JPH05507485A - Cephalosporin esters useful as antibiotics - 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] Introduction to Cephalosporin Esters Useful as Antibiotics The present invention relates to novel cephalosporin esters. These compounds are antibiotics As a quality, it primarily affects bacteria that are sensitive to these cephalosporin compounds. resisting, preventing, or combating pathogenic infections caused by Useful for treating warm-blooded animals.

Background of the invention The cephalosporin antibiotic ceftiofur is a 7-C2-(amino-1,3- thiazol-4-yl)-2-(methoxyimino)acetamide]-3-[(ph) Named as 2-ylcarbonyl)thiomethyl]-3-cephemu-4-carboxylic acid However, its carboxylic acid group and easily hydrolyzable ester group are alkali Along with metal salts, alkaline earth metal salts and amine salts, Labeau w) et al., U.S. Pat. No. 4,464,367.

The hydrohalides of sethiopher, especially its hydrochloride salts, have been described by Amfn et al. No. 4,902,683.

Ochiai U.S. Patent No. 4.278.671 and related patents Nos. 4.510.138 and 4.520.194 contain several 7-[2- (2-aminothiazol-4-yl)-2-(syn)-methquiniminoacetoa [Mido]cephalosporins are disclosed. R8 or 3 of the cephalosporin molecule Many groups have been described that are positioned at (Rs-CH2-). many like this Among the R1 groups, hydroxy and mercapto are listed in lines 11167 and 68. It is listed.

Desacetylcefotaxime, i.e. 7-[2-(2-amino-1,3-thia sol-4-yl)-(syn)-2-methoxyiminoacetamide]-3-hydro Roxymethylcepha-3-em-4-carboxylic acid is an alkyl ester Shung Drug Research (＾rzneimittel Forschun g Drug Research), Volume 34 (II), No. 12 (1984), 1V1 9~] Page 723 CM McDonald (C), Macdonald et al. ``Properties of Cefotaxime in Rats, Dogs, and Humans.'' Disclosed in the published paper.

Published PCT Application No. VOG 2103395 (IO 148/1982) has at least one group containing the structural formula -diS''-R and has therapeutic activity. discloses several organic compounds that

Disclosure of information Y, Yoshimura et al., International Jar International Jour nal of Pharmaceutics), Volume 38, Pages 179-190 (1 987) is 7β-(2-(2-aminothiazol-4-yl)acetamide )-3-(((1-(2-dimethylamineethyl)-1H-tetrazole-5- yl)thio)-methyl)cepha-3-em-4-carboxylic acid (cefotiam) The synthesis and oral absorption of acyloxymethyl esters is disclosed.

Yoshimura (Y, Yoshimura), N Hamaguchi (N, fla maguchi) and The Jar by T, Yashiki The Journal of Antibiotics iotics>, Volume 39, Issue 9, Issues 1329-1342 (September 1986), 7-[2-(2-aminothiazol-4-yl)acetamide]-3-[[[1 -(2-dimethylaminoethyl)-1H-tetrazol-5-yl]thiocome 1-anoloxy of cepha-3-em-4-carboxylic acid (cefotiam) Discloses the preparation of ethyl esters and their oral absorption in mice.

The Journal of A by T. NishiN15hi et al. The Journal of Antibiotics ), Vol. 40, No. 1, pp. 81-90 (January 1987) 1-(cyclohexyloxycarbonyloxy)alkyl ester active in Discloses Rodrug.

Summary of the invention The invention particularly relates to compounds of formula 1 In formula c, R1 is (a) -S-(CHz)--CHx, (b)-5-(4-methoxyphenyl), (C)-3-(3,4-dimethoxyphenyl) phenyl), (d) -5-C+=Ca alkyl, or (e) -3-(CHz).

-Ruffles.

R2 is (a)-CHR3-0-C(0)-R4 or (b)-C)(R1-〇-C( 0)-〇-R4; R3 is (a,) is hydrogen, (b) is C, -C, alkyl, or (C) is cyclohexyl: R4 is (a) is hydrogen, (b) is CI-C, alkyl, or (C) is cyclohexyl: Provided that n is 1 to 5.

The carbon atom content of various hydrocarbon-containing moieties is determined by the minimum and maximum carbon of this moiety. Indicated by a prefix indicating the number of atoms. That is, the prefixes C8-C7 are integers " i" to an integer "j" carbon atoms. Therefore, C, −C4 a Alkyl means alkyl of 1 to 4 carbon atoms, i.e. methyl, ethyl, means lopyru, butyl, and their isomeric forms.

Compounds of formula I are useful in pharmaceuticals for the treatment of certain warm-blooded animals or humans. It is useful as an active antibiotic drug compound in a therapeutic dosage form. Currently this The compound is particularly suitable for Pasteurella hemolytica (Pasteurella hemolytica). lytica), Pasteurella fultocida (P, multocida), Haemophilus pleuropneu moniae), Haemophilus somnus (L somnus), Escherichia ・Escherichia coli, Salmone lla spp, ), Staphylococcus aureus aureus), Streptococcus agalacte (Strep tococcus agalactiae), Streptococcus bovis (S trep, bovis), Streptococcus disgalacche (Str. p, dysgalactiae), Streptococcus faecatis (St rep, faecatis), Streptococcus uberis (Strep.

uberis), Salmonella typhimurium (Salmonella typ. himurium), Escherichia coli (E. coli), Staphylococcus Microorganisms such as Staphyloccus aureus to combat the effects of bacterial infections caused by orchids, horses, sheep, and Antibiotics in veterinary medicine to treat valuable warm-blooded animals such as animals, goats, dogs, and cats. It is expected to be useful as a drug. Some of these microorganisms are commonly found in animals. It is associated with an infectious disease called ``shipping disease.''

Chart A Chart A describes the preparation of esters of the invention.

Compounds of formula A, 1 are described in PCT International Publication No. WO39104313 (May 1989). This compound is prepared by the method described in In the presence of formamide, as described in 43 JA CS 660 (1921) When reacted with a compound of formula A-2 prepared as follows, a compound of formula A-3 is obtained. Ru. In these formulas, the variables have the same meanings as above.

Other compounds of the invention, including other esters of the invention, can be prepared using methods analogous to those described above. as will be clear to those skilled in the art of organic chemistry.

Chart B Chart B shows the R1-desfuroylceft used as the starting material in Chart A. The preparation of ophthalmic acid sulfide sodium salt will be described.

In the formula of Chart B, the variables have the same meanings as above.

The compounds of the present invention have a superior oral biological activity compared to other cephalosporin compounds. This has the advantage of increased utilization. For example, these compounds Oral bioavailability is higher than the rosporin antibiotic ceftiofur.

The compounds of the invention are preferably prepared, for example, in tablets, capsules and soluble powders. It is administered orally. Such means of administration are already known and are readily available to those skilled in the art. can be used.

Compounds of the invention are administered according to the above description and can be administered in doses ranging from about 1 mg to about 1 mg per dose. Gives approximately 500 mg of compound. Effective amount of compound given per dose is an amount sufficient to obtain an antibiotic effect within the above-mentioned non-toxic range. Special Unless otherwise specified, an effective amount of a compound is approximately It is given within the range of 0.2 mg to about 100 mg.

The preferred dosage for most uses will depend on the animal being treated; The amount of the compound is 0.2 mg to 10.0 mg per kg of body weight. Semi-solid for topical use For ointment formulations, the concentration of the compound in the carrier, such as a pharmaceutical or cream base, is 1. % to 20%, preferably 5% to 10%.

Thus, the compounds of the invention may be of value to mammals, such as dogs, cats, horses, etc. non-toxic and effective amounts of the compounds of the invention in warm-blooded animals and other commercially valuable animals. It is useful to obtain the effect of antibiotics in these mammals by administering It is.

Description of preferred embodiments Preparation I For the preparation of R3-desfuroylceftiophage sulfide sodium General steps to (See Chart B, variables have the same meanings as above) R-Desfroilceftiof Dissolve ardisulfide in tetrahydrofuran (10ml) and cool to 0°C. do. A solution of sodium 2-ethylhexanoate in tetrahydrofuran (14 m Upon addition of 1.6 g of L), a white solid precipitates out. Filter it and acetate Wash with water to obtain a white solid.

Example 1 Methyl- and furfuryl-desfuroylceftiophage sulfi 1-acyloxyalkyl ester and 1-(alkyloxyalkyl ester of sodium salt) General procedure for the synthesis of cyclocarbonyloxy)alkyl esters (Chart A (see: variable has the same meaning as above) Dissolve the above sodium salt in dimethylformamide (10ml) and Cool to iodoalkyloxyanlate or alkyl-iodoalkyl Carbonate (2.44 mmol 1) was added with stirring and the mixture was heated to room temperature. Stir for 30 minutes. It was combined with ethyl acetate (50 ml) and ice-cold H20 (4, 0 ml) of the mixture and separate the organic layer. The aqueous layer was extracted with ethyl acetate (40 m Extract with l). Wash the combined ethyl acetate layers with water-cooled HzO (3X40ml) and dry over magnesium sulfate. Evaporate the organic layer in vacuo and salify the residue. Dissolve in methylene and filter the insoluble portion. The filtrate was flashed onto a silica gel column. Subjected to chromatography and eluted with 11 ethyl acetate:methylene chloride. suitable The relevant fractions are combined and evaporated in vacuo. The residue was dissolved in ethyl acetate-ethyl ether. Crystallization or recrystallization from hexane gives white crystals.

Example 25-Thia-1-azabicyclo[4,2,0]oct-2-ene-2-ka Rubonic acid, 7-lo[(2-amino-4-thiazolyl)(methoxyimino)acetyl 8-oxo-3-[(propyldithio)methylco, (acetyl- xy) methyl ester, [6R-[6α,7β(Z)]co (formula A-3: R1 is -5-(CH2)z-CHs) See chart A.

Propyl-desfuroylceftiophage sulfide sodium (445mg) Dissolve in dimethylformamide (3.0ml) and cool to -10 to -20°C .

iodomethyl acetate (0.2 g) in dimethylformamide (0.5 ml) is added gradually with stirring and the mixture is stirred at room temperature for 30 minutes. child The mixture was poured into a mixture of ethyl acetate (25ml) and cold water (10ml). stir and separate the organic layer. The aqueous layer is extracted with ethyl acetate (2x15ml). If The combined organic layers were washed with cold water (3X15m, I) and saturated sodium chloride solution (15 ml) and dry over sodium sulfate. Evaporate the organic layer in vacuo , a brown viscous oil is obtained. Dissolve it in methylene chloride and add 8g of silica gel. Apply to the column and elute with 1:1 methylene chloride/ethyl acetate. Contains pure product The fractions are combined and concentrated in vacuo to give a yellow viscous oil. Add it to acetic acid Crystallized from thyl-ethyl ether-hexane to give 81 mg of slightly gray color. A pale white solid is obtained.

The physical properties are as follows.

HPLC of the product showed no peaks in 1:1 methanol:water.

Mass spectrum, FAB[m+H]-376°TLC, RF 0.34 (S 1 02) 1:lCH2Cl2: EtOAc0 Example 35-thia-1-azabishik ro[4,2,Oi oct-2-ene-2-carboxylic acid, 7-[[(2-amino- 4-thiazolyl)(methquinimino)acetylcoamino]-3-[[(4methquinimino) cyphenyls)diheocomethylcou8~ox'8(acetyloxy)methylester [6R-(6α,7β(Z)co]-(Formula A-3: R1 is -5-(4-methoxy Cyphenyl)) See Chart A.

4-Methoxyphenyl-desfuroylceftiophage sulfide sodium ( 474 mg) was dissolved in dimethylformamide (3.0 ml), and -10 to -20 Cool to ℃. iodomethylacetate in dimethylformamide (0.5ml) Gradually add a solution of Le (0.2 g) with stirring and let the mixture stand for 30 minutes at room temperature. Stir for a while.

This mixture was poured into a mixture of ethyl acetate (25 ml) and cold water (10 ml). and separate the organic layer. The aqueous layer is extracted with ethyl acetate (2X15ml). Match The combined organic layer was dissolved in cold water (3 x 15 ml) and saturated sodium chloride solution (15 ml). and dry over sodium sulfate. Concentrate the organic layer in vacuo to give a brown Obtain solids.

It was dissolved in methylene chloride and applied to an 8 g silica gel column to give a 1:1 methylene chloride solution. Ren: Elute with ethyl acetate. Combine fractions containing pure product and concentrate in vacuo A yellow viscous oil is obtained. It was crystallized from ethyl acetate-ethyl ether. to give 106 mg of a slightly off-white solid.

Physical properties are as follows: HPLC of the product showed slight broadening in l:1 methanol:water at about 20 min. A peak appeared.

iji spectrum, FAB [m+H]”640° TLC, RF, 0.36 (Si O□)1:ICHzCIt:EtOAc0Example 43.4-dimethoxyphenyl - desfuroylceftiophage sulfide acetyloxymethyl ester (formula A-3: R4 is -3-(3,4-dimethoxyphenyl)) See Chart 8.

3.4-Dimethquine phenyludesfuroylceftiophage sulfide natri (538 mg) was dissolved in dimethylformamide (3.0 ml), -10 ~ Cool to -20°C. Acetic acid iodine in dimethylformamide (0.5 ml) A solution of domethyl (0.2 g) was added slowly with stirring and the mixture was allowed to stand at room temperature. Stir for 30 minutes. This mixture was combined with ethyl acetate (25 ml) and cold water (10 ml). ) mixture and separate the organic layer. The aqueous layer was diluted with ethyl acetate (2X15ml). ) to extract. The combined organic layers were washed with cold water (3X15ml) and saturated sodium chloride. solution (15 ml) and dry over sodium sulfate. Organic layer in vacuum Evaporate to give a brown solid. Dissolve it in methylene chloride and add 10 g of silica. Apply to a silica gel column and elute with 1:1 methylene chloride/ethyl acetate. pure raw The fractions containing the product are combined and concentrated in vacuo to give a yellow solid. Add it to acetic acid Recrystallized from thyl-ethyl ether to give 99 mg of a slightly off-white Obtain solids.

Physical properties are as follows: HPLC of the product included slightly broad chromatography in 11 methanol:water at approximately 16 minutes. A peak has appeared.

Mass spectrum, FAB [m+Hr”670° TLC, RF O, 21 (S 1 oz) 1:ICH2C1z:EtOAc0 Example 55-Thia-1-azabinclo [4,2,0 cooct-2-ene-2-carboxylic acid, 7-[[(2-amino-4 -thiazolyl)(methquinimino)acetylcoamino]-3-[(methyldithio ) methyl]-8-oxo-(acetyloxy)methyl ester, [6R-[6α , 7β(Z)] - (Formula A-3.R1 is -5-CH,) See chart A.

Methyl-desfuroylceftiophage sulfide sodium (0.50g) Dissolve in dimethylformamide (3.7 ml) and cool to -10 to -20°C. Ru. Iodomethyl acetate (0 ml) in dimethylformamide (1.0 ml) , 25 g) was slowly added with stirring, and the mixture was stirred for a further 10 g at room temperature. Stir for a minute. This mixture was diluted with ethyl acetate (30 ml) and cold water (15 ml). Pour into the mixture and separate the organic layer. The aqueous layer was diluted with ethyl acetate (2X20ml). Extract. The combined organic layers were washed with cold water (3 x 20 ml) and saturated sodium chloride solution. solution (20 ml) and dry over sodium sulfate. Evaporate the organic layer in vacuo. Evaporation gives a pale yellow solid. Dissolve it in methylene chloride and add 6g of silica. Apply to a gel column and elute with 1:1 methylene chloride/ethyl acetate. pure generation The fractions containing the product are combined and concentrated in vacuo to give a pale yellow solid. meta it Recrystallization from alcohol-ethyl acetate-ethyl ether gave 92 mg of a white solid. obtain.

Physical properties are as follows: HPLC of the sample showed a single peak in 1:1 methanol:water.

Mass spectrum, FAB [m+H]”548° TLC, RF O, 34 (S 1 02), 1:I CHICI! : Et 0Ac0 Example 6 In vivo Mouse infection protection test For mouse infection protection test, mice weighing 12 to 14 g, 21 to 2 5-day-old weaned female mouse Crl: CD-1 (ICR) BR Swiss mouse Use In the infectious portion of the test, the bacteria (Pasteurella haemolytica) urella hemolytica) or Salmonella typhimurium (S a1mone41a typhi+1uriua+)) with (infection adjuvant) ) and mixed with 2% brewer's yeast and administered intraperitoneally at approximately 100 times the LD50 dose. . Antibiotics (0.1 ml) immediately and 24 and 48 hours after challenge exposure. , orally into the stomach using a 22G oral administration needle. From 6-10 mice groups were injected with each dose level of antibiotic, and for a single measurement, the antibiotic Use serial dilutions of at least 5.2 times the material. Measures of antibiotic effectiveness are , calculated on the 6th day after challenge exposure, EDD　%, i.e. 50% of infected mice. Report as the amount of antibiotic required for protection (in mg/kg·yo). this Values are evaluated by the statistical method of probit analysis. As mentioned above, all In experiments, the dose of challenge exposure is approximately 100 times the LD50. against bacteria LD50 is determined for each experiment. In addition, in each experiment, non-human subjects administered saline Use treatment groups (1 to confirm lethality of 100x LD50 doses. All In an experiment, as a result of inoculation with bacteria, 90-100% of untreated mice developed infection. died by.

The test compound was dissolved in 95% ethanol and the final concentration was determined in excipient 122. Sterile vehicle 122 (0,25 % methylcellulose).

The results of this test for compounds of the invention are shown in Table 1.

Preparation 2 Desfuroylceftiofur Ceftiofur sodium (25.0 g) was dissolved in 500 ml of R20 and the The pH of the solution (which is approximately 5) is adjusted to 9 with aqueous ammonia. Then 250m1 A solution of dithioerythritol (10.1 g) in R20 of The mixture is stirred at room temperature for 1 hour. This mixture was diluted with 85% phosphoric acid to pH 3.0-3. ．． 5, a white solid precipitate is obtained. Filter this solid and wash with R20. Purify. Drying this solid under vacuum in a desiccator yields the title compound. The amount is approximately 16g.

Preparation 3 Methyl-desfuroylceftiophage sulfide Preparation 2 of Ceftioph Sodium (5,000 g) was dissolved in 100 ml of R20, and the pH of this solution was Adjust to 9 with NH and ○H. Then dithioeryth in 5 ml of R20 Adding a solution of litol (2,25 g) gives a cloudy solution and this mixture Stir at room temperature for 1 hour. Add MeOH (140 ml) until the mixture becomes clear. ) was then added to the mixture and methylmethanethiol in MeOH (30ml) was added to the mixture. Sulfonate (2.65 g) is added slowly to make the mixture clear. child The mixture is stirred at room temperature for 1 hour. Decant the liquid into another flask until it reaches an orange consistency. leave behind a substance. When the decanted MeOH is evaporated in vacuum, viscosity forms on the inner wall of the flask. A yellow viscous semi-solid substance remains. I threw away the remaining R20 in the flask. Afterwards, dissolve the residue in the flask in a minimum amount of MeOH and then add enough ice water. A slightly off-white solid mass precipitates into the white liquid.

The liquid was discarded and the solid was washed with ice water and dried under vacuum in a Tenkater. , 4.65 g of slightly off-white crystals are obtained.

Physical properties are as follows: HPLC, TBA (0.005M tetrabutyl hydroxide adjusted to pH 7 with acetic acid) about 9 minutes in 1:I MeOH:R20) containing a solution of ammonium.

MS, FABCm 10H]”476° Preparation 4 Methyl-desfuroylceftiophage sulfide sodium Preparation 3 Methyl-desfuroylceftiophage sulfide (4.65g) was added to the tetrahydride. Dissolve in lofuran (10 ml) and cool to 0°C. Sodium 2-ethylhexane When a solution of noate in tetrahydrofuran (14 ml, 1.6 g) was added, a white Precipitation of solids occurs. It was filtered and washed with acetone to yield 2.91 g. The title product is obtained.

Example 7 Methyl-desfuroylceftiophage sulfide acetyloxyp lobil ester Dissolve the sodium salt of Preparation 4 (1,00 g) in dimethylformamide (10 ml). Dissolve and cool to -5°C. Stir 1-iodomethylpropionate (0.55 g) Add with stirring and stir the mixture for 30 minutes at room temperature. Add it to ethyl acetate (50 ml) and ice-cold HzO (40 ml) and separate the organic layer. Let go. The aqueous layer is extracted with ethyl acetate (40ml). Cool the combined ethyl acetate layers. Wash with water (3 x 40 ml) and dry over magnesium sulfate. Vacuum the organic layer Concentrate in water to give a pale yellow solid. Dissolve it in methylene chloride and remove the insoluble part filter. The filtrate was subjected to flash chromatography on a silica gel column. and elute with 1:1 ethyl acetate:methylene chloride. Combine appropriate fractions and in vacuo Evaporate to give a yellow oil. It is converted into ethyl acetate-ethyl ether- Crystallization from xane gives 75 mg of white crystals.

Physical properties are as follows: HPLC, peakless MS in 1:IMeOH:HzO or TBA, FAB[ m+H]”576 TLC, Rf O, 39(SiOz)11cH2c12: EtOAc.

Examples 8-11 Other compounds of the invention shown below are prepared by methods analogous to those described above. However, this is clear to those skilled in the art of organic chemistry.

Example 8 Methyl-desfuroylceftiophage sulfide 1-(isopropylene) The physical properties of hydroxycarponyloxy)ethyl ester are as follows: HPLC, peakless MS in 1:IMeOH:HzO or TBA, FAB[ m10H]”606 TLC, Rf 0.28 (SiOz) 1:lCH2Cl2:EtOAc.

Example 9 Furfuryl-desfuroylceftiophage sulfide 1-(isopropylene) The physical properties of propyloxycarponyloxy)ethyl ester are as follows: HPLC, no peaks in 1:IMeOH:H2O or TBA MS, FAB[ m+H]'672 TLC, Rf O, 39 (SiOz) 1:lCH2Cl2:EtOAc0 Example 10 Methyl-desfuroylceftiophage sulfide 1-(ncrohexyl Acetoxy/)ethyl ester The physical properties are as follows. HPLC, no peaks in 1:IMeOH:H2O or TBA MS, FAB[ m+H]”645 TLC, Rf O, 45 (SiOz) 1:ICHzClz:EtOAC.

Example 11 Furfuryl-desfuroylceftiophage sulfide 1-(sic) lohexyl acetate/)ethyl ester Physical properties are as follows: HPLC, 1:t:'-ref;MS in IMeOH:H2O or TBA, FAB[m+H]”711 TLC, Rf　O,44(Sich)1:lCH2Cl2:EtOAc0char A + R2-T A, -2 Chart B hand abstract [wherein R3 is a disulfide group and R2 provides an ester terminal group] Ru.

These compounds reduce the susceptibility of pathogenic bacteria that cause diseases such as what is commonly known as “shipping disease.” It is useful as an antibiotic to treat warm-blooded animals to fight infectious diseases.

Claims (11)

[Claims] 1. Compounds of formula I ▲There are mathematical formulas, chemical formulas, tables, etc.▼I [In the formula, R1 is (a) -S-(CH2)n-CH3, (b) -S-(4-methoxyphenyl), (c) -S-(3,4-dimethoxyphenyl) phenyl), (d) -S-C1-C6 alkyl, or (e) -S-(CH2)n - frill; R2 is (a) -CHR3-O-C(O)-R4 or (b) -CHR3-O-C(O )-O-R4; R3 is (a) is hydrogen, (b) is C1-C6 alkyl, or (c) is cyclohexyl; R4 is (a) is hydrogen, (b) is C1-C6 alkyl, or (c) is cyclohexyl; n is 1 to 5]. 2. R1 is (a) -S-(CH2)2-CH3, (b) -S-(4-methoxyphenyl), (c) -S-(3,4-dimethoxyphenyl) phenyl), or (d)-S-CH3, or (e) -S-CH2-furyl: R2 is (a) -CH-O-C(O)-CH3, (b) -CH(CH2CH3)-O-C (O)-CH3, (c)-CH(CH3)-O-C(O)-O-CH(CH3) 2, or (d) -CH(CH3)-O-C(O)-CH2cyclohexyl; A compound according to claim 1. 3.5-thia-1-azabicyclo[4,2,0]oct-2-ene-2-carbo acid, 7-[[(2-amino-4-thiazolyl)(methoxyimino)acetyl] amino]-8-oxo-3-[(propyldithio)methyl], (acetyloxy ) methyl ester, [6R-[6α,7β(Z)]]- Compound. 4.5-thia-1-azabicyclo[4,2,0]oct-2-ene-2-carbo acid, 7-[[(2-amino-4-thiazolyl)(methoxyimino)acetyl] amino]-3-[(4methoxyphenyl)dithio]methyl]-8-oxo-, ( acetyloxy)methyl ester, [6R-[6α,7β(Z)]]- A compound according to claim 2. 5.3,4-dimethoxyphenyl-desfuroylceftiophage sulfide 3. The compound according to claim 2, which is cetyloxymethyl ester. 6.5-thia-1-azabicyclo[4,2,0]oct-2-ene-2-carbo acid, 7-[[(2-amino-4-thiazolyl)(methoxyimino)acetyl] amino]-3-[(methyldithio)methyl]-8-oxo-, (acetyloxy ) methyl ester, [6R-[6α,7β(Z)]]- Compound. 7. Methyl-desfuroylceftiophage sulfide acetyloxypropyl 3. The compound according to claim 2, which is an ester. 8. Methyl-desfuroylceftiophage sulfide 1-(isopropyloxide) 3. The compound according to claim 2, which is carbonyloxyethyl ester. 9. furfuryl-desfuroylceftiophage sulfide 1-(isopropyl 3. The compound according to claim 2, which is oxycarbonyloxy)ethyl ester. 10. Methyl-desfuroylceftiophage sulfide 1-(cyclohexyl 3. The compound according to claim 2, which is acetoxy)ethyl ester. 11. furfuryl-desfuroylceftiophage sulfide 1-(cyclohexyl) 3. The compound according to claim 2, which is silacetoxy)ethyl ester.