NL7907881A - NEW CEPHALOSPORIN ANTIBIOTICS, METHOD FOR THE PREPARATION THEREOF AND PHARMACEUTICAL PREPARATIONS CONTAINING THEM. - Google Patents

Description

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Novel cephalosporin antibiotics, process for their preparation and pharmaceutical preparations containing them.

The invention relates to cephalo-sporine compounds which have valuable antibiotic properties.

The cephalosporin compounds in the present application have been named with reference to "cefam" according to J.Amer.Chem.Soc.j 1962, 84, 3400, the term "cefem" referring to the cefam base structure with one double bond.

Cephalosporin antibiotics are widely used in the treatment of diseases caused by pathogenic gene bacteria in humans and animals and are particularly useful in the treatment of diseases caused by bacteria resistant to other antibiotics such as penicillin compounds, and in the treatment of patients hypersensitive to penicillin. In many instances, it is desirable to use a cephalo-15 sporine antibiotic that shows activity against both gram-positive and gram-negative microorganisms, and a considerable amount of research has been directed to the development of various types of cephalosporin antibiotics with a wide range of applications.

For example, applicant's British Patent No. 1,399,086 describes a new class of cephalosporin antibiotics containing a 7B (α-etherified oxyimino) acylamido group, the oxyimino group having the syn-configuration.

This class of antibiotic compounds is characterized by a high antibacterial activity against a variety of gram-positive and gram-negative organisms coupled with a particularly high stability against 0-lactamases produced by various gram-negative organisms. .

Finding this class of compounds has stimulated further research in the same field in attempts to find compounds with improved properties, for example against specific classes of organisms, in particular gram-negative organisms.

Applicants' British Patent Specification 1,496,757 discloses cephalosporin antibiotics containing a 78-acylamido group of formula 12 (wherein R is a thienyl or furyl group; R 1 and R 1 can vary considerably and, for example, alkyl groups of 1 to 4 carbon atoms together with the carbon atom to which they are attached form a cycloalkylidene group having 3 to 7 carbon atoms, and m and n are each 0 or 1 such that the sum of m and n is 0 or 1), the compounds being syn-iso 15 or mixtures of syn and anti isomers with at least 90% of the syn isomer. The 3-position of the cephalosporin molecule may be unsubstituted or may contain any of a wide variety of possible substituents. These compounds have been found to have particularly good activity against gram-negative organisms.

Other compounds of similar structure have been developed from these compounds in further attempts to find antibiotics with improved broad-spectrum antibiotic activity and / or high activity against gram-negative organisms.

Such developments have involved variations in not only the 78-acylamido group of formula 12, but also the introduction of certain groups in the 3-position of the cephalosporin molecule.

For example, South African Patent 78/1870 describes cephalosporin antibiotics in which the 78-acylamido side chain includes 2- (2-aminothiazol-4-yl) -2- (optionally substituted alkoxyimino) -acetamido group and the 3 position may be substituted, for example, by the group -C ^ Y, wherein Y is the residue of a nucleophile. The said patent contains, among many other preliminary baths, references to compounds in which the above optionally substituted alkoxyimino group is a carboxyalkoxyimino or carboxycycloalkoxyimino group. With regard to the 3-position, reference is made to mono and di-alkylaminoalkyl substituent and, among many other possibilities. South African Patent 78/2168 generally describes sulfoxide compounds similar to the sulfides described in the latter patent.

Furthermore, Belgian Patent Specification 836,813 describes cephalosporin compounds in which the group R in formula 12 may be replaced by, for example, 2-aminothiazol-4-yl, and the oxyimino group is a hydroxyimino or blocked hydroxyimino group 10, for example a methoxyimino group. In such compounds, the 3-position of the cephalosporin molecule is substituted by a methyl group which may itself be optionally substituted by any of a variety of nucleophilic compound residues disclosed therein. N-alkylaminomethyl groups are mentioned as possible substituents in the 3 position, but only mono- and di-alkylaminomethyl groups are specifically mentioned. In the above-mentioned patent specification no antibiotic activity is attributed to such compounds, which are only mentioned as intermediates for the preparation of antibiotics described in the above-mentioned patent specification.

It has now been found that by appropriately selecting a small number of specific groups in the 78 position in combination with a trialkylammoniomethyl group in the 3 position, cephalosporin compounds have a particularly advantageous activity (described in more detail below) against a wide variety of common pathogenic organisms can be obtained.

The present invention provides cephalosporin antibiotics of formula 1, wherein Ra and R 1, which may be the same or different, each represent an alkyl group having 1 to 4 carbon atoms (preferably a straight alkyl group, ie methyl, ethyl, n-propyl or n-butyl and especially methyl or ethyl) or Ra and together with the carbon atom to which they are attached form a cycloalkylidene group of 3 to 7 and preferably 3 to 5 carbon atoms; and R 1, and R 1, which may be the same or different, each represent an alkyl group having 1 to 4 carbon atoms, for example a methyl group, as well as non-toxic salts 790 7 8 81 * »...

4 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 group of formula 13 relative to the carboxamide group.

In the present application, the syn configuration is structurally represented by formula 14.

It will be understood that since the compounds of the invention are geometric isomers, their only admixture with the corresponding anti-isomer may occur.

The invention also includes the sulfates (especially the hydrates) of the compounds of formula 1. It also includes salts of esters of compounds of formula 1.

The compounds of the invention may exist in tautomeric forms (eg, with respect to the 2-aminothiazolyl group) and it will be understood that such tautomeric forms, for example, the 2-iminothiazolinyl form are within the scope of the invention. Furthermore, the compounds of formula 1 as indicated above may also exist in alternative zwitterionic forms, for example, wherein the 4-carboxyl group is protonated and the carboxyl group is protonated in the 7-side chain.

These laterative forms, as well as mixtures of zwitterionic forms, are within the scope of the invention.

It will also be understood that when Ra and Formula 1 represent different alkyl groups having 1 to 4 carbon -25 atoms, the carbon atom to which they are attached will form a center of asymmetry. A center of symmetry will also be present when R 1, R 1, and R 1 are all different alkyl groups. Such compounds are diastereoisomer and the present invention includes individual diastereoisomers of these compounds as well as mixtures thereof.

The compounds of the invention exhibit a broad spectrum antibiotic activity. The activity is unusually high against gram-negative organisms. This high activity extends to many β-lactamase producing 35 gram negative strains. The compounds also contain high stability to β-lactamases produced by a variety of gram negative and gram positive organisms.

Compounds of the invention have been found to show unusually high activity against strains of Pseudomonas organisms, for example strains of Pseudomonas aeruginosa, as well as high activity against various members of the Enterobacteriaceae (e.g. strains of Escherichia coli, Klebsiella pneumoniae, Salmonella typhimurium, Shigella sonnei, Enterobacter cloacae , Serratia marcescens, Providence species, Proteus mirabilis, and in particular indole-positive Proteus organisms, such as Proteus vulgaris and Proteus morganii) and strains of Haemophilus influenzae.

The antibiotic properties of the compounds of the invention contrast very favorably with those of the aminoglycosides such as amikacin or gentamicin. In particular, this applies to its activity against strains of various Pseudomonas organisms which are not sensitive to most existing commercially available antibiotic compounds. Unlike the aminoglycosides, cephalosporin antibiotics normally exhibit low toxicity in humans. The use of vari aminoglycosides in human therapy is limited or complicated by the relatively high toxicity of these antibiotics. Thus, the cephalosporin antibiotics of the invention have potentially great advantages over the aminoglycosides.

Non-toxic salt derivatives which can be formed by reaction of one or both of the carboxyl groups present in the compounds of formula 1 include salts with an inorganic base, such as alkali metal salts, eg sodium and potassium salts, and alkaline earth metal salts, eg calcium salts; salts with an amino acid, for example lysine and arginine salts and salts with an organic base, for example procaine, phenylethylbenzylamine, dibenzylethylenediamine, ethanolamine, diethanolamine and N-methylglycosamine salts.

Other non-toxic salt derivatives include acid addition salts formed, for example, with hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, formic acid and trifluoroacetic acid. The salts may also be in the form of resinates formed with, for example, 79fl7S31 6 a polystyrene resin or cross-linked polystyrene-divinylbenzene copolymer resin containing amino or quaternary amino groups or sulfonic acid groups, or with a resin containing carboxyl groups, for example a polyacrylic acid resin. Soluble base salts (eg, alkali metal salts, such as sodium salt) of compounds of formula 1 can be used in therapeutic applications in connection with the rapid distribution of such salts in the body upon administration. However, when insoluble salts of compounds of formula 1 are desired in a specific application, for example for use in depot formulations, such salts can be formed in a conventional manner, for example with suitable organic amines.

These and other salt derivatives, such as the salts with toluene-β-sulfonic acid and methanesulfonic acid, can be used as intermediates in the preparation and / or purification of the compounds of formula 1, for example, in the processes described below.

Non-toxic metabolically labile ester derivatives that can be formed by esterification of one or both of the carboxyl groups in the parent compound of formula 1 include acyloxyalkyl esters, for example lower alkanoyloxy-methyl or -ethyl esters, such as acetoxy-methyl or - ethyl or pivaloyloxy methyl esters. In addition to the above ester derivatives, the invention also includes compounds of formula 1 in the form of other physiologically acceptable equivalents, ie physiologically acceptable compounds which, like the metabolically labile esters, are converted in vivo to the basic antibiotic compound of formula 1.

Preferred compounds of the invention include those compounds of formula 1 wherein R1, R2 and R1 are all methyl. A preference also applies to those compounds in which R 1 and R 2 are both methyl or form a cyclobutylidene group together with the carbon atom to which they are attached.

(6R, 7R) —7 / (Z) -2- (2-aminothiazol-4-yl) -2- (1-carboxycyclobut-1 -35 oxyimino) acetamido / -3-trimethylammoniomethyl-cef-3-em-4 -carboxylate and its non-toxic salts and non-toxic metabolically labile * 790 7 8 81 7 esters thereof are particularly preferred compounds of the invention. Other preferred compounds include (6R, 7R) -7 - / (Z) -2- (2-aminothiazol-4-yl) -2- (2-carboxyprop-2-oxy-imino) acetamido / -3-trimethylammoniomethyl-cef -3-em-4-carboxylate-5 acid and its non-toxic salts and non-toxic metabolically labile esters.

Other compounds of the invention include, for example, those wherein the groups R a, R 1, R 1, R 2, and. R ^ in formula 1 have the following meaning: 10 Ra Ή, I R1 R2 R3 3) Alkyl groups '' -ch3- -upi5 ch3 ch3 ch3 -c2h5 -c2h5 ch3 ch3 ch3 -ch3 -ch3 g2h5 ch3 ch3 -CH3 - C2H5 C2H5 CH3 ch3 15 C2H5 -G2H5 C2H5 CH3 CH3 -CH3 -GH3 C2H5 C2H5 CH3 -ch3 -c2h5 o2h5 c2h5 ch3 -c2h5 -c2h5 c2h5 c2a5 cHj -ch3 -ch3 02h5 c2h5 c2h02 -2 C2H5__C2H5, C2H5 C2H5

Ra? ^ E1 E2 R3 b) Cycloalkylidene groups 25 cyclopropylidene -CH3 -CH3 “CH3 cyclopropylidene -CH3 -CH3 -CH3 cyclopropylidene” ^ 2 ^ 5 “CH3 -CH3 cyclobutylidene" "^ 2 ^ 5 ~ CH3" CH3 cyclopentylidene - ^ 2H5 "CH3 -CH3 30 cyclopropylidene -C2H5" ^ 2 ^ 5 ~ CI ^ 3 cyclobutylidene -C2H5 "C2 ^ 5 -C®3 cyclopentylidene -C2H5" C2H5 "CH3 cyclopropylidene" C2H5 -G2H5 cyclobutylidene -G2H5 "C2H5" C2yl G2 ^ 5 -G2 ^ 5 ”C2H5 790 7 8 81 * 8

The compounds of formula 1 can be used to treat a variety of diseases caused by pathogenic bacteria in human beings and animals, such as respiratory and urinary tract infections.

According to another embodiment of the invention, there is provided a process for the preparation of an antibiotic compound of formula 1 as defined above or a non-toxic salt or non-toxic metabolically labile ester thereof, wherein (Δ) is a compound of formula 2, wherein Rj, 10 K-2 and R3 have the above meanings; B is> S or> S + 0 (a- or β-); and the dotted line bridging the 2, 3 and 4 position indicates that the compound is a cef-2-em or cef-3-em compound, or a salt, e.g. an acid addition salt (formed with e.g. a mineral acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid or phosphoric acid or an organic acid such as methanesulfonic acid or toluene-p-sulfonic acid) or an N-silyl derivative thereof, or a corresponding compound of a group of the formula -COOR 4 in the 4-position, wherein R 1 is a hydrogen atom or a carboxyl blocking group, for example the residue of an ester-forming aliphatic or araliphatic alcohol or an ester-forming phenol, silanol or stannanol (wherein the alcohol, phenol, silanol or stannanol is preferably 1 to 20 carbon atoms), and which has an associated anion A, such as halide, for example chloride or bromide, or trifluoroacetate, acylates with an acid of formula 3, wherein and Rg have the above meaning; R ^ is a carboxyl blocking group, for example as described for R ^; and Rg is an amino or protected amino group, or with a corresponding acylating agent; (B) a compound of formula 4, wherein Ra, Rg, Rg, B and the dotted line have the aforementioned meaning; R 1 and R 1 a independently of one another are hydrogen or a carboxyl blocking group; and X is a replaceable residue of a nucleophile, for example an acyloxy group, such as a dichloroacetoxy group, or a halogen atom, such as chlorine, bromine or iodine, or react a salt thereof with a tertiary amine of formula 5, wherein R 1, R En and R ^ have the above meanings; or (C) a compound of formula 6, wherein R &, Rg, Rj, Rl, Rg, B and 790 7 8 81 9 have the dotted line of the aforementioned meaning; and R 1 and R 1 a are both carboxyl blocking groups, alkylates with an alkylating agent to form a group of formula 15 in the 3-position; after which, if necessary and / or desired in each case, one or more of the following reactions are carried out, in an appropriate order:. 2.

1) conversion of a Δ-isomer into the antler, 3.

ste Δ isomer, 2) reduction of the compound in which B> S - * · 0 10 to a compound in which B is> S, 3) conversion of a carboxyl group into a non-toxic salt or non-toxic metabolically labile ester function, and 4) removal of any carboxyl blocking and / or N-protecting groups.

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

Acylating agents which can be used in the preparation of compounds of formula 1 include acid halides, especially acid chlorides or 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.

Acylations using acid halides can be carried out in aqueous or non-aqueous reaction media, suitably at temperatures from -50 to + 50 ° C, preferably -20 to + 30 ° C, if desired in the presence of an acid binding agent. Suitable reaction media include aqueous ketones such as aqueous acetone, esters such as ethyl acetate, halogenated hydrocarbons such as methylene chloride, amides such as dimethyl acetamide, nitriles such as acetonitrile or mixtures of two or more such solvents. Suitable acid-binding agents include tertiary amines, for example triethylamine or dimethylaniline, inorganic bases, for example calcium carbonate or sodium bicarbonate, and oxiranes such as lower 1,2-alkylidene oxides (for example 790 7 8 81 10 ethylene oxide or propylene oxide) which bind hydrogen halide released in the acylation reaction.

Acids of formula 3 can themselves be used as acylating agents in the preparation of compounds of formula 1.

Acylations using acids of formula 3 are preferably carried out in the presence of a condensing agent, for example a carbodiimide, such as Ν, Ν'-dicyclohexylcarbodiimide or N-ethyl-N'-dimethyl-aminopropylcarbodiimide; a carbonyl compound such as carbonyldiimidazole; or an isoxazolium-10 salt such as N-ethyl-5-phenylisoxazolium perchlorate,

Acylation can also be performed with other amide-forming derivatives of acids of formula 3, such as, for example, an activated ester, a symmetrical anhydride or a mixed anhydride, for example formed with pivalic acid or with a halo-15 format, such as a lower alkyl haloformate. Mixed anhydrides can also be formed with phosphoric acids (eg phosphoric acid or phosphorous acid), sulfuric acid or aliphatic or aromatic sulfonic acids, eg foluene p-sulfonic acid. An activated ester can be conveniently formed in situ using, for example, 1-hydroxybenzotriazole in the presence of a condensing agent as indicated above. Alternatively, the activated ester can be preformed.

Acylation reactions involving the free acids or the above-mentioned amide-forming derivatives thereof are preferably carried out in an anhydrous reaction medium, for example methylene chloride, tetrahydrofuran, methyl formamide or acetonitrile.

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

The acids of formula 3 and corresponding acylating agents can, if desired, be prepared and used in the form of their acid addition salts. For example, acid chlorides can be suitably used in the form of their hydrochloride salts and acid bromides in the form of their hydrobromide salts. 790 7 8 81 π

The amine compound of formula 5 can act as a nucleophile to displace a wide variety of substituents X of the cephalosporin of formula 4. The ease of displacement is related to some extent to the pK of the acid HX from which the substituent is derived. For example, atoms or groups X derived from strong acids are generally more easily displaceable than atoms or groups derived from weaker acids. The ease of displacement is also somewhat related to the precise identities of the alkyl groups in the compound of formula 5.

The displacement of X by the amine of formula 5 can be conveniently accomplished by keeping the reagents in solution or suspension. The reaction is advantageously carried out using 1 to 20 and preferably 1 to 4 moles of the amine of formula 5.

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

Acy1oxy group and.

Suitable starting materials for use in the nucleophilic displacement reaction with the amine of formula 5 include compounds of formula 4 wherein X is the residue of a substituted acetic acid, for example chloroacetic acid, dichloroacetic acid and trifluoroacetic acid.

The substituent X may also be derived from formic acid, a halomic acid, such as chloroformic acid, or a carbamic acid.

When using a tin of formula 4 wherein X is a substituted acetoxy group, it is generally desirable that the group in formula 4 be a hydrogen atom and that B> S. In this case, the reaction is advantageously effected in an aqueous medium, preferably at a pH of 5 to 8, especially 5.5 to 7.

The above-described method using compounds of formula 4 wherein X is the residue of a substituted acetic acid can be carried out as described in 790 7 8 81 12 in British Patent 1,241,657.

When using compounds of formula 4 wherein X is an acyloxy group, the reaction is conveniently effected at a temperature of -20 to +80 and preferably 50 to + 50 ° C.

Halogens.

Compounds of formula 4 wherein X is chlorine, bromine or iodine may advantageously be used as starting materials in the nucleophilic displacement reaction with the amine of formula 5. When using compounds of formula 4 in this class, B may represent + 0 and R ^ can represent a carboxyl blocking group. The reaction is suitably effected in a non-aqueous medium containing preferably one or more organic solvents, advantageously ethers, for example dioxane or tetrahydrofuran, esters, for example ethyl acetate, amides, for example formamide and Ν, Ν-dimethylformamide, and ketones, for example acetone. Other suitable organic solvents are described in more detail in British Patent No. 1,326,531.

The reaction medium should be neither extremely acidic nor extremely basic. In the case of reactions performed on compounds of formula IV wherein Ry and R1 are carboxyl blocking groups, the 3-trialkylammoniomethyl product will be formed as the corresponding halide salt which may be optionally are subjected to one or more ion exchange reactions to obtain a salt with the desired anion.

When using compounds of formula 4 wherein X is a halogen atom as described above, the reaction is conveniently conducted at a temperature of -10 to +50 and preferably +10 to + 30 ° C.

In the above process (C), the 3-di-C 1-6 alkylaminomethyl compound of formula 6 is advantageously reacted with an alkylating agent having 1 to 4 carbon atoms of the formula R 1 Y, wherein R 1 has the above meaning and Y represents a leaving group, such as halogen (e.g., iodine, chlorine, or bromine), or a hydrocarbyl sulfonate group (e.g., mesylate or tosylate), or R2 is dimethyl sulfate. The alkylation reaction is preferably carried out at a temperature of from 0 to 60, advantageously from 20 to 30 ° C. The reaction may suitably be carried out in an inert solvent, such as an ether, eg tetrahydrofuran, an amide, eg dimethylformamide, or a halogenated hydrocarbon, eg dichloromethane. Alternatively, when the alkylating agent is liquid under the reaction conditions, this agent itself can serve as a solvent.

For example, the compound of formula 6, used as starting material in process (C), can be prepared by reacting a compound of formula 4 as defined above with a secondary amine of formula 7, wherein R 1 and R 2 have the above meaning, analogous to the nucleophilic displacement reaction described with respect to method (B).

This reaction is preferably conducted in the presence of an acid scavenging agent. The amine itself can act as an acid scavenging agent.

The reaction product can be separated from the reaction mixture, which may contain, for example, unaltered cephalosporin starting material and other substances, by a variety of methods including recrystallization, ionophoresis, column chromatography and use of ion exchangers (eg, by chromatography on ion exchange resins) or macro-reticular resins.

2 Δ -cephalosponester ester derivatives obtained according to the method of the invention can be converted into 3 the corresponding Δ derivative by, for example, treatment of 2 the-ester with a base such as pyridine or tnethylamme.

A cef-2-em reaction product may also be oxidized to provide the corresponding cef-3-em-1-30 oxide, for example, by reaction with a peracid, for example per-acetic acid or m-chloro-perbenzoic acid; the resulting sulfoxide can, if desired, then be reduced as described below to provide the corresponding cef-3-em sulfide.

When a compound is obtained in which 35 is B> S -> 0, it can be converted into the corresponding sulfide by, for example, reduction of the corresponding acyloxysulfonium salt or alkoxysulfonium salt prepared in situ by reaction with, for example, acetyl chloride in the case of an acetoxysulfonium salt, the reduction being carried out, for example, by sodium dietionite or by iodide ion as in a solution of potassium iodide 5 in a water-miscible solvent, for example acetic acid, acetone, tetrahydrofuran, dioxane, dimethylformamide or dimethyl acetamide. The reaction can be carried out at a temperature from -20 to + 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 a suitable esterification agent, such as an acyloxy-alkyl halide (eg iodide) in an inert organic suitably solvent, such as dimethylformamide or acetone, followed, if necessary, by removal of any protecting groups.

Base salts of the compounds of formula 1 can be formed by reacting an acid of formula 1 with the appropriate base. For example, sodium or potassium 20 salts can be prepared using the respective 2-ethyl hexanoate 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 in the form of a mixture of isomers, the syn isomer can be obtained, for example, by conventional methods such as crystallization or chromatography.

For use as starting materials for the preparation of compounds of formula 1 according to the invention, preferably compounds of formula 3 and acid halides and anhydrides corresponding therewith in the syn isomeric form or in the form of mixtures of the syn isomers and the corresponding anti-isomers containing at least 90% of the syn isomer.

Zuraiv of formula 3, provided that R & and R 7 together do not form a cyclopropylene group with the carbon atom to which they are attached, can be prepared by etherification of a compound of formula 8, wherein Rg has the above meaning and Rg a carboxyl blocking group, by reaction with a compound 5 of formula 9, wherein R &, Rg and Rg are as defined above and T is halogen, such as chlorine, bromine or iodine, sulfate or sulfonate, such as tosylate, followed by removal of the carboxyl blocking group Rg. Separation of isomers can be accomplished either before or after such etherification. The etherification reaction is generally conducted in the presence of a base, for example, potassium carbonate or sodium hydride, and is preferably conducted in an organic solvent, for example, imethyl 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 oxyimino group remains virtually unchanged during the etherification reaction. The reaction is to be effected in the presence of a base if an acid addition salt of a compound of formula 8 is used. The base should be used in an amount sufficient to quickly neutralize the acid in question.

Acids of the general formula 3 can also be prepared by reacting a compound of formula 10, wherein Rg and Rg have the above meaning, with a compound of formula 11, wherein Ra, Rg and Rg have the above meaning, followed by removal of the carboxyl blocking group Rg, and if necessary by separation of syn and anti isomers.

The latter reaction is particularly applicable to the preparation of acids of formula 3 in which Rf 1 and Rg 30 together with the carbon atom to which they are attached form a cyclopropylidene group. In this case, the relevant compounds of formula 11 can be prepared in a conventional manner, for example, by the synthesis described in Belgian patent 866,422 for the preparation of t-butyl-1-amino-oxycyclo-propane carboxylate.

The acids of formula 3 can be converted to the corresponding acid halides and acid anhydrides and acid addition salts by conventional methods, for example as described above.

When X is a halogen, i.e., 5-gene chlorine, bromine or iodine, in formula 4, cef-3-em starting compounds can be prepared in a conventional manner, for example by halogenating a 7f3-protected amino-3- methylceph-3-em-4-carboxylic acid ester-1-oxide, removal of the 7g protecting group, acylation of the resulting 73-amino compound to form the desired 7β-acylamido group, for example in an analogous manner and the Method (A) described above, followed by reduction of the 1β-oxide group later in the sequence. This is described in the British patent. 1,326,531. The corresponding cef-2-em compounds can be prepared according to the method of Dutch patent application 69.02013 by reacting a 3-methyl-cef-2-em compound with N-bromosuccinimide to provide the corresponding 3-bromomethylcef-2 -em connection.

When X in formula 4 is an acetoxy group, such starting materials can be prepared, for example, by acylation of 7-aminocephalosporanic acid, for example, in an analogous manner to method (A). Compounds of formula 4 wherein X represents other acyloxy groups can be prepared by acylation of the corresponding 3-hydroxymethyl compounds which can be prepared, for example, by hydrolysis of the appropriate 3-acetoxy-25 methyl compounds, for example as described in British Pat. Nos. 1,474,519 and 1,531. 212.

The starting materials of formula 2 are new compounds. These compounds can be prepared in a conventional manner, for example, by deprotecting a corresponding protected 7β-amino compound in a conventional manner, for example using PCl.

It should be noted that in some of the above conversions, it may be necessary to protect any sensitive groups in the molecule of the compound in question in order to avoid unwanted side reactions. For example, during each of the reaction sequences referred to above, it may be necessary to protect the N 2 group of the aminothiazolyl groups, for example, by tritylation, acylation (e.g. chloroacetylation), protonation or other conventional method. The protecting group can then be removed in any suitable manner which does not cause degradation of the desired compound, for example in the case of a trityl group by using an optionally halogenated carboxylic acid, for example acetic acid, formic acid, chloroacetic acid or trifluoroacetic acid or using a mineral acid , hydrochloric acid or 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.

Carboxyl blocking groups used in the preparation of compounds of formula 1 or in the preparation of necessary starting materials are preferably groups which can be readily cleaved at an appropriate stage in the reaction sequence, conveniently at the final stage.

However, it may be convenient in some cases to use non-toxic metabolically labile carboxyl blocking groups, such as acyloxy-methyl or ethyl groups (eg, acetoxymethyl or ethyl or pivaloyloxymethyl) and to include them in the final product. retained to provide a suitable ester derivative of a compound of formula 1.

Suitable carboxyl blocking groups are generally known. A list of representative blocked carboxyl groups is found in British Patent No. 1,399,086. Preferred blocked carboxyl groups include: aryl-lower-alkoxycarbonyl groups, such as p-methoxybenzyloxy-carbonyl, p-nitrobenzyloxycarbonyl and diphenylmethoxycarbonyl; lower alkoxycarbonyl groups such as t-butoxycarbonyl; and lower haloalkoxy-carbonyl groups such as 2,2,2-trichloroethoxycarbonyl. Carboxyl blocking groups can then be removed by any of the appropriate methods found in the literature; for example, acid or base-catalyzed hydrolysis is in many cases applicable, as is enzyme-catalyzed hydrolysis.

The following examples illustrate the invention 790 7 8 81 * 18. All temperatures are in degrees Celsius. Petroleum ether used has a boiling point of 40 to 60 ° C.

Preparation 1

Ethyl 1- (Z) -2- (2-aminothiazol-4-yl) -2- (hydroxyimino) acetate 5 To a stirred and ice-cooled solution of 292 g ethyl acetoacetate in 296 ml glacial acetic acid, a solution of 180 g sodium nitrite in 400 ml of water at such a rate that the reaction temperature was kept below 10 ° C. Stirring and cooling were continued for about 30 minutes, after which a solution of 160 g of potassium chloride in 800 ml of water was added. The resulting mixture was stirred for 1 hour. The lower, oily phase was separated and the aqueous phase was extracted with diethyl ether. The extract was combined with the oil, washed successively with water and saturated brine, dried and evaporated. The residual oil, which solidified on standing, was washed with petroleum ether and dried under vacuum over potassium hydroxide to give ethyl (Z) -2- (hydroxyimino) -3-oxobutyrate (309 g).

A stirred and ice-cooled solution of ethyl (Z) -2- (hydroxyimino) -3-oxobutyrate (150 g) in dichloromethane (400 ml) was treated dropwise with 140 g of sulfuryl chloride. The resulting solution was kept at room temperature for 3 days and then evaporated. The residue was dissolved in diethyl ether, washed with water until the washings were nearly neutral, dried and evaporated. The residue oil (177 g) was dissolved in 500 ml of ethanol and 77 ml of dimethylaniline and 42 g of thiourea was added with stirring. After 2 hours, the mixture was filtered and the residue was washed with ethanol and dried to give 73 g of the title compound, melting at 188 ° C with decomposition.

Preparation 2

Ethyl (Z) -2-hydroxyimino-2- (2-tritylaminothiazol-4-yl) acetate, hydrochloride

Trityl chloride (16.75 g) was added in portions over 2 hours to a stirred and cooled to -30 ° C solution of the product of preparation 1 (12.91 g) and 8.4 ml of triethyl 790 7 8 81 * 19 amine in 28 ml of dimethylformamide. The mixture was allowed to warm to 15 ° G in an hour, stirred for an additional 2 hours and then partitioned between 500 ml of water and 500 ml of ethyl acetate. The organic phase was separated, washed with water (2 x 500 ml) and then shaken with 500 ml 1N HCl. The precipitate was collected, washed successively with 100 ml of water, 200 ml of ethyl acetate and 200 ml of ether and dried in vacuo to give 16.4 g of the title compound as a white solid, melting at 184 to 186 ° C with decomposition.

10 Preparation 3

Ethyl (Z) -2- (2-t-butoxycarbonylprop-2-oxyimino) -2- (2-trityl-aminothiazol-4-yl) -acetate

Potassium carbonate (34.6 g) and t-butyl-2-bromo-2-methylpropionate (24.5 g) were added to a stirred solution under nitrogen of the product of preparation 2 (49.4 g) in 200 ml of dimethyl sulfoxide and the mixture was stirred at room temperature for 6 hours. The mixture was poured into 2 liters of water, stirred for 10 minutes and filtered. The solid was washed with water and dissolved in 600 ml of ethyl acetate. The solution was successively washed with water, 2N hydrochloric acid, water and saturated brine, dried and evaporated. The residue was recrystallized from petroleum ether to give 34 g of the title compound, melting at 123.5 to 125 ° C.

Preparation 4 25 (Z) -2- (2-t-butoxycarbonylprop-2-oxyimino) -2- (2-tritylaminothiazol-4-yl) acetic acid

The product of preparation 3 (2 g) was dissolved in 20 ml of methanol and 3.3 ml of 2N sodium hydroxide was added.

The mixture was refluxed for 1.5 hours and then evaporated. The residue was taken up in a mixture of 50 ml of water, 7 ml of 2N hydrochloric acid and 15 ml of ethyl acetate. The organic phase was separated and the aqueous phase extracted with ethyl acetate.

The organic solutions were combined, washed successively with water and saturated brine, dried and evaporated.

The residue was recrystallized from a mixture of carbon tetrachloride and petroleum ether to give 1 g of the 790 7 8 81 20 title compound, melting at 152 to 156 ° C with decomposition.

Preparation 5

Ethyl (Z) -2- (2-tritylaminothiazol-4-yl) -2- (1-butoxy-carbonylcyclobut-1-oxyimino) -acetate 5 The product of preparation 2 (55.8 g) was stirred under nitrogen in 400 ml of dimethyl sulfoxide with 31.2 g of finely ground potassium carbonate at room temperature. After 30 minutes, 29.2 g of t-butyl-1-bromocyclopentane carboxylate were added. After 8 hours, an additional 31.2 g of potassium carbonate was added. More potassium carbonate (6 servings of 16 g) was added over the next 3 days and after 3 days an additional 3.45 g of t-butyl-1-bromocyclobutanecarboxylate was added. After a total of 4 days, the mixture was poured into ice water (about 3 liters) and the solid was collected by filtration and washed well with water and petroleum ether. The solid was dissolved in ethyl acetate and the solution washed with brine (2x), dried with magnesium sulfate and evaporated to a foam. This foam was dissolved in ethyl acetate / petroleum ether (1: 2) and filtered through 500 g of silica gel. Evaporation gave 60 g of the title compound as a yellow foam, u (CHBr 3) 3400 (NH) 20 'and 1730 cm 2 (ester).

Preparation 6 (Z) -2- (1-t-butoxycarbonylcyclobut-1-oxyimino) -2- (2-tritylamino-thiazol-4-yl) -acetic acid

A mixture of 3.2 g of the product of preparation 5 and 1.65 g of potassium carbonate was heated under reflux in 180 ml of methanol and 20 ml of water for 9 hours and the mixture was cooled to room temperature. The mixture was evaporated and the residue partitioned between ethyl acetate and water to which 12.2 ml of 2N HCl had been added. The organic phase was separated and the aqueous phase extracted with ethyl acetate. The combined organic extracts were washed with saturated brine, dried and evaporated to give the title compound (2.3 g); λ (ethanol) 265 nm (E? ^ 243).

max 1 cm

Example I

A) Diphenylmethyl- (1S, 6R, 7R) -3-bromomethyl-7 - / (Z) -2- (2-t-butoxy-carbonylprop-2-oxyimino) -2- (2-tritylaminothiazol-4-yl ) -acetamido / cef-3-em-4-carboxylate, 1-oxide 790 7 8 81 21

A solution of the product of preparation 4 (0.526 g) in dry tetrahydrofuran (6 ml) was treated successively with 1-hydroxybenztriazole monohydrate (0.141 g) and N, N'-dicyclohexylcarbodiimide (0.198 g) in tetrahydrofuran (4 ml). The developing slurry was stirred at 23 ° C for 30 minutes and then filtered. A solution of diphenylmethyl- (IS, 6R, 7R) -7-amino-3-bromomethyl-cep-3-em-4-carboxylate, 1-oxide (0.427 g) in dichloromethane (260 ml) was treated with the above filtrate. The solution was stirred at 20 to 25 ° C for 18 hours, evaporated to dryness, then the residue was dissolved in dichloromethane and washed successively with saturated aqueous sodium bicarbonate solution, water and brine, then dried and evaporated in vacuo to a foam (1.01 g).

This foam was purified by chromatography on preparative silica plates using toluene, ethyl acetate and acetic acid in the ratio of 190: 50: 2.5 as eluent. The purified product was isolated as a foam which was dissolved in 5 ml of ethyl acetate and precipitated with 200 ml of petroleum ether to give 0.69 g of the title compound in 1% form of a colorless powder; λ (EtOH) 268 nm (E, “182) with <ct Ώ3.Χ 1 cm a valley at 242 nm EJ * 230), v (Nujol) 3375 (NH), 1805 (g-lactam), 1730, (C02R ) and 1688 and 1515 cm-1 (CONH). b) Diphenylmethyl- (1S, 6R, 7R) -7 - / (Z) -2- (2-t-butoxycarbonylprop-2-oxymino) -2- (2-tritylaminothiazol-4-yl) -acetamido / -3- trime-25 thylammoniomethylceph-3-em-4-carboxylate, 1-oxide, bromide salt

The product of step a) (0.154 g), alumina-dried tetrahydrofuran (0.3 ml) and anhydrous trimethylamine in dry tetrahydrofuran (0.155 g trimethylamine in 1 ml solution) (0.065 ml) were stirred at 24 ° C for 1 hour. The reaction mixture was added dropwise to 220 ml of well stirred ether and the resulting suspension was stirred vigorously for 10 minutes. The solid was filtered off, washed with ether and dried under vacuum to give the title compound (0.131 g), mp 158-178 ° C (decomposition); [alpha] 7 + 11 ° (c 35 0.53, CHCl 3).

790 7 8 81 22 c) Diphenyme thy 1- (65., 75.) - 7- / (Z) -2- (2-t-butoxycarbonylprop-2-oxy-imino) -2- (2-tritylaminothiazole-4 -yl) acetamido / -3-trimethyl-ammoniomethylceph-3-em-4-carboxylate, iodide salt

The product of step b) (1.87 g) and acetone 5 (4.7 ml) was stirred as a solution at -10 ° C. Dry powdered potassium iodide (1.14 g) was added and the mixture was stirred at -10 ° C for 2 minutes. Dry powdered potassium iodide (1.14 g) followed by 0.25 ml of acetyl chloride were added and the vigorously stirred mixture was allowed to warm to 0 ° C in 20 minutes.

The mixture was stirred at 0 to + 2 ° C for 1 hour. The mixture was added dropwise to a stirred solution of 0.850 g of sodium metabisulfite in 47 ml of water. The resulting solid was filtered off, washed with water and dried under vacuum over phosphorus pentoxide to give 1.939 g of a solid. The above procedure was repeated using 1.87 g of solid, 4.7 ml of acetone, 1.14 g of powdered potassium iodide, 0.25 ml of acetyl chloride and a reaction time at 0 to + 2 ° C for 25 minutes. This gave 1.951 g of the title compound as a solid, mp. 142 to 176 ° C; 0101 ^ 7 ^ -16 ° (c 0.38, 20 CHCl 3).

d) Diphenylmethyl- (6R, 7R) -7 - / (Z) -2- (2-t-butoxycarbonylprop-2-oxy-imino) -2- (2-tritylaminothiazol-4-yl) -acetamido / -3- trimethyl-ammoniomethylceph-3-em-4-carboxylate, trifluoroacetate salt

The product of step (c) (1.826 g) was dissolved in acetone: ethanol = 9: 1 and chromatographed on "Deacidite" FF SRA 62 ion exchange resin (strong anion exchange resin) in the trifluoroacetate form. The kohm was eluted with the above solvent mixture. A 20 ml head was discarded and the next 250 ml were immediately evaporated in vacuo to give 1.595 g of the title compound as a reddish brown foam.

e) (6R, 7R) -7 - / (Z) -2- (2-aminothiazol-4-yl) -2- (2-carboxyprop-2-oxyiminó) acetamido / -3-trimethylammoniomethylceph-3-em-4 -carboxylate 35 The product of step d) (1.37 g), anisole (1.37 ml) and trifluoroacetic acid (5.5 ml) were swirled together at 790 7 8 81 23 25 ° C for 1 | minute to form a solution, then 1 minute more. The volatile material was evaporated and the residue was azeotroped twice with toluene. The gum was dissolved in 10 ml of acetone and precipitated in 500 ml of petroleum ether.

The brown solid was filtered off, washed with petroleum ether and dissolved in acetone. The solution was evaporated to 1.117 g of a foam.

This entire amount of foam, 0.25 ml of insulin and 5 ml of trifluoroacetic acid were swirled together at 28 ° C for 5 minutes. The volatile material was removed and the residue was azeotroped twice with toluene. The resulting brown oil was precipitated with 10 ml of acetone and 500 ml of petroleum ether boiling from 40 to 60 ° C to give 1.066 g of a solid.

0.2 g of the solid was dissolved in 2 ml of a mixture of trifluoroacetic acid and water in the ratio 1: 1 and the solution was stirred at 28 ° C for 30 minutes. The mixture was evaporated to dryness and the resulting gum was dissolved in 10 ml of water. The cloudy solution was filtered and the residue was washed with water (10ml, 5ml) and the filtrate was lyophilized to give 0.17g of a foam. The foam was triturated with water, the resulting solid filtered quickly and dried under vacuum to provide 0.148 g of the title compound as a solid associated with 1.8 moles of trifluoro-acetic acid; / a + 120 ° (c 0.3; EtOH: H + O = 1: 1); λ. - (pH 6 buf-fer) 230 nm (ε 17,000), λ 260 nm (ε 10,200).

Example II

a) Diphenylmethyl- (IS, 6R, 7R) -3-bromomethyl-7- / (Z) -2- (1-t-butoxy-carbonylcyclobut-1-oxyimino) -2- (2-tritylaminothiazol-4-yl) -30 acetamido / -ceph-3-em-4-carboxylate, 1-oxide

A stirred solution of the product of preparation 6 (1.167 g) in tetrahydrofuran (15 ml) was treated successively with 1-hydroxybenztriazole hydrate (0.337 g) and NjN'-dicyclohexylcarbodixmide (0.495 g) for 30 minutes at 22 ° C.

Filtration gave a solution of the activated ester 790 7 8 81 24 which was added to a solution of diphenylmethyl- (1S, 6R, 7R) -7-amino-3-bromomethylceph-3-em-4-carboxylate -1-oxide (0.95 g) in dichloromethane (550 ml). The solution was stirred for 16 hours and then evaporated to dryness. A solution of the residue in dichloromethane was successively washed with aqueous sodium bicarbonate and brine then dried and evaporated to a foam (2.2 g) which was purified by preparative thin layer chromatography (using a mixture of toluene, ethyl acetate and acetic acid in the ratio 40: 10: 1 for development) to provide 1.4 g of the title compound with λ (EtOH) 266 nm (e] ^ 192) and a trough at 242.5 nm (EY ° 224), v ( Nujol) 3360 (NH), 1805 (β-lactam), 1730 (C0oR) 1 cm max 1 z and 1689 and 1520 cm (CONH).

b) Diphenylmethyl- (IS, 6R, 7R) -7 - / (Z) -2- (1-butoxycarbonylcyclobut-1-oxyimino) -2- (2-tritylamino thiazol-4-yl) -acetamido / -3- trimethylammoniomethylceph-3-em-4-carboxylate, 1-oxide, bromide salt

The product of step a) (1.2 g), alumina-dried tetrahydrofuran (2.5 ml) and anhydrous trimethylamine in dry 20 'tetrahydrofuran (0.49 ml of a solution of trimethylamine (0.155 g) in tetrahydrofuran (1 ml )) were stirred at 24 ° C for 30 minutes. The reaction mixture was added dropwise to 900 ml of stirred ether and the resulting suspension was stirred vigorously for 10 minutes. The solid was filtered off, washed with ether and dried under vacuum to give the title compound (1.16 g), mp. 156 to 170 ° C (dec.); [alpha] 7 + 6 ° (c 0.48, CHCl 3).

c) Diphenylmethyl- (6R, 7R) -7 - / (Z) -2- (1-butoxycarbonylcyclobut-1-oxyimino) -2- (2-tri tylaminothiazol-4-yl) acetamido / -3- trimethylammoniomethylceph- 3-emr-4-earboxylate, iodide salt

The product of step b) (1.05 g) and acetone (2.6 ml) were stirred as a solution at -10 ° C. Dry powdered potassium iodide (0.625 g) was added and the mixture was stirred at -10 ° C for 2 minutes. Another 0.625 g of dry powdered potassium iodide was added followed by 0.14 ml of acetyl chloride. The stirred mixture was allowed to warm to 0 ° C and stirred at 0 to + 2 ° C for one hour. The mixture was added dropwise to a stirred solution of 0.465 g of sodium metabisulfite in 26 ml of water. The resulting solid was filtered off, washed with water and dried under vacuum over phosphorus pentoxide to give 1.072 g of a solid. The above procedure was repeated using the solid (1.072 g), acetone (2.6 ml), dry powdered potassium iodide (0.625 g) and acetyl chloride (0.14 ml) to give the title compound (1.131 g) as a solid, melting at 133 to 170 ° C (dec.); / ~ <x_7D -33 ° (c 0.6, CHCl3).

d) (6R, 7R) -7 - / (Z) -2- (2-aminothiazol-4-yl) -2- (1-carboxycyclobut-1-oxyimino) acetamido / -3-trimethylammoniomethylceph-3-em-4 -carboxylate

The product of step c) (0.2 g) was moistened with 0.2 ml anisole and 0.8 ml trifluoroacetic acid was added.

An immediate precipitate was formed and the suspension was swirled at about 23 ° C for 2 minutes, after which the precipitate became gummy.

The mixture was evaporated to dryness and the residue was triturated with ether to give a solid which was wetted with 0.035 ml of anisole and 4 ml of fluoroacetic acid was added. A very fine precipitate formed and the suspension was swirled at 23 ° C for 15 minutes. The mixture was evaporated to a gum which was triturated with ether to give 0.091 g of the title compound as a solid associated with 1 mole of trifluoro-acetic acid and 0.4 mole of hydrogen iodide, a7p + 45 (c 0.22 ethanol) : water = 1: 1), λ. - (pH 6 buffer) 257.5 nm (e! ^ 240), λ. _. ~ mi 1 cm mi 296 nm (E ° 115).

1 cm

Example III

a) Diphenylmethyl- (1S, 6R, 7R) -7 - / (Z) -2- (1-t-butoxycarbonylcyelobut-30-1-oxyimino) -2- (2-trity-laminothiazol-4-yl) -acetamido / -3-dimethylaminomethylceph-3-em-4-carboxylate, 1-oxide

The product of Example II (a) (0.52 g) in 2 ml of dry tetrahydrofuran was treated with 0.20 ml of a 33% by weight solution of dimethylamine in ethanol. After 15 minutes at 21 ° C, the mixture was partitioned between 25 ml of ethyl acetate and 25 ml of water. The aqueous layer was extracted with an additional 25 ml of 790 78 81 26 ethyl acetate and the total organic solution was washed with 2 x 50 ml of water and dried with Na 2 SO 4 and evaporated to a foam (0.498 g). The crude product was purified by preparative thin layer chromatography on 2 mm thick silica gel plates, eluting with ethyl acetate. The headband, 0.4, yielded 0.331 g of a foam, which was dissolved in 2 ml of ethyl acetate and slowly added to 50 ml of stirred petroleum ether. The precipitate was filtered off and washed with petroleum ether and dried in vacuo to give 0.224 g of the title compound as a solid, α / 1010 -21 ° (c 0.87%, CHCl 3, λ., (EtOH) 245 nm ( e!% 225), 260 in order to int cm (E 210) and 305 nm (Ξ / e 57).

1 cm 1 cm b) Diphenylmethyl- (1S, 6R, 7R) —7 - / (Z) —2— (1-t-butoxycarbonylcyclobut-1-oxyimino) -2- (2-tritylaminothiazol-4-yl) -acetamido / -3-tri-methylammoniomethylceph-3-em-4-carboxylate, 1-oxide, 15 iodide salt

The product from step (a) (0.201 g) was dissolved in 1 ml iodomethane and the solution was left 1 | stand at 21 ° C for hours. 20 ml of diethyl ether were added and the precipitate was triturated, then filtered and washed with ether and dried in vacuo to give 0.199 g of the title compound as a solid, α + 10 ° (c 0.87%). , CHCl ^), λ. ς (EtOH) 260 nm (!160), 265 nm (έ} / ° 154) and 305 nm mf '1 cm M cm (E ° 64) with a v at 394 nm (E, ° 43).

1 cm max J I cm

Example IV

A) Diphenylmethyl- (1S, 6R, 7R) -7-formamido-3-trimethylammonio-methylceph-3-em-4-carboxylate, 1-oxide, bromide salt

A solution of diphenylmethyl- (IS, 6R, 7R) -3-bromomethyl-7-formamidocef-3-em-4-carboxylate, 1-oxide (1.01 g) in dry N, N-dimethylformamide (3 ml) was added treated with a solution (0.8 ml) of anhydrous trimethylamine in tetrahydrofuran (0.155 g trimethylamine per ml solution) and the solution was stirred at 21 ° C for 15 minutes. 10 ml of ether was added and the supernatant was discarded. Trituration of the oily residue with about 15 ml of ether gave a precipitate which was filtered off, washed with ether and dried quickly under vacuum to give 1.002 g of the title compound as a 790 7 8 81 * 4 27 solid melting at 140 to 150 ° C with decomposition), (Nujol) ca. 3400 (NH), 1798 (β-lactam), 1680 (C = O of HCONH), 1732 (CO2R) and 1035 cm * (sulfoxide).

b) Diphenylmethyl- (1S, 6R, 7R) -7-amino-3-trimethylammoniomethylceph-5,3-em-4-carboxylate, 1-oxide, hydrochloride and bromide salt

A mixture of 0.562 g of the product of step (a) in 5 ml of methanol was stirred at 0 ° C and treated dropwise with 0.28 ml of phosphoryl chloride over 10 minutes. The mixture was stirred at 0 ° C for 2 hours to precipitate a light brown-yellow solid. 15 ml of ether was added to the stirred mixture, then the precipitate was filtered and washed successively with ether and ethyl acetate and dried under vacuum to give 0.479 g of the title compound as a solid, λ (EtOH) 280 nm (E, 1%) 117), V (Nujol) 3700 to 2200 (NH4), 15 1807 (β-lactam) and 1734 cm (CO2E.).

c) Diphenylmethyl- (1S, 6R, 7R) -7 - / (Z) -2- (2-t-butoxycarbonylprop-2-oxyimino) —2- (2-tritylaminothiazol-4-yl) -acetamido / - 3- trimethylammoniomethylceph-3-em-4-carboxylate, 1-oxide, bromide salt 20 Phosphorus pentachloride (0.11 g) in dry dichloromethane (10 ml) at 0 ° C was treated with the product of preparation 4 and the solution was Stirred at 0 ° C for 35 minutes. 0.16 ml of triethyl amine was added and stirring was continued at 0 ° C for 5 minutes. The solution was then added dropwise over a period of 25 minutes to a vigorously stirred suspension of 0.286 g of the product of step b) in 15 ml of dichloromethane at 0 ° C. The suspension was stirred at 0 ° C for 15 minutes, at 20 ° C for 2 hours and then the suspension was left overnight at 4 ° C.

The mixture was partitioned between 100 ml of ethyl acetate and 100 ml of water and the emulsion was clarified by filtration.

The organic phase was washed with 100 ml of water, then dried over sodium sulfate and evaporated to a foam. A solution of this foam in 4 ml of ethyl acetate was added dropwise to 120 ml of stirred petroleum ether. The precipitate was filtered and washed with petroleum ether and dried under vacuum 790 7 8 81 28 to give 0.363 g of the crude product as a solid.

Some solid "remained on the sinter, which was dissolved in ethyl acetate and the solution evaporated to a gum (0.019 g). The above combined products (0.33 g) were stirred with 20 ml of ethyl acetate for 15 minutes with trituration of the precipitate The stirred mixture was slowly diluted with 20 ml of ether and after a further 10 minutes the solid was filtered and washed with ether and dried under vacuum to give 0.211 g of the title compound as a solid, λ (EtOH) 10 240 nm (E!% 214), 260 nm (e!% 159), 266 nm (e!% 150), 275.5 l »1 cm cm 1 cm« «nm (E, ° 140) and 305 nm ( E, * 68) with λ at 385 nm (E, ° 32), '1 cm 1 cm max J 1 cm' * v (CHBr_) 3670 (water), 3600 to 2500 (NH), 1804 (8-lactam) , m L L2 «j λ 1730 (CO2R), 1680 and 1513 cm -1 (CONH).

The title compound can be converted to 15 (6R, 7R) -7 - / (Z) -2- (2-aminothiazol-4-yl) -2- (2-carboxyprop-2-oxy-imino) -acetamido / -3 trimethylammoniomethylceph-3-em-4-carboxylate as described in Example I.

The antibiotic compounds of the invention can be formulated into a composition for administration in any suitable manner, analogous to other antibiotics, and the invention therefore includes within its scope pharmaceutical compositions comprising an antibiotic compound of the invention, suitable for use in the human and veterinary medicine. Such formulations can be provided for use in a conventional manner using any necessary pharmaceutical carriers or extenders.

The antibiotic compounds of the invention can be formulated into a formulation for injection and can be provided in unit dosage form in ampoules, or in multi-dose containers, if necessary with an added preservative. The compositions may also be in other forms, such as suspensions, solutions or emulsions in oily or aqueous carriers, and may contain formulating agents, such as suspending agents, stabilizing agents and / or dispersing agents. Alternatively, the active ingredient may be in powder form for preparation with a suitable carrier, for example, sterile, pyrogen-free water, 790 7 8 81 29 before use.

If desired, such powder preparations may contain a suitable non-toxic base to improve the water solubility of the active ingredient and / or ensure that when the powder is prepared with water the pH of the resulting aqueous preparation is physiologically acceptable. Alternatively, the base can be present in the water with which the powder is made. 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.

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

For medication of the eyes or ears, the preparations may be prepared in the form of individual capsules, in liquid or semi-solid form, or used as drops.

For example, veterinary preparations can be prepared as intramammary preparations in either long-acting or fast-releasing bases.

The compositions may contain from 0.1%, e.g. 0.1 to 99%, of the active material, depending on the mode of administration. When the compositions comprise dosage units, each unit should preferably contain from 50 to 1500 mg of the active ingredient. The dosage used for the treatment of adult humans will preferably range from 500 to 6000 mg per day depending on the route and the frequency of administration. For example, in the treatment of adult humans, 1000 to 3000 mg per day administered intravenously or intramuscularly should normally be sufficient. In the treatment of

Pseudomonas infections may require higher daily doses.

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

790 7 8 81 30

Example V

The following composition illustrates how a compound of the invention can be incorporated into a pharmaceutical composition. The preparation is for injection and the composition as indicated below per bottle.

(6R, 7R) -7 - / (Z) -2- (a-mino thiazoo1-4-yl) -2- (1-carboxy-cyclobut-1-oxyimino) -acetamido / -3-trimethylammonio-methyl-cef -3-em-4-carboxylate. 500 mg

Sodium carbonate, anhydrous 49 mg 10 The procedure is as follows. Mix the sterile cephalosporin antibiotic with sterile sodium carbonate under aseptic conditions. Apply aseptically in glass vials under a blanket of sterile nitrogen. Close the vials using rubber discs or stoppers, held in place by aluminum caps, preventing gas exchange or micro-organism ingress. Prepare the product by dissolving in water for injections or other suitable sterile vehicle shortly before administration.

9 20 790 7 8 81

Claims (10)

1. Cephalosporin antibiotics of formula 1, wherein Ra and R1, which may be the same or different, each represent an alkyl group of 1 to 4 carbon atoms or Ra and 5 together with the carbon atom to which they are attached a cycloalkylidene group of 3 to 4 7 carbon atoms; and R 1, R 2, and R 1, which may be the same or freshly different, each represent an alkyl group having 1 to 4 carbon atoms, as well as non-toxic salts and non-toxic metabolically labile esters thereof. Compounds according to claim 1, characterized in that at least one of the groups Ra and R 1 is methyl or ethyl. Compounds according to claim 1, characterized in that R 1 and R 4 together with the carbon atom to which they are attached form a cycloalkylidene group of 3 to 5 carbon atoms. Compounds according to any one of the preceding claims, characterized in that R 1, R 2 and all are methyl groups. 20 5. (6R, 7R) -7 - / (Z) -2- (2-aminothiazoo-1-yl) - 2- (2-carboxyprop-2-oxyimino) -acetamido / -3-trimethylammoniomethyl-cef-3 -em-4-carboxylate. 6. The non-toxic salts of the compound of claim 5. 7. (6R, 7R) -7 - / (Z) -2- (2-aminothiazol-4-yl) -2- (1-carboxycyclobut-1) -oxyimino) -acetamido / -3-trimethylammonio-methyl-cef-3-emr4-earboxylate. The non-toxic salts of the compound of claim 7. Process for the preparation of new antibiotic compounds, characterized in that the compounds of formula 1 as defined in claim 1 and the non-toxic salts and non-toxic metabolically labile esters thereof are prepared as follows: 35 (A) acylation of a compound of formula 2, wherein R 1, R 2 and the meaning defined in claim 1; 790 7 8 81 <ί Β> S or> S + 0 and the dotted line running from the 2 through the 3 to the 4 position indicates that the compound is a cef-2-em or cef-3-em- compound, or a salt or N-silyl derivative thereof or a corresponding compound of a group of the formula 5 -COOR ^ in the 4-position, wherein is a hydrogen atom or a carboxyl blocking group, and having an associated anion A , with an acid of formula 3, wherein-Rq and Rg have the meaning as defined in claim 1, Rx is a carboxyl blocking group and Rg is an amino group or a protected amino group, or with an acylating agent corresponding therewith; (B) reacting a compound of formula 4, wherein R &, Rg, Rg, B and the dotted line have the aforementioned meaning. I am; R 1 and R 3 a independently can represent hydrogen or a carboxyl blocking group and X is a replaceable residue of a nucleophile, or a salt thereof with a tertiary amine of formula 5, wherein R 1, R 4 and R 4 de have the above meaning; or (C) alkylating a compound of formula 6, wherein R 1, R 9, R 1, R 2, R 9, B and the dotted lines have the aforementioned meaning; and R 1 and R 2 a both represent carboxyl blocking groups 20, with an alkylating agent serving to form a group of formula 15, wherein R 1, R 2 and R 2 have the aforementioned meaning in the 3 position; after which, if necessary and / or desired, one or more of the following reactions, in any suitable order, are carried out in each case: 2 25 1) conversion of a Δ isomer m to the desired .3. . Δ isomer, 2. reduction of a compound in which B is> S + 0 to form a compound in which B is> S, 3. conversion of a carboxyl group into a non-toxic salt function or a non-toxic metabolically labile ester function, and 4. removal of any carboxyl blocking and / or N-protecting groups. 10. Pharmaceutical composition for use in human medicine or veterinary medicine, characterized in that it comprises an antibiotic compound according to any one of claims 790 7 8 81 Λ 1 to 8 in association with a pharmaceutical carrier or adjuvant. 11. Methods and articles essentially as described in the description and / or the examples. h ί \! y 790 7 8 81 Hhx j_ | ^ * Η H \ = ZCCO.NH - * _ Rt Η N — 1 — UBn Ri NR »i — N J-chn! Ri o ^ V'CH.NR, OCCOOH o c00s 2 COO® Rj I Rjj * · '5 r4 r4 S- ^ NS Η H b \ = z / - C.COOH \ = / - C.CO.NH-jY R1 Nn R. N R. 0J-NvjAcHX N- Rj • j 0. C. COORj. OXXOR,, COOR d J k k 4? 7 - 5 Ré S ^ N h h ../ r <\ -XcXO.NH - rB] j. , R, ^ R, V_7 n *? * —Nv ^ 'chAd ^ ^ £ -C00Rs v.CXOOR' <W R1 N Rk? * 6 f 8 ° H? * -R4 R * -RXXO.NH- T. CXOORj s7n HJJ.OCCOOR, n R *. R1 - / R10. (CH2) 'C (CH) COOH * 9' - COXOR. Kfc * "> tn 10 11 12 R * iA NH, p -O.CXOOH $ Λν fa Rb \ = ZcXO.NH - 4i 1 13. R. *> Ύχχοοη 15 u k 790 7 8 81 Glaxo Group Limited, London, Great Britain