LU85101A1 - ANTIBIOTICS OF THE KIND OF CEPHALOSPORINS - Google Patents

Description

* * 1

The present invention relates to improvements relating to cephalosporins. More particularly, the invention relates to new compounds from the cephalosporin series and their derivatives which exert an advantageous antibiotic activity.

The compounds of the cephalosporin series referred to in the present specification are named with reference to "cephame'1 according to J. Amer. Chem. Soc., 1962,; 84, 3400, the term '' cephem'1 referring to the structure 10 base cephame which comprises a double bond.

Antibiotics of the cephalosporin series are widely used for the treatment of diseases caused by pathogenic bacteria in both humans and animals and these compounds are particularly suitable for the treatment of diseases caused by pathogenic bacteria. bacteria that resist other antibiotics, such as penicillin-like compounds; Unes and for the treatment of patients who are sensitive to penicillins. In many circumstances, it is desirable to employ a cephalosporin type antibiotic which exhibits activity against; Gram-positive and Gram-negative microorganisms and much research has been devoted to the discovery and development of various types of antibiotics in the series; > 25 of broad spectrum cephalosporins.

Thus, for example, in the specification of British Patent No. 1,399,086, the Applicant describes a new class of antibiotics from the cephalosporin series containing a group 7β- (cs-oximino ether— rifid ^ acylamieb, the oximino group with the | syn configuration This class of antibiotic compounds is characterized by the existence of high antifcacterial activity against a whole series of Gram-positive and Gram-negative organisms, associated with particularly stable ! A- / high against ß-lactamases produced by various Gram-negative organisms.

1 1

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

In British Patent No. 1,604,971, a wide range of cephalosporin-type antibiotics have been described in which the side chain at position 7β can be selected from, among others, a group 2- (2-aminothiazol-4 -yl) -2- (etherified oxyimino) acetamido in which the 3rd etherifying radical may, among many possible groups, be an alkyl radical substituted by a cycloalkyl group, although this is not illustrated specific of compounds! - comprising such a group. The group in position 3 can | also be chosen from a large number of radicals; i and a possible substituent is constituted by a J 20 thiomethyl group substituted by a heterocyclic radical with 5 or * 1 6 6 members, optionally substituted, containing one or more atoms of nitrogen, oxygen or sulfur.

; ”; The specification of the British patent application I, No. IJ 2 027 691A describes antibiotics of the cephalosporin series in which the side chain 7β! consists of a 2- (2-aminothiazol-4-yl) -2- (etherified oxyimino) acetamido radical where the etherifying group, j is a carboxyalkyl or carboxÿcycloalkyl radical. The * substituent in position 3 is a radical of the formula £ 30 syn-2- (2-aminothia zol-4-vl) -2-cvclonropvlaethoxv-lmino- § acetamido in which Y represents a heterocyclic ring $ 5 or 6 members linked via a carbon atom, containing at least one nitrogen atom, which may be substituted by a C 1 -C 4 alkyl group.

3 *

The Applicant has now discovered that by choosing a syn-2- (2-aminothiazol-4-yl) -2-cyclo-propylmethoxy-iminoacetamido radical in position 7β "in combination with certain radicals in position 3 obtain 5 compounds of the genus cephalosporins, possessing a particularly advantageous activity (which will be described in more detail later in the present report), against a wide range of pathogenic organisms than | commonly encountered.

Consequently, the present invention more particularly relates to antibiotics of the cephalosporin series corresponding to the general formula (i). nh2! · - '/ V {1)

S N HH

'15 \ —J c-CO. KH 1—

II J --- CH-SY

N O 2

NSyOCH2- ^ j COOH

i 1 - (in which Y represents an unsaturated heterocyclic ring,; 5 to 6 or 6-membered, linked via the carbon atom, containing at least one nitrogen atom, which ring | may also contain one or more than one sulfur atom I and / or may be substituted by one or more C 1 -C 4 alkyl, oxo, hydroxyl or methylamethyl radicals, as well as the non-toxic salts and the metabolically labile and non-toxic esters of these compounds.

"The compounds according to the present invention are syn isomers. The syn isomer form is defined by the configuration of the group -O.Ch 4 - ^ with respect to the carboxamido radical. In the present specification, the 4 t configuration syn is represented in structure as follows: NH.

X

S N

\ - C.CO.NH—

II

, NOT

5 ^ OCH ^ - ^ 1

It should be understood that, since the compounds in accordance with the present invention are geometric isomers w ', a certain mixture with the anti-cores isomer; 'Laying can happen.

* 10 The scope of the present invention also extends to solvates (more particularly hydrates) of the compounds of formula (i). The invention also extends its scope to solvates of non-toxic salts of formula (I) and to non-toxic salts and solvates of metabolically labile and non-toxic esters of the compounds of formula (i). It must obviously be understood that solvates must be pharmaceutically acceptable.

4- In the above formula (i), the hetero-cyclic ring represented by Y can, for example, contain from 20 1 to k nitrogen atoms and, if desired, a sulfur atom, specific examples of these radicals heterocyclic being the imidazolyl, pyrazolyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, triazolyl, tetrazolyl, thiazolyl, thiadiazolyl, triazinyl and thiazolidinyl groups. The heterocyclic nucleus can, | if desired, be substituted by one or more (par / 5! "example one to three) C 1 -C 4 alkyl radicals (eg methyl), oxo, hydroxyl or carbamoylmethyl. Alkyl or carbamoylmethyl substituents can be attached, for example, to the heteroatom or nitrogen heteroatoms.

The compounds of the present invention exhibit broad spectrum antibiotic activity, both in vitro and in vivo. They exert good activity against ί Gram-positive organisms and Gram-negative organisms, including many strains producing ß-lactamases. The compounds also have high stability to ß-lactamases produced by a series of Gram-negative and Gram-positive organisms.

The compounds according to the present invention have been found to exert good activity against strains of Staphylococcus aureus and Staphylococcus epider-3 midis, including strains producing penicillinase I - - of these Gram-positive bacteria. This characteristic is combined with good activity against various members of the I class of enterobacteriaceae (for example strains of § 20 Escherichia coli, Klebsiella pneumoniae, Enterobacter il cloacae, Serratia marcescens, Proteus mirabillis and Proteus indole-positive organisms such as Proteus vulgaris, Proteus morganii and Providence species and strains of Haemophilus influenzae and Acinetobacter 25 calcoaceticus, as also having activity against certain strains of the species Pseudoœonas. This combination of g J high activity against Gram- organisms positive and high activity against Gram-negative organisms exhibited by the compounds of the present invention is particularly unusual.

Derivatives of the nature of the non-toxic salts which can be formed by the reaction of the carboxyl group present in the compounds of formula (I) or by the reaction of any acidic hydroxyl group which may be found. "6 on the heterocyclic radical Y, include the salts with inorganic bases, such as the alkali metal salts (for example sodium and potassium salts) and the alkaline earth metal salts (for example calcium salts), salts with amino acids (e.g. salts with lysine and 1 Arginine) and salts with other organic bases (e.g. salts with substances

There are: procalne, phenylethylbenzylamine, dibenzylethylenediamine, ethanolamine, diethanolamine and N-methyl-glucosamine). Other derivatives of the nature of non-toxic salts include addition salts of acids, for example generated with hydrochloric acid, the acid! - * ·; hydrobromic, sulfuric acid, nitric acid, phosphoric acid, formic acid and trifluoroacetic acid. | V5 When appropriate, the compounds can also be in the form of an internal salt or an amphion. The salts can also be in the form of resins generated, for example, with a polystyrene resin or a resin of a copolymer of divinylbenzene and of crosslinked polystyrene, containing amino or aminoquaternary radicals or acidic>> sulfonic radicals, or with a resin containing groups | carboxyl for example a polyacrylic acid resin.

ÿ Salts with soluble bases can be used, for example alkali metal salts, such as! sodium, compounds of formula (i), in applica- | therapeutic, due to the rapid distribution of these salts in the body after their administration. However, when it is desired to work with insoluble salts of the compounds (I) for a particular application, for example in the case of the use of depot preparations, these salts can be formed in a conventional manner, by example with appropriate organic amines.

/. ¥ 7

It should be understood that the group Y can carry a positive charge, for example when Y represents a 1-methyl-pyridinium-2-yl radical and, when this is the case, the positive charge must be compensated by a negative charge.

5 Thus, the compounds can be betaines, so that the negative charge is provided by a group -C00 at position 4. The negative charge can also be provided by a g anion A, such an anion must be non-toxic and may originate from any of the acids described above which generate derivatives of the genus of non-toxic salts.

Derivatives of the nature of metabolically labile and non-toxic esters which can be formed by the esterification of the carboxyl group in the related compound of formula (i) include acyloxyalkyl esters, for example oxy (lower alkanoyl) esters -methyl or; -ethyl, such as acetoxy-methyl or j-ethyl or pivaloyloxymethyl esters and alkyl alkoxycarbonyloxy esters, for example ethyl (lower alkoxy) carbonyloxy esters, such as ethoxycarbonyloxyethyl esters. In addition to the aforementioned ester derivatives, the scope of the present invention [also extends to the compounds of formula (i) under the; forms other physiologically acceptable equivalents,! that is, physiologically acceptable compounds which, like the metabolically labile esters, are converted in vivo to the related antibiotic compound of formula (i).

The aforementioned derivatives and other salts and esters, such as the salts with toluene-p-sulfonic and methane-sulfonic acids, or the esters with these t-butyl or diphenylmethyl esterifying groups, can be used as intermediates for the preparation and / or purification of the compounds of formula (i) in accordance with the invention, for example by carrying out the methods described in 35 i following this memo.

/, 8

The preferred compounds according to the present invention are those in which Y represents a 1-methylpyridinium-2-yl, 1-methylpyridinium-4-yl, 1-methyltetrazol-5-yl, 1-methylpyridinium-3 radical. yl, 1,2-5 dimethylpyrazolium-3-yl, 1,3-dimethylimidazolium-3-yl, 1- methylpyrimidinium-2-yl, 1-carbamoylmethylpyridinium-4-yle, 2,5-dihydro-6-hydroxy-2 -methyl-5-oxo-1,2,4-triazin-3-yl, or 4,5-dihydro-6-hydroxy-4-methyl-5-oxo-1,2,4-triazin-3-yl. An especially preferred compound according to the invention is (6R, 7R) -7- ^ rz) -2- (2-aminothiazol-4-yl) -2- cyclopropylmethoxyiminoacetamido7-3- ^ ri-methylpyridinium-4- yl) thiomethyl7-3-th-4carboxylate and its non-toxic salts.

The compounds according to the present invention can exist in tautomeric forms (for example with regard to the 2-aminothiazolyl group or with respect to a substituent in position 3, such as the 2,5-dihydro-6-hydroxy- radical). 2- methyl-5-oxo-1,2,4-triazin-3-yl) and it should be understood that the scope of the invention also extends to the tautomeric forms of the compounds in question.

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

Ü 5 25 According to another of its characteristics, the present | a subject of the invention is also a process for the preparation g I of compounds of the cephalosporin series, which respond; has the general formula:

j ‘R

! 30 Λ

S N HH

! i ÄX = * "· / Tl

\ _ Λ COOR

9 c / 3 in which Y has the meanings which were previously assigned to it, B will represent or> S - ^ 0 (a or ß); the dashed line connecting positions 2,3 and 4 indicates that the compound is a substance 5 of the ceph-2-th or ceph-3-th type; R represents a hydrogen atom or a group blocking the carboxyl function, for example the remainder of an esterogenic araliphatic or aliphatic alcohol or of a stannanol, of a silanol or of an esterogenic phenol (said alcohol, phenol, silanol or stanna-! nol preferably containing from 1 to 20 carbon atoms) i or a group blocking the symmetrical anhydride function or mixed fp, derived from an appropriate acid and R represents a protected amino or amino group7 and their salts, characterized in that! s, - 13 (A) a compound of the formula is acylated

HH

IJ / K

i h2n T; ! } -N>. ^ —CH SY (II)! ^ Y 2 20 I i.

COOR

• J

(in which Y, B, the dashed line and R have the meanings previously assigned to them), or a salt of such a compound, for example an acid addition salt (generated with, for example example a mineral acid "such as hydrochloric acid, hydrobromic acid sulfuric acid, nitric acid or phosphcriqu-acid or an organic acid, such as methanesulfonic acid or toluene-4- acid sulfonic acid) or a 7-lily-silyl derivative of such a substance, or alternatively (when Y contains a quaternary nitrogen atom) a corresponding compound comprising a group of the formula —C00 in position 4, J with an acid of the formula / / j 10 “R2: λ ^ -t — C.COOH ΙΊΊΊ \ (in which has the meanings which have been previously assigned to it) or a salt of such a compound, 10 or with an acylating agent which therein matches; (B) reacting a compound of formula R2 I (IV> *

H H

ί \ f I § B

V - / - C.CO.NH --- * i T lï î 1 Pc J- ^ h2x

x ° ch2-o ° VT

COOR

1 2 (in which R, R, B and the dashed line have the meanings previously assigned to them and X represents the replaceable residue of a nucleophilic substance, for example an acetoxy or dichloroacetoxy radical or an atom of halogen, such as a chlorine, bromine or iodine atom (i) or a salt of such a compound, i on a sulfur-containing nucleophilic substance, | used to form the group -CH ^ SY (where Y has the meanings which have been previously assigned to it) in position 3, or (C) when the heterocyclic ring Y of the compound according to the present invention contains an atom of alkyl substituted or carbamoylmethyl substituted quaternary nitrogen, a compound of formula 4 is reacted

JL

/ »11 R2 (V)

g g B

\ = r ~ J— C. CO. NH - J- ^ j | 5 ^ OCH ^ -COOR1 (in which R2, B and the dashed line have the meanings which were previously given to them [attributed, R represents, in this circumstance, a group blocking the carboxyl function and Y * represents a Ί0 heterocyclic nucleus 5 or 6-membered, linked via a carbon atom, containing a tertiary nitrogen atom), on a C 1 -C 4 alkylating agent or a carbamoylmethylating agent, used to introduce a * alkyl group. · -C 15 or a carbamoylmethyl radical, as a substituent on the tertiary nitrogen atom of the heterocyclic ring re-; presented by Y ’; | then, if this proves necessary and / or desired; table in each circumstance, one implements no matter; Which of the following reactions, in any suitable order:> 2 * 3 ii) conversion of an Δ isomer to the desired Δ isomer, j ii) reduction of a compound in which B represents r> S 0 to form a compound in which B re-; Iii) conversion of a carboxyl group into a metabolically labile and non-toxic ester li function, iv) formation of an non-toxic salt and "v) removal of any groups blocking the carboxyl function and / or protecting K.

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

When the group Y in the formula (il) is charged, for example as in the case of a group K-alkylpyridinium, 12

and that the compound contains a radical of the formula -COOR

(in which R has the abovementioned meanings) in position 4, the compound comprises an associated anion E, such as a halide anion, for example chloride or bromide, 5 or trifluoroacetate.

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

!

Acylations can be carried out using acid halides, in aqueous and non-aqueous reaction media, conveniently at temperatures from -50 to + 50 ° C, preferably from -40 to + 30 ° C, if wish, in the presence! an acid-fixing agent. Reaction media ap- | properties include aqueous ketones, such as aqueous acetone, aqueous alcohols, such as aqueous ethanol, esters, such as ethyl acetate, hydro- halogenated carbides, such as methylene chloride, amides, such as dimethylacetamide, nitriles, such as acetonitrile, or mixtures of two or more of these solvents. Suitable acid scavengers include tertiary amines (eg triethylamine or dimethylaniline), inorganic bases (eg calcium carbonate or sodium bicarbonate) and oxyranes, such as 1,2-alkylene oxides (eg, ethylene oxide or propylene oxide) which bind to the hydrohalic acid released during the acylation reaction.

j The acids of formula (III) can be used | | î I same as acylating agents for the preparation of! t. / '13 compounds of formula (i). It is desirable to carry out the acylations using the acids (III) in the presence of a condensing agent for example a carbo-diiraide, such as Ν, Ν'-dicyclohexylcarbodiimide or 5 N-ethyl-iî'-y- dimethylaminopropylcarbodiimide; a carbonyl compound, such as carbonyldiimidazole, or an isoxazolium salt, such as N-ethyl-5-phenyl- perchlorate

Iisoxazolium.

Acylation can also be carried out with other amidogenic acid derivatives of formula (III), such as, for example, an activated ester, a symmetrical anhydride or a mixed anhydride (eg formed with pivalic acid than or with a haloformate, such as a lower alkyl haloformate). Mixed anhydrides can also be formed with phosphorus acids (eg phosphoric acid or phosphorous acid, sulfuric acid or aliphatic or aromatic sulfonic acids (eg toluene acid). It is convenient to form 1 an activated ester in situ, using, for example 1- I hydroxybenzotriazole, in the presence of a condensing agent as described above. 'ester activated.

It is desirable to carry out acylation reactions involving free acids or their amino derivatives; 25 genes mentioned above operating in an anhydrous reaction medium, for example methylene chloride, tetra-) hydrofuran, diraethylformamide or acetonitrile.

; XJn another activation process consists, for example, J: reacting an acid of formula (III) on a solution! 30 tion or a preformed suspension by adding a housing | carbonyl, more particularly oxalyl chloride, | or phosgene or a phosphoryl halide, such as phosphorus oxychloride, to a solvent, such as a halogenated hydro carbide, for example methylene chloride, containing a lower acyl tertiary amide, such as: Ν, Ν-dimethylformamide. The activated form of the acid of the formula (III) can then be reacted with a compound of the 7-amino type of the formula (II) in a suitable solvent or in a mixture of suitable solvents, for example a halogenated hydrocarbon, for example 5-dichloromethane. The acylation reaction can conveniently be carried out at temperatures from -50 to + 50 ° C, preferably from -40 to + 30 ° C, if desired in the presence of an acid-binding agent, for example as described above (for example dimethylaniline). If desired, the above-mentioned acylation reactions can be carried out in the presence of a catalyst, such as 4-dimethylamino-pyridine.

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, it is convenient to use acid chlorides in the form of their salt hydrochlorides and acid bromides in the form of their salt hydrobromides.

In the aforementioned process (B), the sulfurized, i.e. sulfur-containing, nucleophilic substance can be used to displace a wide variety of cephalosporin X substituents of the formula (IV). To some extent, the ease of displacement is related to the pKa of the HX acid from which the substituent originates.

Thus, atoms or groups X from strong acids tend, in general, to be more easily displaced than atoms or groups from weak acids. The . ease of movement is also related, to some extent, to the accuracy of the sulfurized nucleophilic substance. The latter nucleophilic substance can be used, for example, in the form of a suitable thione or thiol.

The displacement of X by the sulphonated nucleophilic substance sul-35 can conveniently be carried out while maintaining the u i 15.

reagents in solution or in suspension. The reaction is advantageously carried out using equivalents 1 to I-: 10 molar of the nucleophyll substance. Nucleophyll shift reactions can conveniently be carried out on compounds of formula (IV) in which the substituent X represents a halogen atom or an acyloxy group, for example, as described below.

Acyloxy groups

The compounds of formula (IV) in which X re-10 has an acetoxy group constitute convenient starting materials to be used for carrying out the nucleophyll displacement reaction with the sulfurized nucleophyll substance. Other suitable starting materials of this class include compounds of formula (IV) in which X represents the residue of one. ‘Substituted acetic acid, for example chloracetic acid I dichloracetic acid and trifluoroacetic acid.

î | The displacement reactions carried out on compounds (IV) having substituents X of this class, more particularly of the class belonging to the substances in which X represents an acetoxy group,! can be facilitated by the presence in the reaction medium of iodide or thiocyanate ions.

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, it is generally desirable that the group R in formula (IV) is a hydrogen atom and that B represents. In this case, the reaction is advantageously carried out in an aqueous medium.

Under aqueous conditions, the pH value of the reaction solution advantageously remains in the range from 6 to 8, if this proves necessary by the addition of a base. The base is conveniently a baking soda

æL

; / / 16%

Iou alkali metal or alkaline earth metal hydroxide, such as sodium bicarbonate or sodium hydroxide.

When using compounds of formula (IV) in which X represents an acetoxy radical, reaction 5 is conveniently carried out at a temperature which fluctuates from 10 to 110 ° C, preferably from 20 to 80 ° C.

Halogens

The compounds of formula (IV) in which X represents a chlorine, bromine or iodine atom, can also conveniently be used as starting materials for carrying out the nucleophilic displacement reaction with the sulfurized nucleophilic substance. When using compounds of formula (IV) belonging to this class, B can conveniently represent 3> S and R ^ 15 can represent a group blocking the carboxyl function. The reaction is conveniently carried out in a non-aqueous medium which preferably consists of one or more organic solvents, advantageously of a polar nature; such as ethers, for example dioxane or tetrahydro- | Furan, esters, for example ethyl acetate, J amides, for example formaroide and N, N-dimethylformamide * 1 and ketones, for example acetone. Other suitable organic solvents are described in more detail in the specification of British Patent No. 1,326,531. The reaction medium should be neither acidic nor extremely basic.

In the case of reactions carried out on the compounds η of formula (IV) in which R represents a group blocking the carboxyl function and the substituent Y resulting from 30 as long as contains a quaternary nitrogen, the product will be formed in the form of the halide salt corresponding, which can, if desired, be subjected to one or more ion exchange reactions to obtain a salt containing the desired anion.

”L“ ““ ““ / I.

Ί7 "in which X represents a halogen atom as described above, the reaction is conveniently carried out at a temperature of -20 to + 60 ° Cf preferably from 0 to 30 ° C.

When the incoming nucleophile does not generate a compound containing a quaternized nitrogen atom, the reaction is generally carried out in the presence of an acid-binding agent, for example a base, such as triethylamine or | calcium carbonate.

In process (C) above, advantageously | reacting the compound of the formula (V) with a compound of the; formula R ^ Z in which represents an alkyl radical II to C-j-C ^ or a group of the formula i ^ NCOCl · ^ - and Z re- | has a labile substituent, such as a halogen atom (eg, iodine, chlorine or bromine), or a group j. : hydrocarbylsulfonate (for example mesylate or tosylate).

| One can also use a dialkyl sulfate C ^ -C ^,! ^ for example dimethyl sulfate, as agent; alkylation. Iodomethane is preferred as the alkylating agent and iodoacetamide is preferred as the alkylating agent. carbamoylmethylation. The reaction is preferably carried out at a temperature which fluctuates from 0 to 60 ° C, advantageously from 20 to 30 ° C. When the alkylating agent is liquid under the reaction conditions, such as iodomethane, this agent can itself serve as a solvent.

The reaction can also conveniently be carried out in an inert solvent, such as an ether, for example tetrahydro-furan, araide, for example dimethylformamide, a lower alkanol, for example ethanol, a di (lower alkyl) ketone, for example acetone, a halogenated hydrocarbon, for example dichloromethane, or an ester, i for example ethyl acetate.

! The compound of formula (V) used as starting material for carrying out method (C) can be prepared, for example, by the reaction of a substance J ^ of formula (IV) ( as previously defined) on a! 1 I / suitable sulfurized nucleophilic substance, in a manner analogous to that carried out with respect to the nucleophilic displacement reaction described with regard to process (B),

If desired, the above-mentioned ophilic substance can be used in the form of a metal salt thiolate.

When X, in formula (IV), represents a halogen, the reaction is carried out, preferably, in the presence of an I acid-fixing agent, for example a base such as I; triethylamine or calcium carbonate.

| The reaction product can be separated from the reaction mixture which may contain, for example, unmodified cephalosporin starting material and the like: substances, by means of a whole series of processes, comprising recrystallization, iontophoresis, column chromatography and the use of ion exchangers (for example by chromatography on ion exchange resins) or macroreticular resins.

2

We can convert an ester type derivative of Δ -! cephalosporin by implementing the method according to j 3; 20 present invention in the corresponding derivative desired, 2 for example, by treatment of the ester Δ with a base, such as pyridine or triethylamine.

When a compound in which B represents> 3 -> 0 is obtained, it can be converted into the corresponding sulfide, for example by reduction of the corresponding acyloxy sulfonium or alkoxysulfonium salt, prepared in situ by the reaction on, for example acetyl chloride in the case of an acetoxysulfonium salt, the reduction being carried out, for example, using sodium citnionite or iodide ions, as in a solution potassium iodide in a water-miscible solvent, for example acetic acid, acetone, tetrahydrofuran, dioxane, di-methylformamide or dimethylacetamide. The reaction can conveniently be carried out at a temperature of from -20 to + 50 ° C .; r 19

Derivatives of the metaboli-labile ester type of the compounds of formula (I) can be prepared by reacting a compound of formula (i) or a protected salt or derivative of such a compound, on the esterifying agent conve -5 nable, such as an acyloxyalkyl halide or an alkoxy carbonyloxyalkyl halide (for example iodide) conveniently in an organic solvent, such as dimethylformamide or acetone, this reaction being followed, if necessary, the removal of any protecting groups.

Salts of the compounds of formula (I) can be formed with bases by reacting an acid of formula (i) on a suitable base. Thus, for example, the sodium or potassium salts can be prepared using! 15 the salt of the 2-ethylhexanoate type or the hydrogen carbonate j <: respectively. Acid addition salts can be prepared by reacting a compound of formula (I) or a derivative! of the metabolically labile ester type of such a compound, on the suitable 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 crystallization or chroaato- j graphie.

As starting materials for the preparation of compounds of general formula (I) according to the present invention, there are preferably used substances of general formula (III) and amidogenic derivatives of such substances. , such as anhydrides and halo-JO genides of acids which correspond to them, in the form of the isomer I syn or in the form of mixtures of the isomers syn and! anti-corresponding isomers, containing at least 90 de | the syn isomer.

; Acids of formula (III) and J5 J and their derivatives can be prepared by etherification of a compound of! *! / | / 8 t 20 formula R2 I (VII) 20 s Λ.

5 V-J— C. COOR4

II

NOT\

OH

Π0 (in which R ^ has the meanings which have been previously assigned to it and represents a hydrogen atom or a group blocking the carboxyl function) or a salt of such a compound, by the selective reaction on a compound of the general formula 1 15 t.ch2- <1 d (in which T represents a halogen atom, such as a chlorine, bromine or iodine atom, a sulphate group or; a sulphonate group, such as t-toluenesulphonate), this reaction being followed by the elimination of any | 20 group blocking the Ryle carboxyl function. The separation of the isomers can take place either before or after such etherification. The etherification reaction is conveniently carried out in the presence of a base, for example potassium carbonate or sodium hydride and is preferably 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 oxyiroino group remains 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! h i - 21 formula (Vil). The base must be used in a sufficient proportion to quickly neutralize the acid in question.

Acids of formula (III) can also be prepared by the reaction of a compound of formula (IX) 5 20 r2 Λ I S \ _ / H 4 (IX>

I '-1 — CO. COOR

1 2 4 »I (in which R and R have the meanings which I 10 were previously assigned to them), I on a compound of the formula (X)! H2N.O.CH2 - <^ j (x) s I followed by the elimination of any group blocking f Δ ï 15 the carboxyl function R and, if necessary, 3 by the separation of the syn isomers and anti.

J The acids of formula (III) can be converted into the acid addition salts, into the anhydrides and halo-

Ij corresponding acid genides, using conventional methods, for example those previously described, fj When X represents a halogen atom (for example a chlorine, bromine or iodine atom) in the compound i; , of formula (XV), it is possible to prepare the starting substances -i of the ceph-3 ~ th type in a conventional manner, for example; By halogenation of a 1-S-amino acid ester oxide 3-S methylceph-3-èrae-4-carboxylic 7K_Prégégé, removal of the group protecting the position 7ß> acylation of the compound 7p-II amino thus obtained to form the desired 7p-scylamldo-radical, for example in a manner analogous to the above-mentioned process 30 (A), this acylation being followed by the reduction of the Iβ-oxide group later during the course of the operations. . This procedure is described in i / / 22 British patent N ° T 326 53T. The corresponding ceph-2-th type compounds can be separated, by implementing the method described in the published Dutch patent application, N® 6,902,013, by the reaction of a compound 5 of the 3-methylceph-2 type. -th on N-bromosuccinimide, so as to obtain the type 3 compound “bromomethylceph-2— th corresponding.

When X, in formula (IV), represents an acetoxy group, such starting materials can be prepared, for example, by acylation of 7-aminocepha-losporanic acid, for example in a manner analogous to that described in connection with the above-mentioned process (A). The compounds of formula (IV) in which X represents a substituent other than acyloxy radicals, can be prepared Ί5 by the acylation of the corresponding 3-bydroxymethylated compounds, for example, by the hydrolysis of the appropriate methylated 3-acyloxy compounds, for example, as described by way of illustration in the specification of British Patents Nos. 1,474,519 and 1,531,212.

Compounds of formula (II) can also be prepared in a conventional manner, for example by nucleophilic displacement of a corresponding 3-acoxymethylated or 3-halomethylated compound on the suitable nucleophile, for example as described in the patent specification. British N ° 1,012,943, 1,241,657, 2,027,691A and 2,046 26IA.

Another method of preparing the starting materials of formula (II) comprises deprotecting a corresponding protected 7-amino compound, for example, conventionally, for example using PCl ^.

It should be understood that in some of the above-mentioned transformations, it may be necessary to protect any sensitive groups present in the molecule of the compound in question to avoid unwinding-35 | ment of an undesirable side reaction. For example, Γ / / 23

It 1 during any of the reaction sequences described above, it may prove necessary to protect the NH 2 group from the aminothiazolyl radical, for example by tritylation, acylation (for example chloracetylation or formylation), protonation or any other process appropriate, so that the protected group remains stable in

The reaction conditions which govern one or more of the stages of the synthesis. The protecting group can then be removed in any convenient manner which does not cause rupture 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 Ί5 acid, for example hydrochloric acid, or using! mixtures of such acids, for example in the presence of a protic solvent, such as water, or, in the case of a chloroacetyl group, by treatment with thiourea.

The carboxyl blocking groups used [1 20 for the preparation of the compounds of formula (I), or

Fj for the preparation of the necessary starting materials, |: are advantageously groups which can easily be separated during an appropriate stage from the continuation of the reactions, conveniently during the last stage. In such circumstances, however, it may be convenient to use metabolically labile, non-toxic carboxyl blocking radicals, such as acyloxy-methyl or -ethyl radicals (eg acetoxy-methyl or Γ -ethyl or pivaloyloxymethyl). , or alkoxy- radicals! Carbonyloxyalkyl (eg ethoxyc & rbonyioxyethyl) ij | and keep these substituents in the final product so as to obtain a suitable ester derivative of a 5i; composed of formula (i). Suitable carboxyl blocking groups are well known to those skilled in the art, a list of illustrative blocked carboxyl radicals appearing in British Patent No. 1,399,086. Preferred blocked carboxyl radicals include aryl (lower alkoxy) carbonyl groups, such as p-methoxybenzyl- oxycarbonyl, 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 can subsequently be removed by the use of any of the appropriate methods described in the literature; thus, for example, acid or base catalyzed hydrolysis in many cases complicates, as can enzymatically catalyzed hydrolyses.

It should be understood that the use of groups protecting the amino function and blocking the carbo-xyl function is well known to those skilled in the art and relevant examples of such use appear, for example in the works of Theodora W. Green, "Protective Groups in Organic Synthesis" (Wiley-Interscience, New-York, 1981) and JFW HcOmie, "Protective Groups in Organic 20 Chemistry" (Plenum Press, London, 1973).

The antibiotic compounds according to the present invention may be presented in a form suitable for administration by any convenient route, in analogy to other antibiotics, and therefore the scope of the present invention is also extends to pharmaceutical compositions characterized in that they contain an antibiotic compound in accordance with the present invention, suitable for use in human or veterinary medicine. Such compositions can be presented in a conventional manner using any necessary excipienis or pharmaceutical vehicles.

The antibiotic compounds according to the present invention can be introduced into compositions suitable for injection and can be presented in the form of doses / 25 4 contain multiple doses, if necessary with a complementary preservative. The compositions may also adopt forms such as suspensions, solutions or emulsions in oily or aqueous vehicles and may contain composing agents, such as suspending, stabilizing and / or dispersing agents. The active ingredient may furthermore be in the form of a powder to which an appropriate vehicle must be added, 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 mixed "with water, the pH of the aqueous composition thus formed is physiologically acceptable. The base can also be present in the water which is added to the powder. The base can be, for example, an inorganic base, such as sodium carbonate, bicarbonate sodium or sodium acetate, or an organic base, such as lysine or lysine acetate.

The antibiotic compounds can also be presented, for example, in a form suitable for absorption by the gastrointestinal tract, for example in the form of tablets or capsules.

The antibiotic compounds can also be presented, for example, 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 with sustained or rapid release of the active principle.

The compositions can contain from 0.1%, for example 0.1 to 99%, of the active material, depending on the desired mode of administration. When the compositions are in the form of unit doses, each unit dose preferably contains from 100 to 3,000 mg,

For example, 200 to 2,000 mg of the active ingredient. The dose as used for the treatment of adult humans fluctuates, preferably, from 200 to 12,000 mg, for example from 1,000 to 9,000 mg per day, depending on the mode and frequency of administration. For example, for the! treatment of adults, 400 to 6,000 mg of in | 10 active ingredients per day, administered intravenously or intramuscularly, are normally sufficient. Higher daily doses may be required

To treat Pseudomonas infections. It should be understood that in certain circumstances, for example

B

For the treatment of newborns, unit doses and lower daily doses may be desirable.

The antibiotic compounds according to the present invention can be administered in combination with other agents! 20 therapeutic, such as antibiotics, for example | penicillins or other cephalosporins.

! The examples which follow illustrate the present invention without, however, limiting it. In these examples, all temperatures appear in 25 degrees Celsius. Sorbsil U30 is a silica gel manufactured by the company Joseph Crosfield and Son of Varrington, Lancashire, England. The abbreviation THF denotes tetrahydrofuran, DMF denotes N, N-dimethyl-I formamide and DMSO denotes dimethyl sulfoxide.

PREPARATION 1 (Z) -2-CyclopropyImethoxyimino-2- (2-tritylamino- || thiazol-4-yl) ethyl acetate Î * (z) -2-hydroxyimino-2- (2-tritylamino was stirred -

thiazol-4-yl) ethyl acetate ^ hydrochloride salt, (30 g) d- 35 ^ with cyclopropyl bromide (13.5 g) in DMSQ

Γ / 27 ("150 ml) containing potassium carbonate (30 g), under a nitrogen atmosphere, at 21 °, for 7 hours. The mixture was divided between water and methylene chloride. extract the aqueous layer 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 was I introduced into a column of Sorbsil U30 (200 g), the column was eluted with ethyl acetate (10 to 30%) in petroleum ether (PE 40-60 °). Evaporation of the appropriate fractions made it possible to obtain the compound indicated in the title (20.9 g); * max (ethanol) 234.5 nm (^^. 403);! 254.5 nm ( E ™ m 302), 259.5 nm (E ^ 267), 265 nm: (E ^ ffi 229), 271.5 nm (E ^ m 190) and 294 nm (E ^ 111); 15 0max (CHBr3) 3398 (HH), 1730 (ester) and 1593 and 1491 οπΤ1 j (aromatic double bond).

! PREPARATION 2! (Z) -2-Cyclopronylmethoxyirriino-2- (2-tritylamino-i thiazol-4-yl) acetic acid.

The product of Preparation 1 (20 g) was dissolved in ethanol (200 ml) and sodium hydroxide (3 ”* 2 g) was added in water (40 ml) . The mixture was brought to reflux for 45 minutes, during which time precipitation occurred. Etha-nol (about 150 ml) was distilled off and the residue p was cooled. The mixture was partitioned between methylene chloride and water containing 2N c-lorhydriaue 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 with magnesium sulfate and evaporated to give the title compound (20 g); Ä ± nf (ethanol) 234.5 nm (e! J * 383)

TL

/

J

I t 28 259.5 nm (E ^ m 242), 266.5 nm (E ^ m 226) and 272.5 nm ^ E1cm 2π ^ ° max (Nuü ° D 326 ° (NH) and 1685 cm “1 ( acid).

PREPARATION 3 (6R, 7R) -3-Bromomethyl-7- / Tz) -2-cyclopropylinethoxviniino-2- 15 (2-trltylaminothiazol-4-yl) -acetamido7ceph-3-th-4-carboxylate dlphenylmethyl.

Oxalyl chloride (0.57 ml) was added to a solution of DMF (0.38 ml) in methylene chloride | (10 ml) at -20 °, with stirring, under a nitrogen atmosphere.

The mixture was stirred under cooling with ice water for 10 minutes, before being re-cooled to -20 °.

(Z) -2-cyclopropylmethoxyimino-2- (2- J .. "'tritylaminothiazol-4-yl) acetic acid (1.9 g) was added and the solution was stirred under cooling to ice water for $ 10 x 15 minutes before re-cooling to -20 ° C. A suspension of diphenylmethyl (6R, 7R) -7-amino-3-bromomethylceph-3-th-4-carboxylate was added , hydrochloride salt, (1.98 g) in methylene chloride (10 ml) containing | N, N-dimethylaniline (1.76 ml). A clear solution formed when the mixture was heated to at 21 ° over 1 hour The solution was washed with dilute hydrochloric acid and water, each wash liquor being re-extracted with additional methylene chloride and the extracts were dried combined with magnesium sulfate and evaporated to a small volume The solution thus obtained was filtered through Sorbsil U30 (50 g) in acetate | d ethyl and the eluate was evaporated and crystallized! residue (3.54 g) in a mixture of diethyl ether and 1:30 of petroleum ether (P JE. 40-60 °), so as to obtain the compound indicated in the title (2.43 g) PF 135-147 °, IZ "721 -n, 9 ° (c 0.6, CHC13).

r ° "29 PREPARATION 4 (IS, 6R, 7R) -3-Bromomethyl - 7- / 12) -2-cyclopropylmethoxylmino- 2- (2-tritylaminothlazol-4-yl) acetamldo7ceph-3-th-4-carboxylate diphenylmethyl, 1-oxide.

(6R, 7R) -3-kromornethyl-7- ^ rz) -2- was dissolved. cyclopropylmethoxyimino-2- (2-tritylaminothiazaL-4-yl) acetamido7ceph-3-th-4-carboxylate of diphenylmethyl (1.2 g) in methylene chloride (10 ml) and 3 ~ chloroperbenzoic acid was added (292 mg) under agitation-10 tlon and cooling with ice water. After 30 minutes, the solution was washed with an aqueous sodium bicarbonate solution and water (2 times). After drying over magnesium sulfate, the solution was concentrated and purified on a column of Sorbsil I> 30 (50 g) which was eluted using ethyl acetate (50 80%) in petroleum ether (PE 40-60 °) so as to obtain the compound indicated in the title (1.1 g); "+ Ί4> 2 ° (ç 1.23, CHC13); * inf1 244.5 nm (E ^ 260), dd 258.5 nm (E ^ 232), 266 nm (E ^ ffi 225) and 272 nm ( E ^ 214).

20 EXAMPLE 1 | (a) (6R, 7R) -7- / r2) -2-Cyclopropylmethoxyimlno-2- (2-tritvl- • i amlnothiazol-4-yl) acetamido7-5- / T1-methylpyridinium-4-yl) I „thiométhvl7ceph -5-th-4-diphenylmethyl carboxylate, bromide.

II

25 We dissolved di (6R, 7R) -3-broœoir: ethyl-7 - / (Z) -2-cyclopropyl- ir! Îmethoxyimino-2- (2-tritylaminothiazol-4-yl) acetamido7ceph-3-

| th-4-carboxylate. diphenylmethyl (1.2 g) in THF

(20 ml), with stirring, at 21 ° and 1-d: methylpyrid-4-thione (162 mg) was added. After 2.25 h and 3.75 h, f; Additional fractions of 1-methylpyrid-4-thione (50 mg each) were added. After 6 hours, the solution was diluted with diethyl ether (80 ml) and a. stirred the mixture at the temperature of the ice bath for! It's a few minutes. The precipitate was collected by filtration,! r

V

washed with diethyl ether and dried to obtain the title compound (1.27 g), 30% "7q1> 29.7 ° (c 0.71, DMSO) , ^ max (Nu3ol) 1784 (ß-lactam), 1720 (ester) and 1675 and 1520 cm-1 (amide).

5 (b) (6R, 7R) -7- / ΓΖ) -2- (2-Aminothlazol-4-yl) -2-cyclopropyl- methoxyiminoacétamido7 ~ 3- / rl-methylpyridinlum-4-yl) thiomethyl7ceph-3-th -4-carboxylatet dihydrochloride salt The above-mentioned ester (1.1 g) was dissolved in formic acid (4 ml) and concentrated hydrochloric acid (0.29 ml) was added. After shaking at 21 ° pen-! After 1.5 hours, the mixture was filtered and the filter cake was leached with ί formic acid. The combined filtrates were evaporated until a gum was obtained which was triturated with acetone and dried so as to collect the title compound (560 mg), -39 , 7 ° (ç 1,03, DMS0), i> max (Nujol) 3680 - 2200 (OH, NH and 1780 (ß-lactam), i 1710 (COOH) and 1675 and 1550 cm "1 (amide), i !: EXAMPLE 2 '20 (a) (6R, 7R) -7- / Tz) -2-CycloprGpylrnethoxyiroino-2- (2-trityl-! Amlnothiazol-4-vl) acetanildo7-5- / r l-methvlpyridinium-2 (vl) dlphenylmethyl thlomethyl7ceph-3-th-4-carboxylate (6R, 7R) -3-bromomethyl-7- / Tz) -2 was agitated -2-cyclo-propylmethoxyimino-2- (2-tritylaminothiazol-4-yl ) acetamidu7 25-diphenylmethyl ceph-3-th-4-carboxylate with 1-i methylpyrid-2-thione (162 mg) in THF (20 ml) at 21 ° for 2 hours. An additional amount was then added 1-methylpyrid-2-tnione (160 mg) After 4 days at 21 °, the solution was heated to reflux for 3 hours, finely divided calcium carbonate (excess) was added and again waved on mix at 21 ° d for 2 days. The mixture was filtered and the filtrate was diluted with diethyl ether (80 ml). We have ! Collected the precipitate by filtration, washed with ether and dried so as to obtain the title compound. (540 mg), (ethanol) 240.5 nm (E- jpm 245), 265 nm (E ^ m 208), 272 nm (E1 ^ 198), 308 nm 5 (E1cm 9l), s, max (Nu3o1) 3700-2500 (NH), 1790 (ß-lactam), Ί725 (ester), 1680 and 1520 cm "1 (amide).

(b) (6R, 7R) -7- / Tz) -2- (2-Aminothiazol-4-yl) -2-cyclopropyl | methoxyiminoacetamido7-3- / rl-methylpyridlnium-2-yl) | thiomethyl / ceph-3-th-4-carboxylate, dihydrochloride salt 10 The above-mentioned ester (480 mg) was dissolved in formic acid (2 ml) and concentrated hydrochloric acid I was added (0.13 ml). After stirring for 1 hour at 21 °, the mixture was filtered and the filter cake was leached with formic acid. We evaporated. 15 the combined filtrates and the residue was triturated with acetone so as to obtain the compound indicated in the title (300 mg) il Λαν (Nujol) 3700-2300 (1JH® »NH and OH), 1780 (ß-lactam ), jv EQôX η 3 * j 1710 (acid), and 1680 cm "(amide). τ (d ^ -DHSO) includes i 0.90 (d, J6 Hz), 1.58 (t, J 6Hz), 1.88 (d, J 6Hz) and 2.12 (t, J 6Hz) pyridyl protons); 3.09 (thiazole protons); and 8.88, 9.30 to 9.80, multiplets, cyclopropyl protons.

i EXAMPLE 3 (a) (6R, 7R) -7- / Tz) -2-Cyclopropylmethoxyliriino-2- (2-trltyl- amlnothiazol-4-yl) acetamido7-3- / rl-methyl-1H-tetrazol-5- γΙ) 25 thiomethyl7ceph ~ 5 ~ th-4-diphenylmethyl carboxylate

Oxalyl chloride (0.37 ml) was added to a solution of DMF (0.38 ml) in methylene chloride (10 ml), with stirring at -20 °. The mixture was allowed to warm to 0 ° for 5 minutes, before re-cooling to -20 °. Acid (Z) - j was added; 2-cyclopropylmethoxyimino-2- (2-tritylaœinothiazol-4-yl) acetic II (1.94 · g) and the solution was stirred at 0 · for 5 minutes. After re-cooling down to -20 °, we have! 2— i / 32 added a suspension of (6R, 7R) -7-amino-3- ^ r'l-methyl-1-H-tetrazol-5-yl) thiomethyl7ceph-3-th-4-carboxylate (1, 98 g) in methylene chloride (10 ml) containing dlmethylaniline 0.26 ml). The solution was allowed to warm to 21 ° over the course of an hour. We diluted the solution with an additional amount of methylene chloride and washed it with acid! * dilute hydrochloric. The aqueous layer was extracted with; an additional amount of methylene chloride and! The combined organic layers were washed with water, dried over magnesium sulfate and evaporated to a small volume. The solution was chromatographed on Sorbsil U30 (70 g) in a gradient of ethyl acetate (10 to 50%) in petroleum eth (PJ £ 40-60 °), so to obtain the compound indicated '- 21 in the title (3.28 g) in the form of a foam, -83.4 ° (ç 0.91, CHCl3)> 0max (CHBr3) 3400 (NH), 1780 ( p-lactam), 1725 (ester) and 1685 and 1515 cm - "* (amide).

(b) (6R, 7R) -7- / Tz) -2- (2-aminothiazol-4-yl) -2-20 cyclopronylmethoxyiminoacetamldo7-3- / rl-methyl-1H-5-yl) thiomethyl7ceph-3- th-4-carboxylic trifluor-acetate salt

The above-mentioned ester (3.14 g) was dissolved in anisole (6.5 ml) with stirring at 21 ° and trifluoroacetic acid (25 ml) was added. Water (1.5 ml) was added after 1 hour. After an additional 5 minutes, the solution was evaporated to half its volume and diisopropyl ether (about 100 ml) was added thereto. The precipitate was collected by filtration, washed with diisopropyl ether and dried to give the title compound (2.02 g), LUQ1 -40.7 ° (c 0.44, DMSO), \> max (Nujol) 3700-2200 (NHj0, J OH, NH), 1770 (p-lactam), 1725 (acid) and 1690 cm "'(friend-).

r »33 # - EXAMPLE 4 (a) (1S, 6R, 7R) -7- / Tz) -2-Cyclopropylmethoxylmino-2- (2-trltylaminothiazol-4-yl) acetamido7-3- / T1-methylpyrldinium- 4- yl) dlphenylmethyl thiomethyl7ceph-3-eme-4-carboxylate 5 (1S, 6R, 7R) -3-bromomethyl-7- 1-oxide was stirred

^ Z) -2-cyclopropylmethoxyiroino-2- (2-tritylaroinothiazol — 4-yl) dlphenylmethyl acetamido7ceph-3-th-4-carboxylate (700 mg) with N-methylpyrid-4-thione (125 mg) THI

ÎTHF (15 ml) at 21 ° for 3.5 hours. Diethyl ether was added and the precipitate was collected by | filtration, washed with ether and dried | so as to obtain the compound indicated in the title (700 mg) I “31.8 ° (ç 0.75, CHCl3), ^ max (Nujol) 1795 (ß-lactam), h 1722 (ester) and 1675 and 1512 cm - * 1 (amide).

ν '15 (b) (6R, 7R) -7- / TZ) - (2-Cyclopropylmethoxylmlno-2- (2-trityl- I ... aminothlazol-4-yl) acetamido7-3 - / ^ - inethylpyridinium-4 -yl) κι: thiomethyl7céph-3 ~ th-4-carboxylate of diphenylmethyl, ii '' mixed halide

1-oxide bromide (1S, 6R, 7R) -7- / IZ) - was stirred! 20 2-cyclopropylmethoxyimino-2- (2-tritylaminothiazol-4-yl) acetamido7 ~ 3- ^ r1-methylpyridinium-4-yl) thiomethyl7ceph ~ 3-th-4-carboxylate dlphenylmethyl (0.30 g) with I, potassium iodide (0.24 g) in acetone (2 ml): '. i * and DMF (2 ml), under cooling with ice water. Acetyl chloride (0.1 ml) was added and stirring and cooling were continued for 3 hours. We have j | poured the solution into an aqueous solution of metabisul; of sodium and the precipitate was collected by filtration.

The solid was washed with water and diethyl ether; And dried to obtain the title compound (1 mg (230 mg), with magnetic resonance spectra; nuclear tick, infrared and chromatography in; liquid phase under high pressure in accordance with those of! product of Example 1 (a).

AT

34 t

The product can be deprotected as described in Example 1 (b) to obtain (6R, 7R) -7- ^ Tz) -2- (2-aminothiazol-4-yl) -2-cyclopropylmethoxyiminoacetamido7- 3- ^ Tl-methylpyridinium-4-yl) thiomethyl7ceph-3-th-4-5 carboxylate, dihydrochloride salt.

EXAMPLE 3 (a) (1S, 6R, 7R) -7- / Tz) -2-Cyclopropyfnethoxvimino-2- (2-tritylamlnothiazol-4-yl) acetamldo7-5- (pyrid-4-ylthio-methyl) ceph-3 Diphenylmethyl-4-carboxyate ^, 1-oxide 10 1-oxide of (^ S, 6R, 7R) -3-'bΓomomethyl - 7- 7Γz) -2-cyclopropylmethoxyiInino-2- was stirred -tritylaminothiazol-4-yl) i acetamido7 ceph-3-th-4-carboxylate diphenylmethyl J (700 mg) with 4-mercaptopyridine (115 mg) and; finely divided calcium carbonate (700 mg) in acetone (20 ml) at reflux, for 2 hours and 10 minutes.

The mixture was cooled and filtered. The S ’filtrate was concentrated and chromatographed on silica gel (50 g).

; The column was packed with methylene chloride and was | successively eluted with methylene chloride, de | 20 ethyl acetate and 10% ethanol in acetate! ethyl. Evaporation of the appropriate fractions made it possible to obtain the compound indicated in the title (260 mg) under || the shape of a foam; (ZJjp -14.9e (ç 0.81, CHCl ^) \> max fl (CHBr,) 3485 (NH), 1808 (fJ-lactam), 1778 (ester) and 1681 1 3 _ i 25 and 1512 cm- (amide).

l'j (b) (1S.6R.7R) -7- / Tz) -2-Cvclopropylméthoxvimlno.-2- (2- tritylaminothlazol-4-vl) acetamido7-5- / T l-methylpyridinium- lit |: 4 -yl) diphenylmethylthiomethyl7céph-3-èse-4-carboxylate, 1-oxide, iodide djj 30 (1S, 6R, 7R) -7 - / '(Z) -2-cyclo- was dissolved propylmethoxyimino-2- (2-tritylaminothiazol ~ 4-yl) acetamido7-; 3- (pyrid-4-ylthiomethyl) ceph-3-th-4-carboxylate of diphenyl- methyl (100 mg) in methyl iodide (0.5 ml). After ji ^ 2. hours at 21 °, the solution was diluted with ether i! Diethyl and the precipitate was collected by filtration.

This product was washed with ether and dried to give the title iodide (70 mg), which resembled the bromide salt mentioned above by its infrared nuclear magnetic resonance spectrum and its chromatography in liquid phase under high pressure.

The product can be reduced as described in Example 4 (b) and deprotected as described in Example 1 (b), so as to obtain the (6R, 7R) -7- ^ TZ) - 2-10 (2-aminothiazol-A-yl) -2-cyclopropylmethoxyiroinoacétamido7- I3 ~ U1-methyl-pyridinium-4-yl) thiomethyl7ceph-3-th-4-carboxylate, dihydrochloride salt.

| EXAMPLE 6; i (a) Acid (6Rt7R) -7- / Tz) -2-cvclopropylmethoxyimino-2- (2- II 15 tritylaminothiazol-4-yl) acetamido7-3- / T 1.2,5 "6-tetrahydro-! * 2-methyl-5,6-dioxo-1,2,4-triazin-3-yl) thlomethyl7céph-3- I th-4-carboxylic. A solution of DMF (0.4 ml) in dichloromethane (0.5 ml) was treated at -10 ° with oxalyl chloride! 20 (0.15 ml) and the mixture was stirred for 15 minutes at i; -10 °. (Z) -2-cyclopropylmethoxyimino-2- (2-tritylaminothiazol-4-yl) acetic acid (721 mg) was added. We stirred ;; - this solution in an ice bath for 15 minutes.

This solution was then added to a solution of (6R, 7R) -7-amino acid> -3 "^ I1,2,5,6-tetrahydro-2-methyl-5" 6-dioxo-1,2 , 4-triazin-3-yl) thiomethyl7ceph-3-th-4-carboxylic l. (500 mg) (which can be prepared in the manner described t · in the description of European patent application 0065748) in industrial alcohol denatured with methanoi * | 30 (6 ml), water (0.65 ml) and triethylamine (1.9 ml), p The resulting solution was stirred at 0 ° for 1 hour.

After stirring for an additional 10 minutes at 21 °, έοη distributed the reaction mixture between dichloromethane and a 2N hydrochloric acid solution. The organic layer was separated, washed with water, dried and evaporated so as to obtain the acid indicated in the title in the form of a foam (1.12 g); / 07-, -37 * 91 ° (c 0.91; η - u DMS0) '^ max (CHBr5) 3700-2700 (OH), 3395 (NH), 1789 (ß-5 lactam), 1738 (ester group + other carbonyl groups), 11669 and 1523 cm ”^ (amide).

(b) (6R, 7R) -7 / Çz) -2- (2-aminothlazol-4-yl) -2-cyclo-propylmethoxylminoacetamido7-3- / T1,2,5,6-tetrahydro-2-methyl- 5 "6-dioxo-1,214-triazin-3-yl) thlométhvl7céph-3-10 th-4-carboxylic, formate salt IOn the ester of step (a) was dissolved (1.169 g) in formic acid (9.3 ml). The solution was stirred and water (3.2 ml) was added. The mixture was stirred at 21 ° for 1.5 hours. The solid was then separated by; 15 filtration. The filtrate was concentrated to a small eye. volume and diisopropyl ether was added thereto. The solid thus obtained was collected by filtration, washed with diisopropyl ether and dried so as to collect the title compound in the form of a solid (654 mg) ; ZË7D ~ 51.35 ° (ç 0.74; DMS0) »\> max (Nujol) 3650-2700 (OH + NH), 1779 (ß-lactam), 1738 (ester ί + dioxo) 1675 + 1530 (amide) and 1625 cm ”'1 (carboxylate).

i

EXAMPLE A

Dry powder for injection 25 (6R, 7R) -7- / Tz) -2- (2-aminothiazol- 4-yl) -2-cyclopropylmethoxyirr; inoacétaiiiido7-3-Z ^ 1_in®'tByIpyrI “dinium- 4-yl) thiomethyl7ceph-3-ene-4-carboxylate sterile aseptically in glass vials, so that each vial contains 1 g of the pure anhydrous material.

30 The upper spaces of the vials must be purged with sterile nitrogen; the vials must be closed using rubber plugs or discs and metal capsules r 9 37

B

overlapping (applied by crimping). The product can be prepared by dissolving in water for injections or in any other suitable sterile vehicle 'Γ "“ ..........

ï, S

; i ’i i.

i <i b ïi \

Claims (8)

5 S ^ N SS \ = / _ c-CO.NH-1- (I) Il S? - CH SY NO * \ Λ I XOCH2 — Cl COOH (in which Y represents a 5- or 10 6-membered heterocyclic ring, linked by means of a carbon, containing at least one nitrogen atom, which nucleus may also; contain one or more sulfur atoms and / or be substituted by one or more C 1 -C 4 alkyl radicals, oxo, hydroxyl or carbamoylmethyl), as well as the non-toxic salts and the metabolically labile and non-toxic esters of these compounds. 2. Compounds according to claim 1, characterized I in that Y represents a 1-methylpyridinium-2-yl, 1-methylpyridinium-A-yl, 1-methyltetrazol-5-yl, 1-methyl-i pyridinium-5 radical -yle, 1,2-dimethylpyrazolium-3-yl, 1,3-dimethyl- I: - 'imidazolium-3-yle, l-methylpyridinium-2-yl, 1-carbamoyl-! methylpyridinium-4 ~ yle, 2,5-dihydro-6-hydroxy-2-methyl-5 “Oxo-! 1,2,4-triazin ~ 3-yl, or 4,5-dihydro-6-hydroxy-4-methyl-5-oxo-1,2,4-triazin-3-yl. . 25 3 · (6R, 7R) -7 - / ^ Z) -2- (2-Aainothi & zol-4-yl) -2-cyclopropylmethoxyiminoacetamido7-3- / T1-methylpyridinium-4-yl) thiomethyl7ceph-3-th -4-carboxylate and its non-toxic salts. 4. Process for the preparation of compounds according to claim 1, characterized in that 30 J (A) a compound of the formula ί / 39 * H H h2n f ^ is acylated (II) J-Nv CH ^ SY cr 2 5 COOR1 / Hans which Y has the meanings which were allotted to him in claim 1; B represents k * | > S or ^ S - ^ 0 (a or ß); R represents a hydrogen atom or a group blocking the carboxyl function and the line in dashed lines connecting positions 2,3 and i I 4 indicates that the compound is a substance of the ceph-j 2-th or ceph-3 type -ème7, or a salt or 7-N-silyl derivative of such a compound, or a corresponding compound having Θ a group of the formula -C00 in position 4, 15 with an acid of the formula R2 Λ \ = LC. COOH III> II N 20. OCH - <^ j 2 (in which R represents an amino or protected amino group) or a salt of such a compound, or with an acylating agent which corresponds to it, (B) a compound of the formula is reacted 25 R2 H H \ === JLc.co.m --- k — Y% {IV) iv, 0 30. Noch2 ~ <JI Ær "coora" ** 40 V Ί 2 ^ (in which R, R, B and the dashed line have the meanings previously assigned to them and X represents the replaceable remainder of a substance nucleophile), or a salt of such a compound, on a sulfurized nucleophilic substance used to form the group -CH ^ SY (where Y has the meanings which were assigned to it in claim 1) in position 3> or I ^ (C) when, in the desired compound according to claim 1, the heterocyclic ring Y contains an alkyl substituted or carbamoylmethyl quaternary nitrogen atom, a compound of formula 2 is reacted! R t J j 15 HHB {{\ = - J -C.CO.NH --yY '^ dd Il J —- NJ — ch2sy ·! N \ I °° Η2 \ | COOR1 2 (in which R, B and the line in lines interrupted 20 have the meanings previously assigned to them i 1, R represents, in this circumstance, a group blocking the function because boxyl and Y 'represents a 5- or 6-membered heterocyclic ring, linked via a carbon, containing a tertiary nitrogen atom), on a C 1 -C 4 alkylating agent or a carbaraoylmethylating agent used to introduce a C - C alkyl group. or a carbamoylmethyl group as a substituent |> · on the tertiary nitrogen atom in the heterocyclic ring Y ’” ·; Then, if this proves necessary and / or desirable in each circumstance, any of the following reactions is carried out, in any order P *; 4ι>, suitable: i) conversion of an Δ ^ isomer into the desired Δ ^ isomer, v; = ·· ü) reduction of a compound in which B represents ^> S -> 0 to form a compound in which B represents iii) conversion of a carboxyl group into a metabolically labile and non-toxic ester function, i? & £ iv) formation of an non-toxic salt and v) elimination of any groups blocking the carboxyl function and / or protecting N. 5. 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 suitable pharmaceutical excipient or vehicle. n ---- ί1 7 = T I / • v i | I »il ri i 'i · · \ h i' x-! Si ü i || s il i t. i 4 1 t! I î '. Ψ i% <t.