JPS5910592A - Cephalosporin derivative - Google Patents

Abstract

NEW MATERIAL:The compound of formula I {R1 is organic residue known in beta-lactam antibiotic substances; R2 is H or methoxy, provided that when R1 contains group of formula II [R4 is 1-6C alkyl or group of formula III (Ra and Rb are 1-4C alkyl)], R2 is H; X is S or O; R3 is H, salt with organic base, or metallic ion}, its inorganic or organic salt. EXAMPLE:7-(alpha- Methoxyiminofurylacetamido )-3 -[( 2'-amino-2'-carboxyl )ethyl- imidazol- 2-ylthiomethyl]-3-cephem-4-carboxylic acid. USE:An antibacterial agent effective to Gram-negative bacteria and Gram-positive bacteria, etc., and having excellent durability. PROCESS:The objective compound can be prepared e.g. by reacting 7-ACA derivative in the presence of dicyclohexyl carbodiimide, or by converting a compound of formula RCOOH to an active ester mixed acid anhydride, etc., and reacting with a 7-ACA derivative.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a novel cephalosporin derivative, and more particularly to a cephalosporin having excellent antibacterial activity represented by the following general formula (Il).

General formula (IJR.

N.H.

[In the formula, R1 represents an organic residue known in β-lactam antibiotics, and R2 represents hydrogen or a methoxy group. In the case where R2 represents only hydrogen, R4 represents an alkyl group of Ra C, to C6, -C-COOH(Ra, Rh
may be the same or different, each being a C7-C6 alkyl group)'Ik, x#'is or 01R8
represents hydrogen, a salt with an organic base, or a physiologically acceptable metal ion. The object of the present invention is to provide a cephalosporin which has excellent antibacterial activity against a wide range of pathogenic bacteria, mainly including Durum-negative bacteria and Durum-positive bacteria.

Cephalosporin compounds are widely used for the treatment and prevention of infections caused by pathogenic bacteria.

In many cases, it is desirable to use cephalosporin antibiotics that are active against both Durham-positive and Durham-negative bacteria, and various types of broad-spectrum cephalosporins are being developed. .

The cephalosporin of the present invention is a novel cephalosporin having an S bond at histidine at the 3rd position, and these cephalosporins have high antibacterial activity against Durum-positive bacteria and Durum-negative bacteria. The histidine group, which has high stability even against β-lactamase produced by negative bacteria, can be used in any of the D, L, and DL forms. 1 to 4 selected from aromatic phenyl groups, nuclear-substituted aromatic phenyl groups, alkyls, substituted alkyls, or alicyclic hydrocarbons substituted with alicyclic hydrocarbons, or nitrogen, oxygen, and sulfur. Examples of organic residues containing a 4- to 6-membered heterocycle, such as those having an aromatic phenyl group or a nuclear-substituted aromatic phenyl group, include CO NH 1 C=NH 2 NH.

etc. are shown.

Next, as the alkyl-substituted alkyl, NCCH,,N
CCH25-CH, -1HOOC-6H-CH,5-C
11,-NH.

etc. can be mentioned. However, as alicyclic hydrocarbons and substituted alicyclic hydrocarbons, NH2N)].

Next, examples of the 4- to 6-membered heterocycle containing 1 to 4 atoms selected from nitrogen, oxygen, and sulfur include Co(JH 0 NH.

Among these, those having an iminoether bond are preferably in the / configuration.

For example, the following compounds are listed as representative compounds, and their MICs against Durham-negative bacteria are as follows.

Compound (Il) Amount of bacteria: 10'eells/d Compound (Il) Cefotaxime E, coli NIHJ-JC2<, 0.2
0.8E, collW3630
po, 2 <, 0, 2E, colsW363
D RGhN 4 <[1,2<, 0,
2E, coliW3630 RGN238 (0
,2<, 0.2E, coli 0205
0+4 0.4Klebs
, pneumoniae ATCC100315;0.
2 <, 0,2Sh1gella 5onn
ei E35 <, 0.2
<, 0,2Proteus rettgeri AC
R<0.2<, 0.2Enterobac
t, cloacae GN536 5;0.2
<, 0,28erratta marces
cen@＜0.2 ri0.2 inoculated bacteria@: 10
'tells/d Compound I11 Compound 11 Taxime E, eoli NIHJ-JC212,525E, c
olt W3630 6j
6.5E, coil W3630 RG
N14 6,3 100E#co
lt W3650 RGN238 25
) 100g, coli 0205
12,5 50Klebs,
pneumoniae ATCC10031L6
1,68 higella 5onnel E3
5 1.6 3. IP
roteus+ rettgeri ACR251
00Enterobaet, cloacae GN
556 25.
50Serratia marceacens
') 100 > 100 compounds (Il
Comparing cefotaxime, the compound (Il) has the characteristic that it is hardly affected by the amount of inoculated bacteria.
It exhibits particularly low toxicity among third-generation cephalosporins. In acute toxicity studies of this compound in mice, LD, upon intraperitoneal administration. showed 10 to 1297 kg, and the intravenous administration of the compound (Il Blood Concentration Co., Ltd., 3rd generation cephalosporin LMOX (nickname Kikicef), CTX (cefotaxime), CZX (cefmezoxime), CPZ (cefoperazine) ) and found that it has the major feature of being extremely durable, as shown in the drawing.The drawing shows Wistar rats,
The results are shown using 7-week-old mice at a dose of 20 In and 97 kp.

Thus, it has been found that the 3-position histidine derivative has excellent effects such as strong antibacterial activity, low toxicity, and long-lasting blood concentration.

As mentioned above, Esharlchla coli, Kl.
ebmiellapneumonea@,8higel
la 5onne%, EnLsrobaetercro
aeae, 1Serratia mareeseen
It was found that Compound 0 exhibits extremely strong antibacterial activity against indole-positive Proteus and the like, and furthermore, the MIC of Compound 0 below is as follows.

NHL MIC (10” cells/m Compound (II)
Cefavirine E, eoll NIHJ-JC225) 100E, eo
liW3630 Pus 12.5
)100E, caliW3630 RGN2
38 25) I n.

Klebs, pneumoniae ATCC1003
112,5258m1m, enteritidls
Gaertner 25 50Sh
igel1m 5onnet II3
12.5) 100 Next, the following compound (In)
MIC of compound (II) is as follows: MIC (10' cells/d)
I) Cephalothin E, eoll NIHJ-JC26,525E, col
i W3630 PSM 6.5
12,5E, coll RGN 14
12,5 50Klebs, pneumone
ae ATCC100316, 56, 58m1m, en
teritldl@Gaertner 5.1
b, SShigella 5onnet E!
1S 12,5 25 or more compounds (
As seen in the example of Il■(m), the introduction of histidine/ at position 5 greatly contributes to the antibacterial activity. Furthermore, as mentioned earlier, a significant effect can be seen on the persistence of blood concentration. Furthermore, as seen in the example below, intestinal absorption is improved by introducing histidine into the 3-position.

For example, when comparing the maximum blood concentrations of cefotakicum and the compound (Tl) after oral administration in rad, their effects are observed.

Rat: Wistar rat 200-2201 Dose: 50 Ing/ky Blood concentration was measured by HPLC method and bioassay method (E. coli was used as the test organism).

Next, regarding the method for synthesizing the compound of the present invention, it is possible to synthesize it by approximately two routes.

In the synthesis method (1), R,-COON is reacted with a 7-ACA derivative in the presence of a suitable binder, such as dicyclohexylcarbodiimide, or R,-COON is
There is a method in which OH is converted into an active form, such as an active ester mixed acid anhydride, and then reacted with a 7-ACA derivative.

Furthermore, it can be made into an acid chloride like R,-COCt and then reacted. During the above condensation, use organic solvents that do not participate in the reaction, such as tetrahydrofuran, dioxane, ethyl acetate, dimethylformamide,
Methylene chloride, acetone, etc. are selected. Also,
In the reaction of acid chloride, etc., it is also possible to use an aqueous system.

Next, the conversion reaction of the acetoxymethyl group at position 6 with thiolhistidine is carried out in water or a mixed solvent such as methanol, acetone, etc., using sodium hydrogen carbonate or triethylamine as a base, and adjusting the pH of the reaction system to 6 to 6. The 3-position conversion reaction can be carried out by reacting in the range of 30 to 100 C for 1 to 20 hours, preferably 2 to 10 hours, while controlling the temperature to be around 7. During this time, the reaction system must be under a nitrogen atmosphere. is desirable.

Next, regarding the route (11), to give one example, after protecting the amine group of thiolhistidine and, for example, t-butyloxycarbonylation, the acetoxymethyl at the 3-position of 7-ACA (or its derivative) is In a mixed solvent system of water and acetone, using sodium hydrogen carbonate as a base and controlling the pH to 6 to 7,
React at 0-100C for 1-20 hours. The 4-position carboxyl group of the obtained compound 7-ACAI conductor, 3
The carboxyl group of the histidine at position is either trimethylsilylated or, until free, condensed with RCOOH or its carboxylic acid active form (eg, active ester, mixed acid anhydride, acid chloride). after that,
The desired product can be obtained by removing BOC using trif-tetraacetic acid.

Example 1 4.52 of furanglioxylic acid is placed in 50 thialcohol and 6.11 of methoxyamine hydrochloride dissolved in 17c10 of water is added to this solution. Next, while keeping it at 120°C, add diluted caustic soda solution and p)I.
The temperature was adjusted to a to 5, and the mixture was stirred at 20° C. for 15 hours to carry out the reaction.

The alcohol is distilled off under reduced pressure, the reaction solution is brought to pH 7-8 with 50% caustic soda solution, washed with ether, and the aqueous phase is brought to pH 2 with concentrated hydrochloric acid. Next, the mixture is extracted with ethyl acetate, dried over anhydrous magnesium sulfate, and the ethyl acetate is distilled off under reduced pressure to obtain an oily product. Recrystallization from toluene yields 1.21 g of Udo, syn-α-methoxyimino-2-furyl acetic acid.

Next, place 0.6f of sodium hydroxide in 40ml of methanol, and once the sodium has dissolved, cool to 3°C.1. ．． 1.
A methanol solution 10 of 2M' syn-α-methoxyimino-2-furylacetic acid is added. After stirring at 20°C for 20 minutes and distilling off the solvent, the residue was thoroughly dried. Syn-α-methoxyfurylacetic acid sodium 0.65 F obtained here was dissolved in benzene 30-<L,
Add 0.3 ml of oxalyl chloride, stir at 25°C for 30 minutes, and then distill off the benzene under reduced pressure.
Acid chloride is obtained. After dissolving this in 15-acetone, 0.89 of 7-aminocephalosporanic acid, 0.
．． 72 parts of bicarbonate of soda and acetone 5tRt, water 30 parts
- Add an acetone solution of acid chloride to the solution, and
Continue stirring while keeping the pH of 3f1ml at 7. After the reaction was completed, pH 2IC was added with 6N hydrochloric acid, and then XAD-II
When purification is performed using column (organo) K, 7-α-
0.8 pi of methoxyiminofuryl acetamidocephalosporanic acid can be obtained.

Next, 0.81.2-thiol-L-histidine 0.52 of this compound and 0.5 y of sodium bicarbonate were added to 40 y of water, and the mixture was heated under a nitrogen atmosphere while maintaining the % pI (= 6.0 to 6.5). , the reaction was carried out at 60°C for 5 hours. After the reaction was completed, the p)l of the reaction solution was adjusted to 2 with 6N hydrochloric acid, water was partially distilled off, and the target product 7 was purified using an XAD-II column. -(α-methoxyiminofurylacetamide)-5-[:(2'-amino-2'-carboxy)
Add 0.51 ethyl imidazol-2-ylthiomethyl]-6-cephem-4-carboxylic acid.

(Reaction Formula) % Formula % It was confirmed that the product was the desired product by NMR measurement (DMSO/) lifluoroacetic acid).

m Multiplet d Doublet S - Multiplet H-6528d H-7590d Example 2 - Diketene 1.7 cooled to 30°C? Add 15 mef of methylene chloride containing 3.2 f of bromine dropwise into 20+nt of methylene chloride containing f and stir for 15 minutes. Next [,7-amitusephalosboranic acid 51, triethylamine 4ffI: added methylene chloride 7
Add the above-mentioned solution containing 5-oxobutyryl bromide to the solution while keeping it at -30°C. The temperature of the reaction solution was gradually raised to 20° C., and the reaction was carried out for 1 hour. Next, one solvent was distilled off, and the remaining liquid was 50% ethyl acetate and 5%
After shaking with 50-hydrochloric acid and drying the ethyl acetate layer over anhydrous magnesium sulfate, the ethyl acetate layer was distilled off and recrystallized from ether to give 7-(4-promo-3-oxobutyrylamino)cephalon. 3.6 ft. of sporanic acid is obtained.

Next, thiourea 0.6f, sodium hydrogen carbonate 0.66
5' to 100ml of water. Dissolved in tetrahydrofuran 50-7-(4-promo-3-oxinobutyrylamino)cephalosporanic acid 3.6 ? 'i In addition, the reaction is carried out at 20°C for 1 hour. When the reaction solution was concentrated to 173 and allowed to cool, crystals were precipitated, and P was separated to obtain 2.49f of 7-[2-(2-aminothiazol-4-yl)acetamido]cephalosporanic acid.

Next, add 2.41 of this 7-(2-(2-aminothiazol-4-yl)acetamido)cephalosporanic acid, 5.6 f of sodium bicarbonate, 2. , the reaction system is subjected to a reaction at 65°C for 5 hours under a nitrogen atmosphere. During this time, the pH of the reaction solution is 6.
Control to ~6.7.

Next, the reaction solution is concentrated, and then isolated and purified by XAD-III column chromatography to obtain the desired product 1.32.

(reaction formula) The target product was confirmed by NMR. (DMSO.

Trifluoro vinegar r! R) OOH OOH ■Tama-6511d H-7570d Example 3 2-Methoxyimino-2-(2-chloroacetylamido-4-thiazolyl)acetic acid 51 and thionyl chloride 20wrl
Add K and conduct the reaction at 40°C for 50 minutes. After the reaction is completed, thionyl chloride is distilled off under reduced pressure, and the residue is dissolved in acetone 20-. Next, 7-amitusephalosboranic acid 62
, 4.8f of sodium bicarbonate, 30% of water, 5% of acetone
The acid chloride ts obtained by the above method was added dropwise to the solution dissolved in - at 5 to 10°C while maintaining the pH at 7K, and stirred for 40 minutes. After the reaction is completed, the reaction solution is diluted with 6N
After adjusting the pH to 2 with hydrochloric acid, distilling off the acetone and further distilling off some of the water, concentrating and purifying with an XAD-II column, 7β-C(Z)-2-(2-chloro 5.92 of acetamido-4-thiazolyl)-2-(methoxyimino)acetamido]cephalosporanic acid is obtained.

Next, this product is dissolved in 30 ml of water, thiourea 12 is stirred at 20° C. for 6 hours, and the dechloroacetylated product is separated and purified using a column of reaction solution '1XAD-1i. 1.5 p of 7β-[(Z)-2-(2-amino-4-thiazolyl)-2-(methoxyimino)amido]cephalosporanic acid, 0.72.2 p of sodium hydrogen carbonate. -Put 0.81 of thiol-L-histidine in 50 ml of water, 1/C pH 6 to 6.5 under nitrogen atmosphere.
The reaction was carried out at 65°C for 4 hours while controlling the temperature. After the reaction is completed, adjust the pH to 2K with 6N hydrochloric acid, and
Purification is performed using an AD-■ column. 7β-((Z1
2-(2-amino-4-thiazolyl)-2-(methoxyimino)acetamide)-3-((2'-carboxy)
0.99% of ethylimidazol-2-ylthiomethyl]-5-cephem-4-carboxylic acid was obtained.

(Reaction formula) Confirm that it is the target product by NMR () lifluoroacetic acid) K
I did it more.

H-65,04d H-75,67d Example 4 2-thiol-L-histidine s, sy, sodium bicarbonate 4. Of was dissolved in water 150°C by heating at 50°C, and then 1 added cephalothin sodium 5,7 to this solution.
Add fff. The reaction system was replaced with nitrogen, and the reaction temperature was set to 65°C.
The reaction takes place for 5 hours. During that time, the pH of the reaction solution was 46.
Control to ~6.5.

After the reaction was completed, part of the water was distilled off, concentrated, and isolated and purified by XAD-n column chromatography to obtain the desired product 2.4°τ.
I got 2.

The target product was confirmed by NMR (DMSO.

trifluoroacetic acid).

1 H-65,10d H-75,72d Example 5 2-thiol-L-histidine5. Of, 9.1 pi of sodium bicarbonate was dissolved in 150 pi of water at 50°C, and then 1 was added to this solution with 6 of cephapirin sodium, O
f'f: Add. The reaction system was replaced with nitrogen, and the reaction temperature was set to 65.
The reaction was carried out at ℃ for 5 hours. Meanwhile, the pHFi of the reaction solution
Controlled to 6-6.5.

After the reaction, excess 2-thiol-L-histidine was removed by filtration, a portion of water was distilled off and concentrated, and XAD-[
Isolated and purified by column chromatography to obtain the desired product 2.6.
I got 1.

The target product was confirmed by NMR (DMSO, )')7"
oral acetic acid).

0OH H-65,09d H-75,68d Example 6 7-((Zl-2-(2-aminothiazol-4-yl)-2-(2-carboxyprop-2-oximino)
Acetamide cephalosporanic acid 3.51, 2-thiol-L-histidine 2.51, sodium bicarbonate 4
．． The mixture is poured into an aqueous solution containing 6y dissolved therein, and the reaction is carried out at 65C for 5 hours under a nitrogen atmosphere. During this time, the pH of the reaction solution is controlled at 6 to 6.8. After the reaction is complete,
Part of the water was distilled off, the residue was concentrated, and then isolated and purified by XAD-II column chromatography to obtain the desired product 2.12.

cM CO,H The target product was confirmed by NMR (DMSO, )broroacetic acid).

Box-C-5 H1,56 C(JOB H2 H65,11d H75,89d NH2 Example 7 Thiol histidiy 4,7 S' was dissolved in 50-dimethyl sulfoxide, and 1,1,5.3-tetramethylguanidine 5 .IIIF, t-butylphenyl carbonate 5,4 f was added and the reaction was carried out at 20C for 30 hours.
After bringing the aqueous phase to pI (2), extraction was performed twice with ethyl acetate (100), dried over anhydrous magnesium sulfate, and ethyl acetate was distilled off, leaving a residue of 4.61. remain.

Next, 7-ACA3f and the t-
Butyloxycarbonylated thiol histidine 4
．． 61 is placed in 100 mm of water and 50 mm of acetone, 6.52 mm of sodium bicarbonate is added, and the reaction is carried out at 650 mm under nitrogen atmosphere. After 6 hours of reaction, acetone in the reaction solution was distilled off and the desired product was isolated using XAD-II column chromatography to obtain 2.12.

Next, 7-amino-6-((2-t
-butylmexycarponylamino-2-carboxy)ethylimidazol-2-ylthiomethyl]-3-cephem-4-carboxylic acid 2.11 to tetrahydrofuran 60
-, and add 1.2 equivalents of bis(trimethylsilyl)acetamide, which is a merimedyl silylation agent. Next, add 0.61 parts of 2-chenyl acetic acid, 11 parts of N,N-dicyclohexylcarbodiimide to the reaction system. 15
React at C for 10 hours. Separate sediment from door to door. After adding 10 ml of water to the P solution, the solvent was distilled off under reduced pressure, and the residue was dissolved in 601 nt of formic acid, reacted at 5C for 3 hours, and the formic acid was distilled off. When ether is added to the oily residue, crystals precipitate out, which are purified by column chromatography using XAD-■. carboxy)
1.62 ethyl 1 midazol-2-ylthiomethyl]-3-cephem-4-carboxylic acid was obtained, which was obtained in Example 4.
The NMR chemical shifts all matched with those obtained in the following.

NJ'11

[Brief explanation of the drawing]

The figure is a graph showing blood concentrations of Compound I11 and third generation cephalosporin after intravenous injection. Procedural amendment 11 2 Kazuo Wakasugi, Commissioner of the Japan Patent Office, established on September 1988 1 Indication of the case Patent application No. 116945/1982 2 Name of the invention Cephalosporin derivative 3 Person making the amendment Relationship to the case/Patent application Person (003) Asahi Kasei Kogyo Co., Ltd. 4 Agent 5th Floor, Toranomon Sangyo Building, 2-29 Toranomon-chome, Minato-ku, Tokyo Packing of Claims in Specification Column for Detailed Explanation of the Invention Column for Brief Explanation of Drawings Drawing 6: The description in the description of the amendments shall be amended as follows. 111 The scope of the claim is amended as follows. (111 General formula (II 2 NHl [In the formula, RI represents an organic residue known in β-lactam antibiotics, Rtt'i hydrogen or methoxy group, and various residues in R3 -C-1 OR. If contained, R3 represents only hydrogen and R4 is C1
a b or different, each being an alkyl group with C+=C<), X is S or 0, R3 is hydrogen or a salt with an organic group, or a physiologically acceptable represents a metal ion. ] Cephalosporin compounds and physiologically acceptable inorganic and organic salts. 121 R, is an organic residue having an aromatic phenyl group or a nuclear substituted aromatic phenyl group, Claim 1
A cephalosporin compound as described in Section. 2. The cephalosporin compound according to claim 1, wherein +31 R is an alkyl or an organic residue having a substituted alkyl. +41 Claims in which R1 is an alicyclic hydrocarbon or an organic residue having a substituted alicyclic hydrocarbon. A cephalosporin compound according to item 1. 151 R1 is 1~ selected from nitrogen, oxygen, and sulfur
The cephalosporin compound according to claim 1, which is an organic residue containing 4- to 6-membered heterocyclic residue 'Ik'IT'. Cephalosporin compound 2 according to claim 5, which is represented by: Cephalosporin compound 2 according to claim 5, which is represented by: (2) The chemical structure φ formula in the second column of the first column on page 6 is stopped. Chemical structural formula (6) 7th negative 2nd column 2nd chemical structural formula (8) (9) (71 Page 7 4th column 4th chemical structural formula 11 α2 Page 8 1st 3rd column Chemistry 'M formula 8 negative ending line 1st chemical structural formula [NCC) It J meeting 1-NCC horse-'' and stop.Page 9, 1st crotch 4th chemistry Structural formula, page 9, 2nd row from the bottom, 2nd chemical structure f, Page 9, 1st row, 1st row from the bottom, chemical structural formula 0, 10th corner, 3rd row, 3rd chemical structural formula 04 ) The chemical structural formula NH,J at the bottom of page 10 is changed to θ5) Correct 1 cefotaxime in line 5 of page 12 to ``cefotaxime''. Q61 tJ Page 412, line 1s, delete “(Latakikisev) Jwr (Latamokisev)”, OD page 12, line 14, “(Cefmezogisim) j k r (ceftinkishim)”
and revise it. Alpha mark Page 12, lines 15-16, "Extremely persistent as shown in Figure m1" is corrected to "Extremely high blood concentration and persistent as shown in Figure 1" 4 Page 13 1 In line 1, ``In addition, blood concentration persistence, etc.'' should be corrected to ``In addition, blood concentration and persistence, etc.'' (2) On page 13, chemical structural formula C111, 14th negative chemical structural formula is corrected as ``.'' Insert the following statement between lines 4 and 5 from the bottom of page 14. ``Next, compound Blood concentrations of (n) and (III) during intravenous injection were measured using the same method as in the case of the gold compound tIl, and compared with cefavirin and cephalothin, respectively. The results are shown in Figures 2 and 3. To) Page 14, lines 2 to 1 from the bottom, ``Furthermore, the effects can be seen.''
” is corrected as below. "Furthermore, the introduction of histidine into the cephalosporin skeleton has a significant effect on high blood concentration and persistence, as seen in the blood S level during intravenous injection of compounds (Il, (n), OID). C24+ Correct "Rad-1" in line 4 of page 15 to "rat". (C) Chemical structural formula 12+il in the second column of page 16
Brief explanation of the drawings on page 42 r ■ Correct [ ]. ``Figure 1 is a graph showing blood concentrations of compounds (Il and 5th generation cephalosporin) after intravenous injection; Figure 2 is a graph showing the blood concentrations of compounds (Il and 5th generation cephalosporins)
Figure 3 is a graph showing the blood concentrations of compound (11) and cephalothin after intravenous injection. ” Fin The drawing attached at the time of application shall be Figure 1. (To) Submit Figures 2 and 3 as attached. Jin2I21/4
5 [JΣ After U Todoroki (br) ears, 31E1

Claims (1)

[Claims] +11 General formula (I+ ■E2 [In the formula, R1 represents an organic residue known in β-lactam antibiotics, R, halogen, or a methoxy group; When the organic residue of 8.R4 has -C-, R7 represents only hydrogen, and R4 may contain C8-a or nl, each of which is a C1-C4 alkyl group. ), XViS or 0, R8 represents hydrogen, a salt with an organic base, or a physiologically acceptable metal ion, and physiologically acceptable inorganic and organic cephalosporin compounds. 2. The cephalosporin compound according to claim 1, wherein the salt 1211 is an organic residue having an aromatic phenyl group or a nuclear-substituted aromatic phenyl group. The cephalosporin compound according to claim 1, wherein (31R, is an organic residue having an alkyl or substituted alkyl. (41L is an alicyclic hydrocarbon or an organic residue having a substituted alicyclic hydrocarbon) The cephalosporin/compound according to claim 1, wherein +51 R, is 1 to 1 selected from nitrogen, oxygen, and sulfur.
The cephalosporin compound according to claim 1, which is an organic residue having a 4- to 6-membered heterocyclic residue containing 4 atoms. The cephalosporin compound according to claim 5, which is represented by: The cephalosporin compound according to claim 5, which is represented by: