LU85021A1 - ANTIBIOTIC CARBAPENEM DERIVATIVES - Google Patents

Description

É * * * Λ · "*" - * * \ BRISTOL-MYERS COMPANY. For Antibiotic carbapenem derivatives.

1 · Field of the invention.

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

CD.YD.MdC.CH. - 1 - SY-1735A

_5 where A represents an alkylene radical in a straight or branched chain in C ^ -Cg, R ^ represents an aliphatic, cycloaliphatic, cyeloaliphatic-aliphatic, aryl, araliphatic, heteroaryl, heteroaraliphatic, heterocyclic or heterocycloaliphatic radical, optionally substituted, and aromatic nitrogen attached to the alkylene radical A by a ring carbon atom and quaternized by the substituent r5.

2. Known state of the art.

A number of JS-lactam derivatives containing the carbapenem ring:

r-TT

L_n- o 4 have already been described in the literature. These carbapenem derivatives are indicated as being useful antibacterial agents and / or inhibitors of la.j3 -lactamase.

The first carbapenem derivatives were natural products such as thienamycin from

CD.YD.MdC.CH. - 2 - SY-1735A

formula: (pH - <- ^^ \ - sch2ch2ic2 K ---

O COOH

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

Other natural products containing the carbapenem nucleus are in particular derivatives of olivanic acid such as the antibiotic MM 13902 of formula: CH,

P

b.03s D -fjp ce = cknhcoch3

cP “” -koOH

described in US Patent No. 4,113,856, the antibiotic MM 17880 of the formula: CK, € H -K3C0CS, ho3so. I * i 1 J N \

Q- COOH

CD.YD.MdC.CH. - 3 - SY-1735A

described in United States Patent No. 4-162.304, the antibiotic MM 4550A of formula: CH, _ / \ -, / S - CH = CFNH r or? H03S0 I | u‘WflLU 3

° CODH

described in U.S. Patent No. 4,172,129, and the antibiotic 890Ag of the formula: CH3

H03SÖxJN — SCH-ŒHBÎCH3 / "" "-SoOH

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

In addition to natural products, the deacetylated compound 890A ^ o âe formula: CE, I 3 _ - SCH, CE, NK, ho3so J j z A * - ^

ο COOH

is mentioned in US Patent No. 4,264,734 as being prepared by enzymatic deacylation of the corresponding N-acetylated compound. Different derivatives of natural olivanic acids have been

CD.YD.MdC.CH. - 4 - SY-1735A

also synthesized, for example the compounds of formula: X3 ^ N - S (0) _ NHCOŒ- VII \ ^ / / - "where CO2R1 represents a free carboxyl radical, salified or esterified, n represents 0 or 1 and R2 represents H , an acyl radical or a radical of formula R3O3S, where R3 represents a salifying ion or a methyl or ethyl radical, as described in European patent application 8885.

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

"N COOH

while English patent application No. 1,598,062 describes the isolation of the compound:

15 - ^ COOH

G * from a fermentation broth of Streptomyces.

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

CD.YD.MdC.CH. - 5 - SY-1735A

United States of America No. 4,210,661 describes compounds of formula: □ 00

'' COOH

O

where R2 represents phenyl or substituted phenyl, United States patent No. 4,267,177 describes compounds of formula:

çfs COOH

where Rj represents an optionally substituted pyridyl radical, United States Patent No. 4,255,441 describes compounds of formula: / \ N ^ S-CR, * = CR, R.

~ 2 3 4

L— N --‘— COOH

0 where R2 and R3 represent H or alkyl radicals and R4 represents NH-C0nR6, ° ù R6 represents an alkyl, phenyl or substituted phenyl radical and n represents 1 or 2, and United States Patent No. 4,282 .236 describes compounds of formula:

CD.YD.MdC.CH. - 6 - SY-1735A

^ ο Χ00Η where R ^ represents Η or an alkyl radical and R2 represents CN or CO2R3, where R3 represents H or an alkyl, aryl or aralkyl radical.

Carbapenems of the general formula:

ϊΑ $ Η -j-SR

0- N ^ - CQQXJ

O

where Ri represents H or an acyl radical and RÖ represents H or an alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, alkyl, cycloalkyl, aryl, aralkyl, aralkenyl, aralkynyl, heteroaryl or heteroalkyl radical, heteroalkyl, heteroalkyl substituted, are described in U.S. Patent No. 4-218.463. There is no description of heteroaralkyl radicals R ^ of formula: w where A represents an alkylene radical and

CD.YD.MdC.CH. - 7 - SY-1735A

Ο1 represents a quaternized nitrogen aromatic heterocycle united to the alkylene radical A by a ring carbon atom.

Natural thienamycin has the absolute configuration 5R, 6S, 8R. This isomer, as well as the other seven remaining isomers of thienamycin, can be obtained by total synthesis, as described in United States Patent No. 4,234,596. Total synthesis methods for thienamycin are also described, for example, in U.S. Patents 4,287,123, 4,269,772, 4,282,148, 4,273,709, 4,290,947 and European Patent Application 7,973 A key intermediate for the described synthesis processes is of formula:

OH

S C0.pN3 where pNB represents the p-nitrobenzyl radical.

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

CD.YD.MdC.CH. - 8 - SY-1735A

OH

SCH CH K = Ç-HH,

Γ | AT

J? ^ tOOH

described in European patent application 6639, - (2) the N-heterocyclic thienamycin derivatives of formula:

OH

{α? 25η i I \ J · J -'— K »» if

I R

and (Z) ^ \ - n ^ VSCH2ra2 \ <"2> n

[J i \ X

) N coca Jk1

II

where the bifunctional cycle may contain additional cyclic unsaturation, n represents an integer from 1 to 6, p represents 0, 1 or 2, Ri represents H or an alkyl or aryl radical and Z

CD.YD.MdC.CH. - 9 - SY-1735A

represents H or an imino, oxo, amino or alkyl radical, described in the patent of the United States of America No. 4,189,493; (3) substituted N-methylenic derivatives of thienamycin of formula:

OH

cf N C003 where X and Y represent H, R, OR, SR or NR1r2, where R represents an alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl, beteroaralkyl, heterocyclic or hetero-cycloalkyl radical substituted, and R1 and r2 represent H or R, described in US Patent No. 4,194,047; (4) the compounds of formula: OR3 yX SCP'CK-N? .2? .2

I I

0 COOH

where R ^ represents an aryl, alkyl, acyl, or aralkyl radical and Ri and r2 independently represent H or an acyl radical (in particular acyl of type:

O

-C-Rll

where RH can represent, among others, a radical CD.YD.MdC.CH. - 10 - SY-1735A

alkyl substituted by a quaternary ammonium radical, for example: 0, -, h © fs \\ -C-CE ^ V J) described in the patent of the United States of America No. 4,226,870; (5) the compounds of the formula: OR3 XX— SCH2CH2NR1R2 'I | cr cooe where r3 represents H, an acyl radical or an optionally substituted univalent hydrocarbon radical, R1 represents an alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkenylalkyl, cycloalkylalkyl, aryl, aralkyl or heteroaryl radical, heteroaryl or heteroaryl or heteroaryl acyl radical (in particular acyl of type:

O

II

-C-R

where R represents an alkyl radical substituted by a quaternary ammonium radical, for example: ° 6 Γ \, -c-œ2- h y)

CD.YD.MdC.CH. - 11 - SY-1735A

described in British Patent No. 1,604,276 (see also United States Patent No. 4,235,917); (6) the compounds of formula:

OE

- sch, ce, nr5r6r7 —r, r- '—L_cooe where r5, r6 and R ^ independently represent H or an alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkenylalkyl, cycloalkyl, halkylaroyl, aryloalkylaroyl, alkyl or unsubstituted described in U.S. Patent No. 4,235,920; (7) the compounds of formula: OR3 5 1 i ®12 - “T 2 2 '6. * θ.

Jr-v -cox where R1 and R2 each independently represent one of the other a radical of the type defined for R, a hydrogen atom or a radical nitro, hydroxyl, Cj.g-alkoxy, amino, Cj_g-alcoylamino , di (Ci_g-alkyl) amino or tri (Ci_g-alkylamino), an additional anion being present in the latter case; or R ^ and R2 are united together to form, with the nitrogen atom to which they are attached, a heteroaryl or heterocyclic, monocyclic or bicyclic substituted or unsubstituted radical having 4 to 10 ring atoms, one or more of which may be one or more additional heteroatoms

CD.YD.MdC.CH. - 12 - SY-1735A

chosen between oxygen, sulfur and nitrogen, R represents a cyano radical or a car-bamoyl, carboxyl, (Cj_ ^ Q-alkoxy) carbonyl, alkyl, C2-10 alkenyl, C2-io-alkynyl radical, 3-10 "cycloalkyl," ^ ^ - cycloalkylalkyl, C5-12 ~ cycloalcoylalcényle, C3_io-cyloalcényle, C5_i2-cycloalkenylalkyl, C4_; L2-cycloalcénylalcoyle, Ce_io-aryl, C7_ig-aralkyl, Cg-iC-aralkenyl, C8-i6- aralky ”nyl or heteroaryl, heteroalkyl, heterocyclic or heterocycloalkyl monocyclic or bicyclic comprising 4 to 10 ring atoms, one or more of which are heteroatoms chosen from oxygen, sulfur and nitrogen and whose alkyl radical of the hetero-roaralkyl radical or heterocycloalkyl has 1 to 6 carbon atoms in the substituted or unsubstituted state; the substituent (s) on R, R ^, R ^ or the ring formed by the union of Ri and r2 are chloro; bromo; iodo radicals ; fluoro? azido; Ci_4-alkyl; mercapto; sulfo; phosphono; cyanothio (S-CN); nitro; cyano; amino; hydrazino; amino or hydraz ino carrying up to three substituents C ^ g-alkyl; hydroxy; Ci_g-alkoxy; Ci_g-alcoylthio; carboxyl, oxo; (C; j_6-alkoxy) carbonyl; C2_10-acyloxy; carbamoyl; (Cx_4-alkyl) carbamoyl or di (Ci_4-alkyl) carbamoyl; R3 represents a hydrogen atom, an acyl radical or a radical of the type defined for R ^; R ^ represents a C1-20 “alkyl yl 'substituted carbonylmethyl radical; (C ^ _g-alkoxy) - (Ci_5-alkyl), (C3_6-cycloalkoxy) - (Ci_6-alkyl); C2-12 "alkanoyloxyalkyl; C ^ .g-alkyl partially or completely halogenated, the halogen (s) of which are chlorine, bromine or fluorine; aminoalkyl; C2-10” alkenyl; C2-10 -alkyl; acyl; C3_i4- alkoxycarbonyl-alkyl; C4_2i-dialkoylaminoacetoxyalkyl; C2-13-alkanoylaminoalkyl; ar- (Ci_3_alkyl) of which the aryl residue has 6 to 10 carbon atoms; heteroalkyl or

CD.YD.MdC.CH. - 13 - SY-1735A

monocyclic or bicylic heterocycloalkyl having 4 to 10 ring atoms, 1 to 3 carbon atoms in the alkyl residue and 1 to 4 heteroatoms chosen from oxygen, sulfur and / or nitrogen; aralkyl or heteroaralkyl substituted on the nucleus whose substituent is chlorine, fluorine; bromine or iodine or a C1-6alkyl radical; aryl or aryl substituted on the ring having 6 to 10 ring carbon atoms and whose any substituent on the ring is a hydroxyl, C 1-5 -alkyl, chloro, fluoro or bromo radical; aralkoxyalkyl; C2_i2 “alkylthioalcoyl; C4_i2-cycloalcoylthioalcoyle; (C2_io-acylthio) “(Ci_g-alkyl); or phenylalkenyl in which the alkenyl radical has 2 to 6 carbon atoms; r5 represents a radical C ^ iQ-alkyl substituted or not; C2_io-alkenyl or alkynyl; cycloalkyl, cycloalkenyl, cycloalkenylalkyl and cycloalkylalkyl of 3 to 6 ring carbon atoms and having up to 6 carbon atoms in any chain which are substituted or unsubstituted on the ring; Cg- ^ Q-aryl; aralkyl having 6 to 10 ring carbon atoms and 1 to 6 carbon atoms in the alkyl chain; monocyclic or bicyclic heteroaryl or heteroalkyl having 4 to 10 ring atoms of which one or more are chosen from oxygen, nitrogen and sulfur and 1 to 6 carbon atoms in the alkyl chain; and the substituent (s) of the cycle or chain are chloro, bromo, iodo, fluoro, azido, cyano, amino, C ^ -s-alkylamino radicals; di- (Ci_g-alkyl) amino or tri (Ci_g-alkylamino), an additional anion being present in the latter case, hydroxyl, C1_g-alkoxy, 0 ^ -5-alkylthioalkyl; carboxyl; oxo, (Ci-5-alkoxy) carbo-nyl; C2_10-acyloxy; carbamoyl; (C ^ -alkyl) carbamoy-le; di (C1-4alkyl) carbamoyl; cyanothio (-SCN) or nitro; r6 represents a hydrogen atom or

CD.YD.MdC.CH. - 14 - SY-1735A

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

X represents a hydroxyl, mercapto, amino, acyloxy, -0R4, -sr4, -NHR4, -N (r4) 2> -0M, OQ radical or, when the compound is in zwitterionic form, -O ”, in which case A“ is absent; A represents a counter ion when the compound is not in zwitterionic form; M represents a pharmaceutically acceptable cation, and Q represents a blocking radical as defined here, described in English patent n ° 1,604,275, and (8) the compounds of formula: oïï 4 ^ Vj-SCE2CH2NE; - gN © O coo where

R

e | a united to the amino nitrogen radical of thienamycin represents a heterocyclic nitrogen mono- or polycyclic radical and R represents H or an alkyl, aryl, alkenyl, heterocycloalkenyl, aralkenyl, heterocycloalkyl, aralkyl, -NR2 / COR2 radical or substituted or unsubstituted CN, described in the patent application

CD.YD.MdC.CH. - 15 - SY-1735A

European 21082. Among the compounds described in the patent of the United States of America no.

OH

sch2ch2n (ch3) 3] ®

1 I

V N 1 C005 0 where A represents a pharmaceutically acceptable anion. The aforementioned quaternary amine derivative is also described in Recent Advances in the Chemistry of Jb -Lactam Antibiotics, Royal Society of Chemistry, London, 1981, pages 240-254, where its average antibacterial activity is noted as being about 1 / 2 to 2/3 of that of thienamycin.

Carbapenem derivatives carrying a wide variety of substituents in position 6, in addition to those indicated above, have already been synthesized. For example, mention may be made of (1) the compounds described in European patent application 40408 corresponding to the formula: CH 3-CH — j-p --- 51 j j U - ^ ——.

# COOH

where R ^ represents H or a methyl or hydroxyl radical and R51 represents a monovalent organic radical, in particular heterocycloalkyl, among others; (2) the compounds described in the patent application

CD.YD.MdC.CH. - 16 - SY-1735A

European 8514 and corresponding to the formula; __ C-T? (Y 1

V N ~ ^ 'COOH

O

where Rx represents an optionally substituted pyrimidinyl radical and R2 represents a hydrogen atom or radical CR3R4R5, where R3 represents a hydrogen atom or a hydroxyl radical, R4 represents a hydrogen atom or an alkyl radical and R5 represents a d atom hydrogen or an alkyl, benzyl or phenyl radical, or else R5 and Rg together form a carbocycle; (3) the compounds described in European patent application 38869 and corresponding to the formula: R7 · R6 -, - r / '\ r-S * 8

Y_I

0 / coos where R ^, r7 and r8 are independently selected from hydrogen and alkyl, alkenyl and alkynyl radicals of 1 to 10 carbon atoms; cycloalkyl, cycloalkylalkyl and alkylcycloalkyl of 3 to 6 carbon atoms in the cycle of the cycloalkyl radical and from 1 to 6 carbon atoms in the alkyl radicals; aryl such as phenyl, aralkyl, aralkenyl and aralkenyl, the aryl radical of which is a phenyl radical and the aliphatic part has 1 to 6 carbon atoms; heteroaryl, heteroaralkyl, heterocyclic and hetero-

CD.YD.MdC.CH. - 17 - SY-1735A

i cycloalkyl; all substituted or unsubstituted in which the substituent (s) with respect to the abovementioned radicals are chosen from: -X ° halo (chloro, bromo, fluoro) -OH hydroxy “ORl alkoxy, aryloxy 0

He . _

-OCNRJ-R2 carbamoyloxy O

-CNR1r2 carbamoyl -NR ^ -R2 amino NRl U amidino 'nrIr2 r1 -NO2 nitro Θ -N (r1) 3 amino trisubstituted (radicals r! Chosen independently) R1 -C = N0R2 oximino -SRI alcoyl- and arylthio -SO2NRIR2 sulfonamido 0 // -NHCNRIr2 urêido 0

II

-rIcnR2 amido -CO2H carboxy -CO2RI carboxylate 0 “CRi acyl

O

U

-OCRl acyloxy -SH mercapto

CD.YD.MdC.CH. - 18 - SY-1735A

ο 11! -SRI alkyl- and aryl-sulfinyl o

He .

-SRJ- alkyl and aryl-sul £ onyl 0 -CN cyano - N3 azido where, with regard to the substituents listed above on r6, r7 and RS, the radicals Ri and R ^ are chosen independently from hydrogen and the radicals alkyl, alkenyl and alkynyl of 1 to 10 carbon atoms; cycloalkyl, cycloalkylalkyl and alkyl-cloalkyl of 3 to 6 carbon atoms in the ring of the cycloalkyl part and from 1 to 6 carbon atoms in the alkyl parts; aryl such as phenyl; aralkyl, aralkenyl and aralkynyl in which the aryl radical is a phenyl radical and the aliphatic part has 1 to 6 carbon atoms; heteroaryl, heteroaralkyl, heterocyclic and heterocycloalkyl and in which the heteroatom (s) in the aforementioned heterocyclic radicals are chosen from 1 to 4 oxygen, nitrogen or sulfur atoms and in which the alkyl parts associated with these heterocyclic radicals count 1 to 6 carbon atoms (see also European patent applications 1627, 1628, 10317, 17992, 37080, 37081 and 37082); (4) the compounds described in European patent application 24832 and corresponding to the formula: R1 I 12

CE, -CB -, - ^ N-SR

~ 1 y- ”- cDjs

CD.YD.MdC.CH. - 19 - SY-1735A

where Ri represents H or a radical chosen from OH, OSO3H or a Ci_4-alkyl salt or ester thereof, OR2, Sr3, OCOR2, OCO2R3 and OCONHR2, where R2 represents a Cj [_6-alkyl radical or an optionally substituted benzyl radical and R3 represents a Ci_g-alkyl radical or an optionally substituted benzyl or phenyl radical and r! 2 represents a C ^ -g-alkyl, C2-6-alkenyl, C3_6 ~ alkynyl radical whose triple bond does not lead to carbon atom adjacent to the sulfur atom, aralkyl, C1-6-alkanoyl, aralkanoyl, aryl-oxyalkanoyl or arylcarbonyl, any of these radicals R12 being optionally substituted, as antibacterial agents.

European patent application 44170 describes carbapenem derivatives of formula: 3 "P"

T? _ _ S — X — N N

I f cT co2b r where r3 represents a hydrogen atom or an organic radical united by a carbon atom to the carbapenem ring, n represents 0 or 1, X represents a saturated or unsaturated hydrocarbon radical optionally substituted by bromine or chlorine and r4 represents a Ci_g-alkyl, C2-6-alkenyl, Ci_io “aralkyl or aryl radical, each of these radicals r4 being optionally substituted. There is however no mention of any compound whose tetrazole ring is united to X by a quaternized nitrogen atom, that is to say a positively charged nitrogen atom which is not united to a atom d 'hydrogen.

The aforementioned European patent application 38869 CD.YD.MdC.CH. - 20 - SY-1735A

describes the synthesis of carbapenem derivatives using intermediates of the general formula: K7 R6-- y ~ "- ^ tc-R2 where r6 and r7 are as defined above and r2 'represents a protective radical of the carbo function - easy to remove style. This document also describes as an intermediate the compounds of formula: R7

Re - / '"' '•' γ-Χ ^ J-X,

O CO2tC

where X represents a labile radical.

A booklet describing different antibiotic carbapenems was distributed at the Gordon Research Conference on Medicinal Chemistry held August 2-6, 1982 in New London, New Hampshire. Among the compounds cited on page 9 in this booklet, we find the carbapenem of formula: HO H ’_” ~ r i | w 3

o ^ -N — k0zH

which differs from the compounds of the present invention by CD.YD.MdC.CH. - 21 - SY-1735A

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

European patent application 50334 describes carbapenem derivatives of general formula: P7 KR1; / T 2

RS - S-A-ONïTR

0 "K COOH

where r6 and R7 represent, inter alia, each independently a hydrogen atom or an alkyl, alkenyl, aryl or aralkyl radical; A represents a direct single bond between the atoms S and C represented or else represents a cyclic or acylic bridging radical chosen, inter alia, from the alkyl, cycloalkyl, aryl, heteroaryl and heteroalkyl radicals; r1 and R 2 which define the carbami-midoyl function each independently represent a hydrogen atom or an alkyl or aryl radical, this carbimimidoyl radical being, furthermore, characterized by cyclic structures formed by the union of the two nitrogen atoms to the intervention of their substituents and by their union with the radical of bridging A? this document also describes "carbamimidiums" resulting from the quaternization of one of the nitrogen atoms of this carbamimidoyl function. A possible substituent in position 2 indicated on page 12 of this document is the radical:

CD.YD.MdC.CH. - 22 - SY-1735A

e 1 kr -.

It -s-A-c: I 1 ,. '

NR

where R1 represents a hydrogen atom or an alkyl, cycloalkyl, cycloalkylalkyl, alkyl, cycloalkyl, aryl, arylalkyl, heterocyclic or hetero-cycloalkyl radical, each substituted or unsubstituted and the two nitrogen atoms "participate in cyclic structures indicated by the dotted lines ". No indication is given of cyclized carbamimi-doyl radicals containing a quaternized nitrogen atom, but there is an indication on page 22 of a cyclized carbamimidoyl radical of formula s

•-""-'CO

Based on the definitions given for the substituent R1, the Applicant does not believe that the European patent application 50334 generically describes any of the compounds of the present invention. However, the fact that the nature of the cyclic structures envisaged is indicated with such imprecision in the aforementioned document, the Applicant gives the statement in this memo.

As indicated above, there are in the field currently known, carbapenem derivatives bearing in position 2, a substituent of general formula:

CD.YD.MdC.CH. - 23 - SY-1735A

-S-A-Het where A represents an alkylene radical and Het represents a heterocyclic or heteroaromatic radical, but to the knowledge of the Applicant, there is no mention of carbapênèmes whose radical Het is a radical of formula:. - where r5 represents an aliphatic, cycloaliphatic, cycloaliphatic-aliphatic, aryl, araliphatic, heteroaryl, heteroaraliphatic, heterocyclic or heterocycloaliphatic radical optionally substituted, and Ç> * represents a heterocycle-aromatic nitrogen-containing atom by a ring carbon atom. As already specified, the carbapênème carrying the radical CH, e / -E-CB, CH, N-CK, 2 2 \ 3 Œ3 as a substituent in position 2 has already been described, just like the carbapênème comprising a quaternized heteroaromatic ring directly linked to the sulfur atom of the substituent in position 2.

Although many derivatives of carbapê-

CD.YD.MdC.CH. - 24 - SY-1735A

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

Overview of 11 invention.

The subject of the present invention is a new series of carbapenem derivatives bearing in position 2, a substituent of formula: s -S — A- where A represents a C 1 -C 6 alkylene radical in straight or branched chain, r5 represents an aliphatic radical , cycloaliphatic, cycloaliphatic-aliphatic, aryl, araliphatic, heteroaryl, heteroaraliphatic, heterocyclic or heterocycloaliphatic optionally substituted, and.

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

CD.YD.MdC.CH. - 25 - SY-1735A

H R15 _ î tX-S-Λ-Ο "- · '7f T w N" ^ COOR2 where r8 represents a hydrogen atom and Rl is chosen from the hydrogen atom and the alkyl, alkenyl and alkynyl radicals of 1 to 10 carbon atoms; cycloalkyl and cycloalkylalkyl of 3 to 6 carbon atoms in the ring of the cycloalkyl part and from 1 to 6 carbon atoms in the alkyl parts; phenyl; aralkyl, aralkenyl and aralkynyl in which the aryl part is a phenyl radical and the aliphatic part has 1 to 6 carbon atoms; hetero-aryl, heteroaralkyl / heterocyclic and heterocycloalkyl in which the heteroatom (s) in the above-mentioned heterocyclic parts are chosen from 1 to 4 oxygen, nitrogen or sulfur atoms and the alkyl parts associated with the heterocyclic parts have 1 to 6 carbon atoms, all of which are substituted or unsubstituted and whose substituent (s) with respect to the abovementioned radicals are independently chosen from

C ^ -C5-alkyl optionally amino, halogenated, hydroxylated or halo carboxylated -0R3 O

-OCNr3r4 0

It „-CNR3r4 -NR3R4

CD.YD.MdC.CH. - 26 - SY-1735A

/ NR3 - (Λ NR3R4 -S02NR3R4 Ο -NHCNR3R4 ο

Jl.

. R3CNR4 "-C02R3 = 0 0 -oïr3 -SR3 0 -SR9 0 -SR9

II

0

~ CN

-N3 -OSO3R3 0 11 o -OS-R9

II

O

0 -NR3S-R9

II

O

-0P (0) (OR3) (OR4) -NR3C = NR4 R3 -nr3co2r4 -no2 where, with regard to the abovementioned substituents, the radicals R3 and R4 are chosen independently from the hydrogen atom and the alkyl, alkenyl and alkynyl

CD.YD.MdC.CH. - 27 - SY-1735A

from 1 to 10 carbon atoms; cycloalkyl, cycloalkyl-alkyl and alkylcycloalkyl of 3 to 6 carbon atoms in the ring of the cycloalkyl part and from 1 to 6 carbon atoms in the alkyl parts; phenyl; aralkyl, aralkenyl and aralkynyl in which the aryl part is a phenyl radical and in which the aliphatic part has 1 to 6 carbon atoms; and hetero-aryl, heteroaralkyl, heterocyclic and heterocycloalkyl in which the heteroatom (s) in the aforementioned heterocyclic parts are chosen from 1 to 4 nitrogen and sulfur oxygen atoms and in which the alkyl parts associated with the heterocyclic parts count 1 to 6 carbon atoms, or alternatively R3 and R4, taken together with the nitrogen atom to which at least one of them is united, can form a pentagonal or hexagonal nitrogen heterocyclic radical; R9 is defined as r3 except that it cannot be a hydrogen atom; or where R ^ and R ^, taken together, represent a C2-CiQ-alkylidene or C2-Cio-alkylidene radical substituted by hydroxyl; R ^ is chosen from alkyl, alkenyl and alkynyl radicals of 1 to 10 carbon atoms; cycloalkyl and cycloalkylalkyl of 3 to 6 carbon atoms in the ring of the cycloalkyl part and from 1 to 6 carbon atoms in the alkyl parts; phenyl; aralkyl, aralkenyl and aralkynyl in which the aryl part is a phenyl radical and in which the aliphatic part has 1 to 6 carbon atoms; heteroaryl, heteroaralkyl, heterocyclic and heterocycloalkyl in which the heteroatom (s) of the aforementioned heterocyclic parts are chosen from 1 to 4 atoms of oxygen, nitrogen or sulfur and in which the alkyl parts associated with the heterocyclic parts have 1 to 6 atoms of carbon, all substituted or unsubstituted; the aforementioned R 5 radicals being optionally substituted with 1 to 3 chosen radicals

CD.YD.MdC.CH. - 28 - SY-1735A

independently from: C] _- C6-alkyl optionally amino, fluorinated, chlorinated, carboxylated, hydroxylated, or carbamoylated fluoro, chloro or bromo -OR3 -oco2r3

—OCOR3 -OCONR3R4 O

-SR9

II

O

-OXO

-Nr3r4 R3CONR4- -NR3C02R4 -NH3CONR3R4 0 -nr3s-r9

II

0 -SR3

O

1 "-SR9

0 0 ** Q

-S-R9 -SO3R3 -co2r3 -conr3r4

-CN 7 OR

phenyl optionally substituted with 1 to 3 fluoro, chloro, bromo, Ci-C6-alkyl, -OR3, -NR3R4, -S03r4, -C02R3 or -CONR3R4, where R3, R4 and R9 in these R3 substituents are as defined above? or R3 can be combined with

CD.YD.MdC.CH. - 29 - SY-1735A

ex- at another point in the cycle so as to form a condensed heterocyclic or heteroaromatic radical, the cycle of which may contain additional heteroatoms, preferably up to the number of 2, chosen from O, N and S; RIS is chosen from the hydrogen atom and the alkyl, alkenyl and alkynyl radicals of 1 to 10 carbon atoms; cycloalkyl, cycloalkylalkyl and alkyl-cloalkyl of 3 to 6 carbon atoms in the ring of the cycloalkyl part and from 1 to 6 carbon atoms in the alkyl parts; spirocycloalkyl of 3 to 6 carbon atoms; phenyl; aralkyl, aralkenyl and aralkynyl in which the aryl part is a phenyl radical and the aliphatic part has 1 to 10 carbon atoms; heteroaryl, heteroaralkyl, heterocyclic and heterocycloalkyl in which the heteroatom (s) in the aforementioned heterocyclic parts are chosen from 1 to 4 atoms of oxygen, nitrogen and sulfur and the alkyl parts associated with the heterocyclic parts have 1 to 6 carbon atoms, all substituted or unsubstituted and in which the substituent or substituents with respect to the abovementioned radicals are chosen from the amino-, mono-, di-trialkoylamino, hydroxyl, alkoxy, mercapto, alkylthio, phenylthio, sulfamoyl, amidino, guanidino, nitro, chloro radicals , bromo, fluoro, cyano and carboxyl; and in which the alkyl parts in the abovementioned substituents have 1 to 6 carbon atoms; A represents a C ^ -Cg-alkylene radical in a straight or branched chain; r2 represents a hydrogen atom, an anionic charge or a conventional radical easily

CD.YD.MdC.CH. - 30 - SY-1735A

eliminable protective of the carboxyl function, it being understood that when represents a hydrogen atom or a protective radical, a counter ion is also present, and

O

represents a substituted or unsubstituted heterocyclic, aromatic, mono-, bi- or polycyclic radical comprising at least one nitrogen atom in the ring and united to the radical A by a carbon atom of the ring and comprising a ring nitrogen atom which is quaternized by the radical R5? and their pharmaceutically acceptable salts.

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

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

Detailed description of the invention.

The new compounds of general formula I include the carbapenem nucleus: fi 2 0 -4

CD.YD.MdC.CH. - 31 - SY-1735A

and can therefore be called derivatives of 1-carba-2-penem-3-carboxylic acid. Alternatively, the compounds can be considered to include the basic structure 4 and can be called derivatives of 7-oxo-1-azabi-cyclo (3.2.0) hept-2-ene-2-carboxylic acid. The subject of the invention is the compounds whose relative stereochemistry of the protons 5,6 is not only cis, but also trans, but the preferred compounds have the stereochemistry 5R, 6S (trans), as in the case of thienamycin.

The compounds of formula I can be free of substituent in position 6 or can carry there radicals already mentioned for other carbapenem derivatives. More specifically, R8 can represent a hydrogen atom and R1 can represent a hydrogen atom or a substituent other than hydrogen, mentioned, for example, in European patent application 38869 (see definition of Rg). Alternatively, R8 and Ri, taken together, can form a C2-C10-alkylidene radical. or C2-Cio “a-lc ° ylidène substituted, for example by a hydroxyl radical.

The compounds of formula I can also be free of substituent in position 1 (r15 = H) or can carry in this position of the radicals already mentioned for other carbapenem derivatives. More specifically, r! 5 can represent a hydrogen atom or any of the substituents other than hydrogen in

CD.YD.MdC.CH. - 32 - SY-1735A

position 1, indicated, for example, in European patent application 54917 (see the definitions of R1 or R 2 in this document) or in the United States patent; America No. 4,350,631. The substituents R15 other than hydrogen which are preferred are in particular Ci-C6 ~ alkyl radicals, more especially methyl; phenyl; and phenyl (Ci-Cgîalcoyl. The substituent RÎ5 other than hydrogen can have the configuration "^ or and the invention relates to the isomers o (and ^ separated, as well as their mixtures. The compounds substituted in position 1 which especially preferred are those having the J3 configuration and especially those carrying a radical 3-methyl.

To clarify the definitions of Rl, r8 and

R15, the following indications may be given: (a) the aliphatic radicals "alkyl", "alkenyl" and "alkynyl" may be in a straight or branched chain and have 1 to 10 carbon atoms, but preferably have 1 to 6 and most advantageously 1 to 4; when they form part of another substituent, as in cycloalkylalkyl, heteroalkyl or aralkenyl radicals, the alkyl, alkenyl and alkynyl radicals preferably have 1 to 6 and more especially 1 to 4 carbon atoms.

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

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

CD.YD.MdC.CH. - 33 - SY-1735A

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

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

The term "conventional radical which is easy to remove protective of the carboxyl function" should be understood to mean a known ester radical which has already been used to block a carboxyl radical during the chemical reaction stages described below and which can be eliminated when the thing is desired, according to processes which do not bring any appreciable destruction of the rest of the molecule, for example by chemical or enzymatic hydrolysis, treatment using chemical reducers under moderate conditions, exposure to ultraviolet light or catalytic hydrogenation . Examples of such protective ester radicals are the benzhydryl, allyl, p-nitrobenzyl, 2-naphthylmethyl, benzyl, trichloroethyl or silyl radicals, such as trimethylsilyl, phenacyl, p-methoxybenzyl, acetonyl, o-nitrobenzyl, 4-pyridylmethyl and C ^ -Cg-alkyl such as methyl, ethyl or t-butyl. These protective radicals include those which are hydrolyzed under physiological conditions such as the pivaloyloxymethyl, acetoxymethyl, phthalidyl, inda-nyl and methoxymethyl radicals. A protective radical of the carboxyl function which is particularly advantageous is the p-nitrobenzyl radical, easily removed by catalytic hydrogenolysis.

Pharmaceutically acceptable salts

CD.YD.MdC.CH. - 34 - SY-1735A

mentioned above are in particular the addition salts of non-toxic acids, for example the salts formed with mineral acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, phosphoric acid, acid sulfuric, etc., and the salts formed with organic acids such as maleic acid, acetic acid, citric acid, succinic acid, benzoic acid, tartaric acid, fumaric acid, l 'mandelic acid, ascorbic acid, lactic acid, gluconic acid and malic acid. The compounds of formula I in the form of the acid addition salts can be represented by the formula: R8 I f5?} --- a -}; e <y coor2 where r2 represents a hydrogen atom or protective radical and χΘ represents the anion of an acid. Against the . anion xO can be chosen to give a pharmaceutically acceptable salt suitable for administration for therapeutic purposes, but in the case of the intermediate compounds of formula I, xQ can also represent a toxic anion. In such a case, this ion can be eliminated or replaced subsequently by a pharmaceutically acceptable anion giving a clean active final product for therapeutic purposes. When acidic or basic radicals are present in the radical R1 or R5 or in the radical

CD.YD.MdC.CH. - 35 - SY-1735A

ο the subject of the invention is also the base addition or appropriate acid addition salts of these functional radicals, for example the acid addition salts in the case of a basic radical and the salts with metals ( e.g. sodium, potassium, calcium and aluminum), ammonium salt and salts with non-toxic amines (e.g. trialcoylamines, procaine, dibenzylamine, 1-ephenamine, N-benzyl - ^ J3-phenethylamine, N, N'-dibenzylethylenedia-mine, etc.) in the case of an acid radical.

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

According to a preferred embodiment, the invention relates to the compounds of formula I, where R8 represents a hydrogen atom and R1 represents a hydrogen atom or a CH3-CH2 radical “

CH3 CH3 OH OH

'S> Ss ^ CH—, ^ C- or CH3CH- ch3 ^^ ch3 ^^

In this subclass, the preferred compounds are those in the formula of which R1 represents

CD.YD.MdC.CH. - 36 - SY-1735A

OH

CH3CH- and more especially the compounds having the absolute configuration 5R, 6S7 8R.

According to another preferred embodiment, the invention relates to the compounds of formula I where R1 and r2, then together, represent an alkylidene radical of formula: hoch2 V> ^ c = 0Η3 ^

The alkylene radical (that is to say the radical "A") in the compounds of formula I may be in a straight or branched chain and may have 1 to 6 carbon atoms. According to a preferred embodiment, the invention relates to these compounds in the formula of which A represents - (CH2) n_ with n representing 1 or 2 and according to a particularly preferred embodiment, it relates to the compounds in the formula of which A represents -CH2-.

The alkylene part "A" is united by a ring carbon atom to an aromatic heterocycle N-substituted quater-nisê of general formula: 0i ,! where R5 preferably represents a C ^ -Cg-alkyl radical, C2-Cio ~ alkenyl, C2-Cio_alkynyl, C3-C6-cycloalkyl, C3-Cg-cycloalkyl-Ci-Cg-alkyl, phenyl, phenyl-Ci-Cg- alkyl, phenyl-C2-Cg-alkenyl, C2-Cg-

CD.YD.MdC.CH. - 37 - SY-1735A

alkynyl, heteroaryl, heteroaralkyl in which the alkyl part has 1 to 6 carbon atoms, heterocyclic or heterocycloalkyl in which the alkyl part has 1 to 6 carbon atoms. The heteroaryl radical (or the heteroaryl part of a heteroalkyl radical) R 5 can be a mono-, bi- or polycyclic aromatic heterocyclic radical containing 1 to 4 O, N or S atoms, preference being given to pentagonal heterocyclic radicals or hexagonal such as thienyl, furyl, thiadiazoyl, oxadiazolyl, triazolyl, isothiazolyl, thiazolyl, imidazolyl, isoxazolyl, tetrazolyl, oxazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyrida-zinyl, pyrrolyl and pyrazolyl. The heterocyclic radical (or the heterocyclic part of a heterocycloalkyl radical) R 5 can be a saturated or unsaturated, mono-, bi- or polycyclic non-aromatic heterocyclic radical containing 1 to 4 O, N or S atoms, preference being given to pentagonal or hexagonal heterocyclic radicals such as morpholinyl, piperazinyl, piperidyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, pyrrolinyl and pyrroli-dinyl.

The radical R3 may optionally be substituted by 1 to 3 radicals chosen independently from: (a) C ^ -Cg-alkyl optionally substituted by radicals, preferably 1 to 3 in number, which are amino, fluoro, chloro, carbo-xyl, hydroxyl or carbamoyl (b) fluoro, chloro or bromo (c) -OR3 (d) -0C02R3 (e) -OCOR3 (f) -OCONR3r4

CD.ÏD.MdC.CH. - 38 - SÏ-1735A

(g) ο

He α -OS-R9

II

O

(h) -oxo (i) -NR3r4 (j) R3CONR4- (k) -NR3C02R4 (l) -NR3CONR3R4 (m) 0 -NR3S-R9

II

0 (n) -SR3 (o) -S0R9

(p> n Q

-S-R9 II

0 (q) -S03R3 (r) -C02R3 (s) -CONR3R4 (t) -CN; or (u) phenyl optionally substituted with 1 to 3 substituents independently selected from fluoro, chloro, bromo, C ^ -Cg-alkyl, -OR3, -NR3R4, -S03R3, -C02R3 OR -CONR3R4, where, in relation to abovementioned substituents of R5, the radicals R3 and R4 are independently chosen from hydrogen atoms and alkyl, alkenyl and alkynyl radicals of 1 to 10 carbon atoms; cycloalkyl, cycloalkylalkyl and alkylcycloalkyl of 3 to 6 carbon atoms in the ring of the cycloalkyl part and from 1 to 6 carbon atoms in the alkyl parts; phenyl; aralkyl, aralkenyl and aralkynyl in which the aryl part is a phenyl radical and in which the aliphatic part has 1 to 6 carbon atoms; and heteroaryl,

CD.YD.MdC.CH. - 39 - SY-1735A

heteroaralkyl, heterocyclic and heterocycloalkyl in which the heteroaryl and heterocyclic radical or a part of a radical is as defined above with respect to r5 and the alkyl parts associated with these heterocyclic parts have 1 to 6 carbon atoms; or r3 and R4, taken together with the nitrogen atom to which at least one of them is united, form a heterocyclic nitrogen pentagonal or hexagonal radical wine (as defined above with respect to R ^); and R ^ is as defined above with respect to r3, except that it cannot be a hydrogen atom. A radical especially preferred for r5 is a radical C] _-C6-alkyl and especially methyl.

In addition, the radical R5f together with another atom of the radical cycle

O

may form a condensed heterocyclic or heteroaromatic radical the ring of which may contain additional hetero atoms, preferably 1 or 2 in number, chosen from 0, N and s. for example

.— / '"' J

may be

-J or V

\ = JB \ _ / ®

CD.YD.MdC.CH. - 40 - SY-1735A

The radical / '""' N® is preferably a substituted or unsubstituted mono-, bi- or polycyclic aromatic heterocyclic radical comprising at least one nitrogen atom in the ring and 0 to 5 additional ring heteroatoms chosen from O, S and N, this heterocyclic radical being united to the radical A by a ring carbon atom and comprising a nitrogen atom of the · ring quaternized by the radical R ^.

The heteroaromatic radical

-O

may optionally be substituted for the ring carbon atoms available by preferably 1 to 5 and especially 1 to 3 substituents independently chosen from C 1 -C 4 -alkyl radicals; Ci-C4 ~ alkyl substituted by preferably 1 to 3 hydroxyl, amino, C ^ -C4-alkylamino, di (Ci-C4) alkylamino, C ^ -C4-alkoxy, carboxyl, halogeno radicals (considered below as meaning chloro , bromo, fluoro or iodo; preferably chloro, bromo or fluoro) or sulfo; C3-C6 “cycloalkyl; C3-C6-cycloalkyl (C] _- C4) alkyl optionally substituted with 1 to 3 substituents mentioned above in connection with the C1-C4-alkyl radicals; C1-C4-alkoxy; C1-C4-alkylthio; amino; C1-C4-alkylamino; di (C1-C4) alkylamino; halogêno; Ci-C4-alcanoylamino? C1-C4-alkanoyloxy; carboxyl; sulfo; -C02-Ci-C4 ~ alkyl;

CD.YD.MdC.CH. - 41 - SY-1735A

hydroxyl; amidino; guanidino; phenyl; phenyl substituted with 1 to 3 substituents independently selected from amino, halo, hydroxyl, trifluoromethyl, Ci-C4-alkyl, Ci-C4-alkoxy, C1-C4-alkylamino, di (C ^ -C4) alkylamino, carboxyl radicals and sulfo; phenyl (Ci-C4) alkyl in which the phenyl part is optionally substituted with 1 to 3 substituents mentioned above with respect to the phenyl radical and the alkyl part is optionally substituted with 1 to 3 substituents mentioned above with respect to the radicals Cl- C4-alkyl; and weatheraryl or heteroaralkyl in which the heteroatom (s) are chosen from 1 to 4 atoms 0, S or N and in which the alkyl part associated with the heteroaralkyl radical has 1 to 6 carbon atoms, these heteroaryl and heteroaralkyl radicals being optionally substituted in the heterocyclic part with 1 to 3 substituents independently chosen from hydroxyl, amino, halo, trifluoromethyl, C C4 ~ alkyl, Ci-C4-alkoxy, Ci-C4-alkylamino, di (Ci-C4) -alkylamino, carboxyl and sulfo radicals, and in the alkyl part with 1 to 3 substituents chosen from hydroxyl, amino, Ci-C4-alkylamino, di (Ci-C4) alkylamino, Ci-C4-alkoxy, carboxyl, halo and sulfo radicals. In addition, available ring nitrogen atoms (other than the quaternized nitrogen atom) can be substituted with 1 to 3 substituents independently selected from C1-C4-alkyl radicals; Ci-C4-alkyl substituted by preferably 1 to 3 hydroxyl, amino, Cq-C4-alkylamino, di (Ci-C4) alkylamino, C1-C4-alkoxy, carboxyl, halo or sulfo radicals; C3-C5 ~ cycloalkyl; C3-C6-cycloalkyl (C1-C4) alkyl optionally substituted with 1 to 3 substituents mentioned above in connection with the C1-C4-alkyl radicals; phenyl, phenyl optionally substituted with 1 to 3 substituents independently chosen from amino, halogeno,

CD.YD.MdC.CH. - 42 - SY-1735A

hydroxyl, trifluoromethyl, C1-C6 alkyl, C1-C4-al-coxy, C1-C4-alkylamino, di (C1-C4) alkylamino, carbo-xyl and sulfo; phenyl (0 ^ 04) alkyl, the phenyl part of which can optionally be substituted with 1 to 3 substituents mentioned above with respect to the phenyl radical and the alkyl part of which can optionally be substituted with 1 to 3 substituents mentioned above with respect to the phenyl radicals Ci-04-alkyl radicals; and hetero-aryl or heteroaralkyl in which the heteroatom (s) are chosen from 1 to 4 O, S or N atoms and in which the alkyl part associated with the heteroaralkyl radical has 1 to 6 carbon atoms, the heteroaryl and heteroaralkyl radicals being optionally substituted in the heterocyclic part with 1 to 3 substituents chosen independently from the hydroxyl, amino, halogen, trifluoromethyl, C1-C4-alkyl, Ci-C4 ~ alkoxy, Ci-C4-alkylamino, di (C ^ -C4) alkylamino, carboxyl radicals and sulfo and in the alkyl part with 1 to 3 substituents chosen from the hydroxyl, amino, Ci-C4-alkylamino, di (Ci-C4) alkylamino, Ci-C4-alkoxy, carboxyl, halo and sulfo radicals. The substituents especially preferred for the nitrogen and carbon atoms of the ring are the C1-C6-alkyl and especially methyl radicals.

In the preferred embodiment described above, preference is given to the compounds in the formula of which A represents a radical ¾) n,, where n represents 1 or 2 and more especially to those in the formula of which A represents a radical - CH2- and further (a) Ri and RÖ, taken together, represent a radical

CD.YD.MdC.CH. - 43 - SY-1735A

hoch2 ^ c = CH3 or (b) r8 represents a hydrogen atom and Rl represents a hydrogen atom or a CH3CH2 radical “”

CH3 CH3 OH OH

V> N‘CH—, "^ C- or CH3CH- CH3'X ^ CH3 ^

Particularly preferred compounds are those in the formula of which r8 represents a hydrogen atom and Rl represents a radical

OH

CH3CH- and more especially the compounds having the absolute configuration 5R, 6S, 8R.

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

CD.YD.MdC.CH. - 44 - SY-1735A

heptagonal (saturated or unsaturated) comprising 1 to 3 hetero-atoms chosen from 0, S, N or NRÜ, where R11 represents a hydrogen atom or a C ^ -Cg-alkyl radical optionally substituted by 1 or 2 substituents chosen independently from the radicals -0R3, -NR3r4, -CO2R3 # oxo / phenyl, fluoro, chloro, bromo, -SO3R3 and -CONR3r4, or a phenyl radical optionally substituted with 1 to 3 substituents chosen independently from C1-C6-alkyl radicals, - OR3, -Nr3r4, fluoro, chloro, bromo, -SO3R3, -CO2R3 and -CONr3r4, r3 and r4 in these substituents RÜ being defined as above with respect to the substituent R1, or a heteroaromatic pentagonal or hexagonal radical comprising 1 with 3 hetero atoms chosen from 0, S and N or NR11, where RÜ is as defined above. The quaternized pentagonal or hexagonal aromatic ring or, as the case may be, the carbocyclic, heterocyclic or heteroaromatic ring condensed on this first ring or the two rings may optionally be substituted on available ring atoms by substituents, in a total number preferably maximum of five for the whole ring system, which are the substituents mentioned above about the radical

O

In this preferred embodiment described above, preference is given to compounds in the formula of which A represents a radical -CH2) n "° ù n represents 1 or 2 and more especially to those in the formula of which A represents a radical - CH2 ”· and further (a) Rl and R8, taken together, represent a radical

CD.YD.MdC.CH. - 45 - SY-1735A

hoch2 ^ c = CH3 or (b) r8 represents a hydrogen atom and Rl represents a hydrogen atom or a radical CH3CH2 ~ "

ch3 CH3 OH OH

^ CH-, ^ C- or CH3GH- ch3 ^ ch3 ^

Particularly preferred compounds are those in the formula of which R8 represents a hydrogen atom and Rl represents a radical

OH

ch3ch- and more especially the compounds having the absolute configuration 5R, 6S, 8R.

According to another preferred embodiment, the invention relates to the compounds of formula I, where Γ \ -3 represents a radical chosen from Λ

CD.YD.MdC.CH. - 46 - SY-1735A

where R®, and RIO are independently selected from the hydrogen atom and the C1-C4-alkyl radicals; C1 “C4 ~ alkyl substituted by preferably 1 to 3 hydroxyl radicals, Ci-C4 ~ alkyllamino, di (Ci-C4-aicoyl) amino, Ci-C4-alkoxy, amino, sulfo, carboxyl and halo (chloro, bromo, fluoro or iodo; preferably chloro, fluoro or bromo); Cg-Cg-cycloalkyl; Cx-C4-alkoxy; Ci ~ C4-alkylthio; amino; C1-C4-alkylamino; di (Cx-C4 ~ alkyl) amino; halo (chloro, bromo, fluoro or iodo; preferably chloro, fluoro or bromo); C1-C4-alkanoylamino; ci ~ C4-alkanoyloxy; carboxyl; -CO2-C1-C4 * -alkyl; hydroxyl; amidino; guanidino; phenyl, phenyl substituted by one, two or three amino radicals, halo (chloro, bromo, fluoro or iodo; preferably chloro, fluoro or bromo), hydroxyl, trifluoromethyl; Ci-C4-alkyl or Ci-C4 ~ alkoxy; phenyl (Ci ~ C4) alkyl in which the phenyl part can optionally be substituted by 1 to 3 radicals mentioned above with respect to the phenyl radical and the alkyl part can optionally be substituted by 1 to 3 substituents mentioned above in relation to the radicals C1-C4-alkyl; and heteroaryl or heteroaralkyl in which the hetero atom (s) in the aforementioned heterocyclic parts are chosen from 1 to 4 oxygen, nitrogen or sulfur atoms and the alkyl part associated with the heteroaralkyl part has 1 to 6 carbon atoms, or where two of r6, r7 and RIO, taken together, can represent a condensed saturated carbocyclic radical, a condensed aromatic carbocyclic radical, a condensed non-aromatic heterocyclic radical or a condensed heteroaromatic radical, which condensed rings are optionally substituted by 1 or 2 of the substituents defined above with respect to R67 r7 and RIO;

CD.YD.MdC.CH. - 47 - SY-1735A

„5 Λ5 (b) * 7 ei f ·" l „j [] optionally substituted on a carbon atom by 1 to 3 substituents chosen independently from the radicals Ci-C4-alkyl; C] .- C4-alkyl substituted by de preferably 1 to 3 hydroxyl, Ci-C4-alkylamino, di (C1-C4) alkylamino, Ci-C4-alkoxy, amino, sulfo, carboxyl and halogeno radicals (chloro, bromo, fluoro or iodo; preferably chloro, fluoro or bromo ); C3-C6-cycloalkyl; C ^ -C4-alkoxy; Ci ~ C4-alkylthio; amino; Ci-C4-alkylamino; di (Ci-C4-alkyl) amino; halogeno (chloro, bromo, fluoro or iodo; preferably chloro, fluoro or bromo); Ci-C4-alkanoylamino; C1-C4-alkanoyloxy; carboxyl; -C02-Ci-C4-alkyl; hydroxyl; amidino; guanidino; phenyl, phenyl substituted by one, two or three amino radicals, halogeno (chloro, bromo, fluoro or iodo; preferably chloro, fluoro or bromo), hydroxyl, trifluoromethyl; C1-C4-alkyl or C1-C4-alkoxy; phenyl (Ci-C4) alkyl in which the phenyl part may optionally be substituted by 1 to 3 substituents mentioned below above with respect to the phenyl radical and the alkyl part may optionally be substituted by 1 to 3 substituents mentioned above with respect to the C 1 -C 4 alkyl and heteroaryl or heteroaralkyl radicals in which the heteroatom (s) in the aforementioned heterocyclic parts are chosen from 1

CD.YD.MdC.CH. - 48 - SY-1735A

with 4 oxygen, nitrogen or sulfur atoms and the alkyl part associated with the heteroaralkyl part has 1 to 6 carbon atoms, or optionally substituted to form a carbocyclic, heterocyclic or heteroaromatic condensed radical optionally substituted by 1 or 2 of the substituents defined above; (c) R5 f f e \ sl e | -f 1 -Γ '1 R5 f Bl 6 RS JV-s.

\ e ^ N \ f _SL_ x f * \ "_L_ or <j

O - O

optionally substituted on a carbon atom by 1 or 2 substituents chosen independently from C1-C4-alkyl radicals; C1-C4-alkyl substituted by preferably 1 to 3 hydroxyl radicals, Ci-C4-alkylamino, di (C1-C4) alkylamino, cl-c4 “alkoxY” amino, sulfo, carboxyl and halogen (chloro, bromo, fluoro or iodo ; preferably chloro, fluoro or bromo); C3 “C6 ~ cycloalkyl; Cj-C4-alkoxy; C1-C4-alkylthio; amino;

C1-C4-alkylamino; di (C1-C4-alkyl) amino; halogeno (chloro, bromo, fluoro or iodo; preferably chloro, fluoro or bromo); C1-C4-alkanoylamino; C4-C4-alkanoyloxy; carboxyl; -C02-Ci-C4-alkyl; hydroxyl; amidino; guanidino; phenyl, phenyl substituted by one, two or three amino or halogen radicals (chloro, bromo, fluoro or iodo; preferably chloro, fluoro or bromo),

CD.YD.MdC.CH. - 49 - SY-1735A

hydroxyl, trifluoromethyl; C1-C4 ~ alkyl or C1-C4-alkoxy; phenyl (C1-C4) alkyl in which the phenyl part can optionally be substituted with 1 to 3 substituents mentioned above with respect to the phenyl radical and the alkyl part can optionally be substituted with 1 to 3 substituents mentioned above with respect to the radicals Cx-c4-alkyl and heteroaryl or heteroaralkyl in which the heteroatom (s) in the abovementioned heterocyclic parts are chosen from 1 to 4 atoms of oxygen, nitrogen or sulfur and the alkyl part associated with the heteroaralkyl part has 1 to 6 atoms of carbon, or optionally substituted to form a condensed carbocyclic, heterocyclic or heteroaromatic radical optionally substituted with 1 to 2 of the substituents defined above 7 (a> 'P.5 s5 f -j— il. -q— Il .1 / 11 - • fne Ÿ · Ϋ y '* - π ° u L ji

/ yC'N

optionally substituted on a carbon atom by 1 substituent chosen independently from the C 1 -alkyl radicals; Cx-C4 ~ alkyl substituted by preferably 1 to 3 hydroxyl radicals, Cx-C4-alkylamino, di (Cl-c4-alkyl) amino, Cx-C4 ”alkoxy, amino, sulfo, carboxyl and halo (chloro, bromo, fluoro or iodo;

CD.YD.MdC.CH. - 50 - SY-1735A

preferably chloro, fluoro or brorao); c3 ~ Cg-cycloalkyl; C] _- C4-alkoxy; C1-C4-alkylthio; amino; C1-C4-alkylamino; di (C1-C4-alkyl) amino; halo (chloro, bromo, fluoro or iodo; preferably chloro, fluoro or bromo); cl-C4-alkanoylamino; C1-C4-alkanoyloxy; carboxyl; -C02-Ci-C4-alkyl; hydroxyl; amidino; guanidino; phenyl, phenyl substituted with one, two or three amino radicals, halo (chloro, bromo, fluoro or iodo; preferably chloro, fluoro or bromo), hydroxyl, trifluoromethyl; C1-C4-alkyl or C1-C4-alkoxy; phenyl (Cj-C4) alkyl in which the phenyl part can optionally be substituted with 1 to 3 substituents mentioned above with respect to the phenyl radical and the alkyl part can optionally be substituted with 1 to 3 substituents mentioned above with respect to the radicals C1-C4-alkyl; and heteroaryl or heteroaralkyl in which the heteroatom (s) in the aforementioned heterocyclic parts are chosen from 1 to 4 oxygen, nitrogen or sulfur atoms and the alkyl part associated with the heteroaralkyl part has 1 to 6 carbon atoms; (e) e 5 e.

_JT- ÎR ΙΓ f ~? ~

^ ^ J

where X represents 0, S or NR where R represents a C 1 -C 4 -alkyl radical; Ci-C4 ~ alkyl substituted by 1 to 3 hydroxyl, amino, Ci-C4-alkylamino radicals; di (Cx ~ C4) alkylamino; C1-C4-alkoxy; carboxyl; halo or sulfo; C3-C6-cycloalkyl; C3-C6-cycloalkyl (Ci ~ C4) alkyl optionally substituted with 1 to 3 substituents mentioned above in connection with the radicals Ci ~ C4 ~ alkyl; phenyl; phenyl substituted by 1 to 3 sub

CD.YD.MdC.CH. - 51 - SY-1735A

stituants independently selected from amino, halo, hydroxyl, trifluoromethyl, C1-C4-alkyl, C1-C4-alkoxy / Ci-C4-alkylamino, di (Ci-C4) -alkylamino, carboxyl and sulfo radicals? phenyl (Ci-C4) alkyl in which the phenyl part can optionally be substituted with 1 to 3 substituents mentioned above with respect to the phenyl radical and in which the alkyl part can optionally be substituted with 1 to 3 substituents mentioned above in connection with the C ^ -C4 ~ alkyl radicals; and weatheraryl and heteroaralkyl in which the heteroatom (s) are chosen from 1 to 4 atoms 0, S or N and the alkyl part a. associated with the heteroaralkyl radical has 1 to 6 carbon atoms, these heteroaryl and heteroaralkyl radicals being optionally substituted in the part heterocyclic with 1 to 3 substituents independently selected from hydroxyl, amino, halogeno, trifluoromethyl, C C4 ~ alkyl, Ci-C4-alkoxy, Ci-C4-alkylamino, di (Ci-C4) -alkylamino, carboxyl and sulfo radicals, and in the alkyl part with 1 to 3 substituents chosen from the hydroxyl, amino, Ci-C4-alkylamino, di (Ci-C4) alkylamino, Ci-C4-alkoxy, carboxyl, halo and sulfo radicals, this radical being optionally substituted on a carbon atom with 1 or more substituents independently selected from C1-C4-alkyl radicals; Ci-C4-alkyl substituted by preferably 1 to 3 hydroxyl radicals, C ^ -C4-alkylamino, di (Ci-C4-alkyl) amino, Ci-C4 ~ alkoxy, amino, sulfo, carboxyl or halo (chloro, bromo, fluoro or iodo; preferably chloro, fluoro or bromo)? C3-C6-cycloalcoyle? Ci-C4 ~ al-coxy? C ^ -C4-alcoylthio, amino? Ci-C4-alcoylamino? di (Ci-C4 ~ alkyl) amino? halo (chloro, bromo, fluoro or iodo? preferably chloro, fluoro or bromo)? C1-C4-alcanoylamino? Ci-C4 ~ alkanoyloxy? carboxyl? -CO2-C1-C4 ~ alkyl 7 hydroxyl? amidino? guanidino; phenyl?

CD.YD.MdC.CH. - 52 - SY-1735A

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

C1-C4-alkyl or C1-C4-alkoxy; phenyl (C1-C4) alkyl in which the phenyl part may optionally be substituted with 1 to 3 substituents mentioned above with respect to the phenyl radical and in which the alkyl part can optionally be substituted with 1 to 3 substituents mentioned above in connection with the C ^ -C4 ~ alkyl radicals; and heteroaryl and heteroaralkyl in which the heteroatom (s) of the abovementioned heterocyclic parts are chosen from 1 to 4 oxygen, nitrogen or sulfur atoms and the alkyl part associated with the heteroaralkyl part has 1 to 6 carbon atoms, or optionally substituted to form a condensed carbocyclic, heterocyclic or heteroaromatic radical optionally substituted by 1 or 2 of the substituents defined above; (f) E5

X-X * -X

5 11 —j— I -L- -Flb - 'e 5 e 5

X-N-E K-N-E

"“ U1

CD.YD.MdC.CH. - 53 - SY-1735A

where X represents O, S or NR where R represents a Cj-C4-alkyl radical; Ci ~ C4-alkyl substituted by 1 to 3 hydroxyl, amino, Ci-C4-alkylamino? di (C1-C4-alkyl) amino; Cx-C4-alkoxy? carboxyl; halo or sulfo; C3-C6-cycloalkyl; Cs-Cç-cycloalcoyl (Ci ~ C4) alkyl optionally substituted by 1 to 3 substituents mentioned above in connection with the radicals Cq-C4 ~ alkyl? phenyl? phenyl substituted with 1 to 3 substituents independently chosen from amino, halo, hydroxyl, trifluoromethyl, C1-C4 alkyl, Ci-C4-alkoxy, Ci-C4-alkylamino, di (Ci-C4) -alkylamino, carboxyl and sulfo radicals ? phenyl (Ci-C4) alkyl, the phenyl part of which can optionally be substituted with 1 to 3 substituents mentioned above with respect to the phenyl radical and the alkyl part of which can optionally be substituted with 1 to 3 substituents mentioned above with respect to the phenyl radicals C ^ -C4-alkyl radicals; and weatheraryl and heteroaralkyl in which the heteroatom (s) are chosen from 1 to 4 atoms 0, S or N and the alkyl part associated with the heteroaralkyl radical has 1 to 6 carbon atoms, these heteroaryl and heteroaralkyl radicals being optionally substituted in the part heterocyclic with 1 to 3 substituents independently chosen from hydroxyl, amino, halogeno, trifluoromethyl, C4-alkyl, Cx-C4-alkoxy, Cx-C4-alkylamino, di (Ci ~ C4) -alkylamino, carboxyl and sulfo radicals, and in the alkyl part with 1 to 3 substituents chosen from hydroxyl, amino, C1-C4-alkylamino, di (Ci ~ C4) alkylamino, Cx ~ C4-alkoxy, carboxyl, halo and sulfo radicals? this heteroaromatic radical being optionally substituted on a carbon atom by a substituent chosen from C1_c4-alkyl radicals; Ci-C4-alkyl substituted by preferably 1 to 3 hydroxyl radicals, cl-C4-alkylamino, di (Ci-C4 ~ alkyl) amino, Ci-C4-alkoxy,

CD.YD.MdC.CH. - 54 - SY-1735A

amino, tallow, carboxyl or halo (chloro, bromo, fluoro or iodo; preferably chloro, fluoro or bromo); c3 “c6-cycloalkyl; cl “c4" alkoxy; Ci-C4-alkylthio, amino; Ci-C4-alkylamino; di (Ci-C4-alkyl) amino; halo (chloro, bromo, fluoro or iodo; preferably chloro, fluoro or bromo); Ci -C4 ~ alkanoylamino; C1-C4-alkanoyloxy; carboxyl; -C02-Ci-C4-alkyl; hydroxyl; amidino; guanidino; phenyl; phenyl substituted by one, two or three amino, halo (chloro, bromo, fluoro or iodo) radicals ; preferably chloro, fluoro or bromo), hydroxyl, trifluoromethyl; Cj-C4-alkyl or C1-C4-alkoxy; phenyl (Ci-C4) alkyl, the phenyl part of which may optionally be substituted with 1 to 3 substituents mentioned above with regard to the phenyl radical and in which the alkyl part may optionally be substituted by 1 to 3 substituents mentioned above with respect to the C 1 -C 4 -alkyl radicals; and heteroaryl and heteroaralkyl in which the heteroatom (s) of the aforementioned heterocyclic parts are chosen from 1 to 4 oxygen, nitrogen or sulfur atoms and the alkyl part associated with the heteroaralkyl part has 1 to 6 carbon atoms; and (g) ε s

K— -N-R5 R5-K-H N-N

I I * I I / 5th! I

NOT . N-R N. N-R λ -w v K-λ

Y V V

5 6

K-N-R R -K-K — R N-N-R

I j_Rs, Il I or eII 1

CD.YD.MdC.CH. - 55 - SY-1735A

where R represents a C1-C4-alkyl radical, · Ci-C4-alkyl substituted by 1 to 3 hydroxyl, amino, C1-C4-alkylamino radicals; ^ (0 ^ -04) alkylamino; Ci-C4 ~ alkoxy; carboxyl; halo or sulfo; C3-Cg-cycloalcoyle? C3 “Cg-cycloalkyl (Ci-C4) alkyl optionally substituted with 1 to 3 substituents mentioned above with regard to the C 1 -C 4 -alkyl radicals? phenyl; phenyl substituted with 1 to 3 substituents independently selected from amino, halo, hydroxyl, trifluoromethyl, Ci ~ C4-alkyl, Ci-C4-alkoxy, Ci-C4-alkylamino, di (Ci ~ C4) alkylamino, carboxyl and sulfo radicals; phenyl (Ci-C4) -alkyl in which the phenyl part can optionally be substituted by 1 to 3 substituents mentioned above with respect to the phenyl radical and in which the alkyl part can optionally be substituted with 1 to 3 substituents mentioned above in connection with the radical Ci ~ C4-alkyl radicals? and heteroaryl and heteroaralkyl in which the heteroatom (s) are chosen from 1 to 4 O, S or N atoms and the alkyl part associated with the heteroaralkyl radical has 1 to 6 carbon atoms, these heteroaryl and heteroaralkyl radicals being optionally substituted in the part heterocyclic with 1 to 3 substituents independently selected from hydroxyl, amino, halogen, trifluoromethyl, C ^ -C4-alkyl, Ci-C4-alkoxy, Ci-C4-alkylamino, di (Ci-C4) -alkylamino, carboxyl and sulfo radicals , and in the alkyl part with 1 to 3 substituents chosen from the hydroxyl, amino, Ci-C4-alkylamino, di (Ci ~ C4) alkylamino, Ci-C4-alkoxy, carboxyl, halo and sulfo radicals. The radicals R and can also be taken together to form a condensed heterocyclic or heteroaromatic radical.

In the preferred embodiment described above, preference is given to compounds in the formula of which A represents a radical “(CH2) n- where n

CD.YD.MdC.CH. - 56 - SY-1735A

represents 1 or 2 and more especially to those in the formula of which A represents a radical -CH2 "and moreover (a) R1 and R8, taken together, represent a radical HOCH 2 ^ C = ch3 ^ or (b) R8 represents hydrogen atom and Ri represents a hydrogen atom or a CH3CH2- radical ”

ch3 ch3 OH OH

^^ CH-, ^ C- or CH3CH- CH3 ^ ch3 ^

Particularly preferred compounds are those in the formula of which R8 represents a hydrogen atom and R1 represents a radical

OH

CH3CH- and more especially the compounds having the absolute configuration 5R, 6S, 8R.

According to a particularly preferred embodiment, the invention relates to the compounds of formula I where / ^ N © 5 (_ H-ΪΓ represents a radical of formula

CD.YD.Mac.CH. - 57 - SY-1735A

or R? and RIO are independently chosen from hydrogen atoms and Ci ~ C4-alkyl radicals, C ^ "C4 ~ alkoxy, carboxyl and carbamoyl and R ^ is as defined above and is preferably a Ci-Cß radical" alkyl and more advantageously -CH3.

In the preferred embodiment described above, preference is given to compounds where A represents a radical - (CH2) n ~ where n represents 1 or 2 and more especially to those in the formula of which A represents a radical -CH2- and more (a) r! and R ^, taken together, represent a radical HOCH2 ch3 or (b) r8 represents a hydrogen atom and Ri represents a hydrogen atom or a radical CH3CH2- "ch3 ch3 oh oh CH-, C- or CH3CH- ch3 ^ ch3 ^ "

Particularly preferred compounds are those in the formula of which R 1 represents a hydrogen atom and R 1 represents a radical

CD.YD.MdC.CH. - 58 - SY-1735A

OH

CH3CH- and more especially the compounds having the absolute configuration 5R, 6S, 8R.

According to another preferred embodiment, the invention relates to the compounds of formula I where s represents a radical of formula

O

where r5 represents a C ^ -C ^ alkyl radical, preferably methyl, and R6 represents a hydrogen atom or a Cj-C ^ alkyl radical; R5 • I r6 where r5 represents a C ^ -C ^ alkyl radical preferably methyl and r6 and R? represent hydrogen atoms or C] .- C4-alkyl radicals;

CD.YD.MdC.CH. - 59 - SY-1735A

(c) RN ^^ i-R5 "ΊΞ = / where R5 represents a Cx-C4-alkyl radical, preferably methyl, and R represents a Cx-C4 ~ alkyl or phenyl (C1-C4) alkyl radical? is where r5 represents a Cx-C4-alkyl radical, preferably methyl, and R ^ represents a CX-C4-alkyl radical, preferably methyl; "ύ /

R

where r5 represents a Cx-C4 ~ alkyl radical, preferably methyl, and R represents a C1-C4-alkyl radical, preferably methyl; or (f) -fl. s

CD.YD.MdC.CH. - 60 - SY-1735A

where R5 represents a Ci-C ^ alkyl radical, most advantageously a methyl radical.

In the preferred embodiment described above, preference is given to compounds in the formula of which A represents a radical - (CH2) n- where n represents 1 or 2 and more especially to those in the formula of which A represents a radical - CH2- and moreover (a) Ri and R ^, taken together, represent a radical HOCH2 "C = ch3 ^ or (b) r8 represents a hydrogen atom and Ri represents a hydrogen atom or a radical CH3CH2-"

CH3 CH3 OH OH

^ CH-, C- or CH3CH- CH3 ^ CH3 ^

Particularly preferred compounds are those in the formula of which r8 represents a hydrogen atom and Ri represents a radical

OH

CH3CH- and more especially the compounds having the absolute configuration 5R, 6S, 8R.

According to a specially preferred embodiment, the invention relates to the compounds of formula I, where

CD.YD.MdC.CH. - 61 - SY-1735A

Γ ^ \ Β 5

_L N-R

W

represents a radical of formula // J /

(a) L N — CH3 (b) —V U

\ ê CH3 (c) - ^ y (d) —c: -i .Cn, CH, CH ® - // ‘‘ Λ ρ V -ir ·

CH

(9) 3 <h> cg3 β CB, xy *, CH3

CD.YD.MdC.CH. - 62 - SY-1735A

(i) “0 <j) / O

e, ch, '- 7 CH3

\\ J

N- <® / CH3 ^ (1) CH3 ^ -p-iv ^ CH 3 CH3 ©

(m) Γ \ ^ or (n) “O

\ s / 3 N-N

/ · CB3

In the preferred embodiment described above, preference is given to compounds in the formula of which A represents a radical ~ (CH2) n "'° ù n represents 1 or 2 and more especially to those in the formula of which A represents a radical -CH2 ~ and further (a) Ri and RÖ, taken together, represent a radical HOCH2 CH3 ^

CD.YD.MdC.CH. - 63 - SY-1735A

or (b) R8 represents a hydrogen atom and Rl represents a hydrogen atom or a CH3CH2- 'radical

CH3 CH3 OH OH

\ V I I

CH-, ^ C- or CH3CH- CH3 ^ CH 3 ^

Particularly preferred compounds are those in the formula of which RÖ represents a hydrogen atom and Rl represents a radical

OH

CH3CH- and more especially the compounds having the absolute configuration 5R, 6S, 8R.

Specific compounds in accordance with the invention are those of formula:

OH

! R) "Ί— -N -v 2 0 TOOR ^ where r2 represents a hydrogen atom, an anionic charge or a conventional radical easy to remove protective of the carboxyl function, it being understood that when r2 represents a hydrogen atom or a protective radical, a counter ion is also present and where

CD.YD.MdC.CH. - 64 - SY-1735A

—S — A - / - _5 l ^ —R est // ^ ® // (a) -SCE_ r N — CH, (b) -SCH CH Λ

\ = / 2 \ ^ / J

CH 3 (c) -SCE ^ - <y Λ (d) _SCH2_f ~ \ W \ = / CH 3 CH-,

© V

(e) -SCH2CH2 (f) -SCH2 2CH2CK ^ CH-, \ · ® CH-, / N- \ N6 "3 (g) -SCH2— (h) - £ CH2— ^ CH3 CE3

CD.YD.MdC.CH. - 65 - SY-1735A

CH

CH 8 / CK3 “- ** A 1“ T \ Χΐ · ^ '5εΗ2 ~ \ Ε A ~ CH3 CH3 / S1 Îh3 jf ~ \ e (k) -ech2 - (^ J] (1) -SCE — Γ V —Ce3 “3

OJ

CH_-% (m) i 2 (n) -SCH_ — f

-SCH ^ J X J

X — l CH / 0 ® / CH, CK3 3 CH-I 3 (o) -sch2 ^) (P) - ^ rf> '—N-ra3 KJ # ^ CH3 CH3 where the 1 H NMR spectrum (D2O) presents the peaks characteristics at 6; 1.23 (3H, d, J = 6.4 Hz), 3.12 (2H, q, J = 1.4, 8.9 Hz), 3.39 (1H, q, J = 2.7, 6.0 Hz), 4.07-4.68 (10H,

CD.YD.MdC.CH. - 66 - SY-1735A

m) f 8.19 (1H, s);

“" “RQL

ch3 where the 1 H NMR spectrum (D2O) presents the characteristic peaks at <5: 1.23 (3H, d, J = 6.4 Hz), 3.15 (2H, q, J = 3.7, 9.0 Hz ), 3.37 (1H, q, J = 2.6, 6.0 Hz), 3.95-4.65 (10H, m), 8.62 (1H, s); coo6 -SCH2-t-N | 02 // W X.

\ Xîv H2 -SCH -— ([; E \\ / V_K — CH- CH,

Ie3 ÇH3 (t) -ECH _ / V. (u) / "t -f> ^ -K-CHCOO® N_ / or CE3 ch3 / -v

(v) _ // I

\ s? " ch3

According to an embodiment especially CD.YD.MdC.CH. - 67 - SY-1735A

preferred, the invention relates to the compounds of formula I, where {S ~ \ e 5

- ^ ^ Ji — R

represents CH,

I J

The

-O

In the preferred embodiment described above, preference is given to the compounds in the formula of which A represents a radical - (CH2) n- where n represents 1 or 2 and more especially to those in the formula of which A represents a radical - CH2- and moreover (a) Rl and R8, taken together, represent a HOCHo radical> ch3 ^ or (b) R8 represents a hydrogen atom and R ^ represents a hydrogen atom or a CH3CH2- # radical

CH3 CH3 OH OH

"^" ‘CH-, C- or CH3CH- CH3 ^ CH3 ^

Particularly preferred compounds are those in CD.YD.MdC.CH. - 68 - SY-1735A

the formula of which represents a hydrogen atom and r! represents a radical:

OH

i CH3ch “and more especially the compounds having the absolute configuration 5R, 6S, 8R.

The carbapenem derivatives of general formula I are prepared from compounds of formula:

I F

„_Τα __2 '~ COOk

III

where Ri, r8 and Ri5 are as defined above and r2 'represents a conventional radical which is easy to remove, protective of the carboxyl function. Compounds of formula III have already been described, for example in European patent application 38869 (compound T) and in European patent application 54917, and can be obtained according to the general methods which are described therein.

The process for preparing the compounds of formula I from the compounds of formula III can be summarized by the following reaction scheme: * 8 I f 51 n [o ->

III

CD.YD.MdC.CH. - 69 - SY-1735A

r8 f

r, l ëHS — A-L— N

R f] T - sfr ~ N "ΤΟΟΕ2’

L = classical labile radical 'IV

R8 f f5 ri t -.— i- K 5 Γ I S.S * i ~ N-SW '^

0 II

- r15 _ S R Ci R r 1 Λ χ, θ __— A — r— deprotection j | J possible V N COOR2 '0 R8 = f15 _ TT il ^ cr ^ coor2

CD.YD.MdC.CH. - 70 - SY-1735A

A variant of the above process is illustrated by the following reaction scheme:

R8 H ®15 HS — A

r1_pVL - /) K 2 'ÿ COOn

IV

15

_ 8 Y

-T> I deprotection ^ J. - N ^ x: 00R2 '

II

R15

r8? A / -N

R — J - £ —Ä — f- N r I | r —x1 ..y

N ^ COOH

lia R15 “p il ^ y ~ ^ - ^ e o ^ cocr la

For the conduct of the above process, the CD.YD.MdC.CH. - 71 - SY-1735A

starting compound III is reacted in an inert organic solvent such as methylene chloride, acetonitrile or dimethylformamide with an approximately equimolar amount of a reagent R ° -L such as p-toluenesulfonic anhydride, p-nitrobenzenesulfonic, 2,4,6-triisopropylbenzenesulfonic, methane-sulfonic or trifluoromethanesulfonic, diphenyl chlorophosphate, toluenesulfonyl chloride, p-bromobenzenesulfonyl chloride, etc., where L represents the labile radical corresponding such as toluenesulfonyloxy, p-nitrobenzenesulfonyloxy or diphé-noxyphosphinyloxy or other well known labile radicals provided in a conventional manner. The reaction fixing the labile radical in position 2 of intermediate III is advantageously carried out in the presence of a base such as diisopropylethylamine, triethylamine, 4-dimethylaminopyridine, etc., at a temperature of approximately -20 ° C. at + 40 ° C, and more preferably around 0 ° C. The labile radical L of intermediate compound III can also be a halogen, in which case the radical is provided by reaction of intermediate III with a halogenating agent such as 03PCI21 $ 3ΡΒγ2, (0O) 3PBr2 # (C00C1) 2 / etc ., in a solvent such as CH2CI2 # CH3CN, THF, etc., in the presence of a base such as diisopropylethylamine, triethylamine, 4-dimethylaminopyridine, etc. Intermediate IV can be isolated, if desired, but is advantageously carried out at the next stage without isolation or purification.

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

CD.YD.MdC.CH. - 72 - SY-1735A

HS ^ 0 where A represents a C ^ -Cg-alkylene radical in a straight or branched chain, and ._0 represents a heterocyclic aromatic mono-, bi- or polycyclic radical containing a nitrogen atom quater-nisable in the cycle, the cycle being united to the radical A by a carbon atom of this ring, in an inert organic solvent such as dioxane, dimethylformamide, dimethylsulfoxide or acetonitrile and in the presence of a base such as diisopropylethylamine, triethylamine , Sodium hydrogen carbonate, potassium carbonate or 4-dimethylaminopyridine. The temperature for the displacement reaction is not critical, but is advantageously from about -40 ° C to + 25 ° C. Most advantageously, the reaction is carried out under cooling, for example from about 0 ° C. to -10 ° C.

The quaternization of ring nitrogen in the heteroaralkyl radical of intermediate II is carried out by reaction of intermediate II in an inert organic solvent with an amount at least equivalent (up to a molar excess of about 50%) an alkylating agent of formula: R5- x '

CD.YD.MdC.CH. - 73 - SY-1735A

where r5 is as defined above and X 'represents a conventional labile radical such as halo (chloro, bromo or iodo, but preferably iodo) or a sulphonic ester radical such as mesylate, tosylate or triflate. Examples of suitable inert organic solvents are chloroform, methylene chloride, tetrahydrofuran, dioxane, acetone, dimethyl sulfoxide and dimethylformamide. The temperature for the alkylation reaction is not critical and temperatures of about 0 ° C to 40 ° C are preferred. Most advantageously, the reaction is carried out at room temperature.

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

The deprotection stage aimed at eliminating the radical r2 'protecting the carboxyl function of intermediate 1' is carried out according to conventional techniques such as solvolysis, chemical reduction or hydrogenation. When the protective radical used is eliminable by catalytic hydrogenation, such as a p-nitrobenzyl, benzyl, benzhydryl or 2-naphthylmethyl radical, the intermediate 1 'in a suitable solvent such as dioxane-water-ethanol, tetrahy-drofuran-hydrogenophosphate of aqueous dipotassium-isopropanol or a similar solvent can be reacted under a hydrogen pressure of 1 to 4 atmospheres in the presence of a hydrogenation catalyst such as palladium on carbon, palladium hydroxide, oxide

CD.YD.MdC.CH. - 74 - SY-1735A

of platinum, etc., at 0 to 50 ° C for about 0.24 to 4 hours. When r2 ‘is a radical such as the o-nitrobenzyl radical, photolysis is also suitable for deprotection. Protective radicals such as the 2,2,2-trichloroethyl radical can be eliminated by moderate reduction using zinc. The protective allyl radical can be removed using a catalyst comprising a mixture of a palladium compound and triphenylphosphine in an aprotic solvent such as tetrahydrofuran, diethyl ether or methylene chloride. Likewise, other conventional radicals which protect the carboxyl function can be eliminated according to methods well known to the specialist. Finally, as already indicated, the compounds of formula 1 'where r2' represents a physiologically hydrolyzable ester radical such as acetoxy-methyl, phthalidyl, indanyl, pivaloyloxymethyl, methoxymethyl, etc., can be administered directly to the host without deprotection, because these esters are hydrolyzed in vivo under physiological conditions.

It should be noted that when the substituent Ri, r8, r5 or Ri5 or the heteroaromatic radical united with the substituent A contains a functional radical which could interfere with the desired course of the reaction, this radical can be protected using a blocking or conventional protection radical and then be deprotected for the restoration of the desired functional radical. Suitable protective groups and methods for introducing and removing them are well known to those skilled in the art.

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

CD.YD.MdC.CH. - 75 - SY-1735A

carboxyl is removed as described above to give rise to the corresponding free carboxylic acid and the latter is then quaternized using the alkylating agent R5 ~ X 'to yield the desired quaternized product of formula I. For the quaternization of the deprotected intermediate 11a, the solvent can be water or a non-reactive organic solvent or a mixture of these. Examples of suitable solvents are water, organic solvents such as chloroform, methylene chloride, tetrahydrofuran, dioxane, acetone, dimethyl sulfoxide and dimethylformamide, in addition to mixtures of water and organic solvent such as water-acetone or water-dimethylformamide mixtures. The temperature for the quaternization of intermediate 11a is not critical and temperatures of about -40 ° C to room temperature are suitable. Most advantageously, the reaction is carried out at around 0eC.

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

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

CD.YD.MdC.CH. - 76 - SY-1735A

CH3 OH H V, ® (R1 no ^ Y-KV * SCH2 — w} N ^ cooe from the intermediate of formula: OH H N—.

(R) -Y_i ^ \ p_SCE2- "N ^ coo '^' xî ^ the removal of the protective allyl radical before quaternization significantly improves the yield of the desired end product.

The process described above lends itself to the preparation of the compounds of the invention, but a new process applicable to the preparation of the compounds of formula I has also been discovered. This other method is described below and in the examples.

According to the other process for the preparation of the compounds of formula I, an intermediate of formula: 8 f

π T

<r ~~ 'coor2'

IV

where Ri, r8 and r! 5 are as defined above, R ^ 'is a classic radical easy to remove protective

CD.YD.MdC.CH. - 77 - SY-1735A

of the carboxyl function and L is a conventional labile radical such as toluenesulfonyloxy, p-nitrobenzene-sulfonyloxy, diphenoxyphosphinyloxy or halo, is reacted with a thiol of formula: r ^ \ ® 5

HS-A-h K-R

W £> where A and Ό * are as defined above and χΘ represents a counter ion, in an inert solvent and in the presence of a base for the formation of a carbapenem of formula: R15, R8? JL c / "" \ © 5 ‘tO '^ ^ /) - w \ 2’

Cr COOR

or r1, r8, r2 'r A, r! 5 5 and 70 are as defined above and, if desired, the radical R ^ 1 protecting the function

CD.YD.MdC.CH. - 78 - SY-1735A

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

This other process uses 11 intermediate of formula: „15

* 8 h I

EtTï cr N coor2 '

IV

which, as already indicated, is described for example in European patent applications 38869 and 54917 and which can be obtained according to the general methods which are described therein. L represents a conventional labile radical (defined as "X" in European patent application 38869) for example chloro, bromo, iodo, benzenesulfonyloxy, p-toluenesulfonyloxy, p-nitroben-zenesulfonyloxy, metbanesulfonyloxy, trifluoromethane-sulfonyloxy, diphenoxyphosphinyloxy or di ( trichloroethoxy) phosphinyloxy. The preferred protective radical is the diphenoxyphosphinyloxy radical.

Intermediaries of formula IV are generally formed in situ by reaction of an intermediate of formula: 8 R15 R °, - "- \ 2 '

0X COOR

III

CD.YD.MdC.CH. - 79 - SY-1735A

where Ri, r8, r15 and r2 'are as defined above, with an appropriate RÛ-L acylating agent. The preferred intermediate IV where L represents a diphenoxy-phosphinyloxy radical can be obtained by reaction of a ketoester III in an inert organic solvent, such as methylene chloride, acetonitrile or dime-thylformamide, with a quantity of little near equimolar of diphenyl chlorophosphate in the presence of a base such as diisopropylethylamine, triethylamine, 4-dimethylaminopyridine, among others, at a temperature of about -20 ° C. to + 40 ° C. and more advantageously of approximately 0 ° C. Intermediate IV can be isolated, if desired, but is usually used as a starting material for the other synthetic process without having been isolated or purified.

Carbapenem intermediate IV is reacted with a quarternary aminothiol of formula: 5

HS —- A — N —R

χθ

VII

where 5

A — JSL —R

is as defined above and X0 represents a counter anion. The reaction is carried out in an inert solvent such as acetonitrile, acetonitrile-dimethylforma-mide, tetrahydrofuran, tetrahydrofuran-H2 ° "acetonitrile-H2O or acetone, in the presence of a

CD.YD.MdC.CH. - 80 - SY-1735A

based. The nature of the base is not critical. Suitable bases include sodium hydroxide, diisopropylamine, 1,8-diazabicyclo / 5.4.o7undec-7-ene, 1,5-diazabicyclo / 4.3.o7non-5-ene and tri (Ci-C ^ alkylamines such as triethylamine, tributylamine or tripropylamine. The reaction of intermediate IV and thiol VII can be carried out over a wide temperature range, for example from -15 ° C to room temperature, but is preferably at a temperature of about -15 ° C to + 15 ° C and most advantageously about 0 ° C.

The carbapenem obtained by the reaction of quaternary aminothiol VII with intermediate IV comprises an associated counter anion (for example (ο6η5ο) 2ρο ^>, Cl © or the anion associated with quaternary thiol) which can be replaced at this stage by another counter anion, for example a pharmaceutically more acceptable counter anion, according to conventional techniques. Alternatively, the counter anion can be removed during the later deprotection stage. When the quaternized carbapenem and the counter anion form an insoluble product, this can be separated by crystallization as it is formed and be collected in the purity state by filtration.

After the formation of the desired carbapenem, the radical protecting the carboxyl function of the compound I1 can optionally be removed according to conventional techniques, such as solvolysis, chemical reduction or hydrogenation. When the protective radical used is eliminable by catalytic hydrogenation, such as a p-nitrobenzyl, benzyl, benzhydryl or 2-naphthylmethyl radical, the intermediate 1 'in a suitable solvent such as dioxane-water-ethanol, tetrahydrofuran-diethyl ether- buffer, dipotassium tetrahydrofuran-hydrogen phosphate

CD.YD.MdC.CH. - 81 - SY-1735A

aqueous-isopropanol or a similar solvent can be reacted under a hydrogen pressure of 1 to 4 atmospheres in the presence of a hydrogenation catalyst such as palladium on carbon, palladium hydroxide, platinum oxide, etc., at a temperature of 0 to 50 ° C for about 0.25 to 4 hours. When is a radical such as the o-nitrobenzyl radical, photolysis is also suitable for deprotection.

Protective radicals such as the 2,2,2-trichloroethyl radical can be removed by moderate reduction using zinc. The protective allyl radical can be removed using a catalyst comprising a mixture of a palladium compound and triphenylphosphine in a suitable aprotic solvent such as tetrahydrofuran, diethyl ether or methylene chloride. Similarly, other conventional radicals protecting the carbo-xyl function can be eliminated according to methods well known to the specialist. Finally, as already indicated, the compounds of formula I 'where R ^' represents a physiologically hydrolysable ester radical such as acetoxy-methyl, phthalidyl, indanyl, pivaloyloxymethyl, methoxymethyl, etc., can be administered directly to the host without deprotection because these esters are hydrolyzed in vivo under physiological conditions.

The intermediate thiols of formula VII can be prepared, for example, from the corresponding thiol-acetates of formula: if Λ - CH3CS-A— ^

CD.YD.MdC.CH. - 82 - SY-1735A

where A is as defined above, and represent a heterocyclic aromatic mono-, bi- or polycyclic radical containing a nitrogen atom which can be quaternized in the ring, which radical is joined to the radical A by a ring carbon atom. The thiol acetate is quaternized by reaction, in an inert organic solvent, such as diethyl ether, dichloromethane, dioxane, benzene, xylene, toluene or a mixture of these, with an alkylating agent. suitable of formula: r5-X 'where r5 * is as defined above and X' represents a conventional labile radical such as halo (chloro, bromo or iodo, but preferably iodo) or a sulphonic ester radical such as mesylate, tosylate or triflate. The temperature for the alkylation reaction is not critical and temperatures from about 0 ° C to 40 ° C are preferred.

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

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

CD.YD.MdC.CH. - 83 - SY-1735A

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

As in the case of other antibiotic 3-lactams, the compounds of general formula I can be converted according to known techniques into pharmaceutically acceptable salts which, for the purposes of the invention! vention, are substantially equivalent to non-salified compounds. For example, one can dissolve a compound of formula I where r2 represents an anionic charge in an appropriate inert solvent ion and then add an equivalent of a pharmaceutically acceptable acid. The desired acid addition salt can be isolated according to conventional techniques, for example precipitation by a solvent, lyophilization, etc. When other basic or acidic functional radicals are present in the compound of formula I, base addition salts and pharmaceutically acceptable acid addition salts can be prepared in an analogous manner according to known techniques.

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

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

SY-1735A

CD.YD.MdC.CH. - 84 - represents a physiologically hydrolyzable ester radical or else a compound of formula I, where r2 represents a conventional radical protecting the carbo-xyl function can be converted into the corresponding compound in the formula of which r2 represents a hydrogen atom , an anionic charge or a physiologically hydrolyzable ester radical, or else a pharmaceu-tically acceptable salt of this compound.

The new carbapenem derivatives of general formula I, where r2 represents a hydrogen atom, an anionic charge or a physiologically hydrolysable radical protecting the carboxyl function, as well as their pharmaceutically acceptable salts, are powerful antibiotic agents against different bacteria gram-positive and gram-negative and can be used, for example, as additives for animal feed to promote growth, as preservatives for food, as bactericides in industrial applications, such as water-based paints and white stationery waters to hinder the growth of harmful bacteria, as well as disinfectants for the destruction of harmful bacteria or for inhibiting their growth on medical and dental equipment. However, they are especially useful for the treatment of infectious diseases caused in humans or other animals by gram-positive or gram-negative bacteria.

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

CD.YD.MdC.CH. - 85 - SY-1735A

the topical route and the parenteral route (for example by intravenous or intramuscular injection). The pharmaceutical compositions can be presented in solid form such as capsules, tablets, powders, etc. or in liquid form such as solutions, suspensions or emulsions. The compositions for injection, which is the preferred route of administration, may be presented in unit dose ampoules or in multidose containers and may contain accessory agents such as suspending agents, stabilizers and dispersants . The compositions can be ready for administration or presented in the form of a powder to be reconstituted at the time of administration with an appropriate vehicle such as sterile water.

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

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

t

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h., ο ,, ΪΓ σιιηιη r-> c \ oor-i-c <3icocor-cnr-i <o <n "η" · η o

P Φ ω -P P ...... ........ * * 3Ô (E

O'dpC \ ^ oo ^ init ^ oicovDO ^ ’^ invDinin ^ iH’ ^ r'CD'Oix! "J

. Ë m iHrHrHrH riHriHNrlHHHHrlrlHrlMM J) fi H

„G“ J n u œ “JS .2 M 3 c v co

^ r +> § <d C φ P

. > d rr Ό P · Η O

5 L -h u> »S‘ d io d i g § c 'Φ3 · Η0)

ϋ5 O »» EU

rn 10 -H -H O) -M

2 a + J h CD * 0 (Ö 5 m <0 -H <D -

Ti ® Vi P '(D lÎH

2, +) = = = 3> H

? S "<CÛO r -) <D ^ (ô

5 5 -H = =: OH / iO

g ‘JJ C» ® Ό

w 2, -ri onn ^ inmin t ^ -cooio Μ Ό C

.,? g HNOl ^ lfMC ^ OlOtHHHr ^ HHH H H H M + J CO

P 5 Ό C +> O Oi 5 5 id> cu φφΦφΦΦΦφΦΦΦΦΦΦΦΦΓ-'ΦΦΦΦΟβαω J “(0 i—! I — fi — li — It — li — li — I i — I i—! 1 — I rl Η HHI— \ H CO HH i — II — I CD O CD Φ ^^ co o ααααα & ο, α & Οιαα & Οιαί & ^ ααιαα ω φ m S w »Ol HEËËEËËËËËEEEEEËOgËËË» cm 2 pg φφφφφφφφφφφφφφφφ φφφφ'φφμο 5 ao xxxKxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx u

£ 2 ^ CO

% O rd + j <• c o>

He II

CO CO

φ Φ * P J * *

C3D.YD.MdC.CH. - 102 - SY-1735A

The following examples illustrate the invention without limitation.

EXAMPLE Preparation of the internal salt hydroxide of l-methyl-4- / 2-carboxy-6 << - / i (R) -hydroxyéthyl7-7-oxo-l-azabicyclo- / 3.2.07hept-2-en-3-thiométbyl7pyridinium T. / v. e -CH3 h * —Sa, ·

0Ξ E

- \ _ _ 7 çf N '' "C02pK3

OF

ECHz- / ^

1 I ZW

2

OH

! H J-- 1 // W xe <-K N-CH, 1 [J I ^ = / 3 I-K_ ^

// ^ CO, pNB

0 2 ‘3 GNP = -N02

CD.YD.MdC.CH. - 103 - SY-1735A

Cooled to -10 ° C in a nitrogen atmosphere a solution of 673 mg (1.86 millimole) of 6oi- / l- (R) -hydro-xyethyl7 * -3, 7-dioxo-l-azabicyclo / ~ 3.2 .0 / hept-2-ene-2-car-boxylate of p-nitrobenzyl (1) in 10 ml of acetonitrile. To this is added a solution of 245 mg (1.90 millimole) of diisopropylethylamine in 1 ml of acetonitrile and then dropwise 510 mg (1.90 millimole) of diphenyl chlorophosphate in 1 ml of acetone nitrile in 2 minutes. The resulting solution is stirred at -10 ° C for 15 minutes to obtain 3- (diphenyl-phosphoryloxy) -60 (- ^ 1- (R) -hydroxyethyl / -7-oxo-1-azabicy-clo / * 3.2. P-Nitrobenzyl Q7hept-2-ene-2-carboxylate A solution of 245 mg (1.90 millimole) of diisopropylethylamine in 0.5 ml of acetonitrile is added to this solution, followed by a solution of 270 mg (2, 16 millimoles) of 4-mercaptomethylpyridine in 0.5 ml of acetonitrile The reaction mixture is stirred at -10 ° C for 60 minutes and the resulting white precipitate is collected by filtration and washed with 5 ml of ice-cold acetonitrile to collect 660 mg (yield of 76%) of compound 2 presenting in white crystals, mp 145 ° C.

NMR (DMSO-6) 6: 1.20 (3H, d, J = 6.0Hz), 3.2-3.4 (3H, m), 3.7-4.1 (2H, m), 4 , 25 (2H, s), 5.05 (1H, d, J = 4.0Hz), 5.25 (1H, d, J = 14.0Hz), 5.48 (1H, d, J = 14, 0Hz), 7.40 (2H, d, J = 5.5Hz), 7.70 (2H, d, J = 8.5Hz), 8.23 (2H, d, J = 8.5Hz) and 8, 58 (2H, d, J = 5.5Hz).

IR (KBr) \? max î 3400, 1790, 1695 and 1600 cm "1.

Analysis for C22H21N3O6S

Calculated: C, 58.01, H, 4.56, N, 9.12, S, 7.04%

Found: C, 57.74, H, 4.56, N, 9.58, S, 7.21%.

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

CD.YD.MdC.CH. - 104 - SY-1735A

under vacuum to obtain a slightly yellow solid which is triturated in diethyl ether to obtain 779 mg (90% yield) of compound 3 ^ in the form of a white amorphous solid, m.p. 130eC (decomposition).

NMR (DMSO-6) 6: 1.15 (3H, d, J = 6.0Hz), 3.2-3.4 (3H, m), 3.7-4.1 (2H, m), 4 , 25 (3H, s), 4.30 (2H, s), 5.25 (1H, d, J = 14.0Hz), 5.50 (1H, d, J = 14.0Hz), 7.70 (2H, d, J = 9.0Hz), 8.10 (2H, d, J = 7.0Hz), 8.25 (2H, d, J = 9.0Hz) and 8.90 (2H, d, J = 7.0 Hz).

IR (KBr) l ^ max: 3400, 1770, 1690 and 1640 cm ~ l.

Analysis for C23H24N3O6SI.H2O

Calculated: C, 44.39, H, 4.22, N, 6.82, S, 5.20%

Found C, 44.66, H, 4.01, N, 6.84, S, 5.64%.

'N-CH- pi N - "2;' · ρΓΥ" Ό “· g ~ S‘ —CO * 4

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

CD.YD.MdC.CH. - 105 - SY-1735A

10% and the mixture is hydrogenated in a Parr shaker for 45 minutes at 276 hPa. The mixture is filtered and the catalyst is washed with water (2x10 ml). The mixture of filtrate and washing water is extracted with diethyl ether (150 ml), then lyophilized to obtain a brown powder. This crude product is purified on a phase inversion column C ^ g BONDAPAK (30 g) (Waters Associates), which is eluted with water, under a pressure of 55 kPa. Each fraction (20 ml) is examined by high pressure liquid chromatography and the fractions having an absorption in the ultraviolet at Xmax = 300 nm are collected, then they are lyophilized to collect 135 mg (yield of 32%) of the desired compound 4 which is a slightly yellow solid. NMR (D20) <5: 1.25 (3H, d, J = 6.0Hz), 2.7-3.2 (3H, m), 3.40 (1H, q, J = 9.0 and 2 , 5Hz), 3.9-4.2 (2H, m), 4.40 (3H, s), 4.72 (2H, s), 8.10 (2H, d, J = 6.0Hz) and 8.72 (2H, d, J = 6.0Hz).

JR (KBr) t max: 3400, 1755, 1640 and 1590 cm “l.

UvAmax (H20): 2.96 nm (£ = 7782), 258 nm (£ = 6913).

EXAMPLE 2.- 0H, -ve I ^ // w V ·. / X. _SCHACH * / N-CH, (R) J | \ = - / J-N- ^ 0 C02

CD.YD.MdC.CH. - 106 - SY-1735A

OH K2 (W 'S—— ”

_NS

// ο 1

OH

VT -> —N-L--.

O CO-PNB

2

OH

J "'I — i ^^ Y'5“ 2®2' \ 3 J-N - ^

WHERE C02? NB

3 PNB = p-Nitrobenzyl.

Nitrogen is bubbled at room temperature for 5 minutes in a suspension of 1.1 g (2.93 millimoles) of the diazo-compound _1 in 30 ml of dry benzene. 25 mg of dimeric rhodium acetate are added to the suspension and the mixture is heated to reflux for 45 minutes. The hot solution is diluted with ethyl acetate (25 ml), filtered to separate the catalyst and the filtrate is evaporated to dryness to obtain ketone 2 in the form of a white solid. This is dissolved in dry acetonitrile (20 ml) and

CD.YD.MdC.CH. - 107 - SY-1735A

the solution is cooled to -10 ° C. Under this atmosphere of nitrogen, diisopropylethylamine (417 mg, 3.2 millimoles) is added to this solution first, then 810 mg (3.0 millimoles) of diphenyl chlorophosphate and the reaction mixture is stirred at -10 ° C for 20 minutes. Then added to this reaction mixture diisopropylethylamine (420 mg, 3.2 millimoles) and 2- (4-pyridyl) ethanethiol (560 mg, 4.03 millimoles) in 2 ml of acetonitrile / 0. Org. Chem. 26; 82 (1961) Ludwig Bauer and Libero A. Gardella JtJ. The reaction mixture is stirred for 1 hour between -5 ° C and -10 ° C, then diluted with methylene chloride (100 ml) and washed thoroughly with brine-water (III), H3PO4 at 4%, 5% NaHC03, water and brine. The organic phase is dried (MgSO 4) and evaporated to collect a white solid. The solid is washed with diethyl ethe hexane (1: 1) and dried under high vacuum to isolate 901 mg (63.9%) of compound 3.

IR (KBr) ’tf max: 1790 and 1690 cm" l.

NMR (CDCI3 / DMSO) ό: 1.20 (3H, d, J = 3.0Hz, CH3), 2.8-3.2 (7H, m), 3.9-4.4 (2H, m) , 5.1 (1H, d), 5.4 (2H, q), 7.3 (2H, d,), 8.5 (2H, q), 7.76 (2H, d) and 8.3 (2H, q).

B.

J ~: 15-S: o2pnb 3 \

CD.YD.MdC.CH. - 108 - SY-1735A

OH

I Ie <^ ^ DD - CH 3

0 / ^ C02PKS

_4

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

IR (KBr) l ^ max: 1765 and 1690 cm ~ l.

NMR (DMSO) 6: 1.3 (3H, d, J = 3.0Hz), 3.1-3.7 (7H, m), 4.1 (3H, m), 4.3 (3H, s ), 5.38 (2H, d, J = 7.0Hz), 8.1 (2H, d, J = 3.0Hz), 8.9 (2H, d, J = 3.0Hz), 7.6 (2H, d, J = 4.0Hz) and 8.2 (2H, d, J = 4.0Hz).

c * Te «‘ * 1- (H) \ I 1 I -7

/ 7 K CO-PNB

0 2

AT

J - »- ^ co, e 0 S 2

CD.YD.MdC.CH. - 109 - SY-1735A

265 mg (1.51 millimole) of dibasic potassium phosphate, 190 mg (1.9 millimole) of potassium hydrogen carbonate and 800 mg of 10% palladium on carbon are added to carbapenem 4 (920 mg, 1 , 47 millimole) dissolved in 90 ml of tetrahydrofuran, 90 ml of diethyl ether and 90 ml of water. The compound is hydrogenated for 1 hour at 310 kPa. The catalyst is separated by filtration on CELITE and the filtrate is washed with diethyl ether (3 × 25 ml). The aqueous layer is lyophilized to collect a brown material which is then purified twice by chromatography on a phase inversion column C ^ g BONDAPAK (Waters Associates) of 12 g to collect 55 mg of compound J5.

IR (KBr) Vmax: 1750 and 1640 cm "!.

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

EXAMPLE 3.

Preparation of 3- (N-methylpyridine-3-yl-methanethio) -6 <Κ- / 1 · - (R) -hydroxyethylj-7-oxo-l-azabicyclo (3.2.0) -hept-2-ene-2 -carboxylate

0H

A-r "\, Os- 0 I 0 C02u

CD.YD.MdC.CH. - 110 - SY-1735A

. r.

"U>‘ - <I 0 I i> o - clPCOg ° 2 ^ CO ^ pNB HSW ^ K ^: 5

OH

• ^ p ”-o

C02pNB

19 3- (Pyridine-3-yl-methanethio) -6Q (- / 1- (R) -hydroxyéthyjj -7-oxo-l-azabicyclo (3.2.0) - hept-2-ene-2-carboxylate p- nitrobenzyl

A solution of 377 mg (2.9 millimoles) of diisopropylethylamine in 1 ml of acetonitrile is added, then 786 mg (2.9 millimoles) of diphenyl chlorophos-phonate in 1 ml of acetonitrile, in an atmosphere of nitrogen, 'to a solution cooled to 0 ° C of 925 mg (2.66 millimoles) of the ketone intermediate! 5 in 14 ml of acetonitrile. The resulting solution is stirred for 15 minutes at 0 ° C, then added with a solution of 377 mg (2.9 moles) of 3-mercaptomethylpyridine / prepared as described in Can.

J. Chem., 56, 3968 (1978/7 in 2 ml of acetonitrile. The reaction solution is stirred for 90 minutes at 0 ° C. The precipitate is collected by filtration and washed

CD.YD.MdC.CH. - 111 - SY-1735A

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

NMR (DMSO-6) 0: 1.30 (3H, d, J = 6.0Hz), 3.4-4.2 (5H, m), 4.25 (2H, s), 5.1 (1H , d, J = 4.5Hz), 5.40 (2H, ABq, J = 14.4Hz), 7.2-8.5 (8H, m).

IR (KBr) L ^ max: 3500, 1775 and 1580 cm * 1.

Analysis for C22H21N3O6S1

Calculated ï C, 58.01, H, 4.65, N, 9.23, S, 7.04%

Found: C, 57.19, H, 5.19, N, 8.76, S, 7.08%.

0H

-r ^ \ J | 1 “s1

0 J

19 C02pNB

0H

r, “3 ο I i0

C0, pNB

20

Pd / C, H2

OH V

J Π © J— «· ^ CH3 0 -2Θ 21

CD.YD.MdC.CH. - 112 - SY-1735A

3- (N-Methylpyridine-3-yl-methanethio) -β (Χ- / l- (R) -hydroxyéthy37-7-oxo-l-azabicyclo (3.2 "0) -hept-2-ene-2-carboxylate

5 ml of methyl iodide are added to a solution of 730 mg (1.56 millimoles) of compound Γ9 in 120 ml of acetone and the reaction mixture is stirred for 18 hours at room temperature. The precipitate is collected by filtration and washed with acetone (10 ml) to obtain 940 mg (100% yield) of the quaternized pyridine 20 ^ which is a slightly yellow powder.

NMR (DMSO-d6) 6: 1.25 (3H, d, J = 5.8Hz), 3.6-4.3 (5H, m), 4.20 (3H, s), 4.25 (2H , s), 5.25 (1H, d, J = 7.2Hz), 5.40 (2H, ABq, J = 12.16Hz), 7.6-9.2 (9H, m).

IR (KBr) i ^ max: 3300, 1765 and 1690 cm “!.

Analysis for C23H24N306SiIi

Calculated ï C, 46.24, H, 4.05, N, 7.03, S, 5.37%

Found: C, 45.82, H, 4.11, N, 6.87, S, 6.10%.

200 mg of potassium bicarbonate and 349 mg of dibasic potassium phosphate in 90 ml of water are added, then 1.0 g of palladium on carbon to a solution of 933 mg (1.6 millimole) of compound in 90 ml of tetrahydrofuran and 90 ml of ether. The mixture is hydrogenated in a Parr shaker for 45 minutes at 310 kPa. The mixture is filtered on a layer of CELITE and the catalyst is washed with water (2x10 ml). The mixture of filtrate and washing waters is extracted with ether (2 × 100 ml) and lyophilized to obtain a yellow solid which is purified on a column for inversion of phase C ^ g BONDAPAK (Waters Associates) (8. g) which is eluted with 5% acetonitrile in water under a pressure of 55 kPa. Each fraction of 15 ml is examined by high pressure liquid chromatography and the fractions are collected.

CD.YD.MdC.CH. - 113 - SY-1735A

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

NMR (° 20) 6: 1.25 (3H, d, J = 7.0Hz), 3.12 (2H, dd, J = 7.9Hz, 1.6Hz), 3.42 (2H, q, J = 7.2Hz, 1.6Hz), 3.9-4.6 (3H, m), 4.25 (2H, s), 4.42 (3H, s) and 8.0-9.0 (4H , m). IR (KBr) l ^ max: 3400, 1750 and 1580 cm “1 · UVλ max (H20): 298 nm (6 = 8058).

Analysis for C16H18N2O4S1.2H2O

Calculated: C, 51.87, H, 5.44, N, 7.56%

Find ; C, 51.95, H, 5.66, N, 7.56%.

EXAMPLE 4.

Preparation of 3- (N-methylpyridine-3-yl-methanethio) -6ot- / l- (R) -hydroxyethyl7-7-oxo-l-azabicyclo (3.2.0) -hept-2-ene-2-carboxylate

0H

J-Cf 8 Ύ 0 * η ch 0 C0®

D <C

0H

\ 0 -j-V Cl P (00) 2 C02pNB * _5

CD.YD.MdC.CH. - 114 - SY-1735A

OH

C02pN * B

22 3- (Pyridine-3-yl-methanethio) -6ot- / l- (R) -hydroxyéthyl7-7-oxo-l-azabicyclo (3.2.0) -hept-2-ene-2-carboxylic acid p-nitrobenzyle

A solution of 377 mg (2.92 millimoles) of diisopropyletbylamine in 1 ml of acetonitrile is added, then 786 mg (2.90 millimoles) of diphenyl chlorophos-phonate in 1 ml of acetonitrile, in an atmosphere of nitrogen, to a solution cooled to 0 ° C of 925 mg (2.65 millimoles) of the ketone intermediate 5_ in 14 ml of acetonitrile. The resulting solution is stirred for 15 minutes at 0 ° C., then a solution of 377 mg (2.92 millimoles) of diisopropylethylamine in 1 ml of acetonitrile is added thereto, followed by 350 mg (3.0 millimoles) of 2 -mercaptomethylpyridine / prepared as described in Can. J. Chem., 56, 3068 (1978) 7 in 1 ml of acetonitrile. The reaction solution is stirred for 2 hours at -10 ° C. The precipitate is collected by filtration which is washed with 20 ml of methylene chloride to obtain 650 mg (yield of 54%) of the desired compound which is a yellow powder.

NMR (DMSO-d6) <5: 1.26 (3H, d, J = 7.0Hz), 2.7-3.5 (4H, m), 3.9-4.3 (2H, m), 4.2 (2H, s), 5.42 (2H, ABq, J = 14.4Hz) and 7.2-8.8 (8H, m).

IR (KBr) l ^ max: 3400, 1775 and 1690 cm “1 ·

CD.YD.MdC.CH. - 115 - SY-1735A

Analysis for C22H21N3O6S1

Calculated î C, 58/01, H, 4.65, N, 9.23, S, 7.04%

Find ; C, 57.56, H, 4.92, N, 8.94, S, 7.03%.

0H

xrry> X) 1_N // "acetone

C0_pNB

22

OH

0 * ch „Te

C02pNB

23

Pd / C H2 OH V

JL

Ύτ> Λ) en i © 0 1 a I «* C02 ° Œ3 24 3- (N-Methylpyridine-3-yl-methanetliio) -60C-

Zl- (R) -hydroxyethyl7‘-7-oxo-l-azabicyclo (3.2.0) - hept-2-ene-2-carboxylate

4 ml of methyl iodide are added to a solution of 650 mg (1.39 millimoles) of compound 2j2 in 100 ml of acetone. The reaction mixture is stirred

CD.YD.MdC.CH. - 116 - SY-1735A

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

NMR (DMS0-d6) <5: 1.26 (3H, d, J = 7.0Hz), 3.9-4.2 (2H, m), 4.4 (3H, s), 4.78 ( 2H, s), 5.2 (2H, d, J = 3.9Hz), .5.50 (2H, Abq, J = 14Hz) and 7.8-9.4 (8H, m).

IR (KBr) l <? Max: 3400, 1765 and 1690 cm ”l.

Analysis for C23H24N3O6S1I1

Calculated: C, 46.24, H, 4.05, N, 7.03, S, 5.37%

Found: C, 45.62, H, 4.27, N, 6.80, S, 5.30%.

215 mg (2.15 millimoles) of potassium bicarbonate and 374 mg (2.1 millimoles) of dipotassium hydro-genophosphate are added in 90 ml of water, followed by 1.0 g of 10% palladium on carbon at a solution of 1.0 g (1.167 millimole) of compound 23 ^ in 90 ml of tetrahydrofuran and 90 ml of ether. The mixture is hydrogenated in a Parr shaker for 45 minutes at 310 kPa. The mixture is filtered on a layer of CELITE and the catalyst is washed with water (2x10 ml). The mixture of filtrate and washing waters is extracted with ether (2x200 ml) and lyophilized to obtain a yellow solid which is purified on a column for inversion of phase C ^ g BONDAPAK (Waters Associates) (10 g ) which is eluted with 5% acetonitrile in water under a pressure of 55 kPa. Each 15 ml fraction is examined by liquid chromatography under high pressure and the fractions having an absorption in the ultraviolet at λ max 300 nm are combined, then lyophilized to obtain 390 mg (yield of 44%) of the desired compound. By recrystallization of this in water-acetone-ethanol, fine needles are obtained, m.p. 194-196 ° C (decomposition).

NMR (D2 °) Ô:! ”30 (3H, at, J = 6.2Hz), 3.2 (2H, q,

CD.YD.MdC.CH. - 117 - SY-1735A

J = 9, OHz, 3.6Hz), 3/46 (1H, q, J = 6.0Hz, 2.7Hz), 4.1-4.6 (3H, m), 4.60 (3H, s ) and 7.9-8.9 (4H, m).

IR (KBr) ïPmax: 3400, 1755 and 1590 cm-1.

UVλmax (H2 °): 298 r ™ (£ = 8058).

Analysis for C16h28N204Si.2H20

Calculated: C, 51.87, H, 5.44, N, 7.56%

Found: C, 51.37, H, 5.69, N, 7.37%.

EXAMPLE 5.

Preparation of 3- (N-methylpyridine-3-yl-ethanetliio) -6o (- / i- (R) -hydroxyéthylj -7-oxo-l-azabicyclo (3.2.0) -Îiept-2-ene-2-carboxylate

° H

* I CH

1 Θ * co2 S, -i \ ._ CTP (Qg)? CCLPNB L 1!

L ^ \ SH

5 54

CD.YD.MdC.CH. - 118 - SY-1735A

OH

^ vrVxJO

/ - * Ύ

COgPNB

53 3- (Pyr idine-3-yl-ethanethio) -6 ° (- / l- (R) -hydroxyéthyl7 - 7-oxo-l-azabicyclo (3.2.0) hept-2-ene-2-carboxy-late p-nitrobenzyl

710 mg (5.5 millimoles) of diisopropylethylamine in 1 ml of acetonitrile are added, followed by 1.4 g (5.0 millimoles) of diphenyl chlorophosphate in 1 ml of acetonitrile, in a nitrogen atmosphere, at a cooled solution of 1.78 g (5.0 millimoles) of the intermediate ketone 5 ^ in 25 ml of acetonitrile. The resulting solution is stirred for 20 minutes at 0 ° C. and then a solution of 710 mg (5.5 millimoles) of diisopropylethylamine in 1 ml of acetonitrile is added thereto, followed by a solution of 850 mg (6.1 millimoles) of thiol 54 / prepared as described in J. Org. Chem., 26, 82 (1961) 7 in 2 ml of acetonitrile. The reaction solution is stirred for 60 minutes at 0 ° C. The precipitate is collected by filtration which is washed with methylene chloride (20 ml) to obtain 1.3 g (57%) of the desired product which is a yellow solid.

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

IR (KBr) V? Max î 3400, 1780 and 1680 cm “!.

'CD.YD.MdC.CH. - 119 - SY-1735A

OH

'Vr'Y s ^ O - * J-' -f

C02PNB

! 3

OH

A ^ jA

r] ©

CO / NB CH ~ J

Pd / C

Ho I2 ®

OH

1 r ^ N

; o® <* 3 56

CD.YD.MdC.CH. - 120 - SY-1735A

3- (N-Methylpyridine-3-yl-ethanethio) -6C (- /Ï-(R)-hydroxyéthyl7-7-oxo-l-azabicyclo(3.2.0)- hept-2-ene-2-carboxylate

5 ml of methyl iodide are added to a solution of 800 mg (1/7 millimole) of compound 53 ^ in 50 ml of acetonitrile. The reaction mixture is stirred for 48 hours at room temperature. The precipitate is collected by filtration and washed with acetonitrile (15 ml) to obtain 810 mg (yield of 76%) of the quaternized pyridine _55 which is a slightly yellow powder.

NMR (DMSO-d6) <5: 1.20 (3H, d, J = 5.6Hz), 3.2-4.3 (9H, m), 4.20 (3H, s), 5.26 and 5.55 (1H each, Abq, J = 15Hz) and 7.8-9.2 (8H, m).

IR (KBr) l? Max: 3400, 1770 and 1690 cm-1.

100 ml of a buffer solution of pH 7.0 are added, then 1.0 g of 10% palladium on carbon to a solution of 790 mg (1.27 mmol) of compound J55 in 100 ml of tetrahydrofuran and 100 ml of 'ether. The mixture is hydrogenated in a Parr shaker for 40 minutes at 276 kPa. The mixture is filtered on a layer of CELITE and the catalyst is washed with water (2x10 ml). The mixture of filtrate and ether washings is extracted (3 × 100 ml) and lyophilized to obtain a yellow powder which is purified on a Ci8 BONDAPAK column (Waters Associates) (30 g) which is eluted with 10% acetonitrile in water at a pressure of 55 fcPa.

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

CD.YD.MdC.CH. - 121 - SY-1735A

NMR (D20) 6I 1.25 (3H, <3, J = 6.2Hz), 3.1-3.6 (7H, m), 4.0-4.3 (2H, m), 4.32 (3H, s) and 7.8-8.9 (4H, m).

IR (KBr) l ^ max: 3400, 1750 and 1590 cm-1.

UV ^ max (Η20) ϊ 300 nm (£ = 8108).

EXAMPLE 6.

Preparation of 3- (l-propylpyridine-4-yl-methanethio) -60 (- / 1- (R) -hydroxyéthyjj ^ -oxo-l-azabicyclo (3.2.0) -hept-2-ene-2-carboxylate

OH

γΌ- · CO ©

° H OH

p> -

C02pNB C02pNB

£ 51 3- (Pyr idine-3-yl-methanethio) -6 <X- / I- (R) -hydroxyethyl7-7-oxo-l-azabicyclo (3.2.0) -hept-2-ene-2-carboxylate p-nitrobenzyl

A solution of 673 mg (1.86 millimole) of 6o (- / "(R) -hydroxy-ethyl7-3,7-dioxo-1-azabicyclo / 3.2) is cooled to -10 ° C. in a nitrogen atmosphere. > P-nitrobenzyl (_5) 7hept-2-ene-2-carbo-xylate in 10 ml of acetonitrile, then add a solution of 245 mg (1.90 millimole) of diisopropylethylamine in 1 ml of acetonitrile, then drop drop 510 mg (1.90 millimole) of chlorophos-

CD.YD.MdC.CH. - 122 - SY-1735A

diphenyl phate in 1 ml of acetonitrile, in 2 minutes. The resulting solution is stirred for 15 minutes at -10 ° C to obtain 3- (diphenylphosphoryloxy) -6o (- / i- (R) -hydroxyéthyl7-7-oxo-l-azabicyclo- (3.2.0) hept-2 p-nitrobenzyl ene-2-carboxylate A solution of 245 mg (1.90 millimoles) of diisopropylethylamine in 0.5 ml of acetonitrile is added to this solution, followed by a solution of 270 mg (2.16 millimoles) of 4-mercaptomethylpyridine in 0.5 ml of acetonitrile. The reaction mixture is stirred at -10 ° C. for 60 minutes and the resulting white precipitate is collected by filtration and washed with 5 ml of ice-cold acetonitrile to collect 660 mg ( yield of 76%) of compound _51 presenting in white crystals, mp 145 ° C.

NMR (DMSO-d6) 6: 1.20 (3H, d, J = 6.0Hz), 3.2-3.4 (3H, m), 3.7-4.1 (2H, m), 4 , 25 (2H, s), 5.05 (1H, d, J = 4.0Hz) 5.35 (1H, d, J = 14.0Hz), 5.48 (1H, d, J = 14.0Hz ), 7.40 (2H, d, J = 5.5Hz), 7.70 (2H, d, J = 8.5Hz), 8.23 (2H, d, J = 8.5Hz) and 8.58 (2H, d, J = 5.5Hz).

IR (KBr) 1? Max s 3400, 1790 and 1695 cm "!.

Analysis for C22H21N3O6S

Calculated: C, 58.01, H, 4.56, N, 9.23, S, 7.04%

Found: C, 57.74, H, 4.56, N, 9.58, S, 7.21%.

0H

Vr> o - ~ Λ> / ÿ \ - / acetone

0 Na I

C02pNB

51

CD.YD.MdC.CH. - 123 - SY-1735A

OH

j — K W

0 C02pNB I “52 3- (1-Allylpyridine-4-yl-methanethio) -6 <* - / 1- (R) -hydroxyethyl7-7-oxo-l-azabicyclo (3.2.0) - hept-2-ene -2-carboxylate

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

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

IR (KBr) Vmax: 3400, 1770 and 1690 cm “1.

Analysis for C25H26N3O6S1I1

Calculated: C, 48.16, H, 4.21, N, 6.74, S, 5.15%

Found: C, 48.55, H, 4.46, N, 6.69, S, 5.15%.

0H

\ j-> P d / C

C02pNB I "52

CD.YD.MdC.CH. - 124 - SY-1735A

OH

Vr- \

Ar XV

Co2- S3 3- (l-Propylpyridine-4-yl-methanethio) -60 (- / 1- (R) -hydroxyéthyl7-7-oxo-l-azabicyclo (3.2.0) hept-2-ene-2-carboxylate

100 ml of buffer solution of pH 7.0 are added, then 1.0 g of 10% palladium on carbon to a solution of 1.27 g (2.15 millimoles) of compound 52 in 100 ml of tetrahydrofuran and 100 ml of 'ether. The mixture is hydrogenated in a Parr shaker for 40 minutes at 276 kPa. The mixture is filtered on a layer of CELITE and the catalyst is washed with water (2x10 ml). The mixture of filtrate and washing waters is extracted with ether (3 × 100 ml) and lyophilized to obtain a yellow powder which is purified on a column of C ^ q BONDAPAK (Waters Associates) (40 g). eluted with 10% acetonitrile in water under a pressure of 55 kPa. Each fraction of 15 ml is examined by liquid chromatography under high pressure and the fractions having an absorption in the ultraviolet at ^ max 300 nm are combined, then lyophilized to obtain 48 mg (yield of 6%) of the desired compound which is a yellow powder.

NMR (D20) 6: 0.95 (3H, t, J = 7.5Hz), 1.25 (3H, d, J = 7.0Hz), 2.05 (2H, sextuplet, J = 7.5Hz) , 3.10 (2H, dd, J = 10Hz, 2.5Hz), 3.35 (1H, dd, J = 6.5Hz, 2.5Hz), 4.0-4.8 (6H, m), 7.1 (2H, d, J = 6.0Hz) and 7.80 (2H, d, J = 6.0Hz). IR (KBr) i ^ max: 3400, 1750 and 1590 cm ~ l.

CD.YD.MdC.CH. - 125 - SY-1735A

Analysis for C18h22N204S.2H20

Calculated: C, 54.52, H, 6.10, N, 7.0%

Found s C, 54.32, H, 6.03, N, 6.99%.

EXAMPLE 7.

Preparation of 3- (N-methyl-3-methylpyridine - 2-methane-thio) -6c <- / l- (R) -hydroxyethyl7 ~ 7-oxo-l-azabicyclo- (3.2.0) hept-2- ene-2-carboxylate

OH

0 lop r ^ YCH3 1) hA „2 ^ -> lis.

2) NaOH HCl 37 3-Methyl-2-mercaptomethylpyridine

A solution of 2.45 g (17.0 millimoles) of the chlorinated compound 36 and 1.37 g (18.0 millimoles) of thiourea in 60 ml of absolute ethanol is heated at reflux for 5 hours. By evaporation of the ethanol, then addition of ether, 3.08 g (72% yield) of the isothiouronium salt are obtained which is dissolved in 10 ml of water containing 1.44 g (26 millimoles) d hydroxide

CD.YD.MdC.CH. - 126 - SY-1735A

sodium. The solution is then heated at 100 ° C for 5 minutes in a nitrogen atmosphere. The reaction mixture is cooled to 5 ° C, adjusted to pH 6.4 by addition of acetic acid and extracted with ether (4x50 ml). The mixture of ethereal extracts is washed with 5% aqueous sodium bicarbonate and with brine. By evaporating the dried solvent (MgSO 4), 1.4 g (83% yield) of the 3T thiol are obtained in the form of a yellow oil which is used in the following stage without further purification.

NMR (CDCI3) <5: 2.20 (3H, s), 2.5-2.7 (1H, wide s), 3.8 (2H, t, J = 6.5Hz) and 6.9-8 , 2 (3H, m).

1)> -i- <

OH

A fi ττΛ ^ ο ciPcog) *, 4-N --- / 2) 0 ^ CH_. / v.

C02pNB 3 d] 5 h 37

OH

I ch

C02pNB

38

CD.YD.MdC.CH. - 127 - SY-1735A

3- £ 3-Methylpyridine-2-yl-methanethio7- 6ü / ï- (R) -hydroxyethyl7-7-oxo-1-azabicyclo (3.2.0) - p-nitrobenzyl hept-2-ene-2-carboxylate

960 mg (5.8 millimoles) of diisopropyl pylethylamine in 2 ml of acetonitrile are added, followed by 1.4 g (5.8 millimoles) of diphenyl chlorophosphate in 2 ml of acetonitrile, in a nitrogen atmosphere, at a solution cooled to 0 ° C. of 1.74 g (5.0 millimoles) of the intermediate ketone 5_ in 25 ml of acetonitrile. The resulting solution is stirred for 20 minutes at 0 ° C., then a solution of 760 mg (5.8 millimoles) of diisopropylethylamine in 2 ml of acetonitrile is added thereto, followed by another 810 mg of mercaptomethyl-pyridine 37 in 3 ml acetonitrile. The reaction mixture is stirred for 1 hour at 0 ° C. The precipitate is collected by filtration which is washed with acetonitrile to obtain 1.56 mg (yield of 66%) of the desired compound which is a white solid, m.p. 145 ° C.

NMR (DMSO-d6) 6: 1/23 (3H, d, J = 6.5Hz), 2.30 (3H, s), 3.1-4.3 (6H, m), 4.35 (2H , s), 5.20 and 4.45 (1H each, ABq, J = 15.0Hz) and 7.3-8.4 (7H, m).

IR (KBr) i? Max: 3400, 1767 and 1695 cm-1.

Analysis for C24H26N3 ° 9S2F

Calculated: C, 47.91, H, 4.69, N, 6.98, S, 10.66% Found: C, 47.72, H, 4.34, N, 6.72, S, 11, 22%.

0H

A ^ 1-fA JA FS03CH3 j 1 ^

C02pNB

38

CD.YD.MdC.CH. - 128 - SY-1735A

OH

Cli3 £ Q ~ s ~ Ù CO_pNB CH „® 2 ^ ύ

Pd / C 39 Θ N / A „F

H ^ OH V 2 '© CH' ® C02U CH3 40 3- (N-Methyl-3-methylpyridine-2-yl-methanethio) -6 ** - £ X ~ (R) -hydroxyethyl7-7-oxo-l- azabicyclo (3.2.O) hept- 2-ene-2-carboxylate

270 mg (2.33 millimoles) of methyl fluorsulfonate are added to a solution of 680 mg (1.45 millimoles) of compound J8 in 120 ml of methylene chloride. The reaction mixture is stirred for 3 hours at room temperature. The precipitate is collected by filtration and washed with methylene chloride (5 ml) to obtain 840 mg (yield of 99%) of the quaternized pyridine _39 having white crystals.

NMR (DMSO-d6) ô: 1.15 (3H, d, J = 5.8Hz), 2.62 (3H, s), 3.2-4.4 (5H, m), 4.45 (3H , s), 4.60 and 4.82 (1H each, ABq, J = 9.2Hz), 5.30 and 5.46 (1H each, ABq, J = 12.8Hz) and 7.6-8, 9 (7H, m).

IR (KBr) l ^ max s 3400, 1750 and 1590 cm ~ l.

CD.YD.MdC.CH. - 129 - SY-1735A

Analysis for C24H24N3O9S2F

Calculated: C, 49.14, H, 4.47, N, 7.13, S, 11.43% Found: C, 49.56, H, 4.16, N, 7.26, S, 11, 03%.

100 ml of buffer solution of pH 7.0 is added, then 750 mg of 10% palladium on carbon to a solution of 810 mg (1.39 millimole) of compound 39 in 100 ml of tetrahydrofuran and 100 ml of ether. The mixture is hydrogenated in a Parr shaker for 60 minutes at 310 kPa in a cold room (4 to 6 ° C). We . filter the mixture on a layer of CELITE and wash the catalyst with ether (2x10 ml) · Extract the mixture of filtrate and washing liquor with ether (2x40 ml) and lyophilize it to obtain a yellow solid which is purified on a column of Ci8 B0NDAPAK (Waters Associates) (20 g) which is eluted with 5% acetonitrile in water under a pressure of 55 kPa. Each 15 ml fraction is checked by high pressure liquid chromatography and pn brings together the fractions having an absorption in the ultraviolet at λ max 300 nm, then they are lyophilized to collect 141 mg (yield of 30%) of the desired compound which is a yellow solid.

NMR (D20) <5: 1.24 (3H, d, J = 7.0Hz), 2.62 (3H, s), 3.2-3.5 (3H, m), 4.2-4, 4 (2H, m) 4.45 (3H, s), 4.50 and 4.59 (1H each, ABq, J = 12.6Hz), 7.82 (1H, q, J = 7.0Hz, 6 , 5Hz), 8.35 (1H, d, J = 7.0Hz) and 8.65 (1H, d, J = 6.5Hz). IR (KBr) l ^ max: 3400, 1750 and 1580 cm-1.

UvX max (H20) ï 296 nm (£ = 8014).

Analysis for C17H2oN204SiΛΗ20

Calculated: C, 57.85, H, 5.85, N, 7.94%

Found: C, 58.60, H, 5.86, N, 7.87%.

CD.YD.MdC.CH. - 130 - SY-1735A

EXAMPLE 8.

Preparation of 3- (2-methyl-N-methyltbiazol-4-yl-methanethio) -6ot- / J- (R) -hydroxyethyl 7-7-oxo-1-aza-bicyclo (3.2.0) hept-2-ene -2-carboxylate

OH

Vo-'O

OH

I 0 i ^ h -r ^ \ cipco0) 2 V0 -—>

O = HS I

C02pNB

w> s_

OH

C02pNB

9_

CD.YD.MdC.CH. - 131 - SY-1735A

3- / 3-Methylthiazol-4-yl-methanethig7-60 (- / 1- (R) -hydroxyethyl7-7-oxo-l-azabicyclo (3.2.0) hept-2-ene-2-carboxylic acid p-nitrobenzyl

0.83 ml (4.6 millimoles) of diisopropylethylamine is added, then 1.16 g (4.3 millimoles) of diphenyl chlo-rophosphate in 2 ml of acetonitrile, under nitrogen, to a solution cooled to 0 ° C of 1.4 g (4.0 millimoles) of the intermediate ketone in 12 ml of acetonitrile. The resulting solution is stirred for 30 minutes at 0 ° C to obtain 3- (diphenylphosphoryloxy) -60 (- / 1- (R) -hydroxyethyl / -7-oxo-1-azabicyclo (3.2.0) hept- P-nitrobenzyl 2-ene-2-carboxylate A solution of 0.83 ml (4.6 millimoles) of diisopropylethylamine in 2 ml of acetonitrile is added to this solution, followed by a solution of 0.62 g (4, 2 millimoles) of 2-methyl-4-mercaptomethylthiazole / prepared as described in J. Amer. Chem. Soc., 71, 3570 (1949d [7 in 3 ml of acetonitrile. The reaction solution is stirred for 40 minutes at 0 ° C. The precipitate is collected and washed with ether (30 ml) to obtain 943 mg of the desired compound which is a white solid.

NMR (CDC13) <5: 1.32 (3H, d, J = 7Hz), 2.68 (3H, s), 3.20 (2H, m), 3.76 (1H, d, J = 5, 5Hz), 4.16 (2H, s), 4.20 (1H, m), 5.40 (2H, q, J = 14Hz), 7.06 (1H, s), 7.68 (2H, d , J = 8Hz) and 8.24 (2H, d, J = 8Hz)).

IR (KBr) i? Max: 3500, 1770 and 1700 cm “!.

0H

Λ ^ ^ '1-r \ // s ch, oso9f! \ o | _y CH2C12 ο 1 -5

C0_pNB

L

CD.YD.MdC.CH. - 132 - SY-1735A

OK

002ρΝβ CH_ 12. fso3®

Pd / C, H2 OH v 0 'o 1 3 co2w ch3 3- (2-Methyl-N-methylthiazol-4-yl-methanethio) -6-of- / l- (R) -hydroxyethyl7-7-oxo-1 -azabicyclo (3.2. Q) hept-2-ene-2-carboxylate

0.27 ml (3.3 millimoles) of methyl fluoro-sulfonate is added to a solution of 525 mg (1.1 millimoles) of compound j) in 20 ml of methylene chloride. The reaction mixture is stirred for 90 minutes at room temperature. The precipitate is collected by filtration and washed with methylene chloride (50 ml) to collect 650 mg (100% yield) of the quaternized thiazole] L0 which is used without further purification in the following stage.

Thus, 100 ml of a buffer solution of pH 7.0 is added, then 500 mg of 10% palladium on carbon to a solution of compound JL0 in 100 ml of tetrahydrofuran and 100 ml of ether. The mixture is hydrogenated in a

Parr shaker for 45 minutes at 241 kPa. The mixture is filtered on a layer of CELITE

CD.YD.MdC.CH. - 133 - SY-1735A

and the catalyst is washed with water (2x10 ml). The mixture of filtrate and washing waters is extracted with ether (2 × 100 ml) and lyophilized to obtain a yellow powder which is purified on a column for inversion of phase C ^ g BONDAPAK (8 g) (Waters Associates ) which is eluted with 5% acetonitrile in water under a pressure of 55 kPa. Each fraction of 15 ml is checked by liquid chromatography under high pressure and the fractions having an absorption in the ultraviolet at X max 300 nm are combined, then they are lyophilized to collect 145 mg (yield of 48%) of the desired compound which is a pale yellow powder.

NMR (CDCl3) <5î 1.20 (3H, d, J = 7Hz), 2.92 (3H, s), 3.8 (1H, d, J = 3.5Hz), 3.20 (3H, d , J = 3Hz), 3.44 (1H, dd, J = lHz, J = 3.5Hz), 4.00 (3H, 5), 4.20 (3H, m), 4.36 (2H, m ) and 7.88 (1H, s).

IR (KBr) lXnax: 3400, 1750 and 1585 cm ~ l. υνλ max (H2O): 296 nm (6 = 7500).

Analysis for C15H18N2O4S2 · 2H2O

Calculated: C, 46.15, H, 5.64, N, 7.17, S, 16.41% Found: C, 46.50, H, 5.26, N, 7.13, S, 16, 20%. EXAMPLE 9.

Preparation of 3- (N, N'dimethylimidazol-2-yl-methane-thio) -6 {A- / Î- (R) -hydroxyéthyj ^ -7-oxo-l-azabicyclo- (3.2.0) hept-2 -ene-2-carboxylate

° H CH

I I 3 ©

CO O CHS

CD.YD.MdC.CH. - 134 - SY-1735A

CH3 CH

J AH <· l »V -> Q ~ - j HC1 HCl

- H

2-Mercaptomethyl-N-methylimidazole

7.1 g (60 millimoles) of N-acetylthiourea are added to a solution of 10.4 g (58 millimoles) of 2-chloromethyl-N-methylimidazole 31 ^ / prepared as described in J. Amer. Chem. Soc., 71, 383 (1949/7 in 200 ml of acetonitrile and the reaction mixture is heated under reflux for 90 minutes. The precipitate is filtered and washed with acetonitrile (20 ml) to obtain the isothiouronium salt which then dissolved in 120 ml of ethanol and heated under reflux for 18 hours under a nitrogen atmosphere, the reaction mixture is cooled to room temperature and concentrated in vacuo to a volume. about 60 ml and the precipitate is separated by filtration. By evaporation of the filtrate under vacuum, 2-mercaptomethyl-N-methylimidazole 32 ^ is obtained in the form of a yellow oil which is used in the next stage without further purification. .

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

CD.YD.MdC.CH. - 135 - SY-1735A

1) —N -

OH

I o "'' N - [" "Λ c {OÎ) 2 0Ρ» -> tî- *

"r ^ K

[Γ V-SH

HC1 s ïxH) 0 *

C02pNß 5J

3- / N-Methylimidazole-2-yl-methanetliio7-eo (- / l- (R) -hydroxyethyl7-7-oxo-l-azabicyclo (3.2.0) hept-2-ene-2-carboxylate

2f8 g (21.3 millimoles) of diisopropyl pylethylamine in 2 ml of acetonitrile are added, then 5.5 g (20.4 millimoles) of diphenyl chloropbosphate in 2 ml of acetonitrile, under a nitrogen atmosphere, to a solution cooled to 0 ° C of 7.24 g (20.3 millimoles) of the intermediate ketone 5 ^ in 35 ml of acetonitrile. The resulting solution is stirred for 15 minutes at 0 ° C. and then a solution of 4.1 g (3.0 millimoles) of diisopropylethylamine in 2 ml of acetonitrile, then 4.6 g (31.0 millimoles) is then added to it. thiol 32 / The reaction mixture is stirred for 60 minutes at 0 ° C.

CD.YD.MdC.CH. - 136 - SY-1735A

The white precipitate is collected by filtration and washed with methylene chloride (20 ml) to obtain

6.6 g (71% yield) of the desired compound which is a white solid, m.p. 142 ° C

NMR (DMSO-d6) Ô: 1.32 (3H, d, J = 7.0Hz), 3.2-4.5 (5H, m), 3.2 (2H, s), 3.9 (3H , s), 5.50 (2H, ABq, J = 14.0Hz), 7.65 (2H, d, J = 6.5Hz), 7.70 (2H, s) and 8.24 (2H, d , J = 6.6 Hz).

IR (KBr) Όmax: 3450, 1770 and 1690 cm-1.

Analysis for C2iH20N4 ° 6sl * 1 ^ H2 °

Calculated: C, 52.18, H, 4.79, N, 11.59%

Found: C, 52.22, H, 4.91, N, 12.16%.

Oïî Me A — 1 ^ \ / A αι3ι C ° 2PNB „

° H CH

NOT

0 ‘I © r C02pNB CH3 Ie 34

Pd / C, H2

OH V CH

Α-τλ _ / s ΓΟ w UU2 CH3 35

CD.YD.MdC.CH. "137 - SY-1735A

3- (N / N 'Dimethylimidazol-2-yl-methanethio) -6ot- / l- (R) -hydroxyéthyj7-7-oxo-l-azabicyclo (3.2.0) hept- 2-ene-2-carboxylate

20 ml of methyl iodide are added to a suspension of 1.34 g (3.0 millimoles) of compound 33 in 270 ml of acetone. The reaction mixture is stirred for 4 days at room temperature. The precipitate is collected by filtration and washed with acetone (20 ml) to obtain 1.70 g (yield of 96%) of the quaternized imidazole 34 which occurs in yellow crystals, m.p. 175-177 ° C.

NMR (DMSO-d6) 6: 1.10 (3H, d, J = 6.2Hz), 3.30 (2H, s), 3.2-4.3 (6H, m), 3.95 (6H , s), 5.45 (2H, ABq, J = 14Hz) and 7.65 (2H, d, J = 6.0Hz).

IR (KBr) l? Max ï 3400, 1750 and 1600 cm-1.

Analysis for C21H22N4O6S1

Calculated: C, 43.08, H, 9.60, N, 5.48%

Found: C, 43.02, H, 9.02, N, 5.44%.

120 ml of buffer solution of pH 7.0 are added, followed by 900 mg of CELITE palladium on 30% to a solution of 1.30 mg (1.86 millimole) of compound 34 in 120 ml of tetrahydrofuran and 120 ml of ether . The mixture is hydrogenated in a Parr shaker for 40 minutes at 276 kPa. The mixture is filtered on a layer of CELITE and the catalyst is washed with water (2x15 ml). The mixture of filtrate and washing waters is extracted with ether (3 × 100 ml) and lyophilized to obtain a yellow amorphous powder which is purified on a column of C ^ g BONDAPAK (Waters Associates) (30 g) which 'is eluted with 10% acetonitrile in water under a pressure of 55 kPa. Each 20 ml fraction is verified by high pressure liquid chromatography and the fractions having an absorption in the ultraviolet at Λ max 300 nm are collected, then they are lyophilized to obtain 220 mg (yield of 35%) of the compound

CD.YD.MdC.CH. - 138 - SY-1735A

searched for which is a yellow powder.

NMR (D20) 6: 1.12 (3H, d, J = 7.0Hz), 3.08 (1H, dd, J = 13.0Hz, 6.4Hz), 3.15 (1H, dd, J = 13.0Hz, 6.4Hz), 3.45 (1H, dd, J = 3.2Hz, 4.5Hz), 3.85 (6H, s), 4.1-4.3 (2H, iti), 4.40 (1H, d, J = 13.5Hz), 4.52 (1H, d, J = 13.5Hz) and 7.40 (2H, s).

IR (KBr) Vmax: 3500, 1750 and 1590 cm “l.

UV ^ max (H2O) s 296 nm (£ = 8411).

Analysis for ^ 5 ^ 9 ^ 043. ^ 0

Calculated: C, 51.68, H, 5.67, N, 12.06, S, 9.50% Found î C, 49.93, H, 5.94, N, 11.46, S, 9, 03%. EXAMPLE 10.-

Preparation of 3- (2,3,4-trimethylthiazol-5-yI-methane-thio) -6o (- / l- (R) -hydroxyéthyl7-7-oxo-l-azabicyclo- (3.2.0) hept-2 -ene-2-carboxylate

? H CH „CH

I Θ / 3 0> Θ C02u s CHTv c j!

V \ U Η, Ν ^ ΝΗ, SH

He | TJ KS0H ^ ^ CH, CH3 HCl 46 ’il 2,4-Dimethyl-5-mercaptoinethylthiazole

2.4 g (30 millimoles) of thiourea are added to a solution of 4.8 g (26.0 millimoles) of the chlorinated compound 46 / prepared as described in J. Amer. Chem.

CD.YD.MdC.CH. - 139 - SY-1735A

Soc., 104, 4461 (1982) 7 in 50 ml of absolute ethanol. The reaction mixture is heated at reflux for 18 hours. The precipitate is collected by filtration and washed with ether (20 ml) to obtain the isothiouronium salt which is dissolved in 22 ml of IN sodium hydroxide and which is heated at 100 ° C. for 4 minutes. in a nitrogen atmosphere. The reaction mixture is cooled to room temperature, adjusted to pH 7.0 with 1N hydrochloric acid and extracted with ether (3x50 ml). The mixture of ethereal phases is washed with water and with brine, then dried over MgS04 *

By evaporation of the dried solvent, 780 mg (yield of 49%) of thiol_47 are obtained in the form of a colorless oil which is used in the following stage without further purification.

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

J3> -, C <0H ^ ^ A ^ "\" I V, C] P (O0) 2 isi ^ ° ί / CH3 C0 pNB / S _ \\

S HsWyN

CH3 47

CD.YD.MdC.CH. - 140 - SY-1735A

OH

Xn s -. CH.

rrVsVxύ 4 o.V;

* PH

C02pNB S

il 3- / 2/4-Dimethylthiazol-5-yl-methanethio7-6ol- / I- (R) -hydroxyâthyl7-7-oxo-l-azabicyclo (3.2.0) hept-2-ene-2-carboxylate -nitrobenzyl

610 mg (4.7 millimoles) of diisopropyl pylethylamine in 1 ml of acetonitrile are added, followed by 1.15 g (4.3 millimoles) of diphenyl chlorophosphate in 1 ml of acetonitrile, in a nitrogen atmosphere, at a solution cooled to 0 ° C of 1.4 g (4.0 millimoles) of the intermediate ketone 5 in 25 ml of acetonitrile. The resulting solution is stirred for 20 minutes at 0 ° C. and then a solution of 610 mg (4.7 millimoles) of diisopropylethylamine in 1 ml of acetonitrile is added thereto, followed by 750 mg (4.7 millimoles) of thiol 47 in 2 ml of acetonitrile. The reaction mixture is stirred for 3 hours at 0 ° C. The precipitate is collected by filtration and washed with methylene chloride (20 ml) to obtain 1.14 g (65% yield) of the desired compound which is a white solid.

NMR (DMSO-d6) <5: 1.25 (3H, d, J = 6.4Hz), 2.30 (3H, s), 2.65 (3H, s), 3.1-3.4 ( 3H, m), 4.10 (1H, wide s), 4.0- 4.5 (3H, m), 5.25 and 5.50 (1H each, ABq, J = 4Hz), 7.68 ( 2H, d, J = 8.5Hz) and 8.25 (2H, d, J = 8.5Hz).

IR (KBr) D max: 3500, 1770 and 1690 cm-1.

CD.YD.MdC.CH. - 141 - SY-1735A

Analysis for C22H23N3 ° 6S2

Calculated: C, 53.73, H, 4.71, N, 8.57, S, 13.44% Found: C, 53.97, H, 4.74, N, 8.58, S, 13, 10%.

OH

C02pNB CH3 48

OH

1 c-, CH „C0„ tNB CH 0

50, F

49 3

Pd / C, H2 OH Ψ 1 c CH ~ π> -ΛΙθ Y- 50 3- (2,3,4-Trimethylthiazol-5-yl-methanethio) -63- / 1- (R) -hydroxyéthyjj-7-oxo -l-azabicyclo (3.2.0) hept-2-ene- 2-carboxylate

A solution of 0.98 ml (13 millimoles) of methyl fluorosulfonate in 2 ml of

CD.YD.MdC.CH. - 142 - SY-1735A

methylene chloride to a solution of 1.97 g (4.0 millimoles) of the chlorinated compound 48 in 180 ml of methylene chloride. The reaction mixture is stirred for 70 minutes at room temperature. The reaction mixture is poured into a solution of ether (400 ml) and pentane (100 ml). The precipitate is collected by filtration and washed with ether (20 ml) to obtain 1.6 g (65.5% yield) of the quaternized thiazole 49 in the form of a white powder.

NMR (DMSO-d6) 1/ 1/25 (3H, s, J = 6.5Hz), 2.45 (3H, s), 2.80 (3H, s), 3.2-4.5 (6H , m), 3.90 (3H, s), 5.30 (2H, wide s), 7.60 and 8.2 (1H each, d, J = 8.5Hz).

IR (KBr) l? Max: 3400, 1770 and 1690 cm-1.

Analysis for C23H26N3C> 9S3F ^ H20

Calculated: C, 45.09, H, 4.44, N, 6.86%

Found: C, 44.50, 4.38.74, N, 6.58%.

100 ml of a buffer solution of pH 7.0 is added, then 1.0 g of 10% palladium on carbon to a solution of 1.0 g (1.72 millimole) of compound 49 in 100 ml of tetrahydrofuran and 100 ml of ether. The mixture is hydrogenated in a Parr shaker for 40 minutes at 276 kPa. The mixture is filtered on a layer of CELITE and the catalyst is washed with water (2x10 ml). The mixture of filtrate and washing waters is extracted with ether (3 × 100 ml) and lyophilized to obtain a yellow powder which is purified on a column of C ^ g BONDAPAK (Waters Associates) (40 g) than eluted with 10% acetonitrile in water under a pressure of 55 kPa. Each fraction of 15 ml is checked by liquid chromatography under high pressure and the fractions having an absorption in the ultraviolet at λ max 300 nm are combined, then they are lyophilized to obtain 315 mg (yield of 50%) of the desired compound which is a yellow solid.

CD.YD.MdC.CH. - 143 - SY-1735A

NMR (D20) <5: 1.25 (3H, d, J = 7.0Hz), 2.25 (3H, s), 2.90 (3H, s), 3.0-3.30 (3H, m), 3.90 (3H, s) and 4.1-4.4 (4H, m).

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

UvXmax: (H2 °): 297 nm (£ = 8994).

Analysis for C15h19N304S.2H20

Calculated: C, 48.25, H, 6.09, N, 7.79%

Find ; C, 47.96, H, 5.83, N, 7.89%.

EXAMPLE Preparation of 3- / 2- (N-niethylthiazolium) inethylthio7-6oi- £ i .- (R) -hydroxyéfhyl7- oxo-l-azabicyclo (3.2.0) hept- 2-ene-2-carboxylate

OH

ο Θ © C02 CH3 (T / SoH SOClp ï Sî _1—> ^ HCl HCl 1? -H2n \ kh2 \ -J ”* ·

CD.YD.MdC.CH. - 144 - SY-1735A

eJ'V —► Cr-

NH

ZHC1 3 4 2-Mercaptomethylthiazole

3.60 g (26 millimoles) of hydroxymethylthiazole 1 are added at room temperature to a solution of thionyl chloride (3.81 ml, 52 millimoles) in chloroform (30 ml), then the solution is heated to 50 ° C for 2 hours. The chloroform is evaporated under vacuum to obtain a brown solid which is dissolved in 30 ml of absolute ethanol. Then added 2.04 g (26 millimoles) of thiourea. The mixture is heated at reflux for 18 hours. The precipitate is collected by filtration and washed with ethanol and ether to collect 3.4 g (55% yield) of the isothiouronium salt 3 ^. The isothiouronium salt 3 is dissolved in 30 ml of water and nitrogen is bubbled through the solution for 20 minutes. 1.10 g (27 millimoles) of sodium hydroxide are then added and the mixture is heated at 100 ° C for 2 minutes. The cooled solution was adjusted to 0 ° C at pH 6.0 using acetic acid, then extracted with ethyl acetate (2x35 ml). The organic layer is dried (MgSO 4 and evaporated under vacuum to obtain 0.75 g (42% yield) of thiol 4_ which is a yellow oil which is used without further purification.

NMR (CDC13) <5.1 2.1 (1H, t), 4.0 (2H, d, J = 10Hz), 7.27 (1H, d, J = 3.0Hz) and 8.85 (1H, d , J = 3.0 Hz).

CD.YD.MdC.CH. - 145 - SY-1735A

3H

'r — T ^ K Ί) VP

L> ~ o o J — w / ci-ftot), CT | _5 ”CO / MB 3) 5 4

Gold

r Y \ J

COgPNB

6 • N # 3-Z? (Thiazol) methylthio7-60 (- / 1 - (R) -hydroxyéthylj -7-oxo-l-azabicyclo (3.2.0) p-nitrobenzyl hept-2-ene-2-carboxylate

0.79 ml (4.4 millimoles) of diisopropylethylamine is added, then 1.17 g (4.4 millimoles) of diphenyl chlo-rophospbate, in a nitrogen atmosphere, to a solution cooled to 0 ° C. 1.4 g (4.0 millimoles) of the intermediate ketone 5 ^ in 8 ml of acetonitrile. The resulting solution is stirred for 30 seconds at 0 ° C to obtain 3- (diphenylphosphoryloxy) -6- / 1- (R) -hy-

CD.YD.MdC.CH. - 146 - SY-1735A

droxyethyl / -7-oxo-l-azabicyclo (3.2.0) hept-2-ene-2-car-boxylate of p-nitrobenzyl. To this solution is added a solution of 0.79 ml (4.4 millimoles) of diisopropyl pylethylamine in 2 ml of acetonitrile, then a solution of 0.72 g of thiol 4 in 2 ml of acetonitrile. The reaction solution is stirred for 60 minutes at 0 ° C, then diluted with 50 ml of ethyl acetate and washed with 30 ml of water, 20 ml of 10% aqueous H3PO4 and 30 ml of brine. By evaporation of the dried solvent (MgSO.4), a crystalline solid is obtained which is triturated in ether to collect 782 mg (yield of 42%) of the desired compound 6 ^ which is a white crystalline material, PF 158-160 ° C.

NMR (CDCI3) <5: 1.32 (3H, d, J = 7.0Hz), 3.28 (3H, m), 4.20 (2H, m), 4.36 (2H, s), 5 , 40 (2H, q), 7.40 (1H, d, J = 4.0Hz), 7.64 (2H, d, J = 8Hz), 7.76 (1H, d, J = 4.0Hz) and 8.24 (2H, d, J = 8Hz).

IR (KBrJl ^ max: 3500, 1770 and 1700 cm-1.

Analysis for C20H19N3O6S2

Calculated î C, 52.05, H, 4.15, N, 9.10, S, 13.89% Found: C, 52.35, H, 4.40, N, 8.72, S, 13, 90%.

J ..

s »J N — u

C02PNB

6

CD.YD.MdC.CH. - 147 - SY-1735A

CH

'V® | h © M / C ’FSO © DH.

5 W ί "3®.

3-Z2- (N-methylthiazolium)) xaethyltTiio7-60Î- / l- (R) - hydroxyethyl7-7-oxo-l-azabicyclo (3. 2.0) hept-2-ene-2-carboxylate

0.5 ml of methyl fluorosulfonate is added to a solution of 782 mg (1.36 millimole) of compound 6 in 55 ml of methylene chloride and the mixture is stirred for 90 minutes at room temperature. The precipitate is collected by filtration, which is washed with methylene chloride (30 ml) and with ether (20 ml) to collect 630 mg of the crude quaternized thiazole 1 which is used in the next stage without further purification.

Thus, 140 ml of a buffer solution of pH 7.0 is added, then 650 mg of 10% palladium on carbon to a solution of compound _7 in 140 ml of tetrahydrofuran and 120 ml of ether. The mixture is hydrogenated in a Parr shaker for 35 minutes at 207 hPa. The mixture is then filtered and the

CD.YD.MdC.CH. - 148 - SY-1735A

water catalyst (2x10 ml). The mixture of filtrate and washing waters is extracted with ether (2 × 150 ml) and lyophilized to obtain a yellow powder. The raw yellow powder is purified on a phase inversion column of C18 BONDAPAK (7 g) (Waters Associates) which is eluted with 5% acetonitrile in water under a pressure of 55 kPa. Each fraction of 15 ml is checked by liquid chromatography under high pressure and the fractions having an absorption in the ultraviolet at ^ max 300 nm are combined, then they are lyophilized to collect 23 mg (yield of 5%) of the desired compound which is a solid yellow amorphous.

NMR (D20) 6: 1.28 (3H, d, J = 7.0Hz), 3.12 (2H, d, J = 7.0Hz), 3.44 (1H, dd, J = l, 0Hz and 3.0Hz), 4.20 (3H, s), 4.24 (2H, m), 4.76 (3H, m), 8.12 (1H, d, J = 4Hz) and 8.24 (1H , d, J = Hz).

IR (KBr) Vrnax: 3400, 1740 and 1580 cnr *.

UV ^ max (H20) ï 292 nm (£ = 7285).

EXAMPLE 12.-

Preparation of 3- / Î (RS) -methyl-N-methylpyridine-3-yl-methanethiô7-6ο (-, £ 3.- (R) -hydroxyéthyl7-7-oxo-l-azabi-cyclo (3.2.0) hept-2-ene-2-carboxylate to ©

CD.YD.MdC.CH. - 149 - SY-1735A

Orl 31 — N— I d o π - "(θφ) J-l J = ° -► Ο I 2) CH, co9PNB 3

HS

5 27 F Ç »3 ^ 5Ύ il ° iv> co £ pnb 28 3- / J (R, S) -Methyl pyridine-3-yl-methanetTiio7-6K- / I- (R) -hydroxyethyl7-7-oxo- l-azabicyclo (3.2. Q) p-nitrobenzyl hept-2-ene-2-carboxylate

754 mg (5.8 millimoles) of diisopropyl pyletbylamine are added in 1 ml of acetonitrile, then a solution of 1.57 g (5.84 millimoles) of diphenyl chloropbosphate in 2 ml of acetonitrile, in an atmosphere

CD.YD.MdC.CH. - 150 - SY-1735A

of nitrogen to a solution cooled to 0 ° C of 1.85 g (5.3 millimoles) of the intermediate ketone 5 ^ in 20 ml of acetonitrile. The resulting solution is stirred for 15 minutes at 0 ° C., then a solution of 754 mg (5.8 millimoles) of diisopropylethylamine in 1 ml of acetonitrile is added thereto, followed by 814 mg (5.8 millimoles) of thiol Z7 in 2 ml of acetonitrile. The reaction mixture is stirred for 3 hours at 0 ° C., then diluted with 200 ml of ethyl acetate, washed with ice brine (200 ml), with water (200 ml), aqueous bicarbonate (100 ml) and brine (100 ml). By evaporation of the dried solvent (MgSO /[.)/ a yellow oil is obtained which is purified by chromatography on a column of silica gel which is eluted with a mixture of 50% acetone and 50% chloride methylene in order to obtain 1.65 g of the desired compound which is a yellow solid.

NMR (CDC13) <S: 1.22 and 1.25 (3H each, d, J = 7.0Hz), 1.46 and 1.50 (3H each, d, J — 7.2Hz), 2.4 —3.3 (3H, m), 3.8-4.2 (3H, m), 5.35 (2H, ABq, J = 14.5Hz) and 7.2-8.6 (8H, m) .

IR (KBr) 1? Max: 3400, 1765 and 1690 cm ~ l.

Analysis for C23H23N3O3S1

Calculated ï C, 58.83, H, 4.94, N, 8.95, S, 6.83%

Found: C, 57.15, H, 5.04, N, 8.28, S, 6.78%.

γΟΗ SOCI, S / 25

CD.YD.MdC.CH. - 151 - SY-1735A

y1 VSH

J \ υ î X

r i h2nAnh2rX

L I ^ i

), iâDH

- HCl 26 27 4- (1'-Mercaptoethyl) pyridine

50 g of thionyl chloride are added to a solution of 25 g of 1- (4-pyridyl) ethanol 2.5 / prepared as described in J. Chem. Soc., Perkin II, 1462 (1974/7 in 100 ml of chloroform. The mixture is heated at reflux for 2 hours. By evaporation of the solvents under vacuum, the chlorinated compound 26 is obtained in the form of a semi-solid which used in the next step without further purification, so a hot solution of 14.4 g of thiourea in 75 ml of ethanol is added to a solution of compound 26 ^ in 160 ml of ethanol. The reaction mixture is heated at reflux for 18 hours, the ethanol is evaporated off and the residue is dissolved in 100 ml of ether, then the pH is adjusted to 10 by addition of 2N NaoH, the mixture is stirred at ambient temperature for 90 minutes, then adjusts it to pH 6.0 by adding 6N HCl and extracts it with ether (2x200 ml). Evaporation of the dried solvent (MgSO 4) / a yellow oil is obtained which is distilled under 5 mm Hg (667 Pa) and which is collected in the boiling range of 60-65 ° C to obtain

CD.YD.MdC.CH. - 152 - SY-1735A

11.0 g (38% yield) of pure thiol 2Ί_ in the form of a colorless oil.

NMR (CDC13) 6: 1.70 (3H, d, J = 6.0Hz), 2.05 (1H, d, J = 5.8Hz), 4.20 (1H, t, J = 6.0Hz, 5.8Hz), 7.20 (2H, d, J = 6.2Hz) and 8.5 (2H, d, J = 6.2Hz).

3H

CH3 ^ '} CH3! ^ he - *

r I

: o2pnb 28

0H

co2pnb NV - * \ Cu P 3 29

Pd / C

t * 2 ^ f3

r-Ί kA

*% C-3 30 “·”

CD.YD.MdC.CH. - 153 - SY-1735A

3- / 1 (RS) -Methyl-N-methylpyridine-3-yl-methanethio7-6o (- ^ - (Rj-hydroxyéthyjj ^^ - oxo-l-azabicycloC 3.2.0) hept-2-ene-2-carboxylate

10 ml of methyl iodide are added to a solution of 1.1 g (2.34 millimoles) of compound 28 in 100 ml of acetone. The reaction mixture is stirred at room temperature for 18 hours. The precipitate is collected by filtration and washed with methylene chloride (10 ml) to obtain 1.4 g (100% yield) of the quaternized pyridine 2j) which is a yellow powder.

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

IR (KBr) L? Max: 3400, 1770 and 1190 cm “!.

Analysis for C24H26N3O6S1I1

Calculated: C, 47.14, H, 4.29, N, 6.87, S, 5.24%

Found C, 47.19, H, 4.78, N, 6.11, S, 5.41%.

120 ml of a buffer solution of pH 7.0 are added, then 1.5 g of 10% palladium on charcoal to a solution of 1.45 g (2.37 millimoles) of compound 29 in 120 ml of tetrahydrofuran and 120 ml of ether. The mixture is hydrogenated in a Parr shaker for 60 minutes at 310 kPa. The mixture is filtered on a layer of CELITE and the catalyst is washed with water (2x15 ml). The mixture of filtrate and washing waters is extracted with ether (2 × 200 ml) and lyophilized to obtain a yellow solid which is purified on a column of C ^ g BONDAPAK phase (50 g) (Waters Associates) which are eluted with 5% acetonitrile in water under a pressure of 55 kPa. Each fraction of 20 ml is checked by liquid chromatography under high pressure and the fractions having an absorption in the ultraviolet at Amax 300 nm are combined, then they are lyophilized to collect

CD.YD.MdC.CH. - 154 - SY-1735A

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

NMR (D20) <5: 1.32 (3H, d, J = 7.0Hz), 1.63 (3H, d, J = 7.2Hz), 2.5-4.6 (6H, m), 4.32 (3H, s) and 8.2-8.9 (4H, m).

IR (KBr) Vmax: 3400, 1750 and 1590 cm-1.

UV \ max (H2O): 296 nm (ε = 7573).

Analysis for C17h2oN204Si. IÎ5H2O

Calculated: C, 54.38, H, 5.77, N, 7.46%

Found: C, 54.39, H, 5.98, N, 7.68%.

EXAMPLE 13.-

Preparation of 3- / N-methyl-N'-benzylimidazol-2-yl-methanethiô / -60C- / 1- (R) -hydroxyethyl7-7-oxo-l-azabi-cyclo (3.2.0) hept-2- ene-2-carboxylate

0H

X r ^> K> "Û I © C0 ©" 3 ”C1 1) H2N - N-Ac" Γ * if —a- 2) EtOH, \ HCl Φ 41 "

CD.YD.MdC.CH. - 155 - SY-1735A

N-Benzyl-2-mercaptomethylimidazole

1.72 g (14.5 millimoles) of N-acetylthiourea are added to a solution of 3.23 g (13.0 millimoles) of the chlorinated compound 41 / prepared as described in J. Amer. Chem. Soc., 71 ^ 383 (1949) 7 in 80 ml of acetonitrile. The reaction mixture is heated at reflux for 3 hours. The precipitate is collected by filtration, which is washed with acetonitrile (10 ml) to obtain the isothiouronium salt which is then dissolved in 80 ml of absolute ethanol and which is heated at reflux for 18 hours in an atmosphere of 'nitrogen. The reaction mixture is cooled to room temperature, concentrated in vacuo to a volume of about 30 ml and the precipitate is separated by filtration. By evaporation of the filtrate under vacuum, 3.5 mg (yield of 97%) of thiol 42 is obtained, which is a thick yellow syrup.

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

7 ”> - £ <! 0, 'rrV η ^ ίοφ) 2 J ~ * </ V) -r ** 0 Βο, ρνβ 5 "

CD.YD.MdC.CH. - 156 - SY-1735A

ΟΗ Λ co £ pnb 43 3- / N-benzylimidazol-2-yl-methanethio7-60Ç- / 1- (R) -hydroxyéthyl7-7-oxo-l-azabicyclo (3.2.0) hept-2-ene-2- p-nitrobenzyl carboxylate

1.17 g (9.0 millimoles) of diisopropylethylamine in 2 ml of acetonitrile are added, followed by 2.4 g (9.0 millimoles) of diphenyl chlorophosphate in 2 ml of acetonitrile in a nitrogen atmosphere , to a solution cooled to 0 ° C of 3.03 g (8.5 millimoles) of the intermediate ketone 5_ in 70 ml of acetonitrile. The resulting solution is stirred for 20 minutes at 0 ° C., then a solution of 1.17 ml (9.0 millimoles) of diisopropylethylamine in 2 ml of acetonitrile is added thereto, and then 4.8 g (15 millimoles) of thiol 42. An additional 1.93 g (15 millimoles) of diisopropylethylamine is added and the reaction mixture is stirred for 2 hours at 0 ° C. The precipitate is collected by filtration and washed with cold methylene chloride (20 ml) to obtain 2.5 g (yield of 55%) of the desired compound which is a white solid. NMR (DMS0-d6) <5: 1.23 (3H, d, J = 7.2Hz), 2.5-4.1 (6H, m), 4.25 (2H, s), 5.20 ( 2H, s), 5.20 and 5.45 (1H each, d, J = 14.5Hz) and 6.9-8.3 (11H, m).

IR (KBr) Vmax ï 3400, 1775 and 1690 cm-1.

CD.YD.MdC.CH. - 157 - SY-1735A

0H

J

1 l ^^ \ - c VI FSOjCKj J-L / \ J— *.

O

co £ pnb 43 “r4 ξ ~ n" ^ / ° 2PNB ti • 44

Pd / C

h2 1 r * co9 \ + 2 “3 45

CD.YD.MdC.CH. - 158 - SY-1735A

3- / N-Methyl-N '-benzylimidazol-3-yl-methanethiç [7-60 (- / 1- (R) -hydroxyethyl7--7-oxo-l-azabicyclo (3.2.0) hept-2-ene -2-carboxylate

1.15 ml (13.4 millimoles) of methyl fluoro-sulfonate are added to a solution of 1.76 g (3.3 mil-1 limoles) of compound 43 in 1100 ml of methylene chloride. The reaction mixture is stirred for 2 hours at room temperature. The reaction mixture is concentrated in vacuo to a volume of about 15 ml. The precipitate is collected by filtration and washed with methylene chloride (10 ml) to obtain 1.58 g (yield, 74%) of the quaternized imidazole 44 which is a white solid.

NMR (DMSO — d6) δ: 1.15 (3H, d, J = 7.0Hz), 3.2-4.4 (6H, m), 4.70 and 5.0 (1H each, ABq, J = 10.8Hz), 5.24 and 5.46 (1H each, ABq, J = 14Hz), 5.50 (2H, s) and 7.4-8.4 (11H, m).

IR (KBr) Vmax: 3500, 1770 and 1700 cm “3-.

Analysis for 028 ^ 29 ^ 4 ^ 9 ^ 2 ^

Calculated: C, 51.48, H, 4.47, N, 8.67, S, 10.20%

Found: C, 51.84, H, 4.52, N, 8.65, S, 9.87%.

120 ml of a buffer solution of pH 7.0 are added, then 1.0 g of 10% palladium on carbon to a solution of 1.11 g (1.71 millimole) of compound 44 in 100 ml of tetrahydrofuran 'and 100 ml of ether. The mixture is hydrogenated in a Parr shaker for 45 minutes at 276 kPa. The mixture is filtered on a layer of CELITE and the catalyst is washed with water (2x10 ml). The mixture of filtrate and washing waters is extracted with ether (2x70 ml) and lyophilized to obtain a yellow powder which is purified on a column of C ^ g BONDAPAK (50 g) (Waters Associates) than eluted with 10% acetonitrile in water under a pressure of 55 hPa. Each 15 ml fraction is checked by liquid chromatography under

CD.YD.MdC.CH. - 159 - SY-1735A

high pressure and the fractions having an absorption in the ultraviolet are pooled at “X max 300 nm, then they are lyophilized to collect 305 mg (43%) of the desired compound which is a slightly yellow amorphous solid. NMR (DMSO) &: 1.40 (3H, d, J = 7.0Hz), 2.9-3.4 (3H, m), 3.98 (3H, s), 4.0-4.2 (2H, m); 4.23 (2H, broad s), 5.57 (2H, s) and 7.2-7.65 (7H, m).

IR (KBr) Vmax: 3400, 1760 and 1590 cm "!.

Uv "Xmax (H2O): 299 nm (E = 8807).

Analysis for C21H23N3 ° 4S1 ·

Calculated: C, 57.25, H, 5.94, N, 9.54, S, 7.28%

Found C, 56.66, H, 5.70, N, 9.49, S, 8.30%. EXAMPLE 14.-

Preparation of 3- £ 2-methyl-N-methylpyridine-3-yl-methanethiq7-6d- / l- (R) -hydroxyethyl7-7-oxo-l-azabi-cyclo (3.2.0) hept-2-ene- 2-carboxylate

OH

/ j = Q ~ sCQ

co2q ch3 CO, Et LAH / Wv

I --f IJ \ 0H

^ N ^ CH3 1? 13 · * »»

CD.YD.MdC.CH. - 160 - SY-1735A

S0C1?;,

S

1) H nÄnH

sy ^ 1 __ "

W ^ CH3 2) te0H

HCl 14 1!

MT "V

2-Methyl-3-mercaptomethylpyridine

The ester 12 ^ is prepared as described in J. Org. Chem., 21, 800 (1956). A solution of 6.23 g (38 millimoles) of ester _12 in 15 ml of tetrahydrofuran is added dropwise over 15 minutes to a suspension cooled to 0 ° C. of 2.86 g of lithium aluminum hydride in 50 ml of dry tetrahydrofuran. The mixture is stirred at 0 ° C for 60 minutes, then 50 ml of ethyl acetate is added thereto. The precipitate is separated by filtration and washed with saturated aqueous ammonium chloride. The organic layer is dried over MgSOA, filtered and evaporated in vacuo to obtain 3.2 g (70% yield) of hydroxymethyl pyridine 33 as a yellow oil.

NMR (CDCI3) of compound 13 0: 2.46 (3H, s), 4.73 (2H, s), 5.1 (1H, broad), 7.2 (1H, dd, J = 8Hz), 7 , 8 (1H, dd, J = 8Hz, J = lHz) and 8.3 (1H, dd, J = 7Hz, J = lHz).

A solution of 3.2 g (26 millimoles) of alcohol 33 in 10 ml of methylene chloride is added dropwise over 15 minutes. in a nitrogen atmosphere, to a solution cooled to 0 ° C of 4 ml of

CD.YD.MdC.CH. - 161 - SY-1735A

thionyl chloride in 10 ml of methylene chloride. The cooling bath is removed and the reaction mixture is stirred for 3 hours at room temperature. All the solvents are removed in vacuo to obtain compound 14_ in the form of a brown solid which is used in the next stage without further purification. The crude brown solid is dissolved in 30 ml of absolute ethanol. 2.5 g (32 millimoles) of thiourea are then added and the mixture is heated to 65-70 ° C for 18 hours. The mixture is cooled to room temperature. The precipitate is collected by filtration and washed with ethanol (20 ml) and ether (50 ml) to obtain 30 g of the isothiouronium salt. This salt is dissolved in 10 ml of water and a solution of 640 mg (16 millimoles) of sodium hydroxide in 10 ml of water is added thereto under nitrogen. The reaction mixture is heated at 100 ° C for 2 minutes, then cooled to 0 ° C, adjusted to pH 6.0 with acetic acid and extracted with chloroform (2x35 ml). By evaporation of the dried chloroform (MgSO 4), 941 mg (46% yield) of thiol] J>, which is a yellow oil, are obtained.

NMR (C0C13) of thiol 3 ^ 6: 1.8 (1H, t), 2.60 (3H, s), 3.73 (2H, d, J = 10Hz), 7.13 (1H, dd, J = 8Hz), 7.57 (1H, dd, J = 8Hz) and 8.43 (1H, dd, J = 8Hz, 3Hz).

0H ^ I I \ = 0 01 ^ (0 (^ 2 co2p "b hS-0 5 15 l3

CD.YD.MdC.CH. - 162 - SY-1735A

OH 1

^ '^> sCO

CÔ2pNB * Ί6 3- (2-Methylpyridine-3-yl-methanethio) -6o (- / I- (R) -hydroxyéthyl7-7-oxo-l-azabicyclo (3.2.0) hept-2-ene-2-carboxylate p-nitrobenzyl

0.86 ml (4.80 millimoles) of diisopropylethylamine is added, then a solution of 1.17 g (4.37 millimoles) of diphenyl chlorophosphate in 3 ml of acetonitrile, under a nitrogen atmosphere, to a solution cooled to 0 ° C of 1.52 g (4.37 millimoles) of the intermediate ketone in 5 ml of acetonitrile. The resulting solution is stirred for 30 minutes at 0 ° C to obtain 3-diphenylphosphoryoxy) -6ol- / l- (R) -hy-droxyethyl7-7-oxo-1-azabicyclo (3.2.0) hept-2-ene -2-carboxylate of p-nitrobenzyl. To this solution is added a solution of 0.86 ml (4.80 millimoles) of diisopropyl pylethylamine in 2 ml of acetonitrile, then a solution of 940 mg (6.76 millimoles) of thiol 15 ^ in 2 ml of acetonitrile. The reaction mixture is stirred for 60 minutes at 0 ° C. The precipitate is collected by filtration and washed with ether (30 ml) to obtain 1.12 g (55% yield) of the desired compound which is a pale yellow solid, m.p. 186-188eC (decomposition).

NMR (DMSO-d6) 6: 1.20 (3H, d, J = 7Hz), 2.60 (3H, s), 3.40 (2H, m), 4.16 (2H, m), 4, 32 (2H, s), 5.16 (1H, d,

CD.YD.MdC.CH. - 163 - SY-1735A

J = 5Hz), 5.44 (2H, q, J = 14Hz), 7.32 (2H, ni), 7.8 (2H, d, J = 8Hz), 8.36 (2H, d, J = 8Hz) and 8.48 (1H, dd, J = 5.5Hz, 1.5Hz).

IR (KBr) i ^ max: 3500, 1770 and 1750 cm-l.

Analysis for C23H24N306S

Calculated: C, 58.83, H, 4.94, N, 8.94, S, 6.83%

Found: C, 58.63, H, 4.99, N, 9.06, S, 6.58%.

OH

[ΖΪ ^ / ^ Λ DL0S0 „F

^ 1 Y ^ l - CO, PNB II J CH3 16

CD.YD.MdC.CH. - 164 - SY-1735A

OH

1 1 0 C02pNB CH3

FS03G

17

Pd / C, H2 OH v CO © cîSk 2 LH3 X® 18 013 3- (2-Methyl-N-methylpyridine-3-yl-methanethio) -6 <* ~ / 1- (R) -hydroxyethy377-7-oxo -l-azabicyclo (3.2.0) hept-2-ene-2-carboxylate

0.5 ml (6.18 millimoles) of methyl fluorosulfonate is added dropwise at 10 ° C. over 10 minutes to a solution of 697 mg (1.19 millimoles) of compound 16 ^ in 100 ml of methylene chloride. The reaction mixture is stirred for 2.5 hours at room temperature. The precipitate is collected by filtration and washed with 30 ml of methylene chloride to obtain 777 mg (90%) of pyridine quater-

CD.YD.MdC.CH. - 165 - SY-1735A

nisêe 17_ which is a yellow solid.

NMR (C0C13) of compound Γ7 <5: 1.20 (3H, d, J = 7Hz), 2.82 (3H, s), 4.36 (3H, s), 4.16 (2H, m), 4.60 (2H, s) 5.20 (1H, m), 5.42 (2H, q, J = 14Hz), 7.80 (2H, d, J = 8Hz), 8.04 (1H, dd , J = 7Hz, 6.5Hz), 8.32 (2H, d, J = 8Hz), 8.64 (1H, d, J = 7.5Hz) and 9.08 (1H, d, J = 7, 5Hz)).

IR (KBr) Vmax: 3500 and 1765 cm-1.

Analysis for C24H26FN309S

Calculated; C, 48.91, H, 4.55, N, 7.23, S, 11.04% Found î C, 49.39, H, 3.97, N, 7.20, S, 10.98% .

80 ml of a buffer solution of pH 7.0 is added, then 800 mg of 10% palladium on carbon to a solution of 1.10 g (1.88 millimole) of compound 17 in 80 ml of tetrahydrofuran and 80 ml of 'ether. The mixture is hydrogenated in a Parr shaker for 40 minutes at 207 kPa. The mixture is filtered on a layer of CELITE and the catalyst is washed with water (2x10 ml). The mixture of filtrate and washing waters is extracted with ether (2 × 100 ml) and lyophilized to obtain a yellow powder which is purified by chromatography on an HP-20 column which is eluted with water, then with 5% acetonitrile in water. Each fraction of 15 ml is checked by liquid chromatography under high pressure and the fractions having an absorption in the ultraviolet at ^ max 300 nm are combined, then they are lyophilized to obtain 614 mg (yield of 42%) of the desired compound occurring in the form of a slightly yellow powder.

NMR (D20) 6: 1.28 (3H, d, J = 7Hz), 2.86 (3H, s), 3.20 (2H, dd, J = 10Hz, 3.5Hz), 3.42 (1H , dd, J = 5.4Hz, 3.5Hz), 4.20 (3H, m), 4.32 (3H, s), 4.35 (2H, s), 9.88 (1H, dd, J = 7.2Hz, 6.5Hz), 8.5 (1H, d, J = 8Hz) and 8.70 (1H, d, J = 8Hz).

IR (KBr) Vmax: 3400, 1760 and 1590 cm-1. υνλπκιχ (H2 °) ** 298 nm (£ = 8391).

CD.YD.MdC.CH. - 166 - SY-1735A

Analysis for C17H2oN2C> 3S.H20

Calculated: C, 55.73, H, 5.46, N, 7.65, S, 8.74%

Found: C, 55.50, H, 6.05, N, 7.74, S, 8.68%. EXAMPLE 15.-

Preparation of 3- / 4 ~ (N, N-dimethyl-1,2,3-triazolium) -methylthiô7-6c (- ^ l- (R) -hydroxyéthyl7-7-oxo-l-azabicyclo- (3.2.0) hept-2-ene-2-carboxylate

OH

X b? C02® ^ Ά: η3

A. Preparation of isomer A

fH H

ÎSAc a) MeOTf Af_A \ fe b) Aq. MaOH \ pi \ - \ c) "h o ^ Hcoe if V A | L \" L °

Me 1 V- ° P (οψ) 2

u C02PNB

d) H2 / Pd-C

Methyl trifluoromethane sulfonate (0.58 ml, 5.16 millimoles) is added dropwise to an ice-cold, stirred solution of 4- (methanethiolacetate) -1-methyl-1,2,3-triazole (590 mg, 3.52 millimoles) in dry methylene chloride (2 ml), in a nitrogen atmosphere. After 0.5 hours, the cooling bath is removed and after 1 hour the solvent is pumped off. We

CD.YD.MdC.CH. - 167 - SY-1735A

dissolve the residual oil in a few ml of water and this solution is cooled in an ice bath. A cold solution of sodium hydroxide (305 mg, 7.59 millimoles) in a few ml of water is then added and the reaction mixture is stirred for 0.75 hours. The solution is diluted to 25 ml with water and the pH is adjusted to 7.5 by addition of solid sodium hydrogen phosphate monohydrate. 14 ml of this solution (approximately 1.9 millimole of the triazolium-thiol) are then added to an ice-cold and stirred solution of the enol phosphate (1.0 g, 1.72 millimole) in tetrahydro-furan (10 ml) . The mixture is stirred for 0.75 hours (a certain amount of crystalline material, probably Na2HPO4> is deposited during this reaction). The suspension is poured into an autoclave with a little tetrahydrofuran (20 ml) and water (20 ml). Ether (30 ml) and 10% palladium on carbon (1.0 g) are added, then the mixture is hydrogenated for 1 hour (276 kPa). The organic phase is separated and washed with water (2x5 ml). The mixture of aqueous phases is filtered and the filtrate is concentrated under high vacuum (approximately 0.5 mm, ie 67 Pa, 90 minutes). The yellow solution is then chromatographed (phase inversion column under medium pressure, 35 × 90 mm, H 2 O as eluent) to obtain, after lyophilization, 395 mg of the carbapenem weakly contaminated with a little inorganic substance. It is purified by high pressure liquid chromatography (10x300 mm column Waters Microbon-dapack C-18, with multiple injections, taking water as eluent) to obtain 310 mg (57%) of the A isomer under the form of a tan powder. RMNH1 (D20) 5: 1.23 (3H, d, J = 6.4Hz), 3.10 (2H, d, J = 9.1Hz), 3.24 (1H, q, J = 2.7Hz, 6.1Hz), 4.03-4.71 (10H, m) and 8.46 (1H, s).

IR (Nujol): 1760 cm-1.

CD.YD.MdC.CH. - 168 - SY-1735A

UV (phosphate buffer, pH 7.4, M = 0.05) λmax: 296 nm (£ = 7,500).

B. Preparation of isomer B and isomer C

a) MeOTf SAc ^ b) aq. NaOH χ

The ^ *

O "“ ALiU

ΙΑ λ- ° νοφ> (attempt β

structure) C02PNB

d) H2 / Pd-C OH

V h? I \ —S .Me -

Jr-H // T> ^ 2

0 Λο / V

Methyl trifluoromethane sulfonate (1.60 ml, 14.0 millimoles) is added dropwise to an ice-cold solution of 4- (methanethiolacetate) -2-methyl-1,2,3-triazole (1.20 g, 7.02 millimoles) in dry methylene chloride (6 ml) under nitrogen. The mixture is allowed to warm to room temperature and stirred for 16 hours. Additional methyl trifluoromethanesulfonate (0.40 ml, 3.56 mmol) is added and after 3 hours at room temperature, the solvent is pumped off. The residual oil is triturated with ether and the resulting gum is dissolved in water (5 ml). The solution is cooled in an ice bath and added to it

CD.YD.MdC.CH. - 169 - SY-1735A

a solution of sodium hydroxide (844 mgf 21 # 1 millimoles) in water (5 ml). After 0.75 hours of stirring # the solution is diluted to 60 ml with water and the pH is adjusted to 8 by addition of solid potassium dihydrogenophos-phate. 40 ml of this solution (approximately 4.7 millimoles of a mixture of triazolium-isomeric thiols) are then added to a stirred and ice-cold solution of enol phosphate (2 # 00 g, 3.45 millimoles) in tetrahydrofuran ( 60 ml). The mixture is stirred in an ice bath for 0 # 5 hours, then it is transferred to an autoclave containing a suspension of 10% palladium on carbon (2.00 g) in ether (60 ml). The mixture is hydrogenated (276 kPa) for 1 hour. The organic phase is separated and washed with water (2x10 ml). The mixture of aqueous phases is filtered and the filtrate is concentrated under high vacuum (approximately 0.5 mm, 67 Pa, 1.5 hours). The remaining solution is chromatographed (phase inversion column under medium pressure, 45 × 130 mm, H 2 O as eluent) to obtain, after lyophilization, 595 mg of a mixture of isomeric carbapenems contaminated with a small amount of inorganic substance. They are separated and purified by high pressure liquid chromatography (10x300 mm column Waters Microbondapack C-18, with multiple injections, water as eluent) to obtain in order of elution:

Isomer B, 153 mg (13%); 1 H NMR (D20) S: 1.23 (3H, d, J = 6.4Hz), 3.12 (2H, q, J = 1.4Hz, 8.9Hz), 3.39 (1H, q, J = 2.7Hz, 6.0Hz), 4.07-4.68 (10H, m) and 8.19 (1H, s).

IR (Nujol): 1755 cm- !.

UV (phosphate buffer, pH 7.4, M = 0.05) \ max: 296 nm (€ = 6700).

Isomer C, 284 mg (24%).

BMNH1 (D20) <5 ï 1.23 (3H, d, J = 6.4Hz), 3.15 (2H, q,

CD.YD.MdC.CH. - 170 - SY-1735A

J = 3.7Hz, 9.0Hz), 3.37 (1H, q, J = 2.6Hz, 6.0Hz), 3.95- 4.65 (10H, m) and 8.62 (1H, s ).

IR (Nujol): 1750 cm-1.

UV (phosphate buffer, pH 7.4, M = 0.05) Xmax: 298 nm (6 = 7600).

EXAMPLE 16.- (5R, 6S) -6- (1R-hydroxyethyl) 3- (2-methyl-1,2,3-thia-.diazolium-4-yl-methylthio) -7-oxo-1-azabicyclo- (3.2.0) hept-2-ene-2-carboxylate

OH

J— 5] Γ \ θ 0 “3 A. Ethyl 1,2,3-Thiadiazol-4-yl-carboxylate C.D. Hurd and R.I. Mori, J. Am. Chem. Soc., 77, 5359 (1955)? ï ^ NHCOEt -, Œt X - ^ 0

Stirred at 23 ° C for 3 hours and heated at 70 ° C for 20 minutes a solution of ethyl e <-N-car-bethoxyhydrazonopropionate (31.2 g, 0.154 mol) in thionyl chloride (80 ml). The thionyl chloride is evaporated and the residue is triturated in hexane (4x30 ml). The red solid was dissolved in dichloromethane (150 ml) and the solution was washed with saturated sodium bicarbonate solution and with water. After drying over Na2SO4, we con

CD.YD.MdC.CH. - 171 - SY-1735A

centers the solution until the compound crystallizes. After standing at 23 ° C for some time, the crystals are collected by filtration: 16.8 g, m.p. 86 ° C, 69%. The filtrate is concentrated and purified by chromatography on a column of silica gel which is eluted with dichloromethane to obtain 3.17 g, m.p. 86 ° C, 13%.

IR (KBr) î ^ max: 1720 (ester) cm-1.

1 H NMR (CDC13) S: 1.52 (3H, t, J = 7, lHz, CH3CH2O), 4.57 (2H, q, J = 7, lHz, CH3CH2O) and 9.47 (1H, s, H of thia- diazole).

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

O 0

Lithium aluminum hydride (2.47 g, 65 millimoles) is gradually added over 1 hour to a suspension of ethyl 1,2,3-thiadiazol-4-yl-carboxylate (18.35 g , 116 millimoles) in ether (400 ml). The reaction mixture is stirred at 23 ° C for 7 hours and lithium aluminum hydride (2.47 g, 65 millimoles) is added thereto. Stirring is continued for 24 hours before successively adding water (7 ml), 15% sodium hydroxide solution (7 ml) and water (21 ml). After 15 minutes of stirring, the ethereal solution is decanted and the gum is extracted with ether (5 × 100 ml). The ethereal extracts are combined, dried (MgSO4) and concentrated (5.4 g). The crude compound is purified on a column of silica gel (120 g, 4x16 cm) which is eluted with ether

CD.YD.MdC.CH. - 172 - SY-1735A

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

IR (film) t max: 3380 (OH) cm-1 RMNH1 (CDC13) S: 2.31 (1H, s, OH), 5.22 (2H, s, CH20) and 8.50 (1H, s, H of thiadiazole).

C. 1,2,3-Thiadiazol-4-yl-methanol methanesulfonate ^ CH? OH CH OMs rt - ^ - ► ΐy

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

IR (film) APmax î 1350 (S02) cm “!, 1172 (S02) cm“ 1.

1 H NMR (CDCI3) <S: 3.09 (3H, s, CH3), 5.75 (2H, s, CH2) and 8.72 (1H, s, H of thiadiazole).

ÜV (CH2C12 ^ max: 251 nm (8 = 1990).

Analysis for C6H6N203S

Calculated: C, 24.73, H, 3.11, N, 14.42, S, 33.02%

Found: C, 24.78, H, 3.09, N, 14.66, S, 31.94%, as well as 0.13 g (19%) of di- (1,2,3-thiadiazol ether) -4-yl-methyl,

CD.YD.MdC.CH. - 173 - SY-1735A

IR (film) 'tfmaxt 1272, 1242, 1200, 986, 805 and 728 em “l, RMNHl (CDC13) (5: 5.16 (4H, s, CH2) 8.42 (2H, s, H of thiadiazole ).

D. 4-Acetylthiomethyl-1,2,3-thiadiazole

_ / CH OMs p P

n, rfA>

E

An aqueous solution (2 ml) of sodium thiolacetate / prepared from thiolacetic acid (0.38 ml, 5.3 mmol) and sodium bicarbonate (0.445 g, 5.3 mmol) is added to a methanesulfonate solution. 1,2,3-thiadiazol-4-yl-methanol (0.90 g, 4.6 millimoles) in tetrahydro-furan (9 ml). The resulting mixture was stirred at 23 ° C for 1 hour and was stirred. diluted with ether (75 ml), the organic solution is washed with water (3 × 3 ml) and dried (MgSO 4), then concentrated, the crude mixture is purified by chromatography (column of silica gel: 1.4x19 cm) with elution using 50% ether in hexane to obtain 0.60 g (75%) of the compound.

IR (film) Vmax: 1675 (C = 0) cm-1, RMNH1 (CDC13) <5: 2.37 (3H, s, CH3), 4.58 (2H, s, CH2) and 8.44 (1H , s, H of thiadiazole).

Analysis for C5H6N2OS2

Calculated: C, 34.47, H, 3.47, N, 16.08, S, 36.80%

Found: C, 34.48, H, 3.83, N, 16.28, S, 36.80%.

CD.YD.MdC.CH. - 174 - SY-1735A

E. 4-acetylthiomethyl-2-methyl-1,2,3-thiadiazolium trifluoromethanesulfonate and 4-acetylthiomethyl-3-methyl-1,2,3-thiadiazolium chsEch K —z '' 2 3 CF SO Me Ç> ? CH SCCK \ _ / C ~ £ CCh

i- \ -. . „K

/ ’Vg / cf3so3 ^ λ 3

A few crystals of the advertised compounds and trifluoromethanesulfonate (0.407 ml, 3.6 millimoles) are added over 5 minutes to a solution of 4-acetylthiomethyl-1,2,3-thiadiazole (0.60 g, 3.44 millimoles) mixture of ether (4 ml) and dichloromethane (0.4 ml). The reaction mixture is stirred at 23 ° C in a nitrogen atmosphere for 6 hours. The white solid, which is a mixture of the two desired compounds, is filtered and washed with ether so as to obtain 1.5 g (90%).

IR (KBr) "^ max: 1675 (C = 0) cm-1, 1 H NMR (DMS0-d6) <5: 2.43 (3H, s, CH3COS), 3.33 (s, CH3 on N-3) , 4.57 (s, CH3 on N-2), 4.66 (2H, s, CH2),

CD.YD.MdC.CH. - 175 - SY-1735A

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

Analysis for C7H9N2O4S3F3

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

F. 4-Mercaptomethyl-2-methyl-1,2,3-thiadiazolium trifluoromethanesulfonate and 4-mercaptomethyl-3-methyl-1,2,3-thiadiazolium £ 3L sEch trifluoromethane sulfonate

-HC1 -—- * CF N / A. ' CF SO ”15 0 3 3

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

CD.YD.MdC.CH. - 176 - SY-1735A

G. (5R, 6S) -6- (1R-hydroxyethyl) -3- (2-methyl-1,2,3-thiadiazolium-4-yl-methylthio) -7-oxo-l-azabicyclo- / 3.2.Çj7hept -2-ene-2-carboxylate? *: - A, —T- \ Ç aV ° 3. “0 N, pB 7.2

CODPNB

OH

X ^ 10% Pd / C ^ "1-r -“ \

Ether, THF / A / '/ ~ K \ W

HO 1. <LJ · - * 2 coo s To a solution cooled to 5 ° C of (5R, 6S) -6- (1R-hydroxyethyl) -3- (diphenylphosphono) -7-oxo-l-azabi-cyclo (2.2.0 ) p-nitrobenzyl hept-2-ene-2-carboxylate (1.7 g, 2.92 millimoles) in tetrahydrofuran (10 ml), a solution of a crude mixture of 4-mercaptomethyl-2 trifluoromethanesulfonate is added -methyl-1,2,3-tîiiadiazolium and 4-mercaptomethyl-3-methyl-1,2,3-thiadiazolium trifluoromethanesulfonate (0.9 g) in a mixture of phosphate buffer (pH 7.2, 0, 3M, 15 ml) and tetrahydrofuran (5 ml). The reaction mixture is stirred for 1 hour and the pH is maintained at 7.2 with a 2N sodium hydroxide solution. Stirring is continued for 1 hour before adding ether (50 ml) and 10% palladium-on-charcoal (1 g). The resulting mixture is hydrogenated at 23 ° C for 2 hours under 310 kPa and filtered through a layer of CELITE. The organic phase is separated and diluted with ether (50 ml) and with phosphate buffer (pH 7.2, 0.3M, 20 ml), then hydrogenated (2 g of palladium-on-carbon.

CD.YD.MdC.CH. - 177 - SY-1735A

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

IR (KBr) l ^ max: 3400 (large, OH), 1745 (C = 0 of ^ / 3 -lactam), 1580 (carboxylate) cm-1, 1 H NMR (D20) £: 1.23 (3H, d, J = 6.3Hz, CH3CHOH), 3.04, 3.05, 3.16 (2H, ni, H-4), 3.38 (1H, ~ dd, J = 2.8Hz, J = 6.0Hz , H-6), 3.9-4.6 (2H, m, H-5, CH3CHOH), 4.51, 4.53 (2 "s", SCH2), 4.61 (s, N + CH3 ) · UV (H20) ^ Xmax î 224 (fc'4345), 262 (64980), 296 (£ 6885). / oç ^ 23 18 ° (c = 0.18, H2O); = 9.8 hours (measurement at a concentration of 10 “4 in phosphate buffer pH 7.4 at 36.8 ° C).

EXAMPLE 17.- 3- / 5- (l-Carboxylatomethyl-3-methyl-1,2,3-triazolium) -methanethio7-6c (- £ i- (R) -hydroxyéthyl7-7-oxo-l-azabicy-clo /3.2.Ç^hept-2-ène-2- potassium carboxylate.

co ©

V

2 i

CD.YD.MdC.CH. - 178 - SY-1735A

5

Ηθ6Ν K. D IAH

Y> -►

Nj 2) MsCl / NSt

KSCOCH

K

BrCH EoEt.

'^ -CO And

Θ) 2 Q

AcS ^ E- ”* ε) KOH ^ ~ N /

OH I

1 H H D

w CO PNB 2

c) H2 / Pâ-C

i © ©

OH K COW

Yortf '\ o2u 1

CD.YD.MdC.CH. - 179 - SY-1735A

Lithium aluminum hydride (2.83 g, 70.9 millimoles) is added little by little to a stirred suspension of 1-methyl-1,2,3-triazole-4-carboxylic acid (9.00 g , 70.9 millimoles) (see C. Pederson, Acta. Chem. Scand., 1959, JL3, 888) in dry tetrahydrofuran (200 ml). The mixture is stirred at room temperature for 15 hours, then carefully added in aliquots of about 1 ml, a 20% aqueous solution of sodium hydroxide (20 ml). The resulting granular suspension is filtered and the solid is washed with additional tetrahydrofuran (5x75 ml). The mixture of solutions is dried in tetrahydrofuran (MgSO4) and the solvent is removed. The residual yellow oil is subjected to rapid chromatography on a column of silica gel (90 × 35 mm) / fractions of 100 ml of hexane, mixture of ethyl acetate and hexane (1: 1) and (1 : 3) and finally mixture of ethyl acetate and methanol (9: 1) as eluent7 · 4-hydroxymethyl-1-methyl-1,2,3-triazole is thus obtained (3.18 g, 40% ) which is a colorless oil: 1 H NMR (CDCl 3) 6 4.07 (3H, s), 4.73 (2H, d), 7.52 (1H, s); IR (pure) 3320 cm ~ i.

Ulf onyl methane chloride (3.82 ml, 49.6 millimoles) is added dropwise to a stirred, ice-cold solution of alcohol (4.67 ml, 41.3 millimoles) and triethylamine (7, 47 ml, 53.7 millimoles) in methylene chloride (20 ml). After 0.5 hour, the solvent is removed and the residual solid is taken up in acetonitrile (30 ml). Then potassium thiolacetate (7.06 g, 62.0 millimoles) is added and the suspension is stirred at room temperature for 3 hours. An additional potassium thiolacetate (3.0 g, 26.3 mmol) is added and the suspension is stirred for a further 16 hours.

CD.YD.MdC.CH. - 180 - SY-1735A

res. The dark suspension is then concentrated and water (10 ml) is added thereto. The mixture is extracted with methylene chloride (5 × 40 ml). The combined extracts are dried (MgSO4) and the solvent is removed. The residual oil is subjected to rapid chromatography on a column of silica gel (90 × 36 ml) / hexane then mixture of hexane and ethyl acetate (1: 1) as eluent7 · The 4- ( methanethiolacetate) -1-methyl-1,2,3-triazole (5.95 g, 84%) in the form of a slightly pink solid: 1 H NMR (CDCl 3) 6 2.40 (3H, s), 4.10 (3H, s), 4.20 (2H, s), 7.53 (1H, s)? IR (Nujol) 1675cm “l.

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

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

CD.YD.MdC.CH. - 181 - SY-1735A

the mixture of aqueous phases is filtered and the filtrate is concentrated under high vacuum. The residue is chromatographed on a phase inversion column (35 × 120 mm) which is eluted with water. By lyophilization of the fractions containing carbapenem, 1.20 g of a green solid are obtained. We rechromatogaphy it on the high pressure liquid chromatography device Waters Prep. 500 HPLC (PrepPAk-500 / Ci8 column) using 2% acetonitrile in water as eluent. The fractions containing the carbapenem are combined and lyophilized. The residue is rechromatographed in a liquid chromatography device under high pressure (10x300 mm column Waters Microbondapack C-18) with elution with water to collect, after lyophilization, the desired pure compound (190 mg, 17%) which occurs as a pale yellow solid.

1 H NMR (D20) 6 1.24 (3H, d, J = 6.4 Hz), 3.07 (2H, d, J = 9 Hz), 3.38 (1H, q, J = 2.7, 6 , 0 Hz) 4.02-4.30 (3H, m), 4.29 (3H, s), 5.23 (2H, s), 8.52 (1H, s); IR (Nujol) 1750 cm-1, UV (phosphate buffer, pH 7.4) Xmax 296 nm (* - = 7.520). EXAMPLE 18.- 3- / 4- (l-Carboxylatomethyl-3-methyl-1,2,3-triazolium) -methanethiolJ-6c (- / l- (R) -hydroxyéthyl7-7-oxo-l-azabicy-clo /3.2.Ô7hept-2-ène-2- potassium carboxylate.

OH

n) - £ / ï \ ^ a © γ 2 L 0 ^ c02

CD.YD.MdC.CH. - 182 - SY-1735A

P F

Γ HOC v HOC- = N- CO „£ t __w Π- / 'ç ^

EtOCCH2K

BD ‘^ y ===== \ - ^ K N v J: 02And

a) EtOCCl.NEt X'X

O 3

b) Ka3H

4 "P

> _ot-K =) 2 Ρφ3

HSCCE

o 3 ▼

AcS "^ =, C02And ^ r r ~. _ - b K ·· ^ a) WeOTr.

b) KOB K

OH

t B H

c) O ^ M 2 C0PN3 2

â) K ^ / Pc-C OH

AT

cT ^ ^ 0 IT '/ co2 L Θ 2

CD.YD.MdC.CH. - 183 - SY-1735A

A mixture of ethyl azidoacetate (30.0 g, 0.23 mole) and propiolic acid (14.3 ml, 0.23 mole) in toluene (75 ml) is stirred at room temperature. The reaction remains moderately exothermic for 90 minutes, at the end of which it becomes strongly exothermic, which makes it necessary to cool using an ice bath. After this development of heat, the reaction mixture is heated to reflux for 0.5 hour. After cooling in an ice bath, a crystalline material is collected by filtration, which is washed with a little toluene. The raw material thus collected (33.3 g, 72%) consists of a single isomer which is probably l- (ethylcarboxymethyl) -l, 2,3-triazole-4-carbo-xylic acid, according to an analogy with previous work (see C. Pederson, Acta Chem. Scand., 1959, 13 ^, 888. (rmNh! (DMSO-dg) 6 1.20 (3H, t, J = 7 Hz), 4.15 ( 2H, q, J = 7 Hz), 5.42 (2H, s), 8.67 (1H, 3) j.

A solution of the carboxylic acid (5.00 g, 25.1 mmol) and triethylamine (3.68 ml, 26.4 mmol) in dry methylene chloride (50 ml) is added to a stirred, ice-cold solution. ethyl chloroformate (2.52 ml, 26.4 mmol) in dry methylene chloride (50 ml). The purple solution is stirred for 30 minutes, at the end of which it is washed with water (10 ml), dried (MgSO 4) and the solvent is removed. The crude mixed anhydride is dissolved in tetrahydrofuran (50 ml) and added slowly to an ice-cold suspension of sodium borohydride (0.72 g, 18.9 mmol) in tetrahydrofuran (50 ml). After 30 minutes of stirring, additional sodium borohydride (0.30 g, 7.9 millimoles) is added and the reaction mixture is allowed to stand in an ice bath for 1 hour. Then add water (5 ml) and after 10 minutes,

CD.YD.MdC.CH. - 184 - SY-1735A

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

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

Diisopropyl azodicarboxy-late (4.11 ml, 20.8 mmol) is added dropwise to an ice-cold solution of triphenylphosphine (5.47 g, 20.8 mmol) in dry tetrahydrofuran (100 ml) nitrogen atmosphere. After 30 minutes, an ice-cold solution of alcohol (1.93 g, 10.4 millimoles) and thiolacetic acid (1.49 ml, 20.8 millimoles) in dry tetrahydrof uranium is added to this mixture under nitrogen. (50 ml). The reaction mixture is allowed to stand for 2 hours in an ice bath, then for another 12 hours at room temperature, after which the solvent is removed. The reaction mixture is subjected to rapid chromatography on silica gel (40 g; elution with fractions of 100 ml of hexane and 5, 10, 15 ... 50% of ethyl acetate in hexane). The fractions containing the thiolacetate are combined and rechromatographed on silica gel (60 g) / elution with fractions of 200 ml of hexane and 5, 10, 15 and 20% of ethyl acetate in hexane then 22.5, 25, 27.5 ... 35% ethyl acetate in hexane /. 1.24 g (49%) of l- (ethyl-

CD.YD.MdC.CH. - 185 - SY-1735A

carboxymethyl) -4-methanethiolacetate-1,2,3-triazole as a crystalline solid.

/ 1 H NMR 1.28 (3H, t, J = 7 Hz), 2.37 (3H, s), 3.87 (2H, s), 3.90 (2H, q, J = 7 Hz), 5 , 12 (2H, s), 7.63 (1H, s), IR (Nujol), 1735, 1780 cm ~ lj, in addition to an additional 1.40 g of substance contaminated with triphenylphosphine oxide.

Methyl trifluoromethane sulfonate (0.51 ml, 4.53 millimoles) is added dropwise to a stirred, ice-cold solution of the triazole (1.00 g, 4.12 millimoles) in dry methylene chloride (5 ml ). The ice bath is removed after 30 minutes and after another 30 minutes, the solvent is suctioned off. The residual white solid is suspended in water (15 ml) and the mixture is stirred and cooled in an ice bath. A solution of KOH (0.69 g, 12.4 millimoles) in water (5 ml) is added thereto and the reaction mixture is stirred for 1 hour. It is then diluted to 30 ml with water and to it is added solid potassium dihydrogen phosphate until the pH is brought to 8.0. A fraction of this solution (22 ml, about 3.0 millimoles of thiolcarboxylate) is added to a stirred, ice-cold solution of etenol phosphate (1.60 g, 2.76 millimoles) in tretrahydrofuran (30 ml). After 30 minutes, the reaction is stopped and the tetrahydrofuran is removed under high vacuum. The yellow solution is then chromatographed on a phase inversion column (35 × 120 ml) which is eluted with water (300 ml) then with 100 ml aliquots of 5, 10, 15 ... 30% acetonitrile in water. By lyophilization of the appropriate fractions, the p-nitrobenzyl ester is obtained in the form of a yellow solid (930 mg). This is introduced into an autoclave containing ether (25 ml), tetrahydrofuran (25 ml) and phosphate buffer / 25 ml, obtained by

CD.YD.MdC.CH. - 186 - SY-1735A

dissolution of potassium dihydrogen phosphate (1.36 g, 0.01 mole) in water (100 ml) and adjustment of the pH to 7.4 by addition of 45% aqueous KOH 7 and 10% palladium on carbon ( 900 mg). The hydrogenation is carried out at 276 kPa for 1 hour, at the end of which the organic phase is separated and washed with water (2x5 ml). The mixture of aqueous phases is filtered and then concentrated under high vacuum. The residual solution is chromatographed on a phase inversion column (35 × 120 mm) which is eluted with water. The fractions containing the carbapenem are combined and lyophilized to collect 1.21 g of a pale greenish solid. The latter is purified by liquid chromatography under high pressure (10 × 300 mm column, Waters Microbondapack C-18, eluted with water) to obtain 480 mg (41%) of the desired pure compound.

1 H NMR (D20) 6 1.13 (3H, d, J = 6.4 Hz), 3.11 (2H, d, J = 9 Hz), 3.37 (1H, q, J = 3.0, 6 , 1 Hz), 4.02 (7H, m), 5.18 (2H, s), 8.53 (1H, s).

IR (Nujol) 1750 cm “1 · ÜV (phosphate buffer, pH 7.4) Amax 205 nm (£ = 7.810). EXAMPLE 19 · - 3- / 5- (1,4-Dimethyl-1,2,4-triazolium) methanethig7-60 (- / 1- (R) -hydroxyethyjJ-7-oxo-l-azabicyclo / 3.2.o7hept- 2-ene-2-carboxylate - 03; if Λ K '/ CÛ ^

CD.YD.MdC.CH. - 187 - SY-1735A

A. 1-Methyl-5-methanethiolacetate-1,2,4-triazole / T “K, OH a) KsCl / KEt fj— N sA <= <v_y. -2 - * - / V_y b) CH ÇSK / KEt V.K ^

I 3fc 3 I

Methanesulfonyl chloride (0/46 ml, 6.0 millimoles) is added dropwise to an ice-cold, stirred solution of 1-methyl-5-hydroxymethyl-1,2-4-triazole (RG Jones and C. Ainsworth, J. Amer. Chem. Soc., 1955, 77, 1938), (565 mg, 5.0 millimoles) and triethylamine (0.91 ml, 6.5 millimoles) in methylene chloride (5 ml). After 20 minutes, additional triethylamine (1.05 ml, 7.5 millimoles) is added, followed by thiolacetic acid (0.53 ml, 7.5 millimoles) and stirring is continued for 45 minutes. The reaction mixture is then diluted with methylene chloride and washed with water. The aqueous phase is extracted with methylene chloride (3 × 5 ml) and the mixture of organic phases is dried (MgSO 4), then the solvent is removed. Chromatography on a column of silica gel gives pure 1-methyl-5-methanethiolacetate-2,4,4-triazole (570 mg) in the form of a yellow oil / in addition, an impure fraction is rechromatographed (200 mg ) to obtain by preparative thin layer chromatography on silica gel another 100 mg of pure compound (total yield 85% 27 · 1 H NMR (CDC13) Ô 2.38 (3H, s), 3.90 (3H, s), 4 , 25 (3H, s), 7.80 (1H, s).

CD.YD.MdC.CH. - 188 - SY-1735A

B. 3- / 5- (1,4-dimethyl-1,2,4-triazolium) -methanethig7 ~ 60I- / I- (R) -hydroxyethyl7-7-oxo-l-azabicyclo / 3.2. q7 ~ hept-2-ene-2-carboxylate a) MeOTf

[î— »ZKc b) KaOH

/ \ -J -OH-► r o Au p C0_PN3 2

d) H / Pâ-C

OH

TJ 9

1 p) '' '- • N

CO ^ 2

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

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

CD.YD.MdC.CH. - 189 - SY-1735A

a stirred and ice-cold solution of enol phosphate (2.00 g, 3.45 millimoles) in tetrahydrofuran (25 ml). After 30 minutes, the reaction mixture is introduced into an autoclave containing ether (40 ml) and 10% palladium-on-charcoal (2.0 g). The mixture is hydrogenated (310 kPa) for 75 minutes. The reaction mixture is then diluted with ether (25 ml) and filtered. The organic phase is separated and washed with water (2x5 ml). The mixture of aqueous phases is washed with ether (3x25 ml), then concentrated in vacuo. By column chromatography (phase inversion, 45 × 130 ml, elution with water) then lyophilization of the fractions containing carbapenem, 650 mg of crude compound are obtained. This is rechromatographed to obtain the purity of the desired compound (450 mg, 39%).

1-NMR (D20) 0 1.24 (3H, d, J = 6.4 Hz), 3.19 (2H, q, J = 2.6, 9.2 Hz), 3.45 (1H, q, J = 2.8, 6.0 Hz), 3.91 (3H, s), 4.06 (3H, s), 4.08-4.36 (2H, m), 4.54 (2H, d, J = 2.8 Hz), 8.71 (1H, s).

IR (Nujol) 1755 cm “1.

UV (phosphate buffer, pH 7.4) Amax 294 nm (€ = 8.202); t ^ (phosphate buffer, pH 7.4, M = 0.067, T = 37ec) 9.1 h.

EXAMPLE 20.- (1, 5R, 6S) -3- / 1,3-dimethyl-5-tetrazolium) -methyl-thio7-6- (1-hydroxyethyl) -7-oxo-1-azabicyclo ^ 3. 2.07-hept-2-ene-2-carboxylate

OE

Λ-γΛ s-cB2-y Y3 C02w 3

CD.YD.MdC.CH. - 190 - SY-1735A

A. 5-Carbethoxy-2-methyltetrazole and 5-carbethoxy-1-methyltetrazole

CH »ν, ^ κ 0 N« * 5 * ® P

i y-c ° ^ —s— "p> - <+ l) ^ L · '<a -,> Λ *" <> -, 3 la. Methylation by diazomethane

A solution of 5-carbethoxytetrazole is cooled to 0 ° C. (see: D. ModerhacK, Chem. Ber.f 108, 887 (1975) (9.17 g, 64 millimoles) in ethyl ether (80 ml) ( a mixture of ethanol and ether leads to the same ratio between the isomers) and a solution of diazomethane (3 g, 71 millimoles) in ether (200 ml) is added dropwise (15 minutes). the light yellow solution is stirred for 30 minutes and the excess diazomethane is destroyed by adding acetic acid (1 ml). By evaporation of the solvent and distillation of the residue, a clear oil is obtained, m.p. 95-100 ° C / 0.5 torr (67 Pa); 9.64 g (96%) The proton nuclear magnetic resonance spectrum indicates that it is a mixture of the 1-methylated and 2-methylated isomers in the ratio 6: 4 Separation of isomers is impossible by distillation and by high pressure liquid chromatography.

IR (filnOOjnax: 1740 cm-1 (C = 0 of the ester).

RMNH1 (CDCI3) δ: 1.53 (3H, two overlapping t, J = 7.0, CH2CH3), 4.46 and 4.53 (3H, 2s, CH3 of 1-methyltetrazole and 2-methyltetrazole in the report 6: 4, the methyl radical of isomer 2 is located in the lower field and corresponds to the minor product), 4.5 ppm (2H, two overlapping qs, CH2CH3)

CD.YD.MdC.CH. - 191 - SY-1735A

lb. 5-Carbethoxy-2-methyltetrazole

N ^ Nv K · ^ CH I cüN

- || \ _CO Et + \ λ-CO Et-2 ^ f \ co Et K-V 2. 2 130 ° C i Γ 2 CB, CBf ^ · ·

A mixture of 5-carbethoxy-2-methyltetrazole and 5-carbethoxy-1-methyltetrazole (0.252 g, 1.61 millimole, ratio of the two isomers III) in 11 iodomethane (0.5 ml) is introduced into a tube. glass which is sealed and heated at 100 ° C for 15 hours and at 130 ° C for 6 hours. By distillation of the reaction mixture, the desired compound which is a light yellow oil is obtained: 0.139 g (55%); P.Eb. 95-100 ° C / 0.5 torr (67 Pa) (air bath temperature). IR (film) V? Max: 1740 cm-1 (C = 0 of the ester).

RMNH1 (CDCI3) δ: 1.46 (3H, t, J = 7.0, CHgCi ^), 4.53 53H, s, CH3-2), 4.5 (2H, q, J = 7.0, CH2CH3).

2. Methylation with dimethyl sulfate

Anhydrous potassium carbonate (1.38 g, 0.01 mole) and dimethyl sulfate (1.26 g, 0.01 mole) are added to a solution of 5-carbethoxytetrazole (1.42 g, 0.01 mole) in dry acetone (20 ml). The mixture is heated at reflux for 12 hours. The carbonate is separated by filtration and the solvent is evaporated off under reduced pressure. The residue is diluted with dichloromethane (30 ml), washed with saturated sodium bicarbonate (10 ml) and brine (10 ml), then dried over anhydrous sodium sulfate. By evaporation of the solvent and distillation under vacuum, a clear oil is obtained: 1.45 g (93%); P.Eb. 85-110 ° C / 0.5 torr (67 Pa). The 1 H NMR spectrum indicates the presence of the two isomers in the 1: 1 ratio.

CD.YD.MdC.CH. - 192 - SY-1735A

B. 5-Hydroxymethyl-2-methyltetrazole

+ ^ ^ I

1. By reducing the mixture of esters

Cooled to 0 ° C, a mixture of 5-carbethoxy-1-methyltetrazole and 5-carbethoxy-2-methyltetrazole (ratio 6: 4) (7.60 g, 49 millimoles) in dry tetrahydrofuran (50 ml) and sodium borohydride (1.06 g, 49 millimoles) is added thereto gradually over 15 minutes. The mixture is kept at 10 ° C for another 10 minutes, then stirred at 20 ° C for 4 hours. The mixture is cooled to 4 ° C. and the excess hydride is carefully destroyed by adding 6N HCl (pH 7 at the end of the evolution of gas). The solvent is concentrated in vacuo and the residual oil is diluted with dichloromethane (200-ml), washed with brine (10 ml) and finally dried over Na2SO4 · By concentration of the solvent and distillation of the residue in vacuo , 1.83 g (33%) of a clear oil are obtained. The 1 H NMR spectrum of the product indicates that it consists of 5-hydroxymethyl-2-methyltetrazole.

2. By reduction of 5-carbethoxy-2-methyltetrazole

Solid lithium borohydride (19 mg, 0.87 millimole) is added to a solution of 5-carbethoxy-2-methyltetrazole (0.139 g, 0.89 millimole obtained by isomerization of the mixture of esters using iodide of methyl) in dry tetrahydrofuran (1 ml) at 10 ° C. The mixture is warmed slowly to room temperature and stirred for 4 hours. Excess borohydride is destroyed by careful addition of 6N HCl at 0 ° C (pH 7). The solvent is evaporated off and the residue is dissolved in dichloromethane (25 ml), then

CD.YD.MdC.CH. - 193 - SY-1735A

the solution is dried over anhydrous sodium sulfate. By evaporation of the solvent, the desired compound is obtained which is a clear oil: 0.092 g (91%)? P.Eb. 90-120 ° C / 0.5 torr (67 Pa) with decomposition.

IR (film) Omax - 3350 cm-1 (wide, OH); 1 H NMR (CDCI3) Ô: 4.4 (2H, s, CH3-2), 4.93 (2H, s, CH2 ~ 5).

C. 5-Acetylmercaptomethyl-2-methyltetrazole

1) MsCl, And ^ K

2) CH3C0SK,

i ---— I

Methanesulfonyl chloride (1.47 g, 12.9 millimoles) is added then triethylamine (1.30 g, 12.9 millimoles) dropwise over 5 minutes to a solution of 5-hydroxymethyl-2-methyltetrazole ( 1.83 g, 11.7 millimoles) in dry dichloromethane (25 ml) at 0 ° C. The mixture is stirred at 0 ° C for 1 hour, then a solution of potassium thioacetate (1.60 g, 14.0 millimoles) in dry N, N-dimethylformamide (10 ml) is added thereto. The resulting gel is stirred at 0 ° C for 3 hours. The reaction mixture is diluted with dichloromethane (200 ml), washed with brine (20 ml) and dried over anhydrous sodium sulfate. By evaporation of the solvent under vacuum and chromatography of the resulting oil on silica gel (2x15 cm, elution with dichloromethane and dichloromethane-acetone 5%), the desired compound is obtained which is a clear oil: 1.31 g (65 %).

IR (film) l? Max: 1696 cm “l (C = 0 of the thioester).

1 H NMR (CDCI3) S: 2.43 (3H, s, SAc), 4.36 (3H, s, 2-CH3) * 4.38 ppm (2H, s, 5-CH2).

CD.YD.MdC.CH. - 194 - SY-1735A

D. 5-Mercaptomethyl-1,3-dimethyltetrazolium trifluoromethanesulfonate

î '\ CH_SO CH

i y-rd2sKc -

/ 'K

CK3 / CE3 CF ^ EO ^

Na OH ïv ^. At 3

K Jk £)) ~ cH2sH

»Rv“ 3

Methyl trifluoromethanesulfonate (0.76 g, 4.64 millimoles) is added to a solution of 5-acetylmercaptomethyl-2-methyltetrazole (0.400 g, 2.32 millimoles) in dry dichloromethane (3 ml) and the solution is stirred at 22 ° C for 16 hours. By evaporation of the solvent under vacuum, a red oil is obtained. This salt is dissolved in cold deoxygenated water (5 ml) and 4M sodium hydroxide (0.8 ml, 3.2 millimoles) is added thereto. The mixture is stirred at 0 ° C for 40 minutes, diluted with water (7 ml) and the pH is adjusted to 7.3 with saturated potassium dihydrogen phosphate. The resulting clear solution is stored under nitrogen and used immediately in the next step.

CD.YD.MdC.CH. - 195 - SY-1735A

E. (1 'R, 5R, 6S) -3- / 1,3-dimethyl-5-tetrazolium) -methyl-thiol7-6- (1-hydroxyethyl) -7-oxo-l-azabicyclo- (3.2.0 ) hept-2-ene-2-carboxylate OH - cri ©, ra CF SO_

V O? (Οφ) + F \ -CK.SK

COFKB

2 C, .3

OH

^ X ^ -echXÔÎ 3 CO PNB 3 2 Θ CF SOU 3 3

OK

N / "3 H Pq / c] î \ / f \\

—Ï-► i-JX "ECB = XUJ

10 ch; CO ^ 3 2

A solution of enol phosphate (0.915 g, 1.58 millimole) in tetrahydro-furan (8 ml) is cooled to 0 ° C. and the solution of 5- trifluoromethanesulfonate is added dropwise therein over 20 minutes. mercaptomethyl-1,3-dimethyltetrazolium (2.32 millimoles, prepared above). The pH of the reaction mixture is stable at 6.5 during the whole addition. After another 20 minutes, the pH of the solution is adjusted to 7.0 with saturated sodium bicarbonate. The mixture is introduced into a hydrogenation autoclave, diluted with tetrahydrofuran (10 ml), ether (20 ml) and ice (10 g). The carbapênème is hydrogenated on 10% palladium on activated carbon at 310 kPa, while

CD.YD.MdC.CH. - 196 - SY-1735A

slowly increases the temperature to 22 ° C for 90 minutes. The catalyst is filtered off and washed with cold water (5 ml) and ether (20 ml). The aqueous phase is washed with ether (20 ml) and kept under vacuum for 20 minutes to remove traces of organic solvent. By chromatography on PrePak 500-C / 18 and elution with water, the desired compound is obtained which, after lyophilization, is a white powder: 0.266 g (49%).

fajQ3 + 13 ° (c lr04, H20) * ÜV (H20, pH 7.4) Λ max: 294 nm (£ 7,500).

IR (KBr) \? Max: 1755 (C = 0 of Ji-lactam), 1600 cm ”! (large, C = 0 carboxylate).

1 H NMR (D20) If 1.24 (3H, d, J = 6.4 Hz, CH3CHOH), 3.0- 3.3 (2H, m, H-4), 3.42 (1H, dd, J = 5.8, J = 2.9, H-6), 4- 4.2 (2H, m, H-5 and CH3CHOH), 4.34 and 4.57 (2x3H, 2s, CH3-I and 3 of tetrazole), 4.49 and 4.51 (2H, 2s, CH2S). The product has a half-life of 10.5 hours at 37 ° C (concentration 10 ~ 4 m in phosphate buffer of pH 7.4).

EXAMPLE 21.-

Other preparation process for 3- (N-methylpyridine-2-yl-methanethio) -60 ^ - ^ 1- (R) -hydroxyéthyj ^ -7-oxo-l-azabi-cyclo / 3 · 2.Ô7hept-2- ene-2-carboxylate / - K — L © ®î CS · CO2 ch3 A.

^ X ^ co2ch3. + ^

CD.YD.MdC.CH. - 197 - SY-1735A

4.0 moles (342 ml) of methyl acetoacetate and 8.0 moles (464.6 g) of allyl alcohol are introduced into a 2000 ml flask fitted with a magnetic stirrer, a distillation column of Vigreux, a heating jacket and a nitrogen intake. The reaction mixture is distilled for 12 hours at 92 ° C. 136 ml (2.0 moles) of allyl alcohol are added and the reaction mixture is distilled for 23 hours. Then 136 ml (2.0 moles) of allyl alcohol are added and the reaction mixture is distilled for 16 hours. Finally, the reaction mixture is distilled under vacuum and the product is collected at 105-110 ° C / 35 mm Hg (4.7 hPa). 414 g of allyl acetoacetate are thus obtained (73% yield).

B.

0 TsN, A ^ r 2

P-toluenesulfonyl azide (345.3 ml, 1.753 mole) is added over 1 hour to a solution of allyl acetoacetate (226.5 g, 1.594 mole) in 3000 ml of acetonitrile and triethylamine (243 , 4 ml, 1.753 mole) while maintaining the temperature in the vicinity of 20 ° C. using a cooling bath. The reaction mixture turns yellow. The reaction mixture is then stirred at room temperature for 18 hours in a nitrogen atmosphere. The mixture is concentrated on a rotary evaporator. The residue is dissolved in diethyl ether (2600 ml) and 1M aqueous KOH (800 ml). The organic phase is washed five times with KOH IM (500 ml) and once with brine (400 ml). After drying over MgS04 and concentration with evapora-

CD.YD.MdC.CH. - 198 - SY-1735A

rotary tor (temperature less than or equal to 30 ° C), 260.2 g (97%) of the desired compound are obtained.

C. I, V0 ^ - »i * 2 K2. K2

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

D.

.OCOCK, JTIh -1— -> 0 / ZnCl2 OSi-f- N, J_àn o

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

CD.YD.MdC.CH. - 199 - SY-1735A

j (28.7 g, 0.1 mole) and freshly molten zinc chloride (6.8 g, 0.05 mole) in dry methylene chloride (700 ml). The mixture is stirred at room temperature for 2 hours, at the end of which thin layer chromatography indicates the presence of a small amount of residual starting compound. An additional 2-diazo-3-t-butyldimethyl-silyloxy-3-butenate allyl (4.23 g, 0.015 mol) in 10 ml of methylene chloride is added over 1 hour and stirring is continued at temperature. room for 10 hours. The reaction mixture is then diluted with ethyl acetate (750 ml), washed (2x300 ml of saturated sodium bicarbonate and 300 ml of brine), dried (MgSO4) and evaporated to obtain 62.5 g of a dark orange oil which is dissolved in methanol (500 ml) and to which aqueous IN HCl (110 ml) is added. The resulting mixture is stirred at room temperature for 2 hours, after which 10 ml of 1N HCl is added, before further stirring for another 2 hours. The reaction mixture is concentrated to volume and poured into a mixture of ethyl acetate (800 ml) and water (800 ml). The organic phase is separated, washed with water (800 ml) and the mixture of aqueous extracts is washed with ethyl acetate (400 ml). The mixture of organic extracts is washed with brine (2 × 400 ml), dried (MgSO 4) and concentrated to obtain 32 g of a dark orange-red oil. By rapid chromatography, 9.33 g (yield of 33%) of the desired compound is obtained, which is a golden yellow oil which takes on a light yellow solid.

1 H NMR (CDCl3) <5: 6.20-5.72 (m, 2H), 5.48-5.21 (m, 2H), 4.74 (dt, J = 5.8, J '= 1, 2 Hz, 2H), 4.30-3.88 (m, 2H), 3.30-3.20 (m, 2H), 2.89 (dd, J = 7.3, J '* 2, l , 1H), 2.18 (s, 1H), 1.32 (d, J = 6.2, 3H).

CD.YD.MdC.CH. - 200 - SY-1735A

E.

I.

nc <_L. NOT

ur- ^ t ^ 2

OH

The mixture is refluxed for 1 hour, a mixture of 1W-diazoester prepared in stage D above (9.2 g, 32.7 millimoles) and rhodium acetate / Rh2 (OAc) 47 in benzene (1000 ml ). Activated charcoal is added to the solution and filtered through a layer of Celite. The Celite is washed with 100 ml of hot benzene. By concentrating the filtrate, 8.08 g (yield 97%) of the desired compound are obtained in the form of a light brown crystalline solid.

1 H NMR (CDCI3) <5: 6.15-5.68 (m, 1H), 5.45-5.18 (m, 2H), 4.71-4.60 (m, 2H), 4.40- 4.05 (m, 2H), 3.17 (dd, J = 7, l, J '= 2.0, 1H), 2.95 (dd, J = 6.9, J' = 18.9, 1H), 2.42 (dd, J = 7.6, J '= 18.8, 1H), 188 (s, 1H), 1.39 (d, J = 6.3, 3H).

F.

OH

- *

OH

CD.YD.MdC.CH. - 201 - SY-1735A

Diisopropylamine (6.08 ml, 0.035 mole) is added at 0 ° C. in a nitrogen atmosphere, then diphenylphosphoryl chloride to a solution of the ketoester prepared in stage E (7.5 g, 0.03 mole). After 15 minutes, thin layer chromatography indicates that no starting compound remains. To this reaction mixture is added diisopropylamine (6.26 ml, 0.036 mole) and a solution of freshly distilled 2-mercaptomethylpyridine (4.5 g, 0.036 mole) in 5 ml of acetonitrile. After 2 hours of stirring at 0 ° C., the mixture is poured into ethyl acetate (1000 ml), the mixture is washed with water (2x150 ml), with saturated sodium bicarbonate (150 ml) , water (150 ml) and brine (200 ml). The organic phase is dried (MgSO 4) and concentrated in a dark orange-yellow gum. Rapid chromatography gives the product as a golden yellow oil. The product is dissolved in diethyl ether and the solution is cooled to 0 ° C. By filtration, 4.8 g (yield of 44%) of the desired pure compound in the form of cream-colored crystals are obtained.

1 H NMR (CDCl3) 6; 8.6-8.4 (m, 1H), 7.85-7.15 (m, 3H), 6.20-5.74 (m, 1H, 5.54-5, 15 (m, 2H), 4.80-4.66 (m, 2H), 4.29-4.03 (m, 1H), 4.19 (s, 2H), 3.69-2.85 ( m, 1H), 2.97 (s, 1H), 1.32 (d, J = 6.2, 3H).

G.

Your —► cr xo2

CD.YD.MdC.CH. - 202 - SY-1735A

OH

A solution of potassium 2-ethylhexanoate (1.085 g, 5.96 millimoles) in ethyl acetate (12 ml) is added to a solution of the allyl ester prepared in Stage F (1.79 g, 4 , 97 millimoles), tetrakistriphenylphosphine-palladium (175 mg, 0.15 millimole) and triphenylphosphine (175 mg, 0.67 millimole) in methylene chloride (25 ml) · After 1 hour of stirring at room temperature , thin layer chromatography only reveals a trace of the starting compound. The reaction mixture is diluted with anhydrous diethyl ether (150 ml) and the precipitate is collected by filtration, then washed with ethyl acetate and then with ether to obtain a light brown solid. The solid is dissolved in water (10 ml) and purified by phase inversion chromatography to collect 1.85 g of the desired compound which is in the form of a cream-colored solid. This is further purified by dispersing it in acetone to collect 1.47 g (83%) of the desired pure compound.

1 H NMR (D20); 8.45-8.36 (m, 1H), 7.92-7.22 (m, 3H), 4.78-3.91 (m, 2H), 4.69 (s, 2H), 3, 34-2.71 (m, 3H), 1.19 (d, J = 6.4, 3H).

H.

OE

CD.YD.MdC.CH. - 203 - SY-1735A

OH

j-N -Λ; 0 © Θ CH

Where u2

Toluenesulfonic acid (27f6 mg, 0.16 millimole) is added to a suspension cooled to 0 ° C of potassium 6-hydroxyethyl-2- (2-pyridylmethylthio) -carbapé-nème-3-carboxylate (53.8 mg, 0.15 millimole) in acetone (2 ml). The mixture is stirred at 0 ° C for 20 minutes, then methyl trifluoro-methanesulfonate (0.02 ml) is added thereto. After 60 minutes of stirring at 0 ° C., LA-1 resin is added, then hexane (6 ml). The mixture is extracted with water (4x0.5 ml) and the mixture of the aqueous phases is purified by liquid chromatography under high pressure with phase inversion to collect 10 mg of the desired compound.

EXAMPLE 22.-

Preparation of 3- (N-methylpyridine-2-yl-metthanethio) -60C- / I- (R) -hydroxyethyl7-7-oxo-l-azabicyclo / 3.2.07 ~ hept-2-ene-2-carboxylate with "single reactor" process oh ,, u ÇH3 T h H ® T 3

CD.YD.MdC.CH. - 204 - SY-1735A

CF -SD.® OK CK, ä ä X___ ® {= Λ ^ fLy- ° (Qj ac

® C02? NB

i 3 o

CH3CN C1P (0 ^) 2 KaOH

0CC, 45 min. EtK (iPr) 2 p ^ Ö, OeC, 1 h.

V Ψ 0H. n T · Ç, + pN Çfc3 CF-SO, 0 CT “0X /„ ^ OPKB X / 4 VVVSVVSSSSv | // ^^ 5-7.5 THF f H20 OK CK, pr Φ i -1 ώ ΓΙ y \ ^ ° op (o ^)

o ICOjPNE

5 K2 Pq-C 10% 5CC, 2 h.

Ψ

CD.YD.MdC.CH. - 205 - SY-1735A

OH

- CB, X. © 1 3 £ A. Preparation of enol phosphate (2)

OH OH

T H H J H H P

x ^ opW) 2 J-N-V * 0 ->

0 'tO-, ΡΝΒ ° C02PKB

i 2

Ethyldiisopropylamine (9 millimoles, 1.04 equivalent, 1.57 ml) is added (in approximately 2 minutes) and diphenyl chlorophosphate (9 millimoles, 1.04 equivalent, 1.87 ml) (in approximately 2 minutes) ) to an ice-cold solution of the ketone £ (3 g, 8.61 millimoles) in acetonitrile (30 ml). The reaction mixture is stirred for 45 minutes, at the end of which the thin layer chromatography (ethyl acetate, silica gel) indicates the disappearance of the ketone £. The solution is diluted with ethyl acetate (60 ml), washed with cold water (2x50 ml) and with brine, dried over sodium sulfate and concentrated (lower bath temperature at 20 ° C) to obtain a foam which is used as it is.

CD.YD.MdC.CH. - 206 - SY-1735A

B. Preparation of thiol (4) O <a i “3 U nboh / h-o 0

TrJ D., i Tf '

Op “'> © p ^ 2) KH2P04 1 i

Nitrogen is bubbled for 5 minutes into an ice-cold solution of thiacetate 3 ^ (3.31 g, 10 millimoles), then a cooled solution of sodium hydroxide is added dropwise (in about 5 minutes) 1.75 equivalent, 17.5 millimoles, 0.7 g) in water (8 ml). The mixture turns yellow. After 75 minutes under nitrogen, the pH is adjusted to 7.4 with a saturated aqueous solution of potassium dihydrogen phosphate. The reaction mixture is diluted with water (15 ml). This aqueous solution of thiol 4 is used as is (50 ml, 0.2 millimole per ml).

C. Condensation OH £ J O __> ^ I! thf-H-5 P ^ V 2 pB 6.5-7.5 0 *, 1 h.

U C02PNB

2 jP rw A ^

^ C02PNB

5

The aqueous solution CD.YD.MdC.CH. is added dropwise. - 207 - SY-1735A

thiol 4 prepared in B (5 ml of solution per 5 minutes) to an ice-cold solution of compound 2 (crude, prepared in A, 8/62 millimoles) in tetrahydrofuran (50 ml). During the reaction, the pH of the mixture is kept in the region of 6.5-7.5 (preferably 7) by the addition of a cooled 2N sodium hydroxide solution. The progress of the reaction is observed by thin layer chromatography (a) on silica gel with ethyl acetate and (b) with phase inversion Analtech RPSP, CH3CN- in pH 7 buffer (4: 6) .

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

D. Hydrogenation OH / -> 4 5 osi V yß CH, ^ © j, 3 H2 / Pd-C 10% (3 THr-E2o-ether ^ CCLPKB 0-C, 2 h.

- 0H CH

© il · 3 6

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

CD.YD.MdC.CH. - 208 - SY-1735A

(3x10 ml), after which the pH is adjusted to 6.2 by careful addition of cold 2N NaOH. Ether is added and the aqueous phase is separated and washed again with ether. The organic solvent is removed from the aqueous phase under vacuum, then the aqueous phase is purified on a Bondapak C-18 column (100 g, 4.5 × 13 cm) using cold distilled water. The light yellow fractions containing the product are lyophilized (verification by UV and thin layer chromatography) to obtain 1.46 g (50% based on bicyclic ketone) of the compound <o which is a yellow powder.

UV: λ 293, £ = 9000, λ 271, ε = 11064.

EXAMPLE 23.-

According to the general procedures of Examples 1 to 20, the carbapenems below are prepared using the intermediate compound of formula s

0H CP

J H A3 (R) I \ - *

C02pNB

OH CH, A. LA ‘

"’ FTT

A- —w> 0®R 5

Ex. N ° A V_A

CD.YD.MdC.CH. - 209 - SY-1735A

/ Γ \\ © 23a -CH2- -T N-CH3 / “λ © 23b -CH2CH2" y 23c -CH2- / xCH3 CH3fô

\ N — V

/ '/ \\ 23d -CH2- CH- ^ 23e -CH2CH2- / T ^ © 23f -CH2 "- ^ N-CH2CH2CH3 CH3 © K ~ \ 23g -CH2- ^ CH3® 23h -CH2"

--S

CD.YD.MdC.CH. - 210 - SY-1735A

FH3 23i -CH2- | \ v ^ CE3 CF ® 23 d -CHo- ϋί13Ί-N-CE, I> 4

23k -CH2- “C I

© I

CH

L 3 231 <f3 \ ®h3 -CH- \ = - / / “2-0 23m -CH2-. - <^ @y - CH3 23n -CH2 ch3V © 6h3

CD.YD.MdC.CH. - 211 - SY-1735A

23o -CH2- —N ^ (mixture of 3 isomers j— Cri * CH ^ possible) 23p -CB2- 1 | î [© ks> «3

cocF

/ T2 23q -CH2- ^ '

--NOT

CE3

23r -CH2- iP

ch2-cocP

CH, 23s -CH2- || : s— N CH3 J ~ V & * 23t -CH2- - ('®cl.

EXAMPLE 24.-

According to the general procedures of Examples 1 to 20, the carbapenems below are prepared for

CD.YD.MdC.CH. - 212 - SY-1735A

using the intermediate compound of formula: OH CE.

0 ^ - K-! S.

. u C02pNB

OH CH- x.

"Π i ^ <r ~ —Ko £>

Ex. N ° A

/ T ^ \ © 24a -CH2- -Γ K-Cfi 24b -CH2CH2- “(γ“ ° Ε3

24c -CHo- -M V

\ = <© CH3

CD.YD.MdC.CH. - 213 - SY-1735A

^ Ν— ^ 24d -CH2- -Μ Μ 24e -CH2CH2- - / Γ ~ ν \ Θ 24f -CH2- -r ^ N-CK2CH2CE3 CH3 ©

N "~ V

24g -CH2- ~ Λ J

C3 ^ T

CE® l 3 ✓ RwCH, 24h -CH2- -J | Y 3 J — ε B "

24i -CH2- I

CK,

CD.YD.MdC.CH. - 214 - SY-1735A

Cr ©

3 "ï-N-CE

J] il 3 24 j -CH2- <g / ~ CE3 24k -CH2 ”©! CH.

J5 241 fH3 E, -CH- \ = - / / CH2- ^ 3

NOT

24m -CH2- “Tj" T

CK3 24n —CH o—

X.J

CK3 * © CH3 24o -0Η2- ^ (mixture of 3 isomers

“CN

J possible)

CD.YD.MdC.CH. - 215 - SY-1735A

24p -CH2- -Ij— ”© ^ £> -CB3

COtP

/ f2 24q -CH2- ^ I® ΐ CK3 f3 © 24r -CH2- “ff iß I ο CH2 ~ COu CH_ i ^ © 24s -ch2- -r ^ ^

N- N

CH3 N— N-CE3 24t -CH2- j

r- WK

© I

CE3 EXAMPLE 25.- OH “3 o” S3 t H? S © * "T T Ύοΐ

αίί-κ— ^ ocP l \ / J

CD.YD.MdC.CH. - 216 - SY-1735A

XÙ rôr- '

CO ^ GNP

O

il CIP (00), \ J / 2 ^ Ç / - \. CF3 £ 0® A »I (§1"

OE CE, ffiÎE3 © M

T ί ε j ^ 18 ^ 0? (0i5) 2 tuf \ 0j

0 ^ ”& 02 GNP

Ψ

CF

OH CH * © I 3 πΎ loj

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

CD.YD.MdC.CH. - 217 - SY-1735A

EXAMPLE 26.- OH CH, ÇE3

Th e I. s / linked ^ tVXo; 0 ^ ^ "COCp1

By replacing the intermediate ketone 1 ^ in the procedure of Example 22 with an equimolar amount of the intermediate lo (-methylated corresponding), the final carbapênème indicated above is obtained.

CD.YD.MdC.CH. - 218 - SY-1735A

Claims (221)

1.- Compound of formula: rb h ΓΛ _, _ (5 'Γ o ^ -K-Vcoor2 where r8 represents a hydrogen atom and r! Is chosen from the hydrogen atom and the alkyl, alkenyl and alkynyl of 1 to 10 carbon atoms; cycloalkyl and cycloalkylalkyl of 3 to 6 carbon atoms in the ring of the cycloalkyl part and of 1 to 6 carbon atoms in the alkyl parts; phenyl; aralkyl; aralkenyl and aralkynyl including the aryl part is a phenyl radical and the aliphatic part of which has 1 to 6 carbon atoms; hetero-aryl, heteroaralkyl, heterocyclic and heterocycloalkyl in which the heteroatom or atoms of the aforementioned heterocyclic parts are chosen from 1 to 4 atoms of oxygen, nitrogen or sulfur and in which the alkyl parts associated with the heterocyclic parts comprise 1 to 6 carbon atoms, all of which are substituted or unsubstituted, in which the substituent or substituents with respect to the abovementioned radicals are independently chosen from: Ci-Cß-alkyl optionally amino, haloed born, hydroxylated or halogenated carboxylated -OR3 O II -OCNR3r4 CD.YD. MdC.CH. - 219 - SY-1735A ο -CNR3r4 -NR3r4 y NR4 V.NR3r4 -S02NR3r4 O II -NHCNR3r4 0 r3cNR4- -CO2R3 = 0 O -OCR3 -SR3 0 -SR9 O -SR9 II 0 -CN -n3 -0S03r3 Λ -OS-R9 II O 0 -NR3S-R9 II 0 -0P (0) (OR3) (OR4) -NR3c = NR4 R3 -NR3c02r4 -NO 2 CD.YD.MdC.CH. - 220 - SY-1735A where, with regard to the abovementioned substituents, the radicals R 3 and r4 are independently chosen from the hydrogen atom and the alkyl, alkenyl and alkynyl radicals of 1 to 10 carbon atoms; cycloalkyl, cycloalkyl-alkyl and alkylcycloalkyl of 3 to 6 carbon atoms in the ring of the cycloalkyl part and from 1 to 6 carbon atoms in the alkyl parts; phenyl; aralkyl, aralkenyl and aralkynyl in which the aryl part is a phenyl radical and the aliphatic part has 1 to 6 carbon atoms; and hetero-aryl, heteroalkyl, heterocyclic and heterocycloalkyl in which the heteroatom (s) in the aforementioned heterocyclic parts are chosen from 1 to 4 oxygen, nitrogen or sulfur atoms and in which the alkyl parts associated with these heterocyclic parts count 1 to 6 carbon atoms, or alternatively R 3 and R ^, taken together with the nitrogen atom to which at least one of them is linked, can form a pentagonal or hexagonal nitrogen heterocyclic radical; R ^ is defined as R ^, except that it cannot be a hydrogen atom; or where Ri and r8, taken together, represent a C2-Cio-alkylidene or c2 "c10" alk! Oy1; hydroxylated Î-â®ne radical; r5 is chosen from alkyl, alkenyl and alkynyl radicals of 1 to 10 carbon atoms; cycloalkyl and cycloalkylalkyl of 3 to 6 carbon atoms in the ring of the cycloalkyl part and from 1 to 6 carbon atoms in the alkyl parts; phenyl; aralkyl, aralkenyl and aralkynyl in which the aryl part is a phenyl radical and in which the aliphatic part has 1 to 6 carbon atoms; hetero-aryl, heteroaralkyl, heterocyclic and heterocycloalkyl in which the heteroatom (s) in the aforementioned heterocyclic parts are chosen from 1 to 4 oxygen, nitrogen or sulfur atoms and in which the alkyl parts associated with the heterocyclic parts CD.YD .MdC.CH. - 221 - SY-1735A have 1 to 6 carbon atoms, all substituted or unsubstituted? the aforementioned r5 radicals optionally carrying one to three substituents chosen independently from: cl-C6-alkyl optionally amino, fluorinated, chlorinated, carboxylated, hydroxylated, or carbamoylated fluoro, chloro or bromo -OR3 -0C02r3 —OCOR3 -OCONR3r4 O Il 9 -OS -R II 0 -oxo -NR3R4 R3CONR4- -NR3C02R4 -NR3CONR3R4 O -NR3S-R9 II O -SR3 0 -SR9 0 0 K * a -S-R9 -SO3R3 -C02r3 -CONr3r4 -CN; or phenyl optionally substituted with 1 to 3 fluoro, chloro, bromo, Ci-C6 ~ alkyl, -Or3, -Nr3r4, -S03r3, -CO2R3 or -C0NR3r4, where R3, R4 and R9 in these substituents of r5 are such that defined above; CD.YD.MdC.CH. - 222 - SY-1735A or r5 can be joined to o ·· at another point in the cycle to form a condensed heterocyclic or heteroaromatic radical, the cycle of which may contain additional heteroatoms, chosen from 0, S and N; A represents a radical C ^ —Cg — alkylene in straight or branched chain; R2 represents a hydrogen atom, an anionic charge or a conventional radical which is easy to remove protective of the carboxyl function, it being understood that when R2 represents a hydrogen atom or a protective radical, there is also a counter ion, and / * e -f K— represents a heterocyclic aromatic, mono-, bi- or polycyclic substituted or unsubstituted radical containing at least one nitrogen atom in the ring and united to the radical A by a carbon atom of the ring and comprising an atom d 'nitrogen which is quaternized by the radical R ^; or a pharmaceutically acceptable salt of this compound. 2.- Compound according to claim 1, in the formula of which Ri represents a hydrogen atom or a CD.YD.MdC.CH radical. - 223 - SY-1735A ch3 CH3 OH OH CH3CH2-, CH-, or CH3CH- ch3 ^ ch3 ^ 3. Compound according to claim 1, in the formula of which Ri and R8, taken together, represent a radical HOCH2 ch3- ^ 4. Compound according to claim 1, in the formula of which R1 represents an OH CH3CH- radical. 5. A compound according to claim 1, in the formula of which R1 represents an OH CH3CH- radical and the absolute configuration is 5R, 6S, 8R. 6. Compound according to claim 1, 2, 3, 4 or 5, in the formula of which A represents a radical -CH2- or -CH2CH2- · 7. Composed of formula CD.YD.MdC.CH. - 224 - SY-1735A ηΨ'γ-Ο * Ν COOR2 where RÖ represents a hydrogen atom and Rl is chosen from the hydrogen atom and the alkyl, alkenyl and alkynyl radicals of 1 to 10 carbon atoms; cycloalkyl and cycloalkylalkyl of 3 to 6 carbon atoms in the ring of the cycloalkyl part and from 1 to 6 carbon atoms in the alkyl parts; phenyl; aralcoyl; aralkenyl and aralkynyl in which the aryl part is a phenyl radical and in which the aliphatic part has 1 to 6 carbon atoms; hetero-aryl, heteroaralkyl, heterocyclic and heterocycloalkyl in which the heteroatom (s) of the aforementioned heterocyclic parts are chosen from 1 to 4 oxygen, nitrogen or sulfur atoms and in which the alkyl parts associated with the heterocyclic parts comprise 1 to 6 carbon atoms, all of which are substituted or unsubstituted, the substituent or substituents of which, with respect to the abovementioned radicals, are independently chosen from: Ci-Cö-alkyl optionally amino, halogenated, hydroxylated or carboxylated halo -0R3 0 11. X -OCNR3r4 0 II -CNR3r4 -NR3R4 CD.YD.MdC.CH. - 225 - SY-1735A _rR4 \ NR3R4 -S02NR3r4 0 -NHCNR3r4 0 O11 „R3CNR4- -CO2R3 = 0 O -OCR3 -SR3 0 -SR9 O -SR9 II O -CN“ N 3 -0S03r3 O Il Λ -OS-R9 II OO -NR3S-R9 II O -0P (0) (OR3) (OR4) -NR3c = NR4 R3 -NR3c02R4 -no2 where, with regard to the aforementioned substituents, the radicals R3 and R4 are chosen independently from the atom of hydrogen and the alkyl, alkenyl and alkynyl radicals CD.YD.MdC.CH. - 226 - SY-1735A from 1 to 10 carbon atoms; cycloalkyl, cycloalkyl-alkyl and alkylcycloalkyl of 3 to 6 carbon atoms in the ring of the cycloalkyl part and from 1 to 6 carbon atoms in the alkyl parts; phenyl; aralkyl, aralkenyl and aralkynyl in which the aryl part is a phenyl radical and the aliphatic part has 1 to 6 carbon atoms; and heteroaryl, heteroaralkyl, heterocyclic and heterocycloalkyl in which the heteroatom (s) in the aforementioned heterocyclic parts are chosen from 1 to 4 oxygen, nitrogen or sulfur atoms and in which the alkyl parts associated with these heterocyclic parts count 1 to 6 carbon atoms, or alternatively r3 and r4, taken together with the nitrogen atom to which at least one of them is united, can form a pentagonal or hexagonal nitrogen heterocyclic radical; R ^ is defined as r3, except that it cannot be a hydrogen atom; or where Ri and r8 taken together represent a C2-Cio_a ^ -coyli ^ ®ne or C2-Cio-alkylidene hydroxyl radical; R 5 is chosen from alkyl, alkenyl and alkynyl radicals of 1 to 10 carbon atoms; cycloalkyl and cycloalkylalkyl of 3 to 6 carbon atoms in the ring of the cycloalkyl part and from 1 to 6 carbon atoms in the alkyl parts; phenyl; aralkyl, aralkenyl and aralkynyl in which the aryl part is a phenyl radical and in which the aliphatic part has 1 to 6 carbon atoms; heteroaryl, heteroalkyl, heterocyclic and heterocycloalkyl in which the heteroatom (s) in the aforementioned heterocyclic parts are chosen from 1 to 4 oxygen, nitrogen or sulfur atoms and in which the alkyl parts associated with the heterocyclic parts have 1 to 6 carbon atoms , all substituted or unsubstituted; the aforementioned R5 radicals optionally carrying one to three substituents chosen independently from: CD.YD.MdC.CH. - 227 - SY-1735A Ci-C6-alc ° yle optionally amino, fluorinated, chlorinated, carboxylated, hydroxylated, or carbamoylated fluoro, chloro or bromo -OR3 -0C02r3 -OCOR3 -OCONR3r4 0 11 Q -OS-R9 II 0 -OXO -NR3r4 R3CONR4- -NR3c02r4 -NR3CONR3R4 O -NR3S-R9 II O -SR3 0 -SR9 0 O -S-R9 -SO3R3 -C02R3 -conr3r4 -CN; or phenyl optionally substituted with 1 to 3 fluoro, chloro, bromo, Ci-Cg-alkyl radicals, -OR3, -NR3R4, -S03r3, -CO2R3 or -C0NR3r4, where R3, R4 and R9 in these substituents of R3 are such that defined above; or R5 can be combined with CD.YD.MdC.CH. - 228 - SY-1735A θ'- at another point in the cycle to form a condensed heterocyclic or heteroaromatic radical, the cycle of which may contain additional heteroatoms, chosen from O, S and N; A represents a C ^ -Cß-alkylene radical in a straight or branched chain; R 2 represents a hydrogen atom, an anionic charge or a conventional radical which is easy to remove protective of the carboxyl function, it being understood that when r2 represents a hydrogen atom or a protective radical, there is also a counter ion, and o · - represents a nitrogen heterocyclic radical, mono-, bi- or polycyclic containing 0 to 5 additional heteroatoms chosen from O, S and N, the heterocyclic radical being united to the radical A by a carbon atom of the ring and comprising an atom of nitrogen of the ring quaternized by the radical r5, and this heterocyclic radical being optionally substituted for the carbon atoms of the ring available by 1 to 5 substituents chosen independently from the C1-C4-alkyl radicals; C] _- C4-alkyl substituted by 1 to 3 hydroxyl, amino, C ^ -C4-alkylamino, di (Cq-C4) alkylamino, Ci-C4 “alk ° xy / carboxyl, halo or sulfo, Cg-Cg- cycloalkyl; C3-C6-cycloalcoyl (Ci-C4) -alkyl optionally substituted with 1 to 3 substituents CD.YD.MdC.CH. - 229 - SY-1735A mentioned above in connection with the C1-C4-alkyl radicals; C1-C4-alkoxy; C1-C4-alkylthio; amino; C1-C4 alkyllamino; di (C ^ -C4) alkylamino; halo; C1-C4-alkanoylamino; C1-C4-alkanoyloxy; carboxyl; sulfo; -C02-o-Ci-C4-alkyl; hydroxyl; amidino; guanidino; phenyl; phenyl substituted by 1 to 3 radicals independently chosen from amino / halogeno, hydroxyl, trifluoromethyl, Ci-C4-alkyl, Ci-C4 ~ al-coxy, Ci-C4-alkylamino, di (C1-C4) alkylamino, carboxyl and sulfo; phenyl (C1-C4) alkyl in which the phenyl part is optionally substituted with 1 to 3 substituents mentioned above with respect to the phenyl radical and the alkyl part is optionally substituted with 1 to 3 substituents mentioned above with respect to the radicals C ^ -C4-alkyl; and heatheraryl or heteroalkyl in which the heteroatom (s) are chosen from 1 to 4 atoms 0, S or N and in which the alkyl part associated with the heteroaralkyl radical has 1 to 6 carbon atoms, these heteroaryl and heteroaralkyl radicals being optionally substituted in the heterocyclic part with 1 to 3 radicals independently chosen from hydroxyl, amino, halogeno, trifluoromethyl, C ^ -C4 ~ alkyl, C1-C4-alkoxy, C1-C4-alkylamino, di (Οχ-C4) alkylamino, carboxyl and sulfo radicals , and in the alkyl part with 1 to 3 radicals chosen from hydroxyl, amino, Ci-C4-alkylamino, di (C ^ -C4) alkylamino, Ci-C4-alkoxy, carboxyl, halo and sulfo radicals and the heterocyclic radical being optionally substituted for the ring nitrogen atoms available with 1 to 3 radicals chosen independently from C1-C4-alkyl radicals; Ci-C4 ~ alkyl substituted by 1 to 3 hydroxyl, amino, Ci-C4-alkylamino, di (C ^ _C4) alkylamino, Ci-C4-alkoxy, carboxyl, halo or sulfo radicals; C3-C6-cycloalkyl; C3-C6-cycloalcoyl (Ci-C4) -alkyl optionally substituted with 1 to 3 substituents CD.YD.MdC.CH. - 230 - SY-1735A mentioned above in connection with the radicals CJ-C4-alkyl; phenyl, phenyl substituted by 1 to 3 substituents independently chosen from amino, halogenO / hydroxyl, trifluoromethyl, Ci-C4_aicoyl® / Cl-C4-alkoxy / Ci-C4-alkylamino, di (C1-C4) alkylamino, carboxyl and sulfo radicals ; phenyl (Ci-C4) alkyl, the phenyl part of which can optionally be substituted with 1 to 3 substituents mentioned above with respect to the phenyl radical and the alkyl part of which can optionally be substituted with 1 to 3 substituents mentioned above with respect to the C1-C4-alkyl radicals; and heteroaryl or heteroaralkyl in which the heteroatom (s) are chosen from 1 to 4 atoms 0, S or N and in which the alkyl part associated with the heteroaralkyl radical has 1 to 6 carbon atoms, the heteroaryl and heteroaralkyl radicals being optionally substituted in the heterocyclic part with 1 to 3 substituents chosen independently from the hydroxyl, amino, halogen, trifluoromethyl, C2 ~ C4-alkyl, C ^ -C4-alkoxy, Ci-C4-alkylamino, di (C1-C4) alkylamino, carboxyl radicals and sulfo and in the alkyl part with 1 to 3 substituents chosen from hydroxyl, amino, C 1 -C 4 -alkylamino, di (C 1 -C 4) alkylamino, C1-C4-alkoxy, carboxyl, halo and sulfo radicals; or a pharmaceutically acceptable salt of this compound. 8. A compound according to claim 7, in the formula of which Ri represents a hydrogen atom or a CH3 CH 3 OH OH CH3CH2-, CH-, OR CH3CH- CH3 ^ CH3 ^ radical. 9. Compound according to claim 7, in which formula Ri and R8, taken together, represent CD.YD.MdC.CH. - 231 - SY-1735A a radical HOCH 2 ^ C = CH3 ^ 10. Compound according to claim 7, in the formula of which Ri represents an OH ch3ch- radical. 11. A compound according to claim 7, in the formula of which Ri represents an OH ch3ch- radical and the absolute configuration is 5R, 6S, 8R. 12. Compound according to claim 7, 8, 9, 10 or 11, in the formula of which A represents a radical -CH2- or -CH2CH2- · 13. Compound of formula © B p 4nr <> g N ^ —COOR2 where r8 represents a hydrogen atom and Rl is chosen from the hydrogen atom and the alkyl, alkenyl and alkynyl radicals of 1 to 10 carbon atoms ; cycloalcoyl and cycloalcoylalcoyl of 3 to 6 atoms of CD.YD.MdC.CH. - 232 - SY-1735A carbon in the cycle of the cycloalkyl part and from 1 to 6 carbon atoms in the alkyl parts; phenyl; aralcoyl; aralkenyl and aralkynyl in which the aryl part is a phenyl radical and in which the aliphatic part has 1 to 6 carbon atoms; hetero-aryl, heteroaralkyl, heterocyclic and heterocycloalkyl in which the heteroatom (s) of the aforementioned heterocyclic parts are chosen from 1 to 4 oxygen, nitrogen or sulfur atoms and in which the alkyl parts associated with the heterocyclic parts comprise 1 to 6 carbon atoms, all of which are substituted or unsubstituted, the substituent or substituents of which, with respect to the abovementioned radicals, are independently chosen from: C ^ -Cg-alkyl optionally amino, halogenated, hydroxylated or carboxylated halo -0R3 0 -OCNr3r4 0 -CNR3r4 -Nr3r4 _ / NR4 'Nr3r4 -SC> 2Nr3r4 OH o „-NHCNR3r4 O R3cNR4- -CO2R3 = 0 O -0CR3 -SR3 CD.YD.MdC.CH. - 233 - SY-1735A ο II Λ -SR9 Ο “SR9 Μ ο -CN -n3 -OSO3R3 0 -0S-R9 II OO -NR3s-r9 II O -OP (O) (OR3) (OR4) -NR3c = NR4 R3 -NR3C02R4 -no2 where, with regard to the abovementioned substituents, the radicals r3 and R4 are independently chosen from the hydrogen atom and the alkyl, alkenyl and alkynyl radicals of 1 to 10 carbon atoms; cycloalkyl, cycloalkyl-alkyl and alkylcycloalkyl of 3 to 6 carbon atoms in the ring of the cycloalkyl part and from 1 to 6 carbon atoms in the alkyl parts; phenyl; aralkyl, aralkenyl and aralkynyl in which the aryl part is a phenyl radical and the aliphatic part has 1 to 6 carbon atoms; and hetero-aryl, heteroaralkyl, heterocyclic and heterocycloalkyl in which the heteroatom (s) in the aforementioned heterocyclic parts are chosen from 1 to 4 oxygen, nitrogen or sulfur atoms and in which the alkyl parts associated with these heterocyclic parts count 1 to 6 carbon atoms, or else R3 and R4 »CD.YD.MdC.CH. - 234 - SY-1735A taken together with the nitrogen atom to which at least one of them is united, can form a pentagonal or hexagonal nitrogen heterocyclic radical; R9 is defined as R3, except that it cannot be a hydrogen atom; or where Ri and r8, taken together, represent a C2-Cio-alkylidene or C2-Cio ~ alkc Ylid®ne hydroxylê radical; r5 is chosen from alkyl, alkenyl and alkynyl radicals of 1 to 10 carbon atoms; cycloalkyl and cycloalkylalkyl of 3 to 6 carbon atoms in the ring of the cycloalkyl part and from 1 to 6 carbon atoms in the alkyl parts; phenyl; aralkyl, aralkenyl and aralkenyl in which the aryl part is a phenyl radical and in which the aliphatic part has 1 to 6 carbon atoms; hetero-aryl, heteroaralkyl, heterocyclic and heterocycloalkyl in which the heteroatom (s) in the aforementioned heterocyclic parts are chosen from 1 to 4 oxygen, nitrogen or sulfur atoms and in which the alkyl parts associated with the heterocyclic parts count 1 to 6 carbon atoms, all substituted or unsubstituted; the abovementioned R9 radicals optionally carrying one to three substituents chosen independently from: C ^ -Cg-alkyl optionally amino, fluorinated, chlorinated, carboxylated, hydroxylated, or carbamoylated fluoro, chloro or bromo -0R3 -oc2r3 -oco2r3 -OCONR3r4 O 11 Λ - OS-R9 II O -oxo -NR3r4 CD.YD.MdC.CH. - 235 - SY-1735A r3cONR4- -NR3C02R4 -NR3CONR3R4 O -NR3S-R9 II 0 -SR3 O î -SR9 0 O -SO3R3 -C02r3 -CONR3R4 -CN; or phenyl optionally substituted by 1 to 3 fluoro, chloro, bromo, C ^ -Cg-alkyl radicals, -0R3, -Nr3r4x -SO3R3, -C02R3 or -CONr3r4, where r3, r4 and R9 in these substituents of R 5 are such as defined above; or else R ^ can be joined to O- at another point in the cycle to form a condensed heterocyclic or heteroaromatic radical, the ring of which can contain additional heteroatoms, chosen from O, S and N; A represents a Ci-Cg-alkylene radical in a straight or branched chain; r2 represents a hydrogen atom, an anionic charge or a conventional radical which is easy to remove protective of the carboxyl function, it being understood that when R2 represents a hydrogen atom or a protective radical, there is also a counter CD.YD.MdC .CH. - 236 - SY-1735A ion, and ® 5 R represents a pentagonal or hexagonal aromatic nitrogen heterocyclic radical containing 0 to 3 additional heteroatoms chosen from O, S and N, this heterocyclic radical being optionally substituted for the carbon atoms of the ring available by 1 with 5 substituents chosen independently from the radicals Ci ~ C4-alkyl; C] .- C4-alkyl substituted by 1 to 3 hydroxyl, amino, Ci-C4-alkylamino, di (Ci ~ C4) alkylamino, C] _- C4 ~ alkoxy, carboxyl, halo or sulfo, C3-C6-cycloalkyl radicals ; C3-C6-cycloalkyl (C] .- C4) -alkyl optionally substituted with 1 to 3 substituents mentioned above in connection with the C1-C4-alkyl radicals; C ^ -C4-alkoxy; C2 ~ C4-alkylthio; amino; C1-C4-alkylamino; di (C1-C4) alkylamino; halo; C1-C4-alkanoylamino; C ^ - ^ - alkanoyloxy; carboxyl; sulfo; -C02-0-Ci-C4-alkyl; hydroxyl; amidino; guanidino; phenyl; phenyl substituted by 1 to 3 radicals independently chosen from amino, halogeno, hydroxyl, trifluoromethyl, C1-C4-alkyl, C ^ -C4-al-coxy, Ci-C4-alkylamino, di (Ci-C4) alkylamino, carboxyl and sulfo; phenyl (C1-C4) alkyl in which the phenyl part is optionally substituted with 1 to 3 substituents mentioned above with respect to the phenyl radical and the alkyl part is optionally substituted with 1 to 3 substituents mentioned above with respect to the radicals Ci- C4-alkyl; and heatheraryl or hetero-aralkyl in which the heteroatom (s) are chosen from 1 to 4 O, S or N atoms and in which the alkyl part associated with the heteroaralkyl radical has 1 to 6 atoms CD.YD.MdC.CH. - 237 - SY-1735A of carbon, these heteroaryl and heteroaralkyl radicals being optionally substituted in the heterocyclic part by 1 to 3 substituents chosen independently from the hydroxyl, amino, halogen, trifluoromethyl, <-i-C4-alkyl, Ci radicals -C4-alkoxy, cl_c4 ~ alkylamino, di (Ci-C4) alkylamino, carboxyl and sulfo, and in the alkyl part with 1 to 3 substituents chosen from hydroxyl, amino, Ci-C4 ~ al-coylamino, di (C ^ -C4) alkylamino, Ci-C4-alkoxy, carboxyl, halo and sulfo and the heterocyclic radical being optionally substituted for the nitrogen atoms of the ring available by 1 to 3 substituents chosen independently from the radicals C] _- C4-alkyl; C1-C4-alkyl substituted by 1 to 3 hydroxyl, amino, Ci-C4-alkylamino, di (Ci-C4) alkylamino, Ci-C4-alkoxy, carboxyl, halo or sulfo radicals; C3-C6 ~ cycloalkyl; C3-Ce-cycloalkyl (C1-C4) alkyl optionally substituted with 1 to 3 substituted mentioned above with respect to the C1-C4-alkyl radicals; phenyl, phenyl substituted with 1 to 3 substituents independently chosen from amino, halo, hydroxyl, trifluoromethyl, Ci-C4-alkalkyl, Cq-C4-alkoxy, Cl-C4-alkylylri.no, di (Cq-C4) radicals alkyllamino, carboxyl and sulfo; phenyl (Ci-C4) alkyl in which the phenyl part can optionally be substituted by 1 to 3 substituents mentioned above with respect to the phenyl radical and in which the alkyl part can optionally be substituted with 1 to 3 substituents mentioned above in relation to the Cj-C4-alkyl radicals; and heteroaryl or heteroaralkyl in which the heteroatom (s) are chosen from 1 to 4 atoms 0, S or N and in which the alkyl part associated with the heteroaralkyl radical has 1 to 6 carbon atoms, the heteroaryl and heteroaralkyl radicals being optionally substituted in the heterocyclic part by 1 to 3 substituents chosen independently CD.YD.MdC.CH. - 238 - SY-1735A among the hydroxyl, amino, halogen, trifluoromethyl, Cx-C4-alkyl, Cx-C4 ~ alkoxy, CX-C4-alkylamino, di (Cx-C4) alkylamino, carboxyl and sulfo radicals and in the alkyl part with 1 to 3 substituents chosen from the hydroxyl, amino, O ^ -04-alkylamino, di (Cx-C4) alkylamino, Cx-C4 ~ alkoxy carboxyl, halo and sulfo radicals; or a pharmaceutically acceptable salt of this compound. 14. Compound according to claim 13, in the formula of which the heterocyclic radical -O5 is optionally substituted for the nitrogen or carbon atoms of the ring available with up to 5 substituents chosen independently from one another from lower alkyl radicals. 15. Compound according to claim 14, in the formula of which A represents a radical -CH2 ~> -CH2CH2- or \ CH (CH3). 16. A compound according to ‘claim 13, 14 or 15, in the formula of which R ^ · represents an OH CH3CH- radical and the absolute configuration is 5R, 6S, 8R. 17. Composed of formula CD.YD.MdC.CH. - 239 - SY-1735A r8 - R- -Af K — R5 Γ W g N '~' '~ COOR ^ where R8 represents a hydrogen atom and Rl is chosen from the hydrogen atom and the alkyl radicals, alkenyl and alkynyl of 1 to 10 carbon atoms; cycloalkyl and cycloalkylalkyl of 3 to 6 carbon atoms in the ring of the cycloalkyl part and from 1 to 6 carbon atoms in the alkyl parts; phenyl; aralcoyl; aralkenyl and aralkynyl in which the aryl part is a phenyl radical and in which the aliphatic part has 1 to 6 carbon atoms; hetero-aryl, heteroaralkyl, heterocyclic and heterocycloalkyl in which the heteroatom (s) of the aforementioned heterocyclic parts are chosen from 1 to 4 oxygen, nitrogen or sulfur atoms and in which the alkyl parts associated with the heterocyclic parts comprise 1 to 6 carbon atoms, all of which are substituted or unsubstituted, the substituent or substituents of which, with respect to the abovementioned radicals, are independently chosen from: C ^ -Cg-alkyl optionally amino, halogenated, hydroxylated or halogenated carboxylated -0R3 O -0CNR3R4 0 li -CNR3r4 - NR3r4 CD.YD.MdC.CH. - 240 - SY-1735A / NR4 —é \ nr3R4 -S02NR3R4 0 -NHCNR3r4 0 R3CNR4 “-C02R3 = 0 0 -0CR3 -SR3 0 -SR9 0 -SR9 II 0 -CN —n3 -OSO3R3 O Il Q -OS-R9 II 0 0 -nr3s-r9 il 0 -0P (0) (0R3) (OR4) -NR3C = NR4 R3 -NR3c02R4 -no2 where, with regard to the aforementioned substituents, the radicals r3 and R4 are chosen independently from the atom d and the alkyl, alkenyl and alkynyl radicals CD.YD.MdC.CH. - 241 - SY-1735A from 1 to 10 carbon atoms; cycloalkyl, cycloalkyl-alkyl and alkylcycloalkyl of 3 to 6 carbon atoms in the ring of the cycloalkyl part and from 1 to 6 carbon atoms in the alkyl parts; phenyl; aralkyl, aralkenyl and aralkynyl in which the aryl part is a phenyl radical and the aliphatic part has 1 to 6 carbon atoms; and hetero-aryl, heteroaralkyl, heterocyclic and heterocyloalcoyl in which the heteroatom (s) in the aforementioned heterocyclic parts are chosen from 1 to 4 oxygen, nitrogen or sulfur atoms and in which the alkyl parts associated with these heterocyclic parts count 1 to 6 carbon atoms, or else r3 and r4, taken together with the nitrogen atom to which at least one of them is united, can form a pentagonal or hexagonal nitrogen heterocyclic radical; R9 is defined as r3, except that it cannot be a hydrogen atom; or where R1 and R ^, taken together, represent a radical c2 “c10“ alkylene or C2-C10 ”alk ° yliâène hydroxylê; R5 is chosen from alkyl, alkenyl and alkynyl radicals of 1 to 10 carbon atoms; cycloalkyl and cycloalkylalkyl of 3 to 6 carbon atoms in the ring of the cycloalkyl part and from 1 to 6 carbon atoms in the alkyl parts; phenyl; aralkyl, aralkenyl and aralkynyl in which the aryl part is a phenyl radical and in which the aliphatic part has 1 to 6 carbon atoms; hetero-aryl, heteroaralkyl, heterocyclic and heterocycloalkyl in which the heteroatom (s) in the aforementioned heterocyclic parts are chosen from 1 to 4 oxygen, nitrogen or sulfur atoms and in which the alkyl parts associated with the heterocyclic parts count 1 to 6 carbon atoms, all substituted or unsubstituted; the above-mentioned radicals R ^ optionally carrying one to three substituents chosen independently CD.YD.MdC.CH. - 242 - SY-1735A dante among: cl ~ C6-alkyl optionally amino, fluorinated, chlorinated, carboxylated, hydroxylated, or carbamoylated fluoro, chloro or bromo -OR3; -OCO2R3 -OCOR3 -OCONR3R4 0 II û -OS-R9 II O -oxo -NR3R4 R3CONR4- -NR3C02r4 -NR3CONR3R4 O -NR3S-R9 II 0 -SR3 0 -SR9 0 O \ ß n -S-R9 -SO3R3 -co2r3 -CONR3R4 -CN; or phenyl optionally substituted with 1 to 3 fluoro, chloro, bromo, Ci-Cg-alkyl radicals, -OR3, -NR3R4, -SO3R3, -C02R3 or -CONR3R4, where R3, R4 and R9 in these substituents of r5 are such that defined above; or R5 can be combined with CD.YD.MdC.CH. - 243 - SY-1735A GL at another point in the cycle to form a condensed heterocyclic or heteroaromatic radical, the cycle of which may contain additional heteroatoms, chosen from 0, S and N; A represents a Cq-Cβ-alkylene radical in a straight or branched chain; R2 represents a hydrogen atom, an anionic charge or a conventional radical which is easy to remove protective of the carboxyl function, it being understood that when r2 represents a hydrogen atom or a protective radical, there is also a counter ion, and f ~ ^ es represents a radical chosen between <a> where r6, R? and RIO are independently selected from the hydrogen atom and the C1-C4-alkyl radicals; -C4-alkyl substituted by hydroxyl, Ci-C4-alkylamino, di (Ci-C4-alkyl) amino, Ci-C4-alkoxy, amino, sulfo, carboxyl and halo; C3-C6-cycloalkyl; C1-C4-alkoxy; C1-C4-alkylthio; amino; Cx-C4_alcoylamino; di (C1-C4-alkyl) amino; halo; C1-C4-alkanoylamino; CD.YD.MdC.CH. - 244 - SY-1735A Ci-C4-alkanoyloxy; carboxyl; -C02 “Ci-C4-alkyl; hydroxyl; amidinoy guanidino? phenyl, phenyl substituted by one, two or three amino, halo, hydroxyl, trifluoromethyl radicals; Ci-C4 ~ alkyl or C1-C4 “alkoxy; phenyl (C ^ -C4) alkyl in which the phenyl part can optionally be substituted with 1 to 3 substituents mentioned above with respect to the phenyl radical and the alkyl part can optionally be substituted with 1 to 3 substituents mentioned above with respect to the Ci-C4-a.lcoyl radicals; and heteroaryl or heteroaralkyl in which the heteroatom (s) in the aforementioned heterocyclic parts are chosen from 1 to 4 oxygen, nitrogen or sulfur atoms and the alkyl part associated with the heteroaralkyl part has 1 to 6 carbon atoms; or where two of r6, r7 and r8, taken together, can represent a condensed saturated carbocyclic radical, a condensed aromatic carbocyclic radical, a condensed non-aromatic heterocyclic radical or a condensed heteroaromatic radical, which condensed rings are optionally substituted by 1 or 2 of the substituents defined above with respect to r6, r7 and rIO. (b) 5 af R5 f N s / 1 - I or k-E R5 ®l CD.YD.MdC.CH. - 245 - SY-1735A optionally substituted on a carbon atom by 1 to 3 substituents independently chosen from cx-C4-alkyl radicals; Cx-C4 ~ hydroxy-substituted alkyl, Cx-C4-alkylamino, di (Cx-C4-alkyl) amino, Cx-C4-alkoxy, amino, sulfo, carboxyl and halo; c3 “Cß-cycloalcoyle? Cx-C4 ~ alkoxy; Cx-C4-alkylthio; amino; C1-C4-alkylamino; di (C1-C4-alkyl) amino; halo; C] _- C4-alkanoylamino; Cx-C4 ~ alkanoyloxy; carboxyl; -C02 "Ci-C4-alkyl; hydroxyl; amidino; guanidino; phenyl; phenyl substituted by one, two or three amino, halo, hydroxyl, trifluoromethyl; Cx-C4-alkyl or Cx-C4-alkoxy; phenyl (Cx- C4) alkyl, the phenyl part of which may optionally be substituted with 1 to 3 substituents mentioned above with respect to the phenyl radical and the alkyl part, which may optionally be substituted with 1 to 3 substituents mentioned above with regard to the radicals Cx-C4- alkyl; and heteroaryl or heteroaralkyl in which the heteroatom (s) in the aforementioned heterocyclic parts are chosen from 1 to 4 oxygen, nitrogen or sulfur atoms and the alkyl part associated with the heteroaralkyl part has 1 to 6 carbon atoms, or optionally substituted to form a condensed carbocyclic, heterocyclic or heteroaromatic radical optionally substituted by 1 or 2 of the substituents defined above; (c) 5 5 R IC £ © I © I fis r 1] _ç jj N CD.YD.MdC .CH. - 246 - SY-1735A „5 ? β | 5 pi optionally substituted on a carbon atom by 1 or 2 substituents chosen independently from the cl * -C4-alkyl radicals; C1-C4 ~ hydroxy-substituted alkyl, Ci-C4 ~ alkyllamino, di (Ci-C4 “alkyl) amino, Ci-C4-alkoxy / amino, sulfo, carboxyl and halo; C3-C6-cycloalkyl; Ci-C4 ~ alkoxy; C1-C4-alkylthio; amino; C1-C4-alkylamino; di (C1-C4-alkyl) amino; halo; Οχ-C4-alkanoylamino; Cx-C4 ~ alkanoyloxy; carboxyl; -C02-Cx ~ C4-alkyl; hydroxyl; amidino; guanidino; phenyl, phenyl substituted by one, two or three amino, halo, hydroxyl, trifluoromethyl radicals; Cx-C4 ~ alkyl or Ci-C4-alkoxy; phenyl (Ci-C4) alkyl in which the phenyl part can optionally be substituted by 1 to 3 substituents mentioned above with respect to the phenyl radical and the alkyl part can optionally be substituted by 1 to 3 substituents mentioned above with respect to the radicals Cx-C4-alkyl; and heteroaryl or heteroaralkyl in which the heteroatom (s) in the aforementioned heterocyclic parts are chosen from 1 to 4 oxygen, nitrogen or sulfur atoms and the alkyl part associated with the heteroaralkyl part has 1 to 6 carbon atoms, or optionally substituted to form a carbocyclic, heterocyclic or heteroaromatic radical condensed optionally substituted by 1 or 2 of the substituents defined above; CD.YD.MdC.CH. - 247 - SY-1735A (d) R5 R5 f © I eI ei -fl ~ f1 f 1 R5 r5 r5 lg I g I Ay f> II il ou il "V ^ '^ optionally substituted on a carbon atom by a substituent independently selected from C ^ -C4-alkyl radicals; C ^ -C4-alkyl substituted by hydroxyl, Ci-C4-alkylamino, di (Ci-C4-alkyl) amino, Ci ~ C4-alkOxy, amino, sulfo, carboxyl and halo; C3 ~ Cg-cycloalkyl? Ci-C4-alkoxy? Ci ~ C4-alcoylthio? amino? cl ”C4-alkylamino? di (Ci-C4-alkyl) amino? halo? C] _- C4-alkanoylamino? Ci -C4 ~ alkanoyloxy? Carboxyl? -C02 ~ C ^ -C4-alkyl? Hydroxyl? Amidino? Guanidino? Phenyl, phenyl substituted by one, two or three amino, halo, hydroxyl, trifluoromethyl? Cj, -C4 ~ alkyl or Ci -C4-alkoxy? Phenyl (Ci-C4) alkyl in which the phenyl part can optionally be substituted by 1 to 3 substituents mentioned above with respect to the phenyl radical and the alkyl part can optionally be substituted by 1 to 3 substituents mentioned above above about C ^ -C4-alco radicals yle? and heteroaryl or heteroaralkyl in which the heteroatom (s) in the aforementioned heterocyclic parts are chosen from 1 to 4 oxygen, nitrogen or sulfur atoms and the alkyl part associated with the heteroaralkyl part has 1 to CD.YD.MdC.CH . - 248 - SY-1735A 6 carbon atoms; e r e 5 {®] ------ K-R -K ~ ïT - or —H- i where X represents 0, S or NR where R represents a C-L-c ^ alkyl radical; C1-C4-alkyl substituted by 1 to 3 hydroxyl, amino, Cx-C4-alkylamino radicals; di (Cx ~ C4) alcoylamino? C1-C4-alkoxy; carboxyl; halo or sulfo; C3-C6-cycloalkyl; C3-C6-cycloalkyl (Ci-C4) alkyl optionally substituted with 1 to 3 substituents mentioned above in connection with the C 1 -C 4 -alkyl radicals; phenyl; phenyl substituted with 1 to 3 substituents independently chosen from amino, halo, hydroxyl, trifluoromethyl, C1-C4-alkyl, C ^ -C4-alkoxy, Ci-C4-alkylamino, άί (0χ-04) -alkoylamino, carboxyl and sulfo; phenyl (C1-C4) alkyl, the phenyl part of which can optionally be substituted with 1 to 3 substituents mentioned above with respect to the phenyl radical and the alkyl part of which can optionally be substituted with 1 to 3 substituents mentioned above with respect to the C ^ -C4-alkyl radicals; and heatheraryl and heteroaralkyl in which the heteroatom (s) are chosen from 1 to 4 atoms 0, S or N and the alkyl part associated with the heteroaralkyl radical has 1 to 6 carbon atoms, these heteroaryl and heteroaralkyl radicals being optionally substituted in the heterocyclic part by 1 to 3 substituents chosen independently from the hydroxyl, amino, halo, trifluoromethyl, c χ-C4-alkyl, Cx-C4-alkoxy, Cx-C4-alkylamino, di (Cx-C4) _ alkylamino, carboxyl and sulfo radicals, and in the alkyl part with 1 to 3 substituents chosen from CD.YD.MdC.CH. - 249 - SY-1735A hydroxyl, amino, C1-C4-alkylamino / di (Ci-C4) alkylamino / Ci-C4-alkoxy, carboxyl, halo and sulfo radicals, this radical being optionally substituted on a carbon atom by 1 or several substituents independently chosen from C1-C4-alkyl radicals; C1-C4-alkyl substituted by hydroxyl, C1-C4-! alkyllamino, diCi - ^ - alkyl) amino, C1-C4-alkoxy, amino, sulfo; carboxyl or halo; C3-C6_cycl ° “alkyl; Ci-C4 ~ alkoxy; C; p-C4-alkylthio, amino; C1-C4-alkylamino; di (C1-C4-alkyl) amino; halo; C1-C4-alkylamino; C1-C4-alkanoyloxy; carboxyl; -CO2-C1-C4-alkyl; hydroxyl; amidino; guanidino; phenyl; phenyl substituted by one, two or three amino, halo, hydroxyl, trifluoromethyl radicals; Ci-C4 ~ alkyl or Ci-C4-alkoxy; phenyl (Ci-C4) alkyl, the phenyl part of which can optionally be substituted with 1 to 3 substituents mentioned above with respect to the phenyl radical and the alkyl part of which can optionally be substituted with 1 to 3 substituents mentioned above with regard to the C1-C4-alkyl radicals; and hetero-aryl and heteroaralkyl in which the heteroatom (s) of the abovementioned heterocyclic parts are chosen from 1 to 4 oxygen, nitrogen or sulfur atoms and the alkyl part associated with the heteroaralkyl part has 1 to 6 carbon atoms, or optionally substituted to form a condensed carbocyclic, heterocyclic or heteroaromatic radical optionally substituted by 1 or 2 of the radicals defined above; (f) B 5 6 5 (f) Π- -Mf »X_ K-JT σ- · k4 CD.YD.MdC.CH. - 250 - SY-1735A s 5 N-X N N-R5 R \ ®_ 5. T "JJ ° u π- where X represents O, S or NR where R represents a C2-C4-alkyl radical; Ci-C4-alkyl substituted by 1 to 3 hydroxyl, amino, cl-C4_alkylamino; di (C ] _- C4) alkyl C1-C4-alkoxy; carboxyl; halo or sulfo; C3-Cg-cycloalkyl; C3-Cg-cycloalkyl (Ci-C4) alkyl optionally substituted with 1 to 3 substituents mentioned above in connection with C ^ -C4-alkyl radicals; phenyl; phenyl substituted by 1 to 3 substituents independently chosen from amino, halo, hydroxyl, trifluoromethyl, C1-C4-alkyl, Cj-C4 ~ alkoxy, -C4-alkylamino, di (Ci -C4) - alkylamino, carboxyl and sulfo; phenyl (C1-C4) alkyl in which the phenyl part can optionally be substituted with 1 to 3 substituents mentioned above with respect to the phenyl radical and in which the alkyl part can optionally be substituted with 1 with 3 substituents mentioned above with respect to the C 1 -C 4 -alkyl radicals; and heatheraryl and heteroaralkyl in which the heteroatom (s) are chosen from 1 to 4 a volumes 0, S or N and the alkyl part associated with the heteroaralkyl radical has 1 to 6 carbon atoms, these heteroaryl and heteroaralkyl radicals being optionally substituted in the heterocyclic part by 1 to 3 substituents chosen independently from the hydroxyl, amino and halogen radicals, trifluoromethyl, C ^ -C4-alkyl, Ci-C4-alkoxy, Ci-C4-alkylamino, di (Ci ~ C4) -alkylamino, carboxyl and sulfo, and in the alkyl part with 1 to 3 substituents chosen from hydroxyl radicals, amino, C1_c4-alcoylamino, di (Ci ~ CD.YD.MdC.CH. - 251 - SY-1735A C ^ Jalkoylamino, C ^ -C ^ alkoxy, carboxyl, halogeno and sulfo, this radical being optionally substituted on a carbon atom by a substituent chosen independently from the radicals C] _- C4-alkyl; C1-C4 ~ hydroxy-substituted alkyl, C1-C4-alkylamino di (Ci-C4-alkyl) amino, Cx-C4-alkoxy, amino, sulfo; carboxyl or halogeno; Cg-Cg-cycloalkyl; Cx-C4-alkoxy; C1-C4-alkylthio, amino; Ci-C4 ~ alkyllamino; di (C1-C4) alkylamino; halogêno; cl ~ C4-alkanoylamino; Cl-C4-alkanoyloxy; carboxyl; -C02-Ci-C4-alkyl; hydroxyl; amidino; guanidino; phenyl; phenyl substituted with one, two or three amino, halogen, hydroxyl, trifluoromethyl radicals; cl-C4-alkyl or Ci-C4 ~ alkoxy; phenyl (C1-C4) alkyl, the phenyl part of which can optionally be substituted with 1 to 3 substituents mentioned above with respect to the phenyl radical and the alkyl part of which can optionally be substituted with 1 to 3 substituents mentioned above with respect to the phenyl radicals C ^ -C4-alkyl radicals; and heteroaryl and heteroaralkyl in which the heteroatom (s) of the aforementioned heterocyclic parts are chosen from 1 to 4 oxygen, nitrogen or sulfur atoms and the alkyl part associated with the heteroaralkyl part has 1 to 6 carbon atoms; and © 5 s5 (g) y: _ MR \ 7. L. "1 -KK - --- K. N __- KP, R5 -J, -R5 'IT e CD.YD.MdC.CH. - 252 - SY-1735A R5 e -NR îj-NR I ° u © »s ^ sM ES-N where R represents a Cq - ^ - alkyl radical; Ci-C4-alkyl substituted by 1 to 3 hydroxyl, amino, C1-C4 radicals -alkylamino; âi (C ^ -C4) alkylamino; Ci-C4 ~ alkoxy; carboxyl; halo or sulfo; C3-C6-cycloalkyl; C3-C6-cycloalkyl (C1-C4) alkyl optionally substituted with 1 to 3 substituents mentioned above above with regard to the Ci-C4-alkyl radicals; phenyl; phenyl substituted by 1 to 3 substituents chosen independently from the amino, halogeno, hydroxyl, trifluoromethyl, Ci-C4-alkyl, Ci-C4 ~ alkoxy, Cl_C4-alkylamino radicals, di (C ^ -C4) alkylamino, carboxyl and sulfo; phenyl (Ci-C4) -alkyl in which the phenyl part can optionally be substituted by 1 to 3 substituents mentioned above in connection with the phenyl radical and in which the alkyl part can optionally be substituted by 1 to 3 substituents mentioned above about the C] _- C4-alkyl radicals; and heteroaryl and heteroaralkyl in which the heteroatom (s) are chosen from 1 to 4 atoms 0, S or N and the alkyl part associated with the heteroaralkyl radical has 1 to 6 carbon atoms, these heteroaryl and heteroaralkyl radicals being optionally substituted in the part heterocyclic with 1 to 3 substituents independently selected from hydroxyl, amino, halogen, trifluoromethyl, C ^ -C4-alkyl, Ci-C4-alkoxy, Ci-C4-alkylamino, di (Ci-C4) -alkylamino, carboxyl and sulfo radicals , and in the alkyl part with 1 to 3 substituents chosen from hydroxyl, amino, Ci-C4-alkylamino, di (Ci ~ CD.YD.MdC.CH. - 253 - SY-1735A C4) alkylamino, Ci-C4 radicals -alkoxy, carboxyl, halo and sulfo, or a pharmaceutically acceptable salt of this compound. 18.- Compound according to claim 17, in the formula of which represents a radical chosen from (a) -.5 R7 \ ^> <4 — R6 R Y where r5 represents a Ci-Cβ-alkyl radical and r6, R? and RIO each independently represent a hydrogen atom or a radical C ^ -C4 ~ alkyl <b) 4 R5 e? the | . "Λ Λ" / where R5 represents a C ^ -Cg-alkyl radical and the available ring carbon atoms are optionally substituted with 1 to 3 substituents chosen independently- CD.YD.MdC.CH. - 254 - SY-1735A among the radicals Ci-C / j-alkyl; (c) f Te -f II '-f II R5 f I © 1 © K ^ N ^ -v R5 g? \ ^ N \ IH) oa I ij— where r5 represents a C ^ -Cg-alkyl radical and the available ring carbon atoms are optionally substituted with 1 or 2 substituents chosen independently from C 1 -C 4 -alkyl radicals; (d) r 5 r; R Λ | p I g I © J -fl -fl ï il r5 R5 r £ rei x if v. I> L ^ BNv /% yf? Hj II 11 or I CD.YD.MdC.CH. - 255 - SY-1735A or represents a radical C ^ - Cg-alkyl and a ring carbon atom is optionally substituted by a ci-C4-alkyl radical * (e) U5 _ —k J or “x I SX Sx ^. Where r5 represents a radical C ^ -Cß —Alkyl, X represents O, S or NR where R represents a Ci-C / j-alkyl radical and one or more ring carbon atoms available s have optionally substituted with C1-C4-alkyl radicals? (f), -, r — X5 x— S-r5 SS I3 ~ · kx ® C R5 .1 N — R ^ V © -x N * R \ K - X - ~ tJ “i'X where r5 represents a C1-C6-alkyl radical, X represents O, S or NR where R represents a C1-C4-alkyl radical and one or more available ring carbon atoms are optionally substituted by C1-C4-alkyl radicals; and CD.YD.MdC.CH. - 256 - SY-1735A (g) e 5 R5 θ Νν = · ί'Κ .......- "N -------- K, KK" R R5 -Jc ^ jR - -RS TI 6 r5 e ^ * E - WR îj-NrR | or © "*" "where r5 represents a radical C ^ Cg-alkyl and R represents a radical Ci-C4-alkyl. 19. Compound according to claim 18, in the formula of which R ^ represents a hydrogen atom or a CH3 CH3 OH OH CH3CH2-, ^^ CH-, or CH3CH- CH3 ^ CH3 ^ radical. 20. Compound according to claim 18, in the formula of which R1 and r8 together represent a radical CD.YD.MdC.CH. - 257 - SY-1735A HOCH p CH3 ^ 21. Compound according to claim 18, in the formula of which R1 represents an OH CH3CH- radical. 22. Compound according to claim 18, in the formula of which Ri represents an OH CH3CH- radical and the absolute configuration is 5R, 6S, 8R. 23. Compound according to claim 17, 18, 19, 20, 21 or 22, in the formula of which A represents a radical -CH2- or -CHpCHp- · 24. Compound of formula R6 5 ΤΠ_Γ X7 / y K ^ COOR ^ 0 where RÔ represents a hydrogen atom and R ^ is chosen from the hydrogen atom and the alkyl, alkenyl and alkynyl radicals of 1 to 10 atoms carbon; cycloalkyl and cycloalkylalkyl of 3 to 6 carbon atoms in the cycle of the cycloalkyl part and of 1 CD.YD.MdC.CH. - 258 - SY-1735A with 6 carbon atoms in the alkyl parts; phenyl; aralcoyl; aralkenyl and aralkynyl in which the aryl part is a phenyl radical and in which the aliphatic part has 1 to 6 carbon atoms; hetero-aryl, heteroaralkyl, heterocyclic and heterocycloalkyl in which the heteroatom (s) of the aforementioned heterocyclic parts are chosen from 1 to 4 oxygen, nitrogen or sulfur atoms and in which the alkyl parts associated with the heterocyclic parts comprise 1 to 6 carbon atoms, all of which are substituted or unsubstituted, the substituent or substituents of which, with respect to the abovementioned radicals, are independently chosen from: C ^ -Cg-alkyl optionally amino, halogenated, hydroxylated or carboxylated halogen -OR3 O -0CNR3r4 O -CNR3r4 -NR3R4 _ // m4 \ NR3R4 -S02NR3R4 O -NHCNr3r4 0 R3CNR4- -co2r3 = 0 O -OCR3 -SR3 CD.YD.MdC.CH. 259 - SY-1735A ο Il -SR9 O -SR9 II O -CN -n3 -OSO3R3 O Il _ -OS-R9 II OO -NR3S-R9 II O -0P (0) (0R3) (0r4) -nr3c = nr4 r3 -NR3C02R4 -no2 where, with regard to the aforementioned substituents, the radicals R3 and r4 are chosen independently from the hydrogen atom and the alkyl, alkenyl and alkynyl radicals of 1 to 10 carbon atoms; cycloalkyl, cycloalkyl-alkyl and alkylcycloalkyl of 3 to 6 carbon atoms in the ring of the cycloalkyl part and from 1 to 6 carbon atoms in the alkyl parts; phenyl; aralkyl, aralkenyl and aralkynyl in which the aryl part is a phenyl radical and the aliphatic part has 1 to 6 carbon atoms; and hetero-aryl, heteroaralkyl, heterocyclic and heterocycloalkyl in which the heteroatom (s) in the aforementioned heterocyclic parts are chosen from 1 to 4 oxygen, nitrogen or sulfur atoms and in which the alkyl parts associated with these heterocyclic parts count 1 to 6 carbon atoms, or else R3 and R4, CD.YD.MdC.CH. - 260 - SY-1735A j taken together with the nitrogen atom to which at least one of them is united, can form a heterocyclic nitrogen pentagonal or hexagonal radical; r9 is defined as r3, except that it cannot be a hydrogen atom; or where R1 and r8, taken together, represent a C2-Cio-alkylidene or C2-C10 “alko ylene hydroxyl radical; R 5 is chosen from alkyl, alkenyl and alkynyl radicals of 1 to 10 carbon atoms; cycloalkyl and cycloalkylalkyl of 3 to 6 carbon atoms in the ring of the cycloalkyl part and from 1 to 6 carbon atoms in the alkyl parts; phenyl; aralkyl, aralkenyl and aralkynyl in which the aryl part is a phenyl radical and in which the aliphatic part has 1 to 6 carbon atoms; hetero-aryl, heteroaralkyl, heterocyclic and heterocycloalkyl in which the heteroatom (s) in the aforementioned heterocyclic parts are chosen from 1 to 4 oxygen, nitrogen or sulfur atoms and in which the alkyl parts associated with the heterocyclic parts count 1 to 6 carbon atoms, all substituted or unsubstituted; the aforementioned r5 radicals optionally carrying one to three substituents chosen independently from: Ci-Cg-alkyl optionally amino, fluorinated, chlorinated, carboxylated, hydroxylated, or carbamoylê fluoro, chloro or bromo -OR3 -oco2r3 -OCOR3 -OCONR3r4 OQ -0S-R9 II O -oxo -NR3r4 CD.YD.MdC.CH. 261 - SY-1735A r3conr4- -NR3C02r4 -NR3C0NR3r4 0 -NR3s-R9 kl 0 -SR3 O 'f -SR9 O O 0 -S-R9 -SO3R3 -C02r3 -CONR3r4 -CN; or phenyl optionally substituted by 1 to 3 fluoro, chloro, bromo, C ^ -Cg-alkyl radicals, -OR3, -nr3r4, -SO3R3, -CO2R3 or -CONr3r4 / where r3, r4 and R9 in these substituents of R5 are such as defined above; or else r5 can be united with o ~ at another point of the cycle to form a heterocyclic or condensed heteroaromatic radical, the cycle of which can contain additional heteroatoms, chosen between 0, S and N; A represents a C ^ -Cg-alkylene radical in a straight or branched chain; r2 represents a hydrogen atom, an anionic charge or a conventional radical which is easy to remove protective of the carboxyl function, it being understood that when R2 represents a hydrogen atom or a protective radical, there is also a counter CD.YD.MdC .CH. - 262 - SY-1735A ion, and Ae.s -r h-Λ X— / represents a radical chosen between where r6, r7 and RIO are chosen independently from the hydrogen atom and the radicals C - ^ - C ^ alkyl; Οχ-C4-alkyl substituted by hydroxyl, Ci-C4 ~ alkylamino, di (Cx-C4-alkyl) amino, Ci-C4 ~ alkoxy, amino, sulfo, carboxyl and halogeno; Cg-Cg-cycloalkyl; C1-C4-alkoxy; Cx-C4-alcoylthio? amino; C1-C4-alkylamino; di (Cx-C4-alkyl) amino; halogêno; Cx-C4-alkanoylamino; C2-C4-alkanoyloxy; carboxyl; -CC> 2-Cx-C4-alkyl; hydroxyl; amidino; guanidino; phenyl, phenyl substituted by one, two or three amino, halogen, hydroxyl, trifluoromethyl radicals; Cx-C4-alkyl or Cx-C4 ~ al-coxy; phenyl (Cx-C4) alkyl in which the phenyl part can optionally be substituted with 1 to 3 substituents mentioned above with respect to the phenyl radical and the alkyl part can optionally be substituted with 1 to 3 substituents mentioned above with respect to the radicals Cx ~ C4-alkyl and heteroaryl or heteroaral-coyle in which the heteroatom (s) in the aforementioned heterocyclic parts are chosen from 1 to 4 oxygen, nitrogen or sulfur atoms and the alkyl part associated with the heteroaralkyl part has 1 to 6 carbon atoms, or where two of R.6, r7 and CD.YD.MdC.CH. - 263 - SY-1735A RIO, taken together, can represent a condensed saturated carbocyclic radical, a condensed aromatic carbocyclic radical, a condensed non-aromatic heterocyclic radical or a condensed heteroaromatic radical, which condensed rings are optionally substituted by 1 or 2 of the defined substituents above about r6, r7 and RIO; or a pharmaceutically acceptable salt of this compound. 25. A compound according to claim 24, in the formula of which R1 represents a hydrogen atom or a CH3 CÜ3 OH OH CH3CH2-, ^ C- or CH3CH- CH; T CH3 ^ radical. 26. A compound according to claim 24, in the formula of which R1 and R8 together represent a radical hoch2 ch3 ^ 27. Compound according to claim 24, in the formula of which R1 represents a radical 0Η CH3CH- 28. A compound according to claim 24, in the formula of which Ri represents an OH CH3CH_ CD.YD.MdC.CH radical. - 264 - SY-1735A and the absolute configuration is 5R, 6S, 8R. 29. Compound according to claim 24, 25, 26, 27 or 28, in the formula of which A represents a radical -CH2- or -CH2CH2- · 30. Compound of formula rS -h1— Τ 'Γ q K "COOR2 where RS represents a hydrogen atom and R ^ is chosen from the hydrogen atom and the alkyl, alkenyl and alkynyl radicals of 1 to 10 atoms carbon; cycloalkyl and cycloalkylalkyl of 3 to 6 carbon atoms in the ring of the cycloalkyl part and from 1 to 6 carbon atoms in the alkyl parts; phenyl; aralkyl; aralkenyl and aralkynyl of which the aryl part is a phenyl radical and of which the aliphatic part has 1 to 6 carbon atoms; hetero-aryl, heteroaralkyl, heterocyclic and heterocyclo-alkyl of which the hetero-atom (s) of the above-mentioned heterocyclic parts are chosen from 1 to 4 atoms of oxygen, nitrogen or sulfur and the alkyl parts associated with heterocyclic parts comprise 1 to 6 carbon atoms, all of which are substituted or unsubstituted, the substituent or substituents of which, with respect to the abovementioned radicals, are independently chosen from: CD.YD.MdC.CH. - 265 - SY-1735A C ^ -Cg-alkyl eventual Amino, halogenated, hydroxylated or halogenated carboxylated -OR3 O -OCNR3r4 0 -CNR3r4 -Nr3r4 _ //, Ri \ Nr3r4 -so2nr3r4 O -NHCNR3r4 0 R3CNR4- -co2r3 = 0 O -OCR3 -SR3 0 -R9 0 -CN -N3 -0S03r3 0 Il Q -0S-R9 II 0 CD.YD.MdC.CH. - 266 - SY-1735A ο -NR3S-R9 II ο -0P (0) (0R3) (0R4) -NR3c = NR4 r3 -NR3C02R4 -no2 where, with regard to the aforementioned substituents, the radicals r3 and R4 are chosen independently from the hydrogen atom and the alkyl, alkenyl and alkynyl radicals of 1 to 10 carbon atoms; cycloalkyl, cycloalkyl-alkyl and alkylcycloalkyl of 3 to 6 carbon atoms in the ring of the cycloalkyl part and from 1 to 6 carbon atoms in the alkyl parts; phenyl; aralkyl, aralkenyl and aralkynyl in which the aryl part is a phenyl radical and the aliphatic part has 1 to 6 carbon atoms; and hetero-aryl, heteroaralkyl, heterocyclic and heterocyloalkyl in which the heteroatom (s) in the aforementioned heterocyclic parts are chosen from 1 to 4 oxygen, nitrogen or sulfur atoms and in which the alkyl parts associated with these heterocyclic parts count 1 to 6 carbon atoms, or alternatively r3 and R4, taken together with the nitrogen atom to which at least one of them is united, can form a pentagonal or hexagonal nitrogen heterocyclic radical; R ^ is defined as r3, except that it cannot be a hydrogen atom; or where Ri and r8, taken together, represent a C2-C10-alkylene radical or C2-C10 "alkyl1; * - hydroxylated d®ne; r5 is chosen from alkyl, alkenyl and alkynyl radicals of 1 to 10 carbon atoms ; cycloalkyl and cycloalkylalkyl of 3 to 6 carbon atoms in the cycle of the cycloalkyl part and from 1 to 6 carbon atoms in the alkyl parts; CD.YD.MdC.CH. - 267 - SY-1735A phenyl; aralkyl, aralkenyl and aralkynyl in which the aryl part is a phenyl radical and in which the aliphatic part has 1 to 6 carbon atoms; hetero-aryl, heteroaralkyl, heterocyclic and heterocycloalkyl in which the hetero-atom or atoms in the abovementioned heterocyclic parts are chosen from 1 to 4 oxygen, nitrogen or sulfur atoms and of which the alkyl parts associated with the heterocyclic parts have 1 to 6 carbon atoms, all substituted or unsubstituted; the abovementioned radicals R3 optionally carrying one to three substituents chosen independently from: C ^ -Cg-al optionally amino, fluorinated, chlorinated, carboxylated, hydroxylated, or carbamoylated coro fluorine, chloro or bromo -OR3 -oco2r3 -OCOR3 -OCONR3r4 O 11 Q -SR9 II O -0X0 -NR3R4 R3CONR4- -NR3C02R4 -NR3CONR3r4 O -NR3S-R9 II O -SR3 O ♦ -SR9 O O —S-R9 CD.YD.MdC.CH. - 268 - SY-1735A -so3r3 -C02R3 -CONR3r4 -CN; or phenyl optionally substituted by 1 to 3 fluoro, chloro, bromo, Ci-C6 ~ alkyl, -0R3, -Nr3r4, -SO3R31 -C02R3 or -CONr3r4, where r3, r4 and r9 in these substituents of r5 are as defined above; or r5 may be joined to O at another point in the cycle to form a condensed heterocyclic or heteroaromatic radical, the ring of which may contain additional heteroatoms, chosen from O, S and N; A represents a C ^ -Cg-alkylene radical in a straight or branched chain; r2 represents a hydrogen atom, an anionic charge or a conventional radical which is easy to: remove protective from the carboxyl function, it being understood that when r2 represents a hydrogen atom or a protective radical, there is also a counter ion, and i ~ ^ e 5 - 'NR represents a radical of formula CD.YD.MdC.CH. - 269 - SY-1735A R5 R5 e | e | Λ! or 4 optionally substituted on a carbon atom by 1 to 3 substituents independently chosen from cl-C4-alkyl radicals; Ci-C / j-alkyl substituted by hydroxyl, Cj-C ^ alkyllamino, di (C; [- C4-alkyl) amino, C ^ -C4-alkoxy, amino, sulfo, carboxyl and halogeno; C3-C6-cycloalkyl; C1-C4-alkoxy; C1-C4-alkylthio; amino; cl-c4-alcoylamino? di (C1-C4-alkyl) amino; halogêno; C] _- C4 ~ alkanoylamino; C1-C4-alkanoyloxy; carboxyl; -C02 “cl-C4" alkyl; hydroxyl; amidino; guanidino; phenyl., Phenyl substituted by one, two or three amino, halogen, hydroxyl, trifluoromethyl; Cj-C4-alkyl or Ci-C4-alkoxy; phenyl (Ci -C4) alkyl, the phenyl part of which may optionally be substituted with 1 to 3 substituents mentioned above with respect to the phenyl radical and the alkyl part, which may optionally be substituted with 1 to 3 substituents mentioned above with respect to the C1-C4 radicals ~ alkyl and heteroaryl or heteroaralkyl in which the heteroatom (s) in the aforementioned heterocyclic parts are chosen from 1 to 4 oxygen, nitrogen or sulfur atoms and the alkyl part associated with the heteroaralkyl part has 1 to CD.YD.MdC .CH. - 270 - SY-1735A 6 carbon atoms, or optionally substituted to form a carbocyclic, heterocyclic or heteroaromatic radical condensed optionally substituted by 1 or 2 of the substituents defined above; or a pharmaceutically acceptable salt thereof posed. 31. Compound according to claim 30, in the formula of which = 5 Kj - * represents a radical K5 J 's 32. Compound according to claim 30, in the formula of which - \ '€ -R5 w represents a radical R5 ®l CD.YD.MdC.CH. - 271 - SY-1735A 33. A compound according to claim 30, in the formula of which 0! represents a radical K5 © I 34. Compound according to claim 30, 31, 32 or 33, in the formula of which Ri represents a hydrogen atom or a CH3 CH3 OH OH CH3CH2-,> ^ CH-, '"^ C- or CH3CH- CH3 ^ radical. CH3 ^ * 35. Compound according to claim 30, 31, 32 or 33, in the formula of which r! and r8 together represent a HOCH 2 ^ c = ch3 ^ 36 radical. - Compound according to claim 30, 31, 32 or 33, in the formula of which R1 represents a radical CD.YD.MdC.CH. - 272 - SY-1735A OH CH3CH- 37. Compound according to claim 30, 31, 32 or 33, in the formula of which R1 represents an OH »CH3CH- radical and the absolute configuration is 5R, 6S, 8R. 38. Compound according to claim 30, 31, 32 or 33, in the formula of which A represents a radical -CH2- or -CH2CH2-, R ^ represents an OH radical CH3CH- and the absolute configuration is 5R, 6S, 8R. 39. Compound of formula ^ I wz --w where RÔ represents a hydrogen atom and Rl is chosen from the hydrogen atom and the alkyl, alkenyl and alkynyl radicals of 1 to 10 carbon atoms 7 cycloalkyl and cycloalkyl of 3 to 6 carbon atoms in the ring of the cycloalkyl part and from 1 to 6 carbon atoms in the alkyl parts; CD.YD.MdC.CH. - 273 - SY-1735A phenyl; aralkoyley aralkenyl and aralkynyl in which the aryl part is a phenyl radical and in which the aliphatic part has 1 to 6 carbon atoms; heteroaryaryl, heteroaralkyl, heterocyclic and heterocycloalkyl in which the heteroatom (s) of the abovementioned heterocyclic parts are chosen from 1 to 4 oxygen, nitrogen or sulfur atoms and in which the alkyl parts associated with the heterocyclic parts comprise 1 to 6 carbon atoms, all of which are substituted or unsubstituted, the substituent or substituents of which, with respect to the abovementioned radicals, are independently chosen from: Ci-Cß-alkyl optionally amino, halogenated, hydroxylated or carboxylated halogen -OR3 O -OCNR3r4 0 -CNR3r4 -NR3R4 _TR4 \ Nr3r4 -so2nr3r4 0 -NHCNR3R4 0 R3CNR4- -CO2R3 = 0 O -OCR3 -SR3 O it -SR9 CD.YD.MdC.CH. - 274 - SY-1735A ο -SR9 II ο -CN -n3 -OSO3R3 0 MQ -0S-R9 II 0 0 -NR3S-R9 ii o -OP (O) (OR3) (or4) -NR3c = NR4 R3 -NR3c02R4 “NO 2 where, with regard to the abovementioned substituents, the radicals R 1 and R 4 are independently chosen from the hydrogen atom and the alkyl, alkenyl and alkynyl radicals of 1 to 10 carbon atoms; cycloalkyl, cycloalkyl-alkyl and alkylcycloalkyl of 3 to 6 carbon atoms in the ring of the cycloalkyl part and from 1 to 6 carbon atoms in the alkyl parts; phenyl; aralkyl, aralkenyl and aralkynyl in which the aryl part is a phenyl radical and the aliphatic part has 1 to 6 carbon atoms; and hetero-aryl, heteroaralkyl, heterocyclic and heterocycloalkyl in which the heteroatom (s) in the aforementioned heterocyclic parts are chosen from 1 to 4 oxygen, nitrogen or sulfur atoms and in which the alkyl parts associated with these heterocyclic parts count 1 to 6 carbon atoms, or else r3 and R4 / taken together with the nitrogen atom to which at least one of them is united, can form a hetero radical CD.YD.MdC.CH. - 275 - SY-1735A cyclic nitrogen pentagonal or hexagonal; r9 is defined as r3, except that it cannot be a hydrogen atom; or alternatively where R1 and RÖ, taken together, represent a C2-Cio-alkylidene or C2-Cio ~ hydroxylated alkylene radical; R5 is chosen from alkyl, alkenyl and alkynyl radicals of 1 to 10 carbon atoms; cycloalkyl and cycloalkylalkyl of 3 to 6 carbon atoms in the ring of the cycloalkyl part and from 1 to 6 carbon atoms in the alkyl parts; phenyl; aralkyl, aralkenyl and aralkynyl in which the aryl part is a phenyl radical and in which the aliphatic part has 1 to 6 carbon atoms; hetero-aryl, heteroaralkyl, heterocyclic and heterocycloalkyl in which the heteroatom (s) in the aforementioned heterocyclic parts are chosen from 1 to 4 oxygen, nitrogen or sulfur atoms and in which the alkyl parts associated with the heterocyclic parts count 1 to 6 carbon atoms, all substituted or unsubstituted; the aforementioned r5 radicals optionally carrying one to three substituents chosen independently from: Ci-C6-alkyl optionally amino, fluorinated, chlorinated, carboxylated, hydroxylated, or carbamoylated fluoro, chloro or bromo -OR3 -0C02R3 -0C0R3 -OCONR3r4 0 II .9 - 0S-R II 0 -0X0 -NR3r4 R3CONR4- -NR3co2r4 ÔD.YD.MdC.CH. - 276 - SY-1735A -NR3CONR3R4 ο -NR3S-R9 II 0 -SR3 0 t -SR9 0 0 -SO3R3 -CO2R3 -CONR3R4 -CN; or phenyl optionally substituted with 1 to 3 fluoro, chloro, bromo, Ci-Cg-alkyl radicals, -OR3, -NR3R4, -SO3R3, -C02R3 or -CONR3R4, where R3, R4 and r9 in these substituents of R 5 are such as defined above; or R ^ may be united with O at another point in the cycle to form a condensed heterocyclic or heteroaromatic radical, the cycle of which may contain additional heteroatoms, chosen from O, S and N; A represents a C ^ -Ce-alkylene radical in a straight or branched chain; r2 represents a hydrogen atom, an anionic charge or a conventional radical which is easy to remove, protective of the carboxyl function, it being understood that when r2 represents a hydrogen atom or a protective radical, there is also a counter ion, and CD. YD.MdC.CH. - 277 - SY-1735A represents a radical of formula K5 K5 f el 5 e | - / Ί -fa n / f or f \ _ optionally substituted on a carbon atom by 1 to 3 substituents chosen independently from the Ci-C4-alkyl radicals; C 1 -C 4 alkyl substituted by hydroxyl, C 1 -C 4 alkylamino, di (C 1 -C 4 alkyl) amino, C 1 -C 4 alkoxy, amino, sulfo, carboxyl and halogeno; C3-Cg-cycloalkyl; C1-C4-alkoxy; Cj - ^ - alcoylthio; amino; C ^ -C4-alkyllamino; di (C1-C4-alkyl) amino; halogêno; C] _- C4-alkanoylamino; cl-C4-alkanoyloxy; carboxyl; -CO2-Ci-C4 ~ alkyl; hydroxyl; amidino; guanidino; phenyl, phenyl substituted by one, two or three amino, halogeno, hydroxyl, trifluoromethyl radicals; C1-C4-alkyl or C1-C4-alkoxy; phenyl (Ci-C4) alkyl in which the phenyl part can optionally be substituted by 1 to 3 substituents mentioned above with respect to the phenyl radical and the alkyl part can optionally be, CD.YD.MdC.CH. - 278 - SY-1735A substituted with 1 to 3 substituents mentioned above with respect to the C 1 -C 4 -alkyl radicals; and heteroaryl or heteroaralkyl in which the heteroatom (s) in the aforementioned heterocyclic parts are chosen from 1 to 4 oxygen, nitrogen or sulfur atoms and the alkyl part associated with the heteroalkyl part has 1 to 6 carbon atoms, or optionally substituted to form a condensed carbocyclic, heterocyclic or heteroaromatic radical optionally substituted with 1 to 2 of the substituents defined above; or a pharmaceutically acceptable salt of this compound. 40. Compound according to claim 39, in the formula of which R1 represents a hydrogen atom or a CH3 CH3 oh oh CH3CH2-, CH-, C- or CH3CH- ch3 ^ ch3 ^ radical. 41. Compound according to claim 39, in the formula of which R1 and RÖ together represent a radical HOCH 2 ^ C = ch3 ^ 42. Compound according to claim 39, in the formula in which Ri represents an OH CH3CH- radical. 43. Compound according to claim 39, in the formula of which Ri represents a radical CD.YD.MdC.CH. - 279 - SY-1735A OH CH3ch- and the absolute configuration is 5R, 6S, 8R. 44. A compound according to claim 39, 40, 41, 42 or 43, in the formula of which A represents a radical -CH2- or -CH2CH2-. 45. Compound of formula RB - 't ^ r vj1 *' —K- ^ 2 0 ^ C00R where r8 represents a hydrogen atom and Rl is chosen from the hydrogen atom and the alkyl, alkenyl and alkynyl radicals of 1 to 10 carbon atoms; cycloalkyl and cycloalkylalkyl of 3 to 6 carbon atoms in the ring of the cycloalkyl part and from 1 to 6 carbon atoms in the alkyl parts; phenyl; aralcoyl; aralkenyl and aralkynyl in which the aryl part is a phenyl radical and in which the aliphatic part has 1 to 6 carbon atoms; heteroaryl, heteroaralkyl, heterocyclic and heterocycloalkyl in which the heteroatom (s) of the abovementioned heterocyclic parts are chosen from 1 to 4 oxygen, nitrogen or sulfur atoms and in which the alkyl parts associated with the heterocyclic parts comprise 1 to 6 carbon atoms, all of which are substituted or unsubstituted, in which the substituent or substituents with respect to the abovementioned radicals are independently chosen from; C ^ -Cg-alkyl optionally amino, halogenated, CD.YD.MdC.CH. - 280 - SY-1735A hydroxylated or halogenated carboxylated -0R3 0 Il „-OCNR3r4 O II -CNR3r4 -NR3r4 / NR3 - (\ Nr3r4 -S02NR3r4 O -NHCNR3r4 0 r3cNR4“ -CO2R3 = 0 O -OCR3 -S3 0 -SR9 II O -CN “N 3 -0S03r3 0 II -0S-R9 II 0 O -NR3s-R9 II 0 CD.YD.MdC.CH. - 281 - SY-1735A -0P (0) (0R3) (OR4 ) -NR3c = NR4 R3 -NR3C02R4 -no2 where, with regard to the abovementioned substituents, the radicals r3 and R4 are chosen independently from the hydrogen atom and the alkyl, alkenyl and alkynyl radicals of 1 to 10 carbon atoms; cycloalkyl , cycloalkylalkyl and alkylcycloalkyl of 3 to 6 carbon atoms in the ring of the cycloalkyl part and of 1 to 6 carbon atoms in the alkyl parts; phenyl; aralkyl, aralkenyl and aralkynyl of which the aryl part is a phenyl radical and the aliphatic part has 1 to 6 carbon atoms; and hetero-aryl, heteroaralkyl, heterocyclic and heterocycloalkyl of which the heteroatom (s) in the heterocyclic parts mentioned above are chosen from 1 to 4 oxygen, nitrogen or sulfur atoms and of which the alkyl parts associated with these heterocyclic parts have 1 to 6 carbon atoms, or else R3 and R4, taken together with the atom of nitrogen to which at least one of them is linked, can form a pentagonal or hexagonal nitrogen heterocyclic radical; r9 is defined as r3, except that it cannot be a hydrogen atom; or where R1 and R ^, taken together, represent a C2-Cio-alkylidene or C2-C; Li) -alkyllene hydroxyl radical; r5 is chosen from alkyl, alkenyl and alkynyl radicals of 1 to 10 carbon atoms; cycloalkyl and cycloalkylalkyl of 3 to 6 carbon atoms in the ring of the cycloalkyl part and from 1 to 6 carbon atoms in the alkyl parts; phenyl; aralkyl, aralkenyl and aralkynyl in which the aryl part is a phenyl radical and in which the aliphatic part has 1 to 6 carbon atoms; hetero- CD.YD.MdC.CH. - 282 - SY-1735A aryl, heteroaralkyl, heterocyclic and heterocycloalkyl in which the heteroatom (s) in the aforementioned heterocyclic parts are chosen from 1 to 4 oxygen, nitrogen or sulfur atoms and in which the alkyl parts associated with the parts heterocyclic have 1 to 6 carbon atoms, all substituted or unsubstituted, · the abovementioned R5 radicals optionally carrying one to three substituents chosen independently from: C ^ -Cg-alkyl optionally amino, fluorinated, chlorinated, carboxylated, hydroxylated, or carbamoylated fluoro , chloro or bromo -OR3 -0C02r3 -OCOR3 -OCONR3R4 0 I "Q -OS-R9 II O -oxo -NR3R4 r3conr4- -NR3q02R4 -NR3CONR3R4 O -NR3S-R9 II O -SR3 O î -SR9 OO -S -9 -SO3R3 -C02r3 -CONR3R4 CD.YD.MdC.CH. - 283 - SY-1735A “CN; or phenyl optionally substituted with 1 to 3 fluoro, chloro, bromo, Ci-Cg-alkyl radicals, -0R3, -nr3r4, -S03r3 # -CO2R3 OR -CONR3R4, where R3, R4 and R $ in these substituents of R 5 are as defined above? or R5 can be joined to o · - at another point in the cycle to form a condensed heterocyclic or heteroaromatic radical, the cycle of which can contain additional heteroatoms, chosen from 0, S and N; A represents a C1-C6-alkylene radical in straight or branched chain; r2 represents a hydrogen atom, an anionic charge or a conventional radical which is easy to remove protective of the carboxyl function, it being understood that when r2 represents a hydrogen atom or a protective radical, there is also a counter ion, and 5 - represents a radical of formula R5 R5 f5 e I eI ed ^ O H '* CD.YD.MdC.CH. - 284 - SY-1735A a5 f 'f 6 eN eiL î ^ nV> XN I l I il or i X' ^ optionally substituted on a carbon atom by a substituent chosen independently from the radicals C] .- C4-alkyl; Ci-C / j-alkyl substituted by hydroxyl, Ci-C4-alkylamino, di (Ci-C4) alkylamino, Ci-C4-alkoxy "amino, sulfo, carboxyl and balogeno; C3-C5-cycloalkyl; C1-C4-alkoxy; C1-C4-alkylthio; amino; cl “C4-alkylamino; di (C1-C4) alkylamino; balogeno; C χ-C4-alkanoylamino; Cx-C4-alkanoyloxy; carboxyl; -CO2-Ci-C4-alkyl; hydroxyl; amidino; guanidino; phenyl, phenyl substituted by one, two or three amino, halo, hydroxyl, trifluoromethyl radicals; C1-C4-alkyl or Ci-c4-alkoxy; phenyl (Cx-C4) alkyl in which the phenyl part can optionally be substituted with 1 to 3 substituents mentioned above with respect to the phenyl radical and the alkyl part can optionally be substituted with 1 to 3 substituents mentioned above with respect to the radicals Cx-C4 ~ alkyl; and beteroaryl or heteroaralkyl in which the beteroatom (s) in the abovementioned heterocyclic parts are chosen from 1 to 4 oxygen, nitrogen or sulfur atoms and the alkyl part associated with the heteroaralkyl part has 1 to 6 carbon atoms; or a pharmaceutically acceptable salt of this compound. 46.- Compound according to claim 45, in the formula of which R1 represents a hydrogen atom or a CD.YD.MdC.CH. radical. - 285 - SY-1735A CH3 CH3 (j) H OH CH3CH2-, "^ CH-, ^^ C- or CH3CH- ch3 ^ ch3 ^ 47. A compound according to claim 45, in the formula of which R1 and r8 together represent a radical HOCH2 ^ C = ch3 ^ 48. Compound according to claim 45, in the formula of which R ^ represents an OH ch3ch- radical. 49. A compound according to claim 45, in the formula of which R1 represents an OH ch3ch- radical and the absolute configuration is 5R, 6S, 8R. 50. Compound according to claim 45, 46, 47, 48 or 49, in the formula of which A represents a radical -CH2- or -CH2CH2- · 51. Compound of formula CD.YD.MdC.CH. - 286 - SY-1735A * B s ^ / ~ \ e R1 - A-Γ N-R5 [Γ 0 <i? K ^ COOR2 where r8 represents a hydrogen atom and Rl is chosen from the hydrogen atom and the alkyl, alkenyl and alkynyl radicals of 1 to 10 carbon atoms; cycloalkyl and cycloalkylalkyl of 3 to 6 carbon atoms in the ring of the cycloalkyl part and from 1 to 6 carbon atoms in the alkyl parts; phenyl; aralcoyl; aralkenyl and aralkynyl in which the aryl part is a phenyl radical and in which the aliphatic part has 1 to 6 carbon atoms; hetero-aryl, heteroaralkyl, heterocyclic and heterocycloalkyl in which the heteroatom (s) of the aforementioned heterocyclic parts are chosen from 1 to 4 oxygen, nitrogen or sulfur atoms and in which the alkyl parts associated with the heterocyclic parts comprise 1 to 6 carbon atoms, all of which are substituted or unsubstituted, the substituent or substituents of which, with respect to the abovementioned radicals, are independently chosen from: C] _- Cg-alkyl optionally amino, halogenated, hydroxylated or carboxylated halo -0R3 0 -OCNr3r4 0 11 -CNR3r4 -NR3R4 CD * YD.MdC.CH. - 287 - SY-1735A, NR3 - / 7 \ nr3R4 -S02NR3r4 O -NHCNr3r4 O R3CNR4- -co2R3 = 0 0 -OCR3 -SR3 0 -SR9 O II O -SR9 II 0 -CN -n3 -0S03r3 OHQ -OS- R9 II 0 0 -NR3S-R9 II 0 -0P (0) (OR3) (0R4) -NR3c = NR4 R3 -NR3c02R4 -no2 where, with regard to the aforementioned substituents, the radicals R3 and r4 are chosen independently from the atom of hydrogen and the alkyl, alkenyl and alkynyl radicals CD.YD.MdC.CH. - 288 - SY-1735A from 1 to 10 carbon atoms; cycloalkyl, cycloalkyl-alkyl and alkylcycloalkyl of 3 to 6 carbon atoms in the ring of the cycloalkyl part and from 1 to 6 carbon atoms in the alkyl parts; phenyl; aralkyl, aralkenyl and aralkynyl in which the aryl part is a phenyl radical and the aliphatic part has 1 to 6 carbon atoms; and hetero-aryl, heteroaralkyl, heterocyclic and heterocyloalkyl in which the heteroatom (s) in the aforementioned heterocyclic parts are chosen from 1 to 4 oxygen, nitrogen or sulfur atoms and in which the alkyl parts associated with these heterocyclic parts count 1 to 6 carbon atoms, or alternatively R3 and r4, taken together with the nitrogen atom to which at least one of them is united, can form a pentagonal or hexagonal nitrogen heterocyclic radical; R ^ is defined as r3, except that it cannot be a hydrogen atom; or where Ri and R ^, taken together, represent a radical C2 “Cio-alk ° ylidene or C2-Cio-alkylidene hydroxylated; R ^ is chosen from alkyl -, alkenyl and alkynyl radicals of 1 to 10 carbon atoms; cycloalkyl and cycloalkylalkyl of 3 to 6 carbon atoms in the ring of the cycloalkyl part and from 1 to 6 carbon atoms in the alkyl parts; phenyl; aralkyl, aralkenyl and aralkynyl in which the aryl part is a phenyl radical and in which the aliphatic part has 1 to 6 carbon atoms; hetero-aryl, heteroaralkyl, heterocyclic and heterocycloalkyl in which the heteroatom (s) in the aforementioned heterocyclic parts are chosen from 1 to 4 oxygen, nitrogen or sulfur atoms and in which the alkyl parts associated with the heterocyclic parts count 1 to 6 carbon atoms, all substituted or unsubstituted; the aforementioned r5 radicals optionally carrying one to three substituents chosen independently CD.YD.MdC.CH. - 289 - SY-1735A especially among: cl ~ C6-alkyl optionally amino, fluorinated, chlorinated, carboxylated, hydroxylated, or carbamoylated fluoro, chloro or bromo -OR3 -OC02r3 -OCOR3 -0C0NR3r4 O 1 'Q -OS-R9 il O -0X0 -Nr3r4 R3CONR4- -NR3co2R4 -NR3CONR3r4 0 Jl Λ -NR3S-R9 II 0 -SR3 î Q -SR9 0 O -S-R9 -SO3R3 -co2r3 -C0NR3r4 -CN 7 or phenyl optionally substituted by 1 to 3 , chloro, bromo, Ci-C6-alkyl, -OR3, -NR3R4, -S03r3 # -co2R3 or -CONR3r4, where R3, r4 and R9 in these substituents of R 5 are as defined above; or r5 can be combined with CD.YD.MdC.CH. - 290 - SY-1735A Oe- at another point in the cycle to form a condensed heterocyclic or heteroaromatic radical, the cycle of which may contain additional heteroomes, chosen from 0, S and N; A represents a Cji-Cg-alkylene radical in a straight or branched chain; r2 represents a hydrogen atom, an anionic charge or a conventional radical which is easy to remove protective of the carboxyl function, it being understood that when R2 represents a hydrogen atom or a protective radical, there is also a counter ion, and / ' '"Λ6 5 represents a radical of formula 6 5 6 5 _K-K -NH -P- OR -f 1 where X represents O, S or NR where R represents a radical Ci ~ C4-alkyl; Ci-C4 ~ substituted alkyl by 1 to 3 hydroxyl, amino, Ci-C4-alkylamino; di (Ci-C4-alkyl) amino; Cj-C4-alkoxy; carboxyl; halo or sulfo; C3-C6-cycloalkyl; C3-C6-cycloalkyl (Ci ~ C4) alkyl optionally substituted with 1 to 3 CD.YD.MdC.CH. - 291 - SY-1735A killers mentioned above in connection with the Οχ-C4 radicals ~ alkyl; phenyl; phenyl substituted with 1 to 3 selected substituents independently from amino, halo, hydroxyl, trifluoromethyl, C1-C4-alkyl, C ^ -C4-alkoxy, Cx-C4-alkylamino, di (Cx-C4) -alkylamino, carboxyl and sulfo; phenyl (Cx ~ C4) radicals alkyl d have the phenyl part may optionally be substituted with 1 to 3 substituents mentioned above with respect to the phenyl radical and the alkyl part of which may optionally be substituted with 1 to 3 radicals mentioned above with regard to the radicals 0 ^ -04-alkyl ; and heteroaryl and heteroaralkyl in which the heteroatom (s) are chosen from 1 to 4 atoms 0, S or N and the alkyl part associated with the heteroaralkyl radical has 1 to 6 carbon atoms / these heteroaryl and heteroaralkyl radicals being optionally substituted in the part heterocyclic with 1 to 3 substituents chosen independently from the hydroxyl, amino, halogen, trifluoromethyl, 0χ-C4-alkyl, Cx-C4-alkoxy, Cx-C4-alkylamino, di (Cx ~ C4) -alkoylamino, carboxyl and sulfo radicals, and in the alkyl part with 1 to 3 substituents chosen from hydroxyl, amino, Cx-C4-alkyllamino, di (Cx ~ C4) alkylamino, Cx-C4 ~ alkoxy, carboxyl, halo and sulfo radicals, this heteroaromatic radical being optionally substituted on a carbon atom with 1 or more substituents independently chosen from Cx-C4-alkyl radicals; Cx ~ C4-alkyl substituted by hydroxyl, C1-C4-alkylamino, di (Cx-C4) alkylamino, Cx-C4-alkoxy, amino, sulfo, carboxyl or halo; C3-C0-cyclo-alkyl; C ^ -C4-alkoxy; Cx-C4-alkylthio, amino; CX-C4-alkyllamino; di (Cx-C4) alkylamino; halo; CX-C4-alkanoylamino; Cx ~ C4-alkanoyloxy; carboxyl; -CO2-CX-C4-alkyl; hydroxyl; amidino; guanidino; phenyl; phenyl substituted by one, two or three amino radicals, CD.YD.MdC.CH. SY-1735A halo, hydroxyl, trifluoromethyl; C ^ -C4-alkyl or Ci-C4-alkoxy? phenyl (Ci-C4) alkyl, the phenyl part of which can optionally be substituted with 1 to 3 substituents mentioned above with respect to the phenyl radical and the alkyl part of which can optionally be substituted with 1 to 3 substituents mentioned above with respect to the phenyl radicals C1-C4-alkyl radicals; and heteroaryl and heteroaralkyl in which the heteroatom (s) of the abovementioned heterocyclic parts are chosen from 1 to 4 oxygen, nitrogen or sulfur atoms and the alkyl part associated with the heteroaralkyl part has 1 to .6 carbon atoms, or optionally substituted to form a condensed carbocyclic, heterocyclic or heteroaromatic radical optionally substituted by 1 or 2 of the radicals defined above; or a pharmaceutically acceptable salt of this compound. 52. A compound according to claim 51, in the formula of which Ri represents a hydrogen atom or a CH3 CH3 OH OH CH3CH2-, ^ CH-, ^ C- or CH3CH- ch3 ^ ch3 ^ radical. 53. A compound according to claim 51, in the formula of which Ri and R ^ · together represent a radical hoch2 ^ c = CH3 ^ 54. A compound according to claim 51, in the formula of which Ri represents a CD.YD.MdC.CH. radical. - 293 - SY-1735A OH CH3CH- 55. A compound according to claim 51, in the formula of which r1 represents an OH radical CH3CH- and the absolute configuration is 5R, 6S, 8R. 56. A compound according to claim 51, 52, 53, 54 or 55, in the formula of which A represents a radical -CH2- or -CH2CH2-. 57. Compound of formula> * '/ λ *. * - ("VV * g K ^ COOR2 where r8 represents a hydrogen atom and R ^ is chosen from the hydrogen atom and the alkyl, alkenyl and alkynyl radicals of 1 to 10 carbon atoms; cycloalkyl and cycloalkylalkyl 3 to 6 carbon atoms in the ring of the cycloalkyl part and from 1 to 6 carbon atoms in the alkyl; phenyl; aralkoyl; aralkenyl and aralkynyl parts of which the aryl part is a phenyl radical and of which the aliphatic part has 1 to 6 carbon atoms; hetero-aryl, heteroaralkyl, heterocyclic and heterocycloalkyl in which the heteroatom (s) of the aforementioned heterocyclic parts are chosen from 1 to 4 atoms CD.YD.MdC.CH. - 294 - SY-1735A of oxygen, d nitrogen or sulfur and in which the alkyl parts associated with the heterocyclic parts comprise 1 to 6 carbon atoms, all of which are substituted or unsubstituted, in which the substituent or substituents with regard to the abovementioned radicals are independently chosen from: Ci-Cß-alkyl optionally amino , halogen, hyd roxylated or halogenated carboxylated -0R3 O -0CNR3r4 0 -CNR3r4 -Nr3r4 _ /, nr3 \ NR ^ R4 -SC> 2NR3R4 0 -NHCNR3r4 0 „II R3CNR4- -CO2R3 = 0 O -OCR3 -SR3 O -SR9 O 0 -CN -N 3 -OSO3R3 CD.YD.MdC.CH. - 295 - SY-1735A ο 11 Q -OS-R9 II 0 0 -NR3S-R9 S -0P (0) (0R3) (or4) -NR3c = NR4 r3 -NR3C02R4 -no2 where, with regard to the aforementioned substituents, the radicals r3 and R4 are chosen independently among the hydrogen atom and the alkyl, alkenyl and alkynyl radicals of 1 to 10 carbon atoms? cycloalkyl, cycloalkyl-alkyl and alkylcycloalkyl of 3 to 6 carbon atoms in the ring of the cycloalkyl part and from 1 to 6 carbon atoms in the alkyl parts; phenyl; aralkyl, aralkenyl and aralkynyl, the aryl part of which is a phenyl radical and the aliphatic part has 1 to 6 carbon atoms; and hetero-aryl, heteroaralkyl, heterocyclic and heterocycloalkyl in which the heteroatom (s) in the aforementioned heterocyclic parts are chosen from 1 to 4 oxygen, nitrogen or sulfur atoms and in which the alkyl parts associated with these heterocyclic parts count 1 to 6 carbon atoms, or alternatively r3 and R4, taken together with the nitrogen atom to which at least one of them is united, can form a pentagonal or hexagonal nitrogen heterocyclic radical; R9 is defined as r3, except that it cannot be a hydrogen atom; or where Ri and R ^ taken together, represent a radical c2-CiO_alc ° y1; * - dane or C2-Cio-alkylene alkylene; r5 is chosen from alkyl, alkenyl and alkynyl radicals of 1 to 10 carbon atoms; CD.YD.MdC.CH. - 296 - SY-1735A cycloalkyl and cycloalkylalkyl of 3 to 6 carbon atoms in the ring of the cycloalkyl part and from 1 to 6 carbon atoms in the alkyl parts; phenyl? aralkyl, aralkenyl and aralkynyl whose aryl part is a phenyl radical and whose aliphatic part has 1 to 6 carbon atoms? hetero-aryl, heteroaralkyl, heterocyclic and heterocycloalkyl in which the heteroatom (s) in the above-mentioned heterocyclic parts are chosen from 1 to 4 oxygen, nitrogen or sulfur atoms and in which the alkyl parts associated with the heterocyclic parts have 1 to 6 carbon atoms, all substituted or unsubstituted; the aforementioned r5 radicals optionally carrying one to three substituents chosen independently from: Ci-C6-alkyl optionally amino, fluorinated, chlorinated, carboxylated, hydroxylated, or carbamoylated fluoro, chloro or bromo -OR3 -0C02R3 —OCOR3 -OCONR3R4 0 -OS-R9 II 0 -oxo -NR3R4 R3CONR4- -nr3co2r4 -nr3conr3r4 O -NR3S-R9 II 0 -SR3 CD.YD.MdC.CH. - 297 - SY-1735A ο t -SR9 Ο Ο -S-R9 -SO3R3 -C02r3 -conr3r4 -CN; or phenyl optionally substituted with 1 to 3 fluoro, chloro, brorao, Ci-Cg-alkyl radicals, -OR3, -NR3R4, -S03r3, -CO2R3 or -CONR3R4, where R3, r4 and R9 in these substituents of R 5 are such as defined above; or R3 can be joined to O at another point in the cycle to form a condensed heterocyclic or heteroaromatic radical, the ring of which can contain additional heteroatoms, chosen from O, S and N; A represents a C ^ -Cg-alkylene radical in a straight or branched chain; R ^ represents a hydrogen atom, an anionic charge or a conventional radical which is easy to remove protective of the carboxyl function, it being understood that when R2 represents a hydrogen atom or a protective radical, there is also a counter ion, and 5 -r- K — R represents a radical of formula CD.YD.MdC.CH. - 298 - SY-1735A 5. e '5. - -Kr R X_ KR ΊΓ I-r5, 1 -j—, i J, ® 5 R5 lî-X ", -K'E \ Jy" U "where X represents 0, S or NR where R represents a radical Ci -C4-alkyl; C] .- C4-alkyl substituted by 1 to 3 hydroxyl, amino, Ci ~ C4-alkylimino; di (Ci ~ C4) alkylamino; Ci-C4-alkoxy; carboxyl, balogeno or sulfo radicals; C3- C6-cycloalkyl; C3-C6-cycloalkyl (Ci-C4) alkyl optionally substituted with 1 to 3 substituents mentioned above with respect to the C 1 -C 4 -alkyl radicals; phenyl; phenyl substituted with 1 to 3 substituents chosen independently from amino, balogeno, hydroxyl, trifluoromethyl, C1-C4-alkyl, C1-C4-alkoxy, C; L-C4-alkylamino, di (C ^ -C4) -alkylamino, carboxyl and sulfo; phenyl (Ci-C4) alkyl radicals whose phenyl part can optionally be substituted by 1 to 3 substituents mentioned above with respect to the phenyl radical and whose alkyl part can optionally be substituted by 1 to 3 substituents mentioned above with respect to the C 1 -C 4 -alkyl radicals ; and waryaryl and heteroar alkyl in which the heteroatom (s) are chosen from 1 to 4 atoms 0, S or N and the alkyl part associated with the heteroalkyl radical has l ^ to 6 carbon atoms, these radicals CD.YD.MdC.CH. - 299 - SY-1735A heteroaryl and heteroaralkyl being optionally substituted in the heterocyclic part by 1 to 3 substituents chosen independently from the hydroxyl, amino, halo, trifluoromethyl, C] _- C4 ~ alkyl, Ci-C4-alkoxy, Ci- radicals C4-alkylamino di (Ci-C4) -alkylamino, carboxyl and sulfo, and in the alkyl part with 1 to 3 substituents chosen from hydroxyl, amino, Ci-C4-alkylamino, di (Ci ~ C4) alkylamino, Ci- C4-alkoxy, carboxyl, halo and sulfo, this heteroaromatic radical being optionally substituted on a carbon atom by a substituent chosen from C 1 -C 4 -alkyl radicals; C1-C4-alkyl substituted by hydroxyl, C1-C4-alkylamino, di (Ci-C4) alkylamino, Ci-C4-alkoxy, amino, sulfo; carboxyl or halo; Cg-Cg-cycloalkyl; C1-C4-alkoxy; C1-C4-alkylthio, amino; C1-C4-alkylamino; di (C1-C4) alkylamino; halo; C] _- C4-alkanoylamino; cl ~ c4 ~ alkanoyloxy; carboxyl; -C02-Ci-C4-alkyl; hydroxyl; amidino; guanidino; phenyl; phenyl substituted with one, two or three amino, halo, hydroxyl, trifluoromethyl radicals; C1-C4-alkyl or C1-C4-alkoxy; phenyl (Ci-C4) alkyl, the phenyl part of which can optionally be substituted with 1 to 3 substituents mentioned above with respect to the phenyl radical and the alkyl part of which can optionally be substituted with 1 to 3 substituents mentioned above with respect to the phenyl radicals C ^ -C ^ -alkyl radicals; and heteroaryl and heteroaralkyl in which the heteroatom (s) of the abovementioned heterocyclic parts are chosen from 1 to 4 oxygen, nitrogen or sulfur atoms and the alkyl part associated with the heteroaralkyl part has 1 to 6 carbon atoms; or a pharmaceutically acceptable salt of this compound. 58.- Compound according to claim 57, in the formula of which R1 represents a hydrogen atom or CD.YD.MdC.CH. - 300 - SY-1735A a radical ch3 CH 3 OH OH CH3CH2-, CH-, ^ C- or CH3CH- ch3 ^ CH3 ^ 59. Compound according to claim 57, in the formula of which Ri and r8 together represent a radical HOCH2 CH3 ^ 60. Compound according to claim 57, in the formula of which R1 represents an OH CH3CH- radical. 61. A compound according to claim 57, in the formula of which R1 represents an OH CH3CH- radical and the absolute configuration is 5R, 6S, 8R. 62. Compound according to claim 57, 58, 59, 60 or 61, in the formula of which A represents a radical -CH2- or -CH2CH2- · 63. Compound of formula CD.YD.MdC.CH. - 301 - SY-1735A 4K ~ {> ON "" "COOR2 where R8 represents a hydrogen atom and R1 is chosen from the hydrogen atom and the alkyl, alkenyl and alkynyl radicals of 1 to 10 carbon atoms; cycloalkyl and cycloalkylalkyl of 3 to 6 carbon atoms in the ring of the cycloalkyl part and of 1 to 6 carbon atoms in the alkyl parts; phenyl; aralkyl; aralkenyl and aralkynyl of which the aryl part is a phenyl radical and of which the aliphatic part has 1 to 6 carbon atoms; hetero-aryl, heteroaralkyl, heterocyclic and heterocycloalkyl of which the heteroatom (s) of the above-mentioned heterocyclic parts are chosen from 1 to 4 atoms of oxygen, nitrogen or sulfur and of which the alkyl parts associated with the heterocyclic parts comprise 1 to 6 carbon atoms, all of which are substituted or unsubstituted, the substituent or substituents of which, with respect to the abovementioned radicals, are independently chosen from: Cj-Cg-alkyl optionally amino, halogenated, hydroxylated or carbo xylated halo -0R3 0 -0CNR3R4 0 II -CNR3r4 -Nr3r4 CD.YD.MdC.CH. - 302 - SY-1735A / NR3 - (λ NR3R4 -S02NR3R4 0 II -NHCNR3r4 0 „II R3CNR4- -CO2R3 = 0 O -OCR3 -SR3 0 -SR9 0 -SR9 II 0 -CN -n3 -0S03r3 O 11 a - OS-R9 il 0 O -nr3s-r9 II O -0P (0) (OR3) (or4) -nr3c = nr4 R3 -NR3C02R4 -no2 where, with regard to the aforementioned substituents, the radicals R3 and R4 are chosen independently from l hydrogen and alkyl, alkenyl and alkynyl radicals CD.YD.MdC.CH. - 303 - SY-1735A with 1 to 10 carbon atoms; cycloalkyl, cycloalkyl-alkyl and alkyl with 3 to 6 carbon atoms in the cycle of the cycloalkyl part and from 1 to 6 carbon atoms in the alkyl parts; phenyl; aralkyl, aralkenyl and aralkynyl in which the aryl part is a phenyl radical and the aliphatic part has 1 to 6 carbon atoms; and hetero-aryl , heteroaralkyl, heterocyclic and heterocyloalkyl in which the heteroatom (s) in the aforementioned heterocyclic parts are chosen from 1 to 4 oxygen, nitrogen or sulfur atoms fre and whose alkyl parts associated with these heterocyclic parts have 1 to 6 carbon atoms, or else r3 and r4, taken together with the nitrogen atom to which at least one of them is united, can form a pentagonal or hexagonal nitrogen heterocyclic radical; R9 is defined as R3 except that it cannot be a hydrogen atom; or where R ^ and R ^, taken together, represent a radical c2 ”c10_alcoY1; i-â®ne or C2-Ci0“ alc ° y1; i-â®ne hydroxylated? R 5 is chosen from alkyl, alkenyl and alkynyl radicals of 1 to 10 carbon atoms; cycloalkyl and cycloalkylalkyl of 3 to 6 carbon atoms in the ring of the cycloalkyl part and from 1 to 6 carbon atoms in the alkyl parts; phenyl; aralkyl, aralkenyl and aralkynyl in which the aryl part is a phenyl radical and in which the aliphatic part has 1 to 6 carbon atoms; hetero-aryl, heteroaralkyl, heterocyclic and heterocycloalkyl in which the heteroatom (s) in the above-mentioned heterocyclic parts are chosen from 1 to 4 oxygen, nitrogen or sulfur atoms and in which the alkyl parts associated with the heterocyclic parts have 1 to 6 carbon atoms, all substituted or unsubstituted; the aforementioned r5 radicals optionally carrying one to three substituents chosen independently CD.YD.MdC.CH. - 304 - SY-1735A dämment among: Cl-Cg-alkyl optionally amino, fluorinated, chlorinated, carboxylated, hydroxylated, or carbamoylated fluoro, chloro or bromo -OR3 -0C02r3 -OCOR3 -OCONR3r4 0 11 Q -OS-R9 II 0 -oxo -NR3R4 R3CONR4- -NR3co2r4 -NR3CONR3R4 0 -NR3S-R9 il 0 -SR3 0 -SR9 0 ^ ° 9 -S-R9 -so3r3 -co2r3 -conr3r4 -CN; or phenyl optionally substituted by 1 to 3 fluoro, chloro, bromo, Ci-Cß-alkyl, -OR3, -NR3r4, -SO3r3, _co2R3 or -CONR3r4, where R3, r4 and R9 in these substituents of R5 are as defined above; or R5 can be combined with CD.YD.MdC.CH. - 305 - SY-1735A ο at another point in the cycle to form a condensed heterocyclic or heteroaromatic radical, the cycle of which may contain additional heteroatoms, chosen from 0, S and N; A represents a Cj-Cß-alkylene radical in a straight or branched chain? R 2 represents a hydrogen atom, an anionic charge or a conventional radical which is easy to remove and protective of the carboxyl function, it being understood that when r2 represents a hydrogen atom or a protective radical, there is also a counter ion, and 5 - represents a radical of formula Θ r- __5 —K. »= *, K r5 -J 'T Te CD.YD.MdC.CH. - 306 - SY-1735A κ5 e * '\ vi - N-R 1 - K - R! OR -β | NR "K where R represents a C-L_c4-alkyl radical; Ci-C4 ~ alkyl substituted by 1 to 3 hydroxyl, amino, C1-C4-alkylamino, di (ci ~ C4) alkylamino, Ci-C4 ~ alkoxy, carboxyl radicals , halo or sulfo; C3-C6-cycloalkyl; C3-C6-cycloalkyl (C1-C4) alkyl optionally substituted with 1 to 3 substituents mentioned above in connection with C 1 -C 4 -alkyl radicals; phenyl; phenyl substituted with 1 with 3 substituents independently chosen from amino, halo, hydroxyl, trifluoromethyl, Ci-C4-alkyl, C] .- C4-alkoxy, Ci-C4-alkylamino, di (Ci-C4) alkylamino, carboxyl and sulfo (phenyl ( C1-C4) -alkyl, the phenyl part of which can optionally be substituted with 1 to 3 substituents mentioned above with respect to the phenyl radical and the alkyl part of which can optionally be substituted with 1 to 3 substituents mentioned above with regard to the radicals C \ -C4 ~ alkyl; and heatheraryl and heteroaralkyl in which the heteroatom (s) are chosen from 1 to 4 atoms O, S or “N and the part al coyl associated with the heteroalkyl radical has 1 to 6 carbon atoms, these heteroaryl and heteroaralkyl radicals being optionally substituted in the heterocyclic part by 1 to 3 substituents chosen independently from the hydroxyl, amino, halo, trifluoromethyl, C ^ - C4- radicals alkyl, Ci-C4-alkoxy, Ci-C4-alkylamino, di (Ci-C4) -alkylamino, carboxyl and sulfo, and in the alkyl part with 1 to 3 substituents chosen from CD.YD.MdC.CH. SY-1735A hydroxyl, amino, ci-C4-alkylamino, di (Ci-C4) alkylamino, C] .- C4-alkoxy, carboxyl, halo and sulfo radicals; or a pharmaceutically acceptable salt of this compound. 64. A compound according to claim 63, in the formula of which R1 represents a hydrogen atom or a CH3 CH3 OH OH CH3CH2-1 ^ CH-, C- or CH3CH- CH3 ^ ch3 ^ radical. 65. Compound according to claim 63, in the formula of which R1 and RÖ together represent a radical HOCHo \ c = ch3 * ^ 66. Compound according to claim 63, in the formula of which R1 represents an OH CH3CH- radical. 67. A compound according to claim 63, in the formula of which R1 represents an OH ch3ch- radical and the absolute configuration is 5R, 6S, 8R. 68. A compound according to claim 63, 64, 65, 66 or 67, in the formula of which A represents a CD.YD.MdC.CH. - 308 - SY-1735A radical -CH2- or -CH2CH2-. 69.- Compound of formula Ί-ί '1 ^ cy "" coor2 where R8 represents a hydrogen atom and Rl is chosen from the hydrogen atom and the alkyl, alkenyl and alkynyl radicals of 1 to 10 carbon atoms ; cycloalkyl and cycloalkylalkyl of 3 to 6 carbon atoms in the ring of the cycloalkyl part and from 1 to 6 carbon atoms in the alkyl parts; phenyl; aralcoyl; aralkenyl and aralkynyl in which the aryl part is a phenyl radical and in which the aliphatic part has 1 to 6 carbon atoms; hetero-aryl, heteroaralkyl, heterocyclic and heterocycloalkyl in which the heteroatom (s) of the abovementioned heterocyclic parts are chosen from 1 to 4 oxygen, nitrogen or sulfur atoms and in which the alkyl parts associated with the heterocyclic parts comprise 1 to 6 carbon atoms, all of which are substituted or unsubstituted, in which the substituent or substituents with respect to the abovementioned radicals are independently chosen from; Ci-Cg-alkyl optionally amino, halogen, hydroxylated or halo carboxylated -0R3 0 II -OCNR3r4 O If -CNR3r4 CD.YD.MdC.CH. - 309 - SY-1735A -NR3r4 / NR3 -i XNR3r4 -S02NR3R4 0 -NHCNR3R4 0 R3CNR4 “-C02R3 = 0 O -OCR3 -SR3 0 -SR9 O -SR9 11 0 -CN -n3 -OSO3R3 0 Il Λ -OS R9 II OO -NR3S-R9 II 0 -0P (0) (OR3) (OR4) -NR3C = NR4 R3 -NR3C02R4 ~ no2 where, with regard to the aforementioned substituents, the radicals R3 and R4 are chosen independently from the atom d 'hy- CD.YD.MdC.CH. SY-1735A drogen and the alkyl, alkenyl and alkynyl radicals of 1 to 10 carbon atoms; cycloalkyl, cycloalkyl-alkyl and alkylcycloalkyl of 3 to 6 carbon atoms in the ring of the cycloalkyl part and from 1 to 6 carbon atoms in the alkyl parts; phenyl; aralkyl, aralkenyl and aralkynyl in which the aryl part is a phenyl radical and the aliphatic part has 1 to 6 carbon atoms; and hetero-aryl, heteroaralkyl, heterocyclic and heterocycloalkyl in which the heteroatom (s) in the abovementioned heterocyclic parts are chosen from 1 to 4 oxygen, nitrogen or sulfur atoms and in which the alkyl parts associated with these heterocyclic parts count 1 to 6 carbon atoms, or alternatively R 3 and R ^, taken together with the nitrogen atom to which at least one of them is linked, can form a pentagonal or hexagonal nitrogen heterocyclic radical; r9 is defined as r3, except that it cannot be a hydrogen atom; or where R1 and R ^, taken together, represent a radical c2 ”ClO“ al-coylene or ^ -Cig-alkylidene hydroxylê; r5 is chosen from alkyl, alkenyl and alkynyl radicals of 1 to 10 carbon atoms; cycloalkyl and cycloalkylalkyl of 3 to 6 carbon atoms in the ring of the cycloalkyl part and from 1 to 6 carbon atoms in the alkyl parts; phenyl; aralkyl, aralkenyl and aralkynyl in which the aryl part is a phenyl radical and in which the aliphatic part has 1 to 6 carbon atoms; hetero-aryl, heteroaralkyl, heterocyclic and heterocycloalkyl in which the heteroatom (s) in the above-mentioned heterocyclic parts are chosen from 1 to 4 oxygen, nitrogen or sulfur atoms and in which the alkyl parts associated with the heterocyclic parts have 1 to 6 carbon atoms, all substituted or unsubstituted; the aforementioned r5 radicals carrying CD.YD.MdC.CH. - 311 - SY-1735A optionally one to three substituents chosen independently from: ^ l-Cg-alkyl optionally amino, fluorinated, chlorinated, carboxylated, hydroxylated, or carbamoylated fluoro, chloro or bromo -OR3 -OCO2R3 —OCOR3 -OCONR3r4 OH -OS -R9 II 0 -oxo -NR3R4 R3CONR4- -NR3co2R4 -NR3CONR3R4 0 -nr3s-r9 II 0 -SR3 0 -SR9 0 0 Q -S-R9 -SO3R3 -co2r3 -conr3r4 -CN; or phenyl optionally substituted with 1 to 3 fluoro, chloro, bromo, C ^ -Cg-alkyl radicals, -OR3, -NR3R4, -S03r3, -C02R3 or -CONR3R4, where R3, R4 and R9 in these substituents of R 5 are as defined above; A represents a Ci-Cg-alkylene radical in a straight or branched chain; R3 represents a hydrogen atom, CD.YD.MdC.CH. - 312 - SY-1735A an anionic charge or a conventional radical which is easy to remove, protective of the carboxyl function, it being understood that when R2 represents a hydrogen atom or a protective radical, there is also a counter ion, and 5 -UN - RW represents a radical of formula where r6, R? and RIO are independently chosen from the hydrogen atom and the C 1 -C 4 -alkyl radicals; C.i-C4-alkoxy, carboxyl and carbamoyl, or a pharmaceutically acceptable salt of this compound. 70. Compound according to claim 69, in the formula of which R1 represents a hydrogen atom or a CH3 CH3 OH OH CH3CH2-, ^ CH-, ^ C- or CH3CH- ch3 ^ "ch3 ^ radical. 71. Compound according to claim 69, in the formula of which Ri and r8 together represent a radical CD.YD.MdC.CH. - 313 - SY-1735A hoch2 c = CH3 ^ 72. Compound according to claim 69, in the formula of which Ri represents an OH CH3CH- radical. 73. A compound according to claim 69, in the formula of which R1 represents an OH CH3CH- radical and the absolute configuration is 5R, 6S, 8R. 74. A compound according to claim 69, 70, 71, 72 or 73, in the formula of which A represents a radical -CH2- or -CH2CH2-. 75. Compound of formula ÎH -? A. ___ e — a —— R ^ ^ "" '' tOOR2 where A represents a C ^ -Cg-alkylene radical in straight or branched chain; R 2 represents a hydrogen atom, an anionic charge or a conventional radical easy to remove protective from the carboxyl function, it being understood that when R2 represents a hydrogen atom or a protective radical, a counter ion is also CD.YD.MdC.CH. - 314 - SY-1735A present; and Λ · 5 _I N —R 5 Ό represents a radical of formula u, ^> f where r5 represents a Ci-C4-alkyl radical and R6 represents a hydrogen atom or Ci-C4-alkyl radical? R5 6 i® R6 (b) / V -4 ^ -R7 "J_E where r5 represents a C ^ -C4-alkyl radical and R6 and R? represent hydrogen atoms or C ^ - C4-alkyl radicals; (c) _j_ where r5 represents a Ci-C4 ~ alkyl radical and R represents a Ci ~ C4-alkyl or phenyl (Ci-C4) alkyl radical; CD.YD.MdC.CH. - 315 - SY-1735A (a> -y-6 i5 where R5 represents a Ci-c4-alkyl radical and R6 represents a Ci-C4_alkyl radical; R5 I® (e) _ \ I _1! / R where r5 represents a radical C ^ H ^ -alkyl and R represents a radical Ci-C4 ~ alkyl7 or _N, <f> _ü_ 1 c 1 'K®. R 5 where r5 represents a radical Ci-C4-alkyl; or a pharmaceutically acceptable salt of this compound. 76.- Compound of formula ‘» JT _JU \ .S 5 '' '1-y Λ i K-p. I I ^ K ^ toOR2 where A represents a Ci-Ce radical “0-1-00 ^ 1®11® in straight or branched chain; r2 represents a hydrogen atom, an anionic charge or a classical radical easy to CD.YD.MdC.CH. - 316 - SY-1735A eliminate protector from the carboxyl function, it being understood that when a hydrogen atom or a protective radical represents, a counter ion is also present; and Λλ · 5 -LN — R represents a radical of formula (a) -O9 '“3 (bl" O® ch30 --- <C) _ / λ (d) - ^ ÿ,' CH2CH2CH3 “3® CH, “~ Ç>" CH3 CD.YD.MdC.CH. - 317 - SY-1735A CE, 9H3 Cfc5. e / 3 "-O" -IK, XN ^ J “3 jD -p ~ i'j CH, © | * CH3 (î) __ ^ N® 00. s diSf" T1 "a 3 â3 ch3 ch3“ -ô / CB., Or a pharmaceutically acceptable salt of this compound. 77. “Compound of formula 0H H (R) —Ai ^ \ e-R5 'I w * ^ OOR2 or R2 represents a hydrogen atom, an anionic charge or a conventional radical which is easy to remove and protects the carboxyl function, being understood that CD.YD.MdC.CH. - 318 - SY-1735A when r2 represents a hydrogen atom or a protective radical, a counter ion is also present, and -8- is î- \ / -v (a) -SCH —V ^ CH, (b) -SCE CH0 — VW / 3 2 2 \ - / 3 CH, -S CH 2 ^ ch3 C \ 3 0 ', \ / 7 ~ ^ \ _crw _Ù ^ K®-CH0CH „CH0 (e) -SCH2CH2 — V ( f) SCH2 \ __ / 2/3 CH, \ 3ffi CH- (g) -SCH2 - ^ y (h) -SCH2- ^ yr- CH3 CK 3 CD.YD.MdC.CH. - 319 - SY-1735A (i) CH-. (j) rp a I 3, Ί -sch2 — I 1 / \ -SCH2- \ £]> - CH3 CH3 ch3 <"> Cîip ^ <"> -SCHfY ^ - -SCH “s'S? ®, - CH CH3 (o)? H3 (p) s _SCH -sch ^ ^ 2 ^ *> 3 it '·· where the 1 H NMR spectrum (D2O) has characteristic peaks at 6: 1.23 (3H, d, J = 6.4 Hz), 3.12 (2H, q, J = 1.4, 8.9 Hz), 3.39 (1H, q, J = 2.7, 6.0 Hz), 4, 07-4.68 (10H, m), 8.19 (1H, s); ~ £ cE ^ fjC CH3 CD.YD.MdC.CH. - 320 - SY-1735A where the 1 H NMR spectrum (D2O) has characteristic peaks at 6: 1.23 (3H, d, J = 6.4 Hz), 3.15 (2H, q, J = 3.7, 9.0 Hz), 3.37 (1H, q, J = 2.6, 6.0 Hz), 3.95-4.65 (10H, m), 8.62 (1H, s); COO ^ (r) (s) CH2 -SCH, -, KU ^ ^ ® "CH3 -SCHg - ^^ K s VL_N-CH3 CH, ÇH3 (t) (u) U -scH ^ \ ye -scHäT> '- N-CH2COO N - N r "H j CH, / 3 / N-iS OR (v) - (/ I. ® / CH3 or a pharmaceutically acceptable salt of this compound. 78.- Compound of formula OH H '»ιΑρ ^ -γ ^ -L 2 O COOR CD.YD.MdC.CH. - 321 - SY-1735A where R2 represents a hydrogen atom, an anionic charge or a conventional radical which is easy to remove protective of the carboxyl function, it being understood that when R2 represents a hydrogen atom or a protective radical, a counter ion is also present; or a pharmaceutically acceptable salt of this compound. 79. A compound according to claim 78, in which formula R2 represents a p-nitro-benzyl radical. 80. A compound according to claim 78, in which formula R2 represents an anionic charge. 81. Compound of formula OH H / -y _ ^ X \ / SCH CH ™ P Γ TP σ N ^ "COOR2 Œ3 where R2 represents a hydrogen atom, an anionic charge or a classic radical easy to eliminate protective of the function carboxyl, it being understood that when R2 represents a hydrogen atom or a protective radical, a counter ion is also present; or a pharmaceutically acceptable salt of this compound. 82. A compound according to claim 81, in which formula R2 represents a p-nitro-benzyl radical. 83. A compound according to claim 81, in which formula R2 represents an anionic charge. 84. Compound of formula CD.YD.MdC.CH. - 322 - SY-1735A 0H H yv J. - // \\ ® - ^ \ ^ sce2ch2V / k-CH- (R) IJ 2 1 \ - / 3 cr N c: ocr2 where r2 represents a hydrogen atom , an anionic charge or a conventional radical easy to remove protective of the carboxyl function, it being understood that when r2 represents a hydrogen atom or a protective radical, a counter ion is also present? or a pharmaceutically acceptable salt of this compound. 85. A compound according to claim 84, in the formula of which r2 represents a p-nitro-benzyl radical. 86. A compound according to claim 84, in the formula of which r2 represents an anionic charge. 87. Compound of formula CH- T -? > Ή ÎR) '- | s CH y * coor2 where r2 represents a hydrogen atom, an anionic charge or a conventional radical which is easy to remove protective of the carboxyl function, it being understood that when r2 represents a hydrogen atom or a protective radical, a counter ion is also present; or a pharmaceutically acceptable salt of this compound. 88. Compound according to claim 87, in CD.YD.MdC.CH. - 323 - SY-1735A the formula of which r2 represents a p-nitro-benzyl radical. 89. A compound according to claim 87, in the formula of which r2 represents an anionic charge. 90. Compound of formula OH _ (R) —k ° / h ^ tOOR2 CH3 where r2 represents a hydrogen atom, an anionic charge or a conventional radical easy to remove protective of the carboxyl function, it being understood that when r2 represents a hydrogen atom or a protective radical, a counter ion is also present; or a pharmaceutically acceptable salt of this compound. 91. A compound according to claim 90, in the formula of which r2 represents a p-nitro-benzyl radical. 92. A compound according to claim 90, in the formula of which r2 represents an anionic charge. 93. Compound of formula 0H "/ -V ^ ---— s CH —r -CHCHCH, ii 2 \ ^ y -2 2 3 ry -" - "k 2 ° COOR where r2 represents a hydrogen atom, a anionic charge or a conventional radical which is easy to remove protective of the carboxyl function, it being understood that CD.YD.MdC.CH. - 324 - SY-1735A when R2 represents a hydrogen atom or a protective radical, a counterion is also present; or a pharmaceutically acceptable salt of this compound. 94. A compound according to claim 93, in the formula of which R2 represents a p-nitro-benzyïe radical. 95. A compound according to claim 93, in which formula R2 represents an anionic charge. 96. Compound of formula CK-, OH _ \ £ e K -V. -y · 0 COOR2 CH3 where R2 represents a hydrogen atom, an anionic charge or a conventional radical which is easy to remove protective of the carboxyl function, it being understood that when R2 represents a hydrogen atom or a protective radical, a counter ion is also present ; or a pharmaceutically acceptable salt of this compound. 97. A compound according to claim 96, in which formula R2 represents a p-nitro-benzyl radical. 98. A compound according to claim 93, in which formula R2 represents an anionic charge. 99. Compound of formula CD.YD.MdC.CH. - 325 - SY-1735A f? U3 <R) - "r- ^ VY ^ E3 N c: oor2 where R2 represents a hydrogen atom, an anionic charge or a conventional radical easy to remove protective of the carboxyl function, it being understood that when R2 represents a atom d hydrogen or a protective radical, a counter ion is also present; or a pharmaceutically acceptable salt of this compound. 100. A compound according to claim 99, in which formula R2 represents a p-ni-tro) benzyl radical. 101. A compound according to claim 99, in the formula of which r2 represents an anionic charge. 102. Compound of formula Œ oh 1R) scr2 ^ \ I I I \ - ^ 1 I // - K-2 CH, 0 COOR J where R2 represents a hydrogen atom, an anionic charge or a conventional radical which is easy to remove protective of the carboxyl function, it being understood that when R2 represents a hydrogen atom or a protective radical, a counter ion is also present ; or a pharmaceutically acceptable salt of this compound. CD.YD.MdC.CH. - 326 - SY-1735A 103. A compound according to claim 102, in which formula R2 represents a p-ni-trobenzyl radical. 104. A compound according to claim 102, in which formula R2 represents an anionic charge. 105. Compound of formula CH, © / CH3 0H "H-N T | 2 \ e / ^ ch3 r & N X. 2 0 COOR where R2 represents a hydrogen atom, an anionic charge or an easy classical radical. removing protective from the carboxyl function, it being understood that when R2 represents a hydrogen atom or a protective radical, a counter ion is also present; or a pharmaceutically acceptable salt of this compound. 106. A compound according to claim 105, in which formula R2 represents a p-ni-trobenzyl radical. 107. A compound according to claim 105, in which formula R2 represents an anionic charge. 108. Compound of formula f f s (R> --U, —Y ^ \ ^ scb2- | I ©; // - N- \ 2 CH, 0 COOR 3 CD.YD.MdC.CH. - 327 - SY-1735A where R2 represents a hydrogen atom, an anionic charge or a conventional radical which is easy to remove protective of the carboxyl function, it being understood that when R2 represents a hydrogen atom or a protective radical, a counter ion is also present; or a pharmaceutically acceptable salt of this compound. 109. A compound according to claim 108, in the formula of which r2 represents a p-ni-trobenzyl radical. 110. A compound according to claim 108, in which formula R2 represents an anionic charge. 111. Compound of formula OH __k ™ -Λ J / N V. 2 O COOR where R2 represents a hydrogen atom, an anionic charge or a conventional radical easy to remove protective of the carboxyl function, it being understood that when R2 represents a hydrogen atom or a protective radical, a counter ion is also present; or a pharmaceutically acceptable salt of this compound. 112. A compound according to claim 111, in which formula R2 represents a p-ni-trobenzyl radical. 113. A compound according to claim 111, in which formula R2 represents an anionic charge. 114. Compound of formula CD.YD.MdC.CH. - 328 - SY-1735A 9 0Κ Η CE- (R) J Hrir K V. 2 CH ° COOR 3 where r2 represents a hydrogen atom, an anionic charge or a classic radical easy to remove protective of the carboxyl function, being understood that when R2 represents a hydrogen atom or a protective radical, a counter ion is also present; or a pharmaceutically acceptable salt of this compound. 115. A compound according to claim 114, in which formula R2 represents a p-ni-trobenzyl radical. 116. A compound according to claim 114, in which formula R2 represents an anionic charge. 117. Compound of formula ° H H SCHj- i | & ^ - ^ OOH2 3 Ie ch3 where R2 represents a hydrogen atom, an anionic charge or a conventional radical easy to remove the protector of the carboxyl function, it being understood that when R2 represents a hydrogen atom or a protective radical, a counter ion is also present; or a pharmaceutically acceptable salt of this compound. CD.YD.MdC.CH. - 329 - SY-1735A 118. A compound according to claim 117, in which formula R2 represents a p-ni-trobenzyl radical. 119. A compound according to claim 117, in which formula R2 represents an anionic charge. 120. Compound of formula OH E <R) SCH2 τΛ · _ _ l | (/ - “a O * N ^ COOR2 where r2 represents a hydrogen atom, an anionic charge or a conventional radical easy to remove protective of the carboxyl function, it being understood that when r2 represents a hydrogen atom or a protective radical , a counter ion is also present; or a pharmaceutically acceptable salt of this compound. 121. A compound according to claim 120, in which formula R2 represents a p-ni-trobenzyl radical. 122. A compound according to claim 120, in which formula R2 represents an anionic charge. 123. Compound of formula ^ cooe 0H s P2 (R) ^ * _ ^ \ pSCH2-K * // N V 2 CH 0 COOR 3 CD.YD.MdC.CH. - 330 - SY-1735A where R2 represents a hydrogen atom, an anionic charge or a conventional radical which is easy to remove protective of the carboxyl function, it being understood that when r2 represents a hydrogen atom or a protective radical, a counter ion is also present; or a pharmaceutically acceptable salt of this compound. 124. A compound according to claim 123, in which formula R2 represents a p-ni-trobenzyl radical. 125. A compound according to claim 123, in which formula R2 represents an anionic charge. 126. Compound of formula ° HH ÇH HO [c „„ __ k® "v \ T '2 ~ T% K® -Ns. · 5 i Θ CT ^ 300R2 CH2-COO® where R2 represents a hydrogen atom, a anionic charge or a conventional radical which is easy to remove, protective of the carboxyl function, it being understood that when R2 represents a hydrogen atom or a protective radical, a counter ion is also present; or a pharmaceutically acceptable salt of this compound. 127. A compound according to claim 126, in which formula R2 represents a p-ni-trobenzyl radical. 128. A compound according to claim 126, in which formula R2 represents an anionic charge. CD.YD.MdC.CH. - 331 - SY-1735A 129. Compound of formula CH, ° H hy (R) - "" ry / ^ X —'SCH2- <ζ (] FC cf-KX, 2 3 U COOR where R2 represents a hydrogen atom, an anionic charge or a conventional radical which is easy to remove protective of the carboxyl function, it being understood that when r2 represents a hydrogen atom or a protective radical, a counter ion is also present; or a pharmaceutically acceptable salt of this compound. 130. A compound according to claim 129, in which formula R2 represents a p-ni-trobenzyl radical. 131. A compound according to claim 129, in which formula R2 represents an anionic charge. 132. Compound of formula OH CH —S - ^ \ - sch2 - <(| 1 eï rf- »- \ 2 ' 0 COOR CH3 where R2 represents a hydrogen atom, an anionic charge or a conventional radical which is easy to remove protective of the carboxyl function, it being understood that when r2 represents a hydrogen atom or a protective radical, a counter ion is also present ; or a pharmaceutically acceptable salt from this CD.YD.MdC.CH. - 332 - SY-1735A compound. 133. A compound according to claim 132, in which formula R2 represents a p-ni-trobenzyl radical. 134. A compound according to claim 132, in which formula R2 represents an anionic charge. 135 · - Compound of formula? Ξ H CH3 (R) -AX / \ _ sch2— I I I, K J 1. 0 * K ^ 2, β coda ck_ ^ or R2 represents a hydrogen atom, an anionic charge or a conventional radical which is easy to remove protective of the carboxyl function, it being understood that when R2 represents a hydrogen atom or a protective radical , a counter ion is also present; or a pharmaceutically acceptable salt of this compound. 136. A compound according to claim 135, in which formula R2 represents a p-ni-trobenzyl radical. 137. A compound according to claim 135, in which formula R2 represents an anionic charge. 138. Compound of formula 02 e tR) £ CK 2- 1 I A-N: -n. I ο XOD6 CH 3 CD.YD.MdC.CH. - 333 - SY-1735A in which the 1 H NMR spectrum (D2O) has characteristic peaks at 6: 1.23 (3H, d, J = 6.4 Hz), 3.12 (2H, q, J = 1.4, 8.9 Hz), 3.39 (1H, q, J = 2.7, 6.0 Hz), 4.07-4.68 (10H, m), 8.19 (1H, s), or a a pharmaceutically acceptable salt or ester of this compound. 139. A compound according to claim 138, the carboxyl radical of which is protected in the form of the p-nitrobenzyl ester. 140. Compound of formula ° H H (R> 1. W ¥ ^ cb3 κ Ν: οοθ ch3 whose RMNHl spectrum (D2O) has characteristic peaks at 6: 1.23 (3H, d, J = 6.4 Hz), 3.12 (2H, q, J = 3.7, 9.0 Hz), 3.37 (1H, q, J = 2.6, 6.0 Hz), 3.95-4.65 (10H, m), 8.62 (1H, s), or a pharmaceutically acceptable salt or ester of this compound. 141. A compound according to claim 140, the carboxyl radical of which is protected in the form of a p-nitrobenzyl ester. 142. Process for the preparation of a compound of formula CD.YD.MdC.CH. - 334 - SY-1735A E H15 Rfc H îg IC --— S-A-r K — R5 'il J-K-2 0. COOR where RÖ represents a hydrogen atom and Rl is chosen from the hydrogen atom and the alkyl, alkenyl and alkynyl radicals of 1 to 10 carbon atoms; cycloalkyl and cycloalkylalkyl of 3 to 6 carbon atoms in the ring of the cycloalkyl part and from 1 to 6 carbon atoms in the alkyl parts; phenyl; aralkyl, aralkenyl and aralkynyl in which the aryl part is a phenyl radical and the aliphatic part has 1 to 6 carbon atoms; hetero-aryl, heteroaralkyl, heterocyclic and heterocycloalkyl in which the heteroatom (s) in the abovementioned heterocyclic parts are chosen from 1 to 4 oxygen, nitrogen or sulfur atoms and the alkyl parts associated with the heterocyclic parts have 1 to 6 carbon atoms, all of which are substituted or unsubstituted and whose substituent (s) with respect to the abovementioned radicals are independently chosen from optionally amino, halogenated, hydroxylated or halogenated C1-C6-alkyl -OR3 O »O, -OCNR3R4 0 M -CNR3r4 -NR3R4 CD.YD.MdC.CH. - 335 - SY-1735A zNR3 -i \ nR3R4 -S02NR3R4 O -NHCNR3r4 0 R3CNr4- -co2R3 = 0 0 -OCR3 -SR3 O -SR9 O -SR9 li O -CN -n3 -OSO3R3 0 il Λ -OS-R9 M 0 0 -NR3S-R9 II O -OP (O) (OR3) (Or4) -NR3C = Nr4 R3 -NR3C02R4 -no2 where, with regard to the aforementioned substituents, the radicals R3 and r4 are chosen independently from the atom of hydrogen and the alkyl, alkenyl and alkynyl radicals CD.YD.MdC.CH. - 336 - SY-1735A of 1 to 10 carbon atoms; cycloalkyl, cycloalkyl-alkyl and alkylcycloalkyl of 3 to 6 carbon atoms in the ring of the cycloalkyl part and from 1 to 6 carbon atoms in the alkyl parts; phenyl; aralkyl, aralkenyl and aralkynyl in which the aryl part is a phenyl radical and in which the aliphatic part has 1 to 6 carbon atoms; and hetero-aryl, heteroaralkyl, heterocyclic and heterocycloalkyl in which the heteroatom (s) in the aforementioned heterocyclic parts are chosen from 1 to 4 oxygen, nitrogen and sulfur atoms and in which the alkyl parts associated with the heterocyclic parts count 1 with 6 carbon atoms, or else r3 and R ^, taken together with the nitrogen atom to which at least one of them is united, can form a pentagonal or hexagonal nitrogen heterocyclic radical; R9 is defined as R ^ except that it cannot be a hydrogen atom; or where R1 and RÖ, taken together, represent a C2-C10 alkylidene or C2-Cioalkylene radical substituted by hydroxyl; R 5 is chosen from alkyl, alkenyl and alkynyl radicals of 1 to 10 carbon atoms; cycloalkyl and cycloalkyl and cycloalkyl-alkyl of 3 to 6 carbon atoms in the ring of the cycloalkyl part and from 1 to 6 carbon atoms in the alkyl parts; phenyl; aralkyl, aralkenyl and aralkynyl in which the aryl part is a phenyl radical and in which the aliphatic part has 1 to 6 carbon atoms; heteroaryl, heteroaralkyl, heterocyclic and heterocycloalkyl in which the heteroatom (s) of the aforementioned heterocyclic parts are chosen from 1 to 4 oxygen, nitrogen or sulfur atoms and in which the alkyl parts associated with the heterocyclic parts have 1 to 6 carbon atoms, all substituted or unsubstituted; the aforementioned R 5 radicals being optionally substituted with 1 to 3 chosen radicals CD.YD.MdC.CH. - 337 - SY-1735A independently from: cl-C6-alkyl optionally amino, fluorinated, chlorinated, carboxylated, hydroxylated, or carbamoylated fluoro, chloro or bromo -0r3 -0C02r3 -OCOR3 -OCONR3r4 O Il Q -0S-R9 II o - 0X0 -NR3r4 R3CONR4- -NR3co2r4 -Nr3cONr3r4 0 -NR3S-R9 II O -SR3 0 t Λ -SR9 0 0 o -S-r9 -so3r3 -co2r3 -CONR3r4 -CN; or phenyl optionally substituted by 1 to 3 fluoro, chloro, bromo, Ci-C6 ~ alkyl, -Or3, -Nr3r4, -S03r3, -C02r3 or -CONR3R4, where R3, r4 and R ^ in these substituents of R 5 are as defined above? or R5 can be combined with CD.YD.MdC.CH. - 338 - SY-1735A 1 ο at another point in the cycle so as to form a heterocyclic or condensed heteroaromatic radical, the cycle of which may contain additional heteroatoms, chosen from 0, N and S; r! 5 is chosen from the hydrogen atom and the alkyl, alkenyl and alkynyl radicals of 1 to 10 carbon atoms; cycloalkyl, cycloalkylalkyl and alkyl-cloalkyl of 3 to 6 carbon atoms in the ring of the cycloalkyl part and from 1 to 6 carbon atoms in the alkyl parts; spirocycloalkyl of 3 to 6 carbon atoms; phenyl; aralkyl, aralkenyl and aralkynyl in which the aryl part is a phenyl radical and the aliphatic part has 1 to 6 carbon atoms; heteroaryl, heteroaralkyl, heterocyclic and heterocycloalkyl in which the heteroatom (s) in the aforementioned heterocyclic parts are chosen from 1 to 4 oxygen, nitrogen or sulfur atoms and the alkyl parts associated with the heterocyclic parts have 1 to 6 carbon atoms, all substituted or unsubstituted and whose substituent (s) with respect to the abovementioned radicals are chosen from amino, mono-, di- and trialcoylamino, hydro-xyl, alkoxy, mercapto, alkylthio, phenylthio, sulfa-hub, amidino, guanidino radicals , nitro, chloro, bromo, fluoro, cyano and carboxyl; and in which the alkyl parts in the abovementioned substituents have 1 to 6 carbon atoms; A represents a C 4 -C 6 alkylene radical in a straight or branched chain; r2 represents a hydrogen atom, an anionic charge or a classical radical easily CD.YD.MdC.CH. - 339 - SY-1735A eliminable protector of the carboxyl function, it being understood that when R2 represents a hydrogen atom or a protective radical, a counter ion is also present, and fe represents a heterocyclic, aromatic, mono-, bi- radical or substituted or unsubstituted polycyclic comprising at least one nitrogen atom in the ring and united to the radical A by a carbon atom of the ring and comprising a ring nitrogen atom which is quaternized by the radical R5; or a pharmaceutically acceptable salt of this compound, characterized in that (1) An intermediate of formula 8 ^ 15 RHT r1 — r> 111 <y 1 ^ coor2 'is reacted where Ri, r8 and r! 5 are such as defined above and R2 ′ represents a conventional radical which is easy to remove, protective of the carboxyl function, in an inert organic solvent, with a reagent capable of introducing a conventional labile radical L in position 2 of intermediate III to form an intermediate of formula CD.YD.MdC.CH. - 340 - SY-1735A B H R15 R B j r-LJ-IV fû-K- “s. 2 * Or COOK where rI, r8, r15 and R2 'are as defined above and L represents a classical labile radical? (2) Intermediate IV is reacted in an inert organic solvent and in the presence of a base with a mercaptan of formula HS-A - (-. K where A is as defined above, and O represents a radical "heterocyclic, aromatic, mono-, bi- or polycyclic containing a nitrogen atom which can be quaternized in the ring, which radical is joined to the radical A by a ring carbon atom, to form an intermediate of formula R15" 'II / - s K1-11 AN \ 2 '& COOR CD.YD.MdC.CH. - 341 - SY-1735A where R1, R8, R15, A, R2' and O are as defined above? (3) we do react intermediate II in an inert organic solvent with an alkylating agent of formula r5-x 'where R8 is as defined above and X1 represents a conventional labile radical so as to quaternize by means of the radical R8, an atom of nitrogen in the ring of substituent O of intermediate II and form a compound of formula R15 R8 K! = R1 — ISA— ^ K-R5 X ·· r CX CDDR2 'OÙ Rl, R8, Rl5 # r2', A , Ov and X 'son t as defined above and, if the thing CD.YD.MdC.CH. - 342 - SY-1735A is desired, the counter ion X * is replaced by a different counter ion and, if desired, the protective radical r21 of the carboxyl function is eliminated to obtain the desired deprotected compound of formula I or a pharmaceutically acceptable salt of this compound. 143. Method according to claim 142, characterized in that the quaternization is carried out after having eliminated the radical 'protecting the carboxyl function. 144. Process for the preparation of a compound of formula 15 B »* = JL R1 - sA- (K — R5 jZ! Γ N ^ COOR2 where r8 represents a hydrogen atom and R ^ is chosen from the atom d hydrogen and alkyl, alkenyl and alkynyl radicals of 1 to 10 carbon atoms? cycloalkyl and cycloalkylalkyl of 3 to 6 carbon atoms in the ring of the cycloalkyl part and of 1 to 6 carbon atoms in the alkyl parts; phenyl; aralkyl, aralkenyl and aralkynyl in which the aryl part is a phenyl radical and the aliphatic part has 1 to 6 carbon atoms; hetero-aryl, heteroaralkyl, heterocyclic and heterocycloalkyl in which the hetero or atoms in the aforementioned heterocyclic parts are chosen from 1 with 4 oxygen, nitrogen or sulfur atoms and the alkyl parts associated with the heterocyclic parts have 1 to 6 carbon atoms, all of which are substituted or unsubstituted and whose substituent (s) with respect to the abovementioned radicals are chosen independently from CD .YD. MdC.CH. - 343 - SY-1735A C ^ -C5 ~ optionally amino alkyl, "halogenated, hydroxylated or halogenated carboxylated -OR3 O -OCNR3r4 0 -CNR3R4 -NR3R4 / NR3 - (\ NR3r4 -S02NR3R4 O -NHCNR3r4 0 r3cNR4-r 0 -OCR3 -SR3 O -SR9 0 -SR9 il 0 -CN -n3 -OSO3R3 O 11 Q -OS-R9 li 0 CD.YD.MdC.CH. - 344 - SY-1735A ο -NR3S-R9 II ο -OP (0) (OR3) (or4) -NR3C = NR4 R3 -NR3C02R4 -no2 where, with regard to the aforementioned substituents, the radicals R3 and R4 are chosen independently from the hydrogen atom and the alkyl, alkenyl and alkynyl radicals of 1 to 10 carbon atoms, ·, cycloalkyl, cycloalkyl-alkyl and alkylcycloalkyl of 3 to 6 carbon atoms in the cycle of the cycloalkyl part and from 1 to 6 carbon atoms in the alkyl parts; phenyl; aralkyl, aralkenyl and aralkynyl in which the aryl part is a phenyl radical and in which the aliphatic part has 1 to 6 carbon atoms; and hetero-aryl, heteroaralkyl, heterocyclic and heterocycloalkyl in which the heteroatom (s) in the aforementioned heterocyclic parts are chosen from 1 to 4 oxygen, nitrogen and sulfur atoms and in which the alkyl parts associated with the heterocyclic parts count 1 with 6 carbon atoms, or else R3 and R4, taken together with the nitrogen atom to which at least one of them is linked, can form a pentagonal or hexagonal nitrogen heterocyclic radical; R9 is defined as R3, except that it cannot be a hydrogen atom; or where R1 and R3, taken together, represent a radical c2 ~ c10 alkylidene or c2-c10 “alc ° y1; i-â®ne substituted by hydroxyl; r5 is chosen from alkyl, alkenyl and alkynyl radicals of 1 to 10 carbon atoms; cycloalkyl and cycloalkylalkyl of 3 to 6 carbon atoms in the cycle of the cycloalkyl part and from 1 to 6 carbon atoms in the parts CD.YD.MdC.CH. - 345 - SY-1735A alkyl; phenyl; aralkyl, aralkenyl and aralkynyl in which the aryl part is a phenyl radical and in which the aliphatic part has 1 to 6 carbon atoms? heteroaryl, heteroaralkyl, heterocyclic and heterocycloalkyl in which the heteroatom (s) of the above-mentioned heterocyclic parts are chosen from 1 to 4 oxygen, nitrogen or sulfur atoms and in which the alkyl parts associated with the heterocyclic parts have 1 to 6 atoms carbon, all substituted or unsubstituted; the aforementioned R 5 radicals being optionally substituted by 1 to 3 radicals chosen independently from: Cq-Cg-alkyl optionally amino, fluorinated, chlorinated, carboxylated, hydroxylated, or carbamoylated fluoro, chloro or bromo -OR3 -OCO2R3 -OCOR3 -OCONR3r4 0 11 Q -OS-R9 II O -0X0 -NR3R4 r3conr4- -nr3co2r4 -NR3CONR3r4 0 -NR3S-r9 II 0 -SR3 0 t -SR9 0 0 ** "-S-r9 CD.YD.MdC.CH. - 346 - SY-1735A -so3r3 -C02R3 -CONR3r4 -CN; or phenyl optionally substituted with 1 to 3 fluoro, chloro, bromo, Ci-Cg-alkyl radicals, -OR3, -Nr3r4, -SO3r3, -C02R3 or -CONr3r4, where r3, r4 and r9 in these substituents of R 5 are such as defined above; or r5 can be united with O at another point of the cycle so as to form a heterocyclic or condensed heteroaromatic radical, the cycle of which can contain additional heteroatoms, chosen from O, N and S; is chosen from the hydrogen atom and the alkyl, alkenyl and alkynyl radicals of 1 to 10 carbon atoms; cycloalkyl, cycloalkylalkyl and alkyl-cloalkyl of 3 to 6 carbon atoms in the ring of the cycloalkyl part and from 1 to 6 carbon atoms in the alkyl parts; spirocycloalkyl of 3 to 6 carbon atoms; phenyl; aralkyl, aralkenyl and aralkynyl in which the aryl part is a phenyl radical and the aliphatic part has 1 to 6 carbon atoms; heteroaryl, heteroaralkyl, heterocyclic and heterocycloalkyl in which the heteroatom (s) in the above-mentioned heterocyclic parts are chosen from 1 to 4 oxygen, nitrogen or sulfur atoms and the alkyl parts associated with the heterocyclic parts have 1 to 6 carbon atoms, all substituted or unsubstituted and whose substituent (s) with respect to the abovementioned radicals are chosen from CD.YD.MdC.CH. - 347 - SY-1735A amino, mono-, di- and trialcoylamino, hydro-xyl, alkoxy, mercapto, alkylthio, phenylthio, tallow, amidino, guanidino, nitro, chloro, bromo, fluoro, cyano and carboxyl radicals; and in which the alkyl parts in the abovementioned substituents have 1 to 6 carbon atoms; A represents a Cj-Cg-alkylene radical in a straight or branched chain; r2 represents a hydrogen atom, an anionic charge or an easily removable conventional radical protecting the carboxyl function, it being understood that when p2 represents a hydrogen atom or a protective radical, a counter ion is also present, and -Lr represents a substituted or unsubstituted heterocyclic, aromatic, mono-, bi- or polycyclic radical comprising at least one nitrogen atom in the ring and united to the radical A by a carbon atom of the ring and comprising a ring nitrogen atom which is quaternized by the radical R ^ · or a pharmaceutically acceptable salt of this compound, characterized in that an intermediate of formula R15 ε "i. * i I Λ — 1 T ^ λ-h - \ 2 '(y coor CD.YD.MdC.CH. - 348 - SY-1735A where Rlf R ^, r1 ^, A, r21 are as defined above , and O represents a heterocyclic, aromatic, mono-, bi- or polycyclic radical containing a nitrogen atom which can be quaternized in the ring, which radical is united to the radical A by a carbon atom in the ring, in an inert organic solvent, with an alkylating agent of formula r5-x * where r5 is as defined above and X 'represents a conventional labile radical, so as to quaternize by means of the radical R ^, a ring nitrogen atom of the substituent O of intermediate II, to form a compound of formula K15 R8 KI / ~ \ S tr> I K-R5 X'e TT T w A— Ns 2 '(y COOR where Rl, r8, r15, r2', A , CD.YD.MdC.CH. - 349 - SY-1735A ο * and X 'are as defined above and, if desired, the counter ion X' is replaced by a different counter ion and, if the thing is desired, the protective R21 radical of the carboxyl function is eliminated in order to obtain ir the desired deprotected compound of formula I, or a pharmaceutically acceptable salt of this compound. 145. A method according to claim 144, characterized in that the quaternization is carried out after having removed the radical R2 'protecting the carboxyl function. 146. Compound of formula c R15 I = 1 1. W 0s — N v coo? 2 where r8 represents a hydrogen atom and R ^ is chosen from the hydrogen atom and the alkyl, alkenyl and alkynyl radicals of 1 to 10 carbon atoms; cycloalkyl and cycloalkylalkyl of 3 to 6 carbon atoms in the ring of the cycloalkyl part and from 1 to 6 carbon atoms in the alkyl parts; phenyl; aralkyl, aralkenyl and aralkynyl in which the aryl part is a phenyl radical and the aliphatic part has 1 to 6 carbon atoms; hetero-aryl, heteroaralkyl, heterocyclic and heterocycloalkyl in which the heteroatom (s) in the aforementioned heterocyclic parts are chosen from 1 to CD.YD.MdC.CH. - 350 - SY-1735A 4 oxygen, nitrogen or sulfur atoms and the alkyl parts associated with the heterocyclic parts have 1 to 6 carbon atoms, all of which are substituted or unsubstituted and whose substituent (s) in relation to the abovementioned radicals are independently chosen from Ci-Cg-alkyl optionally amino, halogenated, hydroxylated or halogenated carboxylated -0R3 0 -OCNr3r4 0 -CNR3r4 -Nr3r4 _ <r3 'NR3r4 -S02NR3R4 0 -NHCNR3r4 0 Jl. R3CNR4- -co2r3 = 0 O -OCR3 -SR3 0 -SR9 0 »O -SR9 II O -CN -n3 -0S03r3 CD.YD.MdC.CH. - 351 - SY-1735A ο * ι η -OS-R9 II 0 o -NR3S-R9 II O -OP (O) (OR3) (or4) -NR3c = NR4 R3 -NR3C02R4 -no2 where, in relation to the aforementioned substituents , the radicals r3 and R4 are independently chosen from the hydrogen atom and the alkyl, alkenyl and alkynyl radicals of 1 to 10 carbon atoms; cycloalkyl, cycloalkyl-alkyl and alkylcycloalkyl of 3 to 6 carbon atoms in the ring of the cycloalkyl part and from 1 to 6 carbon atoms in the alkyl parts; phenyl; aralkyl, aralkenyl and aralkynyl in which the aryl part is a phenyl radical and in which the aliphatic part has 1 to 6 carbon atoms; and hetero-aryl, heteroaralkyl, heterocyclic and heterocycloalkyl in which the heteroatom (s) in the aforementioned heterocyclic parts are chosen from 1 to 4 oxygen, nitrogen and sulfur atoms and in which the alkyl parts associated with the heterocyclic parts count 1 with 6 carbon atoms, or r3 and R4, taken together with the nitrogen atom to which at least one of them is united, can form a pentagonal or hexagonal nitrogen heterocyclic radical; R9 is defined as r3, except that it cannot be a hydrogen atom; or where R1 and R®, taken together, represent a radical c2 ”c10 alkylidene or 02-010 ^ 1 ^ 711 ^^ 6 substituted by hydroxyl; r5 is chosen from alkyl, alkenyl and alkynyl radicals of 1 to 10 atoms CD.YD.MdC.CH. - 352 - SY-1735A carbon? cycloalkyl and cycloalkylalkyl of 3 to 6 carbon atoms in the ring of the cycloalkyl part and of 1 to 6 carbon atoms in the alkyl parts? phenyl? aralkyl, aralkenyl and aralkynyl the aryl part of which is a phenyl radical and the aliphatic part of which has 1 to 6 carbon atoms? heteroaryl, heteroaralkyl, heterocyclic and hetero-cycloalkyl in which the heteroatom (s) of the above-mentioned heterocyclic parts are chosen from 1 to 4 oxygen, nitrogen or sulfur atoms and in which the alkyl parts associated with the heterocyclic parts have 1 to 6 atoms carbon, all substituted or unsubstituted? the aforementioned r5 radicals being optionally substituted by 1 to 3 radicals chosen independently from i C ^ -Cg-alkyl optionally amino, fluorinated, chlorinated, carboxylated, hydroxylated, or carbamoylated fluoro, chloro or bromo -OR3 -oco2r3 -OCOR3 -OCONR3r4 0 - 0S-R9 <1 o -0X0 -Nr3r4 R3CONR4- -NR3c02R4 -NR3CONR3R4 O -NR3S-R9 (IO -SR3 CD.YD.MdC.CH. - 353 - SY-1735A ο t -SR9 Ο Ο -SR 9 -SO3R -C02r3 -CONR3R4 -CN; or phenyl optionally substituted with 1 to 3 fluoro, chloro, bromo, Ci-C6-alkyl radicals, -OR3, -NR3R4, -S03r3, -C02R3 or -CONR3r4, where R3, R4 and r9 in these substituents of R5 are as defined above; or else R3 can be united with o · - at another point of the cycle so as to form a condensed heterocyclic or heteroaromatic radical, the cycle of which can contain additional heteroatoms, chosen from 0, N and S; r! 5 is chosen from the hydrogen atom and the alkyl, alkenyl and alkynyl radicals of 1 to 10 carbon atoms; cycloalkyl, cycl oalkoylalkoyl and alcoylcy-cloalcoyl of 3 to 6 carbon atoms in the cycle of the cycloalkyl part and from 1 to 6 carbon atoms in the alkyl parts; spirocycloalkyl of 3 to 6 carbon atoms; phenyl; aralkyl, aralkenyl and aralkynyl in which the aryl part is a phenyl radical and the aliphatic part has 1 to 6 carbon atoms; heteroaryl, heteroaralkyl, heterocyclic and heterocycloalkyl in which the heteroatom (s) in the aforementioned heterocyclic parts are chosen from 1 to 4 atoms of oxygen, nitrogen or sulfur and CD.YD.MdC.CH. - 354 - SY-1735A the alkyl parts associated with the heterocyclic parts have 1 to 6 carbon atoms, all of which are substituted or unsubstituted and whose substituent (s) with respect to the abovementioned radicals are chosen from amino, mono-, di- and trialcoylamino, hydro-xyle, alkoxy, mercapto, alkylthio, phenylthio, sulfa-moyle, amidino, guanidino, nitro, chloro, bromo, fluoro, cyano and carboxyl; and in which the alkyl parts in the abovementioned substituents have 1 to 6 carbon atoms; A represents a Cj-Cβ-alkylene radical in a straight or branched chain; r2 represents a hydrogen atom, an anionic charge or a conventional easily removable radical protecting the carboxyl function, it being understood that when r2 represents a hydrogen atom or a protective radical, a counter ion is also present, and -r N - represents a heterocyclic, aromatic, mono-, bi- or polycyclic radical substituted or unsubstituted comprising at least one nitrogen atom in the ring and united to the radical A by a carbon atom of the ring and comprising a nitrogen atom of cycle which is quaternized by the radical r5; or a pharmaceutically acceptable salt of this compound. 147.- Composed of formula CD.YD.MdC.CH. - 355 - SY-1735A 16 f gA ^ ΤΓΤ / 0 ^ ~ N - '' 'COOR2 where r8 represents a hydrogen atom and R1 is chosen from the hydrogen atom and the alkyl, alkenyl and alkynyl radicals of 1 to 10 carbon atoms; cycloalkyl and cycloalkylalkyl of 3 to 6 carbon atoms in the ring of the cycloalkyl part and of 1 to 6 carbon atoms in the alkyl parts; phenyl; aralkyl, aralkenyl and aralkynyl in which the aryl part is a phenyl radical and the aliphatic part has 1 to 6 carbon atoms; hetero-aryl, heteroaralkyl, heterocyclic and heterocycloalkyl in which the heteroatom (s) in the aforementioned heterocyclic parts are chosen from 1 to 4 oxygen, nitrogen or sulfur atoms and the alkyl parts associated with the heterocyclic parts have 1 to 6 carbon atoms, all of which are substituted or unsubstituted and whose substituent (s) with respect to the abovementioned radicals are independently chosen from optionally amino, halogenated, hydroxylated or halogenated Ci-Cg-alkyl -OR3 O -ocnr3r4 O -CNR3r4 -NR3R4 CD. YD.MdC.CH. - 356 - SY-1735A __ // NR3 'NR3R4 -S02NR3R4 0 -NHCNR3r4 0 r3cnr4- -C02R3 = 0 O -OCR3 -SR3 0 11 Q -SR9 0 Il. -SR9 II 0 -CN -N3 -OSO3R3 0 II -OS-R9 II 0 O —NR3S — R9 II O -OP (O) (OR3) (OR4) -NR3C = NR4 R3 -NR3C02R4 -NO 2 where, by the way of the aforementioned substituents, the radicals r3 and R4 are independently chosen from the hydrogen atom and the alkyl, alkenyl and alkynyl radicals CD.YD.MdC.CH. - 357 - SY-1735A with 1 to 10 carbon atoms? cycloalkyl, cycloalkyl-alkyl and alkylcycloalkyl of 3 to 6 carbon atoms in the ring of the cycloalkyl part and from 1 to 6 carbon atoms in the alkyl parts; phenyl; aralkyl, aralkenyl and aralkynyl whose aryl part is a phenyl radical and whose aliphatic part has 1 to 6 carbon atoms? and hetero-aryl, heteroaralkyl, heterocyclic and heterocycloalkyl in which the heteroatom (s) in the aforementioned heterocyclic parts are chosen from 1 to 4 oxygen, nitrogen and sulfur atoms and in which the alkyl parts associated with the heterocyclic parts count 1 with 6 carbon atoms, or r3 and r4 (taken together with the nitrogen atom to which at least one of them is linked, can form a heterocyclic nitrogen pentagonal or hexagonal radical? R 9 is defined as r3 , except that it cannot be a hydrogen atom? or else where Rl and R ^, taken together, represent a C2-C10 alkylidene or C2-Cioalkylene radical substituted by hydroxyl? R 5 is chosen from alkyl radicals , alkenyl and alkynyl of 1 to 10 carbon atoms - cycloalkyl and cycloalkylalkyl of 3 to 6 carbon atoms in the ring of the cycloalkyl part and of 1 to 6 carbon atoms in the alkyl? phenyl? aralkyl, aralkenyl and aralkynyl parts the aryle part is a radica l phenyl and whose aliphatic part has 1 to 6 carbon atoms? heteroaryl, heteroaralkyl, heterocyclic and heterocycloalkyl in which the heteroatom (s) of the aforementioned heterocyclic parts are chosen from 1 to 4 atoms of oxygen, nitrogen or sulfur and in which the alkyl parts associated with the heterocyclic parts have 1 to 6 atoms of carbon, all substituted or unsubstituted? the aforementioned R 5 radicals being optionally substituted by 1 to 3 independently chosen radicals CD.YD.MdC.CH. - 358 - SY-1735A dämment among: cl-Ce-alkyl optionally amino, fluorinated, chlorinated, carboxylated, hydroxylated, or carbamoylated fluoro, chloro or bromo -OR3 -0C02r3 -OCOR3 -OCONR3r4 0 HQ -0S-R9 II 0 -oxo -NR3r4 R3C0NR4- -NR3co2R4 -NR3CONR3R4 O -NR3S-R9 II 0 -SR3 0 t -SR9 0 0 O -S-R9 -S03R3 -C02r3 -conr3r4 -CN; or phenyl optionally substituted by 1 to 3 fluoro, chloro, bromo, Cx-Cs-alkyl, -Or3, -Nr3r4, -S03r3, -C02r3 or -C0NR3r4, where R3, R4 and R9 in these substituents of R3 are such that defined above; or R5 can be combined with CD.YD.MdC.CH. - 359 - SY-1735A ο- at another point in the cycle so as to form a heterocyclic or condensed heteroaromatic radical, the cycle of which may contain additional heteroatoms, chosen from 0, N and S; r1 6 is chosen from alkyl, alkenyl and alkynyl radicals of 1 to 10 carbon atoms; cycloalkyl, cycloalkylalkyl and alkylcycloalkyl of 3 to 6 carbon atoms in the ring of the cycloalkyl part and from 1 to 6 carbon atoms in the alkyl parts; spirocycloalkyl of 3 to 6 carbon atoms; phenyl; aralkyl, aralkenyl and aralkynyl in which the aryl part is a phenyl radical and the aliphatic part has 1 to 6 carbon atoms; hetero-aryl, heteroaralkyl, heterocyclic and heterocycloalkyl in which the heteroatom (s) in the above-mentioned heterocyclic parts are chosen from 1 to 4 oxygen, nitrogen or sulfur atoms and the alkyl parts associated with the heterocyclic parts have 1 to 6 carbon atoms, all of which are substituted or unsubstituted and whose substituent (s) with respect to the abovementioned radicals are chosen from amino, mono-, di- and trialcoylamino, hydroxyl, alkoxy, mercapto, alkylthio, phenylthio, sulfamoyl, amidino, guanidino radicals , nitro, chloro, bromo, fluoro, cyano and carboxyl; and in which the alkyl parts in the abovementioned substituents have 1 to 6 carbon atoms; A represents a Ci-Cg-alkylene radical in a straight or branched chain; R2 represents a hydrogen atom, an anionic charge or a conventional easily removable radical protecting the carboxyl function, being CD.YD.MdC.CH. SY-1735A understood that when R2 represents a hydrogen atom or a protective radical, a counter ion is also present, and f * represents a substituted or unsubstituted heterocyclic, aromatic, mono-, bi- or polycyclic radical comprising at least one nitrogen atom in the ring and united to the radical A by a carbon atom of the ring and comprising a ring nitrogen atom which is quaternized by the radical R ^; or a pharmaceutically acceptable salt of this compound. 148. A compound according to claim 147, in the formula of which Ri represents an OH CH3CH- radical and r! 6 represents a methyl radical. 149. A compound according to claim 147, in the formula of which R1 represents an OH radical CH3CH-r16 represents a methyl radical and the absolute configuration is 5R, 6S, 8R. 150. A compound according to claim 147, 148 or 149, in the formula of which A represents a radical -CH2- or -CH2CH2-. 151. Compound of formula CD.YD.MdC.CH. - 361 - SY-1735A ~ ε »R1 * Λ Λ, y. 1 I ί S -5) ι | v_y ^ κ ^ C00? 2 where r8 represents a hydrogen atom and Rl is chosen from the hydrogen atom and the alkyl, alkenyl and alkynyl radicals of 1 to 10 carbon atoms; cycloalkyl and cycloalkylalkyl of 3 to 6 carbon atoms in the ring of the cycloalkyl part and from 1 to 6 carbon atoms in the alkyl parts; phenyl; aralkyl, aralkenyl and aralkynyl in which the aryl part is a phenyl radical and the aliphatic part has 1 to 6 carbon atoms; hetero-aryl, heteroaralkyl, heterocyclic and heterocycloalkyl in which the heteroatom (s) in the aforementioned heterocyclic parts are chosen from 1 to 4 oxygen, nitrogen or sulfur atoms and the alkyl parts associated with the heterocyclic parts count 1 to 6 carbon atoms, all of which are substituted or unsubstituted and whose substituent (s) with respect to the abovementioned radicals are independently chosen from C ^ -Cg-alkyl optionally amino, halogenated, hydroxylated or carboxylated halo -OR3 0 -ocnr3r4 0 -CNR3r4 -NR3R4 ÔD .YD.MdC.CH. - 362 - SY-1735A / NR3 - (\ nR3R4 -S02NR3R4 0 -NHCNR3R4 O R3CNR4- -CO2R3 = 0 O -OCR3 -SR3 O -SR9 o -SR9 II o -CN -n3 -OSO3R3 0 11 Q -OS-R9 II OO -NR3S-R9 II 0 -0P (0) (OR3) (0R4) -NR3C = Nr4 R3 -NR3CO2R4 -no2 where, with regard to the aforementioned substituents, the radicals R3 and R4 are chosen independently among the hydrogen atom and the alkyl, alkenyl and alkynyl radicals CD.YD.MdC.CH. - 363 - SY-1735A of 1 to 10 carbon atoms; cycloalkyl, cycloalkyl-alkyl and alkylcycloalkyl of 3 to 6 carbon atoms in the ring of the cycloalkyl part and from 1 to 6 carbon atoms in the alkyl parts; phenyl; aralkyl, aralkenyl and aralkynyl in which the aryl part is a phenyl radical and in which the aliphatic part has 1 to 6 carbon atoms; and hetero-aryl, heteroaralkyl, heterocyclic and heterocycloalkyl in which the heteroatom (s) in the aforementioned heterocyclic parts are chosen from 1 to 4 oxygen, nitrogen and sulfur atoms and in which the alkyl parts associated with the heterocyclic parts count 1 with 6 carbon atoms, or r3 and R4, taken together with 11 nitrogen atoms to which at least one of them is united, can form a pentagonal or hexagonal nitrogen heterocyclic radical; R ^ is defined as r3, except that it cannot be a hydrogen atom; or where Rl and R ^, taken together, represent an alkylidene radical or c2 “Cio_alkyllidene substituted by hydroxyl; r5 is chosen from alkyl, alkenyl and alkynyl radicals of 1 to 10 carbon atoms; cycloalkyl and cycloalkylalkyl of 3 to 6 carbon atoms in the ring of the cycloalkyl part and from 1 to 6 carbon atoms in the alkyl parts; phenyl; aralkyl, aralkenyl and aralkynyl in which the aryl part is a phenyl radical and in which the aliphatic part has 1 to 6 carbon atoms; heteroaryl, heteroaralkyl, heterocyclic and hetero-cycloalkyl in which the heteroatom (s) of the abovementioned heterocyclic parts are chosen from 1 to 4 oxygen, nitrogen or sulfur atoms and in which the alkyl parts associated with the heterocyclic parts have 1 to 6 atoms of carbon, all substituted or unsubstituted; the aforementioned R5 radicals being optionally substituted by 1 to 3 independently chosen radicals CD.YD.MdC.CH. - 364 - SY-1735A especially among: cl-Cg-alkyl optionally amino, fluorinated, chlorinated, carboxylated, hydroxylated, or carbamoylated fluoro, chloro or bromo -OR3 -0C02r3 —OCOR3 -OCONr3r4 0 II “-OS-R9 II 0 - oxo -NR3r4 R3CONR4- -nr3co2r4 -NR3C0NR3R4 0 -NR3S-R9 II 0 -SR3 0 -SR9 0 O -S-R9 -so3r3 -C02r3 -CONR3R4 -CN; or phenyl optionally substituted with 1 to 3 fluoro, chloro, bromo, C ^ -Cg-alkyl radicals, -OR3, -NR3R4, -SO3r3, -co2R3 or -CONr3r4, where R3, R4 and R9 in these R3 substituents are such as defined above; or R5 can be combined with CD.YD.MdC.CH. - 365 - SY-1735A * G6- at another point in the cycle so as to form a condensed heterocyclic or heteroaromatic radical, the cycle of which may contain additional heteroatoms, chosen from 0, N and S; R16 is chosen from alkyl, alkenyl and alkynyl radicals of 1 to 10 carbon atoms; cycloalkyl, cycloalkylalkyl and alkylcycloalkyl of 3 to 6 carbon atoms in the ring of the cycloalkyl part and from 1 to 6 carbon atoms in the alkyl parts; spirocycloalkyl of 3 to 6 carbon atoms; phenyl; aralkyl, aralkenyl and aralkynyl in which the aryl part is a phenyl radical and the aliphatic part has 1 to 10 carbon atoms; heteroaryl, hetero-aralkyl, heterocyclic and heterocycloalkyl of which the heteroatom (s) in the above-mentioned heterocyclic parts are chosen from 1 to 4 atoms of oxygen, nitrogen or sulfur and the alkyl parts associated with the heterocyclic parts have 1 to 6 atoms of carbon, all substituted or unsubstituted and whose substituent (s) with respect to the abovementioned radicals are chosen from amino, mono-, di- and tri-alkylamino, hydroxyl, alkoxy, mercapto, alkylthio, phenylthio, sulfamoyl, amidino, guanidino radicals , nitro, chloro, bromo, fluoro, cyano and carboxyl; and in which the alkyl parts in the abovementioned substituents have 1 to 6 carbon atoms; A represents a C ^ -Cg-alkylene radical in a straight or branched chain; R 2 represents a hydrogen atom, an anionic charge or a conventional radical easily CD.YD.MdC.CH. SY-1735A eliminable protector of the carboxyl function, it being understood that when R 2 represents a hydrogen atom or a protective radical, a counter ion is also present, and O represents a nitrogen heterocyclic radical, mono-, bi- or polycyclic containing 0 to 5 additional heteroatoms chosen from 0, S and N, the heterocyclic radical being united to the radical A by a ring carbon atom and comprising a ring nitrogen atom quaternized by the radical R5, and this heterocyclic radical being optionally substituted for the carbon atoms of the available ring by 1 to 5 substituents independently chosen from C1-C4-alkyl radicals; Ci ~ C4-alkyl substituted by 1 to 3 hydroxyl, amino, C1-C4-alkylamino, di (C1-C4) alkylamino, Ci-C4-alkoxy, carboxyl, halo or sulfo, C3-C6-cycloalkyl radicals? Cs-Cg-cycloalkyl (C1-C4) alkyl optionally substituted with 1 to 3 substituents mentioned above in connection with the radicals Ci-C4 ~ alkyl; C1-C4-alkoxy C1-C4-alkylthio; amino; C1-C4-alkylamino; di (C1-C4) alkylamino; halo; C1-C4-alkanoyl-amino; C ^ -C4-alkanoyloxy; carboxyl; sulfo; -CO2-C1-C4-.alkyl; hydroxyl; amidino; guanidino; phenyl; phenyl substituted with 1 to 3 substituents independently chosen from amino, halo, hydroxyl, trifluoromethyl, Ci-C4-alkyl, Ci-C4 ~ al-coxy, C ^ -C4 ~ alkylamino, di (Ci-C4) alkylamino, carboxyl radicals and sulfo; phenyl (C1-C4) alkyl, the phenyl part of which is optionally substituted with 1 to 3 substituents mentioned above with respect to the phenyl radical CD.YD.MdC.CH. SY-1735A and the alkyl part is optionally substituted with 1 to 3 substituents mentioned above with respect to the Cq-C4-alkyl radicals; and heteroaryl or hetero-aralkyl in which the heteroaroma (s) are chosen from 1 to 4 O, S or N atoms and in which the alkyl part associated with the heteroaralkyl radical has 1 to 6 carbon atoms, these heteroaryl and heteroaralkyl radicals being optionally substituted in the heterocyclic part with 1 to 3 substituents independently chosen from hydroxyl, amino, halogeno, trifluo-romethyl, C ^ -C ^ alkyl, Ci-C4-alkoxy, Cx-C4 ~ alkylamino, di (Ci-C4) alkylamino radicals , carboxyl and sulfo, and in the alkyl part with 1 to 3 substituents chosen from the hydroxyl, amino, Cx-C4-alkylamino, di (Cx-C4) alkylamino, Cx-C4-alkoxy, carboxyl, halogen and sulfo radicals and the heterocyclic radical being optionally substituted for the nitrogen atoms of the ring available by 1 to 3 substituents chosen independently from the Ci-C4-alkyl radicals; Cx-C4-alkyl substituted by 1 to 3 hydroxyl, amino, Cx-C4-alkyl-amino, di (Cx ~ C4) alkylamino, Ci-C4-alkoxy, carboxyl, halogen or sulfo radicals; Cg-Cg-cycloalkyl; C3-Cg-cycloal-coyl (Cx-C4) alkyl optionally substituted with 1 to 3 substituents mentioned above in connection with the radicals Cx-C4 ~ alkyl; phenyl, phenyl optionally substituted with 1 to 3 substituents independently chosen from amino, halogeno, hydroxyl, trifluoro-romethyl, Ci-C4-alkyl, Cx-C4 ~ alkoxy, Cx ~ C4-alkyl-amino, di (Cx-C4) radicals ) alkyllamino, carboxyl and sulfo; phenyl (Cx-C4) alkyl, the phenyl part of which can optionally be substituted with 1 to 3 substituents mentioned above with respect to the phenyl radical and the alkyl part of which can optionally be substituted with 1 to 3 substituents mentioned above with respect to the phenyl radicals Cx-C4-alkyl radicals; and heteroaryl or CD.YD.MdC.CH. - 368 - SY-1735A heteroaralkyl in which the heteroatom (s) are chosen from 1 to 4 O, S or N atoms and in which the alkyl part associated with the heteroalkyl radical has 1 to 6 carbon atoms, the heteroaryl and heteroaralkyl radicals being optionally substituted in the heterocyclic part with 1 to 3 substituents chosen independently from the hydroxyl, amino, halo, trifluoromethyl, Ci-C4-alkyl, C1-C4 “alkoxy, C1-C4-alkylamino, di (Ci-C4) alkylamino, carboxyl and sulfo radicals and in the alkyl part with 1 to 3 substituents chosen from hydroxyl, amino, Ci-C4-alkylamino, di (C1-C4) alkylamino, C1-C4-alkoxy, carboxyl, halo and sulfo radicals; or a pharmaceutically acceptable salt of this compound. 152. A compound according to claim 151, in the formula of which R1 represents an OH radical CH3CH- and r! 6 represents a methyl radical. 153. A compound according to claim 151, in the formula of which Ri represents an OH radical CH3CH-R16 represents a methyl radical and the absolute configuration is 5R, 6S, 8R. 154. A compound according to claim 151, 152 or 153, in the formula of which A represents a radical -CH2- or -CH2CH2-. 155. Compound of formula CD.YD.MdC.CH. - 369 - SY-1735A R6 H r16 1. i, A c_ 5 K — f ~ i | p Λ £ K "COO? 2 where R8 represents a hydrogen atom and Rl is chosen from the hydrogen atom and the alkyl, alkenyl and alkynyl radicals of 1 to 10 carbon atoms; cycloalkyl and cycloalkylalkyl of 3 to 6 carbon atoms in the ring of the cycloalkyl part and of 1 to 6 carbon atoms in the alkyl parts; phenyl; aralkyl, aralkenyl and aralkynyl in which the aryl part is a phenyl radical and the aliphatic part has 1 to 6 carbon atoms; hetero-aryl, heteroaralkyl, heterocyclic and heterocycloalkyl in which the heteroatom (s) in the aforementioned heterocyclic parts are chosen from 1 to 4 atoms of oxygen, nitrogen or sulfur and the alkyl parts associated with the heterocyclic parts have 1 to 6 carbon atoms, all of which are substituted or unsubstituted and whose substituent (s) with respect to the abovementioned radicals are chosen independently from Ci-Ce -alkyl possibly aminated, halogenated, hydroxyl or halo carboxylated -OR3 0 -0CNR3R4 O -CNR3r4 -NR3R4 CD.YD.MdC.CH. - 370 - SY-1735A / NR3 - {'NR3R4 -S02NR3r4 0 -NHCNR3r4 O r3cNR4 “-CO2R3 = 0 O -ocr3 -SR3 O -SR9 0 -SR9 II 0 -CN“ N 3 -OSO3R3 O 11 Q -OS-R9 II O 0 -nr3s-r9 II 0 -0P (0) (0R3) (OR4) -nr3c = nr4 R3 -NR3C02R4 -no2 where, with regard to the aforementioned substituents, the radicals R3 and R4 are chosen independently from the hydrogen atom and the alkyl, alkenyl and alkynyl radicals CD.YD.MdC.CH. - 371 - SY-1735A from 1 to 10 carbon atoms; cycloalkyl, cycloalkyl-alkyl and alkylcycloalkyl of 3 to 6 carbon atoms in the ring of the cycloalkyl part and from 1 to 6 carbon atoms in the alkyl parts; phenyl; aralkyl, aralkenyl and aralkynyl in which the aryl part is a phenyl radical and in which the aliphatic part has 1 to 6 carbon atoms; and hetero-aryl, heteroaralkyl, heterocyclic and heterocycloalkyl in which the heteroatom (s) in the aforementioned heterocyclic parts are chosen from 1 to 4 oxygen, nitrogen and sulfur atoms and in which the alkyl parts associated with the heterocyclic parts count 1 with 6 carbon atoms, or r3 and r4, taken together with the nitrogen atom to which at least one of them is united, can form a pentagonal or hexagonal nitrogen heterocyclic radical; R 9 is defined as r3, except that it cannot be a hydrogen atom; or where Ri and R®, taken together, represent a radical c2 ”c10 alkylidene or C2-Cio_alcoYliâ®ne substituted by hydroxyl; r5 is chosen from alkyl, alkenyl and alkynyl radicals of 1 to 10 carbon atoms; cycloalkyl and cycloalkyl and cycloalcoylalkyl of 3 to 6 carbon atoms in the ring of the cycloalkyl part and from 1 to 6 carbon atoms in the alkyl parts; phenyl; aralkyl, aralkenyl and aralkynyl in which the aryl part is a phenyl radical and in which the aliphatic part has 1 to 6 carbon atoms; heteroaryl, heteroaralkyl, heterocyclic and heterocycloalkyl in which the heteroatom (s) of the abovementioned heterocyclic parts are chosen from 1 to 4 oxygen, nitrogen or sulfur atoms and in which the alkyl parts associated with the heterocyclic parts have 1 to 6 carbon atoms, all substituted or unsubstituted; the aforementioned r5 radicals being optionally substituted with 1 CD.YD.MdC.CH. - 372 - SY-1735A with 3 radicals chosen independently from: C ^ -Cg-alkyl optionally amino, fluorinated, chlorinated, carboxylated, hydroxylated, or carbamoylated fluoro, chloro or bromo -0R3 -0C02r3 -ocor3. -OCONR3R4 0 -SR9 11 0 -0X0 -NR3R4 R3CONR4- -Nr3c02r4 -NH 3 CONR 3 r4 0 -NR3S-R9 II O -SR3 0 1 n -SR9 0 0 \ / Q -S-R9 -SO3R3 -co2r3 -conr3r4 -CN; or phenyl optionally substituted by 1 to 3 fluoro, chloro, bromo, Cx-Cg-alkyl, -OR3, -NR3r4, -SO3r3, -C02R3 or —CONR3R4, where R3, R4 and R9 in these substituents of R 5 are such as defined above; or R5 can be combined with CD.YD.MdC.CH. - 373 - SY-1735A ο at another point in the cycle so as to form a heterocyclic or condensed heteroaromatic radical, which cyclic radical may contain additional heteroatoms, chosen from 0, N and S; H16 is chosen from alkyl, alkenyl and alkynyl radicals of 1 to 10 carbon atoms; cycloalkyl, cycloalkylalkyl and alkylcycloalkyl of 3 to 6 carbon atoms in the ring of the cycloalkyl part and from 1 to 6 carbon atoms in the alkyl parts; spirocycloalkyl of 3 to 6 carbon atoms; phenyl; aralkyl, aralkenyl and aralkynyl in which the aryl part is a phenyl radical and the aliphatic part has 1 to 6 carbon atoms; hetero-aryl, heteroaralkyl, heterocyclic and heterocycloalkyl in which the heteroatom (s) in the aforementioned heterocyclic parts are chosen from 1 to 4 oxygen, nitrogen or sulfur atoms and the alkyl parts associated with the heterocyclic parts have 1 to 6 carbon atoms, all of which are substituted or unsubstituted and whose substituent (s) with respect to the abovementioned radicals are chosen from amino, mono-, di- and trialcoylamino, hydroxyl, alkoxy, mercapto, alkylthio, phenylthio, sulfamoyl, amidino, guanidino radicals , nitro, chloro, bromo, fluoro, cyano and carboxyl; and in which the alkyl parts in the abovementioned substituents have 1 to 6 carbon atoms; A represents a radical (^ -Cß-alkylene in a straight or branched chain; R2 represents a hydrogen atom, an anionic charge or a conventional radical easily removable protecting the carboxyl function, being CD.YD.MdC.CH. - 374 - SY-1735A understood that when r2 represents a hydrogen atom or a protective radical, a counter ion is also present, and jT \ -k5 w represents a nitrogen heterocyclic radical, aromatic pentagonal or hexagonal containing 0 to 3 additional heteroatoms chosen between 0, S and N, this heterocyclic radical being optionally substituted for the ring carbon atoms available by 1 to 5 substituents chosen independently from the radicals Ci “C4 ~ alkyl; Ci-C4-alkyl substituted by 1 to 3 hydroxyl, amino radicals, Ci-C4-alkylamino, di (C1-C4) alkylamino, Ci-C4-alkoxy, carboxyl, halo or sulfo? C3-Cg-cycloalkyl? C3-C6-cycloalkyl (C1-C4) alkyl optionally substituted by 1 to 3 substituents mentioned above about radica ux Cx-C4-alkyl; cl ~ c4 “alcoxY · Ci-C4-alcoylthio; amino? C ^ -C4-alkyl-amino? di (C1-C4) alkylamino; halo? Ci-C4-alkanoyl- · amino? Ci ~ C4-alkanoyloxy? carboxyl? sulfo? -CO2-C1-C4-alkyl? hydroxyl? amidino? guanidino? phenyl? phenyl substituted with 1 to 3 substituents independently selected from amino, halo, hydroxyl, trifluoromethyl, Ci-C4-alkyl, Ci-C4-al-coxy, Cx-C4-alkylamino, di (C1-C4) alkylamino, carboxyl and sulfo? phenyl (C ^ -C4) alkyl in which the phenyl part is optionally substituted with 1 to 3 substituents mentioned above with respect to the phenyl radical and the alkyl part is optionally substituted with 1 to 3 substituents mentioned above with respect to the radicals Ci -C4 “alkyl? and heatheraryl or hetero-roaralcoyl of which the heteroatom (s) are chosen CD.YD.MdC.CH. - 375 - SY-1735A from 1 to 4 atoms 0, S or N and whose alkyl part associated with the heteroaralkyl radical has 1 to 6 carbon atoms, these heteroaryl and heteroaralkyl radicals being optionally substituted in the heterocyclic part by 1 to 3 substituents independently selected from hydroxyl, amino, halo, trifluo-romethyl, Ci-C4-alkyl, Ci-C ^ alkoxy, Ci ~ C4-alkyl-amino, di (Ci-C4) alkylamino, carboxyl and sulfo radicals, and in the alkyl part with 1 to 3 substituents chosen from hydroxyl, amino, Ci-C4-alkylamino, di (0 ^ -04) alkylamino, Ci-C4-alkoxy, carboxyl, halo and sulfo radicals and the heterocyclic radical being optionally substituted for atoms ring nitrogen available with 1 to 3 substituents independently selected from C1-C4-alkyl radicals; Ci-C4-alkyl substituted by 1 to 3 hydroxyl, amino, Ci-C4 ~ alkyl-amino, di (Ci-C4) alkylamino, Ci-C4-alkoxy, carboxyl, halo or sulfo radicals; C3-Cg-cycloalkyl; C3-Cg-cycloal-coyl (C ^ -C4) alkyl optionally substituted with 1 to 3 substituents mentioned above in connection with the radicals C ^ -C4-alkyl7 phenyl; phenyl substituted with 1 to 3 substituents independently chosen from amino, halo, hydroxyl, trifluoromethyl, Ci-C4-alkyl, C2-C4-alkoxy, Cj-C4-alkylamino, di (C ^ -C4) alkylamino, carboxyl and sulfo radicals ; phenyl (C1-C4) - alkyl in which the phenyl part may optionally be substituted with 1 to 3 substituents mentioned above with respect to the phenyl radical and in which the alkyl part can optionally be substituted with 1 to 3 substituents mentioned above in connection with the radical radicals (ϋχ-C4 ~ alkyl; and heteroaryl or heteroaralkyl in which the heteroatom (s) are chosen from 1 to 4 O, S or N atoms and in which the alkyl part associated with the heteroaralkyl radical has 1 to 6 carbon atoms, the heteroaryl radicals and heteroaralkyl possibly being CD.YD.MdC.CH. - 376 - SY-1735A L substituted in the heterocyclic part by 1 to 3 substituents chosen independently from the hydroxyl, amino, halogen, trifluoromethyl, C C4-alkyl, Ci-C radicals ^ alkoxy, Ci-C4-alkylamino, di (Ci-C4) ~ alkyllamino, carboxyl and sulfo and in the alkyl part with 1 to 3 substituents chosen from hydroxyl, amino, C1-C4-alkylamino, di (C] radicals. -C4) alkyllamino, C] .- C4-alkoxy, carboxyl, halogeno and sulfo; or a pharmaceutically acceptable salt of this compound. 156. A compound according to claim 155, in which formula the heterocyclic radical - K-R5 W is optionally substituted on the ring nitrogen or carbon atoms available with up to 5 independently selected (lower) alkyl radicals. 157. A compound according to claim 156, in the formula of which A represents a radical -CH2- / -CH2CH2- or -CH3CH-. 158. A compound according to claim 155, 156 or 157, in the formula of which represents an OH radical CH3CH- r! 6 represents a methyl radical and the absolute configuration is 5R, 6S, 8R. 159. Compound of formula CD.YD.MdC.CH. - 377 - SY-1735A] 8 s “Ri; -S—, ü-f K — R2 1 1" N COOR2 where R8 represents a hydrogen atom and Rl is chosen from the hydrogen atom and the alkyl radicals , alkenyl and alkynyl of 1 to 10 carbon atoms; cycloalkyl and cycloalkylalkyl of 3 to 6 carbon atoms in the ring of the cycloalkyl part and of 1 to 6 carbon atoms in the alkyl parts; phenyl; aralkyl, aralkenyl and aralkynyl of which the aryl part is a phenyl radical and the aliphatic part has 1 to 6 carbon atoms; hetero-aryl, heteroaralkyl, heterocyclic and heterocycloalkyl in which the heteroatom (s) in the aforementioned heterocyclic parts are chosen from 1 to 4 oxygen atoms , nitrogen or sulfur and the alkyl parts associated with the heterocyclic parts have 1 to 6 carbon atoms, all of which are substituted or unsubstituted and whose substituent (s) with respect to the abovementioned radicals are independently chosen from C ^ -Cß-alkyl optionally amine, halogenated, hy droxylated or halo carboxylated -0R3 0 -0CNR3r4 0 -CNr3r4 -NR3R4 CD.YD.MdC.CH. - 378 - SY-1735A »Nr3 Nr3r4 -S02NR3r4 0 II -NHCNR3R4 0 R3CNR4 ~ -CO2R3 = 0 0 11 * -OCR3 -SR3 O -SR9 0 -SR9 II 0 -CN -N3 -OSO3R3? -0S-R9 II 0 0 J! o -NR3S-r9 II 0 -0P (0) (0R3) (0R4) -NR3C = NR4 R3 -NR3C02R4 -no2 where, with regard to the aforementioned substituents, the radicals R3 and r4 are chosen independently from the hydrogen atom and the alkyl, alkenyl and alkynyl radicals CD.YD.MdC.CH. - 379 - SY-1735A from 1 to 10 carbon atoms; cycloalkyl, cycloalkyl-alkyl and alkylcycloalkyl of 3 to 6 carbon atoms in the ring of the cycloalkyl part and from 1 to 6 carbon atoms in the alkyl parts; phenyl; aralkyl, aralkenyl and aralkynyl in which the aryl part is a phenyl radical and in which the aliphatic part has 1 to 6 carbon atoms; and hetero-aryl, heteroaralkyl, heterocyclic and heterocycloalkyl in which the heteroatom (s) in the aforementioned heterocyclic parts are chosen from 1 to 4 oxygen, nitrogen and sulfur atoms and in which the alkyl parts associated with the heterocyclic parts count 1 with 6 carbon atoms, or else R.3 and r4, taken together with the nitrogen atom to which at least one of them is united, can form a pentagonal or hexagonal nitrogen heterocyclic radical; r9 is defined as r3, except that it cannot be a hydrogen atom; or where R ^ - and r8, taken together, represent a C2-C10 alkylidene or C2-Cio-alkylidene radical substituted by hydroxyl; r5 is chosen from alkyl, alkenyl and alkynyl radicals of 1 to 10 carbon atoms; cycloalkyl and cycloalkyl and cycloalcoylalkyl of 3 to 6 carbon atoms in the ring of the cycloalkyl part and from 1 to 6 carbon atoms in the alkyl parts; phenyl; aralkyl, aralkenyl and aralkynyl in which the aryl part is a phenyl radical and in which the aliphatic part has 1 to 6 carbon atoms; heteroaryl, heteroaralkyl, heterocyclic and heterocycloalkyl in which the heteroatom (s) of the aforementioned heterocyclic parts are chosen from 1 to 4 oxygen, nitrogen or sulfur atoms and in which the alkyl parts associated with the heterocyclic parts have 1 to 6 carbon atoms, all substituted or unsubstituted; the aforementioned R5 radicals being optionally substituted with 1 CD.YD.MdC.CH. - 380 - SY-1735A with 3 radicals independently chosen from: C ^ -C6-alkyl optionally amino, fluorinated, chlorinated, carboxylated, hydroxylated, or carbamoylated fluoro, chloro or bromo -0R.3 -OCO2R3 -0C0R3 -OCONR3R4 O II - OS-R9 H 0 -oxo -NR3r4 r3c0NR4- -NR3C02R4 -NR3CONR3R4 OJ _ -NR3 ^ -r9 0 -SR3? -SR9 0, ° -S-R9 -SO3R3 -C02r3 -CONR3R4 -CN; or phenyl optionally substituted by 1 to 3 fluoro, chloro, bromo, Ci-Cg-alkyl, -0R3, -Nr3r4, -SO3r3, -C02r3 or -CONR3r4, where r3, r4 and R9 in these substituents of r5 are such that defined above; or R5 can be combined with CD.YD.MdC.CH. - 381 - SY-1735A ο * - at another point in the cycle so as to form a condensed heterocyclic or heteroaromatic radical, the cycle of which may contain additional heteroatoms, chosen from 0, N and S; r16 is chosen from alkyl, alkenyl and alkynyl radicals of 1 to 10 carbon atoms; cycloalkyl, cycloalkylalkyl and alkylcycloalkyl of 3 to 6 carbon atoms in the ring of the cycloalkyl part and from 1 to 6 carbon atoms in the alkyl parts; spirocycloalkyl of 3 to 6 carbon atoms; phenyl; aralkyl, aralkenyl and aralkynyl in which the aryl part is a phenyl radical and the aliphatic part has 1 to 10 carbon atoms; hetero-aryl, heteroaralkyl, heterocyclic and heterocycloalkyl in which the heteroatom (s) in the aforementioned heterocyclic parts are chosen from 1 to 4 oxygen, nitrogen or sulfur atoms and the alkyl parts associated with the heterocyclic parts have 1 to 6 carbon atoms, all of which are substituted or unsubstituted and whose substituent (s) with respect to the abovementioned radicals are chosen from amino, mono-, di- and trialcoylamino, hydroxyl, alkoxy, mercapto, alkylthio, phenylthio, sulfamoyl, amidino, guanidino radicals , nitro, chloro, bromo, fluoro, cyano and carboxyl; and in which the alkyl parts in the abovementioned substituents have 1 to 6 carbon atoms; A represents a Ci-Ce-alkylene radical in a straight or branched chain; r2 represents a hydrogen atom, an anionic charge or a classic easily removable radical protecting the carboxyl function, being CD.YD.MdC.CH. - 382 - SY-1735A understood that when r2 represents a hydrogen atom or a protective radical, a counter ion is also present, and _JTV, 5 represents a radical chosen between (a) I II Λν where r6, r7 and RIO are independently selected from the hydrogen atom and the Cx-C4-alkyl radicals; Οχ-C4-alkyl substituted by hydroxyl, Ci-C4-alkylamino, di (Cx-C4-alkyl) amino, Ci-C4-alkoxy, amino, sulfo, carboxy and halo; Cj-Cß-cycloalcoyle? Cx ~ C4-alkoxy; cl-c4-alcoylthio; amino; Cx-C4-alkyllamino; di (C1-C4 ~ alkyl) amino; halo; cl ”C4-alkanoylamino; C1-C4-alkanoyloxy; carboxyl; -C02-Cx-C4-alkyl; hydroxyl; amidino; guanidino; phenyl, phenyl substituted by one, two or three amino, halo, hydroxyl, trifluoromethyl radicals; Cx-C4-alkyl or C1-C4-alkoxy; phenyl (Ci-C4) alkyl in which the phenyl part can optionally be substituted by 1 to 3 substituents mentioned above with respect to the phenyl radical and the alkyl part can optionally be substituted by 1 to 3 radicals mentioned above with regard to the radicals Cx-C4 ~ alkyl; and heteroaryl or heteroaralcoyl in which the heteroatom (s) in the aforementioned heterocyclic parts are chosen from 1 to 4 oxygen, nitrogen or sulfur atoms and the CD.YD.MdC ♦ CH part. - 383 - SY-1735A! alkyl associated with the heteroaralkyl part has 1 to 6 carbon atoms, or else where two of r6, R 7 and RIO, taken together, can represent a condensed saturated carbocyclic radical, a condensed aromatic carbocyclic radical, a non-aromatic heterocyclic radical condensed or a condensed heteroaromatic radical, which condensed rings are optionally substituted by 1 or 2 of the substituents defined above with respect to R6, r7 and RIO; (b) -5 c ί R "®l and ^ \ j] '|] e | optionally substituted on a carbon atom by 1 to 3 substituents chosen independently from the radicals C ^ -C4-alkyl; Cx-C4-alkyl substituted by hydroxyl, Cx-C4-alkylamino, di (Cx-C4-alkyl) amino, C ^ -C4-alkoxy, amino, sulfo, carboxyl and halo; c3 ~ Ce-cycloalkyl; Cx-C4 ~ alkoxy; Cx-C4 -alkyllio; amino; cl-C4-alkylamino; di (Cx-C4-alkyl) amino; halo; Οχ-C4-alkanoylamino; Cx-C4-alkanoyloxy; carboxyl; -C02 “Ci-C4-alkyl; hydroxyl; amidino; guanidino; phenyl, phenyl substituted by one, two or three amino, halo, hydroxyl, trifluoromethyl radicals; Cx-C4-alkyl or Cx-C4-alkoxy; phenyl (Cx-C4) alk ° yl of which the part CD.YD.MdC .CH. - 384 - SY-1735A phenyl may optionally be substituted with 1 to 3 substituents mentioned above with respect to the phenyl radical and the alkyl part may optionally be substituted with 1 to 3 radicals mentioned above with respect to the radicals C ^ -C4-alkyl; and heteroaryl or heteroaral coyl in which the heteroatom (s) in the aforementioned heterocyclic parts are chosen from 1 to 4 oxygen, nitrogen or sulfur atoms and the alkyl part associated with the heteroaralkyl part has 1 to 6 carbon atoms, or optionally substituted to form a carbocyclic, heterocyclic or heteroaromatic condensed radical optionally substituted with 1 or 2 of the substituents defined above; (c) R5 f and ej e „-f 11. —F it _5 _5 fH- optionally substituted on a carbon atom by 1 or 2 substituents independently chosen from C 1 -C 4 -alkyl radicals; C1-C4-alkyl substituted by hydroxyl, Ci-C4-alkylamino, di (C] .- C4-alkyl) amino, C1-C4-alkoxy, amino, sulfo, carboxyl and halo; C3-Ce-cycloalcoyle; C1-C4-alkoxy; C1-C4- * alkylthio; amino; C1-C4-alkylamino; di (C1-C4-alkyl) amino; halo; C1-C4-alkanoylamino; C1-C4-alkanoyloxy; carboxyl; -C02- CD.YD.MdC.CH. - 385 - SY-1735A C ^ -C4-alkyl; hydroxyl; amidino; guanidino; phenyl, phenyl substituted by one, two or three amino, halogeno, hydroxyl, trifluoromethyl radicals; C2_C4-alkyl or C1-C4-alkoxy; phenyl (Ci-C4) alkyl in which the phenyl part can optionally be substituted by 1 to 3 substituents mentioned above with respect to the phenyl radical and the alkyl part can optionally be substituted by 1 to 3 substituents mentioned above with respect to the radicals C1-C4-alkyl; and heteroaryl or heteroaralkyl in which the heteroatom (s) in the aforementioned heterocyclic parts are chosen from 1 to 4 oxygen, nitrogen or sulfur atoms and the alkyl part associated with the heteroaralkyl part has 1 to 6 carbon atoms, or optionally substituted to form a carbocyclic, heterocyclic or heteroaromatic condensed radical optionally substituted by 1 or 2 of the substituents defined above; (d) -5 -5 RS R Λ êJ, cJ, eK Λ. f Î ef i I il it optionally substituted on a carbon atom by 1 substituent chosen independently from the radicals <-l-C4-alkyl; Ci-C4 ~ alkyl substituted by hydroxyl, Cl "C4-alkylamino, di (Ci-C4-alkyl) amino, Ci-C4 ~ alkoxy, CD.YD.MdC.CH. s - 386 - SY-1735A amino, sulfo, carboxyl and halo; Cg-Cg-cyclo-alkyl? Ci-C4-alkoxy; Ci-C4-alkylthio; amino; C1-C4-alkylamino; di (C ^ -C4-alkyl) amino; halo; C1-C4-alkanoylamino ; Ci-C4-alkanoyloxy; carboxyl; -CO2-C1 “C4 ~ alkyl; hydroxyl; amidino; guanidino; phenyl, phenyl substituted by one, two or three amino, halo, hydroxyl, trifluoromethyl radicals; C ^ -C4-alkyl or Ci-C4-alkoxy; phenyl (Ci-C4) alkyl in which the phenyl part can optionally be substituted with 1 to 3 substituents mentioned above with respect to the phenyl radical and the alkyl part can optionally be substituted with 1 to 3 substituents mentioned above above with regard to C1-C4-alkyl radicals and heteroaryl or heteroaralkyl in which the heteroatom (s) in the aforementioned heterocyclic parts are chosen from 1 to 4 oxygen, nitrogen or sulfur atoms and the alkyl part ass associated with the heteroaralkyl part has 1 to 6 carbon atoms; (e) e e 5 ...— Κ-3Γ -K-R - or -4- I where X represents 0, S or NR where R represents a cl_C4-alkyl radical; Ci-C4-alkyl substituted by 1 to 3 hydroxyl, amino, Ci-C4-alkylamino radicals; di (C] _- C4) -alkylamino; Ci-C4 ~ alkoxy; carboxyl; halo or sulfo; C3-Cg-cycloalkyl; C3-C6-cycloalkyl (Ci-C4) - alkyl optionally substituted with 1 to 3 substituents mentioned above in connection with the C1-C4-alkyl radicals; phenyl; phenyl substituted with 1 to 3 substituents independently chosen from amino, - halo, hydroxyl, trifluoromethyl, Ci-C4 ”alkyl, CD.YD.MdC.CH. - 387 - SY-1735A Ci ~ C4-alkoxy, Ci-C4-alkylamino, di (Ci-C4) alkylamino, carboxyl and sulfo; phenyl (Ci-C4) alkyl, the phenyl part of which can optionally be substituted with 1 to 3 substituents mentioned above with respect to the phenyl radical and the alkyl part of which can optionally be substituted with 1 to 3 substituents mentioned above with respect to the phenyl radicals C ^ H ^ -alkyl radicals; and weather-aryl and heteroaralkyl in which the heteroatom (s) are chosen from 1 to 4 O, S or N atoms and the alkyl part associated with the heteroaralkyl radical has 1 to 6 carbon atoms, these heteroaryl and heteroaralkyl radicals being optionally substituted in the part heterocyclic with 1 to 3 substituents independently selected from hydroxyl, amino, halogeno, trifluoromethyl, C ^ -C4-alkyl, C1-C4-alkoxy, C1-C4-alkylamino, di (Cx-C4) alkylamino, carboxyl and sulfo radicals, and in the alkyl part with 1 to 3 substituents chosen from hydroxyl, amino, Ci-C4-alkylamino, di (C2.-C4) alkylamino, C1-C4-alkoxy, carboxyl, halo and sulfo radicals, this radical being optionally substituted on a carbon atom with 1 or more substituents chosen independently from the Ci-C4 ~ alkyl radicals; C1-C4-hydroxy substituted alkyl, Ci-C4-alkylamino, di (C1-C4-alkoylanu.no, Ci ~ C4-alkoxy, amino, sulfo; carboxyl or halo; C3-C6-cycloalkyl; Ci-C4-alkoxy; Ci-C4-alkylthio, amino; Ci-C4-alkylamino; di (Ci-C4-alkyl) amino; halo; Ci-C4-alkanoylamino; Ci-C4-alkanoyloxy; carboxyl; -C02 “Ci-C4-alkyl; hydroxyl ; amidino; guanidino; phenyl; phenyl substituted by one, two or three amino, halo, hydroxyl, trifluoromethyl radicals; Ci-C4 ~ alkyl or Ci-C4 ~ alkoxy; phenyl (C1-C4) alkyl of which the phenyl part may optionally be substituted by 1 to 3 substituents mentioned above in connection with the phenyl radical and the alkyl part of which may optionally CD.YD.MdC.CH. - 388 - SY-1735A be substituted by 1 to 3 substituents mentioned above in connection with the Ci-C4-alkyl radicals, and hetero-aryl and heteroaralkyl of which the beta-atom (s) of the aforementioned heterocyclic parts are chosen from 1 to 4 oxygen, nitrogen or sulfur atoms and the associated alkyl part to the heteroaralkyl part has 1 to 6 carbon atoms, or optionally substituted to form a carbocyclic, heterocyclic or heteroaromatic radical condensed optionally substituted by 1 or 2 of the substituents defined above? (£) | j-1 i- “r * 5? -Ξ-” 5 '* * 5 R5 _ __ „KN-R5 _“ & where X represents O, S or NR where R represents a radical Cl-C4- C1-C4 alkyl ~ alkyl substituted by 1 to 3 hydroxyl, amino, Ci-C4-alkylamino radicals; άί (0χ-04) -alkylamino; C1-C4-alkoxy; carboxyl; halo or sulfo; Cg-Cg-cycloalkyl; C3-C6-cycloalkyl (C] [- C4) - alkyl optionally substituted with 1 to 3 substituents mentioned above in connection with the C1-C4-alkyl radicals; phenyl; phenyl substituted with 1 to 3 substituents independently selected from amino, halogen, hydroxyl, trifluoromethyl, C1-C4 "alkyl yl 'C1-C4-alkoxy, C; [- C4-alkylamino, di (Ci-C4) alkylamino , carboxyl and sulfo; phenyl (Ci-C4) alkyl of which the part CD.YD.MdC.CH. - 389 - SY-1735A phenyl may optionally be substituted by 1 to 3 substituents mentioned above in connection with the phenyl radical and of which the alkyl part may optionally be substituted by 1 to 3 substituents mentioned above with respect to the C 1 -C 4 -alkyl radicals; and weather-aryl and beta-aralkyl in which the heteroatom (s) are chosen from 1 to 4 atoms 0, S or N and the alkyl part associated with the heteroaralkyl radical has 1 to 6 carbon atoms, these heteroaryl and heteroaralkyl radicals being optionally substituted in the heterocyclic part by 1 to 3 substituents chosen independently from the hydroxyl, amino, halogeno, trifluoromethyl, C ^ -C radicals ^ alkyl, C1-C4-alkoxy, Cx-C4-alkoyl amino, di (Cx-C4) alkyllamino, carboxyl and sulfo, and in the alkyl part with 1 to 3 substituents chosen from hydroxyl, amino, Cx-C4-alkylamino, di (Cx-C4) alkyl, C1-C4- alkoxy, carboxyl, halo and sulfo, this heteroaromatic radical being optionally substituted on a carbon atom by a substituent chosen from the radicals Ci ~ C4-alkyl; Cx-C4-alkyl substituted by hydroxyl, Cx-C4-alkylamino, di (Cx-C4-alkyl) amino, Ci-c4-alkoxy, amino, sulfo, carboxyl or halo; C3-C6-cycloalkyl; Cx-C4-alkoxy; C1-C4-alkylthio, amino; C1-C4-alkylamino; di (C1-C4-alkyl) amino; halo; C] _- C4-alkylamino; Ci-C4 ~ alkanoyloxy; carboxyl; -CC ^ -C] .- C4 ~ alkyl; hydroxyl; amidino; guanidino; phenyl; phenyl substituted with one, two or three amino, halo, hydroxyl, trifluoromethyl, Cx-C4-alkyl or Ci ~ c4-alkoxy radicals; phenyl (Οχ-C4) alkyl of which the phenyl part may optionally. be substituted by 1 to 3 substituents mentioned above with respect to the phenyl radical and the alkyl part of which may optionally be substituted by 1 to 3 substituents mentioned above with respect to the Cx-C4-alkyl radicals; and hetero- CD.YD.MdC.CH. - 390 - SY-1735A aryl and heteroaralkyl in which the heteroatom (s) of the abovementioned heterocyclic parts are chosen from 1 to 4 oxygen, nitrogen or sulfur atoms and the alkyl part associated with the heteroalkyl part has 1 to 6 atoms carbon; and (g) F - S- * 5 f .____ K ‘I * S §k '' I Te -5 B Λ 6 -JÇ-S K-N-R OR ζθ j where R represents a C ^ -C4-alkyl radical; Ci-C4-alkyl substituted by 1 to 3 hydroxyl, amino, C1-C4-alkylamino, di (<3 ^ -04) alkylamino, Ci-C4-alkoxy, carboxyl, halo or sulfo radicals; C3-C6 ~ cyclo) alkyl; C3-Ce-cycloalkyl (C1-C4) alkyl optionally substituted with 1 to 3 substituents mentioned above with regard to the C1-C4-alkyl radicals; phenyl; phenyl substituted with 1 to 3 substituents independently selected from amino, halo, hydroxyl, trifluoromethyl, CD.YD.MdC.CH. - 391 - SY-1735A Ci-C4-alkyl, Ci-C4-alkoxy, Ci-C4-alkylamino, pii (Ci-C4) alkyllaraino, carboxyl and sulfo? phenyl (C1-C4) -alkyl, the phenyl part of which can optionally be substituted with 1 to 3 substituents mentioned above with respect to the phenyl radical and the alkyl part of which can optionally be substituted with 1 to 3 substituents mentioned above with regard to the radical C ^ -C4-alkyl radicals? and heatheraryl and heteroaralkyl in which the heteroatom (s) are chosen from 1 to 4 atoms 0, S or N and the alkyl part associated with the heteroaralkyl radical has 1 to 6 carbon atoms, these heteroaryl and heteroaralkyl radicals being optionally substituted in the part heterocyclic with 1 to 3 substituents independently chosen from hydroxyl, amino, halogeno, trifluoromethyl, C4-alkyl, Ci ~ C4-alkoxy, Ci-C4-alkylamino, di (Ci-C4) -alkylamino, carboxyl and sulfo radicals, and in the alkyl part with 1 to 3 substituents chosen from hydroxyl, amino, c1-C4-alkylamino, di (Ci ~ C4) alkylamino, Ci-C4-alkoxy, carboxyl, halo and sulfo radicals, or a pharmaceutically acceptable salt of this compound . 160.- Compound according to claim 159, in the formula of which represents a radical chosen from CD.YD.MdC.CH. - 392 - SY-1735A (a) R5 R? where r5 represents a C ^ -Cg-alkyl radical and R ^, R? and rIO each independently represent a hydrogen atom or a C1-C4-alkyl radical: (b) 5 -5 R Λ 01 J. e l | , H 0.1 where R5 represents a Ci-Cβ-alkyl radical and the available ring carbon atoms are optionally substituted with 1 to 3 Ci-C4-alkyl radicals chosen independently; (VS) 5 R R I © I © ^ v. -p CD.YD.MdC.CH. - 393 - SY-1735A 5 * 5 RI 1 © 1 e M '"V' * 5" / kjr where r5 represents a Ci-Cg-alkyl radical and the available ring carbon atoms are optionally substituted by 1 or 2 radicals Ci ~ C4-alkyl chosen independently; (d) R5 R5 fe I e * e. I -f '} f>, K5 ï f 1. il ° u | where R5 represents a radical ^ -Cß-alkyl and an atom of available ring carbon is optionally CD.YD.MdC.CH. - 394 - SY-1735A substituted by a C ^ -C4-alkyl radical; (e) ee 5 _N-R 5 _N-R - I —rr | where r5 represents a C ^ -Cg-alkyl radical, X represents O / S or NR where R represents a Ci-C4-alkyl radical and one or more available ring carbon atoms are optionally substituted by C1-C4-alkyl radicals; ( f) .r-,, _k-r5 * _1-K5 N · 1-5 I “Π- I ' 6. R5 K-X N, -N'R \ v - x 5. I -f- —τγ I 1 -r where r5 represents a C ^ -Cg-alkyl radical, X represents 0, S or NR where R represents a Ci-C4-alkyl radical and one or more ring carbon atoms available are optionally substituted with C1-C4-alkyl radicals; and CD.YD.MdC.CH. - 395 - SY-1735A (g) 6, „5 e jK K-RS _ A # · _ / ¼ rî ^ v. ^ S-R '1 J-.,' 1 i N ------- K. 'NK-?'? 5 -K _ ^ îi-R5 I - T 6 R5 B -:; - R "-KR or εθ 1 NR" "K where r5 represents a Ci-Cg-alkyl radical and R represents a radical Cj-C ^ alkyl. 161. A compound according to claim 160, in the formula of which R1 represents an OH ch3ch- radical and r! 6 represents a methyl radical. 162. A compound according to claim 160, in the formula of which R ^ represents an OH radical CH3ch_ CD.YD.MdC.CH. - 396 - SY-1735A r16 represents a methyl radical and the absolute configuration is 5R, 6S, 8R. 163. A compound according to claim 159, 160, 161 or 162, in the formula of which A represents a radical -CH2- or -CH2CH2-. 164. Compound of formula iK - Γ3 π "1, 5s — s" IIW r # N 2 O. COOR where A represents a C ^ -Cg-alkylene radical in a straight or branched chain; R2 represents a hydrogen atom, an anionic charge or a conventional radical which is easy to remove protective of the carboxyl function, it being understood that when R2 represents a hydrogen atom or a protective radical, a counter ion is also present; and w represents a radical of formula (a) R5 J * “O where R5 represents a C1-C4-alkyl radical and R6 represents a hydrogen atom or a Ci-C4-alkyl radical; CD.YD.MdC.CH. - 397 - SY-1735A (b) R5 r r6 Ü_ ~ a where r5 represents a Ci-C4-alkyl radical and R6 and R? represent hydrogen atoms or C] _- C4-alkyl radicals; (c) —R5 _1_ where r5 represents a Ci- radical C4-alkyl and R represents a C1-C4-alkyl or phenyl (Ci-C4) alkyl? (Cl) —U iL_R6 n2 ^ ± _-N Ls where r5 represents a C2-C4-alkyl radical and R ^ represents a Ci-C4-alkyl radical; (e) r R * 5 f K t ~ I N_K / R where r5 represents a C2-C4-alkyl radical and R represents a Ci-C4-alkyl radical? or CD.YD.MdC.CH. - 398 - SY-1735A (f) - * 1 Γ! Κβ η5 ks ^ -a where r5 represents a Ci-C4-alkyl radical; or a pharmaceutically acceptable salt of this compound. 165.- Composed of formula OK CH, "_jl vCs _, _ / ~" v s N '"n. 2 where A represents a Ci-Cg-alkylene radical in a straight or branched chain; R ^ represents a hydrogen atom, an anionic charge or a conventional radical which is easy to remove protective of the carboxyl function, it being understood that when R 2 represents a hydrogen atom or a protective radical, a counter ion is also present; and 5 -L K — R represents a radical of formula -6 - “>“ -O. CD.YD.MdC.CH. - 399 - SY-1735A CH_e CE, \ k (f) KG -0 "iVCK3 CH3 CH cl J CF ce, e / -3 - <J” i Ν'ν ^ ε, u '* 3 "- <' l -O • ·? __ / K CH3 \\ // β | - CE- J oo -γ ^ ι (i) CH 3 3 CH3 CH, CD.YD.MdC.CH. - 400 - SY-1735A CH, / s I er "(m) -}: -? Or (n), Î <// \\ e —fi) \ / ° 3 VJ / / ch3 or a pharmaceutically acceptable salt of this compound. 166. Compound of formula DH H ce3 sg2 ~ ^ ~ J-E3 / 7 N - 2 O COOR where r2 represents a hydrogen atom, an anionic charge or a conventional radical easy to remove protective of the carboxyl function, it being understood that when r2 represents a hydrogen atom or a protective radical, a counter ion is also present; or a pharmaceutically acceptable salt of this compound. 167. Compound of formula CH3 X r_lJ-L'SCK2cs2JrV. <s> O _jT epd) N COOK2 Œ3 where r2 represents a hydrogen atom, an anionic charge or a classic radical easy to remove protective of the carboxyl function, it being understood that when R2 represents a hydrogen atom or a CD.YD.MdC.CH. - 401 - SY-1735A protective radical, a counter ion is also present? or a pharmaceutically acceptable salt of this compound. 168. Compound of formula OH g f3 t »IY 2 2 \ = * / 3 N ^ COO * 2 where R 2 represents a hydrogen atom, an anionic charge or a classic radical easy to remove protective of the carboxyl function, being understood that when R 2 represents a hydrogen atom or a protective radical, a counter ion is also present; or a pharmaceutically acceptable salt of this compound. 169. Compound of formula CK, 0E "9H" V, © w · "* —N ™, 'where r2 represents a hydrogen atom, an anionic charge or a conventional radical easy to remove protective of the carboxyl function, it being understood that when r2 represents a hydrogen atom or a protective radical, a counter ion is also present; or a pharmaceutically acceptable salt of this compound. 170. Compound of formula CD.YD.MdC.CH. - 402 - SY-1735A ° E g fE3 / -v "VVQ é K ^ toos2 'Cfi3 where R2 represents a hydrogen atom, an anionic charge or a classic radical easy to remove protective of the carboxyl function, it being understood that when r2 represents a hydrogen atom or a protective radical, a counter ion is also present; or a pharmaceutically acceptable salt of this compound. 171. Compound of formula qv τ CE, (R) sch2— ^ J — ch2ch.ch3 0 ^ N ^ COOR2 where r2 represents a hydrogen atom, an anionic charge or a classic radical easy to remove protective of the carboxyl function, it being understood that when r2 represents a hydrogen atom or a protective radical, a counter ion is also present; or a pharmaceutically acceptable salt of this compound. 172. Compound of formula CD.YD.MdC.CH. - 403 - SY-1735A CE- ψ H ^ -V ts) -k ΓΥ ^ γ SCH2- ^ Tj> ^ N ^ tOOK2 CE 2 where r2 represents a hydrogen atom, an anionic charge or a classic radical easy to remove protector of the carboxyl function, it being understood that when r2 represents a hydrogen atom or a protective radical, a counter ion is also present; or a pharmaceutically acceptable salt of this compound. 173. Compound of formula OH CH, ÇH3 1 fl3 ’e <κ) ΛΓ + ίSCH2— (V3 J—“ N-2 0 COOR where r2 represents a hydrogen atom, an anionic charge or a conventional radical which is easy to remove protective of the carboxyl function, it being understood that when r2 represents a hydrogen atom or a protective radical, a counter ion is also present; or a pharmaceutically acceptable salt of this compound. 174. Compound of formula ° B E fs3 eü! 3 (R) [: J \ / ^ 1 —SCH -? I · | * · "" COOR2 “3 CD.YD.MdC.CH. - 404 - SY-1735A where r2 represents a hydrogen atom, an anionic charge or a conventional radical which is easy to remove protective of the carboxyl function, it being understood that when r2 represents a hydrogen atom or a protective radical, a counter ion is also present; or a pharmaceutically acceptable salt of this compound. 175. Compound of formula OE CH, “3 VC83 1 | ~ 3 TO-N-7 0 COOR2 where R 2 represents a hydrogen atom, an anionic charge or a conventional radical which is easy to remove protective of the carboxyl function, it being understood that when r2 represents a hydrogen atom or a protective radical, a counter ion is also present ; or a pharmaceutically acceptable salt of this compound. 176. Compound of formula OH CH_ 7. I 3 (po 1 \ / τι Tri-3 rf K ^ 2 CH, D COOR ^ 3 where r2 represents a hydrogen atom, an anionic charge or a classic radical easy to remove protective of the carboxyl function, it being understood that when R2 represents a hydrogen atom or a protective radical, a counter ion is also CD.YD.MdC.CH. - 405 - SY-1735A present; or a pharmaceutically acceptable salt of this compound. 177. Compound of formula OH E T3 (R) _1 1 / \\ 6 1 I \ = / J N - coos2 where r2 represents a hydrogen atom, an anionic charge or a conventional radical which is easy to remove protective of the carboxyl function, it being understood that when r2 represents a hydrogen atom or a radical protective, a counter ion is also present; or a pharmaceutically acceptable salt of this compound. 178. Compound of formula .. P CB, T OH g. 3 "Vr · ^ r? N: 2 CH, c CODR 3 where r2 represents a hydrogen atom, an anionic charge or a conventional radical easy to remove protective of the carboxyl function, it being understood that when r2 represents an atom of hydrogen or a protective radical, a counter ion is also present; or a pharmaceutically acceptable salt of this compound. 179. Compound of formula CD.YD.MdC.CH. - 406 - SY-1735A On g | * (R> ^ 'vr- | ^' ECH2— i A____. CE. Hp ^ 2. ”Ie ο COOR '^ 3 where r2 represents a hydrogen atom, an anionic charge or a classic radical easy to remove protective of the carboxyl function, it being understood that when r2 represents a hydrogen atom or a protective radical, a counter ion is also present; or a pharmaceutically acceptable salt of this compound. 180. Compound of formula OE CH (r) 1; ^ -SCE .-, - K 1 || O * - “. '- te. "/ where r2 represents a hydrogen atom, an anionic charge or a conventional radical which is easy to remove protective of the carboxyl function, it being understood that when r2 represents a hydrogen atom or a protective radical, a counter ion is also present; or a pharmaceutically acceptable salt of this compound. 181. Compound of formula CD.YD.MdC.CH. - 407 - SY-1735A ^ coo® ΟΞ CH7 CH- i H, 3 i, e2 (R) -ζ B 1 i 1 / * 'Noos2 = i where r2 represents a hydrogen atom, an anionic charge or a radical easy to remove conventional protector of the carboxyl function, it being understood that when R 2 represents a hydrogen atom or a protective radical, a counter ion is also present; or a pharmaceutically acceptable salt of this compound. 182. Compound of formula 0Ξ E T * 3 CH (R) I c __J; * 3 1. L> κ é '* N: oor2 ch2-coo6 where r2 represents a hydrogen atom, an anionic charge or a classic radical easy to remove protective of the carboxyl function, it being understood that when r2 represents a hydrogen atom or a protective radical, a counter ion is also present; or a pharmaceutically acceptable salt of this compound. 183. Compound of formula CD.YD.MdC.CH. - 408 - SY-1735A CH, CS. 02. I 3 I 3 (R> —X, —E ^:, - 1 |) "* 0 * K ^ 00S2" S "where R2 represents a hydrogen atom, an anionic charge or a classic radical easy to remove protector of the carboxyl function, it being understood that when r2 represents a hydrogen atom or a protective radical, a counter ion is also present; or a pharmaceutically acceptable salt of this compound. 184. Compound of formula OS F “3 _ (*> j! Λ // 1 -" S - (/ | ^ N-L3 where r2 represents a hydrogen atom, an anionic charge or a classic radical easy to remove protector of the carboxyl function, it being understood that when r2 represents a hydrogen atom or a protective radical, a counter ion is also present; or a pharmaceutically acceptable salt of this compound. 185. Compound of formula CD.YD.MdC.CH. - 409 - SY-1735A „CH, On v, CH-, {R) - HJ. It l // O * ^ \, ηΓ ^ 2 the ^ COOrv pîj u-3 where R2 represents a hydrogen atom, an anionic charge or a classic radical easy to remove protective of the carboxyl function, it being understood that when r2 represents a hydrogen atom or a protective radical, a counter ion is also present; or a pharmaceutically acceptable salt of this compound. 186. Compound of formula 0Ξ ch3 (s) E 1 I \ —CE .3 I 1T-f-N 3 J — N— \ 2 L 0 COOR CE3 where r2 represents a hydrogen atom, an anionic charge or a conventional radical which is easy to remove protective of the carboxyl function, it being understood that when r2 represents a hydrogen atom or a protective radical, a counter ion is also present ; or a pharmaceutically acceptable salt of this compound. 187. Compound of formula CD.YD.MdC.CH. - 410 - SY-1735A CH 3 OH a “3 \ ® (S> 2- JK— \ U CODk where r2 represents a hydrogen atom, an anionic charge or a classic radical easy to remove protective of the carboxyl function, being understood that when r2 represents a hydrogen atom or a protective radical, a counter ion is also present, or a pharmaceutically acceptable salt of this compound. CD.YD.MdC.CH. - 411 - SY-1735A