JPH0454675B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention is based on the general formula The present invention relates to a cephalosporin derivative represented by [wherein R represents a 2-methylbutyl group or a 1-ethylpropyl group]. 7β-[2-(2-aminothiazol-4-yl)
Acetamide]-3-[[[1-(2-dimethylaminoethyl)-1H-tetrazol-5-yl]thio]methyl]cef-3-em-4-carboxylic acid (Japanese Patent Publication No. 55-12913) is an oral It has been proposed to change the carboxyl group at the 4-position to pivaloyloxymethyl ester in order to improve absorption in the body upon administration (Japanese Unexamined Patent Publications No. 53-21192, No. 54-67036). As a result of various studies on compounds with excellent absorption, stability, etc., we found the above cephalosporin derivative () (hereinafter referred to as compound ()).
is well absorbed from the gastrointestinal tract, and quickly produces the non-ester form of the compound () in the body after absorption, resulting in high blood concentrations of the non-ester form of the compound (), and is effective against Gram-positive bacteria and Gram-positive bacteria. It is useful as an orally administrable broad-spectrum antibiotic that has antibacterial activity against both negative bacteria and resistant bacteria;
They also discovered that the acid addition salt of the present compound () increases the water solubility of the ester and improves the absorption efficiency, while at the same time facilitating the stabilization, isolation operation, and formulation of the compound (), and completed the present invention. Since the compound () is basic in character, it can be made into an addition salt with an acid, for example. Preferred non-toxic acids that are usually used as acids for acid addition salts include inorganic acids such as hydrochloric acid, sulfuric acid, and phosphoric acid;
Maleic acid, acetic acid, citric acid, succinic acid, tartaric acid, malic acid, malonic acid, fumaric acid, benzoic acid,
Examples include acids known as acids that form pharmaceutically acceptable salts in the field of penicillin or cephalosporin, such as organic acids such as malderic acid, ascorbic acid, and methanesulfonic acid. Note that the aminothiazole group in compound () may exist as an iminothiazoline group, which is its tautomer. Such a compound () or a salt thereof is easily absorbed from the gastrointestinal tract, and immediately after absorption, the ester moiety of the 4-position carboxyl group is hydrolyzed by oxygen in the body and converted into a non-ester form of the compound (). Particularly preferred are compounds in which the ester residue at position 4 is pentyl, 2-methylbutyl, butyl, 1-propylbutyl, or 1-butylpentyl. The non-ester form of this compound () is a compound that has significantly superior antibacterial activity. That is, the non-ester form of compound () is suitable for Gram-positive bacteria such as Staphylococcus aureus, Gram-negative bacteria such as Escherichia coli, and Klebsiella pneumoniae.
It exhibits excellent antibacterial activity against bacteria such as Pneumoniae), Proteus vulgaris, Proteus mirabilis, and Proteus morganii. The compound () exhibits high blood concentrations upon oral administration and is effective in the treatment of infections caused by these bacteria in humans and mammals, such as bacterial inflammation, respiratory infections, and urinary tract infections. . The compound () of the present invention has low toxicity;
(LD ₅₀ 5g/Kg or more, mouse) Can be administered orally and contains known pharmaceutically acceptable excipients (e.g., starch, lactose, calcium carbonate, calcium phosphate, etc.), binders (starch, gum arabic, etc.) , carboxymethylcellulose, hydroxypropylcellulose, crystalline cellulose, etc.), a lubricant (e.g., magnesium stearate, talc, etc.), and a disintegrant (e.g., carboxymethylcalcium, talc, etc.), and prepare capsules and powders by a conventional method. , fine granules, granules, and tablets. In addition, solid organic acids (e.g. citric acid, malic acid, tartaric acid,
succinic acid, ascorbic acid, mandelic acid, etc.) to produce granules by a conventional method.
These granules can be made into capsules, tablets, etc. by known methods. The dosage for adults is 0.3 to 5 g, preferably 0.5 to 3 g, of the compound () or its salt per day, divided into 3 to 4 doses. Such compounds () can be produced by methods known per se (for example, the methods described in JP-A-51-56487 and JP-A-53-21192). For example, the non-ester form of compound () is expressed as It is produced by esterification with a compound represented by the formula [wherein R has the same meaning as above] or a reactive derivative thereof. As reactive derivatives, derivatives known per se are used, in particular those of the general formula [Wherein, R has the same meaning as above, X is a halogen atom,
For example, esterification using a compound represented by chlorine, bromine, iodine, etc. (preferably a compound in which X is iodine (), i.e., iodomethyl acylate, iodoalkyl sylate, etc.) is preferred. Non-esterified forms of compound () include acid addition salts of inorganic acids such as hydrochloric acid, sulfuric acid and nitric acid, organic acids such as oxalic acid and p-toluenesulfonic acid, or alkali metals such as sodium and potassium, e.g. It may be subjected to the reaction as a salt with an alkaline earth metal such as calcium or magnesium, or a base such as an organic amine such as triethylamine, trimethylamine, pyridine, collidine, or lutidine. The esterification reaction is usually carried out in a solvent inert to the reaction. Such solvents include amides,
Examples include ketones, nitriles and liquefied sulfites. Specifically, acetonitrile, N,N
-dimethylformamide (hereinafter abbreviated as DMF),
N,N-dimethylacetamide (hereinafter abbreviated as DMAC), hexamethylphosphorotriamide (hereinafter abbreviated as DMAC)
HMPA), dichloromethane, chloroform, dimethyl sulfoxide (DMSO), diethyl ether, dioxane, tetrahydrofuran (THF), acetone, methyl ethyl ketone, dimethoxyethane, etc. Among these, particularly preferred solvents are DMF, DMAC,
These include HMPA, acetone, acetonitrile, and liquefied anhydrous sulfite. The esterification reaction is generally carried out at a temperature of -20 to 20°C, and may be carried out without a catalyst, but a catalyst such as a phase transfer catalyst such as 18-crown-6 may also be used. When using liquefied anhydrous sulfite as a solvent, the boiling point of this solvent (−
10°C), ie -10 to -20°C. The time required for this reaction varies depending on the type of reactant and solvent, but is generally about 10 minutes to 6 hours. Furthermore, the compound () or its acid addition salt,
For example, general formula [In the formula, A represents an amino group or an acylamino group other than 2-(2-aminothiazol-4-yl)acetylamino group] and compound () in the same manner as the above esterification reaction. When A is an acylamino group, the resulting ester is further reacted with phosphorus pentachloride and then with an alcohol (e.g., methanol, ethanol, propanol, isopropanol, n-butanol, etc.).
(e.g. Journal of Medicinal Chemistry)
Volume 18, page 992 (1975), West German Published Patent Application No.
2460331 and West German Published Patent Application No. 2460332). [Symbols in the formula have the same meanings as above] A compound represented by the formula It can be produced by acylation with a compound represented by 2-(2-aminothiazol-4-yl)acetic acid or a reactive derivative thereof. In the above general formula [], when A is an acylamino group, any acyl group known per se in the field of cephalosporin compounds can be used as this acyl group. Preferred acylamino groups include, for example, acetylamino, benzoylamino, phenylacetylamino, thienylacetylamino, phenyloxyacetylamino, 5-
An amino-5-carboxyvalerylamide group (the amino group may be protected with, for example, phthaloyl), etc. are used. When A is an amino group or an amino group-substituted acylamino group, this amino group is preferably protected during the reaction, and the protecting group for this amino group is a known protecting group for amino groups, such as t-butoxycarbonyl. , carboxybenzyloxy, 2-hydroxy-1-naphthocarbonyl, trichloroethoxycarbonyl, 2-ethoxytocarbonyl-1-methylvinyl, and 2-methoxycarbonyl-1-methylvinyl groups. The deacylation reaction of the ester compound obtained by reacting the compound () (when A is an acylamino group) with the compound () can be carried out by a method known per se, for example, by adding phosphorus pentachloride and alcohol (e.g. methanol, alcohol) to the raw material ester. etc.). Normal raw material ester compound 1
About 2 to 5 times the mole of phosphorus pentachloride and about 10 to 40 times the mole of alcohol are used. The reaction is usually carried out in an inert solvent such as a halogenated hydrocarbon such as dichloromethane or chloroform. Further, to accelerate the reaction, a tertiary amine such as triethylamine, pyridine, N,N-dimethylaniline, etc. may be added. The reaction temperature is about -40 to -20°C. A reaction time of about 1 hour is sufficient. When the compound () thus obtained is reacted with the compound () to produce the compound () or its acid addition salt, the amino group of the compound () is
It is preferably protected, and the same protecting group as that for the amino group of compound () is used as this protecting group. In this reaction, the compound () may be used as its reactive derivative, for example, the corresponding acid halide, acid anhydride, mixed acid anhydride, activated amide, activated ester, etc. may be used in the acylation reaction as a reactive derivative thereof. Ru. Among these, mixed acid anhydrides, activated esters, etc. are preferred. Examples of the activated ester include p-nitrophenyl ester, 2,4-dinitrophenyl ester, pentachlorophenyl ester, and N-hydroxyphthalimide ester. Examples of mixed acid anhydrides include mixed acid anhydrides with carbonic acid monoesters such as carbonic acid monomethyl ester and carbonic acid monoisobutyl ester, and lower (carbon number 2 to 5) alkanes that may be substituted with halogen such as pivalic acid and trichloroacetic acid. Mixed acid anhydrides with acids are used. When the compound () is used in the form of a free acid or a salt, a suitable condensing agent is used. Suitable condensing agents include, for example, N,N'-disubstituted carbodiimides such as N,N'-dicyclohexylcarbodiimide, N,N'-carbonylimidazole, N,
Azolide compounds such as N'-thionyldiimidazole, N-ethoxycarbonyl-2-ethoxy-
Dehydrating agents such as 1,2-dihydroquinoline, phosphorus oxychloride, and alkoxyacetylene (eg, ethoxyacetylene) are used. When these condensing agents are used, the reaction is believed to proceed via reactive derivatives of carboxylic acids. This reaction can normally be carried out smoothly in a solvent. As a solvent, water, acetone, diisobutyl ketone,
THF, ethyl acetate, dioxane, acetonitrile, chloroform, dichloromethane, dichloroethylene, pyridine, dimethylaniline, DMF,
Common solvents such as DMAC, DMSO, etc. or mixtures thereof may be used as long as they do not inhibit the reaction of the present invention. The reaction temperature is not particularly limited, but it is usually carried out with cooling to room temperature. When the reaction proceeds in a deoxidizing manner, a base is allowed to coexist if necessary. Bases used here include aliphatic, aromatic or heterocyclic nitrogen bases or alkali metal carbonates or bicarbonates, such as triethylamine, N,N
-Dimethylaniline, N-ethylmorpholine, pyridine, collidine, 2,6-lutidine, sodium carbonate, potassium carbonate, potassium bicarbonate, sodium bicarbonate, and the like are frequently used. When the acylation reaction is mainly a dehydration reaction, it is preferable to exclude water from the solvent. In some cases, the process may be carried out in an inert gas such as nitrogen to avoid moisture. When the reaction product has a protecting group, the protecting group is removed by a method known per se. Furthermore, compound () or its acid addition salt can be added to compound () and diketene with a halogen (e.g. chlorine,
4 obtained by reacting equimolar amounts of bromine, iodine)
- General formula obtained by reacting with halogeno-3-oxobutyryl halide [In the formula, R has the same meaning as above, Y represents a halogen atom (e.g., chlorine, bromine, iodine atom)]] and then reacting it with thiourea to produce it. Can be done. In the reaction between compound () and thiourea, thiourea is preferably used as it is, but thiourea may be subjected to the reaction as a salt with an alkali metal such as lithium, sodium or potassium, or as an ammonium salt. The reaction is usually carried out by mixing equimolar amounts of both in a solvent, but it may be carried out in the presence of 1 to 2 equivalents of a base if necessary. As a solvent suitable for this reaction,
For example, water, methanol, ethanol, acetone, dioxane, acetonitrile, chloroform, ethylene chloride, THF, ethyl acetate, DMF,
DMAC, DMSO, etc. are used. Among these, hydrophilic solvents can also be used in combination with water. The bases used include alkali metal hydroxides such as sodium hydroxide and potassium hydroxide, alkali metal carbonates such as sodium carbonate and potassium carbonate, alkali metal hydrogen carbonates such as sodium hydrogen carbonate, and organic hydroxides such as triethylamine, trimethylamine, and pyridine. A base such as a grade amine is used.
The reaction temperature is not particularly limited, but it is usually preferable to carry out the reaction under cooling. The reaction generally proceeds rapidly10
It is usually completed within minutes, but in some cases it may take more than 30 minutes. Compound () can be easily produced by the above method or other methods known per se. Furthermore, the compound () or its acid addition salt has the general formula Compounds represented by [wherein W represents an acetoxy group or an acetoacetoxy group] and compounds ()
General formula obtained by reacting with in the same manner as the above esterification reaction It can be produced by reacting a compound represented by the formula [wherein the symbols have the same meanings as above] and 1-(2-dimethylaminoethyl)-5-mercapto-1H-tetrazole. In this reaction, the raw material 1-(2-dimethylaminoethyl-5-mercapto-1H-tetrazole is used in an approximately equimolar amount to the compound (). This reaction can be normally carried out smoothly in a solvent. Solvent Examples include water, acetone, THF, ethyl acetate,
Dioxane, acetonitrile, chloroform, dichloromethane, DMF, DMAC, DMSO, etc. are used, and when water is used, a solvent with which water is well miscible may be used. This reaction is usually carried out in the presence of a base.
Examples of the base used in this case include weak bases such as alkali metal carbonates or bicarbonates (eg, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, etc.). The amount of base used in the reaction is approximately equimolar to the starting compound 1-(2-dimethylaminoethyl)-5-mercapto-1H-tetrazole. Although the reaction temperature is not particularly limited, it is usually carried out at room temperature to 40 to 60°C. The reaction time varies depending on the type of solvent used, reaction temperature, etc., but is about 30 minutes to about 3 hours. In these reactions, if the target compound () or its acid addition salt Δ ² -isomer is present, a method known per se, such as Journal of Medicinal Chemistry, may be used as necessary. Volume 18 986
(1975), or by deriving the corresponding S-oxide form to convert it back to the ^{△ 3 -isomer} , and then reducing the compound () or a salt thereof. The compound () or its acid addition salt can be prepared by When the resulting compound () is obtained in free form, it is dissolved in an inert solvent such as dichloromethane or chloroform, and the compound () is added to this.
An acid addition salt of the target compound () can be obtained by reacting with an acid in an amount of about 1 to 10 times the molar amount. When the compound () or its acid addition salt is obtained in the form of a racemate, it can be isolated as an optically active form (D-isomer, L-isomer) by optical resolution by means known per se. The compound () or its acid addition salt thus obtained can be isolated and purified by means known per se, such as solvent extraction, liquid conversion, dissolution transfer, crystallization, recrystallization, chromatography, etc. . The compound represented by the general formula (), which is a raw material compound, is produced according to the following reaction formula. [Symbols in the formula have the same meanings as above] For example, compounds in which X is iodine in the general formula (), i.e., iodomethyl acylate, iodoalkyl acylate, etc., are acid chloride () and paraformaldehyde, paraaldehyde, or acetaldehyde. It is produced by reacting aldehydes such as () in the presence of a Lewis acid, and then reacting with sodium iodide. The first stage of the reaction is carried out in the presence of a Lewis acid catalyst such as anhydrous zinc chloride, aluminum chloride or tin chloride. This reaction proceeds by cooling to -40 to 30°C, preferably -40 to 0°C, or heating to 30 to 140°C, preferably 90 to 140°C. The reaction time varies depending on the reaction temperature, but suitable is 1 to 3 hours under cooling, and 1 to 6 hours under heating. The reaction proceeds satisfactorily even in the absence of a reaction solvent. After the first stage reaction is completed, chloromethyl acylate or chloroalkyl acylate is obtained by distilling the reaction solution or subjecting it to column treatment. By reacting this with sodium iodide, iodomethyl acylate or iodoalkyl acylate is obtained (second stage reaction).
This second-stage reaction is carried out in the presence of a general-purpose solvent such as acetone, acetonitrile, DMF, or MDSO. The reaction temperature may be room temperature or heating to about 40 to 50°C. The reaction time is 15 minutes to 6 hours, preferably 15 minutes to 2 hours. The reaction product can be isolated and purified by means known per se, such as solvent extraction, liquid conversion, dissolution, crystallization, recrystallization, chromatography, and the like. The present invention will be explained in more detail with reference to specific examples below, but the present invention is not limited to these in any way. Note that the symbols used in Reference Examples, Examples, etc. have the following meanings. s: singlet, b-s: wide singlet, d: doublet, dd: double doublet,
t: triplet, q: quartet, AB-
q: AB type quartet, m: multiplet, bp: melting point reference example 1 1-iodoethyl 3-methylvalerate (1) 50 g of 3-methylvaleric acid chloride, 18 g of paraaldehyde and a catalytic amount of anhydrous zinc chloride were mixed at 130 g of anhydrous zinc chloride.
Heat at -140°C for 4 hours. The reaction solution is subjected to vacuum distillation and a fraction with a bp of 80-100°C/32mmHg is collected. Distill under reduced pressure again, bp92-94℃/37mm
Collecting the Hg fraction yields 7 g of 1-chloroethyl 3-methylvalerate. IR (liquid film) cm ^-1 : 1765, 1750, 660 (2) Heat 100 ml of acetonitrile to 40°C and dissolve 15 g of sodium iodide. above in this solution
Add 6 g of 1-chloroethyl 3-methylvalerate obtained in (1) and stir for 30 minutes. Remove insoluble materials and concentrate under reduced pressure. A mixture of petroleum ether and 5% aqueous sodium thiosulfate solution is added to the residue, and the petroleum ether layer is separated. Further washing is performed with a 5% aqueous sodium thiosulfate solution. After drying over anhydrous magnesium sulfate and evaporating the solvent under reduced pressure, 5 g of the title compound are obtained. IR (liquid film) cm ^-1 : 1760 Reference example 2 1-iodoethyl 2-ethyl butyrate (1) 1-chloroethyl 2-ethyl butyrate 2-
25 g of ethylbutyric acid chloride and a catalytic amount of anhydrous zinc chloride are cooled to -40°C. 10 ml of acetaldehyde was added dropwise with stirring, and the temperature of the reaction solution was raised to room temperature over 2 hours. The reaction solution was subjected to silica gel column chromatography (70-230 mesh, 100 ml) and eluted with 300 ml of petroleum ether. The eluate is collected, the solvent is distilled off under reduced pressure, and the residue is subjected to vacuum distillation. bp83−85℃/35mmHg
Collecting the fractions yields 22 g of 1-chloroethyl 2-ethyl butyrate. bp83-85℃/35mmHg IR (liquid film) cm ^-1 : 1760, 670 (2) Using the compound obtained in (1) above, reference example 1.(2)
The title compound is obtained in a similar manner. IR (liquid film) cm ^-1 : 1755 Example 1 1-(3-methylpentanoyloxy)ethyl
7β-[2-(2-aminothiazol-4-yl)
Acetamide]-3-[[[1-(2-dimethylaminoethyl)-1H-tetrazol-5-yl]
thio]methyl]cef-3-em-4-carboxylate 7β-[2-(2-aminothiazol-4-yl)
Dissolve 5.0 g of sodium salt of cef-3-em-4-carboxylic acid in 50 ml of dimethylformamide. and cool to -5°C. While stirring, add 5 g of 1-iodoethyl 3-methylvalerate all at once,
Stir for a minute. Mix the reaction solution with 300ml of ethyl acetate and ice water.
Pour into 200ml of the mixture and separate the organic layer. The aqueous layer is extracted with 200 ml of ethyl acetate, and the organic layers are combined and washed three times with 150 ml of ice water and three times with saturated brine. After drying over anhydrous magnesium sulfate, the solvent is distilled off under reduced pressure. Add isopropyl ether to the residue and take the resulting powder. After washing with isopropyl ether and drying, the title compound is obtained.
2.5g is obtained. IR (nujiyor) cm ^-1 : 1780, 1750, 1710,
1670, 1640 NMR ( _d6 -DMSO) δ: 0.81 (t, J=6Hz,
3H), 0.87 (d, J=6Hz, 3H), 1.0−1.4 (m,
2H), 1.47−1.51 (two α, J=6Hz, 3H),
1.65−1.95 (m, 1H), 2.17 (s, 6H), 2.23 (t,
J = 6Hz, 2H) 2.67 (t, J = 6Hz, 2H),
3.37 (s, 2H), 3.57 and 3.84 (Abq, J=18Hz,
2H), 4.14 and 4.36 (ABq, J=13.5Hz, 2H),
4.37 (t, J=6Hz, 2H), 5.00−5.17 (m,
1H), 5.6-5.9 (m, 1H), 6.23 (s, 1H,) 6.68
-7.12 (m, 3H), 8.85 (d, J = 9Hz, 1H) Elemental analysis value C ₂₆ H ₃₇ N ₉ O ₆ S ₃ Calculated value (%): C, 46.76; H, 5.58; N, 18.88 Actual measurement Value (%): C, 46.65; H, 5.46; N, 18.96 Example 2 1-(3-methylpentanoyloxy)ethyl
7β-[2-(2-aminothiazol-4-yl)
Acetamide]-3-[[[1-(2-dimethylaminoethyl)-1H-tetrazol-5-yl]
thio]methyl]cef-3-em-4-carboxylate dihydrochloride 1 g of the compound obtained in Example 1 was added to 20 ml of ethyl acetate.
Dissolve in ml. Add ethereal hydrochloric acid solution to this and take the resulting powder. After washing with ether and drying, 0.9 g of the title compound is obtained. IR (nujiol) cm ^-1 : 1785, 1780, 1680 NMR (d ₆ -DMSO) δ: 1.17 (t, J = 6 Hz,
3H), 1.20 (d, J = 6Hz, 3H), 1.85 (d, J
=6Hz, 3H), 1.97-2.41 (m, 1H), 2.58 (t,
J = 6Hz, 2H, ) 3.38 (s, 6H), 4.12 (b-s,
2H), 4.70 (b-s, 2H), 5.24 (t, J=6Hz,
2H), 5.47 (d, J = 4.5Hz, 1H), 5.98 (d, J
=4.5Hz, 1H), 7.02(s, 1H), 7.21(q, J=
6.0Hz, 1H) Elemental analysis value C ₂₆ H ₃₇ N ₉ O ₆ S ₃・2HCl・2H ₂ O Calculated value (%): C, 40.25; H, 5.60; N, 16.25 Actual value (%): C, 40.31; H, 5.54; N, 16.02 Example 3 1-(2-ethylbutyryloxy)ethyl 7β-
[2-(2-aminothiazol-4-yl)acetamide]-3-[[[1-(2-dimethylaminoethyl)-1H-tetrazol-5-yl]thio]methyl]cef-3-em-4 -Carboxylate The title compound is obtained in the same manner as in Example 1 using 1-iodoethyl 2-ethyl butyrate. IR (nujiol) cm ^-1 : 1780, 1750, 1675 NMR (d ₆ -DMSO) δ: 0.84 (t, J = 7Hz,
6H), 1.2-1.75 (m, 7H), 2.21 (s, 6H),
2.69 (t, J=6Hz, 2H), 3.83 and 3.58 (ABq,
J = 18Hz, 2H), 4.00 and 4.17 (ABq, J = 13.5
Hz, 2H), 4.37 (t, J=6Hz, 2H), 5.08 (d,
J = 4.5Hz, 1H), 5.63-5.83 (m, 1H), 6.25
(s, 1H), 6.63−7.17 (m, 3H), 8.89 (d, J
= 8.9Hz, 1H) Elemental analysis value C ₂₆ H ₃₇ N ₉ O ₆ S ₃ Calculated value (%): C, 46.75; H, 5.59; N, 18.88 Actual value (%): C, 46.76; H, 5.49 ;N, 19.04 Example 4 1-(2-ethylbutyryloxy)ethyl 7β-
[2-(2-aminothiazol-4-yl)acetamide]-3-[[[1-(2-dimethylaminoethyl)-1H-tetrazol-5-yl]thio]methyl]cef-3-em-4 -Carboxylate dihydrochloride The compound obtained in Example 3 is treated in the same manner as in Example 2 to obtain the title compound. IR (nujiol) cm ^-1 : 1785, 1755, 1675 NMR (D ₂ O) δ: 1.05 (t, J = 7Hz, 6H), 1.55
-2.00 (m, 7H), 2.55 (t, J=6Hz, 2H),
3.27 (s, 6H), 3.85-4.25 (m, 5H), 4.52 (b
-s, 2H), 5.15 (t, J=6Hz, 2H), 5.38
(d, J=4.5Hz, 1H), 5.88 (d, J=4.5Hz,
1H), 6.93 (s, 1H), 7.17 (q, J=6Hz,
1H) Elemental analysis value C ₂₆ H ₃₇ N ₉ O ₆ S ₃・2HCl・1.5H ₂ O Calculated value (%): C, 40.67; H, 5.51; N,
16.24; Cl, 9.24 Actual value (%): C, 40.70; H, 5.89; N,
16.17; Cl, 9.74 Experimental example (bioavailability test) 1-pivaloyloxymethyl 7β-[2-
(2-aminothiazol-4-yl)acetamide]-3-[[[1-(2-dimethylaminoethyl)-
1H-tetrazol-5-yl]thio]methyl]
Cef-3-M-4-carboxylate (abbreviated as compound A) was administered to each mouse at 100%
mg/Kg (body weight) (as the non-ester form of compound ()) in an aqueous solution of 2.5 times mol of tartaric acid (the amount of water is
Dissolve in 10ml/Kg (body weight) and administer orally. At 0.25, 0.5, 1.0, and 2.0 hours after administration, the concentration of the non-ester form of compound () in the plasma of mice was measured using the Cupp method (Proteus mirabilis (P.
mirabilis) using Eb ₃₁₃ ), 0-2
Calculate the area under the plasma concentration curve (AUC) over time. * Non-ester form of compound () 100 as a control
mg/Kg (body weight) is subcutaneously administered to mice as an aqueous solution (the amount of water is 10 ml/Kg (body weight)), and the AUC value is calculated in the same manner as above. The area under the blood concentration curve (AUC) is calculated by the trapezoidal method, and the bioavailability is determined by the following formula. Bioavailability (%) = AUC (oral administration) / AUC (subcutaneous administration) x 100 The results are shown in Table 1. *Calculated from the average value of 4 mice.

【table】

[Table] ** Subcutaneous administration

Claims (1)

[Claims] 1. General formula A cephalosporin derivative represented by the formula [wherein R represents a 2-methylbutyl group or a 1-ethylpropyl group] or a salt thereof.