JPH064644B2 - Novel cephalosporin derivative and antibacterial agent - Google Patents

Description

TECHNICAL FIELD The present invention relates to a novel cephalosporin derivative having a broad antibacterial spectrum including Pseudomonas aeruginosa, more specifically, 2- (2-aminothiazole-4) at the 7-position. -Yl) -2- (1,
The present invention relates to a novel cephalosporin derivative having a 3-dihydroxy-2-pyridone-6-carboxamide) acetamide group, which has an excellent therapeutic effect against diseases caused by human and animal pathogens, and is useful as a medicinal and veterinary drug. is there.

[Conventional technology]

Cephalosporin antibiotics are widely used to treat diseases caused by pathogenic bacteria and are particularly effective in treating diseases caused by bacteria resistant to other antibiotics such as penicillin antibiotics, but opportunistic infections It is difficult to say that the so-called third-generation cephem antibiotics, which have recently appeared as antibacterial agents against Gram-negative bacteria including bacteria, have sufficient clinical therapeutic effects.

For example, an amide-substituted product of diaminobenzoic acid at the 2-position amino group of the aminothiazolylglycyl group substituted at the 7-position of cephalosporin exhibits particularly strong antibacterial activity against Pseudomonas aeruginosa (Japanese Patent Laid-Open No. 59-139387) It has the drawback of being easily deactivated by O-methylation in vivo.

[Problems to be solved by the invention]

The present inventors have conducted extensive studies to overcome this drawback, and as a result, 1,3-dihydroxy-2- was used as a constituent component of the amide-substituted compound of the 2-amino group of the aminothiazolylglycyl group.
We came to discover pyridone-6-carboxylic acid.

The compound of the present invention has 1,3-dihydroxy-2-pyridone-6 in the substituent of the amino group at the 7-position of cephalosporin.
-It is characterized by having a carboxylic acid, and exhibits a strong antibacterial activity against Pseudomonas aeruginosa. It also has excellent water solubility as an injection. The present invention specifically discloses the usefulness of the compounds of the present invention.

[Means for solving problems]

It is an object of the present invention to provide a novel derivative and a pharmacologically acceptable salt thereof which overcome the drawbacks of the existing cephalosporin antibiotics.

That is, the invention has the general formula (I) [In formula, A is a C2-C5 alkanoyloxy group, Formula {R ¹ and R ² may be the same or different and each may be a hydrogen atom, a halogen atom or a carbon atom which may be substituted with a halogen atom.
~ 5 alkyl group, R ³ is a linear or branched alkyl group having 1 to 5 carbon atoms or-(CH ₂ ) m-COOH (m is 0 or an integer of 1 to 3) group, n is 0 or A group represented by an integer of 3 to 5} or -SY (Y is an alkyl group, an amino group, an alkyl-substituted amino group, an aminoalkyl group, an alkyl-substituted aminoalkyl group, a carboxyl group, a carboxyalkyl group,
A 5-membered ring which may be substituted with a hydroxyl group and which has 1 to 4 nitrogen atoms and 0 or 1 sulfur atom and which may be condensed with a benzene ring). The present invention relates to a novel cephalosporin compound, a pharmacologically acceptable salt thereof, and an antibacterial agent containing the same as an active ingredient.

The α-carbon of the aminothiazolylglycyl substituent of the general formula I can exist in D-form and L-form, but the present invention includes both and DL-form.

Further, the 1,3-dihydroxy-2-pyridone-6-carboximide portion of the 7-position substituent can have the following tautomers, and the present invention includes both of them, but the naming and the structural description Has a pyridone type.

The pharmacologically acceptable salts of the compound having the above formula I of the present invention include medically acceptable salts, especially conventional non-toxic salts, and the inorganic salts include salts with inorganic bases, for example, sodium salts, Alkali metal salts such as potassium salts, alkaline earth metal salts such as calcium salts and magnesium salts, ammonium salts, salts with organic bases such as triethylamine salts, pyridine salts, ethanolamine salts, triethanolamine salts, dicyclohexylamine salts, etc. Organic amine salts and basic amino acid salts such as lysine and arginine.

Specific examples of the 3-position substituent of the compound of formula (I) of the present invention include the followings, but the present invention is not limited thereto.

(1-methylpyridinium-4-yl) thiomethyl,
(1-Methylpyridinium-3-yl) thiomethyl,
(1-methylpyridinium-2-yl) thiomethyl,
(1-ethylpyridinium-4-yl) thiomethyl,
(1-Carboxymethylpyridinium-4-yl) thiomethyl, (2,3-cyclopenteno-1-methylpyridinium-4-yl) thiomethyl, (2,3-cyclopenteno-1-ethylpyridinium-4-yl) thiomethyl, ( 2,3-Cyclopenteno-1-carboxymethylpyridinium-4-yl) thiomethyl, (5,6-cyclopenteno-1-methylpyridinium-2-yl) thiomethyl, (5,6-cyclopenteno-1-carboxyethylpyridinium-2) -Yl) thiomethyl, (2,3-
Cyclohexeno-1-methylpyridinium-4-yl)
Thiomethyl, (2,3-cyclohexeno-1-carboxyethylpyridinium-4-yl) thiomethyl, (1-
Methyl-1H-tetrazol-5-yl) thiomethyl,
(1-Amino-1H-tetrazol-5-yl) thiomethyl, [1- (2-aminoethyl) -1H-tetrazol-5-yl] thiomethyl, [1- (2,2-dimethylaminoethyl) -1H- Tetrazol-5-yl] thiomethyl, [1- (2-carboxyethyl) -1H-tetrazol-5-yl) thiomethyl- (2-methyl-1,
3,4-thiadiazol-5-yl) thiomethyl, (2
-Carboxy-1,3,4-thiadiazol-5-yl) thiomethyl, (2-carbamoyl-1,3,4-thiadiazol-5-yl) thiomethyl, (1,2,3-)
Thiadiazol-5-yl) thiomethyl, (benzthiazol-2-yl) thiomethyl, (benzoxazol-2-yl) thiomethyl, (benzimidazol-2-
Il) Thiomethyl.

The above-mentioned 3-position substituent is synthesized by a known method, for example, “Heterocyclic Compounds Pyridine and It's Derivatives”, “Hetero-cyclic Compounds, Pyr-id”.
ine and its Derivatives vol 14 Part 1 ~ 4, Interscie
nce publishers LTD. ”, but in particular, the synthesis of cycloalkanothiopyridone and substituted alkylthiocycloalkanopyridines is carried out by the present inventors in Japanese Patent Application No. 59-33747,
It was carried out according to the method disclosed in JP-A-59-138206 and JP-A-59-254518.

1,3-dihydroxy-2 which is a constituent after substitution at the 7-position
-Pyridone-6-carboxylic acid or a protected form thereof is a 3-hydroxy-2-pyridone-6-carboxylic acid or a halogen-substituted form of a protected form thereof by an oxidizing agent. (In the formula, R ⁶ represents a removable holding group such as methyl, isopropyl, t-butyl, benzyl, p-nitrobenzyl, o-nitrobundyl, phenacyl, and methoxyethoxymethyl) of the N-oxide obtained by oxidation. Obtained by hydrolysis.

As used herein, 3-hydroxy-2-pyridone-6-
The carboxylic acid or its protected form is synthesized by the following two methods. A) D-Glyconotol 1,5-lactam (Agr, Biol, Chem. 34,
3-hydroxy-6-hydroxymethyl-2-pyridone obtained by subjecting 966 (1979)) to acetic anhydride and pyridine, followed by alkali hydrolysis to give 3-hydroxy-2-pyridone by oxidation with active manganese dioxide and silver oxide. -6-carboxylic acid. B) D-glucaro-1,5-lactam (Patent Publication 45-2837)
5) is converted to 3-hydroxy-2-pyridone-6-carboxylic acid by hydrolyzing acetic anhydride and pyridine, and then by alkali hydrolysis.

Here, the compound obtained by both the methods 1) and 2) can be used by protecting the hydroxy at the 3-position, if necessary.

The cephalosporin compound of the general formula (1) of the present invention can be produced by the following methods A, B and C. That is, A) general formula II (Wherein R ⁷ is a hydrogen atom or an amino group protecting group, R ⁸ is a hydrogen atom or a carboxyl group protecting group, A is the above-mentioned meaning), or a salt or silylated compound of the formula III (R ⁶ and R ⁹ represent the same or different hydrogen atom or a removable protecting group such as methyl, isopropyl, t-butyl, benzyl, p-nitrobenzyl, o-nitrobenzyl, phenacyl and methoxyethoxymethyl. ) Is reacted with a compound represented by) or a reactive derivative of carboxylic acid, and then,
Prepared by removing the protecting group if necessary.

B) General formula IV (Wherein R ⁸ and A are as defined above), the compound represented by the general formula (V) (R ⁶ , R ⁷ and R ⁹ are as defined above) or a reactive derivative of a carboxylic acid thereof is reacted, and then a protecting group, if present, is removed to give a compound of the general formula I can get.

C) General formula [VI] (Wherein R ⁶ , R ⁷ , R ⁸ and R ⁹ are as defined above, and X is an acetoxy group or a halogen atom), the compound represented by the general formula [VII] (R ¹ , R ² , R ³ and n are as defined above) or a compound represented by the general formula [VIII] HS-Y [VIII] (Y is as defined above) is reacted,
Thereafter, if necessary, the protecting group is removed to obtain the compound of general formula [I].

As the protecting group for the amino group and the carboxyl group in the above general formula, those used for this purpose in the field of β-lactam and peptide synthesis are appropriately adopted.

Examples of the amino-protecting group include phthaloyl, formyl, monochloroacetyl, dichloroacetyl, trichloroacetyl, methoxycarbonyl, ethoxycarbonyl, t-butoxycarbonyl, trichloroethoxycarbonyl, benzyloxycarbonyl, p-nitrobenzyloxycarbonyl, diphenyl. Examples thereof include enylmethyloxycarbonyl, methoxymethyloxycarbonyl, trityl, trimethylsilyl, and the like. Examples of the protective group for the carboxyl group include t-butyl, t-amyl, benzyl, p-nitrobenzyl, p-methoxybenzyl, benzhydryl. , Phenyl, p-nitrophenyl, methoxymethyl, ethoxymethyl, benzyloxymethyl, acetoxymethyl, methylthiomethyl, trityl, trichloroethyl, trime Rushiriru, dimethylsilyl, dimethylaminoethyl and the like.

In both the production methods A and B), the basic reaction is a condensation reaction by acylation, and the general acylation method used for penicillin and cephalosporin is applied.

Examples of the reactive derivative include acid halides, acid anhydrides, active amides, active esters and the like. Preferred examples include acid chlorides, acid bromides, mixed acid anhydrides such as acetic acid, pivalic acid, isovaleric acid and trichloroacetic acid, active amides with pyrazole, imidazole, dimethylpyrazole, benzotriazole and p-nitrophenyl ester. , 2,4-dinitrophenyl ester, trichlorophenyl ester, 1-hydroxy-1H-2-pyridone, N-hydroxysuccinimide, N-hydroxyphthalimide and the like active esters.

Further, in this reaction, when the compounds [III] and [V] are used in the form of a free acid, it is preferable to carry out the reaction in the presence of a condensing agent. Examples of the condensing agent include, for example,
N, N-dicyclohexylcarbodiimide, N-cyclohexyl-N'-morpholinoethylcarbodiimide, N
A carbodiimide compound such as -cyclohexyl-N '-(4-diethylaminocyclohexyl) carbodiimide,
Amide compounds such as N-methylformamide, N, N-dimethylformamide and thionyl chloride, phosphorus oxychloride,
It can be carried out in the presence of a reagent (so-called Vilsmeier reagent) produced by reaction with a halide such as phosgene.

Among the reactive derivatives in this reaction, acid halides,
The reaction in acid anhydrides requires the presence of an acid condensing agent, and examples of acid binders include triethylamine, trimethylamine, ethyldiisopropylamine, N, N-
Examples thereof include organic bases such as dimethylaniline, N-methylmorpholine and pyridine, alkali metal compounds such as sodium, potassium or calcium hydroxides, carbonates and bicarbonates, and oxiranes such as ethylene oxide and propylene oxide.

The present invention is usually carried out in a solvent that does not adversely influence the reaction, and water, acetone, acetonitrile, dioxane, tetrahydrofuran, methylene chloride, chloroform, dichloroethane, N, N-dimethylformamide, or a mixed solvent thereof is used as the solvent. used.

The reaction temperature is not particularly limited, but it is usually -30 to 40 ° C, and the reaction time is 30 minutes to 10 hours until the completion of the reaction.

When the acylated product thus obtained has a protecting group, it is necessary to remove the protecting group. The method for removing the protecting group may be an acid method, a base method, a hydrazine method, etc. depending on the type of the protecting group. These methods are conventional methods used in the field of β-lactam and peptide synthesis. It can be appropriately selected and performed.

The compound of the general formula II, which is a synthetic intermediate of the production method A, is described in Journal of Antibiotics, Vol. 35, p. 1022 (198
0) (J. Antibiotics 35 , 1022 (1980)) and the like.

General formula [VI] and general formula [VII] in the production method (C),
For the reaction with [VIII], the method commonly used in the chemistry of cephalosporins is adopted. That is, in the general formula [VI], when X is an acetoxy group, the reaction is usually water, phosphate buffer, acetone, acetonitrile, N, N-dimethylformamide, N, N-dimethylacetamide, tetrahydrofuran, dimethylsulfoxide. It is preferably carried out in a polar solvent such as side, dioxane, methanol or ethanol, or a mixed solvent with water. The reaction is preferably carried out near neutral, and the reaction temperature is not particularly limited,
Usually, it is suitable to carry out from room temperature to around 70 ° C.

The time required for the present invention varies depending on the reaction conditions, but is usually 1 to 10 hours. In addition, this reaction is conducted with sodium iodide,
It is promoted by carrying out in the presence of an alkali metal halide such as potassium iodide.

When the target compound is produced from the compound in which X in the general formula [VI] is halogen, examples of the halogen include chlorine, bromine and iodine, and iodine is generally preferred because of its reactivity. A compound of the general formula [VI] in which X is iodine can be easily prepared by a known method (for example, JP-A-56-131590) from a protected amino group or carboxyl group of the compound in which X is an acetoxy group. It

This reaction is usually preferably carried out in a solvent such as acetone, dioxane, tetrahydrofuran, ethyl acetate, acetonitrile, N, N-dimethylformamide, N, N-dimethylacetamide and the like under non-aqueous conditions. The reaction is usually preferably 0 to 50 ° C., and the reaction is completed in 1 to 5 hours.

The compound of general formula [I] thus obtained is collected from the reaction mixture by a conventional method.

For example, Amberlite XAD-2 (Rohm and Haas (R
(manufactured by Ohm and Hass)), Diaion HP-20 (manufactured by Mitsubishi Kasei Co., Ltd.) and the like, and can be achieved by appropriately combining purification, precipitation, crystallization and the like with an adsorptive resin.

Antibacterial agents containing a compound represented by general formula (I) or a salt thereof as a main component are mainly injections such as intravenous injection, intramuscular injection, etc., oral preparations such as capsules, tablets, powders or rectal preparations, oils and fats. It is used in various dosage forms such as sex suppositories and water-soluble suppositories. These various formulations are commonly used excipients, bulking agents,
Manufactured by a conventional method using a binder, a wetting agent, a disintegrating agent, a surfactant, a lubricant, a dispersant, a buffer, a preservative, a solubilizing agent, an antiseptic, a flavoring agent, a soothing agent, etc. be able to. A specific example of the formulation method will be described in more detail with reference to Examples below.

The dose is appropriately determined depending on the individual case in consideration of symptoms, age, sex, etc., but is usually 250 to 300 per adult per day.
It is 0 mg, which is administered in 1 to 4 divided doses daily.

〔The invention's effect〕

The object compound (I) of the present invention or a salt thereof is a novel compound, and exhibits high antibacterial activity for inhibiting the growth of a wide range of pathogenic microorganisms including Gram positive and negative bacteria. In order to show the usefulness of the target compound (I), the antibacterial activity measured for representative ones of the compounds (I) of the present invention is shown in Table 1 below.

2- (2-aminothiazol-4-yl) -2- (1,3-dihydroxy-2-pyridone-6 at the 7-position of the present invention
-Carboxamide) acetamido group-containing cephalosporin derivative exhibits a broad antibacterial activity in combination with the effect of the 3-position substituent, and has particularly strong activity against Pseudomonas aeruginosa, and against water, which is an important requirement as an injection. Excellent in solubility.

As a result of the acute toxicity test using the compound of the present invention in mice, LD50
Has a low toxicity above 1 g / kg.

〔Example〕

The present invention is further described in detail in the following examples, but these examples are merely examples and do not limit the present invention, and various modifications and alterations can be made without departing from the scope of the present invention. Needless to say.

The NMR data in the examples are 60 MHz or 400 MHz NM.
R is used, unless otherwise specified, in heavy water, the δ value is shown when the water peak is set to a δ value of 4.82, and in the case of other heavy solvents, δ value based on TMS is shown. Showed the value.

Reference Example 1,3-dihydroxy-2-pyridone-6-carboxylic acid (a) 3-hydroxy-2-pyridone-6-carboxylic acid (1
5.5 g) was suspended in 250 ml of water, potassium carbonate (27.6 g) was added and dissolved, and to this was dissolved dioxane (75 ml) and methyl iodide.
(25 ml) was added, and the mixture was reacted at 70 ° C for 7 hours. After the reaction,
The precipitated crystals are collected by filtration and dissolved in 300 ml of water. The pH was adjusted to 1.5 with 6N hydrochloric acid, and the precipitated crystals were collected by filtration, washed with water and dried,
12.5 g of 3-methoxy-2-pyridone-6-carboxylic acid was obtained.

^{_{PMR (D 6 - DMSO) δ}} : 3.77 (3H, s), 6.83 (1H, d), 6.96 (1H, d) (b) 3- methoxy-2-pyridone 6-carboxylic acid (16
g) is suspended in phosphorus oxychloride (150 ml) and heated under reflux at 100 to 110 ° C for 20 hours. The insoluble matter is filtered off, the filtrate is concentrated to dryness, 200 ml of ice water is added to the residue, and the mixture is stirred for 1 hour. The precipitate is collected by filtration, added with 100 ml of water and adjusted to pH 10 with 5N-NaOH to dissolve. After decolorizing at the terminal, filter and filter the filtrate with 5N-HCl
The pH is adjusted to 2 and the precipitate formed is filtered off. This was recrystallized from a mixed solution of chloroform-methanol to give 6-carboxy-2.
14.2 g of -chloro-3-methoxypyridine was obtained.

PMR (D ₆ ^- DMSO) δ3.95 (3H, s), 7.64 (1H, d), 8.05 (1H, d) (c) 6-carboxy-2-chloro-3-methoxypyridine (6.8g) was added to trifluoro Dissolve in acetic acid (70 ml), add 30% hydrogen peroxide solution (35 ml), and stir at 80 ° C. for 2 hours. Toluene was added, the mixture was concentrated under reduced pressure, methanol (20 ml) was added to the residue, and the precipitated crystals were collected by filtration and dried to give 6-carboxy-2.
-Chloro-3-methoxypyridine-N-oxide 7.2 g
Got

^{_{PMR (D 6 - DMSO) δ4.06}} (3H, s), 7.66 (1H, d), 8.23 (1H, d) (d) 6- carboxy-2-chloro-3-methoxypyridine -N- oxide (15.5 g) is suspended in 300 ml of water, sodium hydroxide (28.6 g) is added, dissolved, and heated under reflux for 1.5 hours.

After cooling, the pH was adjusted to 1.5 with concentrated hydrochloric acid, and the resulting crystals were collected by filtration,
After washing with cold water and drying, 14.9 g of 1-hydroxy-3-methoxy-2-pyridone-6-carboxylic acid was obtained.

^{_{PMR (D 6 - DMSO) δ3.85}} (3H, s), 6.81 (1H, d), 7.03 (1H, d) (e) 1- hydroxy-3-methoxy-2-pyridone -6
-Carboxylic acid (1.58 g) was added to 1,2-dichloroethane (50 m
l), and N, O-bis-trimethylsilyl trifluoroacetamide (6 ml) was added under ice cooling. After stirring at room temperature for 1.5 hours, trimethylsilane iodide (3.6 ml) was added, and the temperature was 50 ° C.
Stir for 20 hours. Dilute with dichloromethane (50 ml), add water (2 ml) under ice cooling and stir for 15 minutes. The precipitate formed was collected by filtration, washed twice with water and once with acetone, and dried to give 1,3-
805 mg of dihydroxy-2-pyridone-6-carboxylic acid was obtained.

PMR (D ₂ O + NaHCO ₃ ) δ: 6.87 (1H, d) 7.09 (1H, d) Mass M ⁺ 171 Example 1 (6R, 7R) -7-[(RS) -2- (2-aminothiazole) −
4-yl) -2- (1,3-dihydroxy-2-pyridone-6-carboxamido) acetamido] -3-acetoxymethyl-cef-3-em-4-carboxylate (a) 1,3-di- ( β-methoxyethoxymethoxy)-
2-Pyridone-6-carboxylic acid β-methoxyethoxymethyl ester 1,3-dihydroxy-2-pyridone-6-carboxylic acid
(1.344 g) is dissolved in DMF (20 ml), sodium hydride (60%, 1.22 g) is added under ice cooling, and the mixture is stirred for 30 minutes. Next, β-methoxyethoxymethyl chloride (3.5 ml) was added under ice cooling, and the mixture was stirred at room temperature for 3 hours. After adding methanol (0.5 ml), dilute with ethyl acetate and wash with water three times. After dehydration with magnesium sulfate, ethyl acetate was distilled off and the residue was purified with silica gel (100 g). Elution with chloroform containing 3% methanol gave 1.867 g of the desired product.

PMR (CDCl ₃ ) δ: 3.38 (9H, br.s), 3.4〜3.65 (6H) 3.7〜4.1 (6H), 5.34 (4H, s), 5.52 (2H, s), 6.76 (1H, d), 7.00 (1H, d) (d) 1,3-di- (β-methoxyethoxymethoxy)-
2-Pyridone-6-carboxylic acid 1,3-di- (β-methoxyethoxymethoxy) -2-
Pyridone-6-carboxylic acid] [β-methoxyethoxymethyl ester (2.5 g) is dissolved in a mixture of tetrahydrofuran (8 ml) and methanol (2 ml), 1N-sodium hydroxide (8 ml) is added, and the mixture is stirred at room temperature for 1 hour. . After evaporating the solvent under reduced pressure, 1 ml of saline was added, the pH was adjusted to 2 with 1N hydrochloric acid, and the mixture was extracted 10 times with dichloromethane. After dehydration with magnesium sulfate and molecular sieves 4A, dichloromethane was distilled off to obtain 1.73 g of the desired product.

PMR (CDCl ₃ ) δ: 3.37 (6H, s), 3.43〜3.68 (4H), 3.7〜4.2 (4H), 5.38 (4H, s), 6.85 (1H, d), 7.07 (1H, d) (c ) (6R, 7R) -7-{(RS) 2- (2-aminothiazole-
4-yl) -2- [1,3-di- (β-methoxyethoxymethoxy) -2-pyridone-6-carboxamido] acetamido} -3-acetoxymethyl-cef-3-em-4-carboxylate 1, 3-di- (β-methoxyethoxymethoxy] -2-
Pyridone-6-carboxylic acid (392 mg) was dissolved in a mixed solution of dichloromethane (3 ml) and DMF (1 ml), dicyclohexylcarbodiimide (245 mg) and 1-hydroxybenztriazole (153 mg) were added, and the mixture was stirred at room temperature for 1 hour. The insoluble material was filtered off, and the filtrate was (6R, 7R) -7-[(RS) -2- (2-aminothiazol-4-yl) -2-aminoacetamido] -3-acetoxymethyl-cef-3-. M-4-carboxylate hydrochloride (577 mg) and triethylamine (0.26
(ml) is added to a solution of DMF (6 ml) and the mixture is stirred at room temperature for 2.5 hours. After adding toluene and concentrating under reduced pressure, isopropyl ether is added and the precipitate is obtained by decantation. Water is added to this precipitate and the pH is adjusted to 7.1 with aqueous NaHCO ₃ . The insoluble material is filtered off, and the filtrate is charged with HP-20 (75 ml). After washing with water (250 ml), the desired product was eluted with 5 to 10% acetone and freeze-dried to obtain 483 mg of the desired product as a triethylamine salt.

PMR (D ₂ O) δ: 1.29 (9H, t), 2.11 (3H, s), 3.22 (6H, q), 3.31 (3H), 3.34 (3H, s) 3.3〜3.9 (10H), 4.65〜4.95 (2H), 5.13 (0.5H, d), 5.17 (0.5H, d), 5.30 (1H), 5.42 (4H), 5.65 (1H), 6.81 to 6.9 (2H), 7.26 (1H, d) (d ) The compound of Example 1- (c) (465 mg) was added to anisole (2 m
l) was added, and trifluoroacetic acid (4 ml) was added to room temperature under ice cooling.
React for hours. Add isopropyl ether (60 ml),
The resulting precipitate was collected by filtration, suspended in water, and washed with NaHCO ₃ water.
Adjust to pH 7.5 and dissolve. It was charged with HP-20 (70 ml), eluted from water and freeze-dried to obtain 185 mg of the desired product of Example 1.

PMR (D ₂ O) δ: 2.08 (1.5H, s), 2.09 (1.5H, s), 3.31 (0.5H, d), 3.37 (0.5H, d), 3.61 (0.5H, d), 3.64 ( 0.5H, d), 4.76-4.90 (2H), 5.10 (0.5H, d) 5.14 (0.5H, d), 5.54 (0.5H, s), 5.57 (0.5H, s) 5.63 (0.5H, d) , 5.74 (0.5H, d), 6.75-6.85 (2H), 7.23 (1H,
d) Example 2 (6R, 7R) 7-[(RS) 2- (2-aminothiazole-4-
Yl) -2- (1,3-dihydroxy-2-pyridone-
6-carboxamido) acetamido] -3- (1-methyl-2,3-cyclopentenopyridinium-4-yl)
Thiomethyl-ceph-3-em-4-carboxylate (6R, 7R) 7-[(RS) 2- (2-aminothiazole-4-
Yl) -2- (1,3-dihydroxy-2-pyridone-
6-Carboxamide) acetamido] -3-acetoxymethyl-cef-3-em-4-carboxylate (90 mg)
Was dissolved in a mixed solution (1.4 ml) of acetonitrile-water (1: 1),
Sodium iodide (230 mg), 2,3-cyclopenteno-1-
Methyl-4-mercaptopyridine (51 mg) is added, and the pH is adjusted to 6.8 with 10% aqueous phosphoric acid. After reacting at 70 ° C for 3 hours, acetone was added, the precipitate was collected by filtration, HP-20 (10 ml) (5-15% acetone water elution), then LH-20 (30 ml, 50% methanol water)
After purification by freeze-drying, 28 mg of the desired product was obtained.

PMR (D ₂ O) δ: 2.26 (2H, m), 2.90 (2H, m), 3.21 (2H, m), 3.37 (0.5H, d), 3.43 (0.5H, d), 3.62 (0.5H, d), 3.66 (0.5H, d), 4.01 (3H, s) 4.10 (0.5H, d), 4.12 (0.5H, d), 4.35 (0.5H, s) 4.39 (0.5H, d) 5.05 (0.5 H, d), 5.07 (0.5H, d), 5.57 (1H, s), 5.58 (0.5H, d), 5.68 (0.5H, d), 6.75 (0.5H, s), (6.78 (0.5H, s), 6.80 (0.5H, d), 7.14 (0.5H, d), 7.52 (1H, m), 8.15 (1H, m) Example 3 (6R, 7R) -7-[(RS) -2- (2-aminothiazole-
4-yl) -2- (1,3-dihydroxy-2-pyridone-6-carboxamido) acetamide] -3- (1,
2,3-Thiadiazol-5-yl) thiomethyl-ceph-3-em-4-carboxylate In the same manner as in Example 2, 5-mercapto-1,2,3-
The title compound was obtained using thiadiazole.

PMR (D ₂ O) δ: 3.33 (0.5H, d), 3.40 (0.5H, d), 3.66 (0.5H, d), 3.70 (0.5H, d), 3.80 to 3.90 (1H) 4.32 (0.5H , d), 4.37 (0.5H, d), 5.06 (0.5H, d) 5.08 (0.5H, d), 5.55 ~ 5.60 (1H + 0.5H), 5.66 (0.5H, d), 6.74 (0.5H, s), 6.77 (0.5H, s), 6.88 (1H, d), 7.21 (1H, d), 8.78 (0.5H, s) 8.79 (0.5H, s) Example 4 (6R, 7R) -7- [(RS) -2- (2-aminothiazole-
4-yl) -2- (1,3-dihydroxy-2-pyridone-6-carboxamido) acetamide] -3- (1-
Carboxymethyl-2,3-cyclopentenopyridinium-4-yl) thiomethyl-ceph-3-em-4-carboxylate 1-Carboxymethyl-cyclopentano [b] -4-thiopyridone was prepared in the same manner as in Example 2. Used to give the title compound.

PMR (D ₂ O) δ: 2.2 to 2.35 (2H), 2.90 to 3.0 (2H), 3.13 to 3.23 (2H), 3.40 (0.5H, d), 3.46 (0.5H, d), 4.15 (0.5H, d), 4.16 (0.5H, d), 4.42 (0.5H, d), 4.45 (0.5H, d), 4.95 (2H, s), 5.08 (0.5H, s), 5.11 (0.5H, s), 5.58 ~ 5.62 (1H + 0.5H), 5.72 (0.5H, d), 6.78 (0.5H, s), 6.81 (0.5H, s), 6.89 ~ 6.93 (1H), 7.17 (1H, d), 7.60 ( 1H, d), 8.18 to 8.22 (1H) Example 5 (6R, 7R) -7-[(RS) -2- (2-aminothiazole-
4-yl) -2- (1,3-dihydroxy-2-pyridone-6-carboxamido) acetamido] -3- (benzthiazol-2-yl) thiomethyl-cef-3-em-4-carboxylate Example 2 The title compound was obtained using 2-mercaptobenzothiazole in a similar manner to.

PMR (D ₂ O) δ: 3.28 (0.5H, d), 3.34 (0.5H, d) 3.62 (0.5H, d), 3.66 (0.5H, d), 4.04 (0.5H, d), 4.06 (0.5 H, d), 4.45 (0.5H, d), 4.52 (0.5H, d), 4.95 (0.5H, d), 4.99 (0.5H, d), 5.54 ~ 5.59 (1H + 0.5H) 5.69 (0.5H , d), 6.7 to 6.85 (2H), 7.13 to 7.18 (1H), 7.25 to 7.35 (1H), 7.43 to 7.48 (1H), 7.7 to 7.85 (2H) Example 6 Injectable preparation Example 1 in 1 vial Example 2 Was aseptically dispensed so as to contain 1000 mg (potency) of the compound of.

Example 7 Capsule Compound of the invention Compound of Example 2 250 parts (potency) 60 parts lactose 5 parts magnesium stearate These were uniformly mixed and filled into capsules at 250 mg (potency) / capsule.

Example 8 Soft capsule for rectal administration Olive oil 160 parts Polyoxyethylene lauryl cartel 10 parts To a uniform base consisting of 5 parts sodium hexametaphosphate, 25 parts (potency) of the compound of Example 2 was added and uniformly mixed to give 250 mg (force). Value) / capsule in a soft capsule for rectal administration.

 ─────────────────────────────────────────────────── ─── Continuation of front page (72) Inventor Ryoichi Okamoto 1-18-16 Matsunami, Chiba-shi, Chiba (72) Inventor Takashi Yoshida 2-9-22 Himonbunya, Meguro-ku, Tokyo (72) Masatsugu Sezaki 1-12-16 Sangenjaya, Setagaya-ku, Tokyo (72) Inventor Shin-ichi Kondo 1157-1, Midori-ku, Yokohama-shi, Kanagawa City 1157, Oo Annex 801 (56) Reference Japanese Patent Laid-Open No. 59-118792 (JP, A) Kai 60-64988 (JP, A) JP 60-41682 (JP, A) JP 60-178890 (JP, A)

Claims (2)

[Claims] 1. A formula [In formula, A is a C2-C5 alkanoyloxy group, Formula {R ¹ and R ² may be the same or different and each may be a hydrogen atom, a halogen atom or a carbon atom which may be substituted with a halogen atom.
~ 5 alkyl group, R ³ is a linear or branched alkyl group having 1 to 5 carbon atoms or-(CH ₂ ) m-COOH (m is 0 or an integer of 1 to 3) group, n is 0 or A group represented by an integer of 3 to 5} or -SY (Y is an alkyl group, an amino group, an alkyl-substituted amino group, an aminoalkyl group, an alkyl-substituted aminoalkyl group, a carboxyl group, a carboxyalkyl group,
A 5-membered ring which may be substituted with a hydroxyl group and which has 1 to 4 nitrogen atoms and 0 or 1 sulfur atom and which may be condensed with a benzene ring). A novel cephalosporin compound and a pharmacologically acceptable salt thereof. 2. A formula [In formula, A is a C2-C5 alkanoyloxy group, Formula {R ¹ and R ² may be the same or different and each may be a hydrogen atom, a halogen atom or a carbon atom which may be substituted with a halogen atom.
~ 5 alkyl group, R ³ is a linear or branched alkyl group having 1 to 5 carbon atoms or-(CH ₂ ) m-COOH (m is 0 or an integer of 1 to 3) group, n is 0 or A group represented by an integer of 3 to 5} or -SY (Y is an alkyl group, an amino group, an alkyl-substituted amino group, an aminoalkyl group, an alkyl-substituted aminoalkyl group, a carboxyl group, a carboxyalkyl group,
A 5-membered ring which may be substituted with a hydroxyl group and which has 1 to 4 nitrogen atoms and 0 or 1 sulfur atom and which may be condensed with a benzene ring). A novel cephalosporin compound having a salt and a pharmacologically acceptable salt thereof as an active ingredient.