AU604641B2 - Derivatives of 1-dethia 2-thia cephalosporanic acid and their salts, their preparation process and their use as medicaments - Google Patents

Abstract

The derivatives in question are the products of formula I <IMAGE> R = either <IMAGE> Ra = an organic group; <IMAGE> R'A and R'B are either a hydrogen atom or an alkyl radical; ZA = single bond, sulphur, optionally oxidised, or oxygen, R3A = in particular, aryl, optionally substituted, quaternary ammonium, acetyl, carbamoyl, alkoxycarbonyl, alkyl, haloalkyl, nitrile or azido; R4 = H or OCH3; A = in particular, H, alkali metal equivalent, ester or CO2A; CO2<(-)>; n2 = integer equal to 0, 1 or 2; and the salts of the products of formula IA with inorganic or organic acids.

Description

!i n, i d~tail oi AssignpOuec ate of Ms ign- Itttol insuifficient.

Ih'Irte for Non.Convention Appylication.i I Tier placc nnd- a~i3f Slt.

(in The said Company would, if a patent were to be granted upon an application made by the said actual inventors, be entitled to have the patent assigned to it.

application referred, to in paragraph 2 of this Dclaration was the first made in a Convention country in respect of thc invention the subject of the atParis, France

SIGN

this 17th dlay of July 1986.

j .1- Australia 60464 1 PATENTS ACT 1952 Farm COMPLETE SPECIFICATION

(ORIGINAL)

FOR OFFICE USE Short Title: 0 00 0 0 610 16 )S6 00 0 Lodged: 'fAfl~ nrn, tflrot:vt.,Owwr, ft ft it 1. ,ft ft ft ift

I

ft its 7 7 ,Complete Specification-Lodged: Accepted: Lapsed: Published: P rjority: Related Art: 4 4 4 0 6 TO BE COMPLETED BY APPLICANT Name of Applicant: Address of Applicant: Actual Inventor: Address for Service:

ROUSSEL-UCLAF

35, Boulevard des Invalides, 75007 Paris, France.

JEAN GEORGES TEUTSCH, ALAIN BONNET and JOZSEF ASZODI.

CALLINAN AND ASSOCIATES, Patent Attorneys, of 48-50 Bridge Road, Richmond, State of Victoria, Australia.

"DERIVATIVES OF 1-DETHIA 2-THIA CoplteSpciictin orth Ivetin nttld:CEPHALOSPORANIC ACID AND THEIR SALTS, CoplteSpciictin orth Ivetin nttld THEIR PREPARATION PROCESS AND THEIR USE AS MEDICAMENTS" The following statement is a full descmlption of this invention, including the best method of performing it kno~wn to Me-'* Note. Theo description Is to be typed In double spacing, pica type face, In an area not exceeding 250 mmn in depthi and 160 mmn it, width, on tought white Paper of good quality and It Is to be Insetted inside this form, i ^1 la In the European Patent application no 0153229 the requerant described new derivatives of l-dethia 2-thia cephalosporanic acid and their salts, their preparation process and their use as S, medicaments.

The products described in the patent answer to general formula R ,4 (O)n 2 SR 2 I OM 1 in which R represents either a radical Ra-C-NH- in which Ra 0 represents an organic radical, or a radical 'N-CH= I- in Rj which Ri and Rj, being the same or different, represent a hydrogen atom or an aliphatic or aromatic hydrocarbon radical or a heterocyclic radical or Ri and Rj form, with the nitrogen atom to which they are bonded, a possibly-substituted cyclic radical, or a radical Rb-NH- in which Rb represents a possibly-substituted carbocyclic or heterocyclic aryl radical,

R

1 represents: a) a radical -Z-R 2 in which R 2 is an alkyl, alkenyl or alkynyl radical possibly substituted or interrupted by a heteroatcm and Z represents a possibly-oxidized sulphur atom, a selenium atom, an oxygen atcm or -NH- b) a radical -Za-R 3 in which R 3 represents a possibly-substituted carbocyclic or heterocyclic aryl radical or a possibly-substituted quaternary ammonium radical and Za represents a methylene radical, a sulphur, selenium or oxygen atom or -NH- or Za represents a simple bond or Za represents a radical -CH2-S- _L~l~l~i S0 0 0 lb c) an alkyl, alkenyl or alkynyl radical having from 2 to 8 carbon atoms possibly substituted or interrupted by a heteroatom, d) a halogen atom, a nitrile, possibly-esterified or-salified carboxy, azido, thiocyanato gr isothiocyanato radical or e) an azidomethyl, amino or :mono- or di-substituted methyl amino, thiocyanato methyl, isothiocyanatomethyl, carbamoyloxymethyl, semicarbazonomethine, possibly-substituted arylhydrazonomethine, nitromethyl or di or tri-halomethyl radical, -CH 2

-ONO

2 0 -CI-P(alk) or -CH2--P(Oalk) alk representing an alkyl radical containing from 1 to 4 carbon atoms,

R

4 represents a hydrogen atom or a methoxy radical, COM represents

-CO

2 A in which A represents a hydrogen atom, an equivalent of an alkali metal, an alkaline-earth metal, of magnesium, of ammonium or of an organic amino base or A represents an ester group, or -CO 2

A

represents a group CO 2 or R 1 and CO 2 A form, together with the carbon atoms to which they are bonded, a residue 00c 0 00 00 0 N -6 or

OH

O

a oa i0 0 0 BO or COM represents a possibly-substituted carbamoyl radical and n2 represents an integer equal to 0, 1 or 2, as well as the salts of the products of formula with mineral or organic acids.

The products answering to the general formula above can be presented in racemic or optically-active form.

-3- The subject of the present application is the compounds corresponding to the general formula I

NN

0 oN coR o in which Ra represents either a radical 00 0-R Sin which Rc represents a radical being one of 2-amino-thiazolyl, chloro-thiazolyl, 5-amino-l,2,4-thiadiazolyl, 4-thiazolyl, 2-thienyl or 2-furyl, Rd represents: either an atom of hydrogen, or else an alkyl, alkenyl, or alkynyl or cycloalkyl radical having at the imost 6 atoms of carbon, or a phenyl radical, said alkyl, alkenyl, alkynyl, cycloalkyl or phenyl radical optionally being substituted by a radical selected from among halogen, cyano, carbamoyl, nitro, amino, Shydroxy, mercapto, oxo, carboxyl (free, esterified or salified), or else a difluoromethyl, trifluoromethyl, methoxymethyl,

CH

NNH

I/c-h L v "ilX)s""P Ulr~-N-_UIN i -4- R1A represents: either a radical

RB

c= c RA CH 2

-ZA-R

3

A

or a radical

CH

2

-ZA-R

3

A

C=I C RA R A B in which R'A and R'B, being identical or different, represent either an atom of hydrogen or else an alkyl radical having from 1 to 4 atoms of carbon, ZA represents a simple bond, an atom of sulphur, optionally oxidised, or an atom 4.15 of oxygen,

R

3 A represents either an aryl, carbocyclic or heterocyclic radical selected from among phenyl, diphenyl, naphthyl, thienyl, furyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl, thiadiazolyl, oxadiazolyl, tetrazolyl, pyridiny, pyrimidinyl, pyrazinyl, pyridazinyl, thiazinyl, .O oxazinyl, tetrazinyl, imidazolinyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, or a quaternary ammonium radical selected from among pyridinium, thienopyridinium, quinolinium, isoquinolinium, cyclopentepyridinium, trimethylammonium, cyclohexenopyidinium, imidazopyridinium, or thiazolopyridinium; the radicals R 3 A being able to be substituted by one or more radicals selected from among either alkyl radicals having 1 to 4 atoms of carbon, these alkyl radicals being themselves optionally substituted by a phenyl or thienyl radical, the radicals phenoxy, methoxy, ethoxycarbonyl, halogens, hydroxy, carboxyl (free, esterified or salified), or amino, or else the radicals vinyl, allyl, butenyl, ethynyl, propargyl, phenyl, tolyl, halogens, amino, nitro, '.130 carboxyl (free, esterified or salified), or carbamoyl, or else a radical acetyl, carbamoyl, alkoxycarbonyl, alkyl or haloalkyl having 1 to 6 atoms of carbon, nitrile or azido,

R

4 represents an atom of hydrogen or a methoxy radical, i ~I i y rrVYURM i .ill A represents an atom of hydrogen, an equivalent of alkali metal, alkaline earth metal, of magnesium, of ammonium or organic amino base or A represents an ester group or CO 2 A represents a C0 2 group, and also the salts of the products of formula I with mineral or organic acids.

Among the products with the formula in which ZA represents a sulphur or an oxygen atom and R 3 A represents a quaternary ammonium, the products are preferred in which ZA is not connected directly to the nitrogen atom.

The products with the formula can be presented in the racemic or the optically active form.

PI

I 4 t

~--II

-6 Preferred values of Rd are: -C/43 C- N 3 CH4F2I

CA,

-C-ct Y- H -cCc/13,) C 0, 7K j 144 4 4 I

AI

CU

phenyl, Among the values for Rd, the methyl, hydrogen, ethyl, allyl 1-methyl-icarboxyethyl, carboxymethyl or difluoromnethyl are preferred.

7- Compounds are preferred in which Ra has the following values: C/NO

M-

5y1 N' Syn A/1- v Co 00' 0 ~00000 o1' 0000 1,000 ~ICC 000

CC

CC 00C0

N'H~

s'NA/ t K. CCL IT

N.,

S* tv

C

5* A" tv//I S A' 000 0 C 0 0 0 0 0b 0 t o R 3 A can also prefenrab-1y--represent a non-cyclic qujatarnarly .ammen4m= Tdk-l Among the values for 9 99 9 9 0 99r~~ (.9 9 0 999999 0 9 9 o 99 9 0 0 1 -C jj W -C)4 oC C H P.112 C CR Rthe following 14

S

S V, \Coo- \~IV F1 are preferred NL;C I NV\ J, 9 9 9 9 *0 0 14 (b (3 3 053 di- CF 3 .3

CH

0 SI) ri 4 N~-o" 4 0/

A--

p ,~9 '9 CO3 O C"- 3 x00) '0 cti: K OCHl '0 cvi- 0 0 15 0 C0 2 .Cvi 3 cI1-4 3 00 H30 cH~ 3 /O

H

0 40 4 0 4 0 0 0 04 0 0 0 4 *0 0

CH

CH~

Q

r4.

CH

3

H

3 CAL C-NN' N~N-A4~IX co-s 1-44C 00-1 CC CHC 3

(H

3 .H3 cH3

CHO

4 40 a a 0 r4,4(4 stat 4 4 0 4* cc 1 &0 c I/

NO-

ONCH 2 -9~ CF 3 4 +,9N -C go 0 3 CH 3 S N 0 CH 3 N -CH 3 S0,

CH

3 Among the values for A, there can be cited an equivalent of sodium, potassium, lithium, calcium, magnesium, ammonium or of an organic base. Among the organic bases, there can be cited methylamine, propylamine, trimethylamine, diethylamine, triethylamine, N,N-dimethylethanolamine, tris(hydroxymethyl)amino methane, ethanolamine, pyridine, picoline, dicyclohexylamine, morpholine, benzylamine, prccaine, lysine, arginine, histidine, and N-methylglucamine.

Among other residues of easily cleavable ester groups which A can represent, there can be cited the following groups methoxymethyl, Isopropyloxymethyl, -methoxyethyl, -ethoxyethyl, methylthiomethyl, ethyithiomethyl, isopropylthiomethyl, pivaloyloxymethyl, acetoxymethyl, propionyloxymethyl, butyryloxymethyl, isobutyryloxymethyl, valeryloxymethyl, Isovaleryloxymethyl, tert-butylcarbonyloxymethyl, hexodeconoyloxymethyl, propionyloxyethvl, isovaleryloxyethyl, -acetyloxyethyl, i-proplonyloxyethyl, I-butyryloxyethyl, I-tertbutylcarbonyloxyethyl, I-acetyloxypropyl, 1-hexadecanoyloxyetthyl, t-proplonyloxypropyl, 1-ethoxycarbonyloxyethyl, methoxycarbonyloxymethyl, 1-acetyloxybutyl I-acotyloxyhexyl, I-acetyloxyheptyl, phkidlidyl, 5,6-dimethoxyphthal Idyl, tort-butylcarbonylmethyl, allyl, 2-cliloroallyl, iethoxycarbonylmethylt benzyl or tert-butyl.

There can also be cited other residues of ester gjroups which A can represent; the groups niethoxyethoxymethyl, Ltmethylarnlnoothyl, cyanomethylt tert-butyloxycarbonymethyl, 2 ,2-ethylenedloxyethyi, cyanoethyli 2 ,2-dimethoxyethyl, 2-chloroothoxyiethyll 2-hydroxyethoxy- .~ethyl, 2,3-epoxypropyl, 3-dimethylaino, 2-hydroxypropyl, 2-hydroxyethyl, o ~tn~hx~ty ,2ai ~oy~ah 3--tathoxy-2 4thiadiazoi-6-yll 2-totrohydropyranyl, 2-methoxyprop-2-yl) 1-hydroxyprop-2-yl, Isopropyl, carbarnoylmethyl, chiorornethyll 2-chlorOethyl* acotylniethyl, 2-methylthloethyi or thiocyanatornethyl.

Among other residues of ester groups which A can rapreont) there can also be cited the following groups v. 2-chloro-I-acetyloxyethyl, 9-brono-I-~actyloxyethyl, 2-f luoro- 1-acotyloxyethyll 2-nmthoxy-lacetyloxyethyll 2-tnethyl- 1-acetyloxypropyll 2-acetyloxyprop-2-ylt 1-methoxyacetyloxyethyl, I-acetyicarbonyloxyethyl i-hydroxyaetyl- 3s oxyothyi l-formylCarbonyloxyethyl,, 1-(2-thlenyi )carbonyloxyethyl, l-(2-furyl )darbonyloxydthyi, 1-(S-nitro-2Z-furyl )carboniyloxye-thyl,, I-(2-Pyrrolyi )carbonyloxyethyi, l-(propionyioxycarbonyloxy)ethyl, 1-(propyloxycarbonyloxy)ethyl, 1-(isopropyloxycarbonyloxy)ethyl, 1-(methoxyethoxycarbonyloxy)ethyl, 1-(allyloxycarbonyloxy)ethyl, 1-(2,3-epoxy)propyloxycarbonyloxyethyl, 1-(2-furyl)methyloxycarbonyloxyethyl, 1-(2-fluoro)ethyloxycarbonyloxyethyl, 1-(methoxycarbonyloxy)propyl, (2-methoxycarbonyloxy)prop-2-yl, (methoxycarbonyloxy)chloromethyl, 1-(methoxycarbonyloxy)-2-chloroethyl, 1-(methoxycarbonyloxy)-2-methoxyethyl, 1-(methoxycarbonyloxyl)-1-allyl.

A can also represent the group -c 0 The products with the formula can also be presented in the form of salts of organic or mineral acids.

Among the acids with which the amino group or groups or the quaternary ammonium group of the products can be salified, there S can be mentioned, among others, the following acids: acetic, trifluoroacetic, maleic, tartaric, methanesulphonic, benzenesulphonic, p-toluenesulphonic, trifluoromethanesulphonic, formic, phosphoric, sulphonic, hydrochloric, hydrobromic, hydrlodic.

Among the values for A, there can be cited particularly the ester groups with the formula CHO-C- -CH-0-C-D in which 8 represents a hydrogen atom or a linear or branched alkyl 2i radical, possibly substituted, containing from I to 5 carbon atoms, and 0 represents an alkyl or alkoxy radical, linear or branched, Spossibly substituted, containing from 1 to 15 carbon atoms and in particular from 1 to 5 carbon atoms, and more particularly the ester groups in which B represents hydrogen atom or a methyl or ethyl radical and D represents a methyl, ethyl, methoxy or ethoxy radical.

Among the values for A, there can be cited the radical

-CH

2 -C=CHRy in which Rx represents the values hydrogen, alkyl, Rx particularly methyl and ethyl, halogen, particularly chlorine, and Ry represents the values hydrogen, halogen, aryl, particularly phenyl possibly substituted by methyl, methoxy or halogen, or Ry represents the alkyl value possibly substituted by acyloxy, by alkoxyearbonyl, or by halogen.

Among the values for A, there can also be cited the radical /alkI -CHg-CaC in which Rx is defined as above and alk, and alk 2 Rx alk 2 identical or different, represent an alkyl radical containing from 1 to 4 carbon atoms, -13- Among the compounds with the formula the present application has more specifically as its subject the compounds answering to the formula (IA): MZ c'O/vH \R1 CO;LP 3 in which R'represents a hydrogen atom or an alkyl, alkenyl, alkynyl or cycloalkyl radical having at the most 6 carbon atoms, optionally substituted by a radical selected from among halogen, cyano, carbamoyl, nitro, amino, hydroxy, mercap to, oxo, carboxyl (free, esterified or salified), or else a phenyl radical, ZA is as defined in claim 1, and

W'

3 represents either a phenyl, thienyl, furyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, Isothinzolyl, oxazolyl, isoxazolyl, triazolyl, thiadiazolyl, oxadiazolyl, tetrazolyl, pyridinyl, pryiidinyl, pyrazinyl, pyradazinyl, thiazinyl, oxazinyl, tetrazinyl, imidiazolinyl, benzoimidazolyl, benzothlazolyl, benzoxazolyl, or a quaternary ammoniumi radical selected from among pyridinium, thienopyridinium, quinolinium, isoquinolinium, cyclopentenopyridinium, cyclohexenopyridinium, and imidazopyridinium, the radicals optionally being

A

"Crlr l rrmri 14 substituted by one or more radicals selected from among either alkyl radicals, having 1 to 4 carbon atoms, these alkyl radicals optionally being substituted by a phenyl or thienyl radical, phenoxy, methoxy or ethoxy-carbonyl radicals, halogens, hydroxy, carboxyl (free, esterified or salified), amino, or else the radicals vinyl, allyl, butenyl, ethynynl, propargyl,,therny, tolyl, halogens,amino, nitro, carboxyl (free, esterified or salified) or carbamoyl, or an acetyl or carbamoyl radical.

Among the compounds already mentioned with the formula IA, compounds are preferred in which R' represents a hydrogen atom, or a methyl or isopropyl radical, optionally substituted by a carboxy, carbamoyl, nitrile, methylthio or methoxy radical, a difluoromethyl or trifluoromethyl radical, a phenyl radical, a cyclobutyl radical, or a cyclopropyl radical optionally substituted by carboxy radical, an allyl radical possibly substituted by a chlorine or bromine atom, and compounds in which ZA represents a simple bond and R' 3 A represents an optionally substituted pyrindinium radical.

4 a

L

Among the preferred products, there can be cited those described further on in tho examples, and particularly the following products: the internal salt of 7/3-/7-//C2-amino 4-thiazolyl) 2-/Z-(trifluoromethoxy) imino/ acetyl/ amino/ 2-carboxy 8-oxo 4-thia 1-azabicyclo oct-2-en-3-yl/ 2- (E)-propenyl/ thieno pyridinium (6S) (7S); the internal salt of 5-/3-/7-//(2-amino 4-thiazolyl) (methoxyimino) acetyl/amino! 2-carboxy 8-oxo- 4-thia 1azabicyclo oct-2-en-3-yl/ 2(E)-propenyl/ 2methyl. thiazolo pyridinium syn (6S)(7S); the internal salt of 7-/3-/7-//(2-amino 4-thiazolyl) 2-(Z)-(methoxyimino) acetyl! amino/ 2-carboxy 8-oxo 4-thia 1-azabicyclo oct-2-en-3-yl/ propen-2thieno pyridinium 1 *400Q4

Q

*0 e004 0 ~0 0 C S C 0/ -16- 7-//(2-amino 4-thiazolyl) (methoxyimino) acetyl/ amino/ 3-//3-(1,3,4-thiadiazol-2-yl) thio/l-(E)-propenyl/ 8-oxo 4-thia 1-azabicyclo oct-2-en-2-carboxylique syn (6S)(7S) acid; the internal salt of 5-/3-/7-//(2-amino 4-thiazolyl) (difluoromethoxy) imino/ acetyl/ amino/ 2-carboxy 8-oxo 4-thia 1-azabicyclo oct-2-en-3-yl/ 2-(E)-propenyl/ 2methyl thiazolo pyridinium (6S)(7S) Z.

The invention also has as its subject a preparation process for the products with the general formula I as defined above, characterized in that a product with the formula VII: R4 RA S (VII)

OH

,°fi 0

CO

2

A

in which R 4 and A have the significance indicated above and either RA represents an amino radical, free or protected by a monovalent or divalent protector group, S a or RA represents the radical S' a C-NH- Ra having the significance indicated above, is treated either with a halogenation agent, or with a sulphonation agent then with triphenylphosphine, or with a reagent with the formula (P(OAlk) 3 in which Alk represents an alkyl radical having from 1 to 4 carbon atoms, in order to obtain either a product with the formula (VIII A): 16A RA S (VIII A) N P (C 6

H

5 3 x 0 C0 2

A

in which RA, R 4 and A have the previous significance and XO represents the residue of an anion, or a product with the formula (VIII A) a a a an a a a a np a a a (OANk 2 0 (VIII

A)

C0 2

A

t a l.a.

4

I

OU LcIIUuAyI \iLCU, cLLL.I c I ul v a1LLL-u I, VL1 %ILUILiA-alJAyl, or else a radical acetyl, carbamoyl, alkoxycarbonyl, alkyl or haloalkyl having 1 to 6 atoms of carbon, nitrile or azido,

R

4 represents an atom of hydrogen or a methoxy radical, 17 .n which RA, R 4 A and Alk have the previous significance, which products with the formulae (VIII A) or (VIII'A), if desired, are treated first with a strong base then by an alkyl halogenide with the formula hal-RA" in which has represents a halogen atom and R"A has the values of R'A other than a hydrogen atom, so as to obtain the products with the formulae (VIIIB) or (VIII'B) CU) Js COLA C L OI2I io .formulae in which R'A has the significance indicated above, the products with the formulae(VIII or (VIIIB) representing the whole of the starting products VIIIA and VIII'A and of products obtained after reacting, said derivatives, with a derivative of formula hal-R"A, products with the formulae (VIII

B

or (VIII'B) are treated with a product with the formula: R'B'NOGp in which R'B has the value indicated above and Gp represents a S 4B protector group of the hydroxyl radical in order to obtain a product 1 5

B

with the formula (IX S. (IX) tco in the form of a mixture of E and Z isomers or in the form of isomer E or Z on which product with the formula (IX the following reactions are carried out in any order whatsoever a) separation of the protector group Gp f b) when RA represents an amino radical protected by a mono- or divalent protector group, elimination of this protector group and treatment of product in which RA represents an amino radical either with an acid with the formula (IV a RaC02H (IVa) c0

LC

in which formula in which Ra represents an organic group or with a functional derivative of this acid, h.--,efE-with e ID" 'S K~1 j N CH Xb Rj (IVb) in which Ri and Rj have the significance indicated above and Xb represents a sulphur or an oxygen atom, or by a product with the formula (IVc) Rb Xc (IVc) in whbi-ehbIas the significance indicated above and Xc represents ah-Togen=a-tom,-" c) separation of the isomers E and Z, in order to obtain a product with the formula (X) 0 u 0 44 j 4 404.

It 4 43 4, P (X in which R has the significance indicated above, on which product with the formula (X either a derivative of the group R 3 A is made to act in order to obtain a product with the formula (XI A S3A (XI

A

CI Oz A or by a derivative of an activation group of the hydroxyl radical then by a derivative or a reactivederivative of the group R 3 or a reactive derivative of this group in order to obtain a product with the formula (XIB) (XI B) or by a then of this c.OZ A derivative of an activation group of the hydroxyl radical the product with the formula HS-R 3 Aor a reactive derivative product in order to obtain a product with the formula (XI C) p 4 5 I3 CoLA (XI c) L phenyl, Among the values for Rd, the methyl, hydrogen, ethyl, allyl 1-methyl-1carboxyethyl, carboxymethyl or difluoromethyl are preferred.

(ii 1. I which products with the formulae (XI (XI B or (Xl C) are submitted if necessary or if desired, to any one or more of the following reactions in any order whatsoever a) separation by hydrolysis, hydrogenolysis or by the action of thiurea of all or part of the protector group or groups.

b) esterification or salification by a base of the carboxy or sulpho group or groups c) salification by an acid of the amino group or groups d) resolution of the molecule in order to obtain an optically active product e) oxidation of the sulphur atom in position 2 of the ooo 0 0 isocephem ring.

The halogenation agent which is preferably used is thionyl chloride in a chlorated solvent such as methylene chloride or in 1oO°: dimethyl formamide. Then, intermediately, there is obtained a product with the formula (VII a) I t 0 9 I t 4 S44t 4 4 4 4 4 I 44i 0 (VII a) 4 There can also be used other halogenation reagents such as phosphorus pentachloride, phosphorus oxychloride or tosyl chloride.

The sulphonation agent can be, for example, trifluoromethylsulphonic anhydride. The operation can then be done in the presence of a base, preferably in 2,6-dimethylpyridine or lutidine. In a general way, the sulphonation products are unstable and are not isolated.

The action of triphenylphosphine or of the reagent with the formula P(04k) 3 in which Alk represents preferably an ethyl radical is carried out in the usual conditions. The action of triphenylphosphine or of the reagent with the formula P(OAlk) 3 is preferably carried out in the presence of silica on the halogenated product with the formula (VII,) generally, the operation is done by heating to reflux a solvent such as toluene or chloroform. If a sulphonation agent is reacted on a product with the formula (VII), the action of triphenylphosphine or of the product with the formula P(0Alk) 3 is preferably carried out at the same time because of the instability of the sulphonation products.

OC i The strong base with which the products with the formulae (VIII A) and (VIII'A) can be treated can be chosen from potassium tert-butylate, lithium tert-butylate, lithium diisopropylamide, or lithium bis-trimethylsilyl amide.

The alkyl halogenide with the formula hal.R"A is preferably the chloride or the bromide.

The action of the product with the formula on the products with the formulae (VIII B) or (VIII'B) is preferably carried out in a chlorated solvent such as methylene chloride. The operation can be done in the presence of a relatively weak base such O o° as triethylamine or DBU (1,8-diazabicyclo[5,4,0]undec-7-ene), or .0 DaN (1,5-diazabicyclo[4,3,0]non-5-ene). The operation is then done at ambient temperature or by heating.

It is equally possible to operate in the presence of a strong base such as tert-butyl lithium or an alcoholate such as lithium tert-butylate, lithium bistrimethylsilyl amide or lithium diisopropylamide. The operation is then done at a low temperature.

S The reaction can, for example, be conducted from -700 C to the ambient temperature.

The protector group which Gp represents can be a silyl group Ssuch as trimethylsilyl or tert-butyl-dimethylsilyl. A group such as tetrahydropyranyl can however be used.

The separation of the protection group Gp is carried out in i| standard conditions. The operation is done for example in the presence of an acid or a fluoride ion brought in by hydrofluoric acid or tetrabutylammonium fluoride.

When a product with the formula (IX is obtained in which RA represents an amino radical, in a preferred way of carrying out the process, the product with the formula (IX is treated with a functional derivative of a product with the formula (IV This functional derivative can for example be a halogenide, a symmetrical or mixed anhydride, an amide or an activated ester.

As an example of a mixed anhydride, there can be cited for example the one formed with isobutyl chloroformate and the one formed with pivaloyl chloride and the carboxylic-sulphonic mixed anhydrides formed for example with paratoluenesulphonyl chloride. As an example of an activated ester, the ester formed with 2,4-dinitrophenol and the one formed with hydroxybenzothiazole can be mentioned.

i 0. C O 3 I t F As an example of a halogenide, the chloride or the bromide can be cited.

There can equally be cited the acid azide or the acid amide.

The anhydride can be formed in situ by the action of disubstituted NN' carbodiimide, for example, N,N-dicyclohexylcarbodiimide.

The acylation reaction is preferably carried out in an organic solvent such as methylene chloride. Other solvents such as tetrahydrofuran, chloroform or dimethylformamide can however be used.

When an acid halogenide is used, and in a general way, when a molecule of a hydrohalic acid is liberated during a reaction, the reaction is preferably carried out in the presence of a base such as sodium hydroxide, potassium hydroxide, the carbonates and acid carbonates of sodium or potassium, sodium acetate, triethylamine, pyridine, morpholine or N-methylmorpholine.

The reaction temperature is in general lower than or equal to the ambient temperature.

In a preferred way of carrying out the process, the products with the formula (IVb) are converted into reactive derivatives such as the halogenides of acides, which can be prepared by making ,b the products with the formula (IVb) react with halogenation agent such as phosgene, oxalyl chloride, thionyl chloride. There can also be prepared complexes with dialkyl sulphates, preferably dimethyl sulphate.

The operational conditions for such reactions are known to experts. Such reactions are described, for example, in the French patent 2,073,338.

In a preferred way of carrying out the process, the halogens used in the products with the formula (IV are the chloride or the fluoride. It is preferred to use a pyridinium derivative. The counterion is then preferably an iodide, tosylate, bromide, or BF4 ion.

The preparation of the products with the formula (IV and the reaction of these products with the products with the formula (IX are carried out in the conditions described for example in the Journal of Medicinal Chemistry 1982, Vol. 25, No. 4, p. 457-469.

The subsequent reaction if required of separation of the E and F isomers is carried out according to the usual techniques. It is preferred to use chromatography on silica.

i 'ii ,11 CH

-C-NHI

3 C H t The conversion of the products with the formula (X into products with the formula (XIA is also done by standard methods.

The derivative of the group R 3 A which is used can, for example be a halogenide derived from an aryl carboxylic or heterocyclic aryl radical, possibly substituted. For preference, the fluoride is then used when R 3 A represents, for example, an acetyl or carbamoyl. It is preferred to operate in the presence of a reactive derivative such as an anhydride or a halogenide.

The conversion of the products with the formula (X into products with the formula (XI B) is preferably carried out according to the following conditions; an activated derivative of the hydroxyl radical is prepared by the action, for example, of a derivative of a o °sulphonic acid such as the anhydride of trifluoromethylsulphonic S acid. The operation is done at low temperature or at ambient temperature.

When R 3 A does not represent a quaternary ammonium, it is preferred to operate in the presence of a base.

The conversion of the products with the formula (X into Sproducts with the formula (XIC) is carried out in similar conditions.

First, an activated derivative of the hydroxyl group is prepared in the previously stated conditions, in particular, starting with the anhydride of trifluoromethylsulphonic acid. The action of the product with the formula HS-R 3 is preferably carried out in the o presence of an organic base such as 2,6-dimethylpyridine and of a soluble iodide source. It is then preferred to operate in the presence of tetra-alkylammonium iodide.

The products with the formulae (XI (XI B) and (XI C) constitute products with the formula (IA) when they do not include any protector group and when A does not represent, among the easily cleavable ester groups, one of those which it is desired to eliminate.

In the other cases, the action on the products with the formula (XI (XI 8) or (XI C) of one or more hydrolysis or hydrogenolysis agents or of thiurea has the object of eliminating the protector group or groups which the different products may contain.

The nature of the reagents to be put into action in all these cases is well known to an expert. Examples of such reactions are given further on in the experimental part.

!I

U C H 3 3 -I I i- I- I- A non-exhaustive list of the means which can be used to eliminate the different groups is now given.

The elimination of the protector group or groups can be done by hydrolysis, this being acid, basic, or by using hydrazine.

5 It is preferred to use acid hydrolysis to eliminate possibly substituted alkoxy and cycloalkoxycarbonyl groups such as tertpentyloxycarbonyl or tert-butyloxycarbonyl, possibly substituted aralkoxycarbonyl groups such as benzyloxycarbonyl, and the trityl, benzhydryl, tert-butyl or 4-methoxybenzyl groups.

The acid which is preferably utilized can be chosen from the group constituted by hydrochloric, benzene sulphonic or paratoluenesulphonic, formic or trifluoroacetic acid. Other mineral or organic acids can however be used.

Basic hydrolysis is used preferentially to eliminate acyl groups such as trifluoroacetyl.

The base which is preferably used is a mineral base such as sodium or potassium hydroxide. There can also be used magnesia, baryta, or a carbonate or acid carbonate of an alkali metal such as the carbonates and acid carbonates of sodium or potassium or other bases.

Sodium or potassium acetate can also be used.

Hydrolysis using hydrazine is used for preference to eliminate groups such as phthaloyl.

Certain groups can also be eliminated by the zinc-acetic acid 4, system (for the trichloroethyl group). The benzhydryl and benzyloxycarbonyl groups are eliminated for preference by hydrogen in the presence of a catalyst.

The chloroacetyl group is eliminated by the action of thiurea in a neutral or acid medium according to the type of reaction described by MASAKI, J.A.C.S.,90, 4508, (1968) Other methods of deprotection known in the literature can also be used.

Among the preferred groups, there can be cited formyl, acetyl, ethoxycarbonyl, mesyl, trifluoroacetyl, chloroacetyl, trityl.

Trityl and chloroacetyl radicals are particularly preferred.

The acid preferably used is trifuloroacetic acid.

Salification of the products can be carried out by the usual methods.

Salification can, for example, be obtained by action on a product in the form of an acid or on a solvate, for example the ethanol solvate or a hydrate of this acid of a mineral base such as S sodium or potassium hydroxide, the carbonate or acid carbonate of S sodium or potassium. There can also be used the,salts of mineral acids such as the tri-sodic phosphate. Use can also be made of salts 4 i of organic acids.

As salts of organic acids, there can be mentioned, for example, the sodium salts of aliphatic carboxylic acids, linear or branched, saturated or unsaturated, with 1 to 18 and preferably with 2 to carbon atoms. These aliphatic radicals can be interrupted by one or more hetetvoatons such as oxygen or sulphur, or can be substituted be aryl radicals, such as, for example phenyl, thienyl, furyl or by one or more aryl radicals, such, for example, as :phenyl, thienyl, furyl: or by one or more hydroxyl radicals orby one or more halogen atoms such as fluorine, chlorine or bromine, preferably chilorinet by one or more lower carboxyllic or alkoxycarbonyl radicals, preferably methoxycarbonyl, ethoxycarbonyl or propyloxycarbonyl by one or more aryloxy radicals, preferably phenoxy.

Furthermore, there can be used as organic acids the sufficiently soluble aromatic acids such, for example, as benzoic acids, preferably substituted by lower alkyl radicals.

As examples of such organic acids, there can be mentioned the following :formic, acetic, acrylic, butyric, adipic, isobutyric, n-caproic, isocaproic, chloroproplonic, crotonic, phenylacetic, 2-thlenylacetic, 3-thionylacetic, 4-ethylphenylacetic, glutaric tile monoethyl ester of adiplc acid *the following acids hexanoic, heptanoic, decanoic, oletc, stearic, palmitic, 3-hydroxypropionic, 3-methoxypropionic, 3-methyithiobutyrtc, 4-chiorobutyric, 4-phenylbutyric, 3-phenoxybutyric, 4-ethylbenzoic, I-propylbenzole.

However, it Is preferred to use as salts of sodium, the acetate, the 2-ethythexanoate or the diethylacetate.

Salificatton can also be obtained by thle action of an organic base such as one of 'the following 1triethylamine, diethylamine, trimethylamine, propylailne, N,N~-dmthylethanolamInej trIS(hydroxymethyl)amIno, methane, methylarninew othanolamine, pyridine, picollne, dicyclohexylantne, morphol Ine and 1jnzylamine.

It cant also be obtained by the action of arginineo of lysine, of procaine, of histidine and of N-inothyl glucamine.

This salification Is preferably carried out in a solvent or a mnixture of solvents such as water, ethyl ether, methanol, ethanol or acetone, The salts are obtained In the amorphous or crystallizod form according to the reactional conditions employed.

Crystallized salts are preferably prepared by making the free acids react with one of the salts of aliphatic carboxylic acids mentioned above, preferably with sodium acetate.

The salification of the products by mineral or organic acids is carried out in the usual conditions.

The eventual esterification of the products is carried out in standard conditions. In general, the S 10 operation is done by making the acid of formula (I) j react with a derivative with the formula; S ^s in which Z represents a hydroxyl radical or a halogen atom such as chlorine, bromine or iodine, and R s designates the ester group to be introduced, of which groups a non-exhaustive list appears above. In certain cases, o it can be advantageous to carry out an esterification on a product of which the amine is blocked before removing I the protector group of the amine.

"20 The possible resolution of the compounds with the I general formulae (XI (XI B) and (XI C) can be carried i out by means of an optically active carboxylic or j sulphonic organic acid, such as tartaric, dbenzoyli! tartaric, camphosulphonic or glutamic acid, the docomo2r position o£ the salt so obtained being effected by means o£ a mineral base such as sodium bicarbonate or an organic base such as a tertiary amine such as triethylamino. In addition, there can also be used an optically active base.

The possible oxidation of the products with the formulae (XI (XI B) or (XI C) can be carried out by means of oxygen, peroxides, hydroperoxides, peracids or hydrogen peroxide. The reaction is advantageously sensitized by light. These reagents can be mixed with organic or mineral acids. It is preferred to use metachloroperbenzoic acid. The reactional conditions are known to an expert. Such conditions are set out, for example, in the French patent 2,387,234.

The products with the general formula as well as their pharmaceutically acceptable salts possess a very good anti-biotic activity on the gram bacteria, such as the staphylococci, the streptococci and, in particular, on the penicillium-resistant staphylococci. Their effectiveness on the gram bacteria, particularly on the coliform, the klebsiella, the salmonella and the proteus bacteria is particularly notable.

These properties make the said products suitable S for use as medicaments in the treatment of infections by sensitive germs and, notably, in that of staphylococci, such as septicemias by staphylococci, malignant staphylococcal infection of the face or cutaneous, pyodermitis, septic or suppurating wounds, anthrax, phlegmons, erysipelas, acute primitive or postinfluenzal staphyloccocia, bronchopneuomonia, pulmonary suppuration.

These products can also be used as medicaments in the treatment of colibacilloses and associated infect- ^2 ions, in infections due to proteus, klebsiolla and salmonella and in other affections caused by gram bacteria.

Therefore, the present invention has also as its subject, as medicaments and particularly as anti-biotic medicamonts, the products with the formula as defined above, as well as their pharmaceutically acceptable salts of acids, m I 6 II~)CYIYILLI~-- LII-CIC The invention has particularly as its subject, as medicaments and notably as anti-biotic medicaments, the products with the formula (IA): oN/I NH2 CO (In) syn isomer, '"in which R' represents a hydrogen atom or an alkyl, alkenyl or alkynyl or cycloalkyl radical having at the most 6 carbon atoms, possibly substituted, or an aryl radical. ZA has the values indicated above and R' 3

A

o represents a phenyl radical, a heterocyclic aryl radical Oc7 possibly substituted or an ammonium radical possibly substituted, or an acetyl or a carbamoyl radical.

Among these products, the invention has particularly as its subject as medicaments and notably anti- I 0 biotic medicaments, the previously mentioned products with the formula i A in which R' 0 represents a hydrogen atom, or a methyl or isopropyl radical possibly substituted by a carboxy, carbamoyl, nitrile methylthio or methoxy radical, a difluoromethyl or trifluoromethyl radical, a phenyl radical, a cyclobutyl or cyclopropyl radical possibly substituted by a carboxy radical, an allyl radical possibly substituted by a chlorine or bromine atom and zrepresents a simple bond and R' 3 A represents a possibly substituted pyridinium radical.

Quite particularly, the invention has as its subject, as medicaments and notably as anti-biotic medicaments, the products described further on in the examples.

The invention is extended to the pharmaceutical compositions S, containing as active principle at least one of the medicaments defined above.

These compositions can be administered by oral, rectal, parenteral, intramuscular route, or by local route as topical applications on the skin and the mucosa.

In particular, the products with the formula in which A ,j represents a cleavable ester group such as the propionyloxymentyl ester 20 can be administered by oral route.

They can be solid or liquid and are presented in the pharmaceutical forms currently used in human medicine, such as, for example, plain or sugar-coated tablets, capsules, granules, supposo itories, injectable preparations, ointments, creams, gels; they are prepared according to the usual methods. The active principle or principles can be incorporated with the excipients usually employed in these pharmaceutical compositions, such as talc, gum arabic, lactose, starch, magnesium stearate, cocoa butter, aqueous or non-aqueous vehicles, fatty substances of animal or vegetable origin, paraffin derivatives, glycols, various wetting, dispersing or emulsifying agents and preservatives.

In particular, these compositions can be presented in the form of a powder intended to be dissolved extemporaneously in an appropriate vehicle, for example in apyrogenous sterile water.

The dose administered is variable according to the affection treated, the subject concerned, the administration route and the product under consideration. It can be, for example, between ,rrr 0.500 g and 1 g three times a day, by intramuscular route for the products of examples 1 or 2.

The products with the formula (I can also be used as disinfectants for surgical instruments.

The products with the formula (VII used at the start of the preparation process for the products with the formula (IA) can be prepared according to the process described in the french patent 2.559.486 and recalled above.

An example of such preparation is given further on in the reference examples.

In addition to the products described further on in the examples which illustrate the invention without nevertheless limiting it, the following products constitute the products which can be j obtained in the scope of the present invention.

i )I 1The products answering to the formula I C O A in which R, R

I

A and n 2 have the significance indicated in the tables which follow 'i, 0

CC

C C C C

CCC

C

C

C

C

C R RIAn2

CO

2 A R R A n2 C2A C14 0 C 02,

CONN

3

'N,

OH

Ap

CUR

R lA n2 C0 2 AR1A2 co 2A 0 SCONH- 0 c Q COH NI sN cH 3

SO

CU02 6-CH~x, col or by a then of this c4 A derivative of an activation group of the hydroxyl radical the product with the formula HS-R 3 Aor a reactive derivative product in order to obtain a product with the formula (XI C) a, r i .i/ 1(34 0 .I cCA 'A (XI C Yvi I Lim Iuil mui a kv iiJ Yterdally, zne operation is cone Dy heating to reflux a solvent such as toluene or chloroform. If a sulphonation agent is reacted on a product with the formula (VII), the action of triphenylphosphine or of the product with the formula P(OAlk) 3 is preferably carried out at the same time because of the instability of the sulphonation products.

II

o5 E33 ~a o aI 8

U

IJ U Q-U Zr: 3'

'/I

(N( 0~ w Vtc iUti t=AdIIIPit utie one Tormed with isobutyl chioroformate and the one formed with pivaloyl chloride and the carboxylic-sulphonic mixed anhydrides formed for example with paratoluenesuiphonyl chloride. As an example of an activated ester, the ester formed with 2,4-dinitrophenol and the one formed with hydroxybenzothiazole can be mentioned.

VS~

4' Q 0' C) 4' F, Journal of Medicinal Chemistry 1982, Vol. 25, No. 4, p. 457-469.

The subsequent reaction if required of separation of the E and F isomers is carried out according to the usual techniques. It is preferred to use chromatography on silica.

S0 Ccy

I

B0 0 0- I ii I. gN I U Q-U^ Ija a3 UycIIL" UI UI iiti a ia L i uujei -LL UI ti iiiiiiiauiiLiy Lie protector group or groups which the different products may contain.

The nature of the reagents to be put into action in all these cases is well known to an expert. Examples of such reactions are given further on in the experimental part.

IV

4 Salification of the products can be carried out by the usual methods.

Salification can, for example, be obtained by action on a product in the form of an acid or on a solvate, for example the ethanol solvate or a hydrate of this acid of a mineral base such as sodium or potassium hydroxide, the carbonate or acid carbonate of sodium or potassium. There can also be used the salts of mineral acids such as the tri-sodic phosphate. Use can also be made of salts _8NT ol tDC 0UVl -Ifiva:A ov' a

I'

I

r&o At gDs~J-~

~-I

1 'fr'\A X-de 1~~ jo 0 eD rnv Z31 Zo4 D zHN 4 tOD z Vi a VZDVa

~~I

0 P a o RIA n 2 O 2 A R R A 2 C02A N14, co~ coO co coN14cCH3 Ot i ~LXI ls-cu 3

C

~$hII~IIL

NH-.

r- L 00 0 00 7 0 00~ 0 O 0 0 O 0 0 S 0 00 0 0 *0 o C 0 00 I I I I I

C'

~6~

'-C

('7

T

02 AN 6 lf I rc

A

rH~ £11 ~~jA6\ oN

"HN

A

tI\ -e zoJ e

I

4 v uVI H' vzO zuj via H1

I.

4 0 Oo 0 0 vz0 VT HI V zOD zTJ YTU

ENON

'C4 c 4f elf oft ire V~OD YTOD ID 0 o z 0~ 'd v z OD au VI v 0a ao c 0 4 003 40 4 9 0 0 0 C0 2 H 4 0 0 0 0 *N 0 9 0 OOQ 4 ~ci

N

c H.9 Q0 b S 00 a o 0* a 0 a S 0 a a a a a a a a 0 a ata 4 M- 00 0 n Co A R R n Co AR 2 2 1A 2 2 N14,

NH,~

0f C02-H o CCON VS c 14 N -l 0 kN~P 53d a a a a a Ga a a 4 4 04 0 9 00 4 C a a a.

c c a a a 4 4 4 0 4 a a 044 a aaa

NHI

-NCON

c H.7 a a a a O~Q L/2n .5 5N j 4 5 -c 3 Na- ro COfl

CH

3 0010 0 0 'l

.C

dJ

H-'

sIrs>sv

'CCC

CCIrk ia EN A-A Ire 4170D

I

hi 0 a t

O

LI

-I

~gIJ .zr R C0"j X 2 A R RA n2 CD2A R; 2 JO 1A oJH CCi3 Q c A/ Ic c.cH 3 0 C nr

Y

0 0I 'CAI2 NO

ASA

\Ad~S~fl=C~~COA4 COAR R 1A n2 C0 2

AX

co"NK-

H

4S-

F

#0 0* 0 0 09 0 0 0 0 0 0 0 0 0 0 0

n2 C O A 0 r

I-

R

NH,

A

t oI4 R 1A

R

R 1A co 2

A

~1A I Ii I

N,

C14 3 Cfu 3 0 C 2

H

0 ICRH1

V::V~SCN

I I_ I I 7-- <:1

R

I-I±

~A I U-

AJ

co 2A R R 1An2 C2A C, ~ON 'Oz~ H

CO

I 1 off C.lHs- N3/

H

R COAR Ri1A n c C 2

A

1A 2 O 2

A

tv 0, N NUHS 3 i n o2 AR R 1A2 co 2

A

CH3 0 G NQ.

HH

CHu3 Flo-. s1 1\N1 Ri CO 2 A P-9O NH~ e NH~. II ce COf Ci43 4 24~ '4

C'

4 4 cc '4 48 N O~ V~

CCO)

0 xIM C- .r 2 P:

ZG

N I Vt=r Ir3 -t a a.

S O C 3 5 3 J

O

DCI j O~ Bs CO gP

C

R RA n2 Co 2 A R R 1 A n 2 Co 2

A

0 Co 2 0 0 o G S-co-uH 2 2

SIN

It It II 3 tr Girlrr, u ac I, S. fI I I Ii N~31I~ II .3 I)I f3I I, I, El *1

CLI,

460 W 0 e ,I it

I

Sol 5 (a j L a cc ~m -z 4 7- a

IED

'-io1t4Q) CM If H m1 00 0 o t v 00 C 0 a a a a a a t a a a a a 0 0 0 a 0 0 &0 In to(N~ 06EHD

I.

J0 HN CO ~HN Y~D~I 7 J I0 tn

-HNHN

v zO uV dvz OD uVIT

-U

'F

N"V

6- -r

C'\AV'A

';HN

v{O OD u

A

R1RA n2 CO 2 A R RIA n 2

CO

2

A

IvH Rc CC: 0, cCox 7N I-qf S-S-xjal N I'IN' 4a 0 a 0 0 n2O R n O A 2C1AA 2 e Na l 0CH COH>1 cHY3 -9-9 -w

A

A

C143 0 0 00 CON -CH co0N So- 0 00 VON_ CH 3 .9y-(

QC

3 1910l a cc, a w- *94 0 400 S 0 0 0 4 4 0 o 4 a a *0 9 0 0 a 40 Vi 0 9 00 0 0 4 0 00

Ole, 0 *0 c 0 c0-

CH

2 SCQX H

H

3 it

LO)

1k2 HC /2 a ti "H Si$r\ CG 0

~L

cx..

NE

cc2 0 e OD H Co CV HC 0 -S INC 0 HNSC VI vz()o VtA a a a a #0 o o ,a 00 0 a a o 0 e o 000 1AA 2

H

c o0l 0* 0 0 4 9 0*0 a Rl A n2 co 2A R RlA n2 CO 2A 002- \C H 3 7 ;oQAH L c H~ C141 c 3 C9 3 9 14 3 C14 3 cf4 3 c-H.3 OH CH4 3 NI4~ >4

U

.7 7 R 1An 2 CO2A R RlA n o2A 0 co

H

3 00,C H 3 Ccq& ',Co0o IcI

EH

-HNOD~ Nj~N9 -HNvo::) ZHN

H

vz 03 zuVT d zOD

HN

n CO A R RlA n2 C2A 2c 2

NJ-IL

>1 rc ii

C

14,

-N"

-j K)i

K--

I

-I

NN

Ho

N-N

1 gos- N, \cH N ZHN 1>_HN- VZOD zu VTD \dv0 uVTd 'rHN

R

NI4)NH

N

R 1A ,C H 3 C O, C14 3 2 CO 2 A

R

O soo

NH,.

NI

I

c HF.,

CA/

V/1 VN -CA/

CH

3 n 2 0

V

-p 1 co2A co C 0 1

R

C

N* p L U R/ 2 2lCO A R *R 1An 2 CO2A ~NI _o CQ 0 OCH C14, >4~1 N jNH 14 oN -SCI r

>N

C"1 3 c 0.

Sc H 3

I

R0C0 R

IA

CC)2 2 c Co 2

NW.-

CO~ CWOG0

I

co SC C OQO C C C V a C a a .3 C CC a 00 0 C Ca a C a

'CC

CC)C

6)NO zHN VZOD zu IH li VOD ouV

I,

*0c 0 9 0 0 a p. 4 p p a a R Ri1A 1 n 2 co 2 A R R 1A n 2 co2A '-00 I ~5CHCH3 P4 V OD VI x o VT vzO z i' C r s <x\ 6D ~z's PJ~'\A NV S yH HlOOD 'rHN ;oQD edz0 0 vi d z OD 0u

ZTH

N 14, c~rc Q 0 CO-n

NW.

(9 NN C0014COOH CO~l! C02-I

CH

3

OH

NH~

j'J r tIN

~HN

*0O 0 4 *0 4 4 0* S 0 4, 4 08 4 a 00 0 N C556' H No 9 v zOZ)D VITdvz D z r r T TI R Ri1A n2 co 2

A

NW.

N.

a

N

c o. u

AI-\

SI,

CI-,

0C~a

NW.

N.

a H COAJIA c O~ H '9 Ri1A \VsK j l-i yvs~K/NH3 (E)V (C 14,) n 0 .91" C OH c 0 2 ,-a

R

IvH.

C o,,H i I I.

CA4

R

H

0 s9 V~~h- RT

A

%)a

Q

0 c0 2

R

NH,

or No 01 R 1A 6 y ijS C4 3 0 .2 CD2A ee C Oa _1~~11 v W'\ L V1 0

BO

";HN

7ZO VIvo VT H VO uVl Arm UH p.

p a, 0 00 00 C 0 00 0 00 C 0 0 0 00 C C 4 0 0 0 0 0 C 0 0 0 0 0 040 0 000 0 p. CP 0 p C 00 ji- CO C p C 0 00 0 o a C 0 0*0 0 0*Q

NW.

N

tI/I R R 1A 2 co 2 A R R 1A n2 co 2

A

0 0O~ S. N N Sjsz~cooli 0 0OaH CON

CH;

CQAI 04

C#!

3 C11 3

CH

3 H3 N 9 )v OHv 0 NJ4~ 5' N Hr 7'HN RR 1An 2 CO2A R R A n2 c lA 2 2, R COA NH 10I.H 0I o O->1Co COL-/S S. V.

CQ'I N cc, N/C V.1-

AI(CH

3 3 lb 6) 01 1 <i i 40 4 4 4 0 00 4 4 40 *0 C 4 0 4 C 0 0 C 4 a 4 0 4 0 4 a aoa 0 000 4

NW.

N.

S. N r

UN.

98d C9% Wr9'9

CI

R

NMI.

Ri1A 9NI

F

C4 3 -Al~ 0 n 2 0 CO 2A R CO 14 0 2 COC hi V d u

C-

N>1 r- t

I

4 \off a S -coflf)- KI4il cau7

JO

xxfIcofl 0 (D2 I

CH)

2 A R nR C0 2

A

NUH3 01 0 O, 910,,FO,0, 21N41

-r r r R IA C2A 4 1i i OP/f- '3 0f, GO..

G

I NHI.

R 1

A

S~~.K7IJCO Iiol \x~v Afp\ n 2 0 CO A 2 OOL/4 C~ O~L

'-F

i L I. J 02 0 0 0 00 P n CA R n CO it2 2R A1 II "-CHO-CJH, *0 a CO a a C a a 05 C C R R 1A 2 CO A R 1A n2 c NHI ox N4 0H-

CO

>1

F/\

"53 R R 1An2 CO2A R R 1A n2 co 2

AR

I CO TcuH YRCF

L

F3 0 Csid(CH)

I II II I R 1A CO 2

A

co2A I. I I I t CON)f-

VN

I- 2 H4 3 coz- C 0.9 CONH) CH3 CO2. 0I C- OL.

i. 1_ L I_

16-- No 4-) 00 i (n a a a a a a 0 a a a.

a 'cc

EHO

ttoj" Zw H 'Q9 fAt -HNODjHN- .9 Y t

-~HNV:

frI~Qc? 0 I7O j-jvaa{ v o f u_ a Ca R R IA n2 C 2 A R RA n2 co A NH41 Q COZH '00 C,4 C4 3 cH3 f f 0

-IC4 0 4 a 4a 46 9

H

0 ~cH coco 0 C~ 6 r CH.

0 Y Y.1-Z 9 0 000 0 000 0 0 0 a 0 0 0 0 o o I 0 0 0 0 0 00 0 0 0 1 00 0 00 0 0 00 0 00 a a no R n-A COA R R A 22 R 1AO2

NN

NN

cjC_ C)" CC, cH301 03 -q

A

o 00 00 0 C C 0 0 C 0 000 0 00 0 00 0 0 0 0 0 0 000 0 R 1A n2 co 2A R R A n o2A r CN- t'I4CH3 -1 9,

/\A

cH 3 cH

IV

1A 2 2

CU'

3 00" o 0~a Co 2 0cj

C-

3 NPY N SCHkD

.0 0 C Oa cc

H

&Cfl

N

0o

VVN

!Pv Y-l -1-1 'l 00 2 2 1 An 2 CO2 NHH3

N

u-c- W I 1

CHCH

v ~r 0,Nel

I

I l 00 0* 0 0 0* 0 0 C 0 *0 0 0 00 0 o 0* 00 0 0 0 0 0* a 00 0 0 a C 0 0 0 0 0 0 0 0 0~ S 0 0 0 00* 0 00* 0

IVI

rH 'N -0~ rHN U9

T

H

vio: NS 0HNZ3 Nu IdvOS o 00 0 7 0 a a 0 0 a0 0 0 to 0 0 0 0 0 0Ax 0 Co 00 0 000s 0 0 0

NN

CVH 3 CH0.

NH

0

ON

OH p N14,

I

I

L I -C M 0 0~ 00 0 0 0~ 0 COH3 NN1v 0c 00

COIN

/V/

A(-I

OY

I

Ri1A n2 CO 2A R R IAn 2 co 2A 9! it

VIVN

Cu' J.9, tCH 3

HO

I

-1

~HN

4 L V L4 REFERENCE EXAMPLE A 7-[2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-8-oxo-4-thia-3-methoxymethyl--azabicyclo[4,2,0]-oct-2-en- -2-carboxylic acid syn, cis, racemic.

STAGE A methoxyacetaldehyde.

100 cm 3 of dimethyl ketal of methoxyacetaldehyde, 100 cm 3 of water and 3.2 cmconce'ntrated hydrochloric acid are taken to reflux, then several fractional distillations are carried out and 8.7 g of the expected product is obtained.

STAGE B 2-chloro-3-methoxymethyloxirane carboxylate of 1,1-dimethyl ethyl.

A mixture of 2.106 g of methoxyacetaldehyde, 3.8 cm 3 of I tertbutyl dichloroacetate and 25 cm 3 of tetrahydrofuran is cooled to C. Over 15 minutes, 29 cm 3 of potassium tertbutylate in i tetrahydrofuran (0.9 Ml.) is introduced and left in contact for 1 hour 20 minutes. 25 cm of ether and 25 cm of water are added, and Iextraction is done with ether. The organic phase is washed with water saturated with sodium chloride, then dried and concentrated to dryness Sunder reduced pressure. The residue obtained is chromatographed on silica, eluting with methylene chloride, and 1.44 g of the expected product is obtained.

STAGE C 7-[2-(2-tritylaminothiazol-4-yl)-2-methoxyiminoacetamido]i i 8-oxo-2-hydroxy-3-methoxymethyl-4-thia-l-azabicyclo[4,2,0]octane-2- -carboxylate of 1,1-dimethylethyl.

I1.38 g of 2-chloro-3-methoxymethyloxirane carboxylate of 1,1-dimethylethyl, 2.736 g of 4-mercaptomethyl-3-[2-(2-tritylaminothiazol-4-yl)-2-methoxyiminoacetamido]-2-oxo-l-azetidine, cis, syn, i racemic, prepared according to the process described in the Belgian patent 894,795, and 12 cm 3 of dimethylformamide are mixed together.

After 10 minutes of contact, 458 mg of lithium carbonate is added, with agitation for 2 hours 50 minutes. The reactional mixture is poured into 100 cm 3 of water and 60 cm 3 of ethyl acetate. Extraction is done with ethyl acetate, the organic phase is washed with water, dried and concentrated to dryness under reduced pressure. The residue is taken up with ether and 3.058 g of the expected product is obtained.

Analysis C 38

H

4 1 0 7

N

5

S

2 743,91 Calculated C% 61.35 H% 5.56 N% 9.41 S% 8.62 Found 61.1 5.7 8.9 8.4

I

-A 00 STAGE 0 7-C2-(2-tritylamlnothiazol-4-yl)-2-methoxyininoacetamldoj- -8-oxo-3-methoxymethyl-4-thia-i-azabicycloE4,2,0Joct-2-en-2-carboxylate of 1,1-dimethylethyl.

4.44 g of diphosphorus tetralodide is put into suspension In cm 3 of pyridine, and after agitation for 5 minutes, there Is added in a single lot, 3.058 g of 7-(2-(2-tritylaminothiazol-4-yl)-2-methoxy- -lmlnoacetamido-8-oxo-2-hydroxyy-3-methoxymethyl-4-thla-1-azabicyclo- C4,2,03octane-2-carboxylate of 1,1-dimethylethyl, with agitation for 2 hours 40 mInutes. The pyridine is distilled off, the residue Is taken up with 50 cm 3 of ethyl acetate, and after filterIng, 50 cm 3 of N hydrochloric acid is added to the filtrate, with vigorous agitation.

The organic phase is decanted, washed with water, dried, and concentrated to dryness under reduceu pressure. The residue Is chromnatographed on silica, eluting with a ifixture of methylene chloride and ethyl acetate (85-15). The fractions of interest are concentrated to dryness, re-crystallized from methanol, and 703 mg of the expected product is obtained.

Analysis C 38 39 0 6

N

5

S

2 -725.89 Calculated C% 62.88 H% 5.41 N% 9.65 S% 8.83 Found 62.7 5.4 9.6 8.8 STAGE E 7- 2-(2-amiinothlazo1-4-yl )-2-methoxyimlno-acetamldo-8-oxo- 4-thia-3-methoxymethyl-l.azabicyclto[4,Z,0-oct-2-en-2-carboxylic acid syn, cis, racemic, 246 ing of 7-C2-(2-tritylamlnothiazol-4-yl )-2-methoxyiminaacetamido)-8.oxo.3.methoxymethyl-4-thia-l-azabicyclo(4,2,0)oct-2-en- -2-carboxylate of 1,1-dimethylethyl Is dissolved in 1 cm 3 of trifluoroacetic acid and left in contact for 50 minutes at ambiant temperature. 12 cm 3 of Isopropy ether is added, the precipitate formed is filtered off, and 176 mg of crude trifluoroacetate is obtaIned, which Is dissolved in ethanol. 2 drops of pyridine are added, crystallzation is allowed for 1 hour, and 88 mg of the expected product Is obtained.

Analysi C 5 I1 17 0 6 N5S 2 427,46 Calculated C% 42.15 11% 4.01 N% 16.38 S% 15.00 Found 42.2 4,0 16.2 15.0 r REFERENCE EXAMPLE B :7-[2-(2-aminothiazol 4 -yl )-2-rnethoxyiminoacetamido]-8-oxo-3-C(l-methyl -1H-tetrazol -5-yl )thiomethyl J-4-thia-1azabicyclor4,2,0]oct-2-en-2-carboxylic acid, syn, cis, racemic.

STAGE A 2C(1,1-dirnethylethyl )diin!thylsilyloxylethanol.

At 200 C and under nitroger 18 g of tertbutyl-methyl sily', 150 cm 3 of dichioro methane 17.5 cm 3 of dimethyl formamidce 33.6 cm 3 of ethylene glycol, are mixed together.

After solution is complete, 20.1 cm 3 of triethylamine is added over 5 minutes, then 1.8 g of 4-dimethylamino pyridine is added. After 2 hours 45 minutes of agitation, the solution is poured into 120 cm 3 of water and neutralized with N iydrochloric acid (about 40 cm 3 so as to obtain a pH of 3. After cecanting, the aqueous phase is re-extracted with 20 cm 3 of pentine, then the organic phase is washed with 60 cm 3 of water, which is extracted again with 20 cm 3 of pentane. The organic phase is c,,ied and distilled under reduced pressure, after which, 13.9 g of the expected product is isolated.

b.p. at 16 mm/Hg. 820-860 C.

STAGE B 2-C(1, 1-dimethyl ethyl )a methyl s ilyloxylacetal dehyde.

Under nitrogen and with agitition, 4.71 cm 3 of oxalyl chloride is dissolved in 120 cm 3 of dichloromethane. The solution is cooled to -7011 C, and over 12 minutes, while maintaining the temperature at -660 C, a solution comprising 8 cm 3 of dimethylsuiphoxide and 26 cm 3 of dichioromethane is introduced. Then, after 10 minutes of contact at this temperature, over 12 minutes and at -660 C there is introduced the following solution, comprising 8.81 g of 2-L(1,1-dhntethylethyl )dimethylsilyloxylethanol, obtained at stage A, 36j 60cm of dichloromethane and 8.86 cm 3 of pyridine. After minutes of contact at this temperature, over 8 minutes and at -650 C,

CM

3 of triethylamine is added. At 130 CI the pH is adjusted to 4 by adding N hydrochloric acid. After decanting, re-extracting with cm 3 of dichloromethane, drying the organic phase and distilling under reduced pressure, the crude product obtained is chromatagraphed on silica, eluting with dichloroinethane. Finally, 95 g of the expected product is isolated.

STAGE C :2-chloro-3-(tertbutyldimethylsilyoxymethyl )oxirane- -carboxylate of 1,1-dimethylethyl The operation is done as in taking the precaution of introduc potassium tertbutylate and 7.95 -200 C, into a solution of 1,1-dj after chromatography on silica( 9.4 g of the expected product is STAGE 0 7-f2-(2-tritylaminothi -8-oxo-2-hydroxy-3-[(1,1-dimethy -1-azabicycloC4.2.0]octane-2-car The operation is done as in reaction time of 16 Mours. Afte with dichioromethane and ethyl a.

2-mercaptomethyl-3-[2-(2-tritylajacetamido]-2-oxo-l-azetidine, ci, above, 9.09g of cyclized product STAGE E 7-[2-(2-tritylaminothi -8-oxo-3-E(1,1-dlmnethylethyl )dime cyclo[4,2,0Joct-2-ene-2-carboxyla tage B of reference example A, while ng at the same time the solutions of of aldehyde obtained at stage B at iethylethyl dichioroacetate and, .uent :hexane-dichioromethane 6-4), ibtai ned.

.,ol-4-yl )-2-methoxyiminoacetamidojithy1 )dimethylsilyloxymethyl]-4-thia- )xylate of 1,1-dimethylethyl.

,tage C of reference example A, with a chromatography on silica and elut ion itate (75-25), starting with 8.31 g of nothiazol-4-yl )-2-methoxyiminosyn, and with the product obtained s isolated.

o1-4-yl )-2-methoxyiminoacetamidoji of 1,1-dimethylethyl.

The operation is done as pre 'ously in reference example A, stage D. The contact is reduced to 55 mn nutes. The reactional mixture is poured into water, acidified with A hydrochloric acid to pH 1.6, and extracted ethyl acetate. By starting with 9.09 g of the product obtained above, after chromatography, 4 g of the expected product is isolated.

UVSpectrum in ethanol.

infl. ;233 nm Ell 364 infl. :265 nm El 173 max. nm Ell 229 E 18,900 STAGE F 7-E2-(2-tritylaminothiazol-4-yl )-2-inethoxyinilnoacetainido)- -8-oxo-3',hydroxymethyl -4-thi a-l-azabi cycloC4, 2, )oct-2-ene-2-ca rboxylate of 1,1-dimethylethyl.

2.595 g of the silyl derivative obtained at stage E is put into suspension in 30 cm 3 of acetone and 4 cm 3 of N hydrochloric acid.

The solution clears little by little and after 3 hours of agitation, 7.7 cm 3 of water saturated with bicarbonate is added, and the acetone is distilled off under reduced pressure. The residual gum is dissolved in 5.5 cm 3 of ethyl acetate, to which 43 cm 3 of ether is added.

After 3 hours 15 minutes of agitation, the crystals formed are filtered off, rinsed and dried. In this way, 2.232 g of the expected product is isolated.

STAGE G 7-[2-(2-tritylaminothiazol-4-yl)-2-methoxyiminoacetamido- -8-oxo-3-chloromethyl-4-thia-l-azabicyclo[4,2,0]oct-2-ene-2-carboxylate of 1,1-dimethylethyl.

623 mg of the alcohol obtained at stage F is dissolved in 8 cm 3 of dichloromethane with 834 mg of tosyl chloride, and, over 20 minutes, there is introduced the following solution, comprising 534 mg of 4-dimethylaminopyridine and 5 cm 3 of dichloromethane. After agitating for one hour, 2.2 cm 3 of N hydrochloric acid is added with agitation, and after decanting, the organic phase is dried then distilled under reduced pressure. The residue is chromatographed on silica, eluting with dichloromethane ethyl acetate The expected product crystallizes out from ether, yielding 245 mg.

UV Spectrum in EtOH infl. 224 nm E 1 1 441 E= 38,200 infl. 264 nm E 1 179 infl. 271 nm E 1 1 164 max. 306 nm E 1 1 222 E= 19,200 STAGE H -tritylaminothiazol-4-yl-2-methoxyiminoacetamido]- -8-oxo-[(1-methyl-1H-tetrazol-5-yl )thiomethyl]-8-oxo-4-thia-l-azabicyclo[4,2,0]oct-2-ene-2-carboxylate of 1,1-dimethylethyl.

301 mg of the product obtained at stage G, and 114 mg of the sodium salt of 1-methyl-5-mercapto-1,2,3,4-tetrazole are dissolved in 3 cm 3 of dimethylformamide. After 1 hour 40 minutes of agitation, the solution is poured into 30 cm 3 of water and extracted with ethyl acetate. The organic phase is dried and distilled under reduced pressure. The gum obtained is dissolved in ethyl acetate (2 cm 3 and 0 ether is added to the limit of solubility. The crystals obtained are filtered off after 45 minutes, rinsed with ether, dried, and there are obtained in two lots 183 mg of the derivative sought.

Stage I 7-[2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-8-oxo- 3-C(l-methyl-lH-tetrazol-5-yl)thiomethyl]-4-thia-l-azabicyclo[4,2,0]oct-2-en-2-carboxylic acid.

The operation is done as in example 1 stage E, but the crude product is dissolved in bicarbonated water and acidified to pH then filtered after having distilled off a large part of the water. Starting with 371 mg of the product obtained at stage H, 61 mg of the expected product is isolated.

UV Spectrum, 1) in Et0H max. :302 nm Ei:295 15,100 2) in EtOHIHCl 0.1 N infl. 273 nm Eli 304 max. 285 nm E 1 i 318 a 16,300 infl. 292 nm Eli 312 16,000 infl. 309 nm Eli 245 12,500 The corresponding optically active products are prepared, and in particular 7-[2-(2-tritylaminothiazol-4-yl )-2-mnithoxyiminoacetamidoJ- -8-oxo-3-hydroxymethyl-4-thia-1-azabicyclo[4,2,0]oct-2-ene-2carboxy..

ate of 1,1-dimethylethyl, syn, (65,7S), by operating as in reference example A, starting with 3-mercaptomethyl-34[2-(2-tritylaminothiazol- 4 -yl )-2-methoxiininoacetamido]-2-oxo-1-azetidine, cis, syn, (3S,4s), described in the French application RF 2,538,389.

The product obtained possesses the following physico-chemico characteristics m.p. 1800 C.

UV Spectrum in ethanol infl. :222 nm Ell 444 infl 237 nm Eli ~=352 max 302 nm Ell 223 E~15,900 2) in ethanol HCl 0.1 N infl. :221 nm Eli -464 infl. :263 nm Ell -204 infi. :285 nm Eli -294 max. 293 nm Eli 340 E. 22,000 inc. 300 nm Eli 299 inc. :310 nm Ell 230 REFERENCE EXAMPLE C 7-C/(2-triphenylmethylaminothlazol-4-yl -methoxyinminoacetyl/amino]-2-C(1,1-dimethylethyl )oxycarbonylJ-8-oxo-4thlaAl-azabicycloE4,2,Ooct-2-ene-3-yl/methyl-triphenyl-phosphonium (6S,7S).

2.182 g of 7-E2-(2-trltylaniinothiazol-4-yl )-2-methoxyimino- I acetamido]-8-oxo-3-chloromethyl-4-thia-1-azabicyclo[4,2,0]oct-2-en- -2-carboxylate of 1,1-dimethylethyl(6S,7S), prepared as at stage G of reference example B and 1.679 g of triphenyl phosphine are dissolved in 24 cm 3 of tetrahydrofuran, and 14.1 g of silica is added; the tetrahydrofuran is distilled off under reduced pressure over 2 hours, the remainder is cooled, agitated for 26 hours at 200 C, then chromatographed on silica (eluent, dichloromethane-methanol, 9/11). 1.89 g of the product sought is obtained.

I Example 1 :Trifluoromethane sulphonate of 7-[3-[7-[/(2-amino-4- -thiazolyl )-(methoxyimino)acetyl/amino]-2-carboxy-8-oxo-4-thia-l-azabicyclo_[4,2,0joct-2-en-3-yl]propen-2(E)-yl]thieno[2,3-b]pyridinium (6S,75), syn.

Stage-A :7-E/2-(triphenylmethylamino-thiazol-4-yl)-2(Z)-methoxyiminoacetyl/amino]-3-[3-[/(1,1-dimethylethyl)dimethylsilyl/oxy]propen-1-yl J-8-oxo-4-thia-l-azabicyclo[4,2,0]oct-2-en-2-carboxylate of 1,1-dimethylethyl (6S,7S).

1.89 g of hydrochloride of 7-E/2-(triphenylmiethylamino-thiazol- -4-yl )-2(Z)-methoxyiminoacetyl/amino]-3-[methyltriphenyl-phosphonium]- -8-oxo-4-thia-1-azabicyclo[4.2.Ojoct-2-en-2-carboxylate of 1,1-dimethyl- -ethyl, 30 cm 3 of dichioromethane, 0.68 cm 3 of 2-(1,1-dimethylethyl- -dimethylsilyl-oxy)acetaldehyde, and 0.53 cm 3 of triethylamine are mixed together, and agitated at 200 C, for 14 hours The sol ution is then chromatographed on silica, eluting with a mixture of dichioro- -methane and ethyl acetate and 1.305 g of the expected product is isolated, containing a mixture of isomer E and Z NMR Spectrum (CoDC 3 0.90 0.92 ppm SitBu 1.50 1.53 ppm CO 2 tBu 2.95 3.11 ppm CHS 4.05 ppm OCH 3 4.31 4.37 ppm CHO 4.11 ppm H 6 5.4 -5.5 ppm H 7 5.75 5.87 ppm and Z (1/3) 6.11 6.24 ppm 6.17 6.34 ppm and E(2/3) 6.97 7.16 ppm 6.50 6.56 ppm H 5 thiazole, syn 7.34 PPM Stage B :7-[/2-(2-triphenylmethiylamino-thiazol-4-yl )-2(Z)-methoxy- -iminoacetyl/aminoJ-3-[3-hydroxypropen-1(E)-yl]-8-oxo-4-thia-1-aza- -bicyclo[4,2,0)oct-2-en-2-carboxylate of 1,1-dimethylethyl and 7-[/2-(2-triphenylnethylamino-thiazol-4-yl )-2(Z)-methoxy- -iioctlaio--3hdoyrpnlZ-l--x--halaa -bicyclo[4,2,0)oct-2-en-2-carboxylate of 1,1-dimethylethyl.

L_*L-CIIIC_;I _iil(iiiil-ii i.II- 1.305 g of the product obtained at stage A of example 1 is dissolved in 15 cm 3 of acetone, 2 cm 3 of an aqueous normal solution of hydrochloric acid is added, with agitation for 2 hours 30 minutes, followed by concentrating to dryness by distillation under reduced pressure. After adding bicarbonated water, extracting with dichloromethane, and concentrating the extracts to dryness by distilling under reduced pressures, the residue is chromatographed on silica, eluting with a mixture of dichloromethane and ethyl acetate so obtaining 536 mg of the E isomer and 369 mg of the Z isomer of the expected product.

Check of isomer E I.R. Spectrum (chloroform) 3607 cm-1 OH 3405 cm 1 amide NM 1684 cm- 1 C 0 1515 cm 1 amide II 1772 cm 1 lactame C 0 1595 cm 1 1544 cm-1 1527 cm'- aromatic, thiazole, conjugated system.

1700 cm 1 tertbutyl ester 1370 cm- 1

CH

3 1154 cm- 1

C-O-C

2820 cm- 1 OMe 1049 cm- 1

C=N-OR

U.V. Spectrum ethanol max. 231 nm E11 497 infl. 258 nm Eli 290 infl. 264 nm E11 264 infl. 270 nm E1 240 max. 320 nm E 1 1 245 NMR Spectrum (CDC1 3 1.51 ppm tBu 3.05 ppm CH 2

S

4.02 ppm OCH 3 4.28 ppm CH 2 0H 5.48 ppm

H

7 6.24 6.41 and 6.97 -7.13 p| E= 32,200 S= 18,100 pm, H of ethylenes, E J 15 Hz 7.29 ppm3 6.53 ppm H 5 thiazole, syn Check of isomer Z I.R. Spectrum (chloroform) 3605 cm- 1

OH

3405 cm- 1 NH amide 1685 cm- 1 C=0 1505 cm- 1 amide 11 1773 cm- 1 lactame C=0 1704 cm- 1 tertbutyl ester 1368 cm- 1 Me 1154 cm- 1 C-0-C 1585 cm- 1 1573 cm- 1 1527 cm- 1 1493 cm- 1 trityl, aromatics, thiazole, conjugated system 2820 cm-1 C=N-OMe 1050 cm- 1 C=N-0R U.V. Spectrum (ethanol) infi. 230 nm 'Ell 1 411 infl. 260 nm ElI=220 infi. 265 nm E 1 1 198 infl. 271 nm El= 176 max. 308 nm 194 =S19414,300 NMR Spectrum (COCl 3 1.49 ppm tBu 3.06 ppm S.-CH 2 4.04 p pm OMe 4.27 ppm CH 2 0H 5.48 ppm

H

7 5.85 ppm 5.98 ppm and 6.21 -6.34 ppm, H of ethylenes 6~Z J =11 Hz 6.56 ppm H 5 thiazole "syn" 7.29 ppm 0 Stage C :Trifluorornethane suiphonate of 7-[3-[7-[/2-(2-triphenylmethylamino-thiazol-4-yl )-2(Z)-methoxyiminoacetyl/amino]-2-E/1,1- -dimethyl/oxycarbonyl]-8-oxo-4-thia-1-azabicycloE4,2,]oct-2-el- 3 -yl]- -propen-2(E)-yl~thienoC2,3-b~pyridinium (65,7S).

222 mg of the E isomer obtained at stage B of example 1 is dissolved in 4.8 cm 3 of dichloroinethane, and to this is added 3 cm 3 arr ,3 of a solution made up of 536 mg of thienopyridine for 10 cm 3 of methylene chloride. After cooling this to -700 C, 2.7 cm 3 of a solution made up of 0.43 cm 3 of trifluoroethane sulphonic anhydride for 10 cm 3 of methylene chloride is added drop by drop. The temperature is then brought up slowly to 20° followed by concentrating to dryness by distilling under reduced pressure. Ethyl i acetate is added to the residue, which is then washed with water containing 0.7 cm 3 of an N aqueous solution of hydrochloric acid, decanted, washed with water, extracted with ethyl acetate, and the i 10 extracts concentrated to dryness by distilling under reduced pressure.

The residue is chromatographed on silica, eluting with a mixture of dichloromethane and methanol and 236 mg of the expected compound is isolated (isomer E).

I Stage C' Trifluoromethane sulphonate of 7-[3-[7-[/(2-triphenylmethylamino-thiazol-4-yl)-2(Z)-methoxyiminoacetyl/amino]-2-[/1,1- -dimethylethyl/oxycarbonyl]-8-oxo-4-thia-1-azabicyclo[4,2,0]oct-2-en-3- -yl]propen-2(Z)-yl]thieno[2,3-b]pyridinium (6S,7S).

145 mg of the Z isomer obtained at stage B of example 1 is dissolved in 5 cm 3 of dichloromethane, to this is added 120 ul. of thieno[2,3-b]- -pyridine, followed by cooling to -700 C. 1.76 cm 3 of a solution of trifluoromethane sulphonic anhydride in methylene Schloride, made up of 0.42 cm 3 of anhydride for 10 cm 3 of methylene *I chloride, is added drop by drop, then the temperature is brought back I slowly to +200 C. The solution is chromatographed on silica, eluting with a mixture of dichloromethane and methanol (92/8) and 157 mg of the Sexpected compound is isolated.

Stage 0 Trifluoromethane sulphonate of 7-[3-[7-[/(2-amino-4- -thiazolyl)-(methoxyimino)acetyl/amino]-2-carboxy-8-oxo-4-thia-l-azabicyclo[4,2,0]oct-2-en-3-yl]propen-2(E)-yl]thieno[2,3-b]pyridinium (6S,7S), syn.

221 mg of isomer E obtained at stage C of example 1, and 2.5 cm 3 of a 33 aqueous solution of formic acid are mixed together and heated to 650 C for 55 minutes, then cooled, diluted with water, filtered and washed with ether. The aqueous phase is concentrated to dryness by distilling under reduced pressure, water is added and after separating and drying, 93 mg of the expected product is obtained.

-v .4-40 I.R. Spectrum (nujol) 170crm lactane C V 1660 crlf' 1550 and 1535 cm-I aromatic amide II thiazole +conjugated sys temn.

1030 cm- CFSO U.V. Spectrum (ethanol) max. 238 nm El 625 Z 44,200 max. 307 nm El= 251 17,700 infi 318 nm El 232 f1 *infi. 338 nm El 166 NMR Spectrum (DMSO) 3.83 ppm OCH 3 5.55 to 6.44 ppm CH 2 1H ethylene 6.81 ppm H 5 thiazole 7.23 ppm

NH

2 7.84 to 9,24 ppm aromatics By hydrolysis with formic acid, the isomer Z hydrolyses entirely into isomer E (isomerisation).

Example 2 :7-[/2-(2-aminothiazol -4-yl )-2(Z)-methoxyiminoacetyl/i{ -8-oxo-4-thia-l-azabicyclor4,2,0Joct-2-en-2-carboxylic acid (6S,7S), Stage A :7-[/2-(2-triphenylniethylamino-thiazol-4-yl )-2(Z)-methoxyiminoacetyl/aminoJ-3-[3-/(1-methyl -lH-1,2,3,4-tetrazol-5-yl )thio/propen-(E )-yl J-8-oxo-4-thia-1-azabicyclo[4,2 ,Oj-oct-2-en-2-carboxylate of 1,1-dimethyl ethyl.

37 mg of 7-E/2-(2-triphenylmethylamino-thiazol-4-yl)-2(Z)- -methoxyiminoacetyl/amino]-3-[3-hydroxypropen-l(E)-ylJ-8-oxo-4-th ia-la -azabicyclo-[4,2)0]oct-2-en-2-carboxylate of 1,1-dimethylethyl, 24 mg of tetrabutyl ammonium iodide, 0.8 cm 3 of methylene chloride and 23 ul. of 2,6-lutidine are mixed together and cooled to C.

Then, drop by drop, 0.25 cm 3 of a solution of trichloromethane sulphonic anhydride, titrating 0.42 cm 3 of anhydride for 10 cm 3 of methylene chloride, is added, followed by 14 mng of the sodium salt of (iJ 1 I I- -1,2,3,4-tetrazole and then 0.5 cm 3 of dimethylformamide. After agitating at 200 C and concentrating to dryness, the residue is chromatographed on silica, eluting with a mixture of methylene chloride and ethyl acetate, and the expected product is isolated.

Stage B 7-[/2-(2-aminothiazol-4-yl)-2(Z)-methoxyiminoacetyl/-amino]- -3-[3-/(1-methyl-1H-1,2,3,4-tetrazol-5-yl)thio/propen-(E)-yl]-8-oxo- -4-thia-l-azabicyclo[4,2,0]oct-2-en-2-carboxylic acid.

329 mg of the compound obtained at stage A of example 2, and 10 9.6 cm 3 of a 33 aqueous solution of formic acid are mixed together, heated for one hour and 15 minutes at +65° C, then cooled, diluted with water, filtered, and concentrated to dryness by distilling under reduced pressure. The residue is triturated in water, the insoluble matter formed is eliminated by filtering, and after concentrating to dryness, 142 mg of the expected compound is isolated.

]D 990 (c 0.8 DMSO).

I.R. Spectrum (nujol) 3410 cm 1 3300 cm-1 3210 cm 1 absorption OH/NH 1775 cm-1 1770 cm-1 /Z lactame C 1665 cm"1 other carbonyl 1626 cm-1 1556 cm-1 aromatic conjugated system NH 2 U.V. Spectrum max. 239 nm max. 266 nm infl. 280 nm max. 329 nm NMR Spectrum 3.86 and 3.94 4.03 4.10 5.56 to 5.73 (ethanol HC1, El =390 E1 414 E11 390 E1 304

(DMSO)

ppm

NC

ppm

=C

ppm

H

7

H

ppm

CH

2 0.1 N) 21,000 22,300 E= 16,300

H

3 and OMe

-CH

2

S

lactame (cis) ethylene aE 6.07 to 6.39 6.88 to 7.05 ppm 6.84 7.22 9.17 9.27

H

'"*CH

2

H

H

5 thiazole syn

NH

2

NHCO

ppm ppm ppm Example 3 Internal salt of 7-r3-r7-[2-(2-aminothiazol-4-yl)-2- -(methoxyimi no)acetamido]-2-carboxy-8-oxo-4-thia-l-azabicl o[4,2,O]oct-2-en..3-yl]propen-2-(E)-yllthieno[2,3-bpyridilium, syn (6S,7S).

281 mg of product obtained at stage C of example 1 is dissolved in 3.17 cm 3 of 66% formic acid, and the solution is heated to 650 C for two hours. It is then diluted with 3.2 cm 3 of water, filtered, and the filtrate is concentrated to dryness under reduced pressure. The residue is dissolved in 1.3 cm 3 of a 1M aqueous solution of tri ethylamine carbonate and 1.3 c 3 of acetonitrile and chromatographed on silica (eluent :water-acetonitrile 9-1, then 85-15). 77 mg of the expected product is obtained.

NMR Spectrum (OMSO) 3.83 ppm OCH 3 5.49 ppm H 7 .6-lactame, cis 5.88 7.48 ppm H of ethylenes 6.80 ppm H 5 thiazole IR Spectrum (nujol) NH/OH -lactame C=O 1760cm- 1 amide c=o 1665cm- 1

NH

2 def. aromatic, COO-, amide 11 thiazole 1635cm 1 l, 1600cm- 1 1558cnf 1 1540cm- 1 IiC=N OR 1035cm- 1 Example 4 :Trifluoroacetate of 7-[2-(2-aminothiazol-4-yl)-2-.

(methoxyimino )acetamido]-3-t13-acetoxy-l- E-poenyl}'8-oxo-4-thia- -1-azabicyclo[4,2,0]oct-2-en-2-carboxylic acid, syn (6S,7S).

Stage A :7-[2-(2-tritylaminothiazol-4-yl)-2-(Z)- -methoxyiminoacetamido]-3-[(3-acetoxy)propen-1(E)-yl]-8-oxo- 4 -thia-lazabicyclo-[4.2.O.]oct-2-en-2-carboxylate of 1,1-dimethylethyl.

300 mg of the E isomer obtained at example 1, stage B, 1.5 cm 3 of pyridine and 0.73 cm 3 of acetic anhydride are agitated for 2 hours at ambient temperature. 20 cm 3 of water and 10 3of N hydrochloric acid are added, followed by extraction with methylene chloride. 395 mg of crude product is obtained which is chromatographed on silica, eluting with a mixture of methylene chloride and ethyl acetate 255 mg of the expected product is obtained, m.p.,y 1700 C.

C1 V Stage B Trifluoroacetate of 7- 12-(2-aminothiazol-4-yi )-2-(methoxyimino)acetamido]-3-[3-acetoxy-1- :-)-propenyl]-8-oxo-4-thia-1- -azabicyclo[4,2,0]-oct-2-en-2-c7 'boxylic acid, syn (6S,7S).

210 mg of the product obt6 *ed above and 1.05 cm 3 of tnifluoroacetic acid with 10 water are agitated for 55 minutes at ambient temperature. 5 cm 3 of -)er is added, with agitation for a further hour, then, after separ ing, 133 mg of the expected product is obtained.

NMR Spectrum (DMS0) 6.92 ppm

H

5 of the thiazole 9,27-9.37 ppm H amido 5.63 to 5.68 ppm H 7 4.02-4.08 ppm H 6.22 to 6.3 and 7.09 to 6.93 pp H ethylenes 2.07 ppm H of acetyl IR Spectrum (nujol) Absorption region OH/NH -lactai. C=0 1767cm 1 1740cm- 1 1698cm-' 1667cm- 1 1640cm-1, absorptions 1140m 1 -120m UV Spectrum 1) EtOH max. 236 nm E 1 l1 387 F- 23, 10 0 infi. 260 nm EI=256 max. 320 nm El= 260 15,500 2) EtOH HC1 0.1N max. 238 nm E1=291 Z= 17,300 max. 266 nm E l= 331 19,700 infi. 283 nm 1 i= 289 max. 324 nm Ell 234 13900 Example 5 :Trifluoromethane suiphonate of 3-[7-[2-[2-(aminothiazol- -4-y1 )-2-methoxyimi noacetimido]-2-carbopxy-8-oxo-4-thia-1-azabi cyclo [4.2.0.]oct-2-en-3-yl]-2-(Z)-propeny1 trimethylanunonium syn (6S,7S) and isomer propenyl.

Stage A :Trifluoromethane suiphonate of 3-[7-[2-(2-tritylaminothiazol- -4-yl )-2-mnethoxyiminoacetamido]-2-[(1,1-dimethylethoxy)calbonylII-8-oxo- -4-thia-1-azabicycloE4,2,0]oct-2-en-3-yllpropen-2-(E)-yl-trimethyl-4 ammonium, syn (6S)(7S) and the isomer (propen-2(Z)-yl).

282 mg of 7-C2-(2-tritylaminothiazol-4-yl)-2-(mpethoxyinino)acetamidoJ-3- 3-hydroxy-1(E Z)-propenylj-8-oxo-4-thia-1-azabicyclo- [4,2,O1oct-2-en-2-carboxylate of tertbutyl is dissolved in 3 cm 3 of methylene chloride, then cooled to -700 C and 1.6 cm 3 of a 1.53 nmole of trimethylamine is added. 0.094 cm 3 of trifluoromnethane suiphonic anhydride is added drop by drop, with agitation at -70" C for 30 minutes. 7 cm 3 of nethylene chloride and em 3 of .1.N hydrochloric acid are added. The mixture is allowed to warm up again, the organic phase is separated and dried, then chrcatographed on silica, witm elution by a mixture of nethylene chloride ana methanol The products obtained are 108 mg of isomer Z 117 mg of isomer E and 53 mg of a mixture of E and Z.

Stace B Trifluoromethane sulphonate of 3-[7-C2-(2-aminothiazol- -4-yl )-2-metnoxyimnlnoacetamido)-2-carboxy-8-oxo-4-thi3a--azabicyclo- S4.2,0,Joct-2-en-3.yl32-(Z)-propenyl trimethylammonium syn (6S,7S) and the 2.(E)-propenyl Isomer.

108 mg of the Isomer product obtained is dissolved in 2 cm 3 of formic acid with 66% of water and agkated for 2 hours at 650 C, after which it is cooled and dih.ted with 2 cm 3 of water, The reactional mixture is washed with ether, then with methylene chloride, and the aqueous phase is evaporated off. The residue is taken up 3 times with 5 cm 3 of acetonitrile and 1 cm 3 of methanol. 5 cm 3 of methylene chloride is added to the residue, and after agitation for 1 hour and separation, 55 mg of the expected product is obtained.

NMRSpectrum (OMSO) 3.06 ppm N (D(C0 3 3 3.86 ppm CS) 0C11 3 4.10 ppm CHZ-NC 3.02 to 3.27 ppm S, SI%2 6.72 ppm aCIINCICH 2 4Z 6.81 ppm :H 5 thiazole syn 9.3 ppm NHCO 1) Ctoll max. 231 nm Ell 336 6,ft 21,200 max. 302 nm Ell 202 a* 12,700 t Y 2) EtOH HC1 0.1N max. 232 nm El 257 e= 16,200 max. 261 nm El 250 C- 15,800 max. 284 nni El 237 =14,900 infi 310 nm El 179 By starting from the isomer obtained at stage A, and operating as above, 56 mg of the expected product is obtained.

NMR Spectrum (DMS0) 3.02 ppm :NO~ (Me) 3 3.87 ppm :OMe 3 4.11 ppm :CH 2 -1#9 5.61 to 5.78 ppm :H 7 (cis) 6.73 ppm :HS thiazole syn 5.96 to 6.22 ppm H ethylene aF 7.11 7.28 ppm UV Spectrum 1) EtOll max. 235 nm Eli a 381 IE= 24,000 max. 325 nm Eli a 244 S 15,400 2) EtOJI HCl 0.1N infi. 245 nm Ell a 299 max. 263 nm Eli a 318 6f 20,100 max. 332 nm Ell 212 Ea 13,400 Example 6 Internal salt of 34[3-C7-C(2-aminothiazol-4-yl)-2- -methoxyiminoacetamidol-2-carboxy-8-oxo-4-thia--azabicycloC4,2,0Joct-2-en-3-vl-3-2-(E),-propenloxycarbonyl]--methypyridium syn_ (6s,7S).

Stage A -2(-rtlmntizl--l--Z-mtoymn) acetamido3-3-Cnicotinoyloxy)-1-(E)-propenylJ-8-oxo-4-th ia-l- -azabicycloEt2,0Joct-2-en-2-carboxylate of 1,1-diinethylethyl, (6S,75).

1.5 g of nicotinic acid is heated to reflux in 1.8 cm 3 of thionyl chloride for one and a* half hours. After taking up with toluene and evaporating, the residue is triturated with ether, then dried, and 2,12 9 of nicotinoyl chloride hydrochloride is obtained.

258 mg of the E isomer obtained at Stage B of example 1 is dissolved in 1 cm 3 of pyridine* and 93 mg (0.526 mM) of the freshly prepared nicotinoyl chloride hydrochloride is added and agitated for 2 hours under an inert atmosphere. After diluting with 10 cm 3 of methylene chlk.ide, washing with 1N hydrochloric acid and then with a solution of sodium bicarbonate, drying and evaporating, the residue obtained is chromatographed on silica, eluting with a mixture of methylene chloride and acetone and 232 mg of the expected product is obtained.

Stage B Iodide of 3-[3-[7-[2-(2-tritylaminothiazol-4-yl)-2-(Z)- -methoxyiminoacetamido]-2-(1,1-dimethylethoxycarbonyl )-8-oxo-4-thia- -1-azabicycloC4,2,0]oct-2-en-3-yll]-l-(E)-propenyloxycarbonyl-l-methyl pyridinium (6S,7S) E.

225 mg of the product obtained above is dissolved in 1 cm 3 of dimethylsulphoxide, 0.168 cm 3 of methyl iodide is added, and the whole is agitated for 5 hours. The dimethyl sulphoxide is evaporated off under reduced pressure at 400 C, and the residue is chromatographed on silica (eluent methylene chloride methanol 92-8), and 187 mg of the expected product is obtained.

Stage C Internal salt of 3-[3-[7-[(2-aminothiazol-4-yl)-2- -methoxyiminoacetamido]-2-carboxy-8-oxo-4-thia-l-azabicycloC4,2,0]oct-2-en-3-yl]-2-(E)-propenyloxycarbonyl]-l-methylpyridinium syn (6S,7S).

3 187 mg of the product obtained at stage B is dissolved in 1 cm of trifluoroacetic acid and left at ambient temperature for 10 minutes.

The product is precipitated with 10 cm 3 of isopropyl ether. After separation, the residue is dissolved in 5 cm 3 of hot ethanol, then concentrated to about 1 cm 3 and redissolved by heating, after which 0.05 cm 3 of pyridine is added. By cooling, agitating for 10 minutes, separating, washing with ethanol and then with ether, 34 mg of the expected product is obtained.

NMR Spectrum (DMSO) 3.78 4.86 ppm OCH 3 4.05 ppm Hg 4.37-4.44 ppm N+-CH 3 5.05 ppm -CH 2 0- 5.66 ppm H 7 6.24 ppm ,CH-CH 2 7.15 ppm -CH-CH-CH 2 6.82 ppm Hg thiazole syn 7.23 ppm NH 2 8.06 to 9.57 ppm :H pyridine and H mobile $l -Di Example 7 1Trfluoromethane sulphonate of 143-i7-L-(2-ami nothiazol- 1 ,)-2-(methoxyImino acetamido -2-carbox -8-oxo-4-thia-l-azabic dlo- [412,0)oct-2-en-3-yl]-2-(Z)-propenyl]-1,4-dlazabcyclooctane Stage A Trifiuoromethane sulphonate of 7-[2-(2-tritylami nothi azol- -4-yl )-2-(methoxlmino)acetamido-3-3-(1,4-diazabicyclooctane)-1(Z)propenyl J .oxo-4-thia-l-azabicyclo-E4,2,0joct-2-en-carboxylate of 1,1-dimethylethyl (6S.7S) 300 mg of 7-E2-(2-trtylamlnothazol-4-yl)-2-(methoxyino)acetamido)3- 3-hydroxy-1- (Z )-propenyl )-8-ox-4-thi a-1-azab cyclo- E4,2,0)oct-2-en-carboxylate of 1,1-dimethylethyl (6S,7S), 6 cm 3 Of methylene chloride and 179 mg of 1,4-diazabicyclo octane are mixed together than cooled to -700 C. Drop by drop, 0.114 cm 3 of trifluoromethane suiphonic anhydride Is added over 25 minutes at this temperature. After being left for 15 minutes at -150 C and agitated, 20 cm 3 of water and 6 cm 3 of 0.1M hydrochloric acid are poured In.

extraction is done with methylene chloride, the extracts are dried and concentrated to dryness, and 350 mg of crude product is obtained which is then chromatographed on silica, eluting with a mixture of methylene chloride and methanol 240 mg of the expected product is -0 recovered.

Stage B Trifluoronethane sulphonate of 1-L3-[7-EC2-(2-arinothmazol- 4-yl)-2-(methoxyimino)-acetomldoj-2-carboxy-8-oxo-4-thia-l-azablcyclo- (4,2,ojoct-2-en-3-y1J.2-(Z)-propenylJ-1,4-diazabicyclooctane.

190 mg of the product obtained above and 1 cm 3 of trifluoroacetic acid with 10% of water are agitated for 60 minutes.

Precipitation is caused by adding 6 cm 3 of ether, and after filtering and drying, 146 mg of the expected product Is obtained. m.p. 1900 C.

NMR Spectre (DMSO) 6.88 pp H 5 of the thiazole 9.3 9.4 ppm H of the amido 5.58 to 6.73 ppm H 6 6.73 6.87 pp I H etbylenes4Z 5.86 to 6.11 ppm UV Spectrum 1) EtOH 36 max. 231 nm Ell 236 6- 18,800 max, 303 nm Ell*- 150 E 12,0000 2) EtOH 0.1 N HC1 max. 233 nm El1 176 E= 14,000 max. 261 nm E 1 1 177 14,000 infl. 283 nm Eli 164 infl. 291 nmi E1 157 infl. 311 nm El 1 119 Example 8 Internal salt of 4-[3-C7-[2-(2-aminothiazol-4-yl)-2- -(methoxyimino)acetamido]-2-carboxy-8-oxo-4-thia-1-azabicyclo-[4,2,0]oct-2-en-3-yl]-2-(E)-propenyl]-2-methylthiazoloC5,4-b]pyridinium syn (6S,7S) Stage A Trifluorosulphonate of 4-[[7-[2-(2-tritylaminothiazol-4-yl)- 2-(Z)-methoxyimino)azetimidoj-2-[1,1-diinethylethyloxycarbonylJ-8-oxo- -4-thia-1-azabicyclo-[4,2,0]oct-2-en-3-ylJ-2-(E)-propenyl]-2-methylthiazolo pyridinium syn (6S,7S).

350 mg of the Z isomer obtained at stage B of example 1 in cm3 of methylene chloride and 356 mg of methylthiazolo-pyridine are cooled to -70* C. 2.34 cm 3 of a solution made up of 0.5 cm 3 of trifluorosulphonic anhydride in 10 cm 3 of methylene chloride is introduced and the whole is agitated for 5 minutes at -700 C under nitrogen, then the temperature is allowed to return to 200 C. After diluting with methylene chloride, washing with water, drying and taking to dryness under reduced pressure, a residue is obtained which is chromnatographed on silica (eluant methylene chloride acetone, 9-1, then methylene chloride methanol 92-8), so obtaining 347 mg of the expected product.

Stage B Internal salt of 4-[3-[7-[2-(2-aminothiazol-4-yl)-2- -methoxyimino)acetamido]-2-carboxy-8-oxo-4-thia-1-azabicyclo-[4,2,0oct-2-en-3-yl]-2-(E)-propenyl]-2-methyl thiazoloC5,4-b]pyridinium syn (6S,75).

The operation is done as in example 3, starting with 330 mg of the product obtained above. Eluton is done with distilled water containing 5 of acetonitrile, then 10 and finally 20 The acetonitrile is evaporated off, the residue is taken up with 1 cm 3 of acetone, isolated and rinsed with a minimum of acetone by centrifuging, and 98 mg of the expected product is obtained.

1. NMR Spectrum (DMS0) 3.84 ppm :OC 6.80 ppm :H 5 5.58 ppm :H 6 5.93 and 7.41 ppm UV Spectrum 1) EtOH max. 225 nm El infi. 260 nm Ell infi. 295 nm El max. 304 nin El 1 infi. 320 nm El 2) Et0H HCl 0.1 max. 220 nm E max. 265 nm E infi. 280 nm E infi. 289 nm E infi. 299 nm El max. 331 nm El

H

3 of the thiazole -lactame, cis H ethylenes, :1E.

N

598 332 306 333 256 526 413 381 357 316 200 salt 8= 34,200 6= 19,000 5= 30, 100 23,600 11,400 of 1-[3-[7-[2-(2-aminothiazol-4-yl Example 9 :Internal -methoxyiminoacetamido]-2-carboxy-8-oxo-4-thia-l-azabicycloC4,2,0]oct-2-en-3-yl]-2-(E)-propenyl]-5,6,7,8-tetrahydroguinolinium syn (6S,7S) Stage A Trifluoromethane sulphonate of 1-[3-[7-C2-(2-tritylaminothiazol-4-yl )-2-methoxyiminoacetamnido]-2-(1,1-dimethylethyloxycarbonyl )-8-oxo-4-thia-1-azabi cyclo 2,0]oct-2-en-3-yl J-2- (E)-propenyl -5,6,7,8-tetrahydroquinolinium,syn (6S,7S).

By operating as at stage A of example 8, using 162 ul. of 2,3- -cyclohexenopyridine, 73 mg of the expected product is obtained.

Stage B :Internal salt of 1-E3-E7-[2-(2-aminothiazol-4-yl)-2- -methoxyiminoacetamido]-2-carboxy-8-oxo-4-thia-l-azabicyclo[4,2,0]oct-2-en-3-yl]-2-(E)-propenylj-5,6,7,8-tetrahydroquinolinlum syn (6S,7S) 136 mg of product obtained as above is dissolved in 1.5 cm 3 of 66 formic acid and the operation is continued as in example 3, so as to obtain 25 mg of the product expected.

NMR Spectrum (DMSO) 3.84 ppm 0GH 3 5.46 ppm H 7 -lactame (cis) 6.8 ppm H 5 of the thiazole syn 7.09 ppm :H ethylenes a E max. 232 nm E =411 e= 22,800 infi. 264 nm E 1 290 infi. 274 nm Eli 1 269 infi. 282 nm E 1 239 max. 317 nm E 1 =27 Example 10 :Internal salt of 7-[3-[7-[2-(2-aminothiazol-4-yl)-2- -difluoromethoxyiminoacetamido]-2-carboxy--8-oxo-4-thia-1-azabicyclo- £4,2,0]oct-2-en-3-yl]-2-(E)-propenyljthienoC2,3-b]pyridinium syn (6S, The operation is done as in example 5, starting with 2.527 g of 7-E2-(2-tritylaminothiazol-4-yl )-2-(Z)-difluoroxnethoxyiminoacetamidoJ- -2-(3-hydroxy-(E Z)-propen-1-yl)-8-oxo-4-thia-1-azabicycloc4,2,0]- 2-carboxylate of 1 ,1-dimethyl ethyl prepared according to the usual methods, and 1.89 cm 3 of thieno-C2.3-bjpyridine, and after hydrolysis with formic acid, 813 mg of the expected product is obtained.

[oD=132.50 20 1% in mixture of H 2 0-CH 3

CN).

NMR Spectrum (DMSO) 2.89 to 3.06 ppm :S-CH 2 5.51 *ppm :H 7 -lactame (cis) 7.06 ppm :H 5 of the thiazole, syn.

7.48 ppm H ethylenes, aE UV Spectrum ethanol -HCl 0.1 N max. 240 nm Ell= 614 ~=36,400 infl.260 m El 316 infl. 28 nm El 296 infi. 300 nm El 1 258 max. 329 nm El 238 C= 14,100 Example11 :Internal salt of 4-[3-[7-[2-(2-aminothiazol-4-yl)-2-* -difluoromethoxiyiminoacetamido]-2-carboxy-8-oxo-4-thia-l-azabicyclo- [4,2,2oct-2-en-3-yll-2-(E)-propenyllthienoC3.2-b]pyridinium (6S,7S) The operation is done as in example 5, starting with 300 mg of 7-[2-(2-tritylami nothiazol -4-yl (Z )-(difl uoromethoxyimino)acetamidoj- 3-[3-hydroxy-(E)-propen-1-ylJ-8-oxo-4-thia-1-azabicyclo[4,2,O~oct-2-en- -3-yl-2-carboxylate of ],1-dimethylethyl and 210 mg of thieno[3,2-b] pyridine. After treatment with formic acid and then with trifluoro- P acetic acid, 117 mg of product is obtained which is taken up with Ucm 3 of acetonitrile ind 0.5 cm 3 of triethylamine carbonate, then chrcuiatographed on silica, eluting with a mixture of acetonitrile with of water, then with~ 10 and finally with 15 %of water. 43 mg of the expected product is obtained.

UV Spectrum Et0H -HCl 0.1 N max. 239 nm E 1 i 569 6~ 33,700 260nm ofi27 -azabicyclo[4,2,Ojoct-2-en-3-yl_]-2-(E)-propenyl Jthieno[2,3_-b]pyridinium, syn (6S,7S) The operation is done as in example 5, starting with 160 mg of 7-[2-(2-tritylaminothiazol -4-yl )-2-(Z)-propenyloxyimi noacetamido]-3- -(3-hydroxy-(E)-propenyl )-8-oxo-4-thia-1-azabi cyclo[4,2,0]oct-2-en-2- -carboxylate of 1,1-dirnethylethyl and with 2.2 cm 3 of a solution of thienylpyridine (266 mg/S cm 3 of CH 2 C1 2 After hydrolysis with formic acid, 53 mg of the expected product is obtained.

NMR Spectrum (DMSO) 6.80 ppm H 5 of the thiazole 6.33 ppm H ethylenes, trans 7.18 ppm 5.95 ppm :-CH=CH 2 7.88 ppm :H 3 8.27 ppm H 2

H

8.14 ppm :H 6 )aromiatic bicycle 9.08 ppm :H 9.22 ppm :H 7 UV Spectrum 1) EtOH max. 239 nm E 1 686 E 50,600 infl. 260 nm E I 263 max. 306 rim El 264 E= 19,500 infi. 322 nm El 1 244 2) EtOH HCl 0.1 N max. 240 rim E 612 ~=45,200 max. 270 rim El 363 ~=25,500 incl. 280 rim E 1 I 3 mc. 91n 288 incl. 301 rim Ell 237 max. 330 rim El I 218 ~=16,100 Example 13 :7-C/2-(2-aminothiazol-4-yl )-2-methoxyiminoacetyl /ami no]- -3rF/5-methyl-1,3,4-thiadiazol-2-yl/thio]-l-(E)-propenyl]-8-oxo-4-thia- -1-azabicyclo[4,2,0]oct-2-en-2-carboxylic acid, syn (6S,7S) Stage A :7-[(2-triphenylmethylaminothiazol-4-yl)-2-(methoxyimino)- -propenylJ-8-oxo-4-thia-1--azabicyclo[4,2,0]-oct-2-ei-carboxylate of 1,1-dimethylethyl, syn, (6S,7S).

184.5 mg of the E isomer obtairied at stage B of example 1 in 4 cm 3 of anhydrous methylene chloride, 120 mg of tetrabutylammonium iodide arid 116 ul. of 2,6-lutidirie are cooled to -700 C.

Drop by drop 620 ul. of a solution (0.609 of trifluoromethaie suiphonic anhydride in methylene chloride is added. After 10 minutes at C, the temperature is allowed to return to 200 C and the solvent is evaporated off under reduced pressure. Then there are added successively while agitating, 66.1 mg of 5-methyl-1,3,4-thiadiazole, cm 3 of dimethylformamide and 104 mg of anhydrous potassium carbonate. The whole is agitated for half-an-hour at 20-250 C, then poured on to 10 cm 3 of N hydrochloric acid and extracted with ethyl acetate. The extracts are washed with a 5 aqueous solution of sodium bicarbonate, then with water, dried and evaporated to dryness under reduced pressure. The residue is chrmatographed on silica, eluting with a mixture of ethyl acetate and methylene chloride (15-85) and 147 mg of the expected product is recovered.

H AL3 Stage B 7-[/2-(2-aminothiazol-4-yl )-2-methoxyiminoacetyl/amino]- -3[[/5-methyl-1,3,4-thiadiazol-2-yl/thio]-1-(E)-propenyl ]-8-oxo-4-thia- -1-azabicyclo[4,2,O]oct-2-en-2-carboxylic acid, syn (6S,7S) At ambient temperature, 118 mg of the product obtained above and 2.3 cm 3 of trifluoroacetic acid are agitated for 20 minutes. Drop by drop, 25 cm 3 of anhydrous ether is added; the whole is centrifuged, the residue is taken up with 5 cm 3 of ether, then the centrifuging is repeated, with the residue again taken up witN 5 cm 3 of ether, followed by drying under reduced pressure. The product is taken up in 1.5 cm 3 of ethanol and 100jpl.of a 1 M/l. solution of pyridine in ethanol, then centrifuged twice more, with the residue taken up by 1 cm 3 of ether each time. After drying, 52 mg of the expected product is obtained.

NMR Spectrum (DMSO) 6.81 ppm H 5 Of the thiazole 5.64 ppm H 7 4.01 ppm :H 6 6.96 and 6.19 ppm :H ethynes 0 7.23 ppm H of amino 3.85 ppm H of the methoxy 2.68 ppm :H of the methyl of the thiadiazole.

46 UV Spectrum EtOH -HCl 0.1 N infl. 243 nm E =430 1 max. 267 nm E 580 FE 29,300 max. 329 nm El 340 6. 18,800 IR Spectrum (nujol) General absorption NH/OH -lactame C =0 1759cm- 1 others C 0 l66Ocm-1 region C C; C N: 1630cm- 1 amide II :1540cm- 1 Example 14 7-[2-(2-aminothiazol-4-yl )-2-(Z)-(methoxyimino)acetamido]- -3-[3-(1H-tetrazol-1-yl )-l-(E)-pr'openyl]-8-oxo-4-thia-1-azabicyclo- 14,2,O1oct-2-en-2-carboxylic acid (6S,7S) and 7-r2-(2-amlnothiazol-4- -yl )-2-(Z)-(methoxyimino)acetamido]-3-[3-(2H-tetrazol-2-yl -propenyl]-8-oxo-4-thia-l-azabicyclo[4,2,O]oct-2-en-2-carboxylic acid (6S ,7S) L 24z Stage A 7-[2-(2-tritylaminothiazol-4-yl)-2-(Z)-(methoxyimino)acetamido]-3-[3-(1H-tetrazol-1-yl )-1-(E)-propenyl]-8-oxo-4-thia-lazabicyclo[4,2,0]oct-2-en-2-carboxylate of 1,1-dimethylethyl and 7-[2-(2-tritylaminothiazol-4-yl )-2-(Z)-(methoxyimino)acetamido]-3- -[3-(2H-tetrazol-2-yl)-l-(E)-propenyl]-8-oxo-4-thia-l-azabicyclo- [4,2,0]oct-2-en-2-carboxylate of 1,1-dimethylethyl.

230 mg of the isomer obtained at stage B of example 1, 149 mg of tetrabutylammonium, and 0.143 cm 3 of 2,6-lutidine are dissolved in cm 3 of dichloroethane. The soiution is cooled to -700 C, and, drop by drop, 1.7 cm 3 of a solution of trifluoromethyl sulphonic anhydride (0.42 cm 3 in q.s. for 10 cm 3 of CH 2 C1 2 is added. The temperature is allowed to return to 200 C, the solvent is evaporated off and 44 mg of 1H-tetrazole, 131 mg of potassium carbonate and 3 cm 3 of dimethylformamide are added. After 1 hour and 10 minutes of agitation, the solution is poured into water containing 1.5 cm 3 of 2N hydrochloric acid, and extracted with ethyl acetate. The organic phase is washed with water containing 0.2 N thiosulphate in excess, then dried and concentrated to dryness. The residue is chromatographed on silica, eluting with a mixture of methylene chloride and ethyl acetate, first (7S,25), then (50-50). 90 mg of the "position 2" isomer and 99 mg of the "position 1" isomer are isolated.

Stage B: 7-[2-(2-aminothiazol-4-yl)-2-(Z)-(methoxyimino)acetamido]- -3-[3-(1H-tetrazol-1-yl)-l-(E)-propenyl]-8-oxo-4-thia-l-azabicyclo- [4,2,0]oct-2-en-2-carboxylic acid (6S,7S).

The 99 mg of the "position 1" isomer is dissolved in 1.2 cm 3 of 66 formic acid. The solution is heated to 650 C for 2 hours, then cooled, diluted with 1.5 cm 3 of water, filtered, and the filtrate is concentrated to dryness. The residue is triturated in water, filtered, rinsed with water, then with ether, and 49 mg of the expected product NMR Spectrum (DMSO) 3.87 ppm H OCH 3 6.11 to 6.41 and 6.84 to 7.0 ppm H ethylenes AE 6.84 ppm H 5 of the thiazole, syn.

5.61 to 5.76 ppm H 7 d -lactame cis

H

6.88 to 7.05 ppm CH 2

H

6.84 ppm H 5 thiazole syn 7.22 ppm

NH

2 9.17 9.27 ppm NHC0

A

4S- UV Spectrum EtOH HC1 0.1 N max. 238 nm E 377 18,500 max. 263 nm 419 6= 20,600 infi. 280 nm E 356 max. 325 nm E 299 14,700 Stage C 7-[2-(2-aminothiazol-4-yl)-2-(Z)-(methoxyimino)acetamido]- -3-[3-(2H-tetrazol -2-yl )-1-(E)-propenyl ]-8-oxo-thia-1-azabicyclo[4,2,0]oct-2-en-2-carboxylic acid, (6S,7S).

By operating as in stage B, starting with 90mg of the "position 2" isomer, 31 mg of the expected product is obtained.

NMR Spectrum (DMSO) 3.88 ppm H of OCH 3 6.11 to 6.44 and 6.9 7.07 ppm 6.87 ppm H 5 of the thiazole, syn 5.7 ppm H 7 lactame, cis.

UV Spectrum EtOH max. 234 nm El 1 470 E= 23,400 infl. 260 nm E 1 302 max. 320 nm Eli 303 E= 15,100 Example 15 7-r2-(2-aminothiazol-4-yl)-2-(methoxyimino)acetamido]- -3-U3-(2-methyl-1H-imidazol-4-yl)-1-(E)-propenyl]-8-oxo-4-thia-l- -azabicyclol4,2,0]oct-2-en-2-carboxylic acid, syn, (6S,7S).

Stage A 7-[2-(2-tritylaminothiazol-4-yl)-2-(methoxyimino)acetamido]- 3-[3-(2-methyl imidazol -4-yl (E)-propenyl J-8-oxo-4-thia-1-azabi cyclo- [4,2,0]oct-2-en-2-carboxylate of 1,1-dimethylethyl, syn, (65,7S).

By operating as in stage A of example 13, starting with 62 mg of 2-methylimidazole, 82 mg of the expected product is obtained.

Stage B 7-E2-(2-aminothiazol-4-yl)-2-(methoxyimino)acetamidoj- -3-[3-(2-methyl-1H-imidazol-4-yl)-1-(E)-propenylJ-8-oxo-4-thia-l- -azabicyclo[4,2,0]oct-2-en-2-carboxylic acid, syn, (6S,7S).

80.5 mg of the product obtained above and 1 cm 3 of 66 formic acid are heated for 3 hours at 60 650 C, then evaporated to dryness .inder reduced pressure. The residue is taken up twice consecutively with 5 cm 3 of water, then evaporated to dryness. The residue is taken up with 7 cm 3 of ether, agitated for half-an-hour, then separated, and 41.5 mg of the expected product is obtained.

1 il__ili Ijl_ NMR Spectrum (DMSO) 3.85 ppm

OCH

3 6.55 6.61 ppm J 16) H ethylenes aE 5.58 to 5.64 ppm H 7 lactame, cis 7.13ppm H 5 of the thiazole UV Spectrum EtOH HCl 0.1 N infl. 217 nm max. 238 nm 17 300 max. 264 nm 19,100 infi. 281 nm max. 327 nm 13,100 Example 16 7-C2-(2-aminothiazol-4-yl)-2-(methoxyimino)acetamidol- -3-C/(5-methylthio-1,3,4-thiadiazol-4-yl)thio/-l-(E)-propenyl1-8-oxO- -4-thia-1-azabicyclo[4,2,]oct-2-en-2-carboxylic acid, syn (6S,7S) The operation is done as in example 13, using the -methylthio-1,3,4-thiadiazole, and eluting the chromatography with a mixture of methylene chloride and ethyl acetate then After unblocking the functions and punification,69 mg of the expected product is obtained.

NMR Spectrum (DMSO) 6.81 ppm H 5 of the thiazole, syn 5.85 ppm 0CH 3 5.64 ppm H 7 -lactame, cis 6.18 and 6.98 ppm H of ethylenes, transs 2.74 ppm S-CH UV Spectrum 1) EtOH (1 cm 3

DMSO)

max. 298 nm 378 E 22,100

I

infi. 320 nm El 350 F 20,500 2) EtOH HCl 0.1 N max. 280 nm Eli 469 27,500 max, 330 nm E 1 310 e 18,200 Example 17 7-[2-(2-aminothiazzol-4-yl)-2-(methoxyimino acetamido]- -3-3-/(5-methylthio-1,3,4-thiadiazol-4-y~ho-1()poey]8 -oxo-4-thia-l-azabicyclor4,2,0]oct-2-en-2-carboxylic acid, syn, (6S,7S) The operation is done as in example 13, starting with 184.5 mg of the E isomer obtained at stage B of example 1, and using 66.6 mg of Lj -4-yl I ehxiioctm o]2[11dmtyIehx~abnl]8oo ammonium, syn (6S)(7S) and the isomer (propen-2(Z)-yl).

2-amino-5-mercapto-1,3,4-thiadiazole in dimethylformamide. The chromnatography on silica is eluted with a mixture of methylene chloride and ethyl acetate the blocked functions are freed by trifluoroacetic acid, and 60.5 mg of the expected product is obtained.

NMR Spectrum (DMSO) 6.82 ppm :H 5 of the thiazole 3.86 ppm OCH 3 5.64 ppm H 7 6.90 ppm (d J 6.15 ppm (d J 7.5 and 15) HetynsE UV Spectrum 1) EtOH max. 287 nm El1 411 -S 22,800 infl. 282 nm El= 309 max. 322 nm ElI= 312 17,300 2) Et0H HCl 0.1 N max. 271 nm El= 472 E 26,200 max. 330 nm E 1 1 285 F- 15,800 Example 18 7-[2-(2-aminothiazol-4-yl)--2-(methoxyimino)acetamido]- £3-[C(9H--purin-6-yl) thio1-1- ropenyl] -8-oxo-4-thia-1-azabicyclo- [4,2,0]oct-2-en-2-carboxylic acid, syn, (6S,7S).

The operation is done as in example 13, using 76 mg of 6-mercaptopurine. The product is chromatographed on silica, eluting first with a mixture of methylene chloride and ethyl acetate (75-25), then with ethyl ac'etate alone and finally with a mixture of methylene chloride and methanol (95-5) After the unblocking and the purification, 76 mg of the expected product is obtained.

NMR Spectrum (DMSO) 6.82 ppm :H 5 of the thiazole 5.64 ppm :H 7 i-lactame, cis 4 6.26 ppm ii H ethylenes AE 7.06 ppm UV Spectrum 1) EtOH 2 cm 3

DMSO

max, 240 nm El 1 x 401 S 23,000 max. 292 nm Eli 423 6 24,300 max. 320 nm El i 311 E -17,800 infl. 257.410 nm 2) Et0H HC1 0.1 N Infl. 240 nm Ell 319 infi. 264 nm Ell 375 max. 287 nm Ell 475 F a 27,200 max. 323 im El 311 16,400 Example 19 7-C -(2-aminothiazol-.4yll-2-(methoxyimino)acetamido]- 3-[3.L(1,314- 4thiadia azol -2-ylI)thiol*12- E)-propnyl -8-~xo-4-th ia -lazabicycloC4,2,0]oct-2-en-2-carboxylic acid syn, (6S,7S)- By operating as Indicated in example 13, using 59,1 mg of S-mercapto-1,3,4-thiadiazoleo 47.1mg of the expected product is obtained.

NMR Spectrum (DMSO) :11 of the thiazole 6.85 ppm

OCH

3 3.87 ppin -lactame, cis 3.65 ppm 6.01 ppm (d J *15.5) Bi, ethylenes, 6S 7.06 ppm (d J 15.5 and 7) UV Spectrum EtOU 111 0.1 N infi, 241 nm Ell mnax. 269 nm Ell a a 22,900 Max, 329 nm Ell 15,000 Example300.-.* 3431, -triazo l thiiaol4.1 ()ylropeny-8oximijno 4 tami-do1 The operation is done as in example 13, using sodium thfolate, without addition of potassium carbonate. The chromatography is done by lut'ing with a mixture of methylene chloride and ethyl acetate (75-25).

The deblockIng of the functions Is done with formic acid 2 cm 3 at 66 for 149 mg of blocked product. Agitation Is maintained for 3 hours at 60-661 C, the formic acid is expo-lled at 300 C under reduced ,429 pressure, the residue being taken up twice with water, evaporating off each time. The residue is triturated with ether, then separated, and 89 mg of product is obtained which is dissolved in 6 cm 3 of tetrahydrofuran and 1 cm 3 of methanol. This solution is introduced drop by drop into 100 cm 3 of ether under vigorous agitation, then after separation, 69.5 mg of product is obtained.

NMR Spectrum (DMSO) 6.81 ppm H 5 of the thiazole, syn 3.85 ppm

OCH

3 5.63 ppm H 7 -lactame, cis 6.76 ppm H ethylenes

E

6,08 ppm UV Spectrum EtOH HC1 0.1 N max. 240 nm E 1 1 a 396 E a 20,700 max. 266 nm Eli 416 E a 21,700 infl. 282 nm El 1 387 max. 328 nm El a 320 em 16,700 Example 21 7-[2-(2-aminothiazol-4-yl )-2-(methoxyimino)acetamido]-3- -[3-[/4-methyl-5-trifluoromethy1-4H-1,2,4-triazol-3-yl/thi propenyl -8-oxo-4-thia--azabi cyclo4, 2,Ooct-2-en-2-carboxylic acid, syn. (6S,7S) The operation is done as in example 13, by using 90 mg of -trifluoromethyl-4H-1,2,4-triazol-3-thione. Chromnatography is done eluting with a mixture of methylene chloride and ethyl acetate (75-25).

After treatment with 66 formic acid, 78 mg of the expected product is obtained.

NMR Spectrum (DMSO) 3.67 and 3.85 ppm N-CH 3 and O-CH 3 5.64 ppm 7 -lactame, cis 6.2 and 6.89 ppm ethylenes, E 6.81 ppm E H 5 1 of the triazole.

UV Spectrum EtOll HCI 0.1 N infl. 240 nm E1 a 328 max. 260 nm E1 a 345 E 20,900 infl. 280 nm E 1 l a 303 max. 326 nm Ell a 215 6 13,000 Example 22 7-r2-(2-aminothiazol-4-yl)-2-(methoxyimino)acetamido]-3- -C3-/(thiazolo[5,4-bpyridin-2-yl)thio/-l-(E)-propenyl]-8-oxo-4-thia- V1-azabicycloE4,2,0]oct-2-en-2-carboxylic acid, syn, (6S,7S) The operation is done as in example 13, by using 295 mg of 2-mercaptothiazoloE5,4-bjpyridine, and chronatographing, eluting with a mixture of methylene chloride and acetone The functions are unblocked by formic acid on 150 mg of the product obtained and 67 mg of crude product is obtained. 45 mg of this latter is chrcatographed on silica, eluting with ethyl acetate, then with a mixture of acetone, ethyl acetate and water 17 mg of the expected product is obtained.

NMR Spectrum (DMSO) 6.79 ppm H 5 of the triazole 3.84 ppm OCH 3 5.54 ppm H 7 d- lactame 5.98 and 7.27 ppm H ethylenes IR Spectrum (nujol) General absorption region OH/NH c-o -lactame 1754cm 1 shoulder 1660cm- 1 maximum 1650cm- 1 region -C-C C-N large absorptlom aromatic 1580cm- 1 1620cm 1 NH def, amide I 1535cm- 1 region -CK=CH- 075cmn' Example 23 7-2-(2-aminothiazol-4-yl ).-2-(methoxyimino)acetamido]-3- -3-/(H-1,2,4-tri aol 3-y~thio/-l-:(E)-propenyl 1-8-oxo-4-thia-1- -azabicycloC4,2,0]oct-2-en-2-carboxlic acid, syn (6S,7S)_.

By operating as in example 21, using 50 mg of IH-1,2,4-trlazol-3- -thione, 62 mg of the expected product is obtained.

NMR Spectrum (OMSO) 5.56 to 5.71 ppm H 7 2-lactame 6.04 to.6.4 ppm HI ethylenes A E and 6.84-7.02 ppm 6.84 ppm HS of the triazole, syn.

UV Spectrum EtOH max. 234 nm El 481 c 25,100 max. 320 nm E 1 1 323 16,900 Example 24 Internal salt of 2-[3-[7-[2-(2-aminothiazol-4-yl)-2- -methoxyimino)acetamido]-2-carboxy-8-oxo-4-thia-1-azabicycloC4,2,0]oct-2-en-3-yl]-2-(E)-propenyl]isoquinolinium syn. (6S,7S) The operation is done as in example 21, starting with 148 mg of I the E isomer obtained at stage B of example 1. After adding the trii fluoromethane sulphonic anhydride and distilling off the solvent, 5 cm 3 of acetonitrile and 52 ul. of isoquinoline are added. After 1 hour minutes, the acetonitrile is driven off, the residue is dissolved in ethyl acetate, washed with water containing an excess of 0.2N sodium thiosulphate, washed with water, dried and concentrated to dryness.

The residue is chromatographed on silica, eluting with a mixture of methylene chloride and methanol and 83 mg of the blocked intermediate product is isolated. After treatment with 66 formic acid, filtering and evaporating the solvent, the residue obtained is taken up in 1 cm 3 of acetonitrile and 1 cm 3 of a 1M solution of triethylamine, then chranatographed on silica, eluting first with a water-acetonitrile mixture and then with a (85-15) mixture.

16.76 mg of the expected product is obtained.

NMR Spectrum (DMSO) 3.83 ppm OCH 3 5.45 ppm H 7 and CH 2

-NE

6.79 ppm H 5 of the triazole 5.91-7.42 ppm H ethylenes, AE UV Spectrum EtOH max. 224 nm El 951 E= 52,400 infl. 232 nm El 840 infl. 262 nm El 296 infl. 277 nm El1 252 max. 289 nm El1 226 6~ 12,400 max. 323 nm El 1 280 15,400 max. 224 nm inYfL. W~ rim infl. 262 rim infL. 277 rim max. 289 rim max. 323 nm ExempLes 2 5 to 39 El= 951 Ell =840 El1=296 Ell =252 El= 226 Ell 1=280 52400 12400 15400 The products of the tables hereafter have been obtained by the process of the invention.

ni2 C 02 A 0I CF so® 0 jCO 2

H

0O2 It 9, I

'I

00 2 H~ CO 2 6

I

I

I

.H3 'I I hi-N H I0 C :3

C.O.

H

3 C -C O 1 0 C3o t0 r-NH n2 0l Co 2 H CO )H Co 2 co2H C02A NW, PC.3CO, H C112:COhi

I

0 5 5' II I II CO 0 NO 2

N

0 CFISO.s j 0 H CO H 2 0.~O a Example -A preparation for injection has been made up with the formnula internal salt of 7-/3-/7-//(2-amino-4-thiazoLyL) (trifLuorom~thoxy) imino/ acbtyL/ amino/ 2-carboxy 8-oxo 4-thia 1-azabicycLo oct-2-6,-3-yL/ 2-(E)-prop~nyL/ thi~no pyridinium 500 mg sterile aqueous excipientq.s.p 5 cm3.

PHARMACOLOGICAL STUDY OF THE PRODUCTS OF THE INVENTION Activity in vitro, method of dilutions in liquid medium.

A series of tubes is prepared, in each of which the same quantity of a sterile nutritive medium is distributed, together with an increasing quantity of the product under study; then each tube is inoculated with a bacterial strain. After incubation for twenty-four or forty-eight hours in an oven at 370 C, the inhibition to growth is evaluated by transillumination, which enables the minimum inhibiting 3 concentrations expressed in jg/cm to be determined.

l The following results were obtained.

0 Prod. Ex. 3 Prod. Ex.

STRAINS

24 H 48 H 24 H 48 H Staphylococcus aureus SG 511 0,08 0,15 0,08 0,15 Staphylococcus aureus 285 0,15 0,3 0,08 0,15 Staphylococcus aureus 54146 0,15 0,15 0,15 0,3 Streptococcus pyogenes A 561 0,01 0,01 0,01j 0,01 Streptococcus pyogines 77 A 0,01 (0,01 <0,01i 0,01 Escherichia Coil 1894 0,01 0,01 0,01 \0,01 078 0,01 0,01 \<0,01 0,01 TEM 0,01 ~0,04 0,04 0,08 1507 E 4 0,01 0,01 0,01 /.0,01 CO 0,01 <0,02 0,02 0,4C OC2 (0,01 0,01 <0,01 0,01 Salmonella typhimurium MZ 11 0,01 0,01 00 0,04 0,04 Klebsiella pneumoniae 52145 0,04 0,04 0 04 0,04 Klebsiella aerogenes 1522 E 0,08 0,08 0,15 0,15 Enterobacter cloacae 1321 E j 0,01 \0,01 0,02 0,02 Proteus mirabilis A 235 0,02 0,02 0,04 0,04 Proteus vilgaris A 232 0,081 03 0,081 0O8 ~-AS6' I Prod. Ex. 30 IProd. Ex. 19

I

STRAINS f 24 H 48H I24H: 48 H I Staphylococcus aureus SG 511 I 0,3 0,3 I0,6 0,6 I Staphylococcus aureus 285 I 0,3 0,3 0,6 :0,6 I Staphylococcus aureus 54146 f 0,3 :0,6 I0,6 1,2 I Streptococcus pyog~nes A 561 I40,01 :0,01 ,0,01 ,01 I streptococcus pyog~nes 77 A 40,01 :0,01 4 0,01 0, 01I I Escherichia Coli 1894 j 0,01 :~0,01 10,01 0,01I oIt078 j40,01 :0 ,01 j0,04 :0,04 iTEM I 0,02 0,02 I0,15 0,15 it" 1507 E I40,01 40,01 10,01 <,0i i DCO I 0,04 0,04 I 0,15 0,15 ifDC2 I40,01 :40,01 0 0, 01 <0,01 I SalmonelLa typhimurium MZ 11 I 0,02 :0,02 0,15 0,15 I KLebsieLLa prieumoniae 52145 0,02 :0,02 I0,3 0,3 I KLebsieLLa aerog~nes 1522 E f 0,04 0,04 0,3 0,3 I Enterobacter cLoacae 1321 E I <0,01 0 ,01 I0,04 :0,08 I Proteus mirabilis A 235 I 0,02 :0,04 I0,08 0,08 I Proteus vuLgaris A 232 I 0,02 :0,04 I0,04 :0,04 9 I 91

Claims (4)

137- The claims defining the invention are as follows: 1. The compounds corresponding to the general formula I R NH R4 a R A 1) 0 N: RiA CO 2 A in which Ra represents either a radical Rc N O Rd 44 4 in which Rc represents a radical being one of 2-amino-thiazolyl, chloro-thiazolyl, 5-amino-1,2,4-thiadiazolyl, 4-thiazolyl, 2-thienyl or 2-furyl, Rd represents: either an atom of hydrogen, or else an alkyl, alkenyl, or alkynyl or cycloalkyl radical having at the most 6 atoms of carbon, or a phenyl radical, said alkyl, alkenyl, alkynyl, cycloalkyl or phenyl radical optionally being substituted by 441a radical selected from among halogen, cyano, carbamoyl, nitro, amino, hydroxy, mercapto, oxo, carboxyl (free, esterified or salified), or else a difluoromethyl, trifluoromethyl, methoxymethyl, CH2 CH2- or else a radical NH S N SCCH2- separated, and 41.5 mg of the expected product is obtained. -138- R1A represents: either a radical R, R CH 2 -ZA-R 3 RA 2 A 3 or a radical SC CH 2 -ZA-R 3 A A RB in which R'A and R'B, being identical or different, represent either an atom of hydrogen or else an alkyl radical having from 1. to 4 atoms of carbon, ZA represents a simple bond, an atom of sulphur, optionally oxidised, or an atom of oxygen, R3A reprents either an aryl, carbocyclic or heterocyclic radical selected from among phernyl, diphenyl, naphthyl, thienyl, furyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl, thiadiazolyl, oxadiazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, thiazinyl, oxazinyl, tetrazinyl, imidazolinyl, benzimidazolyl, benzothiazo!l, benzoxazolyl, Sor a quaternary ammonium radical selected from among pyridinium, thienopyridinium, quinolinium, isoquinolinium, cyclopentepyridinium, trimethylammonium, cyclohexenopyridinium, imidazopyridinium, or thiazolopyridinium; the radicals R 3 A being able to be substituted by one or more radicals selected from among either alkyl radicals having 1 to 4 atomis of carbon, these alkyl radicals being themselves optionally substituted by a phenyl or thienyl radical, the radicals phenoxy, methoxy, ethoxycarbonyl, halogens, hydroxy, carboxyl (free, esterified or salified), or amino, or else the radicals vinyl, allyl, butenyl, ethynyl, propargyl, phenyl, tolyl, halogens, amino, nitro, carboxyl (free, esterified or salified), or carbamoyl, L 138A or else a radical acetyl, carbamoyl, alkoxycarbonyl, alkyl or haloalkyl having 1 to 6 atoms of carbon, nitrile or azido, R 4 represents an atom of hydrogen or a methoxy radical, A represents an atom of hydrogen, an equivalent of alkali metal, alkaline earth -139- metal, of magnesium, of ammonium or organic amino base or A represents an ester group or CO 2 A represents a C0 2 group, and also the salts of the products of formula I with mineral or organic acids. 2. The compounds as claimed in claim 1 having general formula (IA) N1-I. *4 4 CONH 0 N IN N U(A) ROX syn isomer in which R' represents a hydrogen atom or an alkyl, alkenyl, alkynyl or cycloalkyl radical having at the most 6 carbon atoms, optionally substituted by a radical selected from among halogen, cyano, carbamoyl, nitro, amino, hydroxy, mercapto, oxo, carboxyl (free, esterified or salified), ill. or else a phenyl radical, ZA is as defined in claim 1, and R'3A represents either a phenyl, thievyl, furyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl, thiadiazolyl, oxadiazolyl, tetrazolyl, pyridinyl, pryimidinyl, pyrazinyl, pyradazinyl, thiazinyl, oxazinyl, tetrazinyl, imidlazolinyl, benzoimidazolyl, benzothiazolyl, benzoxazolyl, or a quaternary ammonium radical selected from among pyridinium, thienopyridinium, quinolinium, isoquinolinium, cyclopentenopyridinium, cyclohexenopyridinium, and imidazopyridinium, the radicals optionally being 140 substituted by one or more radicals selected from among either alkyl radicals, having 1 to 4 carbon atoms, these alkyl radicals optionally being substituted by a phenyl or thienyl radical, phenoxy, methoxy or ethoxy-carbonyl radicals, halogens, hydroxy, carboxyl (free, esterifled or salified), amino, or else the radicals vinyl, allyl, butenyl, ethynyni, propargyl, 1 ten' tolyl, halogens,amino, nitro, carboxyl (free, esterified or salified) or carbamoyl, or an acetyl or carbamoyl radical. 3. Products with the formula (IA) as claimed in Claim 2, in which R' represents a hydrogen atom, or a methyl or isopropyl radical, optionally substituted by a carboxy, carbamoyl, nitrile, methylthio or methoxy radical, a 0 difluoromethyl or trifluoromethy] Adcal, a phenyl radical, a cyclobutyl or cyclopropyl radical, optionally substituted by a carboxy radical, an allyl radical, 0 optionally substituted by a chlorine or bromine atom. 0 0 0 4. Products with the formula (IA) as claimed in either Claims 2 or 3 in which ZA represents a simple bond and R' 3 A represents a pyridinium radical optionally substituted by one or more radicals selected from among either alkyl *0radicals having 1 to 4 atoms of carbon, these alkyl radicals being themselves optionally substituted by a phenyl or thienyl radical, the radicals phenoxy, methoxy, ethoxycarbonyl, halogens, hydroxy, carboxyl (free, este:ified or a 0 salified) or amno else the radicals vinyl, allyl, butenyl, ethynynl, propargylOthenyl, tolyl, halogens,amino, nitro, carboxyl (free, esterified or salified) or carbamoyl. Products with the formula the names of which follow: -the internal salt of 7-[3-[7-[/(2-amino-4-thiazolyl)-2-(Z)-(trifluoromethoxy) iminoacetyl/amino]-2-carboxy-8-oxn-4-thia--azabicyclo-[4,2,0]oct-2-en-3-yl]-2-(E)- propenyl]thienoE2,3-b] pyridinium (6S,7S); -the internal salt 5-[3-[7-[/(2-amino-4-thiazolyl)-(methoxyimino)- acetyl/amino]-2-carboxy- ,oxo-4-thia-1-azabicyclo[4,2,0]oct-2-en-3-y]-2-(E)- propenyl]]-2-methylthiazolo[4.,5-clpyridinium, syn, (6S,7S); -the internal salt of 7-[3-(7-[1/(2-amino-4-thiazolyl)-2-(Z)- -141 (methoxyimino)acetylamino-2-carboxy-8-oxo-4-thia-l-azabicyclo-[4,2, O]oct-2-en-3- yl]propen-2-(E)-yl] thieno[2,3-b]pyridinium, (6S, 7S); [/(2-amino-4- thiazolyl) -(me th oxyi mino) ace tyl/a mino]-3 3,4- thiadiazo-2-y) thio -1 -prop enyll -8 -oxo thia-1 -azabicyclo 0] -oct-2-en-2- carboxylic acid, syn, (6S,7S); -the internal salt of 5-[3-[7-I/(2-amino-4-thiazolyl)- (difluoromethoxy)iminoacetyl/amino]-2-carboxy-8-oxo-4-thia-'I-azabicyclo[4,2,O]-oct- 2-en-3-yl]-2-(E)propenyl]-2-methylthiazolo[4, 5-cipyridinium (6S, 7S), Z. 6. Process for the preparation of the products with the formula as described in Claim 1, characterized in that a product with the formula (VII): RA S (VII) N OH 0 CO 2 A in which R 4 and A have the significance indicated in Claim 1 and either RA represents an amino radical, free or protected by a monovalent or divalent protector group, or RA represents tbe radical A 0 Ra having he significance indicated in Claim 1, is treated eitherx with a halogenation agent or with a sulphonation agent, then with triphenylphosphine or with a reagent with the formula P(OAlk) 3 in which Alk represents an alkyl radical having from 1 to 4 carbon atoms, in order to obtain eithe a product with the formula (VIlLA): )R4 RA7( 'S N P (C 6 HS) 3 X®D (VII,) 0 (2 C0 2 A 1_ 142 in which RA, R 4 and A have the previous significance and X- represents the residue of an anion, or a produ with the formula (VIII'A): RR 0 PSJ/ (OPiAz I II coal? t 0 in which RA, R 4 A and l/k have the previous significance, which products with the formulae (VIIIA) or (VIII'A) are, if desired, treated first with a strong base, then with an alkyl halide with the formula hal-R"A in which hal represents a halogen atom and R"A has the values of R'A other than a hydrogen atom, in order to obtain the products with the formulae (VIIIB) or (VII'B): R4 RR 0 cO R &lJIT-) r- i-r~ 143 0 II ECo1 0 0$ 0000 00Oa IL 1f(a a a (vm'B) in which formulae R'A has the significance indicated in Claim 1, and which products with the formulae (VIIIB) or (VIII'B) are treated with a product: in which R'B has the value indicated in Claim 1 and Gp represents a protector group of the hydroxyl radical, in order to obtain a product with the formula (IX): I RR p (T) 0 COR KR in the form of a mixture of isomers E or Z or in the form of isomer E or isomer Z, on which product with the formula (IX) the following reactions are carried out in any order: a) separation of the protector group Gp; b) when RA represents an amino radical protected by a monovalent or ~I

144- divalent protector group, elimination of this protector group and treatment of the product in which RA represents an amino radical either with an acid with the formula (IVa): RaCO 2 H (IVa) in which formula Ra represents an organic group or with a functional derivative of this acid, c) Separation of the isomers E and Z; in order to obtain a product with the formula X: 0 0 0 0 00I 0 00000 0 CR 0010 0 0040r 000.~ 0 I rI II% in which RA has the significance indicated in Claim 1, on which product with the formula there is made to react either a reactive derivative of the group R3A in order to obtain a product with the formula (XIA): B lu.n -145- /R c° (XIA) I CR In COI or a derivative of an activation group of the hydroxyl radical, then a derivative i or a reactive derivative of this group R 3 A in order to obtain a product with the S formula (XIB): or a derivative of an activation group of the hydroxyI radical then the product eire to a oe o ore of the ooin rect in n a) separation by hydrolysis, hydrogenolysis, or by the action of thiurea, of COwR F (XIB) 4:44 or a derivative of an activation group of the hydroxyl radical then the product with the formula HS-R 3 A or a reactive derivative of this product, in order to obtain a product with the formula (XI): i I C which products with formulae XI, XI or XIC are subject, to if necessary or if desired, to any one or more of the following reactions, in any order: a) separation by hydrolysis, hydrogenolysis, or by the action of thiurea, of i 146 all or part of the protector group or groups; b) esterification or salification by a base of the carboxy or sulpha group or groups; c) salification by an acid of the amino group or groups; d) resolution of the molecule in order to obtain an optically active product. -1 _gre-1QE pt~pfl or v Po F 'iprzrll4 "v r4 q L u 0 00 4 a a Q0 4 '000 04 a 4 0414a ft *4 7. As medicaments, the products with the formula as claimed in Claim 1, as well as their pharmaceutically acceptable salts of acids. 8. As medicaments, the products with the formula (IA) as claimed in any one of the Claims 2 to 4, as well as their salts of pharmaceutically acceptable acids. 9. Pharmaceutical compositions containing, as active principle, at least one of the medicaments as claimed in either of Claims 7 to 9, in association with a pharmaceutically acceptable excipient. 10. A method of treatment of infections caused by gram-positive or gram- negative bacteria wherein is administered one or more products of formulae (I) or (IA) as claimed in any one of Claims 1 to 11. A method of treatment of staphylococcal septicemias, malignant staphylococcal infection of the face or skin, pyodermitis, septic or suppurating wounds, anthrax, phlegmons, erysipelas, acute primitive or post-influenzal staphylococcia, bronchopneumonia, pulmonary suppuration, colibacilloses or associated infections, or infections due to proteus, klebsiella or salmonella, wherein is administered one or more products of formulae or (IA) as claimed in any one of Claims 1 to 12. A product of formula I as claimed in any one of Claims 1 to substantially as hereinbefore described with reference to the tables or to any 4 LI I--Ll~uuW~rrCC~F~L;rrrilii~-i~_i

147- one of Reference Examples A to C or to any one of Examples 1 to 39. 13. A process as claimed in Claim 6, substantially as hereinbefore described with reference to any one of Reference Examples A to C or to any one of Examples 1 to 39. 14. A pharmaceutical composition as claimed in Claim 9, substantially as hereinbefore described with reference to Example A method of treatment as claimed in either Claim 10 or Claim 11, substantially as hereinbefore described. 0 C oo., 0 C ooo O o 0 0 00 0 0 0 0 DATED this 26th day of July ROUSSEL-UCLAF By its Patent Attorneys CALLINAN LAWRIE

1990. ii 0 0 0 0 va 00 0 9t 4 1 1 i L r I _i