JPH06788B2 - Antibacterial agent - Google Patents

Description

The present invention relates to a cephalosporin derivative suitable for oral administration, more specifically a general formula In the formula, R ¹ represents a hydrogen atom or a C _{1 to} C ₄ alkyl group, and R ² represents a C _{1 to} C ₈ alkyl group, a C _{3 to} C ₆ cycloalkyl group or a C _{3 to} C ₆ cycloalkylmethyl group. The present invention relates to an antibacterial agent suitable for oral administration, which comprises the compound represented by

The following formula The compound represented by or a pharmaceutically acceptable salt thereof,
Gram-positive bacteria such as Staphylococcus aureus and Streptococcus pneumoniae; Escherichia coli, Klebsiella pneumoniae, Klebsiella pneumoniae
teus vulgaris) Serratia marcescens
marcescens), Enterobacter cloacae (Entero)
It is known to exhibit excellent antibacterial activity against a wide range of bacteria including Gram-negative bacteria such as bacter cloacae) (JP-A-57-59895).

In particular, the compound of the above formula (IV) is a synthetic penicillin such as methicillin (dimethoxyphenylpenicillin) which is a synthetic penicillin for Staphylococcus aureus and resistant staphylococcus which is not so effective as a conventional so-called third-generation cephalosporin derivative. β-
Not only does it have excellent antibacterial activity against Gram-positive bacteria such as Staphylococcus aureus that is resistant to lactam-based antibacterial agents (see Fig. 1), but also, for example, Staphylococcus aureus. It has a strong bactericidal action against bacillus, Klebsiella pneumoniae, Escherichia coli, etc. at a low concentration and can suppress re-growth.
(See the figure), and has excellent features such as stability against β-lactamase, and has recently attracted attention as an antibiotic for the next generation.

On the other hand, most of the currently used antibiotics are injections. When injection is administered to patients with various infectious diseases,
It is required to be administered under the supervision of a doctor,
There is no problem when administered to inpatients, but in the case of outpatients, there is the inconvenience of having to go to the hospital each time injections are administered. There are problems such as onset of cerebral shortening and the like, and recently, development of orally-administered antibiotics, which are easy to handle and safe, has been actively conducted. In particular, the formula (I
There is a great need for the development of an oral preparation of a broad spectrum antibacterial spectrum antibiotic having excellent properties which have never been seen, such as the compound represented by I). However, the above formula (I
Like the conventional penicillin-based and cephasporin-based antibacterial agents, the compound I) is poorly absorbed from the digestive tract during oral administration, has low bioavailability, and cannot be used as such for oral administration preparations.

Therefore, the inventors of the present invention have the above formula (II), which is sufficiently stable until reaching the absorption site of the digestive tract and has excellent absorbability, and can be rapidly activated in the body during absorption and transferred into blood.
As a result of earnest research to develop a derivative of the compound (1) suitable for oral administration, this time, it was found that the specific ester represented by the formula (I) exhibits good bioavailability in oral administration. Completed the invention.

In the general formula (I), the “alkyl group” may be either a linear or branched alkyl group,
For example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, heptyl, octyl, 2-ethylhexyl, and the like, the "alkoxy group" the alkyl part has the above meaning. Is an alkyloxy group having, for example,
Methoxy, ethoxy, propoxy, isopropoxy, butoxy, tert-butoxy groups and the like can be mentioned. Also, "C
_{The “3-} C ₆ cycloalkyl group” includes cyclopropyl, cyclopentyl, cyclohexyl group and the like.

Therefore, the compound of the above formula (I) (7β- [2-
(2-Aminothiazol-4-yl)-(Z) -2-methoxyiminoacetamido] -3-[(1,2,3-thiazol-5-yl) thiomethyl] cef-3-em-4
Typical examples of (carboxylic acid ester) are as follows (only ester residues are shown).

Acetoxymethyl, 1- (acetoxy) ethyl, 1-
(Acetoxy) propyl, propionyloxymethyl,
1- (propionyloxy) ethyl, n-butyryloxymethyl, 1- (n-butyryloxy) ethyl, iso-
Butyryloxymethyl, 1- (iso-butyryloxy)
Ethyl, n-valeryloxymethyl, 1- (n-valeryloxy) ethyl, 2-methyl-butyryloxymethyl, 1- (2-methyl-butyryloxy) ethyl, piparoyloxymethyl, 1- (pivaloyloxy) ethyl, Isovaleryloxymethyl, 1- (isovaleryloxy) ethyl, n-hexanoyloxymethyl, 1-
(N-hexanoyloxy) ethyl, 1- (n-hexanoyloxy) propyl, 1- (4-methylpentanoyloxy) ethyl, 1- (3-methylpentanoyloxy) ethyl, 2-methylpentanoyloxy Methyl, 1
-(2-methylpentanoyloxy) ethyl, 1- (2
-Ethyl-butyryloxy) ethyl, n-heptanoyloxymethyl, 1- (3-ethylpentanoyloxy)
Ethyl, n-octanoyloxymethyl, 1- (2-n
-Propylpentanoyloxy) ethyl, n-nonanoyloxymethyl, 1- (n-nonanoyloxy) ethyl, 1- (cyclopropanecarbonyloxy) ethyl,
Cyclobutanecarbonyloxymethyl, cyclopentanecarbonyloxymethyl, 1- (cyclopentanecarbonyloxy) ethyl, cyclohexanecarbonyloxymethyl, 1- (cyclohexanecarbonyloxy) ethyl, cyclopropylacetoxymethyl, 1- (cyclopentylacetoxy) ethyl, cyclohexylacetoxy Methyl, 1- (cyclohexylacetoxy) ethyl, ethoxycarbonyloxymethyl, 1- (ethoxycarbonyloxy) ethyl, n-propoxycarbonyloxymethyl, 1- (n-propoxycarbonyloxy) ethyl, 1- (isopropoxycarbonyloxy) ethyl,
n-butoxycarbonyloxymethyl, 1- (n-butoxycarbonyloxy) ethyl, 1- (t-butoxycarbonyloxy) ethyl, 1- (iso-butoxycarbonyloxy) ethyl and the like.

In the general formula (I), R ¹ = H and R ² = OC ₂ H ₅
Compound is a tert-C ₄ H _9, i.e., the formula (IV)
1'-ethoxycarbonyloxymethyl ester and pivaloyloxymethyl ester of the compound of
The above-mentioned Japanese Patent Laid-Open No. 57-59895 suggests its existence, but it does not disclose the physical properties and pharmacological effects of the ester at all.

On the other hand, in the general formula (I), R ¹ = H and R ² = OC ₂
The compound of the present invention except for the case of H ₅ or tert-C ₄ H ₉ is a novel compound which has not been described in the conventional literature.

According to the invention, the compounds of the general formula (I) are of the general formula In the formula, R ³ represents a hydrogen atom or an amino-protecting group. Wherein R ¹ and R ² have the meanings given above, X represents a halogen atom, for example iodine, bromine or chlorine atom, esterified with a compound of the formula (II)
When R ³ in the compound (1) represents an amino-protecting group, it can be produced by removing the amino group from the resulting compound.

The above esterification reaction is usually carried out in an inert solvent, and as a solvent that can be used, for example, polar organic solvents such as dimethyl sulfoxide, N, N-dimethylformamide, acetone, acetonitrile, tetrahydrofuran, dichloromethane, chloroform and the like are preferable. is there.

The temperature which can be used in the esterification is advantageously in the range of about -30 ° C to about 50 ° C, preferably about -20 ° C to room temperature. Further, the ratio of the compound of the formula (III) to the compound of the formula (II) is not exact, but in general, the compound of the formula (I
0.5 mol of the compound of the formula (III) to 1 mol of the compound of I).
Advantageously, it is used in a proportion of 5 mol, preferably 1 to 3 mol. The reaction time varies depending on the type of solvent, reaction temperature and the like, but generally speaking it is about 5 minutes to about 4 hours.

In the above esterification reaction, when the compound of formula (II) is used as it is in the form of a free acid, it is desirable to carry out the reaction in the presence of a suitable acid binding agent. Inorganic bases such as sodium hydroxide, potassium hydroxide, sodium hydrogen carbonate, sodium carbonate and potassium carbonate; alcoholates such as sodium ethoxide, potassium ethoxide and potassium t-butoxide; triethylamine, pyridine, diisopropylethylamine, dicyclohexylamine and the like. Examples thereof include organic amines, and these can be used usually in a proportion of 1 mol or more, preferably 1 to 10 mol, relative to 1 mol of the compound of the formula (II).

In the compound of formula (II), the "amino protecting group" represented by R ³ can be a protecting group usually used as a protecting group for an amino group in penicillin and cefalosporin chemistry, and examples thereof include trityl, formyl and chloro. Acetyl, acetyl, phenylacetyl, t
-Butoxycarbonyl, benzyloxycarbonyl, p
-Nitrobenzyloxycarbonyl, p-methoxybenzyloxycarbonyl, 1-methyl-2-methoxycarbonylvinyl, etc., and salts of the compound of formula (II) include, for example, alkali metals such as lithium, potassium and sodium. And salts of alkaline earth metals such as calcium and magnesium, salts of organic amines such as trimethylamine, triethylamine and pyridine, and sodium salts and potassium salts are preferred.

When a compound in the formula (II) in which R ³ represents an amino-protecting group is used as a starting material, the following formula is obtained by the esterification: Wherein R ¹ and R ² have the meanings given above and R ³¹ is amino-
A compound represented by, which represents a protecting group, is produced. Removal of the amino-protecting group R ³¹ from the compound of formula (V) can be carried out by a method known per se, for example, when the protecting group is a trityl group,
In the case of formyl group, t-butoxycarbonyl group, p-methoxybenzyloxycarbonyl group, etc., by acid treatment, in the case of benzyloxycarbonyl group, p-nitrobenzyloxycarbonyl group, etc., by catalytic reduction, and chloroacetyl group. In the case of a group, it can be smoothly carried out by treatment with thiourea or sodium N-methyldithiocarbamate.

According to another aspect, said compound of formula (I) also has the general formula In the formula, R ⁴ represents an amino-protecting group. In the formula, R ¹ , R ² and X have the above-mentioned meanings, and a general formula obtained by esterification with a compound represented by In the formula, R ¹ , R ² and R ⁴ have the above-mentioned meanings. Then, after removing the amino-protecting group R ⁴ from the compound represented by the general formula, Wherein R ³ has the above meaning, is reacted with a compound of formula or a reactive derivative thereof, and when R ³ in the compound of formula (VIII) above represents an amino-protecting group, the resulting compound From the amino-
It can also be produced by removing the protecting group.

Esterification of a compound of formula (VI) with a compound of formula (III) and an amino-protecting group R ⁴ from the resulting compound of formula (VII), which amino-protecting group is of the same kind as described above for R ³ . Of the amino-protecting group R from the compound of formula (V) obtained by esterification of a compound of formula (II) with a compound of formula (III)
It can be performed in the same manner as described above with respect to the withdrawal of ³ .

Acylation of a compound of formula (VII) with a compound of formula (VIII) or a reactive derivative thereof is a method known per se,
For example, it can be carried out by a method similar to that described in JP-A-57-59895.

The compound of formula (I) of the present invention has excellent bioavailability when orally administered to animals including humans, and is suitable as an active ingredient of an antibacterial agent for oral administration. The excellent bioavailability of the compound of formula (I) for oral administration can be demonstrated by the following in vivo and in vitro tests.

(1) Stability in digestive tract As a model experiment demonstrating that the compound of formula (I) of the present invention is stable in the digestive tract, artificial gastric juice (pH 1.
2, Japanese Pharmacopoeia disintegration test method 1st solution and artificial intestinal fluid (pH 7.
0, the stability test was conducted in the Japanese Pharmacopoeia Disintegration Test Method 2nd Solution pH 6.8 was changed to pH 7.0). A 100 μmol concentration solution of each test compound in the above liquid was shaken at 37 ° C. and the residual amount of each test compound was measured by high performance liquid chromatography.

(2) In-vivo activation As a model experiment to prove that the compound of formula (I) of the present invention is activated in the body after being absorbed, a hydrolysis test was carried out using human serum and pig liver esterase. Human serum and pig liver esterase-containing solution of test compound (2
Table 2 shows the results of measuring the residual amount of each test compound by high performance liquid chromatography after shaking a 100 μmol concentration solution in 0 unit / ml, pH 7.0 Tris buffer) at 37 ° C.

As is clear from Tables 1 and 2, the compound (1) of the formula (I) of the present invention is sufficiently stable in artificial gastric juice and artificial intestinal fluid, and is easily hydrolyzed by human serum and esterase to be antibacterial. It was proved to be converted into the non-ester form of the above formula (II) which is the active compound.

(3) Blood Concentration A male rabbit weighing about 2 kg, which had been fasted for 24 hours, was administered with the compound of formula (I) of the present invention and the non-ester compound of formula (II) as a control at 40 mg / kg (non-ester compound equivalent). Orally,
Table 3 shows the results obtained by measuring the blood concentration of the non-ester form (II) after 0.5, 1, 2 and 5 hours by high performance liquid chromatography.

As is clear from Table 3, the blood concentration of the non-ester compound in the oral administration of the compound of the present invention is much higher than that in the case of administration of the sodium salt of the compound of formula (II), and Significant improvement is observed.

(4) Toxicity test CrjCD (SD) male mice (body weight 20 to 23 g)
Two groups of 10 animals each were used, and 500 mg / kg of the carbapenem compound of the present invention described in Example 8 or 9 below was used in each group.
Was administered.

As a result of observation for 1 week after administration, it was observed that all the mice used in this test survived without abnormality.

As described above, the compound of formula (I) has excellent bioavailability upon oral administration,
It can be administered after being formulated into a dosage form suitable for oral administration.

That is, pharmaceutically acceptable auxiliaries, for example, excipients such as starch, lactose, sucrose, calcium phosphate and the like; binders such as starch, acacia, carboxymethylserose, hydroxypropyl cellulose, crystalline cellulose and the like; Lubricants such as magnesium stearate and talc; for example, oral administration of capsules, powders, fine granules, granules, tablets, dry syrup etc. by mixing with a disintegrating agent such as carboxymethyl calcium and the like The dosage form may be suitable for

The dose varies depending on the age, condition, type of disease, etc. of the patient, but usually, for adults, 0.05 to 2 g is converted to the non-ester form of the formula (II) 1 to 4 times per day. It can be administered orally in divided doses.

Hereinafter, the present invention will be described in more detail with reference to Examples and formulation examples.

Example 1 Acetoxymethyl 7β- [2- (2-aminothiazol-4-yl)-(Z) -2-methoxyiminoacetamido] -3-[(1,2,3-thiadiazol-5-yl) thiomethyl] Cef-3-em-4-carboxylate 7β- [2- (2-aminothiazol-4-yl)-
(Z) -2-Methoxyiminoacetamide] -3-
[(1,2,3-Thiadiazol-5-yl) thiomethyl] cef-3-em-4-carboxylic acid sodium salt 9.
0 g was dissolved in 100 ml of dimethylformamide, and -30
Cool to ° C. 9.0 g of iodomethyl acetate with stirring
Is added at once and stirred at -10 ° C for 15 minutes. The reaction mixture is poured into a mixture of 300 ml of ethyl acetate and 100 ml of water, and the organic layer is separated. The organic layer is 100 ml of water three times, and saturated saline solution is 1 times.
After washing with 50 ml, it is dried over anhydrous magnesium sulfate. The residue obtained by evaporating the solvent under reduced pressure is purified by column chromatography (silica gel, ethyl acetate) to obtain 4.1 g of the title compound.

IR (KBr) cm ^-1 : 1770, 1665, 1610 NMR (CDSO-d ₆ ) δ: 2.07 (S, 3H),
3.64 and 3.76 (ABq, J = 12Hz, 2H),
3.87 (s, 3H), 4.22 (s, 2H), 5.2
3 (d, J = 5 Hz, 1H), 5.77 (S, 2H),
5.70-5.90 (m, 1H), 6.75 (S, 1
H), 7.13 (bs, 2H), 8.84 (s, 1
H), 9.65 (d, J = 9.5 Hz. 1H) Example 2 1-acetoxyethyl 7β- [2- (2-aminothiazol-4-yl)-(Z) -2-methoxyiminoacetamide] -3-[(1,2,3-thiadiazole-5-
Il) thiomethyl] cef-3-em-4-carboxylate 7β- [2- (2-aminothiazol-4-yl)-
(Z) -2-Methoxyiminoacetamide] -3-
[(1,2,3-Thiadiazol-5-yl) thiomethyl] cef-3-em-4-carboxylic acid sodium salt 1.
6 g was dissolved in 15 ml of dimethylformamide, and the temperature was -20 ° C.
Cool to. While stirring, 1.2 g of 1-iodomethyl acetate dissolved in 5 ml of dimethylformamide was added, and -5-
Stir at -10 ° C for 1 hour. The reaction mixture is treated in the same manner as in Example 1 to obtain 0.64 g of the title compound.

IR (KBr) cm ^-1 : 1770, 1675, 1620 NMR (DMSO-d ₆ ) δ: 1.38 (d, 3H),
1.95 and 2.00 (s, 3H), 3.57 (bs, 2)
H), 3.75 (s, 3H), 4.07 (s, 2H),
5.11 (d, J = 5Hz, 1H), 5.5-5.9
(M, 1H), 6.57 (s, 1H), 6.63-6.
76 (m, 1H), 7.02 (bs, 1H), 8.68
And 8.70 (s, 1H), 9.42 (d, J = 8Hz, 1
H) Example 3 Propionyl oxymethyl 7β- [2- (2-aminothiazol-4-yl)-(Z) -2-methoxyiminoacetamide] -3-[(1,2,3-thiadiazole-
5-yl) thiomethyl] cef-3-em-4-carboxylate 7β- [2- (2-aminothiazol-4-yl)-
(Z) -2-Methoxyiminoacetamide] -3-
[(1,2,3-thiadiazol-5-yl) thiomethyl] cef-3-em-4-carboxylic acid sodium salt 4.
0 g was dissolved in 25 ml of dimethylformamide, and the temperature was -20 ° C.
Cool to. Iodomethyl propionate 3.9 with stirring
g once and stir for 15 minutes at -20 ° C. The reaction mixture is treated in the same manner as in Example 1 to obtain 3.6 g of the title compound.

IR (KBr) cm ^-1 : 1780, 1675, 1620 NMR (DMSO, d ₆ ) δ: 1.10 (t, J = 7 Hz,
3H), 2.37 (q, J = 7Hz, 2H), 3.65 and 3.79 (ABq, J = 16Hz, 2H), 3.85.
(S, 3H), 4.22 (s, 2H), 5.24 (d,
J = 5 Hz, 1H), 5.65-5.93 (m, 1H),
5.80 (s, 2H), 6.76 (s, 1H), 7.1
8 (bs, 2H), 8.91 (s, 1H), 9.64
(D, J = 10 Hz, 1H) Example 4 1- [Propioloxy) ethyl 7β- [2- (2-aminothiazol-4-yl)-(Z) -2-methoxyiminoacetamide] -3- [ (1,2,3-Thiadiazol-5-yl) thiomethyl] cef-3-em-4-carboxylate 7β- [2- (2-aminothiazol-4-yl)-
(Z) -2-Methoxyiminoacetamide] -3-
[(1,2,3-thiadiazol-5-yl) thiomethyl] cef-3-em-4-carboxylic acid sodium salt 3.
2 g was dissolved in 20 ml of dimethylformamide, and the temperature was -20 ° C.
Cool to. While stirring, 3.4 g of 1-iodoethyl propionate was added all at once, and the mixture was stirred at -20 ° C for 40 minutes.
The reaction mixture is treated in the same manner as in Example 1 to obtain 1.46 g of the title compound.

IR (KBr) cm ⁻¹ : 1775, 1750, 1675,
_{1620 NMR (DMSO-d 6)} δ: 0.79-1.23
(M, 3H), 1.40 (d, J = 6Hz, 3H), 1.
90-2.30 (m, 2H), 3.63 (bs, 2)
H), 3.81 (s, 3H), 4.10 (s, 2H),
5.14 (d, J = 5Hz, 1H) 5.53-5.90
(M, 1H), 6.61 (s, 1H), 6.57-6.
93 (m, 1H), 7.07 (bs, 2H), 8.71
And 8.75 (s, 1H), 9.48 (d, J = 9Hz, 1
H) Example 5 Pivaloyloxymethyl 7β- [2- (2-aminothiazol-4-yl)-(Z) -2-methoxyiminoacetamido] -3-[(1,2,3-thiadiazole-5]
-Yl) thiomethyl] cef-3-ef-4-carboxylate 7β- [2- (2-aminothiazol-4-yl)-
(Z) -2-Methoxyiminoacetamide] -3-
[(1,2,3-Athidiazol-5-yl) thiomethyl] cef-3-emcarboxylic acid sodium salt 0.54 g
Is dissolved in 5 ml of dimethylformamide and cooled to -20 ° C. While stirring, 0.33 g of iodomethyl pivalate dissolved in 2 ml of dimethylformamide was added, and the temperature was -10 to -5 ° C.
Stir for 1 hour. This reaction solution is treated in the same manner as in Example 1 to obtain 0.52 g of the title compound.

IR (KBr) cm ⁻¹ : 1775, 1740, 1670,
1610 NMR (DMSO-d ₆ ) δ: 1.15 (s, 9H),
3.64-3.76 (ABq, J = 15Hz, 2H),
3.86 (s, 3H), 4.21 (s, 2H), 5.2
2 (d, J = 5Hz, 1H), 5.80 (s, 2H),
5.70-5.89 (m, 1H), 6.73 (s, 1
H), 7.12 (bs, 2H), 8.82 (s, 1
H), 9.62 (d, J = 8 Hz, 1H) Example 6 1- (Pivaloyloxy) ethyl 7β- [2- (2-aminothiazol-4-yl)-(Z) -2-methoxyiminoacetamide] -3-[(1,2,3-thiadiazol-5-yl) thiomethyl] cef-3-em-4-carboxylate 7β- [2- (2-aminothiazol-4-yl)-
(Z) -2-Methoxyiminoacetamide] -3-
[(1,2,3-thiadiazol-5-yl) thiomethyl] cef-3-em-4-carboxylic acid sodium salt 0.
21 g was dissolved in 5 ml of dimethylformamide, and -20 ° C.
Cool to. 1-iodoethyl pivalate 0.3 with stirring
Add 1 g at once and stir at −10 ° C. for 2 hours. This reaction solution was treated as in Example 1 to give the title compound 0.1
8 g are obtained.

IR (KBr) cm ⁻¹ : 1780, 1745, 1675,
1620 NMR (DMSO-d ₆ ) δ: 1.11 (s, 9H),
1.41 (bd, J = 6Hz, 3H), 3.63 and 3.7
7 (ABq, J = 18Hz, 3H), 3.84 (s, 3
H), 4.16 (s, 2H), 5.24 (d, J = 5H)
z, 1H), 5, 76-5.90 (m, 1H), 6.7
4 (s, 1H), 6.78-6.88 (m, 1H),
7.18 (bs, 2H), 8.89 (s, 1H), 9.
61 (d, J = 9.5 Hz, 1H) Example 7 1- (Ethoxycarbonyloxy) ethyl 7β- [2-
(2-Aminothiazol-4-yl)-(Z) -2-methoxyiminoacetamido] -3-[(1,2,3-thiadiazol-5-yl) thiomethyl] cef-3-em-4-carboxylate 7β- [2- (2-aminothiazol-4-yl)-
(Z) -2-Methoxyiminoacetamide] -3-
[(1,2,3-thiadiazol-5-yl) thiomethyl] cef-3-em-4-carboxylic acid sodium salt 6.
0 g was dissolved in 25 ml of dimethylformamide, and the temperature was -20 ° C.
Cool to. 1-iodoethyl carbonate under stirring 6.
Add 0 g at once and stir at −10 ° C. for 30 minutes. This reaction solution was treated as in Example 1 to give the title compound 4.
9 g are obtained.

IR (KBr) cm ^-1 : 1760, 1680, 1620 NMR (CDCl ₃ ) δ: 1.30 (t, 7 Hz, 3)
H), 1.53 (d, J = 5 Hz, 3H), 3.50 (b
s, 2H), 3.9-4.3 (m, 7H), 4.93.
(D, J = 5 Hz, 1 H), 5.6-6.1 (m, 3
H), 6.5-6.8 (m, 2H), 7.8-8.1.
(M, 1H), 8.32 (s, 1H) Example 8 Cyclohexanecarbonyloxy 7β- [2- (2-
Aminothiazol-4-yl)-(Z) -2-methoxyiminoacetamido] -3-[(1,2,3-thiadiazol-5-yl) thiomethyl] cef-3-em-4-
Carboxylate 7β- [2- (2-aminothiazol-4-yl)-
(Z) -2-Methoxyiminoacetamide] -3-
[(1,2,3-thiadiazol-5-yl) thiomethyl] cef-3-em-4-carboxylic acid sodium salt 4.
Dissolve 6 g in 30 ml of dimethylformamide and store at -20 ° C.
Cool to. 5.8 g of iodomethylcyclohexanecarboxylate is added with stirring, and the mixture is further stirred at -20 ° C for 15 minutes. This reaction solution was treated in the same manner as in Example 1,
2.68 g of the title compound are obtained.

IR (KBr) cm ⁻¹ : 1780, 1750, 1680,
1620 NMR (DMSO-d ₆ ) δ: 0.86-1.96
(M, 11H), 3.59 (bs, 2H), 3.73
(S, 3H), 4.08 (s, 2H), 5.06 (d,
J = 5Hz, 1H), 5.62 (s, 2H), 5.46-
5.83 (m, 1H), 6.55 (s, 1H), 7.0
0 (s, 2H), 8.63 (s, 1H), 9.35
(D, J = 9 Hz, 1H) Example 9 1- (Cyclohexylacetoxy) ethyl 7β- [2-
(2Aminothiazol-4-yl)-(Z) -2-methoxyiminoacetamido] -3-[(1,2,3-thiadiazol-5-yl) thiomethyl] cef-3-em-
4-carboxylate 7β- [2- (2-aminothiazol-4-yl)-
(Z) -2-Methoxyiminoacetamide] -3-
[(1,2,3-Thiadiazol-5-yl) thiomethyl] cef-3-em-4-carboxylic acid sodium salt 1.
0 g is dissolved in 5 ml dimethylformamide and cooled to -20 ° C. While stirring, 1-iodoethylcyclohexyl acetate (0.68 g) was added at once, and the mixture was stirred at -20 ° C for 30 minutes. The reaction mixture is treated in the same manner as in Example 1 to obtain 0.73 g of the title compound.

IR (KBr) cm ⁻¹ : 1790, 1750, 1680,
1620 NMR (DMSO-d ₆ ) δ: 0.7-1.9 (m, 1)
4H), 1.9-2.2 (m, 2H), 3.56 (b
s, 2H), 3.73 (s, 3H), 4.00 (bs,
2H), 5.03 (d, J = 5Hz, 1H), 5.45-
5.75 (m, 1H), 6.52 (s, 1H), 6.5
-6.8 (m, 1H), 7.0 (br, 1H), 8.6
0 (s, 1H), 9.33 (d, 1H) Example 10 (A) Pivaloyloxymethyl 7β- [2- (2-chloroacetamidothiazol-4-yl)-(Z) -2-
Methoxyiminoacetamide] -3-[(1,2,3-
Thiadiazol-5-yl) thiomethyl] cef-3-em-4carboxylate 7β- [2- (2-chloroacetamidothiazol-4]
-Yl)-(Z) -2-methoxyiminoacetamide]
-3-[(1,2,3-thiadiazol-5-yl) thiomethyl] cef-3-em-4-carboxylic acid 2.36 g
Was dissolved in 10 ml of dimethylformamide, 0.5 g of triethylamine was added with stirring under ice cooling, and the mixture was further cooled to -20 ° C. 2.2 g of 1-iodomethyl pivalate was added at once with stirring, and the mixture was stirred at -10 ° C for 1 hour. The reaction mixture is poured into a mixture of 100 ml of ethyl acetate and 100 ml of ice water, and the organic layer is separated. The organic layer was washed with 100 ml of cold water three times and saturated brine 7 times.
The extract is washed successively with 0 ml and dried over anhydrous magnesium sulfate.
The solvent is distilled off under reduced pressure and the obtained residue is purified by column chromatography (silica gel, ethyl acetate) to obtain 2.55 g of the title compound.

IR (KBr) cm ⁻¹ : 1785, 1755, 1680 (B) Pivaloyloxymethyl 7β- [2- (2-aminothiazol-4-yl) -2-methoxyiminoacetamide] -3-[(1,2 , 3-Thiadiazol-5-yl) thiomethyl) cef-3-em-4-carboxylate 340 mg of the ester obtained in the above step (A) and 70 mg of thiourea are dissolved in 10 ml of dimethylformamide and stirred at room temperature. 1.5 hours later, sodium bicarbonate 80
mg, and the mixture is further stirred at room temperature for 10 hours. The reaction mixture is poured with a mixture of 30 ml of ethyl acetate and 30 ml of ice water, and the organic layer is separated. The organic layer is washed with 30 ml of cold water three times and then with saturated saline, and then dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the obtained residue was purified by column chromatography (silica gel, ethyl acetate) to give the title compound 12
0 mg are obtained. IR and NMR of this product were consistent with those of Example 5.

(C) Pivaloyloxymethyl 7β- [2- (2-aminothiazol-4-yl) -2-methoxyiminoacetamide] -3-[(1,2,3-thiadiazole-5-
Yl) thiomethyl) cef-3-em-4-carboxylate A solution in which 560 mg of the ester obtained in step (A) was dissolved in 20 ml of tetrahydrofuran and 150 mg of sodium N-methyldithiocarbamate was dissolved in 1 ml of water while stirring with ice cooling. Is added and the mixture is stirred at room temperature for 2 hours. Tetrahydrofuran was distilled off under reduced pressure, 20 ml of saturated saline was added to the obtained residue, and the mixture was extracted twice with 20 ml of ethyl acetate. Combine the extracts,
After drying over anhydrous magnesium sulfate, the solvent is distilled off under reduced pressure.
The obtained residue is purified by column chromatography (silica gel, ethyl acetate) to obtain 290 mg of the title compound. IR and NMR of this product were consistent with those of Example 5.

Formulation Example 1 Tablet The main drug, starch and lactose are mixed, an aqueous solution of hydroxypropyl cellulose is added and kneaded, dried and pulverized, magnesium stearate is added and mixed, and the mixture is compressed into tablets according to a conventional method.

Formulation Example 2 Capsule A main ingredient, starch and magnesium stearate are mixed and filled according to a usual capsule filling method to produce a capsule.

Formulation Example 3 Fine granules The main drug, starch and lactose are mixed, and an aqueous solution of hydroxypropyl cellulose is added and kneaded, followed by drying and pulverizing for sizing, and sieving in the range of 32 to 150 mesh to obtain a fine granule.

Formulation Example 4 Granules The particles are sized by the same method as in Formulation Example 3, and the range of 12 to 48 mesh is sieved to give granules.

Formulation Example 5 Dry syrup The main drug and sucrose are mixed, to which an aqueous solution of hydroxypropyl cellulose is added, kneaded, dried and pulverized to obtain a dry syrup.

[Brief description of drawings]

FIG. 1 shows the antibacterial activity of the chemical compound of formula (II) against methicillin-resistant Staphylococcus aureus (strain 22). FIG. 2 shows the bactericidal action of the compound of formula (II) against various bacteria. In FIG. 2, 2-a shows the results for Staphylococcus aureus, 2-b for Escherichia coli, and 2-c for Klebsiella pneumoniae. Cefperazone was used as a control compound.

Claims (2)

[Claims] 1. A general formula In the formula, R ¹ represents a hydrogen atom or a C _{1 to} C ₄ alkyl group, and R ² represents a C _{3 to} C ₆ cycloalkyl group or a C _{3 to} C ₆ cycloalkylmethyl group. An antibacterial agent suitable for oral administration characterized by being contained as. 2. General formula In the formula, R ¹ represents a hydrogen atom or a C _{1 to} C ₄ alkyl group, and R ² represents a C _{3 to} C ₆ cycloalkyl group or a C _{3 to} C ₆ cycloalkylmethyl group.