CH644867A5 - CEPHEMIC CARBON ACIDS SUBSTITUTED IN THE 3- AND 7-POSITION. - 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 present description are described with reference to "Cepham" according to J. Amer. Chem. Soc. 1962, 84,3400, the term "cephem" referring to the basic cepham structure with a double bond.

Cephalosporin antibiotics are widely used in the treatment of diseases caused by pathogenic germs in humans and animals, and are particularly valuable in the treatment of diseases caused by bacteria resistant to other antibiotics such as penicillin compounds and in the treatment of penicillin sensitive Patient. In many cases it is desirable to have a cephalospo

50 R.C.CO.NH-

II

N RA

\ i

0. (CH2) mC (CH2) "C00H

55 |

RB

(a)

(where R is a thienyl or furyl group; RA and RB can vary widely and can be, for example, Ci-4 60 alkyl groups or together with the carbon atom to which they are attached form a C3-7 cycloalkylidene group and m and n are each 0 or 1 such that the sum of m and n is the number 0 or 1), the compound being syn isomers or mixtures of syn and 65 anti isomers with at least 90% of the syn isomer. The 3-position of the cephalosporin molecule can be unsubstituted or can contain one of a large number of possible substituents. Of these connections

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it has been found that they have particularly good activity against gram-nagative 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 Gram-negative organisms. Such developments included variations not only in the 7β-acylamido group of formula (A), but also the introduction of special groups in the 3-position of the cephalosporin molecule.

For example, cephalsporin antibiotics are described in the South African patent specification 78/1870, in which the 7β-acylamido side chain i.a. is a 2; (2-amino-thiazol-4-yl) -2- (optionally substituted.-alkoxyimino) acetamido group and the 3-position can be substituted, for example, by the group -CH2Y, in which Y represents the residue of a nucleophile. This description, among numerous other examples, also includes references to compounds in which the above-mentioned optionally substituted alkoxyimino group is a carboxyalkoxyimino group or carboxycycloalkoxyimino group. With regard to the 3-position, mono- and dialkylaminomethyl substituents are given under numerous other possibilities. 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 groups R in formula (A) above can be replaced by, for example, 2-aminothiazol-4-yl and the oxyimino group is a hydroxyimino or blocked hydroxyimino group, e.g. a methoxyimino group. In these compounds the 3-position of the cephalosporin molecule is substituted by a methyl group, which in turn can optionally be substituted by one of a large number of residues of the 10 nucleophilic compounds described there. N-alkylaminomethyl groups are described as possible 3-position substituents, but only mono- and dialkylaminomethyl groups are specifically specified. In the mentioned patent, such compounds that are only mentioned as 15 intermediate compounds for the production of antibiotics described in this patent are not ascribed any antibiotic activity.

It has now been found that by a suitable selection of a small number of special groups in the 20 7β position in combination with a trialkylammonomethyl group in the 3 position, cephalosporin compounds with particularly advantageous activity (which is described in more detail below) against a wide range can be obtained from commonly occurring pathogenic organisms.

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

(i)

where Ra and R \ denote the same or different from each other as follows:

are each a Ci-4-alkyl group (preferably a straight-chain alkyl group, such as a methyl, ethyl, n-propyl or 45 j 2 n-butyl group and especially 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, \ / qq; and R ', R2 and R3, which are the same or different from each other 50 ^ *

may be different, each a C1-4 alkyl group, e.g.

is a methyl group, and the non-toxic salts v and the acyloxyalkyl esters of these compounds. \ |

The compounds according to the invention are syn isomers. 0. C. COOH

The synisomeric form is determined by the configuration of the 55 |,

group

It should be mentioned that since the compound R1 'according to the invention are fertilized geometric isomers, a certain

I 60 occur with the corresponding anti-isomers

-O.C.COOH can.

I The invention also includes the solvates, especially the

Rh hydrates of the compounds of formula (I). It further includes the non-toxic salts of the above-mentioned esters of the 65 compounds of formula (I).

The compounds of the invention can in tauto-. defined with regard to the carboxamido group. In the following forms (for example with regard to the 2-amino-description, the syn configuration will structurally be thiazolyl group) and it should be mentioned that such

644867

6

tautomeric forms e.g. the 2-iminothiazolinyl form fall within 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 carboxy 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 also be noted that if Ra and Rb in the above formula represent different Ci-4-alkyl groups, the carbon atom to which they are attached includes an asymmetric center. An asymmetry center is also present when R1, R2 and R3 all represent different alkyl groups. Such compounds are diastereoisomeric and the invention encompasses the individual diastereoisomers of these compounds as well as the mixtures thereof.

The compounds according to the invention show broad-band antibiotic activity. Activity against 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 strains of Pseudomonas organisms, e.g. Strains of Pseudomonas aeruginosa and 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 especially Indolus positive and especially Indol positive) nisms such as Proteus vulgaris and Proteus morganii) and strains of Jaemophilus influenzae.

The antibiotic properties of the compounds according to the invention can be compared favorably with those of the amino glycosides such as amikacin or gentamicin. This is particularly true of their activity against strains of various Pseudomonas organisms which do not respond to the majority of existing, commercially available antibiotics. Unlike the aminoglycosides, the cephalosporin antibiotics are usually of 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 of 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 and arginine salts); Salts of organic bases (e.g. procaine, phenylethylbenzylamine, dibenzylethylenediamine, ethanolamine, diethanolamine and N-methylglycosamine salts). Other non-toxic salt derivatives 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 can also be in the form of resinates, which are formed, for example, by 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 base salts (e.g. alkali metal salts such as the sodium salt) of the compounds of formula (I) can be used in therapeutic applications due to the rapid distribution of such salts in the body after administration. However, when insoluble salts of the compounds of formula (I) are used in a particular application e.g. are desired 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 toluene-p-sulfonic acid and methanesulfonic acid, can be used as intermediates in the preparation and / or purification of the compounds of the formula (I), for example in the processes described below.

Non-toxic metabolically labile esters, which are formed by esterification of one or both carboxyl groups in the parent compound of formula (I), are acyloxyalkyl esters, e.g. Lower alkanoyloxymethyl 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, R2 and R3 all denote methyl groups. Preferred compounds are also 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. (6R, 7R) -7 - [(Z) -2- (2-aminothiazol-4-yl) -2- (l-carboxycyclobut-1-oxyimino) acetamido] -3-trimethylammonio-methylceph-3- em-4-carboxylate and its non-toxic salts and its acyloxyalkyl esters are particularly preferred compounds according to the invention. Other preferred compounds include (6R, 7R) -7 - [(Z) -2- (2-aminothiazol-4-yl) -2- (2-carboxyprop-2-oxyimino) acetamido] -3-trimethyl-ammoniomethyl- ceph-3-em-4-carboxylate acid and its non-toxic salts and acyloxyalkyl esters.

Other compounds according to the invention include those in which, for example, the groups Ra and Rb, R1, R2 and R3 in formula (I) have the following meaning:

Ra R1 '

R1

R-

R5

a) alkyl groups

-ch3 -c2h5

ch3

ch3

ch3

-c2h5 -c2h5

chi ch3

ch3

-ch3 -chB

c2h5

ch3

ch3

-chS -c2h5

c2h5

ch3

ch3

-c2h5 -c2h5

c2h5

ch3

ch3

-ch3 -ch3

c2h5

c2h5

ch3

-ch3 -c2h5

c2h5

c2h5

ch3

-c2h5 -c2h5

c2h5

c2h5

ch3

-ch3 -ch3

c2h5

c2h5

c2h5

-chs -c2h5

c2h5

c2h5

c2h5

-c2h5 -c2h5

c2h5

c2h5

c2h5

R -'- C-R "

1

R1

R-

R5

b) cycloalkylidene groups

Cyclopropylidene

-ch3

-ch3

-ch3

Cyclopentylidene

-ch3

-ch3

-ch3

Cyclopropylidene

-c2h5

-ch3

-ch3

Cyclobutylidene

-c2h5

-ch3

-ch3

Cyclopentylidene

-c2h5

-ch3

-ch3

Cyclopropylidene

-c2h5

-c2h5

-ch3

Cyclobutylidene

-c2h5

-c2h5

-ch3

Cyclopentylidene

-C2h5

-c2h5

-ch3

Cyclopropylidene

-c2h5

-c2h5

-c2h5

Cyclobutylidene

-C2H5

-C2H5

-c2h5

Cyclopentylidene

-c2h5

-c2h5

-C2H5

5

10th

15

20th

25th

30th

35

40

45.

50

55

60

65

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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 and urinary tracts.

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, which comprises

A) The acylation of a compound of the formula:

R

cocr

© <

CH0N - R '

> 3

R

wherein R1, R: and R3 are as defined above and B is or O

N-silyl derivative thereof or a corresponding compound having a group of the formula -COOR4 in the 4-position, wherein R4 is a hydrogen atom or a carboxyl-blocking group, e.g. the remainder of an ester-forming aliphati-5 see or araliphatic alcohol or an ester-forming phenol, silanol or stannanol (which alcohol contains phenol, silanol or stannanol, preferably 1 to 20 carbon atoms) and with an associated anion A®, such as a halide e.g. Chloride or bromide 10 or the trifluoroacetate anion, with an acid of the formula:

R

(ii)

15 /

S N

w_

C.COOH

l!

Rc

25th

0. C. COOR "

! b

(m)

(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 one in which R "and Rb are as defined above; Rs represents a car-boxyl-blocking group eg as described for R4; and 30 R6 is an amino or protected amino group, or with an amide-forming derivative corresponding thereto, or B) the reaction of a compound of the formula:

C.00R

wherein R- 'and Rh, R6 and B are as defined above; R7 and R7a independently represent hydrogen or a carboxyl blocking group, X is a replaceable residue of a nucleophile e.g. an acyloxy group such as a dichloroacetoxy group or a halogen atom such as chlorine, bromine or iodine, or a salt thereof with a tertiary amine of the formula:

R1

I.

N-R- (V)

I.

R3

wherein R1, R: and R3 are as defined above; or C) the alkylation of a compound of the formula:

644867

R

s n \ - /.

-c. co.nh

11 n

^ 0. c. coor ch2n

/

R

coor

V

R

(vi)

wherein Ra, and Rb, R1, R2, R6 and B are as defined above; and R7 and R7 "both mean carboxyl blocking groups, with an alkylating agent serving to form a group of the formula

R1

I.

-CH2N-R2

I.

R3

to form in 3-position; whereupon when using a sulfoxide (B = O

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 R5 and any further carboxyl and / or amino protective groups are removed or after the reaction (B) and 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.

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 prepared by reacting an acid (III) or a salt thereof with a halogenating agent e.g. Phosphorus pentachloride, thionyl chloride or oxalyl chloride.

The acylation using acid halides can be carried out in aqueous or non-aqueous reaction medium, advantageously at temperatures from -50 ° C. to + 50 ° C., preferably from -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 dimethyl acetamide, nitriles such as acetonitrile or mixtures of two or more such solvents. Such suitable acid-binding agents include tertiary amines (e.g. triethylamine or dimethylaniline), inorganic bases (e.g. calcium carbonate or sodium bicarbonate) and oxiranes such as low 1,2-alkylene oxides (e.g. 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 an acid (III) is desirably carried out in the presence of a condensing agent, for example a carbodiimide such as N, N'-dicyclohexylcarbodiimide or N-ethyl-N'-y-dimethylaminopropylcarbodimide; a car

bonyl compound such as carbonyldiimidazole; or an iso-xazolium salt such as N-ethyl-5-phenylisoxazolium perchlorate.

The acylation can also be carried out with other amide-forming derivatives of acids of formula (III), such as, for example, an activated ester, a symmetrical anhydride or a mixed anhydride (e.g. formed with pivalic acid or with a halogen formate such as halogenetic formate, lower alkyl ester). Mixed anhydrides 25 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, 30 1-hydroxybenzotriazole in the presence of a condensing agent as mentioned above. Alternatively, the activated ester can be preformed.

The acylation reactions comprising the free acids or their amide-forming derivatives mentioned above 35 are desirably carried out in an anhydrous reaction medium, for example 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 acylating agents corresponding to them can, if desired, be prepared in the form of their acid addition salts and then used. 45 For example, the acid chlorides can suitably be used as their hydrochlorides and the acid bromides as their hydrobromides.

The amine compound of formula (V) can act as a nucleophile to replace a variety of substituents X from the so cephalosporin of formula (IV). To a certain extent the ease of displacement depends on the pKa of the acid HX from which the substituent is derived. In general, atoms or groups X, which are derived from strong acids, tend to be displaced 55 more easily than atoms or groups,

which come from weaker acids. The ease of exchange is also related to some extent to the precise identity of the alkyl groups in the compound of formula (V).

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

65 nucleophilic exchange reactions can expediently be carried out on those compounds of the formula (IV) in which the substituent X is a halogen atom or an acyloxy group, for example as explained below.

9

644 867

Acyloxy groups

Suitable starting materials for use in the nucleophilic exchange reaction with the amine of formula (V) include compounds of formula (IV) where X is the residue of a substituted acetic acid e.g. Chloroacetic acid, dichloroacetic acid and trifluoroacetic acid.

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

When using a compound of formula (IV) in which X represents a substituted acetoxy group, it is generally desirable that the groups R7 in formula (IV) be a hydrogen atom and that B ^ = 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 compounds of formula (IV) wherein X is the residue of a substituted acetic acid can be carried out as described in British Patent 1,241,657.

When using compounds of the formula (IV),

where X is an acyloxy group, the reaction is expediently carried out at a temperature of from -20 ° C. to + 80 ° C., preferably 0 ° C. to + 50 ° C.

Halogens

Compounds of formula (IV) in which X is a chlorine, bromine or iodine atom can advantageously be used as starting materials in the nucleophilic exchange reaction with the amine of formula (V). When compounds of the formula (IV) are used in this class, B> S-> 0 and R7 can be a carboxyl-blocking group. The reaction is conveniently carried out in a non-aqueous medium which preferably comprises one or more organic solvents, preferably 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 detailed in British Patent 1,326,531. The reaction medium should neither be extremely acidic nor extremely basic. In the case of reactions carried out on compounds of formula (IV) in which R7 and R7a are carboxyl blocking groups, the 3-trialkylammoniomethyl product is formed as a corresponding halide which, if desired, can be subjected to one or more ion exchange reactions to give a salt with the desired one To get anion.

When using compounds of the formula (IV),

where X is a halogen atom as described above, the reaction is expediently carried out at a temperature of from -10 ° C. to + 50 ° C., preferably + 10 ° C. to + 30 ° C.

In process C) mentioned above, the 3-di-Ci-4-alkylaminomethyl compound of the formula (VI) is advantageously carried out using a Ci-4-alkylating agent of the formula (R3Y), in which R- '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 (e.g. mesylate or tosylate) or R3Y means dimethyl sulfate. The alkylation reaction is preferably carried out at a temperature in the range from 0 to 60 ° C., advantageously 20 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. Dimethylformamide or halogenated hydrocarbon e.g. Dichloromethane can be effected. Alternatively, if the alkylating agent is a liquid under the reaction conditions, this agent itself can serve as a solvent.

The compounds of the formula (VI), which are used as starting

Materials used in process # (C) can be, for example, by reacting a compound of formula (IV) (as defined above) with a secondary amine of formula (VII) R1

HN <^. (VII)

\ R2

(wherein R1 and R2 are as defined above) are prepared in an analogous manner to the nucleophilic exchange reactions described in relation to process (B). This reaction is preferably carried out in the presence of an acid-removing agent, the amine itself can serve as an acid-removing agent.

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

If a compound is obtained in which B> S - »- O, it is reduced to the corresponding sulfide, for example by reducing the corresponding acyloxysulfonium or alkoxysulfonium salt, which is prepared in situ by reaction with, for example, acetyl chloride in the case of an acetoxysulfonium salt was, whereby the reaction is effected, for example by 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 carried out at a temperature of from -20 ° C to + 50 ° C.

The metabolically labile acyloxyalkyl esters of the compounds of formula (I) can be prepared 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 are obtained 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 metabolically labile esters thereof mentioned above with the appropriate acid.

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

For use as starting materials for the preparation of the compounds of the general formula (I) according to the invention, the compounds of the general formula (III) and the corresponding acid halides and anhydrides in the syn-isomeric form or in the form of mixtures of the syn-isomeric and the corresponding anti-isomers containing 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 prepared by etherifying the compound of the formula:

5

10th

15

20th

25th

30th

35

40

45

50

55

60

65

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10th

r6 s n c.coor ii n

8th

(viii)

Oh

(wherein R6 is as defined above and R8 represents a carboxyl blocking group) by reaction with a compound of the general formula:

IS

R '

I.

T.C.COOR3 Rh

(IX)

20th

(where Ra, Rb and Rs are as defined above and T is a halogen such as chlorine, bromine or iodine; sulfate; or sulfonate such as tosylate) and then by removing the carboxyl-blocking group Rs. 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 is carried out and is preferably effected in an organic solvent, for example dimethyl sulfoxide, a cyclic ether such as tetrahyxdrofuran or dioxane or an N, N-disubstituted amide such as dimethylformamide. Under such conditions, the configuration of the oxyimino group is essentially unchanged by the etherification reaction. The reaction should be carried out 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 an amount sufficient to rapidly neutralize the acid in question.

Acids of the general formula (III) can also be obtained by reacting a compound of the formula

R

q co.coor

8th

(wherein R6 and R8 are as defined above) with a compound of the formula:

Ra

I.

H2N.O.C.COOR5

I.

Rb

25th

30th

40

45

(x)

50

(XI)

(wherein Ra, Rb and R5 are as defined above) and then removing the carboxyl blocking group R8 and, if necessary, by separating the syn and anti isomers.

The latter reaction is particularly applicable to the preparation of the acids of formula (III), in which Ra and

65

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 prepared in a conventional manner e.g. by the synthesis as described in Belgian patent 866 422 for the preparation of tert-butyl-1-amino-axycyclopropanecarboxylate.

The acids of the formula (III) can be converted into the corresponding acid halides and anhydrides and acid addition salts by customary methods, as described, for example, 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 halogenation of a 7β-protected-amino-3-methyl-ceph-3-em-4-carboxylic acid ester-1-ß-oxide, removal of the 7ß-protecting group, acylation of the resulting 7ß-amino compound to form the desired 7ß Acylamido group, e.g. in an analogous manner to process (A) above, followed by the reduction of the β-oxide group later in the order.

This is described in British Patent 1,326,531. The corresponding ceph-2-em compounds can be prepared by the method of Dutch published 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.

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, for example, by hydrolysis of the appropriate 3-acetoxymethyl compounds, as described, for example, in British Patents 1 474519 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 deprotection of a corresponding protected 7β-amino compound in a conventional manner, e.g. using PCI 5.

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 to avoid undesirable side reactions. For example, during any of the above-mentioned reaction sequences it may be necessary to protect the NH2 group of the aminothiazolyl part, e.g. by tritylation, acylation (e.g. chloroacetylation), protonation or other suitable methods. The protecting group can then be removed in any suitable manner which does not cause the desired compound to be broken down, 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 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 desirably groups which are easily split off at a suitable stage in the reaction sequence, suitably in the last stage. It can

11

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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. aceto-xymethyl or ethyl or pivaloyloxymethyl) and to keep them in the end product in order to obtain a suitable ester derivative of a compound of formula (I ) to result.

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 alkoxy carbonyl groups such as p-methoxybenzyloxycarbonyl, p-nitrobenzylocycarbonyl and diphenylmethoxycarbonyl; lower alkoxycarbonyl groups such as tert-butoxycarbonyl; and low haloalkoxycarbonyl groups such as 2,2,2-trichloroethoxycarbonyl. Carboxyl blocking group (s) can subsequently be removed by any of the appropriate methods described in the literature; for example, acid or base-catalyzed hydrolysis can be used in many cases, such as enzymatically-catalyzed hydrolysis.

The following examples are intended to illustrate the invention. All temperatures are given in ° C. The petroleum ether has a boiling range of 40 to 60 ° C.

Manufacturing 1

Ethyl (Z) -2- (2-aminothiazol-4-yl) -2- (hydrocyimino) 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 potassium chloride in 800 ml 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 solidifies on standing, was washed with petroleum ether and dried in vacuo over potassium hydroxide and gave 309 g of ethyl (Z) -2- (hydroxy-imino) -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 urea were 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 was added in portions over a period of 2 hours to a stirred and cooled to -30 ° C. solution of 12.91 g of the product of preparation 1 and 8.4 ml of triethylamine in 28 ml of dimethylformamide. The mixture was heated to 15 ° C. for one hour, stirred for a further 2 hours and then distributed between 500 ml of water and 500 ml of ethyl acetate. The organic phase was separated off with 2x500 ml

Washed water and then shaken with 500 ml of 1N HC 1. 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 stirred for 6 Stirred for hours at room temperature. The mixture 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 were dissolved in 20 ml of methanol and 3.3 ml of 2N sodium hydroxide were added. The mixture was refluxed 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 crystallized 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-butoxycarbonyl-cyclobut-1-oxyimino) acetate

55.8 g of the product of preparation 2 were 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 tert-butyl-1-bromocyclobutane carboxoxide was added. After 8 hours, 31.2 g of additional potassium carbonate was added. During the next 3 days a further 6 x 16 g portions of potassium carbonate were added and after 3 days 3.45 g of additional tert-butyl-1-bro-mocyclobutane carboxylate were added. After a total of 4 days, the mixture was poured into about 3 liters 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 Vmax (CHBn) 3400 (NH) and 1730 cm-1 (ester).

Manufacturing 6

(Z) -2- (1-t-Butoxycarbonylcyclobut-1-oximino) -2- (2-trity-laminothiazol-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 and the mixture was then cooled to room temperature. The

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The mixture was concentrated and the residue was 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 was 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; A, ma * (ethanol) 265 nm (E | ° c ° m 243).

example 1

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

A solution of 0.526 g of the product of Preparation 4 in 6 ml of dry tetrahydrofuran was treated successively with 0.141 g of l-hydroxybenzotriazole monohydrate and O, 198gN, 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 ° C to 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 evaporated in vacuo to a foam (1 , 01 g).

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 gave 0.69 g of the title compound as a colorless powder; /.max (ÄtOH) 268 nm (El 'c'm 182) with an inflection at 242 nm E | ^ ra 230), Vmax (Nujol) 3375 (NH), 1805 (ß-lactam), 1730 (CChR) and 1688 and 1515 cm1 (CONH).

b) Diphenylmethyl- (1 S, 6R, 7R) -7 - [(Z) -2- (2-t-butoxycar-bonyl-prop-2-oxyimino) -2- (2-tritylaminothiazol-4-yl) - aceta-mido] -3-trimethylammoniomethyl-ceph-3-em-4-carboxylate-1-oxide, bromide salt

0.154 g of the product of step a), 0.3 ml of tetrahydrofuran dried over aluminum oxide and anhydrous trimethylamine in dry tetrahydrofuran (0.155 g of trimethylamine in 1 ml of 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 in vacuo to give 0.131 g of the title compound. F = 158 to 178 ° C (dec.); [ate +11 ° (c 0.53, CHCb)

c) Diphenylmethyl- (6R, 7R) -7 - [(Z) -2- (2-t-butoxycarbonyl-prop-2-oxyimino) -2- (2-tritylaminothiazol-4-yl) -acetamido] -3- trimethyl-ammoniomethyl-ceph-3-em-4-carboxylate, iodide salt

1.87 g of the product from stage b) and 4.7 ml of acetone were stirred at -10 ° C. as a solution. 1.14 g of dry powdered potassium iodide was added and the mixture was stirred at -10 ° C for 2 minutes. Then 1.14 g of dry powdered potassium iodide and then 0.25 ml of acetyl chloride were added and the vigorously stirred mixture was allowed to warm to 0 ° C. over 20 minutes. The mixture was stirred from 0 ° to + 2 ° C for 1 hour. The mixture was added dropwise to a stirred solution of 0.850 g sodium metabisulfite in 47 ml water. The resulting solid was filtered off, washed with water and dried in vacuo 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 dry powdered potassium iodide, 0.25 ml of acetyl chloride and a reaction time of 25 minutes at 0 to + 2 ° C. This gave 1.951 g of the title compound as a solid. F = 142 to 176 ° C; [a] 2D7 -16 ° (c0.38, CHCb).

d) Diphenylmethyl- (6R, 7R) -7 - [(Z) -2 (2-t-butoxycarbonyl-prop-2-oxyimino) -2- (2-tritylaminothiazol-4-yl) -acetamido] -3-trimethy l-amoniomethyl-ceph-3-em-4-carboxylate, trifluoroacetate salt

1.826 g of the product of step c) were in acetone:

Ethanol = 9: 1 dissolved and on «Deacidit» FF SRA 62 ion exchange resin (strong anion exchange resin), trifluoroacetate form chromatography. The column was eluted with the above solvent mixture. A 20 ml forerun was discarded and the next 250 ml was immediately evaporated in vacuo to give 1.595 g of the title compound as a red-brown foam.

e) (6R, 7R) -7 - [(Z) -2- (2-aminothiazol-4-yl) -2- (2-carboxy-prop-2-oxyimino) acetamido] -3-trimethylammoniomethyl-ceph- 3-em-4-carboxylate

1.37 g of the product of step d), 1.37 ml of anisole and 5.5 ml of trifluoroacetic acid were mixed at 25 ° C. for 1.5 minutes when a solution was formed and then for a further minute. The volatile material was evaporated and the residue was subjected to azeotropic distillation twice with toluene. The gummy compound 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 a foam (1.117 g).

1.117 g of the foam, 0.25 ml of anisole and 5 ml of trifluoroacetic acid were mixed together at 28 ° C. for 5 minutes. The volatile material was removed and the residue azeotroped twice with toluene. The resulting brown oil was precipitated with 10 ml of acetone and 500 ml of petroleum ether (boiling range 40 to 60 ° C) and gave 1.066 g of a solid.

0.2 g of the solid was dissolved in 2 ml of trifluoroacetic acid: water = 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, the residue washed with 10 ml and 5 ml of water and the filtrate freeze-dried to give 0.17 g of a foam. The foam was triturated with ether, the solid obtained quickly filtered and dried in vacuo to give 0.148 g of the title compound as a solid associated with 1.8 moles of trifluoroacetic acid; [a] "+ 120 ° (c 0.3; ÄtOrtHiO = 1: 1); Jü„ r (pH6 buffer) 230 nm (8 17,000) Lnr260 nm (e 10,200).

Example 2

a) Diphenylmethyl- (IS, 6R, 7R) -3-bromomethyl-7 - [(Z) -2-lt-butoxy-carbonylcyclobut-l-oxyimino) -2- (2-tritylamino-thiazol-4-yl) - acetaamido] -ceph-3-em-4-carboxylate-1-oxide

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

Filtration gave a solution of the activated ester, which resulted in a solution of 0.95 g of diphenylmethyl- (1S, 6R, 7R) -7-amino-3-bromomethylceph-3-em- ~ 4-carbo-xylate-1 oxide would be added to 550 ml of dichloromethane. The solution was stirred for 16 hours and then to s

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Evaporated to dryness. A solution of the residue in methylene chloride was washed successively with aqueous sodium bicarbonate and brine and then dried and evaporated to 2.2 g of a foam, which was developed by preparative thin layer chromatography using toluene: ethyl acetate: acetic acid = 40: 10: 1 for development, was cleaned and gave 1.4 g of the title compound: Àmas (ÄtOH) 266 nm (Ej °; m 192) and an inflection at 242.5 nm (Ej "jm 224), Vmax (Nujol) 3360 (NH), 1805 ( β-lactam), 1730 (CO: R) and 1689 and 1520 cm - '(CONH).

b) Diphenyl- (IS, 6R, 7R) -7 - [(Z) -2- (1-t-butoxycarbonylcy-clobut-l-oxyimino) -2- (2-tritylaminothiazol-4-yl) -acet-amido ] -3-trimetyhl-ammoniomethyIceph-3-em-4-carboxylate -1-oxide, bromide salt

1.2 g of the product of step a), 2.5 ml of tetrahydrofuran dried over aluminum oxide and anhydrous trimethylamine in dry tetrahydrofuran [0.49 ml of a solution of 0.155 g of trimethylamine in 1 ml of tetrahydrofuran] were added at 24 ° C. for 30 minutes touched. The reaction mixture was added dropwise to 900 ml of stirred ether and the resulting suspension was stirred vigorously for 10 minutes. The solution was filtered off, washed with ether and dried in vacuo to give 1.16 g of the title compound. F = 156-170 ° C (dec.); [cc] d + 6 ° (c 0.48, CHCb).

c) Diphenylmethyl- (6R, 7R) -7 - [(Z) -2- (lt-butoxycarbonyl-cyclobut-1-oxyimino) -2- (2-tritylaminothiazol-4-yl) -aceta-mido] -3- trimethylammoniomethylceph-3-em-4-carboxylate, iodide salt

1.05 g of the product from step b) and 2.6 ml of acetone were stirred at -10 ° C. as a solution. 0.625 g of dry powdered potassium iodide was added and the mixture was stirred at -10 ° C for 2 minutes. 0.625 g of further dry powdered potassium iodide was added and then 0.14 ml of acetyl chloride. The stirred mixture was allowed to warm to 0 ° C and was stirred at 0 to + 2 ° C for half an hour. The mixture was added dropwise to a stirred solution of 0.465 g sodium metabisulfite in 26 ml water. The resulting solid was filtered off, washed with water and dried in vacuo over phosphorus pentoxide to give 1.072 g of a solid. The above procedure was repeated using 1.072 g of solid, 2.6 ml of acetone, 0.625 g of dry powdered potassium iodide and 0.14 ml of acetyl chloride to give 1.131 g of the title compound as a solid. F = 133-170 ° C (dec.) [Cx] d -33 ° (c0.6, CHCb).

d) (6R, 7R) -7 - [(Z) -2- (2-aminothiazol-4-yl) -2- (l-carboxy-cyclobut-1-oxyimino) acetamido] -3-trimethylammoniomet-hylceph- 3-em-4-carboxylate

0.2 g of the product of step c) was moistened with 0.2 ml of anisole and 0.8 ml of trifluoroacetic acid was added. A precipitate formed immediately and the suspension was swirled at about 23 ° C for 2 minutes when the precipitate became gummy. The mixture was evaporated to dryness and the residue triturated with ether to give a solid which was moistened with 0.035 ml anisole and 4 ml trifluoroacetic 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 gummy substance, which was triturated with ether and gave 0.091 g of the title compound as a solid, associated with 1 mol of trifluoroacetic acid and 0.4 mol of hydrogen iodide, [a] jj + 45 ° (c 0.22, ethanol: water = 1: 1), Lnf (pH6 buffer) 257.5 nm (E} ° c ° m 240), X.inr296 nm (Ej °,! M 115).

Example 3

a) Diphenylmethyl- (IS, 6R, 7R) -7 - [(Z) -2- (lt-butoxycarbonylcyclobut-1-oxyimino) -2- (2-tritylaminothiazol-4-yl) -acet-amido] - 3-dimethylaminomethyl ceph-3-em-4-carboxylate-1 oxide

0.52 g of the product of Example 2a in 2 ml of dry tetrahydrofuran was treated with 0.20 ml of a solution of dimethylamine in ethanol (3% w / w). 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 25 ml more ethyl acetate and the entire organic solution was washed with 2 x 50 ml water and dried over sodium sulfate and evaporated to a foam (0.498 g). The crude product was purified by preparative thin layer chromatography on silica gel plates (2 mm thick) while eluting with ethyl acetate. The main band Rf 0.4 gave 0.331 g of a foam, which was dissolved in 2 ml of ethyl acetate and slowly added to 50 ml of petroleum ether with stirring. 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 [a] u -21 ° (c 0.87%, CHCb)? I, n. (ÄtOH) 245 nm E | ^ 225), 260 (E | "cm 210) and 305 nm (E | cm 57).

b) DiphenylmethyHlS, 6R, 7R) -7 - [(Z) -2- (lt-butoxycarbonylcyclobut-1-oxyimino) -2- (2-tritylaminothiazol-4-yl) -aceta-mido] -3-trimethylammoniomethyl ceph -3-em-4-carboxylate-1-oxide, iodide salt

0.201 g of the product from step a) was dissolved in 1 ml of methyl iodide and the solution was left at 21 ° C. for 1 Vi hours. 20 ml of diethyl ether were added and the precipitate was triturated and then filtered off and washed with ether and dried in vacuo to give 0.199 g of the title compound as a solid [<x] d + 10 ° (c 0.87%, CHCb), ki „f ( ÄtOH) 260 nm E | "jm 160), 265 nm (E} ° c0m 154) and 305 nm (Ej" c'm 64) with A-max at 394 nm (E | çm 43).

Example 4

a) Diphenylmethyl- (IS, 6R, 7R) -7-formamido-3-trimethyl-ammoniomethylceph-3-em-4-carboxylate-1-oxide, bromide salt

A solution of 1.01 g of diphenylmethyl (IS, 6R, 7R) -3-bromomethyl-7-formamidoceph-3-em-4-carboxylate-1-oxide in 3 ml of dry N, N-dimethylformamide was mixed with 0.8 ml of a solution of anhydrous trimethylamine in tetrahydrofuran (0.155 g of trimethylamine per ml of solution) was treated and the solution was stirred at 21 ° C. for 15 minutes. 10 ml ether was added and the supernatant solution was discarded. Trituration of the oily residue with about 15 ml of ether gave a precipitate which was filtered off, washed with ether and quickly dried in vacuo to give 1.002 g of the title compound as a solid. F = 140 to 150 ° C (dec.) V max (Nujol) approx. 3400 (NH), 1798 (β-lactam), 1680 (C = 0 from HCONH), 1732 (C02R) and 1035 cm "1 (sulfoxide )

b) Diphenylmethylhl- (IS, 6R, 7R) -7-amino-3-trimethylam-moniomethylceph-3-em-4-carboxylate-1-oxide, hydrochloride and bromide salts

0.562 g of a mixture of the product from step a) in 5 ml of methanol was stirred at 0 ° C. and treated dropwise with 0.28 ml of phosphoryl chloride over the course of 10 minutes. The mixture was stirred at 0 ° C for 2 hours and a leather colored solid precipitated out. 15 ml of ether was added to the stirred mixture, then the precipitate was filtered off and washed successively with ether and ethyl acetate and dried in vacuo to give 0.479 g of the title compound as a solid Xma * (EtOH)

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280 nm (Eì * ° ra 117), Vmax (Nujol) 3700 to 2200 (N + Hj), 1807 (ß-lactam) and 1734 cm- '(CChR).

c) Diphenylmethyl- (1 S, 6R, 7R) -7 - [(Z) -2- (2-t-butoxycar-bonyl-prop-2-oxyimino) -2- (2-tritylaminothiazol-4-yl) - aceta-mido] -3-trimethylammoniomethyl ceph-3-em-4-carboxylate-1-oxide, bromide salt

0.11 g of phosphorus pentachloride in 10 ml of dry methylene chloride was treated with the product of preparation 4 at 0 ° C. and the solution was stirred at 0 ° C. for 35 minutes. 0.16 ml of triethylamine was added and stirring continued at 0 ° C for 5 minutes. The solution was then added dropwise over 5 minutes to a vigorously stirred suspension of 0.286 g of the product from step b) in 15 ml of methylene chloride at 0 ° C. The suspension was stirred at 0 ° C for 15 minutes and then at 20 ° C for 2 hours and then left to stand at 4 ° C overnight.

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 off and washed with petroleum ether and dried in vacuo to give 0.363 g of crude product as a solid. Some solid remained on the sinter; this was dissolved in ethyl acetate and the solution evaporated to a gummy substance (0.019 g). The above combined products (0.33 g) were stirred with 20 ml of ethyl acetate for 15 minutes while triturating the precipitate. The stirred mixture was slowly diluted with 20 ml ether and after a further 10 minutes the solid was filtered off and washed with ether and dried in vacuo to give 0.211 g of the title compound as a solid Xinf (EtOH) 240 nm (Ej ° C 214) , 260 nm (Ei ^ 159), 266 nm (E | "t? M 150), 272.5 nm (E ^" 140) and 305 nm (E | "cm 68) with A. max 385 nm (Ej ° t ; m 32), Vmax (CHBn) 3670 (water). 3600 to 2500 (NH), 1804 (β-lactam), 1730 (CO2R), 1680 and 1513 cm-1 (CONH).

The title compound can be in (6R, 7R) -7 - [(Z) -2- (2-aminothiazol-4-yl) -2- (2-carboxyprop-2-oxyimino) -acetamido] -3-trimteethylammoniomethylceph- 3-em-4-carboxylate as described in Example 1, are transferred.

The antibiotic compounds according to the invention can be formulated for administration in any suitable manner in analogy to other antibiotics and the invention also encompasses pharmaceutical compositions comprising an antibiotic compound according to the invention adapted for use in human or veterinary medicine. Such compositions can be presented 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 an added preservative. The compositions can also take such forms 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 may 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, if 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 e.g. containing common supplement bases such as cocoa butter or other glycerides.

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

Veterinary compositions may, for example, be present as intramammal preparations in either long-acting or quick-release bases.

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 as used for the adult treatment is preferably from 500 to 6000 mg / day depending on the mode of administration and the frequency thereof. For example, in the treatment of an adult, 1000 to 3000 mg / day when administered intravenously or intramuscularly should normally suffice. Higher daily doses may be required to treat 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 is prepared to a pharmaceutical composition.

Formulation for injection

Composition per vial (6R, 7R) -7 - [(Z) -2- (2-aminothiazol-4-yl) -2- (l-carboxycy-clobut-1 -oxyimino) -acetamido] -3-trimethylammoniomethyl-ceph -3-em-4-carboxylate 500 mg

Sodium carbonate, anhydrous 49 mg

method

The sterile cephalosporin antibiotic is mixed with the sterile sodium carbonate under aseptic conditions, then is aseptically filled into glass vials under a protective jacket of sterile nitrogen. The vials are sealed using rubber washers or stoppers that are held in place by aluminum closures, thereby avoiding gas exchange or microorganism penetration. The product is prepared by dissolving in water for injections or other suitable sterile vehicle just prior to administration.

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Claims (10)

644867 1 R3 wherein R1, R2 and R3 are as defined above, in the 3-position, alkylated, b) the optionally present car-boxyl and / or amino protective groups are removed and c) the compound of the formula I obtained, if appropriate, in such a non-toxic salt transferred. 2. (6R, 7R) -7 - [(Z) -2- (2-aminothiazol-4-yl) -2- (2-carboxy-prop-2-oxyimino) acetamido] -3-trimethylammoniomethyl-ceph- 3-em-4-carboxylate according to claim 1. 2nd CLAIMS 1. Cephalosporin antibiotics of the general formula: NH, S V1 \ = l c-co-NH- H f 0 O-C-COOH H N ■ eoo © R l © R2 3rd 644 867 obtained compound of formula I optionally converted into its non-toxic salt. 3. As non-toxic salts according to claim 1, those of the compound according to claim 2. 3rd ■ CH2N ^ —H r (I) wherein R- 'and Rh, which are the same or different from each other, each represent a Ci-4-alkyl group or Ra and Rb together with the carbon atom to which they are attached form a 0 --- cycloalkylidene group; and R1, R2 and R \, which are the same or different, each represent a Ci-4-alkyl group, and the non-toxic salts, the solvates and the acyloxyalkyl esters thereof. 4th wherein Ra and Rb are as defined in claim 1, R6 represents an optionally protected amino group, R7 and R1a, which are the same or different, each for hydrogen R1 I. NO. 2 I. R3 or a carboxyl protecting group and X is a replaceable residue of a nucleophile, or a salt thereof with a tertiary amine of the formula: (v) wherein R1, R2 and R3 are as defined in claim 1, or ai) a compound of the formula: r6 ^ R ch2 — n wherein Ra and Rb are as defined in claim 1, R6 represents an optionally protected amino group and R7 and R "" - 1 both represent carboxyl protecting groups, with an alkylating agent used to form a group of the formula: R1 I. -CHzN ^ -R2 I. R3 wherein R:, R2 and R3 are as defined in claim 1, used in the 3-position, alkylated, 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 group obtained Compound of formula I optionally converted into a non-toxic salt. 4. (6R, 7R) -7 - [(Z) -2- (2-aminothiazol-4-yl) -2- (l-carboxy-cyclobut-1-oxyimino) acetamido] -3-trimethylammonio-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: h h h2n- R / n 0 C00 © wherein R1, R- and R3 are as defined in claim 1, or a salt or N-silyl derivative thereof or a corresponding compound having a group of the formula -COOR4 in 4-position, wherein R4 is hydrogen or a carboxyl protecting group , and with an associated anion A for the Ammonium cation with an acid of the formula: ■ r6 wherein Ra and Rb are as defined in claim 1, R5 is a car-boxyl protecting group and R6 is an optionally 20-protected amino group, or aeylated with a corresponding amide-forming derivative thereof, the protecting group R5 and the optionally further car-boxyl and / or Amino protecting groups removed and the compound of formula I obtained optionally converted into a 2s non-toxic salt. 7 R / SR2 (Via) wherein Rl and Rb are as defined in claim 1, Rr> represents an optionally protected amino group and R7 and R7 "both represent carboxyl protecting groups, with an alkylating agent which is used to form a group of the formula: R ' I. -CH2N -R2 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: R- ch2n ©. coo ^ r- R (Hb, 40 ■ ch, n © —r2 l3 R (IIa) wherein R ', R2 and R3 are as defined in claim 1, or a salt or N-silyl derivative thereof or a corresponding compound with a group of the formula -COOR4 in the 4-position, wherein R4 is hydrogen or a carboxyl protecting group 4s, and with a associated anion A 'for the ammonium cation with an acid of the formula: 50 55 -c-c00h (iii) R "0-c-c00r" s l_ N -c — cooh (iii) like this R R ~ r "0-c-coo r ib wherein Ra and Rh are as defined in claim 1, R5 represents a carboxyl protecting group and R6 represents an optionally protected amino group, or aylated with a corresponding amide-forming derivative thereof, the sulfoxide group of the compound obtained reduced to the sulfide, the protective group R5 and any further carboxyl and / or amino protective groups removed and the 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: R K i S N -C-CO-NH- a R 'O-C-COOR / 7a 0 R H I. N (IVa) ■ ch2x COOR wherein R-1 and Rb are as defined in claim 1, R6 represents an optionally protected amino group, R7 and R7-1, which are the same or different, each for hydrogen R1 or a carboxyl protecting group and X is a replaceable residue of a nucleophile, or a salt thereof with a tertiary amine of the formula: NO. 2 (v) R3 wherein R1, R: and R3 are as defined in claim 1, or ai a compound of the formula: R H H s t I. -C-CO-NH i i "A l N r ^ I 7a 0 "O-C-COOR -ch2-n R COOR 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: -C-CO-NH (IVb) 644867 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. V (VIb) To use rinantibiotikum that shows effectiveness against both Gram-positive and Gram-negative microorganisms and there has been extensive research on the development of various types of broad-spectrum cephalosporin antibiotics. For example, in British Patent 1,399,086 there is a new class of cephalosporin antibiotics with a 7β- (a-etherified oxyimino) acylamido group, the 35 oxymino group having the syn configuration, described. This class of antibiotic compounds is characterized by a high antibacterial activity against a number of Gram-positive and Gram-negative microorganisms, while at the same time there is 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 this area, attempts to find compounds with improved properties, for example against particular classes of organisms, especially Gram-negative organisms. British Patent 1,496,757 describes cephalosporinan tibiotics with a 7β-acylamido group of the formula (A)