BE879664A - NOVEL CEPHALOSPORINS, THEIR PREPARATION AND COMPOSITIONS CONTAINING THEM - Google Patents

Description

       

  New cephalosporins, their preparation

  
and compositions containing them The present invention relates to cephalosporin-like compounds which have valuable antibiotic properties.

  
The nomenclature of the cephalosporins which will be described in this memo will be made with reference to the "cephame" according to J. Amer. Chem. Soc.,
1962, 84, 3400, the term "cephem" referring to the basic cephalic structure comprising a double bond.

  
Antibiotics of the cephalosporin type are widely used for the treatment of diseases caused by pathogenic bacteria in both humans and animals and are more particularly suitable for the treatment of diseases caused by resistant bacteria other antibiotics, such as penicillin-like compounds, and the treatment of penicillin-sensitive patients. In certain circumstances, it is desirable to use a cephalosporin which shows activity against both Gram-positive and Gram-negative microorganisms, and a great deal of research has been carried out on the development of various types of broad spectrum cephalosporins.

  
Thus, for example, the British patent n [deg.] 1,399,086 relates more particularly to a new class of antibiotics of the type of cepha-

  
  <EMI ID = 1.1>

  
fié) -acylamido, the oxyimino group having the syn configuration. This class of antibiotic compounds is characterized by the fact of exerting a high antibacterial activity against a whole range of Gram-positive and Gram-negative organisms, activity combined with a particularly high stability towards

  
  <EMI ID = 2.1>

  
negative.

  
The discovery of this class of compounds has stimulated further research in the same field with a view to discovering new compounds with further improved properties, for example, compounds which exert activity against particular classes of organisms, in particular organisms Gram-negative.

  
British patent n [deg.] 1,496,757 relates to antibiotics of the cephalosporin type containing a 7p-acylamido group corresponding to the following formula:

  

  <EMI ID = 3.1>


  
(in which R represents a thienyl or furyl group, RA and RB can vary very strongly and can be, for example, C1-C4 alkyl groups or form a C3-C7 cycloalkylidene group with the carbon atom to which they are attached and

  
m and n are each equal to 0 or 1, so that the sum of m and n is equal to 0 or 1), the compounds being in the form of syn isomers or mixtures of syn isomers and anti containing at least 90% of the syn isomer. Position 3 of the cephalosporin molecule may not be substituted or may be substituted by a variety of possible substituents. These compounds have been found to exert particularly good activity against Gram-negative organisms.

  
Other compounds of similar structure have been developed from these substances in the course of ongoing research with the aim of discovering antibiotics having improved broad spectrum antibiotic activity and / or high activity against Gram-negative organisms. This research resulted not only in variations of the 7 & -acylamido group of formula (A) but also in the introduction of particular groups in position 3 of the cephalosporin molecule.

  
Thus, for example, in the specification of South African patent 78/1870, antibiotics of the cephalosporin type are described in which the side chain of type 7--acylamido is, among others, a group 2- (2-aminothiazole-4-yl) 2- (optionally substituted alkoxyimino) -acetamido and position 3 can be substituted, for example, by the radical -CH2Y where Y represents the remainder of a nucleophile. The abovementioned specification contains, among many other examples, references to compounds in which the optionally substituted alkoxyimino group mentioned above is a carboxyalkoxyimino or carboxycycloalkoxyimino radical.

  
As for position 3, it carries, among many other possible substituents, mono- and di-alkylaminomethyl radicals. South African patent 78/2168 amply describes compounds of the sulfoxide type corresponding to the sulfides described in South African patent 78/1870.

  
In addition, Belgian patent n [deg.] 836,813 relates to compounds of the cephalosporin type where the group R in formula (A) above can be replaced, for example, by a 2-aminothiazole-4- radical yl and the oxyimino group is a blocked hydroxyimino or hydroxyimino group, for example a methoxyimino group. In compounds of this type, position 3 of the cephalosporin molecule is substituted by a methyl group which can itself be optionally substituted by any of a very large number of residues of nucleophilic compounds described in the patent in question.

  
N-alkylaminomethyl groups are mentioned as possible substituents in position 3 but only the mono- and di-alkylaminomethyl radicals are specifically identified there.

  
In the aforementioned Belgian patent, no antibiotic activity is attributed to these compounds which are only mentioned therein as intermediates making it possible to prepare the antibiotics to which reference is made in its description.

  
It has now been discovered that by an appropriate choice of a small number of particular radicals

  
  <EMI ID = 4.1>

  
ammoniomethyl in position 3, it was possible to obtain compounds of the cephalosporin type having a particularly advantageous activity (described in more detail in the remainder of this document) against a whole series of pathogenic organisms which are very commonly encountered.

  
The present invention therefore more particularly relates to antibiotics of the cephalosporin type corresponding to the following general structural formula:

  

  <EMI ID = 5.1>


  
&#65533; -in which Ra and Rb which may be the same or different, each represents an alkyl group

  
  <EMI ID = 6.1>

  
straight, i.e. methyl, ethyl, n-propyl or n-butyl and, more particularly, methyl or ethyl), or Ra and. Rb form a cyclo- group <EMI ID = 7.1>

  
as well as the non-toxic salts and the metabolically labile and non-toxic esters of the compounds in question.

  
The compounds according to the invention are in the form of syn isomers. The syn isomer form is defined by the group configuration

  

  <EMI ID = 8.1>


  
compared to the carboxamido group. In this memo, the syn configuration can be described in structure as follows:

  

  <EMI ID = 9.1>


  
It should be understood that, since the compounds in accordance with the invention are geometric isomers, there can be a certain mixture

  
to the corresponding anti-isomer.

  
The scope of the present invention also extends to the solvates (in particular hydrates) of the compounds of formula (I). The invention also relates to the salts of esters of compounds corresponding to

  
  <EMI ID = 10.1>

  
The compounds according to the present invention may exist in tautomeric forms (for example with regard to the 2-aminothiazolyl group) and it should be understood that the scope of the present invention also extends to these tautomeric forms, for example the form 2- iminothiazolinyl. In addition, the compounds of the above-mentioned formula (I) can also exist in amphionic forms, for example when the 4-carboxyl group is protonated and the carboxyl group in the side chain in position 7 is deprotonated. The scope of the present invention obviously extends also to these amphionic forms as well as to mixtures of the amphionic forms.

  
It should also be understood that when Ra and Rb in the above formula represent radicals

  
  <EMI ID = 11.1>

  
to which they are attached includes an asymmetry center. An asymmetry center will also be present

  
  <EMI ID = 12.1>

  
different alkyl. These compounds constitute diastereoisomers and it is obvious that the scope of the invention extends both to individual diastereoisomers and to their mixtures.

  
The compounds according to the invention show a broad spectrum antibiotic activity, which activity is, moreover, unusually high against Gram-negative organisms. This high activity is exerted against numerous strains of Gram-negative microorganisms producing
(3-lactamases. The compounds according to the invention also have a high stability towards

  
  <EMI ID = 13.1>

  
Gram-positive and Gram-negative organisms.

  
The compounds according to the invention have been found to exert an unusually high activity against strains of organisms of the Pseudomonas type, for example strains of Pseudomonas aeruginosa, as also a high activity against various organisms belonging to the class of Enterobacteriaceae ( for example strains of the following microorganisms: Escherichia coli, Klebsiella pneumoniae, Salmonella typhimurium, Shigella sonnei, Enterobacter cloacae, Serratia marcescens, Providence species, Proteus mirabilis

  
and, more particularly, organisms of the genus Proteus indole-positive, such as Proteus vulgaris and Proteus morganii) and strains of Haemophilus influenzae.

  
The antibiotic properties of the compounds according to the present invention can very favorably compare to those of aminoglycosides, such as amikacin or gentamicin. This applies more particularly to their activity against strains of various organisms of the genus Pseudomonas

  
which are not sensitive to the majority of antibiotic compounds currently available on the market. Unlike aminoglycosides, cephalosporin-type antibiotics normally show only low toxicity in humans. The use of aminoglycosides in human therapy tends to be limited or complicated by the relatively high toxicity of these antibiotics. Antibiotics of the cephalosporin type according to the present invention therefore have potentially greater advantages than those of aminoglycosides.

  
The non-toxic salts which can be formed by the reaction of one or both carboxyl groups present in the compounds of general formula (I), include the salts with inorganic bases, such as the alkali metal salts (for example the sodium and potassium salts) and alkaline earth metal salts (e.g. calcium salts), salts with amino acids (e.g. salts with lysine and arginine), salts with bases organic (for example the salts with the following bases: procaine, phenylethylbenzylamine, dibenzylethylenediamine, ethanolamine, diethanolamine and N-methylglycosamine). Still other non-toxic salts include acid addition salts,

  
for example those generated with hydrochloric, hydrobromic, sulfuric, nitric, phosphoric, formic and trifluoroacetic acids. The salts in question may also be in the form of resinates generated, for example, with a polystyrene resin or a resin in a crosslinked polystyrene-divinylbenzene copolymer containing quaternary amino or amino groups or sulfonic acid groups, or with a resin containing carboxyl groups, for example a polyacrylic acid resin. It is also possible to use salts of soluble bases (for example alkali metal salts, such as sodium salts) of compounds corresponding to

  
the formula (I) in certain therapeutic applications, due to the very rapid distribution of these salts in the body after their administration. However, when you want to have

  
of insoluble salts of the compounds of formula (I) for a particular application, for example for the preparation of depot preparations, such salts can be formed in a conventional manner, for example by using suitable organic amines.

  
The aforementioned and other salts, such as the salts with toluene-p-sulfonic acids

  
  <EMI ID = 14.1>

  
intermediates for the preparation and / or purification of the compounds of formula (I), for example in accordance with the methods described hereinafter.

  
Metabolically labile and non-toxic esters which can be formed by esterification of one or both carboxyl groups present in the compound of formula (I) include acyloxyalkyl esters, for example oxy-methyl (lower alkanoyl) esters or ( lower alkanoyl) oxyethyl, such as acetoxymethyl or acetoxyethyl or pivaloyloxymethyl esters. In addition to the above-mentioned esters, the scope of the present invention also extends to the compounds of formula (I) which

  
are in the form of other physiologically acceptable equivalents, i.e. physiologically acceptable compounds which, like metabolically labile esters, are converted in vivo to related antibiotic compounds

  
  <EMI ID = 15.1>

  
The preferred compounds in accordance with the invention include the compounds of formula (I) in which R <1>, R <2> and R <3> all represent methyl groups. Preference is also given to compounds in which Ra and Rb both represent methyl groups or form a cyclobutylidene radical with the carbon atom to which they are attached.

  
  <EMI ID = 16.1>

  
ammoniomethyl-ceph-3-th-4-carboxylate and its non-toxic salts, as also its metabolically labile and non-toxic esters, constitute compounds in accordance with the invention which are very particularly advantageous. Other compounds according to the invention also

  
  <EMI ID = 17.1>

  
(2-aminothiazole-4-yl) -2- (2-carboxyprop-2-oxyimino) acetamido7-3-trimethylammoniomethyl-ceph-3-th-4-carboxylate acid and its non-toxic salts as also its metabolically labile and non-toxic esters.

  
Still other compounds according to the present invention include, for example, those

  
  <EMI ID = 18.1>

  
the tables which end this memo.

  
The compounds of the formula can be used
(I) to treat a variety of diseases caused by pathogenic bacteria in humans and animals, such as respiratory tract infections and urinary tract infections.

  
In accordance with another of its characteristics, the present invention also relates to a process for the preparation of an antibiotic compound corresponding to the formula of general structure (I) as defined above or of an atoxic salt or of a metabolically ester labile and non-toxic of such a compound, characterized in that:
(A) a compound corresponding to the following general structural formula is acylated:

  

  <EMI ID = 19.1>


  
  <EMI ID = 20.1>

  
positions 2, 3 and 4 indicates that the compound is a substance of the ceph-2-th or ceph-3-th 7 type or a salt, for example an acid addition salt (formed, for example, with an acid mineral such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid or phosphoric acid or an organic acid, such as methane-sulfonic acid or toluene-p-sulfonic acid) or an N-silyl derivative of such a compound, or a corresponding compound having a group of the formula -COOR in position 4 [pound] -oÙ R4 represents a hydrogen atom or a group blocking the carboxyl function, for example the residue of an esterogenic araliphatic or aliphatic alcohol or a stannanol, a silanol or an esterogenic phenol (said alcohol, phenol, silanol or stannanol preferably comprising

  
1 to 20 carbon atoms) 7 and having an anion

  
  <EMI ID = 21.1>

  
chloride or bromide, or trifluoroacetate,

  
using an acid of the following formula:

  

  <EMI ID = 22.1>


  
(in which Ra and Rb have the meanings previously indicated, R5 represents a group blocking the carboxyl function, for example as described for R4 and R6 represents a protected amino or amino group) or using an acylating agent which there matches;
(B) reacting a compound of the following general structural formula
  <EMI ID = 23.1>
  <EMI ID = 24.1>

  
interrupted have the meanings previously indicated, R7 and R7a can independently represent hydrogen atoms or groups blocking the carboxyl function and X represents the replaceable residue of a nucleophile, for example

  
an acyloxy group, such as a dichloroacetoxy radical or a halogen atom, such as chlorine, bromine or iodine) or a salt of such a compound,

  
on a tertiary amine of the following formula:

  

  <EMI ID = 25.1>


  
(in which R <1>, R <2> and R <3> have the meanings previously indicated); or
(C) a compound of the following general structure is alkylated:

  

  <EMI ID = 26.1>
 

  
  <EMI ID = 27.1>

  
dashed lines have the meanings previously indicated and R7 and R7a both represent radicals blocking the carboxyl function),

  
using an alkylating agent used to form a group of the formula:

  

  <EMI ID = 28.1>


  
in position 3;

  
and then, if this proves necessary and / or desirable in each case, any of the following reactions are carried out, in any desired order:

  
  <EMI ID = 29.1>

  
iii) conversion of a carboxyl group into an atoxic salt or into a metabolically labile and atoxic ester function, and

  
iv) removal of any blocking groups

  
the carboxyl and / or N-protective function.

  
In the above-mentioned process (A), the starting material of formula (II) is preferably a compound in which the dashed line represents a substance of the ceph-3-th type.

  
Acylating agents which can be used for the preparation of the compounds of the formula
(I) include acid halides, in particular bromides or chlorides. Such acylating agents can be prepared by reacting an acid of the formula (III) or a salt of such a compound with a halogenating agent, for example, penta-phosphorus chloride, thionyl chloride or chloride of oxalyl.

  
Acylations carried out using acid halides can be carried out in aqueous and non-aqueous reaction media, conveniently at temperatures which vary from -50 to +50 [deg.] C, preferably from -20 to +30 [ deg.] C, if desired in the presence of an acid-binding agent. Suitable reaction media include aqueous ketones, such as aqueous acetone, esters, such as ethyl acetate, halogenated hydrocarbons, such as methylene chloride, amides, such as

  
  <EMI ID = 30.1>

  
acetonitrile or mixtures of two or more of two such solvents. Mention may be made, as agents fixing the appropriate acids, of tertiary amines.

  
(eg triethylamine or dimethylaniline), inorganic bases (eg calcium carbonate or sodium bicarbonate) and oxiranes, such as lower 1,2-alkylene oxides (eg ethylene oxide or propylene oxide) which bind or fix the hydrohalic acid released during the acylation reaction.

  
The acids of formula (III) can themselves be used as acylating agents for the preparation of compounds of formula (I). Acylations performed using acids of the formula
(III) are advantageously carried out in the presence of a condensing agent, for example, a carbodiimide, such as N, N'-dicyclohexylcarbodiimide or N-ethyl-N'-Y-dimethylaminopropylcarbodiimide, a carbonyl compound, such as carbonyldiimidazole,

  
or an isoxazolium salt, such as N-ethyl-5-phenylisoxazolium perchlorate.

  
It is also possible to carry out the acylation with other amidogenic acid derivatives of formula (III), such as, for example, an activated ester, a symmetrical anhydride or a mixed anhydride (formed, for example, with pivalic acid or with a haloformate, such as a lower alkyl haloformate). It is also possible to form mixed anhydrides with phosphorus acids (for example phosphoric acid or phosphorous acid), sulfuric acid or aliphatic or aromatic sulfonic acids
(e.g. toluene-p-sulfonic acid). One can conveniently form an activated ester in situ using, for example, 1-hydroxy-benzotriazole, in the presence of a condensing agent as described above. You can also preform the activated ester.

  
The acylation reactions involving the free acids or their amidogenic derivatives mentioned above are advantageously carried out in an anhydrous reaction medium, for example methylene chloride, tetrahydrofuran, dimethylformamide or acetonitrile.

  
If desired, the above reactions can be carried out in the presence of a catalyst,

  
such as 4-dimethylaminopyridine.

  
If desired, the acids of formula (III) and the corresponding acylating agents can be prepared and used in the form

  
of their acid addition salts. Thus, for example, the acid chlorides can conveniently be used in the form of their hydrochlorides and

  
acid bromides in the form of their hydrobromides.

  
The amino compound of formula (V) can act as a nucleophile to displace a whole series of X substituents of the cephalosporin of formula (IV). To some extent, the ease

  
  <EMI ID = 31.1>

  
substitute comes from. Thus, atoms or groups X which come from strong acids tend, in general, to be more easily displaced than atoms or groups which come from weak acids. The ease of displacement is also related, to some extent, to the precise identity of the alkyl groups in the compound of formula (V).

  
The displacement of X by the amine of formula (V) can conveniently be carried out while maintaining the reagents in solution or in suspension. The reaction is advantageously carried out using from 1 to 20,

  
preferably 1 to 4, moles of the amine (V).

  
The nucleophilic displacement reactions can conveniently be carried out on compounds of formula (IV) in which the substituent X is

  
a halogen atom or an acyloxy group, for example as described below.

  
Acyloxy groups

  
Convenient starting materials to be used for carrying out the nucleophilic displacement reaction with the amine of formula (V) include the compounds of formula (IV) in which X represents the residue of a substituted acetic acid, for example chloracetic acid, dichloracetic acid and trifluoroacetic acid.

  
The substituent X can also come from

  
  <EMI ID = 32.1>

  
chloroformic acid or a carbamic acid.

  
When using a compound of the formula
(IV) in which X represents a substituted acetoxy group, it is generally desirable for the group R7 in formula (IV) to be a hydro-

  
  <EMI ID = 33.1>

  
advantageously kills the reaction in an aqueous medium, preferably at a pH of 5 to 8, in particular of

  
5.5 to 7.

  
The above-mentioned process using the compounds of formula (IV) in which X represents

  
the remainder of a substituted acetic acid can be carried out as described in British Patent No. [deg.] 1,241,657.

  
When using compounds of formula (IV) in which X represents an acyloxy group, the reaction is conveniently carried out at a temperature of -20 [deg.] To +80 [deg.] C, preferably 0 [ deg.] to +50 [deg.] C.

  
Halogens

  
Compounds of formula (IV) in which X represents a chlorine, bromine or iodine atom can advantageously be used as starting materials for carrying out the nucleophilic displacement reaction with the amine of the formula (V).

  
When using compounds of formula (IV)

  
  <EMI ID = 34.1>

  
may represent a group blocking the carboxyl function. The reaction is conveniently carried out in a nonaqueous medium which preferably comprises one or more organic solvents, advantageously ethers, for example dioxane or tetrahydrofuran, esters, for example ethyl acetate, amides, for example formamide and N, Ndimethylformamide and ketones, for example acetone. Other suitable organic solvents are described in more detail in British Patent No. [deg.] 1,326,531. The reaction medium should be neither extremely acidic nor extremely basic. In the . cases of reactions carried out on compounds of the <EMI ID = 35.1>

  
blocking the carboxyl function, the 3-trialkylammoniomethyl product will be obtained in the form of the salt of the corresponding halide type which can, if desired, be subjected to one or more ion exchange reactions in order to obtain a salt comprising the desired anion.

  
When using compounds of formula (IV) in which X represents a halogen atom as described above, the reaction is conveniently carried out at a temperature which fluctuates from -10 [deg.] To +50 [deg .] C, preferably from +10 to +30 [deg.] C.

  
In process (C) above, the 3-di- (C1-C4 alkyl) aminomethyl compound of formula (VI) is advantageously reacted with an agent for

  
  <EMI ID = 36.1>

  
R <3> has the meanings previously indicated and Y represents a labile group, such as a halogen atom (for example iodine, chlorine or bromine) or a hydrocarbylsulfonate group (for example

  
  <EMI ID = 37.1>

  
dimethyl sulfate. The alkylation reaction is preferably carried out at a temperature which varies

  
from 0 to 60 [deg.] C, advantageously from 20 to 30 [deg.] C. The reaction can conveniently be carried out in an inert solvent, such as an ether, for example tetrahydrofuran, an amide, for example dimethylformamide or a halogenated hydrocarbon, for example dichloromethane. On the other hand, when the alkylating agent is a liquid under the reaction conditions, this agent can itself serve as a solvent.

  
The compound of formula (VI) used as starting material for the implementation of process (C) can be prepared, for example, by reaction of a compound of formula (IV) (as defined above) on a secondary amine of

  
the formula :

  

  <EMI ID = 38.1>
 

  
(in which R <1> and R2 have the meanings previously indicated) in a manner analogous to the nucleophilic displacement reaction described in connection with method (B). This reaction is preferably carried out in the presence of an acid-fixing agent. The amine itself can serve as an acid-binding agent.

  
The reaction product can be separated from the reaction mixture which may contain, for example, unchanged cephalosporin starting material and other substances, by the use of a variety of methods including recrystallization,

  
  <EMI ID = 39.1>

  
use of ion exchangers (for example by chromatography on ion exchange resins) or macroreticular resins.

  
  <EMI ID = 40.1>

  
in accordance with the implementation of the method according to the invention can be converted into derivatives 63 corresponding to

  
  <EMI ID = 41.1>

  
with a base, such as pyridine or triethylamine.

  
It is also possible to oxidize a reaction product of the ceph-2-th type so as to obtain the corresponding 1-oxide of ceph-3-th, for example, by reaction on a peracid, for example the acid.

  
  <EMI ID = 42.1>

  
sulfoxide thus obtained can, if desired, be subsequently reduced as described below to give the corresponding ceph-3-th sulfide.

  
When we obtain a compound in which

  
  <EMI ID = 43.1>

  
corresponding sulfide, for example, by reduction of the corresponding acyloxysulfonium or alkoxysulfonium salt, prepared in situ by reaction on, for example, acetyl chloride in the case of an acetoxysulfonium salt, the reduction being carried out,

  
for example, using sodium dithionite or using iodide ions, as in a solution of potassium iodide in a water-miscible solvent, for example, acetic acid, acetone , tetrahydrofuran, dioxane, dimethylformamide or

  
dimethylacetamide. The reaction can be carried out

  
at a temperature that fluctuates from -20 to +50 [deg.] C.

  
The metabolically labile ester type derivatives of the compounds of formula (I) can be prepared by reacting a compound of the formula
(I) or a protected salt or derivative of such a compound, on a suitable esterifying agent, such as an acyloxyalkyl halide (for example iodide), conveniently in an inert organic solvent, such as dimethylformamide or acetone, this reaction being followed, if necessary, by the elimination of any protective groups.

  
The salts with bases of the compounds of formula (I) can be formed by reacting an acid of formula (I) with the appropriate base. Thus, for example, the sodium or potassium salts can be prepared using the respective 2-ethylhexanoate or bicarbonate. Acid addition salts can be prepared by reacting a compound of formula (I) or a metabolically labile ester type derivative of such a compound on the appropriate acid.

  
When you get a compound of the form

  
  <EMI ID = 44.1>

  
can obtain the syn isomer, for example, by carrying out convenient methods, such as crystallization or chromatography.

  
For use as starting materials for the preparation of compounds of the formula

  
  <EMI ID = 45.1>

  
preferably uses compounds of the general formula (III) and acid halides and anhydrides which correspond to them, in the syn isomer form or in the form of mixtures of the syn isomers and the corresponding anti isomers, containing at least
90% of the syn isomer.

  
We can prepare the acids of the formula
(III) (provided that Ra and Rb form a cyclopropylidene group with the carbon atom to which they are attached) by the etherification of a compound of the formula below:

  

  <EMI ID = 46.1>


  
(in which R6 has the above meanings

  
  <EMI ID = 47.1>

  
boxyle), by reaction on a compound of the general formula below:

  

  <EMI ID = 48.1>


  
(in which Ra, Rb and R5 have the meanings indicated above and T represents a halogen atom, such as chlorine, bromine or iodine, a sulphate group or a sulphonate group, such as tosylate), this reaction being followed of the remover

  
  <EMI ID = 49.1>

  
The separation of the isomers can be carried out either before or after the etherification in question.

  
The etherification reaction is generally carried out in the presence of a base, for example potassium carbonate or sodium hydride and it is advantageously carried out in an organic solvent, for example dimethyl sulfoxide, a cyclic ether, such as tetrahydrofuran or dioxane, or an N, N-disubstituted amide, such as dimethylformamide. Under these conditions, the configuration of the oxyimino group is substantially unchanged by the etherification reaction. The reaction must be carried out in the presence of a base if an acid addition salt of a compound of formula (VIII) is used. The base should be used in an amount sufficient to quickly neutralize the acid in question.

  
The acids of general formula (III) can also be prepared by the reaction of a compound of the following formula:

  

  <EMI ID = 50.1>


  
  <EMI ID = 51.1>

  
previously indicated) on a compound of the formula

  

  <EMI ID = 52.1>


  
  <EMI ID = 53.1>

  
  <EMI ID = 54.1>

  
removal of the group blocking the carboxyl function R8 and, when necessary, separation of the syn and anti isomers.

  
The last mentioned reaction applies particularly well to the preparation of the acids of formula (III) in which Ra and Rb form a cyclopropylidene group with the carbon atom to which they are attached. In this case, the concerned compounds of formula (XI) can be prepared in a conventional manner, for example, by implementing the synthesis described in Belgian patent n [deg.] 866.422 for the preparation of 1-amino-oxycyclopropane t-butyl carboxylate.

  
We can convert the acids of the formula
(III) into corresponding acid anhydrides and halides and acid addition salts by carrying out conventional methods, for example, as described above.

  
When X represents a halogen atom
(for example, chlorine, bromine or iodine) in

  
the formula (IV), it is possible to prepare the starting compounds of the ceph-3-th type in a conventional manner, by

  
  <EMI ID = 55.1>

  
7 &#65533; -amino protected-3-methylceph-3-th-4-carboxylate, elimination of the 79-protective group, acylation of the compound of type 7 &#65533; -amino thus obtained so as

  
  <EMI ID = 56.1>

  
in a manner analogous to the above-mentioned method (A), this operation being followed by the reduction of the 1-oxide group later during the reaction sequence. This process is described in British patent n [deg.] 1,326,531. The corresponding ceph-2-th type compounds can be prepared by implementing the process described in published Dutch patent application no [deg.] 6,902,013 by reaction of the 3-methylceph-2-th type compound on the N-bromosuccinimide, so as to generate the compound of the corresponding 3-bromomethylceph-2-th type.

  
When X in formula (IV) represents an acetoxy group, the starting materials in question can be prepared, for example, by acylation of 7-aminocephalosporanic acid, for example, in a manner analogous to that described in connection with process
(A) above. The compounds of formula (IV) in which X represents other acyloxy groups can be prepared by acylation of the corresponding 3-hydroxymethyl compounds which can be prepared, for example, by the hydrolysis of suitable 3-acetoxymethyl compounds, for example, as described in British Patents No. [deg.]
1,474,519 and 1,531,212.

  
The starting materials of formula (II) are new compounds. These new compounds can be prepared in a conventional manner, for example, by deprotecting a protected 7-amino compound corresponding in a conventional manner, for example,

  
  <EMI ID = 57.1>

  
It should be understood that in some of the above-mentioned transformations, it may be necessary to protect any sensitive groups in the molecule of the compound in question to avoid the appearance of undesirable side reactions. For example, during any of the reactions in the above-mentioned reaction sequence, it may be necessary to protect the NH2 group from the aminothiazolyl radical, for example by tritylation, acylation (for example chloroacetylation), protonation or any other process suitable. The protecting group can then be removed in any convenient manner which does not cause degradation of the desired compound, for example, in the case of a trityl group, using an optionally halogenated carboxylic acid, for example acetic acid, formic acid, chloracetic acid

  
or trifluoroacetic acid, or by using a mineral acid, for example hydrochloric acid or mixtures of such acids, preferably in the presence of a protic solvent, such as water, or, in the case of a chloracetyl group, by treatment with thiourea.

  
The groups blocking the carboxyl function used for the preparation of the compounds of formula (I) or for the preparation of the necessary starting materials are advantageously groups which can easily be separated during a suitable stage from the following reactions, conveniently during the last step of this sequel. However, it may be convenient in certain circumstances to use metabolically labile and non-toxic carboxyl blocking groups, such as acyloxymethyl or acyloxyethyl (e.g. acetoxymethyl or acetoxyethyl or pivaloyloxymethyl) groups' and to keep these groups in the final product. so as to obtain a suitable ester type derivative of a compound of formula (I).

  
Suitable carboxyl blocking groups are well known to those skilled in the art, a list of illustrative blocked carboxyl groups may be found in British Patent No. [deg.] 1,399,086. Preferred blocked carboxyl groups include aryl (lower alkoxy) carbonyl radicals, such as p-methoxybenzyloxycarbonyl, p-nitrobenzyloxycarbonyl and diphenylmethoxycarbonyl; carbonyl (lower alkoxy) groups, such as t-butoxycarbonyl and halo (lower alkoxy) carbonyl groups, such as 2,2,2-trichlorethoxycarbonyl.

  
The carboxyl blocking group or groups can subsequently be removed using any of the suitable methods described in the literature; thus, for example, hydrolysis catalyzed using an acid or a base applies in many cases, just like hydrolyses

  
with enzymatic catalysis.

  
The examples which follow illustrate the present invention without however limiting the latter. All the temperatures shown in the examples appear in degrees Celsius. The term "petroleum" designates petroleum ether (P.E. 40-60 [deg.]). Preparation 1

  
(Z) -2- (2-Aminothiazole-4-yl) -2- (hydroxyimino) ethyl acetate

  
To a stirred solution and cooled to

  
  <EMI ID = 58.1>

  
glacial acetic acid (296 ml), a solution of sodium nitrite (180 g) in water was added
(400 ml) at a rate such that the reaction temperature is kept below 10 [deg.] C. Stirring and cooling were continued for approximately

  
30 minutes, then a solution of potassium chloride (160 g) in water (800 ml) was added. The mixture thus obtained was stirred for one hour.

  
The lower oil phase was separated and the aqueous phase was extracted with diethyl ether. The extract was combined with the oil, the whole washed successively with water and saturated brine, dried and evaporated. The residual oil, which solidified on standing, was washed with petroleum and dried under vacuum over potassium hydroxide, so as to obtain (Z) -2- (hydroxyimino) -3-oxobutyrate d 'ethyl (309 g).

  
An ice-cold stirred solution of ethyl (Z) -2- (hydroxyimino) -3-oxobutyrate (150 g) in dichloromethane (400 ml) was treated dropwise with sulfuryl chloride ( 140 g). The solution thus obtained was kept at room temperature for 3 days, then evaporated. The residue was dissolved in diethyl ether, the solution was washed with water until

  
the washing liquors were practically neutral. After 30 minutes, t-butyl 1-bromocyclobutanecarboxylate (29.2 g) was added. After 8 hours, another 31.2 g of potassium carbonate was added. An additional amount of potassium carbonate (6 fractions of 16 g) was added over the next three days and then an additional amount of t-butyl 1-bromocyclobutanecarboxylate (3.45 g) was added after three days. After a total of four days, the mixture was poured into ice water (about 3 liters) and the solid formed was collected by filtration and washed well with water and petroleum. The solid was dissolved in ethyl acetate and the solution was washed with brine (twice), dried with

  
  <EMI ID = 59.1>

  
obtaining a foam. This foam was dissolved in a mixture of ethyl acetate and petroleum
(1: 2) and filtered through silica gel
(500 g). Evaporation gave the title compound (60 g) as a foam

  
  <EMI ID = 60.1>

  
Preparation 6

  
  <EMI ID = 61.1>

  
2- (2-tritylaminothiazole-4-yl) acetic

  
A mixture of the product of preparation 5 (3.2 g) and potassium carbonate was heated
(1.65 g) at reflux in methanol (180 ml) and water (20 ml) for 9 hours and the mixture was cooled to room temperature. The mixture was concentrated and the residue was partitioned between ethyl acetate and water, to which 2N hydrochloric acid (12.2 ml) was added. The organic phase was separated and the aqueous phase was extracted with ethyl acetate. The combined organic extracts were washed with saturated brine, dried and evaporated to give the compound indicated in, then the solution was dried and evaporated. The residual oil (177 g) was dissolved in ethanol
(500 ml) and dimethylaniline (77 ml) and thiourea (42 g) were added. After two hours, we have

  
  <EMI ID = 62.1>

  
ethanol and then dried to obtain the title compound (73 g); P.F. 188 [deg.]
(decomp.).

  
Preparation 2

  
(Z) -2-hydroxyimino-2- (2-tritylaminothiazole-4-yl) ethyl acetate, hydrochloride

  
Trityl chloride (16.75 g) was added, in portions and over two hours, to a stirred and cooled solution (-30 [deg.]) Of the product of Preparation 1 (12.91 g ) and triethylamine (8.4 ml) in dimethylformamide (28 ml). The mixture was allowed to warm to 15 [deg.] Over the course of an hour, stirred for two more hours and then partitioned between water (500 ml) and ethyl acetate (500 ml). The organic phase was separated, washed with water (2 x

  
500 ml) and then shaken with 1N hydrochloric acid (500 ml). The precipitate was collected, washed successively with water

  
  <EMI ID = 63.1>

  
ether (200 ml) and dried in vacuo to give the title compound as a white solid (16.4 g); P.F. 184 to 186 [deg.]
(decomp.).

  
Preparation 3

  
(Z) -2- (2-t-butoxycarbonylprop-2-oxyimino) -2- (2tritylaminothiazole-4-yl) ethyl acetate

  
Potassium carbonate (34.6 g) and t-butyl 2-bromo-2-methylpropionate (24.5 g) were added to a solution stirred under nitrogen of the product of preparation 2 (49, 4 g) in dimethyl sulfoxide (200 ml) and the mixture was stirred at room temperature for 6 hours. The mixture was poured into water (2 L), stirred for

  
10 minutes and it was filtered. The solid was washed with water and dissolved in ethyl acetate
(600 ml). The solution was washed successively with water, 2N hydrochloric acid, water and saturated brine, then dried and evaporated. The residue was recrystallized from petroleum so as to obtain the title compound

  
(34 g), P.F. 123.5 to 125 [deg.].

  
Preparation 4

  
Acid (Z) -2- (2-t-butoxycarbonylprop-2-oxyimino) -2-
(2-tritylaminothiazole-4-yl) acetic

  
The product of preparation 3 was dissolved
(2 g) in methanol (20 ml) and 2N sodium hydroxide (3.3 ml) was added thereto. The mixture was heated at reflux for 1.5 hours and then concentrated. The residue was taken up in a mixture of water (50 ml), 2N hydrochloric acid

  
(7 ml) and ethyl acetate (50 ml). We separated

  
the organic phase and the aqueous phase was extracted with ethyl acetate. The organic solutions were combined, washed successively with water and saturated brine, then dried and evaporated. The residue was recrystallized from a mixture of carbon tetrachloride and petroleum

  
so as to obtain the compound indicated in the title (1 g), m.p. 152 to 1560 (unpacked).

  
Preparation 5

  
  <EMI ID = 64.1>

  
carbonylcyclobut-1-oxyimino) ethyl acetate

  
The product of preparation 2 was stirred
(55.8 g) under nitrogen, in dimethyl sulfoxide (400 ml), with potassium carbonate
(finely ground, 31.2 g), at room temperature.

  
  <EMI ID = 65.1>

  
diphenylmethyl, 1-oxide

  
A solution of the product of preparation 4 (0.526 g) was treated in dry tetrahydrofuran
(6 ml) with 1-hydroxybenzotriazole monohydrate
(0.141 g) and N, N-dicyclohexylcarbodiimide (0.198 g) in tetrahydrofuran (4 ml). The developing suspension was stirred for 30 minutes at 23 [deg.]

  
and then we filtered it. We processed a solution

  
(1S, 6R, 7R) -7-amino-3-bromomethyl ceph3-th-4-carboxylic acid 1-oxide (0.427 g)

  
in dichloromethane (260 ml), at 23 [deg.], with the above-mentioned filtrate. The solution was stirred for 18 hours at 20-25 [deg.], Evaporated to dryness and the residue was dissolved in dichloromethane and the solution thus obtained was washed successively with a saturated aqueous solution of sodium bicarbonate, water and brine, then dried and evaporated in vacuo to obtain a foam (1.0 g).

  
This foam was purified by chromatography on preparative silica plates using a mixture of toluene, ethyl acetate and acetic acid (190: 50: 2.5) as eluent. The purified product was isolated in the form of a foam which was dissolved in ethyl acetate (5 ml) and then precipitated from petroleum (200 ml), so as to collect the compound. indicated in the title

  
  <EMI ID = 66.1>

  
  <EMI ID = 67.1>

  
  <EMI ID = 68.1>

  
Diphenylmethyl 3-trimethylammoniomethylceph-3-th-4-carboxylate, 1-oxide, bromide

  
The product from step (a) was stirred (0.154 g), alumina-dried tetrahydrofuran (0.3 ml) and dry trimethylamine in dry tetrahydrofuran (0.155 g of trimethylamine in 1 ml of solution)
(0.065 ml) at 24 [deg.], For one hour. The reaction mixture was added dropwise to suitably stirred ether (220 ml) and the suspension thus obtained was vigorously stirred for 10 minutes. The solid was separated by filtration, washed with ether and dried in vacuo to collect the title compound (0.131 g) m.p.

  
  <EMI ID = 69.1>

  
Diphenylmethyl 3-trimethylammoniomethylceph-3-th-4-carboxylate, iodide

  
The product from step (b) (1.87 g) and acetone (4.7 ml) was stirred at -10 [deg.] C until a solution was obtained. Dry powdered potassium iodide (1.14 g) was added and the mixture was stirred.

  
  <EMI ID = 70.1>

  
dry powdery potassium iodide (1.14 g), then acetyl chloride (0.25 ml) was added and the vigorously stirred mixture was allowed to warm to 0 [deg.] 20 minutes. The mixture was stirred at 0 to +2 [deg.] For one hour. The mixture was added dropwise to a stirred solution of sodium metabisulfite
(0.850 g) in water (47 ml). The solid thus obtained was separated by filtration, washed with water and dried under vacuum over phosphorus pentoxide so as to obtain a solid (1.939 g).

  
The procedure described above was repeated using the solid (1.87 g), acetone (4.7 ml), dry powdery potassium iodide (1.14 g), chloride d acetyl (0.25 ml) and a reaction time at a temperature of 0 to +2 [deg.] of 25 minutes. The compound indicated in the title was thus obtained (1.951 g) under

  
  <EMI ID = 71.1> oxyimino) -2- (2-tritylaminothiazole-4-yl) -acetamido73-diphenylmethyl-triethylammoniomethyl ceph-3-th-4-carboxylate, trifluoroacetate

  
The product from step (c) has been dissolved

  
(1.826 g) in a mixture of acetone and ethanol (9: 1) and it was chromatographed on an ion exchange resin "Deacidite" FF SRA 62 (highly anion exchange resin) in the trifluoroacetate form . We

  
eluted the column with the above-mentioned solvent mixture. A 20 ml overhead fraction was discarded and the next 250 ml was immediately evaporated in vacuo

  
so as to obtain the compound indicated in the title
(1.595 g) in the form of a foam of reddish brown color.

  
  <EMI ID = 72.1>

  
niomethylceph-3-th-4-carboxylate

  
The product from step (d) (1.37 g), anisole (1.37 ml) and trifluoroacetic acid were stirred
(5.5 ml) at 25 [deg.] For a minute and a half, so that a solution formed and then stirred for an additional minute. The volatile material was evaporated and the residue was subjected to azeotropic distillation with toluene (twice). The gum was dissolved in acetone (10 ml) and precipitated in petroleum (500 ml). The brown solid was separated by filtration, washed with petroleum ether and dissolved in acetone. The solution was evaporated until a foam (1.117 g) was obtained.

  
The foam (1.117 g), anisole was stirred

  
  <EMI ID = 73.1>

  
for 5 minutes. The volatile material was removed and the residue was azeotropically distilled with toluene (twice). The brown oil thus obtained was precipitated with acetone (10 ml) and petroleum ether (P.E. 40-60 [deg.] - 500 ml), so as to obtain a solid (1.066 g).

  
The solid (0.2 g) was dissolved in a mixture of trifluoroacetic acid and water (1: 1 - 2 ml) and the solution was stirred at 28 [deg.] For 30 minutes. The mixture was evaporated to dryness and the gum thus obtained was dissolved in water (10 ml). The double solution was separated by filtration, the residue was washed with water (10 ml, 5 ml) and the filtrate was dried by freezing so as to obtain a foam (0.17 g). The foam was triturated with ether, the solid obtained was quickly filtered and dried under vacuum so as to collect the title compound (0.148 g), in the form of a solid associated with 1.8.mole of trifluoraceous acid-

  
  <EMI ID = 74.1> carbonylcyclobut-1-oxyimino) -2- (2-tritylaminothiazole-4-yl) acetamido7-diphenylmethyl acetamido7-1-oxide

  
An agitated solution of the product was treated

  
of preparation 6 (1.167 g) in tetrahydrofuran
(15 ml), successively with hydrated 1-hydroxybenztriazole (0.337 g) and N, N'-dicyclohexylcarbodiimide (0.495 g) for 30 minutes, at 22 [deg.].

  
  <EMI ID = 75.1>

  
activated ester added to a solution of 1-oxide of (1S, 6R, 7R) -7-amino-3-bromomethylceph-3-th4-carboxylate (0.95 g) in dichloromethane (550 ml). The solution was stirred for 16 hours and then evaporated to dryness. A solution of the residue was washed in dichloromethane, successively with an aqueous solution of sodium bicarbonate and brine and

  
it was then stirred and evaporated until a foam (2.2 g) was obtained which was purified by thin layer chromatography of preparation (using a mixture of toluene, acetate ethyl and acetic acid 40: 10: 1 for development) so as to obtain the compound indicated in the title

  
  <EMI ID = 76.1> 1-oxyimino) -2- (2-tritylaminothiazole-4-yl) acetamido7-3-diphenylmethylcarboxylate, 1-oxide, bromide

  
The product from step (a) (1.2 g) was stirred, dried tetrahydrofuran on alumina (2.5 ml) and anhydrous trimethylamine in tetrahydro-

  
  <EMI ID = 77.1>

  
amine (0.155 g) in tetrahydrofuran (1 ml) _7 to 24 [deg.] for 30 minutes. The reaction mixture was added dropwise to stirred ether
(900 ml) and the suspension thus obtained was vigorously stirred for 10 minutes. The solid was filtered off, washed with ether and dried in vacuo to give the title compound (1.16 g), PF 156 [deg.] To 170 [deg.] <EMI ID = 78.1>

  
Diphenylmethyl 3-trimethylammoniomethylceph-3-th-4-carboxylate, iodide

  
The product from step (b) (1.0 g) and acetone (2.6 ml) were stirred as a solution,
-10 [deg.]. Powdered potassium iodide was added. <EMI ID = 79.1>

  
for 2 minutes. Additional dry powdered potassium iodide (0.625 g) was added and then acetyl chloride (0.14 ml) was added.

  
The stirred mixture was allowed to warm to

  
0 [deg.] And then stirred at 0 to

  
+2 [deg.] For 0.5 hours. We added the mixture,

  
dropwise to a stirred solution of sodium metabisulfite (0.465 g) in water (26 ml). We

  
separated the solid thus obtained by filtration,

  
washed with water and dried in vacuo on

  
phosphorus pentoxide so as to obtain a solid
(1.072 g). The above procedure was repeated using the solid (1.072 g), acetone (2.6 ml), dry powdery potassium iodide (0.625 g) and acetyl chloride (0.14 ml ), so as to obtain

  
the compound indicated in the title (1.131 g), in the form of a solid, m.p. 133 to 170 [deg.] (decomp.),

  
  <EMI ID = 80.1> carboxycyclobut-1-oxvimino) acetamido7-3-trimethylammoniomethylceph-3-th-4-carboxylate

  
The product from step (c) (0.2 g) was wetted with anisole (0.2 ml) and trifluoroacetic acid (0.8 ml). A precipitate immediately formed and the suspension obtained was stirred for

  
2 minutes at around 23 [deg.], So that the precipitate became gummy. The mixture was evaporated to dryness and the residue was triturated with ether so as to obtain a solid which was wetted with anisole
(0.035 ml) and thereto was added trifluoroacetic acid (4 ml). A very fine precipitate formed and the suspension was then stirred at 23 [deg.] For 15 minutes. The mixture was evaporated until a gum was obtained which was triturated with ether so as to collect the compound indicated in the title (0.091 g), in the form of a solid, associated 1 mole of trifluoroacetic acid and 0.4 mole of hydroiodic acid,

  
  <EMI ID = 81.1> 1-oxyimino) -2- (2-tritylaminothiazole-4-yl) acetamido73-diphenylmethyl acetamido73-dimethylaminomethyl ceph-3-th-4-carboxylate, 1-oxide

  
The product of Example 2 (a) was treated
(0.52 g) in dry tetrahydrofuran (2 ml) with a solution of dimethylamine in ethanol (33% w / w, 0.20 ml). After 15 minutes at 21 [deg.], The mixture was partitioned between ethyl acetate (25 ml) and water
(25 ml). The aqueous layer was extracted with additional ethyl acetate (25 ml) and the total organic solution was washed with water
(2 x 50 ml) and dried (Na2SO4) and evaporated until a foam (0.498 g) was obtained. The crude product was purified by thin layer chromatography of preparation on silica gel plates (thickness: 2 mm), proceeding to elution with ethyl acetate.

   The main band of an Rf of 0.4, gave a foam (0.331 g) which was dissolved in ethyl acetate (2 ml) and slowly added to stirred petroleum (50 ml). The precipitate was separated by filtration and washed with petroleum and dried under vacuum so as to obtain the title compound (0.224 g), in the form of a solid,

  
  <EMI ID = 82.1> 1-oxyimino) -2- (2-tritylaminothiazole-4-yl) acetamido73-trimethylammoniomethyl ceph-3-th-4-carboxylate diphenylmethyl, 1-oxide, iodide

  
We dissolved the product of step (a)
(0.20 g) in iodomethane (1 ml) and the solution was allowed to stand at 21 [deg.] For 1.5 hours.

  
Diethyl ether (20 ml) was added and the precipitate was triturated then separated by filtration and washed with ether and dried in vacuo so as to obtain the compound indicated in the title

  
  <EMI ID = 83.1>

  
EXAMPLE 4 a) (1S, 6R, 7R) -7-Formamido-3-trimethylammoniomethylceph-3-th-4-carboxylate of diphenylmethyl, 1-oxide, bromide

  
A solution of 1-oxide of
(1S, 6R, 7R) -3-bromomethyl-7-formamidceph-3-th-4-diphenylmethylcarboxylate (1.01 g) in dry N, N-dimethylformamide (3 ml) with a solution
(0.8 ml) of anhydrous trimethylamine in tetrahydrofuran (0.155 g of trimethylamine per ml of solution) and the solution was stirred at 21 [deg.] For 15 minutes. Ether (10 ml) was added and the supernatant solution was discarded. Trituration of the oily residue with ether (approximately 15 ml) made it possible to obtain a precipitate which was separated by filtration, washed with ether and quickly dried under vacuum so as to generate the compound indicated in the titer (1.002 g) in the form of a solid, PF 140 [deg.] to 150 [deg.] (with

  
  <EMI ID = 84.1>

  
  <EMI ID = 85.1>

  
(sulfoxide).

  
b) (IS, 6R, 7R) -7-Amino-3-trimethylammoniomethyl ceph3-th-4-diphenylmethyl carboxylate, 1-oxide, hydrochloride and bromide

  
A mixture of the product from step was stirred
(a) (0.562 g) in methanol (5 ml), at 0 [deg.] and treated, dropwise, with phosphoryl chloride (0.28 ml) within 10 minutes .

  
The mixture was stirred at 0 [deg.] For 2 hours so as to cause precipitation of a buff-colored solid. Ether (15 ml) was added to the stirred mixture, then the precipitate formed was separated by

  
  <EMI ID = 86.1>

  
ether and ethyl acetate and dried in vacuo to give the compound indicated in the

  
  <EMI ID = 87.1>

  
3-trimethylammoniomethylceph-3-th-4-carboxylate

  
diphenylmethyl, 1-oxide, bromide

  
We treated phosphorus pentachloride
(0.11 g), in dry dichloromethane (10 ml), at 0 [deg.], With the product of preparation 4 and the solution was stirred at 0 [deg.] For 35 minutes. Triethylamine (0.16 ml) was added and stirring continued

  
at 0 [deg.] for 5 minutes. The solution was then added dropwise over 5 minutes to a vigorously stirred suspension of the product from step <EMI ID = 88.1>

  
The suspension was stirred at 0 [deg.] For 15 minutes,

  
at 20 [deg.] for 2 hours and then allowed to stand at 4 [deg.] overnight.

  
The mixture was partitioned between ethyl acetate (100 ml) and water (100 ml) and the emulsion was clarified by filtration. The organic phase was washed with water (100 ml) and dried over sodium sulfate and evaporated until a foam was obtained. A solution of this foam in ethyl acetate (4 ml) was added dropwise to stirred petroleum (120 ml). The precipitate formed was separated by filtration and washed with petroleum and dried under vacuum so as to obtain the crude product (0.363 g) as a solid. A certain amount of solid remained on the sintered glass filter, this solid was dissolved in ethyl acetate and the solution was evaporated until a gum was obtained.
(0.019 g).

   The above-mentioned combined products were stirred
(0.33 g) with ethyl acetate (20 ml), for
15 minutes, with trituration of the precipitate. The stirred mixture was slowly diluted with ether (20 ml)

  
and, after an additional 10 minutes, the solid was filtered off and washed with ether and dried in vacuo to collect the title compound (0.211 g), as

  
  <EMI ID = 89.1>

  
3600 to 2500 (NH), 1804 (0-lactam), '1730 (C02R), 1680

  
  <EMI ID = 90.1>

  
We converted the compound indicated in the title

  
  <EMI ID = 91.1>

  
carboxyprop-2-oxyimino) acetamido7-3-trimethylammonio-methylceph-3-th-4-carboxylate as described in Example 1.

  
The antibiotic compounds according to the invention can be presented in pharmaceutical compositions which make it possible to administer them in any convenient manner, by analogy to what happens with other antibiotics and, consequently, the subject of the present invention is also pharmaceutical compositions characterized in that they contain

  
  <EMI ID = 92.1>

  
invention, in a manner suitable for use in human or veterinary medicine. The compositions according to the invention can be prepared in conventional manner, using any necessary pharmaceutical excipients or vehicles.

  
From the antibiotic compounds in accordance with the invention, compositions suitable for injection can be prepared and the latter may be in the form of unit doses in ampoules or in containers which contain multiple doses, if necessary. with an additional preservative. The compositions can also adopt forms such as suspensions, solutions or emulsions in oily or aqueous vehicles and can contain composition agents, such as suspension agents, stabilizers and / or dispersants. The active ingredient can also be in the form of a powder intended to be added with an appropriate vehicle, for example sterile pyrogen-free water, with a view to reconstituting the preparation before its use.

  
If desired, such compositions

  
powder may contain an appropriate non-toxic base, in order to improve the water solubility of the active ingredient and / or to ensure, when reconstituting the powder with water, that the pH of the resulting aqueous composition is physiologically acceptable. The base can also be present in the water into which the powder is introduced in order to reconstitute the necessary preparation. The base can be, for example, an inorganic base, such as sodium carbonate, sodium bicarbonate or sodium acetate, or it can be an organic base, such as lysine or lysine acetate.

  
Antibiotic compounds can also be in the form of suppositories, for example, suppositories containing conventional bases, such as cocoa butter or other glycerides.

  
For the treatment of the eyes or the ears, the preparations can be presented in the form of individual capsules, in liquid or semi-solid form or else they can be used in the form of drops.

  
The compositions intended for veterinary medicine can, for example, be presented in the form of intramammary preparations in bases

  
rapid or prolonged release of the active substance.

  
The compositions in accordance with the invention may contain from 0.1%, for example from 0.1 to
99% of active substance, depending on the mode of administration. When the compositions consist of unit doses, each unit dose

  
  <EMI ID = 93.1>

  
active. The dose which is used for the treatment of the adult human being varies, preferably, from 500 to
6000 mg per day, depending on the mode and frequency of administration. For example, for the treatment of an adult human being, 1000 to 3000 mg per day of active substance, administered by the intravenous or intramuscular route, are normally sufficient. Treatment of Pseudomonas infections may require higher daily doses.

  
The antibiotics according to the present invention can be administered in combination with other therapeutic agents, such as other antibiotics, for example penicillins or other cephalosporins.

  
The following composition illustrates how a compound according to the invention can be incorporated into a pharmaceutical composition.

  
Composition - For injection

  
Formula per vial

  
  <EMI ID = 94.1>

  
trimethylammoniomethyl-ceph-3-th-4-

  

  <EMI ID = 95.1>


  
Process

  
Sterile cephalosporin is mixed with sterile sodium carbonate under aseptic conditions. Glass vials of the above composition are filled aseptically under an atmosphere of sterile nitrogen. We close the vials by

  
using discs or rubber stoppers, held in place by aluminum capsules, so as to prevent any gas exchange or entry of microorganisms. The product is reconstituted by dissolving in water for injections or in any other suitable vehicle, shortly before its administration.

  

  <EMI ID = 96.1>
 

CLAIMS

  
1. Antibiotic cephalosporins corresponding to the following general structural formula:

  

  <EMI ID = 97.1>


  
(in which Ra and Rb which may be identical or different, each represent a C1-C4 alkyl radical, or else Ra and Rb form a C3-C7 cycloalkylidene group with the carbon atom to which they are

  
  <EMI ID = 98.1>

  
or different, each represents a C1-C4 alkyl group), as also their non-toxic salts and their metabolically labile and non-toxic esters.


    

Claims (1)

2. Compounds according to claim 1, <EMI ID = 99.1> and Rb represents a methyl or ethyl group. 3. Compounds according to claim 1, characterized in that Ra and Rb form a C3-C5 cycloalkylidene group with the carbon atom to which they are attached. 4. Compounds according to any one of the preceding claims, characterized in that <EMI ID = 100.1> ammoniomethyl-ceph-3-th-4-carboxylate. 6. Non-toxic salts of the compound according to claim 5. <EMI ID = 101.1> 2- (1-carboxycyclobut-1-oxyimino) -acetamido7-3-trimethylammoniomethyl-ceph-3-th-4-carboxylate. 8. Non-toxic salts of the compound according to claim 7. 9. Process for the preparation of an antibiotic compound corresponding to the formula of general structure (I) as defined in claim 1, or of an atoxic salt or of a metabolically labile and atoxic ester of such a compound, characterized in that : (A) a compound of the following formula is acylated: <EMI ID = 102.1> <EMI ID = 103.1> positions 2, 3 and 4 indicates that the compound is of the ceph-2-th or ceph-3-th type), or a salt or an N-silyl derivative of such a compound, or a corresponding compound comprising a group of the formula -COOR4 in position 4 (where R4 represents a hydrogen atom or a group blocking the carboxyl function) and possesses <EMI ID = 104.1> with an acid of the formula: <EMI ID = 105.1> (in which Ra and Rb have the meanings indicated in claim 1, R5 represents a group blocking the carboxyl function and R represents an amino or protected amino group) or with a corresponding acylating agent, (B) a compound of the following formula is reacted: <EMI ID = 106.1> <EMI ID = 107.1> interrupted have the meanings previously <EMI ID = 108.1> ter a hydrogen atom or a group blocking the carboxyl function and X represents the replaceable residue of a nucleophile), or a salt of such a compound, on a tertiary amine of the following formula: <EMI ID = 109.1> <EMI ID = 110.1> previously indicated), or (C) a compound of the following formula is alkylated: <EMI ID = 111.1> <EMI ID = 112.1> dashed lines have the meanings previously indicated and R7 and R7a both represent groups blocking the carboxyl function), using an alkylating agent used to form the group with the following formula: <EMI ID = 113.1> (in which R <1>, R <2> and R <3> have the meanings previously indicated) in position 3, then, if it proves necessary and / or desirable in each case, any of the following reactions are used, in any suitable order: <EMI ID = 114.1> <EMI ID = 115.1> to generate a compound in which B is> S, iii) conversion of a carboxyl group to a function non-toxic salt or metabolically labile and non-toxic ester and iv) elimination of all the groups blocking the carboxyl function and / or N-protectors. 10. Suitable pharmaceutical compositions for use in human or veterinary medicine, characterized in that they contain at least one antibiotic compound according to any one of claims 1 to 8, in combination with a suitable pharmaceutical vehicle or excipient.