JPS6230787A - Novel oxime derivative of 7-aminothiazolylacetamidocephalosporanic acid - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

DETAILED DESCRIPTION OF THE INVENTION The subject of the present invention is the following general formula! (Here, R' represents a saturated alkyl group having 2 to 4 carbon atoms, A#: i represents a hydrogen atom or an equivalent amount of an alkali metal, alkaline earth metal, magnesium or an organic amino base, and the wavy line represents the group OR is a novel oxime derivative of 7-aminothiazolyl acetamidocephalosporanic acid (indicating that ' can be in the syn position).

Examples of R' include ethyl, propyl, inpropyl, butyl, 5ec-butyl, and t-butyl groups.

Among the radicals A, mention may be made in particular of equivalent amounts of sodium, potassium, lithium, calcium or magnesium. Among the organic bases that can be expressed to humans,
In particular, trimethylamino, trinibruamino, methylamino, propylamino, N,N-dimethylethanolamino, tris(hydroxymethyl)aminomethane, arginine or lysine can be used.

Compounds of the invention defined as having syn isomeric forms can be represented by the following general formula.

More particularly, the subject of the invention is a compound of the general formula I in which R' represents a saturated alkyl group having 2 to 4 carbon atoms and A represents a hydrogen atom, n) an IJium atom or an equivalent diethylamino It is.

Among the compounds of general formula 1, mention may be made especially of the compounds described in the Examples, and more specifically, the following compounds.

3-acetoxymethyl-7-(2-(2-amino-4-
Thiazolyl)-2-ethoxyiminoacetamide] Cef-5-em-4-carphonic acid, syn isomer and its salts with alkali metals, alkaline earth metals, magnesium or organic amino bases, 3-acetoxymethyl-7-(2 −(
2-Amino-4-thiazolyl)-2-((1-methylethoxy)imino)acetamide]Sefu-3-M-4-
Carboxylic acids, ayn isomers and their salts with alkali metals, alkaline earth metals, magnesium or organic amino bases.

Note that the compound of the above formula I can be used in (1) in the form represented by the formula (1), or (11)
It is to be understood that it can exist in the form of a compound of formula It 2 .

The compound of the present invention can be obtained by converting 7-amitusephalosboranic acid of the following formula into the following formula (■) (where R1
represents a group that can be easily eliminated by acid hydrolysis or hydrogenolysis, and R' represents a saturated alkyl group having 2 to 4 carbon atoms), a syn isomer or a functional derivative of this acid. The compound of the following formula ■ Kozo (where R1 and R' have the meanings indicated above) is obtained by the reaction, and the syn isomer is obtained, and the compound of the formula II is hydrolyzed or hydrogenolyzed in an acid medium. The following formula ■' (where R' is 2~
(representing a saturated alkyl group having 4 carbon atoms), the syn isomer (corresponding to a compound of the formula (1) in which one represents a hydrogen atom) and optionally a compound of the formula I'
It is obtained by a manufacturing method that specifically involves forming a salt of the compound by a conventional method.

In a preferred method of carrying out the above process, 7-amitusephalosboranic acid is a functional derivative of the acid of formula (1),
For example, treated with anhydrides or acid chlorides. Acid anhydrides can be formed in situ by reacting an acid with an alkyl chloroformate or dicyclohexylcarbodiimide.

other halides or other alkyl chloroformates,
Other anhydrides formed in situ by the action of dialkylcarbodiimides or other dicycloalkylcarbodiimides can also be used. Acid azides, activated acid amides or activated acid esters such as hydroxysuccinimide, p-nitrophenol or 2
．． Other acid derivatives such as the ester formed by 4-dinitrophenol can also be used.

When the reaction of 7-amitusephalosborane acid is carried out with the halide of the acid of general formula It is done below.

As the basic agent, for example, alkali metal carbonate or N-
Trialkylaminos such as methylmorpholine, pyridine or triethylamino can be chosen.

Examples of the acid hydrolyzing agent that acts on the compound (2) include formic acid, trifluoroacetic acid, and acetic acid. These acids can be used in anhydrous form or as aqueous solutions. As the hydrogenolyzing agent, mention may especially be made of a zinc-acetic acid system.

Acid hydrolyzing agents such as anhydrous trifluoroacetic acid or aqueous formic acid or acetic acid are preferably used to remove the t-butoxycarbonyl or trityl group.

Preferably, zinc-
Acetic acid systems are used and catalytic hydrogenation is used to remove benzyl, dibenzyl and hycarbopenzyloxy groups.

The compound of formula 1' can be salt-formed by conventional methods. Salt formation can be carried out, for example, by combining these acids with inorganic bases such as sodium or potassium hydroxide or sodium bicarbonate or with saturated or unsaturated aliphatic carboxylic acids such as diethyl acetate, ethylhexanoate or especially acetic acid. It can be produced by reacting with salt. A preferred salt of the aforementioned acid is the IJ salt.

Similarly, salt formation can be produced by the action of an organic base such as triethylamino.

For the preparation of salts, solvates of the free acid can also be used as starting materials in place of the free acid.

For example, solvates formed with water, formic acid or alcohol can be used.

Solvates with alcohols, especially ethanol, are e.g.
It can be prepared by treating the solvate formed by formic acid with a mixture of alcohol and water and then concentrating the solution.

This salt formation is preferably carried out in a solvent or solvent mixture such as water, ethyl ether, methanol, ethanol or acetone.

Salts can be obtained in amorphous or crystalline form depending on the reaction conditions used.

Crystalline salts are preferably obtained by reacting the free acid or its solvate, for example the solvate formed with formic acid or ethanol, with one of the salts of the aforementioned aliphatic carboxylic acids, preferably sodium acetate. Manufactured by

n) In the production of IJium salts, the reaction is carried out in a suitable organic solvent such as methanol. Such solvents may contain small amounts of water.

Furthermore, it is possible to convert amorphous salts into crystalline salts. For this purpose, the amorphous IJ salt (which may be in the form of a solvate with, for example, 1.0 or 1.5 mol of water) is dissolved in a suitable organic solvent, preferably methanol. dissolved in low molecular weight alcohols such as

Crystallization can then occur almost directly or by addition of other solvents such as ethanol, impropatol, n-butanol, acetone, ether, and generally organic solvents miscible with methanol.

If the starting material, solvent or two components contain any water, crystalline salts can be obtained in the form of hydrates.

In the above production method, the compound of formula (1) is prepared by combining thiourea with the following formula (1) (where R' represents a saturated alkyl group having 2 to 4 carbon atoms and alk has 1 to 4 carbon atoms). (representing an alkyl group) and treated with a base to obtain, after death, a compound of the following formula (where R' and alk have the meanings indicated above), and a compound of formula Treated with a functional derivative of a group that can be easily eliminated by hydrogenolysis, it is treated with the following formula (where R represents a group that can be easily eliminated by acid hydrolysis or hydrogenolysis, and R' is 2 represents a saturated alkyl group having ~4 carbon atoms), prepared by treating a compound of formula V with a base and then with an acid.

In a preferred method of carrying out this preparation, the base used to obtain the compound of formula (1) is potassium acetate.

However, alkali metal carbonates and acid carbonates or dilute soda or potash can be used.

Functional derivatives of groups that are readily removable by acid hydrolysis or hydrogenolysis are preferably used in the presence of triethylamino or other trialkylamino, other tertiary amino bases such as methylmorpholine or pyridine. trityl chloride.

Other functional derivatives of groups that can be easily removed by acid hydrolysis or hydrogenolysis can also be used. Among these derivatives, in situ prepared t-butyl chloroformate, t-butyl azidoformate, trichloroethyl or benzyl chloroformate, in situ prepared hybrid formyl-acetic anhydride, chloride or other halogenated benzyl or dibenzyl, phthalic anhydride or N-carbethoxy 7-talimide.

The base used to saponify the compound of formula V is preferably soda, but other bases such as potash or barita can also be used.

The acid used to isolate the acid of formula (1) is preferably dilute hydrochloric acid, but acetic acid or formic acid can also be used.

Also, a compound of the following formula IVa oR'a (where alk represents an alkyl group having 1 to 4 carbon atoms, and R'a represents a saturated alkyl group having 2 to 4 carbon atoms) ( (corresponding to the compound of the above formula (1) in which R' represents a saturated alkyl group having 2 to 4 carbon atoms) is a compound of the following formula (2) (where alk has the abovementioned meaning) with an alkylating agent. After processing, the following formula ■CH3-C-C-Cog m
It is prepared by obtaining a compound of lk, treating this compound with a brominating agent to obtain a compound of formula (1), and reacting this compound with thiourea and then with a base.

The alkylating agent used to convert the compound of formula 2 to the compound of formula ).

The brominating agent used to convert the compound of formula (1) to the compound of formula (2) is preferably bromine.

The base used after treating thiourea with the compound of formula (1) is preferably an alkali metal carbonate or an acidic carbonate. However, diluted potassium or potassium acetate can also be used.

The compound of formula I' can also be prepared by converting 7-aminocephalosporanic acid of the following formula to formula 1a (where R
' represents a saturated alkyl group having 2 to 4 carbon atoms), a syn isomer or a functional derivative of this acid to give the following formula: co,n.

(wherein R' has the meaning given above) is obtained by obtaining the ayn isomer and reacting this compound with thiourea.

The reaction of 7-aminocephalosporanic acid with the acid of formula 11m is carried out under the same conditions as the reaction of 7-aminocephalosporanic acid with the acid of formula 1.

The reaction of thiourea with a compound of formula (1) is preferably carried out in a neutral or acidic medium.
Reported by Mr. i (JAC3, 90, 450B (196B)).

Compounds of formula 11a used in the above alternative method can be prepared using functional derivatives of the chloroacetyl group of the following formula: represents an alkyl group having 1 to 4 carbon atoms) to obtain a compound of formula V & (where R' represents a saturated alkyl group having 2 to 4 carbon atoms), It is prepared by treating a compound of formula Va with a base and then an acid.

The functional derivative of the chloroacetyl group is preferably a halide such as chloroacetic anhydride or monochloroacetyl chloride.

If the reaction is carried out with a chloroacetyl halide, it is preferably carried out in the presence of the same basic reagents as mentioned above.

The base used to saponify the 2Va compound is preferably soda, but other bases such as potash or barita can also be used.

The acid used to isolate the acid of formula 11m is preferably dilute hydrochloric acid, but acetic acid or formic acid can also be used.

In addition, the following formula vb OR" b (where 81 represents a group that can be easily eliminated by acid hydrolysis or hydrogenolysis, and R'b represents a saturated alkyl group having 2 to 4 carbon atoms. , alk represents an alkyl group having 1 to 4 carbon atoms) (corresponding to a compound of formula V) can be prepared by subjecting an equivalent amount of a compound of formula V to acid hydrolysis or hydrogenolysis. It is prepared by treating with a functional derivative of an easily removable group to obtain a compound of the following formula X miH , which is then treated with an alkylating agent.

The functional derivative of the group that can be easily removed by acid hydrolysis or hydrogenolysis is preferably trityl chloride. The reaction is carried out in the presence of a base, preferably triethylamino. Other bases such as other trialkylaminos, methylmorpholine or pyridine can also be used.

Other functional derivatives of groups which can be easily removed by acid hydrolysis or hydrogenolysis, such as chloroformic acid or L-butyl azidoformate, trichloroether or dibenzyl chloroformate, hybrids prepared in situ. Formyl-acetic anhydride, chlorinated or other halogenated benzyl or dibenzyl, phthalic anhydride or N-carbethoxyphthalimide can also be used.

The alkylating agent used to prepare compounds of formula vb is preferably an alkyl halide, such as an alkyl iodide, or an alkyl sulfate.

Here, since the configuration of the compound obtained from the compound of formula ■ can be maintained during the synthesis, the configuration of the compound of formula I is as follows:
It has been demonstrated that this is related to the configuration of the compound.

The same, of course, also applies to the compounds obtained from the compounds of the formulas iVa, 1b and 2", since the formulas IVa, tvb and 2" are included in the formula 2.

The configuration of compounds of formula (II) depends on several parameters during the preparation of these compounds.

Therefore, the reaction of thiourea with compound 2 in an aqueous solvent such as aqueous acetone or aqueous ethanol or at ambient temperature produces a substantially stoichiometric amount of thiourea from 1 to 3
It has been demonstrated that syn isomers are obtained when carried out by reacting over very short periods of time, on the order of hours, or when all of the above conditions are combined.

Therefore, for example, thiourea and the following formula
(represents a saturated alkyl group having 4 carbon atoms and X represents a chlorine atom) or R'b is a hydrogen atom or 2
represents a saturated alkyl group having ~4 carbon atoms (X
represents a bromine atom)], and the operation is carried out in the presence of a substantially stoichiometric amount of thiourea, and the reaction is carried out for a limited period of several hours. Compounds of formula (1) can be prepared in the syn form by carrying out the work in an aqueous solvent or at ambient temperature, or by carrying out the operation in combination with all of the above conditions.

Therefore, the compound of formula (1) obtained in Example 3 has a syn configuration.

Compounds of general formula IO are useful against Gram-porous bacteria such as Staphylococcus and Streptococcus, in particular against penicillin-resistant Staphylococcus bacteria, and on the other hand against Durham-negative bacteria, in particular Coliform, Klebsiella, Salmonella. It has very good antibiotic activity against bacteria of the genus Proteus and genus Proteus.

These properties make the compound pharmaceutically acceptable for use in the treatment of infections caused by susceptible microorganisms, in particular for example staphylococcal sepsis, malignant facial or cutaneous staphylococcal infections, purulent dermatitis. , putrid or purulent ulcers, charcoal marks,
This makes it suitable for use as a drug in the treatment of staphylococcal infections such as pharyngitis, erysipelas, acute early influenza or post-influenza staphylococcal infections, bronchopneumonia and pulmonary suppuration.

These pharmaceutically acceptable compounds may also be used as drugs for the treatment of colibacillosis and related infections, infections caused by Proteus, Klebsiella, and Salmonella bacteria, and other diseases caused by Durham-negative bacteria. It can be used as

a) 19.4 f of ethyl γ-chloro-α-oximinoacetoacetate in 60 CC of acetone and 14.3 CC of diethyl. Cool the whole thing in a water bath for 10 minutes and
Add 5cc of 2N soda over 30 minutes, then stir the whole thing to 4cc.
Stir for 0 minutes b) Add 7.6 f of thiourea to the reaction medium, heat it at 55°C for 20 minutes to drive off the acetone, dissolve the residue in ethyl acetate and add 6.9 f of potassium carbonate. , stir, decant, extract with ethyl acetate, dehydrate, and concentrate to dryness. The 17.4 fO residue is separated and chromatographed on silica eluting with ether. The desired compound is recovered, dissolved in inglovir ether, applied under vacuum, washed and dried to obtain the desired compound in zar. MP=129°C. The resulting compound has a syn configuration.

Compound obtained in step A of 516t, 6a1. dry dimethylformamide, 12a, methylene chloride and 1.
Place 89 CC of triethylamino under inert gas.

Cool the mixture to -15°C and slowly add 598 g of trityl chloride. Leave the whole thing for half an hour and raise the temperature to +
The temperature is increased to 10° C. and the whole is then kept alive at ambient temperature for 3 hours. 13 times of 1N hydrochloric acid is added, the whole is stirred, decanted, washed with 1N hydrochloric acid, and then washed with water.

Extracted with methylene chloride, dried, concentrated to dryness, 7.89
A crude residue of F is obtained.

The resulting compound has a syn configuration.

The compound obtained in step B of No. 7,899, 40 CC of dioxane and 19.5Q1. Heat the mixture at 110° C. for 1 hour. The mixture is vacuum filtered, washed with an ether-dioxane mixture then ether alone, and dried.

The sodium salt of &25f was obtained, which was dissolved in 60 cc of methylene chloride and 20 cc of 1N hydrochloric acid, the two phases were stirred, 20 CH of methanol was added, the whole was decanted, washed with water, and dissolved with a methylene chloride-methanol mixture. Extract, dry and concentrate to obtain 5.85 f of pure 2-(2
-)literamino-4-thiazolyl)-2-ethoxyiminoacetic acid is isolated.

The resulting compound has a syn configuration.

Step D: 3-acetoxymethyl 127-:,,C~!
The 2-(2-)dithylamino-4-thiazolyl)-2-ethoxyiminoacetic acid obtained in step C of 14f was added to 340H methylene chloride, the suspension was cooled, and the suspension was added to 970M9 dicyclo. Add the xylcarbodiimide, wash the whole with methylene chloride and stir at ambient temperature for 1 hour. Dicyclohexyl urea is heated under vacuum.

The Ffi was cooled to -20°C, and tO2f of 7-amitusephalosboranic acid was mixed with 18cc of methylene chloride and j,0
A solution of 6 CH dissolved in triethylamino (-2
(cooled to 0°C) at once.

Heat the whole for 1.5 hours, add 1.80C acetic acid,
Add CH 1N hydrochloric acid, stir the whole, decant, wash with water, extract with methylene chloride, dry and concentrate to give 4.56 f of the desired compound.

The resulting compound has an ayn configuration.

The compound obtained in Example 1 of 4,56f was converted to 250C050
% aqueous formic acid and heated at 55°C for 15 minutes, then water (
dilute with SOCC) and apply vacuum to triphenylcarbinol. The f solution is concentrated to dryness, dissolved in water, stirred, vacuum filtered, washed, and dried to yield 116 ml of impure product. A secondary yield of 674q of crystalline product is obtained by concentrating the f solution. 790■ in total.

Perform the following purification.

Make a paste of the 1,065 F crude product with SCC water, heat at 70 C for 5 minutes, cool, stir for half an hour,
Vacuum filter, wash, and dry to obtain purified product 815f. This 815 m9 was dissolved in 2 CC of water and SCR of acetone, the insoluble matter was filtered out under vacuum while heating slightly, 3 CH of water was added, the whole was heated to 60 °C, and nitrogen was blown in to drive out the acetone. , the resulting granules were vacuum filtered, washed with water, then with ether, and 458 wg.
Isolate the intended hardware.

Analysis: CttHxeOtNsS嘗Calculation: Cchi4549 Hchi4.08Nchi14.92S
Chi1566 actual measurement: 44.5 44 1ta
153 This compound has a syn configuration.

NMR (60MH2, DM80) p prn: 2
．． 05 (OAc), 6.75 (thiazole ring proton).

59. Add 8 f of ethyl 2-acetyl-2-hydroxyiminoacetate to 200 CC of pure acetone.

The whole is cooled in a water bath and 522 cc of potassium carbonate are added followed by 25 cc of 2-iodopropane over half an hour.

Then stir the whole thing for 2 hours, add 800 water and 5 QOC
Add methylene chloride from C, stir the whole, decant, extract with methylene chloride, dehydrate, vacuum filtrate,
Concentrate, 4 f, 5? The desired compound is isolated.

41. The compound obtained in the above step of 5f was added with a trace amount of p-
) in 190cc of methylene chloride containing luenesulfonic acid. Stir the whole, then add 11.9 bromine to 5
A solution of occ in methylene chloride is introduced at ambient temperature within 1 hour. Stir everything, add ice cold water,
The whole is decanted, extracted with methylene chloride, washed with ice-cold water and concentrated to isolate the desired derivative of 55f.

Ethyl 14,9 f thiourea with 55 CC ethanol and 10
5cc of water, then 45t of a solution of the compound prepared in step B dissolved in 55Cn of ethanol.
Add in 0 minutes. Stir the whole thing at ambient temperature for 2 1/2 hours,
Add 20 cc of 10 thiacid sodium carbonate aqueous solution, stir the whole, vacuum filter, wash, dry, 42.1
The crude product of 5f is isolated and chromatographed on silica eluting with ether. Fractions rich in the desired compound are collected and then concentrated, the crystals are dissolved with inpropyl ether, vacuum filtered and washed to yield the desired compound 11759.

The resulting compound has a syn configuration.

The compound obtained in step C of 112 was mixed with 20 cr of dry dimethylformamide, 40Q1. methylene chloride and &
2C11, in a mixture with triethylamino. Cool the mixture, slowly add 1 & 2f trityl chloride, stir the whole for 2 1/2 hours, add 45 ac of 1N hydrochloric acid, stir the whole, decant/decant at 40C.
Wash with C water, extract with methylene chloride, dry, vacuum filter, and concentrate to dryness to yield the desired compound of 27,71.

The resulting compound has a syn configuration.

d) Acetic acid A mixture of the compound obtained in steps 27 and 79, 150 CC of dioxane and 65 CC of 2N soda is refluxed. The sodium salt crystallizes out, but the mixture is cooled and
Filter under vacuum, wash with 1:1 dioxane mixture and dry to obtain the crude sodium salt of 1&85f. 15
．． This sodium salt i1a of 9f? f of dimethylformamide, 100 g of water and about 500,011. Dissolved in a mixture of water and! Add 5OCH of 2N hydrochloric acid, drive off the methanol, dilute the residue with water, vacuum filter, wash,
Dry the obtained 9820 viscous paulownia product at 220 CC s
Dissolve in o:so methylene chloride/methanol mixture, concentrate to dryness, dissolve in ether, triturate, vacuum filter the crystals, wash and dry. 4.92 of the expected acid is obtained.

MP2170℃0 The crude product of 3001119 was mixed with 2CH methylene chloride and 1
Dissolve in methanol, dilute the whole with water and methylene chloride, then stir, filter the crystals under vacuum, wash with methylene chloride, then water, dry, and isolate 230q of analytically pure compound. do.

Analysis: Calculation: C Chiro & 77 H Chi a34 N Chi & 91 S Chi & 8 Mi 8i II: 6 & 6 5. s aa 6.
8 The resulting compound has a syn configuration.

The acid obtained in Step E of phosphoric acid 4,89 f is added to 155 CC of dimethylformamide under an argon atmosphere.

After dissolution, the solution is cooled in a water bath and a solution of 1.629 dicyclohexylcarbodiimide in 16 cc of methylene chloride is added. Dicyclohexylurea crystallizes out. The mixture is stirred in a water bath, filtered under vacuum, washed with methylene chloride, and dried to separate the 1.424 F dicyclohexyl urea. The P solution is cooled in a methanol-ice bath, and then a solution of 1,419 7-amitusephalosboranic acid dissolved in 30 methylene chloride and 1.45 CC of triethylamino is added. The whole was stirred at ambient temperature for 3 hours, 20 CC of 1N hydrochloric acid was added, the whole was stirred, decanted, extracted with methylene chloride, dried, vacuum filtered, and the desired compound of 9.059 and the starting compound to obtain a mixture of

Dissolve this in methylene chloride, stir to initiate crystallization, filter the crystals under vacuum, wash and dry, 1.6
Obtain the first pure compound of f. 15 is concentrated to dryness and the residue is dissolved in inpropyl ether with vigorous stirring to isolate the insoluble viscous product of the desired compound 4,91f.

The resulting compound has a syn configuration.

The crude product obtained in Example 3 of -amino-4-thiazolyl)-2-(1-4, 919 is added to 30 CC of 50% aqueous formic acid. The whole is stirred in a water bath at 60 °C and diluted with water. The resulting triphenylcarbinol is filtered under vacuum, washed with water and dried to separate 1,399 triphenylcarbinol.

The liquid is concentrated to dryness, washed with water, triturated, vacuum filtered, washed with water, and dried to obtain 800 μm of the desired compound.

972 μ of the crude compound was dissolved in 4 CC of methanol, diluted with 20 °C of ether, and the insoluble matter was vacuum filtered.
Wash and dry to obtain the desired pure acid of Cape 404 for analysis. MP'! 200℃.

Analysis: Calculation: Cchi 44.71H% 4.38N% 14.48S Chi 1526 Actual measurement: 44.5 4.5 14.1
152 This compound has a syn configuration.

NMR (60MH2, DMSO) ppm: 2.01 (
CH3CO), doublet 9.46 J=8Hz (CO
NH), 17 (proton of thiazole ring).

Dilution Method in Liquid Medium Prepare a set of test tubes in which equal amounts of sterile nutrient medium are distributed. Dispense increasing amounts of the study compound into each tube and then seed each tube with the bacterial strain. Incubate for 24 hours (24H) or 48 hours (4H) at 37°C in an incubator.
8H) After incubation, inhibition of proliferation is assessed by light transmission. This is the minimum inhibitory concentration M, 1. C,
(expressed as p f /err?) is determined.

The following results were obtained.

[The compound called compound person is 3-acetoxymethyl-
7-(2-(2-amino-4-thiazolyl)-2-methoxyiminoacetamide]cef-3-em-4-carboxylic acid, anti isomer.]ProteuBMi
Experimental Infection with Proteus Mrabilis The activity of the compound of Example 2 was studied in experimental infection with Proteus Mrabilis in mice.

-7 to a group of 10 mice with an average weight of 222
Proteua Mirabilia A diluted to
24-hour culture of 235 strains of okinoid juice o, s
cc was infected by intraperitoneal injection.

A predetermined amount of the compound was administered by subcutaneous injection 1 hour, 4 hours, and 24 hours after infection.

The results were as follows.

Claims (3)

[Claims] (1) The following formula I ▲Mathematical formulas, chemical formulas, tables, etc.▼(I) (Here, R' represents a saturated alkyl group having 2 to 4 carbon atoms, and A is a hydrogen atom or an equivalent amount of an alkali metal. , represents an alkaline earth metal, magnesium or an organic amino base, and the wavy line indicates that the group OR' is in the syn position). (2) 3-acetoxymethyl-7-[2-(2-amino-4-thiazolyl)-2-ethoxyiminoacetamide] cef-3-m-4-carboxylic acid, syn isomer and its alkali metal, alkaline earth The compound according to claim 1, which is a salt with a metal, magnesium or organic amino base. (3) 3-acetoxymethyl-7-[2-(2-amino-4-thiazolyl)-2-((1-methylethoxy)imino)acetamide]cef-3-em-4-carboxylic acid, syn isomer and its salt with an alkali metal, alkaline earth metal, magnesium or organic amino base.