NL8304024A - CEPHALOSPORINE ANTIBIOTICS AND METHODS FOR PREPARING AND USING THESE ANTIBIOTICS. - Google Patents

Description

- i - i .............. - £ • m.

Phalosporin antibiotics and methods of preparing and using these antibiotics.

The invention relates to improvements in or related to cephalosporins, in particular to new cephalosporin compounds and derivatives thereof with valuable antibiotic properties. The invention also relates to methods of preparing and using these new cephalosporin compounds and derivatives thereof.

The cephalosporin compounds in this specification are referred to as "cefam" according to J. Amer. Chem. Soc., 1962, 84, 3400, wherein the term πeefam ,, refers to the basic cepham structure with a double bond.

Cephalosporin antiobiotics are widely used in treating diseases caused by pathogenic bacteria in humans and animals and are particularly useful in treating conditions caused by bacteria resistant to other antibiotics, such as penicillin compounds and for the treatment of patients sensitive to penicillin. In many instances, it is desirable to use a cephalosporin antibiotic that exhibits both activity against Gram-positive and Gram-negative microorganisms and a great deal of research has been directed to the development of different types of broad-spectrum cephalosporin antibiotics.

For example, applicant's British Patent No. 1,399,086 describes a new class of cephalosporin antibiotics containing a 7β - (etherified oximino) aeylamido group, the oximino group of which has the syn-configuration. This class of antibiotic compounds is characterized by a potent anti-35 ... -2 uucbi-2 bacterial activity against a range of Gram-positive and Gram-negative organisms, coupled with particularly high stability to lactamases which are produced by various gram negative organisms.

The discovery of this class of compounds has stimulated further research in the same field in order to find compounds with better properties, for example against special classes of organisms, in particular Gram-negative organisms.

British patent 1,604,971 discloses a wide variety of cephalosporin antibiotics in which the side chain at the ΐβ position can be selected from among other things a 2- (2-aminothiazol-4-yl) -2- (etherified oximino) acetamido group, wherein the etherifying group, in very many possible meanings, may be a cycloalkyl-substituted alkyl group, although no specific examples of compounds having such a group have been given. The 3-position group can also be selected from a wide variety of alternatives and a possible substituent is a thiomethyl group consisting of an optionally substituted 5- or 6-membered heterocyclic group containing one or more nitrogen? contains oxygen or sulfur atoms is substituted.

British patent application 202769IA to applicant describes cephalosporin antibiotics in which the side chain in the plaatsβ> position is a 2- (2-aminothiazol-4-yl) -2- (etherified oximino) acetamido group, wherein the etherifying group is a carboxyalkyl or carboxycycloalkyl group. The 3 substituent is a group of formula 30 -CH 2 SY, wherein Y is a carbon-linked 5- or 6-membered heterocyclic ring containing at least one nitrogen atom and may be substituted by an alkyl group of 1-4 carbon atoms.

Hen has now found that by choosing a 35-syn (2- (2-aminothiazol-4-yl) -2-cyclopropylmethoxyimino-Q v ί- t * ....... 'i - 3 - acetamido group on the 7β Site combined with certain groups at the 3-position cephalosporin compounds having a particularly beneficial action (described in more detail below) against a wide variety of commonly occurring pathogenic organisms can be obtained.

According to the invention there are therefore provided cephalo-sporine antibiotics of the general formula I, wherein Y represents a carbon-linked unsaturated heterocyclic 5- or 6-ring containing at least one nitrogen-10 atom, which ring also contains one or more sulfur atoms and / or substituted by one or more alkyl groups of 1-4 carbon atoms, oxo, hydroxyl and / or carbamoylmethyl groups, and the non-toxic salts and non-toxic metabolically labile esters thereof.

The compounds of the invention are syn isomers. The syn isomeric form is defined by the configuration of the -O.CR, - ^ 20 group with respect to the carboxamido group.

In this description, the syn configuration is structurally indicated by formula lb.

It will be appreciated that since the compounds of the invention are geometric isomers, some mixing with the corresponding anti-isomer may take place.

Also within the scope of the invention are the solvates (in particular the hydrates) of the compounds of the formula 1. Also within this scope are the solvates of non-toxic salts of the formula 1 and the non-toxic salts and solvates of non-toxic toxic, metabolically labile esters of the compounds of formula 1. It will be understood that the solvates must be pharmacologically acceptable.

S3 040 24. _______ __ e

«V

- 4 -

In the aforementioned formula, the heterocyclic ring represented by Y may contain, for example, 1-4 nitrogen atoms and, if desired, a sulfur atom; special examples of these heterocyclic groups are the imidazolyl, pyrazolyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, triazolyl, tetrazolyl, thiazolyl, thiadiazolyl, triazinyl and triazolidinyl group. If desired, the heterocyclic ring may be substituted by one or more (for example 1-3) alkyl groups with 1-4 carbon atoms (for example methyl), oxo, hydroxyl and / or carbamoylmethyl groups. For example, the alkyl and carbamoylmethyl substituents may be attached to the nitrogen heteroatom or the nitrogen heteroatoms.

The compounds of the invention exhibit broad spectrum antibiotic activity both in vitro and in vivo. They have good activity against both Gram-positive and Gram-negative organisms, including many strains of lactamase. The compounds also have a high stability against β-lactamases formed by a series of Gram negative and Gram positive organisms.

The compounds of the invention have been found to exert good activity against strains of Staphylococcus aureus and Staphylococcus epidermidis species, including penicillase-producing strains of these Gram-positive bacteria. This has been linked to a good action against various members of the Enterobacteriaceae (eg strains of Escherichia coli, Klebsiella pneumoniae, Entero-bacter cloacae, Serratja marcescens, Proteus mirabilis and indole-positive Proteus organisms, such as Proteus vulgaris,

Proteus Morganii and Providence species), and strains of Haemophilus influenzae and Acinetobacter calcoaceticus, as well as an activity against some strains of Pseudomonas species. This combination of potent activity against Gram-35 positive organisms with potent activity against Gram-8304024 -5 - negative organisms possessing the compounds of the invention is particularly rare.

The non-toxic salt derivatives which may be formed by reaction of the carboxyl group present in the compounds of formula I or by reaction of an optionally present acidic hydroxyl group which may be present on the heterocyclic group Y include salts with inorganic bases, such as the alkali metal salts (eg, sodium and potassium salts) and alkaline earth metal salts (eg, calcium salts), amino acid salts (eg, lysine and arginine salts), and salts of other organic bases (eg, salts of procaine, phenyl-ethylbenzylamine, dibenzylethylenediamine) , ethanolamine, diethanolamine and N-methylglucosamine). Non-toxic salt derivatives include acid addition salts, for example formed with hydrogen chloride, hydrogen bromide, sulfuric acid, nitric acid, phosphoric acid, formic acid and trifluoroacetic acid. Suitably, the compounds may also exist in a Zwitterionic or internal salt form. The salts 20 may also be in the form of a resin product, for example, molded with a polystyrene resin or a cross-linked polystyrene-divinylbenzene copolymer resin, which contains amino or quaternary amino groups or sulfonic acid groups, or with a carboxyl group-containing resin, for example, a polyacrylic acid resin. Soluble basic salts (e.g., alkali metal salts, such as the sodium salt) of the compounds of formula 1 can also be used in therapeutic uses due to the rapid distribution of such salts in the body after administration. However, if insoluble salts of compounds of formula 1 are desired for a special application, for example for use in depot preparations, such salts can be prepared in a conventional manner, for example with suitable organic amines.

35 It will be understood that the Y group is an 8304024

t V

- 6 - can carry positive charge, for example if Y is a 1-methyl-pyridinium-2-yl group and if so the positive charge must be balanced with a negative charge. Thus, the compounds may be betain so that the Θ negative charge is provided in the 4-position by a -C00 group. The negative charge can also be provided by 0 through an A anion; such an anion will be non-toxic and can be derived from any of the above-described acids that will form the non-toxic salt derivatives.

The non-toxic, metabolically labile ester derivatives which may be formed by esterification of the carboxyl group in the parent compound of formula 1 are, for example, acyloxyalkyl esters, for example, lower alkanoyl-oxy-methyl or ethyl esters, such as acetoxymethyl or ethyl pivaloyloxymethyl esters and alkoxycarbonyloxyalkyl esters, for example, low alkoxycarbonyloxyethyl esters, such as the ethoxycarbonyloxyethyl ester. In addition to the aforementioned ester derivatives, the invention also includes the compounds of formula 1 in the form of other physiologically acceptable equivalents, i.e. physiologically acceptable compounds which, like the metabolically labile esters, in vivo, in the parent compound having antibiotic activity of formula 1 be converted.

These and other salt and ester derivatives, such as the salts with toluene-β-sulfonic acid and methanesulfonic acids, or the esters with t-butyl or diphenylmethyl esterifying groups, may act as intermediates in the preparation and / or purification of the subject compounds of formula 1, for example, in the processes described below.

Among the recommended compounds of the invention are those wherein Y is a 1-methylpyridinium-2-yl, 1-methylpyridinium-4-yl, 1-methyltetrazol-5-yl, 1-methylpyridinium-3-yl, 1,1 , 2-dimethylpyrazolium-3-yl-, 1,3-dimethylimidazolium-3-yl-, 1-methylpyrimidinium-2-yl-, 8304024 2 «............. Ί« ϊ ' -τι-carbamoylmethylpyridinium-4-yl-, 2,5-dihydro-6-hydroxy-2-methyl-5-oxo-1,2,4-triazin-3-y1- or 4,5-dihydro-6-hydroxy - represents 4-methyl-5-oxo-1,2,4-triazin-3-yl group. A particularly recommended compound of the invention is 5 (6R, 7R) -7- (XZ) -2- (2-aminothiazol-4-yl) -2-cyclopropylmethoxyiminoacetamid [7- / T (1-methylpyridinium-4) -y 1) thiomethyl 1-cef-3-em-4-carboxylate and its non-toxic salts.

The compounds of the present invention may exist in tautomeric forms (e.g., 10 with respect to the 2-aminothiazolyl group or with respect to a 3-substituent, such as a 2,5-dihydro-6-hydroxy-2-methyl-5-oxo-1 2,4-triazin-3-yl group) and it will be understood that such tautomeric forms are also within the scope of the invention.

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

Has another aspect of the invention

relating to a process for preparing cephalosporin compounds of the general formula Ia, wherein Y has a previously defined meaning, B

25 “^ 0 (tl ~ orβ -), the dotted line connecting the 2, 3 and 4 places indicates that the compound is a cef-2-em or cef-3-em compound,

Rj represents a hydrogen atom or a carboxyl group-blocking group 30, for example the remainder of an ester-forming aliphatic or araliphatic alcohol or an ester-forming phenol, dilanol or stannanol (wherein said alcohol, phenol, dilanol or stannanol preferably contains 1-20 carbon atoms) or a symmetrical or mixed anhydride blocking group derived from a suitable acid and R 8 represents an 8304024-8 amino group or a protected amino group, or its salts, comprising (A) acylating a compound of formula 2, wherein Y, B, the dotted line and Rj have the meanings defined above, or a salt thereof, for example an acid addition salt, for example formed with a mineral acid, such as hydrogen chloride, hydrogen bromide, sulfuric, nitric or phosphoric acid, or an organic acid, such as methanesulfonic acid or toluene-4-sulfonic acid, or

10 a 7-N-silyl derivative thereof, or alternatively, if Y

contains a quaternary nitrogen atom, a corresponding Θ compound with a -C00 group in the 4-position, with an acid of formula 3, wherein R heeft has a previously defined meaning, or a salt thereof, or with an acylating agent corresponding therewith, (B) reaction of a compound of formula 4, wherein R 1, R 1, B and the dotted line have the previously defined meanings and X is a replaceable residue of a nucleophile group, for example an acetoxy or dichloroacetoxy group or a halogen atom, such as chlorine, bromine or iodine, or a salt thereof, with a sulfur nucleophile serving to form the -CH ^ SY group, wherein Y has a previously defined meaning, in the 3-position, or (C ) if Y in the compound of the invention contains a quaternary nitrogen atom substituted by alkyl of 1-4 carbon atoms or carbamoylmethyl substituted in the heterocyclic ring, reaction of a compound of formula 5 wherein R 1, B and the dotted line n have the meanings defined above and Rj 30 in this case is a carboxyl blocking group and Y 'represents a carbon-linked 5- or 6-ring heterocycle containing a tertiary nitrogen atom, with an alkylating agent having 1-4 carbon atoms or a carbamoyl methylating agent which serves to introduce a alkyl group with 1-4 carbon atoms or a carhamoylmethyl group

83 04 0 2 A

> - - 9 - as a substituent of the tertiary nitrogen atom in the heterocyclic ring of Y ', after which, if necessary and / or desired in any case, each of the following reactions, in any suitable order, is carried out: 5 i) conversion of a Δ isomer in the desired Λ. isomer, ii) reduction of a compound in which B => 0, forming a compound in which 10 B = ^ S, iii) conversion of a carboxyl group into a non-toxic, metabolically labile, ester function, iv) formation of a non-toxic salt and v) removal of any carboxyl group blocking and / or N-protecting groups present.

In the method (A) described above, the starting material of formula 2 is preferably a compound in which B = s and the dotted line represents a cef-3-em-20 compound.

If the Y group is charged in formula 2, for example, as in an N-alkylpyridinium group, and the compound contains a group of formula -COORj (where Rj has a previously defined meaning) in the 4-position 0, the compound will have a associated anion E, such as a halide, for example, chloride or bromide, or a trifluoroacetate anion.

Acylating agents which can be used in preparing the compounds of formula I include acid halides, especially acid chlorides and bromides. Such acylating agents can be prepared by reacting an acid of formula 3 or a salt thereof with a halogenating agent, for example, phosphorus pentachloride, thionyl chloride or oxalyl chloride.

_: _ M

8304024 -10-

Acylations using acid halides can be carried out in aqueous and non-aqueous reaction media, suitably at temperatures between -50 and + 50 ° C, preferably between -40 and + 30 ° C, optionally in the presence of an acidic 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 dimethyl acetamide, nitriles, such as acetonitrile, or mixtures of two or more of such solvents. Examples of suitable acid-binding agents are tertiary amines, for example triethylamine or dimethylaniline, inorganic bases, for example calcium carbonate or sodium bicarbonate and oxiranes, such as low 1,2-alkylene oxides, for example ethylene oxide or propylene oxide, which contain the hydrogen released in the acylation reaction. halide bind.

Acids of formula 3 can themselves be used as acylating agents in the preparation of compounds of formula 1. It is desirable that acylations using acids of formula 3 in the presence of a condensing agent, for example, a cartodiimide, such as Ν, Ν'-dicyclohexylcarbodiimide or N-ethyl-Nf---dimethyl-aminopropylcarbodiimide, an carbonyl compound, such as carbonyldiimidazole or an isoxazolium salt, such as N-ethyl-5-phenylisoxazolium perchlorate.

The acylation can also be carried out with other amide-forming derivatives of acids of the formula III, such as, for example, an activated ester, a symmetrical anhydride or a mixed anhydride, for example formed with pivalic acid or with a haloformate, such as a lower alkyl haloformate. Mixed anhydrides can also be formed with phosphoric acids, for example, phosphoric or phosphorous, sulfuric or aliphatic or aromatic sulfonic acids, for example, toluene-4-sulfonic acid. An 8304024 * -11-activated ester can conveniently be formed in situ using, for example, 1-hydroxybenzotriazole in the presence of a condensing agent, as mentioned above.

Also, the activated ester can be pre-formed.

It is desirable to conduct the acylation reactions involving the free acids or their aforementioned amide-forming derivatives in an anhydrous reaction medium, for example, methylene chloride, tetrahydrofuran, dimethylformamide or acetonitrile.

An alternative activation method relies, for example, on the reaction of an acid of formula 3 with a solution or suspension previously formed by adding a carbonyl halide, in particular oxalyl chloride or phosgene, or a phosphoryl halide, such as phosphorus oxychloride, to a solvent, such as a halogenated hydrocarbon, for example methylene chloride, which contains a low acyl tertiary amide such as N, N-dimethylformamide. The activated form of the acid of formula 3 can then react with a 7-amino-20 compound of formula 2 in a suitable solvent or mixture of solvents, for example a halogenated hydrocarbon, for example dichloromethane. The acylation reaction can conveniently be carried out at a temperature between -50 and + 50 ° C, preferably -40 to + 30 ° C, optionally in the presence of an acid binding agent, for example as described above, such as dimethylaniline.

If desired, the aforementioned acylation reactions can be carried out in the presence of a catalyst, such as 4-dimethylaminopyridine.

The acids of formula III and acylating agents corresponding thereto can be prepared and used in the form of their acid addition salts, if desired. For example, acid chlorides can suitably be used in the form of their hydrogen chloride salts and acid bromides as their hydrogen bromide salts.

_ _ Λ 8304024 *> -12-

In the method (B) described above, the sulfur nucleophile can be used to replace a wide variety of sugar substituents X in the cephalo-sporine of formula 4. To some extent, the ease of the substitution reaction is related to the pKa of the acid HX from which the substituent is derived. For example, atoms or groups X derived from strong acids generally tend to be more easily replaced than atoms or groups derived from weaker acids. The convenience of the replacement reaction is also related to some extent to the precise nature of the sulfur nucleophile. The latter nucleophile can be used, for example, in the form of a suitable thiol or thion.

The replacement of X with the sulfur nucleophile 15 can conveniently be performed by keeping the reaction components in solution or suspension. The reaction is conveniently performed using 1-10 mole equivalents of nucleophile.

Nucleophilic replacement reactions can conveniently be performed on those compounds of formula 4 wherein the substituent X is a halogen atom or an acyloxy group, as discussed, for example, below.

Acyloxy groups.

25

Compounds of formula 4, wherein X represents an acetoxy group, are suitable starting materials for use in the nucleophilic replacement reaction with the sulfur nucleophile. Other starting materials of this class include compounds of formula IV, wherein X represents the remainder of a substituted acetic acid, for example chloroacetic acid, dichloroacetic acid and trichloroacetic acid,

Substitution reactions of compounds of formula IV containing X substituents of this class, especially in case X is an acetoxy group, may be due to the presence of iodide or thiocyanate ions in the reaction medium facilitates.

Substituent X may also be derived from formic acid, a haloformic acid, such as chloroformic acid, or a carbamic acid.

When using a compound of formula 4, wherein X represents an acetoxy group or a substituted acetoxy group, it is generally desirable that the R 1 group in formula 4 be a hydrogen atom and that B 1 S represents. In that case, the reaction proceeds conveniently in an aqueous medium.

Under aqueous conditions, the pH of the reaction solution can be suitably kept between 6 and 8, if necessary with the addition of a base. The base is suitably an alkali or alkaline earth metal hydroxide or bicarbonate, such as sodium hydroxide or sodium bicarbonate.

When using compounds of formula IV wherein X is an acetoxy group, the reaction is conveniently conducted at a temperature between 10 and 110 ° C, preferably between 20 and 80 ° C.

Halogens.

25

Compounds of formula 4 in which X represents a chlorine, bromine or iodine atom may also be suitably used as starting materials in the nucleophilic substitution reaction with the sulfur nucleophile. When using compounds of formula 4 of this class, B may be suitable and R j may be a blocking group for the carhoxyl group. The reaction may suitably be carried out in a non-aqueous medium, preferably one or a number of organic solvents, suitably of a polar nature, such as ethers, for example dioxane or tetra 8304024

• V

-14- contains hydrofuran, esters, for example, ethyl acetate, amides, for example, formamide and Ν, Ν-dimethylformamide, and ketones, for example, acetone. Other suitable organic solvents are more fully described in British Patent No. 1,326,531. The reaction medium will be neither extremely acidic nor extremely basic.

In the case of reactions affecting compounds of formula 4 ,. wherein R 1 represents a blocking group for the carboxyl group and the resulting Y group contains a quaternary nitrogen atom is carried out, the product will be formed as the corresponding halide salt, which, if desired, is subjected to one or more ion exchange reactions to obtain a salt with the desired anion.

When using compounds of formula 4, wherein X represents a halogen atom as described above, the reaction is conveniently carried out at a temperature between -20 and + 60 ° C, preferably between 0 and + 30 ° C.

If the nucleophile to be incorporated does not give a compound containing a quaternized nitrogen atom, the reaction is generally conducted in the presence of an acid binding agent, for example a base such as triethylamine or calcium carbonate.

In the above-described process (C), the compound of formula 5 is suitably reacted with a compound of formula R 2 Z, wherein R 1 is an alkyl group of 1-4 carbon atoms or a group of formula NCO 3 -1 and Z represent a cleavable group such as a halogen-30 atom (e.g. iodine, chlorine or bromine), or a hydrocarbon sulfonate (e.g. mesylate or tosylate) group. It is also possible to use a di-C 1-6 alkyl sulfate, for example dimethyl sulfate, as the alkylating agent. Iodomethane is preferred as the alkylating agent, while iodoacetamide is preferred as the carba-8304024-15-methyloylating agent. The reaction is preferably carried out at a temperature between 0 and 60 ° C, suitably between 20 and 30 ° C. If the alkylating agent is liquid under the reaction conditions, such as in the case of iodomethane, this agent itself can act as a solvent. It is also possible to conveniently carry out the reaction in an inert solvent, such as an ether, for example tetrahydrofuran, an amide, for example dimethyl-formamide, a low alkanol, for example ethanol, a low dialkyl ketone, for example acetone, a halogenated hydrocarbon, for example dichloromethane, or an ester, for example ethyl acetate.

The compound of formula 5 to be used as starting material in method (C) can be obtained, for example, by reacting a compound of formula 4, as defined above, with a suitable sulfur nucleophile, in a manner analogous to the nucleophilic replacement reaction. described with respect to method (B). If desired, the aforementioned nucleophile can be used in the form of a metal thiolate salt.

When X in formula 4 is a halogen atom, the reaction is preferably carried out in the presence of an acid-binding agent, for example a base, such as triethylamine or calcium carbonate.

The reaction product can be separated from the reaction mixture containing, for example, unaltered cephalosporin starting material and other materials, by a wide variety of methods, including recrystallization, ionophoresis, column chromatography and the use of ion exchangers, eg by chromatography on ion exchange resins, or macro cross-linked resins. .

2

A 1-cephalosporin ester derivative obtained according to the invention can be converted into the corresponding desired Δ ^ derivative by, for example, treatment of the ^ ester with a base, such as pyridine or triethyl- ----- 8304024 -16-amine .

A compound is obtained in which B

It can be converted, for example, by reduction of the corresponding acyloxysulfonium or alkoxy sulfonium salt, which has been prepared in situ by reaction with, for example, acetyl chloride, in the case of an acetoxy sulfonium salt, which is for example, reduction is performed with sodium dithionite or iodide ions as present in a solution of potassium iodide in a water-miscible solvent, for example acetic acid, acetone, tetrahydrofuran, dioxane, dimethylformamide or dimethyl acetamide. The reaction 15 can be carried out at a temperature between -20 and + 50 ° C.

Metabolically labile ester derivatives of the compounds of formula 1 can be prepared by reacting a compound of formula 1 or a salt or protected derivative thereof with the suitable esterification agent, such as an acyloxyalkyl halide or alkoxycarbonyloxyalkyl halide (e.g. iodide suitable in an inert, organic solvent, such as dimethylformamide or acetone, followed if necessary by removal of any protecting groups present.

Base salts of the compounds of formula 1 can be formed by reacting an acid of formula 1 with a suitable base. For example, sodium and potassium salts can be obtained using the respective 2-ethylhexanoate or hydrogen carbonate salt. Acid addition salts can be prepared by reacting a compound of formula 1 or a metabolically labile ester derivative thereof with the appropriate acid.

When a compound of formula 1 is obtained as a mixture of isomers, the syn isomer can be obtained, for example, by conventional methods such as crystallization or chromatography.

For use as a starting material for preparing compounds of the general formula I according to the invention, preferably compounds of the general formula III and the amide-forming derivatives thereof, such as acid halides and anhydrides corresponding thereto, in their syn isomeric form or in the form of mixtures of the syn isomers and the corresponding anti-10 isomers containing at least 90% of the syn isomer.

Acids of formula 3 and their derivatives can be obtained by etherification of a compound of formula 7, wherein a meaning defined above is 15 and R 1 represents a hydrogen atom or a carboxyl group-blocking group, or a salt thereof, by selective reaction with a compound of the general formula 8, wherein T represents a halogen atom, such as a chlorine, bromine or iodine atom, a sulfate group or a sulfonate group, such as p-20 toluenesulfonate, followed by removal of an optionally present carboxyl group blocking group R 4.

The isomers can be separated both before and after such etherification. The etherification reaction is conveniently conducted in the presence of a base, for example, potassium carbonate or sodium hydride, and preferably proceeds in an organic solvent, for example, dimethyl sulfoxide, a cyclic ether, such as tetrahydrofuran or dioxane, or a Ν, Ν-disubstituted amide, such as dimethylformamide . Under these conditions, the configuration of the oximino group hardly changes by the etherification reaction. The reaction will be carried out in the presence of a base if an acid addition salt of a compound of formula 7 is used. The base will be used in an amount sufficient to quickly neutralize the particular acid.

-; _ a 8304024 -18-

Acids of formula 3 can also be obtained by reacting a compound of formula 9, in which and R ^ have the previously defined meanings, with a compound of formula IQ, followed by removal of any carboxyl group-bleaching group R ^ and separation if necessary of the syn and anti isomers.

The acids of formula III can be converted into the corresponding acid halides and anhydrides and acid addition salts by conventional methods, such as, for example, in the manner described above.

X represents a halogen atom, i.e. a chlorine, bromine or iodine atom, in formula 4, then the cef-3-em starting materials can be prepared in a conventional manner, for example, by halogenation of an Ice-protected amino -3-methyl-cep-3-em-4-carboxylic acid ester. Oxide, removal of the β-protecting group, acylation of the obtained 7-amino compound to form the desired acy ^ -acylamido group, for example in a manner analogous to the above-described Method 20 (A), followed by reduction of the 1-oxide group later.

This is described in British Patent No. 1,326,531.

The corresponding cef-2-em compounds can be obtained by reacting a 3-methyl-cef-2-em compound with N-bromosuccinimide to the corresponding 3-bromomethylceph by the method of Netherlands Patent Application 6,902,013 laid open to public inspection. -2-em connection.

In a compound of formula 4, X represents an acetoxy group, such starting materials can be obtained, for example, by acylation of 7-amino-30-cephalosporanic acid, for example in a manner analogous to the above-described process (A). Compounds of formula 4 in which X other acyloxy group can be obtained by acylation of the corresponding 3-hydroxymethyl compounds, which can be prepared, for example, by hydrolysis of the appropriate 3-acetoxymethyl-8304024 * 9-19 compounds, for example in the manner described, for example, in the British patents 1,474,519 and 1,531,212.

Compounds of formula 2 may also be prepared in a conventional manner, for example, by nucleophilic replacement of a corresponding 3-acyloxymethyl or 3-halomethyl compound with the appropriate nucleophile, as described, for example, in British Pat. Nos. 1,012,943, 1,241,657, 2,027 .691A 10 and 2.046.26IA.

Another method of preparing the starting materials of formula 2 involves removing the protecting group from a correspondingly protected 7β-amine compound, for example, in a conventional manner, such as, for example, using phosphorus pentoxide.

It will be clear that in some of the conversions described above it may be necessary to protect any sensitive groups present in the molecule of the compound in question, in order to avoid undesired side reactions. For example, it may be necessary during any of the aforementioned reaction schemes to protect the tphi group of the aminothiazolyl moiety, for example, by tritylation, acylation, for example, chloroacetylation or formylation, protonation, or by any other conventional method, so that the protected group is resistant against the reaction conditions that occur with one or more synthetic steps. The protecting group can then be removed by any suitable method that does not cause degradation of the desired compound, for example, in the case of a trityl group, using an appropriate halogenated carboxylic acid, eg acetic acid, formic acid, chloroacetic acid or trifluoroacetic acid, or by use of a mineral acid, for example hydrogen chloride or 30-20 mixtures of such acids, preferably in the presence of a protic solvent, such as water, or in the case of a chloroacetyl group, by treatment with thiourea .

Desirably, the carhoxyl group blocking groups used in preparing compounds of formula 1 or of the necessary starting materials are groups which can be readily cleaved at an appropriate stage of the reaction sequence, suitably in the last step. However, it may be beneficial in some cases to use non-toxic, metabolically labile, carboxyl group-blocking groups, such as acyloxy-methyl-ethyl groups, for example acetoxy-methyl or -ethyl or pivaloyloxymethyl, or alkoxycarbonyloxyalkyl groups, for example ethoxycarbonyloxyethyl, and these in retain the final product, thereby obtaining a suitable ester derivative of a compound of formula 1.

Suitable groups that block the carboxyl group are also known in the art; a list of representative blocked carboxyl groups 20 is included in British Patent No. 1,399,086. Recommended blocked carboxyl groups include aryl lower alkoxycarbonyl groups, such as p-methoxybenzyloxycarbonyl, p-nitrobenzyloxycarbonyl and diphenylmethoxycarbonyl; low alkoxycarbonyl groups, such as t-butoxycarbonyl; and low haloalkoxycarbonyl groups, such as 2,2,2-trichloroethoxycarbonyl. The carboxyl group blocking group can then be removed by any of the suitable methods described in the art, for example, acid or base catalyzed hydrolysis is useful in many cases, as well as enzyme catalyzed hydrolysis.

It will be understood that the use of amino group and carboxyl group protecting groups is known in the art and relevant examples of such an application are mentioned for example in: 0 "Z i \ A o 9 λ -21-

Theodora W. Greene, "Protective Groups in Organic Synthesis" (Wiley-Interscience, New York, 1981) and J.F.W. McOmie, "Protective Groups in Organic Chemistry" (Plenum Press,

London, 1973).

The antibiotic active compounds according to the invention can be processed by any suitable method for administration purposes, in analogy with other antibiotics, and the invention therefore also comprises pharmaceutical preparations comprising one or a number of antibiotic active compounds according to the invention, suitable for use in the human or veterinary medicine.

If desired, such preparations may be presented for use in a conventional manner with the aid of any necessary pharmaceutical carriers and / or excipients.

The antibiotic active compounds of the invention may be processed for injection purposes and may be presented in unit dosage form, in ampoules or in multiple dose containers, optionally with an added preservative. The compositions may also be in the form of suspensions, solutions or emulsions in oily or aqueous carriers, and may contain processing agents such as suspending agents, stabilizers and / or dispersants. The active ingredient can also be in powder form and processed for use with a suitable carrier, for example sterile, pyrogen-free water.

If desired, such powdered compositions may contain a suitable non-toxic base in order to improve the water solubility of the active ingredient and / or ensure that when the powder is reconstituted with water for use, the pH of the resulting , aqueous preparation is physiologically acceptable. It is also possible that the base 35 is present in the water with which the powder is reconverted for use. For example, the base can be an inorganic base, such as sodium carbonate, sodium bicarbonate or sodium acetate, or an organic base, such as lysine or lysine acetate.

For example, the antibiotic-active compounds may be presented in a form suitable for absorption by the gastrointestinal tract, for example, as tablets or capsules.

The compounds having antibiotic activity can also be processed, for example, into suppositories containing, for example, a conventional suppository base such as cocoa butter or other glycerides.

For example, preparations for veterinary use can be formulated into preparations for use in the breast, which have either a long-acting or a fast-releasing effect.

The compositions may contain from 0.1%, for example 0.1-99%, of active material, depending on the mode of administration. If the compositions consist of dosage units, each dosage unit will preferably contain 100-3000 mg, for example 200-2000 mg, of active ingredient. The dose used for the treatment of adult humans will preferably range from 200-12000 mg, eg 1000-9000 mg, per day, depending on the mode of administration and the frequency of administration.

For example, for the treatment of adult humans, a dose between 400 and 6000 mg per day administered intravenously or intramuscularly is sufficient. Higher daily doses may be required to treat Pseudomonas infections. It will be appreciated that in some cases, for example when treating neonates, smaller dosage units and daily doses may be desirable.

The antibiotic acting compounds of the invention may be administered, if desired, together with other therapeutic agents, such as antibiotics, for example, penicillins or other cephalosporins.

In the following examples, Sorbsil U30 5 is a silica gel from Joseph Crosfield and

Son of Warrington, Lancashire, England. Furthermore, THF is tetrahydrofuran, DME Ν, Ν-dimethylformamide and DMSO dimethyl sulfoxide.

10

Preparation 1:

Ethyl (Z) -2-cyclopropylmethoxyimino-.no-2- (2-tritylamino-thiazol-4-yl) acetate 15

30 g of ethyl (Z) -2-hydroxyimino-2- (2-tritylaminothiazol-4-yl) acetate, hydrochloride, were stirred in a nitrogen atmosphere and at 21 ° C for 7 hours with 13.5 g of cyclopropylmethyl bromide in 150 ml of DMSO. g of potassium carbonate. The mixture was then partitioned between methylene chloride and water. The water layer was extracted with more methylene chloride and the combined organic solutions were washed with water. After drying over magnesium sulfate, the solution was concentrated and brought to 200 g of a Sorbsil U30 column. The column was eluted with ethyl acetate (10-30%) in petroleum ether (bp: 40-60 ° C). Evaporation of the appropriate fractions gave the title compound, (20.9 g); i (ethanol) 234.5 nm (E? 403); ) s.

7 ° 'A. max. 1 cm xnf 30 17 17 1 «7 254.5 nm (E, 302), 259.5 nm (E, 267), 265 nm (E, 229), 1 cm 1 cm 7 1 cm 271.5 nm (e!% 190 ) and 294 nm (El.% 111); V (CHBr_) 7 Icm 1cm 7 max 3 35 3398 (Ni), 1730 (ester) and 1593 and 1491cm (aromatic 3304024-24 double bond).

Preparation 2: 5 (Z) -2-Cyclopropylmethoxyimino-2- (2-tritylaminothiazol-4-yl) acetic acid.

20 g of the product of preparation 10 l were dissolved in 200 ml of ethanol and 3.12 g of sodium hydroxide were added

in 40 ml of water. The mixture was then refluxed for 45 minutes to form precipitate. Part of the ethanol (about 150 ml) was distilled off and the residue was cooled. The mixture was partitioned between methylene chloride and water to 2N

hydrochloric acid (70 ml). The organic phase was washed with water and each water layer was back extracted with more methylene chloride. The combined organic layers were dried over magnesium sulfate and evaporated to give the title compound (20 g); . j. (ethanol) 234.5 nm (38383) 259.5 nm 'xnf. "Icm" (e!% 242), 266.5 nm (E, 1% 226) and 272.5 nm (e!% 217); 1 cm 1 cm 1 cm 25 Sf max (Nujol) 3260 (NH) and 1685 cm 1 (acid).

Preparation 3 Diphenylmethyl (10'-10-S-bromomethyl-1-y-cyelopropyl-methoxyimino-2- (2-tritylaminothiazol-4-yl) -acetamido-7-cep-3-em-4-carboxylate.

0.37 ml of oxalyl chloride was added to an 8304024-25 solution of 0.38 ml of DMF in 10 ml of methylene chloride under stirring, in a nitrogen-35 atmosphere and at -20 ° C. The mixture was first stirred under cooling with ice water for 10 minutes and then further cooled to -20 ° C. 1.94 g of (Z) -2-cyclopropylmethoxyimino-2- (2-trityl-5-aminothiazol-4-yl) -acetic acid was added and stir the solution under cooling with ice water for 10 minutes before further cooling to -20 ° C. Then a suspension of 1.98 g of diphenylmethyl (6R, 7R) -7-amino-3-bromo-methyl- was added cef-3-em-4-carboxylate hydrochloride in 10 ml of methylene chloride containing 1.76 ml of Ν, Ν-dimethylaniline. A clear solution formed when the mixture was allowed to warm to 21 ° C for one hour. The solution was washed with dilute hydrochloric acid and water, each wash back extracted with more methylene chloride and the combined extracts dried over magnesium sulfate. and evaporated to a small volume. This 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 (bp: 40-60 ° C) to afford the title compound (2.43 g), mp 135 to 147 ° £ J. -11.9 ° (c 0.6, chci 3).

25

Preparation 4

Diphenylmethyl (1S, 6R, 7R) -3-bromomethyl-7-jf (Z) -2-cyclopropy1-methoxyimino-2- (2-tritylaminothiazol-4-yl) acetamidoj cef-30 3-em-4-carboxylate, 1 -oxide.

1.2 g of diphenylmethyl (6R, 7R) -3-bromomethyl 1-7- (2) -2-cyclopropylmethoxyimino-2- (2-tritylaminothiazole-4-yl) -acetamidq-7-cep-3-em- were dissolved Dissolve 4-carboxylate in 10 ml of methylene chloride and add 292 mg of 3-chloroperbenzoic acid with stirring and cooling with ice water to this solution after 30 minutes. bicarbonate solution and water (twice) After drying over magnesium sulfate, the solution was concentrated and purified on a column of Sorbsil U30 (50 g), which was treated with ethyl acetate (50-80%) in petroleum ether (bp 40-60 ° C) was eluted to give 1.1 g of the title compound.

io ^ Jll + I4 »2 ° <c ï» 23 'racy5 infl. 244> 5 ™ (e!% 260), 258.5 nm (E, 1% 232), 266 nm (E, 1% 225), and 1 cm 1 cm 1 cm 272 nm (E?% 214).

lcm 15

Example I: (a) Diphenylmethyl (6R, 7R) -7- / ~ (Z) -2-cyclopropylmethoxyimino-20 2- (2-tritylaminotriazol-4-yl) acetamido7-3- / ~ (1-methylpyridinium- 4-yl) thiomethyl 17 cef-3-em-4-carboxylate, bromide.

1.2 g of diphenylmethyl (6R, 7R) -3-bromomethyl-7-ZXZ) -2-cyclopropyl-25-methoxyimino-2- (2-tritylaminothiazol-4-yl) acetamido7-cef were dissolved under stirring and at 21 ° C. - 3-em-4-carboxylate in 20 ml of THF and added 162 mg of 1-methylpyrid-4-thion. After 2 hours and 15 minutes and 3 hours and 45 minutes, 2 more portions, each of 50 mg, of 1-methylpyrid-4-thione were added. After 6 hours, the solution was diluted with 80 ml of dimethyl ether and the mixture was stirred at the temperature of an ice bath for a few minutes. The precipitate was filtered off, washed with diethyl ether and dried, yielding 1.27 g of the title compound, "p (-29.7 ° (c 0.71, DMSO), 35 µm 1784 (^ Lactam), 1720 (ester) and 1675 and 8304024-27-1520 cm 2 (amide).

(b) (6R, 7R) -7-Z (Z) -2- (2-aminothiazol-4-yl) -2-cyclopropyl-methoxyiminoacetamid ^ -3-iC (1-methylpyridinium-4-yl) thio-5 methyl cep-3-em-4-carboxylate, dihydrochloride.

1.1 g of the aforementioned ester were dissolved in 4 ml of formic acid and 0.29 ml of concentrated hydrochloric acid was added. After stirring at 21 ° C for 1.5 hours, the mixture was filtered and the filter cake was leached with formic acid.

The combined filtrates were evaporated to a gum, which was treated with acetone and dried, yielding 560 mg of the title compound, ZToiJp1 -39.7 ° (c 1.03, DMSO), Y (Nujol) 3680-2200 (OH, NH and NH4), 1780 (lactam), 1710 (COOH), and 1675 and 1550 cm @ -1 (amide).

Example II

20 (a) Diphenylmethyl (6R, 7R) -7 - / * (Z) -2-cyclcopropylmethoxyimino-2- (2-tritylafflinothiazol-4-yl) aeeetamidq73-Z ~ (1-methyl-pyridinium-2-y1) thiomethyl7ceph -3-em-4-carboxylate.

Diphenylmethyl (6R, 7R) -3-bromomethyl-7 "2" (Z) -2-cyclopropylmethoxyimino-2- (2-tritylamino-thiazol-4-yl) -acetamido-phen-3-em-4-carboxylate was stirred with 162 mg of 1-methylpyrid-2-thion in 20 ml of THF for 2 hours at 21 ° C. Then another 160 mg of 1-methylpyrid-2-thion were added, and after 4 days at 21 ° C, the solution was boiled for 3 hours. under reflux Then finely divided calcium carbonate (excess) was added and the mixture was stirred again for 2 days at 21 ° C. The mixture was filtered and the filtrate was diluted with 80 ml of diethyl ether, the precipitate was filtered off, washed. with ether and dried, yielding 8304024-28-540 mg of the title compound, ((ethanol) 240.5 nm (E m m 245), 265nm (ε | 208 208), 272nm

17 17 9lD

(E, 198), 308nm (E (\ f> (Nujol)) 3700-2500 (NH), 1790 vcm Icm IV max J, 5 (yl-lactam), 1725 (ester), 1680 and 1520 cm (amide ).

(b) (6R, 7R) -7-J (TZ) -2- (2-Aminothiazol-4-yl) -2-cyclopropyl-methoxyiminoacetamidQ7-3 - / '(1-methylpyridinium-2-yl) thio-methyl7 cef-3-em-4-carboxylate dihydrochloride.

10

480 mg of the aforementioned ester were dissolved in 2 ml of formic acid and 0.13 ml of concentrated hydrochloric acid was added. After stirring at 21 ° C for 1 hour, the mixture was filtered and the filter cake leached with formic acid. The combined filtrates were evaporated and the residue was treated with acetone to give 300 mg of the title compound, ν '(Nujol), a max 3700-2300 (NH3, NH and OH), 1780 (yg - lactam), 1710 (acid), and 1680 cm * (amide).

20 T (d ^ -DMSO) includes 0.90 (d, J6 Hz), 1.58 (t, J 6 Hz), o 1.88 (d, J 6Hz), and 2.12 (t, J 6Hz) pyridyl protons; 3.09 (thiazole proton) and 8.88, 9.30-9.80, multiplets, cyclopropyl protons.

25

Example III

(a) Diphenylmethyl (6R, 7R) -7- / T (Z) -2-cyclopropylmethoxy-imino-2- (2-tritylaminothiazol-4-yl) acetamidoJ-S-ZX1-methy1-30 1H-tetrazole-5- yl) thiomethyl-7ceph-3-em-4-carboxylate.

0.37 ml of oxalyl chloride was added to a solution of 0.38 ml of DMF in 10 ml of methylene chloride under stirring and at -20 ° C. The mixture was allowed to warm to 0 ° C for 5 minutes, then cooled again to 8304024 ». -29- -20 ° C. 1.94 g of (Z) -2-cyclopropyl-methoxyimino-2- (2-tritylaminotriazol-4-yl) acetic acid was then added and the solution was stirred at 0 ° C for 5 minutes. After cooling again to -20 ° C, a suspension of 1.98 g of diphenyl-5 methyl (6R, 7R) -7-amino-3- / ~ (1-methyl-1-HT et razol-5-yl) was added thiomethyl-cep-3-em-4-garboxylate in 10 ml of methylene chloride containing 1.26 ml of dimethylaniline. The temperature of the solution was allowed to rise to 21 ° C for one hour. Then the solution was diluted with more methylene chloride and washed with dilute hydrochloric acid. The water layer was extracted with more 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 (10-50%) in petroleum ether (bp: 40-60 ° C) to give 3.28 g of the title compound in the form of a foam was obtained, ?Γ?? 1.. 83 83 ^ ° ° (c c CH cJ c c c c c c c c c c c c c c c c c c c c c CHClClClClCl, u,, / / u u (((((((CH CH CH CH CH (CH CH CH000000000000000000 NH NH NH NH NH NH NH NH NH NH NH 17 17 17 17 17 1780808080808080808080252525252525252525 est est est est est est est est est est en en en en 1515 cm * (amide).

(b) (6R, 7R) -7- ~ (Z) -2- (2-Aminothiazol-4-yl) -2-cyclopropyl-methoxyiminoacetamido] -3- / t1-methyl-1-H-tetrazole-5- y1) -thiomethyl 17 cef-3-em-4-carboxylic acid. trifinate acetate 25

3.14 g of the aforementioned ester were dissolved with stirring and at 21 ° C in 6.5 ml of anisole and 25 ml of trifluoroacetic acid were added. After 1 hour, 1.5 ml of water was added. After an additional 5 minutes, the solution evaporated to half the volume and about 100 ml of diisopropyl ether was added. The precipitate was filtered off, washed with diisopropyl ether and dried, yielding 2.02 g of the title compound, Γ0 (if1 -40.7 ° (c 0.44, DMS0), V * (Nujol) 3700 - D Π2 & Χ ^ 2200 (NH ^, OH, NH), 1770 (/ Q-lactam), 1725 (acid) and 8304024 - 1 m * -30- and 1690 cm 2 (amide).

Example IV

5 (a) Diphenylmethyl (IS, 6R, 7R) -7- / ~ (Z) -2-cyclopropylmethoxy-imino-2- (2-tritylaminothiazol-4-yl) acetamido7-3- / ~ (1-methy 1- pyridinium-4-yl) thiomethyl-7ceph-3-em-4-carboxylate-1-oxide. bromide.

10

700 mg of diphenylmethyl (1S, 6R, 7R) -3-bromomethyl-7-Z '(Z) -2-cyclopropylmethoxyimino-2- (2-trityl-aminothiazol-4-yl) -acetamido-7-cep-3-em-4- were stirred carboxylate. 1-oxide for 3.5 hours at 21 ° C with 125 mg of N-methylpyrid-4-thione in 15 ml of THF. Diethyl ether was then added and the precipitate was filtered off, washed with ether and dried, yielding 700 mg of the title compound, -31.8 ° (c 0.75, CHCl3, Ϋ (Nujol) 1795 (-lactam), 1722 (ester) and 1675 and 1512 cm (amide).

(B) Diphenylmethyl (6R, 7R) -7- / ~ (Z) -2-cyclopropylmethoxyimino- 2- (2-tritylaminothiazol-4-y1) acetamido7-3-ir (1-methyl-pyridinium-4-y1) thiomethyl Xcef-3-em-4-carboxylate, mixed halide.

25

0.30 g of diphenylmethyl (1S, 6R, 7R) -7- (T (Z) -2-cyclopropylmethoxyimino-2- (2-tritylaminothiazol-4-yl) acetamida7 "3- (1-methylpyridinium-4-) was stirred yl) thiomethyl-cep-3-em-4-carboxylate-1-oxide bromide while cooling with ice water with 0.24 g of potassium iodide in 2 ml of acetone and 2 ml of DMF.

0.1 ml of acetyl chloride was then added and the mixture was stirred and cooled for a further 3 hours. The solution was then poured into an aqueous sodium met abisulfite solution and the precipitate was filtered off. The solid was washed with water and diethyl ether was dried to give 230 mg of 3 0 4 0 2 4

Mb *. '. -31- of the title compound with N.M.R. and I.R. spectra and high-performance liquid chromatography obtained in accordance with the product of Example 1 (a).

This product can be deprotected in the manner described in Example 1 (b) to give the (6R, 7R) -7 - / '(Z) -2- (2-aminothiazol-4-yl) - 2-cyclopropylmethoxyiminoacetamido7-3-Z (1-methyl-pyridinium-4-yl) thiomethyl-17-cep-3-em-4-carboxylate dihydro-10 chloride was obtained.

Example V

15 (a) Diphenylmethyl (IS, 6R, 7R) -7- / TZ) -2-cyclopropylmethoxy-imino-2- (2-tritylaminothiazol-4-yl) acetamidoj-3- (pyrid-4-ylthiomethyl) cef-3 -em-4-carboxylate.1-oxide.

700 mg of diphenylmethyl (1S, 6R, 7R) -20 3-bromomethyl-7- (Z) -2-cyclopropylmethoxyimino-2- (2-trityl-aminothiazol-4-yl) acetamido7 cef-3-em- were stirred 4-Carboxylate-1-oxide with 115 mg of 4-mercaptopyridine and 700 mg of finely divided calcium carbonate for 2 hours and 10 minutes in 20 ml of acetone under reflux. The mixture was then cooled and filtered. The filtrate was concentrated and chromatographed on 50 g of silica gel. The column was made in methylene chloride and eluted successively with methylene chloride, ethyl acetate and 10% ethanol in ethyl acetate. Evaporation of the appropriate fractions gave 260 mg of the title compound as one

O Y.

foam, U 7; -14.9 ° (¢ 0.81, CHCl 3) Y (CHBrJ

D * 3 max 3 3485 (NH), 1808 (β-lactam), 1778 (ester) and 1681 and 1512 cm * (amide). ^ 35 n 8304024 -32- (b) Difsnylmethyl (1S, 6R, 7R) - 7- / '(Z) -2-cyclopropylmethoxy-imino-2- (2-trity laminothiazol-4-yl) -acetamido7-3-ZI (1-methylpyridinium-4-yl) thiomethyl7 cef-3 ~ em-4- carboxylate. 1-oxide iodide.

5

100 mg of diphenylmethyl (1S, 6R, 7R) -7-ZXZ) -2-cyclopropylmethoxyimino-2- (2-tritylaminothiazol-1-4-yl) acetamido7 3- (pyrid-4-ylthiomethyl) cef-3-em-4 -carboxylate. 1-oxide in 0.5 ml of methyl iodide. After the reaction mixture was kept at 21 ° C for 2 hours, the solution was diluted with diethyl ether and the precipitate was filtered off.

This was washed with ether and dried to give 70 mg of the title iodide, which was compared to the aforementioned bromide salt according to N.M.R. and I.R. spectra and under high pressure liquid chromatography.

The product can be reduced in the manner described in Example IV (b) and deprotected according to Example 1 (b) to give the (6R, 7R) -7- / f (Z) -2- (2-Aminothiazol-4-yl) -2-cyclopropylmethoxyiminoacetamido7-3- / T (1-methyl-pyridinium-4-yl) -thiomethyl-7ceph-3-em-4-carboxylate dihydrochloride.

25

Example VI

(a) (6R, 7R) -7 - / '(Z) -2-cyclopropylmethoxyimino-2- (2-trity 1-aminotriazol-4-yl) acetamide q7-3 - / * (1,2,5,6- tetrahydro-2-30 methyl-5,6-dioxo-1,2,4-triazin-3-yl) thiomethyl-7ceph-3-em-4-carboxylic acid.

A solution of 0.4 ml DMF in 0.5 ml dichloromethane was treated with 0.15 ml oxalyl-35 chloride at -10 ° C and this mixture was stirred at -10 ° C for 15 minutes.

8304024

..... J

-33-

721 mg of (Z) -2-cyclopropylmethoxyimino-2- (2-tritylaminotriazol-4-yl) acetic acid was then added. This solution was stirred in an ice bath for 15 minutes. This solution was then added to a solution of 500 mg (6R, 7R) -7-amino-3-jT (1,2,5,6-tetrahydro-2-methyl-5,6-dioxo-1,2, 4-triazin-3-yl) thiomethyl-7-cep-3-em-4-carboxylic acid (which can be prepared as described in European patent application 0065748) in 6 ml of industrial denatured alcohol, 0.65 ml of water and 1.9 ml of triethylamine. The resulting solution was then stirred at 0 ° C for 1 hour. After stirring for an additional 10 minutes at 21 ° C, the reaction mixture was partitioned between dichloromethane and 2N hydrochloric acid. The organic layer was then separated, washed with water, dried and evaporated to give the title acid as a foam (1.12 g), JJD -37.91 ° (c 0.91; DMSO), (CHBr.) 3700-2700 (OH), 3395 (NH), 1789 max j (Δ-lactam), 1738 (ester + other carbonyl groups), 1669-1 and 1523 cm (amide).

(b) (6R, 7R) -7- (Z) -2- (2-aminothiazoo 1-4-y 1) -2-cyclopropy 1-methoxyiminoacetamidoJ-3-Z ~ (1,2,5,6- tetrahydro-2-methyl-5,6,6-dioxo-1,2,4-triazin-3-yl) thiomethyl cep-3-em-4-carboxylic acid formate.

1.169 g of the ester of step (a) were dissolved in 9.3 ml of formic acid. The solution was stirred and 3.2 ml of water was added. The mixture was then stirred at 21 ° C for 1.5 hours. Then the solid was filtered off.

The filtrate was concentrated to a small volume and diisopropyl ether was added. The solid obtained was filtered off, washed with diisopropyl ether and dried, yielding 654 mg of the title compound as a solid, -51.35 ° (c 0.74; DMSO), p (Nujol) 3650-2700 (OH + NH), 1779 (/ - lactam), 1738 (ester + dioxo) 1675 + 1530 (amide) and 1625 cm (car-8 3 0 4 0 2 4 • -34-boxylate).

Example A 5

Dry powder for injection purposes.

Glass vials were aseptically filled with sterile (6R, 7R) -7- (Z) -2- (2-aminothiazol-4-yl) -2-cyclopropylmethoxy-10-iminoacetamido-3-ZX-1-methylpyridinium-4-yl thiomethyl / cef-3-em-4-carboxylate such that each vial contained 1 g of anhydrous pure material. The above volumes were rinsed from the sterile nitrogen vial, closed with rubber discs or stoppers and sealed with metal (used under shrinking). The product can be made ready for use by dissolving it in water for injection or other suitable sterile carriers shortly before administration.

20 83 0 4 0 2 4

Claims (6)

1, Cephalosporin antibiotics of the general formula 1, wherein Y represents a carbon-linked unsaturated 5- or 6-membered heterocyclic ring containing at least one nitrogen atom and also containing one or more 5 sulfur atoms and / or by one or more alkyl groups with 1-4 carbon atoms, oxo, hydroxyl and / or carbamoylmethyl groups can be substituted, as well as the non-toxic salts and the non-toxic, metabolically labile esters thereof. Compounds according to claim 1, wherein Y is a 1-methylpyridinium-2-yl, 1-methylpyridinium-4-yl, 1-methyltetrazol-5-yl, 1-methylpyridinium-3-yl, 1,2- di-methylpyrazolium-3-yl-, 1,3-dimethylimidazolium-3-yl-, 1-methylpyridinium-2-yl-, 1-carbamoylmethylpyridinium-4-yl-, 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- group. 3. (6R, 7R) -7 - / '(Z) -2- (2-Aminothiazol-4-yl) -2-cyclopropylmethoxyiminoacetamido7 "3-ZX1-methylpyridinium-20 4-yl) thiomethyl7ceph" 3- em-4-carboxylate and the non-toxic salts thereof according to claim 1. 4. Process for preparing a heterocyclic compound, characterized in that a heterocyclic compound according to claim I, or a non-toxic salt or non-toxic, metabolically labile ester thereof, is prepared by (A) a compound of formula 2, wherein Y has a meaning defined in claim 1, represents BNS or S0 (IL - or -); R ^ represents a hydrogen atom or a group that blocks the carboxyl group and the dotted line connecting the 2, 3 and 4 position indicates 8304024 - -36- * c that the compound has a cef-2-em or cef -3-em compound is f or a salt or 7 Ns.ylyl derivative thereof, or a corresponding compound with a -COO group in the 4-position, to be acylated with an acid of formula 3, wherein a 5 amino group or a protected, amino group, or a salt thereof, or with an acylating agent corresponding thereto, (B) a compound of formula 4, wherein R 1, R 1, B and the dotted line have the meanings indicated above and X has a residue of is a nucleophile that can be replaced, or a salt thereof, to react with a sulfur nucleophile serving to form the -CI ^ SY group, wherein Y has a meaning defined in claim 1, at the 3 position, or (C) if Y in the desired compound of claim 1 is an alkyl of 1-4 carbon atom n or a carbamoylmethyl group-substituted quaternary nitrogen atom in the heterocyclic ring, a compound of formula 5, wherein R 1, B and the dotted line have the meanings defined above, R 1 in this case is a carboxyl group-blocking group and Y ' represents a carbon-linked 5- or 6-ring heterocycle containing a tertiary nitrogen atom to react with a C 1-4 alkylating agent or a carbamoylmethylating agent which serves to introduce an alkyl group of 1-4 carbon atoms or a carbamoylmethyl group as a substituent to the tertiary nitrogen atom in the heterocyclic ring of Y ', and then, if desired, and / or desired, each time carry out each of the following reactions, in any suitable order: i) conversion of a Δ-isomer to the desired Δ ^ isomer, ii) reduction of a compound in which B = ^ S - * 0 into a compound in which B = ^ S, iii) conversion of a carboxyl group into a non-toxic, metabolism ch labile, ester function, 83 0 4 9 2 ': -37- iv) formation of a non-toxic salt and v) removal of any carboxyl group blocking groups and / or N-resherm groups. Pharmaceutical preparations containing as active ingredient one or more compounds according to claim 1, optionally together with a pharmaceutical carrier and / or excipient. 6. Methods as described in the description and / or examples. 10 U S304 ?? A