LU84674A1 - NOVEL CEPHALOSPORIN DERIVATIVES, PROCESS FOR THEIR PREPARATION AND ANTI-BACTERIAL COMPOSITION CONTAINING THEM - Google Patents

Description

F1 oft 1 »»

The present invention relates to novel cephalosporin derivatives of formula NrC - 'H-NH-jS ^ 1' C0 (F 'ώ3 in which R ^ is hydrogen or a conventional group protecting the amino function and 2 R is a straight chain or branched chain alkyl group containing 1 to 4 carbon atoms, an allyl, 2-butenyl or 3-v butenyl group, or a group of formula 3 I,, R3 —C — R4

COOH

2 in which 3 4, R and R each independently represent hydrogen, methyl group or ethyl group, or 3 4 or R and R may form, together with the carbon atom to which they are bonded, cycloalkylidene nucleus containing 3 to 5 carbon atoms, and their non-toxic pharmaceutically acceptable salts, their physiologically hydrolysable esters and their solvates. Methods for obtaining them are also described.

British Patent No. 1,399,086 includes a general definition covering a very large number of cephalosporins of the formula

/ B

RC-CO-NH-T-> 11 N "OR 1 COOIÎ" in which R is hydrogen or an organic group, R is an etherifying monovalent organic group linked to oxygen by a carbon atom, B represents ^ S or S — K> and * 20 P is an organic group.

^ - However, the group 2-aminothiazole-4-yl is not identified as representing a substituent R and nothing suggests that P may be the group N-methylpyrrolidiniummethyl (or any other fully saturated nucleus containing 3 nitrogen which is linked to the 3-methyl group by its nitrogen atom and which carries another substituent on its nitrogen atom). U.S. Patents 3,971,778 and its divisions for Nos. 4,024,133, 4,024,137, 4,064,346, 4,033,950, 4,079,178, 4,091,209, 4,092,477 and 4,093,803 disclose similar compounds.

U.S. Patent No. 4,278,793 contains a general definition covering a very large number of cephalosporin derivatives of formula R, I 4

Ο I V

\ 2 COOR3 in which the variables 12 3 4

R, R, R, R, X and A

have the general values of the corresponding substituents of the compounds of formula I according to the invention. However, in the 20 columns of definitions of the various substitution groups,. Since the table of structural formulas extends over 78 pages and the 225 examples, there is nothing to indicate that A can be an N-methyl-tj group. 20 pyrrolidiniummethyl (or any other fully saturated nitrogen heterocyclic ring) which is linked to the 3-methyl group by its nitrogen atom and which carries another substituent on its nitrogen atom. British patent No 4 1 604 971 is in concordance with this patent and deals with a practically identical subject. The British patent application filed with the Public Inspection under No. 2 028 305 A, * 5 although appearing to be unrelated as to the formula, contains the same general definition in the broad sense but only indicates hydrogen 'as example illustrating A.

Patent application of the Federal Republic of Germany DE-OS No. 2 805 655 discloses derivatives of 7-C 2- (2-aminothiazole-4-yl) -2- (syn) - acids methoxyiminoacetamidolcephalosporin of formula R 1)

h_S: · -conHt-S ε N

i Tj 1 ^ ocn2 $ coor in which R R NH is an optionally protected amino group, R2 is a halogen or an optionally substituted hydroxyl, thiol, or amino group and COOR is an optionally esterified carboxyl group.

It is also indicated that when R is an amino group, it can be disubstituted and the substituents, taken together with the nitrogen atom, can form, inter alia, a pyrrolidino group. However, there is no mention of an N-methylpyrrolidiniummethyl group (or any other quaternary ammonium group) and the substituent R cannot be linked in position 3 via a methylene group.

U.S. Patent No. 5,478,671 discloses 7- [2- (2-amino-thiazole-1-4-yl) -2- (syn) methoxyiminoacetamido] cephalos-4 porine derivatives of formula

S

\ X

* ^ * c-CONH-J-r 1

II

R.

· 'COOH

wherein R2NH is an optionally protected amino group and R3 is hydrogen or "the residue of a nucleophilic compound".

The term "residue of a nucleophilic compound" is defined broadly and it is then mentioned that 3 R "may alternatively be a quaternary ammonium group". The pyridinium group, variously substituted pyridinium groups, quinolinium, picolinium and lutidinium groups are mentioned as quaternary ammonium groups. There is no evidence to suggest that the quaternary ammonium group can consist of a fully saturated nitrogen heterocyclic ring which is linked by its nitrogen atom and which has another substituent on its nitrogen atom. British Patent No. 1,581,854 is consistent with the foregoing and its terms are practically identical. Other patents in the same name, which are unrelated to the formula, but with similar descriptions, include U.S. Patent No. 4,098,888 and the 5 U.S. Patents America No. 4,203,899, 4,205,180 and No. 4,298,606 resulting from its division, and British Patent No. 1,536,281.

United States Patent No. 4,168,309 discloses cephalosporin derivatives of formula * w R — C — H-NH— | -SS ^ COO® CH ^ - ^ \, O ^ Vi-'0 ”2 '" 00011

K

wherein R is phenyl, thienyl or furyl; a L ·. R and R independently represent hydrogen, alkyl, cycloalkyl, phenyl, naphthyl, * thienyl, furyl, carboxy, alkoxycarbonyl or ^ cyano or Ra and R, taken together with the carbon atom to which they are linked, form a cycloalkylidene or cycloalkenylidene ring; 7 m and n are each equal to 0 or 1 so that the sum of m and n is equal to 0 or 1; and R · * - taken together with the nitrogen atom to which »5 it is linked, is defined in the broad sense but cannot represent, among other things, a saturated pentagonal nucleus 1.

The compound of formula cf3coo © \ “γΟ \ CH3 cooh j O-C-COOH ciî3 L3 is illustrated in Example 5 of this patent. British 10 "" Patent No. 1,591,439 is consistent with the foregoing and its specification is practically identical. Nothing indicates in this patent that the substituent R can be the 2-aminothiazole-4-yl group or that the substituent imino cannot contain a carboxyl group.

The present invention relates to 4 cephalosporin derivatives of formula N-r-C-li-NH-r-S ^ ·> »JC3 \ 2 ..... ^ 1

Lp / y 8 in which R is hydrogen or a conventional group protecting the amino function, and 2 R is a straight chain or branched chain alkyl group containing 1 to 4 carbon atoms, an allyl group, a 2-butenyl group or a 3-butenyl group, or represents a group of formula

G

R3 — C — R4

* I

COOH

in which 34, 10 R and R each independently represent the hydrogen gene, the methyl group or the ethyl group, or else 3 4 R and R taken together with the carbon atom to which they are linked, may be a nucleus 15 cycloalkylidene containing 3 to 5 carbon atoms, and their non-toxic pharmaceutically acceptable salts and their physiologically hydrolysable esters.

The invention also covers the solvates (including hydrates) of the compounds of formula I, as well as the tautomeric forms of the compounds of formula I, for example the 2-iminothiazoline-4- ^ yl form of 2-aminothiazole-4-yl group.

b

As shown in the structural formula, the compounds of formula I have the "syn" or "Z" configuration relative to the alkoxyimino (or alkenyloxyimino) group or the carboxy substituted alkoxyimino group. Because the compounds are geometric isomers, the "anti" isomer may also be present to some extent. The invention covers compounds of formula I containing at least 90% of the "syn" isomer. The compounds of formula I are advantageously "syn" isomers which. 5 are essentially devoid of the corresponding "anti" isomers.

* Pharmaceutically acceptable salts of the compounds of formula I include inorganic base salts such as alkali metal salts (e.g. sodium and potassium salts) and alkaline earth metal salts (e.g. calcium salts), ammonium salts, organic base salts (e.g. with triethylamine, procaine, phenethylbenzylamine, dibenzylethylenediamine and other organic bases which have been used in the field of penicillins and cephalosporins) and acid addition salts (e.g. salts formed with hydrochloric, hydrobromic, formic, nitric, sulfuric, methanesulfonic, phosphoric, acetic or trifluoroacetic acid) and other acids which have been used in the field of penicillins and cephalosporins. Physiologically hydrolyzable esters include acyloxyalkyl esters, for example lower alkanoyl esters such as acetoxymethyl, aceto-toxyethyl, pivaloyloxymethyl, etc. Base salts and esters can be formed with either. carboxyl groups of the compounds of formula I.

The compounds of formula I in which * 3o is hydrogen are endowed with a great anti-bacterial activity against various Gram-positive bacteria and

Gram-negative and they are useful in the treatment of bacterial infections in animals and humans. The compounds of formula I can be formulated for parenteral use in a conventional manner, using known pharmaceutical carriers and excipients and they can be presented in unit dosage form or in packages containing multiple doses. The compositions can be in the form. 5 of solutions, suspensions or emulsions in oily or aqueous vehicles and may contain conventional dispersing, suspending or stabilizing agents. The compositions can also be in the form of a dry powder to be reconstituted before use, for example with sterile pyrogen-free water.

* The compounds of formula I can also be formulated as suppositories using conventional bases for suppositories such as cocoa butter or other glycerides. The compounds of the invention may optionally be administered in conjunction with other antibiotics such as penicillins or other cephalosporins.

When presented in unit dosage forms, the compositions advantageously contain from about 50 to about 1500 mg of the active ingredient of formula I. The dosage for treatment of an adult human is advantageously in the range of about 500 to approximately 5000 mg per day depending on the frequency and route of administration. When administered intramuscularly or intravenously to an adult human, a total dosage of about 750 to about 3000 mg per day, in divided doses, is normally sufficient. fisante, although higher daily doses of some of the compounds may be desirable in the case of Pseudomonas infections.

t: The preferred compounds of formula I are those 1 „2 in which R is hydrogen and R is group 34, - methyl or ethyl, or else R and R each independently represent hydrogen or methyl group. In the most preferred compounds, R is the methyl group, or R and R are each a methyl group. In the primary evaluation of the compounds of the invention, the minimum inhibitory concentrations of the compounds and of two reference compounds (cefotaxime and ceftazidime) ”5 were determined by the double serial dilution methods in Mueller-Hinton agar. against 32 strains of test organisms divided into six groups.

The geometric means of the minimum inhibitory concentrations determined in this test are shown in Tables I and IV.

N — r-c-CONH —- f η H2jCS ^ \ ^ -N-y ^ CH2oücn3

COOH

(Cefotaxime; Comparison compound): K3c- <j: -CH3

COOH

(Ceftazidime; Comparison compound) ”.

CIÏ3 (Test compounds) 12

It can be seen that all of the test compounds were more active than cefotaxime against Gram-negative groups II and III of test organisms, the most preferred compound being significantly more active. All * 5 test compounds were more active than ceftazidime against Gram-positive groups 1a and 1b of test organisms, the most preferred compound being significantly more active than ceftazidime against all groups test organisms except the Gram-negative 10 III group, which was slightly more sensitive to ceftazidime.

The absorption of the most preferred compound and of the reference compounds (cefotaxime and ceftazidime) was determined in mice after a single intramuscular injection of the test compound (dissolved in 0.1 M phosphate buffer; pH 7) at a dose of 20 mg / kg. Blood samples were collected from the orbital sinuses in capillary tubes containing heparin and were titrated in Mueller-Hinton medium using the Morganella Morganii A9695 test organism. The blood levels at various time intervals, the half-life values and the areas below the curve (AUC) are shown in Table II.

Tests for the identification of organisms resistant to both the preferred compound of formula la, cefotaxime and ceftazidime were also carried out. The minimum inhibitory concentrations of these three compounds against 240 strains of Enterobacteriaceae have been determined in Mueller-Hinton medium and a minimum inhibitory concentration equal to or greater than 8 for at least one of the compounds was chosen arbitrarily to designate a resistant organism. Of the 240 strains, 27 were found to be resistant to at least one of the test compounds. The results given in Table 35 III show 3 organisms resistant to compound la, 15 organisms resistant to ceftazidime and 18 organisms resistant to cefotaxime .___________ 1 * 7, / Æ 14 “[Μ J“ --1- “Λ

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TABLE III

Resistance (minimum inhibitory concentration> 8 µg / ml) to one or more test compounds among 2 * 0 strains of Enterobacteriaceae in Mueller-Hinton medium

CIM number * geometric mean (d * g / ml)

Organism of - ~ - ~ strains t = _,, _. .

--------- Ceftazidine C e f a te>: i - e

Escherichia j? 1 0.25 32 e

Escherichia 14 0.5 s

Klebsiella pneumoniae 1 2 16 0 l3

Enterobacter ·, aerogenes 3 0; 25 32 13

Enterobacter aerocenes 1 4 o - ^ - h. s 32

Enterobacter cloacae 1 0.13 4 8

Enterobacter 3 0; 5 40 50

Enterobacter ^ - ° aca.e 3 1; 6 ‘> 63> 63

En terobacter clcacae 1> 32> 63> 63

Eitrobacter freundii 2 0.35 45 32 ”

Ei trobacter species 1 0; 03> 63 32

Proteus

vulgaris 1 0 06 8 S

icrganella Z morganii 1 G ^ '06 32 32

Serratia - i marcescens 1 1 1

Serratia narccscens 1 2 8 16 * 17 »Table ΙΠ (continued), CIM * movenne qéométnque {nq / ml)

Number____:___

Organism of strains Ia Cef tazidiroe Céf atoxir.e

Serratia marcescens 2 2 ^ 8 2 11? Serratia 'narcescens 14 8 63

Serratia xnarcescens 1 8 16 8

Serratia nai'cescens 1 32> 63> 63

Total number of resistant strains 27 3 15 18 * Minimum inhibitory concentration e "Ίΐ 18 'N-r-Ç-CONII - p ^ Λ0Γ, ^ 1 °‘ (Test compound) ^' Table iv

Geometric mean of ICD * ijug / ml)

Compound

Organisms Compound (gjr, t, test Cefotaxime Ceftazidime '“1 (G + J-Ia (5 strains) 14 1.0 5.1 CG - * - J- 1b (5) 35 2, 2 12 (Gj -Ia (5) 0.066 0.015 0.0-0 (GJ-lb (6) 0.79 0.55 1.7 (GJ-II CS J 1.2 4.1 2.6 (G -) - 1 11 (6) 4.0 22 1.8 (G +) * la; s. Aureus sensitive to penicillin (5 strains) Ιό + J-Ib: s. Aureus resistant to penicillin (5 strains) lb-J-la: E. coli (2 strains) Kl. Pneumoniae (1 strain) and

Pr. Mirabi 1 is (2 strains) sensitive to cephalothin (GJ-lb: E. coli (3 strains) and Kl. Pneumoniae (3 strains) resistant to cephalothin s (GJ-II: pr_ morgani (1 strain ), Ent. Cloacae (2 strains) and

Ser. Marcescens (2 strains) W - - (G -) - 111: Ps. aeruginosa (6 strains) (d D Average of 5 trials * Minimum inhibitory concentration 19

It can be seen that the compound lc was more active than cefotaxime against the group (G -) - II of test organisms and clearly more active than cefotaxime against the group (G -) - III of organisms essay (Ps.

. aeruginosa). It was more active than ceftazidime against all groups of Gram-negative test organisms except the Gram-negative group III (Ps. Aeruginosa) which was slightly more sensitive to ceftazidime.

According to another aspect, the invention relates to methods for preparing the compounds of formula I. There are two fundamental modes of transformation of a starting cephalosporin, easy to obtain, into another cephalosporin carrying different substituents in positions 7 and 3. We can first of all eliminate the substituent in position 7 and replace it with the substituent in position 7 desired, then put in place the desired substituent in position 3. As a variant, we can put in place first the desired substituent in position 3 then exchange the substituent in position 7. The compounds of formula I can be prepared by either of these methods and both are included within the scope of the invention, but it is recommended firstly introduce the desired substituent in position 7 and then set up the desired substituent in position 3. The preferred operating mode is illustrated below by reaction scheme 1, while the other operating mode The diagram is illustrated by reaction scheme 2. The abbreviation "Tr" represents the trityl group (triphenyl-methyl) which is a preferred group protecting the amino function. The abbreviation "Ph" denotes the phenyl group.

- Thus, the group -CH (Ph) 2 is the benzhydryl group which is a preferred group protecting the carboxyl function.

„Reaction schemes 3 and 4 illustrate the preparation of the compound (le); in these diagrams, κ is hydrogen and R3 and each represents the methyl group.

20

Reaction diagram 1 N-r-C-COOC-Hc // Tl 25

TrHN '' \ s / \ jH R2X

// Tl 111

TrHN-'X,. / \, R2 OH- JTl IV:

TRHN - ^ \ s / \ r2

Η2Νη- | / N

& ch2ci COOCH (Ph.) 2 - r 21 / S \ // \ l il vi \ or2 / - "\ ^ m: h2ci COOCIï (Ph) 2

Evil Ψ

.rnÄJKj j ^ V

COOCH (Ph) 2 1. II3C-N ^^ j 2. Elimination of the protective group “N-r-C-CONH - f] c // ¥ Li JL © / -! 1

v-V v A'AyO

cocP CH3 22

Reaction scheme 2 / S \

PhCHoC0NH-i-f η

2 VIII

Vj ^ ~ CH2 ° H

COOCH (Ph) 2 PClc

> D

ç pyriaine Φ

/ S

PhCH ^ CONH-i-f> '^ Χλ / —ch2ci COOCH (Ph) 2 Nal

PhCH-jCONH-i-S N

£ X

/ -> V | ^ ~ ch2i COOCH (Ph) 2 H3C - \ ^]

V

23

PhCH_CONH-i r ^ SVv1 D0

. ·> N XI

COOCH (Ph) \ • * ch3 deacylation Φ ΗΛ — p I ^ _ xii

<VΦ ^ α, 2— 'O

COOCH (Ph) _ \ Z CH3

IV

V

g j N r-C-CONH - / 'N j © J- * n ^ cB2? 0 XI111 COOCH (Ph) 2 \! CH 3

Removal of the protective group • 9 i “TS ~ coNH ~ n ^" i \> r2 C "2? 0 ch3 24 *

Reaction diagram 3 _ / 3 ^

N TT * C-COOH H2N "| T

TrHN ^ g / \ CY: H2C1? COOCH (Ph) 2 h3ccch3 (!: OOC (CH3) 3

Ilia ’V

\ l) dicyclohexyl- j 1) bis (trimethyl- \ carbodiimide (DCC) / silyl) acetamide \ / (ESA) \ / 2) Ilia + PC15

S

N T- C-CONH - [- r η / Il JJ i

ΤΓΗΝ- \ ε / '"• ^ ShjCI

H3CÇCH3 COOCH (Ph) 2 cooc (ch3) 3

Nal N / ’v" 25 / s \ N — T- c --- co:; h ----— f η l / \ k J 1 H3CCCH3 COOCH (Ph) 2 "ÔOOC (CIU), \ \

h3c-NQ

sl · N-r-c - COHH --_

fX 1 I ΛP

TrH '/ ^ S ^ ^ N) <y ch2— t / ^ | VIIa, H3C <TCH3 COOCH (Ph) 2

Cooc (ch3) 3 \

Ciî3 I

^ Elimination of the protective group Ψ / S v N - r-C-COKH - f

Il \ IL _ © / ^ ie h2A £ / ^ n> / ’h3c |: ch3 coo0 \ COOH CH3

Reaction scheme 4

PhCH CONH-j-S "N)

VIII

J — Vj ^ ch2oh COOCH (Ph) 2 PC15 pyridine

\VS

26

PhCH2CONH-j-r IX

/ ~ iVj ^ XH2Cl COOCH (Ph) 2 t

Nal Ξ Ψ

PhCH2CONH-t-f ^ χ COOCH (Ph) 2

H3C-nQ

Ψ

PhCH2CONH-d-p | P XI

l © Λ-1

/ J

COOCH (Ph) 2 \ deacylation \ l · 3 27 "" 21-J ©

'(+) ^ XII

T - COOCH (Ph) \ 2 CH3 lila1

DCC

Ψ N— c-C0NH —— ß

Tr ™ · ^^ \? ®Q VIIa H3cicH3 COOCH (Ph) 2 ^ OOC (CH3) 3 \ CH3

Elimination of the protective group.

N r-C-CONH - <

„‘ „2“ O

h3c |: ch3 cocP \ COOH CH3 28

Although the above reaction schemes illustrate preferred multistage procedures for the preparation of the compounds of formula I, it should be noted that other starting materials and other procedures may be used for prepare the intermediate compounds used in the key step of each reaction scheme. Thus, in reaction scheme 1, the key step is the reaction of compound VII with N-methylpyrrolidine. Compound VII can itself be prepared by other methods. Likewise, the key step in reaction scheme 2 is the acylation of compound XII with compound IV. The two compounds XII and - IV can be prepared by other procedures.

The key step in reaction scheme 3 is the reaction of the compound Via with N-methylpyrrolidine. The Via compound can itself be prepared by other methods. Likewise, the key step in reaction scheme 4 is the acylation of compound XII with compound Ilia '. The two compounds XII and Ilia 'can be prepared by other procedures.

The present invention provides a process for the preparation of compounds of formula H-r-C-il-NH-j-S "'h

h „O \ 2“ P'YvvO

"2" S W Î0 (P

in which 2 R is a straight chain or branched chain alkyl group containing 1 to 4 carbon atoms, allyl, 2-butenyl or 3-butenyl, or represents a group of formula 29 R3 - c — R4 l

COOH

in which R ^ and each independently represent hydrogen, the methyl group or the ethyl group, or 3 or 3 4 5 R and R taken together with the carbon atom to which they are linked, may represent a cycloalkylidene ring containing 3 to 5 carbon atoms, and their pharmacologically acceptable non-toxic salts, their physiologically hydrolysable esters and their solation products, process which consists in reacting a compound of formula

0 S

N — rCH - NH- | -'h λΛΗ * RA ·· ”v COOB1 - in which R has the definition given above, 15 B1 is a classical group protecting the carboxyl function and 2 B is a classical group protecting the amino function, with N-methylpyrrolidine to * produce a compound of formula \ 30 Ο ε Ν-γ— C-Ü-ΝΗ- | -S ^

"^ RvyO

COOB (/ Η then to remove all the protective groups by conventional means; or which consists in reacting a compound of formula

O

/ - \ Tfi - ^ - NHn — v // \\ k. i XIVa

B2HN ^ \ s / J ~~ \ j ^ CH2I

R3 -tj: —R4 COOB1 COOB3 in which 5 R 3 and R ^ have the definitions given above, 1 O r B and B are classic groups protecting the carboxyl function and 2 • B is a classic group protecting the amino function , with N-methylpyrrolidine to produce a compound of formula

v O

N-r-C-Ü-NH-i-S 'N es svAjK JXXkâq ~ R3- <U <COOB1 / ^ COOB1 3 r 31 t / then remove all the protective groups by conventional means.

The reaction is carried out in a nonaqueous organic solvent such as methylene chloride, chloroform, ethyl ether, hexane, ethyl acetate, tetrahydrofuran, acetonitrile etc., or mixtures of these solvents. The reaction is advantageously carried out at a temperature ranging from about -10 to about +50 C; it is normally preferred to bring it to room temperature. At least 1 mole of N-methylpyrrolidine must be used per mole of compound XIV or XTVa; it is normally preferred to use about a 50 to 100% excess of N-methylpyrrolidine.

Advantageous carboxyl protecting groups for use as groups B and B in the above reaction are well known to those skilled in the art and include aralkyl groups such as benzyl, p-methoxybenzyl, p- nitrobenzyl and diphenylmethyl (benzhydryl); alkyl groups such as tert-butyl; haloalkyl groups such as 2,2,2-trichlorethyl and other groups protecting the carboxyl function described in the literature, for example in British Patent No. 1,399,086. It is preferred to use groups protecting the carboxyl function which are readily eliminated by treatment with an acid. Particularly preferred groups protecting the carboxyl function are benzhydryl and tert-butyl groups.

Amino protecting groups which are advantageous to use as groups B are also well known in the art and include the trityl group and acyl groups such as the chloracetyl group. It is recommended to use groups protecting the amino function which are easily eliminated by treatment with an acid, for example the trityl group. The present invention also provides a process for the preparation of compounds of formula 32 S-pC-Ü-SH-j-S ^. J $ \>; * in which R 2 is a straight-chain or branched-chain alkyl group containing 1 to 4 carbon atoms, allyl, 2-butenyl or 3-butenyl, or 5 represents a group of formula R3 — C — R4

COOH

in which R ^ and R4 each independently represent hydrogen, the methyl group or the ethyl group, or else R ^ and R4 taken together with the carbon atom to which they are linked, can represent a cycloalkylidene ring containing 3 to 5 carbon atoms, and their pharmacologically acceptable non-toxic salts, their physiologically hydrolysable esters and their solvates, "a process which consists in acylating a compound of formula - H N -, - ^

2 1 I P

J, ^ XVI

coob <4 33 or an N-silyl derivative of this compound, formula in which B is hydrogen or a conventional group protecting the carboxyl function, with an acylating derivative of an acid of formula "

N-r-C-COOH

, -OX,

B HN XS DR

in which 2 B is a conventional group protecting the amino function and 2 R has the definition given above, to produce a compound of formula O s NvC-2 - NH - <- f] P --- C00BX (/ h3 s · and then to remove all the protective groups, or to acylate a compound XVI or an N-silyl derivative of this compound with an acylating derivative of an acid of formula 34

> ς - r— C-COOH

AT ^ K

b2h '' ^ 's' O

r3- <U <I 3 COOB · 3 in which i 2 B is a classic group protecting the amino function, 3 B is a classic group protecting the carboxyl function and R3 and each independently represent hydrogen, the methyl group or the ethyl group, or else 3 4 R and R taken together with the carbon atom to which they are linked, may represent a cycloalkenylidene ring having 3 to 5 carbon atoms, to produce a compound of formula U-- --.- C ---- ^ ---- K'H- | --S "b D0

Ji \ K JI

b2hn ^ \ s / \ 0 - y J xva

r3-C-K4 C0031 / H

* ’J 3 C00B3 then remove all protecting groups.

35

Acylating acid derivatives of formula XVII or XVIIa include acid halides (and in particular acid chloride), mixed acid anhydrides (such as acid anhydrides formed with pivalic acid. or a haloformate such as ethyl chloroformate) and activated esters (such as those which can be formed with N-hydroxybenzotriazole in the presence of a condensing agent such as di-cyclohexylcarbodiimide). The acylation can also be carried out using the free acid of formula XVII or XVIIa in the presence of a condensing agent such as dicyclohexylcarbodiimide, carbonyldiimidazole or an isoxazolium salt. The term "acylating derivative" of the acid of formula XVII or XVIIa which is used in the present specification designates the free acid itself in the presence of a condensing agent as described above. The acylating derivative of the acid of formula XVII or XVIIa which is recommended is acid chloride, advantageously used in the presence of an acid acceptor (and in particular of an acid acceptor of the type of a tertiary amine such as triethylamine, dimethylaniline or pyridine).

When the acylation is carried out with an acid halide, it is possible to use an aqueous reaction medium, but a non-aqueous medium is preferable. When acid anhydrides, activated esters or free acid in the presence of a condensing agent are used for acylation, the reaction medium must be non-aqueous. Particularly ap-30 solvents specified for the acylation reaction are halogenated hydrocarbons such as methylene chloride and chloroform, but tertiary amides such as dimethylacetamide or dimethylformamide and other conventional solvents can be used. such as tetrahydrofuran, acetonitrile, etc.

36

The acylation reaction can be carried out at a temperature of about -50 to about + 50 ° C. However, it is advantageously carried out at a temperature equal to or lower than room temperature and in particular at a temperature of about -30 to about 0 ° C. It is usually preferable to acylate the compound of formula XVI with an approximately stoichiometric amount of the acylating agent of formula XVII or XVIIa, although a slight excess (for example 5 to 25%) of the 'acylating agent.

It is preferable that the compound of formula XVI is acylated in the form of its N-silyl derivative (when a non-aqueous reaction mixture is used). This operation is advantageously carried out in situ by simple addition of a suitable silylating agent (for example N, O-bistrimethylsilylacetamide) to the solution of compound XVI before the addition of the acylating agent of formula XVII or XVIIa. The use of about 3 moles of silylating agent per mole of compound XVI is recommended, although this is not critical. The silylate compound is easily removed after acylation by the addition of water.

The acylating agents of formula XVII or XVIIa, including their derivatives with protected carboxyl and amino functions, are known in the prior art or can be prepared by known methods. Thus, (Z) -2- (2-tertio-butoxycarbonylprop-2-oxyimino) -2- (2-tritylamino-thiazole-4-yl) acetic acid (Ilia) was prepared by the general procedure described. in the patent of

United States of America No. 4,258,041 and in British Patent Application No. 2,025,398. The melting point therein mentioned is 152-156 ° C (decomposition) but by repeating the measurement, found a melting point of 174-175 ° C (decomposition).

37

Preparation No 1 TrHN '^' S '^ OR2 (Z) -2 ~ methoxyimino-2- (2-tritylaminothiazole-4-yl) ethyl acetate 1 (Ilia)

A mixture of (Z) -2-hydroxyimino-2- (2-trityl-5 amino-thiazole-4-yl) ethyl acetate (II) (5.00 g, 10.9 mmol), CH ^ I (2.04 ml, 32.8 mmol) and K ^ CO ^ (4.54 g, 32.8 mmol) in anhydrous dimethyl sulfoxide (DMSO) (100 ml) was stirred at room temperature for about 16 hours then poured into water (250 ml). 2o The precipitate which formed was collected by filtration, washed with water and dried giving the compound indicated in the title (5.15 g, quantitative yield). Melting point: 115 ° C (decomposition).

NMR: <5 CDC13 ppm 1.32 (3H, t), 3.98 (3H, s), 4.30 15 (2H, q), 6.42 (1H, s), 7.2 (1H, m ) 7.25 (15H, s).

The compounds Illb, IIIc and Illd were prepared by the general procedure indicated above, but in replacement of the methyl iodide by the appropriate iodide.

2 38

Compound R yield m.p. (° C) m.p. (eC)% indicated in the literature 1 5 (1)

Ilia methyl 100 115 ° (dec.) Approx. 120 ° (dec.)

Illb ethyl 67 97-98 * IIIc isopropyl 26 51-55 *

Illd allyle * * * 10 * The ester has been hydrolyzed without being isolated (1) Tetrahedron, 34, 2233 (1978)

Preparation No 2 jTVk ”i

TRHN, x \ g / \) j> 2 I

i (Z) -2-methoxyimino-2- (2-tritylaminothiazole-4-yl) acetic acid (IVa) The ethyl ester Ilia prepared in Preparation No 1 (6.00 g, 1 ^, 7 mmol) in ethanol (120 ml) was treated with 2N sodium hydroxide (12.7 ml) at room temperature for about 16 h. The pH of the reaction mixture was adjusted to 8 by the addition of dry ice powder and the solvent was evaporated under reduced pressure. The residue was dissolved in water (100 ml) and the solution was acidified with IN HCl to pH 2 * and then extracted with ethyl acetate (3 x 50 ml). The combined extracts were washed with saturated aqueous NaCl solution, dried and evaporated. The residue was crystallized from a mixture of ethyl acetate and hexane to give 5.56 g (98% yield) of the product indicated in the title, m.p. 138-143 ° C (decomposition).

39 NMR: iCDC13 ppm 3.89 (3H, s), 6.52 (1H, s), 7.2 (15H, s).

Compounds IVb, IVc and IVd were prepared by the general procedure indicated above, s 5 Compound R yield m.p. m.p. (° C, dec.)% (° C, dec.) Indicated in the literature (1) IVa methyl 98 138-143 approx. 140 IVb ethyl 85 140-145 not reported 10 IVc isopropyl 85 166-169 approx. 170

Illd allyle 66 170-178 approx. 170 ς (1) Tétrahédron, 34, 2233 (1978)

Preparation No 3 3-hydroxymethyl-7-phenylacetamido-3-cephem-4-carboxylate 15 of benzhydryl (VIII)

The sodium salt of 7-phenylacetamidocephalosporanic acid (5 g, 12.1 mmol) was added in a single portion to a suspension with stirring of a phosphate buffer (pH 7, 162.5 ml) and its wheat 20 (20 g, dry state) at room temperature. The progress of the reaction was monitored by liquid chromatography under high pressure until the hydrolysis was completed (5 hours). The suspension was filtered to remove wheat bran and the filtrate was cooled to 5-25 10 ° C for esterification of the extracted product. Methylene chloride (32 ml) was added to the cooled solution, followed by a 0.5 M solution of diphenyldiazomethane in methylene chloride (24 ml). The pH was then adjusted to 3.0 with 28% phosphoric acid. After one hour, the temperature of the reaction mixture was allowed to rise to 20 ° C. Heptane (56 ml) was added slowly and the resulting product indicated in the title was collected by filtration, in a crystalline state. The product yield indicated in the title was 3.0 g (50%).

40

Preparation No 4 Benzhydryl (V) 7-amino-3-chloromethyl-3-cephem-4-carboxylate

Pyridine (3.2 g, 40 mmol) was added to a suspension of PCl ^. (8.3 g, 40 mmol) in (100 ml) and the mixture was stirred for 20 minutes at 20 ° C. Benzhydryl 3-hydroxy-methyl-7-phenyl-acetamido-3-cephem-4-carboxylate prepared in Preparation No. 3 (5.1 g, 10 mmol) was added to the mixture with stirring at -40 ° C. , in a single serving. The mixture was stirred at -10 ° C for 15 minutes and allowed to stand at -10 to -15 ° C for 7 hours. Propane-1,3-diol (10 ml) was added to the cooled solution (-20 ° C) and the mixture was allowed to stand at -20 ° C for 16 hours and then stirred at room temperature for 20 minutes. The resulting solution was washed with ice water (2 χ 20 ml) and a saturated aqueous NaCl solution (10 ml), dried over MgSO 4 and concentrated in vacuo. The gummy residue (12 g) was dissolved in a mixture of CHCl 4 and n-hexane (2: 1) and subjected to chromatography using a column of silica gel (200 g) and the same solvent as eluent . The fractions containing the title compound were evaporated in vacuo and the residue was triturated with n-hexane to give the title product (2.1 g, 51%) melting above 110 ° C (decomposition).

, Infrared spectrum 3400, 2800, 1785, 1725 cm ^ xEtOH occ, „1% icm qn UV: r ~ 265 nm (E, 160).

max 1cm ** NMR: SDMS ° “d6 + CDCl3 3.69 (2H, s), 4.43 (2H, s), 5.09 ppm - (1H, d, J = 4.5Hz), 5.24 (1H, d, J = 4.5Hz), 6.87 (1H, s), 7.3 (10, m).

41

Example 1 7- Γ (Z) -2-methoxyimino-2- (2-aminothiazole-4-yl) acetamidp] -3- [. (1-methyl-1-pyrrolidinium) methyl] -3-cephem-4-carboxylate (la) * 5 a. 3-chlorornethy 1-7 d] (Z) -2-methoxyimino-2- (2-tritylamino-thiazole-4-yl) acetamido] -3-benzhydryl-cephem-4-carboxylate (Via1)

The benzhydryl 7-amino-3-chlorornethyl-3-cephem-4-carboxylate obtained in preparation No 4 10 (2.29 g, 5.52 mmol) in CH 4 CN (57 ml) was treated U.

with bis (trimethylsilyl) acetamide (BSA, 4.09 ml, 16.6 mmol) at room temperature for 50 minutes to give a clear solution. To this solution was added an acid chloride solution which had been prepared from (Z) -2-methoxyimino-2- (2-trityl-aminothiazole-4-yl) acetic acid (iVa ) (2.04 g, 4.60 mmol) and PClg (1.15 g, 5.52 mmol) in methylene chloride (20 ml). The mixture was stirred at room temperature for 30 minutes, poured into cold water (200 ml) and extracted with ethyl acetate (3 x 100 ml). The combined extracts were washed with an aqueous solution of sodium chloride, dried and evaporated. The residual syrup (4 g) was chromatographed on a column of silica gel (150 g), elution being carried out with 10: 1 and 3: 1 mixtures of toluene and ethyl acetate, successively . The fractions containing the desired compound were combined and evaporated to give 2.61 g (68%) of compound Via 'in the form of an amorphous powder.

NMR: 5CDC13 3.50 (2H, s), 4.02 (3H, s), 4.33 (2H ,. s), ~ 4.98 (1H, d), 5.87 (1H, q) , 6.65 (1H, s), 6.90 (1H, s), 7.3 (25h, m).

i 42 B. 3-iodomethyl-7 \ [Z) -2-methoxyimino-2- (2-tritylamino-thiazole-4-yl) acetamidcQ -3-benzhydryl carboxylate (VIXa1)

A mixture of the 3-chloromethyl derivative (Via1) 5 (1.50 g, 1.79 mmol) and Nal (1.34 g, 8.93 mmol) in methyl ethyl ketone (30 ml) was stirred at room temperature for one hour. After evaporation of the solvent, the residue was dissolved in ethyl acetate (100 ml) and the solution was washed with water, an aqueous solution of Na 2 S0 4 and an aqueous solution of NaCl, dehydrated and evaporated to give the compound Vlla 'indicated in the title (1.47 g, 89%) in the form of an amorphous powder.

NMR: 5CDC13 1 ppm 3.55 (2H, ABq), 4.00 (3H, s), 15 4.25 (2H, s)., 4.97 (1H, d), 5.80 (1H, q ), 6.65 (1H, s), 6.90 (1H, s), 7.3 (25H, m).

C. 7- Ç (Z) -2-methoxyimino-2- (aminothiazole-4-yl) acetamido] -3- Ç (1-methyl-1-pyrrolidinium) methyl] -3-cephem-4-carboxylate (la )

A mixture of compound Vlla '(4.5 g, 4.83 mmol) and N-methylpyrrolidine (0.65 ml, 6.28 mmol) in C ^ C ^ (45 ml) was stirred at room temperature for 20 minutes. Ether (300 ml) was added to the mixture to separate the quaternary salt from the protected cephalosporin, which was collected by filtration and treated with 90% trifluoroacetic acid (TFA) (40 ml) at room temperature for 1 hour. The mixture was then evaporated below 20 ° C under reduced pressure. The residue was triturated with ether to give the TFA salt of compound la (2.40 g) which was dissolved in methanol (5 ml) and the solution of which was treated with a IM solution of sodium 2-ethylhexoate (SEH) in ethyl acetate (8 ml) at room temperature for 30 minutes.

43

After the addition of ethyl acetate (100 ml), the precipitate (1.94 g) formed was collected by filtration. Analysis by high pressure liquid chromatography showed that the crude product was 7% pure with a 1: 8 ratio of the is-isomer to the is-isomer. The purification of the product by liquid phase chromatography under high pressure was repeated three times (Lichrosorb RP-18, 8 X 300 mm, elution with 5% aqueous methanol or a 0.01 M 10 ammonium phosphate buffer ( pH 7.2) containing 5% methanol to obtain 35 mg (1.5%) of the product indicated in the title, in the form of a colorless powder Estimated purity (by v liquid phase chromatography under high pressure) = 90%, mp = 150 ° C (decomposition).

15 Infrared spectrum: 9KBr cm-1 1770, 1660, 1620 _,, max

Ultraviolet spectrum:> phosphate buffer, pH7 nm (£) 235 (16200), 258 max (15400)

NMR spectrum: ÆD2 ° ppm 2.31 (4H, m), 3.08 (3H, s), 3.63 (4H, m), 4.09 (3H, s), 5.43 (1H, d , J = 4.8 Hz), 5.93 (1H, d), 7.08 (1H, s).

Example 2 7-Û Z) -2-methoxyimino-2- (2-aminothiazole-4-yl) acetamidol -25 3 [(1-methyl-1-pyrrolidinium) methyll -3-cephem-4-carboxylate (la)

2.42 g (28.5 mmol) of 1-methyl-pyrrolidine was added in a single portion at room temperature to a stirred solution of 20.4 g (21.9 mmol) of compound Vlla 'in 150 ml of anhydrous methylene chloride. The mixture was stirred for 5 minutes and poured into 1000 ml of ether with vigorous stirring to form a precipitate which was filtered, washed with ether (5 X 30 ml) and dried under vacuum to give 19.3 g 35 of the protected product in the form of a pale yellow powder.

44

Infrared spectrum cm ”* 3400, 1780 (s), 1740, 1675, 1530

Thin layer chromatography: solvent = ethanol-CHClg (1: 3), Rf = 0.30 (Rf = 0.95 * 5 for the compound Vlla1)

The solid was dissolved in 185 ml of 99: 1 mixture of trifluoroacetic acid and water, stirred for 1 hour at room temperature and concentrated to about 30 ml below 10 ° C. Concentrate 10 was poured into 1000 ml of ether with vigorous stirring to form a precipitate which was filtered, washed with ether (5 X 40 ml) and dried under vacuum to give 10.6 g of a powder of pale yellow color. The powder was dissolved in 20 ml of methanol and the solution was filtered. 45 ml of 0.8 M SEH in ethyl acetate was added to the filtrate. The resulting suspension was poured into 400 ml of ethyl acetate and filtered giving 8.08 g of a solid substance which consisted of a mixture of compound 2 indicated in the title and of the corresponding Δ isomer 2 2 2 20 (Δ / Δ = 1: 8) as represented by analysis by high pressure liquid phase chromatography ("Lichrosorb RP-18", 10-15% methanol in 0.01 M phosphate buffer, pH7) . A second test carried out using 28.9 g (31.0 mmol) of compound VIIa 'gave 16.0 g of the crude product (Δ / Δ = 1: 8). Isolation of the desired Δ isomer from the total crude product (24.08 g) by preparative liquid chromatography under high pressure (system * 500, Waters Associates, PrepPAK 500 / C ^ g, 5-10% CH ^ OH) gave 769 mg of compound la.

Example 3 7- Γ (Z) -2-methoxyimino-2 (2- (2-aminothiazole-4-yl) acetamidol- 3-, [(1-methyl-1-pyrrolidinium) methylj -3-cephem-4- - carboxylate (la)

A series of tests was carried out to determine the effect of the solvent, its quantity and the reaction time on the yield of the compound 1a and on the ratio Δ! b, in the reaction product. The general procedure was as follows:

A solution of N-methylpyrrolidine "5 (0.01 ml, 0.097 mmol) in ether (0.1 ml) was added to a suspension of the 3-iodomethyl derivative Vlla '(45 mg, 0.048" mmol) in the indicated amount of the solvent mentioned, and the mixture was stirred at room temperature for the period indicated. The reaction mixture was diluted with ether (5 ml) and the resulting precipitate was collected by filtration and mixed with 90% TFA. The mixture was stirred for 1 hour and evaporated to dryness under reduced pressure, at a temperature below 20 ° C, 3 2 to obtain the product. The Δ / Δ ratio in product 15 was determined by high pressure liquid phase chromatography ("Lichrosorb RP-18"; mobile phase, 0.01 M ammonium phosphate buffer (pH 7.2) containing 15% of 3 2 CH ^ OH; retention time, Δ 6.60 minutes, Δ 5.56 minutes). The yield of product and the ratio of the 3 2 20 isomers Δ / Δ for each test are indicated below.

Report of

Vlla '(in g) Rendering Time- 25 No of solvent reaction reaction 3/2 ratio Solvent test (in ml) (min.) (%) Δ 1 2 3 4 5 6 7 8

Cri7Cl, 1:20 15 75 1/8 2 CHjCl2-Hther ll / lüj 1: 100 15. 25 4/1 3 5 Ethyl acetate-ether (1/10) l: ldO 15 27 4/1 4 30 4 Ethyl acetate-ether (1/10) 1: 100 60 64 2/1 5

Ether 1: 100 15 31 b / i 6

Etner 1: 100 60 62 5/1 7

Ether 1:60 15 55 5.5 / 1 8

Ether 1:60 60 82 l / l 46

Example 4 7- £ (Z) -2-ethoxyimino- 2- (2-aminothiazole-4-yl) acetamido] - 3- [(1-methyl-1-pyrrolidinium) methvl1 -3-cephem'-4-carboxylate ( Ib) 5 A. 3-chloromethyl-7 [(Z) -2-ethoxyimino-2- (2-tritvlamino-thiazole-4-yl) acetamido! -3-cephem-4-carboxylate. benzhydryl (VIb)

Phosphorus pentachloride (500 mg) was added to a solution of (Z) 2-ethoxyimino-2- (2-10 tritylaminothiazole-4-yl) acetic acid (IVb) (1.095 g, 2.4 mmol) in dichloromethane (20 ml). After stirring for 1 hour at room temperature, the mixture was added in a single portion to an ice-cooled solution of Compound V (1.083 g, 2.4 mmol) and BSA 15 (1 ml) in dichloromethane ( 20 ml). After stirring for 1/2 hour, the reaction mixture was poured into a 10% aqueous solution of sodium bicarbonate (200 ml) and extracted with chloroform (100 ml). The extract was washed with water, dried over magnesium sulfate 20 and evaporated under reduced pressure.

The residue was chromatographed on a column of silica gel. Elution with chloroform gave compound VIb as an amorphous powder, in an amount of 1.76 g (86%).

25 NMR; <5CDCl3 ppm 1.40 (3H, t, CH2CH3), 3.53 (2H, ABq, 2-CH2), 4.37 (2H, s, -CH2C1), 4.60 (2H, q, -CH2CH3) , 4.90 (1H, d, 6-H), 5.89 (1H, d, 7-H), 6.88 (1H, s), (H of thiazole), 6.91 (1H, s, (Benzhydryl CH) 30 B. 7 ((Z) -2-ethoxyimino-2- (2-tritvlamindthiazole-4-yl) acetamidoj-3-iodomethyl-3-cephem-4-carboxylate of diphenylmethyl (Vllb)

A mixture of compound VIb (1.07 g, 1.25 mmol) and Nal (562 mg, 2.75 mmol) in acetone (20 ml) was stirred for 1 hour. The mixture was filtered and the filtrate was poured into water and extracted with ethyl acetate. The organic phase was washed successively with a 5% aqueous solution of Na2S2C> 3, water and a saturated aqueous solution of NaCl, dried over magnesium sulfate and evaporated to give 1.04 g (89%) of compound Vllb.

NMR: ÔCDC13PPm 3.55 (2H, q, 2-CH2), 4.27 (2H, s, CH2-I} 5.02 (1H, d, 6-H), 5.87 (1H, d, 7 -H), 6.68 (1H, s, H of the thiazole nucleus), 6.93 (1H, s, 10 (benzhydryl CH) C. 7 [(Z) -2-ethoxyimino-2- (2- aminothiazole-4-yl) acetamido] - 3-E (1-methyl-1-pyrrolidinium) methyll-3-cephem-4-carboxylate (Ib)

A mixture of compound Vllb (333 mg, 0.35 mmol) and N-methylpyrrolidine (60 mg, 0.7 mmol) in CH2Cl2 (5 ml) was stirred for 1/2 hour at room temperature and then evaporated under empty. The residue was washed with ether and dissolved in 90% aqueous TFA.

After standing for 1/2 hour at room temperature, the mixture was concentrated under reduced pressure. Ether was added to the concentrate to separate the quaternized product which was collected by filtration and dissolved in a small amount of methanol. The solution was chromatographed on an HP-2 column (40 ml).

Elution with 30% aqueous methanol followed by lyophilization gave 0.062 g of a mixture of the 2323 Δ and Δ isomers (δ: Δ = 5: 1). The mixture was purified by * liquid phase chromatography under high pressure ("Lichrosorb RP-18, 8 x 300 min 15% methanol) and -3 30 the desired Δ (Ib) isomer was isolated in the form of a pale yellow powder in an amount of 4.9 mg (2.7%).

Ultraviolet spectrum: Xta, phosphate nPon, pH 7 235 max (15000), 258 (14000) 48 Nuclear magnetic resonance: 6 D2 ° ppm 1.43 (3H, t), 2.33 (4H, m), 3.10 (3H, s, 3.64 (4H, m), 4.36 (2H, q), 5.44 (1H, d), 5.95 (1H, d), 7.08 (1H, s).

* 5 Example 5 7-Γ (Z) -2 ~ (2-propoxyimino) -2- (2-aminothiazole-4- yl) acetamido] -3- [(l-methyl-l-pyrrolidinium) methyi] -3- cephem-4-carboxylate (le) A. 3-chloromethyl-7 Γ (Z) -2- (2-propoxyimino) -2- (2-10 tritylaminothiazole-4-yl) acetamido] -3-cephem-4-carboxylate diphenylmethyl (Life)

A mixture of (Z) -2- (2-propoxyimino) -2- (2-tritylamino-thiazole-4-yl) acetic acid (IVc) (707 mg, 1.5 mmol) and phosphorus pentachloride (344 mg, 1.65 15 mmol) in dichloromethane (14 ml) was stirred at room temperature for 1 hour and poured into a solution of compound V (677 mg, 1.5 mmol) and BSA (1.1 ml , 4.5 mmol) in dichloromethane (15 ml). The reaction mixture was stirred at room temperature for 30 minutes, diluted with ethyl acetate (200 ml) and water (3 X 100 ml), dried over sodium sulfate and evaporated to give 1 , 4 g (100%) of Life compound.

KB37 “1

Infrared spectrum: v ce 25 3360, 3020, 3060, 2960, 1785, 1725, 1680, 1520, 1500, 1450, 1375, 1300, 1250, 1160, 1090, 1060, 1010, 990, 840, 740, 700.

'' Ultraviolet spectrum: AEt0Hnm (6.) 240 (24600), 260 (20700) * max 30 Nuclear magnetic resonance: CDCl δ 3 ppm 1.35 (6H, d, J = 6Hz), 3/50 (2H, s ), 4.35 (2H, s), 4.58 (1H, m, J = 6Hz), 5.00 (1H, d, J = 4.5Hz), 5.91 (1H, dd, J = 4 , 5 $ 9Hz; d by D20 J = 4.5Hz), 6.68 (1H, s), 6.88 (1H, s), 7.25 (25H, s).

49 B. diphenylmethyl-7- [(Z) -2- (2-propoxyimino) -2- (2-trityl-aminothiazole-4-ylacetamido3-3-cephem-4-carboxylate (Vile)

A mixture of Compound Vie (500 mg, 0.55 mmol) * 5 and sodium iodide (248 mg, 1.66 mmol) in acetone (10 ml) was stirred at room temperature for 50 * minutes . After evaporation, the residue was dissolved in ethyl acetate (15 ml, the solution was washed successively with a 10% aqueous solution of sodium thiosulphate (10 ml), water ( 10 ml) and an aqueous NaCl solution (10 ml), dehydrated over sodium sulphate and evaporated to give 494 mg (90%) of the compound (Vile) indicated in the title.

Infrared spectrum: KBr -1 15 v CItl 3360, 3040, 3020, 2960, 1785, 1720, 1680, max 1600, 1520, 1500, 1450, 1370, 1300, 1230, 1150, 1115, 1080, 990, 900, 840 , 750, 700,

Ultra violet spectrum: λ Et0H nm (£) 240 (24900), 260 (19400). max 11111 K 1 20 Nuclear magnetic resonance spectrum: 6CDC13 ppm 1.30 (6H, d, J = 6Hz), 3.37 ^ 3.70 (1H each, d, J = 16Hz), 4.22 (2H, s), 4.55 (1H, m, J = 6Hz), 4.95 (1H, d, J = 4.5Hz), 5.83 (1H, dd, J = 4.5Ç9Hz; d parE ^ O ), 6.66 (1H, s), 6.87 (1H, s), 7.25 (25 (25H, s).

C. 7-C (Z) -2- (2-propoxyimino) -2- (2-aminothiazole-4-yl) acetamidol-3 - [(l-methyl-l-pyrrolidinium) methylj -3-cephem-4- carboxylate

A mixture of the compound Vile (545 mg, 0.55 mmol) and 1-methylpyrrolidine (70 mg, 0.82 mmol) in dichloromethane (10 ml) was stirred at room temperature for 30 minutes and diluted with ether (100 ml). The resulting precipitate was collected by filtration.

50

A solution of the precipitate in 90% TFA (4.5 ml) was stirred at room temperature for 30 minutes and evaporated in vacuo. The residue was triturated with ether to give 317 mg of the crude product which was chromatographed on a column of HP-20 (50 ml), eluted with water (500 ml) and methanol at 30 % (500 ml).

The 30% methanolic eluate was concentrated and lyophilized 2 3 2 / giving 109 mg of a mixture of the isomers a and a (δ Δ = 6/1), of which 100 mg were purified by chromatography in phase 10 liquid under high pressure ("Lichrosorb RP-18, MeOH 15%) giving 5 mg (3%) of the desired compound indicated in the title.

Ultraviolet spectrum: λ -tamP ° na PH 7 nm () 236 (15100), 252 (14600) max 15 Nuclear magnetic resonance spectrum: ôD2 ° ppm 1.42 (6H, d, J = 6Hz), 2.33 (4H, s), 3.10 (3H, s), 3.65 (4H, s), 3.838 * 4.23 (1H each, d, J = 17Hz), 5.45 (1H, d, J = 4.5Hz), 5.95 (1H, d, J = 4.5Hz), 7.05 (1H, s).

Example 6 Z) -2-allyloxyimino-2- (2-aminothiazole-4-yl) acetamidoj-3-C (1-methyl-1-pyrrolidinium) methyl! 1 -3-cephem-4-carboxylate (Id) A 7— C (Z) -2-allyloxyimino-2- (2-tritylaminothiazole-4-25 yl) acetamidoj-3-chloromethyl-3-cephem-4-carboxylate benzhydryl (VId)

BSA (1.1 ml, 4.5 mmol) was added to a suspension of compound V (1.35 g, 3 mmol) in methylene chloride (20 ml), and the mixture was stirred for 30 minutes at room temperature until it becomes a clear solution. A mixture of (Z) -2-allyloxyimino-2- (2-tritylaminothiazole-4-yl) -acetic acid (IVd) (1.40 g, 3.0 mmol) and phosphorus pentachloride (690 mg, 3 , 3 mmol) in methylene chloride (20 ml) was stirred for 15 minutes at room temperature and poured in a single portion into the solution of trimethylsilylated compound V. The mixture was stirred for 20 minutes at room temperature and diluted with ethyl acetate (200 ml), washed with aqueous sodium bicarbonate and water, dried and evaporated under reduced pressure. The oily residue was purified by chromatography on a column of silica gel (Wako-gel, C-200, 30 g). The column was eluted with chloroform and the fractions containing the desired product were combined. By evaporation under reduced pressure, the compound indicated in the title (VId) was obtained in the form of an amorphous powder; yield 2.32 g (89%), melting point 100-115 ° C (decomposition).

Infrared spectrum: TCR * r —1 15 cm 3990, 1790, 1730, 1680, 1530, 1380, 1250, maX 1160, 1020

Nuclear magnetic resonance spectrum 6CDC13 ppm 3'50 (2H '2 "H)' 4'32 (2H 's' 3“ CH2)' 4'6 6.1 (7H, m, CH2CH = CH2 and 6.7- H), 6.70 (1H, 20s, H of thiazole), 6.90 (1H, s, Ph2CH), 7.1-7.6 (30H, m, phenyl protons).

Analysis: • calculated for C ^ qH ^ qN ^ Oç-S ^ I. l / SCHCl ^: C% H% N% S% Cl% 'v 25 64.05 4.45 7.73 7.08 7.82 found: 64.13 4.61 7.50 6.85 7.55 63.99 4.64 7.30 6.85 7.46 52 B. 7- C (Z) -2-Allyloxyimino-2- (tritylaminothiazole) -4-yl) acetamido]] -3-iodomethyl-3-cephem Benzhydryl-4-carboxylate (Vlld)

A mixture of compound VId (2.30 g, 2f65 mmol) and sodium iodide (2 g, 13.3 mmol) in acetone (15 ml) was stirred for 1 hour at room temperature then evaporated under reduced pressure. A solution of the oily residue in ethyl acetate (200 ml) was washed with 10% sodium thiosulfate and water and evaporated 2o under reduced pressure giving the compound Vlld in the form of a amorphous powder which was used in the next step without further purification. Yield 2.52 g (99%).

T C. 7 - C (Z) -2 ~ Allyloxyimino-2- (2-aminothiazole-4-yl) acetamidoj- 3 - [(l-methyl-l-pyrrolidinium) methyl | -3-cephem-4-carboxy- 15 late (Id)

A mixture of compound VIId (478 mg, 0.5 mmol) and N-methylpyrrolidine (0.05 ml, 0.5 mmol) in methylene chloride (5 ml) was stirred for 20 minutes at room temperature and diluted with 2o ether (50 ml) to precipitate the quaternized product (yield 500 mg). A mixture of the quaternized product and TFA (2 ml) was allowed to stand at room temperature for 1.5 hours and diluted with ether to precipitate the crude TFA salt from the product (yield 265 mg) which was chromatographed on an HP-20 column (1.8 x 18 cm). The column was eluted with water and 30% aqueous methanol. The methanolic eluate was evaporated under reduced pressure and the residue was lyophilized "to give an amorphous powder (yield 124 mg) which contains? . 3q held the desired product (17%) and the corresponding Δ isomer (83%). The mixture was purified by chromatography in liquid phase under high pressure (Lichrosorb RP-18; NH4H2P04 Ο, ΟΙΜ (pH 7): CH3OH = 85: 15). The eluate was acidified to pH 3 with dilute hydrochloric acid and chromatographed on an HP-20 column (1.8 x 10 cm).

53

The column was eluted with water and then with 30% aqueous inethanol. The methanolic eluate was evaporated under reduced pressure and the residue was lyophilized to give the compound (Id) indicated in the title, in the form. 5 of an amorphous powder (yield 13 mg, 5.1%). M.p. 155 ° C

(decomposition).

_,. _ KBr -i »Infrared spectrum: v cm max • 3600-2800, 1770, 1670, 1610, 1530, 1200.

^ Ultraviolet spectrum: χ ^ amPon a ^ max 10 nm (s) 235 (16600), 253 (15600).

Nuclear magnetic resonance: 6D2®ppm 2.1-2.5 (4H, m, H of pyrrolidine), 3.10 (3H, s, NCH3), 3.4-3.8 (4H, m, H of pyrrolidine ), 5.95 (1H, d, 4Hz, -H), 7.10 (1H, s, H of thiazole).

Example 7 7- ^ 2- (2-Aminothiazole-4-yl) - (Z) -2- (2-carboxyprop-2-oxyimino) - acetamidoJ-3- (1-methyl-1-pyrrolidinium) methyl J-3- cephem-4-carboxylate (le) 20 A. 3-Chloromethyl-7- Ç (2) -2- (2-t-butoxycarbonylprop-2-oxyimino-2- (2-tritylaminothiazole-4-yl) acetamidoj-3- benzhydryl cephem- 4-carboxylate (Va)

Procedure 1

A mixture of (Z) -2- (2-t-butoxycarbonyl- * prop-2-oxyimino) -2- (2-tritylaminothiazole-4-yl) acetic acid. (Ilia ') (1.94 g, 3.6 mmol), DDC (742 mg, 3.6 mmol) and N-hydroxybenzotriazole (486 mg, 3.6 mmol) in tetrahydrofuran (THF) (45 ml ) was stirred at room temperature for 45 minutes, during which time the dicyclohexylurea separated. The dicyclohexylurea was removed by filtration and the filtrate was mixed with compound V (1.5 g, 3.6 mmol). The mixture was stirred overnight at room temperature and then evaporated in vacuo. The residual oil was dissolved in. 5 chloroform (20 ml), washed with an aqueous solution of sodium bicarbonate and an aqueous solution - saturated with sodium chloride, dehydrated on magnesium sulphate and evaporated to dryness. The residue (3.9 g) was dissolved in a mixture of n-hexane and CHCl 4 (1: 2) and the solution was loaded onto a column of silica gel (40 g) using same mixture of solvents.

The fractions containing the title compound were evaporated in vacuo to give 1.3 g (39%) of compound Va, melting above 100 ° C (decomposing).

15 Infrared spectrum: cm "· ^ 3990, 1790, 1715.1690 max

Ultraviolet spectrum:

TütOH

λ nm 240 (E ** 280), 265 (E ** 190).

max 1nm i icm 1cm Nuclear magnetic resonance: gCDClg ppm 1.45 (9H, s), $ 1.63 1.66 20 (6H, s each), 3.49 (2H, large s), 4.34 (2H , s), 4.96 (1H, d, J = 4.5Hz), 5.90 (1H, dd, J = 4.5 ^ 7.5), 6.66 (1H, s), 6.86 (1H , s), 7.0-7.5 (25H, m), 8.23 (1H, d, J = 7.5Hz).

“Procedure 2 r A solution of compound V (1.86 g, 4.49 mmol) in CH ^ CN (46.5 ml) was treated with BSA (3.33 ml, 13.5 mmol) to room temperature for 50 minutes, giving a clear solution. To the solution 30 was added an acid chloride solution which had been prepared from the compound Ilia '(2.56 g, 4.49 mmol) and PC1,.

(1.12 g, 5.38 mmol) in methylene chloride (26 ml). The mixture was stirred at room temperature for 30 minutes, poured into cold water (100 ml) Ä 5 and extracted with ethyl acetate (3 x 50 ml). The combined extracts were washed with an aqueous solution of *

NaCl, dehydrated and evaporated. The residual syrup (5 g) was chromatographed on a column of silica gel (100 g) by elution with a 10: 1 mixture of toluene and ethyl acetate. The fractions containing the compound

"V

desired were combined and evaporated to give 2.84 g (65%) of compound Va.

B. 7- L (Z) -2- (2-t-Butoxycarbonylprop-l-oxyimino) -2- (2-tri-> tylaminothiazole-4-yl) acetamido.-] -3-iodomethyl-3-cephem- 4-15 benzhydryl carboxylate (Via)

A mixture of compound Va (500 mg, 0.53 mole) and Nal (240 mg, 1.6 mmole) in acetone (3 ml) was stirred for 2 hours at room temperature and then evaporated in vacuo. 20 ml of 2Q CH2Cl2 and 10 ml of water were added to the residue. The organic phase was washed with a 10% w / v solution of sodium thiosulfate (5 ml) and aqueous sodium chloride (5 ml), dried over MgSO 4 and evaporated to dryness giving 540 mg (90% ) of compound Via in the form of an amorphous powder 25, melting at 106 ° C. (decomposition).

Infrared spectrum; vKBr cm-1 3350, 1790, 1690.

max "

Ultraviolet spectrum; \ EtOH nm 340 (e ^ ° 270), 3 o max 1 cm 265 (E1% 190).

1 cm CDC1 Nuclear magnetic resonance î 6 3 ppm 1.44 (9H, s), 1.65 (6H, s), 3.54 (1H), 35 4.28 (2H, s), 4.98 (1H , d, 56 J = 4.5Hz), 5.85 (1H, dd, J = $ 4.5 7.5Hz), 6.70 (1H, s), 6.90 (1H, s), 7, 1-7.5 (25H, m).

C. 7- / 2- (2-aminothiazole-4-yl) - (2) -2- (2-carboxyprop-2-oxyiroino) -acetamido / -3- / (1-methyl-1-pyrrolidinium) methyl / -5 3-cephem-4-carboxylate (le). A mixture of the iodomethyl derivative Via (538 mg, 0.51 mmol) and N-methylpyrrolidine (0.079 ml, 0.076 mmol) in methylene chloride (10.8 ml) was allowed to stand at room temperature for 30 minutes. f> then 10 it was diluted with ether (80 ml). The precipitate which formed was collected by filtration and washed with ether to give 420 mg of the quaternized product which was freed from the protective group with 90% trifluoroacetic acid (TFA) (4.2 ml) at room temperature for one hour. The reaction mixture was then evaporated to dryness. Ether was added to the residue to obtain the crude TFA salt of compound la (245 mg, quantitative yield) which consisted of a 1: 4 mixture of the isomers A3 and û2. The crude product was subjected to purification by high-pressure liquid chromatography / Lichrosorb RP-18, 4 x 300 mm, elution with 0.01 M ammonium phosphate buffer (pH 7.0) containing 10% of CH ^ OH /. The fraction containing the desired product was collected and evaporated to a small volume. The concentrate was adjusted to a pH of about 2 by the addition of 1 M HCl and loaded onto an HP-20 column (2 x 15 cm) to remove the inorganic salt. The column was "washed with water (1000 ml) and eluted with 30% methanol, the eluent was evaporated and the product was lyophi-30 li-sé giving 21 mg (10%) of the compound (le) indicated in U · the title, in the form of a colorless powder. M.p. 160 ° C (decomposition).

Infrared spectrum: vKBr cm ^ 3400, 1775, 1610.

max 57 ultraviolet spectrum, λ tamP'on with Phosphate, max 237 (15700), 257 (155 500).

Nuclear magnetic resonance: 6 D2 ^ ppm 5 1.65 (6H, s), 2.3 (4H, m), 3.09 (3H, s), 3.6 (4H, m), 4.0 (2H , m), 5.44 (1H, d, J = 4.8Hz), 5.94 (1H, d), 7.15 (1H, s).

EXAMPLE 8> The general procedure of Example 7 was followed, except that the acid was replaced? (Z) -2- (2-t ~ butoxycarbonylprop-2-oxyimino) -2- (2-trityl- aminothiazole-4-yl) acetic by an equimolar amount of the following acids: (Z) -2- (t- butoxycarbonylmethoxyimino) -2- (2-tritvl-15 aminothiazole-4-yl) acetic acid (Z) -2- (1-t-butoxycarbonylethoxyimino) -2- (2-trityl- 1 aminothiazole-4-yl) acetic acid ( Z) -2- (2-t-butoxycarbonylbut-2-oxyimino) -2- (2-tritylaminothiazole-4-yl) acetic acid (Z) -2- (3-t-butoxycarbonylpent-3-oxyimino) -1 - (2-tritylaminothiazole-4-yl) acetic acid (Z) -2- (1-t-butoxycarbonylcycloprop-l-oxyimino) -2- (2-tritylaminothiazole-4-yl) acetic acid (Z) -2 - (1-t-butoxycarbonylcyclobut-l-oxyimino) -2-25 (2-tritylaminothiazole-4-yl) acetic, and acid (Z) -2- (1-t-butoxycarbonylcyclopent-l-oxyimino) -2- ( 2-tritylaminothiazole-4-yl) acetic, and the following compounds were produced respectively: 7- / 2- (2-aminothiazoleT14-yl) - (Z) -2- (carboxymethoxyimino) acetamido / - 3- / ( 1-methyl-1-pyrrolidinlum) methyl / -3-cephem-. 4-carboxylate, 7- / 2- (2-aminothiazole-4-yl) - (Z) -2- (1-carboxyethoxyimino) acëtamido / -3 - / (1 -methyl-1 -pyrrolidinium) methyl / -3- cephem-4-carboxylate, 58 7- / 2- (2-aininothiazole-4-yl) - (7,) - 2- (2-carboxybut-2-oxyimi.no) -acetamido / -3- / (1- methyl-1-pyrrolidinium) methy3./-3- cephem-4-carboxylate, 7- / 2- (2-aminothiazole-4-yl) - (Z) -2- (3-carboxypent-3-oxy-. 5 imino) -acetamido / -3 - / (1-methyl-1-pyrrolidinium) methyl / - 3-cephem-4-carboxylate, '7- / 2- (2-aminothiazole-4-yl) - (Z) -2 - (1-carboxycycloprop-l- oxyimino) -acëtamido / -3 - / (1-methyl-l-pyrrolidinium) methyJL / -3-cephem-4-carboxylate, 10 7- / 2- (2-aminothiazole-4- yl) - (Z) -2- (1-carboxycyclobut-l-oxyimino) acëtamido / —3 - / (1-methyl-l-pyrrolidinium) methyl / -3-cephem-4-carboxylate, and - 7- / 2 - (2-aminothiazole-4-yl) - (Z) -2- (1-carboxycyclopent-l- oxyimino) acëtamido / -3- / (1-methyl-l-pyrrolidinium) methyl / -15 3-cephem-4 -carboxylate, respectively. 1

Claims (10)

59 1 Jl 1 Γ Θ / "", XVa bhnA, s / Xj, ^ H2-N R3-Ç-R COOB1 / I 3 CH3 COOB J 65 then remove all protecting groups by conventional means. 1. Compounds characterized in that they correspond to the formula: 8 NCCC-NH-Ir η in which R1 is hydrogen or a conventional group / 5 protecting the amino function and R is ion straight or chain alkyl group branched containing 1 to 4 carbon atoms, an allyl, 2-butenyl or 3 ~ butenyl group or a group of formula: 2. 7 - / (Z) -2-methoxyimino-2 · ^ (2-aminothiazole- 4-yl) acetamido / -3 - / (l-methyl-l-pyrrolidinium) -methyl / -3- 20 cephem- 4-carboxylate, 7 - / '(Z) -2-ethoxyimino-2 ^ (2-amino-thiazole-4-yl) acetamido / ~ 3- (l-methyl-1-pyrrolidinium) -methyl / -3- cephem-4-carboxylate, 7- / Tz) -2- (2-propoxy-imino) -2- (2-aminothiazole-4-ylacetamido7_3- (1-methyl-1-pyrrolidinium) methyl} -3-cephem- 4-carboxylate, 7 - / (Z) - 60 2-allyloxyimino-2- (2-aminothiazole-4-yl) -acetamido / -3- (1 -methy1-1 -pyrrolidinim) methyl7-3-cephem-4 ~ carboxylate or a non-toxic pharmaceutically acceptable salt or a solvate of these compounds or 7- / 2- (2-aminothiazole-4-yl) - (Z) -2- (2-carboxyprop-2-oxydiriino) * 5 acetaMdo7-3- / Tl -methyl 1-1 -pyrrolidinium) methyl7-3-cephem-4-carboxylate or a non-toxic pharmaceutically acceptable salt or a physiologically hydrolysable ester or a solvate of this compound according to claim 1. 3 I 4 R3 — C — R4 COOH 64 3 4 wherein R and R each independently represent hydrogen, methyl group or ethyl group, or 3 4 well R and R may form, together with the atom carbon to which they are linked, a cycloalkylidene ring. 5 containing 3 to 5 carbon atoms, and their salts right? toxic pharmaceutically acceptable, their physiologically hydrolysable esters or their solvates, process characterized in that it consists in reacting a compound of formula: r. N-rr-C-6-NH-S ^ // ^ \ Î! \ f I xiv b2hn / \ s / \ qr2 ÿ ZU2I n COOB1 π s N - r-C-Ö-Mp —_ \, y / Vk i. XIVa · p3_Lr4 1 RPK COOB • 3 COOB · 5 2 3 4 10 in which R, R and R have the definitions given 1 3 above, B and B are classic groups protecting 2 the carboxyl function, B is a classic group protecting the amino function, with N-methylpyrrolidine to produce a compound of formula N-rC-Ü-NH-iS ^ J9 COOB1 or O ^ 3 N - rC-Ü-NH-i- "N jp 3 I 4 R3 — C — R4 COOH * 3 4 wherein R and R each independently represent hydrogen, methyl group or ethyl group, or 3 4 well R and R, taken together with the atom of carbon to which they are attached, can represent a cycloalkylidene ring containing 3 to 5 carbon atoms, or a non-toxic pharmaceutically acceptable salt, a physiologically hydrolysable ester or a solvate of this compound, process characterized in what it consists of acylating a compound of formula / S. H2NT-f η p I xvi coob1 üj 10 or iin N-silyl derivative of this compound, formula in which B "*" is hydrogen or a conventional group protecting the carboxÿLe function, with wine acylating derivative of an acid of formula N-χ-Ç-COOH // XVII or b'hAs / V NrC-COOH O XVIIa R3-: -B4: oob3 2 63 in which B is a classic group protecting the 3 amino function, B is a classic group protecting the 3 4 carboxyl function and R and R have the definitions given above, to produce a compound of formula NrC-Ü-NH-iS 'N p) / ¾ Π b2hn ^ V s / \ or2 J H2-N 1 xv coob1 or B2nr \ s) \ r3-c-r4 coob1 / „I 3 -3 COOB-3 5 and then removing any protective group. 3. Antibacterial composition, characterized in that it comprises an antibacterial effective amount of at least one compound according to claim 1, preferably 7- / Tz) -2-methoxy-imino-2- (2-aminothiazole-4-yl) -acetamidc7-3- / fl-methyl 1- 1-1 -pyrrolidinium) -rethyl7-3-cephem-4-carboxylate or a non-toxic pharmaceutically acceptable salt or a solvate of this compound and an inert pharmaceutical excipient. 3 I 4 R3 — C — 'R4 COOH 3 4 10 wherein R and R each independently represent hydrogen, methyl group or ethyl group, or 3 4 well R and R may form, together with the atom of carbon to which they are linked, a cycloalkylidene nucleus containing 3 to 5 carbon atoms, this compound also existing in the form of a non-toxic, pharmaceutically acceptable salt or of a physiologically hydrolysable ester or of 'a solvate. 4. Antibacterial composition in unit dosage form, characterized in that it contains approximately 50 to approximately 1500 mg of at least one compound according to claim 1 and an inert pharmaceutical excipient, the compound preferably being 7- / TZ) -2- 20 methoxyimino-2- (2-aminothiazole-4-yl) -acetamido7-3 - / _ (1 -methy 1-1 -pyrro lidinium) methyl-3-cephem-4-carboxylate or a pharmaceutically non-toxic salt acceptable or a solvate for this compound. 5. Antibacterial composition active against Gram-negative bacteria, characterized in that it comprises an antibacterial effective amount of at least one compound according to claim 1, * in which R1 has the definition given in the claim - 3 4 cation 1 and R and R each independently represent hydrogen, methyl group or ethyl group, or R 3 and R 3 may well form, together with the carbon atom u 'to which they are linked, a cycloalkylidene ring containing 3 to 5 carbon atoms, or a non-toxic pharmaceutically acceptable salt, a physiologically hydrolysable ester or a solvate of this compound and an inert pharmaceutical excipient, the compound preferably being 7- / 2- (2-aminothiazole-4-yl) - (Z) -2- (2-carboxyprop-2-oxyimino) acet ami do / - 3- / (1-methyl-3 - / (1 -methyl-1-pyrrolidinium) methyl / -3-cephem-4- * 5 carboxylate or a non-toxic pharmaceutically acceptable salt, an ester p hysiologically hydrolyzable or a solvate of this compound. 6. Antibacterial composition active against Gram-negative bacteria in unit dosage form, characterized in that it comprises from about 50 w to about 1500 mg of at least one compound according to claim 1, wherein R1 has the given definition - In claim 1 and R ^ and R ^ independently represent hydrogen, the methyl group or the group - 3 4 15 ethyl or R and R may form, together with the carbon atom to which they are bonded, cycloalkylidene ring containing 3 to 5 carbon atoms, preferably 7- / 2- (2-aminothiazole-4-yl) - (Z) -2- (2-carboxy-prop-2-oxyimino) acetamido7-3- / (1-methyl-1-pyrrolidinium) methyl / -3-cephem-4-carboxylate or a pharmacologically acceptable non-toxic salt or a physiologically hydrolyzable ester or a solvate of this compound. 7. Process for the preparation of compounds of formula Nr- C-- HN HjS ^ c0 ° éj * a- in which R1 is hydrogen or a conventional group 2 j 25 protecting the amino function and R is an alkyl group - chain straight or branched chain containing 1 to 4 carbon atoms, an allyl, 2-butenyl or 3-butenyl group or represents a group of formula 62 8. A process for the preparation of compounds of formula Nr— Ç-Ü-NH-jS ^ h2N ^ 5 \ or2 c “2/0 1 • 'co ° éa3 * 2 wherein R is a straight chain alkyl group or» branched chain containing 1 to 4 carbon atoms, allyl, 2-butenyl or 3-butenyl, or represents a group of formula 9. Method according to one of claims 7 and 8, for the preparation of 7- / 2- (2-aminothiazole-4-5 yl) - (Z) -2- (2-carboxyprop-2-oxyimino) -acetamido / -3 - / (1-? Methyl-1-pyrrolidinium) methyl / -3-cephem-4-carboxylate i (le) or a non-toxic pharmaceutically acceptable salt, a physiologically hydrolysable ester or a product of solvation of this compound, process characterized in that it consists in reacting a mixture of benzhydryl 7-amino-3- ^ chloromethyl-3-cephem-4-carboxylate, of (Z) -2- ( 2-t-butoxycarbonylprop-2-oxyimino) -2- (2-tritylamino-thiazole-4-yl) acetic, DCC, of N-hydroxybenzotriazole in an organic solvent to form 3-chloromethyl-7- / Tz) -15 2- (2-tertio-butoxycarbonylprop-2-oxyimino-2- (2-tritylamino-thiazole-4-yl) -acetamido / -3-cephem-4-carboxylate of benzhydryl (If) or alternatively, reacting a mixture of benzhydryl and bis- (trimethylsilyl) acetamide 7-amino-3-chloromethyl-3-cephem-4-carboxylate of (Z) -2- (2-t-butoxycarbonylprop-2-oxyimino) -2- (2-tritylaminothiazole-4-yl) acetic acid, to form the compound (If), then reacting the latter with a iodide, to obtain 7 - / (Z) -2- (2-t-butoxycarbonylprop-2-oxyimino) -2- (2-tritylaminothiazole-4-yl) -acetamido / -3-25 iodomethyl-3-cephem- Benzhydryl 4-carboxylate (Ig) which is then reacted with N-methylpyrrolidine in an organic solvent to obtain the compound (Ih), and finally, to eliminate the protection of the compound (Ih) to obtain the compound ( le) indicated in the title, melting at * 30 160 ° C. while decomposing and / or, if necessary, converting the compound (le) into its non-toxic pharmaceutically acceptable salts, its physiologically hydrolysable esters and its products. solvation. 10. Method according to one of claims 7 35 and 8, for the preparation of compounds of formula: y 66 r, 8 __ · ^ sHor2 j — 1 - 'c0 ° A, * w * 1 2' in which κ is hydrogen and κ is methyl, ethyl, isopropyl, or allyl, or a non-toxic, pharmaceutically acceptable salt or a solvate of this compound, process characterized in that it consists in reacting a mixture of benzhydryl 7-amino-3-chloromethyl-3-cephem-4-carboxylate and bis- (trimethylsilyl) acetamide with (Z) -2-methoxyimino-2- (2-tritylaminothiazole-4 acid chloride) -yl) acetic or (Z) -2-ethoxyimino-2- (2-tritylamino-thiazole-4-10 yl) acetic or (Z) -2- (2-propoxyimino) -2- ( 2-trityl-amino-thiazole-4-yl) acetic or (Z) -2-allyloxy-imino-2- (2-tritylaminothiazole-4-yl) acetic acid to form the corresponding condensed derivative containing a 2- group methoxyimino or 2-ethoxyimino or 2-propoxyimino or 2-15 allyloxyimino, then reacting the condensed derivative a with iodide to obtain the corresponding 3-iodomethyl derivative, then reacting said 3-iodo-methyl derivative with N-methyl-pyrrolidine in an organic solvent or in a mixture of organic solvents to obtain the corresponding pyrrolidinium derivative and , finally, to eliminate the protection of said derivative of * pyrrolidinium to obtain 7 - / (Z) -2-methoxyimino-2- (2- * aminothiazole-4-yl) acetamido / -3 - / (1-methyl-l -pyrrolidinium) - * methyl7-3-cephem-4-carboxylate or 7 - / (Z) -2-ethoxyimino- ^ 25 2- (2-aminothiazole-4-yl) acetamido / -3- / (1-methyl -l-pyrroli- V1 dinium) -methyl ./- 3-cephem-4-carboxylate or 7 - / (Z) -2- - (2-propoxyimino) -2- (2-aminothiazole-4-yl) acetamido / -3- (1-methyl-1-pyrrolidinium) methy] ./- 3-cephem-4-carboxylate, or 7 - / (Z) -2-allyloxyimino-2- (2-aminothiazole-4-yl) t ι · Γ 67 ac§tamido7-3- / Tl-methyl-l-pyrrolidinium) methyl / -3-cephem- 4-carboxylate and / or, if necessary, to convert the said derivatives removed from the protective groups into a se l or pharmaceutically acceptable non-toxic solvate 5. »3 * 1 Λ