JPH05255346A - Carbapenem compound - Google Patents

Abstract

PURPOSE:To provide the new compound having a strong antibacterial activity, an excellent beta-lactamase-inhibiting action and an excellent renal dehydrogenase- resistant property and useful as an antibacterial agent. CONSTITUTION:(1R,5S,6S)-2-[(6,7-Dihydro-5H-pyrazolo[1,2-a]pyrazolium-6- yl)-6-[(R)-hydroxyethyl]-1-methylcarbapen-2-em-3-carboxylate of formula I. The compound is obtained by reacting a compound of formula II (R<1> is carboxyl- protecting group; R<a> is acyl) with 6,7-dihydro-6-mercapto-5H-pyrazolo[1,2- a]pyrazolium salt and subsequently releasing a carboxyl-protecting group R<1> from the produced compound of formula IV.

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention relates to carbapenem antibiotics, and more specifically, β at the 1-position of the carbapenem skeleton.
Having a methyl group in the -configuration and in the 2-position (6,7-dihydro-5H-pyrazolo [1,2-a] pyrazolium-6
And a carbapenem compound having an -yl) thio group, an antibacterial agent containing the compound as an active ingredient, and a method for producing the compound.

[0002]

2. Description of the Related Art Conventionally, the following formula (A) has been used for the purpose of various antibacterial activities.

[0003]

[Chemical 6]

A large number of carbapenem antibiotics having a basic skeleton of carba-2-penem-3-carboxylic acid represented by

For example, early carbapenem antibiotics were
Streptomyces cattley
The following formula (B) obtained from the fermentation of a)

[0006]

[Chemical 7]

It is a naturally-occurring carbapenem compound such as thienamycin. This thienamycin has an excellent antibacterial spectrum against a wide range of Gram-positive and Gram-negative bacteria, and although its development was expected as a highly useful compound, its chemical stability was poor,
It has not been put to practical use.

Therefore, many researchers have made efforts to develop a carbapenem compound having the antibacterial activity of thienamycin represented by the above formula and ensuring its chemical stability. The following formula (C) in which the amino group of the chain is formimidylated

[0009]

[Chemical 8]

Imipenem (IN)
N) has emerged as a practical antibacterial agent.

However, the imipenem represented by the above formula (C) exhibits an antibacterial activity superior to that of thienamycin and is chemically stable to some extent, but is inactive by renal dehydropeptidase (DHP) in vivo. It has a drawback that the change 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 cilastatin (ci
ININ) is used in combination with imipenem / cilastatin.

However, as a practical antibacterial agent used clinically, it is preferable that the original antibacterial activity of the antibacterial agent is exhibited as it is, and the DHP inhibitor used in combination is not preferable in other tissues in the living body. Needless to say, it is best to avoid compounding and prescribing as much as possible, because side effects may occur. Therefore, there is a strong demand for the development of carbapenem compounds having antibacterial activity and resistance to DHP.

Recently, as a means for achieving the above object, a methyl group was introduced at the 1-position and a monocyclic or bicyclic quaternary heteroarylalkylthio substituent was introduced at the 2-position of the carbapenem skeleton. A 1-methylcarbapenem compound has been proposed, for example, JP-A-61-636.
No. 79 (corresponding US Patent Application No. 626822, 1
(Filed on July 2, 984), the following general formula (D)

[0014]

[Chemical 9]

2-quaternary heteroarylalkylthio-1-methylcarbapenems represented by the following formula have been disclosed. These compounds have excellent antibacterial activity and, at the same time, are extremely resistant to degradation and inactivation by DHP. It is reported to be improved and highly useful.

However, in the above publication, these 1β
Although there is a broad description of the -methyl-carbapenem compound as a superordinate concept, there are few specific examples, and it is generally stated that the antibacterial activity is excellent, but there is no description of specific antibacterial activity data. .. In particular, regarding the carbapenem compound included in the above formula, the above publication exemplifies a large number of compounds of about 300 kinds, but only 16 kinds of the compounds whose production was confirmed in the Examples are present. No specific description is given regarding the compound provided by the above. Therefore, the above publication does not give any suggestion as to the compounds of the present invention having the pharmacologically superior properties disclosed and claimed herein.

[0017]

[Means for Solving the Problems]
Position is methyl-substituted in the β-configuration and is one of the quaternary ammonium functional groups as the 2-position side chain (6,7-dihydro-5H-pyrazolo [1,2-a] pyrazolium-
A carbapenem compound in which a 6-yl) thio group is introduced and whose side chain forms an intramolecular quaternary ammonium salt with a carboxylate at the 3-position shows a strong antibacterial activity and, in addition, a β-lactamase inhibitory action and They have found that they have excellent resistance to renal dehydropeptidase and have completed the present invention.

The present invention thus has the formula (I)

[0019]

[Chemical 10]

(1R, 5S, 6S) -2-
[(6,7-Dihydro-5H-pyrazolo [1,2-a] pyrazolium-6-yl) thio] -6-[(R) -hydroxyethyl] -1-methylcarbapene-2-em-3-
The present invention provides a carboxylate and a pharmaceutically acceptable salt thereof.

The invention also relates to formula (II)

[0022]

[Chemical 11]

In the formula, R ¹ represents a carboxyl-protecting group and R ^a represents an acyl group.

[0024]

[Chemical 12]

[0025] In the formula, X ^- represents a salt-forming anion,
6,7-dihydro-6-mercapto-5H-
Reacting with a pyrazolo [1,2-a] pyrazolium salt and then obtaining formula (IV)

[0026]

[Chemical 13]

In the formula, R ¹ and X ⁻ are as defined above, and the carbapenem compound represented by the above formula (I) or a salt thereof is characterized in that the protecting group R ¹ is eliminated from the compound represented by The present invention also provides a method of manufacturing the same.

The carbapenem compound of the present invention can be included in the comprehensive disclosure based on the superordinate concept of the prior art document, for example, the above-mentioned Japanese Patent Laid-Open No. 61-63679. It is a novel compound for which no physical data has been described, and is characterized by its uniquely superior antibacterial activity.

As the "carboxyl protecting group" represented by R ¹ in the formula (II), for example, an ester residue can be exemplified, and such an ester residue can be methyl, ethyl or n-propyl. , Lower alkyl ester residues such as isopropyl, n-, iso-, tert-butyl, n-hexyl ester; benzyl, p
-Araalkyl ester residues such as nitrobenzyl, o-nitrobenzyl, m-nitrobenzyl, 2,4-dinitrobenzyl, p-chlorobenzyl, p-bromobenzyl, p-methoxybenzyl; acetoxymethyl, acetoxyethyl, propionyl Oxymethyl, n-, iso
And lower aliphatic acyloxymethyl residues such as-, butyryloxymethyl and pivaloyloxymethyl.

The term "lower" as used herein means that the group or compound to which the term is attached has 1 to 7, preferably 1 to 4 carbon atoms.

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

Furthermore, X in formula (III) ^- the "salt-forming anion" represented by an anion is encompassed corresponding to the cation of the quaternary ammonium, specifically, hydroxy anion; methoxy anion, Examples thereof include alkoxy anion such as ethoxy anion; halogen anion such as chloro anion, bromo anion, iodo anion, and fluorine anion; or “acid anion” described below. The "acid anion" means, in a broad sense, an atomic group remaining after removing a hydrogen atom from a proton donating molecule, and typical examples thereof include organic acid residues such as acetic acid and propionic acid.
Lower fatty acids such as butyric acid, trifluoroacetic acid and trichloroacetic acid; substituted or unsubstituted benzoic acid such as benzoic acid and p-nitrobenzoic acid; (halo) lower alkyl sulfonic acids such as methanesulfonic acid and trifluoromethanesulfonic acid; benzene Sulfonic acid, p-nitrobenzenesulfonic acid, p-
Bromobenzenesulfonic acid, toluenesulfonic acid, 2,
Substituted or unsubstituted aryl sulfonic acid such as 4,6-triisopropylbenzene sulfonic acid; remaining atomic group obtained by removing hydrogen atom from organic phosphoric acid such as diphenyl phosphoric acid: inorganic acid residue such as nitrous acid, nitric acid, The remaining atomic groups obtained by removing hydrogen atoms from sulfuric acid or hydrohalogenated acids such as perchloric acid and borofluoric acid can be exemplified.

The reaction scheme A is shown schematically when the method for producing the compound of formula (I) of the present invention is schematically shown.

[0034]

[Chemical 14]

In the formula, R ¹ , R ^a and X ⁻ are as defined above.

The reaction of the compound of formula (II) with the 6,7-dihydro-6-mercapto-5H-pyrazolo [1,2-a] pyrazolium salt of formula (III) is carried out, for example, by
The compound of the formula (II) is used in a suitable solvent such as tetrahydrofuran, dichloromethane, dioxane, dimethylformamide, dimethylsulfoxide, acetonitrile, hexamethylphosphoramide, etc. in a molar amount of about 0.5 to about 5 times, preferably about 0.1. A temperature in the range of about -40 to about 25 ° C in the presence of 8 to about 3 times the molar amount of the mercapto reagent of the formula (III) and preferably a base such as sodium hydrogen carbonate, potassium carbonate, triethylamine, diisopropylethylamine. Can be carried out 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.

The compound of formula (IV) is obtained by this reaction, and the reaction solution can be used as it is in the next step. In some cases, the reaction solution is subjected to a conventional purification means to obtain a compound of formula (IV) The compound of IV) can also be isolated and purified.

If necessary, the compound of the formula (IV) obtained by the above-mentioned method may be a fatty acid, a substituted or unsubstituted benzoic acid, a substituted or unsubstituted aryl, as exemplified in the above definition of "acid anion". By treatment with an organic acid typified by sulfonic acid, organic phosphoric acid or the like, or an inorganic acid typified by nitric acid, sulfuric acid, hydrohalic acid, etc., a salt with any salt-forming anion is obtained. You can also get it.

The compound of formula (IV) obtained by the above reaction can then be eliminated by removing the carboxyl protecting group R ¹ to give the compound of formula (I).

Removal of the carboxyl protecting group R ¹ can be carried out by a known protecting group reaction such as solvolysis or hydrogenolysis.

Specifically, the compound of the formula (IV) is added to, for example, an acetate buffer having a pH of 5.5, a morpholinopropanesulfonic acid-sodium hydroxide buffer having a pH of 5.5, and a pH of 5.
5 in a mixed solvent of phosphate buffer, dipotassium phosphate, sodium bicarbonate, etc., such as tetrahydrofuran-water, tetrahydrofuran-ethanol-water, dioxane-water, dioxane-ethanol-water, n-butanol-water. Using hydrogen at about 1 to 4 atm, in the presence of a hydrogenation catalyst such as platinum oxide, palladium-activated carbon, or palladium hydroxide-activated carbon, at a temperature in the range of about 0 to about 50 ° C., about 0.2.
It can be carried out by treating for 5 to about 5 hours.

The elimination of the protecting group R ¹ 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 buffer having a pH of 5 to 7, such as phosphate buffer, acetate buffer, citrate buffer, morpholinopropane sulfonate buffer, N-methylmorphophosphate buffer. It can be performed by processing. Examples of zinc that can be used include zinc powder, white zinc, and granular zinc. The amount of zinc used is not particularly limited, but in general, 1 is used per 1 part by weight of the compound of the formula (IV).
It can be in the range of 10 to 10 parts by weight, preferably 1 to 5 parts by weight. In this elimination reaction, an organic solvent may be used in combination if necessary, and as such a solvent, alcohol solvents such as ethanol, propanol and n-butanol; ether solvents such as diethyl ethanol and tetrahydrofuran; acetonitrile. , Dimethylformamide, dimethylacetamide and the like. The reaction is usually about -20 to about 50 ° C, preferably room temperature to about 30 ° C.
It can be completed by treating at the temperature of 0.1 to 5 hours.

Thus, (1R, 5S, 6S) -2-[(6,7-dihydro-5H-pyrazolo [1,2-a] pyrazolium-6- of the formula (I) which is the object compound of the present invention.
Il) thio] -6-[(R) -hydroxyethyl] -1
-Methylcarbapene-2-em-3-carboxylate can be obtained in high yield, and the compound can be highly purified by using an ion exchange resin or a polymer adsorption resin, if necessary. It can be isolated.

If necessary, the compound of formula (I) obtained by the above method may be treated with the above-mentioned organic acid or inorganic acid to be isolated as an arbitrary acid addition salt of the compound of formula (I). You can also do it.

The compound of formula (II) used as a starting material in the above-mentioned production method is known per se, and is produced, for example, according to the method described in JP-A-2-62877. be able to.

The 6,7-dihydro-6-mercapto-5H-pyrazolo [1,2-a] pyrazolium salt of the above formula (III) can be produced, for example, by the method shown in the following reaction formula B. You can

[0048]

[Chemical 15]

In the formula, R ² represents a hydroxyl protecting group, and R ^a and X ⁻ are as defined above.

The "hydroxyl protecting group" represented by R ² is, for example, acetyl, benzoyl,
Aliphatic or aromatic acyl groups such as methanesulfonyl and p-toluenesulfonyl; aralkyl groups such as benzyl and triphenylmethyl; benzyloxycarbonyl, p-
A substituted or unsubstituted benzyloxycarbonyl group such as nitrobenzyloxycarbonyl and p-methoxybenzyloxycarbonyl; tert-butyldimethylsilyl,
Substituted silyl groups such as tert-butyldiphenylsilyl, phenylisopropyldimethylsilyl and the like; tetrahydropyranyl group and the like can be exemplified, but preferably triphenylmethyl group, tert-butyldimethylsilyl group or tetrahydropyranyl group. Can be used.

In the above reaction formula B, the acyl group R ^a is first eliminated from the compound of the formula (V) derived from pyrazole to form a mercapto compound, and then this compound is oxidized to form the compound of the formula (VI). A compound which is a disulphide derivative of).

For elimination of the acyl group R ^a , the compound of the formula (V) is treated with a base, for example, a metal alkoxide such as sodium methoxide or sodium ethoxide, sodium hydroxide, potassium hydroxide or water in a suitable alcohol solvent. It can be carried out by treating with a metal hydroxide such as calcium oxide; a metal carbonate such as sodium carbonate and potassium carbonate, and the like, whereby a mercapto compound is obtained. Then, the obtained mercapto compound uses a suitable oxidizing agent, for example, oxygen, hydrogen peroxide, peracid, cupric chloride, bromine, iodine, halosuccinimide, air oxidation (in the presence of a base or iron), etc. The compound of formula (VI) can be converted by a known thiol oxidation reaction.

The compound of formula (VI) thus obtained is
The compound of formula (VII) can be prepared by removing the hydroxyl protecting group R ² .

The elimination reaction of the above-mentioned hydroxyl protecting group R ² can be carried out by a method usually carried out as the elimination reaction of the hydroxyl protecting group, and examples thereof include water, methanol, ethanol, tetrahydrofuran, benzene, chloroform and dichloromethane. Inorganic acid such as hydrochloric acid and sulfuric acid, or organic acid such as formic acid, acetic acid, oxalic acid, benzoic acid, trichloroacetic acid, trifluoroacetic acid, and toluenesulfonic acid in an inert solvent of Or by carrying out hydrogenolysis in the presence of a catalyst in the above inert solvent.

The compound of formula (VII) obtained by the above reaction can then be ring-closed to give a compound of formula (VIII).

The ring-closing reaction of the compound of the formula (VII) can be carried out, for example, by converting the hydroxyl group of the compound of the formula (VII) into methanesulfonyl chloride, toluenesulfonyl chloride, naphthalenesulfonyl chloride or a sulfonic acid chloride which is a derivative of these compounds. By processing with
It can be performed by once forming a reactive derivative and then heating and stirring in an inert organic solvent.

Furthermore, the desired compound of formula (III) can be produced by reducing the obtained compound of formula (VIII).

The reduction reaction of the compound of the formula (VIII) can be carried out under a reducing condition generally used for cleaving the sulfur-sulfur bond of disulphide in a usual organic chemical reaction, and specifically, for example, Method using trialkylphosphine such as trimethylphosphine, triethylphosphine and tributylphosphine, triarylphosphine such as triphenylphosphine or reduction with metal, or sodium borohydride, lithium aluminum hydride, triethyl hydride Reduction with a metal hydride compound such as lithium borohydride is preferable, and among these, a method using tributylphosphine or triphenylphosphine is preferable. The reaction is usually performed in a solvent,
The solvent that can be used can be arbitrarily selected as long as it has no direct effect on the reaction. Depending on the reducing reagent used, water, alcohols such as methanol, ethanol and isopropanol; ether solvents such as ether, tetrahydrofuran and dioxane. Can be used in appropriate combination as necessary.

After completion of the reaction, the compound of formula (III) can be isolated by a method known per se, for example, by appropriately combining means such as solvent removal, extraction, washing, lyophilization and crystallization. it can.

In the method described above, the formula (VII
The compounds I) and (III) can usually be isolated in the form of salts of quaternary ammonium. The anion moiety forming the quaternary ammonium salt corresponds to an acid residue,
As the acid constituting the acid residue, as described above, a fatty acid, a substituted or unsubstituted benzoic acid, a substituted or unsubstituted arylsulfonic acid, an organic acid represented by organic phosphoric acid, nitric acid,
Examples thereof include inorganic acids represented by sulfuric acid and hydrohalic acid, and among them, organic acids such as methanesulfonic acid, p-toluenesulfonic acid, naphthalenesulfonic acid, trifluoroacetic acid, trichloroacetic acid and trifluoromethanesulfonic acid, or Inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, borohydrofluoric acid, perchloric acid and nitrous acid are preferred.

Accordingly, the formulas (VIII) and (II
The compound of I) is formed as a salt with any anion by treating in the reaction solution after being formed in each step, or after being isolated and then dissolved in a suitable solvent, and treated with the above-mentioned acid. It can be separated and purified. Then, the formula (VII
The compounds I) and (III) can be isolated as stable solids, for example in the case of p-toluenesulfonate, naphthalenesulfonate or trifluoroacetate.

As described above, the carbapenem compound of the formula (I) provided by the present invention is a novel compound which has not been specifically disclosed in the conventional literature, and has an excellent antibacterial activity. ing.

The excellent antibacterial activity of the compounds of the present invention can be demonstrated by the results of the following antibacterial test.

[Antibacterial test] 1. Test Method Japanese Society of Chemotherapy Standard Method [Chemotherapy, vol 29, 7
6-79 (1981)] according to the agar plate dilution method. That is, about 10 ⁶ cells of the overnight culture of the test bacteria on Mueller-Hinton (MH) agar liquid medium at 37 ° C were used.
Buffered saline gelatin (BS
G) Diluted with the solution, inoculated to the test compound-containing MH agar medium with a microplanter in an amount of about 5 μl and cultured at 37 ° C. for 18 hours.
The minimum inhibitory concentration (MIC) was used.

Standard strains were used as the strains used.

The compound (14) described in Example 2 below was used as the test compound.

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

[0068]

[Table 1] Table 1 : MIC (μg / ml) ───────────────────────── Tested bacterial compound (14) ──── ───────────────────── S.aureus Terajima 0.025 S.aureus MS353 0.025 S.pyogenes Cook 0.025 B.subtilis ATCC6633 0.1 E.coli NIHJ JC-2 0.05 E .coli K-12 C600 0.78 E.cloacae 963 0.1 E.aerogenes ATCC1304 0.78 S.typhimurium 11D971 0.2 S.paratyphi 1015 ≤0.006 S.schottmuelleri8006 0.39 S.enteritidis G14 ≤0.006 S.marcescens IAM1184 0.1 P.morganii IFO3848 0.2 P. mirabilis IFO3849 3.13 P.vulgaris OX-19 1.56 P.rettgeri IFO3850 0.05 P.aeruginosa IFO3445 0.78 P.aeruginosa NCTC10490 0.78 P.aeruginosa PAO1 6.25 ───────────────────── From the above results, it is clear that the carbapenem compound of the present invention has excellent antibacterial activity.

Furthermore, the compounds of the present invention are methyl-substituted at the 1-position in the β-configuration, and the unique quaternary ammonium functional group at the 2-position side chain and the carboxylate at the 3-position are intramolecular. Due to structural features such as the formation of a quaternary ammonium salt, it is predicted that it will be extremely stable against attack by renal dehydropeptidase (DHP) and that it will also have high chemical and physical stability. ..

Therefore, the compound represented by the formula (I) can be used alone without the need for combined use with a renal DHP inhibitor, and moreover, in treating or preventing bacterial infections caused by various pathogenic bacteria. It is expected to be an extremely useful antibacterial agent.

When the compound of formula (I) or a pharmaceutically acceptable salt thereof is used as an antibacterial agent, it can be used in the form of a pharmaceutical composition containing an antibacterial effective amount thereof, including humans. Can be administered to any mammal. 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 and the like, but in general, for adults, it is about 20 per day.
Doses in the range of 0 to about 3,000 mg are standard,
Usually, it can be administered orally, parenterally or topically once or several times a 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, hydroxypropyl cellulose, alginic acid, gelatin, polyvinylpyrrolidone; Lubricants such as stearic acid, magnesium stearate, calcium stearate, talc, hydrogenated vegetable oils; processed starch , Calcium carboxymethyl cellulose, low-substituted hydroxypropyl cellulose and other disintegrants; dosage forms suitable for oral, parenteral or topical administration together with dissolution aids such as nonionic 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 pharmaceutical science.

The carbapenem compounds of the present invention are particularly preferably administered parenterally in the form of injections.

[0075]

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

Each symbol in the following description has the following meaning.

Trt: triphenylmethyl Ms: methanesulfonyl Ac: acetyl Ts: p-toluenesulfonyl PNB: p-nitrobenzyl Production Example 1

[0078]

[Chemical 16]

A solution of 6.80 g of pyrazole (1) in 125 ml of absolute ethanol was added with 6.62 ml of glycidol (2).
Is added and the mixture is heated under reflux for 4 hours under a nitrogen gas stream. After the reaction was completed, the solvent was distilled off under reduced pressure and the resulting residue was subjected to silica gel column chromatography (dichloromethane: acetone = 1: 2).
Then, the compound (3) as white crystals was 12.00 g.
(Yield 84.5%) was obtained.

¹ H-NMR (CDCl ₃ ) δ: 3.50 and 3.59 ( AB X, 2H, J = 4.4, 5.2, 11.5)
Hz), 3.85 (bs, 2H), 4.02 to 4.13
(M, 1H), 4.16 and 4.26 ( AB X, 2H, J
= 5.1, 5.9, 13.9 Hz), 6.25 (dd, 1)
H, J = 2.0,2.2Hz, 7.44 (d, 1H, J
= 2.2 Hz), 7.48 (d, 1H, J = 2.0 Hz) Production Example 2

[0081]

[Chemical 17]

Compound (3) obtained in Preparation Example 1 above 4.
To a solution of 61 g of anhydrous acetonitrile in 90 ml of nitrogen gas, 3.94 ml of pyridine and 15.95 g of triphenylmethyl chloride were added, and the mixture was stirred at room temperature for 13.5 hours. After completion of the reaction, the solvent was distilled off under reduced pressure and 150 ml of ethyl acetate was added to the residue to dissolve the residue.
Wash sequentially with 00 ml and saturated saline 100 ml. The obtained organic layer is dried over magnesium sulfate, and then the solvent is distilled off under reduced pressure. The obtained residue was subjected to silica gel column chromatography (dichloromethane: ethyl acetate = 5: 1) to obtain 16.20 g (yield 81.2%) of compound (4) as white crystals.

¹ H-NMR (CDCl ₃ ) δ: 2.94 and 3.22 ( AB X, 2H, J = 5.0, 6.4, 9.5H
z), 4.10 to 4.30 (m, 4H), 6.18 (d
d, 1H, J = 2.0, 2.2 Hz), 7.18 to 7.46
(M, 17H) Production Example 3

[0084]

[Chemical 18]

Compound (4) obtained in Preparation Example 2 above 2.
To a solution of 58 g of anhydrous dichloromethane in a nitrogen gas stream under ice cooling, 1.86 ml of triethylamine and 0.78 ml of methanesulfonyl chloride were added, and the mixture was stirred at the same temperature for 30 minutes. After the reaction was completed, the solvent was distilled off under reduced pressure, and 100 ml of ethyl acetate was added to the resulting residue to dissolve it.
The solution is washed successively with 70 ml of water and 70 ml of saturated saline. The obtained organic layer is dried over magnesium sulfate, and then the solvent is distilled off under reduced pressure. The obtained residue is subjected to silica gel column chromatography (dichloromethane: ethyl acetate = 10:
In addition to 1), the compound (5) was obtained as white crystals in 3.01.
g (yield 97.0%) was obtained.

¹ H-NMR (CDCl ₃ ) δ: 2.52
(S, 3H), 3.29 and 3.55 ( AB X, 2H, J
= 4.3, 4.4, 10.9 Hz), 4.41 (d, 2H,
J = 6.1 Hz), 5.00-5.10 (m, 1H), 6.
23 (dd, 1H, J = 2.0, 2.2Hz), 7.20
~ 7.51 (m, 17H) Production Example 4

[0087]

[Chemical 19]

Compound (5) obtained in Preparation Example 3 above 2.
To a solution of 77 g of anhydrous dimethylformamide in 20 ml, 1.37 g of potassium thioacetate was added under a nitrogen gas stream,
Stir at 80 ° C. for 20 hours. After completion of the reaction, 100 ml of ethyl acetate is added to the reaction solution, and washed successively with 70 ml of water and 70 ml of saturated saline. After drying the organic layer with magnesium sulfate, the solvent is distilled off under reduced pressure. The obtained residue is subjected to silica gel column chromatography (n-hexane: ethyl acetate =
2: 1) to obtain 1.89 g (yield: 71.3%) of compound (6) as a yellow oily substance.

¹ H-NMR (CDCl ₃ ) δ: 2.31
(S, 3H), 3.19 (d, 2H, J = 4.6Hz),
4.07-4.18 (m, 1H), 4.39 and 4.49
( AB X, 2H, J = 4.6,5.9,11.1Hz),
6.05 (dd, 1H, J = 2.0, 2.2Hz), 7.2
0 to 7.45 (m, 17H) Production Example 5

[0090]

[Chemical 20]

Compound (6) 22 obtained in Preparation Example 4 above
To a solution of 1.0 mg of anhydrous methanol in a nitrogen gas stream under ice cooling, 96.5 mg of 28% methanol solution of sodium methoxide was added and stirred at the same temperature for 20 minutes, and then added with 63.5 mg of iodine. 40 at the same temperature
Stir for minutes. After completion of the reaction, the solvent was distilled off under reduced pressure and 50 ml of ethyl acetate was added to the residue to dissolve it. The solution was washed successively with 30 ml of 10% sodium thiosulfate aqueous solution and 30 ml of saturated saline. The organic layer was dried over magnesium sulfate, and the solvent was evaporated under reduced pressure to give compound (6) as a yellow oily substance, 217.9 mg (quantitative).

¹ H-NMR (CDCl ₃ ) δ: 3.02 ~
3.28 (m, 6H), 4.20-4.46 (m, 4)
H), 6.08 (dd, 2H, J = 2.0, 2.2H
z), 7.08 to 7.42 (m, 34H) Production Example 6

[0093]

[Chemical 21]

Compound (7) 96 obtained in Preparation Example 5 above
In a solution of 2.1 mg of trifluoroacetic acid in 3 ml, under nitrogen gas stream, 20 ml of methanol, 5 ml of 10% hydrochloric acid and 9 ml of
Add 1 ml of 8% formic acid and stir at room temperature for 2 hours. After completion of the reaction, the solvent is distilled off under reduced pressure, the resulting residue is dissolved in a mixed solvent of tetrahydrofuran / methanol (1: 1), and sodium hydrogen carbonate is added to make the solution alkaline. The solvent of the resulting solution was distilled off under reduced pressure and the residue obtained was subjected to silica gel column chromatography (dichloromethane: acetone = 1: 1) to give 348.6 mg of compound (8) as a yellow oil (yield 91. 7%) was obtained.

¹ H-NMR (CDCl ₃ ) δ: 3.27-
3.39 (m, 2H), 3.57 to 3.77 (m, 6
H), 4.41 (d, 4H, J = 7.1 Hz), 6.26
(Dd, 2H, J = 2.0, 2.1Hz), 7.43
(D, 2H, J = 2.0 Hz), 7.52 (d, 2H, J
= 2.1 Hz) Production Example 7

[0096]

[Chemical formula 22]

Compound (8) 34 obtained in Preparation Example 6 above
To a solution of 8.6 mg of pyridine in 18 ml, 1.27 g of paratoluenesulfonyl chloride was added under a nitrogen gas stream,
Stir at room temperature for 20 hours. After completion of the reaction, the solvent is distilled off under reduced pressure and 50 ml of ethyl acetate is added to the residue to dissolve it. The solution is washed successively with 30 ml of water and 30 ml of saturated saline. The organic layer was dried over magnesium sulfate, the solvent was distilled off under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (dichloromethane: ethyl acetate = 3:
Compound (9) as a yellow oil 377.
2 mg (yield 55.0%) was obtained.

¹ H-NMR (CDCl ₃ ) δ: 2.46
(S, 6H), 3.37 to 3.67 (m.2H), 4.0
0-4.12 (m, 4H), 4.16-4.49 (m, 4
H), 6.15 to 6.27 (m, 2H), 7.32 to 7.8
0 (m, 12H) Production Example 8

[0099]

[Chemical formula 23]

Compound (9) 37 obtained in Preparation Example 7 above
A solution of 7.2 mg of anhydrous ethanol in 45 ml is heated under reflux for 2.5 hours under a nitrogen gas stream. After completion of the reaction, the solvent was distilled off under reduced pressure to obtain 371.7 mg of a reaction mixture containing the compound (10) as a yellow oily substance. This reaction mixture was directly used in the next reaction without purification.

Production Example 9

[0102]

[Chemical formula 24]

371.7 mg of tetrahydrofuran 4 containing a reaction mixture containing the compound (10) obtained in Preparation Example 8 above.
4 ml of water and 0.15 ml of tributylphosphine are added to the ml solution under a nitrogen gas stream, and the mixture is stirred at room temperature for 50 minutes. After completion of the reaction, the solvent is distilled off under reduced pressure and the resulting residue is washed 3 times with 6 ml of ethyl acetate. The obtained residue is dried under reduced pressure, 10 ml of diethyl ether is added, and the mixture is stirred. The precipitated solid was collected by filtration, washed with diethyl ether, and dried under reduced pressure to give 6,7-
Dihydro-6-mercapto-5H-pyrazolo [1,2-
a] Pyrazolium p-toluenesulfonate (11)
Was obtained as a white solid in an amount of 234.8 mg (yield of 62.7% from the compound (9) of Production Example 8).

¹ H-NMR (CD ₃ OD) δ: 2.37
(S, 3H), 4.39 to 4.54 (m, 3H), 4.8
5 to 5.03 (m, 2H), 6.91 (dd, 1H, J =
2.7, 2.9 Hz), 7.22 (d, 2H, J = 8.1H
z), 7.68 (d, 2H, J = 8.1 Hz), 8.31
(D, 2H, J = 2.9 Hz) Example 1

[0105]

[Chemical 25]

The p-toluenesulfonate (11) 48 of 6,7-disidro-6-mercapto-5H-pyrazolo [1,2-a] pyrazolium obtained in the above Preparation Example 9 was obtained.
To a solution of 6.4 mg of anhydrous acetonitrile in 15 ml of diisopropylethylamine was added under ice-cooling in a nitrogen gas stream.
A solution of 145 ml and 234.8 mg of compound (12) in 5 ml of anhydrous acetonitrile is added, and the mixture is stirred at the same temperature for 40 minutes. After the reaction is completed, the solvent is distilled off under reduced pressure, and the yellow oily substance obtained is washed 4 times with 7 ml of ethyl acetate. The resulting oily residue is dried under reduced pressure to give compound (1
632.7 mg of the crude product of 3) was obtained as a yellow oil.

¹ H-NMR (CDCl ₃ , CD ₃ OD)
δ: 1.35 (d, 3H, J = 1.8Hz), 1.38
(D, 3H, J = 1.6Hz), 2.35 (s, 3H),
2.98-3.09 (m, 1H), 3.26-3.31
(M, 1H), 4.02 to 4.46 (m, 2H), 4.4
7-5.34 (m, 5H), 5.18 and 5.44 ( A
B , 2H, J = 14.4 Hz), 7.00 to 8.36
(M, 1H) Example 2

[0108]

[Chemical formula 26]

615 mg of the crude product of the compound (13) obtained in Example 1 above was added to a 0.1 M acetate buffer (pH 5.5).
20 ml of n-butanol was added to this solution.
And 10% palladium-carbon (150 mg) were added, and the mixture was stirred at room temperature under hydrogen gas (4 atm) for 1.5 hours. 30 ml of n-butanol was added to the filtrate obtained by filtering the reaction solution through Celite.
Is added to separate the aqueous layer. The pH of the resulting aqueous layer is 5.
After adjusting to 5, the solution is concentrated under reduced pressure to obtain an aqueous solution of about 10 ml. The obtained aqueous solution was subjected to column chromatography (5% isopropanol water) with 100 ml of SepaBeads SP-207 (manufactured by Mitsubishi Kasei Co., Ltd.) to obtain (1R, 5S, 6S) -2-[(6, 7-dihydro-5H-pyrazolo [1,2-a] pyrazolium-6-yl) thio] -6-[(R) -hydroxyethyl] -1-
Methylcarbapene-2-em-3-carboxylate (14) was obtained as a pale yellow solid, 302.8 mg (yield 92.
7%) was obtained.

¹ H-NMR (CD ₃ OD) δ: 1.17
(D, 3H, J = 7.3 Hz) 1.23 (d, 3H, J
= 6.3 Hz), 3.25 to 3.35 (m, 1H), 3.4
0 (dd, 1H, J = 3.0, 6.0Hz), 4.15 ~
4.25 (m, 2H), 4.40 to 4.60 (m, 3
H), 4.80 to 5.00 (m, 2H), 6.80 (d
d, 1H, J = 3.0, 3.0 Hz), 8.10 (d, 1
H, J = 3.0 Hz, 8.12 (d, 1H, J = 3.0)
Hz) Next, a formulation example using the carbapenem compound of the present invention is as follows.

Formulation Example 1 (Injection) (1) Suspended injection Compound (14) 0.25 g Methylcellulose 0.5 g Polyvinylpyrrolidone 0.05 g Methyl paraoxybenzoate 0.1 g Polysorbate 80 0.1 g Lidocaine hydrochloride 0.5 g Distilled water Appropriate amount / total volume 100 ml The above components are mixed to give a suspension injection with a total volume of 100 ml.

(2) In the case of freeze-drying A suitable amount of distilled water was added to 20 g of compound (14) to obtain a volume of 100.
Set to ml.

2.5 ml or 5 ml of the above aqueous solution (500 mg or 1000 mg of the respective compound) in one vial.
(containing mg) and lyophilize. At the time of use, about 3 to 4 ml of distilled water is added to make an injection.

(3) Filling with powder Fill one vial with 250 mg of the compound (14) 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 (14) 250 mg Lactose 250 mg Hydroxypropyl cellulose 1 mg Magnesium stearate 10 mg 1 tablet: 511 mg The above components were mixed and tableted by a conventional method, and then as necessary. Then, sugar coating or film coating is carried out by a conventional method to give sugar-coated tablets or film coated tablets.

Formulation Example 3 (Lozenge) Compound (14) 200 mg Sucrose 770 mg Hydroxypropylcellulose 5 mg Magnesium stearate 20 mg Flavor 5 mg 1 tablet: 1000 mg The above ingredients are mixed and tableted by a conventional method to give a troche.

Formulation Example 4 (Capsule) Compound (14) 500 mg Magnesium stearate 10 mg 1 capsule: 510 mg The above components are mixed and filled into a normal hard gelatin capsule to give a capsule.

Formulation Example 5 (Dry syrup preparation) Compound (14) 200 mg Hydroxypropyl cellulose 2 mg Sucrose 793 mg Perfume 5 mg Total: 1000 mg The above ingredients are mixed to give a dry syrup preparation.

Formulation Example 6 (Powder) Compound (14) 200 mg Lactose 800 mg Total: 1000 mg The above components are mixed to give a powder.

Formulation Example 7 (Suppository) Compound (11) 500 mg Witetpsol H-12 700 mg (manufactured by Dynamite Nobel) 1 suppository: 2200 mg The above ingredients are mixed and made into a suppository by a conventional method.

Claims (3)

[Claims] 1. Formula (I): (1R, 5S, 6S) -2-[(6,7-dihydro-5H-pyrazolo [1,2-a] pyrazolium-6
-Yl) thio] -6-[(R) -hydroxyethyl]-
1-Methylcarbapene-2-em-3-carboxylate and its pharmacologically acceptable salts. 2. An antibacterial agent comprising a carbapenem compound represented by the formula (I) according to claim 1 or a pharmaceutically acceptable salt thereof as an active ingredient. 3. Formula (II): In the formula, R ¹ represents a carboxyl protecting group and R ^a represents an acyl group, and a compound represented by the formula (III) In the formula, X ⁻ represents a salt-forming anion.
7-dihydro-6-mercapto-5H-pyrazolo [1,
2-a] pyrazolium salt and then the resulting formula (IV) Wherein R ¹ and X ⁻ are as defined above, and the protecting group R ¹ is eliminated from the compound represented by the formula (I) (1R, 5S, 6S) -2-[(6,7-dihydro-5H-pyrazolo [1,2-a] pyrazolium-6
-Yl) thio] -6-[(R) -hydroxyethyl]-
A method for producing 1-methylcarbapene-2-em-3-carboxylate or a salt thereof.