JPS6034976A - Cephalosporin compound for oral administration - Google Patents

Abstract

NEW MATERIAL:To compound of formula I [R1 is H or lower alkyl; R2 is lower alkyl; Y is phthalidyl or group of formula II (R3 is H or methyl; R4 is lower alkyl or lower alkoxy); excluding the case that R1 is methyl or ethyl, R2 is methyl and Y is pivaloyloxymethyl, or the case that R1, R2 and R3 are methyl and R4 is lower alkoxy] and its acid addition salt. EXAMPLE:7-[ 2-( 2-Aminothiazol-4-yl)-2-methoxyiminoacetamido ]-3-methoxymethyl-3-cephem-4-carboxylic acid pivaloyloxymethyl ester. USE:A remedy for bacteriosis for oral administration. It can be absorbed easily through the digestive tracts, and gives high blood concentration of a carboxylic acid-type compound. PREPARATION:The compound of formula I can be prepared by condensing the compound of formula III with the compound of formula IV (R5 is NH2, etc.; R6 is OH, etc.), and removing the protecting group from the reaction product.

Description

[Detailed description of the invention] The present invention relates to cephalosporin compounds for oral administration.

More specifically, the present invention relates to compounds of the general formula (+) [wherein R1 is a hydrogen atom or a lower alkyl group].

R2 is lower alkyl group, Y is phthalidyl group or formula -C
It represents a H0OORa group (in the formula, R3 is a hydrogen atom or a methyl group, and wRA represents a lower alkyl group or a lower alkoxy group). However, R1 is a methyl or ethyl group, and 'fL2 is a methyl group.

When Y is a pivaloyloxymethyl group, R1, R
Excludes the case where 2 and Y are a methyl group and R is a lower alkoxy group. The present invention relates to a cephalosporin compound (syn isomer) represented by the above formula, a pharmaceutically acceptable acid addition salt thereof, a method for producing the same, and an orally administered bacterial infection therapeutic agent containing the compound as an active ingredient.

In the above general formula, R1 is preferably a hydrogen atom or, for example, methyl, ethyl, n-propyl, inglovir, n-butyl, inbutyl.

It represents a linear or branched alkyl group having 1 to 4 carbon atoms such as 5ee-butyl and tert-butyl, and R2 is, for example, methyl or ethyl.

1 carbon number such as n-propyl, isopropyl, n-butyl, isobutyl, 5ee-butyl, tert-butyl
4 represents a linear or branched alkyl group, Y represents a phthalidyl group or a methyl group, and 4 represents, for example, methyl, ethyl,
1 carbon number such as n-propyl, isopropyl, n-butyl, isobutyl, 5ec-butyl, tert-butyl
Straight-chain or branched alkyl groups having from
It represents a linear or branched chain alkoxy group having 1 to 4 carbon atoms, such as rt-butoxy. It shows.

The compound having the general formula (D) according to the present invention is a new compound and is well absorbed from the gastrointestinal tract.

In addition, since the 4-position ester moiety decomposes quickly in the body to form the carboxylic acid type, a high blood concentration of the carboxylic acid type compound can be obtained, and therefore, oral administration can inhibit Durham-positive bacteria, Gram-negative bacteria, etc. It is a broad-spectrum antibiotic with very significant efficacy in the treatment of infectious diseases. Carboxylic acid type compounds are also new compounds, and have extremely excellent antibacterial activity as described below.

There are many compounds in the penicillin and cephalosporin antibiotics that have excellent effects, but very few of them are well absorbed from the gastrointestinal tract, and for this reason, their development has been abandoned even though they were put into practical use. There are also many compounds. In particular, among cephalosporin antibiotics, only compounds having a limited tM structure, such as cephalexin or its analogues, are in practical use. For example, when cephalothin, cefazolin, cefmetazole, etc., which are widely used as injectable cephalosporins, are orally administered, the urinary recovery rate is around 5% of the administered dose, and it is known that absorption from the gastrointestinal tract is extremely poor. It is being The reason for this is that the carboxyl group at the 4-position of cephalosporin has a large degree of dissociation (low pka value) and is highly acidic.

Attempts have been made to improve absorption from the gastrointestinal tract by esterifying the carboxyl group at the 3-position of penicillin and the 4-position of cephalosporin.
Some penicillin-based compounds have been used as drugs, but cephalosporin-based compounds have not.

For example, regarding the acetoxymethyl ester of cefamandole, The Journal of Antibiodef.
32, No. 11, p. 1155 (1979), it is reported that esterification does not improve absorption because it becomes poorly soluble in water; therefore, it is administered as a solution in an organic solvent such as propylene glycol. It has been described that absorption can be improved to some extent only by doing so. On the other hand, as an ester that is easily soluble in water, Journal of Medicinal Chemistry, Vol. 22, 65
The research results are reported on page 7 (1979), and it is stated that absorption was not improved in this case because it was chemically unstable.

The present inventor has spent many years conducting research on improving absorption from the gastrointestinal tract by chemically modifying cephalosporin compounds and increasing blood concentration through oral administration. Regarding this, I learned that if there is a change in part of the structure, the absorption from the gastrointestinal tract cannot be predicted at all even if chemical modifications such as esterification are performed. The present invention was made as a result of such research.

That is, synthesize pivaloyloxymethyl ester of the following known compound whose structure is seemingly similar to the compound of the present invention,
When testing the urinary recovery rate by oral administration, good results were not necessarily obtained, and it was found that the substituent at the 3-position plays an extremely important role in this family of compounds.

Compound 2 FL,=Ql(6A=OH20000H5 Item 5) The compound having the formula (1) according to the present invention can be prepared by the method described below, namely (a) X-esterified 1-amino-3-alkoxymethylcephalosporin. Phosphorus (n) acylation method) Carboxylic acid corresponding to compound (1) or its amine group and hydroxyl group protected compound (V) esterification method and deprotection method or (c) 7-position acyl method It can be produced by a method in which a desired acyl group is derived from another acyl group by a chemical reaction.

The above method is specifically implemented as follows.

(a) is a general formula [wherein R2 is a lower alkyl group, Y is a phthalidyl group or the formula -〇HOOOR4 (wherein R5 is a hydrogen hole 3 atom or a methyl group e RA is a lower alkyl group or a lower alkoxy group] A compound represented by the general formula (wherein R5 represents an amine group or a protected amino group,
几. represents a hydroxyl group, a protected hydroxyl group or a lower alkoxy group) or a reactive derivative thereof, and the reaction mixture is reacted with a carboxylic acid represented by the general formula (wherein R2, R5, R6 and Y have the same meanings as above). ), and when R5 is a protected amine group and R6 is a protected hydroxyl group, the target compound (1) is obtained by removing the protecting group.
is manufactured.

In the above formula, when R5 is a protected amine group, the protecting group for the amine group is preferably one that is easily removed and restored to the amine group.

Protecting groups known per se, such as trityl group, formyl group, t-butoxycarbonyl group, 2-ethoxycarbonyl-1-methylvinyl group, which can be removed by acid treatment, 2,2. A chloroethoxycarponyl group, a 2-methylsulfonylethyloxycarbonyl group which can be removed by treatment with an alkali, a chloroacetyl group which can be removed by treatment with thiourea, and the like are used.

In addition, when R6 is a protected hydroxyl group, the protecting group for the hydroxyl group is preferably one that can be easily removed and restored to a hydroxyl group, and is a known protecting group such as a to-1-notyl group that can be removed by acid treatment. , dichloroacetyl group, etc. are used.

This method consists of two steps: an acylation step and, if necessary, a B-immunization step.

In the acylation step, the compound having the formula (1) is used in its free form or as a reactive derivative thereof, and when used in its free form, a suitable condensing agent is used. As a condensing agent, diw such as dicyclohexylcarbodiimide is used.
Vilsmeier prepared from converted carbodiimides, cal, imidazolides such as carbonyldiimidazole, thionyldiimidazole, N-ethoxycarbonyl-2-ethoxy-1,2-dihydroxyphosphorus or dimethylformamide and phosphorus oxychloride, thionyl chloride, etc. Examples include reagents. Reactive derivatives of the compound having formula (1) include acid norides, acid anhydrides, mixed acid anhydrides, active esters, active amides, acid azides, and the like. As mixed acid anhydrides, mixed acid anhydrides with carbonic acid mono-lower alkyl esters such as carbonic acid monomethyl ester and carbonic acid monoisobutyl ester, and mixed acid anhydrides with lower alkanoic acids such as hybaric acid and trichloroacetic acid are used. Examples of the ester include p-nitrophenyl ester, pentacool phenyl ester, N-hydroxyphthalimide ester, and N-hydroxybenztriazole ester.

This step is usually preferably carried out in a solvent.

The solvent used is not limited as long as it does not adversely affect this reaction, and examples include acetone, methyl ethyl ketone, tetrahydrofuran, dioxane, ethyl acetate, chloroform, dichloromethane, acetonitrile, and dimethylformamide.

An inert organic solvent such as dimethyl sulfoxide or a mixed solvent with water is used. Depending on the type of reactive derivative used, a base may be present as necessary. Examples of bases are alkali metal compounds such as sodium bicarbonate.

Potassium bicarbonate, sodium carbonate, potassium carbonate, etc.
Examples of aliphatic, aromatic, nitrogen-containing heterocyclic radicals include triethylamine, dimethylaniline, diethylaniline, N-methylpiperidine, N-methylpyrrolidine, pyridine, collidine, and lutidine. There is no particular limitation on the reaction temperature, but the reaction is usually carried out at room temperature or under cooling. The time required for the reaction mainly depends on the type of acylation method.

Although it varies depending on the reaction temperature etc., it is usually several tens of minutes to several tens of hours. After completion of the reaction, the compound having formula 1 (6)) is collected from the reaction mixture by a conventional method.

For example, if the reaction solvent is water-miscible, it is first distilled off under reduced pressure and then replaced with a water-immiscible bath medium; if the solvent is immiscible, it is washed directly with an acid or base.

It is obtained by distilling off the solvent after drying. If necessary, it can be purified by conventional methods such as various chromatography methods.

As described above, in the deprotection step, the protecting groups are removed by a conventional method based on the characteristics of each protecting group, and the crude product is purified to obtain the target compound having the formula (D).

In addition, Φ) is a carboxylic acid compound having the general formula (in the formula, R5 and R6 have the same meanings as described above) or a reactive derivative thereof, phthalidyl halide or the general formula (in the formula, R3 and Machi have the same meanings as above) or a reactive derivative thereof to obtain a compound having the above formula trunk), and further when R5 and R6 are protected groups, ( ]) The target compound (I) is produced by deprotection in the same manner as in the method.

In this reaction, one or both of the two starting materials may be used as reactive derivatives to favor the condensation. Reactive derivatives of the carboxylic acid moiety of the compound having formula (V) include 1, for example sodium.

Salts with metals such as potassium, salts with organic amines such as triethylamine, acid chlorides.

Acid halides and anhydrides such as acid bromides.

Examples include mixed acid anhydrides with carbonic esters such as ethyl carbonate and isobutyl carbonate. Examples of reactive derivatives of the alcohol moiety of compounds having the formula (1) include methanesulfonyl ester, ionasulfonyl ester of p-toluenesulfonyl ester, and halogen-substituted compounds in which the hydroxyl group is replaced with chlorine, bromine, or iodine. The reaction is preferably carried out in a suitable solvent, and such solvents include those that do not adversely affect the reaction, such as dimethylformamide, dimethylacetamide,
Dimethyl sulfoxide, hexamethyldriamide phosphate.

Examples include acetonyl, IJ, etc., and mixed solvents with other inert organic solvents. The reaction is usually preferably carried out at room temperature or under cooling. The time required for the reaction is usually several minutes to several hours. After the reaction is complete.

The target compound of this reaction can be obtained by diluting the reaction mixture with a water-immiscible solvent, washing with an aqueous potassium monobisulfate solution and an aqueous base solution, drying, and then distilling off the solvent.

This product can be further purified by conventional methods such as various types of chromatography. When the amino group and hydroxyl group are protected, they are converted into the amino group and hydroxyl group in the same manner as the deprotection of the compound having formula (IV).

In addition, (C) is a general formula (wherein, X represents a halogen atom such as chlorine or bromine,
R2 and Y have the same meanings as above. ) is converted into a hydroxyimino compound having the general formula (wherein X, R2 and Y have the same meanings as above) and then reacted with thiourea. A compound having the above formula (+) (however,
R1 represents a hydrogen atom. ) can be manufactured.

This method consists of two steps: nitrosation step and thiazole term formation step.
Consists of processes.

The nitrosation step is carried out analogously to the nitronation of conventional β-diketones. That is, under acidic conditions, nitrite compounds such as nitrous acid (IJum).

This is accomplished by the action of a nitrite such as potassium nitrite, a nitrite ester such as amyl nitrite, or butyl nitrite. Although there is no particular limitation on the reaction temperature, it is usually preferable to carry out the reaction at room temperature or lower. The time required for the reaction varies mainly depending on the type of nitrifying reagent, but is usually from several tens of minutes to several hours. After the reaction, the formula (
) is collected from the reaction mixture by conventional methods. For example, it can be obtained by distilling off the solvent from the reaction mixture under reduced pressure. This product can be further purified by conventional methods such as various chromatography methods.

The step of forming a thiazole ring is a ring-forming reaction between an α-haloketo compound and thiourea, and is carried out by bringing the two into contact in a suitable solvent. The solvent used is not limited as long as it does not have a negative effect on this reaction, but
Those with high solubility such as dimethylformamide, dimethylacetamide, and acetonitrile are preferred. The presence of a base is preferred to complete the reaction (bicarbonate) IJ
Preferably, potassium bicarbonate or the like is used. Although there is no particular limitation on the reaction temperature, the reaction usually proceeds sufficiently at about room temperature. Although the time required for the reaction depends on the reaction conditions, it is usually several tens of minutes to several hours. After completion of the reaction, the compound having the formula (1) in which R1 represents a hydrogen atom is collected from the reaction mixture by a conventional method. For example, it can be obtained by concentrating the reaction mixture under reduced pressure after the completion of the reaction, dissolving the residue in a suitable organic solvent, washing with water, drying, and then distilling off the bath medium. This product can be purified by conventional methods such as various chromatography methods.

The compound of the present invention having the formula (1) obtained by the above production method is well absorbed from the gastrointestinal tract as described above,
It provides high blood concentrations of carboxylic acid-type compounds, so it can be administered orally, and can be administered by conventional pharmaceutical methods, such as starch,
Lactose, white sugar.

2 excipients such as calcium carbonate, calcium phosphate, polyethylene glycol, etc. 2 binders such as gum arabic, carboxymethyl cellulose, hydroxypropyl cellulose 0 lubricants such as magnesium stearate, talc, monotrium lauryl sulfate 1 lubricant such as carboxylic acid Orally administered preparations such as capsules, powders, and granules can be prepared by mixing with a disintegrant such as methylcellulose calcium. The dosage varies depending on age, body weight, symptoms, etc., but is approximately 0.42 to 5 g per day for adults, preferably 5 to 3 g, and can be given in 3 to 4 doses.

In addition, when using the compound having the formula (+), not only the free form but also pharmaceutically acceptable acid addition salts such as jJtl acids such as hydrochloric acid, sulfuric acid, and nitric acid, 7+ tansulfonic acid, It is also used as acid addition salts of organic acids such as benzenesulfonic acid, malonic acid, etc.

When the compound of the present invention is orally administered, as described above, it is easily absorbed from the intestinal tract and hydrolyzed in the body, resulting in the corresponding carbon ff (1')C, where ``Sho'' and ``Shi'' have the same meanings as above. ) or become its salt. The antibacterial activity (minimum inhibitory concentration, μ9/ml) of compound (■') against Durham-positive and -negative bacteria was extremely remarkable as shown below.

Compound (Iυ R1=H, R2miOHx, R1=l'L2=(Bl.

Staphylococcus arareus 209P 01 0°4 Escherichia coli NIHJ O,40,4 Shigella flexinelli 0.8 0.8 Klebsiella pneumoniae 0.2 0.1 Proteus vulgaris 0.2 0
．． 01 Salmonella enteritidis 0.4 0.2 Also, the compounds of the present invention and the aforementioned analogue compounds (compound 1.
2 and 3) were orally administered to mice. Urinary recovery rate (
The corresponding amount of carboxylic acid) is as specified in each method.

Urinary recovery rate (%) Compound of Example 1 40 or more Compound of Example 2 50 or more Compound 115 Compound 2B Compound 314 As described above, the present invention uses an alkoxymethyl group as the substituent at the 3-position of the cephalosporin. It is characterized by extremely good absorption in the gastrointestinal tract.

Next, the method for producing the compound of the present invention having the formula (1) will be specifically explained with reference to Reference Examples and Examples; however, the present invention is not limited thereto. Note that all isomers of the oxime moiety of the compounds of the present invention are syn-type.

Reference example 1゜7-(2-(2-chloroacetamidothiazole-4-
yl)-2-methoxyiminoacetamide]-3-methoxymethyl-3-cephem-4-carboxylic acid diphenylmethyl ester (t) To 0.057 ml of dimethylformamide, add 0.0 ml of phosphorus oxychloride while cooling with water and stirring. Add 0.61 ml.

After heating to 40° C. and stirring for 1 hour, azeotroping is carried out twice using dry methylene chloride. To this was added 1 ml of ethyl acetate, and while stirring vigorously at room temperature, 200 ml of 2-(2-chloroacetamidothiazol-4-yl)-2-methoxyiminoacetic acid was added and reacted for 30 minutes.

(b) On the other hand, T-amino-3-methoxymethyl-3-cephem-4-carboxylic acid diphenylmethyl ester 20
0η, 145trg of ethyl aniline, and 5 units of dried methylene chloride? lC! Dissolve, cool to -5°C and stir.

The above reaction solution (1) was added dropwise to this mixed solution (B), and after stirring for 15 minutes, the reaction solution (9) was concentrated under reduced pressure.

The residue is separated using 20 gt of ethyl acetate and 5 d of water. Separate the ethyl acetate layer, and then wash with 5 ml of 5% hydrochloric acid (5 ml of 5% hydrochloric acid) and dehydrate by adding anhydrous magnesium sulfate. The r-liquid was concentrated under reduced pressure, and the resulting residue was purified with silica gel (Kieslgel-60) 30
f, g reel chromatography using n-hexane-ethyl acetate (3:2) to give 7-(2-(2-chloroacetylaminothiazol-4-yl)-2-methoxyiminoacetamide]-3- Methoxime fk-3-
Cephem-4-carboxylic acid diphenylmethyl ester 2
13■ I got it.

Nuclear magnetic resonance spectrum (0DC713) δppm3.1
9 (311,8, 3rd place 00H6) 3.51 (2H,
s, 2nd CH2) 409 (3H,s, 0OHs
) 4.20 (2H,s, 3rd place OH2) 4.22 (
2H,s, OJ Kotan・Co)5.02 (IH,d,
J=5Hz, 6th place) 5.86 (IH, d, d,
J=5.9Hz, 7th place) 6.7~7.6 (12H,
m) Reference example 2゜7-(2-(2-chloroacetaminothiazole-4-
7-(2-(2-Chloracetaminothiazol-4-yl) obtained by the method of Reference Example 1) )-2-methoxyiminoacetamide]-3-methoxymethyl-3-cephem-4-
Carboxylic acid diphenyl methyl ester 7.659 methylene chloride 25 m/, anisole 5 dew L) I
After reacting for 30 minutes at room temperature with J fluoroacetic acid 20 resistant, 300 ml of isopropyl ether was added to remove the precipitate.
5.95 g of -(2-(2-chloroacetamidothiazol-4-yl)-2-methoxyiminoacetamide]-3-methoxymethyl-3-cephem-4-carboxylic acid (syn isomer) was obtained.

Nuclear magnetic resonance spectrum (heavy acetone and heavy DMSO mixture)
δppm 3.30 (3H, S, 0OH53rd position) 3.60 (
2H, s, 2nd place 0H2) 3.97 (3H, S, 0
OH5) 4.25 (2H,s, 3rd place -〇H2-)4.37
(2H,s,0JOH200)5.20 (IH,d
, 6th place H) 5.90 (IH, d, d, 7th place H) 7.40 (
IHoS, thiazole 5th place) 9.50 (IH, d,
7th place 0ONH) Reference example 3? -(2-(2-chloroacetamidothiazole-4-
yl)-2-methoxyiminoacetamide]-3-methoxymethyl-3-cephem-4-carboxylic acid diphenylmethyl ester (200fflF) was dissolved in 5 ml of N,N-dimethylacetamide, 4511 g of thiourea was added and dissolved, and the mixture was heated to room temperature. React for 2 hours. Saturated bicarbonate (IJ) aqueous solution was added to the reaction solution, and 20s+t of ethyl acetate was added.
Extract using. The ethyl acetate layer is thoroughly washed with water to remove excess thiourea, dehydrated and dried over anhydrous magnesium sulfate, and after removing the desiccant, the P solution is concentrated under reduced pressure. The residue thus obtained was chromatographed on 3M silica gel (Wakogel O-100) using ethyl acetate.
(2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamide]-3-methoxymethyl-3
-cephem-4-carboxylic acid diphenylmethyl ester 63η was obtained.

Dissolve this in 2 ml of anisole and stir under water cooling.
Add 1 ml of IJ fluoroacetic acid, bring to room temperature, and treat for 30 minutes. The reaction solution was concentrated under reduced pressure, and isopropyl ether was added to collect the resulting precipitate, which was dried. -(2-(2
-aminothiazol-4-yl)-2-methoxyiminoacetamide]-3-methoxymethyl-3-cephem-
27μ of 4-carboxylic acid trifluoroacetate was obtained.

Nuclear magnetic resonance spectrum (addition of deuterated water in deuterated acetone) δ
ppm 3.29 (3H,s, 3rd position -00H,n3,M (
2H,s, 2nd position cH2)3.96 (3H,S,0
0H3) 4.27 (2H,s, 3rd position cH2)5.15 (
IH, d, J=5Hz, 6th place) 5.97 (IH, d
, J=5Hz, 7th position) 6.59 (IH,s) Reference example 4゜1-phenoxyacetamide-3-methoxymethyl-3
-Production method of cephem-4-carboxylic acid diphenylmethyl ester T-phenoxyacetamide-3-acetoxymethyl-
10.91 of 3-cephem-4-carboxylic acid and 2.259 of sodium bicarbonate were dissolved in 20 of water (1 m/ml).
10f of freeze-dried bacterial cells of S. llus 5ubtillis ATOO6633 were added, the pH was adjusted to 7.5-1], and the mixture was stirred at 40°C for one day. Remove the bacterial cells, adjust the pH of the P solution to 2-3% with hydrochloric acid, and add acetic acid! -F-Jl, 200+t
Te three times.

A total of 600 samples are extracted, and after washing with 5 samples of saturated saline, anhydrous magnesium sulfate is added to dehydrate and dry. Remove the desiccant, add 6.31 g of diphenyldiazomethane,
The mixture was allowed to stand for 2 hours and then concentrated under reduced pressure. Ether 5 in the residue
00g/ was added and stirred, the resulting solid was removed and dried,
1-phenoxyacetamide-3-hydroxymethyl-
3-cephem-4-carboxylic acid diphenylmethyl ester 12f was obtained.

Nuclear magnetic resonance spectrum (in heavy DM80) δppm3,s
s (2H1S, 2nd place 0H2) 4.29 (2H,
d, J=3H2, 3rd position OH2) 4.65 (2H,
s, OH2) 5.17 (IH, t, J=3Hz, 3rd place 0I(
)5.19 (iH, d, J=5Hz, 6th place)5.
76 (IH, d, d, J=5.9Hz, 7th place)6
．． 7-7.8 (16H, m) 9.11 (IH, d, J = 9H2, NH) 7-phenoxyacetamido-3-hydroxymethyl-3-cephem-4-carboxylic acid diphenylmethyl ester 5f was dried and chlorinated Dissolved in 4QOml of methylene, added 100ml of boron trifluoride ethyl ether, and cooled to -5~0°C.
Add an excess of diazomethane (approximately 39.N-methyl-N-nitro-1)-)luenesulfonamide (21.49 mL of ether solution prepared by heating and blowing in) and stir for one day. Concentrate the reaction solution under reduced pressure.

Purification using silica gel 250 f, solvent system n-hexane-ethyl acetate (3:2) gave T-phenoxyacetamide-3-methoxymethyl-3-cephem-4-carboxylic acid diphenylmethyl ester 4.31 .

Nuclear magnetic resonance spectrum (0DOz3) δppm3.
20 (3H, s, 3rd place 00H3) 3.50 (
2H, s, 2nd place OH2) 4.25 (2H, S
, 3rd place OH2) 4.57 (2H,s, OH2
) 5.00 (IH, d, J=SH2, 6th place) 5.8
7 (IH, d, d, J-5, 9Hz, 7th place)
6.7-7.6 (17H, m) According to a conventional method using the compound obtained here.

Treatment with phosphorus pentachloride and pyridine followed by n-propyl alcohol gives 7-amino-3-methoxymethyl-
3-cephem-4-carboxylic acid diphenylmethyl ester is obtained, also on treatment with anisole and trifluoroacetic acid.

1-phenoxyacetamido-3-methoxymethyl-3
-cephem-4-carboxylic acid was obtained.

Reference example 5゜7-(2-(2-aminothiazol-4-yl)-2-
Hydroxyiminoacetamide]-3-methoxymethyl-3-cephem-4-carboxylic acid trifluoroacetate production method Diketene 168m! ? was dissolved in 2 ttl of methylene chloride, cooled to -30°C and stirred. In this, bromine 320nf
! is dissolved in 2dVC of methylene chloride and added dropwise. This reaction solution was added dropwise to a methylene chloride solution containing 362 g of 7-amino-3-methoxymethyl-3-cephem-4-carboxylic acid diphenylmethyl ester and 299 g of diethylaniline, which had been cooled to -5°C, for 30 minutes. react. The reaction solution was concentrated under reduced pressure and dissolved in ethyl acetate (5 (1+/)).
We water.

Wash with 5% hydrochloric acid and saturated brine, dehydrate and dry over anhydrous magnesium sulfate, remove the dehydrating agent, and concentrate the P solution under reduced pressure. The residue thus obtained was mixed with 30 g of silica gel and the solvent system n-
Chromatography using hexane-ethyl acetate (1:1) and 7-promacetylacetamide 3-
11,811 g of methoxymethyl-3-cephem-4-carboxylic acid diphenylmethyl ester was obtained.

This was dissolved in 5 g of acetic acid, and 16 g of sodium nitrite was added little by little while stirring gently at room temperature, and the mixture was stirred for 30 minutes. Add 20% of ethyl acetate to this.

After washing three times with saturated brine, the mixture is dehydrated and dried using anhydrous magnesium sulfate, the desiccant is removed, and the mixture is concentrated under reduced pressure. The resulting residual 1 of silica gel solvent system n-hexane-
Chromatography with ethyl acetate (1:1)
7-(2-bromoacetyl-2-hydroxyiminoacetamide)-3-methoxymethyl-3-cephemu 4-
Carboxylic acid diphenylmethyl ester 76η was obtained.

This compound 76# was converted into N,N-dimethylacetamide 3
Dissolve the solution in ml Kg, add 19q of thiourea, and stir for 2 hours. Add 20 ml of ethyl acetate to the reaction mixture, wash with saturated bicarbonate, remove excess thiourea, remove excess thiourea over anhydrous magnesium sulfate, remove the desiccant, and concentrate under reduced pressure.

The residue thus obtained was treated with silica gel 51. Chromatography using solvent ethyl acetate.

r-(2-(2-aminothiazol-4-yl)-2-
49 quarts of hydroxyiminoacetamide]-3-methoxymethyl-3-cephem-4-carboxylic acid diphenylmethyl ester were obtained.

This compound (49Mg) was dissolved in anisole (1g), trifluorophoric acid (05g) was added thereto, the mixture was allowed to stand at room temperature for one hour, and the reaction solution was concentrated under reduced pressure. Dissolve this in 1*1 IICIIN of acetone, add 20 s of inpropyl ether, remove the resulting precipitate, and dry. -(2-(2-aminothiazole-4
-yl)-2-hydroxyiminoacetamide]-3-
28 ml of methoxymethyl-3-cephem-4-carboxylic acid trifluoroacetate was obtained.

Nuclear magnetic resonance spectrum (heavy methanol da) δpμn3
．． 2B (3H, s, 3rd place 0OH5) 3,! 15
(2H, S, 2nd place o) 12) 4.29 (2H
,s, 3rd position OH2)5.11 (II(,d,
J = '51 (Z, s position) 5.81 (IH, d, J
=5Hz, 7th position) 6.83 (IH, s) Reference Example 6 T-phenoxyacetamido-3-methoxymethyl-3
-Cephem-4-carboxylic acid hino (method for producing loyloxymethyl ester, 7-phenoxyacetamide-3-methoxymethyl-3-cephem-4-carboxylic acid sodium salt 1f was dissolved in 50 ml of dimethyl sulfoxide, pivaloyloxy After adding 975 η of methylbromide and stirring at room temperature for 15 minutes, add 20 (lt/ml) of ethyl acetate and add saturated bicarbonate.
IJum aqueous solution 50g, saturated potassium bisulfate aqueous solution 5g
After washing sequentially with 100ml and dehydrating and drying with anhydrous magnesium sulfate.

Remove the desiccant and concentrate under reduced pressure.

The residue thus obtained was chromatographed using 100'l of silica gel with the solvent group n-hexane-ethyl acetate (2i) to give 1-phenoxyacetamide-3-methoxymethyl-3-cephem-4-iylhydrubonic acid. 150 g of yloxymethyl ester was obtained.

Nuclear magnetic resonance spectrum k (0 DOIj 5 ) δpp
m1.2-5 (9H, S) 3.35 (3H, s, 3rd place 00H5) 3.54
(2H, S, 2nd OH2) 4.29 (2H,
s, 3rd place OH2) 4.58 (2H, s, 0
H2-0-Pbe)5.01 (IH, d, J=
5Hz, 6th place) 5.6-6.1 (3H, m,
7-position and OH2) 6.7-7.6 (6H, m,
I'henyl and NH) Example 1゜7-[2-(2-aminothiazol-4-yl)-2-
Methoxyiminoacetamide]-3=methoxymethyl-
Method for producing 3-cephem-4-carboxylic acid pivaloyloxymethyl ester Phosphorus pentachloride 48 BtllFl was dissolved in 5 ml K'm of dry methylene chloride, phosphorus oxychloride 121119 was added, and pyridine 24 was added with stirring at room temperature.
7 Add Mli. This was cooled to -10℃ and T-
Phenoxyacetamide-3-methoxymethyl-3-cephem-4-carboxylic acid pivaloyloxymethyl ester 169Q is added, and the mixture is gradually warmed to room temperature. After stirring for 2 hours, the mixture was cooled to 0° C. again, n-propyl alcohol j5+Z was added, and the mixture was stirred for 30 minutes. Add a further small amount of water, stir for 15 minutes, add 50 ml of ethyl acetate, and wash with saturated sodium bicarbonate water. Dry the ethyl acetate layer over anhydrous magnesium sulfate.

The drying agent was removed and the mixture was concentrated under reduced pressure. Add isopropyl ether to this, rub it, remove the precipitated P, and dry it.
441 g of -amino-3-methoxymethyl-3-cephem-4-carboxylic acid pivaloyloxymethyl ester was obtained.

121 kg of γ-amino-3-methoxymethyl-3-cephem-4-carboxylic acid pivaloyloxymethyl ester thus obtained, 141 mg of diethylaniline and 7 lQ of dimethylformamide.

Phosphorus oxychloride 1351!17.2-(2-Chloracetamidothiazol-4-yl)-2-methoxyimino a[2265r+y was used to amidate in the same manner as in Reference Example 1, and the two reaction solutions were separated and extracted to obtain the desired product. obtain a residue containing
This was chromatographed using silica gel 10f solvent system ethyl acetate-n-hexane (2:1).
Tβ-[2-(2-chloroacetamidothiazole-4
551 ng of hivaloyloxymethyl ester of -2-methoxyiminoacetamide]-3-methoxymethyl-3-cephem-4-carboxylic acid was obtained.

This was dissolved in 1 volume of N,N-dimethylacetamide, 135% of thiourea was added, and after stirring at room temperature for 2 hours, 2% of ethyl acetate was added.
The mixture was washed thoroughly with saturated sodium bicarbonate, dried over anhydrous magnesium sulfate, the desiccant was removed, and the mixture was concentrated under reduced pressure. This was chromatographed using silica gel and ethyl acetate n-hexane (3:1) as a solvent to obtain 7-(2-(2-aminothiazol-4-yl)-2-methoxyimino). Acetamide] -
36 ml of 3-methoxymethyl-3-cephem-4-carboxylic acid pivaloyloxymethyl ester was obtained.

Nuclear magnetic resonance spectrum (in deuterated acetone) δppm1.
19 (9H, s) 3.23 (3H, s, 3rd place 00H5) 3.52
(2H, s, 2nd place 0H2) 3.90 (3H,
S, 0OH3) 4.18 (2H, s, 3rd place
OH2) 5.12 (IH, d, J=5Hz,
6th position) 5.8 to 6.1 (3H, m, 7th position and O
H, 2) 6.78 (IH, s) s, s~r, 1 (2H, bs, NH2) 8.01
(IH, d, J=9Hz, NH) Example 2゜7-(2-(2-aminothiazol-4-yl)-2-
Hydroxyiminoacetamide]-3-methoxymethyl-3-cephem-4-carboxylic acid pivaloyloxymethyl ester production method Diketene 1 samg, Bromine 320117.7-amino-
Using 3-methoxymethyl-3-cephem-4-carboxylic acid pivaloyloxymethyl ester 322trg and diethylaniline 29911tg, the reaction treatment was carried out in the same manner as in Reference Example 5. Purification using hexane-ethyl acetate (1:1) gave 288 7-promacetylacetamide 3-methoxymethyl-3-cephem-4-carboxylic acid pivaloyloxymethyl ester. This was dissolved in 5 yl of acetic acid and reacted and treated in the same manner as in Reference Example 5 using sodium nitrite ssmy.
Purified using hexane-ethyl acetate (1:1) and
200 μm of (2-bromoacetyl-2-hydroxyiminoacetamide)-3-methoxymethyl-3-cephem-4-carboxylic acid pivaloyloxymethyl ester was obtained. This was dissolved in 5Mt of N,N-dimethylacetamide and subjected to chromatography, and 7-C2-(2-aminothiazol-4-yl)-2-hydroxyiminoacetamide]-3-methoxymethyl-3-cephem-4 −
118η of carboxylic acid pivaloyloxymethyl ester was obtained.

Nuclear magnetic resonance spectrum (in deuterated acetone) δppm1.
21 (9] (, S ) 3.28 (3H, s, 3rd place 00H3) 3.61
(2H, s, 2nd place 0H2) 4.27 (211
, S, 3rd place OH2) 5, old (IH, d, J=5H
z, 6th position) 5.8-6.2 (3H, m, 7th position and OH2) 6.87 (IH, s) 6.4-16 (3H, m, NH2, OH) 9.0 (
IH, d, J=9Hz, NH) Example 3゜? -(2-(z-chloroacetamidothiazole-4-
yl)-2-methoxyiminoacetamide]-3-methoxymethyl-3-cephem-4-carboxylic acid (syn isomer) 1 f, Vivari, phosphoric acid bromomethyl ester a
Add aomy and potassium fluoride 240ml to 10 ml of dimethyl sulfoxide.

Stir for 1 hour at room temperature. Add ethyl acetate to the reaction solution/
The mixture is washed successively with water, 5% dehydrated water, 10% aqueous potassium bisulfate solution, and saturated brine, dried over magnesium sulfate, and then the solvent is distilled off under reduced pressure. The residue was purified by column chromatography using silica gel [solvent: chloroform-ethyl acetate (1:1)] to give r-(2-(2-chloroacetamidothiazol-4-yl)-2-methoxyiminoacetamide)- 3-Methoxymethyl-3-cephem-4-carboxylic acid pivaloyloxymethyl ester 3001V Obtained in the form of a pale yellow powder.

The above compound and thiourea somy are dissolved in 3 ml of dimethylacetamide and stirred at room temperature for 4 hours. The reaction solution was poured into 10 ttl of saturated it water and extracted with ethyl acetate. The extract was washed successively with a 10% aqueous potassium bisulfate solution and saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to column chromatography using silica gel (J medium, ethyl acetate-n-hexane (3:1
)]. -(2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamide]-3
-Methoxymethyl-3-cephem-4-carboxylic acid pivaloyloxymethyl ester 20079 was obtained. Motoichi confirmed by nuclear magnetic resonance spectrum and infrared absorption spectrum that the compound is the same as the compound obtained by the method of Example 1.

Example 4 According to the method of Example 3, 360 ml of isobutyric acid bromomethyl ester was used instead of piparic acid bromomethyl ester, and total (by the same treatment, ty
, (z-(2-aminothiazol-4-yl)-2-methoxyiminoacetamide]-3-methoxymethyl-3
-Cephem-4-carboxylic acid isobutyryloxymethyl ester 180 tXfl is obtained in the form of a pale yellow powder.

Nuclear magnetic resonance spectrum (0DOj13) δppm:
1.20 (6H, d, J=6.5) 166 (
IH, 5eptet, J=6.5) 3.21 (
3H, s) 3.40 (2H, ABQ) 4.01 (3H, S) 4゜1B (211, 3) 5.05CIH, d, J=5) 5.6-6.2 (5H, m) 6.65 (LH, s) 8.06 (IH, d, J=9) Example 5゜According to the method of Example 3, bromomethyl propionate 340 instead of bromomethyl pivalate ester
By reacting with η and treating in exactly the same way, 7-C2-(2-aminothiazol-4-yl)-2
-Methoxyiminoacetamide]-3-methoxymethyl-3-cephem-4-carboxylic acid propionyloxymethyl ester was obtained in the form of an almost colorless powder.

Nuclear magnetic resonance spectrum (0DO15) δppI'r]
:1.1r (3H, t, , r=es)2.41
(2H, q, J=6.5)3.20 (3H,
8) 3.35 (2H, ABq) 4.02 (3H, s) 4.17 (2H, s) 5.09 (IH, d, J-5) 5.6-6.3 (5H, m) 6.68 (IH, s) 8.25 (IH, d, J=9) Example 6゜According to the method of Example 3, α-ethoxycarbonyloxyethyl bromide (α- 7-C2-
(2-Aminothiazol-4-yl)-2-methoxyiminoacetamide J-a-methoxymethyl-3-cephem-4-carboxylic acid 1-ethoxycarbonyloxyethyl ester GOrpy is obtained as a pale yellow powder.

Nuclear magnetic resonance spectrum (0DO715) δppm:
1.30 (3H, t, J=7) 1.61 (3H
, d, J=5) 3.22 (3H, s) 3.42 (2H, ABq) 4.03 (3H, s) 4.15 (2H, s) 4.21 (2H, Q, J=7 )5.10(IH
, d, J=5) 5.6-6.2 (3H, m) 6.70 (IH, s) 6.92 (IH, q) 8.20 (IH, d, , r=9) Example 7゜y-(z-(z-chloroacetamidothiazole-4-
yl)-2-methoxyiminoacetamide]-3-methoxymethyl-3-cephem-4-carboxylic acid (syn isomer) was added to 10 g of dimethyl sulfoxide, 200 μl of triethylamine was added, and then 420 mfl of phthalidyl bromide was added. Add. After stirring for 30 minutes at room temperature,
100 g of ethyl acetate was added, and the mixture was washed successively with water, 5% deuterated water, saturated aqueous potassium bisulfate solution, and saturated brine.

After drying over magnesium sulfate, the solvent is distilled off under reduced pressure. The residue was subjected to column chromatography using silica gel [
Purification with solvent chloroform-ethyl acetate (1:1) gave 7-[2-(2-chloroacetamidothiazol-4-yl]-2-methoxyiminoacetamide)-
710 μm of 3-methoxymethyl-3-cephem-4-carbon phthalidyl ester is obtained as a pale yellow powder.

When the above compound 3001111F was reacted with thiourea somy in 3 ml of dimethylacetamide at room temperature for 4 hours and treated according to the method of Example 3, T-(2-<2-
aminothiazol-4-yl)-2-methoxyiminoacetamide]-3-methoxymethyl-3-cephem-
Obtain 4-carboxylic acid phthalidyl ester 120μ, nuclear magnetic resonance spectrum k (0DOJ3) δppm
:3.22 (3H, s) 3.50 (2H, S) 3.95 (3H, S) 4.17 (2H, S) 5.10 (1H, d) 5.82 (IH, m) 6 .58 (0,6H, S) 6.67 (0,4H, s) 7.3-8.3 (5H, m) 8.5 (2H, br) Example 8゜ Follow the method of Example 2 The following compound is obtained.

(11r-(z-(z-aminothiazol-4-yl)
-2-hydroxyiminoacetamide] -3-methoxymethyl-3-cephem-4-carboxylic acid acetoxymethyl ester +21 7-(2-(2-aminothiazol-4-yl)-2-hydroxyiminoacetamide)
-3-methoxymethyl-3-cephem-4-carboxylic acid isovaleryloxymethyl ester +31 7-(2-(2-aminothiazol-4-yl)-2-hydroxyiminoacetamide]-3-methoxymethyl-3 -Cephem-4-carboxylic acid phthalidyl ester Example 9 The following compound was obtained according to the method of Example 1.

(117-(2-(2-aminothiazol-4-yl)
-2-methoxyiminoacetamide]・-13-methoxymethyl-3-cephem-4-carboxylic acid acetoxymethyl ester +21 7-(2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamide)
-3-methoxymethyl-3-cephem-4-carboxylic acid isovaleryloxymethyl ester +31 7-(2-(2-aminothiazol-4-yl)-2-ethoxyiminoacetamide]-3-methoxymethyl-3 -Cephem-4-carboxylic acid pivaloyloxymethyl ester +4+ 7-(2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamide)-3-ethoxymethyl-3-cephem-4-carboxylic acid Pivaloyloxymethyl ester Example 10゜7-[2-(2-aminothiazol-4-yl)-2-
Hydroxyiminoacetamide]-3-methoxymethyl-3-cephem-4-carboxylic acid pivaloyloxymethyl ester 5o.

To a solution prepared by dissolving 1 in 20 liters of ethyl acetate, add 2 liters of ether saturated with hydrogen chloride, concentrate under reduced pressure to about 5 liters, and then add 20 liters of diisopropyl ether. The precipitated crystals were collected, washed with diisopropyl ether, and dried to give 7-(2-(2-aminothiazol-4-yl)-2-hydroxyiminoacetamide]-3-methoxymethyl-3-cephem-4- Carboxylic acid pivaloyloxymethyl ester hydrochloride is obtained. Yield: 48
0 N.

In exactly the same manner, 7-(2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamide]-3
-Methoxymethyl-3-cephem-4-carboxylic acid From 500q of pivaloyloxymethyl ester, 470TItg of its hydrochloride are obtained.

Example 11゜7-(2-(2-aminothiazol-4-yl)-2-
Propyloxyiminoacetamide]-3-methoxymethyl-3-cephem-4=carboxylic acid Process for producing pivaloyloxymethyl ester a) 2-(2-)rithylaminothiazol-4-4yl)-2-propyloxy 472 grams of iminoacetic acid was dissolved in 20 g of methylene chloride, 0.14 tgl of triethylamine was added, and the mixture was cooled to -5°C. 0.105 to this liquid
Add ml oxolyl chloride and 1 drop DMF, -
After stirring for 40 minutes at 5°C, the solvent is distilled off under reduced pressure to give the acid chloride as a foam. Add this to methylene chloride 5
ml, 'r-amino-3-methoxymethyl-3
-cephem-4-carboxylic acid pivaloyloxymethyl ester tosylate 370η and diethylaniline 0.
27g/ in a solution of 20gt of methylene chloride = 5
Add at ℃ and stir for 20 minutes. The solvent was distilled off under reduced pressure, and the residue was dissolved in ethyl acetate and 3% hydrochloric acid.

After sequentially washing with IJum and 10% saline (10% saline, 5% bicarbonate), drying over magnesium sulfate and distilling off the solvent, the resulting residue was subjected to silica gel column chromatography (solvent: benzene-ethyl acetate). (3:1)), 7-(2-(2-)ditylaminothiazole-
4-yl)-2-propyloxyiminoacetamide]
-3~Methoxymethyl-3-cephem-4-carboxylic acid pivaloyloxymethyl ester as colorless powder 1
871111F was obtained.

b) Dissolve the above compound 187 in 5 liters of 90% acetic acid 3
After stirring for 4 hours at 0° to 35'C, most of the acetic acid is distilled off under reduced pressure. The residue was dissolved in ethyl acetate and washed with 5% sodium bicarbonate and brine.

After drying over magnesium sulfate, the solvent was distilled off and the residue was purified by column chromatography on silica gel (I medium: benzene-ethyl acetate (1:1)) to yield the title compound 1.
10 ml was obtained as a colorless powder.

Nuclear magnetic resonance spectrum (oDoA5) δppm: 0
．． 93 (3H, t, J=7.0) 1.25 (
9H, s) 1.40-2.00 (2H, m) 3.32 (3H, s) 3.53 (2H, bs) 4.17 (2H, t, , r=7.o) 4.30
(2H, s) 5.05 (IH, d, J=4.0) 5.68"
6.15 (5H, m) 6.77 (IH, S) 7.70 (IH, d, , r=9.o) Patent applicant Sankyo Co., Ltd. Agent Patent attorney Shoji Kashiyama Continued from page 1 0 shots Author: Makoto Sugawara - Inside Hiromachi, Tokyo Parts Building 0 Inventor: Isamu Arashi Inside Hiromachi, Tokyo Parts Building

Claims (1)

[Claims] (11 general formula [wherein, R4 is a hydrogen atom or a lower alkyl group, R2 is a lower alkyl group, Y is a phthalidyl group or 15 is a methyl group, and 4 is a lower alkyl group or a lower alkoxy group] ). However, R1 is a methyl or ethyl group, and R2 is a methyl group. When Y is a pivaloyloxymethyl group, R,, R
2 and R5 are methyl groups, and R4 is a lower alkoxy group. ] A cephalosporin compound (syn isomer) and a pharmaceutically acceptable acid addition salt thereof. (2) General formula [In the formula, R5 is a lower alkyl group, Y is a phthalidyl group or a -01100OR4 group (in the formula, R5 is a hydrogen L3 atom or a methyl group, and R5 is a lower alkyl group or a lower alkoxy group) )],
General formula (wherein 5 represents an amine group or a protected amino group,
Represents a hydroxyl group, a protected hydroxyl group, or a lower alkoxy group. ) or its reactive derivative. (In the formula, R2, R5, R6 and Y have the same meanings as described above.) When it5 is a protected amine group and R6 is a protected hydroxyl group, the protection A general formula characterized by removing the group (wherein R1 represents a hydrogen atom or a lower alkyl group,
R2 and Y have the same meanings as described above. however,
R1 is a methyl or ethyl group, R2 is a methyl group,
When Y is a pivaloyloxymethyl group, and 几1. R
2 and 几 are methyl groups, except when R4 is a lower alkoxy group. ) A method for producing a cephalosporin compound (syn isomer) and a pharmaceutically acceptable acid addition salt thereof. (3) General formula (In the formula, 几2 is a lower alkyl group, R5 is an amine group or a protected amino group, and 几 is a hydroxyl group. It represents a protected hydroxyl group or a lower alkoxy group.)
A carboxylic acid compound or its reactive derivative represented by phthalidylamide or the general formula % (wherein, 几 represents a hydrogen atom or a methyl group, and A represents a lower alkyl group or a lower alkoxy group) Reacted with the compound shown or a reactive derivative thereof, representing a general formula group (wherein R5 and R4 have the same meanings as defined above), and R2, R5 and R6 have the same meanings as defined above. .], R5
is a protected amine group, and when 马 is a protected hydroxyl group, the protecting group is removed (wherein R1 represents a hydrogen atom or a lower alkyl group,
R2 and Y have the same meanings as described above. however,
R1 is a methyl or ethyl group. When R2 is a methyl group and Y is a pivaloyloxymethyl group, and when Sho, R2 and 几6 are methyl groups,
Except when is a lower alkoxy group. ) A method for producing a cephalosporin compound (syn isomer) and a pharmaceutically acceptable acid addition salt thereof. (4) General formula [wherein R2 is a lower alkyl group, Y is a phthalidyl group or the formula -0HOOOR4 (in the formula, 3 represents a hydrogen atom or a methyl group, and R4 represents a lower alkyl group or a lower alkoxy group) ), and X represents a halogen atom. ] The compound represented by is nitrosated to convert it into a hydroxyimino compound represented by the general formula (wherein R2, Y and X have the same meanings as described above).
A cephalosporin compound (syn isomer) represented by the general formula (wherein R2 and Y have the same meanings as described above), which is then reacted with thiourea.
and a method for producing a pharmaceutically acceptable acid addition salt thereof. (5) General formula [wherein R4 is a hydrogen atom or a lower alkyl group] R2 represents a lower alkyl group, Y represents a phthalidyl group or 5 represents a methyl group, and R4 represents a lower alkyl group or a lower alkoxy group. ) is shown. However, R1 is a methyl or ethyl group, and R2 is a methyl group. When Y is a pivaloyloxymethyl group, and R1, R
2 and TL5 are methyl groups, and RA is a lower alkoxy group. ] The cephalosporin compound moiety (
A therapeutic agent for bacterial infections for oral administration, which contains as an active ingredient a syn isomer) and a pharmaceutically acceptable acid addition salt thereof.