Technical Field

The present invention is directed to novel cephalosporins of the formula (I), a process for their preparation, the pharmaceutical compositions containing compounds of the formula (I) as active ingredients and their use in therapy as antibiotics.

Background of the Invention The antibiotics of cephalosporin type possess a prominent role in the treatment of human infectious diseases. Thus, e.g. Cephalotine, Cephaloglycine, Cephazoline and Cephalexine (c.f. Belgian patent specification No. 618,663; British patent specifi- cation No. 985,747; US patent specification No.

3,516,997; Belgian patent specification No. 696,026, respectively) are widely known, valuable caphalo- sporin derivatives possessing antibacterial activity. Contemporaneously great efforts are made in order to prepare novel antibiotics suitable for the treatment of different infectious diseases.

Originally the semisynthetic cephalosporin derivatives were prepared by acylating the 7-amino group of 7-amino-cephalosporanic acid (furtherly referred to as 7-ACA) , but the later extensive experiments enabled the preparation of novel deriva-

SUBSTITUTE SHΞE

tives by changing the substituents in the positions 7 and/or 3 of the cephalosporin ring as well /Fortsehritte der Chemie Organischer Naturstof , 28, P. 343-403 (1970)/. A great number of cephalosporin derivatives as well as pharmaceutical compositions were prepared till now. Numerous scientific publications, techni¬ cal books and patents relating to this subject are known /e.g. Plynn, E.H.: "Cephalosporin and Penni- cillins", Academic Press, New York and London, 1972; Perlman, D. : "Structure-activity Relationship Among the Semisynthetic Antibiotics", New York, 1977; O'Callaghan, C.H. : Anti icrob. Chemother. j>, 635 (1979)/.

Summary of the Invention

The invention is directed to novel cephalosporins of the formula (I) and the pharmaceutically accept¬ able salts thereof

wherein is alkyl; C ₂ . alkenyl; phenyl; benzyl; phenyl substituted by one or more different or same halo atom(s); or benzyl substituted by one or more different or same halo atom(s); M is hydrogen or an alkaline metal,

R is 3-phenyl-5-methylisoxazol-4-yl if a=0 and b=0;

SUBSTITUTE SH-ΞT

2-thienyl if a=0 and b__l; halo if a=0 and b=l, 2, 3 and 4; and tetrazolyl, thiadiazolyl, thiazolyl, oxadiazolyl, oxazolyl, triazolyl, imidazolyl, pirimidinyl, triazinyl or thiatriazolyl, all these groups being optionally substituted by halo, amino, nitro, alkyl, alkoxy, aryl, aralkyl, alkylamino, thioalkyl, furyl or thienyl if a=l and b=l, a process for their preparation, pharmaceutical compositions containing the same and their use as antibiotics.

The antibiotics according to the invention have not .only much broader spectrum of efficiency than the penicillins from the respect that beyond the Gram-positive bacteria they are effective against the most Gram-negative bacteria as well but in vitro they are also stable against β-lactamases produced by different microorganism strains.

The compounds of the formula (I) according to the invention structurally differ from the known cephalosporin derivatives in the feature that they comprise an acylaminomethyl group in the position 3 of the dihydrothiazine moiety. The Japanese published patent application No. 56-140997 includes a method ^' for the preparation of 7-amino-3-(substitutedJmethyl- ceph-3-em-4-carbox lic acids of similar structure.

Detailed Description of the Invention

The compounds of the formula (I) according to the invention are prepared by reacting a compound of the formula (II)

wherein R and Lϊ are the same as set forth above, with an appropriately substituted isoxazole-carbonyl chloride, 2-thien lacetyl chloride or with a compound of the formula (ill)

—e. in which formula Z is a halo atom and b is equal to 1, 2, 3 or 4, in a mixture of water and an organic solvent, preferably in aqueous acetone, in the presence of an alkaline metal hydroxide as acid binding agent, at pH 7 to 8 at a temperature of 0 to 40°C, preferably C to 10°C_ After the reaction is accomplished, the products of the formula (l) are separated by known techniques, e.g. by evaporation of the solvent, addition of water, extraction with water inmiscible organic solvent in an acidic medium.

As an alternative method for the preparation of the products of the formula (i) the compounds of the formula (IV),

OMH

wherein R , M, I and b are aa defined herelnabove, forming a narrower group of the compounds of the formula (i) and being prepared by the aid of the acid halides of the formula (ill), axe reacted with a heteroarylthiole of the formula

. . . . (TI), ( I),

(Tin ⁾ . (IX), (I).

i ^~ t). (rri),

(HII) or (∑IV),

in which formulae Y represents a halo, amino, nitro, alkyl, alkoxy, aryl, aralkyl, alkylamino, thioalkyl, furyl or thienyl group.

The compounds of the formula (IV) and the heteroaryl thioles of the above formulae are employed in a substantially equivalent amount. The salts of the thioles preferably employed in this reaction can be prepared by methods known per se, e. g. by means of alkaline metal carbonates, e.g. sodium carbonate, potassium carbonate or similar compounds. If the metal salts of the thioles are used, the reaction is carried out in the presence of water or a water-miscible organic solvent, e.g. dioxane, tetrahydrofurane, methanol, ethanol or, preferably, acetone. The reaction is conducted at room temperature in a weakly basic medium, and a base, e. g. sodium hydrocarbon te, potassium carbonate or triethyl amine is used as acid-binding agent. If the reactants' decomposition is expected under the conditions of the reaction, the reaction is carried out in an anhydrous medium and/or at low temperature.

According to an especially preferred embodiment of the process of the invention the starting materials are used in the form of a free acid, and the reaction is carried out in a neutral medium, e.g. anhydrous acetone or anhydrous dimethyl formamide, in the presence of an alkaline metal carbonate, e.g. potassium carbonate, as acid-binding agent. After the reaction is accomplished the compounds of the formula (I) prepared as deacribed hβreinabove are separated from the reaction mixture by methods

J SUBSTITUTE SH T

known per se, e.g. by solvent change, evaporation of the solvent, extraction with a wafer-inmiscible organic solvent in acidic medium. The crude products can further be purified by methods known per se e.g. by recr stallization, chroma ography or similar methods.

The invention further relates to pharma¬ ceutical compositions comprising as active ingredient a compound of the formula (i) or a pharmaceutically acceptable salt thereof in association with at least one organic or inorganic, solid or liquid pharmaceutically acceptable adjuvant being suitable e. g. for oral or parenteral administra ion. The pharmaceutical compositions may be presented in solid unit dosage forms, e.g. in the form of tablets or capsules, or in solutions, suspensions or emulsions. The pharmaceutical compositions can also contain such excipientε as e.g. protecting agents, stabilizing agents, wetting agents, emulgeating agents or buffers.

Table I contains the MIC values of the most effective compounds according to the invention.

OMP- v- . WIPO

[able I

Cdnpound Gram-positive Gram-negative prepared strains strains according to example

5 o, , 06 -» 100 50 — - 100

6 o, , 004 10 25 -* 100

8 o, - υ3 → 10 100

14 o _s , 03 —__ 10 > 100

15 o _s , 03 -* 10 > 100

The examinations were carried out by using the bacteria strains listed hereinbelow: Gram-positive strains S. aureus 112002 S. aureus 112003 S. epidermidis 110001 S. faecalis 80171 Gram-nega ive strains E. coli 35034 Klebsiella 52001 Klebsiella ATCC 1200 S. hartford 10063 P. mirabilis 60012 P. morganii 63002 P. rettgeri 65002 P. inconstans 67001 P. aeruginosa ATCC 27853

The invention is illustrated by the following, non-limiting examples.

OMH

The following methods were employed in the course of the determination of the identifying data given in the examples: The melting points were determined by a Thiele device. The thin-layer chromatography examinations were carried out by using a DC Alufolien Kiesel- gel 60 P254 adsorbent and acetone/acetic acid (95 : ^' 5) / f/ or benzene/methanol (l : l) /R^/ eluent. The IR spectra were measured by an ϋ_HCA___ SP 200 G εpectrophotometer and the lE-P. sprectra were measured by a BRUKΞR V,T 200 SY instrument. Example 1

2.72 g. of 7-aminocephaloεporanic acid (7-ACA) were suspended in 15 ml. of anhydrous acetonitrile and 5.68 g. of boron trifluoride etherate were added. The reaction mixture was stirred at 40°C for 5 hours. The solvent was evap¬ orated in vacuo and the residue was taken up with 30 ml. of water. The pH of the solution was adjusted to 3.5 by adding about 10 ml. of a 25 % aqueous sodium hydroxide solution and the precipitate separated (the unreacted 7-ACA) was filtered off. The pH of the mixture was adjusted to 7 by adding potassium phosphate solution, thereafter the mixture was diluted with 10 ml. of acetone. 2.4 g. (0.015 moles) of 2-thien lacetyl chloride dissolved in 4 ml. of anhydrous acetone were added to the mixture dropwise at 0 to 5°C and during the addition the pH of the mixture was maintained between 7 and 8. After the mixture had been stirred for a further hour at room temperature at a pH of 7 to 8 the reaction ^~~ s ^~

accomplished. The pH of the reaction mixture was adjusted to 5 by adding some diluted sulphuric acid, and then the solution was extracted with 30 ml. of ethyl acetate. The pH of the aqueous phase was adjusted to 2 by adding some diluted sulphuric acid and the mixture was extracted with 60 ml. of ethyl acetate. The organic extract was dried over magnesium sulphate. The solvent was evaporated in vacuo, the residue was treated with ether, filtered and washed. 2.76 g. of 7-(2-thienyl)acetylamino-3- acetylaminomethylceph-3-em-4-carbox lic acid were obtained in powder form.

The product was dissolved in 20 ml. of anhydrous acetone and an equi olar amount of sodium acetate dissolved in anhydrous methanol was added. The substance separated was recovered by filtration, washed with ether and dried in vacuo.

Yield: 70 %_.

Example 2

2.72 g. of 7-ACA were dissolved in 19 ml. of trifluoroacetic acid, then 5.68 g. of boron tri- fluoride etherate and 0.74 g. of acrylnitrile were added. The reaction mixture was stirred at 40°C for

4 hours. Then the method disclosed in Example 1 was followed. 2.4 g. of 7-(2-thienyl)acetylamino-

3-acroylaminomethylceph-3-em-carboxylic acid were obtained in powder form. M.p.: 182 - 185 °C (decomp.)

R*_ 0.51 l-lMB. ( £ ppm) DMS0-d ₆ :

3.17 (ABq, 2H, H-2); 3.75 (a, 2H, CS-CO) ; 4.06 (ABdq,

2H, H-10); 4.88 (d, 1H-H-6); 5.45 (q, IH, H-7);

5.53-6.36 ( , 3H, -CH__CH ₂ );6. 2-7.37 (m, 3H, H-Ar); 8.17 (t, IH, C ¹⁰ -HH); 8.95 (d, IH, C ⁷ -HH).

Yield: 59 %.

Example 3

The method of Example 1 was followed with the difference that 3.56 g. of 3-phenyl-5-methylisoxazole-

4-carbonyl chloride were employed.

3.09 g. of 7-(3-phenyl-5-methyl-isoxazole-4- yl)carboxamido-3-acetylaminomethyl-ceph-3-em- carboxylic acid were obtained. The product was dis- solved in 25 ml. of anhydrous acetone and an equivalent amount of sodium acetate dissolved in anhydrous ethanol was added. The substance separated was filtered, washed with ether and dried in vacuo.

Weight: 2.6 g.

H-6); 5.83 (q, IH, H-7); 7.50-7.73 (m, 5H, H-Ar);

8.16 (t, IH, C ^L0 -HH); 9.53 (d, ]_H-C ⁷ -.HH).

Yield: 67 %.

SUBSTITUTE SHΞώT

OMPI

Example 4

The method described in Example 2 was followed with the difference that 3.56 g. of 3-phen l-5- methylisoxazole-4-carbonyl chloride were used. 2.63 g. of 7-(3-phenyl-5-ι_ιet__yl-isoxazole-4-yl)- carboxamido-3-acr lox lamino ethylceph-3-em-4- carbox lic acid were recovered.

2H, H-2); 4.06 (ABdq, 5,83 (q, IH, H-7);

5.53-6.36 ( , 3H, -CH=CH ₂ ); 7.50-7.73 (m, 5H, H-Ar);

8.17 (t, IH, C ¹⁰ -NH); 8.95 (d, IK, C ⁷ -ITH).

Yield: :-.

Example 5

2.72 g. of 7-ACA were dissolved in 19 ml. of trifluoroacetic acid, then 5.68 g. of boron trifluoride etherate and 2,12 g. of 4-cyanomethylchlorobenzene were added. The reaction mixture was stirred at 40 °C for 4 hours. The further steps were the same as in Example 1. Thus, 3.13 g. of 7-(2-thieήyl)- acetylamino-3-(4-chlorophenylacetylamino)methylceph- -3-em-4-carboxylic acid were obtained.

IH, ; Yield: 62 ...

Example 6

2.72 g. of 7-AC were dissolved in 19 ml. of trifluoroacetic acid, then 5.68 g. of boron trifluo¬ ride etherate and 2.4 g. of 2,6-dichlorobenzoyl nitrile were added. The reaction mixture was stirred at 50°C for 5 hours. The further steps were the same as in Example 1. Thus 3.42 g. of 7-(2-thienyl)acetylamino-3-(2,6-dichlorobenzamino)- methylceph-3-em-4-carboxylic acid were obtained.

IH, H-7); ; Yield: 65 %.

Example 7 2.72 g. of 7-ACA were suspended in 150 ml. of anhydrous acetonitrile and 56.8 g. of boron trifluoride etherate were added. The reaction mixture was stirred at 40 C for 5 hours. The solvent was evaporated in vacuo and the residue was taken up with 200 ml. of water. The pH of the solution waa adjusted to 7 by adding potassium phosphate solu¬ tion and the mixture was diluted with 100 ml. of acetone. 16.9 g. of chloroacetyl chloride dissolved in 80 ml. of anhydrous acetone were added to the solution dropwise at a temperature of 0 to 5°C and during the addition the pH of the mixture was

SUBSTITUTE SHE ".?"*

OMPI

maintained between 7 and 8. After the mixture was stirred for two further hours at 25°C and at a pH of 7 to 8 the reaction was accomplished. The pH of the reaction mixture was adjusted to 5 by adding diluted sulphuric acid and the solution was extracted with 300 ml. of ethyl acetate. The pH of the aqueous phase was adjusted to 2 and it was extracted with 600 ml. of ethyl acetate. The organic extract was dried over magnesium sulphate. The solvent was evaporated in vacuo, the residue was treated with ether, washed and dried. 25 g. of 7-chloroacetylamino-3-acetylaminometh lceph-3-em- 4-carbox lic acid were obtained. r.ι.p.: 192 - 196°C (decomp.) R : 0.34

¹ H-3MR (5 ^" ppm) DKSO-dg:

1.08 (ε, 3H, -CH ₃ ); 3.47 (ABq, 2K, H-2); 4.05 (s, 2H, Cl-CHg-); 5.07 (d, H-7); 8.13 (t, IH, C ¹⁰ -ϊ.H); Yield: 71.7 %,

Example 8

1.75 g. of 7-chloroacetylamino-3-acetylamino- methylceph-3-em-4-carbox lic acid and 0.42 g. of sodium hydrocarbonate were dissolved in 10 ml. of water. Thereafter 0.9 g. of 2- henyl-5-mercapto- 1,3,4-oxadiazole and 0.42 g, of sodium hydrocarbonate dissolved in a mixture of 10 ml, of water and 5 ml, ^" of acetone were added. The reaction mixture was stirred at room temperature for 12 hours. The acetone

was evaporated in vacuo. The pH of the residue was adjusted to 2 by adding some diluted sulphuric acid. The precipitate separated was removed by filtra¬ tion and dried. Thus 1.83 g. of 7-(2-phenyl-l,3,4- oxadiazole-5-ylthio)acetylamino-3-acetylaminomethyl- ceph-3-em-4-carbox lic acid were obtained.

H-2); 4,05 (ABdq, 06 (d, IH, H-6); _t H-A ); 8.15 ). Yield: 75 %.

Example 9

1.96 g.α 7-bromoacetylamino-3-acetylamino- methylceph-3-em-4-carboxylic acid and 1.45 g. of 2-(4-chlorophenoxymethyl)-5-__.ercapto-l,3,4-oxa- diazole were dissolved in 20 ml. of anhydrous di¬ methyl formamide and 1,52 g, of calcinated potassium carbonate were added thereto. The reaction mixture was stirred at ambient temperature for 8 hours. 50 ml. of ether were added, the precipitate was filtered off and dissolved in 50 ml. of water.

The pH of the solution was adjusted to 5 by adding some diluted sulphuric acid and then it was extracted with 30 ml, of ethyl acetate. The pH of the aqueous phase was adjusted to 2 by adding some diluted sulphuric acid and the mixture was extracted with 60 ml. of ethyl acetate. The organic

extract was dried over magnesium sulphate. The solvent was evaporated in vacuo and the residue was treated with ether. Thus 2.07 g. of 7-/2-(4- chlorophenoxymethyl)-l,3,4-oxadiazole-5-ylthio7- acetamido-3-acetylaminomethylceph-3-em-4-carboxylic acid were obtained.

Yield: 75 .

Example 10

1.0 g. of 7-bromoacetamido-3-acetylamino- methylceph-3-em-4-carboxylic acid, 0.23 g. of 2- amino-5-mercapto-l,3,4-thiadiazole and 0.7 g. of calcinated potassium carbonate were dissolved in 10 ml. of anhydrous dimethyl formamide. The reac¬ tion mixture was stirred at room temperature for 2 hours. 30 ml. of diethyl ether were added, the precipitate separated was filtered off and the product was recrystallized from aqueous acetone. Thus 0.78 g. of the potassium salt of 7-(2-amino- l»3,4-thiadiazole-5-ylthio)acetamido-3-acetylamino- methylceph-3-em-4-carboxylic acid were obtained. M.p.: 243 - 245 °C (decomp.) R^s 0.24

SUBSTITUTE SHEET O PI

¹ H-NLIR ( 6 ^" ppm) DLISO-d g :

1.82 (s, 3H, -CH ₃ ); 3.30 (ABq, 2H, H-2); 3.87 (s, 2H, S-CHg- 4.02 (ABdq, 2H H-10); 4,91 (d,lH H-6); 5.47 (q, IH, H-7); 7.47 (a, 2H, - H ₂ ) 7.88 (t, IH, C ¹⁰ -im); 9.06 (d, IH, C ⁷ -_.H). Yield: 67 _.

Example 11

Similar v to the process of Example 10 the potassium salt of 7-( l-amino-2-phen 1-1,3, 4-triazole-

5-ylt-_io)acetamido-3-acetylaminomet_-ylceph-3-em-4- carboxylic acid was prepared by starting from 7- bromoacetamido-3-acetylaminometh lceph-3-e -4- carboxylic acid and l-amino-2-phenyl-5-mercapto- 1,3,4-triazole.

M.p.: 126 - 127°C. ^• : 0.41

^• ^-I-I-R (<Tppm) DLISO-dg:

1.85 , 3H-CH ₃ ); 3.45 (ABq, 2H, H-2); 4.02 (ABdq, 2H, H-10); 4.07 (s, 2H, S-CH ₂ ) 5.06 (d,

IH, H-6); 5.67 (q, IH, H-7); 7.50 (s, 2H, -HE-}}

7.52-7.96 (m, 5H, H-Ar); 8.15 (t, IH, C ¹⁰ -!T?l);

9.30 (d, IH, C ⁷ -UH).

Yield: 65 £.

Example 12

1,0 g, of 7-bromoacetamido-3-acetylamino- methylceph-3-em-4-carboxylic acid, 0,3 g, of 1- methyl-5-mercapto-lH-tetrazole and 9.1 g. of tri- ethyl a ine were dissolved in 20 ml. of anhydrous dimethyl formamide. The eflc i ,r nr_.~i.ire was stirred

OMPI

^-?N _A ?ι

at room temperature for 12 hours. First 0.7 g. of calcinated potassium carbonate, then 30 ml. of ether were added to the reaction mixture. The precipitate separated was filtered off, dissolved in water, the pH of the solution was adjusted to 2 by adding diluted sulphuric acid and the mixture was extracted with ethyl acetate. The organic extract was dried over anhydrous magnesium sulphate. The solvent was evaporated in vacuo and the residue was treated with diethyl ether. Thus 0.76 g. of 7-(l-methyl-lH-tetrazole-5-ylthio)- acetamido-3-acetylaminomethylceph-3-em-4-carboxylic acid were obtained.

Yield: 71 %.

Example 13

13.6 g. of 7-ACA were dissolved in 95 ml. of trifluoroacetic acid, then 28.40 g. of boron tri¬ fluoride etherate and 12.0 g. of 2,6-dichlorobenzoyl nitrile were added. The reaction mixture was stirred at 50 C for 5 hours. The solvent was evaporated in vacuo and the residue was suspended in 50 ml. of water. The pH of the suspension was adjusted to 3.5 by adding sodium hydroxide solution and the

SUBSTITUTE SHEET

OMH

precipitate separated was removed by filtration. 13-15 g. of the solid substance obtained and 8 g. of sodium hydrocarbonate were dissolved in a mixture of 200 ml. of water and 200 ml. of acetone. 8 g. of bro oacetyl chloride dissolved in 20 ml. of anhydrous acetone were added to the solution drop- wise at 0 to 5°C, while the pK of the reaction mixture was maintained between 7 and 8 by adding a solution of potassium phosphate. Vhen stirring the mixture at 25 °C at pH 8 for 2 further hours the reaction was accomplished. The pH of the reaction mixture was adjusted to 5 by adding a diluted solution of sulphuric acid and the solu¬ tion waε extracted with 300 ml. of ethyl acetate. The organic extract was dried over magnesium sulphate. The solvent was evaporated in vacuo, the residue was treated with ether, filtered and dried, 13.9 g. of 7-bromoacetamido-3-(2,6-dichloro- benzamino)methylceph-3-em-4-carbox lic acid were obtained in powder form (53 %) . LI.p.: 110 - 113°C (decomp.) R : 0.58

^ ^■ H-IΪMR (Tpprn) D__S0-d 6 ^*

3.60 (ABq, 2H, H-2); 4.17 (s, 2H, Bτ-CE- ) ; 4.32 (ABdq, 2H, H-10); 5.11 (d, IH, H-6); 5.65 (q, IH, H-7); 7.32-7.57 (m, 3H, H-Ar); 9.27 (d, IH, c ⁷ -ι*ra).

Yield: 53 %.

Example 14

1.0 g. of 7-bromoaceta___ido-3-(2 _f 6-dichlorobenz-

OMH -?NA?1

aπ_ino)methylceph-3-em-4-carbox lic acid, 0.23 g. of l-methyl-5-mercapto-lH-tetrazole and 9.1 g. of triethylamine were dissolved in 10 ml. of anhydrous acetone. The reaction mixture was stirred at room temperature for 4 hours. Working up the solution 10 ml, of water were added, the pH was adjusted to 2 by adding a solution of diluted sulphuric acid and the mixture was extracted with 30 ml. of ethyl acetate. The organic extract was dried over magnesium sulphate. The solvent was evaporated under vacuo and the residue was treated with ether and dried, 0.7 g. (62 o) of 7-(l-methyl-lH-tetrazole-5-yl- thio)acetamido-3-(2,6-dichlorobensamino)raetr_ylceph- 3-em-4-carbox lic acid were obtained.

; Yield: 62 %.

Example 15 1.0 g, of 7-bromoacetamido-3-(2,6-dichloro- benzaπ_ino)meth lceph-3-em-carbox lic acid and 0.36 g. of 2-phenyl-5-mercapto-l,3,4-oxadiazole were dis¬ solved in 10 ml. of dimethyl formamide and 0.28 g. of calcinated potassium carbonate were added. The reaction mixture was stirred at room temperature for 8 hours, 30 ml. of ether were added, the precip-

OMPI

itate was filtered off and dissolved in 30 ml. of water. The solution was adjusted to pH 5 by adding dilute sulphuric acid and extracted with 20 ml, of ethyl acetate. The aqueous layer was adjusted to pH 2 by adding dilute sulphuric acid and extracted with 60 ml. of ethyl acetate. The organic extract was dried over magnesium sulphate. The solvent was evaporated in vacuo and the residue was treated with ether and dried. 0.72 g. of 7-(2-phen 1-1,3,4- oxadiazole-5-ylthio)acetamido-3-(2,6-dichlorobenz- aι__ino)meth lceph-3-em-4-carbox lic acid were obtained.

H, H-7); 7.35-8.02 (m, 8H, _^ H-Ar) ; 9.00 (t, IH, C ¹⁰ -ITH); 9.38 (d, IH, C ⁷ -NH). Yield: 58 ...

Example 16

1.0 g. of 7-bromoacetamido-3-(2,6-dichloro- benzamino)methylceph-3-em-4-carbox lic acid and 0.39 g. of 2-mercapto-4-phenyl-l,3-thiazole were reacted and worked up according to the method of Example 15.

Thus 0.78 g. o(62 %) of 7-(4-ρhen l-l,3-thiazole-2- ylthio )aceta__άdo-3-( 2, 6-dichlorobenzamino )meth l- ceph-3-em-4-carboxylic acid were obtained . - i-NIG. ( 5 ^* ppm) DMS0-d _g :

3.47 (ABq, 2H, H-2) ; 4.07 ( s , 2H, S-CH ₂ -) j 4.32

O PI

(ABdq, 2H, H-10); 4.95 (d, 1H-H-6); 5.50 (q, IH, H-7); 5.83 (s, IH, H S); 7.2-7.5 (m, 5H, H-Ar); 8.67 (t, IH, C ¹⁰ -T.H); 9.03 (d, 1H,C ⁷ -1TH). Yield: 62 ...

Example 17

1.0 g. of 7-bromoacetamido-3-(2,6-dichloro- benza___ino)methylceph-3-eπ_-4-carbox lic acid and

0.23 g. of l-methyl-2-mercapto-imidazole were C reacted and worked up according to Example 15. Thus

0.67 g. (60 f-) of 7-(l-methyli idazole-2-ylthio)- acetamido-3-(2,6-dichlorobenzamino)methylceph-3-eπι-

4-carbox lic acid were obtained.

^■ ^H-l-L-F. ( <f ppm) DLϊ30-dg: 5 3.45 (ABq, 2H, H-2); 4.00 (s, 3H, I;-CH ₃ ) 4,02

(ABdq, 2H-H10); 4.15 (s, 2H, -S-CHg-); 4.92 (d,

IH, H-6); 5.60 (q, IH, H-7); 7.10-7.30 (m, 2H, H-Ar);

8.65 (t, IH, C ^1C -1TK); 9.04 (d, IH, C ⁷ -I7H) .

Yield : 6C ... 0

Example 18

1.0 g, of 7-bromoacetamido-3-(2,6-dichloroben_.- amino)methylceph-3-em-4-carbox lic acid and 0.24 g, of 5-n_ercapto-l,2,3,4-thiatriazole were reacted and worked up according to the method of Example 15. 5 Thus 0.73 g. (65 %) of 7-(l,2,3,4-thiatriazole-5- ylt_ιio)-aceta__ do-3-(2,6-dichlorobenzamino)methyl- ceph-3-em-4-carbox lic acid were obtained,

¹ H-m_R ( <T ppm) DI.IS0-d ₆ :

3.49 (ABq, 2H, H-2); 4.05 (s, 2H, -S-CHg); 4.35 0 (ABdq, 2H, H-10.); 4.95 (d, IH, H-6); 5.52 (q, IH,

:_-7); 8.67 ^' (t, IH, C ¹⁰ -IJH); 9.03 (d, IH, C ⁷ -Ϊ.H).

Yield: 65 ._.

ty^ WΣPO ^X &- AT