JPH051074A - Cephem compound - Google Patents

Abstract

PURPOSE:To provide the subject novel compound having both excellent antibacterial power and wide antibacterial spectrum, excellent in oral absorbability, thus useful as a therapeutic agent for microfism. CONSTITUTION:The objective compound of formula I (R<1> is 1-3C alkyl; R<2> is 3-5C alkyl or 3-5C cycloalkyl), for example, 7beta-[2-(2-aminothiazol-4-yl)-(Z)-2- hydroxyiminoacetamide]-3-[(2-methyl-1,3,4-thiadiazol-5-yl)thiomethyl]- 3-cephem-4- carboxylic acid 1-(isopropoxycarbonyloxy)ethyl ester. This compound is obtained by reaction at -20 to 30 deg.C of (A) a compound of formula II with (B) a compound of formula III (X is eliminable group) in an organic solvent such as DMF in the presence of a base such as triethylamine (the amount of the compound of the formula II to be used is pref. 1-5 molar times that of the compound of the formula III).

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a novel oral cephem compound or a salt thereof which is useful as a chemotherapeutic agent.

[0002]

2. Description of the Related Art There are many compounds having excellent antibacterial activity as cephem antibacterial agents, most of which are injections and few oral preparations. On the other hand, the antibacterial activity and antibacterial spectrum of the oral cephem preparation are inferior to those of the injectable cephem preparation. In order to solve this problem, an ester (eg, Advances in Drug Research) which deesterifies the carboxyl group at the 4-position of a cephem compound for injection or a compound having low oral absorbability as it is in vivo. DrugResearc
h), p. 17, p. 62 (1988), etc., so-called ester type prodrugs such as cefuroxime axetil, cefotiam hexetyl, cefpodoxime proxetil, cefteram pivoxil, etc. However, what has been sufficiently satisfied in terms of antibacterial activity and antibacterial spectrum has not been obtained yet.

[0003]

The problem to be solved by the invention:

[Chemical 3] 7β- [2- (2-aminothiazol-4-yl)-(Z) -2-hydroxyiminoacetamide] -3-
[(2-methyl-1,3,4-thiadiazol-5-yl)
Thiomethyl] -3-cephem-4-carboxylic acid (hereinafter referred to as "the cephemcarboxylic acid") is known to have excellent antibacterial activity and a broad antibacterial spectrum (Japanese Patent Publication No. 60-11713). However, it was not practical for oral use as it is because of poor oral absorbability. Further, the pivaloyloxymethyl ester and 1- (ethoxycarbonyloxy) ethyl ester of the cephemcarboxylic acid were synthesized as ester type prodrugs (Japanese Patent Publication No. 60-96).
98), but these esters were not sufficient in terms of oral absorbability. The present invention provides a novel oral cephem compound having an excellent antibacterial activity and a broad antibacterial spectrum and improved oral absorbability.

[0004]

Means for Solving the Problems As a result of intensive studies on the oral cephem compound, the present inventors have selected the cephem carboxylic acid from an extremely large number of cephem compounds, and selected the carboxyl group at the 4-position thereof. Of the numerous ester residues, the formula:

[Chemical 4] [Wherein R ¹ represents an alkyl group having 1 to 3 carbon atoms, and R ² represents an alkyl group having 3 to 5 carbon atoms or a cycloalkyl group having 3 to 5 carbon atoms branched at the α-position]. By selecting the group represented and introducing it into the 4-position carboxyl group of the compound as an ester residue, the formula:

[Chemical 5] The cephem compound represented by [the symbols in the formula have the same meaning as described above] or a salt thereof was successfully created, and unexpectedly (i) the absorption from the digestive tract was good, (ii) The blood concentration of the cephemcarboxylic acid is high and the half-life is long, (iii) the urinary recovery rate of the cephemcarboxylic acid is good, (iv) the therapeutic effect of oral administration against intraperitoneal infection of Staphylococcus aureus or Escherichia coli is excellent. It has been found that (v) it has various excellent properties as an oral cephem compound, such as less side effects and higher safety. And the ester residue that brought about these excellent properties is

[Chemical 6] (2) R ² is an alkyl group having 3 to 5 carbon atoms. (3) The alkyl having 3 to 5 carbon atoms represented by R ² is a branched alkyl. (4) The branched alkyl represented by R ² is branched at the α-position (having 3 to 5 carbon atoms). (Including cycloalkyl of) and the like are mentioned as structural features. The present inventors have completed the present invention based on these new findings and further studies.

That is, the present invention provides (1) a cephem compound
[I] or a salt thereof, (2) a compound [I] or a salt thereof in which R ² is isopropyl, (3) 7β- [2- (2-aminothiazol-4-yl)-(Z) -2-hydroxy Iminoacetamide] -3-[(2-methyl-1,3,4-thiadiazol-5-yl) thiomethyl] -3-cephem-4-carboxylic acid 1- (isopropoxycarbonyloxy) ethyl ester or salt thereof , (4) 7β- [2- (2-aminothiazol-4-yl)-(Z) -2-hydroxyiminoacetamide] -3-[(2-methyl-1,3,4-thiadiazole-5] -Yl) thiomethyl] -3-cephem-4-
The present invention relates to an orally-administered therapeutic agent for bacterial infection, which comprises carboxylic acid 1- (cyclopentyloxycarbonyloxy) ethyl ester or a salt thereof, and (5) cephem compound [I] or a salt thereof. In the above formula,
The alkyl group having 1 to 3 carbon atoms represented by R ¹ is, for example, methyl, ethyl, propyl or the like, preferably methyl or the like is used.

Examples of the alkyl group having 3 to 5 carbon atoms which is branched at the α-position represented by R ² include alkyl groups having 3 to 5 carbon atoms such as isopropyl, 1-methylpropyl and 1-ethylpropyl. Yes, isopropyl or the like is preferably used. As the cycloalkyl group having 3 to 5 carbon atoms represented by R ² , for example, cyclopropyl, cyclobutyl, cyclopentyl and the like are used, and preferably cyclopentyl and the like are used. Also,
The compound [I] of the present invention can be used as a salt. In that case, an acid addition salt or the like is used, and as such an acid,
Mineral acids such as hydrochloric acid, sulfuric acid, phosphoric acid, etc., such as maleic acid, acetic acid, citric acid, succinic acid, tartaric acid, malic acid, malonic acid, fumaric acid, benzoic acid, mandelic acid, ascorbic acid, methanesulfonic acid, etc. An acid known as an acid forming a pharmaceutically acceptable salt in the field of penicillin or cephalosporin such as acid is used.

Compound [I] or a salt thereof has an asymmetric carbon atom at the ester portion of the carboxyl group at the 4-position of the cephem skeleton. Therefore, two optically active compounds (R
-Isomers, S-isomers). Therefore, the compound [I]
Alternatively, the salt thereof may be a mixture of diastereomers in an appropriate ratio, but it may be used after separating the R-isomer or the S-isomer according to a conventional method. Compound
[I] or its salt is well absorbed from the digestive tract, and after absorption, the ester moiety of the 4-carboxyl group is hydrolyzed immediately by an in vivo enzyme to give a non-ester form of compound [I], that is, the cephemcarboxylic acid. Is converted to. Compound [I] or a salt thereof is a valuable antibiotic showing excellent antibacterial activity against Gram-positive and Gram-negative bacteria including clinical isolates, and is an infectious disease of humans and livestock caused by various bacteria. It is safely used as an antibacterial agent for treating and preventing. That is, the compound [I] or a salt thereof is used as a therapeutic agent for bacterial infections, for example, respiratory infections in humans and other mammals,
It can be used for the treatment and prevention of urinary tract infection, purulent disease, biliary tract infection, intestinal infection, obstetrics and gynecology infection, otolaryngology infection, surgical infection and the like.

The compound [I] of the present invention or a salt thereof is orally administered, and a pharmaceutically acceptable excipient known per se (eg starch, lactose, calcium carbonate, calcium phosphate, etc.), a binder (eg starch, arabic gum). , Carboxymethyl cellulose, hydroxypropyl cellulose,
(Crystalline cellulose etc.), lubricants (eg magnesium stearate, talc etc.), disintegrating agents (eg carboxymethyl cellulose calcium, talc etc.) and the like are blended, and capsules, powders, fine granules, granules, It can be a tablet or the like. Further, about 1 to 5 times mol of a solid organic acid (for example, citric acid, malic acid, tartaric acid, succinic acid, ascorbic acid, mandelic acid, etc.) is mixed with the compound [I] or a salt thereof, and granules are prepared by a conventional method. Can be manufactured. The granules can be made into capsules, tablets and the like by a known method. The daily oral dose of Compound [I] or a salt thereof against bacterial infection varies depending on the condition and weight of the patient, but the active ingredient (Compound [I]
Or a salt thereof) about 0.5 mg to 100 mg, preferably 1 mg to
It is 20 mg. This amount is administered once a day or divided into 2 to 3 times, preferably once a day or divided into 2 times. Compound [I] or a salt thereof can be produced by the following method.

Manufacturing method 1 Compound [I] or a salt thereof is

[Chemical 7] And a salt thereof, and a formula:

[Chemical 8] [In the formula, X represents a leaving group, and R ¹ and R ² have the same meanings as described above.]
It is obtained by reacting with a compound represented by Examples of the leaving group represented by X in the above formula [III] include halogen such as chlorine atom, bromine atom and iodine atom, and aryl having 6 to 10 carbon atoms such as phenylsulfonyloxy group and p-toluenesulfonyloxy group. A sulfonyloxy group, for example, an alkylsulfonyloxy group having 1 to 6 carbon atoms such as methylsulfonyloxy group is used. Of these, an iodine atom is particularly preferable as X. Further, since the compound [III] has an asymmetric carbon atom, it is used for the reaction as an R-isomer or an S-isomer, or a mixture thereof by performing optical resolution by means known per se.

On the other hand, the starting compound [II] is combined with an alkali metal such as sodium and potassium, an alkaline earth metal such as calcium and magnesium, and a base such as organic amines such as triethylamine, trimethylamine, pyridine, collidine and lutidine. The salt may be used in the reaction. This reaction is usually carried out in a solvent inert to the reaction. The inert solvent is not particularly limited as long as it does not interfere with the reaction, but suitable solvents include, for example, N, N-
Dimethylformamide (hereinafter abbreviated as "DMF"), N, N
-Amides such as dimethylacetamide (hereinafter abbreviated as "DMA"), halogenated hydrocarbons such as dichloromethane and chloroform, dioxane, tetrahydrofuran (hereinafter "T")
Ethers such as HF ", ketones such as acetone and methyl ethyl ketone, nitriles such as acetonitrile, sulfoxides such as dimethyl sulfoxide (hereinafter abbreviated as" DMSO "), sulfolane, and liquefied anhydrous sulfurous acid are used.

The compound [III] is preferably used in a 1- to 5-fold molar quantity versus the compound [II] or a salt thereof. The reaction temperature will differ depending on differences in various conditions such as the type of raw material compound and solvent, but is usually -30 ° C to 60 ° C, preferably -2.
It is 0 ° C to 30 ° C. The reaction time varies depending on differences in various conditions such as the raw material compound, the type of solvent and the reaction temperature,
It is usually 1 minute to 24 hours, preferably 5 minutes to 5 hours. The starting compound [II] used in this reaction is Japanese Patent Publication No. 60-
It can be synthesized by the method described in 11713 or a method analogous thereto. The starting compound [III] can be prepared by known methods (for example, JP-A-59-225192 and JP-A-60-2
18394, JP-A-60-239490) or a method analogous thereto.

Manufacturing method 2 The compound [I] or a salt thereof has the formula:

[Chemical 9] [The symbols in the formula have the same meanings as defined above] and the cephem compound [IV] or a salt thereof and the formula:

[Chemical 10] Wherein the protecting group of R ³ is a hydrogen atom or an amino group, R ⁴
Represents a hydrogen atom or a hydroxyl-protecting group] or a salt thereof or a reactive derivative of the carboxyl group thereof, and further removes the protecting group if necessary.

In the formula [V], as the protecting group for the amino group represented by R ³ , those used in the field of β-lactams and peptides can be appropriately adopted, among which formyl, chloroacetyl, Tertiary butoxycarbonyl, benzyloxycarbonyl, p-methoxybenzyloxycarbonyl, p-nitrobenzyloxycarbonyl,
2-trimethylsilylethoxycarbonyl, 2,2,2-
Trichloroethoxycarbonyl, trityl and the like are preferable. Of these, chloroacetyl, tertiary butoxycarbonyl, trityl and the like are particularly preferable. Examples of the hydroxyl-protecting group represented by R ⁴ include chloroacetyl, benzyl, p-nitrobenzyl, methylthiomethyl, methoxymethyl, trimethylsilyl, tert-butyldimethylsilyl, 2-tetrahydropyranyl, 4-methoxy-4-. Tetrahydropyranyl, trityl and the like are used. Among them, 2-tetrahydropyranyl, 4-methoxy-4-tetrahydropyranyl, trityl and the like are particularly preferable.

As the salt of the compound [IV], for example, a salt with an acid similar to the salt of the compound [I] is used. As the salt of the compound [V], the same salt as described in the above [II] is used.

Examples of the reactive derivative at the carboxyl group of the compound [V] include acid halides, acid anhydrides, active amides, active esters, which can be produced by a conventional method.
An active thioester or the like is used, and the reactive derivative is specifically described as follows. 1) Acid halide: For example, acid chloride, acid bromide, etc. are used. 2) Acid anhydride: For example, a mono-lower alkyl carbonic acid mixed anhydride or the like is used. 3) Active amides such as pyrazole, imidazole, 4-
Amides with substituted imidazoles, dimethylpyrazoles, benzotriazoles, etc. are used. 4) Active ester: for example, methoxymethyl ester, benzotriazole ester, 4-nitrophenyl ester,
In addition to esters such as 2,4-dinitrophenyl ester, trichlorophenyl ester and pentachlorophenyl ester, esters with 1-hydroxy-1H-2-pyridone, N-hydroxysuccinimide, N-hydroxyphthalimide and the like are used. 5) Active thioesters such as 2-pyridylthiol, 2
-A thioester or the like with a heterocyclic thiol such as benzothiazolylthiol is used. In this reaction, the compound [V] or its salt or its reactive derivative at the carboxyl group is used in an amount of 1 mol or more, preferably about 1 to 4 mol, per 1 mol of the compound [IV] or its salt. This reaction is usually carried out in a solvent. Examples of the solvent include water, ketones such as acetone, THF,
Ethers such as dioxane, nitriles such as acetonitrile, halogenated hydrocarbons such as dichloromethane, chloroform, 1,2-dichloroethane, esters such as ethyl acetate, amides such as DMF and DMA are used. One kind may be used alone, or two or more kinds may be mixed and used at an appropriate ratio.

When the compound [V] is used in the free state or when it is used as a salt thereof, it is preferable to carry out the reaction in the presence of a condensing agent. Examples of the condensing agent include 1,3-dicyclohexylcarbodiimide, 1-cyclohexyl-3-morpholinoethylcarbodiimide, 1-cyclohexyl-3
-(4-Diethylaminocyclohexyl) carbodiimide, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide and the like are used. Also, for example, alkali metal carbonates such as sodium carbonate, potassium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, etc., such as triethylamine,
Carrying out the reaction in the presence of a base such as tertiary amines such as tributylamine, N-methylmorpholine and N-methylpiperidine, for example, aromatic amines such as pyridine, picoline, lutidine, collidine and N, N-dimethylaniline. You can also These bases have the effect of accelerating the reaction, neutralizing the acid produced in the reaction, or facilitating the dissolution of the raw materials, and are generally used in an amount of about 0.01 to 5 relative to compound [V] or its salt. Double moles, preferably about 0.1 to 2 moles, are used. The reaction temperature varies depending on the conditions such as the starting compound and the type of solvent, but it is from -50 ° C to 100
C, preferably -20 to 50 ° C. The reaction time varies depending on various conditions such as the raw material compound, the type of solvent and the reaction temperature, but it is 1 minute to 24 hours, preferably 5 minutes to 1
It's 0 hours. The starting compound [IV] used in this reaction is
For example, it can be synthesized according to the method described in JP-A-60-239490. In addition, the raw material compound [V]
Can be synthesized according to, for example, the method described in JP-A-62-181248.

Manufacturing method 3 The compound [I] or a salt thereof has the formula:

[Chemical 11] [Wherein Y is a halogen atom and other symbols have the same meanings as defined above] and thiourea are reacted with each other in an inert solvent. Examples of the halogen atom represented by Y include a chlorine atom, a bromine atom,
An iodine atom or the like is used, and preferably a chlorine atom,
A bromine atom or the like is used. The cyclization of compound [VI] with thiourea is a method known per se (for example, Japanese Patent Publication No. 60-117).
13). The reaction temperature is -20 ° C to 50 ° C, preferably 0 ° C to 30 ° C, although it varies depending on various conditions such as the kind of the raw material compound and the solvent. The reaction time is 5 minutes to 24 hours, preferably 10 minutes to 5 hours, varying depending on various conditions such as the raw material compound, the type of solvent and the reaction temperature. The reaction is preferably carried out in an inert solvent, and such an inert solvent is not particularly limited as long as it does not interfere with the reaction, but amides, ketones, acetonitrile and the like as described in the above Production Method 2 can be used. preferable. The starting compound [VI] can be obtained by a method known per se (for example, the method described in JP-B-60-11713).
When diketene is reacted with halogen (particularly preferably chlorine or bromine) according to the above and the resulting product is reacted with compound [IV] or a salt thereof, the formula:

[Chemical 12] A compound represented by the formula [wherein the symbols have the same meaning as defined above] is obtained, and then the compound [VI] is obtained by nitrosating this compound. When a protective group is contained in the reaction products of the above Production Methods 1 to 3, the compound [I] or a salt thereof can be obtained by removing the protective group by a conventional method, if necessary. The target product [I] or a salt thereof thus obtained can be isolated and purified by known means, for example, solvent extraction, liquid conversion, phase transfer, salting out, crystallization, recrystallization, chromatography and the like. Production method 1 above
~ 3, the compound [I] (syn [Z] -form) or a salt thereof may be obtained as a mixture with its anti- [E] -isomer. The desired syn isomer (i.e. compound
For separating [I] or a salt thereof, a method known per se or a method analogous thereto is applied. As those methods, for example, a fractionation method utilizing a difference in solubility and crystallinity, a separation method by chromatography and the like are used.

[0018]

The compound [I] or a salt thereof obtained by the present invention has excellent properties as an oral cephem compound. As a specific example thereof, the therapeutic effect on intraperitoneal infection in mice by oral administration and oral administration to mice. The urinary recovery rate and blood concentration sustaining effect of the cephemcarboxylic acid upon administration are described below in comparison with a control compound. (1) Therapeutic effect on mouse intraperitoneal infection Animal: Slc: ICR, 4-week-old male mouse (body weight 20 to 22 g) was used. Creation of experimental infection (infected mouse): Staphylococcus aureus
aureus) 308A-1 or Escherichia coli (Esch
erichia coli) 0-111 was cultured in Brain Heart Infusion broth (Difco) at 37 ° C. for 20 hours, then 8%
2 × 10 ⁸ colony forming units (Colony Forming Unit) were added to each mucin solution (manufactured by Difco).
s, hereinafter abbreviated as “CFU”) / ml and 2 × 10 ⁵ CFU / ml
Each suspension was intraperitoneally administered at 0.5 ml per mouse. Treatment method: Staphylococcus was prepared by dissolving 25 mg of the test compound and each control compound in 0.5 ml of DMSO and then diluting with distilled water.
In case of Aureus infection 2.5mg / ml to 0.156m
g / ml 0.15 in case of Escherichia coli infection
Two-fold serial dilutions of each compound were prepared in the concentration range of 6 mg / ml to 0.01 mg / ml. Immediately after infection with each dilution 1
A group of 5 infected mice was orally administered once intragastrically with 0.2 ml per mouse using a mouse probe. Efficacy evaluation: Survival of mice was observed for 5 days, the survival rate at each dose was calculated, and Reed and Munch (Reed
The ED ₅₀ (mg / kg) value was calculated by the and Muench method. The ED ₅₀ value of each compound was expressed as a value converted to the cephemcarboxylic acid. The results are shown in the table below.

[Table 1]

[Table 2]

[Table 3]

This test shows that the compound [I] has excellent antibacterial activity. (2) Urinary recovery rate in mice Test animal: Slc: ICR, 4-week-old male mice (body weight 20 to 22 g) were used. Dose of drug: 10 mg of test compound and each control compound were dissolved in 0.5 ml of DMSO and then 5
1 with 0% (v / v) polyethylene glycol-200 aqueous solution
It was diluted to 0 times (volume). Each diluted solution was added to 5 healthy mice per group using a mouse probe for 0.1 g per 10 g of body weight.
It was orally administered once per ml into the stomach. Sample collection: After drug administration, place in individual metabolic cage,
Urine was collected between 0 and 24 hours. Measurement of drug concentration: The concentration of the cephemcarboxylic acid in urine was measured by Escherichia coli NIHJ and Proteus.
Let Gerry (Proteus rettgeri) ATCC 9250
Was measured by the agar well method using S. The results are shown below.

[Table 4]

[Table 5] This test shows that the compound [I] has a higher urinary recovery rate as compared with the control compound. (3) Blood concentration test animal in mice: Slc: ICR, 4-week-old male mice (body weight 20 to 22 g) were used. Dose of drug: 10 mg of the test compound and each control compound were dissolved in 0.5 ml of DMSO and then diluted 10 times (volume ratio) with 50% (v / v) polyethylene glycol-200 aqueous solution. Each diluted solution was orally administered to 5 healthy mice per group once intragastrically with 0.1 ml per 10 g of body weight using a mouse sonde. Sample collection: Blood was collected at a predetermined time after drug administration. Measurement of drug concentration: The concentration of cephemcarboxylic acid in blood was measured by Escherichia coli NIHJ and Proteus.
It was measured by the agar well method using Rett Gerry ATCC 9250 as a test strain. The results are shown below.

[Table 6] This test shows that the administration of the compound [I] has a high concentration of the cephemcarboxylic acid in blood and lasts for a long time.

[0020]

EXAMPLES The present invention will be described in more detail with reference to the following examples. However, these are merely examples and do not limit the present invention in any way. The NMR spectra of the following examples are Gemini (G
It was measured with an emini) 200 (200 MHz) spectrometer, and all δ values are shown in ppm. The symbols in the examples have the following meanings. s: singlet d: doublet t: triplet ABq: AB type quartet dd: double doublet m: multiplet br .: wide J: coupling constant sh: shoulder

Example 1 7β- [2- (2-aminothiazol-4-yl)-(Z)
2-Hydroxyiminoacetamide] -3-[(2-methyl-1,3,4-thiadiazol-5-yl) thiomethyl]
-3-Cephem-4-carboxylic acid 1- (isopropoxycarbonyloxy) ethyl ester 7β- [2- (2-aminothiazol-4-yl)-(Z)
2-Hydroxyiminoacetamide] -3-[(2-methyl-1,3,4-thiadiazol-5-yl) thiomethyl]
-3-Cephem-4-carboxylate sodium (0.2g)
Was dissolved in DMA (3.5 ml), and 1- (isopropoxycarbonyloxy) ethyl iodide (0.3 g) was added with stirring under ice-cooling. After stirring at the same temperature for 30 minutes, ice water was added to the reaction solution, which was then extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was dissolved in acetone (3 ml), and isopropyl ether (30 ml) was added with stirring at room temperature (20 ° C.). The precipitate was collected by filtration, washed with isopropyl ether, and dried to give the title compound as a pale-yellow powder of a diastereomeric mixture of two types (about 1: 1).
mg was obtained. IR (KBr) cm ^-1 : 3325, 3200, 2980, 1780, 1755, 167
0, 1610, 1530 ¹ H-NMR (DMSO-d ₆ ) δ: 1.20 to 1.25 (6H, m), 1.5
0 and 1.53 (3H, each d, J = 5Hz), 2.68 and 2.69 (3H, each
s), 3.71 (2H, ABq, J = 18Hz), 4.34 and 4.36 (2H,
ABq, J = 14Hz), 4.71 to 4.86 (1H, m), 5.16 and 5.19 (1H, d, J = 5Hz each), 5.79 to 5.88 (1H, m), 6.66 (1)
H, s), 6.77 to 6.92 (1H, m), 7.25 (2H, brs), 9.48 and 9.49
(1H, each d, J = 8Hz)

Example 2 7β- [2- (2-aminothiazol-4-yl)-(Z)
2-Hydroxyiminoacetamide] -3-[(2-methyl-1,3,4-thiadiazol-5-yl) thiomethyl]
-3-Cephem-4-carboxylic acid 1- (isopropoxycarbonyloxy) ethyl ester hydrochloride The compound (100 mg) obtained in Example 1 was converted into ethyl acetate (1
5 ml) and 0.4N hydrochloric acid ethyl acetate solution (0.5 ml) was added with stirring under ice cooling. The precipitated powder was collected by filtration, washed with ethyl acetate, and dried under reduced pressure to give the title compound as 2
78 mg were obtained as a pale yellow powder of a diastereomeric mixture of seeds (ca. 1: 1). IR (KBr) cm ^-1 : 2980, 1780, 1750, 1670, 1620, 152
0 ¹ H-NMR (DMSO-d ₆ ) δ: 1.22-1.26 (6H, m), 1.5
1 and 1.53 (3H, d, J = 5Hz each), 2.69 (3H, s), 3.59−3.8
9 (2H, m), 4.34 and 4.40 (2H, ABq, J = 13Hz, respectively), 4.72-
4.87 (1H, m), 5.21 and 5.23 (1H, d, J = 5Hz), 5.79−
5.89 (1H, m), 6.81 and 6.88 (1H, q, J = 5Hz each), 6.85 (1
H, s), 9.72 and 9.73 (1H, d, J = 8Hz each)

Example 3 7β- [2- (2-aminothiazol-4-yl)-(Z)
2-Hydroxyiminoacetamide] -3-[(2-methyl-1,3,4-thiadiazol-5-yl) thiomethyl]
-3-Cephem-4-carboxylic acid 1- (cyclopentyloxycarbonyloxy) ethyl ester Example 1 using 1- (cyclopentyloxycarbonyloxy) ethyl iodide instead of 1- (isopropoxycarbonyloxy) ethyl iodide When reacted in the same manner as above, the title compound is a mixture of two diastereomers.
(Approx. 1: 1). IR (KBr) cm ^-1 : 3325, 3190, 2970, 2875, 1780, 175
5, 1675, 1610, 1530 ¹ H-NMR (DMSO-d ₆ ) δ: 1.4-1.9 (11H, m), 2.69
(3H, s), 3.55−4.60 (4H, m), 4.96−5.07 (1H, m), 5.17 and 5.19 (1H, d, J = 5Hz), 5.80−5.90 (1H, m), 6.66 (1
H, s), 6.80 and 6.88 (1H, q, J = 5Hz, respectively), 7.21 (2H, br
s), 9.48 and 9.49 (1H, d, J = 8Hz, respectively)

Example 4 7β- [2- (2-aminothiazol-4-yl)-(Z)
2-Hydroxyiminoacetamide] -3-[(2-methyl-1,3,4-thiadiazol-5-yl) thiomethyl]
-3-Cephem-4-carboxylic acid 1- (cyclopentyloxycarbonyloxy) ethyl ester hydrochloride The compound obtained in Example 3 was treated in the same manner as in Example 2 to give the title compound as a mixture of two diastereomers (about 1:
Obtained as 1). IR (KBr) cm ^-1 : 2970, 1785, 1750, 1675, 1620, 152
0 ¹ H-NMR (DMSO-d ₆ ) δ: 1.45-1.90 (11H, m), 2.
69 (3H, s), 3.74 and 3.75 (2H, ABq, J = 18Hz, respectively), 4.33
And 4.39 (2H, each ABq, J = 13Hz), 4.96-5.06 (1H, m),
5.78-5.88 (1H, m), 6.77-6.91 (1H, m), 6.84 (1H, s), 9.
05 (2H, brs), 9.73 (1H, d, J = 8Hz)

Example 5 7β- [2- (2-aminothiazol-4-yl)-(Z)
2-Hydroxyiminoacetamide] -3-[(2-methyl-1,3,4-thiadiazol-5-yl) thiomethyl]
-3-Cephem-4-carboxylic acid 1- (cyclobutyloxycarbonyloxy) ethyl ester hydrochloride 1- (cyclobutyloxycarbonyloxy) ethyl iodide was used in place of 1- (isopropoxycarbonyloxy) ethyl iodide Then, the title compound was obtained as a mixture of two diastereomers (about 1: 1) by reacting in the same manner as in Examples 1 and 2. IR (KBr) cm ^-1 : 2990, 1780, 1760, 1675, 1625, 152
5 ¹ H-NMR (DMSO-d ₆ ) δ: 1.5-2.4 (6H, m), 1.51
And 1.53 (3H, d, J = 5Hz each), 2.69 (3H, s), 3.74 and 3.
75 (2H, ABq, J = 18Hz), 4.33 and 4.40 (2H, ABq, J, respectively)
= 14Hz), 4.75−4.96 (1H, m), 5.20 and 5.22 (1H, d, respectively
J = 5Hz), 5.78-5.88 (1H, m), 6.75-6.91 (1H, m), 6.85
(1H, s), 9.72 and 9.73 (1H, each d, J = 8Hz)

Example 6 7β- [2- (2-aminothiazol-4-yl)-(Z)
2-Hydroxyiminoacetamide] -3-[(2-methyl-1,3,4-thiadiazol-5-yl) thiomethyl]
-3-Cephem-4-carboxylic acid 1- (1-ethylpropoxycarbonyloxy) ethyl ester hydrochloride 1- (1-ethylpropoxycarbonyloxy) ethyliodide instead of 1- (isopropoxycarbonyloxy) ethyliodide Was reacted in the same manner as in Examples 1 and 2 to obtain the title compound as a mixture of two diastereomers (about 1: 1). IR (KBr) cm ^-1 : 2975, 1780, 1750, 1675, 1620, 152
5 ¹ H-NMR (DMSO-d ₆ ) δ: 0.78-0.89 (6H, m), 1.4
5-1.65 (7H, m), 2.69 (3H, s), 3.73 and 3.75 (2H, each AB
q, J = 18Hz), 4.14-4.60 (3H, m), 5.21 and 5.23 (1H, each
d, J = 5Hz), 5.78-5.88 (1H, m), 6.80 and 6.88 (1H, each
q, J = 6Hz), 6.84 and 6.85 (1H, s each), 9.72 and 9.74 (1
H, each d, J = 8Hz)

Reference Example 1 In the same manner as in Example 1 except that 1- (cyclohexyloxycarbonyloxy) ethyl iodide was used instead of 1- (isopropoxycarbonyloxy) ethyl iodide, 7β- [2- (2- Aminothiazole-4-
Il)-(Z) -2-hydroxyiminoacetamide] -3-
[(2-methyl-1,3,4-thiadiazol-5-yl)
Thiomethyl] -3-cephem-4-carboxylic acid 1- (cyclohexyloxycarbonyloxy) ethyl ester was obtained as a mixture of two diastereomers (about 1: 1). IR (KBr) cm ^-1 : 3325, 2930, 2860, 1780, 1755, 167
5, 1620, 1520 ¹ H-NMR (DMSO-d ₆ ) δ: 1.10-1.94 (13H, m), 2.
69 (3H, s), 4.13-4.65 (3H, m), 5.17 and 5.20 (1H, each
d, J = 5Hz), 5.79-5.88 (1H, m), 6.70 and 6.71 (1H, each
s), 6.81 and 6.88 (1H, q, J = 6Hz, respectively), 7.2-7.7 (2H, d
r), 9.54 and 9.55 (1H, d, J = 8Hz each)

[0028]

INDUSTRIAL APPLICABILITY The compound [I] of the present invention or a salt thereof is deesterified in the body by oral administration to give a high blood concentration of the cephemcarboxylic acid, and therefore, the treatment of infectious diseases caused by bacteria of humans and mammals. For example, it is effective in treating respiratory infections caused by bacterial inflammation, urinary tract infections and the like.

Claims (5)

[Claims] 1. The formula: [Wherein R ¹ represents an alkyl group having 1 to 3 carbon atoms, and R ² represents an alkyl group having 3 to 5 carbon atoms or a cycloalkyl group having 3 to 5 carbon atoms branched at the α-position]. The represented cephem compound or a salt thereof. 2. The compound according to claim 1, wherein R ² is isopropyl, or a salt thereof. 3. 7β- [2- (2-aminothiazole-4-
Il)-(Z) -2-hydroxyiminoacetamide] -3-
[(2-methyl-1,3,4-thiadiazol-5-yl)
Thiomethyl] -3-cephem-4-carboxylic acid 1- (isopropoxycarbonyloxy) ethyl ester or a salt thereof. 4. 7β- [2- (2-aminothiazole-4-
Il)-(Z) -2-hydroxyiminoacetamide] -3-
[(2-methyl-1,3,4-thiadiazol-5-yl)
Thiomethyl] -3-cephem-4-carboxylic acid 1- (cyclopentyloxycarbonyloxy) ethyl ester or a salt thereof. 5. The formula: [Wherein R ¹ represents an alkyl group having 1 to 3 carbon atoms, and R ² represents an alkyl group having 3 to 5 carbon atoms or a cycloalkyl group having 3 to 5 carbon atoms branched at the α-position]. A therapeutic agent for bacterial infection for oral administration, which comprises the represented cephem compound or a salt thereof.