LU85840A1 - CEPHEMES - Google Patents

Description

¢ 3

DESCRIPTIVE MEMORY

FILED IN SUPPORT OF A REQUEST FOR

PATENT

FORMED BY

BRISTOL-MYERS COMPANY for

Cephemes.

OVERVIEW OF THE INVENTION

4 "“ The present invention relates to 7— [2— (5— amino-1,2,4-thiadiazol ~ 3-yl) -2-iminoacetamido (substituted) 3-3-C3- (quaternary ammonio) -l- propen-l-yl] -3-cephè-me-4-carboxylates of the formula

V

where and are as defined below and ΛξΟ represents a quaternary ammonio radical as defined below, or their salts and esters. It also relates to methods for preparing the compounds of formula I, the pharmaceutical compositions containing at least one compound of formula I and the intermediates for their preparation.

Known state of the art A) Patent EUA 4,390,534 of June 28, 1983 “(Tsutomu Teraji et al.) Describes cephemas and cephams of formula i5 where R · *" represents a protected amino or amino radical; R represents an atom of hydrogen, an acyl, optionally substituted aryl, substituted alkyl, alkenyl, alkynyl, cycloalkyl optionally substituted or cycloalkenyl or a 5-membered heterocyclic radical containing sulfur or oxygen and sub- - 3 titrated by one or more oxo radicals; R represents a 4 hydrogen atom or an alkyl radical; R represents MT o te a hydrogen atom or an acyloxyalkyl, acylthioalkyl, optionally substituted pyridinioalkyl, heterocyclothioalkyl, optionally substituted alkyl, halogen, optionally substituted hydroxyl or thiazolioalcoyl; R represents a protected carboxyl or carboxyl radical, it being understood that represents r _ 4 C00 when R represents an optionally substituted pyridinioalkyl radical or thia zolioalcoyle optionally substituted, and the dotted line indicates a single or double bond.

European patent application 13 762 published on August 6, 1980 is in accordance with this patent and describes the same compounds.

The patents EUA 4,381,299 (April 26, 1983), 4,331,665 (May 25, 1982) and 4,332,798 (June 1, 1982) resulting from applications which are at the origin of the patent EUA 4,390,534 apply to the same matter.

B) European patent application 62.321 published on October 13, 1982 describes cephemas of formula R1 - Ç — CONH-1- / V, L2 J —'i \ ωΓ “* - * '®,' where R" * " represents an amino or protected amino radical, 2 R represents an optionally substituted lower aliphatic hydrocarbon radical or a cyclo-alkenyl radical and the radical of formula * / '~ \ —N © ”is an optionally substituted heterocyclic cationic radical containing more than one nitrogen atom, and their pharmaceutically acceptable salts. This document also describes intermediates of formula ’’ ——r ~ C '"i.

: ^ b A

T4 CHj— N © 7 y 2 i where K and K are as defined above, x represents a protected carboxyl radical and X- represents the remainder of an acid.

C) European patent application 74.653 published on March 23, 1983 describes cephemes of formula 1 -Ç-CONH - T ^ Svi J_ _3, p.A-4 / τγ where R ^ represents a protected amino or amino radical; 2 R represents an optionally substituted lower aliphatic, lower cycloalkyl or lower cycloalkenyl hydrocarbon radical; R represents an alkyl (lower) amino, alkyl (lower) amino N-protected radical, dialcoyl (lower) v amino, sulfoalkoyl (lower) amino, hydroxyalkoyl (lower) amino, hydroxyalcoyl (lower) amino N-protected- , lower acyloxyalkyl, lower (alkoxy) lower (lower) alkoxy, dialkoyl (lower) amino lower alkyl, lower (lower) alkyl thioalkyl, lower (lower) thio, lower alkoxy, lower (lower) alkoxy, hydroxyalkoxy lower, ^ lower acylalkyl, hydroxyalkyl (lower) thio, dialcoyl (lower) aminoalkyl (lower) thio, heter-? nitrogen-containing 5-membered unsaturated rocyclic, nitrogen-containing 5-membered unsaturated heterocyclothio or less than 5 or 6-membered nitrogen-containing unsaturated heterocyclothioalkyl, which may be substituted by appropriate substituent (s), and represents an atom of hydrogen or lower alco-yl radical, or their salts.

D) The patent EUA 4,332,800 of June 1, 1982 (Tsutomu Teraji et al.) Describes, among others, compounds of formula where R · * "represents a protected amino or amino radical, R represents a lower alkyl radical and X represents a hydrogen atom or carbamoyl radical.

E) European patent application 47.977 published on March 24, 1982 describes cephemes of formula (0) / S v

Am — T — C CONH -f

H

* O-R, lKV? \ * Ο * Θ cocr where m represents 0 or 1; Am represents an optionally substituted amino * radical; T represents a thiadiazolyl entity (joined to other radicals by two of its carbon atoms); R2 represents a hydrogen atom or an optionally substituted alkyl, cycloalkyl or optionally substituted carbamoyl radical; e and R1 represents an optionally substituted thiazolio, optionally substituted pyrazolio, trialkyl radical (lower Jammonio or pyridinio of formula R * where R represents a substituted lower alkyl radical î [the substituent being a cycloalkyl, phenyl, hydroxyl, alkoxy, halo radical, cyano, carbamoyl, carbo-xyl or sulfo], lower alkenyl or lower alkenyl carboxy-substituted, (lower) thio or lower alkyl) thio carboxy-substituted, amino or mono mono substituted [the substituent being a lower alkyl, lower alkanoyl or aminobenzenesulfonyl], dialcoyl- (lower) amino, substituted carbamoyl [the substituent being a lower alkyl, lower hydroxyalkyl, lower alkoxy, hydroxyl or cyano], dialcoyl- (lower) carbamoyl, thiocarbamoyl, cycloalkyl, phenyl, hydroxyl, lower alkoxy, halo, alco-xy (lower) carbonyl, lower alkanoyloxy, lower alkanoyl, carboxyl, sulfo, cyano, nitro or hydro- / xysulfoalkyl inferior; R ° represents a hydrogen gene or carbamoyl radical or has the same meaning a c * ί as R; and R represents a hydrogen atom or has the same meaning as R, CD.MJ - 6 - and their salts.

- Although not formally related, European patent application 25.017 published on March 11, 1981 applies to the same subject.

F) European patent application 30.630 published on June 24, 1981 describes 3-vinyl cephemes of formula g R1— A — CONH - <> // - Ns> ^^ ch * ch, 0 2 R2 where R · 1 2 3 "represents an optionally protected substituted amino- ~ heterocyclic radical which can also be halogenated, or a radical of formula R ^ Y ~ y_ 2 where R represents a lower alkyl radical; R represents a protected carboxyl or carboxyl radical; A represents an alkylene radical lower which can carry a substituent chosen from the amino, protected amino, hydroxyl, oxo radicals and of formula = N * v OR, v 4 or R represents a hydrogen atom or lower cy-cloalkenyl, lower alkynyl, lower alkenyl radical [ optionally substituted by a carboxyl or protected carboxyl radical V], lower alkyl 2 [optionally substituted by one or more carboxyl, protected carboxyl, amino, protected amino 3, cyano, phosphono, protected phosphono or a heterocyclic radical which can itself be substituted] - and their ls.

This thesis specifically describes the compounds of formula ii.

jT ^ _com ^ rr "s'1

h> h-Vn V

COOH

where OR ^ represents a methoxy, carboxymethoxy, t-butoxycarbonylmethoxy or 1-t-butoxycarbonylethoxy radical.

G) British Patent No. 1,399,086 of June 25, 1975 includes a general description applying to a large number of cephalosporins of formula / B s.

R-C-CO-NH - f N »»

COOH

where R represents a hydrogen atom or organic radical, Ra represents an etherifying monovalent organic radical united to the oxygen atom by a carbon atom, B represents or -> 0 and P represents * an organic radical. In one embodiment, P can represent, inter alia, a vinyl radical s of formula / r3

-CH = C

3 4 where R and R may independently represent a hydrogen atom, a nitrile or alkoxy (lower) - carbonyl radical, or a substituted or unsubstituted aliphatic, cycloaliphatic, - araliphatic or aromatic radical.

However, the 5-amino-1,2,4-thiadiazol-3-yl radical is not identified as a possible R substituent and there is no disclosure or suggestion that P may represent a propenyl radical carrying a quaternary ammonio radical as a substitute. The patent EUA 3,971,778 and the corresponding divisional patents EUA 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 apply to the same subject .

H) European patent application 88.385 published on September 14, 1983 describes compounds of formula i \

R— | —C0NH - J

L2 d—

R

where R "* - represents a thiadiazolyl radical (not substi-2 killed); R represents a lower carboxyalkyl radical or protected lower carboxyalkyl; R represents a hydrogen or halogen atom or a lower alkenyl radical and R ^ represents a protected carboxyl or carboxyl radical. Although the 1-propenyl radical is included among the possible meanings of R, the specification cites as an example only * compounds in which R represents a hydrogen or chlorine atom or a vinyl radical .

I) EUA patent 4,307,233 of December 22, 1981 (Daniel Farge et al.) Describes, inter alia, 3-vinylcephalosporins of formula Ül N-T-Ç-CONH -, -, Χ? \, ^. 2 OR5 ÿ | ch-ch-nVr4

COOH

5, where R can represent, inter alia, an alkyl, vinyl or cyanomethyl radical or a protective radical such as 2-methoxyprop-2-yl, and R and R represent alkyl radicals (optionally substituted by hydro-xyl, alkoxy, amino, alkyllamino or dialkoylamino) or phenyl, or else R ^ and R ^ taken together with the nitrogen atom to which they are united can form a saturated hetero-cycle of 5 or 6 members optionally containing another hetero atom chosen from N, 0 and S and optionally substituted by an alkyl radical. These compounds are useful as intermediates for the preparation of 3-thiovinylcephalosporin derivatives.

No disclosure or suggestion is made of a 5-amino-1,2,4-thiadiazol-3-yl entity instead of the 2-aminothiazol-4-yl substituent, nor of a propenyl entity carrying an ammonio radical quaternary as a substitute for occupying position 3. The published English patent application 2,051,062 is corresponding and applies to the same material.

J) European patent application 53.537 published "on June 9, 1982 describes, inter alia, 3-vinyl cephalosporins of formula

N — Γ-Ç, -CONH-1-r ^ SvS

H / X \ c COORC

2 ° °> C \ “5 OJ" Ί "4 * 5 * 5 COORj where R, - and Rj. Are identical or different and represent hydrogen atoms or alkyl radicals or else, taken together, form an alkylene radical of 2 or 3 carbon atoms, Rj. Represents a protective radical of the acid function, R_ represents a protective radical L 3

acid function such as an ester radical, R

4 and R, identical or different, each represent a hydrogen atom or an alkyl radical (optionally substituted by hydroxyl, alkoxy, amino, alkylamino or dialkoylamino) or phenyl, or else R ^ and R4, taken together with the atom nitrogen to which they are united, can form a saturated heterocycle of 5 or 6 members optionally containing another hetero atom chosen between N, 0 and S and optionally substituted by an alkyl radical. These compounds are useful as intermediates for the preparation of 3-thiovinylcephalosporin derivatives. There is no disclosure or suggestion of a 5-amino-1,2,4-thiadiazol-3-yl entity in place of the 2-aminothiazol-4-yl substituent or of a propenyl radical bearing an am- radical mono quaternary as a substitute to occupy the *> position 3.

The patent EUA 4.423.214 is corresponding and * applies to the same material.

K) European patent application 53.074 published on June 2, 1982 includes a general description applying to a large number of 3-vinylcephalosporins of formula ‘(0) J *; Rla “NH" | -f] r'yK r 3

0 I CH = C-RJ

c00R * 2a where Re, (in one of several embodiments) can represent N ---- C-CO- XXi; = H2 / SX ° R5 where R ,, may, inter alia, represent a hydrogen atom or an alkyl, vinyl or cyanomethyl radical, a radical protecting the oxime function such as trityl, etc., or else a radical of formula - C-COORC ^

Ra ^ \ R1> R 5 R 5 sb where R and R 5 are identical or different and may represent a hydrogen atom or an alkyl radical or, taken together, an alkylene radical of 2 or 3 carbon atoms and R j represents a hydrogen atom - or protective radical of the acid function; R ° 2a re_ has a hydrogen atom or a protective radical ^ of the acid function such as methoxymethyl; Re (in one of several embodiments) may represent a methyl radical substituted by a 5 or 6-membered aromatic hetero ring containing a single hetero atom such as 2- or 3-pyridyl, 2- or 3-thienyl 3 i or 2 - Or 3-furyl, and R represents a radical of formula R.S0o0- »4 2 £ where R ^ can represent an alkyl, trihalomethyl or phenyl radical optionally substituted.

- These compounds are described as being intermediates for the preparation of compounds in which the substituent at position 3 is a radical of formula R e

-CH = C-SR

which are described as having antibacterial activity.

_ Although this thesis includes the possibility that Re represents a methyl radical substituted by a heterocycle containing nitrogen, in the "intermediate and final product compounds (thus leading to a heterocyclo-subsituted propenyl radical), it only indicates that The heterocycle is united by one of its carbon atoms. There is therefore no suggestion of a propenyl radical carrying a quaternary ammonio radical as a substituent. This memoir cites only the methyl radical as an example of R ° in the intermediate compounds and the final product. In addition, in the intermediate compounds and the final product, the propenyl radical must contain a second substituent (-O ^ SR ^ or-SR, respectively). There is also no disclosure nor the suggestion of a 5-amino-1,2,4-thiadiazol-3-yle entity instead of the 2-ami-nothiazol-4-yle substituent.

L) European patent application 53.538, published on June 9, 1982, describes, among other things, 3-vinylcephaloporins of formula <0) n L · <♦ · Π N C-CONH S è \:, / 7v TV -

COOH

5 where n represents 0 or 1, R represents a hydrogen atom or an alkyl, vinyl or cyanomethyl radical or a protective radical of the oxime function and represents a halogen atom. There is no disclosure or suggestion of a 5-amino-1,2,4-thiadia-zol-3-yl entity in place of the 2-aminothiazol-4-yl substituent nor of a 3- substituent halo-l-propen-l-yle occupying position 3.

Detailed description of the invention The subject of the invention is new derivatives of cephalosporin which are powerful anti-bacterial agents. More particularly, it relates to the compounds of formula: N -— Ç-- CONH — S \ ilίκ 11 OR2 CT ~ NN ^ Sh-CH-CH ®NS0 ccxP i X 1 or R represents a hydrogen atom or a radical classic protector of the amino function, R2 represents a hydrogen atom, a straight or branched chain alkyl radical of 1 to 4 carbon atoms, a cycloalkyl or cycloalkenyl radical of 3 to 6 carbon atoms, a radical of formula

nn ki T Ί A

R4 r4 R4

I 3 »3 V yCÛ0H I

s -C-CH = CH-R, -jC * CR, or -C-COOH, R5 R5 ^ \ R5 x 3 where R represents a hydrogen atom or lower alkyl or carboxyl radical, X represents a halogen atom or hydroxyl or lower alkoxy radical and R and R each independently represent a hydrogen atom or methyl or ethyl radical or alternatively R and R taken together with the carbon atom to which they are united may represent a cycloalkylidene radical from 3 to 5 carbon atoms and Θ -represents a quaternary ammonio radical, and their non-toxic pharmaceutically acceptable salts and physiologically water-soluble esters. A subject of the invention is also the solvates (in particular hydrates) of the compounds of formula I, as well as the tautomeric forms of the compounds of formula I, for example the 2-iminothiazolin-4-yl form of the 2-aminothiazol entity -4-yle.

According to another aspect, the invention relates to a process for the preparation of the compounds of formula I, as well as certain intermediates for their preparation.

As is apparent from the structural formula, the compounds of formula I have the "syn" or "Z" configuration with respect to the alkoxyimino radical. Because the compounds are geometric isomers, a certain amount of the "anti" isomer may be present. The subject of the invention is the compounds of formula I containing at least 90% of the "syn" isomer.

Preferably, the compounds of formula I are the "syn" isomers substantially free of the corresponding "anti" isomers.

In addition to the possible geometric isomers - relative to the alkoxyimino radical, the compounds of formula I (and the intermediates of formulas VIII and IX) also form geometric isomers (cis and trans) relative to the double bond of the propenyl radical. Both the cis ("Z") and trans ("E") isomers of these compounds are specifically within the scope of the invention.

The non-toxic pharmaceutically acceptable salts of the compounds of formula I include the salts formed with mineral acids such as hydrochloric acid, hydrobromic acid, phosphoric acid and sulfuric acid, or with organic acids. carboxylic or sulfonic, such as acetic acid, trifluoroacetic acid, citric acid, / formic acid, maleic acid, oxalic acid, succinic acid, benzoic acid, tarric acid, fumaric acid, mandelic acid, ascorbic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, or with d other acids known and used in the chemistry of penicillins and cephalosporins. The preparation of these acid addition salts is carried out according to the usual techniques.

Examples of physiologically hydrolyzable esters of the compounds of formula I are in particular esters comprising an indanyl, phta-lidyl, methoxymethyl, acetoxymethyl, pivaloyloxy-methyl, glycyloxymethyl, phenylglycyloxymethyl or t 5-methyl-2-oxo-l, 3- radical. dioxolen-4-ylmethyl and other physiologically hydrolyzable esters known and used in the chemistry of penicillins and cephalosporins. These esters are prepared according to the usual techniques.

; The compounds of formula I in which represents a hydrogen atom have a high antibacterial activity against various Gram-positive and Gram-negative bacteria and are useful for the treatment of bacterial infections in animals including humans. The compounds of formula I can be formulated for parenteral administration in a conventional manner using known pharmaceutical carriers and carriers and can be presented in unit doses or in multi-dose containers. The compositions may be in the form of solutions, suspensions or emulsions in aqueous or oily vehicles and may contain dispersants, suspending agents or conventional stabilizers; 51 sic. The compositions may also have the form of a dry powder to be diluted immediately before use, for example with pyrogen-free sterile water.

The compounds of formula I can also be formulated as suppositories using bases for common suppositories such as cocoa butter or other glycerides. If desired, the compounds of the invention can be administered in conjunction with other antibiotics such as penicillins and other cephalosporins.

When presented in unit doses, the compositions preferably contain about 50 to about 1500 mg of the active ingredient of formula I. The dose of a compound of formula I depends on factors such as weight and age of the patient, in addition to the nature and severity of the condition and is V left to the discretion of the doctor. However, the dose for an adult human being is usually about 500 to about 5000 mg per day, depending on the frequency and route of administration. In r'n MT administration _ 1 "7 _ intravenously or intramuscularly to adult humans, at a total dose of about 750 to about 3000 mg per day, divided into several doses, is normally ~ sufficient, but daily doses higher k of some of the compounds may be desirable against Pseudomonas infections.

The quaternary ammonio radical of formula

@ N = Q

can be acyclic and / or cyclic and can contain one or more additional hetero atoms chosen from nitrogen, sulfur and oxygen atoms.

An example of an acyclic quaternary ammonio radical is a radical of formula Θ | 1 7

i3 -N-R

CD.MJ - 18 - 7 8: where R, R and R may be the same or different and may represent, for example, a lower alkyl or substituted lower alkyl radical whose substituents are, for example, a halogen atom, a amino radical with the restriction that it cannot be carried by an oc carbon atom, a hydroxyl radical with the restriction that it cannot be carried by an oc carbon atom f a lower alkoxy radical with the restriction that it does not can be carried by an oc carbon atom, an (lower) alkyl thio radical, an (lower) amino alkyl radical, an amino (lower) dialkoyl radical, a carbamoyl radical, a lower alkyneyl radical, a lower phenylalkyl radical, a phenyl radical or a substituted phenyl radical J (the substituents of which can be, for example, halogen atoms or hydroxyl, amino, (lower) amino, dialkoyl (lower) amino, acyl-amino, lower alkyl, alkyl radicals (lower) thio, lower alxy co o u analogues).

Examples of cyclic quaternary ammonio radicals are monocyclic heterocyclic radicals which are completely unsaturated and bicyclic heterocyclic radicals in which at least one ring containing nitrogen is completely unsaturated. Suitable cyclic quaternary ammonium radicals are in particular those of the formulas 'OC -? OC'. · "CX.

? N_? N- -N

Rp · 1 ^ sXRio Ν> Χ ^ Χο s ^ r10 "ta- · - Λ- ··· - ¥ 3 ^ · · Ί * * £", · -, ri6 9 10 and the like, where R and R, identical or different, can each represent, for example, a hydrogen or halogen atom or amino, lower alkyl, lower alkenyl, (lower) thio, carboxyl, hydroxyl, lower alkoxy, (lower) alkoxy, lower alkyl, haloalkyl lower, * lower hydroxyalkyl, lower aminoalkyl, lower alkyl lower aminoalkyl, dialkoyl- (lower) lower aminoalkyl, lower alkylamino, dialkoyl (lower) amino, lower carboxyalkyl, carboxyalkyl (lower) amino, carboxyalkyl (lower ) thio, carbamoyl, N-alkyl (lower) car-bamoyl, formylamino, acylamino, acyloxy, phenyl, pyridyl, amidino, guanidino and the like. When the structure of the heterocycle allows, R9 and R10, taken together, can represent an alkylene radical of 3 to 5 carbon atoms, for example propylene.

Examples of combined acyclic / cyclic quaternary ammonio radicals are for example those .J- of the formulas> 0 ”/ O“ · X> ‘· ·

Rn / & ^ xf χτ ”y \ -i - R12 ys-T yQr» JÇ®- '· ·% / »-îlcovle V ~ N 13 -1 where R ^ can represent, for example, a radical al- = coyl lower, lower alkoxy lower alkyl, lower hydroxyalkyl with the restriction that the - hydroxyl radical may not be carried by a carbon atom "lower carboxyalkyl, lower aminoalkyl with the restriction that the amino radical may not be borne by a carbon a, lower alkenyl, lower haloalkyl, allyl and the like and R may represent, for example, a hydrogen or halogen atom or a hydroxyl radical, lower alkyl, lower hydroxyalkyl, (lower) alkoxy lower alkyl, haloalkyl lower, lower aminoalkyl, lower alkoxy, lower (thio) alkyl, lower alkenyl, amino, lower (lower) amino, dialkoyl (lower) amino, acylamino, acyloxy, carbamoyl, lower amidinoalkyl, phenyl, pyridyl, amidino, guanidino and the like.

Preferred quaternary ammonio radicals are those of the formulas • fa14> · TJ1 2 3 4 5 R5 * © I Θ θ '· pr · «£ χχ 14 15 2 ~ or R, R and R, identical or different, represent 3 each a lower alkyl, lower alkenyl, lower aminoalkyl radical with the restriction that the amino radical cannot be carried by a carbon atom or lower hydroxyalkyl 5 with the restriction that the hydroxyl radical cannot be carried by an atom of carbon a; 16 K represents a hydrogen atom or radical lower alkyl, lower alkoxy, alkyl (lower) thio, amino, alkyl (lower) amino, dialcoyl (lower) amino, formylamino, alkanoyl (lower) amino , carboxyl, hydroxyl, lower carboxyalkyl, car-c boxyalcoyl (lower) thio, lower hydroxyalkyl, lower haloalkyl, lower aminoalkyl, (lower) alkoxy lower alkyl, carbamoyl or 1 g N-(lower) carbamoyl, or R ~ may represent a divalent alkylene radical of 3 to 5 atoms e carbon; R represents a lower alkyl radical, lower alkoxy- (lower) alkyl, lower haloalkyl, allyl, lower hydroxyalkyl with the restriction that the hydroxyl radical is not carried by the carbon atom at t lower aminoalkyl with J ' the restriction that the amino radical is not carried by the carbon atom a, or lower phenylalkyl; 18 R represents a hydrogen atom or radical lower alkyl, lower alkoxy, lower (lower) alkoxy-lower alkyl, lower (thio) alkyl, amino, lower (amino) amino, lower (lower) amino, carboxyl, hydroxyl, lower carboxyalkyl , lower hydroxyalkyl, lower aminoalkyl, formylamino, alkanoyl (lower) amino, carbamoyl or N-alkyl (lower) carbamoyl; n represents 1, 2 or 3; Z represents CH „or, when n represents 2, Z can ✓ ^ ^ 9 \ 19 / - also represent S, O or N-R“, where R represents a hydrogen atom or lower alkyl radical; and 20 21 3 R and R *, which are identical or different, each represents a hydrogen atom or lower alkyl radical, lower alkoxy, lower (thio) alkyl, amino, lower (amino) amino, lower (dialkyl) amino, carboxyl, hydroxyl, lower hydroxyalkyl, lower aminoalkyl, lower (alkoxy) lower alkyl, lower carboxyalkyl, carboxyalkyl (lower) amino, lower alkanoyl amino, carboxyalkanoyl-C (lower) amino, carbamoyl or N-lower alkyl - carbamoyl .

s Particularly preferred quaternary ammonio radicals are the N-alkyl (lower) pyrrolidinio (and especially N-methylpyrroli-dinio), trialcoyl (lower) ammonio (and especially trimethylammonio), pyridinio, aminopyridinio, formyl-aminopyridinio, carbamoylpyrin radicals. (lower) pyridinio, carboxypyridinio, hydroxyalkyl (lower) pyridinio, N-alkyl (lower) carbamoylpyridi-nio, alkylene (lower) pyridinio, 2-methylthiazolio v- and 2-amino-5-thiazolo- [4,5-c] pyridinio.

In the compounds of formula I, it is particularly preferred that R represents a lower alkyl radical (and especially methyl), cyclo-alkyl of 3 to 5 carbon atoms, 1-carboxycyclo-alco-l-yl of 3 to 5 carbon atoms, allyl, pro-pargyl or lower carboxyalkyl (and especially 2-carboxyprop-2-yl).

The specially preferred compounds of the invention are: 1) 7- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2-methoxy-iminoacetamido] -3- [3- (trimethylammonio ) -l ~ propen-1-yl] -3-cephem-4-carboxylate, 2) 7- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2-methoxy- z iminoacetamido] -3- [3- (1-methylpyrrolidinio) -1-prop pen-1-yl] -3-cephem-4-carboxylate, sf 3) 7- [2- (5-amino-1,2) , 4-thiadiazol-3-yl) -2-methoxy-iminoacetamido] -3- [3-pyridinio-l-propen- yl] -3-ce- pheme-4-carboxylate, 4) 7- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2-methoxy- rn mt _ 9 9 _ iminoacetamido 3-3-L 3- (3-aminopyridinio) -1-propen-3 l-yl ] -3-cephem-4-carboxylate, 5) 7- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2-methoxy-iminoacetamido3-3- [3- (3- formylaminopyridinio) -1- ta propen-1-yl] -3-cephem-4-carboxylate, 6) 7- [2- (5-amino-1,2,4,4-thiadiazol-3-yl) -2-methoxy - s iminoacetamido3-3- [3- (3-aminomethylpyridinio) -1- propen-1-yl3-3-cephem-4-carboxylate, 7) 7- [2- (5-amino-1,2,4-) thiadiazol-3-yl) -2-methoxy-iminoacetamido 3-3-13- (3-carbamoylpyridinio) -1-propen-1-yl 3-3-cephem-4-carboxylate, 8) 7- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2-methoxy-iminoacetamido 3 —3— [3- (4-carbamoylpyridinio) -1-pro-pen-1-yl3-3-cephem-4-carboxylate, 9) 7- [2- (5-amino-1,2,4-thiadiazol -3-yl) -2-methoxy- v "iminoacetamido3-3- [3- (2-methylthiazolio) -l-propen- 1-yl3-3-cephem-4-carboxylate, 10) on 7- [2- ( 5-amino-1,2,4-thiadiazol-3-yl) -2-methoxy-iminoacetamido3-3- [3 - (2-ramino-5-thiazolo [4,5-c 3pyri-dinio) -l-propen -l-yl3-3-cephem ~ 4-carboxylate, 11) 7- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2-methoxy-iminoacetamido3-3- [3- (4-hydroxymethylpyridinio) -l-propen-1-yl3-3-cephem-4-carboxylate, 12) 7- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2- methoxy-iminoacetamido3-3- [3- (3-hydroxymethylpyridinio) -l-propen-1-yl3-3-cephem-4-carboxylate, 13) 7- [2- (5-amino-1,2,4-) thiadiazol-3-yl) -2-methoxy-iminoacetamido 3 —3 - C 3- (4- | N-methylcarbamoylJ.pyridi-nio) -1-propen-1-yl3-3-cephem-4-carboxylate, - 14 ) 7- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2-methoxyiminoacetamido3-3- [3 - (2,3-propylenepyridinio) -1-5 ~ propen-l-yl3-3-cephem-4-carboxylate, 15) 7- [2- (5-amino-1,2,4-thiadiazol-3- yl) -2-ethoxy- 'iminoacetamido3-3- [3- (4-carbamoylpyridinio) -1-pro pen-l-yl 3-3-cephem-4-carboxylate, 16) on 7- [2- (5- amino-1,2,4-thiadiazol-3-yl) -2-cyclo-pentyloxyiminoacetamido] -3- [3- (4-carbamoylpyridi-nio) -l-propen-l-yl] -3-cephem-4- carboxylate, 17) 7- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2-allyloxy- * iminoacetamido] -3- [3- (4-carbamoylpyridinio) -l-pro - pén-l-yl] -3-cephème-4-carboxylate, 5 18) le 7- [2- (5-amino-l, 2,4-thiadiazol-3-yl) -2-propar- gyloxyiminoacétamido] - 3 —C 3— (4-carbamoylpyridinio) -l-propen-1-yl] -3-cephem-4-carboxylate, 19) 7- [2- (5-amino-1,2,4-thiadiazol ~ 3 -yl) -2-methoxy-iminoacetamido] -3- [3- (4-carboxypyridinio) -1-propen-1-yl] -3-cephem-4-carboxylate, 20) on 7- [2- (5- amino-1,2,4-thiadiazol-3-yl) -2-ethoxy-iminoacetamido] -3- [3- (4-carboxypyridinio) -2-propen-l-yl] -3-cephem-4-carboxylate, ύw 21) 7- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2-methoxy- iminoacetamido] -3- [3- (3-carboxymethylpyridinio) -l- 'propen-1-yl] -3-cephem-4-carboxylate and 22) 7- [2- (5-amino-1,2,4-thiadiazol-3-yl) - 2-methoxy-iminoacetamido] -3- [3- (4-carboxymethylthiopyridinio) -l-propen-1-yl] -3-cephem-4-carboxylate.

The numbering system used for the various intermediate reactants and final products is as follows:

[Number _ I Arabic number! Letter J

Roman J L (if appropriate) J [_ (if appropriate) J.

The Roman numeral indicates whether the compound is a final product [I] or an intermediate or other reactant [all other Roman numerals]. Arabic numerals and letters are not used when dealing with the general class (genre) of compounds.

The Arabic numeral denotes the particular meaning 2 2 of the substituent R. If the particular radical R contains a carboxyl radical which is protected by a conventional radical protecting the carboxyl function, the indication "prime" (') is used after the Arabic numeral to indicate this fact. If the carboxyl radical is not protected, "prime" is not used. A “prime” sign is also used with the generic substituent R (namely R) 2 ‘to designate a radical R containing a protected boxyl radical.

The letter affixed to the number of the compound indicates the particular meaning of the quaternary ammonio radical Θ - N == Q.

For convenience, the Arabic numerals and 2 letters assigned to some of the preferred R and quaternary ammonium radicals are detailed below.

2

Arabic numeral R

1 = methyl 2 = ethyl 3 s allyl 4 = propargyl 5 = cyclopentyl Θ

Letter _-nsq_ A = 1-methylpyrrolidinio B = pyridinio C = 2-amino-5-thiazolo [4,5-c] pyridinio D = trimethylammonio E = 3-aminopyridinio F = 3-formylaminopyridinio 5 G 3-carbamoylpyridinio H = 4 -carbamoylpyridinio I = 3-aminomethylpyridinio J - 2-methylthiazolio K = 3-hydroxymethylpyridinio? L = 4-hydroxymethylpyridinio M = 4- (N-methylcarbamoyl) pyridinio. N = 4-carboxypyridinio 0 = 2,3-propylenepyridinio P = 3-carboxymethylpyridinio Q = 4-carboxymethylthiopyridinio

For the evaluation of the compounds of the invention as a first approximation, the minimum inhibitory concentrations (MIC) of the compounds were determined by serial dilution of reason two in Mueller-Hinton agar with respect to 32 strains of test organizations in six groups. The geometric means of the MIC determined in this way are given in Table 1.

* “* I .......... I '' —..... ............

H

H

H f * i— <ί ^ φΐηα) 'ΐη'ίΝ ^ οΐΓΐΦ - ~ t—

W I '-' CM H i— | Γ0 CO CN3 H H H H O CO H

O

H σ> ^ h coi'-Hincovûtoocnoocr'in HI Λ CM HH ΓΟ O CM H Ο I — IH VO rt £ * ^ · m ”• .svk *.”. **. ·. · 'Sv ^ I' - P ooooooooooooo Φ Ü 2 ^ - ΣΛ t * ro to σ co ro co vo HH inin ^ Hnovoi'-cMcofo ^ or ''

U I - I — lOOHOCMOOOOOCSO

(D i- ^ ooooooooooooo Ό ü φ ---—_ 0 CT r-1 M * ^ ^ h ns σνο r- σι σι σι ro tn

M H inCMHinOOtnOOOHOCM

»- + J 1 ^ -00000 H O O O O O H O

Ό) - ^ ιη

ε i w OOOOOOOOOOOOO

H O O

'0) ^

O DI

- <- ω <ü J G £ 1 WS h oinooo moomo tn <Q) I p- 'r'-ro << i <cocM-0'in',! i, '3 <ro- * i, vDro

Eh 'tn **. "** ^ ** ·" *. ".". ".

O + ^ OOOOO HOOOOOH O

S O

Mm · '(0 H conotnoHoomooot ^

I ^ CM H CM CO H V £> H CM H CM CM CO H

--- in - ~ - + ~ ooooooooooooo

O

s «/

1 <D

fO Ή r-J

b A £ H H "tf H ^ 2 C G O \ \ \ \ 0

CJI 0 O CO i— | t ^ · H r— | H

• H H Ό H II II II II II

m-p co nnwnwnnwwmwww G <0 -H \ \ \\ OHHwmwwh

O

M

'0)

to ccmmuQQWfc.uxH'-D

OHHHHHHHHHHHHH

a c i i i i i i i i i i i i i

E HHHHHHHHHHHHH

O

U__

H

H

H

1 Λ mvomr ^ r- cd o cm. - r- "> v ^

P I rOCMCMlOM1 — l'â'O — ICM'tf'Çf'T

ü H —1 r-l -1 ·

H

~ H

H i * - oior-o-iLOiocr <cMO - "c o E ^ in cm —ι —i oo —i —i m ld 10 vo —i ro cm \ I —- - O1 U oooooooooocmoo 3 w

M

Σ £ HH <ΦΟΟιχ> ΟΟΓ ~ t "· * 3 <(J I - M’CCOLDCOLO-lLOO-lLOCO'tf

- LO Ο Ο —I O O O H -1 —1 -I O O

03 I - - .........

Ό Ü oocoooooooooo „OJ___ a> g, -P θ’

> rJ -fl fO LO

; —PH û) (T. Mroo'iifl’it'ifl ro σ>

^ 3 4- »I · - · CM CM CM -1 CM -1 -! LO LD O - I O

___ "03 r— LO OOOOOOOOOOCMOO

E I - - ~ ~ -

-10 O OOOOOOOOOOOOO

Ό) w t * · D tT> __ <M 0) j C £ P3CH O — IO LOO O LD O cm

C (U | —- OOvDr-'LDOM'-l-l ^ M '^ LDCD

E-c> λ - LO ~

ο + --- OOOHOOCMOOOO-IO

Σ O

m H lOldlo t ^ o ovoro | - * rOCMrOCM — ICMCM ^ iCMCM — lœr- —- LO '' 'k ‘' ......

f W OOOHOO — 1—100000

U

I O

CÖ H

U £ C h 3 C 3 O ^ .JJ.® -o-h ωκκ ιιωωωΝωΜωωκι

μ-l + J CO N

“C ni -h ^ 0 H H w

U

/ tfl

'<D

oo ^ jszoEzzxxxoïa λ j-t - 1 - 1 - 1 - 1 - 1 CM CM CM -Ο · Μ * LO - 1 - i

3 * I I I I I! I I I I I I I

Q HHHHHHHHMHHMH

sà_L__ (G +) - Ia: S. aureus sensitive to penicillin ^ (5 strains) (G +) - Ib: S. aureus resistant to penicillin (5 strains) * (G-) -la: E_. coli (2 strains), _K1. pneumoniae (1 strain) and Pr. mirabilis (2 strains) sensitive to cephalothin (G -) - Ib: J2_. coli (3 strains) and Kl. pneumoniae (2 strains) resistant to cephalothin (G -) - II: M. morqanii (1 strain), Ent. cloacae (2 strains) and Ser. marcescens (2 strains) (G -) - III: JPs. aeruginosa (7 strains)

Table 2 below indicates the protective dose 50 (DP5Q) in mice for a certain number of the compounds of formula I with respect to selected microorganisms. Table 3 shows the blood levels of various compounds of formula I after intramuscular administration of these experimental compounds to mice in a dose of 20 mg / kg.

TABLE 2 DP50 (mg / kg)

Compound S.aureus E. coli P. aeruginosa n ° Smith Juhl A9843A_ I-1B 0.44 0.028 7.7

I-1B 0.65 0.072 NT

I-1C 0.22 0.013 NT

I-lG 0.96 0.021 5.92 I-1H 0.39 0.015 3.9

I-1J 0.35 0.029 NT

I-1K 0.53 NT NT

I-1M 0.96 NT NT

> I-1N 2.0 NT NT

1-10 0.26 0.17 NT

I-2N 5.0 NT NT

NT = not tested r'Tt MT __ TABLE 3

; Compound n ° Cmax Tl / 2 CUA

_ (^ ug / ml) (min) (, ug h / ml) I-1B 17 21 11 ln I-1C 21 32 18 I-1D 20 19 11 I-1H 23 16 14 I-1J 19 16 9.7 I-1K 24 14 14 I-1M 20 23 14 I-1N 24 19 18 1-10 28 32 17 I-2N 22 20 12 I-3H 19 47 25. I-4H 27 22 16 I-5H 22 32 18 * According to another aspect, the invention relates to h · a process for preparing the compounds of formula I.

The preferred procedures are illustrated below in reaction schemes la, 1b and le, while a procedure constituting a variant is illustrated in reaction scheme 2. The abbreviation "Ph" represents the phenyl radical. Thus, the radical -CHiPh ^ is the benzhydryl radical, which is a preferred radical protecting the carboxyl function. When R comprises a carboxyl radical, it is desirable to protect the carboxyl radical using a conventional radical protecting the carboxyl function such as the t-butyl radical. Y represents a chloro, bromo or iodo radical.

Reaction diagram la "ΐΛ N \ j ^ lvCH2Cl; COOCH (Ph) 2

N-r-C-COOH

// \ Vs 111 h2n “S: 7 \ 2

2 XS ^ OR

y N —-r C-CONH 1 f / (Tv

HjN DR 0 'X | CH2C1 COOCE (Ph) 2

Nal or Kl \ 1 s \ N-r-C-CONH --.- S N \ N. " COOCH (Ph). P (Ph) 3 V * P (Ph) 3 "/ N-r-C-CONH - S S N _ £ \

// Vv il * VI

H / S / \ r2 ® H2N * 0R 0 'J CH2P (Ph) 3 COOCH (Ph) 2 base

V

N-r-C-CONH - <X

// \\ | Ί 1 ™ V0R2 COOCH (Ph) 2

CICHjCHO

V

N-T — C-CONH-- ./7^. TVL-v. ”2 COOCH {Phjj

Nal or Kl Y

. i "

N ^ j: CONH - ^ S X

· /> C ^ Y ^ CB-CBC ^ X

IX COOCH (Ph) 2 \ ✓ *!

IN

V 0 = N

(secondary amine) vt

V

(amine jtc — C0 "tO.

X * = / - γ COOCH (Ph) 2 ^ R ’

X

R ** Φ / TvT ^ TÇl t / H <fxs ^ nor1 θ 'N ^ Xh-chch2-n = o XII COOCH (Ph) 2 release k'

V

/ - \ ~ n — coNs —— rs "î 'N * 2 <y V' ^^ h-CilCR ^ hl = XÎ coo®

The reaction scheme illustrates it two different ways of going from compound IX to compound XII.

The direct route through the tertiary amine (XI) is applicable to the preparation of all the compounds of formula I. The indirect route through the compound X involves as reactant a secondary amine which is quaternized in the i "next step. secondary amine RR'NH can be acyclic (such as dimethylamine) or cyclic (such as pyrrolidine) and this indirect route is therefore suitable for preparing compounds of formula I in which the quaternary ammonio radical is acyclic or acyclic / cyclic "mixed ". This indirect route is not suitable for the preparation of compounds of formula I in which the quaternary nitrogen is part of a completely unsaturated heterocycle (such as pyridinio, thiazolio, 2-amino-5-thia-zolo [4,5-c ] pyridinio etc.).

Reaction diagram 1b * Il, £> *

V

d ^ -Ny ^ cH2ci COOCH (Ph), Ψ · £

Nal or Kl \ V \ Ψ \ 0 · “'νγΥ5Ί COOCH (Ph) 2 PlPfl, 3 P (Ph) 3 /

f XV

cT N'Sl ^ st: H2P (Ph) 3 COOCH {Ph) 2 base y ^ "" ΓίΊ CT "* VJ ^ CH" P (Ph) 3 COOCH (Ph> 2

- CICHjCHO

V

P N Xr ^ CH-CHCHjCl COOCH {Ph) 2 Reagent T of Girard or Φ HCl ma hv ^ -ch-chch2ci COOCH (Ph) j • S »Ά7Κ *

V

—.......... "I" J

VIII as in the diagram

Reaction scheme 1b is a variant of reaction scheme la in that the 7-amino radical of the starting compound (II) is protected in the form of a Schiff base during most of the reaction stages and that the acidic side chain at 7 is added.

later during the synthesis. The general operating mode is also the same.

Ô-pÇx reaction scheme

y i 'CH * CH-CH2C1 XVII

COOCH (Ph) 2

Nal or Kl

0 NCH-CH-CH2I XIX

COOCH (Ph), λ

HN

V

* (secondary amine) // ^ CH-CHCH2-N '(tertiary amine XX 0 I) COOCH (Ph) 2 R "ï Ο ^ Τί *' '! ϊΘ XXX t Ν" γ ^ Η'εΗ £: Η2

COOCH (Ph) J

V

J ~ \ A ©

, Γ O T CH * CHCH, -N = Q

XXII 1 © 2 coo ^ ^ V &

N-acylation by means (äe III

N-π— c-CORH \ ΓΊΓ s \] V ©

ο T CH «CHCH, -N == Q

COO ©

Another variation of reaction scheme 1b is the reaction scheme 1c. In reaction schemes 1a and 1b, the quaternization of the side chain at 3 is the last stage, but in reaction scheme 1a, the last stage is the acylation of the 7-amino radical. The relation between the reaction diagrams la, 1b and the spring of the following table.

5 / “Vx => / γτ COOCH (Ph), \ 1 2 \ lb o ~ jxx IV COOCH (Ph), XIIIJ 0 I ^ H2C1 4 COOCH (Ph) 2 '' V / la \ / ^> 'le

ψ V

^ CrÇL ^, * = r- o

COOCH (Ph) J 0 I

νπΐ XVIII COOCH (Ri) 2

Quaternization. .Quaternization Unlocking lc Unlocking 'i' NK J7-N-Acylation e

'· Θ' I

coo ©

XXII

In the reaction schemes la, 1b and le, i the benzhydryl radical is indicated as being the preferred radical for the protection of the carboxyl function. It is obvious to the specialist that other well-known radicals which protect the carboxyl function are suitable. Acylation acid III can be used in the form of a derivative such as its halide, an activated ester, a mixed anhydride etc., which are all known compounds. The Applicant prefers to use it in the form of acid chloride.

In acylation acid III, the amino radical can also be protected by any of the current radicals which protect the amino function, for example N-trityl, N-formyl etc. The base used to convert phosphonium iodide (VI or XV) into phos-phorylide (VII or XVI) can be NaOH, ^ 200 ^, resin IRA-410 (0H ~), resin IRA (C0j-) , etc. or a mixture of such bases. The chloroacetaldehyde used to convert phosphorylide VII to 3-chloropropenyl-3-cephem VIII (or to convert compound XVI to compound XVII) may be the 40-50% aqueous solution which is marketed, a distilled solution (for example at 70%) or anhydrous aldehyde.

The Applicant has observed that compound VIII prepared from compound VII (scheme la) typically has a Z: E ratio of approximately 2: 1 at the double bond of the propenyl radical.

Compound VIII prepared from compound XVIII (Scheme 1b), on the other hand, is typically almost exclusively the Z isomer. The difference may result not from the synthetic route, but from the conditions; applied for the Wittig reaction (VII to VIII

or XVI to XVII). The Applicant has also observed that the use of an appropriate silylating reactant such as N, 0-bis (trimethylsilylJacetamide for the Wittig reaction (VII to VIII: in scheme la and XVI to XVII in scheme 1b) improves the yields and the purity of VIII and XVII. The reaction is preferably carried out using 2 to 5 equivalents of the silylating reactant. When the chloropropenyl cephem (VIII) reacts with Nal in acetone * - to give iodopropenyl cephem (IX) , the double bond of the propenyl radical isomerizes from Z to E during iodization. A brief reaction retains the configuration of the starting compound VIII to a large extent "while a long reaction leads mainly to the E isomer of the compound IX However, an exaggerated reaction time at a high temperature leads to a compound IX of lower purity The Applicant considers that 10 minutes at 25 ° C. and 2 hours at 5 ° C. give the compound IX pure with good yield. The Applicant has found in appl iquing the reaction scheme that when iodizing compound XIV with NaI, it obtains a purer compound if the acetone solution is diluted with CCl ^ when iodization is substantially completed and if the isomerization which is part of the reaction is carried out in the acetone-CCI ^ mixture. When the iodination of chloropropenyl cephem (XVII) to iodopropenyl cephem (XIX) is carried out with K1 in DMF, the isomerization of the double bond from Z to E progresses at the same rate as iodization. The entire reaction is completed within 45 minutes at room temperature to give pure compound XIX without dilution with CCl ^ during the reaction.

Compound XII is normally released without purification and the final product (I) is purified by column chromatography with "phase inversion" in a glass column containing the coating removed from a Waters' Associates cartridge.

PrepPAK-500 / C18.

Reaction scheme 2 rvr ~ r ('\ rW ^ S ^ \ r2 <r V ^ ch «ch-ch2i 30: 111 COOCH (Ph) 2 ψ f. — jr-s—“ τΓ Ί 1 JL Jn \ 2 7 - V 30:17

R -œr ^ S '^ X0R2 0X ^ Y ^ CH-CH-C ^ I

COOCH (Ph) 2 Ψ te J.

T, Π “Tl ^ J® îA /’ V 0 ^ -KvfA ”.c„ -OTf ”.Q m COOCH (Ph) 2 Reduction Ψ N - [- C-CONH — j β

R1-HN ^ XS ^ \ η2 Γ NNiÿ ^ CH-CH-CHfN = Q XXVI

COOCH (Ph) j release, Ψ jnrr_ “TX, v · 1

^ OR2 NnS ^ C "* CH2N = Q

cocß

The reaction scheme 2 sketched above is similar to the reaction scheme la, except that the 1 compound XXIII (equivalent to compound IX of the reaction scheme la) is converted to its S-oxide before; quaternization. Compound XXV is then reduced and reaction scheme 2 then continues as reaction scheme la. In reaction scheme 2, v 11 is preferable to protect the amino radical of the side chain in position 7 using a known radical which protects the amino function, such as the trityl radical.

The acylation acids of formula III are known compounds or are easily obtained by known methods. European patent 7470 published on October 12, 1983 (application published on February 6, 1980) - gives an example of the preparation of compounds of * 2 formula III where R represents a methyl, ethyl, propyl or isopropyl radical. The aforementioned EUA patent 4,390,534 gives as an example the preparation of numerous compounds of formula III where R represents, for example, a cyclopentyl, 2-cyclopenten-lyl, allyl, 2-propynyl, it-butyloxycarbonyl-1-methylethyl radical, 1 -t-butyloxycarbonyl-1-cyclopentyl, 1-ethoxycarbonyl-1-methylethyl, t-butyloxycarbonylmethyl, 1-t-butyloxy-carbonyl-2-methylpropyl, trityl etc.

Compound II of the invention (7-amino-3-chloromethyl-3-cephem-4-carboxylate) starting material for reaction schemes la, 1b and le is a known compound.

The tertiary amines of formula XI (and the secondary amines RR'NH) used to prepare the quaternary ammonio derivatives of the invention are known compounds or easily obtained by known methods. Many of these amines are commercially available.

The invention also relates to a process CD.MJ - 42 - for the preparation of compounds of formula. 1; î ^ HN ^ s' ^ OR2 <y \ ^ \: h-ch-ch2-n = .o

cocP

V · where R “represents a hydrogen atom or a conventional radical protecting the amino function, R represents a hydrogen atom, a straight or branched chain alkyl radical of 1 to 4 carbon atoms, a cycloalkyl or cycloalkenyl radical from 3 to 6 carbon atoms, a radical of formula 4 4 4

R R rooH R

I 3 I 3 \> C00H I

-C-CH = CH-R -C-C == C-R, V OR -C-COOH, R5 ^ <Ç> it5

s X

3 where R represents a hydrogen atom or lower alkyl or carboxyl radical, X represents a halogen atom or hydroxyl or lower alkoxy radical and R and R each independently represent a hydrogen atom or methyl or ethyl radical, or alternatively R * and 5 R, taken together with the carbon atom to which they are united, can represent a cycloalkyl-lidene radical of 3 to 5 carbon atoms, and

@ N == Q

represents a quaternary ammonio radical, and non-toxic pharmaceutically acceptable salts and physiologically hydrolysable esters of these; compounds which includes the reaction of a compound of formula (Ο): ® ν —π — S — coNH — ι — S ε Ν

//> 'N I

b2hm ^ s ^ V · fr ^ '^ K

Ο CH = CHCH22 COOB1 21 2 where R has the same meaning as R or represents a radical of formula C ° ob1 b4 Λ 1 i

Y

x R

ht - v 4 5, 1 or X, R and R are as defined above, B ~ represents a classic radical protecting the carboxyl function, B represents a hydrogen atom or classic radical protecting the function amino, Z represents a chloro, bromo or iodo radical and m represents zero or one with a tertiary amine Q ^ = N (or successively with a secondary amine RR'NH and a compound of formula R "Z) and in the case where m represents 1, the reduction of the sulfoxide in a conventional manner, then the elimination of all blocking radicals in a conventional manner.

A subject of the invention is also a process for the preparation of compounds of formula ΙΠΓΓ - ‘" "ίΥ’Ί r ^ ki ^ s' or2 y NN ^ \: h" ch-ch2®nsq

cocP

h where R ~ represents a hydrogen atom or a conventional radical protecting the amino function, R represents a hydrogen atom, a straight or branched chain alkyl radical of 1 to 4 carbon atoms, a cycloalkyl or cycloalkenyl radical of 3 to 6 carbon atoms or a radical of formula 4 4 4

R R rnop R

I 3 I 3 \ ^ COOH I

-C-CH = CH-R, -CC = CR, V or -C-COOH, 15 * 5 <Ç> ^ x where R ^ represents a hydrogen atom or lower alkyl or carboxyl radical, X represents a d atom halogen or hydroxyl or lower alkoxy radical 4 5 and R and R each independently represent a hydrogen atom or methyl or ethyl radical, or 4 5 well R and R, taken together with the carbon atom to which they are united, may represent a cycloalkylene radical of 3 to 5 carbon atoms and

®N = Q

represents a quaternary ammonio radical, and non-toxic pharmaceutically acceptable salts and physiologically hydrolysable esters of these compounds ί which comprises the acylation of a compound of formula / -VÄ ®

0 I CH = CHCH2-N = Q

COO © XXII

with an acid of formula

N-rr-C — COOH

2 \ 2B ^ HN OR ^ w '= ·

21 or with an acylating derivative of this acid, where R

is identical to R or represents a radical of formula 1 4

COOB R

X OR -C “COOB1 Y * 5 x 4 5 i where X, R and R are as defined above, B“ represents a conventional protective radical of the carboxyl function and B represents a hydrogen atom or conventional protective radical of the amino function.

The reactions are carried out in a non-aqueous organic solvent such as dimethyl sulfoxide, hexamethylphosphoramide, methylene chloride, chloroform, ethyl ether, hexane, ethyl acetate, tetrahydrofuran, acetonitrile etc.

or mixtures of these solvents. The reactions are advantageously carried out at a temperature of from about -10 ° C to about + 50 ° C and preferably at room temperature M T _ A Λ _ ture. For quaternization, it is necessary to use. ser at least one mole of the tertiary amine per mole of compound IX, XIX, XXIII or XXIV; the Applicant normally prefers to use an excess of about 25% to 100% of the tertiary amine.

Protective radicals of the carboxyl function which are suitable as radicals B “in the above reactions are well known to the specialist and are in particular aralkyl radicals such as ben-zyle, p-methoxybenzyl, p-nitrobenzyl and diphenyl-methyl (benzhydryl ); alkyl radicals such as t-butyl; haloalkyl radicals such as 2,2,2-trichloroethyl, in addition to other protective radicals of the carboxyl function described in the literature, for example in English patent 1,399,086. The Applicant prefers to use protective radicals of the carboxyl function which are easily removed by treatment with an acid. Protective radicals of the carboxyl function which are particularly preferred are the benzhydryl and t-butyl radicals.

Amino protecting radicals suitable as radicals B are also well known and are in particular the trityl radical and acyl radicals such as chloroacetyl, formyl and trichloroethoxycarbonyl. Protective radicals of the amino function which are easily removed by treatment with an acid, for example the trityl radical, are preferred.

ü When the cephalosporin nucleus is used in the form of the 1-oxide (m = 1), this 1-oxide is & prepared according to known procedures such as oxidation using m-chloroperbenzoxque acid, k d peracetic acid, sodium tungstate etc.

The 1-oxide can be further reduced

r'rs m T λ H

known, for example the reduction of the corresponding alkoxysul-ÿ fonium salt with the iodide ion in an aqueous medium. The alkoxysulfonium salt can itself be obtained by reaction of the 1-oxide with, for example, acetyl chloride.

According to another aspect, the invention relates to the new intermediates of formula ΓΤΤ ”” Τ ~ 0

COOH

XXVIII

* 'where Z represents a chloro, bromo or iodo radical, 2 R represents a hydrogen atom, a straight or branched chain alkyl radical of 1 to 4 carbon atoms, a cycloalkyl or cycloalkene-alkyl radical of 3 to 6 atoms of carbon or a radical of formula 4 4 4

R R v COOH R

»3 1 3 V I

-C-CH = CH-R, -C-C = C-R, / \ or -C-COOH, i5 O i5

X

3 where R represents a hydrogen atom or lower alkyl or carboxyl radical, X represents a halogen atom or hydroxyl or lower alkoxy radical and R and R each independently represent a hydrogen atom or methyl or ethyl radical, 4 5 £ or R and R, taken together with the carbon atom to which they are united, can represent a cycloalkylidene radical of 3 to 5 carbon atoms, in addition to their salts and esters.

The subject of the invention is also the compounds of formula XXVIII in which the amino and / or carboxyl radicals are protected by conventional radicals which protect the amino function or the carboxyl function.

According to another aspect, the invention relates to the new intermediates of formula R23 R24 — fi ch * n—— * 2 5 ο ch-chch2 2

COOR22 XXIX

22 where R represents a hydrogen atom or a conventional u * radical protecting the carboxyl function and 23 24 23 R, R and R, identical or different, each represent a hydrogen atom or hydroxyl, lower alkyl or lower alkoxy radical ; in addition to their salts, solvates, hydrates or esters.

According to another aspect, the invention relates to the new intermediates of formula v — r-y ^ 1 Θ

coo ° XXII

. Θ where -N ~ Q represents a quaternary ammonio radical, in addition to their salts, esters, solvates or hydrates.

For the purposes of the invention, the terms acylamino and acyloxy denote an acylated amino or acylated hydroxy radical whose acyl entity is a lower alkanoyl radical (for example formyl, acetyl, propionyl, butyryl, isobutyryl, isovaleryl, etc.) .), aroyl (for example benzoyl, etc.), alkane- (lower) sulfonyl (for example mesyl, ethanesul-fonyl, etc.) or arylsulfonyl (for example benzene-tallow onyl, tosyle, etc.).

For the purposes of the invention, by the expressions "lower alkyl", "lower alkoxy", "alkyl (lower) thio" and similar expressions is meant an alkyl, alkoxy or alkylthio (or an analogous radical) in straight or branched chain having 1 to 6 carbon atoms inclusive. Likewise, by lower alkenyl or lower alkynyl is meant "an alkenyl or alkynyl radical of 2 to 6 carbon atoms.

l * EXAMPLE 1 - h — Π — C0NHyYSNi 4

\) CH3 H-CH-CH ^ J ^ I

CH3 I-1A * Z / E "1/1 7- [2- (5-Amino-1.2.4-thiadiazol-3-yl) -2-methoxyimino-acetamido] -3-C 3- (1-methvlpvrrolidinio) -1-propen-l-yl] - 3-cephem-4-carboxylate (I-lA)

A solution of 1-methylpyrrolidine (36 mg, 0.42 milli- = mol) in ethyl acetate (1 ml) is added all at once with stirring to a solution of 7- [2- (5- diphenylmethyl amino-1,2,4-thiadiazol-3-yl) -2-me-thoxyiminoacetamido] -3- (3-iodo-l-propen-l-yl) -3-ce-pheme-4-carboxylate ( IX — 1) (Z / E = 2/1, 150 mg, 0.21 millimole) in ethyl acetate * (2 ml). The mixture is stirred for 15 minutes and diluted with isopropyl ether (10 ml) to form a precipitate which is collected by filtration. A mixture of the solid (130 mg), formic acid (1 ml) and concentrated HCl (0.1 ml) is stirred at room temperature. After 1 hour, the reaction mixture is concentrated under reduced pressure, diluted with water (20 ml) and filtered. The aqueous solution is passed through a phase inversion column (packed with a PrepPAK-500 / C.Q cartridge, lo 100 ml) which is eluted with water and 10% methanol.

The desired fractions are collected and concentrated in vacuo to a small volume, then lyophilized to obtain 13 mg (12%) of the compound announced in (I-1A) (Z / E = l / 1), melting at ^ 280 ° C (decomposition).

IR: Vmax S "". 1760, 1660, 1610.

OV * “λ tamPon with phosphate (pw 7] w max 'nm (E,) 236 (372), 288 (322). 1 cm NMR: 6ppm 2.31 (4H, ^ m, ^ 3fl2 (3H> ^ N_CH3) f (5H, m, 2-H &), 3.79 (1H ^ 2-H), 4.1 (2H, l-üKS 9? 2! 0 '(3H' S '° CH3}' 5'36 ( lH 'd' J = 4'5 '3 ch' cis) 3H 'm' 7 H & 3 ~ CH = aCH), 6.66 (1 / 2H, d, J = 10, 3-CH cis), 7 0 (1 / 2H (df j ~~,,.

EXAMPLE 2 _ '3 “CH tr ^ ns).

ΓΤΙ— “\ '\ * Q - °° Η3 Vs ^ IvCH = CH-CH2-N // Λ

locß W

I-1B

* E

- ζ “j

CD. MJ

7— [2 - (5-Amino-l. 2.4-thiadiazol-3-vl) -2-methoxvimino-; acetamido] -3- [3-pvridinio-l-propen-l-yl] -3-cephem- 4-carboxvlate (I-1B)

A mixture of 7- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2-methoxyiminoacetamido] -3- (3-iodo-1-propen) is stirred for 1 hour at room temperature. -l-- yl) -3-diphenylmethyl (IX-1) -3-cephem-4-carboxylate (E, 716 mg, 1 millimole) and pyridine (158 mg, 2 millimoles) in dimethyl sulfoxide (DMSO) (1 ml) . Ethyl acetate (20 ml) is added to the mixture to precipitate a solid (620 mg), which is added to formic acid (6 ml) containing sodium bisulfite (60 mg). The mixture is stirred for 30 minutes at 40 ° C and concentrated to dryness. The residue is dissolved in water (40 ml) and some insolubles are separated. The aqueous solution is applied to a phase inversion column (PrepPAK-500 / Clg, 100 ml) which is eluted with water (300 ml) and 5% aqueous methanol (800 ml), monitoring the eluate in UV (254 nm) and by HPLC. The fractions (5% aqueous methanol) containing the desired product are combined, concentrated to small volume and lyophilized to obtain 40 mg (8%) of the title compound (I-1B), melting at> 200eC ( decomposition).

IfTSy * 1 IR: ·>? cm “3350, 1760, 1660, 1600.

max lit λ phosphate buffer <pH 7) nm 1%, 24g (352) max 1 cm 258 (366), 267 (279), 290 (469).

NMR: δ D20 + DMS0 "d6 3.74 (2H, S 1, 2-H), 4.20 (3H, s, OCH3), 5.92 (1H, d, J = 4.5, 7-H ), 6.15 (1H, m, 3-CH = CH), 7.04 (1H, d, J = 16, 3-CH trans), 8.2 (2H, m, Py-H3 5), 8 , 62 (1H, m, Py-H4), 8.97 (2H, m, Py-H2 g).

EXAMPLE 3 -

N-d-j — C-CONH — d-f S N

η2ν ^ 8 / Μ ^ och3 d? N ch ^ ch-ch2% ^ ~~ ^ I-XB * Z / E = 4/1 7- [2- (5-Amino-1.2.4-thiadiazol-3-yl) -2-methoxyimino-acetamido] - 3- [3-pvridinio-1-propen-1-yl3-3-cephem-4-carboxylate (I-1B).

Add 7- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2-methoxyiminoacétamido3-3- (3-chloro-l-propen-1-yl) -3-cephem- Diphenylmethyl 4-carboxylate (VIII-1) (Z, 937 mg, 1.5 millimole), which is the chloropropenyl compound, to a stirred solution of pyridine (237 mg, 3 millimoles) in DMSO (3 ml) containing Nal (11 mg, 0.075 millimole). The mixture is allowed to stand at room temperature overnight in the dark. The mixture is diluted with ethyl acetate (30 ml) to separate a precipitate which is then collected by filtration, which is washed with ethyl acetate (10 ml) and dried for collect 350 mg of the blocked product. The precipitate is reacted for 30 minutes at 40 ° C with formic acid (3.4 ml) containing sodium bisulfite (34 mg). After elimination of the formic acid, the residue is purified by chromatography on a phase inversion column (filling with PrepPAK-500 / C ^ g cartridge, 100 ml) which is eluted with 5% aqueous methanol. On the basis of the analysis by HPLC, the fractions containing the desired product are combined, they are evaporated under reduced pressure and they are lyophilized to collect 41 mg (5.5%) of the title compound (I-1B) (Z / E = 4 / l). PF. > 200 ° C (decomposition).

IR: VKBr cm “1 3300, 1760, 1660, 1600.

- max 'UV: phosphate buffer <pü 7) ω (E1 *, 237 (386) max 1cm' J 250 (377), 258 (369), 265 (347), 280 (311).

NMR: <5 ° 2 ° 3.45 and 3.76 (each 1H, d, J = 16, 2-H), * 4.18 (3H, s, OCH3), 5.34 (3H, m, CH = CH ~ CH2 and 6-H), 5.92 (1H, d, J = 4.5, 7-H), 6.58 (4 / 5H, d, J = f11, 3-CH cis), 7, 03 (1 / 5H, d, J = 16, 3-CH trans), 8.12 (2H, m, Py-H3 5), 8.56 (1H, m, Py-H4), 8.82 (2H , m, Py-H2 g). EXAMPLE 4 - s nh2

I-1C * E

hr 7- [2- (5-Amino-1.2. 4-thiadiazol-3-yl) -2-methoxyimino-acetamido] -3- [3- (2-amino-5-thiazolo [4,5-c ] pyridinio) -1-propen-1-yl] -3-cephem-4-carboxylate (I-1C)

A stirred solution of 7-C2- (5-amino- 1,2,4-thiadiazol-3-yl) -2 ~ methoxyiminoacetamido] -3- (3-iodo-l-propen) is kept for 1 hour at room temperature. -l-yl) -3-cephem-4-carboxylate of diphe-nylmethyl (IX-1) (isomer E, 714 mg, 1 millimole) and of 2-aminothiazolo [4, 5-cjpyridine [prepared according to T, Takahashi and al. . Pharm. Bull (Japan), 2_, 34: (1954)] in dry DMSO (1 ml). Ethyl acetate (20 ml) is added to the reaction mixture to obtain a yellow powder (710 mg). Formic acid (7 ml) and sodium bisulfite (70 mg) are added to the powder (700 mg), then the mixture is stirred for 30 minutes at 40-45 ° C. After evaporation, we sort

r * r \ MT E A

ture the residue in water (40 ml). The insolubles are separated by filtration and the filtrate is chromatographed on a phase inversion column (PrepPAK-500 / C18, 100 ml) which is eluted with water and 10% methanol. The fractions containing the desired product are combined and the solvent is removed under reduced pressure. By lyophilization, the desired product (I-1C) is obtained in the form of a colorless amorphous powder which is the E isomer. Production 110 mg (19%). Mp.> 200 ° C (decomposition).

IR: VKBr cm "1 3300, 1760, 1660, 1630, 1600.

max 'UV; Phosphate buffer (PH 7) ^ (E1%, 245 (499) max 1 cm' 285 (286).

NMR: 6B ^ 0 "d6 + D20 3.86 (3H, s, OCH,), 4.98 (1H, d, _ J = 4.5, 6-H), 5.2 (2H, m, CH = CH-CH2), 5.57 (1H, m, 3-CH = CH), 5.96 (1H, m, 7-H), 7.16 (1H, d, J = 16, 3-CH trans ), 8.36 and 8.45 (each 1H, d, J = 7, Py-H), 8.92 (1H, S, Py-H).

EXAMPLE 5 contA * ® 'OCHj & VJ ^ CH-CH-CH2-N (CH3) 3 coo® I-1D * 2 / E - 1/1 7- [2- (5-Amino-1.2.4-thiadiazol- 3-vl) -2-methoxyimino-acetamido] -3- (3-trimethvlammonio-l-propen-l-yl) -3-ce-phème-4-carboxylate (I-1D)

A 0.1 M solution of trimethylamine in ether (13.6 ml) is added all at once to a solution of 7- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2-methoxyiminoacetamido] -3- (3-iodo-l-propen-l-yl) -3- CD.MJ - 55 - diphenylmethyl cephem-4-carboxylate (IX-1) - (Z / E = 2 / 1.490 mg, 0.68 millimole) in ethyl acetate (14 ml). The mixture is stirred for 10 minutes and evaporated to dryness, then the residue is triturated in ether (20 ml). The resulting solid (490 mg) is added to trifluoro- = acetic acid (0.2 ml) containing one drop of anisole.

After 1.5 hours of stirring, the mixture is evaporated to dryness under reduced pressure and the residual oil is triturated in ether (20 ml). The resulting precipitate is collected by filtration and dissolved in water (20 ml). The insolubles are separated by filtration and the aqueous solution is applied to a phase C inversion column. G (filling with the PrepPAK-500 / C ^ g cartridge, Waters 30 ml) which is eluted - with water . The fractions containing the desired com posed are combined and concentrated to a small volume, then they are lyophilized to obtain 30 mg (9.2%) of the title compound (X-1D) (Z / E = 1/1) in the form of a colorless amorphous powder melting at> 150 ° C (decomposition).

IR cm * 3300, 1770, 1670, 1605.

max uv. λ phosphate buffer (pH 7) nm (E1X, 236 (389) max I cm 287 (343).

NMR: <5 D2 ° 3.45 and 3.7 (1H, d ^ J = 16, 2-H), 3.81 (1H, s, ppm (+) 2-H), 4.1 (2H, d, J = 8, -CH ^ ïT), 4.21 (3H, s, OCH3), 5.39 (1H, d, J = 4.5, 6-H), 5.95 (2H, m, 3-CH = CH and 7-H), 6.61 (1 / 2H, d, J = ll, 3-CH cis), 7.05 (1 / 2H, d, J = 16,: 3-CH trans ).

EXAMPLE 6 - N-r-C — CONH —- S S \ VX. J J- ‘,% fÇ COO0 '-'

I-1E * E

7 — C 2— (5-Amino-1.2.4-thiadiazol-3-vl) -2-methoxyimino-acetamido] —3— [3- (3-aminopyridinio) -1-propen-1-yl3-3-cephem -4-carboxylate (I-1E)

Add 7- [2- (5-amino-1,2,4-thiadiazol-3-yl) —2 — methoxyiminoacetamido] —3— (3 — iodo — 1-propen-l-yl) —3 — cephemus Diphenylmethyl (IX-1) carboxylate (E, 716 mg, 1 millimole) to a stirred solution of 3-aminopyridine (188 mg, 2 millimoles) in DMSO (1 ml). The mixture is stirred for 1 hour and diluted with ethyl acetate (20 ml). The resulting precipitate is collected by filtration which is washed with ethyl acetate and dried to collect 520 mg of a yellow powder. A mixture of the powder (500 mg), formic acid (5 ml) and sodium bisulfite (50 mg) is stirred for 30 minutes at 40 ° C. The mixture is concentrated in vacuo, dissolved in water (40 ml) and the insolubles are separated by filtration. The aqueous solution is chromatographed on a phase inversion column (packed with a PrepPAK-500 / C1g cartridge, 100 ml) which is eluted with; 7.5% aqueous methanol. The fractions containing the desired product are evaporated and lyophilized to collect the title compound (I-1E) (7 mg, 1.4%) melting at> 185 ° C (decomposition).

IR cm "“ 3400, 1765, 1675, 1620, 1600.

max,,,, CD.MJ - 57 - ÜV s Ät.jpo „phosphate (pH 7) nm (EW, 246 <403)> 290 (468).

NMR: 4 ppm 3.72 (2H 'm · 2-H), 4.14 (3H, s, OCHj), 5.35 J (3H, m, 6-H and CH = CH-CH2), 5 ^ 9 (1H # d; J = 4.5f 7-H), 6.1 (1H, m, 3-CH = CH ^, 7.05 (1Hf d | j-16, 3-CH, trans), 8, 1 "(1H / py-H5) * 8'54 (1H, s 1, Py-Hg), 8.68 (1H, m,

Py-H4), 9.4 (1H, m, Py-H2).

By reaction of ΐχ_ι (716 mg, 1 millimole) with 3-t-butoxycarbonylaminopyridine (324 mg, 2 millimoles) in a manner similar to that described above, 12 mg (2.3%) of I- are obtained. 1E.

EXAMPLE 7 -

S

ίΠΓ \ jri JL * © λ - ^ “2 H2ir ^ S / xoch3 <k ss ^^ ch * chch2-n 'y cocß I-1E * 2 / E * 1/1 7- [2- (5-Amino- 1,2,4-thiadiazol-3-yl) -2-methoxyimino-acetamido 3 —3 - [3- (3-amino-1-pyridinio) —1-propen — 1 — yl] - 3-cephem-4- (I-1E) carboxvlate

A mixture of 7- [2- (5-amino-1,2,4,4-thiadiazol-3-yl) -2-methoxyiminoacetamido] -3- (3-iodo-l-propen) is stirred for 20 minutes at room temperature. -l-yl) -3-diphenylmethyl (IX-I) -3-cephem-4-carboxylate (Z / E = 2 / l, 500 mg, 0.7 millimole) and 3-aminopyridine: (66 mg, 0.7 millimole) in dimethyl sulfoxide (1 ml).

The mixture is diluted with ethyl acetate (10 ml) and with ether (10 ml) and the resulting precipitate is collected by filtration, which is washed with ether (10 ml) and dried. The quaternized salt is dissolved in formic acid (3 ml) containing concentrated HCl CD.MJ - 58 - (0.3 ml) and the mixture is stirred at ambient temperature for 1.5 hours. The mixture is concentrated to dryness under reduced pressure. The residue is dissolved in 2% HCl (10 ml) and the solution is filtered.

“The aqueous layer is chromatographed on a phase inversion column (PrepPAK-500 / c18, 100 ml). After washing with water (500 ml), the column is eluted with 5% aqueous methanol. The fractions containing the title compound are combined, concentrated in vacuo and lyophilized to collect 15 mg (4.2%) of the title compound (I-1E) (Z / E = 1/1) the form of a colorless amorphous powder.

PF. > 160 ° C (decomposition).

IR: VKBr cm "1 3400, 1765, 1675, 1620, 1600. max ,, ^ phosphate buffer (pH 7), 1¾,,, max 1 cm '287 (333).

NMR: 6 DMSO_d6 + D2 ° 3.73 (2H, m), 4.14 (3H, s, OCH ..), ppm at 5.35 (3H, m, 6-H and CH = CH-CH_2), 6.0 (2H, m, 7-H and 3-CH = CH), 6.6 (1 / 2H, d, J = ll, 3-CH cis), 7.05 (1 / 2H, d, J = 16.3-CH trans), 8.08 (1H, m, Py-H5), 8.6 (2H, m, Py-H4 6), 9.4 (1H, m, Py-H2).

EXAMPLE 8 cocP '-'

; I-IF * E

7- [2- (5-Amino-1.2.4-thiadiazol-3-yl) -2-methoxyimino-acetamido3-3- [3- (3-formylaminopyridinio) -l-propen-l-vl] -3-cephem -4-carboxvlate (I-1F) CD.MJ - 59 -

Stir for 1 hour at room temperature, then pour into ethyl acetate (200 ml) a mixture of 7- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2-methoxyiminoacetamido] -3- (3-iodo-l-propen-l-yl) -3-cephem-4-carboxylate of diphenylmethyl (IX-1) (E, 716 mg, 1 millimole) and 3-formylaminopyridine - [prepared according to N. Enomoto et al. , Bull. Chem.

Soc. Japan, 45, 2665 (1972)] (244 mg, 2 millimoles) in DMSO (2 ml). The precipitate is collected by filtration, which is washed carefully with ethyl acetate and dried. The mixture is stirred for 80 minutes at 40-50 ° C., then a mixture of the quaternized salt (500 mg) and sodium bisulfite (50 mg) in formic acid (5 ml) is evaporated to dryness under vacuum. The residue is dissolved in water (40 ml), the sodium bicarbonate solution is neutralized and the insolubles are separated by filtration. The clear filtrate is chromatographed on a phase inversion column (PrepPAK-500 / C18, 100 ml) with water, 5% methanol, 10% methanol, 20% methanol and 20% methanol. 30%. The fractions containing the desired compound are combined, concentrated in vacuo and lyophilized to collect 16 mg (2.9%) of the title compound (I-1F) (E) in the form of a yellowish powder. PF. > 170 ° C (decomposition).

cm * 3340 (1), 1760, 1670, 1620 (1), 1590.

max λtampon ai phosphate (pH 7) 1% max 1 cm '248 (362), 290 (474).

= NMR: <5 p2 ° + NaHC03 3.68 (2H, 1, 2-H), 4.15 (3H, s, OCHg), 5.91 (1H, d, J = 4.5, 7-H ), 6.25 (1H, m, CH = CH-CH2), 5 '6.98 (1H, d, J = 16, 3-CH trans), 8.8-7.9 (4H, m, Py -H), 9.38 (1H, 1, NHCHO).

EXAMPLE 9 - .ε

N-P G-CONH —.- f N

I 1 \ j jj \ * e / 7 ~ ^ om2

HjN ^ s ^ N'och3 <y n ^^ ch-chch2-n / y COcß ''

I-1G * E

7- [2- (5-Amino-1.2.4-thiadiazol-3-vl) -2-methoxyimino-acetamido] -3- [3- (3-carbamovlpvridinio) -1-propen-l-vl] - 3- cephem-4-carboxvlate (I-1G)

Nicotinamide (244 mg, 2 millimoles) is added to a solution of 7- [2- (5-amino-1,2,4-thiadi-azol-3-yl) -2-methoxyiminoacetamido] -3- (3- iodo-1-pro-pen-1-yl) -3-cephem-4-carboxylate of diphenylmethyl (IX-1) (E, 716 mg, 1 millimole) in DMSO (2 ml) and the mixture is stirred with room temperature for 1.5 hours, then poured with stirring into ethyl acetate (200 ml). The resulting precipitate is collected by filtration. The quaternized salt (500 mg) is dissolved in formic acid (5 ml) in the presence of sodium bisulfite (50 mg) and the mixture is heated at 40-50 ° C for 40 minutes with stirring, then it is evaporates to dryness. The residue is dissolved in water (40 ml) and an insoluble solid is filtered off which is washed with a little water. The filtrate and the washing water are combined and chromatographed on a phase inversion column (PrepPAK-500 / C ^ g, 100 ml). After elution with water and 5% aqueous methanol; 10% and 20%, successively, the fractions containing the desired substance are combined, they are concentrated under vacuum and they are lyophilized to collect 21 mg (3.8%) of the compound announced in the title (I-1G) (E) under shape; of a yellow powder. PF. > 175eC (decomposition).

IR: tfKBr cm-1 3340 (1), 1760, 1670, 1600. max '' BV:> '^ POn 3 “phOSphate (PH 7) n„, (E «) 235 (326), max 1 cm 274 ( shoulder, 405), 290 (446).

NMR: op ^ + NaHC ° 3 3.68 (2H, 1, 2-H), 4.15 (3H, s, OCH3), 5.32 (1H, d, J = 4.5, 6-H) , 5.45 (1H, d, J = 7, CH = CH-CH2), 5.88 (1H, d, J = 4.5, 7-H), 6.15 (1H, dt, J = 16 and 7, 3-CH = CH), 7.00 (1H, d, J = 16, 3-CH trans), 8.23 (1H, m, Py-H5), 9.03 (2H, m, Py -H4 and g), 9.34 (1H, s, Py-H2).

EXAMPLE 10 -

N-J-Jj—— CONH — J-S "N

H2nAS / ^ OCHg ^ CH.HC ^ ONH2

I-1H * E

V "" T

7- [2- (5-Amino-1.2.4-thiadiazol-3-vl) -2-methoxyimino-acetamido] -3- [3- (4-carbamovlpyridinio) -1-propen-l-yl] - ^ 3 -cephem-4-carboxylate (I-1H)

11isonicotinamide (244 mg, 2 millimoles) is added to a stirred solution of 7- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2-methoxyiminoacetamido] -3- (3-iodo -1-propen-1-yl) -3-cephem-4-carboxylate of diphenyl-methyl (IX-1) (E, 716 mg, 1 millimole) in dry DMSO (2 ml). The mixture is stirred at room temperature for 1 hour, then poured into ethyl acetate (200 ml). The resulting precipitate is collected by filtration, which is washed thoroughly with ethyl acetate and dried. The mixture is heated at 40-50 ° C. for 1 hour, then evaporated to dryness "under reduced pressure, a stirred mixture of the quaternized compound (400 mg) and sodium bisulfite (40 mg) 'in formic acid (4 ml) Dissolve the crude solid in water (40 ml) After separating an insoluble material by filtration, the filtrate is chromatographed on a phase inversion column (packed with PrepPAK / C ^ g, 100 ml) with 1 ml. water and 5%, 10%, 20% and 30% aqueous methanol as eluent The fractions containing the desired compound are combined, evaporated, the residue is lyophilized to collect 21 mg (3.8%) of the compound announced under (I-1H) (E) in the form of a pale yellow powder PF> 180 ° C (decomposition).

IR: VKBr cm-1 3340 (1), 1760, 1670, 1600. max '' 'uv phosphate buffer (pH 7) nm (B1 *, 222 (362) max 1 cm 285 (452).

NMR: 6 D20 + NaHC03 3.68 (2H, 1, 2-H), 4.15 (3H, s, OCH,), ppm 3 5.33 (1H, d, J = 4.5, 6-H ), 5.46 (2H, d, J = 7, CH = CH-CH2), 5.90 (1H, d, J = 4.5, 7-H), 6.17 (1H, dt, J = 16 and 7, 3-CH = CH), 7.02 (1H, d, J = 16, 3-CH trans), 8.43 and 9.09 (each 2H, d, J = 7, Py-H) . w "EXAMPLE 11 - g --jj-Cj-C0NH- | —S>? h2nh2 η2Λ5 / ν nnoch3 cocß

X-1I * E

7 — Ç 2 - (5-Amino-1.2.4-thiadiazol-3-vl) -2-methoxyimino-acetamido] -3- [3- (3-aminométhvlpyridinio) -l-propén-1-rVl] -3- cephem-4-carboxylate (I-III)

A mixture of 7- [2- (5-amino-1,2,4-thiadiazol-; 3-yl) -2-methoxyiminoacetamido] -3- (3-iodo-l- is stirred for 30 minutes at room temperature. diphenylmethyl (IX-1) '(E, 716 mg, 1 mmol) and 3- (t-butyloxycarbonylaminomethyl) pyridine (516 mg, 2 mmol) propen-1-yl) -3-cephem-4-carboxylate in DMSO (2 ml). The mixture is poured into ethyl acetate (200 ml) and the precipitate is collected by filtration, which is washed thoroughly with ethyl acetate and dried. Stirred at 40-50 ° C for 80 minutes and evaporated to dryness under reduced pressure a mixture of the quaternized salt (500 mg) and sodium bisulfite (50 mg) in formic acid (5 ml). Dissolve the residual solid in water (40 ml) and neutralize the mixture with sodium bicarbonate. The insolubles are separated by filtration and the filtrate is chromatographed on a phase inversion column (packing with PrepPAK-500 / C cartridge, g, 100 ml) which is eluted with water and 5% aqueous methanol. , 10%, 20% and 30%, successively. The fractions containing the desired compound are combined, evaporated and lyophilized to collect 10 mg (1.8%) of the compound mentioned in the title (I-1I) (E) in the form of a yellowish powder.

IR: VKBr cm-1 3380 (1), 1760, 1650 (shoulder), 1620 raax '(shoulder).

UV; ^ phosphate buffer (pH 7) (E "> 235 (max 1 cm, 260), 286 (370).

NMR: δ p £ m + NaHC ° 3.68 (2H, 1, 2-H), 4.16 (3H, s, OCHg), 6.98 (1H, d, J = 16, 3-CH trans ), 8.05 (1H, m, Py-H5), 8.50 (1H, m, Py-H4), 8.80 (2H, m, Py-H2 g).

EXAMPLE 12 ϊΠΓΐ ~ “” Τθ

I-lB * E

7- [2 - (5-Amino-l f 2.4-thiadiazol-3-yl) -2-methoxvimino-acetamido3-3- [3- (4-carbamovlpyridinio) -1-propen-l-yl] - 3-cephem -4-carboxylate (1-1H)

A mixture of 7-t2- (5-amino-1,2,4-thiadiazol-3-yl) -2-methoxyiminoacetamido 3-3- (3-iodo-1-propen-1-yl) -3- is stirred diphenyl methyl cephem-4-carboxylate (IX-1) (E isomer, 4.1 g, 5.7 millimoles) and isonicotinamide (1.4 g, 11 millimoles) in dry DMSO (6 ml) at temperature ambient for 2 hours during which it is monitored by TLC (silica gel plate, chloroform: methanol = 3: 1). The reaction mixture is diluted with ethyl acetate (100 ml) to separate a yellow gum which is heated for 30 minutes at 45 ° C. in formic acid (40 ml) containing sodium bisulfite (390 mg) .

The resulting solution is concentrated to dryness. The residue is dissolved in water (100 ml) and the insolubles are separated by filtration. The mixture of filtrate and washing water is deposited on top of a column containing a phase inversion packing (PrepPAK-500 / C ^ g, 120 ml). The column is eluted with water. The eluate is collected in 300 ml fractions which are observed in UV (254 nm) and by HPLC (Lichrosorb RP-18, 4 x 300 mm, 0.01 M ammonium phosphate buffer, pH, 7.2 , containing 20% methanol). Fractions 4 and 5 are combined and concentrated to small volume. By lyophilization, 250 mg (8.1%) of the compound mentioned in title I-1H are collected, melting at> 180 ° C. (decomposition).

The spectra indicate that the product is identical to that obtained in Example 10.

- Preparation of the hydrochloride - 10% HCl (0.1 ml) is added to a suspension of compound I-1H (98 mg, 0.18 millimole) in methanol (1 ml) and the mixture is stirred for 5 minutes . Acetone (100 ml) is added to the resulting yellow solution to form a precipitate which is collected by filtration, which is washed with acetone (2 x 10 ml) and which is dried under vacuum for collect the I-1H hydrochloride in the form of a colorless powder. Production 88 mg (79%). Mp.> 190 ° C (decomposition).

IR: O KBr cm “1 3300, 1770, 1680, 1620. max uv: Phosphate buffer (pH 7) (EW, 227 (385) i max 1 cm 286 (374).

NMR: <5 D2 ° 2.32 (1H, s, acetone-H), 3.79 (2H, si, 2-H), ppm 4.17 (3H, S, OCH3), 5.34 (1H, d, J = 4.5, 6-H), 5.49 (2H, d, J = 7, CH = CH-CH2), 5.93 (1H, d, J = 4.5, 7-H) , 6.28 (1H, dt, J = 16 and 7, 3-CH = CH), 7.15 (1H, d, J = 16, 3-CH), 8.43 & 9.1 (each 2H, d, J = 7, Py-H).

T EXAMPLE 13 -

S

V N-r-C-C0NH -— "- S N

i 01 Τ '1 H2k ^ s / Xoch3 "nyîch = chck% -.

^ vJp 1-1J * e 7- [2- (5-Amino-1.2.4-thiadiazol-3-vl) -2-methoxyimino-acetamido] -3- [3- (2-methvlthiazolio) -l-propen- l-vl] - 3-cephem-4-carboxvlate (I-1J)

AgBF ^ (90% purity, 217 mg, 1 millimole) is added at -20 ° C to a mixture of 7— [2— (5— amino-1,2,4-thiadiazol-3-yl ) -2-methoxyiminoacetamido] - 3- (3-iodo-l-propen-l-yl) -3-cephem-4-carboxylate of diphenylmethyl (IX-1) (E, 714 mg, 1 millimole) and 2- methylthiazole [prepared according to RP Kurkjy, EV Brown, J. Am. Chem. Soc., 74 ^, 5778 (1952)] (198 mg, 2 millimoles) in dry methylene chloride (10 ml). The mixture is stirred for 30 minutes at room temperature and filtered. The precipitate is extracted with 10 $ Ci ^ OH-CHCl ^ (3 x 20 ml). The combined extracts are washed with brine (2x5 ml), sèche dried over MgSO 4 and evaporated to dryness to obtain a yellow residue which is triturated in isopropyl ether and filtered to collect 350 mg of the quaternized product. A mixture of this solid, sodium bisulfite (35 mg) and formic acid (3.5 ml) is stirred at 40 ° C for 30 minutes. The mixture is concentrated to remove the formic acid and the residue is diluted with water (40 ml). Some insolubles are separated by filtration. The filtrate is deposited on a phase inversion column (PrepPAK-500 / C .. Q, lo 100 ml). The column is eluted with water (200 ml), 5% aqueous methanol (400 ml) and 10% aqueous methanol (300 ml), successively. The fractions containing the desired product are collected on the basis of the analysis by HPLC (Lichrosorb RP-18, 4 x 300 mm, 0.01 fl ammonium phosphate buffer of pH 7.2 containing 20 $ of methanol). The combined solution is concentrated to small volume and lyophilized to collect 40 mg ($ 7.7) of the title compound (I-1J) (E). Mp> 195 ° C (decomposition).

IR: \> KBr cm-1 3300, 1760, 1660, 1600. max ’uv. ‘X phosphate buffer (pH 7) nm (£ 1%, 238 (442) max 1 cm '292 (421).

NMR: δ D2 ° '+ DMSO "d6 3.06 (3H, s, thiazole-CH-), 3.74 ppm —3 (2H, si, 2-H), 4.19 (3H, S, OCH3) , 5.92 (1H, d, J = 4.5, 7-H), 6.1 (1H, m, 3-CH = CH), 6.8 (1H, d, J = 16, 3-CH trans), 8.04 and 8.23 (each 1H, d, J = 4, thiazole-H).

EXAMPLE 14 - J [T \ ~ C0 "BXÎS1 *

H2N ^ \ S ^ XOCH3 V ^^ CH-CHCH ^ k '' ^ Y-CH-OH

Lp w

I-1L * E

7- [2- (5-Amino-1.2.4-thiadiazol-3-vl) -2-methoxvimino-acetamido] -3- [3- (4-hydroxymethvlpyridinio) -1-propen-l-y1 J -3- cephem-4-carboxylate (I-1L)

A mixture of 7- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2-methoxyiminoaceta-mido] -3- is stirred at room temperature for 1 hour under a nitrogen atmosphere. 3-iodo-1-propen-1-yl) -3-cephem-4-carboxy-late of diphenylmethyl (IX-1) (isomer E, 1.07 g, 1.5 millimole) and of 4-hydroxymethylpyridine (818 mg, 7.5 millimoles) in acetonitrile (4.5 ml) and ethanol (3 ml). After removing the solvents by evaporation, the oil is triturated in isopropyl ether, the solid is collected by filtration and washed with a mixture of isopropyl ether and methanol (10 ml, 3: 1) to obtain 1.28 g of the quaternized cephem ester which is a yellow powder. A solution of the quaternized ester (1.25 g) and sodium bisulfite (600 mg) in 85% formic acid (10 ml) is stirred at ambient temperature for 1 hour in a nitrogen atmosphere. After addition of 85% formic acid (5 ml), the mixture is stirred under the same conditions for a further 1 hour. Toluene is added and the reaction mixture is evaporated by azeotropy under reduced pressure. The residue is triturated in acetone to obtain 1.17 g of the crude form of the title compound. A suspension of this compound (1.15 g) is filtered in water (100 ml) to separate the insolubles which are washed with water (2 x 10 ml). The filtrate and the washings are combined and deposited on a phase inversion chromatography column. This column is developed, which contains packing taken from a prepPAK-500 / C ^ g cartridge (Waters) (60 ml) with water, 5% methanol and 10% methanol successively. The fractions containing the desired compound are combined, concentrated under reduced pressure and the compound is precipitated by addition of acetone to obtain 100 mg of the title compound (I-1L) which is a pale yellow powder. IM HCl in methanol (0.5 ml) is added to a suspension of this powder (90 mg) in methanol (9 ml) and the mixture is stirred at room temperature, then concentrated in vacuo. Isopropanol is added to the concentrate to precipitate 77 mg of the hydrochloride of the title compound which is a powder u =. pale yellow. M.p.> 190 ° C (decomposition).

IR:%> KBr cm "1, 1775, 1670, 1635, 1530. max UV: \ phosphate buffer nm 230 (22600) 264 max '' (shoulder, 16300) NMR: 6 ^ 2 ° 3.83 (2H, 1 2-CH), 4.17 (3H, s, OCH,), ppm '3 5.06 (2H, s, N ^^ - CH2OH), 5.36 (1H, d, J = 4.5 Hz , 6-H), 5.41 (2H7d, J = 7 Hz, CH = CH-CH2), 5.94 (1H, d, J = 4.5 Hz, 7-H), 6.36 (1H, dt, J = 16 and 7 Hz, CH = CHCH2), 7.13 (1H, d, J = 16 Hz, CH = CH-CH2), 8.08 and 8.83 (each 2H, d, J = 7 Hz, Py-H).

EXAMPLE 15 - im Λ v N-c-CONH —— r η ‘Xoc2h5 / -m- ^ cb-chch®h ^) - conh2

I-2H * E

7-Γ2- (5-Amino-l, 2.4-thiadiazol-3-vl) -2-ethoxvimino-acetamido] -3- [3- (4-carbamovlpyridinio) -1-propen-l-yl] -3-cephem -4-carboxylate (I-2H)

190 mg of 2-ethoxyimino-2- (5-amino-1,2,4-thia-diazol-3-yl) acetyl chloride hydrochloride are added little by little (prepared according to the process described in the patent application Japanese (Kokai) 57-24389 (8/2/82).] to a 200 mg solution of 7-amino-3- [3- (4-carbamoylpyridinio) -1-propen-l-yl] -3 hydrochloride -cephem-4-carboxylate (isomer E) in 5 ml of 50% aqueous acetone and the mixture is adjusted to pH 6.5-7.0 using 2N sodium carbonate (approximately 1 ml). The reaction mixture is stirred at 10 ° C for 1 hour, acidified to pH 2 with 1N HCl and evaporated in vacuo. The residue is filtered and the filtrate is chromatographed on an HP-20 column which is eluted with 500 ml of water and 25% aqueous isopropanol, successively. The fractions containing the product are combined and evaporated under reduced pressure, isopropanol (20 ml) is added to the oily residue to collect 263 mg (93%) of the title compound (I-2H), mp 170 "C (decomposition).

1 ml of IN HCl in methanol is added to a stirred suspension of 225 mg (0.40 millimole) of the above zwitterion in 10 ml of methanol and the mixture is stirred at room temperature for 30 minutes. The solution is filtered and concentrated under reduced pressure. 15 ml of isopropanol are added to the residue and the resulting precipitate is collected by filtration and dried under vacuum to obtain the title compound in the form of its

- hydrochloride. Production 146 mg (57%). M.p. 160 ° C

(decomposition). Estimated purity 65%.

IR: \> KBr cm-1, 3300, 1780, 1680, 1620. max 'υν, amp phosphate buffer (pH 7) nm 227 (22300) max' '288 (22800).

NMR: 6p2 ° 1.44 (3H, t, J = 7 Hz, OCH2 ~ CH3), 3.74 (2H, si, 2-H) 4.45 (2H, q, J = 7 Hz, OCH2-CH3 ), 5.36 (1H, d, J = 4.5 Hz, 6-H), 5.46 (2H, d, J = 7 Hz, 3-CH = CH-CH2), 5.92 (1H, d, J = 4.5 Hz, 7-H), 6.20 (1H, m, 3-CH = CH), 7.04 (1H, d, J = 16 Hz, 3-CH = CH), 8 , 43 (2H, d, J = 7 Hz, Py-HÂ), 9.10 (2H, d, J = 7 Hz, Py-Hß).

EXAMPLE 16 - 7- [2- (5-Amino-1.2.4-thiadiazol-3-vl) -2-methoxvimino-acetamido] —3— [3— (4-carbamovlpvridinio) -1-propen-l-yl] -3-cephem-4-carboxvlate (I-1H) (E-isomer)

This example illustrates the preparation of compound I-1H by the last few stages of the reaction scheme la or 1b where the formate of 7-C 2- (5-amino-1,2,4-thiadiazol-3-yl) is isolated. -2-methoxyimino-acetamido] -3- [3- (4-carbamoylpyridinio) -1-propen-1-yl] -3-cephem-4-carboxylate intermediate benzhydryl (XXVII-1H).

A. 7- [2- (5-amino-1.2.4-thiadiazol-3-yl) - 2-methoxviminoacetamido] -3- [3- (4-carbamovl-l-pyridi-nio) -l-propen formate -l-yl1-3-benz-hydryl cephem-4-carboxylate (E-isomer) (XXVII-1H)

We apply a solution of XII-1H (= A

isomer E) (34 g, 75% purity) in a mixture of acetone and methanol (1/1, 200 ml) on a column of Amberlite IRA-410 (formate form 340 ml).

The column is eluted with the same solvent system.

The first fraction (1000 ml) is evaporated to approximately 100 ml and the brown residue is triturated in isopropyl ether (400 ml). The resulting powder is collected by filtration ", which is dried under vacuum to obtain 29 g (75% purity according to HPLC) of the compound mentioned in title XXVII-1H (isomer E) which is a brown powder melting at> 150 ° C (decomposition).

IR: *? KBr cm "1 3300, 1780, 1680, 1630, 1600.

ΓΠ21X

UV:} Et0H nm (E1? É) 282 (186).

max 1 cm racetone-d ^ / CHo0H-d. (1/1). n, NMR: 0 6 3 4 4.0 (3H, s, OCH,), 5.26, ppm '—3, * (1H, d, J = 4.5 Hz, 6-H), 5.43 (2H, d, J = 7 Hz, CH2N +), 5.99 (1H, d, J = 4.5 Hz, 7-H), 6.5 (1H, m, 3-CH = CH), 6, 92 (1H, s, CHPh2), 7.1 (1H, d, J = 16 Hz, 3-CH), 7.35 (10H, m, Ph-H), 8.36 (1H, s, HCOO) , 8.46 and 9.12 (2H, each, d, J = 8 Hz, Py-H).

B. 7- [2- (5-Amino-1.2.4-thiadiazol-3-vl) -2-methoxy-iminoacetamido] —3— [3- (4-carbamovl-l-pyridinio) -1-propen-l -vl] -3-cephem-4-carboxvlate (I-1H) (isomer E)

A mixture of XXVII-1H (isomer E) of stage A (29 g, purity 75/6) and 85% formic acid (290 ml) is stirred for 2 hours at room temperature. By evaporation of the mixture, a brown oil is obtained which is triturated in acetone (500 ml). The powder is collected by filtration, washed with acetone (2 x 100 ml) and dried under vacuum to obtain 24 g (purity of 50% according to HPLC) of the crude compound mentioned in the title. The brown solid is treated twice with 2N HCl (1000 ml and 500 ml). The aqueous extracts are combined and applied to a column of Diaion HP-20 (1500 ml). The column is washed with water (8000 ml) and eluted with 30% methanol (5000 ml). The fraction containing the desired product is evaporated to around 30 ml. Acetone (200 ml) is added to the concentrate to form a precipitate which is collected by filtration and which is dried under vacuum to obtain 10.1 g (85% purity) of the title compound (zwitterionic form) in the form of a yellow powder.

Jr- HCl N in methanol (55 ml) is added at room temperature to a suspension of this product in methanol (100 ml) and the mixture is stirred for 30 minutes. The resulting clear solution CD.MJ - 72 - is filtered in order to separate the insolubles, it is concentrated to about 50 ml and the compound is precipitated with isopropanol (200 ml). The resulting powder is collected and washed with isopropanol (50 ml) and dried under vacuum to obtain 10.5 g (85% purity) of the title compound I-1H (E isomer) ( hydrochloride) melting at> 180 ° C (decomposition).

It is a pale yellow powder.

EXAMPLE 17 - 7- [2- (5-Amino-1.2.4-thiadiazol-3-vl) -2-methoxyimino-acetamido] -3- [3- (4-carbamoylpyridini o) -1-propen-l-yl ] - 3-cephem-4-carboxylate (I-1H) (E-isomer)

The present example illustrates the preparation of compound I-1H by the last few stages of the reaction scheme la or 1b where the intermediate XXVII-1H (formate) is not isolated.

A solution of IX-1 (isomer E) (27.6 g, 38.5 millimoles) and iso-nicotinamide (22.8 g, 187) is stirred for 1 hour at room temperature, under a nitrogen atmosphere. millimoles) in a mixture of acetonitrile (120 ml) and methanol (100 ml).

After evaporation of the organic solvents, the oily residue is triturated in isopropyl ether to obtain 50.5 g of a mixture of the quaternized salt and isonicotinamide. Stirred at room temperature for 40 minutes and then at 40 ° C. for 1 hour under nitrogen a solution of the mixture (50.3 g) and sodium bisulfite (.16 g) in 85% formic acid (160 ml ). The mixture is evaporated under vacuum. The residual oil is mixed with toluene (50 ml), the mixture is evaporated by azeotropy and? triturates the solid in acetone (400 ml) to obtain 27.8 g of the crude compound announced in the title. This compound is treated twice with 2N HCl (1000 ml and 500 ml). The acid extracts are combined and applied to a column of HP-20 resin (1500 ml). The column is eluted with water (9000 ml) and with 30% methanol (10,000 ml). The fractions containing the desired compound are combined and concentrated to obtain a yellow oil which is triturated in acetone (300 ml) to collect 9.35 g of the zwitterionic form of the title compound.

IN HCl in methanol (55 ml) is added to a suspension of the product (9.3 g) in methanol (180 ml) to obtain a clear solution. The solution is concentrated to approximately 100 ml and diluted with isopropanol to precipitate 9.50 g (75% purity) of the title compound I-1H (isomer E) in the form of its hydrochloride. It is a yellow amorphous powder. PF. > 195eC (decomposition).

EXAMPLE 18 - 7 - C 2— (5-Amino-1,2,4-thiadiazol-3-yl) -2-methoxyimino-acetamido3-3- [3- (4-carbamoylpyridinio) -l-propen-l-yl ] -3-cephème-4-carboxvlate (I-1H) (E-isomer)

The present example illustrates the preparation of compound I-1H by the last stage (7-N-acylation) of reaction scheme le.

Sodium bicarbonate is gradually added to an ice-cold suspension of 7-amino cephem XXII-H hydrochloride (E-isomer) (5.0 g, 12.6 millimoles) in 50% aqueous acetone (100 ml). The pH of the mixture is monitored using a pH meter during the reaction. 2- (5-Amino-1,2,4-thiadiazol-3-yl) -2-me-thoxyiminoacetyl chloride hydrochloride (4.02 g, 15.6 millimoles) is added gradually over 1 hour to the neutralized solution cold (pH about 7) and the pH of the reaction mixture is kept in the range of 6.8-7.5 by occasional additions of sodium bicarbonate. The reaction is also monitored by TLC. After consumption of nr \ MT n to all the compound XXII-H, the mixture is acidified to pH 3 by addition of 2N HCl. The mixture is filtered and the filtrate is concentrated under reduced pressure. The residue is diluted with acetone (400 ml) in order to separate a precipitate which is collected by filtration to obtain 9.59 g of the crude compound announced>> which is a light yellow powder. The purity estimated by HPLC is 40%. A suspension of the crude product (9.5 g) is filtered in 2N HCl (150 ml) and the filtrate is adsorbed on a column of HP-20 resin (500 ml). After washing with water (1500 ml), the column is eluted with 25% aqueous isopropanol and the eluate is collected in 100 ml fractions. The useful fractions are collected, acidified with 2N HCl (10 ml) and concentrated. The residual oil is triturated in isopropanol (200 ml) and the precipitate is collected by filtration. After drying over phosphorus pentoxide, 5.18 g of the hydrochloride of the compound mentioned in title I-1H (isomer E) are obtained in the form of a yellow amorphous powder. PF. > 190 ° C (decomposition). The estimated purity is 75%.

EXAMPLE 19 -

Purification and crystallization of compound I-1H (isomer E)

The hydrochloride of compound I-1H obtained in Example 16 is a pale yellow amorphous powder with a purity of 85%.

Procedure 1

6 g of the 85% purity hydrochloride are dissolved in 20 ml of water and the solution is filtered through ς of Celite. passing the amber-colored filtrate (pH 2) through a phase inversion column (packed with a prepPAK-500 / C .. 0 cartridge, Waters; lo 120 ml) which is eluted with water. The eluate is collected in 120 ml fractions which are examined by HPLC [Lichrosorb RP-18 column, 4 x 300 mm, mobile phase: 0.01 M phosphate buffer (pH 7.2) / methanol = 85/15 ; detection: UV (254 nm) 3. The fractions ^ 3 to 5 are combined and concentrated to about 10 ml, then the compound is precipitated by adding acetone ^ (100 ml) to collect 3.3 g of the zwitterionic form of I-1H (pale yellow amorphous powder, with an estimated purity of 95%).

HCl N in methanol (18 ml) is added to a suspension of the powder of 95% purity (3.2 g) in methanol (32 ml) and the mixture is stirred at room temperature until obtain a clear solution. The solution is filtered and the filtrate is concentrated to about 10 ml. Isopro-panol (100 ml) is added to the concentrate to separate a pale yellow precipitate which is collected by filtration, which is washed with isopropanol (5 ml) and dried to obtain 2, 6 g of the hydrochloride (amorphous powder, with an estimated purity of 95%).

A solution of the hydrochloride of a purity of 95% (1 g) in water - (4 ml) at pH 6.5 is adjusted using sodium bicarbonate (200 mg) and the mixture is stirred for 30 minutes. . The separated crystals are collected by filtration during stirring, washed with water (2 x 5 ml) and dried under vacuum to obtain 710 mg of I-1H (zwitterionic form) in the form of pale yellow prisms. Mp.> 185 ° C (decomposition).

Microanalysis indicates that it is the trihydrate.

IR cm-1 1780, 1695, 1660, 1630, 1610.

UV: XmaxP ° n ph ° Sphate (PH?) Nm (e) 227 (22000), '290 (23000).

NMR: <5 pp ^ ° ~ d6 + D2 ° 3.45 (2H, s 1, 2-H), 3.9 (3H, s, OCH3), 4.99 (1H, d, J = 4.5 Hz, 6-H), 5.16 (2H, d, J = 7 Hz CD.MJ - 76 - CH2N +), 5.61 (1H, d, Js = 4.5 Hz, 7-H), 5, 8 (1H, dt, J = 16 and 7 Hz, 3-CH = CH), 6.93 (1H, d, J = 16 Hz, 3-CH), 7 8.18 and 8.89 (each 2H, d, J = 7 Hz, Py-H).

Analysis for C21H20NgO6S2.3H20 calculated C, 42.14; H, 4.38; N, 18.72; S, 10.71%% found C, 42.41; H, 4.35; N, 18.86; S, 11.00% Procedure 2

After obtaining the crystalline I-1H by procedure 1, it is possible to obtain the crystalline zwitterionic form of I-1H directly from the crude I-1H hydrochloride by seeding using a few crystals of pure I-1H .

Charcoal is added to a solution of the hydrochloride of 85% purity (250 mg) in water (1 ml). The solution is adjusted to pH 6.5 using sodium bicarbonate (60 mg) and discolored using charcoal. The filtrate is seeded with a few small crystals obtained in procedure 1 and stirred overnight at room temperature. The crystals which have separated are collected by filtration, washed with water (2 x 2 ml) and dried under reduced pressure to obtain 170 mg (yield of 80%) of pale yellow prisms of I- 1H (zwitterionic form) melting at> 185 ° C (decomposition) which is identical to the product obtained by procedure 1 (as indicated by the IR, UV and NMR spectra).

The crystalline zwitterionic form of compound I-1H is sparingly soluble in water (6 mg / ml in physiological saline solution at 23 ° C.).

EXAMPLE 20 -

I-1X * E

7- [2- (5-Amino-lf2 r4-thiadiazol-3-vl) -2-methoxvimino-acetamido] -3- [3- (3-hvdroxvméthvlpyridinio) -1-propenvl1- 3-cephem-4-carboxylate ( I-1K) (isomer E) Ä. lodide of 7-r2- (5-amino-l, 2.4-thiadiazol-3-vl) - ^ 2-methoxviminoacétamido1-3-Γ 3- (3-hydroxvméthvlpvridi- nio) -l-propénvl] -3-cephème-4 -diphenvl-methylcarboxvlate (E-isomer) (XII-1K)

3-hydroxymethylpyridine (545 mg, 5 millimoles) is added to a solution of IX-1 (E-isomer, 1.79 g, 2.5 millimoles) in 2.5 ml of methanol and 7.5 ml of acetonitrile and the mixture is stirred at room temperature for 3 hours. The reaction mixture is poured into ethyl acetate (100 ml) with vigorous stirring. The resulting precipitate is collected by filtration, which is washed with a small volume of ethyl acetate and dried to collect 2.06 g (100%) of the compound mentioned in title XII-1K, which is a yellowish powder. PF. 170-180eC (decomposition).

IR: ^ max (KSr) in cm-1 1780 »1725, 1675, 1615, 1530, 1385, 1225, 1040, 750, 700.

uv v (C-Η, -ΟΗ) in nm (E, *,) 290 (196). max 2 d 1 cm NMR: <Ç (DMSO + D20) in ppm 3.7 (2H, s 1, 2-H), 3.91 (3H, s, OCH3), 4.70 (2H, s, Py -CH2-OH), 5.28 (2H, m, CH2-N +), 5.23 (1H, d, J = 5Hz, 6-H), 5.90 (1H, d, J = 5Hz, 7- H), 6.34 (1H, m, 3-CH = CH), 6.86 (1H, d, J = 16Hz, 3-CH), 6.89 (1H, s, CHPh2), 7.35 ( 10H, m, Ph-H), 7.9-8.9 (4H, m, Py-H).

B. 7- [2- (5-Amino-1.2.4-thiadiazol-3-vl) -2-methoxv-iminoacetamido 3—3— [3- (3-hvdroxvméthvlpyridinio) -1-propenyl] -3-cephem- 4-carboxylate (I-1K) (E-isomer)

A mixture of XII-1K (E-isomer, 2.0 g, 2.4 millimoles) and sodium bisulfite (1 g) in CD.MJ - 78 - is stirred for 2 hours at room temperature. 85% (10 ml). The reaction mixture is concentrated to about 5 ml under reduced pressure. The oily residue is poured into acetone (100 ml) with stirring. The precipitate is collected by filtration and washed with a small volume of acetone and dried to collect 1.1 g of a yellowish powder which is purified by column chromatography [containing the packing of a PrepPAK cartridge. -500 / Clg (Haters)] to collect 283 mg (22%) of I-1K which is an amorphous powder. The powder is crystallized from 4N sulfuric acid and acetone to obtain 144 mg of compound I-1K advertised as consisting of colorless needles, PF. 185-188eC (decomposition).

IR: V χ (KBr), in cm-1 1775, 1680 shoulder, 1660, 1630, 1225, 1045, 850.

UV: X (phosphate buffer, pH 7) in nm (E,) max * r r r v 1 cm 236.5 (283), 275 shoulder (280), 292.5 (330).

NMR: 6 (D20) in ppm 3.75 (2H, s, 2-H), 4.18 (3H, s, OCH3), 4.97 (2H, s, Py-CH2OH), 5.35 (1H , d, J = 4Hz, 6-H), 5.43 (2H, d, J = 6.5 Hz, CH2-N +), 5.92 (1H, d, J = 4 Hz, 7-H), 6.18 (1H, dt, J = 16 Hz, J = 6.5 Hz, 3-CH = CH-), 6.97 (1H, d, J = 16 Hz, 3-CH), 8.13 ( 1H, dd, J = 8Hz, J = 6Hz, Py-H), 8.60 (1H, d, J = 8 Hz, Py-H), 8.84 (1H, d, J = 6Hz, Py-H ), 8.90 (1H, S, Py-H).

EXAMPLE 21 - j | —p —- Tfl · ® / _ ^ OCHj cY N CH-CH-CHj-N ^ y-CONHCH3 cocß

D-1M * E

7- [2- (5-Amino-1.2.4-thiadiazol-3-vl) -2- (Z) -methoxyimi-no-acetamido] —3 - [3— (4-N-methvlcarbamoylpyridinio) -1-propenvl ] -3-céDhème-4-carboxvlate (I-1M) (isomer E) i * ύ * 70

Stirred for 5 hours at room temperature, under a nitrogen atmosphere, a mixture of 7 - [2 - (5-amino-1,2,4-thiadiazol-3-yl) -2-methoxyiminoaceta-mido] -3 - (3-iodo-1-propenyl) -3-cephem-4-carboxylate of diphenylmethyl (IX-1) (isomer E, 450 mg, 0.62 millimole) and of 4-N-methylcarbamoylpyridine [prepared - according to M. Samejima, Yakugaku Zasshi, 80_, 1706 (I960)] (215 mg, 1.58 millimole) in acetonitrile (2 ml). The mixture is evaporated under reduced pressure and the residue is triturated in ether to obtain 530 mg of the quaternary salt. The mixture is stirred for 4 hours, then heated at 40 ° C. for 30 minutes a mixture of the solid and sodium bisulfite (150 mg) in 85% formic acid (2 ml). The mixture is evaporated under reduced pressure. The residue is triturated in acetone, and the crude product is collected by filtration. The crude product is chromatographed on a column of HP-20 resin (1.5 x 18 cm) and the column is eluted with water and 30% aqueous methanol. The methanolic eluate is evaporated off under reduced pressure and the residue is lyophilized to obtain 140 mg of an amorphous powder which is further purified by HPLC (column: Lichrosorb RP-18, solvent: 15% methanol), then lyophilized the HPLC eluate to collect 60 mg (18%) of the title compound I-1M. PF. 180-183 ° C (decomposition). Purity is estimated at 80%.

IR: (KBr) in cm “1 1760, 1660, 1600.

max '' UV: ^ max (phosphate buffer, pH 7) in nm (£) 230 (22100), 286 (22100).

NMR: 6 (D20) in ppm 3.08 (3H, s, CONHCH_3), 3.72 (2H, s, I 2-H), 4.16 (3H, s, OCH3), 5.35 (1H, d, J = 4.5 Hz, 6-H), 5.95 (1H, d, J = 4.5 Hz, 7-H), 7.00 (1H, d, J = 16 Hz, 3-CH ), 8.35 (2H, d, J-6 Hz, pyridine-H), 9.05 (2H, d, J = 16 Hz, pyridine-H).

EXAMPLE 22 - ΙΠΠ— “χΓ * '!

, Η2Ν \ cH3 V Ν V ^ CH.CH-CH2? F \ coOH

"cocP \ = / Ι-1Ν * Ε / 2 7/1 7— [2— (5-Amino-1.2.4-thiadiazol-3-yl) -2-methoxyimino-acetamido] -3- [3- (4 -carboxvpyridinio) -1-propénvl] -3-cephème-4-carboxylate (I-1N)

N, Ο-bis (trimethylsilyl) acetami-de (0.7 ml, 2.8 millimoles) is added in a nitrogen atmosphere to a stirred suspension of isonicotinic acid (340 mg, 2.8 millimoles) in DMF dry (3.5 ml). To the resulting clear solution, 7- [2 - (5-amino-1,2,4-thiadiazol-3-yl) -2-methoxyimino-acetamido] -r3- (3-iodo-1) is added at once. -propenyl) -3-cephem-4-carbo-xylate of diphenylmethyl (IX-1) (isomer E, 720 mg, 1 millimole) and the red solution is stirred for 1.5 hours at room temperature. The reaction mixture is added dropwise to a stirred saturated sodium chloride solution (50 ml) containing sodium thiosulfate (150 mg). The yellow precipitate is collected by filtration, which is washed with water and dried to obtain 722 mg of a pale yellow powder. The powder (700 mg) and sodium bisulfite (70 mg) are dissolved in 85% formic acid (5 ml) and the solution is allowed to stand for 1.5 hours at room temperature. The mixture h is suspended in toluene (50 ml) and concentrated. The residue is triturated in acetone; (70 ml) and the precipitate is collected by filtration to obtain 421 mg of a yellow powder. This crude powder (400 mg) is suspended in water (2 ml) and sodium bicarbonate is added to the / - »• r-v kl T Γ» Λ suspension. The resulting dark solution is adsorbed on a packing column (50 ml) of a PrepPAK / C ^ g cartridge (Water's System 500), then the column is eluted with water (200 ml). The eluate is divided into 10 fractions (each of 20 ml) and the desired fractions (Nos. 4 to 7) are combined, then acidified to pH 3 with 2N HCl and concentrated.

The residue is triturated in acetone (30 ml) and the precipitate is collected by filtration to obtain 201 mg (37%) of the title compound I-1N which is a yellow powder. E / Z = 7/1; 80% purity. Mp.> 189 ° C (decomposition).

IR: O (KBr) in cm “1 1770, 1665, 1600. max UV: (phosphate buffer, pH 7) in nm (£) 227 ^ (22500), 290 (22100).

NMR: 0 (D20 + NaHCOg) in ppm 3.7 (2H, s 1), 4.15 (3H, ^ s), 5.32 (1H, d, J = 4Hz), 5.39 (2H, d , J = 6Hz), 6.14 (1H, dt, J = 15.5 and 6 Hz), 7.03 (1H, d, J = 15.5 Hz), 8.31 (2H, d, J = 7 Hz), 8.94 (2H, d, J = 7 Hz).

EXAMPLE 23 - ΪΠΤΙ-CONB-pYS ^ \> CH3 & N vyi: M-CH-CH2®N ^ \ cocP J— (

1-10 * E

* 7— [2— (5-Amino-1.2.4-thiadiazol-3-vl) -2- (Z) -methoxv- iminoacetamido] -3- [3- (2.3-cyclopentenopvridinio) -1-ί propenyl] - 3-cephem-4-carboxylate (1-10) (E-isomer)

A mixture of 7 - [2 - (5-amino-1,2,4-thiadiazol-3-yl) -2-methoxyiminoacetamido-3 is stirred under nitrogen for 4 "hours at room temperature. - diphenylmethyl (IX-1) (E-isomer, 450 mg, 0.62 r millimole) and 2,3-cyclopentenopyridine (217 mg, 1 (3-iodo-1-propenyl) -3-cephem-4-carboxylate 83 mmol) in acetonitrile (2 ml). After evaporation under reduced pressure, the mixture is triturated in ether to give 560 mg of the quaternary salt. The mixture is stirred under nitrogen for 3 hours at room temperature and then a mixture of this solid with 85% formic acid (2 ml) is heated at 40 ° C. for 30 minutes. The mixture is evaporated under reduced pressure and the residue is triturated to obtain 391 mg of a product. crude which is purified by chromatography on a column of HP-20 resin (1.5 x 18 cm), the column is eluted with water and 30% aqueous methanol.

By evaporation of the methanolic eluate under reduced pressure, then lyophilization, 160 mg of an amorphous powder are obtained which are further purified by HPLC (column: Lichrosorb, solvent: 10% methanol). The HPLC eluate is lyophilized to obtain 50 mg (15%) of product 1-10 announced in the title. PF. > 190 ° C (decomposition). Purity is estimated at 75%.

IR (KBr) in cm "1 1765, 1670, 1600.

max '' UV: λ (phosphate buffer, pH 7) in nm (6) 235 (20000), 283 (25000).

NMR: 6 (D20 + NaHCO ^) in ppm 2.2-2.6 (2H, m, -CH2 ~), 3.1-3.6 (4H, m, -CH2-), 3.72 (2H , s, 2-H), 4.17 (3H, OCH3), 5.33 (1H, d, J = 4.5 Hz, 6-H), 5.90 (1H, d, J = 4.5 Hz, 7-H), 6.75 (1H, d, J = 16 Hz, 3-CH), 7.65-8.2 (3H, m, pyridine-H).

EXAMPLE 24 -

N-r-C-CONH —- S S

Ji i — 1 Θ / ΓΛ H2N Ό CY Y ch “ch-ch2-n '/' Vcooh C2H5 coo® \ = i /

I-2N

7- [2- (5-Amino-1.2.2-thiadiazol-3-vl) -2- (Z) -ethoxvimino-acetamidol-3-Γ 3- (4-carboxvpvridinio) -l-propenvl] -3 -cephem-4-carboxvlate (I-2N. isomer E) and .7- [2- (5-Amino-1.2.4-thiadiazol-3-vl) -2- (z) -ethoxvimino-acetamido] -3- [3- (4-carboxypyridinio) -l-propenvl] -3- ^ cephem-4-carboxylate (I-2N. Z-isomer)

IX-2 (from Preparation No. 21) (1.0 g, 1.37 mmol) is added to a cooled mixture of bis-trimethylsilylacetamide (1.0 ml, 4.12 mmol) and isonicotinic acid (506 mg , 4.12 millimoles) and the mixture is stirred under nitrogen at room temperature for 2 hours. The mixture is poured into 10% sodium thiosulfate (20 ml) to precipitate 1.3 g of the quaternary salt which is collected by filtration, which is washed with water and dried.

The mixture is heated at 40 ° C. for 1 hour, then a mixture of the solid and sodium bisulfite (0.3 g) in formic acid (98%, 5 ml) is evaporated under reduced pressure. The residue is triturated in acetone - and 900 mg of the crude product is collected by filtration (E-propenyl isomer: Z-propenyl isomer = 2: 1).

The isomers are separated by HPLC (column: Lichrosorb, solvent: 15% methanol). The fastest HPLC fractions are collected, evaporated under reduced pressure and lyophilized to obtain the E-propenyl isomer of I-2N (44 mg, yield 6%). nits give the Z-propenyl isomer of I-2N (32 mg, yield 4%) by a similar procedure.

* I-2N, isomer E

PF. > 200 ° C (decomposition) IR: >> (KBr) in cm ”1 1765, 1660, 1620, 1380.

max ÜV: λ (Water) in nm (6) 228 (22200), 291 (23600). max NMR: 6 (D20) in ppm 1.45 (3H, t, J = 6Hz, CH2CH3), 3.72 (2H, s, 2-H), 4.45 (2H, q, CH ^ CH ^, 5.40 (1H, d, J = 4Hz, 6-H), 5.90 (1H, d, J = 4Hz, 7-H), 7.05 (1H, d, J = 15 Hz, 3-CH ), 8.30 (2H, d, J = 6 Hz, Py-H), 8.95 (2H, d, J = 6 Hz, Py-H).

I-2N, Z isomer

PF. > 200 ° C (decomposition) IR (KBr) in cm "^ 1760, 1660 (shoulder), 1620,

max i r, I

J 1370.

UV: (phosphate buffer, pH 7) in nm (£) 225 max (22400), 275 (shoulder, 16000).

NMR: <5 (D20) in ppm 1.45 (3H, t, J = 7Hz, CH2CH3), 3.50 (1H, d, J = 17 Hz, 2-H), 3.75 (1H, d, J = 17 Hz, 2-H), 5.38 (1H, d, J = 4 Hz, 6-H), 5.95 (1H, d, J = 4Hz, 7-H), 6.62 (1H , d, J = 11 Hz, 3-CH), 8.35 (2H, d, J = 6 Hz, Py-H), 8.92 (2H, d, J = 6 Hz, Py-H).

EXAMPLE 25 - JDt — rû ..

O O 'y CH «CH-CH2-NV' VcONHj CHj-CH-CHj COO® \ = y

I-3H * E

7- [2- (Amino-1.2.4-thiadiazol-3-yl) -2- (propen-3-yloxy- • imino) acetamido] - 3 - [3— (4-carbamovlpyridinio) -1-propenyl ] -3-cephem-4-carboxvlate (I-3H) (E-isomer)

52 mg of 2- [5-amino-1,2,4-thiadiazol-3-yl] -2- (propen-3-? Yloxyimino) acetyl chloride hydrochloride (from Preparation No. 25) is added to a solution 35 mg (80 micromoles) of 7- * amino-3- [3- (4-carbamoylpyridinio) -1- (E) -propenyl] -3- cephem-4-carboxylate hydrochloride in 2 ml of aqueous acetone * 50% and the mixture is adjusted to pH 6.5-7.0 using 2N sodium carbonate. The mixture is stirred at room temperature for 1 hour, acidified to pH 2 with IN HCl and concentrated under reduced pressure. The residue is chromatographed on a column of HP-20 resin which is eluted with 300 ml of water and 30% aqueous me-thanol. The fractions containing the product are combined and evaporated under reduced pressure. The 73 mg residue is purified on a column = £ of a phase inversion carrier taken from a PrepPAK-500 / C18 car key (Waters, 30 ml). The column is eluted with water and 5%, 10% and 20% methanol, respectively. The product-containing fractions are combined and lyophilized to obtain 26 mg (62%) of the title compound I-3H. PF. 160 ° C (decomposition).

IR: X? Max (KBr) in crn "~ 3400" 1765, 1680, 1605, 1400. uv (phosphate buffer, pH 7) in nm (€) 226 (24600), 288 (22800).

NMR: 6 (D20) in ppm 3.75 (2H, s, 2-H), 5.41 (1H, d, J = 5 Hz, 6-H), 5.50 (4H, m, CH2N + and CH = CH2), 5.98 (1H, d, J = 5Hz, 7-H), 6.20 (1H, m, 3-CH = CH), 7.09 (1H, d, J = 17 Hz, 3-CH), 8.50 (2H, d, J = 7 Hz, Py-H), 9.16 ς (2H, d, J = 7 Hz, Py-H).

EXAMPLE 26 - N-pC-CONH — j H2N ^ S ^ \ Nx ^ ch-ch-ch®n ^) - conh2 àHjCSCH ccxß

I-4H * E

7- [2- (5-Amino-1.2. 4-thiadiazol-3-vl) -2-proparqvloxv-iminoacétamido] -3- [3- (4-carbamoylpyridinio) -1-propé-nyl3-3-cepheme -4-carboxylate (I-4H) (E-isomer)

63 mg of 2-propargyloxyimino-2- (5-amino-1,2,4-thiadiazol-3-yl) acetyl chloride hydrochloride 4 (from preparation No. 26) is added to a solution of 86 mg (0 , 19 millimole) 7-amino- 3 - C 3— (4-carbamoylpyridinio) -1- (E) -propenyl] -3-cephem- 4-carboxylate (XXII-H) hydrochloride in 2 ml of aqueous acetone at 50%. The suspension is kept at pH 6.5-7.0 using 2N sodium carbonate, then stirred at room temperature for 1 hour. The reaction mixture is acidified to pH 2 with IN HCl and concentrated in vacuo. The residue is diluted with 30 ml of water, neutralized with sodium bicarbonate ** and filtered. The filtrate is deposited at the top of a column packed with a phase inversion carrier (30 ml) taken from a PrepPAK-500 / C18 cartridge (Waters). The column is eluted with water and 5% methanol, 10% and 20%, successively. The fractions containing the product are combined and lyophilized to obtain 13 mg (12%) of the compound I-4H mentioned in the title. The estimated purity is 70%. PF. 160eC.

IR (KBr) in cm "1 3400, 2120, 1765, 1680, 1610.

UV: ^ max (phosphate buffer, pH 7) in nm () 229 (24000), 288 (21200).

NMR: <5 (D20) in ppm 3.78 (2H, s, 2-H), 5.15 (2H, d, J = 1 Hz, -CH2-C = CH), 5.40 (1H, d , J = 5Hz, 6-H), 5.50 - (2H, m, CH-N +), 5.98 (1H, d, J = 5 Hz, 7-H), 6.20 (1H, m, 3-CH = CH), 7.05 (1H, d, J = 17 Hz, 3-CH), 8.50 (2H, d, - »J = 7 Hz, Py-H), 9.16 (2H , d, J = 7 Hz, Py-H).

EXAMPLE 27 Η2ΑΑά J ^^ ch-ch-ch®N ^ coNh2

I-5H * E

"R 7- [2- (5-Amino-1.2.4-thiadiazol-3-vl) -2-cvclopentvloxy-iminoacétamido] -3-C 3- (4-carbamoylpyridinio) -1-propé-nyl3-3-cephem -4-carboxvlate (I-5H) (E-isomer)

120 mg (0.44 millimole) of 2- (5-amino-1,2,4-thiadiazol-3-yl) -2-cyclopentyloxyiminoacetyl chloride (from preparation No. 27) is gradually added to a stirred solution of 139 mg (0.31 millimole) of 7-amino-3- [3- ^ (4-carbamoylpyridinio) -1-propenyl] -3-cephem-4-carboxylate hydrochloride in 3.5 ml d 50% aqueous acetone maintained in an ice bath. The mixture is adjusted to pH 6.5-7.0 using 2N sodium carbonate (0.9 ml) and stirred for 1 hour at 10 ° C. The reaction mixture is acidified to pH 2 with IN HCl and evaporated under reduced pressure. The residue is chromatographed on a column of HP-20 resin (20 ml) and eluted with 300 ml of water and 30% aqueous methanol, successively. The fractions containing the product are combined and concentrated in vacuo. 60 ml of acetone are added to the residue to obtain 111 mg (83%) of the title I-5H compound. PF. 160 ° C (decomposition). The estimated purity is 70%.

IR (KBr) cm-1 3400, 1770, 1680, 1605, 1530.

max 'UV: λ (phosphate buffer, pH 7) in nm (£) 224 max' (23300), 286 (24600).

NMR: 6 (DMSO-dg) in ppm 1.70 (8H, si, H- ^ J), 4.68 (1H, si, j / I), 5.05 (1H, d, J = 5Hz, 6 -H), 5.30 (2H, m, O '- CH2N +), 5.67 (1H, dd, J = 5Hz & 7 Hz, 7-H), 6.20 (1H, m, 3-CH = CH), 7.08 (1H, d, J = 17 Hz, 3-CH), 8.34 (2H, fd, J = 7 Hz, Py-H), 9.11 (2H, d, J = 7Hz , Py-H), 9.38 (1H, d, J = 7 Hz, 7-NH). ï EXAMPLE 28 -

cocP

I-1P * E

7- [2- (5-Amino-1.2.4-thiadiazol-3-vl) -2-methoxyimino-acetamidol-3-Γ 3- (3-carboxymethylpvridinio) -1-propenvl] -3-cephem-4-carboxvlate (I-lP) (E-isomer) A. 7- [2- (5-amino-1.2.4-thiadiazol-3-vl) -2-methoxvimi- ^ noacetamido 3-3-C 3- (3-carboxvmethvlpyridinio) -1-propenvl] -3-cephem-4-carboxylate of diphenvlmethvle (XII-1P. Iodide. Isomer E)

N, Ο-bis (trimethylsilyl) acetamide (4.97 ml, 18 millimoles) is added to a suspension of 3-carboxymethylpyridine hydrochloride (0.89 g, 5 millimoles) in 10 ml of methylene chloride and the mixture is stirred. mix at room temperature until a clear solution is obtained. IX-1 (1.79 g, 2.5 millimoles) is added to the solution and the mixture is allowed to stand at room temperature. After 3 hours, 3 ml of methanol are added to the cooled mixture and the solution is evaporated under vacuum to obtain an oil which is triturated in ethyl acetate to collect 2.28 g - · of compound XII-1P announced in title which is a yellowish powder. PF. 161 ° C (decomposition).

IR: λ) (KBr) in cm-1 1780, 1720, 1675, 1630, 1530, max 1385, 1225, 1045, 755, 700.

T 0 / UV: λ (CoHc0H) in nm (E,) 295 (188) max 25 l cm NMR: 6 (DMS0 + D20) in ppm 3.70 (2H, si, 2-H), 3.90 ( 5H, s, OCH3etPy-CH2CO), 5.25 (3H, m, -CH2N + and 6-H), 5.92 (1H, d, J = 4.5 Hz, 7-H), 6.35 ( 1H, m, 3-CH = CH-). 6.90 (1H, d, J = 16 Hz, 3-CH), 6.92 (1H, s, CHPh2), 7.35.

(10H, m, Ph-H), 8.8-9.0 (4H, m, Py-H). i B. 7— [2— (5-Amino-l.2.4-thiadiazol-3-vl) -2-methoxvin-minoacetamido] -3- [3- (3-carboxvmethvlpvridinio) -1-pro-penyl] -3 -cephem-4-carboxylate (I-1P) (isomer E)

A mixture of XII-1P (iodide) (2.28 g) and sodium bisulfite (1.1 g) in 85% formic acid (10 ml) is stirred for 2 hours at room temperature. The reaction mixture is concentrated to about 5 ml under reduced pressure. The oily residue is triturated in acetone (100 ml) to collect 1.22 g of the crude product which is purified by column chromatography (HP-20, 420 ml) in order to obtain 533 mg of the advertised compound I-1P (38% on the basis of IX-1) in the form of a pale yellow amorphous powder. PF. 165 ° C (decomposition).

IR (KBr) in cm "1 1770, 1670, 1600, 1530, 1385, max '' 1140, 1040.

1% UV: A (phosphate buffer, pH 6.2) in nm (E,) max ^ / 1 cm 234 (374), 277 shoulder (390), 290 (402).

NMR: 6 (D20 + NaHC03) in ppm 3.78 (2H, s, 2-H), 3.92 (2H, s, Py-CH2CO), 4.22 (3H, s, OCHj), 5.40 (1H, d, J = 4 Hz, 6-H), 5.44 (2H, d, J = 6.5 Hz, -CH2-N +), 5.97 (1H, d, J = 4 Hz, 7 -H), 6.20 (1H, dt, J = 16 and 6.5 Hz, 3-CH = CH), 7.08 (1H, d, J = 16 Hz, 3-CH), 8.11 (1H , dd, J = 8 and 7 Hz, Py-H5), 8.53 (1H, d, J = 8 Hz, Py-H4), 8.82 (1H, d, J = 7 Hz, Py-Hg) , 8.86 (1H, s, Py-H2). EXAMPLE 29 - te N-1 — Ç ------- COMH—] f ^ X iT \ TTÎ .J, *

OCHj a CH-CH-CHj-N7 'V-S-CH2C00H

cocß \ = z /

I-1Q * E

7— C 2— (5-Amino-lf 2, 4-thiadiazol-3-vl) -2-methoxvimino- acetamido] -3- [3- (4-carboxvmethylthiopvridinio) -1-propenyl] -3-cephem- 4-carboxylate (1-10) (E-isomer) A. 7- [2- (5-Amino-1.2.4-thiadiazol-3-vl) -2-methoxv- iminoacetamido] —3 - C 3 - (4- carboxymethylthiopyridinio) -l-propenvl] -3-cephem-4-carboxvlate (XII-10. iodide. E-isomer)

N, Ο-bis (trimethylsilyl) aceto-mide (5 ml, 18 millimoles) is added to a suspension of 4-car-boxymethylthiopyridine (0.88 g, 5 millimoles) in 10 ml of methylene chloride and the mixture is stirred. mix at room temperature until a clear solution is obtained. IX-1 (isomer E, 1.79 g, 2.5 millimoles) is added to the solution and the mixture is allowed to stand at room temperature. After 3 hours, 3 ml of methanol are added to the cold mixture and the solution is evaporated under vacuum to obtain an oily residue which is triturated in ethyl acetate in order to collect 2.43 g of the compound XII-1Q advertised in title (iodide) which is a yellowish powder. PF. 155eC (decomposition). IR = ^ max (KBr) in cm-1 1780, 1720, 1670, 1625, 1525, 1385, 1225, 1115, 1040, 755, 700.

UV: λ (C, H.OH) in nm (E **) 312 (299) max 25 1 cm NMR: δ (DMSO-dg + D20) in ppm 3.70 (2H, si, 2-H), 3.93 (3H, s, OCH3), 5.07 (2H, m, CH2-N +), 5.23 (1H, d, J = 5 Hz, 6-H), 5.90 (1H, d, J = 5Hz, 7-H), 6.29 (1H, m, 3-CH * CH), 6.87 (1H, d, J = 16Hz, 3-CH), 6.91 (1H, s, CHPh2), 7.35 (10 H, m, Ph-H), 7.88 and 8.58 (each 2H, d, J = 6 Hz, Py-H).

B7-C 2- (5-Amino-1,2,4-thiadiazol-3-yl) -2-methoxy- ..iminoacetamido 3 -3- [3- (4-carboxvmethvlthiopyridinio) - 1 - propenyl] - 3-cephem-4-carboxylate (I-1Q) (E-isomer)

A mixture of XII-1Q (iodide, 2.43 g) and CD.MJ - 91 - sodium bisulfite (1.1 g) in 85% formic acid is stirred at room temperature for 2 hours ( 10 ml). The reaction mixture is concentrated to about 5 ml under reduced pressure. The oily residue is triturated in acetone (100 ml), filtered and the solid is dried to obtain the crude product (1.39 g) which is purified by column chromatography (HP-20, 20 ml) in order to to obtain 577 mg of the compound I-1Q announced in the title (39% on the basis of IX-1) which is a pale yellow amorphous powder. PF. 188 ° C (decomposition).

IR: N) max (KBr) in Cm_1 1765 '1670, 1625, 1530, 1380, 1110, 1035.

uv: λ (phosphate buffer, pH 6.2) in nm (Et ^) max * · i cm 234 (459), 310 (678).

NMR: 6 (d20 + NaHC03) in ppm 3.79 (2H, si, 2-H), 4.10 ~ (2H, s, S-CH2), 4.23 (3H, s, OCH3), 5, 25 (2H, d, J = 6.5

Hz, CH2-N +), 5.39 (1H, d, J = 4.0 Hz, 6-H), 5.97 (1H, ~ d, J = 4 Hz, 7-H), 6.18 ( 1H, dt, J = 15.5 Hz and 6.5 Hz, 3-CH = CH), 7.05 (1H, d, J = 15.5 Hz, 3-CH), 7.84 and 8.55 (each 2H, d, J = 7Hz, Py-H).

EXAMPLE 30

N-r-Ç-CONH — d-N

Tl iïl Π I. v9 / - XOCH3 0 ^ ~

C (xP

I-lA * E / 2 - 7/1

Sulfate of 7- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2-mé-thoxyiminoacetamido] —3— [3— (1 — méthyipyrrolidinio) —1— 'propényll-S-giphème ^ -carbox ^ iate (i_ia. sulfate) ^ · Z ~, [(5-Amino-1,2,4 ~ .thj.adiazol -3-yl) -2-methoxv- iminoacetamido] -3- [3- (l -methvlpvrroiidinio) -i-Pro-penyl] -3-cephem-4-carboxylate of diphenvlmethvle (XII-lA. iodide)

A solution of

1- methylpyrrolidine (2.55 g, 30 millimoles) in ethyl acetate (300 ml) in 1 hour between -5 ° C

_ and 0 ° C, with stirring, to a cold solution of 7- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2-methoxyimino-acetamido] -3- (3- diphenylmethyl (IX-1) iodopropenyl) -3-cephem-4-carboxylate (IX-1) (from preparation No. 14) (21.5 g, 30 millimoles) in ethyl acetate (300 ml). After another 10 minutes of stirring, the resulting precipitate is collected by filtration and washed with chloroform (200 ml) to obtain 23.0 g (95.8%) of the title compound (IX-1A, iodide) fondant at> 175 ° C (decomposition).

IR (KBr) in cm-1 3300, 1780, 1730, 1685, 1615.

max c, UV: λ (CoHc0H) in nm (E,) 218 (435), 295 (188).

^ max 25 1 cm B. 7- [2- (5-Amino-lf 2,4-thiadiazol-3-vl) -2-méthoxvimi-noacétamido] —3— [3— (1-méthvlpyrrolidinio) -1-propénvl ] - U * diphenylmethyl 3-cephem-4-carboxylate (XII-1A, chloride)

The compound (XII-1A, iodide) (23 g, 28.7 millimoles) is dissolved in a mixture of acetone and me-thanol (1: 1, 230 ml) and the solution is adsorbed on an Amberlite column. IRA-410 (chloride form, 230 ml) treated beforehand with the same mixture of solvents. The column is developed using the solvent and the fractions containing the desired compound are combined, then they are concentrated in an oily residue which is triturated in ethyl acetate (300 ml) to collect 17.9 g (87, 7%) of the title compound (XII-1A, chloride), melting at 190 ° C (decomposition).

“IR: Ό (KBr) in cm-1 3380, 1780, 1680, 1620.

UV: λ {CoHc0H) in nm (E,) 220 (369), 290 (232).

max 25 1 cm '* C. Sulfate of 7-Γ2- (5-amino-1.24-thiadiazol-3-yl) - 2-methoxviminoacétamido Ü —3 - Γ3- (1-methvlpyrrolidinio) - CD.MJ - 93 - 1-propenyl3-3-cephem-4-carboxyIate (I-1A, sulfate) A mixture of the compound (XII-1A, chloride) is stirred at ambient temperature for 2 hours (17.8 g, 25 millimoles) in 85% formic acid (178 ml). The mixture is evaporated in vacuo and the oily residue is triturated in acetone to obtain 9.80 g of crude I-1A. By concentration of the filtrate and acetone washing liquors, an additional 2.95 g of I-1A crude. The two harvests of crude product are combined and extracted with 2N HCl (1000 ml and 500 ml). The combined extracts are adsorbed on Diaion HP-20 resin (1500 ml column) than eluted with water and 30% aqueous methanol, the useful fractions are collected and evaporated in vacuo to an oily residue which is triturated in isopropanol (200 ml) and acetone. (200 ml), in succession to obtain 7.09 g of a light yellow powder.

This substance (6.80 g) is dissolved in water (20 ml), then subjected to chromatography on a column packed with a PrepPAK-500 / C ^ g cartridge (90 ml) which eluted with water and 10% aqueous methanol. The eluate is collected in 20 ml fractions which are examined by HPLC. [Nucleocil SSC-ODS-262 column, 8 x 100 mm; mobile phase, 0.01M phosphate buffer (pH 7.2) / methanol = 90:10; detection in UV (254 nm) 3. Fractions 4 to 10 are combined, evaporated under reduced pressure and lyophilized to obtain 2.28 g of a yellow powder (E / Z = 7/1, 70% purity) [harvest 13. the way described above "fractions 11 to 85 to collect 3.27 g of a yellow powder (E / Z = 5/1, purity of 70%) [harvest 23. One part of crop 1 is purified ( 1.0 g) by a new chromatography on the lining of a PrepPAK ~ 500 / C18 cartridge (90 ml). The column is eluted with water and 5% aqueous methanol, successively. The eluate containing the desired compound is concentrated and lyophilized to obtain 638 mg * (E / Z = 7/1, 80% purity) of a yellow powder. Another part of the crop 1 is also treated (1.14 g) to collect 880 mg (e / Z = 7/1, 80% purity) of a yellow powder. The two purified samples are combined and part of them (1.45 g) are dissolved in IN sulfuric acid (5 ml). The solution is diluted with acetone (315 ml) with stirring. We re-. the creamy precipitate is filtered off to obtain 1.48 g of the title compound (1-1A, sulfate) (E / Z = 7/1, 80% purity) melting at> 185 ° C (decomposition).

IR: ^ max (KBr) in cm "1 3380, 3000, 1765, 1675, 1630, 1535, 1390, 1115.

UV: ^ max (phosphate buffer, pH 7) in nm {B) 236 (19900), 291.5 (22500).

NMR: "S (D20 + NaHC03) in ppm 2.36 (4H, 1,), 3.15 (3H, S, CH3 + (]), 3.62 (5H, 1, 2-H and), 3, 83 (1H, 1, 2-H), 4.13 (2H, d, J = 8Hz, CH2N +), 4.22 (3H, s, 0CH3), 5.39 (1H, d, J = 4.5 Hz, 6-H), 5.96 (1H, d, J = 4.5 Hz, 7-H), 6.00 (1H, m, 3-CH = CH), 6.67 (1 / 8H, d, J = 10Hz, 3-CH, cis), 7.04 (7 / 8H, d, J = 16Hz, 3-CH, trans).

EXAMPLE 31 - l-t — C-CONH— | - ^ ^ y | NKX / "y * 0 HN ^ OCH, CY Y CH" CH-CH, -N (CH,), 2 3 Joß 233 I-lD * E / Z "10/1 7- [2- (5-Amino- l.2.4-thiadiazol-3-vl) -2-methoxvimino-acetamido3-3-r 3-trimethylammonio-l-propenvl3-3-cephem- 4-carboxylate (I-1D) A. 7- [2- (5- amino-l r2 r4-thiadiazol-3-yl) -2-methoxvimi-noacetamido] -3- (3-trimethylammonio-l-propenyl) -3-cepheme-4-diphenylmethyl carboxylate (XII-1D, io- tough ).

1.75 ml (19.1 millimoles) of tri-methylamine 1, IN in ethyl acetate at -5 ° C. are added to a solution of 13.0 g (19 millimoles) of 7— [2— (5-amino-1,2,4-thiadiazol-3-yl) -2-methoxyiminoacétamido 3-3- (3-iodopropenyl) -3-diphenylmethyl-3-cephem-4-carboxylate (IX-1 of preparation No 10) in 38 ml of dry ethyl acetate and the mixture is stirred for 1 hour at -5 ° C. The resulting precipitate is collected by filtration, which is washed carefully with chloroform and dried to obtain 12.5 g (88%) of the laid corn advertised under title (XII-1D), in the form of l 'io-dur.

IR (KBr) in cm ”1 3300, 1765, 1720, 1665.

max tit UV: λ (CoHc0H) in nm (6) 300 (18400). max zb B. 7- [2- (5-Amino-1,2.4-thiadiazol-3-vl) -2-methoxv-iminoacetamido 3-3- (3-trimethylammonio-1-propenyl) -3-cephem-4- diphenylmethyl carboxvlate (XII-1D. chloride)

The iodide (XII-1D, 12.5 g) is dissolved in 60 ml of methanol-acetone (1: 1) and the solution is passed through an ion exchange resin [IRA-410 (Cl-), 125 ml]. The column is eluted with 300 ml of methanol-acetone (1: 1) and the eluate is evaporated under vacuum, then the residue is triturated in 300 mg of isopropyl ether to collect 10.4 g (91%) of the salt , quaternary (XII-1D, chloride).

IR (KBr) in cm-1 3300, 1765, 1710, 1665.

max UV: λ (CoHc0H) in nm (8) 298 (15100). max zd C. 7- [2- (5-Amino-1,2,4-thiadiazol-3-vl) -2-methoxv-iminoacetamido] —3 - [3-trimethvlammonio-l-propenvl] -3-cephem- 4-carboxylate (I-1D. Sulfate, isomer E).

It is left to stand for 3 hours at room temperature, then a solution of 10.4 g (16.0 millimoles) of XII-1D (chloride) in 20.8 ml of 85¾ formic acid is concentrated under vacuum. 210 ml of isopropanol is added to the residue and the precipitate is collected by filtration. The solid (10.1 g) is triturated in 210 ml of water and the mixture is neutralized with sodium bicarbonate. The suspension is filtered and the filtrate is chromatographed on a column of HP-20 (300 ml) which is eluted with water (1000 ml), 10¾ methanol (200 ml) and 30¾ methanol (150 ml) , successively. The fractions containing the desired product are combined and concentrated under reduced pressure. The residue is purified by chromatography with phase inversion. The column is packed by packing a PrepPAK-500 / C1g cartridge (Waters, 200 ml). By elution with water (600 ml) and with methanol at 30¾ (200 ml), successively, then concentration of the fractions containing the desired compound, 2.52 g (18¾) of the title compound are obtained. A solution of the zwitterionic product (1.5 g) in IN sulfuric acid (5 ml) is gradually added to 300 ml of acetone and the resulting precipitate is collected by filtration and dried. The production of I-1D, sulfate is 1.42 g (80¾). The E / Z ratio is approximately 10/1, based on HPLC.

IR (KBr) in cm-1 3380, 1765, 1665.

UV: λ „= ν (phosphate buffer, pH 7) in nm (ε) 237

^ Πια X

- (19500), 293 (22400).

NMR: 6 (d20) in ppm 3.25 (9H, s, N + -CH3), 3.94 (2H, s, 2-H), 4.14 (2H, d, J = 7Hz, CH2N +), 4 , 23 (3H, s, 0-CH3), 5.42 (1H, d, J = 4.5 Hz, 6-H), 6.00 (1H, d, J = 4.5 Hz, 7-H ), 6.23 (1H, dt, J = 7 and 16 Hz, 3 ^ CH = CH), 7.23 (1H, d, J = 16 Hz, 3-CH).

EXAMPLE 32 - * H, NlCH, '• VcOHBj 3 é «P w

I-1H * E

7- [2- (5-Amino-1.2.2-thiadiazol-3-vl) -2-methoxvimino-acetamido] -3- [3- (4-carbamovlpyridinio) -1-propenvl] - 3-cephem- 4-carboxylate (I-1H, isomer E)

2- (5-amino-1,2,4-thiadiazol- ^ 3-yl) -2-benzotriazol-1-yl-methoxyiminoacetate (479 mg, 1.5 millimole) (from preparation No. 28) is added to μ- a mixture of 7-amino-3- [3- (4- carbamoylpyridinio) -1 hydrochloride -1- (E) -propenyl] -3-cephem-4-carboxylic acid (XXII-H, 397 mg, 1 millimole ) and sodium bicarbonate (168 mg, 2 millimoles) in aqueous DMF (water, 3.5 ml and DMF 7.5 ml). The mixture is stirred at room temperature for 3.5 hours. The reaction mixture is adjusted to pH 3-4 using 3N HCl and diluted to 200 ml with acetone to give a precipitate which is collected by filtration. The crude product is dissolved in a small volume of aqueous THF and the solution is adjusted to pH 6.8 with sodium bicarbonate, then treated with bleaching charcoal, concentrated to about 1 ml and we seed it with some crystals - of I-1H. After stirring overnight, the crystalline precipitate is collected by filtration to obtain the compound I-1H announced in the title (zwitterionic form). Production 83 mg (16%). Mp> 185 ° C (decomposition). The physicochemical properties of this compound are identical to those of the compound of Example 10.

Preparation No. 1 7- [2- (5-Amino-1,2,4-thiadiazol-3-vl) -2-methoxyimino-acetamidoj-3-chloromethyl-3-cephem-4-carboxylate * diphenylmethyl (IV-1 )

PCI, - (2.09 g, 10 millimoles) is added at -30 ° C to a stirred suspension of 2- (5-amino-1,2,4-thiadiazol-3-yl) -2-methoxyiminoacetic acid (III -1) (2.1 g, 10 millimoles) in dry methylene chloride (50 ml) and the mixture is stirred for 20 minutes between -15 ° C and -20eC. To the above acid chloride solution is added a solution of 7-amino-3-chloromethyl-3-cephem-4-carboxy-diphenylmethyl (II) hydrochloride (4.5 g, 10 millimoles) in methylene chloride (50 ml) containing w N, 0-bis- (trimethylsilyl) acetamide (10 g, 50 millimoles) at -30 ° C. After stirring for 1 hour at -10 ° C., the methylene chloride is removed from the mixture and the concentrate is diluted with ethyl acetate (200 ml). The mixture is washed with 10% aqueous sodium bicarbonate (2 x 40 ml), water (2 x 20 ml) and brine (10 ml), successively, then dried over anhydrous magnesium sulfate The solvent is evaporated under vacuum and the resulting oily residue is dissolved (10 g) in chloroform (20 ml), then it is chromatographed on silica gel (Wako C-200 gel, 100 g containing 10 ml of buffer with 1 / 1.5 M phosphate, pH 7) using 1 - 3% methanol-chloroform. The fractions containing the title compound are evaporated to v; collect 5.7 g (95%) of IV-1 under the form of a yellow amorphous powder, mp.> 140 ° C (decomposition).

fCRr * 1 IR cm '"3300, 1780, 1720, 1680, 1620.

max '' ''

.% F.tOH

UV: λ nm (£) 245 (1800), 280 (9900).

max NMR: ^ ppm ° ~ ^ 6 3'53 (2H 'q AB' 2_H) »3.94 (3H, s, OCH3), 4.42 (2H, s, 3-CH2), 5.22 (1H , d, J = 4.5, 6-H), 5.92 (1H, dd, J = 4.5 and 6.7-H), 6.93 (1H, s, CHPh2), 7.36 ( 10H, m, Ph-H), 8.1 (2H, si, NH2), 9.58 (1H, d, J = 6.7-NH).

Preparation No 2 7— [2— (5-Amino-1,2,4-thiadiazol-3-yl) -2-methoxyimino-acetamido] -3-iodomethyl-3-cephem-4-carboxylate diphenylmethyl (V-1)

A mixture of IV-1 of preparation No 1 (5.7 g, 9.5 mmol) and Nal (4.3 g, 29 mmol) in dry acetone (5 g at room temperature is stirred for 5 minutes at room temperature. 50 ml). The mixture is concentrated under reduced pressure and the residual oil is stirred with a mixture of ethyl acetate (100 ml) and water (10 ml). The organic layer is separated and washed with 10% w / v sodium thiosulfate and brine, successively. After drying, the ethyl acetate is removed in vacuo to obtain 6.1 g (93%) of the title compound (V-1) in the form of a yellow amorphous powder melting at> 120 ° C (decomposition).

IR: 0KBr cm "1 3300, 1780, 1725, 1680, 1620.

max f i>> UV: λΕΐ0Η nm (£) 245 (17000), 282 (12000). max 'NMR: <5 BpB0 "d6 3.72 (2H, q AB, 2-H), 3.94 (3H, S, OCH3), 4.23 (2H, s, 3-CH2), 5.21 (1H, d, J = 4.5, 6-H), 5.89 (1H, dd, J = 4.5 and 6, 7-H), 6.94 (1H, s, CHPh2), 7, 35 (10H, m, Ph-H), 8.12 (2H, si, NH2), 9.65 (1H, d, J = 6.7-NH).

Preparation No 3 “7- [2- (5-amino-lr2r4-thiadiazol-3-vl) -2- methoxyiminoacetamido i-3-triphenvlphosphoniométhvl-3-- cephem-4-carboxyl-diphenylmethyl (VI-1) iodide

A mixture of Vl of preparation No 2 (690 mg, 1 millimole) and triphenylphosphine (786 mg, 3 millimoles) in ethyl acetate is stirred overnight at room temperature at room temperature. (20 ml). The solid which has separated is collected, washed with ethyl acetate (2 x 10 ml) and dried to obtain 950 mg (100%) of phosphonium iodide VI-1. PF. 186eC (decomposition).

IR; ΌKBrcm-1 3300, 1780, 1710, 1680, 1610. max 999β

~ ptnH

UV: λ nm (£) 268 (15000), 275 (13000), 300 (7300). max NMR: (5DMSO_d6 3.52 (2H, si, 2H), 3.94 (3H, s, OCH0), ppm —3 5.34 (1H, d, J = 4.5, 6-H), 5 , 9 (1H, m, 7-H), 6.3 (1H, s), 7.3 (10H, m, Ph-H), 7.8 (15H, m, Ph-H).

Preparation No 4 7- [2- (5-Amino-1,2,4-thiadiazol-3-vl) -2-methoxyimino- • s- acetamido] -3 - [(triphenylphosphoranylidene) methyl] -3-cephem-4 -diphenylmethylcarboxvlate (VII-1)

A mixture of VI-1 of preparation No 3 (952 mg, 1 millimole), Amberlite IRA-410 (OH- form, 500 mg) and NaOH N (4 ml) is stirred for 1 hour at room temperature. in methylene chloride (10 ml).

The mixture is filtered and the organic layer is separated, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residual oil is triturated in ethyl acetate and the resulting yellow precipitate is collected by filtration to obtain 740 mg (90%) of the compound mentioned in title VII-1. PF.

> 180 ° C (decomposition).

IR: ΌKBr cm-1 3400, 1750, 1630. max 'UV: XEt0Hnm (8) 268 (12000), 276 (10000), 384 max (23000).

Preparation No 5 7- [2- (5-Amino-l.2,4-thiadiazol-3-vl) -2-methoxyimino-CD.MJ - 101 - acetamido3-3- (3-chloro-l-propen-l -yl) -3-cephem- diphenylmethyl 4-carboxylate (VIII-1)

MgSO4 (3 g) and 40% chloroaldehyde (810 mg, 8.4 millimoles) are added to a solution of VII-1 of preparation No 4 (6.9 g, 8.4 millimoles) . The mixture is stirred for 1.5 hours at room temperature and then filtered. The filtrate is eluted on a column of silica gel (Wakogel C-200, 100 g containing 10 ml of 1 / 1.5 M phosphate buffer) using chloroform and chloroform containing methanol. The fractions containing the desired product (0.5 - 1% methanol-chloroform) are evaporated under vacuum to obtain 1.6 g (30%) of the compound mentioned in title VIII-1 in the form of a yellow amorphous powder which is a mixture of “Z and E isomers with respect to the chloropropenyl radical (Z / E = 2/1, by NMR). Mp> 130 ° C (decomposition).

* IR: \) KBr cm “1 3300, 1780, 1725, 1680, 1620.

UV:> Et0H nm (£) 240 (20000), 286 (12000). max NMR: 6DMSO “d6 + D2 ° 3.5 6 and 3.8 (m, 2-H), 3.94 (3H, s, OCH3), 4.16 (d, J = 7.5, CH ^ Cl), 5.26 (1H, d, J = 4.5, 6-H), 5.87 (1H, d, J = 4.5, 7-H), 6.28 (2 / 3H, d , J = U, 3-CH cis-H), 6.72 (1 / 3H, d, J = 16, 3-CH trans-H), 6.81 (2 / 3H, s, CHPh2), 6, 92 (1 / 3H, s, CHPh2), 7.4 (10H, m, Ph-H). Preparation No 6 7-Benzylidèneamino-3 - [(triphenylphosphoranylidene) -methvl] -3-cephème-4-carboxvlate de diphenvlméthyl (XVI)

NaOH N (140 ml) and Amber- * lite IRA-410 (OH form, 35 g) are added at 5 ° C to a solution of 7-benzylideneamino-3-C iodide (triphenylphospho- „ nio) methyl] diphenylmethyl (XV) -3-cephem-4-carboxylate (XV) [prepared according to Japanese patent application CD.MJ - 102 - published (.Kokai) 56-86187 (7/31/81)] (60 g , 70 millimoles) in methylene chloride (350 ml). The mixture is stirred for 1 hour at 5 ° C and filtered. The organic layer is separated, dried over anydre magnesium sulfate, concentrated to about 100 ml and the compound is precipitated by addition of ethyl acetate (500 ml). The resulting yellow solid is collected by filtration, which is dried under vacuum to obtain 48 g (94%) of compound XVI, advertised as melting at 195-198 ° C (decomposition).

IR: S) KBr cm “1 1770, 1620. max '

Preparation No 7 7-Benzylideneamino-3- (3-chloro-l-propen-l-yl) -3-cephem-4-carboxylate diphenylmethyl (XVII) ~ Anhydrous chloroacetaldehyde (800 mg) is added at room temperature at a stirred solution of XVI of preparation No 6 (2.9 g, 4 millimoles) in a mixture of methylene chloride (40 ml) and water (10 ml). An additional 800 mg of chloroacetaldehyde in three fractions is added to the mixture in 1 hour while the pH of the mixture is maintained between 6 and 9 by addition of NaOH N. After 15 minutes, the aqueous layer is separated and the layer is dried organic on magnesium sulfate. By evaporation of the solvent, a red oil is obtained which is dissolved in a mixture of ethyl acetate and isopropyl ether (1/2, 80 ml). The solution is washed with saturated aqueous sodium bicarbonate (10 ml) and water (10 ml), successively. After drying over magnesium sulfate and removing the

V

; solvent, 3.3 g of a yellow oil are obtained. A solution of the oil is filtered in methylene chloride (50 ml) on silica gel (12 g, Wakogel

C-200) containing 1 / 1.5 M phosphate buffer

(1.2 ml, pH 6.4) and the silica gel is washed with methylene chloride (50 ml). The filtrate and the washing liquors are mixed and evaporated to dryness.

The residue is triturated in n-hexane to obtain * 1.7 g (80¾) of the compound mentioned in the title (XVII) under.

the shape of a yellow powder. The NMR spectrum indicates - that the chloropropenyl radical has the Z configuration.

M.p.> 50 ° C (decomposition).

IR: »KBr cm“ 1 3400, 1775, 1720, 1630.

UV: λΒ ^ Η nm (6) 253 (11000), 258 (11000), 265 (10000), lu ci λ 273 (8300), 281 (7000), 290 (6300).

NMR: ^ ppm ° ~ d6 3.63 (2H 'S 1' 2 “H) '4' ° (2H 'm' cÎi2-Cl), 5.42 (2H, m, 6-H and 3-CH = CH), 5.72 (1H, d, J = 4.5, 7-H), 6.27 (1H, d, J = U, 3-CH), 6.85 (1H, s, CHPh2), 7.33 (10H, m, Ph-H).

Preparation of anhydrous chloroacetaldehyde

Anhydrous calcium chloride is added to an ice-cold solution of 50% aqueous chloroacetaldehyde (50 ml) with stirring to separate it into two layers. The layer of chloroacetaldehyde hydrate is separated (upper layer) [R.P. Kurkjy, E.V. Brown, J. Amer. Chem. Soc., 7 £, 5778 (1952)] and diluted with chloroform (100 ml), mixed with anhydrous magnesium sulfate (20 g), heated under reflux for 5 minutes and filtered.

The solvent and the water are removed by azeotropy (P.Eb.

56-64 ° C) [S. Tripett, D. M. Walker, J. Chem. Soc., 1961 1266] and the residue is distilled to obtain anhydrous chloroacetaldehyde, P.Eb. 70-82 ° C / 760 mm [H.O. House, V. K. Jones, G. A. Frank, J. Org. Chem., I 29, 3327 (1964)].

IR: -0film cm “1 1720 max

Preparation No 8 7-Amino-3- (3-chloro-l-propen-l-yl) -3-cephem-4-carbo- diphenylmethyl xylate (XVIII)

A solution of XVII of preparation No 7 (180 mg, 0.34 millimole) in ethyl acetate (10 ml) is added to a solution of the reagent T of Girard - (hydrazide of (carboxymethyl) trimethylammo chloride - nium) (251 mg, 1.5 millimole) in methanol (10 ml) „containing acetic acid (0.25 ml) at 5 ° C. After

30 minutes of stirring at 5 ° C, the mixture is concentrated to remove the methanol, then ethyl acetate (20 ml) is added. The ethyl acetate solution is washed with water (2 x 5 ml), saturated aqueous sodium bicarbonate (5 ml) and brine (5 ml) successively, then dried over sodium sulfate. anhydrous magnesium. By evaporation of the solvent, 145 mg (91%) of the compound XVIII mentioned in the title (iso- ~ mother Z) are obtained in the form of a yellow powder. P.P.> 100 ° C

(decomposition).

IR: OKBr cm-1 3400, 1770, 1720.

max '' ÜV: λEt0H nm (6) 252 (3700), 258 (3800), 260 (4000), max 274 (4000), 285 (4000).

Preparation No 9 7- [2- (5-Amino-1.2.4-thiadiazol-3-vl) -2-methoxyimino-acetamido 3-3- (3-chloro-l-propen-l-vl) -3-cephem -4-diphenvlmethvic carboxvlate (VIII-1)

A mixture of 2- (5-amino-1,2,4-thiadiazol-3-yl) -2-methoxyiminoacetic acid (III-1) is stirred for 2 hours between -7 ° C and -15 ° C (10 , 1 g, 50 millimoles) and PC15 (10.4 g, 50 millimoles) in dry methylene chloride (100 ml). The clear solution is poured into n-hexane (500 ml) to obtain a precipitate. The organic layer is discarded and the remaining solid is triturated in n-hexane (100 ml). The yellow precipitate is collected by filtration and dried under vacuum to obtain 12.5 g (99%) of the acid chloride melting at 80 ° C (decomposition).

IR: ^ ° 1 cm “1 1770. max

The acid chloride (25 mg, 0.1 millimole) is added with stirring to a solution of XVIII (Z isomer) of preparation No 8 (44 mg, 0.1 millimole) in dry methylene chloride (5 ml ) at ~ room temperature. After 30 minutes, the mixture is concentrated under reduced pressure and diluted with ethyl acetate (20 ml) and saturated aqueous sodium bicarbonate (5 ml). The organic layer is washed with saturated aqueous sodium bicarbonate (5 ml), brine (5 ml), 10¾ HCl (5 ml) and brine (5 ml). The solution is dried over anhydrous magnesium sulfate and brought to dryness to obtain the product in the form of a yellow foam. The foam is purified by chromatography on a column of silica gel (Wakogel C-200, 1g, containing * 0.1 ml of 1 / 1.5 M phosphate buffer, pH 6.4) by elution with chloride methylene-methanol (100: 1) to collect 31 mg (50¾) of compound VIII-1 announced in the title (Z isomer) which is a yellow powder.

P. F.> 150eC (decomposition).

IR: ^ max cm_1 3400, 1775 '1720' 1675 '163 ° * UV nm (£) 240 (17000), 280 (10000).

NMR: <5ppm ° "d6 3'6 (2H 'm' 2" H) '3'92 (3H "s, 0-CH3), 4.0 (2H, m, CH ^ Cl), 5.27 ( 2H, m, 6-H and 3-CH = CH), 5.83 (1H, dd, J-4.5 and 10, 7-H), 6.25 (1H, d, ju, 3-CH) , 6.83 (1H, s, CHPh2), 7.33 (10H, m, Ph-H), 8.0 (2H, s 1, NH2), 9.57 (1H, d, J = 10, 7 -NH).

Preparation No 10 "7 ~ [(5-Ammo-l. 2.4 — thiadiazol - 3 — vl) - 2 — méfboxvimino— Βοέΐ3Π) ίάο3-„ 3. · ^ ΐ3-ΐοάο-1-ΡΓθΡ0η-1-ν1) -3 -Γ · έηΗέ> Γη0- / ΐ-η ^ 7 · -diphenvlmethvboxylate (IX-1).

A solution of VIII-1 of preparation No 5 (Z / E = 2 / l, 480 mg, 0.77 mmol) in dry acetone (10 ml) containing is stirred for 30 minutes at room temperature. Nal (346 mg, 2.3 millimoles). The reaction mixture is evaporated under reduced pressure. The oil is partitioned between ethyl acetate (50 ml) and water (10 ml). „The upper layer is washed with a 10% w / v aqueous solution of sodium thiosulfate (10 ml) and brine (10 ml) successively, then dried over MgSO 4. By evaporation of the solvent, 540 mg (98%) of the compound mentioned in title IX-1 (Z / E = 1/1) are obtained in the form of a reddish amorphous solid melting at> 120 ° C. (decomposition).

IR: O KBr cm-1 3300, 1780, 1720, 1680, 1620 max '' '' c * uv nm (6) 240 (21000), 290 (12000).

max 'NMR: δ pp ^ 0 + D2 ° 3.67 (2H, m, 2-H), 5.29 (1H, d, J = 4.5, 6-H), 5.95 (1H, d , J = 4.5, 7-H), 6.27 (1 / 2H, d, J = ll, 3-CH cis), 6.72 (1 / 2H, d, J = 16, 3-CH trans ), 6.87 and 6.96 (each 1/2 H, s, CHPh2), 7.4 (10 H, m, Ph-H). Preparation No 11 7 ~ [2- (5-Amino-1,2,4-thiadiazol-3-vl) -2-methoxyimino-acetamido] -3- (3-iodo-l-propen-l-vl) -3 - diphenvlmethvle cephem-4-car-boxylate (IX-1)

A mixture of VIII-1 (Z-isomer) of preparation No 9 (5.6 g, 9 millimoles) and Nal (4 g, 27 millimoles) in acetone is stirred for 1.5 hours at room temperature. dry (100 ml).

The mixture is evaporated and the resulting oil is diluted with ethyl acetate (90 ml). The layer of ethyl acetate was washed with a 10% w / v aqueous solution of sodium thiosulfate (10 ml) and water (10 ml).

By removing the dried solvent (MgSO 4), a yellow oil is obtained which is made to solidify by trituration in isopropyl ether. By filtration of the precipitate, 4.3 g (67%) of the announced compound are obtained

as IX-1 in the form of the isomer E.P.F.> 165 ° C.

(decomposition).

IR:>) KBr cm-1 3400, 1780, 1725, 1680, 1610.

^ max,,,, UV: XEt0H nm (6) 240 (18000), 297 (11000).

max

I * NMR: 6DMSO "d6 + D2 ° 3.90 (3H, s, OCH,), 5.25 (1H, m, 6-H), ppm 3 '' '5.95 (1H, m, 7- H), 6.72 (d, J = 16.3-CH trans), 6.96 (1H, s, CH-Ph2), 7.4 (10H, m, Ph-H).

Preparation No 12 7-Amino-3-C3-chloro-l-propen-l -vl] -3-benzophryl-4-carbo-xylate (Z-isomer) (XVIII)

Compound XVIII is the common intermediate used in reaction schemes 1b and 1c.

* - A. Benzhydryl-3-triphenylphospho- niomethyl-3-cephem-4-carboxylate (XV) 7-benzvlideneamino chloride (XV).

* NaOH IN (440 ml) is added at ambient temperature to a suspension of benzhydryl 7-amino-3-chloromethyl-3-cephem hydrochloride - 4-carboxylate (II hydrochloride) (200 g, 0, 44 mol) in methylene chloride (940 ml). The mixture is stirred for 10 minutes and the organic layer is separated. MgSO 4 (75 g) and benzaldehyde (51 g, 0.48 mole) are added to the organic layer and the mixture is allowed to stand for 3 hours. The reaction mixture is filtered and the insolubles are washed with methylene chloride (200 ml). Triphenylphosphine (126 g, 0.48 mole) is added to the mixture of the filtrate and the washing liquors. The mixture is concentrated to about 400 ml and allowed to stand for 4 days. The resulting viscous oil is diluted with ethyl acetate (1000 ml) and triturated to separate the compound mentioned in title XV in the form of a pale yellow crystalline powder which is collected by filtration and qu 'vacuum drying.

Production 322 g (96%). Mp 185-190 ° C (decomposition).

IR: 'OKBr cm-1 1780, 1720, 1630. max' ÜV: XCH2C12 nm (£) 260 (24100) max B. 7-Benzylidéneamino-3 - [(triphenvlphosphoranylidene) - ~ methyl3-3-cephem-4-carboxylate benzhydryl (XVI)

A mixture of XV (322 g, 0.42 mole) and 5 N sodium carbonate (252 ml) in methylene chloride (1600 ml) is stirred vigorously for 15 minutes at room temperature. The organic layer is separated and dried over MgSO 4 and concentrated to around 500 ml. Acetone (1000 ml) is added with stirring to the concentrate to obtain a light yellow crystalline powder which is collected by filtration to isolate 237 g (78%) of XVI melting at 195-198 ° C (decomposition) .

IR KBr cm "1 1770, 1620 max 'UV: λ CH2C12 nm (£) 254 (23000), 389 (22000) max NMR: 6 cdc13 2.56 and 3.16 (2H, q AB), 5.00 ( 1H, d, ppm J = 4 Hz), 5.23 (1H, d, J = 4 Hz), 5.47 (1H, d, J = 22 Hz), 6.95 (1H, s), 7, 2-7.8 (30H, m), 8.55 (1H, s).

C. 7-Amino-3- [chloro-l-propen-l-vl] -3-cephem-4-benzhydryl carboxylate (Z-isomer) (XVIII hydrochloride)

A 50% solution of chloroacetaldehyde (93 g, 0.59 mole) in chloroform in 15 minutes is added dropwise with stirring to a reflux solution of XVI (214 g, 0.294 mole) and N, 0-bis - (trimethylsilylJacétamide (40 ml, 0.15 mole) in dry methylene chloride (2900 ml) After 30 minutes' rest, the mixture is concentrated to dryness.

Methylene chloride (1500 ml), Girard T reagent (99 g, 0.59 mole) and 10% aqueous HCl (300 ml) are added to the residual oil and the mixture is stirred for 1 hour at Room temperature. The organic layer is washed with water (200 ml) and a saturated NaCl solution (200 ml), dried over MgSO4, added to charcoal (5 g) and filtered. The strand-rat is cooled to -10 ° C and 1N HCl in methanol (300 ml) is added thereto. The mixture is stirred for 30 minutes at room temperature and concentrated to about 300 ml. The concentrate is diluted with ethyl acetate (400 ml) and seeded with a few crystals of XVIII hydrochloride. After 2 hours, the crystals which have separated are collected by filtration, washed with ethyl acetate (200 ml) and dried under vacuum to isolate 74 g (53%) of the title compound. XVIII in the form of its hydrochloride, melting at> 185 ° C (decomposition), c These are pale yellow needles.

IR; \) KBr cm “1 2830, 1780, 1720.

max '' UV; XEt0H nm (g) 286 (8800). max NMR: ($ DMS0-d6 3 73 (2H, s 1, 2-H), 3.97 (2H, m, ppm CH2C1), 5.22 (1H, d, J = 4.5 Hz, 6- H), 5.37 (1H, d, J = 4.5 Hz, 7-H), 5.77 (1H, m, 3-CH = CH), 6.45 (1H, d, J = ll Hz , 3-CH), 6.88 (1H, s, CHPh2), 7.33 (10H, s 1, Ph-H).

Analysis for N2O3SCI. HCl calculated C, 57.87; H, 4.65; N, 5.87; S, 6.72; Cl, 14.85% found C, 57.62; H, 4.53; N, 5.70; S, 6.64; Cl, 14.89%

Preparation No 13 .7- [2- (5-Amino-1.2.4-thiadiazol-3-vl) -2-methoxyimino-acetamido] -3- [3-chloro-l-propen-l-vl] -3- benzhvdrvle cephem-4-carboxvlate (Z-isomer) (VIII-1)

2- (5-amino-1,2,4-thiadiazol-3-yl) -2-methoxyiminoaceous-tyle hydrochloride hydrochloride (15.2 g, 59 millimoles) is added in three portions over 30 minutes between -10 ° C and 0 ° C to a stirred solution of XVIII (Z isomer) (20 g, 42 millimoles) in methylene chloride (420 ml) containing N, 0-bis (trimethylsilyl) -acetamide (34 ml, 125 millimoles). ; The mixture is stirred for 30 minutes at 0-5 ° C and concentrated under reduced pressure. We dissolve. the residual brown oil in ethyl acetate (420 ml) and the solution is washed successively with saturated aqueous NaHCOg (3 x 15 ml), saturated aqueous NaCl (15 ml), 10% HCl ( 15 ml) and saturated aqueous NaCl (15 ml), then concentrated to about 50 ml. N-heptane (200 ml) is added to the concentrate to obtain 28.5 g (90% purity) of the compound described in title VIII-1 (Z-isomer) in the form of a colorless powder. Mp.> 150 ° C (decomposition).

IR:>) KBr cm-1 3400, 1780, 1720, 1680, 1620. max UV: XEt0H nm (6) 240 (20000), 283 (12000). max NMR: 6 acet0ne_d6 3.6 (2H, m, 2-H), 3.95 (3H, s, OCH-.), ppm '' —3 4.0 (2H, m, CH2C1), 5.32 (1H, d, J = 4.5 Hz, 6-H), 5.62 (1H, m, 3-CH = CH), 6.03 (1H, d, J = 4.5 Hz, 7-H ), 6.32 (1H, d, J = 11 Hz, 3-CH), 6.8 7 (1H, s, CHPh2), 7.33 (10H, s 1, Ph-H). preparation No 14 7— [2— (5-Amino-1.2.4-thiadiazol-3-vl) -2-methoxvimino-acetamido] -3-C3-iodo-l-propen-l-vl] -3-cephem- Benzhvdrvle 4-car-boxvlate (isomer E) (IX-1)

Stirred for 10 minutes at room temperature and then allowed to stand at 5 ° C for 2 hours a mixture of VIII-1 (Z isomer) (28.5 g, 90% purity) and sodium iodide (19 g) in ** dry acetone (420 ml). The mixture is concentrated under reduced pressure. Add acetate

kC

ethyl (420 ml) and a 10% w / v aqueous solution of sodium thiosulfate (30 ml) to the residue and the mixture is stirred. The organic layer is washed with water (30 ml), dried over MgSO 4 and evaporated to approximately 50 ml. The concentrate is diluted with n-heptane (200 ml) to obtain 30.6 g (* 95% purity) of the compound mentioned in title IX-1 (isomer E)

in the form of a yellow powder melting at> 120 “C

* (decomposition).

IR KBr cm'1 3400, 1780, 1725, 1680, 1620. max '' '' UV: λΕΐ0Η nm (6) 306 (15000) max RMN: £ acetone-d6 3 71 (2H, m, 2-H), 3.97 (3H, s, OCH,), ppm —3 4.0 (2H, d, J = 8 Hz, CH2I), 5.26 (1H, d, J = 4.5 Hz, 6-H) , 6.03 (1H, dd, J = 4.5 and 8 Hz, changed to doublet J = 4.5 Hz in D20, 7-H), 6.32 (1H, dt, J = 15 and 8 Hz, 3-CH = CH), 6.79 (1H, d, J = 15 Hz, 3-CH), 6.98 (1H, s, CHPh2), 7.35 (10H, m, Ph-H), 7 , 63 (2H, s 1, deleted by D20, NH ,,), 8.52 (1H, d, J = 8 Hz, deleted by D20, * - 7-NH).

Preparation No 15

7- [2- (5-amino-1.2.4-thiadiazol-3-yl) -2-methoxyiminoacetamido] -3- [3- (4-carbamovl-1-pyridinio) -l-propen-1-yl iodide ] -3-cephem-4-benzhydryl carboxylate (E-isomer) (XII-1H)

Methanol (100 ml) is added to a suspension of IX-1 (E-isomer) (30.5 g) and isonicotinamide (26 g, 212 mmol) in acetonitrile (120 ml) until the mixture becomes clear. The solution is stirred for 2 hours in a nitrogen atmosphere at room temperature and concentrated to about 100 ml under reduced pressure. The residual semi-solid is triturated in isopropyl ether (200 ml). The solvent is separated by decantation and the residual yellow powder is washed with a mixture of isopropyl ether and methanol (3/1, 120 ml). The powder is collected by filtration and dried under vacuum to obtain 36 g (purity estimated at 75% by HPLC) of the compound mentioned in title XII-1H (isomer E) in the form of a light yellow powder melting at> 150 ° C (decomposition).

IR: λ7ΚΒγ cm-1 3300, 1780, 1720, 1680, 1620.

£ max '' '' UV: XEt0H nm (E ^) 282 (170) max 1 cm NMR: 6 pp ^ ° ~ d6 3.72 (2H, m, 2-H), 3.90 (3H, s, OCH3), 5.25 (3H, m, 6-H & CH2N +), 5.9 (1H, dd, J = 4.5 and 8 Hz, changed to doublet J = 4.5 Hz by addition of D20, 7 -H), 6.35 (1H, m, 3-CH = CH), 6.89 (1H, s, CHPh2), 6.9 (1H, d, J = 16 Hz, 3-CH), 7, 35 (10H, m, Ph-H), 8.06 (2H, s 1, deleted by D20, NH ,,), 8.21 (2H, s 1, deleted by addition of D20, NH2), 8.36 and 9.07 (each 2H, d, J = 6 Hz,

Py-H), 9.57 (1H, d, J = 8 Hz, deleted by addition of, D20, 7-NH).

Preparation No 16 7-Benzvlideneamino-3-r 3-chloro-l-propen-l-yl] -3-cephem-4-benzhydryl carboxvlate (XVII) (Z-isomer)

0.5 N sodium hydroxide (56 ml, 28 millimoles) is added dropwise over 20 minutes to an ice-cold mixture of the crystalline intermediate 7-amincephem XVIII (Z-isomer) (13.4 g, 28 millimoles) and benzaldehyde (3.3 g, 31 millimoles) in ethyl acetate (150 ml) so as to keep the temperature of the reaction mixture below 10 ° C. The mixture is stirred under cooling for a further 15 minutes, the organic layer is separated and washed with saturated aqueous sodium bicarbonate (2 x 100 ml) and dried over magnesium sulfate *. Add a small amount of good wood char to the dried solution and filter the mixture. The filtrate is concentrated to dryness. The residual oil is dissolved in carbon tetrachloride (50 ml) and concentrated again. The operation is repeated 3 times and the mixture is examined by reverse phase TLC to confirm that all of the starting 7-amincephalosporin has been converted to Schiff base. After having removed the solvent under vacuum, 16.45 g of the compound announced in title XVII (Z isomer) are obtained in the form of a pale yellow powder (purity estimated at 85%, mp 74 ° C (decomposition). 'is used without purification in the next stage.

IR: ^ max cm-1 1780, 1725, 1635 UV: λCH2Cl2 nm (E, *.) 257 (400) max 1 cm '' w / RMN î 6 5 ^ 3 6.18 (1H, d, J = ll Hz), ppm ''

Preparation No 17

Benzhydryl 7-benzylideneamino-3- [3- (4-carbamoyl-l- ~ pyridinio) -1-propen-y-yl] -3-cephem-4-carboxvlate (XXI-H) (E-isomer) - A solution of sodium iodide (6.3 g, 42 millimoles) in acetone (30 ml) is added dropwise over 10 minutes under nitrogen to a cooled mixture of 3-chloropropenyl cephem XVII (Z-isomer). ) (16.4 g) in acetone (5 ml) and the mixture is stirred at room temperature.

The reaction is observed by determining the absorption ratio in the UV [E ^ (255 nm) / E ^ (320 nm)].

When this ratio falls to a value less than 1.30 (after 45 minutes), the mixture is diluted with carbon tetrachloride (400 ml) and allowed to stand at room temperature. When the ratio falls below 1.10 (after 3 hours), the mixture is concentrated to half volume. Add a small amount of charcoal and diatomaceous earth to the centered con-ζ and filter everything. The filter cake is washed with a 1: 1 mixture (100 ml) of methylene chloride and CD.MJ-114-carbon tetrachloride. To the mixture of the filtrate and the washing liquors, a solution of isonicotinamide (3.5 g, 28.7 millimoles) in dimethylformamide (20 ml) is added and the mixture is concentrated under reduced pressure. The concentrate is left to stand at room temperature for 1.5 hours and washed with isopropyl ether (3 x 100 ml). The residual brown semi-solid is dissolved in methylene chloride (50 ml) and the solution is added dropwise with stirring to ethyl acetate (1500 ml). The resulting precipitate is collected by filtration and washed with ethyl acetate (200 ml). After drying over phosphorus pentoxide under vacuum, 17 g of the title compound XXI-H (isomer E) are obtained. It is a yellow amorphous powder. Mp 150- ^ 155 ° C (decomposition). Purity is estimated at 80% by NMR.

Kur Ί ir IR cm-- 1775, 1725, 1590, 1635.

max '' UV: ACH2C12 nm (E ^) 258 (335), 298 (255).

max I cm NMR: <5ppm ° ~ d6 3'4 "3'8 <2H, D. 5.35 (2H, 1), 5.41 (1H, d, J = 4 Hz), 5.73 (1H , d, J = 4 Hz), 6.93 (1H, s), 6.97 (1H, d, J = 16 Hz), 7.3-7.5 (15H, si), 8.40 (2H , d, J = 6.5 Hz), 9.15 (2H, d, J = 6.5 Hz).

Preparation No 18 7-Amino-3- [3- (4-carbamoyl-l-pyridinio) -1-propén-l-_vl] -3-cephème-4-carboxvlate (XXII-H) (E-isomer)

Concentrated hydrochloric acid (5 ml) is added dropwise to a suspension of the quaternized cephem XXI-H (17 g) in 85% formic acid (25 ml) and the mixture is stirred at temperature * · Ambient for 1.5 hours, then add a small amount of charcoal. The mixture is filtered and the solids are washed with 85% formic acid (5 ml). The CD.MJ - 115 - filtrate increased by washing liquors in acetone (1000 ml) is poured with stirring. The resulting precipitate is collected by filtration to obtain 9.52 g of crude product, yellow in color. A small amount of charcoal is added to a suspension of the crude product (9.5 g) in water (50 ml) and the mixture is filtered. The filtrate is added dropwise and with stirring to isopropanol (700 ml). The resulting precipitate is collected by filtration, which is washed with a little methanol (30 ml) and dried to obtain 7.58 g of the title compound XXII-H (isomer E) in the form of the hydrochloride. It is a light yellow powder. The purity estimated by UV is 85%. PF. 173-188 ° C (decomposition).

IR: O KBr cm-1 1795, 1680, 1620, 1575, 1540.

max! r g r UV: phosphate buffer (pH 7) M (£ .1X> 294 max 1 cm (457).

NMR: ôJ? 22 + DC1 3'82 (2H 's)' 5'17 (1H 'd' J = 5 Hz) 'ppm lit ri i 5.33 (2H, d, J = 7 Hz), 5, 43 (1H, d, J = 5 Hz), 6.37 (1H, dt, J = 16 and 7 Hz), 7.23 (1H, d, J = 16 Hz), 8.34 (2H, d, J = 7 Hz), 9.00 (2H, d, J = 7 Hz).

Preparation No 19

2- (5-amino-1,2,4-thiadia-zol-3-yl) -2-methoxyiminoacetyl chloride hydrochloride (III-1 as its chloride hydrochloride) A. 2-Cyano-2-methoxyiminoacetamide

Acetic acid (371 ml, 10 moles) is added at 5-10 ° C over 1.5 hours to a stirred mixture of <X-cyanoacetamide (252 g, 3 moles) and sodium nitrite (414 g , 6 moles) in water (600 ml).

The mixture is stirred for a further 1.5 hours and adjusted to pH 8.5 with 6N NaOH. Dimethyl sulfate (568 ml, 6 moles) is added at 15-20 ° C to the mixture which is stirred at 45 ° C for 1.5 hours.

The reaction mixture is adjusted to pH 8.5 with 6N NaOH and allowed to stand at 5 ° C overnight to separate a precipitate which is collected by filtration, which is washed with cold water * and air-dried to obtain 292 g (77%) of the title compound presented in 4 brown needles melting at 170-172 “C.

IR crn 3400, 3180, 1720 (shoulder), 1715, 1690, 1615, 1570.

UV: λ ^ 2 ° nm (£) 238.5 (8290), 268 (shoulder, 3870).

NMR: $ pp ^ ° "d6 4.20 (3H, s, OCH3), 7.85 (2H, 1, NH2).

Analysis for C4H5N3 ° 2 calculated C, 37.80; H, 3.97; N, 33.06% found C, 37.43; H, 3.75; N, 32.51% ^ B. 2-Methoxyiminopropanedinitrile

A stirred mixture of 2-cyano-2-methoxyiminoacetamide (88.9 g, 0.7 mole), sodium chloride (70 g) and phosphorus oxychloride (97 ml, 1 is heated at reflux for 16 hours. 0.05 mole) in dry 1,2-dichloroethane (350 ml). The insolubles are separated by filtration on a layer of Dicalite which is washed with dichloroethane. The filtrate and the washing liquors are mixed and the mixture is poured into stirred ice water (1500 ml) to decompose the excess phosphorus oxychloride. The organic phase is washed with 10% sodium bicarbonate (500 ml), water (3 x 500 ml) and a saturated NaCl solution (500 ml), then dried over MgSO4. Distilled *> the filtrate under reduced pressure to collect 61.5 g (81%) of the title compound boiling at 62 ° C / -. 24 mm Hg. (P.Eb. 47-48 ° C / 12 mm Hg according to the literature).

IR liquid -1 3020, 2960, 2245, 2020, 1530, max iii ,, 1455, 1080.

NMR: <5 cdc13 4 35 (3H, s OCH,). ppm '' '3 C. 2-cyano-2-methoxyiminoacetamidinium acetate

A solution of 2-methoxyiminopropanedinitrile (58.0 g, 0.53 mol) * in ethanol (120 ml) is added dropwise at -15 ° C to -10 ° C over 30 minutes with stirring to a solution. ammonium chloride (28.4 g, 0.53 mole) in 28% aqueous ammonia (355 ml) and ethanol (180 ml). The mixture is stirred at -10 ° C overnight, then at room temperature (20-25eC) for 1 day.

The reaction mixture is subjected to partitioning between water (350 ml) and methylene chloride (350 ml), then the aqueous phase is saturated with sodium chloride and it is again extracted with methylene chloride (300 ml). The organic extracts are combined and dried over MgSO 4 and evaporated in vacuo.

A solution of the residue in ethyl acetate (1600 ml) at pH 3-4 is adjusted with acetic acid to precipitate the title compound in the form of crystals which are collected by filtration and qu 'Washed with ethyl acetate. Production 67.6 g (69%). PF. 152-154eC (decomposition). [PF. 150-155eC (decomposition according to the literature)].

IR:>) KBr cm-1 3160, 2900, 2360, 2235, 2000, 1665, 1555, 1495, 1415.

UV: AEt0H nm (C) 243 (8500), 265 (shoulder, 5380), max 305 (shoulder, 1400).

NMR: 6DMS0_d6 1.88 (3H, s, CH, COOH), 4.15 (3H, s, OCH3), 7.60 (4H, 1).

Analysis for c4HgN40.CHgCOOH

* calculated C, 38.71; H, 5.41; N, 30.09% found C, 38.71; H, 5.59; N, 29.51% D. 2- (5-Amino-1,2,4-thiadiazol-3-yl) -2-methoxy-iminoacetonitrile r * r-v w t 1 1 Λ

Triethylamine (234 ml, 1.68 mole) is added dropwise at -10 ° C and then Br2 (41.6 ml, 0.806 mole) in 20 minutes between -15 ° C and -10 ° C to a suspension of 2-cyano-2- "methoxyiminoacetamidinium acetate (125 g, 0.672 mole) in methanol (1250 ml) and the mixture is stirred for 20 minutes. A solution of KSCN (78.3 g, 0.806 mole) in methanol (550 ml) is added to this mixture dropwise over 1 hour between -15 ° C and -10eC. After stirring at 0-5 ° C. for 1 hour, the mixture is poured into ice water (12 liters) to form a crystalline precipitate which is collected by filtration, which is washed with water and dried at air to obtain 120 g (98%) of the title compound. PF. 263-265 ° C (decomposition). The PF. of the compound Ç prepared by the Applicant is approximately 60 ° C. higher than that mentioned in the literature [PF. 210-215 ° C (decomposition)], Japan Kokai 57-158769 published on September 30, 1982 by Fujisawa (English patent application 3/3/81), but the spectral and microanalytical data noted by the Applicant agree with the structure.

IR: \> KBr cm “1 3435, 3260, 3120, 2960, 2245, 2020, max i t i >> i 1630, 1545, 1455, 1415 UV:> Et0H nm (C) 248 (13300), 310 (3470). max NMR: 6DMSO “d6 4.21 (3H, S, OCH,), 8.30 (2H, 1, NH„) ppm '' '3' '' '2

Analysis for C ^ H5N ^ 0S

calculated C, 32.78; H, 2.75; N, 38.23; S, 17.50% found C, 32.76; H, 2.51; N, 38.02; S, 17.50% E. Acid 2- (5-amino-1,2,4-thiadiazol-3-yl) -2-metho- * xyiminoacetic (III-l)

Heated to 50-55 ° C with stirring for 3 hours a mixture of 2- (5-amino-1,2,4-thiadiazol-3-yl) -2-methoxyiminoacetonitrile (18.3 g, 0.1 mole) in 4N NaOH (250 ml). The reaction mixture was adjusted to pH 1 with H 2 PO 4 and washed with ethyl acetate (100 ml), saturated with NaCl and extracted three times with an acetate mixture ethyl and tetrahydrofuran (3: 1, 2 x 300 ml and 1 x 200 ml). The extracts are combined, dried over MgSO 4 and concentrated under reduced pressure. The residue is triturated in isopropyl ether to obtain pale yellow crystals of the title acid. Yield 16.8 g (83%). PF. 184-185 ° C (decomposition).

[PF. 180-182 ° C (decomposition according to the literature)], Japan Kokai 57-158769 published on September 30, 1982 by Fujisawa (English patent application 6/3/81), IR:>) KBr cm "1 3460, 3260, 3140 , 1725, 1620, 1605, max '1545 UV: λΗ2 ° nm (€) 234 (13200), 288 (shoulder, 3620) max i t- ~ * F. 2- (5-amino-l chloride chloride hydrochloride, 2,4-thia-diazol-3-yl) -2-methoxyiminoacetyl

PCl ^ (41.6 g, 0.2 mol) is added all at once at -50 ° C to a 2- (5-amino-1,2,4-thiadiazol-3-yl) acid suspension - 2-methoxyiminoacetic (III-1) (40.4 g, 0.2 mole) in dry methylene chloride (400 ml). The mixture is stirred for 4 hours between -20 ° C and -5 ° C and poured into a mixture of n-heptane and isopropyl ether (2: 1, 2000 ml). The yellow precipitate is collected by filtration, which is washed with the same mixture of solvents and dried with KOH under reduced pressure to collect 46.0 g (90%) A of the acid chloride mentioned in the title.

* IR cm "1 1775.

max

Preparation No 20

S

N --- C - CONH-T-S N

| IN »1 * <X N'V ^^ CH« CH-CH2-C1 C2Hs COOCH (Ph) 2 VIII-2 * 2 7- [2- (5-Amino-l, 2.4-thiadiazol-3-vl) - 2- (Z) -ethoxyimi-noacetamido] -3- [3-chloro-1-propenyl] -3-cephem-4- • ^ diphenylmethyl arboxvlate (VIII-2, isomer 2)

2- (5-amino-1,2,4,4-thiadiazol-3-yl) -2- (Z) -ethoxyiminoacetylchloride hydrochloride (800 mg, 2.95 milliliters) is added gradually with stirring. ) at -10 ° C to a mixture of N, o-bis (trimethylsilyl) ~ acetamide (2.3 ml, 9 millimoles) and 7-amino-3- [3-chloro-1- (Z) propen hydrochloride -l-yl] -3-cephem- crystalline diphenylmethyl 4- carboxylate (XVIII) (1.338 g, 2.8 millimoles) (of preparation No 12) in methylene chloride (10 ml) and the mixture is left to stand for 2 hours at 0 ° C. The mixture is diluted with ethyl acetate (200 ml), washed with water and evaporated under reduced pressure. By trituration of the residue in isopropyl ether, the product announced in title VIII-2 is obtained, which is an amorphous powder. Production 1.70 g (95%); PF.> 150eC (decomposition).

IR: Ό (KBr) in cm-1 3300, 1780, 1720, 1690, 1380, max '1220.

~ UV: λ (CoH_0H) in nm (e) 285 (11000).

“Max zd NMR: 6 (DMSO-dg) in ppm 1.26 (3H, t, 3 = 1 Hz, CH2CH3), 4.25 (2H, q, J = 7 Hz, CH2CH3), 5.90 (1H , dd, J = 4 and 8 Hz, 7-H), 6.26 (1H, d, J = 11 Hz, 3-CH), 6.85 (1H, s.

CHPh2), 9.53 (1H, d, J = 8 Hz, 7-NH)

Preparation No 21

^ S

* N-r — C-CONH— | -f V

XX JXX · C2H5 COOCH (Ph) 2.

^ ^ A mixture of isomers

E and Z

7— [2 - (5-Amino-1,2,4-thiadiazol-3-yi \ 0.

--— 1—1-Z) -ethoxyimxno-, acetamido] -3-n-iodp ^ -propénYl] -3-cephfe | lle_4_c! Irbti; tv_ late of diphenylmethyl (IX-2)

The mixture is stirred for 10 minutes at room temperature and then left to stand at 5 ° C. for 3 hours a mixture of VIII-2 (1.90 g, 3 millimoles) (of preparation No 20) and iodide of sodium (1.4 g, 9 millimoles) in acetone (20 ml), the mixture is evaporated under reduced pressure, diluted with ethyl acetate (100 ml), washed with thiosulphate 10% sodium and water and evaporated under reduced pressure. By trituration of the residue in isopropyl ether, 1.82 g (84%) of the product mentioned in title IX-2 is obtained, which is a light brown amorphous powder.

IR: O (KBr) in cm “1 3290, 1770, 1720, 1670, 1530, 1370, 1220 UV: λ (CoHc0H) in nm (E1%) 304 (199) max 25 1 cm

Preparation No 22 m.

* ^ ^ ^

Nvs ^ * CI ^ CH-CH2-N ^^ CONH2 COOCH (Ph) 2

XXI-H iodide * E

? -Benzylideneamino-3 - [(E) -3- (4-carbamoylpyridinio) -1- propenyl] -3-cephem-4-carboxylate (diphenylmethyl (XXI-H iodide) (E isomer)

Kl (20 g, 120 millimoles) is added in one portion to a cooled solution of 3-chloropropenyl cephem (XVII, Z-isomer, 42.8 g, 90 millimoles): (of preparation No 16) in DMF dry (80 ml) and stir the mixture at room temperature. The progress of the reaction is observed by means of the ratio 1 1¾ of the absorptions in the UV [E ^ (255 nm) / Εη (320 nm)].

When the ratio has dropped below 1.10 (after 45 minutes), the mixture is diluted with 800 ml of methylene chloride, activated carbon (4 g) is added thereto and filtered. The filter cake is washed with 100 ml of methylene chloride. Isotonicotinamide (14.64 g) is added to the filtrate mixture and wash liquors and the mixture is concentrated under reduced pressure. The concentrate is allowed to stand at room temperature for 1.5 hours and washed with a mixture of toluene and n-heptane (1: 1, 600 ml). The residual brown semi-solid is dissolved in methylene chloride (100 ml) and the solution is added dropwise to ethyl acetate (3000 ml) with vigorous stirring. After drying over P2 ° 5 under vacuum, 57.37 g (88%) of the quaternized compound mentioned in title XXI-H is collected in the form of the iodide. It is a yellow amorphous powder. PF. 150-155eC (decomposition).

This product is identical to that obtained by iodization using Nal (preparation No 17).

- Preparation No 23; HCl-HjN— | -S ^ CH «CH-CH2-C1 C00CH (Ph) 2 XVIII * z

7-amino-3- (3-chloro-1-propenvl) -3-cephem-4-carboxyl-diphenylmethyl hydrochloride (Z-isomer) (XVIII. Hydrochloride)

25% chloroaceous solution is added ”. taldehyde (69 g, 0.22 mole) in chloroform at one time to a solution of XVI (80 g, 0.11 mole) in methylene chloride (1100 ml) containing N, 0-bis (trimethylsilyl) acetamide (16.2 ml, 0.06 mole) at -10 ° C and the mixture is left to stand overnight at 5 ° C. The mixture is concentrated to approximately 300 ml, diluted with a mixture of ethyl acetate and isopropyl ether (1/2, 600 ml). Silica gel (Wakogel C-100, 60 g) is added thereto and the whole is filtered through a layer of Dicalite. The filter cake is washed with the same mixture of solvents (200 ml). ^ The filtrate and the washing liquors are combined and concentrated to around 200 ml, Girard T reagent (60 g, 0.26 mole) and 4N HCl (220 ml) are added thereto, then the mixture is inoculated. resulting with some XVIII hydrochloride crystals. After 3 hours of stirring, the resulting crystals are collected by filtration, which is washed with water (500 ml) and with ethyl acetate (500 ml), then dried under vacuum to obtain 37 g (70%) of the title compound, which is XVIII hydrochloride, melting at> 185 ° C (decomposition). They are pale yellow needles. This product is identical to that obtained in preparation No 12.

Preparation No 24

* HCl * H2N— | -f S

J — N * cr ch “ch-ch2 ci

COOCH (Ph) 2 XVIII * Z

7-amino-3- (3-chloro-1-propenyl) -3-cephem-4-diphenylmethyl hydrochloride (Z-isomer) (XVIII hydrochloride)

N, 0-bis- * (trimethylsilyl) acetamide (0.135 ml, 0.5 millimole) and XVI (728 mg, 1 millimole) are successively added at 5 ° C. to a solution of chlo-roacetaldehyde (25% solution in chloroform, 628 mg, 2 millimoles) in methylene chloride (10 ml). The mixture is left to stand overnight at 5 ° C. The mixture is evaporated and diluted with a mixture of ethyl acetate and isopropyl ether (1/2, 10 ml). The insolubles are separated by filtration and the filtrate is concentrated to approximately 5 ml.

4N HCl (2 ml) is added to the concentrate which is seeded with XVIII hydrochloride and stirred for 1 hour at room temperature. The crystals are collected by filtration, which is washed with ethyl acetate * (10 ml) and with water (10 ml), then dried under vacuum to obtain 384 mg (80%) of the advertised compound. under the title which is the hydrochloride of XVIII, melting at> 185 ° C. (decomposition). They are pale yellow needles.

This product is identical to that obtained in preparation No 12.

Preparation No 25

2- (5-amino-1,2,4-thiadia-zol-3-yl) -2- (propen-3-yloxvimino) -acétvle hydrochloride hydrochloride (III-3 as its chloride hydrochloride acid) A. 2- (5-t-Butoxycarbonvlamino-1.2.4-thiadiazol-3-yl) - 2- (propen-3-yloxyimino) methyl acetate *

A mixture of 685 mg (3.37 millimoles) of N- (propen-3-yloxy) phthalimide [prepared according to E. Grochosaki and J. Jurczak, Synthesis 1976 682] and 175 is stirred for 1 hour at room temperature. mg (3.35 millimoles) of hydrazine hydrate in 5 ml of ethanol. The resulting precipitate is filtered off and the filtrate and the washing liquors are combined. 967 mg (3.37 millimoles) of 2- (5-t-butoxycarbonylamino-1,2,4-thiadiazol-3-yl) -2-methyl oxoacetate are added to the solution and the mixture is allowed to stand. for 1 hour at room temperature, then concentrated on a rotary evaporator. The residue is purified by chromatography on silica gel. The column is eluted with n-hexane: ethyl acetate (4: 1) and the fractions containing the main product are combined, then they are evaporated under reduced pressure. Production 514 mg (46%).

PF. 83-86 ° C.

IR (KBr) in cm "1 3100, 1745, 1710, 1610 max uv: ^ mav (C, H, 0H) in nm (€) 223 (9700), 242 (10000).

^ NMR: δ (CDC13) in ppm 1.55 (9H, s, BOC-H), 4.40 (2H, d, J = 5 Hz, 0-CH2), 5.21 (2H, m, CH2 = CH), 5.90 (1H, m, -CH = CH2), 9.50 (1H, S 1, NH).

B. Acid 2- (5-t-butoxvcarbonvlamino-l.2,4-thiadiazol- 3- vl) -2- (propén-3-vloxvimino) acetic1 ^

A solution of 770 mg (2.3 moles) of 2- (5-t-butoxycarbo-nylamino-1,2,4-thiadiazol-3-yl) -2- (propen-3- is heated at reflux for 30 minutes. yloxy-imino) methyl acetate and 3.5 ml of 2N NaOH solution (7.0 millimoles) in 15 ml of methanol.

The reaction mixture is concentrated in vacuo and diluted with 10 ml of ethyl acetate: H2O (1: 1). The aqueous layer is separated, acidified to pH 2 with 6N HCl and extracted with ethyl acetate *. (2 x 10 ml). The ethyl acetate solution is dried over MgSO 4 and concentrated in a rotary evaporator to obtain 596 mg (81%) of the title compound. PF. 134-135 ° C (mp 135-136 ° C in the literature1 ^).

IR: ^ max (Nu ^ ol) in cm_1 315 °, 1745, 1710, 1550.

UV: λ (C0H-OH) in nm (£) 223 (11000), 242 (11300).

max 2 5 NMR: 6 (DMSO-dg) in ppm 1.55 (9H, s, BOC-H), 4.77 (2H, d, J = 5 Hz, 0-CH2), 5.22 (2H, m, CH2 = CH), 6.0 (1H, m, ch = ch2).

1) I. Csendes, et al., J. Antibiotics, 366-1020 (1983). vs. 2- (5-amino-1,2,4-thiadiazol-3-yl) -2- (propen- 3-yloxyimino) acetic acid (111-3) ^

A solution of 570 mg (1.74 millimole) of 2- (5-t-butoxycarbonylamino-1,2,4-thia-diazol-3-yl) -2- is allowed to stand for 1 hour at room temperature. (propen-3-yloxyimino) -acetic in 6 ml of trifluoroacetic acid. By evaporation, then trituration in 30 ml of isopropyl ether, 376 mg (95%) of the title compound are obtained. PF. 109 ° C (decomposition).

IR: Ό (Nujol) in cm-1 3180, 1710, 1545, 1460.

UV: λ (C „H, OH) in nm (£) 245 (13500).

"max 2 d NMR: <5 (DMSO-dg) in ppm 4.77 (2H, d, J = 5 Hz, 0-CH2), 5.20 (2H, m, CH = CH), 6.0 ( 1H, m, CH = CH2).

1) Japan Kokai 57-112396 (13/7/82, Fujisawa) English patent application 7935538 (12/10/79).

D. 2- (5-Amino-1,2,4-thia-diazol-3-yl) -2- (propen-3-yloxyimino) acetyl chloride hydrochloride

A solution of 350 mg (1.54 millimole) of III-3 and 410 mg (1.97 millimole) of phosphorus pentachloride in dichloromethane (5 ml) is stirred for 1 hour at 25 ° C. The reaction mixture is poured into 60 ml of n-hexane and the precipitate Ä is collected by filtration. Production 323 mg.

* IR: A:) max (Nujol) in cm-1 1765.

Preparation No. 26 v 2- (5-amino-1,2,4-thiadia-zol-3-yl) -2-proparqvloxviminoacétvle chloride hydrochloride (III-4 as its acid chloride hydrochloride) A. 2- (5-t-Butoxycarbonylamino-1.2. 4-thiadiazol-3-vl) 7 2- methyl proparqvloxyiminoacetate

The mixture is stirred at 25 ° C. for 1 hour and a suspension of 870 mg (4.32 millimoles) of N-propyloxyphthalimide * and of 200 mg (4.0 millimoles) of hydrazine hydrate in 5 is filtered. ml of ethanol. To the mixture of filtrate and washing liquors are added 1.0 g (3.86 millimoles) of 2- (5-t-butoxycarbonylamino- 2) 1,2,4-thiadiazol-3-yl) -2-oxoacetate methyl. The solution is left to stand for 1 hour and concentrated under reduced pressure. By purification by chromatography on silica gel, then evaporation, 319 mg (27%) of the title compound is obtained. PF. 72-75eC.

IR (KBr) in cm-1 3200, 2380, 1745, 1710, 1610.

max i i i i UV: λ (C-H-OH) in nm (£) 235 (12200).

max 2 5 NMR: δ (DMSO-dg) in ppm 1.56 (9H, s, BOC-H), 3.55 (1H, t, J = 2 Hz, C = CH), 4.85 (2H, d, J = 2 Hz, -CH ^ -C = CH), 8.9 (1H, s 1, NH).

1) Marketed product, Aldrich company.

2) I. Csendes et al., J. Antibiotics 3 £, 1020 (1983).

B. 2- (5-t-butoxycarbonylamino-1,2,4-thiadiazol-3-yl) -2-proparqyloxyiminoacetic acid

A solution of 490 mg (1.4 millimole) of 2- (5-t-butoxy-carbonylamino-1,2,4-thiadiazol-3-yl) -2-propargyloxy-iminoacetate is heated under reflux for 30 minutes. and 2.2 ml of 2N aqueous NaOH solution (4.4 millimoles) in 14 ml of methanol. The reaction mixture is concentrated under reduced pressure and 10 ml of ethyl acetate: Η £ θ (1: 1) ^ are added to the solution. The aqueous layer is separated and acidified to pH 2 with 6N HCl and extracted * with ethyl acetate (2 x 10 ml). By drying on

MgS04, then evaporation of the organic layer, CD.MJ - 128 - obtains 149 mg (89%) of the title compound.

PF. 135eC (decomposition).

IR: ^ max {Nu3ol) in cm_1 3350, 1720, 1670, 1550.

uv: λ v (C, H_0H) in nm (6) 233 (11500).

- max to d 1 NMR: <5 (DMSO-dg) in ppm 1.55 (9H, s, BOC-H), 3.55 (1H, t, J = 2 Hz, C = CH), 4.89 (2H, d, J = 2 Hz, CH2CSCH), 9.0 (1H, s, NH).

C. 2- (5-amino-1.2.4-thiadiazol-3-vl) -2-pro 3) parqyloxyiminoacetic acid (III-4)

A solution of 410 mg (1.26 millimole) of 2- (5-t-butoxycarbonylamino-1,2,4-thiadiazol-3-yl) -2-propargyloxyiminoacetic acid is allowed to stand at 25 ° C. for 1 hour. 5 ml of trifluoro-roacetic acid. By evaporation, then trituration of the residue in 25 ml of isopropyl ether, * "204 mg (72%) of the title compound are obtained. Mp. 156-158 ° C (decomposition).

i IR: λ) (Nuiol) in cm “1 3300, 2480, 1730, 1610.

max · * 'UV: λ (CoHc0H) in nm (6) 234 (12000) max 2 5 NMR: 6 (DMSO-dg) in ppm 3.52 (1H, t, J = 2Hz, C = CH), 4 , 86 (2H, d, J = 2Hz, CH2-C = CH), 8.10 (2H, s 1, NH2).

3) Japan Kokai 57-112396 (13/7/82, Fujisawa) English patent application 7935538 (12/10/79).

D. 2- (5-amino-l. 2.4-thia-diazol-3-yl) -2-proparavloxviminoacetvle chloride hydrochloride

A mixture of 175 mg (0.07 millimole) of III-4 and 182 mg (0.88 millimole) of phosphorus pentachloride in dichloromethane (2 ml) is stirred for 1 hour at -5 ° C. The reaction mixture is poured into 30 ml of n-hexane and the precipitated t is collected by filtration. Production 65 mg (34%).

IR: O (Nujol) in cm ““ 1770. max J

»Preparation No 27

2- (5-amino-1,2,4-thiadia-zol-3-yl) -2-cyclopentyloxyiminoacetylchloride hydrochloride (III-5 in the form of its acid chloride hydrochloride) A. 2- ( Methyl 5-t-Butoxycarbonylamino-1,2,4-thiadiazol-3-_yl) -2-cyclopentyloxyiminoacetate

The mixture is stirred for 1 hour at room temperature, then a suspension of 860 mg (3.7 millimoles) of N- (cyclopentyloxyphthalimide) and of 185 mg (3.7 millimoles) of hydrazine hydrate in 5 ml is filtered. ethanol. Combine the filtrate and wash liquors and add them to 1.06 g (3.7 millimoles) of 2- (5-t-butoxycarbonylamino-1,2,4-thia-diazol-3- yl) -2-methyl oxoacetate The solution is left to stand for 1 hour at room temperature and evaporated in vacuo, the residue is purified by chromatography on a column of silica gel, by elution with n-hexane: ethyl acetate ** (4: 1), then evaporation, the title compound is obtained, production 906 mg (81%), mp 115-118 ° C.

IR: "\) (KBr) in cm" 1 3200, 1745, 1710, 1550 max '' 'UV: λ (CoHc0H) in nm (8) 217 (1800), 252 (7600). max î 5 'NMR: <5 (CDCl3) in ppm 1.51 (9H, s, BOC-H), 1.60 (8H, s 1, H- ^ J), 3.88 (3H, s, OCH3 ), 4.90 (1H, s 1,), 8.70 (1H, s 1, NH).

1) Patent EUA 3,971,778 (27/7/76; Glaxo), English patent application 49255 (25/10/72).

2) I. Csendes et al. , J. Antibiotics 36, 1020 (1983).

B. 2- (5-t-butoxycarbonylamino-1,2,4-thiadiazol- * 3-yl) -2-cvclopentvloxviminoacetic acid

A solution of 500 mg (1.34 millimole) of 2- (5-t-butoxycarbonylamino-1,2,4-thiadiazol-3-yl) -2-cyclopentyloxy-iminoacetate is heated at reflux for 30 minutes. methyl and a solution of 2N NaOH (2 ml, 4 millimoles) in 15 ml of methanol. The reaction mixture is evaporated and 10 ml of ethyl acetate (1: 1) are added to the solution. The aqueous layer is separated, acidified to pH 2 with 6N HCl and extracted with ethyl acetate (2 x 10 ml).

The organic layer is washed with brine, dried over MgSO 4 and concentrated under reduced pressure to obtain 377 mg (18%) of the title compound. PF. 185 ° C (decomposition).

IR:>) max (KBr) in cm_1 3160 »1710, 1550.

UV: λ (CoHc0H) in nm (ε) 238 (13300) max 2 5 NMR: 6 (DMSO) in ppm 1.51 (9H, s, BOC-H), 1.70 (8H, s 1, H- ^ J), 4.82 (1H, m,).

C. 2- (5-Amino-1,2,4-thiadiazol-3-yl) -2-cyclopen- 3) tyloxyiminoacetic acid (III-5, Z-isomer)

A solution of 348 mg (0.97 milli mole) of 2- (5-t-butoxycarbonylamino-1,2,4-thia-diazol-3-yl) solution is allowed to stand for 1 hour at room temperature. ) -2-cyclopentyloxyiminoacetic in 2 ml of trifluoroacetic acid. The reaction mixture is concentrated under reduced pressure. The residue is triturated in 5 ml of isopropyl ether and 10 ml of hexane is added thereto to collect 215 mg (86%) of the title compound. PF. 162-165 ° C (decomposition) 3) [PF. 160-165 ° C (decomposition) in the literature].

IR: Λ> (Nujol) in cm "1 3290, 3200, 1710, 1615, 1600.

max J "'' 'UV: λ (C" HcOH) in nm (€) 238 (13300) max 2 5 NMR: 6 (DMSO-dg) in ppm 1.17-2.10 (8H, m), 4 , 60-4.98 "(1H, m), 8.22 (2H, s).

3) Japan Kokai 57-158769 (30/9/82, Fujisawa) English patent application 8107134 (6/3/81).

D. 2- (5-amino-1,2,4-thia- * diazol-3-vl) -2-cvclopentvloxviminoacétvle chloride hydrochloride

A solution of 190 mg (0.74 millimole) of III-5 and 219 mg (1.0 millimole) of phosphorus pentachloride in dichloromethane (5 ml) is stirred for 1 hour at room temperature. The reaction mixture is poured into 50 ml of n-hexane. The resulting precipitate is collected by filtration.

Production 122 mg (60/6).

IR (Nujol) in cm- ^ 1760.

max

Preparation No. 28 2- (5-Amino-1,2,4-thiadiazol-3-yl) -2-methoxyiminoacetate benzotriazol-1-yl.

A mixture of 1-hydroxybenzotriazole (2.7 g, 20 millimoles) and dicyclohexylcarbodiimide (4.12 g, 20 millimoles) in 65 ml of DMF is stirred at room temperature. After 15 minutes, III-1 (4.04 g, 20 millimoles) is added to the stirred mixture at 0 ° C and stirring is continued for 3 hours. The reaction mixture is filtered to separate the insoluble urea; and the filter cake is washed with a small volume of DMF. The filtrate and the washing liquors are combined and poured into 800 ml of ice water. The precipitate is collected by filtration to obtain 5.24 g (82%) of the title compound, which is a light gray powder. PF. 189-192 ° C (decomposition).

IR î '* „(KBr) in cm-1 1815, 1620, 1540, 1415, 1090, max 1060, 1005, 945, 865, 740.

UV: X (C ^ Ht-OH) in nm (E ^) 246 (580), 283 epau- max 25 1 cm also (228).

a »Α ν V»

Claims (71)

1. Composed of form N-r-C-CONH —____ ^ s \ Ji it! "f ^ R1 ™ s 'OR2 <yn \ î ^' ch-ch-ch2-n = q cocß 1 where R1 represents a hydrogen atom or a classical radical protecting the amino function, R2 represents a hydrogen atom , A straight or branched chain alkyl radical of 1 to 4 carbon atoms, a cycloalkyl or cycloalkenyl radical of 3 to 6 carbon atoms, a radical of formula 4 4 4 vf R COOH R -C-CH = CH -R3, -Ç-C = C-R3, X or -C-COOH, ^ i5 Ÿ ^ X 3 where R represents a hydrogen atom or lower alkyl or carboxyl radical, X represents a halogen atom or hydroxyl radical or lower alkoxy and R and R each independently represent a hydrogen atom or methyl or ethyl radical. or R 5 and R 5 taken together with the carbon atom to which they are united may represent a cycloalkylene radical of 3 to 5 atoms of carbon and ΘΝ = q * represents a quaternary ammonio radical, or non-toxic pharmaceutically acceptable salt, solvated, hydrates or physiologically hydrolyzable ester of this compound. 2. Compound according to claim 1, in which is chosen from • ü. . . 4fY ‘. .à »W /" R17 R17 1 © I © "T>“ 'T ~ fv "· *'" uri% 13 14 15 or R, R “and R“, identical or different, each represents a lower alkyl radical, lower alkyne, lower aminoalkyl with the restriction that the amino radical may not be borne by - an a carbon atom, or lower hydroxyalkyl with the restriction that the hydroxyl radical may not be borne by an a carbon atom; 16, R "represents a hydrogen atom or radical lower alkyl, lower alkoxy, alkyl (lower) thio, amino, alkyl (lower) amino, dialcoyl (lower) amino, formylamino, alkanoyl (lower) amino, carboxyl, hydroxyl, carboxyalkyl, car-boxyalcoyl (lower) thio, lower hydroxyalkyl, lower haloalkyl, lower aminoalkyl, (lower) alkoxy lower alkyl, carbamoyl or N-lower (carbamoyl) N-alkyl well R * ^ may represent a divalent alkylene radical of 3 to 5 carbon atoms ; 17 R represents a lower alkyl radical, lower (lower) alkoxy, lower alkyl, lower haloalkyl, allyl, lower hydroxyalkyl with the restriction that the hydroxyl radical is not carried by the carbon atom a, lower aminoalkyl with the restriction that the amino radical is not carried by the carbon atom ce, or lower phenylalkyl; • j 8 R “represents a hydrogen atom or radical lower alkyl, lower alkoxy, alkoxy (lower) -lower alkyl, alkyl (lower) thio, amino, al-coyl (lower) amino, dialcoyl (lower) amino, because -boxyl, hydroxyl, lower carboxyalkyl, hydroxy-lower alkyl, lower aminoalkyl, formylami-no, alkanoyl (lower) amino, carbamoyl or N-alkyl (lower) carbamoyl; n represents 1, 2 or 3; Z represents CKL · or; when n represents 2, Z can 4 19 19 also represent S, 0 or N-R ~, where R represents a hydrogen atom or lower alkyl radical; and 20 21 R and R, identical or different, each represent a hydrogen atom or lower alkyl, lower alkoxy, lower alkyl thio, amino, lower alkyl amino, lower dialkylamino, carboxyl, hydroxyl, lower hydroxyalkyl, lower aminoalkyl, (lower) alkoxy lower alkyl, lower carboxyalkyl, carboxyalkyl (lower) amino, alkanoyl (lower) amino, carboxyalkanoyl- (lower) amino, carbamoyl or N-alkyl (lower) -carbamoyl. 3. X where R represents a hydrogen atom or lower alkyl or carboxyl radical, X represents a halogen atom or 4 5, „hydroxyl or lower alkoxy radical and R and R each independently represent a hydrogen atom or radical _, 4 5; methyl or ethyl, or else R and R taken together with the carbon atom to which they are united may represent a cycloalkylidene radical of 3 to 5 carbon atoms, B ^ - represents a hydrogen atom or rm u radical -r classic TAA protecting the carboxyl function and Z represents a chloro, bromo or iodo radical, or a salt, hydrate, solvate or ester of this compound. 3. Compound according to claim 2, in 2 the formula in which R represents a lower alkyl, cycloalkyl radical of 3 to 5 carbon atoms, 1-carboxycycloalco-l-yl of 3 to 5 carbon atoms, allyl, propargyl or lower carboxyalkyl . 4. The compound of claim 3 which * is 7- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2-metho-xyiminoacetamido 3-3- [3- (trimethylammonio) -1-propen-1-yl] -3-cephem-4-carboxylate, or a non-toxic pharmaceutically acceptable salt, the solvate, hydrate or physiologically hydrolyzable ester thereof. 5. The compound of claim 3 which is 7- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2-methoxy-iminoacetamido] -3- [3- (1-methylpyrrolidinio ) -1-propen-1-yl] -3-cephem-4-carboxylate, or a non-toxic pharmaceutically acceptable salt, solvate, hydrate or physiologically hydrolyzable ester thereof. 6. A compound according to claim 3 which is 7- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2-methoxy-iminoacetamido] -3- [3-pyridinio-l- propen-1-yl] -3-cephem-4-carboxylate, or a non-toxic pharmaceutically acceptable salt, solvate, hydrate or physiologically hydrolyzable ester thereof. 7. The compound of claim 3 which is 7- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2-methoxy-iminoacetamido] —3 - [3— (3-aminopyridinio ) -1-propen-1-yl] - 3-cephem-4-carboxylate, or a non-toxic pharmaceutically acceptable salt, solvate, hydrate or physiologically hydrolyzable ester thereof. 8. The compound of claim 3 which is 7- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2-methoxy-iminoacetamido 3 - 3 - [3 - (3-formylaminopyridinio ) -1-propen-1-yl] -3-cephem-4-carboxylate, or a non-toxic pharmaceutically acceptable salt, solvate, hydrate or physiologically hydrolyzable ester thereof. 9. A compound according to claim 3 which is 7- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2-methoxyiminoacetamido] -3- [3- (3- aminomethylpyridinio) -1-pro- * pen-1-yl] -3-cephem-4-carboxylate, or a non-toxic pharmaceutically acceptable salt, solvate, hydrate or physiologically hydrolyzable ester thereof. 10. The compound of claim 3 which is 7- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2-methoxy-iminoacetamido] -3- [3- (3-carbamoylpyridinio ) -l-propen-1-yl] -3-cephem-4-carboxylate, or a non-toxic pharmaceutically acceptable salt, solvate, hydrate or physiologically hydrolyzable ester thereof. 11. The compound of claim 3 which is 7- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2-methoxy-iminoacetamido] -3- [3- (4-carbamoylpyridinio ) -1-propen-1-yl] -3-cephem-4-carboxylate, or a non-toxic pharmaceutically acceptable salt, solvate, hydrate or physiologically hydrolyzable ester thereof. 12. The compound of claim 3 which is 7- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2-methoxy-iminoacetamido] -3- [3- (2-methylthiazolio ) -l-propen-1-yl] - v 3-cephem-4-carboxylate, or a non-toxic pharmaceutically acceptable salt, solvate, hydrate or physiologically hydrolyzable ester thereof. 13. The compound of claim 3 which is 7- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2-methoxy-iminoacetamido] -3- [3- (2-amino -5-thiazolo [4,5-c] pyridi-nio) -l-propen-l-yl] -3-cephem-4-carboxylate, or a non-toxic pharmaceutically acceptable ester, solvate, hydrate or physiologically hydrolyzable ester of it. 14. The compound according to claim 3, which - is 7- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2-methoxyiminoacetamido] -3- [3- (4- hydroxymethylpyridinio) -1- * propen-1-yl] -3-cephem-4-carboxylate, or a non-toxic pharmaceutically acceptable salt, solvate, hydrate or physiologically hydrolyzable ester thereof. 15. The compound of claim 3 which is 7- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2-methoxy-iminoacetamido] -3- [3- (3-hydroxymethylpyridinio ) -1-pro-pen-1-yl] -3-cephem-4-carboxylate, or a non-toxic pharmaceutically acceptable salt, solvated, hydrate or physiologically hydrolyzable ester thereof. 16. The compound of claim 3 which is 7- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2-methoxy-iminoacetamido] - 3 - [3- (4- ^ N-methylcarbamoylJpyridinio) -1-propen-1-yl] -3-cephem-4-carboxylate, or a non-toxic pharmaceutically acceptable salt, solvate, hydrate or physiologically hydrolyzable ester thereof. 17. The compound according to claim 3, which is 7- [2- (5-amino-1,2,4-thiadiazol-3-yi) -2-methoxyiminoacetamido] -3- [3- (2, 3-propylenepyridinio) -1-pro-. · Pen-1-yl] -3-cephem-4-carboxylate, or a non-toxic pharmaceutically acceptable salt, solvate, hydrate or physiologically hydrolyzable ester thereof. 18. The compound of claim 3 which is 7- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2-ethoxy-iminoacetamido] -3- [3- (4-carbamoylpyridinio ) -1-propen-1-yl] -3-cephem-4-carboxylate, or a non-toxic pharmaceutically acceptable salt, solvate, hydrate or physiologically hydrolyzable ester thereof. 19. The compound of claim 3 which * is 7- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2-cyclopentyloxyiminoacetamido] -3- [3- (4- carbamoylpyridinio) - Ξ 1-propen-l-yl] -3-cephem-4-carboxylate, or a non-toxic pharmaceutically acceptable salt, solvate, hydrate or physiologically hydrolyzable ester thereof. 20. The compound of claim 3 which is 7- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2-allyloxy-iminoacetamido] -3- [3- (4-carbamoylpyridinio ) -1-propen-1-yl] -3-cephem-4-carboxylate, or a non-toxic pharmaceutically acceptable salt, solvate, hydrate or physiologically hydrolyzable ester thereof. 21. The compound of claim 3 which is 7- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2-propar-gyloxyiminoacétamido 3—3-C3- (4-carbamoylpyridinio) -1-propen-1-yl] -3-cephem-4-carboxylate, or a non-toxic pharmaceutically acceptable salt, solvate, hydrate or physiologically hydrolyzable ester thereof. 22. The compound of claim 3 which is 7- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2-methoxy-iminoacetamido] -3- [3- (4-carboxypyridinio ) -1-propen-1-yl] -3-cephem-4-carboxylate, or a nontoxic, pharmaceutically acceptable, solvated, hydrated or physiologically hydrolyzable salt thereof. 23. The compound of claim 3 which is 7- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2-ethoxy-iminoacetamido] -3- [3- (4-carboxypyridinio ) -2-propen-1-yl] -3-cephem-4-carboxylate, or a non-toxic pharmaceutically acceptable salt, solvate, hydrate or physiologically hydrolyzable ester thereof. 24. The compound of claim 3 which is 7- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2-methoxy-iminoacetamido] —3 - [3— (3-carboxymethylpyridinio ) - • ht - 1-propen-1-yl] -3-cephem-4-carboxylate, or a non-toxic pharmaceutically acceptable salt, solvate, hydrate or physiologically hydrolyzable ester thereof. 25. A compound according to claim 3, which. is 7- [2- (5-amino ~ 1,2,4-thiadiazol-3-yl) -2-methoxyiminoacetamido 3-3-C3- (4-carboxymethylthiopyridinio) -1-propen-l-yl] -3-cephem-4-carboxylate, or a non-toxic pharmaceutically acceptable salt, solvated, hydrate or physiologically hydrolyzable ester thereof. 26. Compound of formula 11 --- dd-CONH - {X0R2 c / ~ ”2 COOB1 where R1 represents a hydrogen atom or a classic 2 u radical protecting the amino function, R represents a hydrogen atom or a straight or branched chain alkyl radical of 1 to 4 carbon atoms, a cycloalkyl or cycloalkenyl radical of 3 to 6 carbon atoms or a radical of formula 4 4 4 RR rnnn RI 3 I 3 vj -C-CH = CH -R, -CC = CR, V or -C-COOH J 'À * Λ 27. Compound according to claim 26, * in the formula of which Z represents a chloro 7 * or iodo radical and R represents a lower alkyl radical, cycloalkyl of 3 to 5 carbon atoms, 1-carboxycy-cloalco-l-yl 3 to 5 carbon atoms, allyl, propargyl or lower carboxyalkyl, or a salt, hydrate, solvate or ester of this compound. 28. A compound according to claim 27, 2 in the formula of which R represents a methyl, ethyl, cyclopentyl, allyl or propargyl radical. 29. Compound according to claim 28, in the formula of which B ~ represents a hydrogen atom or benzhydryl radical and R "represents a hydrogen atom or trityl radical. ** '30 - A compound according to claim 29 which is 7- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2-methoxyiminoacetamido] -3- (3-iodo-1 -propen-1-yl) -3-cephem-4-carboxylate of diphenylmethyl, or a salt, hydrate, solvate or ester thereof. 31. The compound of claim 29 which is 7- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2-etho-xyiminoacetamido] -3- (3-iodo-l- diphenylmethylpropen-1-yl) -3-cephem-4-carboxylate, or a salt, hydrate, solvate or ester thereof. 32. The compound of claim 29 which is 7- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2- r cyclopentyloxyiminoacetamido] -3- (3-iodo-l-propen -l- yl) -3-cephem-4-carboxylate of diphenylmethyl, or a salt, hydrate, solvate or ester thereof. 33. A compound according to claim 29 which is 7- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2-allyloxyiminoacetamido] -3- (3-iodo-l-propen- 1-yl) -3- cephem-4-carboxylate of diphenylmethyl. or a salt, hydrate, solvate or ester thereof. 34. A compound according to claim 29 which is 7- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2- ~ propargyloxyiminoacétamido] -3- (3-iodo-l-propen -l-yl) - diphenylmethyl 3-cephem-4-carboxylate. u or a salt, hydrate, solvate or ester thereof. 35. A compound according to claim 29 which is 7- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2-methoxyiminoacetamido] -3- (3-chloro-1-propen- l-yl) -3-cephem-4-diphenylmethyl carboxylate. or a salt, hydrate, solvate or ester thereof. 36. The compound of claim 29 which is 7- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2-etho-xyiminoacetamido] -3- (3-chloro-l- propen-1-yl) -3-cephem- i diphenylmethyl 4-carboxylate. or a salt, hydrate, solvate or ester thereof. 37. A compound according to claim 29 which is 7- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2-cy-clopentyloxyiminoacetamido] -3- (3-chloro-l- diphenylmethylpropen-1-yl) -3-cephem-4-carboxylate, or a salt, hydrate, solvate or ester thereof. 38. The compound of claim 29 which is 7- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2-allyloxyiminoacetamido] -3- (3-chloro-1-propen- 1-yl) -3-cephem-4-diphenylmethyl carboxylate, or a salt, hydrate, solvate or ester thereof. 39. The compound of claim 29 which is 7- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2-, propargyloxyiminoacetamido] -3- {3-chloro-1-propen -l-yl) - diphenylmethyl 3-cephem-4-carboxylate. 40. Compound of formula HN — i-r '·' SN * I xxii N 'N ^ kCH * CH-CH2-N = Q cocß • i, © where -N = Q represents a quaternary ammonio radical or a salt, ester , solvate or hydrate of this compound. 41. Compound according to claim 40, in the formula of which @N = Q is chosen from ·· &. * <y ”? 17 R17 i © I © • O · 'i- CD. ,, r18 / r2 (/ R 131415 where R ~, R“ and R “, identical or different, each represents a lower alkyl radical, alcé -lower alkyl, lower aminoalkyl with the restriction that the amino radical cannot be carried by a carbon atom, or lower hydroxyalkyl with the restriction that the hydroxyl radical cannot be carried by a carbon atom tt; - R represents an atom hydrogen or lower alkyl, lower alkoxy, lower (alkyl) thio, amino, lower (amino) amino, dialkoyl (lower) amino, formylamino, lower (alkanoy) amino, carboxyl, hydroxyl, lower carboxyalkyl, carboxyalkyl (lower) thio, lower hydroxyalkyl, lower haloalkyl, lower aminoalkyl, alkoxy (lower) lower alkyl, carbamoyl or N-alkyl (lower) carbamoyl, or R ^ may represent a divalent alkylene radical of 3 to 5 carbon atoms; 17 / R represents a lower alkyl radical, alkoxy- (lower ur) lower alkyl, lower haloalkyl, allyl, lower hydroxyalkyl with the restriction that the hydroxyl radical is not carried by the carbon atom a, lower aminoalkyl with the restriction that the amino radical is not carried by the atom carbon a, or lower phenylalkyl; 18 Rx represents a hydrogen atom or lower alkyl, lower alkoxy, (lower) alkoxy-lower alkyl, lower (thio) alkyl, amino, al-u coyl (lower) amino, dialcoyl (lower) amino, boxyl, hydroxyl, lower carboxyalkyl, lower hydroxyalkyl, lower aminoalkyl, formylami-no, alkanoyl (lower) amino, carbamoyl or N-alkyl (lower) carbamoyl; n represents 1, 2 or 3; Z represents CH? or, when n represents 2, Z can also represent S, 0 or N-R, where R represents a hydrogen atom or lower alkyl radical; and 20 21 R and R “, identical or different, each represent a hydrogen atom or radical lower alkyl, lower alkoxy, alkyl (lower) thio, ^ amino, alkyl (lowerJamino, dialcoyl (lower) - amino, carboxyl, hydroxyl , lower hydroxyalkyl, ^ lower aminoalkyl, lower alkoxy lower alkyl, lower carboxyalkyl, carboxyalkyl (lower) amino, alkanoyl (lower) amino, carboxyalkanoyl- (lower) amino, carbamoyl or N-alkyl (lower) - carbamoyl, or a salt, ester, solvate or hydrate of this compound. 42. Compound according to claim 40, in the formula of which © N ^ = Q represents a 1-methylpyrrolidinio radical. 43. Compound according to claim 40, * 'in the formula of which © N "Q represents a pyridinio radical. 44. A compound according to claim 40, in the formula of which © N ^ = Q represents a 2-amino-5-thiazolo [4,5-cjpyridinio radical. 45. A compound according to claim 40, in the formula of which © represents a trimethylammonio radical. 46. A compound according to claim 40, "in the formula of which © NsQ represents a 3-aminopyridinio radical. 47. A compound according to claim 40, in the formula of which © N ^ = Q represents a 3-formylaminopyridinio radical. 48. A compound according to claim 40, ff) _, in the formula of which ^ N ^ = Q represents a 3-carbamoylpyridinio radical. 49. A compound according to claim 40, in the formula of which © represents a 4-carbamoylpyridinio radical. 50. Compound according to claim 40, in the formula of which © n == Q represents a 3-aminomethylpyridinio radical. 51. Compound according to claim 40, in the formula of which © N ^ = Q represents a radical '• b. h 2-methylthiazolio. 52. Compound according to claim 40, in the formula of which © n == q represents a 3-hydroxymethylpyridinio radical. ^ 1 A C 53. Compound according to claim 40, - in the formula of which ® N = p represents a 4-hydroxymethylpyridinio radical. 54. A compound according to claim 40, ί in the formula of which ^ N ^ = Q represents a 4- (N-methylcarbamoyl) pyridinio radical. 55. Compound according to claim 40, in the formula of which © N ==== Q represents a 4-carboxypyridinio radical. 56. Compound according to claim 40, in the formula of which ® NS = Q represents a 2,3-propylenepyridinio radical. 57. Compound according to claim 40, in the formula of which © n = q represents a 3-carboxymethylpyridinio radical. 58. Compound according to claim 40, in the formula of which © N == sQ represents a 4-carboxymethylthiopyridinio radical. 59. Compound of formula r23 R24 — Ù y-CH = N - f ^ S ^ \ _ / I xxix N ^ R25 $ NVs ^ XB = CHCH22 cooir * 22 where R represents a hydrogen atom or classical protecting radical from the carboxyl function and - 23 24 25 R, R and R are identical or different and each represents a hydrogen atom or a hydroxyl, lower alkyl or lower alkoxy radical and Z represents a chloro, bromo or iodo radical, or a salt, solvated , hydrate or ester of this compound. 60. Compound according to claim 59, 22 in the formula of which R represents the benzhydryl radical and Z represents a chloro or iodo radical. 61. A compound according to claim 60, 232425 * in the formula of which R, R and R represent hydrogen atoms. 62. The compound according to claim 61, which is benzhydryl 7-benzylideneamino-3- [3-chloro-1-propen-1-yl] -3-cephem-4-carboxylate. 63. The compound of claim 61 which is benzhydryl 7-benzylideneamino-3- [3-iodo-1-propen-1-yl] -3-cephem-4-carboxylate. 64. Process for the preparation of compounds of formula cocP or R “represents a hydrogen atom or a conventional radical protecting the amino function, R represents a hydrogen atom, a straight or branched chain alkyl radical of 1 to 4 atoms of carbon, a cycloalkyl or cycloalkenyl radical of 3 to 6 carbon atoms, a radical of formula 4 4 4. RR R4 I 3 I ο COOH, -C-CH.CH-R, -CC == C-RJ, \ Y or -C-COOH, i * ^ <S i5 X - 3 where R represents a hydrogen atom or lower alkyl or carboxyl radical, X represents a halogen atom or hydroxyl or lower alkoxy radical 4 5 and R and R each independently represent a hydrogen atom or a methyl or ethyl radical, or else R1 and 5 R, taken together with the carbon atom to which they are united, can represent a cycloalkoxy-lidene radical of 3 to 5 carbon atoms, and Ä @ N = Q represents a quaternary ammonio radical and non-toxic pharmaceutically acceptable salts and physiological esters ment hydrolysable these compounds, characterized in that it comprises the reaction of a compound of formula ^ Àjxnxxc ο I CH * CHCH2Z COOB1 21 2 where R has the same meaning as R or represents a radical of formula COOB1. . X? ! \> OR -C - COOB Y â * 2 X CD.MJ - 148 - 5, 1 where X, R and R are as defined above, B represents a classic radical protecting the function 2 carboxyl, B represents a hydrogen atom 't or conventional radical protecting the amino function, Z represents a chloro, bromo or iodo radical and m represents zero or a 2 with a tertiary amine Q = n (or successively with a secondary amine RR'NH and a compound of formula R "Z) and in the case where m represents 1, the reduction of the sulfoxide in a conventional manner, then the elimination of all the blocking radicals in a conventional manner. * 65. Process for the preparation of compounds of formula, 1 or R represents a hydrogen atom or a conventional radical 2 protecting the amino function, R represents a hydrogen atom, an alkyl radical in - straight or branched chain from 1 to 4 carbon atoms, a cycloalkyl or cycloalkenyl radical of 3 to 6 * carbon atoms or a radical of formula 4 4 4 RR ΓΟΟΗ RI 3 I 3 ^ .COOH, -C-CH = CH-R, -CC = CR. V OR -C-COOH, i "5 / \ * 5 R5 R \> RX 3 where R represents a hydrogen atom or lower alkyl or carboxyl radical, X represents a halogen atom or hydroxyl or lower alkoxy radical and R and R each independently represent a hydrogen atom or a methyl or ethyl radical or alternatively R and R, taken together with the carbon atom * to which they are united, can represent a cycloalkylidene radical of 3 to 5 carbon atoms and "K Θ represents a quaternary ammonio radical and non-toxic pharmaceutically acceptable salts - / -Ί t- \ w T i has physiologically hydrolyzable cables and esters of these compounds, characterized in that it comprises the reaction of a compound of formula V-rY'S f-vA © 0. CH "CHCH2-N = Q C00® with an acid of formula rjXT b2hn ^ or2 * 2 1 or else with an acylating derivative of this acid, where R 2 is identical to R or represents a radical of formula COOB1 R1" i Λ or -C— COOB Y * 2 X CD.MJ _ ιςη - 5, 1 where X, R and R are as defined above, B “represents a classical radical protecting the carboxyl function and B represents an atom d hydrogen or 4 conventional radical protecting the amino function. 2 66. Process according to claim 64, £ characterized in that the compounds 1-22, 1. the 7- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2- are prepared. methoxyiminoacetamido 3 - 3 - [3- (trimethylammonio) -1-propen-yl] - 3-cephem-4-carboxylate, 2. 7- [2- (5-amino-1,2,4-thiadiazol- 3-yl) -2-methoxy-iminoacetamido] -3- [3- (1-methylpyrrolidinio) -l-propen-1-yl] -3-cephem-4-carboxylate, 3. on 7- [2- (5 -amino-1,2,4-thiadiazol-3-yl) -2-methoxy-iminoacetamido] -3- [3-pyridinio-l-propen-l-yl] -3-ce-phème-4-carboxylate, " 4) 7- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2-methoxyiminoacetamido] -3- [3- (3-aminopyridinio) -1-propen-l- yl] -3-cephem-4-carboxylate, 5. 7- [2- (5-amino-l # 2,4-thiadiazol-3-yl) -2-methoxy-iminoacetamido] —3— [3 - ( 3-formylaminopyridinio) -l-propen-1-yl] -3-cephem-4-carboxylate, 6. le 7- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2- methoxy-iminoacetamido] -3- [3- (3-aminomethylpyridinio) -1-propen-1-yl] -3-cephem-4-carboxylate, i 7) on 7- [2- (5-amino-1,2) , 4-thiadiazol-3-yl) -2-methoxy- iminoacetamido] -3- [3- (3 -carbamoylpyridinio) -1-propen- ~ 1-yl] -3-cephem-4-carboxylate, 8. le 7— [2 - (5-amino-1,2,4-thiadiazol-3-yl) -2- methoxy-iminoacetamido 3—3 — C 3 - (4-carbamoylpyridinio) -1-propen-1-yl] -3-cephem-4-carboxylate, 9. 7- [2- (5-amino-1,2,, 4-thiadiazol-3-yl) -2-methoxy-iminoacetamido] -3- [3- (2-methylthiazolio) -1-propen-lyl] -3-cephem-4-carboxylate, 10. 7- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2-methoxy-iminoacetamido] -3- [3- (2-amino-5-thiazolo [4,5-c] pyri-dinio) - l-propen-tyl] -3-cephem-4-carboxylate, 11. 7- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2-methoxy-imi η o acetamido] -3- [3- (4-hydroxymethylpyridinio) - 1- ΐ propen-1-yl] -3-cephem-4-carboxylate, 12. le 7- [2- (5-amino-1,2,4-thiadiazol -3-yl) -2-methoxy- 'Ί iminoacetamido] —3— [3 - (3-hydroxymethylpyridinio) -1-pro- pen-l-yl] -3-cephem-4-carboxylate, 13. 7- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2-methoxy-iminoacetamido] —3— [3- (4-N-methylcarbamoylpyridinio) - 1-propen-l-yl] - 3-cephem-4-carboxylate, 14. 7- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2-me thoxy-iminoacetamido] -3- [3- (2,3-propylenepyridinio) -1-pro-pen-1-yl] -3-cephem-4-carboxylate,% 15) on 7— [2— (5-amino -1,4,4-thiadiazol-37yl) -2-ethoxyiminoacetamido] -3- [3- (4-carbamoylpyridinio) -1-propen-1-yl] -3-cephem-4-carboxylate, 16. le 7- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2-cyclo-pentyloxyiminoacetamido] -3- [3- (4-carbamoylpyridinio) -1-propen-l-yl] - 3-cephem-4-carboxylate, 17. 7- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2-allyloxy-iminoacetamido] —3 - C3- (4-carbamoylpyridinio) -1-propen-1-yl] -3-cephem-4-carboxylate, 18. 7- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2-propar-gyloxyiminoacetamido] -3- [3- (4-carbamoylpyridinio) -1- V propen-1-yl] -3-cephem-4-carboxylate, 19. le 7-C2— (5-amino-1,2,4-thiadiazol- 3-yl) -2-metho- "'xyiminoacétamido] -3- [3- (4-carboxypyridinio) -1-propén- 1-yl] -3-cephème-4-carboxylate, 20. le 7- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2-ethoxy-iminoacetamido] —3 - [3 - (4-carboxypyridinio) -2-propen-l-yl] -3-cephem ~ 4 -carboxylate, 21. 7- [2- (5-amino-1,2,4-thiadiazol-3 -yl) -2-methoxy-iminoacetamido] —3 - [3 - (4-carboxymethylpyridinio) -1-pro-pen-l.yl] -3-cephem-4-carboxylate, and 22. 7- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2-methoxy-iminoacetamido] -3- [3- (4-carboxymethylthiopyridinio) -1-propen-l-yl] -3-cephem-4 -carboxylate, 67. Process for the preparation of compounds of * formula VIII R23 „“ - / "Vch-H — ργ8 'S' ^“ R25 COOR22 22 where R represents a hydrogen atom or classical radical protecting the carboxyl function and ^ 23 24 25 R, R and R, identical or different, each represent a hydrogen atom or hydroxyl, lower alkyl or lower alkoxy radical and Z represents a chloro, bromo or iodo, v or salt, solvate, hydrate or ester radical of these compounds, characterized in that it comprises the reaction of a compound of formula II, R24- ^ y — CHC II '^ R25 2 ^ 2 ^ 2 ^ V where R ^, R ^ and R ^ are such that defined above, with a compound of formula III, M - f ^ SXs ni σ cH2m COOR22 22 where R represents a conventional radical protecting the carboxyl function ,, to give a compound of formula IV, R23 R24—- | ^ SN IV ï T ** 5 d ^ “NV ^ CH2Cl COOR22 then the reaction of the compound of formula IV with the hard sodium io- —- - - 1 C" S or potassium iodide to give a compound of formula V , N, 25 COO R22 then the reaction of the compound of formula V with triphenylphosphine to give a compound of formula VI, R23 v, r25 <^ NNï ^ sCH2P (Ph) 3 COOR22 or the reaction of a compound of formula IV with triphenylphosphine to give a compound of formula VI, then reacting the compound of formula VI with a base to give a compound of formula VII, R23 R2 * —N ^ "" nR25 c ^ ~ NV ^^ vCH * P (Ph) 3 VH COOR22 read then the reaction of the compound of formula VII with ZCf ^ CHO, where Z represents a chlorine, bromine or iodine atom, to give a compound of formula VIII, __, 1 r 4 R24 — CHeN ^ - f ^ S ^ ^ 25 <ô nvs ^> x: h-cb-ch2z VIn TooR22 Sî and finally, if desired, the elimination, 22 by conventional means, of the radical R protecting the carboxyl function to give the corresponding free acid and the conversion of this free acid to its salt or ester. 68. Process for the preparation of compounds of formula - | - -jj-CONH-jp> R ^ HÏT ^ S ^ ^ OR2 CK COOB1 where R "*" represents a hydrogen atom or a classical radical protecting the function amino, R represents a hydrogen atom, a straight or branched chain alkyl radical of 1 to 4 carbon atoms, a cycloalkyl or cycloalkenyl radical of 3 to 6 carbon atoms or a radical of formula - 4 4 4 RRRI Ί I ο ΡΟΠΗ I ^ -C-CH = CH-R, -CC = CR, \ / OR -C-COOH, 4 * ks Λ k5 X 3 where R represents a hydrogen atom or lower alkyl or carboxyl radical, X represents a halogen atom or hydroxyl or lower alkoxy radical, and R and R each independently represent a hydrogen atom or methyl or ethyl radical, or R 5 - well R and R, taken together with the carbon atom to which they are united, can represent a o cycloalkylidene radical of 3 to 5 carbon atoms, represents a hydrogen atom or a classic radical protecting the carb function oxyl and Z represents a chloro, bromo or iodo radical, or of a salt, hydrate, solvate or ester of these compounds, characterized in that it comprises the reaction of a compound of formula I, ΎιΛ J— 1 COOB1 with a compound of formula II N --- C-COOH, 12 1 or R, R and B 'are as defined above, to give a compound of formula III,; jxctçc. COOB1 then the reaction of the compound of formula III with sodium iodide or potassium iodide to give a compound of formula IV, Nr-Ç-CONH-1- ^ ή. / 0 As COOßl then the reaction of the compound of formula IV with triphenylphosphine to give a compound of formula V, NrC-CONH - SSSQ // ^ 11 IY .. "A .- * v rA" ,,, COOB1 V or the reaction of a compound of formula III with triphenylphosphine to give a compound of formula V, then the reaction of the compound of formula V with a base to give a compound of formula VI, N rC-CONH -SS 'S // \\ | i 1 R1Hir \ g ^ s \ or2 oA-H'NiiACH-p (Ph) 3 COOB1 * VI then the reaction of the compound of formula VI with ClCt ^ CHO to give a compound of formula VII, J7 ^ T "7iX, COOB1 VII then the reaction of the compound of formula VII with sodium iodide or potassium iodide to give a compound of formula VIII, or the reaction of the compound of formula VII with sodium bromide or potassium bromide to give a compound of formula IX N ----- p-CONH - "- S 6 N .wv v COOB * yjjj N r — C-CONH — i SN i iTt UJ IX R HN OR2 y NNy ^ H" CHCH2Br COOB1 ^ and finally the elimination of all blocking radicals by conventional means and, if thing A is desired, the conversion of the free acid to its salt or ester. 69. Process for the preparation of compounds of formula XI HjN-- // © XI N ch-ch-ch2-n = q * * ö cocH% © or -N == Q represents a quaternary ammonio radical or a salt, ester, solvate or hydrate of these compounds, characterized in that it comprises the reaction of a compound of formula I —CHO I with a compound of formula II, Vpf'S II 0 ^ Nv ^^ CH2C1 C00CH (Ph) 2 to give a compound of formula III, Οκ “·” τΓ''Ί COOCH (Ph) 2 then the reaction of the compound of formula III with sodium iodide or potassium iodide to give a compound of formula IV, Ott "' ) COOCH {Ph) 2 then the reaction of the compound of formula IV with triphenylphosphine, or the reaction of the compound of formula III with triphenylphosphine to give a compound of formula V,,, e N ν ^ ΧΗ2Ρ (Ph) 3 COOCH (Ph) 2 then the reaction of the compound of formula V with a base to give a compound of formula VI, {SN d ^ "NN ^ CH-P (Ph) 3 VI COOCH (Ph> 2 - l £ U; · ta then the reaction of the compound of formula VI with ClCf ^ CHO for don ner a compound of formula VII, 0 ~ τΛι COOCH (Ph) 2 then the reaction of the compound of formula VII with sodium iodide or potassium iodide to give a compound of formula VIII, fi ^ S ^ A vm ο ] nCH * CH-CH2I - COOCH (Ph) 2 then the reaction of the compound of formula VIII with a secondary amine RR'NH where R and R 'each represent a methyl radical or together form pyrrolidine, to give a compound of formula IX , ^ CH'N —- SSN Ix // XH «= CHCH2-N ^ ^ ^ R * COOCH (Ph) J then the reaction of the compound of formula IX with R" Y where R "represents a tertiary amine o == n and Y represents a chloro, bromo or iodo radical, to give a compound of formula X, (3 ^ x0 * θ ff \ ^> CH = CHCH2 -âî = Q x COOCH (Ph) 2 or else the reaction of the compound of formula VIII with a tertiary amine Q5 £ N where Q is as defined above, to give a compound of formula X, then the reaction of the compound of formula X with a reagent T of Girard or HCl to give a compound of formula XI , and if the thing is t desired, the conversion of the free acid into a salt, ester, solvate or hydrate thereof. 70. Pharmaceutical composition, characterized in that it comprises an effective antibacterial amount i of at least one compound of formula I or of a salt, hydrate or solvate thereof, in addition to a pharmaceutically acceptable excipient. 71. A method of treating bacterial infections in a mammal including man by expressing the need, characterized in that one administers to this mammal, in effective antibacterial amount, at least one compound of formula I or a salt, hydrate or solvated thereof in a pharmaceutically acceptable excipient.