JPH07196661A - 2-(1-substituted-3-(heteroaryl-1-yl)-propan-2-yl)thiocarbapenem derivative - Google Patents

Abstract

PURPOSE:To obtain a thiocarbapenem derivative useful as an antimicrobial agent, having excellent resistance to beta-lactase and renal dehydropeptidase and strongly antimicrobial activity, shown by a specific formula, containing a methyl group of beta configuration on a carbapenem skeleton. CONSTITUTION:The compound of formula I [R<1> is OH, mercapto, amino or a halogen; X, Y and Z each is N, CR<2> (R<2> is H, carboxyl, a lower alkoxycarbonyl, carbamoyl or mono-or a lower alkyl-substituted amido)] such as (1R,5S,'6S)-2[(2R or S)-1-hydroxy-3(1,2-pyrazol-1-yl)propan-2-yl]thio-6-[(1R)-1- hydroxyethyl]-1-methylcarbapen-2-em-3-carboxylic acid, etc. The compound, for example, is preferably obtained by reacting a compound of formula II with a thiol compound of formula III in a solvent such as tetrahydrofuran in the presence of a base such as sodium hydrogencarbonate.

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.
Has a methyl group in the configuration and [1-substituted-3-
(Heteroaryl-1-yl) -propan-2-yl]
The present invention relates to a carbapenem compound having a thio group, and an antibacterial agent containing the compound as an active ingredient.

[0002]

Conventionally, the following formula (A) has been used for the purpose of various antibacterial activities:

[0003]

[Chemical 2]

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

For example, early carbapenem antibiotics were
Streptomyces cattleya
) The following formula (B) obtained by the fermentation of

[0006]

[Chemical 3]

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 it was expected to be developed as a highly useful compound as a drug, it has poor chemical stability and is put to practical use. It hasn't arrived yet.

Therefore, many researchers have examined a large number of compounds in order to develop a carbapenem compound having the antibacterial activity of thienamycin represented by the above formula and ensuring its chemical stability, and as a result, thienamycin has been investigated. Of the following formula (C) in which the amino group of the 2-position side chain of

[0009]

[Chemical 4]

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

However, the imipenem represented by the above formula (C) exhibits an antibacterial activity superior to that of thienamycin, and although it has a certain degree of chemical stability, it is inactive by renal dehydropeptidase (DHP) in vivo. It has a drawback that the conversion 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), a DHP inhibitor.
It is a combination prescription of imipenem / cilastatin in combination with lastatin; INN).

However, as a practical antibacterial agent used clinically, it is preferable that the original 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 possible to exert the effect. Therefore, there is a strong demand for the development of a carbapenem compound having antibacterial activity and resistance to DHP.

In recent years, as a means for achieving the above object, a 1-methylcarbapenem compound having a methyl group at the 1-position of a carbapenem skeleton and a sulfide having various substituted side chains at the 2-position has been proposed. There is. inside that,
As the prior art most closely related to the present invention, there is, for example, JP-A-63-63,680. In the present publication, the following formula (D) having an imidazolylethylthio group as the 2-position side chain:

[0014]

[Chemical 5]

The 1-substituted carbapenem-3-carboxylic acid derivative represented by the following is specifically disclosed. Further, it is described that this compound has an excellent antibacterial action and can be a useful antibacterial agent.

However, among the compounds described in this publication, those similar to the compound of the present invention include aromatic compounds at the terminal of the alkylthio group at the 2-position side chain, including the specific compound of the above formula (D). As for the carbapenem compound having only two compounds whose cyclic groups are substituted and having two independent functional groups in the alkylthio group at the 2-position side chain as in the present invention, not only a concrete description but also its suggestion is recognized at all. Absent. Therefore, the above publication does not give any suggestion as to the characteristic structure as well as the pharmacological properties of the compound of the present invention.

Some carbapenem compounds exhibit antibacterial activity against a wide variety of fungal species. However, as is the case with β-lactam antibiotics that are commonly used in clinical settings, it is fully expected that new carbapenem compounds will initially be effective but gradually develop resistant bacteria. It Therefore, the development of carbapenem antibiotics having a unique structure is awaited for the countermeasure against infectious diseases caused by resistant bacteria that will appear in the future.

[0018]

[Means for Solving the Problems] In view of such circumstances, as a result of study to develop a carbapenem antibiotic having a unique structure different from the compounds found so far and clinically useful, The inventors have methyl-substituted the 1-position in the β-configuration and have [1-substituted-3- as the 2-position side chain.
(Heteroaryl-1-yl) -propan-2-yl]
The present inventors have found that a carbapenem compound having a thio group introduced has a strong antibacterial activity against a wide variety of bacterial species and has excellent resistance to β-lactamase and renal dehydropeptidase, and completed the present invention. Thus, the present invention provides formula (I):

[0019]

[Chemical 6]

In the formula, R ¹ represents a hydroxyl group, a mercapto group, an amino group or a halogen atom, and X, Y and Z each independently represent a nitrogen atom or CR ² (wherein R ² is a hydrogen atom, a carboxyl group). Group, a lower alkoxycarbonyl group, a carbamoyl group, or a mono- or di-lower alkyl-substituted amido group), (1R, 5S, 6S)
-2- [1-substituted-3- (heteroaryl-1-yl)
-Propan-2-yl] thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbapene-2-em-
The present invention provides 3-carboxylic acid, and a pharmacologically acceptable salt thereof.

As described above, the carbapenem compound of the present invention is a novel compound which is not described in the prior art documents at all, and is characterized by its excellent antibacterial activity and its extremely unique structure. It has characteristics.

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

The "halogen atom" is chlorine, fluorine, bromine, iodine or the like, preferably chlorine or fluorine.

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, n-heptyl, isoheptyl and the like, but preferably methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec- Butyl and tert-butyl.

"Lower alkoxy group" means a lower alkyl-substituted oxy group in which a lower alkyl group has the above-mentioned meaning, for example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, Examples thereof include tert-butoxy, n-pentyloxy, isopentyloxy, n-hexyloxy, isohexyloxy, n-heptyloxy, isoheptyloxy and the like, but preferably methoxy, ethoxy, n-propoxy, isopropoxy, n. -Butoxy, isobutoxy, sec-butoxy, tert-butoxy.

Representative examples of the compounds of formula (I) provided by the present invention are shown in Tables 1 and 2 below.

[0027]

[Table 1]

[0028]

[Table 2]

Although the 2-position substituent of the compound of the present invention has an asymmetric carbon, each isomer produced thereby can be separated from the mixture by a usual isolation and purification means (see Examples below). It is needless to say that each isomer itself is a compound included in the present invention as well as a mixture of isomers.

Furthermore, among the compounds of formula (I) of the present invention, more preferred specific embodiments are as follows. (1R, 5S, 6S) -2 [(2R or S) -1-hydroxy-3- (1,2-pyrazol-1-yl) propan-2-yl] thio-6-[(1R)- 1-hydroxyethyl] -1-methylcarbapene-2-em-3-carboxylic acid; (1R, 5S, 6S) -2 [(2R or S)-
1-hydroxy-3- (1,2,4-triazol-1
-Yl) propan-2-yl] thio-6-[(1R)-
1-hydroxyethyl] -1-methylcarbapene-2-
Em-3-carboxylic acid; (1R, 5S, 6S) -2
[(2R or S) -1-fluoro-3- (1,2,4-
Triazol-1-yl) propan-2-yl] thio-
6-[(1R) -1-hydroxyethyl] -1-methylcarbapene-2-em-3-carboxylic acid; (1R, 5
S, 6S) -2 [(2R or S) -1-amino-3-
(1,2,4-triazol-1-yl) propane-2
-Yl] thio-6-[(1R) -1-hydroxyethyl] -1-methylcarbapene-2-em-3-carboxylic acid; (1R, 5S, 6S) -2 [(2R or S) -1 −
Mercapto-3- (1,2,4-triazol-1-yl) propan-2-yl] thio-6-[(1R) -1-
Hydroxyethyl] -1-methylcarbapene-2-em-3-carboxylic acid; (1R, 5S, 6S) -2 [(2R
Or S) -1-hydroxy-3- (1,2,3,4-tetrazol-1-yl) propan-2-yl] thio-6
-[(1R) -1-Hydroxyethyl] -1-methylcarbapene-2-em-3-carboxylic acid; (1R, 5S,
6S) -2-[(2R or S) -3- [3- (N, N-
Dimethylcarbamoyl) -1,2-pyrazol-1-yl] -1-hydroxypropan-2-yl] thio-6-
[(1R) -1-hydroxyethyl] -1-methylcarbapene-2-em-3-carboxylic acid; (1R, 5S, 6
S) -2-[(2R or S) -3- [3,5-bis (N, N-dimethylcarbamoyl) -1,2-pyrazol-1-yl] -1-hydroxypropan-2-yl]
Thio-6-[(1R) -1-hydroxyethyl] -1-
Methylcarbapene-2-em-3-carboxylic acid; (1
R, 5S, 6S) -2-[(2R or S) -3- [3,
5-bis (N, N-dimethylcarbamoyl) -1,2-
Pyrazol-1-yl] -1-fluoropropane-2-
Il] thio-6-[(1R) -1-hydroxyethyl]
-1-methylcarbapene-2-em-3-carboxylic acid;
(1R, 5S, 6S) -2-[(2R or S) -3-
[3,5-bis (N, N-dimethylcarbamoyl)-
1,2-pyrazol-1-yl] -1-aminopropan-2-yl] thio-6-[(1R) -1-hydroxyethyl] -1-methylcarbapene-2-em-3-carboxylic acid, etc.

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

[0032]

[Chemical 7]

In the formula, R ^a represents an acyl group, R ^1a represents a halogen atom, or an optionally protected hydroxyl group, a mercapto group or an amino group, and X ^a , Y ^a and Z ^a are each independently, Represents a nitrogen atom or CR ^2a (where R
^2a represents a hydrogen atom, or an optionally protected carboxyl group, lower alkoxycarbonyl group, carbamoyl group or mono- or di-lower alkyl-substituted amide group), R ³ represents a carboxyl protecting group, and R ¹ , X , Y
And Z are as defined above.

The "acyl group" represented by the substituent R ^a in the above formula (II) is not limited to the rest of the atomic groups obtained by removing the OH group from the carboxyl group of the organic carboxylic acid, but also in a broad sense. It also includes an acyl group derived from an acid or an organic phosphoric acid, for example, a lower alkanoyl group such as acetyl, propionyl, butyryl; a (halo) lower alkylsulfonyl group such as methanesulfonyl, trifluoromethanesulfonyl group; benzenesulfonyl, p- A substituted or unsubstituted arylsulfonyl group such as nitrobenzenesulfonyl, p-bromobenzenesulfonyl, toluenesulfonyl, 2,4,6-triisopropylbenzenesulfonyl; a diphenylphosphoryl group and the like can be exemplified, but a diphenylphosphoryl group is preferable. Is used.

Examples of the protective group for the hydroxyl group represented by the substituent R ^1a include aliphatic or aromatic acyl groups such as acetyl and benzoyl; aralkyl groups such as benzyl and triphenylmethyl; benzyloxycarbonyl and p. −
A substituted or unsubstituted benzyloxycarbonyl group such as nitrobenzyloxycarbonyl and p-methoxybenzyloxycarbonyl; tert-butyldimethylsilyl,
Substituted silyl groups such as tert-butyldiphenylsilyl and phenylisopropyldimethylsilyl; tetrahydropyranyl groups and the like can be exemplified, but preferably triphenylmethyl group, tert-butyldimethylsilyl group or tetrahydropyranyl group is used. To be

Similarly, examples of the protecting group for the mercapto group include any protecting group generally known as a protecting group for the mercapto group of cysteine in peptide chemistry, preferably benzyl, p-nitrobenzyl and p-methoxy. Aralkyl groups such as benzyl, diphenylmethyl and trityl: benzyloxycarbonyl, p-nitrobenzyloxycarbonyl: t-butyldimethylsilyl, t
-A silyl group such as a butyldiphenylsilyl group is used.

Examples of the amino-protecting group include any protecting group generally known as an amino-protecting group in the field of peptide chemistry, preferably ethoxycarbonyl, tert-butoxycarbonyl and allyloxy. Saturated or unsaturated alkoxycarbonyl groups such as carbonyl, substituted or unsubstituted benzyloxycarbonyl groups such as benzyloxycarbonyl, p-methoxybenzyloxycarbonyl and the like are used.

Further, when the substituent R ^{2a of} CR ^{2a which} can be selected as the substituents X ^a , Y ^a and Z ^a is a protected carboxyl group, the protecting group and the carboxyl group represented by the substituent R ³ Examples of the protecting group of are ester residues, and examples of such ester residues include methyl, ethyl, n-propyl, isopropyl, allyl, n-, iso-, tert-butyl, n-hexyl ester. Lower alkyl ester residues such as benzyl,
Aralkyl ester residues such as p-nitrobenzyl, o-nitrobenzyl, m-nitrobenzyl, 2,4-dinitrobenzyl, p-chlorobenzyl, p-bromobenzyl, p-methoxybenzyl; acetoxymethyl, acetoxyethyl, propionyl Oxymethyl, n-, iso-
Examples thereof include lower aliphatic acyloxymethyl residues such as butyryloxymethyl and pivaloyloxymethyl.

The compound of formula (II) of reaction formula A and the compound of formula (II)
[1-substituted-3- (heteroaryl-1) represented by I)
The reaction with -yl) -propan-2-yl] thiol
For example, in a suitable solvent such as tetrahydrofuran, dichloromethane, dioxane, dimethylformamide, dimethylsulfoxide, acetonitrile, hexamethylphosphoramide and the like, the compound of the formula (II) is used in a molar amount of about 0.5 to about 5 times, preferably about 1: 1. To about 3 times the molar amount of thiol compound of formula (III), preferably in the presence of a base such as sodium hydrogen carbonate, potassium carbonate, triethylamine, diisopropylethylamine, at a temperature in the range of about -40 to about 25 ° C. It can be performed by stirring 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 above reaction gives the compound of formula (IV), which can be used as it is in the next step in the next step. In some cases, the reaction solution may be subjected to a conventional purification means to give a compound of the formula The compound of (IV) can also be isolated and purified.

The formula (I
In the case where the substituent R ^1a of the compound V) is an unprotected hydroxyl group, this compound is reacted with thionyl chloride, triphenylphosphine-carbon tetrachloride or carbon tetrabromide to give a compound of the formula (IV It is also possible to obtain a compound in which the substituent R ^{1a in} ) is a halogen atom.

The compound of formula (IV) obtained by the above reaction can then be converted to the compound of formula (I) of the present invention by eliminating the carboxyl protecting group R ³ .

Removal of the carboxyl protecting group R ³ can be carried out by a known protecting group reaction such as solvolysis or hydrogenolysis. Specifically, the formula (I
The compound of V) is added to, for example, an acetate buffer solution having a pH of 5 to 7, a morpholinopropanesulfonic acid-sodium hydroxide buffer solution or a phosphate buffer solution, a mixed solvent of these buffer solutions and an alcoholic solvent, or a phosphate dibasic solution. In a mixed solvent of tetrahydrofuran-water containing potassium, sodium bicarbonate, etc., tetrahydrofuran-ethanol-water, dioxane-water, dioxane-ethanol-water, n-butanol-water, etc., using hydrogen at about 1 to 4 atm, In the presence of a hydrogenation catalyst such as platinum oxide, palladium-activated carbon, palladium hydroxide-activated carbon, etc., at a temperature in the range of about 0 to about 50 ° C., about 0.
It can be performed by treating for 25 to about 5 hours.

The elimination of the protecting group R ³ 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 is generally 1 to 1 part by weight of the compound of the formula (IV).
It may be in the range of 10 parts by weight, preferably 1 to 5 parts by weight. In this elimination reaction, if necessary, an organic solvent may be used in combination, and examples of such a solvent include alcohol solvents such as ethanol, propanol, and n-butanol; ether solvents such as diethyl ether and tetrahydrofuran. Solvents: acetonitrile, dimethylformamide, dimethylacetamide and the like can be mentioned.
The reaction is usually performed at about -20 to about 50 ° C, preferably room temperature to
It can be completed by treating at a temperature of about 30 ° C. for about 0.1 to 5 hours.

Also, the substituent X of the compound of the above formula (IV)
^a, substituent group CR ^2a that can be selected in Y ^a and Z ^a R
^{When 2a} is a protected carboxyl group, the protecting group can be eliminated simultaneously with the substituent R ³ by the above reaction.

It should be noted that the substituent R ^1a of the compound of formula (IV) or CR ^{2a which} can be selected for the substituents X ^a , Y ^a and Z ^a .
When a protecting group is present in the hydroxyl group, mercapto group or amino group of the substituent R ^2a of, the protecting group is preferably removed prior to the removal of the carboxyl protecting group. The elimination reaction of each protective group of the hydroxyl group, the mercapto group and the amino group in the compound of the formula (IV) can be carried out under a per se known deprotecting group reaction condition such as solvolysis or hydrogenolysis. methanol,
In a solvent such as ethanol, acetonitrile, tetrahydrofuran, dioxane, in the presence of an acid such as Lewis acid, hydrofluoric acid, hydrochloric acid, sulfuric acid, formic acid, acetic acid, etc., at a temperature of about 0 ° C. to about 100 ° C. for about 30 minutes or It can be performed by stirring for about 24 hours. Further, the elimination reaction of the protective group for the hydroxyl group is carried out in the same solvent as described above or a mixed solvent of these with water in the presence of an ammonium acetate or the like in the compound of the formula (IV), with hydrofluoric acid or fluorination. It can also be carried out by reacting a fluorine compound such as potassium, cesium fluoride or tetrabutylammonium fluoride.

The compound of formula (II) used as a starting material in the above-mentioned production method is known per se, and is produced by the method described in JP-A-56-123,985. Or preferably, it can be produced in a highly stereoselective manner by the method described in JP-A-63-284,176.

[1-Substituted-3- (heteroaryl-1-) of the formula (III) which is also used as a starting material.
The (yl) -propan-2-yl] thiol can be synthesized, for example, by the production method schematically shown in Reaction Formula B below. The outline is as follows.

[0050]

[Chemical 8]

In the formula, R ⁴ represents an active group of hydroxyl group, X,
^{Y, Z, X a, Y} a, Z a and R ^1a are as defined above.

The compound of formula (V) of reaction formula B and the compound of formula (VI)
The reaction with the oxirane derivative represented by, for example, a compound of the formula (V) in a suitable solvent such as methanol, ethanol, tetrahydrofuran, dichloromethane, dioxane, dimethylformamide, dimethylsulfoxide, acetonitrile, hexamethylphosphoramide, About 0.5
To about 5 times, preferably about 0.8 to about 3 times the oxirane derivative of formula (VI) is stirred at a temperature in the range of about 0 to about 80 ° C. for about 30 minutes to about 24 hours. It can be done by

As the oxirane derivative used in this reaction, for example, glycidol, epichlorohydrin, epibromhydrin, epifluorohydrin, and their mercapto-substituted or amino-substituted compounds can be used, preferably glycidol or epi-hydrazine. Fluorohydrin can be used.

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

When the substituent R ^1a of the compound of the formula (VII) obtained by the above reaction is a group other than a hydroxyl group, that is, a protected hydroxyl group, a halogen atom, an optionally protected mercapto group or an amino group. Is the formula (V
By reacting the compound of II) with a hydroxyl group activating reagent, for example, an organic sulfonyl halide such as methanesulfonyl chloride or 4-toluenesulfonyl chloride; an acyl halide such as acetyl chloride,
It can lead to the compound represented by III). Specifically, the reaction is carried out in a solvent such as methylene chloride or chloroform, preferably in the presence of a base such as sodium hydrogen carbonate, potassium carbonate, triethylamine or diisopropylethylamine, with a compound of the formula (VII) in an amount of about 0.8 to about 0.8. 1.
It can be carried out by stirring with a 5-fold molar amount of the above-mentioned activating reagent, and is carried out at -20 ° C to room temperature, preferably about 0 ° C, and is completed in about 10 minutes to about 5 hours.

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

On the other hand, when the substituent R ^1a of the compound of the above formula (VII) is an unprotected hydroxyl group, first,
The primary hydroxyl group, which is the substituent R ^1a of the compound (VII), is protected by an ordinary protecting group introduction reaction, and the remaining secondary hydroxyl group is activated by the above reaction to obtain the compound of the formula (VII
It is preferable to lead to the compounds of I).

Also, the substituent R ^1a of the compound of formula (VII)
Is an unprotected hydroxyl group, the formula (V
The compound of formula (VII) in which the substituent R ^1a is a protected amino group can also be obtained by treating the compound of II) by the following method. That is, the expression (VI
The primary hydroxyl group represented by R ^1a of the compound I) is directly reacted with an activating reagent according to the method described above, and then the remaining secondary hydroxyl group is protected and then reacted with sodium azide. As a result of this reaction, a compound in which the primary hydroxyl group is substituted with an azido group is obtained. Next, the azido group is reduced, the amino group obtained by this reduction reaction is protected, and then the secondary group previously protected is obtained. If the protecting group for the hydroxyl group is eliminated, a compound of formula (VII) in which the desired substituent R ^1a is a protected amino group can be obtained. The compound of formula (VII) obtained by the above method can be converted to the formula (VIII) by the above method.

Formula (VIII) obtained by the above reaction
The compound (1) can be isolated by conventional purification means, but may be used as it is in the next reaction without isolation and purification.

The resulting compound of formula (VIII) is converted to the compound of formula (IX) by stirring with about 1 to about 3 times the molar amount of potassium thioacetate in the above-mentioned suitable solvent. be able to. The reaction is preferably carried out in a stream of an inert gas such as nitrogen gas or argon gas, and is completed at a relatively high temperature of room temperature to about 80 ° C. for about 1 hour to 3 days.

The compound of formula (IX) obtained by the above reaction can be isolated by a conventional purification means, but may be directly used in the next reaction without purification.

The reaction for converting the compound of formula (IX) into the compound of formula (III) is a conventional hydrolysis reaction,
It can be carried out by stirring in a suitable solvent described above, such as an alcoholic solvent, in the presence of an alkali such as sodium hydroxide or potassium hydroxide at a relatively low temperature of about room temperature for a few minutes to about 2 hours. .

The compound of formula (III) obtained by the above reaction can be easily isolated by a conventional purification means.

Thus, (1R, 5S, 6S) -2- [1-substituted-3- of the formula (I) which is the object compound of the present invention.
(Heteroaryl-1-yl) -propan-2-yl]
Thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbapene-2-em-3-carboxylic acid can be obtained in a high yield, and the compound is an ion exchange resin if necessary. Alternatively, it can be isolated with high purity by purifying using a polymer adsorption resin.

(1) of the formula (I), which is the object compound of the present invention,
R, 5S, 6S) -2- [1-Substituted-3- (heteroaryl-1-yl) -propan-2-yl] thio-6-
[(R) -1-Hydroxyethyl] -1-methyl-carbapene-2-em-3-carboxylic acid may exist as an inner salt per se when the substituent R ¹ is an amino group. Alternatively, it can be isolated as an arbitrary acid addition salt by treating with an organic acid or an inorganic acid, if necessary. Examples of the organic acid used here include formic acid, acetic acid, propionic acid, butyric acid, trifluoroacetic acid,
Lower fatty acids such as trichloroacetic acid; substituted or unsubstituted benzoic acids such as benzoic acid and p-nitrobenzoic acid; (halo) lower alkyl sulfonic acids such as methanesulfonic acid and trifluoromethanesulfonic acid; benzenesulfonic acid and p-nitrobenzene Sulfonic acid, p-bromobenzenesulfonic acid,
Substituted or unsubstituted aryl sulfonic acids such as toluene sulfonic acid and 2,4,6-triisopropylbenzene sulfonic acid; and organic phosphoric acids such as diphenyl phosphoric acid can be mentioned. Examples of the inorganic acid include hydrochloric acid, sulfuric acid, Examples thereof include hydrobromic acid, hydroiodic acid, borofluoric acid, perchloric acid, and nitrous acid.

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. . 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 [Chemothrapy, vol 29,76
~ 79 (1981)] according to the agar plate dilution method.
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.
The tory concentration (MIC) was used.

Here, the strain used was a standard strain.

As the test compounds, the compound (15a) described in Example 3 and the compound (15b) described in Example 5 below were used.

2. Results The results are shown in Table 3 below.

[0071]

[Table 3]

From the above results, it was confirmed that the carbapenem compound of the present invention has excellent antibacterial activity.

Further, the compounds of the present invention are methyl-substituted at the 1-position in the β-configuration, and at the 2-position are unique [1-substituted-3- (heteroaryl-1) s as side chains.
-Yl) -propan-2-yl] thio group and other structural features make it extremely stable against attack by renal dehydropeptidase (DHP) and chemically and physically It is clear that the stability is also high.

[Toxicity test] CrjC weighing 20 to 23 g
Ten male D (SD) mice were used and the carbapenem compound (1) of the present invention described in Examples 3, 5 and 8 below was used.
The solution containing 5a), (15b) and (18) was subcutaneously administered and observed for 1 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.

From the results of the above antibacterial test and toxicity test,
The compound represented by the formula (I) does not need to be used in combination with a renal DHP inhibitor and can be used alone, and is an extremely useful antibacterial agent for treating and preventing bacterial infections caused by various pathogenic bacteria. It is expected.

The compound of the formula (I) or a pharmacologically acceptable salt thereof, when used 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. Further, 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.

The carbapenem compound of the present invention is particularly preferably administered parenterally in the form of an injection.

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.

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

Production Example 1 (a) Production of 1- (2-hydroxy-3-tert-butyldimethylsilyloxypropyl) -1,2,4-triazole (2)

[0083]

[Chemical 9]

1- (2,3-dihydroxypropyl)-
11.76 g of 1,2,4-triazole hydrochloride was suspended in 100 ml of anhydrous methylene chloride, and 19.2 ml of triethylamine and 2.65 of dimethylaminopyridine were suspended in the suspension.
g and tert-butyldimethylsilyl chloride 9.85 g were sequentially added at room temperature and then stirred for 16 hours. 10% aqueous citric acid solution, water, saturated NaH
After washing with CO ₃ water and saturated saline and drying, the solvent was distilled off under reduced pressure. The obtained solid was washed with a small amount of n-hexane to obtain 11.1 g (yield 66%) of the title compound (2). ¹ H-NMR (CDCl ₃ ) δ: 0.08 (s, 6
H), 0.91 (s, 9H), 3.58 (d, J = 5.
60Hz, 2H), 4.00-4.10 (m, 1H),
4.10 to 4.40 (m, 2H), 7.94 (s, 1
H), 8.18 (s, 1H)

(B) 1- (2-acetylthio-3-te
rt-butyldimethylsilyloxypropyl) -1,
Production of 2,4-triazole (3)

[0086]

[Chemical 10]

Compound (2) obtained in (a) above.
To a solution of 1 g of anhydrous methylene chloride in 150 ml, at 0 ° C.,
Triethylamine 8.5 ml and methanesulfonyl chloride 4.0 ml were added dropwise, and the mixture was stirred at the same temperature for 30 minutes. The reaction solution was diluted with 10% citric acid aqueous solution and saturated NaHCO _3.
The extract was washed with water and saturated saline and dried, and the solvent was distilled off under reduced pressure. 14.4 g of the obtained residue was dissolved in 150 ml of anhydrous dimethylformamide, and potassium thioacetate 1 was added to this solution.
5 g was added and the mixture was stirred at 60 ° C. for 16 hours. The reaction mixture was concentrated under reduced pressure, the obtained residue was dissolved in ethyl acetate,
It was washed with water and brine. The organic layer was dried over magnesium sulfate, the solvent was evaporated under reduced pressure, and the obtained residue was subjected to silica gel chromatography (elution solvent-chloroform: acetone = 9: 1) to give 10 the title compound (3). .9
g (yield 81%) was obtained. ¹ H-NMR (CDCl ₃ ) δ: 0.07 (s, 6
H), 0.92 (s, 9H), 2.36 (s, 3H),
3.59 (dd, J = 5.6, 10.6 Hz, 1H),
3.69 (dd, J = 3.9, 10.6 Hz, 1H),
3.05 to 3.85 (m, 1H), 4.41 (dd, J
= 6.3, 13.9 Hz, 1H), 4.52 (dd, J
= 6.6, 13.9 Hz, 1H), 7.96 (s, 1
H), 8.11 (s, 1H)

(C) 1- (2-mercapto-3-ter
Preparation of t-butyldimethylsilyloxy) -1,2,4-triazole (4)

[0089]

[Chemical 11]

Compound (3) obtained in the above (b) 10.
To a solution of 9 g of methanol in 100 ml, 17.3 ml of 2N aqueous potassium hydroxide solution was added dropwise at 0 ° C.
After stirring for 1 minute, 35 ml of 1N hydrochloric acid was added. The reaction mixture was diluted with 300 ml of methylene chloride, washed with saturated brine, dried over magnesium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (4) (9.2 g, yield 97%). ¹ H-NMR (CDCl ₃ ) δ: 0.08 (s, 3
H), 0.10 (s, 3H), 0.93 (s, 9H),
1.77 (d, J = 9.9 Hz, 1H), 3.25 to
3.40 (m, 1H), 3.60 (dd, J = 5.3,
10.6 Hz, 1 H), 3.68 (dd, J = 3.6,
10.6 Hz, 1H), 4.30 (dd, J = 6.9,
13.9 Hz, 1H, 4.49 (dd, J = 6.6,
13.9 Hz, 1H), 7.97 (s, 1H), 8.1
8 (s, 1H)

Production Example 2 (a) 3,5-bis (N, N-dimethylcarbamoyl)
Production of pyrazole (6)

[0092]

[Chemical 12]

2.01 g of 3,5-pyrazole dicarboxylic acid monohydrate (5) was dissolved in 9 ml of thionyl chloride, and heated under reflux for 5 hours in a nitrogen stream. The residue obtained by concentrating the reaction solution was dissolved in 20 ml of tetrahydrofuran, and a solution obtained by diluting 5.2 ml of 50% dimethylamine aqueous solution with 40 ml of tetrahydrofuran was added dropwise to the obtained solution at 0 ° C. in a nitrogen stream, The mixture was stirred at the same temperature for 1 hour. The residue obtained by evaporating the solvent of the reaction solution under reduced pressure was subjected to silica gel column chromatography (eluting solvent-methylene chloride:
The mixture was subjected to acetone = 1: 1) to obtain 1.73 g (yield 71.5%) of the title compound (6) as white crystals. ¹ H-NMR (CDCl ₃ ) δ: 3.15 (s, 6
H), 3.37 (s, 6H), 7.04 (s, 1H)

(B) 1- (2,3-dihydroxypropyl) -3,5-bis (N, N-dimethylcarbamoyl)
Production of pyrazole (7)

[0095]

[Chemical 13]

Compound (6) 1.7 obtained in the above (a)
To a solution of 3 g of absolute ethanol in 11 ml of glycidol.
6 ml was added, and the mixture was heated under reflux in a nitrogen stream for 6 hours.
The residue obtained by evaporating the solvent of the reaction solution under reduced pressure was subjected to silica gel column chromatography (eluting solvent-methylene chloride: acetone = 1: 2) to give 1.98 g of the title compound (7) as white crystals. (Yield 84.4%) was obtained. ¹ H-NMR (CDCl ₃ ) δ: 3.11 (s, 3
H), 3.12 (s, 3H), 3.19 (s, 3H),
3.34 (s, 3H), 3.54 (d, J = 4.6H
z, 2H), 4.11 (m, 1H), 4.42 (m, 2)
H), 6.84 (s, 1H)

(C) Preparation of 1- (3-tert-butyldimethylsilyloxy-2-hydroxy) -3,5-bis (N, N-dimethylcarbamoyl) pyrazole (8)

[0098]

[Chemical 14]

Compound (7) 1.9 obtained in the above (b)
To a solution of 8 g of anhydrous methylene chloride in 35 ml, 47.5 mg of dimethylaminopyridine, 1.2 ml of triethylamine and 1.15 g of tert-butyldimethylsilyl chloride.
Was added, and the mixture was stirred at room temperature in a nitrogen stream for 16 hours. The solvent of the reaction solution was distilled off under reduced pressure and the resulting residue was diluted with ethyl acetate 5
It was dissolved in 0 ml and washed with water and 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-methylene chloride: acetone = 4: 1) to give the title compound (8). As a white solid 2.35 g
(Yield 84.9%) was obtained. ¹ H-NMR (CDCl ₃ ) δ: 0.08 (s, 6
H), 0.91 (s, 9H), 3.11 (s, 6H),
3.17 (s, 3H), 3.36 (s, 3H), 3.6
2 (dd, J = 6.3, 10.2 Hz, 1H), 3.6
8 (dd, J = 5.0, 10.2 Hz, 1H), 4.0
4 (m, 1H), 4.40 (m, 3H), 6.82
(S, 1H)

(D) Preparation of 1- (3-tert-butyldimethylsilyloxy-2-mesyloxy) -3,5-bis (N, N-dimethylcarbamoyl) pyrazole (9)

[0101]

[Chemical 15]

Compound (8) 2.3 obtained in the above (c)
In a solution of 5 g of anhydrous methylene chloride in 20 ml, 0 in a nitrogen stream
At 65 ° C., 1.65 ml of triethylamine and 0.69 ml of mesyl chloride were added, and the mixture was stirred at the same temperature for 30 minutes. The residue obtained by concentrating the reaction solution under reduced pressure was dissolved in 50 ml of ethyl acetate, and washed with water and 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-methylene chloride: acetone = 7: 1) to give the title compound (9). As a white solid 2.51 g
(Yield 89.3%) was obtained. ¹ H-NMR (CDCl ₃ ) δ: 0.09 (s, 6
H), 0.91 (s, 9H), 2.84 (s, 3H),
3.10 (s, 6H), 3.17 (s, 3H), 3.3
6 (s, 3H), 3.83 (t, J = 4.3 Hz, 2
H), 4.69 (m, 2H), 5.01 (m, 1H),
6.82 (s, 1H)

(E) 1- (2-acetylthio-3-te
rt-Butyldimethylsilyloxy) -3,5-bis (N, N-dimethylcarbamoyl) pyrazole (10)
Manufacturing of

[0104]

[Chemical 16]

Compound (9) 1.7 obtained in the above (d)
To a solution of 7 g of anhydrous dimethylformamide in an amount of 4.25 g of potassium thioacetate in a nitrogen stream, the mixture was stirred at 60 ° C. for 47 hours. After adding 50 ml of ethyl acetate to the reaction solution, it was washed with water and 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-methylene chloride) to give the title compound (10) as a brown solid. 01 g (yield 59.7%) was obtained. ¹ H-NMR (CDCl ₃ ) δ: 0.06 (s, 6
H), 0.90 (s, 9H), 2.25 (s, 3H),
3.10 (s, 3H), 3.11 (s, 3H), 3.1
5 (s, 3H), 3.38 (s, 3H), 3.67 (d
d, J = 5.6, 10.6 Hz, 1H) 3.78 (d
d, J = 4.0, 10.6 Hz, 1H), 4.04
(M, 1H), 4.53 (dd, J = 8.3, 14.0)
Hz, 1H), 4.75 (dd, J = 5.9, 14.0)
Hz, 1H), 6.79 (s, 1H)

(F) 1- (3-tert-butyldimethylsilyloxy-2-mercapto) -3,5-bis (N, N-dimethylcarbamoyl) pyrazole (11)
Manufacturing of

[0107]

[Chemical 17]

Compound (10) 48 obtained in the above (e)
To a solution of 2 mg of methanol in 11 ml was added 7 ml of a 1N sodium hydroxide aqueous solution in a nitrogen stream, and the mixture was stirred at room temperature for 3 hours. After adding 30 ml of ethyl acetate to the reaction solution, 1
It was washed with 0% aqueous citric acid solution, water and saturated saline. 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-methylene chloride: acetone = 10:
After subjecting to 1), 250 mg (yield 57.0%) of the title compound (11) was obtained as a brown oil. ¹ H-NMR (CDCl ₃ ) δ: 0.08 (s, 6
H), 0.92 (s, 9H), 1.65 (d, J = 8.
9Hz, 1H), 3.11 (s, 6H), 3.17
(S, 3H), 3.37 (s, 3H), 3.40 (m,
1H), 3.67 (dd, J = 5.9, 10.2 Hz,
1H) 3.78 (dd, J = 4.6, 10.2 Hz, 1
H), 4.45 (dd, J = 8.6, 13.9 Hz, 1
H), 4.66 (dd, J = 5.6, 13.9 Hz, 1)
H), 6.80 (s, 1H). After 30 ml of ethyl acetate was added to the reaction solution, it was washed with 10% aqueous citric acid solution, water and 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-methylene chloride: acetone = 10: 1) to give the title compound (1
250 mg of 1) as a brown oil (yield 57.0%)
Obtained. ¹ H-NMR (CDCl ₃ ) δ: 0.08 (s,
6H), 0.92 (s, 9H), 1.65 (d, J = 8.9Hz, 1H), 3.11
(S, 6H), 3.17 (s, 3H), 3.37 (s,
3H), 3.40 (m, 1H), 3.67 (dd, J =
5.9, 10.2 Hz, 1H) 3.78 (dd, J =
4.6, 10.2 Hz, 1H), 4.45 (dd, J =
8.6, 13.9 Hz, 1H), 4.66 (dd, J =
5.6, 13.9 Hz, 1H), 6.80 (s, 1H)

Example 1 p-Nitrobenzyl (1R, 5S, 6S) -2-
[(2R) -1-tert-Butyldimethylsilyloxy-3- (1,2,4-triazol-1-yl) propan-2-yl] thio-6-[(1R) -1-hydroxyethyl]- 1-Methylcarbapene-2-em-3-carboxylate (13a), and p-nitrobenzyl
(1R, 5S, 6S) -2-[(2S) -1-tert
-Butyldimethylsilyloxy-3- (1,2,4-triazol-1-yl) propan-2-yl] thio-6
-[(1R) -1-hydroxyethyl] -1-methylcarbapene-2-em-3-carboxylate (13b)
Manufacturing of

[0110]

[Chemical 18]

P-Nitrobenzyl (1R, 5R, 6
S) -2- (diphenylphosphoryloxy) -6-
[(1R) -1-Hydroxyethyl] -1-methylcarbapene-2-em-3-carboxylate (12) 1
9.99 g of the compound (4) obtained in (b) of the above Preparation Example 1 was added to 9.996 g of anhydrous acetonitrile solution under ice cooling.
In anhydrous acetonitrile (20 ml) and diisopropylethylamine (7.04 ml) were sequentially added, and the mixture was stirred for 1 hour. The solvent of the reaction solution was evaporated under reduced pressure and the obtained residue was dissolved in 400 ml of ethyl acetate and washed with 10% aqueous citric acid solution, water, saturated aqueous NaHCO ₃ solution and saturated saline. After the organic layer 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 =
3: 1), and 8.92 g of the title compound (13a).
(Yield 43%), 8.13 g of (13b) (yield 43
%)Obtained. ¹ H-NMR (CDCl ₃ ) δ: (13a); 0.06 (s, 6H), 0.90 (s, 9)
H), 1.03 (d, J = 7.3 Hz, 3H), 1.3
4 (d, J = 6.3 Hz, 3H), 3.26 (dd, J
= 2.6, 6.3 Hz, 1H), 3.35 (dq, J =
7.3, 9.2 Hz, 1H), 3.60-3.80
(M, 3H), 4.00 to 4.20 (m, 3H), 4.
60-4.67 (m, 1H), 5.23 (d, J = 1
3.9 Hz, 2H), 5.48 (d, J = 13.9H
z, 2H), 7.65 (d, J = 8.6Hz, 2H),
7.98 (s, 1H), 8.16 (s, 1H), 8.2
2 (d, J = 8.6 Hz, 2H) (13b); 0.09 (s, 6H), 0.91 (s, 9)
H), 1.17 (d, J = 7.3 Hz, 3H), 1.3
4 (d, J = 5.9 Hz, 3H), 3.22 (dd, J
= 2.3, 6.6 Hz, 1H), 3.25 to 3.34
(M, 1H), 3.68 to 3.80 (m, 1H), 3.
80-3.88 (m, 2H), 4.06 (dd, J =
2.3, 9.6 Hz, 1H), 4.17 to 4.25
(M, 2H), 4.60 to 4.68 (m, 1H), 5.
23 (d, J = 13.9 Hz, 2H), 5.50 (d,
J = 13.9 Hz, 2H), 7.66 (d, J = 8.3)
Hz, 2H), 8.00 (s, 1H), 8.10 (s,
1H), 8.22 (d, J = 8.3Hz, 2H)

Example 2 p-Nitrobenzyl (1R, 5S, 6S) -2 [(2
R) -1-hydroxy-3- (1,2,4-triazo-
Lu-1-yl) propan-2-yl] thio-6 [(1
R) -1-Hydroxyethyl] -1-methylcarbapene-2-em-3-carboxylate (14a)

[0113]

[Chemical 19]

Compound (13a) obtained in Example 1 above
To a solution of 8.36 g of anhydrous acetonitrile in 68 ml, 2.33 ml of acetic acid and 23 ml of a 1.1 M tetrahydrofuran solution of tetra-n-butylammonium fluoride were added at room temperature, and the mixture was stirred for 3 hours. The solvent of the reaction solution was evaporated under reduced pressure and the obtained residue was dissolved in 500 ml of ethyl acetate and washed with water, saturated NaHCO ₃ and saturated saline. After the organic layer was dried over magnesium sulfate, the solvent was distilled off under reduced pressure, and the resulting residue was subjected to silica gel column chromatography (elution solvent-chloroform: methanol =
9: 1) and 5.54 g of the title compound (14a).
(Yield 81%) was obtained. ¹ H-NMR (CDCl ₃ ) δ: 1.04 (d, J =
7.3 Hz, 3 H), 1.31 (d, J = 6.4 Hz,
3H), 3.10 to 3.20 (m, 1H), 3.26.
(Dd, J = 2.6, 6.3 Hz, 1H), 3.30-
3.40 (m, 1H), 3.60-3.85 (m, 3
H), 4.25 (dd, J = 2.6, 9.2 Hz, 1
H), 4.30 to 4.40 (m, 1H), 4.56 to
4.63 (m, 1H), 5.17 (d, J = 13.9H
z, 2H), 5.46 (d, J = 13.9 Hz, 2
H), 7.62 (d, J = 8.9 Hz, 2H), 7.9
7 (s, 1H), 8.19 (s, 1H), 8.19
(D, J = 8.9Hz, 2H)

Example 3 (1R, 5S, 6S) -2 [(2R) -1-Hydroxy-3- (1,2,4-triazol-1-yl) propan-2-yl] thio-6 -[(1R) -1-Hydroxyethyl] -1-methylcarbapene-2-em-3-carboxylic acid (15a)

[0116]

[Chemical 20]

Compound (14a) obtained in Example 2 above
2.5 g of n-butanol and 0.1 M acetate buffer (p
H6.4) was dissolved in 75 ml, 10% palladium-carbon (420 mg) was added to this solution, and the mixture was stirred under a hydrogen atmosphere of 4 kg / cm ² for 1.5 hours. The insoluble material was filtered off, the organic layer was separated, and the resulting aqueous layer was concentrated under reduced pressure. The obtained concentrated liquid was subjected to "Diaion" SP-207 column chromatography (eluting solvent: 20% IPA-water) to give 556 mg (yield 30%) of the title compound (15a).
Obtained. IR (KBr) cm ⁻¹ : 1750, 1600 ¹ H-NMR (CDCl ₃ ) δ: 0.88 (d, J =
7.3 Hz, 3 H), 1.27 (d, J = 6.3 Hz,
3H), 3.30 (dq, J = 7.3, 9.3 Hz, 1
H), 3.38 to 3.40 (m, 1H), 3.60 to
3.70 (m, 1H), 3.70-3.80 (m, 2
H), 4.16 to 4.25 (m, 2H), 4.42 (d
d, J = 9.6, 14.8 Hz, 1H), 4.67 (d
d, J = 3.6, 14.8 Hz, 1H), 8.11
(S, 1H), 8.57 (s, 1H)

Example 4 p-Nitrobenzyl (1R, 5S, 6S) -2 [(2
S) -1-Hydroxy-3- (1,2,4-triazo-
Lu-1-yl) propan-2-yl] thio-6 [(1
R) -1-Hydroxyethyl] -1-methylcarbapene-2-em-3-carboxylate (14b)

[0119]

[Chemical 21]

According to the method described in Example 2 above,
The title compound (14b) was obtained using the compound (13b) obtained in Example 1 as a starting material. ¹ H-NMR (CDCl ₃ ) δ: 1.18 (d, J =
7.3 Hz, 3 H), 1.32 (d, J = 6.3 Hz,
3H), 3.20 to 3.30 (m, 2H), 3.60 to
3.85 (m, 3H), 4.10 to 4.15 (m, 1
H), 4.20-4.35 (m, 2H), 4.59 (d
d, J = 5.3, 14.2 Hz, 1H), 5.21
(D, J = 13.9 Hz, 2H), 5.48 (d, J =
13.9 Hz, 2H), 7.64 (d, J = 8.9H
z, 2H), 7.97 (s, 1H), 8.15 (s, 1
H), 8.20 (d, J = 8.9 Hz, 2H)

Example 5 (1R, 5S, 6S) -2 [(2S) -1-Hydroxy-3- (1,2,4-triazol-1-yl) propan-2-yl] thio-6 -[(1R) -1-Hydroxyethyl] -1-methylcarbapene-2-em-3-carboxylic acid (15b)

[0122]

[Chemical formula 22]

According to the method described in Example 3 above,
The title compound (15b) was obtained using the compound (14b) obtained in Example 4 as a starting material. IR (KBr) cm ⁻¹ : 1750, 1590 ¹ H-NMR (CDCl ₃ ) δ: 1.11 (d, J =
7.3 Hz, 3 H), 1.29 (d, J = 6.3 Hz,
3H), 3.13 (dd, J = 7.3, 9.2 Hz, 1
H), 3.37 (dd, J = 2.3, 6.3 Hz, 1
H), 3.60 to 3.98 (m, 4H), 4.22 (q
uint, J = 6.3 Hz, 1H), 4.39 (dd,
J = 9.6, 14.2 Hz, 1H), 4.67 (dd,
J = 4.3, 14.2 Hz, 1H), 8.14 (s, 1
H), 8.44 (s, 1H)

Example 6 p-Nitrobenzyl (1R, 5S, 6S) -2- [1
-Tert-butyldimethylsilyloxy-3- [3,3
5-bis (N, N-dimethylcarbamoyl) -1,2-
Pyrazol-1-yl] propan-2-yl] thio-6
-[(1R) -1-Hydroxyethyl] -1-methylcarbapene-2-em-3-carboxylate (16)

[0125]

[Chemical formula 23]

To a solution of 250 mg of the compound (11) obtained in (f) of Preparation Example 2 above in 15 ml of anhydrous acetonitrile, p-nitrobenzyl was added under a nitrogen stream at -20 ° C.
(1R, 5R, 6S) -2- (Diphenylphosphoryloxy) -6-[(1R) -1-hydroxyethyl] -1
-Methylcarbapene-2-em-3-carboxylate (12) 399 mg anhydrous acetonitrile solution 5 ml,
And 0.3 ml of diisopropylethylamine were added, and the mixture was stirred at the same temperature for 1 hour and at room temperature for 1 hour. The solvent of the reaction solution was distilled off under reduced pressure, and the obtained residue was dissolved in 400 ml of ethyl acetate and washed with water and saturated saline. The organic layer 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-methylene chloride: acetone = 5: 1) to give the title compound (16). As a yellow oil 258
mg (yield 56.4%) was obtained. ¹ H-NMR (CDCl ₃ ) δ: 0.03 (s, 3
H), 0.04 (s, 3H), 0.88 (s, 9H),
0.96 (d, J = 6.9 Hz, 3H), 1.28
(D, J = 13.9 Hz, 3H), 3.09 (s, 6
H), 3.20 to 3.23 (m, 1H), 3.21.
(S, 3H), 3.33 (s, 3H), 3.42 (m,
1H), 3.67 to 3.85 (m, 3H), 4.20.
(M, 2H), 4.50 (dd, J = 8.9, 14.2)
Hz, 1H), 4.65 (m, 1H), 5.34 (d)
d, J = 13.9, 65.7 Hz, 2H), 6.76
(S, 1H), 7.64 (d, J = 8.3 Hz, 2
H), 8.21 (d, J = 8.3Hz, 2H)

Example 7 p-Nitrobenzyl (1R, 5S, 6S) -2- [3
-[3,5-bis (N, N-dimethylcarbamoyl)-
1,2-pyrazol-1-yl] -1-hydroxypropan-2-yl] thio-6-[(1R) -1-hydroxyethyl] -1-methylcarbapene-2-em-3-carboxylate ( 17) Manufacturing

[0128]

[Chemical formula 24]

Compound (16) 2 obtained in Example 6 above
To a solution of 58 mg of anhydrous acetonitrile in 3.4 ml, 0.06 ml of acetic acid and 0.62 ml of a 1.1 M tetrahydrofuran solution of tetra-n-butylammonium fluoride were added in a nitrogen stream, and the mixture was stirred for 5.5 hours. The solvent of the reaction solution was distilled off under reduced pressure and the resulting residue was diluted with ethyl acetate 1
It was dissolved in 0 ml and washed with saturated NaHCO ₃ . The organic layer was dried over magnesium sulfate, and the solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography.
It was subjected to (elution solvent-methylene chloride: acetone = 2: 1) to give 184 mg of the title compound (17) as a yellow oil.
(Yield 84.0%) was obtained. ¹ H-NMR (CDCl ₃ ) δ: 1.14 (d, J =
6.9 Hz, 3 H), 1.33 (d, J = 5.9 Hz,
3H), 3.24 (m, 1H), 3.10 (s, 6)
H), 3.15 (s, 3H), 3.36 (s, 3H),
3.47 (m, 1H), 3.57 (d, J = 5.6H
z, 2H), 3.80 (m, 1H), 4.22 (m, 2)
H), 4.64 (d, J = 5.9 Hz, 2H), 5.2
0 (d, J = 13.5 Hz, 1H), 5.48 (d, J
= 13.9 Hz, 1H), 6.81 (s, 1H), 7.
65 (d, J = 7.3 Hz, 2H), 8.21 (d, J
= 7.3 Hz, 2H)

Example 8 (1R, 5S, 6S) -2- [3- [3,5-bis (N, N-dimethylcarbamoyl) -1,2-pyrazol-1-yl] -1-hydroxypropane- 2-yl]
Thio-6-[(1R) -1-hydroxyethyl] -1-
Methylcarbapene-2-em-3-carboxylic acid (18)
Manufacturing of

[0131]

[Chemical 25]

Compound (17) 1 obtained in Example 7 above
84 mg was dissolved in 15 ml of n-butanol and 15 ml of 0.1M acetate buffer (pH 5.5), and 10 ml of this solution was dissolved.
% Palladium-carbon (111 mg) was added, and the mixture was stirred under a hydrogen atmosphere at 4 atm for 1.5 hours. The insoluble matter was removed by filtration through a Celite pad, the organic layer was separated, and the resulting aqueous layer was concentrated under reduced pressure. The resulting concentrate is "Diaion" HP-4
Subjected to 0 column chromatography to give the title compound (18) as a diastereomeric mixture as a pale yellow solid 91.4
mg (yield 62.8%) was obtained. ¹ H-NMR (CD ₃ OD) δ: 0.91 (d, J =
6.9 Hz, 3 H), 1.24 (d, J = 6.3 Hz,
3H), 3.08 (s, 3H), 3.09 (s, 3
H), 3.16 (s, 3H), 3.29 (m, 2H),
3.36 (s, 3H), 3.61 (m, 3H), 4.0
5 (m, 2H), 4.58 (m, 2H), 6.81
(S, 1H)

[0133] The above components are mixed to give a suspension injection with a total volume of 100 ml.

(2) Freeze-drying To 20 g of compound (15a), an appropriate amount of distilled water was added, and the volume was adjusted to 1
Make up to 00 ml. 2.5 ml of the above aqueous solution in one vial
Or 5 ml (compound 500 mg or 10 respectively)
(Containing 00 mg) and lyophilized. When in use,
About 3-4 ml of distilled water is added to make an injection.

(3) Filling with powder Powder of 250 mg of the compound (15a) is filled in one vial as it is. At the time of use, about 3 to 4 ml of distilled water is added to make an injection.

[0136] The above ingredients are mixed and tableted by a conventional method to give tablets, and if necessary, sugar-coated or film-coated by a conventional method to give sugar-coated tablets or film-coated tablets.

[0137] The above ingredients are mixed and compressed into tablets by a conventional method.

[0138] The above ingredients are mixed and filled into a usual hard gelatin capsule to give a capsule.

[0139] The above ingredients are mixed to form a dry syrup.

[0140] The above ingredients are mixed to give a powder.

[0141] The above ingredients are mixed and made into a suppository by a conventional method.

Claims (2)

[Claims] 1. Formula (I): In the formula, R ¹ represents a hydroxyl group, a mercapto group, an amino group or a halogen atom, and X, Y and Z each independently represent a nitrogen atom or CR ² (wherein R ² is a hydrogen atom, a carboxyl group, a lower group). (1R, 5S, 6S) -2- [1-substituted-3- (heteroaryl-1-yl) -propane-, which is an alkoxycarbonyl group, a carbamoyl group, or a mono- or di-lower alkyl-substituted amide group). Two
-Yl] thio-6-[(R) -1-hydroxyethyl]
-1-Methyl-carbapene-2-em-3-carboxylic acid, and pharmacologically acceptable salts thereof. 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.