JPH07196659A - 2-((substituted 1,3-thiazolium-3-yl)alkylthio)carbapenem derivative - Google Patents

Abstract

PURPOSE:To obtain a carbapenem 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 (R1 and R2 each is H, a lower alkenyl, a halogen, hydroxy, a lower alkoxy or a lower alkyl which may be substituted with mercapto or a lower alkylthio; n is 1-4) such as (1R,5S,6 S)-6-[(R)-1-hydroxyethyl]-2-[2-[5-(2hydroxyethyl)-4-methyl-1,3-thiazol ium-3- yl]ethylthio]-1methylcarbapen-2-em-3-carboxylate, etc. The compound, for example, is preferably obtained by reacting a compound of formula II (R<9> is an acyl) as a starting substance with a mercaptoalcohol of formula III in the presence of a solvent such as tetrahydrofuran.

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 is substituted at the 2-position (1,
A carbapenem compound having a 3-thiazolium-3-yl) alkylthio group and an antibacterial agent containing the compound as an active ingredient.

[0002]

2. Description of the Related Art 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 its development was expected as a highly useful compound as a drug,
It has poor chemical stability and has not yet been put to practical use.

[0008] 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 4]

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 although its chemical stability is ensured to some extent, it is inactive by decomposition 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 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 better to avoid compounding and prescribing as much as possible, because side effects may be exhibited. Therefore, there is a strong demand for the development of a carbapenem compound having antibacterial activity and resistance to DHP.

Recently, as a means for achieving the above-mentioned object, a methyl group was introduced at the 1-position of the carbapenem skeleton,
1-having a mercapto group having various side chains at the 2-position
Methylcarbapenem compounds have been proposed. For example,
Japanese Unexamined Patent Publication (Kokai) No. 61-63679 discloses the following formula (D) having a nitrogen-containing quaternary heteroarylium alkylthio group at the 2-position of the carbapenem skeleton.

[0014]

[Chemical 5]

1-substituted carbapenem-3-carboxylic acid derivatives of the formula: have been described. The publication also reports that this compound is a highly useful antibacterial agent with improved resistance to degradation inactivation by DHP and chemical stability.

The compound of the present invention in which the substituent at the 2-position of the carbapenem skeleton is a substituted (1,3-thiazolium-3-yl) alkylthio group is literally a compound represented by the general formula in the above publication. Although included, the publication discloses a specific method for producing the compound of the present application, a method for obtaining the starting compound, physical property data of the final product, antibacterial activity data, and
The specific structure is not described at all. Further, the (1,3-thiazolium-3-yl) alkylthio group, which is the mother nucleus of the substituent at the 2-position of the carbapenem skeleton of the compound of the present invention, is any compound whose production method is specifically described in the above publication. It also has a structure that is significantly different from the substituents. Therefore, the above publication does not disclose or suggest any compounds disclosed and claimed herein.

[0017]

[Means for Solving the Problems]
-A novel carbapenem compound having excellent resistance to lactamase and renal dehydropeptidase and having a strong antibacterial activity and expected to be used as a highly useful antibacterial agent was discovered, and the present invention was completed. The compound of the present invention is methyl-substituted at the 1-position in the β-configuration, and further,
Substituted as the 2-position substituent (1,3-thiazolium-
3-yl) alkylthio group is introduced, which is a structural feature, and specifically, is represented by the formula (I)

[0018]

[Chemical 6]

In the formula, R ¹ and R ² are each independently hydrogen, a lower alkenyl group, halogen, hydroxy,
Represents a lower alkyl group which may be substituted with lower alkoxy, mercapto or lower alkylthio (provided that R ¹ and R ² are both hydrogen atoms), and n
Represents an integer of 1 to 4 (1R, 5S, 6
S) -6-[(R) -1-Hydroxyethyl] -1-methyl-2-[(substituted-1,3-thiazolium-3-yl) alkylthio] carbapene-2-em-3-carboxylate. .

The compound of formula (I) itself is an intramolecular quaternary amine salt, but a pharmacologically acceptable salt can be prepared by adding an appropriate base or acid to this compound. You can also Such salts include inorganic and organic non-toxic salts that are ordinarily acceptable as pharmaceuticals. Examples of the inorganic salt include alkali metal salts such as sodium salt and potassium salt; alkaline earth metal salts such as calcium salt and magnesium salt; ammonium salt. Examples of the organic salt include a base such as triethylamine salt, pyridine salt, picoline salt, ethanolamine salt, triethanolamine salt, dichlorohexylamine salt, N, N′-dibenzylethylenediamine salt, and other such amine salts. Salts: Inorganic acid addition salts such as hydrochloride, hydrobromide, sulfate, phosphate, etc .; Formate, acetate, trifluoroacetate, maleate, tartrate, methanesulfonate, benzenesulfonate Examples thereof include salts with acids such as organic acid addition salts such as salts; salts with basic amino acids or acid amino acids such as arginine, aspartic acid and glutamic acid.

The carbapenem compound of the present invention is a novel compound which has not been disclosed in the prior art documents, and is expected to be highly useful as an antibacterial agent because of its uniquely superior antibacterial activity.

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

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

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-
Examples include heptyl and isoheptyl.

The term "halogen" means any one of fluorine, chlorine, bromine and iodine unless otherwise specified.

The "lower alkoxy group" may be linear or branched and is, for example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy,
Examples thereof include isobutoxy, sec-butoxy, tert-butoxy, n-pentoxy, isopentoxy, n-hexyloxy, isohexyloxy, n-heptoxy, isoheptoxy and the like.

The "lower alkylthio group" may be linear or branched and is, for example, methylthio, ethylthio, n-propylthio, isopropylthio, n-butoxythio, sec-butoxythio, tert-butoxythio, n-pentoxythio. , N-hexyloxythio,
Examples thereof include isohexyloxythio, n-heptoxythio, and isoheptoxythio.

The compound of formula (I) provided by the present invention has a 1,3-thiazolium group at its 2-position side chain,
It preferably has a substituent represented by R ¹ at the 4-position, and further has a substituent represented by R ² at the 5-position.

Representative examples of the substituents R ¹ , R ² and n of the compound of formula (I) provided by the present invention are as shown in Tables 1 to 5 below.

[0030]

[Table 1]

[0031]

[Table 2]

[0032]

[Table 3]

[0033]

[Table 4]

[0034]

[Table 5]

The preferred specific examples of the compound of formula (I) are as follows.

(1R, 5S, 6S) -6-[(R) -1
-Hydroxyethyl] -2- [2- [5- (2-hydroxyethyl) -4-methyl-1,3-thiazolium-3
-Yl] ethylthio] -1-methylcarbapene-2-em-3-carboxylate; (1R, 5S, 6S) -6
-[(R) -1-hydroxyethyl] -2- [5- (2
-Hydroxyethyl) -4-methyl-1,3-thiazolium-3-yl] methylthio-1-methylcarbapene-
2-M-3-carboxylate; (1R, 5S, 6
S) -6-[(R) -1-Hydroxyethyl] -2-
[2- [5- (2-mercaptoethyl) -4-methyl-
1,3-thiazolium-3-yl] ethylthio] -1-
Methylcarbapene-2-em-3-carboxylate;
(1R, 5S, 6S) -6-[(R) -1-Hydroxyethyl] -2- [5- (2-mercaptoethyl) -4-
Methyl-1,3-thiazolium-3-yl] methylthio-1-methylcarbapene-2-em-3-carboxylate; (1R, 5S, 6S) -6-[(R) -1-hydroxyethyl ] -1-Methyl-2- [2- (4-methyl-1,3-thiazolium-3-yl) ethylthio] carbapene-2-em-3-carboxylate; (1R, 5
S, 6S) -6-[(R) -1-Hydroxyethyl]-
1-Methyl-2- (4-methyl-1,3-thiazolium-3-yl) methylthiocarbapene-2-em-3-carboxylate; (1R, 5S, 6S) -2- [2-
(5-Vinyl-4-methyl-1,3-thiazolium-3
-Yl] ethylthio-6-[(R) -1-hydroxyethyl] -1-methylcarbapene-2-em-3-carboxylate; (1R, 5S, 6S) -2- (5-vinyl- 4-Methyl-1,3-thiazolium-3-ylmethylthio) -6-[(R) -1-hydroxyethyl] -1-
Methylcarbapene-2-em-3-carboxylate;

The reaction scheme A below is a schematic representation of the method for producing the compound of formula (I) of the present invention.

[0038]

[Chemical 7]

In the above reaction formula A, R ³ represents a carboxyl protecting group, R ^a and R ⁴ each independently represent an acyl group, X ⁻ represents a salt-forming anion, and R ¹ and R 4 represent R ¹ and R 4.
² and n are as defined above.

Examples of the “carboxyl protecting group” represented by R ³ include ester residues, and examples of such ester residues include methyl, ethyl,
n-propyl, isopropyl, n-, iso-, ter
Lower alkyl ester residues such as t-butyl and n-hexyl ester; benzyl, p-nitrobenzyl, o-nitrobenzyl, m-nitrobenzyl, 2,4-dinitrobenzyl, p-chlorobenzyl, p-bromobenzyl, p
-Aralkyl ester residues such as methoxybenzyl; lower aliphatic acyloxymethyl residues such as acetoxymethyl, acetoxyethyl, propionyloxymethyl, n-, iso-butyryloxymethyl, pivaloyloxymethyl, etc., and preferred. Is an aralkyl ester residue.

The "acyl group" represented by R ^a and R ⁴ is not limited to the rest of the atomic groups obtained by removing the OH group from the carboxyl group of an organic carboxylic acid, but in a broad sense,
It also represents an acyl group derived from an organic sulfonic acid or an organic phosphoric acid, and examples thereof include a lower alkanoyl group such as acetyl, propionyl and butyryl; a (halo) lower alkylsulfonyl group such as methanesulfonyl and trifluoromethanesulfonyl group; benzenesulfonyl, A substituted or unsubstituted arylsulfonyl group such as p-nitrobenzenesulfonyl, p-bromobenzenesulfonyl, toluenesulfonyl and 2,4,6-triisopropylbenzenesulfonyl; and a diphenylphosphoryl group.

[0042] X ^- the "salt-forming anion" represented by are encompassed anion corresponding to the cation of the quaternary ammonium, specifically, hydroxy anion; methoxy anion, an alkoxy such as ethoxy anion Examples thereof include anions; halogen anions such as chloro anions, bromo anions, iodo anions, and fluorine anions; or “acid anions” described below. The term "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, propionic acid, butyric acid, trifluoroacetic acid, trichloroacetic acid, etc. Lower fatty acids of benzoic acid, p
-Substituted or unsubstituted benzoic acid such as nitrobenzoic acid; (halo) lower alkyl sulfonic acid such as methanesulfonic acid and trifluoromethanesulfonic acid; p-nitrobenzenesulfonic acid, p-bromobenzenesulfonic acid, toluenesulfonic acid, 2 A substituted or unsubstituted arylsulfonic acid such as 4,4,6-triisopropylbenzenesulfonic acid;
Remaining atomic groups obtained by removing hydrogen atoms from organic phosphoric acid such as diphenylphosphoric acid: inorganic acid residues such as nitrous acid, nitric acid,
The remaining atomic groups obtained by removing hydrogen atoms from sulfuric acid or hydrohalic acids such as perchloric acid and borofluoric acid can be exemplified.

In the synthetic route represented by reaction formula A, step (a) is the reaction of the compound of formula (II) with the mercapto alcohol of formula (III), for example:
A compound of formula (II) in a suitable solvent such as tetrahydrofuran, dichloromethane, dioxane, dimethylformamide, dimethylsulfoxide, acetonitrile, hexamethylphosphoramide, preferably acetonitrile,
About 0.5 to about 5 times, preferably about 0.8 to about 3 times the molar amount of the mercapto alcohol of the formula (III), and preferably sodium hydrogen carbonate, potassium carbonate, triethylamine, diisopropylethylamine and the like. In the presence of a base, particularly preferably diisopropylethylamine, about-
The reaction can be performed at a temperature within the range of 40 to about 25 ° C., preferably under ice cooling for about 30 minutes to about 24 hours.

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

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

Then, the compound of formula (IV) thus obtained is subjected to the reaction of step (b) to activate the hydroxyl group on the side chain at the 2-position to obtain the compound of formula (V).

As the hydroxyl group activating reagent used in this step (b), an organic carboxylic acid, an organic sulfonic acid, or an organic halide of an acid such as an organic phosphoric acid exemplified in the description of the "acyl group", for example, , Methanesulfonyl chloride, 4-toluenesulfonyl chloride, acetyl chloride and the like.

In this step, specifically, the compound represented by the formula (IV) and the activating reagent in an amount of about 1 to about 4 molar equivalents are suitably exemplified, for example, in the step (a). About 20 to 6 in a different solvent, preferably tetrahydrofuran, in the presence of a base as exemplified in step (a) above.
The reaction can be carried out at 0 ° C., preferably about −20 ° C. to room temperature for about 30 minutes to about 4 hours.

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

The hydroxyl group-activated derivative (V) obtained in this step can be used as it is in the above reaction solution for the next reaction, but depending on the case, it may be subjected to the usual purification means exemplified above. It can be isolated and purified by.

The following step (c) is a reaction for obtaining the compound of formula (VII) by reacting the compound of formula (V) obtained by the above reaction with the thiazole derivative of formula (VI).

This step (c) can be carried out, for example, by either of the following two methods. That is, according to the method (i), the compound of the formula (V) and the thiazole derivative of the formula (VI) are preferably used in a solvent or the like used in the above step (a), preferably from 30 ° C to a solvent. It can be carried out by reacting for about 30 minutes to about 10 hours while heating to a temperature of about the boiling point.

According to the method (ii), the activated hydroxyl group of the compound of formula (V) is halogenated, and then the obtained halide is reacted with the thiazole derivative of formula (VI). It can also be carried out under milder conditions than the above method (i). In this case, for example, first,
The compound of formula (V) and the metal salt of halogen are heated in a suitable solvent such as acetone or a mixed solvent of methylene chloride and dimethylmeformamide at a temperature of about 0 ° C. to the boiling point of the solvent, preferably under reflux conditions. The compound of formula (V) is obtained as a halide by reacting for about 30 minutes to about 60 hours. The halide obtained here can be directly subjected to the next reaction, or can be purified by the above-mentioned purification means, for example. Subsequently, the halide is combined with the thiazole derivative represented by the formula (VI) in a suitable solvent, for example, the solvent used in the above step (a), preferably acetonitrile or the like, preferably the presence of a silver salt. The reaction is conducted at about −20 ° C. to room temperature, preferably under ice cooling, for about 30 minutes to about 10 hours to react with the compound of formula (VI).
The compound of formula I) is obtained.

The "halogen metal salt" used in the production method of the above method (ii) is, for example, a salt of the above-mentioned halogen, preferably bromine or iodine, and an alkali metal such as sodium or potassium, preferably Examples thereof include sodium bromide and sodium iodide.

Similarly, as the "silver salt", for example,
Examples thereof include silver carbonate, silver nitrate, silver acetate, silver trifluoroacetate, silver tetrafluoroborate, silver phosphate, silver perchlorate, and the like, and preferably silver perchlorate.

The formula (VI) obtained by the above step (c)
The salt of I) can be purified, if necessary, by the usual purification means mentioned above.

[0057] Incidentally, X of the compound of formula (VII) ^- salt-forming anion represented by the, OR ⁴ anion eliminated from the compound of the case of using the method (i) in this step formula (V) However, when the method (ii) is used, the halogen anion is eliminated from the halide which is a production intermediate.

The salt of the formula (VII) obtained by the above step is subjected to a deprotection reaction known per se such as solvolysis or hydrogenation in the subsequent step (d) to remove the protecting group R ³ of the carboxyl group. It can be eliminated and converted to the compound of formula (I).

The step (d) is specifically represented by the formula (VII)
Is added to a buffer solution having a pH of 5 to 7, for example, an acetic acid buffer solution, a morpholinopropanesulfonic acid-sodium hydroxide buffer solution, a phosphate buffer solution, dipotassium phosphate, tetrahydrofuran-water containing sodium bicarbonate and the like. , Tetrahydrofuran-ethanol-water, dioxane-water, dioxane-ethanol-water, n-butanol-water and the like in a mixed solvent of hydrogen at about 1 to 4 atm, platinum oxide, palladium- About 1 at a temperature in the range of about 0 to about 50 ° C. in the presence of a hydrogenation catalyst such as activated carbon or palladium hydroxide-activated carbon.
It can be performed by treating for 5 minutes to about 5 hours.

This step can also be carried out by treating with zinc in a buffer solution. For example, the formula (VI
By treating the compound of I) with zinc in a buffer having a pH of 5 to 7, for example, phosphate buffer, acetate buffer, citrate buffer, morpholinopropane sulfonate buffer, N-methylmorphophosphate buffer. It can be carried out. Examples of zinc that can be used include zinc powder, zinc-like zinc, and granular zinc. The amount of zinc used is not particularly limited, but is generally 1 to 10 parts by weight, preferably 1 part by weight, preferably 1 part by weight of the compound of the formula (VII). Can be in the range of 1 to 5 parts by weight. In addition, in this elimination reaction, an organic solvent may be used in combination, if necessary, and such solvents include alcohol solvents such as ethanol, propanol and n-butanol; ether solvents such as diethyl ethanol and tetrahydrofuran. Solvents: acetonitrile, dimethylformamide, dimethylacetamide and the like can be mentioned. 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.

The compound of formula (I) can also be produced by the method shown in the following reaction scheme B.

[0062]

[Chemical 8]

In reaction formula B, R ¹ , R ² , R ³ , X ⁻ , R
^a and n are as defined above.

The reaction of the compound of formula (II) with the 3- (mercaptoalkyl) thiazolium derivative of formula (VIII) can be carried out, for example, under the same conditions as in step (a) of the above reaction formula A.

By this reaction, the compound of formula (VII) is obtained, and the reaction solution can be used as it is in the next step. In some cases, the reaction solution is subjected to usual purification means to obtain the compound of formula (VII). The compound of 1 can also be isolated and purified.

Then, the formula (V
The carboxyl protecting group R ³ of the compound of II) is, for example,
The compound of formula (I) can be produced by elimination by the same means as in step (d) of reaction formula A above.

The 3- (mercaptoalkyl) thiazolium derivative (VIII) used as a starting material in the reaction represented by the reaction formula B can be produced, for example, by the method represented by the following reaction formula C.

[0068]

[Chemical 9]

In reaction formula C, R represents a thiol protecting group,
R ¹ , R ² , X ⁻ and n are as defined above.

Examples of the thiol protecting group include benzyl, p-methoxybenzyl, diphenylmethyl, triphenylmethyl, t-butyl, acetyl and the like, preferably p-methoxybenzyl and triphenyl. Methyl etc. are mentioned.

The reaction represented by the reaction formula C is a reaction between the compound of the formula (IX) and the thiazole derivative of the formula (VI), and the two production methods used in the step (c) of the reaction formula A above. It can be carried out by reacting in the same manner as in (i) and (ii), and then subjecting the thiol protecting group to a deprotecting group reaction which is usually carried out.

If necessary, the compound of formula (VI) obtained as an intermediate in the production method shown in the reaction formulas A and B is used.
The compound of I) is a fatty acid exemplified in the above definition of “acid anion”, a substituted or unsubstituted benzoic acid, a substituted or unsubstituted arylsulfonic acid, an organic acid represented by an organic phosphoric acid, or nitric acid, By treating with an inorganic acid typified by sulfuric acid and hydrohalic acid, a salt with any salt-forming anion can be obtained.

Thus, (1R, 5S, 6S) -6-[(R) -1-hydroxyethyl] -1-methyl-2-[(substitution-1, of the formula (I) which is the object compound of the present invention. Three
-Thiazolium-3-yl) alkylthio] carbapene-2-em-3-carboxylates can be obtained in high yields, which compounds are optionally purified using ion exchange resins or polymeric adsorption resins. Thus, it can be isolated with high purity.

As mentioned above, if the compound of the formula (I) obtained by the above-mentioned method is treated with the above-mentioned organic or inorganic acid or base, if desired, any addition of the compound of the formula (I) can be carried out. It can also be isolated as a salt.

The compounds of the above formula (II) used as starting materials in the production methods represented by the above reaction formulas A and B are known per se, for example, JP-A-56-1.
It can be produced by the method described in JP-A No. 23985 or, preferably, highly stereoselectively by the method described in JP-A-63-284176.

Further, as the thiazole derivative of the above formula (VI) used as a raw material in the production method represented by the above reaction formulas A and C, 4-methylthiazole, 2,
Commercially available compounds such as 4,5-trimethylthiazole, 5-hydroxymethyl-4-methylthiazole and 4-methyl-5-vinylthiazole, or 4-methyl-5-vinylthiazole The commercially available compound of 1 can be used by appropriately modifying it by a known method.

Examples of the compound of the formula (IX) used as a raw material in the production method represented by the reaction formula C include, for example, commercially available mercapto alcohol such as ethylene thioglycol, hydroxypropyl chloride and hydroxybutyl chloride. A mercapto group of a mercapto alcohol obtained by reacting a commercially available compound such as the above with hydrogen sulfide is appropriately protected by the above-mentioned protecting group by a known method.

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 point is characteristic. The excellent antibacterial activity of this compound is proved by the results of the following antibacterial tests.

[Antibacterial Test] 1. Test method Japanese Society of Chemotherapy Standard Method [Chemothrapy, vol. 29, 7
6-79 (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. was diluted with Buffered saline gelatin (BSG) solution to about 10 ⁶ cells / ml, and a microplanter was prepared. MH agar medium containing the test compound was inoculated with about 5μ and incubated at 37 ° C for 18 hours.
Bitory concentration (MIC) was used.

Here, the standard strain was used as the strain used.

The compound (6) described in Example 5 below was used as the test compound.

2. Results The results are shown in Table 6 below.

[0083]

[Table 6]

From the above results, it is understood 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 are uniquely substituted as the 2-position substituent (1,3-thiazolium-3.
-Yl) having an alkylthio group and other structural features, it is extremely stable against attack by renal dehydropeptidase (DHP) and is highly chemically and physically stable. Is.

[Toxicity test] CrjC weighing 20 to 23 g
Ten male D (SD) mice were used, and Example 5 described below was used.
The solution containing the carbapenem compound (6) of the present invention described in 1. was subcutaneously administered, and observation was performed for 1 week. As a result, the carbapenem compound (6) of the present invention was 500 mg /
It was observed that even if the dose of kg was administered, all survived without any abnormality.

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

The compound of the formula (I) or a pharmaceutically 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, particularly 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.

The symbols in the following description have the following meanings.

Me: Methyl Et: Ethyl PNB: p-Nitrobenzyl Ph: Phenyl Ms: Methanesulfonyl chloride

Example 1

[0096]

[Chemical 10]

To a solution of 1.8 g (3 mmol) of compound (1) in 30 ml of anhydrous acetonitrile, under nitrogen atmosphere, in an ice bath, 0.23 ml (3.3 m) of 2-mercaptoethanol was added.
mol), and then diisopropylethylamine 0.5
8 ml (3.3 mmol) was added, and the mixture was stirred at the same temperature for 1.5 hours. The reaction mixture was concentrated under reduced pressure, the obtained residue was dissolved in ethyl acetate, washed successively with 1N-hydrochloric acid, saturated aqueous sodium carbonate solution and saturated brine, dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent-chloroform: acetone = 1: 1) to obtain 825 mg (yield 65%) of compound (2) as a pale yellow solid. ¹ H-NMR (CDCl ₃ ) δ: 1.27 (d, J =
7.3 Hz, 3 H), 1.36 (d, J = 6.3 Hz,
3H), 1.89 (bs, 1H), 2.17 (bs, 1
H), 2.92 (ddd, J = 5.6, 6.3, 13.
5 Hz, 1 H), 3.21 (ddd, J = 5.6, 6.
3, 13.5 Hz, 1H), 3.28 (dd, J = 2.
6, 6.6 Hz, 1H), 3.50 (m, 1H), 3.
85 (m, 2H), 4.22 to 4.32 (m, 2H),
5.28 (d, J = 13.8 Hz, 2H), 5.51
(D, J = 13.8 Hz, 2H), 7.66 (d, J =
8.9 Hz, 2H), 8.22 (d, J = 8.9 Hz,
2H)

Example 2

[0099]

[Chemical 11]

825 mg (1.95 mmo) of compound (2)
l) anhydrous tetrahydrofuran 10 ml solution at -15 ° C
Cooled to 0.16 ml (2 mmol) of methanesulfonyl chloride and 0.3 of triethylamine under a nitrogen atmosphere.
ml (2 mmol) was added, and the mixture was stirred at the same temperature for 30 minutes. Ethyl acetate was added to the reaction solution, which was washed with water, 1N-hydrochloric acid and saturated saline and then dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue is subjected to silica gel column chromatography- (eluent-chloroform: acetone =
2: 1) and the compound (3) as a pale yellow solid 7
76 mg (yield 80%) was obtained. ¹ H-NMR (CDCl ₃ ) δ: 1.27 (d, J =
7.6 Hz, 3 H), 1.36 (d, J = 6.3 Hz,
3H), 1.80 (bs, 1H), 3.04 (s, 3
H), 3.03 to 3.12 (m.1H), 3.21 to
3.30 (m, 2H), 3.48 (m, 1H), 4.2
2 to 4.45 (m, 4H), 5.23 (d, J = 13.
8Hz, 2H), 5.50 (d, J = 13.8Hz, 2
H), 7.65 (d, J = 8.3 Hz, 2H), 8.2
2 (d, J = 8.3Hz, 2H)

Example 3

[0102]

[Chemical 12]

678 mg (1.36 mmo) of compound (3)
l) in a solution of 30 ml of acetone, 40 parts of sodium iodide
0 mg (2.72 mmol) was added, and under a nitrogen atmosphere, 4
The mixture was heated under reflux for 5 hours. The reaction solution was cooled to room temperature, the precipitate was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent-methylene chloride: ethyl acetate = 1: 1) to obtain 642 mg (88.6%) of compound (4) as a pale yellow solid. ¹ H-NMR (CDCl ₃ ) δ: 1.28 (d, J =
7.3 Hz, 3 H), 1.37 (d, J = 6.3 Hz,
3H), 1.80 (bs, 1H), 3.14 to 3.44.
(M, 6H), 4.11 to 4.29 (m, 2H), 5.
24 (d, J = 13.5 Hz, 2H), 5.51 (d,
J = 13.5 Hz, 2H), 7.66 (d, J = 8.9)
Hz, 2H), 8.22 (d, J = 8.9Hz, 2H)

Example 4

[0105]

[Chemical 13]

Compound (4) 910 mg (1.7 mmo
l) and 4-methyl-5- (2-hydroxyethyl)-
To a solution of 244 mg (1.7 mmol) of 1,3-thiazole in 10 ml of anhydrous acetonitrile, under ice cooling, silver perchlorate-
A solution of 385 mg of the hydrate in 10 ml of anhydrous acetonitrile was added dropwise over 30 minutes under a nitrogen atmosphere, and the mixture was stirred at the same temperature for 1 hour and at room temperature for 2 hours. The reaction solution is filtered through Celite,
The filtrate was concentrated under reduced pressure, the obtained residue was washed with iso-propyl ether, iso-propyl ether was removed by decantation, and 1.1 g of the crude compound (5) as a pale yellow oily substance was obtained. Obtained. ¹ H-NMR (CDCl ₃ ) δ: 1.22 (d, J =
7.3 Hz, 3 H), 1.28 (d, J = 6.3 Hz,
3H), 2.54 (s, 3H), 3.03 to 3.10.
(M, 2H), 3.25 to 3.61 (m, 4H), 3.
77-3.82 (m, 2H), 4.12-4.17
(M, 1H), 4.21 (dd, J = 2.6, 9.6H
z, 1H), 4.68 to 4.79 (m, 2H), 5.3.
0 (d, J = 13.9 Hz, 2H), 5.46 (d, 1
3.9 Hz, 2 H), 7.71 (d, J = 8.6 Hz,
2H), 8.22 (d, J = 8.6, 2H), 9.67
(S, 1H)

Example 5

[0108]

[Chemical 14]

648 mg (1 mmol) of compound (5) was dissolved in 3 ml of tetrahydrofuran, and n-butanol 1 was added.
5 ml, 0.1 M phosphate buffer (pH 6.5) 15 ml
Then, 200 mg of 10% palladium-carbon was added, and catalytic hydrogenation was carried out at 4 atm for 2 hours. The reaction solution was filtered through Celite, the Celite pad was washed with water, and the filtrate was washed with n-butanol. The pH of the obtained aqueous layer was 5.5.
And was concentrated to 5 ml by vacuum concentration. The obtained aqueous solution is Diaion-SP resin (manufactured by Mitsubishi Kasei)
The product was purified with (distilled water and 5% isopropyl alcohol water) to obtain 206 mg (yield 50%) of compound (6) as a pale yellow solid. ¹ H-NMR (D ₂ O) δ: 1.06 (d, J = 7.3)
Hz, 3H), 1.20 (d, J = 6.3Hz, 3
H), 2.47 (s, 3H), 3.05 to 3.20.
(M, 4H), 3.33 to 3.42 (m, 2H), 3.
78 to 3.82 (m, 2H), 3.91 (m, 1H),
4.15 (m, 1H), 4.69 (m, 1H), 4.9
3 (m, 1H), 9.67 (s, 1H)

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

[0111] The above components are mixed to give a suspension injection with a total volume of 100 ml.

(2) In the case of freeze-drying To 20 g of compound (6), an appropriate amount of distilled water was added, and the volume was adjusted to 100
Set to ml. 2.5 ml or 5 ml of the above aqueous solution (500 mg or 1000 compound, respectively) 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) In case of powder filling In one vial, 250 mg of the compound (6) is charged as powder. At the time of use, about 3 to 4 ml of distilled water is added to make an injection.

[0114] 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.

[0115] The above ingredients are mixed and compressed into tablets by a conventional method.

[0116] The above ingredients are mixed and filled into a usual hard gelatin capsule to give a capsule.

[0117] The above ingredients are mixed to form a dry syrup.

[0118] The above ingredients are mixed to give a powder.

[0119] 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 and R ² each independently represent hydrogen, a lower alkenyl group, or a lower alkyl group which may be substituted with halogen, hydroxy, lower alkoxy, mercapto or lower alkylthio (provided that R ¹ and R 2 ²
Are both hydrogen atoms), and n is an integer of 1 to 4 (1R, 5S, 6S) -6-
[(R) -1-hydroxyethyl] -1-methyl-2-
[(Substituted-1,3-thiazolium-3-yl) alkylthio] carbapene-2-em-3-carboxylates and pharmaceutically acceptable salts thereof. 2. An antibacterial agent comprising the carbapenem compound according to claim 1 or a pharmacologically acceptable salt thereof as an active ingredient.