CH644868A5 - CEPHEMIC CARBONIC ACID (ESTER) SUBSTITUTED IN 3 AND 7 POSITIONS. - Google Patents

Description

The invention relates to cephalosporin compounds with valuable antibiotic properties, processes for their preparation and pharmaceutical preparations containing them.

The cephalosporin compounds in the following description are described with reference to "Cepham" according to J. Amer. Chem. Soc. 1962,84,3400 named, where the term "cephem" refers to the basic cepham structure with a double bond.

Cephalosporin antibiotics are widely used in the treatment of diseases caused by pathogenic bacteria in humans and animals, and are particularly valuable in the treatment of diseases caused by bacteria which are resistant to other antibiotics such as penicillin compounds and in which Treatment of penicillin sensitive patients. In many cases, it is desirable to use a cephalosporin antibiotic that is effective against both Gram-positive and Gram-negative microorganisms, and considerable research has been directed to the development of various types of broad-spectrum cephalosporin antibiotics.

For example, British Patent 1,399,086 describes a new class of cephalosporin antibiotics with a 7β- (cc-etherified oxyimino) acylamido group, the oxyimino group having the syn configuration. This class of antibiotic compounds is characterized by a high antibacterial activity against one

^ 0. (CH2) mC (CH2) nC00H

RB

(where R is a thienyl or furyl group; RA and RB can vary widely and can be, for example, Ci-4 alkyl groups or, together with the carbon atom to which they are attached, a C3-7 cyclo form alkylidene group 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 isomers or mixtures of syn-50 and anti isomers with at least 90% of the syn isomer are. The 3-position of the cephalosporin molecule can be unsubstituted or can contain one of a large number of possible substituents. These compounds were found to have particularly good activity against 55 gram-negative organisms.

Other compounds of similar structure have been developed from these compounds in further attempts to find antibiotics with improved broad-spectrum anti-biotic activity and / or high activity against 60 gram-negative organisms. Such developments included variations not only in the 7β-acylamido group of formula (A) but also in the introduction of special groups in the 3-position of the cephalosporin molecule.

For example, cephalosporin antibiotics are described in South African patent specification 65/1870, in which the 7β-acylamido side chain includes i.a. is a 2- (2-amino-thiazol-4-yl) -2- (optionally substituted-alkoxyimino) acetamido group and the 3-position may be substituted

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may, for example, by the group -CH2Y, where Y represents the residue of a nucleophile; the description contains numerous examples of such nucleophiles, including nitrogen nucleophiles. The specification includes references to compounds in which the optionally substituted alkoxyimino group mentioned above is a carboxyalkoxyimino or carboxycycloalkoxyimino group, among many other examples. In the South African patent specification 78/2168 sulfoxide compounds corresponding to the sulfides described in the latter description are given in a broad scope.

Furthermore, Belgian patent 836 813 describes cephalosporin compounds in which the group R in the above formula (A) can be replaced, for example, by 2-aminothiazol-4-yl and the oxyimino group is a hydroxyimino or blocked hydroxyimino group, e.g. a methoxyimino group. In these connections the nh "

3-position of the cephalosporin molecule substituted by a methyl group, which in turn can optionally be substituted by any large number of residues of the nucleophiles described therein. In the above patent, such compounds mentioned only as intermediates for the manufacture of antibiotics described in this specification are not considered to have antibiotic activity.

It has now been found that through a suitable selection of a small number of special groups in the 7β-position in combination with a 3-alkyl-l, 2,3-triazo-lium-l-yl-methyl group in the 3-position Cephalosporin compounds with particularly advantageous activity (which is explained in more detail below) can be obtained over a wide range 15 of commonly occurring pathogenic organisms.

The invention therefore relates to cephalosporin antibiotics of the general formula;

s n

\ - /■■c.cocnh

11 a n r

\ I

0.c.cooh rb in which Ra and Rb, which are identical or different, each have a Ci-4-alkyl group (preferably a straight-chain alkyl group such as a methyl, ethyl, n-propyl or n-butyl group and in particular a methyl - or ethyl group) or Ra and Rb together with the carbon atom to which they are attached form a C3-7-cycloalkylidene group, preferably a C3-s-cycloalkylidene group; and R1 represents a Ci-4 alkyl group e.g. a methyl group, and their non-toxic salts and the sol-vate and the acyloxyalkyl esters of these compounds.

The compounds according to the invention are syn isomers. The syn-isomeric form is determined by the configuration of the group

R '

I.

-O.C.COOH

Rb defined with reference to the carboxamido group. In the following description, the syn configuration is structurally referred to as follows:

feeds eoo

Nv

1

ch n f_u) n - r

2kil /

(i)

NS

s n ul

• c. co.nh - Ii

H Ra

0. C.COOH

lb

It should be mentioned that since the compounds according to the invention are geometric isomers, a certain mixture with the corresponding anti-isomer can occur.

The invention also relates to the solvates (especially the hydrates) of the compounds of the formula (I). It also includes the non-toxic salts of the mentioned esters of Verbin-40 fertilizer of formula (I).

The compounds according to the invention can exist in tautomeric forms (for example in relation to the 2-aminothiazolyl group) and it should be mentioned that such tautomeric forms e.g. the 2-iminothiazolinyl form are included in the scope of the invention. In addition, the compounds of formula (I) above can also exist in alternative zwitterionic forms, for example where the 4-carboxyl group is protonated and the carboxyl group in the 7-side chain is deprotonated. These alternative forms as well as the mixtures of zwitterionic forms are also included in the scope of the invention.

It should further be noted that if Ra and Rb in the above formula mean different Ci-4-alkyl groups, the carbon atom to which they are attached comprises an asymmetry center. Such compounds are diastereoisomeric and the invention also encompasses the individual diastereoisomers of these compounds and the mixtures thereof.

The compounds according to the invention show a broad-60 band antibiotic activity. The activity towards grief-negative organisms is unusually high. This high activity extends to many β-lactamase-producing gram-negative strains. The compounds also have high stability for β-lactamases, which are produced by a number of Gram-negative and Gram-positive organisms.

It has been found that the compounds according to the invention have an unusually high activity against

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Strains of Pseudomonas organisms, e.g. Strains of Pseudomonas aeruginosa, as well as high activity against various members of the Enterobacteria ceae (e.g. strains of Escherichia coli, Klebsiella pneumoniae, Salmonella typhimurium, Shigella sonnei, Enterobacter cloacae, Serratia marcescens, Providence species, Proteus mirabilis and especially Proteus mirabilis Organisms such as Proteus vulgaris and Proteus morganii) and strains of Haemophilus influenzae.

The antibiotic properties of the compounds according to the invention can be compared favorably with those of the aminoglycosides such as amikacin or gentamicin. In particular, this applies to their activity against strains from various Pseudomonas organisms which are not sensitive to the majority of existing, commercially available antibiotic compounds. Unlike the aminoglycosides, the cephalosporin antibiotics usually show low toxicity in humans. The use of aminoglycosides in human therapy is limited or complicated by the relatively high toxicity of these antibiotics. The cephalosporin antibiotics according to the invention therefore have extremely great advantages over the aminoglycosides.

The non-toxic salts which can be formed by reaction of one or both of the carboxyl groups present in the compounds of general formula (I) include salts with inorganic bases such as alkali metal salts (e.g. sodium and potassium salts) and alkaline earth metal salts (e.g. calcium salts); Amino acid salts (e.g. lysine or arginine salts); Salts of organic bases (e.g. procaine, phenylethylbenzylamine, dibenzylethylenediamine, ethanolamine, diethanolamine and N-methylglycosamine salts). Other non-toxic salts include acid addition salts e.g. formed 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 which have been formed, for example, with a polystyrene resin or crosslinked polystyrene-divinylbenzene copolymer resin containing amino or quaternary amino groups or sulfonic acid groups or with a resin containing carboxyl groups, e.g. a polyacrylic acid resin. Soluble salts of bases (e.g. alkali metal salts such as the sodium salt) of compounds of formula (I) can be used in therapeutic applications due to the rapid distribution of such salts in the body after administration. However, if insoluble salts of compounds of formula (I) are desired in a particular application e.g. for use in depot preparations, 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 p-toluenesulfonic acid and methanesulfonic acid, can be used as intermediates in the preparation and / or purification of the present compounds of the formula (I), for example in the processes described below.

Non-toxic metabolically labile esters which can be formed by esterification of one or both of the carboxyl groups contained in the parent compound of formula (I) are the acyloxyalkyl esters, e.g. lower alkanoyl oxymethyl or ethyl ester such as acetoxymethyl or ethyl ester or pivaloyloxymethyl ester.

Preferred compounds according to the invention include those compounds of the formula (I) in which R1 denotes a methyl group. Also preferred are those compounds in which Ra and Rb both represent methyl groups or together with the carbon atom to which they are attached form a cyclobutylidene group. Particularly preferred compounds according to the invention include the following compounds of the formula (I) and their non-toxic salts and their acyloxyalkyl esters:

(6R, 7R) -7 - [(Z) -2- (2-aminothiazol-4-yl) -2- (2-carboxyprop-2-oxyimino) acetamido] -3- (3-methyl-1,2 , 3-triazolium-1-yl) methyl ceph-3-em-4-carboxylate and (6R, 7R) -7 - [(Z) -2- (2-aminothiazol-4-yl) -2- ( 1-carboxycyclobut-1-oxyimino) acetamido] -3- (3-methyl-l, 2,3-triazolium-l-yl) methyl ceph-3-em-4-carboxylate.

Other compounds according to the invention include, for example, those in which the groups Ra, Rb and R1 have the following meanings:

ra rb r1

a) alkyl groups

-CHa

-C2H5

-CH3

-C2H5

-C2H5

-CHs

-CH3

-CH3

-C2H5

-CHJ

-C2H5

-C2H5

-C2H5

-C2H5

-C2H5

b) cycloalkylidene groups

1

(Ra-C-Rb)

1

Cyclopropylidene

-CH3

Cyclopentylidene

-CH3

Cyclopropylidene

-C2H5

Cyclobutylidene

-C2H5

Cyclopentylidene

-C2H5

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

According to the invention, a method for producing an antibiotic compound of the general formula (I) as defined above or a non-toxic salt thereof is also provided, which is characterized in that

that he

A) a compound of the formula:

h h i i

'1 T>

h n—, r> n

2i 1 / \ 1 0 * j ch2, \ © / -r c00® (xi)

wherein R1 is as defined above and is ^> S or ^> S- * 0 (a- or ß-), or a salt, e.g. an acid addition salt (formed with, for example, 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 p-toluenesulfonic acid) or an N-silyl derivative thereof or a corresponding compound with a group of the formula -COOR2 in 4- Position where R2 is a hydrogen atom or a carboxyl blocking group, e.g. the rest of an ester-forming aliphatic or ara-

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lipatic alcohol or an ester-forming phenol, silanol or stannanol (this alcohol, this phenol, silanol or stannanol preferably having 1 to 20 carbon atoms)

r4

contains atomic atoms), and with an associated anion Ae, such as a halide e.g. Chloride or bromide or the trifluoroacetate anion, with an acid of the formula:

SS

S n \ - /

c.cooh ii n,

rc

(iii)

o.c. coor3

L

wherein Ra and Rb are as previously defined; R3 represents a carboxyl blocking group, e.g. as described for R2 and R4 is an amino or protected amino group, or

B) a compound of the formula:

r4

r

20 aeylated with a corresponding amide-forming derivative; or that one s n

U.

c.co.nh ii

N

H

J »

i

0

h i i r

-n b

ch2x

0.C.COOR ^ a coor "

r wherein Ra, Rb, R4 and B are as defined above; R5 and R5a can independently represent hydrogen or a carboxyl-blocking group and X is an exchangeable radical

.n

S \

(iv)

a nucleophile, e.g. an acetoxy or dichloroacetoxy group or a halogen atom such as chlorine, bromine or iodine or a salt thereof with a compound of the formula:

NO

w

(v)

wherein R1 is as defined above to react; or that one

C) a compound of the formula:

a ch2n n

/ ^

IT

w

(VI)

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wherein Ra, Rb, R4 and B are as previously defined and R5 and R5a both represent carboxyl blocking groups, alkylated with an alkylating agent which serves to introduce the R 'substituent into the above triazole ring in formula (VI); what to do when using a sulfoxide

(B => S-0)

as the starting product of the formula II, IV or VI, the corresponding sulfoxide obtained is reduced to the sulfide, after the acylation (A) the protective group R3 and any further carboxyl and / or amino protective groups present are removed or after the reaction (B) and the Alkylation (C) removes the carboxyl and / or amino protective groups which may be present and, if appropriate, converts the compound of the formula I obtained into a non-toxic salt.

The acylating agents which can be used in the preparation of the compounds of formula (I) include acid halides, especially acid chlorides or bromides. Such acylating agents can be obtained by reacting an acid (III) or a salt thereof with a halogenating agent, e.g. Phosphorus pentachloride, thio-nyl chloride or oxalyl chloride can be produced.

The acylation using the acid halides can advantageously be carried out in aqueous or non-aqueous reaction media at temperatures from -50 ° C. to + 50 ° C., preferably -20 ° C. 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 dimethylacetamide, nitriles such as acetonitrile or mixtures of two or more such solvents. 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 oxide (for example ethylene oxide or propylene oxide) which bind the hydrogen halide released in the acylation reaction .

Acids of formula (III) can themselves be used as acylating agents in the preparation of the compounds of formula (I). The acylation using the acids (III) is expediently carried out in the presence of a condensing agent, for example a carbodiimide such as N, N'-dicyclohexylcarbodiimide or N-ethyl-N'-y-dimethylaminopropylcarbodiimide; a carbonyl compound such as carbonyldiimidazole; or an isoxazolium salt such as N-ethyl-5-phenylisoxazolium perchlorate.

The acylation can also be effected with other amide-forming derivatives of the acids of formula (III) such as an activated ester, a symmetrical anhydride or a mixed anhydride (e.g. formed with pivalic acid or with a haloformic acid ester such as haloformic acid lower alkyl ester). Mixed anhydrides can also be formed with phosphoric acids (e.g. phosphoric acid or phosphorous acid), sulfuric acid or aliphatic or aromatic sulfonic acids (e.g. p-toluenesulfonic acid). An activated ester can conveniently be formed in situ using, for example, 1-hydroxybenzotriazole in the presence of a condensing agent as mentioned above. Alternatively, the activated ester can be preformed.

The acylation reactions, which include the free acids or their amide-forming derivatives mentioned above, are desirably carried out in an anhydrous reaction medium e.g. Methylene chloride, tetrahydrofuran, dimethylformamide 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 (III) and the corresponding acylating agents can, if desired, be prepared and used in the form of their acid addition salts. For example, the acid chlorides can suitably be used as their hydrochloride salts and the acid bromides as their hydrobromide salts.

The compounds of formula (V) can act as a nucleophile to displace a large number of substituents X from the cephalosporin of formula (IV). To some extent, the ease of displacement is related to the pKa of the acid HX from which the substituent originates. For example, atoms or groups X that come from strong acids tend to be displaced more easily than atoms or groups that come from weaker acids. The ease of displacement or replacement also depends to some extent on the precise identity of the alkyl group in the compound of formula (V).

The displacement of X by the compound of formula (V) can expediently be carried out by maintaining the reactants in solution or suspension. The reaction is advantageously effected using 1 to 20, preferably 1 to 4, moles of the compound of the formula (V).

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

Acyloxy groups

Compounds of formula (IV) in which X is an acetoxy group are useful starting materials for use in the nucleophilic exchange reaction with the compound of formula (V). Alternative starting materials in this class include compounds of formula (IV) wherein X is the residue of a substituted acetic acid e.g. Chloroacetic acid, dichloroacetic acid and trifluoroacetic acid.

The displacement reactions on compounds of formula (IV) with X substituents of this class, especially in the case where X is an acetoxy group, can be facilitated by the presence of iodide or thiocyanate ions in the reaction medium.

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

When using a compound of formula (IV) in which X represents an acetoxy group or substituted acetoxy group, it is generally desirable that the group R5 in formula (IV) is a hydrogen atom and that B represents Z ^ S. In this case, the reaction is advantageously carried out in an aqueous medium, preferably at a pH of 5 to 8, particularly 5.5 to 7.

The process described above using the compounds of formula (IV), wherein X is the residue of a substituted acetic acid, can be carried out as described in British patent 1 241657.

When using compounds of the formula (IV),

wherein X is an acetoxy group, the reaction is conveniently carried out at a temperature of 30 ° C to 110 ° C, preferably 50 ° C to 80 ° C and

Halogens

Compounds of formula (IV) in which X is a chlorine, bromine or iodine atom can also be suitably used as starting materials in the nucleophilic displacement reaction with the compound of formula (V). At Ver8

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Using compounds of the formula (IV) in this class, B

and R5 can be a carboxyl blocking group. The reaction is conveniently effected in a non-aqueous medium, which preferably comprises one or more organic solvents, advantageously of a polar nature, such as ether, e.g. Dioxane or tetrahydrofuran, esters e.g. Ethyl acetate, amides e.g. Formamide and N, N-dimethylformamide and ketones e.g. Acetone. Other suitable organic solvents are described in detail in British Patent 1326531. The reaction medium should neither be extremely acidic nor extremely basic. In the case of reactions which are effected on compounds of the formula (IV) in which R5 and R5a are carboxyl-blocking groups, the 3- (3-alkyl-l, 2,3-triazolium) methyl product is formed as the corresponding halide, if desired can be subjected to one or more ion exchange reactions to obtain a salt with the desired anion.

When using the compounds of formula (IV), wherein X is a halogen atom as described above, the reaction can conveniently be carried out at a temperature of -10 ° C to + 50 ° C, preferably + 10 ° C to + 30 ° C.

In process (C) above, the triazolylmethyl compound of the formula (VI) is advantageously reacted with a Cw-alkylating agent of the formula R1 Y, where R1 is as defined above and Y is a remaining group such as a halogen atom (e.g. iodine , Chlorine or bromine) or a hydrocarbyl sulfonate group (eg mesylate or tosylate) or R1 Y means dimethyl sulfate. The alkylation reaction is preferably carried out at a temperature in the range from 0 ° to 60 ° C., advantageously 20 ° C. to 30 ° C. The reaction may conveniently be carried out in an inert solvent such as an ether e.g. Tetrahydrofuran, an amide e.g. Dimethylform amide or a halogenated hydrocarbon e.g. Dichloromethane can be effected. Alternatively, if the alkylating agent is liquid under the reaction conditions, this agent itself can serve as a solvent.

The compounds of formula (VI) which are used as starting material in process (C) can, for example, by reacting a compound of formula (IV) (as defined above) with a triazole of formula (VII)

n * nh (vii)

w are prepared in an analogous manner to the nucleophilic displacement reaction as described in relation to (B). This reaction is preferably carried out in the presence of an acid removing agent. The triazole itself can act as an acid removing agent.

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

If a compound is obtained in which B is ^ 5S- * 0, it is reduced to the corresponding sulfide, for example by reducing the corresponding acyloxysulfonium or alkoxysulfonium salt which can be obtained in situ by reaction with e.g. Acetyl chloride in the case of an acetoxysulfo-

sodium salt, the reduction being effected by, for example, sodium dithionite or iodide ion as in a solution of potassium iodide in a water-miscible solvent e.g. Acetic acid, acetone, tetrahydrofuran, dioxane, dimethylformamide or dimethylacetamide. The reaction can be effected at a temperature of from -20 ° to + 50 ° C.

The metabolically labile acyloxyalkyl esters of the compounds of formula (I) can be obtained by reacting a compound of formula (I) or a salt or protected derivative thereof with a suitable esterifying agent such as an acyloxyalkyl halide (e.g. iodide), suitably in an inert organic solvent such as dimethylformamide or acetone and then, if necessary,

by removing any protecting groups.

The salts of the compounds of formula (I) with bases can be formed by reacting an acid of formula (I) with the appropriate base. For example, the sodium or potassium salts can be prepared using the corresponding 2-ethyl hexanoate or hydrogen carbonate. The acid addition salts can be prepared by reacting a compound of formula (I) or one of the previously mentioned metabolically labile esters thereof with the appropriate acid.

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

For use as starting materials for the preparation of a compound of the general formula (I) according to the invention, the compounds of the general formula (III) and the corresponding acid halides and anhydrides in their syn-isomeric form or in the form of mixtures of syn-isomers and the corresponding anti-isomers, which contain at least 90% of the syn isomer, are preferably used.

Acids of formula (III) (provided that Ra and Rb together with the carbon atom to which they are attached do not form a cyclopropylidene group) can be obtained by etherification of a compound of formula (VIII)

R4

/ V

s n

^ c.coor6 (viii)

Ii n

(wherein R4 is as previously defined and R6 represents a carboxyl-blocking group) by reaction with a compound of the general formula (IX)

Ra

I.

T.C.COOR3 (IX)

Rb

(wherein Ra, Rb and R3 are as defined above and T is a halogen such as chloro-, bromo- or iodo, sulfate or sulfonate such as tosylate), and then removing the carboxyl blocking group R6. The

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The isomers can be separated either before or after such etherification. The etherification reaction is generally carried out in the presence of a base e.g. Potassium carbonate or sodium hydride and is preferably effected in an organic solvent e.g. Dimethyl sulfoxide, a cyclic ether such as tetrahydrofuran or dioxane or an N, N-disubstituted amide such as dimethylformamide. Under these conditions, the configuration of the oxyimino group is essentially unchanged by the etherification reaction. The reaction should be effected in the presence of a base when an acid addition salt of a compound of formula (VIII) is used. The base should be used in sufficient quantities to quickly neutralize the acid in question.

The acids of the general formula (III) can also be obtained by reacting a compound of the formula (X)

co. coor6

(wherein R4 and R6 are as defined above) with a compound of formula (XI)

Ra

I.

H2N.O.C.COOR3 (XI)

I.

Rb

(in which Ra, Rb and R3 are as defined above) and then removing the carboxyl-blocking group R6 and, if necessary, separating the syn and anti isomers.

The latter reaction is particularly applicable to the preparation of acids of formula (III) in which Ra and Rb together with the carbon atom to which they are attached form a cyclopropylidene group. In this case, the corresponding compounds of formula (XI) can be e.g. by means of the synthesis described in Belgian patent 866 422 for the preparation of tert-butyl-1-amino-oxycyclopropane carboxylate.

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

When X is a halogen atom (e.g. chlorine, bromine or iodine) in formula (IV), the ceph-3-em starting compounds can be prepared in a conventional manner e.g. by halo generation of a 7ß-protected-amino-3-methylceph-3-em-4-carboxylic acid ester-lß-oxide, removal of the 7ß-protecting group, acylation of the 7ß-amino compound formed to form the desired 7ß-acylamido group e.g. in an analogous manner to process (A) described above and subsequent reduction of the β-oxide group later in the sequence. This is described in British Patent 1,326,531. The corresponding ceph-2-em compounds can be prepared by the method of the published Dutch patent application 6 902 013 by reacting a 3-methyl-ceph-2-em compound with N-bromosuccinimide to form the corresponding 3-bromomethyl ceph-2-em Connection to be established.

When X in formula (IV) is an acetoxy group, such starting materials can be prepared, for example by acylation of 7-aminocephalosporanic acid e.g. in an analogous manner to process (A) above. Compounds of formula (IV) in which X represents other acyloxy groups can be prepared by acylation of the corresponding 3-hydroxymethyl compounds which can be prepared e.g. by hydrolysis of the appropriate 3-acetoxymethyl compounds e.g. as described in British Patents 1,474,519 and 1,531,212.

The starting materials of formula (II) are new compounds. These compounds can be prepared in a conventional manner, for example by nucleophilic displacement of the corresponding 3-acetoxymethyl compound with the appropriate nucleophile.

Another method for the preparation of the starting materials of the formula (II) comprises the removal of the protective group of a corresponding protected 7β-amino compound in a conventional manner, e.g. using PCls.

It should be noted that with some of the above conversions, it may be necessary to protect any sensitive groups in the molecule of the compound in question to avoid undesirable side reactions. For example, during any of the reactions mentioned above, it may be necessary to protect the NH2 group on the aminothiazolyl half, for example by tritylation, acylation (e.g. chloroacetylation), protonation, or other common method. The protecting group can then be removed in any suitable manner which does not cause degradation of the desired compound, e.g. in the case of a trityl group by using an optionally halogenated carboxylic acid e.g. Acetic acid, formic acid, chloroacetic acid, or trifluoroacetic acid or by using a mineral acid e.g. 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.

The carboxyl-blocking groups which are used in the preparation of the compounds of the formula (I) or in the preparation of the necessary starting materials are expediently groups which are easily split off in a suitable stage of the reaction sequence, expediently in the last stage. However, in some cases it may be appropriate to use non-toxic metabolically labile carboxyl blocking groups such as acyloxymethyl or ethyl groups (e.g. acetoxymethyl or ethyl or pivaloyloxymethyl) and to retain them in the end product in order to obtain a suitable ester derivative of a compound of formula (I) surrender.

Suitable carboxyl blocking groups are well known to those skilled in the art and a list of representative blocked carboxyl groups is contained in British Patent 1,399,086. Preferred blocked carboxyl groups include aryl-lower alkoxycarbonyl groups such as p-methoxybenzyloxycarbonyl, p-nitrobenzyloxycarbonyl and diphenylmethoxycarbonyl, lower alkoxycarbonyl groups such as tert-butoxycarbonyl; and low haloalkoxy carbonyl groups such as 2,2,2-trichloroethoxycarbonyl. Carboxyl blocking group (s) can then be removed by any suitable method described in the literature; for example in many cases acid or base-catalyzed hydrolysis can be used like enzymatically-catalyzed hydrolysis.

The following examples are intended to explain the invention in more detail. All temperatures are in ° C. The petroleum ether has a boiling range of 40 to 60 ° C. T.l.c. is thin layer chromatography using pre-coated plates

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(Merck F254.0.25 mm thick coating), which were tested under ultraviolet light at 254 nm and developed with iodine.

The magnetic proton resonance spectra (p.m.r.) were used where appropriate and were determined at 100 MHz. The integrals are in accordance with the assignments; the coupling constants J are in Hz, the characters have not been determined; s is a singlet, d = doublet, dd = double doublet, m = multiple «and ABq = AB quartet.

Manufacturing 1

Ethyl (Z) -2- (2-aminothiazol-4-yl) -2- (hydroxyimino) acetate.

To a stirred and ice-cooled solution of 292 g of ethyl acetoacetate in 296 ml of glacial acetic acid was added a solution of 180 g of sodium nitrite in 400 ml of water at such a rate that the reaction temperature was kept below 10 ° C. Stirring and cooling continued for about 30 minutes, then a solution of 160 g of potassium chloride in 800 ml of water was added. The resulting mixture was stirred for one 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 saline, dried and evaporated. The remaining oil, which solidified on standing, was washed with petroleum ether and dried in vacuo over potassium hydroxide and gave 309 g of ethyl (Z) -2- (hydroxyimino) -3-oxobutyrate.

A stirred and ice-cooled solution of 150 g of ethyl (Z) -2- (hydroxyimino) -3-oxobutyrate in 400 ml of methylene chloride was treated dropwise with 140 g of sulfuryl chloride. The resulting solution was kept at room temperature for 3 days, then evaporated. The residue was dissolved in diethyl ether, washed with water until the washings were almost neutral, dried and evaporated. The remaining 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 washed with ethanol and dried to give 73 g of the title compound; F = 188 ° C (dec.)

Manufacturing 2

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

16.75 g of trityl chloride were added in portions over a period of 2 hours to a stirred solution of 12.91 g of a product of preparation 1 and 8.4 ml of triethylamine in 28 ml of dimethylformamide and cooled to -30 ° C. The mixture was allowed to warm to 15 ° C over an hour, then 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 2 × 500 ml of water and then shaken with 500 ml of 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; F = 184 to 186 ° C (dec.)

Manufacturing 3

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

34.6 g of potassium carbonate and 24.5 g of tert-butyl-2-bromo-2-methylpropionate were added under nitrogen to a stirred solution of 49.4 g of the product of Preparation 2 in 200 ml of dimethyl sulfoxide and the mixture was run for 6 hours long at room temperature. The mixture

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was poured into 21 water, stirred for 10 minutes and filtered. The solid was washed with water and dissolved in 600 ml of ethyl acetate. The solution was washed successively with water, 2N hydrochloric acid, water and saturated brine, dried and evaporated. The residue was recrystallized from petroleum ether and gave 34 g of the title compound; F = 123.5 to 125 ° C.

Manufacturing 4

(Z) -2- (2-t-Butoxycarbonylprop-2-oxyimino) -2- (2-trityl-aminothiazol-4-yl) acetic acid

2 g of the product of Preparation 3 was dissolved in 20 ml of methanol and 3.3 ml of 2N sodium hydroxide was added. The mixture was heated to reflux for 1.5 hours and then concentrated. The residue was taken up in a mixture of 50 ml of water, 7 ml of 2N hydrochloric acid and 50 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 saline, dried and evaporated. The residue was recrystallized from a mixture of carbon tetrachloride and petroleum ether to give 1 g of the title compound; F = 152 to 156 ° C (dec.)

Manufacturing 5

Ethyl- (Z) -2- (2-tritylaminothiazol-4-yl) -2- (1-t-butoxycar-bonylcyclobut-1-oximino) acetate

55.8 g of the product of preparation 2 were stirred under nitrogen in 400 ml of dimethyl sulfoxide with a finely ground potassium carbonate (31.2 g) at room temperature. After 30 minutes, 29.2 g of tert-butyl-1-bromocyclobutancar boxylate were added. After 8 hours a further 31.2 g of potassium carbonate were added. Over the next 3 days, 6 x 16 g portions of potassium carbonate were added and a further 3.45 g of tert-butyl-1-bromocyclobutane carboxylate were added after 3 days. After a total of 4 days, the mixture was poured into about 3 l of ice water 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 twice with brine, dried over 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 iW (CHBd) 3400 (NH) and 1730 cm-1 (ester).

Manufacturing 6

(Z) -2- (1-t-Butoxycarbonylcyclobut-1-oximino) -2- (2-tri-tylaminothiazol-4-yl) acetic acid

A mixture of 3.2 g of the product of Preparation 5 and 1.65 g of potassium carbonate was refluxed in 180 ml of methanol and 20 ml of water for 9 hours with stirring and the mixture was cooled to room temperature. The mixture was concentrated and the residue was partitioned between ethyl acetate and water to which 12.2 ml of 2N HCl was 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 2.3 g of the title compound; Âmax (ethanol) 265 nm (Ell 243).

example 1

a) Diphenylmethyl- (IS, 6R, 7R) -3-bromomethyl-7 - [(Z) -2- (2-t-butoxycarbonyl-prop-2-oxyimino) -2- (2-tritylamino-thiazole-4- yl) -acetamido] -ceph-3-em-4-carboxylate-1-oxide

A solution of 0.526 g of the product of manufacture 4 in

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

This foam was purified by chromatography on preparative silica plates using toluene-ethyl acetate-acetic acid = 190: 50: 2.5 as the eluent. The purified product was isolated as a foam, which was dissolved in 5 ml of ethyl acetate and precipitated from 200 ml of petroleum ether, and 0.69 g of the title compound gave as a colorless powder; Xmax (ÄtOH) 268 nm (Ei ^ 0m 182) with an inflection at 242 nm (EÌ * ° m 230), Vmax (Nujol) 3375 (NH), 1805 (ß-lactam), 1730 (CO2R) and 1688 and 1515 cm-1 (CONH).

b) Diphenylmethyl- (IS, 6R, 7R) -3- (3-methyl-l, 2,3-triazolium-1-yl) methyl-7 - [(Z) -2- (2-t- butoxycarbonylprop-2-oxy-imino) -2- (2-trityl-aminothiazol-4-yl) -acetamido] -ceph-3-em-4-carboxylate-l-oxide, bromide salt

A mixture of 1.05 g of diphenylmethyl- (IS, 6R, 7R) -3-bromomethyl-7 - [(Z) -2- (2-t-butoxycarbonylprop-2-oxyimino) -2- (2-tritylaminothiazole-4 -yl) -acetamido] -ceph-3-em-4-carboxylate-l-oxide and 1.19 g of l-methyl-l, 2,3-triazole in 15 ml of tetrahydrofuran was at 22 ° C to 30 ° C for 4 , Stirred for 7 days in the absence of light. The mixture was evaporated and the residue triturated with ether and ethyl acetate to give 1 g of the title compound as a solid; Infection (CHCb) 267 nm (E | 'L 155 e 17.300) and Vmax (Nujol) 3600 to 2500 (NH and water), 1798 (ß-lactam), 1725 (CO2R) and 1678 and 1515 cm-1 (CONH) .

c) Diphenylmethyl- (6R, 7R) -3- (3-methyl-1,2,3-triazolium-

1-yl) methyl-7 - [(Z) -2- (2-t-butoxycarbonylprop-2-oxyimino) -

2- (2-tritylaminothiazol-4-yl) acetamido] -ceph-3-em-4-carboxylate, bromide and iodide salts

0.8 g of the product from step b) in 5 ml of acetone were treated at -10 ° C. with 0.427 g of potassium iodide and stirred for 10 minutes.

A further portion of 0.427 g potassium iodide and 0.11 ml acetyl chloride was added and the mixture was stirred vigorously at -10 ° C to 0 ° C for 30 minutes. The mixture was added dropwise to a solution of 0.35 g of sodium metabisulfite in 20 ml of water to give a gummy substance. The mixture was extracted with dichloromethane and brine and the organic phase was washed with brine and then dried and evaporated to a foam (t.l.c. indicated some unchanged starting material).

The above reduction sequence using potassium iodide and acetyl chloride was repeated exactly as described above and gave 0.6 g of the title compound, mainly as the iodide salt, TLC, Rf 0.7 (chloroform: methanol: acetic acid = 90:16:20), x (DMSO-d6) 1.08 and 1.15 (2s, triazole 4 and 5-H), 3.22 (s, thiazol-5-yl-proton), 4.03 (dd, J 9 and 5Hz, 7-H), 5.70 (s, ÄMe) and 8.60 broad s, CMe2 and t-butyl).

d) (6R, 7R) -7 - [(Z) -2- (aminothiazol-4-yl) -2- (2-carboxy-prop-2-oxyimino) acetamido] -3- (3-methyl-l , 2,3-triazolium-1-yl) methylceph-3-em-4-carboxylate

1.72 g of the product of step c) were suspended in a mixture of 1.7 ml of anisole and 7 ml of trifluoroacetic acid at 22 ° C. for one minute. The mixture was evaporated in vacuo to an oil which was then azeotroped with toluene. The toluene was removed in vacuo and the resulting oil was triturated with ether to give 1.3 g as a solid.

A suspension of the above solid in 1.3 ml anisole and 15 ml trifluoroacetic acid was stirred for 15 minutes. The supernatant liquid was decanted off and the solid was washed with 10 ml of trifluoroacetic acid. The combined trifluoroacetic acid solutions were concentrated in vacuo to an oil which, after trituration with ether, gave 0.9 g of a solid.

A 0.85 g portion of this solid was stirred for 10 minutes with a mixture of 4 ml of trifluoroacetic acid and 150 ml of water, and the mixture was extracted successively with ethyl acetate and ether. The aqueous layer was freeze-dried to give 0.75 g of the title compound as a solid, associated with 1.3 moles of trifluoroacetic acid; [cc] d -17.9 ° (c 0.56, DMSO), A, inr (pH 6-phosphate) 235 nm (E ™ ra 224) with further inflections at 255 nm (E'çm 207) and 300 ( EU 82).

Example 2

a) Diphenylmethyl- (IS, 6R, 7R) -3-bromomethyl-7 - [(Z) -2- (1-t-butoxycarbonylcyclobut-1 -oxyimino) -2- (2-tritylamino-thiazol-4-yl) -acetamido] -ceph-3-em-4-carboxylate-1-oxide

A stirred solution of 1.167 g of product of preparation 6 in 15 ml of tetrahydrofuran was treated successively with 0.337 g of 1-hydroxybenzotriazole hydrate and 0.495 g of N, N'-di-cyclohexylcarbodiimide for 30 minutes at 22 ° C.

Filtration gave a solution of the activated ester, which resulted in a solution of 0.95 g (IS, 6R, 7R) -7-amino-3-bromomethylceph-3-em-4-carboxylate-1-oxide in 550 ml of dichloromethane was given. The solution was stirred for 16 hours and then evaporated to dryness. A solution of the residue in dichloromethane was washed successively with aqueous sodium bicarbonate and brine and then dried and evaporated to a foam (2.2 g) which was purified by preparative thin layer chromatography (using toluene / ethyl acetate / acetic acid = 40: 10: 1 for development) and 1.4 g of the title compound gave A, max (EtOH) 266 nm (Ej c ° m 192) and an inflection at 242.5 nm (Ei 1224), Vmax (Nujol) 3360 (NH) , 1805 (β-lactam), 1730 (CO2R) and 1689 and 1520 cm-1 (CONH).

b) Diphenylmethyl- (IS, 6R, 7R) -3- (3-methyl-l, 2,3-triazo-lium-1 -yl) -methyl I-7 - [(Z) -2- (1 -t- butoxycarbonylcyclobut-1-oxyimino) -2- (2-tritylaminothiazol-4-yl) -acetamido] -ceph-3-em-4-carboxylate-1-oxide, bromide salt

A mixture of 1.04 g of diphenylmethyl- (1 S, 6R, 7R) -3-bromomethyl-7 - [(Z) -2- (1-t-butoxycarbonylcyclobut-1-oxy-imino) -2- (2- tritylaminothiazol-4-yl) -acetamido] -ceph-3-em-4-carboxylate-l-oxide and 1.240 g of l-methyl-l, 2,3-triazoline 8 ml of tetrahydrofuran was stirred at about 21 ° C for 50 hours.

The solution was evaporated to an oil which, when leached several times with ether, gave 0.910 g of the title compound as an amorphous solid [a] "- 2 ° (c 0.9, DMSO), Am (EtOH) 243 nm (El ° '^ m 207, e23,270) with further inflections at 265 nm (Ei ° 'Jm 170, el9,110) and 310 nm (EU 50, e5, 620) and A, max 390 nm (EU 31, s3,485).

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c) Diphenylmethyl- (6R, 7R) -3- (3-methyl-1,2,3-triazolium-1-yl) methyl-7 - [(Z) -2- (1-t-butoxycarbonylcyclobut-1 - oxy-imino) -2- (2-tritylaminothiazol-4-yl) -acetamido] -ceph-3-em-4-carboxylate, iodide salt

0.481 g of potassium iodide was added to a mixture of 0.816 g of the product from stage b) cooled to -10 ° C. and the mixture was stirred at -10 ° C. for 10 minutes. A further portion of 0.481 g of potassium iodide was added and then 0.12 ml of acetyl chloride and the resulting suspension was stirred at -10 ° C to 0 ° C for 30 minutes. The mixture was poured into a stirred solution of 0.36 g of sodium metabisulfite in 20 ml of water and the gummy solid was extracted with dichloromethane. The organic layer was washed with brine, dried and evaporated to a foam (T.L.C. indicated some starting material).

The above product was subjected to a similar reduction sequence (using potassium iodide and acetyl chloride as described above) to give 0.713 g of the title compound as a foam, TLC Rt0.45 (chloroform: methanol: acetic acid = 90:16:20) and x (DMSO -d6) 1.06 and 1.12 (2s, triazole 4 and 5-H), 3.22 (s, thiazol-5-yl-proton), 4.05 (dd, J 9 and 5Hz, 7-H ), 5.70, (s, EA), 7.2 to 7.8 (m, cyclobut-2-yl protons) and 7.8 to 8.4 (m, cyclobut-3-yl protons).

d) (6R, 7R) -7 - [(Z) -2- (2-aminothiazol-4-yl) -2- (l-carboxy-cy clobut-1 -oxyimino) -acetamido] -3 - (3 - methyl 1,2,3-triazolium-1-yl) methyl ceph-3-em-4-carboxylate

0.65 g of the product of step c) in 0.6 ml of anisole and 2.4 ml of trifluoroacetic acid were stirred at 20 ° C for one minute and concentrated in vacuo to give an oil.

Trituration of this oil with ether gave a powder which was treated with 0.6 ml anisole and 12 ml trifluoroacetic acid. After stirring for 15 minutes, the solution was decanted and left a black amorphous paste which was leached with trifluoroacetic acid.

The combined trifluoroacetic acid solutions were concentrated in vacuo to an oil which, when treated with ether, gave 0.35 g of a colorless solid. A portion (0.32g) of this solid was treated with a mixture of 0.6 ml anisole, 10 ml trifluoroacetic acid and 10 drops water at 22 ° C for 15 minutes.

The mixture was concentrated to about 3 ml and then poured into 100 ml of benzene. Ethyl acetate and tetrahydrofuran were added to give a solution. This solution was concentrated in vacuo to an oil which was stirred with ether to give 0.31 g of a powder.

A portion (0.1 g) of this powder was stirred with 50 ml of water and 1 ml of trifluoroacetic acid for 10 minutes. The mixture was washed with ethyl acetate and ether and the aqueous phase was freeze-dried to give 0.09 g of the title compound associated with 1.2 mol of trifluoroacetic acid: [<x] d -13.2 ° (c 0.49, DMSO), A.max (pH6 phosphate) 248.5 nm (Ej °° m 21, el6.050) with inflections at 243 nm (E | "at 221, 816,000) and 296 nm (EU 98,86,860).

Example 3

a) Diphenylmethy! - (1S, 6R, 7R) -7-formamido-3- (3-methyl-1,2,3-triazolium-1-yl) -methylceph-3-em-4-carboxylate-l oxide, bromide salt

A solution of 1 g diphenylmethyl- (1S, 6R, 7R) -3-bro-momethyl-7-formamidoceph-3-em-4-carboxylate-1-oxide in 3 ml N, N-dimethylformamide was stirred at 22 for 19 hours ° C stirred with 1.10 g of 1-methyl-1,2,3-triazole. The reaction mixture was added dropwise to ether to give 1.13 g of the title compound as a solid; Vmax (Nujol) 3390 (NH), 1795 (ß-lactam), 1726 (CO2R) and 1684 cm- '

(CONH) and x (DMSO-d6) 1.07 and 1.22 (2s triazole-4H and 5H, respectively), 1.77 (s, HCONH), 3.82 (dd, J 9 and 5Hz, 7-H ), 4.84 (d, J 5Hz, 6-H), 5.73 (s, N-Me) and 5.90 and 6.19 (ABqJ 18Hz, 2-H2).

5

b) Diphenylmethyl- (1S, 6R, 7R) -7-amino-3- (3-methyl-1,2,3-triazolium-1-yl) -methyl-ceph-3-em-4-carboxylate-1 - oxide, hydrochloride and bromide salts

A stirred suspension of 1.00 g of the product of stage 10) in dry methanol was treated with 0.48 ml of phosphoryl chloride at 0 ° C. to 5 ° C. for 2 hours. The resulting solution was added dropwise to 100 ml of ether to give a gummy substance, which was stirred with 50 ml of ethyl acetate for VA hours. The resulting powder was washed with ether and gave 0.700 g of the title compound as a solid ^ max (ÄtOH) 278 nm (E | ° L 107) Vmax (Nujol) 3700 to 2200 (ftHa), 1805 (ß-lactam ) and 1729 cm "1 (CO2R).

20 c) Diphenylmethyl- (1S, 6R, 7R) -3- (3-methyl-l, 2,3-triazolium-1-yl) methyl-7 - [(Z) -2- (2-t -butoxycarbonylprop-2-oxy-imino) -2- (2-trityl-aminothiazol-4-yl) -acetamido] -ceph-3-em-4-carboxylate-l-oxide, bromide salt

0.11 g of phosphorus pentachloride in 10 ml of dry methylene chloride was treated at 0 ° C. with 0.295 g of the product of preparation 4 and the solution was stirred at 0 ° C. for 30 minutes. 0.16 ml of triethylamine was added and stirring continued at 0 ° C for 10 minutes. The resulting solution was added dropwise over 5 to 30 minutes to a vigorously stirred suspension of 0.303 g of the product of step b) in 15 ml of dichloromethane at 0 ° C. The mixture was stirred at 0 ° C to 15 ° C for VA hours and the resulting solution was kept at -20 ° C for 15 hours. The solution was poured into 100 ml of ethyl acetate and 100 ml of water; the organic phase was separated and washed successively with water and brine, then dried and evaporated in vacuo to a foam (0.4 g). This foam was stirred with 30 ml ether for 30 minutes to give 40 a solid which was washed with ether and gave 0.35 g of the title compound as a solid [a] o -16 ° (c 1.0, DMSO) ta "F (CHCb) 267 nm (E | ° i 169).

The title compound can then be converted into (6R, 7R) -7 - [(Z) -2- (2-aminothiazol-4-yl) -2- (2-carboxyprop-2-oxyimino) acet-45 amido] -3- (3-methyl-1,2,3-triazolium-1-yl) methylceph-3-em-4-carboxylate as described in Example 1, are transferred.

Example 4

a) Diphenylmethyl- (1S, 6R, 7R) -3- (l, 2,3-triazolium-l-yl) -50 methyl-7 - [(Z) -2- (1-t-butoxycarbonylcyclobut-1-oxyimino ) -2- (2-tritylaminothiazol-4-yl) -acetamido] -ceph-3-em-4-carb-oxylate-l-oxide

A solution of 1 g of the product from Example 2a) in 3 ml of N, N-dimethylformamide was treated with 0.113 g of 1,2,3-triazole SS. The reaction mixture was stirred at about 20 ° C for 24 hours and then 0.113 g of triazole was added again and the mixture was stirred at about 20 ° C for about 2 hours and then cooled for about 60 hours. The mixture was diluted with 150 ml of ethyl acetate and the organic solution was washed with 2 × 50 ml of 2N hydrochloric acid and 50 ml of brine and then dried over magnesium sulfate and evaporated in vacuo to a foam (0.88 g). Chromatography of this foam on preparative thin-layer plates 5 using toluene: ethyl acetate: acetic acid = 20: 40: 1 as eluent gave 0.1 g of the title compound as a solid with Xm (EtOH) 260 nm (E | ° c: m 199) and 300.5 nm (Ej "^ m 61) and x (DMSO-d6), 2.03 and 2.26 (2s, triazolium-

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protons), 3.19 (s, thiazole 5-H), 3.8 to 4.1 (m, 7-H), 4.92 (d, J 5 Hz, 6-H), 7.4 to 7 , 8 (m, cyclobut-2- and 4-yl protons), 7.8 to 8.2 (m, cyclobut-3-yl protons) and 8.62 (s, tert-butyl).

b) Diphenylmethyl- (1 S, 6R, 7R) -3- (3-methyl-1,2,3-triazo-lium-1-yl-methyl-7 - [(Z) -2- (l -t- butoxycarbonyl-cyclobut-1-oxyimino) -2- (2-tritylaminothiazol-4-yl) -acetamido] -ceph-3-em-4-carboxylate-1-oxide, iodide salt

A solution of 0.08 g of the product of step a) in 2 ml of iodomethane was stirred at 22 ° C. for 66 hours. The excess iodomethane was evaporated in vacuo to give a solid. This product was triturated with ether and the solid was collected by filtration and dried in vacuo over phosphorus pentoxide to give 0.067 g of the title compound as a solid [a] ^ -16.2 ° (c 0.5; DMSO), hm (ÄtOH) 260 nm (Ej ^ m 160) and 305 nm (Ell 58).

Example 5

a) t-Butyl- (6R, 7R) -3-acetoxymethyl-7 - [(Z) -2- (2-t-butoxy-carbonyl-prop-2-oxyimino) -2- (2-tritylaminothiazole-4- yl) -acetamido] -ceph-3-em-4-carboxylate

A stirred solution of 572 mg of the product of preparation 4 and 328 mg of tert-butyl- (6R, 7R) -3-acetoxymethyl-7-aminoceph-3-em-4-carboxylate in 10 ml of dimethylformamide was cooled to 0 ° C and 150 mg of 1-hydroxybenzotriazole were added and then 225 mg of dicyclohexyl-carbodiimide. The mixture was warmed to room temperature, stirred for 5 hours and left overnight. The mixture was filtered and the white solid washed with a little ether. The filtrate and the washing liquids were diluted with 50 ml of water and extracted with ethyl acetate. The organic extracts were combined, washed successively with water, 2N hydrochloric acid and water, sodium bicarbonate solution and saturated saline, dried and evaporated. The residue was eluted through a silica column with ether. The eluate containing the product was collected and concentrated to give 533 mg of the title compound. A portion was recrystallized from diisopropyl ether, F = 103 to 113 ° C (dec.); [alo + 8.5 ° (c, 1.0, DMSO).

b) (6R, 7R) -3-acetoxymethyl-7 - [(Z) -2- (2-aminothiazol-4-yl) -2- (2-carboxyprop-2-oxyimino) acetamido] -ceph-3- em-4-carboxylic acid hydrochloride.

200 g of the product from step a) were dissolved in 800 ml of formic acid pre-cooled to + 10 ° C. and 60 ml of concentrated hydrochloric acid were added to the stirred mixture within 5 minutes. Stirring was continued at 20-22 ° C for 1XA hours before cooling to + 10 ° C and filtering. The bed was washed with 30 ml of formic acid. The filtrate combined with the washing liquids was concentrated by evaporation at 20 ° C. to a yellow foam which was triturated with 800 ml of ethyl acetate. The solid that settled was collected by filtration, washed with 200 ml of ethyl acetate and dried in vacuo at room temperature overnight to give 124.6 g of the title compound Ama * (ethanol) 234.5 nm (EU 311).

c) (6R, 7R) -7 - [(Z) -2- (2-aminothiazol-4-yl) -2- (2-carboxy-prop-2-oxyimino) acetamido] -3- (3-methyl -1,2,3-triazolium-1-yl) methyl ceph-3-em-4-carboxylate, sodium salt.

0.564 g (6R, 7R) -3-acetoxymethyl-7 - [(Z) -2- (2-aminothiazol-4-yl-2- (2-carboxyprop-2-oxyimino) acetamido] -ceph-3 -em-4-carboxylic acid hydrochloride salt, 0.27 g of sodium hydrogen carbonate, 1.8 g of sodium iodide, 0.30 ml of water and 0.25 ml of 1-methyl-1,2,3-triazole were on for 1'A hours

Heated to 80 ° C and the solution was allowed to cool. The resulting solid was triturated with 10 ml of acetone and the product was filtered off, washed with acetone and ether and quickly dried in vacuo to give 0.66 g of a solid. This product was purified on a column of 100 g of Amberlite XAD-2 resin which was eluted sequentially with water and then with water / ethanol (4: 1). The appropriate fractions were pooled, evaporated to about 150 ml and then freeze-dried to give 0.203 g of the title compound as a foam with tana * (pH6 buffer) 238 nm (Eil 295) with reflections at 256 nm (Ejl 270) and 295 nm (EU 141) and x (D20) 1.39 and 1.49 (2 broad s, triazole-pro-ton), 3.00 (broad s, thiazole 5-H), 5.69 (s, NCH3), 6.29 and 6.62 (ABq, J approx. 18 Hz, 2-H2) and 8.52 (s, CMe2).

The antibiotic compounds according to the invention can be formulated for administration in any suitable manner in analogy with other antibiotics and the invention therefore also includes the pharmaceutical compositions which comprise an antibiotic compound according to the invention adapted for use in human or veterinary medicine. Such compositions can be offered for use in the usual manner with the aid of any necessary pharmaceutical carriers or excipients.

The antibiotic compounds according to the invention can be formulated for injection and can be presented in unit dose form in ampoules or in multidose containers, if necessary, with added preservative. The compositions can also take forms such as suspensions, solutions or emulsions in oily or aqueous vehicles and can contain formulating agents such as suspending, stabilizing and / or dispersing agents. Alternatively, the active ingredient can also be in powder form for preparation with a suitable carrier e.g. sterile pyrogen-free water before use.

If desired, such powder formulations may contain a suitable non-toxic base to improve the water solubility of the active ingredient and / or to ensure that when the powder is prepared with water the pH of the resulting aqueous formulation is physiologically acceptable. Alternatively, the base can be present in the water used to prepare the powder. The base can be, for example, an inorganic base such as sodium carbonate, sodium bicarbonate or sodium acetate or an organic base such as lysine or lysine acetate.

The antibiotic compounds can also be formulated as suppositories which contain, for example, conventional suppository bases such as cocoa butter or other glycerides.

For medication for the eyes and ears, the preparations can be formulated as individual capsules in liquid or semi-liquid form or they can be used as drops.

The compositions for veterinary medicine can be formulated, for example, as intramammal preparations with either long-term action or fast-acting base bodies.

The compositions can range from 0.1% e.g. Contain 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 50 to 1500 mg of the active ingredient. The dosage used for an adult in human medicine will preferably be from 500 to 6000 mg / day depending on the route of administration and the frequency of administration. For example, in an adult in human medicine,

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Iung 1000 to 3000 mg / day administered intravenously or intramuscularly are sufficient. Higher daily doses may be required in the treatment of pseudomonas infections.

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

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

Formulation - for injection

Formulation per vial (6R, 7R) -7 - [(Z) -2- (2-aminothiazol-4-yl) -2- (l-carboxycy-clobut-1-yl-oxyimino) -acetamido] -3- ( 3-methyl-1,2,3-triazolium-1-yl) methyl ceph-3-em-4-carboxylate 500 mg sodium carbonate, anhydrous 47 mg

15 644 868

method

The sterile cephalosporin antibiotic is mixed with the sterile sodium carbonate under aseptic conditions. It is filled aseptically in a glass bottle under a protective jacket of sterile nitrogen. The vials are made using rubber washers or stoppers,

which are held in position by aluminum closures or capsules, thereby preventing gas exchange or the penetration of microorganisms. The product is prepared by dissolving in water for injections or in another suitable sterile vehicle shortly before administration.

(6R, 7R) -7 - [(Z) -2- (aminothiazol-4-yl) -2- (2-carboxyprop-2-oxyimino) acetamido] -3- (3-methyl-1,2,3- triazolium-1 -yl) -ls methyl ceph-3-em-4-carboxylate can be formulated in a similar manner.

b

Claims (10)

644868 2nd CLAIMS 1. Cephalosporin antibiotics of the general formula: NH, ul -c-co-nh 1 vo-c-cooh C00 © -R (I) R wherein Ra and Rb, which are the same or different, each represent a Ci-4 alkyl group or Ra and Rb together with the carbon atom to which they are attached form a C3-7 cycloalkylidene group; and R1 represents a Ci-4 alkyl group, and the non-toxic salts, the sol-vates and the acyloxyalkyl esters thereof. 2. (6R, 7R) -7 - [(Z) -2- (2-aminothiazol-4-yl) -2- (2-carboxy-prop-2-oxyimino) acetamido] -3- (3-methyl -1,2,3-triazolium-l-yl) methyl ceph-3-em-4-carboxylate according to claim 1. 3. As non-toxic salts according to claim 1, those of the compound according to claim 2. 4. (6R, 7R) -7 - [(Z) -2- (2-aminothiazol-4-yl) -2- (l-carboxy-cyclobut-1-oxyimino) acetamido] -3- (3-methyl -1,2,3-triazo-lium-1-yl) methyl ceph-3-em-4-carboxylate according to claim 1. 5. As non-toxic salts according to claim 1, those of the compound according to claim 4. 6. A process for the preparation of an antibiotic compound of the formula I specified in claim 1 or a non-toxic salt thereof, characterized in that a compound of the formula: 20th 25th wherein Ra and Rb are as defined in claim 1, R3 is a carboxyl protecting group and R4 is an optionally protected amino group, or aeylated with a corresponding amide-forming derivative thereof, the protecting group R3 and any other carboxyl and / or amino protecting groups present are removed and the resulting ones Compound of formula I optionally converted into a non-toxic salt. 7. A process for the preparation of an antibiotic compound of the formula I specified in claim 1 or a non-toxic salt thereof, characterized in that a compound of the formula: 30th h h 0 p 35 h2n- / n 0 ch2n \ n / —RJ eoo0 (IIb) 40 N ch2n eoo © \ —R1 vzy 45 (IIa) wherein R1 is as defined in claim 1, or a salt or N-silyl derivative thereof or a corresponding compound with a group of the formula -COOR2 in the 4-position, wherein R2 is hydrogen or a carboxyl protecting group, and with an associated anion A0 for that Triazolium cation with an acid of the formula: r ^ wherein R1 is as defined in claim 1, or a salt or N-silyl derivative thereof or a corresponding compound with a group of the formula -COOR2 in the 4-position, wherein R2 is hydrogen or a carboxyl protecting group, and with an associated anion A® for the triazolium cation with an acid of the formula: Rl 50 S l -c-cooh R (III) 'o-c-coor' I. -C — COOH 60 R il R r 3 'o-c-coo r R wherein Ra and Rb are as defined in claim 1, R3 represents a (III) carboxyl protecting group and R4 represents an optionally protected amino group, or aeylated with a corresponding amide-forming derivative thereof, which reduces the sulfoxide group of the compound obtained to the sulfide which Protective group R3 and any other carboxyl and / or amino protective groups present are removed 3rd 644868 and optionally converting the compound of formula I obtained into its non-toxic salt. 8. A process for the preparation of an antibiotic compound of the formula I specified in claim 1 or a non-toxic salt thereof, characterized in that ai) a compound of the formula: 'o-c-coor R (iv) coor ' wherein Ra and Rb are as defined in claim 1, R4 is a or a carboxyl protecting group and X is an exchange optionally protected amino group means R5 and 20 bar residue of a nucleophile, or a salt thereof with R5a, which are the same or different, in each case for hydrogen an alkyltriazole of the formula: N S NO y (v) wherein R1 is as defined in claim 1, or a2) a compound of the formula: , 4th ch2-n wherein Ra and Rb are as defined in claim 1, R4 represents an optionally protected amino group and R5 and R5a both represent carboxyl protecting groups, alkylated with an alkylating agent which serves to introduce the R'-substituent into the triazole ring in formula Via , b) any carboxyl and / or amino protection coor ' removed groups and c) the compound of formula 45 I optionally converted into a non-toxic salt. 9. A process for the preparation of an antibiotic compound of the formula I specified in claim 1 or a non-toxic salt thereof, characterized in that ai) a compound of the formula: wherein Ra and Rb are as defined in claim 1, R4 is a or a carboxyl protecting group and X is an exchange optionally protected amino group means R5 and the residue of a nucleophile, or a salt thereof with R5a, which are the same or different, in each case for hydrogen, an alkyltriazole of the formula: 644 868 ✓N n \ = J (v) wherein R1 is as defined in claim 1, or a2) a compound of the formula: > 4 n coor ' (vib) wherein Ra and Rb are as defined in claim 1, R4 represents an optionally protected amino group and R5 and R5a both represent carboxyl protecting groups, alkylated with an alkylating agent which serves to introduce the R'-substituent into the triazole ring in formula Vib, b ) the sulfoxide group of the compound obtained is reduced to the sulfide, c) the carboxyl and / or amino protective groups which may be present are removed and d) the compound of the formula I is converted, if appropriate, into a non-toxic salt. 10. Pharmaceutical preparations for use in human or veterinary medicine, containing an antibiotic compound according to one of claims 1 to 5 together with a pharmaceutical carrier or excipient. Characterized a number of Gram-positive and Gram-negative organisms, with a particularly high stability for β-lactamases, which are produced by different Gram-negative organisms. The discovery of this class of compounds stimulated further research in the field to try to find compounds with improved properties, for example against particular classes of organisms, especially Gram-negative organisms. British Patent 1,496,757 describes cephalosporin antibiotics with a 7β-acylamido group of the formula (A) 35 R.C.CO.NH- N RA (A)