FR2533568A1 - NOVEL ANTIBIOTICS OF THE CARBAPENEMS CLASS AND THEIR PHARMACEUTICAL APPLICATION - Google Patents

Abstract

THE SUBJECT OF THE PRESENT INVENTION A NEW CLASS OF CARBAPENEM DERIVATIVES CHARACTERIZED IN THAT IT PRESENTS A SUBSTITUTE IN POSITION 2 PRESENTING THE FORMULA: (CF DRAWING IN BOPI) IN WHICH: A REPRESENTS A RADICAL ALKYLENE WITH LINEAR OR BRANCHED CHAIN 1 INCLUDED A 6ATOMS OF CARBON; R REPRESENTS A RADICAL BELONGING TO THE FOLLOWING GROUP, WHICH COULD POSSIBLY CARRY ONE OR MORE SUBSTITUENTS, ALIPHATIC, CYCLOALIPHATIC, CYCLOALIPHATIC-ALIPHATIC, ARYL, ARALIPHATIC, HETEROARYLE, HETEROARALIPYCLER, AND HETEROARALIPHATIC, HETEROARALIPHATIC, HETEROARALIPHATIC AND HETEROARYCL-HETEROARALIPHATIC AND HETEROARALIPHATIC, OR HETEROCINOUS-HETEROARALIPHATIC, UCLYERO-HETEROCINAL, UCLEROCINAL, OUEROCINARY, OR HETEROARALIPYERIC. NITROGEN BOUND TO THE ALKYLENE GROUP A ON A CARBON ATOM OF THE CORE AND QUATERNIZED BY SUBSTITUTE R. THESE DERIVATIVES ARE USEFUL AS ANTIBACTERIAL AGENTS.

Description

NEW ANTIBIOTICS IN THE CLASSES OF

  CARBAPENEMS AND THEIR PHARMACEUTICAL APPLICATION

  The subject of the present invention is novel carbapenem antibiotics in which the 2-position substituent has the formula: -SA x <YN-R 5 where: A is a straight or branched chain alkylene radical

  comprising 1 to 6 carbon atoms;

  Rs represents a radical, optionally substituted, aliphatic,

  cycloaliphatic, cycloaliphatic-aliphatic, aryl, araliphatic

  tick, heteroaryl, heteroaraliphatic, heterocyclyl or hetero

  cyclyl-aliphatic; and represents an aromatic heterocycle containing a nitrogen atom bonded to the alkylene radical A by a carbon atom of the ring and

quaternized with substituent R 5.

  We know of technical literature a certain number of

  e-lactam containing the carbapenem nucleus

  These carbapenem derivatives are known to be useful as anti-cancer agents.

  bacterial and / or β-lactamase inhibitors.

  The initially known carbapenem compounds are natural products such as thienamycin having the formula YH H obtained by fermentation of Streptomyces cattleya (United States Patent No. 3,950,357). Thienamycin is an exceptionally potent broad-spectrum antibiotic which exhibits notable activity against various species of Pseudomonas, organisms which, it is

  well known, are resistant to antibiotics-based lactam.

  Other natural products containing the carbapenem core

  in derivatives of olivanic acid such as:

  the antibiotic MM 13902 described in the United States patent of

  that 4 113 856 having the formula:

  antibiotic MM 17880 described in the United States patent of

  that 4 162 304 presenting the formula:

H 035 O

CH 2 C 2 N Coc 3

// COO

  the antibiotic MM 4550 A described in US Pat. No. 4,545,149, describes the antibiotic MM 4550 A described in US Pat. antibiotic 890 A 9 described in US Pat. No. 4,264,735 having the formula: ## STR2 ## In addition to the abovementioned natural products, it is also known

  deacetyl compound 890 A 10 described in US Pat.

  4 264 734 having the formula: CE 3 / 'f SCI 2 CH 2 NH 2

0 O COOR

  this product having been prepared by enzymatic deacylation of the compound.

N-acetyl corresponding.

  Other naturally occurring olivicanic acid derivatives have also been synthesized, for example, the compounds as described in European Patent Application 8885 having the formula:

S (O) NHCOCH 3

  wherein: C 02 R 1 is an esterified, salified or free carboxyl group; n is 0 or 1;

  R 2 is a hydrogen atom, an acyl radical or a group of

  mule R 303 S wherein R 3 is a salification ion or a

methyl or ethyl radical.

  U.S. Patent No. 4,235,922 (see also European Patent Application 2058) describes the carbapenem derivative of the formula:

N SCH 2 CH 22 NH

N COOH

  whereas published British Patent Application No. 1,598,062 describes the isolation of the compound of the formula:

CH 2 CH 2 NHCOCE 3

Q. ' "COOH

O.

  from a fermentation broth of Streptomyces.

  Carbapenems, unsubstituted in position-6, were also able to

be prepared by synthesis.

  For example, U.S. Patent 4,210,661 discloses compounds of the formula: R 2

0 I 1

N COOH

  wherein R 2 is phenyl or substituted phenyl; U.S. Patent 4,267,177 discloses compounds of the formula: NOT

0 / COOH

  wherein: R 1 is an optionally substituted pyridyl group; U.S. Patent 4,255,441 discloses compounds of the formula:

-CR 2 = CR 3 R 4

  wherein R 2 and R 3 are a hydrogen atom or an alkyl radical; R 4 is NH-C; R 6 with R 6 being alkyl, phenyl, or substituted phenyl; and N is 1 or 2; U.S. Patent 4,282,236 discloses compounds of formula: wherein R 1 is a hydrogen atom or an alkyl radical; and R 2 is CN or C 02 R 3 wherein R 3 is a hydrogen atom or a

alkyl, aryl or aralkyl radical.

  Carbapenems having the general formula

R 1 NH SR

/ 'N OOH

  wherein: R1 is a hydrogen atom, or an acyl radical; and R 8 is a hydrogen atom or a radical, substituted or unsubstituted,

  alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, alkyl-

  cycloalkyl, -aryl, aralkyl, aralkenyl, aralkynyl, heteroaryl, heteroaralkyl, heterocyclyl or heterocyclylalkyl are described in US Pat. No. 4,218,463. In this patent there is absolutely no mention of any substituent R 8 consisting of a heteroaralkyl radical of the type

-A N-R 5

with A being an alkylene and N -

  consisting of an aromatic heterocycle containing a nitrogen atom of

  tainted bound to the alkylene group A on a carbon atom of the ring.

  The natural product of thienamycin is

  This isomer, together with the other seven isomers of thienamycin, can be obtained by total synthesis as described in US Pat. No. 4,234,596. thienamycin are also described, for example, in US Pat. Nos. 4,287,123, 4,269,772, 4,282,148, 4,273,709, US Pat.

  4,290,947 and in European Patent Application 7973.

  A key intermediate of these synthetic methods thus described is the compound OH L

NO CO 2 GNP

O

  wherein p NB represents the p-nitrobenzyl radical.

  Due to the exceptional biological activity of thienamycin, a large number of derivatives have been prepared and have been described in the technical literature. Among these, mention may be made of: (1) Nformimidoyl thienamycin described in the European patent application 6639 presenting the formula

OH

SCH 2 CH 2 NC-NH 2

  OOH (2) N-heterocyclic thienamycin derivatives described in US Pat. No. 4,189,493 having the formulas CS 2 C E 2 N 2) n

22 N

  COOR x 1 I (z) and OH g>, C 2 12 C 2 i 2 (CH 2) No. NO 2 2 II

  in which the bifunctional cycle may contain insaturations

  additional contributions in the cycle; and n is an integer from 1 to 6, inclusive; * p is 0, 1 or 2; R 1 is a hydrogen atom, an alkyl or aryl radical; and Z is imino, oxo, hydrogen, amino or alkyl;

  (3) the substituted N-methylene derivatives of thienamycin as de-

  in United States Patent 4,194,047 having the formula OH

SCH 2 CE 2 N = 1-X

  ## STR1 ## wherein:

  X and Y are H, R, OR, SR or NRIR 2 with R being a sub-radical

  stituted or unsubstituted, selected from the group consisting of

  alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkyl radicals

  alkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heteroaralkyl,

  rocyclyl or heterocyclylkyl; and R1 and R 2 are a hydrogen atom or an R group;

  (4) compounds as described in the United States patent of

  4 226 870 with the OR 3 formula

_SCH 2 CH 2 NR R

2 2

O COOS

  wherein: R 3 is aryl, alkyl, acyl or aralkyl; and

  R 1 and R 2 are, independently of one another, a hydrogen atom

  a gene or an acyl radical, including an acyl radical of the -C (O) -RH, R 11 type which may be, for example, an alkyl radical substituted with a quaternary ammonium group, for example

-C-CH 2-C

  (5) the compounds as described in British Patent 1,604,276

  (see also United States Patent 4,235,917)

feeling the formula

OR 3

_ SCH 2 CH 2 NR R

NOT

0 'COOR

  wherein: R 3 is a hydrogen atom or an acyl group or a univalent substituted hydrocarbon radical; RI is a radical, optionally substituted, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkenylalkyl,

  cycloalkylalkyl, aryl, aralkyl, heteroaryl or heteroaral-

  kyle; and R 2 is an acyl radical, including an acyl radical of the -C (O) -R type in which R is an alkyl radical substituted by a quaternary ammonium group such as, for example, O

-C-CH 2 N

  (6) compounds as described in US Pat.

  4 235 920 having the formula OH

SCH 2 CH 2 NR 5 R 6 R 7

  In which: R 5, R 6 and R 7 are, independently of each other, hydrogen or a radical, substituted or unsubstituted, belonging to the group comprising: alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkenylalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl or heteroaralkyl; (7) the compounds as described in British Patent 1,604,275 having the formula

OR 3

_, CH 2 CE 21 = N R R

  wherein: each of R 1 and R 2, independently of each other, is a radical of the type as defined for R, a hydrogen atom or a nitro, hydroxyl, alkoxyl group comprising 1 to 6 carbon

  of carbon, amino, alkylamino comprising 1 to 6 carbon atoms.

  bone, di (C 1 -C 6 alkyl) amino or tri (C -C 6 alkyl), an additional anion being present in the latter case; or R 1 and R 2 are bonded together to form together with the nitrogen atom to which they are attached a monocyclic or bicyclic, heteroaryl or heterocyclyl residue, substituted or unsubstituted, containing from 4 to 10 atoms in the ring, one or more of these may be an additional hetero atom selected from oxygen, sulfur and nitrogen; R is a cyano group or a substituted or unsubstituted radical belonging to the group comprising the radicals: carbamoyl,

  carboxyl, (C 1-10 alkoxy) carbonyl, C 1-6 alkyl, C 2-10 al-

  kenyl, C 2-10 alkynyl, C 3-10 cycloalkyl, C 4-12 cycloalkyl-

  alkyl, C 5-12 cycloalkylalkenyl, C 3-10 cycloalkenyl, Cs-12 cycloalkenylalkenyl, C 4-12 cycloalkenylalkyl, C 6 -0 aryl,

  C, -16 aralkyl, Cs-16 aralkenyl, C 8-16 aralkynyl or monocy-

  clique or bicyclic heteroaryl, heteroaralkyl, heterocyclyl or heterocyclylalkyl comprising 4 to 10 atoms in the ring, one or more of them being a hetero atom selected from oxygen, sulfur and nitrogen and wherein the alkyl residue

  heteroaralkyl or heterocyclylalkyl radical contains 1.

  at 6 carbon atoms; the substituent (s) on the groups R, R 1, R 2 or on the ring formed by the junction of R 1 and R 2 being chlorine, bromine, iodine, fluorine or

  azido groups, C 1 -C 4 alkyl, mercapto, sulfo, phosphono, cyano

  nothio (-SCN), nitro, cyano? amino, hydrazino, amino or hy-

  drazino up to 3 alkyl substituents

  taking from 1 to 6 carbon atoms; hydroxy, C 1 -C 6 alkoxy, C 1 -C 6 alkylthiocarboxyl, oxo, (C 1 -C 6) alkoxycarbonyl, C 2 -C 4 acyloxy, carbamoyl, (C 1 -C 4 alkyl) carbamoyl or di (C 1 -C 4 alkyl) carbamoyl;

  R 3 is a hydrogen atom or an acyl radical or a radical

  dical of the type as defined for R 4; R 4 is C 1 -C 10 alkyl, substituted carbonylmethyl, (C 1 -C 6 alkoxy) - (C 1 -C 6 alkyl); (C 3 -C 6 cycloalkoxy) - (C 1 -C 6)

  alkyl); C 2 -C 12 alkanoyloxyalkyl; an alkyl radical comprises

  1 to 6 carbon atoms, partially or fully halogenated, wherein the halogen atom (s)

  chlorine, bromine or fluorine, aminoalkyl radicals, C 2 -Co 10

  kenyl, C 2 -Calkynyl, acyl, C 1 -C 4 -alkoxycarbonylalkyl, C 4 -C 21 dialkylaminoacetoxyalkyl, C 2 -C 13 alkanoylaminoalkyl, ar- (C 1 -C 3 alkyl) wherein the aryl residue contains 6

  at 10 carbon atoms; heteroaralkyl or heterocyclylal

  monocyclic or bicyclic kyl containing 4 to 10 ring atoms, 1 to 3 carbon atoms in the alkyl residue, and 1 to 4 hetero atoms consisting of oxygen, sulfur and / or nitrogen;

  aralkyl or substituted heteroaralkyl radicals.

  in which the substituent is a chlorine, bromine, fluorine or iodine atom or an alkyl radical comprising

  1 to 6 carbon atoms; an aryl or substituted aryl radical

  a nuclear compound containing from 6 to 10 carbon atoms in the ring and wherein any substituent of the ring belongs to the group consisting of the hydroxy radical, the C 1 -C 6 alkyl group, the

  atoms of chlorine, fluorine or bromine, the aralkoxygen radicals

  alkyl, C 2 -C 12 alkylthioalkyl, C 4 -C 12 cycloalkylthioalkyl,

  (C 2 -C 10 acylthio) - (C 1 -C 6 alkyl), or phenylalkenyl in

  which alkenyl radical comprises from 2 to 6 carbon atoms;

  R 5 is a substituted or unsubstituted radical belonging to the group

  eg C 1 -C 10 alkyl, C 2 -C 10 alkenyl or alkynyl; the

  substituted or unsubstituted cycloalkyl, cycloalkyl radicals

  e + nyl, cycloalkenylalkyl, and cycloalkylalkyl comprising from 3 to 6 carbon atoms on the ring and up to 6 carbon atoms in any chain; C 6 -C 10 aryl, aralkyl comprising 6 to 10 carbon atoms in the ring and 1 to 6

  carbon atoms in the alkyl chain; heteroaryl or heteroaryl

  roaralkyl, monocyclic or bicyclic, containing from 4 to 10 atoms

  in the cycle, one or more of them consisting of oxygen, nitrogen and / or sulfur, and 1 to 6

  carbon atoms in the alkyl chain and the substituent (s)

  keratin, bromine, iodine, fluorine or an azido, cyano, amino, C1-C6alkylamino, di (C1-C6alkyl) amino or tri (C1-C6 alkylamino), an additional ion being present in the latter case, or a hydroxy, C1-C6 alkoxy, C 1 -C6 alkylthioalkyl, carboxyl, oxo, C 1 -C 6 alkoxycarbonyl, C 2-Clo acyloxy, carbamoyl, (CC 4 alkyl) carbamoyl; di (C 1 -C 4 alkyl) carbamoyl; cyanothio (-SCN) or nitro; R 6 is a hydrogen atom or a hydroxy, mercapto, R, -OR, -SR or NRIR 2 group, with R, R 1 and R 2 as defined above; X is hydroxy, mercapto, amino, acyloxy-OR 4, -SR 4, -NHR 4, -N- (R 4) 2, -OM, or, when the compound is in zwitterionic form, O, in which case A is absent; A when the compound is not in zwitterionic form is a counterion; M is a pharmaceutically acceptable cation; and Q is a blocking group as defined below; (8) compounds as described in European Patent Application Publication No. 21082 having the formula wherein R NX e '

  linked to the amino group nitrogen of thienamycin represents a group

  heterocyclic, mono or polycyclic, containing nitrogen; and

  R is a hydrogen atom or a radical, substituted or unsubstituted

  killed, alkyl, alkenyl, alkenyl, heterocyclylalkenyl, aralkenyl,

  heterocyclylalkyl, aralkyl, -NR 2, COOR, CONR 2, -OR, or CN.

  Among the compounds described in U.S. Patent 4,235,920 is the compound OH SCH 2 CH 2 N (EC 3) 3 I N X GCOOH

  wherein A is a pharmaceutically acceptable anion.

  The quaternary amine derivative mentioned above is also described in the Recent Advances in the Chemistry of G-Lactam Antibiotics Journal, Royal Society of Chemistry, London, 1981, pages 240-254, where its activity

  anti-bacterial medium is mentioned as being of the order of approxi-

  1/2 to 2/3 that of thienamycin.

  Carbapenem derivatives with a wide variety of

  In addition to those mentioned above, it has also been possible to synthesize them at the 6-position, for example: (1) European Patent Application 40408 describes compounds of formula R t: H 3CH SR

CE 3-CH 53

  Wherein: R1 is a hydrogen atom or a methyl or hydroxyl group; and RP is a monovalent organic group comprising, inter alia, the heterocyclylalkyl group; (2) the published European patent application 8514 discloses compounds of formula

R 2 O -

N OH -E

  wherein: R 1 is an optionally substituted pyrimidinyl group; and R 2 is a hydrogen atom or a CR 3 R 4 R 5 group in which: R 3 is a hydrogen atom or a hydroxy group; R 4 is a hydrogen atom or an alkyl group; and R 5 is a hydrogen atom or an alkyl, benzyl group

  or phenyl, or R 5 and R 4 together form a core

  bocyclique; (3) European Patent Application 38869 describes compounds of the formula R 7 R 6 in which: R 6, R 7 and R 5, independently of one another, are selected from the group consisting of the atom of hydrogen and substituted or unsubstituted radicals: alkyl, alkenyl and alkynyl,

  comprising from 1 to 10 carbon atoms; cycloalkyl, cycloalkyl

  kylalkyl, and alkylcycloalkyl comprising from 3 to 6 carbon atoms in the cycloalkyl ring and 1 to 6 carbon atoms in the alkyl part; aryl, such as phenyl; aralkyl, aralkenyl, and aralkynyl wherein the aryl portion is a phenyl radical and the aliphatic moiety

  comprises from 1 to 6 carbon atoms; heteroaryl, heteroaral-

  kyle, heterocyclyl and heterocyclylalkyl; in which the substituent (s) relative to the abovementioned radicals are chosen from the group comprising: -X halo (chloro, bromo, fluoro) -OH hydroxy -OR 'alkoxy, aryloxy O n -OCNR 1 R 2 carbamoyloxy

O

  -CNR 1 R 2 carbamoyl -NR 1 R 2 amino NRI '/ amidino

NRI R 2 -

  R 1 -NQ 2 nitro-N (RI) 3 tri-substituted amino (the R 1 groups being independent) R 1 R 1 -C = NOR 2 oximino -SR alkyl and arylthio -SO 2 NR 1 R 2 sulfonamido

O O

  1 -NHCN R 1 R 2 ureido I -R 1 CNR 2 amido -CO 2 H carboxy -C 02 R 1 carboxylate -CR 1 acyl OI -OCR 'acyloxy -SH mercapto O -SR' alkyl and aryl sulfinyl -SRI alkyl and aryl sulfonyl -CN cyano -N 3 azido being understood that, as regards the aforementioned substituents on R 6, R 7 and R 8, the groups R - and R 2 are chosen,

  independently of each other, among the group includes

  the hydrogen atom and the alkyl and alkenyl radicals

  and alkynyl comprising from 1 to 10 carbon atoms; cyclohexane

  alkyl, cycloalkylalkyl and alkylcycloalkyl comprising 3

  6 carbon atoms in the cycloalkyl part and 1 to 6 atoms

  carbon atoms in the alkyl part; aryl, such as phenyl; aralkyl, aralkenyl and aralkynyl in which the part

  aryl is formed by a phenyl radical and the aliphatic

  tick comprises from 1 to 6 carbon atoms; heteroaryl, heteroaryl

  roaralkyl, heterocyclyl and heterocyclylalkyl and wherein the hetero atom (s) of the aforementioned heterocyclic moieties are selected from the group consisting of 1 to 4 oxygen atoms,

  of nitrogen or sulfur atoms and where the alkyl parts

  These heterocyclic moieties comprise from 1 to 6 carbon atoms (see also published European patent applications 1627, 1628, 10317, 17992, 37080, 37081 and

37082).

  (4) published European Patent Application 24832 discloses compounds of formula

R 1 1

3 SR 12

N CO

  wherein: R 'is a hydrogen atom or a group comprising OH, OSO 3 H, or a salt or alkyl ester comprising 1 to 4 carbon atoms derived therefrom, OR 2, SR 3, OCOR 2, OC 02 R 3 or OCONHR 3, with R 2 being an alkyl radical comprising 1 to 6 carbon atoms or an optionally substituted benzyl radical, and R 3 is a

  alkyl radical having 1 to 6 carbon atoms or a radical

  phenyl or benzyl cal, optionally substituted, and R 2 is a C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 3 -C 6 alkynyl radical, it being understood that the triple bond is not present on the atom of carbon adjacent to the sulfur atom, aralkyl,

  C1-C6 alkanoyl, aralkanoyl, aryloxyalkanoyl or arylcarbonyl

  nyle, any of the groups R 12 being presently

  substituted, these compounds acting as compounds

  having anti-bacterial properties.

  Published European Patent Application 44170 discloses carbapenem derivatives of the formula ## STR2 ##

R 3 S-X N

N 4

  o CO 2 a in which: R 3 is a hydrogen atom or an organic radical bonded by a carbon atom to the carbapenem ring; n is 0 or 1; X is a hydrocarbon radical, saturated or unsaturated, optionally substituted with a bromine or chlorine atom; and R 4 is C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 1 -C 10 aralkyl or

  aryl, any of the groups D being optionally substituted

  kill. There is no mention in this published patent application, however, of any compound in which the tetrazole ring is attached to X by a quaternized nitrogen atom, i.e. a positively charged nitrogen.

  which is not bound to the hydrogen atom.

  Published European Patent Application 38869 mentioned above describes the synthesis of carbapenem derivatives by the intermediates of general formula R 7 R R 2 'in which: R 6 and R 7 are as defined above and

  R 2 'is a carboxyl protecting group easily separable.

  Also described as intermediates are the compounds of formula

mule R 7 x in which:

  X is described as a separable group.

  During the Gordon Research Conference on Medicinal Chemistry held in New London, New Hampshire from August 2 to 6, 1982, a leaflet was published in which a large number of carbapenem antibiotics have been described. this notice, is the carbapenem having the formula - H -s 21 H which differs from the compounds according to the present quaternized heteroaromatic of the substituent ment to the sulfur atom instead of being

alkylene group.

  The European patent application 50334 penem of general formula in that the core

in position-2 is directly related-

at the carbon atom of a

describes carbamide derivatives

4, N R 1 Il 1 2

S-A-C-NR R

  Wherein R 6 and R 7 are, inter alia, independently of one another, selected from the group consisting of hydrogen, alkyl, alkenyl, aryl and aralkyl; A is a single direct bond to the indicated sulfur and carbon atoms, or A is a selected cyclic or acyclic bond group,

  among others, among the radicals alkyl, cycloalkyl, aryl, hetero-

  aryl or heteroalkyl; RI and R 2 which define the carbamimidoyl function are, inter alia,

  independently selected from each other, from the hydrogen atom

  and the alkyl and aryl groups, said carbamimidoyl being further characterized by cyclic structures obtained by bonding the two nitrogen atoms via their substituents and by joining to the linking groups A; in addition, carbamimidiums are described by quaternizing one of the nitrogen atoms of said carbamimidoyl.

  Page 12 of this patent application, is described, as possible sub-

  stituant in position-2, the group N Ri il%

-S-A-C O

  Wherein R 1 may be a hydrogen atom, or a substituted or unsubstituted radical: alkyl, cycloalkyl, cycloalkylalkyl, alkylcycloalkyl, aryl, arylalkyl, heterocyclyl or heterocyclylalkyl and the two nitrogen atoms "participate in cyclic structures that are indicated

by the dashed lines ".

  This patent application does not contain any description which is specific

  to cyclized carbamimidoyl groups containing a quaternized nitrogen atom, although page 22 is described a cyclized carbamimidoyl group of the formula:

-S-CH 2-C U I

  N CH 3 - On the basis of the given definitions of the substituent RI, the applicant does not

  does not believe that published European patent application 50334 describes the

  However, since the definitions given in the application in reference are very vague, as to the nature of the cyclic structures involved, the applicant refers to this patent application only to make known that he had

  knowledge and that it is totally different from it.

  Whereas, as indicated above, the prior art discloses

  written carbapenem derivatives having a substituent in position-2 of general formula -S-A-Het wherein: A represents an alkylene group; and Het represents a heterocyclic or heteroaromatic group, there is no document of which the applicant is aware which describes carbapenems in which Het is a radical of formula N-R with:

R 5 being a radical, optionally substituted, aliphatic, cycloalkyl,

  phaetic, cycloaliphatic-aliphatic, aryl, araliphatic, hetero-

  roaryl, heteroaraliphatic, heterocyclyl or heterocyclylalipha-

  tick; and represents an aromatic heterocycle containing a quaternized nitrogen atom bonded to a carbon of an alkylene radical by an atom of

core carbon.

  As has been described above, carbapenem whose substituent at the 2-position is formed by the CH 3 group

-S-CH 2 CH 2 N CH 3

CH 3

  has already been described, as well as carbapenem with a heteroaromatic

  quaternized tick directly bonded to the sulfur-2-position substituent. Despite the large number of carbapenem derivatives described in the technical literature, we are still looking for new carbapenems because

  these known derivatives may show improvements in their

  their activity, their power, their stability and / or their secondary effects.

toxic agents.

  The subject of the present invention is a new series of derivatives

  of carbapenem characterized in that they comprise a substitute for

  2-tion having the formula wherein: A is a linear or branched chain alkylene radical having 1 to 6 carbon atoms;

  RB is a radical, optionally substituted, aliphatic, cycloaliphatic,

  tick, cycloaliphatic-aliphatic, aryl, araliphatic, hetero-

  aryl, heteroaraliphatic, heterocyclyl or heterocyclylaliphatic

  than; and represents an aromatic heterocycle containing a quaternized nitrogen atom bound to the alkylene radical A by a ring carbon atom. More specifically, the present invention relates to carbapenem derivatives of the formula

H R 15

  Embedded image in which: Re is a hydrogen atom; and

  IR is selected from the group consisting of hydrogen as well as

  substituted or unsubstituted organic radicals of the following list: alkyl, alkenyl and alkynyl having 1 to 10 carbon atoms; cycloalkyl and cycloalkylalkyl 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 wherein the aryl portion is formed by a phenyl radical and the aliphatic portion comprises from 1 to 6 carbon atoms; heteroaryl, heteroaralkyl, heterocyclyl and heterocyclylalkyl wherein the one or more hetero atoms of said heterocyclic moieties are selected from the group consisting of 1 to 4 oxygen atoms, nitrogen

  or sulfur and the alkyl part associated with these heterocyclic moieties

  1 to 6 carbon atoms, being understood that the substituent (s) relative to the aforementioned radicals are, independently of one another, selected from the group comprising: C 1 -C 6 alkyl, optionally substituted by a amino, halo, hydroxy or carboxyl group; halo -OR 3 I

-OCNR 3 R 4

-CNR 3 R 4

-NR 3 R 4

NR 3

<NR 3 R 4

-502 NR 3 R 4

on I

-NHCNR 3 R 4

R CNR 4-

-C 02 R 3

-OP (O) (OR 3) (OR 4)

= O O I, to

-OCR 3

-SR 3 O

-SR 9

O n -SR 9 I O O -CN

-N 3

-O 503 R 3

I

-OS-R 9

your

O

I

-NR 35-R 9

-NR 3 C = NR 4

R 3

-NR 3 CO 2 R 4

  -NO 2 in which; as regards the aforementioned substituents:

  the groups R 3 and R 4, independently of one another,

  hydrogen, or alkyl, alkenyl and alkynyl radicals of 1 to 10 carbon atoms; cycloalkyl, cycloalkylalkyl and alkylcycloalkyl comprising 3 to 6 carbon atoms in the cycloalkyl part and i to 6 carbon atoms in the alkyl part; phenyl; aralkyl, aralkenyl and aralkynyl wherein the aryl portion is a phenyl radical and

  the aliphatic portion comprises 1 to 6 carbon atoms; and

  roaryl, heteroaralkyl, heterocyclyl and heterocyclylalkyl in

  which the hetero ring hetero ring (s)

  cited consist of 1 to 4 atoms of oxygen, nitrogen or sulfur

  and the alkyl portion associated with said heterocyclic portions

  take from 1 to 6 carbon atoms; or R 3 and R 4 together with the nitrogen to which at least one of them is bound, form a 5- or 6-membered nitrogen-containing heterocyclic ring; - R 9 is similar to R 3 except that it can not be hydrogen; or, wherein R 1 and R 2 taken together form a C 2 -C 8 alkylidene or C 2 -C 10 alkylidene radical substituted with a hydroxy group; R 5 belongs to the group of radicals, optionally substituted: alkyl, alkenyl, alkynyl comprising 1 to 10 carbon atoms;

  cycloalkyl and cycloalkylalkyl comprising -3 to 6 carbon atoms;

  bone in the cycloalkyl part and 1 to 6 carbon atoms in the alkyl parts; phenyl; aralkyl, aralkenyl and aralkynyl wherein the aryl portion is a phenyl radical and the aliphatic portion of which has 1 to 6 carbon atoms; heteroaryl, heteroaralkyl, heterocyclyl and heterocyclylalkyl wherein the one or more hetero atoms of the aforementioned heterocyclic moieties consist of 1 to 4 oxygen, nitrogen and / or

  sulfur and the alkyl moieties associated with said hetero-

  cyclic include 1 to 6 carbon atoms; the radicals Rs mentioned above are optionally substituted with 1 to 3 substituents chosen independently of each other from the group comprising: C 1 -C 6 alkyl, optionally substituted by amino, fluoro, chloro, carboxyl, hydroxy or carbamoyl groups; fluoro, chloro or bromo;

-OR 3;

-0 C 02 R 3;

-OCOR 3;

-OCONR 3 R 4;

he

-OS-R 9;

I * O oxo;

-NR 3 R 4;

R 3 CONR 4-;

-NR 3 CO 2 R 4;

-NR 3 CONR 3 R 4;

O

I-NR 35-Rg;

-SR 3;

-S-R 9;

0 O

-S R 9, -

-503 R 3;

-C 02 R 3;

-CONR 3 R 4;

  CN; or phenyl, optionally substituted with 1 to 3 fluorine, chlorine or bromine atoms, or 1 to 3 C 1 -C 6 alkyl groups, -OR 3, -NR 3 R 4, 503 R 4, -C 02 R 3 or -CONR 3 R 4, wherein R 3, R 4

  and R 9 in these substituents Rs are as defined above.

  above; or Rs can be linked to the group

  at another point in the nucleus, so as to form a heterogeneous nucleus

  aromatic or fused heterocyclic ring, which ring may further contain up to two additional hetero atoms consisting of oxygen, nitrogen or sulfur; Rs is chosen from the group comprising hydrogen as well as the radicals, substituted or unsubstituted, from the following list:

  alkyl, alkenyl and alkynyl, comprising from 1 to 10 carbon atoms

  bone; cycloalkyl, cycloalkylalkyl and alkylcycloalkyl,

  3 to 6 carbon atoms in the cycloalkyl part and 1 to 6 carbon atoms in the alkyl parts; spirocycloalkyl having 3 to 6 carbon atoms; phenyl; aralkyl, aralkenyl

  and aralkynyl in which the aryl part consists of a radical

  phenyl call and whose aliphatic part includes 6 atoms

  of carbon; heteroaryl, heteroaralkyl, heterocyclyl and hetero-

  cyclylalkyl wherein the one or more hetero atoms of the aforementioned heterocyclic moieties consist of 1 to 4 oxygen, nitrogen or sulfur atoms and the alkyl moieties associated with said heterocyclic moieties comprise from 1 to 6 carbon atoms;

  in which the substituent or substitutes relating to the radicals

  are selected from the group consisting of: amino, mono-, di- and trialkylamino, hydroxyl, alkoxyl, mercapto, alkylthio, phenylthio, sulfamoyl, amidino, guanidino, nitro, chloro, bromo, fluoro, cyano and carboxy; and wherein the alkyl portions of the aforementioned substituents comprise from 1 to 6 carbon atoms; A is a linear or branched chain alkylene radical; R 2 is a hydrogen atom, a charge anionic or a carboxyl group easily separable conventional, it being understood that when R 2 is a hydrogen atom or a protecting group is also piezent a counter-ion; and represents a mono-, bi or polycyclic aromatic heterocyclic radical substituted or unsubstituted, containing at least one nitrogen atom

  in the nucleus and bound to A by a carbon atom of the nucleus and pos-

  sedant, in addition, a nitrogen atom in the nucleus that is quater-

established by the RS group;

  The invention also relates to the pharmaceutically acceptable salts of

from the aforementioned compounds.

  The compounds of formula I are potent anti-bacterial agents

  or intermediates useful for the preparation of such agents.

  Also within the scope of the present invention are processes for the preparation of novel carbapenem derivatives described above, as well as pharmaceutical compositions containing carbapenem derivatives, which are hiolonically active, in combination with diluents or

  pharmaceutically acceptable carriers.

  The novel compounds of general formula I above contain the carbapenem ring

1 3 '.

  and can therefore be called derivatives of 1-carba-2-acid

  penem-3-carboxylic acid. Alternatively, the compounds can be considered to have the following basic structure

675 3

So X

  and be called derivatives of 7-oxo-1-azabicyclo (3,2,0) hept-2-ene-

  2-carboxylic acid. While the subject of the present invention is compounds in which the relative stereochemistry of protons at the -5,6 and cis-positions

  as well as trans, the preferred compounds exhibit the sterile structure

  re-chemistry 5 R, 6 S (trans) as is the case of thienamycin.

  The compounds of formula I may not be substituted in

  or substituted by substituents previously described in connection with other carbapenem derivatives. More specifically,

  R 8 may be hydrogen and RI may be hydrogen or a substitute

  non-hydrogenated killing such as described for example in European Patent Application 38869 (cf definition of R 6) According to one variant, R 8 and R 1, taken together, can form a radical C 2-C 1 o alkylidene or C 2- Co 10 alkylidene

  substituted, for example, with a hydroxy group.

  The compounds of formula I can also remain unsubstituted

  (Rs 5 = H) or be substituted with substituents previously described for

  other carbapenem derivatives More precisely, R 15 can be a hydro-

  toedhdo or any of the substituents other than 1-position hydrogen as described, for example, in European Patent Application 54917, given by reference (in which R1 and R2 are precisely defined) or in the US Pat. United States of America n 4350631 R 15 substituents other than hydrogen which are preferred by the radicals C 6 C 6 alkyl, especially the methyl radical and

  alkyl-phenyl whose alkyl part contains from 1 to 6 carbon atoms

  R 1 other than hydrogen can have the a or 8 configuration and, of course, the present invention extends to the individual isomers and as well as to their mixtures. The 1-substituted derivatives which are nested are those

  having the configuration 3, especially those substituted with an R-methyl.

  To be more specific about the definitions of R 1, R 8 and R 15: (a) the alkyl, alkenyl and alkynyl radical may be a chain radical

  linear or branched comprising 1 to 10 carbon atoms, preferably

  rence comprising 1 to 6 and more particularly 1 to 4; when part of another substituent for example as this is the case in

  cycloalkylalkyl, or heteroaralkyl or aralkenyl radicals,

  if it is alkyl, alkenyl or alkynyl, it will preferably contain from 1 to 6 and more preferably from 1 to 4 carbon atoms; (b) heteroaryl means mono-, bi and polycyclic aromatic heterocyclic groups containing 1 to 4 oxygen, nitrogen and / or sulfur atoms; preferably, heterocyclic rings are meant

  with 5 or 6 atoms, such as thienyl, furyl, thiadiazolyl, oxadiazo-

  lyle, triazolyl, isothiazolyl, thiazolyl, imidazolyl, isoxazolyl,

  tetrazolyl, oxazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazine

nyl, pyrrolyl, pyrazolyl, etc .;

  (c) heterocyclyl means non-aromatic heterocyclic groups;

  Saturated or unsaturated, mono-, bi and polycylic

  4 atoms of oxygen, nitrogen and / or sulfur; we hear more

  specifically, 5- or 6-membered heterocyclic rings, such as morpholinyl, piperazinyl, piperidyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, pyrrolinyl, pyrrolidinyl, etc .; (d) halo means the atoms of chlorine, bromine, fluorine and iodine

  + * and, more particularly, chlorine, fluorine or bromine.

  By the term "easily separable carboxyl protecting group

  This is an ester group known to be able to block a carboxyl group during the chemical reaction steps described below.

  which may be separated, where appropriate, by methods which do not lead to

  no appreciable destruction of the recent part of the

  for example by chemical or enzymatic hydrolysis, treatment with chemical reducing agents under mild conditions, irradiation

  using ultraviolet light or catalytic hydrogenation.

  Examples of such protecting groups consisting of esters include

  benzhydryl, allyl, p-nitrobenzyl, 2-naphthylmethyl, benzyl, trichlo-

  roethyl, silyl such as trimethylsilyl, phenacyl, p-methoxybenzyl, acetonyl, o-nitrobenzyl, 4-pyridylmethyl and C 1 -C 6 alkyl such as methyl, ethyl or t-butyl fall within the scope of such protecting groups, those which are hydrolysed under physiological conditions such as

  pivaloyloxymethyl, acetoxymethyl, phthalidyl, indanyl and methyl

  thoxymethyl A particularly advantageous carboxyl protecting group

  is p-nitrobenzyl which is easy to separate by catalytic hydrogenolysis

  tick. By the term pharmaceutically acceptable salts

  as used in the present description, is meant the salts of

  of non-toxic acids such as salts of mineral acids, such as hydrochloric acid, bromidic acid, iodide, phosphoric acid, sulfuric acid, etc. as well as salts with organic acids such as maleic, acetic, citric, succinic, benzoic, tartaric, fumaric,

  mandelic, ascorbic, lactic, gluconic and malic.

  Compounds of formula I in the form of acid addition salts can be formed into

R 8 H R 15

R 1 R

R <S A -R 5 X

OOR 2

  with: R 2 = a hydrogen atom or a protecting group;

X 8 an acid anion.

  The counter anion X can be chosen to provide acceptable salts.

  pharmaceutically suitable for therapeutic administration.

  but in the case of the intermediate compounds of formula I, X O may also be a toxic anion In such a case, the ion may be subsequently removed or substituted with a pharmaceutically acceptable anion suitable for therapeutic use.

  acids or alkalis are present in the RI or RB groups or on the

  This N - the present invention may also include salts of acids or bases

  suitable functional groups, namely, addition salts of

  in which a basic group and metal salts, ie sodium, potassium, calcium and aluminum salts, ammonium salts and salts

  with non-toxic amines (eg trialkylemines, procaine, dibenzines,

  zylamine, 1-ephenamine, N-benzyl-B-phenethylamine, N, N'-dibenzylethylene

  diamine, etc.) in the case of an acid group.

  Compounds of formula I in which R 2 is a hydrogen atom,

  an anionic charge or a hydrolysable ester group from the physiological point of view

  As well as the pharmaceutically acceptable salts derived therefrom are useful as anti-bacterial agents. In accordance with a preferred aspect of the present invention, it relates to compounds of formula I wherein R 8 is hydrogen, and RI is hydrogen

or a CH 3 CH 2 group

CH 3 CH 3 OH OH

CH-, C or CH 3 CH-

CH 3 CH 3

  Of this subclass, the compounds which are preferably employed are those in which R1 is

OH

CH 3 CH-

  and more particularly the compounds having the absolute configuration

+5 R, 65, 8 R.

  According to another aspect of the present invention, the subject of the invention is compounds of formula I in which R 1 and R 8 together form an alkylidene radical of formula

HOCH 2

CH 3 /

  The alkylene radical (that is, the substituent A) in the compounds

  poses of formula I may have a linear or branched chain and may

  contain from 1 to 6 carbon atoms According to a particular embodiment

  the subject of the invention are compounds in which A is - (CH 2) n-

  N being equal to I 1 or 2 and according to a very particular aspect, this

  The subject of the invention is compounds in which A is equal to -CH 2.

  The alkylene part "A" is attached by a carbon atom of

  nucleus has a l-substituted quaternized aromatic heterocycle of general formula

R

  wherein the substituent R 5 is preferably a radical, optionally

  C 1 -C 6 alkyl, C 2 -C 10 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, C 3 -C 6 cycloalkylC 1 -C 6 alkyl,

  phenyl, phenyl-C 1 -C 6 alkyl, phenyl-C 2 -C 6 alkenyl, phenyl-C 2 -C 6 alkyl-

  nyl, heteroaryl, heteroaralkyl wherein the alkyl portion comprises

  from 1 to 6 carbon atoms, heterocyclyl or heterocyclylalkyl in the

  wherein the alkyl portion has 1 to 6 carbon atoms The heteroaryl substituent (or the heteroaryl portion of a heteroaralkyl) Rs may be a mono-, bi or polycyclic aromatic heterocyclic group containing 1 to 4 oxygen atoms, nitrogen or sulfur; 5-membered or 6-membered heterocyclic rings such as

  radicals thienyl, furyl, thiadiazolyl, oxadiazolyl, triazolyl, iso-

  thiazolyl, thiazolyl, imidazolyl, isoxazolyl, tetrazolyl, oxazolyl,

  pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrrolyl and pyrazolyl.

  The heterocyclyl substituent R 5 (or the heterocyclyl portion of a heterocyclyl

  clylalkyl) may be a saturated or unsaturated, mono-, bi or polycyclic non-aromatic heterocyclic group containing 1 to 4 oxygen atoms,

  nitrogen or sulfur. Heterocyclic rings should preferably be used.

  5 or 6 members such as morpholinyl, piperazinyl, piperidyl, pycazolinyb, pyrazolidinyl, imidazolinyl, imidazolidinyl, pyrrolinyl and pyrrolidinyl. The substituent R 5 may be optionally substituted with 1 to 3 substituents chosen, independently of one another, from the groups comprising:

  (a) C, -C 6 alkyl radicals, optionally substituted with, preferably

  1 to 3 amino, fluoro, chloro, carboxyl, hydroxy or carbamoyl groups; (b) fluoro, chloro or bromo; (c) -OR 3; (d) -OC 02 R 3; (e) -OCOR 3; (f) QCONR 3 R 4; (g) O-OS-Rg; O: (h) -oxo; (i) -NR 3 R 4; (j) R 3 CONR 4-; (k) -NR 3 CO 2 R 4;

(1) -NR 3 CONR 3 R 4;

(me

-NR 35-R 9;

O (n) -SR 3; (o) -SOR 9; (p) o i I

-S-R 9;

  O (q) -503 R 3; (r) -C 02 R 3; (s) -CONR 3 R 4; (t) -CN; or (u) a phenyl radical, optionally substituted with 1 to 3 substituents independently selected from the group consisting of fluorine, chlorine or bromine atoms, and C 1 -C 6 alkyl, -OR 3, -NR 3 R 4 groups, -503 R 3,

  -C 02 R 3 or -CONR 3 R 4, wherein, relative to the substituents R 5 pre-

  R 3 and R 4 are independently of each other 4 + selected from the following groups: hydrogen, alkyl, alkenyl and alkynyl, having from 1 to 10 carbon atoms; cycloalkyl, cycloalkylalkyl and alkylcycloalkyl comprising 3 to 6

  carbon atoms in the cycloalkyl ring and 1 to 6 carbon atoms.

  bone in the alkyl part; phenyl, aralkyl, aralkenyl and aralkynyl

  wherein the aryl part is a phenyl radical and the

  phatique has from 1 to 6 carbon atoms; heteroaryl, heteroaral-

  kyle, heterocyclyl and heterocyclylalkyl in which the heteroaryl and heterocyclyl groups or a part of these groups is such

  as defined above for the radical R 5 and the alkyl parts

  These heterocyclic moieties comprise 1 to 6 carbon atoms.

  or R 3 and R 4 together with the nitrogen atom to which

  at least one of them is attached, a heterocyclic ring containing

  5 or 6 membered nitrogen (as defined above for R 5); R 9 is as defined above for R 3 except that it can not be a hydrogen atom A more particularly preferred radical R 5

  is the radical C 1 -C 6 alkyl, particularly methyl.

  In addition, the substituent R 5 together with another atom of the CN_ ring may form a heterocyclic or heteroaromatic ring, which ring may contain additional hetero atoms, preferably 1 or 2 hetero atoms selected from oxygen, nitrogen and / or or sulfur For example, 1 Ne-R 5 can be, N or o The group

* NOT-

  preferably represents an aromatic heterocycle, mono-, bi or poly-

  cyclic, substituted or unsubstituted, containing at least one nitrogen atom in the ring and from 0 to 5 hetero atoms of the additional ring selected from oxygen, nitrogen or sulfur, said heterocyclic ring being bound to

  A via a carbon atom of the nucleus and comprising an ato-

  of nitrogen in the quaternized nucleus by the Rs group.

  The heteroaromatic ring e may be optionally substituted on available carbon atoms of the

  preferably from 1 to 5, and more preferably 1 to 3,

  independently selected from the group consisting of C 1 -C 4 alkyl, C 1 -C 4 alkyl substituted with, preferably 1 to 3 hydroxy, amino, C 1 -C 4 alkylamino, di (C 1 -C 4) alkylamino, CI -C 4 alkoxy, carboxy, halo (which is meant in the present invention to cover chloro, bromo, fluoro or iodo, and preferably chloro, bromo or fluoro) or sulfo; C 3 -C 6 cycloalkyl;

  C 3 -C 6 cycloalkyl (C 1 -C 4) alkyl optionally substituted with 1 to 3 of the substituents

* aforementioned killers in relation to C 1 -C 4 alkyl; C 1 -C 4 alkoxy; C 1 -C 4 alkyl

  thio; amino; C, -C 4 alkylamino; di (C 1 -C 4) alkylamino; halo; Cl-C 4 alkanoyl

  amino; C 1 -C 4 alkanoyloxy; carboxy; sulfo; -C (O) -O-C 1 -C 4 alkyl; hydroxy; amidino; guanidino; phenyl; phenyl substituted with 1 to 3 substituents selected independently of one another from amino, halo, hydroxy, trifluoromethyl, C 1 -C 4 alkyl, C 1 -C 4 alkoxy; C, -C, alkylamino, di (C 1 -C 4) alkylamino, carboxy and sulfo; phenyl (C 1 -C) alkyl in which

  the phenyl part may be substituted with 1 to 3 substituents

  above mentioned in relation to the phenyl group and the alkyl part may be optionally substituted with 1 to 3 of the substituents mentioned

  above in relation to the C 1 -C 4 alkyl group; as well as heterosexual

  aryl and heteroaralkyl wherein the one or more hetero atoms are selected from the group consisting of 1 to 4 oxygen, sulfur or nitrogen atoms and the alkyl moiety associated with the heteroaralkyl comprises from 1 to 6 atoms

  of carbon, said heteroaryl and heteroaralkyl groups being optionally

  substituted on the part of the heterocyclic ring by 1 to 3

  selected from each other independently of the hydroxy groups,

  amino, halo, trifluoromethyl, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, C 1 -C 4 alkyl

  mino, di (C 1 -C 4) alkylamino, carboxy and sulfo and comprising on the part

  alkyl 1 to 3 substituents selected from those belonging to the group

  taking the hydroxy, amino, C 1 -C 4 alkylamino, di (C 1 -C 4) alkylamino, ClC 4 alkoxy, carboxy, halo and sulfo, further, said heterocyclic ring being

  be optionally substituted on available nitrogen atoms of

  1 to 3 substituents, independently selected from the group consisting of

  C 1 -C 4 alkyl; C 1 -C 4 alkyl substituted with, preferably 1 to 3 hydroxy, amino, C 1 -C 4 alkylamino, di (C 1 -C 4) alkylamino, C 1 -C 4 alkoxy, carboxy, halo or sulfo; C 3 -C cycloalkyl: C 3 -C 6 cycloalkyl (C 1 -C 4) alkyl optionally substituted with 1 to 3 of the substituents mentioned above in connection with

  the radical C 1 -C 4 alkyl; phenyl; phenyl substituted with 1 to 3 of the

  independently selected from the group consisting of amino, halo, hydroxy, tri-

  fluoromethyl, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, C 1 -C 4 alkylamino, di (C 1 -C 4) -

  alkylamino, carboxy and sulfo; phenyl (C 1 -C 4) alkyl in which the phenyl part may be optionally substituted with 1 to 3 substituents

  mentioned above in connection with the phenyl radical and the

  kyle may be optionally substituted with 1 to 3 of the substituents

  cited in connection with the radical C 1 -C 4 alkyl; heteroaryl and heteroaral-

  wherein the one or more hetero atoms are selected from the group consisting of i to 4 oxygen, sulfur or nitrogen atoms, and the part

  alkyl associated with the heteroaralkyl has 1 to 6 carbon atoms,

  so-called heteroaryl and heteroaralkyl groups being optionally substituted

  killed on the part of the heterocyclic ring by 1 to 3 independent substituents

  selected from the group consisting of hydroxy, amino, halo, trifluoromethyl, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, C 1 -C 4 alkylamino, di (C 1 -C 4)

  alkylamino, carboxy and sulfo and on the alkyl part by 1 to 3 of the

  selected from the group consisting of hydroxy, amino, C 1 -C 4 alkylamino, di (C 1 -C 4) alkylamino, C 1 -C 4 alkoxy, carboxy, halo and sulfo. Substituents of nitrogen and carbon of the core used preferably, are alkyl radicals comprising from 1 to 6 carbon atoms, and more particularly

methyl.

  Among the embodiments described above, the compounds used

  Preferred are those in which A is - (CH 2) n with N equal to 1 or 2, and more particularly those in which A is: -CH 2 and o: (a) R 1 and RB together form the group

HOCH 2

  0 C = CH 3 or (b) R 8 is hydrogen and RI is hydrogen or a group

CH 3 CH 2,

CH 3 CH 3 OH OH

CH-, 3 C or CH 3 CH-

CH 3 '/ CH 3 "'

  Particularly preferred are the compounds wherein R 8 is hydrogen and R 1 is OH

CH 3 CH-

  and especially compounds having the absolute configuration R, 65, 8 R. According to a preferred aspect of the invention, the group represents a 5- or 6-membered nitrogen-containing heterocyclic ring having from 0 to 3 additional hetero atoms These aromatic heterocycles may, if possible, be fused to another ring which may be a saturated or unsaturated carbocyclic ring, preferably a carbocyclic ring having 4 to 7 carbon atoms, a ring aromatic carbocyclic

  preferably a phenyl ring, a heterocyclic ring comprising from 4 to 7 members

  (saturated or unsaturated) having 1 to 3 hetero atoms consisting of

  oxygen, sulfur, nitrogen or NR 11 in which R 'is hydrogen, a radical

  alkyl group having 1 to 6 carbon atoms, optionally substituted with one to two substituents independently selected from each other from OR 3, -NR 3 R 4, -CO 2 R 3, oxo, phenyl, fluoro, chloro , bromo, -SO 3 R 3 and

  w 5 -CONR 3 R 4, or a phenyl radical optionally substituted with 1 to 3 substituents

  selected from C 1 -C 6 alkyl, -OR 3, -NR 3 R 4, fluoro, chloro, bromo, -SO 3 R 3, -CO 2 R 3 and -CONR 3 R 4, wherein R 3 and R 4 for such substituents R 1 are as defined above in conjunction with the substituent R 1, or a 5- or 6-membered heteroaromatic ring containing 1 to 3 hetero atoms consisting of oxygen, sulfur, nitrogen or NR 11 in

  which R11 is as defined above.

  The 5- or 6-membered quaternized aromatic nuclei or, where appropriate, the heteroaromatic, heterocyclic or carbocyclic rings fused to them, or both, may be optionally substituted on available ring atoms by, preferably, up to a total of substituents for the entire ring system, by the substituents mentioned above in connection with the group

NOT

  In the embodiment mentioned above, the compounds used

  are those in which A is a group - (CH 2) n with N equal to 1 or 2, and more particularly those in which A is -CH 2 and o: (a) Ri and Rs, together form

HOCH 2

C =

CH 3 'or (b) Re is a hydrogen atom and R 1 represents a hydrogen atom,

a CH 3 CH 2 group,

CH 3 CH 3 OH OH

-CH-, C or CH 3 CH-

CH CH 3 / CHC

  The compounds in which Re is a hydrogen atom and RI is an OH group are particularly preferred.

CH 3 CH-

  and in particular the compounds having the absolute configuration R, 65, 8 R. In another aspect of the present invention, the subject of the present invention is the compounds of formula I in which - ff NR 5

-T N

  represents a radical selected from the group consisting of:

5 R 7

1 10

  wherein R 6, R 7 and R 10 are independently selected from ato-

  hydrogen, and C, -C 4 alkyl, C 1 -C 4, alkyl substituted by, preferably 1 to 3 hydroxy, C 1 -C 4 alkylamino, di (C 1 -C 4 alkyl) amino, C 1-C 4 alkoxy, amino, sulfo, carboxy or halo (chloro, bromo,

  fluoro or iodo; preferably chloro, fluoro or bromo); C 3 -C 6 Cyclo

  alkyl; C 1 -C 4 alkoxy; C 1 -C 4 alkylthio; amino; C 1 -C 4 alkylamino;

  di (C 1 -C 4 alkyl) amino; halo (chloro, bromo, fluoro or iodo;

  chloro, fluoro or bromo); C 1 -C 4 alkanoylamino; C 1 -C 4 alkanoyl

  oxy; carboxy; -C (O) -OC 1 -C 4 alkyl; hydroxy; amidino; guanidino; phenyl; phenyl substituted with 1, 2 or 3 amino groups, halo (chloro,

  bromo, fluoro or iodo; preferably chloro, fluoro or bromo), hydro-

  xyl, -trifluoromethyl, C 1 -C 4 alkyl or C 1 -C 4 alkoxy; phenyl (C 1 -C) alkyl in which the phenyl portion may be optionally

  substituted by 1 to 3 of the substituents mentioned above in relation to

  with the phenyl and the alkyl part may be optionally substituted with 1 to 3 of the substituents mentioned above in relation to C 1 -C 4 alkyl; and heteroaryl and heteroaralkyl in which the

  or the hetero atoms of the aforementioned heterocyclic moieties are selected

  in the group consisting of 1 to 4 atoms of oxygen, nitrogen or

  sulfur and the alkyl part associated with a heteroaralkyl part

  carries 1 to 6 carbon atoms; or in which two of the

  groups R 6, R 7 or Rio taken together can form a carbocyte ring.

  fused saturated clique, a fused aromatic carbocyclic ring,

  a fused non-aromatic heterocyclic ring or a hetero ring.

  fused aromatic ring, these fused rings being optionally substituted

  killed by 1 or 2 of the substituents defined above for R 6, R 7 and R 1 o; (b) _ 5 R 5 el ei el

R 5

  -I N optionally substituted on a carbon atom with 1 to 3 substituents chosen independently of one another from C 1 -C 4 radicals

  alkyl; CI-C 4 alkyl substituted with, preferably 1 to 3 hydroxy; Cl

  C 4 alkylamino, sulfo, di (C 1 -C 4 alkyl) amino, C 1 -C 4 alkoxy, amino, car-

  * boxy or halo (chloro, bromo, fluoro or iodo, preferably chloro, fluoro or bromo); C 3 -C 6 cycloalkyl; C 1 -C 4 alkoxy; C 1 -C 4 alkylthio; amino; C 1 -C 4 alkylamino; di (C 1 -C 4 alkyl) amino; halo (chloro, bromo,

  fluoro or iodo; preferably chloro, fluoro or bromo); C 1 -C 4 alka

  noylamino; C 1 -C 4 alkanoyloxy; carboxy; -C (O) -OC 1 -C 4 alkyl; hydroxy; amidino; guanidino; phenyl; phenyl substituted with 1, 2 or 3 amino groups, halo (chloro, bromo, fluoro or iodo, preferably chloro, fluoro or bromo), hydroxyl, trifluoromethyl, C 1 -C 4 alkyl or C 1 -C 4 alkoxy; phenyl (C 1 -C 4) alkyl wherein the phenyl moiety may be optionally substituted with 1 to 3 of the substituents mentioned above in relation to the phenyl radical and the alkyl moiety

  may be optionally substituted with one of the 3 substituents

  born above in relation to the radical C 1 -C 4 alkyl; heteroaryl or

  heteroaralkyl in which the hetero atom (s) of the heteroaralkyl

  The aforementioned rocyclic compounds are selected from the group consisting of 1 to 4 atoms

  oxygen, nitrogen or sulfur, and the alkyl part

  said heteroaralkyl moiety has 1 to 6 carbon atoms or

  replaced in order to form a carbocyclic ring, hetero

  rocyclic or heteroaromatic fused, optionally substituted by one or two of the substituents defined above; (c) Rs R

R 5 R 5

e e R 5 el

<N N

  N - N RN or optionally substituted on a carbon atom with 1 or 2 substituents

  chosen independently of each other selected from the group

  taking C 1 -C 4 alkyl; C 1 -C 4 alkyl substituted with, preferably 1 to

  3 hydroxy, C 1 -C 4 alkylamino, sulfo, di (C 1 -C 4 alkyl) amino, Cl-C 4 al-

  koxy, amino, carboxy or halo (chloro, bromo, fluoro or iodo;

  chloro, fluoro or bromo); C 3 -C 6 cycloalkyl; C 1 -C 4 alkoxy; C 1 -C 4 alkylthio; amino, C 1 -C 4 alkylamino; di (C 1 -C 4 alkyl) amino; haio (chloro, bromo, fluoro or iodo, preferably chloro, fluoro or bromo); C 1 -C 4 alkanoylamino; C 1 -C 4 alkanoyloxy; carboxy; -C (O) -OC 1 -C 4 alkyl; hydroxy; amidino; guanidino; phenyl; phenyl substituted with one, two

  or three amino groups, halo (chloro, bromo, fluoro or iodo;

  chloro, fluoro or bromo), hydroxyl, trifluoromethyl, C 1 -C 4 alkyl or C 1 -C 4 alkoxy; phenyl (C 1 -C 4) alkyl in which the phenyl part may be optionally substituted with 1 to 3 of the substituents mentioned above in relation to the phenyl radical and the alkyl part may be optionally substituted with 1 to 3 of the substituents mentioned ci above in relation to the radical CI-C 4 alkyl; and heteroaryl or heteroaralkyl wherein the one or more hetero atoms of the heterocyclic moieties mentioned above are selected from the group consisting of 1 to 4 oxygen, nitrogen or sulfur atoms and the alkyl moiety associated with said heteroaralkyl moiety comprises I to 6 carbon atoms or optionally substituted to form fused carbocyclic, heterocyclic or heteroaromatic ring,

  optionally substituted with 1 or 2 of the aforementioned substituents.

(d) N e IR 5 N e t ff

NN N

  or N <N optionally substituted on a carbon atom with a substituent selected independently from each other in the groups formed by the C1-C4 alkyl radicals; CI-C 4 alkyl substituted with, preferably 1 to 3 hydroxy, C 1 -C 4 alkylamino, di (C 1 -C 4 alkyl) amino, sulfo, C 1 -C 4

  alkoxy, amino, carboxy or halo (chloro, bromo, fluoro or iodo;

  chloro, fluoro or bromo); C 3 -C 6 cycloalkyl; C 1 -C 4 alkoxy; C 1 -C 4 alkylthio; amino; C 1 -C 4 alkylamino; di (C 1 -C 4 alkyl) amino; halo (chloro, bromo, fluoro or iodo, preferably chloro, fluoro or bromo); C 1 -C 4 alkanoylamino; C 1 -C 4 alkanoyloxy; carboxy; -C (O) -OC 1 -C 4 alkyl; hydroxy; amidino; guanidino; phenyl; phenyl substituted with 1, 2 or 3 amino, halo (chloro, bromo, fluoro or iodo, preferably chloro, fluoro or bromo), hydroxyl, trifluoromethyl, C 1 -C 4 alkyl or C 1 -C 4 alkoxy; phenyl (C 1 -C 4) alkyl in which the phenyl part may be optionally substituted with 1 to 3 of the aforementioned substituents in

  relationship with the phenyl groups and the alkyl part may be

  replaced by 1 to 3 of the substituents mentioned above

  in relation to the group C 1 -C 4 alkyl; and heteroaryl or heteroaral-

  wherein the hetero atom (s) of the aforementioned heterocyclic moieties are selected from the group consisting of 1 to 4 oxygen, nitrogen or sulfur atoms and the alkyl portion which is associated with said heteroaralkyl moieties has 1 to 6 carbon atoms; 1 '(e) N-R 5 or <or L, X wherein X is O, S or NR with R being C 1 -C 4 alkyl; C1-C4 alkyl substituted with 1 to 3 hydroxy, amino, C1-C4 alkylamino, di (C1-C4) alkylamino, C1-C4 alkoxy, carboxy, halo or sulfo; C 3 -C 6 cycloalkyl; C 3 -C 6 cycloalkyl (C 1 -C 4) alkyl optionally substituted with 1 to 3 of the substituents mentioned above in relation to C 1 -C 4 alkyl;

  phenyl; phenyl substituted with 1 to 3 of the substituents chosen inde-

  from each other among amino, halo, hydroxy, trifluoro-

  methyl, C 1 -C 4 alkyl C -C 4 alkoxy, C 1 -C 4 alkylamino, di (C 1 -C 4) alkyl-

  amino, carboxy and sulfo; phenyl (C 1 -C 4) alkyl in which the phenyl part may be optionally substituted with 1 to 3 of the substituents mentioned above in relation to the phenyl radical and the alkyl part may be optionally substituted with 1 of the 3 substituents mentioned below above in relation to the radical C 1 -C 4 alkyl;

  and heteroaryl and heteroaralkyl in which the at least one heteroaryl

  mes are selected from the group consisting of 1 to 4 oxygen atoms,

  of sulfur or nitrogen and the alkyl part associated with the hetero radical.

  aralkyl contains 1 to 6 carbon atoms, these heteroaryl and heteroaralkyl groups being optionally substituted in the part of the heterocyclic ring by 1 to 3 substituents independently selected

  from each other among the hydroxy, amino, halo, trifluoro-

  methyl, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, C 1 -C 4 alkylamino, di (C 1 -C 4) alkyl-

  amino, carboxy and sulfo and the alkyl part is substituted with 1 to 3 substituents belonging to the groups comprising hydroxy, amino, C 1 -C 4 alkylamino, di (C 1 -C 4) alkylamino, C 1 -C 4 alkoxy, carboxy halo and sulfo; this heteroaromatic radical being optionally substituted

  on the carbon atom by one or more substituents selected inde-

  pendant from each other from the group consisting of C 1 -C 4 alkyl; C 1 -C 4 alkyl substituted with, preferably 1 to 3 hydroxy, amino, C 1 -C 4 alkylamino, di (C 1 -C 4 alkyl) amino, C 1 -C 4 alkoxy, sulfo, carboxy or halo (chloro, bromo, fluoro or iodo, preferably chloro, fluoro or bromo);

  C 3 -C 6 cycloalkyl; C 1 -C 4 alkoxy; CG-C 4 alkylthio; amino; C 1 -C 4 alkyl

  amino; di (C 1 -C 4 alkyl) amino; halo (chloro, bromo, fluoro or iodo;

  preferably chloro, fluoro or bromo); C 1 -C 4 alkanoylamino; Ct-C 4 alka-

  noyloxy; carboxy; -C (O) -OC 1 -C 4 alkyl; hydroxy; amidino; guanidino: phenyl; phenyl substituted with 1, 2 or 3 amino groups, halo (chloro, bromo, fluoro or iodo, preferably chloro, fluoro or bromo), hydroxyl, trifluoromethyl, C 1 -C, alkyl or C 1 -C 4 alkoxy; phenyl (C 1 -C 4) alkyl in which the alkyl part may be optionally substituted with 1 to 3 of the substituents mentioned above in relation to the phenyl radical and / or the alkyl part may be optionally substituted with 1 to 3 substituents mentioned above in relation to the C1-C4 alkyl radical; and heteroaryl and heteroaralkyl wherein the one or more hetero atoms of the aforementioned heterocyclic moieties are selected from the group consisting of 1 to 4 oxygen atoms, nitrogen

  or sulfur and / or the alkyl part associated with said hetero portion

  aralkyl has 1 to 6 carbon atoms or optionally

  killed to form a heteroaromatic, heterocyclic ring or

  fused carbocyclic ring, optionally substituted with 1 or 2

  stituents defined above; (f) R R 5

X N

R X N

  and wherein X is O, S or NR with R being a C 1 -C alkyl radical; C1-C4 alkyl substituted with 1 to 3 hydroxy, amino, C 1 -C 4 alkylamino, di (C 1 -C 4) alkylamino, C 1 -C 4 alkoxy, carboxy, halo or sulfo; C 3 -C 6 cycloalkyl; C 3 -C 6 cycloalkyl (C 1 -C 4) alkyl optionally substituted with 1 to 3 of the substituents mentioned above in relation to the C 1 -C 4 alkyl radical; phenyl; phenyl substituted with 1 to 3 substituents independently selected from the group consisting of amino, halo, hydroxy, trifluoromethyl, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, C 1 -C 4 alkylamino, di (C 1 -C 4) alkylamino, carboxy and sulfo; phenyl e 1-C 4) alkyl wherein the phenyl moiety may be optionally substituted with 1 to 3 of the substituents mentioned above in connection

  with the phenyl radical and / or the alkyl part may be

  substituted by 1 to 3 of the substituents mentioned above in

  lation with the radical Cú-C 4 alkyl; and heteroaryl and heteroaralkyl

  in which the hetero atom (s) are selected from the group

  taking 1 to 4 atoms of oxygen, sulfur and / or nitrogen and where the

  alkyl group associated with the heteroaralkyl radical has 1 to 6 atoms

  these heteroarayl and heteroaralkyl groups being substituted

  killed in the heterocyclic ring portion by 1 to 3 substituents independently selected from the group consisting of hydroxy, amino, halo, trifluoromethyl, C 1 -C alkyl, C 1 -C 4 alkoxy, C 1 -C 4 alkylamino , di (C 1 -C 4) alkylamino, carboxy and sulfo and where

  The alkyl part may have from 1 to 3 substituents selected from

  xy, amino, Cl-C 4 alkylamino, di (C 1 -C 4) alkylamino, C 1 -C 4 alkoxy, carboxy,

  halo and sulfo; this heteroaromatic radical being optionally substituted

  killed on a carbon atom by a substituent selected from the group consisting of C1-C4alkyl; C 1 -C 4 alkyl substituted with, preferably, 1 to 3 hydroxy, amino, C 1 -C 4 alkylamino, di (C 1 -C 4 alkyl) amino, C 1 -C 4 alkoxy, sulfo, carboxy or halo (chloro bromo, fluoro or iodo, preferably chloro, fluoro or bromo); C 3 -C 6 cycloalkyl; C -C 4 alkoxy; C 1 -C 4 alkylthio; amino; C 1 -C 4 alkylamino; di (C 1 -C 4 alkyl) amino; halo

  (chloro, bromo, fluoro or iodo, preferably chloro, fluoro or bro-

  mo); C 1 -C 4 alkanoylamino; C 1 -C 4 alkanoyloxy; carboxy; -C (O) -O Cl-C 4.

  alkyl; hydroxy; amidino; guanidino; phenyl; phenyl substituted with 1, 2 or 3 amino, halo (chloro, bromo, fluoro or iodo, preferably chloro, fluoro or bromo), hydroxyl, trifluoromethyl, C, -C 4 alkyl

  or C 1 -C 4 alkoxy; phenyl (C 1 -C 4) alkyl in which the phenyl part

  nyle may be optionally substituted with 1 to 3 substituents

  mentioned above in relation to the phenyl radical and / or the

  The alkyl group may be optionally substituted with 1 to 3

  mentioned above in relation to the radical C 1 -C 4 alkyl; and heteroaryl or heteroaralkyl wherein the one or more hetero atoms in the aforementioned heterocyclic moieties are selected from the group consisting of 1 to 4 oxygen, nitrogen and / or sulfur atoms and wherein the alkyl moiety associated with said heteroaralkyl moiety comprises at 6 carbon atoms; and (g) N g '- N - R 5RS - N N N - AN 2 I -% - 21 e 1 2 ,, N - R R

N-N-R R - N-R N N-R

He f or S IQ

N: -N

  in which R is a C 1 -C 4 alkyl radical; C, -C 4 alkyl substituted

  killed by 1 to 3 hydroxy, amino C 1 -C 4 alkylamino, di (C 1 -C 4) alkylamino,

  C 1 -C 4 alkoxy, carboxy, halo or sulfo; C 3 -C 6 cycloalkyl; C 1 -C 4 Cyclo

  alkyl (C 1 -C 4) alkyl optionally substituted with 1 to 3 of the substituents mentioned above in relation to the C 1 -C 4 alkyl radical; phenyl; phenyl substituted with 1 to 3 substituents independently selected from

  each other in the group consisting of amino, halo, hydroxy, tri-

  fluoromethyl, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, C 1 -C 4 alkylamino, di (C 1 C 4)

  alkylamino, carboxy and sulfo; phenyl (C 1 -C 4) alkyl in which the

  The phenyl moiety may be substituted with 1-3 substituents

  mentioned above in relation to the phenyl radical and where the alkyl part may be optionally substituted with 1 to 3 of the

  substituents mentioned above in relation to the radical Cl-C 4-

  alkyl; and heteroaryl and heteroaralkyl in which the one or more

  tero atoms are selected from the group consisting of 1 to 4 oxy-

  gene, sulfur and / or nitrogen and o the alkyl part associated with the

  heteroaralkyl group having 1 to 6 carbon atoms, wherein said heteroaryl and heteroaralkyl groups are optionally substituted in the heterocyclic ring portion by 1 to 3 of the substituents independently selected from hydroxy, amino, halo, trifluoromethyl, C 1- C 4 alkyl, C 1 -C 4 alkoxy, C 1 -C 4 alkylamino,

  di (C 1 -C 4) alkylamino, carboxy and sulfo and where the alkyl part is

  optionally substituted with 1 to 3 substituents selected from the group consisting of hydroxy, amino, C 1 -C 4 alkylamino, di (C 1 -C 4) alkylamino,

  C 1 -C 4 alkoxy, carboxy, halo and sulfo -

  The groups R and R 5 can also together form a heterogeneous nucleus

  rocyclic or heteroaromatic fused.

  In the aforementioned preferred aspect of the present invention, the compounds preferably involved are those in which A is - (CH 2) n with N equal to 1 or 2 and more particularly those in which A is -CH 2 and o: (a ) R 1 and R 8 together form the group

HOCH 2

C =

CH 3- /

  or (b) R 8 is hydrogen and R 1 is hydrogen, or one of the groups

CH 3 CH 2,

CH 3 CH 3 OH OH

CH-, C, or CH 3 CH-

CH'3 CH 3

  Especially preferred are compounds wherein Re is hydrogen and RI is OH

CH 3 CH-

  and especially compounds having the absolute configuration R, 65, 8 R. Another particularly preferred aspect of the present invention is the compounds of formula I wherein N 5 is a radical of the formula R 5 RR 6 R 1 wherein : R 6, R? and R1 are, independently of one another, selected from the group consisting of hydrogen and C 1 -C 4 alkyl, C 1 -C 4 alkoxy, carboxyl and carbamoyl radicals; and R 5 is as defined above and consists, preferably, of a C 1 -C 6 alkyl radical, and more particularly of -CH 3 are still in a particularly interesting aspect of the invention.

  the present invention, the preferred compounds wherein A is - (CH 2) n-

  with N equal 1 or 2, and more particularly those in which A is -CH 2 and o: (a) R 'and R 8 together form a group

HOCH 2

  CH 3 or (b) R 8 is hydrogen, and RI is hydrogen or one of the radicals

CH 3 CH 2,

CH 3 CH 3 OH OH

NCH O

-'CH-, C, or CH 3 CH-

CH 3 / CH 3

  The compounds in which Ra is hydrogen and R 'is OH are particularly preferred.

CH 3 CH-

  and in particular, the compounds having the absolute configuration R, 65, 8 R. According to another aspect of the invention, the subject of the invention is the compounds of formula I in which De 5 N-R represents a radical of formula

(5 6

  (a) R N with: Rs is a C 1 -C 4 alkyl radical, and more particularly methyl; and R 6 is hydrogen or a Cl-CL 4 alkyl radical; (b) R 5 1 R 6 wherein: R 5 is C 1 -C 4 alkyl, and more particularly methyl; and

  R 6 and R? are hydrogen or a C 1 -C 4 alkyl radical ;.

(C)

R-N CN R 5

  in which: Rs is C 1 -C 4 alkyl, more particularly methyl; and R is a C1-C4 alkyl or phenyl (C1-C4) alkyl radical; (d) k R 6 in which: R 5 is a C1-C4 alkyl radical, more particularly methyl; and R 6 is a C 1 -C 4 alkyl radical, more particularly methyl; (e) R R wherein: Rs is a C1-C4 alkyl radical, more particularly methyl; and R is a C1-C4 alkyl radical, more particularly methyl; or s -R in which:

  R 5 is C 1 -C 4 alkyl, more particularly methyl.

  According to yet another aspect of the invention, the subject of the invention is the following preferred compounds in which A is - (CH 2) n with N equal to 1 or 2, more particularly those in which A is -CH 2 and (a ) R 1 and R 8 together form the group

HOCH 2

C Z C =

CH 3 '/

  or (b) R 8 is hydrogen; and R 1 represents hydrogen or one of the radicals

CH 3 CH 3 OH

\ CH-, \ C-, or

CH 3 'CH 3

  Especially preferred are the compounds in hydrogen and R 1 is OH

CH 3 CH 2- ,.

OH

CH 3 CH-

which R 8 is

CH 3 CH-

  and in particular the compounds having the absolute configuration R, 65, 8 R. The present invention also relates to compounds of formula I in which represents a radical belonging to the following groups: (a) ## STR2 ## (b) CH 3 s CH 3 (f) i

-H 2 CH 2 CH 3

CH 3 l e

N CH 3

CH 3 ED CH

  CH 3 CH 3 CH 3 CH 2 CH 3 CH 3 CH 3 (n) N? ## STR3 ## wherein in this particular form of the compound of the formula (I) In the invention, the compounds preferably used are those in which A is - (CH 2) n with N equal to 1 or 2, more particularly those in which A is - (CH 2) and o (a) R 1 and R 8 together form the group

HOCH 2

C =

CH 3 '/

or (b) R 8

* R 1

  is hydrogen; and represents hydrogen or the

CH 3 CH 3 OH

CH-, \ C-

CH CH 3 /

  Particularly preferred are hydrogen and R 1 radicals of the group CH 3 CH 2, OH

or CH 3 CH-

compounds in which R 8 is OH

CH 3 CH-

  and in particular, compounds having the absolute configuration R, 65, 8 R.

  The compounds according to the present invention, especially

  are those with the OH formula

(R) -S S-A _R 5

(R) '' I

  wherein: R 2 is hydrogen, anionic charge or a readily removable carboxyl protecting group provided that when R 2

  is hydrogen or a protecting group, also

a counter-ion and in which

-S-A __R 5

  is one of the following radicals:

M /// _ \ O

  (a) -SC 2 \ N-CH 3 (c) -SCH N CH 3 (b) -SeH CH 2 CH 2 2 (d) (f) -SCH 2 CH CH 3

2 2 2

(e) -s CH CH -

2

CH 3

\ E) N (g) y -SCH

CH 3

CH 3 ED 1 N (i) - SCH 2 1 '

'CH 3

(H)

CH ED CH 3

1 l M

-SCH 2 S _CH 3-

(J)

(1) Y \ ED

-SCH CH 3

S (k) -SCHG H 253356 e CH 2

NOT*

(m) SCH 2 N N D CH 3 CH 3 (O) "It

-SCH 2 \ N

"/ e (n) SCH (p)

-SCH 2

N CH 3

CH 3

  it being understood that the 1 H (D 20) NMR spectrum has the characteristic peaks

  at 6: 1.23 (3H, d, I = 6.4 Hz); 3.12 (2H, q, I = 1.4, -8.9 Hz); 3.39 (1H, q, I = 2.7, 6.0 Hz); 4.07-4.68 (10H, ni); 8.19 (1H, s); (q) CH CH 3, whose IH NMR spectrum (D 20) has the characteristic peaks at 6: 1.23 (3H, d, 1 = 6.4 Hz); 3.15 (2H, q, I = 3.7, 9.0 Hz); 3.37 (1H, q, 1 = 2.6, 6.0 Hz); 3.95-4.65 (10H, mi); 8.62 (1H, s); (r) _SCH I 2-C

3 I- ,, H

g (s) (u) CH (t) CH 3 N

-SCH N 2

N-H COO and N, N / CH 3 N

-SCH 2

  According to a most preferred aspect of the present invention, this relates to compounds of formula I in which: N-R 5 represents CH 3 Im. According to this embodiment, the preferred compounds are

  those in which A is - (CH 2) n with N equal to 1 or 2, more particularly

  remnient those in which A is -CH 2 and o (a) R 1 and RB together form the radical

HOCH 2

  c: CH 3 CH, or (b) R 8 is hydrogen; and RI represents hydrogen or one of the radicals CH 3 CH 2,

CH 3 CH 3 OH

\ CH-, C, or C

CH, CH

OH

H 3 CH-

(V)

CH 3 I-11

CH 3 /

  Especially preferred are the compounds wherein Re is hydrogen and R1 is OH.

CH 3 CH-

  in particular, the compounds having the absolute configuration R, 65, 8 R. The carbapenem derivatives of general formula I are prepared from the starting materials having the formula

H R 15

RO

ON COR 2

  OOR 20 III in which: RI, RE and Rs are as defined above and R 2 'represents a

  carboxyl protecting group, easily separable conventional.

  The compounds of formula III have been described, for example in European Patent Application 38869 (compound 7) and in the European patent application

  54917, and may be prepared by the general methods described therein.

in these patent applications.

  The process for preparing compounds I from starting materials III can be summarized by the following reaction scheme

8 R 5

R

R COOR

RS H R 5

1 L HS-A N

  gb L = classical separable group IV

R 8 HI R 15

o i

RS-X '1

  possible deblocking I 0 R 2 I A variation of the process the following reaction scheme: ## STR2 ## described above is represented on HS-AN

J _ _ _ _ _ _ _

IV

8 R 15-

R H

R 1 -A- (AT

N 00 O R 21

1 unlock I Ri I Ia

8 R 15

  In order to carry out the above 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 carbon dioxide. an agent R -L such as

  p-toluenesulfonic acid, p-nitrobenzenesulfonic acid anhydride

  * 2,4,6-triisopropylbenzenesulphonic acid anhydride, the anhydride

  of methanesulphonic acid, the anhydride of trifluoromethyl

  thanesulfonic acid, diphenyl chlorophosphate, toluene chloride,

  sulfonyl chloride, p-bromobenzenesulfonyl chloride or the like, in the

  which L is the corresponding separable group such as toluenesulfonyloxy,

  p-nitrobenzenesulfonyloxy, diphenoxyphosphinyloxy, and other se-

  parables that are well known to those skilled in the art and used in this

type of process.

  The reaction to place the separable group in position-2 of the intermediate

  III is preferably carried out in the presence of a base such as

  isopropylethylamine, triethylamine, 4-dimethylaminopyridine or similar

  at a temperature between -20 and + 40 C, more particularly

  of the order of about 0 C The separable group L of intermediate IV may also be a halogen of which, in which case, such a group is

  formed by reaction of the intermediate compound III with a halogenated

  such as 03 P Cl, 03 P Br 2, (o 00) 3 P Br 2, oxalyl chloride or the like in a solvent such as CH 2 C 12, CH 3 CN, THF, or the like in the presence of a base such as diisopropylethylamine, triethylamine, 4-dimethylaminopyridine, or the like Intermediate compound IV may be isolated, if appropriate, but is preferably used as such for the next step without

  isolation or intermediate purification.

  The intermediate compound IV is first converted to the intermediate compound II by a conventional de-shift reaction.

  intermediate compound IV can be reacted with approximately one

  equimolar content of a heteroaralkyl mercaptan reagent of the formula

HS-A N

  wherein: A is a straight or branched chain alkylene radical having 1 to 6 carbon atoms; and N represents a bi- or polycyclic aromatic heterocyclic radical containing a quaternizable nitrogen in the ring, which ring is connected to A by a carbon atom of the ring, in an inert organic solvent formed of dioxane, dimethylformamide, dimethylsulfoxide or

  acetonitrile and in the presence of a base such as isopropylethyl-

  amine, triethylamine, sodium hydrogen carbonate, potassium carbonate

  sium or 4-dimethylaminopyridine The displacement temperature is notcritical but an advantageous temperature can be between about -40 to 25.degree. C. More particularly, the reaction is carried out with cooling, that is to say at about 0.degree.

at -10 C.

  Quaternization of the ring nitrogen in the heteroaralkyl group

  of the intermediate compound II is carried out by reaction of the compound

  intermediate II in an inert organic solvent with at least one equiva-

  slow (up to about a 50% niolar excess) of an alkylating agent of the formula wherein: R 5 is as defined above; and X 'is a conventional separable group such as halo (chloro, bromo or iodo, more particularly iodo) or a residue of a sulfonate such as mesylate, tosylate, or triflate. Examples of organic solvents

  suitable non-reactive substances are chloroform, methyl chloride

  lene, tetrahydrofuran, dioxane, acetone, dimethylsulfoxide and dimethylformamide The reaction temperature of the alkylation is not critical and the temperatures between about 0 and 40 C are preferred. More particularly, the reaction step

  is carried out at room temperature.

  Intermediate I 'has a counter ion X' (i.e., derived from the alkylating agent used) with which it is associated, which at this stage or at a higher stage is that is, following the deblocking step, may be substituted with a different counterion, for example a counterion which is more pharmaceutically acceptable, by conventional methods. can be later

  eliminated during the unblocking step.

  The deblocking step for removing the carboxyl protecting group R 2 'from the intermediate compound I' is carried out by conventional methods such as solvolysis, chemical reduction or hydrogenation. When a protecting group such as p-nitrobenzyl, benzyl, benzhydryl or 2-naphthylmethyl

  is used and is likely to be removed by catalytic hydrogenation.

  "lytic, the intermediate I ', in a suitable solvent such as a mixture

  dioxane or ethanol, tetrahydrofuran, dipotassium hydrogen phosphate

  Isopropanol aqueous solution or the like may be treated at a hydrogen pressure of between 1 and 4 atmospheres in the presence of a hydrogenation catalyst such as palladium-on-carbon, palladium hydroxide, platinum oxide or the like at a temperature of between 0.degree. For about 0.24 to 4 hours When R 2 'is a group such as o-nitrobenzyl, photolysis can also be used to effect deblocking. Protective groups such as 2,2,2-trichloroethyl can be removed by mild reduction. Zinc The allyl protecting group can be

  removed by a catalyst comprising a mixture of a palladium-based compound

  and triphenylphosphine in an aprotic solvent such as tetra-

  In the same way, other conventional carboxyl protecting groups can be removed by the method known to those skilled in the art. Finally, as mentioned above, the compounds of formula I 'in which R 2 'is a physiologically hydrolyzable ester such as acetoxymethyl, phthalidyl, indanyl, pivaloyloxymethyl, methoxymethyl, etc., can be administered directly to the patient without deblocking because such esters are hydrolysed in vivo under physiological conditions. It should be understood that when R ', R 8, R 5 or RS as substituents or when the aromatic ring bonded to the substituent A contains a functional group capable of interfering with the expected development of the reaction, such a group may be protected by conventional blocking group and subsequently released for regeneration of desired functional groups Suitable blocking groups and procedures for introducing and eliminating them are well known in the art.

  Those skilled in the art According to a variant of the aforementioned process, the group

  The carboxyl group of Intermediate II can be removed prior to the quaternization step. Thus, the carboxyl protecting group was removed as described above to give the corresponding free carboxylic acid and then the The free acid is then quaternized with the alkylating agent R 5 -Xg to give the quaternized product of the formula I sought. When the intermediate compound de-Ie protected Ia is quaternized, the solvent can be water or a solvent. Non-reactive organic compounds or mixtures thereof Examples of suitable solvents include water, organic solvents such as chloroform, methylene chloride, tetrahydrofuran, dioxane, acetone, dimethylsulfoxide and dimethylformamide.

  mide and mixtures of water-organic compounds such as water-

  acetone or water-dimethylformamide The temperature for the quaternization of the intermediate I Ia is not particularly critical although temperatures in the range of about -40 to about room temperature

  can be used without inconvenience More advantageously, the reaction

  When the de-protected intermediate compound Ia is obtained in the form of the carboxylate, it is desirable to add a strong acid such as toluenesulphonic acid in order to regenerate the free carboxylic acid beforehand. to quaternization It has been found that this facilitates

  greatly preferred quaternization of the nitrogen of the nucleus.

  The process described in variant above is particularly

  useful when the carboxyl protecting group is more easily removed.

  of the non-quaternized intermediate compound when it is not

intermediate quaternized I '.

  For example, to prepare the product of formula CH 3

OH H

(R) / \

  N 'o COO from the intermediate compound of formula

OH H N

(R) N SCH 2

  removal of the allyl protecting group prior to quaternization

  This leads to significantly improved yields of the final product.

  While the above method is particularly suitable for the preparation of the compounds according to the present invention, a new process has been invented by Pierre Dextraze, this process being capable of being used to prepare compounds of formula I This variant which is described and claimed in a patent application of the same date filed

  in the United States is described below and in the examples that follow.

  In the process variant for preparing the compounds of formula I according to this invention, an intermediate of formula

R -

N C R 21

  COOR IV wherein: R1, RB and R's are as defined above; R 2 'is a conventional easily removable carboxyl protecting group; and

  L is a conventional secant group such as toluenesulfonyloxy, p-nitro-

  benzenesulfonyloxy, diphenoxyphosphinyloxy or halo is reacted with a thiol of formula

HS-A N-R

  A: x in which: A and are as defined above; and X is a counter-anion,

  in an inert solvent and in the presence of a base for the purpose of

  to obtain a carbapenem of formula R 1 I '

in which: -

  R 1, RB, R 2 ', A, R 15, and X are as defined above, and, where appropriate, the carboxyl protecting group R 2' is (to yield the corresponding unlocked compound of formula

  one of its pharmaceutically acceptable salts.

  According to this variant of the process, the formula intermediate

R 8 E 15

3 R

R 1

IV VII removed I or G 5

- (NR

/ 1 I (D 5

  is used, which as mentioned above has been described for example in the European Patent Applications 38869 and 54917 and which can be prepared according to the general method described in these European patent applications L represents a conventional separable group (defined as "X" in this European Patent Application 38869) as

  chloro, bromo, iodo, benzenesulfonyloxy, p-toluenesulfonyloxy, p-nitro-

  benzenesulphonyloxy, miethanesulphonyloxy, trifluoromethylsulphonyloxy, diphenyl

  noxyphosphinyloxy or di (trichloroethoxy) phosphinyloxy The breakable group

  preferred is diphenoxyphosphinyloxy.

  Intermediates of formula IV are generally formed in situ by reaction.

  an intermediate of formula 8 R p 15

R H

R 1 -

O, COOR 2

III in which:

  R1, Re, R'5 and R 2 'are as defined above with an acylating agent.

R 0-L suitable.

  The preferred intermediate IV in which L is the diphenoxygen group

  phosphinyloxy can be prepared by reaction of a keto ester III in an inert organic solvent such as methylene chloride, acetonitrile or dimethylformamide with about an equimolar amount of chlorophosphate

  diphenyl in the presence of a base such as diisopropylethylamine,

  thylamine, 4-dimethylaminopyridine or the like at a temperature

  between -20 C and + 40 C, and more particularly of the order of O C.

  Intermediate compound IV may be isolated, if appropriate, but is preferably used as the starting material of the alternative method

  in requiring isolation or purification.

  The carbapenem IV intermediate compound is then required to

  gir with a quaternary thiol amine of formula

HS-A N -R

X 8 VII in which:

A N -R 5

  is as defined above and X O is a counteranion.

  The reaction is carried out in an inert solvent formed, for example,

  nitrile, acetonitrile-dimethylformamide, tetrahydrofuran, tetrahydrofuran

  ranne-H 20, acetonitrile-H 20 or acetone in the presence of a base Nature

  basic is not critical.

  sodium hydroxide, diisopropylethylamine, 1,8-diazabicyclo {5,4, 0} undec-7-ene, 1,5-diazabicyclo {4,3,0} non-5-ene and tri (C 1 -C 4) alkylamines such as triethylamine, tributylamine or tripropylamine. The reaction of intermediate IV and thiol VII can be carried out over a wide

  temperature range, for example from -15 C to room temperature

  te, but preferably it is carried out at a temperature between

  about -150 ° C and + 15 ° C, and more particularly of the order of about 0 ° C.

  The carbapenem produced by the reaction of the quaternary amine thiol VII with the intermediate compound IV has a counteranion which is

  associated (e.g. (C 6 H 50) 2 P 029, Cli or the anion associated with thiol quater-

  which at this stage may be substituted by a different counter-anion,

  for example, a counter-anion that is more acceptable from the phar-

  By a variant, the countercurrent

  anion can be removed during the subsequent deblocking stage When the quaternized carbapenem and the counter anion form an insoluble product, the product can crystallize out as it passes.

  is formed and collected pure by simple filtration.

  After formation of the desired carbapenem, the car-

  R 2 'boxyl of the compound I' can be optionally removed by conventional methods such as solvolysis, chemical reduction or hydrogenation.

  a protecting group such as p-nitrobenzyl, benzyl, benzhy-

  dryle or 2-naphthylmethyl which can be removed by hydrogenation

  talytic, the intermediate compound I ', in a suitable solvent such

  dioxane-water-ethanol, tetrahydrofuran-diethyl ether buffer, tetrahydrofuran

  drofuran-aqueous solution of dipotassium phosphate isopropa-

  or the like may be treated under hydrogen pressure in the range of 1 to 4 atmospheres in the presence of a hydrogenation catalyst such as palladium onion, palladium hydroxide, platinum oxide or the like

  a temperature between 0 C and 50 C for about 0.24 to 4 hours.

  When the group R 2 'is a group such as o-nitrobenzyl, photolysis can also be used to enable this release.

  such as 2,2,2-trichloroethyl may be separated by

  Zinc-sweetening The allyl protecting group can be removed by using a catalyst consisting of a mixture of a compound based on

  palladium and triphenyl phosphine in a suitable aprotic solvent.

  such as tetrahydrofuran, methylene chloride or diethyl ether.

  Similarly, other conventional carboxyl protecting groups which can be separated by methods known to those skilled in the art may be employed. Finally, as mentioned above, the compounds

  of formula I 'in which R 2' is a physiologically hydrolysable ester

  logic such as acetoxymethyl, phthalidyl, indanyl, pivaloyloxymethyl, methoxymethyl, etc., can be administered directly to the patient without the need for deblocking, since such esters are hydrolysed in vivo in

physiological conditions.

  The thiol intermediate compound of formula VII can be prepared, for example, from the corresponding thioacetate of formula R

* CH 3 CS-A

  wherein: A is as defined above; and -Q>

  represents an aromatic heterocyclic radical mono, bi or poly-

  cyclic ring containing a quaternizable nitrogen in the nucleus, this nucleus

  being connected to A via a carbon atom

holding to the core.

The thio acetate is quaternized by reaction in an organic solvent such as diethyl ether, dichloromethane, methylene chloride, dioxane, benzene, xylene or toluene, or mixtures thereof, with a suitable alkylating agent of formula

R 5 X '

  wherein: R 5 is as defined above; and X 'is a conventional divisible group such as halo (chloro, bromo or iodo, more particularly iodo) or a sulphonate such as mesylate, tosy-

late or triflate.

  The temperature of the alkylation reaction is not critical and temperatures

  temperatures between 00 C and 40 C are preferably used.

  Prior to reaction with the carbapenem IV intermediate, the quaternized thiolacetate is subjected to acidic or basic hydrolysis

  to generate a quaternary thiol intermediate compound VII

  The lysis is preferably carried out immediately prior to coupling with the compound IV so as to reduce the decomposition of the quaternary thiol.

unstable VII.

  By suitable selection of the solvents, the reaction from the

  from intermediate III to final product I can be carried out without

  Isolation of the various intermediates, that is to say in a reactor salt.

  As an example of such a method, Example 2 below constitutes

A picture.

  As with other lactam antibiotics, the compounds of general formula I can be converted by known methods into pharmaceutically acceptable salts which, for the purpose of

  the present invention are substantially equivalent to non-saline compounds

  Thus, for example, a compound of formula I in which R 2 is an anionic charge can be dissolved in a suitable inert solvent.

  then add an equivalent of a pharmaceutically acceptable acid.

  The desired acid addition salt can be recovered by

  conventional methods, for example solvent precipitation, freeze-drying,

  tion, etc. O other acidic or basic functional groups are

  in the compound of formula I, addition salts of a pharmaceutical base,

  ceutically acceptable or pharmaceutically acceptable acids, may be

  can be prepared in a similar way by known methods.

  It is obvious that certain compounds falling within the scope of formula I can

  It is clearly stated that the present invention covers both optical isomers and epimeric mixtures. For example, when the substituent at the 6-position is a hydroxyethyl group. such a substituent can be either in the R configuration, or in the S configuration, and the resulting isomers as well as the mixtures

  epimers they form are covered by the present invention.

  A compound of formula I wherein R 2 is hydrogen or an anionic charge or a pharmaceutically acceptable salt derived therefrom may also be converted by conventional methods into a corresponding compound wherein R 1 is a physiologically hydrolyzable ester or a compound of formula I wherein R 2 is a conventional carboxyl protecting group can be converted to the corresponding compound in

  which R 2 is a hydrogen atom, an anionic charge or a hy-

  physiologically drolysable or their acceptable salts from the point

pharmacy.

  The novel carbapenems of the general formula I in which R 2 is hydrogen, anionic charge or a physiologically hydrolyzable carboxyl protecting group, or their pharmaceutically acceptable salts, are potent active antibiotics for many gram bacteria. -positive and gram-negative and they can be used for example as food additives for

  animals in order to accelerate their growth, as agents of conservation

  in foodstuffs, as bactericides in industrial applications eg for aqueous paints as well as in paper mill effluents to inhibit the growth of harmful bacteria and still as a disinfectant to destroy or inhibit the growth of harmful bacteria in the environment. dental or medical equipment These compounds

  especially useful for the treatment of infectious diseases.

  in humans and other animals caused by bacteria

gram-positive or gram-negative.

  The active compounds from the pharmaceutical point of view according to

  invention can be used alone or in the form of

  pharmaceutical products comprising in addition to the active carbapenem ingredient,

  a carrier or diluent or a pharmaceutically acceptable carrier

  The compounds according to the present invention can be administered by a large number of methods, those of the greatest interest are the oral, topical or parenteral routes (i.e.

  intravenous or intramuscular). The pharmaceutical compositions may

  * be in solid form such as capsules, tablets, powders etc. or in liquid form such as in the form of solutions, suspensions or emulsions. Compositions for administration by injection, which is the preferred method of administration, may be prepared

  in unit dosage form in ampoules or in multi-containers

  doses and may contain, in addition, additional agents such as suspending, stabilizing and dispersing agents.

  may be in ready-to-use form, or in powder form,

  intended to be reconstituted at the time of their administration by addition

  a suitable vehicle such as sterile water.

  The dosage to be administered depends to a large extent on the particular compound used, the prepared composition prepared, the method of administration, the nature and condition of the patient and the site and the particular organism to be treated. The choice of the method of administration

  and the dose to be used are left to the discretion of the therapist.

  In general, however, the compounds can be administered parenterally.

  renal or oral mammal in an amount of 5 to 200 mg / kg / day.

  Administration is generally carried out as a divided dose

  for example, three to four daily administrations.

  To illustrate the spectrum of broad anti-bacterial activity and

  carbapenems according to the present invention, both in vitro and in vivo, as well as the low toxicity of the compounds, are given below biological data relating to the preferred carbapenem compound according to the present invention.

present invention.

  In Vitro Activity Carbapenem samples prepared according to Examples 1 and 2 after dissolving in water and dilution in a nutrient broth showed the following minimum inhibitory concentrations (M I C)

  expressed in mcg / ml with respect to the indicated micro-organisms, these concentrations

  are determined after incubation for the duration of one night

  at 37 C by the dilution tube method.

  N-formimidoyl thienamycin is included in these tables for comparison. In vitro anti-bacterial activity of the carbapenem derivative of Example 1 MIC (mcg / ml) organism New N-Fomlimidoyl Compound thienamycin S pneumoniae A-9585 0.25 0.004 S pyogenes A-9604 0.06 0.001 S aureus A- 9537 0.13 0.004 S aureus + 50% serum A-9537 0.03 0.016 S aureus (Pen-res) A-9606 0.06 0.008 S aureus (Meth-res) A 15 097 4 0.5 S faecalis A 20688 0 0.5 Coli (10-4 dil) A 15119 0.06 0.016 E Coli

(10-3) A 15119 0.03

E coli

(10-2) A 15119 0.06

E Coli

(10-4) A 20341-1 0.03 0.03

E coli

(10 -3) To 20341-1 -0.03

E coli

(10-2) A 20341-1 0.13

  K pneumoniae A-9664 0.25 0.13 K pneumoniae A 20468 0.25 0.06 20.p mirabilis A-99000.3.6 P vulgaris A 21559 0.13 0.03 * Pnmorganii A 15153 0, 13 0 , 13 P rettgeri A 22424 0.25 0.25 S marcescens A 20019 0.13 0.03 E cloacae A-9569 0.13 0.06 E cloacae A-9656 0.13 0.06 P aeruginosa A-9743 A 4 1 P aeruginosa A 21213 i 0.25 H influenzae A-9833 16 16 H influenzae A 20178 32 32 H influenzae A 21518 16 32 H influenzae A 21522 8 32 B frag ilis A 22862 0.03 0.016 B fragilis A 22053 0, 0.06 B fragilis A 22696 0, 0.13 B fragilis A 22863 0.03 1 S pr S p S ai S ai In vitro antibacterial activity of the carbapenem derivative of Example 2 MIC (mcg / ml) New N-Formimidoyl Compound thienamycin neumoniae A-9585 0.001 0.002 yogenes A-9604 0.001 0.002 ureus A-9537 0.004 0.004 ureus A9537 0.016 0.016 (+ 50% serum) S aureus (Pen-res) S aureus (Meth-res)

A-9606

A-15097

  0.008 0.008 S faecalis A 20688 0.25 0.5 E coli A 15119 0.016 0.016 E coli A 20341-1 0.016 0.03 K pneumoniae A-9664 0.06 0.06 K pneumoniae A 20468 0.13 0.13 P mirabilis A-9900 0.03 0.06 P vulgaris A 21559 0.016 0.03 P morganii A 15153 0.06 0.13 P rettgeri A 22424 0.13 0.13 S marcescens A 20019 0.03 0.03 E cloacae A-9659 0.13 0.06 E cloacae A-9656 0.25 0.06 P aeruginosa A-9843 A 8 1 P aeruginosa A 21213 2 0.25 In vivo activity The therapeutic efficacy in vivo of the compound of the Example 1 and Nformimifoyl thienamycin after intramuscular administration to

  mice experimentally infested by various organisms are

in the following table.

  PD 50 (mg / kg dose required to provide 50% protection against

infested ris) is given.

  Protective effect of intramuscular treatment of PD 50 infested mice / treatment (mg / kg) Organism Performed (out of number Nformimidoyl compounds of organisms) Example 1 Thienamycin P mirabilis A-9900 3, 6 x 106 3.3 3 * / 15 * aeruginosa A-9843 at 5.5 x 104 0.3 0.5 * P aeruginosa A-20481 5.4 x 104 0.63 0.4 * P aeruginosa A-20599 1.4 x 105 0, 7 0.18 * S aureus A-9606 6.6 x 108 0.09 0.07 * S faecalis A-20688 2.3 x 108 3.3 2.8 * E coli A-15119 6.2 x 106 0, 6 2.5 * K pneumoniae A-9964 5.1 x 106 2.5 2.2 * Historical Data Treatment Mode: With the exception of E. coli A-15119 and K pneumoniae A-9964, mice were treated with the other compounds intramuscularly by said drug O and 2 hours after infection For E coli and K pneumoniae, the treatment was carried out 1 and 3.5 hours after infection Five mice were used to

each dose and in each test.

Toxicity

  The toxicity of the compound of Example 1 after intranasal adminsitration

  cranial to specific mice is recorded in the following table.

  Toxicity after intra-cranial administration to a mouse Compound * LD 50 highest dose (mg / kg) (mg / kg) without clinical risk of toxicity Compound of example 1 14 5 N-formimidoyl thienamycin 32 b 5 * Average of 25 mice / compound Blood level of the mouse after intramuscular administration The blood levels and the half-life (period) of the compound of Example 1 after intramuscular administration of 20 mg / kg in the

  mice are recorded in the table below.

  blood level (μg / ml) compound 10 20 30 45 60 90 * tl / 2 ** AUC Minutes after administration (min) (μg h / ml (min) (μg h / ml 1) Compound of Example i 14 10 , 8 6.8 N-formimidoyl thienamycin 12.6 9.9 7.3

2.6 0.8 <0.6

2.6 0.7 <0.3

  The compounds are solubilized in a 0.1 M phosphate buffer of pH 7.

  The values are those of a simple test; four mice are used

by compound.

  * tl / 2 refers to the half-life in minutes.

  AUC refers to the area under the curve.

Urinary recovery rate

  Urinary recovery of the compound of Example 1, after administration

  intramuscular (20 mg / kg) treatment in mice is shown in

following table.

Compound Composed of

* example 1

  N-formimidoyle Urinary recovery after intramuscular administration of 20 mg / kg to the mouse Percentage of recovered dose

0-3 3-6 6-24 0-24

Hours after administration 26.1

0.5 0.1

26.7 + 6.7

  thienamycin 12.1 0.1 0.1 12.2 + 3.6 The compounds are solubilized in 0.1 M phosphate buffer of

p H 7.

  The values are those of a simple test; four mice per

compound tested.

  Additional biological data In vitro activity Samples of the carbapenem compounds shown below

  (identified by their preparation example number) after being

  6.3% in water and dilution in a nutrient broth, were presented the following minimum inhibitory concentrations (M I Co), expressed in mcg / ml with respect to the indicated microorganisms, these concentrations being

  determined by incubation overnight at 37 C by the

  so-called dilution tube The N-formimidoyl thienamycin is given

  in these different paintings as a control compound.

  s Organisms S pneumonia JS pyogenes S faecalis PS aureus IS aureus P + 50% serum S aureus A (Pen-res) S aureus I (Meth-res) E coli E coli i K pneumoniae IK pneumoniae IE cloacae & E cloacae IP mirabilis IP vulgaris i M morganii i P rettgeri IS marcescens f P aeruginosa IP aeruginosa f H influenzae f H influenzae f B fragilis PB fragilis I

A-9585

A-9604

A 20688

A-9537

A-9537

A-9606

A 15097

A 15119

A 20341-1

A-9664

A 20468

A-965A-9656

A-9900

A 21559

A 15153

A 22424

C 19

A-9843 a.

A 21213

A-9833

A 21518

A 22862

A 22696

  Ex 3 0.002 0.002 0.5 0.016 0.016 Ex 4 0.002 0.001 0.5 0.008 0.03 Ex 5 0.04 0.004 0.25 0.004 0.016 Ex 6 0.004 0.004 0.5 0.03 0.06

0.016 0.016 0.008 0.03

  Ex 7 0.004 0.004 0.13 0.008 0.03 MK 0787 l 0.002 0.002 0.5 0.004 0.016

0.016 0.008

4 4 8 4 2 4

  0.03 0.016 0.06 0.06 0.13 0.13 0.13 0.016 0.13 0.25 0.016 0.5 0.25 0.5 0.016 0.016 0.03 0.03 0.06 0 , 06 0.016 0.016 0.13 0.02 0.13 0.06 0.5 0.016 0.016 0.03 0.06 0.06 0.13 0.03 0.06 0.06 0.13 0.06 0.03 0.25 0.06 0.06 0.13 0.25 0.25 0.25 0.025 0.06 0.13 0.25 0.13> 32> 32 0.03 0.25 0.004 0.004 0.016 0.016 0.016 0.016 0.016 0.008 0.026 0.06 0.008 0.25> 32> 32 0.03 0.25 0.016 0.03 0.06 0.13 0.06 0.06 0.06 0.03 0.13 0, 13 0.03 0.25 0.25 0.66 0.13

N-formimidoyl thienamycin.

  tr 4 r MIU (119 / ml) Organisms S pneumonia SSS pyogenes faecalis aureus S aureus + 50% serum S aureus (Pen-res) S aureus (Meth-res) E coli E coli K pneumoniae K pneumoniae E cloacae E cloacae P mirabilis P vulgaris M Morganii P rettgeri S marcescens P aeruginosa P aeruginosa

A-9585

A-9604

A 20688

A-9537

A-9537

A-9606

Ex 8 Ex 9

0.002 0.001

0.002 0.001

0.5 0.13

0.008 0.004

0.03 0.008

MIC (iq / ml) Ex 10 Ex 11

0.001 0.002

0.001 0.002

0.25 0.5

0.008 0.004

0.06 0.016

0.03 0.008 0.008

0.016

A 15097

A 15119

A 20341-1

A-9664

A 20468

A-9659

A-9656

A-9900

A 21559

A 15153

A 22424

A 20019

A-9843 A

A 21213

  0.016 0.03 0.03 0.13 0.13 0.06 0.13 0.03 0.13 0.13 0.06 0.25 0.008 0.004 0.016 0.03 0.03 0.03 0.016 0.008 0, 03 0.06 0.016 0.13 0.016 0.008 0.06 0, 13 0.13 0.13 0.13 0.016 0.13 0.13 0.06 0.016 0.03 0.03 0.13 0.06 0, 13 0.03 0.06 0.13 0.06 0.5 0.13 * N-formimidoyl thienamycin

MK 0787 *

  0.002 0.002 0.25 0.002 0.016 0.008 0.016 0.016 0.03 0.13 0.13 0.06 0.03 0.016 0.06 0.13 0.03 0.13

-2533568

  MIC (pg / ml) Organisms Ex 12 Ex 13 Ex 14 MK 0787 * S pneumoniae A-9585 0.002 0.005 0.005 0.002 S pyogenes A-9604 0.004 0.0005 0.0005 0.002 S faecalis A 20688 0.5 0.13 0.13 0.25 S aureus A-9537 0.008 0.008 0.008 0.002 S aureus A-9537 0.016 0.016 0.03 0.008 + 50% serum S aureus A-9606 0.03 0.008 0.016 0.008 <Pen-res) S aureus A 15097 (Meth-res) E Coli A 15119 0.016 0.004 0.008 0.016 E Coli A 20341-1 0.008 0.008 0.008 0.016 K pneumoniae A-9664 0.03 0.03 0.03 0.03 K pneumoniae A 20468 0.06 0 , 13 0.03 0.06 E cloacae A-9659 0.06 0.06 0.03 0.06 E cloacae AX-9656 0.03 0.03 0.03 0.06 P mirabilis A-9900 0.03 0.016 0.016 0.016 P vulgaris A 21559 0, 016 0.008 0.016 0.016 M inorganic A 15-153 0.06 0.016 0.03 0.06 P rettger A 22424 0.13 0.25 0.06 0.13 S marcescens A 20019 0 , 0.016 0, 016 0.03 P aeruginosa A-9843 A 16 32 8 1 P aeruginosa A 21213 2 2 0.5 0, 13 * N formimidoyl thienamycin

MIC M Iigm) -

  Organisms Ex 15 'A "Ex 15" B "Ex 15" C "MK 0787 * S pneumoniae A-9585 0, 0005 0.0005 0.0005 0.002 S pyogenes A-9604 0.0005 OM 00 0.0003 0.002 S faecalis A 20688 0.13 0.5 0.5 0.25 S aureus A-9537 0.03 0.004 0.016 '0.004 S aureus A-9537 0.03 0.016 0.06 0.008 + 50% serum S aureus A-9606 0, 004 0.008 0.03 0.008 (Pen-res) S aureus A 15097 (Meth-res) E Coli A 15119 0.004 0.008 0.06 0.008 E coli A 20341-1 0.004 0.008 0.03 '0.016 K pneumoniae A-9664 0.008 0.03 0.06 0.03 K pneumoniae A 20468 0.008 0.016 0.01 0.06 E cloacae A-9659 0.016 0.016 0.913 0.13 E cloacae A-9656 0.016 0.03 0.13 0.13 P mirabilis A-9900 0.008 0.03 0.06 0.06 P vulgaris A 21559 0.000 0.008 0.06 0.016 M morganii A 15153 0.03 0.06 0.25 0.13 P rettger A 22424 0.03 0 13 0.25 0.13 S marcescens A 20019 0.008 0.016 0.13 0.016 P aeruginosa A-9843 A 0.5 -2 8 0.5 P aeruginosa A 21213 0.03 0.13 0.5 0.13 * N formimidoyl thienamycin

253356 8

  N-formimidoyl thienamycin MIC (μg / ml) Ex 19 Ex 20

MK 0787 *

  S pneumoniae S pyogenes S faecalis S aureus S aureus + 50% serum S aureus (Penres) S aureus (Meth-res) E col E K pneumoniae K pneumoniae E cloacae E cloacae P mirabilis P vulgaris M morganii P rettgeri S marcescens P aeruginosa P aeruginosa * N formimidoyl thienamycin Organisms Ex 18

A-9585-

A-9604

A 20688

A-9537

A-9537

A-9606

  0.002 0.002 0.5 0.004 0.008 0.06 0.13 0.5 0.001 0.002 0.25 0.002 0.004 0, 016

A 15097

0,004

A 15119

A 20341-1

A-9664

A 20468

A-9659

A-9656

A-9900

A 21559

A 1.5153

A 22424

A 20019

A-9843 A

A 21213

  0.008 0.008 0.03 0.06 0.03 0.03 0.03 0.016 0.06 0.13 0.03 0.5 0.06 0.016 0.016 0.03 0.06 0.06 0.06 0.016 0.016 0.06 0.13 o 0.03 0.5 0.13 In vivo activity

  The in vivo therapeutic efficacy of certain compounds of the present invention

  invention and N-formimidoyl thienamycin (MK 0787), after admi-

  Intramuscular administration to experimentally infected mice of different organisms is given below. The PD 50 (dose in mg / kg) required to provide protection for 50% of the infected mice is given. Protective effect by intramuscular treatment of infected mice PD 50 / treatment (mg / kg) Ex.6 Ex 8 Ex 9 S aureus E coli K pneumonia P mirabilis P aeruginosa P aeruginosa

A-9606

A 15119

A-9664

A-9900

A 9843 A

A 24081

0.21 0.86 1.8 1.4

0.4 0.19

  0.33 1.2 1.8 7.1 0.19 0.19 Ex.12 Ex 14 Ex 15 Ex 15 MKO 0787

("A") ("B")

0.89 0.07 0.07

1.8 0.44 0.38 0.89 1

  0.4 Ex.3 Ex 4 Ex 7 MK 0787 S aureus A-9606 0.07 0.1 0.2 0.07 E coli A 15119 i 0.4 0.2 3 K pneumoniae A-9664 3 3 1 3 P mirabilis A-9900 2 4 2.4 9 P aeruginosa A 9843 A 0.5 0.2 0.2 0.5 P aeruginosa A 24081 0.8 0.2 0.1 0.4 Ex 5 MK 0787 S aureus 0.2 0.07 E coli 4 2.2 K pneumoniae 3 2.3 P mirabilis 10 9 P aeruginosa A 9843 A 1.6 0.5 tj at, X Blood level in mice after intramuscular administration Blood levels and The half-life of some compounds of the present invention after intramuscular administration at 20 mg / kg to mice are given below. Cmax * T 1/2 ** compound AUC (ig / ml) (min) (pg h / ml)

Example 1

Example 2

Example 3

Example 4

Example 5

Example 6

Example 7

Example 8

Example 9

Example 10

Example 11

* Example 13

Example 14

Example 15

Example 15

Example 15

MK 0787

Example 17

Example 18

Example 19

Example 20

  13.9 14.5, 5 17.7 19.2 18.8 16.7, 1 14.9 14.8, 8

"A" 16.7

"B" 15.9

"C" 15.1

14.6 to 14.9 28.4

  The compounds are solubilized in 0.1 M phosphate buffer, pH 7.

  The values are based on a simple test; four mice per compound.

  * T 1/2 corresponds to the half-life in minutes.

  AUC refers to the area under the concentration curve

blood pressure as a function of time.

  Other objects and advantages of the present invention will be apparent from

  the reading of the description of the examples given in a non-limiting manner.

  he 11 11 11 11 10 16.7 6.3, 3 6.9 7.7 8.5 11.8, 8.5 9.5 7.4 6.4 7.6 9, 5 -7.4 7.3 3.4 3.9, 1, 6

EXAMPLE 1

  Preparation of the inner salt of 1-methyl-4- (2-carboxy-6-hydroxyl) -hydroxide

  {1 (R) -hydroxyethyl-7-oxo-1-azabicyclo {3.2.0 O} hept-2-en-3-thiomethyl} yri di (CH 2) N CH 3 H 3 C

  2 GNP

i OH SC Hr \ N Co 2 GNP

S CHZ Q N-CH 3

N -3

co 2 p NB p NB = CH r 'NO 2 s 4

CH 3 I

OH t e

  A solution of 673 mg (1.86 mmol) of p-nitrobenzyl 6- {1- (R) -

  hydroxyethyl-3,7-dioxo-1-azabicyclo {3,2,0} hept-2-ene-2-carboxylate (1)

  in 10 ml of acetonitrile and cooled to -10 ° C. under a nitrogen atmosphere.

  A solution of 245 mg (1.90 mmol) of diisopropylethylamine in 1 ml of acetonitrile is then added, then 510 mg (1.90 mmol) of diphenyl chlorophosphate in 1 ml of acetonitrile are added dropwise.

  over a period of 2 minutes The resulting solution is stirred at -10 C

  15 minutes to give p-nitrobenzyl 3 (diphenylphosphoryl)

  loxy) -6- {1- (R) -hydroxyethyl} -7-oxo-1-azabicyclo [3,2,0] hept-2-ene-2-

carboxylate.

  This solution is added to a solution of 245 mg (1.90 mmol) of diisocyanate

  propylethylamine in 0.5 ml of acetonitrile and then a solution of 270 mg

  (2, 16 mmol) of 4-mercaptomethylpyridine in 0.5 ml of acetonitrile.

  The reaction mixture is stirred at -10 C for 60 minutes and the precipitate

  white which is formed is collected by filtration and then washed with 5 ml

  cold tonitrile; 660 mg (yield 76%) of the compound II are thus obtained

  in the form of white crystals, melting point 145 C.

  NMR (DMSO-d 6) d: 1.20 (3H, d, I = 6.0Hz); 3.2-3.4 (3H, m); 3.7-4.1 (2H, m); 4.25 (2H, s); 5.05 (1H, d, I = 4.0 Hz); 5.25 (1H, d, I = 14.0 Hz); 5.48 (1H, d, I = 14.0 Hz); 7.40 (2H, d, I = 5.5 Hz); 7.70 (2H, d, I = 8.5 Hz); 8.23 (2H, d, I = 8.5 Hz) and

8.58 (2H, d, I = 5.5 Hz).

  IR (K Br) γ max: 3400, 1790, 1695 and 1600 cm -1.

  On analysis, it is found that the product obtained has the formula C 22 H 21 N 3065 and the following values are obtained:

C H N S

  calculated 58.01 4.56 9.23 7.04 found 57.74 4.56 9.58 7.21 To a solution of 660 mg (1.41 mmol) of intermediate compound 2

  In 140 ml of acetonitrile, 5 ml of methyl iodide are added.

  The reaction mixture is stirred for 8 hours at 25 ° C. The solvent is evaporated.

  pored under vacuum, we thus obtain a light yellow solid which we triturate

  in the presence of diethyl ether; it forms 779 mg (yield: 90%) of the

  enumerated in the form of a white amorphous solid whose point of

  melting is 130 C (with decomposition).

  NMR (DMSO-d 6) d: 1.15 (3H, d, 1 = 6.0Hz); 3.2-3.4 (3H, m); 3.7-4.1 (2H, m); 4.25 (3H, s); 4.30 (2H, s); , (1H, d, I = 14.0 Hz); 5.50 (1H, d, 1 = 14.0 Hz) 7.70 (2H, d, I = 9.0 Hz); 8.10 (2H, d, I = 7.0Hz) 8.25 (2H, d, I = 9.0Hz); and 8.90 (2H, d, I = 7.0 Hz).

  IR (K Br) -max: 3400, 1770, 1690 and 1640 cm -1.

  On analysis, it is found that the product obtained has the formula

C 23 H 24 N 3065 I, H 20

  and the following values are obtained:

C H N S

  calculated 44.39 4.22 6.82 5.20 found 44.66 4.01 6.84 5.64 B. ie

OH H

ON O 2 GNP H 2

H

2 SCH / -SCH 3

  To a solution of 779 mg (1.27 mimol) of compound 3 in a tetrahydrofuran water-diethyl ether mixture (80 m I-80 m I-100 ml) is added mg (1 to 4 mmol) of potassium bicarbonate and 125 mg (127 mmol) of dibasic potassium phosphate Then 700 mg of palladium-on-charcoal are added and the mixture is hydrogenated at 2.8 bars for 45 minutes.

  in a shaker of Parr said Parr Shaker The mixture is from a-

  filtered edge and the catalyst is washed with water (2 x 10 ml) The combined washings and filtrate are extracted with diethyl ether (150 ml) and then lyophilized. A brown powder is thus obtained This raw material is purified on a Bondapak C 18 phase inversion column (30 g) (manufactured by Waters Associates), eluted with water at a pressure of 0.56 bar. pass is subjected to high pressure liquid chromatography and the fraction exhibiting ultraviolet absorption for A max

  300 nm are collected and lyophilized. 135 mg (yield

  32%) of the title compound 4 as a light yellow solid.

  NMR (DMSO-d 6) d: 1.25 (3H, d, I = 6.0Hz); 2.7-3.2 (2H, m); 3.40 (1H, q, I = 9.0 and 2.5 Hz); 3.9-4.2 (2H, m); 4.40 (3H, s); 4.72 (2H, s); 8.10 (2H, d, I = 6.0 Hz); 8.72 (2H, d, I = 6.0 Hz)

  IR (K Br) γ max: 3400, 1755, 1640 and 1590 cm -1.

  UV max (H 2 O): 296 nm (c = 7782), 258 nm (e = 6913).

EXAMPLE 2

  OH (R) SCH 2 CH 2 CH 3 e A. (R). O OH r O

CO 2 GNP

at OH

S SC 2 EC 2 Q

NOT -

O C 02 GNP

P-nitrobenzyl PNB.

  A suspension of 1.1 g (2.93 mmol) of the compound diaza 1 is purged at room temperature using a stream of nitrogen for 5 minutes in 30 ml of dry benzene. It is then treated with 25 mg rhodium acetate dimer and the mixture is heated at reflux for 45 minutes The hot solution is diluted with 25 ml of ethyl acetate, filtered

  to remove the catalyst and evaporated to dryness.

  This is dissolved in dry acetonitrile (20 ml) and is cooled to -10 ° C.

  added, under a nitrogen atmosphere, 417 g (3.2 mmol) of diisopropylethyl

  mine, then 810 mg (3.0 mmol) of diphenyl chlorophosphate, and then

  The reaction mixture is stirred at -10 ° C. for 20 minutes. The reaction mixture

  is then treated with 420 mg (3.2 mmol) of diisopropylethylamine

  and 560 mg (4.03 mmol) of 2- (4-pyridyl) ethane thiol in 2 ml of acetonitrile.

  trile (J Org Chem 26: 82 (1961) Ludwig Bauer and Libero A Gardella Jr) The reaction mixture is stirred at -5 ° C. to 10 ° C. for one hour, then diluted with methylene chloride (100 ml) and washed successively with ugly

  brine-water mixture (1/1), H 3 PO 4 to 4%, Na HCO 3 to 5%, H 2 O and brine.

  The organic phase is dried over MgSO 4 and evaporated, which gives a white solid. This solid is washed with a hexane (1: 1) diethyl ether mixture and dried under high vacuum; 901 mg (63.9%) of compound 3 are obtained. The physical properties are as follows:

IR (K Br): 1790, 1690 cm -1.

  NMR (CD C 13 / DMSO) d: 1.20 (3H, d, I = 3.0 Hz, CH 3); 2.8 to 3.2 (7H, m); 3.9 to 4.4 (2H, m); 5.1 (1H, d); 5.4 (2H, q); 7.3 (2H, d); 8.5 (2H, q); 7.76 (2H, d);

8.3 (2H, q).

OH B.

CH 3 I

  * w> O OH t 3 A solution of 890 mg (1.85 mmol) of carbapenem 3 and 7 ml

  of iodomethane in 200 ml of dry acetone and 12 ml of

  The mixture is stirred for 24 hours at 25 ° C.

  A clear solution is obtained in 18 hours. The solvent is removed under pressure.

  The residue is then washed with diethyl ether to give 920 mg (1.48 mmol) (79.8% yield) of the title compound 4.

form of a foamy solid.

  The physical properties are as follows:

IR (K Br): 1765, 1690 cm -1.

  NMR (DMSO) δ: 1.3 (3H, d, 1 = 3.0 Hz); 3.1 to 3.7 (7H, m); 4.1 (3H, m); 4.3 (3H, s); 5.38 (2H, q, I = 7.0 Hz); 8.1 (2H, d, I = 3.0Hz); 8, 9 (2H, d, I = 3.0 Hz); 7.6 (2H, d, I = 4.0 Hz);

8.2 (2H, d, I = 4.0 Hz).

C. (H) Co 2 PNB OH o CH 3

N O

w 5

  920 g (1.47 mmol) of carbapenem 4, dissolved in 90 ml of tetrahydrofuran,

  hydrofuran, 90 ml of diethyl ether and 90 ml of water are treated with 265 mg (1.5 mmol) of potassium phosphate dibasic, 190 mg (1.9 mmol) of potassium hydrogen carbonate and 800 mg of palladium on charcoal at 10% On

  then hydrogenates at a pressure of 3.1 bar for one hour.

  The lysate is filtered off over Celite, and the filtrate is washed with diethyl ether (3 x 25 ml). The aqueous layer is freeze-dried, which leads to obtaining a brownish material which is purified at

  twice by chromatography on a 12 g * C 18 (H 20) column;

  thus holds 55 ml of the compound 5. The physical properties are as follows:

IR (Br K): 1750, 1640 cm -1.

  NMR (δ 20) δ: 1.30 (3H, d, I = 3.0 Hz); 3.0 to 3.5 (7H, m); 4.3 (3H, s);

  4.0 to 4.5 (3H, m); 7.90 (2H, d); 8.70 (2H, d).

OH S N A "-s CH o

EXAMPLE 3 G 2

  Preparation of 3- (N-methylpyridin-3-yl-methanethio) -6- {1- (R) hydroethyl} -

  7-oxo-1-azabicyclo (3,2,0) hept-2-4-n-2-carboxylate o N OH O Ci P (O O) 2 No 2)

0

  o HS C 02 p NB N BONDAPAK C 5 phase diversion column (Waters Associates) ç BONDAPAK C 18 phase inversion column (Waters Associates) y; OH S X C 02 p NB

  p-Nitrobenzyl-3- (pyridin-3-yl-methanothio) -6- {1- (R) -hydroxyethyl} -7-

  oxo-1-azabicyclo (3,2,0) hept-2-ene-2-carboxylate

  To a cooled solution (0 ") of 925 mg (2.66 nimoles)

  Keto mediator in 14 ml of acetonitrile, a solution of 377 mg (2.9 mmol) of diisopropylethylamine in 1 ml of acetonitrile is added.

  then 786 mg (2.9 mmol) of diphenyl chlorophosphonate in 1 ml of acetaminophosphonate

  The resulting solution is stirred for 15 minutes at 0 ° C and then a solution of 377 mg (2.9 mmol) of 3-mercaptomethylpyridine (prepared by the method described in Can J Chem 56, 3068) is added thereto. (1978), in 2 ml of acetonitrile The solution

  The reaction mixture is stirred for 90 minutes at 0 ° C. The precipitate is

  collected by filtration and washed with 20 ml of ethylacetate.

  950 mg (60% yield) of the product compound as white crystals.

  The physical properties are as follows: NMR (DMSO-d 6) 6: 1.30 (3H, d, I = 6.0 Hz); 3.4-4.2 (5H, m); 4.25 (2H, s); , 1 (1H, d, I = 4.5 Hz); 5.40 (2H, A Bq, I = 14.4 Hz);

7.2-8.5 (8H, m).

  IR (K Br) y max: 3500, 1775 and 1580 cm The analysis shows that the product obtained has the formula

C 22 H 21 J 30651

  and the following values are obtained:

C H N S

  calculated 58.01 4.65 9.23 7.04 found 57.19 5.19 8.76 7.08 OH

CH _> 'I

S J 3

0, S N -

  C 02 p NB OH O C C N N N C N / S o N CH 3

C Q 2 P

OH

2

  3- (N-methylpyridin-3-yl-methanothio) -6c- {1- (R) -hydroxyethyl} -7-oxo-1-

  azabicyclo (3,2,0) hept-2-ene-2-carboxylate To a solution of 730 mg (1.56 mmol) of compound 19 in 120 ml of acetone was added 5 ml of methyl iodide, followed by the reaction mixture

  It is stirred for 18 hours at room temperature.

  collected by filtration and washed with acetone (10 ml); 940 mg (100% yield) of the quaternized pyridine 20 are obtained in the form of

a light yellow powder.

  The physical properties are as follows: NMR (DMSO-d 6) 6: 1.25 (3H, d, I = 5.8 Hz); 3.6-4.3 (5H, m); 4.20 (3H, s); 4.25 (2H, s); 5.25 (1H, d, I = 7.2 Hz); , 40 (2H, A Bq, I = 12Hz); and 7.6-9.2 (9H, m).

  IR (K Br) λ max: 3300, 1765 and 1690 cm -1

  On analysis, it is found that the product obtained has the formula C 23 H 24 N 30651 II and the following values are obtained:

C H N S

  calculated 46.24 4.05 7.03 5.37 found 45.82 4.16 6.87 6.10 To a solution of 933 mg (1.6 mmol) of compound 20 in 90 ml of tetrahydrofuran and 90 ml of ether, 200 mg of KHC 03 and 349 mg of K 2 HPO 4 in 90 ml of water are added, followed by 1.0 g of palladium-carbon.

  is hydrogenated under 3.1 bars in the Parr shaker for 45 minutes.

  The mixture is filtered through a pad of Celite and the catalyst is washed with (2 x 10 ml) of water. Washings and filtrate combined

  extracted with ether (2 x 100 ml) and lyophilized

  This gives a yellow solid which is purified on a column

  phase inversion agent BONDAPAK C 18 (Waters Associates) (8 g), with

  with 5% acetonitrile in water at a pressure of 0.24 bar.

  Each fraction of 15 ml that passes is subjected to chromatography

  in the liquid phase under high pressure and the fractions having an ab-

  Ultraviolet sorption for 300 nm Xmax are collected and freeze-dried.

  230 mg (yield 43%) of the title compound is thereby obtained.

  clear yellow crystals; melting point 130 ° C (with decomposition).

  The physical properties are as follows: NMR (D 20) 6: 1.25 (3H, d, I = 7.0 Hz); 3.12 (2H, dd, I = 7.9Hz, 1.6Hz); 3.42 (1H, q, I = 7.2 Hz, 1.6 Hz); 3.9-4.6 (3H, m);

  4.25 (2H, s); 4.42 (3H, s); and 8.0-9.0 (4H, m).

  IR (K Br) ymax: 3400, 1750 and 1580 cm

UV X max (H 20): 298 (E = 8058).

  On analysis, it is found that the product obtained has the formula C 16 H 18 N 2045 1.2 H 20 and the following values are obtained:

C H N

  calculated 51.87 5.44 7.56 found 51.95 5.66 7.56 OH so 4 N

OG (3

EXAMPLE 4

  Preparation of 3- (N-methylpyridin-2-yl-methane thio) -6? - (1- (R) -hydroxy)

  ethyl-7-oxo-1-azabicyclo (3,2,0) hept-2-ene-2-carboxylate Idc

OH OH

  o Ii cip (O) 2 ^ S => Cl P (052> S No N 02) N C 02 p NB HS N C 2 GNP

  p-Nitrobenzyl-3- (pyridin-2-yl-methanothio) -6? - {1- (R) -hydroxyethyl} -7-

  oxo-1-azabicyclo (3,2,0) hept-2-ene-2-carboxylate

  To a cooled solution (O) of 925 mg (2.65 mmol)

  Keto mediator in 14 ml of acetonitrile is added a solution of 377 mg (2.92 mmol) of diisopropylethylamine in 1 ml of acetonitrile,

  then 786 mg (2.90 mmol) of diphenyl chlorophosphate in 1 ml of

  The resulting solution is stirred for 15 minutes at 0, then a solution of 377 mg (2.92 mmol) of diisopropyl ethylamine in 1 ml of acetonitrile and 350 mg (3.0 mmol) is added thereto. 2-mercaptomethylpyridine (prepared by the method described in Can J Chem 56, 3068 (1978) in 1 ml of acetonitrile The resulting reaction solution is stirred for 2 hours at -10 ° C. The precipitate

  collected by filtration is washed with 20 ml of methylene chloride.

  Thus, 650 mg (54% yield) of the title compound under

form of a yellow powder.

  The physical properties are as follows: NMR (DMSO-d 6) 6: 1.26 (3H, d, I = 7.0 Hz); 2.7-3.5 (4H, m); 3.9-4.3 (2H, m); 4.2 (2H, s); , 42 (2Ha, Bq, I = 14.4Hz) and 7.2-8.8 (8H, m). IR (K Br) y max: 3400, 1775 and 1690 cm The analysis shows that the product obtained has the formula C 22 H 21 N 3065 1: 4 and the following values are obtained:

C H N S

  calculated 58.01 4.65 9.23 7.04 found 57.56 4.92 8.94 7.03 o OH N> 4 acetone C 02 p NB OH

0 3 I

  CO 2 p NB CH 3 IG o Pd / C H 2 OHV CO 2 CH 3. CH 3

  3- (N-methylpyridin-2-yl-methanothio) -6- {1- (R) -hydroxyethyl} -7-oxo-1-

  azabicyclo (3,2,0) hept-2-ene-2-carboxylate To a solution of 650 mg (1.39 mmol) of compound 22 in 100 ml of acetone was added 4 ml of methyl iodide. The precipitate is collected by filtration and washed with acetone (10 ml). 500 mg (yield 60%) of quaternized pyridine 23 are thus obtained in the form of a solid.

pale yellow.

  The physical properties are as follows: NMR (DMSO-d 6) 6: 1.26 (3H, d, J = 7.0 Hz); 3.9-4.2 (2H, m); 4.4 (3H, s); 4.78 (2H, s); 5.2 (1H, d, I = 3.9 Hz); , 50 (2H, A Bq, I = 14Hz); and 7.8-9.4 (8H, m).

  IR (K Br) γ max: 3400, 1765 and 1690 cm -1.

  On analysis, it is found that the product obtained has the formula

C 23 H 24 N 30651 I 1-

  and the following values are obtained:

C H N

  calculated 46.24 4.05 7.03 found 45.62 4.27 6.80 To a solution of 1.0 g (1.167 mmol) of tetrahydrofuran 23 and 90 ml of ether was added 215 mg (2mg). 15, 37, 30 in 90 ml mmol) of

  KHCO 3 and 374 mg (2.1 mmol) K 2 HP 04 in 90 ml of water and then 1.0 g of charcoal.

  good palladium 10% The mixture is hydrogenated at 3.1 bars in a Parr shaker for 45 minutes The mixture is filtered through a pad of Celite

  and the catalyst is washed with (2 x 10 ml) water.

  The combined filtrate and filtrate are extracted with (2 x ml) ether and lyophilized to give a yellow solid which is purified on a BONDAPAK C 18 phase inversion column (Waters Associates). (10 g), eluted with a solution of 5% acetonitrile in water at a pressure of 0.56 bar each 15 ml fraction which

  pass is subjected to high pressure liquid chromatography.

  vee and fractions with ultraviolet absorption for Xmax

  300 nm are collected and lyophilized. Thus 390 mg (yield

  44% of the title compound. The recrystallization of this compound in a water-acetone-ethanol mixture leads to the production of fine needles;

  melting point: 194-196 C (with decomposition).

  The physical properties are as follows: NMR (D 20) 6: 1.30 (3H, d, J = 6.2 Hz); 3.2 (2H, q, J = 9.0Hz, 3.6Hz); 3.46 (1H, q, I = 6.0 Hz, 2.7 Hz); 4.1-4.6 (3H, m);

  4.60 (3H, s) and 7.9-8.9 (4H, m).

  IR (K Br) y max: 3400, 1755 and 1590 cm

UV X max (H 20): 292 nm (E = 8092).

  On analysis, it is found that the product obtained has the formula

C 16 H 28 N 20451.2 H 20

  and the following values are obtained:

C H N

  Calculated 51.87 5.44 7.56 found 51.37 5.69 7.37 OH

CH 3

CO 2

EXAMPLE 5

  Preparation of 3- (N-methylpyridin-2-yl-ethane thio) -6- {1- (R) -hydroxy)

  ethyl-7-oxo-1-azabicyclo (3,2,0) hept-2-ene-2-carboxylate ## STR2 ## Ci P (QO) 2 2) C 02 PNB i SH

54

OH

C 02 GNP

  P-Nitrobenzyl-3- (pyridin-2-yl-ethane thio) -6? - (1- (R) -hydroxyethyl) -7-

  oxo-1-azabicyclo (3,2,0) hept-2-ene-2-carboxylate

  To a cooled solution of 1.78 mg (5.0 mmol) of the intermediate

  Keto acetone in 25 ml of acetonitrile, 710 mg (5.5 mmol) of diisopropylethylamine in 1 ml of acetonitrile and then 1.4 g (5.0 mmol) of diphenyl chlorobphosphate in 1 ml of acetonitrile under an atmosphere are added. The resulting solution is stirred for 20 minutes at 0 ° C. and then a solution of 710 mg (5.5 mmol) of diisopropylethylamine in 1 ml of acetonitrile and finally a solution of 850 mg (6.1 mmol) of Thiol 54 (prepared by the method described in J Org Chem, 26, 82 (1961)).

  in 2 ml of acetonitrile The reaction mixture is stirred for 60 minutes.

  The precipitate is collected by filtration and washed with methylene chloride (20 ml) to give 1.3 g (57% yield).

  of the title compound as a yellow solid.

  The physical properties are as follows: NMR (CDCl 3) δ: 1.25 (3H, d, I = 6.5 Hz); 2.6-3.4 (7H, min); 4.2-4.6 (2H, m); 5.30 and 5.65 (1 H each, A Bq, I = 14 Hz);

* and 7.2-8.5 (8H, 1in).

  IR (K Br) -ymax: 3400, 1780 and 1680 a-1. OH

I CH 3 I

S

5

OH t H 9 Pd / C c 3

-J '55

WH

o D

2 (3

  3-N-ethylenio) -6-x- {1- (R) -hydroxyethyl] -7-oxo-1-

  azabicyclo (3,2,0) hept-2-ene-2-carboxylate To a suspension of 800 mg (1.7 mmol) of compound 53 in 50 ml of acetone was added 5 ml of methyl iodide. The reaction mixture is stirred for 48 hours at room temperature. The precipitate is collected by filtration and washed with 15 ml of acetonitrile. 810 mg (yield 76%) of quaternized pyridine 55 are thus obtained in the form of a powder.

pale yellow.

  The physical properties are as follows: NMR (DMSO-d 6) 6: 1.20 (3H, d, I = 5.6 Hz); 3.2-4.3 (9H, m); 4.20 (3H, s); 5.26 and 5.55 (1 H each, A Bq, I = 15 Hz);

and 7.8-9.2 (8H, m).

  IR (K Br) y max: 3400, 1770 and 1690 cm -1.

  To a solution of 790 mg (1.27 mmol) of compound 55 in 100 ml of tetrahydrofuran and 100 ml of ether is added 100 ml of a buffer solution at pH 7.0 and 1.0 g of charcoal. palladium 10% The mixture is

  hydrogenated under 2.8 bar in a Parr shaker for 40 minutes. The mixture is then filtered through a pad of Celite and the catalyst is

  washed with (2 x 10 ml) water.

  The washing waters and the combined filtrate are then extracted with (3 x 100 ml) of ether and then lyophilized, which leads to the production of a yellow powder which is purified on a column. BONDAPAK C 18 (Waters Associates) (30 g) then eluted with a 10% solution

  acetonitrile in water at 0.56 bar.

  Each fraction of 15 ml that passes is subjected to a chromatography in

  liquid phase under high pressure and the fractions having an absorp-

  Ultraviolet at 300 nm Xmax are collected and lyophilized. 65 mg (15% yield) of the title compound are thus obtained.

a yellow powder.

  The physical properties are as follows: NMR (D 20) 6: 1.25 (3H, d, I = 6.2 Hz); 3.1-3.6 (7H, m); 4.0-4.3 (2H, m);

  4.32 (3H, s) and 7.8-8.9 (4H, m).

  IR (K Br) γ max: 3400, 1750 and 1590 cm -1.

UV max (H20): 300 nm (E = 8108).

OH $ S <Ns

-

CO

EXAMPLE 6

  Preparation of 3- (1-propylpyridin-4-yl-methane thio) -6- {1- (RJ-hydroxy)

  ethyl-7-oxo-1-azabicyclo (3,2,0) hept-2-ene-2-carboxylate

OH OH

S <> <S e

0 l six C 02 p NB C 02 p N '

  P-Nitrobenzyl-3- (pyridin-4-yl-methanothio) -6 L- {1- (R) -hydroxyethyl} -7-

  oxo-1-azabicyclo (3,2,0) hept-2-ene-2-carboxylate

  A solution of 673 mg (1.86 moles) of p-nitrobenzyl a - {- (R) -

  hydroxyethyl-3,7-dioxo-1-azabicyclo (3,2,0 hept-2-ene-2-carboxylate (5)

  in 10 ml of acetonitrile is cooled to -10 C under a nitrogen atmosphere.

  A solution of 245 mg (1.90 mmol) of diisopropylethylamine in 1 ml of acetonitrile is then added, then 510 mg (1.90 mmol) of diphenyl chlorophosphate in 1 ml of acetonitrile are added dropwise.

  a period of 2 minutes The resulting solution is stirred at -10 C

  After 15 minutes, p-nitrobenzyl-3- (diphenylphosphoryl) is obtained.

  oxy) -6 c- {1- (R) -hydroxyethyl} -7-oxo-1-azabicyclo- (3,2,0) hept-2-ene-2-

  To this solution is added a solution of 245 mg (1.90 mmol) of diisopropylethylamine in 0.5 ml of acetonitrile, followed by a solution of

  270 mg (2.16 mmol) of 4-mercaptomethylpyridine in 0.5 ml of acetonitrile.

  The reaction mixture is stirred at -10 C for 60 minutes, then the

  The white precipitate which forms is collected by filtration and washed with 5 ml of ice-cold acetonitrile. 660 mg (76% yield) of

  compound 51 under white crystals; m.p. 145 C.

  The physical properties are as follows: NMR (DMSO-d 6) 6: 1.20 (3H, d, I = 6.0 Hz); 3.2-3.4 (3H, m); 3.7-4.1 (2H, m); 4.25 (2H, s); 5.05 (1H, d, I = 4.0 Hz); 5.35 (1H, d, I = 14.0 Hz); , 48 (1H, d, I = 14.0 Hz); 7.40 (2H, d, I = 5.5 Hz); 7.70 (2H, d, I = 8.5 Hz); 8.23 (2H, d, I = 8.5 Hz) and

8.58 (2H, d, I = 5.5 Hz).

  IR (K Br) y max: 3400, 1790 and 1695 cm On analysis, it is found that the product obtained has the formula

C 22 H 21 N 3065

  and the following values are obtained:

C H N S

  calculated 58.01 4.56 9.23 7.04 found 57.74 4.56 9.58 7.21 OH S

NX -

O

C 02 p NB OH

\ -

Br'X% S N Z "-

acetone O 'Na I C 02 p NB I

52

  3- (1-allylpyridin-4-yl-methanothio) -6- {1- (R) -hydroxyethyl} -7-oxo-1-

  azabicyclo (3,2,0) -hept-2-ene-2-carboxylate To a solution of 900 mg (2.13 mmol) of compound 51 in 150 ml

  acetone, 2 ml of allyl bromide and 380 mg of sodium iodide are added.

  The mixture is stirred for 48 hours at ambient temperature and the solvent is then evaporated under vacuum to give a yellow solid.

  The material is suspended in 120 ml of acetonitrile, filtered and

  pores under vacuum. 1.0 g (yield 87%) of the title compound are obtained.

in the form of a yellow solid.

  The physical properties are as follows: NMR (CD 3 CN) 6: 1.20 (3H, d, 1 = 6.2 Hz); 3.0-3.4 (4H, m);

  4.0-4.4 (4H, m); 5.1-5.6 (4H, m) and 7.4-7.9 (8H, m).

  IR (K Br) y max: 3400, 1770 and 1690 cm The analysis shows that the product obtained has the formula:

C 25 H 26 N 3065 II 1

  and the following values are obtained:

C H N S

  calculated 48.16 4.61 6.74 5.15 found 48.55 4.66 6.69 5.15 s 5 OH OH | v} X 2 _ S LON z Pd / C S

-O _ CO 2

-H 2-

2 + c O C 02 p NB I

52 53

  3- (1-propylpyridin-4-yl-methane thio) -6- {1- (R) -hydroxyethyl} -7-oxo

  1-azabicyclo (3,2,0) hept-2-ene-2-carboxylate To a solution of 1.27 g (2.15 mmol) of compound 52 in 100 ml of tetrahydrofuran and 100 ml of ether is added 100 ml of a buffer solution of p H = 7.0, then 1.0 g of 10% palladium on carbon The mixture is hydrogenated under a pressure of 2.8 bar in a Parr shaker during

  minutes The mixture is filtered through a pad of Celite then the cata-

  The water is washed with (2 x 10 ml) of water. The washing water and the combined filtrate are extracted with ether (3 x 100 ml) and then lyophilized to give a yellow powder. that is purified in a column of BONDAPAK C 18 (Waters Associates) (40 g), and eluted at

  using a solution of 10% acetonitrile in water at 0.56 bar.

  Each fraction of 15 ml that passes is subjected to a chromatography in

  liquid phase under high pressure and the fractions having an absorp-

  ultraviolet light for kmax 300 nm are collected and lyophilized.

  48 g (6% yield) of the title compound are thus obtained.

a yellow powder.

  The physical properties are as follows: NMR (D 60): 0.95 (3H, t, I = 7.5 Hz); 1.25 (3H, d, 7.0Hz); 2.05 (2H, sextet, I = 7.5Hz); 3.10 (2H, dd, I = 1.0 Hz, 2.5 Hz); 3.35 (1H, dd, I = 6.5 Hz, 2.5 Hz); 4.0-4.8 (6H, m);

  7.1 (2H, d, I = 6.0Hz); and 7.80 (2H, d, I = 6.0 Hz).

  IR (K Br) y max: 3400, 1750 and 1590 cm On analysis, it is found that the product obtained has the formula: C 1 to H 22 N 2045.2 H 20 and the following values are obtained:

C H N

  Calculated 54.52 6.10 7.07 Found 54.32 6.03 6.99 OH

X T X CH

N / CO O Co O CH 3

EXAMPLE 7

  Preparation of 3- (N-methyl-3-methylpyridine-2-methane thio) -6 1- (R) -

  hydroxyethyl-7-oxo-1-azabicyclo (3,2,0) hept-2-ene-2-carboxylate

S CH

H 3 1) H N 3 INH 2

SHI N 2) NaOH N HC 1

36 37

  3-methyl-2-mercaptomethyl pyridine A solution of 2.45 g (17.0 mmol) of chlorinated compound 36 and 1.37 g (18.0 mmol) of thiourea in 60 ml of absolute ethanol is heated to room temperature. reflux for 5 hours Evaporation of ethanol followed

  addition of the ether gives 3.08 g (72% yield) of the isopropyl salt.

  thiouronium which is dissolved in 10 ml containing 1.44 g (26 mmol) of hy-

  The solution is then heated at 100 ° C. for 5 minutes under a nitrogen atmosphere. The reaction mixture is cooled to 5 ° C. and its pH is adjusted to 6.4 by addition of acetic acid and then extraction with the aid of sodium hydroxide. ether (4 x 50 ml) The ethereal and combined extracts are washed

  with a 5% aqueous solution of sodium bicarbonate and sodium

  The evaporation of the dried solvent (Mg SO 4) gives 1.4 g (yield

  83%) of the thiol 37 as a yellow oil which is used for

  subsequent step without further purification.

  The physical properties are as follows: NMR (CD C 13) d: 2.20 (3H, s); 2.5-2.7 (1H, broad s);

  + 3.8 (2H, t, I = 6.5Hz); and 6.9-8.2 (3H, m).

OH 1)> - N- <OH

% O CH 3

> o Ci P 0) 2

-N O 2:

o 2) CH $ Co 2 p NB C 2 PN'B NHSv,%

38

  P-Nitrobenzyl-3- {3-methylpyridin-2-yl-methane thio} -6 c- {1- (R) -hydroxy)

  ethyl-7-oxo-1-azabicyclo (3,2,0) hept-2-ene-2-carboxylate to a cooled solution (0 C) of 1.74 g (5.0 mmol) of the compound

  intermediate keto in 25 ml of acetonitrile, 960 mg (5.8 mmol) is added.

  the diisopropylethylamine in 2 ml of acetonitrile then 1.4 g (5.8 g)

  mmol) of diphenyl chlorophosphate in 2 ml of acetonitrile under atmospheric

  The resulting solution is stirred for 20 minutes at 0 ° C.

  then a solution of 760 g (5.8 mmol) of diisopropylethyl

  lamine in 32 ml of acetonitrile then 810 g of mercaptomethylpyridine 37

  in 3 ml of acetonitrile The reaction mixture is maintained under stirring.

  The precipitate is collected by filtration and washed with acetonitrile. 1.56 g (66% yield) of the title compound is then obtained in the form of a white solid; melting point: C. The physical properties are as follows: NMR (DMSO-d 6) 6: 1.23 (3H, d, I = 6.5 Hz); 2.30 (3H, s); 3.1-4.3 (6H, m); 4.35 (2H, s); 5.20 and 4.45 (1 H each, A Bq, I = 15.0 Hz); and

7.3-8.4 (7H, m).

  IR (K Br) γ max: 3400, 1767 and 1695 cm -1.

  On analysis, it can be seen that the product obtained

C 24 H 26 N 30952 F

  and the following calculated values are obtained: ## EQU2 ## 47.91 47.72 H 4.69 4.34 N 6.98 6.72 the formula: S, 66 11.22 OH 1 CH 3 St

FSO 3 CH 3

33>

Pd / C 39 503 F H 2

  3- (N-methyl-3-methylpyridin-2-yl-methanothio) -6? - {1- (R) -hydroxyethyl} -

  7-oxo-1-azabicyclo (3,2,0) hept-2-ene-2-carboxylate To a solution of 680 mg (1.45 mmol) of compound 38 in 120 ml of methylene chloride was added 270 mg. (2.33 mmol) methyl fluorosulfonate The reaction mixture is stirred for 3 hours at room temperature. The precipitate is collected by filtration and washed with methylene chloride (5 ml) to give 840 mg (99% yield). ) of

  quaternized pyridine 39 as white crystals.

  The physical properties are as follows: NMR (DMSO-d 6) 6: 1.15 (3H, d, I = 5.8 Hz); 2.62 (3H, s); 3.2-4.4 (5H, m); 4.45 (3H, s); 4.60 and 4.82 (1 H each, A Bq, I = 9.2 Hz); , 30 and 5.46 (1 H each, A Bq, 1 = 12.8 Hz) and

7.6-8.9 (7H, min).

  IR (K Br) y max: 3400, 1750 and 1590 cm OH The analysis shows that the product obtained has the formula

C 24 H 24 N 30952 F

  and the following values are obtained:

C H N S

  calculated 49.14 4.47 7.13 11.43 found 49.56 4.16 7.26 11.03 To a solution of 810 mg (1.39 mmol) of compound 39 in 100 ml of tetrahydrofuran and 100 ml of ether, 100 ml of a buffer solution of pH = 7.0, then 750 mg of 10% palladium on carbon are added. The mixture is hydrogenated under a pressure of 3.1 bars in a Parr shaker.

  for 60 minutes in a cold chamber (4 to 6 C) The mixture is

  on a celite pad and the catalyst is washed with ether

  (2 x 10 ml) The combined washings and filtrate are ex-

  traction with (2 x 40 ml) of ether and lyophilization A yellow solid is thus obtained which is purified in the BONDAPAK column

  C 18 (Waters Associates) (20 g) involving elution with a solution

  5 ml of acetonitrile in water at a pressure of 0.56 bar. Each 15 ml fraction that passes is subjected to high pressure liquid chromatography and the fractions having ultraviolet absorption for Xmax 300 nm. are collected and lyophilized. 141 mg (30% yield) of the title product is thus obtained in the form of a yellow solid. The physical properties are as follows: NMR (D 20) 6: 1.24 (3H, d, I = 7.0 Hz); 2.62 (3H, s); 3.2-3.5 (3H, m); 4. 2-4.4 (2H, m); 4.45 (3H, s); 4.50 and 4.59 (1 H each, A Bq, I = 12.6 Hz); 7.82 (1H, q, I = 7.0 Hz;

  6.5 Hz); 8.35 (1H, d, I = 7.0 Hz); and 8.65 (1H, d, I = 6.5 Hz).

  IR (K Br) γ max: 3400, 1750 and 1580 cm -1.

UV X max (H 20): 296 nm (E = 8014).

  On analysis, it is found that the product obtained has the formula

C 17 H 20 N 204 S, 1/4 4

  and the following values are obtained:

C H N

  calculated 57.85 5.85 7.94 found 58.60 5.86 7.87 OH from N / S to -M

  3- (2-Methyl-N-methylthiazol-4-yl-methane thio) -6 "- {1- (R) -

  hydroxyethyl-7-oxo-1-azabicyclo (3,2,0) hept-ene-2-carboxylate and P (00) 2

: N 2) /

Co 2 p NB HSCH 3 OH o CH 3

CO 2 GNP

  p-nitrobenzyl 3- {2-methylthiazol-4-yl-methanothiol-6 to L- {1- (R) hydroxy}

  ethyll-7-oxo-1-azabicyclo (3,2,0) hept-2-ene-2-carboxylate to a solution cooled to (QO) of 1.4 g (4.0 mmol) of the compound

  intermediate keto in 12 ml of acetonitrile, add 0.83 ml (4.6 mmol) of

  the) diisopropylethylamine and then 1.16 g (4.3 mmol) of diphenylchloro

  phosphate in 2 ml of acetonitrile under a nitrogen atmosphere. The resulting solution is stirred at 00 for 30 minutes.

  p-Nitrobenzyl 3- (diphenylphosphoryloxy) -6? - (1- (R) -hydroxyethyl] -7-oxo]

  azabicyclo (3,2,0) hept-2-ene-2-carboxylate To this solution is added a solution of 0.83 ml (4.6 mmol) of diisopropylethylamine in 2 ml.

  acetonitrile and then a solution of 0.62 g (4.2 mmol) of 2-methyl-4-

  mercaptomethylthiazole (prepared according to the method described in J. Amer.

  Chem Soc. 71, 3570 (1949)) in 3 ml of acetonitrile.

  The precipitate is collected and washed with ether (30 ml). 943 mg of the compound are thus obtained.

  heading in the form of a white solid.

  The physical properties are as follows: NMR (CD C 13) 6: 1.32 (3H, d, I = 7 Hz); 2.68 (3H, s); 3.20 (2H, m); 3.76 (1H, d, I = 5.5 Hz); 4, 16 (2H, s); 4.20 (1H, m); , 40 (2H, q, I = 14Hz); 7.06 (1H, s);

  7.68 (2H, d, I = 8Hz) and 8.24 (2H, d, I = 8Hz).

  IR (K Br) γ max: 3500, 1770 and 1700 cm -1.

  OH s CHOSOF N 1 X _ X Ni CH CH 2 C 12 C 02 p NB t OH

* 25 N / <N CH

C 02 p NB CH

FSO 3

Pd / C, H 2 OH 1 s CH $ CH

<CNC CH 3

2 3

  3- (2-methyl-N-methyl-thiazol-4-yl-methanothio) -6- {1- (R) hydroxyethyl} -

  7-oxo-1-azabicyclo (3,2,0) hept-2-ene-2-carboxylate To a solution of 525 mg (1.1 mmol) of compound 9 in 20 ml of chloride

  of methylene, 0.27 ml (3.3 mmol) of methyl fluorosulfonate is added.

  The reaction mixture is stirred for 30 minutes at room temperature.

  The precipitate is collected by filtration and washed with methylene chloride (50 ml). 650 mg (100% yield) of thiazole are thus obtained.

  quaternized 10 which is used for the subsequent step in a purification stage.

intermediate.

  Thus, to a solution of the compound 10 in 100 ml of tetrahydrofuran and ml of ether, 100 ml of a buffer solution at pH 7.0 and then

  500 mg of 10% palladium on carbon The mixture is hydrogenated under a

  The mixture is filtered through a pad of Celite and the catalyst is washed with water (2 x 10 ml).

  extraction with (2 x 100 ml) of ether and then lyophilized.

  A yellow powder is thus obtained which is purified on a column of

  phase version BONDAPAK C 18 (8 g) (Waters Associates) then eluted by

  a solution of 5% acetonitrile in water at a pressure of 0.56 bar.

  Each 15 ml fraction that passes is subjected to high pressure liquid chromatography and fractions with ultraviolet absorption for Xmax 300 nm are collected and lyophilized. 145 mg (48% yield) of the title compound are thus obtained. form

a pale yellow powder.

  The physical properties are as follows: NMR (CDC 13) 6: 1.20 (3H, d, I = 7 Hz); 2.92 (3H, s); 3.08 (1H, d, I = 3.5 Hz); 3.20 (1H, d, H = 3Hz); 3.44 (1H, dd, I = 1 Hz, I = 3.5 Hz); 4.00 (3H, 5); 4.20 (3H, m); 4.36 (2H, m); and

7.88 (1H, s).

  IR (K Br) γ max: 3400, 1750 and 1585 cm -1.

UV X max (H 20): 296 nm (c = 7500).

  On analysis, it is found that the product obtained has the formula C 15 He 18 N 20452.2 H 20 and the following values are obtained:

C H N S

  calculated 46.15 5.67 7.17 16.41 found 46.50 5.26 7.13 16.20

OH CH

* 5 N / S ') J

N Os I

CO O CH

2 3

EXAMPLE 9

  Preparation of 3- (N, N'-dimethylimidazol-2-yl-methane thio) -6 a- {1- (R) -

  hydroxyethyl-7-oxo-1-azabicyclo (3,2,0) hept-2-ene-2-carboxylate

CH CH 3

  3 s H SH N Cl H 2 NJ N-Ac N I I I I c i _ _ _ _ _ _ _ _ _ _ _ _ _ S H N N 2) And OH, A N H Cl HC 1

31 32

  2-mercaptomethyl N-methylimidazole

  To a solution of 10.4 g (58 mmol) of 2-chloromethyl-N-methyl-

  Imidazole 31 (prepared by the method in Amer Chem Soc. 71, 383 (1949)) in 200 ml of acetonitrile was added with 7.1 g (60 mmol) of Nacetyl thiourea and the reaction mixture was heated to room temperature. reflux

  during 90 minutes The precipitate is filtered and washed with acetonitrile

  trile (20 ml) The isothiouronium salt is thus obtained which is dissolved in 120 ml of ethanol and heated at reflux temperature for 18 hours under a nitrogen atmosphere. The reaction mixture is cooled to room temperature and condensed under vacuum. to about 60 ml of volume and the precipitate was filtered off Evaporation of the filtrate in vacuo gave 2-mercaptomethyl-N-methylimidazole 32 as a yellow oil which was used for subsequent step without intermediate purification. The physical properties are as follows:

  NMR (D 20) 6: 3.90 (3H, s); 4.10 (2H, s) and 7.25 (2H, S).

t

1)> N J

OH

OH H

o It N \ I) i H 95 X

C 02 PN-B N Co 02 p NB.

$ H '

"'33

  p-Nitrobenzyl-3- {N-methylimidazol-2-yl-methane thio} 6α- {1- (R) -hydroxy)

  ethyl-7-oxo-1-azabicyclo (3,2,0) hept-2-ene-2-r-carboxylate

  To a cooled solution (O C) of 7.24 g (20.3 mmol) of

  Keto mediator in 35 ml of acetonitrile, 2.8 g (21.3 mmol) is added.

  of diisopropylethylamine in 2 ml of acetonitrile and then 5.5 g (20.4 mmol

dichlorophosphate of diphenyl in 2 ml of acetonitrile under atmospheric pressure.

  The resulting solution is stirred at 0 ° C. for 15 minutes.

  then a solution of 4.1 g (3.0 mmol) of diisopropylethyl

  lamine in 2 ml of acetonitrile and 4.6 g (31.0 mmol) of thiol 32

  The reaction mixture is stirred for 60 minutes at 0 C.

  The white precipitate is collected by filtration and washed with chlorine

  Methylene chloride (1 ml) gives 6.6 g (71% yield) of

  in heading in the form of a white solid; melting point: 142 C.

  Physical properties: NMR (DMSO-d 6): 1.32 (3H, d, 1 = 7.0 Hz); 3. 2-4.5 (5H, m); 3.2 (2H, s); 3.9 (3H, s) -; 5.50 (2H, A Bq, I = 14.0 Hz); 7.65 (2H, d, 1 = 6.5Hz); 7.70 (2H, s) and

8.24 (2H, d, I = 6.6Hz).

  IR (K Br) y max: 3450, 1770 and 1690 cm. On analysis, it can be seen that the product obtained has the formula

C 2 H 2 O N 40651.11 / 2 H 20 -

  and the following values are obtained:

C H N

  calculated 52.18 4.79 11.59 found 52.22 4.91 12.16 OOH the CH 3 33 H o N

OH CHN

<N 3

CH 3 CH

CO 2 p NB Pd? C, "2

  3- (N, N '-dimethylimidazol-2-yl-methanothio) -6? - (1- (R) -hydroxyethyl) -7-

  To a suspension of 1.34 g (3.0 mmol) of compound 33 in 270 ml of acetone was added oxo-1-azabicyclo (3,2,0) hept-2-ene-2-carboxylate. methyl iodide The reaction mixture

  is stirred for 4 days at room temperature The precipitate is collected

  Filtration and washing with acetone (20 ml) gave 1.70 g (96% yield) of quaternized inridazole 34 as yellow crystals; melting point: 175-1770 C. The physical properties are as follows: NMR (DMSO-d 6): 1.10 (3H, d, H = 6.2 Hz) 3.30 (2H, s); 3.24 (6H, m); NOT

C H N

  calculated 43.08 9.60 5.48 Fitted 43.02 9.02 H 5.44

  3- (N, N '-dimethylimidazol-2-yl-methane thio) -6 α- {1- (R) -hydroxyethyl}

  oxo-1-azabicyclo (3,2,0) hept-2-ene-2-carboxylate has a solutspension of 1.30 g (1.86 mmol) of compound 34 in 120 ml of tetrahydrofuran and 120 m of ether, 120 ee ml of a sludge

  p H = 7.0 and then 900 mg of M celate at 30% of palladium.

  It is filtered off and washed with acetone (20 ml) to give 1.70 g (96% yield) of quaternized imidazole 34 as crystals.

  yellow; melting point: 175-177 ° C.

  The physical properties are as follows: NMR (DMSO-d 6) 6: 1.10 (3H, d, H: 6.2 Hz); 3.30 (2H, s); 3.2-4.3 (6H, m);

  : 3.95 (6H, s); 5.45 (2H, A Bq, I: 14Hz); 7.65 (2H, d, I: 6.0Hz).

  IR (K Br) ν max: 3400, 1750 and 1600 cm -1.

  On analysis, it is found that the product obtained has the formula C 2 H 22 N 4065 1 and the following values are obtained:

C H N

  calibrated 43.08 9.60 5.48 found 43.02 9.02 5.44 To a solution of 1.30 g (1.86 mmol) of compound 34 in 120 ml of tetrahydrofuran and 120 ml of ether, 120 ml of a buffer solution p H = 7.0 and 900 mg of Celite at 30% of palladium are added. The mixture is hydrogenated under a pressure of 2.80 bar in a Parr shaker for 40 minutes. The mixture is filtered through a Celite pad and the catalyst is washed with water (2 x 15 ml) The combined washings and filtrate are extracted with (3 x 100 ml) and freeze dried. yellow amorphous powder, which is tested on a BONDAPAK C 18 column (Waters Associates) (30 g), then eluted with a 10% solution of acetonitrile in water under 0.56 bar Each fraction of 20 ml that passes is subject

  high pressure liquid chromatography and the fractionation of

  Ultraviolet absorption for max 300 nm is collected and lyophilized to give 220 mg (35% yield).

  of the title compound as a yellow powder.

  The physical properties are as follows: NMR (D 20) 6: 1.12 (3H, d, I = 7.0 Hz); 3.08 (1H, dd, I = 13.0 Hz, 6.4 Hz); 3.15 (1H, dd, I = 13.0Hz), 6.4Hz); 3.45 (1H, dd, I = 3.2 Hz, 4.5 Hz); 3.85 (6H, s); 4.1-4.3 (2H, m); 4.40 (1H, d, I = 13.5Hz); 4.52 (1H, d, I = 13.5 Hz) and

7.40 (2H, s).

  IR (K Br) at max: 3500, 1750 and 1590 cm

UV X max (H 20): 296 nm (E = 8411).

  On analysis, it is found that the product obtained has the formula

C 15 H 19 N 3045 H 20

  and the following values are obtained:

C H N S

  calculated 51.68 5.67 12.06 9.50 found 49.93 5.94 11.46 9.03 OH

CH 3 9 / CH 3

CO 2 C

EXAMPLE 10

  Preparation of 3- (2,3,4-trimethylthiazol-5-yl-methanothio) -6 OE- {1- (R) -

  hydroxyethyl-7-oxo-1-azabicyclo (3,2,0) hept-2-ene-2-carboxylate

CH 3 S S H 2 N S

I 1) H N -kNH> c 3-

Cl> C N due 2) Na OH 3 CHX

S CH 3 3

  HC 1 * s 46 47 2,4-Dimethyl-5-mercaptomethylthiazole

  To a solution of 4.8 g (26.0 mmol) of the chlorinated compound 46 (pre-

  prepared by the method described in J Amer Chem Soc, 104, 4461 (1982)}

  in 50 ml of absolute ethanol, 2.4 g (30 mmol) of thiourea are added.

  The reaction mixture is heated at reflux temperature for 18 hours.

  The precipitate is collected by filtration and washed with ether (20 ml). The isothiouronium salt is obtained, which is dissolved in 22 ml of 1N sodium hydroxide and heated at 100 ° C. for 4 minutes. under

  Nitrogen atmosphere The reaction mixture is then cooled to room temperature.

  ambient temperature, its pH is adjusted to 7.0 by addition of hydrochloric acid

  1 N and then extracted with ether (3 x 50 ml).

  The combined ether phases are washed with water, brine and

dried on Mg SO 4.

  Evaporation of the dried solvent gives 780 mg (49% yield) of the thiol.

  which is in the form of a colorless oil which is used for

  subsequent step without purification step.

  The physical properties are as follows:

  NMR (CDCl 3) 6: 2.05 (3H, s), 2.35 (3H, s) and 3.60 (2H, d, I = 6.5Hz).

  ## STR2 ## ## STR2 ##

HS N

CH i OH

S CH '

N / S C 02 p NB CH 3

48

  P-Nitrobenzyl-3- {2,4-dimethylthiazol-5-yl-methane thio} -6 a- {1- (R) hydroxy)

  ethyl-7-oxo-1-azabicyclo (3,2,0) hept-2-ene-2-carboxylate

  To a cooled solution (0 C) of 1.4 g (4.0 mmol) of the intermediate

  In a 25 ml acetonitrile solution, 610 mg (4.7 mmol) of diisopropylethylamine in 1 ml of acetonitrile and then 1.15 g (4.3 mmol) of diphenyl chlorophosphate in 1 ml of acetonitrile under an atmosphere are added. The resulting solution is stirred for 20 minutes at 0 ° C. and then a solution of 610 mg (4.7 mmol) of diisopropylethylamine in 1 ml of acetonitrile and finally 750 mg (4.7 mmol) of thiol 47 are added. 2 ml of acetonitrile The reaction mixture is stirred for 3 hours at DC The precipitate is collected by filtration and washed

  With the aid of methylene chloride (20 ml), 1.14 g

  61%) of the title compound as a white solid.

  The physical properties are as follows:

  NMR (DMSO-d 6) δ: 1.25 (3H, d, I = 6.4 Hz); 2.30 (3H, s); 2.65 (3H, s);

  3.1-3.4 (3H, m); 4.10 (1H, broad s); 4.0-4.5 (3H, m); 5.25 and 5.50 (1 H each, A Bq, I = 4 Hz);

  7.68 (2H, d, I = 8.5Hz) and 8.25 (2H, d, I = 8.5Hz).

  IR (K Br) -max: 3500, 1770 and 1690 cm -1.

  On analysis, it is found that the product obtained has the formula

C 22 H 23 N 30652

  and the following values are obtained:

C H N S

  Calculated 53.73 4.71 8.57 13.44 Found 53.97 4.74 8.58 13.10 OH Co p "ci 13 * 48 C 02 p NB CH 3 OH

CH 3

C 02 p NBCH 3

49,503 F

Pd / C, H 2

OH>, OH

S -CH 3

S CH

C H $

"G 'N CH $ 3

2 C 3 CH H

  3- (2,3,4-trimethylthiazol-5-yl-methanothio) -6? - (1- (R) -hydroxyethyl) -7-

  oxo-1-azabicyclo (3,2,0) hept-2-ene-2-carboxylate To a solution of 1.97 g (4.0 mmol) of compound 48 in 180 ml of methyl chloride, a solution of 0.98 ml (13 mmol) of methyl fluorosulfonate in 2 ml of methylene chloride. The reaction mixture is stirred for 70 minutes at room temperature, then

  is poured into a solution of ether (400 ml) and n-pentane (100 ml).

  The precipitate is collected by filtration and washed with ether (20 ml).

  1.6 g (65.5% yield) of the quaternized thiazole 49 are thus obtained.

white amorphous powder form.

  The physical properties are as follows: NMR (DMSO-d 6) 6: 1.25 (3H, s, I = 6.5 Hz); 2.45 (3H, s); 2.80 (3H, s); 3.2-4.5 (6H, m); 3.90 (3H, s); , (2H, broad s); 7.60 and 8.2 (1 H each, d, I = 8.5 Hz). IR (K Br) y max: 3400, 1770 and 1690 cm The analysis shows that the product obtained has the formula

C 23 H 26 N 30953 F, / 2 H 20

  and the following values are obtained:

C H N

  calculated 45.09 4.64 6.86 found 44.50 4.38 6.58 To a solution of 1.0 g (1.72 mmol) of compound 49 in 100 ml of tetrahydrofuran and 100 ml of ether, add 100 ml of a buffer solution p H = 7.0 and 1.0 g of 10% palladium charcoal.

  hydrogenation under a pressure of 2.8 bar in the Parr shaker for 40 minutes The mixture is filtered through a pad of Celite

  then the catalyst is washed with water (2 x 10 ml).

  The combined filtrate and filtrate were extracted with ether (3 x 100 ml) and lyophilized to give a yellow powder which was purified on a BONDAPAK C 18 (Waters Associates) (40 g). and elution with a 10% aqueous solution of acetonitrile

a pressure of 0.56 bar.

  Each fraction of 15 ml that passes is subjected to a chromatography in

  liquid phase under high pressure and the fractions having an absorp-

  Ultraviolet irradiation for Xmax 300 nm is collected and freeze-dried.

  315 g (yield 50%) of the title compound are thereby obtained.

of a yellow solid.

  The physical properties are as follows: NMR (D 20) 6: 1.25 (3H, d, 1 = 7.0 Hz); 2.25 (3H, s); 2.90 (3H, s); 3.0-3.30 (3H, m); 3.90 (3H, s) and

4.1-4.4 (4H, m).

  IR (K Br) γ max: 3400, 1750 and 1580 cm -1.

UV X max (H 20): 297 nm (c = 8994).

  On analysis, it is found that the product obtained has the formula

C 15 H 19 N 3045.2 H 20

  and the following values are obtained:

C H N

  calculated 48.25 6.09 7.79 found 47.96 5.83 7.89

EXAMPLE 11

  Preparation of 3- {2- (N-methylthiazolol) ethylthio} -6 a- {1- (R) hydroxy)

  ethyl-7-oxo-1-azabicyclo (3,2,0) hept-2-ene-2-carboxylate

SOC? 2

> (15 / e Cl r c

H 2 N J, NH 2

HC 1 i / Il H

2 HC 1 3

  2-mercaptomethylthiazole To a chloroform solution (30 ml) of (3.81 ml, 0.052 mol) thionyl chloride, 3.60 g (0.026 mole) of hydroxymethyl thiazole 1 are added at room temperature and the mixture is then heated. The chloroform was evaporated under vacuum to give a brown solid which was dissolved in 30 ml of absolute ethanol. 2.04 g (0.026 mol) of thiourea was then added. The mixture was then heated. at reflux temperature for 18 hours The precipitate is collected by filtration, washed with ethanol and with ether. 3.4 g is then obtained at 100 ° C. HNH Cl - (yield 55%) of the isothiouronium salt 3 This isothiouronium salt 3 is

  dissolved in 30 ml of water and purged by passing nitrogen for 20 minutes.

  1.10 g (0.027 mol) of sodium hydroxide are then added and the mixture is then heated to 100 for 2 minutes. The pH of the solution cooled to 0 is adjusted to 6 by addition of acetic acid and then extraction with (2 × 5 ml) of ethyl acetate The organic layer is dried over MgSO 4 and evaporated under vacuum to give 0.75 g (yield

  42%) of thiol 4 as a yellow oil which is used without

later.

  The physical properties are as follows: NMR (CDCl 3) δ: 2.1 (1H, t); 4.0 (2H, d, I = 10Hz);

  7.27 (1H, d, I = 3.0Hz) and 8.85 (1H, d, I = 3.0Hz).

OH r-d1)> -No (

_ _ O

O -, _____- Ci (o 0) 2

CO 2 GNP 3)

HS / /

4

J

I N

O 02 GNP

2

  p-Nitrobenzyl 3 - {(2-thiazole) methylthio} -6- {1- (R) -hydroxyethyl} -7oxy-

  1-azabicyclo (3,2,0) hept-2-ene-2-carboxylate

  To a cooled solution at 0 ° C. of 1.4 g (4.0 mmol) of

  In this case, 0.79 ml (4.4 mmol) of diisopropylethylamine and then 1.17 g (4.4 mmol) of diphenyl chlorophosphate under a nitrogen atmosphere are added in 8 ml of acetonitrile. The resulting solution is stirred. at

  For 30 minutes, p-nitrobenzyl 3- (diphenyl phosphate) is obtained.

  phoryloxy) -6- {1- (R) -hydroxyethyl} -7-oxo-1-azabicyclo (3,2,0) hept-2-ene;

  2-carboxylate To this solution is added a solution of 0.79 ml (4.4 mmol) of diisopropylethylamine in 2 ml of acetonitrile then 0.72 g

  of thiol solution 4 in 2 ml of acetonitrile The reaction solution

  The resulting mixture is stirred for 60 minutes at 0 ° C, then diluted in ml of ethyl acetate and washed with 30 ml of water, 20 ml of 10% aqueous H 3 P 04 and 30 ml of water. ml of brine Evaporation of the solvent dried over MgSO 4 leads to the obtaining of a crystalline solid which is triturated in ether; 782 mg (42% yield) of the title compound 6 is thus obtained as a white crystalline product; point

melting point: 158-160 ° C

  The physical properties are as follows: NMR (CDCl 3) d: 1.32 (3H, d, I = 7.0 Hz); 3.28 (3H, m); 4.20 (2H, m); 4.36 (2H, s); 5.40 (2H, q); 7.40 (1H, d, I = 4.0 Hz); 7.64 (2H, d, 1 = 8Hz);

  7.76 (1H, d, I = 4.0 Hz) and 8.24 (2H, d, I = 8 Hz).

  IR (K Br) ymax: 3500, 1770 and 1700 cm The analysis shows that the product obtained presents the formula

C 20 H 19 N 30652

  and the following values are obtained:

C H N S

  Calculated 52.05 4.50 9.10 13.89 Found 52.35 4.40 8.72 13.90 EH, F 5020, the

CO 2 GNP

2533568-

OH

02 GNP

Pd / C, H 2 FSO 03

OH 3

t O-i 8 CH H 3

  3- {2- (N-methylthiazolium) methylthio} -6- {1- (R) -hydroxyethyl} -7-oxo-1-

  azabicyclo (3,2,0) hept-2-ene-2-carboxylate To a solution of 782 mg (1.36 mmol) of compound 6 in 55 ml of methylene chloride was added 0.5 ml of methyl fluorosulfonate. then stirred the mixture for 90 minutes at room temperature The precipitate

  collected by filtration is washed with 30 ml of methylene chloride.

  This gives 630 mg of a crude quaternized thiazole 7 which is used for the subsequent step without this requiring

an intermediate purification.

  Thus, to a solution of compound 7 in 140 ml of tetrahydrofuran and ml of ether, 140 ml of a buffer solution of p H = 7.0 and then 600 ml of 10% palladium on carbon are added. The mixture is hydrogenated at 2 ° C. The mixture is then filtered and the catalyst is washed with water (2 × 10 ml). The washings and the filtrate are combined, extracted, and stirred for 1 hour in a Parr shaker for 35 minutes. using (2 x 150 ml) ether and freeze-drying to obtain a yellow powder This crude yellow powder is purified on a BONDAPAK C 18 reverse phase column (Waters Associates) (7 g) eluted with a solution of% acetonitrile in water at a pressure of 0.56 bar each fraction.

  15 ml pass is subjected to free-phase chromatography.

  high pressure fraction and fractions with ultraviolet absorption for Xmax 300 nm are collected and lyophilized. 23 mg (5% yield 1) of the title compound is thus obtained in the form of a solid.

yellow amorphous.

  The physical properties are as follows: NMR (D 20) 6: 1.28 (3H, d, 1 = 7.0 Hz); 3.12 (2H, d, I = 7.0 Hz); 3.44 (1H, dd, 1 = 1.0 Hz and 3.0 Hz); 4.20 (3H, s); 4.24 (2H, m); 4.76 (3H, m); 8.12 (1H, d, I = 4Hz);

and 8.24 (1H, d, I = Hz).

  IR (K Br) ν max: 3400, 1740 and 1580 cm -1

UV λmax (H20): 292 nmf (c = 7285).

r

CH - CH 3

EXAMPLE 12

  Preparation of 3- {1- (1- (RS) -methyl-N-methyl-pyridin-3-yl-methane thio} -6 ct

  {1- (R) -hydroxyethyl] -7-oxo-1-azabicyclo [3,2,0] hept-2-ene-2-carboxylate ## STR1 ## W 2) HS 27 H

| CH 3

_ _ -

C 02 GNP

  P-Nitrobenzyl-3- {1- (RS) methyl-pyridin-3-yl-methane thio} -60 - {1- (R) -

  hydroxyethyl-7-oxo-1-azabicyclo (3,2,0) hept-2-ene-2-carboxylate

  To a cooled solution at 0 ° C. of 1.85 g (5.3 mmol) of

  In this case, 754 mg (5.8 mmol) of diisopropylethylamine in 1 ml of acetonitrile is added to the keto intermediate in 20 ml of acetonitrile and then a solution of

  1.57 g (5.84 mmol) of diphenyl chlorophosphate in 2 ml of acetonitrile

  nitrile under nitrogen atmosphere The resulting solution is stirred for minutes at 0 ° C., then a solution of 750 'mg (5.8 mmol) of diisopropylethylamine in 1 ml of acetonitrile and then 814 mg (5.8 mmol) of the thiol is added thereto. The mixture is stirred at 0 ° C. for 2 hours, then the reaction mixture is diluted with 200 ml of ethyl acetate and washed with ice-cold brine (200 ml) and water (200 ml). )

  an aqueous solution of bicarbonate (100 ml), and brine (100 ml).

  Evaporation of the solvent dried over MgSO 4 leads to the production of a yellow oil which is purified by chromatography on a column of silica gel and then eluted with a mixture of 50% acetone and 50% chloride. methylene; 1.65 g of the title compound are thereby obtained.

of a yellow solid.

  The physical properties are as follows: NMR (CD C 13) d: 1.22 and 1.25 (3 H each, d, I = 7 I, 0 Hz); 1.46 and 1.50 (3H each, d, I = 7.2 Hz); 2.4-3.3 - (3H, m); 3.8-4.2 (3H, m); 5.35 (2H, A Bq, I = 14.5 Hz) and

7.2-8.6 (8H, m).

  IR (K Br) ν max: 3400, 1765 and 1690 cm -1.

25 26 27

  4- (1'-mercaptoethyl) -pyridine To a solution of 25 g of 1- (4-pyridyl) ethanol (prepared by the method described in J Chem Soc, Perkin II, 1462 (1974) -) in 100 ml of chloroform, 50 g of thionyl chloride is added. The mixture is kept under reflux for 2 hours Evaporation of the solvents under vacuum leads to the production of the chloro compound 26 in the form of a semi-solid which is used for next step without further purification

  to a solution of compound 26 in 160 ml of ethanol, a solution of

  14.4 g of thiourea in 75 ml of ethanol. The reaction mixture

  ? The ethanol is evaporated, the residue is dissolved in 100 ml of water and its pH is adjusted.

  at a value of 10 by addition of 2N NaOH, the mixture is stirred at room temperature

  room temperature for 90 minutes The pH is adjusted to 6.0 by addition

  of HCl, 6 N and extracted with (2 x 200 ml) of ether.

  poration of the solvent dried over MgSO 4 leads to the production of a yellow oil which is distilled under 5 mm of mercury and collected in the boiling range of between 60 and 65 ° C. 11.0 g are thus obtained ( yield

  38%) of the pure thiol 27 as a colorless oil.

  The physical properties are as follows: NMR (CD C 13) d: 1.79 (3H, d, I = 6.0 Hz); 2.05 (1H, d, I = 8.5 Hz); 4.20 (1H, t, I = 6.0 Hz, 5.8 Hz); 7.20 (2H, d, I = 6.2Hz);

and 8.5 (2H, d, I = 6.2Hz).

CH 3 I

  Co 2 PNB OH p H Pd / C r t H 2, \ H 3

  3- {1- (1- (RS) -methyl-N-methyl-pyridin-3-yl-methane thio} -6- {1- (R) hydroxy);

  ethyl-7-oxo-1-azabicyclo (3,2,0) hept-2-ene-2-carboxylate To a solution of 1.1 g (2.34 mmol) of compound 28 in 100 ml of acetone, 10 ml of methyl iodide are added. The reaction mixture

  The precipitate is collected for 18 hours at room temperature.

  The mixture is filtered off and washed with methylene chloride (10 ml) to give 1.4 g (100% yield) of the quaternized pyridine 29.

  is in the form of a yellow powder.

  The physical properties are as follows: NMR (DMSO-d 6) d: 1.10 (3H, d, I = 6.5 Hz); 1.62 (3H, d, I = 7.5 Hz); 2.6-4.2 (6H, m); 4.39 (3H, s); 5.42 (2H, A Bq, I = 16.6Hz) and 7.9-9.2 (8H, m).

  IR (K Br) ν max: 3400, 1770 and 1190 cm -1.

  On analysis, it is found that the product obtained has the formula C 24 H 26 N 30651 II and the following values are obtained:

C H N S

  calculated 47.14 4.29 6.87 5.24 found 47.19 4.78 6.11 5.41 To a solution of 1.45 g (2.37 mmol) of compound 29 in 120 ml of tetrahydrofuran and 120 ml of ether, 120 ml of a buffer solution at pH = 7.0 and then 1.5 g of 10% palladium-on-charcoal are added. The mixture is

  hydrogenated at a pressure of 3.15 bar in a Parr shaker

  The mixture is then filtered through a pad of Celite and the catalyst is washed with (2 x 15 ml) of water. The combined washings and filtrate are extracted with ( 2 x 100 ml) of ether and then lyophilized A yellow solid is obtained which is purified on a BONDAPAK C 18 reverse phase column (Waters Associates) (50 g) eluted with a 5% acetonitrile solution in the water at a pressure of 0.56 bar. Each passing 20 ml fraction is subjected to high pressure liquid chromatography and the fractions having an ultraviolet absorption for Xmax 300 nm are collected and lyophilized. mg (yield 24%) of the compound

  heading which is in the form of an amorphous yellow solid.

  The physical properties are as follows: NMR (D 20) 6: 1.32 (3H, d, I = 7.0 Hz); 1.63 (3H, d, I = 7.2 Hz); 2.5-4.6 (6H, m); 4.32 (3H, s) and 8.2-8.9 (4H, m)

  IR (K Br) νmax: 3400, 1750 and 1590 cm -1.

UV X max (H 20): 296 nm (E = 7573).

On analysis, it is found that the product obtained has the formula C 17 H 20 N 204 S111 / 2 HO 20 and the following values are obtained:

C H N

  Calculated 54.38 5.77 7.46 Found 54.39 5.98 7.68 -i OH

/ 1 2

fl.11-IC 2 GB r-. "CH 3

EXAMPLE 13

  Preparation of 3- (N-methyl-N'-benzyl imidazol-2-yl-methane thio) -6 c- {1-

  (R) -hydroxyethyl-7-oxo-1-azabicyclo (3,2,0) hept-2-ene-2-carboxylate SH 1) H 2 N-1-N-Ac 2) and OH, A HC 1 N benzyl-2-mercaptomethyl imidazole

  To a solution of 3.23 g (13.0 mmol) of the chlorinated compound 41 (pre-

  prepared by the method described in J Amer Chem Soc., 71, 383 (1949)} in

  ml of acetonitrile was added 1.72 mg (14.5 mmol) of N-acetylthiourea.

  The reaction mixture is heated at reflux temperature for 3 hours.

  The precipitate is collected by filtration and washed with acetonitrile (10 ml) to give the isothiouronium salt which is dissolved in 80 ml of absolute ethanol and heated at reflux temperature for 18 hours. hours under nitrogen atmosphere The reaction is cooled to room temperature, condensed under vacuum to about 30 ml of its volume and the precipitate is removed by filtration Evaporation of the filtrate under vacuum gives 3.5 g (yield 97%) of thiol 42 under

form of a thick yellow syrup.

  HC 1 4 N ci - The physical properties are as follows: t 4 NMR (CD C 13) 6: 2.1 (1H, t, I = 4.5 Hz); 3.80 (2H, s); 5.20 (2H, s) and

6.8-7.5 (7H, m).

OH 1)

I o Cl-P (O) 2 N 0: 2) / - t Co 2 GNP

-5 42

3

-

CO 2 GNP

2

  P-Nitrobenzyl-3- {N-benzylimidazol-2-yl-methane thio} -6? - (1- (R) -hydroxy)

  ethyl-7-oxo-1-azabicyclo (3,2,0) hept-2-ene-2-carboxylate to a cooled solution at 0 ° C. of 3.03 g (8.5 mmol) of the compound

  Keto intermediate 5 in 70 ml of acetonitrile, 1.17 g (9.0 mmol

  diisopropylethylamine in 2 ml of acetonitrile and then 2.4 g (9.0 mmol) of

  1) of diphenyl chlorophosphate in 2 ml of acetonitrile under atmospheric pressure.

  The resulting solution is stirred for 20 minutes at 0 ° C.

  then a solution of 1.17 g (9.0 mmol) of diisopropylethyl

  dissolved in 2 ml of acetonitrile and 4.8 g (15 mmol) of thio 42

  An additional 1.93 g (15 mmol) of diisopropylethylamine is added to the reaction mixture, which is then stirred for 2 hours at 0 ° C. The precipitate is collected by filtration and washed.

  With the aid of methylene chloride (20 ml) 2.5 g (yield

  55%) of the title compound which is in the form of a white solid. The physical properties are as follows: NMR (DMSO-d 6) 6: 1, 23 (3H, d, 1 = 7.2 Hz); 2.5-4.1 (6H, mi); 4.25 (2H, s); , (2H, s) 5.20 and 5.45 (1H each, d, I = 14.5Hz) and

6.9-8.3 (11H, m).

  IR (K Br) γ max: 3400, 1775 and 1690 cm -1

FSO 3 CH 3

IJ s 1 + CH 3

  3- (N-methyl-N'-benzylimidazol-2-yl-methanothio) -6 o - {1- (R) -hydroxy-

  Ethyl-7-oxo-1-azabicyclo (3,2,0) hept-2-ene-2-carboxylate

  To a solution of 1.76 g (3.3 mmol) of compound 43 in 1.1

  methyl chloride, 1.15 ml (13.4 mmol) of fluorosulphonate are added.

  Methyl fonate The reaction mixture is stirred for 2 hours at room temperature. The reaction is concentrated in vacuo to about 15 ml of the volume. The precipitate is collected by filtration and washed with methylene chloride (10 ml). 58 g (74% yield)

  quaternized imidazole 44 as a white solid.

  The physical properties are as follows: NMR (DMSO-d 6) 6: 1.15 (3H, d, I = 7.0 Hz); 3.2-4.4 (6H, m); 4.70 and 5.0 (1 H each, A Bq, I = 10.8 Hz); 5.24 and, 46 (1H each, A Bq, I = 14Hz), 5.50 (2H, s) and

7.4-8.4 (11H, m).

  IR (K Br) y max: 3500, 1770 and 1700 cm The analysis shows that the product obtained has the formula

C 28 H 29 N 40952 F

  and the following values are obtained:

C H N S

  calculated 51.48 4.47 8.67 10.20 found 51.84 4.52 8.65 9.87 To a solution of 1.11 g (1.71 mmol) of compound 44 in 100 ml + of tetrahydrofuran and 100 ml of ether, 120 ml of a buffer solution of p H = 7.0, then 1.0 g of 10% palladium-on-charcoal are added. The mixture is

  hydrogenated at a pressure of 3.15 bar in a Parr shaker

  45 minutes The mixture is filtered through a pad of Celite and the catalyst is washed with the aid of (2 × 10 ml) of water.

  the combined filter are extracted with (2 x 70 ml)

  Ther are then lyophilized. A yellow powder is thus obtained which is purified on a BONDAPAK C 18 column (Waters Associates) (40 g) eluted with a 10% aqueous solution of acetonitrile under a pressure of

0.56 bar.

  Each fraction of 15 ml that passes is subjected to a chromatography in

  liquid phase under high pressure and the fractions having an absorp-

  Ultraviolet irradiation for 300 nm max is collected and lyophilized. Thus, 305 mg (45%) of the title compound is obtained as a solid.

light yellow amorphous.

  The physical properties are as follows: NMR (DMSO) d: 1.40 (3H, d, 1 = 7.0 Hz); 2.9-3.4 (3H, m); 3.98 (3H, s); 4.0-4.2 (2H, m); 4.23 (2H, broad s); 5.57 (2H, s);

and 7.2-7.65 (7H, m).

  IR (K Br) y max 3400, 1760 and 1590 cm -1.

UV: umax (H 2 O): 299 nm (= 8507).

  On analysis, it is found that the product obtained has the formula

C 21 H 23 N 304 S 1 11 /: ZH 20

  and the following calculated values are obtained: 57.25 56.66 H, 94, 70 N 9.54 9.49 s 7.28 8.30 OH 1 12

EXAMPLE 14

  Preparation of 3- (2-methyl-N-methylpyridin-3-yl-methane thio) -6 and-{1 (R) -

  Hydroxyethyl J-7 oxo-1-azabicyclo (3,2,0) hept-2-ene-2-carboxylate Co 2 and LAH i to NCH 3 H CI s) HN) k NH 2 2) NaOH 2-methyl 3- Mercaptomethyl pyridine - H 3 The ester 12 is prepared by the method described in the review J Org. Chel, 21,800 (1956) To a cooled suspension (OC) of 2.86 g of lithium aluminum hydride in 50 ml of dry tetrahydrofuran was added dropwise a solution of 6.23 g (0.038 mol) of the ester 12 in 15 ml of tetrahydrofuran over a period of 15 minutes The mixture is stirred for 60 minutes at 0 ° C. and then 50 ml of ethyl acetate are added thereto. The precipitate is filtered and washed with the aid of saturated solution of ammonium chloride -The organic layer is dried over MgSO 4, filtered and evaporated under vacuum. 3.2 g (yield 70%) of hydroxymethylpyridine is thus obtained.

13 in the form of a yellow oil.

  The physical properties are as follows: NMR (CD C 13) of Compound 13 6: 2.46 (3H, S); 4.73 (2H, s); 5.1 (1H, broad) 7.2 (1H, dd, I = 8Hz); 7.8 (1H, dd, I = 8Hz, I = 1Hz) and 8.3 (1H, dd, I = 7Hz, I = 1Hz) and

8.3 (1H, -dd, I = 7 Hz, I = 1 Hz).

  A solution of 3.2 g (0.026 mol) of the alcohol 13 in 10 ml of

  a 15-minute period under a nitrogen atmosphere. The refrigeration bath

  The reaction is removed and the reaction is allowed to continue

  3 hours at room temperature All solvents are evaporated

  4 * under vacuum, which leads to obtaining a residue consisting of

  14 which is in the form of a brown solid which is used for

  the subsequent step without intermediate purification The raw solid

  plucked is dissolved in 30 ml of absolute ethanol. 2.5 g

  (0.032 mol) of thiourea and the mixture is heated at 65-70 ° C. for 18 hours.

  The mixture is cooled to room temperature The precipitate is re

  collected by filtration and washed with ethanol (20 ml) and ether (50 ml).

  30 g of the isothiouronium salt are thus obtained. This salt is dissolved in 10 ml of water and a solution of 640 mg (0.016 mole) of sodium hydroxide.

  in 10 ml of water is added under a nitrogen atmosphere. The reaction mixture

  It is heated at 100 ° C. for 2 minutes and then cooled to 0 ° C. and its pH adjusted to a value of 6 by adding acetic acid. the reaction mixture is extracted with (2 x 35 ml)

  Chloroform Evaporation of the chloroform dried over Mg SO 4 leads to the ob-

  941 mg (46% yield) of the thiol as a yellow oil. The physical properties are as follows: Thiol NMR (C 0 C 13) 5: 1.8 (1H, t); 2.60 (3H, S); 3.73 (2H, d, I = 0 Hz); 7, 13 (1H, dd, 1 = 8Hz); 7.57 (1H, dd, I = 8Hz) and

8.43 (1H, dd, I = 8 Hz, 3 Hz).

OH 5 OH

  ## EQU1 ##

15 H 16

  P-Nitrobenzyl-3- (2-methylpyridin-3-yl-methane thio) -6 L- {1- (R) -hydroxy)

  ethyl-7-oxo-1-azabicyclo (3,2,0) hept-2-ene-2-carboxylate

  To an O-cooled solution of 1.52 g (4.37 mmol) of

  In 5 ml of acetonitrile, 0.86 ml (4.80 mmol) of diisopropylethylamine were added, followed by a solution of 1.17 g (4.37 mmol) of

  diphenylchlorophosphate in 3 ml of acetonitrile under a nitrogen atmosphere.

  The resulting solution is stirred for 30 minutes at 0 ° C, which leads to the production of p-nitrobenzyl-3- (diphenylphosphoryloxy) -6 a- {1 (R) -hydroxy)

  ethyl-7-oxo-1-azabicyclo (3,2,0) hept-2-ene-2-carboxylate to this solution.

  a solution of 0.86 ml (4.80 mmol) of diisoporpylethyl is added.

  lamine in 2 ml of acetonitrile, then a solution of 940 mg (6.76 mmol) of the thiol in 2 ml of acetonitrile The reaction mixture is stirred for 60 minutes at 0 ° C. The precipitate collected by filtration is washed

  with 30 ml of ether, which gives 1.12 g (yield

  55%) of the title compound as a pale yellow solid; point

  melting point 186-188 C (with decomposition).

  The physical properties are as follows: NMR (DMSO-d 6) d: 1.20 (3H, d, I = 7 Hz); 2.60 (3H, S); 3.40 (min, 2H); 4.16 (m, 2H); 4.32 (2H, s); 5.16 (1H, d, I = 5Hz); , 44 (2H, q, 1 = 14Hz); 7.32 (2H, m); 7, 8 (2H, d, I = 8Hz); 8.36 (2H, d, I = 8Hz) and

  8.48 (1H, dd, I = 5.5 Hz, 1.5 Hz)

  IR (K Br) ymax: 3500, 1770 and 1750 cm The analysis shows that the product obtained has the fonula

C 23 H 20 N 3065

  and the following values are obtained: calculated C 58.83 58.63 H 4, 94 4.99

CH 30502 F

OH N 8.94 9.06 S 6.83 6.58 OH

F 50 (D

Pd / CH 2 I 1 I

  3- (2-methyl-N-methylpyridin-3-yl-methanothio) -6- (1-R) -hydroxyethyl} -

  7-oxo-1-azabicyclo (3,2,0) hept-2-ene-2-carboxylate

  To a solution of 697 mg (1.19 mmol) of compound 16 in 100 ml of methylene chloride, 0.5 ml (6.18 mmol) of fluorosulfonate is added dropwise at 10 ° C. over a period of 10 minutes. The mixture is stirred for 150 minutes at room temperature. The precipitate is

  collected by filtration and washed with 30 ml of methyl chloride

  Thus, 777 mg (yield 90%) of quaternized pyridine is obtained 17

in the form of a yellow solid.

  The physical properties are as follows: NMR (COC 13) of compound 17d: 1,20- (3H, d, I = 7Hz); 2.82 (3H, s); 4.36 (3H, s); 4, 16 (2H, m); 4.60 (2H, s); , (1H, m); 5.42 (2H, q, I = 14Hz); 7, 80 (2H, d, 1 = 8Hz); 8.04 (1H, dd, 1 = 7Hz, 6.5Hz); 8.32 (2H, d, I = 8Hz);

  8.64 (1H, d, I = 7.5Hz) and 9.08 (1H, d, I = 7.5Hz).

IR (K Br) νmax: 3500 and 1765 cm -1.

  On analysis, it is found that the product obtained has the formula

C 24 H 26 FN 3095

  and the following values are obtained:

C H N S

  Calculated 48.91 4.55 7.23 11.04 found 49.39 3.97 7.20 10.98 To a solution of 1.10 g (1 88 mmol) of compound 17 in 80 ml of tetrahydrofuran and 80 ml of ether, 80 ml of a buffer solution of pH 7.0 and 800 mg of 10% palladium-on-charcoal are added. The mixture is hydrogenated.

  under a pressure of 2.1 bar in a Parr shaker for 30 minutes.

  The mixture is filtered through a pad of Celite and the catalyst is washed

  with water (2 x 10 ml) The washings and the combined filtrate su-

  extract (2 x 100 ml) of ether and then lyophilize

  thus obtains a yellow powder which is purified on a chromato-

  HP-20 graphite eluted with water, then with a 5% aqueous solution of acetonitrile. Each 15 ml fraction that passes is subjected to high pressure liquid chromatography and the fractions ultraviolet absorption for Xmax 300 nm are collected and lyophilized. 614 mg (42% yield) of the compound are thus obtained.

  heading in the form of a light yellow powder.

  NMR (δ 20) δ: 1.28 (d, 3H, I = 7Hz); 2.86 (3H, s); 3.20 (2H, dd, I = 10Hz, 3.5Hz); 3.42 (1H, dd, I: 5.4 Hz, 3.5Hz) 4.20 (3H, m); 4.32 (3H, s); 4.35 (2H, s); 9.88 (1H, dd, I = 7.2 Hz, 6.5 Hz); 8.5 (1H, d, I = 8 Hz) and

8.70 (1H, d, I = 8 Hz).

  IR (K Br) y max: 3400, 1760 and 1590 cm.

UV X max (H 20): 298 nm (E = 8391).

  On analysis, it is found that the product obtained has the formula C 17 H 2 O N-2035, H 20 and the following values are obtained: C, 73, 50 calculated

EXAMPLE 15

  OH H, 46 6.05 CH 3 A Preparation of the A. / S isointer

N \ N

  Me a) Me O Tf b) NaOH aqueous solution c) OH d) H 2 / Pd-C

) 2 GNP

  0.58 ml (5.16 mmol) of methyltrifluoromethane sulfonate are -

  added dropwise to a cooled and stirred solution containing 590 mg (3.52 mmol) of 4- (methanethiolacetate) -1-methyl-1,2,3-triazole in dry methylene chloride (2 ml) under a brine atmosphere. After 30 minutes, the bath is removed, then after one hour the solvent is removed using a vacuum cleaner. The residual oil is dissolved in a few milliliters of water and the cooled solution in an ice bath. of sodium hydroxide (305 mg, 7.59 mmol) in a few milliliters of water is then added and the reaction is stirred for 0.75 hours. The solution is diluted to 25 ml by addition of water and the pH is adjusted to 7.5 by the addition of di-sodium hydrogen phosphate solid monohydrate. Then 14 ml of this solution (i.e., approximately N 7.65 7.74 S 8.74 8.68 Meole 1.9 mmol of triazolium thiol) are added to a refrigerated solution and

  stirred with enol phosphate (1.0 g, 1.72 mmol) in 10 ml of tetrahydrofuran

  hydrofuran (THF) The mixture is left stirring for 45 minutes (a deposit of crystalline material, probably Ha 2 HP 4 is formed during the development of the reaction). The suspension is sent to a pressure bottle using a small amount of THF (20 ml) and water (20 ml) 30 ml of ether and 1.0 g of 10% palladium on charcoal are then added and the mixture undergoes hydrogenation (under 2.8 bar during

  The organic phase is separated and washed with water (2 × 5 ml).

  The aqueous phases are combined, are filtered and the filtrate is concentrated.

  The yellow solution is then chromatographed (on a medium pressure reverse phase column, × 90 mm, H 20 as eluent), which leads, after freeze-drying, to a high vacuum (about 0.5 mm, 90 minutes).

  obtaining 315 mg of carbapenem slightly contaminated by some

  Magnesium is purified by high pressure liquid chromatography (Waters microbondapack C 18 column, 10 × 300 mm,

  multiple injections, the eluent being water), which leads to obtaining

  310 mg (57%) of the isomer A as a brown powder.

  The physical properties are as follows: 1 H NMR (D 20) 6: 1.23 (3H, d, I = 6.4 Hz); 3.10 (2H, d, I = 9.1 Hz); 3.24 (1H, q, I = 2.7, 6.1 Hz); 4.03-4.71 (10, m); 8.46 (1H, s);

IR (: 1760 cm -1.

  uv (phosphate buffer, p H 7.4, M = 0.05) X max: 296 (E = 7500).

  B Preparation of Isomer B and Isomer C OH a) Me O Tf, H H S Ac b) NaOH solution aqu use S Me 2 Me H E

P (O 4)

  (N probable structure) CO 2 GNP d) H 2 / Pd-C

  1.60 ml (14.0 mmol) of methyltrifluoroisulfonate sulfonate

  methane are added dropwise to an ice-cold solution of 1.20 g (7.0 mmol) of 4- (methanethiolacetate) -2-methyl-1,2,3-triazole in 6 ml of dry methylene chloride under a brine atmosphere. The mixture is allowed to return to room temperature and is stirred for 16 hours. A further amount of methyltrifluoromethane sulfonate (0.40 ml, 3.56 mmol) is added after 3 hours at room temperature. The residual oil is triturated with ether and the resulting gum is dissolved in 5 ml of water. The mixture is cooled on an ice bath and solution of

  844 mg (21.1 mmol) of sodium hydroxide in 5 ml of water is added thereto.

  After stirring for 45 minutes, the solution is diluted by addition of 60 ml of water and the pH adjusted to a value of 8 by addition of solid potassium dihydrogen phosphate phosphate. Next, 40 ml of this solution (approximately 4.7 mmol of the mixture). isomeric triazolium thiols) is added to an ice-cold solution of enol phosphate (2.0 g, 3.45 mmol) in ml of THF. The mixture is stirred over an ice bath for 30 minutes. after which he is transferred to a bottle

  resistant to pressure containing a suspension of 2.0 g of

  The mixture is hydrogenated (at a pressure of 2.8 bar) for one hour. The organic phase is separated and washed with 2 × 10 ml of water. The combined aqueous phases are diluted with 10% and 60 ml of ether. are filtered and

  the filtrate is concentrated under high vacuum (about 0.5 mm for 90 minutes).

  The resulting solution is then chromatographed (medium pressure reverse phase column, 45 × 130 mm, the eluent being water) to yield, after lyophilization, 595 mg of a mixture of carbapenem isomer

  which is contaminated by a little organic matter These materials are sepa-

  and proceeded to a purification by high pressure liquid chromatography (10 x 300 mm, Waters microbondapack C 18 column, multiple injections, the eluent being water), thus obtaining, in the order elution: isomer B: 153 mg (13% yield): RM Ni H (D 20) d: 1.23 (3H, d, I = 6.4 Hz); 3.12 (2H, q, I = 1.4, 8.9Hz); 3.39 (1H, q I = 2.7, 6.0 Hz); 4.07-4.68 (1 OH, m);

8.19 (1H, s).

IR (nujol): 1755 cm -1.

  UV (phosphate buffer, p H = 7.4, M = 0.55 x max: 296 nm (E = 6700), and the C isomer: 284 mg (24% yield): 1 H NMR (D 20): 1.23 (3H, d, H = 6.4 Hz), 3.15 (2H, q, I + 3.7, 9.0Hz), 3.37 (1H, q, 1 = 2, 6, 6.0 Hz), 3.95-4.65 (1 OH, m), 8.62 (1H, s), IR (nujol): 1750 cm -1

  UV (phosphate buffer, pH 7.4, M = 0.05) X max: 298 nm (c = 7,600).

EXAMPLE 16

  (5R, 6S) 6- (1R-hydroxyethyl) -3- (2-methyl-1,2,3-thiadiazolium-4-ylmethyl)

  thio) -7-oxo-1-azabicyclo {3,2,0} hept-2-ene-2-carboxylate OH s 2 A Ethyl 1,2,3-thiadiazol-4-ylcarboxylate o NH 4 and Et CH 3 / A solution of ethyl-N-carbethoxyhydrazonoproprionate (31.2 g, 0.154 mol) in 80 ml of thionyl chloride is stirred at 23 ° C. for 3 hours and heated at 70 ° C. for 20 minutes. The thionyl chloride is evaporated. and the residue is triturated in 40 x 30 ml of hexane The red solid obtained is dissolved in 150 ml of dichloroethane and the solution is washed with a saturated solution of sodium bicarbonate and then with water After drying over Na 2 SO 4, the solution is concentrated until the compound crystallizes After standing at 23 for a period of time, the crystals are separated by filtration; 16.8% of a compound having a melting point of 86 ° C. (69% yield) is thus obtained. The filtrate is concentrated and purified by chromatography on a gel column.

  silica, dichloromethane being used as the eluting solvent.

  This gives 317 g of a compound whose melting point is 86 C (13% yield) and having the following properties:

  1 C.D. Hurd and R. Mori, J. Am Chem Soc., 77, 5359 (1955).

IR (K Br) ν max: 1720 (ester) cm -1.

  1 H NMR (CDCl 3) δ: 1.52 (3H, t, I = 7.1 Hz, CH 3 CH 2 O); 4.57 (2H, q, I = 7.1 Hz,

  CH 3 CH 20); 9.47 (1H, s, H thiadiazole).

  Z 5 B 1,2,3-thiadiazol-4-ylmethanol 1 * SO and C'2 OH N -Li Al H 4 S s

  To a suspension of 18.35 g (0.116 mol) of 1,2,3-thiadiazol-4-yl-

  ethyl carboxylate in 400 ml of ether is added per part 2.47

  (0.065 moles) of lithium aluminum hydride over a period of one hour.

  The reaction mixture is stirred at 23 ° C. for 7 hours and then treated with 2.47 g (0.065 ml) of additional aluminum hydride.

  Lithium Stirring is continued for 24 hours before successive addition.

  1 ml of water (7 ml), 15% sodium hydroxide solution (7 ml) and water (21 ml). After stirring for 15 minutes, the ethereal solution is decanted and the gum undergoes extraction with (5 x 100 ml) ether The ether extracts are combined, dried over MgSO 4 and concentrated (5.4 g). The crude material is purified on a column of silica gel (120 g,

  4 x 16 cm), the ether being used as an eluting solvent.

  thus holds 1.3 g (yield 7%) of 1,2,3-thiadiazol-4-yl-carboxylate

  of ethyl and 2.45 g (yield 18%) of 1,2,3-thiadiazol-4-yl-methanole.

  The physical properties are as follows:

ir (film) vmax 3380 (OH) cm-1.

  1 H NMR (CDCl3) δ: 2.31 (1H, s, OH); 5.22 (2H, s, CH 2 O);

8.50 (1H, s, H thiadiazole).

  C 1,2,3-thiadiazol-4-ylmethanol methanesulfonate

CH 2 OH

N 1 is C 1 NH 20 Ms

N N

"3 'N And 3

S

  S.I. Ramsby, S. Ogren, S. B Ross and N. E. Stjernstrem, Acta Pharm.

  Succica, 10, 185-96 (1973); C A, 79, 137052 W (1973).

  A solution of 0.75 g (6.5 mmol) of 1,2,3-thiadiazol-4-yl-metha-

  in 15 ml of dichloromethane is cooled to 5 ° C. under a nitrogen atmosphere and treated with 1.18 ml (7.3 mmol) of triethylamine and 0.565 ml (7.3 mmol) of methanesulfonyl chloride. iced is removed and the reaction mixture is stirred for 2 hours.

  The solution is washed with (2 x 2 ml) a solution of hydrochloric acid

  1 N drique, then water and finally dried over Mg SO 4 + Mg O, then concentrated.

  The residue is purified by chromatography (column of silica gel, 1.5 × 21 cm), the solvent being constituted by ether.

  0.90 g (71% yield) of 1,2,3-thiadiazol-4-yl-methanol methanesulfonate.

  The physical properties are as follows: ir (film) v max: 1350 (502) cm 1172 (502) cm -1; 1 H NMR (CD C 13) δ: 3.09 (3H, s, CH 3), 5.75 (2H, s, CH 2); 8.72 (1H, s, H thiadiazole);

uv (CH 2 Cl 2) X max 251 (- = 1990.

  On analysis, it is found that the product obtained has the formula

C 6 H 6 N 2035

  and the following values are obtained:

C H N S

  calculated 24.73 3.14 14.42 33.02 found 24.78 3.09 14.66 31.94

  and 0.13 g (19% yield) of di- (1,2,3-thiadiazole) are also obtained.

  4-yl-methyl) ether, whose physical properties are as follows: ir (film) v max: 1272, 1242, 1200, 986, 805, 728 cm

  1 H NMR (CEC 13) δ: 5.16 (s, 4H, CH 2); 8.42 (s, 2 H 1, H 2 of thiadiazole).

  D 4-acetylthiomethyl-1,2,3-thiadiazole X CH 2 O MS CS Na N y -CH 2 SC 3 X ,, y N% s S s A solution of 1,2,3-thidiazol-4-yl -méthanolméthanesulfonate

  (0.9 g, 4.6 mmol) in 9 ml of tetrahydrofuran, a solution is added.

  aqueous solution (2 ml) of sodium thiolacetate (prepared from thiolacetic acid 0.38 ml, 5.3 mmol) and sodium bicarbonate (0.445 g, 3 mmol). The reaction mixture is stirred at 23 ° C. C. for one hour and then diluted in 75 ml of ether. The organic solution is washed with water (3 × 3 ml), dried over MgSO 4 and concentrated. The crude mixture is purified by chromatography on a gel column. of silica (134 x 19 cm) with a 50% ether solution in hexane was used as the eluting solvent. 0.60 g (75% yield) of the title compound was thus obtained. The physical properties are as follows: IR (film) ν max: 1657 (C = O) cm NMR 1 H (CD C 13) δ: 2.37 (3H, s, CH 3); 4. 58 (2H, s, CH 2); 8.44 (1H, s, H

of thiadiazole.

  On analysis, we see that the product obtained has the formula:

C 5 H 6 N 2052

  and the following values are obtained:

C H N S

  calculated 34.47 3.47 16.08 36.80 found 34.48 3.83 16.28 36.80 E 4-acetylthiomethyl-2-methyl-1,2,3-thiadiazolium trifluoromethanesulfonate and 4-acetylthiomethyl-3-methyl- 1,2,3-thiadiazolium trifluoromethanesulfonate

CH SÀCH BH 2 SCH 3 CH 25 ACH 3

  2 3 CF SO Me 3 SO 3 + "1 / d> 1 C CF 3503Nf 3

  To a solution of 0.60 g (3.44 mmol) of 4-acetylthiomethyl-1,2,3-

  thiadiazole in a mixture of 4 ml of ether and 0.4 ml of dichloromethane are added some crystals of the title compounds and 0.47 ml (3.6 mmol) of trifluoromethanesulfonate over a period of 5 minutes The reaction mixture is The white solid, which is a mixture of the two title compounds which are formed, is filtered and washed with ether to give 1.05 g.

(90% yield).

  The physical properties are as follows: Ir (K Br) v max: 1675 (C = O) cm 1 H NMR (DMSO-d 6) δ: 2.43 (3H, s, CH 3 COS); 3.33 (s, CH 3 over N-3); 4.57 (s, CH 3 over N-2); 4.66 (2H, s, CH 2); 9.55 (H on thiadiazolium N2);

9.66 (H on thiadiazolium N-3).

  a In the analysis, it can be seen that the product obtained has the formula

C 7 H 9 N 20453 F 3

  and the following values are obtained:

C H N S

  calculated 20.27 2.38 9.45 32.46 found 24.61 2.57 8.47 28.21 F 4mercaptomethyl-2-methyl-1,2,3-thiadiazolium trifluoromethanesulfonate and 4-mercaptomethyl-3-methyl- 1,2,3-thiadiazolium trifluoromethanesulfonate

* H 25 CH

Me 2 3

N S CF 3 SO 3

3 3

MHC 1, 6 N

%. CH SH Me- /; e F 3 + 3

N CF N / A

S 3 3

  A solution of a mixture of 4-acetylthiomethyl-2-methyl-1,2,3-

  thiadiazolium trifluoromethanesulfonate and 4-acetylthiomethyl-3-methyl-

  1,2,3-thidiazolium trifluoromethanesulfonate (1.05 g, 3.1 mmol) in ml of 6 N hydrochloric acid is heated at 65 ° C. under a nitrogen atmosphere for 105 minutes. The solvent is evaporated off under reduced pressure; a yellow syrup (0.91 g) is thus obtained, this compound is used as it is in the stage

  next, without the need for intermediate purification.

G. OH

L S?

p OP (O Ph)

N GNP

COOPNB

Me N CHH 25 H

-S CF 3s 3-

  p H 7 2% Pd / C Ether, THF, H 20 COO N - s - _

  A cold solution at 5 C of (5 R, 6 S) paranitrobenzyl-6- (1 R-hydroxy-

  ethyl) -3- (diphenylphosphono) -7-oxo-1-azabicyclo (3,2,0) -hept-2-ene-2-car-

  Boxylate (1.7 g, 2.92 mmol) in 10 ml of tetrahydrofuran is treated

  by a solution of a crude mixture of 4-mercaptomethyl-2-methyl-1,2,3-

  thidiazolium trifluoromethanesulfonate and 4-mercaptomethyl-3-methyl-

  1,2,3-thidiazolium trifluoromethanesulfonate (0.9 g) in a

  phosphate (p H 7.2, 0.3 M, 15 ml) and tetrahydrofuran (5 ml).

  The reaction mixture is stirred for one hour and the pH is maintained at 7.2 by addition of a 2N sodium hydroxide solution. The stirring is continued for an additional hour before addition of ether (50 ml) and 1 g of 10% palladium on carbon The reaction mixture is hydrogenated at 23 ° C. under 31.5 bar for 2 hours and filtered through a pad of Celite The organic phase is separated, diluted in 50 ml of ether and 20 ml of a phosphate buffer of pH 7.2 and 0.3 M, then hydrogenated with 2 g of palladium-on-charcoal for 2 hours at 3.5 bar. The aqueous phases are combined (those resulting from the first and second hydrogenolyses), washed at

  ether and purified by chromatography on Pre Pak 500-C 18, the water acts

  As an elution solvent, 0.22 g of crude material is obtained. The eluant water is repurified by high pressure liquid chromatography under high pressure, which gives 0.040 g.

  (yield 4%) of the title compound, after lyophilization.

  The physical properties are as follows: ir (K Br) v max: 3400 (br, OH); 1745 (C = O from B-lactam),

1580 (carboxylate) cm-.

  1 H NMR (D 20) δ: 1.23 (3H, d, I = 6.3 Hz, CH 3 CHOH); 3.04, 3.05, * 3, 16 (2H, m, H-4); 3.38 (1H, dd, I = 2.8 Hz, I = 6.0 Hz, H-6); 3.9-4.6 (2H, m, H-5, CH 3 CHOH), 4.51, 4.53 (2 "s", SCH 2); 4.61 (s, N CH 3);

  uv (H 2 O) λmax: 224 (e = 4345), 262 (e = 4980, 296 (c = 6885).

  180 (c 0.18, H 20); T 1 /, = 9.8 hours (measured at a concentration of 10-4 moles)

  in phosphate buffer of pH 7.4 to 36.8 ° C).

EXAMPLE 17

  Potassium 3- {5- (1-carboxylatomethyl-3-methyl-1,2,3-triazolium) methanethio}

  6, - {1- (R) -hydroxyethyl} -7-oxo-1-azabicyclo 3,2,0 hept-2-ene-2 carboxylate oj 4 _ co?

OHH H C 2

* C O (I) z N + Co

2 days

  1 e H Nx 1) The Ac SN \\ r i 2) Mscl / l And 3

KSCOCH 3

  ## EQU1 ## ## STR2 ##

2 H H OH

(b) '(b) o' ')' 2

CO 2 GNP

  c) H 2 / Pa-C 2.83 g (70.9 mmol) of lithium aluminum hydride are added

  in small portions to a stirred suspension of 1-methyl-

  1,2,3-thiazole-4-carboxylic acid (9.00 g, 70.9 mmol) (preparation of C Pederson method, Acta Chem Scand 1959, 13, 888) in 200 ml of dry THF The mixture is maintained with stirring at room temperature for 15 hours, after which an aqueous solution containing 20% hydroxide

  Sodium (20 ml) is carefully added in about 1 ml aliquots.

  The resulting granular suspension is filtered and the resulting solid

  is washed with additional (5 x 75 ml) THF.

  The solutions resulting from the washing of THF are combined and are then dried over MgsO.sub.4 and the solvent is removed therefrom. The residual yellow oil undergoes a so-called "flash" chromatography on a column of silica gel (90 × 35 mm) ( the portions of 100 ml of hexane, mixtures of ethyl acetate and hexane 1/1 and 1/3, and finally ethyl acetate and methanol 9/1 being used as eluent Thus, 3.18 g (40% yield) of 4-hydroxynethyl-1-methyl-1,2,3-triazole is obtained.

  in the form of a colorless oil.

  The physical properties are as follows:

  1 H NMR (CD C 13) δ: 4.07 (3H, s); 4.73 (2H, d); 7.52 (1H, s).

  IR (net): 3320 m-1 '3.82 ml (49.6 amoles) of methanesulfonyl chloride are added dropwise to a stirred, ice-cold solution of 4.67 ml (41.3 mmol) of alcohol and 7.47 ml (53.7 mmol) of triethylamine in 20 ml of chloride

  After 30 minutes, the solvent is removed and the solid

  The dual test is taken up in 30 ml of acetonitrile (7.06 g, 62.0 mmol) of thiol

  potassium acetate are then added and the suspension is maintained

  stirring at room temperature for 3 hours.

  addition of 3.0 g (26.3 mmol) of potassium thiolacetate is added

  and the suspension is stirred for an additional 16 hours.

  The resulting dark black suspension was then concentrated and 10 ml of water was added. The mixture was extracted with (5 × 40 ml) methylene chloride. The combined extracts were dried over

  Mg SO 4 and the solvent is removed The residual oil is chromatographed

  Flash chromatography on a column of silica gel (90 × 36 mm), the eluent being firstly formed of hexane and then of a mixture of hexane and ethyl acetate 1/1. 95 g (80% yield) of 4 (methanethiolacetate) -1-methyl-1,2,3-triazole as a solid

weakly colored in vi Dlet.

  The physical properties are as follows: NMRH (CDCl 3) d: 2.40 (3H, s); 4.10 (3H, s); 4.20 (2H, s); 7.53 (1H, s);

IR (nujol): 1675 cm-r.

  A solution of 1.00 g (5.85 mmol) of triazole and 1.48 ml (13.3 mmol) of ethyl bromoacetate in 10 ml of dry acetonitrile is heated at 60 ° C. for 90 hours under a vacuum. The solvent is removed and the residual oil is triturated in the presence of (4 x 65 ml)

  of ether. 1-Methyl-3- (ethyl carboxymethyl) bromide is thus obtained.

  4-methanethiolacetate-1,2,3-triazolium which is in the form of a

  brownish gum that is used directly.

  A cold solution of 0.66 g (12 mmol) of KOH in 5 ml of water is added to a stirred solution and cooled with ice, triazolium bromide in 20 ml of water. After 20 minutes, dilute to 35 ml and add a sufficient quantity of solid dipotassium phosphate acid so that the pH of the solution is brought to a value of about 8. To the mixture thus formed, an ice-cold solution stirred with enol phosphate is then added. in 35 ml of THF After 30 minutes, the mixture is transferred to a pressure-resistant bottle containing 35 ml

  of ether and 1.5 g of 10% palladium on carbon is hydrogenated under

  The organic phase is then separated and washed with water (2 × 5 ml). The aqueous phases are combined, filtered and the filtrate is concentrated under high vacuum. The residual material

  is chromatographed on a reversed phase column (35 x 120 ml) the water acts

  as an eluant Freeze-drying of the fractions containing the car-

  bapenem leaves 1.20 g of a green solid This one undergoes a

  new chromatography in a device manufactured by Waters said Prep.

  500 under HPLC (ie high pressure liquid chromatography) in a so-called Pre Pak 500 / C 18 column. A 2% aqueous solution of acetonitrile being used as eluent. Fractions containing carbapenem are combined and lyophilized The resulting product is

  again chromatographed by liquid chromatography under presumptive

  high voltage (a C 18 microbondapack column called Waters of 10 x 300 mm) -

  water being used as an eluent, which leads to obtaining after lyophilization of 190 mg (17% yield) of pure title compound

in the form of a pale yellow solid.

  The physical properties are as follows: 1 H NMR (D 20) 6: 1.24 (3H, d, I = 6.4 Hz); 3.07 (2H, at, I = 9Hz); 3.38 (1H, q, I = 2.7, 6.0 Hz); 4.02-4.30 (3H, m);

  4.29 (3H, s); 5.23 (2H, s); 8.52 (1H, s).

IR (nujol) 1750 cm

  UV (phosphate buffer, pH 7.4) λ max: 296 nm (E = 7520).

EXAMPLE 18

  Potassium 3- {4- (1-carboxylatomethyl-3-methyl-1,2,3-triazolium) -methane

  thio} -6? - {1- (R) -hydroxyethyl} -7-oxo-1-azabicyclo 3,2,0 hept-2-ene-2-

  carboxylate ## STR1 ## a) and OC 1, N and 3 b) Na BH 4

> O-N =) 2

P 43

HSCH 3

OH AH H CH c f l 2> \\

3 00 2

  ## STR5 ##

C 2 GNP

  2) 2 A mixture of 30.0 g (0.23 mmol) of ethyl azidoacetate and 14.3 ml

  (0.23 mmol) of propiolic acid in 75 ml of toluene is stirred at room temperature.

  The reaction remains slightly exothermic for 90 minutes.

  after which it rapidly becomes vigorously exothermic and the cooling of the ice bath becomes necessary When this phase HO N N '%, O 2 Et - e

  When exothermic is passed, the reaction mixture is heated to room temperature.

  After cooling for 30 minutes after cooling with an ice bath, a crystalline material is collected after filtration and washed with a little toluene. The crude material thus obtained (33.3.degree. 72% yield) consists of a single isomer. The physical properties are as follows: 1 H NMR (DMSO-d 6) d: 1.20 (3H, t, I = 7 Hz); 4.15 (2H, q, I = 7Hz, 42 (2H, s), 8.67 (1H, 3).

  this product probably consisting of 1- (ethylcarboxymethyl) -1,2,3-

  triazole-4-carboxylic by what we deduce from an analogy with

  previous works (see C Pederson, Acta Chem Scand 1959, 13, 888).

  A solution of 5.00 g (25.1 mmol) of carboxylic acid and 3.68 ml, 26.4 mmol) of triethylamine in 50 ml of dry methylene chloride is added to an ice-cold stirred solution of chloroformate. ethyl

  (2.52 ml, 26.4 mmol) in 50 ml of dry methylene chloride.

  Purple color is stirred for 30 minutes after which it is washed with 10 ml of water, dried over MgSO 4 and the solvent is removed. The crude mixed anhydride is dissolved in 50 ml of THF and slowly added to an ice-cold suspension of sodium borohydride

  (0.72 g, 18.9 mmol) in 50 ml of THF After stirring for 30 minutes,

  0.30 g (7.9 mmol) of further sodium borohydride is added and the reaction mixture is kept on an ice bath for one hour. Then 5 ml of water are added and after 10 minutes To the aqueous solution at 10% HCl 2 g of solid potassium carbonate are added, and the mixture is stirred. The organic phase is then removed and the white residual paste undergoes extraction. using an extra amount of THF

  The combined organic phases are dried over MgSO 4 and the solvent is removed.

  The flask chromatography on silica gel column and elution with hexane, ethyl acetate / hexane and finally ethyl acetate mixtures

  resulted in 2.04 g (44% yield) of 1- (ethylcarboxymethyl)

  4-hydroxymethyl-1,2,3-triazole as a crystalline solid.

  The physical properties are as follows: 1 H NMR (CD C 13): 1.28 (3H, t, I = 7 Hz); 4.23 (2H, q, I = 7Hz);

  4.75 (2H, s); 4.85 (2H, s); 7.73 (1H, s).

  4.11 g (20.8 mmol) of diisopropylazodicarboxylate are added dropwise to a solution cooled with ice of 5.47 g (20.8 mmol)

  of triphenylphosphine in 100 ml of dry THF under a nitrogen atmosphere.

14 E 5

  After 30 minutes, a solution cooled with ice-cream of 1.93 g (10.4 mmol) of alcohol and 1.49 ml (20.8 mmoles) of thiolacetic acid.

  in 50 ml of dry THF under a nitrogen atmosphere is added to said mixture.

  The mixture is then kept for 2 hours on an ice bath and then for another 12 hours at room temperature after which the

  solvent is removed The reaction mixture is chromatographed by chromatography

  silica gel flash matography (40 g, alution with 100 ml portions of hexane, then 5:%, 10%, and 50% ethyl acetate / hexane). The thiolacetate-containing fractions are combined and rechromatographed on 60 g of silica gel (elution with 200 ml portions of hexane and 5%, 5%, 5%, 5% ethyl acetate-hexane mixtures). % then of 22.5% ethyl acetate-hexane mixture, 25%, 27.5% up to

  %) 1.24 g (yield 49%) of 1- (ethylcarboxymethyl) are thus obtained.

  4-methanethiolacetate-1,2,3-triazole in the form of a crystalline solid whose physical properties are as follows: 1 H NMR 6: 1, 28 (3H, t, I = 7 Hz); 2.37 (3H, s); 3.87 (2H, s);

  3.90 (2H, q, I = 7Hz); 5.12 (2H: s) 7.63 (1H s).

IR (nujol) 1735, 17 mmol-1.

  and 1,409 of a material contaminated with triphenylphosphine oxide

  and 1.40 g of additional material contaminated with triphenyl ether.

  nylphosphine. 0.51 ml (4.53 mimoles) of methyltrifluoromethane sulfonate are added dropwise to a solution cooled with an ice bath

  and stirred with 1.0 g (4.12 mmol) of triazole in 5 ml of

  dry thylene The bath is removed after 30 minutes, then after another 30 minutes, the solvent is removed by suction under vacuum.

  a white solid which is suspended in 15 ml of water and the

  The mixture obtained is then stirred while being cooled by an ice bath.

  A solution of 0.69 g (12.4 mmol) of KOH in 5 ml of water is added and the reaction is stirred for one hour. It is then diluted to 30 ml by addition of water and then add solid dipotassium acid phosphate so that the p H is brought to an order value

  A 22 ml portion (i.e., about 3.0 mmoles of thiolcarbohydrate)

  xylate) of said solution is added to an ice cold solution and stirred with enol phosphate (1.60 g, 2.76 mmol) in 30 ml of THF. After 30 minutes, the reaction mixture is taken up and put under

  high vacuum to remove THF The yellow solution is then chromatographed

  on a reverse phase column (35 x 120 ml) and eluted with water and then with 100 ml portions of acetonitrile-water mixtures at 10-15% up to 30%. Suitable fractions give a p-nitrobenzyl ester as a yellow solid

  (930 mg) The whole is transferred to a pressure-resistant bottle.

  containing 25 ml of ether, 25 ml of THF and 25 ml of a phosphate buffer

  (prepared by diluting 1.36 g (0.01 mol) of monopotasic acid phosphate in 100 ml of water and adjusting the pH to 7.4 by adding a solution of

  45% aqueous solution of KOH) and 900 mg of 10% pailadié

  Generation is carried out under a pressure of 2.8 bar for one hour after which the organic phase is separated and washed with (2 × 5 ml) of water. The combined aqueous phases are filtered and then concentrated under high vacuum. residual solution is chromatographed on a column at

  reversed phase (35 x 120 ml) and eluted with water.

  In this way 1.21 g of a pale yellow solid is obtained. This is purified by high pressure liquid chromatography (10 × 300 mm, C 18 microbondapack column).

  Waters, water acting as an eluent); 480 mg is obtained

  41%) of the product under pure heading, showing the physical properties

  following: 1H NMR (D 20) d: 1.23 (3H, d, I = 6.4Hz); 3.11 (2H, d, I = 9Hz); 3.37 (1H, q, I = 3.0, 6.1 Hz); 4.02 (7H, m); , 18 (2H, s); 8.53 (1H, -s). IR (nujol) 1750 cm -1

  UV (phosphate buffer, pH 7.4) X max: 205 (c = 7810).

EXAMPLE 19

  3- {5- (1,4-dimethyl-1,2,4-triazolamine) methanethio} -6? - {1- (R) hydroxyethyl} -7-oxo-1-azabicyclo 3,2,0 hept -2-ene-2-carboxylate

OH-C 2

  1-methyl-5-methanethiolacetate-1,2,4-triazole i-N OH a) Ms C 1 / N and 3

, 3 'X'

b) CH 3 SH / N and 3 I

I I

3568

  0.46 ml (6.0 mmol) of methanesulfonyl chloride are added dropwise to an ice-cold stirred solution containing 565 mg (5.0 mmol) of 1-methyl-5-hydroxymethyl-1,2,4-triazole (RG Jones and C Ainsworth, J.

  Amer Chem Soc 1955, 77, 1938) and 0.91 ml (6.5 mmol) of triethyl

  After 20 minutes, an additional 1.05 ml (7.5 mmol) of triethylamine and then 0.53 ml (7.5 mmol) of thiolacetic acid are added and the mixture is added. stir during the 45

  The reaction medium is then diluted with methylene chloride.

  The aqueous phase is extracted with methylene chloride (3 × 5 ml) and the combined organic phases are dried over Mg 504 and the solvent is removed.

  column of silica gel leads to obtaining 570 mg of 1-methyl-5-

  pure methanethiolacetate-1,2,4-triazole, in the form of a yellow oil (in addition, an impure fraction (200 mg) is rechromatographed (by thin layer chromatography, so-called preparative and silica gel) which leads to obtain an additional 100 mg of pure material

(total yield 85%).

  The physical properties are as follows: 1 H NMR (CDCl 3): 2.38 (3H, s); 3.90 (3H, s); 4.25 (3H, s);

7.80 (1H, s).

  B 3- {5- (1,4-dimethyl-1,2,4-triazolium) -methanethio} -6? - (1- (R) -hydroxy);

  ethyl-7-oxo-1-azabicyclo (3,2,0) hept-2-ene-2-carboxylate OH

02 GNP

  d) a) 2 / Pd-C 1.20 ml (10.7 mmol) of methyl trifluoromethanesulfonate are added dropwise to an ice-cold solution containing 730 mg (4.27 mmol) of 1-methyl-5-methanethiolacetate. 1,2,4-triazole in 7 ml of chloride of

  methylene The reaction mixture is slowly brought to room temperature.

  1 35 bient over a period of 3 hours, after which it is concentrated

  residual is triturated in the presence of ether which leads to obtaining

  1.46 g of 1,4-dimethyl-5-methanethiolacetate-1,2,4-triazolium trifluoro-

  crude methanesulfonate which is used as is.

  A solution of 512 mg (12.8 mmol) of sodium hydroxide in 5 ml of water is added to a solution cooled with ice containing 1.45 g

  (4.35 mmol) of triazolium salt in 5 ml of water After 45 minutes, the

  The solution is then diluted to 25 ml by addition of water and the pH is brought to 7.6 by addition of solid potassium dihydrogen phosphate. The solution is then added to a stirred solution and cooled with phosphate ice. Enol (2.00 g, 3.45 minoles) in 25 ml of THF After 30 minutes, the reaction medium is transferred to a resistant bottle

  at the pressure containing 40 ml of ether and 2.0 g of 10% palladium on charcoal.

  The whole is hydrogenated at 3.1 bars for 75 minutes. The reaction medium

  is then diluted by the addition of 25 ml of ether and then undergoes a

  The organic phase is separated and washed with water (2 × 5 ml).

  The combined aqueous phases are washed with ether (3 × 25 ml) and then concentrated under vacuum. Column chromatography (reverse phase

  45 x 130 mm, water acting as eluent), followed by lyophilization

  fractions containing carbapenem leads to 650 mg

  of raw material This is rechromatographed, which leads to the ob-

  product content in pure form (450 mg yield 39%).

  The physical properties are as follows: 1 H NMR (D 20) 6: 1.24 (3H, d, I = 6.4 Hz); 3.19 (2H, q, I = 2.6, 9.2 Hz); 3.45 (1H, q I = 2.8, 690 Hz); 3.91 (3H, s); 4.06 (3H, s); 4.08-4.36 (2H, m);

  4.54 (2H, d, 1 = 2.8Hz); 8.71 (1H, s).

IR (nujol) 1755 cm -1.

  UV (phosphate buffer, pH 7.4) Amax: 294 nm (c = 8202).

  TI / 2 (phosphate buffer, pH 7.4, M = 0.067, T = 37 C) 9.1 hours.

EXAMPLE 20

  (1 R, SR, 6S) 3 - {(1,3-dimethyl-5-tetrazolium) methylthio} -6- (ihydroxyethyl) -7-oxo-1-azabicyclo {3,2,0} hept- 2-ene-2-carboxylate OHCN

3

  5-carbethoxy-2-methyletrazole and 5-carbethoxy-1-methyletrazole

CH 2 N 2

II -Co 2 And gold

N AN (CH 3) 2504

H (HS

N -N OE tNt N And + CH 3

-H%

  Methylation with diazomethane A solution of 9.17 g (0.064 mmol) of 5-carbethoxytetrazole

  (according to D Moderhack, Chem Ber, 108, 887 (1975) in 80 ml of ethyl ether.

  (the use of a mixture of ethanol and ether leads to the same

  portions of isomers) is cooled to 0 ° C and treated by addition, dropwise

  dropwise (in 15 minutes) of a solution of 3 g (0.071 mmol) of diazo-

  methane in 200 ml of ether The light yellow solution formed is stirred for 30 minutes and the excess diazomethane is destroyed by addition of

  1 ml of acetic acid. The evaporation of the solvent and the distillation of the

  sidu leads to a clear, clear oil whose point of

  The boiling point is 95-100 ° C. at 0.5 torr. 9.64 g are obtained (yield

  96%) of product of which 1 RMH indicates a mixture of 1-methyl isomers and 2-

  methyl in a ratio of 6/4 The separation of the two isomers can not be carried out by distillation or by liquid chromatography

under high pressure.

  The physical properties are as follows: ir (film) v max: 1740 cm (C = O ester); 1 H NMR (CD C 13) δ: 1.53 (3H, two t overlapping, I = 7.0, CH 2 CH 3); 4.46 and 4.53 (3 H, 2 S, 1-methyl CH 3 and 2-methyl tetrazoles, 6/4 ratio methyl of isomer 2

  being, in the lowest field, consisting of

  obtained in the lowest proportion).

  4.5 ppm (2H, 2q overlapping, CH 2 CH 3).

5-carbethoxy-2-methyltetrazole

N-N

i Co 2 And + t Co 2 And *

\ CH 3 CH 3

CH I C c 02 And CH -

3 / N

  A mixture of 5-carbethoxy-2-methyltetrazole and 5-carbethoxy-1-

  methyltetrazole (0.252 g, 1.61 mmol, ratio of two isomers 1/1) in 0.5 ml of iodomethane is sealed in a glass ampoule and heated at C for 15 hours, then at 130 ° C. for 6 hours. of the reaction mixture gives the title compound, in the form of a light yellow oil. Thus, 0.139 g (yield 55%) of a product whose boiling point is 95-100 ° C. at 0.5 torr is obtained.

(temperature of the air bath).

  The physical properties are as follows: ir (film) v max: 1740 cm (C = O ester); RM 1 H (CDCl 3) δ: 1.46 (3H, t, I = 7.0, CH 3 CH 2); 4.53 (3H, s, CH 3-2);

4.5 (2H, q, 1 = 7.0, CH 2 CH 3).

  2 Methylation with dimethyl sulphate A solution of 1.42 g (0.01 mol) of 5-carbethoxytetrazole in 20 ml of dry acetone is treated with anhydrous potassium carbonate (1.38 g; 01 mol) and dimethyl sulphate (1.26 g, 0.01 mol) The mixture is heated at reflux temperature for 12 hours The carbonate is filtered and the solvent evaporated under reduced pressure The residue is diluted with 30 ml of dichloromethane washed with 10 ml of bicarbonate

  saturated sodium, 10 ml of brine and then dried over anhydrous sodium sulphate.

  Evaporation of the solvent and vacuum distalization lead to the ob-

  a clear oil 1.45 g (93% yield) with a boiling point

  the ratio is 85-110 C at 0.5 torr 1 RMH indicates the presence of two

isomers in a ratio 1/1.

  B 5-hydroxymethyl-2-methyltetrazole

* 3 N S

  c H 3 C C Et + Li O 4 H 1 By reducing the ester mixture

  A mixture of 5-carbethoxy-1-methyltetrazole and 5-carbethoxy-2-

  methyltetrazole (6/4 ratio) (7.60 g, 0.049 mol) in 50 ml of tetra

  dry hydrofuran is cooled to 0 ° C. and treated with 1.06 g (0.049 mmol) of lithium borohydride added in small portions over 15 minutes. The mixture is kept at 10 ° C. for 30 minutes of addition and is then stirred at 20 ° C. for 4 hours. The mixture is cooled to 0 ° C. and the excess of hydride is carefully destroyed by addition of 6 N HCl (p H of 7 after no more gas evolution). The solvent is concentrated under vacuum and the residue oily diluted with 200 ml of dichloromethane, washed with 10 ml of brine and finally dried over Na 2 SO 4 The concentration of the solvent and the distillation of the residue under vacuum lead to 1.83 g (33% yield) of a clear oil RM 1 H of this material shows that the product is -hydroxymethyl-2-methyltetrazole. 2 By reduction of 5-carbethoxy-2-methyltetrazole to a solution of 5-carboxy-2-methyltetrazole (0.139 g, 0.89 g)

  mmole, obtained by isomerization of the ester mixture with the metal iodide

  thyl) in 1 ml of 10% dry tetrahydrofuran, solid lithium borohydride (0.019 g, 0.87 mmol) is added slowly to the mixture

  to room temperature and stirred for 4 hours. Excess borohydride

  The solid is destroyed by careful addition of HCl 6 N to OC (p H 7). The solvent is evaporated and the residue dissolved in 25 ml of dichloromethane and dried over anhydrous sodium sulfate. Evaporation of the solvent gives the title compound presenting in the form of a clear oil.

  0.092 g (91% yield) of a product having a boiling point of 90-

   C under 0.5 torr with decomposition.

  The physical properties are as follows: ir (film) v max: 3350 cm -1 (

  RM 1 H (CD C 13) δ: 4.4 (2H, s, CH 3-2); 4.93 (2H, s, CH 2-5).

  C 5-Acetylmercaptomethyl-2-methyltetrazole) F20 H 1) 1 C 1, and 3 N

CH OH 2) CH 3 COSKC 25 A 3

/ N CH 3

CH 3) -N

  To a solution of 1.83 9 (11.7 mmol) of 5-hydroxymethyl-2-methyl-

  Tetrazole in 25 ml of dry dichloromethane was added 1.47 g (12.9 mmol) methanesulfonyl chloride, then 1.30 9 (12 mmol) detriethyl

  amine, drop by drop, over a period of 5 minutes The mixture is stirred.

  at OC for one hour, then treated with a solution of 1.60 g (14.0 mmol) of potassium thioacetate in 10 ml of dry N, N-dimethylformamide. The resulting gel is stirred at 0 ° C. for 3 hours. diluted with 200 ml of dichloromethane, washed with 20 ml of brine and dried over anhydrous sodium sulfate Evaporation of the solvent in vacuo and chromatography of the resulting oil on silica gel (2 x 15 ml, dichloromethane and the 5% acetone dichloromethaneacetone mixture being used as the eluent) leads to the title compound which is in the form of a clear oil. 1.31 g (yield

%) of the title compound.

  The physical properties are as follows: ir (film) vmax: 1696 cma (C = O thioester); RM 1 H (CDCl 3): 2.43 (3H, s, S Ac); 4.36 (3H, s, 2-CH 3);

4.38 ppm (2H, s, 5-CH 2).

  D 5-mercaptomethyl-1,3-dimethyltetrazolium trifluoromethanesulfonate 1 v C 35 O 3 CH

CH SAC CFSO

  I> Bsac 3 -, CH 3 / c H 3 CF 350 Na OH 3 3

-4 CH SH

CH 3

  A solution of 0.400 g (2.32 mmol) of 5-acetylmercaptomethyl-2-

  methyltetrazole in 3 ml of dry dichloromethane is treated with 0.76 g

  (4.64 mmol) of methyltriflate and stirred at 22 ° C. for 16 hours.

  poration of the solvent under vacuum leads to the production of a red oil.

  The salt is dissolved in cold oxygen-free water (5 ml) and is

  then treated with 0.8 ml (3.2 mmol) of 4 M sodium hydroxide.

  The mixture is stirred at 0 ° C. for 40 minutes and then diluted with 7 ml of water, then its pH is adjusted to 7.3 by addition of KH 2 PO 4 saturated solution.

  resulting limpid is maintained under a nitrogen atmosphere and used -

  immediately for the next step.

  E (1 'R, SR, 6S) 3- {1,3-dimethyl-5-tetrazolium) -methylthio} -6- (1-, hydroxy-

  ethyl) -7-oxo-1-azabicyclo (3,2,0) hept-2-ene-2-carboxylate OH

3 3 3

002 P 2 + 2 HH 25 H

CO GN

2 CH 3

OH OS

X SCH 2 N

CO 2 GNP 3

Cs 2 Q OH N l CH 3

2 SH N

CH 3

  CO 2 * A solution of 0.915 g (1.58 mmol) of enol phosphate in 8 ml of tetrahydrofuran is cooled to 0 ° C and treated dropwise by the addition of a solution of 5-mercaptomethyl-1,3-dimethyltetrazolium trifluoromethanesulfonate (2 32 mmoles prepared above) over a period of 20 minutes The pH of the reaction mixture remains stabilized at 6.5 during the addition. After 20 minutes more, the pH of the solution is

  adjusted to 7.0 by addition of a saturated solution of sodium bicarbonate.

  The mixture is transferred to a hydrogenation bottle in which it is diluted by addition of 10 ml of THF, 20 ml of ether and 20 g of

  carbapenem is hydrogenated on activated charcoal at 10% palladium

  dium under a pressure of 3.1 bar while the temperature is slowly

  increased to 22 ° C in 90 minutes The catalyst is separated by filtration.

  The aqueous phase is washed with 20 ml of ether and kept under vacuum for 5 minutes. The mixture is washed with 5 ml of cold water and then with 20 ml of ether.

  minutes to eliminate all traces of organic solvent The chromatogra-

  on a column called Pre Pak 500 / C 18 and elution with water leads to the title compound which, after freeze drying as a

  white powder gives 0.266 g (49% yield), presenting the

  following properties: {} D 23 + 130 (c 1.04, H 20); UV (H 2 O), pH 7.4) λ max: 294 nm (s = 7500); ir (K Br) ν max: 1755 (C = O from ε-lactam), 1600 cm -1 (broad, C = O carboxylate);

  RM 1 H (D 20) δ: 1.24 (3H, d, I = 6.4 Hz, CH 3 CHOH), 3.0-3.3 (2H, m, H-4);

  3.42 (1H, dd, I = 5.8, I = 2.9, H = 6); 4-4.42 (2H, m, H-5 and CH 3 CHOH), 4.34 and 4.57 (2 x 3H, 2S, CH 3-1 and 3 of tetrazole);

4.49 and 4.51 (2H, 2S, CH 25).

  The product has a half-life (period of 10.5 hours at 37 C (c

  -4 M in a phosphate buffer of pH 7.4).

EXAMPLE 21

  Another process for preparing 3- (N-methylpyridin-2-yl-methanethio) -6 a-

  {1- (R) -hydroxyethyl} -7-oxo-1-azabicyclo {3,2,0} -hept-2-ene-2-carboxylate OG Gl

C O CH 3

  2 3

AT.

  C 2 C O3 + CE 3 G

  In a 2 liter flask equipped with a magnetic stirrer and Vigreaux column for distillation, a heating jacket and under an atmosphere, 432 ml (4.0 moles) of acetoacetate are added. of methyl and 464.6 g (8.0 moles) of allyl alcohol. The reaction mixture is distilled for 12 hours at 92 ° C. 136 ml (2.0 moles) are then added.

  of allyl alcohol and then the mixture is distilled for 23 hours.

  It is then added 136 ml (2.0 moles of allyl alcohol, then it is subjected to an additional distillation for 16 hours The mixture

  The reaction mixture is then distilled under vacuum and the product collected at 105.degree.

   C under 35 ml of mercury is thus obtained 414 g of allyl acetoacetate

(73% yield).

  To a solution of 226.5 g (1.594 moles) of allyl acetoacetate in 3 liters of acetonitrile and 243.4 ml (1.753 moles) of triethylamine was added 345.3 ml. (1.753 moles) of Ptoluenesulphonyl azide over a period of one hour while maintaining the temperature at about 20 ° C. using a cooling bath. The reaction mixture turns yellow. The reaction mixture is then stirred at room temperature under an atmosphere of The mixture is concentrated on a rotary evaporator. The residue is dissolved in 2.6 liters of diethyl ether and 800 ml of a 1 M aqueous KOH solution. The organic phase is washed five times at room temperature.

  using 1 M KOH (500 ml) and is taken up with brine (400 ml).

  After drying over MgSO 4 and concentrating on a rotary evaporator (temperature

  at 30 ° C), 260.2 g (97% yield) of the title compound are obtained.

C.

o t If 4-

2 O 2

N 2 N 2

  To a stirred suspension of 203 g (1.195 moles) of allyl diazoacetoacetate in 2 liters of methylene chloride and 190 ml (1.434 moles)

  of triethylamine at 5 ° C., 302 ml (1.315 mole) of t-butyldimethyl

  silyl triflate over a period of 45 minutes The mixture is agitated during

  one hour at 5 C, then for an additional hour without

  The reaction mixture is washed four times with 500 ml.

  of water, then taken up with 500 ml of brine.

  on Na 2 SO 4 and concentrated to a volume of 344 g where it is obtained in the form of an orange oil This oil is used directly in the stage

higher.

D. o Si + i

OCOCH 3 X

H 2

O Zn C 12 osi + N

H O

  To a mixture of (R, 3 R, 4 R) -3- (1-tert-butyldimethylsilyloxyethyl)

  4-acetoxy-azetidin-2-one (28.7 g, 0.1 mol) and freshly melted Zn C 12 (6.8 g, 0.05 mol) in CH 2 C 12 sec (700 ml) is added , dropwise, a solution of allyl-2-diazo-3-tert-butyldimethylsilyloxy-3-butenoate (33.84 g, 0.12 mol) in CH 2 Cl 2 (50 ml) over a period of 5 hours The mixture is stirred at room temperature for 2 hours, after which it can be seen that the thin layer chromatography shows the presence of a

  small amount of residual starting material An additional amount

  The mixture of allyl-2-diazo-3-tert-butyldimethylsilyloxy-3-butenoate (4.23 g, 0.015 mol) in 10 ml of CH 2 C 12 is added over a period of one hour and stirring is continued. room temperature for 10 hours The reaction mixture is then diluted in 750 ml of ethyl acetate, washed twice with 300 ml of a saturated solution of Na HCO 3, then with 300 ml of brine), dried over MgSO 4 and evaporated. 62.5 g of a dark organ oil are thus obtained which are dissolved in 500 ml of methanol and then treated with 1N aqueous HCl solution (110 ml). The resulting mixture is stirred at room temperature for 2 hours after which time it is

  10 ml of 1 N HCl are added, followed by stirring for an additional 2 hours.

  The reaction mixture is concentrated to half its volume and poured into a mixture of 800 ml of ethyl acetate and 800 ml of water. The organic phase is separated, washed with 800 ml of water and extracts

  A combined aqueous solution is washed with 400 ml of ethyl acetate.

  organic lines are combined, washed with (2 x 400 ml)

  brine, dried over MgSO 4 and concentrated to a volume of 32 g of a red, dark orange oil Flash chromatography gives 9.33 g (33% yield) of the title compound which is in the form of of a golden yellow oil which, when solidified, is in the form of

a light yellow solid.

  The physical properties are as follows: 1 H NMR (CD C 13) d: 6.20-5.72 (m, 2H); 5.48-5.21 (m, 2H); Δ 4.74 (dt, I = 5.8, I '= 1.2 Hz); 4.303.88 (m, 2H); 3.30-3.20 (m, 2H); 2.89 (dd, I = 7.3, I '= 2.1, 1H);

  2.18 (s, 1H); 1.32 (d, 1 = 6.2, 3H).

E. O Si + N OH o S 2

I-M 2

H 2 N

  A mixture of 9.2 g (32.7 mmol) of the u-diazo ester prepared in step D above and of rodium acetate (Rh 2 (OAc) 4) in benzene were added. The solution is treated with activated charcoal and filtered through a pad of Celite. The buffer is washed with 100 ml of hot benzene. The concentration of the filtrate gives 8 , 08 g (97% yield) of the compound

  section which is in the form of a light brown crystalline solid.

  The physical properties are as follows: 1 H NMR (CD C 13) d: 6.15-5.68 (m, 1H); 5.45-5.18 (m, 2H) 4.71-4.60 (m, 2H); 4.40-4.05 (m, 2H); 3.17 (dd, I = 7.1, I '= 2.0, 1H); 2.95 (dd, I = 6.9, I '= 18.9, 1H); 2.42 (dd, I = 7.6, I '= 18.8, 1H); 1.88 (s, 1H);

1.39 (d, I = 6.3H).

F OH

I

Y O

o N ECOT * 2 OH

"35 <

  To a solution of keto ester prepared in step E (7.5 g, 0.03 g)

  mole), 6.08 ml (0.035 mole) of

  propylamine and then diphenylphosphoryl chloride After 15 minutes, the

  Thin layer chromatography shows that there are no

  To the reaction mixture is then added 6.26 ml (0.036 mole) of

  isopropylamine and a solution of 4.5 g (0.036 mol) of 2-mercaptomethyl-

  pyridine freshly distilled in 5 ml of acetonitrile After stirring at 0 ° C. for 2 hours, the mixture is poured into ethyl acetate

  (1 liter), then washed with water (2 x 150 ml) of a saturated solution

  Na HCO 3 (150 ml), water (150 ml) and brine (250 ml). The organic phase is dried over Mg 504 and concentrated. An orange-yellow gum is obtained. Flash chromatography leads to The product is dissolved in diethyl ether and cooled to 0 ° C. Filtration gives 4.8 g (44% yield) of composed in section, purified,

  presenting in the form of creamy colored crystals.

  The physical properties are as follows: 1 H NMR (CD C 13) 6: 8.6-8.4 (m, 1H); 7.85-7.15 (m, 3H); 6.20-5.74 (mni, 1H); 5.54-5.15 (m, 2H); 4.80-4.66 (m, 2H); 4.29-4.03 (m, 1H); 4.19 (s, 2H);

  3.69-2.85 (m, 1H); 2.97 (s, 1H); 1.32 (d, I = 6.2, 3H).

G OH

O OH

CO 2 K

  5 335 N 8 To a solution of the allyl ester prepared in step F. (1.79 g, 4.97 mmol), tetrakistriphenylphosphine palladium (175 mg, 0.15 mmol) and triphenylphosphine (175 mg 0.67 mmol) in 25 ml of CH 2 Cl 2, a solution of potassium 2-ethylhexanoate (1.085 g, 5.96 mmol) in 12 ml of ethyl acetate is added after stirring at room temperature. for one hour, the thin layer chromatography shows that a trace of starting material The reaction mixture is diluted with 150 ml of anhydrous diethyl ether and the precipitate is collected

  by filtration, washed with ethyl acetate and then with ether.

  A light brown solid is thus obtained. This is dissolved in 10 ml of water and purified by reverse phase chromatography. 1.85 g of the title compound, which is in the form of a cream-colored solid, is thus obtained. It undergoes a new purification by suspension in acetone. 1.47 g (83% yield) of

  pure heading compound.

  The physical properties are as follows: 1 H NMR (D 20): 8.45-8.36 (m, 1H); 7.92-7.22 (m, 3H); 4.78-3.91 (m, 2H); 4.69 (s, 2H); 3.34-2.71 (m, 3H);

1.19 (d, I = 5.4, 3H).

H OH

OH t N 02 K OH N o (CH 3

O 2

  27.6 mg (0.16 mmol) of toluenesulfonic acid are added to a

  O-cooled suspension of 6-hydroxyethyl-2- (2-pyridylmethylthio) -

  potassium carbapenem-3-carboxylate (53.8 mg, 0.15 mole) in 2 ml of

  The mixture is stirred at 0 ° C. for 20 minutes and then treated with 0.02 ml of methyl triflate. After stirring at 0 ° C. for 60 minutes, LA-1 resin is added, followed by 6 ml of hexane. The mixture is then subjected to stirring. extraction with (4 x 0.5 ml) water and the combined aqueous phases are purified by high pressure liquid chromatography in a reverse phase apparatus, resulting in 10 g of i

composed in section.

EXAMPLE 22

  Preparation of 3- (N-methylpyridin-2-yl-methanethio) -6- {1- (R) -hydroxy)

  Ethyl-7-oxo-1-azabicyclo {3,2, Olhept-2-ene-2-carboxylate in a process known as a single pot "

OHH H

NOT

2

CF SQ

OH CH 3 3

  Q S Ac i 3 HC Nil Na OH OOC, 45 hand and N (i Pr) H 0, O 0 C, i h.

OH CH 3 (

0 CF 35 O 3

OP (00) 2 SH

O O O PNB

TF

OH CH

O V 9: 2 GNP

  H 2 Pd-C 100% $ C 2 hrs. OH A Preparation of enol phosphate (2) OH y HHH (oX) 2 PNB A solution cooled with ice ketone 1 (3 g, 8.62 mmol) in 30 ml of acetonitrile is treated with 9 mmol (1.04 eq, 1.57 ml) of ethylisopropylamine (addition time about 2 minutes) and 9 mmol (1.04 eq, 1.87 ml) of chlorodiphenyl phosphate (duration of addition about 2 minutes) The reaction mixture is stirred for 45 minutes and the thin layer chromatography (ethyl acetate and silica gel) shows the disappearance of acetone 1 The solution is diluted by addition of 60 ml of ethyl acetate, then washed with (2 x 50 ml) cold water and brine and finally dried over sodium sulphate and concentrated (bath temperature below 20 ° C.) A foam is thus obtained which

is used as is.

  E 9 PNB B Preparation of thiol (4)

CH CH

  T f C + NCH 3 1) NaOH / H 20 CH 3 Q XS Ac 0.1 ho Q SH

2) KH 2 PO 4

3 4

  A solution cooled with ice of thioacetate 3 (3.31 g, mmol) in water purged with a stream of nitrogen for 5 minutes is added dropwise (for about 5 minutes) of cooled solution of sodium hydroxide (1.75 eq 17.5 mmol, 0.7 g) in 8 ml of water The mixture turns yellow After 75 minutes under a nitrogen atmosphere,

  the pH is adjusted to a value of 7.4 with the aid of an aqueous solution of

  The reaction mixture is diluted with 15 ml of water.

  aqueous solution of thiol 4 (50 ml, 0.2 mmol / ml) is used as it is.

C coupling

OH 4

Y _ _ _ _ _ _ _

p "U THF-H 2 O 2 p H 6 5-7 5

C 2 GNP

22 O%

C 02 GNP

  An ice cooled solution of compound 2 (crude,

  prepared in step A, 8.62 mmol) in 50 ml of tetrahydrofuran is treated dropwise with an aqueous solution of thiol 4 prepared in

  Step B (in 5 ml of solution, every five minutes) during the

  development of the reaction, the pH of the reaction medium is maintained at a value of the order of 6.5-7.5 (preferably of the order of 7) by addition of a 2N sodium hydroxide solution cooled The reaction is monitored by thin layer chromatography:

$ 3568

  (a) on silica gel and ethyl acetate as solvents; (b) in an Anatech RPSF reverse phase column, CH 3 CN-, of p H 7

as a buffer (4/6).

  At the end of the reaction, 1.15 eq of thiol are added (50 ml of solution). The reaction is complete after one hour at 0 ° C and the mixture is used as it is for the hydrogenation step, after which

  p H has been set to a value of about 7.

  D Hydrogenation CH H 45 psi 2 "XS 'i 3 H 2 / Pd-C 10% QN THF-H 20-ether 0 0 C, 2 hrs C 02 CBN, 2 hrs

5, _, OH

  The reaction mixture containing compound 5 (prepared in C) is

  transferred to a Parr flask with 10 ml of THF, 10 ml of a phos-

  (7.01 M), 75 ml of ether and 5 g of 10% palladium on carbon.

  The mixture is hydrogenated under a pressure of 3.1 bar at a temperature of 3 to 10 hours for 2 hours. Next, the catalyst is filtered and washed with (3 × 10 ml) of water, and then the pH is adjusted to 6.2 carefully using cold 2N NaOH Ether is then added and the aqueous phase is separated and washed again with ether The aqueous phase is purged of any organic solvent under empty, and then purified on a Bondapack C 18 column (100 g, 4.5 x 13 cm) using cold distilled water.

  light yellow fractions containing the product (determined by U V and chroma-

  thin layer graphing) are lyophilized. 1.46 g (60% yield) are thus obtained; (yield calculated from bicyclic acetone)

  Couiposed 6 as a yellow powder.

  The physical properties are as follows:

X 293; c = 9000; X 271; a = 11064.

2533568-

EXAMPLE 23

  By operating according to the same methods as those of Examples 1 to 4, the following carbapenems are produced from the intermediates of formula (2).

-CH 2-

-CH 2 CH 2-

G-R

N- 11 CH 3

- / G \ '- CH 3

-CH - CH 3 CH

352 3 d-CH 2-

  OH (R) OH (R) Ex No. 23 to 23 b 23 c 23 d CH

-CE, CH -

z 2 23 nd H 2 CH 2 CH 3

CH 3 OE)

-CH 2-

23 f

-CH 2-

23 g 23 h

-CH 2-

23 i

-CH 2-

-CH 2-

23 to 23 k

-CH 2-

CH 3 -uri- CH c 11, 2 N

NL '

9 'l CH 3 23 m H 3 N CH 3

CH E)

3 N CH 3

T -ST CH 3

N (D 1 Uh 3

-2 H 3

23 N - CH 2 H C

3

  23 o -CH N 'mixture 23 o -CH 2 -de 3 ÄCH 3 possible isomers

23 p -CH 2 N-

2

N 23 g -CH 2 H 3

* 111

23 r -CH 2-

CH-COOP

  C 2 23 S -CH 2 i CJ 3 3023 t -CH 2 -H

EXAMPLE 24

  Following the procedure generally described for Examples 1 to 20, the following carbapenems are produced from: ## STR5 ## the G G_ 5 RN 3 G + - CH 3

CH 3 (D H 3

'Z N A

-CH 2-

24 b

-CH 2 CH 2-

24c

-CH 2-

-CH 2-

24 d EC

-CH 2 CH 2-

24 e f 24 f -1-CH 2 / F

CH 2 CH 2 CH 3

CH 3 (S)

24 g -CH 2-

192 CH

CH 24h-CH 2 3s H 3 (D

24 i -CH 2-

CH 3 24 d, -CH CH 3 -N-CH

2 3

TCH 3

24 k -CH 2-

N (D 1 CH 3

241 CH 3

-CH- CH

N 2

24m -CH IIL N CH 3

24 N -CH 2-

  24 o -CH 2 C 13 a H mixture C Hde 3 possible isomers 24 p -CH 2 NG-H

S CH 3 P

24 q -CH 2 2 t 24 r -CH H

NOT

C 2 -CO Cd-

24 S -CH 2 H

C H

24 t -CH 2 J

EXAMPLE 25

OH CH C

OH 3 N OP C N

CO GN

2.

2 I

CH H 3 3 3 C s

N CF53

N 1OP (O) 2 SE

Co 2 PNBL OH CH 3 H 3 e

3 O

0 O 2 GNP

  If in the process of Example 26, intermediate 1 is

  replaced by an equimolar amount of the corresponding intermediate methyl-1

  in the final product, the carbapenen mentioned above is

EXAMPLE 26

OH CH CH 3

  In the process of Example 22, the keto intermediate 1 is

  replaced by an equimolar amount of the corresponding intermediate la-methyl

  the end product, the carbapenern indicated above.

Claims (42)

As new industrial products, the compounds having the following formula: R 8 H R -RA N-R 5 N COOR wherein: Re is a hydrogen atom; and R is selected from the group consisting of hydrogen and the radicals, substituted or unsubstituted, of the following list: alkyl, alkenyl and alkynyl having 1 to 10 carbon atoms; cycloalkyl and cycloalkylalkyl 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 wherein the aryl portion is formed by a phenyl radical and the aliphatic portion comprises from 1 to 6 carbon atoms; heteroaryl, heteroaralkyl, heterocyclyl and heterocyclylalkyl wherein the one or more hetero atoms of the aforementioned heterocyclic moieties are selected from the group consisting of 1 to 4 oxygen, nitrogen or sulfur atoms and the alkyl moiety associated with these heterocyclic moieties comprises from 1 to 6 carbon atoms, it being understood that the substituents relative to the abovementioned radicals are independently of one another, chosen from the group comprising: Cl-C 6 alkyl, optionally substituted with an amino group, halo, hydroxy or carboxyl; ## STR2 ## O 503 R 3 <0 NR 3 R 4 -SR -SO 2 NR 3 R 4 -OS-R 9 I 0 I 01 O O O O -NHCNR 3 R 4 -NRS-R 9 O fi II OR 2 CNR 4- -NR 3 C = NR 4 -C 02 R 3 R 3 -OP (O) (OR 3) (OR 4) -NR 3 CO 2 R 4 = O -NO 2 "6 in which, with regard to the substituents R 3 and R 4, independently of one another, consist of hydrogen atonia or of alkyl, alkenyl and alkynyl radicals comprising from 1 to 10 carbon atoms, cycloalkyl, cycloalkylalkyl and alkylcycloalkyl radicals comprising from 1 to 10 carbon atoms; 6 carbon atoms in the cycloalkyl part and 1 to 6 carbon atoms in the alkyl part; phenyl; aralkyl, aralkenyl and aralkynyl wherein the aryl part is a phenyl group and the aliphatic part is 1 to 6 carbon atoms, and heteroaryl, heteroaralkyl, heterocyclyl and heterocyclylalkyl wherein the one or more hetero atoms said heterocyclic moieties consist of 1 to 4 oxygen, nitrogen or sulfur atoms and the alkyl moiety associated with said heterocyclic moieties comprises from 1 to 6 atoms of carbon; or R 3 and R 4 together with the nitrogen to which at least one of them is bound, form a 5- or 6-membered nitrogen-containing heterocyclic ring; R 9 is similar to R 3 except that it can not be hydrogen; or, wherein R 1 and R 2 taken together form a C 2 -alkylidene or C 2 -C 20 alkylidene radical substituted by a hydroxy group; R 5 belongs to the group of radicals, optionally substituted: alkyl, alkenyl, alkynyl comprising 1 to 10 carbon atoms; cycloalkyl and cycloalkylalkyl having 3 to 6 carbon atoms in the cycloalkyl portion and 1 to 6 carbon atoms in the alkyl moieties; phenyl; aralkyl, aralkenyl and aralkynyl wherein the aryl moiety is a phenyl radical and the aliphatic portion of which has 1 to 6 carbon atoms; heteroaryl, heteroaralkyl, heterocyclyl and heterocyclylalkyl wherein the one or more hetero atoms of said heterocyclic moieties consist of 1 to 4 oxygen atoms of nitrogen and / or sulfur and the alkyl moieties associated with said heterocyclic moieties comprise from 1 to 6 atomnies of carbon; the radicals R 5 mentioned above are optionally substituted with 1 to 3 substituents chosen independently of each other from the group comprising: C 1 -C 6 alkyl, optionally substituted with amino, fluoro, chloro, carboxyl, hydroxy or carbamoyl groups; fluoro, chloro or bromo; -OR 3; -OC 02 R 3; -OCOR 3; -OCONR 3 R 4; I-OS-Rs; oxo; -NR 3 R 4; R 3 CONR 4; -NR 3 CO 2 R 4; -NR 3 CONR 3 R 4; O -NR 35-R 9; I -SR 3; -SR 9; O -S-Rg; 5 -503 R 3; -C 02 R 3; -CONR 3 Rt; -CN; or phenyl, optionally substituted with 1 to 3 fluorine, chlorine or bromine atoms, or 1 to 3 groups C 1 -C 6 alkyl, OR 3, -NR 3 R 4, -503 R 4, -C 02 R 3 or -CONR 3 R 4, in which R 3, R 4 and R 9 in these substituents Rs are such as defined above, or R 5 may be attached to the N - group at another point in the ring, so as to form a fused heteroaromatic or heterocyclic ring, which ring may further contain up to two hetero rings. additional atoms consisting of oxygen, nitrogen or sulfur; A is a linear or branched chain alkylene radical; R 2 is a hydrogen atom, an anionic charge or a readily separable carboxylic protecting group, it being understood that when R 2 is a hydrogen atom or a protecting group is also present a counter-ion; a substituted or unsubstituted mono-, bi or polycyclic aromatic heterocyclic radical containing at least one nitrogen atom in the ring and bonded to A via a carbon atom of the ring and also having a nitrogen atom; in the kernel that is quaternised by the RS group; as well as the pharmaceutically acceptable salts derived therefrom. S 2. As new industrial compounds, the compounds of formula: R 8 H R H E? In which: Re is a hydrogen atom; and R 'is selected from the group consisting of hydrogen as well as the radicals, substituted or unsubstituted, of the following list: alkyl, alkenyl and alkynyl having 1 to 10 carbon atoms; cycloalkyl and cycloalkylalkyl 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 wherein the aryl portion is formed by a phenyl radical and the aliphatic portion comprises from 1 to 6 carbon atoms; heteroaryl, heteroaralkyl, heterocyclyl and heterocyclylalkyl wherein the one or more hetero atoms of the aforementioned heterocyclic moieties are selected from the group consisting of 1 to 4 oxygen, nitrogen or sulfur atoms and the alkyl moiety associated with these heterocyclic moieties comprises from 1 to 6 carbon atoms, being understood that the substituents relating to the aforementioned radicals are independently of one another, selected from the group consisting of: C1-C6 alkyl, optionally substituted with an amino, halo, hydroxy or carboxyl group; -0 CR 3 halo -SR 3 -OR 3 OO 0 f II II -SR 9 -OCNR 3 Rk 0 'o -S Rg -CNR 3 R 40 -NR 3 R 4 -CN -N 3 s R 3 -OSO 3 R 3 O NR 3 R 4 -OS-R 9 -SO 2 NR 3 R 4 OJO '-NHCNR 3 R. -NRS-R 9 OIt, IR -CNR 4 -NR 3 C = NR 4 -CO 2 R 3 R 3 -OP (O) (O Rs) (OR 4) -NR 3 CO 2 R 4 = O -NO 2 in which, with respect to the abovementioned substituents: the groups R 3 and R 4, independently each other consists of a hydrogen atom or alkyl, alkenyl and alkynyl radicals 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 part; phenyl; aralkyl, aralkenyl and aralkynyl * s in which the aryl portion is a phenyl radical and the aliphatic portion comprises 1 to 6 carbon atoms; and heteroaryl, heteroaralkyl, heterocyclyl and heterocyclylalkyl wherein the one or more hetero atoms of said heterocyclic moieties consist of 1 to 4 oxygen, nitrogen or sulfur atoms and the alkyl moiety associated with said heterocyclic moieties. - take from 1 to 6 carbon atoms; or R 3 and R 4 together with the nitrogen to which at least one of them is bound, form a 5- or 6-membered nitrogen-containing heterocyclic ring; R 9 is similar to R 3 except that it can not be hydrogen; or, wherein R1 and RB taken together, form a C 2 -Clo alkylidene or C 2 -C 4 alkylidene radical substituted with a hydroxy group; R 5 belongs to the group of radicals, optionally substituted: alkyl, alkenyl, alkynyl comprising 1 to 10 carbon atoms; cycloalkyl and cycloalkylalkyl having 3 to 6 carbon atoms in the cycloalkyl portion and 1 to 6 carbon atoms in the alkyl moieties; phenyl; aralkyl, aralkenyl and aralkynyl wherein the aryl moiety is a phenyl radical and the aliphatic portion of which comprises from 11 to 6 carbon atoms; heteroaryl, heterocyclyl heterocyclyl and heterocyclylalkyl wherein the hetero atom (s) of the aforementioned heterocyclic moieties consist of 1 to 4 oxygen, nitrogen and / or sulfur atoms and the alkyl moieties associated with said heterocyclic moieties comprise from 1 to at 6 carbon atoms ;. the radicals R 5 mentioned above are optionally substituted with 1 to 3 substituents chosen independently of each other from the group comprising: C 1 -C 6 alkyl, optionally substituted with amino, fluoro, chloro, carboxyl, hydroxy or carbamoyl groups; fluoro, chloro or bromo; -OR 3; -OC 02 R 3; -OCOR 3; -OCONR 3 R 4; O IJ-OS-Rg; I OXO; oxo; -NR 3 R 4; R 3 CONR 4-; -NR 3 CO 2 R 4; -NR 3 CONR 3 R 4; O-fi-NR 35-Rg; he o -SR 3; -S-R 9; O -S-R 9; 0 o -503 R 3; -C 02 R 3; -CONR 3 R 4; CN; or phenyl, optionally substituted with 1 to 3 fluorine, chlorine or bromine atoms, or I to 3 C 1 -C 6 alkyl groups, -OR 3, -t '5 -NR 3 R 4, -503 R 4, -C 02 R 3 or -CONR 3 R 4, wherein R 3, R 4 and R 9 in these substituents R 5 are as defined above; or R 5 may be bonded to the N group at another point in the ring so as to form a fused heteroarunatic or heterocyclic ring, which ring may further contain up to two additional hetero atoms consisting of oxygen, nitrogen or sulfur; A is a linear or branched chain alkylene radical; R 2 is a hydrogen atom, an anionic charge or a carboxyl group easily separable conventional, it being understood that when R 2 is a hydrogen atom or a protecting group is also present a counter-ion; and represents a substituted or unsubstituted mono-, bi- or polycyclic aromatic heterocyclic radical containing 0-5 additional hetero atoms consisting of O, S or N, said heterocyclic ring being bound to A by a carbon atom of nucleus and having a nitrogen atom of the ring quaternized by the group R 5, and said heterocyclic ring being optionally substituted on available ring atoms by 1 to 5 substituents independently selected from the group consisting of C 1 -C 4 alkyl, C 1-C 4 alkyl substituted with, preferably 1 to 3 hydroxy, amino, C 1 -C 4 alkylamino, di (C 1 -C 4) alkylamino, C 1 -C 4 alkoxy, carboxy, halo or sulfo; C 3 -C 6 cycloalkyl; C 3 -C 6 cycloalkyl (C 1 -C 4) alkyl optionally substituted with 1 to 3 of the abovementioned substituents in relation to C 1 -C 4 alkyl; C 1 -C 4 alkoxy; C 1 -C 4 alkylthio; amino; C 1 -C 4 alkylamino; di ((C1-C4) alkylamino; halo; C 1-4 alkanoylamino; C 1-4 alkanoyloxy; carboxy; sulfo; -C (O) -O-C 1-4 alkyl; hydroxy; amidino; guanidino; phenyl substituted with 1 to 3 substituents selected independently of each other from amino, halo, hydroxy, trifluoromethyl, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, C 1 -C 4 alkylamino, di (C 1 -C 4) alkylamino, carboxy and sulfo; phenyl (C 1 -C 4) alkyl wherein the phenyl moiety may be optionally substituted with 1 to 3 substituents mentioned above in relation to the phenyl group and the alkyl moiety may optionally substituted with 1 to 3 substituents mentioned above in relation to the C 1 -C 4 alkyl group, and also heteroaryl and heteroaralkyl wherein the hetero atom (s) are selected from the group consisting of 1 to 4 oxygen atoms , sulfur or nitrogen and the heteroaralkyl-associated alkyl moiety comprises from 1 to 6 carbon atoms, said heteroaryl and heteroaric groups alkyl being optionally substituted on the part of the heterocyclic ring by 1 to 3 substituents selected independently from each other from hydroxy, amino, halo, trifluoromethyl, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, C 1 -C 4 alkylamino, di (C 1 -C 4) alkylamino, carboxy and sulfo and comprising on the alkyl part 1 to 3 substituents selected from those belonging to the group comprising hydroxy, amino, C 1 -C 4 alkylamino, di (CI- C 4) alkylamino, C 1 -C 4 alkoxy, carboxy, halo and sulfo, said heterocyclic ring being optionally substituted on available nitrogen atoms of the ring with 1 to 3 substituents, independently selected from the group comprising C 1 -C 4 alkyl C 1 -C 4 alkyl substituted with, preferably 1 to 3 hydroxy, amino, C 1 -C 4 alkylamino, di (C 1 -C 4) alkylamino, C 1 -C 4 alkoxy, carboxy, halo or sulfo; C 3 -C 6 cycloalkyl; C 3 -C 6 cycloalkyl (C 1 -C 4) alkyl optionally substituted with 1 to 3 of the substituents mentioned above in connection with the C 1 -C 4 alkyl radical; phenyl; phenyl substituted with 1 to 3 of the substituents independently selected from amino, halo, hydroxy, trifluoromethyl, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, C 1 -C 4 alkylamino, di (C 1 -C 4) alkylamino, carboxy and sulfo; phenyl (C 1 -C 4) alkyl in which the phenyl part may be optionally substituted with 1 to 3 of the substituents mentioned above in connection with the phenyl radical and the alkyl part may be optionally substituted with 1 to 3 of the substituents mentioned above in connection with the radical CI-C 4 alkyl; heteroaryl and heteroaralkyl wherein the one or more hetero atoms are selected from the group consisting of 1 to 4 oxygen, sulfur or nitrogen atoms, and the alkyl moiety associated with the heteroaralkyl contains 1 to 6 carbon atoms, said heteroaryl and heteroaralkyl groups being optionally substituted on the heterocyclic ring portion by 1 to 3 substituents independently selected from hydroxy, amino, halo, trifluoromethyl, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, C 1 -C 4 alkylamino, di (C 1 -C 4) alkylamino, carboxy and sulfo and on the alkyl part with 1 to 3 substituents selected from the group consisting of hydroxy, amino, C 1 -C 4 alkylamino, di (Cl- C 4) alkylamino, C 1 -C 4 alkoxy, carboxy, halo and sulfo, as well as the pharmaceutically acceptable salts derived therefrom. 3. As new industrial products, the compounds of formula R 8 H 5 R 1 S R N OOOR 2 in which: Re is a hydrogen atom; and R is selected from the group consisting of hydrogen and the radicals, substituted or unsubstituted, of the following list: alkyl, alkenyl and alkynyl having 1 to 10 carbon atoms; cycloalkyl and cycloalkylalkyl 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 wherein the aryl portion is formed by a phenyl radical and the aliphatic portion comprises 1 to 6 carbon atoms; heteroaryl, heteroaralkyl, heterocyclyl and heterocyclylalkyl wherein the one or more hetero atoms of the aforementioned heterocyclic moieties are selected from the group consisting of 1 to 4 oxygen, nitrogen or sulfur atoms and the alkyl moiety associated with these heterocyclic moieties comprises from 1 to 6 carbon atoms, being understood that the substituents relating to the aforementioned radicals are independently of one another, selected from the group consisting of: C1-C6 alkyl, optionally substituted by an amino, halo, hydroxy or carboxyl group; A o It -OCR 3 halo -SR 3 -OR 3 0 O Il It -SR 9 -OCNR 3 R 4 o O II II -SR 9 -CNR 3 R 4 il O -NR 3 R 4 -CN -N 3 NR 3 -OSO 3 R 3 O NR 3 R 4 -OS-R 6 -50 2 NR 3 R 4 I 0 O 'O -NHCNR 3 R 4 -NRIS-R 3 O O RCNR'4- -NR 3 C = NR 4 -C 02 R 3 R 3 -OP (O) (OR 3) (OR 4) -NR 3 CO 2 R 4 = O-NO 2 in which, with respect to the abovementioned substituents: the groups R 3 and R 4, independently of each other, consist of a hydrogen atom or alkyl, alkenyl and alkynyl radicals comprising 1 to 10 carbon atoms; cycloalkyl, cycloalkylalkyl and alkylcycloalkyl having 3 to 6 carbon atoms in the cycloalkyl part and 1 to 6 carbon atoms in the alkyl part; phenyl; aralkyl, aralkenyl and aralkynyl wherein the aryl portion is a phenyl radical and the aliphatic portion comprises 1 to 6 carbon atoms; and heteroaryl, heteroaralkyl, heterocyclyl and heterocyclylalkyl wherein the one or more hetero atoms of the heterocyclic moieties are 1 to 4 oxygen, nitrogen or sulfur atoms and the alkyl moiety associated with said heterocyclic moieties comprises take from 1 to 6 carbon atoms; or R 3 and R 4 together with the nitrogen to which at least one of them is bound, form a 5- or 6-membered nitrogen-containing heterocyclic ring; 184 - R 9 is similar to R 3 except that it can not be hydrogen; or, wherein R1 and Ra taken together form a C 2 -Clo alkylidene or C 2 -C 10 alkylidene radical substituted with a hydroxy group; Rs belongs to the group of optionally substituted radicals: alkyl, alkenyl, alkynyl having 1 to 10 carbon atoms; cycloalkyl and cycloalkylalkyl having 3 to 6 carbon atoms in the cycloalkyl portion and 1 to 6 carbon atoms in the alkyl moieties; phenyl; aralkyl, aralkenyl and aralkynyl wherein the aryl moiety is a phenyl radical and the aliphatic portion of which has from 1 to 6 carbon atoms; heteroaryl, heteroaralkyl, heterocyclyl and heterocyclylalkyl wherein the one or more hetero atoms of said heterocyclic moieties comprise from 1 to 4 oxygen, nitrogen and / or sulfur atoms and the alkyl moieties associated with said heterocyclic moieties comprise from 1 to at 6 carbon atoms; the radicals Rs mentioned above are optionally substituted with 1 to 3 substituents chosen independently of each other from the group comprising: C 1 -C 6 alkyl, optionally substituted by amino, fluoro, chloro, carboxyl, hydroxy or carbamoyl groups; fluoro, chloro or bromo; -OR 3; -0 C 02 R 3; -OCOR 3; -OCONR 3 R 4; I-OS-R 9; O oxo; -NR 3 R 4; R 3 CONR 4-; -NR 3 CO 2 R 4; -NR 3 CONR 3 R 4; O-NR 3 S-R 9; If -SR 3; o -S-R 9; O -S-Rg; -SOR 3; -CO 2 R 3; -CONR 3 R 4; CN; or phenyl, optionally substituted with 1 to 3 fluorine, chlorine or bromine atoms, or 1 to 3 C 1 -C 6 alkyl groups, -OR 3, -NR 3 R 4, 503 R 4, -CO 2 R 3 or -CONR 3 R 4, wherein R 3, R 4 and R 9 in these substituents R 5 are as defined above; or Rs may be bonded to group e at another point in the ring so as to form a fused heteroaromatic or heterocyclic ring, which ring may further contain up to two additional hetero atoms consisting of oxygen, nitrogen or sulfur, A is a straight or branched chain alkylene radical; R 2 is a hydrogen atom, an anionic charge or a carboxyl group easily separable conventional, it being understood that when R 2 is a hydrogen atom or a protecting group is also present a counter-ion; and NR 5 N represents an aromatic heterocyclic radical containing 5 or 6 membered nitrogen and containing 0-3 additional hetero atoms consisting of O, S and / or N, said heterocyclic ring being optionally substituted on available atoms of the ring with 1 to 5 substituents independently selected from the group consisting of C 1 -C 4 alkyl, C 1 -C 4 alkyl substituted with, preferably 1 to 3 hydroxy, amino, C 1 -C 4 alkylamino, di (C 1 -C) 4) alkylamino, C 1 -C 4 alkoxy, carboxy, halo or sulfo; C 3 -C 6 cycloalkyl; C 3 -C 6 cycloalkyl (C 1 -C 4) alkyl optionally substituted with 1 to 3 of the above-mentioned substituents in relation to C 1 -C 4 alkyl; C 1 -C 4 alkoxy; C, 4 alkylthio; amino; C 1 -C 4 alkylamino; di ((C 1 -C 4) alkylamino; halo; C 1 -C 4 alkanoylamino; C 1 -C 4 alkanoyloxy; carboxy; sulfo; -C (O) -O-C 1 -C 4 alkyl; hydroxy; amidino; guanidino, phenyl substituted with 1 to 3 substituents independently selected   4 + from each other from amino, halo, hydroxy, trifluoro-   methyl, C 1 -C 4 alkyl, C 4 -C 4 alkoxy; C 1 -C 4 alkylamino, di (C 1 -C 4) alkylamino, carboxy and sulfo; phenyl (C 1 -C 4) alkyl wherein the phenyl portion may be optionally substituted with 1 to 3   substituents mentioned above in relation to the phenyl group and the   The alkyl group may be optionally substituted with 1 to 3 substituents mentioned above in relation to the C 1 -C 4 alkyl group; as well as heteroaryl and heteroaralkyl wherein the one or more hetero atoms are selected from the group consisting of 1 to 4 oxygen, sulfur or nitrogen atoms and the alkyl moiety associated with the heteroaralkyl comprises from 1 to 6 carbon atoms , said heteroaryl and heteroaralkyl groups being optionally substituted on the part of the heterocyclic ring by 1 to 3 substituents independently selected   from each other among the hydroxy, amino, halo, trifluoro-   Methyl, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, C 1 -C 4 alkylamino, di (C 1 -C 4) alkylamino, carboxy and sulfo and comprising on the alkyl part 1 to 3 substituents selected from those belonging to the a group comprising hydroxy, amino, C 1 -C 4 alkylamino, di (C 1 -C 4) alkylamino, C 1 -C 4 alkoxy, carboxy, halo and sulfo, said heterocyclic ring being optionally substituted on available nitrogen atoms of the ring with 1 to 3 substituents, independently selected from the group consisting of C 1 -C 4 alkyl, C 1 -C 4 alkyl substituted with, preferably 1 to 3 hydroxy, amino, C 1 -C 4 alkylamino, di (C 1 -C 4 ) alkylamino, C 1 -C 4   alkoxy, carboxy, halo or sulfo; C 3 -C cycloalkyl; C 3 -C 6 cycloalkyl   kyl (C1-C4) alkyl optionally substituted with 1 to 3 of the substituents mentioned above in connection with the radical C 1 -C 4 alkyl; phenyl; phenyl substituted with 1 to 3 substituents independently selected from amino, halo, hydroxy, trifluoromethyl, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, CC 4 alkylamino, di (C 1 -C 4) alkylamino, carboxy and sulfo ;   phenyl (C 1 -C 4) alkyl in which the phenyl part may be optionally   1 to 3 of the substituents mentioned above in 2533568 '   bond with the phenyl radical and the alkyl part may be   optionally substituted with 1 to 3 of the above-mentioned substituents in connection with the C 1 -C 4 alkyl radical; heteroaryl and heteroaralkyl wherein the one or more hetero atoms are selected from the group consisting of 1 to 4 oxygen, sulfur or nitrogen atoms, and the alkyl moiety   associated with the heteroaralkyl has 1 to 6 carbon atoms,   so-called heteroaryl and heteroaralkyl groups being optionally   substituted on the part of the heterocycic ring by 1 to 3 * independently leaving selected from the group consisting of hydroxy, amino, halo, trifluoromethyl, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, C 1 -C 4 alkylamino, di (C 1 -C 4) alkylamino, carboxy and sulfo and on the alkyl part by 1 to 3 substituents selected from the group consisting of hydroxy, amino, C 1 -C 4 alkylamino, di (C 1 -C 4) alkylamino, C 1 -C 4 alkoxy, carboxy, halo and sulfo -   as well as the pharmaceutically acceptable salts derived therefrom.   4. Compound according to claim 3, characterized in that the heterocyclic ring   is optionally substituted on available carbon or nitrogen atoms.   up to 5 substituents consisting of lower alkyl radicals   independent of each other.   Compound according to claim 4, characterized in that A is CH 2, -CH 2 -CH 2, or -CH-. l CH 3   6. As new industrial products, the compounds of mule R 8 H O in which: - Re is a hydrogen atom; and   IR is selected from the group consisting of hydrogen as well as   substituted or unsubstituted dicycls, of the following list: alkyl, alkenyl and alkynyl comprising 1 to 10 carbon atoms; cycloalkyl and cycloalkylalkyl 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 wherein the aryl portion is formed by a phenyl radical and the aliphatic portion comprises 1 to 6 carbon atoms; heteroaryl, heteroaralkyl, heterocyclyl and heterocyclylalkyl wherein the one or more hetero atoms of said heterocyclic moieties are selected from the group consisting of 1 to 4 oxygen atoms, nitrogen   or sulfur and the alkyl part associated with these heterocyclic moieties   1 to 6 carbon atoms, it being understood that the substituents relating to the abovementioned radicals are independently of one another, chosen from the group comprising: C1-C6 alkyl, optionally substituted by an amino group, halo hydroxy or carboxyl; O I i-CR 3 halo -OCR- ' -SR 3 -OR 3 0 O i OI -SR 9 -OCNR 3 R 4 O O O _SR 9 -CNR 3 R 4 -SR 9 O-NR 3 R 4 -CN NR 3 -N 3 NR -O 503 R 3 <NR 3 R O NR 3 R 4 -OS-R 9 -502 NR 3 R 4 -OS-R O   0 he t O "O-NHFCNR 3 R 4 -NR-S-R 9 he l R CNR 4- -NR 3 C = NR 4 -CO 2 R 3 R 3 -OP (O) (OR 3) (OR 4) -NR 3 CO 2 R 4 = O   -NO 2 in which, with regard to the abovementioned substituents:   the groups R 3 and R 4, independently of one another,   hydrogen, or alkyl, alkenyl and alkynyl radicals of 1 to 10 carbon atoms; cycloalkyl, cycloalkylalkyl and alkylcycloalkyl comprising 3 to 6 carbon atoms in the cycloalkyl part and i to 6 carbon atoms in the alkyl part; phenyl; aralkyl, aralkenyl and aralkynyl wherein the aryl portion is a phenyl radical and   the aliphatic portion comprises 1 to 6 carbon atoms; and   roaryl, heteroaralkyl, heterocyclyl and heterocyclylalkyl in   which the hetero ring hetero ring (s)   cited consist of 1 to 4 atoms of oxygen, nitrogen or sulfur   and the alkyl portion associated with said heterocyclic portions   take from 1 to 6 carbon atoms; or R 3 and R 4 together with the nitrogen to which at least one of them is bound, form a 5- or 6-membered nitrogen-containing heterocyclic ring; R 9 is similar to R 3 except that it can not be hydrogen; or wherein R 1 and R 3 together form a C 2 -C 10 alkylidene or C 2 -C 10 alkylidene radical substituted by a hydroxy group; RS belongs to the group of radicals, optionally substituted: alkyl, alkenyl, alkynyl comprising 1 to 10 carbon atoms;   cycloalkyl and cycloalkylalkyl having 3 to 6 carbon atoms   bone in the cycloalkyl part and 1 to 6 carbon atoms in the alkyl parts; phenyl; aralkyl, aralkenyl and aralkynyl wherein the aryl portion is a phenyl radical and the aliphatic portion of which has 1 to 6 carbon atoms; heteroaryl, heteroaralkyl, heterocyclyl and heterocyclylalkyl wherein the one or more hetero atoms of said heterocyclic moieties consist of i to 4 oxygen, nitrogen and / or   sulfur and the alkyl moieties associated with said hetero-   cyclic include 1 to 6 carbon atoms; the radicals Rs mentioned above are optionally substituted with 1 to 3 substituents chosen independently of one another from the group comprising: C1-C6 alkyl, optionally substituted with amino, fluoro, chloro, carboxyl, hydroxy or carbamoyl groups; fluoro, chloro or bromo; -OR 3; -0 C 02 R 3; -OCOR 3; -OCONR 3 R 4; he -OS-R 9; he oxo; -NR 3 R 4; R 3 CONR 4-; -NR 3 CO 2 R 4; -NR 3 CONR 3 R 4; o It -NR 35-Rg; he -SR 3; o -S-R 9; O O -S-R 9; -503 R 3; -C 02 R 3; -CONR 3 R 4;   CN; or phenyl, optionally substituted with 1 to 3 fluorine, chlorine or bromine atoms, or 1 to 3 C, -C e alkyl groups, -OR 3, -NR 3 R 4, -503 R 4, -C 02 R 3 or -CONR 3 R 4, wherein R 3, R 4   and R 9 in these substituents Rs are as defined above.   above; or R 5 can be linked to the group   at another point in the nucleus, so as to form a heterogeneous nucleus   aromatic or fused heterocyclic ring, which ring may further contain up to two additional hetero atoms consisting of oxygen, nitrogen or sulfur; A is a straight or branched chain alkylene radical; R 2 is a hydrogen atom, an anionic charge or a carboxyl group easily separable conventional, it being understood that when R 2 is a hydrogen atom or a protecting group is also present a counter-ion; and N-R 5 N R-   represents a radical selected from the group consisting of: I R 7   R 4 of hydrogen, and the radicals C 1 -C 4 alkyl, C 1 -C 4 alkyl substituted with, preferably 1 to 3 hydroxy, C 1 -C 4 alkylamino, di (C 1 -C 4 alkyl)   amino, C 1 -C 4 alkoxy, amino, sulfo, carboxy or halo; C 3 -C 6 Cyclo   alkyl; C 1 -C 4 alkoxy; C 1 -C 4 alkylthio; amino; C, -C 4 alkylamino;   di (C 1 -C 4 alkyl) amino; halo C 1 -C 4 alkanoylamino; C 1 -C 4 alkanoyl   oxy; carboxy; -C (O) -OC 1 -C 4 alkyl; hydroxy; amidino; guanidino;   phenyl; phenyl substituted with 1, 2 or 3 amino groups, halo, hydro-   xyl, trifluoromethyl, C 1 -C 4 alkyl or C 1 -C 4 alkoxy; phenyl (C, -C 3) alkyl in which the phenyl portion may be optionally   substituted by 1 to 3 of the substituents mentioned above in relation to   with the phenyl and the alkyl part may be optionally substituted with 1 to 3 of the substituents mentioned above in relation to C 1 -C alkyl; and heteroaryl and heteroaralkyl in which the   or the hetero atoms of the aforementioned heterocyclic moieties are selected   in the group consisting of 1 to 4 atoms of oxygen, nitrogen or   sulfur and the alkyl part-associated with a heteroaralkyl part   carries 1 to 6 carbon atoms; or in which two of the   groups R 6, R 7 or Rio taken together can form a carbocyte ring.   fused saturated clique, a fused aromatic carbocyclic ring,   a fused non-aromatic heterocyclic ring or a hetero ring.   fused aromatic ring, these fused rings being optionally substituted   killed by 1 or 2 of the substituents defined above for R 6, R 7 and R 'O (b) R * eje or R 5 ele optionally substituted on a carbon atomnie by 1 to 3 substituents independently selected from each other among the radicals Cl-C 4   alkyl; C 1 -C, alkyl substituted with, preferably 1 to 3 hydroxy; Cl   C 4 alkylamino, sulfo, di (C 1 -C 4 alkyl) amino, C 1 -C 4 alkoxy, amino, car-   boxy or halo; C 3 -C 6 cycloalkyl; C 1 -C 4 alkoxy; C1-C4 alkylthio;   * + amino; C1-C4 alkylamino; di (C 1 -C 4 alkyl) amino; halo; Cl-C 4 alka-   noylamino; C 1 -C alkanoyloxy; carboxy; -C (O) -OC 1 -C 4 alkyl; hydroxy; amidino; guanidino; phenyl; phenyl substituted with 1, 2 or 3 amino, halo, hydroxyl, trifluoromethyl, C 1 -C 4 alkyl or C 1 -C 4 alkoxy groups; phenyl (C 1 -C 4) alkyl in which the phenyl part may be optionally substituted with 1 to 3 of the substituents mentioned above in relation to the phenyl radical and the alkyl part   may be optionally substituted with one of the 3 substituents   born above in relation to the radical C 1 -C 4 alkyl; heteroaryl or   heteroaralkyl in which the hetero atom (s) of the heteroaralkyl   The aforementioned rocyclic compounds are selected from the group consisting of 1 to 4 atoms   oxygen, nitrogen or sulfur, and the alkyl part   said heteroaralkyl moiety has 1 to 6 carbon atoms or   replaced in order to form a carbocyclic ring, hetero   rocyclic or heteroaromatic fused, optionally substituted by one or two of the substituents defined above; (C) R 5 R R e J l) _ NOT KNN N;, N N NOT R I   RS 'or optionally substituted on a carbon atom with 1 or 2 substituents   chosen independently of each other selected from the group   taking C 1 -C 4 alkyl; C 1 -C 4 alkyl substituted with, preferably 1 to   3 hydroxy, C1-C4 alkylamino, sulfo, di (C1-C4alkyl) amino, C1-C4alpha.   koxy, amino, carboxy or halo; C 3 -C 6 cycloalkyl; C 1 -C 4 alkoxy; C 1 -C 4 alkylthio; amino, C 4 -C 4 alkylamino; di (C1-C4 alkyl) amino; C 1 -C 4 alkanoylamino halo; C, -C 4 alkanoyloxy; carboxy; -C (O) -OC 1 -C 4 alkyl; hydroxy; amidino; guanidino; phenyl; phenyl substituted with one, two or three amino, halo, hydroxyl, trifluoromethyl, C 1 -C 4 alkyl or C 1 -C 4 alkoxy groups; phenyl (C 1 -C 4) alkyl wherein the phenyl moiety may be optionally substituted with 1 to 3 of the substituents mentioned above in relation to the phenyl radical and the alkyl moiety may be optionally substituted with 1 to 3 substituents mentioned above in relation to the radical C 1 -C 4 alkyl; and heteroaryl or heteroaralkyl wherein the one or more hetero atoms of the aforementioned heterocyclic moieties are selected from the group consisting of 1 to 4 oxygen, nitrogen or sulfur atoms and the alkyl moiety associated with said heteroaralkyl moiety comprises from 1 to 6 atomnies of carbon or optionally substituted so as to form a fused carbocyclic, heterocyclic or heteroaromatic ring,   optionally substituted with 1 or 2 of the aforementioned substituents.   (d) ## STR5 ## optionally substituted on a carbon atom with a substituent selected independently from one another in the groups formed by the C 1 -C 4 alkyl radicals; C 1 -C 4 alkyl substituted with, preferably 1 to 3 hydroxy, C 1 -C 4 alkylamino, di (C 1 -C 4 alkyl) amino, -sulfo, C 1 -C 4 alkoxy, amino, carboxy or halo; C 3 -C 6 cycloalkyl; C 1 -C 4 alkoxy; C 1 -C 4 alkylthio; amino; C 1 -C 4 alkylamino; di (C 1 -C 4 alkyl) amino; halo C 1 -C 4 alkanoylamino; C 1 -C 4 alkanoyloxy; carboxy; -C (O) -OC 1 -C 4 alkyl; hydroxy; amidino; guanidino; phenyl; phenyl substituted with 1, 2 or 3 amino, halo, hydroxyl, trifluoromethyl, C 1 -C 4 alkyl or C 1 -C 4 alkoxy; phenyl (C 1 -C 4) alkyl in which the phenyl part may be optionally substituted with 1 to 3 of the abovementioned substituents in   relationship with the phenyl groups and the alkyl part may be   replaced by 1 to 3 of the substituents mentioned above f   in relation to the group C 1 -C 4 alkyl; and heteroaryl or heteroaral-   wherein the hetero atom (s) of the aforementioned heterocyclic moieties are selected from the group consisting of 1 to 4 oxygen, nitrogen or sulfur atoms and the alkyl moiety associated with said heteroaralkyl moieties has 1 to 6 carbon atoms; (e), to N-R 5 g R 5 or wherein X is O, S or NR with R being C 1 -C alkyl; C 1 -C 4 alkyl substituted with 1 to 3 hydroxy, amino, C 4 -C 4 alkylamino, di (C 1 -C 4) alkylamino, C 1 -C 4 alkoxy, carboxy, halo or sulfo; C 3 -C 6 cycloalkyl; C 3 -C 6 cycloalkyl (C 1 -C 4) alkyl optionally substituted with 1 to 3 of the   substituents mentioned above in relation to Cl-C 4 alkyl ;.   phenyl; phenyl substituted with 1 to 3 of the substituents chosen inde-   from each other among amino, halo, hydroxy, trifluoro-   methyl, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, C 1 -C 4 alkylamino, di (C 1 -C 4) alkyl-   amino, carboxy and sulfo; phenyl (C 1 -C 4) alkyl in which the phenyl part may be optionally substituted with 1 to 3 of the substituents mentioned above in relation to the phenyl 'radical and the alkyl part may be optionally substituted with 1 of the 3 substituents mentioned ci above in relation to the radical CI-C 4 alkyl;   and heteroaryl and heteroaralkyl in which the at least one heteroaryl   mes are selected from the group consisting of 1 to 4 oxygen atoms,   of sulfur or nitrogen and the alkyl part associated with the hetero radical.   aralkyl contains 1 to 6 carbon atoms, these heteroaryl and heteroaralkyl groups being optionally substituted in the part of the heterocyclic ring by 1 to 3 'substituents chosen independently   from each other among the hydroxy, amino, halo, trifluoro-   methyl, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, C 1 -C 4 alkylamino, di (C 1 -C 4) alkyl-   amino, carboxy and sulfo and the alkyl part is substituted with 1 to 3 substituents belonging to the groups comprising hydroxy, amino, C 1 -C 4 alkylamino, di (C 1 -C 4) alkylamino, C 1 -C 4 alkoxy, carboxy halo and sulfo; this heteroaromatic radical being optionally substituted   on the carbon atom by one or more substituents selected inde-   pendant from each other from the group consisting of C 1 -C 4 alkyl; $ 253356   C 1 -C 4 alkyl substituted with, preferably 1 to 3 hydroxy, amino, C 1 -C 4 alkylamino, di (C 1 -C 4 alkyl) amino, C 1 -C 4 alkoxy, sulfo, carboxy or halo   C 3 -C 6 cycloalkyl; C1-C4 alkoxy; C 1 -C 4 alkylthio; amino; C 1 -C 4 alkyl   amino; di (C 1 -C 4 alkyl) amino; halo; C 1 -C 4 alkanoylamino; CI-C 4 alka-   noyloxy; carboxy; -C (O) -OC 1 -C 4 alkyl; hydroxy; amidino; guanidino: phenyl; phenyl substituted with 1, 2 or 3 amino groups, halo; hydroxyl, trifluoromethyl, C 1 -C 4 alkyl or C 1 -C 4 alkoxy; phenyl (C 1 -C 4) alkyl in which the alkyl part may be optionally substituted with 1 to 3 of the substituents mentioned above in relation to the phenyl radical and / or the alkyl part may be optionally substituted with 1 to 3 of the substituents mentioned above in relation to the radical C 1 -C 4 alkyl; and heteroaryl and heteroaralkyl wherein the one or more hetero atoms of the aforementioned heterocyclic moieties are selected from the group consisting of 1 to 4 oxygen atoms, nitrogen   or sulfur and / or the alkyl part associated with said hetero portion   aralkyl has 1 to 6 carbon atoms or optionally   killed to form a heteroaromatic, heterocyclic ring or   fused carbocyclic ring, optionally substituted with 1 or 2   stituents defined above; (f) 4 25 R - N -XN R 9   wherein X is 0, S or NR with R being a C 1 -C 4 alkyl radical; C 1 -C 4 alkyl substituted with 1 to 3 hydroxy, amino, C 1 -C 4 alkylamino, di (C 1 -C 4) alkylamino, C 1 -C 4 alkoxy, carboxy, halo or sulfo; C 3 -C 6 cycloalkyl; C 3 -C cycloalkyl (C 1 -C 4) alkyl optionally substituted with 1 to 3 of the substituents mentioned above in relation to the radical C 1 -C 4 alkyl; phenyl; phenyl substituted with 1 to 3 substituents independently selected from the group consisting of amino, halo, hydroxy, trifluoromethyl, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, C 1 -C 4 alkylamino, di (C 1 -C 4) alkylamino, carboxy and sulfo; phenyl e 1-C 4) alkyl wherein the phenyl moiety may be optionally substituted with 1 to 3 of the substituents mentioned above in connection   with the phenyl radical and / or the alkyl part may be   substituted by 1 to 3 of the substituents mentioned above in   with the radical C 1 -C, alkyl; and 6 teroaryl and heteroaralkyl   in which the hetero atom (s) are selected from the group   taking 1 to 4 atoms of oxygen, sulfur and / or nitrogen and where the   alkyl group associated with the heteroaralkyl radical has 1 to 6 atoms   carbon, these heteroarayl and heteroaralkyl groups being substituted   killed in the part of the heterocyclic ring by 1 to 3 substituents independently selected from the group consisting of hydroxy, amino, halo, trifluoromethyl, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, C 1 -C 4 alkylamino , di (C 1 -C 4) alkylamino, carboxy and sulfo and where   The alkyl part may have from 1 to 3 substituents selected from   xy, amino, C 1 -C 4 alkylamino, di (C 1 -C 4) alkylamino, C 1 -C 4 alkoxy, carboxy,   halo and sulfo; this heteroaromatic radical being optionally substituted   killed on a carbon atom by a substituent selected from the group consisting of C 1 -C 4 alkyl; C 1 -C 4 alkyl substituted with, preferably, 1 to 3 hydroxy, amino, C 1 -C 4 alkylamino, di (C 1 -C 4 alkyl) amino, C 1 -C 4 alkoxy, sulfo, carboxy or halo; C 3 -C 6 cycloalkyl; C 4 -C 4 alkoxy; C 1 -C 4 alkylthio; amino; C 1 -C 4 alkylamino; di (C 1 -C 4 alkyl) amino; halo; C 1 -C 4 alkanoylamino; C 1 -C 4 alkanoyloxy; carboxy; -C (O) -OC 1 -C 4 alkyl; hydroxy; amidino; guanidino; phenyl; phenyl substituted with 1, 2 or 3 amino, halo, hydroxyl, trifluoromethyl, C 1 -C 4 alkyl   or C 1 -C 4 alkoxy; phenyl (C 1 -C 4) alkyl in which the phenyl part   nyl may be optionally substituted with 1 to 3 substituents   mentioned above in relation to the phenyl radical and / or the   The alkyl group may be optionally substituted with 1 to 3   mentioned above in relation to the radical C 1 -C 4 alkyl; and heteroaryl or heteroaralkyl wherein the one or more hetero atoms in the aforementioned heterocyclic moieties are selected from the group consisting of I to 4 oxygen, nitrogen and / or sulfur atoms and wherein the alkyl moiety associated with said heteroaralkyl moiety comprises at 6 carbon atoms; and (g) N = N-R R $ -N N NN N -___ 56 _ - 1 N -R Rt-I | | or l {-Ny   in which R is a C 1 -C 4 alkyl radical; Cl-C 4 alkyl substituted   killed by 1 to 3 hydroxy, amino Cl-C 4 alkylamino, di (Cl-C 4) alkylamino,   C 1 -C 4 alkoxy, carboxy, halo or sulfo; C 3 -C 6 cycloalkyl; C, -C 4 cyclo-   alkyl (C 1 -C 4) alkyl optionally substituted with 1 to 3 of the substituents mentioned above in relation to the C1-C4 alkyl radical; phenyl; phenyl substituted with 1 to 3 substituents independently selected from   each other in the group consisting of amino, halo, hydroxy, tri-   fluoromethyl, Cl-C 4 alkyl, Cl-C 4 alkoxy, Cl-C 4 alkylamino, di (Cl-C 4)   alkylamino, carboxy and sulfo; phenyl (C 1 -C 4) alkyl in which the   The phenyl moiety may be substituted with 1-3 substituents   mentioned above in relation to the phenyl radical and where the alkyl part may be optionally substituted with 1 to 3 of the   substituents mentioned above in relation to the radical C 1 -C 4   alkyl; and heteroaryl and heteroaralkyl in which the one or more   tero atoms are selected from the group consisting of 1 to 4 oxy-   gene, sulfur and / or nitrogen and o the alkyl part associated with the   heteroaralkyl group having 1 to 6 carbon atoms, these heteroaryl and heteroaralkyl groups being optionally substituted in the part of the heterocyclic ring by 1 to 3 of the substituents chosen independently of each other from hydroxy, amino, halo, trifluoromethyl, C 1- C 4 alkyl, C 1 -C 4 alkoxy, C 1 -C 4 alkylamino,   di (C 1 -C 4) alkylamino, carboxy and sulfo and where the alkyl part is   optionally substituted with 1 to 3 substituents selected from the group consisting of hydroxy, amino, C 4 C 4 alkylamino, di (C 1 -C 4) alkylamino,   C 1 -C 4 alkoxy, carboxy, halo and sulfo.   as well as the pharmaceutically acceptable salts derived therefrom. 7. A compound according to claim 6, characterized in that the group represents a radical selected from the group consisting of radicals (a) 1 5 L R 6   Where: Rs is a C1-C6 alkyl radical; and, R 6, R 7 and R 10 are independently of each other hydrogen or a C 1 -C 4 alkyl radical; (B) R $ RS S N N N R 5 1 S f or N in which:-   R 5 is a C 1 -C 6 alkyl radical and the carbon atoms are   kernel are optionally substituted by 1 to 3   killers consisting of independently alkylated C 1 -C 4 radicals; 25356 G (c) R 5 Ne or in which:   R 5 is a C 1 -C 6 alkyl radical and the carbon atoms are   kernel are optionally substituted by 1 or 2   substituents consisting of C 1 -C 4 alkyl radicals, if any,   substituted; R 5> 4 R 5 N R 5 or v) L N e R 5 NS R 5 u N R 5 k * (d) R 5 N 1 w N i R 5 e 1 N h N in which:   Rs is a C 1 -C 6 alkyl radical and the carbon nuclei are   of the nucleus are eventually substituted by radi-   CI-C 4 alkyl; (e) XR-R 5 or x wherein: R 5 is C 1 -C 6 alkyl, X is O, S or NR with R being alkyl, and o one or more available carbon atoms of the ring are optionally substituted with C1-C4 alkyl radicals; (f) a 5 _R " 'X', ' x 1 R g _ _ 5 N J-R   or R 5% N x wherein: is a C 1 -C 6 alkyl radical; is 0, S or NR with R = C 1 -C 4 alkyl radical, and o one or more of the available ring carbon atoms is optionally substituted with a C 1 -C 4 alkyl radical; R 5 y 'W- hiÀ - f 1%, N- in R 4 X (g) -g N N N-R R 54 TJ-R He has R 5 GRR -t N-R N N-R Il or e l N, R-   in which: R 5 is a C1-C6 alkyl radical; and, R is a C 1 -C 4 alkyl radical.   8. As new industrial products, the compounds of formula RBH S-A N-R N OOR 2   wherein: R 8 is a hydrogen atom; and   R is selected from the group consisting of hydrogen as well as   substituted or unsubstituted organic radicals of the following list: alkyl, alkenyl and alkynyl having 1 to 10 carbon atoms; cycloalkyl and cycloalkylalkyl 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 wherein the aryl portion is formed by a phenyl radical and the aliphatic portion comprises 1 to 6 carbon atoms; heteroaryl, heteroaralkyl, heterocyclyl and heterocyclylalkyl wherein the one or more hetero atoms of said heterocyclic moieties are selected from the group consisting of 1 to 4 oxygen atoms, nitrogen   or sulfur and the alkyl part associated with these heterocyclic moieties   This comprises, for example, 6 carbon atoms, it being understood that the substituent (s) relative to the abovementioned radicals are independently of each other, chosen from the group comprising: (C 1 -C 6) alkyl, optionally substituted by an amino group, halo hydroxy or carboxyl; e-OCR 3 halo -SR 3 -OR 3 O O -SR 9 OCNR 3 R 4 0 O -SR 9 -CNR 3 R 4 e O-NR 3 R 4 CN -N 3 NR 3 -O 503 R 3 * "-SNR 3 R" -OS-R 9 -SO 2 NR 3 R 4 e ' O O I 0 i o -NHCNR 3 R 4 -NR 2 S-R 9 O tl o = R 3 CNR 4- -NR 3 C = NR 4 -C 02 R 3 R 3 -OP (O) (OR 3) (OR 4) -NR 3 C 02 R 4 = O   -NO 2 in which, with regard to the abovementioned substituents:   the groups R 3 and R 4, independently of one another,   hydrogen, or alkyl, alkenyl and alkynyl radicals of 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 part; phenyl; aralkyl, aralkenyl and aralkynyl wherein the aryl portion is a phenyl radical and   the aliphatic portion comprises 1 to 6 carbon atoms; and   roaryl, heteroaralkyl, heterocyclyl and heterocyclylalkyl in 5335 '68   which the hetero ring hetero ring (s)   cited consist of 1 to 4 atoms of oxygen, nitrogen or sulfur   and the alkyl portion associated with said heterocyclic portions   take from 1 to 6 carbon atoms; or R 3 and R "together with the nitrogen to which at least one of them is bound, form a 5- or 6-membered nitrogen-containing heterocyclic ring; R 9 is similar to R 3 if it can not be hydrogen, or in which R 1 and R 8 taken together form a C 2 -alkylidene or C 2 -alkylidene radical substituted by a hydroxy group; to the group of optionally substituted radicals: alkyl, alkenyl, alkynyl having 1 to 10 carbon atoms;   cycloalkyl and cycloalkylalkyl having 3 to 6 carbon atoms   bone in the cycloalkyl part and 1 to 6 carbon atoms in the alkyl parts; phenyl; aralkyl, aralkenyl and aralkynyl wherein the aryl portion is a phenyl radical and the aliphatic portion of which has 1 to 6 carbon atoms; heteroaryl, heteroaralkyl, heterocyclyl and heterocyclylalkyl wherein the one or more hetero atoms of the aforementioned heterocyclic moieties consist of 1 to 4 oxygen, nitrogen and / or   sulfur and the alkyl moieties associated with said hetero-   cyclic include 1 to 6 carbon atoms; the radicals R 5 mentioned above are optionally substituted with 1 to 3 substituents chosen independently of each other from the group comprising: C 1 -C 6 alkyl, optionally substituted with amino, fluoro, chloro, carboxyl, hydroxy or carbamoyl groups; fluoro, chloro or bromo; -OR 3; -0 C 02 R 3; -OCOR 3; -OCONR 3 R 4; O l -OS-R 9; He oxo; -NR 3 R 4; R 3 CONR 4-; -NR 3 CO 2 R 4; -NR 3 CONR 3 R 4; O II-NR 35-Rg; g ' -SR 3; on -S-Rg; 0 O -S-R 9; -503 R 3; -C 02 R 3; -CONR 3 R 4;   CN; or phenyl, optionally substituted with 1 to 3 fluorine, chlorine or bromine atoms, or I to 3 Ci-C 6 alkyl groups, -OR 3, -NR 3 R 4, 503 R 4, -C 02 R 3 or -CONR 3 R 4, wherein R 3, R 4   and R 9 in these RB substituents are as defined above.   above; or Rs can be linked to the group * f e r o -   at another point in the nucleus, so as to form a heterogeneous nucleus   aromatic or fused heterocyclic ring, which ring may further contain up to two additional hetero atoms consisting of oxygen, nitrogen or sulfur; -   A is a linear or branched chain alkylene radical; R 2 is a hydrogen atom, an anionic charge or a carboxyl group easily separable conventional, it being understood that when R 2 is a hydrogen atom or a protecting group is also present a counter-ion; and & '<< represents a radical selected from the group consisting of: R 7 RS R R   wherein R 6, R 7 and R 10 are independently selected from ato-   hydrogen, and C1-C4 alkyl, C1-C4 alkyl substituted by, preferably 1 to 3 hydroxy, C, -C4 alkylamino, di (C1-C4 alkyl) amino, C 1 -C 4 alkoxy, amino, sulpho, carboxy or halo (chloro, bromo,   fluoro or iodo; preferably chloro, fluoro or bromo); C 3 -C 6 Cyclo   alkyl; C 1 -C 4 alkoxy; C, -C 4 alkylthio; amino; C1-C4 alkylamino;   di (C 1 -C 4 alkyl) amino; halo (chloro, bromo, fluoro or iodo;   chloro, fluoro or bromo); C 1 -C 4 alkanoylamino; C 1 -C 4 alkanoyl   oxy; carboxy; -C (O) -OC, -C 4 alkyl; hydroxy; amidino; guanidino; phenyl; phenyl substituted with 1, 2 or 3 amino groups, halo (chloro,   Bromo, fluoro or iodo; preferably chloro, fluoro or bromo), hydro-   xyl, trifluoromethyl, C 1 -C 4 alkyl or C 1 -C 4 alkoxy; phenyl (C 1 -C 4) alkyl in which the phenyl part may be optionally   substituted by 1 to 3 of the substituents mentioned above in relation to   with the phenyl and the alkyl part may be optionally substituted with 1-3 of the substituents mentioned above in relation to C 1 -C 4 alkyl; and heteroaryl and heteroaralkyl in which the   or the hetero atoms of the aforementioned heterocyclic moieties are selected   in the group consisting of 1 to 4 atoms of oxygen, nitrogen or   sulfur and the alkyl part associated with a heteroaralkyl part   carries 1 to 6 carbon atoms; or in which two of the   groups R 6, R? taken together, can form a carbocyte nucleus   fused saturated clique, a fused aromatic carbocyclic ring,   a fused non-aromatic heterocyclic ring or a hetero ring.   fused aromatic ring, these fused rings being optionally substituted   killed by 1 or 2 of the substituents defined above for R 6, R? and R1'o; as well as the pharmaceutically acceptable salts derived therefrom. 9. As new industrial products, the compounds of formula R 8 H R 5 N OR 2   wherein: R 8 is a hydrogen atom; and   IR is selected from the group consisting of hydrogen as well as   substituted or unsubstituted alkyl groups of the following list: alkyl, alkenyl and alkynyl having 1 to 10 carbon atoms; cycloalkyl and cycloalkylalkyl comprising 3 to 6 carbon atoms in the cycloalkyl ring and I to 6 carbon atoms in the alkyl part; phenyl; aralkyl, aralkenyl and aralkynyl wherein the aryl portion is formed by a phenyl radical and the aliphatic portion comprises 1 to 6 carbon atoms; heteroaryl, heteroaralkyl, heterocyclyl and heterocyclylalkyl wherein the one or more hetero atoms of said heterocyclic moieties are selected from the group consisting of 1 to 4 oxygen atoms, nitrogen   or sulfur and the alkyl part associated with these heterocyclic moieties   C 1 -C 6 alkyl, optionally substituted by an amino group, halo hydroxy or carboxyl; -OCR 3 halo -OR 3 -SR 3. 0 O _C Dg -OCNR 3 R 4 -._ v " 0 O -SR 9 -CNR-R 4 II O -NR 3 R 4 - "-CN-N 3 5 NR 3 -N 3 -OSO 3 R 3 NR 3 R 4 -OS-R 9 -502 NR 3 R 4 O 0 -NHCNR 3 R " I -NR 3 S-R 9 I II Ol R CNR 4- -NR 3 C = NR 4 -CO 2 R 3 R 3 -OP (O) (OR 3) (OR 4) -NR 3 CO 2 R 4 = O   -NO 2 in which, with regard to the abovementioned substituents:   4 * the groups R 3 and R 4, independently of one another, consist of   hydrogen, or alkyl, alkenyl and alkynyl radicals of 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 part; phenyl; aralkyl, aralkenyl and aralkynyl wherein the aryl portion is a phenyl radical and   the aliphatic portion comprises 1 to 6 carbon atoms; and   roaryl, heteroaralkyl, heterocyclyl and heterocyclylalkyl in   which the hetero ring hetero ring (s)   cited consist of 1 to 4 atoms of oxygen, nitrogen or sulfur   and the alkyl portion associated with said heterocyclic portions   take from 1 to 6 carbon atoms; or R 3 and R "together with the nitrogen to which at least one of them is bound, form a 5 or 6 membered nitrogen-containing heterocyclic ring; R 9 is similar to R 3 if it is not is that it can not be hydrogen, or, where R 1 and R taken together, form a C 2 -C 10 alkylidene or C 2 -C 10 alkylidene radical substituted with a hydroxy group; R belongs to the group optionally substituted radicals: alkyl, alkenyl, alkynyl having 1 to 10 carbon atoms;   cycloalkyl and cycloalkylalkyl having 3 to 6 carbon atoms   bone in the cycloalkyl part and i to 6 carbon atoms in the alkyl parts; phenyl; aralkyl, aralkenyl and aralkynyl wherein the aryl portion is a phenyl radical and the aliphatic portion of which has 1 to 6 carbon atoms; heteroaryl, heteroaralkyl, heterocyclyl and heterocyclylalkyl wherein the one or more hetero atomies of the aforementioned heterocyclic moieties consist of i to 4 oxygen, nitrogen and / or   sulfur and the alkyl moieties associated with said hetero-   cyclic include 1 to 6 carbon atoms; -   the radicals R 5 mentioned above are optionally substituted with 1 to 3 substituents chosen independently of each other from the group comprising: C 1 -C 6 alkyl, optionally substituted by amino, fluoro, chloro, carboxyl, hydroxy or carbamoyl groups; fluoro, chloro or bromo; -OR 3; -0 C 02 R 3; -OCOR 3; -OCONR 3 R 4; O O It -OS-Rg; I È oxo; -NR 3 R 4; R 3 CONR 4-; -NR 3 CO 2 R 4; -NR 3 CONR 3 R 4; O -0 the -NR 35-R 9; he -SR 3; -35- -S-R 9; 0 O -S-R 9; "" v 503 R 3; -C 02 R 3; -CONR 3 R 4;   CN; or phenyl, optionally substituted with 1 to 3 fluorine atoms, chlorine or bromine, or 1 to 3 C 1 -C 6 alkyl groups, -OR 3, -NR 3 R 4, SO 3 R ", -C O 2 R 3 or -C Oti R 3 R 4, wherein R 3, R 4   and R 9 in these substituents R 5 are as defined above.   above; or R 5 can be linked to the group   at another point in the nucleus, so as to form a heterogeneous nucleus   aromatic or heterocyclic fused, which ring may further contain up to two additional hetero atoms consisting of 4 + oxygen, nitrogen or sulfur; A is a straight or branched chain alkylene radical; R 2 is a hydrogen atom, an anionic charge, or a conventional easily separable carboxyl protecting group, it being understood that when R 2 is a hydrogen atom or a protecting group is also present a counterion; and N R 5 represents a radical of formula r S I_ 5   and optionally substituted on a carbon atom with 1 to 3 substituents chosen independently of one another from C 1 -C 4 radicals   alkyl; C 1 -C 4 alkyl substituted with, preferably 1 to 3 hydroxy; C -   C 4 alkylamino, sulfo, di (C 1 -C 4 alkyl) amino, C 1 -C 4 alkoxy, amino, car-   boxy or halo (chloro, bromo, fluoro or iodo, preferably chloro, fluoro or bromo); C 3 -C 6 cycloalkyl; C 1 -C 4 alkoxy; C 1 -C 4 alkylthio; amino; C1-C4 alkylamino; di (C1-C4alkyl) amino; halo (chloro, bromo,   fluoro or iodo; preferably chloro, fluoro or bromo); Cl-C 4 alka-   noylamino; C, -C 4 alkanoyloxy; carboxy; -C (O) -OC 1 -C 4 alkyl; hydroxy; amidino; guanidino; phenyl; phenyl substituted with 1, 2 or 3 amino groups, halo (chloro, bromo, fluoro or iodo, preferably chloro,   fluoro or bromo), hydroxyl, trifluoromethyl, C1-C4 alkyl or C 1 -C.   alkoxy; phenyl (C 1 -C 4) alkyl wherein the phenyl moiety may be optionally substituted with from 1 to 3 of the substituents mentioned above in connection with the phenyl radical and the alkyl moiety   may be optionally substituted with one of the 3 substituents   born above in relation to the radical Cl-C 4 alkyl; heteroaryl or   heteroaralkyl in which the hetero atom (s) of the heteroaralkyl   The aforementioned rocyclic compounds are selected from the group consisting of 1 to 4 atoms   oxygen, nitrogen or sulfur, and the alkyl part   said heteroaralkyl moiety has 1 to 6 carbon atoms or   replaced in order to form a carbocyclic ring, hetero   rocyclic or heteroaromatic fused, optionally substituted by one or two of the substituents defined above;   as well as pharmaceutically acceptable salts which endérivent.   10. Compound according to claim 9, characterized in that <the pis-   R 5 to 1, is 11. Compound according to claim 9, characterized in that R 5 el -7 N -R 5   12. Compound according to claim 9, characterized in that R 5 el N is   13. A compound according to any one of claims 9 to 12, in that A = -CH 2 RI = CH 3 CH- OH OH or -CH 2 CH 2-   and in that the absolute configuration is R, 65, 8 R. 14. As new industrial products, the compounds of the formula: N ED -R 5 in which: Re is a hydrogen atom; and -   R 1 is selected from the group consisting of hydrogen as well as   substituted or unsubstituted organic radicals of the following list: alkyl, alkenyl and alkynyl having 1 to 10 carbon atoms; cycloalkyl and cycloalkylalkyl 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 wherein the aryl portion is formed by a phenyl radical and the aliphatic portion comprises 1 to 6 carbon atoms; heteroaryl, heteroaralkyl, heterocyclyl and heterocyclylalkyl wherein the one or more hetero atoms of said heterocyclic moieties are selected from the group consisting of 1 to 4 oxygen atoms, nitrogen   or sulfur and the alkyl part associated with these heterocyclic moieties   comprises from 1 to 6 carbon atoms, it being understood that the substituent (s) relative to the abovementioned radicals are independently of one another, chosen from the group comprising: C 1 -C 6 alkyl, optionally substituted with an amino group halo, hydroxy or carboxyl; O It -OCR 3 halo -SR 3 -OR 3 0 O II II -SR 9 -OCNR 3 R 4 O, -SR 9 -CNR 3 R 4 I o -NR 3 R 4 -CN N NR 3 -N 3> -O 503 R 3 -3 O NR 3 R -S-R -502 NR 3 R 4 -OS -Rg "O 0 ,, 0 NHCNR 3 R 4 -NR 3 S-R 9 O i R 3 CNR'4- -NR 3 C = NR 4 -COR 3 R 3 -OP (O) (OR 3) (OR 4) -NR 3 CO 2 R 4 ", 2 -NO 2   in which, with regard to the abovementioned substituents:   the groups R 3 and R 4, independently of one another,   in a hydrogen atom or in alkyl, alkenyl and alkynyl radicals 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 part; phenyl; aralkyl, aralkenyl and aralkynyl wherein the aryl portion is a phenyl radical and   the aliphatic portion comprises 1 to 6 carbon atoms; and   roaryl, heteroaralkyl, heterocyclyl and heterocyclylalkyl in   which the hetero ring hetero ring (s)   cited consist of 1 to 4 atoms of oxygen, nitrogen or sulfur   and the alkyl portion associated with said heterocyclic portions   take from 1 to 6 carbon atoms; or R 3 and R 4 together with the nitrogen to which at least one of them is bound, form a 5- or 6-membered nitrogen-containing heterocyclic ring; R 9 is similar to R 3 except that it can not be hydrogen; or wherein R 'and R 8 taken together form a C 2 -C 10 O alkylidene or C 2 -C 10 alkylidene radical substituted with a hydroxy group; R 5 belongs to the group of radicals, optionally substituted: alkyl, alkenyl, alkynyl comprising 1 to 10 carbon atoms;   cycloalkyl and cycloalkylalkyl having 3 to 6 carbon atoms   bone in the cycloalkyl part and 1 to 6 carbon atoms in the alkyl parts; phenyl; aralkyl, aralkenyl and aralkynyl wherein the aryl moiety is a phenyl radical and the aliphatic portion of which has from 1 to 6 carbon atoms; heteroaryl, heteroaralkyl, heterocyclyl and heterocyclylalkyl wherein the one or more hetero atoms of the aforementioned heterocyclic moieties consist of 1 to 4 oxygen, nitrogen and / or   sulfur and the alkyl moieties associated with said hetero-   cyclic include 1 to 6 carbon atoms; the R 5 sprecified radicals are optionally substituted with 1 to 3 substituents chosen independently of one another from the group comprising: C 1 -C 6 alkyl, optionally substituted with amino, fluoro, chloro, carboxyl, hydroxy or carbamoyl groups; fluoro, chloro or bromo; -QR 3; -0 C 02 R 3; -OCOR 3; -OCONR 3 R 4; 4 ,, -OS-Rs; I oxo; -NR 3 R 4; R 3 CONR 4-; -NR 3 CO 2 R 4; -NR 3 CONR 3 R 4; o -NR 35-Rg; I. O -SR 3; -S-R 9, O O -S-R 9; -503 R 3; -C 02 R 3; -CONR 3 R 4;   CN; or phenyl, optionally substituted with 1 to 3 fluorine, chlorine or bromine atoms, or 1 to 3 C 1 -C 6 alkyl groups, -OR 3, -NR 3 R 4, 503 R 4, -C 02 R 3 or -CONR 3 R 4, wherein R 3, R 4   and R 9 in these substituents Rs are as defined above.   above; or * on it; or R 5 can be linked to the group Ne   at another point in the nucleus, so as to form a heterogeneous nucleus   aromatic or fused heterocyclic ring, which ring may further contain up to two additional hetero atoms consisting of oxygen, nitrogen or sulfur; A is a straight or branched chain alkylene radical; R 2 is a hydrogen atom, an anionic charge, or a readily-separable carboxyl-protecting group, it being understood that when R 2 is a hydrogen atom or a protecting group is also present a counter-ion; and represents a radical selected from the group consisting of: ## STR2 ## or optionally substituted radicals on a carbon atom of 1 or 2 substituents   chosen independently of each other selected from the group   taking C 1 -C 4 alkyl; C 1 -C 4 alkyl substituted with, preferably 1 to 5   3-hydroxy, C1-C4 alkylamino, sulfo, di (C1-C4alkyl) amino, C 1 -C al.   koxy, amino, carboxy or halo (chloro, bromo, fluoro or iodo;   chloro, fluoro or bromo); C 3 -C 6 cycloalkyl; C 1 -C 4 alkoxy; ClC 4 alkylthio; amino, C 1 -C 4 alkylamino; di (C 1 -C 4 alkyl) amino; halo (chloro, bromo, fluoro or iodo, preferably chloro, fluoro or bromo); C 1 -C 4 alkanoylamino; C 1 -C 4 alkanoyloxy; carboxy; -C (O) -OC 1 -C 4 alkyl; hydroxy; amidino; guanidino; phenyl; phenyl substituted with one, two   or three amino groups, halo (chloro, bromo, fluoro or iodo;   chloro, fluoro or bromo), hydroxyl, trifluoromethyl, Cl-C 4. alkyl or C 1 -C 4 alkoxy; phenyl (C1-C4) alkyl in which the phenyl part may be optionally substituted with 1 to 3 of the substituents mentioned above in relation to the phenyl radical and the alkyl part may be optionally substituted with 1 to 3 of the substituents mentioned hereinabove; above in relation to the CI-C 4 alkyl radical; and heteroaryl or heteroaralkyl wherein the one or more hetero atoms of the aforementioned heterocyclic moieties are selected from the group consisting of 1 to 4 oxygen, nitrogen or sulfur atoms and the alkyl moiety associated with said heteroaralkyl moiety comprises from 1 to 6 carbon atoms or optionally substituted so as to form a fused aromatic, heterocyclic or heteroaromatic nucleus, optionally substituted with 1 or 2 of the aforementioned substituents;   as well as the pharmaceutically acceptable salts derived therefrom.   15. As new industrial products, the compounds of formula R 1 R A N-R COOR 2   in which: Re is a hydrogen atom; and   R is selected from the group consisting of hydrogen as well as   substituted or unsubstituted organic radicals of the following list: alkyl, alkenyl and alkynyl having 1 to 10 carbon atoms; cycloalkyl and cycloalkylalkyl 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 wherein the aryl portion is formed by a phenyl radical and the aliphatic portion comprises from 1 to 6 carbon atoms; heteroaryl, heteroaralkyl, heterocyclyl and heterocyclylalkyl wherein the one or more hetero atoms of said heterocyclic moieties are selected from the group consisting of 1 to 4 oxygen atoms, nitrogen   or sulfur and the alkyl part associated with these heterocyclic moieties   comprises from 1 to 6 atoms of carbon, it being understood that the substituent (s) relative to the aforementioned radicals are, independently of one another, chosen from the grolupe comprising: Cl-C 6 alkyl, optionally substituted by an amino group halo, hydroxy or carboxyl; he -OCR 3 halo -SR 3 -OR 3 0 0 II I -SR 9 -OCNR 3 R 4 0 o -SR 9 -CNR 3 R 4 It o O -NR 3 R 4 CN NR 3 -N 3 NR 3 -0503 R 3 OS 3- / NR 3 R 4 -OS-R 9 "-502 NR 3 R 4 -OS-Rg o O 0 II 0 -NHCNR 3 R 4 -NR 3 _-R 9 O I o O 3 CNR 4- -NR 3 C = NR 4 -CO 2 R 3 R 3 -OP (O) (OR 3) (OR 4) -NR 3 CO 2 R 4 = O   -NO 2 in which, with regard to the abovementioned substituents:   The groups R 3 and R 4, independently of one another, consist of   hydrogen, or alkyl, alkenyl and alkynyl radicals of 1 to 10 carbon atoms; cycloalkyl, cycloalkylalkyl and alkylcycloalkyl having 3 to 6 carbon atoms 219 -   carbon in the cycloalkyl part and 1 to 6 carbon atoms in the alkyl part; phenyl; aralkyl, aralkenyl and aralkynyl wherein the aryl portion is a phenyl radical and   the aliphatic portion comprises 1 to 6 carbon atoms; and   roaryl, heteroaralkyl, heterocyclyl and heterocyclylalkyl in   hetero atoms of the heterocyclic parts   cited consist of 1 to 4 atoms of oxygen, nitrogen or sulfur   and the alkyl portion associated with said heterocyclic portions   take from 1 to 6 atomnies of carbon; or -   R 3 and R 4 together with the nitrogen to which at least one of them is bound, form a 5- or 6-membered nitrogen-containing heterocyclic ring; R 9 is similar to R 3 except that it can not be hydrogen; or, wherein R1 and Ra taken together form a C 2-Cib alkylidene or C 2 -C 10 alkylidene radical substituted with a hydroxy group; Rs belongs to the group of radicals, optionally substituted: alkyl, alkenyl, alkynyl comprising 1 to 10 carbon atoms;   cycloalkyl and cycloalkylalkyl comprising 3 'to 6 carbon atoms;   bone in the cycloalkyl part and I to 6 carbon atoms in the alkyl parts; phenyl; aralkyl, aralkenyl and aralkynyl wherein the aryl moiety is a phenyl radical and the aliphatic portion of which has 1 to 6 carbon atoms; heteroaryl, heteroaralkyl, heterocyclyl and heterocyclylalkyl wherein the one or more hetero atoms of the aforementioned heterocyclic moieties consist of 1 to 4 atoms of oxygen, nitrogen and / or   sulfur and the alkyl moieties associated with said hetero-   cyclic include 1 to 6 carbon atoms; the radicals Rs mentioned above are optionally substituted with 1 to 3 substituents chosen independently of one another from the group comprising: C1-C6 alkyl, optionally substituted with amino, fluoro, chloro, carboxyl, hydroxy or carbamoyl groups; fluoro, chloro or bromo; -OR 3; -0 C 02 R 3; -OCOR 3; -OCONR 3 R 4; o It -OS-Rs; He OXO oxo; -NR 3 R 4; R 3 CONR 4-; -NR 3 CO 2 R 4; -NR 3 CONR 3 R 4; o -NR 35-R 9; I.-S-Ro 9; 0 O -S-R 9; -503 R 3; -C 02 R 3; -CONR 3 R 4;   CN; or phenyl, optionally substituted with 1 to 3 fluorine, chlorine or bromine atoms, or 1 to 3 C 6 -C 6 alkyl groups, -OR 3, -NR 3 R ", -SO 3 R 4, -C O 2 R 3 or -CONR 3 R 4, wherein R 3, R 4   and R 9 in these substituents Rs are as defined above. above; or be linked to the group   at another point in the nucleus, so as to form a heterogeneous nucleus   aromatic or heterocyclic fused, which ring may further contain up to two additional hetero atoms consisting of oxygen, nitrogen or sulfur; R 5 may * 1 t. A is a linear or branched chain alkylene radical; R 2 is a hydrogen atom, an anionic charge, or a conventional easily separable carboxyl protecting group, it being understood that when R 2 is a hydrogen atom or a protecting group is also present a counterion; and N-R represents a radical selected from the group consisting of: R 5 45 N <N 3> vl-; N 4 N N N N   N or optionally substituted on a carbon atom with a substituent chosen independently of one another in the groups formed by the radicals C 1 -C 4 alkyl; C 1 -C 4 alkyl substituted with, preferably 1 to 3 hydroxy, C 1 -C 4 alkylamino, di (C 1 -C 4 alkyl) amino, sulfo, C 1 -C 4   alkoxy, amino, carboxy or halo (chloro, bromo, fluoro or iodo;   chloro, fluoro or bromo); C 3 -C 6 cycloalkyl; C 1 -C 4 alkoxy; C 1 -C 4 alkylthio; amino; C 1 -C 4 alkylamino; di (C 1 -C 4 alkyl) amino; halo (chloro, bromo, fluoro or iodo, preferably chloro, fluoro or bromo); C 1 -C 4 alkanoylamino; C 1 -C 4 alkanoyloxy; carboxy; -C (O) -OC 1 -C 4 alkyl; hydroxy; amidino; guanidino; phenyl; phenyl substituted with 1, 2 or 3 amino, halo (chloro, bromo, fluoro or iodo, preferably chloro, fluoro or bromo), hydroxyl, trifluoromethyl, C 1 -C 4 alkyl or C 1 -C 4 alkoxy; phenyl (C 1 -C 4) alkyl in which the phenyl part may be optionally substituted with 1 to 3 of the aforementioned substituents in   relationship with the phenyl groups and the alkyl part may be   replaced by 1 to 3 of the substituents mentioned above   in relation to the group C 1 -C 4 alkyl; and heteroaryl or heteroaral-   wherein the one or more hetero atoms of the aforementioned heterocyclic moieties are selected from the group consisting of 1 to 4 oxygen, nitrogen or sulfur atoms and the alkyl moiety which is associated with said heteroaralkyl moieties has 1 to 6 carbon atoms. carbon;   as well as the pharmaceutically acceptable salts derived therefrom.   16. As new industrial products, compounds of formula R 8 H i -A COOR   wherein: Re is a hydrogen atom; and   R is selected from the group consisting of hydrogen as well as   substituted or unsubstituted organic radicals of the following list: alkyl, alkenyl and alkynyl having 1 to 10 carbon atoms; cycloalkyl and cycloalkylalkyl 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 wherein the aryl portion is formed by a phenyl radical and the aliphatic portion comprises 1 to 6 carbon atoms; heteroaryl, heteroaralkyl, heterocyclyl and heterocyclylalkyl wherein the one or more hetero atoms of said heterocyclic moieties are selected from the group consisting of 1 to 4 oxygen atoms, nitrogen   or sulfur and the alkyl part associated with these heterocyclic moieties   This comprises from about 6 carbon atoms, meaning that the substituents relating to the radicals mentioned above are independently of one another, selected from the group consisting of: C 1 -C 6 alkyl, optionally substituted by an amino, halo, hydroxy or carboxyl group; e O It -OCR 3 halo -SR 3 -OR 3 0 O SR 9 -OCNR 3 R 4 0 O -SR 9 -CNR 3 R 4 O-NR 3 R 4 CN -N 3 NR 3 -OSO 3 R 3 0 <NR 3 R 4 -OS-R 9 -SO 2 NR 3 R 4 I, 0 O he O -NHCNR 3 Rk He -NR 3 S-R 9 O II 0 R 3 CNR 4- -NR 3 C = NR 4 -CO 2 R 3 R 3 -OP (O) (OR 3) (OR 4) -NR 3 CO 2 R 4 = O   -NO 2 in which, with regard to the abovementioned substituents:   the groups R 3 and R 4, independently of one another,   hydrogen, or alkyl, alkenyl and alkynyl radicals of 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 part; phenyl; aralkyl, aralkenyl and aralkynyl wherein the aryl portion is a phenyl radical and   the aliphatic portion comprises 1 to 6 carbon atoms; and het   roaryl, heteroaralkyl, heterocyclyl and heterocyclylalkyl in   which the hetero ring hetero ring (s)   cited consist of 1 to 4 atoms of oxygen, nitrogen or sulfur   and the alkyl part associated with said heterocyclic portions   take from 1 to 6 carbon atoms; or R 3 and R 4 together with the nitrogen to which at least one of them is bound, form a 5- or 6-membered nitrogen-containing heterocyclic ring; R 9 is similar to R 3 except that it can not be hydrogen; or wherein R1 and Re taken together form a hydroxy-substituted C 2 -alkylidene or C 2 -alkylidene radical; R 5 belongs to the group of radicals, optionally substituted: alkyl, alkenyl, alkynyl comprising 1 to 10 carbon atoms;   cycloalkyl and cycloalkylalkyl having 3 to 6 carbon atoms   bone in the cycloalkyl part and 1 to 6 carbon atoms in the alkyl parts; phenyl; aralkyl, aralkenyl and aralkynyl wherein the aryl portion is a phenyl radical and the aliphatic portion of which has 1 to 6 carbon atoms; heteroaryl, heteroaralkyl, heterocyclyl and heterocyclylalkyl wherein the one or more hetero atoms of the aforementioned heterocyclic moieties consist of 1 to 4 oxygen, nitrogen and / or   sulfur and the alkyl moieties associated with said hetero-   cyclic include 1 to 6 carbon atoms; the aforementioned R 5 radicals are optionally substituted with 1 to 3 substituents chosen independently of each other from the group comprising: C 1 -C 6 alkyl, optionally substituted with amino, fluoro, chloro, carboxyl, hydroxy or carbamoyl groups; fluoro, chloro or bromo; -OR 3; -0 C 02 R 3; -OCOR 3; -OCONR 3 R 4; -OS-R 9; oxo; -NR 3 R 4; R 3 CONR 4-; -NR 3 CO 2 R 4; 1-NR 3 CONR 3 R 4; O I-NR 35-Rg; I -SR 3; o -S-R 9; O-Rg; -503 R 3; -C 02 R 3; -CONR 3 R 4;   CN; or phenyl, optionally substituted with 1 to 3 fluorine, chlorine or bromine atoms, or 1 to 3 C 1 -C 6 alkyl groups, -OR 3, -NR 3 R 4, 503 R 4, -C 02 R 3 or -CONR 3 R 4, wherein R 3, R 4   and R 9 in these substituents Rs are as defined above.   above; or R 5 can be linked to group N   at another point in the nucleus, so as to form a heterogeneous nucleus   aromatic or heterocyclic fused, which ring may further contain up to two additional hetero atoms consisting of oxygen, nitrogen or sulfur; A is a linear or branched chain alkylene radical; R 2 is a hydrogen atom, an anionic charge or a carboxyl group easily separable conventional, it being understood that when R 2 is a hydrogen atom or a protecting group is also present a counter-ion; and N-5 represents a radical selected from the group consisting of: N S _ or 2533 6   wherein X is 0, S or NR with R being C r -C, alkyl; C 1 -C 4 alkyl substituted with 1 to 3 hydroxy, amino, C 1 -C alkylamino, di (C 1 -C 4) alkylamino, C 1 -C 4 alkoxy, carboxy, halo or sulfo; C 3 -C 6 cycloalkyl; C 3 -C 6 cycloalkyl (C 1 -C 4) alkyl optionally substituted with 1 to 3 of the substituents mentioned above in relation to C 1 -C 4 alkyl;   phenyl; phenyl substituted with 1 to 3 of the substituents chosen inde-   from each other among amino, halo, hydroxy, trifluoro-   methyl, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, C 1 -C 4 alkylamino, di (C 1 -C 4) alkyl-   amino, carboxy and sulfo; phenyl (C 1 -C 4) alkyl in which the phenyl part may be optionally substituted with 1 to 3 of the substituents mentioned above in relation to the phenyl radical and the alkyl part may be optionally substituted with 1 of the 3 substituents mentioned hereinabove; above in relation to the radical Cl-C 4 alkyl;   and heteroaryl and heteroaralkyl in which the at least one heteroaryl   mes are selected from the group consisting of 1 to 4 oxygen atoms,   of sulfur or nitrogen and the alkyl part associated with the hetero radical.   aralkyl has 1 to 6 carbon atoms, these heteroaryl and heteroaralkyl groups being optionally substituted in the heterocyclic ring portion by 1 to 3 substituents independently selected   from each other among the hydroxy, amino, halo, trifluoro-   methyl, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, C 1 -C 4 alkylamino, di (C 1 -C 4) alkyl-   amino, carboxy and sulfo and the alkyl part is substituted with 1 to 3 substituents belonging to the groups comprising hydroxy, amino, C 1 -C 4 alkylamino, di (C 1 -C 4) alkylamino, C 1 -C 4 alkoxy, carboxy, halo and sulfo; this heteroaromatic radical being optionally substituted   on carbon atomization by one or more substituents selected inde-   pendammient from each other from the group consisting of C, -C alkyl; C 1 -C 4 alkyl substituted with, preferably 1 to 3 hydroxy, amino, C 1 -C 4 alkylamino, di (C 1 -C 4 alkyl) amino, C 1 -C 4 alkoxy, sulfo, carboxy or halo 3 ( chloro, bromo, fluoro or iodo, preferably chloro, fluoro or bromo);   C 3 -C 6 cycloalkyl; C 1 -C alkoxy; C, -C 4 alkylthio; amino; C, -C, alkylamino; di (C 1 -C 4 alkyl) amino; halo (chloro, bromo, fluoro or iodo;   * + preferably chloro, fluoro or bromo); C 1 -C 4 alkanoylamino; C 1 -C 4 alka   noyloxy; carboxy; -C (O) -OC 1 -C 4 alkyl; hydroxy; amidino; guanidino: phenyl; phenyl substituted with 1, 2 or 3 amino groups, halo (chloro, bromo, fluoro or iodo, preferably chloro, fluoro or bromo), hydroxyl, trifluoromethyl, C 1 -C 4 alkyl or C 1 -C 4 alkoxy; phenyl (C 1 -C 4) alkyl in which the alkyl part may be optionally substituted with 1 to 3 of the substituents mentioned above in relation to the phenyl radical and / or the alkyl part may be optionally substituted with 1 to 3 of the substituents mentioned above in relation to the radical C 1 -C 4 alkyl; and heteroaryl and heteroaralkyl wherein the one or more hetero atoms of the aforementioned heterocyclic moieties are selected from the group consisting of 1 to 4 oxygen atoms, nitrogen   or sulfur-and / or the alkyl part associated with said hetero portion   aralkyl has 1 to 6 carbon atoms or optionally   killed to form a heteroaromatic, heterocyclic ring or   fused carbocyclic ring, optionally substituted with 1 or 2 stituents defined above;   as well as the pharmaceutically acceptable salts derived therefrom.   17. As new industrial products, the compounds of formula R 8 H he <N -R 5 N OOR 2   wherein: Re is a hydrogen atom; and   R is selected from the group consisting of hydrogen as well as   substituted or unsubstituted diols, of the following list: alkyl, alkenyl and alkynyl having 1 to 10 carbon atoms; cycloalkyl and cycloalkylalkyl 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 wherein the aryl portion is formed by a phenyl radical and the aliphatic moiety comprises from 1 to 6 carbon atoms; heteroaryl, heteroaralkyl, heterocyclyl and heterocyclic alkyl wherein the hetero ring hetero atom (s) are selected in the group comprising 1 to 4 oxygen atoms, nitrogen   or sulfur and the alkyl part associated with these heterocyclic moieties   1 to 6 carbon atoms, meaning that the substituents relating to the aforementioned radicals are independently of one another, selected from the group consisting of: C, -C-alkyl, optionally substituted with an amino, halo, hydroxy or carboxyl group; ; It -OCR 3 halo -SR 3 -OR 3 0 O Hl He 2 * 5 -SR 9 -OCNR 3 R 4 0 O He He -SR 9 -CNR 3 R 4 0 -NR 3 R 4 CN -N 3 NR 3 -OSO 3 R 3 < O NR 3 R " -S-R -502 NR 3 R 4 -OS-R 9 i O O OI o O -NHCNR 3 R 4 I -NR 3 S-R O tl l Il O I 0 R CNR 4- -NR 3 C = NR 4 -C 02 R 3 3 -OP (O) (OR 3) (OR 4) -NR 3 CO 2 R 4 = O   -NO 2 in which; as regards the above-mentioned substituents:   the groups R 3 and R 4, independently of one another,   hydrogen, or alkyl, alkenyl and alkynyl radicals of 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 part; phenyl; aralkyl, aralkenyl and aralkynyl wherein the aryl portion is a phenyl radical and   the aliphatic portion comprises 1 to 6 carbon atoms; and   roaryl, heteroaralkyl, heterocyclyl and heterocyclylalkyl in   which the hetero ring hetero ring (s)   cited consist of 1 to 4 atoms of oxygen, nitrogen or sulfur   and the alkyl portion associated with said heterocyclic portions   take from 1 to 6 carbon atoms; or R 3 and R 'together with the nitrogen to which at least one of them is bonded, form a 5- or 6-membered nitrogen containing terocyclic ring; 229 2533568   R 9 is similar to R 3 except that it can not be hydrogen; or wherein R 1 and R 8 taken together form a C 2 -C 10 alkylidene or C 2 -C 8 alkylidene radical substituted with a hydroxy group; R 5 belongs to the group of radicals, optionally substituted: alkyl, alkenyl, alkynyl comprising 1 to 10 carbon atoms;   cycloalkyl and cycloalkylalkyl having 3 to 6 carbon atoms   bone in the cycloalkyl part and i to 6 carbon atoms in the alkyl parts; phenyl; aralkyl, aralkenyl and aralkynyl wherein the aryl moiety is a phenyl radical and the aliphatic portion of which has 1 to 6 carbon atoms; heteroaryl, heteroaralkyl, heterocyclyl and heterocyclylalkyl wherein the one or more hetero atoms of said heterocyclic moieties consist of I to 4 oxygen, nitrogen and / or   sulfur and the alkyl moieties associated with said hetero-   cyclic include 1 to 6 carbon atoms; the radicals Rs mentioned above are optionally substituted with 1 to 3 substituents chosen independently of each other from the group comprising: C 1 -C 6 alkyl, optionally substituted with amino, fluoro, chloro, carboxyl, hydroxy or carbamoyl groups; fluoro, chloro or bromo; -OR 3; -OC 02 R 3; -OCOR 3; -OCONR 3 R 4; O Il -OS-Rg; oxo; -NR 3 R 4; R 3 CONR 4-; -NR 3 CO 2 R 4; -NR 3 CONR 3 R 4; O -NR 35-Rg; -SR 3; we -S-R 9; O?: -S-Rg; -SO 3 R 3; -C 02 R 3; -CONR 3 R 4;   CN; or phenyl, optionally substituted with 1 to 3 fluorine, chlorine or bromine atoms, or 1 to 3 C 1 -C 6 alkyl groups, -OR 3, -NR 3 R 4, SO 3 R ", -C 02 R 3 or -C Otl R 3 R 4, wherein R 3, R 4   and R 9 in these substituents Rs are as defined above.   above; or R 5 can be linked to the group   at another point in the nucleus, so as to form a heterogeneous nucleus   aromatic or fused heterocyclic ring, which ring may further contain up to two additional hetero atoms consisting of oxygen, nitrogen or sulfur; A is a linear or branched chain alkylene radical; R 2 is a hydrogen atom, an anionic charge or a carboxyl group easily separable conventional, it being understood that when R 2 is a hydrogen atom or a protecting group is also present a counter-ion; and N-R 5 represents a radical selected from the group consisting of: * S R 5 X   And wherein X is O, S or NR with R being a C 1 -C 4 alkyl radical; C 1 -C 4 alkyl substituted with 1 to 3 hydroxy, amino, C 1 -C 4 alkylamino, di (C 1 -C 4) alkylamino, C 1 -C 4 alkoxy, carboxy, halo or sulfo; C 3 -C 8 cycloalkyl; C 3 -C 6 cycloalkyl (C 1 -C 4) alkyl optionally substituted with 1 to 3 of the substituents mentioned above in relation to the C 1 -C 4 alkyl radical; phenyl; phenyl substituted with 1 to 3 substituents independently selected from the group consisting of amino, halo, hydroxy, trifluoromethyl, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, C 1 -C 4 alkylamino, di (C 1 -C) 4) alkylamino, carboxy and sulfo; phenyl P1-C4) alkyl in which the phenyl moiety may be optionally substituted with 1 to 3 of the substituents mentioned above in relation to   with the phenyl radical and / or the alkyl part may be   substituted with 1 to 3-substituents mentioned above in * lation with the radical C 1 -C, alkyl; and heteroaryl and heteroaralkyl   in which the hetero atom (s) are selected from the group   taking 1 to 4 atoms of oxygen, sulfur and / or nitrogen and where the   alkyl moiety associated with the heteroaralkyl radical has from 1 to 6 atoms   carbon, these heteroarayl and heteroaralkyl groups being substituted   killed in the heterocyclic ring portion by 1 to 3 substituents independently selected from the group consisting of hydroxy, amino, halo, trifluoromethyl, CC 4 alkyl, C 1 -C 4 alkoxy, C 1 -C 4 alkylamino, di ( C 1 -C 4 alkylamino, carboxy and sulfo and where   The alkyl part may have from 1 to 3 substituents selected from   xy, amino, C 1 -C 4 alkylamino, di (C 1 -C 4) alkylamino, C 1 -C 4 alkoxy, carboxy,   halo and sulfo; this heteroaromatic radical being optionally substituted   killed on a carbon atom by a substituent selected from the group consisting of C 1 -C 4 alkyl; C 1 -C 4 alkyl substituted with, preferably, 1 to 3 hydroxy, amino, C 1 -C 4 alkylamino, di (C 1 -C 4 alkyl) amino, C 1 -C 4 alkoxy, sulfo, carboxy or halo (chloro bromo, fluoro or iodo, preferably chloro, fluoro or bromo); C 3 -C 6 cycloalkyl; C 1 -C 4 alkoxy; C 1 -C 4 alkylthio; amino; C 1 -C 4 alkylamino; di (C1-C4alkyl) amino; halo (chloro, bromo, fluoro or iodo, preferably chloro, fluoro or bromo); C 1 -C 4 alkanoylamino; C 1 -C 4 alkanoyloxy; carboxy; -C (O) -OC 1 -C 4 alkyl; hydroxy; amidino; guanidino; phenyl; phenyl substituted by 1, 2 or 3 amino, halo (chloro, bromo, fluoro or iodo, preferably chloro, fluoro or bromo), hydroxyl, trifluoromethyl, C 1 -C 4 alkyl   or C 1 -C 4 alkoxy; phenyl (C 1 -C 4) alkyl in which the phenyl part   nyle may be optionally substituted with 1 to 3 substituents   mentioned above in relation to the phenyl radical and / or the   to alkyl may be substituted by 1 to 3 substitutions   mentioned above in relation to the radical C 1 -C 4 alkyl; and heteroaryl or heteroaralkyl wherein the one or more hetero atoms in said heterocyclic moieties are selected from the group consisting of 1 to 4 oxygen, nitrogen and / or sulfur atoms and wherein the alkyl moiety associated with said heteroaralkyl moiety comprises at 6 carbon atoms; and   as well as the pharmaceutically acceptable salts thereof.   18. As new industrial products, compounds of formula RB H RS N-R N OOR 2 '   wherein QOR is a hydrogen atom; and   RI is selected-in the group comprising hydrogen as well as   substituted or unsubstituted organic radicals of the following list: alkyl, alkenyl and alkynyl having 1 to 10 carbon atoms; cycloalkyl and cycloalkylalkyl 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 wherein the aryl portion is formed by a phenyl radical and the aliphatic portion comprises from 1 to 6 carbon atoms; heteroaryl, heteroaralkyl, heterocyclyl and heterocyclylalkyl wherein the one or more hetero atoms of said heterocyclic moieties are selected from the group consisting of 1 to 4 oxygen atoms, nitrogen   or sulfur and the alkyl part associated with these heterocyclic moieties   C is 1 to 6 carbon atoms, it being understood that the substituent (s) relative to the aforementioned radicals are, independently of one another, selected from the group comprising: C 1 -C 6 alkyl, optionally substituted with an amino group halo, hydroxy or carboxyl; O If -OCR 3 halo -SR 3 -OR 3 0 O -SR 9 -OCNR 3 R 4 O O itt -SR 9 -CNRR ' I 0 -NR 3 R 4 CN -N 3 NR 3 -O 503 R 3 O NR 3 R 4 f I -OS-Rs -502 NR 3 R 4 Is O O Io 0 -NHCNR 3 R 4 -NR-S-R 9 O he R _ He I 0 R 3 CNR 4- -NR 3 C = NR 4 -CO 2 R 3 R 3 -OP (O) (OR 3) (OR 4) -NR 3 CO 2 R = O -NO 2   in which, with regard to the abovementioned substituents:   the groups R 3 and R 4, independently of one another,   hydrogen, or alkyl, alkenyl and alkynyl radicals of 1 to 10 carbon atoms; cycloalkyl, cycloalkylalkyl and alkylcycloalkyl comprising 3 to 6 carbon atoms in the cycloalkyl part and i to 6 carbon atoms in the alkyl part; phenyl; aralkyl, aralkenyl and aralkynyl wherein the aryl portion is a phenyl radical and   the aliphatic portion comprises 1 to 6 carbon atoms; and   roaryl, heteroaralkyl, heterocyclyl and heterocyclylal-1, in   which the heteroatom (s) of the heterocyclic   1 to 4 atoms of oxygen, nitrogen or sulfur and the alkyl portion associated with said heterocyclic portions comprise from 1 to 6 carbon atoms, or R 3 and R "together with nitrogen to which at least one of them is bonded, a 5- or 6-membered nitrogen-containing heterocyclic ring; R 9 is similar to R 3 except that it can not be hydrogen; or, wherein R 1 and R 8 taken together form a C 2 -C 10 alkylidene or C 2 -C 10 alkylidene radical substituted with a hydroxy group; R 5 belongs to the group of radicals, optionally substituted: alkyl, alkenyl, alkynyl comprising I to 10 carbon atoms;   cycloalkyl and cycloalkylalkyl having 3 to 6 carbon atoms   carbon in the cycloalkyl part and 1 to 6 carbon atoms in the alkyl parts; phenyl; aralkyl, aralkenyl and aralkynyl wherein the aryl moiety is a phenyl radical and the aliphatic portion of which has 1 to 6 carbon atoms; heteroaryl, heteroaralkyl, heterocyclyl and heterocyclylalkyl wherein the one or more hetero atoms of the aforementioned heterocyclic moieties consist of 1 to 4 oxygen, nitrogen and / or   sulfur and the alkyl moieties associated with said hetero-   cyclic include 1 to 6 atomnies of carbon; the radicals R 5 mentioned above are optionally substituted with 1 to 3 substituents chosen independently of each other from the group comprising: C 1 -C 6 alkyl, optionally substituted with amino, fluoro, chloro, carboxyl, hydroxy or carbamoyl groups; fluoro, chloro or bromo; -OR 3; -OC 02 R 3; -OCOR 3; * 5 -OCONR 3 R 4; O-a-05-Rs; O oxo; -NR 3 R 4; R 3 CONR 4-; -NR 3 CO 2 R 4; -NR 3 CONR 3 R 4; O I -NR 35-R 9; I o -SR 3; -S-R 9; O -S-Rg; -SO 3 R 3; -CO 2 R 3; -CONR 3 R 4;   CN; or phenyl, optionally substituted with 1 to 3 fluorine, chlorine or bromine atoms, or 1 to 3 C 1 -C 6 alkyl groups, -OR 3, -NR 3 R 4, SO 3 R 4, -CO 2 R 3 or -CONR 3 R 4, wherein R 3, R 4   and R 9 in these substituents R 5 are as defined above.   above; or Rs can be linked to the group   at another point in the nucleus, so as to form a heterogeneous nucleus   aromatic or heterocyclic fused, which ring may further contain up to two additional hetero atoms consisting of oxygen, nitrogen or sulfur; A is a linear or branched chain alkylene radical; R 2 is a hydrogen atomase, anionic charge or a readily separable carboxyl-protecting group, it being understood that when R 2 is a hydrogen atom or a protecting group is also present a counter-ion; and represents a radical selected from the group consisting of: t 2 J-RY N-R R 5-I il-R N N-R R -N N-R N N-R   j J 5 1 l or r Jf Eh R N ON has 5 _ -N t   in which R is a C 1 -C 4 alkyl radical; C 1 -C 4 alkyl substituted   killed by 1 to 3 hydroxy, amino C 1 -C 4 alkylamino, di (C 1 -C 4) alkylamino,   C 1 -C 4 alkoxy, carboxy, halo or sulfo; C 3 -C 6 cycloalkyl; C 1 -C 4 Cyclo   alkyl (C 1 -C 4) alkyl optionally substituted with 1 to 3 of the substituents mentioned above in relation to the radical C 1 -C 4 alkyl; phenyl; phenyl substituted with 1 to 3 substituents independently selected from   each other in the group consisting of amino, halo, hydroxy, tri-   fluoromethyl, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, C 1 -C 4 alkylamino, di (C 1 C 4)   alkylamino, carboxy and sulfo; phenyl (C 1 -C 4) alkyl in which the   The phenyl moiety may be substituted with 1-3 substituents   mentioned above in relation to the phenyl radical and where the alkyl part may be optionally substituted with 1 to 3 of the   substituents mentioned above in relation to the radical C 1 -C 4   alkyl; and heteroaryl and heteroaralkyl in which the one or more   tero atoms are selected from the group consisting of 1 to 4 oxy-   gene, sulfur and / or nitrogen and o the alkyl part associated with the   heteroaralkyl group having 1 to 6 carbon atoms, these heteroaryl and heteroaralkyl groups being optionally substituted in the part of the heterocyclic ring by 1 to 3 of the substituents chosen independently of each other from hydroxy, amino, halo, trifluoromethyl, C 1- C 4 alkyl, C 1 -C 4 alkoxy, C 1 -C 4 alkylamino,   di (C 1 -C 4) alkylamino, carboxy and sulfo and the alkyl part is   optionally substituted with 1 to 3 substituents selected from the group consisting of hydroxy, amino, C1-C4 alkylamino, di (C1-C4) alkylamino,   C1-C4 alkoxy, carboxy, halo and sulfo.   Groups R and RS can also together form a heterogeneous nucleus   rocyclic or fused heteroaromatic -   In the aforementioned preferred aspect of the present invention, the compounds preferably involved are those wherein A is - (CH 2) n with N being 1 or 2 and more particularly those in which A is -CH 2 and o: ( a) R 1 and RI together form the group HOCH 2 C = CH 3, /   or (b) RB is hydrogen and RI is hydrogen, or one of the groups CH 3 CH 2, CH 3 CH 3 OH OH CH-, C or CH 3 CH- C 3 CH 3 CH 3   Especially preferred are the compounds wherein R 8 is hydrogen and R 1 is OH CH 3 CH-   and in particular, the compounds having the absolute configuration b R, 65, 8 R. Another particularly preferred aspect of the present invention consists in the compounds of formula I in which represents a radical of formula R 6 R 1 in which: R 6, R 7 and R 10 are, independently of one another, selected from the group consisting of hydrogen and C 1 -C 4 alkyl, C 1 -C 4, alkoxy, carboxyl and carbamoyl; as well as the pharmaceutically acceptable salts derived therefrom. 19. As new industrial products, compounds of formula H 8- R. S-A-R COOR 2   wherein: Re is a hydrogen atom; and   R is selected from the group consisting of hydrogen as well as   substituted or unsubstituted organic radicals of the following list: alkyl, alkenyl and alkynyl having 1 to 10 carbon atoms; cycloalkyl and cycloalkylalkyl 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 wherein the aryl portion is formed by a phenyl radical and the aliphatic portion comprises 1 to 6 carbon atoms; heteroaryl, heteroaralkyl, heterocyclyl and heterocyclylalkyl wherein the one or more hetero atoms of said heterocyclic moieties are selected from the group consisting of 1 to 4 oxygen atoms, nitrogen   or sulfur and the alkyl part associated with these heterocyclic moieties   1 to 6 carbon atoms, it being understood that the substituent (s) relative to the abovementioned radicals are independently of one another, chosen from the group comprising: C 1 -C 6 alkyl, optionally substituted with an amino group halo, hydroxy or carboxyl; I-OCR 3 halo -SR 3 -OR 3 0 O II II -SR 9 -OCNR 3 R 4 0 O II He -SR 9 -CNRR 4- a o ,, -NR 3 R 4 -CN -N 3 NR 3 -O 503 R 3 o <NR RR -OS-R 9 -502 NR 3 R 4 oo II 0 O -NHCNR 3 R 4 f I -NR 3 S-R 9 O he 0 R S CNR 4- -NR 3 C = NR "-C 02 R 3 R 3 -OP (O) (OR 3) (OR 4) -NR 3 CO 2 R 4 = O   -NO 2 in which, with regard to the abovementioned substituents:   the groups R 3 and R, independently of each other,   hydrogen, or alkyl, alkenyl and alkynyl radicals of 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 part; phenyl; aralkyl, aralkenyl and aralkynyl wherein the aryl portion is a phenyl radical and   the aliphatic moiety comprises 1 to 6 carbon atoms; and   roaryl, heteroaralkyl, heterocyclyl and heterocyclylalkyl in   which the hetero ring hetero ring (s)   cited consist of 1 to 4 atoms of oxygen, nitrogen or sulfur   and the alkyl portion associated with said heterocyclic portions   take from 1 to 6 atomnies of carbon; or R 3 and R 4 together with nitrogen to which at least one of them is attached form a 5- or 6-membered nitrogen-containing heterocyclic ring; 240 2533568   R 9 is similar to R 3 except that it can not be hydrogen; or wherein R 1 and R 2 taken together form a C 2 -C 12 alkylidene or C 2 -C 8 alkylidene radical substituted with a hydroxy group; R 5 belongs to the group of radicals, optionally substituted: alkyl, alkenyl, alkynyl comprising 1 to 10 carbon atoms;   cycloalkyl and cycloalkylalkyl having 3 to 6 carbon atoms   bone in the cycloalkyl part and 1 to 6 carbon atoms in the alkyl parts; phenyl; aralkyl, aralkenyl and aralkynyl wherein the aryl portion is a phenyl radical and the aliphatic portion of which has 1 to 6 carbon atoms; heteroaryl, heteroaralkyl, heterocyclyl and heterocyclylalkyl wherein the one or more hetero atoms of the aforementioned heterocyclic moieties consist of 1 to 4 oxygen, nitrogen and / or   sulfur and the alkyl moieties associated with said hetero-   cyclic include 1 to 6 carbon atoms; the radicals R 5 mentioned above are optionally substituted with 1 to 3 substituents chosen independently of each other from the group comprising: C 1 -C 6 alkyl, optionally substituted with amino, fluoro, chloro, carboxyl, hydroxy or carbamoyl groups; 4 + fluoro, chloro or bromo; -OR 3; -0 C 02 R 3; -OCOR 3; -OCONR 3 R 4; -OS-Rg; I oxo; -NR 3 R 4; R 3 CONR 4-; -NR 3 CO 2 R 4; -NR 3 CONR 3 R 4; O -NR 35-R 9; O -50 -SR 3; o -S-R 9; 0 O oo -S-R 9; -SO 3 R 3; -CO 2 R 3; -CONR 3 R 4;   CN; or phenyl, optionally substituted with 1 to 3 fluorine, chlorine or bromine atoms, or 1 to 3 C 1 -C 6 alkyl groups, -OR 3, -NR 3 R 4, 503 R 4, -C 02 R 3 or -COIR 3 R 4, wherein R 3, R 4   and R 9 in these substituents Rs are as defined above.   above; or Rs can be linked to the group {A V N-   at another point in the nucleus, so as to form a heterogeneous nucleus   aromatic or fused heterocyclic ring, which ring may further contain up to two additional hetero atoms consisting of oxygen, nitrogen or sulfur; A is a linear or branched chain alkylene radical; R 2 is a hydrogen atom, an anionic charge or a carboxyl group easily separable conventional, it being understood that when R 2 is a hydrogen atom or a protecting group is also present a counter-ion; and N u represents a radical of formula: in which: R 6, R 7 and R 10 are, independently of one another, chosen from the group comprising the hydrogen atom and the C 1 -C 4 alkyl radicals, C 1 -C 4 C 4 -alkoxy, carboxy and carbamoyl, and their pharmaceutically acceptable salts derived therefrom.   Compounds according to any of claims 1, 2, 6 to 19,   characterized in that R1 represents a hydrogen atom or a radical CH 3 -CH 2, CH 3 CH 3 OH OH NOT CH, C-C or CH 3-CH- CH 3, / CH 3 /   Compounds according to any of claims 1, 2, 6 to 19,   characterized in that R and R 8 together form a radical HOCH 2 XC = CH 3 '/   22. Compounds according to any of claims 1, 2, 6 to 20,   characterized in that RI is a radical OH CH 3-CH-   23. Compounds according to any of claims 1 to 12 and 14   at 20, characterized in that R 1 is the radical CH 3 CH- OH   and in that the absolute configuration is R, 65, 8 R.   24. Compounds according to any one of claims 1 to 23,   characterized in that A is -CH 2 or -CH 2 CH 2.   25. As new industrial products, the compounds of formula OH R - (R) |, _ <   wherein: A is a linear or branched chain alkylene radical; R 2 is a hydrogen atom, an anionic charge or a carboxyl group easily separable conventional, it being understood that when R 2 is a hydrogen atom or a protecting group is also present a counter-ion; and iron 5 -C N-R represents a radical of formula 6   (a) R with: R 5 is a C 1 -C 4 alkyl radical, and R 6 is hydrogen or a C 1 -C 4 alkyl radical; (b) wherein Rs is C 1 -C 4 alkyl, and R 6 and R 7 are hydrogen or a C 1 -C 4 alkyl radical; (c) R-N R in which: - Rs is C 1 -C 4 alkyl, and 2533568-   R is a C 1 -C 4 alkyl or phenyl (C 1 -C 4) alkyl radical; (d) R in which: R 5 is a C 1 -C 4 alkyl radical, and R 6 is a C 1 -C 4 alkyl radical, R 5 (e) R in which: R 5 is a C 1 -C radical 4 alkyl, and R is a C 1 -C 4 alkyl radical, or 2 ON * (fe) No - '-   wherein: R 5 S is C 1 -C 4 alkyl,   as well as their pharmaceutically acceptable salts derived therefrom.   26. As new industrial products, compounds of the formula OH (R) e N 2 R OO / R   in which A is a linear or branched chain alkylene radical; R 2 is a hydrogen atom, an anionic charge or a conventional easily separable carboxyl protecting group, it being understood that when R 2 is a hydrogen atom; or a protecting group is also present a counter-ion, and R is a radical belonging to the following groups: (a) ## STR2 ## N "CH - CH 3 CH 3 (c) () / NC 2 2 CH 3 CH CH on 2530 3 CH 3 <h) i CH 3 H 35 CH 3 This H 3 CH 3 H N I (g) (h) 3 CH 2533568-   (i) (k) CH 3 Cl C 2 N CH 3 x e H 3 H 3 N -S> CH 3 CH 3 NH (n) "N N or CH 3   as well as their pharmaceutically acceptable salts thereof.   27. As new industrial products, the compounds having the formula ## STR2 ## in which: R 2 is hydrogen, an anionic charge or a carboxyl group easily separable classical provided that when R 2   is hydrogen or a protecting group, also a counter-ion and in which -S-S-A R 5 __ __ _R   is one of the following radicals: ## STR1 ## SCH 2 N CH 3 -SCH -SCH H 2 CH 2 CH 3 * (f) (h) (g) CH 3 CH and 3 N -SCH 2 N Lon 3s -SCH 2 G H CH O CH 3 111, N - -SCÉ 2 S -CH (j) (i) -SCH 3   (k) CH (mi) -SCH 2 N CH 3 (n) (P) CH (O) -SCH 2 N Ie -SCH 2 d N- N C CH 3 CH 3   it being understood that the 1H NMR spectrum (D 20) has the characteristic peaks   at 6: 1.23 (3H, d, I = 6.4 Hz); 3.12 (2Hl, q, I = 1.4, 8.9Hz); 3.39 (1H, q, I = 2.1, 6.0 Hz); 4.07-4.68 (10H, ni); 8.19 (1H, s); (q) SC Hi CH 3, whose 1H NMR spectrum (D, 20) has the characteristic peaks at 6: 1.23 (3H, d, I = 6.4 Hz); 3.15 (2H, q, I = 3.7, 9.0 Hz); 3.37 (1H, q, I = 2.6, 6.0 Hz); 3.95-4.65 (10H, m); 8.62 (1H, s); (R) _SCH S H 3 (S) - -SCH 2- -t. Jf (t) CH 3 (u) CH 3 ie 3 (u 3 N N -SCH 2 i N -SCH 2 or _ / NCH 2 COO N N CH (v) / H 3 NYN 1 CH 3   as well as their pharmaceutically acceptable salts thereof.   28. As new industrial products, the compound of the formula OH H (R) ç <r O COOR 2   A is a linear or branched chain alkylene radical; R 2 is a hydrogen atom, an anionic charge or a carboxyl group easily separable conventional, it being understood that when R 2 is a hydrogen atom or a protecting group is also present a counter-ion;   as well as the pharmaceutically acceptable salts derived therefrom.   29. As new industrial products, the compound of formula OH H (R "SCH 2 CH (R) 2/2 - NOT N COOR 2 3   A is a straight or branched chain alkylene radical; R 2 is a hydrogen atom, an anionic charge or a carboxyl group easily separable conventional, it being understood that when R 2 is a hydrogen atom or a protecting group is also present a counter-ion;   as well as the pharmaceutically acceptable salts derived therefrom.   30. As new industrial products, the compound of formula OH H (R) SCH 2 CH 2 / CH (R) N-CH 3   N 2 OOR A is a straight or branched chain alkylene radical; R 2 is a hydrogen atom, an anionic charge or a carboxyl group easily separable conventional, it being understood that when R 2 is a hydrogen atom or a protecting group is also present a counter-ion;   as well as the pharmaceutically acceptable salts derived therefrom.   31. As new industrial products, the compound of formula CH OH HN (SCH 2   ## STR2 ## is a straight or branched chain alkylene radical; R 2 is a hydrogen atom, an anionic charge or a carboxyl group easily separable conventional, it being understood that when R 2 is a hydrogen atom or a protecting group is also present a counter-ion;   as well as the pharmaceutically acceptable salts derived therefrom.   32 As new industrial products, the compound of formula OH H (R) SCH 2 NOT O OR 2 CH 3   A is a linear or branched chain alkylene radical; R 2 is a hydrogen atom, an anionic charge or a carboxyl group easily separable conventional, it being understood that when R 2 is a hydrogen atom or a protecting group is also present a counter-ion;   as well as the pharmaceutically acceptable salts derived therefrom.   33. As new industrial products, the compound of the formula OH H (R) SCH 2 N-CH 2 CH 2 CH 3   ## STR5 ## is a linear or branched chain alkylene radical; R 2 is a hydrogen atom, an anionic charge or a carboxyl group easily separable conventional, it being understood that when R 2 is a hydrogen atom or a protecting group is also present a counter-ion;   as well as the pharmaceutically acceptable salts derived therefrom.   34. As new industrial products, the compound of formula CH <R) OHSCH N 2 OORCH 3   A is a straight or branched chain alkylene radical; R 2 is a hydrogen atom, an anionic charge or a carboxyl group easily separable conventional, it being understood that when R 2 is a hydrogen atom or a protecting group is also present a counter-ion;   as well as the pharmaceutically acceptable salts derived therefrom.   35. As new industrial products, the compound of formula OH H CH 3 SCH N : (R) <SCN 2 <> H 3   OOR 2 A is a straight or branched chain alkylene radical; R 2 is a hydrogen atom, an anionic charge or a carboxyl group easily separable conventional, it being understood that when R 2 is a hydrogen atom or a protecting group is also present a counter-ion;   as well as the pharmaceutically acceptable salts derived therefrom.   As novel industrial products, the compound of formula (R) has J SCH 2 N A is a straight or branched chain alkylene radical; R 2 is a hydrogen atom, an anionic charge or a carboxyl group easily separable conventional, it being understood that when R 2 is a hydrogen atom or a protecting group is also present a counter-ion;   as well as the pharmaceutically acceptable salts derived therefrom.   37. As new industrial products, the compound of formula CH H) CC CH 3 OH H 3 - / 3   (R) A is a straight or branched chain alkylene radical; R 2 is a hydrogen atom, an anionic charge, or a readily-separable carboxyl-protecting group, it being understood that when R 2 is a hydrogen atom or a protecting group is also present a counter-ion;   as well as the pharmaceutically acceptable salts derived therefrom.   38. As new industrial products, the compound of formula OH C s "N 00 OR 2 CH 13   A is a straight or branched chain alkylene radical; R 2 is a hydrogen atom, an anionic charge or a carboxyl group easily separable conventional, it being understood that when R 2 is a hydrogen atom or a protecting group is also present a counter-ion;   as well as the pharmaceutically acceptable salts derived therefrom.   39. As new industrial products, the compound of formula OH C (R) H 2 / S-_CH I \ N-_CH 3   COR 2 A is a linear or branched chain alkylene radical; R 2 is a hydrogen atom, an anionic charge or a carboxyl group easily separable conventional, it being understood that when R 2 is a hydrogen atom or a protecting group is also present a counter-ion;   as well as the pharmaceutically acceptable salts derived therefrom.   40. As new industrial products, the compound of the formula OH H CH 2 (R) SCH N OOR 2 CH 3   A is a straight or branched chain alkylene radical; R 2 is a hydrogen atom, an anionic charge or a carboxyl group easily separable conventional, it being understood that when R 2 is a hydrogen atom or a protecting group is also present a counter-ion;   as well as the pharmaceutically acceptable salts derived therefrom.   41 As new industrial products, the compound of formula OH ? O N 00-OCR 2 C 1   R H CH 3 A is a straight or branched chain alkylene radical; R 2 is a hydrogen atom, an anionic charge or a carboxyl group easily separable conventional, it being understood that when R 2 is a hydrogen atom or a protecting group is also present a counter-ion;   as well as the pharmaceutically acceptable salts derived therefrom.   42. As new industrial products, the compound of formula OH H (R) "SCH 2 3   ## STR2 ## is a straight or branched chain alkylene radical; R 2 is a hydrogen atom, an anionic charge or a carboxyl group easily separable conventional, it being understood that when R 2 is a hydrogen atom or a protecting group is also present a counter-ion;   as well as the pharmaceutically acceptable salts derived therefrom.   43. As new industrial products, the compound of formula COO '/ co O e OH 'CH H (R) CH 2 N OOR 2 CH 3   A is a straight or branched chain alkylene radical; R 2 is a hydrogen atom, an anionic charge or a carboxyl group easily separable conventional, it being understood that when R 2 is a hydrogen atom or a protecting group is also present a counter-ion;   as well as the pharmaceutically acceptable salts derived therefrom.   44. As new industrial products, the compound of formula OH H CH OH SC   ## STR2 ## is a straight or branched chain alkylene radical; R 2 is a hydrogen atom, an anionic charge or a carboxyl group easily separable conventional, it being understood that when R 2 is a hydrogen atom or a protecting group is also present a counter-ion;   as well as the pharmaceutically acceptable salts derived therefrom.   45. As new industrial products, the compound of formula CH OH HJIÀ 3 (R) _AXSCH 2 N H 3 C O 00 ICOR 2   A is a straight or branched chain alkylene radical; R 2 is a hydrogen atom, an anionic charge or a carboxyl group easily separable conventional, it being understood that when R 2 is a hydrogen atom or a protecting group is also present a counter-ion;   as well as the pharmaceutically acceptable salts derived therefrom.   As new industrial products, the compound of the formula OH HCH 3 SCHN C f N 5 -N N 'I, -CO O R 2 O COOR CH   A is a straight or branched chain alkylene radical; R 2 is a hydrogen atom, an anionic charge or a carboxyl group easily separable conventional, it being understood that when R 2 is a hydrogen atom or a protecting group is also present a counter-ion;   as well as the pharmaceutically acceptable salts derived therefrom.   47. As new industrial products, the compound of formula OH H CH (R) I '3 N N WE O,   e A is a linear or branched chain alkylene radical; R 2 is a hydrogen atom, an anionic charge or a carboxyl group easily separable conventional, it being understood that when R 2 is a hydrogen atom or a protecting group is also present a counter-ion;   as well as the pharmaceutically acceptable salts derived therefrom.   48. Compounds according to any one of claims 28 to 47,   characterized in that R 2 is p-nitrobenzyl radical.   Compounds according to any one of claims 28 to 47,   characterized in that R 2 is an anionic charge.   50. As new industrial products, the compound of formula OE VECE er for which the 1 H NMR spectrum (D 20) has characteristic pyes for 6: 1.23 (3 H, d, I = 6.4 Hz) ; 3.12 (2H, q, I = 1.4, 8.9Hz); 3.39 (1H, q, I = 2.7, 6.0 Hz); 4.07-4.68 (OH, m); 8.19 (1H, s);   as well as the pharmaceutically acceptable salts thereof.   51 As new industrial products, the compound of formula OH SC 'N 3.   For which the NMR spectrum (D 20) has characteristic peaks for 6: 1.23 (3 H, d, I = 6.4 Hz); 3.15 (2H, qI = 3.7, 9.0 Hz); 3.37 (1H, qI = 2.6, 6, 0 Hz); 3.95-4.65 (10 μH,); 8.62 ((1H, s);   as well as the pharmaceutically acceptable salts thereof.   52. Compounds according to claim 50 or 51, characterized in that   the carboxyl group is protected by a p-nitrobenzyl ester.   53. As new industrial products, the compounds of * t Xformul e BZ   Wherein: Ra is a hydrogen atom; and   R is selected from the group consisting of hydrogen as well as   substituted or unsubstituted organic radicals of the following list: alkyl, alkenyl and alkynyl having 1 to 10 carbon atoms; cycloalkyl and cycloalkylalkyl 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 wherein the aryl portion is formed by a phenyl radical and the aliphatic portion comprises 1 to 6 carbon atoms; heteroaryl, heteroaralkyl, heterocyclyl and heterocyclylalkyl wherein the one or more hetero atoms of said heterocyclic moieties are selected from the group consisting of 1 to 4 oxygen atoms, nitrogen   or sulfur and the alkyl part associated with these heterocyclic moieties   comprises from 1 to 6 carbon atoms, it being understood that the substituents relating to the abovementioned radicals are, independently of one another, selected from the group comprising: C 1 -C 6 alkyl, optionally substituted with an amino group, halo, hydroxy or carboxyl; O O halo _OCR 3 -_SR 3 -OR 3 IR _SR 9 -OC) R 2 R 4 0 0 -59; Rops o _ 3 R 3 R 4 -CN NR 3 -N 3 NR 3 -OSO 3 R 3 O-NR 3 R 4 _ 502 NR 3 R 4 _-OS-R 9 -SO 2 NRR I 0- 0 i, 0 -NHCNR; R 4 the -NR 3 S-R 9 O he O R 3 CNR 4- -NR 3 C = NR 4 -C 02 R R, '-OP (O) (OR 3) (OR 4) -NR 3 CO 2 R 4 = O   -NO 2 in which, with regard to the abovementioned substituents:   the groups R 3 and R 4, independently of one another,   hydrogen, alkyl, alkenyl and alkynyl radicals of 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 part; phenyl; aralkyl, aralkenyl and aralkynyl wherein the aryl portion is a phenyl radical and   the aliphatic portion comprises 1 to 6 carbon atoms; and   roaryl, heteroaralkyl, heterocyclyl and heterocyclylalkyl in   which the hetero ring hetero ring (s)   cited consist of 1 to 4 atoms of oxygen, nitrogen or sulfur   and the alkyl portion associated with said heterocyclic portions   take from 1 to 6 carbon atoms; or R 3 and R 4 together with the nitrogen to which at least one of them is bound, form a 5- or 6-membered nitrogen-containing heterocyclic ring; R 9 is similar to R 3 except that it can not be hydrogen; or wherein R1 and RB taken together form a C 2 -C 10 alkylidene or C 2 -C 10 alkylidene radical substituted with a hydroxy group; Rs belongs to the group of radicals, optionally substituted: alkyl, alkenyl, alkynyl comprising 1 to 10 carbon atoms;   cycloalkyl and cycloalkylalkyl having 3 to 6 carbon atoms   bone in the cycloalkyl part and 1 to 6 carbon atoms in the alkyl parts; phenyl; aralkyl, aralkenyl and aralkynyl wherein the aryl portion is a phenyl radical and the aliphatic portion of which has 1 to 6 carbon atoms; heteroaryl, heteroaralkyl, heterocyclyl and heterocyclylalkyl * in which the one or more hetero atoms of said heterocyclic moieties consist of 1 to 4 atoms of oxygen, nitrogen and / or   sulfur and the alkyl moieties associated with said hetero-   cyclic include 1 to 6 carbon atoms; the radicals R 5 mentioned above are optionally substituted with 1 to 3 substituents chosen independently of each other from the group comprising: Cl-C 6 alkyl, optionally substituted by amino, fluoro, chloro, carboxyl, hydroxy or carbamoyl groups; fluoro, chloro or bromo; -OR 3; -OC 02 R 3; -OCOR 3; -OCONR 3 R 4; ol -OS-R 9; oxo; -NR 3 R 4; R 3 CONR 4-; NR 3 C 02 R 4; -NR 3 CONR 3 R 4; -NR 35-R-9; he o -SR 3;   R 15 is selected from the group consisting of hydrogen and the radicals, substituted or unsubstituted, of the following list:   alkyl, alkenyl and alkynyl, comprising from 1 to 10 carbon atoms   bone; cycloalkyl, cycloalkylalkyl and alkylcycloalkyl,   3 to 6 carbon atoms in the cycloalkyl part and 1 to 6 carbon atoms in the alkyl parts; spirocycloalkyl having 3 to 6 carbon atoms; phenyl; aralkyl, aralkenyl k   and aralkynyl in which the aryl part consists of a radical   phenyl cal and whose aliphatic part comprises from 6 atoms   of carbon; heteroaryl, heteroaralkyl, heterocyclyl and hetero-   cyclylalkyl wherein the one or more hetero atoms of said heterocyclic moieties consist of 1 to 4 oxygen, nitrogen or sulfur atoms and the alkyl moieties associated with said heterocyclic moieties comprise from 1 to 6 carbon atoms;   in which the substituent or substitutes relating to the radicals   are selected from the group consisting of: amino, mono-, di- and trialkylamino, hydroxyl, alkoxyl, mercapto, alkylthio, phenylthio, sulfamoyl, amidino, guanidino, nitro, chloro, bromo, fluoro, cyano and carboxy; and wherein the alkyl portions of the aforementioned substituents comprise from 1 to 6 carbon atoms; As new industrial products, the compounds of the formula IR H R 5 I-A X   wherein: R 8 is a hydrogen atom; and   R is selected from the group consisting of hydrogen as well as   substituted or unsubstituted organic radicals of the following list: alkyl, alkenyl and alkynyl having 1 to 10 carbon atoms; cycloalkyl and cycloalkylalkyl 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 wherein the aryl portion is formed by a phenyl radical and the aliphatic portion comprises 1 to 6 carbon atoms; heteroaryl, heteroaralkyl, heterocyclyl and heterocyclylalkyl wherein the one or more hetero atoms of said heterocyclic moieties are selected from the group consisting of 1 to 4 oxygen atoms, nitrogen   or sulfur and the alkyl part associated with these heterocyclic moieties   comprises from 1 to 6 carbon atoms, it being understood that the substituents relative to the abovementioned radicals are, independently of one another, selected from the group consisting of: C1-C6 alkyl, optionally substituted by an amino group, halo, hydroxy or carboxyl; I -0 OCR 3 halo -SR 3 -OR 3 1 0 0 -SR 9 -OCNR 3 R 4 0 O He Il t ,, -SR 9 -CNR 3 R 4 o -NR 3 R 4 CN H -rt 3 NR 3 -OSO 3 R 3 0 NR 3 R 4 * R -502 NR 3 R 4 -OS-R 9 0 I o O -NHCNR 3 R 4 -NR 3 S-R 9 t, t, 0 R-CNR "- -NR 3 C = NR 4 -C 02 R 3 R 3 -OP (O) (OR 3) (OR 4) -NR 3 CO 2 R 4 = O   -NO 2 in which, with regard to the abovementioned substituents:   the groups R 3 and R 4, independently of one another,   hydrogen, or alkyl, alkenyl and alkynyl radicals of 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 part; phenyl; aralkyl, aralkenyl and aralkynyl wherein the aryl portion is a phenyl radical and   the aliphatic portion comprises 1 to 6 carbon atoms; and   roaryl, heteroaralkyl, heterocyclyl and heterocyclylalkyl in   which the hetero ring hetero ring (s)   cited consist of 1 to 4 atoms of oxygen, nitrogen or sulfur   and the alkyl portion associated with said heterocyclic portions   take from 1 to 6 carbon atoms; or -R 3 and R 4 together with the nitrogen to which at least one of them is bound, form a 5- or 6-membered nitrogen-containing heterocyclic ring; R 9 is similar to R 3 except that it can not be hydrogen; or, wherein R 1 and R 2 taken together form a C 2 -C 10 alkylidene or C 2 -C 4 alkylidene radical substituted with a hydroxy group; R 5 belongs to the group of radicals, optionally substituted: alkyl, alkenyl, alkynyl comprising 1 to 10 carbon atoms;   cycloalkyl and cycloalkylalkyl having 3 to 6 carbon atoms   bone in the cycloalkyl part and 1 to 6 carbon atoms in the alkyl parts; phenyl; aralkyl, aralkenyl and aralkynyl wherein the aryl moiety is a phenyl radical and the aliphatic portion of which has 1 to 6 carbon atoms; heteroaryl, heteroaralkyl, heterocyclyl and heterocyclylalkyl wherein the one or more hetero atoms of the aforementioned heterocyclic moieties consist of 1 to 4 oxygen, nitrogen and / or   sulfur and the alkyl moieties associated with said hetero-   cyclic include 1 to 6 carbon atoms; the radicals Rs mentioned above are optionally substituted with 1 to 3 substituents chosen independently of each other from the group comprising: Ci-C 6 alkyl, optionally substituted by amino, fluoro, chloro, carboxyl, hydroxy or carbamoyl groups; fluoro, chloro or bromo; -OR 3; -0 C 02 R 3; -OCOR 3; -OCONR 3 R 4; O -OS-R 9; O oxo; -NR 3 R 4; R 3 CONR 4-; -NR 3 CO 2 R 4; -NR 3 CONR 3 R 4; O -NR 35-Rg; 15.-SR 3; -S-R 9; 0 O -S-R 9; -SO 3 R 3; -CO 2 R 3; -CONR 3 R 4;   CN; or phenyl, optionally substituted with 1 to 3 fluorine, chlorine or bromine atoms, or 1 to 3 CI-C 6 alkyl, -OR 3, -NR 3 R 4, 503 R 4, -C 02 R groups 3 or -CONR 3 R 4, wherein R 3, R 4   and R 9 in these substituents Rs are as defined above.   above; or Rs can be linked to group e NOT   at another point in the nucleus, so as to form a heterogeneous nucleus   aromatic or fused heterocyclic ring, which ring may further contain up to two additional hetero atoms consisting of oxygen, nitrogen or sulfur; R 16 is selected from the group consisting of: radicals, substituted or unsubstituted, of the following list:   alkyl, alkenyl and alkynyl, comprising from 1 to 10 carbon atoms   bone; cycloalkyl, cycloalkylalkyl and alkylcycloalkyl,   3 to 6 carbon atoms in the cycloalkyl part and 1 to 6 carbon atoms in the alkyl parts; spirocycloalkyl having 3 to 6 carbon atoms; phenyl; aralkyl, aralkenyl   and aralkynyl in which the aryl part consists of a radical   phenyl call and whose aliphatic part includes 6 atoms   of carbon; heteroaryl, heteroaralkyl, heterocyclyl and hetero-   cyclylalkyl wherein the one or more hetero atoms of said heterocyclic moieties consist of 1 to 4 oxygen, nitrogen or sulfur atoms and the alkyl moieties associated with said heterocyclic moieties of 1 to 6 carbon atoms;   in which the substituent or substitutes relating to the radicals   are selected from the group consisting of: amino, mono-, di- and trialkylamino, hydroxyl, alkoxyl, mercapto, alkylthio, phenylthio, sulfamoyl, amidino, guanidino, nitro, chloro, bromo, fluoro, cyano and carboxy; and wherein the alkyl moieties of the above substituents comprise from 1 to 6 carbon atoms; A is a straight or branched chain alkylene radical; R 2 is a hydrogen atom, an anionic charge or a carboxyl group easily separable conventional, it being understood that when R 2 is a hydrogen atom or a protecting group is also present a counter-ion; and represents a mono-, bi or polycyclic aromatic heterocyclic radical substituted or unsubstituted, containing at least one nitrogen atom   in the nucleus and bound to A by a carbon atom of the nucleus and pos-   sedant, in addition, a nitrogen atom in the nucleus that is quater- established by the Rs group;   as well as the pharmaceutically acceptable salts derived therefrom.   As new industrial products, the compounds of the formula RB R 16 R e 5 -c 35 o -COOR _ 3568   wherein: RB is a hydrogen atom; and   IR is selected from the group consisting of hydrogen as well as   substituted or unsubstituted organic radicals of the following list: alkyl, alkenyl and alkynyl having 1 to 10 carbon atoms; cycloalkyl and cycloalkylalkyl comprising 3 to 6 carbon atoms in the cycloalkyl ring and I to 6 carbon atoms in the alkyl part; phenyl; aralkyl, aralkenyl and aralkynyl wherein the aryl portion is formed by a phenyl radical and the aliphatic portion comprises 1 to 6 carbon atoms; heteroaryl, heteroaralkyl, heterocyclyl and heterocyclylalkyl wherein the one or more hetero atoms of said heterocyclic moieties are selected from the group consisting of 1 to 4 oxygen atoms, nitrogen   or sulfur and the alkyl part associated with these heterocyclic moieties   1 to 6 carbon atoms, it being understood that the substituents relating to the abovementioned radicals are independently of one another selected from the group comprising: C 1 -C 6 alkyl, optionally substituted with an amino group, halo, hydroxy or carboxyl; O -OCR 3 halo -SR 3 -OR 3 0 O -S Ro -OCNR 3 R 4 O O -SR 9 -CNR 3 R 4 I ' È -NR 3 R 4 -CN NR 3 -O 503 R 3 0 NR 3 R 4 -OS-R 9 -SO 2 NR 3 R 4 0 ON 0 -NHCNR 3 R 4 3-NROS-R O I ' o R 3 CNR "- -NR 3 C = NR 4 -CO 2 R 3 R 3 -OP (O) (OR 3) (OR 4) -NR 3 CO 2 R 4 = O   -NO 2 in which, with respect to the abovementioned substituents:   the groups R 3 and R 4, independently of one another,   hydrogen, or alkyl, alkenyl and alkynyl radicals of 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 part; phenyl; aralkyl, aralkenyl and aralkynyl wherein the aryl portion is a phenyl radical and   the aliphatic portion comprises 1 to 6 carbon atoms; and   roaryl, heteroaralkyl, heterocyclyl and heterocyclylalkyl in.   which the hetero ring hetero ring (s)   cited consist of 1 to 4 atoms of oxygen, nitrogen or sulfur   and the alkyl portion associated with said heterocyclic portions   take from 1 to 6 carbon atoms; or R 3 and R 4 together with the nitrogen to which at least one of them is bound, form a 5- or 6-membered nitrogen-containing heterocyclic ring; R 9 is similar to R 3 except that it can not be hydrogen; or wherein R 1 and Re taken together form a C 2 -C 10 alkylidene or C 2 -C 12 alkylidene radical substituted with a hydroxy group; Rs belongs to the group of radicals, optionally substituted: alkyl, alkenyl, alkynyl comprising 1 to 10 carbon atoms;   cycloalkyl and cycloalkylalkyl having 3 to 6 carbon atoms   bone in the cycloalkyl part and 1 to 6 carbon atoms in the alkyl parts; phenyl; aralkyl, aralkenyl and aralkynyl wherein the aryl moiety is a phenyl radical and the aliphatic portion of which comprises from 1 to 6 carbon atoms; heteroaryl, heteroaralkyl, heterocyclyl and heterocyclylalkyl wherein the hetero atom (s) of the aforesaid heterocyclic moieties consist of 1 to 4 oxygen, nitrogen and / or   sulfur and the alkyl moieties associated with said hetero-   cyclic include 1 to 6 carbon atoms; the radicals Rs mentioned above are optionally substituted with 1 to 3 substituents chosen independently of each other from the group comprising: - Cl-C 6 alkyl, optionally substituted by amino, fluoro, chloro, carboxyl, hydroxy or carbamoyl groups; fluoro, chloro or bromo; -OR 3; -0 C 02 R 3; -OCOR 3; -OCONR 3 R 4; o the -OS-R 9; I * OXO oxo; -NR 3 R 4; R 3 CONR 4-; -NR 3 CO 2 R 4; -NR 3 CONR 3 R 4; where n = NR 35 -R 9; 4 o -SR 3; -S-R 9; 0 O -S-R 9; -SO 03 R 3; -CO 2 R 3; -CONR 3 R 4;   CN; or phenyl, optionally substituted with 1 to 3 fluorine, chlorine or bromine atoms, or 1 to 3 C 1 -C 6 alkyl, -OR 3, -NR 3 R 4, SO 3 R 4, -C 02 R groups 3 or -CONR 3 R 4, wherein R 3, R "   and R 9 in these substituents Rs are as defined above.   above; or R 5 can be linked to the group   at another point in the nucleus, so as to form a heterogeneous nucleus   aromatic or fused heterocyclic ring, which ring may further contain up to two additional hetero atoms consisting of oxygen, nitrogen or sulfur; R 16 is selected from the group consisting of: radicals, substituted or unsubstituted, of the following list:   alkyl, alkenyl and alkynyl, comprising from 1 to 10 carbon atoms   bone; cycloalkyl, cycloalkylalkyl and alkylcycloalkyl,   3 to 6 carbon atoms in the cycloalkyl part and 1 to 6 carbon atoms in the alkyl parts; spirocycloalkyl having 3 to 6 carbon atoms; phenyl; aralkyl, aralkenyl   and aralkynyl in which the aryl part consists of a radical   phenyl callus andtheipartitepart of 6 atoms   of carbon; heteroaryl, heteroaralkyl, heterocyclyl and hetero-   cyclylalkyl wherein the one or more hetero atoms of the aforementioned heterocyclic moieties consist of 1 to 4 oxygen, nitrogen or sulfur atoms and the alkyl moieties associated with said heterocyclic moieties comprise from 1 to 6 carbon atoms;   in which the substituent or substitutes relating to the radicals   are selected from the group consisting of: amino, mono-, di- and trialkylamino, hydroxyl, alkoxyl, mercapto, alkylthio, phenylthio, sulfamoyl, amidino, guanidino, nitro, chloro, bromo, fluoro, cyano and carboxy; and wherein the alkyl moieties of the above substituents comprise from 1 to 6 carbon atoms; A is a straight or branched chain alkylene radical; R 2 is a hydrogen atom, an anionic charge or a carboxyl group easily separable conventional, it being understood that when R 2 is a hydrogen atom or a protecting group is also present a counter-ion; and represents an aromatic heterocyclic radical mono-, bi or   polycyclic substituted or unsubstituted, containing 0-5 additional hetero atoms   0, S or N, said heterocyte nucleus   clique being bound to A by a carbon atom of the ring and having a nitrogen atom of the quaternized ring by the Rs group, and said heterocyclic ring being optionally   substituted on available atoms of the ring by i to 5   independently selected from the group consisting of C 1 -C 4 alkyl, C 1 -C 4 alkyl substituted with, preferably 1 to 3 hydroxy, amino, C 1 -C 4 alkylamino, di (C 1 -C 4) alkylamino, C 1-C 4 alkoxy, carboxy, halo or   sulfo; -C 3 -C 6 cycloalkyl; C 3 -C 6 cycloalkyl (C 1 -C 4) alkyl optionally   substituted with 1 to 3 of the above-mentioned substituents in relation to C 1 -C 4 alkyl; C 1 -C 4 alkoxy; C 1 -C 4 alkylthio; amino; C 1 -C 4 alkylamino; di ((C 1 -C 4) alkylamino; halo; C 1 -C 4 alkanoylamino; C 1 -C 4 alkanoyloxy; carboxy; sulfo; -C (O) -O-C 1 -C 4 alkyl; hydroxy; amidino; guanidino, phenyl substituted with 1 to 3 substituents independently selected   from each other among the amino, halo, hydroxy, trifluoro-   methyl, C 1 -C 4 alkyl, C 1 -C 4 alkoxy; C 1 -C 4 alkylamino, di (C 1 -C 4) alkylamino, carboxy and sulfo; phenyl (C 1 -C 4) alkyl wherein the phenyl portion may be optionally substituted with 1 to 3   substituents mentioned above in relation to the phenyl group and the   The alkyl group may be optionally substituted with 1 to 3 substituents mentioned above in relation to the C 1 -C 4 alkyl group; as well as heteroaryl and heteroaralkyl wherein the one or more hetero atoms are selected from the group consisting of 1 to 4 oxygen, sulfur or nitrogen atoms and the alkyl moiety associated with the heteroaralkyl comprises from 1 to 6 carbon atoms , said heteroaryl and heteroaralkyl groups being optionally substituted on the part of the heterocyclic ring by 1 to 3 substituents independently selected   from each other among the hydroxy, amino, halo, trifluoro-   methyl, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 alkylamino, di (C1-C4) alkylamino, carboxy and sulfo and comprising on the alkyl part 1 to 3 substituents selected from those belonging to the group consisting of hydroxy, amino, C 1 -C 4 alkylamino, di (C 1 -C 4) alkylamino, C 1 -C 4 alkoxy, carboxy, halo and sulfo, said heterocyclic ring being optionally substituted on available nitrogen atoms of the ring by 1 with 3 substituents, independently selected from the group consisting of C 1 -C 4 alkyl, C 1 -C 4 alkyl substituted with, preferably 1 to 3 hydroxy, amino, C 1 -C 4 alkylamino, di (C 1 -C 4) alkylamino, CI- C 4   alkoxy, carboxy, halo or sulfo; C 3 -C cycloalkyl; C 3-This cycloaluminate   alkyl (C1-C4) alkyl optionally substituted with 1 to 3 of the substituents mentioned above in connection with the radical CI-C 4 alkyl; phenyl; phenyl substituted with 1 to 3 of substituents independently selected from amino, halo, hydroxy, trifluoromethyl, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, C 1 -C 4 alkylamino, di (C 1 -C 4) alkylamino, carboxy and sulfo;   phenyl (C 1 -C 4) alkyl in which the phenyl part may be optionally   substituted by 1 to 3 of the substituents mentioned above in   bond with the phenyl radical and the alkyl part may be   optionally substituted with 1 to 3 of the above-mentioned substituents in connection with the C 1 -C 4 alkyl radical; heteroaryl and heteroaralkyl wherein the one or more hetero atoms are selected from the group consisting of 1 to 4 oxygen, sulfur or nitrogen atoms, and the alkyl moiety   associated with the heteroaralkyl has 1 to 6 carbon atoms,   so-called heteroaryl and heteroaralkyl groups being optionally   substituted on the part of the heterocyclic ring by 1 to 3   independently selected from hydroxy groups,   amino, halo, trifluoromethyl, C 1 -C 4 alkyl C 1 -C 4 alkoxy, C 4 -C 4   alkylamino, di (C 1 -C 4) alkylamino, carboxy and sulfo and on the alkyl part by 1 to 3 substituents selected from the group consisting of hydroxy, amino, C 1 -C 4 alkylamino, di (C 1 -C 4) alkylamino , C 1 -C 4 alkoxy, carboxy, halo and sulfo,   as well as the pharmaceutically acceptable salts derived therefrom.   As new industrial products, the compounds of the formula R 5 H R 16   R wherein: RE is a hydrogen atom; and   IR is selected from the group consisting of hydrogen as well as   substituted or unsubstituted organic radicals of the following list: alkyl, alkenyl and alkynyl having 1 to 10 carbon atoms; cycloalkyl and cycloalkylalkyl 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 wherein the aryl portion is formed by a phenyl radical and the aliphatic portion comprises 1 to 6 carbon atoms; heteroaryl, heteroaralkyl, heterocyclyl and heterocyclylalkyl wherein the one or more hetero atoms of said heterocyclic moieties are selected from the group consisting of 1 to 4 oxygen atoms, nitrogen   or sulfur and the alkyl part associated with these heterocyclic moieties   1 to 6 carbon atoms, it being understood that the substituent (s) relative to the abovementioned radicals are independently of one another selected from the group consisting of: C 1 -C 6 alkyl, optionally substituted by an amino, halo, hydroxy or carboxyl group; O i-CR 3 halo _OCR 3 4 * -SR 3 -OR 3 00 II o Io I _-SR 9 -OCNR 3 R 4 O t ' -SR 9 -CNR 3 R 4 o -NR 3 R 4 -CN -N 3 NR 3 -N 3 3 O -O 503 R 3 NR 3 R 4 o "i-R -SO 2 NR 3 R 4 -OS-R 9 O O 0 i 9 O -NHCNR 3 R 4 O-NR-z SR 9 i I he RR '-CNR 4- -NR 3 C = NR 4 l -CO 2 R 3   nniln m Dn: / n DL 4 * R 3 -urtu; \ V 1 \ 1, -NR 3 CO 2 R 4 = O   -NO 2 in which, with regard to the abovementioned substituents:   the groups R 3 and R 4, independently of one another,   hydrogen, or alkyl, alkenyl and alkynyl radicals of 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 part; phenyl; aralkyl, aralkenyl and aralkynyl wherein the aryl portion is a phenyl radical and   the aliphatic portion comprises 1 to 6 carbon atoms; and   roaryl, heteroaralkyl, heterocyclyl and heterocyclylalkyl in   which the heteroatom (s) of the heterocyclic   cited consist of 1 to 4 atoms of oxygen, nitrogen or sulfur   and the alkyl portion associated with said heterocyclic portions   take from 1 to 6 carbon atoms; or R 3 and R 4 together with the nitrogen to which at least one of them is bound, form a 5- or 6-membered nitrogen-containing heterocyclic ring; R 9 is similar to R 3 except that it can not be hydrogen; or, wherein R1 and Re taken together form a C 2 -C 20 alkylidene or C 2 -C 15 alkylidene radical substituted with a hydroxy group; Rs belongs to the group of radicals, optionally substituted: alkyl, alkenyl, alkynyl comprising 1 to 10 carbon atoms;   cycloalkyl and cycloalkylalkyl having 3 to 6 carbon atoms   bone in the cycloalkyl part and 1 to 6 carbon atoms in the alkyl parts; phenyl; aralkyl, aralkenyl and aralkynyl wherein the aryl moiety is a phenyl radical and the aliphatic portion of which has 1 to 6 carbon atoms; heteroaryl, heteroaralkyl, heterocyclyl and heterocyclylalkyl wherein the one or more hetero atoms of the aforementioned heterocyclic moieties consist of 1 to 4 oxygen, nitrogen and / or   sulfur and the alkyl moieties associated with said hetero-   cyclic include 1 to 6 carbon atoms; the Rs radicals mentioned above are optionally substituted with 1 to 3 substituents chosen independently of each other from the group comprising: C 1 -C 6 alkyl, optionally substituted by amino, fluoro, chloro, carboxyl, hydroxy or carbamoyl groups; fluoro, chloro or bromo; -OR 3; -OCOR 3; -OCOR 3; -OCONR 3 R 4; -OS-Rg; IO oxo; -NR 3 R 4; R 3 CONR 4-; -NR 3 CO 2 R 4; -NR 3 CONR 3 R 4; I -NRIS-Rg; I -SR 3; -S-R 9; 0 O -S-R 9; -SO 3 R 3; -CO 2 R 3; -CONR 3 R 4;   CN; or phenyl, optionally substituted with 1 to 3 fluorine, chlorine or bromine atoms, or 1 to 3 CI-C 6 alkyl groups, -OR 3, -NR 3 R 4, 503 R 4, -CO 2 R 3 or -CONR 3 R 4, wherein R 3, R 4   and R 9 in these substituents R 5 are as defined above.   above; or Rs can be linked to the group N   at another point in the nucleus, so as to form a heterogeneous nucleus   aromatic or fused heterocyclic ring, which ring may further contain up to two additional hetero atoms consisting of oxygen, nitrogen or sulfur; R 16 is selected from the group consisting of: radicals, substituted or unsubstituted, of the following list:   alkyl, alkenyl and alkynyl, comprising from 1 to 10 carbon atoms   bone; cycloalkyl, cycloalkylalkyl and alkylcycloalkyl,   3 to 6 carbon atoms in the cycloalkyl part and 1 to 6 carbon atoms in the alkyl parts; spirocycloalkyl having 3 to 6 carbon atoms; phenyl; aralkyl, aralkenyl   and aralkynyl in which the aryl part consists of a radical   phenyl * and whose aliphatic part consists of 6 atoms   of carbon; heteroaryl, heteroaralkyl, heterocyclyl and hetero-   cyclylalkyl wherein the one or more hetero atoms of the aforementioned heterocyclic moieties consist of 1 to 4 oxygen, nitrogen or sulfur atoms and the alkyl moieties associated with said heterocyclic moieties comprise from 1 to 6 carbon atoms;   in which the substituent or substitutes relating to the radicals   are selected from the group consisting of: amino, mono-, di- and trialkylamino, hydroxyl, alkoxyl, mercapto, alkylthio, phenylthio, sulfamoyl, amidino, guanidino, nitro, chloro, -bromo, fluoro, cyano and carboxy; and wherein the alkyl moieties of the above substituents comprise from 1 to 6 carbon atoms; A is a linear or branched chain alkylene radical; R 2 is a hydrogen atom, an anionic charge or a carboxyl group easily separable conventional, it being understood that when R 2 is a hydrogen atom or a protecting group is also present a counter-ion; and QN R 5   <N-R represents an aromatic heterocyclic radical containing nitrogen   with 5 or 6 members and containing 0-3 additional hetero atoms   both O, S and / or N, said heterocyclic ring being optionally substituted on available ring atoms by 1 to 5 substituents independently selected from the group consisting of C 1 -C 4 alkyl,   C 1 -C 4 alkyl substituted with preferably 1 to 3 hydroxy, amino, C 4. alkylamino, di (C 1 -C 4) alkylamino, C 1 -C 4 alkoxy, carboxy, halo or   sulfo; C 3 -C 6 cycloalkyl; C 3 -C 6 cycloalkyl (C 1 -C 4) alkyl optionally   are substituted with 1 to 3 of the above-mentioned substituents in relation to C 1 -C 4 alkyl; C 1 -C 4 alkoxy; C 1 -C 4 alkylthio; amino; C1-C4 alkylamino; di ((C 1 -C 4) alkylamino; halo; C 1 -C 4 -alkanoylamino; C 1 -C 2 alkanoyloxy; carboxy; sulfo; -C (O) -O-C 1 -C 4 alkyl; hydroxy; amidino; guanidino; phenyl substituted with 1 to 3 substituents independently selected   from each other among the amino, halo, hydroxy, trifluoro-   Methyl, C 1 -C 4 alkyl, C 4 -C 4 alkoxy; C 1 -C 4 alkylamino, di (C 1 -C 4) alkylamino, carboxy and sulfo; phenyl (C 1 -C 4) alkyl in which the phenyl moiety may be optionally substituted with 1 to 3   substituents mentioned above in relation to the phenyl group and the   The alkyl group may be optionally substituted with 1 to 3 substituents mentioned above in relation to the C 1 -C 4 alkyl group; as well as heteroaryl and heteroaralkyl wherein the one or more hetero atoms are selected from the group consisting of 1 to 4 oxygen, sulfur or nitrogen atoms and the alkyl moiety associated with the heteroaralkyl comprises from 1 to 6 carbon atoms , said heteroaryl and heteroaralkyl groups being optionally substituted on the part of the heterocyclic ring by 1 to 3 substituents independently selected   from each other among the hydroxy, amino, halo, trifluoro-   methyl, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, C 1 -C 4 alkylamino, di (C 1 -C 4) alkylamino, carboxy and sulfo and comprising on the alkyl part 1 to 3 substituents chosen from those belonging to the a group comprising hydroxy, amino, C 1 -C 4 alkylamino, di (C 4 -C 4) alkylamino, C 4 -C 4 alkoxy, carboxy, halo and sulfo, said heterocyclic ring being optionally substituted on available nitrogen atoms of ring with 1 to 3 substituents, independently selected from the group consisting of C 1 -C 4 alkyl, C 1 -C 4 alkyl substituted with, preferably 1 to 3 hydroxy, amino, C 1 -C 4 alkylamino, di (C 1 -C 4) alkylamino, CI-C 4   alkoxy, carboxy, halo or sulfo; C 3 -C 6 cycloalkyl; C 3-This cycloaluminate   alkyl (C1-C4) alkyl optionally substituted with 1 to 3 of the substituents mentioned above in connection with the radical CI-C 4 alkyl; phenyl; phenyl substituted with 1 to 3 of substituents independently selected from amino, halo, hydroxy, trifluoromethyl, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, C 1 -C 4 alkylamino, di (C 1 -C 4) alkylamino, carboxy and sulfo; phenyl (C 1 -C 4) alkyl in which the phenyl portion may be optionally substituted with 1 to 3 of the substituents mentioned above in   bond with the phenyl radical and the alkyl part may be   optionally substituted with 1 to 3 of the above-mentioned substituents in connection with the C1-C4 alkyl radical; heteroaryl and heteroaralkyl wherein the one or more hetero atoms are selected from the group consisting of 1 to 4 oxygen, sulfur or nitrogen atoms, and the alkyl moiety   associated with the heteroaralkyl has 1 to 6 carbon atoms,   so-called heteroaryl and heteroaralkyl groups being optionally   substituted on the part of the heterocyclic ring by 1 to 3   independently selected from the group consisting of hydroxy, amino, halo, trifluoromethyl, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, C 1 -C 4 alkylamino, di (C 1 -C 4) alkylamino, carboxy and sulfo and on the alkyl part by 1 to 3 substituents selected from the group consisting of hydroxy, amino, C 1 -C 4 alkylamino, di (C 1 -C 4) alkylamino, C 1 -C 4 alkoxy, carboxy, halo and sulfo,   as well as the pharmaceutically acceptable salts derived therefrom.   57. Compound according to claim 56, characterized in that the heterocyclic ring   is optionally substituted on available carbon or nitrogen atoms   up to 5 substituents consisting of alkyl radicals   older independent of each other.   Compound according to claim 57, characterized in that A is -CH 2-, -CH 2 -CH 2-, or -CH-   CH 3 59. As new industrial products, the compounds of formula -16 M in which: Re is a hydrogen atom; and   IR is selected from the group consisting of hydrogen as well as   substituted or unsubstituted organic radicals of the following list: alkyl, alkenyl and alkynyl having 1 to 10 carbon atoms; cycloalkyl and cycloalkylalkyl 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 wherein the aryl portion is formed by a phenyl radical and the aliphatic portion comprises 1 to 6 carbon atoms; heteroaryl, heteroaralkyl, heterocyclyl and heterocyclylalkyl wherein the one or more hetero atoms of said heterocyclic moieties are selected from the group consisting of 1 to 4 oxygen atoms, nitrogen   or sulfur and the alkyl part associated with these heterocyclic moieties   These compounds comprise from 1 to 6 carbon atoms, it being understood that the substituent (s) relative to the abovementioned radicals are independently of one another, chosen from the group comprising: Cl-C 6 alkyl, optionally substituted with an amino group halo, hydroxy or carboxyl; O i-CR 3 halo _OCR 3 -SR 3 -OR 3 0 O I _-SR 9 -OCNR 3 R 4 O O -SR 9 -CNR 3 R 4 _SR 9 "-NR 3 R 4 o -CN NR 3 -N 3 / R -O 50 03 R 3 NR 3 R 4- -OS-R -502 NR 3 R 4 -S-R 9 I O 0 " 0 -NHCNR 3 R 4 I 10 -NR 3 S-R 9 i, "R CNR 4- I -NR 3 C = NR 4 -CO 2 R 3 R 3 -OP (O), (OR 3) (OR 4) -NR 3 CO 2 R 4 = O   -NO 2 in which, with regard to the abovementioned substituents:   the groups R 3 and R 4, independently of one another,   hydrogen, or alkyl, alkenyl and alkynyl radicals of 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 part; phenyl; aralkyl, aralkenyl and aralkynyl wherein the aryl portion is a phenyl radical and   the aliphatic portion comprises 1 to 6 carbon atoms; and   roaryl, heteroaralkyl, heterocyclyl and heterocyclylalkyl in   which the hetero ring hetero ring (s)   cited consist of 1 to 4 atoms of oxygen, nitrogen or sulfur   and the alkyl portion associated with said heterocyclic portions   take from 1 to 6 carbon atoms; or -R 3 and R 4 together with the nitrogen to which at least one of them is bound, form a 5- or 6-membered nitrogen-containing heterocyclic ring; R 9 is similar to R 3 except that it can not be hydrogen; or, wherein R 'and R 8 taken together form a hydroxy-substituted C 2 -Co alkylidene or C 2 -Co 10 -alkylidene radical; R 5 belongs to the group of radicals, optionally substituted: alkyl, alkenyl, alkynyl comprising 1 to 10 carbon atoms;   cycloalkyl and cycloalkylalkyl having 3 to 6 carbon atoms   bone in the cycioalkyl part and i to 6 carbon atoms in the alkyl parts; phenyl; aralkyl, aralkenyl and aralkynyl wherein the aryl moiety is a phenyl radical and the aliphatic portion of which has 1 to 6 carbon atoms; heteroaryl, heteroaralkyl, heterocyclyl and heterocyclylalkyl wherein the one or more hetero atoms of the aforementioned heterocyclic moieties consist of 1 to 4 oxygen, nitrogen and / or   sulfur and the alkyl moieties associated with said hetero-   cyclic include 1 to 6 carbon atoms; the radicals R 5 mentioned above are optionally substituted with 1 to 3 substituents chosen independently of each other from the group comprising: C 1 -C 6 alkyl, optionally substituted with amino, fluoro, chloro, carboxyl, hydroxy or carbamoyl groups; fluoro, chloro or bromo; -OR 3; -OCO 2 R 3; -OCOR 3; -OCONR 3 R 4; II-OS-Rg; He * l O oxo; -NR 3 R 4; R 3 CONR 4-; -NR 3 CO 2 R 4; -NR 3 CONR 3 R 4; o I ' * -NR 35-R 9; o -SR 3; -S-R 9; 0 O -S-R 9; -503 R 3; -C 02 R 3; -CONR 3 R "; CN; or-   phenyl, optionally substituted with 1 to 3 fluorine atoms, chlorine or bromine, or 1 to 3 C 1 -C 6 alkyl groups, -OR 3, -NR 3 R 4, -SO 3 R ", -C O 2 R 3 or -COIR 3 R 4, wherein R 3, R 4   and R 9 in these substituents R 5 are as defined above.   above; or R 5 can be linked to the group   at another point in the nucleus, so as to form a heterogeneous nucleus   aromatic or heterocyclic fused, which ring may further contain up to two additional hetero atoms consisting of oxygen, nitrogen or sulfur; Ri 6 is selected from the group consisting of: radicals, substituted or unsubstituted, of the following list:   alkyl, alkenyl and alkynyl, comprising from 1 to 10 carbon atoms   bone; cycloalkyl, cycloalkylalkyl and alkylcycloalkyl,   3 to 6 carbon atoms in the cycloalkyl part and 1 to 6 carbon atoms in the alkyl parts; spirocycloalkyl having 3 to 6 carbon atoms; phenyl; aralkyl, aralkenyl   and aralkynyl in which the aryl part consists of a radical   phenyl callus andtheipartitepart of 6 atoms   of carbon; heteroaryl, heteroaralkyl, heterocyclyl and hetero-   cyclylalkyl wherein the one or more hetero atoms of the aforementioned heterocyclic moieties consist of 1 to 4 oxygen, nitrogen or sulfur atoms and the alkyl moieties associated with said heterocyclic moieties comprise from 1 to 6 carbon atoms;   in which the substituent or substitutes relating to the radicals   are selected from the group consisting of: amino, mono-, di- and trialkylamino, hydroxyl, alkoxyl, mercapto, alkylthio, phenylthio, sulfamoyl, amidino, guanidino, nitro, chloro, bromo, fluoro, cyano and carboxy; and wherein the alkyl moieties of the above-mentioned substituents comprise from 1 to 6 carbon atoms; A is a straight or branched chain alkylene radical; R 2 is a hydrogen atom, an anionic charge, or a conventional readily separable carboxyl protecting group, it being understood that when R 2 is hydrogen atonia or a protecting group is also present a counterion; and represents a radical selected from the group consisting of: (a) t- * R 5 e R 7 | 7 R 6   wherein R 6, R 7 and R 10 are independently selected from ato-   hydrogen, and C 1 -C 4 alkyl, C 1 -C 4 alkyl substituted by, preferably 1 to 3 hydroxy, C 1 -C 4 alkylamino, di (C 1 -C 4 alkyl) amino, Cl -C 4 alkoxy, amino, sulpho, carboxy or halo (chloro, bromo,   fluoro or iodo; preferably chloro, fluoro or bromo); C 3 -C 6 Cyclo   alkyl; C 1 -C 4 alkoxy; C, -C 4 alkylthio; amino; C 1 -C 4 alkylamino;   di (C 1 -C 4 alkyl) amino; halo (chloro, bromo, fluoro or iodo;   chloro, fluoro or bromo); C 1 -C 4 alkanoylamino; C 1 -C 4 alkanoyl   oxy; carboxy; -C (O) -OC, -C 4 alkyl; hydroxy; amidino; guanidino; phenyl; phenyl substituted with 1, 2 or 3 amino groups, halo (chloro,   bromo, fluoro or iodo; preferably chloro, fluoro or bromo), hydro-   xyl, trifluoromethyl, C 1 -C 4 alkyl or C 1 -C 4 alkoxy; phenyl (C 1 -C 4) alkyl in which the phenyl portion may be optionally   substituted by 1 to 3 of the substituents mentioned above in relation to   with the phenyl and the alkyl part may be optionally substituted with 1 to 3 of the substituents mentioned above in relation to Cl-C 4 alkyl; and heteroaryl and heteroaralkyl in which the   or the hetero atoms of the aforementioned heterocyclic moieties are selected   in the group consisting of 1 to 4 atoms of oxygen, nitrogen or   sulfur and the alkyl part associated with a heteroaralkyl part   carries 1 to 6 carbon atoms; or in which two of the   groups R 6, R 7 or Rio taken together can form a carbocyte ring.   fused saturated clique, a fused aromatic carbocyclic ring,   a fused non-aromatic heterocyclic ring or a hetero ring.   fused aromatic ring, these fused rings being optionally substituted   killed by 1 or 2 of the substituents defined above for R 6, R 7 and Ro; (b) 6 X, X or N and optionally substituted on a carbon atom with 1 to 3 substituents chosen independently of one another from the radicals C 1 -C 4   alkyl; C 1 -C 4 alkyl substituted with 9, preferably 1 to 3 hydroxy; C 1-   C, alkylamino, sulfo, di (C 1 -C 4 alkyl) amino, C 1 -C 4 alkoxy, amino, car-   boxy or halo (chloro, bromo, fluoro or iodo, preferably chloro, fluoro or bromo); C 3 -C 6 cycloalkyl; C -C 4 alkoxy; C 1 -C 4 alkylthio; amino; C 1 -C 4 alkylamino; di (C1-C4alkyl) amino; halo (chloro, bromo,   fluoro or iodo; preferably chloro, fluoro or bromo); C 1 -C 4 alka   noylamino; C1-C4 alkanoyloxy; carboxy; -C (O) -OC 1 -C 4 alkyl; hydroxy; amidino; guanidino; phenyl; phenyl substituted with 1, 2 or 3 amino groups, halo (chloro, bromo, fluoro or iodo; preferably, chloro, fluoro or bromo), hydroxyl, trifluoromethyl, C 1 -C 4 alkyl or C 1 -C 4 alkoxy; phenyl (C 1 -C 4) alkyl in which the phenyl part may be optionally substituted with 1 to 3 of the substituents mentioned above in relation to the phenyl radical and the alkyl part   may be optionally substituted with one of the 3 substituents   born above in relation to the radical C 1 -C 4 alkyl; heteroaryl or   heteroaralkyl in which the hetero atom (s) of the heteroaralkyl   The aforementioned rocyclic compounds are selected from the group consisting of 1 to 4 atoms   oxygen, nitrogen or sulfur, and the alkyl part associated with   said heteroaralkyl moiety has 1 to 6 carbon atoms or   replaced in order to form a carbocyclic ring, hetero   rocyclic or fused heteroaromatic, possibly substituted by   by one or two of the substituents defined above; (C) R $ R $ 5 R 5 R 5 N N r N e l R N N To l or RNN <N N NY>   optionally substituted on a carbon atom with 1 or 2 substituents   chosen independently of each other selected from the group   taking C 1 -C 4 alkyl; C1-C4 alkyl substituted with, preferably 1 to   3 hydroxy, C1-C4 alkylamino, sulfo, di (C1-C4 alkyl) amino, C1-C4 al-   koxy, amino, carboxy or halo (chloro, bromo, fluoro or iodo;   chloro, fluoro or bromo); C 3 -C 6 cycloalkyl; C1-C4 alkoxy; C 1 -C 4 alkylthio; amino, C 1 -C 4 alkylamino; di (C 1 -C 4 alkyl) amino; halo (chloro, bromo, fluoro or iodo, preferably chloro, fluoro or bromo); C 1 -C 4 alkanoylamino; C 4 alkanoyloxy; carboxy; -C (O) -OC 1 -C 4 alkyl; hydroxy; amidino; guanidino phenyl; phenyl substituted with one, two   or three amino groups, halo (chloro, bromo, fluoro or iodo;   chloro, fluoro or bromo), hydroxyl, trifluoromethyl, C 1 -C 4 alkyl or C 1 -C 4 alkoxy; phenyl (C 1 -C 4) alkyl wherein the phenyl moiety may be optionally substituted with 1 to 3 of the substituents mentioned above in relation to the phenyl radical and the alkyl moiety may be optionally substituted with 1 to 3 of the substituents mentioned herein above in relation to the radical C 1 -C 4 alkyl; and heteroaryl or heteroaralkyl wherein the one or more hetero atoms of the aforementioned heterocyclic moieties are selected from the group consisting of 1 to 4 oxygen, nitrogen or sulfur atoms and the alkyl moiety associated with said heteroaralkyl moiety comprises from 1 to 6 carbon atoms or optionally substituted to form a fused carbocyclic, heterocyclic or heteroaromatic ring,   optionally substituted with 1 or 2 of the aforementioned substituents. (d) 5 RS i O N 4 N -N N N N   optionally substituted on a carbon atom with a substituent selected independently from each other in the groups formed by C 7 -C 4 alkyl radicals; C1-C4 alkyl substituted with, preferably 1 to 3 hydroxy, C 1 -C 4 alkylamino, di (C 1 -C 4 alkyl) amino, sulfo, C 1 -C 4   alkoxy, amino, carboxy or halo (chloro, bromo, fluoro or iodo;   chloro, fluoro-or bromno); C 3 -C 6 cycloalkyl; C 1 -C 4 alkoxy; C 1 -C 4 alkylthio; amino; C1-C4 alkylamino; di (C1-C4alkyl) amino; halo (chloro, bromo, fluoro or iodo, preferably chloro, fluoro or bromo); C 1 -C 4 alkanoylamino; C 1 -C 4 alkanoyloxy; carboxy; -C (O) -OC 1 -C 4 alkyl; hydroxy; amidino; guanidino; phenyl; phenyl substituted with 1, 2 or 3 amino, halo (chloro, bromo, fluoro or iodo, preferably chloro, fluoro or bromo), hydroxyl, trifluoromethyl, C 1 -C 4 alkyl or C 1 -C 4 alkoxy; phenyl (C 1 -C 4) alkyl in which the phenyl portion may be optionally substituted with 1 to 3 of the aforementioned substituents in   relationship with the phenyl groups and the alkyl part may be   replaced by 1 to 3 of the substituents mentioned above   "in relation to the Cv-C 4 alkyl group; and heteroaryl or heteroaral-   wherein the hetero atom (s) of the aforementioned heterocyclic moieties are selected from the group consisting of 1 to 4 oxygen atoms,   of nitrogen or sulfur and the alkyl part which is associated with   heteroaralkyl moieties have 1 to 6 carbon atoms; (e) N-R 5 1 R 12 or X wherein X is O, S or NR with R being Cl-C 4 alkyl; ClC 4 alkyl substituted with 1 to 3 hydroxy, amino, C 1 -C 4 alkylamino, di (C 1 C 4) alkylamino, C 1 -C 4 alkoxy, carboxy, halo or sulfo; C 3 -C 6 cycloalkyl; C 3 -C 6 cycloalkyl (C 1 -C 4) alkyl optionally substituted with 1 to 3 of the substituents mentioned above in relation to C 1 -C 4 alkyl;   phenyl; phenyl substituted with 1 to 3 of the substituents chosen inde-   from each other among amino, halo, hydroxy, trifluoro-   methyl, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, C 1 -C 4 alkylamino, di (C 1 -C 4) alkyl-   amino, carboxy and sulfo; phenyl (C 1 -C 4) alkyl in which the phenyl part may be optionally substituted with 1 to 3 of the substituents mentioned above in relation to the phenyl radical and the alkyl part may be optionally substituted with 1 of the 3 substituents mentioned below above in relation to the radical C 1 -C 4 alkyl;   and heteroaryl and heteroaralkyl in which the at least one heteroaryl   mes are selected from the group consisting of 1 to 4 oxygen atoms,   of sulfur or nitrogen and the alkyl part associated with the hetero radical.   aralkyl contains 1 to 6 carbon atoms, these heteroaryl and heteroaralkyl groups being optionally substituted in the part of the heterocyclic ring by 1 to 3 substituents independently selected   from each other among the hydroxy, amino, halo, trifluoro-   methyl, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, C 1 -C 4 alkylamino, di (C 1 -C 4) alkyl-   amino, carboxy and sulfo and the alkyl part is substituted with 1 to 3 substituents belonging to the groups comprising hydroxy, amino, C 1 -C 4 alkylamino, di (C 1 -C 4) alkylamino, C 1 -C 4 alkoxy, carboxy, halo and sulfo; this heteroaromatic radical being optionally substituted   on the carbon atom by one or more substituents selected inde-   pendant from each other from the group consisting of C 1 -C 4 alkyl; C 1 -C 4 alkyl substituted with, preferably 1 to 3 hydroxy, amino, C 1 -C 4 alkylamino, di (C 1 -C 4 alkyl) amino, C 1 -C 4 alkoxy, sulfo, carboxy or halo (chloro, bromo, fluoro or iodo, preferably chloro, fluoro or bromo);   C 3 -C 6 cycloalkyl; C 1 -C 4 alkoxy; C 1 -C 4 alkylthio; amino; C 1 -C 4 alkyl   amino; di (C1-C4alkyl) amino; halo (chloro, bromo, fluoro or iodo;   preferably chloro, fluoro or bromo); C, -C 4 alkanoylamino; C 1 -C 4 alka   noyloxy; carboxy; -C (O) -OC'-C 4 alkyl; hydroxy; amidino; guanidino: phenyl; phenyl substituted with 1, 2 or 3 amino groups, halo (chloro, bromo, fluoro or iodo, preferably chloro, fluoro or bromo), hydroxyl, trifluoromethyl, C 1 -C 4 alkyl or C 1 -C 4 alkoxy; phenyl (C 1 -C 4) alkyl in which the alkyl part may be optionally substituted with 1 to 3 of the substituents mentioned above in relation to the phenyl radical and / or the alkyl part may be optionally substituted with 1 to 3 of the substituents mentioned above in relation to the C 1 -C 4 alkyl radical; and heteroaryl and heteroaralkyl wherein the heteroaryl or hetero atoms of the aforementioned heterocyclic moieties are selected from the group consisting of 1 to 4 oxygen atoms, nitrogen   or sulfur and / or the alkyl part associated with said hetero portion   aralkyl has 1 to 6 carbon atoms or-optionally substituted   killed to form a heteroaromatic, heterocyclic ring or   fused carbocyclic ring, optionally substituted with 1 or 2   stituents defined above; (f) R $ X 51 A 1 I R X B 1 -R Nx X B 5   X NR 5 or N-NR where X is O, S or NR with R being a C 1 -C 4 alkyl radical; C 1 -C 4 alkyl substituted with 1 to 3 hydroxy, amino, C 1 -C 4 alkylamino, di (C 1 -C 4) alkylamino, C 1 -C 4 alkoxy, carboxy, halo or sulfo; C 3 -C 6 cycloalkyl; C 3 -C 6 cycloalkyl (C 1 -C 4) alkyl optionally substituted with 1 to 3 of the substituents mentioned above in relation to the C 1 -C 4 alkyl radical; phenyl; phenyl substituted with 1 to 3 substituents independently selected from the group consisting of amino, halo, hydroxy, trifluoromethyl, C 1 -C 4 alkyl, CC 4 alkoxy, C 1 -C 4 alkylamino, di (C 1 -C 4) alkylamino carboxy and sulfo; phenyl -C 4) alkyl in which the phenyl part may be optionally substituted with 1 to 3 of the substituents mentioned above in relation   with the phenyl radical and / or the alkyl part may be   substituted by 1 to 3 of the substituents mentioned above in   lation with the radical C, -C ,, alkyl; and hteroaryl and heteroaralkyl   in which the hetero atom (s) are selected from the group   taking 1 to 4 atoms of oxygen, sulfur and / or nitrogen and where the   alkyl group associated with the heteroaralkyl radical has 1 to 6 atoms   carbon, these heteroarayl and heteroaralkyl groups being substituted   killed in the heterocyclic ring portion by 1 to 3 substituents independently selected from the group consisting of hydroxy, amino, halo, trifluoromethyl, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, C 1 -C 4 alkylamino, di (Cl-C 4) alkylamino, carboxy and sulfo and o la   The alkyl part may have from 1 to 3 substituents selected from   xy, amino, C 1 -C 4 alkylamino, di (C 1 -C 4) alkylamino, C 1 -C 4 alkoxy, carboxy,   halo and sulfo; this heteroaromatic radical being optionally substituted   killed on a carbon atom by a substituent selected from the group consisting of C 1 -C 4 alkyl; C 1 -C 4 alkyl substituted with, preferably, 1 to 3 hydroxy, amino, C 1 -C 4 alkylamino, di (C 1 -C 4 alkyl) amino, C 1 -C 4 alkoxy, sulfo, carboxy or halo ( chloro, bromo, fluoro or iodo, preferably chloro, fluoro or bromo); C 3 -C 6 cycloalkyl; C, -C 4 alkoxy; C 1 -C 4 alkylthio; amino; C 1 -C 4 alkylamino; di (C 1 -C 4 alkyl) amino; halo   (chloro, bromo, fluoro or iodo, preferably chloro, fluoro or bro-   mo); C 1 -C 4 alkanoylamino; C 1 -C 4 alkanoyloxy; carboxy; -C (O) -OC 1 -C 4 alkyl; hydroxy; amidino; guanidino; phenyl; phenyl substituted by 1, 2 or 3 amino, halo (chloro, bromo, fluoro or iodo, preferably chloro, fluoro or bromo), hydroxyl, trifluoromethyl, C 1 -C 4 alkyl   Or C, -C 4 alkoxy; phenyl (C 1 -C 4) alkyl in which the phenyl part   nyle may be optionally substituted with 1 to 3 substituents   mentioned above in relation to the phenyl radical and / or the   The alkyl group may be optionally substituted with 1 to 3   mentioned above in relation to the radical C 1 -C 4 alkyl; and heteroaryl or heteroaralkyl wherein the one or more hetero atoms in the aforementioned heterocyclic moieties are selected from the group consisting of 1 to 4 oxygen, nitrogen and / or sulfur atoms and wherein the alkyl moiety associated with said heteroaralkyl moiety comprises at 6 carbon atoms; and (g) e e: N, N-R 5 RN-N, N N 22-R l N-R R 5-J i-R N-RN 5 * N N-R R -N N-R N N-R He 1-ARS H He l or l N N R   in which R is a C 1 -C 4 alkyl radical; C 1 -C 4 alkyl substituted   killed by 1 to 3 hydroxy, C 1 -C 4 amino, alkylamino, di (C 1 -C 4) alkylamino,   C 1 -C 4 alkoxy, carboxy, halo or sulfo; C 3 -C 6 cycloalkyl; C 1 -C 4 Cyclo   alkyl (C 1 -C 4) alkyl optionally substituted with 1 to 3 of the substituents mentioned above in relation to the radical C 1 -C 4 alkyl; phenyl; phenyl substituted with 1 to 3 substituents independently selected from the group consisting of amino, halo, hydroxy, trifluoromethyl, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, C 1 -C 4 alkylamino, di (C 1 -C 4) C 4)   alkylamino, carboxy and sulfo; phenyl (C 1 -C 4) alkyl in which the   The phenyl moiety may be substituted with 1-3 substituents   mentioned above in relation to the phenyl radical and where the alkyl part may be optionally substituted with 1 to 3 of the   substituents mentioned above in relation to the radical C 1 -C 4   alkyl; and heteroaryl and heteroaralkyl in which the one or more   tero atoms are selected from the group consisting of 1 to 4 oxy-   sulfur and / or nitrogen and o the alkyl part associated with the   heteroaralkyl group having 1 to 6 carbon atoms, these heteroaryl and heteroaralkyl groups being optionally substituted in the part of the heterocyclic ring by 1 to 3 of the substituents chosen independently of each other from hydroxy, amino, halo, trifluoromethyl, C 1- C 4 alkyl, C 1 -C 4 alkoxy, C 1 -C 4 alkylamino,   di (C 1 -C 4) alkylamino, carboxy and sulfo and where the alkyl part is   optionally substituted with 1 to 3 substituents selected from the group consisting of hydroxy, amino, C1-C4 alkylamino, di (C1-C4) alkylamino,   C 1 -C 4 alkoxy, carboxy, halo and sulfo.   as well as the pharmaceutically acceptable salts derived therefrom. 60. A compound according to claim 59, characterized in that * e represents a selected radical (a) R 5 R 7 R 6   Wherein: R 5 is a C 1 -C 6 alkyl radical; and R 6, R 7 and R 10 are, independently of each other, hydrogen or a C 1 -C 4 alkyl radical; (b) (b) R 5 R 5 NOT N N R 5 or leO in which:   R 5 is a C 1 -C 6 alkyl radical and the carbon atoms are   kernel are optionally substituted by 1 to 3   killers consisting of C1-C4 alkyl radicals independently of one another; (c) R 5, R 5, R 5, or R 5 R 5 N, R and t in which:   R-5 is a C 1 -C 6 alkyl radical and where the carbon atoms are   kernel are optionally substituted by i or 2   substituents consisting of optionally substituted CI-C 4 alkyl radicals.   substituted; (d) R 5 e 1 N R 5 x NN R 5 and N -g or R 5 _e 'N _N II'II in which: R 5 is a C 1 -C 6 alkyl radical and the carbon nuclei are   Nucleic acids are optionally substituted with alkyl radicals C 1 -C 4; in which: Rs is a C 1 -C 6 alkyl radical, X is O, S or NR with R being an alkyl radical, and o one or more available carbon atoms. of the ring are optionally substituted with C 1 -C 4 alkyl radicals; (f) He N J R-N A 51 E; he NOT - i I 1 JR X_ -R 5   In which: R 4 is a C 1 -C 6 alkyl radical; X is 0, S or NR with R = C1-C4 alkyl radical, and o one or more of the available carbon atoms of the ring is optionally substituted with a C 1 -C 4 alkyl radical; (g) t 1 R 5 e R IR T I G C R r S-R _f N S N R G 5 N N R e RS e "N _NR ,, _ _N-R   or in which: R 5 is a C 1 -C 6 alkyl radical; and, R is a C 1 -C 4 alkyl radical   61. A compound according to any one of claims 54 to 60,   characterized in that R 1 is CH 3 -CH; and OH R 16 is a methyl radical.   62. A compound according to any one of claims 54 to 60,   in which R 1 is CH 3 CH-, OH R 16 is a methyl radical and the ab configuration   and the absolute configuration is R, 65, 85.   63. A compound according to any of claims 54 to 62, which is   characterized in that A is -CH 2 or -CH 2 -CH 2.   64. As new industrial products, the compounds of formula OH CH 3   (R) S-A-r wherein: A is a straight or branched chain alkylene radical; R 2 is a hydrogen atom, an anionic charge or a carboxyl group easily separable conventional, it being understood that when R 2 is a hydrogen atom or a protecting group is also present a counter-ion; and CN-R 5   represents a radical of formula (Ta) with R 5 is a C 1 -C 4 alkyl radical, and more particularly methyl; and R 6 is hydrogen or a C1-C4 alkyl radical; (b) R 1 R 6 in which: R 5 is C 1 -C 4 alkyl, and more particularly methyl; and R 6 and R 7 are hydrogen or a C 1 -C 4 alkyl radical; (c) 5 R-N -R 5   in which: Rs is C 1 -C 4 alkyl, more particularly methyl; and R is a C 1 -C 4 alkyl or phenyl (C 1 -C 4) alkyl radical; in which: Rs is a C 1 -C 4 alkyl radical, plus R 6 is a C'-C 4 alkyl radical, plus (e) wherein: R 5 is a C 1 -C 4 radical R is a C 1 radical -C 4 (f) R 5 4 a RR alkyl, more alkyl, more particularly methyl; and particularly methyl; especially methyl; and particularly methyl; or N _ in which:   R 5 is C 1 -C 4 alkyl, more particularly methyl.   as well as their pharmaceutically acceptable salts thereof.   65. As new industrial products, the compounds of formula (R) in which: A is a linear or branched chain alkylene radical; R 2 is a hydrogen atom, an anionic charge or a carboxyl group easily separable conventional, being understood (d) R 6 R 5 that when R 2 is a hydrogen atom or a protecting group is also present a counter- ion; and F & N-R 5   represents a radical belonging to the following groups: (a) NCH 3 (b) \ H 3 - -CH 3 CH% 30 c- N-C H 2 CH 2 CH 3   e CH (c) CH 3 (e) (d) (f) (g) CH 3 I CH (h) - CDQ È 1 2 (we N CH 3 N (m) a S H 3 or CH 3 (n) N-N C / 3 CH 3   as well as the pharmaceutically acceptable salts thereof.   66. As new industrial products, the compound of formula OH (II) in which: R 2 is hydrogen, an anionic charge or a carboxyl group easily separable conventional provided that when R 2 is hydrogen or a protecting group, there is also a counterion,   as well as the pharmaceutically acceptable salts thereof.   (i) CH 3 CH 3 (k) (1) 67. As novel industrial products, the compound of the formula CH OH H 3 Ij S CH CF 2 (R) 2 N COOR 2 3   wherein: R 2 is hydrogen, an anionic charge or a readily removable carboxyl protecting group provided that when R 2 is hydrogen or a protecting group, a counterion is also present,   as well as the pharmaceutically acceptable salts thereof.   68. As new industrial products, the compound of formula CH OH H CH 3 (R) SC H 2 C -c H 3 N 00 OR 2   wherein: R 2 is hydrogen, an anionic charge or a readily removable carboxyl protecting group provided that when R 2 is hydrogen or a protecting group, a counterion is also present,   as well as the pharmaceutically acceptable salts thereof.   69. As new industrial products, the compound of formula CH, (R) in which: R 2 is hydrogen, an anionic charge or a carboxyl group easily separable conventional provided that when R 2 is hydrogen or a protecting group, is also present a counter-ion,   as well as the pharmaceutically acceptable salts thereof.   70. As new industrial products, the compound of formula OH (R) CH - CH 3 in which: R 2 is hydrogen, an anionic charge or a carboxyl group easily separable conventional provided that when R 2 is hydrogen or a protecting group, is also present - a counter-ion,   as well as the pharmaceutically acceptable salts thereof.   71. As new industrial products, the compound of formula OH CH 3 I 1 e S CH 2 A N CH 2 CH 2 CH 3   wherein: R 2 is hydrogen, an anionic charge or a readily removable carboxyl protecting group provided that when R 2 is hydrogen or a protecting group, a counterion is also present,   as well as the pharmaceutically acceptable salts thereof.   72. As new industrial products, the compound of formula CH: OHCH 3 C \ 3 e SR CH 2 N OOR 2 CH   wherein: R 2 is hydrogen, an anionic charge or a readily removable carboxyl protecting group provided that when R 2 is hydrogen or a protecting group, a counterion is also present,   as well as the pharmaceutically acceptable salts thereof.   - 301 - 73. As new industrial products, the compound of formula (R) CH 1 03 sc N H 3 S CH 2 / I \ 2 \ r - ZOCR 2   wherein R 2 is hydrogen, an anionic charge or a readily removable carboxyl protecting group provided that when R 2 is hydrogen or a protecting group, a counterion is also present,   as well as the pharmaceutically acceptable salts thereof.   74. As new industrial products, the compound of formula (R) OH CH 3   wherein: R 2 is hydrogen, an anionic charge or a readily removable carboxyl protecting group provided that when R 2 is hydrogen or a protecting group, a counterion is also present,   as well as the pharmaceutically acceptable salts thereof.   75. As new industrial products, the compound of formula (R) in which: R 2 is hydrogen, an anionic charge or a carboxyl group easily separable conventional provided that when R 2 is hydrogen or a protecting group, is also present a counter-ion,   as well as the pharmaceutically acceptable salts thereof.   As new industrial products, the compound of formula OH (R) CH / S CH 3 in which: R 2 is hydrogen, an anionic charge or a carboxyl group easily separable conventional provided that when R 2 is hydrogen or a protecting group, is also present a counter-ion,   as well as the pharmaceutically acceptable salts thereof.   W 77. As new industrial products, the compound of formula (OR) (R) ,. CH E 3 3 S-CH -CH   wherein: R 2 is hydrogen, an anionic charge or a readily removable carboxyl protecting group provided that when R 2 is hydrogen or a protecting group, a counterion is also present,   as well as the pharmaceutically acceptable salts thereof.   As new industrial products, the compound of formula OH (R) "   wherein: R 2 is hydrogen, an anionic charge or a conventional readily separable carboxyl protecting group provided that when R 2 is hydrogen or a protecting group, a counterion is also present,   as well as the pharmaceutically acceptable salts thereof.   As new industrial products, the compound of formula OH CH 3 (R) CH 3 in which: R 2 is hydrogen, an anionic charge or a carboxyl group easily separable conventional provided that when R 2 is hydrogen or a protecting group, is also present a counter-ion,   as well as the pharmaceutically acceptable salts thereof.   As new industrial products, the compound of formula O H CH 3 SCH 2 - 52 3   ) R 2 in which: R 2 is hydrogen, an anionic charge or a carboxyl group easily separable conventional provided that when R 2 is hydrogen or a protecting group, is also present a counter-ion,   as well as the pharmaceutically acceptable salts thereof.   M (R) 81. As new industrial products, the compound of formula / CO Oe O H C 3 CH 2 H the 2 CH \ N KE 2 e O N OOR 2 CH   In which: R 2 is hydrogen, an anionic charge or a carboxyl group easily separable conventional provided that when R 2 is hydrogen or a protecting group, is also present a counter-ion,   as well as the pharmaceutically acceptable salts thereof.   82 As new industrial products, the compound of formula OH CH 3 C S C 2 Kt ORH CH 2-COO   wherein: R 2 is hydrogen, an anionic charge or a readily removable carboxyl protecting group provided that when R 2 is hydrogen or a protecting group is also present a counterion,   as well as the pharmaceutically acceptable salts thereof.   As new industrial products, the compound of formula OH CH 3 CF 3 (R) in which: R 2 is hydrogen, an anionic charge or a carboxyl group easily separable conventional provided that when R 2 is hydrogen or a protecting group, is also present a counter-ion,   as well as the pharmaceutically acceptable salts thereof.   84 As new industrial products, the compound of formula O (CH 3 /   CH 3 in which: R 2 is hydrogen, an anionic charge or a carboxyl group easily separable conventional provided that when R 2 is hydrogen or a protecting group, is also present a counter-ion,   as well as the pharmaceutically acceptable salts thereof.   zbn - 85. As new industrial products, the compound of formula OH (R) J.   CH 3 in which: R 2 is hydrogen, an anionic charge or a carboxyl group easily separable conventional provided that when R 2 is hydrogen or a protecting group, is also present a counter-ion,   as well as the pharmaceutically acceptable salts thereof.   86. As new industrial products, the compound of formula OH E CH 3 (X SCH 2 N  '' 'COOR 2 CE 3   wherein: R 2 is hydrogen, an anionic charge or a readily removable carboxyl protecting group provided that when R 2 is hydrogen or a protecting group, a counterion is also present,   as well as the pharmaceutically acceptable salts thereof.   87. As new industrial products, the compound of formula CH 3 CHH OS H 3 N (R) SCH 2 < N 2. COOR   wherein: R 2 is hydrogen, an anionic charge or a readily removable carboxyl protecting group provided that when R 2 is hydrogen or a protecting group, a counterion is also present,   as well as the pharmaceutically acceptable salts thereof.   88. Process for the preparation of compounds having the formula R 8 H 1 R At N-Re 5 N's COOR 2 O   wherein: R 8 is a hydrogen atom; and   R 1 is selected from the group consisting of hydrogen as well as   substituted or unsubstituted organic radicals of the following list: alkyl, alkenyl and alkynyl having 1 to 10 carbon atoms; cycloalkyl and cycloalkylalkyl-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 wherein the aryl portion is formed by a phenyl radical and the aliphatic portion comprises 1 to 6 carbon atoms; heteroaryl, heteroaralkyl, heterocyclyl and heterocyclylalkyl wherein said one or more hetero atoms of said heterocyclic moieties are selected from the group consisting of 1 to 4 oxygen atoms, nitrogen   or sulfur and the alkyl part associated with these heterocyclic moieties   comprises from 1 to 6 carbon atoms, it being understood that the substituent (s) relative to the aforementioned radicals are, independently of each other, selected from the group comprising: C 1 -C 6 alkyl, optionally substituted by a group amino, halo, hydroxy or carboxyl; I. -OCR 3 halo -SR 3 -OR 3 0 O He II SRD -OCNR 3 R 4 O O   ## STR5 ## -N 3 NR -O 503 R 3 O NR 3 R 4 -OS-R 9 -502 NR 3 R 4 O 0 O II o -NHCNR 3 R 4 II -NR 3 S-R 9 O it's you o R 3 CNR 4- -NR 3 C = NR 4 -C 02 R 3 R 3 -OP (O) (OR 3) (OR 4) -NR 3 C 02 R 4 = O   -NO 2 in which, with regard to the abovementioned substituents:   the groups R 3 and R 4, independently of one another,   hydrogen, or alkyl, alkenyl and alkynyl radicals of 1 to 10 carbon atoms; cycloalkyl, cycloalkylalkyl and alkylcycloalkyl having 3 to 6 carbon atoms in the cycloalkyl part and 1 to 6 atomnies of carbon in the alkyl part; phenyl; aralkyl, aralkenyl and aralkynyl wherein the aryl portion is a phenyl radical and   the aliphatic portion comprises 1 to 6 carbon atoms; and   roaryl, heteroaralkyl, heterocyclyl and heterocyclylalkyl in   which the hetero ring hetero ring (s)   cited are 1 to 4 oxygen, nitrogen or sulfur atoms and the alkyl moiety associated with said heterocyclic moieties comprises from 1 to 6 carbon atoms; or R 3 and R 4 together with the nitrogen to which at least one of them is bound, form a 5- or 6-membered nitrogen-containing heterocyclic ring; R 9 is similar to R 3 except that it can not be hydrogen; or, wherein R1 and Re taken together form a C 2 -C 10 alkylidene or C 2 -C 10 alkylidene radical substituted with a hydroxy group; Rs belongs to the group of radicals, optionally substituted: alkyl, alkenyl, alkynyl comprising 1 to 10 carbon atoms;   cycloalkyl and cycloalkylalkyl having 3 to 6 carbon atoms   bone in the cycloalkyl part and 1 to 6 carbon atoms in the alkyl parts; phenyl; aralkyl, aralkenyl and aralkynyl wherein the aryl portion is a phenyl radical and the aliphatic portion of which has 1 to 6 carbon atoms; heteroaryl, heteroaralkyl, heterocyclyl and heterocyclylalkyl wherein the one or more hetero atoms of the aforementioned heterocyclic moieties consist of 1 to 4 oxygen, nitrogen and / or   sulfur and the alkyl moieties associated with said hetero-   cyclic include 1 to 6 atomnies of carbon; the radicals R 5 mentioned above are optionally substituted with 1 to 3 substituents chosen independently of each other from the group comprising: C 1 -C 6 alkyl, optionally substituted by amino, fluoro, chloro, carboxyl, hydroxy or carbamoyl groups; fluoro, chloro or bromo; -OR 3; -0 C 02 R 3; -OCOR 3; -OCONR 3 R 4; on-O-Rg; _ O oxo; -NR 3 R 4; R 3 CQNR 4-; -NR 3 CO 2 R 4; -NR 3 CONR 3 R 4; knew -NR 35-R 9; -SR 3; oo -S-R 9; O-S-Rg; -SO 3 R 3; -CO 2 R 3; -CONR 3 R 4;   CN; or phenyl, optionally substituted with 1 to 3 fluorine, chlorine or bromine atoms, or 1 to 3 C 1 -C 6 alkyl groups, -OR 3, -NR 3 R ", 503 R 4, -C 02 R 3 or -CONR 3 R 4, wherein R 3, R 4   and R 9 in these substituents Rs are as defined above.   above; or Rs can be linked to group N   at another point in the nucleus, so as to form a heterogeneous nucleus   aromatic or heterocyclic fused, which ring may further contain up to two additional hetero atoms consisting of oxygen, nitrogen or sulfur; R'5 is chosen from the group comprising hydrogen and the radicals, substituted or unsubstituted, from the following list:   alkyl, alkenyl and alkynyl, comprising from 1 to 10 carbon atoms   bone; cycloalkyl, cycloalkylalkyl and alkylcycloalkyl,   3 to 6 carbon atoms in the cycloalkyl part and 1 to 6 carbon atoms in the alkyl parts; spirocycloalkyl having 3 to 6 carbon atoms; phenyl; aralkyl, aralkenyl   and aralkynyl in which the aryl part consists of a radical   phenyl cal and whose aliphatic part comprises from 6 atoms   of carbon; heteroaryl, heteroaralkyl, heterocyclyl and hetero-   cyclylalkyl wherein the one or more hetero atoms of the aforementioned heterocyclic moieties consist of 1 to 4 oxygen, nitrogen or sulfur atoms and the alkyl moieties associated with said heterocyclic moieties comprise from 1 to 6 carbon atoms;   in which the substituent or substitutes relating to the radicals   are selected from the group consisting of: amino, mono-, di- and trialkylamino, hydroxyl, alkoxy, mercapto, alkylthio, phenylthio, sulfamoyl, amidino, guanidino, nitro, chloro, bromo, fluoro, cyano and carboxy; and wherein the alkyl moieties of the above substituents comprise from 1 to 6 carbon atoms; A is a straight or branched chain alkylene radical; R 2 is a hydrogen atom, an anionic charge, or a readily-separable carboxyl-protecting group, it being understood that when R 2 is a hydrogen atom or a protecting group is also present a counter-ion; and represents a mono-, bi or polycyclic aromatic heterocyclic radical substituted or unsubstituted, containing at least one nitrogen atom   in the nucleus and bound to A by a carbon atom of the nucleus and pos-   sedant, in addition, a nitrogen atom in the nucleus that is quater-   nized by the group R 5; as well as the pharmaceutically acceptable salts thereof; this compound comprising the steps of: 1) reaction of an intermediate compound of formula RB R 15 R III   OOR 2 -4 wherein: R 1, R 8 and R 18 are as defined above, and R 2 'is a conventional easily removable carboxyl protecting group,   in an inert organic solvent, with a reagent capable of introducing   leaving a conventional cleavable group L in the position of intermediate compound III to yield the intermediate compound of formula IV 8am R 15 R L II COOR 2   wherein: R 1, R 8 and R 15, L and R 2 'are as defined above; and, L is a classical cleavable group;   2) reaction of the intermediate compound IV in an inert organic solvent;   and present a base with a reagent having a mercaptan function of formula HS-A + N   wherein: A is as defined above and represents   an aromatic heterocyclic radical mono-, bi or polycyclic   that the core comprises a quaternizable nitrogen, said core   being bound to A by a carbon atom of the nucleus so as to con-   to an intermediate compound of formula II R 15 8 H R 8 RI S-A "N I II COOR 2 in which:   R 1, R 5, R 1 S A, R 2 'and are as defined above. t é -   3) reacting the intermediate II in an inert organic solvent with an activating agent of the formula Rs-X 'wherein: Rs is as defined above; and X is a conventional cleavable group so as to quaternize with the group R 5 a nitrogen atom of the ring of the substituent N on the intermediate II and form a compound of the formula: R 15 IRBH / L e , <SA 4 N-Xs Xs II COQR 2 ' in which: R 1, R 8, RIB, R 2 ', A, (N-R 5 and X' are as defined above.   above, and, if necessary, replace the counterion X 'with another counterion   and, where appropriate, removing the carboxyl protecting group R 2 'to   to the desired unblocked compound of formula I, or a pharmaceutically acceptable salt thereof. Maceutically acceptable.   Process for the preparation of compounds having the formula O COOR   in which R is a hydrogen atom; and   Ri is selected from the group consisting of hydrogen as well as   substituted or unsubstituted alkyl groups of the following list: alkyl, alkenyl and alkynyl having 1 to 10 carbon atoms; cycloalkyl and cycloalkylalkyl 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 wherein the aryl portion is formed by a phenyl radical and the aliphatic portion comprises 1 to 6 carbon atoms; heteroaryl, heteroaralkyl, heterocyclyl and heterocyclylalkyl wherein the one or more hetero atoms of said heterocyclic moieties are selected from the group consisting of 1 to 4 oxygen atoms, nitrogen   or sulfur and the alkyl part associated with these heterocyclic moieties   which comprises 6 carbon atoms, provided that the   substituents relating to the radicals mentioned above are independently   each other, selected from the group consisting of: C 1 -C 6 alkyl, optionally substituted with amino, halo, hydroxy or carboxyl; B -OCR 3 halo -SR 3 -OR 3 o o -SR 9 -OCNR 3 R 4 0 0 o Bl He I -SR 9 -CNR 3 R " O-NR 3 R 4 CN N 3 SNR 3 -O 503 R 33 0 NR 3 R " not -S-R -502 NR 3 R 4 OOS Rg o -NHCNR 3 R 4 -NRS-R 9 O o R 3 CNR 4- -NR 3 C = NR 4 -CO 2 R 3 -OP (O) (OR 3) (OR 4) -NR 3 CO 2 R 4 =   -NO 2 in which as regards the above-mentioned substituents:   the groups R 3 and R 4, independently of one another,   hydrogen, or alkyl, alkenyl and alkynyl radicals having 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 part; phenyl; aralkyl, aralkenyl and aralkynyl wherein the aryl portion is a phenyl radical and   the aliphatic portion comprises 1 to 6 carbon atoms; and   roaryl, heteroaralkyl, heterocyclyl and heterocyclylalkyl in   which the hetero ring hetero ring (s)   cited consist of 1 to 4 atoms of oxygen, nitrogen or sulfur   and the alkyl portion associated with said heterocyclic moieties   take from 1 to 6 carbon atoms; or R 3 and R "together with the nitrogen to which at least one of them is bound, form a 5 or 6 membered nitrogen-containing heterocyclic ring; R 9 is similar to R 3 if it is not is that it can not be hydrogen, or where R and R taken together form a C 2 -C 10 alkylidene or C 2 -C 10 alkylidene radical substituted by a hydroxy group; R 5 belongs to the group of radicals, optionally substituted: alkyl, alkenyl, alkynyl having 1 to 10 carbon atoms;   cycloalkyl and cycloalkylalkyl having 3 to 6 carbon atoms   bone in the cycloalkyl part and 1 to 6 carbon atoms in the alkyl parts; phenyl; aralkyl, aralkenyl and aralkynyl wherein the aryl portion is a phenyl radical and the aliphatic portion of which has 1 to 6 carbon atoms; heteroaryl, heteroaralkyl, heterocybyl and heterocyclylalkyl wherein the one or more hetero atoms of said heterocyclic moieties consist of 1 to 4 oxygen, nitrogen and / or   sulfur and the alkyl moieties associated with said hetero-   cyclic include 1 to 6 carbon atoms; the radicals R 5 mentioned above are optionally substituted with 1 to 3 substituents chosen independently of each other from the group comprising: C 1 -C 6 alkyl, optionally substituted with amino, fluoro, chloro, carboxyl, hydroxy or carbamoyl groups; fluoro, chloro or bromo; -OR 3; -OC 02 R 3; at -OCOR 3; -OCONR 3 R 4; O O I -OS-R 9; O oxo; -NR 3 R 4; R 3 CONR 4-; -NR 3 CO 2 R 4; -NR 3 CONR 3 R 4; O-NR 35-Rg; -SR 3; O -S-R 9; O, R 9; -S-R 9; -SO 03 R 3; -CO 2 R 3; -CONR 3 R 4;   CN; or phenyl, optionally substituted with 1 to 3 fluorine, chlorine or bromine atoms, or 1 to 3 C 1 -C 6 alkyl groups, -OR 3, -NR 3 R 4, SO 3 R 4, -C O 2 R 3 or -CONR 3 R 4, wherein R 3, R 4   and R 9 in these substituents Rs are as defined above.   above; or R 5 can be linked to the group Ne   at another point in the nucleus, so as to form a heterogeneous nucleus   aromatic or heterocyclic fused, which ring may further contain up to two additional hetero atoms consisting of oxygen, nitrogen or sulfur; 35 8   Rs 5 is chosen from the group comprising hydrogen as well as the radicals, substituted or unsubstituted, from the following list:   alkyl, alkenyl and alkynyl, comprising from 1 to 10 carbon atoms   bone; cycloalkyl, cycloalkylalkyl and alkylcycloalkyl,   3 to 6 carbon atoms in the cycloalkyl part and 1 to 6 carbon atoms in the alkyl parts; spirocycloalkyl having 3 to 6 carbon atoms; phenyl; aralkyl, aralkenyl   and aralkynyl in which the aryl part consists of a radical   phenyl call and whose aliphatic part comprises more than 6 atoms   of carbon; heteroaryl, heteroaralkyl, heterocyclyl and heterocyclyl   cyclylalkyl wherein the one or more hetero atoms of the aforementioned heterocyclic moieties consist of 1 to 4 oxygen, nitrogen or sulfur atoms and the alkyl moieties associated with said heterocyclic moieties comprise from 1 to 6 carbon atoms;   in which the substituent or substitutes relating to the radicals   are selected from the group consisting of: amino, mono-, di- and trialkylamino, hydroxyl, alkoxy, mercapto, alkylthio, phenylthio, sulfamoyl, amidino, guanidino, nitro,   chloro, bromo, fluoro, cyano and carboxy; and -   wherein the alkyl moieties of the above substituents comprise from 1 to 6 carbon atoms; A is a straight or branched chain alkylene radical; R 2 is a hydrogen atom, an anionic charge or a carboxyl group easily separable conventional, it being understood that when R 2 is a hydrogen atom or a protecting group is also present a counter-ion; and e represents a mono-, bi or polycyclic aromatic heterocyclic radical substituted or unsubstituted, containing at least one nitrogen atom   in the nucleus and bound to A by a carbon atom of the nucleus and pos-   sedant, in addition, a nitrogen atom in the nucleus that is quater-   nized by the group R 5; as well as the pharmaceutically acceptable salts thereof; this compound comprising the steps of: 1) reacting an intermediate compound of formula R 5 R 1 SA N in which COR 2 R 1, R, R 5, A and R 2 'are as defined above X N   represents an aromatic heterocyclic radical mono-, bi and poly-   cyclic ring whose ring comprises a quaternizable nitrogen atom, said ring being bonded to A via a carbon atom of the ring, in an organic solvent inert with an alkylating agent of formula RsX, in which: Rs is as defined above; and X 'is a conventional cleavable group so as to quaternize with a Rs-a nitrogen atom of the N-substituent ring of Intermediate II and form a compound of formula 8 RB S-A X Xth I_ COOR 2 in which:   R 1, R 6, R 15, R 2, A, (N-R and X 'are as defined above.   above, and, if necessary, replace the counterion X 'with another counterion, and optionally eliminate the carboxyl protecting group R 2' to obtain the unlocked compound of the formula I sought, or an acceptable salt thereof from the pharmaceutical point of view.   90 Process according to claim 88 or 89, characterized in that the quaternization step is carried out after elimination of the group R 2 'carboxyl protector.   91. As new industrial products, the compounds according to   any of claims 1 to 87, for anti-tampering bacterial.