JPH05230068A - 3-di-substituted carbamoyloxymethylcephalosporin compound, its production and intermediate compound - Google Patents

Abstract

PURPOSE:To obtain a new compound having excellent absorption from an digestive tract and useful as an antimicrobial agent, etc., for Gram-positive bacteria and Gram-negative bacteria. CONSTITUTION:A compound of formula I [R<1> and R<2> are lower alkyl, etc.; R<3> is (esterified) carboxyl; R<4> is H or amino-protecting group; R<5> is H, lower alkyl or hydroxy protecting group], e.g. 7-amino-3-(N,N- dimethylcarbamoyloxymethyl)-3-cephem-4-carboxylic acid. Furthermore, the compound of formula I is obtained by reacting a compound of formula II with a compound of formula III in an organic solvent such as THF in the presence of a condensing agent such as N,N'-dicyclohexylcarbodiimide.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a novel cephalosporin compound useful as a prophylactic / therapeutic agent for bacterial infections, a method for producing the same, and an intermediate compound for producing the cephalosporin compound.

[0002]

BACKGROUND OF THE INVENTION In recent years, the progress of research on cephalosporin compounds as therapeutic agents for infectious diseases has been remarkable, and various cephalosporin compounds having a strong antibacterial activity and a broad antibacterial spectrum have been developed. However, the emergence of various cephalosporin compounds having characteristic antibacterial properties and antibacterial spectra according to the emergence of resistant bacteria and disease states is further desired.

The inventors of the present invention also previously described the following formula (A):

[0004]

[Chemical 10]

A compound represented by the formula (wherein R represents a hydrogen atom or a lower alkyl group) [hereinafter referred to as compound (A)] is proposed. These compounds have strong antibacterial activity, have a broad antibacterial spectrum, and can be extremely useful injections for treating infectious diseases, but generally have poor oral absorbability, and esterify the carboxyl group at the 4-position of the cephalo ring. However, there is a problem that oral absorption is not sufficiently improved even by using the so-called prodrug method.

In addition, even conventionally known cephalosporin compounds are generally poor in oral absorbability, and usually exert an effect by injection. As cephalosporin compounds for oral administration, cephalexin, cefatrizine, cefaclor, cefixime, cefdinir, cefteram pivoxil, cefpodoxime proxetil, cefotiam hexetil, etc. have been developed, but these have somewhat antibacterial activity. Weak, slightly narrow antibacterial spectrum,
Moreover, since the effect is particularly weak against Gram-positive bacteria represented by Staphylococcus aureus, the emergence of a cephalosporin compound for oral administration having improved antibacterial properties against Gram-positive bacteria is desired. There is.

[0007]

Under such circumstances, the inventors of the present invention have conducted various studies and found that the compound (A)
The following compound obtained by di-substituting the carbamoyl group at the 3-position has an excellent antibacterial property such as a strong antibacterial property against Gram-positive bacteria and has a broad antibacterial spectrum. It was found that it has excellent absorbency. Further, the present invention has been completed by establishing a method for producing the compound and finding a novel compound used for producing the compound.

That is, the present invention is firstly the general formula (I):

[0009]

[Chemical 11]

(In the formula, R ¹ and R ² are the same or different and each represents a lower alkyl group or a group which may be bonded to each other to form a ring, and R ³ is a carboxyl group or an esterified carboxyl group. R ⁴ represents a hydrogen atom or an amino-protecting group, and R ⁵ represents a hydrogen atom, a lower alkyl group or a hydroxy-protecting group.) [Hereinafter, referred to as a cephalosporin compound (I)]
Alternatively, it relates to a pharmacologically acceptable addition salt thereof. The present invention is secondly represented by the general formula (II):

[0011]

[Chemical 12]

A 7-aminocephalosporin compound represented by the following formula (wherein R ¹ , R ² and R ³ have the same meanings as defined above) [hereinafter referred to as compound (II)] or a pharmacologically acceptable compound thereof. Related to added salts. The present invention is the third
A compound represented by the general formula (II) and a general formula (III):

[0013]

[Chemical 13]

(Wherein R ⁴ and R ⁵ are the same as defined above) [hereinafter referred to as compound (III)] or a reactive derivative thereof, or a compound represented by the general formula (IV ):

[0015]

[Chemical 14]

[Wherein R ¹ , R ² , R ⁴ and R ⁵ have the same meanings as defined above]
(IV)] and the general formula (V): X—R ⁶ (V) (wherein R ⁶ represents an ester residue and X represents a carboxyl group or a group capable of reacting with a carboxyl reactive group). A compound represented by the formula [hereinafter referred to as compound (V)] is used, or a compound represented by the general formula (VI):

[0017]

[Chemical 15]

[Wherein R ¹ , R ² , R ³ and R ⁵ have the same meanings as defined above, and Y represents a halogen atom] [hereinafter referred to as compound (VI)], and Expression (V
II):

[0019]

[Chemical 16]

(Wherein R ⁴ has the same meaning as defined above) is reacted with a compound [hereinafter referred to as compound (VII)], or

General formula (VIII):

[0022]

[Chemical 17]

[Wherein R ¹ , R ² , R ³ and R ⁴ have the same meanings as defined above]
(VIII)] with a compound represented by the general formula (IX): H ₂ NOR ⁵ (IX) (wherein R ⁵ has the same meaning as described above) [hereinafter referred to as compound (IX)]. Go through the process,
Or

General formula (X):

[0025]

[Chemical 18]

A step of carbamoylating the 3-position hydroxymethyl group of the compound represented by the formula (wherein R ³ , R ⁴ and R ⁵ are as defined above) [hereinafter referred to as compound (X)] And a method for producing the cephalosporin compound (I) represented by the general formula (I) or a pharmaceutically acceptable addition salt thereof.

The symbols used in this specification will be described below. With respect to R ¹ and R ² , the lower alkyl group preferably has 1 to 6 carbon atoms, and includes, for example, methyl, ethyl, propyl, isopropyl, butyl,
Examples include isobutyl, sec-butyl, t-butyl, pentyl, hexyl and the like.

When R ¹ and R ² combine to form a ring, for example, ethylene, propylene, butylene,
Examples thereof include alkylene groups such as pentylene.

With respect to R ³ , the ester in the esterified carboxyl group means a so-called carboxyl group-protecting group, or an ester which is easily hydrolyzed in vivo to give a free carboxyl group.

Examples of the protective group for the carboxyl group are as follows. t-butyl, t-amyl, benzyl, p-nitrobenzyl, p-
Methoxybenzyl, benzhydryl, p-nitrophenyl, methoxymethyl, ethoxymethyl, benzyloxymethyl, methylthiomethyl, trityl, 2,2,2-trichloroethyl, trimethylsilyl, dimethylsilyl, diphenylmethoxybenzenesulfonylmethyl, dimethylaminoethyl.

Examples of the ester which is easily hydrolyzed in vivo include aryl groups which may have a substituent such as phenyl, tolyl, xylyl and indanyl, 1-alkanoyloxyalkyl groups and 1-alkoxycarbonyl. Examples thereof include an oxyalkyl group, a phthalidyl group and a 5-methyl-1,3-dioxolen-2-on-4-ylmethyl group.

The alkanoyl moiety in the 1-alkanoyloxyalkyl group has 1 to 10 carbon atoms, preferably 1 to 10 carbon atoms.
7 and the alkyl moiety has 1 to 3 carbon atoms, preferably 1 or 2. Examples of such groups include acetoxymethyl, propionyloxymethyl, n-butyryloxymethyl, isobutyryloxymethyl, pivaloyloxymethyl, n-valeryloxymethyl, 2-methylbutyryloxymethyl, isovaleryl. Oxymethyl, n-hexanoyloxymethyl, 3-methylvaleryloxymethyl, neohexanoyloxymethyl, 2-methylhexanoyloxymethyl, 2,2-dimethylbutyryloxymethyl, diethylacetoxymethyl, dipropylacetoxymethyl ,
2,2-Dimethylvaleryloxymethyl, neoheptanoyloxymethyl, cyclohexanecarbonyloxymethyl, cyclohexylacetoxymethyl, 1-acetoxyethyl, 1-propionyloxyethyl, 1-n-butyryloxyethyl, 1-isobutyryl Oxyethyl, 1-n-valeryloxyethyl, 1-pivaloyloxyethyl, 1-isovaleryloxyethyl, 1-n-hexanoyloxyethyl, 1-
Cyclohexane carbonyloxyethyl etc. are mentioned.

The carbon number of the alkoxy moiety in the 1-alkoxycarbonyloxyalkyl group is preferably 1
The number of carbon atoms in the alkyl moiety is preferably 1 to 3, more preferably 1 or 2. Examples of such groups include 1-methoxycarbonyloxyethyl, 1-ethoxycarbonyloxyethyl, 1-n-
Propoxycarbonyloxyethyl, 1-isopropoxycarbonyloxyethyl, 1-n-butoxycarbonyloxyethyl, 1-sec-butoxycarbonyloxyethyl, 1-
Examples thereof include tert-butoxycarbonyloxyethyl, 1-pentyloxycarbonyloxyethyl, 1-cyclohexyloxycarbonyloxyethyl and the like.

With respect to R ⁴ and R ⁵ , those used for this purpose in the field of β-lactam synthesis and peptide synthesis are conveniently adopted as the amino protecting group and the hydroxy protecting group. Are exemplified.

Examples of the amino protecting group include phthaloyl, formyl, monochloroacetyl, dichloroacetyl, trichloroacetyl, trifluoroacetyl, methoxycarbonyl, ethoxycarbonyl, benzyloxycarbonyl, p-nitrobenzyloxycarbonyl, diphenylmethyloxycarbonyl, methoxy. Examples thereof include methylcarbonyl, methoxymethyloxycarbonyl, trimethylsilyl, 2,2,2-trichloroethoxycarbonyl, 2-methylsulfonylethyloxycarbonyl, t-butoxycarbonyl (hereinafter referred to as BOC), trityl and the like.

Examples of the hydroxy protecting group include formyl, acetyl, monochloroacetyl, dichloroacetyl, trifluoroacetyl, methoxycarbonyl, ethoxycarbonyl, benzyloxycarbonyl, 2,2,2-trichloroethoxycarbonyl, benzoyl, trityl,
Trimethylsilyl, tetrahydropyranyl, 1-methyl-1
-Methoxyethyl and the like can be mentioned.

The lower alkyl group for R ⁵ is as follows.
Those mentioned for R ¹ and R ² above may be mentioned.

In the general formula (V), the ester residue represented by R ⁶ is a group capable of reacting with the carboxyl group at the 4-position of the general formula (IV) to form an ester.
Examples thereof include the above-mentioned carboxyl group protecting group or an ester that is easily hydrolyzed in vivo.

In the general formula (V), the "group capable of reacting with carboxyl or a reactive group of carboxyl" represented by X is, for example, halogen (chlorine, bromine, iodine, etc.), alkylsulfonyloxy (methanesulfonyloxy). Etc.) and arylsulfonyloxy (p-toluenesulfonyloxy etc.).

In the general formula (VI), examples of the halogen atom represented by Y include chlorine atom, bromine atom and iodine atom.

The cephalosporin compound (I) and compound (II) may form a pharmacologically acceptable addition salt at their amino groups or carboxyl groups, respectively.

An acid addition salt is formed at the amino group moiety, and the acid for forming such an acid addition salt is particularly preferably an acid that can form a salt with the amino group moiety and is pharmaceutically acceptable. There is no limit. Such acids include hydrochloric acid, sulfuric acid,
Examples thereof include mineral acids such as phosphoric acid and nitric acid, and organic acids such as oxalic acid, fumaric acid, maleic acid, citric acid, tartaric acid, methanesulfonic acid and toluenesulfonic acid.

Examples of the salt at the carboxyl group include alkali metal salts (eg sodium salt, potassium salt etc.), alkaline earth metal salts (eg calcium salt, magnesium salt etc.), organic base salts (eg triethylamine salt, dicyclohexylamine). Salt, pyridine salt, etc.).

Further, the 7-position side chain moiety of compound (I):

[0045]

[Chemical 19]

Although there are syn-isomer and anti-isomer geometric isomers, preferred compounds are syn-isomers.

Cephalosporin compounds (I) and 7-
As the aminocephalosporin compound and its pharmacologically acceptable addition salt, for example, the following compounds are preferable.

(1) 7-amino-3- (N, N-dimethylcarbamoyloxymethyl) -3-cephem-4-carboxylic acid (2) 7-amino-3- (N, N-dimethylcarbamoyloxymethyl) -3-Cephem-4-carboxylic acid benzhydryl ester and its hydrochloride (3) 7-amino-3- (N, N-dimethylcarbamoyloxymethyl) -3-cephem-4-carboxylic acid pivaloyloxymethyl ester And its hydrochloride (4) 7-amino-3- (N, N-dimethylcarbamoyloxymethyl) -3-cephem-4-carboxylic acid 1-isopropoxycarbonyloxyethyl ester and its hydrochloride (5) 7- [ 2- (2-Aminothiazol-4-yl) -2-hydroxyimino-acetamido] -3- (N, N-dimethylcarbamoyloxymethyl) -3-cephem-4-carboxylic acid and its sodium salt (syn isomer ) (6) 7- [2- (2-Aminothiazol-4-yl) -2-hydroxyimino-acetamide] -3- (N, N-dimethylcarbamoyloxymethyl) -3-cephem-4-carboxylic acid pivaloyloxymethyl ester and its hydrochloride salt (syn isomer)

(7) 7- [2- (2-aminothiazol-4-yl)-
2-Hydroxyimino-acetamido] -3- (N, N-dimethylcarbamoyloxymethyl) -3-cephem-4-carboxylic acid
1-isopropoxycarbonyloxyethyl ester and its hydrochloride salt (syn isomer) (8) 7- [2- (2-aminothiazol-4-yl) -2-methoxyimino-acetamido] -3- (N, N -Dimethylcarbamoyloxymethyl) -3-cephem-4-carboxylic acid and its sodium salt (syn isomer) (9) 7- [2- (2-aminothiazol-4-yl) -2-methoxyimino-acetamide] -3- (N, N-Dimethylcarbamoyloxymethyl) -3-cephem-4-carboxylic acid pivaloyloxymethyl ester and its hydrochloride salt (syn isomer) (10) 7-amino-3- (N, N -Dimethylcarbamoyloxymethyl) -3-cephem-4-carboxylic acid 1-sec-butoxycarbonyloxyethyl ester and its hydrochloride salt (11) 7- [2- (2-aminothiazol-4-yl) -2-hydroxy Imino-acetamido] -3- (N, N-dimethylcarbamoyloxymethyl) -3-cephem-4-carvone Acid 1-sec-Butoxycarbonyloxyethyl ester and its hydrochloride salt (syn isomer) (12) 7-amino-3- (N-ethyl-N-methylcarbamoyloxymethyl) -3-cephem-4-carboxylic acid and Its pivaloyloxymethyl ester

(13) 7-Amino-3- (N, N-diethylcarbamoyloxymethyl) -3-cephem-4-carboxylic acid and its pivaloyloxymethyl ester (14) 7-amino-3- (1 -Pyrrolidinyl) carbonyloxymethyl-3-cephem-4-carboxylic acid and its pivaloyloxymethyl ester (15) 7-amino-3- (1-piperidinyl) carbonyloxymethyl-3-cephem-4-carboxylic acid and Its pivaloyloxymethyl ester (16) 7- [2- (2-aminothiazol-4-yl) -2-hydroxyimino-acetamido] -3- (N-ethyl-N-methylcarbamoyloxymethyl) -3 -Cephem-4-carboxylic acid (syn isomer) and its pivaloyloxymethyl ester (17) 7- [2- (2-aminothiazol-4-yl) -2-hydroxyimino-acetamido] -3- ( N, N-Dimethylcarbamoyloxymethyl) -3-cephem-4-carboxylic acid Body) and its pivaloyloxymethyl ester (18) 7- [2- (2-aminothiazol-4-yl) -2-hydroxyimino-acetamido] -3- (1-pyrrolidinyl) carbonyloxymethyl-3- Cephem-4-carboxylic acid (syn isomer) and its pivaloyloxymethyl ester (19) 7- [2- (2-aminothiazol-4-yl) -2-hydroxyimino-acetamido] -3- (1 -Piperidinyl) carbonyloxymethyl-3-cephem-4-carboxylic acid (syn isomer) and its pivaloyloxymethyl ester

The cephalosporin compound (I) and its pharmacologically acceptable addition salt are produced, for example, as follows.

(Production Method 1) A method of reacting the compound (II) with the compound (III) or a reaction derivative thereof.

The compound (III) is used as a free carboxylic acid or as a reactive derivative thereof in this reaction (acylation reaction).
, And any of the embodiments are included in the present invention. That is, as a free acid or a salt of sodium, potassium, calcium, triethylamine, pyridine or the like, or an acid halide thereof (acid chloride, acid bromide, etc.),
Acid anhydride, mixed acid anhydride [substituted phosphoric acid (dialkyl phosphoric acid, etc.), alkyl carbonic acid (monoethyl carbonic acid, etc.), active amide (amide with imidazole, etc.), ester (cyanomethyl ester, 4-nitrophenyl ester) Etc.) and the like as a reactive derivative.

In this reaction, when the compound (III) is used in a free acid or salt state, it is preferable to carry out the reaction in the presence of a condensing agent. Examples of the condensing agent include N, N ' -N, N'-disubstituted carbodiimides such as dicyclohexylcarbodiimide; 1-ethyl-3- (3'-dimethylaminopropyl) carbodiimide, N-cyclohexyl-N'-morpholinoethylcarbodiimide, N-cyclohexyl-N'-
Carbodiimide compounds such as (4-diethylaminocyclohexyl) carbodiimide; dehydrating agents such as azolide compounds such as N, N'-carbonyldiimidazole and N, N'-thionyldiimidazole are used. When these condensing agents are used, the reaction is considered to proceed via the reactive derivative of carboxylic acid.

This reaction is usually carried out in an inert solvent.
As the solvent, specifically, water, acetone, dioxane,
Acetonitrile, chloroform, benzene, methylene chloride, ethylene chloride, tetrahydrofuran, ethyl acetate,
N, N-dimethylformamide, pyridine, etc., and mixtures thereof. This reaction is preferably carried out at room temperature to under cooling (-20 ° C to 0 ° C).

The cephalosporin compound (I) and its pharmacologically acceptable addition salt obtained by the above method usually have a protecting group. As means for removing the protective group, depending on the type of the protective group, decomposition with acid (for example, formyl,
BOC, trityl, tetrahydropyranyl, etc. are decomposed by acids such as hydrochloric acid and trifluoroacetic acid), and are decomposed by bases (for example, dichloroacetyl, trifluoroacetyl, etc. are decomposed by bases such as sodium hydroxide and sodium bicarbonate). , Decomposition with hydrazine (for example, phthaloyl is decomposed with hydrazine), catalytic reduction (for example, benzyl, benzyloxycarbonyl, etc. is decomposed with palladium-carbon, etc.), and these are used for β-lactam synthesis and peptide synthesis. The conventional method used in can be appropriately selected and performed.

The compound (II) has, for example, the formula (II-1):

[0058]

[Chemical 20]

(In the formula, R ¹ and R ² are as defined above, and R ⁷ is a hydrogen atom or an amino-protecting group.)
By esterifying the compound represented by the following (hereinafter referred to as compound (II-1)), particularly compound (II-1) and compound
It is produced by reacting with (V).

With respect to R ⁷ of formula (II-1), the amino protecting group is an amino protecting group known per se, for example, benzylcarbonyl, 2-thienylacetyl, 2-furylacetyl, D-5-.
Amino-5-carboxyvaleryl, BOC, trityl, phthaloyl, o-hydroxybenzylidene and the like can be mentioned.

In this reaction, the compound (II-1) is used as its reactive derivative (for example, alkali metal salt such as sodium salt and potassium salt, alkaline earth metal salt such as calcium salt, triethylamine salt, pyridine salt and the like). It is preferable to subject it to the reaction.

This reaction is usually carried out under cooling at -20 to 40 ° C., preferably at -20 to 0 ° C. in order to avoid the by-product of the Δ ² -isomer, and a solvent which does not inhibit the reaction (eg dimethylformamide). , Dimethylacetamide, hexamethylenephosphoric triamide, acetone, acetonitrile, etc.).

In this reaction, R ⁷ in the formula (II-1) is preferably an amino protecting group, and in this case, the compound (II-1)
The compound (V) is reacted with the compound (V) to give a compound in which the amino group at the 7-position in the formula (II) is protected. The protecting group can be eliminated by a means known per se.

Specific examples of means for eliminating the protective group include benzylcarbonyl, 2-thienylacetyl, 2-furylacetyl, D-5-amino-5-carboxyvaleryl and the like. For example, a method of decomposing with methanol after iminochlorination with phosphorus chloride, a method of treating with an acid (for example, hydrochloric acid, formic acid, trifluoroacetic acid, etc.) for elimination of BOC, trityl, o-hydroxybenzylidene, etc. For elimination of phthaloyl and the like, for example, the ingemans method using hydrazine and the like can be mentioned.

(Production method 2) A method of reacting the compound (IV) with the compound (V).

In this reaction, compound (IV) is used as a reactive derivative thereof (eg, alkali metal salt such as sodium salt or potassium salt, alkaline earth metal salt such as calcium salt, triethylamine salt, pyridine salt, etc.). Preferably.

This reaction is usually carried out under cooling at -20 to 40 ° C., preferably at -20 to 0 ° C. to avoid the by-product of Δ ² -isomer, and a solvent which does not inhibit the reaction (eg, dimethylformamide). , Dimethylacetamide, hexamethylenephosphoric triamide, acetone, acetonitrile, etc.).

In this reaction, a compound as a starting material
(IV) can be produced by reacting compound (II-1) with compound (III) in the same manner as in production method 1.

(Production Method 3) A method of reacting the compound (VI) with the compound (VII).

In this reaction, compound (VI) and compound (VI
The reaction with I) is usually carried out in a solvent such as dimethylformamide, dimethylacetamide, acetonitrile, dioxane, tetradofuran, alcohol or another solvent which does not adversely influence the reaction, or a mixture thereof with water. The time required for the reaction is usually 30 minutes to several dozen hours. Although the reaction temperature is not particularly limited, it is usually performed at room temperature to 60 ° C.

The compound (VI) as a starting material is represented by a known method, that is, a general formula (XI): Y-CH ₂ COCH ₂ CO ₂ H (XI) (wherein Y is as defined above). The compound (II) can be produced by a method of acylating the compound (II) with the compound (XI), followed by nitrosation or oxime formation.

(Production method 4) Compound (VIII) A method of reacting with compound (IX).

In this reaction, compound (VIII) and compound (I
The reaction with X) is usually carried out in a solvent such as dimethylformamide, dimethylacetamide, acetonitrile, dioxane, tetrahydrofuran, alcohol or another solvent which does not adversely influence the reaction, or a mixture thereof with water. The time required for the reaction is usually 30 minutes to several dozen hours. The reaction temperature is not particularly limited, but usually from room temperature to 6
It is carried out between 0 ° C.

The compound (VIII) as a starting material is prepared by a known method, that is, the compound of the general formula (XII):

[0075]

[Chemical 21]

(Wherein R ⁴ is as defined above) can be produced by a method of acylating compound (II) with compound (XII).

(Production method 5) A method of carbamoylating the 3-hydroxymethyl group of the compound (X).

The method for carbamoylating the 3-hydroxymethyl group of the compound (X) is described in, for example, JP-A-55-5759.
As disclosed in Japanese Unexamined Patent Publication (Kokai) No. 2, a hydroxymethyl group is reacted with phosgene or N, N′-carbonyldiimidazole to give a reactive derivative, and then the compound of the general formula (XIII): R ¹ —NH—R ² ( XIII) (wherein R ¹ and R ² have the same meanings as described above) can be produced by reacting the compound (XIII).

In addition, 2-hydroxyimino-2-phenylacetonitrile is reacted with hydroxymethyl group with phosgene to obtain formula (XIV):

[0080]

[Chemical formula 22]

The compound (XIV) represented by
V):

[0082]

[Chemical formula 23]

(Wherein R ³ , R ⁴ and R ⁵ have the same meanings as described above), and the compound (XV) is introduced into the compound (XV) to react with the compound (XIII). ..

The method for carbamoylating the hydroxymethyl group is not limited to the method for producing the cephalophosporin compound (I), but the 3-di-substitution of the compounds (II) and (II-1) can be carried out by the method. A carbamoyloxymethyl cephalosporin derivative can also be synthesized.

In this reaction, compound (X) and compound (XI
The reaction with V) is usually carried out in acetone, dioxane, acetonitrile, tetrahydrofuran, benzene, chloroform, methylene chloride, ethyl acetate or other solvents which do not adversely influence the reaction, and mixtures thereof. The time required for the reaction is usually 30 minutes to several tens of hours. The reaction temperature is not particularly limited, but is preferably room temperature to under cooling (-20 to 0 ° C).

The reaction of the compound (XV) with the compound (XIII) is usually water, acetone, dioxane, acetonitrile, tetrahydrofuran, chloroform, methylene chloride, ethyl acetate or another solvent which does not adversely influence the reaction, and a mixture thereof. Done in. The time required for the reaction is 10
~ 30 minutes. The reaction temperature is not particularly limited, but is preferably room temperature to under cooling (-20 to 0 ° C).

The compound (X) as a starting material can be produced by a known method, that is, by acylating a 7-amino-3-hydroxymethylcephalosporin derivative by the compound (III).

Compound (I) can be produced by a method known per se by
It may be a pharmaceutically acceptable addition salt.

[0089]

[Effect] The cephalosporin compound (I) in which R ³ is a carboxyl group and its pharmacologically acceptable addition salt have excellent antibacterial activity, and Staphylococcus aureus , Staphylococcus ep
Gram-positive bacteria such as idermidis), Escherichia coli (E
scherichia coli), Klebsie pneumoniae (Klebsie
lla pneumoniae), Proteus vulgaris (Proteus v
ulgaris), Proteus mirabilli
s) and gram-negative bacteria such as Morganella morganii. That is, the cephalosporin compound (I) and a pharmacologically acceptable addition salt thereof are valuable antibacterial agents having an improved antibacterial activity against Gram-positive bacteria while maintaining the antibacterial activity against Gram-negative bacteria. Moreover, these compounds have extremely low toxicity.

The cephalosporin compound (I) in which R ³ is an esterified carboxyl group and its pharmacologically acceptable addition salt are rapidly absorbed into the blood by oral administration, A high blood concentration of the cephalosporin compound (I) whose metabolite R ³ is a carboxyl group or a pharmacologically acceptable addition salt thereof is obtained, and the high blood concentration lasts for a long time.

Further, by using cephalosporin compound (I), which is a carboxyl group in which R ³ is esterified, as its addition salt, the solubility in the digestive tract is remarkably increased, the absorption efficiency is further improved, and the absorption efficiency is improved. Is even higher.

The cephalosporin compound (I) and its pharmacologically acceptable addition salts are useful as agents for preventing and / or treating infectious diseases (particularly, bacteriopathies). The preventive / therapeutic agent for bacterial infection is, for example, a warm-blooded animal including a human (dog, cat,
It can be used as a prophylactic / therapeutic agent for diseases (eg, purulent diseases, respiratory infections, biliary tract infections, urinary tract infections, etc.) caused by bacteria of cattle, horses, rats, mice, etc.).

The cephalosporin compound (I) in which R ³ is a carboxyl group and a pharmaceutically acceptable addition salt thereof are formulated as a rectal composition (eg suppository or retention enema) or as an injection. You can also

The preventive / therapeutic agent for infectious diseases comprising the cephalosporin compound (I) in which R ³ is an esterified carboxyl group or a pharmacologically acceptable addition salt thereof has an excellent effect as described above by oral administration. And is orally administered as an oral preparation.

This prophylactic / therapeutic agent for infectious diseases can be produced by diluting with a pharmaceutical excipient according to a method known per se. For example, as the excipient, specifically, starch, lactose, sugar, calcium carbonate, calcium phosphate, etc. are used.

By the way, it is preferable to further add an organic acid to the therapeutic agent for bacterial infection for oral administration. Thus, the cephalosporin compound (I) in which R ³ is an esterified carboxyl group and the pharmacologically acceptable addition salt thereof have higher solubility in the gastrointestinal tract, and are more easily absorbed into the blood. Become.

The organic acid is not particularly limited as long as it is pharmaceutically acceptable. For example, maleic acid, fumaric acid, tartaric acid, citric acid, succinic acid, malic acid, oxalic acid, mandelic acid, malonic acid, benzoic acid. Preferred examples include organic carboxylic acids and the like. The amount of the organic acid added is usually 0.01 to 20 mol, preferably 0.02, per 1 mol of the cephalosporin compound (I) in which R ³ is an esterified carboxyl group or its addition salt.
~ 2 moles.

If desired, the oral therapeutic bacterial infection treating agent may further contain other additives, for example, binders (eg, starch, gum arabic, carboxymethyl cellulose, hydroxypropyl cellulose, crystalline cellulose, etc.). ), A lubricant (eg, magnesium stearate,
Talc etc.), a disintegrating agent (eg, carboxymethyl cellulose calcium, talc etc.) and the like can be mentioned as preferable additives. After mixing the components, the mixture is subjected to a method known per se, for example, capsules, tablets, fine granules, granules,
By preparing a formulation suitable for oral administration such as dry syrup, a therapeutic agent for bacterial infection for oral administration is manufactured.

The dose of the cephalosporin compound (I) and its pharmacologically acceptable salt depends on the administration subject, symptoms,
For example, when administered to adult purulent diseases, the dose is about 1 to 40 mg / kg body weight orally about 1 to 4 times a day.

Cephalosporin compound (I) and its pharmacologically acceptable addition salts, and other antibacterial active substances such as antibacterial agents (penicillins, aminoglucosides, cephalosporins, etc.) or bacterial infection A therapeutic agent for systemic symptoms (antipyretic, analgesic, antiphlogistic, etc.) may be used in combination.

Next, the physical properties and production method of the compound of the present invention will be specifically described with reference to Examples, but the present invention is not limited thereto.

[0102]

【Example】

Example 1 7-Amino-3- (N, N-dimethylcarbamoyloxymethyl)-
3-cephem-4-carboxylic acid

(1) 2-Hydroxyimino-2-phenylacetonitrile (10.96 g) and dimethylaniline (9.09 g) were dissolved in a mixture of benzene (67 ml) and dioxane (6.7 ml),
Trichloromethyl chloroformate 7.42 g benzene 67
The solution was added dropwise to the solution at 0 to 3 ° C. After stirring at 5 ℃ for 1 hour and then at room temperature for 14 hours, 300 ml of tetrahydrofuran
Was added and the mixture was cooled to 3 ° C. 7-t-butoxycarbonylamino
Add 22.3 g of -3-hydroxymethyl-3-cephem-4-carboxylic acid benzhydryl ester and add triethylamine 6.
A solution of 90 ml of tetrahydrofuran (90 ml) was added dropwise at the same temperature, and then the mixture was stirred at room temperature for 28 hours.

The solvent was distilled off under reduced pressure, and the residue was washed with ethyl acetate.
It was dissolved in 400 ml, washed successively with 10% aqueous citric acid solution, saturated aqueous sodium hydrogen carbonate solution, and then saturated saline with 200 ml each, and dried over anhydrous Glauber's salt. After decolorizing carbon treatment, ethyl acetate was distilled off under reduced pressure, 150 ml of diethyl ether and 700 ml of isopropyl ether were added to the residue, and the mixture was stirred at room temperature for 1 hour for crystallization, and the precipitated crystals were collected by filtration, and 7-t-butoxy was added. Carbonylamino-3-[(2-
Phenylacetonitrile-2-yl-iminooxy) carbonyloxymethyl] -3-cephem-4-carboxylic acid benzhydryl ester (22.47 g) was obtained as white crystals.

IR (nujol, cm ^-1 ) 2230, 1790, 1725,
1700 NMR (DMSO -d ₆ , δppm) 1.45 (s, 9H, -OC (CH ₃ ) ₃ ) 3.70 (br.s, 2H, C ₂ -H ₂ ) 4.80 ~ 5.40 (m, 3H, C ₃ -CH _2- , C ₆ -H) 5.65 (d × d, J = 5.0, 9.0Hz, 1H, C ₇ -H) 6.95 (s, 1H, -CO ₂ CH <) 7.10 ~ 8.20 (m, 16H, phenyl × 3, -CONH-)

(2) 22.4 g of the compound of (1) was added to 224 hexane.
The mixture was dissolved in a mixed solution of 15 ml of water and 22 ml of water, and a solution of 3.07 g of 50% dimethylamine aqueous solution in 15 ml of dioxane was added dropwise at 3 ° C. and stirred at the same temperature for 10 minutes. Add 500 ml of ethyl acetate,
It was washed with 300 ml of 10% aqueous citric acid solution, and the aqueous layer was further extracted with 100 ml of ethyl acetate. Combine the ethyl acetate layers,
After washing with 100 ml of saturated saline, it was dried with anhydrous Glauber's salt. Ethyl acetate was evaporated under reduced pressure, the residue was subjected to silica gel column chromatography, and the solvent of the target fraction was evaporated under reduced pressure by elution with n-hexane-ethyl acetate to give 7-t-butoxycarbonylamino- 17.6 g of a foam powder of 3- (N, N-dimethylcarbamoyloxymethyl) -3-cephem-4-carboxylic acid benzhydryl ester was obtained.

IR (nujol, cm ^-1 ) 1785, 1710 NMR (DMSO -d ₆ , δppm) 1.45 (s, 9H, -OC (CH ₃ ) ₃ ) 2.80 (s, 6H, -N (CH ₃ ) ₂ ) 3.60 (s, 2H, C ₂ -H ₂ ) 4.65, 4.95 (ABq, J = 13.0Hz, 2H, C ₃ -CH _2- ) 5.13 (d, J = 5.0Hz, 1H, C ₆ -H) 5.60 (d × d, J = 5.0, 9.0Hz, 1H, C ₇ -H) 6.92 (s, 1H, -CO ₂ CH <) 7.10 to 7.70 (m, 10H, phenyl × 2) 8.00 (d, J = 9.0 Hz, 1H, -CONH-)

(3) 10.0 g of the compound of (2) was added to anisole 1
It was dissolved in 0 ml, 30 ml of trifluoroacetic acid was added at 5 ° C., and the mixture was stirred at the same temperature for 15 minutes. Isopropyl ether 600 ml
It was poured into and the precipitate was collected by filtration to obtain 4.6 g of powder. 4.6 g of this powder was suspended in 46 ml of water, and the pH was adjusted with saturated aqueous sodium hydrogen carbonate under ice cooling.
= 7.0 and dissolved. The pH was adjusted to 3.0 with 2N-hydrochloric acid, the mixture was stirred at the same temperature for 30 minutes, and the precipitate was collected by filtration to give the title compound as a powder (3.07 g).

IR (nujol, cm ^-1 ) 1800, 1695 NMR (DMSO -d ₆ + 20% DCl, δppm) 2.85 (s, 6H, -N (CH ₃ ) ₂ ) 3.65 (s, 2H, C ₂ -H ₂ ) 4.00 to 5.80 (m, 4H, C ₃ -CH _2- , C ₆ -H, C ₇ -H)

Example 2 7-Amino-3- (N, N-dimethylcarbamoyloxymethyl)-
3-Cephem-4-carboxylic acid benzhydryl ester hydrochloride

(1) 10.96 g of 2-hydroxyimino-2-phenylacetonitrile and 9.09 g of dimethylaniline were dissolved in a mixture of 67 ml of benzene and 6.7 ml of dioxane, and 67 ml of benzene containing 7.42 g of trichloromethyl chloroformate.
Was added dropwise at 0 to 3 ° C. Then, after stirring at room temperature for 20 hours, 300 ml of tetrahydrofuran was added and cooled to 0 ° C. 7- (2-phenylacetamido) -3-hydroxymethyl
-3-Cephem-4-carboxylic acid benzhydryl ester 2
3.1 g was added, a solution of triethylamine 6.9 ml in tetrahydrofuran 90 ml was added dropwise at the same temperature, and then at room temperature, 20
Stir for hours. The solvent was distilled off under reduced pressure, and the residue was ethyl acetate.
It was dissolved in 400 ml, washed successively with 10% aqueous citric acid solution, saturated aqueous sodium hydrogen carbonate solution, and then with 200 ml each of saturated saline, and dried over anhydrous Glauber's salt. After decolorizing carbon treatment, ethyl acetate was distilled off under reduced pressure, 300 ml of diethyl ether was added to the crystalline residue, and the crystals were collected by filtration to give 7- (2-phenylacetamide) -3-[(2-phenylacetonitrile-2-yl- Iminooxy) carbonyloxymethyl] -3-cephem-4-carboxylic acid benzhydryl ester (18.6 g) was obtained as white crystals.

IR (nujol, cm ^-1 ) 2350, 1800, 1780,
1730, 1650 NMR (DMSO -d ₆ , δppm) 3.30 ~ 4.10 (m, 2H, C ₂ -H ₂ ) 3.55 (s, 2H, -CH ₂ CO-) 4.80 ~ 5.50 (m, 3H, C ₃ -CH _2- , C ₆ -H) 5.85 (d × d, J = 5.0, 9.0Hz, 1H, C ₇ -H) 6.95 (s, 1H, -CO ₂ CH <) 7.00 to 8.10 (m, 20H, phenyl × 4) 9.16 (d, J = 9.0Hz, 1H, -CONH-)

(2) 17.64 g of the compound of (1) was added to dioxane.
Dissolve in a mixture of 140 ml and 14 ml of water and add dropwise a solution of 50% dimethylamine aqueous solution 2.32 g of dioxane 20 ml at 2 ° C.
The mixture was stirred at the same temperature for 15 minutes. Add 400 ml of ethyl acetate,
It was washed with 200 ml of a 10% aqueous citric acid solution, and the aqueous layer was further extracted with 100 ml of ethyl acetate. The ethyl acetate layers were combined, washed with 100 ml of saturated saline and then dried with anhydrous Glauber's salt.
The ethyl acetate was distilled off under reduced pressure, the residue was subjected to silica gel column chromatography, and eluted with n-hexane-ethyl acetate, and the solvent of the target fraction was distilled off under reduced pressure to give 7- (2-phenylacetamide). 9.1 g of a foamy powder of -3- (N, N-dimethylcarbamoyloxymethyl) -3-cephem-4-carboxylic acid benzhydryl ester was obtained.

IR (nujol, cm ^-1 ) 1780, 1700 NMR (DMSO -d ₆ , δppm) 2.80 (s, 6H, -N (CH ₃ ) ₂ ) 3.55 (s, 2H, -CH ₂ CO-) 3.62 (br.s, 2H, C ₂ -H ₂ ) 4.63, 4.95 (ABq, J = 13.0Hz, 2H, C ₃ -CH _2- ) 5.15 (d, J = 5.0Hz, 1H, C ₆ -H) 5.80 (d × d, J = 5.0, 9.0Hz, 1H, C ₇ -H) 6.95 (s, 1H, -CO ₂ CH <) 7.00 to 7.80 (m, 15H, phenyl × 3) 9.15 (d, J = 9.0 Hz, 1H, -CONH-)

(3) 4.27 g of phosphorus pentachloride was added to 44 m of methylene chloride.
It was suspended in l and cooled to 5 ° C. After adding 1.66 ml of pyridine and stirring at the same temperature for 1 hour, the mixture was cooled to -5 ° C and the compound of (2) was added.
3.21 g was added, and the mixture was further stirred at -5 to 0 ° C for 1 hour. Then cool to -35 ° C and add 8.0 ml of methanol at -35 to -20 ° C.
The mixture was added dropwise to the above, and after stirring at the same temperature for 1 hour, 8.0 ml of water was added and the mixture was stirred at 0 ° C. for 30 minutes. After 50 ml of water was added and the layers were separated, the aqueous layer was further extracted with 20 ml of methylene chloride. The methylene chloride layers were combined, washed successively with 10% aqueous citric acid solution, saturated aqueous sodium hydrogen carbonate solution, and then with 50 ml of saturated saline solution, respectively, and dried over anhydrous Glauber's salt. The solution was concentrated under reduced pressure to about 20 ml and cooled with ice to 9.33.
0.55 ml of N-hydrogen chloride isopropanol solution and 100 ml of diethyl ether were added, and the precipitate was collected by filtration to obtain 2.35 g of the title compound powder.

IR (nujol, cm ^-1 ) 1790, 1710 NMR (DMSO -d ₆ , δppm) 2.80 (s, 6H, -N (CH ₃ ) ₂ ) 3.72 (br.s, 2H, C ₂ -H ₂ ) 4.72, 5.00 (ABq, J = 13.0Hz, 2H, C ₃ -CH _2- ) 5.25 (s, 2H, C ₆ -H, C ₇ -H) 6.95 (s, 1H, -CO ₂ CH <) 7.00 ~7.70 (m, 10H, phenyl × 2) 3.00~5.00 (br, 3H , -N + H 3)

Example 3 7-Amino-3- (N, N-dimethylcarbamoyloxymethyl)-
3-Cephem-4-carboxylic acid pivaloyloxymethyl ester hydrochloride

(1) 500 mg of the compound of Example 1 was suspended in 5 ml of water, and 0.24 ml of triethylamine was added and dissolved. The
-tert-Butyl-di-carbonate 400 mg dioxane 2.5
The solution of ml was added and it stirred at room temperature for 17 hours. 20 ml of water was added and the mixture was washed with 20 ml of ethyl acetate, and the ethyl acetate layer was further extracted with 20 ml of water. The aqueous layers were combined and washed with 10 ml of ethyl acetate, and then the aqueous layer was acidified by adding citric acid and extracted twice with 30 ml of ethyl acetate. The ethyl acetate layers were combined and saturated brine 20 ml
After washing with water and drying over anhydrous Glauber's salt, the ethyl acetate was distilled off under reduced pressure to remove 7-t-butoxycarbonylamino-3- (N, N-dimethylcarbamoyloxymethyl) -3-cephem-4-carboxylic acid. 660 mg of a foamy powder of

IR (nujol, cm ^-1 ) 1785, 1700 NMR (DMSO -d ₆ , δppm) 1.43 (s, 9H, -OC (CH ₃ ) ₃ ) 2.85 (s, 6H, -N (CH ₃ ) ₂ ) 3.55 (br.s, 2H, C ₂ -H ₂ ) 4.65, 5.02 (ABq, J = 14.0Hz, 2H, C ₃ -CH _2- ) 5.05 (d, J = 5.0Hz, 1H, C ₆ -H ) 5.48 (d × d, J = 5.0, 9.0Hz, 1H, C ₇ -H) 7.93 (d, J = 9.0Hz, 1H, -CONH-) 3.10 ~ 4.00 (br, 1H, -CO ₂ H)

(2) 1.05 g of the compound of (1) was dissolved in 5.27 ml of N, N-dimethylacetamide, 0.53 ml of dicyclohexylamine was added, and the mixture was cooled to -5 ° C. 953 mg of pivaloyloxymethyl iodide was added, and the mixture was stirred at -5 to 0 ° C for 1.5 hours. 20 ml of ethyl acetate was added, the insoluble matter was filtered off, the filtrate was washed successively with 10% aqueous citric acid solution, saturated aqueous sodium hydrogen carbonate solution and then saturated saline solution, 20 ml each, dried over anhydrous Glauber's salt, and the ethyl acetate was distilled off under reduced pressure. .. The residue was subjected to silica gel column chromatography, eluted with n-hexane-ethyl acetate, and the solvent of the target fraction was evaporated under reduced pressure to give 7-t-
760 mg of a foamy powder of butoxycarbonylamino-3- (N, N-dimethylcarbamoyloxymethyl) -3-cephem-4-carboxylic acid pivaloyloxymethyl ester was obtained.

IR (nujol, cm ^-1 ) 1790, 1755, 1700 NMR (DMSO -d ₆ , δppm) 1.27 (s, 9H, -COC (CH ₃ ) ₃ ) 1.43 (s, 9H, -OC (CH ₃ ) ₃ ) 2.85 (s, 6H, -N (CH ₃ ) ₂ ) 3.60 (br.s, 2H, C ₂ -H ₂ ) 4.53, 5.00 (ABq, J = 14.0Hz, 2H, C ₃ -CH _2- ) 5.10 (d, J = 5.0Hz, 1H, C ₆ -H) 5.50 (d × d, J = 5.0, 9.0Hz, 1H, C ₇ -H) 5.65 ~ 6.00 (m, 2H, -CO ₂ CH ₂ -) 7.95 (d, J = 9.0Hz, 1H, -CONH-)

(3) 740 mg of the compound of (2) was added to 3.7 m of formic acid.
The solution was dissolved in 1 l, 0.63 ml of 9.33N-hydrogen chloride isopropanol solution was added at 5 ° C., and the mixture was stirred at the same temperature for 5 minutes. 40 ml of diethyl ether and 60 m of isopropyl ether
l was added, and the precipitated gum was separated by decantation, the obtained gum was dissolved in 5 ml of methanol, and 50 ml of isopropyl ether was added. The precipitated crystals are collected by filtration,
590 mg of the title compound was obtained.

IR (nujol, cm ^-1 ) 1785, 1750, 1710 NMR (DMSO -d ₆ , δppm) 1.25 (s, 9H, -COC (CH ₃ ) ₃ ) 2.80 (s, 6H, -N (CH ₃ ) ₂ ) 3.80 (s, 2H, C ₂ -H ₂ ) 4.70, 5.10 (ABq, J = 14.0Hz, 2H, C ₃ -CH _2- ) 5.10 ~ 5.50 (m, 2H, C ₆ -H, C ₇ -H) 5.60 ~ 6.20 (m, 2H, -CO ₂ CH _2- ) 7.00 ~ 11.00 (br, 3H, -N ⁺ H ₃ )

Example 4 7-Amino-3- (N, N-dimethylcarbamoyloxymethyl)-
3-Cephem-4-carboxylic acid 1-isopropoxycarbonyloxyethyl ester hydrochloride

(1) 2.9 g of the compound of Example 2 (2) was dissolved in 2.9 ml of anisole, and trifluoroacetic acid was added at 5 ° C.
8.7 ml was added and the mixture was stirred at the same temperature for 15 minutes. It was poured into 150 ml of isopropyl ether, the precipitate was collected by filtration, and 1.88 g of powder of 7- (2-phenylacetamido) -3- (N, N-dimethylcarbamoyloxymethyl) -3-cephem-4-carboxylic acid was added. Obtained.

IR (nujol, cm ^-1 ) 1780, 1725, 1685 NMR (DMSO -d ₆ , δppm) 2.85 (s, 6H, -N (CH ₃ ) ₂ ) 3.30 to 3.90 (m, 4H, C _2- ) H ₂ , -CH ₂ CO-) 4.75, 5.03 (ABq, J = 14.0Hz, 2H, C ₃ -CH _2- ) 5.08 (d, J = 5.0Hz, 1H, C ₆ -H) 5.70 (d × d , J = 5.0, 9.0Hz, 1H, C ₇ -H) 7.30 (s, 5H, phenyl) 9.08 (d, J = 9.0Hz, 1H, -CONH-)

(2) 1.3 g of the compound of (1) was dissolved in 6.5 ml of N, N-dimethylacetamide, 0.68 ml of dicyclohexylamine was added, and the mixture was cooled to -5 ° C. Add 1.08 g of 1-isopropoxycarbonyloxyethyl iodide-5-
The mixture was stirred at 0 ° C for 2 hours. 20 ml of ethyl acetate was added, the insoluble matter was filtered, 100 ml of ethyl acetate was added to the filtrate, and the mixture was washed with 50 ml of 10% citric acid aqueous solution. The aqueous layer was further extracted with 50 ml of ethyl acetate, and the ethyl acetate layers were combined, washed with 50 ml each of saturated aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous Glauber's salt, and the ethyl acetate was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography, eluted with benzene-ethyl acetate, and the solvent of the target fraction was distilled off under reduced pressure.
-(2-Phenylacetamido) -3- (N, N-dimethylcarbamoyloxymethyl) -3-cephem-4-carboxylic acid 1-isopropoxycarbonyloxyethyl ester foam powder
Obtained 1.2 g.

IR (nujol, cm ^-1 ) 1760, 1700 NMR (DMSO -d ₆ , δppm) 1.25 (d, J = 6.0Hz, 6H,-(CH ₃ ) ₂ ) 1.50 (d, J = 6.0Hz, 3H, -CH ₃ ) 2.85 (s, 6H, -N (CH ₃ ) ₂ ) 3.55 (s, 2H, -CH ₂ CO-) 3.63 (br.s, 2H, C ₂ -H ₂ ) 4.50 ~ 5.00 ( m, 3H, C ₃ -CH _2- , -OCO ₂ CH <) 5.13 (d, J = 5.0Hz, 1H, C ₆ -H) 5.75 (d × d, J = 5.0, 9.0Hz, 1H, C ₇ -H) 6.60 ~ 7.00 (m, 1H, -CO ₂ CH <) 7.30 (s, 5H, phenyl) 9.10 (d, J = 9.0Hz, 1H, -CONH-)

(3) Methyl chloride was added to 1.82 g of phosphorus pentachloride.
It was suspended in ml and cooled to 5 ° C. Pyridine (0.71 ml) was added and the mixture was stirred at the same temperature for 1 hr, cooled to -5 ° C, 1.2 g of the compound of (2) was added, and the mixture was further stirred at -5 to 0 ° C for 1 hr. Then, cool to -35 ° C and add 3.5 ml of methanol to -35 ° C.
Add dropwise at -20 ℃ and stir at the same temperature for 1 hour.
ml was added and the mixture was stirred at 0 ° C for 30 minutes. Methylene chloride 100
ml and water (50 ml) are added, and the aqueous layer is separated after separation.
Extract 4 times with 0 ml. Combine 5% methylene chloride layers
The extract was washed successively with 50 ml each of a saline solution, a saturated sodium bicarbonate solution, and a saturated saline solution, and dried with anhydrous Glauber's salt. Add 0.35 ml of 9.33 N-hydrogen isopropanol solution and add about 10 m of the solution under reduced pressure.
The mixture was concentrated to l, 100 ml of diethyl ether was added, and the precipitate was collected by filtration to obtain 820 mg of powder of the title compound.

IR (nujol, cm ^-1 ) 1790, 1760, 1705 NMR (DMSO -d ₆ , δppm) 1.25 (d, J = 6.0Hz, 6H,-(CH ₃ ) ₂ ) 1.50 (d, J = 6.0 Hz, 3H, -CH ₃ ) 2.85 (s, 6H, -N (CH ₃ ) ₂ ) 3.73 (br.s, 2H, C ₂ -H ₂ ) 4.40 to 5.10 (m, 3H, C ₃ -CH _2- , -OCO ₂ CH <) 5.23 (br.s, 2H, C ₆ -H, C ₇ -H) 6.50 ~ 7.10 (m, 1H, -CO ₂ CH <) 3.00 ~ 10.00 (br, 3H, -N ⁺ H ₃ )

Example 5 7- [2- (2-Aminothiazol-4-yl) -2-hydroxyimino-acetamido] -3- (N, N-dimethylcarbamoyloxymethyl) -3-cephem-4-carvone Acid sodium salt (syn isomer)

(1) 2- (2-tritylaminothiazole-4-
Yl) -2-Trityloxyiminoacetic acid dicyclohexylamine salt (syn isomer) 2.8 g, and the compound of Example 2
1.5 g was suspended in 45 ml of methylene chloride and cooled to -10 ° C. 0.53 ml of pyridine and 0.46 ml of phosphorus oxychloride were sequentially added, and the mixture was stirred at the same temperature for 20 minutes. Ethyl acetate (200 ml) was added, and the mixture was washed successively with 10% citric acid aqueous solution and saturated saline (100 ml) each, dried over anhydrous Glauber's salt, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, eluted with benzene-ethyl acetate, and the solvent of the target fraction was evaporated under reduced pressure to give 7- [2- (2-tritylaminothiazole.
-4-yl) -2-Trityloxyimino-acetamide] -3-
(N, N-dimethylcarbamoyloxymethyl) -3-cephem
-4-Carboxylic acid benzhydryl ester (syn isomer)
2.49 g of a foamy powder of

IR (nujol, cm ^-1 ) 1790, 1690 NMR (DMSO -d ₆ , δppm) 2.80 (s, 6H, -N (CH ₃ ) ₂ ) 3.65 (br.s, 2H, C ₂ -H ₂ ) 4.70, 5.03 (ABq, J = 13.0Hz, 2H, C ₃ -CH _2- ) 5.27 (d, J = 5.0Hz, 1H, C ₆ -H) 5.97 (d × d, J = 5.0, 9.0Hz, 1H, C ₇ -H) 6.60 (s, 1H, thiazole C ₅ -H) 6.95 (s, 1H, -CO ₂ CH <) 7.00 ~ 7.70 (m, 40H, phenyl x 8) 8.75 (br.s, 1H , Thiazole C ₂ -NH-) 9.93 (d, J = 9.0Hz, 1H, -CONH-)

(2) Anisole was added to 2.49 g of the compound of (1).
It was dissolved in 2.5 ml, 7.5 ml of trifluoroacetic acid was added at 5 ° C., and the mixture was stirred at the same temperature for 6 hours. Isopropyl ether 2
It was poured into 00 ml and the precipitate was collected by filtration to obtain 900 mg of powder. Suspend the obtained powder in 90 ml of water and add saturated sodium bicarbonate water.
It was dissolved at pH = 7.5. It was adsorbed on 90 ml of Diaion HP-21, washed with water and eluted with a 7% aqueous solution of acetonitrile, and the target fraction was concentrated under reduced pressure. The obtained solution was freeze-dried to obtain 600 mg of the title compound powder.

IR (nujol, cm ^-1 ) 1765, 1680 NMR (DMSO -d ₆ , δppm) 2.85 (s, 6H, -N (CH ₃ ) ₂ ) 3.40 (br.s, 2H, C ₂ -H ₂ ) 4.75, 5.05 (ABq, J = 13.0Hz, 2H, C ₃ -CH _2- ) 5.05 (d, J = 5.0Hz, 1H, C ₆ -H) 5.70 (br.s, 1H, C ₇ -H) 6.67 (s, 1H, thiazole C ₅ -H) 7.15 (br.s, 2H, -NH ₂ ) 9.45 (br.s, 1H, -CONH-) 10.50 ~ 13.00 (br, 1H, -OH)

Example 6 7- [2- (2-Aminothiazol-4-yl) -2-hydroxyimino-acetamido] -3- (N, N-dimethylcarbamoyloxymethyl) -3-cephem-4-carvone Acid pivaloyloxymethyl ester hydrochloride (syn isomer)

(1) 2- (2-Tritylaminothiazole-4-
Yl) -2-Trityloxyiminoacetic acid dicyclohexylamine salt (syn isomer) 1.25 g and the compound of Example 3
0.55 g was suspended in 25 ml of methylene chloride and cooled to -10 ° C. Pyridine (0.24 ml) and phosphorus oxychloride (0.20 ml) were sequentially added, and the mixture was stirred at the same temperature for 20 minutes. Ethyl acetate (100 ml) was added, and the mixture was washed successively with 10% aqueous citric acid solution and saturated brine (50 ml each), dried over anhydrous Glauber's salt, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, eluted with benzene-ethyl acetate, and the solvent of the target fraction was evaporated under reduced pressure to give 7- [2-tritylaminothiazole-4-
Yl) -2-Trityloxyimino-acetamide] -3- (N, N
-Dimethylcarbamoyloxymethyl) -3-cephem-4-
1.16 g of a foamy powder of carboxylic acid pivaloyloxymethyl ester (syn isomer) was obtained.

IR (nujol, cm ^-1 ) 1795, 1755, 1700 NMR (DMSO -d ₆ , δppm) 1.20 (s, 9H, -COC (CH ₃ ) ₃ ) 2.85 (s, 6H, -N (CH ₃ ) ₂ ) 3.65 (br.s, 2H, C ₂ -H ₂ ) 4.65, 5.00 (ABq, J = 14.0Hz, 2H, C ₃ -CH _2- ) 5.25 (d, J = 5.0Hz, 1H, C ₆ -H) 5.60 ~ 6.10 (m, 3H, C ₇ -H, -CO ₂ CH _2- ) 6.60 (s, 1H, thiazole C ₅ -H) 6.90 ~ 7.50 (m, 30H, phenyl × 6) 8.70 (br .s, 1H, thiazole C ₂ -NH-) 9.95 (d, J = 9.0Hz, 1H, -CONH-)

(2) 1.03 g of the compound of (1) was added to 3.3 ml of formic acid.
Was dissolved in water, 0.82 ml of water was added, and the mixture was stirred at room temperature for 2 hours.
After cooling to 5 ° C, 0.73 ml of 2N-hydrochloric acid was added, and 100 ml of a mixture of isopropyl ether-diethyl ether (2: 1) was added.
And the precipitated gum was separated by decantation. The obtained gum was dissolved in 2.4 ml of methanol, poured into 100 ml of diethyl ether, and the precipitate was collected by filtration to obtain 500 mg of the title compound powder.

IR (nujol, cm ^-1 ) 1790, 1750, 1680 NMR (DMSO -d ₆ , δppm) 1.25 (s, 9H, -COC (CH ₃ ) ₃ ) 2.85 (s, 6H, -N (CH ₃ ) ₂ ) 3.70 (br.s, 2H, C ₂ -H ₂ ) 4.70, 5.10 (ABq, J = 14.0Hz, 2H, C ₃ -CH _2- ) 5.30 (d, J = 5.0Hz, 1H, C ₆ -H) 5.70 to 6.20 (m, 3H, C ₇ -H, -CO ₂ CH _2- ) 6.90 (s, 1H, thiazole C ₅ -H) 9.90 (d, J = 9.0Hz, 1H, -CONH-) 12.50 (br.s, 1H, -OH) 5.00 ~ 11.00 (br, 3H, -N ⁺ H ₃ )

Example 7 7- [2- (2-Aminothiazol-4-yl) -2-hydroxyimino-acetamido] -3- (N, N-dimethylcarbamoyloxymethyl) -3-cephem-4-carvone Acid 1-isopropoxycarbonyloxyethyl ester hydrochloride (syn isomer) (1) 2- (2-tritylaminothiazol-4-yl) -2-trityloxyiminoacetic acid dicyclohexylamine salt (syn isomer) 1.51 g and 0.75 g of the compound of Example 4 was suspended in 22 ml of methylene chloride and cooled to -10 ° C. Pyridine
0.29 ml and phosphorus oxychloride 0.25 ml were sequentially added, and the mixture was stirred at the same temperature for 20 minutes. Add 100 ml of ethyl acetate and add 10
50% citric acid aqueous solution and 50 ml of saturated saline each were successively washed, dried over anhydrous Glauber's salt, and the solvent was distilled off under reduced pressure.
The residue was subjected to silica gel column chromatography, eluted with benzene-ethyl acetate, the solvent of the target fraction was evaporated under reduced pressure, and 7- [2- (2-tritylaminothiazol-4-yl) -2- Trityloxyimino-acetamido] -3- (N, N-
1.46 g of foam-like powder of dimethylcarbamoyloxymethyl) -3-cephem-4-carboxylic acid 1-isopropoxycarbonyloxyethyl ester (syn isomer) was obtained.

IR (nujol, cm ^-1 ) 1790, 1760, 1700 NMR (DMSO -d ₆ , δppm) 1.20 (d, J = 6.0Hz, 6H,-(CH ₃ ) ₂ ) 1.53 (d, J = 6.0) Hz, 3H, -CH ₃ ) 2.85 (s, 6H, -N (CH ₃ ) ₂ ) 3.65 (br.s, 2H, C ₂ -H ₂ ) 4.40 ~ 5.20 (m, 3H, C ₃ -CH _2- , -OCO ₂ CH <) 5.25 (d, J = 5.0Hz, 1H, C ₆ -H) 5.90 (d × d, J = 5.0, 9.0Hz, 1H, C ₇ -H) 6.60 (s, 1H, thiazole C ₅ -H) 6.60 ~ 7.10 (m, 1H, -CO ₂ CH <) 7.00 ~ 7.60 (m, 30H, phenyl x 6) 8.75 (br.s, 1H, thiazole C ₂ -NH-) 9.90 (d, J = 9.0Hz, 1H, -CONH-)

(2) 1.4 g of the compound of (1) was added to 4.5 ml of formic acid.
Was dissolved in water, 1.1 ml of water was added, and the mixture was stirred at room temperature for 2 hours. Thereafter, the mixture was cooled to 5 ° C., 0.97 ml of 2N hydrochloric acid was added, and the mixture was poured into 150 ml of a mixed solution of isopropyl ether-diethyl ether (2: 1), and the precipitated gum was separated by decantation. The obtained gum was dissolved in 2.0 ml of methanol, poured into 100 ml of diethyl ether, and the precipitate was collected by filtration to obtain 660 mg of the title compound powder.

IR (nujol, cm ^-1 ) 1785, 1760, 1680 NMR (DMSO -d ₆ , δppm) 1.25 (d, J = 6.0Hz, 6H,-(CH ₃ ) ₂ ) 1.45 (d, J = 6.0 Hz, 3H, -CH ₃ ) 2.85 (s, 6H, -N (CH ₃ ) ₂ ) 3.63 (br.s, 2H, C ₂ -H ₂ ) 4.40 to 5.10 (m, 3H, C ₃ -CH _2- , -OCO ₂ CH <) 5.20 (d, J = 5.0Hz, 1H, C ₆ -H) 5.85 (d × d, J = 5.0, 9.0Hz, 1H, C ₇ -H) 6.40 to 7.10 (m, 1H , -CO ₂ CH <) 6.85 (s, 1H, thiazole C ₅ -H) 9.70 (d, J = 9.0Hz, 1H, -CONH-) 12.45 (br.s, 1H, -OH) 5.00 ~ 11.00 (br , 3H, -N ⁺ H ₃ )

Example 8 7- [2- (2-Aminothiazol-4-yl) -2-methoxyimino
-Acetamido] -3- (N, N-dimethylcarbamoyloxymethyl) -3-cephem-4-carboxylic acid sodium salt (syn isomer)

(1) 1.0 g of the compound of Example 1 was suspended in 10 ml of methylene chloride to prepare N-trimethylsilylacetamide.
2.61 g was added and the mixture was stirred at 35 ° C for 30 minutes. Dissolve 800 mg of N, N-dimethylformamide in 4.3 ml of ethyl acetate and store at -10 ° C.
Then, 1.02 ml of phosphorus oxychloride was added, and the mixture was stirred at -5 ° C for 30 minutes. To this, 2.2 g of 2- (2-tritylaminothiazol-4-yl) -2-methoxyiminoacetic acid (syn isomer) and 10 ml of methylene chloride were added, and the mixture was brought to the same temperature, stirred for 30 minutes, and then added to the above solution at -10 ° C. It was dripped at. Stir for 30 minutes at the same temperature, add 200 ml of ethyl acetate, and add 10% aqueous citric acid solution.
The extract was washed successively with saturated saline and 100 ml each, dried over anhydrous Glauber's salt, and the solution was concentrated under reduced pressure to about 50 ml. 1.8 g of diphenyldiazomethane was added to the obtained solution, and the solution was cooled with ice to 30
After stirring for a minute, the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography, eluted with benzene-ethyl acetate, and the solvent of the target fraction was evaporated under reduced pressure to give 7- [2-
Of (2-tritylaminothiazol-4-yl) -2-methoxyimino-acetamido] -3- (N, N-dimethylcarbamoyloxymethyl) -3-cephem-4-carboxylic acid benzhydryl ester (syn isomer) 1.47 g of a foamy powder was obtained.

IR (nujol, cm ^-1 ) 1785, 1700 NMR (DMSO -d ₆ , δppm) 2.80 (s, 6H, -N (CH ₃ ) ₂ ) 3.60 (br.s, 2H, C ₂ -H ₂ ) 3.83 (s, 3H, -OCH ₃ ) 4.63, 4.95 (ABq, J = 13.0Hz, 2H, C ₃ -CH _2- ) 5.16 (d, J = 5.0Hz, 1H, C ₆ -H) 5.80 (d × d, J = 5.0, 9.0Hz, 1H, C ₇ -H) 6.72 (s, 1H, thiazole C ₅ -H) 6.90 (s, 1H, -CO ₂ CH <) 7.00 to 7.70 (m, 25H, phenyl × 5) 8.75 (br.s, 1H, thiazole C ₂ -NH-) 9.56 (d, J = 9.0Hz, 1H, -CONH-)

(2) 1.4 g of the compound of (1) was added to 1.
It was dissolved in 4 ml, 4.2 ml of trifluoroacetic acid was added at 5 ° C., and the mixture was stirred at the same temperature for 2 hours. Isopropyl ether
It was poured into 150 ml and the precipitate was collected by filtration to obtain 770 mg of powder. Suspend the obtained powder in 80 ml of water, and adjust the pH with saturated aqueous sodium hydrogen carbonate.
= 7.5 and dissolved. Adsorb to 80 ml of Diaion HP-21, wash with water and elute with 7% aqueous acetonitrile.
The target fraction was concentrated under reduced pressure. The obtained solution was freeze-dried to obtain 520 mg of the title compound powder.

IR (nujol, cm ^-1 ) 1765, 1670 NMR (DMSO -d ₆ , δppm) 2.84 (s, 6H, -N (CH ₃ ) ₂ ) 3.35 (br.s, 2H, C ₂ -H ₂ ) 3.85 (s, 3H, -OCH ₃ ) 4.75, 5.02 (ABq, J = 13.0Hz, 2H, C ₃ -CH _2- ) 5.02 (d, J = 5.0Hz, 1H, C ₆ -H) 5.63 (d × d, J = 5.0, 9.0Hz, 1H, C ₇ -H) 6.72 (s, 1H, thiazole C ₅ -H) 6.90 ~ 7.50 (br, 2H, -NH ₂ ) 9.50 (d, J = 9.0Hz, 1H, -CONH-)

Example 9 7- [2- (2-Aminothiazol-4-yl) -2-methoxyimino
-Acetamido] -3- (N, N-dimethylcarbamoyloxymethyl) -3-cephem-4-carboxylic acid pivaloyloxymethyl ester (syn isomer)

(1) 2- (2-tritylaminothiazole-4)
-Yl) -2-methoxyiminoacetic acid (syn isomer) (1.18 g) and the compound of Example 3 (1.0 g) were suspended in methylene chloride (30 ml),
Cooled to -10 ° C. Pyridine 0.93 ml, phosphorus oxychloride 0.
32 ml was sequentially added, and the mixture was stirred at the same temperature for 30 minutes. Ethyl acetate (200 ml) was added, and the mixture was washed successively with 10% aqueous citric acid solution and saturated brine (100 ml each), dried over anhydrous Glauber's salt, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography and eluted with benzene-ethyl acetate,
The solvent of the target fraction was evaporated under reduced pressure, and 7- [2- (2-tritylaminothiazol-4-yl) -2-methoxyimino-acetamido] -3- (N, N-dimethylcarbamoyloxymethyl)- 1.5 g of a foamy powder of 3-cephem-4-carboxylic acid pivaloyloxymethyl ester (syn isomer) was obtained.

IR (nujol, cm ^-1 ) 1795, 1755, 1700 NMR (DMSO -d ₆ , δppm) 1.20 (s, 9H, -COC (CH ₃ ) ₃ ) 2.85 (s, 6H, -N (CH ₃ ) ₂ ) 3.64 (br.s, 2H, C ₂ -H ₂ ) 3.84 (s, 3H, -OCH ₃ ) 4.65, 5.01 (ABq, J = 13.0Hz, 2H, C ₃ -CH _2- ) 5.18 (d , J = 5.0Hz, 1H, C ₆ -H) 5.60 ~ 6.10 (m, 3H, C ₇ -H, -CO ₂ CH _2- ) 6.71 (s, 1H, thiazole C ₅ -H) 6.98 ~ 7.50 (m , 15H, phenyl × 3) 8.75 (br.s, 1H, thiazole C ₂ -NH-) 9.57 (d, J = 9.0Hz, 1H, -CONH-)

(2) 1.0 g of the compound of (1) was added to 1.
It was dissolved in 0 ml, 3.0 ml of trifluoroacetic acid was added at 5 ° C., and the mixture was stirred at the same temperature for 2 hours. Isopropyl ether
It was poured into 200 ml and the precipitate was collected by filtration to give the title compound powder.
I got 500 mg.

IR (nujol, cm ^-1 ) 1790, 1750, 1680 NMR (DMSO -d ₆ , δppm) 1.25 (s, 9H, -COC (CH ₃ ) ₃ ) 2.85 (s, 6H, -N (CH ₃ ) ₂ ) 3.64 (br.s, 2H, C ₂ -H ₂ ) 3.85 (s, 3H, -OCH ₃ ) 4.70, 5.10 (ABq, J = 13.0Hz, 2H, C ₃ -CH _2- ) 5.20 (d , J = 5.0Hz, 1H, C ₆ -H) 5.60 to 6.15 (m, 3H, C ₇ -H, -CO ₂ CH _2- ) 6.70 (s, 1H, thiazole C ₅ -H) 7.20 (br.s. , 2H, -NH ₂ ) 9.60 (d, J = 9.0Hz, 1H, -CONH-)

Example 10 7-Amino-3- (N, N-dimethylcarbamoyloxymethyl)-
3-Cephem-4-carboxylic acid 1-sec-butoxycarbonyloxyethyl ester hydrochloride This compound was synthesized according to Example 3 or 4.

IR (nujol, cm ^-1 ) 3400, 1790, 1760,
1705 NMR (DMSO -d ₆ , δppm) 0.87 (t, J = 6.0Hz, 3H, -CH ₃ ) 1.21 (d, J = 6.0Hz, 3H, -CH ₃ ) 1.31 to 1.90 (m, 2H, -CH) _2- ) 1.50 (d, J = 6.0Hz, 3H, -CH ₃ ) 2.85 (s, 6H, -N (CH ₃ ) ₂ ) 3.66 (br.s, 2H, C ₂ -H ₂ ) 4.47 ~ 5.00 ( m, 3H, C ₃ -CH _2- , -OCO ₂ CH <) 5.21 (br.s, 2H, C ₆ -H, C ₇ -H) 6.60 ~ 7.00 (m, 1H, -CO ₂ CH <) 5.60 ~ 9.00 (br, 3H, -N ⁺ H ₃ )

Example 11 7- [2- (2-Aminothiazol-4-yl) -2-hydroxyimino-acetamido] -3- (N, N-dimethylcarbamoyloxymethyl) -3-cephem-4-carvone Acid 1-sec-Butoxycarbonyloxyethyl ester hydrochloride (syn isomer) This compound was synthesized according to Example 6 or 7.

IR (nujol, cm ^-1 ) 1790, 1760, 1680,
1635 NMR (DMSO -d ₆ , δppm) 0.85 (t, J = 6.0Hz, 3H, -CH ₃ ) 1.21 (d, J = 6.0Hz, 3H, -CH ₃ ) 1.38 ~ 1.92 (m, 2H, -CH _2- ) 1.50 (d, J = 6.0Hz, 3H, -CH ₃ ) 2.83 (s, 6H, -N (CH ₃ ) ₂ ) 3.64 (br.s, 2H, C ₂ -H ₂ ) 4.40 ~ 5.00 ( m, 3H, C ₃ -CH _2- , -OCO ₂ CH <) 5.24 (d, J = 5.0Hz, 1H, C ₆ -H) 5.90 (d × d, J = 5.0, 9.0Hz, 1H, C ₇ -H) 6.65 ~ 7.07 (m, 1H, -CO ₂ CH <) 6.84 (s, 1H, thiazole C ₅ -H) 6.20 ~ 10.60 (br, 3H, -N ⁺ H ₃ ) 9.75 (d, J = 9.0 Hz, 1H, -CONH-) 12.46 (br.s, 1H, -OH)

Pharmaceutical Formulation Example 1 A tablet having the following composition was produced by a usual method. Compound of Example 6 125 mg Potency Polyvinylpyrrolidone 20 mg Starch 20 mg Magnesium stearate 2.0 mg

Formulation Formulation Example 2 A tablet having the following composition was produced by a usual method. Compound of Example 6 250 mg Potency Citric acid 50 mg Starch 20 mg Magnesium stearate 3.0 mg

Pharmaceutical Formulation Example 3 A tablet having the following composition was produced by a usual method. Compound of Example 6 500 mg Potency Starch 20 mg Hydroxypropyl cellulose 3 mg Magnesium stearate 5 mg

Formulation Formulation Example 4 The compound of Example 6 and tartaric acid were added and mixed to produce a capsule according to a usual capsule filling method. Compound of Example 6 125 mg Potency Tartaric acid 25 mg Magnesium stearate 1 mg Starch is added to make a total amount of 300 mg.

Pharmaceutical Formulation Example 5 According to the method of Pharmaceutical Formulation Example 4, a capsule having the following composition was produced. Compound of Example 6 125 mg Potency Magnesium stearate 2 mg Lactose is added to make a total amount of 200 mg.

Formulation Example 6 A dry syrup was prepared according to the following composition. Compound of Example 6 62.5 mg Potency Citric acid 25 mg Sugar 70 mg CMC-Na 20 mg

Next, in order to clarify the excellent properties of the compound of the present invention, the results of the antibacterial test and the oral absorption test are shown in Table 1.
And shown in Table 2.

[0166]

[Table 1]

[0167]

[Table 2]

[0168]

INDUSTRIAL APPLICABILITY The cephalosporin compound of the present invention has extremely excellent antibacterial activity against Gram-positive bacteria and Gram-negative bacteria, and some of the compounds have excellent absorbability from the digestive tract. Is.

─────────────────────────────────────────────────── ───

[Procedure amendment]

[Submission date] January 21, 1993

[Procedure Amendment 1]

[Document name to be amended] Statement

[Name of item to be amended] Claims

[Correction method] Change

[Correction content]

[Chemical 1] (In the formula, R ¹ and R ² are the same or different and each represents a lower alkyl group or a group which may be bonded to each other to form a ring; R ³ represents a carboxyl group or an esterified carboxyl group; ⁴ is a hydrogen atom or an amino protecting group,
R ⁵ represents a hydrogen atom, a lower alkyl group or a hydroxy protecting group. ] The cephalosporin compound represented by these, or its pharmacologically acceptable addition salt.

4. The general formula (II):

[Chemical 2] (In the formula, R ¹ and R ² are the same or different, and
A group which may combine with a rukyl group or may form a ring.
R ³ is a carboxyl group or an esterified cal
A boxyl group is shown. 7-amino cephalosporin compound or its pharmacologically acceptable addition salt represented by these.

5. A compound represented by the general formula (II) according to claim 4 and the general formula (III):

[Chemical 3] (Wherein R ⁴ and R ⁵ have the same meanings as described above), or a step of reacting with a compound represented by the formula (IV):

[Chemical 4] (Wherein R ¹ , R ² , R ⁴ and R ⁵ are the same as defined above) and a compound represented by the general formula (V): X—R ⁶ (V) (wherein R ⁶ is an ester). The residue is reacted with a compound represented by the formula (X) is carboxyl or a group capable of reacting with a carboxyl-reactive group, or a compound represented by the general formula (VI):

[Chemical 5] (Wherein R ¹ , R ² , R ³ and R ⁵ have the same meanings as described above, and Y represents a halogen atom), and a compound represented by the general formula (VII):

[Chemical 6] (Wherein R ⁴ has the same meaning as defined above), or a compound represented by the general formula (VIII):

[Chemical 7] (Wherein R ¹ , R ² , R ³ and R ⁴ have the same meanings as defined above), and a compound of the general formula (IX): H ₂ NOR ⁵ (IX) (wherein R ⁵ is Or a compound represented by the general formula (X):

[Chemical 8] (Wherein R ³ , R ⁴ and R ⁵ have the same meanings as defined above), and a carbamoylation of the 3-position hydroxymethyl group of the compound represented by the general formula (I):

[Chemical 9] (Wherein R ¹ , R ² , R ³ , R ⁴ and R ⁵ have the same meanings as defined above), and a method for producing a cephalosporin compound or a pharmaceutically acceptable addition salt thereof.

[Procedure Amendment 2]

[Document name to be amended] Statement

[Name of item to be corrected] 0168

[Correction method] Change

[Correction content]

Further, the results of the compound of Example 7 are shown in Table 3 in order to clarify the effect of the addition of the organic acid on the oral absorption.

[Table 3]

INDUSTRIAL APPLICABILITY The cephalosporin compound of the present invention has extremely excellent antibacterial activity against Gram-positive bacteria and Gram-negative bacteria, and some of the compounds have excellent absorbability from the digestive tract. Is. Also, cephalosporin compound
The absorbability of the pharmacologically acceptable addition salt of the product is
As an oral prophylactic / therapeutic agent for infectious diseases,
Especially desirable. ─────────────────────────────────────────────────── ───

[Procedure amendment]

[Submission date] March 24, 1993

[Procedure Amendment 1]

[Document name to be amended] Statement

[Name of item to be amended] Claims

[Correction method] Change

[Correction content]

[Claims]

[Chemical 1] (In the formula, R ¹ and R ² are the same or different and each is a lower alkyl group or a group which may be bonded to each other to form a ring; R ³ is a carboxyl group or an esterified carboxyl group; ⁴ is a hydrogen atom or an amino protecting group,
R ⁵ represents a hydrogen atom, a lower alkyl group or a hydroxy protecting group. ] The cephalosporin compound represented by these, or its pharmacologically acceptable addition salt.

4. The general formula (II):

[Chemical 2] (In the formula, R ¹ and R ² are the same or different and
A group which may combine with a rukyl group or may form a ring.
R ³ is a carboxyl group or an esterified cal
A boxyl group is shown. 7-amino cephalosporin compound or its pharmacologically acceptable addition salt represented by these.

5. A compound represented by the general formula (II) according to claim 4 and the general formula (III):

[Chemical 3] (Wherein R ⁴ and R ⁵ have the same meanings as defined above), or a step of reacting with a compound represented by the formula (IV):

[Chemical 4] (Wherein R ¹ , R ² , R ⁴ and R ⁵ have the same meanings as defined above) and a compound represented by the general formula (V): X—R ⁶ (V) (wherein R ⁶ is an ester). The residue is reacted with a compound represented by the formula (X) is a group capable of reacting with a carboxyl or a carboxyl-reactive group, or a compound represented by the general formula (VI):

[Chemical 5] (Wherein R ¹ , R ² , R ³ and R ⁵ have the same meanings as defined above, and Y represents a halogen atom), and a compound of the general formula (VII):

[Chemical 6] (Wherein R ⁴ has the same meaning as defined above), or a compound represented by the general formula (VIII):

[Chemical 7] (Wherein R ¹ , R ² , R ³ and R ⁴ have the same meanings as defined above) and a compound of the general formula (IX): H ₂ NOR ⁵ (IX) (wherein R ⁵ is Or a compound represented by the general formula (X):

[Chemical 8] (Wherein R ³ , R ⁴ and R ⁵ have the same meanings as defined above) and a carbamoylation of 3-hydroxymethyl group of the compound represented by the general formula (I) is carried out.
:

[Chemical 9] (Wherein R ¹ , R ² , R ³ , R ⁴ and R ⁵ have the same meanings as defined above), and a method for producing a cephalosporin compound or a pharmaceutically acceptable addition salt thereof.

Claims (3)

[Claims] 1. General formula (I): (In the formula, R ¹ and R ² are the same or different and each is a lower alkyl group or a group which may be bonded to each other to form a ring; R ³ is a carboxyl group or an esterified carboxyl group; ⁴ is a hydrogen atom or an amino protecting group,
R ⁵ represents a hydrogen atom, a lower alkyl group or a hydroxy protecting group. ] The cephalosporin compound represented by these, or its pharmacologically acceptable addition salt. 2. General formula (II): (Wherein R ¹ , R ² and R ³ are the same as defined above) or a 7-aminocephalosporin compound or a pharmaceutically acceptable addition salt thereof. 3. A compound represented by the general formula (II) according to claim 2 and a compound represented by the general formula (III): (Wherein R ⁴ and R ⁵ have the same meanings as defined above), or the reaction with a compound represented by the formula (IV): (Wherein R ¹ , R ² , R ⁴ and R ⁵ are as defined above) and the general formula (V): X—R ⁶ (V) (wherein R ⁶ is an ester residue. Group, X is a group capable of reacting with carboxyl or a carboxyl-reactive group, or a compound represented by the general formula (VI): (Wherein R ¹ , R ² , R ³ and R ⁵ have the same meanings as defined above, and Y represents a halogen atom), and a compound of the general formula (VII): (Wherein R ⁴ has the same meaning as defined above) or a compound represented by the general formula (VIII): (Wherein R ¹ , R ² , R ³ and R ⁴ have the same meanings as defined above) and a compound of the general formula (IX): H ₂ NOR ⁵ (IX) (wherein R ⁵ is Or a compound represented by the general formula (X): (Wherein R ³ , R ⁴ and R ⁵ have the same meanings as defined above), and the compound represented by the general formula (I) is characterized in that it undergoes a step of carbamoylating the 3-position hydroxymethyl group of the compound represented by
: [Chemical 9] (Wherein R ¹ , R ² , R ³ , R ⁴ and R ⁵ have the same meanings as defined above), and a method for producing a cephalosporin compound or a pharmaceutically acceptable addition salt thereof.