BE897086A - NEW CARBAPENEM CLASS PRODUCTS AND THEIR APPLICATION AS ANTIBIOTICS - Google Patents

Description

       

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    DESCRIPTIVE MEMORY
 EMI1.1
 FILED IN SUPPORT OF PATENT FOR THE INVENTION OF AN APPLICATION FORMED BY
BRISTOL-MYERS COMPANY for New products from the carbapenem class and their application as antibiotics.
 EMI1.2
 



  Patent applications in the United States of America NO 652 of June 18, 1982 and NO 690 of June 7, 1983 in favor of C. U. KIM and P. F. MISCO, Jr.

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   The subject of the present invention is new antibiotics from the carbapenem class in which the substituent in position 2 has the formula:
 EMI2.1
 in which :
A represents a cyclohexylene, cyclopentylene or alkylene radical with a straight or branched chain; -
R5 represents either: (a) an optionally substituted, aliphatic, cycloaliphatic, cycloaliphatic-aliphatic, aryl, araliphatic, heteroaryl, heteroaraliphatic, heterocyclyl or hetero-cyclylaliphatic radical; or (b) a divalent phenylene radical or a C1-C4 alkylene group
C4 linked to the nitrogen atom, so as to form a bridged polycyclic ring;
 EMI2.2
 and
 EMI2.3
 represents a non-aromatic heterocycle containing a quaternized nitrogen atom.



  We know from the technical literature, a large number of derivatives

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 of ss-lactam containing a carbapenem nucleus
 EMI3.1
 These carbapenem derivatives are known to have some utility as anti-bacterial agents and / or ss-lactamase inhibitors.



   The initial carbapenems compounds are natural products such as thienamycin of formula:
 EMI3.2
 obtained by fermentation of Streptomyces cattleya (cf. United States patent No. 3,950,357).



  Thienamycin is an antibiotic with an exceptionally powerful broad spectrum which has a notable activity vis-à-vis a large number of species of the family of Pseudomonas, organisms which are known to be known to be resistant to antibiotics based on ss- lactam.



   Other natural products containing the carbapenem nucleus consist of derivatives of olivanic acid such as the antibiotic MM 13902 of formula:
 EMI3.3
 described in US Patent No. 4,113,856, the antibiotic MM 17880 of formula:
 EMI3.4
 described in U.S. Patent No. 4. 162-304, the antibiotic MM 4550A of formula:

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 EMI4.1
 described in US Patent No. 4,172,129 and the antibiotic 890A9 of the formula:
 EMI4.2
 described in U.S. Patent No. 4,264,735.



  In addition to these natural products, there is known from United States patent No. 4,264,734 the deacetylated compound 890ais having the formula:
 EMI4.3
 which is prepared by an enzymatic deacylation reaction of the corresponding N-acetylated compound.



  Various derivatives of olivanic acids existing in their natural state have also been obtained by synthesis, for example the compounds of formula:
 EMI4.4
 in which :
CO2R1 is an esterified, salified or free carboxyl group, n is 0 or 1; and
R2 is a hydrogen atom or an acyl radical, or alternatively a group of formula R303S in which R3 is a salifying ion or a methyl or ethyl radical; these compounds are described in European patent application 8885.

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   United States patent No. 4,235,922 (see also European patent application 2058) describes the carbapenem derivatives of formula:
 EMI5.1
 while British patent application 1,598. 062 relates to the isolation of the compound
 EMI5.2
 a fermentation broth based on Streptomyces.



   Carbapenems, which are unsubstituted in position 6, have also been prepared by synthesis. Thus, US Patent No. 4,210,661 describes the compounds of formula:
 EMI5.3
 in which: R2 is a phenyl or substituted phenyl radical, while the patent for
United States of America No. 4,267,177 describes compounds of formula:
 EMI5.4
 in which: R1 is an optionally substituted pyridyl group, and that US Pat. No. 4,255,441 describes compounds of formula:
 EMI5.5
 

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 in which :
R2 and R3 are hydrogen atoms or alkyl radicals;

   and
R4 is an NH-CO R6 group in which R6 is a phenyl or substituted phenyl radical, n being equal to 1 or 2.



  U.S. Patent No. 4,282,236 describes compounds of the formula:
 EMI6.1
 in which: R1 is a hydrogen atom or an alkyl radical; and R2 is CN or CO2R3 in which R3 is a hydrogen atom or an alkyl, aryl or aralkyl radical.



   Carbapenems with the general formula:
 EMI6.2
 in which :
RI is a hydrogen atom or an acyl radical; and Rs is a hydrogen atom or a radical, substituted or unsubstituted: alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, alkylcyoalkalkyl, aryl, aralkyl, aralkenyl, aralkynyl, heteroaryl, heteroaralkyl, heterocyclyl or heterocyclyalkyl; these carbapenems are described in US Patent No. 4,218,463.



  No heterocyclylalkyl substituent Rs of the type is known:
 EMI6.3
 in which :
A is an alkylene radical; and
 EMI6.4
 is a non-aromatic heterocycle containing a quaternized nitrogen atom,

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Thienamycin, a product existing in nature, has the absolute configuration 5R, 6S, 8R. This isomer, as well as the other seven isomers of thienamycin can be obtained by a process of total synthesis as described in US Pat. No. 4,234,596.



  The processes of total synthesis for thienamycin are also described, inter alia, in the patents of the United States of America no. 4,287,123, 4,269. 772.4. 282.148, 4.273. 709.4. 290,947 as well as in European patent application 7973.



  A fundamental intermediary of the method of synthesis thus described is
 EMI7.1
 in which pNB represents p-nitrobenzyl.



   Due to the exceptional biological activity of thienamycin, a large number of derivatives have been prepared and are described in the technical literature. Among these, there may be mentioned: (1) N-formimidoyl thienamycin of formula:
 EMI7.2
 described in European patent application 6639;

   (2) the N-heterocyclic derivatives of thienamycin having the formulas
 EMI7.3
 

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 EMI8.1
   in which the bifunctional cycle may contain additional unsaturation, and n is an integer between 1 and 6, limits included; p is 0.1 or 2; R1 is a hydrogen atom, an alkyl or aryl radical; and
Z is an imino, oxo group, an amino or alkyl atom or also a hydrogen atom; these compounds are described in US Patent No. 4,189,493; (3) substituted N-ethylenic derivatives of thienamycin having the formula:
 EMI8.2
 in which :

   X and Y are hydrogen atoms or groups R, OR, SR or NOIR2 in which R is a radical, substituted or unsubstituted belonging to the following list: alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroalkyl, heteroaralkyl, heterocyclyl or heterocyclylalkyl; and R1 and R2 are hydrogen atoms or R radicals; such products are described in US Patent No. 4,194,047;

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 (4) compounds of formula
 EMI9.1
 in which :
R3 is an aryl, alkyl, acyl or aralkyl radical;

   and R1 and R2 are, independently of one another, chosen from a group formed by the hydrogen atom and acyl radicals, including acyl derivatives of the type
 EMI9.2
 in which R11 may, inter alia, be an alkyl radical substituted by a quaternary ammonium group such as
 EMI9.3
 
Such compounds are described in United States Patent No. 4,226,870;

   (5) compounds of formula:
 EMI9.4
 in which
R3 is a hydrogen atom, an acyl radical or even a hydrocarbon radical, optionally substituted, monovalent;
RI is a radical, optionally substituted, belonging to the list formed by the radicals alkyl, alkenyl, alkynyl, cy-
 EMI9.5
 cloalkyl, cycloalkenyl, cycloalkenylalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl or heteroaralkyl; and R2 is an acyl radical, optionally an acyl radical of the type:

   
 EMI9.6
 in which R is an alkyl radical substituted by an ammonium

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 quaternary, such as
 EMI10.1
 such compounds are described in US Patent No. 1,604,276 (consideration should also be given to United States Patent No. 4,235,917);

   (6) compounds of formula:
 EMI10.2
 in which :
R5, R6 and R7 are independently of each other chosen from a group formed by hydrogen and radicals, substituted or unsubstituted, belonging to the following list: alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkenyl- alkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl or heteroaralkyl; such compounds are described in US Patent No. 4,235,920;

   (7) compounds of formula:
 EMI10.3
 in which each of the radicals:
R'and R2, independently of each other, is a radical of the type defined for R, a hydrogen atom or a nitro, hydroxy, C1 to C6 alkoxy, amino, C1 to C6 alkylamin, di (alkyl in
 EMI10.4
 Ci to C6) -amino or tri (C 1 to Cs alkylamin), an additional anion being present in the latter case; or R'and R2 together form, with the nitrogen atom to which they are linked, a heterocyclyl or heteroaryl, bicyclic or

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 unsubstituted monocyclic, containing 4 to 10 atoms in the ring, one or more of them may be a heteroatom chosen from oxygen, sulfur and nitrogen;

   R is a cyano group or a radical, substituted or unsubstituted,
 EMI11.1
 belonging to the following list: carbamoyl, carboxyl, (C1 to C10 alkoxy); C1 to C10 alkyl; C2 to C10 alkenyl; C2 to C10 alkynyl; C3 to C10 cycloalkyl; C4 to C12 cycloalkylalkyl; C5 to C12 cycloalkylalkenyl; C3 to C10 cycloalkenyl; Cs to Cis cycloalkenylalkenyl; C4 to C12 cycloalkenylalkyl; C6 to C10 aryl; C7 to C16 aralkyl; C 1-6 aralkenyl; C6 to C16 aralkynyl or -carbonylerocyclyl, heteroaralkyl, heteroaryl, monocyclic or bicyclic, comprising 4 to 10 atoms in the ring, one or more of which may be a heteroatom consisting of oxygen, sulfur and nitrogen and in which the alkyl residue of the heteroalkaryl or heterocyclylalkyl radical contains from 1 to 6 carbon atoms;

   the substituent (s) on the radicals R, R1 and R2 or on the nucleus formed by the junction established between R1 and R2 which may be chlorine, bromine, iodine, fluorine or azido groups; C1 to C4 alkyl; mercapto; sulfo; phos- phono; cyanothio (-SCN); nitro; cyano; amino; hydrazino; amino or hydrazino comprising up to three alkyl substituents comprising from 1 to 6 carbon atoms; hydroxy; C1 to C6 alkoxy; C1 to C6 alkylthio; carboxyl; oxo; (C1 to C6 alkoxy) carbonyl; C2 to Co acyloxy; carbamoyl; (C1 to C4 alkyl) carbamoyl or di (C1 to C4 alkyl) carbamoyl; R3 is a hydrogen atom, an acyl radical or a radical of the type defined for R4;
 EMI11.2
 R4 is a C1 to C10 alkyl radical; carbonylmethyl; (C1 to C C1 to C6 alkoxy);

   (C3 to C6 cycloalkoxy) - C1 to C6); C2 to C12 alkanoyloxyalkyl; a partially or completely halogenated alkyl radical comprising from 1 to 6 carbon atoms in which the halogen (s) consist of chlorine, bromine or fluorine; aminoalkyl, alkenyl radicals
 EMI11.3
 in C2 to C10; C2 to C10 alkynyl; acyl; C3 to C14 alkoxycarbonylalkyl; C4 to C21 dialkylaminoacetoxyalkyl; C2 to C13 alkanoylaminoalkyl; ar- in C1 to C3) in which the aryl residue contains from 6 to 10 carbon atoms; heterocyclylalkyl or heteroaralkyl, monocyclic or bicyclic containing ')

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 from 4 to 10 atoms in the ring, 1 to 3 carbon atoms in the alkyl residue and 1 to 4 heteroatoms consisting of oxygen, sulfur and / or nitrogen;

   heteroaralkyl or aralkyl radicals substituted on the ring, in which the substituent is chlorine, fluorine, bromine, iodine or a C1-C6 alkyl radical; aryl or aryl substituted on the ring containing 6 to 10 carbon atoms on the ring and in which any nuclear substituent is a hydroxy group, C1-C6 alkyl; chlorine, fluorine or bromine, aralkoxyalkyl; C2 alkylthioalkyl
 EMI12.1
 to C12; C4 to C12 cycloalkylthioalkyl; (C2 to C10 acylthio) - (C1 to C6 alkyl); or phenylalkenyl in which the alkenyl part comprises from 2 to 6 carbon atoms;

   Rs is a substituted or unsubstituted radical belonging to the group comprising C1 to C10 alkyl radicals; C2 to C10 alkenyl or alkynyl; ring-substituted, substituted or unsubstituted, cyloalkyl, cycloalkenyl, cycloalkenylalkyl, and cycloalkylalkyl radicals comprising from 3 to 6 carbon atoms in the ring and up to 6 carbon atoms in any side chain; C6 to C10 aryl; aralkyl having 6 to 10 carbon atoms in the ring and 1 to 6 carbon atoms in the alkyl chains;

   bicyclic or monocyclic heteroalkyl and heteroaryl having 4 to 10 atoms in the ring, one of which may be at least one oxygen, nitrogen or sulfur atom, and 1 to 6 carbon atoms in the alkylated part and the substituent (s) on the nucleus or on the chain which may be chlorine, bromine, iodine, fluorine, azido, cyano, amino, C1 to C6 alkylamino; di (C1 to C6 alkyl) amino or tri (C1 to C6 alkylamino), an additional anion being present in the latter case, hydroxy, C1 to C6 alkoxy; alkylthioalkyl in
C1 to C6; carboxyl; oxo; (C1 to C6 alkoxy) carbonyl; C2 to C10 acyloxy; carbamoyl;

   (C1-C4 alkyl) carbamoyl; di (C1-C4 alkyl) carbamoyl; cyanothio (-SCN) or nitro; R6 is a hydrogen atom or a hydroxy, mercapto, R, -OR, -SR or NR''R group, in which R, R1 and R2 are as defined above; X is a hydroxy, mercapto, amino, acyloxy-OR, -SR, - NHR4, -N-R4, OM, OQ group or, when the compound is in the form
 EMI12.2
 1 R4

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   zwítteríoníque, -0, in which case A is absent;
A when the compound is not in zwitterionic form, is a counter ion;
M is a pharmaceutically acceptable cation; and
Q is a blocking group as defined below; such compounds are described in British patent n
1.604. 275;

   and (8) compounds having the formula:
 EMI13.1
 
 EMI13.2
 in which: R el o
 EMI13.3
 ne of the amino group of thienamycin a heterocyclic group containing nitrogen, polycyclic or monocyclic, and R is hydrogen or a substituted or unsubstituted radical belonging to the following groups: alkyl, aryl, alKenyl,
 EMI13.4
 heterocyclylalkenyl, aralkenyl, hererocyclylalkyl, aralkyl, -NRs, COOR, CONR2, -OR, or CN; such groups are described in European patent application No. 21082.



   Among the compounds described in US Pat. No. 4,235,920, there may be mentioned the compound:
 EMI13.5
 in which :
A is a pharmaceutically acceptable anion.



   The aforementioned quaternary amine derivative is also described in

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 Recent Advances in the Chemistry of ss-lactam Antibiotics, Royal Society of Chemistry, London, 1981, pages 240-254, where its antibacterial activity is reported to be approximately 1/2 to 2/3 that of thienamycin.



   Carbapenem derivatives having a wide variety of substituents in position 6 in addition to those mentioned above, were also obtained by synthesis. Thus, for example: (1) European patent application 40408 describes compounds of formula:
 EMI14.1
 in which :
R1 is a hydrogen atom, a methyl or hydroxyl radical; and
Zis a monovalent organic group containing inter alia a heterocyclic methyl radical; (2) European patent application No. 8514 describes compounds of the formula:
 EMI14.2
 in which :
Ri is an optionally substituted pyrimidinyl group,
R2 is a hydrogen atom or a CRRRg group in which R3 is a hydrogen atom or a hydroxy group;

   R4 is a hydrogen atom or an alkyl radical and Rg is a hydrogen atom, alkyl, benzyl or phenyl, or Rg and R4 form a carbocyclic ring between them; (3) European patent application No. 38869 describes compounds of the formula:
 EMI14.3
 

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 in which: R6, R7 and R8 are independently each other chosen from the hydrogen atom as well as the radicals, substituted or unsubstituted, belonging to the following list: alkyl, alkenyl and alkynyl, comprising from 1 to 10 carbon atoms; cycloalkyl, cycloalkylalkyle, and alkylcycloalkyle including
3 to 6 carbon atoms in the cycloalkyl ring and 1 to 6 carbon atoms in the alkylated part; aryl, such as phenyl;

   aralkyl, aralkenyl, and aralkynyl in which the aryl part is constituted by a phenyl radical and the aliphatic part comprises from 1 to 6 carbon atoms; hete-
 EMI15.1
 roaryl, heteroaralkyl, heterocyclyl and heterocyclylalkyle, in which the substituent (s) relating to the abovementioned radicals are chosen from the group comprising:

   -X halo (chloro, bromo, fluoro) - OH hydroxy - OR1 alkoxy, aryloxy
 EMI15.2
 o ll - - amino
 EMI15.3
 NR1 - NR-'R
 EMI15.4
 R1 - N02 e - 3 tri-substituted amino (the Ri groups being chosen independently of each other) Ri -
OCNR-'R-SR1 alkyl and arylthio -SO2NR1R2sulfonamido
 EMI15.5
 o 0 -NHCNRlR2 o il R'CNR2-amido ureido-CO2H carboxy -CO2R1carboxylate

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 EMI16.1
 o Il - acyl o Il - acyloxy - mercapto o 0 Il - sulfinyl alkyl and aryl o 0 - sulphonylated alkyl and aryl 0 o
SH- CN cyano - N3 azido in which, compared to the aforementioned substituents on R6,
R7 and Ré, the groups Ri and R2 are chosen, independently of one another, from the hydrogen atom and the alkyl, alkenyl and alkynyl radicals comprising 1 to 10 carbon atoms;

   cycloalkyl, cycloalkylalkyle, and alkylcycloalkyle comprising 3 to 6 carbon atoms in the cycloalkyl ring and 1 to 6 carbon atoms in the alkylated part; aryl such as phenyl; aralkyl, aralkenyl, and aralkynyl in which the aryl part consists of a phenyl radical and the aliphatic part comprises 1 to 6 carbon atoms; heteroaryl, heteroaralkyl, heterocyclyl and heterocyclylalkyl in which the heteroatom (s) in the aforementioned heterocyclic parts are chosen from the group comprising 1 to 4 oxygen, nitrogen or sulfur atoms and in which the alkylated parts associated with these heterocyclic rings comprise from 1 to 6 carbon atoms (see also European patent applications 1627.1628, 10317.17992, 37080.37081, and 37082);

   (4) European patent application 24832 describes compounds of formula:
 EMI16.2
 in which: R1 is a hydrogen atom, a group which is chosen from the group formed by OH, OS03H or one of its salts or alkylated esters

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 (of an alkyl radical comprising from 1 to 4 carbon atoms) OR2, SR3, OCOR2, OCO2R3 or OCONHR3, in which R2 is a
 EMI17.1
 alkyl radical comprising 1 to 6 carbon atoms or a benzyl radical, optionally an alkyl radical comprising 1 to 6 carbon atoms or a benzyl or phenyl radical, optionally substituted, R12 is a C1 to C6 alkyl radical; C2 to C6 alkenyl; C3 to C6 alkynyl; wherein the triple bond is not on the carbon which is adjacent to the sulfur, araylkyle, C1 to C6 alkanole;

   aralkanoyl; aryloxyalkanoyl or arylcarbonyl, all of these R12 groups possibly being substituted, acting as antibacterial agents.



   European patent application 44170 describes carbapenem derivatives of formula:
 EMI17.2
 in which :
R3 is a hydrogen atom or an organic group linked by the carbon atom to the carbapenem nucleus; n is 0 or 1;
X is a saturated or unsaturated hydrocarbon radical, optionally sub-
 EMI17.3
 set up by a bromine or chlorine atom; and R4 is a C1-C6 alkyl, C2-C6 alkenyl radical; C1 to C10 aralkyl or aryl, all of these R4 groups possibly being substituted.



  However, there is no known anticipation of compounds in
 EMI17.4
 which the tetrazole nucleus is linked to X by a quaternized nitrogen atom, that is to say a positively charged nitrogen atom which is not linked to a hydrogen atom.



   European patent application 38869, mentioned above, describes the synthesis of carbapenem derivatives by intermediaries of general formula:

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 EMI18.1
 in which: R6 and R7 are as defined above; and
 EMI18.2
 R2 'R21 an easily separable carboxyl protecting group. Also described as intermediates are the compounds of formula:
 EMI18.3
 in which :
X is described as being a separable group.



   Whereas, as indicated above, the technical literature mentions carbapenem derivatives having a substituent in position 2 of general formula - S-A-Het in which:
A represents an alkylene group; and
Het represents a heteroaromatic or heterocyclic group, no document is known in which carbapenems are taught in which Het is a radical of formula
 EMI18.4
 where: R5 is either:

   (a) a radical, optionally substituted, aliphatic, cycloaliphatic, cycloaliphatic-aliphatic, aryl, araliphatic, heteroaryl, heteroaraliphatic, heterocyclyl or heterocyclylaliphatic, or (b) a divalent phenyl radical or a C1 alkylene radical C4 linked to the nucleus so as to form a bridged polycyclic group
 EMI18.5
 

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 and
 EMI19.1
 represents a non-aromatic heterocycle containing quaternized nitrogen bound to the carbon of alkylene by a quaternary nitrogen atom. As mentioned above, the carbapenem having the group
 EMI19.2
 as a substituent in position 2 is also known.



   Despite the large number of carbapenem derivatives described in the literature, there is still a lack of new carbapenem, because the known derivatives can be improved as regards their activity spectrum, even their stability and / or their toxic side effects.



   The subject of the present invention is a new series of carbapenem derivatives characterized by a substituent in position 2 having the formula:
 EMI19.3
 in which :
A represents a cyclohexylene, cyclopentylene or alkylene group with a straight or branched chain; R5 is either:

   (a) a radical, optionally substituted, belonging to the list formed by the aliphatic, cycloaliphatic, cycloaliphatic-aliphatic, aryl, araliphatic, heteroaryl, heteroaraliphatic, heterocyclyl or heterocyclylaliphatic radical, or (b) a divalent phenylene group or an alkyl group in Ci to C linked to the nucleus
 EMI19.4
 

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 so as to form a bridged polycyclic group; and
 EMI20.1
 represents a non-aromatic heterocycle containing a quaternized nitrogen atom.



  More specifically, the present invention relates to carbapenem derivatives of formula:
 EMI20.2
 in which :
Re is a hydrogen atom, and R1 is chosen from the group comprising hydrogen, as well as the radicals, substituted or unsubstituted, belonging to the following list: alkyl, alkenyl and alkynyl, comprising from 1 to 10 atoms of carbon ; cycloalkyl and cycloalkylalkyle comprising from 3 to 6 carbon atoms in the cycloalkyl ring and 1 to 6 carbon atoms in the alkylated part; phenyl; aralkyl, aralkenyl and aralkynyl, the aryl part of which is constituted by a phenyl radical and the aliphatic part of which comprises from 1 to 6 carbon atoms;

   heteroaryl, heteroaralkyl, heterocyclyl and heterocyclylalkyl in which the heteroatom (s) of the aforementioned heterocyclic parts are chosen from the group comprising 1 to 4 oxygen, nitrogen or sulfur atoms, and the alkylated part is associated with said heterocyclic parts comprising 1 to 6 carbon atoms, in which the substituent (s) relating to the abovementioned radicals are independently chosen from the group comprising: C1 to C6 alkyl radicals, optionally substituted by amino, halo, hydroxy or carboxyl radicals;

   halo - OR3
 EMI20.3
 o he - R

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 EMI21.1
 in which, with respect to the abovementioned substituents, the groups R3 and R4 are independently chosen from hydrogen as well as the alkyl, alkenyl and alkynyl groups comprising from 1 to 10 carbon atoms; cycloalkyl, cycloalkylalkyle and alkylcycloalkyle comprising 3 to 6 carbon atoms in the cycloalkyl ring and 1 to 6 carbon atoms in the alkyl part; phenyl; aralkyl, aralkenyl and aralkynyl in which the aryl part is formed by a phenyl radical and in which the aliphatic part comprises 1 to 6 carbon atoms;

   and heteroaryl, heteroaralkyl, heterocyclyl and heterocyclylalkyl, the

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 or the heteroatoms of the aforementioned heterocyclic parts are chosen from the group comprising 1 to 4 oxygen, nitrogen or sulfur atoms and the alkylated parts associated with said heterocyclic parts comprising from 1 to 6 carbon atoms, or R3 and R4 taken together with the nitrogen atom to which at least one of them is linked, can form a heterocyclic ring with 5 or 6 atoms containing nitrogen;
R9 is as defined for R3, except that it cannot be hydrogen or in which Ri and Rs taken together represent a C2 to C10 alkylidene or C2 to C10 alkylidene radical substituted by hydroxy groups;

     R5 is chosen from the group comprising substituted or unsubstituted radicals belonging to the following list: alkyl, alkenyl and alkyl comprising from 1 to 10 carbon atoms; cycloalkyl and cycloalkylalkyl comprising from 3 to 6 carbon atoms in the cycloalkyl nucleus and 1 to 6 carbon atoms in the alkylated part; phenyl; aralkyl, aralkenyl and aralkynyl, the aryl part of which is constituted by a phenyl radical and the aliphatic part of which comprises 1 to 6 carbon atoms;

     heteroaryl, heteroaralkyl, heterocyclyl and heterocyclylalkyl in which the heteroatom (s) of the aforementioned heterocyclic parts are chosen from the group comprising 1 to 4 oxygen, nitrogen or sulfur atoms and the alkylated part which is associated with said heterocyclic parts comprising from 1 to 6 carbon atoms; in which the abovementioned R5 radicals are optionally substituted with 1-3 substituents independently chosen from the following group: C1 to C6 alkyl, optionally substituted with amino, fluoro, chloro, carboxyl, hydroxy or carbamoyl groups; fluoro, chloro or bromo;

   - OR3 - OCOzRs - OCOR3 -OCONR3R4 -OSO2R3 -oxo - NR3R4 -R3CONR4- -NR3CO2R4 - NR3CONR3R4 - NR SOR

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 EMI23.1
 
 EMI23.2
 phenyl optionally substituted by 1 to 3 fluorine, chlorine, bromine atoms or R, -SOgRs, -CO2R3 groups in which R3, R4 and R9 in these substituents Rs are as defined above where Rs can represent a phenylene group divalent or a C1 to C4 alkylene group linked to the nucleus
 EMI23.3
 
 EMI23.4
 so as to form a bridged polycyclic group; A is a cyclopentylene, cyclohexylene or C2 to C6 alkylene group atky les en.

   Ci to Ce; -ORs, -N Optionally substituted by one or more C1 to C4 alkyl groups; R2 is a hydrogen atom or an anionic charge or a conventional easily separable carboxyl protecting group, it being understood that when R2 is a hydrogen atom or a protecting group, a counterion may also be present; and
 EMI23.5
 represents a heterocyclic non-aromatic, mono-bi-or poly-cyclic radical, substituted or unsubstituted, containing at least one nitrogen atom in the nucleus and linked to A by a nitrogen bond, so as to form a quaternary ammonium group as well as the pharmaceutically acceptable salts of its compounds.



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

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   Also within the scope of the present invention are the processes for the preparation of the above-mentioned new carbapenem derivatives, as well as the pharmaceutical compositions containing biologically active carbapenem derivatives in combination with pharmaceutically acceptable carriers or diluents. .



   The above-mentioned new compounds of general formula 1 contain the carbapenem nucleus
 EMI24.1
 and can be called derivatives of l-carba-2-penem-3-carboxylic acid.



  Alternatively, the compounds can be considered to have the basic structure
 EMI24.2
 and be called derivatives of 7-oxo-1-azabicyclo (3,2, O) hept-2-ene-2-carboxylic acid.



  While the present invention relates to compounds in which the relative stereochemistry of the protons in position 5 and 6 is cis as well as trans, the compounds preferably employed are those having the stereochemical (trans) configuration 5R, 6S, as is the case of thienamycin.



   The compounds of formula I can be unsubstituted in position 6 or substituted by substituent groups previously described for other carbapenem derivatives. More specifically, Rus can be a hydrogen atom and R1 can be a hydrogen atom or a substituent other than the hydrogen described for example in European patent application 38,869 (cf. the definition of Re).



  Alternatively, Rs and R1 taken together can form an alkyl group.
 EMI24.3
 C2 to Ciao lidene, or C2 to Closidylidene to Substituted, for example, by a hydroxy group.



  To give, more precisely, the definition of R1 and RB, note that:

  <Desc / Clms Page number 25>

 (a) the aliphatic alkyl, alkenyl or alkynyl groups can be linear or branched and contain 1 to 10 carbon atoms.



   Preferably, they contain 1 to 6, and more particularly of
1 to 4 carbon atoms. When they are part of another substituent, for example as is the case of the cycloalkylalkyl or heteroaralkyl or aralkenyl groups, the alkyl, alkenyl and alkynyl groups preferably contain 1 to 6, and more particularly 1 to 4 carbon atoms.



   (b) by "heteroaryl" is meant the mono-, bi- and polycyclic aromatic heterocyclic groups containing 1 to 4 oxygen, sulfur or nitrogen atoms; preferably, we mean heterocyclic rings with 5 or 6 atoms such as thienyl, furyl, thia-diazolyl, oxadiazolyl, triazolyl, isothiazolyl, thiazolyl, imidazolyl, isoxazolyl, tetrazolyl, oxazolyl, pyridinyl, pyrazinyl , pyridazinyl, pyrrolyl, pyrazolyl, etc.



   (c) by "heterocydyl" is meant the saturated or unsaturated, mono-, bi- and polycyclic non-aromatic heterocyclic groups containing
1 to 4 oxygen, sulfur or nitrogen atoms; they preferably include heterocyclic rings with 5 or 6 atoms, such as morpholinyl, piperazinyl, piperidyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, pyrrolinyl, pyrrodidinyl, etc.



   (d) "halo" means the chlorine, bromine, fluorine and iodine atoms and, more particularly, chlorine, fluorine or bromine.



   By "conventional easily separable carboxyl protecting group" is meant known ester groups which have been used to block a carboxyl group during the chemical reaction steps described below and which can be removed, if necessary, by methods which do not not lead to appreciable destruction of the remaining part of the molecule, for example by chemical or enzymatic hydrolysis, treatment with reducing chemical agents under mild conditions, irradiation using ultraviolet light or catalytic hydrogenation.

   Examples of such ester protecting groups are benzhydryl, allyl, pnitrobenzyl, 2-naphthylmethyl, benzyl, trichloroethyl, silyl radicals such as
 EMI25.1
 trimethylsilyl, phenacyl, p-methoxybenzyl, acetonyl, o-nitrobenzyl, 4-pyridylmethyl and C1-C6 alkyl such as methyl, ethyl or t-butyl.



  Part of such protective groups are those which are hydrolyzed under physiological conditions such as the pivaloyloxymethyl, acetoxy-, methyl, phthalidyl, indanyl and methoxymethyl radicals.

  <Desc / Clms Page number 26>

 



  Particularly advantageous are the carboxyl protecting groups such as p-nitrobenzyl which are easily separated by catalytic hydrogenolysis and allyl groups which can be removed by catalytic reaction.
 EMI26.1
 lysed by Pd (P03) 4-
The pharmaceutically acceptable salts referred to above include non-toxic acid addition salts such as salts with mineral acids, for example hydrochloric, hydrobromic, hydroiodic, phosphoric, sulfuric, etc. and salts with organic acids such as maleic, acetic, citric, succinic, benzoic, tartaric, fumaric, mandelic, ascorbic, lactic, gluconic and malic acids.

   The compounds of formula I in the form of acid addition salts can be put in the form of
 EMI26.2
 R2 being hydrogen or a protecting group, and
 EMI26.3
 g representing an acid anion. the counterion X be chosen so as to provide pharmacologically acceptable salts which can be administered therapeutically, but in the case of intermediate compounds of formula I,
 EMI26.4
 g can also be a toxic anion. In such a case, the ion can be
Subsequently removed or substituted with an anion acceptable from a pharmacological point of view to form a final product intended for therapeutic use.

   When acidic or basic groups are present in the R1 or R5 group or on the nucleus
 EMI26.5
 the present invention may also include suitable acid or base salts of these functional groups, for example the acid addition salts in the case of a basic group and of metal salts (such as sodium, potassium, calcium and aluminum), the and ammonium salts with

  <Desc / Clms Page number 27>

 non-toxic amines (for example trialkylamines, procaine, dibenzylamine, 1-epphenamine, N-benzyl-ss-phenethylamine, N, N'-dibenzylethylenedia mine, etc.) in the case of an acid group.



   The compounds of formula I in which R2 is a hydrogen atom, an anionic charge or a physiologically active hydrolysable ester group as well as their pharmacologically acceptable salts, are useful antibacterial agents. The remaining components of formula I are intermediates of great interest which can be converted into biologically active compounds mentioned above.



   According to a preferred embodiment of the present invention, this relates to compounds of formula I, in which: Rs is a hydrogen atom; and
 EMI27.1
 R1 a hydrogen atom or a group
 EMI27.2
 CH3 CH3 OH OH 1 CH3CH2-, CH-, 'CHs
 EMI27.3
 Among this subclass are preferred compounds those in which: estR1 is
 EMI27.4
 and, more particularly, the compounds having the absolute configuration 5R, 6S, 8R.



   According to another variant, the subject of the present invention is the compounds of formula I, in which:
Ri and Re, taken together, form an alkylidene radical of formula:
 EMI27.5
 
The alkylene or cucloalkylene substituent A in the compounds of formula 1 can be a C2 to C6 alkylene radical (straight chain) optionally substituted by one or more (preferably one or two) C1 to C4 alkyl groups, or can also be a cyclopentylen or cyclohexylene group.



   The alkylene substituent A is preferably an alkylene radical with a straight or branched chain comprising 2 to 6 carbon atoms. A cycloalkylene substituent A is preferably a cyclopentylene of formula:

  <Desc / Clms Page number 28>

 
 EMI28.1
 
 EMI28.2
 or a cyclohexylene of formula:
 EMI28.3
 
 EMI28.4
 According to a preferred embodiment, the invention relates to the compounds in which: A is
 EMI28.5
 - CH3 H- ,,
 EMI28.6
 or "(CHs), which: n is 2, 3 or 4.



  According to a further preferred embodiment, the invention relates to the compounds in which: A is a radical
 EMI28.7
 - -, - CHsCH -, - CHCHs-, CH3 CH3
 EMI28.8
 The alkylene or cycloalkylene part "A" is a quaternized non-aromatic heterocyclic substituted on the nitrogen atom of general formula
 EMI28.9
 
 EMI28.10
 in which the substituent R5 can be either:

   (a) an alkyl radical, optionally substituted, comprising from 1 to 6 carbon atoms, C2 to C10 alkenyl; C2 to C10 alkynyl;

  <Desc / Clms Page number 29>

 
CH2CH -, - CHCH2-, or - C3 to C6 cycloalkyl, C3-C6 cycloalkyl-C1-C6 alkyl; phenyl, phenyl C1-C6alkyl; Cs to Ce phenylalkenyl; C2 to C6 phenylalkynyl; heteroaryl, heteroaralkyl in which the alkyl part comprises from 1 to 6 carbon atoms, heterocyclyl or hererocyclyl-alkyl in which the alkyl part comprises from 1 to 6 carbon atoms;

   or (b) a divalent phenylene or an alkylene group comprising from 1 to 4 carbon atoms bonded to the nucleus
 EMI29.1
 so as to form a polycyclic group with a bridged nucleus, for example a quinyclidine group. The heteroaryl substituent (or the heteroaryl part of a heteroaralkyl) can be a mono-, bi- or polycyclic aromatic heterocyclic group containing 1 to 4 oxygen, sulfur or nitrogen atoms, preferably heterocyclic rings with 5 or 6 atoms such as thienyl, furyl, thiadiazolyl, oxadiazolyl, triazolyl, isothiazqlyl, thiazolyl, imidazolyl, isoxazolyl, tetrazolyl, oxazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyrida-zinyl, pyrrolyl and pyrazol.



   The heterocyclic substituent (or the heterocyclyl part of the alkyl heterocyclyl) can be a non-aromatic saturated or unsaturated, mono-, bi-or polycyclic heterocyclic group containing from 1 to 4 atoms of oxygen, sulfur or nitrogen ; preferably heterocyclic rings containing 5 to 6 atoms such as morpholinyl, piperazinyl, piperidyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, pyrrolinyl and pyrrolidinyl.



   In the case where the substituent R5 is an alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, phenyl, phenylalkyl, phenylal- radical.
 EMI29.2
 kenyl, phenylalkynyl, heteroaryl, heteroaralkyl, heterocyclyl, heterocyclylalkyl, such groups may be optionally substituted with one to three substituents chosen independently from one another from the following substituents: (a) C1 to C6 alkyl optionally substituted with de preferably 1 to 3, amino, fluoro, chloro, carboxyl, hydroxy or carbamoyl groups.



   (b) fluoro, chloro or bromo, (c) -ORs;

  <Desc / Clms Page number 30>

   (d) -OC02R3; (e) -OCOR3; (f) -OCONR3R4; (g) -OSO2R3; (h) -oxo; (i) -NR3R4; (j) R3CONR4-; (k) -NR3CO2R4; (1) -NR3CONR3R4; (m) -NR3SO2R4; (n) -SR3; (0) -SOR9; (p) -SO2R9; (q) -SORs; (r) -CO2R3; (s) -CONR3R4;

   (t) -CN; or (u) phenyl optionally substituted with 1 to 3 substituents independently chosen from fluoro, chloro, bromo, alkyl in
C1 to C6, -OR3, -NR3R4, -SO3R3, -CO2R3 or -CONR3R4, in which, with respect to the abovementioned substituent Rs, the groups R3 and R4 are independently chosen from hydrogen, or alkyl, alkenyl and alkynyl groups comprising 1 to 10 carbon atoms; cycloalkyl, cycloalkylalkyl and alkylcycloalkyl comprising 3 to 6 carbon atoms in the cycloalkyl part and 1 to 6 carbon atoms in the alkyl, phenyl, aralkyl, aralkenyl and aralkynyl part in the case where the aryl part consists of a phenyl radical and the aliphatic part comprises 1 to 6 carbon atoms;

   and
 EMI30.1
 heteroaryl, heteroaralkyl, heterocyclyl and heterocyclylalkyl in which the heteroaryl and heterocyclic group or portion of a group is as defined above for R5 and the associated alkyl parts or the heterocyclyl parts comprising 1 to 6 carbon atoms; or R3 and R4 taken together form with the nitrogen atom to which at least one of them is linked a heterocyclic ring containing nitrogen and formed from 5 to 6 atoms (as defined above for Rus) ; and R9 is as defined above for R3 except that it cannot be hydrogen. A Rus substituent preferably used is the C1 to 6 alkyl radical (preferably 6 'the methyl radical).

  <Desc / Clms Page number 31>

 



   In the case where R5 is a divalent phenylene radical or a C1 to C6 alkylene group, such a group is linked to another atom of the nucleus
 EMI31.1
 so as to form a polycyclic pontic nucleus, that is to say a nucleus
 EMI31.2
 quaternized quinyclidine, of formula:
 EMI31.3
 Q! n N9 1 The substituent zo NE)
 EMI31.4
 of formula I represents a heterocyclic radical containing optionally substituted non-aromatic mono-, bi- or polycyclic nitrogen (which may be linked to another aromatic or non-aromatic nucleus) linked to the substituent A by a ring nitrogen atom to form a quaternary ammonium group.



  The heterocyclic radical can be saturated or unsaturated (with one or two double bonds) and can contain up to two additional hetero atoms in addition to the quaternary nitrogen, these additional hetero atoms being chosen from 0, S (O) m , N, NR10 or NRisRie in which: m is 0, 1 or 2;
R10 is nitrogen or an optionally substituted radical, alkyl in
C1 to C6, or phenyl; and,
Ris and R16 are both chosen independently of one another from alkyl radicals containing 1 to 6 carbon atoms or optionally substituted phenyl.



   According to a preferred embodiment of the invention
 EMI31.5
 represents a non-aromatic heterocyclic ring containing nitrogen having
 EMI31.6
 from 4 to 7 atoms, preferably 5 or 6 atoms, containing 0 to 2 double bonds and 0 to 2 hetero atoms 0, S N, NR10 or NR15R16

  <Desc / Clms Page number 32>

 in which: m is 0.1 or 2;
Rio is hydrogen, a C1 to Ce alkyl radical optionally substituted by one or two substituents, chosen independently of one another from -OR3, -NR3R4, -CO2R3, oxo, phenyl, fluoro, chloro, bromo, -SO3R3 and -CONR3R4 or phenyl optionally substituted by one to three substituents chosen independently of one another from C1 to C6 alkyl radicals, -OR, -NRR, fluoro, chloro, bromo, -S03R3, -C02R2 and -CONR3R4;

   and,
R15 and Rie-independently of one another are chosen from C1 to Ce alkyl radicals optionally substituted by one or two substituents chosen independently of one another from the
 EMI32.1
 radicals-OR3, -NR3R4. -OR, -NRR.-COzR, oxo, phenyl, fluoro, chloro, bromo, -S03R3 and-CONR3R4 or phenyl radicals optionally substituted with 1 to 3 substituents chosen independently from one another from C1 to alkyl radicals C6, -OR3, -NR3R4, fluoro, chloro, bromo, -SO3R3, -CO2R2 and-CONR3R4, in which:
R3 and R4 in such heterocyclic groups NR10 and NRRie are as defined in relation to the substituent R5.



  In a preferred embodiment, the core
 EMI32.2
 may be optionally substituted by 1 to 3 substituents, chosen independently of one another from: (a) C1-C6 alkyl radicals optionally substituted by 1 or 2 substituents chosen independently of the other among the radicals
 EMI32.3
 fluoro, chloro, bromo, -OR, -OCOR, -ÛCONR,, - COR ", - NRCONRR", - NRSOzR ", - SR, -SOsR, -COzR - (b) aïkênytcsen one or two substituents chosen independently one on the other among the fluoro, chloro, bromo, -OR, -OCOR, -OCONR,, - COR, -NR "CONR = 'R", - NRSOR ", - SR, -SOsR, -COzR R (c ) alkynyles in one or two substituents chosen independently of one another from the fluoro, chloro, bromo, -OR ", - OCOR", - ÛCONR,, -NRCOR, - (d) groups

   cycloatkylesen one or two

  <Desc / Clms Page number 33>

 
 EMI33.1
 substituents chosen independently of one another from the fluoro, chloro, bromo, - groups; (e) cycloalkylalkyls comprising 3 to 6 carbon atoms in the cycloalkyl part and 1 to 6 carbon atoms in the alkyl part, optionally substituted by one or two substituents chosen independently
 EMI33.2
 each of them in the fluoro, chloro, bromo, -ORs, - OCOR3, -OCONR3R4, oxo, -NR3R4, -NR3COR4, -NR3CONR3R4, -NR3SO4, -SR3, -S03R3, and -CO2R3 group CONR3R4;

   (f) heteroaryls in which the hetero atom (s) are chosen from the group comprising 1 to 4 oxygen, nitrogen or sulfur atoms optionally substituted by one or two substituents chosen independently of one another among fluoro, chloro, bromo, - OR3, -OCOR3, -OCONR3R4, oxo, -NR3R4, -NR3COR4, -NR3CONR3R4, - NR2SO2R4, -SR3, -SO3R3, -CO2R3 and-CONR3R4; the heteroaryl radicals preferably used are aromatic heterocyclic rings with 5 or 6 atoms;

   (g) heteroaralkyls in which the heteroatom (s) are chosen from the group comprising 1 to 4 oxygen, nitrogen or sulfur atoms and the alkyl part comprises 1 to 6 carbon atoms, optionally substituted by a with two substituents chosen independently from one another from the fluoro, chloro, bromo, - OR3, -OCOR3, -OCONR3R4, oxo, -NR3R4, -NR3COR4, -NR3CONR3R4, - NR3SO2R4, -SR3, - SO3R3, -CO2R3 and-CONR3R4; the heteroaralkyls preferably used are those in which the heteroaryl radical is an aromatic heterocyclic ring with 5 to 6 atoms and the alkyl part comprises 1 to 2 carbon atoms;

   (h) heterocyclyls according to which the hetero atom (s) are chosen from the group comprising 1 to 4 oxygen, nitrogen or sulfur atoms optionally substituted with one or two substituents chosen independently from one another from the fluoro, chloro groups,
 EMI33.3
 bromo, -; are particularly -OR3, -OCOR3, -OCONR3R4, oxo, -NR3R4, -NR3COR4, -NR3CONR3R4, preferred are heterocyclyl comprising saturated or unsaturated rings with 5 or 6 atoms; (i) heterocyclylalyls in which the hetero atom (s) are chosen from the group comprising 1 to 4 oxygen, nitrogen or sulfur atoms, and the alkyl part comprises 1 to 6 carbon atoms, optionally substituted with one to two substituents independently

  <Desc / Clms Page number 34>

 
 EMI34.1
 chosen from fluoro, chloro, bromo, - 3 ne% 3 e-r% hln3n4.



  -DU m LIU m--: èrer-1 t2 1 - -COzRs R -iement heterocyclylalkyles in which the heterocyclyl part is a saturated or unsaturated ring with 5 or 6 atoms; (j) fluoro, chloro or bromo; (k) -OR3; (1) -OC02R3; (m) -OCOR3; (n) -OCONR3R4; (o) -OSO; (p) oxo; (q) -NR3R4; (r) R3CONR4-; (s) -NR3C02R4; (t) -NR3CONR3R4; (u) -NR3SO2R4; (v) -SR3;
 EMI34.2
 (w) 0 -; ((
S-R9-S-R9; (y) -SO3R3; (z) -Cû; (aa) -CONR3R4;

   (bb) -CN; or (cc) phenyl optionally substituted with 1 to 3 fluorine, chlorine, bromine or C1-C6 alkyl radicals, -OR3, -NR3R4, -SO3R3, -CO2R3 or -CONR3R4; the substituents R3, R4 and R9 mentioned above are defined in relation to the definitions given for the substituent Ri,
The cycle
 EMI34.3
 as defined above is a non-aromatic heterocyclic group.

   This ring, however, can be fused into another ring which can be a saturated or unsaturated carbocyclic ring, preferably a carbocyclic ring

  <Desc / Clms Page number 35>

 
 EMI35.1
 in C4 to C7, a phenyl ring, a heterocyclic ring (saturated or unsaturated) with 4 to 7 atoms containing 1 to 3 hetero atoms chosen from: 0, S NR '' containing Li ct D 0 1 to 3 chosen hetero atoms among: 0, SN, NR10 or NR15R16 in which: m, R10, R15 and R16 are as defined above.



  The fused carbocyclic, phenyl, heterocyclic or heteroaromatic ring may be optionally substituted by one to three substituents chosen independently of one another from C1 to C6 alkyl radicals, -OR3, -NR3R4, fluoro, chloro, bromo, - SO3R3, -CO2R3 and -CONR3R4 in which R3 and R4 are as defined above.
 EMI35.2
 



  According to another preferred embodiment of the present invention, the preferred compounds are those in which A is
 EMI35.3
 - CH2CH-, 1 CH3 CH3 or- --n in which: n is equal to 2,3 or 4,
 EMI35.4
 more particularly according to which A is equal to -CHzCHz -, - CHsCHsCHz-,
 EMI35.5
 - CH3 Chez and in which either (a) R1 and Ra form together
 EMI35.6
 or, (b) Rs is a hydrogen atom and R1 is a hydrogen atom or a CH3CH2- group,
 EMI35.7
 CH3 CHs \ CH-, C-, CH3-,
 EMI35.8
 Particularly preferred are the compounds in which Rs is a hydrogen atom and R is
OH
CH3CH-, and in particular the compounds having the absolute configuration 5R, 6S, BR.

  <Desc / Clms Page number 36>

 
 EMI36.1
 



  According to a preferred embodiment of the present invention, its subject is the compounds of formula I in which:
 EMI36.2
 
 EMI36.3
 represented
 EMI36.4
 
 EMI36.5
 CH "srf 'r i -N or 1 1
 EMI36.6
 and, Y is a hydrogen atom, a C1-C6 alkyl, hydroxy, -S-C1-C6 alkyl, carboxyl, carbamoyl, chloro, bromo, iodo, fluoro or phenyl radical.



  In this subclass, are the compounds in which A is
 EMI36.7
 - CH3
 EMI36.8
 - or 4, or even more particularly according to which A is -CHzCHs -, - CHsCHsCH-,

  <Desc / Clms Page number 37>

 
 EMI37.1
 - CH3
 EMI37.2
 and then CH- (a) R1 together form
 EMI37.3
 
 EMI37.4
 or, (b) Rs is a hydrogen atom and R1 represents a hydrogen atom or a CH3CH2- group,
 EMI37.5
 CH3 CH, C or CH3CH-.



  CH3 / CH3 /
 EMI37.6
 Particularly preferred are the compounds in which Re is a hydrogen atom and R1
 EMI37.7
 
 EMI37.8
 and in particular the compounds having an absolute configuration 5R, 6S, 8R.



  According to yet another preferred embodiment of the present invention, its subject is the compounds of formula 1 in which:
 EMI37.9
 R - N represents
 EMI37.10
 

  <Desc / Clms Page number 38>

 
 EMI38.1
 In this subclass, the compounds preferably used are those in which A is
 EMI38.2
 ¯ruru -0 him 12 5 2% '11 or CH3 eCH3
 EMI38.3
 - in which A = 2, 3 or 4, and more particularly according to
 EMI38.4
 which A is -CHsCHz -, - CHCHz- -CHCH2- and more particularly CHs-- those where A = -CHsCHet where:

   (a) R '' and Rs pns together form
 EMI38.5
 or (b) Rs is a hydrogen atom and R1 is a hydrogen atom or a CH3CH2- group,
 EMI38.6
 CH3 CH3 OH OH 1 CH-, C CH3,.,
 EMI38.7
 Particularly preferred are the compounds in which Rs is hy- or CH3CH-drogen and R1 is
 EMI38.8
 and in particular the compounds having the absolute configuration 5R, 6S, 8R.



   According to yet another embodiment of the present invention, its subject is the compounds of formula I in which
 EMI38.9
   represented
 EMI38.10
 and in which:
Y is hydrogen, C1 to C6 alkyl, hydroxy, -S-C1 to C6 alkyl, carboxyl, carbamoyl, chloro, bromo, iodo, fluoro or phenyl.



  In this preferred subclass, the compounds used more particularly

  <Desc / Clms Page number 39>

 are those in which A is- (CHz) in which n = 2,3 or 4, and more particularly according to which A is -CHCHz- and where (a) R1 and R8 taken together form
 EMI39.1
 or (b) Rs is hydrogen and R1 represents hydrogen or a CH3CH2- group,
 EMI39.2
 CH3 CH3 OH OH 'CH-'1 CH-, CH3 / CH3 /
 EMI39.3
 Particularly preferred are the compounds in which Rs is a hydrogen atom and R1 is
 EMI39.4
 and in particular the compounds having the absolute configuration 5R, 6S, 8R.



   According to a preferred embodiment of the present invention, the subject of the invention is compounds of formula I in which
 EMI39.5
 represented
 EMI39.6
 In this preferred subclass, use will preferably be made of the compounds in which A is - (CH2) - with n = 2.3 or 4, and more particularly according to which A is -CH2CH2- and where either (a) Ri and Re taken together represent
 EMI39.7
 or (b) Rs is hydrogen and R1 represents hydrogen, CH3CH2-,
 EMI39.8
 CH3 CH3 OH OH 1 CH-, C CH3 / CH3 /
 EMI39.9
 Particularly preferred are the compounds in which RB is

  <Desc / Clms Page number 40>

 or CHaCH-hydrogen and R1 is
 EMI40.1
 and in particular the compounds having the absolute configuration 5R, 6S, 8R.



   According to a preferred embodiment of the present invention,
 EMI40.2
 its subject is the compounds of formula
 EMI40.3
 
 EMI40.4
 cl in which. -M) -j \ vJ "\ / e ED \ ¯ -'- 1
 EMI40.5
 cl (both diastereoisomers a- and P-)
 EMI40.6
 CH e- N-CH E) and:
R2 is hydrogen, an anionic charge or a conventional easily separable carboxyl protecting group, it being understood that when
R2 is hydrogen or a protecting group, is also a counterion; also relates to the pharmaceutically acceptable acid addition salts of these compounds.



   It should be noted that certain products which fall within the scope of formula I may be in the form of optical isomers as well as their epimeric mixtures. It is also within the scope of the present invention to protect both the optical isomers and the mixtures of epimers. For example, when the substituent in position 6 is hydroxyethyl, such a substituent can be either in the R configuration or the S configuration and the resulting isomers as well as the resulting epimeric mixtures fall within the scope of the present invention.

  <Desc / Clms Page number 41>

 



   The carbapenems derivatives of general formula I are prepared from starting materials having the formula:
 EMI41.1
 in which: R1 and RB are as defined above; and,
R2 'represents an easily separable conventional carboxyl protecting group.



  Compounds of formula III have been described, for example, in European patent application 38,869 (compound 7) and can be prepared by the general methods which are described in this European patent application.



   A process for the preparation of compounds 1 from materials III can be summarized by the following reaction scheme:
 EMI41.2
 

  <Desc / Clms Page number 42>

 
 EMI42.1
 R ---- YSA-OSOg - "---- L2VI ri N OOR --N ---- LGOCR" "5 Il ter R ... \ O II Rltrì- x. Possible RS. Zoor R5 H - "----" - COOR R ol 0 1
 EMI42.2
 To carry out the abovementioned process, the starting material III is reacted in an inert organic solvent such as methylene chloride, acetonitrile or dimethylformamide with an approximately equimolar amount of diphenyl chlorophosphate in the presence of a base such as diisopropylethylamine, or similar to lead to intermediate V.

   The acylation to produce the separable diphenylphosphoryloxy group in position 2 of intermediate III is preferably carried out at a temperature between -20 and +40 C, more particularly of the order of 0 C. Intermediate IV can be isolated if necessary, but it is used satisfactorily in the next step without requiring isolation or purification.

  <Desc / Clms Page number 43>

 



   FL'intermediate IV is then converted into intermediate V by a conventional displacement reaction. Thus, intermediate IV can be reacted with an approximately equimolar amount of a mercaptan-type reagent having the formula
HS-A-OH in which:
A represents cyclopentylene, cyclohexylene or an alkylene in
C2 to Ce optionally substituted by one or more C1 to C4 alkyl radicals in an inert organic solvent such as dioxane, dimethylformamide, dimethylsulfoxide or acetonitrile and in the presence of a base such as diisopropylethylamine, triethylamine, sodium carbonate, potassium carbonate or 4-dimethylaminepyridine.



  The displacement temperature is not critical but a particularly advantageous temperature is between -40 ° C. and 25 ° C. Particularly satisfactory is a reaction carried out under cooling, for example at a temperature of the order of 0 ° C.



   Intermediate V is then acylated by methanesulfonyl chloride or a functional acylating equivalent of this derivative such as methanesulfonic acid anhydride in an inert organic solvent and in the presence of a base; the separable methanesulfonyloxy group from intermediate VI is thus obtained. The acylation is carried out in an inert organic solvent such as tetrahydrofuran, methylene chloride, acetonitrile or dimethylformamide and in the presence of a suitable base such as diisopropylethylamine, triethylamine, 4-dimethylaminopyridine, and the like.

   The reaction can be carried out over a wide range of temperatures, for example between -40 ° C. and +40 ° C., but is more particularly carried out under cooling, for example at a temperature of the order of -30 ° C. to -400 ° C.



   Intermediate VI is then subjected to a displacement reaction so as to provide on intermediate II a separable iodo group. This particular group has been found to greatly facilitate the preparation of carbapenems end products of formula I.



   The displacement of the separable methanesulfonyloxy group is carried out by reaction of intermediate VI with a source of iodide ions in an inert organic solvent such as acetone, dimethylformamide or dimethyl sulfoxide. Any compound which ionizes in the solvent used to give iodide ions can be used such as for example an alkali metal iodide such as Nal or KI. The displacement temperature is not critical but temperatures of the order of room temperature or

  <Desc / Clms Page number 44>

 higher are particularly advantageous to allow the completion of the reaction in a reasonable period of time.

   The source of the iodide ions is used in an amount such that it provides approximately an equivalent or an excess of iodide ions with respect to intermediate VI.



   The preparation of the desired carbapenem derivative of formula I is carried out by a nucleophilic displacement of the separable iodo group of intermediate II by the heterocyclic nucleophile containing the desired nitrogen.
 EMI44.1
 Intermediate II reacts with at least one equivalent, preferably an excess, of the desired amine reactant in an inert organic solvent in the presence of silver ion. Suitable inert organic solvents may consist, for example, of tetrahydrofuran, dioxane, methylene chloride, diglyme, dimethoxyethane and the like.

   Any silver compound that substantially ionizes in a solvent to lead to the production of silver ions and an inert anion can be used as a source of silver ion, for example AgC104. In general, it is preferable to use an approximately equivalent amount (with respect to intermediate II) of silver ion to facilitate movement.

   The reaction can be carried out over a wide range of temperatures, for example of the order of approximately -25 to +25 ° C., but is more favorably carried out at a temperature of the order of 0 C. The intermediate I should include a contreanion (for example derived from the silver salt used) which is associated with it and can at this stage be substituted by another counter-anion, for example which is acceptable from the pharmaceutical point of view, by conventional methods.



  Alternatively, the counterion can be removed later during the unlocking step.



   The deblocking step to remove the carboxyl protecting group R2 ′ from intermediate I "is carried out by conventional processes such as solvolysis, chemical reduction or hydrogenation. When a protecting group such as p-nitrobenzyl, benzyl, benzhydryl or 2 -naphthylmethyl is used, and is capable of being eliminated by hydrogenation cataly-
 EMI44.2
 tick, the intermediary I'd in a suitable solvent such as dioxane-water-ethanol, tetrahydrofuran-diethyl ether-buffer,

  <Desc / Clms Page number 45>

 dipotassic acid in aqueous solution-isopropanol or the like, can be treated under a hydrogen pressure of the order of 1 to 4 atmospheres in the presence of a hydrogenation catalyst such as palladium on carbon, palladium hydroxide,

   platinum oxide or similar at a temperature between 0 and 50 C for 0.24 to 4 hours. When R21 is a group such as o-nitrobenzyl, photolysis can also be used for deblocking. Protecting groups such as 2,2,2-trichloroethyl can be removed by reduction with mild zinc. The allyl protecting group can be removed using a catalyst comprising a mixture of a palladium compound and triphenyl phosphine in an aprotic solvent such as tetrahydrofuran, diethyl ether or methylene chloride. Likewise, other conventional carboxyl protecting groups can be removed by methods known to those skilled in the art.

   Finally, as mentioned above, compounds of formula II where R21 is a physiologically hydrolysable ester, such as acetoxymethyl, phthalidyl, indanyl, pivaloyloxymethyl, methoxymethyl, etc. may be administered directly to the host without requiring prior unblocking because such esters are hydrolyzed in vivo under physiological conditions.



   The preparation of certain compounds of formula 1 may involve a subsequent reaction step before or after the unblocking reaction. So, for example, when the substituent containing heterocyclic nitrogen desired
 EMI45.1
 contains a sulfoxide group, we can first of all form the corresponding compound having the heterocycle containing sulfur by the aforementioned process and then subject this compound, either before or after the release of the carboxyl, to an oxidation so as to form the final sulfoxide corresponding.



   While the above process is suitable for the preparation of the compounds according to the present invention, Mr. Pierre Dextraze has invented a new process which can be used to prepare the compounds of formula I where the substituent is cyclopentylene, cyctohexylene or
 EMI45.2
 

  <Desc / Clms Page number 46>

 wherein R11, R12, R13 and R14, independently of each other, consist of a hydrogen atom, a C1-C4 alkyl radical. This process, which is described and claimed in a patent application currently pending the same day.

   that the date on which the present continuation-in-part was filed constitutes a preferred process for the preparation of the aforementioned class of compounds.



   According to another variant of preparation of the compounds of formula I where A is cyclopentylene, cyclohexylene or
 EMI46.1
 in which R11, R12, R13 and R14 are independently of one another, hydrogen or a C1-C4 alkyl radical, the reaction of an intermediate of formula
 EMI46.2
 in which R1 and RB are as defined for the compounds of formula 1 and R2 is a conventional easily separable carboxyl protecting group with a thiol of formula
 EMI46.3
 
 EMI46.4
 R in which A and as defined above in re- - N
 EMI46.5
 lation with the compounds of formula 1 and is a counter anion in an inert solvent and in the presence of a base to produce the carbapenem of formula
 EMI46.6
 

  <Desc / Clms Page number 47>

 
 EMI47.1
 R5

   <B 'in and X are as defined in above, and said process involving, where appropriate, the elimination of the carboxyl protecting group R2' to lead to the corresponding deblocked compound of formula I, or to one of acceptable salts of pharmacological point of view.



   The process according to the aforementioned variant uses intermediate IV which can be prepared as described above in the context of the general synthesis process. Intermediate IV is generally prepared in situ from intermediate III and is used without isolation or purification.



   According to a variant of this preparation process, the carbapenem IV intermediate is reacted with a quaternary thiol amine of formula
 EMI47.2
 in which A is cyclopentylene, cyclohexylene or
 EMI47.3
 in which R11, R12, R13 and R14, independently of each other, are
 EMI47.4
 g hydrogen or a C1 to C4 alkyl radical is an associated counter anion
X9 to a strong acid such as Cl-, Br-, CHaSOs-, CFaSOs "or
 EMI47.5
 as defined above.



  The reaction carried out in an inert solvent with acetonitrile, acetonitrile
 EMI47.6
 trile-H20, acetonitrile-dimethylformamide, tetrahydrofuran, tetrahydrofuran-H20 or acetone in the presence of a base. The basic nature is not critical.



  The best results, however, have been obtained when a base consisting of a non-nucleophilic tertiary amine such as diisopropylethylamine, 1, 8-diazabicyclol5, 4, Olundec-7-ene, 1, 5-diazabicyclol4, 3, Olnon-5 -ene or tri (C1-alkyl to be examined such as triethylamine, tributylamine or tripropylamine is used. The reaction of intermediate IV with thiol VII

  <Desc / Clms Page number 48>

 can be carried out over a wide temperature range, for example between -150 and ambient temperature, but preferably it is carried out at a temperature of the order of -15 to +15 C and more particularly of the order of 0 vs.



   The carbapenem produced by the reaction of the quaternary thiol amine VII with intermediate IV has a counter anion associated with it
 EMI48.1
 9 8 (either it is (C6H50) or the anion associated with the quaternary thiol) which can be at this level substituted by another counter anion, for example an anion which is more acceptable from the pharmacological point of view, by methods classics. According to a variant, the counter anion can be eliminated during the subsequent unblocking step. When the quaternized carbapenem produced and the counter anion form an insoluble product, the product can separate by crystallization as it is formed and then be collected in the pure state by filtration.



   Following the formation of the desired carbapenem, in accordance with the above-mentioned reaction step, the carboxyl protecting group R21 of the compound I'm can be optionally removed by the conventional processes as described above in relation to the general synthesis process.



   The intermediate thiols of formula VII can be prepared, for example, by reaction of a sulfide of formula
 EMI48.2
 in which R11, R12, R13 and R14, independently of one another, consist of a hydrogen atom or a C1-C4 alkyl radical, with a heterocyclic amine (as defined above) of formula
 EMI48.3
 and a strong acid.



  The reaction can be carried out in the presence or absence of an inert organic solvent which is preferably a non-polar organic solvent such as methylene chloride, benzene, xylene, toluene or the like.



  When the amine and sulfur reagents are liquids or when a

  <Desc / Clms Page number 49>

 solid amine is soluble in a liquid sulfur reagent, it is preferable to carry out the reaction without using an additional solvent. The particular strong acid used in the reaction is not critical and may, for example, consist of strong organic or mineral acids such as hydrochloric, hydrobromic, methanesulfonic, p-toluenesulfonic, trifluoromethanesulfonic, etc.



   The formation of the intermediate quaternary thiol amine VII can be carried out at a temperature between -20 ° C. and approximately 100 ° C. although preferred temperatures are preferably of the order of 50 to 70 ° C.



   The sulphide, the aromatic amine and the acid are preferably used in a form such that the sulphide and the acid are in approximately equimolar proportions and the amine used is in excess, i.e. say about 2 to 3 moles of amine per mole of sulfide or acid.



   The intermediate quaternary thiol amine has a counter anion associated with it and which is determined according to the particular acid employed. It is, of course, possible to substitute another counter anion at this point, by conventional procedures, intended for use in the subsequent reaction step with the intermediate carbapenems IV.



   It should be noted that, when the substituent R '' and / or Rs or the heterocyclic nucleophile which is attached to the substituent A contains a functional group which can interfere in the context of the reaction concerned, such a group can be protected by a group of classic blocking then, subsequently unlocked to regenerate the desired functional group. Suitable blocking groups and the procedures for introducing and removing such groups are well known to those of skill in the art.



   In the case where certain compounds of formula 1 have a branched cycloalkylene or alkylene A substituent, one or more additional asymmetric carbon atoms can be formed, which leads to the production of diastereoisomers. The present invention includes mixtures of such diastereoisomers as well as each of the individual purified diastereoisomers.



   As is the case with other ss-lactam antibiotics, the compounds of general formula 1 can be converted by known methods into pharmaceutically acceptable salts which, for the purposes of the present invention, are practically equivalent to non-salified compounds. So, for example, you can dissolve a compound of formula 1

  <Desc / Clms Page number 50>

 wherein R2 is an anionic charge in a suitable inert solvent and then add an equivalent of a pharmaceutically acceptable acid thereto. The desired acid addition salt can be recovered by conventional procedures such as, for example, solvent precipitation, lyophilization, etc.

   When other acidic or basic functional groups are present in the compound of formula I, pharmaceutically acceptable base addition salts and pharmaceutically acceptable acid addition salts can be prepared similarly by known methods.



   A compound of formula 1 where R2 is hydrogen or an anionic charge or a pharmaceutically acceptable salt thereof can also be converted by conventional procedures into a corresponding compound in which R2 is an ester-hydrolyzable group physiological, or a compound of formula 1 in which R2 is a conventional carboxyl protecting group can be converted into the corresponding compound where R2 is hydrogen, an anionic charge or a physiologically hydrolysable ester group or one of its acceptable salts pharmacologically.



   The new carbapenem derivatives of general formula I, in which R2 is hydrogen, an anionic charge or a physiologically hydrolysable carboxyl protecting group or one of its pharmacologically acceptable salts, are potent active antibiotics with against many gram-positive and gram-negative bacteria and can be used as food additives or animal feed supplements for the purpose of promoting their growth, as food preservatives, as bactericides in industrial applications, for example for water-based paints,

   and in bleaching papers of a paper industry to inhibit the growth of harmful bacteria and as a disinfectant to destroy or inhibit the growth of harmful bacteria on medical and dental equipment. They are very particularly useful, however, in the treatment of infectious diseases of products in humans and animals due to gram-positive and gram-negative bacteria.



   The pharmaceutically active compounds according to the present invention can be used alone or in the form of a pharmaceutical composition comprising, in addition to the active carbapenem, a carrier or diluent or other acceptable vehicle from the Dharmacoloaioue point of view. Compounds

  <Desc / Clms Page number 51>

 can be administered by a wide variety of methods, the most interesting ones involve the oral, topical or parenteral routes (intravenous or intramuscular injections). The pharmaceutical compositions can be in solid form such as capsules, tablets, powders, etc. or in liquid form such as solutions, suspensions or emulsions.

   The compositions intended for injection, which constitutes the most favorable route of treatment, can be prepared in the form of a unit dose in ampoules or in multidose containers and can contain formulating agents such as suspending, stabilizing and dispersion.



   The compositions can be in a ready-to-use form, or in powder form, intended to be reconstituted at the time of their use, by virtue of the addition of a suitable vehicle such as sterile water.



   The dose to be administered depends to a large extent on the particular constituents used in its formulation and composition or administration, the nature and conditions of the host and the particular site as well as the organism to be treated. The choice of different dosages and different routes of application is left to the therapist's discretion. In general, however, the compounds can be administered perenterally or orally to mammals in amounts on the order of 5 to 200 mg / kg / d. The administration is generally carried out in the form of a divided dose, for example, from 3 to 4 applications per day.



   To illustrate the broad spectrum of antibacterial activity of the carbapenems according to the present invention, the results of the in vitro and in vivo tests are given above, as well as the toxicity of these compounds with regard to the presently preferred carbapenems in accordance with the present invention.



   In vitro activity
A sample of the carbapenem of Example 1, after dissolving in water and diluting in a nutritive broth, reveals the following minimum inhibitory concentrations (M.I.C.) in mcg / ml for the microorganisms indicated; these minimum inhibitory concentrations are determined after incubation for one night at 37 ° C. by the so-called dilution tube method.



  As a control, N-formimidoyl thienamycin was used.

  <Desc / Clms Page number 52>

 In vitro antibacterial activity of the carbapenem derivatives of Example 1
 EMI52.1
 
 <tb>
 <tb> MIC <SEP> (mcg / ml)
 <tb> Organizations
 <tb> compose <SEP> N-formimidoyle
 <tb> new <SEP> thienamycin
 <tb> S. <SEP> pneumoniae <SEP> A-9585 <SEP> 0, <SEP> 002-0, <SEP> 004 <SEP>
 <tb> S. <SEP> pyogenes <SEP> A-9604 <SEP> 0.002 <SEP> 0, <SEP> 001 <SEP>
 <tb> S. <SEP> aureus <SEP> A-9537 <SEP> 0.008 <SEP> 0.004
 <tb> S. <SEP> aureus
 <tb> + <SEP> 50% <SEP> serum <SEP> A-9537 <SEP> 0.016 <SEP> 0.016
 <tb> S. <SEP> aureus
 <tb> (Pen-res. <SEP>) <SEP> A-9606 <SEP> 0.016 <SEP> 0.008
 <tb> S. <SEP> faecal-is <SEP> A20688'1 <SEP> 0, <SEP> 5 <SEP>
 <tb> E. <SEP> col <SEP> i <SEP> A15119 <SEP> 0, <SEP> 03 <SEP> 0.016
 <tb> E. <SEP> coli <SEP> A20341-1 <SEP> 0.03 <SEP> 0.03
 <tb> K.

    <SEP> pneumoniae <SEP> A-9664 <SEP> 0.06 <SEP> 0.13
 <tb> K. <SEP> pneumoniae <SEP> A20468 <SEP> 0.13 <SEP> 0.06
 <tb> P. <SEP> mirabilis <SEP> A-9900 <SEP> 0.13 <SEP> 0.06
 <tb> P. <SEP> seen <SEP> 1 <SEP> ga <SEP> laughed <SEP> s <SEP> A21559 <SEP> 0.03 <SEP> 0.03
 <tb> P. <SEP> morgana <SEP> A15153 <SEP> 0.13 <SEP> 0.13
 <tb> P. <SEP> rettgeri <SEP> A22424 <SEP> 0.25 <SEP> 0.25
 <tb> S. <SEP> marcescens <SEP> A20019 <SEP> 0.06 <SEP> 0.03
 <tb> E. <SEP> cloacae <SEP> A-9569 <SEP> 0.25 <SEP> 0.06
 <tb> E. <SEP> cloacae <SEP> A-9656 <SEP> 0.13 <SEP> 0.06
 <tb> P. <SEP> aeruginosa <SEP> A-9843A <SEP> 4 <SEP> 1
 <tb> P. <SEP> aeruginosa <SEP> A21213 <SEP> 0.25 <SEP> 0.25
 <tb> B. <SEP> fragilis <SEP> A22862 <SEP> 0.13 <SEP> 0.016
 <tb> B. <SEP> fragilis <SEP> A22053 <SEP> 0.25 <SEP> 0.06
 <tb> B. <SEP> fragilis <SEP> A22696 <SEP> 0.5 <SEP> 0.13
 <tb> B.

    <SEP> fragilis <SEP> A22863 <SEP> 0.13 <SEP> 1
 <tb>
 

  <Desc / Clms Page number 53>

 
In vivo activity
The in vivo therapeutic efficacy of the compounds of Example 1 and of N-formimidoyl thienamycin after intramuscular administration in mice experimentally infested with various organisms is shown in the following table.



   The PD50 (dose in mg / kg required to obtain protection for 50% of the infested mice) is given.



   Protective effect by intramuscular treatment on infested mice
 EMI53.1
 
 <tb>
 <tb> PD50 / treatment <SEP> (mg / kg)
 <tb> Organization <SEP> Number <SEP> Compound <SEP> from <SEP> N-formimidoyle
 <tb> of organisms <SEP> example <SEP> 1 <SEP> thienamycin
 <tb> P. <SEP> mirabi1is <SEP> A-9900 <SEP> 4 <SEP> x <SEP> 106 <SEP>> 10 <SEP> 3 * / 15 *
 <tb> P. <SEP> aeruginosa <SEP> A-9843a <SEP> 3 <SEP> x <SEP> 106 <SEP> 3 <SEP> 0.5 *
 <tb>
 
Historical data.



   Treatment: mice are infested intramuscularly with the drug 0 and 2 hours after infection. 5 mice per dose are used for each trial.



   Toxicity
The toxicity of the compound of Example 1, after intracranial administration to mice, is determined and the results are recorded in the following table.



   Toxicity after intracranial administration to mice
 EMI53.2
 
 <tb>
 <tb> Compound <SEP> # @ <SEP> dose <SEP> the <SEP> more <SEP> high <SEP> (mg / kg)
 <tb> (mg / kg) <SEP> without <SEP> signs <SEP> clinics
 <tb> of <SEP> toxicity <SEP>
 <tb> Compound <SEP> from
 <tb> example <SEP> 1 <SEP>> 10 <SEP>> 10
 <tb> N-formimidoyle
 <tb> thienamycin " <SEP> '
 <tb> * <SEP> medium <SEP> from <SEP> 25 <SEP> mouse <SEP> by <SEP> compound
 <tb>
 

  <Desc / Clms Page number 54>

 
Blood level in mice after intramuscular administration
The blood levels and the period of life of the compound of Example 1 after intramuscular administration of 20 mg / kg in mice are indicated in the table below.

   
 EMI54.1
 
 <tb>
 <tb> rate <SEP> blood <SEP> (g / ml) <SEP> * t1 / 2 <SEP> ** AUC
 <tb> Compound
 <tb> 10 <SEP> 20 <SEP> 30 <SEP> 45 <SEP> 60 <SEP> 90 <SEP> (min) <SEP> (g.h / ml)
 <tb> minutes <SEP> after <SEP> administration
 <tb> Compound <SEP> from
 <tb> example <SEP> 1 <SEP> 13.7 <SEP> 10.2 <SEP> 5.7 <SEP> 2.1 <SEP> <0.6 <SEP> <0.6 <SEP> 11 <SEP> 5, <SEP> 4 <SEP>
 <tb> N-formimidoy1e
 <tb> thienamycin <SEP> 12.6 <SEP> 9.9 <SEP> 7.3 <SEP> 2.6 <SEP> 0.7 <SEP> <0.3 <SEP> 9 <SEP> 6
 <tb>
 
The compounds are solubilized in a 0.1 M phosphate buffer of pH 7.



   The values are that of a simple test; 4 mice are used per compound.
 EMI54.2
 



  * duration in minutes ** corresponds to the area below the curve of blood concentration as a function of time.



   The urinary recovery of the compound of Example 1, after intramuscular administration (20 mg / kg) to mice is shown in the following table.



   Urinary recovery after intramuscular administration of 20 mg / kg in mice
 EMI54.3
 
 <tb>
 <tb> Percentage <SEP> from <SEP> dose <SEP> retrieved
 <tb> Compound <SEP> 0-3 <SEP> 3-6 <SEP> 6-24 <SEP> 0-24
 <tb> hours <SEP> after <SEP> administration
 <tb> Compound <SEP> from
 <tb> example <SEP> 1 <SEP> 18.8 <SEP> 0, <SEP> 6 <SEP> 0, <SEP> 1 <SEP> 19, <SEP> 5¯3, <SEP> 2
 <tb> N-formimidoyle
 <tb> thienenomycin <SEP> 12.1 <SEP> 0.1 <SEP> <0.1 <SEP> 12.1¯3.6
 <tb>
 
The compounds are dissolved in a 0.1 M phosphate buffer with a pH of the order of 7; the values are that of a simple test; 4 mice were used per compound.

  <Desc / Clms Page number 55>

 



   Additional biological data related to in vitro activity
Samples of the carbapenem derivatives indicated below (identified by their example n) after being dissolved in water and diluted in a culture broth, reveal the following minimum inhibitory concentrations (MIC) in mcg / ml with respect to the microorganisms indicated; these minimum inhibitory concentrations are determined after incubation for the duration of one night at 37 ° C. by the method known as "dilution tube". N-formimidoyl thienamycin is used as a control.
 EMI55.1
 
 <tb>
 <tb>



  MIC <SEP> (pg / ml)
 <tb> Organizations
 <tb> Compound <SEP> (example <SEP> n)
 <tb> Ex. <SEP> 2 <SEP> MK <SEP> 0787 <SEP>
 <tb> S. <SEP> pneumoniae <SEP> A-9585 <SEP> 0.001 <SEP> 0.002
 <tb> S. <SEP> pyogenes <SEP> A-9604 <SEP> 0.002 <SEP> 0.002
 <tb> S. <SEP> faecalis <SEP> A20688 <SEP> 0.25 <SEP> 0.25
 <tb> S. <SEP> aureus <SEP> A-9537 <SEP> 0.008 <SEP> 0.002
 <tb> S. <SEP> aureus
 <tb> 50% <SEP> serum <SEP> A-9537 <SEP> 0.016 <SEP> 0.016
 <tb> S. <SEP> aureus
 <tb> (Pen-res. <SEP>) <SEP> A-9606 <SEP> 0.016 <SEP> 0, <SEP> 008 <SEP>
 <tb> E. <SEP> coli <SEP> A15119 <SEP> 0.016 <SEP> 0.016
 <tb> E. <SEP> coli <SEP> A20341-1 <SEP> 0.03 <SEP> 0.016
 <tb> K. <SEP> pneumoniae <SEP> A-9664 <SEP> 0.06 <SEP> 0.03
 <tb> K. <SEP> pneumoniae <SEP> A20468 <SEP> 0.13 <SEP> 0.13
 <tb> E. <SEP> cloacae <SEP> A-9659 <SEP> 0.13 <SEP> 0.13
 <tb> E. <SEP> cloacae <SEP> A-9656 <SEP> 0.13 <SEP> 0.06
 <tb> P.

    <SEP> mirabilis <SEP> A-9900 <SEP> 0.06 <SEP> 0, <SEP> 03
 <tb> P. <SEP> vulgaris <SEP> A21559 <SEP> 0.03 <SEP> 0, <SEP> 016
 <tb> M. <SEP> morgani <SEP> A15153 <SEP> 0.06 <SEP> 0.06
 <tb> P. <SEP> rettgeri <SEP> A22424 <SEP> 0.13 <SEP> 0.13
 <tb> S. <SEP> marcescens <SEP> A20019 <SEP> 0.06 <SEP> 0.03
 <tb> P. <SEP> aeruginosa <SEP> A-9843a <SEP> 32 <SEP> 1
 <tb> P. <SEP> aeruginosa <SEP> A21213 <SEP> 8 <SEP> 0.13
 <tb>
 

  <Desc / Clms Page number 56>

 Table (continued)
 EMI56.1
 
 <tb>
 <tb> 1 <SEP> MIC <SEP> (llg / ml) <SEP> 1 <SEP>
 <tb> Organimes
 <tb> Compound <SEP> (example <SEP> n)
 <tb> Ex. <SEP> 3 <SEP> * MK <SEP> 0787 <SEP>
 <tb> S. <SEP> pneumoniae <SEP> A-9585 <SEP> 0, <SEP> 03 <SEP> 0.002
 <tb> S. <SEP> pyogenes <SEP> A-9604 <SEP> 0, <SEP> 03 <SEP> 0.002
 <tb> S. <SEP> faecalis <SEP> A20688 <SEP> 0, <SEP> 5 <SEP> 0, <SEP> 5
 <tb> S.

    <SEP> aureus <SEP> A-9537 <SEP> 0, <SEP> 03 <SEP> 0.004
 <tb> S. <SEP> aureus
 <tb> 50% <SEP> serum <SEP> A-9537 <SEP> 0, <SEP> 13 <SEP> 0.016
 <tb> S. <SEP> aureus
 <tb> (Pen-res.) <SEP> A-9606 <SEP> 0, <SEP> 03 <SEP> 0.008
 <tb> E. <SEP> coli <SEP> A15119 <SEP> 0.03 <SEP> 0.016
 <tb> E. <SEP> col <SEP> A20341-1 <SEP> 0.03 <SEP> 0.03
 <tb> K. <SEP> pneumoniae <SEP> A-9664 <SEP> 0.13 <SEP> 0.06
 <tb> K. <SEP> pneumoniae <SEP> A20468 <SEP> 0.25 <SEP> 0.13
 <tb> E. <SEP> cloacae <SEP> A-9659 <SEP> 0.25 <SEP> 0.06
 <tb> E. <SEP> cloacae <SEP> A-9656 <SEP> 0, <SEP> 5 <SEP> 0.06
 <tb> P. <SEP> mirabilis <SEP> A-9900 <SEP> 0.13 <SEP> 0.06
 <tb> P. <SEP> vulgaris <SEP> A21559 <SEP> 0, <SEP> 03 <SEP> 0.03
 <tb> M. <SEP> morganll <SEP> i <SEP> A15153 <SEP> 0.13 <SEP> 0.13
 <tb> P. <SEP> rettgeri <SEP> A22424 <SEP> 0.5 <SEP> 0.13
 <tb> S. <SEP> marcescens <SEP> A20019 <SEP> 0.06 <SEP> 0.03
 <tb> P.

    <SEP> aeruginosa <SEP> A-9843a <SEP> 63 <SEP> 1
 <tb> P. <SEP> aeruginosa <SEP> A21213 <SEP> 8 <SEP> 0.25
 <tb> Ex. <SEP> 4 <SEP> Ex. <SEP> 5 <SEP> Ex. <SEP> 5 <SEP> * MK <SEP> 0787 <SEP>
 <tb> (comp. <SEP> B) <SEP> (comp. <SEP> A)
 <tb> S. <SEP> pneumonias <SEP> A-9585 <SEP> 0.004 <SEP> 0.004 <SEP> 0.004 <SEP> 0, <SEP> 001
 <tb> S. <SEP> pyogenes <SEP> A-9604 <SEP> 0.004 <SEP> 0.008 <SEP> 0.004 <SEP> 0.001
 <tb> S. <SEP> faecalis <SEP> A20688 <SEP> 2 <SEP> 1 <SEP> 0.05 <SEP> 0.25
 <tb> S. <SEP> aureus <SEP> A-9537 <SEP> 0.03 <SEP> 0.03 <SEP> 0.016 <SEP> 0.002
 <tb> S. <SEP> aureus
 <tb> 50% <SEP> serum <SEP> A-9537 <SEP> 0.06 <SEP> 0.06 <SEP> 0.03 <SEP> 0.004
 <tb> S. <SEP> aureus
 <tb> (Pen-res.

    <SEP>) <SEP> A-9606 <SEP> 0.06 <SEP> 0.06 <SEP> 0.03 <SEP> 0.004
 <tb>
 * N-formimidoylethienamycin

  <Desc / Clms Page number 57>

 table (continued)
 EMI57.1
 
 <tb>
 <tb> MIC <SEP> (g / ml <SEP>
 <tb> Organizations
 <tb> Compose <SEP> (example <SEP> n)
 <tb> Ex. <SEP> 4 <SEP> Ex. <SEP> 5 <SEP> Ex. <SEP> 5 <SEP> * MK <SEP> 0787 <SEP>
 <tb> (comp. <SEP> B) <SEP> (comp. <SEP> A)
 <tb> E. <SEP> col <SEP> i <SEP> A15119 <SEP> 0.13 <SEP> 0, <SEP> 13 <SEP> 0.03 <SEP> 0.016
 <tb> E. <SEP> col <SEP> i <SEP> A20341-1 <SEP> 0.13 <SEP> 0.13 <SEP> 0.03 <SEP> 0.016
 <tb> K. <SEP> pneumoniae <SEP> A-9664 <SEP> 0.25 <SEP> 0.25 <SEP> 0.06 <SEP> 0.03
 <tb> K. <SEP> pneumoniae <SEP> A20468 <SEP> 0.5 <SEP> 0.5 <SEP> 0.13 <SEP> 0.06
 <tb> E. <SEP> cloacae <SEP> A-9659 <SEP> 1 <SEP> 0.5 <SEP> 0.13 <SEP> 0.06
 <tb> E. <SEP> cloacae <SEP> A-9656 <SEP> 2 <SEP> 0.25 <SEP> 0, <SEP> 13 <SEP> 0.06
 <tb> P.

    <SEP> mirabilis <SEP> A-9900 <SEP> 0.25 <SEP> 0.25 <SEP> 0, <SEP> 13 <SEP> 0.03
 <tb> P. <SEP> vulgaris <SEP> A21559 <SEP> 0.25 <SEP> 0.25 <SEP> 0.06 <SEP> 0.016
 <tb> M. <SEP> morganii <SEP> A15153 <SEP> 1 <SEP> 0.5 <SEP> 0.13 <SEP> 0.06
 <tb> P. <SEP> rettgeri <SEP> A22424 <SEP> 1 <SEP> 1 <SEP> 0.25 <SEP> 0.13
 <tb> S. <SEP> marcescens <SEP> A20019 <SEP> 0.25 <SEP> 0.25 <SEP> 0.06 <SEP> 0.03
 <tb> P. <SEP> aeruginosa <SEP> A-9843a <SEP> 16 <SEP> 63 <SEP> 32 <SEP> 1
 <tb> P.

    <SEP> aeruginosa <SEP> A21213 <SEP> 1 <SEP> 32 <SEP> 16 <SEP> 0.13
 <tb>
 * N-formimidoyl tmenamycin
In vivo activity
The in vivo therapeutic efficacy of certain compounds of the present invention and of N-formimidoyl thienamycin (MK 0787), after intramuscular administration in mice experimentally infested with various organisms is shown below. The PD50 (dose in mg / kg required to produce 50% protection for infested mice is indicated.



   Protective effect by intramuscular treatment of infested mice
 EMI57.2
 
 <tb>
 <tb> PDso / processing <SEP> (mg / kg)
 <tb> Compose <SEP> P. <SEP> aeruginosa <SEP> P. <SEP> aeruginosa <SEP> P. <SEP> aeruginosa
 <tb> (examples <SEP> n #) <SEP> * A9843A <SEP> * A20481 <SEP> * A-9606
 <tb> Ex. <SEP> 2 <SEP> 4.7 <SEP> 33 <SEP> 0.72
 <tb> Ex. <SEP> 5 <SEP> compound <SEP> B <SEP> - <SEP> - <SEP> 0, <SEP> 39
 <tb> Ex. <SEP> 5 <SEP> compound <SEP> A <SEP>> 12, <SEP> 5-1, <SEP> 2
 <tb> Ex. <SEP> 4 <SEP> 2, <SEP> 7-1, <SEP> 6
 <tb> MK <SEP> 0787 <SEP> 1 <SEP> 0, <SEP> 4 <SEP> 0, <SEP> 07
 <tb>
 

  <Desc / Clms Page number 58>

 Processing conditions:

   - for the compounds of Example 2, the mice are infested by the
 EMI58.1
 intrapêntonêale by 2 x 109 organizations (A9606), or 1 x 105 organizations (A9843A) and (A20481). for the compounds of examples 4 and 5, the mice are infested intraperitoneally with approximately 9 × 10 7 organisms (A9606) or approximately 8 × 10 4 (A9843A). The mice are treated intramuscularly with drugs, 0 and 2 hours after infestation.



   Blood levels and urine recovery
The blood levels and the period of action of certain compounds of the present invention, after intramuscular administration of 20 mg per kg in mice are recorded below. The urinary recovery of mice is also shown.



  Pharmacokinetic parameters of the mouse after administration of an intramuscular dose of 20 mg / kg
 EMI58.2
 
 <tb>
 <tb> Compound <SEP> Blood <SEP> Recovery
 <tb> (Example <SEP> n) <SEP> Cmax <SEP> * T1 / 2 <SEP> ** AUC <SEP> urinary ***
 <tb> (pg / ml) <SEP> (min) <SEP> (pg. <SEP> h / ml) <SEP>%
 <tb> Ex. <SEP> 3 <SEP> 16 ,. <SEP> 2 <SEP> 8 <SEP> 4.8 <SEP> 15 + 3
 <tb> Ex. <SEP> 4 <SEP> 17.3 <SEP> 12 <SEP> 7.6 <SEP> 33 + 11
 <tb> Ex. <SEP> 5 <SEP> compound <SEP> A <SEP> 10.2 <SEP> 7 <SEP> 3.1 <SEP> 14 + 1
 <tb> Ex. <SEP> 5 <SEP> compound <SEP> B <SEP> 12.6 <SEP> 10 <SEP> 4.6 <SEP> 15 + 3
 <tb> MK <SEP> 0787 <SEP> 14, <SEP> 6 <SEP> 10 <SEP> 6 <SEP> 33 + 8 <SEP>
 <tb>
 
The compounds are dissolved in a 0.1 M phosphate buffer at pH 7.



  The values are expressed on the basis of a simple test at the rate of 4 mice per compound.



     T1 / 2 corresponds to the period, that is to say half of the duration of action in minutes.



   AUC refers to the area under the curve of blood concentration over time. recovery is based on a duration of 0 to 6 hours.



   Other objects and advantages of the present invention will appear on reading the examples given without implied limitation.

  <Desc / Clms Page number 59>

 



  EXAMPLE 1 Preparation of 3- | 2- (N-methylpyrrolidinium) ethylthio | -6 &alpha; - jl- (R) -hydroxyethyl-7-oxo-1-azabicycloj3, 2, 0lhept-2-ene-2 carboxylate
 EMI59.1
 A.-p-nitrobenzyl 3- (2-hydroxyethylthio) -6a-ll- (R) -hydroxy- ethyll-7-oxo-l-azabicyclo 13, 2, Olhept-2-ene-2 carboxylate
 EMI59.2
 
A solution of 1.69 g (4.85 mmol) of p-nitrobenzyl-6a-ll- (R) -hydroxyethyl 1-3, 7-dioxo-1-azabicyclo (3,2,0) hept-2 carboxylate -ene-2 (J) in 20 ml of acetonitrile is cooled to 0 ° C. under a nitrogen atmosphere.

   A solution of 726 mg (7.18 mmol) of diisopropylethylamine in 2 ml of acetonitrile is added, after dropwise addition of 1.51 g (5.60 mmol) of diphenyl chlorophosphate in 12 ml of acetonitrile on a 3 minute period. The resulting solution is stirred at 0 C for 20 minutes to lead to the production of p-nitrobenzyl-3- (diphenylphosphoryloxy) -6 &alpha; - | 1- (R) -hydroxyethyl | -7-oxo-1 carboxylate -azabicyclo- (3, 2, 0) hept-2-ene-2.

   This solution is then added to a solution of 726 mg (7.18 mmol)

  <Desc / Clms Page number 60>

 of diisopropylethylamine in 2 ml of acetonitrile, this addition being followed by the addition of a solution of 439 mg (5.63 mmol) of 2-mercaptoethanol in 2 ml of acetonitrile. The reaction solution is stirred at 0 C for 3 hours then diluted with 200 ml of ethyl acetate and washed with 200 ml of water, 100 ml of aqueous H3PO4 solution and brine.



  Evaporation of the dried solution over (MgSO) leads to a semi-solid which is triturated in the presence of methylene chloride and then filtered. 1.2 g (yield 61%) of the title compound are thus obtained. as a white amorphous solid.



   The physical properties are as follows: NMR (DMSO-de) 6: 1.20 (3H, d, I = 6, OHz); 2.9-3.2 (9H, m);
5.22 (1H, d, I = 8.5Hz); and
8.23 (2H, d, I = 8.5Hz). spectrum ir (KBr) ymax: 3500, 1770 and 1700 cm-1;
The analysis leads to the following contents for the formula:

  
C18H20N2O7S
 EMI60.1
 
 <tb>
 <tb> C <SEP> H <SEP> N <SEP> S
 <tb> - <SEP> calculated <SEP> 52.93 <SEP> 4.94 <SEP> 6.86 <SEP> 7.85
 <tb> - <SEP> found <SEP> 52.83 <SEP> 4.90 <SEP> 6.42 <SEP> 8.31
 <tb>
 P-nitrobenzyl 3- (2-methanesulfonyloxyethylthio) -6a- B.-carboxylate
1- (R) -hydroxyethyl | -7-oxo-1-azabicyclo (3,2, O) hept-2-ene-2
 EMI60.2
 
 EMI60.3
 In a solution of 4.29 (10.3 mmol) of 2 in 200 ml of tetrahydrofuran, approximately 1.3 g (11.3 mmol) of chloride are added. 1.26 (12.4 mmol) of triethylamine in 5 ml of tetrahydrofuran are added dropwise.

   L2 reaction mixture is

  <Desc / Clms Page number 61>

   -400C, stirred for 5 hours at -400C, then stirred for 2 hours at -300C under a nitrogen atmosphere and finally poured into a mixture of ethyl acetate (700 ml) and 5% phosphoric acid in aqueous solution (100 ml). The organic layer is washed with brine, dried over MgSO4, filtered and condensed until a syrup is obtained. This material is then purified by chromatography on a column of silica gel (elution) in a methylene chloride-ethyl acetate solution (3/1 by volume), 3.55 g (yield 75%) of the compound are thus obtained. section in the form of a white amorphous solid.



   The physical properties are as follows:
 EMI61.1
 NMR (CDCIa) 6: 1.25 (3H, d, I = 6, OHz), 3.05 (3H, s); 3.06-3.40 (5H, m); 4.05-4.40 (4H, m); 5.25 (1H, d, I = 14, OHz); 5.50 (1H, d, I = 14, OHz);
7.70 (2H, d, I = 8.5Hz); and 8.23 (2H, d, I = 8.5Hz). ir spectrum (KBr) ymax: 3400.1770 and 1600 cm-1.



   The analysis leads to the following contents for the formula:
C19H22N2O9S2
 EMI61.2
 
 <tb>
 <tb> C <SEP> H <SEP> N
 <tb> - <SEP> calculated <SEP> 46.90 <SEP> 4.56 <SEP> 5.76
 <tb> - <SEP> found <SEP> 46.52 <SEP> 4.32 <SEP> 5.91
 <tb>
   C. - p-nitrobenzyl 3- (2-iodoethylthio) -6 &alpha; - | 1 (R) - carboxylate
 EMI61.3
 hydroxyethyll-7-oxo-l-azabicyclo (3, 2, O) hept-2-ene-2
 EMI61.4
 
 EMI61.5
 4 A solution of 350 mg (0.72 mmol) of intermediate 3 and 216 mg (1.4 mmol) of sodium iodide in 20 ml of acetone is heated at reflux temperature for 4 hours. The evaporation of acetone leads to the production of a white amorphous solid which is put

  <Desc / Clms Page number 62>

 
 EMI62.1
 suspended in an ether (10 ml) -water (10 ml) mixture.

   Filtration of the white solid and drying under vacuum leads to obtaining 300 mg (yield 80%) of compound 4 in the form of a white amorphous.



  The physical properties are as follows: NMR (DMSO-d6) 6: 1.18 (3H, d, I = 6, OHz); 3.20-3.60 (7H, m); 3.80-4.25 (2H, m); 5.10 (1H, d, I = 5.5Hz); 5.25 (1H, d, I = 12, OHz); 5.45 (1H, d, I = 12, OHz); 7.70 (2H, d, I = 8.5Hz); and 8.27 (2H, d, I = 8.5Hz). ir spectrum (KBr) ymax: 3500, 1768 and 1700 cm-1.



  The analysis leads to the following contents for the formula: CisH-OeI
 EMI62.2
 
 <tb>
 <tb> powderC <SEP> H <SEP> N <SEP> I
 <tb> - <SEP> calculated <SEP> 41.72 <SEP> 3.70 <SEP> 5.41 <SEP> 24.48
 <tb> - <SEP> found <SEP> 42.10 <SEP> 3.75 <SEP> 5.97 <SEP> 23.20
 <tb>
 
 EMI62.3
 0. 3-12- hydroxyethyl
 EMI62.4
 OH - SCHCHI -------- <NU 4 OH H CH3 OH Zut C02PNB pNB 0 5 OH H CH i -i / SCHCH - /, -------- N ------------- <2

  <Desc / Clms Page number 63>

 
 EMI63.1
 To a cooled solution (50C) of p-nitrobenzyl carboxylate 3- 2.01 hept-2-ene-2 (728 mg; 1.4 mmol) in 60 ml of dry tetrahydrofuran, 301 mg (3.5 mmol) are added. ) of N-methylpyrrolidine then a solution of silver perchlorate 560 mg (2.8 mmol) in 5 ml of tetrahydrofuran.



  The reaction mixture is stirred at 5 ° C. for 60 minutes. The solvent is then evaporated under vacuum, compound 5 is thus obtained which is in the form of a yellow gum. This gum is digested in 2 g of celite, an amorphous solid is thus obtained. The infrared spectrum KBr is as follows: ymax: 3400, 1775, 1700 and 1100 cm-1 Without further purification, the compound 5 is hydrogenated.
 EMI63.2
 the following way:
To a solution in the form of a suspension of compound 5 in 50 ml of diethyl ether and 100 ml of tetrahydrofuran, a solution of potassium bicarbonate 320 mg (2.2 mmol) and of phosphate dipotassium acid (280 mg, 1 , 6 mmol) in 125 ml of water.

   Then, 1 g of palladium (10%) on charcoal is added and the mixture is hydrogenated under a pressure of 2.8 bars in a Parr type agitator for 60 minutes. The mixture is then filtered and the catalyst is washed with the aid of
 EMI63.3
 of water (2 x 10 ml). The filtrates are combined and added to the washing water and the whole is extracted using (2 x 200 ml) and then lyophilized so as to obtain a brown powder. The raw material obtained is purified on a BONDAPAK Gis reverse phase column (8 g) (manufactured by Waters Associates); eluted using water under a pressure of 0.56 bar. Each fraction (20 ml) is separated by high pressure liquid chromatography and the fractions having an ultraviolet absorption spectrum Xmax of 300 nm are collected and diethyl ether-lyophilized ether.

   65 mg (14% of the yield expressed relative to compound 4) of the title compound are thus obtained in the form of a white solid.



   The physical properties are as follows: NMR (DO) 6: 1.23 (3H, d, I = 6, OHz); 2.1-2.4 (4H, m);
3.10 (3H, s); 3, 13, 4 (12H, m);
3.95-4.30 (2H, m); ir spectrum (KBr) ymax: 3400.1760 and 1590 cm-1.



    UVÀmax (CH3CH20H) 297 nm (E = 6877).

  <Desc / Clms Page number 64>

 
 EMI64.1
 



  EXAMPLE 2 Preparation of the 3-12- 6ci- carboxylate! - hydroxyethyl
 EMI64.2
 
 EMI64.3
 A. of N-methyl-N-
 EMI64.4
 Men 1) MsOH Mek S W - Ü
 EMI64.5
 To 5.00 g (42.7 mmol) of precooled N-methylthiomorpholine * (in an ice bath), 1.47 ml (20.5 mmol) of methanesulfonic acid and 1.30 ml (21.4) are added. mmoles) of ethylene sulfide. The mixture is heated 650C for 24 hours then in water (25 ml).



  The aqueous solution is washed (3 x 25 ml) pumped under vacuum and poured on a column with reverse phase of silica gel. The title compound is eluted using water. The suitable fractions are combined and evaporated. The thiol is thus obtained, ie 4.809 (yield 86%) of an oil having the following physical properties spectrum: 2550 cm-1 (w, SH); 1Hmr (DMSO-d6) 6: 3, 25-2, 95 (6H, m, CH2N); 3.32 (3H, s, CH) 3.20-2.65 (7H, m, CH2S, SH); and 2.32 ppm (3H, s, CHsSOa).



  * M. Lehn and J. Wagner. Tetrahedron, 26, 4227 (1970).



  Para-n diphenyl phosphate B.-carboxylate) ethyl1-thioj-6a-jl'- azabicycloI3, ne-2
 EMI64.6
 OH 1) Etc H '\ S 1 /' "oJ = I {= o 3) HSV 0 C02PNB E1:, & (O) 2 COPNB PNB -t)) 4)

  <Desc / Clms Page number 65>

 
A cold solution (under ice bath) of para-nitrobenzyl 6 &alpha; - | 1- (R) -hydroxyethyl | -3,7-dioxo-1-azabicyclo | 3, 2, 0 | heptane-2 (557 mg; 1.60 mmol) in CH3CN (8 ml), is treated by dropwise addition of diisopropylethyl amine (0.336 ml, 1.92 mmol) and diphenylchlorophosphate (0.400 ml; 1.92 mmol) and stirred for 30 minutes.

   The reaction mixture is treated again with 893 mg (2.29 mmol) of N-methyl-N- (2-mercaptoethyl) thiomorpholinium methanesulfonate in CH3CN (4 ml) and diisopropylethyl amine (0.336 ml, 1, 92 mmol) and the whole is stirred for 30 minutes. The solution is diluted in water (20 ml) and poured onto a silica gel phase inversion column. The desired compound is eluted with a water-acetonitrile mixture of 50-50. The suitable fractions are combined, pumped under vacuum for 2 hours, and lyophilized. The title compound is thus obtained (1.01 g, yield 85%).



   It has the following physical properties:
 EMI65.1
 ir spectrum (nujol): 1760 (s, ss-lactane C = O} and 1510 cm-1 (s, N02); v1Hmr (DMSO-d6) 6: 8.25 (2H, d, I = 8, 8Hz, H -aromatic);
7.70 (2H, d, I = 8.8Hz, H-aromatic);
7.33-6.84 (10H, m, H-aromatic);
5.37 (2H, center of ABq, I = 14.2Hz, CH2);
5.14 (1H, d, I = 4.5Hz, OH);
4.35-3.70 (2H, m, H-1e and H-5);
3.75-3.45 (6H, m, CH2N +); 3.31 (3H, s, CHgN;
3.45-2.75, (9H, m, CH2S, H-6 and H-4); and
1.15 ppm (3H, d, I = 6, 2Hz, CH3).
 EMI65.2
 



  2,0-hydroxyethyl-2-ene-2-ene-2-hydroxyethyl carboxylate
 EMI65.3
 
A solution of para-nitrobenzyl carboxylate 3- | 2- (N-methylthiomorpholinium diphenylphosphate) ethylthio} -6 &alpha; - | 1- (R) -hydroxyethyl | - 7-oxo-1-azabicyclo | 3, 2, 0Ihept -2-ene-2 (1.31 g; 1.76 mmol) in O, 1M phosphate buffer at pH 7.4 (48.8 ml), tetrahydrofuran (20 ml) and

  <Desc / Clms Page number 66>

 diethyl ether (20 ml), is hydrogenated on a catalyst formed from 10% palladium / carbon (1.5 g) in an agitator of the so-called Parr type for 1 hour at 2.8 bars. The reaction mixture is diluted in diethyl ether (40 ml) and the phases are separated. The organic phase is washed with water (2 x 5 ml).

   The aqueous phases are combined, filtered on a hard filter paper of type 52, washed with diethyl ether (2 x 20 ml) and pumped under vacuum. The aqueous solution is poured onto a phase inversion column containing silica gel and the desired carbapenem is eluted by a water-acetomtnia 95-5 mixture.



  The desired fractions are combined and lyophilized; the title compound is thus obtained in the form of an amorphous solid (205 mg, yield 31%).



   The physical properties are as follows:
 EMI66.1
 ir spectrum (nujol): 1750 (s, ss-lactar C = O) and 1590 cm-1 (s, C = O); 1Hmr (DO) 6: 4, 25-3, 95 (2H, m, H-1 ', H-5); 3.70-3.40 (5H, m, CH2N +)
3.35 (1H, dd, I = 6, 1Hz, 1 = 2.6Hz, H-6);
3.08 (3H, s, CH3N); 3.25-2.75 (8H, CH2S, H-4); and
1.24 ppm (3H, d, I = 6.4Hz, CH3); uv (H2O, c 0.062) #max: 299 (10.962)
 EMI66.2
 T1 / 2 17.7 h (phosphate buffer O, 1M, at pH 7, 370C).



  EXAMPLE 3 Preparation of (5R, 6S) - | 2- (1-methylmorpholino) ethylthio carboxylate | -
 EMI66.3
 6- (R) -l-hydroxyethyll-7-oxo-l-azabicyc1o13, 2, 01
 EMI66.4
 
 EMI66.5
 A. of 1-méthy1-l-
 EMI66.6
 
To 3.29 ml (0.030 mole) of N-methylmorpholine, 1.327 ml (0.015 mole) of trifluoromethanesulfonic acid is added dropwise at 10 ° C., then 0.89 ml (0.015 mole) of ethylene sulfide. The yellowish-brown solution

  <Desc / Clms Page number 67>

 The resultant is heated on an oil bath at 50-60 C under a nitrogen atmosphere for 18 hours. The volatiles are removed under vacuum and the residual oil is taken up in 10 ml of water. The aqueous solution is washed with diethyl ether (3 x 5 ml) then the residual organic solvent is removed in vacuo.

   The resulting aqueous solution is unknown.
 EMI67.1
 produced in a C18 phase inversion column which is eluted with HO and then with a mixture of 5% acetonitrile in water and finally 10% acetonitrile in water. The evaporation of the fractions concerned leads to the production of a white solid which is dried under vacuum (PzOs); 1.92 g are thus obtained (yield 41%) of the product in heading.



   The physical properties are as follows: ir spectrum (KBr) vmax: 2560 (SH) cm-1; 1Hnmr (d6-acetone) 6: 4.25-3.6 (m, 8H); 3.49 (s, 3H, N-Me);
3.35-2.7 (m, 5H).



  P-nitrobenzyl B.-carboxylate (5R, 6S) -3- | 2- (1-methylmorpholino) ethylzo (R) -1-hydroxyethyl | -7-oxo-1-azabicyclo | 3, 2, 0Ihept- 2-ene-2 diphenylphosphated
 EMI67.2
 
 EMI67.3
 0.191 ml (1.1 mmol) is added dropwise to a solution of p-nitrobenzyl carboxylate) -1hydroxyêthy1j-3, heptane-2 (0.348 mg, 1.0 mmol) in 25 ml of dry acetonitrile of diisopropylethylamine then 0.228 ml (1.1 mmol) of diphenyl chlorophosphate at 0 ° C. under a nitrogen atmosphere. After stirring at 0 C for
 EMI67.4
 1 hour, 0.226 ml (1.3 mmol) of diisopropylethylamine is added to the resulting enol phosphate, then 0.373 g (1.2 mmol) of 1-methyl-1- (2-mercaptoethyl) morpholinium trifluoromethanesulfonate .

   The reaction mixture is stirred at room temperature for 90 minutes and then concentrated in vacuo. The residual material is taken up in H2O and then treated in a C18 phase inversion column. The elution is carried out using H2O then a mixture of 20% acetonitrile in water and finally a mixture of 30% acetonitrile in water; freeze-drying of the resulting fractions is then carried out, which leads to the production of 0.360 g (40% yield) of the product under heading which is in the form of an amorphous solid.

  <Desc / Clms Page number 68>

 



   The physical properties are as follows: ir spectrum (film): 3300 (-OH); 1770 (ss-lactam CO); 1700 (-COPNB) cm-i; 1Hnmr (de-acetone) 6: 8.25, 7.80 (ABq, I = 8, 6Hz, 4H, aromatic);
7.4-6.8 (m, 10H, diphenylphosphate);
5.56, 5.27 (ABq, I = 14.2Hz, 2H, benzyl);
4.42 (d of t, I = 9.2Hz, I '= 2.7Hz, 1H, H-5);
4.1-2.7 (m, 17H);
3.40 (s, 3H, N-Me);
1.22 (d, I = 6, 2Hz, 3H, -CHMe).



    C. - (5R, 6S) -3- | 2- (1-metylmorpholino) ethylio carboxylate | -6- | (R) -1- hydroxyethyl | -7-oxo-1-azabicyclo | 3, 2, 0 | hept-2-ene-2
 EMI68.1
 
To a solution of (5R, 6S) -3-j2- (1-methylmorpholino) ethylthio | -6- | (R) -1-hydroxyethyl | -7-oxo-1-azabicyclo carboxylate | 3, 2, 01hept- 2-ene-2 diphenylphosphated (0.360 g, 0.49 mmol) in 13 ml of phosphate buffer (0.05 M; pH 7.4), 0.36 g of a catalyst in the form of 10% palladium on is added carbon, 20 ml of tetrahydrofuran and 20 ml of diethyl ether. The mixture is hydrogenated (in a Parr apparatus) under 2.10 bars for 1 hour. The mixture is then filtered through Celite and the
 EMI68.2
 filtration plug is washed with H2O and diethyl ether.

   The aqueous phase is separated and the pH is adjusted to 7.0 by adding an additional phosphate buffer at pH 7.4. After removal of the residual organic solvents under vacuum, the aqueous solution is introduced into a reverse phase C18 column. . Elution is carried out with H2O and then lyophilization of the resulting fractions. 0.130 g of an amorphous solid is thus obtained. This material is repurified by reverse phase chromatography, which leads to the production of a pure product (0.058 g; yield 34%) in the form of an amorphous solid.



   The physical properties are as follows: ir spectrum (BRr) vmax: 3420 (br, OH); 1750 (ss-lacmeCO);
1590 (-CO -) cm-1;
 EMI68.3
 'Hnmr (DO) 6: 1 Hnmr 35-2.77 (m, 17H); 3.18 (s, 3H, N-Me) 1.23 (d, I = 6.3Hz, 3H, CHMe);

  <Desc / Clms Page number 69>

 
 EMI69.1
 uv (H2O) at 300 (e6344) nm; max (020) 0: 4, t, / 2 (pH 7.4, 36, 8 C) 18.5 h.



  EXAMPLE 4 Preparation of (5R, 6S) 3-12- (1,4-dimethyl-1-piperazinium) carboxylate -
 EMI69.2
 ethylthio-6-) 1- hept-2-ene-2
 EMI69.3
 
 EMI69.4
 A.-bromide of 1-
 EMI69.5
 
 EMI69.6
 A solution of 2-bromoethyl * thiolacetate (2.20 g; 0.012 mole) and 1, 4-dimethylpiperazine (1.95 ml; 0.014 mole) in acetone (4 ml) is stirred at 50 ° C. for 65 hours. After cooling to 25 ° C., the liquid phase is separated from the gum which has been triturated twice in diethyl ether. 3.2 g (90% of the theoretical yield) of a hygroscopic yellow powder are obtained, the physical properties of which are as follows:
 EMI69.7
 spectrum ir (Nujol) v: 1685 (C = 0 of thioester) cm-1 max 1Hmr (D20) 6: 2, 37, 2, 39 (2s, 6H,, * \ / C "3 3, 18 (s, 3H, yin.)
 EMI69.8
 * B.

   Hansen, Acta Chem. Scand. 11, 537-40 (1957).



  B.-1,4-Dimethyl-1- (2-mercaptoethyl) piperazinium bromide hydrochloride
 EMI69.9
 
A solution of 1- (2-acetylthioethyl) -1,4-dimethyliperazinium bromide (1.1 g; 3.7 mmol) in 4 ml of 6N hydrochloric acid is heated at 80 ° C. under a nitrogen atmosphere for 1 hour . The solution is concentrated

  <Desc / Clms Page number 70>

 
 EMI70.1
 under reduced pressure; 0.41 9 is thus obtained (38% theoretical yield) of a white powder whose physical properties are as follows:
 EMI70.2
 H 'Hmr (DMSO, de) 6: 2.90 (s ,. N + "").



  - / \ CH3 / \ 113
 EMI70.3
 The analysis leads to the following contents for the formula: CsHsoSBrd. H20
 EMI70.4
 
 <tb>
 <tb> CH3 <SEP> -C <SEP> H <SEP> N <SEP> S
 <tb> - <SEP> calculated <SEP> 31.03 <SEP> 7.16 <SEP> 9.05 <SEP> 10.35
 <tb> - <SEP> found <SEP> 31.62 <SEP> 7, <SEP> 46 <SEP> - <SEP> 9, <SEP> 19 <SEP> 10.19
 <tb>
 
 EMI70.5
 vs. of (5R, 6S) paranitrobenzyl 3-12- ethylthiol-6-11- ene-2 diphenylphosphated
 EMI70.6
 OH NEt (iPr) OH - 2) C1P (OPh) 2 Nose COOPNB-Br SIN OH 4) NEt (iPr) 2 OH --r - \ - (PhO) E N COOPNB
 EMI70.7
 To a cold solution (0 C) of carboxylate of (5R, 6S) paranitrobenzyl 6-11- (0.465 g; 1.33 mmol) in 2 ml of acetonitrile maintained under nitrogen atmosphere, 0.278 is added. ml (1.59 mmol) of diisopropylethylamine and 0.33 ml (1.59 mmol) of diphenyl chlorophosphate.

   The reaction mixture is stirred for 30 minutes and then treated with a suspension of 1,4-dimethyl-1- bromide hydrochloride (0.40 g; 1.37 mmol) in a mixture of 3 ml of acetonitrile and 1 ml water and diisopropylethylamine (0.278 ml; 1.59 mmol). After stirring for 18 hours at 5 ° C., 15 ml of cold water are added to the mixture obtained.



  The resulting solution is chromatographed on a PrepPak-500 / C18 column of 2.5 cm × 7.5 cm, with a solution of 25 to 35% acetonitrile in water which acts as an elution solvent.

  <Desc / Clms Page number 71>

 0.50 9 (50% theoretical yield) of a yellow powder is obtained after lyophilization.



   The physical properties are as follows:
 EMI71.1
 spectrum (KBr) v: 1765 (C = O of ss-lactam); 1690 (C = O of PNB ester); 1585 (phenyl); 1512 (NO,); 875 (NO2) cm-1; 1Hmr (DMSO, d ..: 1, 16, 1, 18 (2d, I = 6, IHz. 3H, CH-CHOH)
 EMI71.2
 - + \ / CH3 2.44 (s, N-CH3); 3, 14 (s, n ir5, 31 (d, I = bHz, UH); 5.39 (center of ABq, I = 13Hz, CH2 of PNB); 6.6-7, 4 (m, 10H, phenyl phosphate); 7.71 (d, l = 8.8Hz, 2H, Ho of PNB); 8.27 (d, I = 8.8Hz, Hm of PNB).
 EMI71.3
 



  D. (5R, 6S) 3-12- Jl-
 EMI71.4
 OH r-TsC) - '' "'' - '//' - 'buffer buffer N OOPNB 1 --- 2 --- COOPNB
 EMI71.5
 
 EMI71.6
 To a solution of carboxylate of (5R, 6S) paranitrobenzy1 3-12-dimethyl1-1-piperazinium) ethy1thioj-6-11- - deazabicyclo carboxylate | 3,2,0 | hetp-2-ene-2 diphenylphosphated (0.47 g; 0.623 mmol) in 25 ml of wet tetrahydrofuran, 25 ml of diethyl ether, 13 ml (pH 7.22) of a sodium hydroxide-potassium diacid phosphate buffer and 0.47 g of palladium (10 %) on coal. The resulting mixture is hydrogenated at 23 ° C. under 2.8 bars for 1 hour. The two layers are separated and the organic phase is extracted using (2 x 7 ml) of water.



  The aqueous layers are combined, filtered on a Celite pad, washed
 EMI71.7
 using (2 x 15 ml) of diethyl ether and chromatographed on a column of (2.5 x 9.5 cm) of PrepPak-500 / C18 (Waters Associates) using

  <Desc / Clms Page number 72>

 
 EMI72.1
 water acting as an elution solvent; 0.097 g (43% of the yield) of the product under heading is obtained after lyophilization.



  The physical properties are as follows: spectrum (KBr) v: 3000-3700 (OH); 1750 (C = O of 3-lactam); 1585 (carboxylate) cm-1 1Hmr (DO) 1.24 (d, 1 = 6.4Hz, 3H, CHCHOH);
 EMI72.2
 CH3 2.33 (s, 3H, 'N-CH) 3.15 (S, "+");
 EMI72.3
 q, U-4, b (m UV max 'lao23 61, 1 (C 0, 26, H20); tel / 2 12, 4 h.



  (measured at a concentration of 10-4 M in a phosphate buffer of pH 7, 4 to 36, 8 C).



  EXAMPLE 5 Preparation of (5R, oxide) ethylthioj-6-11- 3, 2-ene-2 carboxylate
 EMI72.4
 

  <Desc / Clms Page number 73>

 
To a cold solution (-10 C) of (5R, 6S) -carboxylate -3- | 2- | 2- (N-methyl-thiomorpholinium) ethylthio | -6- | 1- (R) hydroxyethyl | -7-oxo-1 - azabicyclo) 3, 2, 0} -hept-2-ene-2- (608 mg, 1.65 mmol) in a 1/1 mixture
 EMI73.1
 acetonitrile-water (9 ml), 334.8 mg (1.65 mmol) of m-chloroperbenzoic acid are added in small portions over a period of about one hour. The mixture is then diluted in 15 ml of water and then washed with (3 x 15 ml) of diethyl ether. The aqueous phase is brought by pumping under vacuum in a column of silica gel with phase inversion (H 0) in order to obtain a solid which consists of a mixture of the compounds.

   This mixture is separated by reverse phase chromatography and leads to 52.4 mg (yield 12%) of a fraction A and to 23.6 mg (yield 6%) of fraction B which are diastereoisomers of the compound in heading .



   The fractions obtained are as follows: Fraction A:
 EMI73.2
 ir spectrum (nujol): 1750 (s, p-lactam C = O); and 1580 cm-1 (s, C = O); 1Hmr (DO) 6: 4, 26-2, 91 (20H, m, H-4, H-5, H-6, H-1 ', CH2S, vinaxCH2S-O, CH3-N and CH2N +); and
1.24 ppm (3H, d, I = 6.4Hz, CH3); uv (H2O, c 0.06) 302 (10425);
 EMI73.3
 12 h (phosphate buffer 0.065 M, pH 7.4, at 370C).



  Fraction B: ir spectrum (nujol): 1750 (s, -lactamC = Û); and 1585 cm- (s, C =; 1Hmr (D20) 6: 3, 86-2, 90 (17 H, m, H-4, H-5, H-6, H-14, CH2S, SH2S-O , CH2N +); 3.25 (3H, s, CH3N); and, 1.25 ppm (3H, d, I = 6.4Hz, CH3);
T1 / 2uv (H2O, c 0.05) TO: 2.99 (6517); T \. 10.75 h (phosphate buffer 0.065 M, pH 7.4, at
37 C).



  EXAMPLE 6 Preparation of (5R, 6S) -3- | 2- (1, 4, 4-trimethyl-1- piperazinium) -ethylthio | -6- | 1R-hydroxyethyl | -7-oxo-1- carboxylate chloride azabicyclo | 3,2,0 |

  <Desc / Clms Page number 74>

 
 EMI74.1
 hept-2-ene-2
 EMI74.2
 
 EMI74.3
 A. of 1- 4, 4-trimethylpiperazinium
 EMI74.4
 Me, OH, ¯ N + CH3 \\ .- i OH, 55-600C CH .'N + \ / \ / ¯ CH3CS
 EMI74.5
 A suspension of 1- - bromoiodurepiperazinium bromide (1.48 g; 5.0 mmol) in 10 ml of isopropyl alcohol is treated with 0.373 ml (6.0 mmol) of methyl iodide and the whole is heated to 55 -60 C for 30 hours.

   The solvents are evaporated under reduced pressure; the residue is triturated in hexane and the solid is filtered; 1.85 g of a product are thus obtained which is dissolved in 8 ml of hot water to obtain a solution which is diluted in acetone until a haze is obtained (70-80 ml). Two successive crystallizations lead to 1.5 g of the title compound (68% yield) having a melting point of 220-5 C (with decomposition).



   The physical properties are as follows:
 EMI74.6
 spectrum (KBr): 1692 cm-1 (C = O); ir'Hmr (D20) 6: 2.40 (s, 3H, CH3COO); 3.37 (s, N-CH3);
3.39 (s, N-CH3); 3.99 (s); uv (H2j max: 226 (E13144).



   The analysis leads to the following contents for the formula:
C11H24N2OSBrI
 EMI74.7
 
 <tb>
 <tb> C <SEP> H <SEP> N
 <tb> - <SEP> calculated <SEP> 30, <SEP> 08 <SEP> 5.51 <SEP> 6.38
 <tb> - <SEP> found <SEP> 30.48 <SEP> 5.53 <SEP> 6.86
 <tb>
 

  <Desc / Clms Page number 75>

 
 EMI75.1
 B. 1- (2-mercaptoethyl) bischloride -1, 4, 4-trimethylpiperazinium
 EMI75.2
 - 6N Pennutite + C \ / \ '"' 0N / +, s
 EMI75.3
 A mixture of 1- bromoiodide
HClpiperazinium (1.84 g; 4.19 mmol) and 15 ml of 6N hydrochloric acid is heated to 570C under nitrogen for 150 minutes. The solution is concentrated to dryness under reduced pressure. The solid is suspended in 10 ml of water and the well-stirred suspension is treated with S-1 Cl- permutite until a solution is obtained.

   The solution is poured onto a permutite column S-1 Cl- (1, 2 x 60 cm). The column is subjected to an elution using water (1.5 ml / min). The suitable fractions are combined and lyophilized; 0.93 g of a white powder is obtained, the melting point of which is 190-191 ° C. (yield 85%).



  * The physical properties are as follows: ir spectrum (nujol) vmax: 2460 (SH); 1Hmr (D2O) #: 3.4 (s, N-CH3); 3.45 (s, N-CH3);
4.07 (s).
 EMI75.4
 



  The analysis leads to the following contents for the formula: CgH22N2SC12. O. 75 H20
 EMI75.5
 
 <tb>
 <tb> C <SEP> H <SEP> N <SEP> S
 <tb> - <SEP> calculated <SEP> 39.34 <SEP> 8.62 <SEP> 10.20 <SEP> 11.67
 <tb> - <SEP> found <SEP> 39.48 <SEP> 8.39 <SEP> 10.55 <SEP> 11.15
 <tb>
 C.- (5R, 6S) carboxylate bischloride paranitrobenzyl 3-12- (1, 4,4-
 EMI75.6
 trmiéthy1-l-piperaz'imum) -éthy1thio) -6-) lR-hydroxyêthy1 j-7-oxo-l-azabicyclo | 3, 2, 0 | htp-2-en-2
 EMI75.7
 OH 1) NEt (iPr) T 9 J '"% 2) r E --COOPNB -' Cl" -r-'OC> PNB p ¯i - "\ / \

  <Desc / Clms Page number 76>

 
 EMI76.1
 OH permutite S-1 Cl --- '' 'r) -s- \ i.

   'N 0 iN - 2Cl COOPNB
To a cold solution (50C) of 2R-carboxylate of (5R, 6S) paranitrobenzyl 6- | 1R-hydroxyethyl | -3,7-dioxo-1-azabicyclo | 3, 2, 0) heptane (0.94 g, 2 0.5 mmol) in 3 ml of acetonitrile maintained under a nitrogen atmosphere, 0.557 ml (3.2 mmol) of diisopropylethylamine and 0.663 ml (3.2 mmol) of diphenyl chlorophosphate are added. The reaction mixture is stirred at 5 ° C. for 30 minutes and treated with 0.599 ml (3.44 mmol) of diisopropylethylamine and an aqueous solution (4 ml) of 0.90 g (3.44 mmol) of 1- bischloride. (2-mercaptoethyl) -1, 4, 4-trimethylpiperazinium. After 85 minutes, 0.1 ml (0.57 mmol) of diisopropylethylamine is added and stirring continues for 120 minutes.

   Part of the acetonitrile
 EMI76.2
 is removed under reduced pressure and the resulting red mixture is chromatographed on a PrepPak-500 / C18 column, the eluent being formed from a solution of 25 to 75% acetonitrile in water. 1.4 g of a yellow powder are thus obtained, after lyophilization. The powder is dissolved in water and the solution is passed through a column (1.2 x 58 cm) of permutite S-1 Cl-, the eluent being formed of water. Lyophilization of suitable fractions leads to 1.17 g of a powder which is repurified on a column of PrePak-500 / C18. Lyophilization of suitable fractions leads to obtaining 0.80 g (53% of the theoretical yield) of a yellow powder.



   The physical properties are as follows: ir spectrum (KBr) vmax 3400 (br, OH); 1770 (C = O of $ -lactam);
1690 (C = O of PNB ester); 1605 (aromatic);
 EMI76.3
 1515 1515 (NO, 1345 (NO, 1HIllr (DsO) 6: 1, 26 (d, I = 6, 3Hz, 3H, CCHOH); 3.39 (s, NCH3); 4.00 (s); 5, 37 (br, s, CH2 of PNB); 7.60 (d, I = 8, 6Hz, 2H, Ho of. PNB); 8.20 (d, I = 8, 7Hz, 2H, Hm of PNB);
 EMI76.4
 uv (H2O) TO: 276 (C12094); 306 (cl0752).



  The analysis leads to the following contents for the formula: CsHseOeSCI 3

  <Desc / Clms Page number 77>

 
 EMI77.1
 
 <tb>
 <tb> H20C <SEP> H <SEP> N <SEP> S <SEP> Cl
 <tb> - <SEP> calculated <SEP> 46.51 <SEP> 6, <SEP> 56 <SEP> 8.68 <SEP> 4.97 <SEP> 10.98
 <tb> - <SEP> found <SEP> 46.31 <SEP> 6.18 <SEP> 8.57 <SEP> 5.36 <SEP> 11.37
 <tb>
 D.- (5R, 6S) -3-) 2- (1, 4, 4-triethyl-1-piperazinium) ethylthio carboxylate chloride | -6- | 1R-hydroxyethyl | -7-oxo-1- azabicyclo | 3, 2, 0 | hept-2- ene-2
 EMI77.2
 A mixture of 0.40 g (0.68 mmol) of carboxylate bischloride
 EMI77.3
 (5R, 6S) paranitrobenzyl 3-12- 4, 4-trimethyl-1-piperazinium) ethylthiol-6- (1, | 1R-hydroxyethyl | -7-oxo-1-azabicyclo | 3,2,0 | hept-2 -ene-2, 30 ml (0.005M, pH 7.0) of phosphate buffer, 10 ml of tetrahydrofuran,

   30 ml. of ether and 0.40 g of 10% palladium on charcoal is hydrogenated at 230C at 2.1 bar for 1 hour. The two phases are separate. The organic phase is extracted with water (10 ml). The aqueous phases are filtered on a pad of Celite, washed with ether (10 ml), concentrated in vacuo until 10 ml and chromatographed on a column of (2.2 x 11 cm) of PrepPak-500 / C, water being used as the eluent. After lyophilization, 70 mg (25% of the theoretical yield) of the product under heading are thus obtained.



   The physical properties are as follows: ir spectrum (KBr) #max: 3400 (br, OH); 1755 (C = O of 6-lactam);
1585 (carboxylate) cm-1;
 EMI77.4
 1Hmr (DsO) 6: 1, 24 (3H, d, I = 6, 3Hz, CCHOH);
3.36 (s, NCH); 3.98 (s); uv (H2O) #max: 296 (7987); ta) 35, 9 (c, 0.30, H2O) Tri / 2 = 9.8 h
 EMI77.5
 (measured a concentration of 10-M in a phosphate buffer of pH 7, 4 to 36, 80C). '

  <Desc / Clms Page number 78>

 
Of course, the invention is not limited to the embodiments described and shown and it is capable of numerous variants accessible to those skilled in the art, without departing from the spirit of the invention. 'invention.


    

Claims (1)

 CLAIMS 1. - As new products, the carbapenem derivatives of formula:  EMI79.1  in which : Rs is a hydrogen atom, and It is chosen from the group comprising hydrogen, as well as the radicals, substituted or unsubstituted, belonging to the following list: alkyl, alkenyl and alkynyl, comprising from 1 to 10 carbon atoms; cycloalkyl and cycloalkylalkyle comprising from 3 to 6 carbon atoms in the cycloalkyl ring and 1 to 6 carbon atoms in the alkylated part; phenyl; aralkyl, aralkenyl and aralkynyl, the aryl part of which is constituted by a phenyl radical and the aliphatic part of which comprises from 1 to 6 carbon atoms;  heteroaryl, heteroaralkyl, heterocyclyl and heterocyclylalkyl in which the heteroatom (s) of the aforementioned heterocyclic parts are chosen from the group comprising 1 to 4 atoms of oxygen, nitrogen or sulfur, and the alkylated part is associated with said heterocyclic parts comprising 1 to 6 carbon atoms, in which the substituent (s) relating to the abovementioned radicals are independently chosen from the group comprising: C1 to C6 alkyl radicals, optionally substituted by amino, halo, hydroxy or carboxyl radicals;    EMI79.2    <Desc / Clms Page number 80>    EMI80.1  in which, with respect to the abovementioned substituents, the groups R3 and R4 are independently chosen from hydrogen as well as the alkyl, alkenyl and alkynyl groups comprising from 1 to 10 atoms  EMI80.2  carbon; cycloalkyl, cycloalkylalkyle and alkylcycloalkyle having 3 to 6 carbon atoms in the cycloalkyl ring and 1 to 6 carbon atoms in the alkyl part; phenyl; aralkyl, aralkenyl and aralkynyl in which the aryl part is formed by a phenyl radical and in which the aliphatic part comprises 1 to 6 carbon atoms;  and heteroaryl, heteroaralkyl, heterocyclyl and heterocyclylalkyl in which the heteroatom (s) of the aforementioned heterocyclic parts are chosen from the group comprising 1 to 4 oxygen, nitrogen or sulfur atoms and the alkylated parts associated with said heterocyclic parts comprising from 1 to 6 carbon atoms, or R3 and R4 taken together with the nitrogen atom to which at least one of them is linked, can form  <Desc / Clms Page number 81>  mer a heterocyclic ring with 5 or 6 atoms containing nitrogen; R9 is as defined for R3 except that it cannot be hydrogen or in which RI and Re taken together represent a radical  EMI81.1  C 1-10 alkylidene or C 2-10 alkylidene substituted with hydroxy groups;  R5 is chosen from the group comprising substituted or unsubstituted radicals belonging to the following list: alkyl, alkenyl and alkynyl comprising from 1 to 10 carbon atoms; cycloalkyl and cycloalkylalkyle comprising from 3 to 6 carbon atoms in the cycloalkyl ring and 1 to 6 carbon atoms in the alkylated part; phenyl; aralkyl, aralkenyl and aralkynyl, the aryl part of which is constituted by a phenyl radical and the aliphatic part of which comprises 1 to 6 carbon atoms; heteroaryl, heteroaralkyl, heterocyclyl and heterocyclylalkyl in which the heteroatom (s) of the abovementioned heterocyclic parts are chosen from the group comprising 1 to 4 oxygen, nitrogen or sulfur atoms and the alkylated part which is associated with said heterocyclic parts comprising 1 to 6 carbon atoms;  in which the abovementioned R5 radicals are optionally substituted with 1-3 substituents independently chosen from the following group: C1-C6 alkyl, optionally substituted with amino, fluoro, chloro, carboxyl, hydroxy or carbamoyl groups; fluoro, chloro or bromo;  EMI81.2    <Desc / Clms Page number 82>  -SO3R3 - COzR - CONR R - CN; or phenyl optionally substituted with 1 to 3 atoms of fluorine, chlorine,  EMI82.1  of bromine or Ci to Ce groups; -OR, -NRR, -SOR, alkyl-CO2R3 or -CONR3R4, in which R3, R4 and R9 in these substituents Rs are as defined above where R5 may represent a phenylene group divalent or an alkylene group. in C1 to C4 linked to the nucleus  EMI82.2  so as to form a bridged polycyclic group;    EMI82.3  A is a C2 to C6 cyclopentylene, cyclohexylene or alkylene group optionally substituted by one or more C1 to C4 alkyl groups; R2 is a hydrogen atom or an anionic charge or a conventional easily separable carboxyl protecting group, it being understood that when R2 is a hydrogen atom or a protecting group, a counterion may also be present; and  EMI82.4  represents a heterocycnic non-aromatic, mono-bi-or po) y-cyclic radical, substituted or unsubstituted, containing at least one nitrogen atom in the nucleus and linked to A by a nitrogen bond, so as to form a group quaternary ammonium as well as the pharmaceutically acceptable salts of its compounds.  2.-As new products, the carbapenem derivatives of formula:  EMI82.5    <Desc / Clms Page number 83>  in which: Rs is a hydrogen atom, and R1 is chosen from the group comprising hydrogen, as well as the radicals, substituted or unsubstituted, belonging to the following list: alkyl, alkenyl and alkynyl, comprising of 1 to 10 carbon atoms; cycloalkyl and cycloalkylalkyle comprising from 3 to 6 carbon atoms in the cycloalkyl ring and 1 to 6 carbon atoms in the alkylated part; phenyl; aralkyl, aralkenyl and aralkynyl, the aryl part of which is constituted by a phenyl radical and the aliphatic part of which comprises from 1 to 6 carbon atoms;  heteroaryl, heteroaralkyl, heterocyclyl and heterocyclylalkyl in which the heteroatom (s) of the aforementioned heterocyclic parts are chosen from the group comprising 1 to 4 oxygen, nitrogen or sulfur atoms, and the alkylated part is associated with said heterocyclic parts comprising 1 to 6 carbon atoms, in which the substituent (s) relating to the abovementioned radicals are independently chosen from the group comprising: C1 to C6 alkyl radicals, optionally substituted by amino, halo, hydroxy or carboxyl radicals;  halo  EMI83.1    <Desc / Clms Page number 84>    EMI84.1  in which, with respect to the abovementioned substituents, the groups R3 and R4 are independently chosen from hydrogen as well as the alkyl, alkenyl and alkynyl groups comprising from 1 to 10 carbon atoms; cycloalkyl, cycloalkylalkyle and alkylcycloalkyle comprising 3 to 6 carbon atoms in the cycloalkyl ring and 1 to 6 carbon atoms in the alkyl part; phenyl; aralkyl, aralkenyl and aralkynyl in which the aryl part is formed by a phenyl radical and in which the aliphatic part comprises 1 to 6 carbon atoms;  and heteroaryl, heteroaralkyl, heterocyclyl and heterocyclylalkyl in which the heteroatom (s) of the aforementioned heterocyclic parts are chosen from the group comprising 1 to 4 oxygen, nitrogen or sulfur atoms and the alkylated parts associated with said heterocyclic parts comprising from 1 with 6 carbon atoms, or R3 and R4 taken together with the nitrogen atom to which at least one of them is linked, can form a heterocyclic ring with 5 or 6 atoms containing nitrogen;  R9 is as defined for R3 except that it cannot be hydrogen or in which R1 and RB taken together represent a radical  EMI84.2  C2 to C10 alkylidene or C2 to C10 alkylidene substituted by hydroxy groups; R5 is chosen from the group comprising substituted or unsubstituted radicals belonging to the following list: alkyl, alkenyl and alkynyl comprising from 1 to 10 carbon atoms; cycloalkyl and cycloal-  <Desc / Clms Page number 85>    EMI85.1  kylalkyl comprising from 3 to 6 carbon atoms in the cycloalkyl ring and 1 to 6 carbon atoms in the alkylated part; phenyl; aralkyl, aralkenyl and aralkynyl, the aryl part of which is constituted by a phenyl radical and the aliphatic part of which comprises 1 to 6 carbon atoms;    heteroaryl, heteroaralkyl, heterocyclyl and heterocyclylalkyl in which the heteroatom (s) of the aforementioned heterocyclic parts are chosen from the group comprising 1 to 4 oxygen, nitrogen or sulfur atoms and the alkylated part which is associated with said heterocyclic parts comprising from 1 to 6 carbon atoms; in which the abovementioned R5 radicals are optionally substituted with 1-3 substituents independently chosen from the following group: C1 to C6 alkyl, optionally substituted with amino, fluoro, chloro, carboxyl, hydroxy or carbamoyl groups; fluoro, chloro or bromo;    EMI85.2  phenyl optionally substituted with 1 to 3 fluorine, chlorine, bromine or C1 to C6 alkyl groups; -OR3, -NR3R4, -S03R3,  <Desc / Clms Page number 86>    EMI86.1  - R, in which R3, R4 in these substituents R5 are as defined above can represent a divalent phenylene group or a C1 to C4 alkylene group linked to the nucleus  EMI86.2    EMI86.3  so as to form a bridged polycyclic group; A is a C2 to C6 cyclopentylene, cyclohexylene or alkylene group optionally substituted by one or more C1 to C4 alkyl groups;  R2 is a hydrogen atom or an anionic charge or a conventional easily separable carboxyl protecting group, it being understood that when R2 is a hydrogen atom or a protecting group, a counterion may also be present; and  EMI86.4  represents a non-aromatic heterocyclic ring containing nitrogen having from 4 to 7 atoms, preferably 5 or 6 atoms, containing 0 to 2 doubles  EMI86.5  bonds and 0 to 2 hetero atoms 0, S N, NR10 or NR15R16 in which: m is 0, 1 or 2;  Rio is hydrogen, a C1 to C6 alkyl radical optionally substituted by one or two substituents, chosen independently of one another from -OR, -NRR, -CORs, oxo, phenyl, fluoro, chloro, bromo, -SO3R3 and -CONR3R4 or phenyl optionally substituted with one to three substituents chosen independently of one another from C1 to C6 alkyl radicals, -OR3, -NR3R4, fluoro, chloro,  EMI86.6  bromo, -SURE, -COJ R;  and, and-CONRRis and Rie-independently of one another are chosen from C1 to C6 alkyl radicals optionally substituted by one or two substituents chosen independently of one another from the radicals -OR3, -NR3R4 , -CO2R3, oxo, phenyl, fluoro, chloro, bromo,  EMI86.7  - R "or by the substituent chosen independently of one another from, - - ..  <Desc / Clms Page number 87>  C1 to C6 alkyl radicals, -OR3, -NR3R4, fluoro, chloro, bromo, -SO3R3, -CO2R2 and-CONR3R4, in which: R3 and R4 in such heterocyclic groups NR10 and NR'BR'6 are as defined in relation to the substituent R5. In a preferred embodiment, the core  EMI87.1  may be optionally substituted by 1 to 3 substituents, chosen independently of one another from: (a) C1-C6 alkyl radicals optionally substituted by 1 or 2 substituents chosen independently of the other among the fluoro, chloro, bromo, -OR3, -OCOR3, -OCONR3R4, oxo, -NR3R4 radicals,  EMI87.2  - COR ", - NRCONRR", - NRSOzR ", - SR, -SOaR, -COR and 4 - R (b) a1kény1osen one or two substituents chosen independently of each other from fluoro, chloro, bromo, -OR, -OCOR, -OCONRR ",, - COR", - NRCONRR ", - NRSOzR", - SR, -SOsR, -COsR R "(c) alkynyles in one or two substituents chosen independently of the other fluoro, chloro, bromo, -OR, -OCOR, -OCONR,, -NRCOR ", - CONRR", - NRSOR ", - SR", - SOsR, -COR;  (d) cycloalkylesen with one or two substituents chosen independently of one another from the fluoro, chloro, brama, - R4 groups; (e) cycloalkylalkyls comprising 3 to 6 carbon atoms in the cycloalkyl part and 1 to 6 carbon atoms in the alkyl part, optionally substituted by one or two substituents chosen independently of one another from the group fluoro, chloro, bromo, -OR3, -OCOR3, -OCONR3R4, oxo, -NR3R4, -NR3COR4, -NR3CONR3R4, -NR3SO2R4, - SR3, -SO3R3, -CO2R3 and-CONR3R4;  (f) heteroaryls in which the hetero atom (s) are chosen from the group comprising 1 to 4 oxygen, nitrogen or sulfur atoms optionally substituted by one or two substituents chosen independently of one another among the fluoro, chloro, bromo,  <Desc / Clms Page number 88>    EMI88.1  - -; the heteroaryl radicals preferably used are aromatic heterocyclic rings with 5 or 6 atoms;  (g) heteroaralkyls in which the heteroatom (s) are chosen from the group comprising 1 to 4 oxygen, nitrogen or sulfur atoms and the alkyl part comprises 1 to 6 carbon atoms, optionally substituted by a with two substituents chosen independently from each other from the fluoro, chloro, bromo, -OR3, -OCOR3, -OCONR3R4, oxo, -NR3R4, -NR3COR4, -NR3CONR3R4, - NR3SO2R4, -SR3 groups - SO3R3, -CO2R3 and-CONR3R4; the heteroaralkyls preferably used are those in which the heteroaryl radical is an aromatic heterocyclic ring with 5 to 6 atoms and the alkyl part comprises 1 to 2 carbon atoms;  (h) heterocyclyls according to which the hetero atom (s) are chosen from the group comprising l. with 4 oxygen, nitrogen or sulfur atoms optionally substituted by one or two substituents chosen independently from one another from the fluoro, chloro,  EMI88.2  bromo, -OR, -OCOR, -OCONRR,, -NRCOR, -NRCONRR, oxo, -NR = 'R- NR3SO2R4, -SR3, -S03R3, -CO2R3 and-CONR3R4; particularly preferred are heterocyclytes comprising saturated or unsaturated rings with 5 or 6 atoms;  (i) heterocyclylalyls in which the hetero atom (s) are chosen from the group comprising 1 to 4 oxygen, nitrogen or sulfur atoms, and the alkyl part comprises 1 to 6 carbon atoms, optionally substituted with one to two substituents independently chosen from fluoro, chloro, bromo, -OR3, -OCOR3, -OCONR3R4, oxo, -NR3R4, -NR3COR4, -NR3CONR3R4, -NR3SO2R4, -SR3, -SO3R3, -CO2R3 and -CONR3R4; particularly preferred are heterocyclylalkyls in which the heterocyclyl part is a saturated or unsaturated ring with 5 or 6 atoms; (j) fluoro, chloro or bromo; (k) -OR3;  (1) -OC02R3; (m) -OCOR; (n) -OCONRR; (o) -OSO; (p) oxo;  <Desc / Clms Page number 89>    EMI89.1    (cc) phenyl optionally substituted with 1 to 3 atoms of fluorine, chlorine, bromine or C1 to C6 alkyl radicals, -OR3, -NR3R4, -SO3R3, -CO2R3 or -CONR3R4; the substituents R3, R4 and R9 mentioned above are defined in relation to the definitions given for the substituent R1.  The cycle  EMI89.2  as defined above is a non-aromatic heterocyclic group. This ring, however, can be fused into another ring which can be a saturated or unsaturated carbocyclic ring, preferably a C4 to C7 carbocyclic ring, a phenyl ring, a heterocyclic (saturated or unsaturated) ring.  EMI89.3  with 4 to 7 atoms containing 1 to 3 hetero atoms chosen from: 0, SN, ni 'NR10 or NR15R16 or a hetero aromatic ring with 5 or 6 atoms containing 1 to 3 hetero atoms chosen from: 0, SN, NR10 or NR''R'6 in which: m, R10, Ris and R16 are as defined above. The fused carbocyclic, phenyl, heterocyclic or heteroaromatic ring may be optionally substituted with one to three substituents chosen independently of one another from C 1 alkyl radicals  EMI89.4  to C6, fluoro, chloro, bromo, -SOaRs, -CO in which R3 and R4 are as defined above.  <Desc / Clms Page number 90>    -OR3, -NR3R4,3.-As new products, the carbapenem derivatives of formula:  EMI90.1  in which :  EMI90.2  Ra is a hydrogen atom, and R1 is chosen from the group comprising hydrogen, as well as the radicals, substituted or unsubstituted, belonging to the following list: alkyl, alkenyl and alkynyl, comprising from 1 to 10 atoms of carbon ; cycloalkyl and cycloalkylalkyle comprising from 3 to 6 carbon atoms in the cycloalkyl ring and 1 to 6 carbon atoms in the alkylated part; phenyl; aralkyl, aralkenyl and aralkynyl, the aryl part of which is constituted by a phenyl radical and the aliphatic part of which comprises from 1 to 6 carbon atoms;  heteroaryl, hetero-aralkyl, heterocyclyl and heterocyclylalkyl in which the heteroatom (s) of the aforementioned heterocyclic parts are chosen from the group comprising 1 to 4 oxygen, nitrogen or sulfur atoms, and the alkylated part is associated with said heterocyclic parts comprising 1 to 6 carbon atoms, in which the substituent (s) relating to the abovementioned radicals are independently chosen from the group comprising: C1 to C6 alkyl radicals, optionally substituted by amino, halo, hydroxy or carboxyl radicals;  halo  EMI90.3    <Desc / Clms Page number 91>    EMI91.1  in which, with respect to the abovementioned substituents, the groups R3 and R4 are independently chosen from hydrogen as well as the alkyl, alkenyl and alkynyl groups comprising from 1 to 10 carbon atoms; cycloalkyl, cycloalkylalkyle and alkylcycloalkyle comprising 3 to 6 carbon atoms in the cycloalkyl ring and 1 to 6 carbon atoms in the alkyl part; phenyl; aralkyl, aralkenyl and  EMI91.2  aralkynyl, the aryl part of which is formed by a phenyl radical and the aliphatic part of which comprises 1 to 6 carbon atoms;  and heteroaryl, heteroaralkyl, heterocyclyl and heterocyclylalkyl in which the heteroatom (s) of the aforementioned heterocyclic parts are chosen from the group comprising 1 to 4 oxygen, nitrogen or sulfur atoms and the alkylated parts associated with said heterocyclic parts comprising from 1 to 6 carbon atoms, or R3 and R4 taken together with the nitrogen atom to which at least one of them is linked, can form a heterocyclic ring with 5 or 6 atoms containing nitrogen;  <Desc / Clms Page number 92>  R9 is as defined for R3 except that it cannot be hydrogen or in which R1 and Ra taken together represent a C2-C10 alkylidene or C2-C10 alkylidene radical substituted by hydroxy groups;  A is a cyclopentylene, cyclohexylene or C2 to C6 alkylene group optionally substituted by one or more C1 alkyl groups  EMI92.1  to C4 R2 is a hydrogen atom or an anionic charge or a conventional easily separable carboxyl protecting group, it being understood that when R2 is a hydrogen atom or a protecting group, A counterion may also be present; and  EMI92.2  represented  EMI92.3    <Desc / Clms Page number 93>  and, Y is a hydrogen atom, a C1-C6 alkyl, hydroxy, -S-C1-C6 alkyl, carboxyl, carbamoyl, chloro, bromo, iodine, fluoro or phenyl radical. as well as the pharmaceutically acceptable salts of said compounds.  4.-As new products, the carbapenem derivatives of formula:  EMI93.1  in which :  EMI93.2  Rs is a hydrogen atom, and R 'is chosen from the group comprising hydrogen, as well as the radicals, substituted or unsubstituted, belonging to the following list: alkyl, alkenyl and alkynyl, comprising from 1 to 10 carbon atoms; cycloalkyl and cycloalkylalkyle comprising from 3 to 6 carbon atoms  EMI93.3  in the cycloalkyl ring and 1 to 6 carbon atoms in the alkylated part; phenyl; aralkyl, aralkenyl and aralkynyl in which the aryl part consists of a phenyl radical and in which the aliphatic part comprises from 1 to 6 carbon atoms;  heteroaryl, heteroaralkyl, heterocyclyl and heterocyclylalkyl in which the heteroatom (s) of the aforementioned heterocyclic parts are chosen from the group comprising 1 to 4 oxygen, nitrogen or sulfur atoms, and the alkylated part is associated with said heterocyclic parts comprising 1 to 6 carbon atoms, in which the substituent (s) relating to the abovementioned radicals are independently chosen from the group comprising: C1 to C6 alkyl radicals, optionally substituted by amino, halo, hydroxy or carboxyl radicals;  halo  EMI93.4    <Desc / Clms Page number 94>    EMI94.1  in which, with respect to the abovementioned substituents, the groups R3 and R4 are independently chosen from hydrogen as well as the alkyl, alkenyl and alkynyl groups comprising from 1 to 10 carbon atoms; cycloalkyl, cycloalkylalkyle and alkylcycloalkyle comprising 3 to 6 carbon atoms in the cycloalkyl ring and 1 to 6 carbon atoms in the alkyl part; phenyl; aralkyl, aralkenyl and aralkynyl in which the aryl part is formed by a phenyl radical and in which the aliphatic part comprises 1 to 6 carbon atoms;  and heteroaryl, heteroaralkyl, heterocyclyl and heterocyclylalkyl, the  <Desc / Clms Page number 95>    EMI95.1  or the heteroatoms of the aforementioned heterocyclic parts are chosen from the group comprising 1 to 4 oxygen, nitrogen or sulfur atoms and the alkylated parts associated with said heterocyclic parts comprising from 1 to 6 carbon atoms, or R3 and R4 taken together with the nitrogen atom to which at least one of them is linked, can form a heterocyclic ring with 5 or 6 atoms containing nitrogen; R9 is as defined for R3 except that it cannot be hydrogen or in which R '' and taken together represent a C2-C10 alkylidene radical or C2-C10 alkylidene substituted by hydroxy groups;  A is a C2 to C6 cyclopentylene, cyclohexylene or alkylene group optionally substituted by one or more C1 to C4 alkyl groups; R2 is a hydrogen atom or an anionic charge or a conventional easily separable carboxyl protecting group, it being understood that when R2 is a hydrogen atom or a protecting group, A counterion may also be present; and  EMI95.2  R - N N represents  EMI95.3    EMI95.4  as well as the pharmaceutically acceptable salts of said compounds.  <Desc / Clms Page number 96>    Rs5.-As new products, the carbapenem derivatives of formula:  EMI96.1    EMI96.2  in which: Re is a hydrogen atom, and R1 chosen from the group comprising hydrogen, as well as the radicals, substituted or unsubstituted, belonging to the following list: alkyl, alkenyl and alkynyl, comprising from 1 to 10 atoms of carbon ; cycloalkyl and cycloalkylalkyle comprising from 3 to 6 carbon atoms in the cycloalkyl ring and 1 to 6 carbon atoms in the alkylated part; phenyl; aralkyl, aralkenyl and aralkynyl in which the aryl part consists of a phenyl radical and in which the aliphatic part comprises from 1 to 6 carbon atoms;  heteroaryl, heteroaralkyl, heterocyclyl and heterocyclylalkyl in which the heteroatom (s) of the aforementioned heterocyclic parts are chosen from the group comprising 1 to 4 oxygen, nitrogen or sulfur atoms, and the alkylated part is associated with said heterocyclic parts comprising 1 to 6 carbon atoms, in which the substituent or substituents relating to the abovementioned radicals are independently chosen from the group comprising: C1 to C6 alkyl radicals, by amino, halo, hydroxy or carboxyl radicals; halo  EMI96.3    <Desc / Clms Page number 97>    EMI97.1  in which, with respect to the abovementioned substituents, the groups R3 and R4 are independently chosen from hydrogen as well as the alkyl, alkenyl and alkynyl groups comprising from 1 to 10 carbon atoms;  cycloalkyl, cycloalkylalkyle and alkylcycloalkyle comprising 3 to 6 carbon atoms in the cycloalkyl ring and 1 to 6 carbon atoms in the alkyl part; phenyl; aralkyl, aralkenyl and aralkynyl in which the aryl part is formed by a phenyl radical and in which the aliphatic part comprises 1 to 6 carbon atoms;  and heteroaryl, heteroaralkyl, heterocyclyl and heteri, ocyclylalkyl in which the heteroatom (s) of the aforementioned heterocyclic parts are chosen  EMI97.2  in the group comprising 1 to 4 oxygen, nitrogen or sulfur atoms and the alkylated parts associated with said heterocyclic parts comprising from 1 to 6 carbon atoms, or R3 and R4 taken together with the nitrogen atom at which the less one of them is linked, can form a heterocyclic ring with 5 or 6 atoms containing nitrogen;    <Desc / Clms Page number 98>  R9 is as defined for R3, except that it cannot be hydrogen or in which R'and Rs taken together represent a C2 to C10 alkylidene radical or C2 to C10 alkylidene substituted by hydroxy groups;  EMI98.1  A is a group or C2 to C6 alkylene cyclopentylene, cyclohexylene optionally substituted by one or more C1 to C4 alkyl groups;  R2 is a hydrogen atom or an anionic charge or a conventional easily separable carboxyl protecting group, it being understood that when R2 is a hydrogen atom or a protecting group, A counterion may also be present; and  EMI98.2  Y is a hydrogen atom, a C1-C6 alkyl, hydroxy, -S-C1-C6 alkyl, carboxyl, carbomoyl, chloro, bromo, iodo, fluoro or phenyl radical. In this subclass, preferred are compounds in which A is  EMI98.3  - (CH2) n -andetentendu that n = 2, 3 or 4, or even more particularly according to which A is -CHs -, - CHsCHCHs-, as well as the pharmaceutically acceptable salts of said compounds.  6.-As new products, the carbapenem derivatives of formula:  EMI98.4  in which :  EMI98.5  Rs is a hydrogen atom, and Ri is chosen from the group comprising hydrogen, as well as the radicals, substituted or unsubstituted, belonging to the following list: alkyl, alkenyl and alkynyl, comprising from 1 to 10 atoms of carbon ; cycloalkyl and cycloalkylalkyle comprising of. 3 to 6 carbon atoms in the cycloalkyl ring and 1 to 6 carbon atoms in the alkylated part; phenyl; aralkyl, aralkenyl and aralkynyl, the aryl part of which is constituted by a phenyl radical and the aliphatic part of which comprises from 1 to 6 carbon atoms;  heteroaryl, heteroaralkyl, heterocyclyl and heterocyclylalkyl in which the one or more  <Desc / Clms Page number 99>  heteroatoms of the aforementioned heterocyclic parts are chosen from the group comprising 1 to 4 oxygen, nitrogen or sulfur atoms, and the alkyl part is associated with said heterocyclic parts comprising 1 to 6 carbon atoms, in which the relative substituent (s) the aforementioned radicals are independently chosen from the group comprising: C1 to C6 alkyl radicals, optionally substituted by amino, halo, hydroxy or carboxyl radicals;  halo  EMI99.1    <Desc / Clms Page number 100>    EMI100.1  in which, with respect to the abovementioned substituents, the groups R3 and R4 are independently chosen from hydrogen as well as the alkyl, alkenyl and alkynyl groups comprising from 1 to 10 atoms  EMI100.2  carbon; cycloalkyl, and alkylcycloalkyl comprising 3 to 6 carbon atoms in the cycloalkyl ring and 1 to 6 carbon atoms in the alkyl part; phenyl; aralkyl, aralkenyl and aralkynyl in which the aryl part is formed by a phenyl radical and in which the aliphatic part comprises 1 to 6 carbon atoms;  and heteroaryl, heteroaralkyl, heterocyclyl and heterocyclylalkyl in which the heteroatom (s) of the abovementioned heterocyclic parts are chosen from the group comprising 1 to 4 oxygen, nitrogen or sulfur atoms and the alkylated parts associated with said heterocyclic parts comprising from 1 to 6 carbon atoms, or R3 and R4 taken together with the nitrogen atom to which at least one of them is linked, can form a heterocyclic ring with 5 or 6 atoms containing nitrogen; R9 is as defined for R3 except that it cannot be hydrogen or in which R1 and R8 taken together represent a radical  EMI100.3  C2 to C10 alkylidene or C2 to C10 alkyliden substituted by hydroxy groups;  A is a C2 to C6 cyclopentylene, cyclohexylene or alkylene group optionally substituted by one or more C1 to L alkyl groups; R2 is a hydrogen atom or an anionic charge or a conventional easily separable carboxyl protecting group, it being understood that when R2 is a hydrogen atom or a protecting group, a counterion may also be present; as well as the pharmaceutically acceptable salts of said compounds.  7.-As new products, the carbapenem derivatives of formula:  EMI100.4    <Desc / Clms Page number 101>    EMI101.1  in which: Ra is a hydrogen atom, and R1 is chosen from the group comprising hydrogen, as well as the radicals, substituted or unsubstituted, belonging to the following list: alkyl, alkenyl and alkynyl, comprising of 1 to 10 carbon atoms; cycloalkyl and cycloalkylalkyle comprising from 3 to 6 carbon atoms in the cycloalkyl ring and 1 to 6 carbon atoms in the alkylated part; phenyl; aralkyl, aralkenyl and aralkynyl, the aryl part of which is constituted by a phenyl radical and the aliphatic part of which comprises from 1 to 6 carbon atoms;  heteroaryl, heteroaralkyl, heterocyclyl and heterocyclylalkyl in which the heteroatom (s) of the aforementioned heterocyclic parts are chosen from the group comprising 1 to 4 oxygen, nitrogen or sulfur atoms, and the alkylated part is associated with said heterocyclic parts comprising 1 to 6 carbon atoms, in which the. or the substituents relating to the abovementioned radicals are independently chosen from the group comprising: C1 to C6 alkyl radicals, optionally substituted by amino, halo, hydroxy or carboxyl radicals;  halo  EMI101.2  - o he -OCNR3R4 o he -CNR3R4 - -  EMI101.3    <Desc / Clms Page number 102>    EMI102.1    EMI102.2  in which, with respect to the substituents es and R4 are independently chosen from hydrogen as well as the alkyl, alkenyl and alkynyl groups comprising from 1 to 10 carbon atoms; cycloalkyl, cycloalkylalkyle and alkylcycloalkyle comprising 3 to 6 carbon atoms in the cycloalkyl ring and 1 to 6 carbon atoms in the alkyl part; phenyl; aralkyl, aralkenyl and aralkynyl in which the aryl part is formed by a phenyl radical and in which the aliphatic part comprises 1 to 6 carbon atoms;  and heteroaryl, heteroaralkyl, heterocyclyl and heterocyclylalkyl in which the heteroatom (s) of the aforementioned heterocyclic parts are chosen from the group comprising 1 to 4 oxygen, nitrogen or sulfur atoms and the alkylated parts associated with said heterocyclic parts comprising from 1 with 6 carbon atoms, or R3 and R4 taken together with the nitrogen atom to which at least one of them is linked, can form a heterocyclic ring with 5 or 6 atoms containing nitrogen; R9 is as defined for R3 except that it cannot be hydrogen or in which Ri and Rs taken together represent a radical  EMI102.3  C2 to C10 alkylidene or C2 to C10 alkylidene through hydroxy groups;  R5 is chosen from the group comprising substituted or unsubstituted radicals belonging to the following list: alkyl, alkenyl and alkynyl comprising from 1 to 10 carbon atoms; cycloalkyl and cycloalkylalkyle comprising from 3 to 6 carbon atoms in the cycloalkyl ring and 1 to 6 carbon atoms in the alkylated part; phenyl;  <Desc / Clms Page number 103>  aralkyl, aralkenyl and aralkynyl, the aryl part of which is constituted by a phenyl radical and the aliphatic part of which comprises 1 to 6 carbon atoms;  heteroaryl, heteroaralkyl, heterocyclyl and heterocyclylalkyl in which the heteroatom (s) of the aforementioned heterocyclic parts are chosen from the group comprising 1 to 4 oxygen, nitrogen or sulfur atoms and the alkylated part which is associated with said heterocyclic parts comprising from 1 to 6 carbon atoms; in which the abovementioned R5 radicals are optionally substituted with 1-3 substituents independently chosen from the following group: C1-C6 alkyl, optionally substituted with amino, fluoro, chloro, carboxyl, hydroxy or carbamoyl groups; fluoro, chloro or bromo; -OR3 - OCOzR - OCOR3 -OCONR3R4 -OSO2R3 - oxo -NR3R4 -R3CONR4- - NR3C02R4 -NR3CONR3R4 -NR3SO2R4  EMI103.1  -SO3R3 -CO2R3 - CONR R - CN;  or phenyl optionally substituted with 1 to 3 atoms of fluorine, chlorine, bromine or C1 to C6 alkyl groups; -OR3, -NR3R4, -SO3R3, -CO2R3 or-CONR3R4, in which R3, R4 and R9 in these R5 substituents are as defined above where R5 can represent a group  <Desc / Clms Page number 104>    EMI104.1  divalent phenylene or a C1 to C4 alkylene group linked to the nucleus  EMI104.2    EMI104.3  so as to form a polycyclic group;  A is a C2 to C6 cyclopentylene, cyclohexylene or alkylene group optionally substituted by one or more C1 to C4 alkyl groups; bridgedR2 is a hydrogen atom or an anionic charge or a conventional easily separable carboxyl protecting group, it being understood that when R2 is a hydrogen atom or a protecting group, A counterion may also be present; and  EMI104.4  represents a non-aromatic heterocyclic ring containing nitrogen having  EMI104.5  from 4 to 7 atoms, preferably 5 or 6 atoms, containing U has 2 bonds and 0 to 2 hetero atoms 0, S N, NR10 or NR''sR in which: m is;  Rio is hydrogen, a C1 to C6 alkyl radical optionally substituted by one or two substituents, chosen independently of one another from -OR, -NRR, -COR, chloro, bromo, double-SO3R3 and -CONR3R4 or phenyl optionally substituted with one to three substituents chosen independently of one another from C1 to C6 alkyl radicals, -OR3, -NR3R4, fluoro, chloro, bromo, -SO3R3, -CO2R3 and -CONR3R4;  and, R15 and R16, independently of one another, are chosen from C1 to C6 alkyl radicals optionally substituted by one or two substituents chosen independently from one another from the  EMI104.6  radicals-OR3 &commat; -NR-IR4. -OR, -NRR, -COR, oxo, phenyl, fluoro, chloro, bromo, -SO3R3 and -CONR3R4 or phenyl radicals optionally substituted with 1 to 3 substituents chosen independently from one another from C1-C4 radicals to C6, -OR3, -NR3R4, fluoro, chloro, bromo,  <Desc / Clms Page number 105>  -SO3R3, -CO2R2and-CONR3R4, in which: R3 and R4 in such heterocyclic groups are as defined above, said heterocyclic ring being attached to A by a nitrogen atom so as to form a quaternary ammonium group and said heterocyclic ring being optionally substituted by 1 to 3 substi- killing, chosen independently of one another from:  (a) the end-C6 alkyl radicals optionally substituted by or 2 substitutes chosen independently from one another from the radicals  EMI105.1  fluoro, chloro, bromo, -OR ", - OCOR, -OCONRR", R ", - COR", - NRCONR, -NROzR ", - SR", - SOaR, -COzR and - (b) akénycsen one or two substituents chosen on the other from the fluoro, chloro, bromo, -OR ", - OCOR", - OCONR,, - COR ", - NRCONRR, -NRSOsR", - SR, -SOaR, -COzR R "radicals (c) C6 alkynyls optionally one or two substituents chosen from the other from the groups fluoro, chloro, bromo, -OR, -OCOR, -OCONRR ", R", - NRCOR ", - CONRR", - NRSOzR ", - SR, -SOsR, -COzR; (d) cycloalkyls with one or two substituents chosen independently of one another from the fluoro, chloro, brama, - groups;  (e) cycloalkylalkyl containing 3 to 6 carbon atoms in the cycloalkyl part and 1 to 6 carbon atoms in the alkyl part, optionally substituted by one or two substituents chosen independently of one another from the fluoro group , chloro, bromo, -OR3,  EMI105.2  - OCOR3, -OCONR3R4, oxo, -NR3R4, -NR3COR4, -NR3CONR3R4, -NR3SO4, -SR3, -S03R3, -C02R3 and-CONR3R4;     (f) heteroaryls in which the hetero atom (s) are chosen from the group comprising 1 to 4 oxygen, nitrogen or sulfur atoms optionally substituted by one or two substituents chosen independently of one another among the fluoro, chloro, bromo,  EMI105.3  - - hetero radicals OR3, -OCOR3, -OCONR3R4, oxo, -NR3R4, -NR3COR4, -NR3CONR3R4, aryls preferably used are aromatic heterocyclic rings with 5 or 6 atoms;    <Desc / Clms Page number 106>    (9) heteroaralkyls in which the heteroatom (s) are chosen from the group comprising 1 to 4 oxygen, nitrogen or sulfur atoms and the alkyl part comprises 1 to 6 carbon atoms, optionally substituted by a with two substituents chosen independently from each other from the fluoro, chloro, bromo, -OR3, -OCOR3, -OCONR3R4, oxo, -NR3R4, -NR3COR4, -NR3CONR3R4, - NR3SO2R4, -SR3 groups - SO R3, -CO2R3 and-CONR3R4; the heteroaralkyls preferably used are those in which the heteroaryl radical is an aromatic heterocyclic ring with 5 to 6 atoms and the alkyl part comprises 1 to 2 carbon atoms;  (h) heterocyclyls according to which the hetero atom (s) are chosen from the group comprising 1 to 4 oxygen, nitrogen or sulfur atoms optionally substituted with one or two chosen substituents  EMI106.1  independently of each other from fluoro, chloro, bromo, -OR, -OCOR, -OCONRR, R, -NRCOR, -NRCONR, - -SR3, -SO, -CO2R3; are particularly oxo -NRpreferred heterocyclyl comprising saturated or unsaturated rings with 5 or 6 atoms;  (i) heterocyclylalyls in which the hetero atom (s) are chosen from the group comprising 1 to 4 oxygen, nitrogen or sulfur atoms, and the alkyl part comprises 1 to 6 carbon atoms, optionally substituted with one to two substituents independently chosen from fluoro, chloro, broma, -OR3, -OCOR3, -OCONR3R4, oxo, -NR3R4, -NR3COR4, -NR3CONR3R4, -NR3SO2R4, -SR3, -SO3R3, -CO2R3 and -CONR3R4; (j) fluoro, chloro or bromo; (k) -OR3; (1) -OC02R3; (m) -OCOR3; (n) -OCONR3R4; (o) -OSO2R3; (p) oxo; (q) -NR3R4; (r) R3CONR4-; (s) -NR3CO2R4; (t) -NR3CONR3R4; (u) -SO;  (v) -SR3;  <Desc / Clms Page number 107>    EMI107.1    (cc) phenyl optionally substituted with 1 to 3 fluorine, chlorine, bromine or C1-C6 alkyl radicals, -OR3, -NR3R4, -SO3R3, -CO2R3 or -CONR3R4; where the substituents R3, R4 and R9 mentioned above are as defined above or else said non-aromatic heterocyclic ring containing nitrogen can be fused in a carbocyclic ring in C4 to C7, a phenyl ring, a heterocyclic ring with 4 to 7 atoms  EMI107.2  containing 1 to 3 hetero atoms chosen from: 0, SN, NR10 or NR15R16 a hetero aromatic ring containing 5 or 6 atoms containing 1 to 3 hetero atoms chosen from: 0, SN, NRIO or in which: m, RIO, R15 and R16 are as defined above. Said fused carbocyclic, phenyl, heterocyclic or heteroaromatic ring which may be optionally substituted by one to three substituents chosen independently of one another from the radicals al-  EMI107.3  C1 to Ce kyles, -OR, -NRR, fluoro, chloro, bromo, -SORs, -C02R3 and-CONR3R4 in which R3 and R4 are as defined above, as well as the pharmaceutically acceptable salts of these compounds.  8.-As new products, the carbapenem derivatives of formula:  EMI107.4  in which : R8 is a hydrogen atom, and R1 is chosen from the group comprising hydrogen, as well as the radicals, substituted or unsubstituted, belonging to the following list:  <Desc / Clms Page number 108>  alkyl, alkenyl and alkynyl, comprising from 1 to 10 carbon atoms; cycloalkyl and cycloalkylalkyle comprising from 3 to 6 carbon atoms  EMI108.1  in the cycloalkyl ring and 1 to 6 carbon atoms in the alkylated part; phenyl; aralkyl, aralkenyl and aralkynyl in which the aryl part consists of a phenyl radical and in which the aliphatic part comprises from 1 to 6 carbon atoms;  heteroaryl, heteroaralkyl, heterocyclyl and heterocyclylalkyl in which the heteroatom (s) of the aforementioned heterocyclic parts are chosen from the group comprising 1 to 4 oxygen, nitrogen or sulfur atoms, and the alkylated part is associated with said heterocyclic parts comprising 1 to 6 carbon atoms, in which the substituent or substituents relating to the abovementioned radicals are independently chosen from the group comprising: C1 to C6 alkyl radicals, optionally substituted by amino, halo, hydroxy or carboxyl radicals;  halo  EMI108.2    <Desc / Clms Page number 109>    EMI109.1  in which, with respect to the abovementioned substituents, the groups R3 and R '* are independently chosen from hydrogen as well as the alkyl, alkenyl and alkynyl groups comprising from 1 a. 10 carbon atoms; cycloalkyl, cycloal. kylalkyl and alkylcycloalkyl having 3 to 6 carbon atoms in the cycloalkyl ring and 1 to 6 carbon atoms in the alkyl part; phenyl; aralkyl, aralkenyl and aralkynyl in which the aryl part is formed by a phenyl radical and in which the aliphatic part comprises 1 to 6 carbon atoms;  and heteroaryl, heteroaralkyl, heterocyclyl and heterocyclylalkyl in which the heteroatom (s) of the aforementioned heterocyclic parts are chosen from the group comprising 1 to 4 oxygen, nitrogen or sulfur atoms and the alkylated parts associated with said heterocyclic parts comprising from 1 has 6 carbon atoms, or R3 and R4 taken together with the nitrogen atom to which at least one of them is linked, can form a heterocyclic ring with 5 or 6 atoms containing nitrogen; R9 is as defined for R3 except that it cannot be hydrogen or in which R1 and RB taken together represent a radical  EMI109.2  C2 to C10 alkylidene or C2 to C10 alkylidene through hydroxy groups;  A is a cyclopentylene, or C2 to C6 alkylene group optionally substituted by one or more C1 C alkyl groups; R2 is a hydrogen atom or an anionic charge or a conventional easily separable carboxyl protecting group, it being understood that when R2 is a hydrogen atom or a protecting group, a counterion may also be present;  <Desc / Clms Page number 110>  as well as the pharmaceutically acceptable salts of said compounds.  9.-As new products, the carbapenem derivatives of formula:  EMI110.1  in which: Rs is a hydrogen atom, and It is chosen from the group comprising hydrogen, as well as the radicals, substituted or unsubstituted, belonging to the following list: alkyl, alkenyl and alkynyl, comprising from 1 to 10 carbon atoms; cycloalkyl and cycloalkylalkyle comprising from 3 to 6 carbon atoms in the cycloalkyl ring and 1 to 6 carbon atoms in the alkylated part; phenyl; aralkyl, aralkenyl and aralkynyl, the aryl part of which is constituted by a phenyl radical and the aliphatic part of which comprises from 1 to 6 carbon atoms;  heteroaryl, heteroaralkyl, heterocyclyl and heterocyclylalkyl in which the heteroatom (s) of the aforementioned heterocyclic parts are chosen from the group comprising 1 to 4 oxygen, nitrogen or sulfur atoms, and the alkylated part is associated with said heterocyclic parts comprising 1 to 6 carbon atoms, in which the substituent (s) relating to the abovementioned radicals are independently chosen from the group comprising: C1 to C6 alkyl radicals, optionally substituted by amino, halo, hydroxy or carboxyl radicals;  halo  EMI110.2    <Desc / Clms Page number 111>    EMI111.1  in which, with respect to the abovementioned substituents, the groups and R4 are independently chosen from hydrogen as well as the alkyl, alkenyl and alkynyl groups comprising from 1 to 10 carbon atoms; cycloalkyle, cycloalkylalkyle et alkylcycloalkyle compre-. having 3 to 6 carbon atoms in the cycloalkyl ring and 1 to 6 carbon atoms in the alkyl part; phenyl; aralkyl, aralkenyl and aralkynyl in which the aryl part is formed by a phenyl radical and in which the aliphatic part comprises 1 to 6 carbon atoms;  and heteroaryl, heteroaralkyl, heterocyclyl and heterocyclylalkyl in which the heteroatom (s) of the abovementioned heterocyclic parts are chosen from the group comprising 1 to 4 oxygen, nitrogen or sulfur atoms and the alkylated parts associated with said heterocyclic parts comprising from 1 to 6 carbon atoms, or R3 and R4 taken together with  <Desc / Clms Page number 112>  the nitrogen atom to which at least one of them is not, can form a heterocyclic ring with 5 or 6 atoms containing nitrogen; R9 is as defined for R3 except that it cannot be hydrogen or in which Ri and Rs taken together represent a radical  EMI112.1  C'z'alkylidene or C2 to C10 alkylidene by hydroxy groups;  A is a C2 to C8 cyclopentylene, cyclohexylene or alkylene group optionally substituted by one or more C1 to C4 alkyl groups; CioR2 is a hydrogen atom or an anionic charge or a conventional easily separable carboxyl protecting group, it being understood that when R2 is a hydrogen atom or a protecting group, A counterion may also be present; and  EMI112.2  Y is a hydrogen atom, a C1-C6 alkyl, hydroxy, - S-C1-C6 alkyl, carboxyl, carbamoyl, chloro, bromo, iodo, fluoro or phenyl, as well as the pharmaceutically acceptable salts of said compounds.  10.-As new products, the carbapenem derivatives of formula:  EMI112.3    Rs is a hydrogen atom, and R1 is chosen from the group comprising hydrogen, as well as the radicals, substituted or unsubstituted, belonging to the following list: alkyl, alkenyl and alkynyl, comprising from 1 to 10 atoms of carbon ; cycloalkyl and cycloalkylalkyle comprising from 3 to 6 carbon atoms  EMI112.4  in the cycloalkyl ring and 1 to 6 carbon atoms in the alkylated part; phenyl; aralkyl, aralkenyl and aralkynyl in which the aryl part consists of a phenyl radical and in which the aliphatic part comprises from 1 to 6 carbon atoms;  heteroaryl, heteroaralkyl, heterocyclyl and heterocyclylalkyl in which the heteroatom (s) of the aforementioned heterocyclic parts are chosen from the group comprising 1 to 4 oxygen, nitrogen or sulfur atoms, and the alkylated part is associated with said heterocyclic parts  <Desc / Clms Page number 113>  comprising 1 to 6 carbon atoms, in which the substituent or substituents relating to the abovementioned radicals are independently chosen from the group comprising: C 1 -C 6 alkyl radicals, optionally substituted by amino, halo, hydroxy or carboxyl radicals;  halo  EMI113.1    <Desc / Clms Page number 114>  in which, with respect to the abovementioned substituents, the groups R3 and R4 are independently chosen from hydrogen as well as the alkyl, alkenyl and alkynyl groups comprising from 1 to 10 carbon atoms; cycloalkyl, cycloalkylalkyle and alkylcycloalkyle comprising 3 to 6 carbon atoms in the cycloalkyl ring and 1 to 6 carbon atoms in the alkyl part; phenyl; aralkyl, aralkenyl and aralkynyl in which the aryl part is formed by a phenyl radical and in which the aliphatic part comprises 1 to 6 carbon atoms;  and heteroaryl, heteroaralkyl, heterocyclyl and heterocyclylalkyl in which the heteroatom (s) of the aforementioned heterocyclic parts are chosen from the group comprising 1 to 4 oxygen, nitrogen or sulfur atoms and the alkylated parts associated with said heterocyclic parts comprising from 1 to 6 carbon atoms, or R3 and R4 taken together with the nitrogen atom to which at least one of them is linked, can form a heterocyclic ring with 5 or 6 atoms containing nitrogen; R9 is as defined for R3. otherwise it cannot be hydrogen or in which R1 and R8 taken together represent a radical  EMI114.1  C2 to C10 alkylidene or C2 to C10 alkylidene substituted by hydroxy groups;  A is a C2 to C6 cyclopentylene, cyclohexylene or alkylene group optionally substituted by one or more C1 to C4 alkyl groups; R2 is a hydrogen atom or an anionic charge or a conventional easily separable carboxyl protecting group, it being understood that when R2 is a hydrogen atom or a protecting group, a counterion may also be present; as well as the pharmaceutically acceptable salts of said compounds.    11.-As new products, the carbapenem derivatives of formula:  EMI114.2  in which :  EMI114.3  RB is a hydrogen atom, and R 'is chosen from the group comprising hydrogen, as well as the radicals, substituted or unsubstituted, belonging to the following list:  <Desc / Clms Page number 115>  alkyl, alkenyl and alkynyl, comprising from 1 to 10 carbon atoms; cycloalkyl and cycloalkylalkyle comprising from 3 to 6 carbon atoms in the cycloalkyl ring and from 1 to 6 carbon atoms in the alkylated part; phenyl; aralkyl, aralkenyl and aralkynyl in which the aryl part consists of a phenyl radical and in which the aliphatic part comprises from 1 to 6 carbon atoms;    heteroaryl, heteroaralkyl, heterocyclyl and heterocyclylalkyl in which the heteroatom (s) of the aforementioned heterocyclic parts are chosen from the group comprising 1 to 4 oxygen, nitrogen or sulfur atoms, and the alkylated part is associated with said heterocyclic parts comprising 1 to 6 carbon atoms, in which the substituent or substituents relating to the abovementioned radicals are independently chosen from the group comprising: C1 to C6 alkyl radicals, optionally substituted by amino, halo, hydroxy or carboxyl radicals;  halo  EMI115.1    <Desc / Clms Page number 116>    EMI116.1  in which, with respect to the abovementioned substituents, the groups R3 and R4 are independently chosen from hydrogen as well as the alkyl, alkenyl and alkynyl groups comprising from 1 to 10 carbon atoms; cycloalkyl, cycloalkylalkyle and alkylcycloalkyle comprising 3 to 6 carbon atoms in the cycloalkyl ring and 1 to 6 carbon atoms in the alkyl part; phenyl; aralkyl, aralkenyl and aralkynyl in which the aryl part is formed by a phenyl radical and in which the aliphatic part comprises 1 to 6 carbon atoms;  and heteroaryl, heteroaralkyl, heterocyclyl and heterocyclylalkyl in which the heteroatom (s) of the abovementioned heterocyclic parts are chosen from the group comprising 1 to 4 oxygen, nitrogen or sulfur atoms and the alkylated parts associated with said heterocyclic parts comprising from 1 to 6 carbon atoms, or R3 and R4 taken together with the nitrogen atom to which at least one of them is linked, can form a heterocyclic ring with 5 or 6 atoms containing nitrogen; R9 is as defined for R3 except that it cannot be hydrogen or in which R1 and RB taken together represent a radical  EMI116.2  C2 to C10 alkylidene or C2 to C alkylidene, by hydroxy groups;  A is a C2 to C6 cyclopentylene, cyclohexylene or alkylene group optionally substituted by one or more C1 to C4 alkyl groups R2 is a hydrogen atom or an anionic charge or a conventional easily separable carboxyl protecting group, it being understood that when R2 is a hydrogen atom or a protecting group, May also be present a counterion; and  <Desc / Clms Page number 117>   Y is a hydrogen atom, a C to C alkyl, hydroxy, -S-C to C alkyl, carboxyl, carbamoyl, chloro, bromo, iodo, fluoro or phenyl radical; as well as the pharmaceutically acceptable salts of said compounds.  12.-As new products, the carbapenem derivatives of formula:  EMI117.1  in which: Rs is a hydrogen atom, and R1 is chosen from the group comprising hydrogen, as well as the radicals, substituted or unsubstituted, belonging to the following list: alkyl, alkenyl and alkynyl, comprising of 1 to 10 carbon atoms; cycloalkyl and cycloalkylalkyle comprising from 3 to 6 carbon atoms in the cycloalkyl ring and 1 to 6 carbon atoms in the alkylated part; phenyl; aralkyl, aralkenyl and aralkynyl in which the aryl part is constituted by a phenyl radical and in which the ali-  EMI117.2  phatic comprises from 1 to 6 carbon atoms;  heteroaryl, heteroaralkyl, heterocyclyl and heterocyclylalkyl in which the heteroatom (s) of the aforementioned heterocyclic parts are chosen from the group comprising 1 to 4 oxygen, nitrogen or sulfur atoms, and the alkylated part is associated with said heterocyclic parts comprising 1 to 6 carbon atoms, in which the substituent or substituents relating to the abovementioned radicals are independently chosen from the group comprising: C1 to C6 alkyl radicals, optionally substituted by amino, halo, hydroxy or carboxyl radicals;  halo  EMI117.3    <Desc / Clms Page number 118>    EMI118.1  in which, with respect to the abovementioned substituents, the groups R3 and R4 are independently chosen from hydrogen as well as the alkyl, alkenyl and alkynyl groups comprising from 1 to 10 carbon atoms; cycloalkyl, cycloalkylalkyle and alkylcycloalkyle comprising 3 to 6 carbon atoms in the cycloalkyl ring and 1 to 6 carbon atoms in the alkyl part; phenyl; aralkyl, aralkenyl and aralkynyl in which the aryl part is formed by a phenyl radical and in which the aliphatic part comprises 1 to 6 carbon atoms;  and heteroaryl, heteroaralkyl, heterocyclyl and heterocyclylalkyl, the  <Desc / Clms Page number 119>  or the heteroatoms of the aforementioned heterocyclic parts are chosen from the group comprising 1 to 4 oxygen, nitrogen or sulfur atoms and the alkylated parts associated with said heterocyclic parts comprising from 1 to 6 carbon atoms, or R3 and R4 taken together with  EMI119.1  the nitrogen atom at least one of them is bonded, can form a heterocyclic ring with 5 or 6 atoms containing nitrogen; R9 is as defined for R3 except that it cannot be hydrogen or in which Ri and Rs taken together represent a radical  EMI119.2  C2 to C10 alkylidene or C2 to C10 alkylidene through hydroxy groups;  A is a C2 to C6 cyclopentylene, cyclohexylene or alkylene group optionally substituted by one or more C1 to C4 alkyl groups; substitutedR2 is a hydrogen atom or an anionic charge or a conventional easily separable carboxyl protecting group, it being understood that when R2 is a hydrogen atom or a protecting group, a counterion may also be present; as well as the pharmaceutically acceptable salts of said compounds.  13.-As new products, the carbapenem derivatives of formula:  EMI119.3  in which :  EMI119.4  R8 is a hydrogen atom, and R1 is chosen from the group comprising hydrogen, as well as the radicals, substituted or unsubstituted, belonging to the following list: alkyl, alkenyl and alkynyl, comprising from 1 to 10 atoms of carbon ; cycloalkyl and cycloalkylalkyle comprising from 3 to 6 carbon atoms in the cycloalkyl ring and 1 to 6 carbon atoms in the alkylated part; phenyl; aralkyl, aralkenyl and aralkynyl, the aryl part of which is constituted by a phenyl radical and the aliphatic part of which comprises from 1 to 6 carbon atoms;  heteroaryl, heteroaralkyl, heterocyclyl and heterocyclylalkyl in which the heteroatom (s) of the abovementioned heterocyclic parts are chosen from the group comprising 1 to 4 oxygen, nitrogen or sulfur atoms,  <Desc / Clms Page number 120>  and the alkylated part is associated with said heterocyclic parts comprising 1 to 6 carbon atoms, in which the substituent or substituents relating to the abovementioned radicals are independently chosen from the group comprising: C1 to C6 alkyl radicals, optionally substituted by amino radicals, halo, hydroxy or carboxyl;  halo  EMI120.1    <Desc / Clms Page number 121>    EMI121.1  -NR3C02R4 - in which, with respect to the abovementioned substituents, the groups R3 and R "are independently chosen from hydrogen as well as  EMI121.2  alkyl, alkenyl and alkynyl groups comprising from 1 to 10 carbon atoms; cycloalkyl, cycloa1ky1a1ky1e and alkylcycloalkyle comprising 3 to 6 carbon atoms in the cycloalkyl ring and 1 to 6 carbon atoms in the alkyl part; phenyl; aralkyl, aralkenyl and ara1kyny1e whose aryl part is formed by a phenyl radical and whose aliphatic part contains 1 to 6 carbon atoms;  and heteroaryl, heteroaryl, heterocycle and heterocyclylalkyl in which the heteroatom (s) of the aforementioned heterocyclic parts are chosen from the group comprising 1 to 4 oxygen, nitrogen or sulfur atoms and the alkylated parts associated with said heterocyclic parts comprising from 1 to 6 carbon atoms, or R3 and R4 taken together with the nitrogen atom to which at least one of them is linked, can form a heterocyclic ring with 5 or 6 atoms containing nitrogen; R9 is as defined for R3 except that it cannot be hydrogen or in which R '' and Rs taken together represent a radical  EMI121.3  C2 to C10 alkylidene or C2 to C10 alkylidene substituted by hydroxy groups;  A is a C2 to C6 cyclopentylene, cyclohexylene or alkylene group optionally substituted by one or more C1 to C4 alkyl groups; R2 is a hydrogen atom or an anionic charge or a conventional easily separable carboxyl protecting group, it being understood that when R2 is a hydrogen atom or a protecting group, A counterion may also be present; and  EMI121.4  Y is a hydrogen atom, a C1-C6 alkyl, hydroxy, -S-C1-C6 alkyl, carboxyl, carbamoyl, chloro, bromo, iodo, fluoro or phenyl radical; as well as the pharmaceutically acceptable salts of said compounds.  14.-As new products, the carbapenem derivatives of formula:  EMI121.5    <Desc / Clms Page number 122>  in which: Ra is a hydrogen atom, and It is chosen from the group comprising hydrogen, as well as the radicals, substituted or unsubstituted, belonging to the following list: alkyl, alkenyl and alkynyl, comprising from 1 to 10 carbon atoms; cycloalkyl and cycloalkylalkyle comprising from 3 to 6 carbon atoms in the cycloalkyl ring and 1 to 6 carbon atoms in the alkylated part; phenyl; aralkyl, aralkenyl and aralkynyl, the aryl part of which is constituted by a phenyl radical and the aliphatic part of which comprises from 1 to 6 carbon atoms;  heteroaryl, heteroaralkyl, heterocyclyl and heterocyclylalkyl in which the heteroatom (s) of the aforementioned heterocyclic parts are chosen from the group comprising 1 to 4 oxygen, nitrogen or sulfur atoms, and the alkylated part is associated with said heterocyclic parts comprising 1 to 6 carbon atoms, in which the substituent (s) relating to the abovementioned radicals are independently chosen from the group comprising: C1 to C6 alkyl radicals, optionally substituted by amino, halo, hydroxy or carboxyl radicals;  halo  EMI122.1    <Desc / Clms Page number 123>    EMI123.1  in which, with respect to the abovementioned substituents, the groups R3 and R4 are independently chosen from hydrogen as well as the alkyl, alkenyl and alkynyl groups comprising from 1 to 10 carbon atoms; cycloalkyl, cycloalkylalkyle and alkylcycloalkyle comprising 3 to 6 carbon atoms in the cycloalkyl ring and 1 to 6 carbon atoms in the alkyl part; phenyl; aralkyl, aralkenyl and  EMI123.2  aralkynyl, the aryl part of which is formed by a phenyl radical and the aliphatic part of which comprises 1 to 6 carbon atoms;  and heteroaryl, heteroaralkyl, heterocyclyl and heterocyclylalkyl in which the heteroatom (s) of the abovementioned heterocyclic parts are chosen from the group comprising 1 to 4 oxygen, nitrogen or sulfur atoms and the alkylated parts associated with said heterocyclic parts comprising from 1 to 6 carbon atoms, or R3 and R4 taken together with the nitrogen atom to which at least one of them is linked, can form a heterocyclic ring with 5 or 6 atoms containing nitrogen;  R9 is as defined for R3 except that it cannot be hydrogen or in which R1 and RB taken together represent a C2 to C10 alkylidene radical or C2 to C10 alkylidene substituted by hydroxy groups;  EMI123.3  A is a C2 to C6 cyclopentylene, cyclohexylene or alkylene group optionally substituted by one or more C1 to C4 alkyl groups;  <Desc / Clms Page number 124>   R2 is a hydrogen atom or an anionic charge or a conventional easily separable carboxyl protecting group, it being understood that when R2 is a hydrogen atom or a protecting group, a counterion may also be present; as well as the pharmaceutically acceptable salts of said compounds.  15.-As new products, the carbapenem derivatives of formula:  EMI124.1  in which: Rs is a hydrogen atom, and Is chosen from the group comprising hydrogen, as well as the radicals, substituted or unsubstituted, belonging to the following list:  EMI124.2  alkyl, alkenyl and alkynyl, comprising from 1 to 10 carbon atoms; cycloalkyl and cycloalkylalkyl comprising from 3 to 6 carbon atoms in the cycloalkyl ring and 1 to 6 carbon atoms in the alkylated part; phenyl; aralkyl, aralkenyl and aralkynyl in which the aryl part consists of a phenyl radical and in which the aliphatic part comprises from 1 to 6 carbon atoms;  heteroaryl, heteroaralkyl, heterocyclyl and heterocyclylalkyl in which the heteroatom (s) of the aforementioned heterocyclic parts are chosen from the group comprising 1 to 4 oxygen, nitrogen or sulfur atoms, and the alkylated part is associated with said heterocyclic parts comprising 1 to 6 carbon atoms, in which the substituent or substituents relating to the abovementioned radicals are independently chosen from the group comprising: C1 to C6 alkyl radicals, optionally substituted by amino, halo, hydroxy or carboxyl radicals;  halo  EMI124.3    <Desc / Clms Page number 125>    EMI125.1  in which, with respect to the abovementioned substituents, the groups R3 and R4 are independently chosen from hydrogen as well as the alkyl, alkenyl and alkynyl groups comprising from 1 to 10 carbon atoms; cycloalkyl, cycloalkylalkyle and alkylcycloalkyle comprising 3 to 6 carbon atoms in the cycloalkyl ring and 1 to 6 carbon atoms in the alkyl part; phenyl; aralkyl, aralkenyl and aralkynyl in which the aryl part is formed by a phenyl radical and in which the aliphatic part comprises 1 to 6 carbon atoms;  and heteroaryl, heteroaralkyl, heterocyclyl and heterocyclylalkyl, the  <Desc / Clms Page number 126>  or the heteroatoms of the aforementioned heterocyclic parts are chosen from the group comprising 1 to 4 oxygen, nitrogen or sulfur atoms and the alkylated parts associated with said heterocyclic parts comprising from 1 to 6 carbon atoms, or R3 and R4 taken together with the nitrogen atom to which at least one of them is linked, can form a heterocyclic ring with 5 or 6 atoms containing nitrogen; R9 is as defined for R3 except that it cannot be hydrogen or in which R1 and RB taken together represent a radical  EMI126.1  C2 to C10 alkyliden or C2 to C10 alkylidene through hydroxy groups;  A is a C2 to C6 cyclopentylene, cyclohexylene or alkylene group optionally substituted by one or more C1 to C4 alkyl groups; R2 is a hydrogen atom or an anionic charge or a conventional easily separable carboxyl protecting group, it being understood that when R2 is a hydrogen atom or a protecting group, A counterion may also be present; and  EMI126.2  Y is a hydrogen atom, a C1-C6 alkyl, hydroxy, - S-C1-C6 alkyl, carboxyl, carbamoyl, chloro, bromo, iodo, fluoro or phenyl; as well as the pharmaceutically acceptable salts of said compounds.  16.-As new products, the carbapenem derivatives of formula:  EMI126.3  in which : Re is a hydrogen atom, and R 1 is chosen from the group comprising hydrogen, as well as the radicals, substituted or unsubstituted, belonging to the following list: alkyl, alkenyl and alkynyl, comprising from 1 to 10 carbon atoms; cycloalkyl and cycloalkylalkyle comprising from 3 to 6 carbon atoms in the cycloalkyl ring and 1 to 6 carbon atoms in the alkylated part; phenyl; aralkyl, aralkenyl and aralkynyl, the aryl part of which is constituted by a phenyl radical and the aliphatic part of which comprises from 1 to 6 carbon atoms;  heteroaryl, heteroaralkyl, heterocyclyl and heterocyclylalkyl in which the one or more  <Desc / Clms Page number 127>  heteroatoms of the aforementioned heterocyclic parts are chosen from the group comprising 1 to 4 oxygen, nitrogen or sulfur atoms, and the alkylated part is associated with said heterocyclic parts comprising 1 to 6 carbon atoms, in which the relative substituent (s) to the aforementioned radicals are independently chosen from the group comprising: C1 to C6 alkyl radicals, optionally substituted by amino, halo, hydroxy or carboxyl radicals;  halo  EMI127.1    <Desc / Clms Page number 128>    EMI128.1  in which, with respect to the abovementioned substituents, the groups R3 and R4 are independently chosen from hydrogen as well as the alkyl, alkenyl and alkynyl groups comprising from 1 to 10 carbon atoms; cycloalkyl, cycloalkylalkyle and alkylcycloalkyle comprising 3 to 6 carbon atoms in the cycloalkyl ring and 1 to 6 carbon atoms in the alkyl part; phenyl; aralkyl, aralkenyl and aralkynyl in which the aryl part is formed by a phenyl radical and in which the aliphatic part comprises 1 to 6 carbon atoms;  and heteroaryl, heteroaralkyl, heterocyclyl and heterocyclylalkyl in which the heteroatom (s) of the aforementioned heterocyclic parts are chosen  EMI128.2  in the group comprising 1 to 4 oxygen, nitrogen or sulfur atoms and the alkylated parts associated with said heterocyclic parts comprising from 1 to 6 carbon atoms, or R3 and R4 taken together with the nitrogen atom at which the less one of them is linked, can form a heterocyclic ring with 5 or 6 atoms containing nitrogen; R9 is as defined for R3 except that it cannot be hydrogen or in which R '' and Rs taken together represent a radical  EMI128.3  C2 to C10 alkylidene or hydroxy groups;  A is a C2 to C6 cyclopentylene, cyclohexylene or alkylene group optionally substituted by one or more C1 to (4 alkyl) groups substituted by C2 to C10 alkylidene, R2 is a hydrogen atom or an anionic charge or a carboxyl protecting group easily separable conventional, it being understood that when R2 is a hydrogen atom or a protective group, a counterion may also be present, as well as the pharmaceutically acceptable salts of said compounds.  17.-As new products, the carbapenem derivatives of formula:  EMI128.4    <Desc / Clms Page number 129>  in which: Rs is a hydrogen atom, and R1 is chosen from the group comprising hydrogen, as well as the radicals, substituted or unsubstituted, belonging to the following list: alkyl, alkenyl and alkynyl, comprising of 1 to 10 carbon atoms; cycloalkyl and cycloalkylalkyle comprising from 3 to 6 carbon atoms in the cycloalkyl ring and 1 to 6 carbon atoms in the alkylated part; phenyl; aralkyl, aralkenyl and aralkynyl, the aryl part of which is constituted by a phenyl radical and the aliphatic part of which comprises from 1 to 6 carbon atoms;  heteroaryl, heteroaralkyl, heterocyclyl and heterocyclylalkyl in which the heteroatom (s) of the aforementioned heterocyclic parts are chosen from the group comprising 1 to 4 oxygen, nitrogen or sulfur atoms, and the alkylated part is associated with said heterocyclic parts comprising 1 to 6 carbon atoms, in which the substituent (s) relating to the abovementioned radicals are independently chosen from the group comprising: C1 to C6 alkyl radicals, optionally substituted by amino, halo, hydroxy or carboxyl radicals;  halo  EMI129.1    <Desc / Clms Page number 130>    EMI130.1  in which, with respect to the abovementioned substituents, the groups R'- and R4 are independently chosen from hydrogen as well as the alkyl, alkenyl and alkynyl groups comprising from 1 to 10 atoms  EMI130.2  carbon; cycloalkyl, cycloalkylalkyle and alkylcycloalkyle comprising 3 to 6 carbon atoms in the cycloalkyl ring and 1 to 6 carbon atoms in the alkyl part; phenyl; aralkyl, aralkenyl and aralkynyl in which the aryl part is formed by a phenyl radical and in which the aliphatic part comprises 1 to 6 carbon atoms;  and heteroaryl, heteroaralkyl, heterocyclyl and heterocyclylalkyl in which the heteroatom (s) of the abovementioned heterocyclic parts are chosen from the group comprising 1 to 4 oxygen, nitrogen or sulfur atoms and the alkylated parts associated with said heterocyclic parts comprising from 1 to 6 carbon atoms, or R3 and R4 taken together with the nitrogen atom to which at least one of them is linked, can form a heterocyclic ring with 5 or 6 atoms containing nitrogen; R9 is as defined for R3 except that it cannot be hydrogen or in which RI and RI 'taken together represent a radical  EMI130.3  C2 to C10 alkylidene or C2 to C10 alkylidene substituted by hydroxy groups;  A is a C2 to C6 cyclopentylene, cyclohexylene or alkylene group optionally substituted by one or more C1 to C4 alkyl groups;  <Desc / Clms Page number 131>  R2 is a hydrogen atom or an anionic charge or a conventional easily separable carboxyl protecting group, it being understood that when R2 is a hydrogen atom or a protecting group, a counterion may also be present; and  EMI131.1  Y is a hydrogen atom, a C1 to C6 alkyl radical, hydroxy, S-C1 to C6 alkyl, carboxyl, carbamoyl, chloro, bromo, iodine, fluoro or phenyl; as well as the pharmaceutically acceptable salts of said compounds.  18.-As new products, the carbapenem derivatives of formula:  EMI131.2  in which: Re is a hydrogen atom, and R1 is chosen from the group comprising hydrogen, as well as the radicals, substituted or unsubstituted, belonging to the following list: alkyl, alkenyl and alkynyl, comprising of 1 to 10 carbon atoms; cycloalkyl and cycloalkylalkyle comprising from 3 to 6 carbon atoms in the cycloalkyl ring and 1 to 6 carbon atoms in the alkylated part; phenyl; aralkyl, aralkenyl and aralkynyl, the aryl part of which is constituted by a phenyl radical and the aliphatic part of which comprises from 1 to 6 carbon atoms;  heteroaryl, heteroaralkyl, heterocyclyl and heterocyclylalkyl in which the heteroatom (s) of the aforementioned heterocyclic parts are chosen from the group comprising 1 to 4 atoms of oxygen, nitrogen or sulfur, and the alkylated part is associated with said heterocyclic parts. comprising 1 to 6 carbon atoms, in which the substituent (s) relating to the abovementioned radicals are independently chosen from the group comprising: C1 to C6 alkyl radicals, optionally substituted by amino, halo, hydroxy or carboxyl radicals;  halo  EMI131.3    EMI131.4  .  <Desc / Clms Page number 132>    EMI132.1  in which, with respect to the abovementioned substituents, the groups R3 and R4 are independently chosen from hydrogen as well as the alkyl, alkenyl and alkynyl groups comprising from 1 to 10 carbon atoms; cycloalkyl, cycloalkylalkyle and alkylcycloalkyle comprising 3 to 6 carbon atoms in the cycloalkyl ring and 1 to 6 carbon atoms in the alkyl part; phenyl; aralkyl, aralkenyl and aralkynyl in which the aryl part is formed by a phenyl radical and in which the aliphatic part comprises 1 to 6 carbon atoms;  and heteroaryl, heteroaralkyl, heterocyclyl and heterocyclylalkyl, the  <Desc / Clms Page number 133>  or the heteroatoms of the aforementioned heterocyclic parts are chosen from the group comprising 1 to 4 oxygen, nitrogen or sulfur atoms and the alkylated parts associated with said heterocyclic parts comprising from 1 to 6 carbon atoms, or R3 and R4 taken together with the nitrogen atom to which at least one of them is linked, can form a heterocyclic ring with 5 or 6 atoms containing nitrogen; R9 is as defined for R3 except that it cannot be hydrogen or in which R '' and Rs taken together represent a radical  EMI133.1  C2 to C10 alkylidene or C2 to C10 alkylidene substituted by hydroxy groups;  A is a C2 to C8 cyclopentylene, cyclohexylene or alkylene group optionally substituted by one or more C1 to C4 alkyl groups; R2 is a hydrogen atom or an anionic charge or a conventional easily separable carboxyl protecting group, it being understood that when R2 is a hydrogen atom or a protecting group, A counterion may also be present; as well as the pharmaceutically acceptable salts of said compounds.    19. Compounds according to any one of Claims 1 to 18, characterized in that R1 is a hydrogen atom, or a CH3CH2- group,  EMI133.2    20.-Compounds according to any one of claims 1 to 18, characterized in that R1 and Re together form a group  EMI133.3   21. Compounds according to any one of Claims 1 to 18, characterized in that R1 is  EMI133.4   22.- Compounds according to any one of claims 1 to 18, characterized in that Ri is  EMI133.5  and the absolute configuration is 5R, 6S, 8R.    23. Compounds according to any one of Claims 1 to 22,  <Desc / Clms Page number 134>  characterized in that A is:  EMI134.1  24.-As new products, the compounds of formula:  EMI134.2  in which : R2 is a hydrogen atom or an anionic charge or a conventional easily separable carboxyl protecting group, it being understood that when R2 is a hydrogen atom or a protecting group, a counterion may also be present; as well as the pharmaceutically acceptable salts of said compounds.  25.-As new products, the compounds of formula:  EMI134.3  in which : R2 is a hydrogen atom or an anionic charge or a conventional easily separable carboxyl protecting group, it being understood that when R2 is a hydrogen atom or a protecting group, a counterion may also be present; as well as the salts pharmaceutically acceptable of said compounds.  26.-As new products, the compounds of formula:  EMI134.4    <Desc / Clms Page number 135>  in which : R2 is a hydrogen atom or an anionic charge or a conventional easily separable carboxyl protecting group, it being understood that when R2 is a hydrogen atom or a protecting group, a counterion may also be present; as well as the pharmaceutically acceptable salts of said compounds.    27. - As new products, the compounds of formula:  EMI135.1  in which : R2 is a hydrogen atom or an anionic charge or a conventional easily separable carboxyl protecting group, it being understood that when R2 is a hydrogen atom or a protecting group, a counterion may also be present; as well as the pharmaceutically acceptable salts of said compounds.  28.-As new products, the compounds of formula:  EMI135.2  in which : R2 is a hydrogen atom or an anionic charge or a conventional easily separable carboxyl protecting group, it being understood that when R2 is a hydrogen atom or a protecting group, a counterion may also be present; as well as the pharmaceutically acceptable salts of said compounds.  29.-As new products, the compounds of formula:  EMI135.3    <Desc / Clms Page number 136>  in which : R2 is a hydrogen atom or an anionic charge or a conventional easily separable carboxyl protecting group, it being understood that when R2 is a hydrogen atom or a protecting group, a counterion may also be present; as well as the pharmaceutically acceptable salts of said compounds.  30.-As new products, the compounds of formula:  EMI136.1  in which : R2 is a hydrogen atom or an anionic charge or a conventional easily separable carboxyl protecting group, it being understood that when R2 is a hydrogen atom or a protecting group, a counterion may also be present; as well as the pharmaceutically acceptable salts of said compounds.    31.-Compounds according to any one of claims 24 to 30, characterized in that R2 is nitrobenzyl.    32.-Compounds according to any one of claims 24 to 30, characterized in that R2 is an anionic charge.  33.-Process for the preparation of carbapenem derivatives of formula:  EMI136.2  in which : Ra is a hydrogen atom, and R 1 is chosen from the group comprising hydrogen, as well as the radicals, substituted or unsubstituted, belonging to the following list: alkyl, alkenyl and alkynyl, comprising from 1 to 10 carbon atoms; cycloalkyl and cycloalkylalkyle comprising from 3 to 6 carbon atoms in the cycloalkyl ring and 1 to 6 carbon atoms in the part  <Desc / Clms Page number 137>    alkylated; phenyl; aralkyl, aralkenyl and aralkynyl in which the aryl part consists of a phenyl radical and in which the aliphatic part comprises from 1 to 6 carbon atoms;  heteroaryl, heteroaralkyl, heterocyclyl and heterocyclylalkyl in which the heteroatom (s) of the aforementioned heterocyclic parts are chosen from the group comprising 1 to 4 oxygen, nitrogen or sulfur atoms, and the alkylated part is associated with said heterocyclic parts comprising 1 to 6 carbon atoms, in which the substituent or substituents relating to the abovementioned radicals are independently chosen from the group comprising: C1 to C6 alkyl radicals, optionally substituted by amino, halo, hydroxy or carboxyl radicals;  halo  EMI137.1    <Desc / Clms Page number 138>  - CN - N3 - OSO RS - OSO -NR3SO2R4  EMI138.1  - CNR R3 - CO NR- N02 in which, with respect to the abovementioned substituents, the groups R3 and R4 are independently chosen from hydrogen as well as the alkyl, alkenyl and alkynyl groups comprising from 1 to 10 carbon atoms; cycloalkyl, cycloalkylalkyle and alkylcycloalkyle comprising 3 to 6 carbon atoms in the cycloalkyl ring and 1 to 6 carbon atoms in the alkyl part; phenyl; aralkyl, aralkenyl and aralkynyl in which the aryl part is formed by a phenyl radical and in which the aliphatic part comprises 1 to 6 carbon atoms;  and heteroaryl, heteroaralkyl, heterocyclyl and heterocyclylalkyl in which the heteroatom (s) of the abovementioned heterocyclic parts are chosen from the group comprising 1 to 4 oxygen, nitrogen or sulfur atoms and the alkylated parts associated with said heterocyclic parts comprising from 1 to 6 carbon atoms, or R3 and R4 taken together with the nitrogen atom to which at least one of them is linked, can form a heterocyclic ring with 5 or 6 atoms containing nitrogen;  R9 is as defined for R3 except that it cannot be hydrogen or in which R1 and R8 taken together represent a radical  EMI138.2  C2 to C10 alkylidene or C2 to C10 alkylidene through hydroxy groups; Rs is chosen from the group comprising substituted or unsubstituted radicals belonging to the following list: alkyl, alkenyl and alkynyl comprising from 1 to 10 carbon atoms; cycloalkyl and cycloalkylalkyle comprising from 3 to 6 carbon atoms in the cycloalkyl ring and 1 to 6 carbon atoms in the alkylated part; phenyl; aralkyl, aralkenyl and aralkynyl in which the aryl part is constituted by a phenyl radical and in which the aliphatic part comprises 1 to 6 carbon atoms;    heteroaryl, heteroaralkyl, heterocyclyl and heterocyclylalkyl of which the heteroatom (s) of the heterocyclic parts  <Desc / Clms Page number 139>  aforementioned are chosen from the group comprising 1 to 4 oxygen, nitrogen or sulfur atoms and the alkylated part which is associated with said heterocyclic parts comprising from 1 to 6 carbon atoms; in which the abovementioned R5 radicals are optionally substituted with 1-3 substituents independently chosen from the following group: C1-C6 alkyl, optionally substituted with amino, fluoro, chloro, carboxyl, hydroxy or carbamoyl groups; fluoro, chloro or bromo;  - OR3 -OCO2R3 - OCOR3  EMI139.1  - R -OS02 fez -oxo OCONR- NR3R4 -R3CONR4- -NR3CO2R4 -NR3CONR3R4  EMI139.2  - SOR "- o - 0 0 NR # # -S-R9 -SO3R3 -CO2R3 -CONR3R4 - CN; or phenyl optionally substituted by 1 to 3 atoms of fluorine, chlorine, bromine or C1 to C6 alkyl groups; - OR3, -NR3R4, -SO3R3, -CO2R3 or -CONR3R4, in which R3, R4 and R9 in these R5 substituents are as defined above where Rs can represent a divalent phenylene group or a C1 to C4 alkylene group bonded to core  EMI139.3    <Desc / Clms Page number 140>    EMI140.1  so as to form a bridged polycyclic group;  A is a C2 to C6 cyclopentylene, cyclohexylene or alkylene group optionally substituted by one or more C1 to C4 alkyl groups; R2 is a hydrogen atom or an anionic charge or a conventional easily separable carboxyl protecting group, it being understood that when R2 is a hydrogen atom or a protecting group, a counterion may also be present; and  EMI140.2  represents a heterocyclic non-aromatic, mono-bi-or poly-cyclic radical, substituted or unsubstituted, containing at least one nitrogen atom in the nucleus and linked to A by a nitrogen bond, so as to form a quaternary ammonium group as well as the pharmaceutically acceptable salts of its compounds, this process comprising the steps of:  (1) reaction of an intermediate of formula:  EMI140.3  in which : Ri and Ra are as defined above; and, R21 is a conventional easily separable carboxyl protecting group, in an organic solvent inert in the presence of diphenyl chlorophosphate and in the presence of a base so as to lead to the production of an intermediate of formula:  EMI140.4    <Desc / Clms Page number 141>  in which: R1, R8 and R2 'are as defined above. (2) reacting an intermediate IV in an inert organic solvent and in the presence of a base with a reagent of mercaptan type having the formula HS-A-OH in which:  EMI141.1  A is as described above so as to lead to the intermediate of formula:  EMI141.2  in which: R1, Rs, A and R2 'are as defined above; (3) reaction of intermediate V in an inert organic solvent and in the presence of a base with methanesulfonile chloride or a functional acylating equivalent of this chloride so as to lead to the production of an intermediate of formula:  EMI141.3  in which: RI, R8, A and R2 'are as defined above;  (4) reacting an intermediate VI in an inert organic solvent with a source of iodide ion so as to displace the methane-sulfonyloxy group by an iodo group and form an intermediate of formula:  EMI141.4    <Desc / Clms Page number 142>  in which: R1, R, A and R 'are as defined above; and (5) subjecting intermediate II to nucleophilic displacement in  EMI142.1  an inert organic solvent and in the presence of a silver ion by a  EMI142.2  amine of formula: j - \ No in which:  EMI142.3  is as defined above so as to displace the iodo group from intermediary II by the group  EMI142.4  and to form a compound of formula:  EMI142.5  in which :    EMI142.6  g is a counterion and, X9Ri, Rs, A, R5,  EMI142.7  and R21 are as defined above, and where appropriate eliminating the carboxyl protecting group R2 'to yield the corresponding deblocked compound of formula I, as well as the pharmaceutically acceptable salts of said compounds.  <Desc / Clms Page number 143>    34.- Pharmacological application of the compounds according to any one of claims 1 to 32 and in particular their application as an antibiotic.