GB2118183A

GB2118183A - Carbapenem antibiotics

Info

Publication number: GB2118183A
Application number: GB08309505A
Authority: GB
Inventors: Choung Un Kim
Original assignee: Bristol Myers Co
Current assignee: Bristol Myers Co
Priority date: 1982-04-08
Filing date: 1983-04-07
Publication date: 1983-10-26
Also published as: IL68295A0; DK155983A; FR2524888A1; IT1168854B; DE3312517A1; ATA125583A; JPH0524156B2; HU190716B; IE830800L; LU84739A1; SE460197B; FI831135A0; ZA832411B; DE3312517C2; NL8301193A; MY8700945A; AT383126B; SE8301928D0; PT76518B; GR78822B

Abstract

Disclosed are novel carbapenem derivatives characterized by a 2- substitutent of the formula <IMAGE> wherein A represents C2-C6 straight or branched chain alkylene group and R<10> and R<11> each independently represents optionally substituted aliphatic, cycloaliphatic, cycloaliphatic- aliphatic, aryl, heterocyclyl, heterocyclyl-aliphatic, heteroaryl or heteroaraliphatic, or R<10> and R<11> taken together with the S<(+)> to which they are attached represent an optionally substituted sulfur-containing heterocyclic ring. Such derivatives are useful as potent antibacterial agents. Also disclosed are processes for the preparation of such derivatives.

Description

SPECIFICATION Carbapenem antibiotics Background of the invention 1. Field of the invention The present invention is directed to new carbapenem antibiotics in which the 2-substituent has the formula

wherein A is C2-C6 straight or branched chain alkylene and R'O and R" each independently represent optionally substituted aliphatic, cycloaliphatic, cycloaliphatic-aliphatic, aryl, heterocyclyl, heterocyclylaliphatic, heteroaryl or heteroaraliphatic radicals, or R10 and R" when taken together with the S to which they are attached represent an optionally substituted sulfur-containing heterocyclic ring.

2. Description of the prior art A number of p-lactam derivatives containing the carbapenem nucleus

have been disclosed in the literature. These carbapenem derivatives have been reported to possess utility as antibacterial agents and/or p-lactamase inhibitors.

The initial carbapenem compounds were natural products such as thienamycin of the formula

obtained by fermentation of Streptomyces cattleya (U.S. Patent 3,950,357). Thienamycin is an exceptionally potent broad-spectrum antibiotic which possesses notable activity against various Pseudomonas species, organisms which have been notoriously resistant to p-lactam antibiotics.

Other natural products containing the carbapenem nucleus include olivanic acid derivatives such as antibiotic MM 13902 of the formula

disclosed in U.S. Patent 4,113,856, antibiotic MM 1 7880 of the formula

disclosed in U.S. Patent 4,162,304, antibiotic MM4550A of the formula

disclosed in U.S. Patent 4,172,129 and antibiotic 890A of the formula

disclosed in U.S. Patent 4,264,735. In addition to the natural products, the compound desacetyl 890A1o of the formula

is disclosed in U.S. Patent 4,264,734 as being prepared by an enzymatic deacylation of the corresponding N-acetyl compound.Various derivatives of the naturally-occurring olivanic acids have also been synthesized, e.g. the compounds of the formula

wherein CO2RJ is a free, salted or esterified carboxyl group, n is O or 1 and R2 is H, an acyl group or a group of the formula F3O3S wherein R3 is a salting ion or a method or ethyl group, disclosed in European Patent Application 8885.

U.S. Patent 4,235,922 (see also European Patent Application 2058) discloses the carbapenem derivative of the formula

while U.K. Patent Application 1,598,062 reports isolation of the compound

from a Streptomyces fermentation broth.

Carbapenems which are unsubstituted in the 6-position have also been synthesized. Thus, U.S.

Patent 4,210,661 discloses compounds of the formula

wherein R2 is phenyl or substituted phenyl, U.S. Patent 4,267,1 77 discloses compounds of the formula

wherein R1 is an optionally substituted pyridyl group, U.S. Patent 4,255,441 discloses compounds of the formula

wherein Rz and R3 are H or alkyl and R4 is NHCOnR6 in which R6 is alkyl, phenyl or substituted phenyl and n is 1 or 2, and U.S. Patent 4,282,236 discloses compounds of the formula

wherein R1 is H or alkyl and R2 is CN or CO2R3 in which R3 is H, alkyl, aryl or aralkyl.

Carbapenems of the general formula

wherein R1 is H or acyl and R8 is H or substituted or unsubstituted: alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, alkylcycloalkyl, aryl, aralkyl, aralkenyl, aralkynyl, heteroaryl, heteroaralkyl, heterocyclyl or heterocyclylalkyl, are disclosed in U.S. Patent 4,218,463. There is no disclosure of any R8 substituents of the type

in which A is alkylene.

The natural product thienamycin has the absolute configuration 5R, 6S, 8R. This isomer, as well as the remaining seven thienamycin isomers, may be obtained via total synthesis as disclosed in U.S.

Patent 4,234,596. Total synthesis procedures for thienamycin are also disclosed, 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 7973. A key intermediate in the disclosed synthetic methods is

wherein pNB represents p-nitrobenzyl.

Because of the exceptional biological activity of thienamycin, a large number of derivatives have been prepared and disclosed in the literature. Among these are (1) N-formimidoyl thienamycin of the formula

disclosed in European Patent Application 6639; (2) N-heterocyclic derivatives of thienamycin having the formula

wherein: the bifunctional ring may contain additional unsaturation in the ring; and wherein n is an integer selected from 1-6; p is 0, 1 or 2; R' is H, alkyl or aryl; and Z is imino, oxo, H, amino or alkyl, disclosed in U.S.Patent 4,189,493; (3) substituted N-methylene derivatives of thienamycin having the formula

wherein X and Y are H, R, OR, SR or NR'R2 in which R is substituted or unsubstituted: alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclyl or heterocyclylalkyl, and R1 and R2, are H or R, disclosed in U.S. Patent 4,194,047; (4) compounds of the formula

wherein R3 is aryl, alkyl, acyl or aralkyl and R' and R2 are independently selected from H and acyl (including acyl of the type

in which R11 may inter alia be alkyl substituted by a quaternary ammonium group, e.g.

disclosed in U.S. Patent 4,226,870; (5) compounds of the formula

wherein R3 is H, acyl or an univalent optionally substituted hydrocarbon radical; R' is optionally substituted alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkenylalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl or heteroaralkyl and R2 is acyl (including acyl of the type

in which R is alkyl substituted by a quaternary ammonium group, e.g.

disclosed in U.K. Patent 1,604,276 (see also U.S. Patent 4,235,917); (6) Compounds of the formula

wherein R5, R6 and R7 are independently selected from H and substituted or unsubstituted: alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkenylalkyl, cycloalkyalkyl, aryl, aralkyl, heteroaryl or heteroaralkyl, are disclosed in U.S.Patent 4,235,920; (7) compounds of the formula

wherein each of R1 and R2, independently of the other, is a radical of the type defined for R, a hydrogen atom, or a nitro, hydroxyl, C1 alkoxyl, amino, C18 alkylamino, di(C1-6 alkyl)amino or tri(C1~6 alkylamino) radical, an extra anion being present in the latter case; or R1 and R2 are joined together to form, together with the nitrogen atom to which they are attached, a substituted or unsubstituted monocyclic or bicyclic heteroaryl or heterocyclyl residue containing 4-1 0 ring atoms, one or more of which may be an additional hetero atom selected from oxygen, sulphur and nitrogen;R is a cyano group or a substituted or unsubstituted carbamoyl, carboxyl, (C1~10 alkoxy)carbonyl, C110 alkyl, C2~10 alkenyl, C2~10 alkynyl, C3-10 cycloalkyl, C412 cycloalkylalkyl, C812 cycloalkylalkenyl, C3-10 cycloalkenyl, C5-12 cycloalkenylalkenyl, C412 cycloalkenylalkyl, C6-10 aryl, C7-16 aralkyl, C8-16 aralkenyl, C8-16 aralkynyl or monocyclic or bicyclic heteroaryl, heteroaralkyl, heterocyclyl or heterocyclylalkyl comprising 4 to 10 ring atoms one or more of which is a hetero atom selected from oxygen, sulphur and nitrogen and in which the alkyl residue of the heteroaralkyl or heterocyclylalkyl radical contains from 1 to 6 carbon atoms; the substituent or substituents on R, R1, R or on the ring formed by joining R1 and R2 are chlorine; bromine; iodine, fluorine; azido; C14 alkyl; mercapto, sulpho; phosphono; cyanothio (-SCN); nitro; cyano; amino; hydrazin; amino or hydrazino having up to three C16 alkyl substituents; hydroxy; C16 alkoxy; C16 alkylthio; carboxyl; oxo; (C16 alkoxy)carbonyl; C2-10 acyloxy; carbamoyl; (C14 alkyl) carbamoyl or di(C1-4 alkyl) carbamoyl; R3 is a hydrogen atom, an acyl radical or a radical of the type defined for R4;R4 is C1-10 alkyl; substituted carbonylmethyl; C18 alkoxy)-(C1-6 alkyl), C36 cycloalkoxy)-(C16 alkyl); C2-12 alkanoyloxyalkyl; partially or completely halogenated C16 alkyl in which the halogen(s) is/are chlorine, bromine or fluorine; aminoalkyl; C2-10 alkenyl; C2-10 alkynyl; acyl; C3-14 alkoxycarbonylalkyl; C41 dialkylaminoacetoxyalkyl;C2-13 alkanoylaminoalkyl; ar-(C1-3 alkyl) in which the aryl residue contains from 6 to 10 carbon atoms; monocyclic or bicyclic heteroaralkyl or heterocyclylalkyl containing 4 to 10 ring atoms, 1 to 3 carbon atoms in the alkyl residue, and 1-4 hetero atoms selected from oxygen, sulphur and/or nitrogen; nuclear-substituted aralkyl or heteroaralkyl in which the substituent is chlorine, fluorine, bromine, iodine or C18 alkyl; aryl or nuclearsubstituted aryl containing 6 to 10 ring carbon atoms and in which any nuclear substituent is hydroxy, C16 alkyl, chlorine, fluorine or bromine; aralkoxyalkyl; C2-,2 alkylthioalkyl; C412 cycloalkylthioalkyl; (C2-,0 acylthio)-(C,~6 alkyl); or phenylalkenyl in which alkenyl has 2-6 carbon atoms; R5 is substituted or unsubstituted C1~,O alkyl, C2-10 alkenyl or alkynyl; ring substituted and unsubstituted cycloalkyl, cycloalkenyl, cycloalkenylalkyl, and cycloalkyl-alkyl having 3-6 ring carbon atoms and up to 6 carbon atoms in any chain; C6~10 aryl, aralkyl having 6-1 0 ring carbon atoms and 1--6 carbon atoms in the alkyl chain; monocyclic or bicyclic heteroaryl or heteroaralkyl containing 4-1 0 ring atoms, one or more of which is oxygen, nitrogen or sulphur, and 1--6 carbon atoms in the alkyl chain; and the ring or chain substituent(s) is/are chlorine, bromine, iodine, fluorine, azido, cyano, amino, C16 alkylamino, di(C1~8 alkyl)amino or tri(C,~6 alkylamino) radical, an extra anion being present in the latter case, hydroxy, C16 alkoxy, C,~6.alkylthioalkyl; carboxyl; oxo, (C,~6 alkoxy)carbonyl; C2~10 acyloxy; carbamoyl; (C14 alkyl)carbamoyl; di(C14 alkyl)carbamoyl; cyanothio (-SCN) or nitro; R6 is hydrogen, hydroxy, mercapto, R,--OR,--SR or NR1R2, where R, R1 and R2 are as defined above; X is hydroxy, mercapto, amino, acyloxy --OR4,--SR4, --NHR4,

-OM, -OQ or,when the compound is in zwitterionic form, -O, in which case A- is absent; A, when the compound is not in zwitterionic form, is a counter ion; M is a pharmaceutically acceptable cation; and Q is a blocking group as herein defined, are disclosed in U.K.Patent 1,604,275; and (8) compounds of the formula

attached to the amino nitrogen group of thienamycin represents a mono- or polycyclic N-containing heterocyclic group and R is H, substituted or unsubstituted: alkyl, aryl, alkenyl, heterocyclylalkenyl, aralkenyl, heterocyclylalkyl, aralkyl, -N P2, COOR, CONR2,--OR, or CN, are disclosed in European Patent Application 21082. Among the compounds disclosed in U.S. Patent 4,235,920 is

wherein A is a pharmaceutically acceptable anin.The above-mentioned quaternary amine derivative is also described in RecentAdvances in the Chemistry ofp-Lactam Antibiotics, Royal Society of Chemistry, London, 1981, pg 240-254, where its antibacterial activity on average is reported as approximately 1/2 to 2/3 that of thienamycin.

Applicants are aware of no literature disclosing carbapenem derivatives of the present invention having a 2-substituent of the type

although there are several recent patent references which, in their broadest disclosure, may generically include such compounds. Thus, for example, European Patent Application 40408 discloses compounds of the formula

wherein R1 is H, methyl or hydroxyl and R51 is a monovalent organic group including inter alia substituted alkyl or a group of the formula -CH2P7 in which R7 is an optionally substituted 5- or 6membered heterocyclic group; (2) European Patent Application 38869 discloses compounds of the formula

wherein R6, R7, and R8 are independently selected from the group consisting of hydrogen, substituted and unsubstituted: alkyl, alkenyl, and alkynyl, having from 1--10 carbon atoms; cycloalkyl, cycloalkylalkyl, and alkylcycloalkyl, having 3-6 carbon atoms in the cycloalkyl ring and 1-6 carbon atoms in the alkyl moieties; aryl, such as phenyl, aralkyl, aralkenyl, and aralkynyl wherein the aryl moiety is phenyl and the aliphatic portion has 1-6 carbon atoms; heteroaryl, heteroaralkyl, heterocyclyl and heterocyclylalkyl; wherein the substituent or substituents relative to the above-named radicals are selected from the group consisting of: --X halo (chloro, bromo, fluoro) -OH hydroxy --OR' alkoxy, aryloxy

carbamoyloxy

carbamoyl --NRR amino

amidino R' -NO2 nitro N(R)3 tri-substituted amino (R group independently chosen)

oximino --SR' alkyl and arylthio SO2NR1R2 sulfonamido

ureido

-amido -CO2H carboxy --CO,R1 carboxylate

acyl

acyloxy -SH mercapto

alkyl and aryl sulfinyl

alkyl and aryl sulfonyl -CN cyano -N3 azido wherein, relative to the above listed substituents on R6, R7, and R8, the groups R' and R2 are independently selected from: hydrogen, alkyl, alkenyl, and alkynyl, having from 1-10 carbon atoms; cycloalkyl, cycloalkylalkyl, and alkylcycloalkyl, having 3-6 carbon atoms in the cycloalkyl ring and 1--6 carbon atoms in the alkyl moieties: aryl, such as phenyl; aralkyl, aralkenyl, and aralkynyl wherein the aryl moiety is phenyl and the aliphatic portion has 1-6 carbon atoms; heteroaryl, heteroaralkyl, heterocyclyl and heterocyclylalkyl and wherein the hetero atom or atoms in the above-named heterocyclic moieties are selected from the group consisting of 1-4 oxygen, nitrogen or sulphur atoms and wherein the alkyl moieties associated with said heterocyclic moieties have 1-6 carbon atoms. (See also European Patent Applications 1627, 1628, 10317, 17992,37080,37081 and 37082); (4) European Patent Application 24832 discloses compounds of the formula

wherein R' is H or a group selected from OH, OSO3H or a salt or C14 alkyl ester thereof, OR2, SR3, OCOR2, OCO2R3 or OCONHR3, where R2 is a C16 alkyl group or an optionally substituted benzyl group and R3 is a C16 alkyl group or an optionally substituted benzyl or phenyl group and R12 is C16 alkyl, C26 alkenyl, C36 aikynyl wherein the triple bond is not present on the carbon adjacent to the sulfur atom, aralkyl, C16 alkanoyl, aralkanoyl, aryloxyalkanoyl or arylcarbonyl, any of such R12 groups being optionally substituted, as antibacterial agents.

European Patent Application 38869 mentioned above discloses synthesis of the carbapenem derivatives vià intermediates of the general formula

wherein R6 and R7 are as defined above and R is a readily removable carboxyl protecting group. Also disclosed as intermediates are compounds of the formula

wherein X is described as a leaving group.

While, as indicated above, the prior art has described carbapenem derivatives having a 2substituent of the type

and derivatives having a 2-substituent of the type --S--AA-S-1R, where R, is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, alkylcycloalkyl, phenyl, aralkyl, aralkenyl, aralkynyl, heteroaryl, heteroaralkyl, heterocyclyl or heterocyclylalkyl, there has been no disclosure of which applicants are aware teaching carbapenems having a 2-substituent wherein the alkylene group A is attached directly to a sulfonium group, i.e. a group of the type

Despite the vast number of carbapenem derivatives disclosed in the literature, there is still a need for new carbapenem since known derivatives may be improved upon in terms of spectrum of activity, potency, stability and/or toxic side effects.

Summary of the invention The present invention provides a novel series of carbapenem derivatives characterized by a 2substituent of the formula

wherein A is C2-C6 straight or branched chain alkylene and R10 and R" each independently represent optionally substituted aliphatic, cycloaliphatic, cycloaliphatic-a liphatic, aryl, heterocyclyl, heterocyclylaliphatic, heteroaryl or heteroaraliphatic radicals, or R10 and P11 when taken together with the S to which they are attached represent an optionally substituted sulfur-containing heterocyclic ring containing 0-2 double bonds and 0-2 additional heteroatoms selected from 0, N and S, said ring being attached to A through a sulfur atom, thereby forming a sulfonium group. More specifically, the present invention provides carbapenem derivatives of the formula

wherein R3 is hydrogen and R is selected from the group consisting of hydrogen; substituted and unsubstituted: alkyl, alkenyl and alkynyl, having from 1-10 carbon atoms; cycloalkyl and cycloalkylalkyl, having 3-6 carbon atoms in the cycloalkyl ring and 1-6 carbon atoms in the alkyl moieties; phenyl; aralkyl, aralkenyl and aralkynyl wherein the aryl moiety is phenyl and the aliphatic portion has 1-6 carbon atoms; heteroaryl, heteroaralkyl, heterocyclyl and heterocyclylalkyl wherein the hetero atom or atoms in the above-named heterocyclic moieties are selected from the group consisting of 4 oxygen, nitrogen or sulfur atoms and the alkyl moieties associated with said heterocyclic moieties have 1-6 carbon atoms; wherein the substituent or substituents relative to the above-named radicals are independently selected from the group consisting of C1-C6 alkyl optionally substituted by amino, halo, hydroxy or carboxyl halo OR3

-NP3P4

SO2NR3R4

--CO2R =0

- SR3

-CN N3 -OSO,R3 -OSO2P3 NR3SO2R4

--NR3CO,R4 -NO2 wherein, relative to the above-named substituents, the groups R3 and R4 are independently selected from hydrogen; alkyl, alkenyl and alkynyl, having from 1-10 carbon atoms; cycloalkyl, cycloalkylalkyl and aíkyícycloalkyl, having 3-6 carbon atoms in the cycloalkyl ring and 1-6 carbon atoms in the alkyl moieties; phenyl; aralkyl, aralkenyl and aralkynyl wherein the aryl moiety is phenyl and the aliphatic portion has 1-6 carbon atoms; and heteroaryl, heteroaralkyl, heterocyclyl and heterocyclylalkyl wherein the hetero atom or atoms in the above-named heterocyclic moieties are selected from the group consisting of 1-4 oxygen, nitrogen or sulfur atoms and the alkyl moieties associated with said heterocyclic moieties have 1-6 carbon atoms, or R3 and R4 taken together with the nitrogen to which at least one is attached may form a 5- or 6-membered nitrogen-containing heterocyclic ring;R9 is as defined for R3 except that it may not be hydrogen; or wherein R' and R6 taken together represent C2-C10 alkylidene or C1--C10 alkylidene substituted by hydroxy; A is C2-C6 straight or branched chain alkylene; R2 is hydrogen, an anionic charge or a conventional readily removable carboxyl protecting group, providing that when R2 is hydrogen or a protecting group, there is also present a counter anion, and R10 and R" each independently represents (a) C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl or cycloalkylalkyl having 3--6 carbon atoms in the cycloalkyl ring and 1-6 carbon atoms in the alkyl moiety, said alkyl, alkenyl, alkynyl, cycloalkyl or cycloalkylalkyl group being optionally substituted by 1-3 substituents independently selected from hydroxy, C1-C6 alkoxy, C1-C6 alkanoyloxy, carboxy, C1-C6 alkoxycarbonyl, amino, C1-C6 alkylamino, di(C1,-C6)alkylamino, C1-C6 alkanoylamino, phenyl, phenyl substituted by 1-3 halo, C 1-C6 alkoxy, C1-C6 alkyl, carboxy, carboxy(C1-C6)alkyl, amino, C1-C6 alkylamino, di(C1-C6)alkylamino or di(C1-C8)alkylamino(C1-C6)alkyl, halo or oxo;; (b) phenyl optionally substituted by 1-3 halo, C1-C6 alkoxy, C1-C6 alkyl, carboxy, amino, C1- C6 alkylamino or di(C1-C6)alkylamino groups; (c) heterocyclyl or heterocyclylalkyl wherein the heterocyclic moiety is a 4-6 membered ring having 1-3 hetero atoms selected from 0, N and S and the alkyl moiety has 1-6 carbon atoms, said heterocyclyl or heterocyclylalkyl ring being optionally substituted by 1-3 C1-C6 alkyl or C1-C6 alkoxy groups; or (d) heteroaryl or heteroaralkyl wherein the heterocyclic moiety is a 5-6 membered aromatic ring having 1-3 hetero atoms selected from 0, N and S and the alkyl moiety has 1-6 carbon atoms, said heteroaryl or heteroaralkyl ring being optionally substituted by 1-3 C1-C6 alkyl, C1-C6 alkoxy, carboxy, carboxy(C1-C6)alkyl, amino, C1-C6 alkyl amino, di(C,-C,)alkylamino, amino(C1-6)alkyl or di(C1-C6)alkylamino(C1-C6)alkyl groups; or wherein R10 and R" taken together with the S to which they are attached represent a 4-6 member sulfur-containing heterocyclic ring containing 0--2 double bonds and 0--2 additional heteroatoms selected from 0, N and S, said ring being attached to A through a sulfur atom, thereby forming a sulfonium group, said heterocyclic ring being optionally substituted by 1-3 substituents independently selected from:: C1--C6 alkyl optionally substituted by 1-3 hydroxy, C16 alkoxy, carboxy, halo, amino, C1-C6 alkylamino or di(C1-C6)alkylamino groups, hydroxy, C1-C6 alkoxy, C1-C6 alkanoyloxy, amino, C1-C6 alkylamino, di(C1-C6)alkylamino, C1-C6 alkanoylamino, carboxy, C1-C6 alkoxycarbonyl, halo, oxo or phenyl; or wherein said heterocyclic ring

is fused to a C5-C6 carbocyclic ring, a phenyl ring, a 5-6 member heterocyclic ring or a 5-6 member heteroaryl ring, all of which rings may be optionally substituted by 1-3 of the substituents referred to above for the

ring; and pharmaceutically acceptable salts thereof.

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

Also included in the invention are processes for preparing the novel carbapenem derivatives described above and pharmaceutical compositions containing the biologically active carbapenem derivatives in combination with pharmaceutically acceptable carriers or diluents.

Detailed description The novel compounds of general formula I above contain the carbapenem nucleus

and may thus be named as 1 -carba-2-penem-3-carboxylic acid derivatives. Alternatively, the compounds may be considered to have the basic structure

and named as 7-oXo-1-azabicyclo(3.2.0)hept-2-ene-2-carboxylicacid derivatives. While the present invention includes compounds wherein the relative stereochemistry of the 5,6-protons is cis as well as trans, the preferred compounds have the 5R,6S (trans) stereochemistry as in the case of thienamycin.

The compounds of formula I may be unsubstituted in the 6-position or substituted by substituent groups previously disclosed for other carbapenem derivatives. More specifically, R8 may be hydrogen and R' may be hydrogen or a non-hydrogen substituent disclosed, for example, in European Patent Application 38869 (see definition of R6). Alternatively, R6 and R' taken together may be C,--C,, alkylidene or C2-C10 alkylidene substituted, for example, by hydroxy.

To eiaborate on the definitions for R' and R6: (a) The aliphatic "alkyl", "alkenyl" and "alkynyl" groups may be straight or branched chain having 1-10 carbon atoms; preferred are 1-6, most preferably 1 4, carbon atoms; when part of another substituent, e.g. as in cycloalkylalkyl, or heteroaralkyl or aralkenyl, the alkyl, alkenyl and alkynyl group preferably contains 1-6, most preferably 1-4, carbon atoms.

(b) "heteroaryl" includes mono-, bi- and polycyclic aromatic heterocyclic groups containing 1-4 O, N or S atoms; preferred are 5- or 6-membered heterocyclic rings such as thienyl, furyl, thiadiazolyl, oxadiazolyl, triazolyl, isothiazolyl, thiazolyl, imidazolyl, isoxazolyl, tetrazolyl, oxazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrrolyl, pyrazolyl, etc.

(c) "heterocyclyl" includes mono-, bi- and polycyclic saturated or unsaturated non-aromatic heterocyclic groups containing 1--4 0, N or S atoms; preferred are 5-or 6-membered heterocyclic rings such as morpholinyl, piperazinyl, piperidyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, pyrrolinyl, pyrrolidinyi, etc.

(d) "halo" (used also to define R'O and P11) includes chloro, bromo, fluoro and iodo and is preferably chloro or bromo.

The term "conventional readily removable carboxyl protecting group" refers to a known ester group which has been employed to block a carboxyl group during the chemical reaction steps described below and which can be removed, if desired, by methods which do not result in any appreciable destruction of the remaining portion of the molecule, e.g. by chemical or enzymatic hydrolysis, treatment with chemical reducing agents under mild conditions, irradiation with ultraviolet light or catalytic hydrogenation. Examples of such ester protecting groups include benzhydryl, p nitrobenzyl, 2-naphthylmethyl, benzyl, trichloroethyl, silyl, such as trimethylsilyl, phenacyl, pmethoxybenzyl, acetonyl, o-nitrobenzyl, 4-pyridylmethyl and C1-C6 alkyl such as methyl, ethyl or tbutyl.Included within such protecting groups are those which are hydrolyzed under physiological conditions such as pivaloyloxymethyl, acetoxymethyl, phthalidyl, indanyl and methoxymethyl. A particularly advantageous carboxyl protecting group is p-nitrobenzyl which may be readily removed by catalytic hydrogenolysis.

The pharmaceutically acceptable salts referred to above include the nontoxic acid addition salts, e.g. salts with mineral acids such as hydrochloric, hydrobromic, hydroiodic, phosphoric, sulfuric, etc.

and salts with organic acids such as maleic, acetic, citric, succinic, benzoic, tartaric, fumaric, mandelic, ascorbic, lactic, gluconic and malic, Compounds of formula I in the form of acid additions salts may be written as

where Xe represents the acid anion. The counter anion Xe may be selected so as to provide pharmaceutically acceptable salts for therapeutic administration but, in the case of intermediate compounds of formula I, X0- may also be a toxic anion. In such a case the ion can be subsequently removed or substituted by a pharmaceutically acceptable anion to form an active end product for therapeutic use.When acidic or basic groups are present in the R1 group or on the R10 or R" substituents, the present invention may also include suitable base or acid salts of these functional groups, e.g.-acid addition salts in the case of a basic group and metal salts (e.g. sodium, potassium, calcium and aluminum), the ammonium salt and salts with nontoxic amines (e.g. trialkylamines, procaine, dibenzylamine, 1 -ephenamine, N-benzyl-B-phenethylamine, N,N'-dibenzylethylenediamine.

etc.) in the case of an acidic group.

Compounds of formula I wherein R2 is hydrogen, an anionic charge or a physiologically hydrolyzable ester group together with pharmaceutically acceptable salts thereof are useful as antibacterial agents. The remaining compounds of formula I are valuable intermediates which can be converted into the above-mentioned biologically active compounds.

A preferred embodiment of the present invention comprises compounds of formula I wherein RB is hydrogen and R' is hydrogen, CH3CH2-,

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

most preferably compounds having the absolute configuration 5R,6S,8R.

Another preferred embodiment comprises compounds of formula I in which R1 and R8 taken together form an alkylidene radical of the formula

The alkylene (i.e. substituent "A") radical in the compounds of formula I may be straight or branched chain and may contain from 2 to 6 carbon atoms. A preferred embodiment comprises those compounds in which A is (CH2)n in which n is 2, 3 or 4 and a particularly preferred embodiment comprises those compounds where A is -CH2CH2-.

The 2-substituent of the present compounds is characterized by the presence of a sulfonium group attached to the alkylene radical A. As indicated above, R10 and R" may each independently be selected from optionally substituted aliphatic, cycloaliphatic, cycloaliphatic-aliphatic, aryl, heterocyclyl, heterocyclyl-aliphatic, heteroaryl or heteroaraliphatic. Alternatively, the R10 and R11 substituents when taken together with the S to which they are attached may form a 4-6 membered, optionally substituted, sulfur-containing heterocyclic ring containing 0--2 double bonds and 0--2 additional heteroatoms selected from 0, N and S, said ring being attached to A through a sulfur atom, thereby forming a sulfonium group.In the latter case where

represents a heterocyclic ring, the ring may also be fused to a C5-C6 carbocyclic ring, a phenyl ring or a 5-6 membered heteroaryl ring (containing 1-40, N or S) and any of such fused rings may also be optionally substituted.

The aliphatic R10 and/or R11 substituents are preferably C1-C6 alkyl, C2-C6 alkenyl or C2-C6 alkynyl. Cycloaliphatic substituents are preferably C3--6 cycloalkyl while cycloaliphatic-aliphatic refers especially to C3-C6 cycloalkyl-C1-C6 alkyl. Such aliphatic, cycloaliphatic and cycloaliphaticaliphatic substituents may be unsubstituted or substituted (preferably by 1-3 substituents) by the following: hydroxy, C1-C6 alkoxy, C1-C6 alkanoyloxy, carboxy, C1-C6 alkoxycarbonyl (e.g.

amino, C1-C6 alkylamino, di(C1-C6)alkylamino, C1-C6 alkanoylamino, phenyl, phenyl substituted by, preferably 1-3 and most preferably 1-2, halo, C1-C6 alkoxy, C1-C6 alkyl, carboxy, carboxy-C1-C6 alkyl, amino, C1-C6 alkylamino, di(C1-C6)alkylamino or di(C1-C6)alkylamino(C1-C6)alkyl, halo or oxo.

The R and/or R" substituents may also be aryl (C6-C10 aromatic hydrocarbon) which is most especially phenyl. The aryl group or groups may be unsubstituted or substituted by 1-3, preferably 1-2, substituents selected from halo, C1-C6 alkoxy, C1-C6 alkyl, carboxy, amino, C1-C6 alkylamino and di(C1-C6)alkylamino.

When R10 and/or R11 represent heterocyclyl or heterocyclyl-aliphatic, the heterocyclyl moiety is a 4-6 membered non-aromatic ring containing 1-3 hetero atoms selected from 0, N and S. The aliphatic moiety associated with heterocyclyl-alphatic is preferably C1-C6 alkyl. The heterocyclic ring of such groups may be unsubstituted or substituted by 1-3, preferably 1-2, C1-C6 alkyl or C1-C6 alkoxy substituents.

When R10 and/or R" represents heteroaryl or heteroaraliphatic, the heterocyclic moiety is a 5--6 membered aromatic ring containing 1-3 hetero atoms selected from 0, N and S and the aliphatic (preferably alkyl) moiety has 1-6 carbon atoms. The heteroaryl ring of such substituents may be unsubstituted or substituted by 1-3, preferably 1-2, substituents selected from C1-C6 alkyl, C1- C6 alkoxy, carboxy, carboxy(C1-C6)alkyl, amino, (C1-C6)alkylamino, di(C1-C6)alkylamino, amino(C1-C6)alkyl and di(C1-C)alkylamino(C1-C8)(C1-C8) alkyl.

The R10 and R" substituents taken together with the SO to which they are attached may also represent a 4--6 member sulfur-containing heterocyclic ring containing 0-2 double bonds and 0-2 additional heteroatoms selected from 0, N and S, said ring being attached to the alkylene (A) group through a sulfur atom, thereby forming a sulfonium group.The heterocyclic ring formed by

may be unsubstituted or substituted by 1-3, preferably 1-2, substituents selected from: C1-C6 alkyl optionally substituted by 1-3 hydroxy; C1-C6 alkoxy, carboxy, halo, amino, C1-C6 alkylamino or di(C1-C6)alkylamino groups; hydroxy; C1-C6 alkoxy; C1-C6 alkanoyloxy; amino; C1-C6 alkylamino; di(C1-C6)alkylamino; C1-C6 alkanoylamino; carboxy; C1-C6 alkoxycarbonyl; halo; oxo; and phenyl.

The heterocyclic ring may also be fused to a C6-C6 carbocyclic ring, a phenyl ring, a 5-6 member heterocyclic (containing 1-4 hetero atoms selected from 0, N and S) ring or a 5-6 member heteroary! (containing 1--4 hetero atoms selected from 0, N and S) ring, all of which fused rings may be optionally substituted by 1-3, preferably 1-2, of the substituents described above in connection with the sulfur-containing heterocyclic ring.

A particularly preferred embodiment of the present invention comprises compounds of formula I wherein either (a) R10 and R11 each independently represents C1-C8 alkyl or (b) R10 and R" taken together with the 6 to which they are attached represent

pharmaceutically acceptable salts thereof.

Examples of preferred 2-substituents wherein R10 and R11 are alkyl include

Within this subclass, the preferred compounds are those wherein A is (CH2)n in which n is 2, 3 or 4, most preferably those in which A is -CH2CH2- and wherein either (a) R1 and R8 taken together represent

or (b) P6 is hydrogen and R represents hydrogen, CH3-CH2-,

Particularly preferred are the compounds wherein Ra is hydrogen and R' is

preferably compounds having the absolute configuration 5R,6S,8R.

A most preferred embodiment of the present invention comprises compounds of formula I wherein

represents

and pharmaceutically acceptable salts thereof. Within this subclass, the preferred compounds are those wherein A is (CH2)n in which n is 2, 3 or 4, most preferably those in which A is -CH2CH2- and wherein either (a) R' and R8 taken together represent

or (b) RB is hydrogen and R' represents hydrogen, CH3CH2-,

Particularly preferred are the compounds wherein RB is hydrogen and R1 is

preferably compounds having the absolute configuration 5R, 6S, 8R.

The most preferred embodiment of the present invention comprises the compounds of the formula

wherein R2 is hydrogen, an anionic charge or a conventional readily removable carboxyl protecting group, providing that when R2 is hydrogen or a protecting group, there is also present a counter anion, and pharmaceutically acceptable acid addition salts thereof.

It will be appreciated that when R'O and R1' in formula I are different, there may be formed both the R and S optical isomers of such compounds as well as epimeric mixtures thereof. It is intended that the present invention include within its scope all such optical isomers and epimeric mixtures. Similarly, the 6-substituent may in certain cases, e.g. as in hydroxyethyl, be in either the R or S configuration and the resulting isomers as well as epimeric mixtures thereof are encompassed by the present invention.

The carbapenem derivatives of general formula I are prepared from starting materials of the formula

wherein R' and R8 are defined above and wherein R2 represents a conventional readily removable carboxyl protecting groups. Compounds of formula Ill have been disclosed, for example, in European Patent Application 38869 (compound 7) and may be prepared by the general methods described therein.

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

To elaborate on the above process, starting material Ill is reacted in the inert organic solvent such as methylene chloride, acetonitrile or dimethylformamide with about an equimolar amount of diphenyl chlorophosphate in the presence of a base such as diisopropylethylamine, triethylamine, 4dimethylaminopyridine or the like to give intermediate IV. The acylation to establish the diphenylphosphoryloxy leaving group at the 2-position of intermediate Ill is advantageously carried out at a temperature of from about --200 to +400C, most preferably at about OOC. Intermediate IV may be isolated if desired, but is conveniently used for the next step without isolation or purification.

Intermediate IV is next converted to intermediate V by a conventional displacement reaction.

Thus, intermediate IV may be reacted with approximately an equimolar amount of a mercaptan reagent of the formula HS-A-OH wherein A represents C2-C6 straight or branched chain alkylene 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 4dimethylaminopyridine. The temperature for the displacement is not critical, but an advantageous temperature range is from about -40"C to 250C. Most conveniently, the reaction is carried out with cooling, e.g. at about OOC.

Intermediate V is then acylated with methanesulfonyl chloride or a functional acylating equivalent thereof such as methanesulfonic acid anhydride in an inert organic solvent and in the presence of base to provide the methanesulfonyloxy leaving group of intermediate VI. The acylation is carried out in an inert organic solvent such as tetrahydrofuran, methylene chloride, acetonitrile or dimethylformamide and in the presence of a suitable base such as diisopropylethylamine, triethylamine, 4dimethylaminopyridine, and the like. The reaction may be carried out over a wide temperature range, e.g. -400C to +400C, but is most advantageously conducted with cooling, e.g. at about -300C to -400C.

Intermediate VI is next subjected to a displacement reaction so as to provide in intermediate li the iodo leaving group. This particular group has been found to greatly facilitate preparation of the carbapenem end-products of formula I. The intermediates of general formula II, therefore, comprise a preferred embodiment of the present invention.

The displacement of the methanesulfonyloxy leaving group is carried out by reacting intermediate VI with a source of iodide ions in an inert organic solvent such as acetone, dimethylformamide or dimethylsulfoxide. Any compound which ionizes in the solvent employed to provide iodide ions may be used, e.g. an alkali metal iodide such as Nal or KI. The temperature for the displacement is not critical, but temperatures of room temperature or above are most advantageous for achieving completion of the reaction in a reasonable time period. The source of iodide ions is employed in an amount so as to provide approximately an equivalent or excess of iodide ion relative to intermediate VI.

Preparation of the desired carbapenems derivatives of formula I is carried out by a nucleophilic displacement of the iodo leaving group of intermediate II by the desired sulfide of the general formula

Intermediate II is reacted with at least an equivalent, preferably an excess, of the desired sulfide in an inert organic solvent and in the presence of silver ion. Suitable inert organic solvents include, for example, tetrahydrofuran, dioxane, methylene chloride, diglyme, dimethyoxyethane, and the like. Any silver compound which substantially ionizes in the solvent and to give silver ions and an inert anion may be used as the source of silver ions, e.g. AgCIO4. Generally, we prefer to use approximately an equivalent amount (relative to intermediate II) of silver ion to facilitate the displacement.The reaction may be carried out over a wide temperature range, e.g. from about -250C to about +25"C, but is preferably conducted at around OOC. Intermediate I' will have a counter anion (derived from the silver salt used) associated with it which may at this stage be substituted by a different counter anion, e.g.

one which is pharmaceutically acceptable, by conventional procedures. Alternatively, the counter ion may be subsequently removed during the de-blocking step.

The de-blocking step to remove the carboxyl protecting group R2' of intermediate I' is accomplished by conventional procedures such as solvolysis, chemical reduction or hydrogenation.

Where a protecting group such as p-nitrobenzyl, benzyl, benzhydryl or 2-naphthylmethyl is used which can be removed by catalytic hydrogenation, intermediate I' in a suitable solvent such as dioxane-waterethanol, tetrahydrofuran-aqueous dipotassium hydrogen phosphate-isopropanol or the like may be treated under a hydrogen pressure of from 1 to 4 atmospheres in the presence of a hydrogenation catalyst such as palladium on charcoal, palladium hydroxide, platinum oxide or the like at a temperature of from 0 to 500C for from about 0.24 to 4 hours. When R2 is a group such as o-nitrobenzyl, photolysis may also be used for deblocking. Protecting groups such as 2,2,2-trichloroethyl may be removed by mild zinc reduction. Similarly, other conventional carboxyl protecting groups may be removed by methods known to those skilled in the art. Finally, as mentioned above, compounds of formula I' where R2 is a physiologically hydrolyzable ester such as acetoxymethyl, phthalidyl, indanyl, pivaloyloxymethyl, methoxymethyl, etc. may be administered directly to the host without de-blocking since such esters are hydrolyzed in vivo under physiological conditions.

It will be understood that where the R1 and/or R8 substituent or the heteroaromatic nucleophile attached to substituent A contain a functional group which might interfere with the intended course of reaction, such group may be protected by a conventional blocking group and then subsequently deblocked to regenerate the desired functional group. Suitable blocking groups and procedures for introducing and removing such groups are well known to those skilled in the art.

As in the case of other ss-lactam antibiotics, compounds of general formula I may be converted by known procedures to pharmaceutically acceptable salts which, for purposes of the present invention, are substantially equivalent to the non-salted compounds. Thus, for example, one may dissolve a compound of formula I wherein R2 is an anionic charge in a suitable inert solvent and then add an equivalent of a pharmaceutically acceptable acid. The desired acid.addition salt may be recovered by conventional procedures, e.g. solvent precipitation lyophilization, etc. Where other basic or acidic functional groups are present in the compound of formula I, pharmaceutically acceptable base addition salts and acid addition salts may be similarly prepared by known methods.

A compound of formula I where R2 is hydrogen or an anionic charge, or a pharmaceutically acceptable salt thereof may also be converted by conventional procedures to a corresponding compound where R2 is a physiologically hydrolyzable ester group, or a compound of formula I wherein R2 is a conventional carboxyl protecting group may be converted to the corresponding compound where R2 is hydrogen, an anionic charge or a physiologically hydrolyzable ester group, or a pharmaceutically acceptable salt thereof.

The novel carbapenem derivatives of general formula I wherein R2 is hydrogen, an anionic charge or a physiologically hydrolyzable carboxyl protecting group, or the pharmaceutically acceptable salts thereof, are potent antibiotics active against various gram-positive and gram-negative bacteria and they may be used, for example, as animal feed additives for promotion of growth, as preservatives in food, as bactericides in industrial applications, for example in waterbased paint and in the white water of paper mills to inhibit the growth of harmful bacteria and as disinfectants for destroying or inhibiting the growth of harmful bacteria on medical and dental equipment. They are especially useful, however, in the treatment of infectious disease in humans and other animals caused by gram-positive or gramnegative bateria.

The pharmaceutically active compounds of this invention may be used alone or formulated as pharmaceutical compositions comprising, in addition to the active carbapenem ingredient, a pharmaceutically acceptable carrier or diluent. The compounds may be administered by a variety of means; those of principal interest include: orally, topically or parenterally (intravenous or intramuscular injection). The pharmaceutical compositions may be in solid form such as capsules, tablets, powders, etc. or in liquid form such as solutions, suspensions or emulsions. Compositions for injection, the preferred route of delivery, may be prepared in unit dose form in ampules or in multidose containers and may contain formulatory agents such as suspending, stabilizing and dispersing agents.The compositions may be in ready to use form or in powder form for reconstitution at the time of delivery with a suitable vehicle such as sterile water.

The dosage to be administered depends to a large extent on the particular compound being used, the particular composition formulated, the route of administration, the nature and condition of the host and the particular situs and organism being treated. Selection of the particular preferred dosage and route of application, then, is left to the discretion of the therapist. In general, however, the compounds may be administered parenterally or orally to mammalian hosts in an amount of from about 5 to 200 mg/kg/day. Administration is generally carried out in divided doses, e.g. three to four times a day.

To illustrate the potent brbad-spectrum antibacterial activity of the carbapenems of the present invention, both in vitro and in vivo, and the low toxicity of the compounds, biological data is provided below relating to the preferred carbapenem compound of the present invention, i.e. 3-[2-(1- tetrahydrothiophenium)ethylthio]-6a-[ 1 -(R)-hydroxyethyl]-7-oxo-l -azabicyclo[3.2.0]hept-2-ene-2- carboxylate prepared in Example 1.

In vitro activity A sample of the above-identified carbapenem compound after solution in water and dilution with Nutrient Broth was found to exhibit the following Minimum Inhibitory Concentration (M.l.C.) in mcg/ml versus the indicated microorganisms as determined by overnight incubation at 370C by tube dilution.

N-Formimidoyl thienamycin was included as a comparison compound.

In vitro antibacterial activity of carbapenem derivative of Example 1 MIC (mcg/mI) Organism New compound N-Formimidoyl thienamycin S. pneumoniae A-9585 0.002 0.004 S. pyogenes A-9604 0.004 0.001 S. aureus A-9537 0.008 0.004 S. aureus A-9537 0.03 0.016 +50% serum S. aureus A-9606 0.016 0.008 (pen-res.) S. aureus A15097 2 0.5 (Meth-res.) S. faecalis A20688 0.5 0.5 E. coli A15119 0.03 0.016 (10-A dil.) E. coli A151 19 0.06 0.03 (10-3) E. coli A15119 0.06 0.06 (10-2) E. coli A20341-1 0.03 0.03 (10-4) E. coli A20341-1 0.03 0.03 ( 1 O-3) E. coli A20341-1 0.06 0.13 (10-2) K. pneumoniae A-9664 0.06 0.13 K. pneumoniae A20468 0.13 0.06 P. mirabilis A-9900 0.13 0.06 P. vulgaris A2 1559 0.03 0.03 P. organic A15153 0.06 0.13 P. rettgeri A22424 0.25 0.25 S. marcescens A20019 0.06 0.03 E. cloacae A-9659 0.13 0.06 E. cloacae A-9656 0.13 0.06 P. aeruglnosa A-9843A 1 1 P. aeruginosa A21213 0.25 0.25 H. influenzae A-9833 8 16 H. influenzae A20178 8 32 H- influenzae A21518 8 32 H. influenzae A21522 8 32 B. fragilis A22862 0.06 0.016 B. fragilis A22053 0.06 0.06 B. fragilis A22696 0.25 0.13 B. fragilis A22863 0.06 1 In vivo activity The in vivo therapeutic efficacy of the compound of Example 1 and N-formimidoyl thienamycin after intramuscular administration to mice experimentally infected with various organisms is shown in the following Table.The PD50 (dose in mg/kg required to give protection to 50% of the infected mice) is indicated.

Protective effect in the intramuscular treatment of infected mice PD5ireatment (mg/kg) Challenge (No. of Compound of N-Formimidoyl Organism. organisms) Example 1 thienamycin S. aureus A-9606 1x109 0.19 0.07* Ecoli A15119 6x106 1.6 2.2* K. pneumoniae A-9664 7x106 5 2.4* E. cloacae A-9659 4x106 1.3 P. mfrabiis A-9900 4x 106 7.7 3*/15* P. vulgaris A21559 4x105 3.3 P. rettgeri A15167-2 3x107 8.7 6.9 M.morganii A15149 7x105 3.3 S. marcescens A203 35 9 x 106 5 P. aeruginosa A-9843a 3x104 0.6 0.5* P. aeruginosa A2048 1 3 x 104 0.8 0.4 P. aeruginosa A20599 9x104 1.3 *Historical data Treatment schedule:Mice were treated i.m. with drugs 0 and 2 hours post-infection (A21559, Al 5167-2, A9900, A9843a, A20481, A20599), or 1 and 3.5 hours (all others); 5 mice were used for each test.

Toxicity The toxicity of the compound of Example 1 after intracranial administration to mice was determined and is shown in the following Table.

Toxicity after intracranial administration to mice Highest dose (mg/kg) *LD50 without clinical Compound (mg/kg) signs of toxicity Compound of Example 1 > 40 5 N-Formimidoyl thienamycin 32 5 *Average of 25 mice/compound Blood levels in mice after intramuscular administration Blood levels and the half-life of the compound of Example 1 after intramuscular administration of 20 mg/kg in mice are shown in the Table below.

Blood level (,ug/ml) 10 20 30 45 60 90 *t1/2 **AUC Compound Minutes after administration (min) (g. h/ml) Compound of Example 1 14.7 13.5 8.7 3.2 0.9 < 0.6 9 7.4 N-Formimidoyl thienamycin 12.6 9.9 7.3 2.6 0.7 < 0.3 9 6 Compounds were solubilized in 0.1 M phosphate buffer pH 7.

Values are from a single test; 4 mice used per compound.

*t1/2 refers to half-life in minutes **AUC refers to the area under the curve.

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

Urinary recovery intramuscular administration of 20 mg/kg to mice Percentage of dose recovered 0--3 3-6 6-24 0-24 Compound Hours after administration CompoundofExample 1 15.6 2.1 < 0.2 17.7+2.9 N-Formimidoyl thienamycin 12.1 0.1 < 0.1 12.2+3.6 Compounds were solubilized in 0.1 M phosphate buffer pH 7. Values are from a single test; 4 mice per compound.

The following Examples illustrate but do not limit the scope of the present invention.

Example 1 Preparation of 3-[2-( 1 -tetrahydrothiopheniu m)ethylthio]-6a-[1 -( R)-hydroxyethyl]-7-oxo-1 azabicyclo [3.2.0]hept-2-ene-2-carboxylate

A. p-Nitrobenzyl 3-(2-hydrnxyethylthio)-6a-[1 -( R)-hydroxyethyl]-7-oxo-1 -azabicyclo [3.2.0] hept 2-ene-2-carboxylate

A solution of 1.69 g (4.85 mmole) of p-nitrobenzyl 6a-[1 -(R)-hydroxyethyl]-3,7-dioxo-l - azabicyclo[3.2.0]hept-2-ene-2-carboxylate (1) in 20 ml of acetonitrile was cooled to 0 C under a nitrogen atmosphere.A solution of 726 mg (7.18 mmole) of diisopropylethylamine in 2 ml of acetonitrile was added followed by a dropwise addition of 1.51 g (5.60 mmole) of diphenyl chlorophosphate in 1 2 ml of acetonitrile over a period of 3 minutes. The resulting solution was stirred at 0 for 20 minutes to provide p-nitrobenzyl 3-(diphenylphosphoryloxy)-6-[1 -(R)-hydroxyethyl]-7- oxy-1-azabicyclo[3.2.0]hept-3-ene-2-carboxylate. To this solution was added a solution of 726 mg (7.18 mmole) of diisopropylethylamine in 2 ml of acetonitrile followed by a solution of 439 mg (5.63 mmole) of 2-mercaptoethanol in 2 ml of acetonitrile.The reaction solution was stirred at OOC for 3 hours and then diluted with 200 ml of ethyl acetate and washed with 200 ml of water,100 ml of 20% aqueous H3PO4, and brine. Evaporation of the dried (MgSO4) solution gave a semisolid which was triturated with methylene chloride and filtered to yield 1.2 g (61 % yield) of title product 2 as a white amorphous solid.

NMR (DMSO-d6) 6: 1.20 (3H, d, J=6.0 Hz), 2.9-3.2 (9H, m), 5.22 (1 H, d, J=8.5 Hz) and 8.23 (2H, d, J=8.5 Hz); ir (KBr) ymax: 3500, 1770 and 1700 cm-l; Anal. Calc'd. for C,8H20N207S: C, 52.93; H, 4.94; N, 6.86; S, 7.85. Found: C, 52.83; H, 4.90; N, 6.42; S, 8.31.

B. p-Nitrobenzyl 3-(2-methanesulfonyloxyethylthio)-6a-[1 -( R)-hydroxyethyl]-7-oxo-1 - azabicyclo(3.2.0)hept-2-ene-2-carboxylate

To a solution of 4.2 g (10.3 mmole) of 2 in 200 ml of tetrahydrofuran there was added at -400C 1.3 g (11.3 mmole) of methanesulfonyl chloride followed buy a dropwise addition of 1.26 g (12.4 mmole) of triethylamine in 5 ml of tetrahydrofuran. The reaction mixture was stirred for 5 hours at -400C, then stirred for 2 hours at -3O0C under a nitrogen atmosphere and then poured into a mixture of ethyl acetate (700 ml) and 5% aqueous phosphoric acid (1000 ml). The organic layer was washed with brine, dried over MgSO4, filtered and condensed to a syrup.This material was purified by silica gel column chromatography [elution with methylene chloride-ethyl acetate (3:1 v/v)] to give 3.55 g (75% yield) of the title compound as a white amorphous solid.

NMR (CDCI3 S: 1.25 (3H, d, J=6.0 Hz), 3.05 (3H, s), 3.06--3.40 (5H, m), 4.05-4.40 (4H, m), 5.25 (1 H, d, J=1 4.0 Hz), 5.50 (1 H, d, J=1 4.0 Hz), 7.70 (2H, d, J=8.5 Hz) and 8.23 (2H, d, J=8.5 Hz); ir (KBr) ymax: 3400, 1770 and 1600 cm~'. Anal. Calc'd. for C1gH22N2OgS2 C, 46.90; H, 4.56; N, 5.76.

found: C, 46.52; H, 4.32; N, 5.91.

C. p-Nitrobenzyl 3-(2-iodoethylethio)-6cg-[1 -( R)-hydroxyethyl]-7-oxo- 1 -azabicyclo(3.2.0)hept-2- ene-2-carboxylate

A solution of 350 mg (0.72 mmole) of intermediate 3 and 21 6 mg (1.4 mmole) of sodium iodide in 20 ml of acetone was heated at reflux for 4 hours. Evaporation of the acetone gave a white amorphous solid which was suspended in ether (10 ml)-water (10 ml). Filtration of the white solid and vacuum drying produced 300 mg (80% yield) of the title compound 4 as a white amorphous powder.

NMR (DMSO-d6) d: 1.18 (3H, d, J=6.0 Hz), 3.20-3.60 (7H, m), 3.80-4.25 (2H, m), 5.10 (1 H, d, J=5.5 Hz), 5.25 (1 H, d, J=1 2.0 Hz), 5.45 (1 H, d, J=1 2.0 Hz), 7.70 (2H, d, J=8.5 Hz), and 8.27 (2H, d, J=8.5 Hz); ir (K8r) ymax: 3500, 1768 and 1700 cm~1; Anal. Calc'd. for C18H1gN2061 C, 41.71; H, 3.70; N, 5.41; I, 24.48. Found: C, 42.10; H, 3.75; N, 5.97; I, 23.20.

D. 3-[2-(1 -Tetrahydrothiophenium)ethylthio] -6a-[1 -(R)-hydroxyethyl]-7-oxo-1 azabicyclo[3.2.0]hept-2-ene-2-carboxylate

To a solution of p-nitrobenzyl 3-(2-iodoethylthio)-6a-[1 -(P)-hydroxyethyl]-7-oxo-1 - azabicyclo[3.2.0]hept-2-ene-2-carboxylate (104 mg; 0.2 mmole) in 5 ml of tetrahydrofuran there was added tetrahydrothiophene (0.3 ml; 0.35 mmole) followed by a solution of silver perchlorate (60 mg; 0.3 mmole) in 0.5 ml of tetrahydrofuran. The mixture was stirred at room temperature for 60 minutes.

The solvent was evaporated in vacuo affording compound 5 as a yellow gum. This gum was digested with 100 ml of Celite to give an amorphous solid.

iR (KBr) ymax: 3400, 1772, 1700 and 1100 cm~'. Without any further purification, compound 5 was hydrogenated as follows: To a suspended solution of compound 5 in 20 ml of ether and 20 ml of tetrahydrofuran there was added a solution of potassium bicarbonate (40 mg; 0.4 mmole) and dibasic potassium phosphate (35 mg; 0.2 mmole) in 20 ml of water. Then, 120 mg of 10% palladium on charcoal was added and the mixture was hydrogenated at 40 psi on the Parr Shaker for 60 minutes.

The mixture was then filtered and the catalyst was washed with water (2x5 ml). The combined filtrate and washing was extracted with ether (2x50 ml) and then lyophilized to give a yellow powder. This crude material was purified on a C,8 Bondapak reverse phase column (7 g) (Waters Associates), eluting with water under a 8 psi pressure. Each fraction (15 ml) was screened by high pressure liquid chromatography, and fractions having an ultravioiet absorption AwmaX 300 nm were collected and lyophilized to give 12 mg (18% yield based on compound 4) of title product as a white solid. NMR (D2O) (3:1.23 (3H, d, J=6.OHz), 2.25-2.45 (4H, m), 3.0-3.70 (11 H, m), 3.95-4.30 (2H, m); ir (KBr) ymax: 3400, 1760 and 1590 cm~1. UV AmaX (CH > CH2OH) 289 nm (E=6200).

Claims

1. A compound of the formula

wherein Rss is hydrogen and R1 is selected from the group consisting of hydrogen; substituted and unsubstituted: alkyl, alkenyl and alkynyl, having from 1-10 carbon atoms; cycloalkyl and cycloalkylalkyl, having 3-6 carbon atoms in the cycloalkyl ring and 1-6 carbon atoms in the alkyl moieties; phenyl; aralkyl, aralkenyl and aralkynyl, wherein the aryl moiety is phenyl and the aliphatic portion has 1-6 carbon atoms; heteroaryl, heteroaralkyl, heterocyclyl and heterocyclylalkyl wherein the hetero atom or atoms in the above-named heterocyclic moieties are selected from the group consisting of 1-4 oxygen, nitrogen or sulfur atoms and the alkyl moieties associated with said heterocyclic moieties have 1-6 carbon atoms; wherein the substituent or substituents relative to the above-named radicals are independently selected from the group consisting of C1-C6 alkyl optionally substituted by amino, halo, hydroxy or carboxyl halo OR3

-NP3P4

--SO2NR3R4

-CO2R3 =0

- SR3

-CN -N3 -OSO3P3 -OSO2P3 --NR3SO,R4

--N R3CO,R4 -NO2 wherein, relative to the above-named substituents, the groups R3 and R4 are independently selected from hydrogen; alkyl, alkenyl and alkynyl, having from 1-10 carbon atoms; cycloalkyl, cycloalkylalkyl and alkylcycloalkyl, having 3--6 carbon atoms in the cycloalkyl ring and 1-6 carbon atoms in the alkyl moieties; phenyl; aralkyl, aralkenyl and aralkynyl wherein the aryl moiety is phenyl and the aliphatic portion has 1-6 carbon atoms; and heteroaryl, heteroaralkyl, heterocyclyl and heterocyclylalkyl wherein the hetero atom or atoms in the above-named heterocyclic moieties are selected from the group consisting of 1-4 oxygen, nitrogen or sulfur atoms and the alkyl moieties associated with said heterocyclicmoieties have 1-6 carbon atoms, or R3 and R4 taken together with the nitrogen to which at least one is attached may form a 5- or 6-membered nitrogen-containing heterocyclic ring; R9 is as defined for R3 except that it may not be hydrogen; or wherein R' and R8 taken together represent C2-C10 alkylidene or C2-C10 alkylidene substituted by hydroxy;A is C2-C6 straight or branched chain alkylene; R2 is hydrogen, an anionic charge or a conventional readily removable carboxyl protecting group, providing that when R2 is hydrogen or a protecting group, there is also present a counter anion, and R10 and R" each independently represents (a) C1--C6 alkyl, C2-C6 alkenyl, C2-C6 al kynyl, C3-C6 cycloalkyl or cycloalkylalkyl having 3--6 carbon atoms in the cycloalkyl ring and 1-6 carbon atoms in the alkyl moiety, said alkyl, alkenyl, alkynyl, cycloalkyl or cycloalkylalkyl group being optionally substituted by 1-3 substituents independently selected from hydroxy, C1-C6 alkoxy, C1-C6, alkanoyloxy, carboxy, C1-C6 alkoxycarbonyl, amino, C1-C6 alkylamino, di(C1-C6)alkylamino, C1-C6 alkanoylamino, phenyl, phenyl substituted by 1-3 halo, C1-C8 alkoxy, C1-C6 alkyl, carboxy, carboxy(C1-C6)alkyl, amino, C1-C6 alkylamino, di(C1-C6)alkylamino or di(C1-C6)alkylamino (C1-C6)alkyl, halo or oxo;; (b) phenyl optionally substituted by 1-3 halo, C1-C6 alkoxy, C1-C6 alkyl, carboxy, amino, C1-C6 alkylamino or di(C1-C6)alkylamino groups; (c) heterocyclyl or heterocyclylalkyl wherein the heterocyclic moiety is a 4--6 membered ring having 1-3 hetero atoms selected from 0, N and S and the alkyl moiety has 1-6 carbon atoms, said heterocyclyl or heterocyclylalkyl ring being optionally substituted by 1-3 C1-C6 alkyl or C1--C6 alkoxy groups; or (d) heteroaryl or heteroaralkyl wherein the heterocyclic moiety is a 5--6 membered aromatic ring having 1-3 hetero atoms selected from 0, N and S and the alkyl moiety has 1--6 carbon atoms, said heteroaryl or heteroaralkyl ring being optionally substituted by 1--3 C1--C6 alkyl, C1-C6 alkoxy, carboxy, carboxy(C1-C6)alkyl, amino, C1-C6 alkylamino, di(C1-C6)alkylamino, amino(C1-C6)alkyl or di(C1-C6)alkylamino(C1-C6)alkyl groups; or wherein R10 and R11 taken together with the S to which they are attached represent a 4--6 member sulfur-containing heterocyclic ring containing .0-2 double bonds and 0--2 additional heteroatoms selected from 0, N and S, said ring being attached to A through a sulfur atom, thereby forming a sulfonium group, said heterocyclic ring being optionally substituted by 1-3 substituents independently selected from:: C1-C6 alkyl optionally substituted by 1--3 hydroxy, C1-C6 alkoxy, carboxy, halo, amino, C1 -C6 alkylamino or di(C1-C5)alkylamino groups, hydroxy, C1--C6 alkoxy, C1-C6 alkanoyloxy, amino, C 1-C6 alkylamino, di(C1-C6)alkylamino, C1-C6 alkanoylamino, carboxy, C1-C6 alkoxycarbonyl, halo, oxo or phenyl; or wherein said heterocyclic ring

is fused to a C5-C6 carbocyclic ring, a phenyl ring, a 5--6 member heterocyclic ring or a 5--6 member heteroaryl ring, all of which rings may be optionally substituted by 1--3 of the substitutents referred to above for the

ring; or a pharmaceutically acceptable salt thereof.

2. A compound according to Claim 1 wherein R' is hydrogen, CH3CH2-,

3. A compound according to Claim 1 wherein R1 and R8 taken together represent

4. A compound according to Claim 1 wherein R' is

5. A compound according to Claim 1 wherein R' is

and the absolute configuration is 5R, 6S, 8R.

6. A compound according to Claim 1, 2, 3, 4 or 5 wherein A is -CH2CH2-.

7. A compound of the formula

wherein R6 is hydrogen and R1 is selected from the group consisting of hydrogen; substituted and unsubstituted: alkyl, alkenyl and alkynyl, having from 1-1 0 carbon atoms; cycloalkyl and cycloalkylalkyl, having 3-6 carbon atoms in the cycloalkyl ring and 1-6 carbon atoms in the alkyl moieties; phenyl; aralkyl, aralkenyl and aralkynyl wherein the aryl moiety is phenyl and the aliphatic portion has 1-6 carbon atoms, heteroaryl, heteroaralkyl, heterocyclyl and heterocyclylalkyl wherein the hetero atom or atoms in the above-named heterocyclic moieties are selected from the group consisting of 1-4 oxygen, nitrogen or sulfur atoms and the alkyl moieties associated with said heterocyclic moieties have 1-6 carbon atoms; wherein the substituent or substituents relative to the above-named radicals are independently selected from the group consisting of C1-C6 alkyl optionally substituted by amino, halo, hydroxy or carboxyl halo OR

-NP3P4

-SO2NP3R4

-CO2P3 =0

-SR3

-CN -N3 -OSO3R3 -OSO2P3 -N R3SO2R4

-N R3CO2P4 -NO2 wherein, relative to the above-named substituents, the groups R3 and R4 are independently selected from hydrogen; alkyl, alkenyl and alkynyl, having from 1-10 carbon atoms; :ycloalkyl, cycloalkylalkyl and alkylcycloalkyl, having 3--6 carbon atoms in the cycloalkyl ring and 1-6 carbon atoms in the alkyl moieties; phenyl; aralkyl, aralkenyl and aralkynyl wherein the aryl moiety is phenyl and the aliphatic portion has 1-6 carbon atoms; and heteroaryl , heteroaralkyl, heterocyclyl and heterocyclylalkyl wherein the hetero atom or atoms in the above-named heterocyclic moieties are selected fromthe group consisting of 1-4 oxygen, nitrogen or sulfur atoms and the alkyl moieties associated with said heterocyclic moieties have 1-6 carbon atoms, or R3 amd R4 taken together with the nitrogen to which at least one is attached may form a 5- or 6-membered nitrogen-containing heterocyclic ring; R9 is as defined for R3 except that it may not be hydrogen; or wherein R1 and R8 taken together represent C2-C10 alkylidene or C2-C10 alkylidene substituted by hydroxy;A is C2-C6 straight or branched chain alkylene; R2 is hydrogen, an anionic charge or a conventional readily removable carboxyl protecting group, providing that when R2 is hydrogen or a protecting group, there is also present a counter anion, and R10 and R11 each independently represents C1-C6 alkyl; or wherein R10 and R11 taken together with the S to which they are attached represent

or a pharmaceutically acceptable salt thereof.

8. A compound according to Claim 7 wherein R1 is hydrogen, CH3CH2-,

9. A compound according to Claim 7 wherein R1 and R8 taken together represent

10. A compound according to Claim 7 wherein R' is

11. A compound according to Claim 7 wherein R1 is

and the absolute configuration is 5R, 6S, 8R.

12. A compound according to Claim 7, 8, 9, 10 or 11 wherein A is -CH2CH3-.

13. A compound of the formula

wherein R8 is hydrogen and R' is selected from the group consisting of hydrogen; substituted and unsubstituted: alkyl, alkenyl and alkynyl, having from 1-10 carbon atoms; cycloalkyl and cycloalkylalkyl, having 3-6 carbon atoms in the cycloalkyl ring and 1-6 carbon atoms in the alkyl moieties; phenyl; aralkyl, aralkenyl and aralkynyl wherein the aryl moiety is phenyl and the aliphatic portion has 1-6 carbon atoms; heteroaryl, heteroaralkyl, heterocyclyl and heterocyclylalkyl wherein the hetero atom or atoms in the above-named heterocyclic moieties are selected from the group consisting of 1-4 oxygen, nitrogen or sulfur atoms and the alkyl moieties associated with said heterocyclic moieties have 1-6 carbon atoms; wherein the substituent or substituents relative to the above-named radicals are independently selected from the group consisting of C1-C6 alkyl optionally substituted by amino, halo, hydroxy or carboxyl halo OR3

-NP3P4

--SO,NR3R4

-CO2P3 =0

-SR3

-CN N3 -OSO3P3 -OSO2P3 --N R3S 02R4

-N R3CO2R4 -NO2 wherein, relative to the above-named substituents, the groups R3 and R4 are independently selected from hydrogen; alkyl, alkenyl and alkynyl, having from 1-10 carbon atoms; cycloalkyl, cycloalkylalkyl and alkylcycloalkyl, having 3--6 carbon atoms in the cycloalkyl ring and 1-6 carbon atoms in the alkyl moieties; phenyl; aralkyl, aralkenyl and aralkynyl wherein the aryl moiety is phenyl and the aliphatic portion has 1-6 carbon atoms; and heteroaryl, heteroaralkyl, heterocyclyl and heterocyclylalkyl wherein the hetero atom or atoms in the above-named heterocyclic moieties are selected from the group consisting of 1-4 oxygen, nitrogen or sulfur atoms and the alkyl moieties associated with said heterocyclic moieties have 1-6 carbon atoms, or R3 and R4 taken together with the nitrogen to which at least one is attached may form a 5- or 6-membered nitrogen-containing heterocyclic ring; R9 is as defined for R3 except that it may not be hydrogen; or wherein R' and R8 taken together represent C2-C10 alkylidene or C2-C10 alkylidene substituted by hydroxy; A is C2-C6 straight or branched chain alkylene; R2 is hydrogen, an anionic charge or a conventional readily removable carboxyl protecting group, providing that when R2 is hydrogen or a protecting group, there is also presentin counter anion; and R'O and R" taken together with the S to which they are attached represent

or a pharmaceutically acceptable salt thereof.

14. A compound according to Claim 13 wherein R1 is hydrogen, CH3CH2-,

15. A compound according to Claim 13 wherein R' and R8 taken together represent

16. A compound according to Claim 13 wherein R' is

17. A compound according to Claim 13 wherein R' is

and the absolute configuration is 5R, 6S, 8R.

18. A compound according to Claim 13, 14, 15, 16 or 1 7 wherein A is -CH2CH2-.

19. A compound of the formula

wherein R2 is hydrogen, an anionic charge or a conventional readily removable carboxyl protecting group, providing that when R2 is hydrogen or a protecting group, there is also present a counter anion, or a pharmaceutically acceptable salt thereof.

20. The compound according to Claim 19 wherein R2 is p-nitrobenzyl.

21. The compound according to Claim 19 wherein R2 is an anionic charge.

22. A process for the preparation of a compound of the formula

wherein P6 is hydrogen and R1 is selected from the group consisting of hydrogen; substituted and unsubstituted: alkyl, alkenyl and alkynyl, having from 1-10 carbon atoms; cycloalkyl and cycloalkylalkyl, having 3-6 carbon atoms in the cycloalkyl ring and 1-6 carbon atoms in the alkyl moieties; phenyl; aralkyl, aralkenyl and aralkynyl wherein the aryl moiety is phenyl and the aliphatic portion has 1-6 carbon atoms; heteroaryl, heteroaralkyl, heterocyclyl and heterocyclylalkyl wherein the hetero atom or atoms in the above-named heterocyclic moieties are selected from the group consisting of 1-4 oxygen, nitrogen or sulfur atoms and the alkyl moieties associated with said heterocyciic moieties have 1-6 carbon atoms; wherein the substituent or substituents relative to the above-named radicals are independently selected from the group consisting of C1-C6 alkyl optionally substituted by amino, halo, hydroxy or carboxyl halo OR3

--N R3R4

--SO,NR3R4

-CO2P3 =0

-SR3

-CN -N3 -OSO3P3 -OSO2P3 --NR3SO2R4

--NR3CO,R4 -NO2 wherein, relative to the above-named substituents, the groups R3 and R4 are independently selected from hydrogen; alkyl, alkenyl and alkynyl, having from 1-10 carbon atoms; cycloalkyl, cycloalkylalkyl and alkylcycloalkyl, having 3--6 carbon atoms in the cycloalkyl ring and 1-6 carbon atoms in the alkyl moieties; phenyl; aralkyl, aralkenyl and aralkynyl wherein the aryl moiety is phenyl and the aliphatic portion has 1-6 carbon atoms; and heteroaryl, heteroaralkyl, heterocyclyl and heterocyclylalkyl wherein the hetero atom or atoms in the above-named heterocyclic moieties are selected from the group consisting of 1-4 oxygen, nitrogen or sulfur atoms and the alkyl mcieties associated with said heterocyclic moieties have 1-6 carbon atoms, or R3 and R4 taken together with the nitrogen to which at least one is attached may form a 5- or 6-membered nitrogen-containing heterocyclic ring; R9 is as defined for R3 except that it may not be hydrogen; or wherein R' and R8 taken together represent C2-C10 alkylidene or C2-C10 alkylidene substituted by hydroxy; A is C2-C6 straight or branched chain alkylene;R2 is hydrogen, an anionic charge or a conventional readily removable carboxyl protecting group, providing that when R2 is hydrogen or a protecting group, there is also present a counter anion, and R10 and R" each independently represents (a) C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl or cycloalkylalkyl having 3--6 carbon atoms in the cycloalkyl ring and 1-6 carbon atoms in the alkyl moiety, said alkyl, alkenyl.

alkynyl, cycloalkyl or cycloalkylalkyl group being optionally substituted by 1-3 substituents independently selected from hydroxy, C1-C6 alkoxy, C1-C6 alkanoyloxy, carboxy, C1-C6 alkoxycarbonyl, amino, C 1-C6 alkylamino, di(C1-C6)alkylamino, C1-C6 alkanoylamino, phenyl, phenyl substituted by 1-3 halo, C1-C6 alkoxy, C1-C6 alkyl, carboxy, carboxy(C1-C6)alkyl, amino, C1-C6 alkylamino, di(C1-C6)alkylamino or di(C1-C6)alkylamino(C1-C6)alkyl, halo or oxo;; (b) phenyl optionally substituted by 1-3 halo, C1-C6alkoxy, C1-C6 alkyl, carboxy, amino, C1- C6 alkylamino or di(C1-C6)alkylamino groups; (c) heterocyclyl or heterocyclylalkyl wherein the heterocyclic moiety is a 4--6 membered ring having 1-3 hetero atoms selected from 0, N and S and the alkyl moiety has 1-6 carbon atoms, said heterocyclyl or heterocyclylalkyl ring being optionally substituted by 1-3 C1--C6 alkyl or C1-C6 alkoxy groups; or (d) heteroaryl or heteroaralkyl wherein the heterocyclic moiety is a 5--6 membered aromatic ring having 1-3 hetero atoms selected from 0, N and S and the alkyl moiety has 1-6 carbon atoms, said heteroaryl or heteroaralkyl ring being optionally substituted by 1-3 C1--C6 alkyl, C1-C6 alkoxy, carboxy, carboxy(C1-C6)alkyl, amino, C1-C6 alkylamino, di(C1-C6)alkylamino, amino(C1-C6)alkyl or di(C1-C6)alkylamino(C1-C6)alkyl groups; or wherein R10 and R11 taken together with the S to which they are attached represent a 4-6 member sulfur-containing heterocyclic ring containing 0-2 double bonds and 0-2 additional heteroatoms selected from 0, N and S, said ring being attached to A through a sulfur atom, thereby forming a sulfonium group, said heterocyclic ring being optionally substituted by 1-3 substituents independently selected from:: C1-C6 alkyl optionally substituted by 1-3 hydroxy, C1-C6 alkoxy, carboxy, halo, amino, C1-C6 alkylamino or di(C1-C6)alkylamino groups, hydroxy, C1-C6alkoxy, C1-C6 alkanoyloxy, amino, C1-C6 alkylamino, di(C1-C6)alkylamino, C1-C6 alkanoylamino, carboxy, C1-C6 alkoxycarbonyl, halo, oxo or phenyl; or wherein said heterocyclic ring

is fused to a C5-C6 carbocyclic ring, a phenyl ring, a 5--6 member heterocyclic ring or a 5--6 member heteroaryl ring, all of which rings may be optionally substituted by 1-3 of the substituents referred to above for the

ring; or a pharmaceutically acceptable salt thereof, which process comprises subjecting an intermediate of the formula

wherein R1, R8 and A are as defined above and P2 is a conventional readily removable carboxyl protecting group to nucleophilic displacement in an inert organic solvent and in the presence of silver ion with a sulfide reagent of the formula

wherein R10 and R" are as defined above so as to displace the iodo group of intermediate II with the group

and form a compound of the formula

wherein X is a counter anion and R', R8, A, R10, R" and R2' are as defined above, and, if desired, removing the carboxyl protecting group R2 to give the corresponding deblocked compound of the formula I, or a pharmaceutically acceptable salt thereof.

23. A process for the preparation of a compound of the formula

--N R3R4

--SO,N R3R4

-CO2P3 =0

-SR3

-CN -N3 -OSO3P3 -OSO2R3 NR3SO2R4

--NR3CO2R4 -NO2 wherein, relative to the above-named substituents,the groups R3 and R4 are independently selected from hydrogen; alkyl, alkenyl and alkynyl, having from 1-10 carbon atoms; cycloalkyl, cycloalkylalkyl and alkylcycloalkyl, having 3--6 carbon atoms in the cycloalkyl ring and 1-6 carbon atoms in the alkyl moieties; phenyl; aralkyl, aralkenyl and aralkynyl wherein the aryl moiety is phenyl and the aliphatic portion has 1-6 carbon atoms; and heteroaryl, heteroaralkyl, heterocyclyl and heterocyclylalkyl wherein the hetero atom or atoms in the above-named heterocyclic moieties are selected from the group consisting of 1-4 oxygen, nitrogen or sulfur atoms and the alkyl moieties associated with said heterocyclic moieties have 1-6 carbon atoms, or R3 and R4 taken together with the nitrogen to which at least one is attached may form a 5- or 6-membered nitrogen-containing heterocyclic ring;R9 is as defined for R3 except that it may not be hydrogen; or wherein R1 and R6 taken together represent C2--C10 alkylidene or C2--C10 alkylidene substituted by hydroxy; A is C2-C6 straight or branched chain alkylene;R is hydrogen, an anionic charge or a conventional readily removable carboxyl protecting group, providing that when R is hydrogen or a protecting group, there is also present a counter anion, and R10 and P11 each independently represents (a) C1--C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl or cycloalkylalkyl having 3--6 carbon atoms in the cycloalkyl ring and 1-6 carbon atoms in the alkyl moiety, said alkyl, alkenyl, alkynyl, cycloalkyl or cycloalkylalkyl group being optionally substituted by 1-3 substituents independently selected from hydroxy, C1-C6 alkoxy, C1-C6 alkanoyloxy, carboxy, C1-C6 alkoxycarbonyl, amino, C 1-C6 alkylamino, di(C1-C5)alkylamino, C1-C6 alkanoylamino, phenyl, phenyl substituted by 1-3 halo, C1-C6 alkoxy, C1-C6 alkyl, carboxy, carboxy(C1-C6)alkyl, amino, C1-C6 alkylamino, di(C1-C6)alkylamino or di(C1-C6)alkylamino(C1-C6)alkyl, halo or oxo; (b) phenyl optionally substituted by 1-3 halo, C1-C6 alkoxy, C1-C6 alkyl, carboxy, amino, C1- C6 alkylamino or di(C1-C6)alkylamino groups;; (c) heterocyclyl or heterocyclylalkyl wherein the heterocyclic moiety is a 4--6 membered ring having 1-3 hetero atoms selected from 0, N and S and the alkyl moiety has 1-6 carbon atoms, said heterocyclyl or heterocyclylalkyl ring being optionally substituted by 1-3 C1--C6 alkyl or C1-C6 alkoxy groups; or (d) heteroaryl or heteroaralkyl wherein the heterocyclic moiety is a 5--6 membered aromatic ring having 1-3 hetero atoms selected from 0, N and S and the alkyl moiety has 1-6 carbon atoms, said heteroaryl or heteroaralkyl ring being optionally substituted by 1-3 C1--C6 alkyl, C1-C6 alkoxy, carboxy, carboxy(C1-C6)alkyl, amino, C1-C6 alkylamino, di(C1-C6)alkylamino, amino(C1-C6)alkyl or di(C1-C6)alkylamino(C1-C6)alkyl groups; or wherein R10 and R'1 taken together with the S to which they are attached represent a 4--6 6 member sulfur-containing heterocyclic ring containing 0--2 double bonds and 0-2 additional heteroatoms selected from 0, N and S, said ring being attached to A through a sulfur atom, thereby forming a sulfonium group, said heterocyclic ring being optionally substituted by 1-3 substituents independently selected from:: C1-C6 alkyl optionally substituted by 1-3 hydroxy, C1-C6 alkoxy, carboxy, halo, amino, C1 -C6 alkylamino or di(C1-C6)alkylamino groups, hydroxy, C1-C6 alkoxy, C1-C9 alkanoyloxy, amino, C1-C6 alkylamino, di(C1-C6)-alkylamino, C1-C6 alkanoylamino, carboxy, C1-C6 alkoxycarbonyl, halo, oxo or phenyl; or wherein said heterocyclic ring

is fused to a C96 carbocyclic ring, a phenyl ring, a 5-6 member heterocyclic ring or a 5-6 member heteroaryl ring, all of which rings may be optionally substituted by 1-3 of the substituents referred to above for the

ring; or a pharmaceutically acceptable salt thereof, which process comprises the steps of (1) reacting an intermediate of the formula

wherein R' and R8 are as defined above and R2 is a conventional readily removable carboxyl protecting group in an inert organic solvent with diphenyl chlorophosphate in the presence of base to give an intermediate of the formula

wherein R1, R8 and R2 are as defined above; (2) reacting intermediate IV in an inert organic solvent and in the presence of base with a mercaptan reagent of the formula HS-A-OH wherein A is as defined above to give an intermediate of the formula

wherein R', R8, A and R2 are as defined above; ; (3) reacting intermediate V in an inert organic solvent and in the presence of base with methanesulfonyl chloride or a functional acylating equivalent thereof to give an intermediate of the formula

wherein R1, R6, A and R2 are as defined above; (4) reacting intermediate VI in an inert organic solvent with a source of iodide ion so as to displace the methanesulfonyloxy group with an iodo group and form an intermediate of the formula

wherein R', R8, A and R2, are as defined above; and (5) subjecting intermediate II to nucleophilic displacement in an inert organic solvent and in the presence of silver ion with a sulfide reagent of the formula

wherein R10 and R1' are as defined above so as to displace the iodo group of intermediate II with the group

and form a compound of the formula

wherein X is a counteranion and R1, R8, A, R10, R11 and R2 are as defined above, and, if desired, removing the carboxyl protecting group R2 to give the corresponding deblocked compound of formula l, or a pharmaceutically acceptable salt thereof.

24. A process as claimed in Claim 22, substantially as described in the foregoing Example.

25. A carbapenem derivative prepared by a process as claimed in Claim 22, 23 or 24.

26. A pharmaceutical composition containing a biologically active carbapenem derivative as claimed in any of Claims 1 to 21, or Claim 25, totether with a pharmaceutically acceptable carrier or diluent.