LU84739A1 - NEW CARBAPENEM TYPE ANTIBIOTICS - Google Patents

Description

*

NEW CARBAPENEM TYPE ANTIBIOTICS

The subject of the present invention is new antibiotics of the carbapenem type in which the substituent in position 2 has the formula: _ Rio - © / —S — A — Sv

V

wherein: 10 A is a straight or branched chain alkylene radical having 2 to 6 carbon atoms; and,

Rio and Ru, independently of one another, represent aliphatic, cycloaliphatic, cycloaliphatic-aliphatic, aryl, heterocyclyl, hetero-cyclyclyl -aliphatic, heteroarylic or heteroaliphatic radicals, optionally substituted, Rio and Ru possibly forming with atom S to which they are linked a heterocyclic ring containing sulfur, optionally substituted.

A number of O-lactam derivatives containing the carbapenem 2 ° 6 nucleus have been described in the literature. These carbapenem derivatives have been described as being of interest as an anti-bacterial agent and / or inhibitor of B_- lactamas.

The fnital carbapenem compounds already known are natural products such as thienamycin of formula: Z 30

0H H

__S CH - CH -NH -

3 =! J I

I-N -—- C00H

O

2 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 a large number of Pseudomonas-like species, organisms which are known for their notable resistance to $ -lactam antibiotics.

Other natural products containing the carbapenem nucleus consist of derivatives of olivanic acid such as the antibiotic MM 13902 of formula: '10 CH, - H03S0 ^ f \ ____ SCH = CHNHCOCH3

} -N-U— COOH

O

15 · described in United States patent No. 4,113,856, the antibiotic MM 17880 of formula: CH,

20 I

__SCH, CH, NHCOCH, ho3sot p jT ^ z Δ

J-N-U— C00H

0 25 described in United States patent No. 4,162,304, the antibiotic MM 4550A of formula:

CH, O

JL ^ 1 _S-CH = CHNHCOCH,

30 H03S <r T “] Y

çfi-N - COOH

described in US Patent No. 4,172,129 as well as the antibiotic 890A of formula: 35 CH, 1 0 1 11 ^ 3CH = CHNHCCH,

H03S0 I

cf N COOH

described in U.S. Patent No. 4,264,735.

In addition to natural products, the deacetyl compound 890A1o of formula: 3 * 5 CH3 ÎVArva ^

Y N COOH

10. described in US Patent No. 4,264,734, was prepared by enzymatic deacylation of the corresponding N-acetyl compound. Various derivatives of naturally occurring olivanic acids: could also have been prepared by synthesis, for example the compounds of formula:

CH J

^ 5 (0) nhcoch3

* 2® I I IX

Q * N C02R1 wherein: C02R1 is a free, salified or esterified carboxyl group; ] 25 n is 0 or 1; and, R2 is a hydrogen atom, an acyl group or a group of formula R3O3S in which R3 is a salified ion or a methyl or ethyl group, as described in European patent application No. 8885.

30 U.S. Patent No. 4,235,922 (see also European Patent Application No. 2058) describes a carbapenem derivative having the formula: -f ^^> r'SCH2CH2NH2

35 (T N- ^ COOH

while British patent application No. 1,598,062 describes the isolation of the compound:% 5 4 ^ SCH2CH2NHCOCH3 ο N COOH.

a fermentation broth of Streptomyces.

Carbapenems which are not substituted in position 6 could also be obtained by synthesis. Thus, United States patent No. 4,210,661 describes compounds of the formula: composés 10 r

N COOH

In which: R2 is a phenyl or substituted phenyl radical; US Pat. No. 4,267,177 describes compounds of formula: 20 -f σ N cooh wherein: R1 is an optionally substituted pyridyl group; United States Patent No. 4,255,441 describes compounds of the formula: _-S ~ CR0 = CRrjR.

ΓΊ II

30 I

çy N cooh

O

in which: ~ R2 and R3 are a hydrogen atom or an alkyl radical and, R ^ is an NH-C0nR6 group in which R6 is an alkyl, phenyl, or substituted phenyl radical and n is equal to 1 or 2; and United States Patent No. 4,282,236 describes compounds of the formula: 5 5 -

-N-U — COOH

in which:

Ri is a hydrogen atom or an alkyl radical; and, R2 is a CN or CO2R3 radical in which R3 is a hydrogen atom, or an alkyl, aryl or aralkyl radical.

5 io The carbapenems of general formula: HAI—-

cr N COOH

In which: R1 is a hydrogen atom or an acyl radical; and, R8 is a hydrogen atom or an alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, alkylcycloalkyl, aryl, aralkyl, aralkenyl, aralkynyl, heteroaryl, heteroaralkyl, heterocyclyl or heterocyclylalkyl group, substituted or unsubstituted, are substituted or unsubstituted, U.S. Patent No. 4,218,463. There is no known description of substituents R8 having the type: -A-SC ^ in which: A is an alkylene radical.

The natural product consistingenthienamycin has the absolute configuration 5R, 5S, 8R. This isomer, as well as the seven remaining thiena-30 mycinic isomers, can be obtained by total synthesis as described in US Patent No. 4,234,596. The pro-cedures of total synthesis of thienamycin are also described, for example, in United States patents 4,287,123; 4,269,772; "4,282,148; 4,273,709; 4,290,947 and in European patent application 35,797. A fundamental intermediary of the methods of synthesis described is the compound consisting of: 6 5

j ~ H

(f "N C02pNB

in which: pNB represents paranitrobenzyl.

Due to the exceptional biological activity of thienamycin, a large number of its derivatives have been prepared and are described in the technical literature.

Among these, there may be mentioned: ~ 1.- the N-formimidoyl thienamycins of formula:

OH

15 / '\ r __ / V ^ SCH2CH2N = Ç-NR2 i 11 cr N cooh described in European patent application No. 6639; and, 20 2.- the N-heterocyclic thienamycin derivatives having the formulas: -, β »τΟ 25 - / '" N ^ -SCH CH2N “^ n y

R

30 <î> p

:: “T

35 A_ / V: “W. (CH2) TT \> J N U “~“ xooh A1

II

“7 in which: the bifunctional nucleus may contain additional unsaturations in the nucleus; and, in which: 5 n is an integer between 1 and 6; p is 0, 1 or 2; R1 is a hydrogen atom or an alkyl or aryl radical; and, k Z is an imino, oxo group, a hydrogen atom, or a no or alkyl friend group, as described in United States Patent No. 4,189,493; and, s 3.- substituted N-methylene derivatives of thienamycin having the formula:

OH

15 / ^ \ __ y ^^ y - SCH2CH2N = ^ ”x

N COOH

in which:

20 X and Y are hydrogen atoms or groups R, OR, SR

or NR-1R2 in which R is an alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclyl or heterocyclyl-substituted or unsubstituted alkyl radical; and, R1 and R2 are a hydrogen atom or an R radical, as described in United States Patent No. 4,194,047; 4.- compounds of formula: OR3 I 15

30 / \ ^ SCH2CH2NR R

ο * N ^^ COOH

v in which: R3 is an aryl, alkyl, acyl or aralkyl radical and, R1 and R2 are independently of one another chosen from the group comprising hydrogen and the acyl radical (including 8 the acyl radicals of type: 0

II

-C-R11 in which: 5 R11 may inter alia be an alkyl radical substituted by a quaternary ammonium group, such as: if Θ / Γ ^ -c-ch2— m_y): 10 described in the United States patent No. 4,226,870; 5.- compounds of formula: OR3> / * ss ^^ sch2ch2nr1r2

COOH

in which: R3 is a hydrogen atom or an alkyl radical or an optionally substituted monovalent hydrocarbon radical; R1 is an optionally substituted alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkenylalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl or heteroaralkyl radical; and, R2 is an acyl radical (including acyl radicals of the type: 0

II

-C-R

wherein: R is an alkyl radical substituted by a quaternary ammonium group, i.e.: ï -c-ch2-_y) â described in British Patent No. 1,604,276 (see also US Pat. United States of America No. 4,235,917); 9 6. - compounds of formula:? H ^ JL ys. 05 6 7

X \ X ^ Vj ^ SCH2CH2NR R R

5 J-H-Lcop

O

^ in which: R5, R6 and R7, independently of one another, consist of hydro-, gene or alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkenylalkyl, - cycloalkylalkyl, aryl, aralkyl, heteroaryl or heteroaralkyl radicals, optionally substituted, as described in United States Patent No. 4,235,920; 7. - compounds of formula: 0r3 5 I? ® 2 sch, çh, n-ç = hrV αΘ

20 I L R

"- ^ - cox

O

in which each of the groups:

Ri and Ra, independently of each other, is a radical of the type defined for R, a hydrogen atom or a nitro, hydroxyl, alkoxyl group comprising 1 to 6 carbon atoms, ami no, alkylamino comprising 1 with 6 carbon atoms, di (alkyl comprising 1 to 6 carbon atoms) -amino or tri (alkyl comprising 1 to 6 carbon atoms) -30 amino, an additional anion being present in the latter case; - where Ri and Ra are linked to each other so as to form, together with the nitrogen atom to which they are linked, a heterocyclyl or heteroaryl bicyclic or monocyclic, optionally substituted residue, the nucleus of which contains 4 to 10 atoms, one or more of them can be an additional hetero atom consisting of oxygen, sulfur and nitrogen; 10 R is a cyano group or a carbamoyl, carboxyl, (alkoxy comprising 1 to 10 carbon atoms) -carboxyl, alkyl comprising 1 to 10 carbon atoms, alkenyl comprising 2 to 10 carbon atoms, alkynyl 5 comprising 2 with 10 carbon atoms, cycloalkyl comprising 3 to 10 carbon atoms, cycloalkylalkyl comprising 4 to 12 carbon atoms, cycloalkylalkenyl comprising 5 to 12 carbon atoms, cycloalkenyl „comprising 3 to 10 carbon atoms, cycloalkenylalenophenyl comprising 5 with 12 carbon atoms, cyclo-, alkenylalkyl comprising 4 to 12 carbon atoms, aryl comprising 6 to 10 carbon atoms, aralkyl comprising 7 to 16 carbon atoms, ara! kenyl comprising 8 to 16 carbon atoms, aralkynyl Having 8 to 16 carbon atoms, or heteroaryl, hetero-roaralkyl, heterocyclyl or heterocyclylalkyl monocyclic or bicyclic comprising 4 to 10 carbon atoms, one or more of which may consist of a hetero atom consisting of ox ygene, sulfur and nitrogen, and wherein the alkyl residue of the heteroalkyl or heterocyclylalkyl radical comprises 1 to 6 carbon atoms; these radicals possibly being substituted; the substituent (s) on the groups R, R1, R2 or on the ring formed by linking R1 and R2 consist of chlorine, bromine, iodine, fluorine atoms, or azido, alkyl groups comprising 1 to 4 carbon atoms, mercapto, sulfo, phos-phono, cyanothio (-SCN), nitro, cyano, amino, hydra-zine, amino or hydrazino having up to three alkyl substituents comprising 1 to 6 carbon atoms, t hydroxy, alkoxy having 1 to 6 carbon atoms, alkylthio having 1 to 6 carbon atoms; carboxyl, c oxo, (alkoxy comprising 1 to 6 carbon atoms) -carbonyl, acyloxy comprising 2 to 10 carbon atoms, carbamoyl, (alkyl comprising 1 to 4 carbon atoms) - carbamoyl or di (alkyl comprising 1 to 4 carbon atoms) -carbamoyl; R3 is a hydrogen atom, an acyl radical or a radical of the type defined for R ^; R4 is an alkyl radical comprising 1 to 10 carbon atoms; substituted carbonylmethyl; (alkoxy comprising 1 to 6 carbon atoms) - (alkyl comprising 1 to 6 5 carbon atoms), (cycloalkoxy comprising 3 to 6 carbon atoms) - (alkyl comprising 1 to 6 carbon atoms); alkanoyloxyalkyl comprising 2 to 12 w carbon atoms; an alkyl radical comprising 1 to 6 carbon atoms partially or totally halogenated in which the halogen (s) consist of chlorine, bromine or fluorine; aminoalkyl; alkenyl having 2 to 10 carbon atoms; alkynyl comprising 2 to 10 carbon atoms; acyl; alkoxycarbonylalkyl comprising 3 to 14 carbon atoms; dialkylaminoacetoxyalkyl having 4 to 21 carbon atoms; alkanoyaminoalkyl comprising 2 to 13 carbon atoms; aralkyl in which the alkyl radical contains 1 to 3 carbon atoms in which the aryl residue contains from 6 to 10 carbon atoms; monocyclic or bicyclic heteroaralkyl or hetero-cyclyalkyl containing 4 to 10 atoms in the ring, 1 to 3 carbon atoms in the alkyl residue and 1 to 4 hetero atoms consisting of oxygen, sulfur and / or nitrogen; aralkyl or heteroalkyl substituted on the nucleus in which the substituent is chlorine, fluorine, bromine, iodine or an alkyl radical comprising 1 to 6 carbon atoms; aryl or substituted aryl on the ring containing 6 to 10 carbon atoms in the ring and the ring substituent of which is hydroxy, alkyl having 1 to 6 carbon atoms, chlorine, fluorine or bromine; aralkoxyalkyl; alkylthioalkyl comprising 2 to 12 carbon atoms; cycloalkylthioalkyl comprising 4 to 12 carbon atoms; (acylthio comprising c 2 to 10 carbon atoms) - (alkyl comprising 1 to 6 35 carbon atoms); or phenylalkenyl, the alkenyl part of which comprises 2 to 6 carbon atoms;

Rs is an alkyl radical comprising 2 to 10 carbon atoms, substituted or unsubstituted; alkenyl or ί 12 alkynyl having 2 to 10 carbon atoms; cycloalkyl, cycloalkenyl, cycloalkenylalkyl with substituted or unsubstituted ring having 3 to 6 carbon atoms in the ring and up to 6 carbon atoms on any side chain; aryl having 6 to 10 carbon atoms; aralkyl having 6 to 10 carbon atoms in the nucleus and 1 to 6 carbon atoms in the alkyl chain; monocyclic or bicyclic hetero * aryl or heteroalkyl containing 4 to 10 atoms in the nucleus of which one or more of them consist of oxygen, nitrogen or sulfur and containing 1 to 6 carbon atoms in c alkyl chain; the substituents of the chain nucleus consisting of one or more chlorine, bromine, fluorine or azido, cyano, ami no, alkylamino groups containing 1 to 6 carbon atoms, di (alkyl comprising 1 to 6 atoms) carbon) -amino or tri (alkyl comprising 1 to 6 carbon atoms) -amino, an additional anion being present in the latter case, hydroxy, alkoxy comprising 1 to 6 carbon atoms, alkylthioalkyl comprising 1 to 6 carbon atoms ; carboxyl; oxo, (alkoxy having 1 to 6 carbon atoms) -carbonyl; acyloxy comprising 2 to 10 carbon atoms; carbamoyl; (alkyl containing 1 to 4 carbon atoms) -carbamoyl; di (alkyl having 1 to 4 carbon atoms) -carbamoyl; cyanothio (-SCN) or nitro; R6 is a hydrogen atom or a hydroxy radical, mer-capto or alternatively is the radical R, -OR, -SR or NR1R2, in which R, R1 and R2 are as defined above; X is a hydroxy group, mercapto, ami no, acyloxy, t -OR *, -SR *, -NHR *, -N - $ *) a, -0M, -0Q or when the compound is in the form of a zwitterion, - O ”, in which 35 cases A" is absent "; A when the compound is not in the form of a switerion is an opposite ion; M is a pharmaceutically acceptable cation; and 13 Q is a blocking group as defined in the present, as described in British patent n ° 1.604.275; and, 8.- the compounds of formula: 5 JF é? S CT 2CH 2NH— / "N Λ

i — N- ^ cocP

. o 10

in which: O

0 15. linked to the amino group nitrogen of thienamycin represents a heterocyclic group containing mono- or polycyclic nitrogen and, R is hydrogen, or a substituted or unsubstituted radical: alkyl, aryl, alkenyl, heterocyclylal-20 alkenyl, aralkenyl, heterocyclylalkyl, aralkyl, -NRa, COOR, C0NR2, -OR, or CN, as described in European patent application No. 210.82.

Among the compounds described in United States Patent No. 4,235,920 is described the compound of formula:

25 QH

1 ^ θ Θ X \ v> ‘^ xV ^^ SCH2CH2N (CH3) 3] a

J 'N' ^ COOH O

- in which: A is a pharmaceutically acceptable anion.

The aforementioned quaternary amine derivative is also described in the journal Recent Advances in the Chemistry of ß-Lactam Antibiotics, Royal Society 35 of Chemistry, London, 1981, pages 240-254, where its average bacterial activity is mentioned as being approximately the half to 2/3 that of thienamycin.

The applicants do not know of any technical article describing i 14 of the carbapenem derivatives of the present invention comprising a position 2 substituent of the type: φ -SAS <^ although they are aware of a number of relatively recent patents which, in their aspect the broadest, can generally include such compounds. Thus, for example: 1. - European patent application 40.408 describes compounds of formula: 10 ^

g-N LL - COOH

15. in which:

Ri is a methyl or hydroxyl atom or radical; R51 is a monovalent organic group comprising inter alia a substituted alkyl radical or a group of formula -CH2R7 in which R7 is an optionally substituted 5 or 6 membered heterocyclic group with 5 or 6 members; 2. - European patent application 38.869 describes compounds of formula:

8? ^ B

h6-- 25

g N fcoOH

wherein: R6, R7 and R8 are independently of each other selected from the group consisting of hydrogen and the following substituted or unsubstituted radicals: alkyl, alkenyl, and alkynyl having 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 in the alkyl part; aryl, such as phenyl; aralkyl, aralkenyl and aralkynyl in which the aryl part consists of a phenyl radical and the aliphatic part comprises 1 to 6 carbon atoms; heteroaryl, heteroaralkyl, heterocyclyl and heterocyclylalkyl, in which the substituent or substituents relating to the abovementioned radicals are chosen from the group comprising: -X ° halo (chlorine, bromine, fluorine) 5 -OH hydroxy -OR1 alkoxy, aryloxy * 0

II

-0CNR1R2 carbamoyloxy * 0

II

10 -CNR1R2 carbamoyl? -NR1R2amino ^ NR1 amidino N'vNR1R2 15 R1 -N02 ni tro © -N (R1) 3 no trisubstituted friend (the R1 groups can be chosen independently of each other) 20 R1 -C = N02 oxymino -SR1 alkyl- and arylthio -S02NR1R2 sulfonamido 0, Il 25 -NHCNR1R2 ureido 0 R1CNR2 friend do -CO2H carboxy -CO2R1 carboxylate 30 0

II

.. -CR1 acyl 0 11 c -OCR1.acyloxy -SH. mercapto 35 0

II

-SR1 alkyl etarylesulfonyl 0

II

-SR1 alkyl and arylesulfonyl 16 -CN cyano -N3 azido in which, as regards the abovementioned substituents on R6, R7 and R8, the groups R1 and R2 are independently chosen from the group comprising the hydrogen atom and the alkyl, alkenyl, and alkynyl e radicals comprising 1 to 10 carbon atoms; cycloalkyl, cycloalkylalkyl and alkyl cycloalkyl comprising 3 to 6 carbon atoms in the cycloalkyl ring and 1 to 6 carbon atoms in the alkyl chain; aryl, such as phenyl; aralkyl, aralkenyl and aralkynyl in which the aryl part consists of a phenyl radical and in which the aliphatic part comprises 1 to 6 carbon atoms; heteroaryl, heteroaralkyl, heterocyclyl and heterocyclylalkyl in which the hetero atom (s) 15 is / are chosen from the group comprising 1 to 4 oxygen, nitrogen or sulfur atoms and in which the alkyl part associated with said heterocyclic part comprises 1 to 6 carbon atoms (see also European patent applications 1627, 1628, 10.317, 17.992, 37.080, 37.081 20 and 37.082); 4.- European patent application No. 34.832 describes compounds of form: t / V u

CH -— CH '—- f -SR

25 '5 * C02h in which: R1 is a hydrogen atom or a group OH, OSO3H or also a salt or ester of an alkyl radical comprising 1 to 4 carbon atoms of these compounds, OR2, SR3, 0C0R2, 0C02R3 or 0C0NHR3, in which R2 is an alkyl radical comprising 1 to 6 carbon atoms or an optionally substituted benzyl group, R3 is an alkyl group comprising 1 to 6 carbon atoms or an optionally substituted phenyl or benzyl group, while , R12 is an alkyl radical comprising 1 to 6 carbon atoms, alkenyl comprising 2 to 6 carbon atoms, alkynyl comprising 17 to 6 carbon atoms the triple bond of which is not present on the carbon adjacent to the sulfur atom, aralkyl, alkanoyl comprising 1 to 6 carbon atoms, aralkanoyl, aryloxyalkanoyl or arylcarbonyl, each of these R12 groups being optionally substituted and these compounds being further described as antibacterial agents.

European patent application 38,869 described above describes the synthesis of carbapenem derivatives by passage through intermediates of general formula: R7 R6 __ ^ T °

15 O ° 2R

in which: R6 and R7 are as defined above; and, R2 'is an easily removable carboxyl protecting group.

Also described as intermediates of the compounds of formula -20: R7 rS -or 25> - "- ^ co2r2 'wherein: X is a breakable group.

Then, as indicated above, the state of the art of carbapenem derivatives having a substituent in position 2 of the type: -SAN ^ as well as derivatives comprising a substituent in position 2 of the type: SASR ·, 35 in which: R1 is a hydrogen atom, an alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, alkylcycloalkyl, phenyl, aralkyl, aralkenyl, aralkynyl, heteroaryl, heteroaralkyl, heterocyclyl 18 or heterocyclyl none onalkyl document in which are described carbapenems comprising a substituent in position 2 in which the alkylene group A is directly attached to a sulfonium group, that is to say a group of the 5 type: φ -SAS <

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

* The present invention relates to a new series of carbapenem derivatives characterized by a substituent in position 2 of formula: T- Rio

V

15. -S-A-SiT

R11 in which: A is an alkylene radical with a straight or branched chain comprising 2 to 6 carbon atoms; and, 20 R10 and R11, independently of each other, represent aliphatic, cycloaliphatic, cycloaliphatic-aliphatic, aryl, heterocyclyl, heterocyclyl-aliphatic, heteroaryl or heteroaliphatic radiocals, optionally substituted, or alternatively R10 and R11 between them with: 25 S® to which they are linked a heterocyclic ring containing sulfur, and optionally substituted, containing from 0 to 2 double bonds and from 0 to 2 additional hetero atoms consisting of 0, N and S, this ring being linked to A by a sulfur atom to form a sulfonium group.

More specifically, the present invention relates to carbapenem derivatives of formula:: R8 g © R10 35 R1—— J - '* - ^ Coor8 19 in which: R8 is a hydrogen atom; and, R1 is chosen from the group comprising the hydrogen atom, or the substituted or unsubstituted radicals, belonging to the list comprising the alkyl, alkenyl and alkynyl radicals comprising 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 alkylated side chain; phenyl, aralkyl, aralkenyl and aralkynyl in which the aryl part is a phe-nyl radical and the aliphatic part contains 1 to 6 carbon atoms; heteroaryl, heteroaralkyl, heterocyclyl and heterocyclylalkyl in which the hetero atom (s) of the aforementioned heterocyclic parts comprise 1 to 4 atoms chosen from the group of oxygen, nitrogen or sulfur and the alkyl chains which are associated with said ring heterocyclic comprise 1 to 6 carbon atoms; in these radicals, the substituent or substituents are independently chosen from the group comprising: alkyl radicals comprising 1 to 6 carbon atoms optionally substituted by amino, halo, hydroxy or carboxyl radicals; halo; -OR3

O

U 3 4 —OCNR R

25 n -cnr3r4 -nr3r4 / NR3 30 ^ \ jr3r4 -so2nr3r4

O

Jl 3 4

0r -NHCNR R

35

O

3 II 4 RCNR- -co2r3 = 0 20 Ο U 3

-OCR

5 -Sr3

O

// 9

-SR

O

Il 9 -SR *

II

10 o

-CN

'"3 3 -oso3r -OSO, R3 15 Δ • 3 4 -nr so2r 3 4

-NRJÇ = NR

R3 20 -nr3co2r4 -no2 in which, with respect to the aforementioned substituents, the groups R3 and R4 * are independently chosen from hydrogen, and the alkyl, alkenyl and alkynyl groups comprising 1 to 10 carbon atoms; cycloalkyl, cycloalkylalkyle and alkylcycloalkyle comprising 3 to 6 carbon atoms in the cycloalkyl ring and 1 to 6 carbon atoms in the alkyl chain; phenyl, aralkyl, aralkenyl and aralkynyl in which the aryl part consists of a phenyl radical and the aliphatic part contains 1 to 6 carbon atoms; and hetero-aryl, heteroaralkyl, heterocyclyl and heterocyclylalkyl in which the hetero atom (s) of the abovementioned heterocyclic parts consist of 1 to 4 atoms chosen from the group of oxygen, atom or sulfur and the alkyl chains which associated with them include 1 to 6 carbon atoms, R3 and R * can together form with the nitrogen atom to which at least one of them is linked a heterocyclic ring, containing nitrogen, to 5 or 6 atoms, 21 R9 being similar to R3 except that it cannot be hydrogen; or in which: R1 and R8 taken together are constituted by an alkylidene group comprising 2 to 10 carbon atoms or alkylidene comprising 2 to 10 carbon atoms substituted by a hydroxy radical; A is straight or branched chain alkyl having 2 to 6 carbon atoms; R2 is a hydrogen atom or an anionic charge or an easily divisible carboxylic protecting group, it being understood that when R2 is hydrogen or a protecting group, a counter anion is also present, while, R1 ° and R11 independently of one another represent the radicals: a) alkyl comprising 1 to 6 carbon atoms, alkenyl comprising 2 to 6 carbon atoms, alkynyl comprising 3 to 6 carbon atoms, cycloalkyl or cycloalkylalkyl comprising 3 to 6 atoms of carbon in the cycloalkyl ring and 1 to 6 carbon atoms in the alkyl chain, the said alkyl, alkenyl, alkynyl, cycloalkyl or cycloalkylalkyl groups being optionally substituted with 1 to 3 substituents chosen independently from one another from the groups hydroxy, alkoxy comprising 1 to 6 carbon atoms, alkanoyloxy comprising 1 to 6 carbon atoms,. carboxy, alkoxycarbonyl comprising 1 to 6 carbon atoms, ami-no, alkylamino comprising 1 to 6 carbon atoms, di (alkylamino comprising 1 to 6 carbon atoms), alkanoylamino comprising 1 to 6 carbon atoms, phenyl, substituted phenyl by 1 to 3 halo, alkoxy comprising 1 to 6 carbon atoms, alkyl comprising 1 to 6 carbon atoms, carboxy, carboxy (alkyl comprising 1 to 6 carbon atoms), ami no, alkylamino comprising 1 to 6 carbon atoms, di (alkyl containing 1 to 6 carbon atoms) -30 amino or di (alkyl containing 1 to 6 carbon atoms) amino alkyl comprising 1 to 6 carbon atoms, halo or oxo; b) phenyl optionally substituted with 1 to 3 halo, or alkoxy groups comprising 1 to 6 carbon atoms, alkyl comprising 1 to 6 carbon atoms, carboxy, amino, alkylamino comprising 1 to 6 carbon atoms or di (alkyl comprising 1 to 6 carbon atoms) ~ amino; c) heterocyclyl or heterocyclylalkyl in which the heterocyclic part is a nucleus formed from 4 to 6 atoms comprising 1 to 22 3 hetero atoms consisting of 0, N and S and the alkyl chain contains 1 to 6 carbon atoms, said heterocyclyl nucleus or heterocyclylalkyl being optionally substituted by 1 to 3 alkyl groups comprising 1 to 6 carbon atoms or alkoxy com-5 taking 1 to 6 carbon atoms; or, d) heteroaryl or heteroaralkyl of which the heterocyclic part is an aromatic ring with 5-6 atonies of which 1 to 3 hetero-atom s consist of 0, N and S and the alkyl chain contains 1 to 6 carbon atoms, said nucleus heteroaryl or heteroaralkyl being optionally substituted by 1 to 3 alkyl radicals comprising 1 to 6 carbon atoms, alkoxy comprising 1 to 6 carbon atoms, carboxy, carboxy (alkyl comprising 1 to 6 carbon atoms), amino, alkylamino comprising 1 to 6 carbon atoms, di (alkylamino with 1 to 6 carbon atoms), amino (alkyl with 1 to 6 carbon atoms) or di (alkylamino with 1 to 6 carbon atoms) - (alkyl with 1 to 6 carbon atoms ); or R1 ° and R11 together with: s® to which they are linked constitute a heterocyclic ring containing sulfur containing 4-6 atoms containing 0 to 2 double bonds and 0 to 2 additional heteror atoms consisting of 0, N and S, said nucleus being linked to A by a sulfur atom, so as to form a sulfonium group, this heterocyclic nucleus being optionally substituted by 1 to 3 substituents chosen independently from one another from the radicals: alkyl comprising 1 to 6 carbon atoms optionally substituted by 1 to 3 hydroxy groups, alkoxy comprising 1 to 6 carbon atoms, carboxy, halo, amino, alkylamino comprising 1 to 6 carbon atoms or di (alkylamino comprising 1 to 6 atoms carbon); hydroxy; Alkoxy having 1 to 6 carbon atoms; alkanoyloxy having 1 to 6 carbon atoms; amino; alkylamino comprising 1 to 6 carbon atoms; di (alkyl having 1 to 6 carbon atoms) ami no; alkanoylamino having 1 to 6 carbon atoms, carboxy, alkoxy-carbonyl having 1 to 6 carbon atoms, halo, oxo or phenyl; or having a heterocyclic ring

<B

R10-S — Ru is fused to a carboxyclic ring comprising 5 to 6 carbon atoms 23, phenyl, heterocyclic to 5-6 atoms or hetero-aryl to 5-6 atoms, all these latter rings being optionally substituted by 1 to 3 of the substituents mentioned above for the nucleus:

Ri ° -S-R11. as well as their pharmaceutically acceptable salts.

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

Also within the scope of the present invention are processes for preparing the new carbapenem derivatives described above as well as pharmaceutical compositions containing these derivatives! biologically active carbapenem in combination with carriers or! * diluents or other pharmaceutically acceptable vehicles.

15. The new compounds of general formula I above-mentioned contain the carbapenem nôf nucleus

k_N_IL

20 Ö 4 3 and can therefore also be called derivatives of l-carba-2-penem-3-carboxylic acid. Alternatively, the compounds can also be considered to have the basic structure 25 3

Ln-U2 O 1 30 and therefore 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 the protons 5,6 is in the cis position as well as in the trans position, the preferred compounds have the stereochemical configuration 5R, 6S trans, as in the case thienamycin.

The compounds of formula I can be unsubstituted in position 6 or substituted by the substituent groups previously described for the other carbapenem derivatives. More specifically, R8 can be hydrogen and R1 can be hydrogen or a substituent other than hydrogen as described for example in European patent application 38 86â (cf., definition of R6, According to a variant R8 and R1 can together form an alkylidene radical comprising 2 to 10 carbon atoms 5 or such a radical substituted for example by a hydroxy radical.

In fact, the following definitions can be given more precisely for R1 and R8: a) the aliphatic radicals "alkyl", "alkenyl" and "alkynyl" can consist of branched linear chains comprising 1 to 6 and 10 preferably 1 to 4 carbon atoms; when they are part of another substituent such as for example in the cycloalkylalkyl or heteroalkyl or aralkenyl groups, these alkyl, alkenyl and * alkynyl radicals preferably contain 1 to 6 and more particularly 1 to 4 carbon atoms.

B) the "heteroaryl" radicals can consist of heterocyclic aromatic mono-, bi- or polycyclic groups containing 1 to 4 atoms of oxygen, nitrogen or sulfur; more particularly preferred are the heterocyclic rings containing 5 or 6 atoms such as thienyl, furyl, thiadiazolyl, oxadiazolyl, triazolyl, isothiazolyl, thiazolyl, imidazolyl, isoxazolyl, tetrazolyl, oxazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridinyl , etc.

c) the "heterocyclyl" radicals can consist of non-aromatic, saturated or unsaturated, mono-, bi- and polycyclic heterocyclic radicals containing 1 to 4 oxygen, sulfur or nitrogen atoms; particularly preferred are heterocyclic rings comprising 5 or 6 atoms such as morpholinyl, piperazinyl, piperidyl, pyrazo- 1î ny1, pyrazoli di nyl, i mi dazoli nyl, i mi dazol i di nyl, pyrroli nyl, py r-rolidinyl, etc.

D) the "halo" groups (also used to define R10 and R11) consist of chlorine, bromine, fluorine or iodine and more particularly chlorine or bromine.

“The expression" conventional easily dryable carboxyl protecting group "means any known ester group which is used to block a carboxyl group during the chemical reaction steps described below and which can be removed if necessary by methods which do not lead to appreciable destruction of the remaining part of the molecule, for example by chemical or enzymatic hydrolysis, treatment with chemical reducing agents under mild conditions, irradiation with ultraviolet light or catalytic hydrogenation . Examples of such ester protecting groups include benzhydryl, p-nitrobenzyl, 2-naphthylmethyl, benzyl, trichloroethyl, silyl such as trimethylsilyl, phenacyl, p-methoxy-benzyl, acetonyl, o-nitrobenzyl, 4-pyridylmethyl, and alkyl radicals comprising 1 to 6 carbon atoms such as methyl, ethyl or t-butyl. Included in such protective groups are those which are hydrolyzed under physiological conditions such as pivaloyloxymethyl, acetoxymethyl, phthalidyl, indanyl and methoxymethyl. A particularly advantageous carboxyl protecting group is p-nitrobenzyl which can be easily separated by catalytic hydrogenolysis.

"The pharmaceutically acceptable salts referred to above are the addition salts of non-toxic acids such as for example the salts with mineral acids such as hydrochloric, hydrochloric, hydroiodic, phosphoric, sulfonic, etc. thus the salts with organic acids such as maleic, acetic, citric, succinic, benzoic, tartaric, fumaric, mande-20, ascorbic, lactic, gluconic and malic acids.

The compounds of formula I in the form of salts of suitable acid additions can be put in the form: r8 <±> ^ r1 ° Θ 25 r1 - RH x -N-Li-coor2

O

R2 being a hydrogen atom or a protective group g when X represents the acid anion, g

Counter anion X can be chosen so as to obtain pharmaceutically acceptable salts intended for therapeutic administration, but in the case of intermediate compounds of formula I, X can also be a toxic anion. In such a case, 1 ion can be subsequently removed or replaced with a pharmaceutically acceptable anion to form an active final product suitable for therapeutic purposes. When acidic or basic groups 26 are present in the group R1 or on the substituents R10 and / or R11, the present invention also includes salts of acids or bases of these functional groups such as, for example, the salts of addition of acids in the case of a basic group and the metal salts, for example sodium, potassium, calcium and aluminum, the ammonium salt and the salts with non-toxic amines, for example trialkylami ne, procaine, dibenzylamine , 1-ephenamine, N-benzyl-g-phenethylamine, N, N'-dibenzyl-thylenediamine, etc., in the case of an acid group.

Compounds of formula I in which R2 is hydrogen, an anionic charge or a physiologically hydrolysable ester group associated with their pharmaceutically acceptable salts are used with advantage as antibacterial agents. The remaining compounds of formula I are valuable intermediates which can be converted into the biologically active compounds mentioned above.

According to an advantageous form of the present invention, it relates to compounds of formula I: in which: R8 is a hydrogen atom; and, R1 is hydrogen or one of the groups CH3CH2-,

Œ3 \? B T

CH-, C- CH CH- / / or · * CHf CH3

Among this subclass, the preferred compounds are those in which R1 is OH

CH3CH- and the most interesting compounds are those having the absolute configuration 5R, 6S, 8R.

The present invention, according to another embodiment, also relates to compounds of formula I: in which: R1 and R8 together form an alkylidene radical of formula: HOCH- 35% =

The alkylene radical (that is to say the substituent "A") of the compounds 27! of formula I can have a straight chain or a branched chain and contain from 2 to 6 carbon atoms. According to a particular embodiment, the invention relates to compounds in which A is - (CH2) n- where n is 2, 3 or 4, and according to a very particular mode of the invention, this- this relates to compounds or A equals -CH2CH2- ·

The substituent in position 2 of the compounds according to the present invention is characterized by the presence of a sulfonium group linked to the alkylene radical A. As has been indicated above, R10 · and R11 can all. two, independently of one another, be chosen from the following radicals, optionally substituted, the following: aliphatic, cycloaliphatic, cycloaliphatic-aliphatic, aryl, heterocyclyl, heterocyclyl-aliphatic, heteroaryl or heteroaraliphatic radicals. According to a variant, the substituents R10 and R11 can form, between themselves, in association with S® 15 to which they are linked, a heterocyclic ring containing sulfur, optionally substituted, with 4-6 atoms, containing from 0 to 2 double bonds and 0 to 2 additional hetero atoms consisting of 0, N and S, this nucleus being linked to A by a sulfur atom so as to form a sulfonium group. In the latter case, when 20 θ

RIO-S-RH

represents a heterocyclic ring, the ring can also be fused to a carbocyclic ring comprising 5 to 6 carbon atoms, a phenyl ring or a heteroaryl ring with 5-6 atoms (containing 1 to 4 oxygen-gene atoms, of sulfur or nitrogen) and each of these fused rings can also be optionally substituted.

The aliphatic substituents R1 ° and / or R11 are preferably alkyl radicals comprising 1 to 6 carbon atoms, alkenyl comprising 2 to 6 carbon atoms, alkynyl comprising 2 to 6 carbon atoms. The cycloaliphatic substituents are preferably cycloalkyl radicals comprising 3 to 6 carbon atoms whereas by cycloaliphatic-aliphatic is meant very particularly cycloalkyl radicals comprising 3 to 6 carbon atoms, alkyl comprising 1 to 6 carbon atoms. These aliphatic, cycloaliphatic and cycloaliphatic-aliphatic substituents can be unsubstituted or substituted (in which case preferably with 1 to 3 substituents) with one or more of the following radicals: hydroxy, alkoxy comprising 1 to 6 carbon atoms, alkanoyloxy comprising 1 to 6 carbon atoms, carboxy, alkoxycarbonyl comprising 28 1 to 6 carbon atoms, that is to say: 0 0 -C-0C2H5 or -C-OC3H7, ami no, alkylamino comprising 1 to 6 carbon atoms, di (alkyl comprising 5 1 to 6 carbon atoms) -ami no, alkanoylamino comprising 1 to 6 carbon atoms, phenyl, phenyl preferably substituted by 1 to 3 and more particularly 1 to 2 halo, alkoxy comprising 1 to 6 atoms carbon, * alkyl comprising 1 to 6 carbon atoms, carboxy, carboxy-alkyl comprising 1 to 6 carbon atoms, ami no, alkylamino comprising 1 to 6 carbon atoms, di (al kyl.e comprising 1 to 6 carbon atoms carbon) -amino or di (alkyl comprising 1 to 6 carbon atoms) ami no- (alkyl compr enant 1 to 6 carbon atoms), halo or oxo.

The substituents R1 and / or R11 can also be 1 “aryl radicals (aromatic hydrocarbon comprising 6 to 10 carbon atoms) and more particularly the phenyl radical. The aryl group (s) may be unsubstituted or substituted by 1 to 3, preferably 1 to 2 substituents chosen from halo, alkoxy comprising 1 to 6 carbon atoms, alkyl comprising 1 to 6 carbon atoms, carboxy, ami no, alkylamino comprising 1 to 6 carbon atoms and di (alkyl comprising 1 to 6 carbon atoms) ami no.

When R10 and / or Ru represent a heterocyclyl or heterocyclyl-aliphatic radical, the heterocyclyl part is a non-aromatic ring with 4-6 atoms containing 1 to 3 hetero atoms consisting of 0, N or S. The aliphatic chain associated with the aliphatic heterocyclyl ring is preferably an alkyl radical comprising 1 to 6 carbon atoms. The heterocyclyl ring of such groups can be unsubstituted or substituted by 1 to 3, preferably 1 to 2 alkyl substituents comprising 1 to 6 carbon atoms or alkoxy substituents comprising 1 to 6 carbon atoms.

When R10 and / or R11 consist of a heteroaryl or heteroaraliphatic radical, the heterocyclic part is an aromatic ring containing 5-6 atoms containing 1 to 3 hetero atoms consisting of 0, N and S and the aliphatic part (preferably alkyl) present 1 to 6 carbon atoms. The heteroaryl ring of these substituents may be unsubstituted or substituted by 1 to 3, preferably 1 to 2 substituents consisting of alkyl comprising 1 to 6 carbon atoms, alkoxy comprising 1 to 6 carbon atoms, carboxy, carboxy- (alkyl comprising 1 to 6 carbon atoms), ami no, (al kyle comprising 1 to 6 carbon atoms) -ami no, di (al kyle comprising 1 to 6 carbon atoms) -amino, ami no "(al kyle comprising 1 with 6 carbon atoms 29 and di (alkyl comprising 1 to 6 carbon atoms ^ aniino {alkyl comprising 1 to 6 carbon atoms).

Q

The substituents R10 and R11 can form, together with S to which they are linked, a heterocyclic ring containing sulfur formed from 4 to 6 5 atoms containing 0 to 2 double bonds and 0 to 2 additional hetero atoms consisting of 0, N and S, this ring being linked to the alkylene group A by a sulfur atom so as to form a sulfonium group. The heterocyclic cycle formed by ®

R-io-S-R-M

10 may be unsubstituted or substituted by 1 to 3, preferably 1 to 2 substituents consisting of:. alkyl comprising 1 to 6 carbon atoms optionally ς substituted with 1 to 3 hydroxy; 15. alkoxy comprising 1 to 6 carbon atoms, carboxy, halo, ami no, alkylamino comprising 1 to 6 carbon atoms or di (alkyl comprising 1 to 6 carbon atoms) -amino; . hydroxy; . alkoxy having 1 to 6 carbon atoms; · Alkanoyloxy comprising 1 to 6 carbon atoms; . friend no; . alkylamino comprising 1 to 6 carbon atoms; . di (al kyle having 1 to 6 carbon atoms) -ami no; . alkanoylamino comprising 1 to 6 carbon atoms; 25. carboxy; . alkoxycarbonyl comprising 1 to 6 carbon atoms; . halo; . oxo; and. phenyl.

The heterocyclic ring can also be fused to a carbocyclic ring comprising 5 to 6 carbon atoms, a phenyl ring, a heterocyclic ring with 5 or 6 atoms (containing 1 to 4 hetero atoms consisting of 0, N and S) or a heteroaryl with 5-6 atoms (containing * 1 to 4 hetero atoms consisting of 0, N and S), which fused nuclei can be optionally substituted by 1 to 3, preferably 1 to 2 of the above-mentioned substituents in relation to the heterocyclic nucleus containing sulfur defined above.

According to a preferred embodiment of the present invention, the subject of the invention is compounds of formula I in which either: a) R10 and R11, independently of one another, represent an alkyl carbon comprising 1 to 6 carbon atoms; or, b) R10 and R11, taken together with s® 5 to which they are linked, consist of groups © / ^ © / “\ - \ J or \ _J 'and 10 and also refer to their acceptable salts from the point of pharmaceutical view.

Examples of substituents in position 2 preferably used in which R1 ° and R11 are alkyl radicals consist of: / ÎS CH, 15 vP / 3 -S-CH2CH2-S ^ ch3 0 / CH3 -S-CH2CH2CH2-S ^ 20 C2H5 0 / C2H5

- S -CH 2CH 2CH 2CH 2-S

C2h5 -S-CH ~ CH_-S ^ i-propyl 25 2 2 ^ i-propyl © / CSH11 —S — CH-CH “—S ^ 30 ©, ®3 -S-CH2CH2CH2CH2CH2CH2-S ^ CH 3 and © C2H5 -s-ch2ch2ch2ch2ch2-s ^

35 r H

L2n5

In this subclass, the preferred compounds are those in which A is - (CH2) n ~ with n equal to 2, 3 or 4, and more particularly according to which A is -CH2CH2- and where: a) R1 and R8 form together the radical HOCH 2 ^ 5 C = c or b) R8 is hydrogen and R1 is hydrogen or a group 10 ch3-ch2-,

CH, CH, PH OH

3 \ \ l I

vs- . C- or CH, Œ-.

/ 3; ch ^ CH3 Very particularly preferred are the compounds in which R8 is! hydrogen and R1 is; Oh ! CH3CH-, these compounds preferably having the absolute configuration 5R, 6S, 8R.

According to a very particularly preferred embodiment of the present invention, it relates to compounds of formula I in which: "R10-S-R11 represents

'I

25 Ό and also their pharmaceutically acceptable salts.

In this subclass, the preferred compounds are those in which A is - (CH2) n ~ with n equal to 2, 3 or 4, and more particularly according to which A is -CH2CH2- and where: a) R1 and R8 form together: HOCH- 35 2 \ ch3 32 i or b) R® is hydrogen and R1 is a hydrogen atom or a group CH3CH2-, CH3X CT3 \ ÏH f 5 C-, C- or CH-CH- / ^ 3 CH2 CH3

Particularly preferred are the compounds in which R8 is hydrogen and R1 is:: 10 ·? H: CH3CH-, i w · preferred compounds having the absolute configuration 5R, 6S, 8R.

; According to a particularly preferred aspect of the present! "invention, it relates to compounds of formula: 15 · OH _ __ i I ^ ®ΓΛ —s-ch2ch2 Ss \ # N“ COOR2

20 O

in which: R2 is hydrogen, an anionic charge or an easily breakable carboxyl protecting group, conventional, it being understood that when R2 is hydrogen or a protecting group, a counteranion is also present, as well as of course the pharmaceutically acceptable acid addition salts which result therefrom.

Note that when Rio and Ru in formula I are

30 different, the R and S optical isomers can form as well

of these constituents as their epimeric mixtures. All these optical isomeric and spinal mixtures fall within the scope of the present invention.

Likewise, the substituent in position 6 can be, in certain cases, for example in the case of hydroxyethyl, either in R or S configuration and the resulting isomers as well as the epimeric mixtures which are obtained are thus covered by the present invention.

The carbapenem derivatives of general formula I are prepared from raw materials having the formula: 33

R8 H

i-N- ^ 21

5 cT IXI COOR

in which: R1 and Re are as defined above, and in which: Ra 'represents conventional easily breakable carboxyl protecting groups.

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

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

R8 H

1,1 — τγ, - *

20 ^, y -COOR

XII

p8 O

II

25 R1 --— OP * OC6H5 * 2 - * / r- ~ N .1—. 2 '

g COOR

IV

30

R8 H

35 Rl ~ ft "V‘A‘0H _> g N ^^ COOR2 '

V

d 34

R8 H

j ip ^ r ^ -A- ° S02CH3 _ ^ 5 fi - “- L-COOR2 '

0 VI

R10 # g / RR T <11 10 R Γ Γ - + —-— * 21 Ä9 ^

_ # -N ----- COOR

. O

11 s H © „Θ

15. R H ^ / X

"Yx". g _ ^ _ c --- ^ <11 Release 1 R possible v J 2 'fi- --— -COOR -►

O

I * 20 ® / r1 ° R ΊΊ \ T r11 25 £ 7 - N - ^ - COOR ^

To carry out the abovementioned process, the starting material III is reacted in an inert organic solvent such as methylene chloride, acetonitrile or dimethylformamide with approximately an equimolar amount of diphenyl chlorophosphate in the presence of a base consisting for example of diisopropylethylamine, triethylamine, 4-dimethylaminopyridine or the like to lead to the intermediate IV. The acylation to form the breakable diphenylphosphoryloxy group in position 2 of the intermediate product III is preferably carried out at a temperature between -20 ° and + 40 ° C and more particularly of the order of 0 ° C. Intermediate IV can be isolated if desired, but is suitably used for the next step without isolation or purification.

Intermediate IV is then converted to intermediate V by conventional displacement reaction. Thus, intermediate IV can be reacted with approximately an equimolar amount of a mercaptan-type reagent having the formula:

HS-A-OH

in which: A represents an alkylene radical with a straight or branched chain comprising 2 to 6 carbon atoms, 10 in an inert organic solvent such as dioxane, dimethylformamide, dimethylsulfoxide or acetonitrile and in the presence of a base such as diisopropylethylamine, triethylamine, carbonate sodium acid, potassium carbonate or 4-dimethylaminopyridine. The displacement temperature is not critical, but an advantageous temperature range is that between -40 ° C and 25 ° C. Preferably, the reaction is carried out with cooling, for example, approximately, at 0 ° C.

Intermediate V is then acylated with methanesulphonyl chloride or a functional acylating equivalent of this compound such as methanesulfonic acid anhydride in an inert organic solvent and in the presence of a base to lead to the breakable group. or separable methanesulfonyloxy from intermediate product VI. The acylation carried out in an inert organic solvent, such as tetrahydrofuran, methylene chloride, acetonitrile or dimethylformamide and in the presence of a suitable base such as diisopropylethylamine, triethylamine, 4-dimethylami-25 nopyridine, and the like. The reaction can be carried out over a wide temperature range, for example -40 ° C to + 40 ° C, but preferably carried out under cooling, for example -30 ° C to -40 ° C.

Intermediate VI is then subjected to a displacement reaction so as to lead to intermediate II having the breakable or separable group iodo. This particular group has been found to greatly facilitate the preparation of the final carbapenem product of formula I. The intermediates of general formula II therefore constitute one of the products of interest of the present invention.

The displacement of the breakable or separable group methanesulfonyloxy 35 is carried out by reaction of intermediate VI with a source of iodide ions in an inert organic solvent such as acetone, dimethylformamide or dimethyl sulfoxide. Any compound which ionizes in the solvent used to lead to the formation of iodide ions can be used, for example an alkali metal iodide such as Nal or Kl. The displacement temperature is not critical, but temperatures on the order of room temperature or above are most advantageous to allow the reaction to be completed in a reasonable period of time.

The source of iodide ions is used in an amount such that one obtains approximately an equivalent or an excess of iodine ions with respect to intermediate VI.

The preparation of the desired carbapenem derivatives of formula I is carried out by a nucleophilic displacement of the iodo breakable group of intermediate II using the sulfide of the following general formula: .R10 \ XR11 i · 'Intermediate II is brought reacting with at least one equivalent, preferably an excess, of the desired sulfide in an inert organic solvent and in the presence of a silver ion. Suitable inert organic solvents include, for example, tetrahydrofuran, dioxane, methylene chloride, diglyme, dimethoxyethane, and the like. Any silver compound which substantially ionizes in the solvent and which leads to the formation of silver ions and an inert anion can be used as a source of silver ion, for example AgClOi *. In general, it is preferred to employ approximately an equivalent amount (relative to intermediate compound II) of silver ion to facilitate movement. The reaction can be carried out over a wide temperature range, for example between about -25 ° and about 25 ° C, and preferably carried out about at 0 ° C.

Intermediate T will have a counter anion (derived from the silver salt used) associated with it and may at this stage be substituted by a different counter anion, for example a counter anion which is acceptable from the point of view pharmaceutical, by conventional methods. According to a variant, the counterion can be removed later during the unlocking step.

The deblocking step to remove the R2 carbo-xyl protecting group from intermediate 1 'is carried out by conventional methods such as solvolysis, chemical reduction or hydrogenation. When a protective group such as p-nitrobenzyl, benzyl, benzhydryl or 2-naphthylmethyl capable of being eliminated by catalytic hydrogenation is used, the intermediate T in a suitable solvent such as a dioxane-water-ethano, tetrahydrofuran mixture -dipotassium acid-isopropanol phosphate water or the like, can be treated under a hydrogen pressure of between 1 and 4 atmospheres in the presence of a hydrogenation catalyst such as palladium on activated carbon, palladium hydroxide, platinum oxide 5 or similar, at a temperature between 0 and 50 ° C for 0.24 to 4 hours. When R2 'is a group such as o-nitro-benzyl, photolysis can also be used for deblocking. Protective groups such as 2,2,2-trichloroethyl can be removed by gentle reduction with zinc. Likewise, other conventional carboxyl protecting groups can be removed by methods known to those skilled in the art. Finally, as mentioned above, the compounds of formula Γ where R2 'is a physiologically hydrolysable ester such as acetoxymethyl, phthalidyl, indanyl, pivaloyloxymethyl, methoxymethyl, etc., can be administered directly to the patient without unlocking because of such esters are hydrolyzed in vivo under physiological conditions.

It is understood that when the substituent R1 and / or R8 or the heteroaromatic nucleophile linked to the substituent A contains a functional group which can interfere with the expected course of the reaction, such a group can be protected by a conventional blocking group and then subsequently unlocked to reconstitute the functional group sought. Suitable blocking groups and methods for introducing and removing such groups are well known to those skilled in the art.

As with other β-lactam antibiotics, the compounds of general formula I can be converted by known methods into pharmaceutically acceptable salts which, in the context of the present invention, are substantially equivalent to non-salified compounds. Thus, for example, one can dissolve a compound of formula I in which R2 is an anionic charge in a suitable inert solvent, and then add an equivalent of a pharmaceutically acceptable acid. The desired acid addition salt can be recovered by conventional methods, for example solvent precipitation, lyophilization, etc. When other acidic or basic functional groups are present in the compound of formula I, the pharmaceutically acceptable base addition salts and pharmaceutically acceptable acid addition salts can be similarly prepared by known methods.

A compound of formula I in which R2 is hydrogen or an anionic charge or one of their pharmaceutically acceptable salts, 38 can be converted by the known methods into the corresponding compound in which R2 is a physiologically hydrolyzable ester group, or a compound of formula I "in which R2 is a conventional carboxyl protecting group, can be converted into the corresponding compound where R2 is hydrogen-5, an anionic charge or a physiologically hydrolyzable ester group or one of their pharmaceutically acceptable salts .

The new carbapenem derivatives of general formula I in which R2 is hydrogen, an anionic charge or a physiologically hydrolysable carboxyl protecting group or their pharmaceutically acceptable salts, are potent antibiotics which are active against of a large number of gram-positive and gram-negative bacteria and they can be used for example as food additives for animals, facilitating growth, as food preservatives, as bactericides in industrial applications for example for the production of aqueous paint and for white waters of the paper industry in order to prevent the growth of harmful bacteria and as disinfectants to destroy or inhibit the growth of harmful bacteria in medical equipment and dental. They are particularly useful, however, in the treatment of infectious disorders of humans and other animals caused by gram-positive or gram-negative bacteria.

The pharmaceutically active compounds according to the present invention can be used alone or in combination in pharmaceutical compositions comprising, in addition to the active carbapenem component, a pharmaceutically acceptable carrier or diluent. The compounds can be administered by a large number of methods, the most interesting of which are the methods: oral, topical or parenteral (by intravenous or intramuscular injection). The pharmaceutical compositions can be in solid form, such as capsules, tablets, powders, etc. or in liquid form such as solutions, suspensions or emulsions. Compositions for injection, the preferred route of action, may be prepared as a unit dose in ampoules or in multi-dose containers and may contain additional agents such as suspending, stabilizing and dispersion. The compositions can be in a ready-to-use form or in powder form intended to be reconstituted at the time of their use by the addition of a suitable vehicle such as sterile water.

39

The dosage to be administered depends to a large extent on the particular compound tested, on the particular composition produced, on the mode. administration, nature and condition of the patient and the particular site or organism to be treated. The selection of doses and the route used is left to the therapist's choice. In general, however, the compounds can be administered parenterally or orally to mammals in an amount on the order of 5 to 200 mg / kg / day. Administration is generally carried out in divided doses, for example three to four times a day.

In order to illustrate the broad spectrum of potent antibacterial activity of carbapenem according to the present invention, both in in vitro and in vivo treatments, and their low toxicity, are given below! data from biological results relating to the preferred carba penem compound according to the present invention, i.e. 3- {2- (l-15 tetrahydrothiophenium) ethylthio} -6a- {l- (R) -hydroxyethyl} ~ 7-oxo-l-azabicyclo {3,2,0} hept-2-ene-2-carboxylate prepared in Example 1.

In Vitro Activity: A sample of the aforementioned carbapenem compound, after implementation | solution in water and dilution in a culture broth, appears to have the following minimum inhibitory concentrations (MIC) in mcg / ml relative to the microorganisms indicated, these concentrations being determined after overnight incubation at 37 ° C. by the so-called dilution tube method.

By way of comparison, tests were carried out on N-formimidoyl thienamycin.

- In Vitro antibacterial activity of the Carbapenem derivative of Example 1

_MIC organism (mcg / ml) _ new N-Formimidoyle 30 ___ compounds__Thienamycin_ S. ' pneumoniae A-9585 0.002 0.004 S. pyogenes A-9604 0.004 0.001 S. aureus A-9537 0.008 0.004 S. aureus 35 + 50% serum A-9537 0.03 '0.016 S. aureus (Pen-res.) A-9606 0.016 0.008 S. aureus (Meth-res.) A15097 2 0.5 40!

Organism ._MIC (mcg / ml) _.

new N-Formimidoyl ___ compounds__Thienamycin S. faecalis A20688 0.5 0.5 5 E. coli (lO- * dil.) A15119 0.03 “0.016 E. coli (ΙΟ-3) A15119 0.06 0.03 E. coli 10 (ΙΟ “2) A15119 0.06 0.06: - E. coli (10- *) A20341-1 0.03 0.03 E. coli (ΙΟ-3) A20341-1 0.03 0.03 15 E. coli (ΙΟ "2) A20341-1 0.06 0.13 K. pneumoniae A-9664 0.06 0.13: K. pneumoniae A20468 0.13 0.06 P. mirabilis A-9900 0.13 0.06 20 P. vulgaris A21559 0.03 0.03 P. morganii A15153 0.06 0.13 P. rettgêri A22424 0.25 0.25 S. rnarcescens A20019 0.06 0.03 E. cloacae A-9659 0.13 0.06 25 E. cloacae A-9656 0.13 0.06 P. aeruginosa A-9843A -1 · 1 - P. aeruginosa A21213 0.25 0.25 H. influenzae A-9833 8 16 H. influenzae A20178 8 32 30 H. influenzae A21518 8 32 H. influenzae A21522 8 32 B. fragilis A22862 0.06 0.016 B. fragilis A22053 0.06 0.06 B. fragilis A22696 0.25 0.13 35 B. fragilis A22863 _0 ^ 06__1

In Vivo Activity The in vivo therapeutic efficacy of the compound of Example 1 and of N-formimidoyl thienamycin after intramuscular administration 41 in mice infested experimentally with various organisms is shown in the following table. The PD50 (dose in mg / kg required to produce 50% protection for infested mice) is indicated.

Protective effect by intramuscular treatment 5 of infested mice 'PD5o / treatment (mg / kg) _

Organism number composed of N-Formimidoyl __organisms__example 1 Thienamycin S. aureus A-9606 1 x 109 0.19 0.07 * 10 E. coli A15119 6 x 10® 1.6 2.2 * K. pneumoniae A-9664 7 x 10® 5 2.4 * E. cloacae A-9659 4 x 10® 1.3 P. mirabilis A-9900 4 x 10® 7.7 3 * / 15 * P. vulgaris A21559 4 x 105 3.3 15 P. rettgeri A15167-2 3 x 107 8.7 6.9 M. morganii A15149 7 x 105 3.3 S. marcescens A20335 9 x 10® 5 P. aeruginosa A-9843a 3 x 10 ** 0 , 6 0.5 * P. aeruginosa A20481 3 x 10 ^ 0.8 0.4 20 P. aeruginosa A20599 9 x 104 1.3 * the treatment carried out is as follows: the mice are treated intramuscularly with the drugs 0 and 2 hours after infection (A21559, A15167-2, A9900, A9843a, A20481, A20599), or 1 and 3.5 hours for the older ones. Five mice are used for this test. __! Toxicity

The toxicity of the compound of Example 1, after intra-, cranial administration to determined mice, leads to the results recorded in the following table.

30 Toxicity after intracranial administration ‘·’ _ to mice * LDso Highest dose

Compound (mg / kg) without clinical sign of toxicity (mg / kg) 35 Compound of Example 1> 40 '^ 5 N-Formimidoyle Thienamycin 32 __ ^ 5 * average of 25 mice per compound 42

Blood levels in your mouse after intramuscular administration

The blood levels and the half-life of the compound of Example 1 after muscle administration of 20 mg / kg in mice are shown in the table below. ’_ Blood levels (ug / mlV __

Compound ÏÔ ["ÜÔ j 30 | 45 | 60 90 * tl / 2 ** AUC

minutes after administration (min) (pg.h / ml) - Compound of 10 Example 1 14.7 13.5 8.7 3.2 0.9 <0.6 9 7.4 N-Fonnimidoyle

Thienamycin 12.6 9.9 7.3 2.6 0.7 <0.3 9__6

The compounds are dissolved in a 0.1 M phosphate buffer at pH 7. The values are those of a single test; four mice are used per compound.

* tl / 2 refers to the half-life period in minutes, ** AUC refers to the area under the curve._ Urinary recovery

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

Urine recovery after _ intramuscular administration of 20 mg / kg to mice_

Percentage of dose recovered_ 25 Compound 0-3 d 3-6 D 6-24 | 0-24 _ hours after administration.

Compound of example 1 15.6 2.1 <0.2 17.7 + 2.9. N-Fdrmimidoyle Thienamycin 12.1 0.1 <0.1 12.2 + 3.6

The compounds are dissolved in a 0.1 M phosphate buffer at pH 7. The values are those of a single test; four mice per test.

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

EXAMPLE 1 Preparation of 3- {2- (l-tetrahydrothiophenium) ethylthio} -6g- {l- (R) -hydroxy-ethyl} -7-oxo-l-azabicyclo {3t2,0} hept-2-ene- 2-carboxylate? HH ^ © / "" 1 ^ 1 ^ Y-.sch2ch2-s 43 A.- p-nitrobenzyT 3- (2-hydroxyethylthio) -6g- {l- (R) -hydroxyethyl} -7-oxo -l - azabicyc1o {3,2,0} hept-2-ene-2-carboxylate

OH

1 - »/ 1" N II '///

O / C02pNB

10

OH

J H _

<* _- l / ^ v »T-'SCH2CH2OH rf N C0opNB

15 ° 2 pNB = -CH2 20

A solution of 1.69 g (4.85 mmol) of p-nitrobenzyl 6ct- {l- (R) ~ hÿdroxyethyl} -3,7-dioxo-l-azabicyclo (3,2,0) hept-2-ene -2-carboxylate (!) In 20 ml of acetonitrile, is cooled to 0 ° C. under a nitrogen atmosphere. A solution of 726 mg (7.18 mmol) of diisopropylethylamine in 2 ml of acetonitrile is added after which 1.51 g (5.60 mmol) of diphenyl chlorophosphate in 12 ml of is added dropwise. acetonitrile over a period of 3 minutes. The resulting solution is stirred at 0 ° for 20 minutes, p-nitrobenzyl 3- (diphenyl-30 phosphoryloxy) -6α- {1- (R) -hydroxyëthy1} -7-oxo-l-azabicyclo (3, 2.0) hept-2-ene-2-carboxylate. To this solution is added a solution of 726 mg (7.18 mmol) of diisopropylethylamine in 2 ml t \ acetonitrile followed by a solution of 439 mg (5.63 mmol) of 2-mercapto-ethariol in 2 ml acetonitrile. The reaction solution is stirred at 0 ° C for 3 hours then diluted with 200 ml of ethyl acetate and washed with 200 ml of water, 100 ml of an aqueous solution at 20% of ^ POi * and brine. Evaporation of the dried solution (MgSOi,) leads to the production of a semi-solid 44 which is triturated in the presence of methylene chloride and filtered, 1.2 g (yield 61%) of compound 2 are thus obtained. in heading which is in the form of a white amorphous solid.

The physical properties are as follows: 5 - NMR spectrum (DMS0-d6): δ: 1.20 (3H, d, J = 6.0 Hz); 2.9-3.2 (9H, m); 5.22 (1H, d, J = 8.5 Hz) and 8.23 (2H, d, J = 8.5 Hz); - Ir spectrum (KBr): ymax: 3500; 1770 and 1700 cnr1.

On analysis, it is found that the product obtained has the formula 10 C18H2ON207S, and the following values are obtained:

C H N S

- calculated ... 52.93 4.94 6.86 7.85 - found ---- 52.83 4.90 6.42 8.31 B.- p-nitrobenzyl 3- (2-methanesulfony1oxyethylthio) -6a - {1- (R) -hydroxy-15 éthy1} -7-oxo-l-azabicyclo (3,2,0) hept-2-ene-2-carboxylate

OH

4 \ ^ _ sch2ch2oh _ 20 J-— · ’1 * -

C02pNB

2

- OH

λ 4 \ _sch2ch2oso2ch3

θ 'N CO ~ pNB

3 * To a solution of 4.2 g (10.3 mmol) of compound 2 in 200 ml of tetrahydrofuran, about 1.3 g (11.3 mmol) of methanesulfonyl chloride is added at -40 ° C. after which 1.26 g (12.4 mmol) of triethylamine in 5 ml of tetrahydrofuran are added dropwise. The reaction mixture is stirred for 5 hours at -40 ° C and then stirred for 2 hours at -30 ° C under a nitrogen atmosphere then poured into a mixture of ethyl acetate (700 ml) and a 5% aqueous phosphoric acid solution (1,000 ml). The organic layer is washed with brine, dried over MgSOz *, filtered and condensed until a syrup is obtained. The product obtained is 45 ί purified by chromatography on a column of silica gel (elected using a methylene chloride-ethyl acetate mixture 3/1 by volume), 3.55 g are thus obtained (yield 75¾) of the title compound in the form of an amorphous white solid.

5 The physical properties obtained are as follows: - NMR (CDCl3): 6: 1.25 (3H, d, J = 6.0 Hz); 3.05 (3H, s); 3.06-3.40 (5H, m); 4.05-4.40 (4H, m); 5.25 (1H, d, J = 14.0Hz); 5.50 (1H, d, J = 14.0 Hz); 7.70 (2H, d, J = 8.5Hz); and 8.23 (2H, d, J = 8.5 Hz); 10 - Ir (KBr): ymax: 3400, 1770 and 1600 cm-1.

On analysis, it is found that the product obtained has the formula C19H22N2O9S2, and the following values are obtained:

C H N

: - calculated ... 46.90 4.56 5.76 15 - found ---- 46.52 4.32 5.91 C.- p-nitrobenzy1 3- (2-iodoethy1thiο) -6α- {1- (R) -hydroxyethyl} -7-oxo-l-azabicyclo (3,2,0.) Hept-2-ene-2-carboxylate

OH

. J H

20 <v ". sch2ch2oso2çh3 ί I - *

0's N C02pNB

3 25 l ^ + '' s / \ ^ 50Η20Η2Ι 30 "-Κο2ΡΝΒ

AT

A solution of 350 mg (0.72 mmol) of the intermediate compound 3 and 216 mg (1.4 mmol) of sodium iodide in 20 ml of acetone is heated at reflux temperature for 4 hours. Evaporation of the acetone leads to the production of a white amorphous solid which is suspended in an ether (10 ml) -water (10 ml) mixture.

46 the filtration of the white solid and the drying under vacuum leads to obtaining 300 mg (yield 80%) of compound 4 in the heading in the form of an amorphous white powder.

- NMR (DMS0-d6): 6: 1.18 (3h, d, J = 6.0 Hz); 3.20-3.60 (7H, m); 5 3.80-4.25 (2H, m); 5.10 (1H, d, J = 5.5 Hz); 5.25 (1H, d, J = 12.0 Hz); 5.45 (1H, d, J = 12.0 Hz); 7.70 (2H, d, J = 8.5 Hz); and 8.27 (2H, d, J = 8.5 Hz); - Ir (KBr): Ymax: 3500, 1768 and 1700 cm-1.

10 Upon analysis, it can be seen that the product obtained has the formula

Ci8Hi9N206I, and we obtain the following values:

C H N I

- calculated ... 41.71 3.70 5.41 24.48; : - found ____ 42.10 3.75 5.97 23.20 15 D.- 3- (2- (l-tetrahydrothiophenium) ethy1thio} -6a- {l- (R) -hydroxyethyl} -, 7-oxo- l-azabicyclo (3,2,0.) hept-2-ene-2-carboxylate

; H H

Ί — _ ”

20 / "" "N ^’ ^ CO-pNB

O 2 _4 f i © ΓΛ Θ __- SCHACH, .— S y CIO y O 2 5

30 OH

1 H ® / ^] 1 0J ^ N - “^ cocß 35 ------ To a solution of p-nitrobenzyl 3- (2-iodoethylthio) -6a“ {l- (R) - hydroxyethyl} -7- oxo-l-azabicyclo (3,2,0) hept “2-ene-2-carboxylate (104 mg, 0.2 minole) in 5 ml of tetrahydrofuran, 0.3 ml 47 (0.35 nimole) is added of tetrahydrothiophene then a solution of silver perchlo-spleen 60 mg (0.3 mmol) in 0.5 ml of tetrahydrofuran.

The mixture is stirred at room temperature for 60 minutes.

The solvent is evaporated in vacuo, thus obtaining the compound 5 which is in the form of a yellow gum. This gum is digested in 100 ml of CELITE 99 which leads to the production of an amorphous solid, the infrared spectrum of which is as follows: * - Ir (KBr): Ymax: 3400, 1772, 1700 and 1100 cm- ".

Without further purification, compound 5 is hydrogenated as follows: to a suspension of compound 5 in 20 ml of ether and 20 ml of tetrahydrofuran, a solution of potassium bicarbonate (40 mg, 0.4 mmol) is added and dipotassium acid phosphate (35 mg; 0.2 mmol) in 20 ml of water. Then 120 mg of palladium (10%) on charcoal is added and the mixture is hydrogenated under a pressure of 2.8 bars, in the apparatus sold under the trade name of Parr Shaker, for 60 minutes. The mixture is then filtered and the catalyst is washed with the aid of 2 x 5 ml of water. The filtrates and mud waters are combined and the whole is extracted with ether (2 x 50 ml) and then lyophilized, a yellow powder is thus obtained. The raw material is purified on a C1S B0NDAPAK reverse phase column (7g) (Waters Associates), eluted with water under a pressure of 0.56 bars.

Each fraction (15 ml) is treated by liquid chromatography under high pressure and the fractions having an absorption spectrum of ultraviolet Xmax 300 nm are collected and freeze-dried, which leads to 12 mg ( yield 18% expressed relative to compound 4) of the title compound which is in the form of a white solid.

It has the physical properties: 30 - NMR spectrum (Da0): 6: 1.23 (3H, d, J = 6.0 Hz); 2.25-2.45 (4H, m); 3.0-3.70 (11H, m); 3.95-4.30 (2H, m); - sprectre Ir (KBr): Ymax: 3400, 1760 and 1590 cm’1.

- UV spectrum xmax (CH2CH20H) 289 nm (ε = 6200).

Claims (5)

48 1 R j RB H i 25 i T 12 '- N -—COOR χχ in which R1, R8, A and R2 are as defined above then V) submission of intermediate II to a nucleophilic displacement in a ^ 30 inert organic solvent and in the presence of an ion using a sulfide {of formula ✓R13a - \ 35 R ”in which R10 and R11 are as defined above, 70 so as to move the iodo group from intermediate II using a group Θ / R10 1.- As new industrial products, the compounds consisting of: 5 R8. H 0 R10 r1— <r11 qM- ÎOOR ^ 10 in which: Ra is a hydrogen atom; and, - R1 is chosen from the group comprising the hydrogen atom, or the substituted or unsubstituted radicals, belonging to the list com; ; taking the alkyl, alkenyl and alkynyl radicals containing 1 to 10 carbon atoms; cycloalkyl and cycloalkylalkyle comprising 3 to 6 carbon atoms in the cycloalkyl ring and 1 to 6 carbon atoms in the alkylated side chain; phenyl, aralkyl, | aralkenyl and aralkynyl of which the aryl part is a phenyl radical and the aliphatic part comprises 1 to 6 carbon atoms 20 heteroaryl, heteroaralkyl, heterocyclyl and heterocycly1alkyle in which the hetero atom (s) of the aforementioned heterocyclic parts comprise 1 to 4 atoms chosen from the group oxygen, nitrogen or sulfur and the alkyl chains which are associated with said heterocyclic ring comprise 1 to 6 carbon atoms; In these radicals, the substituent or substituents are independently chosen from the group comprising: alkyl radicals comprising 1 to 6 carbon atoms optionally substituted by amino, halo, hydroxy or carboxyl radicals; 30 ha10; -OR3 O -ocnr3r4 'ï 3 4 35 -CNR R -nr3r4 / NR3 \ * r3r4 49 J -S02NR3R4 O J! 3 i -NHCNR R * O 5 3 / f 4 R CNE - -COjR3 = 0 ”, 10 -OCR3 -SR3 0 Il 9 -SR 15 ° 9 Ύ 0 -CN -n3 J 3 20 -0S03R -oso2r3 3 4 - NR S02R 25 -NR3Ç = NR4 P 3 4 -NR C02R -no2 3Q in which, with respect to the abovementioned substituents, the groups R3 and R4 are independently chosen from hydrogen, and the alkyl, alkenyl and alkynyl groups comprising 1 to 10 atoms carbon; cycloalkyl, cycloalkylalkyl and alkylcycloalkyl having 3 to 6 carbon atoms in the cycloalkyl ring and 1 to 6 carbon atoms in the alkyl chain; phenyl, aralkyl, aralkenyl and aralkynyl in which the aryl part consists of a phenyl radical and the aliphatic part contains 116 carbon atoms; and hetero-aryl, heteroaralkyl, heterocyclyl and heterocyclylalkyl in which the hetero atom (s) of the aforementioned heterocyclic parts 50 consist of 1 to 4 of the atoms chosen from the group of oxygen, nitrogen or sulfur and the alkyl chains which are associated include 1 to 6 carbon atoms, R3 and R4 'can together form with the nitrogen atom to which at least one of them is linked a heterocyclic ring "containing T nitrogen, to 5 or 6 atoms ,. . R9 being similar to R3 if it is not that it cannot be hydrogen; or in which: R1 and R8 taken together are constituted by an alkylidene group comprising 2 to 10 carbon atoms or an alkylidene comprising 2 to 10 carbon atoms substituted by a hydroxy radical; A is straight or branched chain alkyl having 2 to 6 carbon atoms; R3 is a hydrogen atom or an anionic charge or an easily breakable carboxylic protecting group, it being understood that when R3 is hydrogen or a protecting group, a counter anion is also present, while R10 and R11 independently l 'one of the other represent the radicals: a) alkyl comprising 1 to 6 carbon atoms, alkenyl comprising 2 to 6 carbon atoms, alkynyl comprising 3 to 6 carbon atoms, cycloalkyl or cycloalkylalkyl comprising 3 to 6 carbon atoms in the cycloalkyl nucleus and 1 to 6 carbon atoms in the alkyl chain, the said alkyl, alkenyl, alkynyl, cycloalkyl or cycloalkylalkyl groups being optionally substituted with 1 to 3 substituents chosen independently from one another from the hydroxy groups, alkoxy comprising 1 to 6 carbon atoms, alkanoyloxy comprising 1 to 6 carbon atoms, carboxy, alkoxycarbonyl comprising 1 to 6 carbon atoms, ami-no, alkylamino comprising 1 to 6 carbon atoms, di (alkylamino comprising 1 to 6 carbon atoms), alkanoylamino comprising 1 to 6 carbon atoms, phenyl, phenyl substituted by 1 to 3 halo, alkoxy comprising 1 to 6 carbon atoms, alkyl comprising 1 to 6 carbon atoms, carboxy , carboxy (alkyl comprising 1 to 6 carbon atoms), amino, alkylamino comprising 136 carbon atoms, di (alkyl containing 13 6 carbon atoms) - * 35 amino or di (alkyl containing 1 to 6 carbon atoms) amino alkyl comprising 136 carbon atoms, halo or oxo; b) phenyl optionally substituted by 1 3 3 halo, or alkoxy groups comprising 136 carbon atoms, alkyl comprising 1 51 to 6 carbon atoms, carboxy, ami no, alkylamino comprising 1 to 6 carbon atoms or di (alkyl comprising 1 6 carbon atoms) ~ amino; c) heterocyclyl or heterocyclylalkyl in which the heterocyclic part is a nucleus formed from 4 to 6 atoms comprising 1 to 3 hetero atoms consisting of 0, N and S and the alkyl chain contains 1 to 6 carbon atoms, said heterocyclyl nucleus or heterocyclylalkyl being optionally substituted by 1 to 3 alkyl groups comprising 1 to 6 carbon atoms or alkoxy corn- »· I 10 taking 1 to 6 carbon atoms; or,, d) heteroaryl or heteroaralkyl in which the heterocyclic part is an aromatic ring with 5-5 atoms of which 113 hetero atoms consist of 0, N and S and the alkyl chain contains 1 to 6 carbon atoms, said heteroaryl ring or heteroaralkyl being optionally substituted by 1 to 3 alkyl radicals comprising 1 to 6 carbon atoms, alkoxy comprising 1 to 6 carbon atoms, carboxy, carboxy (alkyl comprising 1 to 6 carbon atoms), ami no, alkylamino comprising 1 to 6 carbon atoms, di (alkylamino comprising 1 to 6 carbon atoms), ami no (alkyl 20 comprising 1 to 6 carbon atoms) or di (alkylamino comprising 1 to 6 carbon atoms) - (alkyl comprising 1 to 6 atoms of carbon); or R10 and R11 together with: S® - to which they are linked constitute a heterocyclic ring containing sulfur containing 4-6 atoms containing 0 to 2 double bonds and 0 to 2 additional hetero atoms consisting of 0, N and S, said nucleus being linked to A by a sulfur atom, so as to form a sulfonium group, this heterocyclic nucleus being optionally substituted by 1 to 3 substituents chosen independently from one another from the radicals: alkyl comprising 1 to 6 carbon atoms optionally substituted by 1 to 3 hydroxy groups, alkoxy comprising 1 to 6 carbon atoms, carboxy, halo, ami no, alkylamino comprising 1 to 6 carbon atoms or di (alkylamino · comprising 1 to 6 atoms of carbon); hydroxy; Alkoxy having 1 to 6 carbon atoms; alkanoyloxy having 1 to 6 carbon atoms; amino; alkylamino comprising 1 to 6 carbon atoms; di (alkyl having 1 to 6 carbon atoms) ami no; alkanoylamino comprising 1 to 6 carbon atoms, carboxy, alkoxy-carbonyl comprising 1 to 6 carbon atoms, 52 halo, oxo or phenyl; or whose heterocyclic ring ® R10-S-R11 is fused with a carboxyclic ring comprising 5 to 6 carbon atoms, phenyl, heterocyclic with 5-6 atoms or heteroaryl with 5-6 atoms, all these latter nuclei being optionally substituted by 1 to 3 of the substituents mentioned above for the nucleus: è · * · i © R'I0-S-R11 as well as their pharmaceutically acceptable salts. 2.- As new industrial products, the compounds of formula! 8 H Θ R10 „1 _s — a _% / 15. RXi J-N - 2 --- COOFT in which: 20 R8 is a hydrogen atom; and, R1 is chosen from the group comprising the hydrogen atom, or the substituted or unsubstituted radicals, belonging to the list comprising the alkyl, alkenyl and alkynyl radicals comprising 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 alkylated side chain; phenyl, aralkyl, aralkenyl and aralkynyl.e, the aryl part of which is a phenyl radical and the aliphatic part of which comprises 1 to 6 carbon atoms; heteroaryl, heteroaralkyl, heterocyclyl and heterocyclylalkyl including the hetero atom (s) of the above heterocyclic moieties. comprise 1 to 4 atoms chosen from the group of oxygen, nitrogen or sulfur and the alkyl chains which are associated with said heterocyclic ring comprise 1 to 6 carbon atoms; '· in these radicals, the substituent (s) are independently selected from the group comprising: alkyl radicals comprising 1 to 6 carbon atoms optionally substituted with ami no, halo, hydroxy or carboxyl radicals; hal o; -OR3 53 fl 3 4 -CNR ΙΓ 3.- As new industrial products, the compounds of formula R8. H © R10 5 r1— ^ S ~ A_SOi c / T - ^ ~ tOOR2 1) t * ”in which: R8 is a hydrogen atom; and, R1 is chosen from the group comprising the hydrogen atom, or the substituted or unsubstituted radicals, belonging to the list comprising the alkyl, alkenyl and alkynyl radicals comprising 1 to 10 carbon atoms; cycloalkyl and cycloalkylalkyl comprising 15 '3 to 6 carbon atoms in the cycloalkyl ring and 1 to 6 carbon atoms in the alkyl side chain; phenyl, aralkyl, aralkenyl and aralkynyl of which the aryl part is a phe-nyl radical and the part aliphatic 'comprises 1 to 6 carbon atoms ·, heteroaryl, heteroaralkyl, heterocyclyl and heterocyclylalkyle 20 or the hetero atom (s) of the above-mentioned heterocyclic parts comprise' 1 to 4 atoms chosen from the group consisting of oxygen, nitrogen or sulfur and the alkyl chains which are associated with said heterocyclic ring comprise 1 to 6 carbon atoms; in these radicals, the substituent or substituents are independently chosen from the group comprising: alkyl radicals comprising 1 to 6 carbon atoms optionally substituted by amino, halo, hydroxy or carboxyl radicals; halo; 30 -OR3 O -ocnr3r4 î 34 -CNR R 35 -N R3 R4 / NR3 \ r3r4 56 -so2nr3r4 q il 3 4 -NHCNITir 5 3¾ 4 RCNR- -co2R3 * 0 0 • 10 -o $ r3 -SR3 O r 4r9 15 ”-1r9 r O -CN -N J 3 20 -QSQ ^ R -oso2r3 -nr3so2r4 25 -NR3Ç = NR4! In which, with respect to the abovementioned substituents, the groups R3 and R ** are independently chosen from hydrogen, and the alkyl, alkenyl and alkynyl groups comprising 1 to 10 carbon atoms; cycloalkyl, cycloalkylalkyle and alkylcycloalkyle having 3 to 6 carbon atoms in the cycloalkyl ring and 1 to 6 carbon atoms in the alkyl chain; phenyl, aralkyl, aralkenyl and aralkynyl in which the aryl part consists of a phenyl radical and the aliphatic part comprises 1 to 6 carbon atoms; and hetero-aryl, heteroaralkyl, heterocyclyl and heterocyclylalkyl in which the hetero atom (s) of the aforementioned heterocyclic parts. 57 consist of 1 to. 4 'of the atoms chosen from the group of oxygen, of tax or of sulfur and the alkyl chains which are associated with them comprise 1 to 6 carbon atoms, R3 and being able together to form with the nitrogen atom to which at at least one of them is linked to a heterocyclic ring containing nitrogen, with 5 or 6 atoms, R9 being similar to R3 except that it cannot be hydrogen; or in which: R1 and R8 taken together consist of an alkylidene group comprising 2 to 10 carbon atoms or alkylidene comprising 2 to 10 atoms of. carbon substituted by a hydroxy radical; A is straight or branched chain alkyl having 2 to 6 carbon atoms; Ra is a hydrogen atom or an anionic charge or an easily breakable carboxylic protecting group, it being understood that when R2 is hydrogen or a protecting group, a counter anion is also present, while, R1 ° and R11 together with, S ® to which they are linked consist of 5 ′ -eO as well as their pharmaceutically acceptable salts. 4. Compounds according to any one of Claims 1 to 3, characterized in that R1 consists of a hydrogen atom, a CH3CH2 "radical or one of the ru ru OH OH CH3 CH3 radicals. »\ W -, VC - or CH3CH— 30 CH ^ CH3 ^ 5. Compounds according to any one of claims 1 to 3, characterized in that R1 and R3 together form a radical H0CHa 35 XC ch3x 58 6. Compounds according to any one of claims 1 to 3, characterized in that R1 is OH CH3CH - 5 7. Compounds according to any one of Claims 1 to 3, characterized in that R1 is OH ch3-ch - 10 and in that the absolute configuration is 5R, 6R, 8R 8. Compounds according to any one of Claims 1 to 7, characterized in that A · is - CH2CH2— 9. As new industrial products, the compounds of formula ΟΠ H © / V 20 i— N -—COOR2 in which R2 is a hydrogen atom, an anionic charge or an easily divisible carboxyl protecting group, it being understood that when • R2 is the hydrogen atom or the protecting group, there is also present • a counter anion as well as their pharmaceutically acceptable salts 10.- Compounds according to claim 9, characterized in that R2 is p-nitrobenzyl. 11.- Compounds according to claim 9, characterized in that R2 is an anionic charge. 12.- Process for the preparation of compounds of formula R8 H © R10 R --- i / \ __ S — A — s ^ n O "^ ~~ COOR2 - 59 wherein: RB is a hydrogen atom; and, R1 is chosen from the group comprising hydrogen atony, or substituted or unsubstituted radicals, belonging to the list comprising the alkyl, alkenyl and alkynyl radicals comprising 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 alkylated side chain; phenyl, aralkyl, aralkenyl and aralkynyl, the aryl part of which is a phe-10 nyl radical and the aliphatic part contains 1 to 6 carbon atoms with 4 atoms selected from the group of oxygen, nitrogen or sulfur and the alkyl chains which are associated with said heterocyclic ring comprise 1 to 6 carbon atoms; in these radicals, the substituent or substituents are independently chosen from the group comprising: alkyl radicals comprising 1 to 6 carbon atoms optionally substituted by amino, halo, hydroxy or carboxyl halo radicals; ......; -or3 * O I II 3 4! —OCNR R ¥ 25 O '-cnr3r4' -nr3r4 / N R3 - -i- \ * r3r4 3 4 -S02NR R r O Jl 34 35 -NHCNR RO 3. ii 4 RCNR- -co2r3 = 0 [60 Ο -OCR3 5 "Sr3 Ο // 9 -SK * ο Il 9 —SR“ 7 if -10 o -CN -N-, J 3 -oso3r —OSO ^ R3 15 3 4 -NR S02R 3 4 -NR Ç = NR R3 20 -nr3co2r4 -no2 'in which, with respect to the abovementioned substituents, the groups; R3 and R4 * are independently chosen from hydrogen, and alkyl, alkenyl and alkynyl groups comprising 1 to 10 carbon atoms; cycloalkyl, cycloalkylalkyl and alkylcycloTkyle comprising 3 to I 6 carbon atoms in the cycloalkyl ring and 1 to 6 carbon atoms in the alkyl chain; phenyl, aralkyl, aralkenyl and Aralkynyl of which the aryl part consists of a phenyl radical and the aliphatic part comprises 1 to 6 carbon atoms; and heteroaryl, heteroaralkyl, heterocyclyl and heterocyclylalkyl in which the hetero atom (s) of the aforementioned heterocyclic parts consist of 1 to 4 atoms selected from the group of oxygen, az 35 te or sulfur and the alkyl chains which ur are associated include 1 to 6 carbon atoms, R3 and R4 can together. form with the nitrogen atom to which at least one of them is linked a heterocyclic ring, containing nitrogen, with 5 or 6 atoms; 61 R9 being similar to R3 except that it cannot be hydrogen; or in which; R1 and R8 taken together are constituted by an alkylidene group comprising 2 to 10 carbon atoms or alkylidene comprising 2 to 10 carbon atoms substituted by a hydroxy radical; A is straight or branched chain alkyl having 2 to 6 carbon atoms; P R2 is a hydrogen atom or an anionic charge or an easily breakable carboxylic protecting group, it being understood that when 10 R2 is hydrogen or a protective group, is also present a counter anion, while, ^ R10 and R11 independently of one another represent the radicals: a) alkyl comprising 1 to 6 carbon atoms, alkenyl comprising 2 to 6 carbon atoms, alkynyl comprising 3 to 6 carbon atoms, cycloalkyl or cycloalkylalkyl comprising 3 to 6 carbon atoms in the cycloalkyl ring and 1 to 6 carbon atoms in the alkyl chain, said alkyl, alkenyl groups , alkynyl, cycloalkyl or cycloalkylalkyl being optionally substituted by 1 to 3 substituents chosen independently of one another from the hydroxyl groups, alkoxy comprising 1 to 6 carbon atoms, alkanoyloxy comprising 1 to 6 carbon atoms, carboxy, al koxycarbonyl.e comprising 1 to 6 carbon atoms, ami-no, alkylamino comprising 1 to 6 carbon atoms, di (alkylamino | comprising 1 to 6 carbon atoms), alkanoylamino comprising 1 to 6 carbon atoms, phenyl , phenyl s ubstituted by 1 to 3 days halo, alkoxy comprising 1 to 6 carbon atoms, alkyl comprising 1 to 6 carbon atoms, carboxy, carboxy (alkyl comprising 1 to 6 carbon atoms), ami no, alkylamino comprising 1 to 6 atoms carbon, di (alkyl having 1 to 6 carbon atoms) - 30 amino or di (alkyl having 1 to 6 carbon atoms) no- * alkyl friend having 1 to 6 carbon atoms, halo or oxo; * 3 b) phenyl optionally substituted by 1 to 3 halo, or alkoxy groups comprising 1 to 6 carbon atoms, alkyl comprising 1 to 6 carbon atoms, carboxy, amino, alkylamino comprising 1 to 6 carbon atoms or di ( alkyl comprising 1 to 6 carbon atoms) -amino; c) heterocyclyl or heterocyclylalkyl in which the heterocyclic part is a nucleus formed from 4 to 6 atoms comprising 1 to 62 3 heterO'-atoms consisting of 0, N and S and the alkyl chain contains 1 to 6 carbon atoms, said heterocyclyl nucleus or heterocyclylalkyl being optionally substituted by 1 to 3 alkyl groups comprising 1 to 6 carbon atoms or alkoxy com-5 taking 1 to 6 carbon atoms; or, d) heteroaryl or heteroaralkyl in which the heterocyclic part is an aromatic ring with 5-6 atoms of which 1 to 3 hetero atoms consist of 0, N and S and the alkyl chain contains 1 to 6 carbon atoms, the said heteroaryl ring or heteroaralkyl being JO optionally substituted by 1 to 3 alkyl radicals comprising 1 to 6 carbon atoms, alkoxy comprising 1 to 6 carbon atoms, carboxy, carboxy (alkyl comprising 1 to 6 carbon atoms), ami no, alkylamino comprising 1 to 6 carbon atoms, di (alkylamino with 1 to 6 carbon atoms), ami no (alkyl 15 with 1 to 6 carbon atoms) or di (alkylamino with 1 to 6 carbon atoms) - (alkyl with 1 to 6 carbon atoms); or R10 and R11 together with: s® to which they are linked constitute a heterocyclic ring containing sulfur containing 4-6 atoms containing 0 to 2 double bonds and 0 to 2 additional hetero atoms consisting of 0, N and S , said nucleus being linked to A by a sulfur atom, so as to form a sulfonium group, this heterocyclic nucleus being possibly substituted by 1 to 3 substituents chosen independently from one another from the radicals : alkyl comprising 1 to 6 carbon atoms optionally substituted by 1 to 3 hydroxy groups, alkoxy comprising 1 to 6 carbon atoms, carboxy, halo, ami no, alkylamino comprising 1 to 6 carbon atoms or di (alkylamino * comprising 1 to 6 carbon atoms); hydroxy; ¥ 30 alkoxy comprising 1 to 6 atoms of carbon; alkanoyloxy having 1 to 6 carbon atoms; friend no; alkylamino comprising 1 to • · -6 carbon atoms; di (alkyl containing 1 to 6 carbon atoms) amino; alkanoylamino comprising 1 to 6 carbon atoms, carboxy, àlkoxy'-carbonÿlecomprising 1 to 6 carbon atoms, halo, oxo or phenyl; or whose heterocyclic nucleus © R10 ~ S-R11 is fused to a carboxyclic nucleus comprising 5 to 6 carbon atoms, phenyl, heterocyclic with 5-6 atoms or hetero-aryl with 5-6 atoms, all of these latter nuclei being optionally substituted with 1 to 3 of the substituents mentioned above for the nucleus: 5 '0 R-io -S-Rii and their pharmaceutically acceptable salts, this process being characterized in that an intermediate of formula io f? ~ £ - N - 1-CooR II 15 in which R1, R8 and A are as defined above and R2 is a carboxyl protecting group easily breakable to a nucleophilic displacement in an inert organic solvent and in the presence of an ion silver with a sulfur-containing reagent of formula: R1 ° S R11 in which 25 R1 ° and R11 are as defined above | so as to move the iodo group from intermediary II through the group • + R10 —S 30 R11 and form a compound of formula R8 J Θ _io pl__S-AS XO * I ^ 11 -N -J — 2 * COOR 3b I * in which X "is a counter anion and R1, R8, A, R1 °, R11 are as defined cl · above, 64 2 1 and, where appropriate, elimination of the protective group R to lead to the corresponding blocked com compound of formula I, as well as to one of its pharmaceutically acceptable salts. 13.- Process for the preparation of compounds having the formula 5 R8 H © K1 “pi - S A Sv τι --Y! Vr11 OT "" - ^ - tOOR2 10. I in which: • “R8 'is a hydrogen atom; et, R1 is chosen from the group comprising the hydrogen atom, or the substituted or unsubstituted radicals, belonging to the list comprising the alkyl, alkenyl and alkynyl radicals comprising 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 alkylated side chain; phenyl, aralkyl, aralkenyl and aralkynyl of which the aryl part is a phenyl radical and the aliphatic part comprises 1 with 6 carbon atoms; heteroaryl, heteroaralkyl, heterocyclyl and heterocyclylalkyl; in which the hetero atom (s) of the abovementioned heterocyclic parts comprise 1 to 4 atoms chosen from the group consisting of oxygen, nitrogen or sulfur and the alkyl chains which are associated with said heterocyclic ring comprise 1 to 6 atoms carbon; in these radicals, the substituent or substituents are independently chosen from the group comprising: alkyl radicals comprising 1 to 6 carbon atoms optionally substituted by amino, halo, hydroxy or carboxyl radicals; halo; ; "-OR1 O Il 3 A -OCNR R 35 ü 3 4 -CNR R 3 A -NR-V r '/ NR3 -4 \ îR3R4 -so2nr3r4 10 * tt Jl 3 4 -NHCNR * 3/1 4 R CNR - -CO-R3: 15 = 0 0 H 3 -OCR · 3 20 -Sr3 O // 9 -SR3 O • - // g -SR3 „11 25 O I -CN! -0S03R3 -OSO-R3 30 3 4! -NR SO2R 3 4 -NRJÇ = NR R3 35 -nr3co2r4 -ho2 in which, with respect to the abovementioned substituents, the groups R3 and R4 are independently chosen from hydrogen, and the groups 54 alkyl, alkenyl and alkynyl comprising 1 to 10 carbon atoms; cycloalkyl, cycloalkylalkyle and alkylcycloalkyle comprising 3 to 6 carbon atoms in the cycloalkyl ring and 1 to 6 carbon atoms in the alkyl chain; phenyl, aralkyl, aralkenyl and aralkynyl in which the aryl part consists of a phenyl radical and the aliphatic part contains 1 to 6 carbon atoms; and hetero-aryl, heteroaralkyl, heterocyclyl and heterocyclylalkyl in which the hetero atom (s) of the aforementioned heterocyclic parts, consist of 1 to. 4 'of the atoms chosen from the group of oxygen, Vazo "10 te or sulfur and the alkyl chains which are associated with them include 1 to 6 carbon atoms, R3 and R *' being able together to form with nitrogen atom to which at least one of them is linked a heterocyclic ring containing nitrogen, with 5 or 6 atoms; .. r 15 R "being similar to R3 except that cannot be hydrogen; or in which: R1 and R8 taken together are constituted by an alkylidene group comprising 2 to 10 carbon atoms or alkylidene comprising 2 to 10 carbon atoms substituted by a hydroxy radical; 20. is an alkyl straight or branched chain comprising 2 to 6 carbon atoms; R2 is a hydrogen atom or an anionic charge or a protecting group. easily breakable carboxylic group, it being understood that when R2 is hydrogen or a protecting group, is also have a counter anion, while R'16 and R11 independently of each other represent radicals alkyls comprising 1 to 6 carbon atoms where R10 and R11 * together with S® 30 to which they are linked, are a group groupe <^ ι Φ / \ -O or -s \ _ / 35 as well as their pharmaceutically acceptable salts. > f 55 J i 4 -NR R 65 / NR3 -4 \ * r3r4 \ 5 -S02NR3R4! q Ü 3 i -NHCNR R * * O 3 ^ 4 R CHR - “10 -¾ -C02RJ = 0 n 3“ -OCR 15 -SR3 O II 9 —Sk o II $ -SIC 20 jl o -CN -N3 3 -0S03R '25 -OS02R3 -NR3S02R4 3 4 -NRJC = NR R3 30 3 4 -NR COjR -N02 in which, compared to substituents mentioned above, the groups R3 and R4 are independently chosen from hydrogen, and the alkyl, alkenyl and alkynyl groups comprising 1 to 10 carbon atoms; cycloalkyl, cycloalkylalkyle and alkylcycloalkyle comprising 3 to 6 carbon atoms in the ‘cycloalkyl ring and 1 to 6 carbon atoms in the alkyl chain; phenyl, aralkyl, aralkenyl and aralkynyl, the aryl part of which consists of a phenyl radical and the aliphatic part comprises 1 to 6 carbon atoms; and hetero-aryl, heteroaralkyl, heterocyclyl and heterocyclylalkyl in which the hetero atom (s) of the abovementioned heterocyclic parts 5 consist of 1 to 4 atoms chosen from the group of oxygenated, Tä te or sulfur and the alkÿlés chains which are their associated corn-I take 1 to 6 carbon atoms, R3 and R4 can together form with the nitrogen atom to which at least one of them is linked a heterocyclic ring containing nitrogen, to 5 or 6 atoms, lO R ° being similar to R3 except that it cannot be hydrogen; 9 or in which: R1 and R® taken together are constituted by an alkylidene group comprising 2 to 10 carbon atoms or alkylidene comprising 2 to 10 carbon atoms substituted by a hydroxy radical; ! v 15 A is straight or branched chain alkyl having 2 to 6 carbon atoms; R2 is a hydrogen atom or an anionic charge or an easily breakable carboxylic protecting group, it being understood that when R2 is hydrogen or a protecting group, is also pre-; 20 feels a counter anion, while <R10 and R11 independently of one another represent the radicals: i i a) alkyl comprising 1 to 6 carbon atoms, alkenyl comprising; 2 to 5 carbon atoms, alkynyl comprising 3 to 6 carbon atoms, cycloalkyl or cycloalkylalkyl having 3 to 6 carbon atoms in the cycloalkyl ring and 1 to 6 carbon atoms in the alkyl chain, said alkyl groups, alkenyl , • alkyl, cycloalkyl or cycloalkylalkyle being optionally substi-; killed by 1 to 3 substituents chosen independently of one another from the hydroxyl groups, alkoxy comprising 1 to 6 carbon atoms, alkanoyloxy comprising 1 to 6 carbon atoms, carboxy, alkoxycarbonyl. comprising 1 to 6 atoms carbon, ami-no, alkylamino comprising 1 to 5 carbon atoms, di (alkylamino comprising 1 to 6 carbon atoms), alkanoylamino comprising 1 to 6 carbon atoms, phenyl, phenyl substituted by 1 to 3 halo, alkoxy comprising 1 with 6 carbon atoms, alkyl containing 1 to 6 carbon atoms, carboxy, carboxy (alkyl comprising 1 to 6 carbon atoms), amino, alkylamino comprising 1 to 6 carbon atoms, di (alkyl containing 1 to 6 carbon atoms ) - * amino or di (alkyl containing 1 to 6 carbon atoms) amino-alkyl comprising 1 to 6 carbon atoms, halo or oxo; B) pheqyle optionally substituted by 1 to 3 halo, or alkoxy groups comprising 1 to 6 carbon atoms, alkyl comprising 1 to 6 carbon atoms, carboxy, ami no, alkylamino comprising 1 to 6 carbon atoms or di (alkyl comprising 1 to 6 carbon atoms) -amino; | c) heterocyclyl or heterocyclylalkyl in which the part! heterocyclic is a ring formed from 4 to 6 atoms comprising 1 to 3 hetero atoms consisting of 0, N and S and the alkyl chain contains 1 to 6 carbon atoms, said heterocyclyl "10 or heterocyclylalkyl ring being optionally substituted by 1 to 3 alkyl groups comprising 1 to 6 carbon atoms or alkoxy groups comprising 1 to 6 carbon atoms; or, d) heteroaryl or heteroaralkyl the heterocyclic part of which is an aromatic ring containing 5-6 atoms of which 1 to 3 hetero atoms are 15 exist in 0, N and S and the alkyl chain contains 1 to 6 carbon atoms, said heteroaryl or heteroaralkyl ring being optionally substituted by 1 to 3 alkyl radicals comprising 1 to 6 carbon atoms, alkoxy comprising 1 to 6 carbon atoms -i bone, carboxy, carboxy (alkyl containing 1 to 6 carbon atoms), amino, alkylamino comprising 1 to 6 carbon atoms,; di (alkylamino comprising 1 to 6 carbon atoms), amino (S alkyl comprising 1 to 6 carbon atoms) or di (alkylamino compr enant; 1 to 6 carbon atoms) - (alkyl containing 1 to 6 carbon atoms); or alternatively R10 and R11 together with: I 25 S®; to which they are attached constitute a heterocyclic ring containing sulfur containing 4-6 atoms containing 0 to 2 double bonds and 0 to 2 additional hetero atoms consisting of 0, N and S, i said ring being linked to A by a sulfur atom, so! Forming a sulfonium group, this heterocyclic ring being possibly substituted by 1 to 3 substituents chosen independently from each other from the radicals: alkyl comprising 1 to 6 carbon atoms optionally substituted by 1 to 3 groups; hydroxy, alkoxy having 1 to 6 carbon atoms, carboxy, halo, amino, alkylamino having 1 to 6 carbon atoms or di (alkylamino * having 1 to 6 carbon atoms); hydroxy; * alkoxy comprising 1 to 6 · · carbon atoms; alkanoyloxy comprising 1 to 6 carbon atoms; amino; alkylamino comprising 1 to 68 6 carbon atoms; di (al kyle comprising 1 to 6 carbon atoms) amino; alkanoylamino comprising 1 to 6 carbon atoms, carboxy, àlkoxy-carbonÿlecomprenant 1 to 6 carbon atoms, halo, oxo or phenyl; or whose heterocyclic nucleus 5 © I R10-S-R'11! I is fused to a carboxyclic ring comprising 5 to 6 carbon atoms, phenyl, heterocyclic to 5-6 atoms or hetero-aryl to 5-6 atoms, all these latter rings being optionally substituted by 1 to 3 of the substituents mentioned above for the nucleus: i · ®: ^ R1 ° -S-R11 i ·! * as well as their pharmaceutically acceptable salts, this process consisting in carrying out the following steps I) reaction of an intermediate of formula j> 8 H! 20 I 2 * i-N - —- C00R I O t i! III i j 25 in which R1 and R8 are as defined above and R2 is a | classic, also sharable, carboxyl protecting group j in an inert organic solvent with diphenyl chlorophosphate in the presence of a base to give an intermediate of formula 30 R8 J II rL_L_4 / '' V0P <OC6H5) 2 'I J-N - ^ - COOR2' U IV. In which R, R and R are as defined above II) reaction of intermediate IV in an inert organic solvent and in the presence of a base with a mercaptan of formula HS-A-OH where H is such as defined above i *. '69 R8 5 ^ —N -—CÖOR2 * 5 V in which R1, R8, A and R2 are as defined above * III) reaction of intermediate V in an inert organic solvent at 4 and in the presence of a base with methanesulfonyl chloride or a functional equivalent acylating agent to lead to an intermediate of 10 formula ^ * '8 „' RH ^ T SA-OSO-CH, ra - γ Λ 15 i / N --COOR2 * O _________vi l in which R1» R8, A and F. 2 are as defined above h IV) reaction of intermediate VI in an inert organic solvent with! 20 a source of iodine ion so as to displace the methanesulfonyloxy group i using an iodo group and to form an intermediate of formula l i 5. S and formed of a compound of formula * 8 I © R10 Q, 1 x ° R: —Γ T Jr— N - * - COOR2 *; ^ in which P is a counter anion and R1, R8, A, R10, R11 and R2 • 15 are as defined above "vt then, if necessary, eliminate the protective carboxyl group R2 to obtain the corresponding unlocked compound of formula I, or a pharmaceutically acceptable salt thereof. î | i i \ i i î! r j] - * »N