GB1604740A

GB1604740A - 7-isothiazolylthioacetamido-7-methoxycephalosporanic acid derivatives

Info

Publication number: GB1604740A
Application number: GB24853/80A
Authority: GB
Original assignee: Yamanouchi Pharmaceutical Co Ltd
Current assignee: Yamanouchi Pharmaceutical Co Ltd
Priority date: 1977-06-10
Filing date: 1978-05-31
Publication date: 1981-12-16
Also published as: AU3698878A; UA5922A1; BE867994A; DE2857816C2; SU904525A3; AU518620B2; SE454512B; FR2405953B1; SE8306298L; JPS543090A; UA5924A1; FR2405953A1; JPS5854157B2; HU184788B; SU843752A3; SE8306298D0

Description

(54) 7,B -ISOTHIAZOLYTHIOACETAMID0-7 -METHOXY CEPHALOSPORANIC ACID DERIVATIVES (71) We, YAMANOUCHI PHARMACEUTICAL COMPANY LIMITED, a company organised and existing under the laws of Japan, of No. 5-1 Nihonbashi Honcho 2-chome, Chuo-ku, Tokyo, Japan, do hereby declare the invention, for which we pray that a patent may be granted to us, and the method by which it is to be performed, to be particularly described in and by the following statement:- This invention relates to 7ss-isothiazolylthioacetamido-7a-methoxycephalosporanic acid derivatives and pharmaceutical compositions containing them.

Over the past several decades various antibiotics have been investigated and used for the treatment of various infectious diseases of animals including man, but since resistant bacteria appear in many cases, there are infectious diseases which are not adequately treated by known antibiotics.

New antibiotics are constantly being sought to supplement and expand the physician's armoury, particularly for the treatment of injection involving pathogens which become resistant to the chemotherapeutic agents now in use.

Various cephalosporins are known and a number of disclosures such as German Offenlegungsschrift No. 2,356,388 disclose a variety of cephalosporin compounds having heterocyclic acyl groups.

According to this invention, there are provided 7B-isothiazolylthioacetamido-7a- methoxycephalosporanic acid derivatives represented by general formula:

wherein Y represents

R1 represents a hydroxy group, an amino group or an alkoxy(C1-C4) group; R2 represents a hydrogen atom, an amino group, a cyano group, a carboxy group, a carbamoyl group, a carbazoyl group, an aryl group, a hydroxy alkyl (C1-C4) group, an alkoxy(C1-C4)carbonylamino group, a di-alkyl(C1-C4)carbamoyl group; R3 represents an alkyl(ClC4) group or a hydroxyalkyl (C1-C4) group; and R' represents an alkyl(ClC4) group; and the pharmaceutically acceptable salts thereof.

The cephalosporanic acid derivatives of this invention can have useful antibacterial activity, particularly against gram negative bacteria.

The invention also provides processes for preparing the aforesaid cephalosporanic acid derivatives of general formaula I.

Examples of the aryl group represented by R2 of general formula I are phenyl and naphthyl.

The cephalosporanic acid derivatives of general formula I can be prepared by reacting a compound of formula II

wherein A represents NH2- or X-CH2CONH- (wherein X is a halogen atom), and B represents an acetoxy group, a carbamoyloxy group or

(wherein R4 has the same significance as above), with a compound of general formula III, or 1112 or IIIa

wherein D represents -CH2COOH or a reactive derivative of the carboxy group thereof when A is NH2- and a hydrogen atom when A is X-CH2CONH-, and R1, R2 and R2 have the same significance as above, and when B is an acetoxy group or a carbamoyl group, further reacting the product with a compound of general formula IV

or an alkali metal salt thereof.

When reacting a compound of general formula II wherein A is NH2- with a compound of general formula 1112 or III,3 wherein D is -CH2COOH or a reactive derivative of the carboxy group thereof, the reaction is usually performed in an inert solvent such as, preferably, one or more of acetone, chloroform, methylene chloride, ethylene chloride, tetrahydrofuran, dimethylformamide, acetonitrile, ethyl acetate, and ethyl formate under heating or cooling. If the solvent is water-soluble, it can be used with water where this does not hinder the reaction.

The preferred examples of reactive derivative of the carboxy group of D of general formula 1112 or III, are an acid halide, a mixed acid anhydride, an active ester, an active amide, an acid anhydride and an acid azide. When the carboxy group is free, it is suitable to use a condensing agent such as N,N'-dicyclohexylcarbodiimide or N,N'-diethylcarbodiimide. Also, when R2 of general formula 1112 or III, is a reactive group which may hinder the reaction, such as a carboxy group or hydroxymethyl group, it is preferred to use the compound of general formula 1112 or III2 in the reaction after introducing a conventional protective group to the reactive group.

In this case, it is preferred to release the protective group after obtaining the compound of general formula I.

When a compound of formula II wherein A is X-CH2CONH- is reacted with a compound of formula III2 or III, wherein D is a hydrogen atom, the reaction is usually carried out in a solvent at room temperature or under cooling. Any solvents which do not affect the reaction may be used, but usually one or more of water, methanol, acetone, tetrahydrofuran, and dimethylformamide is used as the solvent.

The compound of formula 1112 or 111a may be used as the alkali metal salt thereof at the mercapto group, but when the free mercapto compound is used the reaction is best carried out in the presence of an aliphatic, aromatic or heterocyclic base such as triethylamine, N,N-dimethylaniline, N-ethylmorpholine, pyridine, collidine or 2,6 lutidine, or an alkali metal carbonate or alkali metal hydrogencarbonate such as sodium carbonate, potassium carbonate, sodium hydrogencarbonate or potassium hydrogen carbonate.

The reaction of a compound in which B is an acetoxy group or a carbamoyl group prepared by the above process with a compound of formula IV is usually carried out at room temperature or under heating in an inert solvent. Examples of the inert solvent are acetone, dimethylformamide, methanol, ethanol, water, and a phosphate buffer and, if necessary, they are used in admixture. When the compound of general formula IV is used in the free state, it is preferred to perform the reaction in the presence of a base such as an alkali metal hydroxide, an alkali metal carbonate, an alkali metal hydrogencarbonate, trialkylamine, pyridine or dimethylaniline. After the reaction is over, the product is isolated by acidifying the reaction mixture and recover ing the precipitates thus formed or by subjecting the reaction mixture to solvent extraction.

Compounds of general formula I have exhibited antibacterial activity against gram negative bacteria as shown below: TABLE (M.I.C.) (y/ml) Klebsiella Proteus Proteus Example Escherichia pneumoniae vulgaris morganii Seratia No. Coli NIHJ ATCC 10031 OXK US Kono marcescens 1 0.2 0.2 1.56 1.56 3.13 2 0.78 1.56 3 13 12.5 6.25 4 0.78 0.78 3.13 6.25 6.25 Some compounds of general formula I are also useful as intermediates for the preparation of other useful cephalosporin compounds, that is, 7a-methoxy-7ss-(4- substituted-1,3-dithietan-2-carboxamido )cephalosporanic acid derivatives represented by formula V

wherein R2, R3 and R4 have the same significance as above.

The compounds of general formula V possess excellent antibacterial activity and can be prepared by treating the compound of general formula I under a weak base such as sodium hydrogencarbonate, potassium hydrogencarbonate or sodium carbonate in water or an organic solvent miscible with water, such as one or more of methanol, acetone, tetrahydrofuran and dimethylformamide, at room temperature or under cooling.

Moreover, pharmaceutical compositions having an antibacterial activity comprising a pharmaceutical carrier and an active but non-toxic amount of a compound of general formula I in which Y is (6) wherein Rl is hydroxy and R2 is hydrogen, aryl, carboxyl, carbamoyl, carbazoyl or cyano are also the subject of this invention.

The latter compounds of the invention may be administered orally, rectally, or by injection such as subcutaneously, intramuscularly, or intravenously; the injection of suitably prepared sterile solutions or suspensions containing an effective but non-toxic amount of these compounds is the preferred route of administration; the doses of these compounds are usually 250-3000 mg per day for an adult and can be variously changed according to the condition of the disease, the age, weight, and the state of the patient The invention is illustrated by the following Examples.

Example 1.

In 10 ml. of liquid ammonia was suspended 270 mg. of 4-carboxy-5-ethylene-3hydroxyisothiazole. After cooling the suspension to - 500 C. and adding thereto 100 mg. of metallic sodium, the mixture was stirred for 30 minutes at temperatures of from 50 C. to -330C.

Liquid ammonia was distilled off from the reaction mixture, the residue obtained was dissolved in 20 ml. of methanol, then 10 ml. of a methanol solution of 600 mg.

of 7-bromoacetamido-7a-methoxy-3 - (1 -methyltetrazol-5-yl ) thiomerhyl-s-cephem-4- carboxylic acid was added dropwise to the solution under ice-cooling, and after stirring the mixture for 30 minutes under ice-cooling, the mixture was further stirred for 30 minutes at room temperature. After the reaction was over, the reaction mixture was adjusted to pH 4 with 4 normal hydrochloric acid and then the reaction solvent was distilled off under reduced pressure.

To the residue formed was added water and after adjusting the mixture to pH 1 with 4 normal hydrochloric acid, the product was extracted with 50 ml. of a mixture of butanol and ethyl acetate of 1:1 by volume ratio. The organic layer formed was washed twice with water, then once with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. To the residue was added 30 ml. of ether and the precipitates formed were recovered by filtration, washed three times each with 20 ml. of ether, and dried under reduced pressure to provide 560 mg. of the powder of 7 - (4carboxy- 3 - hydroxyisothiazol - 5 - yl)thioacetamido - 7 a - methoxy - 3 - (1methyltetrazol - 5 - yl)thiomethyl - A3 - cephem - 4 - carboxylic acid.

Nuclear magnetic resonance spectra (D6-DMSO) #(p.p.m.): 3.41 (3H), 3.58 (2H), 3.93 (3K), 3.99 (2H), 4.28 (2H), 5.10 (1H).

Example 2.

After cooling 40 ml. of liquid ammonia to -700C., 183 mg. of 4-amino-5-ethvl- thio-3-hydroxyisothiazole, and then 55 mg. of sodium was added to liquid ammonia.

The mixture was stirred for 10 minutes at the same temperature and then liquid ammonia was distilled off. To the residue was added 15 ml. of methanol followed by cooling to 20C. And 15 ml. of a methanol solution of 300 mg. of 7,B-bromo-7a- methoxy-3-(1-methyltetrazol-5-yl)thiomethyl-S-cephem-4-carboxylic acid was added dropwise to the mixture over a period of 30 seconds followed by stirring for 10 minutes at the same temperature. The solvent was distilled off under reduced pressure and after adding 15 ml. of water to the residue, the mixture was adjusted to pH 2.5 by adding 5% hydrochloric acid. The precipitates formed were extracted with 100 ml. of a mixture of n-butanol and ethyl acetate of 1:1 volume ratio and the extract was washed with water and then with a saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate. The solvent was distilled off and the residue formed was subjected to a silica gel column chromatography to provide 180 mg. of 7- (4-amino-3 -hydroxyisothiazol-5-yl )thioacetamido-7,8-methoxy- 3-(1-methyltetrazol-5-yl)thiomethyl-aS-cephem-4-carboxylic acid using a mixture of chloroform, methanol, and formic acid of 8:2:0.2 by volume ratio as the eluent.

Nuclear magnetic resonance spectra (DG-DMSO) #(p.p.m.): 3.36 (3H), 3.54 (2H), 3.58 (2H), 3.94 (2H), 4.30 (2H), 5.09 (1H).

Example 3.

By following the same procedure as in Example 2, 50 mg. of 78 - (4 - ethoxycarbonylamino - 3 - hydroxyisothiazol - 5 - yl)thio - acetamido - 7a - methoxy - 3- (1 - methyltetrazol - 5 - yl)thiomethyl - As - cephem - 4 - carboxylic acid was obtained from 300 mg. of 4 - ethoxycarbonylamino - 5 - ethylthio - 3 - hydroxyisothiazole and 300 mg. of 7ss - bromoacetamido - 7α - methoxy - 3 - (1 - methyltetrazol - 5 - yJ)thiomethyl - A3 - cephem - 4 - carboxylic acid.

Nuclear magnetic resonance spectra (D6-DMSO) #(p.p.m.): 1.14 (3H), 3.38 (3H), 3.60 (2H), 3.81 (H), 3.92 (3H), 4.06 (2H) 4.06 (2H), 4.29 (2H), 5.11 (1H).

Example 4.

By following the same procedure as in Example 2, 100 mg. of 7ss - (4carbazoyl - 3 - hydroxyisothiazol - 5 - yl) - thioacetamido - 7a - methoxy - 3 - (1methyltetrazol - 5 - yl)thiomethyl - A: - cephem - 4 - carboxylic acid was obtained from 220 mg. of 4-carbazoyl-5-ethylthio-3-hydroxyisothiazole and 400 mg.

of 7ss - bromoacetamido - 7 < t - methoxy - 3 - (1 - methyltetrazol - 5 - yl)thiomethyl as - cephem - 4 - carboxylic acid.

Nuclear magnetic resonance spectra (D6-DMSO) #(p.p.m.): 3.39 (3H), 3.63 (2H), 3.90 (2H), 3.93 (3H), 4.30 (2H), 5.13 (1H).

Reference Example.

To 6 ml. of water were added 300 mg of 7P-[4-(carbamoyl) (carboxy)- methylene-1,3-dithietan-2-yl]carboxamido-7tt-methoxy caphalosporanic acid, 67.2 mg.

of S-mercapto-1-methyltetrazole and 146 mg. of sodium hydrogencarbonate followed by stirring for 16 hours at 60-620C. The reaction mixture was adjusted to pH 1 with 2 normal hydrochloric acid under ice-cooling, and the precipitates formed were recovered by filtration, and dried over phosphorus pentoxide under reduced pressure to provide 75 mg. of light yellow powdery 7ss - [4 - (carbamoyl) (carboxy)- methylene - 1,3 - dithietan - 2 - yl]carboxamido - 7a - methoxy - 3 - (1 - methyltetrazol - 5 - yl)thiomethyl - A3 - cephem - 4 - carboxylic acid.

Example 5.

(a) In 60 ml. of methanol was dissolved 6.1 g. of 7B-bromoacetamido-7n methoxycephalosporanic acid. Then 15 ml. of an ice-cooled aqueous solution of 4.3 g. of trisodium salt (trihydrate) of 4-carboxy-3-hydroxy-5-mercaptoisothiazole was added dropwise to the solution at 0-5 C. After stirring the mixture for 30 minutes at the same temperature, methanol was distilled off under reduced pressure. The residue was mixed with 40 ml. of water, adjusted to pH 3 with 2 normal hydrochloric acid, and washed with ethyl acetate. The aqueous layer was further adjusted to pH 1 with 2 normal hydrochloric acid and then extracted twice each with a mixture of n-butanol and ethyl acetate of 1:1 by volume ratio. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off to provide a powdery crude product. The product was dissolved in a small amount of methanol and the solution was allowed to cool with ice to form crystals. The crystals were recovered by filtration to provide 4.8 g.

(64.2% yield) of the purified white crystals of 7B-(4-carboxy-3-hydroxy-isothiazol 5-yl)thioacetamido-7α-methoxy-cephalosporanic acid.

Nuclear magnetic resonance spectra (D6-DMSO)

(b) By following the procedure of the Reference Example using 7(3 - (4- carboy - 3 - hvdroxyisothiazol - 5 - yl)thio - acetamido - 7a - methoxy - cephalo snoranic acid and 5 - mercanto - 1 - methylrtrazole, 7ss - (4 - carboxy - 3 - hydroxyisothiazol - 1 - 5 - yl)thioacetamido - 7a - methoxy - 3 - (1 - methyltetrazol - 5 - yl)thiomethvl - A' - cenhem - 4 - carboxvlic acid was obtained.

By the same procedure as in Example 1, the following compounds were obtained: Example 6.

7(3 - (4 - cyano - 3 - hydroxvisothiazol - 5 - yl)thioacetamido - 7tt - methoxy- 3 - (1 - methyltetrazol - 5 - yl)thiomethyl - hi3 - cephem 4 - carboxylic acid.

Nuclear magnetic resonance spectra (D6-DMSO) #(p.p.m.): 3.39 (3H), 3.59 (2H), 3.92 (3H), 4.11 (2H), 4.28 (2H), 5.10 (1H).

Example 7.

7ss - (4 - cyano - 3 - 4 - phenylisothiazol - 5 - thioacetamido - 7a methoxy 3 - (1 - methyltetrazol - 5 - yl)thiomethyl - A3 - cephem - 4 - carboxylic acid.

Nuclear magnetic resonance spectra (D-DMSO) #(p.p.m.): 3.40 (3H), 3.56 (2H), 3.87 (2H), 3.92 (3H), 4.27 (2H), 5.05 (1H).

Example 8.

7ss - (3 - amino - 4 - cyanoisothiazol) - 5 - yl)thioacetamido - 7α - methoxy- 3 - (1 - methyltetrazol - 5 - yl)thiomethyl - ti3 - cephem - 4 - carboxylic acid.

Nuclear magnetic resonance spectra (D,;-DMSO) #(p.p.m.): 3.40 (3H), 3.60 (2H), 3.95 '3H), 4.08 (2H), 4.31 (2H), 5.11 (1H).

Example 9.

7ss -(4 - dimethylcarbamoyl - 3 - hydroxyisothiazol - 5 - yl) - thioacetamido 7e - methoxy - 3 - (1 -methyltetrazol - 5 - yl)thiomethyl - aS - cephem - 4carboxylic acid.

Nuclear magnetic resonance spectra (Df-DMSO) #(p.p.m.): 2.88 (6H), 3.38 (3H), 3.56 (2H), 3.90 (5H), 4.26 (2H), 5.04 (1H).

Example 10.

7ss - (3 - hydroxyisothiazol - 4 - yl)thioacetamido - 7a - methoxy - 3 - (l- methyltetrazol - 5 - yl)thiomethyl - As - cephem - 4 - carboxylic acid.

Nuclear magnetic resonance spectra (Dl-DMSO) #(p.p.m.): 3.39 (3H), 3.48 (2H), 3.66 (2H), 3.94 (3H), 4.26 (2M), 511. (1H), 7.59 (1H).

Example 11.

7ss - (4 - cyano - 2 - methyl - 3 - oxo - 2,3 - dihydroisothiazol - 5 - yl)- thioacetamido - 7a - methoxy - 3 - (1 - methyltetrazol - 5 - yl) - thiomethyl cephem - 4 - carboxylic acid.

Nuclear magnetic resonance spectra (Ds-DMSO) 8 (p.p.m.): 3.40 (3H), 3.64 (2H), 3.92 (8H), 4.30 (2H), 5.16 (1H).

Example 12.

7ss - [4 - cyano - 2 - (2 - hydroxvethyl- 3 - oxo - 2,3 - dihydroisothiazol - 5- ylithioacetamido - 7a - methoxy - 3 -(1 - methyltetrazol - S - yl)thiomethyl - '- cephem - 4 - carboxylic acid.

Nuclear magnetic resonance spectra (D6-DMSO) #(p.p.m.): 3.40 (3H), 3.3-3.6 (3H), 3.76 (2H), 3.93 (3H), 4.16 (2H), 4.32 (2H), 5.14 (1H).

Example 13.

7ss - (4 - carbamoyl - 3 -hydroxyisothiazol - S - yl)thioacetamido - 7a - methoxy- 3 - (1 - methyltetrazol - 5 - yl)thiomethyl - A8 - cephem - 4 - carboxylic acid.

Nuclear magnetic resonance spectra (D6-DMSO) #(p.p.m.): 3.39 (3H), 3.49 (2H), 3.64 (2H), 3.93 (3H), 4.28 (2H), 5.07 (1H).

Example 14.

7ss - (3 - hydroxy - 4 - hydroxymethylisothiazol - 5 - yl)thioacetamido - 7amethoxy - 3 - (1 - methyltetrazol - 5 - yl)thiomethyl - A' - cephem - 4 - carboxylic acid.

Nuclear magnetic resonance spectra (D6-DMSO) #(p.p.m.): 3.40 (3H), 3.58 (2H), 3.83 (2H), 3.92 (3H), 4.12 (2H), 4.30 (2H), 5.10 (1H).

Example 15.

In 7 ml. of methylene chloride was dissolved 300 mg. of 7(3-amino-7a-methoxy- 3- (1 -methyltetrazol-S-yl )thiomethyl-A3-cephem-4-carboxylic acid benzhydryl ester, chilled to -30 C and 460 mg. of pyridine was added. Separately, an acid chloride solution was prepared from the suspension of 240 mg. of potassium (4-cyano-3methoxyisothiazol-5-yl)thioacetate in 10 ml. of methylene chloride, 170 mg. of oxalyl chloride and a drop of dimethylformamide. The acid chloride solution was added dropwise to the above solution at -300C to -200C and stirred for one hour at the same temperature. To the reaction mixture was added 30 ml. of chloroform, followed by washing twice with 2% hydrochloric acid and twice with saturated sodium hydrogen carbonate, and the organic layer was separated and dried over anhydrous magnesium sulfate. The organic layer was condensed under reduced pressure and the residue obtained was subjected to silica gel column chromatography using as eluent a mixture of chloroform and isopropanol (10:1 by volume ratio), and 190 mg. of 7ss - (4 - cyano3 - methoxyisothiazol - 5 - yl)thioacetamido - 7α - methoxy - 3 -(1 - methyltetrazol 5 - yl)thiomethyl - as - cephem - 4 - carboxylic acid benzhydryl ester was obtained.

In 2 ml. of methylene chloride was dissolved the above product and a mixture of 1.6 ml. of trifluoroacetic acid and anisol (3:1 by volume ratio) was added dropwise at - 1S0C to --50C and stirred for 40 minutes at the same temperature; then the solvent wis distilled off under reduced pressure, the residue was triturated with 10 ml.

of ether, filtered and dried under reduced pressure to provide 120 mg. of powder of 7ss - (4 - cyano - 3 - methoxyisothiazol - 5 - yl)thioacetamido - 7cr - methoxy - 3 (1 - methyltetrazol - 5 - yl)thiomethyl - As - cephem - 4 - carboxylic acid.

Nuclear magnetic resonance spectra (D,;-DMSO) 8 (p.p.m.): 3.40 (3H), 3.58 (2H), 3.92 (3H), 3.99 (3H), 4.15 (2H), 4.18 (2H), 5.12 (1H).

WHAT WE CLAIM IS: 1. A 7ss-isothiazolylthioacetamido-7a-methoxycephalosporanic acid derivative represented by the general formula

wherein Y represents

R1 represents a hydroxy group, an amino group or an alkoxy (C2-C .) group; R2 represents a hydrogen atom, an amino group, a cyano group, a carboxy group, a carbamoyl group, a carbazoyl group, an aryl group, a hydroxyalkyl (C1-C4) group, an alkoxy (C,--C:) carbonylamino group, or a di-alkyl (C1-C4) carbamoyl group; R3 represents an alkyl (C-C4) group or a hydroxyalkyl (C-C4) group; and R4 represents an alkyl (C1-C4) group; or a pharmaceutically acceptable salt thereof.

2. A process for the preparation of a 7ss-isothiazolylthioacetamido-7α-methoxy- cephalosporanic acid derivative represented by the general formula

wherein Y, Rl, R3, R3 and R4 have the same significance as in claim 1, which comprises reacting a compound of the general formula

wherein A represents NH2- or X-C11,CONH- (wherein X is a halogen atom), and B represents an acetoxy group, a carbamoyloxy group or

with a compound of the general formula

**WARNING** end of DESC field may overlap start of CLMS **.

Claims

**WARNING** start of CLMS field may overlap end of DESC **. In 2 ml. of methylene chloride was dissolved the above product and a mixture of 1.6 ml. of trifluoroacetic acid and anisol (3:1 by volume ratio) was added dropwise at - 1S0C to --50C and stirred for 40 minutes at the same temperature; then the solvent wis distilled off under reduced pressure, the residue was triturated with 10 ml. of ether, filtered and dried under reduced pressure to provide 120 mg. of powder of 7ss - (4 - cyano - 3 - methoxyisothiazol - 5 - yl)thioacetamido - 7cr - methoxy - 3 (1 - methyltetrazol - 5 - yl)thiomethyl - As - cephem - 4 - carboxylic acid. Nuclear magnetic resonance spectra (D,;-DMSO) 8 (p.p.m.): 3.40 (3H), 3.58 (2H), 3.92 (3H), 3.99 (3H), 4.15 (2H), 4.18 (2H), 5.12 (1H). WHAT WE CLAIM IS:

1. A 7ss-isothiazolylthioacetamido-7a-methoxycephalosporanic acid derivative represented by the general formula

wherein Y represents

with a compound of the general formula

wherein D represents -CH2COOH or a reactive derivative of the carboxy group thereof when A is NH2- and a hydrogen atom when A is X-CH2CONH-, and when B is an acetoxy group of a carbamoyloxy group, further reacting the product with a compound of the general formula

or an alkali metal salt thereof.

3. 7(3 (4 - Carboxy - 3 - hydroxyisothiazol - 5 - yl)thioacetamido - 7a methoxy - 3 (1 - methyltetrazol - 5 - yl )thiomethyl - A - cephem - 4 - carboxylic acid.

4. A compound according to claim 1 substantially as hereinbefore described in any of Examples 1 and 13 to 15.

5. A compound according to claim 1 substantially as hereinbefore described in any of Examples 7 to 12.

6. A compound according to claim 1 substantially as hereinbefore described in any of Examples 2 to 6.

7. A pharmaceutical composition comprising a compound according to claim 1 where Y is (b) in which R' is hydroxyl and R2 is hydrogen, aryl, carboxyl, carbamoyl, carbazoyl or cyano in a pharmaceuticallv acceptable carrier.

8. A method of preparing a compound according to claim 1, the method being substantially as hereinbefore described in any of Examples 1 and 13 to 15.

9. A method of preparing a compound according to claim 1, the method being substantially as hereinbefore described in any of Examples 7 to 12.

10. A method of preparing a compound according to claim 1, the method being substantially as hereinbefore described in any of Examples 2 to 6.