CA1340154C - Substituted vinylcephalosporins, processes for their preparation and their use as medicaments - Google Patents

Abstract

A .beta.-lactam antibiotic of the formula (see fig. I) in which R1, R2, R3 and R4 each independently is hydrogen or one of various organic radicals, and R5 is halogen, CN, CF3, COOH, alkoxycarbonyl, alkyl- or aryl-sulphonyl, alkyl - or aryl-sul-phonyloxy, optionally substituted H2NSO2-; or optionally substituted cycloalkyl, cycloalkylalkyl, alkinyl, aryl or heterocyclyl, or a salt thereof.

Description

1341315~

It is known that various representatives of 7-~-aminoacylcephalosporins with different substituents in the 3-position of the molecule, thus, for example, cephalexin t7-(D-~-phenylglycylamido)-3-methyl-3-cephem-4-carboxylic acid, compare DE-OS (German Published Specification) 2,432,485], cefaclor [7-(D-~-phenylglycylamido)-3-chloro-3-cephem-4-carboxylic acid, compare DE-OS (German Published Specifica-tion) 2,408,698 and 2,728,578] and cefadroxil [7-(D-~-p-hydroxyphenylglycylamido)-3-methyl-3-cephem-4-carboxylic acid, compare DE-OS (German Published Specification) 2,718,741] have a good antibiotic activity.
3-~lk~nyl-substituted cephalosporins are furthermore described as compounds with an oral action in DE-OS (German Published Specification) 3,402,642 and U.S. Patent 4,619,925.
The invention now relates to ~-lactam compounds of the general formula (I) R

N ~ ICH-CO-~ ~ S RS

N
CoOR4 in which 1~

Rl represents hydrogen, or represents straight-chain or br~nc~sA alkyl, cycloalkyl or alkenyl which ha~ up to 6 carbon atoms and can be ~ub~tituted by fluorine, chlorine, methoxy, cyano, - la -.A~

phenyl, dimethylamino, hydroxyl or diethylamino, or represents phenyl, which can be substituted by fluorine, chlorine, methyl, methoxy, trifluoromethyl, amino or trifluoromethoxy, or represents chlorine, alkoxy or alkylsulphonyl with in each case up to 4 carbon atoms, mercapto, hydroxyl, SO3H, SO2NH2, guanidino, NH-NH2 or NH-OH, or represents a group of the formula -NHR6, wherein R6 denotes hydrogen, alkyl with up to 4 carbon atoms, phenyl, benzyl or an amino-protective group from the series comprising 4-methoxyphenyl, 4-methoxybenzyl, 2,4-dimethoxybenzyl, 3,4-dimethoxybenzyl and tert.-butyl-dimethylsilyl, R2 represents hydrogen, hydroxyl or NO2, R3 represents hydrogen, or represents 4-methoxyphenyl, 4-methoxybenzyl, 2,4-dimethoxybenzyl, 3,4-dimethoxybenzyl, tert.-butyl-dimethylsilyl, 1-methyl-2-methoxy-vinyl (MMV) or tert.-butoxycarbonyl (Boc), R4 represents hydrogen, or represents methyl, ethyl, tert.-butyl, diphenylmethyl, 2,2,2-trichloroethyl, allyl, acetoxymethyl, 4-nitrobenzyl, 2-nitrobenzyl, 4-methoxybenzyl, benzyl or tri-methylsilylethyl, or represents a radical of the formula ~_' 13~0154 ~ ~ , -CH(CH3)-OCOOC2Hs, or -CH2-OCO-C(CH3)3 and R5 represents chlorine, bromine, chloromethyl, trifluoromethyl, carboxyl, alkoxycarbonyl or alkylsulphonyloxy with in each case up to 4 ~ 1340154 carbon atoms, phenylsulphonyloxy, tolylsulphonyloxy, cyclo-propyl, cyclopentyl, cyclohexyl, cyclopropylmethyl or cyclopentyl-methyl, or represents alklnyl whlch has up to 4 carbon atoms and can be substituted by phenyl, carboxyl or alkoxycarbonyl wlth up to 4 carbon atoms, or represents phenyl, or represents a radlcal of the formula ~;3 N~N~C 1 N~

i~S . ~ 3 ~ ,J ~ NO2 ~ ¢ ~ 5-~ N_N N -N

W~ . S~CH2~S~S-CH2-~o ~-H2C-s~;~

~S - - H 2ClS~C H 3 and salts thereof.
An amlno-protectlve group ln the context of the deflnltlon glven above ln general represents one of the protectlve groups customary ln ~-lactam chemistry from the serles comprlslng 4-methoxyphenyl, 4-methoxymethyloxyphenyl, 4-[t2-methoxyethoxy)-methyloxy]phenyl, 3,4-dlmethoxy- phenyl, benzyl, 2-nltrobenzyl, 4-nltrobenzyl, 4-methoxybenzyl, 2,4-dlmethoxybenzyl, 3,4-dlmeth-oxybenzyl, 2,4,6-trlmethoxybenzyl, tert.-butoxycarbonyl benzyloxy-13401~

carbonyl, 2-nltrobenzyloxycarbonyl, 4-nltrobenzyloxycarbonyl, formyl, acetyl, chloroacetyl, trlchloroacetyl, trlfluoroacetyl, benzoyl, methoxycarbonyl, allyloxycarbonyl, 2,4-dlmethoxybenzyl-oxycarbonyl, methoxycarbonylmethyl tert.-butoxycarbonylmethyl, allyloxymethyl, bls-~4-methoxyphenyl)methyl, methoxymethyl, methylthlomethyl, methoxyethoxymethyl, 2-(methylthlomethoxy)-ethoxycarbonyl, 2-hydroxy-2-phenylmethyl, methoxy-(4-methoxy-phenyl)methyl, trlmethyl-, trlethyl- and trlphenylsllyl, tert.-butyl-dlmethylsllyl, tert.-butyl-dlphenylsllyl, [2-(trlmethylsilyl)ethoxylmethyl, 1-methyl-2-benzoyl-vlnyl, l-methyl-2-ethoxy- or -2-methoxyvlnyl, mesyl and ethylsulphonyl.
Carboxyl-protectlve group ln the context of the deflnl-tlon glven above represents the carboxyl-protectlve groups customary ln ~-lactam chemlstry. Groups whlch can easlly be spllt off may be mentloned as preferred, such as, for example: methyl, ethyl, tert.-butyl, decyl, 2-chloroethyl, 2,2,2-trlchloroethyl, cyanoethyl, dlphenylmethy, benzhydryl, trlphenylmethy, acetoxy-methyl, allyl, benzyl, 4-methoxyphenyl, 4-nltrobenzyl, 2-nltro-benzyl, 4-methoxybenzyl, 2,4-dlmethoxybenzyl, trlmethylsllylethyl, trl-methylsllyl, tert.butyl-dlmethylsllyl, acetonyl, l-phenoxy-ethyl and 2-methyl-2-propenyl.
If R represents an ester radlcal whlch can easlly be spllt off ln vlvo, by these are meant pharmaceutlcally tolerated ester radlcals whlch can easlly behydrolyzed ln vivo to glve free carboxyl groups (R4 = H).
Such ester radicals are well known ln the ~-lactam field. In most cases, they lmprove the absorptlon propertles of lL"
. ~

the ~-lactam compounds. The radlcal R4 should furthermore be such that lt lmparts pharmaceutlcally acceptable propertles to a compound of the formula (I) and releases pharmaceutlcally acceptable fragments when spllt ln vlvo.
Examples of such groups are to be found ln DE-OS (German Publlshed Speclflcatlons) 2,350,230 and DE-OS 2,228,255. Preferred ester groups whlch can be spllt off ln vlvo are those of the followlng formulae t ~ o~ o,~
O O

R14 o -CH'I 'R13 -C-O-C-R16 or ~ ~ ~ ' R15 o R14 o _C_o_c_o-Rl6 whereln R and R are ldentlcal or dlfferent and represent hydrogen or phenyl, or represent Cl-C4-alkyl, preferably methyl, R and R are ldentlcal or dlfferent and represent hydrogen or Cl-C4-alkyl, preferably methyl, and R represents Cl-c6-alkyl, preferably Cl-C4-alkyl.
The compounds of the general formula (I) accordlng to the lnventlon can be ln the form of free aclds, esters, lnner salts 1~401Sd Rl~ S
Il I ~
H3C ~ -_N-CH3 Exa~Ple of R2 CH-CO-NH ~ S~ an inner cOOe or non-toxlc physlologlcally tolerated salts wlth a counter-catlon Rl~
Il I Example of ~ . a salt R2 CH-C0-N ~ ~ CF3 ~i th a NHR3 ~ counter-I cation ~COOeN~

or, if R ls a posltlvely charged radlcal, non-toxlc, physlologl-cally tolerated salts ulth a counter-anlon Rl S
Il 1 ~
~ ~ H3C ~ ~N-CH3 Exa~Ple R2 ~ NHR3 ~ ~i th a Cle counter COOH
(COOAlkyl) anlon Preferred counter-catlons whlch may be mentloned are alkall metal or alkallne earth metal catlons, such as, for example, sodlum, potasslum, magnesium or calclum lons, or alumlnlum or ammonlum lons, and non-toxlc substltuted ammonlum , U~

lons from amlnes such as dl-lower alkylamlnes, trl-lower alkylamlnes, procalne, dibenzylamlne, N,N'-dibenzylethylene-dlamlne, N-benzyl-~-phenylethylamlne, N-methylmorphollne, l-ephenamlne, dlhydroabletylamlne, N,N'-bls-dlhydroabletylethyl-enedlamlne, N-lwver alkylplperidlne or other amlnes whlch can be used to form salts of ~-lactam compounds.
Preferred counter-anlons whlch may be mentloned are lnorganlc or organlc acld radlcals, such as, for example, chlorlde, bromlde, lodlde, sulphate, hydrogen sulphate, phosphate, hydrogen phosphate, carbonate or blcarbonate, or sulphonates, such as methanesulphonate, ethanesulphonate, toluenesulphonate, benzenesulphonate or naphthalenedlsulphonate, or carboxylates, such as acetate, formate, oxalate, tartrate, cltrate, maleate, fumarate, benzoate, succ lnate and lactate.
The compounds of the general formula (I) exlst (ln respect of the double bond) ln the Z-(cls) and in the E-(trans) conflguratlon. The compounds wlth the Z-(cls) conflguratlon are preferred. Because of the presence of the asymmetrlc carbon atom labelled * (see formula I), the ~-lactam antlblotlcs of the general formula (I) accordlng to the lnventlon lnclude the D-l L-and D,L- forms. Both the dlastereomer mlxtures and the D-form and L-form of the compounds accordlng to the lnventlon can be used for the treatment of bacterlal lnfectlon dlseases. The D-forms of the compounds accordlng to the lnventlon are partlcularly preferred.

- - 13 1015~

Especlally preferred compounds are moreover those llsted ln the followlng table~

R2~H - CO - Nl~f R5 NH2 ~J
CoOR4 Rl R2 R4 RS

H2N H H ~ CH2-H2N H H CH3-C~C-CH3 H CH2-OCOC(CH3)3 CF3-H2N- H H ~ sC-H2N- OH CH2OcocH3 ~ ~
S

H2N- OH H -N(CH3)2 ~ H H CF3 Hj~N H H CH2C1 B~

' ~ 13~01~4 H2N H H ¢ ~

H2N H H ~ N

H2N 02N , ~3 A proce~ has moreover been found for the preparation of the subqtituted vinylcephalosporin compounds of the general formula (I~ according to the invention, which i~
characterized in that [A] sub~tituted cephalosporin compounds of the general formula (II) R2 NHR3 N~4,H2_(Il) COOR

13~015~
in which R1 and R2 have the abovementioned meaning, R3 represents an amino-protective group, R4 represents a carboxyl-protective group and X represents a group of the formula p(R17) ~ , _ p- R17 or ~ ~R17 O
wherein R17 and R18 are identical or different and denote alkyl, phenyl or tolyl and Z ~ denotes a halide anion, preferably chloride, bromide or iodide, are reacted with aldehydes of the general formula (III) R5-CHo (III) in which R5 has the abovementioned meaning, in inert solvents in the presence of bases, or in that [B] phosphonium compounds of the general formula (IV) R5-CH2-X (IV) in which R5 has the abovementioned meaning and X represents a group of the formula -13~0154 P(R17)3~ , p--R17 or ,~----oR17 O

wherein R17 and R13 are identical or different and denote alkyl, phenyl or tolyl and Z ~ denotes a halide anion, preferably chloride, bromide or iodide, are reacted with cephalosporin aldehydes of the general formula (V) R~S
N~

~CH--CO--NH S (V) R2 /~CHO

~0 in which R1 and R2 have the abovementioned meaning, R3 represents an amino-protective group and R4 represents a carboxyl-protective group, in inert solvents in the presence of bases, or in that [C] carboxylic acids of the general formula (VI) X

134015~

R~S

~¦ (VI) IHR3' in which R1 and R2 have the abovementioned meaning and R3 represents an amino-protective group, after activation of the carboxyl group by conversion into a mixed anhydride, for example with ethyl chloroformate or isobutyl chloroformate or methanesulphonyl chloride, or by conversion into the acid halide, or by conversion into an activated ester, for example with dicyclohexylcarbodiimide (DCC), if appropriate in the presence of N-hydroxybenzotriazole, are reacted with the vinylcephalo-sporinamines of the general formula (VII) H2N ~ S~ RS

/~N~ (VII) CoOR4 in which R4 and R5 have the abovementioned meaning, and, if appropriate, the protective groups are split off and the desired salts are prepared or the free acids are prepared from the salts.

X

The process according to the invention can be illustrated by the following equation:
Process variant A:

H3C ~

ICH - CO-NH S
NHBoc O I H2 P(C6H5)3 COOCH(C6Hs)2 B~e ~ N

H3C ~ CHO

ICH - CO-NH S
NHBoc ~ ~

COOCH(C6Hs)2 Boc = (H3C)3C-O-CO-X

13~0154 Process variant B:

CH--CO--NH S
NHBoc 'nN' ~

COOCH(C6Hs)2 Base N~CH2--p~E3 (C6H5)3I

H3C~

CH--CO--NH S ¢~
NHBoc ~N ~

COOCH(C6Hs)2 Boc = (H3C) 3C-O-CO-X

- 134015~

Process variant C

ICH - COOH / ~ ~ N
NHBoc CoocH(c~Hs)2 ~ S coupling ICH--CO-- S ¢~J
NH

o/~N~ ~
COOCH(C6Hs)2 * Boc = (H3C)3C-O-CO-Explanations onprocess variants A and B
Suitable inert solvents for process variants A and B

are the customary organic solvents which do not change under the reaction conditions. These include, preferably, ethers, such as diethyl ether, butyl methyl ether, dioxane or tetrahydrofuran, or hydrocarbons, such as benzene, toluene, xylene or cyclohexane, or amides, such as dimethylformamide or hexamethylphosphoric acid triamide, or alcohols, such as methanol, ethanol, propanol or isopropanol, or chlorohydrocarbons, such as methylene chloride, chloroform or carbon tetrachloride, or acetone, acetonitrile or ethyl acetate. It is also possible to use mixtures of the solvents mentioned.
Suitable bases for process variants A and B are the customary basic compounds. These include, preferably, alkali metal or alkaline earth metal hydroxides, such as, for example, sodium hydroxide, potassium hydroxide or barium hydroxide, or alkali metal carbonates, such as sodium carbonate, sodium bicarbonate or potassium carbonate, or alkali metal alcoholates, such as sodium methanolate, sodium ethanolate, potassium methanolate, potassium ethanolate or potassium tert.-butylate.
The choice of solvent or base depends on the stability, hydrolysis-sensitivity or CH-acidity of the corresponding phosphorus compound. Solvents which are particularly preferably used are chlorohydrocarbons, such as, for example, methylene chloride, chloroform or carbon tetrachloride, in the presence of dimethylformamide as a co-solvent. Bases which are particularly preferably used arealkali metal carbonates, such as sodium carbonate, sodium bicarbonate or potassium carbonate, or alkali metal or alkaline earth metal hydroxides, such as, for example, sodium hydroxide, potassium hydroxide or barium hydroxide, particularly preferably in the form of their aqueous solutions.

I3~ 015~

The reaction is in general carried out in a temperature range from -30~C to +80~C, preferably from 0~C to +30~C.
The reaction can be carried out under normal, increased or reduced pressure tfor example in a range from 0.5 to 5 bar). It is in general carried out under normal pressure.
In carrying out process variants A and B, the phosphorus compound (II) or (IV) is in general employed in an amount of 1 to 3 mol, preferably in molar amounts, per mol of the aldehyde (III) or (V). The bases are in general employed in an amount of 1 to 5 mol, preferably 1 to 2 mol, per mol of the phosphorus compounds.
Process variants A and B are particularly preferably carried out as a Wittig reaction. In carrying out the process according to the invention, it is also possible, instead of the phosphonium salts [X = -P(R17)3~ ~ ], for the corresponding phosphoranes R~
~S
N~

R NHR3 ~ ~P(R )3 COOR
X

134015~

which have previously been prepared from the corresponding phosphonium salts and base in a separate reaction, to be employed directly. However, it has proved to be advantageous to carry out the reaction with the triphenylphosphonium salts (X = P~(C6H5)3Z~) in the presence of bases as a one-pot process. As a particular variant of a one-pot process, the reaction can also be carried out in the form of a phase transfer-catalyzed reaction, depending on the stability of the phosphorus compounds, ethers, hydrocarbons and 1~ halogenohydrocarbons being used as solvents and aqueous sodium hydroxide or potassium hydroxide solutions being used as bases.
Alternatively, if the reaction is carried out by a proce~ure in which the corresponding phosphorane is isolated as an intermediate compound and is reacted with the aldehyde in a second step, it has moreover been found that the yield and the ratio of Z/E isomer in the end products of the general formula (I) is improved by adding a suitable lithium halide, such as, for example, lithium chloride, lithium bromide or lithium iodide. The reaction here is preferably carried out with 10 to 15 equivalents of lithium halide.
However, it is particularly preferable to carry out process variants A and B as a one-pot reaction without isolation of the intermediate product. The process variants according to the invention can be carried out, for example, by a procedure in which the base and then an appropriate aldehyde, if appropriate in a suitable solvent, are added to the phosphonium compounds, dissolved or suspended in a - 13401~4 suitable solvent, and the mixture is warmed, if appropriate.
Working up is carried out in the customary manner by extraction, chromatography and/or crystallization.
Other specific process variants of the Wittig reaction are described, inter alia, in the following references: J. Fuhrop and G. Penzlin: Organic Synthesis, Verlag Chemie, 1983, pages 26 - 35; R.K. Mackie and D.M.
Smith: Guidebook to Organic Synthesis, Longman Group Limited, 1982, pages 93 - 99; H.O. House: Stereochemistry of the Wittig Reaction with stabilized ylides: J. Org. Chem. 29, 3327 - 3333 (1964).
Process variant C
It has proved advantageous to activate the amino acids and then to couple them with the ~-lactams, which are dissolved as salts with amines.
Activation of carboxylic acids of the general formula (VI) with (a) sulphonic acid derivatives of the general formula (VIII) or with (b) chloroformic acid esters, preferably ethyl chloroformate, to give anhydrides of the general formula (IX), as illustrated in the following equation, is particularly advantageous:

134015~

R
R ~ a)T-S02- R19~n~ N ~

N ~ R2 1CH-cooso2Rl9 R2 CH-COOH R ~ rXa Vl b)ClCOOC2Hs R2 ICH COOCOOC 2Hs NHR
r~b In this equation, in the formulae (VIII) and (IXa) T represents the radical R19-SO2-O- or halogen and R19 represents alkyl which has up to 10 carbon atoms and is optionally substituted by fluorine, chlorine, cyano or alkyl, alkoxycarbonyl, alkoxy or alkyl with in each case up to 4 carbon atoms, or represents phenyl, which is optionally sub-stituted by fluorine, chlorine, bromine, cyano, alkyl, alkoxy, alkylthio or alkoxycarbonyl with in each case up to 4 carbon atoms, nitro, tri-fluoromethyl or phenyl.

If R19 is substituted, 1 to 3 substituents are preferably present, and particularly preferably those mentioned above.

13401S~
R19 especially preferably represents a methyl or p-tolyl radical.
The mixed anhydrides of the general formula (IXa,b) are prepared by a procedure in which the carboxylic acids of the general formula (VI) and 1 to 1.4 equivalents of an amine are dissolved in a solvent and are reacted with 1 to 1.2 equivalents of a sulphonic acid derivative of the formula (VIII) or of a chloroformic acid ester.
Suitable solvents are all the solvents which do not change under the reaction conditions. These include, preferably, ethers, such as, for example, diethyl ether, dioxane or tetrahydrofuran, or chlorohydrocarbons, such as methylene chloride, chloroform or carbon tetrachloride, or amides, such as dimethylformamide or hexamethylphosphoric acid triamide, or acetonitrile or acetone. It is also possible to use mixtures of the solvents mentioned.
Suitable amines are tertiary amines, such as, for example, triethylamine, ethyl-diisopropylamine or tributylamine, but also sterically hindered secondary amines, such as, for example, diisopropylamine. Mixtures of the amines mentioned can also be used.
The reactions can be carried out at temperatures between -80~C and room temperature. The activation is advantageously carried out with methanesulphonyl chloride in dimethylformamide at -40~C to -60~C in the course of 0.2 to 24 hours, preferably 0.5 to 5 hours.
The solvents mentioned in the preparation of the compounds of the formula (IX) or water can be used to dissolve 13~01 ~4 the vinylcephalosporinamines of the formula (VII), and the amines mentioned there can be used as the base.
Activation of the carboxylic acids of the general formula (VI) by conversion into an activated ester with, for example, dicyclohexylcarbodiimide, if appropriate in the presence of N-hydroxysuccinimide or 1-hydroxybenzotriazole, is also particularly advantageous.
Suitable solvents here are all the solvents which are also suitable for the preparation of anhydrides of the general formula (IX) and have already been mentioned there.
The reactions can be carried out at temperatures between -30~C and +100~C. Activation is advantageously carried out with 1-hydroxybenzotriazole and dicyclohexylcarbodiimide in dimethylformamide at room temperature for 2 to 6 hours, and the dicyclohexylurea which has precipitated out is then filtered off with suction and reacted with the vinylcephalosporinamines of the formula (VII) in the form of a solution of its amine salt in the course of 2 to 24 hours. The solvents mentioned for the preparation of the compounds of the formula (IX) can be used to dissolve the vinylcephalosporinamines of the formula (VII), and the amines mentioned there can be used as the base.
The aldehydes of the general formula (III) used as starting substances are known or can be prepared by known methods [Houben-Weyl's "Methoden der organischen Chemie"
("Methods of Organic Chemistry") Volume VII/1; E2].
The cephalosporin aldehydes of the general formula (V) used as starting compounds are known or can be prepared by ~ ~ 13401.~
known methods by oxidation of the corresponding 3-hydroxymethyl-cephalosporin compounds with chromium trioxide in acetone (Jones reagent), such as is described, for example, by J.A. Webber, J.L. Ott and R.T. Vasileff in J. Med.
Chemistry I8, 986 (1987).
The phosphonium compounds of the general formula (IV) used as starting substances are known or can be prepared by known methods [Houben-Weyl's "Methoden der organischen Chemie" ("Methods of Organic Chemistry") Volume V/lb, 383 and 872, Volume XII/1, 33, 167].
The substituted cephalosporin compounds of the general formula (II) used as starting substances are new in some cases.
A process has been found for the preparation of the substituted cephalosporin compounds of the general formula (II), which is characterized in that halogeno-methylcephalosporin compounds of the general formula (X) NR ~ CIH-CO-NH

CoOR4 in which R1, R2, R3 and R4 have the abovementioned l3~ol5~
meaning and Z represents halogen, preferably chlorine, bromine or iodine, are reacted with phosphorus compounds of the general formula (XI) X¦ (XI) wherein X¦ represents a phosphorus compound of the formula XIa, XIb or XIc IP(R )3 ~ R18 or ¦-~ OR18 O

XIa XIb XIc whereln R17 and R18 are identical or different and represent alkyl, phenyl or optionally substituted phenyl, without solvents or in inert solvents.
The process according to the invention can be illustrated by the following equation:

X

-3401~4 ll H--CO--NH~S~
o ,~Cl COOCH(C 6H5)3 H3C~S + NaI
N~

CH--CO--NH S

/~I

COOCH(C6H5)2 + ¦ P(C6H5)3 W~CH--CO--NH S

o~N/~P (c6H5)3I(3 COOCH(C6H5)2 Suitable inert solvents are the customary organic solvents which are not changed under the reaction conditions.

These include, preferably, ethers, such as diethyl ether, butyl methyl ether, dioxane, tetrahydrofuran or glycol dimethyl ether, or hydrocarbons, such as benzene, toluene, xylene, hexane or cyclohexane, or petroleum fractions, or 134~15~
halogenohydrocarbons, such as methylene chloride, chloroform, carbon tetrachloride or chlorobenzene, or ethyl acetate, acetone, dimethylformamide, hexamethylphosphoric acid triamide or dimethylacetamide. It is also possible to use mixtures of the solvents mentioned.
The reaction is in general carried out in a temperature range from 0~C to +150~C, preferably from +20~C to +180~C.
The reaction can be carried out under normal, increased or reduced pressure. The reaction is in general carried out under normal pressure.
The reaction is in general carried out by a procedure in which the halogenomethylcephalosporin compound and the phosphorus compound are mixed in an inert solvent and the mixture is warmed, if appropriate. The phosphorus compound is in general employed here in an amount of 1 to 5, preferably 1 to 2 mol per mol of the chloromethylcephalosporin compound.
In carrying out the process according to the invention, it has proved to be particularly advantageous to use the corresponding iodine compounds (X = I) as the halogenomethylcephalosporin compounds, these being obtained from the corresponding chloromethyl or bromomethyl compounds by treatment with sodium iodide in dimethylformamide or acetone. It is moreover possible, if the chloromethyl or bromomethyl compounds are used, to carry out the conversion into the iodine compound and the reaction with the phosphorus compound as a one-pot reaction. For this, the corresponding 134015~

bromomethyl- or chloromethylcephalosporin compounds are reacted in a suitable solvent, such as, for example, ethers, acetates, hydrocarbons or chlorohydrocarbons, but preferably acetone, with sodium iodide and the corresponding phosphorus compounds.
The halogenomethylcephalosporin compounds of the general formula (X) used as starting substances are new.
A process has been found for the preparation of the halogenomethylcephalosporins of the general formula (X), which is characterized in that carboxylic acids of the general formula (VI) R ~ S

'T~q (VI) R2 ~ CH - COOH
NHR

in which R1 and R2 have the meaning given and R3 represents an amino-protective group, after activation of the carboxyl group by conversion into a mixed anhydride, for example with ethyl chloroformate, isobutyl chloroformate or methanesulphonyl chloride, or by conversion into the acid halide, or by conversion into an activated ester with, for example, N-hydroxybenzotriazole and dicyclohexylcarbodiimide, are reacted with a ~-lactam compound of the general formula (XII) 13~015~

H2N~'~S~
o/J N~,Z (XII) CoOR4 in which R4 and Z have the abovementioned meaning, if appropriate, protective groups are then split off and the desired salts are prepared or the free acids are prepared from the salts.
A large number of methods known from cephalosporin or penicillin chemistry can be used for coupling carboxylic acids (VI) to the ~-lactum compound (XII). It has proved to be advantageous to activate the carboxylic acids of the general formula (VI) without an amine-protective group and then to couple them with the ~-lactam compounds of the formula (XII), which have been dissolved as salts with an amine.
Activation of carboxylic acids of the general formula (VI) with (a) sulphonic acid derivatives of the general formula (VIII) or with (b) chloroformic acid esters, preferably ethyl chloroformate, to give anhydrides of the general formula (IXa, b), as illustrated in the following equation, is particularly advantageous:

X

R~ 134015~
a)T-S02--Rl9 (Vlll)N~'fH--COOS02R19 ~H--COOH IXa R NHR R~
b) ClCOOC2Hs ~

~H--COOCOOC2Hs IXb In this equation, in formula (VIII) and (IXa) T represents the radical R19-S02-0- or halogen and R19 represents alkyl which has up to 10 carbon atoms and is optionally substituted by fluorine, chlorine, cyano or alkyl, alkoxycarbonyl, alkoxy or alkyl with in each case up to 4 carbon atoms, or represents phenyl, which is optionally sub-' stituted by fluorine, chlorine, bromine, cyano, alkyl, alkoxy, alkylthio or alkoxycarbonyl with in each case up to 4 carbon atoms, nitro, tri-fluoromethyl or phenyl.

X

- 134~154 If R19 is substituted, 1 to 3 substituents are preferably present, and particularly preferably those mentioned above.
R19 especially preferably represents a methyl or p-tolyl radical.
The mixed anhydrides of the general formula (IXa, b) are prepared by a procedure in which the carboxylic acids of the general formula (VI) and 1 to 1.4 equivalents of an amine are dissolved in a solvent and are reacted with 1 to 1.2 equivalents of a sulphonic acid derivative of the formula (VIII) or of a chloroformic acid ester.
Suitable solvents are all the solvents which do not change under the reaction conditions. These include, preferably, ethers, such as, for example, diethyl ether, dioxane or tetrahydrofuran, or chlorohydrocarbons, such as methylene chloride, chloroform or carbon tetrachloride, or amides, such as dimethylformamide or hexamethylphosphoric acid triamide, or acetonitrile or acetone. It is also possible to use mixtures of the solvents mentioned.
Suitable amines are tertiary amines, such as, for example, triethylamine, ethyl-diisopropylamine or tributylamine, but also sterically hindered secondary amines, such as, for example, diisopropylamine. Mixtures of the amines mentioned can also be used.
The reactions can be carried out at temperatures between -80~C and room temperature. The activation is X

13~01~
advantageously carried out with methanesulphonyl chloride in dimethylformamide at -40~C to -60~C in the course of 0.2 to 24 hours, preferably 0.5 to 5 hours.
The solvents mentioned in the preparation of the compounds of the formula (IX) or water can be used to dissolve the ~-lactam compound of the formula (XII), and the amines mentioned there can be used as the base.
Activation of the carboxylic acids of the general formula (VI) by conversion into an activated ester with, for example, dicyclohexylcarbodiimide, if appropriate in the presence of N-hydroxysuccinimide or 1-hydroxybenzotriazole, is also particularly advantageous.
Suitable solvents here are all the solvents which are also suitable for the preparation of anhydrides of the general formula (IX) and have already been mentioned there.
The reactions can be carried out at temperatures between -30~C and +100~C. Activation is advantageously carried out with l-hydroxybenzotriazole and dicyclo-hexylcarbodiimide in dimethylformamide at room temperature for 2 to 6 hours, and the dicyclohexylurea which has precipitated out is then filtered off with suction and reacted with the ~-lactam compound of the formula (XII) in the form of a solution of the amine salt in the course of 2 to 24 hours. The solvents mentioned for the preparation of the compounds of the formula (IX) can be used to dissolve the ~-lactam compound of the formula (XII), and the amines mentioned there can be used as the base.

X

,_ 13~0l~4 The carboxylic acids of the general formula (VI) used as starting substances are known or can be prepared by known methods [DE-OS (German Published Specification) 3,508,258].
The amino-~-lactams of the general formula (VII +
XII) employed as starting substances are known only in some cases or can be prepared by known methods [DE-OS (German Published Specification) 3,402,642; U.S. Patent Specification 4,639,448].
The compounds of the general formula I according to the invention have a broad antibacterial spectrum against Gram-positive and Gram-negative germs, coupled with a low toxicity. These properties enable them to be used as chemotherapeutic active compounds in human and veterinary medicine.
The compounds according to the invention are active against a very broad spectrum of microorganisms. Gram-negative and Gram-positive bacteria and bacteria-like microorganisms and the diseases caused by these pathogens can be prevented, alleviated and/or cured with the aid of these compounds.
The compounds according to the invention are particularly active against bacteria and bacteria-like microorganisms. They are therefore particularly suitable in human and veterinary medicine for the prophylaxis and chemotherapy of local and systemic infections caused by these pathogens.

13~lOlS~

For example, local and/or systemic diseases which are caused by the following pathogens or by mixtures of the following pathogens can be treated and/or prevented: Gram-positive cocci, for example Staphylococci (Staph. aureus and Staph. epidermidis) and Streptococci (Strept. agalactiae, Strept. faecalis, Strept. pneumoniae and Strept. pyogenes);
Gram-negative cocci (Neisseria gonorrhoeae) and Gram-negative rod-shaped bacilli, such as Enterobacteriaceae, for example Escherichia coli, Haemophilus influenzae, Citrobacter (Citrob.
freundii, Citrob. divernis), Salmonella and Shigella; and furthermore Klebsiella (Klebs. pneumoniae and Klebs. oxytoca), Enterobacter (Ent. aerogenes and Ent. agglomerans), Hafnia, Serratia (Serr. marcescens), Proteus (Pr. mirabilis, Pr.
rettgeri and Pr. vulgaris), Providencia, Yersinia and the genus Acinetobacter. The antibacterial spectrum moreover includes the genus Pseudomonas (Ps. aeruginosa and Ps.
maltophilia) and strictly anaerobic bacteria, such as, for example, Bacteroides fragilis, representatives of the genus Peptococcus, Peptostreptococcus and the genus Clostridium; and furthermore Mycoplasma (M. pneumoniae, M. hominis and M.
urealyticum) and mycobacteria, for example Mycobacterium tuberculosis. The substances according to the invention have an action in particular against Staphylococci, Streptococci, Enterococci and Haemophilus influenzae. On parenteral or, in particular, oral administration, the new compounds have a very good action against microorganisms such as Staphylococci, X

13401t~
Streptococci, Enterobacteriaceae, Escherichia coli, Klebsiella, Salmonella, Shigella, anaerobic bacteria (for example Bacteroides) and Proteus.
The above list of pathogens is given merely by way of example and is in no way to be interpreted as limiting.
Examples which may be mentioned of diseases which can be caused by the pathogens or mixed infectious agents mentioned and can be prevented, alleviated or cured by the compounds according to the invention are: infectious diseases in humans, such as, for example, otitis, pharyngitis, pneumonia, peritonitis, pyelonephritis, cystitis, endocarditis, systemic infections, bronchitis (acute and chronic), septic infections, diseases of the upper respiratory tract, diffuse panbronchiolitis, pulmonary emphysema, dysentery, enteritis, liver abscesses, urethritis, prostatitis, epididymitis, gastrointestinal infections, bone and joint infections, cystic fibrosis, skin infections, postopertive wound infections, abscesses, phlegmons, wound infections, infected burns, burn wounds, infections in the oral region, infections following dental operations, osteomyelitis, septic arthritis, cholecystitis, peritonitis with appendicitis, cholangitis, intraabdominal abscesses, pancreatitis, sinusitis, mastoiditis, mastitis, tonsillitis, typhus, meningitis and infections of the nervous system, salpingitis, endometritis, genital infections, pelveoperitonitis and eye infections.
As well as in humans, bacterial infections can also be treated in other species. Examples which may be mentioned are: pigs: coli-diarrhoea, enterotoxaemia, sepsis, dysentery, X

_ 13401.5~
salmonellosis, metritis-mastitis-agalactiae syndrome and mastitis; ruminants (cattle, sheep, goats): diarrhoea, sepsis, bronchopneumonia, salmonellosis, pasteurellosis, mycoplasmosis and genital infections; horses: bronchopneumonia, joint ill, puerperal and postpuerperal infections and salmonellosis; dogs and cats: bronchopneumonia, diarrhoea, dermatitis, otitis, urinary tract infections and prostatitis; poultry (chickens, turkeys, quails, pigeons, ornamental birds and others):
mycoplasmosis, E. coli infections, chronic respiratory tract diseases, salmonellosis, pasteurellosis and psittacosis.
Bacterial diseases in the breeding and rearing of stock and ornamental fish can also be treated, the antibacterial spectrum being extended beyond the above-mentioned pathogens to further pathogens, such as, for example, Pasteurella, Brucella, Campylobacter, Listeria, Erysipelothrix, Corynebacteria, Borellia, Treponema, Nocardia, Rickettsia and Yersinia.
The present invention includes pharmaceutical formulations which, in addition to non-toxic, inert, pharmaceutically suitable excipients, contain one or more compounds according to the invention or consist of one or more active compounds according to the invention, and to processes for the preparation of these formulations.
The present invention also includes pharmaceutical formulations in dosage units. This means that the formulation is in the form of individual parts, for example tablets, dragees, capsules, pills, suppositories and ampoules, the active compound content of which corresponds to a fraction or 13~0151 a multiple of an individual dose. The dosage units can contain, for example, 1, 2, 3 or 4 individual doses or 1/2, 1/3 or 1/4 of an individual dose. An individual dose preferably contains the amount of active compound which is given in one administration and which usually corresponds to a whole, one half, one third or one quarter of a daily dose.
By non-toxic inert pharmaceutically suitable excipients there are to be understood solid, semi-solid or liquid diluents, fillers and formulation auxiliaries of all kinds.
Tablets, dragees, capsules, pills, granules, suppositories, solutions, suspensions and emulsions, pastes, ointments, gels, creams, lotions, dusting powders and sprays may be mentioned as preferred pharmaceutical formulations.
Tablets, dragees, capsules, pills and granules can contain the active compound or compounds, in addition to the customary excipients, such as (a) fillers and extenders, for example starches, lactose, sucrose, glucose, mannitol and silicic acid, (b) binders, for example carboxymethylcellulose, alginates, gelatine or polyvinylpyrrolidone, (c) humectants, for example glycerol (d) disintegrating agents, for example agar-agar, calcium carbonate and sodium carbonate, (e) solution retarders, for example paraffin and (f) resorption accelerators, for example quaternary ammonium compounds, (g) wetting agents, for example cetyl alcohol and glycerol monostearate, (h) adsorbents, for example kaolin and bentonite X

I3401 ~4 and (i) lubricants, for example talc, calcium stearate and magnesium stearate and solid polyethylene glycols, or mixtures of the substances mentioned under (a) to (i).
The tablets, dragees, capsules, pills and granules can be provided with the customary coatings and shells, optionally containing opacifying agents, and can also be of such composition that they release the active compound or compounds only or preferentially in a certain part of the intestinal tract, if appropriate in a delayed manner, examples of embedding compositions which can be used being polymeric substances and waxes.
The active compound or compounds can also be in microencapsulated form, if appropriate with one or more of the abovementioned excipients.
Suppositories can contain, in addition to the active compound or compounds, the customary water-soluble or water-insoluble excipients, for example polyethylene glycols, fats, for example cacao fat, and higher esters (for example C14-alcohol with C16-fatty acid), or mixtures of these substances.
Ointments, pastes, creams and gels can contain, in addition to the active compound or compounds, the customary excipients, for example animal and vegetable fats, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures of these substances.
Dusting powders and sprays can contain, in addition to the active compound or compounds, the customary excipients, for example lactose, talc, silicic acid, aluminium hydroxide, X

~ 1~4015~

calcium silicate and polyamide powder, or mixtures of these substances. Sprays can additionally contain the customary propellants, for example chlorofluorohydrocarbons.
Solutions and emulsions can contain, in addition to the active compound or compounds, the customary excipients, such as solvents, solubilizing agents and emulsifiers, for example water, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils, in particular cottonseed oil, groundnut oil, maize germ oil, olive oil, castor oil and sesame oil, glycerol, glycerolformal, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, or mixtures of these substances.
For parenteral administration, the solutions and emulsions can also be in a sterile form which is isotonic with blood.
Suspensions can contain, in addition to the active compound or compounds, the customary excipients, such as liquid diluents, for example water, ethyl alcohol or propylene glycol, suspending agents, for example ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminium metahydroxide, bentonite, agar-agar and tragacanth, or mixtures of these substances.
The formulation forms mentioned can also contain colouring agents, preservatives and additives which improve - 13~0154 the smell and taste, for example peppermint oil and eucalyptus oil, and sweeteners, for example saccharin.
The therapeutically active compounds should preferably be present in the abovementioned pharmaceutical formulations in a concentration of about 0.1 to 99.5, preferably about 0.5 to 95% by weight of the total mixture.
The abovementioned pharmaceutical formulations can also contain other pharmaceutical active compounds in addition to the compounds according to the invention.
The abovementioned pharmaceutical formulations are prepared in the customary manner by known methods, for example by mixing the active compound or compounds with the excipient or excipients.
The formulations mentioned can be used on humans and animals either orally, rectally, parenterally (intravenously, intramuscularly or subcutaneously), intracisternally, intravaginally, intraperitoneally or locally (dusting powders, ointment, drops) and for the therapy of infections in hollow spaces and body cavities. Suitable formulations are injection solutions, solutions and suspensions for oral therapy, gels, infusion formulations, emulsions, ointments or drops.
Ophthalmological and dermatological formulations, silver salts and other salts, eardrops, eye ointments, dusting powders or solutions can be used for local therapy. In the case of animals, intake can also take place via the feed or drinking water, in suitable formulations.
Gels, powders, dusting powders, tablets, sustained release tablets, premixes, concentrates, granules, pellets, X

boli, capsules, aerosols, sprays and inhalates can furthermore be u~ed on humans and animals. The compounds according to the invention can furthermore be incorporated into other carrier materials, such as, for example, plastics (chains of plastic for local therapy), collagen or bone cement.
In general, it has proved advantageous both in human and in veterinary medicine to administer the active compound or compounds according to the invention in total amounts of about 0.5 to about 500, preferably 5 to 100 mg/kg of body weight every 24 hours, if appropriate in the form of several individual doses, in order to achieve the desired results. An individual dose preferably contains the active compound or compounds according to the invention in amounts of about 1 to about 80, in particular 3 to 30 mg/kg of body weight.
However, it may be necessary to deviate from the dosages mentioned, and in particular to do 50 as a function of the nature and body weight of the subject to be treated, the nature and severity of the disease, the nature of the formulation and of the administration of the medicament and the period or interval within which administration takes place.
Thus, in some cases it may suffice to manage with less than the abovementioned amount of active compound, whilst in other cases the abovementioned amount of active compound must be exceeded. The particular optimum dosage required and mode of administration of the active compounds can easily be specified by any expert on the basis of his expert knowledge.

X

134015~

The new compounds can be administered in the customary concentrations and formulations together with the feed or with feed formulations or with the drinking water.
Infection by Gram-negative or Gram-positive bacteria can thereby be prevented, alleviated and/or cured, and a promotion in growth and an improvement in feed conversion can thereby be achieved.
The compounds according to the invention can be combined with other antimicrobial active compounds and lactamase inhibitors, for example with penicillins which are particularly penicillinase-resistant and clavulanic acid, for the purpose of increasing the action spectrum and in order to achieve an increase in action, especially against ~-lactamase-forming bacteria. Such a combination would be, for example, that with oxacillin or dicloxacillin.
The compounds according to the invention can also be combined with aminoglycoside antibiotics, such as, for example, gentamicin, sisomicin, canamicin, amicacin or tobramycin, for the purpose of broadening the action spectrum and achieving an increase in action.
The present invention also includes a commercial package containing as active ingredient a compound according to the invention together with instructions for the use thereof as an antibacterial agent.

X

134015~

Preparation ExamPles Example 1 Benzhydryl 7-amino-3-chloromethyl-3-cephem-4-carboxylate N ~ Cl COOCH(C6Hs)2 19.64 ml (0.242 mol) of pyridine are added to a suspension of 50 g (0.0972 mol) of benzhydryl 7-phenyl-acetamido-3-hydroxymethyl-3-cephem-4-carboxylate in 500 ml of methylene chloride at room temperature. After cooling to -20~C, 40.48 g (0.0972 mol) of phosphorus pentachloride are added and the mixture is stirred at -20~C for 5 minutes. It is warmed to 0~C with an icebath and stirred for 10 minutes, and is then warmed to 15~C with a waterbath and stirred for 1 hour. Thereafter, the mixture is cooled to -70~C and 720 ml of cold methanol are quickly added. The mixture is then stirred at -70~C for 5 minutes, at 0~C for 10 minutes and at +15~C for 25 minutes. The solution is subsequently concentrated to a high degree in vacuo and 1,400 ml of saturated sodium bicarbonate solution are added. This solution is extracted three times with methylene chloride and the organic phase is dried with sodium sulphate and concentrated in vacuo. The crude product is chromatographed on 500 g of silica gel 60(0.04 - 0.063 mm) with methylene chloride.

X

134015~

Yield: 29.0 g (72% of theory) C21HlgClN2O3S (414.9) NMR (CDC13): ~ = 2.06 (s, 2H); 3.45 (d, lH); 3.62 (d, lH);
4.25 - 4.41 (q, 2H); 4.75 (d, lH); 4.93 (d, lH); 6.97 (s, lH);
7.25 - 7.46 (m, 10H) ppm.
Example 2 Benzhydryl D-7-[2-(t-butoxycarbonylamino)-2-(2-amino-benzothiazol-6-yl)-glycylamido]-3-chloromethyl-3-cephem-4-carboxylate ~ IH - CO - NH ~ ~

COOC(CH3)3 COOCH(C6H5)2 18.07 g (0.0875 mol) of N,N'-dicyclohexylcarbodiimide (DCC), dissolved in 150 ml of tetrahydrofuran, are added to a mixture of 28.3 g (0.0875 mol) of D-~-t-butoxycarbonylamino-~-(2-aminobenzothiazol-6-yl) acetic acid and 24.1 g (0.058 mol) of benzhydryl 7-amino-3-chloromethyl-3-cephem-4-carboxylate (Example 1) in 136 ml of tetrahydrofuran and 77 ml of dimethylformamide at 0~C and the mixture is subsequently stirred at room temperature for 2 hours and concentrated to dryness. The residue is suspended in 1,200 ml of ethyl acetate, the suspension is stirred for 10 minutes and X

-undissolved constituents are then removed by filtration with suction. After the ethyl acetate has been distilled off, the residue is chromatographed on silica gel 60 (0.04 - 0.063 mm) with toluene/ethyl acetate (1 : 1).
Yield: 17.6 g (42% of theory) C35H34ClN5S2O6 (720.3) NMR (DMSO): ~= 1.37 (s, 9H); 3.46 (d, lH); 3.64 (d, lH); 4.32 - 4.43 (q, 2H); 5.11 (d, 5 Hz, lH); 5.31 (d, lH); 5.8 - 5.86 (q, lH); 6.98 (s, lH); 7.15 - 7.5 (mm, 14H); 7.67 (s, lH) ppm Example 3 Benzhydryl D-7-[2-(t-butoxycarbonylamino)-2-(2-amino-benzothiazol-6-yl)glycylamido]-3-iodomethyl-3-cephem-4-carboxylate ~1 ~\CH--CO--NH ~S~
NH ~ ~CH2I
COOC(CH3)3 COOCH(C6H5)2 A mixture of 20.3 g (0~0282 mol) of benzhydryl D-7-[2-(t-butoxycarbonylamino)-2-(2-aminobenzothiazol-6-yl)-glycylamido]-3-chloromethyl-3-cephem-4-carboxylate (Example 2) and 12.68 g (0.0846 mol) of sodium iodide in 300 ml of acetone is stirred at room temperature for 2 hours and evaporated to dryness. The residue is taken up in 500 ml of ethyl acetate and the mixture is washed with aqueous sodium thiosulphate X

solution, water and sodium chloride solution. After drying over sodium sulphate, the solvent is distilled off and the residue is digested in ether.
Yield: 22 g The compound is used directly in the next stage.
Example 4 Benzhydryl D-7-[2-(t-butoxycarbonylamino)-2-(2-amino-benzothiazol-6-yl)glycylamido]-3-(triphenylphosphonio)-methyl-3-cephem-4-carboxylate iodide N ~

~ CH-CO-NH S
1 o~N/~CH2P(C6H5)3 COOC(CH3)3 COOCH(C6HS)2 A mixture of 22 g (0.0271 mol) of benzhydryl D-7-[2-(t-butoxycarbonylamino)-2-(2-aminobenzothiazol-6-yl)-glycylamido]-3-iodomethyl- 3-cephem-4-carboxylate (Example 3) and 21.32 g (0.0813 mol) of triphenylphosphine in 500 ml of ethyl acetate is stirred at room temperature for 1 hour. After 30 minutes, the product precipitates out. The mixture is concentrated to about 150 ml under reduced pressure and 500 ml of ether are added to the concentrate. The resulting precipitate is filtered off with suction and rinsed with ether.

X

13401~i Yield: 19.6 g (67% of theory) C53H49INsO6PS2 (1074.1) NMR (DMSO): ~= 1.35 (s, 9H); 3.32 - 3.42 (dd, 2H); 4.81 - 4.93 (t, 2H); 5.2 (d, lH); 5.33 (d, lH); 5.72 - 5.79 (q, lH); 6.24 (s, lH); 7.2 - 7.49 (mm, 15H); 7.6 - 7.79 (m, 15H) ppm.
ExamPle 5 Benzydryl D-7-[2-(t-butoxycarbonylamino)-2-(2-amino-benzothiazol-6-yl)glycylamido]-3-[(Z)-2-cyclopropylvinyl]-3-cephem-4-carboxylate H2N~S

~CH--CO--NH S
1 ~N/~

COOC(CH3)3 COOCH(C6H5)2 6.34 g (0.091 mol) of cyclopropanecarboxaldehyde and 7.6 g (0.007 mol) of benzhydryl D-7-[2-(t-butoxy-carbonylamino)-2-(2-aminobenzothiazol-6-yl)glycylamido]-3-(triphenylphosphonio)methyl-3-cephem-4-carboxylate iodide (Example 4) are added to a cold solution of 6.08 g (0.07 mol) of lithium bromide in 50 ml of dimethylformamide and 150 ml of methylene chloride at -5~C. The mixture is stirred at -5~C
for 20 hours and then at room temperature for 5 hours. The solution is concentrated to about 50 ml in vacuo and the concentrate is partitioned between a solvent mixture of 200 ml of ethyl acetate and 200 ml of water. The upper layer is X

-separated off and washed once with aqueous sodium chloride solution. After drying over sodium sulphate and distilling off the solvent, the residue is taken up in toluene and introduced onto a column packed with silica gel (0.04 - 0.063 mm). The column is eluted first with toluene and then with the solvent mixture toluene/ethyl acetate (5:1) and toluene/ethyl acetate (1:1).
Yield: 3.0 g (57.5% of theory) C39H37N5O6S2 (737 9) Calculated: C 63.48 H 5.33 N 9.49 S 8.69 Found: C 62.8 H 5.01 N 9.18 S 7.93 Example 6 D-7-[(2-Aminobenzothiazol-6-yl)glycylamido]-3-[(Z)-2-cyclopropyl-vinyl]-3-cephem-4-carboxylic acid, cis-isomer H2N~S

CH-CO-NH S

2 O ~ ~ CiS
COOH

2.9 g (3.9 mmol) of benzhydryl D-7-[2-(t-butoxy-carbonylamino)-2-(2-aminobenzothiazol-6-yl)glycylamido]-3-[(Z)-2-cylclopropyl-vinyl]-3-cephem-4-carboxylate (Example 5) are dissolved in 20 ml of methylene chloride, 40 ml of trifluoroacetic acid (TFA) are added and the mixture is - 1~40154 stirred with a magnetic stirrer at room temperature for 60 minutes. The methylene chloride and trifluoroacetic acid are removed in vacuo, the semi-solid red oil which remains is triturated in ether and the product is filtered off with suction and washed with ether. The pale yellow trifluoroacetate is dried in vacuo and then suspended in 100 ml of water and insoluble yellow flocks are filtered off with suction over kieselguhr and rinsed again with 30 ml of water.
The still slightly cloudy solution is filtered again over a membrane filter (Millipore , 0.45 ~m). The filtrate is pumped onto an RP 18 column (Hibar 250-25, Merck). The column is eluted first with 200 ml of water (fraction 1), then with 400 ml of 5% strength methanol (fraction 2) and finally with 10%
strength methanol, in each case 300 ml fractions being collected (fraction 3 to 12).
The fractions are investigated by means of analytical HPLC and fractions 6 to 10, which contain the desired peak, are combined, the methanol is distilled off in vacuo and the residue is lyophilized.

Yield: 480 mg (25.9% of theory) C21H21N5~4S2 (471.5) NMR (DCOOD): ~= 0.48 (m, 2H); 0.81 (m, 2H); 1.37 - 1.48 (m, lH); 3.48 - 3.68 (q, 2H); 5.1 - 5.18 (t, lH); 5.28 (d, lH);

5.72 (s, lH); 5.82 (d, lH); 6.15 - 6.2 (d, lH); 7.8 (q, 2H);
8.12 (s, lH) ppm.

Trade-Mark X

Example 7 Benzhydryl 7-phenylacetamido-3-(triphenylphosphonio)-methyl-3-cephem-4-carboxylate iodide CH2-CO-NH ~ S~

0~--N ~ \CH2P(C6Hs)3 COOCH(C6H5)2 32.5 g (0.0609 mol) of benzhydryl 7-phenylacetamido-3-chloromethyl-3-cephem-4-carboxylate are dissolved in 330 ml of acetone, and 10.1 g (0.0674 mol) of NaI and 17.6 g (0.0671 mol) of triphenylphosphine are added in succession, with stirring. After the mixture has been stirred at room temperature for 1.5 hours, the insoluble material is removed by filtration with suction and the clear mother liquor is stirred into 1,000 ml of ether. The white flocculent material which precipitates out is filtered off with suction, washed with 300 ml of ether and dried in vacuo.
Yield: 51 g (94% of theory) C47H40INO2O4PS (886.8) NMR (DMSO): ~ = 3.51 - 3.61 (q, 4H); 4.93 - 5.05(t, lH); 5.22 - 5.33 (d and t, 2H); 5.7 - 5.76 (q, lH); 6.26 (s, lH); 7.21 -7.46 (mm, 15H); 7.68 - 7.79 (m, 15H); 9.14 (d, lH) ppm.

_ 134015i Example 8 Benzhydryl 7-phenylacetamido-3-[(Z)-2-cyclopropyl-vinyl]-3-cephem-4-carboxylate CH2-CO-NH ~ S~
O N ~

COOCH(C6HS)2 15.9 g (17.9 mmol) of benzhydryl 7-phenylacetamido-3-(triphenylphosphonio)methyl-3-cephem-4-carboxylate iodide (Example 7) are taken in 100 ml of methylene chloride and 17.56 g (250.6 mmol) of cyclopropanecarboxaldehyde in a 250 ml three-necked flask. The mixture is cooled to 0~C and 100 ml of water are added. 16.3 ml of lN NaOH are then added dropwise in the course of 4 hours, the pH being kept constant at 8.6. The reaction solution is diluted with methylene chloride and the organic phase is separated off, washed once with water and then dried over sodium sulphate. After the drying agent has been removed, a further 13 ml (233 mmol) of cyclopropanecarboxaldehyde are added to the methylene chloride solution and the mixture is stirred overnight. The reaction solution is then concentrated to dryness, the residue is again dissolved in a little methylene chloride and the mixture is introduced onto a column filled with 500 ml of silica gel (0.04 - 0.063 mm). 400ml fractions are collected and all the fractions are investigated for the cis-isomer compound by means of analytical HPLC.

X

r--~
134~151 Yield: 4.5 g (45.6% of theory) C33H30N2O4S (550.7) Calculated: C 71.97 H 5.49 N 5.09 S 4.58 Found : C 70.5 H 5.11 N 4.81 S 4.05 NMR (CDCl3) ~ = 0.19-0.25 (m, lH); 0.34-0.42 (m, lH); 0.63-0.78 (mm, 2H); 1.24-1.35 (m, lH); 3.4-3.6 (dd, 2H); 3.66 (q, 2H); 4.87-4.93 (t, lH); 5.01 (d, lH); 5.77-5.81 (q, lH); 6.08-6.12 (d, lH); 6.15 (d, lH); 6.93 (s, lH); 7.27-7.41 (mm, 15H) ppm.

Example 9 7-Phenylacetamido-3-[(Z)-2-cyclopropylvinyl]-3-cephem-4-carboxylic acid ~CH2 CO~

COOH

12.5 g (0.0227 mmol) of benzhydryl 7-phenylacetamido-3-[(Z)-2-cyclopropyl-vinyl]-3-cephem-4-carboxylate are dissolved in 23 ml of methylene chloride with the addition of 7.2 ml of anisole, the solution is cooled to 0~C and 23 ml of trifluoroacetic acid are added. The mixture is stirred at 0~C for 30 minutes and 46 ml of water are then added. 400 ml of diisopropyl ether are subsequently added to the reaction solution and the mixture is stirred at 0~C for 30 minutes. The product which has crystallized out is filtered off with suction and washed with diisopropyl ether.

~; 13401~4 Yield: 6.9 g (79.1% of theory) C22H20N2O4S (384.45) NMR (DMSO): ~= 0.39-0.47 (m, 2H); 0.75-0.83 (m, 2H); 1.44-1.60 (m, lH); 3.55 (d, 2H); 3.61 (d, lH); 3.77 (d, lH); 4.93-5.04 (m, lH); 5.16 (d, lH); 5.59-5.69 (q, lH); 6.08-6.15 (d, lH); 7.20-7.35 (m, 5H) ppm.

Example 1 0 7-Amino-3-[(Z)-2-cyclopropyl-vinyl]-3-cephem-4-carboxylic acid H2N S H2C~CH2 COOH

6 g (0.0156 mol) of 7-phenylacetamido-3-[(Z)-2-cyclopropyl-vinyl]-3-cephem-4-carboxylic acid are suspended in 320 ml of water and the suspension is brought to pH 7.8 with half-concentrated ammonia solution, whereupon an almost clear solution forms. The solution is warmed to 37~C and 35 g of penicillin-acylase resin are added. The reaction solution is titrated further to pH 7.8 with ammonia and kept at 37~C for 5 hours. The resin is then filtered off with suction and the filtrate is concentrated down to a volume of 50 ml. The concentrated solution is brought to pH 4.2 with 2 N HCl, ~0 whereupon the product precipitates out and is filtered off with suction and washed with water and acetone.
Yield: 3.6 g (86.7~ of theory) C12H14N2O3S (266.32) NMR (DCOOD): ~= 0.53-0.61 (m, 2H); 0.88-O 1 5 ~
0.98 (m, 2H); 1.45-2.0 (m, lH); 3.58 (d, lH); 3.72 (d, lH);
5.25-5.38 (t, lH); 5.39 (d, lH); 5.48 (d, lH); 6.44-6.50 (d, lH) ppm.
Example 11 D-7-[(2-Aminobenzothiazol-6-yl)glycylamido]-3-[(Z)-2-cyclopropyl-vinyl]-3-cephem-4-carboxylic acid, cis-isomer CH-CO-N

COOH

a) Activation of the precursor acid 4.12 g [corresponds to 3.54 g (0.0103 mol) of pure substance] of sodium D-~-[(1-methyl-2-methoxycarbonyl-vinyl)-amino]-(2-amino-benzothiazol-6-yl)acetate (content: 86~) are dissolved in 30 ml of dimethylformamide and 10 ml of acetonitrile to give a clear solution. The solution is cooled to -70~C, 5 drops of 3-dimethylaminopropanol and 1.0 ml (0.0104 mol) of ethyl chloroformate are added and the mixture is stirred at -60~C for 30 minutes.
b) Preparation of the cePhalosporin component 2.5 g (9.39 mmol) of 7-amino-3-[(Z)-2-cyclopropyl-vinyl]-3-cephem-4-carboxylic acid are suspended in 20 ml of ~o dimethylformamide and 7 ml of acetonitrile and the suspension 52a X

13~0151 is cooled to 0~C and converted into a clear solution by addition of 1 N sodium hydroxide solution (about 9 ml) to pH

8.5. The solution is cooled to -50~C.
c) Coupling, deblocking and isolation of the crude betaine:
The cooled cephalosporin solution (b) is added to the solution of the mixed anhydride of the precursor acid (a) at -60~C. The temperature is then allowed to rise to -10~C in the course of 90 minutes (without a cooling bath) and the solution is additionally stirred with 500 mg of active charcoal and 500 mg of kieselguhr for a further 10 minutes, whereupon the temperature rises up to +10~C. The reaction mixture is filtered over a Seitz filter, the residue is rinsed with a little dimethylformamide, and 2 ml of concentrated hydrochloric acid are added to the filtrate at 0~C. After 15 minutes, the solution is concentrated in vacuo and the salt which has precipitated out is filtered off with suction and rinsed with a little dimethylformamide. The filtrate is brought to pH 4.6 with 25% strength ammonia solution and is then stirred into 500 ml of acetone, whereupon the crude betaine precipitates out. The precipitate is filtered off with suction and rinsed with acetone and the material is dried in vacuo.
Yield: 6.1 g d) Chromatoqraphy:
The crude betaine is suspended in 80 ml of water and the pH is brought to 1.4 with 2 N HCl (clear solution). The 52b solution is introduced onto a column filled with 800 ml of adsorber resin LPG 4429 (Lewatit OC 1062, particle size 0.1 to 0.5 mm, BAYER). The column is first eluted with 1,300 ml of water. The column is then washed with water, to which an increasing content of acetone of 0% to 20% is continuously added. A total of 18 fractions of 200 ml of eluate are collected, fractions 9-15 containing the desired compound, according to analytical HPLC control. The fractions with the Z-isomer are combined, the acetone is distilled off in vacuo and the aqueous filtrate is lyophilized.
Yield: 1.42 g (29% of theory) C21H21Ns~4S2.3H2O (525.61) Calculated: C 48.0 H 5.18 N 13.32 S 12.20 Found : C 47.9 H 5.0 N 12.5 S 11.7 NMR (DMSO): ~ = 0.48 (narrow m, 2H); 0.81 (narrow m, 2H);
1.37-1.48 (m, lH); 3.48-3.68 (q, 2H); 5.1-5.18 (t, lH); 5.28 (d, lH); 5.72 (s, lH); 5.82 (d, lH); 6.15-6.2 (d, lH); 7.8 (q, 2H); 8.12 (s, lH) ppm.
Exam~le 12 Benzhydryl 7-phenylacetamido-3-[(triphenylphosphoran-ylidene)methyl]-3-cephem-4-carboxylate 2 ~ NH ~ S~

N ~ P(C~H~3 COOCH(C6H~

52c X

13401~
14.0 g (0.132 mol) of Na2CO3, dissolved in 150 ml of water, are added to a suspension of 78.0 g (0.088 mol) of benzhydryl 7-phenylacetamido-3-(triphenylphosphonio)methyl-3-cephem-4-carboxylate iodide (Example 7) in 400 ml of methylene chloride and the mixture is stirred vigorously at room temperature for 15 minutes. The CH2Cl2 layer is separated off, the aqueous phase is extracted again with 200 ml of CH2Cl2 and the combined organic phases are dried over sodium sulphate. The methylene chloride phase is concentrated to dryness and the residue is stirred in about 600 ml of acetone for 1 hour. The product is filtered off with suction and rinsed thoroughly with acetone.
Yield: 58.9 g (88.3% of theory) C47H39N2O4SP (758.8) NMR (DMSO): ~= 2.4 (d, lH); 3.2 (d, lH); 3.49 (s, 2H); 5.1 (d, lH); 5.19 - 5.24 (q, lH); 5.43 (d, lH); 6.75 (s, lH); 7.2 - 7.49 (broad m, 15H); 7.62 - 7.78 (m, 15H); 8.84 (d, lH) ppm.
Exam~le 13 Benzhydryl 7-phenylacetamido-3-[(Z)-3-(3,3,3-trifluoro-propenyl]-3-cephem-4-carboxylate CH2- CO-NH ~ S

N ~

COOCH(C~Hs)2 A solution of 385 ml of methylene chloride and 38.5 ml of methanol, to which 257 mg (1.13 mmol) of 52d 134015~
-p-benzoylbenzoic acid have been added, is cooled to +8~C.
32.5 g tO.332 mol) of trifluoroacetaldehyde are added in the course of 10 minutes, whereupon the temperature of the solution is allowed to rise to +15~C. 5 minutes after the addition, 12.6 g (0.0166 mol) of benzhydryl 7-phenylacetamido-3-[(triphenylphosphoran-ylidene)methyl]-3-cephem-4-carboxylate (Example 12) are added, the low temperature bath is removed and the mixture is stirred at +35~C with exclusion of light and under nitrogen for 4 hours. The dark red solution is then concentrated to dryness and ether is added to the oil which remains, crystallization gradually starting.
Yield: 6.2 g (64.6% of theory) C31H25F3N2~4S (578.6) Calculated: C 64.35 H 4.36 N 4.84 S 5.54 F 9.85 Found: C 63.72 H 4.10 N 4.27 S 5.02 F 9.27 Exam~le 14 Benzhydryl 7-amino-3-[(Z)-3-(3,3,3-trifluoro-propenyl]-3-cephem-4-carboxylate H2N ~ S~ CF3 N ~

COOCH(C6Hs)2 6.0 g (0.0104 mol) of benzhydryl 7-phenylacetamido-3-[(Z)-3-(3,3,3-trifluoropropenyl]-3-cephem-4-carboxylate (Example 13) are dissolved in 64 ml of methylene chloride, the solution is cooled to -40~C with a dry ice bath and 2.1 ml 52e (0.026 mol) of pyridine and 2.17 g (0.0104 mol) of phosphorus pentachloride are added in succession. After 5 minutes, the mixture is allowed to warm to -20~C, and thereafter the temperature should rise to -10~C in the course of 20 minutes and finally to +10~C. The solution is now stirred at +10~C to +15~C for 1 hour. The mixture is subsequently cooled to -40~C, 70 ml of methanol (-30~C) are added and the mixture is stirred at +10~C for a further 30 minutes. The reaction solution is concentrated gently, the oil which is obtained is dissolved in 600 ml of methylene chloride, the solution is stirred into 800 ml of sodium bicarbonate solution and the mixture is stirred for 10 minutes. The methylene chloride phase is separated off, washed once with water and dried over sodium sulphate. The methylene chloride filtrate is chromatographed on 400 ml of silica gel (0.04 - 0.063 mm), elution being carried out first with methylene chloride and then with methylene chloride with the addition of methanol (gradient up to 10%). The eluate is investigated by means of analytical HPLC and thin layer chromatography (TLC: methylene chloride/methanol = 100:1).
Yield: 3.4 g (71.1% of theory) C23H19F3N2O3S (460.5) NMR (CDCl3): ~= 3.3 (d, lH); 3.48 (d, lH); 4.75 (d, lH); 4.98 (d, lH); 5.45 - 5.55 (d - q, lH); 6.07 (d, lH); 6.96 (s, lH);
7.23 - 7.42 (m, lOH); 8.6 (d, 2H) ppm.
Example 15 7-Amino-3-[(Z)-3-(3,3,3-trifluoro-propenyl]-3-cephem-4-carboxylic acid 52f o/~
COOH

3.1 g (6.73 mmol) of benzhydryl 7-amino-3-[(Z)-3-(3,3,3-trifluoropropenyl]-3-cephem-4-carboxylate (Example 14) are added to a stirred solution of 30 ml of trifluoroacetic acid (TFA) and 1.5 ml of anisole, which is cooled to 0~C. The mixture is stirred at room temperature for 1 hour and then concentrated at 30~C in vacuo and the oily residue is stirred with 100 ml of ether for 1 hour. The precipitate is filtered off with suction and washed with 50 ml of ether and the residue on the filter is dried in vacuo for 3 hours. The trifluoroacetate is suspended in 20 ml of water, the suspension is cooled to +5~C and the pH is brought to 0.2 -0.4 with 12 N HCl. The clear solution formed is cooled to +5~C and stirred with 300 mg of active charcoal for 10 minutes. The mixture is filtered with suction over kieselguhr and the residue is rinsed with about 20 ml of 0.1 N HCl. The filtrate is brought to pH 2.1 with 20% strength NaOH at +5~C
and the product which has precipitated out is left to stand in a refrigerator for 1 hour in order to bring the crystallization to completion. The crystal sludge is filtered off with suction, washed with 20 ml of water and 80 ml of acetone and dried in vacuo.

52g X

134015~

Yield: 1.45 g (73.2% of theory) C1oHgF3N2O3S (294.3) Calculated: C 40.81 H 3.08 N 9.52 S 10.89 F 19.37 Found: C 39.60 H 2.91 N 9.02 S 10.18 F 18.52 ExamPle 16 D-7-[(2-Aminobenzothiazol-6-yl)glycyl-amido]-3-[(Z)-3-(3,3,3-trifluoro-propenyl]-3-cephem-4-carboxylic acid, cis-isomer H2~

CH--CO-N~f F3 COOH

a) Activation of the precursor acid:

1.72 g [corresponds to 1.63 g (4.75 mmol)] of sodium D-~-[(1-methyl-2-methoxycarbonyl-vinyl)-amino]-(2-aminobenzothiazol-6-yl)acetate (content = 95%) are dissolved in 15 ml of dimethylformamide and the solution is then diluted with 7 ml of acetonitrile. The solution is cooled to -70~C, 40 ~l of 3-dimethylaminopropanol and 0.456 ml (4.75 mmol) of ethyl chloroformate are added in succession and the mixture is stirred at -70~C for 20 minutes.

52h ' _ 1340154 b) Preparation of the cephalosPorin comPonent 1.4 g (4.75 mmol) of 7-amino-3-[(Z)-3-(3,3,3-trifluoropropenyl]-3-cephem-4-carboxylic acid (Example 15) are suspended in 15 ml of dimethylformamide and 7 ml of acetonitrile and the suspension is converted into a clear solution by addition of 1 N sodium hydroxide solution (4.2 ml) to pH 8.5 at room temperature. The solution is cooled to -20~C to -30~C.
c) Couplinq, deblockinq and isolation of the crude betaine The cooled solution of the 3-trifluoropropenyl-cephalosporin b) (-20~C) is slowly added dropwise to the solution of the mixed anhydride of the precursor acid according to a) at -70~C and the mixture is subsequently stirred at -70~C for 10 minutes. The temperature of the solution is then allowed to come to 0~C in the course of 45 minutes (without cooling) and the solution is stirred with 150 mg of active charcoal and 500 mg of kieselguhr for a further 10 minutes. The reaction mixture is filtered over a Seitz filter, the residue is rinsed with a little dimethylformamide, and 1 ml of concentrated hydrochloric acid is added to the filtrate. The volume of the solution is concentrated to 25 ml, the salts which have precipitated out being separated off.
The filtrate is brought to pH 4.0 with 25% strength NH3 solution, while stirring with a magnetic stirrer, and 100 ml of acetone are added, whereupon the crude betaine precipitates 52i out. The precipitate is stirred for 10 minutes, filtered off with suction and rinsed with acetone and the material is dried in vacuo.
Yield: 1.9 g (74.5% of theory) The crude betaine is suspended in water and dissolved with half-concentrated hydrochloric acid at pH 1.2 and the solution is stirred with 190 mg of active charcoal for 15 minutes. The mixture is filtered with suction over a kieselguhr bed, the residue is rinsed with 15 ml of 0.1 N
hydrochloric acid and the filtrate is pumped onto an RP 18 column (Hibar 250-25, Merck). The column is eluted first with water and then with 5% strength methanol. The fractions are investigated by means of analytical HPLC and the fractions which contain the Z-isomer derivative are combined, the methanol is distilled off in vacuo and the aqueous solution is lyophilized.
Yield: 520 mg (31.7% of theory) ClgHl6F3NsO4s2 ~ 2H2~ (535-5) NMR (DCOOD): ~- 3.21 (d, lH); 3.52 (d, lH); 5.19 (d, lH); 5.78 - 5.91 (m, 3H); 6.25 (d, lH); 7.81 - 7.9 (q, 2H); 8.18 (s, lH) ppm.
ExamPle 17 D-7-[(2-Aminobenzothiazol-6-yl)glycylamido]-3-[(E)-3-(3,3,3-trifluoropropenyl]-3-cephem-4-carboxylic acid, trans-isomer 52j ' _ 134~

H2~
~S

~H--CO-O --N~--CF3 COOH

The trans-isomer compound is obtained as a by-product from the methanol-containing eluates of Example 16 by preparative HPLC separation on a Hibar column, RP-18.
IR: Nujol v max. 1780, 1690, 1620, 1520, 1470, 1380, 1350, 1280 cm~1 ExamPle 18 D-7-[(2-Aminobenzothiazol-6-yl)glycylamido]-3-[2-(3-pyridyl)vinyl]-3-cephem-4-carboxylic acid, cis-isomer H2~
~S

'l~3~CH--CO~

COOH

Trade-Mark 52k X

~ - 13~015A

Analogously to Example 16, 1.6 g, corresponding to 1.52 g (4.43 mmol) of sodium D-~-[(l-methyl-2-methoxy-carbonyl-vinyl)-amino]-(2-aminobenzothiazol-6-yl)acetate (content: 95%) are activated with 0.425 ml (4.43 mmol) of ethyl chloroformate with catalytic amounts of 3-dimethylaminopropanol in dimethylformamide/acetonitrile and reacted with a solution of 1.34 g (4.43 mmol) of 7-amino-3-[2-(3-pyridyl)vinyl]-3-cephem-4-carboxylic acid in dimethylformamide/acetonitrile and sodium hydroxide solution (lN).
After isolation of the crude betaine analogously to Example 16, the cis-isomer compound is purified with the aid of preparative HPLC.
Yield: 735 mg (30.5% of theory) C23H20N6o4s2 ~ 2H2~ (544-6) IR (Nujol), max.: 1775, 1690, 1620, 1530 cm~l.

Claims (21)

1. Compounds of the general formula (I) in which R1 represents hydrogen, or represents straight-chain or branched alkyl, cycloalkyl or alkenyl which has up to 6 carbon atoms and can be substituted by fluorine, chlorine, methoxy, cyano, phenyl, dimethylamino, hydroxyl or diethylamino, or represents phenyl, which can be substituted by fluorine, chlorine, methyl, methoxy, trifluoromethyl, amino or trifluoromethoxy, or represents chlorine, alkoxy or alkylsulphonyl with in each case up to 4 carbon atoms, mercapto, hydroxyl, SO3H, SO2NH2, guanidino, NH-NH2 or NH-OH, or represents a group of the formula -NHR6, wherein R6 denotes hydrogen, alkyl with up to 4 carbon atoms, phenyl, benzyl or an amino-protective group from the series comprising 4-methoxyphenyl, 4-methoxybenzyl,

2,4-dimethoxybenzyl, 3,4-di-methoxybenzyl and tert.-butyl-dimethylsilyl, R2 represents hydrogen, hydroxyl or NO2, R3 represents hydrogen, or represents 4-methoxyphenyl, 4-methoxybenzyl, 2,4-dimethoxybenzyl, 3,4-dimethoxybenzyl, tert.-butyl-dimethylsilyl, 1-methyl-2-methoxy-vinyl (MMV) or tert.-butoxycarbonyl (Boc), R4 represents hydrogen, or represents methyl, ethyl, tert.-butyl, diphenylmethyl, 2,2,2-trichloroethyl, allyl, acetoxymethyl, 4-nitrobenzyl, 2-nitrobenzyl, 4-methoxybenzyl, benzyl or trimethylsilylethyl, or represents a radical of the formula , -CH(CH3)-OCOOC2H5, or -CH2-OCO-C(CH3)3, and R5 represents chlorine, bromine, chloromethyl, trifluoromethyl, carboxyl, alkoxycarbonyl or alkylsulphonyloxy with in each case up to 4 carbon atoms, phenylsulphonyloxy, tolylsulphonyloxy, cyclopropyl, cyclopentyl, cyclohexyl, cyclopropylmethyl or cyclopentylmethyl, or represents alkinyl which has up to 4 carbon atoms and can be substituted by phenyl, carboxyl or alkoxycarbonyl with up to 4 carbon atoms, or represents phenyl, or represents a radical of the formula , or and salts thereof.

2. Compounds of the general formula (I) as defined in claim 1, wherein the double bond is in the Z-(cis) configuration.

3. Compounds of the general formula (I) as defined in claim 1 or 2, wherein the asymmetric carbon atom is in the D-form.

4. Compounds of the general formula (I) as defined in claim 1, 2 or 3 wherein R1 represents an NH2, cyclopropyl or methyl group.

5. Compounds of the general formula (I) as defined in any one of claims 1 to 4, wherein R2 represents a hydrogen atom or a hydroxy or nitro group.

6. Compounds of the general formula (I) as defined in any one of claims 1 to 5, wherein R3 represents a hydrogen atom or a tert.-butyloxycarbonyl group.

7. Compounds of the general formula (I) as defined in any one of claims 1 to 6, wherein R4 represents a hydrogen atom or a benzhydryl, methoxycarbonylmethyl or tert.-butoxycarbonyl-methyl group.

8. Compounds of the general formula (I) as defined in any one of claims 1 to 7, wherein R5 represents a chlorine atom or a cyclopropyl, cyclopropylmethyl, chloromethyl, trifluoromethyl, propyn-1-yl, phenylethynyl, 1,3-thiazol-5-yl, imidazol-2-yl, pyrazol-3-yl-thiomethyl, phenyl, 2-furyl or 3-pyridyl group.

9. Compounds of the general formula (I) as defined in claim 1 wherein the double bond is in the Z-(cis) configuration, the asymmetric carbon atom is in the D-form, R1 represents an NH2, cyclopropyl or methyl group, R2 represents a hydrogen atom or a hydroxy or nitro group. R3 represents a hydrogen atom or a tert.-butoxycarbonyl group, R4 represents a hydrogen atom or a benzhydryl, acetoxymethyl or tert.-butyryloxymethyl group and R5 represents a chlorine atom or a cyclopropyl, cyclopropylmethyl, trifluoromethyl, propyn-1-yl, phenylethynyl, 1,3-thiazol-5-yl, imidazol-2-yl, pyrazol-3-yl-thiomethyl, phenyl, 2-furyl or 3-pyridyl group.

10. Compounds of the general formula (I) as defined in claim 1, wherein the double bond is in the Z-(cis) configuration, the asymmetric carbon atom is in the D-form, R1 represents an NH2 group, R2 represents a hydrogen atom, R3 represents a hydrogen atom or a tert.-butyloxycarbonyl group, R4 represents a hydrogen atom or a benzhydryl group and R5 represents a cyclopropyl, trifluoromethyl or 3-pyridyl group.

11. The compound benzhydryl D-7-[2-(t-butoxycarbonyl-amino)-2-(2-aminobenzothiazol-6-yl)-glycylamido]-3-[(Z) -2-cyclopropyl-vinyl]-3-cephem-4-carboxylate or a pharmaceutically acceptable salt thereof.

12. The compound D-7-[(2-aminobenzothiazol-6-yl)-glycylamido]-3-[(Z)-2-cylopropyl-vinyl]-3-cephem-4-carboxylic acid or a pharmaceutically acceptable salt thereof.

13. The compound D-7-[(2-aminobenzothiazol-6-yl) glycylamido]-3-[(Z)-3-(3,3,3-trifluoropropenyl)]-3-cephem-4-carboxylic acid or a pharmaceutically acceptable salt thereof.

14. The compound D-7-[(2-aminobenzothiazol-6-yl)-glycylamido]-3-[(E)-3-(3,3,3-trifluoropropenyl)]-3-cephem-4-carboxylic acid or a pharmaceutically acceptable salt thereof.

15. The compound D-7-[(2-aminobenzothiazol-6-yl)-glycylamidol-3-[(Z)-2-(3-pyridylvinyl)]-3-cephem-4-carboxylic acid or a pharmaceutically acceptable salt thereof.

16. Process for the preparation of .beta.-lactam compounds of the general formula (I) in which R1 represents hydrogen, or represents straight-chain or branched alkyl, cycloalkyl or alkenyl which has up to 6 carbon atoms and can be substituted by fluorine, chlorine, methoxy, cyano, phenyl, dimethylamino, hydroxyl or diethylamino, or represents phenyl, which can be substituted by fluorine, chlorine, methyl, methoxy, trifluoromethyl, amino or trifluoromethoxy, or represents chlorine, alkoxy or alkylsulphonyl with in each case up to 4 carbon atoms, mercapto, hydroxyl, SO3H, SO2NH2, guanidino, NH-NH2 or NH-OH, or represents a group of the formula -NHR6, wherein R6 denotes hydrogen, alkyl with up to 4 carbon atoms, phenyl, benzyl or an amino-protective group from the series comprising 4-methoxyphenyl, 4-methoxybenzyl, 2,4-dimethoxy-benzyl, 3,4-di-methoxybenzyl and tert.-butyl-dimethylsilyl, R2 represents hydrogen, hydroxyl or NO2, R3 represents hydrogen, or represents 4-methoxyphenyl, 4-methoxybenzyl, 2,4-dimethoxybenzyl, 3,4-dimethoxybenzyl, tert.-butyl-dimethylsilyl, 1-methyl-2-methoxy-vinyl (MMV) or tert.-butoxycarbonyl (Boc), R4 represents hydrogen, or represents methyl, ethyl, tert.-butyl, diphenylmethyl, 2,2,2-trichloroethyl, allyl, acetoxymethyl, 4-nitrobenzyl, 2-nitrobenzyl, 4-methoxybenzyl, benzyl or trimethylsilylethyl, or represents a radical of the formula , -CH(CH3)-OCOOC2H5, or -CH2-OCO-C(CH3), and R5 represents chlorine, bromine, chloromethyl, trifluoromethyl, carboxyl, alkoxycarbonyl or alkylsulphonyloxy with in each case up to 4 carbon atoms, phenylsulphonyloxy, tolylsulphonyl-oxy, cyclopropyl, cyclopentyl, cyclohexyl, cyclopropylmethyl or cyclopentylmethyl, or represents alkinyl which has up to 4 carbon atoms and can be substituted by phenyl, carboxyl or alkoxycarbonyl with up to 4 carbon atoms, or represents phenyl, or represents a radical of the formula , or characterized in that, [A] a substituted cephalosporin compound of the general formula (II) in which R1 and R2 have the above mentioned meaning, R3 represents an amino-protective group, R4 represents a carboxyl-protective group and X represents a group of the formula ~(R-17)3Z~, or wherein R17 and R18 are identical or different and denote alkyl, phenyl or tolyl and Z denotes a halide anion, is reacted with an aldehydo of the general formula (III) R5-CHO (III) in which R5 has the abovementioned meaning, in an inert solvent in the presence of a base, or in that [B] a phosphonium compound of the general formula (IV) R5-CH2-X (IV) in which R5 has the abovementioned meaning and X represents a group of the formula , or wherein R17 and R18 are identical or different and denote alkyl, phenyl or tolyl and Z~ denotes a halide anion, is reacted with a cephalosporin aldehyde of the general formula (V) in which R1 and R2 have the abovementioned meaning, R3' represents an amino-protective group and R4' represents a carboxyl-protective group, in an inert solvent in the presence of a base, or in that [C] a carboxylic acid of the general formula (VI) in which R1 and R2 have the abovementioned meaning and R3' represents an amino-protective group, after activation of the carboxyl group by conversion into a mixed anhydride, or by conversion into the acid halide, or by conversion into an activated ester is reacted with a vinylcephalosporinamine of the general formula (VII) in which R4 and R5 have the abovementioned meaning, and, if appropriate, the protective groups are split off and the desired salts are prepared or the free acids are prepared from the salts.

17. An antibiotic composition which comprises a .beta.-lactam compound of formula (I) as defined in any one of claims 1 to 15 or a pharmaceutically acceptable salt thereof, together with a suitable diluent or carrier.

18. A composition according to claim 17 wherein the composition is an animal feed composition and the diluent or carrier is an animal feed.

19. A method of preparing a composition for use as an antibacterial agent, which method comprises incorporating a .beta.-lactam compound of formula (I) as defined in any one of claims 1 to 15 or a pharmaceutically acceptable salt thereof as active ingredient in the composition with a suitable diluent or carrier.

20. The use of a compound of formula (I) as defined in any one of claims 1 to 15, or a pharmaceutically acceptable salt thereof, as an antibactorial agent.

21. A commercial package containing as active ingredient a .beta.-lactam compound of formula (I) as defined in any one of claims 1 to 15, or a pharmaceutically acceptable salt thereof, together with instructions for the use thereof as an antibacterial agent.