LU84886A1 - ANTIBIOTICS OF THE NATURE OF CEPHALOSPORINS AND THEIR PREPARATION PROCESS - Google Patents

Description

The present invention relates to improvements relating to cephalosporins. The invention relates more particularly to new cephalosporins and to their derivatives which have an interesting antibiotic activity.

5 The compounds of the nature of the cephalosporins which will be discussed in the present document are called with reference to the "cephal" after the book J. Amer. Chem. Soc., 1952 ”64, 3400, the term“ cephem ”* referring to the basic cephalic structure which comprises a double bond.

"• O. Antibiotics of the cephalosporin type are widely used for the treatment of diseases caused by pathogenic bacteria in humans and an imam: and are particularly useful for the treatment of diseases caused by bacteria which re-15 if stenting to other antibiotics, such as penicillin-like compounds and for the treatment of penicillin-sensitive patients. Under many circumstances, it is desirable to employ a cephalosporin-type antibiotic which exhibits both counteracting activity. Gram-positis microorganisms as against Gram-negative microorganisms and considerable research has been devoted to the development of various types of broad-spectrum cephalosporin antibiotics, for example, the specification from British patent 25 "K® 1,399,086 describes a new class of cephalosporins which contain a 7ß- (c-oximino etherified) -acy group lamido, the oximino group having the syn configuration. This class of antibiotic compounds is characterized by high antibacterial activity against a variety of Gram-positive and Gram-negative organisms, associated with particularly high stability against ß-lactaffiases generated by various Gram-negative organisms .

The discovery of this class of compounds has stimulated further research in the same field, aimed at discovering compounds with improved properties, for example, vis-à-vis particular classes of organisms, 2 especially Gram-negative organisms.

The description of the British trefoil K® 1 604 971 describes a whole range of antibiotics of the nature of cephalosporins in which the side chain in posi-5 ^ i5_on 7ß can be chosen, among others, from a group 2- (2- aininothia2ole-4-yl) -2- (o>: yiinino 'etherified) acetamido,. or the etherifying group, among many other possible meanings, may be an alkyl radical substituted with a cycloalkyl group, although no specific illustration of compounds having such a group is given.

The radical in position 3 can also be chosen from a large number of possibilities and a possible substituent in »position 3 is an optionally substituted pyridiniummethyl radical, although no specific illustration is given of the preparation of compounds comprising such a substituent in position 3.

The specification of the British patent i; ° 2,025,398 k describes, inter alia, the compound which is (6R, 7R) -7- £ Tz) -2- (2-aminothiazole * -4-yl) -2 - (2-carboxyprop-2-o>: yimino) acétajnido7-20 3- (l-pyridiniumnethyl) ceph-3-èms-4-carboxylate, which we currently know under the name of 1 ' ceftazidime1 'Other compounds of the nature of cephalosporins, which have a 2- (2-aminothiazole-4-yl) -2- (etherified oxyimino) acetamido radical in position> 7ß are described, for example, in 25 * the descriptive memories of the British patents K® 1,536,281 and 1,576,625.

The Applicant has now discovered that by the choice of a radical (Z) -2- (2 ~ aminothiazole-4-yl) -2-cyclop: opylne-thoxyimino-acetamido in position 7ß in combination with a group pyriά 1 niummethyl or a 3- or 4- carbamoylpyri-diniummethyl group in position 3, it was possible to obtain compounds of the type of cephalosporins possessing a particularly advantageous activity (which will be described in more detail later in the present specification) against a whole series 35 · Pathogenic organisms that are commonly encountered.

χ \ 3

Consequently, the present invention relates to antibiotics of the genus cephalosporins which have the general formula (I) KH,

' AT

s. tf HH

* \ _ / I V.

Il 1 e / Λ H Λ <«

° -κ ^ ~ <3 i. R

in which R represents a 3- or 4-carbamoyl group or a hydrogen atom, as well as the non-toxic salts and the labile and non-toxic metabolic esters of these corooses.

The compounds according to the present invention are syn isomers. The syn isomeric force is defined by the configuration of the group -o.U.2 with respect to the carboxamido radical. In this memo, 5 'the syn configuration is represented in structure by the formula cm \ "- * γ ^ τ, Ο ·; 'KH- A, V / \ = Λ— C.CO.KH- "ï 0CH2 - <3

It should be understood that since the compounds according to the present invention are geometric isomers, some mixture with the corresponding anti-isomer may occur.

The scope of the present invention also extends to solvates (more particularly hydrates) of the compounds of formula (i) and their non-toxic salts. The scope of the present invention also extends to non-toxic salts and to solvates of metabolically labile and non-toxic esters

AT

compounds of formula (i). One can easily grasp that the solvates must be pharm; - ^ logically compatible.

The compounds according to the present invention can exist in tautomeric forms (for example with regard to the 2-aminothiazolyl radical) and it is obvious that the scope of the present invention also extends to these tautomeric forms, for example the 2-iminothiazolinyl form.

The compounds according to the present invention exhibit broad spectrum antibiotic activity, both in vitro and in vivo. These compounds exert a high activity against both Gram-negative and Gram-positive organisms among which numerous strains producing ß-lacta-mases. The compounds in question are also endowed with a high stability towards β-lactanases generated by a variety of Gram-negative and Gram-positive organisms.

The compounds according to the present invention have been found to exert a high activity against strains of Staphylocoocus aureus, Staphylococous epidermidis and Streptococcus species comprising the penicillinase producing strains of these Gram-positive bacteria. This - activity is associated with a high effect against various orga-nisaes belonging to the class of enterobacteriaceae (for example strains with * Escherichia coli, of Klebsiella pneumoniae, of Enterobacter cloacae, of Serratia marcescens, of Proteus 25 “mirabilis and of Proteus indole-positive, such as Proteus vulgaris, .Proteus morganii and species of Providence), and strains of Haemophilus influenzae and Acinetobacter calco-aceticus, as well as good activity against species of Pseudomonas. This combination of high activity against Gram-positive organisms and high activity against Gram-negative organisms possessed by the compounds according to the present invention is particularly unusual.

Non-toxic salts which can be formed by the reaction of the carboxyl group present in the compounds of formula (D, include salts obtained with inorganic bases, such as alkali metal salts (e.g. sodium and potassium salts) and alkaline earth metal salts>: (for example calcium salts), salts obtained with amino acids (for example lysine and arginine salts) 5 salts obtained with organic bases (for example procalne salts , phenylethylbenzylamine, this dibenzylethylene-diaffiine, ethanolaaine, diethanolamine and this K-ethyl-glucosamine). Other non-toxic salts include acid addition salts, for example those formed with hydrochloric and hydrobromic acids. , sulfuric, nitric, phosphoric, formic and trifluoroacet.l The salts can also be in the form of resins obtained, for example, with a polystyrene resin or a resin in a copolymer of civinylbenzene and po crosslinked lystyrene, containing these sulfonic acid groups or these quaternary amino groups, or a resin containing carboxyl groups, for example a polyacrylic acid resin. The salts with these soluble bases (e.g., alkali metal salts, such as sodium salts) of the compounds of formula (I) can be used in the therapeutic field, due to the rapid distribution or distribution of these salts in the body after their administration. However, when it is desired to obtain insoluble salts of the compounds of formula (I) for a particular application, for example for the manufacture of depot preparations, these salts can be obtained in a conventional manner, for example using suitable organic amines.

Metabolically labile and non-toxic esters which can be formed by esterification of the carboxyl group of the related compound of formula (I) include acyloxy-alkyl esters, for example alkanoyloxy-methyl or ethyl esters, such as acetoxy esters -methyl or -ethyl or pivaloyloxymethyl and alkoxy-carbonyloxy-alkyl esters, for example (lower alkoxy) -carbonyloxy-ethyl esters, such as ethoxycarbonyloxy-ethyl esters. Besides the derivatives of type 6 ester mentioned above, the scope of the present invention also extends to the compounds of formula (I) in the form of other physiologically compatible equivalents, that is to say c. Physiologically compatible compounds which, like the labile metabolic esters, transform in vivo into the related antibiotic compound of formula (I).

These salts and esters and other derivatives, such as the salts obtained with thuene-p-sulfonic and methane-sulfonic acids and the esters with the esterifying t-butyl or diphenyInethyl radicals, can be used as intermediates for the preparation and / or the purification, • of the compounds of formula (I) in accordance with the present invention, for example, during the implementation of the methods described below.

It should be understood that the compounds according to the present invention are usually in the form of a betalne containing a carboxylate group and a positively charged pyridinium radical and that, therefore, the esters and the salts of the compounds of formula ( I) with uases will be associated with an anion A “to balance the positive charge existing on the pyridinium nucleus. Such an anion must also be non-toxic and can originate from any of the acids described above, which are capable of generating derivatives of the nature of the non-toxic salts.

-. The compound according to the present invention which is preferred because of its potent antibiotic activity is the compound of the above-mentioned formula (i) in which R represents a hydrogen atom, namely the compound of the formula NH2

S '^ N H H

20 \ / I \ - c- CO.KH -—- / f ~~ \ I o ^ v ^ -CKA / (îa)

>> Noch - <1 I

co * 7 and ataxic salts and metabolic and non-toxic metabolic esters derived therefrom. The compound of formula (la) has the general antibiotic properties set out more Laut about the compounds of general formula (I). More particularly, it has been found that the compound in question exhibits excellent activity in vitro against strains of Staphylococcus aureus and Staohvlococcus erdcermis, as associated with potent activity against Gram-negative organisms. The in vitro antibacterial properties of the aforementioned compound 10 are not compromised by human serum and it has also been found that the minimum inhibitory concentrations were generally not affected by increased inocula. The compound is rapidly bactericidal with concentrations close to these minimum inhibitory concentrations.

In vivo, experimental infections caused in mice by Gram-positive organisms, including Staphylococcus aureus, and Gram-negative organisms, including Lscherichia coli, could be successfully treated with the compound of formula (la) . The acute toxicity tests f, 0 carried out with the compound on mice gave these values of LB-q greater than 2.0 g / kg when the compound was administered by the s or s-eu tan ée route. No manifestation of nephrotoxicity was observed in mice at subcutaneous doses of 2.0 g / kg.

The compounds according to the present invention can be used for the treatment of various diseases caused by pathogenic bacteria in humans and animals, such as respiratory tract infections and urinary tract infections.

According to another of its particularities, the subject of the present invention is a process for the preparation of an antibiotic compound of the general formula (I) as defined above, or of an etoxic salt or of a metabolically labile ether and non-toxic of such a compound, characterized in that Que w.

6 (A) a compound of the formula vj-H .fi; acyl is acylated)

3 ° "T '\ JtB

cooe ^ in which R has the meanings which have been assigned to it above, B represents> s or> s 0 (a or β) 10 and the dashed line which bridges between positions 2,3 and 4, ^ nique that the corrosive is a substance of the ceph-2-nd or ceph-3 ~ th7 type or a salt, for example an acid addition salt with an ore, <^ e 1 had the acid hydrochloric acid, hydrochloric, sulfuric, nitric or phphoricus or with an organic acid, such as ethanesulphene or toluene-p-sulford acid), or a K-silyl derivative thereof, or a corresponding compound having a radical of the formula —COOR in position 4 £ where R represents a hydrogen atom or a group blocking the carboxyl function, for example the residue of an esterogenic aliphatic or araliphatic alcohol or of an esterogenic phenol, silanol or stannanol ( said alcohol t pheno], silanol or stannanol preferably containing from 1 to 20 carbon27 atones and comprising an associated anion E ”, such 25- - than a halide anion, for example chloride or bromide, or trifluoroacetate, with an acid of the formula.

Λ \ - / (iii>

- C.COOH

3rd day II

• V K

f V / 1 9 (in which R represents a protected amino or arcino radical), or a salt of such a compound, or with an acylating agent which corresponds to it, or (E) a compound of formula 5 ′ is reacted /

S ^ N H H

\ _ „1 VB X l1 ·’) i 0J-L> v io "" *> <> 3

COOR

r, (in which Rc, E and the dashed line have the meanings which were allotted to them above, represents a hydrogen atom or a radical blocking the carboxyl function and X represents the rest replaces-15 ·; cable d a nucleophilic compound, for example an aoé-toxy or dichlc acetoxy radical or a halogen atom, such as a chlorine, bromine or iodine atom) or a salt of such a compound, on a compound of pyridine of the formula f ~ \ N ^ (V) 20 \ -

R

(in which R has the meanings which have been assigned to it above), then, if it proves necessary and / or desirable in each circumstance, one proceeds to the implementation of any of the reactions which follow , in any suitable order: P xi) conversion of an Δ isomer into the ù isomer. desired, ii) reduction of a compound in which B represents 30!> S -> 0, by closing a caspase in which B is S, iii) conversion of a carboxyl group into an ester function; metabolically labile and atoxic, iv) formation of an atoxic salt function and v) removal of any groups blocking the carboxyl function and / or protecting the K function.

The above-mentioned reactions i) to v) can be carried out in conventional manner.

In the process (A.) described above, the starting material of formula (II) is preferably a compound in which B represents ^ S, and the dashed line represents a substance of the eeph-3 type -en. One such starting material which has been found to be particularly suitable for carrying out the process (A.) is (6R, 7R) -7- Eino-3- (1-pyridiniui) dichlorohydrate: Biethyl) -céph-3-en “4-carboxylate.

Acylating agents which can be used for the preparation of compounds of formula (i) include acid halides, more particularly acid bromides or chlorides. These acylating agents can be prepared by the reaction of an acid (III) or a salt thereof with a halogenating agent, for example phosphorus pentachloride, thionyl chloride or oxalyl chloride .

Acylations using acid halides can be used in aqueous and non-aqueous reaction media, conveniently at temperatures from -50 to + 50 ° C, preferably from -40 to + 30 ° C, if desired, in the presence of 'an acid-fixing agent. Suitable reaction media include aqueous ketones, such as aqueous acetone, aqueous alcohols, such as aqueous ethanol, esters, such as ethyl acetate, halogenated hydrocarbons, such as methylene chloride, amides, such as di-methylacetamide, nitriles, such as acetonitrile or mixtures of 2 or more of 2 of these solvents. As suitable acid-binding agents, there may be mentioned tertiary amines (for example triethylamine or dimethylaniline), inorganic bases (for example calcium carbonate or sodium bicarbonate) and oxyranes, such as oxides of? 11 1 2-lower alkylene (eg ethylene oxide or propylene oxide), which bind the released hydrogen halide to the heart of the acylation reaction.

The acids of formula (III) themselves can be used as acylating agents for the preparation of 3 compounds of formula (I). Acylations which use acids (III) are advantageously carried out in the presence of a condensing agent, for example a carbodi-imide, such as Κ, Κ'-dicyclohexylcarbodiimide or K-ethyl-10 N'- y-àiméthylaminopropylcarbodiinide, a carbonyl compound, such as carbonyldiinidazole, or an isoxazolium salt, such as N-ethyl-5-phenylisoxazoliuin 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 (for example generated with the acid pivalic or with a haloformate, such as a lower alkyl haloformate), Mixed anhydrides can also be formed with phosphorus acids (e.g. phosphoric or phosphorous acids), sulfuric acid or aliphatic acids or sulfonic aromatics (e.g. toluene-p-sulfonic acid). An activated ester can conveniently be formed in situ using, for example, 1-hydroxybenzo-triazole in the presence of a condensing agent, as described above. You can also preform the activated ester.

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

Another activation method consists, for example, in reacting an acid of formula (III) on a preformed solution or suspension by adding a carbonyl halide ^ 12 more particularly phosgene or oxalyl chloride, or a phosphoryl halide, such as phosphorus oxychloride, to a solvent, such as a halogenated hydrocarbon, for example methylene chloride, containing a lower acyl acid) ~ tertiary amide, such as Κ, Ν-dimethylformamide. The activated form of the acid of formula (III) can then be reacted with a compound of the 7-amino type of formula (II) in a suitable solvent or in a suitable mixture of solvents, for example an alkanol, such as an alcohol, for example ethanol in aqueous solution or industrial alcohol denatured with methanol, in aqueous solution. The acylation reaction can conveniently be carried out at temperatures which vary from -50 to + 50 ° C., preferably from -40 to + 50 ° C., if desired, in the presence of an agent fixing the 15 acids, for example a substance as described above (for example triethylamine).

If desired, the above acylation reactions can be carried out in the presence of a catalyst, such as -; - dimethylaminopyridine.

If desired, the acids of ï-rr = n .. e (III) and the acylating agents which correspond thereto and can be used in the form of their addition salts acids. Thus, for example, it is convenient to use ‘acid chlorides in the form of their chlorhy-25 drate type salts and acid bromides in the form of their brozihydrate type salts.

A pyridine compound ‘of formula (V) can serve as a nucleophilic substance to displace a whole series of X substituents of a cephalosporin of formula (IV). To some extent, the ease of this displacement is proportional to the pK of the KX acid from which the substituent originates.

U

Therefore, atoms or groups X which derive from strong acids tend, in general, to be more easily displaced than atoms or groups which originate from weaker acids. The ease of movement also depends, v

Jr i 13 to a certain extent, the precise nature of the substituent R in the compound of formula (V).

The displacement of X by the pyridine compound of formula (V) can conveniently be carried out while maintaining the 5 ‘reagents in solution or in suspension. The suspension is advantageously carried out using from 1 to 10 moles of the pyridine compound.

The nucleophilic displacement reactions can conveniently be carried out on the compounds of formula 10 (IV) in which the substituent X is a halogen atom or an acyloxy group, for example as described below.

Acyloxy groups

The compounds of formula (IV) in which X represents an acetoxy radical are convenient starting materials to be used for carrying out the nucleophilic displacement reaction on the pyridine compound of formula (V). Other starting materials which belong to this class 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.

Displacement reactions on compounds of formula (IV) having substituents X of this class, more particularly in the case where X represents the acetoxy radical, can be facilitated by the presence of io-hard or isocyanate ions in the reaction medium. Reactions of this type are described in more detail in the specification of British patents N® 1,132,621 and 1,171,603.

The substituent X can also come from formic acid, a haloformic acid, such as chloroformic acid, or a carbamic acid.

When a compound of formula (IV) is used in which X represents an acetoxy or substituted acetoxy radical, 35; it is generally desirable that the symbol F. ^ in the. * '

V

14 formula (IV) represents a hydrogen atom and that B represents' p S. In this case, the reaction is advantageously carried out in an aqueous medium, preferably a size from 5 to 8, more particularly from 5.5 to 7.

5. The process described above, which uses the compounds of formula (IV) in which X represents the remainder of a substituted acetic acid, can be carried out as described in the specification of British patent No. 1 241,657.

When using compounds of formula (IV) in which X represents the acetoxy radical, the reaction is conveniently carried out at a temperature of 30 ° C to 110 ° C, preferably from 50 to 80 ° C.

Halogens It is also convenient to use compounds of formula (IV) in which X represents a chlorine, bromine or iodine atom, as starting materials for carrying out the nucleophilic displacement reaction on the pyridine compound of formula (V). When 20 compounds of formula (IV) of this class are used, B can resize ^ S -> 0 and R can represent a group blocking the carboxyl function. The reaction is conveniently carried out in a non-aqueous medium which preferably comprises one or more organic solvents, advantageously of a polar nature, such as these ethers, for example di-oxane or tetrahydrofuran, esters , for example ethyl acetate, amides, for example formamide and Ν, Ν-dimethylformamide and ketones, for example acetone. In certain cases, the pyridine compound may itself constitute the solvent * Other suitable organic solvents are described in more detail in the specification of British Patent K® 1 32β 531. The reaction medium should not be neither extremely acidic, nor extremely basic. In the case of reactions carried out on compounds of formula (IV) in which ί 15 represents a radical blocking the carboxyl function, the product of the 3-pyridiniummetLyl type will be formed in the form of the corresponding halide salt which can, if one if desired, be subjected to one or more 5 'ion exchange reactions to obtain a salt containing 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 of from -10 to + 50 ° C, preferably from +10 at + 30cC.

The reaction product can be separated from the reaction mixture which may contain, for example, an unmodified cephalosporin type starting material and other substances, by the use of a variety of methods including recrystallization, iontophoresis, column chromatography and the use of ion exchangers (for example by using chromatography or ion exchange resins) or macroreticular resins.

One can transform a derivative of the ester type of Δ - ‘.-Ephalosporin. obtained by implementing the method according to the present invention. in the corresponding corresponding Lr derivative,

τ ^ P

For example, by treating Itester Δ with a base, such as pyridine or triethylamine.

> It is also possible to oxidize a reaction product of the ceph-2-th type to obtain the corresponding 1-ceph-3-th oxide, for example by the reaction on a peracid, for example peracetic acid or the m-chloroperbenzolque acid, the sulfoxide thus obtained can subsequently be reduced as described hereinafter, in order to obtain the corresponding corresponding ceph-3-th sulfide.

When you get a dar compound. 3 which B represents o, this compound can be transformed into the corresponding sulfide, for example, by reduction of the corresponding acyloxy-sulf onium salt or of tallow onium co-oxy, prepared in situ by the reaction on, for example acetyl chloride in 1 * ............

16 in the case of an acetoxysulfonium salt, the drafting being carried out by, for example, sodium dithionite or by an iodide ion, as in a potassium iodide solution in a water-miscible solvent, for example 1 * 5-acetic acid, acetone, tetrahyorofuran, Te dioxane, dimethylformamide or dimethylacetamide. The reaction can be carried out at a temperature yes varies from -20 to + 50 ° C.

The labile metabolic esters of the compounds of formula (I) can be prepared by the reaction of a compound of formula (I) or a protected salt or derivative thereof, with the esterifying agent. suitable, such as an acyloxyalkyl halide (eg iodide), the reaction being carried out conveniently in an inert organic solvent, such as aminoethylamide or acetone, this reaction being followed, where appropriate. proves necessary, the removal of any protective groups.

The salts with bases of the compounds of formula (I) can be formed by reacting an acid of formula (I) to a suitable base. Thus, for example, the sodium or potassium salts can be prepared using the salt of the type 2-ethylhexanoate or of the respective bicarbonate type.

The acid addition salts can be prepared by reacting a compound of formula (i) or a metaholic ester of such a labile compound with the appropriate acid.

When a compound of formula (I) is obtained in the form of a mixture of isomers, the syn isomer can be obtained, for example, by means of conventional methods, such as by crystallization or by chromatography.

For use as starting materials for the preparation of compounds of the general formula (X) according to the present invention, use is preferably made of compounds of the general formula (III) and anhydrides and Acid halides which correspond to them, in their syn-isomer form, or in the form of mixtures of syn-isomers and correspondants17 anti-corresponding isomers, which contain at least 90% of the 'syn-isomer.

The acids of formula (III) and their derivatives themselves constitute new compounds and it is obvious that the scope of the present invention also extends to them.

m

They can be prepared by the etherification of a compound of the formula T * v ^

K

Λ \ J 4 <VI>

c.coOR

10 25 || \

OH

2 (in which R has the meanings yes have been assigned # * 1 above and Fv represents a hydrogen atom or a group blocking the carboxyl function) or a salt of such a compound, by selective reaction on a compound of the general formula t.ch2 - ™ <^ J (VII) 20 '(in which T represents a halogen atom, such as chlorine, bromine or iodine, a sulphate or sulphonate radical, * such as tosylate), this etherification being followed by the elimination of any group blocking the carboxyl function. The iso-25 mothers can be separated either before or after the etherification reaction of this kind. The etherification reaction is conveniently carried out in the presence of a base, for example potassium carbonate or sodium hydride and is carried out, preferably in an organic solvent, for example dimethyl sulfoxide, a cyclic ether, such as tetrahyrofuran or dioxane, or a Ν, Ν-disubstituted amide, such as dimethylformamide. Under these conditions, the configuration of the oxy- / imiro group remains substantially unmodified by the implementation and the etherification reaction. When using the compound of *

Λ Q

IG

formula (VI) in the form of a free acid or a salt with a base, the etherification reaction is generally carried out in the presence of a strong base, for example potassium t-butoxide, a sufficient amount strong base being 5 - added to form a bi-anion. In addition, the reaction must be carried out in the presence of a base if an acid addition salt of a compound of formula (VI) is used, the amount of base sufficient to quickly neutralize the acid in question.

Acids of the formula (III) can also be prepared by reacting a compound of the formula: K2, c.

V- / <tv: il) '........... c01COOR ·, 2 4 15 ïin which R and R have the meanings previously indicated) on im composed of the formula H2K.C.CH2 ™ < ^ j (IX) followed by the removal of any radical blocking the carboxyl function and, if necessary, the 20 = separation of the syn and anti isomers.

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

When X represents a halogen atom (that is to say chlorine, bromine or iodine) in formula (IV), it is possible to prepare the starting compounds of the ceph-3-th type of a conventional manner, for example by halogenation of a 7β-protected amino-3-methylceph-3-ene-4-carboxylate 1β-oxide, elimination of the group protecting the 7ß function, acylation of the 7ß-amino compound thus obtained to form the radical 7ß- i. acylamido, for example in a manner analogous to that described l, ‘9 * π ε in connection with the process (A.) above, followed by reduction to the 1β-oxide group later during the subsequent operations. This way of doing is described in the British patent lî ° 1 326 531. We can prepare the conpo-5. its corresponding ceph-2-th type by the process described in published Dutch patent application K 6,902,013, by the reaction of a compound of the 3-methyl-ceph-2-th type on N-bromosuccinimide, so to obtain the compound of the type 3-bromomethylceph ~ 2-th corresponding.

When X represents an acetoxy group in formula (IV), such starting materials can be prepared, for example, by acylation of 7-aminocephalosporonic acid, for example in a manner analogous to that described in connection with the implementation of the above-mentioned process (k),'n '15 can prepare the compounds of formula (IV) in which X represents other acyloxy radicals by the acylation of the corresponding 3-hyoroxymethyl compounds than l it is possible to prepare, for example, by the hydrolysis of suitable 3-acetoxy-methyl compounds, for example as described, in particular, in the descriptions of British patents K® 1,474,519 and 1,531,212.

The starting materials of formula (II) can also be prepared in a conventional manner, for example, by nucleophilic displacement of the corresponding 3-acetoxymethyl compound by the suitable nucleophile, for example, as described in the specification of the British patent Kc 1 028 563, or by the implementation of the process described tf-ns the description of British patent No. 2,052,490A. Another process for the preparation of the starting materials of formula (II) is characterized by deprotection of a corresponding protected 7β-amino compound, carried out in a conventional manner, for example using PCI, -.

5 <Â - t 20

It should be understood that, in the case of the abovementioned transformations, it may prove necessary to protect any sensitive radicals present in the molecule of the compound in question, in order to avoid the appearance of undesirable side reactions. As an example, during the course of the implementation of any of the reaction sequences listed above, it may prove necessary to protect the KHg radical of the aminothia-zolyl group, for example by tritylation, acylation (for example chloracetylation or formylation), protonation or by using any other conventional method. The protective group can subsequently be removed via any convenient method which does not cause degradation or decomposition of the desired compound, for example in the case of a trityie radical, by the use of a optionally halogenated carboxylic acid, for example acetic acid, formic acid, chloracetic acid or J. * trifluoroacetic acid, or by using a mineral acid "for example hydrochloric acid, or mixtures of these 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 carboxyl blocking radicals used for the preparation of compounds of formula (i) or for the preparation of necessary starting materials are advantageously radicals which can easily be separated during an appropriate step. from the rest of the reactions, conveniently in the last step. However, under certain circumstances it may be convenient to use metabolically labile and non-toxic carboxyl blocking groups, such as acyloxymethyl or acyloxyethyl (e.g. acetoxymethyl or acetoxyethyl or pivaloyloxy-methyl) and keep them in the final product so t! obtain a suitable ^ ster of a compound of formula (i) N 'ï 21

Suitable carboxyl blocking groups are well known to those skilled in the art, an illustrative list of blocked carboxyl groups appearing in the specification of British Patent K 1 399 08β. The preferred 5 - blocked carboxyl groups are aryl (lower alkoxy) carbonyl radicals, such as p-methoxybenzylcxy-carbonyl, p-nitrobenzylcxycarbonyl and cliphenylrethoxy-c & rbonyl, (lower alkoxy) carbonyl radicals, such as t-butoxycarbonyl and halo radicals. (lower alkoxy) carbonyl, such as 2,2,2-trichlorethoxycarbonyl. The carboxyl blocking radical can subsequently be removed using any of the suitable methods described in the technical literature, thus, for example, acid or base catalyzed hydrolysis can be applied in many cases. , just as one can proceed to hydrolyses with enzymatic catalysis.

The antibiotic compounds according to the present invention may be presented for administration in any suitable form, by analogy to the administration forms used for other antibiotics, and therefore the scope of the present invention extends also to pharmaceutical compositions which comprise at least one antibiotic compound according to the present invention, suitable for use in human or veterinary medicine. With a view to their use, these compositions can be prepared in conventional manner using any necessary pharmaceutical excipients or vehicles.

The antibiotic compounds according to the present invention may be presented in the form of compositions suitable for injection and these preparations may take the form of unit doses, be introduced in ampoules or in containers which contain multiple doses thereof, if necessary. with an additional preservative. The compositions may also adopt forms such as suspensions, solutions or emulsions in oily or aqueous vehicles and may contain these agents or in composition, such as suspending, stabilizing and / or dispersing agents . The active ingredient may also be in the form of a powder suitable for reconstituting the desired pharmaceutical composition with a suitable vehicle, for example sterile pyrogen-free water, before use.

If desired, these powder compositions may contain a suitable non-toxic base, in order to improve the water solubility of the active ingredient and / or to ensure that when the powder is added to the reconstitution water , the pH of the aqueous composition thus obtained is physiologically compatible. The base can also be present in the water used to reconstitute the pharmaceutical composition with the powder. The box can be, for example, an inorganic base, such as sodium carbonate, sodium bicarbonate or sodium acetate, or an organic base, such as lysine or lysine acetate.

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

The compositions for use in veterinary medicine may, for example, be in the form of intramammary preparations in bases for rapid or delayed release of the drug substance.

The compositions can contain from 0.1% f for example from 0.1 to 99 the active material, depending on the mode of administration. When the compositions are in the form of unit doses, each unit dose preferably contains from 100 to 3000 mg of active ingredient, for example from 200 to 2000 mg of this active ingredient. The daily dose intended for the treatment of adult humans varies, preferably, from 200 to 12,000 mg, for example 35, to 1000 to 9000 mg of active principle per ^ our, depending,

"T

y 23 among others / the nature of the infection and the mode and frequency of administration. In general, intravenous or intramuscular administration may be used, for example using 400 to 4000 mg per day (day 5 of the active ingredient for the treatment of adult humans For the treatment of Pseudomonas infections, higher daily doses may be necessary, and it is well understood that in certain circumstances, for example for the treatment of this newborn, it may be desirable to use only unit doses and reduced daily doses.

The antibiotic compounds of the present invention can be administered in combination with other therapeutic agents, such as antibiotics, for example these penicillins or cephalosporins.

The following examples illustrate the present invention. In these examples, all Γ: 3ε temperatures are indouced in degrees Celsius. The abbreviation LMSO stands for dimethyl sulfoxide. Sorbsil U30 is a silica gel manufactured by the company Joseph Crosfield and Son of Warrington, Lancashire, England. Amberlite LA-2 is a weakly basic liquid anion exchange resin, Amberlite XAD-2 is a non-functional macroreticular resin, these two resins being manufactured by the company Rohm and Haas of Ph 25 Philadelphia, USA.

Preparation 1 (Z) -2-Cyclopropylmethoxyimino-2- (2-tritylaminothiazole-4-yl) -ethyl acetate

(Z) -2-hydroxyimino-2- (2-tritylaminothiazole- .50 * 4-yl) ethyl acetate, hydrochloride salt (30 g) was stirred; with cyclopropylmethyl bromide (13.5 g) in dimethyl sulfoxide (150 ml) containing potassium carbonate (30 g) at 21 °, under nitrogen, for 7 hours. The second mixture was partitioned between methylene chloride and water. The aqueous layer was ex-i treated with an additional amount of methylene chloride and the combined organic solutions were washed with water. After drying with magnesium sulfate, the solution was concentrated and introduced into a column of Sorbsil U30 silica gel (200 g). The column content was eluted with ethyl acetate (10 to 30%) in petroleum ether (P.Z. 40-60 °). Evaporation of the appropriate fractions made it possible to obtain the compound indicated in the title (20.9 g); λ (ethanol) 234n5nm (E ** 403); f 254.5nm (EÎ * 302); 259.5nm 10 {Elcm 267) i 265nm <Eicirt 229); 271 *> 5mr ‘190) and 294nm (eJ * ^ 111); νΓΛχ (CHBr3) 3398 (KH), 1730 (ester), 1593 and 1491er “· 1 (aromatic double bond).

Prep ^ ation 2

Acid (Z) -2-cvclooror-vlmétho>: yiEino-2- (2-tritylaEinothia20le-15 4-yl) acgtioue

The product of Preparation 1 (20 g) was dissolved in ethanol (200 m)) and sodium hydroxide (2.12 g) was added to it (40 ml). The mixture was brought to reflux for 45 minutes, during which the precipitation took place. Some ethanol (about 150 ml) was removed by distillation and the residue was cooled. The mixture was partitioned between methylene chloride and water containing 2N hydrochloric acid (70 ml). The organic layer was washed with water, each aqueous layer being reextracted with an additional amount of methylene chloride. The combined organic layers were dried using magnesium sulfate and evaporated to give the title compound (20 g); hnf. (ethanol) 234.5 = m (E ^ ffi 383); 259.5nm 242); 266.5nm 3 ° 4cm 226> and 272> 5nm (Eicm 217) i ° max (Ku3ol> 3260 (KH) and! 1685cm "’ '' (acid).

J- 'Λ 25

Preparation 3 16Rt7R) "^ Brocîoi3éthyl-7 ~ l23j“ 2-çyclopropylcétho>: viEincr2 ~ (2-trityl8mlnothiazole-4-vl) - a ç étami do7-ceph-3-ene-4-carboxylate dejditjh | ny1methyli 5 * On added oxalyl chloride (0.37 cl) to a solution of IC, K-imimethylformamide (0.38 El) in methylene chloride (10 ml) at -20 °, with stirring and under a nitrogen atmosphere. The mixture was stirred under cooling with ice water for 10 minutes, then cooled to -20 ° C. (Z) -2-cyclopropyl-methoxyimino-2- acid was added ( 2-tritylaminothiazole-4-yl) acetic (1.94 g) and the solution was stirred under cooling with ice water for 10 minutes before cooling to -20 ° C. A suspension of (6R, 7R) -7-amino-3-bromethylceoh-3-sne-4-15 diphenylmethyl carboxylate (1.98 g) in methylene chloride (10 ml) containing this K, K-dimethylaniline (1.76 ml) A clear solution forms when the mixture is allowed to warm to 21st over the course of an hour. washed the solution with dilute hydrochloric acid and water, each wash liquor being reextracted with additional methylene chloride and the combined extracts were dried with magnesium sulfate and evaporated to to a small volume. The solution was filtered through Sorbsil U30 (50 g) in ethyl acetate and the eluate was evaporated. The residue (3.54 g) was crystallized from a mixture of diethyl ether and petroleum ether (m.p. 40 at 60 °), so as to obtain the compound indicated in the title 2.43 g); Mp 135-147 °, 11.9 ° (c 0.6, CHCl 4).

EXAMPLE 1 30 (6R, 7R) -7- / Tz) -2- (2-Aminothiazole-4-yl) -2-cyclopropylmethoxy- iminoacetamido7-3- (1 -pvridinlummethyl) ceph-3-species-4-carboxy-

M · ——- p-yj Τι | ·· | Γ * rfT · Ι · ΙΙ | Ι · ΙΙ IM ................ I ~ I I ‘~ I Il I I

late, dihydrochloride salt

Oxalyl chloride (0.74 ml) was added to a solution. stirred tion of Ν, Ν -imethylformamice (0.76 ml) in methylene chloride (20 ml) at -20®, under a nitrogen atmosphere.

vs,

V

i 26

The mixture was stirred under cooling in ice water for 10 minutes and then cooled to -20 °.

(Z) -2-cycloprcpyimethoxyim.ino - 2 (2-tritylaminothiazole-4-yl) acetic acid (3.8 µg) was added, and the solution was stirred with ice-cooling. for 10 minutes. The solution was cooled to -20 ° and added to a (6R, 7E) -7-amino- 3- (1 -pyridiniuramethyl) ceph-3-ems-4-car 'dihydrochloride solution. boxylate dihydrate (3.04 g) in industrial alcohol denatured with methanol 10 (24 ml) and water (6 ml) containing diethylamine (4.7 ml) at -7 °, with vigorous stirring. The solution was allowed to warm to 21 ° over the course of 15 minutes. It was then washed twice with water, each time being extracted with Ί5 methylene chloride. The combined organic layers were dried with magnesium sulfate and evaporated until a gummy oil was obtained which was triturated with diethyl ether to obtain a solid (4.56 g). This solid (4.31 g) was dissolved in formic acid and concentrated hydrochloric acid (1.6 ml) was added thereto. After stirring for 1 hour at 21 °, the mixture was filtered and the filter cake was subjected to leaching with formic acid. The combined filtrates were evaporated and the residue was triturated with acetone so as to obtain the 25 'title compound (3.20 g); -38.0e (c 1.26, DM3 °) i W (taEpon at pK 6) 255nm <E1cm 307); \ nî 240 nm, E1cm 287) and 289.5nm (E ^ m 128).

EXAMPLE 2 (a) (6R, 7R) -5-Acetoxymethyl-7- / TZ) -2-cvcIopropvlmethoxvimino) -30 2- (2-tritylaminothiazole-4-yl-) acetamido7-cer) h-3-th-4 - t-butyl carboxylate

Oxalyl chloride (0.74 ml) was added to a solution; tion of dimethylformamide (0.76 ml) in methylene chloride (20 ml) at -20 °, with stirring and under a JW "atmosphere.

Λ 27 nitrogen. After 10 minutes of stirring under ice cooling, the mixture was cooled to -20 ° and acid (Z) -2-cyclopropylmethoxyimino ~ 2 (2-trityl-aminothiazole-4- was added) yl) acetic (3.63 g). After 10 minutes of cooling with water, the solution was cooled to “20e and a solution of 3-aC6ioxvmeihyl“, 7 · "aminceph-3-èBe-4-carboxylate was added thereto. butyl (3.28 g) in methylene chloride (20 ml) containing K, N-dinethyl-aniline (2.52 ml). The solution was stirred at 210 for 1 hour. solution successively with dilute hydrochloric acid and water, each time carrying out an extraction with methylene chloride.

The combined organic solutions were dried over magnesium sulphate, concentrated and chrenatogra-15 phies on Sorfcsil U30 (150mg) in ethyl acetate pO a 40 in petroleum ether (M, f. 4G-6G ° ^ 7 to give the title compound (5.79 g); £ c7 £ + 25.3e (c 1.11, CHC13), ^ Rgx (CHBr3) 3400 (KH ), 1790 (ß-lactase), 1729 (esters) and 1689 and 1512 cm ”1 (acid).

(B) (6R, 7R) -5-acetoxvmethvl-7- / TZ) -2- (2-aminc> thiazole- 4 “yl)“ 2 “cyclopropylmethoxvimino7scetamidocéph-3“ th “4“ carboxylic. hydrochloride salt

The product from step (a) (5.60 g) was dissolved in formic acid (22 ml) and concentrated hydrochloric acid was added. The solution was stirred at 210 for 1 hour and the mixture was filtered. The filter cake was subjected to formic acid leaching and the combined filtrates were added to stirred diisopropyl ether (620 ml). The precipitate was collected by filtration, washed with diisopropyl ether and dried to give the title compound (3.73 g), (a? ^ +37.25 ° (c 0.59, BKSO), \> maX (Nujol) 3700-2300 (3H3 and OH), 1780 (ß-lactam), 1725 (ester and acid)! And 1662 and 1543 cm ”1 (amide).

HL

2ε (c) (6Rt7R) -7- / Tz) "2 ~ (2 ~ Aminothi5ZOle-4-yl)“ 2-cvcloüroDvl ~ ffiethoxviminoacét £ midc7-3 ~ (4-carbareovl-1-pvridiniumisethyl) -c eqh-3 -eine-4-c srboxyl a te

The product from step (b) (1.58 g) was mixed with sodium 5-bicarbonate (500 mg) and water (2 ml) was slowly added under heating to 50 °, operation which caused the syrup to form. Iso-nicotinamide (1.45 g) was added, followed by that of additional sodium bicarbonate to adjust the pH of the mixture to 7.0. Sodium iodide (6.67 g) was added and the solution was heated to 80 ° with stirring. This solution was kept at 80 ° for 3.5 hours. We have it: -sep the syrup to cool and diluted it with acetone (250 ml) with stirring. The solid was collected by wire-15 trat ion and washed properly with acetone for

then dry under vacuum. The solid was dissolved in water and the solution was introduced into a column of Amberlite XAB-2 resin. The column was eluted with water and then 25% ethanol in water. The fractions were analyzed at 0 by examining their UV spectra and the appropriate eluate fractions were pooled and then evaporated until an oil was obtained. This oil was triturated with acetone so as to collect the compound indicated-E

* title (360mg); λ (pH6 phosphate buffer) 231. nm (Elcm 338); Xinfl 251.5 nm (E ^ 308) and 292 nm (EÎ% 146); (Nujol) 1775 (ß-lactane> 1680 (amide) and 1615 cm (carboxylate).

Example 3 (6R, 7R) -7-f (Z) -2- (2-AininothiazGl & -4-yl) -2-cyclopropyl- v / / \ méthoxyiminoacetair.ido) -3- (l-pyridiniummethyl) ceph-3 -eme-4 ~ carboxylate

The dihydrochloride salt of the compound indicated in was stirred; titer (420 mg) with water (5 ml) and ethyl acetate (4 ml), and V * 12 resin was added dropwise

Affiberlite LA-2 (0.6 ml), to adjust the pH of the mixture to 5.2. The organic layer was extracted with additional water and the combined aqueous layers were washed with ethyl acetate. Evaporation allowed ob-5 * to hold a gum which was triturated with this acetone so as to collect the compound indicated in the title (270 mg); ß7 ^ 1 - 69.7% (c 1.14, DKSO); λ (buffer at pH6) 255 nm ^ S1cm362 ^; kinfl 241 nm (Ε ^ 340) and 292 nm (1¾ 145).

i ce 'î cm * EXAMPLE 4 10 (a) (1S. 6R “7R.) rl -5romomethyl-7- / Tz) -2-cyciopr ·: pvlméthoxy- iminO“ 2- (2-tritylaminothiazole-4-vl) acetamiào7céoh-3-th-4-eartoxylete of diphenylcethyl, 1- »oxyce We dissolved (6R, 7R) -3-broQomethyl-7 * - £ (z) -2-cyciopropyl-aethoxyiminO“ 2- (2 ~ tritylaminothiazcle -4-yl) acetamido7 ceph-15 3-th-4-diphenyl methyl acetate (1.2 g) in methylene chloride (10 ml) and 3-chloroperbenzoic acid (292 mg) was added with stirring and chilled water cooling. After 50 minutes, the solution was washed with an aqueous solution of sodium bicarbonate 20 and water (twice). After drying with magnesium sulfate, the solution was concentrated and purified on a column of Sorbsil U-30 (50 g) which was eluted with ethyl acetate (50 to 80 S ”) in ether. r petroleum (PS 40 at 60 °), so as to obtain the compound indicated in the "title (270 mg); [0) ^ - 69 ^ 7% (ç 1514, DMSO); Xirax (pH6 buffer at 256 nm (E ** m362); Xinfl 24i nm (E ^ m 340) and 292 nm (£ ^ 145) · (b) (1S, 6R, 7R) “7- / Tz) -2-Cyclopropylmethoxvimino-2- ( 2-triethylaminothiazole-4-yl) acetamido7-5- (1-pyridiniummethyl) 30-ceph-3-th-4-carboxylate of diphenyl methyl, 1-oxide, bromide / The product of step (a) was dissolved in pyridine (0.2 ml) and the solution was stirred at 21 ° for about 2.5 hours. The solution was diluted with diethyl ether (8 ml) and, after stirring for 10 minutes, the precipitate was collected by filtration, washed with diethyl ether and dried so as to obtain compound 5. indicated in the title (90 mg); £ 17 ^ 1-65.20 (c 1.38, CHCl3); V> max (Nujol) 3700-3100 (KH and Η £ 0), 1803 (ß-lactam), 1727 (ester), 1682 + 1514 (amide) and 1028 cm “1 (sulfoxide).

(c) (6R, 7R) -7 - / 'tZ) -2-CvclopropvImethoxvimlno-2- (2-trityl-aminothia2ole-4-yl) acetamico7-5- (lp% yidiniuirÆethyl) cer? h- 10 5-th -4-diphenylmethyl carboxylate, mixed halide

With stirring, 1-oxide bromide of (1S, .6R, 7R) -7- / TZ) -2-cyclopropylmethoxyimino-2- (2-tritylamino-thiazole-4-yl) acetamido7-3- ( Diphenylmethyl 1 -pyridiniummethyl) ceph-3-ene-4-carboxylate (300 mg) suspended with potassium iodide (0.24 g) in acetone (2 ml), under cooling to frozen water. Acetyl chloride (0.1 cl) was added. After stirring under cooling for about 1.5 hours, the solution was poured into a solution of sodium metabisulfite (0.12 g) in water. (15 ml). The precipitate thus obtained was collected by filtration, washed with water and diethyl ether and dried to collect the title compound (300 mg) ^ maX ( Nujol) 3700-3100 (KH), 1790 (ß-lactam), = 1721 (ester) and 1689 and 1518 cnT ^ (amide); T (dg-DKSO) containing 25 - 1.03, 1.33 and 1.82 (pyridinium protons), 3.08 (COOCK), 3.23 (proton thiazole), 4.05 (d, d, J 9 and 5HZ; 7-K) and 6.08 (d, J 6HZ; NOCH2-).

(d) (6R, 7R) -7- / TZ) -2- (2-Aminothiazole-4-yl) -2-cyclopropyl · -Eethoxviminoacetamido7 "> 3- (l-pyriQiniumméthvl) ceph-3-th 30 4- carboxylate, dihydrochloride salt

(6R, 7R) -7- £ TZ) -2-cyclopropylmethoxyimino- 2- (2-tritylaminothiazole-4-yl) acetamido7-3- (1 -pyridinium-methyl) ceph-3-th-4- were mixed diphenylmethyl carboxylate, mixed halide (200 mg); to formic acid (0.8 ml) at 21 ° and concentrated hydrochloric acid (0.06 ml) was added. We have ί; The mixture was stirred at 21 ° for 2 hours and then filtered. The filter cake was subjected to a leachate! tion with formic acid and the combined filtrates were added to acetone (10 ml) and ether (3 ml). We collected 3. the precipitate by filtration, it was washed and dried so as to obtain the compound indicated in the title (22 mg) whose * spectroscopic characteristics resembled those of the product of 1 * example 1.

, 3XEKPLg_5 10 (a) (6H> .. 7R / ji7r / TZ ^ 2 ~ Cy £ lpjgi ^ 3ylaj1jio ^ ij ^ j ^ ~ 2r (2 »tritvlaPino ·· thiazole-4-yl) ecét8mido7-3- (1- DyridiniuiEEéthvl) -céph-2-ice »4» diphenylmethyl carboxylate, brocride We dissolved (6R, 7R) -3-brononethyl-7- ^ TZ) -2-cyciopropyl-methoxyiminc-2- (2-Îritylaminothiazole-4 -yl) acetamico7céph-3-13 th-4-diphenylmethyl carboxylate (100 mg) in pyridine (0.2 ml) and was stirred ~ a solution at 210 for 3 hours. The solution was diluted with diethyl ether (8 ml) and after 10 minutes the precipitate was collected by filtration, washed with diethyl ether and dried to obtain the compound indicated in the title (100 mg); vrava (Nujol) 3390 (NH), 1809 (8-lactarne), 1730 (ester) and 1682 and 1513 cm ”1 (amide); τ (dg-DMSO) included 1.00, 1.42 and 1.93 (pvridinium protons), 30 3j5 (COOCH), 3.21 (2-H), 3.24 (proton thiazole), 25, 4, 42 (d, d, J 9 and 5EZ; 7-H) and 6.12 (d, J 6HZ; NOCH2 “).

(-b) (1S, 6R, 7R) -7- / TZ) -2-Cyclopropylmethoxyimino-2- (2-trityl-aminothiazole-4-yl) acetmido7-3- (1-pyrldiniummethyl) ceph- 3-th- Diphenylmethyl 4-carboxylate, 1 -> xyde, bromide (6R, 7R) -l-ftZ) -2-cyclopropyl- methoxyimino-2- (2-tritylaminothiazole-4-yl) acetamido7- Diphenylmethyl ceph-2-th-4-carboxylate 3- (1- pyridiniummethyl) (300 mg) in methylene chloride (5 ml), with stirring and cooling in ice. Acid, _y * 'c, .. ^ 32 3-cMoroperbenzoic (70 mg) was added. After 1.5 hours, the solution was washed with sodium bicarbonate solution and water and dried over magnesium sulfate. The solution was evaporated until a gum was obtained which 5 * was triturated with diethyl ether to obtain a solid. This solid was dissolved in methylene chloride (5 ml) and additional 3-chloroperbenzoic acid was added at 30-minute intervals. The solution was washed with sodium bicarbonate solution, with sodium methabisulfite solution and with water and then dried over magnesium sulfate. After evaporation, the residues were triturated with diethyl ether to obtain the title compound, crude (230 mg). A sample of product 15 was purified by chromatography on Sorbsil U3Q (5 g) in methanol and a mixture of propanol and water to obtain the title compound whose spectroscopic characteristics resembled those of the product. Example 4 (b). The product of Example 5 (b) can be reduced and deprotected as described in Example 4 (c) and 4 (d), so as to obtain the dihydrochloride salt of (6R, 7R) -7- ^ TZ) -2- (2-aminothiazole-4-yl) -2-cyclopropylmethoxyiminoacétaffiido7-3- (1-pyridiniummethyl) ceph-3-th-4-carboxylate.

EXAMPLE A

25 "Dry powder for injection

Introduce (6R, 7R) -7- / Tz) -2- (2-aminothiazole- 4- yl) -2-cyclopropylmethoxy imino) ac ét amido7-3- (1 -pyridinium-methyl) ceph-3- a-4-carboxylate aseptically in glass vials, the contents of each container being equivalent to 500 mg of the pure anhydrous material. The upper spaces of the vials should be purged with sterile nitrogen. The flasks must be closed using discs or rubber stoppers and metal covers, applied by crimping, so as to prevent gas exchange or any entry of microorganisms. The product can be dissolved in J '33 for water. injection or other suitable sterile vehicle shortly before administration.

Claims (8)

34 RE ^ mo 1. Antibiotics of the cephalosporin type corresponding to the following general formula: * NH? 5; 5Χ% Γ HH \ - = J— C- CO.NH --- [P "b / Γ ~ \ H J_L J_chJ (\ Π) \. ° WR 0C" 2 ^! ^ 10 (in which R represents a 3 or 4-carbamoyl radical or a hydrogen atom), as well as the non-toxic salts and the metabolically labile and non-toxic esters of these compounds. 2. (6R, 7R) -7- ^ TZ) -2- (2- <4mino thiazole -4-yl) -2-cyclopro-pylmethoxyiminoacétaniiâo7-3- (1 -pyridiniusmethyl) ceph-3-th- 15 4- carboxylate. 3. Non-toxic salts and metabolically labile and non-toxic esters of the compound according to claim 2. 4. Forms with protected K function and with blocked carboxyl group of the compounds according to claim 1. 5. Process for the preparation of a compound according to claim 1, characterized in that: (A) a compound of the formula H h H2N ~ j Γ .'ΓΛ ni) acyl is coo® (in which R meanings ascribed to it in claim 1, B represents Z> S or 30. and the dashed line which bridges positions 2,3 and 4 indicates that the compound is τ t ^ 35 a substance of ceph-2-th or ceph-3-èse type) or a K-sylilic salt or derivative of such a compound, or a corresponding compound Λ having a group of the formula -COOR in position 4 (where R represents a hydrogen atom or a 5 * group blocking the carboxyl function) and having an anion E “/ associated with an acid of the formula A \ - / (ni) '-1— C.COOH II V ° CH2— p (in which R represents a protected amino or emino group) or with a salt of such an acid, or with an acylating agent which corresponds to it, or else (B) a compound of the formula S ^ KHH \ _ / Ξ | / B \ (iv) -L_c c0 NH if "i V» 2K | T, COOR 2 (in which R, B and the line in interrupted treaties have the meanings which have been given to them assigned above, R represents a hydrogen atom or a radical blocking the carboxyl function and X represents the replaceable residue of a nucleophile), or a salt of such a compound, on a pyridine compound of the formula: JV (V) 30. V, -> p 36 (in which R has the meanings which were assigned to it in claim 1, then, if this proves necessary and / or desirable in each circumstance, any 5 is used. of the following reactions, in any suitable order: ÿ p 3 • i) conversion of an Δ isomer into the desired Δ isomer, * ii) reduction of a compound in which 5 represents 0 to form a compound in which B represents> S, iii) conversion of a carboxy group into a metabolically labile and non-toxic ester function, iv) formation of an atoxic salt function and v) elimination of any groups blocking the carboxyl function and / or protecting the K function. 6. Method according to claim 5, characterized in that the compound this formula (II) is the dichlorhycrate of (6R, 7R) -7-amino-3- (1-pyridiniummethyl) -cé? H-3-th -4-carboxylate. 7. Pharmaceutical compositions, characterized in that they contain, as active ingredient, at least one compound according to any one of claims 1 to 3, in combination with a pharmaceutical excipient or vehicle. 8. An acid of formula (III) as defined in claim 5 as well as its reactive salts, esters and derivatives. ..... cü— ,, ...... ____ "'* te 1 i