BE897854A - ANTIBIOTIC CARBAPENEM DERIVATIVES - Google Patents

Abstract

New carbapenems substituted by 2 with (I), where A is a C1-C6-alkylene radical in a straight or branched chain, R5 an aliphatic, cycloaliphatic, cycloaliphatic-aliphatic, aryl, araliphatic, heteroaryl, heteroaraliphatic, heterocyclic or heterocyclic radical substituted or not, and (II), a nitrogen aromatic heterocycle united to A by a ring carbon atom and quaternized by R5.

Description

       

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  BRISTOL-MYERS COMPANY. for Antibiotic carbapenem derivatives.



   Patent applications in the United States of America No. 425755 of September 28, 1982 and No. 530011 of
September 9, 1983 in favor of C. UN KIM.



  1. Field of the invention.



   The present invention relates to new antibiotic carbapenems whose substituent in position 2 has the formula:

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 EMI2.1
 where A represents a straight chain or branched C1-C alkylene radical R represents an aliphatic, cycloaliphatic, cycloaliphatic-aliphatic, aryl, araliphatic, heteroaryl, heteroaraliphatic, heterocyclic or heterocycloaliphatic radical optionally, and
 EMI2.2
 represents a nitrogen aromatic heterocycle attached to the alkylene radical A by a ring carbon atom and quaternized by the substituent R5.



  2. Known state of the art.



   A number of ss-lactam derivatives containing the carbapenem ring:
 EMI2.3
 have already been described in the literature. These carbapenem derivatives are indicated as being useful antibacterial agents and / or inhibitors of ia / 3-lactamase.



   The first carbapenem derivatives were natural products such as thienamycin from

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 formula :
 EMI3.1
 obtained by fermentation of Streptomyces cattleya (United States patent No. 3,950,357). Thienamycin is an exceptionally powerful broad-spectrum antibiotic that exhibits notable activity against various species of Pseudomonas, which are organisms whose resistance to antibiotics of the lactam-type is well known.



   Other natural products containing the carbapenem nucleus are in particular derivatives of olivanic acid such as the antibiotic MM 13902 of formula:
 EMI3.2
 
 EMI3.3
 described in US Pat. No. 4,113,856, the antibiotic MM 17880 of the formula:
 EMI3.4
 

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 EMI4.1
 described in US Pat. No. 4,162,304, the antibiotic MM 4550A of formula:
 EMI4.2
 described in US Patent No. 4,172,129, and the antibiotic 890A9 of the formula:
 EMI4.3
 described in U.S. Patent No. 4,264,735.



  In addition to natural products, the deacetylated compound 890alto of formula:
 EMI4.4
 is mentioned in US Patent No. 4,264,734 as being prepared by enzymatic deacylation of the corresponding N-acetylated compound. Different derivatives of natural olivanic acids have been

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 also synthesized, for example the compounds of formula:
 EMI5.1
 
 EMI5.2
 where a free, salified carboxyl radical 'C02R, represents 0 or esterified, n represents 0 or 1 and R2 represents H, an acyl radical or a radical of formula R303S, where R3 represents a salifying ion or a methyl or ethyl radical, as described European patent application 8885.



   U.S. Patent No. 4,235,922 (see also European Patent Application 2058) describes the carbapenem derivative of the formula:
 EMI5.3
 while English patent application No. 1,598,062 describes the isolation of the compound:
 EMI5.4
 from a Streptomyces fermentation broth.



   Carbapenems unsubstituted in position 6 have also been synthesized. Thus, the patent of

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 United States of America No. 4,210,661 describes compounds of formula:
 EMI6.1
 where R2 represents phenyl or substituted phenyl, United States Patent No. 4,267,177 describes compounds of the formula:
 EMI6.2
 where RI represents an optionally substituted pyridyl radical, United States Patent No. 4,255,441 describes compounds of formula:
 EMI6.3
 where R2 and R3 represent H or alkyl radicals and R4 represents NH-COnR6, where R6 represents an alkyl, phenyl or substituted phenyl radical and n represents 1 or 2, and United States patent No. 4,282. 236 describes compounds of formula:

   

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 EMI7.1
 where RI represents H or an alkyl radical and R2 represents CN or C02R3 'where R3 represents H or an alkyl, aryl or aralkyl radical.



   Carbapenems of the general formula:
 EMI7.2
 where R1 represents H or an acyl radical and R8 represents H or an alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, alkyl, cycloalkyl, aryl, aralkyl, aralkenyl, aralkynyl, heteroaryl or substituted heterocyclic, heteroaryl, in U.S. Patent No. 4,218. 463. There is no description of heteroaralkyl radicals R8 of formula:
 EMI7.3
 where A represents an alkylene radical and

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 EMI8.1
 represents a quaternized nitrogen aromatic heterocycle united to the alkylene radical A by a ring carbon atom.



   Natural thienamycin has the absolute configuration 5R, 6S, 8R. This isomer, along with the other seven remaining isomers of thienamycin, can be obtained by total synthesis, as described in U.S. Patent No. 4,234,495. Methods of total synthesis for thienamycin are also described, for example, in United States Patent Nos. 4,287,123,4,269,772,4,282,148,273,709,490,949 and European Patent Application 7,973 A key intermediate for the described synthesis processes is of formula:
 EMI8.2
 where pNB represents the p-nitrobenzyl radical.



   Due to the exceptional biological activity of thienamycin, a large number of its derivatives have been prepared and described in the literature. Among these, mention should be made of: (1) N-formimidoyl-thienamycin of formula:

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 EMI9.1
 described in European patent application 6639; (2) N-heterocyclic thienamycin derivatives of formula:
 EMI9.2
 OH P '- S CE C'7 (M 2) n 2 2 1 1 N N -' CC> DH 1 1 *.



  CODU and '2 -2) N \ "l et et (Z) Il -------" - D l il II
 EMI9.3
 where the bifunctional ring may contain additional cyclic unsaturation, n represents an integer from 1 to 6, p represents 0, 1 or 2, RI represents H or an alkyl or aryl radical and Z

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 represents H or an imino, oxo, amino or alkyl radical, described in US Pat. No. 4,189. 493;

   (3) substituted N-methylenic derivatives of thienamycin of formula:
 EMI10.1
 where X and Y represent H, R, OR, SR or NRlR2, where R represents an alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclic or heterocycloalkyl or substituted and R substituted R2 represents H or R, described in United States Patent No. 4,194,047;

   (4) the compounds of formula:
 EMI10.2
 where R3 represents an aryl, alkyl, acyl or aralkyl radical and Rl and R2 independently represent H or an acyl radical (in particular acyl of type:
 EMI10.3
 where Rll can represent, among other things, a radical

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 alkyl substituted by a quaternary ammonium radical, for example:
 EMI11.1
 described in U.S. Patent No. 4,226,870;

   (5) the compounds of the formula:
 EMI11.2
 where R3 represents H, an acyl radical or an optionally substituted univalent hydrocarbon radical, RI represents an alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkenylalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl or heteroaryl radical (in particular acyl type:
 EMI11.3
 where R represents an alkyl radical substituted by a quaternary ammonium radical, for example:
 EMI11.4
 

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 described in English Patent No. 1,604,276 (see also United States Patent No. 4,235,917);

   (6) the compounds of formula:
 EMI12.1
 where R5, R6 and R independently represent H or an alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkenylalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl or heteroaralkyl, substituted or unsubstituted US patent n or substituted 4, 235,920;

   (7) the compounds of formula:
 EMI12.2
 where R1 and R2 each independently of one another represent a radical of the type defined for R, a hydrogen atom or a nitro, hydroxyl, C1-6-
 EMI12.3
 alkoxy, amino, CI-6-alkylamino, amino or tri (C-alkylamino), an additional anion being present in the latter case;

   or RI and R2 are united together to form, with the nitrogen atom to which they are attached, a heteroaryl or heterocyclic, monocyclic or bicyclic substituted or unsubstituted radical having 4 to 10 ring atoms, one or more of which may be a or additional heteroatoms

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 chosen from oxygen, sulfur and nitrogen, R represents a cyano radical or a carbamoyl or carboxyl radical (ci-lo-alkoxy) carbonyl, Ci-ioalkyl, C2-10-alkssyl, C2-10-alkynyl, C3-10cycloalkyl, C4-12-cycloalkylalkyl, C5-12cycloalkylalkenyl, Ciocyloalkenyl, C5-12cycloalkenylalkenyl, C4-12-cycloalcssnylalkyl, C6-10aryle, C7-16-aralkyl-C8-aralkyl-C8-16 heteroalkyl,

   heterocyclic or heterocycloalkyl monocyclic or bicyclic comprising 4 to 10 ring atoms, one or more of which are heteroatoms chosen from oxygen, sulfur and nitrogen and whose alkyl radical of the heteroaralkyl or heterocycloalkyl radical has 1 to 6 carbon atoms the substituted or unsubstituted state; the substituent (s) on R, Ri, R2 or the ring formed by the union of Rl and R2 are chloro radicals; bromo; iodo; fluoro; azido; Cl-4-alkyl; mercapto; sulfo; phosphono; cyanothio (S-CN); nitro; cyano; amino; hydrazino; amino or hydrazino carrying up to three C1-6-alkyl substituents; hydroxy; Cl-6-alkoxy; Cl-6alcoylthio; carboxyl, oxo; (C1-6-alkoxy) carbonyl;

   C2-10-acyloxy; carbamoyl; (Cl-4-alkyl) carbamoyl or di (C1-4-alkyl) carbamoyl; R3 represents a hydrogen atom, an acyl radical or a radical of the type defined for R4; R4 represents a C1-20-alkyl radical; substituted carbonylmethyl; (C1-6-alkoxy) - (C1-6alkyl), (C3-6-cycloalkoxy) - (C1-6-alkyl); C2-12alkanoyloxyalkyl; Cl-6-alkyl partially or completely halogenated, in which the halogen (s) are chlorine, bromine or fluorine; aminoalkyl; C2-10alkenyl; C2-10-alkynyl; acyl; C3-14-alkoxycarbonylalkyl;

   C4-21-dialcoylaminoacsstoxyalcoyl; C2-13-alkanoylaminoalkyl; ar- (C1-3-alkyl), the aryl residue of which has 6 to 10 carbon atoms; heteroalkyl or

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 monocyclic or bicylic heterocycloalkyl having 4 to 10 ring atoms, 1 to 3 carbon atoms in the alkyl residue and 1 to 4 heteroatoms chosen from oxygen, sulfur and / or nitrogen; aralkyl or heteroaralkyl substituted on the nucleus whose substituent is chlorine, fluorine; bromine or iodine or a Cl-6-alkyl radical; aryl or aryl substituted on the ring having 6 to 10 ring carbon atoms and whose any substituent on the ring is a hydroxyl, Cl-6-alkyl, chloro, fluoro or bromo radical; aralkoxyalkyl; C2-12-alkylthioalkyl;

   C4-12-cycloalcoylthioalcoyl; (C2-10-acylthio) - (Cl-6-alkyl); or phenylalkenyl in which the alkenyl radical has 2 to 6 carbon atoms; R5 represents a substituted or unsubstituted Cl-o-alkyl radical; C2-10-alkenyl or alkynyl; cycloalkyl, cycloalkenyl, cycloalkenylalkyl and cycloalkylalkyl of 3 to 6 ring carbon atoms and having up to 6 carbon atoms in any chain which are substituted or unsubstituted on the ring; C6-10-aryl; aralkyl having 6 to 10 ring carbon atoms and 1 to 6 carbon atoms in the alkyl chain;

   monocyclic or bicyclic heteroaryl or heteroalkyl having 4 to 10 ring atoms of which one or more are chosen from oxygen, nitrogen and sulfur and 1 to 6 carbon atoms in the alkyl chain; and the substituent (s) of the cycle or chain are chloro, bromo, iodo, fluoro, azido, cyano, amino, Cri-6-alkylamino radicals; di- (Cl-6-alkyl) amino or tri (Ci-6-alkylamino), an additional anion being present in the latter case, hydroxyl, Cl-6-alkoxy, Cl-6alkoylthioalkyl; carboxyl; oxo, (Cl-6-alkoxy) carbonyl; C2-10-acyloxy; carbamoyl; (Cl-4-alkyl) carbamoyl; di (Cl-4-alkyl) carbamoyl; cyanothio (-SCN) or nitro;

   R6 represents a hydrogen atom or

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 hydroxyl radical, mercapto; R, -OR, -SR or NRlR2, where R, Ri and R2 are as defined above.



   X represents a hydroxyl, mercapto, amino radical,
 EMI15.1
 acyloxy, -OR4, -SR4, -NHR4, -N (R4) 2'-OM, or, when the compound is in zwitterionic form, in which case A-is absent;
A represents a counter ion when the compound is not in zwitterionic form;
M represents a pharmaceutically acceptable cation, and
Q represents a blocking radical as defined here, described in English patent No. 1,604,275, and (8) the compounds of formula:

   
 EMI15.2
 
 EMI15.3
 C) 1 where
 EMI15.4
 united with the amino nitrogen radical of thienamycin represents a mono or polycyclic nitrogen heterocyclic radical and R represents H or an alkyl, aryl, alkenyl, heterocycloalkenyl, aralkenyl, heterocycloalkyl, aralkyl, -NR2, COOR, or CONR, -OR radical or not, described in the patent application

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 European 21082. Among the compounds described in US Pat. No. 4,235,920, there is that of formula:
 EMI16.1
 where A represents a pharmaceutically acceptable anion.



  The aforementioned quaternary amine derivative is also described in Recent Advances in the Chemistry of / 3-Lactam Antibiotics, Royal Society of Chemistry, London, 1981, pages 240-254, where its average antibacterial activity is noted as being about the 1/2 to 2/3 of that of thienamycin.



   Carbapenem derivatives carrying a wide variety of substituents in position 6, in addition to those indicated above, have already been synthesized. For example, mention may be made of (1) the compounds described in European patent application 40408 corresponding to the formula:
 EMI16.2
 where RI represents H or a methyl or hydroxyl radical and R51 represents a monovalent organic radical, in particular heterocycloalkyl, among others;

   (2) the compounds described in the patent application

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 EMI17.1
 European 8514 and meeting the formula
 EMI17.2
 
 EMI17.3
 where Ri represents an optionally substituted pyrimidinyl radical and R2 represents a hydrogen atom or radical CR3R4R5, where R3 represents a hydrogen atom or a hydroxyl radical, R4 represents a hydrogen atom or an alkyl radical and R5 represents a d atom hydrogen or an alkyl, benzyl or phenyl radical, or else Rs and R6 together form a carbocycle;

   (3) the compounds described in European patent application 38869 and corresponding to the formula:
 EMI17.4
 
 EMI17.5
 where R6, R and are independently selected from hydrogen and alkyl, alkenyl and alkynyl radicals of 1 to 10 carbon atoms; cycloalkyl, cycloalkylalkyl and alkylcycloalkyl of 3 to 6 carbon atoms in the cycle of the cycloalkyl radical and from 1 to 6 carbon atoms in the alkyl radicals; aryl such as phenyl, aralkyl, aralkenyl and aralkenyl in which the aryl radical is a phenyl radical and the aliphatic part has 1 to 6 carbon atoms; heteroaryl, heteroaralkyl, heterocyclic and hetero-

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 EMI18.1
 cycloalkyl; all substituted or unsubstituted in which the substituent (s) with respect to the abovementioned radicals are chosen from:

   - halo (chloro, bromo, fluoro) - hydroxy - alkoxy, aryloxy
 EMI18.2
 o Il - 0 -CNRlR2 -NRlR2 amino NRl - RI Ri - nitro G - trisubstituted amino (radicals Ri chosen independently) Ri - oximino - arylthio - NRiR sulfonamido 0 o - ureido 0 81 - amido - H carboxy - Rl carboxylate 0 Il - acyle 0 Il - acyloxy - mercapto

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 EMI19.1
 0 Il - aryl-sulfinyle o Il - alkyl and aryl-sulfonyl Il 0
 EMI19.2
 - cyano X - N3 azido where, with regard to the substituents listed above on R6, R7 and R8, the radicals Ri and R2 are independently chosen from hydrogen and the alkyl, alkenyl and alkynyl radicals of 1 to 10 carbon atoms ; cycloalkyl, cycloalkylalkyl and alkylcycloalkyl of 3 to 6 carbon atoms in the ring of the cycloalkyl part and from 1 to 6 carbon atoms in the alkyl parts;

   aryl such as phenyl; aralkyl, aralkenyl and aralkynyl in which the aryl radical is a phenyl radical and the aliphatic part has 1 to 6 carbon atoms; heteroaryl, heteroaralkyl, heterocyclic and heterocycloalkyl and in which the heteroatom (s) in the aforementioned heterocyclic radicals are chosen from 1 to 4 atoms of oxygen, nitrogen or sulfur and in which the alkyl parts associated with these heterocyclic radicals have 1 to 6 atoms carbon (see also European patent applications 1627.1628, 10317, 17992.37080, 37081 and 37082);

   (4) the compounds described in European patent application 24832 and corresponding to the formula:
 EMI19.3
 

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 where RI represents H or a radical chosen from OH, OS03H or salt or Cl-4-alkyl ester thereof, OR2, SR3, OCOR2, OC02R3 and OCONHR3, where R2 represents a Cl-6-alkyl radical or a benzyl radical optionally substituted and R3 represents a C1-6-alkyl radical or an optionally substituted benzyl or phenyl radical and R12 represents a C1-6-alkyl, C2-6alkenyl, C3-6-alkynyl radical whose triple bond does not lead to the carbon atom adjacent to the sulfur atom, aralkyl, Cl-6-alkanoyl, aralcanoyl, aryl-oxyalkanoyl or arylcarbonyl,

   any of these radicals R12 being optionally substituted, as antibacterial agents.



   European patent application 44170 describes carbapenem derivatives of formula:
 EMI20.1
 where R3 represents a hydrogen atom or an organic radical united by a carbon atom to the carbapenem ring, n represents 0 or 1, X represents a saturated or unsaturated hydrocarbon radical optionally substituted by bromine or chlorine and R4 represents a
 EMI20.2
 C1-6-alkyl, C2-6-alkenyl, Cio'Y or aryl radical, each of these radicals R4 being optionally substituted. There is however no mention of any compound whose tetrazole ring is united to X by a quaternized nitrogen atom, that is to say a positively charged nitrogen atom which is not united to a atom d 'hydrogen.



   The aforementioned European patent application 38869

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 describes the synthesis of carbapenem derivatives using intermediates of the general formula:
 EMI21.1
 where R6 and R7 are as defined above and R2 ′ represents a protective radical of the carboxyl function which is easy to eliminate. This document also describes as an intermediate the compounds of formula:
 EMI21.2
 where X represents a labile radical.



   A booklet describing different antibiotic carbapenems was distributed at the Gordon Research Conference on Medicinal Chemistry held August 2-6, 1982 in New London, New Hampshire. Among the compounds cited on page 9 in this booklet, we find the carbapenem of formula:
 EMI21.3
 which differs from the compounds of the present invention by

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 the fact that the quaternized heteroaromatic ring in the substituent in position 2 is linked directly to the sulfur atom, rather than to the carbon atom of an alkylene radical.



   European patent application 50334 describes carbapenem derivatives of general formula:
 EMI22.1
 where R6 and R7 represent, inter alia, each independently a hydrogen atom or an alkyl, alkenyl, aryl or aralkyl radical; A represents a direct single bond between the atoms S and C represented or else represents a cyclic or acylic bridging radical chosen, inter alia, from the alkyl, cycloalkyl, aryl, heteroaryl and heteroalkyl radicals; Rl and R2 which define the carbamimidoyl function each independently represent a hydrogen atom or an alkyl or aryl radical, this carbimimidoyl radical being, furthermore, characterized by cyclic structures formed by the union of the two nitrogen atoms to the intervention of their substituents and by their union with the radical of bridging A;

   this document also describes "carbamimidiums" resulting from the quaternization of one of the nitrogen atoms of this carbamimidoyl function. A possible substituent in position 2 indicated on page 12 of this document is the radical:

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 EMI23.1
 where Ri represents a hydrogen atom or an alkyl, cycloalkyl, cycloalkylalkyl, alkyl, cycloalkyl, aryl, arylalkyl, heterocyclic or heterocycloalkyl radical, each substituted or unsubstituted and the two nitrogen atoms "participate in cyclic structures indicated by the dotted lines ".



  No indication is given of cyclized carbamimidoyl radicals containing a quaternized nitrogen atom, but there is an indication on page 22 of a cyclized carbamimidoyl radical of formula:
 EMI23.2
 
Based on the definitions given for the substituent RI, the Applicant does not believe that the European patent application 50334 generically describes any of the compounds of the present invention.



  However, since the nature of the cyclic structures envisaged is indicated with such imprecision in the aforementioned document, the Applicant gives the statement in this memo.



   As indicated above, we find in the Week currently known, carbapenem derivatives bearing in position 2, a substituent of general formula:

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 - S-A-Het where A represents an alkylene radical and Het represents a heterocyclic or heteroaromatic radical, but to the knowledge of the Applicant, there is no mention of carbapenems of which the Het radical is a radical of formula:
 EMI24.1
 where R5 represents an aliphatic, cycloaliphatic, cycloaliphatic-aliphatic, aryl, araliphatic, heteroaryl, heteroaraliphatic, heterocyclic or heterocycloaliphatic radical optionally, and
 EMI24.2
 represents a quaternized nitrogen aromatic heterocycle united to a carbon atom of the alkylene radical by a ring carbon atom.

   As already specified, the carbapenem carrying the radical
 EMI24.3
 as a substituent in position 2 has already been described, just like the carbapenem comprising a quaternized heteroaromatic ring directly linked to the sulfur atom of the substituent in position 2.



   Although many derivatives of carbape-

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 neme have already been described, it has remained interesting to discover new ones, because these may prove to be superior by the spectrum of activity, the efficacy, the stability and / or the modesty of the toxic side effects.



  Overview of the invention.



   The subject of the present invention is a new series of carbapenem derivatives bearing in position 2, a substituent of formula:
 EMI25.1
 where A represents a C1-C6 alkylene radical in a straight or branched chain, R5 represents an aliphatic, cycloaliphatic, cycloaliphatic-aliphatic, aryl, araliphatic, heteroaryl, heteroaraliphatic, heterocyclic or heterocycloaliphatic radical optionally, and
 EMI25.2
 represents a quaternized nitrogen aromatic heterocyclic linked to the alkylene radical A by a ring carbon atom.



   More specifically, the subject of the present invention is the carbapenem derivatives of formula:

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 EMI26.1
 where R8 represents a hydrogen atom and RI is chosen from the hydrogen atom and the alkyl, alkenyl and alkynyl radicals of 1 to 10 carbon atoms; cycloalkyl and cycloalkylalkyl of 3 to 6 carbon atoms in the ring of the cycloalkyl part and from 1 to 6 carbon atoms in the alkyl parts; phenyl; aralkyl, aralkenyl and aralkynyl in which the aryl part is a phenyl radical and the aliphatic part has 1 to 6 carbon atoms;

   heteroaryl, heteroaralkyl, heterocyclic and heterocycloalkyl in which the heteroatom (s) in the aforementioned heterocyclic parts are chosen from 1 to 4 oxygen, nitrogen or sulfur atoms and the alkyl parts associated with the heterocyclic parts have 1 to 6 carbon atoms, all substituted or unsubstituted and whose substituent (s) with respect to the abovementioned radicals are independently chosen from
Cl-C6-alkyl optionally amino, halogenated, hydroxylated or halogenated carboxylated
 EMI26.2
 

  <Desc / Clms Page number 27>

 
 EMI27.1
 where, with regard to the abovementioned substituents, the radicals R3 and R4 are independently chosen from the hydrogen atom and the alkyl, alkenyl and alkynyl radicals

  <Desc / Clms Page number 28>

 from 1 to 10 carbon atoms;

   cycloalkyl, cycloalkylalkyl and alkylcycloalkyl of 3 to 6 carbon atoms in the ring of the cycloalkyl part and from 1 to 6 carbon atoms in the alkyl parts; phenyl; aralkyl, aralkenyl and aralkynyl in which the aryl part is a phenyl radical and in which the aliphatic part has 1 to 6 carbon atoms; and heteroaryl, heteroaralkyl, heterocyclic and heterocycloalkyl in which the heteroatom (s) in the aforementioned heterocyclic parts are chosen from 1 to 4 atoms of nitrogen and sulfur oxygen and in which the alkyl parts associated with the heterocyclic parts have 1 to 6 carbon atoms , or alternatively R3 and R4, taken together with the nitrogen atom to which at least one of them is united, can form a pentagonal or hexagonal nitrogen heterocyclic radical;

   R9 is defined as R3 except that it cannot be a hydrogen atom; or where RI and R, taken together, represent a
 EMI28.1
 hydroxyl-substituted C-Co-alkylIidene or C-Cio-alkylIidene radical; R5 is chosen from alkyl, alkenyl and alkynyl radicals of 1 to 10 carbon atoms; cycloalkyl and cycloalkylalkyl of 3 to 6 carbon atoms in the ring of the cycloalkyl part and from 1 to 6 carbon atoms in the alkyl parts; phenyl; aralkyl, aralkenyl and aralkynyl in which the aryl part is a phenyl radical and in which the aliphatic part has 1 to 6 carbon atoms;

   heteroaryl, heteroaralkyl, heterocyclic and heterocycloalkyl in which the heteroatom (s) of the above-mentioned heterocyclic parts are chosen from 1 to 4 oxygen, nitrogen or sulfur atoms and in which the alkyl parts associated with the heterocyclic parts have 1 to 6 carbon atoms, all substituted or unsubstituted; the aforementioned R5 radicals being optionally substituted with 1 to 3 selected radicals

  <Desc / Clms Page number 29>

 independently from:
C1-C6-alkyl optionally amino, fluorinated, chlorinated, carboxylated, hydroxylated, or carbamoylated fluoro, chloro or bromo
 EMI29.1
 phenyl optionally substituted by 1 to 3 fluoro, chloro, bromo, Cl-C6-alkyl, -OR3, -NR3R4, - S03R4, -C02R3 or-CONR3R4, where R3, R4 and R9 in these substituents of R5 are as defined above;

   or R5 can be combined with

  <Desc / Clms Page number 30>

 
 EMI30.1
 at another point in the cycle so as to form a condensed heterocyclic or heteroaromatic radical, the cycle of which may contain additional heteroatoms, preferably up to the number of 2, chosen from 0, N and S; R15 is chosen from the hydrogen atom and the alkyl, alkenyl and alkynyl radicals of 1 to 10 carbon atoms; cycloalkyl, cycloalkylalkyl and alkylcycloalkyl of 3 to 6 carbon atoms in the ring of the cycloalkyl part and from 1 to 6 carbon atoms in the alkyl parts; spirocycloalkyl of 3 to 6 carbon atoms; phenyl; aralkyl, aralkenyl and aralkynyl in which the aryl part is a phenyl radical and the aliphatic part has 1 to 10 carbon atoms;

   heteroaryl, heteroaralkyl, heterocyclic and heterocycloalkyl in which the heteroatom (s) in the above-mentioned heterocyclic parts are chosen from 1 to 4 oxygen, nitrogen and sulfur atoms and the alkyl parts associated with the heterocyclic parts have 1 to 6 carbon atoms, all substituted or unsubstituted and whose substituent (s) with respect to the abovementioned radicals are chosen from amino-, mono-, di-trialcoylamino, hydroxyl, alkoxy, mercapto, alkylthio, phenylthio, sulfamoyl, amidino, guanidino, nitro, chloro radicals , bromo, fluoro, cyano and carboxyl; and in which the alkyl parts in the abovementioned substituents have 1 to 6 carbon atoms; A represents a C1-C6-alkylene radical in a straight or branched chain;

   R2 represents a hydrogen atom, an anionic charge or a conventional radical easily

  <Desc / Clms Page number 31>

 removable protective of the carboxyl function, it being understood that when R2 represents a hydrogen atom or a protective radical, a counter ion is also present, and
 EMI31.1
 represents a substituted or unsubstituted heterocyclic, aromatic, mono-, bi- or polycyclic radical comprising at least one nitrogen atom in the ring and united to the radical A by a carbon atom of the ring and comprising a ring nitrogen atom which is quaternized by the radical R5; and their pharmaceutically acceptable salts.



   The compounds of formula I are potent antibacterial agents or useful intermediates for the preparation of such agents.



   The invention also relates to methods for preparing the new carbapenem derivatives described above and the pharmaceutical compositions containing the biologically active carbapenem derivatives associated with pharmaceutically acceptable excipients or diluents.



  Detailed description of the invention.



   The new compounds of general formula I include the carbapenem ring:
 EMI31.2
 

  <Desc / Clms Page number 32>

 and can therefore be called 1carba-2-penem-3-carboxylic acid derivatives. Alternatively, the compounds can be considered to include the basic structure
 EMI32.1
 and may be called derivatives of 7-oxo-1-azabicyclo (3. 2. 0) hept-2-ene-2-carboxylic acid, The subject of the invention is compounds whose relative stereochemistry of protons 5,6 is not only cis, but also trans, but the preferred compounds have the 5R, 6S (trans) stereochemistry, as in the case of thienamycin.



   The compounds of formula I can be free of substituent in position 6 or can carry there radicals already mentioned for other carbapenem derivatives. More specifically, R8 can represent a hydrogen atom and RI can represent a hydrogen atom or a substituent other than hydrogen, mentioned, for example, in European patent application 38869 (see definition of R6). Alternatively, R8 and Ri, taken together, can form a C2-Clo- radical
 EMI32.2
 alkylidene or C-Cio'lcoyIi "substituted, for example by a hydroxyl radical.



   The compounds of formula I can also be free of substituent in position 1 (Rl5 = H) or can carry in this position of the radicals already mentioned for other carbapenem derivatives. More specifically, R15 may represent a hydrogen atom or any of the substituents other than hydrogen in

  <Desc / Clms Page number 33>

 position 1, indicated, for example, in European patent application 54917 (see definitions of Ri or R2 in this document) or in United States patent no. 4,350. 631. RIS substituents other than the hydrogen which are preferred are in particular d-Ce-alkyl radicals, more especially methyl; phenyl; and phenyl (Cl-C6) alkyl.

   The substituent R15 other than hydrogen can have the configuration or afzet the invention relates to the isomers O and ss separated, as well as their mixtures. The compounds substituted in position 1 which are especially preferred are those having the / 3 configuration and especially those carrying a 3-methyl radical,
To clarify the definitions of RI, R8 and R15, we can give the following indications:

   (a) the aliphatic radicals "alkyl", "alkenyl" and "alkynyl" can be in a straight or branched chain and have 1 to 10 carbon atoms, but preferably have 1 to 6 and most preferably 1 to 4; when they form part of another substituent, as in cycloalkylalkyl, heteroalkyl or aralkenyl radicals, the alkyl, alkenyl and alkynyl radicals preferably have 1 to 6 and more especially 1 to 4 carbon atoms.



   (b) the “heteroaryl” radicals are in particular aromatic, mono-, di- and polycyclic heterocyclic radicals containing 1 to 4 atoms 0, N or S, the preference going to pentagonal or hexagonal heterocycles such as thienyl, furyl, thiadiazolyl, oxadiazolyle, triazolyle, isothiazolyle, thiazolyle, imidazolyle, isoxazolyle, tétrazolyle, oxazolyle, pyridyle, pyrazinyle, pyrimidinyle, pyridazinyle, pyrrolyle, pyrazolyle, etc.



   (c) the “heterocyclic” radicals are in particular non-aromatic heterocyclic radicals

  <Desc / Clms Page number 34>

 saturated or unsaturated mono-, di- or polycyclic containing 1 to 4 0, N or S atoms, preference being given to pentagonal or hexagonal heterocyclic radicals such as morpholinyl, piperazinyl, piperidyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, pyrrolinyl, etc.



   (d) the "halo" radicals are the chloro, bromo, fluoro and iodo radicals, the preference going to the chloro, fluoro or bromo radicals.



   The term "conventional radical which is easy to remove protective of the carboxyl function" should be understood to mean a known ester radical which has already been used to block a carboxyl radical during the chemical reaction stages described below and which can be eliminated when the thing is desired, according to processes which do not bring any appreciable destruction of the rest of the molecule, for example by chemical or enzymatic hydrolysis, treatment using chemical reducers under moderate conditions, exposure to ultraviolet light or catalytic hydrogenation .

   Examples of such protective ester radicals are the benzhydryl, allyl, pnitrobenzyl, 2-naphthylmethyl, benzyl, trichloroethyl or silyl radicals, such as trimethylsilyl, phenacyl, p-methoxybenzyl, acetonyl, o-nitrobenzyl, 4pyridylmethyl and Cl-C6 alkyl such as methyl, ethyl or t-butyl. These protective radicals include those which are hydrolyzed under physiological conditions such as the pivaloyloxymethyl, acetoxymethyl, phthalidyl, indanyl and methoxymethyl radicals. A protective radical of the carboxyl function which is particularly advantageous is the p-nitrobenzyl radical, easily removed by catalytic hydrogenolysis.



   Pharmaceutically acceptable salts

  <Desc / Clms Page number 35>

 mentioned above are in particular the addition salts of non-toxic acids, for example the salts formed with mineral acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, phosphoric acid, acid sulfuric, etc., and the salts formed with organic acids such as maleic acid, acetic acid, citric acid, succinic acid, benzoic acid, tartaric acid, fumaric acid, l 'mandelic acid, ascorbic acid, lactic acid, gluconic acid and malic acid. The compounds of formula I in the form of the acid addition salts can be represented by the formula:
 EMI35.1
 where R2 represents a hydrogen atom or protective radical eut &commat; represents the anion of an acid.

   The YB counter anion can be chosen to give a pharmaceutically acceptable salt suitable for administration for therapeutic purposes, but in the case of the intermediate compounds of formula I, yf0 can also represent a toxic anion. In such a case, this ion can be eliminated or replaced subsequently by a pharmaceutically acceptable anion giving a clean active final product for therapeutic purposes.



  When acidic or basic radicals are present in the radical Ri or R5 or in the radical

  <Desc / Clms Page number 36>

 
 EMI36.1
 a subject of the invention is also the base addition or appropriate acid salts of these functional radicals, for example the acid addition salts in the case of a basic radical and the salts with metals (for example example sodium, potassium, calcium and aluminum), ammonium salt and salts with non-toxic amines (e.g. trialcoylamines,
 EMI36.2
 procalne, dibenzylamine, l-ephenamine, Nbenzyl-P-phenethylamine, N, N'-dibenzylethylenediabenzyl-e mine, etc. ) in the case of an acid radical.



   The compounds of formula I, where R2 represents a hydrogen atom, an anionic charge or a physiologically hydrolysable ester radical, as well as their pharmaceutically acceptable salts are useful as antibacterial agents. The other compounds of formula I are interesting intermediates which can be converted into the abovementioned biologically active compounds.



   According to a preferred embodiment, the invention relates to the compounds of formula I, where
 EMI36.3
 R8 represents a hydrogen atom and RI represents a hydrogen atom or a CH3-CH2- radical
 EMI36.4
 CH3 CH3 OH OH 1 1 CH -, "C- or CH3CHCH3./CH3/
 EMI36.5
 In this subclass, the preferred compounds are those in the formula of which RI represents

  <Desc / Clms Page number 37>

 
 EMI37.1
 and more particularly the compounds having the absolute configuration 5R, 6S, BR.



   According to another preferred embodiment, the invention relates to the compounds of formula I where RI and R2, then together, represent an alkylidene radical of formula:
 EMI37.2
 
The alkylene radical (that is to say the radical "A") in the compounds of formula I may be in a straight or branched chain and may have 1 to 6 carbon atoms. According to a preferred embodiment, the subject of the invention is these compounds in the formula of which A represents- (CH) "with n representing 1 or 2 and according to a particularly preferred embodiment, it relates to the compounds in the formula of which A represents -CH2-.



   The alkylene part "A" is united by a ring carbon atom to an N-substituted quaternized aromatic heterocycle of general formula:
 EMI37.3
 where R5 preferably represents a C1-C6-alkyl, C2-Clo-alkenyl, C2-Clo-alkynyl, C3-C6- radical
 EMI37.4
 cycloalkyl, C3-C6-cycloalkyl-Cl-C6-alkyl, phenyl, phenyl-Cl-C6-alkyl, phenyl-C2-C6-alkenyl, C2-C6-

  <Desc / Clms Page number 38>

 alkynyl, heteroaryl, heteroaralkyl in which the alkyl part has 1 to 6 carbon atoms, heterocyclic or heterocycloalkyl in which the alkyl part has 1 to 6 carbon atoms.

   The heteroaryl radical (or the heteroaryl part of a heteroalkyl radical) R5 may be a heterocyclic aromatic mono-, bi- or polycyclic radical containing 1 to 4 atoms 0, N or S, preference being given to pentagonal or hexagonal heterocyclic radicals such as thienyl, furyl, thiadiazoyl, oxadiazolyl, triazolyl, isothiazolyl, thiazolyl, imidazolyl, isoxazolyl, tetrazolyl, oxazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrrolyl and pyrazolyl.

   The heterocyclic radical (or the heterocyclic part of a heterocycloalkyl radical) R5 may be a non-aromatic saturated or unsaturated mono-, bi-or polycyclic heterocyclic radical containing 1 to 4 0, N or S atoms, preference being given to radicals pentagonal or hexagonal heterocyclics such as morpholinyl, piperazinyl, piperidyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, pyrrolinyl and pyrrolidinyl.



   The radical R5 may optionally be substituted by 1 to 3 radicals chosen independently from: (a) Cl-C6-alkyl optionally substituted by radicals, preferably 1 to 3 in number, which are amino, fluoro, chloro, carbo radicals - xyl, hydroxyl or carbamoyl (b) fluoro, chloro or bromo (c) -OR3 (d) -OCOR (e) -OCOR (f) -OCONR3R4

  <Desc / Clms Page number 39>

 
 EMI39.1
 (u) phenyl optionally substituted with 1 to 3 substituents chosen independently from the radicals
 EMI39.2
 fluoro, chloro, bromo, C-Ce-alcoyIe, -OR, 9-C02R3 ou-CONR3R4, 01, - R, -SOR, -COR R, about the abovementioned substituents of R5, the radicals R3 and R4 are chosen independently from hydrogen atoms and alkyl, alkenyl and alkynyl radicals of 1 to 10 carbon atoms;

   cycloalkyl, cycloalkylalkyl and alkylcycloalkyl of 3 to 6 carbon atoms in the ring of the cycloalkyl part and from 1 to 6 carbon atoms in the alkyl parts; phenyl; aralkyl, aralkenyl and aralkynyl in which the aryl part is a phenyl radical and in which the aliphatic part has 1 to 6 carbon atoms; and heteroaryl,

  <Desc / Clms Page number 40>

 heteroaralkyl, heterocyclic and heterocycloalkyl in which the heteroaryl and heterocyclic radical or a part of a radical is as defined above with respect to R5 and the alkyl parts associated with these heterocyclic parts have 1 to 6 carbon atoms ;

   or else R3 and R4, taken together with the nitrogen atom to which at least one of them is joined, form a heterocyclic nitrogen pentagonal or hexagonal radical (as defined above with respect to R5); and R9 is as defined above with respect to R3, except that it cannot be a hydrogen atom. An especially preferred radical for R5 is a C1-C6-alkyl and especially methyl radical.



   In addition, the radical R5, together with another atom of the radical cycle
 EMI40.1
 may form a condensed heterocyclic or heteroaromatic radical the ring of which may contain additional heteroatoms, preferably 1 in number or
 EMI40.2
 2, chosen between 0, N and S. For example
 EMI40.3
 oe-R5 can be lm / r. / \ // \ de \ / \ / N N - 9 th

  <Desc / Clms Page number 41>

 The radical
 EMI41.1
 is preferably a substituted or unsubstituted mono-, bi- or polycyclic aromatic heterocyclic radical comprising at least one nitrogen atom in the ring and 0 to 5 additional ring heteroatoms chosen from 0, S and N, this heterocyclic radical being united to the radical A by a ring carbon atom and comprising a ring nitrogen atom quaternized by the radical R5.



   The heteroaromatic radical
 EMI41.2
 may optionally be substituted for the ring carbon atoms available by preferably 1 to 5 and especially 1 to 3 substituents independently chosen from Cl-C4-alkyl radicals Cl-C4-alkyl radical substituted by preferably 1 to 3 hydroxyl, amino radicals, Cl-C4-alkylamino, di (Cl-C4) alkylamino, Cl-C4-alkoxy, carboxyl, halo (considered below to mean chloro, bromo, fluoro or iodo; preferably chloro, bromo or fluoro) or sulfo; Cg-C-cycloalkyl; C3-C6-cycloalkyl (Cl-C4) alkyl optionally substituted with 1 to 3 substituents mentioned above in connection with the C1-C4-alkyl radicals; Cl-C4-alkoxy; Cl-C4alcoylthio; amino;

   C1-C4-alkylamino; di (Cl-
 EMI41.3
 C4) alcoylamino -alkanoyIamino alkanoyioxy

  <Desc / Clms Page number 42>

 hydroxyl; amidino; guanidino; phenyl; phenyl substituted with 1 to 3 substituents independently chosen from amino, halo, hydroxyl, trifluoromethyl, Cl-C4-alkyl, Cl-C4-alkoxy, Cl-C4alkylamino, di (CI-C4) alkylamino, carboxyl and sulfo radicals; phenyl (CI -C4) alkyl of which the phenyl part is. optionally substituted with 1 to 3 substituents mentioned above with respect to the phenyl radical and the alkyl part is optionally substituted with 1 to 3 substituents mentioned above with respect to the C1 "C4-alkyl radicals;

   and heatheraryl or heteroaralkyl in which the heteroatom (s) are chosen from 1 to 4 atoms 0, S or N and in which the alkyl part associated with the heteroaralkyl radical has 1 to 6 carbon atoms, these heteroaryl and heteroaralkyl radicals being optionally substituted in the heterocyclic part with 1 to 3 substituents independently chosen from hydroxyl, amino, halogen, trifluoromethyl, Cl-C4-alkyl, Cl-C4-alkoxy, C1-C4-alkylamino, di (Cl-C4) - alkyllamino, carboxyl and sulfo radicals, and in the alkyl part with 1 to 3 substituents chosen from hydroxyl, amino, C1-C4-alkylamino, di (Cl-C4) alkylamino, Cl-C4-alkoxy, carboxyl, halo and sulfo radicals.

   In addition, available ring nitrogen atoms (other than the quaternized nitrogen atom) can be substituted with 1 to 3 independently selected substituents
 EMI42.1
 especially among the C-c-alkyl radicals: -C-alkyl
Csubstituted by preferably 1 to 3 hydroxyl, amino, Cl-C4-alkylamino, di (Cl-C4) alkylamino, Cl-C4alkoxy, carboxyl, halo or sulfo radicals:

   Cg-C -cycloalkyl C3-C6-cycloalkyl (Cl-C4) alkyl optionally substituted with 1 to 3 substituents mentioned above with regard to the C1-C4-alkyl phenyl radicals, phenyl optionally substituted with 1 to 3 substituents chosen independently among the amino and halo radicals,

  <Desc / Clms Page number 43>

 hydroxyl, trifluoromethyl, Cl-C4-alkyl, Cl-C4-alkoxy, Cl-C4-alkylamino, di (Cl-C4) alkylamino, carboxyl and sulfo;

   phenyl (Cl-C4) alkyl, the phenyl part of which can optionally be substituted with 1 to 3 substituents mentioned above with respect to the phenyl radical and the alkyl part of which can optionally be substituted with 1 to 3 substituents mentioned above with regard to the radicals CI -C4-alkyloyl and heteroaryl or heteroaralkyl in which the heteroatom (s) are chosen from 1 to 4 atoms 0, S or N and in which the alkyl part associated with the heteroaralkyl radical has 1 to 6 carbon atoms, the heteroaryl and heteroaralkyl radicals being optionally substituted in the heterocyclic part with 1 to 3 substituents independently chosen from the hydroxyl, amino, halogen, trifluoromethyl, CI-C4-alkyl, Cl-C4-alkoxy, Cl-C4-alkylamino, di (ClC4) alkylamino radicals,

   carboxyl and sulfo and in the alkyl part with 1 to 3 substituents chosen from hydroxyl, amino, Cl-C4-alkylamino, di (ClC4) alkylamino, CI-C4-alkoxy, carboxyl, halo and sulfo radicals. The substituents specially preferred for the nitrogen and carbon atoms of the ring are the CI-C6-alkyl and especially methyl radicals.



   In the preferred embodiment described above, preference is given to compounds in the formula of which A represents a radical -CH) *, where n represents 1 or 2 and more especially to those in the formula of which A represents a radical -CH2 - and moreover (a) Ri and R8, taken together, represent a radical

  <Desc / Clms Page number 44>

 
 EMI44.1
 or (b) R8 represents a hydrogen atom and Rl represents
 EMI44.2
 smells of a hydrogen atom or a CH3CH2- 'radical
 EMI44.3
 CH3 CH3 OH OH -cl-, t- HCH3 / CH3 /
 EMI44.4
 Particularly preferred compounds are those in the formula of which R8 represents a hydrogen atom and Ri represents a radical
 EMI44.5
 and more especially the compounds having the absolute configuration 5R, 6S, 8R.



   According to a preferred embodiment, the radical
 EMI44.6
 is an aromatic pentagonal or hexagonal nitrogen heterocyclic radical comprising 0 to 3 additional heteroatoms chosen from 0, S and N. This aromatic heterocycle may, when possible, be condensed with another ring which may be a saturated or unsaturated carbocycle and preferably a C4-C7 carbocycle, an aromatic carbocycle and preferably a phenyl ring, a square heterocycle with

  <Desc / Clms Page number 45>

 heptagonal (saturated or unsaturated) comprising 1 to 3 heteroatoms chosen from 0, S, N or NRll, where Rll represents
 EMI45.1
 feels a hydrogen atom or a C1-C6-alkyl p radical optionally substituted by 1 or 2 substituents chosen independently from the radicals -OR3, -NR3R4, - C02R3, oxo, phenyl,

   fluoro, chloro, bromo, -S03R3 and - CONR3R4, or a phenyl radical optionally substituted with 1 to 3 substituents chosen independently from
 EMI45.2
 the radicals C1-C6-alkyl, -OR3, -NR3R4, fluoro, chloro, bromo, and R4 in these substituents R11 being defined as above with respect to the substituent RI, or a heteroaromatic radical pentagonal or hexagonal comprising 1 to 3 hetero -
 EMI45.3
 atoms chosen from 0, S and N or NRl, where RIl is as defined above.

   The quaternized pentagonal or hexagonal aromatic ring or, as the case may be, the carbocyclic, heterocyclic or heteroaromatic ring condensed on this first ring or else the two rings may optionally be substituted on available ring atoms by substituents, in a total number preferably maximum of five for the whole ring system, which are the substituents mentioned above about the radical
 EMI45.4
 
In this preferred embodiment described above, preference is given to compounds in the formula of which A represents a radical -CH2) n- where n represents 1 or 2 and more especially to those in the formula of which A represents a radical -CH2 - and moreover (a) RI and R8, taken together, represent a radical

  <Desc / Clms Page number 46>

 
 EMI46.1
 or (b)

   R8 represents a hydrogen atom and RI represents a hydrogen atom or a CH3CH2- 'radical
 EMI46.2
 CH3 CHg CH3 OH OH '1 1 CH-, C- or CH3
 EMI46.3
 Particularly preferred compounds are those in the formula of which R8 represents a hydrogen atom and Ri represents a radical
 EMI46.4
 and more especially the compounds having the absolute configuration 5R, 6S, 8R.



   According to another preferred embodiment, the invention relates to the compounds of formula I, where
 EMI46.5
 represents a radical chosen from
 EMI46.6
 

  <Desc / Clms Page number 47>

 where R6, R7 and RIO are independently selected from the hydrogen atom and the C1-C4-alkyl radicals; Cl-C4-alkyl substituted by preferably 1 to 3 hydroxyl radicals, Cl-C4-alkylamino, di (Cl-C4-alkyl) amino,
 EMI47.1
 0 Cl-C4-alkoxy, amino, sulfo, carboxyl and halogen (chloro, bromo, fluoro or iodo; preferably chloro, fluoro or bromo); C3-C6-cycloalkyl Cl-C4-alkoxy Cl-C4-alkylthio amino Cl-C4-alkylamino di (Cl-C4-alkyl) amino; halo (chloro, bromo, fluoro or iodo; preferably chloro, fluoro or bromo);

   Cl-C4alkanoylamino; C1-C4-alkanoyloxy; carboxyl; -C02-Cl-C4-alkyl; hydroxyl; amidino; guanidino; phenyl, phenyl substituted by one, two or three amino radicals, halo (chloro, bromo, fluoro or iodo; preferably chloro, fluoro or bromo), hydroxyl, trifluoromethyl;

   Cl-C4-alkyl or C1-C4-alkoxy; phenyl (Cl-C4) alkyl in which the phenyl part can optionally be substituted by 1 to 3 radicals mentioned above with respect to the phenyl radical and the alkyl part can optionally be substituted with 1 to 3 substituents mentioned above with respect to the radicals Cl-C4-alkyl;

   and heteroaryl or heteroaralkyl in which the heteroatom (s) in the aforementioned heterocyclic parts are chosen from 1 to 4 oxygen, nitrogen or sulfur atoms and the alkyl part associated with the heteroaralkyl part has 1 to 6 carbon atoms, or else where two of R6, R7 and R10, taken together, can represent a condensed saturated carbocyclic radical, a condensed aromatic carbocyclic radical, a condensed non-aromatic heterocyclic radical or a condensed heteroaromatic radical, which condensed rings are optionally substituted by 1 or 2 substituents defined above with respect to R6, R7 and RIO;

  <Desc / Clms Page number 48>

 
 EMI48.1
 r, -5 He (b); ".



  X 1 1 p: 1 1 1 N1 N '= N 1 N optionally substituted on a carbon atom by 1 to 3 substituents chosen independently from the C1-C4-alkyl radicals; Ci-C4-alkyl substituted by preferably 1 to 3 hydroxyl radicals, Cl-C4-alkylamino, di (Cl-C4) alkylamino, Cl-C4-alkoxy, amino, sulfo, carboxyl and halo (chloro, bromo, fluoro or iodo ; preferably chloro, fluoro or bromo); C3-C6-cycloalkyl; Cl-C4-alkoxy; Cl-C4-alkylthio; amino; Cl-C4-alkyllamino; di (Cl-C4-alkyl) amino; halo (chloro, bromo, fluoro or iodo; preferably chloro,
 EMI48.2
 fluoro or bromo); Ci-C-alkanoyIamino; CI-C4alkanoyloxy; carboxyl; ; hydroxyl;

   Q amidino; guanidino; phenyl, phenyl substituted by one, two or three amino radicals, halo (chloro, bromo, fluoro or iodo; preferably chloro, fluoro or bromo), hydroxyl, trifluoromethyl; Cl-C4-alkyl or Cl-C4alkoxy; phenyl (Cl-C4) alkyl in which the phenyl part can optionally be substituted by 1 to 3 substituents mentioned above with respect to the phenyl radical and the alkyl part can optionally be substituted by 1 to 3 substituents mentioned above with respect to the radicals Cl-C4-alkyl and heteroaryl or heteroaralkyl in which the heteroatom (s) in the aforementioned heterocyclic parts are chosen from 1

  <Desc / Clms Page number 49>

 with 4 oxygen atoms,

   of nitrogen or sulfur and the alkyl part associated with the heteroaralkyl part has 1 to 6 carbon atoms, or optionally substituted to form a condensed carbocyclic, heterocyclic or heteroaromatic radical optionally substituted by
 EMI49.1
 1 or 2 of the substituents defined above;
 EMI49.2
 (c) ^ NÌl NO? ' N ', ¯5 or ,, K N
 EMI49.3
 optionally substituted on an atom by 1 or 2 substituents chosen independently from the Ci-C-alkyl radicals; Ci-C -alkylIe substituted by preferably 1 to 3 hydroxyl radicals, Cl-C4-alkylamino, di (Cl-C4) alkylamino, Cl-C4-alkoxy, amino, sulfo, carboxyl and halo (chloro, bromo, fluoro or iodo ; preferably chloro, fluoro or bromo); C3-C6-cycloalkyl; C1-C4-alkoxy;

   C1-C4-alkylthio; amino; Cl-C4-alkyllamino; di (CI-C4-alkyl) amino; halo (chloro, bromo, fluoro or iodo; preferably chloro, fluoro or bromo); Cl-C4-alkanoylamino; Cl-C4alkanoyloxy: carboxyl; -CO2-C1-C4-alkyl; hydroxyl; amidino; guanidino; phenyl, phenyl substituted by one, two or three amino or halo radicals (chloro, bromo, fluoro or iodo; preferably chloro, fluoro or bromo),

  <Desc / Clms Page number 50>

 hydroxyl, trifluoromethyl;

   Cl-C4-alkyl or Cl-C4-
 EMI50.1
 e alkoxy; phenyl (Cl-C4) alkyl in which the phenyl part can optionally be substituted by 1 to 3 substituents mentioned above with respect to the phenyl radical and the alkyl part can optionally be substituted by 1 to 3 substituents mentioned above with respect to the radicals Cl-C4-alkyl and heteroaryl or heteroaralkyl in which the heteroatom (s) in the aforementioned heterocyclic parts are chosen from 1 to 4 atoms of oxygen, nitrogen or sulfur and the alkyl part associated with the heteroaralkyl part has 1 to 6 atoms of carbon, or optionally substituted to form a condensed carbocyclic, heterocyclic or heteroaromatic radical optionally substituted by
 EMI50.2
 1 to 2 of the substituents defined above;
 EMI50.3
 or '6; .



  N W'Q 'N e N / N / ¯5' '"-L' N
 EMI50.4
 optionally substituted on a carbon atom by 1 substituent chosen independently from the radicals 1 -'CI-C4-alkyl Cl-C4-alkyl substituted by preferably 1 to 3 hydroxyl radicals, Cl-C4-alkylamino, di {CI-C4- alkyl) amino, CI-C4-alkoxy, amino, sulfo, carboxyl and halo (chloro, bromo, fluoro or iodo;

  <Desc / Clms Page number 51>

 preferably chloro, fluoro or bromo); C3-C6-cycloalkyl; Cl-C4-alkoxy; Cl-C4-alkylthio; amino; Cl-C4-alkyllamino; di (Cl-C4-alkyl) amino; halo (chloro, bromo, fluoro or iodo; preferably chloro, fluoro or bromo); Cl-C4-alkanoylamino;

   Cl-C4alkanoyloxy; carboxyl; -C02-Cl-C4-alkyl; hydroxyl; amidino; guanidino; phenyl, phenyl substituted by one, two or three amino radicals, halo (chloro, bromo, fluoro or iodo; preferably chloro, fluoro or bromo), hydroxyl, trifluoromethyl; Cl-C4-alkyl or Cl-C4alkoxy; phenyl (Cl-C4) alkyl in which the phenyl part can optionally be substituted by 1 to 3 substituents mentioned above with respect to the phenyl radical and the alkyl part can optionally be substituted by 1 to 3 substituents mentioned above with respect to the radicals Cl-C4-alkyl;

   and heteroaryl or heteroaralkyl in which the heteroatom (s) in the aforementioned heterocyclic parts are chosen from 1 to 4 oxygen, nitrogen or sulfur atoms and the alkyl part associated with the heteroaralkyl part has 1 to 6 carbon atoms;
 EMI51.1
 (e) zo e, J v ou ou 1 dl.
 EMI51.2
 where X represents 0, S or NR where R represents a radical or Cl-C4-alkyl; C1-C4-alkyl substituted by 1 to 3 hydroxyl, amino, Ci-C-alkylamino radicals; di (Cl-C4) alkylamino; Cl-C4-alkoxy; carboxyl; halo or
 EMI51.3
 sulfo; C3-C6-cycloalkyl;

   C3-C6-cycloalkyl (ClC4) alkyl optionally substituted with 1 to 3 substituents mentioned above in connection with the CiC4-alkyl radicals; phenyl; phenyl substituted with 1 to 3 sub-

  <Desc / Clms Page number 52>

 stituants independently selected from amino, halogen, hydroxyl, trifluoromethyl, C1-C4alkyl, C1-C4-alkoxy, C1-C4-alkylamino, di (C1-C4) -alkylamino, carboxyl and sulfo radicals; phenyl (Cl-C4) alkyl in which the phenyl part may optionally be substituted with 1 to 3 substituents mentioned above with respect to the phenyl radical and in which the alkyl part may optionally be substituted with 1 to 3 substituents mentioned above in connection with the radical C1-C4-alkyl radicals;

   and heatheraryl and heteroaralkyl in which the heteroatom (s) are chosen from 1 to 4 atoms 0, S or N and the alkyl part associated with the heteroaralkyl radical has 1 to 6 carbon atoms, these heteroaryl and heteroaralkyl radicals being optionally substituted in the heterocyclic part by 1 to 3 substituents independently chosen from hydroxyl, amino, halo, trifluoromethyl, C1-C4-alkyl, C1-C4-alkoxy, C1-C4-alkylamino, di (C1-C4) - alkylamino, carboxyl and sulfo radicals, and in the alkyl part with 1 to 3 substituents chosen from hydroxyl, amino, Cl-C4-alkylamino, di (ClC4) alkylamino, Cl-C4-alkoxy, carboxyl, halo and sulfo radicals,

   this radical being optionally substituted on a carbon atom by 1 or more substituents chosen independently from C1-C4-alkyl radicals; Cl-C4-alkyl substituted by preferably 1 to 3 hydroxyl radicals, Cl-C4-alkylamino, di (Cl-C4-alkyl) amino, Cl-C4-alkoxy, amino, sulfo, carboxyl or halo (chloro, bromo, fluoro or iodo; preferably chloro, fluoro or bromo); C3-C6-cycloalkyl;

   Cl-C4-alkoxy; Cl-C4-alkylthio, amino; Cl-C4-alkyllamino; di (Cl-C4-alkyl) amino; halo (chloro, bromo, fluoro or iodo; preferably chloro, fluoro or bromo); Cl-C4-alkanoylamino; Cl-C4-alkanoyloxy; carboxyl; -CO-C1-C4-alkyl; hydroxyl; amidino; guanidino; phenyl;

  <Desc / Clms Page number 53>

 phenyl substituted by one, two or three amino, halo (chloro, bromo, fluoro or iodo; preferably chloro, fluoro or bromo), hydroxyl, trifluoromethyl radicals;

   Cl-C4-alkyl or Cl-C4-alkoxy; phenyl (Cl-C4) alkyl, the phenyl part of which can optionally be substituted with 1 to 3 substituents mentioned above with respect to the phenyl radical and the alkyl part of which can optionally be substituted with 1 to 3 substituents mentioned above with respect to the phenyl radicals ClC4-alkyl radicals; and heteroaryl and heteroaralkyl J in which the heteroatom (s) of the above-mentioned heterocyclic parts are chosen from 1 to 4 oxygen, nitrogen or sulfur atoms and the alkyl part associated with the heteroaralkyl part has 1 to 6 carbon atoms, or optionally substituted to form a fused carbocyclic, heterocyclic or heteroaromatic radical optionally substituted by 1 or 2 of
 EMI53.1
 substituents defined above;

   
 EMI53.2
 or K ---- X X .----- ,, ---- K-R rrUe \ 1 e X!) "N

  <Desc / Clms Page number 54>

 where X represents 0, S or NR where R represents a Cl-C4-alkyl radical; Cl-C4-alkyl substituted by 1 to 3 hydroxyl, amino, Cl-C4-alkylamino radicals; di (Cl-C4-alkyl) amino; Cl-C4-alkoxy; carboxyl; halo or sulfo; C3-C6-cycloalkyl;

   C3-C6-cycloalkyl (C1-C4) alkyl optionally substituted with 1 to 3 substituents mentioned above with respect to the C1-C4-alkyl radicals; phenyl; phenyl substituted with 1 to 3 substituents independently chosen from amino, halo, hydroxyl, trifluoromethyl, Cl-C4-alkyl, Cl-C4-alkoxy, Ci-C-alkylamino, di (C1-C4) alkylamino, carboxyl and sulfo radicals; phenyl (Cl-C4) alkyl, the phenyl part of which can optionally be substituted with 1 to 3 substituents mentioned above with respect to the phenyl radical and the alkyl part of which can optionally be substituted with 1 to 3 substituents mentioned above with respect to the phenyl radicals ClC4-alkyl radicals;

   and weatheraryl and heteroaralkyl in which the heteroatom (s) are chosen from 1 to 4 atoms 0, S or N and the alkyl part associated with the heteroaralkyl radical has 1 to 6 carbon atoms, these heteroaryl and heteroaralkyl radicals being optionally substituted in the heterocyclic part by 1 to 3 substituents independently chosen from hydroxyl, amino, halo, trifluoromethyl, ClC4-alkyl, Cl-C4-alkoxy, C1-C4-alkylamino, di (Cl-C4) - alkyllamino, carboxyl and sulfo radicals, and in the part alkyl with 1 to 3 substituents chosen from hydroxyl, amino, Cl-C4-alkylamino, di (ClC4) alkylamino, Cl-C4-alkoxy, carboxyl, halo and sulfo radicals;

   this heteroaromatic radical being optionally substituted on a carbon atom by a substituent chosen from C1-C4-alkyl radicals; Cl-C4-alkyl substituted by preferably 1 to 3 hydroxyl radicals, Ci-C-alkylamino, di (Cl-C4-alkyl) amino, CI-C4-alkoxy,

  <Desc / Clms Page number 55>

 amino, sulfo, carboxyl or halo (chloro, bromo, fluoro or iodo; preferably chloro, fluoro or bromo); C3-C6-cycloalkyl;

   Cl-C4-alkoxy; Cl-C4-alkylthio, amino; Cl-C4-alkyllamino; di (Cl-C4-alkyl) amino; halo (chloro, bromo, fluoro or iodo; preferably chloro, fluoro or bromo); Cl-C4-alkanoylamino; C1-C4-alkanoyloxy; carboxyl; -CO2-C1-C4-alkyl; hydroxyl; amidino; guanidino; phenyl; phenyl substituted by one, two or three amino, halo (chloro, bromo, fluoro or iodo; preferably chloro, fluoro or bromo), hydroxyl, trifluoromethyl radicals; Cl-C4-alkyl or Cl-C4alkoxy;

   phenyl (Cl-C4) alkyl, the phenyl part of which can optionally be substituted with 1 to 3 substituents mentioned above with respect to the phenyl radical and the alkyl part of which can optionally be substituted with 1 to 3 substituents mentioned above with respect to the phenyl radicals Cl-C4-alkyl radicals; and heteroaryl and heteroaralkyl in which the heteroatom (s) of the abovementioned heterocyclic parts are chosen from 1 to 4 oxygen, nitrogen or sulfur atoms and the alkyl part associated with the heteroaralkyl part has 1 to
 EMI55.1
 6 carbon atoms; and
 EMI55.2
 (g) e N '-1 "Í. M.. -R N-P.



  T) 'K ---- K-R -H ---- K-R ---- K-R 1 6 T

  <Desc / Clms Page number 56>

 
 EMI56.1
 where R represents a C-C-alkyl-C1-C4-alkyl radical substituted by 1 to 3 hydroxyl, amino, Ci-C4alkylamino radicals; dKC-calcoyIamino -alkoxy carboxyl; halo or sulfo; C3-C6-cycloalkyl; C3C6-cycloalkyl (CI-C4) alkyl optionally substituted with 1 to 3 substituents mentioned above with respect to the C-c-alkyl radicals; phenyl; phenyl substituted with 1 to 3 substituents independently selected from amino, halo, hydroxyl, trifluoromethyl, Cl-C4-alkyl, Cl-C4-alkoxy, Cl-C4-alkylamino, di (Cl-C4) alkylamino, carboxyl and sulfo radicals;

   phenyl (Cl-C4) - alkyl in which the phenyl part can optionally be substituted by 1 to 3 substituents mentioned above with respect to the phenyl radical and in which the alkyl part can optionally be substituted by 1 to 3 substituents mentioned above in connection with the radical C1-C4-alkyl radicals;

   and heatheraryl and heteroaralkyl in which the heteroatom (s) are chosen from 1 to 4 atoms 0, S or N and the alkyl part associated with the heteroaralkyl radical has 1 to 6 carbon atoms, these heteroaryl and heteroaralkyl radicals being optionally substituted in the heterocyclic part by 1 to 3 substituents independently chosen from hydroxyl, amino, halo, trifluoromethyl, Cl-C4-alkyl, Cl-C4-alkoxy, Cl-C4-alkylamino, di (CI-C4) - alkyllamino, carboxyl and sulfo radicals, and in the alkyl part with 1 to 3 substituents chosen from hydroxyl, amino, C1-C4-alkylamino, di (C1-C4) alkylamino, C1-C4-alkoxy, carboxyl, halo and sulfo radicals.

   The radicals R and R5 can also be taken together to form a condensed heterocyclic or heteroaromatic radical.



   In the preferred embodiment described above, preference is given to compounds in the formula of which A represents a radical - (CH) - where n

  <Desc / Clms Page number 57>

 represents 1 or 2 and more specifically to those in the
 EMI57.1
 formula of which A represents a radical plus (a) Ri and R8, taken together, represent a radical
 EMI57.2
 
 EMI57.3
 or (b) R8 represents a hydrogen atom and Ri represents a hydrogen atom or a CHgCH 'radical
 EMI57.4
 CH3 CH3 OH OH 1 1 CH-, CH3 CH3
 EMI57.5
 Particularly preferred compounds are those in the formula of which R8 represents a hydrogen atom and Ri represents a radical
 EMI57.6
 and more especially the compounds having the absolute configuration 5R, 6S, 8R.



   According to a particularly preferred embodiment, the invention relates to the compounds of formula I where
 EMI57.7
 represents a radical of formula

  <Desc / Clms Page number 58>

 
 EMI58.1
 
 EMI58.2
 where R6, R7 and RIO are independently chosen from hydrogen atoms and C-C-alkyl radicals, -
CC4-alkoxy, carboxyl and carbamoyl and R5 is as defined above and is preferably a C1-C6-alkyl and more preferably-CHg radical.



   In the preferred embodiment described above, preference is given to compounds where A represents a radical- (C112) n- where n represents 1 or 2 and more especially to those in the formula of which A represents a radical -CH2- and moreover (a) Rl and R, taken together, represent a radical
 EMI58.3
 
 EMI58.4
 or (b) R8 represents a hydrogen atom and RI represents a hydrogen atom or a CH3CH2- radical,
 EMI58.5
 CH3 CH3 OH OH '' CH-, CH3 / 'CH3 /'
 EMI58.6
 Particularly preferred compounds are those in the formula of which RS represents a hydrogen atom and Ri represents a radical

  <Desc / Clms Page number 59>

 
 EMI59.1
 and more especially the compounds having the absolute configuration 5R, 6S, 8R.



   According to another preferred embodiment -
 EMI59.2
 The object of the invention is the compounds of formula I where
 EMI59.3
 
 EMI59.4
 represents a radical of formula
 EMI59.5
 
 EMI59.6
 where R5 represents a C1-C4-alkyl radical, preferably methyl, and R6 represents a hydrogen atom or a C1-C4-alkyl radical;
 EMI59.7
 where R5 represents a C1-C4-alkyl radical preferably
 EMI59.8
 e and R7 1 methyl and R6 represent hydrogen atoms m or Cl-C4-alkyl radicals;

  <Desc / Clms Page number 60>

 
 EMI60.1
    and R7 where R5 represents a Cl-C4-alkyl radical, preferably methyl, and R represents a Cl-C4-alkyl or phenyl (Cl-C4) alkyl radical;

   
 EMI60.2
 where R5 represents a Cl-C4-alkyl radical, preferably methyl, and R6 represents a Cl-C4alkyl radical, preferably methyl;
 EMI60.3
 where R5 represents a Cl-C4-alkyl radical, preferably methyl, and R represents a Cl-C4alkyl radical, preferably methyl; or
 EMI60.4
 

  <Desc / Clms Page number 61>

 where R5 represents a Cl-C4-alkyl radical, most advantageously a methyl radical.



   In the preferred embodiment described above, preference is given to compounds in the formula of which A represents a radical- (CH) -where n represents 1 or 2 and more especially to those in
 EMI61.1
 formula which A represents a radical -CH- and further (a) Rl and R8, taken together, represent a radical
 EMI61.2
 
 EMI61.3
 or (b) R8 represents a hydrogen atom and Ri represents a hydrogen atom or a CH3CH2- radical,
 EMI61.4
 CH3 CH3 OH OH - ,, CH-, C- or CH3CHCH3 / '"
 EMI61.5
 Particularly preferred compounds are those in the formula of which R3 represents a hydrogen atom and RI represents a radical
 EMI61.6
 and more especially the compounds having the absolute configuration 5R, 6S, 8R.



   According to an especially preferred embodiment, the invention relates to the compounds of formula I, where

  <Desc / Clms Page number 62>

 
 EMI62.1
 represents a radical of formula
 EMI62.2
 

  <Desc / Clms Page number 63>

 
 EMI63.1
 CH (i) - <N CH3 \\ J N-- 'el CH3) \ c6 -L = H H3 "3 L 3 CH3 N or \ S-K-- 1
 EMI63.2
 In the preferred embodiment described above, preference is given to the compounds in the formula of which A represents a radical n "" represents 1 or 2 and more especially to those in the formula of which A represents a radical -CH "st of plus (a) Ri and R8, taken together, represent a radical
 EMI63.3
 

  <Desc / Clms Page number 64>

 
 EMI64.1
 or (b)

   R8 represents a hydrogen atom and Ri represents a hydrogen atom or a CH3CH2- 'radical
 EMI64.2
 CH3 CH3 OH OH 1 1 or CH3
 EMI64.3
 Particularly preferred compounds are those in the formula of which RS represents a hydrogen atom and Ri represents a radical
 EMI64.4
 and more especially the compounds having the absolute configuration 5R, 6S, 8R.



   Specific compounds in accordance with the invention are those of formula:
 EMI64.5
 where R2 represents a hydrogen atom, an anionic charge or a conventional radical which is easy to remove protective of the carboxyl function, it being understood that when R2 represents a hydrogen atom or a protective radical, a counterion is also present and where

  <Desc / Clms Page number 65>

 
 EMI65.1
 - R5 -R is (a) -SCH2 raw '3 // \\ - \ (c) -SCH-' 3 ciq.



  N cw (e) -SCH - '\ - CHHH CH cw- \' 'r 7 (g) -SCH-) - H3 CH,

  <Desc / Clms Page number 66>

 
 EMI66.1
 where the 1 H NMR spectrum (D20) presents the characteristic peaks at 6: 1.23 (3H, d, J = 6.4 Hz), 3.12 (2H, q, J = 1, 4, 8.9 Hz), 3.39 (1H, q, J = 2.7, 6.0 Hz), 4.07-4, 68 (10H,

  <Desc / Clms Page number 67>

 
 EMI67.1
 m), 8, 19 (1H, s);
 EMI67.2
 
 EMI67.3
 where the 1 H NMR spectrum (D20) presents the characteristic peaks at 6: 1, 23 (3H, d, J = 6, 4 Hz), 3.15 (2H, q, J = 3, 7, 9, 0 Hz), 3.37 (1H, q, J = 2.6, 0.6Hz), 3.95-4.65 (10H, m), 8.62 (1H, s);

   
 EMI67.4
 6 COO coo6 s-C 'CH CH.,' E CH (SCH q coo e \ - N-CHCOO N-N or CH 3 CH, IH3 N'-N (viz a% -n
 EMI67.5
 According to an embodiment specially

  <Desc / Clms Page number 68>

 
 EMI68.1
 preferred, the subject of the invention is the compounds of formula I, where
 EMI68.2
 
 EMI68.3
 represented
 EMI68.4
 
 EMI68.5
 In the preferred embodiment described above, preference is given to compounds in the formula of which A represents a radical ") - one represents 1 or 2 and more especially to those in the formula of which A represents a radical -CH- and of plus (a) RI and R8, taken together, represent a radical
 EMI68.6
 
 EMI68.7
 or (b) R8 represents a hydrogen atom and Rl represents a hydrogen atom or a CH3CH2- radical,

   
 EMI68.8
 CH3 CH3 OH OH 1 C- or CHCH3 / CH3 /
 EMI68.9
 Particularly preferred compounds are those in

  <Desc / Clms Page number 69>

 the formula of which RB represents a hydrogen atom and RI represents a radical
 EMI69.1
 and more especially the compounds having the absolute configuration 5R, 6S, 8R.



   The carbapenem derivatives of general formula I are prepared from compounds of formula:
 EMI69.2
 where R1, R8 and R15 are as defined above and R2 ′ represents a conventional radical which is easy to remove, protective of the carboxyl function. Compounds of formula III have already been described, for example in European patent application 38869 (compound 7) and in European patent application 54917, and can be obtained according to the general methods which are described therein.



   The process for preparing the compounds of formula I from the compounds of formula III can be summarized by the following reaction scheme:
 EMI69.3
 

  <Desc / Clms Page number 70>

 
 EMI70.1
 Z R L L == classical labile radical IV R8 R15 l-N ') -' 'il Rl5 R') Rl) ll '' - ---------- COOR '' 0 8 R8 1 N N OOR2 1

  <Desc / Clms Page number 71>

 
 EMI71.1
 A variant of the above process is illustrated by the following reaction scheme:
 EMI71.2
 R / R H -T-- 'IV IV IV RB -A) protection - 0 "COOR- - R8 R'.



  Rl ..---- "". --- A-- "! OOH lia R R '.



  N f coo Ia la la
 EMI71.3
 For the conduct of the above process, the

  <Desc / Clms Page number 72>

 starting compound III is reacted in an inert organic solvent such as methylene chloride, acetonitrile or dimethylformamide with an approximately equimolar amount of an RO-L reagent such as p-toluenesulfonic anhydride, p -nitrobenzenesulfonic, 2,4,6-triisopropylbenzenesulfonic, methanesulfonic or trifluoromethanesulfonic, diphenyl chlorophosphate, toluenesulfonyl chloride, p-bromobenzenesulfonyl chloride, etc., where L represents the corresponding labile radical such as toluenesulfonyloxy, nitrobenzenesulfonyloxy or diphenoxyphosphinyloxy or other well-known labile radicals provided in a conventional manner.

   The reaction fixing the labile radical in position 2 of intermediate III is advantageously carried out in the presence of a base such as diisopropylethylamine, triethylamine, 4-dimethylaminopyridine, etc., at a
 EMI72.1
 temperature of approximately at +40 ° C., and more advantageously of approximately O * C. The labile radical L of intermediate compound III can also be a halogen, in which case the radical is provided by reaction of intermediate III with a halogenating agent such as 3PC12 '03PBr2, (0) 3PBr2, (COOC1) 2, etc. ., in a solvent such as CHCl, CH CN, THF, etc., in the presence of a base such as diisopropylethylamine, triethylamine, 4-dimethylaminopyridine, etc.

   Intermediate IV can be isolated, if desired, but is advantageously carried out at the next stage without isolation or purification.



   Intermediate IV is then converted to intermediate II by a standard displacement reaction. Intermediate IV can thus be reacted with approximately an equimolar amount of a heteroalkyl mercaptan of formula:

  <Desc / Clms Page number 73>

 
 EMI73.1
 where A represents a Ci-c-alkylene radical in a straight or branched chain, and
 EMI73.2
 represents a heterocyclic aromatic mono-, bi- or polycyclic radical containing a nitrogen atom quaternizable in the ring, the ring being united to the radical A by a carbon atom of this ring, in an inert organic solvent such as dioxane, dimethylformamide, dimethylsulfoxide or acetonitrile and in the presence of a base such as diisopropylethylamine, triethylamine, sodium hydrogencarbonate,

   potassium carbonate or 4-dimethylaminopyridine. The temperature for the displacement reaction is not critical, but is advantageously around -40 C
 EMI73.3
 at +25 C. Very advantageously, the reaction is carried out under cooling, for example from about 0 C to - 10 C.



   The quaternization of the ring nitrogen in the heteroaralkyl radical of intermediate II is carried out by reaction of intermediate II in an inert organic solvent with an amount at least equivalent (up to a molar excess of approximately 50%) an alkylating agent of formula:

  <Desc / Clms Page number 74>

 where R5 is as defined above and X'represents a conventional labile radical such as halo (chloro, bromo or iodo, but preferably iodo) or a sulphonic ester radical such as mesylate, tosylate or triflate. Examples of suitable inert organic solvents are chloroform, methylene chloride, tetrahydrofuran, dioxane, acetone, dimethyl sulfoxide and dimethylformamide.

   The temperature for the alkylation reaction is not critical and temperatures of about 0 ° C to 40 ° C are preferred. Most advantageously, the reaction is carried out at room temperature.



   The intermediary I'inc includes a counter ion X '(for example from the alkylating agent used) which is associated with it and which, at this stage or at a later stage, that is to say after the stage deprotection, can be replaced by a different counter ion, for example a pharmaceutically more acceptable counter ion, according to conventional techniques. Alternatively, the counter ion can be removed later during the deprotection stage.



   The deprotection stage aimed at eliminating the radical R2 ′ protecting the carboxyl function of the intermediate I is carried out according to conventional techniques such as solvolysis, chemical reduction or hydrogenation. When the protective radical used is eliminable by catalytic hydrogenation, such as a p-nitrobenzyl, benzyl, benzhydryl or 2naphthylmethyl radical, the intermediates it in a suitable solvent such as dioxane-water-ethanol, tetrahydrofuran-hydrogen dipotassium aqueous phosphate propanol or a similar solvent can be reacted under a hydrogen pressure of 1 to 4 atmospheres in the presence of a hydrogenation catalyst such as palladium on carbon, palladium hydroxide, oxide

  <Desc / Clms Page number 75>

 platinum, etc.,

   at a temperature of 0 to 50 C for about 0.24 to 4 hours. When R2 is a radical such as the o-nitrobenzyl radical, photolysis is also suitable for deprotection. Protective radicals such as the 2,2,2-trichloroethyl radical can be removed by moderate reduction using zinc.



  The protective allyl radical can be removed using a catalyst comprising a mixture of a palladium compound and triphenylphosphine in an aprotic solvent such as tetrahydrofuran, diethyl ether or methylene chloride. Similarly, other conventional radicals which protect the carboxyl function can be removed according to methods well known to the specialist. Finally, as already indicated, the compounds of formula where R2 ′ represents a physiologically hydrolyzable ester radical such as acetoxymethyl, phthalidyl, indanyl, pivaloyloxymethyl, methoxymethyl, etc., can be administered directly to the host without deprotection, because these esters are hydrolyzed in vivo under physiological conditions.



   It should be noted that when the substituent R1, R8, R5 or R15 or the heteroaromatic radical united with the substituent A contains a functional radical which could interfere with the desired course of the reaction, this radical can be protected using a blocking or conventional protection radical and then be deprotected for the restoration of the desired functional radical. Suitable protective groups and methods for introducing and removing them are well known to those skilled in the art.



   According to a variant of the above process, the protective radical of the carboxyl function in intermediate II can be removed before the quaternization. So the protective radical of the function

  <Desc / Clms Page number 76>

 carboxyl is removed as described above to give rise to the corresponding free carboxylic acid and the latter is then quaternized using the alkylating agent R-X 'to yield the desired quaternized product of formula I. For the quaternization of the deprotected intermediate 11a, the solvent can be water or a non-reactive organic solvent or a mixture of these.

   Examples of suitable solvents are water, organic solvents such as chloroform, methylene chloride, tetrahydrofuran, dioxane, acetone, dimethyl sulfoxide and dimethylformamide, in addition to mixtures of water and organic solvent such as water-acetone or water-dimethylformamide mixtures. The temperature for the quaternization of intermediate 11a is not critical and temperatures of about -40 ° C to room temperature are suitable. Most advantageously, the reaction is carried out at about 0 C.



   When the deprotected intermediate 11a is obtained in the form of a saline carboxylate, it is desirable to add a strong acid such as toluenesulfonic acid to form the free carboxylic acid before the quaternization. This has been found to greatly facilitate preferential quaternization of cycle nitrogen.



   The operating variant described above is especially useful when the protective radical of the carboxyl function is more easily removed from the non-quaternized intermediate II than from the quaternized intermediate. For example for the preparation of the product of formula:

  <Desc / Clms Page number 77>

 
 EMI77.1
 from the formula intermediary:
 EMI77.2
 the elimination of the protective allyl radical before the quaternization significantly improves the yield of the desired final product.



   The process described above lends itself to the preparation of the compounds of the invention, but a new process applicable to the preparation of the compounds of formula I has also been discovered. This other
 EMI77.3
 process described below and in the examples. process
According to the other process for preparing the compounds of formula I, an intermediate of formula:
 EMI77.4
 
 EMI77.5
 N where RI, R8 and R15 are as defined above, Rice is a classic radical easy to remove protective

  <Desc / Clms Page number 78>

 of the carboxyl function and L is a conventional labile radical such as toluenesulfonyloxy, p-nitrobenzenesulfonyloxy, diphenoxyphosphinyloxy or halo, is
 EMI78.1
 reacted with a thiol of formula:

   
 EMI78.2
 
 EMI78.3
 where A and
 EMI78.4
 
 EMI78.5
 are as defined above and xO represents a
 EMI78.6
 against ion, in an inert solvent and in the presence of a base for the formation of a carbapenem of formula:
 EMI78.7
 where Ri, R8, R2 ', A, R15
 EMI78.8
 and XC) are as defined above and, if desired, the radical R2 'protecting the function

  <Desc / Clms Page number 79>

 carboxyl is eliminated for the formation of the corresponding deprotected compound of formula I, or of a pharmaceutically acceptable salt of this compound.



   This other process uses the intermediate of formula:
 EMI79.1
 which, as already indicated, is described for example in European patent applications 38869 and 54917 and which can be obtained according to the general methods which are described therein. L represents a conventional labile radical (defined as "X" in European patent application 38869) for example chloro, bromo, iodo, benzenesulfonyloxy, p-toluenesulfonyloxy, p-nitrobenzenesulfonyloxy, methanesulfonyloxy, trifluoromethanesulfonyloxy, diphenoxyphosphinyloxy or di (trichloro) phosphinyloxy. The preferred protective radical is the diphenoxyphosphinyloxy radical.



   The intermediates of formula IV are generally formed in situ by reaction of an intermediate of formula:
 EMI79.2
 

  <Desc / Clms Page number 80>

 where Ri, R8, R15 and R2 'are as defined above, with an appropriate RO-L acylating agent.

   The preferred intermediate IV where L represents a diphenoxyphosphinyloxy radical can be obtained by reaction of a ketoester III in an inert organic solvent, such as methylene chloride, acetonitrile or dimethylformamide, with an approximately equimolar amount of chlorophosphate diphenyl in the presence of a base such as diisopropylethylamine, triethylamine, 4-dimethylaminopyridine, among others, at a temperature of about -20 C to + 400C and more preferably about 0 C. Intermediate IV can be isolated, if desired, but is usually used as a starting material for the other synthetic process without having been isolated or purified.



   Carbapenem intermediate IV is set to
 EMI80.1
 react with a quaternary aminothiol of formula:
 EMI80.2
 From HS-A - N-R VII xe VII where e A
 EMI80.3
 is as defined above and ± one against
5anion. The reaction is carried out in an inert solvent such as acetonitrile, acetonitrile-dimethylformamide, tetrahydrofuran, tetrahydrofuran-H20, acetonitrile-H20 or acetone, in the presence of a

  <Desc / Clms Page number 81>

 based. The nature of the base is not critical. The suitable bases are in particular sodium hydroxide,
 EMI81.1
 diisopropylamine, 1, 8-diazabicycloL5, 4. o7undec-7-ene, 1, 5-diazabicyclo4. 3. Q7non-5-ene and tri (ClC4) alkylamines such as triethylamine, tributylamine or tripropylamin.

   The reaction of intermediate IV and thiol VII can be carried out over a wide temperature range, for example from -15 "C to room temperature, but is preferably carried out at a temperature of about- 15 C to +15 C and most advantageously roughly to OOC.



   The carbapenem obtained by the reaction of quaternary aminothiol VII with intermediate IV comprises an associated counter anion (for example (C6H50) 2PO-ss, CIe or the anion associated with quaternary thiol) which can be replaced at this stage by another counter anion, for example a pharmaceutically more acceptable counter anion, according to conventional techniques. Alternatively, the counter anion can be removed during the later deprotection stage. When the quaternized carbapenem and the counter anion form an insoluble product, this can be separated by crystallization as it is formed and be collected in the purity state by filtration.



   After the formation of the desired carbapenem, the radical R 2 ′ which protects the carboxyl function of the compound I'm can optionally be eliminated according to conventional techniques, such as solvolysis, chemical reduction or hydrogenation. When the protective radical used can be removed by catalytic hydrogenation, such as a p-nitrobenzyl, benzyl, benzhydryl or 2-naphthylmethyl radical, the intermediate I 'in a suitable solvent such as dioxane-water-ethanol, tetrahydrofuran-diethyl ether- buffer, dipotassium tetrahydrofuran-hydrogen phosphate

  <Desc / Clms Page number 82>

 aqueous-isopropanol or a similar solvent can be reacted under a hydrogen pressure of 1 to 4 atmospheres in the presence of a hydrogenation catalyst such as palladium on carbon,

   palladium hydroxide, platinum oxide, etc., at a temperature of 0 to 50 C for about 0.25 to 4 hours. When R2 is a radical such as the o-nitrobenzyl radical, photolysis is also suitable for deprotection.



  Protective radicals such as the 2,2,2trichloroethyl radical can be removed by moderate reduction using zinc. The protective allyl radical can be removed using a catalyst comprising a mixture of a palladium compound and triphenylphosphine in a suitable aprotic solvent such as tetrahydrofuran, diethyl ether or methylene chloride. Similarly, other conventional radicals which protect the carboxyl function can be removed according to methods well known to the specialist.

   Finally, as already indicated, the compounds of formula where R2 represents a physiologically hydrolysable ester radical such as acetoxymethyl, phthalidyl, indanyl, pivaloyloxymethyl, methoxymethyl, etc., can be administered directly to the host without deprotection because these esters are hydrolysed in vivo under physiological conditions.



   The intermediate thiols of formula VII can be prepared, for example, from the corresponding thiolacetates of formula:
 EMI82.1
 

  <Desc / Clms Page number 83>

 where A is as defined above, and
 EMI83.1
 represent a heterocyclic aromatic mono-, bi- or polycyclic radical containing a nitrogen atom which can be quaternized in the ring, which radical is joined to the radical A by a ring carbon atom.

   The thiolacetate is quaternized by reaction, in an inert organic solvent, such as diethyl ether, dichloromethane, dioxane, benzene, xylene, toluene or a mixture thereof, with an appropriate alkylating agent of formula :
 EMI83.2
 R5¯X 'where R5 is as defined above and X'represent a conventional labile radical like halo (chloro, bromo or iodo, but preferably iodo) or a sulphonic ester radical like mesylate, tosylate or triflate. The temperature for the alkylation reaction is not critical and temperatures of about 0 C to 40 C are preferred.



   Before the reaction with the intermediate carbapenem IV, the quaternized thiolacetate is subjected to an acid or basic hydrolysis which gives off the quaternary intermediate thiol VII. This hydrolysis is preferably carried out immediately before the condensation with intermediate IV in order to minimize the decomposition of the relatively unstable quaternary thiol VII.



   Thanks to the judicious choice of solvents, the reaction of intermediate III to the final product

  <Desc / Clms Page number 84>

 It can be carried out without isolating the various intermediate compounds, that is to say by a process in "a single reactor". Such a process is illustrated below by Example 22.



   As in the case of other antibiotic lactam antibiotics, the compounds of general formula I can be converted according to known techniques into pharmaceutically acceptable salts which, for the purposes of the invention, are substantially equivalent to the non-salified compounds. For example, one can dissolve a compound of formula I where R2 represents an anionic charge in a suitable inert solvent and then add an equivalent of a pharmaceutically acceptable acid. The desired acid addition salt can be isolated according to conventional techniques, for example, precipitation by a solvent, lyophilization, etc.

   When other basic or acidic functional radicals are present in the compound of formula I, base addition salts and pharmaceutically acceptable acid addition salts can be prepared in an analogous manner according to known techniques.



   It should be noted that certain products of formula I can be obtained in the form of optical isomers or in the form of mixtures of epimers. The subject of the invention is all these optical isomers and epimer mixtures. For example, when the substituent in position 6 is a hydroxyethyl radical, this can have the R configuration or else S and the resulting isomers as well as their epimer mixtures are the subject of the invention.



   A compound of formula I, where R2 represents a hydrogen atom or an anionic charge, or else a pharmaceutically acceptable salt of this compound can also be converted according to known techniques into a corresponding compound in the formula of which R2

  <Desc / Clms Page number 85>

 represents a physiologically hydrolyzable ester radical or else a compound of formula I, where R2 represents a conventional radical protecting the carboxyl function can be converted into the corresponding compound in the formula of which R2 represents a hydrogen atom, an anionic charge or a radical physiologically hydrolyzable ester, or a pharmaceutically acceptable salt of this compound.



   The new carbapenem derivatives of general formula I, in which R2 represents a hydrogen atom, an anionic charge or a physiologically hydrolysable radical protecting the carboxyl function, as well as their pharmaceutically acceptable salts, are powerful antibiotic agents against different gram bacteria -positive and gram-negative and can be used, for example, as additives for animal feed to promote growth, as preservatives for food, as bactericides in industrial applications, such as water-based paints and white stationery waters to impede the growth of harmful bacteria, as well as disinfectants for the destruction of harmful bacteria or for inhibiting their growth on medical and dental equipment.

   However, they are especially useful for the treatment of infectious diseases caused in humans or other animals by gram-positive or gram-negative bacteria.



   The pharmaceutically active compounds which are the subject of the invention can be administered as such or in the form of pharmaceutical compositions comprising, in addition to the active carbapenem derivative, a pharmaceutically acceptable excipient or diluent. These
 EMI85.1
 The compounds can be administered in different ways, those of main interest being the oral route,

  <Desc / Clms Page number 86>

 the topical route and the parenteral route (for example by intravenous or intramuscular injection). The pharmaceutical compositions can be presented in solid form such as capsules, tablets, powders, etc. or in liquid form such as solutions, suspensions or emulsions.

   The compositions for injection, which is the preferred route of administration, may be presented in unit dose ampoules or in multidose containers and may contain accessory agents such as suspending agents, stabilizers and dispersants . The compositions can be ready for administration or presented in the form of a powder to be reconstituted at the time of administration with an appropriate vehicle such as sterile water.



   The dose administered largely depends on the nature of the compound, the particular composition, the route of administration, the species and condition of the host, the site of administration and the nature of the organization. The choice of the preferred dose and route of administration in particular is within the competence of the physician. Generally, however, the compounds are administered parenterally or orally to mammals in an amount of about 5 to 200 mg per kg per day. Administration is generally carried out in divided doses, for example in three or four doses per day.



   The powerful broad-spectrum antibacterial activity of the carbapenems of the invention, both in vitro and in vivo, and the low toxicity of the compounds are illustrated by the biological data collected below which relate to the preferred carbapenem derivatives which are the subject of invention.

  <Desc / Clms Page number 87>

 



   In vitro activity Samples of the carbapenem derivatives prepared in Examples 1 and 2, after dissolving in water and diluting with nutritive broth, show the following minimum inhibitory concentrations (MIC), in / μg per ml, at with regard to the microorganisms indicated, as shown by the overnight incubation at 37 ° C. of the dilutions in tubes. N-formimidoyl-thienamycin is listed as a comparison compound in the following tables.
 EMI87.1
 
 <tb>
 <tb>



  Activity <SEP> antibacterial <SEP> in <SEP> vitro <SEP> from <SEP> derivative <SEP> from <SEP> carbapenem <SEP> from <SEP> example <SEP> 1
 <tb> Organization <SEP> CIM <SEP> (/ ug / ml)
 <tb> New <SEP> compound <SEP> N-Formimidoyl-thienamycin
 <tb> S. <SEP> pneumoniae <SEP> A-9585 <SEP> 0.25 <SEP> 0.004
 <tb> S. <SEP> pyogenes <SEP> A-9604 <SEP> 0.06 <SEP> 0.001
 <tb> S. <SEP> aureus <SEP> A-9537 <SEP> 0.13 <SEP> 0.004
 <tb> S. <SEP> aureus <SEP> + <SEP> 50% <SEP> serum <SEP> A-9537 <SEP> 0.03 <SEP> 0.016
 <tb> S. <SEP> aureus <SEP> (Pen-res.) <SEP> A-9606 <SEP> 0.06 <SEP> 0, <SEP> 008 <SEP>
 <tb> S. <SEP> aureus <SEP> (Meth-res. <SEP>) <SEP> A15097 <SEP> 4 <SEP> 0.5
 <tb> S. <SEP> faecalis <SEP> A20688 <SEP> 0.5 <SEP> 0.5
 <tb> E. <SEP> coli <SEP> (10-4 <SEP> dil.) <SEP> A15119 <SEP> 0.06 <SEP> 0.016
 <tb> E. <SEP> coli <SEP> (10-3) <SEP> A15119-0, <SEP> 03
 <tb> E.

    <SEP> coli <SEP> (10-2) <SEP> A15119-0, <SEP> 06
 <tb> E. <SEP> coli <SEP> (10-4) <SEP> A20341-1 <SEP> 0.03 <SEP> 0.03
 <tb> E. <SEP> coli <SEP> (10-3) <SEP> A20341-1-0, <SEP> 03
 <tb> E. <SEP> coli <SEP> (10-2) <SEP> A20341-1-0, <SEP> 13
 <tb>
 

  <Desc / Clms Page number 88>

 In vitro antibacterial activity of the carbapenem derivative of Example 1-continued
 EMI88.1
 
 <tb>
 <tb> Organization <SEP> CIM <SEP> (/ ug / ml)
 <tb> New <SEP> compound <SEP> N-Formimidoy1-thienamycin
 <tb> K. <SEP> pneumoniae <SEP> A-9664 <SEP> 0.25 <SEP> 0, <SEP> 13
 <tb> K. <SEP> pneumoniae <SEP> A20468 <SEP> 0.25 <SEP> 0.06
 <tb> P. <SEP> mirabilis <SEP> A-9900 <SEP> 0, <SEP> 13 <SEP> 0.06
 <tb> P. <SEP> vulgaris <SEP> A21559 <SEP> 0, <SEP> 13 <SEP> 0.03
 <tb> P. <SEP> morganii <SEP> A15153 <SEP> 0, <SEP> 13 <SEP> 0.13
 <tb> P. <SEP> rettgeri <SEP> A22424 <SEP> 0.25 <SEP> 0.25
 <tb> S.

    <SEP> marcescens <SEP> A20019 <SEP> 0, <SEP> 13 <SEP> 0.03
 <tb> E. <SEP> cloacae <SEP> A-9569 <SEP> 0, <SEP> 13 <SEP> 0.06
 <tb> E. <SEP> cloacae <SEP> A-9656 <SEP> 0, <SEP> 13 <SEP> 0.06
 <tb> P. <SEP> aeruginosa <SEP> A-9843A <SEP> 4 <SEP> 1
 <tb> P. <SEP> aeruginosa <SEP> A21213 <SEP> 1 <SEP> 0.25
 <tb> H. <SEP> influenzae <SEP> A-9833 <SEP> 16 <SEP> 16
 <tb> H. <SEP> influenzae <SEP> A20178 <SEP> 32 <SEP> 32
 <tb> H. <SEP> influenzae <SEP> A21518 <SEP> 16 <SEP> 32
 <tb> H. <SEP> influenzae <SEP> A21522 <SEP> 8 <SEP> 32
 <tb> B. <SEP> fragilis <SEP> A22862 <SEP> 0.03 <SEP> 0.016
 <tb> B. <SEP> fragilis <SEP> A22053 <SEP> 0.03 <SEP> 0.06
 <tb> B. <SEP> fragilis <SEP> A22696 <SEP> 0.25 <SEP> 0, <SEP> 13
 <tb> B.

    <SEP> fragilis <SEP> A22863 <SEP> 0.03 <SEP> 1
 <tb>
 

  <Desc / Clms Page number 89>

 In vitro antibacterial activity of the carbapenem derivative of Example 2
 EMI89.1
 
 <tb>
 <tb> Organization <SEP> CIM <SEP> (/ ug / ml)
 <tb> New <SEP> compound <SEP> N-Formimidoyl-thienamycin
 <tb> S. <SEP> pneumoniae <SEP> A-9585 <SEP> 0, <SEP> 001 <SEP> 0.002
 <tb> S. <SEP> pyogenes <SEP> A-9604 <SEP> 0, <SEP> 001 <SEP> 0.002
 <tb> S. <SEP> aureus <SEP> A-9537 <SEP> 0.004 <SEP> 0.004
 <tb> S. <SEP> aureus <SEP> + <SEP> 50% <SEP> serum <SEP> A-9537 <SEP> 0, <SEP> 016 <SEP> 0.016
 <tb> S. <SEP> aureus <SEP> (Pen-res.) <SEP> A-9606 <SEP> 0.008 <SEP> 0, <SEP> 008 <SEP>
 <tb> S. <SEP> aureus <SEP> (Meth.-res.) <SEP> A15097 <SEP> 8 <SEP> 4
 <tb> S. <SEP> faecalis <SEP> A20688 <SEP> 0.25 <SEP> 0.5
 <tb> E. <SEP> coli <SEP> A15119 <SEP> 0, <SEP> 016 <SEP> 0.016
 <tb> E.

    <SEP> coli <SEP> A20341-1 <SEP> 0.016 <SEP> 0.03
 <tb> K. <SEP> pneumoniae <SEP> A9664 <SEP> 0.06 <SEP> 0.06
 <tb> K. <SEP> pneumoniae <SEP> A20468 <SEP> 0.13 <SEP> 0.13
 <tb> P. <SEP> mirabilis <SEP> A9900 <SEP> 0.03 <SEP> 0.06
 <tb> P. <SEP> vulgaris <SEP> A21559 <SEP> 0, <SEP> 016 <SEP> 0.03
 <tb> P. <SEP> morganii <SEP> A15153 <SEP> 0.06 <SEP> 0.13
 <tb> P. <SEP> rettgeri <SEP> A22424 <SEP> 0.13 <SEP> 0.13
 <tb> S. <SEP> marcescens <SEP> A20019 <SEP> 0.03 <SEP> 0.03
 <tb> E. <SEP> cloacae <SEP> A9659 <SEP> 0.13 <SEP> 0.06
 <tb> E. <SEP> cloacae <SEP> A9656 <SEP> 0.25 <SEP> 0.06
 <tb> P. <SEP> aeruginosa <SEP> A9843A <SEP> 8 <SEP> 1 <SEP>
 <tb> P.

    <SEP> aeruginosa <SEP> A21213 <SEP> 2 <SEP> 0.25
 <tb>
 

  <Desc / Clms Page number 90>

 
In vivo activity
The in vivo therapeutic efficacy of the compound of Example 1 and that of N-formimidoyl-thienamycin, after intramuscular administration to mice experimentally infected with various organisms, are given in the following table. The DPo (dose in mg per kg necessary to protect 50% of infected mice) is indicated.



   Protective effect of intramuscular administration in infected mice
 EMI90.1
 
 <tb>
 <tb> Organization <SEP> DP50 / treatment <SEP> (mg / kg)
 <tb> Agent <SEP> infectious <SEP> Compound <SEP> from <SEP> N-Formimidoyl-
 <tb> (number <SEP> of organizations) <SEP> example <SEP> 1 <SEP> thienamycin
 <tb> P. <SEP> mirabilis <SEP> A-9900 <SEP> 3.6 <SEP> x <SEP> 106 <SEP> 3.3 <SEP> 3 * / 15 *
 <tb> P. <SEP> aeruginosa <SEP> A-9843a <SEP> 5.5 <SEP> x <SEP> 104 <SEP> 0.3 <SEP> 0.5 *
 <tb> P. <SEP> aeruginosa <SEP> A-20481 <SEP> 5.4 <SEP> x <SEP> 104 <SEP> 0.63 <SEP> 0.4 *
 <tb> P. <SEP> aeruginosa <SEP> A-20599 <SEP> 1.4 <SEP> x <SEP> l05 <SEP> 0.7 <SEP> 0, <SEP> 18 *
 <tb> S. <SEP> aureus <SEP> A-9606 <SEP> 6, <SEP> 6 <SEP> x <SEP> 108 <SEP> 0.09 <SEP> 0.07 *
 <tb> S. <SEP> faecalis <SEP> A-20688 <SEP> 2, <SEP> 3 <SEP> x <SEP> l08 <SEP> 3.3 <SEP> 2.8 *
 <tb> E.

    <SEP> coli <SEP> A-15119 <SEP> 6.2 <SEP> x <SEP> 106 <SEP> 0, <SEP> 6 <SEP> 2.5 *
 <tb> K. <SEP> pneumoniae <SEP> A-9964 <SEP> 5, <SEP> 1 <SEP> x <SEP> 106 <SEP> 2.5 <SEP> 2.2 *
 <tb>
 
 EMI90.2
 ---------- * Historical data
Treatment program: Except for E. coli A15119 and K. pneumoniae A9964, the mice receive the drug i. m. 0 and 2 hours after infection. For E. coli and
K. pneumoniae, the treatment program begins at 1 and 3.5 hours after infection.



   For each test, 5 mice are taken per dose.

  <Desc / Clms Page number 91>

 



   Toxicity
The toxicity of the compound of Example 1, as determined by intracranial administration to the mouse, is indicated in the following table.



   Toxicity after intracranial administration to mice
 EMI91.1
 
 <tb>
 <tb> Compound <SEP> DL50 * <SEP> (mg / kg) <SEP> Dose <SEP> maximum <SEP> (mg / kg) <SEP> without
 <tb> signs <SEP> clinics <SEP> from <SEP> toxicity
 <tb> Compound <SEP> from <SEP> example <SEP> 1 <SEP> 14 <SEP> 5
 <tb> N-Formimidoyl-thienamycin <SEP> 32 <SEP> au5 <SEP>
 <tb> * <SEP> = <SEP> Average <SEP> on <SEP> 25 <SEP> mouse <SEP> by <SEP> compound.
 <tb>



  Rate <SEP> blood <SEP> at <SEP> the <SEP> mouse <SEP> after <SEP> administration <SEP> intramuscular
 <tb> The <SEP> rate <SEP> blood <SEP> and <SEP> the <SEP> half-life <SEP> from <SEP> compound <SEP> from <SEP> example <SEP> 1, <SEP> after <SEP> administration <SEP>
 <tb> intramuscular <SEP> to <SEP> the <SEP> dose <SEP> from <SEP> 20 <SEP> mg / kg <SEP> at <SEP> the <SEP> mouse, <SEP> are <SEP> indicated <SEP> to <SEP> array <SEP> next.
 <tb>



  Rate <SEP> blood <SEP> (/ ug / ml)
 <tb> Compound <SEP> 10 <SEP> 20 <SEP> 30 <SEP> 45 <SEP> 60 <SEP> 90 <SEP> t * <SEP> ASC **
 <tb> minutes <SEP> after <SEP> administration <SEP> (min) <SEP> (/ ug. <SEP> h / ml)
 <tb> Compound <SEP> from <SEP> example <SEP> 1 <SEP> 14 <SEP> 10, <SEP> 8 <SEP> 6.8 <SEP> 2.6 <SEP> 0.8 <SEP> <0, <SEP> 6 <SEP> 10 <SEP> 6.3
 <tb> N-Formimidoyl-thienamycin <SEP> 12, <SEP> 6 <SEP> 9.9 <SEP> 7.3 <SEP> 2.6 <SEP> 0.7 <SEP> <0, <SEP> 3 <SEP> 9 <SEP> 6
 <tb>
 The compounds are dissolved in 0.1 M phosphate buffer, pH 7.



  The results are recorded by single experiment on 4 mice per compound.



  * = t # corresponds to the half-life in minutes.



  ** = AUC corresponds to the area under the curve.

  <Desc / Clms Page number 92>

 



   Urinary excretion
The urinary excretion of the compound of Example 1, after intramuscular administration at a dose of 20 mg / kg to the mouse, is indicated in the following table
Urinary excretion after intramuscular administration of 20 mg / kg in mice
 EMI92.1
 
 <tb>
 <tb> Compound <SEP> Percentage <SEP> from <SEP> the <SEP> dose <SEP> excreted <SEP> by <SEP> channel <SEP> urinary
 <tb> 0-3 <SEP> 3-6 <SEP> 6-24 <SEP> 0-24 <SEP>
 <tb> Hours <SEP> after <SEP> administration
 <tb> Compound <SEP> from <SEP> example <SEP> 1 <SEP> 26.1 <SEP> 0.5 <SEP> 0, <SEP> 1 <SEP> 26.7 <SEP> i <SEP> 6.7
 <tb> N-Formimidoyl-thienamycin <SEP> 12, <SEP> 1 <SEP> 0.1 <SEP> <0, <SEP> 1 <SEP> 12.2 <SEP>: <SEP> 3, <SEP> 6
 <tb>
 The compounds are dissolved in 0.1 M phosphate buffer, pH 1.



  The values are recorded by single experiment on 4 mice per compound.

  <Desc / Clms Page number 93>

 



   Additional biological data
In Vitro Activity Samples of the carbapenem derivatives indicated below (identified by the example number), after dissolving in water and diluting with nutritive broth, demonstrate the minimum inhibitory concentrations (C.I.M.) below.
 EMI93.1
 / µg per ml with respect to the microorganisms indicated, as shown by incubating overnight 0 at 37 C dilutions in tubes. N-formimidoyl-thienamycin is included for comparison in the tables.
 EMI93.2
 
 <tb>
 <tb>



  Organization <SEP> CIM <SEP> (/ ug / m1)
 <tb> Ex. <SEP> 3 <SEP> Ex. <SEP> 4 <SEP> Ex. <SEP> 5 <SEP> Ex. <SEP> 6 <SEP> Ex. <SEP> 7 <SEP> MK <SEP> 0787 *
 <tb> S. <SEP> pneumoniae <SEP> A-9585 <SEP> 0.002 <SEP> 0.002 <SEP> 0.004 <SEP> 0.004 <SEP> 0.004 <SEP> 0.002
 <tb> S. <SEP> pyogenes <SEP> A-9604 <SEP> 0.002 <SEP> 0, <SEP> 001 <SEP> 0.004 <SEP> 0.004 <SEP> 0.004 <SEP> 0.002
 <tb> S. <SEP> faecalis <SEP> A20688 <SEP> 0, <SEP> 5 <SEP> 0.5 <SEP> 0.25 <SEP> 0.5 <SEP> 0, <SEP> 13 <SEP> 0, <SEP> 5 <SEP>
 <tb> S. <SEP> aureus <SEP> A-9537 <SEP> 0.016 <SEP> 0.008 <SEP> 0.004 <SEP> 0.03 <SEP> 0, <SEP> 008 <SEP> 0.004
 <tb> S. <SEP> aureus <SEP> + 50% <SEP> serum <SEP> A-9357 <SEP> 0, <SEP> 016 <SEP> 0.03 <SEP> 0, <SEP> 016 <SEP> 0.06 <SEP> 0.03 <SEP> 0, <SEP> 016 <SEP>
 <tb> S.

    <SEP> aureus <SEP> (Pen-res) <SEP> A-9606 <SEP> 0, <SEP> 016 <SEP> 0, <SEP> 016 <SEP> 0.008 <SEP> 0.03 <SEP> 0.016 <SEP> 0, <SEP> 008 <SEP>
 <tb> S. <SEP> aureus <SEP> (Meth-res) <SEP> A15097 <SEP> 4 <SEP> 4 <SEP> 8 <SEP> 4 <SEP> 2 <SEP> 4
 <tb> E. <SEP> coli <SEP> A15119 <SEP> 0.03 <SEP> 0.016 <SEP> 0.016 <SEP> 0.06 <SEP> 0.004 <SEP> 0, <SEP> 016
 <tb> E. <SEP> coli <SEP> A20341-1 <SEP> 0.016 <SEP> 0, <SEP> 016 <SEP> 0.016 <SEP> 0.06 <SEP> 0.004 <SEP> 0.03
 <tb> K. <SEP> pneumoniae <SEP> A-9664 <SEP> 0.06 <SEP> 0.03 <SEP> 0.03 <SEP> 0, <SEP> 13 <SEP> 0.016 <SEP> 0.06
 <tb> K. <SEP> pneumoniae <SEP> A20468 <SEP> 0.06 <SEP> 0.03 <SEP> 0.06 <SEP> 0.25 <SEP> 0.016 <SEP> 0, <SEP> 13
 <tb>
 * = N-Formimidoyl-thienamycin

  <Desc / Clms Page number 94>

 
 EMI94.1
 U) <u - ftj + J 1 <u E <U 0 .-) p & -) E -'- 'u u c <u M-H 01 O. r-! a 0) r-i e 4 cn.

   0 UJ Q) 'Q) 1 U 1 u M <u p n Q 'CL) c r.



  Q c
 EMI94.2
 
 <tb>
 <tb> wOrganism <SEP> CIM <SEP> (/ ug / ml)
 <tb> Ex. <SEP> 3 <SEP> Ex. <SEP> 4 <SEP> Ex. <SEP> 5 <SEP> Ex. <SEP> 6 <SEP> Ex. <SEP> 7 <SEP> MK <SEP> 0787 *
 <tb> E. <SEP> cloacae <SEP> A-9659 <SEP> 0.13 <SEP> 0.03 <SEP> 0.06 <SEP> 0.25 <SEP> 0.016 <SEP> 0.06
 <tb> E. <SEP> cloacae <SEP> A-9656 <SEP> 0.13 <SEP> 0.06 <SEP> 0.13 <SEP> 0.25 <SEP> 0.016 <SEP> 0.06
 <tb> P. <SEP> mirabilis <SEP> A-9900 <SEP> 0.13 <SEP> 0.06 <SEP> 0.03 <SEP> 0.025 <SEP> 0.016 <SEP> 0.06
 <tb> P. <SEP> vulgaris <SEP> A21559 <SEP> 0.016 <SEP> 0.016 <SEP> 0.016 <SEP> 0.06 <SEP> 0.008 <SEP> 0.03
 <tb> M. <SEP> morganii <SEP> A15153 <SEP> 0.13 <SEP> 0.016 <SEP> 0.06 <SEP> 0.13 <SEP> 0.016 <SEP> 0.13
 <tb> P. <SEP> rettgeri <SEP> A22424 <SEP> 0.25 <SEP> 0.13 <SEP> 0.13 <SEP> 0.25 <SEP> 0.06 <SEP> 0.13
 <tb> S.

    <SEP> marcescens <SEP> A20019 <SEP> 0.016 <SEP> 0.03 <SEP> 0.06 <SEP> 0.13 <SEP> 0.008 <SEP> 0.03
 <tb> P. <SEP> aeruginosa <SEP> A-9843a <SEP> 2 <SEP> 2 <SEP> 4 <SEP> 8 <SEP> 1 <SEP> 0.25
 <tb> P. <SEP> aeruginosa <SEP> A21213 <SEP> 0.5 <SEP> 0.13 <SEP> 2 <SEP> 1 <SEP> 0.25 <SEP> 0.25
 <tb> H. <SEP> influenzae <SEP> A-9833 <SEP> 2 <SEP> 2 <SEP> 4 <SEP>> 32 <SEP>> 32 <SEP> 16
 <tb> H. <SEP> influenzae <SEP> A21518 <SEP> 2 <SEP> 2 <SEP> 4 <SEP>> 32 <SEP>> 16 <SEP> 16
 <tb> B. <SEP> fragilis <SEP> A22862 <SEP> 0.25 <SEP> 0.06 <SEP> 0.03 <SEP> 0.03 <SEP> 0.016 <SEP> 0.06
 <tb> B. <SEP> frgailis <SEP> A22696 <SEP> 0.5 <SEP> 0.5 <SEP> 0.25 <SEP> 0.25 <SEP> 0.25 <SEP> 0.13
 <tb>
 * = N-Formimidoyl-thienamycin

  <Desc / Clms Page number 95>

 CIM Organism (/ ug / ml)
 EMI95.1
 
 <tb>
 <tb> Ex. <SEP> 8 <SEP> Ex. <SEP> 9 <SEP> Ex. <SEP> 10 <SEP> Them.

    <SEP> 11 <SEP> MK <SEP> 0787 *
 <tb> S. <SEP> pneumoniae <SEP> A-9585 <SEP> 0.002 <SEP> 0.001 <SEP> 0, <SEP> 001 <SEP> 0.002 <SEP> 0.002
 <tb> S. <SEP> pyogenes <SEP> A-9604 <SEP> 0.002 <SEP> 0.001 <SEP> 0, <SEP> 001 <SEP> 0.002 <SEP> 0.002
 <tb> S. <SEP> faecalis <SEP> A20688 <SEP> 0, <SEP> 5 <SEP> 0, <SEP> 13 <SEP> 0.25 <SEP> 0, <SEP> 5 <SEP> 0.25
 <tb> S. <SEP> aureus <SEP> A-9537 <SEP> 0, <SEP> 008 <SEP> 0.004 <SEP> 0.008 <SEP> 0.004 <SEP> 0.002
 <tb> S. <SEP> aureus <SEP> + 50% <SEP> serum <SEP> A-9537 <SEP> 0.03 <SEP> 0, <SEP> 008 <SEP> 0.06 <SEP> 0.016 <SEP> 0.016
 <tb> S. <SEP> aureus <SEP> (Pen-res) <SEP> A-9606 <SEP> 0.03 <SEP> 0.008 <SEP> 0, <SEP> 008 <SEP> 0.016 <SEP> 0, <SEP> 008 <SEP>
 <tb> S. <SEP> aureus <SEP> (Meth-res) <SEP> A15097
 <tb> E. <SEP> coli <SEP> A15119 <SEP> 0, <SEP> 016 <SEP> 0, <SEP> 008 <SEP> 0, <SEP> 016 <SEP> 0, <SEP> 016 <SEP> 0, <SEP> 016
 <tb> E.

    <SEP> coli <SEP> A20341-1 <SEP> 0.03 <SEP> 0.004 <SEP> 0, <SEP> 008 <SEP> 0.03 <SEP> 0, <SEP> 016
 <tb> K. <SEP> pneumoniae <SEP> A-9664 <SEP> 0.03 <SEP> 0, <SEP> 016 <SEP> 0.06 <SEP> 0.03 <SEP> 0.03
 <tb> K. <SEP> pneumoniae <SEP> A20468 <SEP> 0, <SEP> 13 <SEP> 0.03 <SEP> 0, <SEP> 13 <SEP> 0.13 <SEP> 0.13
 <tb> E. <SEP> cloacae <SEP> A-9659 <SEP> 0, <SEP> 13 <SEP> 0.03 <SEP> 0, <SEP> 13 <SEP> 0.06 <SEP> 0.13
 <tb> E. <SEP> cloacae <SEP> A-9656 <SEP> 0.06 <SEP> 0.03 <SEP> 0.13 <SEP> 0, <SEP> 13 <SEP> 0.06
 <tb> P. <SEP> mirabilis <SEP> A-9900 <SEP> 0, <SEP> 13 <SEP> 0, <SEP> 016 <SEP> 0.13 <SEP> 0.03 <SEP> 0.03
 <tb> P. <SEP> vulgaris <SEP> A21559 <SEP> 0.03 <SEP> 0, <SEP> 008 <SEP> 0.016 <SEP> 0.03 <SEP> 0, <SEP> 016 <SEP>
 <tb> M. <SEP> morganii <SEP> A15153 <SEP> 0, <SEP> 13 <SEP> 0.03 <SEP> 0.13 <SEP> 0.06 <SEP> 0.06
 <tb> P.

    <SEP> rettgeri <SEP> A22424 <SEP> 0.13 <SEP> 0, <SEP> 06 <SEP> 0.13 <SEP> 0.13 <SEP> 0.13
 <tb> S. <SEP> marcescens <SEP> A20019 <SEP> 0.06 <SEP> 0.016 <SEP> 0.06 <SEP> 0.06 <SEP> 0.03
 <tb> P. <SEP> aeruginosa <SEP> A-9843a <SEP> 1 <SEP> 2 <SEP> 32 <SEP> 0.5 <SEP> 1
 <tb> P. <SEP> aeruginosa <SEP> A21213 <SEP> 0.25 <SEP> 0.13 <SEP> 2 <SEP> 0.13 <SEP> 0.13
 <tb>
 
 EMI95.2
 * = N-Formimidoyl-thienamycin Q

  <Desc / Clms Page number 96>

 CIM Organism (/ ug / ml)
 EMI96.1
 
 <tb>
 <tb> Ex. <SEP> 12 <SEP> Ex. <SEP> 13 <SEP> Ex. <SEP> 14 <SEP> MK <SEP> 0787 *
 <tb> S. <SEP> pneumoniae <SEP> A-9585 <SEP> 0.002 <SEP> 0.0005 <SEP> 0.0005 <SEP> 0.002
 <tb> S. <SEP> pyogenes <SEP> A-9604 <SEP> 0.004 <SEP> 0.0005 <SEP> 0.0005 <SEP> 0.002
 <tb> S. <SEP> faecalis <SEP> A20688 <SEP> 0.5 <SEP> 0.13 <SEP> 0.13 <SEP> 0.25
 <tb> S.

    <SEP> aureus <SEP> A-9537 <SEP> 0.008 <SEP> 0.008 <SEP> 0.0008 <SEP> 0.002
 <tb> S. <SEP> aureus <SEP> + 50% <SEP> serum <SEP> A-9537 <SEP> 0.016 <SEP> 0.016 <SEP> 0.03 <SEP> 0, <SEP> 008 <SEP>
 <tb> S. <SEP> aureus <SEP> (Pen-res) <SEP> A-9606 <SEP> 0.03 <SEP> 0, <SEP> 008 <SEP> 0, <SEP> 016 <SEP> 0.008
 <tb> S. <SEP> aureus <SEP> (Meth-res) <SEP> A15097
 <tb> E. <SEP> coli <SEP> A15119 <SEP> 0.016 <SEP> 0.004 <SEP> 0, <SEP> 008 <SEP> 0, <SEP> 016
 <tb> E. <SEP> coli <SEP> A20341-1 <SEP> 0, <SEP> 008 <SEP> 0, <SEP> 008 <SEP> 0, <SEP> 008 <SEP> 0.016
 <tb> K. <SEP> pneumoniae <SEP> A-9664 <SEP> 0.03 <SEP> 0.03 <SEP> 0.03 <SEP> 0.03
 <tb> K. <SEP> pneumoniae <SEP> A20468 <SEP> 0.06 <SEP> 0, <SEP> 13 <SEP> 0.03 <SEP> 0, <SEP> 06 <SEP>
 <tb> E. <SEP> cloacae <SEP> A-9659 <SEP> 0.06 <SEP> 0.06 <SEP> 0.03 <SEP> 0.06
 <tb> E.

    <SEP> cloacae <SEP> A-9656 <SEP> 0.03 <SEP> 0.03 <SEP> 0.03 <SEP> 0.06
 <tb> P. <SEP> mirabilis <SEP> A-9900 <SEP> 0.03 <SEP> 0, <SEP> 016 <SEP> 0, <SEP> 016 <SEP> 0, <SEP> 016 <SEP>
 <tb> P. <SEP> vulgaris <SEP> A21559 <SEP> 0, <SEP> 016 <SEP> 0, <SEP> 008 <SEP> 0, <SEP> 016 <SEP> 0, <SEP> 016 <SEP>
 <tb> M. <SEP> morganii <SEP> A15153 <SEP> 0.06 <SEP> 0, <SEP> 016 <SEP> 0.03 <SEP> 0, <SEP> 06 <SEP>
 <tb> P. <SEP> rettgeri <SEP> A22424 <SEP> 0, <SEP> 13 <SEP> 0.25 <SEP> 0.06 <SEP> 0.13
 <tb> S. <SEP> marcescens <SEP> A20019 <SEP> 0.03 <SEP> 0.016 <SEP> 0, <SEP> 016 <SEP> 0.03
 <tb> P. <SEP> aeruginosa <SEP> A-9843A <SEP> 16 <SEP> 32 <SEP> 8 <SEP> 1
 <tb> P. <SEP> aeruginosa <SEP> A21213 <SEP> 2 <SEP> 2 <SEP> 0.5 <SEP> 0, <SEP> 13
 <tb>
 * = N-Formimidoyl-thienamycin

  <Desc / Clms Page number 97>

 CIM Organism (/ ug / ml)
 EMI97.1
 
 <tb>
 <tb> Ex.

    <SEP> 15 "A" Ex. <SEP> 15 "B" Ex. <SEP> 15 "C" MK <SEP> 0787 *
 <tb> S. <SEP> pneumoniae <SEP> A-9585 <SEP> 0.0005 <SEP> 0, <SEP> 0005 <SEP> 0, <SEP> 0005 <SEP> 0.002
 <tb> S. <SEP> pyogenes <SEP> A-9604 <SEP> 0.0005 <SEP> 0, <SEP> 001 <SEP> 0.0003 <SEP> 0.002
 <tb> S. <SEP> faecalis <SEP> A20688 <SEP> 0.13 <SEP> 0.5 <SEP> 0.5 <SEP> 0.25
 <tb> S. <SEP> aureus <SEP> A-9537 <SEP> 0.03 <SEP> 0.004 <SEP> 0.016 <SEP> 0.004
 <tb> S. <SEP> aureus <SEP> + 50% <SEP> serum <SEP> A-9537 <SEP> 0.03 <SEP> 0.016 <SEP> 0.06 <SEP> 0.008
 <tb> S. <SEP> aureus <SEP> (Pen-res) <SEP> A-9606 <SEP> 0.004 <SEP> 0.008 <SEP> 0.03 <SEP> 0.008
 <tb> S. <SEP> aureus <SEP> (Meth-res) <SEP> A15097
 <tb> E. <SEP> coli <SEP> A15119 <SEP> 0.004 <SEP> 0.008 <SEP> 0.06 <SEP> 0, <SEP> 008 <SEP>
 <tb> E. <SEP> coli <SEP> A20341-1 <SEP> 0.004 <SEP> 0, <SEP> 008 <SEP> 0.03 <SEP> 0.016
 <tb> K.

    <SEP> pneumoniae <SEP> A-9664 <SEP> 0, <SEP> 008 <SEP> 0.03 <SEP> 0.06 <SEP> 0.03
 <tb> K. <SEP> pneumoniae <SEP> A20468 <SEP> 0, <SEP> 008 <SEP> 0.016 <SEP> 0.13 <SEP> 0.06
 <tb> E. <SEP> cloacae <SEP> A-9659 <SEP> 0.016 <SEP> 0.016 <SEP> 0.13 <SEP> 0.13
 <tb> E. <SEP> cloacae <SEP> A-9656 <SEP> 0.016 <SEP> 0.03 <SEP> 0.13 <SEP> 0.13
 <tb> P. <SEP> mirabilis <SEP> A-9900 <SEP> 0, <SEP> 008 <SEP> 0.03 <SEP> 0.06 <SEP> 0.06
 <tb> P. <SEP> vulgaris <SEP> A21559 <SEP> 0.008 <SEP> 0.008 <SEP> 0.06 <SEP> 0, <SEP> 016
 <tb> M. <SEP> morganii <SEP> A15153 <SEP> 0.03 <SEP> 0.06 <SEP> 0.25 <SEP> 0.13
 <tb> P. <SEP> rettgeri <SEP> A22424 <SEP> 0.03 <SEP> 0.13 <SEP> 0.25 <SEP> 0.13
 <tb> S. <SEP> marcescens <SEP> A20019 <SEP> 0.008 <SEP> 0, <SEP> 016 <SEP> 0.13 <SEP> 0, <SEP> 016
 <tb> P. <SEP> aeruginosa <SEP> A-9843a <SEP> 0.5 <SEP> 2 <SEP> 8 <SEP> 0.5
 <tb> P.

    <SEP> aeruginosa <SEP> A21213 <SEP> 0.03 <SEP> 0.13 <SEP> 0, <SEP> 5 <SEP> 0, <SEP> 13 <SEP>
 <tb>
 * = N-Formimidoyl-thienamycin

  <Desc / Clms Page number 98>

 CIM Organism (/ ug / ml)
 EMI98.1
 
 <tb>
 <tb> Ex. <SEP> 16 <SEP> Ex. <SEP> 17 <SEP> MK <SEP> 0787 *
 <tb> S. <SEP> pneumoniae <SEP> A-9585 <SEP> 0.002 <SEP> 0.0165 <SEP> 0.001
 <tb> S. <SEP> pyogenes <SEP> A-9604 <SEP> 0.002 <SEP> 0.016 <SEP> 0, <SEP> 001 <SEP>
 <tb> S. <SEP> faecalis <SEP> A20688 <SEP> 1 <SEP> 4 <SEP> 0.25
 <tb> S. <SEP> aureus <SEP> A-9537 <SEP> 0, <SEP> 008 <SEP> 0.25 <SEP> 0, <SEP> 001
 <tb> S. <SEP> aureus <SEP> + 50% <SEP> serum <SEP> A-9537 <SEP> 0.03 <SEP> 1 <SEP> 0.008
 <tb> S. <SEP> aureus <SEP> (Pen-res) <SEP> A-9606 <SEP> 0, <SEP> 016 <SEP> 0, <SEP> 5 <SEP> 0.002
 <tb> S. <SEP> aureus <SEP> (Meth-res) <SEP> A15097
 <tb> E.

    <SEP> coli <SEP> A15119 <SEP> 0.016 <SEP> 0.6 <SEP> 0.008
 <tb> E. <SEP> coli <SEP> A20341-1 <SEP> 0, <SEP> 016 <SEP> 0, <SEP> 6 <SEP> 0, <SEP> 008 <SEP>
 <tb> K. <SEP> pneumoniae <SEP> A-9664 <SEP> 0.06 <SEP> 0, <SEP> 13 <SEP> 0.03
 <tb> K. <SEP> pneumoniae <SEP> A20468 <SEP> 0.06 <SEP> 0.5 <SEP> 0.06
 <tb> E. <SEP> cloacae <SEP> A-9659 <SEP> 0.06 <SEP> 2 <SEP> 0.06
 <tb> E. <SEP> cloacae <SEP> A-9656 <SEP> 0.06 <SEP> 2 <SEP> 0.06
 <tb> P. <SEP> mirabilis <SEP> A-9900 <SEP> 0.06 <SEP> 0.13 <SEP> 0.016
 <tb> P. <SEP> vulgaris <SEP> A21559 <SEP> 0.03 <SEP> 0, <SEP> 13 <SEP> 0, <SEP> 008 <SEP>
 <tb> M. <SEP> morganii <SEP> A15153 <SEP> 0, <SEP> 13 <SEP> 0.5 <SEP> 0.06
 <tb> P. <SEP> rettgeri <SEP> A22424 <SEP> 0.25 <SEP> 2 <SEP> 0, <SEP> 06 <SEP>
 <tb> S. <SEP> marcescens <SEP> A20019 <SEP> 0, <SEP> 06 <SEP> 0.13 <SEP> 0, <SEP> 016 <SEP>
 <tb> P.

    <SEP> aeruginosa <SEP> A-9843a <SEP> 0.25 <SEP>> 63 <SEP> 0.5
 <tb> P. <SEP> aeruginosa <SEP> A21213 <SEP> 0.13 <SEP> 16 <SEP> 0.13
 <tb>
 * = N-Formimidoyl-thienamycin

  <Desc / Clms Page number 99>

 CIM Organism (/ ug / ml)
 EMI99.1
 
 <tb>
 <tb> Ex. <SEP> 18 <SEP> Ex. <SEP> 19 <SEP> Ex. <SEP> 20 <SEP> MK <SEP> 0787 *
 <tb> S. <SEP> pneumoniae <SEP> A-9585 <SEP> 1 <SEP> 0.002 <SEP> 0, <SEP> 06 <SEP> 0, <SEP> 001 <SEP>
 <tb> S. <SEP> pyogenes <SEP> A-9604 <SEP> 2 <SEP> 0.002 <SEP> 0.13 <SEP> 0.002
 <tb> S. <SEP> faecalis <SEP> A20688 <SEP> 63 <SEP> 0.5 <SEP> 16 <SEP> 0.25
 <tb> S. <SEP> aureus <SEP> A-9537 <SEP> 32 <SEP> 0.004 <SEP> 0, <SEP> 5 <SEP> 0.002
 <tb> S. <SEP> aureus <SEP> + 50% <SEP> serum <SEP> A-9537 <SEP>> 63 <SEP> 0.008 <SEP> 2 <SEP> 0.004
 <tb> S. <SEP> aureus <SEP> (Pen-res) <SEP> A-9606 <SEP> 125 <SEP> 0.016 <SEP>> 125 <SEP> 0.004
 <tb> S.

    <SEP> aureus <SEP> (Meth-res) <SEP> A15097
 <tb> E. <SEP> coli <SEP> A15119 <SEP> 16 <SEP> 0.008 <SEP> 1 <SEP> 0, <SEP> 016 <SEP>
 <tb> E. <SEP> coli <SEP> A20341-1 <SEP> 16 <SEP> 0, <SEP> 008 <SEP> 2 <SEP> 0, <SEP> 016 <SEP>
 <tb> K. <SEP> pneumoniae <SEP> A-9664 <SEP> 32 <SEP> 0.03 <SEP> 4 <SEP> 0.03
 <tb> K. <SEP> pneumoniae <SEP> A20468 <SEP> 63 <SEP> 0.06 <SEP> 4 <SEP> 0.06
 <tb> E. <SEP> cloacae <SEP> A-9659 <SEP> 63 <SEP> 0.03 <SEP> 8 <SEP> 0, <SEP> 06 <SEP>
 <tb> E. <SEP> cloacae <SEP> A-9656 <SEP> 125 <SEP> 0.03 <SEP> 16 <SEP> 0.06
 <tb> P. <SEP> mirabilis <SEP> A-9900 <SEP> 32 <SEP> 0.03 <SEP> 4 <SEP> 0, <SEP> 016
 <tb> P. <SEP> vulgaris <SEP> A21559 <SEP> 32 <SEP> 0, <SEP> 016 <SEP> 4 <SEP> 0.016
 <tb> M. <SEP> morganii <SEP> A15153 <SEP> 32 <SEP> 0.06 <SEP> 8 <SEP> 0.06
 <tb> P. <SEP> rettgeri <SEP> A22424 <SEP> 32 <SEP> 0.13 <SEP> 8 <SEP> 0, <SEP> 13
 <tb> S.

    <SEP> marcescens <SEP> A20019 <SEP> 32 <SEP> 0.03 <SEP> 4 <SEP> 0.03
 <tb> P. <SEP> aeruginosa <SEP> A-9843A <SEP> 63 <SEP> 0, <SEP> 5 <SEP> 32 <SEP> 0.5
 <tb> P. <SEP> aeruginosa <SEP> A21213 <SEP> 63 <SEP> 0, <SEP> 06 <SEP> 16 <SEP> 0, <SEP> 13
 <tb>
 * = N-Formimidoyl-thienamycin

  <Desc / Clms Page number 100>

 
In Vivo Activity The in vivo therapeutic efficacy of certain of the compounds of the invention and of
 EMI100.1
 N-formimidoyl-thienamycin (MK 0787), after intramuscular administration to mice experimentally infected with various organisms, is indicated below. The DPQ (in mg / kg) necessary to protect 50% of the infected mice is indicated.



  Protective effect of intramuscular administration in infected mice
 EMI100.2
 
 <tb>
 <tb> DP50 <SEP> by <SEP> treatment <SEP> (mg / kg)
 <tb> Ex. <SEP> Ex. <SEP> Ex. <SEP> Ex. <SEP> Ex. <SEP> Ex. <SEP> Ex. <SEP> MK
 <tb> 6 <SEP> 8 <SEP> 9 <SEP> 12 <SEP> 14 <SEP> 15 <SEP> "A" <SEP> 15 <SEP> "B" <SEP> 0787
 <tb> S. <SEP> aureus <SEP> A9606-0, <SEP> 21-0, <SEP> 89 <SEP> 0, <SEP> 07--0, <SEP> 07
 <tb> E. <SEP> coli <SEP> A15119-0, <SEP> 86 <SEP> 1, <SEP> 2 ---- 3
 <tb> K. <SEP> pneumoniae <SEP> A9664-1, <SEP> 8 <SEP> 1, <SEP> 8 ---- 3 <SEP>
 <tb> P. <SEP> mirabilis <SEP> A9900-1, <SEP> 4 <SEP> 7, <SEP> 1 ---- 9
 <tb> P. <SEP> aeruginosa <SEP> A9843A <SEP> 0.4 <SEP> 0, <SEP> 19 <SEP> 0.19 <SEP> l, <SEP> 8 <SEP> 0.45 <SEP> 0.39 <SEP> 0, <SEP> 89 <SEP> 1
 <tb> P.

    <SEP> aeruginosa <SEP> A24081-0, <SEP> 33 <SEP> 0.19 <SEP> - <SEP> - <SEP> - <SEP> - <SEP> 0, <SEP> 4
 <tb>
 

  <Desc / Clms Page number 101>

 Protective effect of intramuscular administration in infected mice
DP50 per treatment (mg / kg) -continued
 EMI101.1
 
 <tb>
 <tb> Ex. <SEP> 3 <SEP> Ex. <SEP> 4 <SEP> Ex. <SEP> 7 <SEP> MK <SEP> 0787
 <tb> S. <SEP> aureus <SEP> A9606 <SEP> 0.07 <SEP> 0, <SEP> 1 <SEP> 0.2 <SEP> 0.07
 <tb> E. <SEP> coli <SEP> A15ll9 <SEP> 1 <SEP> 0.4 <SEP> 0.2 <SEP> 3
 <tb> K. <SEP> pneumoniae <SEP> A9664 <SEP> 3 <SEP> 3 <SEP> 1 <SEP> 3
 <tb> P. <SEP> mirabilis <SEP> A9900 <SEP> 2 <SEP> 4 <SEP> 2.4 <SEP> 9
 <tb> P. <SEP> aeruginosa <SEP> A9843A <SEP> 0.5 <SEP> 0.2 <SEP> 0.2 <SEP> 0.5
 <tb> P. <SEP> aeruginosa <SEP> A24081 <SEP> 0, <SEP> 8 <SEP> 0.2 <SEP> 0, <SEP> 1 <SEP> 0.4
 <tb> Ex. <SEP> 5 <SEP> MK <SEP> 0787
 <tb> S. <SEP> aureus <SEP> 0.2 <SEP> 0.07
 <tb> E.

    <SEP> coli <SEP> 4 <SEP> 2.2
 <tb> K. <SEP> pneumoniae <SEP> 3 <SEP> 2.3
 <tb> P. <SEP> mirabilis <SEP> 10 <SEP> 9
 <tb> P. <SEP> aeruginosa <SEP> A9843A <SEP> 1.6 <SEP> 0.5
 <tb>
 

  <Desc / Clms Page number 102>

 
Blood levels in mice after intramuscular administration The blood levels and half-lives of some of the compounds of the present invention, after intramuscular administration at a dose of 20 mg / kg in mice, are indicated below.
 EMI102.1
 
 <tb>
 <tb>



  Compound <SEP> Cmax <SEP> (/ ug / ml) <SEP> t # <SEP> (min) <SEP> * <SEP> ASC <SEP> (/ ug. <SEP> h / ml) <SEP> **
 <tb> Example <SEP> 1 <SEP> 14 <SEP> 10 <SEP> 6.3
 <tb> Example <SEP> 2 <SEP> 13, <SEP> 9 <SEP> 9 <SEP> 5, <SEP> 3 <SEP>
 <tb> Example <SEP> 3 <SEP> 14.5 <SEP> 10 <SEP> 6, <SEP> 9 <SEP>
 <tb> Example <SEP> 4 <SEP> 15.5 <SEP> 11 <SEP> 7.7
 <tb> Example <SEP> 5 <SEP> - <SEP> - <SEP> Example <SEP> 6 <SEP> 17, <SEP> 7 <SEP> 9 <SEP> 8, <SEP> 5
 <tb> Example <SEP> 7 <SEP> 19.2 <SEP> 11 <SEP> 11.8
 <tb> Example <SEP> 8 <SEP> 18, <SEP> 8 <SEP> it <SEP> 10, <SEP> 5
 <tb> Example <SEP> 9 <SEP> 16, <SEP> 7 <SEP> 12 <SEP> 8, <SEP> 5 <SEP>
 <tb> Example <SEP> 10 <SEP> 20, <SEP> 1 <SEP> it <SEP> 915 <SEP>
 <tb> Example <SEP> 11 <SEP> 14, <SEP> 9 <SEP> 11 <SEP> 7, <SEP> 4
 <tb> Example <SEP> 13 <SEP> 14, <SEP> 8 <SEP> 11 <SEP> 6, <SEP> 4
 <tb> Example <SEP> 14 <SEP> l5, <SEP> 8 <SEP> 13 <SEP> 7,

    <SEP> 6 <SEP>
 <tb> Example <SEP> 15 "A" 16, <SEP> 7 <SEP> 12 <SEP> 9, <SEP> 5
 <tb> Example <SEP> 15 "B" 15, <SEP> 9 <SEP> 10 <SEP> 7, <SEP> 4
 <tb> Example <SEP> 15 "C" 15, <SEP> 1 <SEP> 10 <SEP> 7, <SEP> 3 <SEP>
 <tb> MK <SEP> 0787 <SEP> 14.6 <SEP> 10 <SEP> 6
 <tb> Example <SEP> 17 <SEP> 11 <SEP> 8 <SEP> 3, <SEP> 4 <SEP>
 <tb> Example <SEP> 18 <SEP> 14.9 <SEP> 6 <SEP> 3, <SEP> 9
 <tb> Example <SEP> 19 <SEP> 27 <SEP> 16.7 <SEP> 15, <SEP> 1
 <tb> Example <SEP> 20 <SEP> 28.4 <SEP> 14 <SEP> 15.6
 <tb>
 The compounds are dissolved in 0.1 M phosphate buffer, pH 7.



  The values are recorded on a single experiment at the rate of 4 mice per compound.



  * = t # corresponds to the half-life in minutes ** = AUC corresponds to the area under the blood concentration-time curve.

  <Desc / Clms Page number 103>

 



   The following examples illustrate the invention without limitation.



  EXAMPLE 1 Preparation of the internal salt of l-methyl-4- / 2- hydroxide
 EMI103.1
 carboxy-6c / 3.
 EMI103.2
 

  <Desc / Clms Page number 104>

 



   A solution of 673 mg (1.86 millimole) of 6- / l- (R) -hydroxyethy17-3,7-dioxo-1-azabicyclo3 is cooled to -10 ° C. in a nitrogen atmosphere. / hept-2-ene-2-carboxylate of p-nitrobenzyl (1) in 10 ml of acetonitrile, to which is added a solution of 245 mg (1.90 millimole) of diisopropylethylamine in 1 ml of acetonitrile and then, dropwise, 510 mg (1.90 millimole) of diphenyl chlorophosphate in 1 ml of acetonitrile in 2 minutes The resulting solution is stirred at -10 ° C. for 15 minutes to obtain 3- (diphenylphosphoryloxy) -6 t- [1- (R) -hydroxyethyl] -7-oxo-1-azabicy-
 EMI104.1
 cloS3. 2. p-nitrobenzyl Q7hept-2-ene-2-carboxylate.

   To this solution is added a solution of 245 mg (1.90 millimoles) of diisopropylethylamine in 0.5 ml of acetonitrile, then a solution of 270 mg (2.16 millimoles) of 4-mercaptomethylpyridine in 0.5 ml of acetonitrile. The reaction mixture is stirred at -10 ° C. for 60 minutes and the resulting white precipitate is collected by filtration, which is washed with 5 ml of ice-cold acetonitrile to collect 660 mg (yield of 76%) of compound 2 which is in crystals. white, PF 145 C.



  NMR (DMSO-6) 6: 1.20 (3H, d, J = 6, OHz), 3.2-3.4 (3H, m), 3.7-4, 1 (2H, m), 4 , 25 (2H, s), 5.05 (1H, d, J = 4, OHz), 5.25 (1H, d, J = 14, OHz), 5.48 (1H, d, J = 14 OHz ), 7.40 (2H, d, J = 5.5Hz), 7.70 (2H, d, J = 8.5Hz), 8.23 (2H, d, J = 8.5Hz) and 8.58 (2H, d, J = 5.5Hz).



  IR (KBr) max: 3400,1790, 1695 and 1600 cm-1.



  Analysis for C22H21N306S
Calculated: C, 58.01, H, 4.56, N, 9.12, S, 7.04%
Found: C, 57.74, H, 4.56, N, 9.58, S, 7, 21%.



   5 ml of methyl iodide are added to a solution of 660 mg (1.41 millimole) of intermediate 2 in 140 ml of acetone. The reaction solution is stirred for 8 hours at 25 C. The solvent is evaporated

  <Desc / Clms Page number 105>

 under vacuum to obtain a slightly yellow solid which is triturated in diethyl ether to obtain 779 mg (90% yield) of compound 3 in the form of a white amorphous solid, P. F. 1300C (decomposition).



  NMR (DMSO-6) 6: 1.15 (3H, d, J = 6, OHz), 3.2-3, 4 (3H, m), 3.7-4, 1 (2H, m), 4 , 25 (3H, s), 4.30 (2H, s), 5.25 (1H, d, J = 14, OHz), 5.50 (1H, d, J = 14, OHz), 7.70 (2H, d, J = 9, OHz), 8.10 (2H, d, J = 7, OHz), 8.25 (2H, d, J = 9, OHz) and 8.90 (2H, d, J = 7, OHz).



  IR (KBr) tlmax: 3400,1770, 1690 and 1640 cm-1.



  Analysis for C23H24N306SI. H20
Calculated: C, 44.39, H, 4.22, N, 6.82, S, 5.20%
Found: C, 44.66, H, 4.01, N, 6.84, S, 5.64%.
 EMI105.1
 



   140 mg (1.4 millimole) of potassium bicarbonate and 125 mg (0.07 millimole) of dibasic potassium phosphate are added to a solution of 779 mg (1.27 millimole) of compound 3 in tetrahydrofuran-water-ether diethyl (80 ml-80 ml- 100 ml). 700 mg of palladium on carbon are then added to

  <Desc / Clms Page number 106>

 10% and the mixture is hydrogenated in a Parr shaker for 45 minutes at 276 kPa. The mixture is filtered and the catalyst is washed with water (2 × 10 ml). The mixture of filtrate and washing water is extracted with diethyl ether (150 ml), then lyophilized to obtain a brown powder. This crude product is purified on a C18 phase inversion column
 EMI106.1
 BONDAPAK (30 g) (Waters Associates), which are eluted with water under a pressure of 55 kPa.

   Each fraction (20 ml) is examined by high pressure liquid chromatography and the fractions showing absorption in the ultraviolet at # max = 300 nm are collected, then they are lyophilized to collect 135 mg (yield of 32%) of compound 4 sought which is a slightly yellow solid.



  NMR (D20) 6: 1.25 (3H, d, J = 6, OHz), 2.7-3, 2 (3H, m), 3.40 (1H, q, J = 9, 0 and 2, 5Hz), 3.9-4, 2 (2H, m), 4.40 (3H, s), 4.72 (2H, s), 8, 10 (2H, d, J = 6, OHz) and 8 , 72 (2H, d, J = 6, OHz).



  IR (KBr) max: 3400, 1755, 1640 and 1590 cm-1.
 EMI106.2
 



  UVmax O): 2.96 nm (E = 7782), 258 nm (E.



  EXAMPLE 2.-
 EMI106.3
 

  <Desc / Clms Page number 107>

 
 EMI107.1
 PNB = p-Nitrobenzyl.



   Nitrogen is bubbled at room temperature for 5 minutes in a suspension of 1.1 g (2.93 millimoles) of diazo-compound 1 in 30 ml of dry benzene. 25 mg of dimeric rhodium acetate are added to the suspension and the mixture is heated to reflux for 45 minutes. The hot solution is diluted with ethyl acetate (25 ml), filtered to separate the catalyst and the filtrate is evaporated to dryness to obtain ketone 2 in the form of a white solid. This is dissolved in dry acetonitrile (20 ml) and

  <Desc / Clms Page number 108>

 the solution is cooled to -10 C. Under a nitrogen atmosphere, diisopropylethylamine (417 mg, 3.2 millimoles) is added to this solution first, then 810 mg (3.0 millimoles) of diphenyl chlorophosphate and the reaction mixture is stirred at -10 ° C for 20 minutes.

   Then added to this reaction mixture diisopropylethylamine (420 mg, 3.2 millimoles) and
 EMI108.1
 2-ethanethiol (560 mg, 4.30 millimoles) in 2 ml of acetonitrile / J. 26: 82 (1961) Ludwig Bauer and Libero A. Gardella Jr.



  /. the reaction mixture is stirred for 1 hour at -5 ° C. to -10 ° C., then diluted with methylene chloride (100 ml) and washed thoroughly with brine-water (1: 1), H3PO4 to 4%, 5% NaHC03, water and brine. The organic phase is dried (MgSO 4) and evaporated to collect a white solid. The solid is washed with diethyl ether: hexane (1: 1) and dried under high vacuum to isolate 901 mg
 EMI108.2
 (63.9%) of compound 3.



  IR (KBr) max: 1790 and 1690 cm-l.



  * NMR (CDC13 / DMSO) J: 1.20 (3H, d, J = 3, OHz, CH3), 2.8-3, 2 (7H, m), 3.9-4, 4 (2H, m ), 5.1 (1H, d), 5.4 (2H, q), 7.3 (2H, d,), 8.5 (2H, q), 7, 76 (2H, d) and 8, 3 (2H, q).
 EMI108.3
 

  <Desc / Clms Page number 109>

 
 EMI109.1
 



   A suspension of carbapenem 3 (890 mg, 1.85 millimole) and 7 ml of iodomethane in 200 ml of dry acetone and 12 ml of methylene chloride is stirred at 25 ° C. for 24 hours. The reaction mixture forms a clear solution in 18 hours. The solvent is removed under reduced pressure, then the residue is washed with diethyl ether to collect 920 mg (1.48 millimole) (79.8%) of compound 4 which is a frothy solid.



  IR (KBr) 9 max: 1765 and 1690 cm-1.



  NMR (DMSO) 6: 1.3 (3H, d, J = 3, OHz), 3.1-3, 7 (7H, m), 4.1 (3H, m), 4.3 (3H, s ), 5.38 (2H, d, J = 7, OHz), 8.1 (2H, d, J = 3, OHz), 8.9 (2H, d, J = 3, OHz), 7.6 (2H, d, J = 4, OHz) and 8.2 (2H, d, J = 4, OHz).
 EMI109.2
 

  <Desc / Clms Page number 110>

 



   265 mg (1.51 millimole) of dibasic potassium phosphate, 190 mg (1.9 millimole) of potassium hydrogen carbonate and 800 mg of 10% palladium on carbon are added to carbapenem 4 (920 mg, 1.47 millimole) dissolved in 90 ml of tetrahydrofuran, 90 ml of diethyl ether and 90 ml of water. The compound is hydrogenated for 1 hour at 310 kPa. The catalyst is separated by filtration on CELITE and the filtrate is washed with diethyl ether (3 × 25 ml). The aqueous layer is lyophilized to collect a brown material which is then purified twice by chromatography on a C18 BONDAPAK (Waters Associates) phase inversion column of 12 g to collect 55 mg of compound 5.



  IR (KBr) 1 / max: '1750 and 1640 cm-l.



  NMR (D20) 6: 1.30 (3H, d, J = 3, OHz), 3.0-3.5 (7H, m), 4.3 (3H, s), 4.0-4.5 (3H, m), 7.90 (2H, d), 8.70 (2H, d).



  EXAMPLE 3.



  Preparation of 3- (N-methylpyridine-3-yl-methanethio) - 6 - [T.- (R) -hydroxyethyl7-7-oxo-l-azabicyclo (3. 2. 0) hept-2-ene-2- carboxylate
 EMI110.1
 

  <Desc / Clms Page number 111>

 
 EMI111.1
 
 EMI111.2
 3- (Pyridine-3-yl-methanethio) - / l- hept-2-ene-2-carboxylate of p-nitrobenzyl
A solution of 377 mg (2.9 millimoles) of diisopropylethylamine in 1 ml of acetonitrile is added, then 786 mg (2.9 millimoles) of diphenyl chlorophosphonate in 1 ml of acetonitrile, in a nitrogen atmosphere, to a solution cooled to 0 C of 925 mg (2.66 millimoles) of the ketone intermediate 5 in 14 ml of acetonitrile.

   The resulting solution is stirred for 15 minutes at 0 ° C., then a solution of 377 mg (2.9 moles) of 3mercaptomethylpyridine [prepared as described in Can.



  J. Chem., 56.3968 (197827 in 2 ml of acetonitrile. The reaction solution is stirred for 90 minutes at 0 C.



  The precipitate is collected by filtration and washed

  <Desc / Clms Page number 112>

 with 20 ml of ethyl acetate to obtain 950 mg (yield of 60%) of the desired compound having white crystals.



  NMR (DMSO-6) 6: 1, 30 (3H, d, J = 6, OHz), 3.4-4, 2 (5H, m), 4.25 (2H, s), 5.1 (1H , d, J = 4.5Hz), 5.40 (2H, ABq, J = 14.4Hz), 7.2-8.5 (8H, m).



  IR (KBr) # max: 3500,1775 and 1580 cm-1.



  Analysis for C22H21N306S1
Calculated: C, 58.01, H, 4.65, N, 9.23, S, 7.04%
Found: C, 57.19, H, 5.19, N, 8.76, S, 7.08%.
 EMI112.1
 

  <Desc / Clms Page number 113>

 



    3- (N-Methylpyridine-3-yl-methanethio) -6 - [1 [(R) -hydroxyethyl] -7-oxo-1-azabicylco (3. 2. 0) - hept-2-ene-2-carboxylate
5 ml of methyl iodide are added to a solution of 730 mg (1.56 millimoles) of compound 19 in 120 ml of acetone and the reaction mixture is stirred for 18 hours at room temperature. The precipitate is collected by filtration and washed with acetone (10 ml) to obtain 940 mg (100% yield) of the quaternized pyridine which is a slightly yellow powder.



  NMR (DMSO-d6) 6: 1.25 (3H, d, J = 5.8Hz), 3.6-4, 3 (5H, m), 4.20 (3H, s), 4.25 (2H , s), 5.25 (1H, d, J = 7.2Hz), 5.40 (2H, ABq, J = 12.16Hz), 7.6-9.2 (9H, m).



  IR (KBr) max: 3300,1765 and 1690 cm-1.



  Analysis for C23H24N306S1Il
Calculated: C, 46.24, H, 4.05, N, 7, 03, S, 5.37%
Found: C, 45.82, H, 4.11, N, 6.87, S, 6, 10%.



   200 mg of potassium bicarbonate and 349 mg of dibasic potassium phosphate in 90 ml of water are added, then 1.0 g of palladium on carbon to a solution of 933 mg (1.6 mmol) of compound 20 in 90 ml of tetrahydrofuran and 90 ml of ether. The mixture is hydrogenated in a Parr shaker for 45 minutes at 310 kPa. The mixture is filtered on a layer of CELITE and the catalyst is washed with water (2 × 10 ml). The mixture of filtrate and washing water is extracted with ether (2 × 100 ml) and lyophilized to obtain a yellow solid which is purified on a column for inversion of phase C18 BONDAPAK
 EMI113.1
 (Waters which are eluted with 5% aceto- (Waters Associates) (8 th nitrile in water under a pressure of 55 kPa.

   Each fraction of 15 ml is examined by liquid chromatography under high pressure and the fractions are combined.

  <Desc / Clms Page number 114>

 tions having an absorption in the ultraviolet at Amax 300 nm, then they are lyophilized to obtain 230 mg (yield of 43%) of the desired compound having slightly yellow crystals, P. F. 130 C (decomposition).



  NMR (D20) #: 1.25 (3H, d, J = 7, OHz), 3.12 (2H, dd,
 EMI114.1
 J = 7.9Hz, 1.6Hz), 3.42 (2H, q, J = 7.2Hz, 1.6Hz), 3.9-4, 6 (3H, m), 4.25 (2H, s ), 4, 42 (3H, s) and 8, 0-9, 0 (4H, m).



  IR (KBr) Vmax: 3400, 1750 and 1580 cm¯ UV # max (H2O): 298 nm (f = 8058).



  Analysis for C16H18N204S1. 2H20
Calculated: C, 51.87, H, 5.44, N, 7.56%
Found: C, 51, 95, H, 5.66, N, 7.56%.



  EXAMPLE 4.
 EMI114.2
 



  Preparation of 3- 6e-rl- hept-2-ene-2-carboxylate
 EMI114.3
 

  <Desc / Clms Page number 115>

 
 EMI115.1
 
 EMI115.2
 3- - / l- p-nitrobenzyl hept-2-ene-2-carboxylate
A solution of 377 mg (2.92 millimoles) of diisopropylethylamine in 1 ml of acetonitrile is added, then 786 mg (2.90 millimoles) of diphenyl chlorophosphonate in 1 ml of acetonitrile, in a nitrogen atmosphere, to a solution cooled to 0 C of 925 mg (2.65 millimoles) of the ketone intermediate 5 in 14 ml of acetonitrile. The resulting solution is stirred for 15 minutes at 0 ° C., then a solution of 377 mg (2.92 millimoles) of diisopropylethylamine in 1 ml of acetonitrile is added thereto, followed by 350 mg (3.0 millimoles) of 2- mercaptomethylpyridine prepared as described in Can. J.

   Chem., 56.3068 (1978 in 1 ml of acetonitrile. The reaction solution is stirred for 2 hours at -10 C. The precipitate is collected by filtration and washed with 20 ml of methylene chloride to obtain 650 mg (54% yield) of the desired compound which is a yellow powder.



  NMR (DMSO-d6) 6: 1.26 (3H, d, J = 7, OHz), 2.7-3.5, (4H, m), 3.9-4.3, (2H, m), 4 , 2 (2H, s), 5.42 (2H, ABq, J = 14, 4Hz) and 7.2-8.8 (8H, m).



  IR (KBr) 1Jmax: 3400.1775 and 1690 cm-1.

  <Desc / Clms Page number 116>

 
 EMI116.1
 



  Analysis for C22H21N306S1 Calculated: C, 58, 01, H, 4, 65, N, 9, 23, S, 7, 04% Found: C, 57, 56, H, 4, 92, N, 8, 94, S , 7.03%.
 EMI116.2
 



  OH \ -s- 'acetone 22 OH if OH r - f, 0, 3 23 Pd / C OH N 2 CH3 oe0 in, 24 24
 EMI116.3
 3- (N-Methylpyridine-3-yl-methanethio) -6c [l- (3. 2. 0) hept-2-ene-2-carboxylate 4 ml of methyl iodide are added to a 650 mg solution ( 1.39 millimoles) of compound 22 in 100 ml of acetone. The reaction mixture is stirred

  <Desc / Clms Page number 117>

 for 3 days at room temperature. The precipitate is collected by filtration and washed with acetone (10 ml) to obtain 500 mg (yield of 60%) of the quaternized pyridine 23 which is a slightly yellow solid.



  NMR (DMSO-d6) 6: 1.26 (3H, d, J = 7, OHz), 3.9-4, 2 (2H, m), 4.4 (3H, s), 4.78 (2H , s), 5.2 (2H, d, J = 3.9Hz), 5.50 (2H, Abq, J = 14Hz) and 7.8-9, 4 (8H, m).



  IR (KBr) Vmax: 3400.1765 and 1690 cm-1.



  Analysis for C23H24N306SlIl
Calculated: C, 46.24, H, 4.05, N, 7.03, S, 5.37%
Found: C, 45.62, H, 4.27, N, 6.80, S, 5.30%.



   215 mg (2.15 millimoles) of potassium bicarbonate and 374 mg (2.1 millimoles) of dipotassium hydrogen phosphate are added to 90 ml of water, followed by 1.0 g of 10% palladium on carbon to a solution of 1.0 g (1.167 millimole) of compound 23 in 90 ml of tetrahydrofuran and 90 ml of ether. The mixture is hydrogenated
 EMI117.1
 in a Parr shaker for 45 minutes, under 310 The mixture is filtered on a layer of CELITE and the catalyst is washed with water (2 × 10 ml). The mixture of filtrate and washing waters is extracted with ether (2 × 200 ml) and lyophilized to obtain a yellow solid which is purified on a column with C18 phase inversion BONDAPAK (Waters Associates) (10 g) which 'is eluted with 5% acetonitrile in water under a pressure of 55 kPa.

   Each fraction of 15 ml is examined by liquid chromatography under high pressure and the fractions having an absorption in the ultraviolet at ^ max 300 nm are combined, then they are lyophilized to obtain 390 mg (yield of 44%) of the desired compound. By recrystallization of this in water acetone-ethanol, fine needles are obtained, P. F. 194-1960C (decomposition).



  NMR (D20) zo: 1.30 (3H, d, J = 6.2Hz), 3.2 (2H, q,

  <Desc / Clms Page number 118>

 J = 9, OHz, 3.6Hz), 3.46 (1H, q, J = 6, OHz, 2, 7Hz), 4.1-4, 6
 EMI118.1
 (3H, m), 4.60 (3H, s) and 7.9-8.9 (4H, m).



  IR (KBr) lJmax: 3400, 1755 and 1590 cm-l.



  W (H20): 298 nm (é = 8058), Analysis for C16H28N2O4S1.2H2O
Calculated: C, 51, 87, H, 5.44, N, 7.56%
Found: C, 51, 37, H, 5.69, N, 7.37%.



  EXAMPLE 5.



  Preparation of 3- (N-methylpyridine-3-yl-ethanethio) - 6 # - [1- (R) -hydroxyethyl] -7-oxo-1-azabicyclo (3. 2. 0) hept-2-ene-2 -carboxylate
 EMI118.2
 

  <Desc / Clms Page number 119>

 
 EMI119.1
   3- (Pyridine-3-yl-ethanethio) -6 # - [1- (R) -hydroxyethyl] - 7-oxo-l-azabicyclo (3. 2, O) hept-2-ene-2-carboxy-late p-nitrobenzyl
710 mg (5.5 millimoles) of diisopropylethylamine in 1 ml of acetonitrile are added, followed by 1.4 g (5.0 millimoles) of diphenyl chlorophosphate in 1 ml of acetonitrile, under nitrogen, to a solution. cooled 1.78 g (5.0 millimoles) of the intermediate ketone 5 in 25 ml of acetonitrile.

   The resulting solution is stirred for 20 minutes at 0 ° C. and then a solution of 710 mg (5.5 millimoles) of diisopropylethylamine in 1 ml of acetonitrile is added thereto, followed by a solution of 850 mg (6.1 millimoles) of thiol 54 ± -Prepared as described in J. Org. Chem., 26.82 (1961) in 2 ml of acetonitrile. The reaction solution is stirred for 60 minutes at 0 C. The precipitate is collected by filtration which is washed with methylene chloride (20 ml) to obtain 1.3 g (57%) of the desired product which is a yellow solid.



  NMR (CDC13) #: 1.25 (3H, d, J = 6.5Hz), 2.6-3.4 (7H, m), 4.2-4.6 (2H, m), 5.30 and 5.65 (1H each, ABq, J = 14Hz) and 7.2-8.5 (8H, m).



  IR (KBr) Vmax: 3400.1780 and 1680 cm-1.

  <Desc / Clms Page number 120>

 
 EMI120.1
 

  <Desc / Clms Page number 121>

 



  3- (N-Methylpyridine-3-yl-ethanethio) -60 (- ± -1- (R) -hydroxyethyl7-7-oxo-1-azabicyclo (3. 2. 0) hept-2-ene-2-carboxylate
5 ml of methyl iodide are added to a solution of 800 mg (1.7 millimole) of compound 53 in 50 ml of acetonitrile. The reaction mixture is stirred for 48 hours at room temperature. The precipitate is collected by filtration and washed with acetonitrile (15 ml) to obtain 810 mg (yield of 76%) of the quaternized pyridine 55 which is a slightly yellow powder.



  NMR (DMSO-d6) 6: 1.20 (3H, d, J = 5.6Hz), 3.2-4, 3 (9H, m), 4.20 (3H, s), 5.26 and 5 , 55 (1H each, Abq, J = 15Hz) and 7.8-9, 2 (8H, m).



  IR (KBr) Omax: 3400, 1770 and 1690 cm-1.



   100 ml of a buffer solution of pH 7.0 are added, then 1.0 g of 10% palladium on carbon to a solution of 790 mg (1.27 millimole) of compound 55 in 100 ml of tetrahydrofuran and 100 ml of 'ether. The mixture is hydrogenated in a Parr shaker for 40 minutes at 276 kPa. The mixture is filtered on a layer of CELITE and the catalyst is washed with water (2x10 ml). The mixture of filtrate and washing waters is extracted with ether (3 × 100 ml) and lyophilized to obtain a yellow powder which is purified on a CI8 BONDAPAK column (Waters Associates) (30 g) which is eluted with 10% acetonitrile in water at a pressure of 55 kPa.



   Each fraction of 15 ml is examined by liquid chromatography under high pressure and the fractions having an absorption in the ultraviolet at X max 300 nm are combined, then they are lyophilized to collect 65 mg (yield of 15%) of the desired compound which is a yellow powder.

  <Desc / Clms Page number 122>

 NMR (D20) 6: 1.25 (3H, d, J = 6, 2Hz), 3, 1-3, 6 (7H, m),
 EMI122.1
 4, 0-4, 3 (2H, m), 4.32 (3H, s) and 7, 8-8, 9 (4H, m).



  IR (KBr) Vmax: 3400, 1750 and 1590 cm-l.



  UVmax (H2O): 300 nm (f = 8108), EXAMPLE 6.



  Preparation of 3- (1-propylpyridine-4-yl-methanethio) - 6 # - [1- (R) -hydroxyethyl] -7-oxo-1-azabicyclo (3. 2. 0) hept-2-ene-2 -carboxylate
 EMI122.2
   3- (Pyridine-3-yl-methanethio) -6 # - [1- (R) -hydroxyethyl] -7-oxo-1-azabicyclo (3. 2. 0) hept-2-ene-2-carboxylate p -nitrobenzyl
Cooled to -10 C in a nitrogen atmosphere
 EMI122.3
 673 mg (1.86 millimole) solution of 6-hydroxy-, L (R) -hydroxy- ethyl] -3,7-dioxo-1-azabicyclo [3.2.0] hept-2-ene-2-carboxylate p-nitrobenzyl (5) in 10 ml of acetonitrile.



  A solution of 245 mg (1.90 millimole) of diisopropylethylamine in 1 ml of acetonitrile is added, then dropwise 510 mg (1.90 millimole) of chlorophos-

  <Desc / Clms Page number 123>

 diphenyl phate in 1 ml of acetonitrile, in 2 minutes. The resulting solution is stirred for 15 minutes at -10 ° C. to obtain 3- (diphenylphosphoryloxy) -6 -
 EMI123.1
 re Lï- 2. 0) hept-2- (R) -hydroxyethyl17-7-oxo-1-azabicyclo- (3, en-2-carboxylate p-nitrobenzyl. To this solution is added a solution of 245 mg (1 , 90 millimole) of diisopropylethylamine in 0.5 ml of acetonitrile, then a solution of 270 mg (2.16 millimoles) of 4mercaptomethylpyridine in 0.5 ml of acetonitrile.

   The reaction mixture is stirred at -10 ° C. for 60 minutes and the resulting white precipitate is collected by filtration, which is washed with 5 ml of ice-cold acetonitrile to collect 660 mg (yield of 76%) of compound 51 which is in crystals. white, PF 145 C.



  NMR (DMSO-d6) 6: 1.20 (3H, d, J = 6, OHz), 3.2-3, 4 (3H, m), 3.7-4, 1 (2H, m), 4 , 25 (2H, s), 5.05 (1H, d, J = 4, OHz) 5.35 (1H, d, J = 14, OHz), 5.48 (1H, d, J = 14, OHz ), 7.40 (2H, d, J = 5.5Hz), 7.70 (2H, d, J = 8.5Hz), 8.23 (2H, d, J = 8.5Hz) and 8.58 (2H, d, J = 5.5Hz).



  IR (KBr) max: 3400,1790 and 1695 cm-1.



  Analysis for C22H2lN306S
Calculated: C, 58.01, H, 4.56, N, 9.23, S, 7.04%
 EMI123.2
 Found: C, 57, 74, H, 4, 56, N, 9, 58, S, 7, 21%.
 EMI123.3
 



  OH i-r \ / s N acetone 0 COpNB if

  <Desc / Clms Page number 124>

 
 EMI124.1
 
 EMI124.2
 3- - /T.- hept-2-ene-2-carboxylate
2 ml of allyl bromide and 380 mg of sodium iodide are added to a solution of 900 mg (2.13 millimoles) of compound 51 in 150 ml of acetone. The mixture is stirred for 48 hours at room temperature and the solvent is evaporated under vacuum to obtain a yellow solid. This is suspended in 120 ml of acetonitrile, the whole is filtered and evaporated to dryness to collect 1.0 g (88% yield) of the desired compound which is a yellow solid.



  NMR (CD3CN) 6: 1.20 (3H, d, J = 6.2Hz), 3.0-3.4 (4H, m), 4.0-4.4 (4H, m), 5.1 -5.6 (4H, m) and 7.4-7.9 (8H, m).



  IR (KBr) Vmax: 3400, 1770 and 1690 cm-l.



  Analysis for C25H26N306S1Il
Calculated: C, 48.16, H, 4, 21, N, 6.74, S, 5.15%
Found: C, 48.55, H, 4.46, N, 6.69, S, 5.15%.
 EMI124.3
 

  <Desc / Clms Page number 125>

 
 EMI125.1
 



    3- (1-Propylpyridine-4-yl-methanethio) -6 # - [1- (R) - hydroxyethyl 7-7-oxo-1-azabicyclo (3.2. 0) hept-2-ene-2carboxylate
100 ml of buffer solution of pH 7.0 is added, then 1.0 g of 10% palladium on carbon to a solution of
 EMI125.2
 1.27 g (2.15 millimoles) of compound 52 in 100 ml of tetrahydrofuran and 100 ml of ether. The mixture is hydrogenated in a Parr shaker for 40 minutes at 276 kPa. The mixture is filtered on a layer of CELITE and the catalyst is washed with water (2 × 10 ml). The mixture of filtrate and washing water is extracted with ether (3 × 100 ml) and lyophilized to obtain a yellow powder which is purified on a column of C18 BONDAPAK (Waters Associates) (40 g) which is eluted with 10% acetonitrile in water at a pressure of 55 kPa.

   Each fraction of 15 ml is examined by liquid chromatography under high pressure and the fractions having an absorption in the ultraviolet at max 300 nm are combined, then they are lyophilized to obtain 48 mg (yield of 6%) of the desired compound which is a yellow powder.



  NMR (D20) 6: 0.95 (3H, t, J = 7.5Hz), 1.25 (3H, d, J = 7, OHz), 2.05 (2H, sextuplet, J = 7.5Hz) , 3.10 (2H, dd, J = 10Hz, 2.5Hz), 3.35 (1H, dd, J = 6.5Hz, 2.5Hz), 4.0-4.8 (6H, m), 7, 1 (2H, d, J = 6, OHz) and 7.80 (2H, d, J = 6, OHz).



  IR (KBr) 0 max: 3400, 1750 and 1590 cm-l.

  <Desc / Clms Page number 126>

 



  Analysis for C18H22N204S, 2H20
Calculated: C, 54.52, H, 6.10, N, 7.0%
Found: C, 54.32, H, 6.03, N, 6.99%.



  EXAMPLE 7.
 EMI126.1
 



  Preparation of 3-thio) -Ll- (N-methyl-3-methylpyridine-2-methane- (3. 2.0) hept-2-ene-2-carboxylate
 EMI126.2
 3-Methyl-2-mercaptomethylpyridine
A solution of 2.45 g (17.0 millimoles) of the chlorinated compound 36 and 1.37 g (18.0 millimoles) of thiourea in 60 ml of absolute ethanol is heated at reflux for 5 hours. By evaporation of the ethanol, then addition of ether, 3.08 g (72% yield) of the isothiouronium salt are obtained which is dissolved in 10 ml of water containing 1.44 g (26 millimoles) d hydroxide

  <Desc / Clms Page number 127>

 sodium. The solution is then heated at 1000C for 5 minutes in a nitrogen atmosphere. The reaction mixture is cooled to 5 ° C., it is adjusted to pH 6.4 by addition of acetic acid and it is extracted with ether (4x50 ml).

   The mixture of ethereal extracts is washed with 5% aqueous sodium bicarbonate and with brine. By evaporating the dried solvent (MgSO 4), 1.4 g (83% yield) of thiol 37 are obtained in the form of a yellow oil which is used in the next stage without further purification.



  NMR (CDC13) 6: 2.20 (3H, s), 2.5-2, 7 (1H, broad s), 3.8 (2H, t, J = 6.5Hz) and 6.9-8, 2 (3H, m).
 EMI127.1
 

  <Desc / Clms Page number 128>

 



  3- [3-Methylpyridine-2-yl-methanethio] - 6 # [1- (R) -hydroxyethyl] -7-oxo-1-azabicyclo (3. 2. 0) hept-2-ene-2-carboxylate p-nitrobenzyl
960 mg (5.8 millimoles) of diisopropylethylamine in 2 ml of acetonitrile are added, then 1.4 g (5.8 millimoles) of diphenyl chlorophosphate in 2 ml of acetonitrile, in a nitrogen atmosphere, to a solution cooled to 0 C of 1.74 g (5.0 millimoles) of the intermediate ketone 5 in 25 ml of acetonitrile. The resulting solution is stirred for 20 minutes at 0 ° C., then a solution of 760 mg (5.8 millimoles) of diisopropylethylamine in 2 ml of acetonitrile is added thereto, followed by another 810 mg of mercaptomethylpyridine 37 in 3 ml of acetonitrile .

   The reaction mixture is stirred for 1 hour at 0 C. The precipitate is collected by filtration which is washed with acetonitrile to obtain 1.56 mg (yield of 66%) of the desired compound which is a white solid, PF 1450C.



  NMR (DMSO-d6) 6: 1, 23 (3H, d, J = 6.5Hz), 2.30 (3H, s), 3.1-4, 3 (6H, m), 4.35 (2H , s), 5.20 and 4.45 (1H each, ABq, J = 15, OHz) and 7.3-8, 4 (7H, m).



  IR (KBr) U? max: 3400.1767 and 1695 cm-l.



  Analysis for C24H26N309S2F
Calculated: C, 47, 91, H, 4.69, N, 6.98, S, 10.66%
Found: C, 47.72, H, 4.34, N, 6.72, S, 11.22%.
 EMI128.1
 

  <Desc / Clms Page number 129>

 
 EMI129.1
 
 EMI129.2
 



  3- (N-Methyl-3-methylpyridine-2-yl-methanethio) -6xLJ- (3. 2. 0) hept- (R) -hydroxyethyl-7-oxo-1-azabicyclo2-ene-2-carboxylate
270 mg (2.33 millimoles) of methyl fluorosulfonate are added to a solution of 680 mg (1.45 millimoles) of compound 38 in 120 ml of methylene chloride. The reaction mixture is stirred for 3 hours at room temperature. The precipitate is collected by filtration, which is washed with methylene chloride (5 ml) to obtain 840 mg (yield of 99%) of the quaternized pyridine 39 having white crystals.



  NMR (DMSO-d6) 6: 1.15 (3H, d, J = 5.8Hz), 2.62 (3H, s), 3.2-4.4 (5H, m), 4.45 (3H , s), 4.60 and 4.82 (1H each, ABq, J = 9.2Hz), 5.30 and 5.46 (1H each, ABq, J = 12, 8Hz) and 7.6-8, 9 (7H, m).



  IR (KBr) Vmax: 3400.1750 and 1590 cm-1.

  <Desc / Clms Page number 130>

 



  Analysis for C24H24N309S2F
Calculated: C, 49.14, H, 4.47, N, 7.13, S, 11, 43%
Found: C, 49.56, H, 4.16, N, 7.26, S, 11.03%.



   100 ml of buffer solution of pH 7.0 is added, then 750 mg of 10% palladium on carbon to a solution of 810 mg (1.39 millimole) of compound 39 in 100 ml of tetrahydrofuran and 100 ml of ether. The mixture is hydrogenated in a Parr shaker for 60 minutes at 310 kPa in a cold room (4 to 60C). The mixture is filtered on a layer of CELITE and the catalyst is washed with ether (2 × 10 ml). The mixture of filtrate and washing liquor is extracted with ether (2x40 ml) and lyophilized to obtain a yellow solid which is purified on a column of C18 BONDAPAK (Waters Associates) (20 g) which is eluted with 5% acetonitrile in water at a pressure of 55 kPa.

   Each fraction of 15 ml is checked by liquid chromatography under high pressure and the fractions having an absorption in the ultraviolet at ^ max 300 nm are combined, then they are lyophilized to collect 141 mg (yield of 30%) of the desired compound which is a yellow solid.



  NMR (D20) #: 1.24 (3H, d, J = 7, OHz), 2.62 (3H, s), 3.2- 3.5 (3H, m), 4.2-4, 4 (2H, m) 4.45 (3H, s), 4.50 and 4.59 (1H each, ABq, J = 12.6Hz), 7.82 (1H, q, J = 7, OHz, 6, 5Hz), 8.35 (1H, d, J = 7, OHz) and 8.65 (1H, d, J = 6.5Hz).



  IR (KBr) L? max: 3400.1750 and 1580 cm-1.



    UV At max (H2O): 296 nm (E = 8014).
 EMI130.1
 



  Analysis for CyHQNsOSi. HO Calculated: C, 57.85, H, 5.85, N, 7.94% Found: C, 58.60, H, 5.86, N, 7.87%.

  <Desc / Clms Page number 131>

 



  EXAMPLE 8.
 EMI131.1
 



  Preparation of 3-methanethio) -6- / T- 7-az bicyclo (3.0) hept-2-ene-2-carboxylate
 EMI131.2
 

  <Desc / Clms Page number 132>

 
 EMI132.1
 P-nitrobenzyl hept-2-ene-2carboxylate 3-2-methylthiazol-4-yl-methanethio7-6d- / l- hydroxyethyl (3. 2. 0)
0.83 ml (4.6 millimoles) of diisopropylethylamine is added, then 1.16 g (4.3 millimoles) of diphenyl chlorophosphate in 2 ml of acetonitrile, under nitrogen, to a solution cooled to 0 ° C. 1.4 g (4.0 millimoles) of the intermediate ketone 5 in 12 ml of acetonitrile. The resulting solution is stirred for 30 minutes at 0 ° C. to obtain 3- (di-phenylphosphoryloxy) -6 # - / 1- (R) -hydroxyethyl 7-7-oxo-1-azabicyclo (3. 2. 0) hept -2-ene-2-carboxylate of p-nitrobenzyl.

   To this solution is added a solution of 0.83 ml (4.6 millimoles) of diisopropylethylamine in 2 ml of acetonitrile, then a solution of 0.62 g (4.2 millimoles) of 2-methyl-4-mercaptomethylthiazole prepared as described in J. Amer. Chem. Soc., 71, 3570 (1949je in 3 ml of acetonitrile. The reaction solution is stirred for 40 minutes at 0 C. The precipitate is collected and washed with ether (30 ml) to obtain 943 mg of the compound sought which is a white solid.



  NMR (CDC13) 6: 1, 32 (3H, d, J = 7Hz), 2.68 (3H, s), 3.20 (2H, m), 3.76 (1H, d, J = 5.5Hz ), 4.16 (2H, s), 4.20 (1H, m), 5.40 (2H, q, J = 14Hz), 7.06 (1H, s), 7.68 (2H, d, J = 8Hz) and 8.24 (2H, d, J = 8Hz)).



  IR (KBr) Vmax: 3500,1770 and 1700 cm-1.
 EMI132.2
 

  <Desc / Clms Page number 133>

 
 EMI133.1
 
 EMI133.2
 



  3- / 'l- (3. 2. 0) hept-2- (2-Methyl-N-methylthiazol-4-yl-methanethio) -6- -ene-2-carboxylate
0.27 ml (3.3 millimoles) of methyl fluorosulfonate is added to a solution of 525 mg (1.1 millimoles) of compound 9 in 20 ml of methylene chloride. The reaction mixture is stirred for 90 minutes at room temperature. The precipitate is collected by filtration and washed with methylene chloride (50 ml) to collect 650 mg (100% yield) of the quaternized thiazole which is used without further purification in the next stage.



   Thus, 100 ml of a buffer solution of pH 7.0 is added, then 500 mg of 10% palladium on carbon to a solution of compound 10 in 100 ml of tetrahydrofuran and 100 ml of ether. The mixture is hydrogenated in a Parr shaker for 45 minutes at 241 kPa. The mixture is filtered on a layer of CELITE

  <Desc / Clms Page number 134>

 and the catalyst is washed with water (2 × 10 ml). The mixture of filtrate and washing water is extracted with ether (2 × 100 ml) and lyophilized to obtain a yellow powder which is purified on a C18 BONDAPAK phase inversion column (8 g) (Waters Associates) which 'is eluted with 5% acetonitrile in water under a pressure of 55 kPa.

   Each 15 ml fraction is checked by high pressure liquid chromatography and the fractions having an absorption in the ultraviolet at max 300 nm are combined, then they are lyophilized to collect 145 mg (yield of 48%) of the desired compound which is a pale yellow powder.



  NMR (CDC13) 6: 1, 20 (3H, d, J = 7Hz), 2.92 (3H, s), 3.8 (1H, d, J = 3.5Hz), 3.20 (3H, d , J = 3Hz), 3.44 (1H, dd, J = lHz, J = 3.5Hz), 4.00 (3H, 5), 4.20 (3H, m), 4.36 (2H, m ) and 7.88 (1H, s).



  IR (KBr) l) max: 3400.1750 and 1585 cm-1. w). max (H2O): 296 nm (6 = 7,500).



  Analysis for Cl5H18N204S2. 2H20
Calculated: C, 46.15, H, 5.64, N, 7.17, S, 16.41%
Found: C, 46.50, H, 5.26, N, 7.13, S, 16.20%.



  EXAMPLE 9.
 EMI134.1
 



  Preparation of 3- thio) -6- / T.- -7-oxo-l-azabicyclo- (3. 2. 0) hept-2-ene-2-carboxylate
 EMI134.2
 

  <Desc / Clms Page number 135>

 
 EMI135.1
 2-Mercaptomethyl-N-methylimidazole
7.1 g (60 millimoles) of Nacetylthiourea are added to a solution of 10.4 g (58 millimoles) of 2-chloromethyl-N-methylimidazole 31 prepared as described in J. Amer. Chem. Soc., 71.383 ze in 200 ml of acetonitrile and the reaction mixture is heated at reflux for 90 minutes.

   The precipitate is filtered and washed with acetonitrile (20 ml) to obtain the isothiouronium salt which is then dissolved in 120 ml of ethanol and which is then heated at reflux for 18 hours in a nitrogen atmosphere. . The reaction mixture is cooled to room temperature, concentrated in vacuo to a volume of about 60 ml and the precipitate is separated by filtration. By evaporation of the filtrate under vacuum, 2mercaptomethyl-N-methylimidazole 32 is obtained in the form of a yellow oil which is used in the following stage without further purification.



  NMR (D20) 6: 3.90 (3H, s), 4.10 (2H, s) and 7.25 (2H, s).

  <Desc / Clms Page number 136>

 
 EMI136.1
 



    3- [N-Methylimidazole-2-yl-methanethio] -6 # - [1- (R) - hydroxyethyl7-7-oxo-l-azabicyclo (3. 2. 0) hept-2-ene-2-carboxylate p-nitrobenzyl
2.8 g (21.3 millimoles) of diisopropylethylamine in 2 ml of acetonitrile are added, followed by 5.5 g (20.4 millimoles) of diphenyl chlorophosphate in 2 ml of acetonitrile, under nitrogen, to a solution cooled to 0 C of 7.24 g (20.3 millimoles) of the intermediate ketone 5 in 35 ml of acetonitrile. The resulting solution is stirred for 15 minutes at OOC and then a solution of 4.1 g (3.0 millimoles) of diisopropylethylamine in 2 ml of acetonitrile is added thereto, followed by 4.6 g (31.0 millimoles) of thiol. 32. The reaction mixture is stirred for 60 minutes at 0 C.

  <Desc / Clms Page number 137>

 



  The white precipitate is collected by filtration and washed with methylene chloride (20 ml) to obtain 6.6 g (yield of 71%) of the desired compound which is a white solid, PF 142 C NMR (DMSO-d6) 6 : 1.32 (3H, d, J = 7, OHz), 3.2-4.5, (5H, m), 3.2 (2H, s), 3.9 (3H, s), 5.50 (2H, ABq, J = 14, OHz), 7.65 (2H, d, J = 6.5Hz), 7.70 (2H, s) and 8.24 (2H, d, J = 6, 6Hz) .



  IR (KBr) max: 3450.1770 and 1690 cm-l.



  Analysis for C21H20N4O6S1.1 # H2O
Calculated: C, 52.18, H, 4.79, N, 11.59%
Found: C, 52.22, H, 4, 91, N, 12.16%.
 EMI137.1
 

  <Desc / Clms Page number 138>

 
 EMI138.1
 



  3- hydroxyethyl-7-oxo-l-azabicyclo 2-ene-2-carboxylate
20 ml of methyl iodide are added to a suspension of 1.34 g (3.0 millimoles) of compound 33 in 270 ml of acetone. The reaction mixture is stirred for 4 days at room temperature. The precipitate is collected by filtration and washed with acetone (20 ml) to obtain 1.70 g (96% yield) of the quaternized imidazole 34 which is present in yellow crystals, mp 175-177 C.



  NMR (DMSO-d6) 6: 1.10 (3H, d, J = 6.2Hz), 3.30 (2H, s), 3.2-4, 3 (6H, m), 3.95 (6H , s), 5.45 (2H, ABq, J = 14Hz) and 7.65 (2H, d, J = 6, OHz).



  IR (KBr) # max: 3400,1750 and 1600 cm-1.



  Analysis for C21H22N406Sl
Calculated: C, 43.08, H, 9.60, N, 5.48%
Found: C, 43.02, H, 9.02, N, 5.44%.



   120 ml of buffer solution of pH 7.0 are added, followed by 900 mg of CELITE palladium on 30% to a solution of 1.30 mg (1.86 millimole) of compound 34 in 120 ml of tetrahydrofuran and 120 ml of ether . The mixture is hydrogenated in a Parr shaker for 40 minutes at 276 kPa. The mixture is filtered on a layer of CELITE and the catalyst is washed with water (2 × 15 ml). The mixture of filtrate and washing water is extracted with ether (3 × 100 ml) and lyophilized to obtain a yellow amorphous powder which is purified on a column of C18 BONDAPAK (Waters Associates) (30 g) which eluted with 10% acetonitrile in water under a pressure of 55 kPa.

   Each fraction of 20 ml is checked by liquid chromatography under high pressure and the fractions having an absorption in the ultraviolet at max 300 nm are collected, then they are lyophilized to obtain 220 mg (yield of 35%) of the compound

  <Desc / Clms Page number 139>

 searched for which is a yellow powder.



  NMR (D20) 6: 1.12 (3H, d, J = 7, OHz), 3.08 (1H, dd, J = 13, OHz, 6.4Hz), 3.15 (1H, dd, J = 13, OHz, 6.4Hz), 3.45 (1H, dd, J = 3.2Hz, 4.5Hz), 3.85 (6H, s), 4.1-4, 3 (2H, m), 4.40 (1H, d, J = 13.5Hz), 4.52 (1H, d, J = 13.5Hz) and 7.40 (2H, s).
 EMI139.1
 



  IR (KBr) 9: 3500, 1750 and 1590 cm-1.



  UV). : 296 nm (6 = 8411).



  Analysis for Cl5H19N304S. H20
Calculated: C, 51.68, H, 5.67, N, 12.06, S, 9.50%
Found: C, 49.93, H, 5.94, N, 11, 46, S, 9.03%.



  EXAMPLE 10.-
 EMI139.2
 Preparation of 3- 3, 4-trimethylthiazol-5-yl-methanethio) -6o (3.2. 0) hept-2-ene-2-carboxylate
 EMI139.3
 2,4-Dimethyl-5-mercaptomethylthiazole
2.4 g (30 millimoles) of thiourea are added to a solution of 4.8 g (26.0 millimoles) of the compound
 EMI139.4
 0 chlorinated 46 prepared as described in J. Amer. Chem.

  <Desc / Clms Page number 140>

 



  Soc., 104, 4461 (198227 in 50 ml of absolute ethanol. The reaction mixture is heated at reflux for 18 hours. The precipitate is collected by filtration and washed with ether (20 ml) to obtain the salt. of isothiouronium which is dissolved in 22 ml of IN sodium hydroxide and heated at 1000C for 4 minutes in a nitrogen atmosphere. The reaction mixture is cooled to room temperature, it is adjusted to pH 7.0 with IN hydrochloric acid and extracted with ether (3 × 50 ml) The mixture of the ethereal phases is washed with water and with brine, then dried over MgSO.



   By evaporation of the dried solvent, 780 mg (yield of 49%) of thiol 47 are obtained in the form of a colorless oil which is used in the following stage without further purification.



  NMR (DC13) 6: 2.05 (3H, s), 2.35 (3H, s) and 3.60 (2H, d, J = 6.5Hz).
 EMI140.1
 

  <Desc / Clms Page number 141>

 
 EMI141.1
 
 EMI141.2
 



  P-nitrobenzyl hept-2-ene-2-carboxylate 3-L2, 4-Dimethylthiazol-5-yl-methanethio7-6 hydroxyethyl 2. 0)
610 mg (4.7 millimoles) of diisopropylethylamine in 1 ml of acetonitrile are added, then 1.15 g (4.3 millimoles) of diphenyl chlorophosphate in 1 ml of acetonitrile, under a nitrogen atmosphere, to a solution cooled to 0 C of 1.4 g (4.0 millimoles) of the intermediate ketone 5 in 25 ml of acetonitrile. The resulting solution is stirred for 20 minutes at 0 ° C. and then a solution of 610 mg (4.7 millimoles) of diisopropylethylamine in 1 ml of acetonitrile is added thereto, followed by 750 mg (4.7 millimoles) of thiol 47 in 2 ml of acetonitrile.

   The reaction mixture is stirred for 3 hours at 0 C. The precipitate is collected by filtration and washed with methylene chloride (20 ml) to obtain 1.14 g (65% yield) of the desired compound which is a white solid .



  NMR (DMSO-d6) #: 1, 25 (3H, d, J = 6.4Hz), 2.30 (3H, s), 2.65 (3H, s), 3.1-3, 4 (3H , m), 4, 10 (1H, broad s), 4.0- 4.5 (3H, m), 5.25 and 5.50 (1H each, ABq, J = 4Hz), 7.68 (2H , d, J = 8.5Hz) and 8.25 (2H, d, J = 8.5Hz).



  IR (KBr) Oman: 3500, 1770 and 1690 cm-l.

  <Desc / Clms Page number 142>

 



  Analysis for C22H23N306S2
Calculated: C, 53.73, H, 4.71, N, 8.57, S, 13.44%
Found: C, 53.97, H, 4.74, N, 8.58, S, 13.10%.
 EMI142.1
 
 EMI142.2
 3- 3, 4-Trimethylthiazol-5-yl-methanethio) -6 hydroxyethyl 7-7-oxo-l-azabicyclo 2-carboxylate
A solution of 0.98 ml (13 millimoles) of methyl fluorosulfonate in 2 ml of

  <Desc / Clms Page number 143>

 methylene chloride to a solution of 1.97 g (4.0 millimoles) of the chlorinated compound 48 in 180 ml of methylene chloride. The reaction mixture is stirred for 70 minutes at room temperature.

   The reaction mixture is poured into a solution of ether (400 ml) and pentane (100 ml). The precipitate is collected by filtration and washed with ether (20 ml) to obtain 1.6 g (65.5% yield) of the quaternized thiazole 49 in the form of a white powder.



  NMR (DMSO-d6) 6: 1.25 (3H, s, J = 6.5Hz), 2.45 (3H, s), 2.80 (3H, s), 3.2-4.5 (6H , m), 3.90 (3H, s), 5.30 (2H, wide s), 7.60 and 8.2 (1H each, d, J = 8.5Hz).
 EMI143.1
 



  IR (KBr): 3400, 1770 and 1690 cm-l.



  Analysis for CHNsOgSF. HsO
Calculated: C, 45.09, H, 4.44, N, 6.86%
Found: C, 44.50, 4.38, 74, N, 6.58%.



   100 ml of a buffer solution of pH 7.0 are added, then 1.0 g of 10% palladium on carbon to a solution of 1.0 g (1.72 millimole) of compound 49 in 100 ml of tetrahydrofuran and 100 ml of ether. The mixture is hydrogenated in a shaker
 EMI143.2
 Leave for 40 minutes at 276 kPa. The mixture is filtered on a layer of CELITE and the catalyst is washed with water (2x10 ml). The mixture of filtrate and washing water is extracted with ether (3x100 ml) and lyophilized to obtain a yellow powder which is purified on a column of C18 BONDAPAK (Waters Associates) (40 g) which is eluted with 10% acetonitrile in water at a pressure of 55 kPa.

   Each fraction of 15 ml is checked by high pressure liquid chromatography and the fractions having an absorption in the ultraviolet at Xmax 300 nm are combined, then they are lyophilized to obtain 315 mg (yield of 50%) of the desired compound which is a solid yellow.

  <Desc / Clms Page number 144>

 NMR (D20) #: 1.25 (3H, d, J = 7, OHz), 2.25 (3H, s), 2.90 (3H, s), 3.0-3, 30 (3H, m ), 3.90 (3H, s) and 4, 1-4, 4 (4H, m).
 EMI144.1
 



  IR (KBr) Vmax: 3400, 1750 and 1580 cm-1.



  UvXmax: (H20): 297 nm (ê.



   = 8994), Analysis for C15Hl9N304S, 2H20
Calculated: C, 48.25, H, 6.09, N, 7.79%
Found: C, 47.96, H, 5.83, N, 7.89%.



  EXAMPLE 11 Preparation of 3- [2- (N-methylthiazolium) methylthio] - 6 # - [1- (R) -hydroxyethyl] -7-oxo-1-azabicyclo (3.2. 0) hept- 2-ene-2 -carboxylate
 EMI144.2
 

  <Desc / Clms Page number 145>

 
 EMI145.1
 2-Mercaptomethylthiazole
3.60 g (26 millimoles) of hydroxymethylthiazole 1 are added at room temperature to a solution of thionyl chloride (3.81 ml, 52 millimoles) in chloroform (30 ml), then the solution is heated to 50 C for 2 hours. The chloroform is evaporated under vacuum to obtain a brown solid which is dissolved in 30 ml of absolute ethanol. Then added 2.04 g (26 millimoles) of thiourea. The mixture is heated at reflux for 18 hours. The precipitate is collected by filtration and washed with ethanol and ether to collect 3.4 g (55% yield) of the isothiouronium salt 3.

   The isothiouronium salt 3 is dissolved in 30 ml of water and bubbled with nitrogen for 20 minutes in the solution. Then 1.10 g (27 millimoles) of sodium hydroxide are added and the mixture is heated at 100 ° C. for 2 minutes. The cooled solution is adjusted to 0 C at pH 6.0 using acid
 EMI145.2
 c with acetic acetate, then it is extracted with ethyl acetate a (2x35 ml). The organic layer is dried (MgSO 4) and evaporated under vacuum to obtain 0.75 g (42% yield) of thiol 4 which is a yellow oil which is used without further purification.



  NMR (CDClg) 6: 2, 1 (1H, t), 4.0 (2H, d, J = 10Hz), 7.27 (1H, d, J = 3, OHz) and 8.85 (1H, d , J = 3, OHz).

  <Desc / Clms Page number 146>

 
 EMI146.1
 
 EMI146.2
 



  3-l2 (Thiazol) methylthio7-6o e 7 e-7 (- / 3-- (R) - 'hydroxyethyl7- 7-oxo-l-azabicyclo (3. 2. 0) hept-2-ene-2carboxylate p -nitrobenzyl
0.79 ml (4.4 millimoles) of diisopropylethylamine is added, then 1.17 g (4.4 millimoles) of diphenyl chlorophosphate, under nitrogen, to a solution cooled to 0 "C of 1.4 g (4.0 millimoles) of the intermediate ketone 5 in 8 ml of acetonitrile The resulting solution is stirred for 30 seconds at 0 ° C. to obtain 3- (diphenylphosphoryloxy) -6- [1- (R) -hy-

  <Desc / Clms Page number 147>

 droxyethyl] -7-oxo-1-azabicyclo (3.2. 0) hept-2-ene-2-carboxylate of p-nitrobenzyl.

   To this solution is added a solution of 0.79 ml (4.4 millimoles) of diisopropylethylamine in 2 ml of acetonitrile, then a solution of 0.72 g of thiol 4 in 2 ml of acetonitrile.



  The reaction solution is stirred for 60 minutes at 0 ° C., then it is diluted with 50 ml of ethyl acetate and washed with 30 ml of water, 20 ml of 10% aqueous H3PO4 and 30 ml of brine . By evaporation of the dried solvent (MgSO), a crystalline solid is obtained which is triturated in ether to collect 782 mg (yield of 42%) of the desired compound 6 which is a white crystalline material, P. F. 158-160 C.



  NMR (CDC13) 6: 1.32 (3H, d, J = 7, OHz), 3.28 (3H, m), 4.20 (2H, m), 4.36 (2H, s), 5, 40 (2H, q), 7.40 (1H, d, J = 4, OHz), 7.64 (2H, d, J = 8Hz), 7.76 (1H, d, J = 4, OHz) and 8.24 (2H, d, J = 8Hz).



  IR (KBr) max: 3500,1770 and 1700 cm-l.



  Analysis for C20H19N306S2
Calculated: C, 52.05, H, 4, 15, N, 9.10, S, 13, 89%
Found: C, 52.35, H, 4.40, N, 8.72, S, 13.90%.
 EMI147.1
 

  <Desc / Clms Page number 148>

 
 EMI148.1
 
 EMI148.2
 



  3- / 2- - / l- e 7 (N-methylthiazolium)) methylthio7-6hydroxyethyl! 7-7-oxo-l-azabicyclo (3.2. 0) hept-2-ene-2carboxylate
0.5 ml of methyl fluorosulfonate is added to a solution of 782 mg (1.36 millimole) of compound 6 in 55 ml of methylene chloride and the mixture is stirred for 90 minutes at room temperature.



  The precipitate is collected by filtration and washed with methylene chloride (30 ml) and with ether (20 ml) to collect 630 mg of the crude quaternized thiazole 7 which is used in the next stage without further purification.



   Thus, 140 ml of a buffer solution of pH 7.0 is added, then 650 mg of 10% palladium on carbon to a solution of compound 7 in 140 ml of tetrahydrofuran and 120 ml of ether. The mixture is hydrogenated in a Parr shaker for 35 minutes at 207 kPa. The mixture is then filtered and the

  <Desc / Clms Page number 149>

 water catalyst (2x10 ml). The mixture of filtrate and washing waters is extracted with ether (2 × 150 ml) and lyophilized to obtain a yellow powder. The crude yellow powder is purified on a phase inversion column of C18 BONDAPAK (7 g) (Waters Associates) which is eluted with 5% acetonitrile in water under a pressure of 55 kPa.

   Each 15 ml fraction is checked by high pressure liquid chromatography and the fractions having an absorption in the ultraviolet at Âmax 300 nm are combined, then they are lyophilized to collect 23 mg (yield of 5%) of the desired compound which is a solid yellow amorphous.



  NMR (D20) 6: 1.28 (3H, d, J = 7, OHz), 3.12 (2H, d, J = 7, OHz), 3.44 (1H, dd, J = 1, OHz and 3, OHz), 4.20 (3H, s), 4.24 (2H, m), 4.76 (3H, m), 8.12 (1H, d, J = 4Hz) and 8.24 (1H , d, J = Hz).



  IR (KBr) max: 3400.1740 and 1580 cm-1.



    UV ^ max (H20): 292 nm (# = 7285).



  EXAMPLE 12 Preparation of 3-gel (RS) -methyl-N-methylpyridine-3-yl-
 EMI149.1
 methanethio-6o e 7 cyclo (3,
 EMI149.2
 

  <Desc / Clms Page number 150>

 
 EMI150.1
 
 EMI150.2
 3-LI (R, S) -Methylpyridine-3-yl-methanethis7-6o hydroxyethyl (3. 2. 0) hept-2-ene-2hydroxy-7-p-nitrobenzyl carboxylate
754 mg (5.8 millimoles) of diisopropylethylamine in 1 ml of acetonitrile are added, then a solution of 1.57 g (5.84 millimoles) of diphenyl chlorophosphate in 2 ml of acetonitrile, in an atmosphere

  <Desc / Clms Page number 151>

 of nitrogen, to a solution cooled to 0 C of 1.85 g (5.3 millimoles) of the intermediate ketone 5 in 20 ml of acetonitrile.

   The resulting solution is stirred for 15 minutes at 0 ° C., then a solution of 754 mg (5.8 millimoles) of diisopropylethylamine in 1 ml of acetonitrile is added thereto, followed by 814 mg (5.8 millimoles) of thiol 27 in 2 ml of acetonitrile. The reaction mixture is stirred for 3 hours at 0 ° C., then it is diluted with 200 ml of ethyl acetate, washed with ice brine (200 ml), with water (200 ml), with bicarbonate aqueous (100 ml) and brine (100 ml). By evaporation of the dried solvent (MgSO 4), a yellow oil is obtained which is purified by chromatography on a column of silica gel which is eluted with a mixture of 50% acetone and 50% methylene chloride in order to 'get 1.65 g of the desired compound which is a yellow solid.



  NMR (CDC13) 6: 1.22 and 1.25 (3H each, d, J = 7, OHz), 1.46 and 1.50 (3H each, d, J = 7.2Hz), 2.4- 3, 3 (3H, m), 3.8-4, 2 (3H, m), 5.35 (2H, ABq, J = 14.5Hz) and 7.2-8.6 (8H, m).



  IR (KBr) 17max: 3400,1765 and 1690 cm-1.



  Analysis for C23H23N303S1
Calculated: C, 58.83, H, 4.94, N, 8.95, S, 6.83%
Found: C, 57, 15, H, 5.04, N, 8.28, S, 6.78%.
 EMI151.1
 

  <Desc / Clms Page number 152>

 
 EMI152.1
 



    4- (l'-Mercaptoethyl) pyridine
50 g of thionyl chloride are added to a
 EMI152.2
 25 g solution of 1- prepared L as described in J. Chem. Soc., Perkin II, 1462 (197417 in 100 ml of chloroform. The mixture is heated under reflux for 2 hours. By evaporation of the solvents under vacuum, the chlorinated compound 26 is obtained in the form of a semi-solid which is used in the next step without further purification, so a hot solution of 14.4 g of thiourea in 75 ml of ethanol is added to a solution of compound 26 in 160 ml of ethanol and the reaction mixture is heated at reflux for 18 hours The ethanol is evaporated off and the residue is dissolved in 100 ml of ether, then the pH is adjusted to 10 by addition of 2N NaoH.

   The mixture is stirred at ambient temperature for 90 minutes, then it is adjusted to pH 6.0 by addition of 6N HCl and it is extracted with ether (2x200 ml). By evaporation of the dried solvent (MgSO4), a yellow oil is obtained which is distilled under 5 mm Hg (667 Pa) and which is collected in the boiling range of 60-650C to obtain

  <Desc / Clms Page number 153>

 11.0 g (38% yield) of pure thiol 27 in the form of a colorless oil.



  NMR (CDC13) 6: 1.70 (3H, d, J = 6, OHz), 2.05 (1H, d, J = 5.8Hz), 4.20 (1H, t, J = 6, OHz, 5.8Hz), 7.20 (2H, d, J = 6.2Hz) and 8.5 (2H, d, J = 6, 2Hz).
 EMI153.1
 

  <Desc / Clms Page number 154>

 
 EMI154.1
 



  3-LI (RS) -Methyl-N-methylpyridine-3-yl-methanethio7-6o [ï- (3. 2. 0) hept-2e 7 (-ene-2-carboxylate
10 ml of methyl iodide are added to a solution of 1.1 g (2.34 millimoles) of compound 28 in
100 ml of acetone. The reaction mixture is stirred at room temperature for 18 hours. The precipitate is collected by filtration and washed with methylene chloride (10 ml) to obtain 1.4 g (100% yield) of the quaternized pyridine 29 which is a yellow powder.



  NMR (DMSO-d6) iS: 1.10 (3H, d, J = 6.5Hz), 1.62 (3H, d, J = 7.5Hz), 2.6-4.2, (6H, m) , 4.39 (3H, s), 5.42 (2H, ABq, J = 13.6Hz) and 7.9-9.2 (8H, m).



  IR (KBr) L? max: 3400.1770 and 1190 cm-1.



  Analysis for C24H26N306S1Il
Calculated: C, 47.14, H, 4.29, N, 6.87, S, 5.24%
Found: C, 47.19, H, 4.78, N, 6, 11, S, 5.41%.



   120 ml of a buffer solution of pH 7.0 are added, then 1.5 g of 10% palladium on carbon to a solution of 1.45 g (2.37 millimoles) of compound 29 in 120 ml of tetrahydrofuran and 120 ml of ether. The mixture is hydrogenated in a Parr shaker for 60 minutes at 310 kPa. The mixture is filtered on a layer of CELITE and the catalyst is washed with water (2 × 15 ml). The mixture of filtrate and washing waters is extracted with ether (2 × 200 ml) and lyophilized to obtain a yellow solid which is purified on a column with C18 phase inversion of BONDAPAK (50 g) (Waters Associates) which is eluted with 5% acetonitrile in water under a pressure of 55 kPa.

   Each fraction of 20 ml is checked by liquid chromatography under high pressure and the fractions having an absorption in the ultraviolet at Àmax 300 nm are combined, then they are lyophilized to collect

  <Desc / Clms Page number 155>

 200 mg (24% yield) of the desired compound which is a yellow amorphous solid.



  NMR (D20) 6: 1.32 (3H, d, J = 7, OHz), 1.63 (3H, d, J = 7.2Hz), 2.5-4.6 (6H, m), 4 , 32 (3H, s) and 8.2-8.9 (4H, m).



  IR (KBr) l? max: 3400.1750 and 1590 cm-1.



    UVAmax (H20): 296 nm (C = 7573).



  Analysis for C17H20N2O4S1.1 # H2O
Calculated: C, 54.38, H, 5.77, N, 7.46%
Found: C, 54.39, H, 5.98, N, 7.68%.



  EXAMPLE 13.-
 EMI155.1
 Preparation of 3-methyl-N'-benzylimidazol-2-ylmethanethis7-60 methanethio cyclo (3. 2. 0) hept-2-ene-2-carboxylate
 EMI155.2
 

  <Desc / Clms Page number 156>

 N-Benzyl-2-mercaptomethylimidazole
1.72 g (14.5 millimoles) of Nacetylthiourea are added to a solution of 3.23 g (13.0 milli-
 EMI156.1
 moles) of the chlorinated compound 41 prepared as described in J. Amer. Chem. Soc., 71, 383 (194917 in 80 ml of acetonitrile. The reaction mixture is heated to reflux for 3 hours. The precipitate is collected by filtration and washed with acetonitrile (10 ml) to obtain the salt of 'isothiouronium which is then dissolved in 80 ml of absolute ethanol and heated under reflux for 18 hours in a nitrogen atmosphere.

   The reaction mixture is cooled to room temperature, concentrated in vacuo to a volume of about 30 ml and the precipitate is separated by filtration. By evaporation of the filtrate under vacuum, 3.5 mg (yield of 97%) of thiol 42 is obtained, which is a thick yellow syrup.



  NMR (CDC1 3) 6: 2.1 (1H, t, J = 4.5Hz), 3.80 (2H, s), 5.20 (2H, s) and 3.8-7.5 (7H, m).
 EMI156.2
 

  <Desc / Clms Page number 157>

 
 EMI157.1
 
 EMI157.2
 



  P / nitrobenzyl hept-2-ene-2- carboxylate
1.17 g (9.0 millimoles) of diisopropylethylamine in 2 ml of acetonitrile are added, followed by 2.4 g (9.0 millimoles) of diphenyl chlorophosphate in 2 ml of acetonitrile, under nitrogen, to a solution cooled to 0 C of 3.03 g (8.5 millimoles) of the intermediate ketone 5 in 70 ml of acetonitrile. The resulting solution is stirred for 20 minutes at 0 ° C., then a solution of 1.17 ml (9.0 millimoles) of diisopropylethylamine in 2 ml of acetonitrile is added thereto, followed by 4.8 g (15 millimoles) of thiol 42.



  An additional 1.93 g (15 millimoles) of diisopropylethylamine is added and the reaction mixture is stirred for 2 hours at 0 C. The precipitate is collected by filtration and washed with cold methylene chloride (20 ml) to obtain 2.5 g (55% yield) of the desired compound which is a white solid.



  NMR (DMSO-d6) #: 1.23 (3H, d, J = 7.2Hz), 2.5-4, 1 (6H, m), 4.25 (2H, s), 5.20 (2H , s), 5.20 and 5.45 (1H
 EMI157.3
 each, d, J = 14.5Hz) and 6.9-8.3 (11H, m).



  IR (KBr) Vmax: 3400, 1775 and 1690 cm-l.

  <Desc / Clms Page number 158>

 
 EMI158.1
 

  <Desc / Clms Page number 159>

 
 EMI159.1
 



  3-N-Methyl-N'-benzylimidazol-3-yl-methanethi7-6o / l- hept-2- (-ene-2-carboxylate
1.15 ml (13.4 millimoles) of methyl fluorosulfonate are added to a solution of 1.76 g (3.3 millimoles) of compound 43 in 1100 ml of methylene chloride. The reaction mixture is stirred for 2 hours at room temperature. The reaction mixture is concentrated in vacuo to a volume of about 15 ml. The precipitate is collected by filtration and washed with methylene chloride (10 ml) to obtain 1.58 g (74% yield) of the quaternized imidazole 44 which is a white solid.



  NMR (DMSO-d6) 6: 1.15 (3H, d, J = 7, OHz), 3.2-4, 4 (6H, m), 4.70 and 5.0 (1H each, ABq, J = 10.8Hz), 5.24 and 5.46 (1H each, ABq, J = 14Hz), 5.50 (2H, s) and 7.4-8.4 (11H, m).



  IR (KBr) # max: 3500, 1770 and 1700 cm-1.



  Analysis for C28H29N409S2F
Calculated: C, 51.48, H, 4.47, N, 8.67, S, 10.20%
Found: C, 51.84, H, 4.52, N, 8.65, S, 9.87%.



   120 ml of a buffer solution of pH 7.0 are added, then 1.0 g of 10% palladium-on-carbon to a solution of 1.11 g (1.71 millimole) of compound 44 in 100 ml of tetrahydrofuran and 100 ml of ether. The mixture is hydrogenated in a Parr shaker for 45 minutes at 276 kPa. The mixture is filtered on a layer of CELITE and the catalyst is washed with water (2 × 10 ml). The mixture of filtrate and washing water is extracted with ether (2x70 ml) and lyophilized to obtain a yellow powder which is purified on a column of C18 BONDAPAK (50 g) (Waters Associates) which is eluted with 10% acetonitrile in water at a pressure of 55 kPa.

   Each 15 ml fraction is checked by liquid chromatography under

  <Desc / Clms Page number 160>

 high pressure and the fractions having an absorption in the ultraviolet at max 300 nm are collected, then they are lyophilized to collect 305 mg (43%) of the desired compound which is a slightly yellow amorphous solid.



  NMR (DMSO) 6: 1.40 (3H, d, J = 7, OHz), 2.9-3, 4 (3H, m), 3.98 (3H, s), 4.0-4, 2 (2H, m); 4.23 (2H, br s), 5.57
 EMI160.1
 (2H, s) and 7, 2-7, 65 (7H, m).



  IR (KBr) Vmax: 3400, 1760 and 1590 cm-lUV '\ max O): 299 nm (E = 8807), Analysis for C21H23N3O4S1. lH20
Calculated: C, 57.25, H, 5.94, N, 9.54, S, 7.28%
Found: C, 56.66, H, 5.70, N, 9.49, S, 8, 30%.



  EXAMPLE 14.-
 EMI160.2
 Preparation of 3- [2-methyl-N-methylpyridine-3-ylmethanethiQ7-6- [i- methanethio cyclo (3. 2. 0) hept-2-ene-2-carboxylate
 EMI160.3
 

  <Desc / Clms Page number 161>

 
 EMI161.1
 2-Methyl-3-mercaptomethylpyridine
Ester 12 is prepared as described in J.



  Org. Chem., 21, 800 (1956). A solution of 6.23 g (38 millimoles) of ester 12 in 15 ml of tetrahydrofuran is added dropwise over 15 minutes to a suspension cooled to O * C of 2.86 g of lithium aluminum hydride in 50 ml of dry tetrahydrofuran.



  The mixture is stirred at 0 ° C. for 60 minutes, then 50 ml of ethyl acetate is added thereto. The precipitate is separated by filtration and washed with saturated aqueous ammonium chloride. The organic layer is dried over
 EMI161.2
 MQSOA, filtered and evaporated in vacuo to obtain 3.2 g (70% yield) of hydroxymethylpyridine 13 in the form of a yellow oil.



    R1-1N (CDC13) of compound Q6: 2.46 (3H, s), 4.73 (2H, s), 5.1 (1H, large), 7.2 (1H, dd, J = 8Hz), 7.8 (1H, dd, J = 8Hz, J = lHz) and 8.3 (1H, dd, J = 7Hz, J = lHz).



   A solution of 3.2 g (26 millimoles) of alcohol 3 in 10 ml of methylene chloride is added dropwise over 15 minutes in a nitrogen atmosphere to a solution cooled to 0 ° C. of 4 ml of

  <Desc / Clms Page number 162>

 thionyl chloride in 10 ml of methylene chloride. The cooling bath is removed and the reaction mixture is stirred for 3 hours at room temperature. All the solvents are removed in vacuo to obtain compound 14 in the form of a brown solid which is used in the next stage without further purification.



  The crude brown solid is dissolved in 30 ml of absolute ethanol. 2.5 g (32 millimoles) of thiourea are then added and the mixture is heated at 65-70oC for 18 hours. The mixture is cooled to room temperature. The precipitate is collected by filtration and washed with ethanol (20 ml) and ether (50 ml) to obtain 30 g of the isothiouronium salt. This salt is dissolved in 10 ml of water and a solution of 640 mg (16 millimoles) of sodium hydroxide in 10 ml of water is added thereto under nitrogen. The reaction mixture is heated at 1000C for 2 minutes, then cooled to 0C, adjusted to pH 6.0 with acetic acid and extracted with chloroform (2x35 ml). By evaporation of the dried chloroform (MgSO), 941 mg (46% yield) of thiol 15, which is a yellow oil, are obtained.



  NMR (COClg) of thiol Ó: 1, 8 (1H, t), 2.60 (3H, s), 3.73 (2H, d, J = 10Hz), 7.13 (1H, dd, J = 8Hz ), 7.57 (1H, dd, J = 8Hz) and 8.43 (1H, dd, J = 8Hz, 3Hz).
 EMI162.1
 

  <Desc / Clms Page number 163>

 
 EMI163.1
 
 EMI163.2
 



  3- hydroxy-hept-2-ene-2- p-nitrobenzyl carboxylate
0.86 ml (4.80 millimoles) of diisopropylethylamine is added, then a solution of 1.17 g (4.37 millimoles) of diphenyl chlorophosphate in 3 ml of acetonitrile, under nitrogen, to a cooled solution at 0 C 1.52 g (4.37 millimoles) of the intermediate ketone 5 in 5 ml of acetonitrile. The resulting solution is stirred for 30 minutes at 0 C
 EMI163.3
 to obtain 3-diphenylphosphoryoxy) -Ll- droxyethyl17-7-oxo-1-azabicyclo (3. 2. 0) hept-2-ene-2-carboxylate of p-nitrobenzyl. To this solution is added a solution of 0.86 ml (4.80 millimoles) of diisopropylethylamine in 2 ml of acetonitrile, then a solution of 940 mg (6.76 millimoles) of thiol in 2 ml of acetonitrile.

   The reaction mixture is stirred for 60 minutes at 0 C. The precipitate is collected by filtration and washed with ether (30 ml) to obtain 1.12 g (55% yield) of the desired compound which is a solid pale yellow, PF 186-188 C (decomposition).



  NMR (DMSO-d6) 6: 1, 20 (3H, d, J = 7Hz), 2.60 (3H, s), 3.40 (2H, m), 4.16 (2H, m), 4, 32 (2H, s), 5.16 (1H, d,

  <Desc / Clms Page number 164>

 J = 5Hz), 5.44 (2H, q, J = 14Hz), 7.32 (2H, m), 7.8 (2H, d, J = 8Hz), 8.36 (2H, d, J = 8Hz) and 8.48 (1H, dd, J = 5.5Hz, l, 5Hz).



  IR (KBr) # max: 3500,1770 and 1750 cm-1.



  Analysis for C23H24N306S
Calculated: C, 58.83, H, 4.94, N, 8.94, S, 6.83%
Found: C, 58.63, H, 4.99, N, 9.06, S, 6.58%.
 EMI164.1
 

  <Desc / Clms Page number 165>

 
 EMI165.1
 
 EMI165.2
 



  3- - / l- 7-7-oxo-l-azabicyclo hept-2e 7 (2-Methyl-N-methylpyridine-3-yl-methanethio) -6ene-2-carboxylate
0.5 ml (6.18 millimoles) of methyl fluorosulfonate is added dropwise to 100 ° C. over 10 minutes to a solution of 697 mg (1.19 millimoles) of compound 16 in 100 ml of methylene chloride. The reaction mixture is stirred for 2.5 hours at room temperature. The precipitate is collected by filtration and washed with 30 ml of methylene chloride to obtain 777 mg (90%) of pyridine quater-

  <Desc / Clms Page number 166>

 
 EMI166.1
 nisée 17 which is a yellow solid.



  PMN (COC13) of compound 176: 1.20 (3H, d, J = 7Hz), 2.82 (3H, s), 4.36 (3H, s), 4.16 (2H, m), 4, 60 (2H, s) 5, 20 (1H, m), 5.42 (2H, q, J = 14Hz), 7.80 (2H, d, J = 8Hz), 8.04 (1H, dd, J = 7Hz, 6.5Hz), 8.32 (2H, d, J = 8Hz), 8.64 (1H, d, J = 7.5Hz) and 9.08 (1H, d, J = 7.5Hz) ).



  IR (KBr)? max: 3500 and 1765 cm-l.



  Analysis for C24H26FN309S
Calculated: C, 48.91, H, 4.55, N, 7.23, S, 11.04%
Found: C, 49.39, H, 3.97, N, 7.20, S, 10.98%.



   80 ml of a buffer solution of pH 7.0 are added, then 800 mg of 10% palladium on carbon to a solution of 1.10 g (1.88 millimole) of compound 17 in 80 ml of tetrahydrofuran and 80 ml of 'ether. The mixture is hydrogenated in a Parr shaker for 40 minutes at 207 kPa. The mixture is filtered on a layer of CELITE and the catalyst is washed with
 EMI166.2
 water (2x10 ml). The mixture of filtrate and washing waters is extracted with ether (2 × 100 ml) and lyophilized to obtain a yellow powder which is purified by chromatography on an HP-20 column which is eluted with water, then with 5% acetonitrile in water.

   Each 15 ml fraction is checked by high pressure liquid chromatography and collected
 EMI166.3
 the fractions having an absorption in the ultraviolet at) 300 nm, then they are lyophilized to obtain 614 mg p (yield of 42%) of the desired compound which is in the form of a slightly yellow powder.



  NMR (D20) zo: 1.28 (3H, d, J = 7Hz), 2.86 (3H, s), 3.20 (2H, dd, J = 10Hz, 3.5Hz), 3.42 (1H , dd, J = 5.4Hz, 3.5Hz), 4.20 (3H, m), 4.32 (3H, s), 4.35 (2H, s), 9.88 (1H, dd, J = 7.2Hz, 6.5Hz), 8.5 (1H, d, J = 8Hz) and 8.70 (1H, d, J = 8Hz).



  IR (KBr) # max: 3400,1760 and 1590 cm-l.



    UVmax (H20): 298 nm (E = 8391).

  <Desc / Clms Page number 167>

 



  Analysis for Cl7H20N203S, H20
Calculated: C, 55.73, H, 5.46, N, 7.65, S, 8, 74%
Found: C, 55.50, H, 6.05, N, 7.74, S, 8.68%.



  EXAMPLE 15.-
 EMI167.1
 Preparation of 3-L4- 2, 3-triazolium) inethylthi7-6c- / Y- 7-7-oxo-l-azabicyclo- (3. 2. 0) hept-2-ene-2-carboxylate
 EMI167.2
 (N, N-dimethyl-1, A. Preparation of the isomer A
 EMI167.3
 
Methyl trifluoromethanesulfonate (0.58 ml, 5.16 millimoles) is added dropwise to an ice-cold, stirred solution of 4- (methanethiolacetate) -1-methyl-1,2,3-triazole (590 mg, 3, 52 millimoles) in dry methylene chloride (2 ml), in a nitrogen atmosphere. After 0.5 hours, the cooling bath is removed and after 1 hour the solvent is pumped off. We

  <Desc / Clms Page number 168>

 dissolve the residual oil in a few ml of water and this solution is cooled in an ice bath.

   A cold solution of sodium hydroxide (305 mg, 7.59 millimoles) in a few ml of water is then added and the reaction mixture is stirred for 0.75 hours. The solution is diluted to 25 ml with water and the pH is adjusted to 7.5 by the addition of solid sodium hydrogen phosphate monohydrate. Then 14 ml of this solution (about 1.9 millimole of the triazoliumthiol) is added to an ice-cold and stirred solution of enol phosphate (1.0 g, 1.72 millimole) in tetrahydrofuran (10 ml). The mixture is stirred for 0.75 hours (a certain amount of crystalline material, probably
 EMI168.1
 Na2HP04 'is deposited during this reaction).



  The suspension is poured into an autoclave with a little tetrahydrofuran (20 ml) and water (20 ml). Ether (30 ml) and 10% palladium on carbon (1.0 g) are added, then the mixture is hydrogenated for 1 hour (276 kPa). The organic phase is separated and washed with water (2x5 ml). The mixture of aqueous phases is filtered and the filtrate is concentrated under high vacuum (approximately 0.5 mm, ie 67 Pa, 90 minutes). The yellow solution is then chromatographed (phase inversion column under medium pressure, 35 × 90 mm, H 2 O as eluent) to obtain, after lyophilization, 395 mg of the carbapenem weakly contaminated with a little inorganic substance.

   It is purified by high pressure liquid chromatography (column of 10 × 300 mm Waters Microbondapack C-18, with multiple injections, taking water as eluent) to obtain 310 mg (57%) of the A isomer in the form of 'a tan powder.



  1 H NMR (D20) 6: 1.23 (3H, d, J = 6.4Hz), 3.10 (2H, d, J = 9, lHz), 3.24 (1H, q, J = 2.7Hz, 6, 1Hz), 4.03-4, 71 (10H, m) and 8.46 (1H, s).



  IR (Nujol): 1760 cm-l.

  <Desc / Clms Page number 169>

 UV (phosphate buffer, pH 7.4, M = 0.05) Amax: 296 nm (E = 7,500), B. Preparation of isomer B and isomer C
 EMI169.1
 a) MeOTf SAC b) c) OH NI N / <L-J- \ '-OP (O) (attempt 0 structure) C02PNB d) H2 / Pd-C OH v H Me o "" <e 2
 EMI169.2
 Methyl trifluoromethanesulfonate (1.60 ml, 14.0 millimoles) is added dropwise to an ice-cold solution of 4- (methanethiolacetate) -2-methyl- 1,2,3-triazole (1.20 g, 7, 02 millimoles) in dry methylene chloride (6 ml) under nitrogen. The mixture is allowed to warm to room temperature and stirred for 16 hours.

   Additional methyl trifluoromethanesulfonate (0.40 ml, 3.56 mmol) is added and after 3 hours at room temperature, the solvent is pumped off. The residual oil is triturated with ether and the resulting gum is dissolved in water (5 ml). The solution is cooled in an ice bath and added to it

  <Desc / Clms Page number 170>

 a solution of sodium hydroxide (844 mg, 21.1 millimoles) in water (5 ml). After 0.75 hours of stirring, the solution is diluted to 60 ml with water and the pH is adjusted to 8 by addition of solid potassium dihydrogen phosphate.

   40 ml of this solution (approximately 4.7 millimoles of a mixture of triazolium-isomeric thiols) are then added to a stirred and ice-cold solution of enol phosphate (2.00 g, 3.45 millimoles) in tetrahydrofuran ( 60 ml). The mixture is stirred in an ice bath for 0.5 hour, then it is transferred to an autoclave containing a suspension of 10% palladium-on-carbon (2.00 g) in ether (60 ml). The mixture is hydrogenated (276 kPa) for 1 hour. The organic phase is separated and washed with water (2x10 ml). The mixture of aqueous phases is filtered and the filtrate is concentrated under high vacuum (approximately 0.5 mm, 67 Pa, 1.5 hours).

   The remaining solution is chromatographed (column with phase inversion under medium pressure, 45 × 130 mm, H2O as eluent) to obtain, after lyophilization, 595 mg of a mixture of isomeric carbapenems contaminated with a small amount of inorganic substance. They are separated and purified by high pressure liquid chromatography (10x300 mm column Waters Microbondapack C-18, with multiple injections, water as eluent) to obtain in the order of elution: Isomer B, 153 mg (13% ); 1 H NMR (D20) 6: 1.23 (3H, d, J = 6.4Hz), 3.12 (2H, q, J = 1.4Hz, 8.9Hz), 3.39 (1H, q, J = 2.7Hz, 6, OHz), 4.07-4.68 (10H, m) and 8.19 (1H, s).



  IR (Nujol): 1755 cm-1.



  UV (phosphate buffer, pH 7.4, M = 0.05) At ailments: 296 nm (= 6700).



  Isomer C, 284 mg (24%).



  1 H NMR (D20) 6: 1.23 (3H, d, J = 6.4Hz), 3.15 (2H, q,

  <Desc / Clms Page number 171>

 J = 3.7Hz, 9, OHz), 3.37 (1H, q, J = 2.6Hz, 6, OHz), 3.95- 4.65 (10H, m) and 8.62 (1H, s ).



  IR (Nujol): 1750 cm-1.



  UV (phosphate buffer, pH 7.4, M = 0.05) At ailments: 298 nm (E = 7600).



  EXAMPLE 16.- (5R, 6S) -6- (1R-hydroxyethyl) 3- (2-methyl-1,2,3-thia-diazolium-4-y1-methylthio) -7-oxo-1-azabicyc10- ( 3. 2. 0) hept-2-ene-2-carboxylate
 EMI171.1
 A. 1,2,3-Thiadiazol-4-yl-ethyl carboxylate
C. D. Hurd and R. I. Mori, J. Am. Chem. Soc., 77,
5359 (1955)
 EMI171.2
 
Stirred at 23 ° C. for 3 hours and heated at 70 ° C. for 20 minutes a solution of ethyl o (-N-carbethoxyhydrazonopropionate (31.2 g, 0.154 mol) in thionyl chloride (80 The thionyl chloride is evaporated and the residue is triturated in hexane (4x30 ml), the red solid is dissolved in dichloromethane (150 ml) and the solution is washed with a saturated sodium bicarbonate solution and with some water.

   After drying over Na2SO4, it is

  <Desc / Clms Page number 172>

 centers the solution until the compound crystallizes.



  After standing at 230C for some time, the crystals are collected by filtration: 16.8 g, P. F. 860C, 69%. The filtrate is concentrated and purified by chromatography on a column of silica gel which is eluted with dichloromethane to obtain 3.17 g, M.P. 86 C, 13%.



  IR (KBr) 9 max: 1720 (ester) cm-l.
 EMI172.1
 



  RMNHl (CDC13) 6: 1.52 (3H, t, J = 7, lHz, CH3CH20), 4.57 (2H, q, J = 7, lHz, CH3CH20) and 9.47 (1H, s, H of thia- diazole).



  B. 1,2,3-Thiadiazol-4-yl-methanol
 EMI172.2
 S. I. Ramsby, S. O. Ögren, S. B. Ross and N. E. Stjernström, Acta Pharm. Succica., 10,285-96 (1973); C. A., 79, 137052W (1973).
 EMI172.3
 



   Lithium aluminum hydride (2.47 g, 65 millimoles) is gradually added over 1 hour to a suspension of ethyl 1,2,3-thiadiazol-4-yl-carboxylate (18.35 g, 116 millimoles) in ether (400 ml).
 EMI172.4
 The reaction mixture is stirred at 230C for 7 hours and lithium aluminum hydride (2.47 g, 65 millimoles) is added thereto. Stirring is continued for 24 hours before successively adding water (7 ml), 15% sodium hydroxide solution (7 ml) and water (21 ml). After 15 minutes of stirring, the ethereal solution is decanted and the gum is extracted with ether (5 × 100 ml). The ethereal extracts are combined, dried (MgSO4) and concentrated (5.4 g).

   The crude compound is purified on a column of silica gel (120 g, 4x16 cm) which is eluted with ether

  <Desc / Clms Page number 173>

 to collect 1.3 g (7%) of ethyl 1,2,3-thiadiazol-4-ylcarboxylate and 2.45 g (18%) of 1,2,3thiadiazol-4-yl-methanol.



  IR (film) max: 3380 (OH) cm-1.



  1 H NMR (CDCI 3) #: 2.31 (1H, s, OH), 5.22 (2H, s, CH2O) and 8.50 (1H, s, H of thiadiazol).



  C. 1,2,3-thiadiazol-4-yl-methanol methanesulfonate
 EMI173.1
 
 EMI173.2
 A solution of 1,2,3-thiadiazol-4-yl-methanol (0.75 g, 5.6 millimoles) in dichloromethane (20 ml) is cooled to 5 ° C. in a nitrogen atmosphere. triethylamine (1.018 ml, 7.3 millimoles) and methanesulfonyl chloride (0.565 ml, 7.3 mil-
 EMI173.3
 slugs). After 15 minutes, the ice bath is removed and the reaction mixture is stirred for 2 hours. The solution is washed with IN hydrochloric acid (2x2 ml) and with water, dried (MgSO4 + MgO) and concentrated. The residue is purified by chromatography (column of silica gel 1.5 × 21 cm) with elution with ether to obtain 0.90 g (71%) of 1,2,3-thiadiazol-4-yl-methanol methanesulfonate.



  IR (film) # max: 1350 (S02) cm-l, 1172 (S02) cm-1.



  1 H NMR (CDCl 3) #: 3.09 (3H, s, CH3), 5.75 (2H, s, CH2) and 8.72 (1H, s, H of thiadiazole).



  UV (CH2C12Â max: 251 nm (= 1990), Analysis for C6H6N203S
Calculated: C, 24.73, H, 3.11, N, 14.42, S, 33, 02%
Found: C, 24.78, H, 3.09, N, 14.66, S, 31.94%, as well as 0.13 g (19%) of di- (1,2,3-thiadiazol ether) -4yl-methyl,

  <Desc / Clms Page number 174>

 IR (film) \? max: 1272.1242, 1200.986, 805 and 728 cm-1, 1 H NMR (CDCl3) #: 5.16 (4H, s, CH2) '8, 42 (2H, s, H of thiadiazole).



  D. 4-Acetylthiomethyl-1,2,3-thiadiazole
 EMI174.1
 
An aqueous solution (2 ml) of sodium thiolacetate / prepared from thiolacetic acid (0.38 ml, 5.3 millimoles) and sodium bicarbonate (0.445 g, 5.3 millimoles) is added to a solution. 1,2,3-thiadiazol-4-ylmethanol methanesulfonate (0.90 g, 4.6 millimoles) in tetrahydrofuran (9 ml). The resulting mixture was stirred at 23 ° C for 1 hour and diluted with ether (75 ml). The organic solution is washed with water (3x3 ml) and dried (MgSO), then concentrated. The crude mixture is purified by chromatography (silica gel column: 1, 4x19 cm) with elution using 50% ether in hexane to obtain 0.60 g (75%) of the compound.



  IR (film) # max: 1675 (C = O) cm-1, RMNH1 (CDC13) #: 2.37 (3H, s, CH3), 4.58 (2H, s, CH2) and 8.44 (1H , s, H of thiadiazol).



  Analysis for C5H6N2OS2
Calculated: C, 34.47, H, 3.47, N, 16.08, S, 36.80%
Found: C, 34.48, H, 3.83, N, 16.28, S, 36.80%.

  <Desc / Clms Page number 175>

 E. 4-acetylthiomethyl- trifluoromethanesulfonate
 EMI175.1
 2-methyl-1,2,3-thiadiazolium and 4-acetylthiomethyl-3-methyl-1,2,3-thiadiazolium trifluoromethanesulfonate
 EMI175.2
 
A few crystals of the advertised compounds and of trifluoromethanesulfonate (0.407 ml, 3.6 millimoles) are added over 5 minutes to a solution of 4acetylthiomethyl-1,2,3-thiadiazole (0.60 g, 3.44 millimoles) in a mixture of ether (4 ml) and dichloromethane (0.4 ml). The reaction mixture is stirred at 230C in a nitrogen atmosphere for 6 hours. The white solid, which is a mixture of the two desired compounds, is filtered and washed with ether so as to obtain 1.5 g (90%).



  IR (KBr) max: 1675 (C = O) cm-l, RMNH1 (DMSO-d6) #: 2.43 (3H, s, CH3COS), 3.33 (s, CH3 on N-3), 4, 57 (s, CH3 on N-2), 4.66 (2H, s, CH2),

  <Desc / Clms Page number 176>

 9.55 (H on N-2 of thiadiazolium) and 9.66 (H on N-3 of thiadiazolium).



  Analysis for C7H9N204S3F3
Calculated: C, 20.27, H, 2.38, N, 9.45, S, 32.46%
Found: C, 24.61, H, 2.57, N, 8.47, S, 28, 21%.



  F. 4-Mercaptomethyl-2-methyl-1,2,3-thiadiazolium trifluoromethanesulfonate and 4-mercaptomethyl-3-methyl-1,2,3-thiadiazolium trifluoromethane sulfonate
 EMI176.1
 
A solution of a mixture of 4-acetylthiomethyl-2-methyl-1,2,3-thiadiazolium and 4-acetylthiomethyl-3-methyl trifluoromethanesulfonate is heated at 65 ° C. in a nitrogen atmosphere for 1.75 hours. -1,2,3-thiadiazolium (1.05 g, 3.1 millimoles) in 6N hydrochloric acid (10 ml). The solvent is evaporated off under reduced pressure to obtain 0.91 g of a yellow syrup. This compound is used in the next stage without purification.

  <Desc / Clms Page number 177>

 
 EMI177.1
 



  G. (5R, 6ê) 2, 3e thiadiazolium-4-yl-methylthio) / 3.
 EMI177.2
 



   To a solution cooled to 5 C of (5R, 6S) -6- (1R-hydroxyethyl) -3- (diphenylphosphono) -7-oxo-1-azabicyclo (2. 2.0) hept-2-ene-2-carboxylate p-nitrobenzyl (1.7 g, 2.92 millimoles) in tetrahydrofuran (10 ml), a solution of a crude mixture of 4-mercaptomethyl-2-methyl-1,2,3-thiadiazolium and a crude mixture of trifluoromethanesulfonate and 4-mercaptomethyl-3-methyl-1,2,3-thiadiazolium trifluoromethanesulfonate (0.9 g) in a mixture of phosphate buffer (pH 7.2, 0, 3M, 15 ml) and tetrahydrofuran (5 ml ). The reaction mixture is stirred for 1 hour and the pH is maintained at 7.2 with a 2N sodium hydroxide solution. Stirring is continued for 1 hour before adding ether (50 ml) and 10% palladium-on-charcoal (1 g).

   The resulting mixture is hydrogenated at 23 ° C. for 2 hours under 310 kPa and filtered through a layer of CELITE. The organic phase is separated and diluted with ether (50 ml) and with phosphate buffer (pH 7.2, 0, 3M, 20 ml), then hydrogenated (2 g of palladium-on-carbon.

  <Desc / Clms Page number 178>

 10%) for 2 hours at 345 kPa. The aqueous phases are combined (of the first hydrogenolysis and of the second), they are washed with ether and they are purified by chromatography on PrepPak 500-C / 18 which is eluted with water so as to collect 0, 22 g of crude substance. This is repurified by liquid chromatography under high pressure with elution with water so as to collect 40 mg (4%) of the desired compound after lyophilization.
 EMI178.1
 



  IR (KBr) Vmax: 3400 (broad, OH), 1745 (C = O lactam), 1580 (carboxylate) cm-1, RMNH1 (D20) &: 1, 23 (3H, d, J = 6, 3Hz, CH3CHOH), 3, 04, 3, 05, 3, 16 (2H, m, H-4), 3.38 (1H, dd, J = 2, 8Hz, J = 6, OHz, H-6), 3 , 9-4, 6 (2H, m, H-5, CH3CHOH), 4, 51, 4, 53 (2 "s", SCH2), 4, 61 (s, N + CHs).



  UV (H max 262 (E4980), 296 (E6885), / Z23 (c = 18, H2O); t = 9.8 hours (measurement [C & -U 2 a concentration of 10-4 in phosphate buffer pH 7.4 to 36.8 C) EXAMPLE 17.-
 EMI178.2
 3 - / '5- 2, 3-triazolium) methanethiq7-6o clo ± 3-. 2. 0 clo / 3. potassium.
 EMI178.3
 

  <Desc / Clms Page number 179>

 
 EMI179.1
 

  <Desc / Clms Page number 180>

 



   Lithium aluminum hydride (2.83 g, 70.9 millimoles) is added little by little to a stirred suspension of 1-methyl-1,2,3-triazole-4-carboxylic acid (9.00 g, 70.9 millimoles) (see C. Pederson, Acta.



  Chem. Scand., 1959, 13, 888) in dry tetrahydrofuran (200 ml). The mixture is stirred at room temperature for 15 hours, then carefully added in aliquots of about 1 ml, a 20% aqueous solution of sodium hydroxide (20 ml). The resulting granular suspension is filtered and the solid is washed with additional tetrahydrofuran (5x75 ml). The mixture of solutions is dried in tetrahydrofuran (MgSO4) and the solvent is removed. The residual yellow oil is subjected to rapid chromatography on a column of silica gel (90 × 35 mm) Z-fractions of 100 ml of hexane, mixture of ethyl acetate and hexane (1: 1) and ( 1: 3) and finally mixture of ethyl acetate and
 EMI180.1
 methanol (9: 1) as an eluent.

   4hydroxymethyl-1-methyl-1,2,3-triazole (3.18 g, 40%) is thus obtained, which is a colorless oil: 1 H NMR (CDCl 3) 6 4.07 (3H, s), 4.73 ( 2H, d), 7.52 (1H, s); IR (pure) 3320 cm-1.



  * Methanesulfonyl chloride (3.82 ml, 49.6 millimoles) is added dropwise to a stirred, ice-cold solution of alcohol (4.67 ml, 41.3 millimoles) and triethylamine (7.47 ml , 53.7 millimoles) in methylene chloride (20 ml).



  After 0.5 hour, the solvent is removed and the residual solid is taken up in acetonitrile (30 ml). Then potassium thiolacetate (7.06 g, 62.0 millimoles) is added and the suspension is stirred at room temperature for 3 hours. Additional potassium thiolacetate (3.0 g, 26.3 mmol) is added and the suspension is stirred for a further 16 hours.

  <Desc / Clms Page number 181>

   res. The dark suspension is then concentrated and water (10 ml) is added thereto. The mixture is extracted with methylene chloride (5 × 40 ml). The combined extracts are dried (MgSO4) and the solvent is removed. The residual oil is subjected to rapid chromatography on a column of silica gel (90 × 36 mil) hexane then mixture of hexane and ethyl acetate (1: 1) as
 EMI181.1
 eluent 7.

   This gives the 4-eluent, methyl-1,2,3-triazole (5.95 g, 84%) in the form of a slightly pink solid: RMNH1 (CDC13) Ó2.40 (3H, s), 4 , 10 (3H, s), 4.20 (2H, s), 7.53 (1H, s); IR (Nujol) 1675cm-l.



   A solution of triazole (1.00 g, 5.85 millimoles) and ethyl bromoacetate (1.48 ml, 13.3 millimoles) in water is heated to 60 ° C. and for 90 hours in a nitrogen atmosphere. dry acetonitrile (10 ml). The solvent is removed and the residual oil is triturated in ether (4x25 ml) to leave l-methyl-3- (ethylcarboxymethyl) -4-methanethiolaceous-1,2,3-triazolium bromide the shape of a brownish gum that we use directly.



   A cold solution of KOH (0.66 g, 12 millimoles) in water (5 ml) is added to an ice-cold and stirred solution of triazolium bromide in water (20 ml). After 20 minutes, the mixture is diluted to 35 ml and enough solid potassium dihydrogen phosphate is added to bring the pH of the solution to 8.0. This solution is added to a stirred and ice-cold solution of enol phosphate in tetrahydrofuran (35 ml). After 0.5 hour, this solution is transferred to an autoclave containing ether (35 ml) and 10% palladium-on-charcoal (1.5 g). The mixture is hydrogenated for 55 minutes at 276 kPa. The organic phase is then separated and washed with water (2x5 ml). We

  <Desc / Clms Page number 182>

 the mixture of aqueous phases is filtered and the filtrate is concentrated under high vacuum.

   The residue is chromatographed on a phase inversion column (35 × 120 mm) which is eluted with water. By lyophilization of the fractions containing carbapenem, 1.20 g of a green solid are obtained. We rechromatogaphy it on the high pressure liquid chromatography device Waters Prep. 500 HPLC (prepPAk-500 / C18 column) using 2% acetonitrile in water as eluent. The fractions containing the carbapenem are combined and lyophilized. The residue is rechromatographed in a liquid chromatography device under high pressure (10x300 mm column Waters Microbondapack C-18) with elution with water to collect, after lyophilization, the desired pure compound (190 mg, 17%) which occurs as a pale yellow solid.



  1 H NMR (D20) 6 1.24 (3H, d, J = 6.4 Hz), 3.07 (2H, d, J = 9 Hz), 3.38 (1H, q, J = 2.7, 6 , 0 Hz) 4.02-4.30 (3H, m), 4.29 (3H, s), 5.23 (2H, s), 8.52 (1H, s); IR (Nujol) 1750 cm-l; UV (phosphate buffer, pH 7.4) max 296 nm (t = 7.520).



  EXAMPLE 18.- 3- [4- (1-Carboxylatomethyl-3-methyl-1, 2, 3-triazolium) - methanethiol7-6o (- [1- (R) -hydroxyethyl] -7-oxo-1-azabicy-
 EMI182.1
 clo ± 3-. 2. 0 th cloL). potassium.
 EMI182.2
 

  <Desc / Clms Page number 183>

 
 EMI183.1
 

  <Desc / Clms Page number 184>

 



   A mixture of ethyl azidoacetate (30.0 g, 0.23 mole) and propiolic acid (14.3 ml, 0.23 mole) in toluene (75 ml) is stirred at room temperature. The reaction remains moderately exothermic for 90 minutes, at the end of which it becomes strongly exothermic, which makes it necessary to cool using an ice bath. After this development of heat, the reaction mixture is heated to reflux for 0.5 hour. After cooling in an ice bath, a crystalline material is collected by filtration and washed with a little toluene. The raw material thus collected (33.3 g, 72%) consists of a single isomer which is probably l- (ethylcarboxymethyl) -1,2,3-triazole-4-carboxylic acid, according to an analogy with previous work (see C.

   Pederson, Acta Chem. Scand., 1959,13, 888. jRMNHl (DMSO-d6) 6 1.20 (3H, t, J = 7 Hz), 4.15 (2H, q, J = 7 Hz), 5.42 (2H, s), 8.67 (1H, 33.



   A solution of the carboxylic acid (5.00 g, 25.1 millimoles) and triethylamine (3.68 ml,
26.4 millimoles) in dry methylene chloride (50 ml) to an ice-cold stirred solution of ethyl chloroformate (2.52 ml, 26.4 millimoles) in dry methylene chloride (50 ml). The purple solution is stirred for 30 minutes, after which it is washed with water (10 ml), dried (MgSO4) and the solvent is removed. The crude mixed anhydride is dissolved in tetrahydrofuran (50 ml) and added slowly to an ice-cold suspension of sodium borohydride (0.72 g, 18.9 mmol) in tetrahydrofuran (50 ml).

   After 30 minutes of stirring, additional sodium borohydride (0.30 g, 7.9 millimoles) is added and the reaction mixture is allowed to stand in an ice bath for 1 hour.



  Then add water (5 ml) and after 10 minutes,

  <Desc / Clms Page number 185>

 10% aqueous HCl (3 ml) is added. At the end of the evolution of gas, solid potassium carbonate (2 g) is added with stirring. The organic phase is evaporated and the residual white paste is extracted with a supplement of tetrahydrofuran. The combined organic phases are dried (MgSO 4) and the solvent is removed. By rapid chromatography on a column of silica gel which is diluted with hexane, mixtures of ethyl acetate and hexane and finally ethyl acetate, 1- (ethylcarboxymethyl) -4 is obtained -hydro- xymethyl-1,2,3-triazole (2.04 g, 44%) as a crystalline solid.



  RMNH1 (CDC13) 6 1.28 (3H, t, J = 7 Hz), 4.23 (2H, q, J = 7 Hz), 4.75 (2H, s), 4.85 (2H, s) , 7.73 (1H, s).



   Diisopropyl azodicarboxylate (4.11 ml, 20.8 mmol) is added dropwise to an ice-cold solution of triphenylphosphine (5.47 g, 20.8 mmol) in dry tetrahydrofuran (100 ml) 'nitrogen. After 30 minutes, an ice-cold solution of alcohol (1.93 g, 10.4 mmol) and thiolacetic acid (1.49 ml, 20.8 mmol) in dry tetrahydrofuran ( 50 ml). The reaction mixture is allowed to stand for 2 hours in an ice bath, then for another 12 hours at room temperature, after which the solvent is removed. The reaction mixture is subjected to rapid chromatography on silica gel (40 g; elution with fractions of 100 ml of hexane and 5, 10.15 ... 50% of ethyl acetate in hexane).

   The fractions containing the thiolacetate are combined and rechromatographed on silica gel (60 g) [elution with fractions of 200 ml of hexane and of 5, 10.15 and 20% ethyl acetate in hexane then 22.5, 25.27, 5 ... 35% ethyl acetate in hexane7. 1.24 g (49%) of 1- (methyl-

  <Desc / Clms Page number 186>

   carboxymethyl) -4-methanethiolacetate-1,2,3-triazole in the form of a crystalline solid.



    / RMNH1 1, 28 (3H, t, J = 7 Hz), 2.37 (3H, s), 3.87 (2H, s), 3.90 (2H, q, J = 7 Hz), 5, 12 (2H, s), 7.63 (1H, s), IR (Nujol), 1735.1780 cm-l /, in addition to an additional 1.40 g of substance contaminated with triphenylphosphine oxide.



   Methyl trifluoromethanesulfonate (0.51 ml, 4.53 millimoles) is added dropwise to a stirred, ice-cold solution of the triazole (1.00 g, 4.12 millimoles) in dry methylene chloride (5 ml). The ice bath is removed after 30 minutes and after another 30 minutes, the solvent is suctioned off. The residual white solid is suspended in water (15 ml) and the mixture is stirred and cooled in an ice bath. A solution of KOH (0.69 g, 12.4 millimoles) in water (5 ml) is added thereto and the reaction mixture is stirred for 1 hour. It is then diluted to 30 ml with water and to it is added solid potassium dihydrogen phosphate until the pH is brought to 8.0.

   A fraction of this solution (22 ml, about 3.0 millimoles of thiolcarboxylate) is added to a stirred, ice-cold solution of enol phosphate (1.60 g, 2.76 millimoles) in tretrahydrofuran (30 ml). After 30 minutes, the reaction is stopped and the tetrahydrofuran is removed under high vacuum. The yellow solution is then chromatographed on a phase inversion column (35 × 120 ml) which is eluted with water (300 ml) then with 100 ml aliquots of 5, 10.15 ... 30% acetonitrile in water.

   By lyophilization of the appropriate fractions, the p-nitrobenzyl ester is obtained in the form of a yellow solid (930 mg). This is introduced into an autoclave containing ether (25 ml), tetrahydrofuran (25 ml) and phosphate buffer [25 ml, obtained by

  <Desc / Clms Page number 187>

 dissolving potassium dihydrogen phosphate (1.36 g, 0.01 mole) in water (100 ml) and adjust
 EMI187.1
 ment of the pH at 7.4 by addition of 45% aqueous KOH L7 of 10% palladium on carbon (900 mg). The hydrogenation is carried out at 276 kPa for 1 hour, at the end of which the organic phase is separated and washed with water (2x5 ml). The mixture of aqueous phases is filtered and then concentrated under high vacuum.

   The residual solution is chromatographed on a phase inversion column (35 × 120 mm) which is eluted with water. The fractions containing the carbapenem are combined and lyophilized to collect 1.21 g of a pale greenish solid. The latter is purified by liquid chromatography under high pressure (10 × 300 mm column, Waters Microbondapack C-18, eluted with water) to obtain 480 mg (41%) of the desired pure compound.



  RMNH1 (D20) 6 1, 13 (3H, d, J = 6.4 Hz), 3.11 (2H, d, J = 9 Hz), 3.37 (1H, q, J = 3, 0, 6 , 1 Hz), 4.02 (7H, m), 5.18 (2H, s), 8.53 (1H, s).



  IR (Nujol) 1750 cm-l.



  UV (phosphate buffer, pH 7.4) max 205 nm (t = 7.810), EXAMPLE 19.-
 EMI187.2
 3- / 5- 2, 4-triazolium) methanethio7-60 e 7 (1,4 [1- (R) -hydroxyethyl] -7-oxo-1-azabicyclo [3.2.0] hept-2- ene-2- carboxylate
 EMI187.3
 

  <Desc / Clms Page number 188>

 A. l-Methyl-5-methanethiolacetate-1,2,4-triazole
 EMI188.1
 
Methanesulfonyl chloride (0.46 ml, 6.0 millimoles) is added dropwise to an ice-cold, stirred solution of 1-methyl-5-hydroxymethyl-1,2,4-triazole (RG Jones and C. Ainsworth, J. Amer.



  Chem. Soc., 1955, 77, 1938), (565 mg, 5.0 millimoles) and triethylamine (0.91 ml, 6.5 millimoles) in methylene chloride (5 ml). After 20 minutes, additional triethylamine (1.05 ml, 7.5 millimoles) is added, followed by thiolacetic acid (0.53 ml, 7.5 millimoles) and stirring is continued for 45 minutes. The reaction mixture is then diluted with methylene chloride and washed with water.



  The aqueous phase is extracted with methylene chloride (3 × 5 ml) and the mixture of organic phases is dried (MgSO 4), then the solvent is removed. The chromato-
 EMI188.2
 written on a column of silica gel gives pure 1-methyl-5-methanethiolacetate-1,2,4-triazole (570 mg) in the form of a yellow oil in addition, an impure fraction (200 mg) is rechromatographed to obtain by preparative thin layer chromatography on
 EMI188.3
 silica still 100 mg of pure compound (total yield 85% S.



  RMNH1 (CDC13) 6 2.38 (3H, s), 3.90 (3H, s), 4.25 (3H, s), 7.80 (1H, s).

  <Desc / Clms Page number 189>

 
 EMI189.1
 



  B. 3- [5- 2, 4-triazolium) -methanethig7- 6- / Y- -e 7 hept-2-ene-2-carboxylate
 EMI189.2
 
Methyl trifluoromethanesulfonate (1.20 ml, 10.7 millimoles) is added dropwise to an ice-cold solution of 1-methyl-5-methanethiolacetate-1,2,4-triazole (730 mg, 4.27 millimoles) in methylene chloride (7 ml). The reaction mixture is allowed to slowly warm to room temperature over 3 hours after which it is concentrated. The residual oil is triturated in ether to obtain 1,4-dimethyl-5-methanethiolacetate-1,4,4-triazolium trifluoromethanesulfonate (1.46 g) which is used directly.



   A solution of sodium hydroxide (512 mg, 12.8 mmol) in water (5 ml) is added to an ice-cold solution of the triazolium salt (1.45 g, 4.36 mmol) in water (5 ml). After 45 minutes, the mixture is diluted to 25 ml with water and the pH is adjusted to 7.6 using solid potassium dihydrogen phosphate. We then add this solution to

  <Desc / Clms Page number 190>

 a stirred and ice-cold solution of enol phosphate (2.00 g, 3.45 millimoles) in tetrahydrofuran (25 ml). After 30 minutes, the reaction mixture is introduced into an autoclave containing ether (40 ml) and 10% palladium-on-charcoal (2.0 g). The mixture is hydrogenated (310 kPa) for 75 minutes. The reaction mixture is then diluted with ether (25 ml) and filtered. The organic phase is separated and washed with water (2x5 ml).

   The mixture of aqueous phases is washed with ether (3 × 25 ml), then concentrated in vacuo. By column chromatography (phase inversion, 45 × 130 ml, elution with water) then lyophilization of the fractions containing carbapenem, 650 mg of crude compound are obtained. This is rechromatographed to obtain the purity of the desired compound (450 mg, 39%).



  1-NMR (D20) 6 1.24 (3H, d, J = 6.4 Hz), 3.19 (2H, q, J = 2.6, 9.2 Hz), 3.45 (1H, q, J = 2.8, 6.0 Hz), 3.91 (3H, s), 4.06 (3H, s), 4.08-4, 36 (2H, m), 4.54 (2H, d, J = 2.8 Hz), 8.71 (1H, s).



  IR (Nujol) 1755 cm-1.



  UV (phosphate buffer, pH 7.4) at max 294 nm (E = 8.220); t (phosphate buffer, pH 7.4, M = 0.067, T = 370C) 9.1 h.



  EXAMPLE 20.- (1, 5R, 6S) -3-rl, 3-dimethyl-5-tetrazolium) -methyl-thio7-6- (1-hydroxyethyl) -7-oxo-1-azabicyclo / 3. 2. Q7- hept-2-ene-2-carboxylate
 EMI190.1
 

  <Desc / Clms Page number 191>

 A. 5-Carbethoxy-2-methyltetrazole and 5-carbethoxy-1-methyltetrazole
 EMI191.1
 the. Diazomethane methylation
A solution of 5carbethoxytetrazole is cooled to 0 ° C. (see: D. Moderhack, Chem.

   Ber., 108.887 (1975) (9.17 g, 64 millimoles) in ethyl ether (80 ml) (a mixture of ethanol and ether gives the same ratio between the isomers) and is added dropwise drop (15 minutes) a solution of diazomethane (3 g, 71 millimoles) in ether (200 ml). The light yellow solution is stirred for 30 minutes and the excess diazomethane is destroyed by the addition of acetic acid (1 ml). By evaporation of the solvent and distillation of the residue, a clear oil, P. Eb. 95-100 C / 0.5 torr (67 Pa); 9.64 g (96%).



  The proton nuclear magnetic resonance spectrum indicates that it is a mixture of the 1- methylated and 2-methylated isomers in the ratio 6: 4. The separation of the isomers is impossible by distillation and by liquid chromatography under high pressure. .



  IR (film) #max: 1740 cm-1 (C = O of the ester).



  1 H NMR (CDCI 3) zo: 1.53 (3H, two overlapping t, J = 7, 0, CH2CH3), 4.46 and 4.53 (3H, 2s, CH3 of 1-methyltetrazole and 2-methyltetrazole in the report 6: 4, the methyl radical of isomer 2 is located in the lower field and corresponds to the minor product), 4.5 ppm (2H, two overlapping qs, CH2CH3) -

  <Desc / Clms Page number 192>

 Ib. 5-Carbethoxy-2-methyltetrazole
 EMI192.1
 
A mixture of 5-carbethoxy-2methyltetrazole and 5-carbethoxy-1-methyltetrazole (0.252 g, 1.61 millimole, ratio of the two isomers 1: 1) in iodomethane (0.5 ml) is introduced into a tube. in
 EMI192.2
 glass which is sealed and heated at 100 ° C. for 15 hours and at 1300 ° C. for 6 hours.

   By distillation of the reaction mixture, the desired compound which is a light yellow oil is obtained: 0.139 g (55%); P. Eb.



    95-100OC / 0.5 torr (67 Pa) (air bath temperature).



  IR (film) 'max: 1740 cm-l (C = O of the ester).



  RMNH1 (CDC13) #: 1, 46 (3H, t, J = 7, 0, CH3CH2), 4.53 53H, s, CH3-2), 4.5 (2H, q, J = 7, 0, CH2CH3 ).



  2. Methylation with dimethyl sulfate
Anhydrous potassium carbonate (1.38 g, 0.01 mole) and dimethyl sulfate (1.26 g, 0.01 mole) are added to a 5-carbethoxytetrazole solution (1.42 g, 0.01). mole) in dry acetone (20 ml). The mixture is heated at reflux for 12 hours. The carbonate is separated by filtration and the solvent is evaporated off under reduced pressure. The residue is diluted with dichloromethane (30 ml), washed with saturated sodium bicarbonate (10 ml) and brine (10 ml), then dried over anhydrous sodium sulfate. By
 EMI192.3
 evaporation of the solvent and distillation under vacuum, a clear oil is obtained: 45 g (93%); P. Eb. 85-
1.110 C / 0.5 torr (67 Pa).

   The 1 H NMR spectrum indicates the presence of the two isomers in the 1: 1 ratio.

  <Desc / Clms Page number 193>

 B. 5-Hydroxymethyl-2-methyltetrazole
 EMI193.1
 1. By reducing the mixture of esters
Cooled to OC, a mixture of 5-carbethoxy-1-methyltetrazole and 5-carbethoxy-2methyltetrazole (ratio 6: 4) (7.60 g, 49 millimoles) in dry tetrahydrofuran (50 ml) and added thereto. sodium borohydride (1.06 g, 49 millimoles) little by little in 15 minutes. The mixture is kept at 100C for another 10 minutes, then stirred at 200C for 4 hours. The mixture is cooled to 4 ° C. and the excess hydride is carefully destroyed by adding 6N HCl (pH 7 at the end of the evolution of gas).

   The solvent is concentrated in vacuo and the residual oil is diluted with dichloromethane (200 ml), washed with brine (10 ml) and finally dried over Naso. By concentration of the solvent and distillation of the residue under vacuum, 1.83 g (33%) of a clear oil is obtained. The 1 H NMR spectrum of the product indicates that it consists of 5-hydroxymethyl-2-methyltetrazole.



  2. By reduction of 5-carbethoxy-2-methyltetrazole
Solid lithium borohydride (19 mg, 0.87 millimole) is added to a solution of 5-carbethoxy-2-methyltetrazole (0.139 g, 0.89 millimole obtained by isomerization of the mixture of esters using iodide of methyl) in dry tetrahydrofuran (1 ml) to
 EMI193.2
 100C. The mixture is warmed slowly to room temperature and stirred for 4 hours. The excess borohydride is destroyed by careful addition of 6N HCl at 0 ° C. (pH 7). The solvent is evaporated off and the residue is dissolved in dichloromethane (25 ml), then

  <Desc / Clms Page number 194>

 the solution is dried over anhydrous sodium sulfate.



  By evaporation of the solvent, the desired compound is obtained which is a clear oil: 0.092 g (91%); P. Eb. 90-120OC / 0.5 torr (67 Pa) with decomposition.



  IR (film) -x: 3350 cm-l (wide, OH); 1 H NMR (CDCl3) 6: 4.4 (2H, s, CH3-2), 4.93 (2H, s, CH2-5).



  C. 5-Acetylmercaptomethyl-2-methyltetrazole
 EMI194.1
 
Add methanesulfonyl chloride (1.47 g, 12.9 millimoles) and then triethylamine (1.30 g, 12.9 millimoles) dropwise over 5 minutes to a solution of 5-hydroxymethyl-2-methyltetrazole (1.83 g, 11.7 millimoles) in dry dichloromethane (25 ml) onc, The mixture is stirred at 0 C for 1 hour, then a solution of potassium thioacetate (1.60 g, 14 , 0 millimoles) in dry N, Ndimethylformamide (10 ml). The resulting gel is stirred at 0 ° C for 3 hours. The reaction mixture is diluted with dichloromethane (200 ml), washed with brine (20 ml) and dried over anhydrous sodium sulfate.

   By evaporation of the solvent under vacuum and chromatography of the resulting oil on silica gel (2x15 cm, elution with dichloromethane and with dichloromethane-acetone 5%) the desired compound is obtained which is a clear oil: 1.31 g (65 %).



  IR (film) max 1696 cm-l (C = O of thioester).



  1 H NMR (CDCl 3) 2.43 (3H, s, SAc), 4.36 (3H, s, 2-CH3), 4.38 ppm (2H, s, 5-CH2).

  <Desc / Clms Page number 195>

 D. 5-Mercaptomethyl- trifluoromethanesulfonate
1,3-dimethyltetrazolium
 EMI195.1
 
Methyl trifluoromethanesulfonate (0.76 g, 4.64 millimoles) is added to a solution of 5acetylmercaptomethyl-2-methyltetrazole (0.400 g, 2.32 millimoles) in dry dichloromethane (3 ml) and the solution is stirred at 220C for 16 hours. By evaporation of the solvent under vacuum, a red oil is obtained. This salt is dissolved in cold deoxygenated water (5 ml) and 4M sodium hydroxide (0.8 ml, 3.2 millimoles) is added thereto.

   The mixture is stirred at 0 ° C. for 40 minutes, diluted with water (7 ml) and the pH is adjusted to 7.3 with saturated potassium dihydrogen phosphate. The resulting clear solution is kept under nitrogen and use immediately at the next stage.

  <Desc / Clms Page number 196>

 E. (1'R, 5R, 6S) -3- / Y, 3-dimethyl-5-tetrazolium) -methyl-thiol] -6- (1-hydroxyethyl) -7-oxo-1-azabicyclo- (3. 2.0) hept-2-ene-2-carboxylate
 EMI196.1
 
A solution of enol phosphate (0.915 g, 1.58 millimole) in tetrahydrofuran (8 ml) is cooled to 0 ° C. and the solution of 5-mercaptomethyl trifluoromethanesulfonate is added dropwise therein over 20 minutes. 1,3-dimethyltetrazolium (2.32 millimoles, prepared above).

   The pH of the reaction mixture is stable at 6.5 during the whole addition. After another 20 minutes, the pH of the solution is adjusted to 7.0 with saturated sodium bicarbonate. The mixture is introduced into a hydrogenation autoclave, diluted with tetrahydrofuran (10 ml), ether (20 ml) and ice (10 g). The carbapenem is hydrogenated on 10% palladium on activated carbon at 310 kPa, while

  <Desc / Clms Page number 197>

 slowly increases the temperature to 22 C for 90 minutes. The catalyst is filtered off and washed with cold water (5 ml) and ether (20 ml). The aqueous phase is washed with ether (20 ml) and kept under vacuum for 20 minutes to remove traces of organic solvent.

   By chromatography on PrePak 500-C / 18 and elution with water, the desired compound is obtained which, after lyophilising
 EMI197.1
 tion, is a white powder: 0.266 g (49%).



  L-723 (c 1, 04, H2O).



  D UV (H2O, pH 7.4) / \ max: 294 nm (E 7,500).



  IR (KBr) '\ max: 1755 (C = O of ss-lactam), 1600 cm-1 (wide, C = O of carboxylate).



  1 H NMR (D20) Ci: 1.24 (3H, d, J = 6.4 Hz, CH3CHOH), 3.0-3.3 (2H, m, H-4), 3.42 (1H, dd, J = 5.8, J = 2.9, H-6), 4- 4.2 (2H, m, H-5 and CH3CHOH), 4.34 and 4.57 (2x3H, 2s, CH3-1 and 3 tetrazole), 4.49 and 4.51 (2H, 2s, CH2S).



  The product has a half-life of 10.5 hours at 370C (concentration 10-4 M in a phosphate buffer of pH 7.4).



  EXAMPLE 21 Another Process for the Preparation of 3- (N-methylpyridine-2-yl-methanethio) -6 # - [1- (R) -hydroxyethyl] -7-oxo-1-azabi-
 EMI197.2
 cyclo ± 3-. 2. 0 cyclo / 3. hept-2-ene-2-carboxylate
 EMI197.3
 

  <Desc / Clms Page number 198>

 
 EMI198.1
 
4.0 moles (342 ml) of methyl acetoacetate and 8.0 moles (464.6 g) of allyl alcohol are introduced into a 2000 ml flask fitted with a magnetic stirrer, a distillation column of Vigreux, a heating jacket and a nitrogen intake. The reaction mixture is distilled for 12 hours at 92 C. 136 ml (2.0 moles) of allyl alcohol are added and the reaction mixture is distilled for
 EMI198.2
 23 hours.

   Then 136 ml (2.0 moles) of allyl alcohol are added and the reaction mixture is distilled for 16 hours. Finally, the reaction mixture is distilled under vacuum and the product is collected at 105-110 ° C./35 mm Hg (4.7 kPa). 414 g of allyl acetoacetate are thus obtained (73% yield).



  B.
 EMI198.3
 
 EMI198.4
 



  P-toluenesulfonyl azide (345.3 ml, 1.753 mole) is added over 1 hour to a solution of allyl acetoacetate (226.5 g, 1.594 mole) in 3000 ml of acetonitrile and triethylamine (243.4 ml, 1.753 mole) by maintaining the temperature in the vicinity of 200C using a cooling bath. The reaction mixture turns yellow. The reaction mixture is then stirred at room temperature for 18 hours in a nitrogen atmosphere. The mixture is concentrated on a rotary evaporator. The residue is dissolved in diethyl ether (2600 ml) and 1M aqueous KOH (800 ml). The organic phase is washed five times with 1M KOH (500 ml) and once with brine (400 ml).

   After drying over MgS04 and concentration with evapora-

  <Desc / Clms Page number 199>

 rotary tor (temperature less than or equal to 300C), 260.2 g (97%) of the desired compound are obtained.
 EMI199.1
 



   302 ml (1.315 mole) of t-butyldimethylsilyl trifluoromethylsulfonate are added over 45 minutes to a stirred suspension of allyl diazoacetoacetate (203 g, 1.195 mole) in 2000 ml of methylene chloride and 199 ml (1.434 mole) of triethylamine to 5 "C. The mixture is stirred for 1 hour at 5 ° C., then for another 1 hour without cooling. The reaction mixture is washed 4 times with 500 ml of water, then 1 time with 500 ml of brine. It is dried on Na2SO4 and concentrated to obtain 344 g of an orange oil. This oil is used directly in the next stage.
 EMI199.2
 



   A solution of allyl 2diazo-3-t-butyldimethylsilyloxy-3-butenoate (33.84 g, 0.12 mol) in methylene chloride (50 ml) is added dropwise over 5 hours to a mixture of ( 1'R, 3R, 4R) -3- (1'- t-butyldimethylsilyloxyethyl) -4-acetoxyazetidine-2-one

  <Desc / Clms Page number 200>

 (28.7 g, 0.1 mole) and freshly molten zinc chloride (6.8 g, 0.05 mole) in dry methylene chloride (700 ml). The mixture is stirred at room temperature for 2 hours, at the end of which thin layer chromatography indicates the presence of a small amount of residual starting compound.

   A supplement of allyl 2-diazo-3-t-butyldimethylsilyloxy-3-butenoate (4.23 g, 0.015 mole) in 10 ml of methylene chloride is added over 1 hour and stirring is continued at room temperature for 10 hours. The reaction mixture is then diluted with ethyl acetate (750 ml), washed (2x300 ml of saturated sodium bicarbonate and 300 ml of brine), dried (MgSO4) and evaporated to obtain 62.5 g of a dark orange oil which is dissolved in methanol (500 ml) and to which is added IN aqueous HCl (110 ml). The resulting mixture is stirred at room temperature for 2 hours, at the end of which 10 ml of 1N HCl is added, before further stirring for another 2 hours.

   The reaction mixture is concentrated to volume and poured into a mixture of ethyl acetate (800 ml) and water (800 ml). The organic phase is separated, washed with water (800 ml) and the mixture of aqueous extracts is washed with ethyl acetate (400 ml). The mixture of organic extracts is washed with brine (2x400 ml), dried (MgSO4) and concentrated to obtain 32 g of a dark orange-red oil. By rapid chromatography, 9.33 g (yield of 33%) of the desired compound is obtained, which is a golden yellow oil taking up into a light yellow solid.



  1 H NMR (CDCI 3) 6: 6.20-5.72 (m, 2H), 5.48-5.21 (m, 2H), 4.74 (dt, J = 5.8, J '= 1.22 Hz, 2H), 4.30-3, 88 (m, 2H), 3.30-3, 20 (m, 2H), 2.89 (dd, J = 7.3, J '= 2.1, 1H), 2.18 (s, 1H), 1.32 (d, J = 6.2, 3H).

  <Desc / Clms Page number 201>

 
 EMI201.1
 



   Is heated at reflux for 1 hour, a mixture of lb <-diazoester prepared in stage D above (9.2 g, 32.7 millimoles) and rhodium acetate / Rh2 (OAc) 4 / in benzene (1000 ml). Activated charcoal is added to the solution and filtered through a layer of Celite. The Celite is washed with 100 ml of hot benzene. By concentrating the filtrate, 8.08 g (yield 97%) of the desired compound are obtained in the form of a light brown crystalline solid.



  RMNH1 (CDC13) 6: 6.15-5, 68 (m, 1H), 5.45-5, 18 (m, 2H), 4.71-4, 60 (m, 2H), 4.40-4 , 05 (m, 2H), 3.17 (dd, J = 7, l, J '= 2, 0, 1H), 2.95 (dd, J = 6.9, J' = 18, 9, 1H ), 2.42 (dd, J = 7.6, J '= 18.8, 1H), 188 (s, 1H), 1.39 (d, J = 6.3, 3H).



  F.
 EMI201.2
 

  <Desc / Clms Page number 202>

 



   Diisopropylamine (6.08 ml, 0.035 mole) is added at 0 ° C. in a nitrogen atmosphere, then diphenylphosphoryl chloride to a solution of the ketoester prepared in stage E (7.5 g, 0.03 mole). After 15 minutes, thin layer chromatography indicates that no starting compound remains. To this reaction mixture is added diisopropylamine (6.26 ml, 0.036 mole) and a solution of freshly distilled 2-mercaptomethylpyridine (4.5 g, 0.036 mole) in 5 ml of acetonitrile.

   After 2 hours of stirring at OOC, the mixture is poured into ethyl acetate (1000 ml), the mixture is washed with water (2x150 ml), with saturated sodium bicarbonate (150 ml), water (150 ml) and brine (200 ml). The organic phase is dried (MgSO 4) and concentrated in a dark orange-yellow gum. Rapid chromatography gives the product as a golden yellow oil. The product is dissolved in diethyl ether and the solution is cooled to 0 C.



  By filtration, 4.8 g (yield of 44%) of the desired pure compound in the form of cream-colored crystals are obtained.



  1 H NMR (CDCl3) 6: 8.6-8.4 (m, 1H), 7.85-7.15 (m, 3H), 6.20-5.74 (m, 1H, 5.54-5, 15 (m, 2H), 4.80-4.66 (m, 2H), 4.29-4.03 (m, 1H), 4.19 (s, 2H), 3.69-2.85 ( m, 1H), 2.97 (s, 1H), 1.32 (d, J = 6, 2, 3H).



  G.
 EMI202.1
 

  <Desc / Clms Page number 203>

 
 EMI203.1
 



   A solution of potassium 2-ethylhexanoate (1.085 g, 5.96 millimoles) in ethyl acetate (12 ml) is added to a solution of the allyl ester prepared in Stage F (1.79 g, 4 , 97 millimoles), tetrakistriphenylphosphine-palladium (175 mg, 0.15 millimole) and triphenylphosphine (175 mg, 0.67 millimole) in methylene chloride (25 ml). After 1 hour of stirring at room temperature, thin layer chromatography reveals only a trace of the starting compound. The reaction mixture is diluted with anhydrous diethyl ether (150 ml) and the precipitate is collected by filtration, then washed with ethyl acetate and then with ether to obtain a light brown solid.

   The solid is dissolved in water (10 ml) and purified by phase inversion chromatography to collect 1.85 g of the desired compound which is in the form of a cream-colored solid. This is further purified by dispersing it in acetone to collect 1.47 g (83%) of the desired pure compound.



  1 H NMR (D20); 8.45-8, 36 (m, 1H), 7.92-7, 22 (m, 3H), 4.78-3, 91 (m, 2H), 4.69 (s, 2H), 3, 34-2, 71 (m, 3H),
 EMI203.2
 1, 19 (d, J = 6, 4, 3H).



  H.
 EMI203.3
 

  <Desc / Clms Page number 204>

 
 EMI204.1
 



   Toluenesulfonic acid (27.6 mg, 0.16 millimole) is added to a suspension cooled to
 EMI204.2
 0 "C of potassium 6-hydroxyethyl-2-nth-3-carboxylate (53.8 mg, 0.15 ml) in acetone (2 ml). The mixture is stirred at OOC for 20 minutes, then methyl trifluoromethanesulfonate (0.02 ml) is added thereto. After 60 minutes of stirring with Ooc, LA-1 resin is added, then hexane (6 ml). The mixture is extracted with water (4 × 10, 5 ml) and the mixture of aqueous phases is purified by liquid chromatography under high pressure with phase inversion to collect 10 mg of the desired compound.



  EXAMPLE 22.-
 EMI204.3
 Preparation of 3- 6e-Lrl- hept-2-ene-2-carboxylate by the "single reactor" process
 EMI204.4
 

  <Desc / Clms Page number 205>

 
 EMI205.1
 

  <Desc / Clms Page number 206>

 
 EMI206.1
 A. Preparation of enol phosphate (2)
 EMI206.2
 
Ethyldiisopropylamine (9 millimoles, 1.04 equivalent, 1.57 ml) (in approximately 2 minutes) and diphenyl chlorophosphate (9 millimoles, 1.04 equivalent, 1.87 ml) (in approximately 2 minutes) are added ) to an ice-cold solution of ketone 1 (3 g, 8.61 millimoles) in acetonitrile (30 ml). The reaction mixture is stirred for 45 minutes, at the end of which the thin layer chromatography (ethyl acetate, silica gel) indicates the disappearance of ketone 1.

   The solution is diluted with ethyl acetate (60 ml), washed with cold water (2x50 ml) and with brine, dried over sodium sulfate and concentrated (lower bath temperature at 20 C) to obtain a scum which is used as it is.

  <Desc / Clms Page number 207>

 



  B. Preparation of thiol (4)
 EMI207.1
 
Nitrogen is bubbled for 5 minutes in an ice-cold solution of thioacetate 3 (3.31 g, 10 millimoles), then a cooled solution of sodium hydroxide (1 in about 5 minutes) is added thereto dropwise. , 75 equivalent, 17.5 millimoles, 0.7 g) in water (8 ml). The mixture turns yellow. After 75 minutes under nitrogen, the pH is adjusted to 7.4 with a saturated aqueous solution of potassium dihydrogen phosphate. The reaction mixture is diluted with water (15 ml). This aqueous solution of thiol 4 is used as is (50 ml, 0.2 millimole per ml).



  C. Condensation
 EMI207.2
 The aqueous solution is added dropwise

  <Desc / Clms Page number 208>

 thiol 4 prepared in B (5 ml of solution per 5 minutes) to an ice-cold solution of the compound (crude, prepared in A, 8.62 millimoles) in tetrahydrofuran (50 ml). During the reaction, the pH of the mixture is kept in the region of 6.5-7.5 (preferably 7) by addition of a cooled 2N sodium hydroxide solution. The progress of the reaction is observed by thin layer chromatography (a) on silica gel with ethyl acetate and (b) with phase inversion Analtech RPSF, CHCN-in pH 7 buffer (4: 6) .



   Finally, 1.15 equivalent of thiol (50 ml of solution) is used. The reaction is completed in 1 hour at 0 ° C. and the mixture is used as it is for hydrogenation, after adjusting the pH to 7.



  D. Hydrogenation
 EMI208.1
 
The reaction mixture containing compound 5 (prepared in C) is introduced into a Parr apparatus with tetrahydrofuran (10 ml), phosphate buffer (pH 7, 0.1 M) (10 ml), ether ( 75 ml) and 10% palladium on carbon (5 g) and the hydrogenation is carried out at 310 kPa at 3-100C for 2 hours. The catalyst is then filtered off and washed with water

  <Desc / Clms Page number 209>

   (3 × 10 ml), after which the pH is adjusted to 6.2 by careful addition of cold 2N NaOH. Ether is added and the aqueous phase is separated and washed again with ether. The organic solvent is removed from the aqueous phase under vacuum, then the aqueous phase is purified on
 EMI209.1
 Bondapak C-18 column (100 g, 4.5 x 13 cm) using cold distilled water.

   The light yellow fractions containing the product are lyophilized (verification by UV and thin layer chromatography) to obtain 1.46 g (50% based on bicyclic ketone) of compound 6 which is a yellow powder.



    UV: # 293, # = 9000, # 271, # = 11064.



  EXAMPLE 23.-
According to the general procedures of Examples 1 to 20, the carbapenems below are prepared using the intermediate compound of formula:
 EMI209.2
 

  <Desc / Clms Page number 210>

 
 EMI210.1
 

  <Desc / Clms Page number 211>

 
 EMI211.1
 

  <Desc / Clms Page number 212>

 
 EMI212.1
 230-CH-'f de; '+ 3 isomers t 3 possible) j 23p-CH2 - T--' <rcz s CH3 cop co </ 23q-CH2-'1 'L u rH3 (t) 23r 1 CE2-CO CH, 1 23s-CH2 - f K - K C CHCL 23t Ck3
 EMI212.2
 EXAMPLE 24 Following the general procedures of Examples 1 to 20, the following carbapenems are prepared:

  <Desc / Clms Page number 213>

 using the intermediate compound of formula:
 EMI213.1
 

  <Desc / Clms Page number 214>

 
 EMI214.1
 

  <Desc / Clms Page number 215>

 
 EMI215.1
 CF "" 3'j - N-CH 24d 24k Ot- + c 241 CH3 "\ -CH.



  - these K 24m-CH2-- "N CE3 24n c cl, 24o-CH2-'T, (mixture of + CH3 isomers possible)

  <Desc / Clms Page number 216>

 
 EMI216.1
 EXAMPLE 25.-
 EMI216.2
 

  <Desc / Clms Page number 217>

 
 EMI217.1
 
By replacing the intermediate ketone 1 in the procedure of Example 22 with an equimolar amount of the corresponding 1ss-methylated intermediate, the final carbapenem indicated above is obtained.

  <Desc / Clms Page number 218>

 



  EXAMPLE 26.-
 EMI218.1
 
By replacing the intermediate ketone 1 in the procedure of Example 22 with an equimolar amount of the corresponding law-methyl intermediate, the final carbapenem indicated above is obtained.


    

Claims (1)

 EMI219.1   R CLAIMS E V E N D I C A T I O N S1.- Composed of formula:  EMI219.2  where R8 represents a hydrogen atom and R1 is chosen from the hydrogen atom and the alkyl, alkenyl and alkynyl radicals of 1 to 10 carbon atoms; cycloalkyl and cycloalkylalkyl of 3 to 6 carbon atoms in the ring of the cycloalkyl part and from 1 to 6 carbon atoms in the alkyl parts; phenyl 7 aralkyl; aralkenyl and aralkynyl in which the aryl part is a phenyl radical and in which the aliphatic part has 1 to 6 carbon atoms;  heteroaryl, heteroaralkyl, heterocyclic and heterocycloalkyl in which the heteroatom (s) of the aforementioned heterocyclic parts are chosen from 1 to 4 oxygen, nitrogen or sulfur atoms and in which the alkyl parts associated with the heterocyclic parts comprise 1 to 6 carbon atoms, all substituted or unsubstituted, the substituent or substituents of which are mentioned above, independently chosen from: Cl-C6-alkyl optionally amino, halogenated, hydroxylated or halogenated carboxylated  EMI219.3    <Desc / Clms Page number 220>    EMI220.1    <Desc / Clms Page number 221>  where, with regard to the abovementioned substituents, the radicals R3 and R4 are independently chosen from the hydrogen atom and the alkyl, alkenyl and alkynyl radicals of 1 to 10 carbon atoms;  cycloalkyl, cycloalkylalkyl and alkylcycloalkyl of 3 to 6 carbon atoms in the ring of the cycloalkyl part and from 1 to 6 carbon atoms in the alkyl parts; phenyl; aralkyl, aralkenyl and aralkynyl in which the aryl part is a phenyl radical and the aliphatic part has 1 to 6 carbon atoms; and heteroaryl, heteroalkyl, heterocyclic and heterocycloalkyl in which the heteroatom (s) in the aforementioned heterocyclic parts are chosen from 1 to 4 atoms of oxygen, nitrogen or sulfur and in which the alkyl parts associated with these heterocyclic parts have 1 to 6 atoms of carbon, or else R3 and R4, taken together with the nitrogen atom to which at least one of them is united, can form a pentagonal or hexagonal nitrogen heterocyclic radical;  R9 is defined as R3, except that it cannot be a hydrogen atom; or where R1 and R8, taken together, represent a C2-Clo-alkylidene or C2-C10-alkylidene hydroxyl radical; R5 is chosen from alkyl, alkenyl and alkynyl radicals of 1 to 10 carbon atoms; cycloalkyl and cycloalkylalkyl of 3 to 6 carbon atoms in the ring of the cycloalkyl part and from 1 to 6 carbon atoms in the alkyl parts; phenyl; aralkyl, aralkenyl and aralkynyl in which the aryl part is a phenyl radical and in which the aliphatic part has 1 to 6 carbon atoms;  heteroaryl, heteroaralkyl, heterocyclic and heterocycloalkyl in which the heteroatom (s) in the aforementioned heterocyclic parts are chosen from 1 to 4 oxygen, nitrogen or sulfur atoms and in which the alkyl parts associated with the heterocyclic parts  <Desc / Clms Page number 222>  have 1 to 6 carbon atoms, all of which are substituted or unsubstituted; the aforementioned R5 radicals optionally carrying one to three substituents chosen independently from: C1-C6-alkyl optionally amino, fluorinated, chlorinated, carboxylated, hydroxylated, or carbamoylated fluoro, chloro or bromo  EMI222.1  - CN; or phenyl optionally substituted with 1 to 3 fluoro, chloro, bromo, C1-C6-alkyl radicals, -OR3, -NR3R4,  EMI222.2  -SO3R3, -C02R3 where R3, R4 and R9 in these substituents of R5 are as defined above;    <Desc / Clms Page number 223>  or R5 can be combined with  EMI223.1  at another point in the cycle to form a condensed heterocyclic or heteroaromatic radical, the cycle of which may contain additional heteroatoms, chosen from 0, S and N; A represents a C-c-alkylene radical in a straight or branched chain;  R2 represents a hydrogen atom, an anionic charge or a conventional radical which is easy to remove protective of the carboxyl function, it being understood that when R2 represents a hydrogen atom or a protective radical, there is also a counterion, and  EMI223.2  represents a substituted or unsubstituted aromatic, mono-, bi- or polycyclic aromatic heterocyclic radical containing at least one nitrogen atom in the ring and united to the radical A by a carbon atom of the ring and comprising a nitrogen atom which is quaternized by the radical R5; or a pharmaceutically acceptable salt of this compound.  2. Compound according to claim 1, in the formula of which Ri represents a hydrogen atom or a radical.  <Desc / Clms Page number 224>    EMI224.1  CH3 CH3 OH OH 1 1 CH3CH2-, CH-, -C- or CH3 CH3./  EMI224.2  3.-Compound according to claim 1, in the formula of which Ri and R8, taken together, represent a radical  EMI224.3   4. Compound according to claim 1, in the formula of which Ri represents a radical  EMI224.4   5. Compound according to claim 1, in the formula of which RI represents a radical  EMI224.5  and the absolute configuration is 5R, 6S, 8R.  6. Compound according to claim 1, 2,3, 4 or 5, in the formula of which A represents a radical - CH2- or -CH2CH2- ' 7.- Compound of formula  <Desc / Clms Page number 225>    EMI225.1  where RS represents a hydrogen atom and R1 is chosen from the hydrogen atom and the alkyl, alkenyl and alkynyl radicals of 1 to 10 carbon atoms; cycloalkyl and cycloalkylalkyl of 3 to 6 carbon atoms in the ring of the cycloalkyl part and from 1 to 6 carbon atoms in the alkyl parts; phenyl; aralcoyl; aralkenyl and aralkynyl in which the aryl part is a phenyl radical and in which the aliphatic part has 1 to 6 carbon atoms;  heteroaryl, heteroaralkyl, heterocyclic and heterocycloalkyl in which the heteroatom (s) of the aforementioned heterocyclic parts are chosen from 1 to 4 oxygen, nitrogen or sulfur atoms and in which the alkyl parts associated with the heterocyclic parts comprise 1 to 6 carbon atoms, all substituted or unsubstituted, the substituent or substituents of which are mentioned above, independently chosen from: Cl-C6-alkyl optionally amino, halogenated, hydroxylated or halogenated carboxylated  EMI225.2    <Desc / Clms Page number 226>    EMI226.1  where, with regard to the abovementioned substituents, the radicals R3 and R4 are independently chosen from the hydrogen atom and the alkyl, alkenyl and alkynyl radicals  <Desc / Clms Page number 227>  from 1 to 10 carbon atoms;  cycloalkyl, cycloalkylalkyl and alkylcycloalkyl of 3 to 6 carbon atoms in the ring of the cycloalkyl part and from 1 to 6 carbon atoms in the alkyl parts; phenyl; aralkyl, aralkenyl and aralkynyl in which the aryl part is a phenyl radical and the aliphatic part has 1 to 6 carbon atoms; and heteroaryl, heteroaralkyl, heterocyclic and heterocycloalkyl in which the heteroatom (s) in the aforementioned heterocyclic parts are chosen from 1 to 4 atoms of oxygen, nitrogen or sulfur and in which the alkyl parts associated with these heterocyclic parts have 1 to 6 atoms of carbon, or else R3 and R4, taken together with the nitrogen atom to which at least one of them is united, can form a pentagonal or hexagonal nitrogen heterocyclic radical;  R9 is defined as R3, except that it cannot be a hydrogen atom;  EMI227.1  or where RI and R8 taken together represent a C-Coicoylidene or C-Cio'coyIidene radical hydroxylated; R5 is chosen from alkyl, alkenyl and alkynyl radicals of 1 to 10 carbon atoms; cycloalkyl and cycloalkylalkyl of 3 to 6 carbon atoms in the ring of the cycloalkyl part and from 1 to 6 carbon atoms in the alkyl parts; phenyl; aralkyl, aralkenyl and aralkynyl in which the aryl part is a phenyl radical and in which the aliphatic part has 1 to 6 carbon atoms;  heteroaryl, heteroalkyl, heterocyclic and heterocycloalkyl in which the heteroatom (s) in the abovementioned heterocyclic parts are chosen from 1 to 4 oxygen, nitrogen or sulfur atoms and in which the alkyl parts associated with the heterocyclic parts have 1 to 6 carbon atoms , all substituted or unsubstituted; the aforementioned R5 radicals optionally carrying one to three substituents chosen independently from:  <Desc / Clms Page number 228>    Cl-C6-alkyl optionally amino, fluorinated, chlorinated, carboxylated, hydroxylated, or carbamoylated fluoro, chloro or bromo  EMI228.1    - CN;  or phenyl optionally substituted by 1 to 3 fluoro, chloro, bromo, Cl-C6-alkyl, -OR3, -NR3R4, -S03R3, -C02R3 or-CONR3R4, where R3, R4 and R9 in these substituents of R5 are such that defined above; or R5 can be combined with  <Desc / Clms Page number 229>    EMI229.1  at another point in the cycle to form a condensed heterocyclic or heteroaromatic radical, the cycle of which may contain additional heteroatoms, chosen from 0, S and N; A represents a C1-C6-alkylene radical in a straight or branched chain;  R2 represents a hydrogen atom, an anionic charge or a conventional radical which is easy to remove protective of the carboxyl function, it being understood that when R2 represents a hydrogen atom or a protective radical, there is also a counterion, and  EMI229.2  represents a nitrogen heterocyclic radical, mono-, or polycyclic containing 0 to 5 additional heteroatoms chosen between 0, S and N, the heterocyclic radical being united to the radical A by a ring carbon atom and comprising a nitrogen atom of the quaternized ring by the radical R5, and this heterocyclic radical being optionally substituted for the carbon atoms of the ring available by 1 to 5 substituents chosen independently from the C1-C4-alkyl radicals;  Cl-C4-alkyl substituted by 1 to 3 hydroxyl, amino, Cl-C4-alkylamino, di (ClC4) alkylamino, CI-C4-alkoxy, carboxyl, halo or sulfo, C3-C6-cycloalkyl radicals; C3-C6-cycloalkyl (Cl-C4) - alkyl optionally substituted with 1 to 3 substituents  <Desc / Clms Page number 230>  mentioned above with respect to the C1-C4-alkyl radicals; Cl-C4-alkoxy; Cl-C4-alkylthio; amino; Cl-C4-  EMI230.1  alkyllamino; di (C e alcoylamino alcoylamino; halo; Cl-C4alkanoylamino;  Cl-C4-alkanoyloxy; carboxyl; sulfo; : di (Cl-C4) - C02-0-Cl-C4-alkyl; hydroxyl; amidino; guanidino: phenyl; phenyl substituted with 1 to 3 radicals independently chosen from amino, halogeno, hydroxyl, trifluoromethyl, Cl-C4-alkyl, Cl-C4-alkoxy, Cl-C4-alkylamino, di (Cl-C4) alkylamino, carboxyl and sulfo radicals; phenyl (Cl-C4) alkyl in which the phenyl part is optionally substituted with 1 to 3 substituents mentioned above with respect to the phenyl radical and the alkyl part is optionally substituted with 1 to 3 substituents mentioned above with respect to the radicals Cl- C4-alkyl;  and heatheraryl or heteroaralkyl in which the heteroatom (s) are chosen from 1 to 4 atoms 0, S or N and in which the alkyl part associated with the heteroaralkyl radical has 1 to 6 carbon atoms, these heteroaryl and heteroaralkyl radicals being optionally substituted in the heterocyclic part with 1 to 3 radicals independently chosen from hydroxyl, amino, halo, trifluoromethyl, Cl-C4-alkyl, Cl-C4-alkoxy, Cl-C4alkoylamino, di (Cl-C4) alkylamino, carboxyl and sulfo radicals, and in the part alkyl with 1 to 3 radicals chosen from hydroxyl, amino, Cl-C4-alkylamino, di (Cl-C4) alkylamino, Cl-C4-alkoxy, carboxyl,  halo and sulfo and the heterocyclic radical being optionally substituted for the ring nitrogen atoms available by 1 to 3 radicals independently chosen from C1-C4-alkyl radicals; Cl-C4-alkyl substituted by 1 to 3 hydroxyl, amino, Cl-C4-alkylamino, di (Cl-C4) alkylamino, Cl-C4-alkoxy, carboxyl, halo radicals  EMI230.2  or sulfo; C3-C6-cycloalkyl;  C3-C6-cycloalkyl (Ci-C4) alkyl optionally substituted with 1 to 3 substituents  <Desc / Clms Page number 231>  mentioned above with respect to the CI-C4-alkyl radicals; phenyl, phenyl substituted with 1 to 3 substituents independently chosen from amino, halogen, hydroxyl, trifluoromethyl, CI-C4-alkyl, d-C-alkoxy, Ci-C-alkylamino, di (Cl-C4) alkylamino, carboxyl and sulfo; phenyl (Cl-C4) alkyl, the phenyl part of which can optionally be substituted with 1 to 3 substituents mentioned above with respect to the phenyl radical and the alkyl part of which can optionally be substituted with 1 to 3 substituents mentioned above with regard to the radicals C1 -C4-alkyl;  and heteroaryl or heteroaralkyl in which the heteroatom (s) are chosen from 1 to 4 atoms 0, S or N and in which the alkyl part associated with the heteroaralkyl radical has 1 to 6 carbon atoms, the heteroaryl and heteroaralkyl radicals being optionally substituted in the heterocyclic part with 1 to 3 substituents independently chosen from hydroxyl, amino, halogen, trifluoromethyl, Cl-C4-alkyl, Cl-C4-alkoxy, Cl-C4-alkylamino, di (Cl-C4) alkylamino, carboxyl and sulfo radicals and in the alkyl part with 1 to 3 substituents chosen from hydroxyl, amino, C1-C4-alkylamino, di (C1-C4) alkylamino, C1-C4-alkoxy, carboxyl, halo and sulfo radicals; or a pharmaceutically acceptable salt of this compound.  8. Compound according to claim 7, in  EMI231.1  the formula of which Ri represents a hydrogen atom or a radical  EMI231.2  CH3 CH3 OH OH & a CH3CH2-, CH3 / '' CH3 / '  EMI231.3  9. Compound according to claim 7, in the formula of which RI and R8, taken together, represent  <Desc / Clms Page number 232>  a radical  EMI232.1  10.-Compound according to claim 7, in  EMI232.2  the formula of which Rl represents a radical  EMI232.3    EMI232.4  11. Compound according to claim 7, in the formula of which RI represents a radical.  EMI232.5    EMI232.6  and the absolute configuration is 5R, 6S, 8R. 12.-Compound according to claim 7, 8, 9, 10 or 11, in the formula of which A represents a radical -CH2 -or-CH2CH2-. 13.- Compound of formula  EMI232.7  where RS represents a hydrogen atom and RI is chosen from the hydrogen atom and the alkyl, alkenyl and alkynyl radicals of 1 to 10 carbon atoms; cycloalcoyl and cycloalcoylalcoyl of 3 to 6 atoms of  <Desc / Clms Page number 233>  carbon in the ring of the cycloalkyl part and from 1 to 6 carbon atoms in the alkyl parts; phenyl; aralcoyl; aralkenyl and aralkynyl in which the aryl part is a phenyl radical and in which the aliphatic part has 1 to 6 carbon atoms;  heteroaryl, heteroaralkyl, heterocyclic and heterocycle-alkyl in which the heteroatom (s) of the aforementioned heterocyclic parts are chosen from 1 to 4 atoms of oxygen, nitrogen or sulfur and in which the alkyl parts associated with the heterocyclic parts comprise 1 to 6 atoms of carbon, all substituted or unsubstituted, in which the substituent or substituents with respect to the abovementioned radicals are independently chosen from: Cl-C6-alkyl optionally amino, halogenated, hydroxylated or halogenated carboxylated  EMI233.1    <Desc / Clms Page number 234>    EMI234.1  where, with regard to the abovementioned substituents, the radicals R3 and R4 are independently chosen from the hydrogen atom and the alkyl, alkenyl and alkynyl radicals of 1 to 10 carbon atoms;  cycloalkyl, cycloalkylalkyl and alkylcycloalkyl of 3 to 6 carbon atoms in the ring of the cycloalkyl part and from 1 to 6 carbon atoms in the alkyl parts: phenyl; aralkyl, aralkenyl and aralkynyl in which the aryl part is a phenyl radical and the aliphatic part has 1 to 6 carbon atoms; and heteroaryl, heteroaralkyl, heterocyclic and heterocycloalkyl in which the heteroatom (s) in the aforementioned heterocyclic parts are chosen from 1 to 4 atoms of oxygen, nitrogen or sulfur and in which the alkyl parts associated with these heterocyclic parts have 1 to 6 atoms carbon, or R3 and R4,  <Desc / Clms Page number 235>  taken together with the nitrogen atom to which at least one of them is linked, can form a pentagonal or hexagonal nitrogen heterocyclic radical;  R9 is defined as R3, except that it cannot be a hydrogen atom;  EMI235.1  or where Ri and R8, taken together, represent a Cz-Cio-alkylidene or C2-CIO-alkylidene radical; R5 is chosen from alkyl, alkenyl and alkynyl radicals of 1 to 10 carbon atoms; cycloalkyl and cycloalkylalkyl of 3 to 6 carbon atoms in the ring of the cycloalkyl part and from 1 to 6 carbon atoms in the alkyl parts; phenyl; aralkyl, aralkenyl and aralkenyl in which the aryl part is a phenyl radical and in which the aliphatic part has 1 to 6 carbon atoms;  heteroaryl, heteroaralkyl, heterocyclic and heterocycloalkyl in which the heteroatom (s) in the above-mentioned heterocyclic parts are chosen from 1 to 4 oxygen, nitrogen or sulfur atoms and in which the alkyl parts associated with the heterocyclic parts have 1 to 6 carbon atoms , all substituted or unsubstituted; the aforementioned R5 radicals optionally carrying one to three substituents chosen independently from: Cl-C6-alkyl optionally amino, fluorinated, chlorinated, carboxylated, hydroxylated, or carbamoylated fluoro, chloro or bromo  EMI235.2    <Desc / Clms Page number 236>    EMI236.1  phenyl optionally substituted with 1 to 3 radicals  EMI236.2  fluoro, chloro, bromo, C-C-alkyl, -OR, -NRR, - So3R3, -C02R3 or-CONR3R4, where R3, R4 and R9 in these substituents of R5 are as defined above;  or R5 can be combined with  EMI236.3  at another point in the cycle to form a condensed heterocyclic or heteroaromatic radical, the cycle of which may contain additional heteroatoms, chosen from 0, S and N; A represents a C1-C6-alkylene radical in a straight or branched chain;  R2 represents a hydrogen atom, an anionic charge or a conventional radical which is easy to remove protective of the carboxyl function, it being understood that when R2 represents a hydrogen atom or a protective radical, there is also a counter  <Desc / Clms Page number 237>  ion, and  EMI237.1  represents a heterocyclic aromatic nitrogen pentagonal or hexagonal radical containing 0 to 3 additional heteroatoms chosen between 0, S and N, this heterocyclic radical being optionally substituted for the carbon atoms of the ring available by 1 to 5 substituents chosen independently from the radicals ClC4-alkyl;  Cl-C4-alkyl substituted by 1 to 3 hydroxyl, amino, Cl-C4-alkylamino, di (C1-C4) alkylamino, C1-C1-alkoxy, carboxyl, halo or sulfo, C3-C6-cycloalkyl radicals; C3-C6-cycloalkyl (Cl-C4) - alkyl optionally substituted with 1 to 3 substituents mentioned above in connection with the Cl-C4alkyl radicals; Cl-C4-alkoxy; Cl-C4-alkylthio; amino; Cl-C4alkoylamino; di (Cl-C4) alkylamino; halo;  Cl-C4alkanoylamino; Cl-C4-alkanoyloxy; carboxyl; sulfo; - CO -O-Ci-C-alkyl; hydroxyl; amidino; guanidino; phenyl; phenyl substituted with 1 to 3 radicals independently chosen from amino, halogeno, hydroxyl, trifluoromethyl, Cl-C4-alkyl, Cl-C4-al-coxy, Cl-C4-alkylamino, di (Cl-C4) alkylamino, carboxyl and sulfo; phenyl (Cl-C4) alkyl in which the phenyl part is optionally substituted with 1 to 3 substituents mentioned above with respect to the phenyl radical and the alkyl part is optionally substituted with 1 to 3 substituents mentioned above with respect to the radicals Cl- C4-alkyl;  and weatheraryl or heteroaralkyl in which the heteroatom (s) are chosen from 1 to 4 atoms 0, S or N and in which the alkyl part associated with the heteroaralkyl radical has 1 to 6 atoms  <Desc / Clms Page number 238>  carbon, these heteroaryl and heteroaralkyl radicals being optionally substituted in the heterocyclic part by 1 to 3 substituents chosen independently from the hydroxyl, amino, halo, trifluoromethyl, Cl-C4-alkyl, Cl-C4-alkoxy, Cl-C4alkoylamino, di radicals (Cl-C4) alkyllamino, carboxyl and sulfo, and in the alkyl part with 1 to 3 substituents chosen from hydroxyl, amino, Cl-C4-al-coylamino, di (Cl-C4) alkylamino, Cl-C4-alkoxy radicals , carboxyl,  halo and sulfo and the heterocyclic radical being optionally substituted for the nitrogen atoms of the ring available by 1 to 3 substituents chosen independently from the C1-C4-alkyl radicals; Cl-C4alkyl substituted by 1 to 3 hydroxyl, amino, Cl-C4-alkylamino, di (Cl-C4) alkylamino, Cl-C4-alkoxy radicals,  EMI238.1  carboxyl, halo or sulfo; C3-C6-cycloalkyl;  C3-C6-cycloalkyl (Cl-C4) alkyl optionally substituted with 1 to 3 substituted mentioned above with respect to the C1-C4-alkyl radicals; phenyl, phenyl substituted with 1 to 3 substituents independently chosen from amino, halo, hydroxyl, trifluoromethyl, Cl-C4-alkyl, Cl-C4-alkoxy, Cl-C4-alkylamino, di (ClC4) alkylamino, carboxyl and sulfo radicals;  phenyl (Cl-C4) alkyl, the phenyl part of which may optionally be substituted with 1 to 3 substituents mentioned above with respect to the phenyl radical and the alkyl part of which can optionally be substituted with 1 to 3 substituents mentioned above with regard to the radicals Cl -C4-alkyl:    and heteroaryl or heteroaralkyl in which the heteroatom (s) are chosen from 1 to 4 atoms 0, S or N and in which the alkyl part associated with the heteroaralkyl radical has 1 to 6 carbon atoms, the heteroaryl and heteroaralkyl radicals being optionally substituted in the heterocyclic part by 1 to 3 substituents chosen independently  <Desc / Clms Page number 239>  among the hydroxyl, amino, halo, trifluoromethyl, Cl-C4-alkyl, CI-C4-alkoxy, Cl-C4-alkylamino, di (CI-C4) alkylamino, carboxyl and sulfo radicals and in the alkyl part with 1 to 3 substituents chosen from hydroxyl, amino, Cl-C4-alkylamino, di (Cl-C4) alkylamino, C1-C4-alkoxy, carboxyl, halo and sulfo radicals;  or a pharmaceutically acceptable salt of this compound.    14.-Compound according to claim 13, in the formula of which the heterocyclic radical  EMI239.1  is optionally substituted for the nitrogen or carbon atoms of the ring available by up to 5 substituents chosen independently of one another from lower alkyl radicals.  EMI239.2   15.-Compound according to claim 14, in  EMI239.3  the formula of which A represents a radical -CH2-, CH - CH- or CH (CH3).  EMI239.4   16. claim 13, 14 or 15, in the formula of which R1 represents a radical  EMI239.5  and the absolute configuration is 5R, 6S, 8R.    17.- Compound of formula  <Desc / Clms Page number 240>    EMI240.1  where R8 represents a hydrogen atom and RI is chosen from the hydrogen atom and the alkyl, alkenyl and alkynyl radicals of 1 to 10 carbon atoms; cycloalkyl and cycloalkylalkyl of 3 to 6 carbon atoms in the ring of the cycloalkyl part and from 1 to 6 carbon atoms in the alkyl parts; phenyl; aralcoyl; aralkenyl and aralkynyl in which the aryl part is a phenyl radical and in which the aliphatic part has 1 to 6 carbon atoms;  heteroaryl, heteroaralkyl, heterocyclic and heterocycloalkyl in which the heteroatom (s) of the aforementioned heterocyclic parts are chosen from 1 to 4 oxygen, nitrogen or sulfur atoms and in which the alkyl parts associated with the heterocyclic parts comprise 1 to 6 carbon atoms, all substituted or unsubstituted, the substituent or substituents of which are mentioned above, independently chosen from: Cl-C6-alkyl optionally amino, halogenated, hydroxylated or halogenated carboxylated  EMI240.2    <Desc / Clms Page number 241>    EMI241.1  where, with regard to the abovementioned substituents, the radicals R3 and R4 are independently chosen from the hydrogen atom and the alkyl, alkenyl and alkynyl radicals  <Desc / Clms Page number 242>  from 1 to 10 carbon atoms;  cycloalkyl, cycloalkylalkyl and alkylcycloalkyl of 3 to 6 carbon atoms in the ring of the cycloalkyl part and from 1 to 6 carbon atoms in the alkyl parts; phenyl; aralkyl, aralkenyl and aralkynyl in which the aryl part is a phenyl radical and the aliphatic part has 1 to 6 carbon atoms; and heteroaryl, heteroaralkyl, heterocyclic and heterocyloalkyl in which the heteroatom (s) in the aforementioned heterocyclic parts are chosen from 1 to 4 atoms of oxygen, nitrogen or sulfur and in which the alkyl parts associated with these heterocyclic parts have 1 to 6 atoms of carbon, or else R3 and R4, taken together with the nitrogen atom to which at least one of them is united, can form a pentagonal or hexagonal nitrogen heterocyclic radical;  R9 is defined as R3, except that it cannot be a hydrogen atom; or where RI and R8, taken together, represent a  EMI242.1  C-CiQ-alkylidene or C-Co-alkylidene radical; R5 is chosen from alkyl, alkenyl and alkynyl radicals of 1 to 10 carbon atoms; cycloalkyl and cycloalkylalkyl of 3 to 6 carbon atoms in the ring of the cycloalkyl part and from 1 to 6 carbon atoms in the alkyl parts; phenyl; aralkyl, aralkenyl and aralkynyl in which the aryl part is a phenyl radical and in which the aliphatic part has 1 to 6 carbon atoms;  heteroaryl, heteroaralkyl, heterocyclic and heterocycloalkyl in which the heteroatom (s) in the aforementioned heterocyclic parts are chosen from 1 to 4 oxygen, nitrogen or sulfur atoms and in which the alkyl parts associated with the heterocyclic parts have 1 to 6 carbon atoms , all substituted or unsubstituted; the aforementioned R5 radicals optionally carrying one to three substituents chosen independently  <Desc / Clms Page number 243>  especially among: Cl-C6-alkyl optionally amino, fluorinated, chlorinated, carboxylated, hydroxylated, or carbamoylated fluoro, chloro or bromo  EMI243.1    - CN;  or phenyl optionally substituted with 1 to 3 fluoro, chloro, bromo, Cl-C6-alkyl, -OR3, -NR3R4, - S03R3, -C02R3 or-CONR3R4, where R3, R4 and R9 in these substituents of R5 are such that defined above; or R5 can be combined with  <Desc / Clms Page number 244>    EMI244.1  at another point in the cycle to form a condensed heterocyclic or heteroaromatic radical, the cycle of which may contain additional heteroatoms, chosen from 0, S and N; A represents a Ci-Ce-alkylene radical in a straight or branched chain;  R2 represents a hydrogen atom, an anionic charge or a conventional radical which is easy to remove protective of the carboxyl function, it being understood that when R2 represents a hydrogen atom or a protective radical, there is also a counterion, and  EMI244.2  represents a radical chosen between  EMI244.3  where R6, R7 and RIO are independently chosen from the hydrogen atom and the C1-C4-alkyl radicals;  C1-C4-alkyl substituted by hydroxyl, C1-C4-alkylamino, di (C1-C4-alkyl) amino, C1-C4-alkoxy, amino, sulfo, carboxyl and halo; C3-C6-cycloalkyl; CI -C4-  EMI244.4  alkoxy; -alkylIthio di (CI-C4-alkyl) amino; -alcanoyIamino  <Desc / Clms Page number 245>    EMI245.1  C-C-alkanoyIoxy -C-C-alcoyIe Ci-Hydroxyl; amidino; guanidino; phenyl, phenyl substituted by one, two or three amino, halo, hydroxyl, trifluoromethyl radicals? C -C-alkyl or Cl-C4alkoxy; phenyl (Cl-C4) alkyl in which the phenyl part can optionally be substituted by 1 to 3 substituents mentioned above with respect to the phenyl radical and the alkyl part can optionally be substituted by 1 to 3 substituents mentioned above with respect to the radicals Cl-C4-alkyl;  and heteroaryl or heteroaralkyl in which the heteroatom (s) in the aforementioned heterocyclic parts are chosen from 1 to 4 oxygen, nitrogen or sulfur atoms and the alkyl part associated with the heteroaralkyl part has 1 to 6 carbon atoms; or where two of R6, R7 and R8, taken together, can represent a condensed saturated carbocyclic radical, a condensed aromatic carbocyclic radical, a condensed non-aromatic heterocyclic radical or a condensed heteroaromatic radical, which condensed rings are optionally substituted by 1 or 2 of the substituents defined above  EMI245.2  above about R6, R7 and ROy  EMI245.3  ex N t R5'-N 1 e) i or.  o e! ) el N D  <Desc / Clms Page number 246>  optionally substituted on a carbon atom by 1 to 3 substituents independently chosen from C1-C4-alkyl radicals; Cl-C4-alkyl substituted by hydroxyl, Cl-C4-alkylamino, di (Cl-C4-alkyl) amino, Cl-C4-alkoxy, amino, sulfo, carboxyl and halo; C3C6-cycloalkyl; Cl-C4-alkoxy; Ci-C-alcoyIthio; amino; Cl-C4-alkyllamino; di (Cl-C4-alkyl) amino; halo; C1-C4-alkanoylamino;  Cl-C4-alkanoyloxy; carboxyl; -C02Cl-C4-alkyl; hydroxyl; amidino; guanidino; phenyl; phenyl substituted with one, two or three amino, halo, hydroxyl, trifluoromethyl radicals; CI-C4-alkyl or CI -C4-alkoxy; phenyl (CI-C4) alkyl in which the phenyl part can optionally be substituted with 1 to 3 substituents mentioned above with respect to the phenyl radical and the alkyl part can optionally be substituted with 1 to 3 substituents mentioned above with respect to the radicals Cl-C4-alkyl;  and heteroaryl or heteroaralkyl in which the heteroatom (s) in the aforementioned heterocyclic parts are chosen from 1 to 4 oxygen, nitrogen or sulfur atoms and the alkyl part associated with the heteroaralkyl part has 1 to 6 carbon atoms, or optionally substituted to form a condensed carbocyclic, heterocyclic or heteroaromatic radical optionally substituted by 1 or 2 of the substituents defined above;  EMI246.1    <Desc / Clms Page number 247>    EMI247.1  -5 '' 61 5 = 1 5 QI N'N R eN r5, -N ", e" "r5--) 1 1) -0 u 1 -), K /  EMI247.2  optionally substituted on a carbon atom by 1 or 2 substituents chosen independently from the C1-C4-alkyl radicals;  Cl-C4-alkyl substituted by hydroxyl, Cl-C4-alkylamino, di (C1-C4-alkyl) amino, Cl-C4-alkoxy, amino, sulfo, carboxyl and halo; C3C6-cycloalkyl; Cl-C4-alkoxy; Cl-C4-alkylthio; amino; Cl-C4-alkyllamino; di (Cl-C4-alkyl) amino; halo; C1-C4-alkanoylamino; Cl-C4-alkanoyloxy; carboxyl; -CO- Cl-C4-alkyl; hydroxyl; amidino; guanidino; phenyl, phenyl substituted by one, two or three amino, halo, hydroxyl, trifluoromethyl radicals;  Cl-C4-alkyl or Cl-C4-alkoxy; phenyl (Cl-C4) alkyl in which the phenyl part can optionally be substituted by 1 to 3 substituents mentioned above with respect to the phenyl radical and the alkyl part can optionally be substituted by 1 to 3 substituents mentioned above with respect to the radicals Cl-C4-alkyl; and heteroaryl or heteroaralkyl in which the heteroatom (s) in the aforementioned heterocyclic parts are chosen from 1 to 4 oxygen, nitrogen or sulfur atoms and the alkyl part associated with the heteroaralkyl part has 1 to 6 carbon atoms, or optionally substituted to form a condensed carbocyclic, heterocyclic or heteroaromatic radical optionally substituted by 1 or 2 of the substituents defined above;    <Desc / Clms Page number 248>    EMI248.1  (d) R5 R5 R5 and /./N) N): 'N EN c-'C' or N f  EMI248.2  optionally substituted on a carbon atom by a substituent chosen independently from the radicals 1 E} tC1-C4-alkyl; C1-C4-alkyl substituted by hydroxyl, Cl-C4-alkylamino, di (C1-C4-alkyl) amino, C1-C4-alkoxy, amino, sulfo, carboxyl and halo; C3-C6-cycloalkyl; Cl-C4-alkoxy; Cl-C4-alkylthio; amino; Cl-C4-alkyllamino; di (C1-C4-alkyl) amino; halo;  Cl-C4-alkanoylamino; Cl-C4-alkanoyloxy; carboxyl; -CO "Cl-C4-alkyl; hydroxyl; amidino; guanidino; phenyl, phenyl substituted by one, two or three amino, halo, hydroxyl, trifluoromethyl; CC-alkyl or Cl-C4-alkoxy; phenyl (Cl- C4) alkyl, the phenyl part of which may optionally be substituted with 1 to 3 substituents mentioned above with respect to the phenyl radical and the alkyl part, which may optionally be substituted with 1 to 3 substituents mentioned above with regard to the radicals C1-C4- alkyl;  and heteroaryl or heteroaralkyl in which the heteroatom (s) in the aforementioned heterocyclic parts are chosen from 1 to 4 oxygen, nitrogen or sulfur atoms and the alkyl part associated with the heteroaralkyl part has 1 to  <Desc / Clms Page number 249>  6 carbon atoms;  EMI249.1  c - e 1 ---  EMI249.2  where X represents 0, S or NR where R represents a radical or 1-1Cl-C4-alkyl; Cl-C4-alkyl substituted by 1 to 3 hydroxyl, amino, Cl-C4-alkylamino radicals; di (ClC4) alkylamino; Cl-C4-alkoxy; carboxyl; halo or sulfo; C3-C6-cycloalkyl;    C3-C6-cycloalkyl (Cl-C4) alkyl optionally substituted with 1 to 3 substituents mentioned above in connection with the ClC4-alkyl radicals; phenyl; phenyl substituted with 1 to 3 substituents independently chosen from amino, halo, hydroxyl, trifluoromethyl, Cl-C4alkyl, Cl-C4-alkoxy, Cl-C4-alkylamino, di (CI-C4) - alkylamino, carboxyl and sulfo radicals; phenyl (Cl-C4) alkyl, the phenyl part of which can optionally be substituted with 1 to 3 substituents mentioned above with respect to the phenyl radical and the alkyl part of which can optionally be substituted with 1 to 3 substituents mentioned above with respect to the phenyl radicals ClC4-alkyl radicals;  and heatheraryl and heteroaralkyl in which the heteroatom (s) are chosen from 1 to 4 atoms 0, S or N and the alkyl part associated with the heteroaralkyl radical has 1 to 6 carbon atoms, these heteroaryl and heteroaralkyl radicals being optionally substituted in the heterocyclic part by 1 to 3 substituents chosen independently from the hydroxyl, amino, halogen, trifluoromethyl, C-C4-alkyl, Cl-C4-alkoxy, Cl-C4-alkylamino, di (Cl-C4) - alkylamino, carboxyl and sulfo radicals, and in the alkyl part with 1 to 3 substituents chosen from  <Desc / Clms Page number 250>  hydroxyl, amino, Cl-C4-alkylamino, di (ClC4) alkylamino, Cl-C4-alkoxy, carboxyl, halo and sulfo radicals,  this radical being optionally substituted on a carbon atom by 1 or more substituents chosen independently from the C1-C4alkyl radicals; Cl-C4-alkyl substituted by hydroxyl, Cl-C4alkoylamino, di (Cl-C4-alkyl) amino, Cl-C4-alkoxy, amino, sulfo; carboxyl or halo; C3-C6-cycloalkyl; Cl-C4-alkoxy; Cl-C4-alkylthio, amino; Cl-C4alkoylamino; di (Cl-C4-alkyl) amino; halo;  Cl-C4alkoylamino; Cl-C4-alkanoyloxy; carboxyl; -C02-Cl-C4-alkyl; hydroxyl; amidino; guanidino; phenyl; phenyl substituted with one, two or three amino, halo, hydroxyl, trifluoromethyl radicals; Cl-C4-alkyl or Cl-C4-alkoxy; phenyl (Cl-C4) alkyl, the phenyl part of which can optionally be substituted with 1 to 3 substituents mentioned above with respect to the phenyl radical and the alkyl part of which can optionally be substituted with 1 to 3 substituents mentioned above with regard to the radicals Ci -C4-alkyl;  and heteroaryl and heteroaralkyl in which the heteroatom (s) of the abovementioned heterocyclic parts are chosen from 1 to 4 oxygen, nitrogen or sulfur atoms and the alkyl part associated with the heteroaralkyl part has 1 to 6 carbon atoms, or optionally substituted to form a condensed carbocyclic, heterocyclic or heteroaromatic radical optionally substituted by 1 or 2 of the radicals defined above;  EMI250.1    <Desc / Clms Page number 251>    EMI251.1  & N i 1 --L or (1-1R5t. 'N And R R5 where X represents 0, S or NR where R represents a Cl-C4-alkyl radical Cl-C4-alkyl substituted by 1 to 3 hydroxyl, amino, Cl-C4-alkylamino radicals; di (ClC4) alkylamino; C1-C4-alkoxy; carboxyl; halo or sulfo;  C3-C6-cycloalkyl; C3-C6-cycloalkyl (C1C4) alkyl optionally substituted with 1 to 3 substituents mentioned above in connection with the ClC4-alkyl radicals; phenyl; phenyl substituted with 1 to 3 substituents independently chosen from amino, halo, hydroxyl, trifluoromethyl, Cl-C4alkyl, Cl-C4-alkoxy, Cl-C4-alkylamino, di (Cl-C4) - alkylamino, carboxyl and sulfo phenyl radicals ( C1-C4) alkyl, the phenyl part of which can optionally be substituted with 1 to 3 substituents mentioned above with respect to the phenyl radical and the alkyl part of which can optionally be substituted with 1 to 3 substituents mentioned above with respect to the radicals CiC4 -alkyl;  and heatheraryl and heteroaralkyl in which the heteroatom (s) are chosen from 1 to 4 atoms 0, S or N and the alkyl part associated with the heteroaralkyl radical has 1 to 6 carbon atoms, these heteroaryl and heteroaralkyl radicals being optionally substituted in the heterocyclic part by 1 to 3 substituents chosen independently from the hydroxyl, amino, halogen, trifluoromethyl, C-C4-alkyl, Cl-C4-alkoxy, Cl-C4-alkylamino, di (Cl-C4) - alkylamino, carboxyl and sulfo radicals, and in the alkyl part with 1 to 3 substituents chosen from hydroxyl, amino, Cl-C4-alkylamino, di (Cl-  <Desc / Clms Page number 252>  C4) alkyllamino, Cl-C4-alkoxy, carboxyl, halo and sulfo,  this radical being optionally substituted on a carbon atom by a substituent chosen independently from the C1-C4-alkyl radicals; Cl-C4-alkyl substituted by hydroxyl, Cl-C4-alkylamino, di C1-C4alkyl) amino, CI-C4-alkoxy, amino, sulfo; carboxyl or halo; C3-C6-cycloalkyl; Cl-C4-alkoxy; CI-C4-alkylthio, amino; Cl-C4-alkyllamino; di (Cl-C4) alkylamino; halo; C-c-alkanoyiamino; Cl-C4alkanoyloxy; carboxyl; -C02-CI-C4-alkyl; hydroxyl; amidino; guanidino; phenyl; phenyl substituted with one, two or three amino, halo, hydroxyl, trifluoromethyl radicals;  C1-C4-alkyl or Cl-C4-alkoxy; phenyl (C1-C4) alkyl, the phenyl part of which may optionally be substituted with 1 to 3 substituents mentioned above with respect to the phenyl radical and the alkyl part of which can optionally be substituted with 1 to 3 substituents mentioned above with respect to the Cl-C4-alkyl radicals; and heteroaryl and heteroaralkyl in which the heteroatom (s) of the abovementioned heterocyclic parts are chosen from 1 to 4 oxygen, nitrogen or sulfur atoms and the alkyl part associated with the heteroaralkyl part has 1 to 6 atom? of carbon ; and  EMI252.1    <Desc / Clms Page number 253>    EMI253.1  <il or rR5 - 'Il N, 1  EMI253.2  where R represents a CI-C4-alkyl radical substituted by 1 to 3 hydroxyl, amino, Cl-C4-ealcoylamino radicals;  di (CI-C4) alkylamino; C1-C4-alkoxy; carboxyl; halo or sulfo; C3-C6-cycloalkyl; C3C6-cycloalkyl (Cl-C4) alkyl optionally substituted with 1 to 3 substituents mentioned above in connection with the C-c-alkyl radicals; phenyl; phenyl substituted with 1 to 3 substituents independently chosen from  EMI253.3  amino, halo, hydroxyl, trifluoromethyl, Cl-C4-alkyl, Cl-C4-alkoxy, Cl-C4-alkylamino, di (Cl-C4) alkylamino, carboxyl and sulfo radicals; phenyl (C1-C4) alkyl, the phenyl part of which can optionally be substituted with 1 to 3 substituents mentioned above with respect to the phenyl radical and the alkyl part of which can optionally be substituted with 1 to 3 substituents mentioned above with regard to the Cl-C4-alkyl radicals;  and heatheraryl and heteroaralkyl in which the heteroatom (s) are chosen from 1 to 4 atoms 0, S or N and the alkyl part associated with the heteroaralkyl radical has 1 to 6 carbon atoms, these heteroaryl and heteroaralkyl radicals being optionally substituted in the heterocyclic part by 1 to 3 substituents independently chosen from hydroxyl, amino, halo, trifluoromethyl, C 1- C4-alkyl, Cl-C4-alkoxy, C1-C4-alkylamino, di (C1-C4) alkylamino, carboxyl and sulfo radicals, and in the alkyl part with 1 to 3 substituents chosen from hydroxyl, amino, C1-C4-alkylamino, di (Cl-  <Desc / Clms Page number 254>    C4) alkyllamino, Cl-C4-alkoxy, carboxyl, halo and sulfo, or a pharmaceutically acceptable salt of this compound.    18.-Compound according to claim 17, in the formula of which  EMI254.1  represents a radical chosen from  EMI254.2  where R5 represents a Cl-C6-alkyl radical and R6, R7 and RIO each independently represent a hydrogen atom  EMI254.3  drogen or a Cl-C4-alkyl radical:  EMI254.4  (b) 1 N '*, -.  Nile or 1 there N And R! X zo 1 N R5  EMI254.5  where R5 represents a Cl-C6-alkyl radical and the available ring carbon atoms are optionally substituted by 1 to 3 substituents chosen independently  <Desc / Clms Page number 255>    EMI255.1  especially among the Cl-C4-alkyl radicals;  EMI255.2  (c) R5) Fi 1 NN R5 fP;.) 'N), R5! N f ze '  EMI255.3  where R5 represents a Cl-C6-alkyl radical and the available ring carbon atoms are optionally substituted with 1 or 2 substituents chosen independently from the Cl-C4-alkyl radicals;    EMI255.4  (d) ¯5 g J rN'K, "t 1 Il K" N / "5 razz r <.. el EN '- -  <Desc / Clms Page number 256>    EMI256.1  where R5 represents a Cl-C6-alkyl radical and a ring carbon atom is optionally substituted by a C-c-alkyl radical  EMI256.2  (e) N-R '"J x xy  EMI256.3  where R5 represents a Cl-C6-alkyl radical, X represents 0, S or NR where R represents a Cl-C4-alkyl radical and one or more available ring carbon atoms are optionally substituted by Cl-C4alkyl radicals  EMI256.4  (f) 6 -R5 n fI "= 'e R II R5-' '  EMI256.5  where R5 represents a Cl-C6-alkyl radical, X represents 0, S or NR where R represents a Cl-C4-alkyl radical and one or more available ring carbon atoms are optionally substituted by Cl-C4alkyl radicals;  and  <Desc / Clms Page number 257>    EMI257.1  (g) r- R5 <--R'-R c-iz 5 t R5 - rR ---- fR! or  EMI257.2  where R5 represents a C1-C6-alkyl radical and R represents a C1-C-alkyl radical. 19.-Compound according to claim 18, in the formula of which R1 represents a hydrogen atom or a radical  EMI257.3  CH3 CH3 1 1 CH3CH2-, CH3 / "  EMI257.4  20.-Compound according to claim 18, in the formula of which Ri and R8 together represent a radical  <Desc / Clms Page number 258>    EMI258.1   R521.-Compound according to Claim 18, in the formula of which R1 represents a radical  EMI258.2  22. Compound according to claim 18, in  EMI258.3  the formula of which Ri represents a radical  EMI258.4  and the absolute configuration is 5R, 6S, 8R.    23.-Compound according to claim 17,18, 19,20, 21 or 22, in the formula of which A represents a radical -CH2- or -CH2CH2-.    24.- Compound of formula  EMI258.5  where R8 represents a hydrogen atom and RI is chosen from the hydrogen atom and the alkyl, alkenyl and alkynyl radicals of 1 to 10 carbon atoms; cycloalkyl and cycloalkyloyl of 3 to 6 carbon atoms in the ring of the cycloalkyl part and of 1  <Desc / Clms Page number 259>  with 6 carbon atoms in the alkyl parts; phenyl; aralcoyl; aralkenyl and aralkynyl in which the aryl part is a phenyl radical and in which the aliphatic part has 1 to 6 carbon atoms;  heteroaryl, heteroaralkyl, heterocyclic and heterocycloalkyl in which the heteroatom (s) of the aforementioned heterocyclic parts are chosen from 1 to 4 oxygen, nitrogen or sulfur atoms and in which the alkyl parts associated with the heterocyclic parts comprise 1 to 6 carbon atoms, all substituted or unsubstituted, the substituent or substituents of which are mentioned above, independently chosen from: Cl-C6-alkyl optionally amino, halogenated, hydroxylated or halogenated carboxylated  EMI259.1    <Desc / Clms Page number 260>    EMI260.1  where, with regard to the abovementioned substituents, the radicals R3 and R4 are independently chosen from the hydrogen atom and the alkyl, alkenyl and alkynyl radicals of 1 to 10 carbon atoms;  cycloalkyl, cycloalkylalkyl and alkylcycloalkyl of 3 to 6 carbon atoms in the ring of the cycloalkyl part and from 1 to 6 carbon atoms in the alkyl parts; phenyl; aralkyl, aralkenyl and aralkynyl in which the aryl part is a phenyl radical and the aliphatic part has 1 to 6 carbon atoms; and heteroaryl, heteroaralkyl, heterocyclic and heterocycloalkyl in which the heteroatom (s) in the aforementioned heterocyclic parts are chosen from 1 to 4 atoms of oxygen, nitrogen or sulfur and in which the alkyl parts associated with these heterocyclic parts have 1 to 6 atoms carbon, or R3 and R4,  <Desc / Clms Page number 261>  taken together with the nitrogen atom to which at least one of them is linked, can form a pentagonal or hexagonal nitrogen heterocyclic radical;  R9 is defined as R3, except that it cannot be a hydrogen atom; or where Ri and R8, taken together, represent a C2-C1o-alkylidene or C2-C10-alkylidene hydroxyl radical; R5 is chosen from alkyl, alkenyl and alkynyl radicals of 1 to 10 carbon atoms; cycloalkyl and cycloalkylalkyl of 3 to 6 carbon atoms in the ring of the cycloalkyl part and from 1 to 6 carbon atoms in the alkyl parts; phenyl; aralkyl, aralkenyl and aralkynyl in which the aryl part is a phenyl radical and in which the aliphatic part has 1 to 6 carbon atoms;  heteroaryl, heteroaralkyl, heterocyclic and heterocycloalkyl in which the heteroatom (s) in the aforementioned heterocyclic parts are chosen from 1 to 4 oxygen, nitrogen or sulfur atoms and in which the alkyl parts associated with the heterocyclic parts have 1 to 6 carbon atoms , all substituted or unsubstituted; the aforementioned R5 radicals optionally carrying one to three substituents chosen independently from: Cl-C6-alkyl optionally amino, fluorinated, chlorinated, carboxylated, hydroxylated, or carbamoylated fluoro, chloro or bromo  EMI261.1    <Desc / Clms Page number 262>    EMI262.1  phenyl optionally substituted with 1 to 3 fluoro, chloro, bromo, Cl-C6-alkyl, -OR3, -NR3R4 radicals,  EMI262.2  31 ¯ - S03R3 where R3, R4 and R9 in these substituents of R5 are as defined above;  or R5 can be combined with  EMI262.3  at another point in the cycle to form a condensed heterocyclic or heteroaromatic radical, the cycle of which may contain additional heteroatoms, chosen from 0, S and N; A represents a C1-C6-alkylene radical in a straight or branched chain; R2 represents a hydrogen atom, an anionic charge or a conventional radical which is easy to remove protective of the carboxyl function, it being understood that when R2 represents a hydrogen atom or a protective radical, there is also a counter  <Desc / Clms Page number 263>  ion, and  EMI263.1  represents a radical chosen between  EMI263.2  where R6, R7 and RIO are independently selected from the hydrogen atom and the C1-C4-alkyl radicals;  ClC4-alkyl substituted by hydroxyl, Ci-C-alkylamino, di (Cl-C4-alkyl) amino, Cl-C4-alkoxy, amino, sulfo, carboxyl and halo; C3-C6-cycloalkyl; Cl-C4-alkoxy; Cl-C4-alkylthio; amino; Cl-C4-alkyllamino; di (Cl-C4-alkyl) amino; halo; C1-C4-alkanoylamino; Cl-C4-alkanoyloxy; carboxyl; -CO2-C1-C4-alkyl; hydroxyl; amidino; guanidino; phenyl, phenyl substituted by one, two or three amino, halo, hydroxyl, trifluoromethyl radicals;  Cl-C4-alkyl or Cl-C4-alkoxy; phenyl (Cl-C4) alkyl in which the phenyl part can optionally be substituted by 1 to 3 substituents mentioned above with respect to the phenyl radical and the alkyl part can optionally be substituted by 1 to 3 substituents mentioned above with respect to the radicals CC-alkyl and heteroaryl or heteroaralkyl in which the heteroatom (s) in the aforementioned heterocyclic parts are chosen from 1 to 4 oxygen, nitrogen or sulfur atoms and the alkyl part associated with the heteroaralkyl part has 1 to 6 carbon atoms , or where two of R6, R7 and  <Desc / Clms Page number 264>  RIO, taken together, can represent a condensed saturated carbocyclic radical, a condensed aromatic carbocyclic radical,  a condensed non-aromatic heterocyclic radical or a condensed heteroaromatic radical, which condensed rings are optionally substituted with 1 or 2 of the substituents defined above with respect to R6, R7 and RIO; or a pharmaceutically acceptable salt of this compound.  EMI264.1   25. A compound according to claim 24, in the formula of which RI represents a hydrogen atom or a radical.  EMI264.2  CH3 CH3 OH OH 1 1 CH3CH2-, / "  EMI264.3  26. Compound according to claim 24, in the formula of which Ri and R8 together represent a radical.  EMI264.4    EMI264.5  27. Compound according to claim 24, in the formula of which RI represents a radical  EMI264.6   CH-, C- or CH3CH-28.-A compound according to claim 24, in the formula of which R1 represents a radical  EMI264.7    <Desc / Clms Page number 265>  and the absolute configuration is 5R, 6S, 8R.    29.-Compound according to claim 24,25, 26,27 or 28, in the formula of which A represents a radical -CH2- or -CH2CH2- ' 30.-Compound of formula  EMI265.1  where R8 represents a hydrogen atom and Ri is chosen from the hydrogen atom and the alkyl, alkenyl and alkynyl radicals of 1 to 10 carbon atoms; cycloalkyl and cycloalkylalkyl of 3 to 6 carbon atoms in the ring of the cycloalkyl part and from 1 to 6 carbon atoms in the alkyl parts; phenyl; aralcoyl; aralkenyl and aralkynyl in which the aryl part is a phenyl radical and in which the aliphatic part has 1 to 6 carbon atoms;  heteroaryl, heteroaralkyl, heterocyclic and heterocycloalkyl in which the heteroatom (s) of the aforementioned heterocyclic parts are chosen from 1 to 4 oxygen, nitrogen or sulfur atoms and in which the alkyl parts associated with the heterocyclic parts comprise 1 to 6 carbon atoms, all substituted or unsubstituted, the substituent or substituents of which are mentioned above, independently chosen from:  <Desc / Clms Page number 266>  C1-C6-alkyl optionally amino, halogenated, hydroxylated or halogenated carboxylated  EMI266.1    <Desc / Clms Page number 267>    EMI267.1  where, with regard to the abovementioned substituents, the radicals R3 and R4 are independently chosen from the hydrogen atom and the alkyl, alkenyl and alkynyl radicals of 1 to 10 carbon atoms;  cycloalkyl, cycloalkylalkyl and alkylcycloalkyl of 3 to 6 carbon atoms in the ring of the cycloalkyl part and from 1 to 6 carbon atoms in the alkyl parts; phenyl; aralkyl, aralkenyl and aralkynyl in which the aryl part is a phenyl radical and the aliphatic part has 1 to 6 carbon atoms;  and heteroaryl, heteroaralkyl, heterocyclic and heterocyloalkyl in which the heteroatom (s) in the aforementioned heterocyclic parts are chosen from 1 to 4 atoms of oxygen, nitrogen or sulfur and in which the alkyl parts associated with these heterocyclic parts have 1 to 6 atoms of carbon, or else R3 and R4, taken together with the nitrogen atom to which at least one of them is united, can form a pentagonal or hexagonal nitrogen heterocyclic radical; R9 is defined as R3, except that it cannot be a hydrogen atom; or where Ri and RS, taken together, represent a C-Cio-alkylidene or C2-CIO-alkylidene radical;  R5 is chosen from alkyl, alkenyl and alkynyl radicals of 1 to 10 carbon atoms; cycloalkyl and cycloalkylalkyl of 3 to 6 carbon atoms in the ring of the cycloalkyl part and from 1 to 6 carbon atoms in the alkyl parts;  <Desc / Clms Page number 268>  phenyl; aralkyl, aralkenyl and aralkynyl in which the aryl part is a phenyl radical and in which the aliphatic part has 1 to 6 carbon atoms; heteroaryl, heteroaralkyl, heterocyclic and heterocycloalkyl in which the heteroatom (s) in the above-mentioned heterocyclic parts are chosen from 1 to 4 oxygen, nitrogen or sulfur atoms and in which the alkyl parts associated with the heterocyclic parts have 1 to 6 carbon atoms , all substituted or unsubstituted;  the aforementioned R5 radicals optionally carrying one to three substituents chosen independently from: Cl-C6-alkyl optionally amino, fluorinated, chlorinated, carboxylated, hydroxylated, or carbamoylated fluoro, chloro or bromo  EMI268.1    <Desc / Clms Page number 269>    EMI269.1    - CN; or phenyl optionally substituted with 1 to 3 fluoro, chloro, bromo, Cl-C6-alkyl, -OR3, -NR3R4, - S03R3, -C02R3 or-CONR3R4, where R3, R4 and R9 in these substituents of R5 are such that defined above; or R5 can be combined with  EMI269.2  at another point in the cycle to form a condensed heterocyclic or heteroaromatic radical, the cycle of which may contain additional heteroatoms, chosen from 0, S and N; A represents a C1-C6-alkylene radical in a straight or branched chain;  R2 represents a hydrogen atom, an anionic charge or a conventional radical which is easy to remove protective of the carboxyl function, it being understood that when R2 represents a hydrogen atom or a protective radical, there is also a counterion, and  EMI269.3  represents a radical of formula  <Desc / Clms Page number 270>    EMI270.1  R5 5 el N (1 "I or 1 1 il 'el e'f R5 el /' N  EMI270.2  optionally substituted on a carbon atom by 1 to 3 substituents chosen independently from the C-C-alkyl--C-alkyl radicals substituted by hydroxyl, Cl-C4-alkylamino, di (CI-C4-alkyl) amino,; CCl-C4-alkoxy, amino, sulfo, carboxyl and halo; C3-C6-cycloalkyl; Cl-C4-alkoxy; Ci-C-alcoyIthio; amino; Cl-C4-alkyllamino; di (C1-C4-alkyl) amino; halo;  Cl-C4-alkanoylamino; C1-C4-alkanoyloxy; carboxyl; -C02-Cl-C4-alkyl; hydroxyl; amidino; guanidino; phenyl, phenyl substituted by one, two or three amino, halo, hydroxyl, trifluoromethyl radicals; Cl-C4-alkyl or C1-C4-alkoxy; phenyl (Cl -C4) alkyl in which the phenyl part can optionally be substituted by 1 to 3 substituents mentioned above with respect to the phenyl radical and the alkyl part can optionally be substituted by 1 to 3 substituents mentioned above with respect to the radicals Cl-C4-alkyl and heteroaryl or heteroaralkyl in which the heteroatom (s) in the aforementioned heterocyclic parts are chosen from 1 to 4 oxygen atoms,  nitrogen or sulfur and the alkyl part associated with the heteroaralkyl part has 1 to  <Desc / Clms Page number 271>  6 carbon atoms, or optionally substituted to form a condensed carbocyclic, heterocyclic or heteroaromatic radical optionally substituted by 1 or 2 of the substituents defined above; or a pharmaceutically acceptable salt of this compound.    31.-Compound according to claim 30, in the formula of which  EMI271.1  represents a radical  EMI271.2   32.-Compound according to claim 30, in the formula of which  EMI271.3  represents a radical  EMI271.4    <Desc / Clms Page number 272>    EMI272.1  33.-Compound according to claim 30, in 1 the formula of which  EMI272.2  represents a radical  EMI272.3   34.-Compound according to claim 30, 31, 32 or 33, in the formula of which RI represents a hydrogen atom or a radical  EMI272.4  CH3 CH3 OH OH CH-, I 1 CH3CH2-, "CH-," C- or CH3 / '"  EMI272.5  35.-Compound according to claim 30, 31, 32 or 33, in the formula of which RI and R8 together represent a radical  EMI272.6   36.-Compound according to claim 30, 31, 32 or 33,  in the formula of which Ri represents a radical  <Desc / Clms Page number 273>    EMI273.1   37.-Compound according to claim 30, 31, 32 or 33, in the formula of which RI represents a radical  EMI273.2  and the absolute configuration is 5R, 6S, 8R.    38.-Compound according to claim 30, 31, 32 or 33, in the formula of which A represents a radical -CH2- or -CH2CH2-, Rl represents a radical  EMI273.3  and the absolute configuration is 5R, 6S, 8R.    39.-Compound of formula  EMI273.4  where RS represents a hydrogen atom and RI is chosen from the hydrogen atom and the alkyl, alkenyl and alkynyl radicals of 1 to 10 carbon atoms; cycloalkyl and cycloalkylalkyl of 3 to 6 carbon atoms in the ring of the cycloalkyl part and from 1 to 6 carbon atoms in the alkyl parts;  <Desc / Clms Page number 274>  phenyl; aralcoyl; aralkenyl and aralkynyl in which the aryl part is a phenyl radical and in which the aliphatic part has 1 to 6 carbon atoms;  heteroaryl, heteroaralkyl, heterocyclic and heterocycloalkyl in which the heteroatom (s) of the aforementioned heterocyclic parts are chosen from 1 to 4 oxygen, nitrogen or sulfur atoms and in which the alkyl parts associated with the heterocyclic parts comprise 1 to 6 carbon atoms, all substituted or unsubstituted, the substituent or substituents of which are mentioned above, independently chosen from: Cl-C6-alkyl optionally amino, halogenated, hydroxylated or halogenated carboxylated  EMI274.1    <Desc / Clms Page number 275>    EMI275.1  where, with regard to the abovementioned substituents, the radicals R3 and R4 are independently chosen from the hydrogen atom and the alkyl, alkenyl and alkynyl radicals of 1 to 10 carbon atoms;  cycloalkyl, cycloalkylalkyl and alkylcycloalkyl of 3 to 6 carbon atoms in the ring of the cycloalkyl part and from 1 to 6 carbon atoms in the alkyl parts; phenyl; aralkyl, aralkenyl and aralkynyl in which the aryl part is a phenyl radical and the aliphatic part has 1 to 6 carbon atoms; and heteroaryl, heteroaralkyl, heterocyclic and heterocycloalkyl in which the heteroatom (s) in the aforementioned heterocyclic parts are chosen from 1 to 4 atoms of oxygen, nitrogen or sulfur and in which the alkyl parts associated with these heterocyclic parts have 1 to 6 atoms of carbon, or else R3 and R4, taken together with the nitrogen atom to which at least one of them is united, can form a hetero radical.  <Desc / Clms Page number 276>  cyclic nitrogen pentagonal or hexagonal;  R9 is defined as R3, except that it cannot be a hydrogen atom; or where RI and R8, taken together, represent a Cz-Cio-alkylidene or C2-ClO-alkylidene radical; R5 is chosen from alkyl, alkenyl and alkynyl radicals of 1 to 10 carbon atoms; cycloalkyl and cycloalkylalkyl of 3 to 6 carbon atoms in the ring of the cycloalkyl part and from 1 to 6 carbon atoms in the alkyl parts; phenyl; aralkyl, aralkenyl and aralkynyl in which the aryl part is a phenyl radical and in which the aliphatic part has 1 to 6 carbon atoms;  heteroaryl, heteroaralkyl, heterocyclic and heterocycloalkyl in which the heteroatom (s) in the above-mentioned heterocyclic parts are chosen from 1 to 4 oxygen, nitrogen or sulfur atoms and in which the alkyl parts associated with the heterocyclic parts have 1 to 6 carbon atoms , all substituted or unsubstituted; the aforementioned R5 radicals optionally carrying one to three substituents chosen independently from: Cl-C6-alkyl optionally amino, fluorinated, chlorinated, carboxylated, hydroxylated, or carbamoylated fluoro, chloro or bromo  EMI276.1    <Desc / Clms Page number 277>    EMI277.1  - CN; or phenyl optionally substituted with 1 to 3 fluoro, chloro, bromo, Cl-C6-alkyl, -OR3, -NR3R4, - S03R3, -C02R3 or-CONR3R4, where R3, R4 and R9 in these substituents of R5 are such that defined above;  or R5 can be combined with  EMI277.2  at another point in the cycle to form a condensed heterocyclic or heteroaromatic radical, the cycle of which may contain additional heteroatoms, chosen from 0, S and N; A represents a C1-C6-alkylene radical in a straight or branched chain; R2 represents a hydrogen atom, an anionic charge or a conventional radical which is easy to remove protective of the carboxyl function, it being understood that when R2 represents a hydrogen atom or a protective radical, there is also a counterion, and  <Desc / Clms Page number 278>    EMI278.1    EMI278.2  represents a radical of formula  EMI278.3  ¯5 r, j ', I El c}' or ¯5 '))) "or" el' ''  EMI278.4  optionally substituted on a carbon atom by 1 to 3 substituents independently chosen from C1-C4-alkyl radicals;  Cl-C4-alkyl substituted by hydroxyl, Cl-C4-alkylamino, di (Cl-C4-alkyl) amino, Cl-C4-alkoxy, amino, sulfo, carboxyl and halo; C3-C6-cycloalkyl; Cl-C4-alkoxy; Cl-C4-alkylthio; amino; Cl-C4-alkyllamino; di (Cl-C4-alkyl) amino; halo; This-  EMI278.5  C4-alkanoylamino; Cl-C4-alkanoyloxy; carboxyl: -COCl-C4-alkyl; hydroxyl; amidino; guanidino; phenyl, phenyl substituted by one, two or three amino, halo, hydroxyl, trifluoromethyl radicals;  Cl-C4-alkyl or Cl-C4-alkoxy; phenyl (Cl-C4) alkyl in which the phenyl part can optionally be substituted with 1 to 3 substituents mentioned above with respect to the phenyl radical and the alkyl part can optionally be  <Desc / Clms Page number 279>  substituted by 1 to 3 substituents mentioned above with respect to the CI-C4-alkyl radicals; and heteroaryl or heteroaralkyl in which the heteroatom (s) in the aforementioned heterocyclic parts are chosen from 1 to 4 oxygen, nitrogen or sulfur atoms and the alkyl part associated with the heteroalkyl part has 1 to 6 carbon atoms, or optionally substituted to form a condensed carbocyclic, heterocyclic or heteroaromatic radical optionally substituted with 1 to 2 of the substituents defined above;  or a pharmaceutically acceptable salt of this compound.  EMI279.1   40.-Compound according to claim 39, in the formula in which Ri represents a hydrogen atom or a radical.  EMI279.2  CH3 CH3 OH OH '1 1 CH3CH2-,' C- or CH3 / 'CH3 /  EMI279.3  41.-Compound according to claim 39, in the formula in which Ri and RS together represent a radical  EMI279.4   42.-Compound according to claim 39, in the formula of which RI represents a radical  EMI279.5   43.-Compound according to claim 39, in the formula of which RI represents a radical  <Desc / Clms Page number 280>    EMI280.1  and the absolute configuration is 5R, 6S, 8R.    44.-Compound according to claim 39, 40, 41,42 or 43, in the formula of which A represents a radical -CH2- or -CH2CH2-.    45.-Compound of formula  EMI280.2  where R8 represents a hydrogen atom and Ri is chosen from the hydrogen atom and the alkyl, alkenyl and alkynyl radicals of 1 to 10 carbon atoms; cycloalkyl and cycloalkylalkyl of 3 to 6 carbon atoms in the ring of the cycloalkyl part and from 1 to 6 carbon atoms in the alkyl parts; phenyl; aralcoyl; aralkenyl and aralkynyl in which the aryl part is a phenyl radical and in which the aliphatic part has 1 to 6 carbon atoms;  heteroaryl, heteroaralkyl, heterocyclic and heterocycloalkyl in which the heteroatom (s) of the aforementioned heterocyclic parts are chosen from 1 to 4 oxygen, nitrogen or sulfur atoms and in which the alkyl parts associated with the heterocyclic parts comprise 1 to 6 carbon atoms, all substituted or unsubstituted, in which the substituent or substituents with respect to the abovementioned radicals are independently chosen from: Ci-Ce-alcoyIe optionally amino, halogenated,  <Desc / Clms Page number 281>  hydroxylated or halogenated carboxylated  EMI281.1    <Desc / Clms Page number 282>    EMI282.1  where, with regard to the abovementioned substituents, the radicals R3 and R4 are independently chosen from the hydrogen atom and the alkyl, alkenyl and alkynyl radicals of 1 to 10 carbon atoms;  cycloalkyl, cycloalkylalkyl and alkylcycloalkyl of 3 to 6 carbon atoms in the ring of the cycloalkyl part and from 1 to 6 carbon atoms in the alkyl parts; phenyl; aralkyl, aralkenyl and aralkynyl in which the aryl part is a phenyl radical and the aliphatic part has 1 to 6 carbon atoms; and heteroaryl, heteroaralkyl, heterocyclic and heterocycloalkyl in which the heteroatom (s) in the aforementioned heterocyclic parts are chosen from 1 to 4 atoms of oxygen, nitrogen or sulfur and in which the alkyl parts associated with these heterocyclic parts have 1 to 6 atoms of carbon, or else R3 and R4, taken together with the nitrogen atom to which at least one of them is united, can form a pentagonal or hexagonal nitrogen heterocyclic radical;  R9 is defined as R3, except that it cannot be a hydrogen atom; or where RI and RS, taken together, represent a  EMI282.2  hydroxylated C-Co'lcoyIidène or C-CQ-alkylIidene radical; R5 is chosen from alkyl, alkenyl and alkynyl radicals of 1 to 10 carbon atoms; cycloalkyl and cycloalkylalkyl of 3 to 6 carbon atoms in the ring of the cycloalkyl part and from 1 to 6 carbon atoms in the alkyl parts; phenyl; aralkyl, aralkenyl and aralkynyl in which the aryl part is a phenyl radical and in which the aliphatic part has 1 to 6 carbon atoms;  hetero-  <Desc / Clms Page number 283>  aryl, heteroaralkyl, heterocyclic and heterocycloalkyl in which the heteroatom (s) in the abovementioned heterocyclic parts are chosen from 1 to 4 oxygen, nitrogen or sulfur atoms and in which the alkyl parts associated with the heterocyclic parts have 1 to 6 carbon atoms , all substituted or unsubstituted; the aforementioned R5 radicals optionally carrying one to three substituents chosen independently from: Cl-C6-alkyl optionally amino, fluorinated, chlorinated, carboxylated, hydroxylated, or carbamoylated fluoro, chloro or bromo  EMI283.1    <Desc / Clms Page number 284>  - CN;  or phenyl optionally substituted with 1 to 3 fluoro, chloro, bromo, Cl-C6-alkyl, -OR3, -NR3R4, - S03R3, -C02R3 or-CONR3R4, where R3, R4 and R9 in these substituents of R5 are such that defined above; or R5 can be combined with  EMI284.1  at another point in the cycle to form a condensed heterocyclic or heteroaromatic radical, the cycle of which may contain additional heteroatoms, chosen from 0, S and N; A represents a C1-C6-alkylene radical in a straight or branched chain;  R2 represents a hydrogen atom, an anionic charge or a conventional radical which is easy to remove protective of the carboxyl function, it being understood that when R2 represents a hydrogen atom or a protective radical, there is also a counterion, and  EMI284.2  represents a radical of formula  EMI284.3    <Desc / Clms Page number 285>    EMI285.1  R5 oR (NY! As K '' 'K 1-1 N. N optionally substituted on a carbon atom by a substituent chosen independently from the C1-C4-alkyl radicals; Cl-C4-alkyl substituted by hydroxyl, Cl-C4-alkylamino, di (Cl-C4) alkylamino, Cl-C4-alkoxy, amino, sulfo, carboxyl and halo; C3-C6-cycloalkyl; Cl-C4-alkoxy; Cl-C4-alkylthio; amino; Cl-C4-alkyllamino; di (Cl-C4) alkylamino; halo; This-  EMI285.2  C4-alkanoylamino; Cl-C4-alkanoyloxy; carboxyl; -CO "Cl-C4-alkyl; hydroxyl; amidino; guanidino; phenyl, phenyl substituted by one, two or three amino, halo, hydroxyl, trifluoromethyl radicals;  Cl-C4-alkyl or Cl-C4-alkoxy; phenyl (Cl-C4) alkyl in which the phenyl part can optionally be substituted by 1 to 3 substituents mentioned above with respect to the phenyl radical and the alkyl part can optionally be substituted by 1 to 3 substituents mentioned above with respect to the radicals Cl-C4-alkyl; and heteroaryl or heteroaralkyl in which the heteroatom (s) in the aforementioned heterocyclic parts are chosen from 1 to 4 oxygen, nitrogen or sulfur atoms and the alkyl part associated with the heteroaralkyl part has 1 to 6 carbon atoms; or a pharmaceutically acceptable salt of this compound.    46.-Compound according to claim 45, in the formula of which Ri represents a hydrogen atom or a radical  <Desc / Clms Page number 286>    EMI286.1  CH3 1 CH3CH2-, CH-, - '"CH-,  EMI286.2  47.-Compound according to claim 45, in the formula of which Ri and R8 together represent a radical  EMI286.3    48.-Compound according to claim 45, in the formula of which R1 represents a radical  EMI286.4  49.-Compound according to claim 45, in  EMI286.5  the formula of which RI represents a radical  EMI286.6  and the absolute configuration is 5R, 6S, 8R.    50.-Compound according to claim 45,46, 47,48 or 49, in the formula of which A represents a radical -CH2 -or-CH2CH2-.    51.-Compound of formula  <Desc / Clms Page number 287>    EMI287.1  where R8 represents a hydrogen atom and RI is chosen from the hydrogen atom and the alkyl, alkenyl and alkynyl radicals of 1 to 10 carbon atoms; cycloalkyl and cycloalkylalkyl of 3 to 6 carbon atoms in the ring of the cycloalkyl part and from 1 to 6 carbon atoms in the alkyl parts; phenyl; aralcoyl; aralkenyl and aralkynyl in which the aryl part is a phenyl radical and in which the aliphatic part has 1 to 6 carbon atoms;  heteroaryl, heteroaralkyl, heterocyclic and heterocycloalkyl in which the heteroatom (s) of the aforementioned heterocyclic parts are chosen from 1 to 4 oxygen, nitrogen or sulfur atoms and in which the alkyl parts associated with the heterocyclic parts comprise 1 to 6 carbon atoms, all substituted or unsubstituted, the substituent or substituents of which are mentioned above, independently chosen from: Cl-C6-alkyl optionally amino, halogenated, hydroxylated or halogenated carboxylated  EMI287.2    <Desc / Clms Page number 288>    EMI288.1  where, with regard to the abovementioned substituents, the radicals R3 and R4 are independently chosen from the hydrogen atom and the alkyl, alkenyl and alkynyl radicals  <Desc / Clms Page number 289>    EMI289.1  from 1 to 10 carbon atoms;  cycloalkyl, cycloalkylalkyl and alkylcycloalkyl of 3 to 6 carbon atoms in the ring of the cycloalkyl part and from 1 to 6 carbon atoms in the alkyl parts; phenyl; aralkyl, aralkenyl and aralkynyl in which the aryl part is a phenyl radical and the aliphatic part has 1 to 6 carbon atoms; and heteroaryl, heteroaralkyl, heterocyclic and heterocyloalkyl in which the heteroatom (s) in the aforementioned heterocyclic parts are chosen from 1 to 4 oxygen, nitrogen or sulfur atoms and in which the alkyl parts associated with these heterocyclic parts have 1 to 6 atoms of carbon, or else R3 and R4, taken together with the nitrogen atom to which at least one of them is united, can form a pentagonal or hexagonal nitrogen heterocyclic radical;  R9 is defined as R3, except that it cannot be a hydrogen atom; or where R1 and R8, taken together, represent a  EMI289.2  hydroxylated C-co-alkydiid or C-Ciocoylidene radical; R5 is chosen from alkyl, alkenyl and alkynyl radicals of 1 to 10 carbon atoms; cycloalkyl and cycloalkylalkyl of 3 to 6 carbon atoms in the ring of the cycloalkyl part and from 1 to 6 carbon atoms in the alkyl parts; phenyl; aralkyl, aralkenyl and aralkynyl in which the aryl part is a phenyl radical and in which the aliphatic part has 1 to 6 carbon atoms;  heteroaryl, heferoaralkyl, heterocyclic and heterocycloalkyl in which the heteroatom (s) in the above-mentioned heterocyclic parts are chosen from 1 to 4 oxygen, nitrogen or sulfur atoms and in which the alkyl parts associated with the heterocyclic parts have 1 to 6 carbon atoms , all substituted or unsubstituted; the aforementioned R5 radicals optionally carrying one to three substituents chosen independently  <Desc / Clms Page number 290>  especially from: Cl-C6-alkyl optionally amino, fluorinated, chlorinated, carboxylated, hydroxylated, or carbamoylated fluoro, chloro or bromo  EMI290.1  -CN;  or phenyl optionally substituted with 1 to 3 fluoro, chloro, bromo, Cl-C6-alkyl, -OR3, -NR3R4, - S03R3, -C02R3 or-CONR3R4, where R3, R4 and R9 in these substituents of R5 are such that defined above; or R5 can be combined with  <Desc / Clms Page number 291>    EMI291.1  at another point in the cycle to form a condensed heterocyclic or heteroaromatic radical, the cycle of which may contain additional heteroatoms, chosen from 0, S and N; A represents a Ci-c-alkylene radical in a straight or branched chain;  R2 represents a hydrogen atom, an anionic charge or a conventional radical which is easy to remove protective of the carboxyl function, it being understood that when R2 represents a hydrogen atom or a protective radical, there is also a counterion, and  EMI291.2    EMI291.3  represents a radical of formula  EMI291.4  e 6 N-R5 or or  EMI291.5  where X represents 0, S or NR where R represents a Cl-C4-alkyl radical; Cl-C4-alkyl substituted by 1 to 3 hydroxyl, amino, Cl-C4-alkylamino radicals; di (Cl-C4alkyl) amino;  Cl-C4-alkoxy; carboxyl; halo or N ¯5sulfo; C3-C6-cycloalkyl; C3-C6-cycloalcoyl (Cl- C4) alkyl optionally substituted with 1 to 3 substi-  <Desc / Clms Page number 292>  kills mentioned above in connection with the C 1 -C 4 alkyl radicals; phenyl; phenyl substituted with 1 to 3 substituents independently chosen from amino, halo, hydroxyl, trifluoromethyl, C1-C4alkyl, C1-C4alkoxy, Ci-C-alkylamino, di (C1-C4) alkylamino, carboxyl and sulfo radicals;  phenyl (CI-C4) alkyl, the phenyl part of which can optionally be substituted with 1 to 3 substituents mentioned above with respect to the phenyl radical and the alkyl part of which can optionally be substituted with 1 to 3 radicals mentioned above with regard to the Cl-C4alkyl radicals;  and weatheraryl and heteroaralkyl in which the heteroatom (s) are chosen from 1 to 4 atoms 0, S or N and the alkyl part associated with the heteroaralkyl radical has 1 to 6 carbon atoms, these heteroaryl and heteroaralkyl radicals being optionally substituted in the heterocyclic part by 1 to 3 substituents chosen independently from the hydroxyl, amino, halo, trifluoromethyl, Cul-C4-alkyl, C1-C4-alkoxy, C1-C4-alkylamino, di (C1-C4) alkylamino, carboxyl and sulfo radicals, and in the alkyl part with 1 to 3 substituents chosen from hydroxyl, amino, Cl-C4-alkylamino, di (ClC4) alkylamino, C1-C4-alkoxy, carboxyl, halo and sulfo radicals,  this heteroaromatic radical being optionally substituted on a carbon atom by 1 or more substituents chosen independently from C1-C4-alkyl radicals; Cl-C4-alkyl substituted by hydroxyl, Cl-C4-alkylamino, di (Cl-C4) alkylamino, C1-C4-alkyl, amino, sulfo, carboxyl or halo; C3-C6-cycloalkyl; Cl-C4-alkoxy; C1-C4-alkylthio, amino; Cl-C4alkoylamino; di (Cl-C4) alkylamino; halo; Cl-C4alkanoylamino; C-c-alkanoyioxy; carboxyl; -C02-CI-C4-alkyl; hydroxyl; amidino; guanidino; phenyl; phenyl substituted by one, two or three amino radicals,  <Desc / Clms Page number 293>  halo, hydroxyl, trifluoromethyl;  Cl-C4-alkyl or Cl -C4-alkoxy; phenyl (Ci-C4) alkyl, the phenyl part of which can optionally be substituted with 1 to 3 substituents mentioned above with respect to the phenyl radical and the alkyl part of which can optionally be substituted with 1 to 3 substituents mentioned above with respect to the radicals Cc -alkyie; and heteroaryl and heteroaralkyl in which the heteroatom (s) of the abovementioned heterocyclic parts are chosen from 1 to 4 oxygen, nitrogen or sulfur atoms and the alkyl part associated with the heteroaralkyl part has 1 to 6 carbon atoms, or optionally substituted to form a condensed carbocyclic, heterocyclic or heteroaromatic radical optionally substituted by 1 or 2 of the radicals defined above;  or a pharmaceutically acceptable salt of this compound.    52.-Compound according to claim 51, in  EMI293.1  the formula of which RI represents a hydrogen atom or a radical  EMI293.2  CH3 CH3 OH OH 1 1 CH3CH2-, CH3 / 'CH3 /'  EMI293.3  53.-Compound according to Claim 51, in the formula of which Ri and R8 together represent a radical  EMI293.4   54.-Compound according to claim 51, in the formula of which RI represents a radical  <Desc / Clms Page number 294>    EMI294.1   55.-Compound according to claim 51, in the formula of which RI represents a radical  EMI294.2  and the absolute configuration is 5R, 6S, 8R.    56.-Compound according to claim 51,52, 53,54 or 55, in the formula of which A represents a radical -CH2- or -CH2CH2-.    57.-Compound of formula  EMI294.3  where R8 represents a hydrogen atom and R1 is chosen from the hydrogen atom and the alkyl, alkenyl and alkynyl radicals of 1 to 10 carbon atoms; cycloalkyl and cycloalkylalkyl of 3 to 6 carbon atoms in the ring of the cycloalkyl part and from 1 to 6 carbon atoms in the alkyl parts; phenyl; aralcoyl; aralkenyl and aralkynyl in which the aryl part is a phenyl radical and in which the aliphatic part has 1 to 6 carbon atoms;  heteroaryl, heteroaralkyl, heterocyclic and heterocycloalkyl in which the heteroatom (s) of the aforementioned heterocyclic parts are chosen from 1 to 4 atoms  <Desc / Clms Page number 295>  of oxygen, nitrogen or sulfur and in which the alkyl parts associated with the heterocyclic parts comprise 1 to 6 carbon atoms, all of which are substituted or unsubstituted, in which the substituent or substituents with respect to the abovementioned radicals are independently chosen from: Cl- C6-alkyl optionally amino, halogenated, hydroxylated or halogenated carboxylated  EMI295.1    <Desc / Clms Page number 296>    EMI296.1  where, with regard to the abovementioned substituents, the radicals R3 and R4 are independently chosen from the hydrogen atom and the alkyl, alkenyl and alkynyl radicals of 1 to 10 carbon atoms;  cycloalkyl, cycloalkylalkyl and alkylcycloalkyl of 3 to 6 carbon atoms in the ring of the cycloalkyl part and from 1 to 6 carbon atoms in the alkyl parts; phenyl; aralkyl, aralkenyl and aralkynyl in which the aryl part is a phenyl radical and the aliphatic part has 1 to 6 carbon atoms; and heteroaryl, heteroaralkyl, heterocyclic and heterocycloalkyl in which the heteroatom (s) in the aforementioned heterocyclic parts are chosen from 1 to 4 atoms of oxygen, nitrogen or sulfur and in which the alkyl parts associated with these heterocyclic parts have 1 to 6 atoms of carbon, or else R3 and R4, taken together with the nitrogen atom to which at least one of them is united, can form a pentagonal or hexagonal nitrogen heterocyclic radical;  R9 is defined as R3, except that it cannot be a hydrogen atom; or where RI and RS taken together represent a  EMI296.2  hydroxylated C-CiolcoyIidene or c-Cio-alkidene radical; R5 is chosen from alkyl, alkenyl and alkynyl radicals of 1 to 10 carbon atoms;  <Desc / Clms Page number 297>  cycloalkyl and cycloalkylalkyl of 3 to 6 carbon atoms in the ring of the cycloalkyl part and from 1 to 6 carbon atoms in the alkyl parts; phenyl; aralkyl, aralkenyl and aralkynyl in which the aryl part is a phenyl radical and in which the aliphatic part has 1 to 6 carbon atoms;  heteroaryl, heteroaralkyl, heterocyclic and heterocycloalkyl in which the heteroatom (s) in the above-mentioned heterocyclic parts are chosen from 1 to 4 oxygen, nitrogen or sulfur atoms and in which the alkyl parts associated with the heterocyclic parts have 1 to 6 carbon atoms , all substituted or unsubstituted; the aforementioned R5 radicals optionally carrying one to three substituents chosen independently from: Cl-C6-alkyl optionally amino, fluorinated, chlorinated, carboxylated, hydroxylated, or carbamoylated fluoro, chloro or bromo  EMI297.1    <Desc / Clms Page number 298>    EMI298.1    - CN; or phenyl optionally substituted with 1 to 3 radicals  EMI298.2  fluoro, bromo, CI-C6-alkyl, -S03R3, -C02R3 where R3, R4 and R9 in these substituents of R5 are as defined above;  or R5 can be combined with  EMI298.3  at another point in the cycle to form a condensed heterocyclic or heteroaromatic radical, the cycle of which may contain additional heteroatoms, chosen from 0, S and N;  EMI298.4  A represents a straight or branched C-C-alkylene radical; R2 represents a hydrogen atom, an anionic charge or a conventional radical which is easy to remove protective of the carboxyl function, it being understood that when R2 represents a hydrogen atom or a protective radical, there is also a counterion, and  EMI298.5  represents a radical of formula  <Desc / Clms Page number 299>    EMI299.1  5 N n --- n, --- n, -R '11-5 - X' "K \ & x" "\ or J e E.  N-N-R 5 eIl 1 1 1 1 C) U i R-N Il L x N-1 P 5 where X represents 0, S or NR where R represents a CI-C4-alkyl radical; C-C-alkyl substituted with 1 to 3 hydroxyl, amino, C1-C4-alkylamino radicals; di (ClC4) alkylamino; Cl-C4-alkoxy; carboxyl, halo or sulfo; C3-C6-cycloalkyl;  C3-C6-cycloalkyl (C1-C4) alkyl optionally substituted with 1 to 3 substituents mentioned above in connection with the ClC4-alkyl radicals; phenyl; phenyl substituted with 1 to 3 substituents independently selected from amino, halo, hydroxyl, trifluoromethyl, Cl-C4-alkyl, Cl-C4-alkoxy, Cl-C4-alkylamino, di (Cl-C4) alkylamino, carboxyl and sulfo radicals; phenyl (Cl-C4) alkyl, the phenyl part of which can optionally be substituted with 1 to 3 substituents mentioned above with respect to the phenyl radical and the alkyl part of which can optionally be substituted with 1 to 3 substituents mentioned above with respect to the phenyl radicals C1-C4-alkyl radicals;  and weatheraryl and heteroaralkyl in which the heteroatom (s) are chosen from 1 to 4 atoms 0, S or N and the alkyl part associated with the heteroaralkyl radical has 1 to 6 carbon atoms, these radicals  <Desc / Clms Page number 300>  heteroaryl and heteroaralkyl being optionally substituted in the heterocyclic part by 1 to 3 substituents chosen independently from the hydroxyl, amino, halo, trifluoromethyl, Cl-C4-alkyl, Cl-C4-alkoxy, C1-C4-alkylamino, di (CI- C4) - alkyllamino, carboxyl and sulfo, and in the alkyl part with 1 to 3 substituents chosen from the hydroxyl, amino, C1-C4-alkylamino, di (Cl- C4) alkylamino, Cl-C4-alkoxy, carboxyl, halo radicals and sulfo,  this heteroaromatic radical being optionally substituted on a carbon atom by a substituent chosen from C1-C4-alkyl radicals; Cl-C4-alkyl substituted by hydroxyl, Cl-C4-alkylamino, di (ClC4) alkylamino, Ci-C-alkoxy, amino, sulfo; carboxyl or halo; C3-C6-cycloalkyl; C1-C4-alkoxy; Cl-C4-alkylthio, amino; C1-C4-alkylamino; di (Cl-C4) alkylamino; halo; Cl-C4-alkanoylamino; Cl-C4-alkanoyloxy; carboxyl; -COs-Ci-C-alkyl; hydroxyl; amidino; guanidino; phenyl; phenyl substituted with one, two or three amino, halo, hydroxyl, trifluoromethyl radicals;  Cl-C4-alkyl or C1-C4-alkoxy; phenyl (Cl-C4) alkyl, the phenyl part of which can optionally be substituted with 1 to 3 substituents mentioned above with respect to the phenyl radical and the alkyl part of which can optionally be substituted with 1 to 3 substituents mentioned above with respect to the phenyl radicals Cl-C4-alkyl radicals; and heteroaryl and heteroaralkyl in which the heteroatom (s) of the aforementioned heterocyclic parts are chosen from 1 to 4 oxygen, nitrogen or sulfur atoms and the alkyl part associated with the heteroaralkyl part has 1 to 6 carbon atoms; or a pharmaceutically acceptable salt of this compound.    58.-Compound according to claim 57, in the formula of which RI represents a hydrogen atom or  <Desc / Clms Page number 301>  a radical  EMI301.1  CH3 CH3 OH OH 1 CH3CH2-, CH3 / '  EMI301.2  59.-Compound according to claim 57, in the formula of which Ri and R8 together represent a radical  EMI301.3   60.-Compound according to claim 57, in the formula of which R1 represents a radical  EMI301.4  61.-Compound according to claim 57, in  EMI301.5  the formula of which RI represents a radical  EMI301.6  and the absolute configuration is 5R, 6S, 8R.    62.-Compound according to claim 57, 58, 59, 60 or 61, in the formula of which A represents a radical -CH2 -or-CH2CH2-.  63.-Compound of formula  <Desc / Clms Page number 302>    EMI302.1  where R8 represents a hydrogen atom and RI is chosen from the hydrogen atom and the alkyl, alkenyl and alkynyl radicals of 1 to 10 carbon atoms; cycloalkyl and cycloalkylalkyl of 3 to 6 carbon atoms in the ring of the cycloalkyl part and from 1 to 6 carbon atoms in the alkyl parts; phenyl; aralcoyl; aralkenyl and aralkynyl in which the aryl part is a phenyl radical and in which the aliphatic part has 1 to 6 carbon atoms;  heteroaryl, heteroaralkyl, heterocyclic and heterocycloalkyl in which the heteroatom (s) of the abovementioned heterocyclic parts are chosen from 1 to 4 oxygen, nitrogen or sulfur atoms and in which the alkyl parts associated with the heterocyclic parts comprise 1 to 6 atom carbon, all substituted or unsubstituted, in which the substituent or substituents with respect to the abovementioned radicals are independently chosen from: Cl-C6-alkyl optionally amino, halogen, hydroxylated or carboxylated halogeno  EMI302.2    <Desc / Clms Page number 303>    EMI303.1  where, with regard to the abovementioned substituents, the radicals R3 and R4 are independently chosen from the hydrogen atom and the alkyl, alkenyl and alkynyl radicals  <Desc / Clms Page number 304>  from 1 to 10 carbon atoms;  cycloalkyl, cycloalkylalkyl and alkylcycloalkyl of 3 to 6 carbon atoms in the ring of the cycloalkyl part and from 1 to 6 carbon atoms in the alkyl parts; phenyl; aralkyl, aralkenyl and aralkynyl in which the aryl part is a phenyl radical and the aliphatic part has 1 to 6 carbon atoms; and heteroaryl, heteroaralkyl, heterocyclic and heterocyloalkyl in which the heteroatom (s) in the aforementioned heterocyclic parts are chosen from 1 to 4 atoms of oxygen, nitrogen or sulfur and in which the alkyl parts associated with these heterocyclic parts have 1 to 6 atoms of carbon, or else R3 and R4, taken together with the nitrogen atom to which at least one of them is united, can form a pentagonal or hexagonal nitrogen heterocyclic radical;  R9 is defined as R except that it cannot be a hydrogen atom; or where R1 and R8, taken together, represent a  EMI304.1  hydroxylated C-Cio-alkylIidene or C-CiocoyIidene radical; R5 is chosen from alkyl, alkenyl and alkynyl radicals of 1 to 10 carbon atoms; cycloalkyl and cycloalkylalkyl of 3 to 6 carbon atoms in the ring of the cycloalkyl part and from 1 to 6 carbon atoms in the alkyl parts; phenyl; aralkyl, aralkenyl and aralkynyl in which the aryl part is a phenyl radical and in which the aliphatic part has 1 to 6 carbon atoms;  heteroaryl, heteroaralkyl, heterocyclic and heterocycloalkyl in which the heteroatom (s) in the above-mentioned heterocyclic parts are chosen from 1 to 4 oxygen, nitrogen or sulfur atoms and in which the alkyl parts associated with the heterocyclic parts have 1 to 6 carbon atoms , all substituted or unsubstituted; the aforementioned R5 radicals carrying  EMI304.2  0 possibly one to three substituents chosen independently  <Desc / Clms Page number 305>  especially among: C1-C6-alkyl optionally amino, fluorinated, chlorinated, carboxylated, hydroxylated, or carbamoylated fluoro, chloro or bromo  EMI305.1    - CN; or phenyl optionally substituted with 1 to 3 fluoro, chloro, bromo, Cl-C6-alkyl radicals, -OR3, -NR3R4,  EMI305.2  - R3, R4 and R9 in these substituents of R5 are as defined above;  or R5 can be combined with  <Desc / Clms Page number 306>    EMI306.1  at another point in the cycle to form a condensed heterocyclic or heteroaromatic radical, the cycle of which may contain additional heteroatoms, chosen from 0, S and N; A represents a C1-C6-alkylene radical in a straight or branched chain; R2 represents a hydrogen atom, an anionic charge or a conventional radical which is easy to remove protective of the carboxyl function, it being understood that when R2 represents a hydrogen atom or a protective radical, there is also a counterion, and  EMI306.2  represents a radical of formula  EMI306.3    <Desc / Clms Page number 307>    EMI307.1  ¯5 e -K ---- S.-R! 'J,. N he or! 1 t <--- K-Roù R represents a Cl-C4-alkyl radical; Cl-C4-alkyl substituted by 1 to 3 hydroxyl, amino, Cl-C4alkylamino, di (Cl-C4) alkylamino, Cl-C4-alkoxy, carboxyl, halo or sulfo radicals; C3-C6-cycloalkyl; C3C6-cycloalkyl (Cl-C4) alkyl optionally substituted with 1 to 3 substituents mentioned above in connection with the C1-C4-alkyl radicals; phenyl; phenyl substituted with 1 to 3 substituents independently chosen from amino, halo, hydroxyl, trifluoromethyl, Cl-C4-alkyl, Cl-C4-alkoxy, Cl-C4-alkylamino, di (C1-C4) alkylamino, carboxyl and sulfo radicals;  phenyl (Cl-C4) - alkyl in which the phenyl part can optionally be substituted by 1 to 3 substituents mentioned above with respect to the phenyl radical and in which the alkyl part can optionally be substituted by 1 to 3 substituents mentioned above in connection with the radical ClC-alkyl radicals;  and heatheraryl and heteroaralkyl in which the heteroatom (s) are chosen from 1 to 4 atoms 0, S or m and the alkyl part associated with the heteroalkyl radical has 1 to 6 carbon atoms, these heteroaryl and heteroaralkyl radicals being optionally substituted in the heterocyclic part by 1 to 3 substituents independently chosen from hydroxyl, amino, halo, trifluoromethyl, ClC4-alkyl, Cl-C4-alkoxy, Cl-C4-alkylamino, di (Cl-C4) - alkylamino, carboxyl and sulfo radicals, and in the part alkyl with 1 to 3 substituents chosen from  <Desc / Clms Page number 308>  hydroxyl, amino, Ci-C-alkylamino, di (ClC4) alkylamino, C1-C4-alkoxy, carboxyl, halo and sulfo radicals; or a pharmaceutically acceptable salt of this compound.    64.-A compound according to claim 63, in  EMI308.1  the formula of which Ri represents a hydrogen atom or a radical  EMI308.2  CH3 CH3 OH OH 1 9 CH3CH2 -, / "CH3CHCH3 / '  EMI308.3  65.-Compound according to claim 63, in the formula of which RI and R8 together represent a radical  EMI308.4   66.-Compound according to claim 63, in the formula of which Ri represents a radical  EMI308.5  1  EMI308.6   67.-Compound according to claim 63, in the formula of which RI represents a radical  EMI308.7  and the absolute configuration is 5R, 6S, 8R.    68.-Compound according to claim 63, 64, 65, 66 or 67, in the formula of which A represents a  <Desc / Clms Page number 309>    radical-CH-or-CHCHs-. 69.-Compound of formula  EMI309.1  where R8 represents a hydrogen atom and Ri is chosen from the hydrogen atom and the alkyl, alkenyl and alkynyl radicals of 1 to 10 carbon atoms; cycloalkyl and cycloalkylalkyl of 3 to 6 carbon atoms in the ring of the cycloalkyl part and from 1 to 6 carbon atoms in the alkyl parts; phenyl; aralcoyl; aralkenyl and aralkynyl in which the aryl part is a phenyl radical and in which the aliphatic part has 1 to 6 carbon atoms;  heteroaryl, heteroaralkyl, heterocyclic and heterocycloalkyl in which the heteroatom (s) of the aforementioned heterocyclic parts are chosen from 1 to 4 oxygen, nitrogen or sulfur atoms and in which the alkyl parts associated with the heterocyclic parts comprise 1 to 6 carbon atoms, all substituted or unsubstituted, the substituent or substituents of which are mentioned above, independently chosen from: Cl-C6-alkyl optionally amino, halogenated, hydroxylated or halogenated carboxylated  EMI309.2    <Desc / Clms Page number 310>    EMI310.1  where, with respect to the abovementioned substituents, the radicals R3 and R4 are independently chosen from the atom of hy-  <Desc / Clms Page number 311>  drogen and the alkyl, alkenyl and alkynyl radicals of 1 to 10 carbon atoms;  cycloalkyl, cycloalkylalkyl and alkylcycloalkyl of 3 to 6 carbon atoms in the ring of the cycloalkyl part and from 1 to 6 carbon atoms in the alkyl parts; phenyl; aralkyl, aralkenyl and aralkynyl in which the aryl part is a phenyl radical and the aliphatic part has 1 to 6 carbon atoms; and heteroaryl, heteroaralkyl, heterocyclic and heterocycloalkyl in which the heteroatom (s) in the aforementioned heterocyclic parts are chosen from 1 to 4 atoms of oxygen, nitrogen or sulfur and in which the alkyl parts associated with these heterocyclic parts have 1 to 6 atoms of carbon, or else R3 and R4, taken together with the nitrogen atom to which at least one of them is united, can form a pentagonal or hexagonal nitrogen heterocyclic radical;  R9 is defined as R3, except that it cannot be a hydrogen atom; or where Ri and R8, taken together, represent a  EMI311.1  hydroxylated C-Cio-alkylIidene or C-C'io'Y 'radical; R5 is chosen from alkyl, alkenyl and alkynyl radicals of 1 to 10 carbon atoms; cycloalkyl and cycloalkylalkyl of 3 to 6 carbon atoms in the ring of the cycloalkyl part and from 1 to 6 carbon atoms in the alkyl parts; phenyl; aralkyl, aralkenyl and aralkynyl in which the aryl part is a phenyl radical and in which the aliphatic part has 1 to 6 carbon atoms;  heteroaryl, heteroaralkyl, heterocyclic and heterocycloalkyl in which the heteroatom (s) in the above-mentioned heterocyclic parts are chosen from 1 to 4 oxygen, nitrogen or sulfur atoms and in which the alkyl parts associated with the heterocyclic parts have 1 to 6 carbon atoms , all substituted or unsubstituted; the aforementioned p5 radicals carrying  <Desc / Clms Page number 312>  optionally one to three substituents chosen independently from: Cl-C6-alkyl optionally amino, fluorinated, chlorinated, carboxylated, hydroxylated, or carbamoylated fluoro, chloro or bromo  EMI312.1    - CN;  or phenyl optionally substituted with 1 to 3 fluoro, chloro, bromo, Cl-C6-alkyl, -OR3, -NR3R4, - S03R3, -C02R3 or-CONR3R4, where R3, R4 and R9 in these substituents of R5 are such that defined above; A represents a C1-C6-alkylene radical in a straight or branched chain;  R2 represents a hydrogen atom,  <Desc / Clms Page number 313>  an anionic charge or a conventional radical which is easy to remove protective of the carboxyl function, it being understood that when R2 represents a hydrogen atom or a protective radical, there is also a counter ion, and  EMI313.1  represents a radical of formula  EMI313.2  where R6, R7 and RO are independently chosen from the hydrogen atom and the C1-C4-alkyl radicals; C1-C4-alkoxy, carboxyl and carbamoyl, or a pharmaceutically acceptable salt of this compound.    70.-Compound according to claim 69, in the formula of which RI represents a hydrogen atom or a radical.  EMI313.3  CH3 CH3 OH OH 1 9 CH3CH2-, CH-, CHCHg  EMI313.4  71.-Compound according to claim 69, in the formula of which Ri and R8 together represent a radical  <Desc / Clms Page number 314>    EMI314.1   C- or CH72.-Compound according to Claim 69, in the formula of which R1 represents a radical  EMI314.2  73.-A compound according to claim 69, in  EMI314.3  the formula of which Rl represents a radical  EMI314.4    EMI314.5  and the absolute configuration is 5R, 6S, 8R. 74.-Compound according to claim 69, 70, 71,72 or 73, in the formula of which A represents a radical -CH2- or -CH2CH2-.    75.-Compound of formula  EMI314.6  where A represents a C1-C6-alkylene radical in a straight or branched chain; R2 represents a hydrogen atom, an anionic charge or a conventional radical which is easy to remove protective of the carboxyl function, it being understood that when R2 represents a hydrogen atom or a protective radical, a counter ion is also  <Desc / Clms Page number 315>  present; and  EMI315.1  represents a radical of formula  EMI315.2  where R5 represents a Cl-C4-alkyl radical and R6 represents a hydrogen atom or Cl-C4-alkyl radical;  EMI315.3  where R5 represents a Cl-C4-alkyl radical and R6 and R7 represent hydrogen atoms or ClC4-alkyl radicals;    EMI315.4  where R5 represents a Cl-C4-alkyl radical and R represents a Cl-C4-alkyl or phenyl (Cl-C4) alkyl radical;  <Desc / Clms Page number 316>    EMI316.1  where R5 represents a Cl-C4-alkyl radical and R6 represents a Cl-C4-alkyl radical;  EMI316.2  where R5 represents a Cl-C4-alkyl radical and R represents a Cl-C4-alkyl radical; or  EMI316.3  where R5 represents a Cl-C4-alkyl radical; or a pharmaceutically acceptable salt of this compound.    76.-Compound of formula  EMI316.4  where A represents a C1-C6-alkylene radical in a straight or branched chain; R2 represents a hydrogen atom, an anionic charge or a conventional radical easy to  <Desc / Clms Page number 317>  eliminating the protector from the carboxyl function, it being understood that when R2 represents a hydrogen atom or a protective radical, a counter ion is also present; and  EMI317.1  represents a radical of formula  EMI317.2    <Desc / Clms Page number 318>    EMI318.1  or a pharmaceutically acceptable salt of this compound.    77.-Compound of formula  EMI318.2  where R2 represents a hydrogen atom, an anionic charge or a conventional radical which is easy to remove and which protects the carboxyl function, it being understood that  <Desc / Clms Page number 319>    EMI319.1  when R2 represents a hydrogen atom or a protective radical, a counter ion is also present, and  EMI319.2    EMI319.3  is / - \ / - \ (a) -SCH -'- CH CH- 2 3 2 2 - UN 3 CH, (c) = e-- 'CH CE3 CH3 (e) -SCH. -CH2CH2C "3 3, CH t- \ Le N NE:  (g) -SCH - / "-CH 2 2 \ / s cH3  <Desc / Clms Page number 320>    EMI320.1  where the 1 H NMR spectrum (D20) has characteristic peaks at 6: 1.23 (3H, d, J = 6.4 Hz), 3.12 (2H, q, J = 1.4, 8.9 Hz), 3.39 (1H, q, J = 2.7, 6.0Hz), 4.07-4.68 (10H, m), 8.19 (1H, s);  EMI320.2    <Desc / Clms Page number 321>    EMI321.1  where the 1 H NMR spectrum (D20) has characteristic peaks at 6: 1, 23 (3H, d, J = 6.4 Hz), 3.15 (2H, q, J = 3.7, 9, 0 Hz), 3.37 (1H, q, J = 2, 6, 6, 0 Hz), 3.95-4.65 (10H,  EMI321.2  m), 62 (1H, s); (r) - -y - K \ -CH-SCH S -KCH - N, in (t) e) ', N -SCH7 - SCH c-2 CH COO N-N 2 / CH3 CH3 N-. N / CH 3 or (v) Eb CH CH  EMI321.3  or a pharmaceutically acceptable salt of this compound. 78.-Compound of formula  EMI321.4    <Desc / Clms Page number 322>  where R2 represents a hydrogen atom, an anionic charge or a conventional radical which is easy to remove protective of the carboxyl function, it being understood that when R2 represents a hydrogen atom or a protective radical, a counter ion is also present; or a pharmaceutically acceptable salt of this compound.    79. A compound according to claim 78, in which formula R2 represents a p-nitrobenzyl radical.    80. A compound according to claim 78, in which formula R2 represents an anionic charge.    81.-Compound of formula  EMI322.1  where R2 represents a hydrogen atom, an anionic charge or a conventional radical which is easy to remove protective of the carboxyl function, it being understood that when R2 represents a hydrogen atom or a protective radical, a counter ion is also present; or a pharmaceutically acceptable salt of this compound.    82.-A compound according to claim 81, in which formula R2 represents a p-nitrobenzyl radical.    83.-Compound according to claim 81, in which formula R2 represents an anionic charge.    84.-Compound of formula  <Desc / Clms Page number 323>    EMI323.1  where R2 represents a hydrogen atom, an anionic charge or a conventional radical which is easy to remove protective of the carboxyl function, it being understood that when R2 represents a hydrogen atom or a protective radical, a counter ion is also present; or a pharmaceutically acceptable salt of this compound.    85.-Compound according to claim 84, in the formula of which R2 represents a p-nitrobenzyl radical.    86. A compound according to claim 84, in which formula R2 represents an anionic charge.    87.-Compound of formula  EMI323.2  where R2 represents a hydrogen atom, an anionic charge or a conventional radical which is easy to remove protective of the carboxyl function, it being understood that when R2 represents a hydrogen atom or a  EMI323.3  p protective radical, a counter ion is also present; or a pharmaceutically acceptable salt of this compound.    88.-A compound according to claim 87, in  <Desc / Clms Page number 324>  the formula of which R2 represents a p-nitrobenzyl radical.    89. A compound according to claim 87, in which formula R2 represents an anionic charge.    90.-Compound of formula  EMI324.1  where R2 represents a hydrogen atom, an anionic charge or a conventional radical which is easy to remove protective of the carboxyl function, it being understood that when R2 represents a hydrogen atom or a protective radical, a counter ion is also present; or a pharmaceutically acceptable salt of this compound.    91.-A compound according to claim 90, in the formula of which R2 represents a p-nitrobenzyl radical.    92.-Compound according to claim 90, in which formula R2 represents an anionic charge.    93 .-- Compound of formula  EMI324.2  where R2 represents a hydrogen atom, an anionic charge or a conventional radical which is easy to remove and which protects the carboxyl function, it being understood that  <Desc / Clms Page number 325>  when R2 represents a hydrogen atom or a protective radical, a counter ion is also present; or a pharmaceutically acceptable salt of this compound.    94.-Compound according to claim 93, in the formula in which R2 represents a p-nitrobenzyl radical.    95.-Compound according to claim 93, in the formula in which R2 represents an anionic charge.    96.-Compound of formula  EMI325.1  where R2 represents a hydrogen atom, an anionic charge or a conventional radical which is easy to remove protective of the carboxyl function, it being understood that when R2 represents a hydrogen atom or a protective radical, a counter ion is also present; or a pharmaceutically acceptable salt of this compound.    97.-Compound according to claim 96, in which formula R2 represents a p-nitrobenzyl radical.    98.-Compound according to claim 93, in the formula in which R2 represents an anionic charge.    99.-Compound of formula  <Desc / Clms Page number 326>    EMI326.1  where R2 represents a hydrogen atom, an anionic charge or a conventional radical which is easy to remove protective of the carboxyl function, it being understood that when R2 represents a hydrogen atom or a protective radical, a counter ion is also present; or a pharmaceutically acceptable salt of this compound.    100.-Compound according to claim 99, in the formula in which R2 represents a p-nitro) benzyl radical.    101.-Compound according to claim 99, in the formula in which R2 represents an anionic charge.    102 .-- Compound of formula  EMI326.2  where R2 represents a hydrogen atom, a charge  EMI326.3  anionic or a conventional radical which is easy to protect the carboxyl function, it being understood that when R2 represents a hydrogen atom or a protective radical, a counter ion is also present; or a pharmaceutically acceptable salt of this compound.  <Desc / Clms Page number 327>      103.-Compound according to claim 102, in which formula R2 represents a p-nitrobenzyl radical.    104. A compound according to claim 102, in which formula R2 represents an anionic charge.    105 .-- Compound of formula  EMI327.1  where R2 represents a hydrogen atom, an anionic charge or a conventional radical which is easy to remove protective of the carboxyl function, it being understood that when R2 represents a hydrogen atom or a protective radical, a counter ion is also present; or a pharmaceutically acceptable salt of this compound.    106.-Compound according to claim 105, in the formula in which R2 represents a p-nitrobenzyl radical.    107.-Compound according to claim 105, in the formula in which R2 represents an anionic charge.    108 .-- Compound of formula  EMI327.2    <Desc / Clms Page number 328>  where R2 represents a hydrogen atom, an anionic charge or a conventional radical which is easy to remove protective of the carboxyl function, it being understood that when R2 represents a hydrogen atom or a protective radical, a counter ion is also present; or a pharmaceutically acceptable salt of this compound.    109.-Compound according to claim 108, in which formula R2 represents a p-nitrobenzyl radical.    110.-Compound according to claim 108, in which formula R2 represents an anionic charge.    111. - Compound of formula  EMI328.1  where R2 represents a hydrogen atom, an anionic charge or a conventional radical which is easy to remove protective of the carboxyl function, it being understood that when R2 represents a hydrogen atom or a protective radical, a counter ion is also present; or a pharmaceutically acceptable salt of this compound.    112.-Compound according to claim 111, in the formula of which R2 represents a p-nitrobenzyl radical.    113. A compound according to claim 111, in the formula of which R2 represents an anionic charge.    114.-Compound of formula  <Desc / Clms Page number 329>    EMI329.1  where R2 represents a hydrogen atom, an anionic charge or a conventional radical which is easy to remove protective of the carboxyl function, it being understood that when R2 represents a hydrogen atom or a protective radical, a counter ion is also present; or a pharmaceutically acceptable salt of this compound.    115.-A compound according to claim 114, in which formula R2 represents a p-nitrobenzyl radical.    116.-Compound according to claim 114, in the formula in which R2 represents an anionic charge.    117.-Compound of formula  EMI329.2  where R2 represents a hydrogen atom, an anionic charge or a conventional radical which is easy to remove protective of the carboxyl function, it being understood that when R2 represents a hydrogen atom or a protective radical, a counter ion is also present; or a pharmaceutically acceptable salt of this compound.  <Desc / Clms Page number 330>      118.-Compound according to claim 117, in which formula R2 represents a p-nitrobenzyl radical.    119.-Compound according to claim 117, in which formula R2 represents an anionic charge.    120 .-- Compound of formula  EMI330.1  where R2 represents a hydrogen atom, an anionic charge or a conventional radical which is easy to remove protective of the carboxyl function, it being understood that when R2 represents a hydrogen atom or a protective radical, a counter ion is also present; or a pharmaceutically acceptable salt of this compound.    121. A compound according to claim 120, in the formula of which R2 represents a p-ni-trobenzyl radical.    122.-Compound according to claim 120, in the formula of which R2 represents an anionic charge.    123.-Compound of formula  EMI330.2    <Desc / Clms Page number 331>  where R2 represents a hydrogen atom, an anionic charge or a conventional radical which is easy to remove protective of the carboxyl function, it being understood that when R2 represents a hydrogen atom or a protective radical, a counter ion is also present; or a pharmaceutically acceptable salt of this compound.    124. A compound according to claim 123, in which formula R2 represents a p-nitrobenzyl radical.    125.-Compound according to claim 123, in the formula in which R2 represents an anionic charge.    126.-Compound of formula  EMI331.1  where R2 represents a hydrogen atom, an anionic charge or a conventional radical which is easy to remove protective of the carboxyl function, it being understood that when R2 represents a hydrogen atom or a protective radical, a counter ion is also present; or a pharmaceutically acceptable salt of this compound.    127. A compound according to claim 126, in which formula R2 represents a p-nitrobenzyl radical.    128.-Compound according to claim 126, in which formula R2 represents an anionic charge.  <Desc / Clms Page number 332>     129 .-- Compound of formula  EMI332.1  where R2 represents a hydrogen atom, an anionic charge or a conventional radical which is easy to remove protective of the carboxyl function, it being understood that when R2 represents a hydrogen atom or a protective radical, a counter ion is also present; or a pharmaceutically acceptable salt of this compound.    130.-Compound according to claim 129, in which formula R2 represents a p-nitrobenzyl radical.    131. A compound according to claim 129, in the formula of which R2 represents an anionic charge.    132.- Compound of formula  EMI332.2  where R2 represents a hydrogen atom, an anionic charge or a conventional radical which is easy to remove protective of the carboxyl function, it being understood that when R2 represents a hydrogen atom or a protective radical, a counter ion is also present; or a pharmaceutically acceptable salt thereof  <Desc / Clms Page number 333>  compound.    133. A compound according to claim 132, in the formula of which R2 represents a p-nitrobenzyl radical.    134.-Compound according to claim 132, in the formula of which R2 represents an anionic charge.    135.-Compound of formula  EMI333.1  where R2 represents a hydrogen atom, an anionic charge or a conventional radical which is easy to remove protective of the carboxyl function, it being understood that when R2 represents a hydrogen atom or a protective radical, a counter ion is also present; or a pharmaceutically acceptable salt of this compound.    136. Compound according to claim 135, in the formula in which R2 represents a p-nitrobenzyl radical.    137. A compound according to claim 135, in the formula of which R2 represents an anionic charge.    138 .-- Compound of formula  EMI333.2    <Desc / Clms Page number 334>  whose 1 H NMR spectrum (D20) has characteristic peaks at 6: 1.23 (3H, d, J = 6.4 Hz), 3.12 (2H, q, J = 1, 4, 8.9 Hz), 3.39 (1H, q, J = 2.7, 6.0 Hz), 4.07-4.68 (10H, m), 8.19 (1H, s), or a pharmaceutically acceptable salt or ester of this compound.    139.-Compound according to claim 138, in which the carboxyl radical is protected in the form of p-nitrobenzyl ester.    140.-Compound of formula  EMI334.1  whose NMRH1 (D20) spectrum has characteristic peaks at 6: 1.23 (3H, d, J = 6.4 Hz), 3.12 (2H, q, J = 3.7, 9.0 Hz), 3.37 (1H, q, J = 2.6, 6.0 Hz), 3.95-4.65 (10H, m), 8.62 (1H, s), or a pharmaceutically acceptable salt or ester of this compound.    141.- A compound according to claim 140, in which the carboxyl radical is protected in the form of p-nitrobenzyl ester.    142.-Process for the preparation of a compound of formula  <Desc / Clms Page number 335>    EMI335.1  where R8 represents a hydrogen atom and RI is chosen from the hydrogen atom and the alkyl, alkenyl and alkynyl radicals of 1 to 10 carbon atoms; cycloalkyl and cycloalkylalkyl of 3 to 6 carbon atoms in the ring of the cycloalkyl part and from 1 to 6 carbon atoms in the alkyl parts; phenyl; aralkyl, aralkenyl and aralkynyl in which the aryl part is a phenyl radical and the aliphatic part has 1 to 6 carbon atoms;  heteroaryl, heteroaralkyl, heterocyclic and heterocycloalkyl in which the heteroatom (s) in the aforementioned heterocyclic parts are chosen from 1 to 4 oxygen, nitrogen or sulfur atoms and the alkyl parts associated with the heterocyclic parts have 1 to 6 carbon atoms, all substituted or unsubstituted and whose substituent (s) with respect to the abovementioned radicals are independently chosen from Cl-C6-alkyl optionally amino, halogenated, hydroxylated or halogenated carboxylated  EMI335.2    <Desc / Clms Page number 336>    EMI336.1  where, with regard to the abovementioned substituents, the radicals R3 and R4 are independently chosen from the hydrogen atom and the alkyl, alkenyl and alkynyl radicals  <Desc / Clms Page number 337>  from 1 to 10 carbon atoms;    cycloalkyl, cycloalkylalkyl and alkylcycloalkyl of 3 to 6 carbon atoms in the ring of the cycloalkyl part and from 1 to 6 carbon atoms in the alkyl parts; phenyl; aralkyl, aralkenyl and aralkynyl in which the aryl part is a phenyl radical and in which the aliphatic part has 1 to 6 carbon atoms; and heteroaryl, heteroaralkyl, heterocyclic and heterocycloalkyl in which the heteroatom (s) in the aforementioned heterocyclic parts are chosen from 1 to 4 atoms of oxygen, nitrogen and sulfur and in which the alkyl parts associated with the heterocyclic parts have 1 to 6 atoms of carbon, or else R3 and R4, taken together with the nitrogen atom to which at least one of them is united, can form a pentagonal or hexagonal nitrogen heterocyclic radical;  R9 is defined as R except that it cannot be a hydrogen atom; or where Ri and R8, taken together, represent a  EMI337.1  hydroxyl-substituted C-co alkylidene or C-Co'lcoyliene radical is chosen from radicals; R5alkyl, alkenyl and alkynyl of 1 to 10 carbon atoms; cycloalkyl and cycloalkyl and cycloalkylalkyl of 3 to 6 carbon atoms in the ring of the cycloalkyl part and from 1 to 6 carbon atoms in the alkyl parts; phenyl; aralkyl, aralkenyl and aralkynyl in which the aryl part is a phenyl radical and in which the aliphatic part has 1 to 6 carbon atoms;  heteroaryl, heteroaralkyl, heterocyclic and heterocycloalkyl in which the heteroatom (s) of the above-mentioned heterocyclic parts are chosen from 1 to 4 oxygen, nitrogen or sulfur atoms and in which the alkyl parts associated with the heterocyclic parts have 1 to 6 carbon atoms, all substituted or unsubstituted; the aforementioned R5 radicals being optionally substituted with 1 to 3 selected radicals  <Desc / Clms Page number 338>  independently from: Cl-C6-alkyl optionally amino, fluorinated, chlorinated, carboxylated, hydroxylated, or carbamoylated fluoro, chloro or bromo  EMI338.1  -CN; or phenyl optionally substituted with 1 to 3 fluoro, chloro, bromo, Cl-C6-alkyl radicals, -OR3, -NR3R4,  EMI338.2  - It or R3 and R9 in these substituents of R5 are as defined above;  or R5 can be combined with  <Desc / Clms Page number 339>    EMI339.1  at another point in the cycle so as to form a condensed heterocyclic or heteroaromatic radical, the cycle of which may contain additional heteroatoms, chosen from 0, N and S; R15 is chosen from the hydrogen atom and the alkyl, alkenyl and alkynyl radicals of 1 to 10 carbon atoms; cycloalkyl, cycloalkylalkyl and alkylcycloalkyl of 3 to 6 carbon atoms in the ring of the cycloalkyl part and from 1 to 6 carbon atoms in the alkyl parts;  spirocycloalkyl of 3 to 6 carbon atoms: phenyl: aralkyl, aralkenyl and aralkynyl of which the aryl part is a phenyl radical and the aliphatic part has 1 to 6 carbon atoms: heteroaryl, heteroaralkyl, heterocyclic and heterocycloalkyl in which the hetero or the aforementioned heterocyclic parts are chosen from 1 to 4 oxygen, nitrogen or sulfur atoms and the alkyl parts associated with the heterocyclic parts have 1 to 6 carbon atoms, all of which are substituted or unsubstituted and whose substituent or substituents are aforementioned radicals are chosen from amino, mono-, di- and trialkylamino, hydroxyl, alkoxy, mercapto, alkylthio, phenylthio, sulfamoyl, amidino, guanidino, nitro, chloro, bromo, fluoro,  cyano and carboxyl: and in which the alkyl parts in the abovementioned substituents have 1 to 6 carbon atoms: A represents a C1-c-alkylene radical in a straight or branched chain; R2 represents a hydrogen atom, an anionic charge or a conventional radical easily  <Desc / Clms Page number 340>  removable protective of the carboxyl function, it being understood that when R2 represents a hydrogen atom or a protective radical, a counter ion is also present, and  EMI340.1  represents a substituted or unsubstituted heterocyclic, aromatic, mono-, bi- or polycyclic radical comprising at least one nitrogen atom in the ring and united to the radical A by a carbon atom of the ring and comprising a ring nitrogen atom which is quaternized by the radical R5;  or a pharmaceutically acceptable salt of this compound, characterized in that (1) An intermediate of formula is reacted  EMI340.2  where RI, R8 and R15 are as defined above and R2 '  EMI340.3  1 represents a conventional radical which is easy to remove, protective of the carboxyl function, in an inert organic solvent, with a reagent capable of introducing a conventional labile radical L in position 2 of intermediate III to form an intermediate of formula  <Desc / Clms Page number 341>    EMI341.1  where Ri, R8, R15 and R2 'are as defined above and L represents a conventional labile radical;  (2) Intermediate IV is reacted in an inert organic solvent and in the presence of a base with a mercaptan of formula  EMI341.2  where A is as defined above, and  EMI341.3  represents a heterocyclic, aromatic, mono-, bi- or polycyclic radical containing a nitrogen atom which can be quaternized in the ring, which radical is joined to the radical A by a ring carbon atom, to form an intermediate of formula  EMI341.4    <Desc / Clms Page number 342>  where Ri, R8, R15, A, R2 'and  EMI342.1  are as defined above;  (3) reacting intermediate II in an inert organic solvent with an alkylating agent of formula  EMI342.2  R5¯X 'where R5 is as defined above and X'represents a conventional labile radical so as to quaternize by means of the radical R5, a ring nitrogen atom of the substituent  EMI342.3  of intermediate II and form a compound of formula  EMI342.4  where Ri, R8, Rl5, R2 ', A,  EMI342.5  and X are as defined above and, if the thing  <Desc / Clms Page number 343>  is desired, the counter ion X ′ is replaced by a different counter ion and, if desired, the radical R2 ′ protecting the carboxyl function is removed to obtain the desired deprotected compound of formula I or a pharmaceutically acceptable salt thereof compound. * 143.-A method according to claim 142, characterized in that the quaternization is carried out after eliminating the radical R2'protector of the carboxyl function.    144.- Process for the preparation of a compound of formula  EMI343.1  where R8 represents a hydrogen atom and RI is chosen from the hydrogen atom and the alkyl, alkenyl and alkynyl radicals of 1 to 10 carbon atoms; cycloalkyl and cycloalkylalkyl of 3 to 6 carbon atoms in the ring of the cycloalkyl part and from 1 to 6 carbon atoms in the alkyl parts; phenyl; aralkyl, aralkenyl and aralkynyl in which the aryl part is a phenyl radical and the aliphatic part has 1 to 6 carbon atoms;  heteroaryl, heteroaralkyl, heterocyclic and heterocycloalkyl in which the heteroatom (s) in the aforementioned heterocyclic parts are chosen from 1 to 4 oxygen, nitrogen or sulfur atoms and the alkyl parts associated with the heterocyclic parts have 1 to 6 carbon atoms, all substituted or unsubstituted and whose substituent (s) with respect to the abovementioned radicals are independently chosen from  <Desc / Clms Page number 344>  Cl-C6-alkyl optionally amino, halogenated, hydroxylated or halogenated carboxylated  EMI344.1    <Desc / Clms Page number 345>    EMI345.1  where, with regard to the abovementioned substituents, the radicals RJ and R4 are chosen independently from the hydrogen atom and the alkyl, alkenyl and alkynyl radicals of 1 to 10 carbon atoms;  cycloalkyl, cycloalkylalkyl and alkylcycloalkyl of 3 to 6 carbon atoms in the ring of the cycloalkyl part and from 1 to 6 carbon atoms in the alkyl parts; phenyl; aralkyl, aralkenyl and aralkynyl in which the aryl part is a phenyl radical and in which the aliphatic part has 1 to 6 carbon atoms; and heteroaryl, heteroaralkyl, heterocyclic and heterocycloalkyl in which the heteroatom (s) in the aforementioned heterocyclic parts are chosen from 1 to 4 atoms of oxygen, nitrogen and sulfur and in which the alkyl parts associated with the heterocyclic parts have 1 to 6 atoms of carbon, or else R3 and R4, taken together with the nitrogen atom to which at least one of them is united, can form a pentagonal or hexagonal nitrogen heterocyclic radical;  R9 is defined as R3, except that it cannot be a hydrogen atom; or alternatively where RI and R8, taken together, represent a C2-CIO alkylidene or C2-CIO-alkylidene radical substituted by hydroxyl; R5 is chosen from alkyl, alkenyl and alkynyl radicals of 1 to 10 carbon atoms; cycloalkyl and cycloalkyloyl of 3 to 6 carbon atoms in the ring of the cycloalkyl part and of 1 to 6 carbon atoms in the parts  <Desc / Clms Page number 346>  alkyl; phenyl; aralkyl, aralkenyl and aralkynyl in which the aryl part is a phenyl radical and in which the aliphatic part has 1 to 6 carbon atoms;  heteroaryl, heteroaralkyl, heterocyclic and heterocycloalkyl in which the heteroatom (s) of the abovementioned heterocyclic parts are chosen from 1 to 4 oxygen, nitrogen or sulfur atoms and in which the alkyl parts associated with the heterocyclic parts have 1 to 6 carbon atoms, all substituted or unsubstituted; the aforementioned R5 radicals being optionally substituted with 1 to 3 radicals chosen independently from: Cl-C6-alkyl optionally amino, fluorinated, chlorinated, carboxylated, hydroxylated, or carbamoylated fluoro, chloro or bromo  EMI346.1    <Desc / Clms Page number 347>    - SOgRS - C02R3 - CONR3R4 - CN;  or phenyl optionally substituted with 1 to 3 fluoro, chloro, bromo, Cl-C6-alkyl, -OR3, -NR3R4, - S03R3, -C02R3 or-CONR3R4, where R3, R4 and R9 in these substituents of R5 are such that defined above; or R5 can be combined with  EMI347.1  at another point in the cycle so as to form a condensed heterocyclic or heteroaromatic radical, the cycle of which may contain additional heteroatoms, chosen from 0, N and S;  R15 is chosen from the hydrogen atom and the alkyl, alkenyl and alkynyl radicals of 1 to 10 carbon atoms; cycloalkyl, cycloalkylalkyl and alkylcycloalkyl of 3 to 6 carbon atoms in the ring of the cycloalkyl part and from 1 to 6 carbon atoms in the alkyl parts; spirocycloalkyl of 3 to 6 carbon atoms; phenyl; aralkyl, aralkenyl and aralkynyl in which the aryl part is a phenyl radical and the aliphatic part has 1 to 6 carbon atoms;  heteroaryl, heteroaralkyl, heterocyclic and heterocycloalkyl in which the heteroatom (s) in the aforementioned heterocyclic parts are chosen from 1 to 4 oxygen, nitrogen or sulfur atoms and the alkyl parts associated with the heterocyclic parts have 1 to 6 carbon atoms, all substituted or unsubstituted and whose substituent (s) with respect to the abovementioned radicals are chosen from  <Desc / Clms Page number 348>  amino, mono-, di- and trialkylamino, hydroxyl, alkoxy, mercapto, alkylthio, phenylthio, sulfamoyl, amidino, guanidino, nitro, chloro, bromo, fluoro, cyano and carboxyl radicals; and in which the alkyl parts in the abovementioned substituents have 1 to 6 carbon atoms; A represents a C-c-alkylene radical in a straight or branched chain;  R2 represents a hydrogen atom, an anionic charge or a conventional easily removable radical protecting the carboxyl function, it being understood that when R2 represents a hydrogen atom or a protective radical, a counter ion is also present, and  EMI348.1  represents a substituted or unsubstituted heterocyclic, aromatic, mono-, bi- or polycyclic radical comprising at least one nitrogen atom in the ring and united to the radical A by a carbon atom of the ring and comprising a ring nitrogen atom which is quaternized by the radical R5;  or a pharmaceutically acceptable salt of this compound, characterized in that an intermediate of formula is reacted  EMI348.2    <Desc / Clms Page number 349>  where RI, R8, R15, A, R2 'are as defined above, and  EMI349.1  represents a heterocyclic, aromatic, mono-, bi- or polycyclic radical containing a nitrogen atom quaternizable in the ring, which radical is united to the radical A by a carbon atom of the ring, in an inert organic solvent, with an agent of formula alkylation  EMI349.2  R5¯X 'where R5 is as defined above and X'represents a conventional labile radical, so as to quaternize by means of the radical R5, a nitrogen atom of the substituent ring  EMI349.3  of intermediate II, to form a compound of formula  EMI349.4  where Ri, R8, R15, R2 ', A,    <Desc / Clms Page number 350>    EMI350.1  and X 'are as defined above and, if the thing is desired, the counter ion X' is replaced by a different counter ion and, if the thing is desired, the radical R2 ′ which protects the carboxyl function is eliminated for obtaining the desired deprotected compound of formula I, or a pharmaceutically acceptable salt of this compound.    145.-A method according to claim 144, characterized in that the quaternization is carried out after eliminating the R2'protector radical of the carboxyl function.    146.-Compound of formula  EMI350.2  where R8 represents a hydrogen atom and R1 is chosen from the hydrogen atom and the alkyl, alkenyl and alkynyl radicals of 1 to 10 carbon atoms; cycloalkyl and cycloalkylalkyl of 3 to 6 carbon atoms in the ring of the cycloalkyl part and from 1 to 6 carbon atoms in the alkyl parts; phenyl; aralkyl, aralkenyl and aralkynyl in which the aryl part is a phenyl radical and the aliphatic part has 1 to 6 carbon atoms;  heteroaryl, heteroaralkyl, heterocyclic and heterocycloalkyl in which the heteroatom (s) in the aforementioned heterocyclic parts are chosen from 1 to  <Desc / Clms Page number 351>  4 oxygen, nitrogen or sulfur atoms and the alkyl parts associated with the heterocyclic parts have 1 to 6 carbon atoms, all of which are substituted or unsubstituted and whose substituent (s) with respect to the abovementioned radicals are independently chosen from Cl-C6-alkyl optionally amino, halogenated, hydroxylated or halogenated carboxylated  EMI351.1    <Desc / Clms Page number 352>    EMI352.1  where, with regard to the abovementioned substituents, the radicals R3 and R4 are independently chosen from the hydrogen atom and the alkyl, alkenyl and alkynyl radicals of 1 to 10 carbon atoms;  cycloalkyl, cycloalkylalkyl and alkylcycloalkyl of 3 to 6 carbon atoms in the ring of the cycloalkyl part and from 1 to 6 carbon atoms in the alkyl parts; phenyl; aralkyl, aralkenyl and aralkynyl in which the aryl part is a phenyl radical and in which the aliphatic part has 1 to 6 carbon atoms; and heteroaryl, heteroaralkyl, heterocyclic and heterocycloalkyl in which the heteroatom (s) in the aforementioned heterocyclic parts are chosen from 1 to 4 atoms of oxygen, nitrogen and sulfur and in which the alkyl parts associated with the heterocyclic parts have 1 to 6 atoms of carbon, or else R3 and R4, taken together with the nitrogen atom to which at least one of them is united, can form a pentagonal or hexagonal nitrogen heterocyclic radical;  R9 is defined as R3, except that it cannot be a hydrogen atom; or where RI and RS, taken together, represent a C2-CIO alkylidene or C2-CIO-alkylidene radical substituted by hydroxyl; R5 is chosen from alkyl, alkenyl and alkynyl radicals of 1 to 10 atoms  <Desc / Clms Page number 353>    EMI353.1  of carbon ; cycloalkyl and cycloalkylalkyl of 3 to 6 carbon atoms in the ring of the cycloalkyl part and from 1 to 6 carbon atoms in the alkyl parts; phenyl;  aralkyl, aralkenyl and aralkynyl in which the aryl part is a phenyl radical and in which the aliphatic part has 1 to 6 carbon atoms; heteroaryl, heteroaralkyl, heterocyclic and heterocycloalkyl in which the heteroatom (s) of the above-mentioned heterocyclic parts are chosen from 1 to 4 oxygen, nitrogen or sulfur atoms and in which the alkyl parts associated with the heterocyclic parts have 1 to 6 carbon atoms, all substituted or unsubstituted; the aforementioned R5 radicals being optionally substituted with 1 to 3 radicals chosen independently from: Cl-C6-alkyl optionally amino, fluorinated, chlorinated, carboxylated, hydroxylated, or carbamoylated fluoro, chloro or bromo  EMI353.2    <Desc / Clms Page number 354>    EMI354.1  -CN;  or phenyl optionally substituted with 1 to 3 fluoro, chloro, bromo, Cl-C6-alkyl, -OR3, -NR3R4, - S03R3, -C02R3 or-CONR3R4, where R3, R4 and R9 in these substituents of R5 are such that defined above; or R5 can be combined with  EMI354.2  at another point in the cycle so as to form a condensed heterocyclic or heteroaromatic radical, the cycle of which may contain additional heteroatoms, chosen from 0, N and S; R15 is chosen from the hydrogen atom and the alkyl, alkenyl and alkynyl radicals of 1 to 10 carbon atoms; cycloalkyl, cycloalkylalkyl and alkylcycloalkyl of 3 to 6 carbon atoms in the ring of the cycloalkyl part and from 1 to 6 carbon atoms in the alkyl parts; spirocycloalkyl of 3 to 6 carbon atoms;  phenyl; aralkyl, aralkenyl and aralkynyl in which the aryl part is a phenyl radical and the aliphatic part has 1 to 6 carbon atoms; heteroaryl, heteroaralkyl, heterocyclic and heterocycloalkyl in which the heteroatom (s) in the aforementioned heterocyclic parts are chosen from 1 to 4 oxygen, nitrogen or sulfur atoms and  <Desc / Clms Page number 355>  the alkyl parts associated with the heterocyclic parts have 1 to 6 carbon atoms, all of which are substituted or unsubstituted and whose substituent (s) with respect to the abovementioned radicals are chosen from amino, mono-, di- and trialkylamino, hydroxyl, alkoxy, mercapto, alkylthio, phenylthio, sulfamoyl, amidino, guanidino, nitro, chloro, bromo, fluoro, cyano and carboxyl;  and in which the alkyl parts in the abovementioned substituents have 1 to 6 carbon atoms; A represents a C1-C6-alkylene radical in a straight or branched chain; R2 represents a hydrogen atom, an anionic charge or a conventional easily removable radical protecting the carboxyl function, it being understood that when R2 represents a hydrogen atom or a protective radical, a counter ion is also present, and  EMI355.1  represents a substituted or unsubstituted heterocyclic, aromatic, mono-, bi- or polycyclic radical comprising at least one nitrogen atom in the ring and united to the radical A by a carbon atom of the ring and comprising a ring nitrogen atom which is quaternized by the radical R5; or a pharmaceutically acceptable salt of this compound.    147.- Compound of formula  <Desc / Clms Page number 356>    EMI356.1  where R8 represents a hydrogen atom and R1 is chosen from the hydrogen atom and the alkyl, alkenyl and alkynyl radicals of 1 to 10 carbon atoms; cycloalkyl and cycloalkylalkyl of 3 to 6 carbon atoms in the ring of the cycloalkyl part and of 1 to 6 carbon atoms in the alkyl parts; phenyl; aralkyl, aralkenyl and aralkynyl in which the aryl part is a phenyl radical and the aliphatic part has 1 to 6 carbon atoms;  heteroaryl, heteroaralkyl, heterocyclic and heterocycloalkyl in which the heteroatom (s) in the aforementioned heterocyclic parts are chosen from 1 to 4 oxygen, nitrogen or sulfur atoms and the alkyl parts associated with the heterocyclic parts have 1 to 6 carbon atoms, all substituted or unsubstituted and whose substituent (s) with respect to the abovementioned radicals are independently chosen from Cl-C6-alkyl optionally amino, halogenated, hydroxylated or halogenated carboxylated  EMI356.2    <Desc / Clms Page number 357>    EMI357.1  where, with regard to the abovementioned substituents, the radicals R3 and R4 are independently chosen from the hydrogen atom and the alkyl, alkenyl and alkynyl radicals  <Desc / Clms Page number 358>  from 1 to 10 carbon atoms;  cycloalkyl, cycloalkylalkyl and alkylcycloalkyl of 3 to 6 carbon atoms in the ring of the cycloalkyl part and from 1 to 6 carbon atoms in the alkyl parts; phenyl; aralkyl, aralkenyl and aralkynyl in which the aryl part is a phenyl radical and in which the aliphatic part has 1 to 6 carbon atoms; and heteroaryl, heteroaralkyl, heterocyclic and heterocycloalkyl in which the heteroatom (s) in the aforementioned heterocyclic parts are chosen from 1 to 4 atoms of oxygen, nitrogen and sulfur and in which the alkyl parts associated with the heterocyclic parts have 1 to 6 atoms of carbon, or else R3 and R4, taken together with the nitrogen atom to which at least one of them is united, can form a pentagonal or hexagonal nitrogen heterocyclic radical;  R9 is defined as R3, except that it cannot be a hydrogen atom; or where RI and R8, taken together, represent a  EMI358.1  hydroxyl-substituted C-Co alkylidene or C-Co'coyliene radical; R5 is chosen from alkyl, alkenyl and alkynyl radicals of 1 to 10 carbon atoms; cycloalkyl and cycloalkylalkyl of 3 to 6 carbon atoms in the ring of the cycloalkyl part and from 1 to 6 carbon atoms in the alkyl parts; phenyl; aralkyl, aralkenyl and aralkynyl in which the aryl part is a phenyl radical and in which the aliphatic part has 1 to 6 carbon atoms;  heteroaryl, heteroaralkyl, heterocyclic and heterocycloalkyl in which the heteroatom (s) of the above-mentioned heterocyclic parts are chosen from 1 to 4 oxygen, nitrogen or sulfur atoms and in which the alkyl parts associated with the heterocyclic parts have 1 to 6 carbon atoms, all substituted or unsubstituted; the aforementioned R5 radicals being optionally substituted with 1 to 3 independently chosen radicals  <Desc / Clms Page number 359>  especially from: Cl-C6-alkyl optionally amino, fluorinated, chlorinated, carboxylated, hydroxylated, or carbamoylated fluoro, chloro or bromo  EMI359.1    - CN;  or phenyl optionally substituted by 1 to 3 fluoro, chloro, bromo, C1-C6-alkyl, -OR3, -NR3R4, - S03R3, -C02R3 or-CONR3R4, where R3, R4 and R9 in these substituents of R5 are such that defined above; or R5 can be combined with  <Desc / Clms Page number 360>    EMI360.1  at another point in the cycle so as to form a condensed heterocyclic or heteroaromatic radical, the cycle of which may contain additional heteroatoms, chosen from 0, N and S; R16 is chosen from alkyl, alkenyl and alkynyl radicals of 1 to 10 carbon atoms; cycloalkyl, cycloalkylalkyl and alkylcycloalkyl of 3 to 6 carbon atoms in the ring of the cycloalkyl part and from 1 to 6 carbon atoms in the alkyl parts; spirocycloalkyl of 3 to 6 carbon atoms; phenyl;  aralkyl, aralkenyl and aralkynyl in which the aryl part is a phenyl radical and the aliphatic part has 1 to 6 carbon atoms; heteroaryl, heteroaralkyl, heterocyclic and heterocycloalkyl in which the heteroatom (s) in the aforementioned heterocyclic parts are chosen from 1 to 4 oxygen, nitrogen or sulfur atoms and the alkyl parts associated with the heterocyclic parts have 1 to 6 carbon atoms, all substituted or unsubstituted and whose substituent (s) with respect to the abovementioned radicals are chosen from amino, mono-, di- and trialcoylamino, hydroxyl, alkoxy, mercapto, alkoylthio, phenylthio, sulfamoyl, amidino, guanidino, nitro, chloro radicals , bromo, fluoro, cyano and carboxyl; and in which the alkyl parts in the abovementioned substituents have 1 to 6 carbon atoms;    EMI360.2  A represents a C-c-alkylene radical in a straight or branched chain R2 represents a hydrogen atom, an anionic charge or a conventional easily removable radical protecting the carboxyl function, being  <Desc / Clms Page number 361>  understood that when R2 represents a hydrogen atom or a protective radical, a counter ion is also present, and  EMI361.1  represents a substituted or unsubstituted heterocyclic, aromatic, mono-, bi- or polycyclic radical comprising at least one nitrogen atom in the ring and united to the radical A by a carbon atom of the ring and comprising a ring nitrogen atom which is quaternized by the radical R5; or a pharmaceutically acceptable salt of this compound.  EMI361.2   148.-Compound according to claim 147, in the formula of which R1 represents a radical  EMI361.3    EMI361.4  and R16 represents a methyl radical. 149.-Compound according to claim 147, in the formula of which RI represents a radical  EMI361.5    R16 represents a methyl radical and the absolute configuration is 5R, 6S, 8R.    150.-Compound according to claim 147, 148 or 149, in the formula of which A represents a radical -CH2- or -CH2CH2- ' 151.- Compound of formula  <Desc / Clms Page number 362>    EMI362.1  where RS represents a hydrogen atom and RI is chosen from the hydrogen atom and the alkyl, alkenyl and alkynyl radicals of 1 to 10 carbon atoms; cycloalkyl and cycloalkylalkyl of 3 to 6 carbon atoms in the ring of the cycloalkyl part and from 1 to 6 carbon atoms in the alkyl parts; phenyl; aralkyl, aralkenyl and aralkynyl in which the aryl part is a phenyl radical and the aliphatic part has 1 to 6 carbon atoms;  heteroaryl, heteroaralkyl, heterocyclic and heterocycloalkyl in which the heteroatom (s) in the aforementioned heterocyclic parts are chosen from 1 to 4 oxygen, nitrogen or sulfur atoms and the alkyl parts associated with the heterocyclic parts have ì to 6 carbon atoms, all substituted or unsubstituted and whose substituent (s) with respect to the abovementioned radicals are independently chosen from Cl-C6-alkyl optionally amino, halogenated, hydroxylated or halogenated carboxylated  EMI362.2    <Desc / Clms Page number 363>    EMI363.1  where, with regard to the abovementioned substituents, the radicals R3 and R4 are independently chosen from the hydrogen atom and the alkyl, alkenyl and alkynyl radicals  <Desc / Clms Page number 364>  from 1 to 10 carbon atoms;  cycloalkyl, cycloalkylalkyl and alkylcycloalkyl of 3 to 6 carbon atoms in the ring of the cycloalkyl part and from 1 to 6 carbon atoms in the alkyl parts; phenyl; aralkyl, aralkenyl and aralkynyl in which the aryl part is a phenyl radical and in which the aliphatic part has 1 to 6 carbon atoms; and heteroaryl, heteroaralkyl, heterocyclic and heterocycloalkyl in which the heteroatom (s) in the aforementioned heterocyclic parts are chosen from 1 to 4 atoms of oxygen, nitrogen and sulfur and in which the alkyl parts associated with the heterocyclic parts have 1 to 6 atoms of carbon, or else R3 and R4, taken together with the nitrogen atom to which at least one of them is united, can form a pentagonal or hexagonal nitrogen heterocyclic radical;  R9 is defined as R3, except that it cannot be a hydrogen atom; or where RI and RS, taken together, represent a  EMI364.1  ene radical C-Co alkylidene or C-Co'coyIidene substituted by hydroxyl; R5 is chosen from alkyl, alkenyl and alkynyl radicals of 1 to 10 carbon atoms; cycloalkyl and cycloalkylalkyl of 3 to 6 carbon atoms in the ring of the cycloalkyl part and from 1 to 6 carbon atoms in the alkyl parts; phenyl; aralkyl, aralkenyl and aralkynyl in which the aryl part is a phenyl radical and in which the aliphatic part has 1 to 6 carbon atoms;  heteroaryl, heteroaralkyl, heterocyclic and heterocycloalkyl in which the heteroatom (s) of the above-mentioned heterocyclic parts are chosen from 1 to 4 oxygen, nitrogen or sulfur atoms and in which the alkyl parts associated with the heterocyclic parts have 1 to 6 carbon atoms, all substituted or unsubstituted; the aforementioned R5 radicals being optionally substituted with 1 to 3 independently chosen radicals  <Desc / Clms Page number 365>  especially among: Cl-C6-alkyl optionally amino, fluorinated, chlorinated, carboxylated, hydroxylated, or carbamoylated fluoro, chloro or bromo  EMI365.1    - CN;  or phenyl optionally substituted by 1 to 3 fluoro, chloro, bromo, C1-C6-alkyl, -OR3, -NR3R4,  EMI365.2  -SO3R3, -C02R3 where R3, R4 and R9 in these substituents of R5 are as defined above; or R5 can be combined with  <Desc / Clms Page number 366>    EMI366.1  at another point in the cycle so as to form a condensed heterocyclic or heteroaromatic radical, the cycle of which may contain additional heteroatoms, chosen from 0, N and S;  R16 is chosen from alkyl, alkenyl and alkynyl radicals of 1 to 10 carbon atoms; cycloalkyl, cycloalkylalkyl and alkylcycloalkyl of 3 to 6 carbon atoms in the ring of the cycloalkyl part and from 1 to 6 carbon atoms in the alkyl parts; spirocycloalkyl of 3 to 6 carbon atoms; phenyl; aralkyl, aralkenyl and aralkynyl in which the aryl part is a phenyl radical and the aliphatic part has 1 to 10 carbon atoms;  heteroaryl, heteroaralkyl, heterocyclic and heterocycloalkyl in which the heteroatom (s) in the aforementioned heterocyclic parts are chosen from 1 to 4 oxygen, nitrogen or sulfur atoms and the alkyl parts associated with the heterocyclic parts have 1 to 6 carbon atoms, all substituted or unsubstituted and whose substituent (s) with respect to the abovementioned radicals are chosen from amino, mono-, di- and trialcoylamino, hydroxyl, alkoxy, mercapto, alkoylthio, phenylthio, sulfamoyl, amidino, guanidino, nitro, chloro radicals , bromo, fluoro, cyano and carboxyl; and in which the alkyl parts in the abovementioned substituents have 1 to 6 carbon atoms; A represents a C1-C6-alkylene radical in a straight or branched chain;  R2 represents a hydrogen atom, an anionic charge or a conventional radical easily  <Desc / Clms Page number 367>  removable protective of the carboxyl function, it being understood that when R2 represents a hydrogen atom or a protective radical, a counter ion is also present, and  EMI367.1  represents a nitrogen heterocyclic radical, mono-, or polycyclic containing 0 to 5 additional heteroatoms chosen between 0, S and N, the heterocyclic radical being united to the radical A by a ring carbon atom and comprising a nitrogen atom of the quaternized ring by the radical R. and this heterocyclic radical being optionally substituted for the carbon atoms of the available ring by 1 to 5 substituents chosen independently from the C1-C4alkyl radicals;  Ci-C -alkylIe substituted by 1 to 3 hydroxyl, amino, Cl-C4-alkylamino, di (Cl-C4) alkylamino, Cl-C4-alkoxy, carboxyl, halo or sulfo radicals, C3-  EMI367.2  C-cycloalkyl -cycloalkyl-Calcium optionally substituted with 1 to 3 substituents mentioned above in connection with the radicals C-C-alkyl Ci-C-alkoxy -alkylIthio -alkylamino di alcoylamino; -C-alkanoyIamino; -C-alkanoyloxy carboxyl; -C-Calcoyl; guanidino; phenyl substituted with 1 to 3 substituents independently chosen from amino, halo, hydroxyl, trifluoromethyl, Cl-C4-alkyl, Cl-C4-alkoxy, Cl-C4-alkylamino, di (Cl-C4) alkylamino, carboxyl and sulfo radicals;  phenyl (Ci-C4) alkyl, the phenyl part of which is optionally substituted with 1 to 3 substituents mentioned above with respect to the phenyl radical  <Desc / Clms Page number 368>  and the alkyl part is optionally substituted with 1 to 3 substituents mentioned above with respect to the C1-C4-alkyl radicals;  and heatheraryl or heteroaralkyl in which the heteroatom (s) are chosen from 1 to 4 atoms 0, S or N and in which the alkyl part associated with the heteroaralkyl radical has 1 to 6 carbon atoms, these heteroaryl and heteroaralkyl radicals being optionally substituted in the heterocyclic part with 1 to 3 substituents independently selected from the hydroxyl, amino, halogen, trifluoromethyl, Cl-C4-alkyl, Cl-C4-alkoxy, Cl-C4-alkylamino, di (Cl-C4) alkylamino, carboxyl and sulfo radicals, and in the alkyl part with 1 to 3 substituents chosen from hydroxyl, amino, Cl-C4-alkylamino, di (Cl-C4) alkylamino, Cl-C4-alkoxy, carboxyl radicals,  halo and sulfo and the heterocyclic radical being optionally substituted for the nitrogen atoms of the ring available by 1 to 3 substituents chosen independently from the C1-C4-alkyl radicals; Cl-C4-alkyl substituted by 1 to 3 hydroxyl, amino, C-C-alkylamino, di (Cl-C4) alkylamino, Cl-C4-alkoxy, carboxyl, halo or sulfo radicals; C3-C6-cycloalkyl; C3-C6-cycloalkyl (Cl-C4) alkyl optionally substituted with 1 to 3 substituents mentioned above with regard to the radicals C1-C4-alkyl;  phenyl, phenyl optionally substituted with 1 to 3 substituents independently chosen from amino, halogen, hydroxyl, trifluoromethyl, Cl-C4-alkyl, Cl-C4-alkoxy, Cl-C4-alkylamino, di (Cl-C4) alkylamino, carboxyl and sulfo; phenyl (C1-C4) alkyl, the phenyl part of which can optionally be substituted with 1 to 3 substituents mentioned above with respect to the phenyl radical and the alkyl part of which can optionally be substituted with 1 to 3 substituents mentioned above with respect to the phenyl radicals Cl-C4-alkyl radicals;  and heteroaryl or  <Desc / Clms Page number 369>  heteroaralkyl in which the heteroatom (s) are chosen from 1 to 4 0, S or N atoms and in which the alkyl part associated with the heteroalkyl radical has 1 to 6 carbon atoms, the heteroaryl and heteroaralkyl radicals being optionally substituted in the heterocyclic part by 1 to 3 substituents chosen independently from the hydroxyl, amino, halogen, trifluoromethyl, Cl-C4-alkyl, Cl-C4alkoxy, C1-C4-alkylamino, di (Cl-C4) alkylamino, carboxyl and sulfo radicals and in the alkyl part by 1 to 3 substituents chosen from hydroxyl, amino, Cl-C4-alkylamino, di (Cl-C4) alkylamino, Cl-C4-alkoxy, carboxyl, halo and sulfo radicals; or a pharmaceutically acceptable salt of this compound.  EMI369.1   152.-Compound according to claim 151, in the formula of which RI represents a radical  EMI369.2    EMI369.3  and R16 represents a methyl radical. 153.-Compound according to claim 151, in the formula of which RI represents a radical  EMI369.4    EMI369.5  Rice is a methyl radical and the absolute configuration is 5R, 6S, 8R.    154.-Compound according to claim 151, 152 or 153, in the formula of which A represents a radical -CH2- or -CH2CH2- ' 155 .-- Compound of formula  <Desc / Clms Page number 370>    EMI370.1  where R8 represents a hydrogen atom and RI is chosen from the hydrogen atom and the alkyl, alkenyl and alkynyl radicals of 1 to 10 carbon atoms; cycloalkyl and cycloalkylalkyl of 3 to 6 carbon atoms in the ring of the cycloalkyl part and from 1 to 6 carbon atoms in the alkyl parts; phenyl; aralkyl, aralkenyl and aralkynyl in which the aryl part is a phenyl radical and the aliphatic part has 1 to 6 carbon atoms;  heteroaryl, heteroaralkyl, heterocyclic and heterocycloalkyl in which the heteroatom (s) in the aforementioned heterocyclic parts are chosen from 1 to 4 oxygen, nitrogen or sulfur atoms and the alkyl parts associated with the heterocyclic parts have 1 to 6 carbon atoms, all substituted or unsubstituted and whose substituent (s) with respect to the abovementioned radicals are independently chosen from Cl-C6-alkyl optionally amino, halogenated, hydroxylated or halogenated carboxylated  EMI370.2    <Desc / Clms Page number 371>    EMI371.1  where, with regard to the abovementioned substituents, the radicals R3 and R4 are independently chosen from the hydrogen atom and the alkyl, alkenyl and alkynyl radicals  <Desc / Clms Page number 372>  from 1 to 10 carbon atoms;  cycloalkyl, cycloalkylalkyl and alkylcycloalkyl of 3 to 6 carbon atoms in the ring of the cycloalkyl part and from 1 to 6 carbon atoms in the alkyl parts; phenyl; aralkyl, aralkenyl and aralkynyl in which the aryl part is a phenyl radical and in which the aliphatic part has 1 to 6 carbon atoms; and heteroaryl, heteroaralkyl, heterocyclic and heterocycloalkyl in which the heteroatom (s) in the aforementioned heterocyclic parts are chosen from 1 to 4 atoms of oxygen, nitrogen and sulfur and in which the alkyl parts associated with the heterocyclic parts have 1 to 6 atoms of carbon, or else R3 and R4, taken together with the nitrogen atom to which at least one of them is united, can form a pentagonal or hexagonal nitrogen heterocyclic radical;  R9 is defined as R3, except that it cannot be a hydrogen atom; or where RI and R8, taken together, represent a  EMI372.1  hydroxyl-substituted C-Co alkylidene or C-Cio'lcoylidene radical; R5 is chosen from alkyl, alkenyl and alkynyl radicals of 1 to 10 carbon atoms; cycloalkyl and cycloalkyl and cycloalkylalkyl of 3 to 6 carbon atoms in the ring of the cycloalkyl part and from 1 to 6 carbon atoms in the alkyl parts; phenyl; aralkyl, aralkenyl and aralkynyl in which the aryl part is a phenyl radical and in which the aliphatic part has 1 to 6 carbon atoms;  heteroaryl, heteroaralkyl, heterocyclic and heterocycloalkyl in which the heteroatom (s) of the abovementioned heterocyclic parts are chosen from 1 to 4 oxygen, nitrogen or sulfur atoms and in which the alkyl parts associated with the heterocyclic parts have 1 to 6 carbon atoms, all substituted or unsubstituted; the aforementioned R5 radicals being optionally substituted by 1  <Desc / Clms Page number 373>  with 3 radicals chosen independently from:  EMI373.1  Cl-C6-alkyl optionally amino, fluorinated, chlorinated, e e, carboxylated, hydroxylated, or carbamoylated fluoro, chloro or bromo  EMI373.2    - CN;  or phenyl optionally substituted with 1 to 3 radicals  EMI373.3  fluoro, chloro, bromo, CI-C6-alkyl, -SO3R3, -C02R3 where R3, R4 and R9 in these substituents of R5 are as defined above; or R5 can be combined with  <Desc / Clms Page number 374>    EMI374.1  at another point in the cycle so as to form a condensed heterocyclic or heteroaromatic radical, which cyclic radical may contain additional heteroatoms, chosen from 0, N and S; R16 is chosen from alkyl, alkenyl and alkynyl radicals of 1 to 10 carbon atoms; cycloalkyl, cycloalkylalkyl and alkylcycloalkyl of 3 to 6 carbon atoms in the ring of the cycloalkyl part and from 1 to 6 carbon atoms in the alkyl parts; spirocycloalkyl of 3 to 6 carbon atoms; phenyl;  aralkyl, aralkenyl and aralkynyl in which the aryl part is a phenyl radical and the aliphatic part has 1 to 6 carbon atoms; heteroaryl, heteroaralkyl, heterocyclic and heterocycloalkyl in which the heteroatom (s) in the aforementioned heterocyclic parts are chosen from 1 to 4 oxygen, nitrogen or sulfur atoms and the alkyl parts associated with the heterocyclic parts have 1 to 6 carbon atoms, all substituted or unsubstituted and whose substituent (s) with respect to the abovementioned radicals are chosen from amino, mono-, di- and trialcoylamino, hydroxyl, alkoxy, mercapto, alkoylthio, phenylthio, sulfamoyl, amidino, guanidino, nitro, chloro radicals , bromo, fluoro, cyano and carboxyl; and in which the alkyl parts in the abovementioned substituents have 1 to 6 carbon atoms;    EMI374.2  A represents a C-c-alkylene radical in straight or branched C R2 represents a hydrogen atom, an anionic charge or a conventional easily removable radical protecting the carboxyl function, being  <Desc / Clms Page number 375>  understood that when R2 represents a hydrogen atom or a protective radical, a counter ion is also present, and  EMI375.1  represents a nitrogen heterocyclic radical, aromatic pentagonal or hexagonal containing 0 to 3 additional heteroatoms chosen between 0, S and N, this heterocyclic radical being optionally substituted for the carbon atoms of the ring available by 1 to 5 substituents chosen independently from the radicals Cl-C -alkyie;  C1-C4-alkyl substituted by 1 to 3 hydroxyl, amino, Cl-C4-alkylamino, di (Cl-C4) alkylamino, Cl-C4-alkoxy, carboxyl, halo or sulfo radicals; C3-  EMI375.2  C-cycloalcoyie; C-C-cycloalkoyl-CalcoyIe optionally substituted with 1 to 3 substituents mentioned above in connection with the C-C-alkyl radicals C-C-alkoxy; -C-alkylIthio amino; -C) alkyllamino; -C-alkanoylamino; -c-alkanoyioxy carboxyl; -C-Calcoyl; guanidino;  phenyl substituted with 1 to 3 substituents independently selected from amino, halo, hydroxyl, trifluoromethyl, Cl-C4-alkyl, Cl-C4-al-coxy, Cl-C4-alkylamino, di (Cl-C4) alkylamino, carboxyl and sulfo phenyl (Cl-C4) alkyl in which the phenyl part is optionally substituted with 1 to 3 substituents mentioned above with respect to the phenyl radical and the alkyl part is optionally substituted with 1 to 3 substituents mentioned above with respect to the radicals Cl -C4-alkyl and heatheraryl or heteroaralkyl in which the heteroatom (s) are chosen  <Desc / Clms Page number 376>  from 1 to 4 atoms 0, S or N and of which the alkyl part associated with the heteroaralkyl radical has 1 to 6 carbon atoms,  these heteroaryl and heteroaralkyl radicals being optionally substituted in the heterocyclic part by 1 to 3 substituents chosen independently from the hydroxyl, amino, halo, trifluoro radicals  EMI376.1  romethyl, Cc-alkyl, Ci-C-alkoxy, Ci-C-alkylamino, di (Ci-C4) alkylamino, carboxyl and sulfo, and in the alkyl part by 1 to 3 substituents chosen from hydroxyl, amino, Ci- C-alkylamino, di (Cl-C4) alkylamino, Cl-C4-alkoxy, carboxyl, halo and sulfo and the heterocyclic radical being optionally substituted for the ring nitrogen atoms available with 1 to 3 substituents chosen independently  EMI376.2  among the C-c-alkyl-alkyl radicals substituted by 1 to 3 hydroxyl, amino, Ci-C-alkylamino, dKC-CJalkylamino, -C-alkoxy, carboxyl, radicals; Ci-Chalogéno or sulfo;  C3-C6-cycloalkyl; C3-C6-cycloalkyl (Cl-C4) alkyl optionally substituted with 1 to 3 substituents mentioned above with respect to the C1-C4-alkyl radicals; phC1-C4nyle; phenyl substituted with 1 to 3 substituents independently chosen from amino, halo, hydroxyl, trifluoromethyl, CI-C4-alkyl, Cl-C4-alkoxy, Cl-C4-alkylamino, di (Cl-C4) alkylamino, carboxyl and sulfo radicals; phenyl (Cl-C4) alkyl, the phenyl part of which can optionally be substituted with 1 to 3 substituents mentioned above with respect to the phenyl radical and the alkyl part of which can optionally be substituted with 1 to 3 substituents mentioned above with respect to the phenyl radicals Cl-C4-alkyl radicals;  and heteroaryl or heteroaralkyl in which the heteroatom (s) are chosen from 1 to 4 atoms 0, S or N and in which the alkyl part associated with the heteroaralkyl radical has 1 to 6 carbon atoms, the heteroaryl and heteroaralkyl radicals being optional-  <Desc / Clms Page number 377>  Lement substituted in the heterocyclic part by 1 to 3 substituents chosen independently from the hydroxyl, amino, halo, trifluoromethyl, C C4-alkyl, Cl-C4-alkoxy, Cl-C4-alkylamino, di (C1-C4) alkylamino, carboxyl radicals and sulfo and in the alkyl part with 1 to 3 substituents chosen from hydroxyl, amino, C1-C4-alkylamino, di (ClC4) alkylamino, CI-C4-alkoxy, carboxyl, halo and sulfo radicals; or a pharmaceutically acceptable salt of this compound.    156. Compound according to claim 155, in the formula of which the heterocyclic radical  EMI377.1  is optionally substituted on the ring nitrogen or carbon atoms available with up to 5 (lower) alkyl radicals chosen independently.  EMI377.2   157.-Compound according to Claim 156, in the formula of which A represents a radical -CH-, - 158.-Compound according to Claim 155, 156 or 157, in the formula of which Rl represents a radical  EMI377.3  R16 represents a methyl radical and the absolute configuration is 5R, 6S, 8R.    159.-Compound of formula  <Desc / Clms Page number 378>    EMI378.1  where R8 represents a hydrogen atom and RI is chosen from the hydrogen atom and the alkyl, alkenyl and alkynyl radicals of 1 to 10 carbon atoms; cycloalkyl and cycloalkylalkyl of 3 to 6 carbon atoms in the ring of the cycloalkyl part and from 1 to 6 carbon atoms in the alkyl parts; phenyl; aralkyl, aralkenyl and aralkynyl in which the aryl part is a phenyl radical and the aliphatic part has 1 to 6 carbon atoms;  heteroaryl, heteroaralkyl, heterocyclic and heterocycloalkyl in which the heteroatom (s) in the aforementioned heterocyclic parts are chosen from 1 to 4 oxygen, nitrogen or sulfur atoms and the alkyl parts associated with the heterocyclic parts have 1 to 6 carbon atoms, all substituted or unsubstituted and whose substituent (s) with respect to the abovementioned radicals are independently chosen from Cl-C6-alkyl optionally amino, halogenated, hydroxylated or halogenated carboxylated  EMI378.2    <Desc / Clms Page number 379>    EMI379.1  where, with regard to the abovementioned substituents, the radicals R3 and R4 are independently chosen from the hydrogen atom and the alkyl, alkenyl and alkynyl radicals  <Desc / Clms Page number 380>  from 1 to 10 carbon atoms;  cycloalkyl, cycloalkylalkyl and alkylcycloalkyl of 3 to 6 carbon atoms in the ring of the cycloalkyl part and from 1 to 6 carbon atoms in the alkyl parts; phenyl; aralkyl, aralkenyl and aralkynyl in which the aryl part is a phenyl radical and in which the aliphatic part has 1 to 6 carbon atoms; and heteroaryl, heteroaralkyl, heterocyclic and heterocycloalkyl in which the heteroatom (s) in the aforementioned heterocyclic parts are chosen from 1 to 4 atoms of oxygen, nitrogen and sulfur and in which the alkyl parts associated with the heterocyclic parts have 1 to 6 atoms of carbon, or else R3 and R4, taken together with the nitrogen atom to which at least one of them is united, can form a pentagonal or hexagonal nitrogen heterocyclic radical;  R9 is defined as R3, except that it cannot be a hydrogen atom; or where Rl and R, taken together, represent a  EMI380.1  hydroxyl-substituted C-Co alkylidene or C-CosIcoyIidene radical; R5 is chosen from alkyl, alkenyl and alkynyl radicals of 1 to 10 carbon atoms; cycloalkyl and cycloalkyl and cycloalkylalkyl of 3 to 6 carbon atoms in the ring of the cycloalkyl part and from 1 to 6 carbon atoms in the alkyl parts; phenyl; aralkyl, aralkenyl and aralkynyl in which the aryl part is a phenyl radical and in which the aliphatic part has 1 to 6 carbon atoms;  heteroaryl, heteroaralkyl, heterocyclic and heterocycloalkyl in which the heteroatom (s) of the above-mentioned heterocyclic parts are chosen from 1 to 4 oxygen, nitrogen or sulfur atoms and in which the alkyl parts associated with the heterocyclic parts have 1 to 6 carbon atoms, all substituted or unsubstituted; the aforementioned R5 radicals being optionally substituted by 1  <Desc / Clms Page number 381>  with 3 radicals independently chosen from: Cl-C6-alkyl optionally amino, fluorinated, chlorinated, carboxylated, hydroxylated, or carbamoylated fluoro, chloro or bromo  EMI381.1    - CN;  or phenyl optionally substituted with 1 to 3 fluoro, chloro, bromo, Cl-C6-alkyl, -OR3, -NR3R4, - S03R3, -C02R3 or-CONR3R4, where R3, R4 and R9 in these substituents of R5 are such that defined above; or R5 can be combined with  <Desc / Clms Page number 382>    EMI382.1  at another point in the cycle so as to form a condensed heterocyclic or heteroaromatic radical, the cycle of which may contain additional heteroatoms, chosen from 0, N and S;  R16 is chosen from alkyl, alkenyl and alkynyl radicals of 1 to 10 carbon atoms; cycloalkyl, cycloalkylalkyl and alkylcycloalkyl of 3 to 6 carbon atoms in the ring of the cycloalkyl part and from 1 to 6 carbon atoms in the alkyl parts; spirocycloalkyl of 3 to 6 carbon atoms; phenyl; aralkyl, aralkenyl and aralkynyl in which the aryl part is a phenyl radical and the aliphatic part has 1 to 10 carbon atoms;  heteroaryl, heteroaralkyl, heterocyclic and heterocycloalkyl in which the heteroatom (s) in the aforementioned heterocyclic parts are chosen from 1 to 4 oxygen, nitrogen or sulfur atoms and the alkyl parts associated with the heterocyclic parts have 1 to 6 carbon atoms, all substituted or unsubstituted and whose substituent (s) with respect to the abovementioned radicals are chosen from amino, mono-, di- and trialcoylamino, hydroxyl, alkoxy, mercapto, alkoylthio, phenylthio, sulfamoyl, amidino, guanidino, nitro, chloro radicals , bromo, fluoro, cyano and carboxyl; and in which the alkyl parts in the abovementioned substituents have 1 to 6 carbon atoms; A represents a Ci-Ce-alkyl radical in a straight or branched chain;  R2 represents a hydrogen atom, an anionic charge or an easily removable conventional radical protecting the carboxyl function, being  <Desc / Clms Page number 383>  understood that when R2 represents a hydrogen atom or a protective radical, a counter ion is also present, and  EMI383.1  represents a radical chosen between  EMI383.2  where R6, R7 and R10 are independently selected from  EMI383.3  hydrogen and C1-C-alkyl radicals C4-alkyl substituted by hydroxyl, Cl-C4-alkylamino, di (Cl-C4-alkyl) amino, Cl-C4-alkoxy, amino, sulfo, carboxy and halogen ; -C-cycloalkyl--C-alkoxy Ci-C-alkylIthio -alkoyIamino di (Cl-C4alkoyl) amino -C-alkanoyIamino alkanoyioxy -C-C-alkoxy;  Camidino; guanidino; phenyl, phenyl substituted by one, two or three amino, halo, hydroxyl, trifluoromethyl radicals; C1-C4-alkyl or C1-C4-alkoxy; phenyl (Cl-C4) alkyl in which the phenyl part can optionally be substituted by 1 to 3 substituents mentioned above with respect to the phenyl radical and the alkyl part can optionally be substituted by 1 to 3 radicals mentioned above with regard to the radicals Cl-C4-alkyl;  and heteroaryl or heteroaralkyl in which the heteroatom (s) in the aforementioned heterocyclic parts are chosen from 1 to 4 oxygen, nitrogen or sulfur atoms and the part  <Desc / Clms Page number 384>  alkyl associated with the heteroaralkyl part has 1 to 6 carbon atoms, or else where two of R6, R7 and R10, taken together, can represent a condensed saturated carbocyclic radical, a condensed aromatic carbocyclic radical, a condensed non-aromatic heterocyclic radical or a condensed heteroaromatic radical, which condensed rings are optionally substituted with 1 or 2 of the substituents defined above with respect to R6, R7 and RIO;      EMI384.1  (b) -D ¯5 "N el there is N or E R 5 e 1 N el J 1 3  EMI384.2  0 optionally substituted on a carbon atom by 1 to 3 substituents chosen independently from the C1-C4-alkyl radicals; Cl-C4-alkyl substituted by hydroxyl, Ci-C-alkylamino, di (Cl-C4-alkyl) amino, Cl-C4-alkoxy, amino, sulfo, carboxyl and halo; C3-C6-cycloalkyl;  Cl-C4-alkoxy; Cl-C4-alkylthio; amino; Cl-C4-alkyllamino; di (Cl-C4-alkyl) amino; halo; C1-C4-alkanoylamino; Cl-C4-alkanoyloxy; carboxyl; -C02-Cl-C4-alkyl; hydroxyl; amidino; guanidino; phenyl, phenyl substituted by one, two or three amino, halo, hydroxyl, trifluoromethyl radicals; Cl-C4-alkyl or Cl-C4-alkoxy; phenyl (Cl-C4) alkyl of which the part  <Desc / Clms Page number 385>  phenyl may optionally be substituted with 1 to 3 substituents mentioned above with respect to the phenyl radical and the alkyl part may optionally be substituted with 1 to 3 radicals mentioned above with respect to the C1-C4-alkyl radicals;  and heteroaryl or heteroaralkyl in which the heteroatom (s) in the aforementioned heterocyclic parts are chosen from 1 to 4 oxygen, nitrogen or sulfur atoms and the alkyl part associated with the heteroaralkyl part has 1 to 6 carbon atoms, or optionally substituted to form a carbocyclic, heterocyclic or  EMI385.1  condensed heteroaromatic optionally substituted by 1 or 2 of the substituents defined above  EMI385.2  (c) R5 R'R 1 eN r s k N '/ ....... -  EMI385.3  optionally substituted on a carbon atom by 1 or 2 substituents chosen independently from the C1-C4-alkyl radicals; Cl-C4-alkyl substituted by hydroxyl, Cl-C4-alkylamino, di (Cl-C4-alkyl) amino, Cl-C4-alkoxy, amino, sulfo, carboxyl and halo; C3-C6-cycloalkyl; Cl-C4-alkoxy; Cl-C4-alkylthio; amino; Cl-C4-alkyllamino; di (Cl-C4-alkyl) amino; halo; C1-C4-alkanoylamino; Cl-C4-alkanoyloxy; carboxyl; -C02-  <Desc / Clms Page number 386>  C1-C4-alkyl; hydroxyl; amidino; guanidino; phenyl, phenyl substituted by one, two or three amino, halo, hydroxyl, trifluoromethyl radicals;  C1-C4-alkyl or CI -C4-alkoxy phenyl (Ci-C4) alkyl in which the phenyl part can optionally be substituted with 1 to 3 substituents mentioned above in connection with the phenyl radical and the alkyl part can optionally be substituted with 1 to 3 substituents mentioned above in connection with the C1-C4-alkyl radicals; and heteroaryl or heteroaralkyl in which the heteroatom (s) in the aforementioned heterocyclic parts are chosen from 1 to 4 oxygen, nitrogen or sulfur atoms and the alkyl part associated with the heteroaralkyl part has 1 to 6 carbon atoms, or optionally substituted to form a condensed carbocyclic, heterocyclic or heteroaromatic radical optionally substituted by 1 or 2 of the substituents defined above;    EMI386.1  (d) R5. el N "N /" R5 R5 î (N, (N'Y n Il N) J,  EMI386.2  optionally substituted on a carbon atom by 1 substituent chosen independently from the radicals ¯5 R5Cl-C4-alkyl; Cl-C4-alkyl substituted by hydroxyl, Cl-C4-alkylamino, di (Cl-C4-alkyl) amino, C1-C4-alkoxy,  <Desc / Clms Page number 387>  amino, sulfo, carboxyl and halo; C3-C6-cycloalkyl; Ci-C-alkoxy; C1-C4-alkylthio; amino; CI-C4-alkylamino; di (CI-C4-alkyl) amino; halo; CI-C4-alkanoylamino; Cl-C4-alkanoyloxy; carboxyl; -CO-C1-C4-alkyl; hydroxyl; amidino; guanidino; phenyl, phenyl substituted by one, two or three amino, halo, hydroxyl, trifluoromethyl radicals;  C1-C4-alkyl or Cl -C4-alkoxy; phenyl (Ci-C4) alkyl in which the phenyl part can optionally be substituted by 1 to 3 substituents mentioned above with respect to the phenyl radical and the alkyl part can optionally be substituted by 1 to 3 substituents mentioned above with respect to the radicals Cl-C4-alkyl; and heteroaryl or heteroaralkyl in which the heteroatom (s) in the aforementioned heterocyclic parts are chosen from 1 to 4 oxygen, nitrogen or sulfur atoms and the alkyl part associated with the heteroaralkyl part has 1 to 6 carbon atoms;  EMI387.1  (e) or 6, ---- K-R, or  EMI387.2  where X represents 0, S or NR where R represents a Ci-C-alkyl--C-alkyl radical substituted by 1 to 3 hydroxyl, amino, Ci-C-alkylamino di (Cl-C4) alkylamino radicals;  C1-C-alkoxy carboxyl; halo or tallow -cycloalkyl -C) alkyl optionally substituted with 1 to 3 substituents mentioned above with regard to the radicals C 4 -C K-Ralcoyle; phenyl; phenyl substituted with 1 to 3 substituents independently chosen from amino, halo, hydroxyl, trifluoromethyl, Ci-C4-alkyl radicals,  <Desc / Clms Page number 388>    C-C-alkoxy, C1-C4-alkylamino, di (Cl-C4) alkylamino, carboxyl and sulfo;  phenyl (Ci-C4) alkyl, the phenyl part of which can optionally be substituted with 1 to 3 substituents mentioned above with respect to the phenyl radical and the alkyl part of which can optionally be substituted with 1 to 3 substituents mentioned above with respect to the radicals Cc -alkyie;    and heatheraryl and heteroaralkyl in which the heteroatom (s) are chosen from 1 to 4 atoms 0, S or N and the alkyl part associated with the heteroaralkyl radical has 1 to 6 carbon atoms, these heteroaryl and heteroaralkyl radicals being optionally substituted in the heterocyclic part by 1 to 3 substituents independently chosen from hydroxyl, amino, halo, trifluoromethyl, Cl-C4-alkyl, Cl-C4-alkoxy, CI-C4-alkylamino, di (Cl-C4) alkylamino, carboxyl and sulfo radicals, and in the alkyl part with 1 to 3 substituents chosen from hydroxyl, amino, Cl-C4-alkylamino, di (Cl-C4) alkylamino, Cl-C4alkoxy, carboxyl, halo and sulfo radicals,  this radical being optionally substituted on a carbon atom by 1 or more substituents chosen independently from Cl-C4-alkyl radicals: C1-C4-substituted alkyl hydroxyl, Cl-C4-alkylamino, di (Cl-C4-alkylamino, Cl- C4-alkoxy, amino, sulfo; carboxyl or halo; C3-C6-cycloalkyl; Cl-C4-alkoxy; C1-C4-alkylthio, amino; Cl-C4-alkylamino; di (Cl-C4-alkyl) amino; halogen; Cl-C4-alkanoylamino; Cl-C4-alkanoyloxy; carboxyl; -CO "Cl-C4-alkyl; hydroxyl; amidino; guanidino; phenyl; phenyl substituted by one, two or three amino, halo, hydroxyl, trifluoromethyl radicals;  C1-C4-alkyl or Cl-C4-alkoxy; phenyl (Cl-C4) alkyl, the phenyl part of which can optionally be substituted with 1 to 3 substituents mentioned above with respect to the phenyl radical and the alkyl part of which can optionally  <Desc / Clms Page number 389>  be substituted by 1 to 3 substituents mentioned above in connection with the C 1 -C 4 alkyl radicals; and heteroaryl and heteroaralkyl in which the heteroatom (s) of the abovementioned heterocyclic parts are chosen from 1 to 4 oxygen, nitrogen or sulfur atoms and the alkyl part associated with the heteroaralkyl part has 1 to 6 carbon atoms, or optionally substituted to form a condensed carbocyclic, heterocyclic or heteroaromatic radical optionally substituted by 1 or 2 of the substituents defined above;    EMI389.1  (f) 6 -'- il "XK zo e R5 ------ x N NF% - ,, ej ou [; 1 'R5¯1' 5" '- t' "iî '" trr -'x 'J  EMI389.2  where X represents 0, S or NR where R represents a Cl-C4-alkyl radical; Cl-C4-alkyl substituted with 1 to 3 hydroxyl, amino, Cl-C4-alkylamino radicals; di (Cl-C4) alkylamino;  Cl-C4-alkoxy; carboxyl; halo or sulfo; C3-C6-cycloalkyl; Cg-Ce-cycloalkylKCi-C) - alkyl optionally substituted with 1 to 3 substituents mentioned above with regard to the radicals C1-C4alkyl; phenyl; phenyl substituted with 1 to 3 substituents independently chosen from amino, halo, hydroxyl, trifluoromethyl, Cl-C4-alkyl, Cl-C4-alkoxy, Cl-C4-alkylamino, di (Cl-C4) alkylamino, carboxyl and sulfo radicals;  phenyl (Cl-C4) alkyl of which the part  <Desc / Clms Page number 390>  phenyl may optionally be substituted with 1 to 3 substituents mentioned above with respect to the phenyl radical and the alkyl part of which may optionally be substituted with 1 to 3 substituents mentioned above with respect to the C1-C4-alkyl radicals;  and heatheraryl and heteroaralkyl in which the heteroatom (s) are chosen from 1 to 4 atoms 0, S or N and the alkyl part associated with the heteroaralkyl radical has 1 to 6 carbon atoms, these heteroaryl and heteroaralkyl radicals being optionally substituted in the heterocyclic part by 1 to 3 substituents chosen independently from the hydroxyl, amino, halogen, trifluoromethyl, Cl-C4-alkyl, Cl-C4alkoxy, Cl-C4-alkylamino, di (Cl-C4) alkylamino, carboxyl and sulfo radicals, and in the alkyl part with 1 to 3 substituents chosen from hydroxyl, amino, Cl-C4-alkylamino, di (Cl-C4) alkylamino, Cl-C4alkoxy, carboxyl, halo and sulfo radicals,  this heteroaromatic radical being optionally substituted on a carbon atom by a substituent chosen from C1-C4-alkyl radicals; Cl-C4-alkyl substituted by  EMI390.1  hydroxyl, Cl-C4-alkylamino, di (Cl-C4-alkyl) amino, Cl-C4-alkoxy, amino, sulfo, carboxyl or halo; C3C6-cycloalkyl; Cl-C4-alkoxy; Cl-C4-alkylthio, amino; Cl-C4-alkyllamino; di (Cl-C4-alkyl) amino; halo; ClC4-alkyllamino;  Cl-C4-alkanoyloxy; carboxyl; -COp-C1C4-alkyl; hydroxyl; amidino; guanidino; phenyl; phenyl substituted with one, two or three amino, halo, hydroxyl, trifluoromethyl, Cl-C4-alkyl or Cl-C4-alkoxy radicals; phenyl (Cl-C4) alkyl, the phenyl part of which can optionally be substituted with 1 to 3 substituents mentioned above with respect to the phenyl radical and the alkyl part of which can optionally be substituted with 1 to 3 substituents mentioned above with respect to the radicals Cc -alkyie;  and hetero-  <Desc / Clms Page number 391>  aryl and heteroaralkyl in which the heteroatom (s) of the aforementioned heterocyclic parts are chosen from 1 to 4 oxygen, nitrogen or sulfur atoms and the alkyl part associated with the heteroalkyl part  EMI391.1  has 1 to 6 carbon atoms; and  EMI391.2  (g). --j.- .. -R'j sel- K - = - K .------ 1 ¯5 ze N N.  EMI391.3  where R represents a Cl-C4-alkyl radical; Cl-C4-alkyl substituted by 1 to 3 hydroxyl, amino, Cl-C4- radicals 5 Ralcoylamino, di (Cl-C4) alkylamino, Cl-C4-alkoxy, carboxyl, halo or sulfo; C3-C6-cyclo) alkyl;  C3C6-cycloalkyl (Cl-C4) alkyl optionally substituted with 1 to 3 substituents mentioned above in connection with the C1-C4-alkyl radicals: phenyl; phenyl substituted with 1 to 3 substituents independently selected from amino, halo, hydroxyl, trifluoromethyl,  <Desc / Clms Page number 392>  C1-C4-alkyl, C1-C4-alkoxy, C1-C-alkylamino, fi (C1-C4) alkylamino, carboxyl and sulfo; phenyl (Cl-C4) - alkyl in which the phenyl part can optionally be substituted by 1 to 3 substituents mentioned above with respect to the phenyl radical and in which the alkyl part can optionally be substituted by 1 to 3 substituents mentioned above in connection with the radical ClC4-alkyl radicals;  and heatheraryl and heteroaralkyl in which the heteroatom (s) are chosen from 1 to 4 atoms 0, S or N and the alkyl part associated with the heteroaralkyl radical has 1 to 6 carbon atoms, these heteroaryl and heteroaralkyl radicals being optionally substituted in the heterocyclic part by 1 to 3 substituents independently chosen from hydroxyl, amino, halo, trifluoromethyl, ClC4-alkyl, CC-alkoxy, Cl-C4-alkylamino, di (Cl-C4) -alkylamino, carboxyl and sulfo radicals, and in the alkyl part by 1 to 3 substituents chosen from hydroxyl, amino, Cl-C4-alkylamino, di (Cl-C4) alkylamino, Cl-C4-alkoxy, carboxyl, halo and sulfo radicals, or a pharmaceutically acceptable salt of this compound.    160. A compound according to claim 159, in the formula of which  EMI392.1  represents a radical chosen from  <Desc / Clms Page number 393>    EMI393.1  where R5 represents a Cl-C6-alkyl radical and R6, R7 and RIO each independently represent a hydrogen atom or a Cl-C4-alkyl radical:  EMI393.2  (b) E5 1 1eN 'p, p F% 5 la R5  EMI393.3  where R5 represents a Cl-C6-alkyl radical and the available ring carbon atoms are optionally substituted by 1 to 3 Cl-C4-alkyl radicals chosen independently;  EMI393.4    <Desc / Clms Page number 394>    EMI394.1  R5 i &commat; 'e N-:  'N rl5 N u L> l, 1 y 1 N 5 R5 R N e 1 e 1 or -e Y .. lN)  EMI394.2  where R5 represents a Cl-C6-alkyl radical and the available ring carbon atoms are optionally substituted by 1 or 2 Cl-C4-alkyl radicals chosen independently;  EMI394.3  (d) N; Yes . "K" ze -!), Fes  EMI394.4  where R5 represents a Cl-C6-alkyl radical and an available ring carbon atom is optionally  <Desc / Clms Page number 395>    EMI395.1  substituted by a C-c-alkyl radical (e)  EMI395.2  -R N-RS N-RS - "'" -r X "  EMI395.3  where R5 represents a Cl-C6-alkyl radical, X represents 0, S or NR where R represents a Cl-C4-alkyl radical and one or more available ring carbon atoms are optionally substituted by Cl-C4alkyl radicals; (f)  EMI395.4  undue 1 \ -R e 'N "-> e N' J  EMI395.5  where R5 represents a Cl-C6-alkyl radical, X represents 0, S or NR where R represents a Cl-C4-alkyl radical and one or more available ring carbon atoms are optionally substituted by Cl-C4alkyl radicals; and  <Desc / Clms Page number 396>    EMI396.1  (g) 6 5 - = - R ".. zo kyJ-R .. "-, ') -----' '" -Z <R e -K ---- rR K ---- K-R f in  EMI396.2  where R5 represents a Cl-C6-alkyl radical and R represents a Cl-C4-alkyl radical. 161.- Compound according to claim 160, in the formula of which RI represents a radical  EMI396.3    EMI396.4  and R16 represents a methyl radical. 162.-Compound according to claim 160, in the formula of which RI represents a radical  EMI396.5    <Desc / Clms Page number 397>   R5R16 represents a methyl radical and the absolute configuration is 5R, 6S, 8R.    163. Compound according to claim 159, 160, 161 or 162, in the formula of which A represents a radical -CH2-or-CH2CH2-.    164.-Compound of formula  EMI397.1  where A represents a C-c-alkylene radical in a straight or branched chain; R2 represents a hydrogen atom, an anionic charge or a conventional radical which is easy to remove protective of the carboxyl function, it being understood that when R2 represents a hydrogen atom or a protective radical, a counter ion is also present; and  EMI397.2  represents a radical of formula (a)  EMI397.3  where R5 represents a C1-C4-alkyl radical and R6 represents a hydrogen atom or a C1-C4-alkyl radical;  <Desc / Clms Page number 398>    EMI398.1  where R5 represents a C1-C4-alkyl radical and R6 and R7 represent hydrogen atoms or C1-C4-alkyl radicals;    EMI398.2  where R5 represents a Cl-C4-alkyl radical and R represents a Cl-C4-alkyl or phenyl (CI-C4) alkyl radical; (d)  EMI398.3  where R5 represents a C1-C4-alkyl radical and R6 represents a C1-C4-alkyl radical;  EMI398.4  where R5 represents a C1-C4-alkyl radical and R represents a C1-C4-alkyl radical; or  <Desc / Clms Page number 399>    EMI399.1  where R5 represents a Cl-C4-alkyl radical; or a pharmaceutically acceptable salt of this compound.    165 .-- Compound of formula  EMI399.2  where A represents a Ci-Ce-alkyl radical in a straight or branched chain; R2 represents a hydrogen atom, an anionic charge or a conventional radical which is easy to remove protective of the carboxyl function, it being understood that when R2 represents a hydrogen atom or a protective radical, a counter ion is also present; and  EMI399.3  represents a radical of formula  EMI399.4    <Desc / Clms Page number 400>    EMI400.1    <Desc / Clms Page number 401>    EMI401.1  or a pharmaceutically acceptable salt of this compound.    166.-Compound of formula  EMI401.2  where R2 represents a hydrogen atom, an anionic charge or a conventional radical which is easy to remove protective of the carboxyl function, it being understood that when R2 represents a hydrogen atom or a protective radical, a counter ion is also present; or a pharmaceutically acceptable salt of this compound.    167.-Compound of formula  EMI401.3  where R2 represents a hydrogen atom, an anionic charge or a conventional radical which is easy to remove protective of the carboxyl function, it being understood that when R2 represents a hydrogen atom or a  <Desc / Clms Page number 402>  protective radical, a counter ion is also present; or a pharmaceutically acceptable salt of this compound.    168.-Compound of formula  EMI402.1  where R2 represents a hydrogen atom, an anionic charge or a conventional radical which is easy to remove protective of the carboxyl function, it being understood that when R2 represents a hydrogen atom or a protective radical, a counter ion is also present; or a pharmaceutically acceptable salt of this compound.    169.-Compound of formula  EMI402.2  where R2 represents a hydrogen atom, an anionic charge or a conventional radical which is easy to remove protective of the carboxyl function, it being understood that when R2 represents a hydrogen atom or a protective radical, a counter ion is also present; or a pharmaceutically acceptable salt of this compound.    170 .-- Compound of formula  <Desc / Clms Page number 403>    EMI403.1  where R2 represents a hydrogen atom, an anionic charge or a conventional radical which is easy to remove protective of the carboxyl function, it being understood that when R2 represents a hydrogen atom or a protective radical, a counter ion is also present; or a pharmaceutically acceptable salt of this compound.    171.- Compound of formula  EMI403.2  where R2 represents a hydrogen atom, an anionic charge or a conventional radical which is easy to remove protective of the carboxyl function, it being understood that when R2 represents a hydrogen atom or a protective radical, a counter ion is also present; or a pharmaceutically acceptable salt of this compound.    172.- Compound of formula  <Desc / Clms Page number 404>    EMI404.1  where R2 represents a hydrogen atom, an anionic charge or a conventional radical which is easy to remove protective of the carboxyl function, it being understood that when R2 represents a hydrogen atom or a protective radical, a counter ion is also present; or a pharmaceutically acceptable salt of this compound.    173.- Compound of formula  EMI404.2  where R2 represents a hydrogen atom, an anionic charge or a conventional radical which is easy to remove protective of the carboxyl function, it being understood that when R2 represents a hydrogen atom or a protective radical, a counter ion is also present; or a pharmaceutically acceptable salt of this compound.    174.-Compound of formula  EMI404.3    <Desc / Clms Page number 405>  where R2 represents a hydrogen atom, an anionic charge or a conventional radical which is easy to remove protective of the carboxyl function, it being understood that when R2 represents a hydrogen atom or a protective radical, a counter ion is also present; or a pharmaceutically acceptable salt of this compound.    175 .-- Compound of formula  EMI405.1  where R2 represents a hydrogen atom, an anionic charge or a conventional radical which is easy to remove protective of the carboxyl function, it being understood that when R2 represents a hydrogen atom or a protective radical, a counter ion is also present; or a pharmaceutically acceptable salt of this compound.    176.-Compound of formula  EMI405.2  where R2 represents a hydrogen atom, an anionic charge or a conventional radical which is easy to remove protective of the carboxyl function, it being understood that when R2 represents a hydrogen atom or a protective radical, a counterion is also  <Desc / Clms Page number 406>  present; or a pharmaceutically acceptable salt of this compound.    177.-Compound of formula  EMI406.1  where R2 represents a hydrogen atom, an anionic charge or a conventional radical which is easy to remove protective of the carboxyl function, it being understood that when R2 represents a hydrogen atom or a protective radical, a counter ion is also present; or a pharmaceutically acceptable salt of this compound.  EMI406.2   178.-Compound of formula 03 r 'E 1-2 1' - - -----? "CODR-3 0-3 where R2 represents a hydrogen atom, an anionic charge or a conventional radical which is easy to remove protective of the carboxyl function, it being understood that when R2 represents a hydrogen atom or a protective radical, a counter ion is also present; or a pharmaceutically acceptable salt of this compound.    179.-Compound of formula  <Desc / Clms Page number 407>    EMI407.1  where R2 represents a hydrogen atom, an anionic charge or a conventional radical which is easy to remove protective of the carboxyl function, it being understood that when R2 represents a hydrogen atom. or a protective radical, a counter ion is also present; or a pharmaceutically acceptable salt of this compound.    180 .-- Compound of formula  EMI407.2  where R2 represents a hydrogen atom, an anionic charge or a conventional radical which is easy to remove protective of the carboxyl function, it being understood that when R2 represents a hydrogen atom or a protective radical, a counter ion is also present; or a pharmaceutically acceptable salt of this compound.    181.-Compound of formula  <Desc / Clms Page number 408>    EMI408.1  where R2 represents a hydrogen atom, an anionic charge or a conventional radical which is easy to remove protective of the carboxyl function, it being understood that when R2 represents a hydrogen atom or a protective radical, a counter ion is also present; or a pharmaceutically acceptable salt of this compound.    182.-Compound of formula  EMI408.2  where R2 represents a hydrogen atom, an anionic charge or a conventional radical which is easy to remove protective of the carboxyl function, it being understood that when R2 represents a hydrogen atom or a protective radical, a counter ion is also present; or a pharmaceutically acceptable salt of this compound.    183.-Compound of formula  <Desc / Clms Page number 409>    EMI409.1  where R2 represents a hydrogen atom, an anionic charge or a conventional radical which is easy to remove protective of the carboxyl function, it being understood that when R2 represents a hydrogen atom or a protective radical, a counter ion is also present; or a pharmaceutically acceptable salt of this compound.    184.-Compound of formula  EMI409.2  where R2 represents a hydrogen atom, an anionic charge or a conventional radical which is easy to remove protective of the carboxyl function, it being understood that when R2 represents a hydrogen atom or a protective radical, a counter ion is also present; or a pharmaceutically acceptable salt of this compound.    185 .-- Compound of formula  <Desc / Clms Page number 410>    EMI410.1  where R2 represents a hydrogen atom, an anionic charge or a conventional radical which is easy to remove protective of the carboxyl function, it being understood that when R2 represents a hydrogen atom or a protective radical, a counter ion is also present; or a pharmaceutically acceptable salt of this compound.    186 .-- Compound of formula  EMI410.2  where R2 represents a hydrogen atom, an anionic charge or a conventional radical which is easy to remove protective of the carboxyl function, it being understood that when R2 represents a hydrogen atom or a protective radical, a counter ion is also present; or a pharmaceutically acceptable salt of this compound.    187 .-- Compound of formula  <Desc / Clms Page number 411>    EMI411.1  where R2 represents a hydrogen atom, an anionic charge or a conventional radical which is easy to remove protective of the carboxyl function, it being understood that when R2 represents a hydrogen atom or a protective radical, a counter ion is also present; or a pharmaceutically acceptable salt of this compound.