25 g Lactose 130 g Crystalline cellulose 20 g Corn starch 20 g 3% Hydroxypropylcellulose aqueous solution 100 ml Magnesium stearate 2 g Compound (6), lactose, crystalline cellulose and corn The starch was sieved through a 60-mesh sieve and mixed uniformly, then put into a kneader and poured into a 3% aqueous solution of hydroxypropyl cellulose to knead. Then, the mixture was sieved and granulated with a 16-mesh sieve, and dried by blowing at 50 ° C. After drying, the mixture was sieved through a 16-mesh sieve, mixed with magnesium stearate, and made into tablets having a diameter of 8 mm and a weight of 200 mg with a tableting machine.

Formulation Example 2 (Capsule) Compound (12) 25.0 g Lactose 125.0 g Cornstarch 48.5 g Magnesium stearate 1.5 g The above components are finely pulverized and sufficiently stirred to form a uniform mixture. After that, 0.2 g of each was filled in a gelatin capsule to obtain a capsule for oral administration.

Formulation Example 3 (Tablets) Compound (19) 25 g Lactose 130 g Crystalline cellulose 20 g Corn starch 20 g 3% Hydrocosylpropyl cellulose aqueous solution 100 ml Magnesium stearate 2 g Lactose, crystalline cellulose and compound (19). The corn starch was sieved through a 60-mesh sieve, mixed uniformly, and then put into a kneader to add a 3% hydroxypropyl cellulose aqueous solution and knead. Then, the mixture was sieved and granulated with a 16-mesh sieve, and dried by blowing at 50 ° C. After drying, the mixture was sieved through a 16-mesh sieve, mixed with magnesium stearate, and made into tablets having a diameter of 8 mm and a weight of 200 mg with a tableting machine.

Formulation Example 4 (Dry syrup) Compound (24) 200 mg Hydroxypropylcellulose 2 mg Sucrose 793 mg Perfume 5 mg The above ingredients were mixed to give a dry syrup.

Formulation Example 5 (Powder) Compound (24) 200 mg Lactose 800 mg The above components were mixed to give a powder.

Claims (3)

[Claims] 1. Formula (I): In the formula, A is a covalent bond or represents a bonding group selected from a lower alkylene group, a lower alkenylene group and a lower alkynylene group, and is represented by (1R, 5S, 6S)
-2-[(pyridyl-substituted) thio] -6-[(R) -1-
Hydroxyethyl] -1-methylcarbapene-2-em-3-carboxylic acid derivative and a pharmaceutically acceptable salt thereof. 2. An antibacterial agent containing the carbapenem compound represented by the formula (I) according to claim 1 as an active ingredient. 3. An antibacterial agent for oral administration containing the carbapenem compound represented by the formula (I) according to claim 1 as an active ingredient.